blanc, guilaine f. (2010) new strategies for pinacol cross
TRANSCRIPT
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thesesglaacuk
Blanc Guilaine F (2010) New strategies for pinacol cross-couplings and alkenation reactions PhD thesis
httpthesesglaacuk2227 Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work full bibliographic details including the author title awarding institution and date of the thesis must be given
Thesis submitted in fulfilment of the requirements for the
Degree of Doctor of Philosophy
New Strategies for Pinacol Cross-Couplings
and Alkenation Reactions
Guilaine F Blanc
Supervisor Dr R C Hartley
Physical Sciences Faculty
August 2010
Abstract
The research described herein involves the study of new approaches to
alkenation and pinacol cross-coupling
The competition between modified Julia alkenation and Peterson alkenation was
studied Heterocyclic sulfides (i) were oxidised to sulfones (ii) by
dimethyldioxirane generated in situ from oxonereg and acetone Reactions
between sulfones (ii) and aldehyde (iii) gave vinyl sulfones (iv) in good yields
rather than vinyl silanes confirming that the Peterson alkenation is preferred in
this system
S SiMe3Ar
S SiMe3Ar
OO
[O]
Ar= BT PYR
H
O
MeO
MeO
SAr
OO
OMe
OMeLDA THF
i ii iv
iii
Pinacol cross-coupling between an aldehyde or ketone in solution and a more
easily reduced aldehyde immobilised on resin was attempted but proved
unsuccessful However aldehydes (v) and (vii) bearing the salts of tertiary
amines were found to be good substrates for pinacol homo-coupling giving diols
(vi) and (viii) respectively The formation of salt (v) avoided unwanted
reduction of the aldehyde to a primary alcohol
Cp2TiCl2 iPrMgClO
O
H
O
O
OH
OH
O
HO
OH
dr (synanti) 5842
THF 78 degC to rt
N
H
O
N
OH
OH
N
H
viii 67
S O
O
O
vii
Cp2TiCl2 iPrMgCl
THF 78 degC to rt
syn only
v vi 56
Et3NH
A wide range of approaches to anisomycin (ix) using titanium reagents were
investigated These were based on the formation of the bond between C-3 and
C-4 by alkylidenation of esters and ring-closing metathesis (RCM) or
intramolecular alkylidenation or radical cyclization The presence and position
of the nitrogen atom proved an insurmountable obstacle to this strategy
ii
NOR1
O
R2R3
PG
R1 = Et Me R2 = H BnR3 = CH2CH(SPh)2
PG = Ts PhCO
Cp2Ti[P(OEt)3]2 N
OR1R2
PG
R1 = Me R2 = BnR3 = allyl PG = PhCO
N
OR1R2
PG
TiCl4 Zn PbCl2 CH3CHBr2TMEDA
R1 = Et BnR2 = H 4-CH3OC6H4CH2
R3 = allyl PG = Boc
NOR1
R2
R3
PGCp2TiMe2
R1 = Et Bn R3 = CH2CHOR2 = H 4-CH3OC6H4CH2
PG = Ts Boc TiCl3 LiAlH4
NOR1
R2PG R1 = Et R2 = H
R3 = allyl PG = Ts
NOR1
R2PG
R1 = Me R2 = BnR3 = CH2CH(SPh)2
PG = PhCO
NO
SPh
PG
R2
LDMAN
R1 = Bn R3 = CH2CHOR2 = 4-CH3OC6H4CH2
PG = Boc
N
O
OH
Cp2TiCl2 iPrMgCl
R2
PG
(a) Cp2TiMe2(b) RCM
R1 = Bn R2 = 4-CH3OC6H4CH2
R3 = allyl PG = Boc
NOR1
R2R3
PG
TiCl4 ZnPbCl2CH3CHBr2TMEDAlarge excess
MeO
2 34HN
OAcix (+)-Anisomycin
OH
The solid-phase synthesis of 4-amino-ketones (xiii) was achieved Resin-bound
esters (x) were alkylidenated using a novel titanium reagent (xi) generated in
situ by reduction of a thioacetal with a low valent titanium reagent Treating
the resulting enol ethers (xii) with acid gave ketones in good yield and high
purity because of the switch in the nature of the linker from acid-stable to acid-
sensitive (a chameleon catch strategy) Amino-ketones (xiii) are potential
precursors of pyrrolidines (xiv)
O R1
O
NBn2Cp2Ti
O
R1
NBn2
CH2Cl2
NHBn2R1
CF3CO2OCF3CO2H
x
xi
xii xiii
NH
R1
xiv
iii
Acknowledgements
I am grateful to the University of Glasgow for the financial support of this work
I would like to thank my supervisor Dr Richard Hartley for his help and
encouragement throughout the course of my PhD and my second supervisor Dr
Graeme Cooke for his contribution
Thanks to all the technical staff who provided excellent advice and support
during my PhD Dr David Adam (NMR spectroscopy) Jim Tweedie (mass
spectrometry) Kim Wilson (microanalysis) and Stuart Mackay (IT) Isabel Freer
Big thanks to Jenny and Freacutedeacuteric for their help during my first time in Glasgow
You helped me a lot through those difficult times Thanks to Louis my mentor
during my first year Thanks to all the members of the Hartley team past and
present Caroline Ching Linsey Calver Adam Stephen
Thanks to all the members of the Sutherland group for the great atmosphere in
the Loudon lab Kate Mike Nicola Louise Lindsay Lorna Fiona Mark All our
tea breaks were a pleasure Aureacutelie thanks for being a little sunshine among the
rain
Special thanks to my family for their love and support It has been a long journey
since my first year at the Uni and you have always been there by my side
To Matthieu Thanks for supporting my speeches for long long hours every day
Your patience your strength and your love made me feel stronger every day for
the last 5 years and will for the next 50 years of our life
iv
Authorrsquos Declaration
This thesis represents the original work of Guilaine Francine Blanc unless
explicitly stated otherwise in the text No part of this thesis has been previously
submitted for a degree at the University of Glasgow or any other University The
research was carried out at the University of Glasgow in the Loudon laboratory
under the supervision of Dr Richard Hartley during the period of October 2006 to
September 2009
v
Abbreviations
[α] specific rotation
Aring angstrom
AA amino acid
Ac acetyl
AcOH acetic acid
aq aqueous
Alk alkyl
Ar Aryl
atm atmosphere (pressure)
Bn benzyl
Boc tert-butoxycarbonyl
Boc2O di-tert-butyldicarbonate
Bu butyl nBu normal butyl secBu secondary butyl tBu tert-butyl
bp boiling point
BT benzothiazole
br d broad doublet (NMR spectroscopy)
br s broad singlet (NMR spectroscopy)
Bz benzoyl
degC degrees Celsius
cat catalytic
CDCl3 deuterated chloroform
CI chemical ionisation
cm centimetre
cm-1 wavenumber
conc concentrated
Cp cyclopentadienyl
Cy cyclohexyl
δ chemical shift (NMR spectroscopy)
d doublet (NMR spectroscopy)
dd doublet of doublets (NMR spectroscopy)
vi
ddd doublet of doublet of doublets (NMR spectroscopy)
dt doublet of triplets (NMR spectroscopy)
DBU 18-diazabicyclo[540]undec-7-ene
DCC NNrsquo-dicyclohexylcarbodiimide
DCM dichloromethane
DCU dicyclohexylurea
DEAD diethyl azodicarboxylate
DEPT distortionless enhancement by polarization transfer
DHQ-CLB O-(4-chlorobenzoyl)hydroquinine
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminium hydride
DIPEA diisopropylethylamine
DIPT diisopropyltartrate
DMAP NN-dimethyl-4-aminopyridine
DME 12-dimethoxyethane
DMF dimethylformamide
DMSO dimethylsulfoxide
DMT dimethyltitanocene
DVB divinyl benzene
dr diastereomeric ratio
EI electron impact ionisation
eq equivalent(s)
Et ethyl
FAB fast atom bombardment
g gram
h hour(s)
Hz Hertz
HCl hydrochloric acid
HMPA hexamethylphosphoramide
HRMS high-resolution mass spectroscopy
HWE Horner-Wadsworth-Emmons reaction
IR infra-red
J NMR spectra coupling constant
Kg kilogram
KHz kiloHertz
vii
L litre
μL microlitre
LAH lithium aluminium hydride
LDA lithium diisopropylamide
LDBB lithium 44-di-tert-butylbiphenylide
LDMAN lithium dimethylamino naphthalenide
lit literature value
LN lithium naphthalenide
m multiplet
M molar
M+ parent molecular ion
m-CPBA meta-chloroperoxybenzoic acid
MALDI-TOF matrix assisted laser desoprtion ionisation-time of flight
MAOS microwave assisted organic synthesis
MAS-NMR magic angle spinning-nuclear magnetic resonance
Me methyl
MHz megaHertz
mequiv milliequivalent
mg milligram
mL millilitre
min(s) minute(s)
mmol millimole
mol moles(s)
MOM methoxymethyl chloride
mp melting point
MP-TsOH macroporous polystyrene-tosic acid resin
Ms mesyl (methanesulfonyl)
MS molecular sieves
MTBD 134678-hexahydro-1-methyl-2H-pyrimido[12-a]pyrimidine
MW microwave irradiations
mz mass-to-charge ratio
N normal
4-NBP 4-nitrobenzylpyridine
NIS N-iodosuccinimide
NMR nuclear magnetic resonance
viii
ODB 2-dichlorobenzene
on overnight
Oxone potassium peroxymonosulfate (2KHSO5KHSO4K2SO4)
PCC pyridinium chlorochromate
PEG polyethylene glycol
PG protecting group
Ph phenyl
phth phthalimido group
ppm part(s) per million
PPTS pyridinium toluene-p-sulfonate
Pr propyl iPr isopropyl
Pyr pyridine
q quartet (NMR spectroscopy)
qn quintet (NMR spectroscopy)
RCM ring closing metathesis
Rƒ retention factor
rt room temperature
s singlet
sat saturated
SET single electron transfer
SM starting material
SPOS solid-phase organic synthesis
t triplet (NMR spectroscopy)
td triplet of doublets (NMR spectroscopy)
TBAI tetrabutylammonium iodide
TBAB tetrabutylammonium bromide
TBAF tetrabutylammonium fluoride
TBDMSCl tert-butyldimethylsilyl chloride
TBHP tert-butyl hydroperoxide
TBS tert-butyldimethylsilyl chloride
TCE trichloroethyl
Tf triflate
TFA trifluoroacetic acid
Tg glass transition temperature
ix
x
THF tetrahydrofuran
THP tetrahydropyran
TIPS triisopropylsilyl
TLC thin layer chromatography
TMEDA NNNN-tetramethyl-ethane-12-diamine
TMS trimethylsilyl
TNBS 246-trinitrobenzenesulfonic acid
TOF-SIMS Time of Flight- Secondary Ion Mass Spectrometry
TPA triphosgene
p-tosic para-toluenesulfonic
Ts tosyl (para-toluenesulfonyl)
p-TsOH para-toluenesulfonic acid
p-TsCl para-toluenesulfonyl chloride
UV ultraviolet
vv volume per unit volume
ww weight per unit weight
Z benzyloxycarbonyl group
Table of Contents Abstract ii
Authorrsquos Declaration v
Abbreviations vi
Table of Contents xi
Part A 1
1 Classical Alkenation Reactions 1
11 Wittig and Horner-Wadsworth-Emmons (HWE) reactions 1 12 Peterson reaction 3 13 Julia and modified Julia reactions 4
2 Peterson versus Modified Julia or Stereocontrolled Synthesis of Alkenes 9
21 Benzothiazol-2-yl sulfone derivatives 10 22 Pyridin-2-yl sulfones derivatives 19 23 Modified Julia versus Peterson 19 24 Conclusion 21
Part B 22
3 Solid-Phase Synthesis 22
31 Background 22 32 Insoluble supports 23 33 Linkers 24 34 IRORI MacroKan technology 27 35 Site-site isolation or site-site interaction 28 36 Monitoring the progress of solid-phase synthesis 29
4 Pinacol Coupling Reactions 32
41 Homo-coupling reactions 32 42 Intramolecular pinacol coupling 35 43 Pinacol cross-coupling reactions 38 44 McMurry reactions 40 45 McMurry cross-coupling reactions 41 46 Alternative pinacol-like approach to 12-diols using chromium reagents 44 47 Conclusion 45
5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling 46
51 Hypothesis 46 52 Solution phase synthesis 47 53 Solid-phase synthesis 55 54 Conclusion 62
Part C 63
6 Alkenation Reactions using Titanium-Based Reagents 63
61 Tebbe reagent 63 62 Petasis reagent 66 63 Takeda reagent 71 64 11-Bimetallic reagents 75 65 Takai reagents 77
xi
xii
7 Microwave Assisted Organic Synthesis (MAOS) 80
71 Background 80 72 A microwave-assisted Ugi reaction 82 73 Petasis methylenation 83 74 Microwave-assisted solid-phase organic synthesis 83 75 Wittig reaction 83 76 Ring closing metathesis reaction 84 77 Conclusion 85
8 Short Routes to Alkaloids using the Petasis Reagent 86
81 Synthesis of pyrrolidine or azepane alkaloids 87 82 Synthesis of pyrrolidine or azepane alkaloids 93 83 Synthesis of pyrrole or piperidinone alkaloids using the Ugi reaction 96 84 General conclusions 100
9 Previous Syntheses of Anisomycin 101
91 Background 101 92 Racemic syntheses of anisomycin 102 93 Chiral pool syntheses from amino acids 105 94 Chiral pool syntheses from tartaric acid 109 95 Chiral pool synthesis from sugars 112 96 Asymmetric synthesis 117
10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin 122
101 Introduction to the first approach based on tyrosine as starting material 123 102 Preparation of N-allyl esters 123 103 Analysis of complexities in NMR data of esters 130 104 Titanium-based strategies for ring-closing 131 105 Model studies using glycine-derivatives 135 106 Model studies using phenylalanine-derivatives 140 107 Conclusion and other potential routes 153
11 Synthesis of Pyrrolines using the Takeda Reaction on Solid-Phase 155
111 Results and discussion 158 112 Conclusion and opening remarks 165
Part D 167
12 Experimental 167
121 General experimental details 167 122 Experimental to chapter 2 169 123 Experimental to chapter 5 178 124 Experimental to chapter 8 187 125 Experimental to chapter 10 199 126 Experimental to chapter 11 231
References 243
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
Part A
1 Classical Alkenation Reactions
Alkenation of carbonyl compounds to produce carbon-carbon double bonds is one
of the most fundamental reactions in organic chemistry due to the reactive
nature of the double bond Wittig Horner-Wadsworth-Emmons Julia
(and modified Julia) and Peterson reactions are among the most widely used
reactions developed to accomplish this transformation A brief description of
these classical alkenation reactions will be provided in this section and although
alkenation reactions can also be promoted by titanium complexes the discussion
relevant to this titanium chemistry will be given in chapter 6
11 Wittig and Horner-Wadsworth-Emmons (HWE)
reactions
Discovered in 19541 and recognised by the Nobel Prize in 1979 the Wittig
reaction is one of the most effective and general methods for the preparation of
alkenes from carbonyl compounds Before Wittigrsquos discovery the synthesis of
alkenes from carbonyl compounds generally involved nucleophilic attack
followed by elimination the double bond position and geometry were difficult to
control Wittig described a reaction which involves the addition of an aldehyde
or ketone 12 to a preformed phosphorus ylide 11 producing alkenes 14 and
15 and phosphine oxide 16 via an oxaphosphacyclobutane 13 (Scheme 11)
Ph3P R1
O
HR2O PPh3
R2 R1
R2
R1
+ Ph3P=O
11 13 14 + 15 16
12Ph3P
(a) R1CH2X(b) Base
Scheme 11 Wittig reaction
1
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
The stereochemistry of the alkene is defined by the nature of R1 With an
unstabilised ylide (R1 = alkyl) the formation of the oxaphosphetane 13 being
syn selective and the elimination step being stereospecific the Z-alkene 14
(kinetic product) is favoured while an ylide stabilised by an electron-
withdrawing group (R1 = CHO CO2R COR) will produce the E-alkene 15
(thermodynamic product) (Scheme 12)2
Ph3P R1
11
R2CHO O PPh3
R2 R1
13
R2
R1
14
R1
R2
15
+12
Scheme 12 Mechanism of Wittig reaction
Recently Aggarwal and co-workers3 have demonstrated that a dipoleminusdipole
interaction between the two reactants controlled the transition state structures
(TS) and explains the E-selectivity in triphenylphosphine stabilized ylides as
well as 12- and 13-steric interactions already described by Vedejsrsquo models
(Figure 11)45 Indeed unstabilized ylides react with aldehydes in a way to
minimize 12 and 13-steric interactions in the early TS and hence the cis-TS is
favored leading to the Z-alkene For stabilized ylides the high E-selectivity is
due to a strong polar interaction at the addition TS added to minimised 12-
interactions which favors the trans-TS and therefore formation of the E-
product
Alk
HP
H
RO
Ph
PhPh
P
CO2R
H
O
Ph
Ph
PhR
H
Non-stabilized ylides
Stabilized ylides
Cis-TS Trans-TS
Favored Favorable dipole-dipole interactions
12-interactions minimised
13-interactions minimised
Z-alkene E-alkene
12-interactions minimised
Figure 11 Aggarwal and co-workersrsquo TS structure model
2
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
However stabilised ylides are rather unreactive and phosphonate esters 17
more nucleophilic reagents are often used instead of phosphorus ylides This
reaction is called the Horner-Wadsworth-Emmons reaction (HWE) and normally
produces the E-alkene 19 (Scheme 13) However by altering R1 or R2 groups a
Z-alkene can be accessed6 The HWE reaction has proven to be effective with
hindered ketones that are unreactive in the classical Wittig reaction7
O
PR1OR2O
O
OR3Base O
PR1OR2O
O
OR3
O
PR1OR2O
O
OR3
RCHO
R
CO2R3
17
19
18
Scheme 13 HWE reaction
12 Peterson reaction
The silicon-based alternative to the Wittig reaction is the Peterson alkenation
This is the reaction of an -silyl carbanion 110 with a carbonyl compound 12
to give -hydroxysilyl intermediates 111 and 112 (Scheme 14) Treated with
either acid or base these intermediates produce alkenes 14 or 15
SiR3R1
O
HR2
R3Si
OHR1
HR2
+
R3Si
OHR1
R2H
Base
Base
R2R1
R2
R1
acid
11012
111
112
14
15
H
H
Scheme 14 Peterson reaction
3
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
Under basic conditions syn-elimination of anti-diastereomer 111 occurs
through the formation of the intermediates 113 and 114 to yield the Z-alkene
14 while elimination in acid follows an E2 mechanism and produces the other
isomer 15 stereospecifically (Scheme 15) Consequently the control of alkene
geometry depends on the ability to make intermediates 111 or 112 as single
diastereoisomers2
R3Si
OHR1
H
H
R2R2R1
R2
R1
111 14
15
R3Si
OR1
H
H
R2 R3Si O
HR1 R2
H
syn-elimination
R3Si
OH2R1
H
H
R2 E2
Nu
113
115
KH
TsOH
114
Scheme 15 Mechanism of the Peterson reaction
13 Julia and modified Julia reactions
Introduced in 1973 by Marc Julia8 the Julia reaction is a reaction of a lithiated
sulfone derivative 116 with a carbonyl compound 12 to give the oxyanions
117 and 118 which are converted into -acyloxysulfones 119 and 120
(Scheme 16) Reduction with a single electron transfer (SET) reagent gives
radicals 121 and 122 and this is followed by elimination of phenyl sulfone to
give radicals 123 and 124 A second reduction provides conformers 125 and
126 with the acyl group arranged anti-periplanar to the lone pair The
geometry of the alkene is independent of the relative configuration of the
intermediate -acyloxysulfones 119 or 120 but depends on the bulk of R1 and
R2 groups In the carbanion conformer 125 the substituents are arranged so
that steric interactions are minimised and this leads to the formation of the E-
alkene 15 occuring rapidly On the other hand the Z-alkene 14 is disfavoured
by interactions between R1 and R2 Furthermore interconversion between
carbanions 125 and 126 takes place very rapidly resulting predominantly in the
4
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
formation of the E-isomer regardless of which diastereoisomeric sulfone 119 or
120 is used The Julia reaction is stereoselective
PhO2S R1
LiR2
R1
O
PhO2S
R1
R2
116 117 + 118
125
R1
R2
PhO2S
AcO
119 + 120
AcCl
OAcR2
HR1
123 + 124
R1
R2
PhS
AcO
121 + 122
OO
R2CHO
R1
R2AcO
HOAcR2
R1
H
H
126
SET
SET
slow fast
R2
R1
14 15
PhSO2
Na
Na
Na
AcO
H R2
HR1
AcO
H R2
R1H
fast
12
Scheme 16 Julia reaction
A one-pot version of the Julia reaction has been developed by Sylvestre Julia9
and has been reviewed by Blakemore10 This reaction requires a
heteroarylsulfone and four heterocyclic activators have been identified which
provide useful levels of stereoselectivity under certain conditions (Figure 12)10
benzothiazol-2-yl (BT) pyridin-2-yl (PYR) 1-phenyl-1H-tetrazol-5-yl (PT) and 1-
tert-butyl-1H- tetrazol-5-yl (TBT)
S
N
N
N
NNN
N
NNN
BT PYR PT TBT
Figure 12 Heterocyclic activators of the modified Julia olefination
5
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
BT-sulfones and PYR-sulfones are commonly used for their stereoselectivity The
presence of an imine-like moiety in the molecule controls their reactivity Like
the classical Julia addition of the lithiated sulfone 127 to an aldehyde 12
generates unstable -alkoxysulfones 128 and 129 which rearrange via Smiles
rearrangement to give sulfinate salts 132 and 133 (Scheme 17) Then
spontaneous elimination (E2 like) of sulfur dioxide 134 and lithium
benzothiazolone 135 yields alkenes 14 and 15 The geometry of the alkene is
then controlled by the geometry of sulfones 128 and 129 and by the reaction
conditions
S
NSO2 S
NSO2
R1
MO R2
R1
S
N
S
O R2
R1
OO
S
NO
R2
R1
S
OO
S
NOLi + SO2 +
R2
R1
127 128 + 129 130 + 131
132 + 13314 + 15135
R2CHO Smiles
12
134
Scheme 17 Modified Julia reaction mechanism
Indeed the elimination of -alkoxy-BT-sulfones 128 and 129 is stereospecific
The syn-diastereoisomer 128 yields the Z-alkene 14 (Scheme 18) as an anti-
periplanar arrangement of BTO- and SO2Li is required in the final elimination
step whereas the anti-diastereoisomer 129 produces the E-alkene 15 (Scheme
19) Then the ratio of ZE alkenes 1415 should reflect the ratio of synanti
sulfones 128129 formed after the nucleophilic addition
6
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
SN
S
NSO2
R2 OLi
R1
R1
128 132 14
R2
HH
R1S
NS
OOOLi
H
R1 SO2BTOLi
R2H
130
R1
O2S
H
O
Li
R2H
OBT
SO2Li
H R1 R2
R2Hfast
Smiles
Scheme 18 Synthesis of Z-alkene 14
S
NSO2
R2 OLi
R1
R1
129 133 15
HR2
H
R1S
NS
OO OLi
H
R1 SO2BTOLi
HR2
131
R1
O2S
H
O
HR2
SN Li
OBT
SO2Li
H R1 R2
slow
Smiles
HR2
Scheme 19 Synthesis of E-alkene 15
However It has been reported by Smith and co-workers11 that the use of -
unsaturated aldehydes and aryl aldehydes improves the E-stereoselectivity
regardless of the ratio of -alkoxysulfones 128 and 129 Julia and co-
workers12 proposed that the reaction followed a E1 mechanism (Scheme 110)
The loss of benzothiazolone 135 from diastereoisomers 132 and 133 would
produce zwitterionic conformers 136 and 137 The carbocation is stabilized by
the -unsaturation of R2 Interconversion would then occur rapidly to form the
7
Guilaine F Blanc Chapter 1 Classical Alkenation Reactions
more stable conformer 137 followed by the loss of sufur dioxide 134 to yield
the E-alkene 15
R1
132 14
SO2Li
HOBT
8
R1 R2R1
R2H
R1
133 15
SO2Li
H R1OBT
HR2
R2
BTOLi
SO2
HR2H
BTOLi
SO2
H R1
HR2
135
135
136
137
SO2
134
Scheme 110 E-stereoselectivity
These alkenations reactions became popular because of their wide applicability
A large variety of carbonyl compounds are suitable and the number of examples
of their application in total synthesis of natural compounds is vast
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
2 Peterson versus Modified Julia or
Stereocontrolled Synthesis of Alkenes
Katritzky et al13 described the lithiation of -silyl BT-sulfide 21 and its
reaction with carbonyl compounds 22 (Scheme 21) Naturally a Peterson
reaction took place and he observed elimination of the silyl group leading to the
formation of a mixture of E and Z-vinyl sulfides 23 The reaction was not
stereoselective
(a) LDA
(b) THF 4 h ndash 78 degCS
N
S S
N
SSiMe3
21
O
R2R1
R1
R2
R1 = aryl alkylR2 = aryl alkyl
22(EZ) 5050 to 6040
23 77-98
Scheme 21 Peterson reaction with a -silyl BT-sulfide
But what if instead of the BT-sulfide we had a BT-sulfone 24 Would we
observe elimination of the silyl group (25) via a Peterson reaction or
elimination of the sulfone (26) via a modified Julia reaction (Scheme 22)
(a) R1R2CO(b) LDA
THF ndash 78 degCS
N
SS
N
SSiMe3
24
R1
R2OO
(a) R1R2CO(b) LDA
THF ndash 78 degCOO
R1
R2Me3Si
25
RRR
26 PetersonModified Julia
Scheme 22 Modified Julia versus Peterson reactions
The increased electrophilicity of the BT moiety bearing a sulfonyl group might
favour the Modified Julia to give the vinyl silane 26 Alternatively the vinyl
sulfone 25 might be produced
Having the works of Julia and Katritzky in mind we proposed the following short
sequence to access -silyl sulfones (Scheme 23) The synthesis would start from
9
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
the appropriate heterocyclic thiol 27 the silyl derivative 28 would be
prepared then alkylation followed by oxidation of the alkyl sulfide 29 would
produce the desired sulfone 210
S SiMe3
ArS SiMe3
ArR
S SiMe3
ArR
OO
Base
RX
[O]
21028 29Ar = BTPYRR = aryl alkylR1 = aryl alkyl
27
ArSH
Scheme 23 Proposed route to sulfone 210
21 Benzothiazol-2-yl sulfone derivatives
According to Katritzkyrsquos procedure13 the silyl derivative 21 was prepared in
good yield by reaction of (chloromethyl)trimethylsilane with benzothiazol-2-thiol
211 and potassium carbonate in acetone (Scheme 24) Deprotonation of silyl
derivative 21 with equimolar LDA (generated in situ) afforded an -lithio
derivative which was alkylated with benzyl bromide13 After purification the
sulfide 212 was isolated in good yield
(a) LDA(b) BnBr
THF 4 hndash 78 degC
Me3SiCH2Cl K2CO3
acetone rt on
S
N
SSH
N
S S
N
S SiMe3SiMe3
211 21 75 212 79
Ph
Scheme 24 Preparation of sulfide 212
Molybdate catalysed oxidation is the most popular method to access heteroaryl
sulfones However treatment of thioether 212 with (NH4)2MoO4 (10 mol) and
H2O2 in ethanol did not lead to the formation of sulfone 213 (Scheme 25) 1H
NMR analysis of the crude mixture showed the formation of the sulfone 214
resulting from the loss of the trimethylsilyl group [1H NMR (400 MHz CDCl3)
305 (2H t J 84 Hz CH2) 365 (2H t J 86 Hz CH2) 700-711 (5H m Ar-H)
743 (1H dt J 14 and 79 Hz H5 or H6) 748 (1H dt J 15 and 78 Hz H5 or
H6) 785 (1H ddd J 09 14 and 79 Hz H4 or H7) 805 (1H ddd J 08 15
10
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
and 80 Hz H4 or H7)] Oxidation conditions were obviously too harsh to allow
the presence of the silyl group on the molecule Therefore several classical
oxidising systems were investigated on either sulfide 21 or sulfide 212 in order
to obtain sulfones Although peracid reagents (particularly m-CPBA) have been
extensively employed for the oxidation of heteroaryl thioethers14 the reaction
of sulfide 212 with m-CPBA in the presence of sodium hydrogenocarbonate in
CH2Cl2 15 did not proceed and we recovered starting material Moreover reaction
using potassium permanganate in acetone at rt performed with the substrate 21
led to recovery of starting material (Scheme 26) After reaction of sulfide 212
with oxone (potassium peroxomonosulfate) in methanol at rt16 we observed
decomposition of the -silyl sulfide and among these by-products we detected
traces of the sulfone 214 from the 1H NMR analysis of the crude mixture
(Scheme 25) The loss of the silyl group was highlighted again and the result
was further confirmed by the oxidation reaction of the sulfide 21 which
provided the sulfone 216 in excellent yield (Scheme 26)
or m-CPBA (22 eq)NaHCO3 (25 eq)CH2Cl2 rt on
H2O2 EtOH(NH4)2MoO4
S
N
S S
N
S
45
6
7SiMe3
212 214 79
Ph
rt onPh
S
N
S SiMe3
213
Ph
OO
oxone (30 eq)
MeOH H2Ort on
OO
Scheme 25 Oxidation reactions
11
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
KMnO4 (30 eq)
H2O acetone35 h rt
S
N
S SiMe3
21
S
N
SOO
SiMe3
oxone (30 eq)MeOH H2Ort on
S
N
SOO
216 98
215
Scheme 26 Oxidation of sulfide 21
An interesting oxidising system based on the use of oxone attracted our
attention as it was reported in the total synthesis of ()-Fortucine (Scheme
27)17 The use of 22-dimethyldioxirane (DMDO) 218 in presence of TFA (to
protect the amine) allows the oxidation of sulfide 217 into sulfone 219 in
excellent yield and tolerates the silyl protection of the alcohol
N
MeO
BnO
O
O SAr
OTBSH
H N
MeO
BnO
SO2Ar
OTBSH
H
HO
(i) LiAlH4 (66)
(ii) DMDO 218 (92)
217 219
Scheme 27 Towards the total synthesis of ()-Fortucine
Similarly Baeschlin et al18 reported oxidation of thioether 220 to give sulfone
221 using oxone and sodium acetate in methanol-THF (Scheme 28) The silyl
protection of alcohols survived these conditions
12
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
O
OH
TBDPSON
NH
O
O
S
O
N
NH
O
O
TBDPSO
O
OH
TBDPSON
NH
O
O
SO2
O
N
NH
O
O
TBDPSO
oxone (41 eq) NaOAc (185 eq)
MeOH-THF H2Ort 2 h
220 221
Scheme 28 Oxidation using oxone- NaOAc
Dioxiranes such as 22-dimethyldioxirane (DMDO) 218 or trifluoromethyl
dioxirane (TFDO) 223 are a class of powerful oxidants which exhibit
electrophilic oxygen transfer to nucleophilic substrates as well as oxidation of
unactivated alkanes19 First reported in 197920 dioxiranes are easily accessed by
the reaction of simple ketones 222 with potassium peroxymonosulfate (also
called oxone or caroat 2KHSO5KHSO4K2SO4) at pH close to neutrality
(Scheme 29) The fact that they perform a variety of versatile oxidations
exhibit unusual reactivity and conduct oxygen transfer highly chemo- regio- and
stereoselectively is responsible for the popularity of these reagents The
oxidation reaction is carried out either with the isolated solution of dioxirane in
acetone or with the in situ generated dioxirane The in situ generated dioxirane
allows the reaction to be carried out on larger scale and can not be applied to
substrates that are water-sensitive
O OKHSO5
+O
R
H2O NaHCO3
pH 74 0 degC R
218 R = CH3223 R = CF3
222
Scheme 29 Formation of dioxiranes
Sulfides 224 may be oxidised to sulfoxides 227 or sulfones 228 depending on
the number of equivalent of the oxidant used However sulfides 224 are more
13
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
easily oxidised than sulfoxides 227 due to the electrophilic character of the
reagent Details of the mechanism of sulfide oxidation with dioxiranes are not
clear Gonzaacutelez-Nuacutentildeez et al21 reported a mechanistic study where they showed
that the first step is an electrophilic attack of dioxiranes 218 or 223 on the
sulfur atom to give the zwitterionic species 225 which undergoes a reversible
cyclisation step to generate the sulfurane intermediate 226 (Scheme 210)
However elimination of acetone from the species 225 occurs faster than the
cyclisation and provides the sulfoxide 227 Indeed the use of a polar solvent
such as acetone solvates the zwitterionic intermediate 225 shifting the
equilibrium away from sulfurane 226 and so favours the formation of sulfoxide
227 Gonzaacutelez-Nuacutentildeez reported -elimination from sulfurane 226 to give
sulfone 228 only in the case of the use of TFDO 223
O OSR1 R2 + S O
R1
R2
OO
S O
R
R2
R1
S OR2
R1
SO
O
R1
225 226
227 228
218 or 223
R
R2
Rk1
k2
218 R = CH3223 R = CF3
RCOCH3
224
223
Scheme 210 Mechanism of oxidation
Applying this procedure to thioether 21 led to the formation of methyl sulfone
216 and sulfoxide 229 (Scheme 211) Since the desilylated sulfoxide was not
observed we concluded that loss of the silyl group occurred after oxidation to
the sulfone Careful addition of the oxidising system in 3 batches avoided the
formation of the methyl sulfone 216 1H NMR analysis of the crude mixture
showed the exclusive formation of sulfoxide 229
14
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
229
ratio (21229)1486
(a) oxone (30 eq) NaOAc (18 eq) MeOH (88 mL) THF (13 mL) H2O (15 mL) 45 min 0 degC to rt(b) repeat (a) (c) repeat (a)
oxone (40 eq)NaOAc (18 eq)
S
N
SOO
S
N
S
O
SiMe3
+
S
N
S SiMe3 MeOH-THF H2O1 h rt
21
ratio (216229) 3664
229216
57 mass recovery of crude
59 mass recovery of crude
Scheme 211 Oxidation with oxone-NaOAc
Thus reaction of sulfide 21 with DMDO 218 [generated in situ from oxone
(30 eq) and acetone (56 eq) in water] and NaHCO3 in dichloromethane provided
the sulfoxide 229 (Scheme 212) However the reaction did not go to
completion (Table 21 entry 1) After several attempts it appeared that a large
excess of DMDO 218 (entries 2 and 3) as well as a longer reaction time [entry
4(i)] did not improve the reaction as the unstable reagent decomposed before
reacting On the other hand after a first overnight reaction we isolated
sulfoxide 229 [entry 4(i)] which was put back into the reaction with DMDO 218
for 2 h [entry 4(ii)] After usual work up we then observed traces of sulfone
215 As predicted by Gonzaacutelez-Nuacutentildeez21 it proved to be necessary to add DMDO
218 in several batches in order to displace the reaction to the sulfone (entries 4
and 5)
oxone acetoneNaHCO3
CH2Cl2 H2O0 degC to rt
S
N
S
O
SiMe3
229
S
N
S SiMe3
21
S
N
SO
SiMe3
215
O
Scheme 212 Oxidation with DMDO
15
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
Entry Acetone (eq) Oxone (eq) Time Ratio (21 229 215)
1 56 30 25 h 36640
2 60 60 3 h 35650
3 30 20 2 h 10000
4 (i) 57 30 on 59410
(ii) 57 30 2 h 08119
5 56 x 7 20 x 7 6 h 08515
Table 21 Oxidation conditions with DMDO
At the same time the oxidation was attempted using in situ generated TFDO
223 (Scheme 213) A first reaction with 6 eq of oxone and 12 eq of 111-
trifluoroacetone provided mainly starting silyl sulfide 21 and traces of sulfoxide
229 The crude mixture was submitted to similar conditions a second time The
sulfoxide 229 was the major product of the reaction but the reaction never
went on to form the sulfone
(i) oxone(6 eq) CF3COCH3 (12 eq) H2O (36 mL) NaHCO3 (36 mL) CH2Cl2 (1 mL) 2 h 0 degC to rt work up
(ii) repeat (i)S
N
S
O
SiMe3
229
S
N
S SiMe3
21
(i) ratio (21 229) 8317(ii) ratio (21 229) 1189
Scheme 213 Oxidation with TFDO
The formation of sulfoxide 229 using DMDO 218 not being optimal we decided
to study the impact of two parameters on its formation the number of
equivalent of acetone and the concentration of the reaction (Scheme 212 Table
22) Standard conditions are reported in entry 1 for a proper comparison The
use of twice the amount of acetone (entry 2) improved considerably the
advancement of the reaction but it was still incomplete Also doubling the
concentration of the reaction led to an improvement compared to standard
conditions (entry 3) Consequently the next logical step was to use 60 eq of
oxone 12 eq of acetone and half the volume of CH2Cl2 (entry 4) We were able
to isolate the sulfoxide 229 in 57
16
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
Entry Acetone (eq) Oxone (eq) Conc of sulfide 21 in CH2Cl2
(mol L-1) Time Ratio (21 229)
1 56 60 023 2 h 919
2 119 60 025 2 h 5644
3 56 60 049 2 h 7030
4 120 60 047 2 h 1684 (57)a
a isolated yield of sulfoxide 229
Table 22 Determination of conditions for an optimum formation of sulfoxide 229
Synthesis of the sulfone 215 was investigated from this isolated sulfoxide 229
(Scheme 214) Thus after 2 h of reaction of sulfoxide 229 with DMDO 218
the sulfone 215 was finally accessible and isolated in a modest yield
oxone (6 eq) acetone (12 eq)NaHCO3
CH2Cl2 H2O 0 degC to rt 2 hS
N
S
O
SiMe3
229
S
N
SO
SiMe3
215 48
O
Scheme 214 Formation of the sulfone 215
From those two series of reactions we obtained important information The
sulfoxide 229 is an intermediate in the synthesis of the sulfone 215 which we
can reach only by the addition of several batches of oxidising system Optimum
conditions to obtain the sulfoxide 229 were established with 12 eq of acetone
60 eq of oxone in presence of NaHCO3 and with a concentration of sulfide in
CH2Cl2 about 05 M With this information in hand we finally optimised the
synthesis of the sulfone 215 (Scheme 215) A first addition of oxidising agent (6
eq acetone 3 eq oxone in water) to the sulfide 21 dissolved in CH2Cl2 and
NaHCO3 was done at 0 degC and the reaction was left for 1 h at rt Then another
addition (6 eq 3 eq in water) was performed and the reaction was left for
another hour After this time and in order to keep a high concentration the
reaction was stopped organic materials were extracted and after removal of the
solvent the crude mixture was submitted to the same oxidation procedure
Then after a total of 24 eq of acetone 12 eq of oxone in 4 batches and after
17
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
4 h of reaction we isolated a clean sulfone 215 in very good yield No
purification was required
21
S
N
S SiMe3 S
N
SO
SiMe3
215 86
O
(i)-(a) oxone(3 eq) acetone (6 eq) H2O (39 mL) NaHCO3 (aq) (77mL) CH2Cl2 (21 mL) 1 h 0 degC to rt
(b) oxone(3 eq) acetone (6 eq) H2O (39 mL) 1 h 0 degC to rt
(ii) repeat (i)
Scheme 215 Synthesis of the sulfone 215
In an attempt to access the sulfone 215 from the methyl sulfone 216 we
carried out the reaction of the lithiated sulfone and trimethylsilyl chloride in
THF (Scheme 216) Unfortunately this reaction was unsuccessful we recovered
starting sulfone 216
S
N
SOO
216
S
N
SOO
215
SiMe3
(a) LDA (11 eq) THF -78 degC
(b) TMSCl (12 eq) THF 4 h 78 degC
Scheme 216 Attempt of formation of sulfone 215
Naturally the oxidation of -silyl sulfide 212 was undertaken following the
optimum conditions just established After 4 h at rt the sulfone 213 was
obtained in poor yield
Since the sequence towards the synthesis of the sulfone intermediate was well
established we prepared the pyridine-2-yl sulfone 232
18
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
22 Pyridin-2-yl sulfones derivatives
First following Kohrarsquos procedure22 S-alkylation of thiol 230 with
(chloromethyl)trimethylsilane gave the thioether 231 in excellent yield
Oxidation of sulfide 231 with DMDO 218 generated in situ provided the
sulfone 232 in excellent yield (Scheme 217)
Me3SiCH2Cl K2CO3 KI EtOH
reflux 23 h
N SH
N S SiMe3 N S SiMe3OO
230
231 85 232 84
(i)-(a) oxone(3 eq) acetone (6 eq) H2O (38 mL) NaHCO3 (75 mL) CH2Cl2 (20 mL) 1 h 0 degC to rt
(b) oxone(3 eq) acetone (6 eq) H2O (38 mL) 1 h 0 degC to rt work up(ii) repeat (i)
Scheme 217 Synthesis of sulfone 232
With three different heterocyclic sulfone intermediates 213 215 and 232 in
hand alkenation was naturally the next target reaction
23 Modified Julia versus Peterson
Modified Julia reactions are particularly successful between alkyl BT-sulfones
and electron-rich conjugated aldehydes and are highly E-stereoselective10 This
reaction was found to be extremely water-sensitive and care had to be taken to
ensure the absence of water Every substrate needed to be dried prior to the
reaction BT-sulfones are particularly sensitive to nucleophilic attack at C2 and
participate in ipso substitution reactions To avoid that the deprotonation of
the sulfone must be done with non-nucleophilic bases (eg LDA) Moreover self-
condensation side reactions usually occur with non-sterically hindered sulfones
and thus the process can be improved by adopting Barbier conditions (the base is
added to a mixture of sulfone and aldehyde) On the other hand PYR-sulfones
19
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
are less susceptible to ipso substitutions The lack of electrophilicity of PYR
moiety results in a better stability of the lithiated PYR-sulfone and then self
condensations are avoided
Modified Julia versus a Peterson reaction was investigated with sulfone 215 and
veratraldehyde 233 and thus gave only the E-vinyl sulfone 234 isolated in
good yield Similarly the E-vinyl sulfone 235 resulted from reaction of PYR-
sulfone 232 and veratraldehyde 233 under Barbier conditions (Scheme 218)
The conclusion is clear Peterson alkenation is faster than the modified Julia
reaction in direct competition
LDA (11 eq)S
Ar
215 Ar = BT
OO+
CHO
OMe
OMe
233
THF78 degCthen rt 2 h-45 h
SiMe3 SAr
234 63 Ar = BT E-alkene only
OO
OMe
OMe
235 58 Ar = PYR E-alkene only232 Ar = PYR
Scheme 218 Peterson wins
Before making further attempts to form various vinyl sulfones we had to think
about how useful our discovery was and what scope we saw for this sequence
Vinyl sulfones are reversible inhibitors of cysteine proteases and more
specifically are effective inhibitors against cruzain a cysteine protease that
plays a crucial role in the life cycle of Trypanosoma cruzi23 Vinyl sulfones have
also been exploited as inhibitors of Staphylococcus aureus sortase and HIV-1
integrase23 For chemists vinyl sulfones play an important role acting as
efficient Michael acceptors and as dienophiles in Diels-Alder and related
reactions and have been reviewed by Simpkins24
We decided to investigate first an easy transformation with the reduction of the
double bond in order to allow access to alkyl sulfones (Scheme 219) Attempts
to reduce vinyl sulfone 235 using sodium borohydride in methanol were
unsuccessful but reaction of PYR-sulfone 235 with NaBH4 in THF provided alkyl
sulfone 236 Conditions were unsuccessful with BT-sulfone 234
20
Guilaine F Blanc Chapter 2 Peterson versus Modified Julia reactions
SOO
SOO
OMe
OMe
OMe
OMeNaBH4 (6 eq)
236 49
THF 8 h 80 degC
235
N N
Scheme 219 Formation of alkanes
24 Conclusion
A short route to heterocyclic vinyl sulfones was developed and it has been
demonstrated that a silyl substituent is more reactive than the heterocyclic
sulfones so that Peterson alkenation is more favourable than Modified Julia
reaction Since an alternative route to similar vinyl sulfones using the HWE
reaction25 appears more straightforward than our Peterson alkenation the
reaction was not studied further
21
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
Part B
3 Solid-Phase Synthesis
31 Background
Since Merrifieldrsquos pioneering work26 in solid-phase peptide synthesis which gave
him a Nobel Prize in 1984 solid-phase organic synthesis (SPOS) has experienced
constant popularity and development At the end of the 70rsquos Freacutechet27 and
Leznoff2829 introduced the concept of solid-phase synthesis for the synthesis of
small molecules by doing organic reactions where a substrate reagent or
catalyst was loaded on an insoluble polymer support Since then a large number
of organic reactions have been translated to the solid phase with success and
this was the origin of the development of combinatorial chemistry in the 90rsquos
In SPOS starting materials are attached to an insoluble support (polymer bead)
by a linker that can later be cleaved under specific reaction conditions30 The
support-bound intermediates are exposed to solutions of the desired reagents
Stoichiometric excesses can be used to obtain completion of the reaction The
excess reagents and by-products formed are removed by simply rinsing the solid
supports with various solvents Finally the products are cleaved from the solid
supports and subjected to purification (Figure 31)
Figure 31 Solid-phase synthesis concept30
SPOS which can be automated proved to be quick and simple providing time
and labour advantages over the corresponding syntheses in solution phase31
Moreover the yields and quality of products were improved by using an excess
of the reagents SPOS worked well for small scale reactions This chemistry
limits the use of toxic and flammable solvents as the only purification step
22
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
consists of a filtration and therefore reduces waste The polymer is also
potentially recyclable and reactions are less harmful and dangerous due to the
high chemical and physical stability of supports Therefore SPOS holds a full
place in the new concept of green chemistry For all these reasons SPOS is now
recognized as an important methodology for constructing libraries of biologically
active small molecules32
32 Insoluble supports
Supports of different macroscopic shape have been used in SPOS33 Although the
supports can take the shape of small discs or sheets they are most commonly
shaped as beads The general requirements for a support are mechanical
stability and chemical inertness under the reaction conditions to be used The
support is functionalized to allow the substrate to be attached to the support via
a linker Two major classes of solid support have been designed for SPOS
polystyrene (Figure 32) and polyacrylamide supports Styrene polymers are
crosslinked with divinyl benzene (styrene-DVB) in order to hold the long chains
of polystyrene together in a spherical bead Styrene-DVB is one of the most
common support33 (Figure 32) and was the one we used through our work in
solid-phase chemistry
Ph Ph Ph
Polystyrene Styrene-DVB
Ph
Ph
Figure 32 Polystyrene supports
23
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
33 Linkers
The linker is the connection between the molecule being synthesized and the
solid support that is cleaved to release the desired molecule (Figure 33)
Spacer Linker Substrate
Figure 33 Connection of the substrate to polymer
It is attached to the substrate through a functional group that is labile to the
cleavage conditions (eg silyl ether esters carbamates etc) and orthogonal to
reaction conditions It is linked to the solid-phase polymer through a covalent
stable bond (eg carbon-carbon ether or thioether) The linker is then
considered as a sort of supported protecting group The ideal linker would fulfil
a number of important criteria It would be cheap and readily available The
attachment of the starting material would be achieved in high yield The linker
would be stable to the chemistry used in the synthesis Cleavage would be
efficient under conditions that do not damage the final product The cleavage
method should be easy to apply and should not introduce impurities that are
difficult to remove34
All linkers must survive the reaction conditions therefore the choice of the
synthetic route may determine the choice of the linker A large variety of
linkers34 has been reported in the literature to allow a correct selection and a
successful synthesis
Three specific linkers have been used through my work Wang and Merrifield
linkers and a p-toluenesulfonic acid linker
24
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
Merrifield linker (chloromethylated polystyrene)
Merrifield Resin 31 is a polystyrene resin based on a copolymer of styrene and
chloromethylstyrene cross-linked with DVB (up to 5)(Figure 34)26
Cl
Cl
PhPh=
31
Figure 34 Merrifield resin
Carboxylic acids 32 are attached to the support 31 as esters 33 via the
formation of their corresponding cesium carboxylate salts using Gisinrsquos method35
and acidic cleavage leads to the regeneration of the carboxylic acid 32 (Scheme
31)
+
O
OHRCl
O
O
R
HF
O
OHR+
DMF
Cs2CO3
31 32 33
32
Scheme 31 Loading and cleavage of Merrifield resin
The lability of this linker depends on the stability of the generated carbocation
The cation formed in this case is relatively unstable making the linker-substrate
bond really strong Consequently a strong acid (HF) is required for the cleavage
from resin which is the major inconvenience of this resin
25
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
Wang linker (hydroxymethylphenoxy linker)
Wang resin 34 first described in 1973 by Wang36 is the most popular support
for SPOS (Figure 35)
O
OH
34
Figure 35 Wang resin
Developed for the attachment of carboxylic acids the Wang resin 34 can be
used for the attachment of alcohols 35 as ethers 36 under Mitsunobu
conditions (Scheme 32) The Wang resin 34 has a greater acid lability
compared to Merrifield resin 31 due to the formation upon cleavage of a
carbocation 37 stabilized by resonance Therefore cleavage is accomplished by
TFACH2Cl2 (50-95) treatment and leads to the regeneration of alcohol 35
O
OH
+ ROH PPh3 DIAD
THFO
OR
TFA -CH2Cl2 (11)
O+ ROH
O
34 35 36
37 35
Scheme 32 Loading and cleavage of Wang resin
p-Toluenesulfonic acid linker (MP-TsOH)
MP-TsOH 38 is a sulfonated polystyrene resin that is a resin-bound equivalent of
the strong acid p-toluenesulfonic acid (TsOH) (Figure 36) It is a strong acid
cation exchange resin Ion exchange is the process in which ions held by
electrostatic forces to charged functional groups on the surface of an ion
26
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
exchange resin are exchanged for ions of similar charge from the solution in
which the resin is immersed
SOH
O O
38
Figure 36 MP-TsOH resin
Resin 38 is used to perform capture and release of amine derivatives 39 in
solution (Scheme 33) The cleavage proceeds by treatment with a base (Et3N or
NaOH) in CH2Cl2 nevertheless the resin 38 can be regenerated by contact with
a strongly acidic solution
MP-TsOH 38 THFS
O
O O
N
R
N
R
H
Base CH2Cl239 310
Scheme 33 Loading of MP-TsOH
34 IRORI MacroKan technology
In my research prior to the synthesis the resin beads are loaded into a
polypropylene reactor called an IRORI MacroKan (Figure 37) This is then
sealed with a cap and the Kan is introduced into the glassware where the
synthesis takes place as reagents flow through the porous reactor The
MacroKan has an internal volume of 24 mL and a pore size of 74 m and
allows easier handling of the solid support It is suitable for use with standard
laboratory glassware and standard conditions (heating cooling mixing etc)
The MacroKan can be filled with a maximum of 300 mg of resin
27
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
Figure 37 IRORI MacroKansTM
35 Site-site isolation or site-site interaction
Among the many advantages of SPOS one unique property is the pseudo-dilution
effect37 In an ideal representation of a resin support the reactive groups are
bound to the insoluble rigid polymer and so they have restricted motion
Intramolecular reactions between reactive groups are minimized and the
situation is approaching infinite dilution while the ldquoconcentrationrdquo of reactive
groups is still relatively high This notion is defined as ldquosite-site isolationrdquo or
pseudo-dilution effect (Figure 38) In reality the structural mobility of a
polymer support is controlled by numerous factors such as cross-linking loading
solvent temperature and reagent concentrations Site-site interactions can
occur when the polymer support is very flexible or the sites are close in space
Figure 38 Site-site isolation and site-site interaction
Considering the pinacol coupling reaction between a supported aldehyde 311
and an aldehyde 312 in solution the pseudo-dilution effect would favour the
formation of the 12-diols 314 whereas homo-dimer 313 would be formed in
the case of site-site interactions (Figure 39) It may be necessary to suppress
site-site interactions to get the desired cross-pinacol products 314
28
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
R1 H
O
O
HR2
R1
OH
R2
OH
Pseudo-dilution effectSite-site interaction
R1
OHR1
OH
311
312
313 314
Figure 39 Pseudo-dilution effect or site-site interaction
These interactions can be limited by choosing a polymer with a high level of
covalent cross-linking and site-site interactions are further reduced by selecting
a lower resin loading or a solvent that does not swell the resin to its maximum or
by using lower reaction temperatures Several reports37383940 provided evidence
that site-site isolation can be enhanced by low reaction temperatures without
being really able to explain the phenomenon Crosby and Kato38 suggested that
low temperatures (close to the polymer glass transition temperature Tg) result in
relatively rigid polymer chains as observed in the dry state More and more
investigations have proved that site-site isolation and site-site interactions are in
a dynamic equilibrium37 By controlling these parameters site-site interactions
can be reduced so that the desired intermolecular reaction dominates
36 Monitoring the progress of solid-phase synthesis
Various methods have been developed for analyses of solid support-bound
intermediates as alternatives to the cleavage of intermediates from the support
and their characterization in solution These techniques are fully described in
Zaragozarsquos work33 and an overview of the most common analytical methods is
given in this paragraph
Combustion analysis this is mainly used to determine the amount of halogens
nitrogen or sulfur present in samples The information allows an estimation of
29
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
the loading of a support and to verify complete displacement of a halide The
technique is destructive not really precise and not fast enough to allow reaction
monitoring
Colorimetric assays this is widely used in solid-phase synthesis of peptides and
the technique allows detection of even small amounts of amines [Kaiser test
TNBS (246-trinitrobenzenesulfonic acid) etc] alcohols [4-NBP (4-nitrobenzyl
pyridine) etc] thiols (Ellmanrsquos reagent)
IR spectroscopy the method is fast easy and cheap for the detection of certain
functional groups on insoluble supports However IR spectroscopy is only
sensitive to some functional groups and therefore not well suited to quantitative
measurements
MS analysis has proven useful for the analysis of resin-bound molecules
Carrasco et al41 developed a simple and general method by MALDI-TOF (Matrix-
Assisted Laser Desorption Ionisation- Time of Flight) allowing direct analysis of
supportndashbound intermediates The method relies on the use of a derivatised
resin that incorporates a dual linker strategy and an ionization sequence (Figure
310) A photocleavable linker is used to attach an ionization sequence to the
resin while a chemically cleavable linker is used to allow release of the target
molecule and the desired final product can be isolated free of the linker
sequences The photocleavable linker and the ionization sequence allow better
detection of small molecules as the global mass is increased identification of
the resin-bound products regardless of the presence of potential protonation
sites on the molecule at any stage of the synthesis and without interfering with
isolation of the products released into solution This sensitive method requires a
few mg of resin and appropriate equipment and skills
30
Guilaine F Blanc Chapter 3 Solid-Phase Synthesis
desired organic substrate
chemically cleavable link
ionization sequence
photocleavable link
MALDI analysis-photochemical cleavage
chemical cleavage
desired organic substrate
chemically cleavable link
ionization sequence desired organic
substrate
Figure 310 Representation of a chemical and a photochemical cleavage of a resin-bound
molecule41
Alternatively the analysis of non-photolabile linkers can be done with TOF-SIMS
(Time of Flight- Secondary Ion Mass Spectrometry)42 This technique is
particularly adequate for analysis of supported peptides
NMR analysis MAS-NMR (Magic Angle Spinning-NMR) has been especially
adapted for recording NMR spectra of support-bound compounds Cross-linked
polymers have anisotropic physical properties The magnetic field is intermittent
at the interface of the polymer which explains the broadness of spectra and the
decrease in the resolution in the NMR spectra This technique consists in keeping
a sample of swollen solid support spinning at 1-2 KHz at the lsquomagic anglersquo (547deg
relative to the orientation of the magnetic field) in order to erase this
discontinuity The method enables the recording of much better resolved
spectra (1H NMR 2D-NMR) However it requires specific apparatus and skills
Indirect analysis this method consists in cleavage of the bound material from
the solid support and analysis of the filtrate The technique relies on sampling as
release of the material from resin terminates synthesis but it does not require
any specific equipment
31
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
4 Pinacol Coupling Reactions
Many pharmacologically active substances contain the 12-diol structural motif
and 12-diols can also serve as key intermediates in total synthesis in chiral
ligands or auxiliaries A powerful way of setting up 12-diols is to form the C-C
bond between the two hydroxyl groups by means of a pinacol reaction43 This
involves the reduction of ketones or aldehydes 41 by a metal or compound
containing a metal in a low oxidation state to give ketyl radicals 42 which then
homo-couple to give 12-syn-diols 45 andor 12-anti-diols 46 after quenching
(Scheme 41) Although a very wide range of metals or low-valent metal ions can
be used including group 1 metals and samarium(II) ions44 my work focuses on
the use of low valent titanium complexes in the synthesis of 12-diols
Therefore a short review of this reaction follows concentrating on the use of
titanium reagents rather than other metal-mediated pinacol reactions Pinacol
reactions can be divided into three categories homo-coupling reactions
intramolecular reactions and cross-coupling reactions and these will be dealt
with in turn While the first two of these involve diastereocontrol the last of
these cross-coupling reactions presents the additional challenge of pairing up
different coupling partners and it is this challenge that I tried to address in my
research
O
R2R1
[M]O[M]
R2R1 R1R2 R2
R1
O[M][M]OO[M
R2R1
4341 42
42
H2O
-2 [M]-OH
OH
R1 R1
OH
R2
R2
OH
R1 R1
R2
R2
OH
45 46
+
44
Scheme 41 Pinacol Coupling Reactions
41 Homo-coupling reactions
Homo-coupling involves two molecules of the same carbonyl compound coupling
to give 12-diols (Scheme 42) Studies have been devoted to the search for a
lowndashvalent titanium compound that would be suitable for the synthesis of
32
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
pinacols with high stereoselectivity They will be presented in the following
section and a comparison will be done based on benzaldehyde
One of the most efficient systems was developed by Corey et al45 in 1976 (Table
41 entry 1) He found that aldehydes (eg benzaldehyde 47) and ketones
(eg cyclohexanone) could be homo-coupled to give the corresponding pinacols
by treatment with a stoichiometric amount of TiCl4 and magnesium amalgam at
0 ordmC in THF Yields were excellent compared with previously reported methods
(Mukaiyama46 Tyrlik47) Clerici et al showed that pinacols 48 and 49 were
quantitatively formed but with poor stereoselectivity [ratio(synanti) 13] by
coupling benzaldehyde 47 with aqueous TiCl3 in basic media (30 NaOH
solution)48 (entry 2) but with anhydrous TiCl3 solution in CH2Cl2 the reaction was
highly diastereoselective (entry 3)49
A few other examples of pinacol coupling mediated by titanium compounds have
been reported Handa and Inanaga50 reported a highly stereoselective pinacol
homo-coupling of aromatic aldehydes and of αβ-unsaturated aldehydes
mediated by titanium(III)-magnesium systems such as Cp2TiCl2iPrMgI or
Cp2TiCl2secBuMgCl (entries 45) The 12-syn-stereoselectivity in the pinacol
coupling of benzaldehyde 47 strongly depends on the reducing agent used for
reduced titanocene dichloride Moreover aromatic aldehydes having less
electron-donating group showed lower reactivity and selectivity when
Cp2TiCl2secBuMgCl is used
O
Ph H
Titanium reagentPh
Ph
OH
OH
+ PhPh
OH
OH
47
syn anti
rac-48 meso-49
Scheme 42 Homo-coupling reaction titanium mediated
33
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
Entry Titanium reagent + conditions Yielda Ratio (synanti) 48 49
1 TiCl4 Mg(Hg) THF minus10 degC to 0 degc 05 h 84
93b Not reported
2 15 aq ac TiCl3 MeOH 30 aq NaOH pH 10 rt 100 13
3 TiCl3 CH2Cl2 rt 05 h 65 2001
4 Cp2TiCl2 iPrMgI THF minus78 degC to rt 05 h Not
reported 801
5 Cp2TiCl2 secBuMgCl THF minus78 degC to rt 1 h 96c 1001
6 Cp2TiCl2 iPrMgCl PhMe minus78 degC to rt 05 h 46 973
7 Cp2TiCl2 iPrMgCl PhMgBr PhMe minus78 degC to rt 1 h 94 6733
8 Cp2TiCl(THF) excess NaCl THF H2O (8020)
0 degC to rt 1 h 84 946
9 3 mol Cp2TiCl2 Zn MgBr2 Me3SiCl rt 2 h 79 928
10 3 mol Cp2Ti(Ph)Cl Zn Me3SiCl THF rt 12 h 88 7129 a reactions based on benzaldehyde b cyclohexanone as substrate c anisaldehyde as substrate
Table 41 Reactions conditions
It has been proposed by Handa and Inanaga50 that the high syn-selectivity for
homo-coupling of aromatic aldehydes is due to the formation of a dimer of ketyl
radicals 410 oriented in a manner which minimizes steric interactions between
the phenyl groups (Figure 41)
OTi Mg
Cl
Cp
Cp
O
ClTi
Cp
Cp
Ar
HAr
H
THF
THFCl Cl
410
Figure 41 Titanium(III)-complex responsible for selectivity
In accordance with these results Yamamoto et al51 developed a system based
on titanium(III) that gave similar selectivity The treatment of Cp2TiCl2 with iPrMgCl followed by addition of benzaldehyde 47 provided the 12-diols 48 and
49 with excellent diastereoselectivity (Table 41 entry 6) On the other hand
Cp2TiPh generated in situ by treatment of Cp2TiCl2 with iPrMgCl and then PhMgBr
34
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
converted benzaldehyde 47 into 12-diols 48 and 49 with lower selectivity but
in higher yield (entry 7)
Barden and Schwartz52 reported a stereoselective pinacol coupling reaction of
benzaldehyde 47 using Cp2TiCl in THF in the presence of saturated aqueous
sodium chloride the diastereoselectivity was very high (entry 8)
Various other reagent combinations employing stoichiometric amounts of
titanium complexes have been used for diastereoselectivity in pinacol coupling
[eg Cp2TiCl2SmI2 50 and Ti(OiPr)4EtMgBr53] However a catalytic version of the
highly diastereoselective stoichiometric protocols established for pinacol homo-
coupling was highly desirable for economic and environmental reasons Recent
studies have revealed that pinacol coupling reactions can be rendered
stereoselective and catalytic in titanium with the use of additives or modified
ligands Maury et al54 reported the first pinacol coupling reaction that was
catalytic in titanium by using the TiCl4 Li(Hg) system in the presence of AlCl3 a
transmetallation reaction of the titanium pinacolate intermediates with AlCl3
regenerated the pre-catalyst TiCl4 and gave aluminium diolates which were inert
towards the reducing agent and not transformed into the alkene
At the same time Gansaumluer55 reported that the pinacol homo-coupling of
benzaldehyde 47 could be catalyzed by a low valent complex derived from
titanocene dichloride in the presence of Me3SiCl and MgBr2 as additives and Zn
as a reducing agent to give the racemic 12ndashdiols 48 and 49 in very good yield
and with excellent diastereoselectivity [ratio (syn anti) gt 964] (entry 9)
Another example of a catalytic system was described by Yamamoto et al5156
who used Cp2Ti(Ph)ClZnMe3SiCl system in the homo-coupling of benzaldehyde
47 (entry 10) However the diastereoselectivity was not as good as other
systems
42 Intramolecular pinacol coupling
Intramolecular pinacol reactions have received less attention compared to the
intermolecular couplings of aldehydes The use of the powerful low valent
35
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
titanium system developed by Corey et al45 in 1976 for intermolecular pinacol
homo-couplings has already been discussed This system proved to be even
better when applied to intramolecular couplings Syn-selectivity is total and
yields varied from modest for a 6-membered ring (32) (Scheme 43 Table 42)
to very good for the formation of a 4-membered ring (81)
CHO
CHOOH
OH
411
OH
OH
Titanium reagent
412 413
+
Scheme 43 Titanium(II)-mediated pinacol coupling
Entry Reaction conditions Yield Ratio (syn anti) 412413
1 TiCl4 Mg(Hg) 32 Syn only
2 TiCl3(DME)2 Zn-Cu 42 h 25 degC 85 Syn only
3 10 mol Cp2Ti(Ph)Cl Zn Me3SiCl THF rt 14 h 60 199
Table 42 Intramolecular couplings yielding 6-membered rings
TiCl3 Zn-Cu introduced by McMurry and Rico57 was used successfully for the
intramolecular coupling of various aldehydes (Scheme 43) It appeared that the
12-syn-isomer dominated for 6-membered ring and smaller (Table 42 entry 2)
whereas the 12-anti-isomer became predominant with rings containing 8 or
more carbons (Scheme 44) In comparison to the results obtained by Corey with
TiCl4 Mg(Hg) yields are much higher
80ratio (synanti) 2575
TiCl3(DME)2 Zn-Cu42 h 25 degC
415
CHO
CHO
414
OH
OH
OH
OH+
416
Scheme 44 Formation of large ring using pinacol coupling reaction
With the idea of promoting anti-selectivity Yamamoto et al51 used his sterically
bulky complex Cp2Ti(Ph)Cl In the presence of 6-10 mol Cp2Ti(Ph)Cl dials 411
and 417 were reduced at ambient temperature to afford 12-diols 412413
36
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
and 418 with excellent anti-selectivity (Scheme 43 Table 42 entry 3 and
Scheme 45)
CHO
CHO
OH
OH
6 mol Cp2Ti(Ph)Cl Zn Me3SiCl
THF rt 14 h
418 78ratio (syn anti) 0100 995 ee
417
Scheme 45 Titanium(III)-mediated catalytic pinacol coupling
The high anti-selectivity observed with this cyclic substrate 417 was explained
as follows (Figure 42) The bulky titanium-bound ketyl can combine only if the
Cp2(Ph)TiO moieties occupy axial positions in order to minimize steric repulsion
and this then favours a 12-anti-relationship
H
H
H
H
H
O[Ti]
O[Ti]
HH
H
H
H
O[Ti]
H
O[Ti]
H
OTi(Ph)Cp2
OTi(Ph)Cp2
OTi(Ph)Cp2
OTi(Ph)Cp2
syn-product anti-product
Figure 42 Mechanism of stereoselection
Following Yamamotorsquos results Handa et al58 published the first successful
diastereoselective pinacol coupling of dicarbonyl species to produce N-protected
heterocyclic 12-diols eg diketones 419 gave diols 420 in high yield (Scheme
46)
37
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
Cp2TiCl2 iPrMgCl PhMgBr
THF rt 12-18 hTsN
OH
OH
anti only
TsN
419 420 64
O
O
Scheme 46 Formation of heterocyclic 12-diols using pinacol coupling
Intramolecular pinacol reactions are not restricted to the use of symmetrical
dialdehydes Corey et al45 tested his system on unsymmetrical aldehyde 421
and observed excellent yield and good diastereoselectivity (Scheme 47)
Nevertheless the system proved to be totally ineffective for a related cyclisation
and had to be modified to CpTiCl3-LiAlH4 (Scheme 48)
O
H
CHO OH
H
OH
422 90ratio (synanti) 8020
TiCl4 Mg(Hg)
THF 0 degC 125 h
421
Scheme 47 Titanium(II)-mediated cross-coupling reaction
O
H
CHOTHPO
OH
H
THPO OH
CpTiCl3 LiAlH4
424 55ratio (synanti) 7129
THF 50 degC 1 h
423
Scheme 48 Intramolecular cross-coupling reaction
43 Pinacol cross-coupling reactions
The synthesis of unsymmetrical pinacols by pinacol cross-coupling remains a
challenge as only a few examples have been reported in the literature and they
are dependant upon the structural or electronic differences between the two
reactants and on the low-valent titanium species used Clerici and Porta59
38
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
reported a pinacol cross-coupling between ketone 425 and acetone using
aqueous titanium trichloride and acetone as co-solvent (Scheme 49) Ketone
425 will be reduced in preference to acetone because it produces a more stable
radical Presumably the large excess of acetone prevented significant homo-
coupling of ketone 425
O
CO2CH3
OH
OH
H3CO2C
excess acetone 1 h rt
15 aq TiCl3 (2 eq)
426 85425
Scheme 49 Titanium(III)-mediated pinacol cross-coupling reaction
Recently Duan et al60 reported a study on the synthesis of unsymmetrical
pinacols by coupling of structurally similar aromatic aldehydes in the presence of
low-valent titanium species They chose benzaldehyde 47 and p-anisaldehyde as
substrates and studied the effect of the low-valent titanium species (nature and
amount) the solvent and the temperature on the formation of the cross-pinacol
It was observed that the reactions initiated by TiCl4 Mn species afforded the
cross-pinacol products in good yield The best selectivity was obtained with 5 eq
of titanium species and additives and temperature had no significant effect on
the transformation however the solvent did The reaction gave alkenes in
acetonitrile while no reaction was observed in dichloromethane Under the
optimized reaction conditions a variety of unsymmetrical pinacols 428 were
efficiently prepared from benzaldehyde 47 and substituted benzaldehyde 427
(Scheme 410 Table 43) Results showed that the cross-couplings proceeded
with high selectivity when substrates containing nitrogen or oxygen-atom
functional groups were used (ie OH OMe NMe2 NHCOPh) On the contrary
reaction with substrates 427 containing F or Me substituents gave a mixture of
the three possible pinacols which were inseparable by chromatography Both
electron-donating and electron-withdrawing aromatic aldehydes gave moderate
to good yields and they observed in every case a high syn-selectivity
Substituents appeared to affect the outcome of the reaction through their strong
affinity to the surface of the titanium particles rather than through altering the
reduction potential or electronic density of the carbonyl moiety
39
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
H
O
H
O
+OH
OH
OH
OH
+
OH
OH
TiCl4 (5 eq)Mn (10 eq)
429
428
430
THF 10 degC 40 min
47 427
R
R
R
R
Scheme 410 Pinacol Cross-coupling reactions
Entry R Time (min) Yielda Ratio (synanti)
1 4-F 22 40b -
2 4-Me 24 41b -
3 4-Me2N 40 76c 8812
4 4-MeO 30 68c 919
5 3-MeO 40 61c 8020
6 4-OH 30 64c 8515
7 4-CO2Me 45 55c 7129
8 34-(MeO)2 30 65c 7921
9 4-NHCOPh 40 70c 8020
10 4-CONEt2 45 66c 7426 a isolated yield of cross-coupling product 428 b mixture of the three coupling products was obtained c ratio of the three compounds (428 429430) ranged from 711 to 3109
Table 43 Conditions for the preparation of unsymmetrical pinacols
44 McMurry reactions
The low valent titanium-mediated pinacol reaction is the first step in an
important alkenation reaction now termed the McMurry reaction In 1973 Tyrlik
and Wolochowics47 discovered that TiCl3-Mg in THF reductively coupled
aldehydes and ketones 431 to produce alkenes 433 and 434 On the other
hand Mukaiyama et al46 found that depending on the reaction conditions the
TiCl4-Zn system selectively coupled aromatic aldehydes or ketones 431 to
40
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
produce either 12-diols 45 and 46 or alkenes 433 and 434 In 1974 McMurry
and Fleming61 described a method for the reductive coupling of aldehydes or
ketones that employed TiCl3 and LiAlH4 and this paper gave rise to the reaction
name The McMurry reaction has been widely used and comprehensively
reviewed62-64 In the vast majority of cases its mechanism is accepted to involve
the conversion of ketones or aldehydes 431 into ketyl radicals which couple to
give titanopinacolate intermediates 432 which are then deoxygenated to give
E and Z alkenes 433 and 434 (Scheme 411) Given the close relationship
between the McMurry and titanium-mediated pinacol reactions it is also worth
considering what is known about McMurry cross-couplings
OR2
R1
R2
R1 R1
R2OO [Ti][Ti]
R2
R1 R1
R2
-2 [Ti]=O
H2O
-2 [Ti]-OH
2 [Ti]
431 432
Z 433
R2
R1
+
E 434
+
R2
R1
OH
R1 R1
OHR2
R2
45
OH
R1 R1
R2OH
R2
46
Scheme 411 McMurry coupling reactions
45 McMurry cross-coupling reactions
The intermolecular McMurry alkenation reaction is usually limited to the
synthesis of symmetrical alkenes by dimerisation of a ketone or aldehyde When
a mixture of two different carbonyl compounds 435 and 436 is subjected to
McMurry alkenation conditions generally a mixture of the cross-coupled product
437 and the two homo-coupled 438 and 439 is produced with the ratio of
products biased away from the statistical 211 by preferential homo-coupling of
the more easily reduced coupling partner (Scheme 412)6265 Generally the way
to get good conversion of a carbonyl compound into the cross-coupled product is
to use an excess of the other carbonyl component
41
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
O O
R2R1 R4R3
435 436
+R1
R2
R1
R2
R3
R4
R3
R4
R1
R2
R3
R4
438 439437
+ +[Ti]
ratio (437438439) 211
Scheme 412 McMurry cross-coupling reaction
The ratio can also be altered to favour cross-coupling if the two carbonyl
compounds have similar reduction potentials and one of the two carbonyl
compounds has a group that coordinates to the metal606667 For example Duan
et al reported cross-coupling between benzophenone 440 and diaryl ketone
441 (Scheme 413) The presence of the amino group favoured the formation of
the cross-coupling 442 over the homo-coupling products 443 and 444
O
O
NH2
TiCl4 Zn
PYR THF H2N NH2
NH2
++
44310
444 7
442 80
441
440
Scheme 413 McMurry cross-coupling reaction
If only one of the coupling partners is a diaryl compound cross-coupling can also
occur because such compounds are very easily reduced Cross-coupling reaction
may take place either through double reduction to a dianion 446 and
nucleophilic attack on the other partner62 447 or possibly titanium carbenoid
generation 451 and alkylidenation (Scheme 414)64
42
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
Ar Ar
O
445
2 [Ti] O
ArAr
O
R2R1
447 Ar
OO
R2
R1Ar
Ar
Ar R1
R2
446 448 449
Ar Ar
O[Ti]
Ar Ar
O
R2R1
447 Ar
Ar R1
R2
452
[Ti]+
Ar
Ar Ar
Ar
450 451 453
Scheme 414 McMurry cross-coupling reaction
A McMurry cross-coupling reaction of this type has been used as the key step in
the synthesis of the anti-tumor drug tamoxifen 456 and several of its analogues
(Scheme 415)68
O
+O
ONMe2
TiCl4 (3eq) Zn (6 eq)
ONMe2
455
456 88
THF reflux 2 h
ratio (ZE) 7525
454
Scheme 415 Example of a cross-coupling reaction
In summary the problem with intermolecular carbonyl coupling is that homo-
coupling competes This is particularly problematic when one coupling partner is
significantly more easily reduced as it will preferentially homo-couple There are
isolated examples of successful pinacol and McMurry cross-couplings but
generally to be successful a large excess of the less reactive carbonyl group must
be used
43
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
46 Alternative pinacol-like approach to 12-diols
using chromium reagents
A chromium catalyzed pinacol-like cross coupling reaction of -unsaturated
carbonyl compounds and aldehydes has been reported by Groth and co-
workers6970 Various vinyl ketones were coupled with aldehydes to afford 12-
diols diastereoselectively Then they extended the method to chromium-
catalysed cross-couplings of sterically demanding acroleins 458 and a variety of
aldehydes 457 to afford highly substituted pinacols 459 and 460 (Scheme
416)
O
HR2
+
O
HR1
(i) CrCl2 (01eq) Mn (2 eq) TMSCl (2 eq) DMF
(ii) Bu4NF THF
R1 = alkyl R2 = alkyl
+R2 R1
OH
OH
R2 R1
OH
OH
54-81ratio (synanti) 2476-982
457 458 syn-459 anti-460
Scheme 416 Chromium-catalysed coupling reactions
Ketyl radicals are not intermediates in this pinacol-like reaction (Scheme 417)
Rather reduction of the acroleins derivative 458 gives an allyl chromium
reagent 463 A mixture of E- and Z- allyl chromium species 463 reacts with
aldehyde 457 via a nucleophilic reaction and affords a mixture of syn and anti-
pinacols 459 and 460
44
Guilaine F Blanc Chapter 4 Pinacol Coupling Reactions
R2
H
O
R2
H
OCrCl2R2
H
OSiMe3Me3SiClR2
H
OSiMe3
Cl2Cr
R2
OSiMe3
R1
OCrCl2
R2
OSiMe3
R1
OSiMe3
R2
OH
R1
OH
Bu4NF
R1CHO
Me3SiCl
CrCl3
CrCl2
12 MnCl212 Mn
CrCl2 CrCl3
12 Mn12 MnCl2
458457
465 464459460
462461 463
Scheme 417 Proposed mechanism for a chromium-catalysed pinacol-like reaction
The origin of the diastereoselectivity is believed to be substrate dependent
Indeed they observed increase of the syn-diastereoselectivity as R2 becomes
bulkier While -branched acroleins lead predominantly to 12-syn-diols 12-
anti-diols are preferred with linear alkyl side chains They also showed the
importance of trimethylsilyl chloride to increase the syn-selectivity71
Although pinacol-like cross-coupling reactions catalysed by chromium catalysts
are efficient reactions with high yields and high and controlled
diastereoselectivity the reaction relies on using an -unsaturated carbonyl
compounds as one of the substrates and its mechanism is different from the
pinacol reaction
47 Conclusion
Pinacol and McMurry coupling reactions are among the most useful synthetic
methods for forming carbonndashcarbon bonds and have served as the key step in
the synthesis of various natural and synthetic products However a general
method of carrying out pinacol cross-couplings is needed Our new approach to
this is described in the next chapter
45
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
5 Application of Solid-Phase Synthesis to Pinacol
Cross-Coupling
51 Hypothesis
Although the pinacol homo-coupling reaction has been widely used the crossndash
coupling reaction has not been exploited so much The difficulty resides in the
homo-coupling byndashproducts generated in the reactions (Scheme 51) Thus
aldehydes 51 and 52 can crossndashcouple to give 12-diols 53 and 54 but can
also form homo-coupled products 55 56 57 and 58 If one of the aldehydes
(51) is much more easily reduced then the homo-coupled product 55 and 56
will be produced rapidly The homo-coupled product 57 and 58 will also form
as there would no longer be any aldehyde 51 available Diastereoselective
pinacol reactions reduce the number of possible products but do not overcome
the competition between homo-coupling and cross-coupling
HR1
O
+HR2
O
R1
OH
R2
OH
cross-coupling
R1
OH
R1
OH
homo-coupling
R1
OH
R1
OH
+
rac-55 meso-56
51 52
rac-53
+R1
OH
R2
OH
rac-54
R2
OH
R2
OHR2
OH
R2
OH
+
rac-57 meso-58
Scheme 51 Homo- and cross-coupling reactions
As discussed in chapter 3 recently there has been great interest in SPOS because
the use of polymer supports makes purification steps easier Pseudo-dilution is a
less exploited property of synthesis on resin but we proposed to demonstrate
that this property might overcome the problem with the pinacol crossndashcoupling
46
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
reaction The more easily reduced carbonyl compound 51 would be attached to
an insoluble support (59) The second reactant 52 would be in solution and
addition of the lowndashvalent metal would begin by generating an immobilised ketyl
radical from the more reactive partner (Scheme 52) Homo-coupling on resin
would be prevented by pseudo-dilution effect and only the crossndashcoupling
product 510 would form on the resin so that 12-diols 53 would be obtained
after cleavage from resin Any homo-dimers 57 produced in solution would be
removed by filtration Furthermore formation of the homo-dimer 57 would be
minimized because it is the product of homo-coupling of the less reactive
carbonyl compound In this way the crossndashcoupling reaction would be optimized
Reagent systems known to favour the syn-diastereomer would be employed so
that a single diol would be produced
HR2
O
R1
OH
R2
OH
R2
OH
R2
OH
HR1
O
59 510
57
52
+M
R1
OH
R2
OH
53
cleavage
filtration
Scheme 52 Pinacol coupling reaction on solid-phase
52 Solution phase synthesis
The first work took place in solution phase and consisted of a simulation of the
linkage between the resin and the substrate in order to enable the observation
of potential problems and to overcome these prior to transfer to solid-phase
synthesis
The first substrate chosen 512 contained an aldehyde for the pinacol coupling
and a carboxylic acid group for making an ester linkage with resins Steglich
esterification72 with benzyl alcohol 511 (which mimics hydroxymethylpoly
styrene) gave the benzyl ester 513 in good yield (Scheme 53) and permitted us
to explore the homo-coupling reaction
47
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
HO
O
H
O
H
O
O
O
OH+ DMAP DCC
CH2Cl2 45 min
511 512 513 74
Scheme 53 Preparation of the substrate
As previously seen Yamamoto et al51 and Handa and Inanaga50 both reported a
highly stereoselective pinacol coupling mediated by titanium-magnesium
complexes Their results convinced us to carry out reactions using the Cp2TiCl2
iPrMgCl system (Scheme 54) By adaptation of their method pinacol coupling
of aldehyde 513 gave 12-diols 514 and 515 with a good syn-selectivity
Several clues allowed us to determine the ratio of isomers obtained Firstly
Handa and Inanaga50 reported determination of the synanti-ratio of isomers by 1H NMR analysis (400 MHz) and established that the proton to the hydroxyl
group in 12-syn-isomer appears 01-02 ppm higher field than the one in 12-
anti-isomer Moreover we saw in the last chapter that Yamamoto et al51
observed formation of the syn-isomer as the major compound in the homo-
coupling of benzaldehyde using the Cp2TiCl2 iPrMgI system Thus we assumed
that the proton to -OH in the 12-syn-isomer 514 corresponds to the signal at
467 ppm whereas the same proton in the 12-anti-isomer 515 corresponds to
the signal at 493 ppm However despite the good selectivity the combined
isolated yield of diols 514 and 515 was low and there was a side-product the
alcohol 516 This was not isolated from other minor impurities but from the 1H
NMR analysis of this fraction we were able to identify the CH2 to OH as a
singlet at 470 ppm (CDCl3)
48
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
BnO
O
H
O513
O
OH
OH
OBn
O
BnO
O
OH
516
BnO
514
+
514 + 515 44ratio (synanti) 8020
O
OH
OH
OBn
O
BnO
515
+
Cp2TiCl2 iPrMgCl THF78 degC to rt 15 h
not isolated
Scheme 54 Homo-coupling of aldehyde 513
The typical mechanism proposed that reduction of titanocene dichloride 517
with the Grignard reagent iPrMgCl 518 gave the titanium(III) reagent 519
used to promote pinacol coupling reactions (Scheme 55) Single electron
reduction of aldehyde 513 would produce a ketyl radical 520 which would
dimerize to form the titanopinacolate intermediate 521 (Scheme 56)
Hydrolysis of the titanopinacolate intermediate 521 would provide the 12ndashdiols
514 and 515 However if the ketyl radical 520 was reduced by a second
equivalent of titanocene chloride 519 before it had the opportunity to
dimerize then extended enolate 522 would be formed and so provide the byndash
product 516 upon quench
2 Cp2TiCl2 + MgCl 2 Cp2TiCl + 2 MgCl2 + +2
517 518 519
Scheme 55 Reduction of titanocene dichloride
49
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
OTiCp2Cl
BnO
ClCp2TiO
H+
BnO
O
OH
OTiCp2Cl OTiCp2Cl
ClCp2TiO
OH
HO
BnO
O
H
O
BnO
O
OBn
O
BnO
O
BnO
O
OBn
O
Cp2TiIIICl
Cp2TiCl
H+
513
522
516
514 + 515
521
520
519
Scheme 56 Hypothetic mechanism for the formation of alcohol 516
Attempts to prevent the formation of the byndashproduct 516 by increasing the
concentration of the aldehyde 513 (08 M up to 2 M) and or decreasing the
number of equivalents of titanocene dichloride 517 (20 to 15 eq) led to an
improvement in terms of proportion of compounds observed (514 + 515516
6434 to 7426) However the alcohol 516 remained a side-product in this
homo-coupling reaction
Recently Aspinall et al73 reported a catalytic pinacol coupling using SmI2 Mg
as the reducing agent The addition of a chelating ligand (tetraglyme) to the
SmI2-promoted pinacol coupling influenced the diastereoselectivity of the
reaction in favour of the 12-anti-isomer in the case of aromatic aldehydes In
order to compare with results obtained using the titanium system we performed
homo-coupling of aldehyde 513 using the same system (Scheme 57)
50
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
BnO
O
H
O
BnO
O
OH
OH
OBn
O
(a) SmI2 Mg Me2SiCl2 tetraglyme THF rt 15 h
(b) Bu4NF
513
514
BnO
O
OH
OH
OBn
O 515ratio (synanti) 3366
+
Scheme 57 Samarium mediated pinacol coupling
As expected analysis of the 1H NMR spectrum of the crude mixture showed the
formation of 12-diols 514 and 515 as a mixture of 12- syn and 12-anti-
isomers with a preference for the 12-anti-isomer 515 Traces of alcohol 516
were also reported which confirmed that the presence of a carboxylic ester in
the para position is not ideal for the pinacol coupling reaction Consequently
the strategy was modified to reduce the electron-withdrawal by using the
carboxylate salt of triethylamine 524 This was expected to reduce the
formation of the alcohol byndashproduct 531 while mimicking the immobilization of
aldehyde 523 on an aminondashfunctionalised resin (Scheme 58) The carboxylate
function present on the substrate 524 should disfavour the double reduction as
this would generate a trianion 530 (regarding the polar covalent O-Ti bond as
ionic) from ketyl radical 525
51
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
OTiCp2Cl
OTiCp2Cl
ClCp2TiO
H+
O
O
H
O
O
O
O
O
O
O
HO
O
OH
O
Et3NHO
O
H
O
Et3NH Et3NH
Cp2TiCl
OTiCp2Cl
O
OTiCp2Cl
H+
HO
O
OH
Et3NH
disfavoured
HO
Et3NH
Et3NH
Cp2TiIIICl
523 524 525
526 + 527530
531528 + 529
OH
Scheme 58 Carboxylate salt of triethylamine
After stirring the aldehyde 523 with triethylamine the resulting salt 524 was
added to the preformed titanium reagent and converted into an inseparable
mixture of 12-syn- and 12-anti-diols 528 and 529 with a modest yield
following acidic work-up (Scheme 59) Formation of alcohol 531 was avoided
nevertheless an optimization of the system was required as the
diastereoselectivity was poor
52
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
(a) Et3N THF(b) Cp2TiCl2 iPrMgClHO
O
H
O
O
OH
OH
O
HO
OH
ratio (synanti) 5842
523
THF 78 degC to rt 15 h O
OH
OH
O
HO
OH
528 + 529 56
+
Scheme 59 Homo-coupling reaction of aldehyde 523
The temperature of the reaction was more carefully controlled in order to
optimise diastereoselectivity A slow increase of the temperature from minus78 to
minus30 degC over 5 h led to an incomplete reaction and a small amount of starting
material 523 was recovered A mixture of both isomers 528 and 529 was
noticed However the temperature of the reaction did not have any effect on
the diastereoselectivity [ratio (synanti) 5743]
Next reversing the polarity of the resin-substrate interaction by using 4-(di
methylamino)benzaldehyde and resin-bound acid was investigated This new
strategy might permit a capturendashrelease strategy of amine with acidic ion-
exchange resin (carboxylic acid resins or MP-TsOH) The resin linkage was first
simulated by the use of acetic acid (Scheme 510) 4-(Dimethylamino)
benzaldehyde 532 was stirred in a solution of AcOH in THF at 25 degC until it
dissolved The mixture was then added to the preformed titanium reagent at
minus78 degC and left at rt for 15 h After quenching with 1N HCl to hydrolyse the
titanopinacolate intermediate treatment with base extraction and evaporation 1H NMR analysis of the crude mixture revealed the formation of a single isomer
and the 12-syn-diol 533 was then isolated in very good yield (78 )
53
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
N
H
O
N
OH
OH
N
(a) AcOH or p-TsOH(b) Cp2TiCl2 iPrMgCl
532 533 78 or 67
THF 78 degC to rt 15 h
Syn only
Scheme 510 Homo-coupling of 4-(dimethylamino)benzaldehyde 532
The same conditions were used with a stronger acid p-TsOH (Scheme 510) The
pinacol coupling product 533 was obtained in good yield (67 ) and as expected
only the 12-syn-isomer 533 was isolated With good conditions for homo-
coupling reactions in hand the next target was a crossndashcoupling reaction
The first coupling partner investigated was a simple aromatic aldehyde
benzaldehyde 534 (= 47 see Scheme 42) First homo-coupling of the
benzaldehyde 534 was performed under standard conditions in order to identify
this potential byndashproduct in the cross-coupling reaction (Scheme 511) The
coupling products 535 and 536 were obtained with a poor yield but with
excellent diastereoselectivity [ratio(synanti) 946]
Cp2TiCl2 iPrMgClH
O OH
OH
ratio (synanti) 946
534 535 + 536 10
THF 78 degC to rt 15 h OH
OH
+
Scheme 511 Homo-coupling reaction of benzaldehyde 534
The crossndashcoupling of aminoaldehyde 532 and benzaldehyde 534 was
conducted in presence of pndashTsOH and with the Cp2TiCl2 iPrMgCl system
nonetheless neither the desired product 537 nor the homo-coupling products
were identified in the crude mixture (Scheme 512) We recovered unchanged
aldehydes
54
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
N
H
O
N
OH
OH+
(a) p-TsOH(b) Cp2TiCl2 iPrMgClH
O
532 534 537
THF 78 degC to rt 15 h
Scheme 512 Cross-coupling reaction
Consequently the solidndashphase synthesis was investigated to demonstrate that
this cross-coupling issue would be improved on solid support
53 Solid-phase synthesis
To begin with the loading of the substrate 532 onto resin had to be
considered pndashToluenesulfonic acid resin 538 (= 38 see Figure 36) was
naturally selected The loading consisted in stirring beads of resin with a
solution of aldehyde 532 in THF Employing an indirect analysis to determine
the yield of loading we finally set optimum conditions of loading at 50 eq of
aldehydes 532 and 10 eq of resin 538 for 15 h at 25 degC (Scheme 513)
Cleavage was performed by stirring kans containing compound 539 in a solution
of Et3N in CH2Cl2 for 05 h and the quantity of aldehyde isolated used to
calculate a loading of 163 mmol g -1
N
H
O
H
SOO
O
N
H
O
THF 15 h
Et3N - DCM (119) 05 h
SO3H
532 539
538
Scheme 513 Loading and cleavage of resin 538
The crossndashcoupling was attempted with 1 eq of benzaldehyde 534 (Scheme
514) The crossndashcoupling product 537 was not observed instead we recovered
55
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
the homo-coupling product of benzaldehyde 535 and starting amino compound
532 which seemed to be cleaved from the resin by Cp2TiIIICl
N N
H
O
H
+(a) Cp2TiCl2 iPrMgCl THF 78 degC to rt 15 hH
O
OH
OH
OH
OH
535
SO3
539534 537
+N
H
O532
52 mass recoveryratio (532535) 2971
(b) 1M NaOH
Scheme 514 Cross-coupling reaction in solid-phase
The decision was taken to change the coupling partner and work with acetone
540 (Scheme 515) which is less easily reduced Homo-coupling of acetone was
considered less likely A solution of aldehyde 532 was treated with p-TsOH in
THF at 25 degC to give the salt A solution of acetone 540 (10 eq) was added and
the mixture transferred into the preformed low valent titanium reagent at
minus78 degC The mixture was stirred for 15 h at rt before quenching As expected
the heterocoupling product 541 was not observed on the other hand we
identified the homo-coupling product 533 of aldehyde 532 in the crude
mixture
N
H
O
N
OH
OH(a) p-TsOH (1 eq)(b) acetone 540 (10 eq)
532 541
(c) Cp2TiCl2 iPrMgCl THF 78 degC to rt 15 h(d) 1M NaOH
Scheme 515 Heterocoupling reaction attempt
In solidndashphase synthesis the formation of the homo-coupling product 533 would
be stopped by the pseudo-dilution effect Consequently we were not expecting
56
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
to observe any homo-coupling products of aminobenzaldehyde 532 or acetone
540 and the cross coupling should be formed Unfortunately in solidndashphase
synthesis the reaction run under standard conditions produced only starting
material 532 after treatment with base (Scheme 516) Clearly immobilised 4-
(dimethylamino)benzaldehyde 539 was not an ideal substrate for the pinacol
cross-coupling
N N
H
O
H (a) acetone 540 (10 eq)(b) Cp2TiCl2 iPrMgCl THF 78 degC to rt 15 h
OH
OH
SO3
539 541
(c) 1M NaOH
Scheme 516 Cross-coupling on solid support
The choice of a new substrate was orientated towards carboxybenzaldehyde as
described in our first strategy however this time we chose meta-substitution of
the carboxylic function The use of m-carboxybenzaldehyde 542 for a pinacol
coupling would not lead to the formation of the product of double reduction as
observed for the para-substituted substrate (Scheme 56) as a second electron
transfer to radical 520 gives extended enolate 522 (Scheme 56) but a second
electron transfer to radical 543 would not and so is disfavoured (Scheme 517)
OTiCp2ClBnO
O
OTiCp2ClBnO
O
OTiCp2ClBnO
O
543
Scheme 517 Resonance forms
Following the same logic as before the resin linkage was first simulated
Therefore benzoate 544 was prepared in excellent yield following conditions
previously described (Scheme 518) Pinacol coupling of aldehyde 544 was
carried out using titanocene dichloride and iPrMgCl at minus78 degC After usual work-
up 12-diols 545 and 546 were isolated as an inseparable mixture of
diastereoisomers [ratio(synanti) 8020] in a very poor yield (21) The ratio of
diastereomers obtained was determined as previously reported for diols 514
57
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
and 515 (Scheme 54) Thus we assumed that the proton α to -OH in the 12-
syn-isomer 545 corresponds to the signal at 467 ppm whereas the same proton
in the 12-anti-isomer 546 corresponds to the signal at 482 ppm (CDCl3)
HO
O
BnO
O
DMAP DCC
CH2Cl2 45 minH
O
H
O
BnO
O
OH
Cp2TiCl2 iPrMgCl THF
OH
O
OBn
BnOH 511
542 544 83
21
78 degC to rt 15 h
ratio (synanti) 8020
BnO
O
OH
OH
O
OBn+
545 546
Scheme 518 Homo-coupling of aldehyde 544
After that a crossndashcoupling reaction was conducted with the substrate 544 in
order to form the 12-diol 547 (Scheme 519) After reaction the crossndashcoupling
product 547 was not observed Instead we recovered the homo-coupling
product 533 (from earlier scheme) of aldehyde 532 in 57 yield This result
confirms that the aminobenzaldehyde 532 homo-coupled faster than aldehyde
544 as we did not observe any homo-coupling product 545 and also homo-
coupling is preferred to cross-coupling reaction The result was unexpected as
aldehyde 532 is electron rich and would be expected to be reduced more slowly
than aldehyde 544 We realised that the same problem would occur if a resin-
bound analogue of aldehyde 544 was used
BnO
O
H
O
+
N
H
O
Cp2TiCl2 iPrMgCl
544 532
THF 78 degC to rt 15 h
BnO
O
NOH
OH
547
Scheme 519 Attempt of cross-coupling reaction
58
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
At the same time a new objective emerged synthesis of catechins with a
pinacol cross-coupling on solid-support as a key step Catechins are present in
nearly all teas made from Camellia sinensis (Figure 51) Catechins are also
present in the human diet in chocolate fruits vegetables and wine and are
found in many other plant species There is evidence that (minus)-epicatechin 548
(Figure 52) can reduce the risk of four of the major health problems stroke
heart failure cancer and diabetes74 Similarly oral administration or topical
application of the antioxidant (minus)-epigallocatechin-3-gallate 549 (Figure 52)
helps protect the skin from UV radiation-induced damage and tumor formation75
Figure 51 Camellia sinensis
O
OH
HO
OH
OH
OH
O
O
OOH
OH
OH
HO
OH
OH
OH
OH
()-Epicatechin ()-Epigallocatechin-3-gallate
548 549
Figure 52 Catechins formed in tea
The idea was to carry out a cross-coupling reaction of aldehyde 550 supported
on Wang resin with fully protected aldehyde 551 (Scheme 520) Then cleavage
under acidic conditions would yield the catechin-like product 553 The
aromatic aldehyde 550 would be expected to be reduced more easily than
aliphatic aldehyde 551 and pseudo-dilution would avoid homo-coupling
59
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
O
R
R
H
O
OBnO
OMOMBnO
O
R
R
OH
OBn
MOMO OBn
OH
H+
HO
R
R
O
OBn
OBn
HO
550
551
552
553
Scheme 520 Towards the synthesis of catechins
Following the same tactic as before we investigated at first the homo-coupling
reaction of two chosen substituted substrates (Scheme 521) 345ndashtri-methoxy
benzaldehyde 554 and 34ndashdimethoxybenzaldehyde 556 Under standard
conditions 12-syn-diols 555 and 557 were isolated with excellent
diastereoselectivity The poor yield observed with compound 556 is explained
by difficulties met in handling the crude mixture and several filtrations during
work up which led to the loss of material Considering other NMR analyses of 12-
diols in this chapter we assumed that the peak observed at 449 ppm (CDCl3) as
a singlet was the proton α to -OH in the 12-syn-isomer as the proton α to -OH in
the 12-anti-isomer usually appears closer to 470 ppm Furthermore 12-diols
557 were obtained as a mixture of syn and anti-isomers The proton α to -OH in
the 12-syn-isomer corresponds to the signal at 443 ppm whereas the same
proton in the 12-anti-isomer corresponds to the signal at 460 ppm (CDCl3)
which confirms the supposition concerning the other compound 555
60
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
MeO
MeO
OMe
H
O
MeO
MeO
H
O
MeO
MeO
OMe
OH
OMe
OMe
OMe
MeO
MeO
OMe
OMe
ratio (synanti) 9010
(a) Cp2TiCl2 iPrMgCl THF 78 degC to rt 15 h
(a) Cp2TiCl2 iPrMgCl THF 78 degC to rt 15 h
OH
OH
OH
554 555 75syn only
556 557 30
(b) NaHCO3 MeOH H2O
(b) NaHCO3 MeOH H2O
Scheme 521 Homo-coupling of methoxybenzaldehydes 554 and 556
Next the objective was to proceed to the crossndashcoupling between the substrate
554 and phenylacetaldehyde 558 to obtain crossndashcoupling products 559
(Scheme 522) The reaction was carried out under standard conditions As
expected the desired 12-diol 559 was not formed instead phenylacetaldehyde
558 and the homo-coupling product 555 were recovered
MeO
MeO
OMe
H
O
MeO
MeO
OMe
MeO
MeOOH
(a) Cp2TiCl2 iPrMgCl THF 78 degC to rt 15 h
H
O+
OMe
OMe
OMe
OMe
OH
OH
OH
559558554
555
(b) NaHCO3 MeOH H2O
Scheme 522 Cross-coupling reaction
In order to prove that solidndashphase synthesis would improve the crossndashcoupling
reaction we considered the loading of a model susbtrate 560 onto Wang resin
61
Guilaine F Blanc Chapter 5 Application of Solid-Phase Synthesis to Pinacol Cross-Coupling
561 (= 34 see Figure 35) (Scheme 523) The loading was done with 50 eq of
4-hydroxybenzaldehyde 560 and 10 eq of resin 561 under Mitsunobu
conditions The loading was assumed to be total Then pinacol coupling of this
supported substrate 562 with phenyl acetaldehyde 558 was performed under
standard conditions Results were not those hoped for no 12-diol 563 was
identified and the crude mixture following cleavage appeared to contain many
unidentified by-products At this stage we concluded that our solid-phase
synthesis approach to the pinacol cross-coupling was not likely to succeed
HO
H
O
O
H
O
Wang resin 561 PPh3DIAD
THF 1 h
O
HO
OH
OH
H
(a) Cp2TiCl2 iPrMgCl THF
78 degC to rt 15 h(b) TFA DCM 11
560 562
563
558
Scheme 523 Pinacol coupling reaction
54 Conclusion
In this project we demonstrated a couple of interesting points concerning
pinacol homo-coupling reactions induced by Cp2TiCl2iPrMgCl The presence of
an electron-withdrawing group in the para-position of an aromatic aldehyde
leads to the formation of the product of double reduction The formation of this
by-product may be avoided by using an electron-withdrawing group in meta-
position or by using a carboxylate salt Although homo-coupling reactions
proceeded well cross-coupling reactions were never observed Immobilization of
an aldehyde that could homo-couple prevented any reaction with the substrate
and a coupling partner in solution simply homo-coupled if it was sufficiently easy
to reduce
62
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
Part C
6 Alkenation Reactions using Titanium-Based
Reagents
The conversion of carbonyl groups such as esters amides thioesters and
carbonates into alkenes is commonly undertaken with titanium-based carbenoids
due to the lack of reactivity of traditional alkenation methods (Wittig HWE
Julia Peterson alkenation) or the undesired cleavage of the ester (or amide)
bond Furthermore Wittig-type reactions require basic conditions which are not
suitable for easily enolisable carbonyl derivatives A range of titanium-
alkylidenes have been designed to overcome these issues They are not basic so
there is no risk of epimerization of a sensitive chiral centre to carbonyl groups
or retro-Michael additions (RMA) Small and reactive they react with even
hindered carbonyl groups This class of reagents have been recently reviewed76
however a brief overview will be given in the following section
61 Tebbe reagent
First reported by Tebbe et al77 in 1978 the Tebbe reagent 62 is a titanium-
aluminium complex usually prepared using the definitive procedure provided by
Pine et al78 in 1990 Its preparation consists of reaction of titanocene dichloride
61 (= 517 see Scheme 55) with AlMe3 in toluene (Scheme 61) However the
reagent is now commercially available as a solution in toluene The titanium-
aluminium metallacycle 62 is activated by a base (pyridine THF) to form the
reactive species 63 which is a highly reactive titanocene methylidene
responsible for methylenation of carbonyl compounds The methylidene 63 is a
typical Schrock carbene being an electron-deficient (16e) complex of titanium in
a high formal oxidation state (TiIV) It is nucleophilic at carbon and electrophilic
at titanium The nucleophilic reagent can react with a wide range of carbonyl
compounds to give alkenes 65 via the decomposition of oxatitanacyclobutane
64 in a manner similar to oxaphosphetane in the Wittig reaction The driving
63
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
force in this reaction is the irreversible formation of a strong Ti-O double bond
in oxide 66
TiAlMe3
2M PhMeTi Al
Me
MeCl
Lewis Base Ti CH2
Ti CH2
O
R2R1Cp2Ti O
R2
R1R2R1
61 62 63
6465
Cp2Ti=O
66
Cl
Cl
Scheme 61 Preparation and use of Tebbe reagent
The Tebbe reagent 62 can methylenate a broad range of carbonyl compounds
including aldehydes ketones esters thioesters amides and carbonates A range
of substrates can be found in the review by Hartley and McKiernan79 Due to the
nucleophilic nature of the reagent the reactivity of the Tebbe reagent is
dependent on the electrophilicity of the substrate In that way selective
methylenation can be achieved in the presence of different types of carbonyl
groups For example aldehydes and ketones are methylenated preferentially to
esters or amides as they are more electrophilic as described by Fukuyama and
Liu80 in the synthesis of diene 68 (Scheme 62)
OO
O
HO
EtO
OO
HO
EtO
Tebbe 62 PhMe
67 68 71
Scheme 62 Example of selectivity of Tebbe reagent
64
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
Steric factors also play a role in determining the reactivity of a substrate
(Scheme 63) In Tebbe methylenation of esters Muumlller et al81 reported
methylenation at the less sterically hindered of the two carbonyl groups The
reaction proceeded with 1 eq of Tebbe reagent 62 and at low temperature to
provide the enol ether 610 in very good yield
OTBDMSH3C
CO2TBDMS
Tebbe 62
THF 70 degC 05 h then rt 1 h
OTBDMSH3C
CO2TBDMSMeOOMeO
69 610 85
Scheme 63 Example of regioselectivity
Nicolaou and co-workers82 showed that the Tebbe reagent 62 may catalyse ring-
closing metathesis (RCM) Indeed they reported that methylenation of ester 611
with the Tebbe reagent at room temperature gave the enol ether 612 and
further addition of the Tebbe reagent led to the cyclisation at higher
temperature (Scheme 64) This tandem methylenation-RCM can be done as a
one-pot procedure
O
OBnO
O
X
H H H
H H H
BnO
O
OBnO
H H H
H H H
BnOOTebbe 62 (13 eq)
THF rt 20 min
611 X = O
612 77 X = CH2
Tebbe 62 (2 eq)
THF reflux 3 h
613 65
Scheme 64 RCM catalysed by Tebbe reagent
Although the Tebbe reagent has the ability to methylenate a wide range of
carbonyl compounds it has the disadvantage of being limited to
methylenation76 Moreover the Tebbe reagent and products of its decomposition
are Lewis acidic The Tebbe reagent is also highly air and moisture sensitive
making its handling delicate
65
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
62 Petasis reagent
Developed as an alternative to the Tebbe reagent dimethyltitanocene (DMT)
614 was used as a methylenating agent of carbonyl derivatives (esters ketones
and amides) by Petasis and Bzowej8384 and is easily prepared by reacting MeLi or
MeMgCl with Cp2TiCl2 (Scheme 65) Definitive procedures for the preparation
and storage have been provided by Payack et al85 moreover a similar procedure
is suitable for the preparation of the reagent on more than a kilogram scale86
DMT is relatively stable to air and moisture unlike the Tebbe reagent and can be
stored for several months if kept at 4 degC and diluted with THF or toluene (10 wt
) as DMT is not stable in a solid state87 Furthermore the Petasis reagent is
non-pyrophoric Another advantage over the Tebbe reagent is the absence of
Lewis acidic by-products Petasis et al8388 showed that when DMT 614 is
heated to 60-75 degC either in THF or toluene the reactive titanium methylidene
63 is formed which reacts rapidly in the presence of a carbonyl compound to
give the alkene 65 via the oxatitanacyclobutane 64 and titanium oxide 66
The titanocene dimer 615 is obtained by further reaction of titanium oxide 66
with DMT 614
Hughes et al89 have provided strong evidence that the methylenation reaction
proceeds by generation of the Schrock carbene 63 via heat-induced -
elimination and that represents the rate-determining step of the reaction The
methylidene 63 can now be generated by microwave irradiation making the
reaction quicker cleaner and requiring fewer equivalents of reagent9091
Furthermore the oxatitanacyclobutane 64 has now been observed by mass
spectroscopy which supports the mechanism92
66
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
TiMeLi or MeMgCl Ti CH2
Ti CH2
O
R2R1Cp2Ti O
R2
R1R2R1
61 63
6465
Cp2Ti=O
66
Cl
ClTi
CH3
CH3
thermally induced-elimination
+
Cp2TiMe2 614
TiCH3
O TiH3C
614
615
Scheme 65 Preparation and use of DMT 614
Like the Tebbe reagent 62 DMT 614 can selectively methylenate aldehydes
and ketones in the presence of esters amides or carbamates or selectively
methylenates the less hindered of two esters93 However DMT will also
methylenate highly strained -lactones9495 where Tebbe methylenation is
unsuccessful A variety of others carboxylic acid derivatives are also converted
into useful hetero-substituted alkenes with DMT eg silyl esters thioesters
selenoesters acylsilanes anhydrides amides etc7679 Above all the Petasis
reagent is not limited to methylenation as the Tebbe reagent is Functionalised
Petasis reagents can be prepared as demonstrated by Petasis and Bzowej84
Reagents 616 617 and 618 (Figure 61) are all converted into Schrock
carbenes 619 upon heating and can effectively alkylidenate carbonyl
compounds
67
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
Ti
X
X
Ti
SiMe3
SiMe3
Ti
X = H F Cl
616 617 618
TiR
619
Figure 61 Functionalised Petasis reagents
For example the lactone 620 is converted into enol ether 621 in quantitative
yield and with complete Z-selectivity by treatment with functionalised Petasis
reagent 616 (Scheme 66)84
O
O
O
Cl616 (30 eq)
PhMe 55 degC
620 621 100
Scheme 66 Example of the use of a functionalised Petasis reagent
The Z-selectivity of the alkene can be explained by considering the
oxatitanacyclobutane intermediates 623 and 624 formed during the
alkylidenation (Scheme 67) In cases where R1 is large the Z-alkene 626 is
favoured in order to minimize steric interactions between the phenyl and R1
groups When R2 is large the formation of intermediate 624 will be
disfavoured However the oxygen acts as a spacer and helps to minimize steric
interactions between a large R2 group and the phenyl group so this interaction is
less significant96
These reagents are useful for alkylidenation of carbonyl compounds only if they
do not have a hydrogen atom on an sp3 carbon to titanium as if they do the
-elimination is faster than -elimination and the Schrock carbene is not
generated
68
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
O
OR2R1
TiCp2
Ph
Cp2TiOH
PhR1
OR2
Cp2TiOH
PhOR2
R1
or
OR2R1 OR2R1
Ph Ph
35-84(EZ) 7426 to 1486
622
619
623 624
E 625 Z 626
Cp2Ti(CH2Ph)2
Scheme 67 Selectivity in alkylidenation with functionalised Petasis reagents
In 2003 Gaunt et al97 reported the synthesis of an intermediate of the synthesis
of Spongistatin 1 with a Petasis methylenation as a key step Treatment of the
ketone 627 with Petasis reagent 614 in toluene at 120 degC generated alkene
628 in 71 yield The reaction proved to be much more efficient when carried
out under microwave irradiations forming the alkene 628 after 10 min in 82
yield (Scheme 68) By adding a small amount of ionic liquid (1-ethyl-3-methyl
imidazoline hexafluorophosphate) to the solvent they increased the solvent
heating temperature98 and minimized safety problem due to over pressurization
of the sealed reaction vessels99
OTBS
TESO OTIPS
OTBS
TESOTIPS
PhMe MW 10 min
Cp2TiMe2 614
MeNNEt PF6
627 628 82
Scheme 68 Microwave assisted Petasis methylenation
Later Galagher and co-workers90 found that under microwave conditions Petasis
alkenation of oxalate 629 gave complete conversion to the enol ether 630 in
69
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
30 min instead of 48 h under thermal conditions (Scheme 69) They observed
selectivity towards the less hindered carbonyl group
MeOO
O
OMeO
O
O
Cp2TiMe2 614
PhMe-THF 48 h with or 05 h with MW
629 630 100
Scheme 69 Microwave-assisted Petasis methylenation
Recently Adriaenssens and Hartley100 produced a highly diastereoselective route
to 26-disubstituted piperidinones using microwave-assisted Petasis
methylenation as one of the key steps (Scheme 610) A chemoselective
methylenation of the ester group of the preformed imine 632 using DMT and
microwave heating provided the enol ether 633 Cyclisation of the enol ether
under acidic conditions gave piperidinones 634 in modest to good yield
CO2MeH3N
R1
Cl
R1 = Me Ph or BnR2 = aryl alkylR3 = H or Me
Et3N CH2Cl2 Na2SO4 rt
R2COR3 R3
NR2
R1
CO2Me
Cp2TiMe2 614PhMe-THF MW 65 degC3-10 min
R3
NR2
R1 OMe
NH
O
R2 R1R3 Acid
12-70 from 631
631 632 55-94
633634
Scheme 610 Synthesis of piperidinones
The popular Petasis methylenation of carbonyl groups presents many advantages
due to its air and moisture stability and the easy preparation of the reagent It
will cleanly methylenate a wide range of carbonyls groups and titanium
containing impurities are easily removed by precipitation and filtration The
reaction conditions are non basic (unlike Wittig) so the epimerization of chiral
centres can be avoided The absence of Lewis acidic by-products (unlike Tebbe)
70
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
results in the tolerance of a wider range of functionality The Petasis
methylenation with microwave assistance is particularly attractive
Disadvantages are the high temperature required to induce -elimination and
the excess reagent needed to get completion of the reaction
63 Takeda reagent
Takeda and co-workers reported that reduction of thioacetals 635 or 636 by a
low-valent titanium(II) reagent 637 produced the titanium(IV) alkylidenes 638
which were then used to alkylidenate carbonyl derivatives 639 and produce
alkenes 640 (Scheme 611) Reduction of titanocene dichloride 61 with excess
magnesium turnings and P(OEt)3 in THF provides the reagent 637101 The
addition of 4 Ǻ molecular sieves is essential as the reduction of thioacetals is
considerably retarded by traces of water A range of thioacetals can be used
Allylic benzylic or alkyl thioacetals are suitable substrates for generating
alkylidenating reagents 638 However methylenation is ineffective under
Takeda conditions Moreover diphenyldithioacetals 635 and 13-dithianes 636
are both reduced effectively but diphenyldithioacetals 635 are more easily
reduced102
S
SR1
R1R2CH(SPh)2
or Cp2Ti[P(OEt)3]2 637
O
XR3R1
R3 X
X = H allyl aryl OR4 SR4 NMePh
635
636
639
640
Cp2TiCl2 61
Mg P(OEt)34 Aring MS THF rt
TiCp2
R2R1
R2
R2
638
Scheme 611 Desulfurisation of thioacetals
This method was applied to alkylidenation of a wide variety of carbonyl
derivatives 639 The reaction proceeds well with a variety of aldehydes and
ketones101 it could also be achieved with carboxylic esters101 lactones101
thioesters103 or N-methylanilides104 The mechanism for the alkylidenation of
71
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
esters is believed to be as follow (Scheme 612)76 A low-valent titanium(II)
species reduces thioacetal 641 prepared by treatment of the corresponding
aldehyde or ketone with thiols in the presence of a Lewis acid The bimetallic
complex 642 is formed as an intermediate in the generation of the titanium
alkylidene 643 which reacts with esters 622 to form oxatitanacyclobutanes
644 and 645 The geometry of the alkene formed follows the same rules as for
the Petasis reagents since the mechanism of reaction of the Schrock carbene
643 is the same in both cases Esters afford mostly Z-enol ether 647101
however the selectivity is often modest Alkylidenation of aldehydes and ketones
shows very poor stereoselectivity
SR4
SR4R3
Cp2TiII SR4
TiCp2
R3 SR4 Cp2TiII Ti
TiCp2
SR4R3
R4SCp2 Cp2Ti
TiCp2
R3
SR4
SR4
TiIVCp2R3
O
OR2R1
TiCp2
OTiCp2
O
R1OR2R2O
R1
R3
R3or
OR2R1 OR2R1
R3R3
Cp2Ti(SR4)2
fast oxidativeaddition
slow oxidative addition641 642
643645
646647
622
644
Scheme 612 Mechanism for the Takeda alkylidenation
Under Takeda conditions titanium alkylidenes are thought to be the active
species as they have been shown to catalyse alkene metathesis79 (Scheme 613)
Indeed it has been reported that RCM of thioacetal 648 proceeds upon
treatment with low-valent titanocene 637 at room temperature and then
heating under reflux to provide the cyclic amine 649 in good yield105
72
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
N
Bn
SPh
SPh Cp2Ti[(POEt)3]2 637
THF rt 2 h then reflux 1 h NBn
648 649 77
Scheme 613 RCM catalysed by Takeda reagent
An advantage of the Takeda procedure is that titanium alkylidenes can be
functionalised as they can be generated from a wide range of thioacetals 650-
656 (Figure 62) Takeda generated alkylidenating agents from thioacetals 650
and 651106-108 Hartley and co-workers developed several functionalised
thioacetals 652-656 for the synthesis of bicyclic aromatic
heterocycles109110111112113 and Knausrsquo group reported the use of benzylic
thioacetal 652 for the synthesis of alkenes114
SPh
SPhR
R = SPh OAlk
S
S
SPh
SPhRMe2Si
R = Me Ph
N(Bn)Boc
X
S
S
OTMS
X
S
S
STBS
SPh
SPh
X
X
X = H OMe F NEt2 OTMS B(OR)2 etc
N(TMS)Boc
S
S
X
650 651 652 653
654 655 656
Figure 62 Functionalised thioacetals
The Takeda reaction has been used to produce various challenging
heterocycles115 (Scheme 614) The thioacetal 657 was reduced by low-valent
titanium species 637 which induced intramolecular alkylidenation of the ester
group and then gave the 7-membered cyclic enol ether 658 in a modest yield
due to competing intermolecular reactions
73
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
O Ph
O
PhS
SPh
OPh
Cp2Ti[(POEt)3]2 637
657 658 32
Scheme 614 Intramolecular alkylidenation
However despite of the fact that a broad range of functionalities tolerate the
Takeda reaction conditions some groups may affect the titanium reagent as
described by Macleod et al110 for unprotected primary amino groups which
prevent the formation of an effective alkylidenating reagent109 Dechlorination
of aryl chlorides can also be observed
A disadvantage of Takedarsquos procedure resides in the requirement for an excess
of titanocene 61 (at least 3 eq) and P(OEt)3 (at least 6 eq) which makes the
purification of the products problematic Hartley and co-workers introduced the
concept of a Takeda alkylidenation on solid-phase which makes the purification
a simple matter of washing109116 and the reagent also allowed the introduction
of functionality in the alkylidenation step Thioacetal 659 was treated with low
valent titanium complex 637 to generate the titanium benzylidene 660 that
benzylidenated Wang resin-bound esters 661 to give enol ethers 662 (Scheme
615) Treatment with acid led to cleavage from the resin and provided the
ketones 663 while deprotection of the silyl ether and then treatment with acid
led to cyclisation and gave benzofurans 664
74
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
SPh
SPh
659
OTBDMS
Cp2Ti[P(OEt)3]2 637
TiCp2
OTBDMS
O
O
R
OTBDMS
ROOTBDMS
R
O
Acid
(i) cleavage(ii) acid
OR
660
661
662663 65-79
664 38-83
Scheme 615 Takeda alkylidenation on solid-phase
The key advantages of the Takeda alkylidenation are the range of alkylidenating
reagents that can be prepared the mildness of the reaction conditions (rt) and
the absence of Lewis acidic conditions The main disadvantages include a poor
selectivity in alkylidenation of aldehydes and ketones no methylenation and the
excess of reagents
64 11-Bimetallic reagents
In 1978 Takai and co-workers117 reported the methylenation of ketones 665
using a new type of titanium carbenoid generated by the addition of TiCl4 in
dichloromethane to a suspension of dibromomethane and zinc dust in THF at rt
The new reactive species is presumably a 11-bimetallic titanium complex 666
(Scheme 616)
75
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
O
R2R1 R2R1
(a) Zn CH2X2 THF(b) TiCl4 CH2Cl2
M = ZnX or TiXnX = Br or In = 1-3
MCH2TiXn
665
666
667
Scheme 616 11-Bimetallic titanium carbenoid
The reaction mechanism is not clear (Scheme 617) It would seem that
diiodomethane 668 is rapidly converted into zinc carbenoid 669 followed by a
second very slow insertion to give the geminal dizinc 670 The addition of
lead(II) chloride accelerates the formation of the geminal dizinc 670 as it acts
as a catalyst118 Takai suggested that transmetallation from zinc to lead occurs
and gives the carbenoid 671 which is more easily reduced by zinc to produce
carbenoid 672 as the Pb-C bond has a greater covalent character A last
transmetallation from lead to zinc gives geminal dizinc79 670 which can react
with titanium(IV) chloride and form methylenating reagent 666
CH2I2
THF
Zn ICH2ZnI Zn
slow
fast
ICH2PbXZn
fast
IZnCH2PbX
CH2(ZnI)2
fast
PbX2
ZnX2
668 669 670
671 672
TiIV MCH2TiXn
666
Scheme 617 Proposed mechanism
Tochtermann and co-workers119 suggested an alternative to the geminal dizinc
670 using the commercially available Nysted reagent 673 in order to
methylenate ketones (Scheme 618) Methylenation of ketone 674 took place at
room temperature in the presence of Nysted reagent 673 (15 eq) and TiCl4
(1 eq) and gave the alkene 675 in good yield
76
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
CO2Me
CO2Me
H
H
O
O
CO2Me
CO2Me
H
H
O
OBrZn
Zn
ZnBr
TiCl4 (1 eq)
THF
673(15 eq)
674 675 63
Scheme 618 Methylenation with Nysted reagent
65 Takai reagents
In 1987 Takai and co-workers120 provided new reagents prepared from
11-dibromoalkanes 676 (22 eq) zinc (9 eq) and TiCl4 (4 eq) and TMEDA (8 eq)
in THF (Scheme 619) Although the reaction mechanism is still to be
established the presence of lead(II) is reported to be vital for the success of the
reaction118 A definitive procedure for the preparation of this reagent has been
published121 These reagents have been used to convert a range of carbonyl
compounds 677 (including esters silyl esters and thioesters) into Z-hetero-
substituted alkenes 678 (E in the case of enamine) The stereoselectivity is
governed by steric interactions
R2CHBr2
(a) TiCl4 (4 eq) TMEDA (8 eq) Zn (9 eq) cat PbCl2 THF-CH2Cl2
(b) 1 eq O
XR1
X = OR3 OSiMe3 SR3
(22 eq)XR1
R2
676 677 678
Scheme 619 Takai reagent
Alkylidenation usually gives better yields than methylenation Many functional
groups are tolerated when esters are alkylidenated under Takai conditions
including ethers alkenes acetals silyl ethers and vinyl and aryl halides76 The
alkylidenes may be functionalised However this has only been demonstrated for
THP acetals122 and for trimethylsilylmethylenation of esters123
77
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
Takai alkylidenation conditions have the advantage that they are mild and
involve a one-pot procedure which allows alkylidenation of a range of carbonyl
derivatives with good stereoselectivity It shows better reactivity than the
Petasis reagent and a lower Lewis acidity compared to the Tebbe reagent The
mechanism of the Takai alkylidenation is not known however recent works
presented by Rainier and co-workers124 would confirm formation of titanium
alkylidenes Indeed in a first paper125 Rainier reported the conversion of
C-glycoside 679 into cyclic enol ether 681 and acyclic enol ether 680 under
Takai conditions (Scheme 620) Submitted to the same conditions the acyclic
enol ether 680 was not converted into the cyclic enol ether 681
Consequently unlike the Tebbe and Petasis reagents which can react
preferentially with esters and then catalyse RCM the Takai methylenating
reagent does not catalyse RCM However it can generate an alkylidenating
species by a metathesis process from an allyl group and then methylenate an
intramolecular carbonyl group inducing cyclisation125 To enable this metathesis
process the methylenating reagent has to be a titanium methylidene rather
than a 11-bimetallic species
O
OBn
BnO O
BnO
OO
OBn
BnO O
BnO
O
OBn
BnO
BnO
O
H
679
680 30
681 50
TiCl4 (6 eq) Zn (13 eq)PbCl2 (072 eq) CH2Br2 (6 eq)
CH2Cl2-THF-TMEDA05 h
Takai conditions+
Scheme 620 Takai methylenation
Later Rainier and co-workers124 found that the nature of the alkylidenating
reagent conditions affects the results of the reaction (Scheme 621) While the
titanium methylidene reagent converted C-glycoside 679 into a mixture (6238)
of cyclic and acyclic compounds 681 680 (Scheme 620) the corresponding
78
Guilaine F Blanc Chapter 6 Alkenation Reactions using Titanium-Based Reagents
titanium ethylidene reagent gave almost exclusively the cyclic enol ether 681
(Scheme 621)
O
OBn
BnO O
BnO
O O
OBn
BnO O
BnO
O
OBn
BnO
BnO
O
H679
680
681
TiCl4 (6 eq) Zn (13 eq)PbCl2 (072 eq) CH3CHBr2 (6 eq)
CH2Cl2 THF TMEDA+
75
681680 gt955
H
Scheme 621 Titanium alkylidene reaction
Furthermore he found that the ethylidene reagent can catalyse RCM even at
room temperature as shown by the conversion of diene 682 into the spirocyclic
ether 683 in quantitative yield (Scheme 622)124
OTiCl4 Zn PbCl2 CH3CHBr2
TMEDA THF rt
O
682 683 100
Scheme 622 Reduced titanium-mediated diene RCM
79
Guilaine F Blanc Chapter 7 Microwave Assisted Organic Synthesis
7 Microwave Assisted Organic Synthesis (MAOS)
71 Background
Located between IR radiation and radio waves126 microwave irradiation is
electromagnetic irradiation in the frequency of 03 to 300 GHz For industrial
and scientific purposes the microwave frequency has been imposed at 245 GHz
in order to avoid interactions with telecommunications and radar equipments
The microwave concept is based on the ability of a specific material (solvent or
reagent) to absorb microwave energy and convert it into heat caused by two
main mechanisms dipolar polarization or ionic conduction127128 At microwave
frequency irradiation of the sample results in the dipoles or ions aligning with
the applied electric field As this electric field is alternating the dipoles or ion
field attempts to realign itself with the oscillating electric field and in this
process energy is lost in the form of heat through molecular friction and
dielectric loss (εrdquo) which is indicative of the efficiency with which
electromagnetic radiation is converted into heat128 The amount of heat
generated is directly linked to the ability of the dipole to align itself at the
frequency of the oscillation of electric field If the dipole does not have enough
time to realign or aligns too fast no heat is generated The 245 GHz frequency
avoids these two extremes The ability of a substrate to generate heat under
microwave irradiation is dependent on its dielectric properties (loss factor tan
and permittivity)127 The higher tan the better is the absorption of the
electromagnetic energy and consequently the more rapid is the heating (Table
71) Furthermore if tan gt05 the solvent is classified as highly microwave
absorbing if tan is 01-05 it is a medium microwave absorber and if
tan lt01 the solvent is a low microwave absorber
Solvent tan Solvent tan
Ethylene glycol 1350 THF 0047
Ethanol 0941 Toluene 0040
Water 0123 Hexane 0020
Table 71 Loss factors of different solvents
80
Guilaine F Blanc Chapter 7 Microwave Assisted Organic Synthesis
However a solvent with a low loss factor is not excluded from microwave
reactions as dielectric properties of substrates reagents or catalysts will allow
sufficient heating Moreover polar additives such as ionic liquids can be added
to the reaction to increase the absorbance level of the medium Heating
reactions with traditional equipment (oil sand baths or heating mantles) is a
slow and inefficient method for transferring energy to the system It depends on
the thermal conductivity of materials resulting in the temperature of the vessel
exceeding that of the reaction mixture it creates a hot surface on the reaction
vessel where products substrates and reagents decompose over time (wall
effects) In contrast microwave irradiations directly heat the reactants and
solvents An example is provided below (Figure 71) where heating performed
with microwave irradiation (left) and heating performed with an oil bath (right)
are compared After 1 min of microwave irradiation the whole volume is heated
whereas with the oil bath only the walls of the tube become hot
Figure 71 Temperature profiles with microwave irradiation (left) and oil bath (right)127
Appropriate vessels have been designed to allow the temperature increase to be
uniform throughout the sample leading to fewer by-products or product
decomposition An efficient internal heat transfer results in minimized wall
effects
Since the first report on the use of microwave heating to accelerate organic
reactions by Giguere et al129 and Gedye et al130 in 1986 the MAOS has become
increasingly popular (over 2000 publications) Many reasons might explain this
passion including the commercial availability of microwave equipment designed
for chemists Above all what makes this technique attractive is a shortened
81
Guilaine F Blanc Chapter 7 Microwave Assisted Organic Synthesis
reaction time (from hours to minutes) reduction of side reactions an increase
on yields and improvement of reproducibility Moreover the development of
solvent-free techniques has also improved the safety aspects of the method In
the next section I will briefly show a few notable applications of microwave
heating to organic reactions which are most relevant to the chemistry developed
in this thesis
72 A microwave-assisted Ugi reaction
Among all the synthetic applications of microwave irradiations developed over
the last 20 years those involving the Ugi reaction or alkenation reactions are
particularly relevant to my work The Ugi reaction is a multi-component reaction
developed by Ugi131 in 1962 which involves condensation of an amine an
aldehyde or ketone a carboxylic acid and an isocyanide to yield an -
acylaminoamide The reaction of levulinic acid 71 with benzylamine 72 and
benzylisonitrile 73 has been reported to proceed at room temperature in
methanol to give the lactam derivatives 74 in moderate yields over a period of
48 h (Scheme 71)132 Tye and Whittaker133 have demonstrated that this reaction
can be speeded-up significantly by performing the reaction under sealed-vessel
microwave conditions A reaction time of 30 min at 100 degC produced a better
yield than the same process at room temperature
OH
O
O
+
NH2
NC
NBn
NH
O
Bn O
71
72
73
74
MeOH
rt 48 h 62MW 05 h 100 degC 90
Scheme 71 Ugi reaction at rt or under microwave irradiation
82
Guilaine F Blanc Chapter 7 Microwave Assisted Organic Synthesis
73 Petasis methylenation
The use of microwave irradiation to carry out Petasis methylenation has already
been described in the chapter about titanium-mediated alkylidenation reactions
(Chapter 6)
74 Microwave-assisted solid-phase organic
synthesis
Sometimes solid-phase synthesis exhibits drawbacks such as slow reactions
solvation problems and degradation of the polymer support because of long
reaction times Microwave-assisted synthesis is able to overcome some of these
issues It has been demonstrated that resins (polystyrenes rink amide
Merrifield Wang etc) can bear microwave irradiations for short periods of time
even at temperatures above 200 degC Kappe and co-workers134 demonstrated that
loading Merrifield and Wang resins using Gisinrsquos method35 under high
temperature microwave heating accelerated significantly the reaction (from 12-
48 h to 3-15 min) and increased the loading A variety of reactions on solid-
support have been assisted by microwave heating including the Ugi reaction135
peptide synthesis136 transition metal mediated synthesis137 and multicomponent
reactions138139 However the lack of suitable technology that would combine
microwave heating and automated solid phase synthesis (ie filtration and
washings) makes this technology not fully exploited
75 Wittig reaction
Wittig alkenation is an important transformation in organic synthesis Dai and co-
workers reported a study on the first regioselective microwave-assisted Wittig
reactions of ketones with a stabilized phosphorus ylide140 They observed that
the regioselectivity of the Wittig reaction of 4-substituted cyclohexanone 75
with a stabilized phosphorus ylide under microwave heating can be controlled
(Scheme 72) The reaction carried out at 190 degC in acetonitrile produced the
83
Guilaine F Blanc Chapter 7 Microwave Assisted Organic Synthesis
exo olefin 76 whereas reaction at 230 degC in DMF in presence of DBU led to
isomerisation to give the thermodynamically more stable endo compound 77
O
R
Ph3P=CHCO2Et+
R
R
EtO2C
EtO2C
R = H alkyl aryl
MeCN
DBU DMF
MW 230 degC 20 min
MW 190 degC 20 min
76 33-66
77 52-78
75
gt99 exo
gt84 endo
Scheme 72 Microwave-assisted Wittig reaction
The microwave-assisted Wittig reaction has also been applied to solid-phase
synthesis Westman141 described a one-pot method for the formation of alkenes
using the Wittig reaction and combining microwave heating and a supported
triethylphosphine reagent 78 (Scheme 73) Yields were always greater than
80 and in most cases 95 However the purification of products was done in a
fully automated system which renders the process not accessible to everybody
PPh3
+O
H+
MeOHMW 150 degC5 min
K2CO3
SS
O
OMe
O
OMeBr
711 9578 79 710
Scheme 73 Microwave-assisted Wittig reaction supported on solid-support
76 Ring closing metathesis reaction
Metathesis reactions generally require at moderate heating for several hours in
order to get complete conversion RCM under microwave irradiation has been
reported to be complete within minutes or even seconds127 Efskind and
84
Guilaine F Blanc Chapter 7 Microwave Assisted Organic Synthesis
Undheim142 reported the RCM reaction of dienyne 712 using Grubbs second
generation catalyst 714 (Scheme 74) Usually the reaction proceeded in
toluene at 85 degC over a period of 9 h after multiple addition of fresh catalyst (3
x 10 mol) and provided the compound 715 in 92 yield Under microwave
irradiations the complete conversion took place in 10 min at 160 degC (5 mol of
catalyst) in toluene They explained that the suppression of wall effects by
microwave irradiation led to an increase in the catalyst lifetime
RuPhCl
Cl
R
PCy3R =
N N
N
N
OMe
MeO
N
OMe
MeO N
N
OMe
MeO
N
OMe
MeO
Grubbs II 714
PhMeMW 160 degC10 min
712 715 100
R = PCy3 Grubbs I 713
Grubbs II 714
Scheme 74 Microwave-assisted RCM
77 Conclusion
Many types of reactions can be carried out using microwave heating In 2006
Kappe and Dallinger128 counted more than 3000 examples published in literature
since the first reports in 1986 and microwaves are an essential tool for the
production of new compounds in pharmaceutical industry Their use leads to
dramatically reduced reaction times higher yields and cleaner reactions One of
the major disadvantages of this technology is the cost of equipment Scaling up
reactions is another drawback of the technique Most of the published examples
were carried out on small scale (lt1 g) However MAOS is a promising technique
which knows a rapid expansion
85
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
8 Short Routes to Alkaloids using the Petasis
Reagent
Used as drugs potions medicines teas and poisons for 4000 years alkaloids
constitute one of the widest classes of natural products being synthesized by
living organisms143 The extraordinary diversity of alkaloid structures and
biological properties has long interested chemists It was in the early 19th
century that therapeutically active compounds were first isolated with the first
crude drug investigation carried out on opium143 The first total synthesis of an
alkaloid was reported in 1886 by Ladenburg for the synthesis of (+)-coniine
81144 Many alkaloids have been used for hundreds of years in medicine and
some are still important drugs today Pharmaceutical industries have used and
will continue to use alkaloids as biological tools and as lead compounds for
development of new drugs Many alkaloids serve as models for the synthesis of
analogues with better properties
The pyrrolidine motif is present in numerous natural alkaloids such as nicotine
82 and hygrine 83 isolated from tobacco and coca leaves (Figure 81) It is
found in many pharmaceutical drugs such as procyclidine 84 an anticholinergic
drug principally used for the treatment of Parkinson disease
N
NH
OH
N
N
O
82 83 84
NH
81
Figure 81 Pyrrolidine and piperidine cores in alkaloids and drugs
The piperidine structural motif is found in several natural alkaloids presenting
biological activity as well such as piperine 85 (black pepper)145 the fire ant
toxins the solenopsin 86 (secreted as a mixture of stereoisomers)146 the
nicotine analogue anabasine 87 (Figure 82) or coniine 81144 (Figure 81)
86
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
N
O
O
O NH
NH
N
85 86 87
10
Figure 82 Piperidines in natural alkaloids
The synthesis of 7-membered amino cycles is also of interest -Glycosidase
inhibitors have proved to be efficient drugs in the treatment of diabetes HIV
infection viral infections or cancer as they inhibit the hydrolysis of the
glycosidic linkage A common strategy for designing such inhibitors is based on
the mimicry of glycosides and for this purpose a large number of nitrogen-
containing ldquosugar-shapedrdquo heterocycles have been synthesized including
azepanes 88 and 89 (Figure 83)147 I explored three short routes for accessing
alkaloids using microwave-assisted Petasis methylenation as the key step
HN
HO
HOOH
HO
HN
HO
HO
HO
88 89
OH
Figure 83 Substituted azepanes mimicking glycosides
81 Synthesis of pyrrolidine or azepane alkaloids
As seen in chapter 6 titanium carbenoids can easily convert carboxylic acid
derivatives directly into hetero-substituted alkenes7679 A range of titanium
carbenoids could be used to methylenate esters as seen in the
literature7783148149 but methylenation of methyl esters in the presence of imines
is best carried out using the Petasis reagent 814 (= 614 see Scheme 65)100 As
reported by Adriaenssens and Hartley100 esters 813 were easily prepared from
amino acids 810 and cleanly converted into enol ethers 815 by using
microwave-assisted Petasis methylenation Cyclisation of enol ether 815 was
87
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
easy and was done under acidic conditions to give cyclic amines 816 (Scheme
81) During this investigation Adriaenssens discovered that ketone 821 (R1 = H
R2 = Ph) could be prepared from the -amino butyric acid (GABA) 817 (Scheme
82)
H2N
O
OH
R1
H3N
O
O
R1
Cl
N
O
O
R1
Ph810 811
N O
R1
Ph
813
815
H2N
Ph
R1
Cp2TiMe2 814PhMe-THFMW 80 degC 10 min
816 62 from 813
R1 = Me or Ph
PhCHO 812
Et3N Na2SO4
46-68 from 810
O
Cl
SOCl2
MeOH CH2Cl2 rt
Acid
Scheme 81 Previous research in the group
Et3N Na2SO4
Cp2TiMe2 814
H2N
O
OHH3N
O
OMe
ClN
O
OMe
NOMeH2N
PhO
817 818 98 819 80
820821 62 from 819
conc HCl(aq)
SOCl2
MeOH CH2Cl2 rt
Ph
Ph
PhMe-THF MW
Cl
PhCHO 812
Scheme 82 Previous research in the group
We thought that by following the same strategy a range of pyrrolidine alkaloids
828 might be prepared and by changing the cyclisation conditions azepanes
827 might also be accessed (Scheme 83) Therefore we proposed to exploit
this reaction sequence to allow general stereocontrolled access to azepanes
88
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
827 and pyrrolidines 828 by varying the type of amino acid 822 aldehydes or
ketones 824 and cyclisation conditions
E = H COR SO2R
Cp2TiMe2 814PhMe-THF MW
Et3N Na2SO4
H2N
O
OH
R1
H3N
O
O
R1
Cl
N
O
O
R1
R2
NO
R1
R2
N
R2
O
R1
N
R2
R1
O
822 823 825
826827828
E+EEor
SOCl2
MeOH
R2CHO 824
CH2Cl2 rt
Scheme 83 Synthesis of cyclic amines using Petasis reagent
We assumed that by varying the nature of the acid Lewis acid or electrophile
used in the cyclisation step we might orientate the reaction towards a
pyrrolidine ring or towards an azepane Indeed treatment of the enol ether
826 with a Broumlnsted acid was expected to isomerise enol ether 829 and so
generate an iminium intermediate 830 (Scheme 84) which would cyclise to
give after hydrolysis the ammonium salt 831 On the other hand the use of a
Lewis acid to treat the enol ether 826 would provide the 7-membered ring 833
via a 7-(enol-endo)-endo-trig cyclisation of iminium complex 832
H+
5-(enol-exo)-endo-trigfast
LAN
O
R2
R1
826
NO
R2
R1
H+
HNO
R2
R1
829
H2N
R2
O
R1
830
NO
R2
HN
R2
O
LAslow
7-(enol-endo)-endo-trig
R1R1
832
831
833
Scheme 84 Towards a 5- or 7-membered ring
89
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
Results and discussion
In my first route -aminobutyric acid (GABA) 817 was used as the starting
material which was converted into the methyl ester 818 by treatment with
thionyl chloride in methanol (Scheme 85) The hydrochloride salt 818 was
cleanly isolated in 95 yield then following a procedure described by
Blommaert et al150 various imines 819 and 837-839 were formed by
condensation of the methyl ester 818 with the corresponding aldehydes 812
and 834-836 in the presence of triethylamine (Table 81)
Et3N Na2SO4H2N
O
OHH3N
O
O
Cl
N
O
O
R1
SOCl2
MeOH rt CH2Cl2 rt on
817 818 95 819 837-839
R1CHO
2 h
Scheme 85 Towards the synthesis of imino esters
Entry R1 Aldehydes Imino esters Yield
1 Ph- 812 819 71
2 CH3CH2(CH3)CH- 834 837 94
3 24-(CH3O)2C6H3- 835 838 23
4 (E)-C6H5CH=CH- 836 839 17 a a yield calculated from analysis of the crude NMR
Table 81 Summary of yields for the synthesis of imino esters
All these imines were highly unstable and therefore purification was quite
delicate which explains the modest yield obtained for imine 838 After aqueous
work up distillation under reduced pressure using a Kugelrohr apparatus was
preferred However careful monitoring of the temperature and the
advancement of the purification were necessary The imino ester 839 was
observed by NMR analysis of the crude mixture (17) but the compound
decomposed during distillation and characterization was not carried out
According to conditions established by Adriaenssens and Hartley100 the Petasis
reagent 814 prepared as described by Payack et al 85 would allow conversion
90
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
of esters into enol ethers under microwave irradiation Although there are
examples reported of selective reaction of nucleophilic organometallic reagents
with the imine group of imino esters151 Adriaenssens and Hartley100 had shown
that the Petasis reagent methylenates the ester selectively under mild
microwave conditions Irradiation of esters 819 837-838 with the Petasis
reagent 814 in a sealed vessel for 10 min provided enol ethers 820 840-841
in modest to excellent yield (Scheme 86 Table 82) Titanium residues were
removed by precipitation by treating the crude mixtures with hexane under
sonication and due to the relative instability of enol ethers the cyclisation was
investigated without further purification
N
O
O
R1
Cp2TiMe2 814
PhMe-THF MW 65 degC10 min
NO
R1
819 837-838 820 840-841
Scheme 86 Petasis methylenation
Entry R1 Imino esters DMT 814 (eq) Enol ethers Yield
1 Ph- 819 61 820 84
2 CH3CH2(CH3)CH- 837 61 840 100
3 24-(CH3O)2C6H3- 838 82 841 28
Table 82 Summary of yields for the synthesis of enol ethers
Many different conditions were attempted to cyclise the enol ether 820
(Table 83) Most conditions gave only decomposition (entries 1-4) The only
conditions which proved to be at all effective for the cyclisation of enol ether
820 was the use of 7 M or Conc HCl in DME (01 M) (entries 5 and 6) A
compound assumed to be the hydrochloride salt 842 was produced in poor yield
and identified from the 1H NMR of the crude mixture (Scheme 87) [1H NMR (400
MHz CDCl3) 200-208 (4H m CH3 and CHAHB-4) 241-250 (1H m CHAHB-4)
303-314 (1H m CHAHB-5) 336-344 (1H m CHAHB-5) 350 (1H q J 94 Hz
CH-3) 456-463 (1H m CH-2) 725-731 (3H m Ar-H) 754-756 (2H m Ar-
H) 963 (1H br s NH2) 1039 (1H br s NH2)]
91
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
NO
Ph
H2N2
34
5
O
820 842 31 crude
7 M HCl
DME 05 h rt
Cl
Ph
HN
OPh
843 23
NaBH4 MeOH1h rt
HN
PhOH
H
Scheme 87 Cyclisation of enol ether 820
Due to purification issues this compound was never isolated Later this result
was supported by further data collected during an attempt at reduction of the
ketone where the free amine 843 was isolated in poor yield Although the
cyclisation of enol ethers 840 and 841 were attempted under the same
conditions (entries 7 8) none of the desired products was detected
Entry R1 Enol ethers Cyclisation conditions Yield
1 Ph- 820 Conc HCl 05 h rt -
2 Ph- 820 7 M HCl 05 h rt -
3 Ph- 820 TsOH (25 eq) DME on rt -
4 Ph- 820 TsOH (20 eq) DME on rt -
5 Ph- 820 7 M HCl DME 05 h rt 842a 31
6 Ph- 820 Conc HCl DME 05 h rt 842a 9
7 CH3CH2(CH3)CH- 840 Conc HCl DME 05 h rt -
8 24-(CH3O)2C6H5- 841 Conc HCl DME 05 h rt -
a crude yield compounds not purified
Table 83 Summary of cyclisation conditions
Another attempt at purification involved the derivatisation of the ammonium
salt 842 (Scheme 88) Reaction of cyclic amine 842 with trifluoroacetic
92
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
anhydride in presence of triethylamine failed to give the amide 844
Decomposition of the compound was noted
N
PhO
H2N
PhO
Cl
TFA anhydride Et3NF3C
O
842 844
CH2Cl2 0 degC on
Scheme 88 Derivatisation of salt 842
In order to access the azepane we decided to activate the imine 820 (Scheme
89) Reaction of mesyl chloride with enol ether 820 in presence of
triethylamine in dichloromethane followed by treatment with aqueous acid did
not give the desired amine 845 NMR analysis of the crude mixture before
acidic conditions revealed that hydrolysis of the imine had occurred Another
reaction carried out with trifluoroacetic anhydride under the same conditions
led to the same conclusion
NO
Ph
(a) MeSO2Cl Et3N CH2Cl2 rt 05 h
(b) 1 M HCl 1 h rt
820 845
NMeO2S
PhO
Scheme 89 Attempt of cyclisation
These results were not enough to convince us of the likely sucess of this
approach Therefore we proposed another route to access to pyrrolidines or
azepanes by using microwave-assisted Petasis methylenation and considering the
methylenation of an amide
82 Synthesis of pyrrolidine or azepane alkaloids
This new route would allow access to alkaloids starting from the same amino
acid GABA 817 (Scheme 810) First protection of the amino group of the
93
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
GABA 817 would allow the formation of acid chloride 846 followed by
formation of the dibenzylamide Deprotection would generate the amine 847
and then according to conditions previously described the imine 848 would be
formed The amide would be selectively methylenated using the Petasis reagent
assisted by microwave heating The difference with the preceding route relies on
this step as an enamine 849 would be formed instead of enol ether Cyclisation
performed under acidic conditions would provide cyclic amines 850 or 851
H2N
O
OH PhthN
O
ClH2N
O
NBn2
N
OPh
N
Ph
NH
O
Ph
NBn2NBn2
817 846 847
848849
850 851
5-(enamine-exo)-endo-trig
HN
PhO
7-(enamine-endo)-endo-trig
Scheme 810 A new route to alkaloids
Results and discussion
According to the procedure provided by Kruper et al152 the free amine of -
aminobutyric acid 817 was protected using phthalic anhydride 852 in the
presence of triethylamine (Scheme 811) The acid 853 obtained in excellent
yield was then treated with thionyl chloride at reflux for 25 h After removal of
SOCl2 under reduced pressure and without further purification the acid chloride
846 was directly used in a reaction with a solution of dibenzylamine 854 and
pyridine in CH2Cl2153 This Schotten-Baumann reaction154155 led to the production
of the amide 855 in good yield
94
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
H2N
O
OHN
O
OHO
O
N
O
ClO
O
N
O
NBn2
O
O
PhMe reflux 15 h
SOCl2reflux 25 h
817 853 84
846855 69 from 853
Phthalic anhydride 852 Et3N
Bn2NH 854 Pyr
CH2Cl2 15 min 0 degC to rt
Scheme 811 Synthesis of the amide 855
Deprotection of the phthalimide 855 using hydrazine 856 in ethanol at reflux
followed by reaction of the freendashamine 847 with benzaldehyde 812 provided
the imino amide 848 in 54 yield (Scheme 812)150156 Petasis methylenation of
the amide 848 was carried out under standard microwave conditions However
the use of 60 eq of the Petasis reagent 814 at 65 degC resulted in a complex
mixture so it was decided to carry out Petasis methylenation and then treat the
resulting mixture with acid
N
O
NBn2
O
O
H2N
O
NBn2
N
O
NBn2
PhN
NBn2
PhCHO 812 Na2SO4 CH2Cl2 rt on
Cp2TiMe2 814
855 847 87
848 54849
EtOH reflux 2 h
H2NNH2 856
MW 10 min 65 degCPh
Scheme 812 Synthesis of the enamine 849
Methylenation of amides have already been reported84 and from further
investigations it appeared that the iminium ion 857 in equilibrium with the
enamine 849 when there is a proton source suffered hydrolysis rather than
95
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
cyclisation (Scheme 813) After treatment with 7 M HCl we recovered
benzaldehyde 812 from the hydrolysis of the imine part and dibenzylamine
hydrochloride salt 854 from the enamine part
N
O
NBn2
Ph
(a) Cp2TiMe2 814
848
H
O
812 86
+
854 14
MW 10 min 65 degC NH2
PhPh
Cl
(b) 7M HCl
NNBn2
Ph849
HN
NBn2
Ph857
H2O
-H
Scheme 813 Decomposition of the substrate under Petasis conditions
The desired amines were not obtained as hydrolysis of the enamine occurred A
final approach to the synthesis of cyclic amines using the Petasis reagent was
then investigated which combined methylenation with the Ugi reaction
83 Synthesis of pyrrole or piperidinone alkaloids
using the Ugi reaction
Petasis methylenation and Ugi reaction were key steps in this new route to
alkaloids Following a similar strategy to that seen in section 81 pyrrole or
piperidinone alkaloids would be prepared starting from glycine 858 or (S)-
alanine 859 (Scheme 814) Formation of imines 863 and 864 would be
performed as previously described then selective methylenation of esters would
provide enol ethers 865 and 866 As described in the previous chapter the Ugi
reaction is a multicomponent reaction involving an imine an isocyanide and a
carboxylic acid 867 Recently Tye and Whittaker133 have provided an optimized
version of this reaction assisted by microwave heating We proposed to use the
Ugi reaction as a cyclisation step
96
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
Cp2TiMe2 814
H2N
O
OHN
O
OH3N
O
O
Cl R2
NO
R2
Ugi reaction
N
OMe
R3
R2
HN
O
C NPh
R3CO2H
Phor
HN
NH
O
R2
R1 R1 R1
R1
R1 R1
MeOH
SOCl2R2CHO 862 Et3NNa2SO4
CH2Cl2 rt on
MW 65 degC 10 min
858 R1 = H859 R1 = CH3
868869
867
Ph
860 R1 = H861 R1 = CH3
863 R1 = H864 R1 = CH3
865 R1 = H866 R1 = CH3
Scheme 814 A new route to alkaloids
Indeed we believed that applying the Ugi conditions on enol ethers 865 and
866 would generate cyclic amines 868 or 869 The proposed mechanisms for
the potential cyclisations are shown in Scheme 815 Under acidic conditions
nucleophilic addition of the isocyanide on the iminium species 871 would result
in the formation of nitrilium intermediates 872 which could cyclise via a 6-
(enol-endo)-exo-trig cyclisation and the resulting enol ether hydrolyse to give
the piperidinone 868 or a second nucleophilic addition takes place with the
carboxylate 870 and provide the intermediate 875 Then a Mumm
rearrangement would yield the compound 876 Finally a 5-(enol-endo)-exo-trig
cyclisation would allow the formation of the cyclic compound 869
97
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
R1
R1
NO R2 N C
Mumm rearrangement13-(ON)-acyltransfer
R1
HNO
NR2
N
OMe
HN
O
R2
H+
O
OR3
871
HNO
NR2
O
OR3
HNO
R1
OCOR3
R2N
NO
R1
NHR2
O
R3
O
868
R3
R1
869
870 872
870
875876
N
OMe
HN
O
R2R3
R1HOHN
R1
O
NHR2
R1
874
HNO
NR2
873
877
Scheme 815 Proposed mechanisms of cyclisations
Results and discussion
The first step consisted in the formation of methyl esters Treatment of the
amino acid 858 or 859 with thionyl chloride in methanol gave esters 860 and
861 in excellent yield (Scheme 816 Table 84) Then the formation of imines
863 and 864 was carried out under well-known conditions150 However
although the imine 863 was observed in the crude mixture the compound
decomposed during the removal of excess aldehyde by distillation Similarly
imine 864 gave a poor yield The use of the Petasis reagent 814 under
microwave irradiation allowed the conversion of the imine 864 into enol ether
866 and the cyclisation via an Ugi reaction was considered
98
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
Cp2TiMe2 814
H2N
O
OH N
O
OH3N
O
O
Cl Ph
NO
Ph
R1 R1 R1
CH3
MeOH
SOCl2PhCHO 812 Et3NNa2SO4
CH2Cl2 rt on
MW 65 degC 10 min
858 R1 = H859 R1 = CH3
866
860 R1 = H861 R1 = CH3
863 R1 = H864 R1 = CH3
Scheme 816 Towards the synthesis of enol ethers
Entry R1 AA Methyl esters and yield Imines and yield
Enol ethers and yield
1 H 858 860 98 863 - -
2 CH3 859 861 92 864 19 866 36
Table 84 Summary of yields
In Tye and Whittakerrsquos studies133 benzylisonitrile and benzoic acid were chosen
to carry out the Ugi reaction (Scheme 817) Therefore a solution of imine 866
(10 eq) benzoic acid (07 eq) and benzylisonitrile (07 eq) in dry DME (04 mL)
was heated in a sealed tube by microwave irradiation at 100 degC for 05 h The
crude mixture after a basic work-up showed decomposed materials This first
unpromising result together with the severe stench of the reagents used
discouraged further exploration
NO
Ph
CH3
N
OMe
PhHN
O
Phor
HN
O
CH3PhCH2NC PhCO2H
DME MW 05 h100 degC
866 879878
CH3
NH
Ph
Scheme 817 Ugi reaction
99
Guilaine F Blanc Chapter 8 Short Routes to Alkaloids using the Petasis Reagent
100
84 General conclusions
To sum up we tested three short routes towards the synthesis of 5- 6- or 7-
membered cyclic amines starting from amino acids with Petasis methylenation as
a key step As expected selective methylenation of esters to give imino enol
ethers generally proceeded well Concerning cyclisations despite various
conditions attempted (acids and Ugi reaction) there was nothing to encourage
further investigations Methylenation of amide 848 under microwave heating is
an unsolved problem It is tricky to be sure if there was competition between
hydrolysis of the enamine and cyclisation or if the methylenation had not taken
place at all and hydrolysis of the amide and imine happened during the acidic
work up
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
9 Previous Syntheses of Anisomycin
91 Background
(minus)-Anisomycin 91 also know as flagecidin is a pyrrolidine antibiotic157 first
isolated from the fermentation of various Streptomyces species by Sobin and
Tanner of Pfizer in 1954158 Its structure was initially elucidated in 1965159 but
the relative and absolute stereochemistry were modified three years later on the
basis of 1H NMR analysis160 and X-ray crystallography161 to the (2R3S4S)
configuration162 (Figure 91)
MeO
2 34
HNOH
OR
()-91 R = Ac ()-anisomycin)-92 R = H ()-deacetylanisomycin
MeO
2 34
HN
OR
(+)-91 R = Ac (+)-anisomycin(+)-92 R = H (+)-deacetylanisomycin
OH
Figure 91 Structures of Anisomycin and derivatives
(minus)-Anisomycin 91 has become a valuable tool in molecular biology as it exhibits
selective and potent activity against protozoa and certain strains of fungi It has
been used successfully in clinical trials for the treatment of both amoebic
dysentery and trichomonas vaginitis163 Anisomycin 91 is also known as a
peptidyl transferase inhibitor binding to eukaryotic ribosomes164 This natural
product and its deacetyl derivative 92 show fungicide163 activity as well (Figure
91) More recently it has been found that (minus)-anisomycin 91 displays high in
vitro antitumor activity [IC50 in the range of 005-034 M against LU99 (human
lung carcinoma) and MCF7 (human breast cancer cell)]165166
A structure-activity relationship indicated that the diverse biological activities
are due to the presence of the chiral pyrrolidine skeleton resulting in
considerable synthetic interest167 Quite a number of enantioselective syntheses
of this simple natural product have been reported since 1970168 In most of
them anisomycin 91 was obtained by transformation of deacetylanisomycin 92
accessed via various chiral pool starting materials
101
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
About 25 syntheses of anisomycin 91 (racemic or enantiopure) or the precursor
deacetylanisomycin 92 can be found in literature A short review of the most
impressive routes established to access anisomycin is given here The few total
syntheses of racemic anisomycin are described first and then those of
enantiopure anisomycin The nature of the starting material has been chosen as
the criterion of classification of the enantioselective routes and so the discussion
is divided into four categories enantioselective routes starting from an amino
acid from a diol from a sugar or from a diverse range of other substrates
92 Racemic syntheses of anisomycin
Only two total syntheses of ()-anisomycin 91 have been reported so far first in
1969 by Oida and Ohki169 and later by Schumacher and Hall170 Considering
Butlerrsquos171 demonstration of tyrosine glycine and methionine involvement in the
biosynthesis of anisomycin Oida and Ohki proposed a total synthesis of ()-
anisomycin in 15 steps from (RS)- or (S)-tyrosine 93 (Scheme 91) The
pyrrolidine compound 97 was obtained after a few steps via a Dieckmann
condensation which led to the loss of the enantiomeric purity in the case of (S)-
tyrosine 93 Then epoxidation of the pyrroline 99 using pertrifluoroacetic acid
was carried out and yielded a mixture of the syn-epoxide and anti-epoxide 910
in a ratio of 51 The epoxides were separated by chromatography and treatment
of anti-epoxide with acetic acid NaOAc then mesylation followed by treatment
with base provided the minor syn-epoxide 910 in good yield The epoxide ring
910 was then opened using trifluoroacetic acid followed by acylation and
deprotection of the amine The major drawback of this sequence came from
random acylation at the last stage requiring separation of isomers This resulted
in an overall isolated yield of 1
102
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
(RS)-93 (RS)-Tyr (S)-93 (S)-Tyr
HOH4C6 CO2Et
HNCO2Et
NAc
O
ArNH
Ar
99 49overall yield 23
NZ
Ar
O
()- 91
(RS)-95 (RS) 85 from 93(S)-95 (S) yield not reported
910 43
minor compound
Ar = 4-CH3OC6H4
NH2
CO2HHOH4C6
(a) KOH(aq) 20 degC
(b) CH2CHCN10 degC then 3h at rt and 2h at 60 degC
HCl(g)
(i) Ac2O MeOH 15 h reflux
(ii) Me2SO4 K2CO3 acetone 3 h reflux
HOH4C6 CO2H
HNCN
(RS)-94(RS)-tyr(S)-94 (S)-tyr
EtOH 2 h60 degC
ArCO2Et
AcNCO2Et
(RS)-96 (RS) 77 (S)-96 (S) yield not reported
CO2Et
NaH
reflux 25 h
(i) AcOH conc HCl 35 h 60 degC
(ii) TsHNNH2 MeOH reflux 1 h
NAc
TsHNN
Ar
98 72 from 9697
(HOCH2CH2)2OKOH 24 h 140 degC
(i) NaHCO3 benzene BnOCOCl 2 h rt(ii) Na2CO3 CH2Cl2 CF3CO3H 1 h reflux
(i) CF3COONa TFA 2h rt
(ii) Pyr Ac2O 1 h rt then HCl(aq)(iii) H2 10 Pd(C) EtOH
NH
Ar
AcO OH
benzene
Scheme 91 Oida and Ohkirsquos synthesis of ()-anisomycin
In 1982 Schumacher and Hall170 reported a convenient and efficient
diastereoselective total synthesis of ()-anisomycin 91 from pyrrole-2-
carboxaldehyde 911 where the overall isolated yield was better than 40 and
the synthesis required 13 steps (Scheme 92) First steps involved formation of
the carbon skeleton of anisomycin by using an alkylation-reduction technique
Thus the 4-methoxybenzylpyrrole 912 was prepared in two steps from the
pyrrole-2-carboxaldehyde 911 Next steps involved the introduction of the
correct stereochemistry
103
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
NH
H
O
NH
Ar
O
()-91 75
(i) Cl3CCH2OCOCl Pyr CH2Cl2(ii) Ac2O Pyr
NZ
Ar
OHHO
NH
Ar
NIS HClO4 (aq) THF
915 53 from 911
911 912 97Ar = 4-CH3OC6H4
92 97
(i) 4-CH3OC6H4Li Et2O(ii) Li-NH3 NH4Cl Zn HCl(aq) EtOH
(ii) 10 Na2CO3 THF BnOCOCl
NR
Ar
99 R = H 67
913 R = Z 94
BnOCOCl PhMeNaOH
NZ
Ar
914
HOI
(i) 5-10 KOH
(ii) H2 10 Pd-C MeOH
(i) TFA CF3CO2Na 120 degC
(i) Zn HOAc-THF then 2N NaOH
NZ
Ar
OAcTCEO
(ii) H210 Pd-C MeOH NH
Ar
OAcHO
916
Scheme 92 Schumacher and Hallrsquos total synthesis of ()-anisomycin
Reduction of pyrrole 912 followed by protection of the amine as a benzyl
carbamate and formation of the halohydrin followed by treatment with base
allowed selective formation of the syn-epoxide 915 The key step of this
synthesis was the regioselective stereospecific ring opening of the syn-epoxide
915 and this was followed by a selective protection-acetylation-deprotection
reaction sequence The ring opening reaction must be performed on the free-
amine epoxide since the regioselectivity is lost with the N-protected syn-
epoxide Furthermore the regioselectivity of the step was extremely dependent
on the conditions of the reaction Biological tests carried out by Schumacher
indicated the synthetic ()-anisomycin 91 to possess half of the activity of the
natural isomer
Based on these publications pyrroline 99169 and deacetylanisomycin 92170 are
reported as final products in many syntheses since they may be transformed
into anisomycin 91 by well-documented sequences172173
104
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
93 Chiral pool syntheses from amino acids
Shono and Kise174 reported the first synthesis of (minus)-anisomycin 91 from an
amino-acid (R)-tyrosine in which the addition of electrochemically generated
enolate of methyl dichloroacetate is used as a key reaction in a 12 step
sequence (Scheme 93)
ArCO2CH3
NHCO2CH3
Ar
NHCO2CH3
OH
CCl2CO2CH3
NH
HO
O
ClCl
Ar
NH
OAr
O
NH
OAr
O
+
NH
Ar
HO OH
()-92 quant
918 919 44 920 65
922923
Ar = 4-CH3OC6H4
82ratio (922923) 11
(i) DIBAL-H
(ii) CCl3CO2CH3 DMF CHCl2CO2CH3 Et4NOTs
(i) HBr AcOH
NH4NO3CH3OH
NH
HO
OAr
Cl
921 80
CH3ONa
MeOH0 degC
(iii) CH3ONa CH3OH 46
(i) BF3AcOH(ii) MsClEt3N
LAH THF
NH
Ar
HO OAc
924 70
O AcOH
BF3
(ii) NaHCO3
Scheme 93 Shono and Kisersquos formal synthesis of (minus)-anisomycin 91
Electrochemical reduction of methyl trichloroacetate using a cell equipped with
carbon rod electrodes and coupling with the aldehyde prepared from protected
(R)-tyrosine gave alcohols 919 After hydrolysis with acid and treatment with
NaHCO3 a mixture of 34-syn and 34-anti--lactams 920 was isolated in good
yield A selective reduction to monochloride and treatment of the mixture with
CH3ONa at 0 degC afforded epoxy--lactams 922 and 923 in a 11 ratio After
separation lactam 922 can be converted into lactam 923 via acidic ring
opening mesylation and treatment with base (minus)-Deacetylanisomycin 92 was
accessed from syn-epoxide 923 after treatment with BF3AcOH and reduction
Shono referred to Schumacherrsquos procedure to convert intermediate 92 into (minus)-
anisomycin 91
105
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
At about the same time Jegham and Das175 reported a completely different
approach to (+) and (minus)-anisomycin 91 via a short synthesis of (R)-pyrroline 99
and its isomer (S)- 99 from (R)- and (S)-tyrosine (Scheme 94) From a fully
protected (R)-tyrosine 925 reduction of the ester function with NaBH4-LiCl
followed by Swern oxidation provided the aldehyde 927 Chain extension via
modified HWE reaction afforded the Z-isomer of β-unsaturated ester 928
Then reduction to the alcohol 929 mesylation intramolecular cyclisation and
N-Boc-deprotection led to the desired pyrroline (minus)-99 with an overall yield of
62 from 925 (+)-Isomer 99 was prepared in the same manner
ArCO2CH3
NHBoc
Ar = 4-CH3OC6H4
Ar
NHBoc
Ar
BocHN R
926 95
928 R=CO2CH380 from 926
929R=CH2OH 98
925
NBoc
Ar
930 88(R)-99 100
(COCl)2 DMSO
CH2Cl2 Et3N 78 degC
DIBAL-H 78 degC
TFA
EtOH-THF rt
NaBH4-LiCl
(CF3CH2O)2P(O)CH2CO2Me
18-crown-6 (Me3Si)2NK78 degC
(i) MsCl CH2Cl2 Et3N 10 degC 20 min
(ii) NaH CH2Cl2 rt on
NH
Ar
CH2Cl2rt 4 h
OH ArCHO
NHBoc
927
Scheme 94 Jegham and Dasrsquo formal synthesis
Later Hulme and Rosser176 envisaged an alternative approach using a tyrosine-
derived aldehyde 931 and the glycolate derivative 932 of Evansrsquo oxazolidinone
to allow a highly efficient synthesis of anisomycin 91 (Scheme 95)
H
NBn2
O
MeO
HN
AcOOH
()-91
MeO
931
+ N O
OO
BnO Bn
932
Scheme 95 Hulme and Rosserrsquos approach
106
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
Tyrosine derivative aldehyde 931 was easily prepared from (R)-tyrosine (R)-93
in 7 steps and 80 overall yield (Scheme 96) A few protection and deprotection
reactions allowed methylation of the phenol and produced the ester 934 NN-
Dibenzylation followed by reduction of the ester provided the amino alcohol
935 in excellent yield The desired aldehyde 931 was obtained after Swern
oxidation
(R)-93 (R)-Tyr
O
OCH3
HONHBoc
Ar
O
OCH3
NH2
Ar = 4-CH3OC6H4
Ar OH
NBn2
Ar H
NBn2
O
Swern
oxidation
933 99
934 97935 83931 100
HO
CO2H
NH2 (ii) Boc2O NaHCO3 EtOH
(i) AcCl MeOH
(ii) TFA CH2Cl2
(i) MeI K2CO3 DMF
(ii) LiBH4 MeOH
(i) BnBr K2CO3 MeCN
Scheme 96 Synthesis of Tyrosine-Derived aldehyde 931
The intermediate 932 was prepared prior to the synthesis from (4R)-
benzyloxazolidine-2-one176177 Then Evansrsquo aldol reaction of compound 932
with aldehyde 931 provided the all syn-aldol 936 as the major diastereoisomer
(Scheme 97) Reductive removal of the chiral auxiliary followed by selective
tosylation of the primary alcohol and treatment with Dowex resin-1 HCl
afforded the pyrrolidinium chloride salt 938 Finally partial deprotection
acylation and total debenzylation allowed isolation of (minus)-anisomycin 91 This
rapid synthesis of (minus)-anisomycin 91 (13 steps) proceeded in an overall yield of
35 and with excellent diastereoselectivity
107
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
Ar = 4-CH3OC6H4
ArNBn2
ArN
OBn
N O
OO
BnOBn
932
OH O
NX
OBn
HO
Bn Bn
ClAr
N
OBnAcO
Bn
Ar
HN
OHAcO
HCl
Pd(OH)2(cat) H2
936 75
938 85()-91 100 939 86
(a) Et3N Bu2BOTf CH2Cl2
(b) 931
(i) TsCl DMAP (ii) Dowex Cl-
LiBH4
MeOH
(i) PdC (cat) K2CO3 H2 MeOH 10 min
HCl MeOH
Ar
NBn2
OH
OH
OBn
937 80
(ii) Ac2O Et3N DMAP CH2Cl2
N
O
O
BnNX =
Scheme 97 Hulme and Rosserrsquos synthesis of (minus)-anisomycin 91
Recently Joo et al178 reported an asymmetric synthetic method for the
preparation of (minus)-anisomycin 91 utilizing oxazine 943 (Scheme 98) The
longest linear sequence consisted of 11 steps from the methyl ester 940 of N-
benzoyl (R)-tyrosine and proceeded in 27 yield The key step is a Pd(0)-
catalyzed intramolecular formation of oxazine 943 and this is followed by
ozonolysis of the alkene to expose the aldehyde and catalytic hydrogenation to
give the pyrrolidine ring via imine formation
Ar
NHBz
Cl
OTBS
N O
OTBS
Ar
Ph
Ar = 4-CH3OC6H4
N O
OAc
Ar
Ph
()-91 65
(ii) Pd(OH)2C H2 MeOH AcOH
941
943944 87
Pd(PPh3)4 NaH Bu4NI
THF 0 degC 12h
+
N O
OTBS
Ar
Ph
942
79ratio (943942) 151
(i) Bu4NF THF
(ii) Ac2O Pyr CH2Cl2
NH
AcO OH
Ar(i) O3 MeOH 78 degC
Ar OMe
NHBz
O6 steps
940
Scheme 98 Joo et alrsquos total synthesis
108
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
94 Chiral pool syntheses from tartaric acid
Five total syntheses of anisomycin 91 from the chiral pool have been reported
starting from tartaric acid or an ester derivative They take advantage of the
presence of two hydroxyl groups with the required relative stereochemistry in
the starting material In the late 60rsquos Wong et al179 reported a synthesis from
tartaric acid and Felner and Schenker180 demonstrated one from diethyl tartrate
in 1970 However both approaches were non stereoselective and resulted in very
low overall yields 16 years later Iida et al173 described an approach relying on
stereocontrolled reduction of a ketone requiring no separation of isomers
together with a more efficient technique for the acetylation of
deacetylanisomycin 92 (Scheme 99) The synthesis starts from diethyl L-
tartrate 945 and allows preparation of L-threose derivative 947 (in 3 steps)
which is used as a chiral building block Then after hydrogenation and Grignard
addition of 4-methoxybenzylmagnesium chloride alcohols 948 and 949
(isolated as a mixture of diastereoisomers) were converted into the ketone 950
via Swern oxidation
BnOH
MOMO
OMOM
O
HO
MOMO
OMOM
Ar
945 947 61
948
Ar = 4-CH3OC6H4
EtO2CCO2Et
OH
OH (i) BnCl 4N NaOH Bu4NBr 50 degC
(i) H2Pd(C) MeOH 2 h(ii) 4-CH3OC6H4CH2MgCl Et2OTHF 14 h
(i) MOMCl iPr2NEt CHCl3 60 degC 36 h
(ii) LiAlH4 Et2O-THF rt 14 h
OMOM
OMOM
HOOH
946 74
(ii) Swern
(i) BnCl 4N NaOH CH2Cl2 Bu4NBr
(ii) SwernBnO
MOMO
OMOM
O
Ar
950 64
OH+HO
MOMO
OMOM
Ar
OH
69 ratio (948949) 7921
949
Scheme 99 Iida et als total synthesis
Treatment with zinc borohydride provided alcohol 951 with perfect control of
the diastereoselectivity (gt991) via chelation control (Scheme 910) The
pyrrolidine ring was easily accessed from the monoazide 953 prepared after
debenzylation and mesylation of alcohol 951 Hydrogenation of the monoazide
109
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
953 gave an amine which spontaneously cyclised via a concerted intramolecular
displacement of the mesylate and produced after MOM-deprotection the
deacetylanisomycin 92 Common problems of random acetylation of
intermediate 92 were overcome by doing a selective protection of the less
hindered C-4 hydroxyl group with bulky TBDMSCl followed by acetylation and
deprotection reactions The bulky silyl protecting group approaches from the
less sterically hindered side thus the opposite side to the bulky p-
methoxybenzyl group at the C-2 position
BnOMOMO
OMOM
Ar
OHMsO
MOMO
OMOM
Ar
OMs
NH
OHHO
Ar
()-91 62
951 91 952 87
()-92 76
(i) BnOCOCl Na2CO3 CH2Cl2 rt 25 h(ii) TBDMSCl DMF rt 1 h
(iii) a-Ac2O Pyr b- Bu4NF(iv) H2Pd(C)
(i) H2Pd(C) MeOH 1 h
(i) H2 Pd(C) MeOH 1 h
(ii) HCl(aq) MeOH reflux 20 h
BnO
MOMO
OMOM
O
Ar
950
Zn(BH4)2
Et2O 0 degC to rt 50 min
NaN3 DMF80 degC 05 h
N3
MOMO
OMOM
Ar
OMs
953 45
NH
OAcHO
Ar
(ii) MsCl Et3N CH2Cl2 10 min
Ar = 4-CH3OC6H4
Scheme 910 Iida et als total synthesis
The route presented the advantages that it was original and did not need
separation of diastereoisomers however the sequence was long with an average
of 16 steps in the longest linear sequence (to 91) and an overall yield of 2
from diethyl tartrate Schwardt et al166 proposed a really similar but improved
approach with a 12 steps sequence from diethyl L-tartrate 945 giving 23
overall yield Stereoselective Grignard reaction is a key step and formation of
the pyrrolidine ring proceeds by intramolecular Mitsunobu reaction Then
selective acetylation was carried out after silylation of the C-4 hydroxyl group
and proper protection of the cyclic amine
Although relatively similar Hutin et alrsquos181 concise synthesis (10 steps) of (minus)-
deacetylanisomycin 92 is based on the stereoselective reductive alkylation of
protected trihydroxynitrile 955 prepared from L-tartaric acid derivative 954
(the ester 954 was easily prepared from tartaric acid in three steps) (Scheme
110
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
911) After condensation of 4-methoxybenzylmagnesium chloride with nitrile
955 followed by trans-imination reduction of the imine with sodium
borohydride afforded a 1981 mixture of diastereomers 956 957 in 80 overall
yield from nitrile 955 After separation primary alcohol 958 was prepared
from amine 957 and was then regioselectively mesylated After acidic cleavage
of the acetonide 958 the resulting aminodiol cyclised to give N-
benzyldeacetylanisomycin 959 Catalytic hydrogenation afforded deacetyl
anisomycin 92
COX
t-BuPh2SiOO
O
t-BuPh2SiOO
O
HN
t-BuPh2SiOO
O
HNBn Bn
Ar
H2Pd(C)
EtOAc
Ar = 4-CH3OC6H4
954
956
HOO
O
HNBn
Ar
957
N
HO OH
Ar
BnNH
HO OH
Ar
()-92 90
958 80
CN
t-BuPh2SiOO
O
955 70
959
80 (957956) 8119
(i) NH3 EtOH
(ii) (CF3CO2)2O Pyr CH2Cl2
(i) 4-CH3OC6H4CH2MgCl Et2O(ii) BnNH2 MeOH(iii) NaBH4
TBAF
THF
(i) MsCl Et3N DMAP CH2Cl2(ii) 10 HCl THF then NaHCO3
+Ar
80 from 957
X = OCH3
Scheme 911 Hutin et alrsquos synthesis of deacetylanisomycin
Ballini et al182 used an original route to prepare (minus)-anisomycin 91 from L-
tartaric acid 960 (Scheme 912) The key step consisted of an attack by a
Grignard reagent on the α-carbon atom of a nitrone system 963 The sequence
proceeded in 11 steps to deacetyl intermediate (-)-92 and in 5 overall yield
from tartaric acid 960
111
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
HO2CCO2H
HO
OH
NBn
HO OH
NH
MOMO OMOM
N
MOMO OMOM
ON
MOMO OMOM
OH Ar
NH
HO OH
Ar
Ar = 4-CH3OC6H4
960
(i) (CH3O)2CH2 P2O5
(ii) H2 20 Pd(OH)2
(i) H2 RaNi(ii) 6 N HCl MeOH 11
961 962 45 from 960
963964
()-92 12 from 962
(i) BnNH2
(ii) NaBH4 BF3Et2O
30 H2O2SeO2
ArCH2MgClMgBr2Et2O
ratio (965964) 73
N
MOMO OMOM
OH Ar
965
+ CH2Cl2
Scheme 912 Ballini et alrsquos formal route
95 Chiral pool synthesis from sugars
Carbohydrates constitute one of naturersquos richest sources of chirality and Moffat
and co-workers183 were first to describe syntheses of anisomycin starting from D-
glucose (Scheme 913) The sequence is consistent with production of (minus)-
anisomycin but the optical rotation reported was positive and did not agree
with the literature they cited as in agreement158 They carried out an 18 step
(85 overall yield) synthesis of (minus)-anisomycin 91 starting from the protected
α-D-glucofuranose 966 After conversion into α-D-allofuranose 967 the
epoxide 970 was formed and allowed access to the amino furanose 971
Heating under reflux for 18 h in the presence of sodium acetate led to
cyclisation and after full protection of the amino and hydroxyl groups and
deprotection of the diol the bicycle 973 was produced Oxidative cleavage of
the diol with sodium periodate gave aldehyde 974 Introduction of the aromatic
substituent was carried out as usual with a Grignard reaction Hydrogenation of
benzylic alcohol 975 proceeded by treatment with trimethylsilane in the
112
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
presence of an acid (ionic hydrogenation) and this was followed by acetylation
and removal of the protecting group to give (minus)-anisomycin 91
966 967 80
970 91971
972 73 from 970
975
(ii) Ac2O Pyr(iii) H2Pd(C) EtOH HCl rt
Ar = 4-CH3OC6H4
O
O
O
HO
HO
O(i) RuO2 NaIO4
(ii) NaBH4(iii) TsCl
O
O
OTsO
HO
O
O
O
OTsO
H
O
70 AcOH
dioxane-H2O100 degC
O
O
O
TsO
HHO
HO
968 68
H
(i) BzCl
969 90
O
O
OTsO
HBzO
MsO H(ii) MsCl
MeOHreflux
NaOMeO
O
OTsO
H
HO
H2N
(i) NaN3 DMF NH3Cl 80 degC
(ii) H2Pd
O
N
HO
H
ZH
(i) NaOAc EtOH reflux 18 h(ii) BnOCOCl
O
O
(i) NaOH BnBr DMF
(ii) 90 TFA rt 4 h
O
N
BnO
H
ZH OH
OH
973 90
NaIO4 Et2O-H2O
Et4N+AcO- N
OH
CHO
BnO
Z
974
4-CH3OC6H4MgBrTHF 20 degC
N
OHBnO
Z
Ar
OH
H
(i) Et3SiH 2 TFA CH2Cl2 0 degC
()-91 38
NH
OAcHO
Ar
HCl H
Scheme 913 Moffat and co-workersrsquo total synthesis
A few years later Buchanan et al184 reported a route starting from D-ribose
976 which was very similar to Moffatrsquos sequence (Scheme 914) Reaction with
4-methoxybenzylmagnesium chloride followed by oxidative cleavage of the
resulting diol gave hemiacetal 977 Oxime 978 obtained after reaction with
hydroxylamine hydrochloride was converted into a nitrile derivative 979 which
cyclised when treated with LiAlH4 to give the pyrrolidine 980 After hydrolysis
of the acetonide treatment of diols with hydrogen bromide in acetic acid gave
bromo derivatives 981 which were further converted into epoxide 915 This
113
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
epoxide has already been described as an intermediate in Oidarsquos or
Schumacherrsquos synthesis (Scheme 91 and Scheme 92) Regioselective opening of
the epoxide 915 provided the allylic ether 982 which was then transformed
into an N-benzyl-O-acetyl derivative (minus)-Anisomycin 91 was accessed after
removal of the protecting group by hydrogenation This sequence is relatively
short (11 steps) nevertheless the overall yield of 4 is modest
976 977 72
980
978 99Ar = 4-CH3OC6H4
O OHHOH2C
O O
(i) 4-CH3OC6H4CH2MgCl THF1 h
(ii) NaIO4 EtOH 05 h
OHO
O O
CH2Ar NH2OHHCl
Pyr 3 h
N HO
OO
ArHO
MsCl Pyr1 h 60 degC
MsO
OO
ArN
979 9
HN
O O
LiAlH4
Et2O 3 h
Ar(i) 1M HCl MeOH reflux 3 h
(ii) HBr AcOH 3-5h
HN
OAc
Ar
Br
KOH(aq) MeOH
981
HN
Ar
915 68 from 979
OCHCl3 HClO460 degC 36 h
CH2=CHCH2OHHN
Ar
OHO
()-91 86
HN
Ar
OAcHO
(i) BnBr Et3N CHCl3(ii) Ac2O 60 degC 5 h
(iii) 2M HCl MeOH Pd(C) H2 reflux 48 h
982 60
HN
Ar+
AcO Br
Scheme 914 Buchanan et alrsquos synthesis
The sequence disclosed at the same time by Baer and Zamkanei185 was
advantageous from an economical point of view because it began from D-
galactose which is cheaper than D-ribose or 1256-di-O-isopropylene-D-glucose
966 However the synthesis reported by Yoda et al186 in 1995 was particularly
good (Scheme 915) Commercially available 235-tri-O-benzyl-β-L-arabino
furanose 983 was converted into furanosylamine 984 which reacted smoothly
with 4-methoxybenzylmagnesium chloride in high yield Then under oxidative
conditions the lactam 986 was produced and this was followed by removal of
114
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
N- and O-benzyl protection Treatment with benzyl chloroformate provided the
pyrrolidine 988 Thus (minus)-anisomycin 91 would be available in 9 steps following
Iida173 route for the transformation of pyrrolidine 988 to (minus)-91
(iii) BnOCOCl NaHCO3 MeOH
983 984 quant 985 78
986 63987 99
Ar = 4-CH3OC6H4
O OH
BnO OBn
BnOBnNH2
CH2Cl2
O
BnO OBn
BnONHBn 4-CH3OBnMgCl
THF 78 degCto 0 degC BnO OBn
NHBnHOBnO Ar
PCCCH2Cl2
BnN
BnO OBn
ArO
Pd(black)HCOOH
MeOH
BnN
HO OH
ArO(i) LiAlH4 THF
(ii) Pd(black) HCOOH MeOH
ZN
HO OH
Ar
988 77
Scheme 915 Yoda et alrsquos synthesis
In 1989 a route to (minus)-anisomycin 91 from (S)-epichlorohydrin 989 prepared
from D-mannitol was reported (Scheme 916)187 The (S)-oxirane 991 was
isolated after treatment of (S)-epichlorohydrin 989 with a cyanylcuprate
derived from 4-bromoanisole and then treatment of alcohol 990 with
methanolic potassium carbonate Interestingly Takano et al showed that the
(R)-enantiomer 989 can be converted into (S)-oxirane 991 as well However a
longer route is required The oxirane 991 was easily transformed into amide
994 through a series of simple reactions Then the amide 994 was exposed to
3 eq of iodine in aqueous acetonitrile for 3 days and provided the pyrrolidine
996 as a 21 mixture of epimers at C-4 Without separation the mixture was
successively submitted to N-protection O-debenzoylation and O-activation and
finally 3-pyrroline 99 was isolated as the major regioisomer (the minor being 4-
pyrroline) after conversion of compound 996 into xanthate 997 and then
elimination upon thermolysis in O-dichlorobenzene (ODB) at reflux
115
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
O
H
O
H
Cl Ar
Ar = 4-CH3OC6H4
ArHO H
ArBzHN H
NH
Ar
(ii) NaOH (CH2OH)2 120degC
NH
BzO
Ar
(S)-989 (S)-991 74
992 85994
996 90
()-99 62
H
4-CH3OC6H4Li-CuCN H
Ar
990
Cl OH
K2CO3
THF 78 degC
lithium acetylide ethylene diamine complex DMSO
(i) H2 Pd(CaCO3) EtOAc
(ii) phthalimide DIAD PPh3 THF 20 degC
ArPhth=N H
993
(i) H2NNH2 EtOH reflux
(ii) BzCl Et3N CH2Cl2
64 overall yield
ArNH
997 87
O
I
Ph
I2 H2O-MeCN
(i) BnOCOCl Et3N CH2Cl2(ii) K2CO3 MeOH
(iii) CS2 NaOH nBu4NHSO4 then MeIC6H6
NZ
MeS2CO
Ar
H
(i) ODB reflux
995
MeOH
Scheme 916 Takano et alrsquos formal synthesis
Reddy et al167 gave another approach starting from D-mannitol and providing
(+)-deacetylanisomycin 92 Grignard reaction and intramolecular cyclisation
reactions are key steps in the the formal synthesis of (+)-anisomycin (11 overall
yield in 10 steps)
An asymmetric amidation of (2S3S)-pent-4-ene-123-triol 999 derived from L-
threitol was a key step in Kang and Choirsquos188 total synthesis of (minus)-anisomycin 91
(Scheme 917) Reaction of acetimidate derivative 999 with iodine
monobromide afforded 6-membered ring giving a mixture of isomers 9100
Methanolysis and Boc protection allowed isolation of the all syn-isomer 9101 in
good overall yield from acetimidate 999 After total protection of hydroxyl
groups and formation of aziridines 9102 9103 the aromatic substituent was
introduced using an organocuprate Then the pyrrolidine 9105 was formed
116
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
under Mitsunobu conditions and this was followed by silylation acetylation and
finally N-Boc deprotection under acidic conditions (minus)-Anisomycin 91 was
produced over 16 steps A really similar but nevertheless shorter route (12 steps)
was published in 1996 by Veith et al189 starting from L-threitol using a Grignard
reaction as the key step
TBSO
OO
OH
RO
OR
OR
O N
OR
I
CCl3
OR
R3O
OR2
OR1
NBoc
OH
OH
OH
NHBoc
Ar
NBoc
HO OH
Ar
(i) TBSCl imidazole DMF 20 degC(ii) Ac2O DMAP Et3N CH2Cl2 20 degC
(iii) HCl MeOH 20 degC
Ar = 4-CH3OC6H4
R = C(=NH)CCl3
998 999 78 9100
9102 R1 = H R2 = R3 = CMe2
9105
HO
OH
OH
INHBoc
9101 75 from 999
9103 R1 = R2 = CMe2 R3 = H
(i) Swern (ii) Ph3P=CH2 THF HMPA 0 degC
(iii) HCl(aq) THF 20 degC(iv) CCl3CN DBU MeCN30 degC
IBr K2CO3
EtCN 60 degC
(i) HCl MeOH 20 degC(ii) Boc2O 0 degC
(i) CF3CO2H acetone 20 degC
(ii) LDA THF 20 degC
9102 and 9103 77
(i) 4-CH3OC6H4MgBr CuBr-Me2S PhMe 30 degC
(ii) CF3CO2H 20 degC(iii) Boc2O NaHCO3 MeOH 0 degC
9104 81
DEAD Ph3PPPTS THF 0 degC
NH
HO OAc
Ar
()-91 88
Scheme 917 Kang and Choirsquos total synthesis
96 Asymmetric synthesis
(minus)-Anisomycin 91 was accessed from the allene 9106 bearing a fructose
derivative (DAF) 9107 as a chiral auxiliary in 10 steps in 8 overall yield
(Scheme 918)168 Since none of the chiral centres or atom of DAF are included in
the final product this is an asymmetric synthesis rather than a synthesis from the
chiral pool DAF-allene 9106 was deprotonated with BuLi and condensed with
sulfonyl derivatives 9108 to afford compound 9109 in good yield but as a 21
mixture of isomers Submitted to strongly basic conditions compound 9109
cyclised and produced the two diastereoisomers 9110 in 65 HPLC permitted
117
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
isolation of (2R)-9110 in 38 yield By treatment with HCl(aq) pyrroline (2R)-
9110 was converted into 2-substituted N-protected pyrrolidinone (2R)- 9111 in
good yield Then conversion of pyrrolidinone 9111 into enol ether 9112 was
followed by hydroboration (BH3 in THF) and oxidative work up and afforded the
monoprotected diols with high yield and excellent diastereoselectivity A one
pot O-Boc and acetyl protection allowed the formation of intermediate 9114
Last transformations consisted in O- and N-deprotection with HCl in dioxane The
major drawback of the method is the moderate diastereoselectivity of the first
step
ODAF
+
NHBoc
TsAr
Ar = 4-CH3OC6H4
O
OO
OO
ODAF
BocHN Ar
NBoc
ODAF
Ar
NBoc Ar
O
NBoc Ar
OTBDMS
NBoc Ar
BocO OAc
NH2
HO OAc
ArCl
HCl dioxane
9106 9108 9109 73
9111 899112 68
9114 83 ()-91 66DAF 9107
BuLi THF78 degC 20 min
then 50 to20 degC 4 h
(i) KOtBu DMSO 50 degC 8 h
(ii) prepHPLC
(2R)-9110 38(2S)-9110 9
6N HClTHF 2 h
(a) LDA THF 45 min 78 degC
(b) tBuMe2SiCl DMPU 05 h 78 degC to rt
BH3THF THF30 degC to rt3 h
then NaOH H2O210 degC to rt 12 h
9113 89
(i) Boc2O DMAP 12 h rt(ii) Bu4NF THF 12 h rt then Ac2O CH2Cl2 Et3N 0 degC to rt 12h
0 degC 35 h
NBoc Ar
HO OTBDMS
Scheme 918 Kaden et alrsquos total synthesis
An asymmetric synthesis of the unnatural enantiomer (+)-anisomycin 91 was
based on an enantioselective alkylation using a chiral auxiliary (Scheme 919)172
Treatment of dihydropyrrole 9115 with (S)-valinol derivative 9116 provided
the key intermediate 9117 Metallation followed by treatment with p-
methoxybenzyl chloride produced regioisomeric compounds 9118 and 9119
resulting from direct and allyl transposed alkylation When treated with
118
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
hydrazine the free amine 99 was obtained from compound 9118 whereas the
undesired compound 9119 decomposed The synthesis was then continued
according to the route established by Schumacher and Hall170 and described
earlier (Scheme 92) The (+)-anisomycin 91 was accessed in 11 steps and in 22
overall yield from key intermediate 9117 and 85-90 ee The use of (R)-valinol
would undoubtedly furnish the natural anisomycin
NH
N
Me2N
O
+N
N
ON
+N
Ar
NH
VBE VBE
Ar
Ar
Ar = 4-CH3OC6H4
(+)-91 98
(i) Zn-HOAc-THF 25 degC
(ii) H2Pd(C) MeOH
9115 9116 9117 90 9118 9119
99
NZ
Ar
9120 52
O
VBE=N
O
PhMe
reflux
(a) t-BuLi THF-Hex 110 degC 15 min
(b) 4-CH3OC6H4CH2Cl
53 from 9117
N2H4
(i) PhCH2OCOCl CH2Cl2 Et3N 25 degC
(ii) HClO4(aq) 0 degC NIS KOH
(i) H2Pd(C) MeOH 2 h(ii) NaO2CCF3-TFA 120 degC
(iii) PhCH2OCOCl THF Na2CO3
NZ
Ar
HO OH
9121 95
(i) CCl3CH2OCOCl DMAP CH2Cl2(ii) Ac2O DMAP
NZ
Ar
CCl3H2COCO OAc
9122 76
NH
HO OAc
Ar
Scheme 919 Meyer and Dupreacutersquos total synthesis
In 1991 a team published a relatively long total synthesis (19 steps) of (minus)-
anisomycin 91 relying on Sharpless oxidation and epoxidation190 The cyclisation
to obtain the pyrrolidine ring appeared in an early stage of the synthesis and
then the synthesis was built around the ring whereas most of the syntheses seen
so far formed the ring in a late step A few years later Shi and Lin191 prepared
(minus)-anisomycin 91 (in 10 steps and 12 overall yield) via Sharpless asymmetric
epoxidation and Sharpless asymmetric dihydroxylation reaction begining from
divinylcarbinol 9123 (Scheme 920) DHQ-CLB (Figure 92) was used as the
119
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
chiral ligand in the dihydroxylation and K3Fe(CN)6 as co-oxidant The pyrrolidine
ring was formed by intramolecular alkylation
Ar = 4-CH3OC6H4
OH
O
OSiMe3 OSiMe3
OMs
Ar
OH
Ar
N3
OAc
Ar
N3OMs
TBDMSO
OAc
Ar
N3O
OAc
Ar
N3
Br
OH
NH
OAcHO
Ar
(i) H2 10 PdC rt 1 atm 2 h (ii) NaOAc MeOH reflux 10 h
9123 9124 65
9126 75
9128 69 9129 91 9130 90
()-91 58
9125 80
(i) D(-)-DIPT TBHP Ti(OiPr)4 CH2Cl2 20 degC
(ii) TMSCl Et3N DMAP CH2Cl2
(i) 4-CH3OC6H4CH2MgBr CuI (10) THF 10 degC
(ii) MsCl Pyr CH2Cl2 rt
NaN3 DMF80 degC 7 h then 2N HCl
OsO4 K3Fe(CN)6K2CO3 DHQ-CLB
OH
Ar
N3OH
HO
(i) TBDMSCl imidazole DMF 0 degC
(ii) AcCl Pyr CH2Cl2 rt 2 h then MsCl 4 h
tBuOH water
Bu4NF THF
0 degC 1 h
LiBr HOAc
THF rt 24 h
9127
Scheme 920 Shi and Linrsquos total synthesis
N
MeO
N
DHQ-CLB
OH
OHO
OO
O
D-()-DIPT
OZ
Figure 92 Reagents used in Shirsquos synthesis
120
Guilaine F Blanc Chapter 9 Previous Syntheses of Anisomycin
Finally Nomura and Richards192 recently published a synthesis of anisomycin 91
Pyrroline 9137 was rapidly accessed from trichloroacetimidate 9132 after
Overman rearrangement and RCM The use of chloride-bridged cobalt oxazoline
palladacycle catalyst 9131 (Figure 93) gave trichloroacetamide 9133 in high
yield and an ee of 91 After hydrolysis and Z-protection allylation proceeded
satisfactory to give amino diene 9135 Then RCM with Grubbs II catalyst 9136
(= 714 see Scheme 74) allowed isolation of pyrroline 9137 with an overall
yield of 58 Nomura suggested that (+)-anisomycin could then be accessed by
following the routes of Schumacher170 or Meyers172
PdCl
2
N
O
iPr
Co
Ph Ph
Ph Ph
9131
Figure 93 Chloride-bridged cobalt oxazoline palladacycle catalyst
HN
OCl3C
HN
Cl3C O
ZHN
ZNZN
Ar = 4-CH3OC6H4
2 mol Grubbs II 9136
9132 9133 89 9134 76
9135 789137 98
Ar Ar Ar
ArAr
075 mol 9131
91 ee
MeCN 70 degC 48 h
(i) NaOH MeOH 50 degC 12 h
(ii) BnOCOCl THF NaHCO3 rt 15 h
(a) NaH THF(b) allyl bromide rt 12 h
CH2Cl2 rt 15 h
Scheme 921 Nomura and Richardsrsquo formal synthesis of (+)-anisomycin
121
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
10 A Titanium Reagent Based Approach to the
Synthesis of Anisomycin
About 25 syntheses of anisomycin 101 (=91 see Figure 91) or its precursor
deacetylanisomycin 102 (=92 see Figure 91) have been reported since 1970
All syntheses of this natural product containing only three stereogenic centres
involve many steps168 The main structural problem is the existence of an
acetoxy and a hydroxyl group in an anti-arrangement More efficient approaches
to anisomycin are of continuing interest Meyers has proposed that ldquoThose
engaged in asymmetric synthesis should periodically prepare the unnatural
enantiomer to demonstrate that the method truly fulfils the requirements set
forth and provide those enantiomers which are either available in very short
supply or are in fact nonexistentrdquo172 Following Meyersrsquo wisdom we initially
proposed to make (+)-anisomycin 101 from (S)-tyrosine 103 (=93 see Scheme
91) which is the natural enantiomer of the amino acid (Scheme 101) The
originality in our sequence would reside in the alkylidenation of benzyl ester
104 using a titanium carbenoid as a key step followed by a ring closing
metathesis reaction to form the pyrroline 107 Hydroboration would then give
the key 34-anti relationship in alcohol 108 This would then be easily
converted into (+)-anisomycin 101 by taking advantage of the orthogonality of
protecting groups according to Iidarsquos and Kadenrsquos works (Scheme 910 Scheme
918)168173
HONH2
CO2H
MeOBocN
CO2Bn
MeOBocN
OBn
MeOBocN
OBn
MeO
23
45BocN1
OBn
MeOHN
OAc
OHOH
R
(+)-101
(S)-103 104 105 R = H
107108
106 R = Me
Scheme 101 Proposed strategy
122
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
101 Introduction to the first approach based on
tyrosine as starting material
First steps of the sequence involved introducing orthogonal protecting groups
and methylation of tyrosine The carboxylic acid would be protected as a benzyl
ester and N-Boc-protection would be used for the amino group The order of
these reactions can be varied Our initial investigation started with benzylation
of the carboxylic acid and then N-Boc-protection and O-methylation
102 Preparation of N-allyl esters
Benzylation of (S)-tyrosine (S)-103 was attempted following various different
processes (Scheme 102 Table 101)
HONH2
CO2H
HONH3
CO2Bn
(S)-103 109
HONHBoc
CO2Bn
1010
MeONHBoc
CO2Bn
1011
conditions
see table 101
conditionssee table 102
Cl
Scheme 102 Strategy A
Esterification of (S)-tyrosine (S)-103 using benzyl alcohol p-toluenesulfonic
acid and p-toluenesulfonyl chloride (Table 101 entry 1) yielded the
hydrochloride salt 109 while reaction with benzyl alcohol in presence of thionyl
chloride (entry 2) failed to give the desired product and left starting materials
unreacted
123
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
Entry (S)-Tyr BnOH Reagents Conditions Yield of 109
1 10 eq 192 eq p-TsOH (10 eq) p-TsCl (12 eq) 80 C 15 h 74
2 10 eq 170 eq SOCl2 (11 eq) or (25 eq)
rt then reflux 25 h -
3 10 eq 29 eq p-TsOH (11 eq) MW 300 W
rt 60 s -
4 10 eq 52 eq TPA (37 eq) THF rt 05 h -
5 10 eq 35 eq AcCl (30 eq) Reflux 4 h 23
6 10 eq 45 eq Conc HCl Benzene 100 C 25 h 40
Table 101 Benzylation conditions
More original methods were investigated such as p-toluenesulfonic acid under
microwave irradiations (Table 6 entry 3) or use of triphosgene (TPA) (entry 4)
however all attempts were unsuccessful Another noteworthy method (entry 5)
adapted from the procedure of Hulme and Rosser176 used benzyl alcohol and
acetyl chloride at reflux for 4 hours but the yield was modest The optimum
result obtained was using benzyl alcohol and concentrated HCl in benzene (entry
6) a procedure described by Viswanatha and Hruby193 The main problem in
using benzyl alcohol is its removal at the end of the reaction Its boiling point is
203 degC under atmospheric pressure Removal by distillation was attempted but
most of the time the crude mixture appeared to decompose before the total
removal of the alcohol Moreover in many attempts the number of equivalents
of benzyl alcohol used was such that the benzyl alcohol hid both reactant and
product in the 1H NMR spectrum of the crude mixture The relatively low
solubility of the salt 109 in common deuterated solvents appeared to be
another issue in analysing the compound Thus we decided to carry out the N-
Boc protection of compound 109 without further attempts at optimisation of
benzylation in order to check the good progress of the sequence but keeping in
mind that the benzylation step had to be optimized later
Five different conditions were tested for N-Boc protection of benzyl ester 109
(Scheme 102) Methods such as Boc anhydride in the presence of sodium
bicarbonate ethanol or in presence of water were not effective (Table 7
entries 1-3) They left starting material unreacted On the other hand an
adaptation of the procedure reported by Hirai et al194 proved to be the
124
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
optimum method (entry 4) giving N-Boc-(S)-tyrosine benzyl ester 1010 in high
yield with no purification needed Another reaction deserved our attention
(entry 5) Using Boc anhydride in cyclohexane overnight195 the desired
compound 1010 was observed in the crude mixture with a small impurity As a
purification step was required we preferred the previous conditions
Entry Ester 109 (eq) Boc2O (eq) Reagents Conditions Yield of 1010
1 10 15 NaHCO3 (2 eq) THFMeOH
rt on SM
2 10 11 H2O 30 oC 25 h SM
3 10 10 EtOHNaHCO3 rt on SM
4 10 11 Et3N (16 eq) H2Odioxane
rt on 87
5 10 10 cyclohexane rt on 86a a minor impurity present
Table 102 Conditions for N-Boc protection
Having optimum conditions in hand for the amine protection but issues with
formation of the benzyl ester we considered reversing the two first steps and
thus beginning the sequence with N-Boc protection of the free amine 103
followed by O-methylation of the phenol 1012 and finally benzylation of the
acid 1013 (Scheme 103)
HONH2
CO2H
HONHBoc
(S)-103 1012
MeONHBoc
CO2H
1013
MeONHBoc
CO2Bn
1014
CO2H
Scheme 103 Strategy B
N-Protection of (S)-tyrosine (S)-103 was carried out according to the procedure
described above (Scheme 104) N-Boc-(S)-tyrosine 1012 was obtained
quantitatively O-Methylation of the free phenolic hydroxyl group using
125
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
iodomethane (15 eq) and potassium carbonate in DMF overnight provided a
4159 mixture of the acid 1013 and the methyl ester 1015 whereas the use of
only 10 eq of MeI improved this ratio to 8812
HONH2
CO2H
(S)-103
HONHBoc
CO2H
1012 100
H2Odioxanert on
Boc2O (11 eq)Et3N (15 eq)
MeI (1 eq)K2CO3 (15 eq)DMF rt on
MeONHBoc
CO2H
88ratio (10131015) 8812
MeONHBoc
CO2Me
+
1013 1015
Scheme 104 First results in strategy B
Purification of acid 1013 was attempted but proved unsucessful and so without
further efforts to improve conditions attempts were made at benzylation of this
mixture
Esterification using the coupling reagent DCC and the nucleophilic catalyst DMAP
provided traces of the ester 1011 (Scheme 105) Results were not encouraging
and I proved to be allergic to DCC so further attempts at benzylation using this
method were deemed too risky The use of benzyl bromide in the presence of
cesium carbonate and potassium iodide in DMF left starting materials unreacted
MeONHBoc
CO2H
MeONHBoc
CO2Bn
BnOH (11 eq) DMAP (01 eq)DCC (11 eq)
BnBr (11 eq) Cs2CO3 (3 eq) KI (5 eq) DMF 80 degC on
1013 (+ 1015) 1011 4
1011
CH2Cl2 25 degC 45 min
Scheme 105 Benzylation conditions
126
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
At the same time a slightly different option stood out (Scheme 106) Allylation
of the N-Boc protected amine 1013 would be done prior to benzylation of the
acid functionality
MeONHBoc
CO2H
1013
MeOBocN
CO2H
MeOBocN
CO2Bn
1016 104
Scheme 106 Strategy C
The 8812 mixture of 1013 and 1015 reacted with allyl bromide in presence of
sodium hydride and provided mainly N-allyl-N-Boc-O-methyl-(S)-tyrosine 1016
and traces of a minor compound which might be compound 1017 (Scheme
107)110 The presence of the desired acid was only confirmed from the 1H NMR
spectrum of the mixture [1H NMRof the acid 1016 (400 MHz CDCl3) 134
(9H s tBu) 290-320 (2H m CH2-3) 330 (3H s OMe) 442-453 (2H m
CH2N) 493 (1H br s CH-2) 533 (1H d J 168 Hz =CHAHB) 519 (1H d J 105
Hz =CHAHB) 592-602 (1H m CH=CHAHB) 676 (2H d J 80 Hz H3rdquo and H5rdquo)
694-703 (2H m H2rdquo and H6rdquo)] The mixture was used without further
purification in the benzylation reaction as compounds were not separable (Table
103)
MeOBocN
CO2HDMF rt 25 h
allyl bromide (13 eq)NaH (23 eq)MeO
NHBoc
CO2H
1013 (+ 1015) 1016
MeOBocN
CO2Bn
Conditions
see table 103
104
MeOBocN
+
ratio (10161017) 802076
1017
O
O
Scheme 107 Synthesis of fully protected tyrosine 104
127
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
All benzylation conditions tested are summed up in Table 103 Firstly reactions
carried out with benzyl bromide in presence of potassium carbonate or cesium
carbonate (entries 1-4) left starting materials unreacted After benzylation with
benzyl alcohol and acetyl chloride (entries 5-6) adapting the conditions
reported by Hulme and Rosser176 distillation of the alcohol led to the
decomposition of the crude material before dryness A last reaction was
attempted with benzyl bromide in the presence of sodium hydride (Table 3
entry 7) Unfortunately unreacted starting materials were recovered
Entry Acid 1016
Reagents Conditions Results
1 10 eq BnBr (2 eq) K2CO3 (4eq) DMF rt 3 h SM
2 10 eq BnBr (2 eq) K2CO3 (4 eq) DMF rt on SM
3 10 eq BnBr (2 eq) Cs2CO3 (6 eq) KI (10 eq)
DMF 80 degC on SM
4 10 eq BnBr (18 eq) Cs2CO3 (38 eq) KI (94 eq) DMF 80 degC on SM
5 10 eq BnOH (65 eq) AcCl (3 eq) reflux 4 h decomposed
6 10 eq BnOH (20 eq) AcCl (1 eq) reflux 4 h decomposed
7 10 eq BnBr (2 eq) NaH (2 eq) DMF rt 2 h SM
8 10 eq Triazene 1019 (25 eq) 5N HCl Et2OTHF rt on decomposed
Table 103 Benzylation conditions
An alternative approach to benzylation was then investigated with a triazene
reagent 1019 The chemistry and applications of triazenes have a long history
dating back to the 19th century196 The most convenient synthesis of triazene
1019 was provided by Mangia and Scandroglio197 The synthesis involves
reacting p-toluidine 1018 with potassium nitrite in acidic conditions (Scheme
108) Benzylamine is then added to the diazonium salt to form the 1-benzyl-3-p-
tolyltriazene 1019 However benzylation of acid 1016 using triazene reagent
1019 was unsuccessful (Scheme 107 Table 103 entry 8) Indeed after 12 h
and appropriate work-up an intractable mixture was obtained
128
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
NH2
(a) KNO2 HCl-H2O 10 degC 2 h
(b) benzylamine 10 degC 4 h
1019 1001018
NN N
Scheme 108 Synthesis of the triazene reagent 1019
Lastly a paper published by Rosenberg et al198 provided a solution to our
problem They reported a one-pot methylation-benzylation of the N-Boc-(S)-
tyrosine 1012 and therefore gave us a new route to exploit (Scheme 109)
HONHBoc
CO2H
MeONHBoc
CO2Bn
MeOBocN
CO2Bn
1012 1011 104
Scheme 109 Strategy D
Sodium hydride and iodomethane were successively added to a solution of N-
Boc-(S)-tyrosine 1012 in DMF followed by addition of benzyl bromide to give a
964 mixture of methyl ether 1011 and phenol 1020 (Scheme 1010)
HONHBoc
CO2H
MeONHBoc
CO2Bn
1012
1011(a) NaH (24 eq) DMF 0 degC 1 h
HONHBoc
CO2Bn
+
ratio (10111020) 964
84
(b) CH3I (1 eq) 0 degC 3 h(c) BnBr (11 eq) rt 2 h
1020
Scheme 1010 One pot O-methylation-benzylation
Separation being impossible the mixture was allylated without further
purification following the procedure previously described (Scheme 1011) This
gave the desired precursor for alkylidenation
129
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
MeONHBoc
CO2Bn
1011 (+ 1020)
MeOBocN
CO2Bn
104 51
(13 eq) NaH (13 eq)
DMF rt 25 h
Br
Scheme 1011 N-allylation
103 Analysis of complexities in NMR data of esters
The 1H NMR spectrum of ester 104 appeared more complicated than might be
expected Indeed in carbamates as in amides the rotation about the C-N bond is
slow because of delocalization of the nitrogen lone pair (Figure 101) At room
temperature this rotation is not fast enough on the NMR timescale causing
broadening of the peaks or sometimes resulting in two sets of signals ie a
mixture of rotamers This may also be observed in the 13C NMR spectrum
CO2Bn
NO
O
ArCO2Bn
NO
O
ArCO2Bn
NO
O
ArCO2Bn
NO
O
Ar
Ar = 4-MeOC6H4
C-N rotation
Figure 101 Rotamers of carbamate 104
The rate of the rotation is defined by the Arrhenius equation (where A is a pre-
exponential factor R is the gas constant Ea is the activation energy and T the
temperature of the analysis)
RT
Ea
eAk Arrhenius Equation
The exponential term is a function of the temperature Therefore increasing
the temperature of the analysis has the effect of increasing the rate of the
rotation so that the 1H NMR spectrum reflects an average of the two rotamers A
130
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
well-resolved average spectrum was observed at T= 363 K (ie 90 degC) This
phenomenon was observed for all tertiary carbamates
This 1H NMR analysis highlighted another phenomenon diastereotopicity of
protons (Figure 102) Indeed C-3 and C-1rsquo methylene units have diastereotopic
protons because of the stereogenic centre nearby and in each case the geminal
protons appear as two different signals in an ABX system One double doublet is
observed for HB-3 with a geminal coupling constant (141 Hz) and a trans-vicinal
coupling constant (91 Hz) whereas HA-3 appears as one double doublet with a
gauche vicinal coupling constant (61 Hz) and a geminal coupling constant (141
Hz)
32
NBoc
1
Ar
HDHC
HBHA
Ar = 4-MeOC6H4
JAX 61 Hz
JAB 141 Hz JAB 141 Hz
JBX 91 Hz
HB-3
O
O Ph
HFHE
104
BocHB
= 320 ppm = 305 ppm
HA-3H
BnO2C N
HAAr
104
Figure 102 Diastereotopicity
The benzylic protons HE and HF are diastereotopic too (Figure 102) However in
compound 104 HE and HF have the same chemical shift and appear as a singlet
on the other hand in compound 1011 they are different and appear as two
doublets with a J value of 12 Hz
104 Titanium-based strategies for ring-closing
Alkylidenation of ester 104 was investigated using standard conditions
established in the Hartley group100 employing the Petasis reagent 1021 (=614
131
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
see Scheme 65) under microwave irradiations for 10 min (Scheme 1012) The
substrate decomposed under these conditions whereas an attempt at
methylenation using dimethyltitanocene 1021 without microwave irradiation
left the starting material unreacted
MeO
CO2Bn
BocNMeO
BocN
OBnor Cp2TiMe2 1021 65 degC on
Cp2TiMe2 1021 MW 65 degC 10 min
104 105
Scheme 1012 Methylenation using Petasis reagent
Following an adaptation of Takairsquos procedure reported by Rutherford et al199
the titanium carbenoid formed in situ from titanium tetrachloride zinc and 11-
dibromoethane in the presence of TMEDA transformed ester 1022 into enol
ether 1023 in modest yield (Scheme 1013) Therefore adaptation of this
procedure to our substrate 104 was expected to generate enol ether 106
(Scheme 1014) Unfortunately the benzyl ester 104 which is very sterically
hindered did not react under Takai conditions Thus we had to consider
another way of forming the pyrrolidine ring
OMe
O
OMeTiCl4 TMEDA Zn PbCl2 CH2CHBr2
THF rt 38 h1022 1023 58
Scheme 1013 Alkylidenation under Takai conditions
MeO
CO2Bn
BocN TiCl4 TMEDA Zn PbCl2 CH2CHBr2
MeOBocN
OBn
104 106
THF 4 h rt
Scheme 1014 Alkylidenation under Takai conditions
Alkene 104 was converted into aldehyde 1024 which we hoped could be
cyclized using low valent titanium chemistry (Scheme 1015) Attempted
132
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
cyclisation using McMurry conditions provided an intractable mixture200201 while
reaction at room temperature with a low valent titanium reagent prepared from
titanocene dichloride and iPrMgCl left the starting aldehyde 1024
unreacted5056 Increasing the temperature of the reaction did not provide any
improvement Indeed heating under reflux in THF for 15 h caused
decomposition of the substrate
MeO
CO2Bn
BocNMeO
CO2Bn
BocNO
K2OsO4H2O NaIO4
THF H2O 05 h rt
MeOBocN
O
MeOBocN
OBn
OH
TiCl3 LiAlH4Et3N DMEreflux 23 h
104
107
1024 60
1025
Cp2TiCl2 iPrMgCl THF rt or reflux 15 h
Scheme 1015 Formation of 5-membered ring
The next route we considered required the formation of thioacetal 1026 from
aldehyde 1024 in order to perform an intramolecular alkylidenation under
Takeda conditions Reaction of the aldehyde 1024 with thiophenol and BF3OEt2
in acetic acid led to removal of the Boc group and provided the free amine
1027 in modest yield (Scheme 1016) Furthermore the reaction suffered from
problems of reproducibility as thioacetal 1027 was not observed afterwards
despite several later attempts at this transformation An attempt to reprotect
amine 1027 failed under standard conditions
133
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
OMeO
CO2Bn
BocN PhSH BF3OEt2
AcOH PhMe 4 h rt
MeO
CO2Bn
HNSPh
SPh
MeO SPhBocN
SPhCO2Bn
Boc2OH2O-dioxanert on
PhSH BF3OEt2 AcOH PhMe 4 h rt
1024
1027 20
1026
Scheme 1016 Formation of thioacetal
The conditions of thioacetal formation were changed to overcome the problem
of deprotection of the amine 1024 (Scheme 1017) First the reaction was
attempted in non-acidic conditions with sodium sulfate or molecular sieves as
dehydrating agents After overnight reactions starting materials were recovered
unchanged Ceschi et al202 reported a chemoselective dithioacetalization of
aldehydes catalyzed by indium tribromide The same procedure adapted to our
substrate 1024 led to a mi
identified
xture of impurities nothing noteworthy was
PhSH MS
CH2Cl2 rt on
PhSH InBr3
CH2Cl2 rt on
PhSH Na2SO4
CH2Cl2 rt on
MeO
CO2Bn
BocNO
1024
1026 1026
1026
Scheme 1017 Attempts of dithioacetalization
nding
of the issues and allow pursuit of an appropriate solution
Taking into consideration difficulties met through this sequence we decided to
test the route with a simple substrate which would allow a better understa
134
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
105 Model studies using glycine-derivatives
The purpose of this new route was to reproduce the sequence previously
described using glycine ethyl ester 1028 and vary conditions and protecting
groups in order to get a better control of the situation (Scheme 1018)
OEt
O
H2NOEt
O
NR1 OEt
NR1 N
OEt
R1N
OEt
1R
OH
R1 = Boc 1029R1 = ArSO2 1030R1 = Bn 1031
1028 1032-1034 1035-1037 1038-1040
Scheme 1018 Model sequence with glycine ethyl ester 1028
Amino acid 1028 was N-Boc protected in quantitative yield and this was
followed by allylation of the secondary amine 1041 to give the carbamate
1029 in high yield (Scheme 1019) A first attempt at methylenating the ester
1029 using the Petasis reagent 1021 under microwave irradiation was
unsuccessful The compound was lost during the purification of the crude
mixture due to instability and difficulty in detecting it Furthermore the use of
carbamates gave rise to the problem of rotamers making spectroscopic analysis
difficult
OEt
O
H3NOEt
O
BocHNOEt
O
BocN
allyl bromideBoc2O Et3N
H2Odioxane
NaH
DMF rt 35 hCl
rt on
i) Cp2TiCl2 1021 10 min 100 W 65degCii) NaHCO3 MeOH H2O 40 degC on
1028 1041 100 1029 91
OEtBocN
1032
Scheme 1019 Carbamate series
135
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
Since we had also shown that N-Boc protection does not survive the use of boron
trifluoride in the preparation of thioacetals the protection of the amino group
was changed
Sulfonamides presented an opportunity to overcome difficulties met with
carbamates They do not give rise to rotamers and should survive the formation
of the thioacetal The ethyl ester of glycine 1028 was protected with tosyl
chloride to give sulfonamide 1042 in high yield (Scheme 1020)203
OEt
O
H3NOEt
O OTsHN
OEtTsNTsCl
CH2Cl2 rt 45 h
Et3Nallyl brNaH
omide
DMF rt 2 h
TsN
Conditions see table 104
1033
1028 1042 80 1030 63
Cl
OEt
Scheme 1020 Sulfonamide series
Allylation of sulfonamide 1042 then provided the ester 1030 in good yield
Various conditions were attempted for methylenation of the ester 1030 using
the Petasis reagent 1021 (Table 104) Entry 1 reaction under Hartley group
conditions resulted in formation of a complex mixture Due to the instability of
the enol ether on silica we chose to submit this crude mixture to acidic
treatment in order to obtain the ketone derivative 1043 which might be
purified by chromatography Thus treatment of the mixture with 1 M HCl in THF
ion and loss of the allyl chain However sulfonamide
1044 was not totally clean and due to it y and high volatility this
for 1 h provided the ketone 1043 in very low isolated yield The isolation of
ketone 1043 is proof of the formation of enol ether 1033 and consequently the
success of the reaction Nevertheless conditions needed to be improved The
same conditions were reproduced with chromatography on alumina as a
purification step and this gave both the enol ether 1033 and a side-product
1044 formed by methylenat
s instabilit
compound was only identified by 1H NMR spectroscopy
136
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
Conditions were obviously too harsh At the same time methylenation was
carried out under milder conditions (Ta entry 3) and the result
confirmed our supposition Microwave irradiation caused break down of the
molecule whereas thermal conditions allowed the conversion of the ester 1030
into enol ether 1033 ter 72 h of reaction the yield obtained
remained modest (entry 5)
ble 104
but even af
Entry Cp2T 21 iMe2 10 Conditions Purification Result system
Ts O
1 30 eq MW 1 M HCl THF
1043 5
N65degC 10 min
NOEtTs
R
2 30 eq 65degC 10 min Al2O3 column MW
1033 R = allyl 211044 R = H 37
3 30 eq 65degC 95 h Al2O3 column 1033 25
4 30 eq 65degC 24 h Al2O3 column 1033 38
5 30 eq 65degC 72 h Al2O3 column 1033 39
Table 104 Methylenation conditions
With the enol ether 1033 in hand the ring closing metathesis appeared to be a
good option to generate the pyrroline ring 1036 (Scheme 1021)
TsN
1033
OEt N
OEt
Ts
Conditions
1036
see table 105
Scheme 1021 Ring closing metathesis
Use of Grubbs 1 generation catalyst 1045 (= 713 see st
conditions did not provide the desired compound 1036 as we
recovered starting material (Table 105 entry 1) A second try using 30 mol of
st y ketone and ter acidic treatment and
chroma n entry 2) As explained earlier both ketones
are derived enol e rsors We could then conclude that the ring
closing reaction did not take place Grubbs 2nd generation catalyst 1046
Scheme 74) (6 mol)
under standard
cataly ielded s 1043 1047 af
tography colum (Table 105
ther precu from
137
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
(5 mol) (= 714 see Scheme 74) did not provide any better results (Table
10 entr fter pu we o isolate ketone 1043 in
modest yield
5 y 3) A rification were able t
Entry Catalyst Conditions Treatment Result
1 Grubbs I 1045 6 mol
C15 h 50degC
oncentration SM 1033 H2Cl2 001 M C
Ts O
2 Grubbs I 1045 CH2Cl2 02 M i) 1M HCl-THF 2
1043 65
N30 mol 6 h 50degC ii) SiO column
+ HN
OTs1047 35
3 Grubbs II 1046 CH2Cl2 001 M i) Al2O3 column 1043 46 5 mol 1 h 50degC ii) 1 M HCl THF
Table 105 Ring closing metathesis
It would probably be worth trying the reaction with a higher loading (ie 30
mol) of Grubbs 2nd ion 1046 but the cost of the catalyst discouraged
us An interesting pe ive would be to consider regeneration of the catalyst
in order to use it several times and then lower the cost of the step Research
into catalyst recycling has been done by others and solutions are available with
ionic liquid-supported ruthenium carbene complex204 fluorous polyacrylate
bound ruthenium carbene complex205 polyethylene glycol-supported (PEG)
carbene complex205206207 butyldiethylsilyl polystyrene-supported ruthenium
carbene
generat
rspect
complex208209 vinyl polystyrene-supported ruthenium carbene
complex210 and poly-divinylbenzene-supported ruthenium carbene complex211
of some substrates takes place with 5
mol loading and the catalyst can be reused after simple precipitation for up to
8 runs
Considering the failure of RCM we decided to prepare aldehyde 1048 in order
to perform an intramolecular alkylidenation under Takeda conditions or a
McMurry type reaction (Scheme 1022)
The PEG supported catalyst represents the most attractive option from an
economic point of view Grubbs 1st generation catalyst 1045 can be
immobilized on PEG in 6 steps metathesis
138
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
O
OEt
O
H3NOEt
O
NTs OEt
NTs N
OEt
Ts
OEt
O
NTs
PhS SPh
OEt
O
NTs
Takeda
1028 1030 1033 1036
1048 1049
Cl
NTs
1050
McMurryO
Scheme 1022 A new pathway
From the ester 1030 the aldehyde 1048 was accessed without any difficulty
following the conditions we had used previously (Scheme 1023) Two distinct
options were considered for the aldehyde 1048 the use of aldehyde 1048
directly in a McMurry type reaction using TiCl3-LiAlH4201
or formation of the
thioacetal 1049 in order to carry out a cyclisation under Takeda conditions
The reaction of TiCl3LiAlH4 with aldehyde 1048 did not produce the expected
cyclic compound 1050 whereas the formation of the thioacetal 1049
proceeded without any problems in a modest yield
1048 71 1049 49
1036
1030
OEt
O
NTs
TsN
OEt
O
NTs
O
OEt
O
NTs
PhS SPh
PhSH BF3OEt2
AcOH PhMert 25 h
Cp Ti[P(OEt) ]THF rt 3 hMS
TiCl3 LiAlH4Et3N DMEreflux 23 h
2 3 2
K2OsO4 2NaIO4
H O
OEtTsN
O
1050
THFH2O 05 hrt
Scheme 1023 Towards the five-membered ring
The Takeda reaction was problematic The reaction is highly water sensitive and
requires a large excess of reagents so the analysis of the 1H NMR spectrum of the
crude mixture was complicated by the presence of reagents such as P(OEt)3
which hide significant areas of the spectrum A small portion of the starting
139
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
material 1049 was recovered other fractions could not be properly identified
but seemed to be products of decomposition As the behaviour of sulfonamides
under Takeda conditions was unknown we considered that the reaction may
ave led to the loss of the tosylate group before or after cyclisation In both
cases the resulting compounds would probably be too volatile to be observed A
e
these products and conclude if the deprotection occurs before or after
used as the starting amino acid The amino
group would be protected with a benzyl group which was known to be tolerated
under Takeda conditions212
106 Model studies using phenylalanine-derivatives
At first we thought of connecting a β-hydroxyethyl chain and then oxidizing the
alcohol via Swern oxidation to give aldehyde 1055 which would allow access to
thioacetal 1056 (Scheme 1024)
h
solution would be to add a heavy substituent on the chain so we might isolat
cyclisation Anyway the protecting group had to be changed as the sulfonamide
appeared not to survive the Takeda reaction To increase the mass and better
mimic tyrosine phenylalanine was
H2NOH
O
Ph
NOMe
O
Ph
PhHN
OMe
O
Ph
Ph NOMe
O
Ph
Ph
NOMe
O
Ph
Ph
O
NOMe
O
Ph
Ph
SPh
PhSNPh
Ph
OMeTakeda
Swern
1051 1052 1053 1054
10561057 1055
OH
Scheme 1024 Effective sequence
The first step consisted in formation of the methyl ester 1058 using methanol
and thionyl chloride (Scheme 1025)213 The hydrochloride salt 1058 was
isolated in quantitative yield and then treated with concentrated ammonia to
obtain the free amine in excellent yield The imine 1052 was formed by
140
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
reaction of free amine with benzaldehyde and then reduced to give the
secondary amine 1053214 Several attemps were made to introduce the β-
hydroxyethyl chain to the amine 1053 (Table 106)215216217218
H2NOH
O
Ph
H3NOMe
O
Ph
NOMe
O
Ph
PhSOCl2 MeOH i) conc NH3 1059
ii) PhCHO CH2Cl2 MgSO4 rt 20 h
HN
OMe
O
Ph
Ph
NaBH4 MeOH0 degC 15 h
reflux 18 h Cl
NOMe
O
Ph
Ph
OH
2-Bromoethanol
N
O
O
Ph
table 106
MeOHreflux 3 h
Ph
1051 1058 100 1052 95
1053 571054
1060 24
entry 6
0
aterial was recovered except for conditions using 2-bromo
ethanol and Et3N in toluene217 The morpholinone 1060 was isolated in low
ield According to the literature219 it would be possible to open the lactone to
get an ester using methanol at reflux Unfortunately we recovered the amine
053
Scheme 1 25 Access to the amine 1054
Each time starting m
y
1
141
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
Entry 2-Bro anol moeth Reagents Conditions Results
1 20 eq NaI DI 0 eq) PEA (1 MeOH 50 degC 21 h SM 1053
2 20 eq Na ) d
D M
MW n de n
6 12 eq Et3N (12 eq) toluene reflux 20 h 1060 24
7 25 eq DIPEA (25 eq)
DMF reflux 7 h SM 1053
8 12 eq DIPEA (12 eq) toluene reflux 20 h decomposition
I DIPEA (10 eq 130 degC 1 h ecomposition
3 2 eq ry K CO (2 eq) 2 3 eOH 74 degC 68 h SM 1053
4 20 eq neat 140 degC 15 min decomposition
5 1 eq neat 100W 85 degC 10 mi compositio
TBAI (25 eq)
9 12eq DIPEA (12 eq) toluene reflux 7 h SM 1053
Table 106 Conditions for the formation of compound 1054
Another route considered involved starting from the secondary amine 1053 and
connecting an acetal instead of an alcohol in order to avoid the formation of
the morpholinone The thioacetal 1056 would be directly accessible from the
acetal 1061 The reaction of the amine 1053 with bromoacetaldehyde
diethylacetal in toluene did not yield the expected acetal 1061 starting
material was recovered (Scheme 1026) Different conditions came up with the
same result220221
OEtOEt
HN
OMe
O
Ph
Ph NOMe
O
Ph
EtOBr
OEtPh
1053 1061
(12 eq)
Et3N (12 eq) PhMe reflux 20 hor
NaHCO3 neat reflux 8 hor
dioxane reflux 8 h
Scheme 1026 Attempt of formation of diethyl acetal 1061
In an alternative route reaction of the methyl ester of phenylalanine 1059 with
dimethoxyacetaldehyde in CH Cl provided the imine 1062 in high yield
(
2 2
n of the imine 1062 using sodium borohydride in
methanol gave the amine 1063 in 6 yield whereas the reduction using
catalytic hydrogenation furnished the amine 1063 in very high yield over two
Scheme 1027) Reductio
142
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
steps Benzylation of the secondary amine 1063 in acetonitrile gave the acetal
1064 in very good yield
H2NOMe
O
PhMeOH rt 20 h
NOMe
O
Ph
MeO
OMeH2Pd-C
BnBr DIPEACH3CNreflux 22 h
NOMe
O
Ph
MeO
OMe
1059 1062 73
1064 76
EtOHrt 22 h
O
HMeO
OMeHN
OMe
O
Ph
MeO
OMe
106390 from 1059
Ph
NOMe
O
Ph
Ph
SPh
PhS
conditionsNOMe
O
Ph
Ph
PhS
OMe
1056
1065
see table 107
Scheme 1027 Using dimethoxyacetaldehyde
The next step was the formation of the substrate for the Takeda reaction
(Scheme 1027) However conversion of the acetal 1064 into thioacetal 1056
represented a problem and screening of conditions had to be performed (Table
107) Standard conditions (BF3OEt2 11 or 23 eq at rt) were not successful
(entries 1-2) Increasing the temperature led to the formation of some mixed
acetal 1065 (entry 3) Conditions proposed by Park and co-workers222 or Nishio
et al did not provide any better results (entries 4-5) Use of molten
tetrabutylammonium bromide (T224
223
BAB) and thiophenol (entry 6) as described by
did not give the thioacetal 1056 however the formation of the mixed
acetal 1065 was greatly improved producing starting material 1064 and mixed
cetal 1065 in a ratio 1783
Ranu
a
143
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
Reagents Conditions Ratio (1 ) Entry 064 1065
1 PhSH (23 eq) BF3OEt2 (11 eq) AcOH Toluene rt 3 h 1000
2 PhSH OH Toluene rt 3 h
Ph
5 PhSH (22 eq)
6 PhSH (23 eq) molten TBAB (30 mol) neat 130 degC 2 h 1783
(23 eq) BF3OEt2 (23 eq) Ac 1000
3 SH (23 eq) BF3OEt2 (23 eq) AcOH Toluene reflux 4 h 8614
4 PhSH (21 eq) MgBr2 (21 eq) Et2O rt 2 h 1000
p-TsOH (011 eq) Toluene reflux 5 h decomposition
Table 107 Conditions for the formation of mixed acetal 1065
The difficulties with obtaining thioacetal 1056 from acetal 1064 were
probably due to the presence of a basic nitrogen atom that would be protonated
under acidic conditions (Scheme 1028 and Scheme 1029) Even when no
additional acid is added thiophenol is sufficiently acidic (pKa 66) to protonate
the amino group and give the ammonium salt 1066 (pKa approximately 10)
Protonation of the acetal and in particular loss of the methanol to give
resonance stabilised carbocation 1068 will be disfavoured by the close
proximity of the positive charge so this is only possible when a high
temperature and an ionic liquid are used Even then the reaction stops at the
mixed acetal because resonance stabilisation of the di-cation 1072 that would
be produced by loss of the second methanol is o p or due to poor orbital overlap
between the lone pair on sulfur and the empty p-orbital on carbon and the
sulfur is cross-conjugated with the phenyl ring225
N CO2Me
Ph
MeO
MeOH N CO2Me
Ph
MeO
MeON CO2Me
Ph
MeO
MeO
H
N CO2Me
Ph
MeON CO2Me
Ph
MeO
HPhS
N CO2Me
Ph
PhS
MeO
1064 1066 1067
10681069
ndash MeOH
H
Ph
Ph Ph
PhPh
Ph
H H
H HH
H
Scheme 1028 Difficulties with thioacetal formation
144
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
N CO2Me
Ph
PhS
MeO
H
N CO2Me
Ph
PhS
MeON CO2Me
Ph
PhS
MeO
H
N CO2Me
Ph
PhS
N CO2Me
Ph
PhS
HPhS
N CO2Me
Ph
PhS
PhS
H
1069 1070 1071
10721074
ndash H H
ndash MeOH
N CO2Me
Ph
PhS
PhSN CO2Me
Ph
PhS
PhS
1075 1056
ndash H
ndash H
Ph Ph Ph
Ph
Ph Ph Ph
Ph
1073
H H H
HHH
H
Scheme 1029 Difficulties with thioacetal formation
Instead of trying to obtain what we could not have we considered what was
possible with what we had Obtaining the thioacetal 1056 was obviously not
possible but we had good conditions for the formation of the mixed acetal
1065 Cohen et al reported a number of examples of reductive lithiation of
thioacetals with reagents such as lithium naphthalenide 1078 (LN)226227 lithium
1-(dimethylamino)naphthalenide 1079 (LDMAN)228229230231 or lithium 44rsquo-di-
tert-butylbiphenylide 1080 (LDBB)232233 (Figure 103) followed by reaction with
an electrophile They found that mixed acetals were good starting materials for
reductive lithiation as well Although an intramolecular version of the reaction
had never been considered we considered the reductive lithiation of mixed
acetal 1065 would give the organolithium 1076 which would spontaneously
cyclise by condensation with the ester group and then form the pyrrolidine
1077 (Scheme 1030)
145
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
OMe
O
Ph
NPhS
OMePh
OMe
O
Ph
N
OMePh
Li
reductive lithiation
1064
OMe
O
Ph
N
Ph
MeO
OMe
1065 1076
1077
N
OMeO
BnBn
Scheme 1030 Possible strategy from acetal 1064
Li
LN
Li
LDBB
LiN
LDMAN1078 1079
1080
Figure 103 Cohens reducing agents
Initially the formation of the mixed acetal 1065 was optimised (Scheme
1031) After addition of 46 eq of thiophenol in two batches and 6 h at 130 degC
the mixed acetal 1065 was isolated in good yield
OMe
O
Ph
NPhS
OMePh
1064
OMe
O
Ph
N
Ph
MeO
OMe
1065 66
(a) PhSH (23 eq) molten TBAB (30 mol) 130 degC for 1 h
(b) PhSH (23 eq) 130 degC for 5 h
Scheme 1031 Synthesis of acetal 1065
The reductive lithiation was investigated by adaptation of Cohenrsquos procedures
(Table 108)229 Cohen demonstrated that LN 1078 is capable of rapid reductive
146
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
lithiation of thioacetals to give α-lithiothioethers226227 The reagent is readily
prepared by stirring naphthalene dissolved in THF with lithium ribbon at 25 degC
for 6 h A dark green colour indicates the formation of the radical anion A
solution of acetal 1065 in THF was added to the reagent prepared in this way
and at 78 degC However despite various different conditions (Table 108 entries
1-4) no reaction was observed Cohen had also developed a reagent LDMAN
1079 228229230231 prepared by stirring 1-(dimethylamino)naphthalene with
lithium ribbon in THF at 45 degC Cohen had noted that this reagent appeared to
decompose to give 1-lithionaphthalene above 45 degC After obtaining the
characteristic dark green-blue colour a solution of mixed acetal 1065 in THF
was added to LDMAN (10 eq) at 78 degC and the mixture left for 15 min After
chromatography we collected a mixture of the starting NN-(dimethylamino)
naphthalene and a minor product masked by the large excess of LDMAN (Table
108 entry 5) Reducing the number of equivalents of LDMAN did not reduce the
problem (Table 108 entry 6) A major disadvantage of this method is the
separation of compounds from excess NN-(dimethylamino)naphthalene
Whether the reaction works or not starting acetal 1065 or cyclised compound
1077 (Scheme 1030) would have similar properties and are hardly separable
from the starting naphthalene
Entry Reagent Conditions Results
1 LN 1078 (2 eq) THF 78 degC 45 min SM 1065
2 LN 1078 (2 eq) THF 78 degC to rt over 2 h SM 1065
3 LN 1078 (21 eq) THF rt 15 min SM 1065
4 LN 1078 (2 eq) THF 78 degC 05 h then rt 25 min SM 1065
5 LDMAN 1079 (10 eq) THF 78 degC 15 min DMAN
6 LDMAN 1079 (25 eq) THF 78 degC 1 h decomposition
7 LDBB 1080 (21 eq) THF 78 degC 2 h then rt 10 min
Table 108 Conditions for the reductive lithiation
Cohenrsquos group also demonstrated reductive lithiation of thioacetals with the
radical anion lithium pprsquo-di-tert-butylbiphenylide (LDBB)232233 LDBB proved to
be a more powerful reducing agent than LN and led to higher yields than LDMAN
147
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
Furthermore since the desired product 1077 is an amine separation from LDBB
would be possible by extraction with acid Thus after formation of the radical
anion at 0 degC LDBB was cooled to 78 degC and the solution of mixed acetal 1065
in THF was added After 2 h of reaction and despite an acid-base work up the
major fraction we obtained contained a large amount of starting DBB as well as a
minor non identified compound which might be the starting acetal but 1H NMR
signals were masked by the excess of reagent
After these results we decided to concentrate on obtaining thioacetal 1056 for
intramolecular Takeda reaction Various conditions for converting acetal 1064
into aldehyde 1081 were tried (Scheme 1032) Adaptation of the procedure
described by Gomez-Gallego et al234 with FeCl3 left starting material 1064
unreacted whereas treatment under acidic conditions (6N HCl) resulted in
decomposition of the substrate Olah et al235 furnished the solution with a
procedure that allowed conversion of dimethyl acetals into carbonyl compound
after reaction with a trichloromethylsilane sodium iodide reagent in
acetonitrile A probable mechanism has been proposed by Olahrsquos group
Dimethyl acetal 1064 reacts rapidly with trichloromethylsilane sodium iodide
reagent to form the unstable intermediate 1082 which is rapidly transformed
into carbonyl 1081 (Scheme 1033) Aldehyde 1081 was obtained without any
difficulties and in excellent yield under these conditions Attempted conversion
of the aldehyde into a thioacetal 1056 according to standard condition widely
described herein was unsuccessful Moreover another unsuccessful effort to
make the thioacetal derivative using thiophenol in TBAB encouraged us to stop
further investigations of this approach
N
O
Ph
OMe
OMe
MeO
Ph NOMe
O
Ph
Ph
O
NaI MeSiCl3CH3CN rt 1 h
BF3OEt2 PhSH AcOH PhMert 15 h
or Bu4NBr PhSH130 degC 15 h
NOMe
O
Ph
Ph
SPh
PhS
1064 1081 73 1056
Scheme 1032 Synthesis of thioacetal 1056
148
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
N
O
Ph
OMe
OMe
MeO
PhNaI MeSiCl3
1064
N
O
Ph
OMe
OMe
MeO
Ph
MeCl2SiI
MeSiCl2(OMe)N
OMe
O
Ph
Ph
OMe I
NOMe
O
Ph
Ph
O
1081
1082 1083
Scheme 1033 Probable mechanism for the cleavage of dimethyl acetals
The presence of a basic amino group in acetal 1064 and in aldehyde 1081 was
believed to be responsible for the failure of routes to thioacetal 1056 Acid-
sensitive Boc protection had prevented access to thioacetal 1026 and
sulfonamides had proved unstable under Takeda conditions We therefore
investigated the use of a robust benzamide protecting group
Amide 1085 was obtained via two different paths (Scheme 1034) First
amidation of phenylalanine methyl ester 1059 using benzoyl chloride proceeded
quantitatively236 Reaction of benzamide 1084 with allyl bromide provided a
mixture that was very difficult to analyse and purify whereas the amide 1085
was easily accessed after reaction of amine 1059 with allyl bromide in the
presence of lithium hydroxide237 followed by benzoylation under basic
conditions238 Bis-allyl compound 1086 was isolated as a by-product of the
allylation
149
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
H2NOMe
O
Ph
NOMe
O
Ph
Ph
O
1059 1085 90
HN
OMe
O
Ph
Ph
O
HNOMe
O
Ph
PhCOCl 2N K2CO3
CHCl3reflux 3 h
allyl bromide NaH
NOMe
O
Ph
+
LiOHH2O4Aring MS allyl bromideDMFrt 16 h
1087 471086 14
DMF 0 degC to rt 25 h
PhCOCl Et3N CH2Cl2 rt 2 h
1084 100
Scheme 1034 Synthesis of amide 1085
Oxidative cleavage of the allyl group in benzamide 1085 gave aldehyde 1088
and then the thioacetal 1089 was finally accessed under standard conditions
(Scheme 1035)
NOMe
O
Ph
Ph
O
1085
K2OsO4H2ONaIO4
THF H2O05 h rt
NOMe
O
Ph
Ph
O
O
1088 87
PhSH BF3OEt2
AcOH PhMert 3 h
NOMe
O
Ph
Ph
O
SPh
1089 41
PhS
Scheme 1035 Synthesis of thioacetal 1089
The Takeda reaction is a delicate reaction so it was necessary to test the
reaction on a simple compound instead of on our precious substrate 1089
(Scheme 1036) Thus thioacetal 1091 was formed by reaction of benzaldehyde
1090 with thiophenol in the presence of acid The Takeda reaction was then
carried out and after 3 h of reflux and an acid-base work up the ketone 1092
was isolated in modest yield
150
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
SPh
SPh
O(ii) 1M HCl THF rt 1 h(iii 1M NaOH THF rt 1 h
O
H
PhSHBF3OEt2
AcOHPhMert 45 h
1090 1091 70 1092 40
(i) methyl 3-phenylpropionate (05 eq) Cp2TiCl2 ( 3 eq) Mg (36 eq) 4Aring MS P(OEt)3 (6 eq) THF reflux 3 h
Scheme 1036 Takeda reaction with thioacetal 1091
Next the reaction was investigated on thioacetal 1089 in order to obtain
pyrroline 1093 (Scheme 1037) Unfortunately instead of cyclisation
fragmentation of the thioacetal chain occurred and the ester 1084 and the
sulfide 1094 were isolated as the main products
NOMe
Ph
Ph
O
SPhPhS
O
1089
HN
OMe
Ph
Ph
O
O
1084 20
PhS
1094 70
+
LDMAN (25 eq) NPh
OPh
O
SPh
1095
N
Ph O
Ph
OMe
1093
Cp2TiCl2 (3 eq) Mg (36 eq)P(OEt)3 (6 eq)
4Aring MS THF rt on THF 78 degC 1 h
Cp2TiCl2 (3 eq) Mg (36 eq)P(OEt)3 (6 eq)
4Aring MS THF rt on
Scheme 1037 Towards five-membered rings
This result is consistent with insertion of the low valent titanium species into the
carbon sulfur bond and then rapid fragmentation to give vinyl sulfide 1094 and
stabilised anion 1097 (Scheme 1038) Unfortunately groups that allow the
formation of the thioacetal starting material by reducing the basicity of the
nitrogen atom will stabilise anions and so favour this fragmentation Clearly
anisomycin cannot be made in this way
151
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
NOMe
Ph
O
1089
Cp2TiN
OMe
Ph
O
1096
O Ph
PhS
PhSO Ph
TiCp2
PhS
PhS NOMe
Ph
O
1097
O Ph
PhS
1094
+
Scheme 1038 Proposed mechanism
An attempt at reductive lithiation using in situ-generated LDMAN 1079 did not
show more promising results A complex mixture was obtained that did not
encourage us to carry on with this approach Lyer and Rainierrsquos124 interesting
results concerning alkene ester cyclisations under Takai conditions then
attracted our attention (Scheme 1039) They had subjected enol ether 1098 to
the in situ-generated titanium ethylidene reagent and were able to isolate the
cyclic enol ether 1099 as the only identifiable product in high yield
O
OBn
BnO O
BnO O
HO
O
BnOH
BnO
OBnH
TiCl4 (31 eq) Zn (72 eq) PbCl2 (38 eq)CH3CHBr2 (32 eq) TMEDA (193 eq)
1098 1099 75
THF 65 degC 2 h
Scheme 1039 Olefinic ester cyclisation
Naturally we applied these conditions to a similar substrate the N-allyl ester
1085 (Scheme 1040) After 2 h of reaction at rt we identified unreacted
starting material 1085 in the crude mixture However considering the huge
amount of reagents required to induce the metathesis-alkylidenation reaction it
is not difficult to imagine that some product may have been masked
NO
O
Ph
Ph
O
NPh
O Ph
OMe
1085 10100
TiCl4 (31 eq) TMEDA (193 eq) Zn (72 eq)PbCl2 (38 eq) CH3CHBr2 (32 eq)
CH2Cl2-THF 0 degC to rt 2 h
Scheme 1040 Cyclisation under Takai conditions
152
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
107 Conclusion and other potential routes
To sum up we explored various pathways and different model strategies
towards the synthesis of (+)-anisomycin F1 and its enantiomer starting from
amino acids Accessing the thioacetal substrates for Takeda reaction proved to
be difficult and when this was achieved fragmentation rather than cyclisation
was observed RCM also failed though it may have been possible with higher
catalyst loading Indeed the use of RCM on insoluble support is an interesting and
not investigated approach to access the alkaloid PEG represents an attractive
support as described by Yao and Motta206207 The catalyst can be easily accessed
in 6 steps from Grubbs 1st generation 1045 (Scheme 1041) and if successful on
our substrate would be reused several times
OH
OH
H
O OiPr
OH
H4 steps
O
OPEGO
O
O
loading 01 mmolg
O
OPEGO
O
O
RuCl
PCy3
Cl
10101
Grubbs I 1045CH2Cl2
Scheme 1041 Synthesis of the catalyst
The metathesis reaction would be performed on a substrate like amine 10102
in dichloromethane and the catalyst would be regenerated by precipitation with
Et2O (Scheme 1042) I believe the conversion into pyrrolines 10103 would
proceed after having chosen appropriate protecting groups for amine and ester
153
Guilaine Blanc Chapter 10 A Titanium Reagent Based Approach to the Synthesis of Anisomycin
OR2N
R3
R1
10102
N
R3OR2
R1
10103
(a) 10101 5 mol reflux(b) Et2O
R1 = ArSO2 Bz Bn R2 = Et Me Bn R3 = Alkyl aryl
Scheme 1042 RCM with PEG supported ruthenium carbene complex
154
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
11 Synthesis of Pyrrolines using the Takeda
Reaction on Solid-Phase
As seen in chapter 6 esters can easily be converted into enol ethers by the use
of titanium carbenoids A range of reagents could be used to alkylidenate esters
but only Takedarsquos and Takairsquos procedures allow hydrogen atoms to the
titanium atom Sequences to N-containing heterocycles (indoles quinolines
cyclic imines) have been previously reported within Hartleyrsquos group using an
alkylidenation reaction on solid-supported esters as a key step110113239240 The
general strategy uses titanium alkylidene reagents 112 containing a masked
nucleophile generated from thioacetals by Takedarsquos method (Scheme 111)
O R1
NuPG
acid-labilelinker
R2
TiCp2
NuPG
R2
R2
NuR1
112
113
O R1
O
Merrifieldresin
111
base-labilelinker
diversity
diversity
diversity
mild acid
114
Nu = O S NRPG = acid-labile protecting group
Scheme 111 Previous work in the group
These convert resin-bound esters 111 which are fairly acid-stable into very
acid-sensitive enol ethers 113 Treatment with mild acid leads to cleavage from
resin and cyclisation to give bicyclic heteroaromatic compounds 114 with
multiple sites of diversity and no trace of the site of attachment to the resin
The linker is switched to one cleaved under orthogonal conditions ensuring that
any unreacted ester 111 remains attached to the resin and so the heterocycles
114 are produced in high purity The term chameleon catch was introduced by
Barrett and co-workers to describe this switch in the nature of a linker241242 In
theory it allows greater diversity to arise from each resin-bound ester 111 as
155
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
other products would be available from cleaving at the ester stage (eg
carboxylic acids alcohols etc) The advantage of this strategy is that it
overcomes the problematic purification so characteristic of Takedarsquos method
Simple washing of the loaded resin with various solvents is all that is required at
the end of the reaction The Hartley team243 have used titanium carbenoids 115
to generate N-Boc and N-alkyl indoles110 119 and 1110 from resin-bound esters
111 (Scheme 112)
O R1
O
N(TMS)Boc
X
(i) 5 eq
(ii) 10 TFA-CH2Cl2(iii) MnO2 CH2Cl2 reflux
N
X
TiCp2
R1
NBoc
R1XNR2
R1
N(R2)Boc
XTiCp2
for R2= TMS
1110 32-70 7 examplesR2 = Me Bn prenyl
(ii) 1 TFA-CH2Cl2(iii) for R1TMS 10 TFA-CH2Cl2 119 34-73
19 examples
111
115
116
for R2 TMS
1111 41-677 examples
(i) 3 eq
(ii) 4 TFA CH2Cl2(iii)(a) NaOH(aq) (b) TMSCl (c) NaBH(OAc)3(iv) H2 PdC
(ii) 4 TFA 1 Et3SiH CH2Cl2(iii) NaOH(aq)
(i) 3 eq
groups included in librariesX = OH OMe OCH2O F NMe2 B(pin)R1 = Me nPr CHMeEt CH2CH(Me)(CH2)3CHMe2 (CH2)2NEt2 Ph (CH2)2Ph CH(Me)PhCH=CMe2 m-MeOC6H4 p-MeOC6H4 3-furyl cyclohexen-4-yl yields based on original loading of Merrifield resin
Cp2TiNHCPh3
3
N R1117
1112 46-876 examples
(i) 3 eqCp2Ti
NHCH(Me)Ph3118
NH
R1
1113 26-6010 examples high ee
NH
R1
or
+ 48 membered-librarycombined with cross coupling
Scheme 112 Previous work in the group
156
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
This approach allows indoles to be obtained in modest to excellent yields based
on resin loading A range of functionality is tolerated within the titanium
benzylidene reagents Following this strategy syntheses of libraries of
quinolines113 1111 various cyclic imines239240 1112 and enantiomerically
enriched piperidines239 1113 were achieved too using alkylidene complexes
116 and 117 and enantiopure titanium alkylidenes (S)-118 and (R)-118
We aimed to enlarge the scope of reagents to allow the synthesis of pyrrolines
(Scheme 113) The biological importance of pyrrolidines has already been
discussed in chapter 8 Thioacetal 1114 would be used to generate the
alkylidenating reagent 1116 under Takeda conditions Resin-bound esters 111
(previously prepared in the group by reacting carboxylic acids with Merrifield
resin in the presence of Cs2CO3 and KI35) would be converted into enol ether
1117 using the titanium alkylidene reagent 1116 Cleavage from the resin
would give trifluoroacetate salts 1118 which would cyclise after deprotection
and so allow access to a range of pyrrolines 1120
O R1
O
NBn2Cp2Ti
3 eq
O
R1
NBn2
NH3R1
Cl
4 CF3CO2H
NaOH(aq)
O
CH2Cl2NHBn2R1
CF3CO2
O
H2 PdCHCl EtOH
111
1116
11201119
11181117
NBn2
SPh
PhS
gt 2 eq Cp2Ti[P(OEt)3]21115
1114
NR1
Scheme 113 General strategy
Thioacetal 1114 would be synthesized in a few steps from methyl 33-
dimethoxypropanoate 1121 (Scheme 114) Conversion of methyl acetal 1121
into thioacetal 1122 would be followed by reduction to give primary alcohol
157
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
1123 Then amines 1114 or 1127 would be isolated after tosylation of
alcohol and reaction of tosylate 1126 with the appropriate amines An
alternative route to amine 1127 would involve oxidising alcohol 1123 to
aldehyde 1124 formation of imine 1125 and reduction to give the amine
1127
OMe
MeO O
O SPh
PhS O
O SPh
PhS OH
SPh
PhS OTs
SPh
PhS
SPh
PhS NR1
SPh
PhS NR1R2
O
1114 R1 = R2 = Bn1127 R1 = Bn R2 = H
1121 1122 1123 1124
11251126
Scheme 114 Access to thioacetals
The benzyl protecting group was chosen as protection of the terminal amine
because of its high stability in particular during alkylidenation Moreover
removal was expected to proceed easily and cleanly by catalysed hydrogenolysis
111 Results and discussion
Our route started with the synthesis of the thioacetal 1122 in excellent yield
from methyl 33-dimethoxypropanoate 1121 by treatment with thiophenol and
boron trifluoride in chloroform (Scheme 115)115 Reduction following the
procedure described by Rahim et al115 gave alcohol 1123 in good yield
Attempted formation of aldehyde 1124 by reaction of alcohol 1123 with the
pyridine sulphur trioxide complex and triethylamine in DMSO was
unsuccessful239244 Indeed the oxidation took place but was rapidly followed by
an elimination step leading to the generation of αβ-unsaturated aldehyde
1128 Decreasing the reaction time from 12 h to 45 min did not give any
158
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
improvement while using 25 eq of DMSO instead of 10 eq left the starting
material unreacted
A route via amide formation was then considered but treatment of ester 1122
with base failed to give the corresponding acid 1129 and provided the αβ-
unsaturated acid 1130 instead
OMe
MeO O
O SPh
PhS O
O SPh
PhS OH
SPh
PhS O
PhSH BF3OEt2
CHCl3 rt on
LiAlH4
THF rt on
PySO3 Et3N DMSO rton or 45 min
PhS H
O
1128 94 ratio (transcis) 71
7M KOH EtOH rt on
SPh
PhS OH
O PhS OH
O
1130 74ratio (transcis) 141
1121 1122 88 1123 80
1124
1129
Scheme 115 Sequence towards the aldehyde 1128
Introduction of the amino group by N-alkylation was then considered Alcohol
1123 was converted into the tosylate 1126 (Scheme 116)105 but the tosylation
proved to be problematic and a 6633 mixture of tosylate 1126 and dimer
1131 was isolated Attempts to purify the tosylate 1126 by chromatography
were unsuccessful due to the high instability of the compound so the crude
mixture was used in the next step without further purification Tosylate 1126
was converted into amine 1127 but the yield was poor
159
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
SPh
PhS OTs
SPh
PhS OHp-TsCl Pyr
rt on+
SPh
PhS O SPh
SPh
ratio (11261131) 6633
H2NBn Pyr
CH2Cl2 40 degC on
SPh
PhS NHBn
10 over 2 steps
1123 1126 1131
1127
Scheme 116 Formation of amine 1127
Synthesis of amine 1114 was attempted via reaction of tosylate 1126 with
dibenzylamine but after 45 h the starting material was recovered and no
further investigations were carried out on this step (Scheme 117)
SPh
PhS OTs
ratio (11261131) 6633
CH2Cl2 rt 45 h
SPh
PhS NBn2HNBn2 (4 eq)
1126 1114
Scheme 117 Synthesis of amine 1114
Next we proposed a new route to dibenzylamine 1114 via formation of an
amide 1132 from acid 1130 then thioacetal formation followed by reduction
(Scheme 118) The acrylic acid 1130 is commercially available as an EZ
mixture and we used this mixture as the starting material in this sequence Acid
1130 was converted into the acid chloride by treatment with thionyl
chloride222 The acid chloride was used directly in the reaction with
dibenzylamine Production of αβ-unsaturated amide 1132 proceeded in
excellent yield Then formation of thioacetal 1133 was undertaken The use of
standard conditions (PhSH BF3OEt2) left the starting material 1132 unchanged
(Table 111 entry 1) while reaction with thiophenol and TBAB provided a 7129
mixture of starting material 1132 and desired compound 1133 (entry 2)224
160
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
PhS OH
O
PhS NBn2
O
PhS NBn2
OSPh(i) SOCl2 80 degC 2 h
(ii) HNBn2 Et3N CH2Cl2 rt 25 h
Conditions
see table 1111130 1132 80 1133
Scheme 118 Towards the thioacetal 1133
Use of acetic acid with the standard conditions at rt improved this ratio (1132
1133) to 3763 but still the reaction was not complete and separation proved to
be difficult (entry 3) Finally reaction at 80 degC overnight provided the
thioacetal 1133 in 52 yield (entry 4)
Entry Amide 1132 Reagents
Ratio (1132 1133)
1 1 eq BF3OEt2 (11 eq) PhSH (1 eq) CHCl3 rt 25 h SM 1132
2 1 eq PhSH (23 eq) TBAB (30 mol) 130 degC 20 h 7129
3 1 eq BF3OEt2 (12 eq) PhSH (25 eq) AcOH PhMe rt 20 h 3763
4 1 eq BF3OEt2 (12 eq) PhSH (25 eq) AcOH PhMe 80 degC 20 h 1133 52a
a isolated yield
Table 111 Conditions for the formation of thioacetal 1133
With thioacetal 1133 in hand the amine 1114 was accessed easily by
reduction with LiAlH4 (Scheme 119) Next the Takeda reaction was
investigated Resins were prepared by previous members of the lab by treatment
of Merrifield resin with the desired carboxylic acid under Gisinrsquos conditions110
Prior to the Takeda reaction on solid support every reagent (including the resin
in the MacroKan) were dried by azeotrope with toluene and left under high
vacuum for 2 h to avoid the presence of water Amine 1114 was treated with 4
eq of pre-formed low valent titanocene complex 1115109116239 After 15 min
Merrifield resin-bound esters 1134-1137 were added and the mixtures were
left at rt overnight (Table 112 entries 1-3) The resulting enol ethers 1138-
1141 (Scheme 119) were cleaved from the resin under mild acid conditions
(TFACH2Cl2 11) to give the ammonium salt 1142-1144 in excellent yields
based on the original loading of the Merrifield resin The sequence with resin-
161
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
bound ester 1137 did not go cleanly and a complex mixture of compounds was
produced (entry 4)
PhS NBn2
OSPh
PhS NBn2
SPhLiAlH4
Et2O rt on
O
RNHBn2
CF3CO2
(a) Cp2Ti[P(OiPr)3]2 1115
TFA CH2Cl2 111 h rt
1133 1114 51
1142-1145
1138-1141
NBn2R
O
(b) resin 1134-1137 17 h rt
Scheme 119 Synthesis of ketones 1142-1145
Entry Resins Ketones Yield
1 O
O
Ph
CH3H
1134
O
Ph
CH3H1142
Bn2HN
CF3CO2
71
2 O
O
H3C H
1135
O
Bn2HN
H3C H
CF3CO2
1143
70
3 O
O
Ph
1136
O
PhBn2HN
CF3CO2
1144
76
4 O
O H3C H
1137
O
Bn2HNCH3H
CF3CO2
1145
mixture
Table 112 Results of the Takeda reaction in solid-phase synthesis
1H NMR analysis of salts 1142 to 1144 highlighted the diastereotopicity of the
benzylic protons (Figure 111) Each proton appears as a double doublet with a
geminal coupling constant (13 Hz) and a coupling to NH (5 Hz)
162
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
2x HA-1 and 2x HB-1
= 422 ppm = 432 ppm1142-1144
Jgem13 Hz Jgem13 Hz
JAN or BN5 HzJAN or BN5 Hz
H
H
Ph HPh R
HA
1
1
major rotamer
N
Ph
HPh
HB
RHA HB
Figure 111 Diastereotopicity
With ketones 1142-1144 in hand the next step consisted in removal of the N-
benzyl protecting group under catalytic hydrogenolysis Several conditions were
tested (Scheme 1110) Debenzylation of ketone 1144 in EtOH and HCl (2 eq)239
in the presence of PdC (25 mol) under hydrogen (atm pressure) at 65 degC for
115 h gave the starting material as the hydrochloride salt Similarly
hydrogenolysis carried out on substrate 1142 under same conditions left the
starting material unreacted The N-benzyl protection appeared to be highly
stable
O
PhBn2HN
CF3CO2
1144
(i) H2 10 PdC 6M HCl EtOH 65 degC 5 h
(ii) repeat (i) for 65 h
O
PhH3N
1146
Cl
O
Ph
CH3H
1142
Bn2HN
CF3CO2H2 10 PdC 6M HCl
O
Ph
CH3H1147
H3N
Cl
EtOH 65 degC 65 h
Scheme 1110 Hydrogenation reactions
Davies and Ichihara245 reported a quantitative debenzylation of a tyrosine
derivative but when the hydrogenolysis conditions were used for ketone 1144
the starting material was recovered unchanged except as a different salt
(Scheme 1111) Using transfer hydrogenation as described by Purchase and
Goel246 followed by addition of HCl(aq) did not lead to the desired compound
1146 and also gave the hydrochloride salt of the starting ketone 1144
163
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
(i) NH4 HCO2 10 PdC MeOH 68 degC 4 h
O
PhBn2HN
CF3CO2
1144
O
Ph
(i) H2 20 Pd(OH)2C H2OMeOH AcOH rt on
(ii) 6M HCl
(ii) 6M HCl
H3N
1146
Cl
Scheme 1111 Hydrogenation reactions
High pressure hydrogenation might solve the problem and an H-Cubereg reactor
was available in the department (Figure 112) This generates the hydrogen gas
necessary for the reaction in situ from electrolysis of water A key feature is the
ability to pressurize up to 100 bar and heat up to 100 degC Furthermore a large
range of catalysts packed in cartridges is available so that no filtrations are
required The substrate is passed through the cartridge under a continuous flow
and reactions scales may vary from 10 mg to 10 g
Figure 112 H-Cubereg reactor
Unfortunately a spare part was required for the apparatus and I did not have
the opportunity to use it or to make further progress within this project due to
time constraint However I was followed by Iain Thistlethwaite an MSci student
164
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
in the team who investigated the hydrogenolysis of dibenzylamines with the H-
Cube reactor
Iain failed to get the H-Cubereg reactor operational so he accessed a Cook
hydrogenation facility Reactions were run at rt for reasons of scale but
pressures of 50 psi (34 atm) could be achieved The trifluoroacetate salt 1144
was reacted in the Cook hydrogenator and then basified Rather than the desired
pyrroline N-benzyl pyrrolidine 1148 was produced
O
NHBn2
CF3CO2 (i) H2 (50 psi) 10 PdC EtOH HCl rt 24 h
(ii) NaOHaq
N
Ph
1144 1148
PhPh
Scheme 1112 Hydrogenolysis of salt 1144
112 Conclusion and opening remarks
A successful sequence for the solid phase synthesis of amino ketones has been
demonstrated Hydrogenolysis of ammonium salts 1142 1144 were attempted
at atmospheric pressure but did not provide the expected free amine Under
pressurized atmosphere the N-benzyl pyrrolidine 1148 was formed from
hydrogenolysis of trifluoroacetate salt 1144 and this has opened up the
possibility of accessing a library of N-alkylated 2-substituted pyrrolidines
However the reaction requires optimization and better purification of the N-
alkylated pyrrolidines product 1148 Other debenzylation conditions such as
Pearlmanrsquos catalyst (20 Pd(OH)2C) or higher reaction temperature might be
worth trying
Another option remains unexplored (Scheme 1113) which is changing the stable
benzyl protection for trityl protection The reaction sequence would start as
previously with formation of amide 1132 followed by reaction with thiophenol
in the presence of BF3OEt2 and glacial acetic acid to give thioacetal 1133 The
amide 1133 would then be reduced to the amine 1115 and protected with
trityl chloride to give thioacetal 1149 This synthetic route should allow access
165
Guilaine F Blanc Chapter 11 Synthesis of Pyrrolines using theTakeda Reaction on Solid-Phase
to the desired cyclic imine products 1120 and pyrrolidine products 1150 as the
cleavage and deprotection steps are known to be successful in the synthesis of
the 6-membered cyclic imines239
CO2HPhS
(i) SOCl2
(ii) conc NH3
PhS
O
NH2
PhSH BF3OEt2AcOH
O
NH2
SPh
PhS
LiAlH4
NH2
SPh
PhS
Ph3CCl
NHCPh3
SPh
PhSNRNH
R
1130 1132 1133
1114114911201150
Scheme 1113 Alternative routes
166
Guilaine F Blanc Experimental
Part D
12 Experimental
121 General experimental details
All reactions were carried out under an inert atmosphere unless otherwise
stated using oven-dried glassware Solutions were added via syringe unless
otherwise stated
DME was freshly distilled from sodium-benzophenone and stored with molecular
sieves diisopropylamine was freshly distilled from NaOH pellets DMF was
distilled from CaH2 under reduced pressure and stored over 4 Aring molecular sieves
benzyl alcohol was freshly distilled from KOH under reduced pressure acetone
was distilled from anhydrous CaSO4 and stored over 4 Aring molecular sieves Benzyl
bromide was distilled from MgSO4 in the dark under reduced pressure Pyridine
was freshly distilled from KOH pellets Diethyl ether tetrahydrofuran
dichloromethane toluene and acetonitrile were dried using a Puresolvcopy solvent
drying system prior to use Petroleum ethers refer to the fraction boiling at 40-
60 degC Brine refers to a saturated sodium chloride solution
With the exception of Cp2TiMe2 produced via the method of Payack et al85
reagents were obtained from commercial suppliers and used without further
purification unless otherwise stated Cp2TiCl2 (Titanocene dichloride) was
purchased from STREM Fine Chemicals or Sigma-Aldrich Lithium was purchased
from Sigma-Aldrich as a ribbon (038 mm thick 23 mm wide 999) p-
toluenesulfonic acid monohydrate was dried prior to use by azeotrope with
toluene p-toluenesulfonyl chloride was dried prior to use putting in solution in
diethyl ether washed with 10 NaOH until the solution became colorless and
then dried (Na2SO4) and crystallised Triethylamine TMEDA were freshly distilled
from CaH2 and stored over 4 Aring molecular sieves Thiophenol was freshly distilled
from CaCl2 under reduced pressure P(OEt)3 was freshly distilled from CaH2 under
reduced pressure TBAB was rescrystallised from benzene n-hexane (13) prior
167
Guilaine F Blanc Experimental
168
to use The molarity of the nBuLi was checked by titration with 13-diphenyl-2-
propanone p-toluenesulfonyl hydrazone prior to use
The solid-phase syntheses were carried out using resin derived from
commercially available Merrifield resin Wang resin or p-toluenesulfonic acid
polymer bound with the loadings described in the general procedures below and
contained in IRORI MacrokanTM (porous polypropylene reactors with an internal
volume 24 mL and a pore size of 74 microm)
Reactions were monitored by TLC performed on Merck Kieselgel 60 F254 plates or
Alugramreg SIL GUV254 and visualization was performed using a UV light (365 nm)
and potassium permanganate or iodine with heat Purification by column
chromatography was carried out using Fluorochem Silica gel 60 Aring (mesh size 35-
70 microm) as the stationary phase or Sigma-Aldrich Aluminium oxide (activated
neutral Brockmann I 150 mesh 58 Aring) previously deactivated with water (6
ww) as the stationary phase All distillations of compounds were carried out
bulb to bulb in a Kugelrohr apparatus Methylenation reactions were carried out
in a CEM Focused Microwave Synthesis System model Discoverreg
Melting points were measured using Gallenkamp apparatus and are uncorrected
IR spectra were recorded using KBr powder NaCl plates on JASCO FTIR 4100
spectrometer or on FTIR-8400S Shimadzu infrared spectrophotometer NMR
spectra were recorded using a Bruker AV400 FT or DPX400 spectrometer at
room temperature unless otherwise stated Chemical shifts in 1H NMR are given
in ppm relative to trimethylsilane Chemical shifts in 13C NMR spectra are given
in ppm relative to CDCl3 (770 ppm) or DMSO-d6 (395 ppm) as internal standard
High temperature NMR experiments were carried out in DMSO-d6 at 90 degC All
NMR J values are given in Hz CH3 CH2 CH and C in 13C NMR spectra were
assigned using DEPT Mass spectra were recorded on a JEOL JMS-700 High
Resolution Mass Spectrometer by the analytical services of the University of
Glasgow Optical rotations were determined using a Autopolreg V automatic
polarimeter [α] values were measured at the concentration and temperature
stated for a path length of 1 dm and a wavelength of 589 nm (Sodium D line)
Elemental analyses were carried out on a Exeter Analytical Elemental Analyser
EA 440
Guilaine F Blanc Experimental
122 Experimental to chapter 2
2-(Trimethylsilylmethylthio)benzothiazole 21
1
2
34
5
6 S
NS
SiMe3
C11H15NS2SiMW 25346
7
Following the procedure described by Katritzky et al13 (chloromethyl)
trimethylsilane (05 mL 36 mmol 10 eq) was added to a stirred mixture of
K2CO3 (594 mg 430 mmol 12 eq) and thiol 211 (599 mg 358 mmol 10 eq)
in dry acetone (4 mL) at 25 degC under argon The mixture was stirred overnight
and then filtered The filtrate was concentrated under reduced pressure Flash
chromatography [SiO2 petroleum ether-Et2O (1000-955)] gave the sulfide 21
(675 mg 75) as needles
R [SiO2 petroleum ether-Et2O (9010)] 053 1H NMR (400 MHz CDCl3) 000 (9H s SiMe3) 241 (2H s SCH2Si) 705 (1H
t J 78 Hz H5 or H6) 719 (1H t J 76 Hz H5 or H6) 752 (1H d J 79 Hz H4
or H7) 767 (1H d J 81 Hz H4 or H7) 1H NMR spectral data in agreement with
those previously reported in the literature247
2-[2rsquo-Phenyl-1rsquo-(trimethylsilyl)ethylthio]benzothiazole 212
1
2
34
5
6 S7
NS
SiMe3
C18H21NS2SiMW 34358
nBuLi [23 M in hexane] (092 mL 212 mmol 21 eq) was added drop-wise to a
stirring solution of freshly distilled diisopropylamine (031 mL 221 mmol
22 eq) in dry THF (19 mL) at 78 degC under argon The solution was stirred for
15 min at 78 degC Silane 21 (500 mg 198 mmol 20 eq) in dry THF (26 mL)
was added drop-wise and the solution left to stir for 1 h at 78 degC Benzyl
bromide (012 mL 10 mmol 10 eq) was added drop-wise to the solution which
169
Guilaine F Blanc Experimental
was left to stir for 4 h Distilled water and Et2O were added and the biphasic
solution was warmed to rt The aqueous layer was extracted with Et2O (3 ) the
organics were washed with brine (2 ) and then dried (MgSO4) The solvent was
evaporated under reduced pressure Flash chromatography [SiO2 petroleum
ether-Et2O (1000-955)] gave the sulfide 212 (269 mg 79) as an oil
R [SiO2 petroleum ether (100)] 048 1H NMR (400 MHz CDCl3) 000 (9H s SiMe3) 309 (2H d J 72 Hz
PhCH2CHS) 357 (1H t J 72 Hz PhCH2CHS) 703 (1H t J 78 Hz H5 or H6)
711-718 (3H m H5 or H6 and Ph) 727-732 (3H m Ph) 760 (1H d J 80 Hz
H4 or H7) 776 (1H d J 80 Hz H4 or H7) 13C NMR (100 MHz CDCl3)C 000
(CH3) 3833 (CH) 4018 (CH2) 12305 (CH) 12357 (CH) 12618 (CH) 12802
(CH) 12858 (CH) 13032 (CH) 13149 (CH) 13768 (C) 14225 (C) 15544 (C)
17035 (C) IR νmax (NaCl)cm-1 1603 (C=C) 1250 (SiMe3) MS (CI+) mz () 344
[(M+H)+ 100] 168 [(BT-SH2)+ 55] HRMS (CI+) 3440960 [(M+H)+ C18H22NS2Si
requires 3440963] All data were consistent with the literature13
2-(Methylsulfonyl)benzothiazole 216
1
2
345
6 S7
NS Me
O
O
C8H7NO2S2MW 21328
A solution of sulfide 21 (304 mg 120 mmol 10 eq) in methanol (46 mL) was
added to a solution of oxonereg (219 g 356 mmol 30 eq) in water (5 mL) The
mixture was left to stir overnight and then diluted with water The organic layer
was separated and the aqueous layer extracted with CH2Cl2 (3 ) The organics
were washed with water (1 ) then brine (1 ) and the solvent was removed
under reduced pressure The sulfone 216 was obtained without further
purification as a yellow oil (250 mg 98)
R [SiO2 petroleum ether-Et2O (7030)] 025 1H NMR (400 MHz DMSO-d6) 342 (3H s CH3) 753 (2H ddd J 11 73 and
81 Hz H5 or H6) 758 (1H t J 74 Hz H5 or H6) 802 (1H br d J 76 Hz H4
or H7) 821 (1H br d J 83 Hz H4 or H7) 1H NMR spectral data in agreement
with those previously reported in the literature248
170
Guilaine F Blanc Experimental
2-(Trimethylsilylmethylsulfinyl)benzothiazole 229
1
2
34
5
6S
7
NS
SiMe3
OC11H15NOS2SiMW 26946
Oxonereg (465 g 756 mmol 60 eq) was dissolved in water (10 mL) at 58 degC
This solution was allowed to cool to rt and then added to a mixture of sulfide
21 (318 mg 126 mmol 10 eq) acetone (11 mL 15 mmol 12 eq) and sat
NaHCO3(aq) (10 mL) in CH2Cl2 (27 mL) at 0 degC The mixture was left to stir at 0
degC for 05 h and then at 20 degC for 2 h The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (3 ) The combined organic layers were
dried (Na2SO4) and the solvent was removed under reduced pressure Flash
chromatography [SiO2 petroleum ether-Et2O (1000-7030)] gave the sulfoxide
229 (192 mg 57) as a yellow oil
R [SiO2 petroleum ether-Et2O (7030)] 034 1H NMR (400 MHz CDCl3) 000 (9H s SiMe3) 253 (1H d J 138 SCHAHBSi)
261 (1H d J 137 Hz SCHAHBSi) 721 (1H ddd J 12 72 and 81 Hz H5 or
H6) 728 (1H ddd J 12 72 and 82 Hz H5 or H6) 772 (1H ddd J 06 13
and 81 Hz H4 or H7) 779 (1H ddd J 06 13 and 81 Hz H4 or H7) 13C NMR
(100 MHz CDCl3)C 000 (CH3) 4746 (CH2) 12306 (CH) 12457 (CH) 12690
(CH) 12758 (CH) 13688 (C) 15440 (C) 18143 (C) IR νmax (NaCl)cm-1 1557
(C=C) 1250 (SiMe3) 1042 (S=O) MS (CI+) mz () 270 [(M+H)+ 100] HRMS (CI+)
2700438 [(M+H)+ C11H16NOS2Si requires 2700443]
2-(Trimethylsilylmethylsulfonyl)benzothiazole 215
1
2
34
5
6 S7
NS
SiMe3
O
O
C11H15NO2S2SiMW 28546
Procedure A The reaction was carried out accroding to the procedure described
for compound 229 using oxonereg (203 g 330 mmol 60 eq) water (44 mL)
sulfoxide 229 (148 mg 055 mmol 10 eq) acetone (048 mL 66 mmol 120
171
Guilaine F Blanc Experimental
eq) and sat NaHCO3(aq) (44 mL) in CH2Cl2 (12 mL)Flash chromatography [SiO2
hexane-EtOAc (1000-9010)] gave the sulfone 215 (75 mg 48) as an oil
R [SiO2 hexane-EtOAc (7030)] 068 1H NMR (400 MHz CDCl3) 029 (9H s SiMe3) 314 (2H s CH2SiMe3) 749
(1H t J 74 Hz H5 or H6) 754 (1H t J 77 Hz H5 or H6) 792 (1H d J
79 Hz H4 or H7) 810 (1H d J 82 Hz H4 or H7) 13C NMR (100 MHz CDCl3)C
000 (CH3) 4628 (CH2) 12291 (CH) 12569 (CH) 12804 (CH) 12828 (CH)
13704 (C) 15299 (C) 16968 (C) IR νmax (NaCl)cm-1 1554 (C=C) 1320 and
1150 (SO2 asymm and sym stretching) 1253 (SiMe3) MS (CI+) mz () 286
[(M+H)+ 88] 214 [(BT-SO2Me+H)+ 90] 136 [(BT+H)+ 100] HRMS (CI+) 2860389
[(M+H)+ C11H16NO2S2Si requires 2860392] Microanalysis Theory C 4632 H
526 N 491 Results C 4631 H 524 N 486
Procedure B Oxonereg (1807 g 2939 mmol 30 eq) was dissolved in water (39
mL) at 58 degC After cooling this solution was added to a stirred mixture of
sulfide 21 (247 g 974 mmol 10 eq) acetone (43 mL 59 mmol 60 eq) and
sat NaHCO3(aq) (77 mL) in CH2Cl2 (21 mL) at 0 degC The mixture was left to stir at
0 degC for 05 h and then at 20 degC for 1 h After 1 h acetone (43 mL) was added
The solution was cooled down to 0 degC and a solution of oxonereg (1807 g
2939 mmol 30 eq) in water (39 mL) was added The reaction was left to stir at
0 degC for 05 h and then 1 h at 20 degC The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (3 ) The combined organics were dried
(Na2SO4) and the solvent was removed under reduced pressure The crude was
submitted to the same process again The sulfone 215 was obtained without
further purification as yellow needles (241 g 86)
mp 80-82 degC
Data as above
172
Guilaine F Blanc Experimental
2-[2rsquo-Phenyl-1rsquo-(trimethylsilyl)ethylsulfonyl]benzothiazole 213
1
2
34
5
6 S7
NS
SiMe3
O
O
C18H21NO2S2SiMW 37558
The reaction was carried out according to the procedure described for compound
229 using oxonereg (163 g 265 mmol 62 eq) water (35 mL) sulfide 212
(146 mg 043 mmol 10 eq) acetone (04 mL 53 mmol 12 eq) and sat
NaHCO3(aq) (35 mL) in CH2Cl2 (095 mL) Flash chromatography [SiO2 petroleum
ether-Et2O (1000-8020)] gave a 4456 mixture of the sulfoxide and the sulfone
213 (58 mg) as an oil The crude was submitted to a second oxidation using
oxonereg (295 mg 048 mmol 30 eq) water (064 mL) the crude mixture from
the previous crude mixture (58 mg 016 mmol 10 eq) acetone (01 mL 10
mmol 60 eq) and sat NaHCO3(aq) (13 mL) in CH2Cl2 (034 mL) at 0 degC The
mixture was left to stir at 0 degC for 05 h and then at 20 degC for 1 h After 1 h
acetone (01 mL 10 mmol 60 eq) was added The solution was cooled down to
0 degC and a solution of oxonereg (295 mg 048 mmol 30 eq) in water (064 mL)
was added The reaction was left to stir at 0 degC for 05 h and then 1 h at 20 degC
The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3
) The combined organics were dried (Na2SO4) and the solvent was removed
under reduced pressure The sulfone 213 was obtained without further
purification as an oil (38 mg 24)
R [SiO2 petroleum ether-Et2O (7030)] 058 1H NMR (400 MHz CDCl3) 028 (9H s SiMe3) 306 (1H dd J 59 and
156 Hz PhCHAHB) 314 (1H dd J 72 and 154 Hz PhCHAHB) 378 (1H t J
66 Hz PhCH2CHS) 674-687 (5H m Ph) 742 (1H ddd J 15 73 and 78 Hz
H5 or H6) 747 (1H ddd J 15 72 and 77 Hz H5 or H6) 779 (1H ddd J 07
15 and 83 Hz H4 or H7) 797 (1H ddd J 08 15 and 83 Hz H4 or H7) 13C
NMR (100 MHz CDCl3)C 000 (CH3) 3306 (CH2) 5685 (CH) 12283 (CH)
12591 (CH) 12712 (CH) 12798 (CH) 12829 (CH) 12885 (CH) 12915 (CH)
13765 (C) 13841 (C) 15331 (C) 16873 (C) IR νmax (NaCl)cm-1 1603 (C=C)
1314 and 1143 (SO2 asymm and sym stretching) 1253 (SiMe3) MS (CI+) mz ()
173
Guilaine F Blanc Experimental
376 [(M+H)+ 100] 304 [(M+H)+ H2C=SiMe2 67] 177 [(M+H)+ BT-SO2H 21] 136
[(BT+H)+ 95] 89 (90) HRMS (CI+) 3760862 [(M+H)+ C18H22NO2S2Si requires
760861]
2-[(Trimethylsilyl)methylthio]pyridine 231
3
1
2
N
34
5
6S SiMe3
C9H15NSSiMW 19737
Following the procedure described by Kohra et al22 (chloromethyl)
trimethylsilane (25 mL 18 mmol 10 eq) was added to a stirred mixture of
K2CO3 (299 g 216 mmol 12 eq) KI (150 g 903 mmol 05 eq) and thiol 230
(200 g 180 mmol 1 eq) in absolute ethanol (206 mL) under argon The
mixture was stirred at reflux for 23 h The mixture was then cooled down and
filtered The filtrate was concentrated under reduced pressure Addition of ethyl
acetate led to the formation of a precipitate After filtration the filtrate was
concentrated under reduced pressure and gave the sulfide 231 as a yellow oil
spectral data in agreement with those previously reported in the
terature22
2-[(Trimethylsilyl)methylsulfonyl]pyridine 232
(303 g 85)
R [SiO2 petroleum ether ndash ethyl acetate (973)] 027 1H NMR (400 MHz Methanol-d4) 014 (9H s SiMe3) 232 (2H s SCH2Si)
704 (1H ddd J 10 48 and 73 Hz H5) 730 (1H td J 11 and 81 Hz H3)
760 (1H ddd J 18 73 and 81 Hz H4) 832 (1H ddd J 10 18 and 50 Hz
H6) 1H NMR
li
1
2
N
34
5
6SO
O
SiMe3 C9H15NO2SSiMW 22937
The reaction was carried out according to procedure B using oxonereg (1750 g
2847 mmol 30 eq) in water (38 mL) sulfide 231 (187 g 947 mmol 10 eq)
174
Guilaine F Blanc Experimental
acetone (42 mL 57 mmol 60 eq) and sat NaHCO3(aq) (75 mL) in CH2Cl2 (20 mL)
The sulfone 232 was obtained (182 g 84) as crystals
R [SiO2 petroleum ether-Et2O (5050)] 059 1H NMR (400 MHz CDCl3) 005 (9H s SiMe3) 279 (2H s CH2Si) 726 (1H
ddd J 12 47 and 76 Hz H5) 768 (1H td J 13 and 77 Hz H3) 780 (1H
ddd J 10 76 and 77 Hz H4) 846 (1H ddd J 10 13 and 49 Hz H6) 13C
NMR (100 MHz CDCl3)C 026 (CH3) 4344 (CH2) 12106 (CH) 12750 (CH)
13875 (CH) 15050 (CH) 16067(C) IR νmax (ATR)cm-1 1578 (C=C) 1300 and
1125 (SO2 asymm and sym stretching) 1242 (SiMe3) MS (CI+) mz () 230
[(M+H)+ 100] HRMS (CI+) 2300673 [(M+H)+ C9H16NO2SSi requires 2300671]
Microanalysis Theory C 4716 H 655 N 611 Results C 4705 H 649
N 610
(E)-2-(3rsquo4rsquo-Dimethoxystyrylsulfonyl)benzothiazole 234
1
2
345
6 S7
NS
OO
12
3
45
6
OMe
OMeC17H15NO4S2MW 36144
nBuLi [212 M in hexane] (028 mL 059 mmol 11 eq) was added drop-wise to a
stirring solution of freshly distilled diisopropylamine (01 mL 07 mmol 13 eq)
in dry THF (14 mL) at 78 degC under argon The solution was left to stir for
15 min at 78 degC The resulting LDA was added drop-wise to a stirring solution of
sulfone 215 (150 mg 053 mmol 10 eq) and veratraldehyde 233 (138 mg
083 mmol 16 eq) in dry THF (14 mL) The solution was warmed to rt and
allowed to stir for 2 h Distilled water and Et2O were added and the organic
layer was washed with sat NH4Cl(aq) (1 ) sat NaHCO3(aq) (1 ) water (1 ) brine
(1 ) then dried (MgSO4) The solvent was evaporated under reduced pressure
Flash chromatography [SiO2 petroleum ether-Et2O (982-7030)] gave the vinyl
sulfone 234 (121 mg 63) as a yellow solid
R [SiO2 petroleum ether-Et2O (3070)] 044
175
Guilaine F Blanc Experimental
1H NMR (400 MHz CDCl3) 376 (3H s OCH3) 379 (3H s OCH3) 676 (1H d
J 82 Hz H5rsquo) 695 (1H s H2rsquo) 696 (1H d J 150 Hz BT-SO2CH=) 704 (1H
d J 82 Hz H6rsquo) 741 (1H t J 82 Hz H5 or H6) 745 (1H t J 80 Hz H5 or
H6) 770 (1H d J 152 Hz ArCH=) 783 (1H d J 76 Hz H4 or H7) 802 (1H
d J 78 Hz H4 or H7) 13C NMR (100 MHz CDCl3)C 5492 (CH3) 5502 (CH3)
1090 (CH) 10997 (CH) 12004 (CH) 12125 (CH) 12357 (CH) 12372 (C)
12420 (CH) 12651 (CH) 12677 (CH) 13578 (C) 14606 (CH) 14825 (C)
15146 (C) 15177 (C) 16643 (C) IR νmax (NaCl)cm-1 1604 (C=C) 1595 (C=C)
1328 and 1138 (SO2 asymm and sym stretching) 1241 (C-O) MS (EI) mz () 361
(M+ 35) 296 (90) 162 [(MeO)2C6H3CCH+ 100] HRMS (EI) 3610439 (M+
C17H15NO4S2 requires 3610443]
(E)-2-(3rsquo4rsquo-Dimethoxystyrylsulfonyl)pyridine 235
1
2
N
34
5
6 S
OO
12
3
45
6
OMe
OMe C15H15NO4SMW 30535
In a same way the reaction was carried out using nBuLi [211 M in hexane] (23
mL 48 mmol 11 eq) diisopropylamine (07 mL 52 mmol 12 eq) in dry THF
(116 mL) sulfone 232 (100 g 437 mmol 10 eq) and veratraldehyde 233
(109 g 656 mmol 15 eq) in dry THF (113 mL) Flash chromatography [SiO2
CH2Cl2ndashMeOH (1000 ndash 9010)] gave the vinyl sulfone 235 (772 mg 58) as a
yellow solid
R [SiO2 CH2Cl2ndashMeOH (955)] 061 1H NMR (400 MHz CDCl3) 390 (3H s OCH3) 392 (3H s OCH3) 658 (1H d
J 81 Hz H5rsquo) 688 (1H d J 154 Hz PyrSO2CH=) 702 (1H s H2rsquo) 713 (1H
d J 81 Hz H6rsquo) 760-764 (1H m H5) 772 (1H d J 154 Hz ArCH=) 796
(1H t J 75 Hz H4) 814 (1H d J 76 Hz H3) 876-879 (1H m H6) 13C NMR
(100 MHz CDCl3)C 5596 (CH3) 11009 (CH) 11106 (CH) 12177 (CH)
12185 (CH) 12383 (CH) 12529 (C) 12698 (CH) 13817 (CH) 14519 (CH)
14934 (C) 15037 (CH) 15206 (C) 15889 (C) IR νmax (ATR)cm-1 1597 (C=C)
176
Guilaine F Blanc Experimental
1303 and 1141 (SO2 asymm and sym stretching) 1269 (C-O ether) MS (EI) mz
() 305 (M+ 10) 240 (94) 179 (74) 162 [(MeO)2C6H3CCH+ 100] 147 (37)
HRMS (EI) 3050723 (M+ C15H15NO4S requires 3050722)
(E)-2-(3rsquo4rsquo-Dimethoxyphenylethylsulfonyl)pyridine 236
1
2
N
34
5
6 S
OO
12
3
45
6
OMe
OMeC15H17NO4SMW 30736
NaBH4 (400 mg 105 mmol 60 eq) was added to a solution of alkene 235
(535 mg 018 mmol 10 eq) in THF (09 mL) The reaction was stirred for 4 h at
80 degC Then water was added and the aqueous layer was extracted with CH2Cl2
The organic layer was dried (MgSO4) and the solvent was removed under reduced
pressure Flash chromatography [SiO2 CH2Cl2-MeOH (1000ndash955)] gave the alkyl
sulfone 236 (27 mg 49) as an oil
R [SiO2 CH2Cl2-MeOH (955)] 063 1H NMR (400 MHz CDCl3) 305 (2H t J 81 Hz CH2) 368 (2H t J 82 Hz
CH2) 384 (6H s OCH3) 666 (1H s H2rsquo) 669 (1H d J 83 Hz H6rsquo) 674 (1H
d J 81 Hz H5rsquo) 753-779 (1H m H5) 793-800 (1H m H3) 806-812 (1H
m H4) 873-874 (1H m H6) 13C NMR (100 MHz CDCl3)C 2602 (CH2) 3807
(CH3) 5139 (CH2) 5391 (CH3) 10940 (CH) 10961 (CH) 11854 (CH) 12024
(CH) 12540 (CH) 12798 (C) 13618 (CH) 14596 (C) 14706 (C) 14815 (CH)
15534 (C) IR νmax (ATR)cm-1 1593 (C=C) 1313 and 1165 (SO2 asymm and sym
stretching) 1265 (C-O ether) MS (EI) mz () 307 (M+ 7) 164
[(MeO)2C6H3CHCH2+ 100] 149 (42) HRMS (EI) 3070880 (M+ C15H17NO4S
requires 3070878)
177
Guilaine F Blanc Experimental
123 Experimental to chapter 5
Benzyl 4-formylbenzoate 513
1
65
4
32
H
O
O
O
C15H12O3MW 24025
Following a procedure described by Gennari et al249 a solution of 4ndashformyl
benzoic acid 512 (800 g 533 mmol 10 eq) benzyl alcohol 511 (61 mL 59
mmol 11 eq) and DMAP (651 mg 532 mmol 01 eq) in dry CH2Cl2 (120 mL)
under argon was treated with a solution of DCC (1210 g 5864 mmol 11 eq) in
dry CH2Cl2 (80 mL) The mixture was stirred at 25 degC for 45 min then cooled
down to 0 degC DCU was removed by filtration and the precipitate washed with
cold CH2Cl2 (2 ) The filtrate was washed with H2O (2 ) 10 AcOH (250 mL)
and H2O (1 ) The organic layer was dried (MgSO4) and the solvent was removed
under reduced pressure Flash chromatography [SiO2 hexane ndash CH2Cl2 (8020 ndash
4060)] gave the aldehyde 513 (945 g 74) as a solid
R [SiO2 hexane ndash CH2Cl2 (2080)] 047 1H NMR(400 MHz CDCl3) 526 (2H s CH2Ph) 725 ndash 740 (5H m Ar-H)
785 (2H d J 84 Hz H2 and H6) 818 (2H d J 84 Hz H3 and H5) 1001 (1H
s CHO) 13C NMR (100 MHz CDCl3) C 6736 (CH2) 12838 (CH) 12854 (CH)
12872 (CH) 12955 (CH) 13034 (CH) 13512 (C) 13555 (C) 13923 (C)
16544 (C) 19169 (CH) NMR spectral data in agreement with those previously
reported in the literature249
(1RS 2RS)ndash and (1RS 2SR)ndash12-Bis[4rsquo-(benzyloxycarbonyl)phenyl]ethanol-
12-diols 514515
O4
O
3
2
1
65
12
OH
1
OH
23
4
56
O
O
C30H26O6MW 48252
178
Guilaine F Blanc Experimental
Procedure A A 2 M solution of iPrMgCl in THF (17 mL 33 mmol 22 eq) was
added to a stirred suspension of titanocene dichloride 517 (747 mg 300 mmol
20 eq) in dry degassed THF (10 mL) under argon at rt After 05 h the mixture
was cooled to 78 degC and the aldehyde 513 (360 mg 150 mmol 10 eq) was
added The mixture was stirred for 5 min and then allowed to warm to rt over
15 h The reaction was quenched by addition of 1 M HCl(aq) (20 mL) and the
mixture was stirred for 05 h The organic layer was separated and washed with
brine (3 ) The aqueous layer was extracted with ethyl acetate (3 ) The
combined organic layers were dried (MgSO4) and the solvent was removed under
reduced pressure Flash chromatography [SiO2 hexanendashethyl acetate (8020 ndash
5050)] gave 12-diols 514 and 515 (160 mg 44) as an inseparable 8020
mixture of the 12-syn and 12-antindashisomers as a yellow oil
R [SiO2 hexanendashethyl acetate (5050)] 045 1H NMR (400 MHz CDCl3) 467 (2Hsyn s CHOH) 493 (2Hanti s CHOH) 528
(4Hsyn s CH2Ph) 529 (4Hanti s CH2Ph) 709 ndash 811 (18Hsyn and 18Hanti m Arndash
H) 13C NMR of major isomer (100 MHz CDCl3)C 6684 (CH2) 7871 (CH)
12703 (CH) 12829 (CH) 12834 (CH) 12865 (CH) 12962 (CH) 12981 (C)
13590 (C) 14467 (C) 16619 (C) IR νmax (KBr)cm-1 3465 (OH) 2956 (CH sp3)
1690 (C=O ester) 1495 (Ph) MS (FAB) mz () 483 [(M+H)+ 3] 148 (24) 92
(C6H5CH2+ 100) HRMS (FAB) 4831813 [(M+H)+ C30H27O6 requires 4831808]
Procedure B Schlenk tube was charged with magnesium turnings (154 mg 643
mmol 64 eq) After vigorous stirring for 1 h under argon to activate the
magnesium a solution of 01 M SmI2 in THF (40 mL 040 mmol 04 eq)
dichlorodimethylsilane (005 mL 04 mmol 04 eq) and tetraglyme (009 mL
04 mmol 04 eq) were added successively to the magnesium A mixture of the
aldehyde 513 (240 mg 10 mmol 10 eq) dichlorodimethylsilane (01 mL 08
mmol 082 eq) and dry THF (4 mL) was then added drop-wise via a syringe pump
at such a rate as to retain the blue colour After the addition the mixture was
filtered quenched with Bu4NF (10 mL) and washed with brine (10 mL) The
mixture was evaporated under reduced pressure and the product was extracted
by continuous extraction with Et2O (200 mL) overnight The solvent was
removed under reduced pressure After analysis of the crude mixture 12-diols
179
Guilaine F Blanc Experimental
was observed as a mixture (6633) of anti and 12-syn-diols 514515 Data as
above
(1RS 2RS)ndash and (1RS 2SR)-12-Bis(4rsquo-carboxyphenyl)ethane-12-diols
528529
HO4
O
3
2
1
65
12
OH
1
OH
23
4
56
OH
O
C16H14O6MW 30228
Triethylamine (020 mL 15 mmol 10 eq) was added to
4-carboxybenzaldehyde 523 (225 mg 150 mmol 10 eq) in dry THF (50 mL)
under argon at rt Meanwhile a 2 M solution of iPrMgCl in THF (17 mL
34 mmol 23 eq) was added to a suspension of Cp2TiCl2 517 (747 mg 300
mmol 20 eq) in dry degassed THF (7 mL) under argon at rt The reaction was
stirred for 05 h The first mixture was added to the mixture containing the
titanium complex at 78 degC The mixture was stirred for 5 min at 78 degC and
warmed up to rt over 15 h The reaction was quenched by 1 M HCl(aq) (10 mL)
and the mixture was stirred for 05 h The organic layer was separated and
washed with brine (3 ) The aqueous layer was extracted with ethyl acetate (3
) The combined organic layers were dried (MgSO4) and the solvent was
removed under reduced pressure Because of a difference of solubility in CHCl3
the crude mixture was placed in a minimal amount of CHCl3 and filtered The
filtrate contained the titanocene complexes while the solid was purified by flash
chromatography [SiO2 CHCl3-MeOH (8020-6040)] and gave an inseparable 5842
mixture of the 12-syn and 12-anti-isomers 528529 (126 mg 56) as a cream
powder
R [SiO2 CHCl3-MeOH (7030)] 022 1H NMR (400 MHz DMSO-d6) 466 (2Hsyn s CHOH) 473 (2Hanti s CHOH)
552 (2Hsyn s OH) 563 (2Hanti s OH) 723 (4Hanti d J 83 Hz H3rsquo and H5rsquo)
735 (4Hsyn d J 83 Hz H3rsquo and H5rsquo) 775 (4Hanti d J 83 Hz H2rsquo and H6rsquo)
783 (4Hsyn d J 83 Hz H2rsquo and H6rsquo) 1282 (2Hsyn s CO2H) 13C NMR (100 MHz
180
Guilaine F Blanc Experimental
DMSO-d6)C 7649 (CH) 7671 (CH) 12716 (CH) 12742 (CH) 12833 (CH)
12843 (CH) 12908 (C) 12916 (C) 14730 (C) 14811 (C) 16730 (C) 16735
(C) IR νmax (KBr)cm-1 3544 (OH) 3450 (OH) 1685 (C=O acid) 1429 (C=C)
Compound reported in the literature without spectroscopic data provided250
(1RS 2RS)ndash12-Bis[4rsquo-(NN-dimethylamino)phenyl]ethane-12-diols 533
N 4
32
1
65
12
OH
1
OH
23
4
56
N
C18H24N2O2MW 30040
Procedure C A 2 M solution of iPrMgCl in THF (17 mL 34 mmol 23 eq) was
added to a stirred suspension of titanocene dichloride 517 (747 mg 300 mmol
20 eq) in dry degassed THF (5 mL) under argon at rt After 05 h the solution
was cooled to 78 degC and a solution of acetic acid (010 mL 17 mmol 11 eq)
and 4ndash(NN-dimethylamino)benzaldehyde 532 (224 mg 150 mmol 10 eq) in
dry THF (7 mL) were added under argon at rt The mixture was stirred for 5 min
and allowed to warm to rt over 15 h The reaction was quenched by addition of
1 M HCl(aq) (10 mL) and the mixture was stirred for 05 h The organic layer
containing titanium residues was separated The aqueous layer was treated by
addition of 1 M NaOH(aq) until pH 9 and extracted with CH2Cl2 (3 ) This organic
layer was washed with brine (3 ) dried (MgSO4) and the solvent was removed
under reduced pressure Flash chromatography [SiO2 CH2Cl2ndashEt2O (1000ndash5050)]
gave the 12-synndashdiols 533 (177 mg 78) as a green oil
R [SiO2 CH2Cl2ndashEt2O (5050)] 060 1H NMR (400 MHz CDCl3) 284 (12H s NCH3) 460 (2H s CHOH) 657 (4H
d J 86 Hz H3rsquo and H5rsquo) 696 (4H d J 88 Hz H2rsquo and H6rsquo) 13C NMR
(100 MHz CDCl3)C 4060 (CH3) 7864 (CH) 11226 (CH) 12784 (CH) 12823
(C) 15018 (C) IR νmax (NaCl)cm-1 3562 (OH) 2957 (CH sp3) 1610 (C=C) 1516
(C=C) 1260 (CndashN) MS (EI) mz () 300 (M+ 04) 282 (M+ H2O 36) 254 (65)
253 (100) 237 (M+ H2O and Me2NH 61) 150 (Me2NC6H4CHOH+ 63) 148 (68)
HRMS (EI) 3001842 (M+ C18H24O2N2 requires 3001838) NMR spectral data in
agreement with those previously reported in the literature251
181
Guilaine F Blanc Experimental
Procedure D A 2 M solution of iPrMgCl in THF (17 mL 34 mmol 23 eq) was
added to a stirred suspension of titanocene dichloride 517 (747 mg 300 mmol
20 eq) in dry degassed THF (5 mL) under argon at rt After 05 h the solution
was cooled to 78 degC and a solution of pndashTsOH (258 mg 136 mmol 09 eq) and
4ndash(NN-dimethylamino)benzaldehyde 532 (224 mg 150 mmol 10 eq) were
added in dry THF (7 mL) under argon at rt The mixture was stirred for 5 min and
allowed to warm to rt over 15 h The reaction was quenched by addition of 1 M
HCl(aq) (10 mL) and the mixture was stirred for 05 h The organic layer was
separated The aqueous layer was treated by addition of 1 M NaOH(aq) until pH 9
and extracted with CH2Cl2 (3 ) This organic layer was washed with brine (2 )
dried (MgSO4) and the solvent was removed under reduced pressure Flash
chromatography [SiO2 CH2Cl2ndashEt2O (1000ndash5050)] gave the 12-synndashdiols 533
(151 mg 67) as a green oil Data as above
(1RS2RS)ndash12ndashDiphenyl ethanendash12ndashdiols 535536
4
32
1
65
12
OH
1
OH
2
3
4
56
C14H14O2MW 21426
The reaction was carried out according to procedure A using a 2 M solution of iPrMgCl in THF (17 mL 34 mmol 17 eq) titanocene dichloride 517 (747 mg
300 mmol 15 eq) in dry THF (10 mL) and benzaldehyde 534 (02 mL 20
mmol 10 eq) The crude mixture was dissolved in a minimal amount of CHCl3
and filtered The filtrate was treated with 1 M NaOH(aq) and stirred for 10 min
The mixture was filtered through a pad of Celitereg The filtrate was extracted
with diethyl ether (2 ) The organic layer was dried (MgSO4) and concentrated
under reduced pressure Flash chromatography [SiO2 hexanendashethyl acetate
(9010ndash6040)] gave the 12-diols (16 mg 10) as an inseparable 946 mixture of
the synndash and antindashisomers 535536 as yellow crystals
R [SiO2 hexanendashethyl acetate (32)] 037
Data on synndashisomer only 1H NMR (400 MHz CDCl3) 280 (2H br s OH)
464 (2H s CHOH) 704 ndash 708 (4H m H2rsquo and H6rsquo) 715 ndash 720 (6H m H3rsquo
H4rsquo and H5rsquo) 13C NMR (100 MHz CDCl3)C 7915 (CH) 12696 (CH) 12798
182
Guilaine F Blanc Experimental
(CH) 12817 (CH) 13983 (C) IR νmax (NaCl)cm-1 3368 (OH) 2923 (CH sp3) MS
(EI) mz () 214 (M+ 01) 107 (C6H5CHOH+ 100) 83 (49) 79 (90) 77 (C6H5+
65) (CI+) mz () 197 [(M+H)+ H2O 100] 107 (C6H5CHOH+ 29) HRMS (CI+)
1970963 [(M+H)+ H2O C14H13O requires 1970966] All Data are consistent with
the literature252253
Loading of 4ndashtoluenesulfonic acid resin 538
N
H
O
H
SO
OO
A solution of 4ndash(NN-dimethylamino)benzaldehyde 532 (564 mg 378 mmol
50 eq) in dry THF (10 mL) was added to a flask containing resinndashbound
toluenesulfonic acid 538 (252 mg of macroporous resin 30ndash60 mesh with a
loading of 20 mmol gndash1 10 eq) contained in an IRORI MacroKanTM (porous
polypropylene reactors with an internal volume of 24 mL and a pore size of
74 m) under argon The mixture was stirred at rt for 15 h and then the
MacroKanTM was removed from the flask and washed with THF (5 ) then
alternately with CH2Cl2 and MeOH (2 ) and finally with CH2Cl2 (1 ) then Et2O
(1 ) before the combined washings were evaporated under reduced pressure
Cleavage of 4ndashtoluenesulfonic acid resin
N
H
O
C9H11NOMW 14919
The MacroKanTM 539 was stirred in a solution of Et3N ndash CH2Cl2 (119) for 125 h
at rt under argon The MacroKanTM was then washed with THF (5 ) then
alternately with CH2Cl2 and MeOH (2 ) and finally with CH2Cl2 (1 ) then Et2O
(1 ) before the combined washings were evaporated under reduced pressure
The aldehyde 532 was recovered (61 mg) yielding 54 of loading
183
Guilaine F Blanc Experimental
Benzyl 3-formylbenzoate 544
O1
O
65
4
3
2
H
O
C15H12O3MW 24025
The reaction was carried out following the procedure described for compound
513 using 3ndashformylbenzoic acid 542 (100 g 666 mmol 10 eq) benzyl
alcohol 511 (080 mL 73 mmol 11 eq) DMAP (82 mg 067 mmol 01 eq) in
dry CH2Cl2 (15 mL) and a solution of DCC (151 g 732 mmol 11 eq) in CH2Cl2
(10 mL) Flash chromatography [SiO2 hexanendashCH2Cl2 (8020ndash4060)] gave the
ester 544 (133 g 83) as an amorphous solid
R [SiO2 hexanendashCH2Cl2 (2060)] 040
mp 55 ndash 57 degC 1H NMR (400 MHz CDCl3) 532 (2H s CH2Ph) 725 ndash 739 (5H m ArndashH)
753 (1H t J 76 Hz H5) 800 (1H d J 78 Hz H4 or H6) 825 (1H d J 78 Hz
H4 or H6) 848 (1H s H2) 998 (1H s CHO) 13C NMR (100 MHz CDCl3)C
6729 (CH2) 12845 (CH) 12855 (CH) 12874 (CH) 12934 (CH) 13125 (C)
13144 (CH) 13320 (CH) 13534 (CH) 13559 (C) 13656 (C) 16535 (C)
19143 (CH) IR νmax (KBr)cm-1 3062 (CH sp2) 2830 (CH sp3) 1704 (C=O) 1592
(C=C) MS (CI+) mz () 241 [(M+H)+ 100] 151 (30) 91 (C6H5CH2+ 52) HRMS
(CI+) 2410862 [(M+H+) C15H13O3 requires 2410865] Microanalysis Theory C
7492 H 503 Results C 7484 H 499
(1RS2RS)ndash and (1RS2SR)ndash12-Bis[3rsquo-(benzyloxycarbonyl)phenyl]ethane-12-
diols 545546
OH
OHC30H26O6
MW 48252O
O
O
O
The reaction was carried out according to procedure A using a 2 M solution of iPrMgCl in THF (17 mL 34 mmol 23 eq) titanocene dichloride 517 (747 mg
300 mmol 20 eq) in dry degassed THF (10 mL) and the aldehyde 544 (360 mg
184
Guilaine F Blanc Experimental
149 mmol 10 eq) After acidic treatment the red crude mixture was stirred
for 5 min with 1 M NaOH(aq) (25 mL) and then filtered through Celitereg The
filtrate was extracted with ethyl acetate (3 ) dried (MgSO4) and the solvent
was removed under reduced pressure Flash chromatography [SiO2 hexanendashethyl
acetate (8020ndash5050)] gave 12-diols (767 mg 21) as an inseparable 8020
mixture of synndash and antindashisomers 545546 as a yellow oil
R [SiO2 hexanendashethyl acetate (5050)] 048 1H NMR (400 MHz CDCl3) 467 (2Hsyn s CHOH) 482 (2Hanti s CHOH) 519
(4Hanti s CH2Ph) 520 (4Hsyn s CH2Ph) 710-718 (6H m Ar-H) 724 ndash 731
(12H m Ar-H) 773-784 (18H m Ar-H) 13C NMR of major isomer (100 MHz
CDCl3)C 6575 (CH2) 7623 (CHanti) 7743 (CHsyn) 12708 (CH) 12717 (CH)
12725 (CH) 12756 (CH) 12824 (CH) 12872 (C) 13080 (CH) 13479 (C)
13915 (C) 16522 (C) IR νmax (NaCl)cm-1 3466 (OH) 2925 (CH sp3) 1717 (C=O
ester) 1497 (Ph) MS (CI+) mz () 305 (45) 241 (C6H5CH2OCOC6H4CHOH+ 100)
151 (51) 91 (C6H5CH2+ 80)
(1RS2RS)ndash12ndashBis(3rsquo4rsquo5rsquondashtrimethoxyphenyl)ethanendash12ndashdiols 555
3
4 56
1
2MeO
MeO
OMe
12
OH
OH
OMe
OMe
OMe C20H26O8MW 39442
The reaction was carried out according to procedure A using a 2 M solution of iPrMgCl in THF (17 mL 34 mmol 23 eq) titanocene dichloride 517 (747 mg
300 mmol 20 eq) in dry degassed THF (10 mL) and the aldehyde 554 (295 mg
150 mmol 10 eq) The combined organics were dried (MgSO4) and
concentrated under reduced pressure Sodium bicarbonate (670 g) methanol
(103 mL) and water (4 mL) were added to the crude mixture The mixture was
heated to 40 degC overnight and then cooled to rt The titanium residues were
removed by filtration The solution was evaporated under reduced pressure
Water (150 mL) and CH2Cl2 (75 mL) were added and the mixture shaken The
organic layer was separated dried (MgSO4) and the solvent was removed under
reduced pressure Flash chromatography [SiO2 CH2Cl2ndashMeOH (991ndash955)] gave
185
Guilaine F Blanc Experimental
the 12-synndashdiols 555 (221 mg 75) as an amorphous solid R [SiO2 CH2Cl2ndash
MeOH (955)] 047
mp 172 ndash 174 degC 1H NMR (400 MHz CDCl3) 366 (12H s 4 OCH3) 373 (6H s 2 OCH3)
449 (2H s CHOH) 628 (4H s 2 H2rsquo and 2 H6rsquo) 13C NMR (100 MHz
CDCl3)C 5607 (CH3) 6085 (CH3) 7924 (CH) 10378 (CH) 13547 (C) 13737
(C) 15288 (C) IR νmax (KBr)cm-1 3482 (OH) 2966 (CH sp2) 2939 (CH sp3) 1592
(C=C arom) MS (EI) mz () 394 [M+ 1] 376 [M+ H2O 3] 360 (13) 347 (8)
345 (7) 198 [(MeO) 3C6H2CH2OH+ 100] (CI+) mz () 377 [(M+H)+ H2O 60]
197 [(MeO) 3C6H2CHOH+ 100] HRMS (EI) 3941627 [M+ C20H26O8 requires
3941628] Microanalysis Theory C 6091 H 660 Results C 6064 H
671 Compound reported in the literature without spectroscopic data
provided
(1RS2RS)ndash and (1RS2SR)ndash12ndashBis(3rsquo4rsquondashdimethoxyphenyl)ethanendash12ndashdiols
557
3
45
6
1
2MeO
MeO
12
OH
OH
OMe
OMe C18H22O6
MW 33436
In a same way the reaction was carried out using a 2 M solution of iPrMgCl in
THF (17 mL 34 mmol 23 eq) titanocene dichloride 517 (747 mg 300 mmol
20 eq) in dry degassed THF (10 mL) and the aldehyde 556 (250 mg 150 mmol
10 eq) Flash chromatography [SiO2 CH2Cl2 - MeOH (1000ndash982)] gave the 12-
diols 557 as an inseparable 9010 mixture of synndash and antindashisomers as a yellow
amorphous solid after recrystallisation in CHCl3 (75 mg 30)
R [SiO2 CH2Cl2-MeOH (955)] 040
mp 150-152 degC (CHCl3)
Data on syn-isomer only1H NMR (400 MHz CDCl3) 363 (6H s OCH3)
371 (6H s OCH3) 443 (2H s CHOH) 647-649 (4H m H2rsquo and H6rsquo) 658
(2H d J 86 Hz H5rsquo) 13C NMR (100 MHz CDCl3)C 5574 (CH3) 5579 (CH3)
7896 (CH) 11002 (CH) 11048 (CH) 11957 (CH) 13255 (C) 14837 (C)
186
Guilaine F Blanc Experimental
14860 (C) IR νmax (NaCl)cm-1 3532 (OH) 1603 (C=C) MS (EI) mz () 316 (M+
H2O 15) 300 (M+ H2O and CH4 26) 287 (M+ H2O and CH=O 100) 167
[(MeO)2C6H3CHOH+ 70] HRMS (EI) 3341414 [M+ C18H22O6 requires 3341416]
Microanalysis Theory C 6467 H 659 Results C 6483 H 667
Compound reported in the literature without spectroscopic data provided254255
Loading of Wang resin with 4-hydroxybenzaldehyde 560
H
O
O
A solution of DIAD (11 mL 56 mmol 56 eq) in dry THF (6 mL) was added drop-
wise at 0 degC to a stirred solution of 4ndashhydroxybenzaldehyde 560 (613 mg
502 mmol 50 eq) PPh3 (138 g 525 mmol 52 eq) and a flask containing
resinndashbound Wang resin 561 (591 g of maroporous resin 150ndash300 μm with a
loading of 17 mmol gndash1 10 eq) contained in an IRORI MacroKanTM (porous
polypropylene reactors with an internal volume of 24 mL and a pore size of
74 m) under argon in dry THF (12 mL) After addition the mixture was stirred
at rt for 1 h and then the MacroKanTM was removed from the flask and washed
with THF (5 ) then alternately with CH2Cl2 and MeOH (4 ) and finally with
Et2O (1 ) before the combined washings were evaporated under reduced
pressure
124 Experimental to chapter 8
Methyl 4-aminobutanoate hydrochloride salt 818
12
O3
O4
H3NCl C5H12ClNO2MW 15361
Thionyl chloride (71 mL 97 mmol 20 eq) was added drop-wise to a stirred
solution of γ-aminobutyric acid 817 (500 g 485 mmol 10 eq) in MeOH
187
Guilaine F Blanc Experimental
(59 mL) at 10 degC under argon The solution was stirred for 5 min and then
allowed to warm to rt and stirred for 2 h The resulting mixture was evaporated
under reduced pressure Washing the crude product with hot hexane left the
hydrochloride salt of the amino ester 818 as an amorphous solid (702 g 95) 1H NMR (400 MHz DMSO-d6) 182 (2H qn J 76 Hz CH2-3) 245 (2H t J
73 Hz CH2-2) 275-283 (2H m CH2N) 361 (3H s OCH3) 806-818 (3H br s
NH3) 1H NMR spectral data in agreement with those previously reported in the
literature256
Methyl 4ndash(benzylidenamino)butanoate 819
12
O3
O4
N C12H15NO2MW 205251
23
45
6
Triethylamine (36 mL 26 mmol 20 eq) and benzaldehyde 812 (17 mL
17 mmol 13 eq) were added to a stirred suspension of the amino ester 818
(200 g 131 mmol 10 eq) and Na2SO4 (223 g 157 mmol 10 eq) in dry CH2Cl2
(40 mL) under argon at rt After stirring overnight the mixture was filtered off
and washed with water (2 ) brine (1 ) then dried (MgSO4) and the solvent was
removed under reduced pressure Excess reagents were removed at 120 degC
under reduced pressure to leave the imine 819 (190 g 71) as a yellow oil 1H NMR (400 MHz CDCl3) 196 (2H qn J 70 Hz CH2ndash3) 235 (2H t J
74 Hz CH2ndash2) 356 (2H t J 68 Hz CH2N) 358 (3H s OCH3) 739-742 (3H
m H3rsquo H4rsquo and H5rsquo) 771-773 (2H m H2rsquo and H6rsquo) 819-821 (1H br s
CH=N) 1H NMR spectral data in agreement with those previously reported in the
literature257
Methyl 4-(2rsquo-methylbutylideneamino)butanoate 837
N12
3
4
O
O
C10H19NO2MW 18526
188
Guilaine F Blanc Experimental
In a same way the reaction was carried out using triethylamine (20 mL 14
mmol 20 eq) 2-methylbutyraldehyde 834 (10 mL 93 mmol 13 eq) the
hydrochloride salt 818 (112 g 732 mmol 10 eq) and Na2SO4 (124 g
873 mmol 12 eq) in dry CH2Cl2 (22 mL) The imine 837 was obtained as a
brown oil (127 g 94) 1H NMR(400 MHz CDCl3) 087 (3H t J 69 Hz CH3CH2) 100 (3H d J
62 Hz CH3CH) 126-148 (2H m CH2CH3) 190 (2H apparent qn J 71 Hz
CH2-3) 218 (1H septet J 67 Hz CHCH3) 230 (2H t J 75 Hz CH2-2) 335
(2H t J 68 Hz CH2N) 363 (3H s OCH3) 743 (1H d J 60 Hz CHN)
Due to the relative instability of this compound we decided to carry on the next
step without more characterization
Methyl 4-(2rsquo4rsquo-dimethoxybenzylidenamino)butanoate 838
N1
16
5
43
2
OMeMeO
2
3
4O
O C14H19NO4MW 26530
In a same way the reaction was carried out using triethylamine (20 mL 14
mmol 20 eq) 24-dimethoxybenzaldehyde 835 (158 g 951 mmol 13 eq)
the hydrochloride salt 818 (112 g 734 mmol 10 eq) and Na2SO4 (124 g
873 mmol 12 eq) in dry CH2Cl2 (22 mL) Excess reagents were removed at 150
degC under reduced pressure to leave the imine 838 as a brown oil (443 mg 23) 1H NMR (400 MHz CDCl3) 204 (2H qn J 69 Hz CH2-3) 243 (2H t J
76 Hz CH2-2) 362 (2H dt J 13 and 64 Hz CH2N) 368 (3H s OCH3)
385 (3H s OCH3) 386 (3H s OCH3) 645 (1H d J 23 Hz H3rsquo) 653 (1H dd
J 23 and 87 Hz H5rsquo) 789 (1H d J 86 Hz H6rsquo) 861 (1H br s CH=N) 13C
NMR (100 MHz CDCl3)C 2633 (CH2) 3184 (CH2) 5152 (CH3) 5544 (CH3)
5547 (CH3) 6070 (CH2) 9803 (CH) 10529 (CH) 11789 (C) 12842 (CH)
15701 (CH) 15998 (C) 16297 (C) 17409 (C) MS (EI) mz () 265 (M+ 43)
234 (M+ MeO 25) 192 (M+ CH2CO2Me 98) 178 (M+ CH2CH2CO2Me 40)
164 [(MeO)2C6H3CNH+ 70] 149 (100)
189
Guilaine F Blanc Experimental
Petasis reagent dimethyltitanocene 814
TiMe
Me
C12H16TiMW 20812
Following the procedure described by Payack et al85 a 14 M solution of MeMgBr
(137 mL 192 mmol 23 eq) in toluene-THF (3010) was added drop-wise to a
stirred solution of titanocene dichloride 61 (2100 g 843 mmol 10 eq) in dry
toluene (230 mL) previously chilled to 5 degC over 1 h with the internal
temperature maintained under 8 degC The resulting orange slurry was stirred for
4 h Meanwhile a stirred solution of 6 aqueous ammonium chloride was chilled
to 1 to 2 degC When the formation of dimethyltitanocene was judged complete
(assayed by NMR) the toluene THF reaction mixture was poured into
ammonium chloride saturated aqueous solution via a cannula over a period of
05 h maintaining an internal temperature between 0 and 5 degC in both flasks
Toluene (15 mL) was used to rinse the reaction flask The aqueous phase of this
biphasic mixture was then removed The organic layer was washed sequentially
with cold water (3 50 mL) and brine (50 mL) and then dried (Na2SO4) The
organic layer was filtered and carefully concentrated under reduced pressure
The resulting orange slurry was assayed by 1H NMR spectroscopy to be 29 weight
percent dimethyltitanocene 814 The reagent was diluted with dry THF until
132 M to be stored more than a week and stored at 4 degC 1H NMR(400 MHz CDCl3) 005 (6H s Me) 618 (10 H s Cp) 1H NMR spectral
data in agreement with those previously reported in the literature85
Nndashbenzylidenndash4ndashmethoxypentndash4ndashenndash1ndashamine 820
1
2
3O4
N
1
23
45
6
C13H17NOMW 20328
5
Following the procedure described by Adriaenssens258 a 132 M solution of
Cp2TiMe2 814 (10 mL 14 mmol 61 eq) in toluene THF (11 by mass) was
190
Guilaine F Blanc Experimental
added to the imino ester 819 (46 mg 022 mmol 10 eq) and sealed in a 10 mL
microwave tube under argon This mixture was irradiated under 100 W
microwave power to raise the internal temperature to 65 degC for 10 min before
cooling The resultant black solution was concentrated under reduced pressure
and then hexane was added The hexane extract was submitted to sonication
and then filtered off The solvent was removed under reduced pressure to yield
the crude enol ether 820 as an orange oil which was used directly in the
cyclisation reaction (38 mg 84) 1H NMR (400 MHz CDCl3) 205 (2H qn J 72 Hz CH2ndash2) 234 (2H t J
72 Hz CH2ndash3) 370 (3H s OCH3) 380 (2H dt J 15 and 68 Hz CH2N)
403 (2H s CH2=) 755ndash760 (3H m H3rsquo H4rsquo and H5rsquo) 785ndash793 (2H m H2rsquo
and H6rsquo) 840-842 (1H br s CH=N) 1H NMR spectral data in agreement with
those previously reported in the literature258
4-Methoxy-N-(2rsquo-methylbutyliden)pent-4-en-1-amine 840
N1
2
34 O
C11H21NOMW 18329
In a same way the reaction was carried out using a 132 M solution of Cp2TiMe2
814 (25 mL 33 mmol 61 eq) the imino ester 837 (100 mg 054 mmol 10
eq) and yielded the crude enol ether 840 as an orange oil which was used
directly in the cyclisation reaction (99 mg 100) 1H NMR (400 MHz CDCl3) 103 (3H t J 71 Hz CH3CH2) 119 (3H d J
68 Hz CH3CH) 150-171 (2H m CH2CH3) 194 (2H qn J 71 Hz CH2-2) 224
(2H t J 71 Hz CH2-3) 236 (1H septet J 67 Hz CHCH3) 350 (2H t J 68
Hz CH2N) 366 (3H s OCH3) 396 (1H d J 19 Hz CHAHB=) 398 (1H d J
21 Hz CHAHB=) 759 (1H d J 63 Hz CHN)
Due to the relative instability of this compound we decided to carry on the next
step without more characterization
191
Guilaine F Blanc Experimental
N-(2rsquo4rsquo-Dimethoxybenzyliden)-4-methoxypent-4-en-1-amine 841
N1
16
5
43
2
OMeMeO
2
34 O
C15H21NO3MW 26333
In a same way the reaction was carried out using a 132 M solution of Cp2TiMe2
814 (24 mL 32 mmol 82 eq) the imino ester 838 (104 mg 039 mmol 10
eq) and yielded the crude enol ether 841 as an orange oil which was used
directly in the cyclisation reaction (29 mg 28) 1H NMR (400 MHz CDCl3) 202-208 (2H m CH2-2) 231 (2H t J 72 Hz
CH2-3) 368 (3H s OCH3) 374 (2H dt J 13 and 68 Hz CH2N) 399 (3H s
OCH3) 400 (3H s OCH3) 403 (1H d J 18 Hz CHAHB=) 404 (1H d J 21 Hz
CHAHB=) 659 (1H d J 22 Hz H3rsquo) 667 (1H dd J 23 and 86 Hz H5rsquo) 807
(1H d J 86 Hz H6rsquo) 874 (1H br s CH=N)
Due to the relative instability of this compound we decided to carry on the step
after without more characterization
(2R3R)-2-phenyl-3-methyloxo-pyrrolidine 843
HN
OPh
C12H15NOMW 18925
A solution of NaBH4 (37 mg 10 mmol 60 eq) in methanol (1 mL) was added to
a stirred aqueous solution of crude mixture 842 (016 mmol 10 eq) in MeOH
H2O (75 vv 09 mL) After stirring 1 h the solvent was removed under
reduced pressure and the aqueous slurry was extracted with CHCl3 then dried
(MgSO4) and the solvent was removed under reduced pressure Flash
chromatography [SiO2 hexanendashethyl acetate (9010ndash7030)] gave the free amine
843 (7 mg 23) as a yellow oil 1H NMR (400 MHz CDCl3) 201 (3H s CH3) 207-214 (2H m CH2-5) 300-
306 (2H m CH2-4) 313-318 (1H m CH-3) 425 (1H d J 73 Hz CH-2)716-
192
Guilaine F Blanc Experimental
721 (2H m Ar-H) 724-731 (3H m Ar-H) 13C NMR (100 MHz CDCl3) C 3000
(CH2) 3023 (CH3) 4676 (CH2) 6008 (CH) 6510 (CH)12673 (CH) 12738
(CH) 12861 (CH) 14311 (C) 20928 (C)
4-(1rsquo3rsquo-Dioxoisoindolin-2-yl)butanoic acid 853
6
5
4
7
N4
3
21
O
O
O
OH
C12H11NO4MW 23322
Following the procedure described by Kruper et al152 phthalic anhydride 852
(148 g 100 mmol 10 eq) γ-aminobutyric acid 817 (1030 g 100 mmol 10
eq) triethylamine (13 mL 93 mmol 01 eq) were placed in a round bottom
flask equipped with a Dean Stark trap and condenser The mixture was brought
to reflux and water was removed azeotropically over 15 h period The solution
was allowed to cool and stand overnight at rt The resulting crystals were
filtered off washed with hexane and dried (MgSO4) The crude crystals were
then washed with 5 of HCl(aq) (250 mL) and cold water (100 mL) The acid 853
was obtained as an amorphous solid (233 g 84) after recrystallisation from
MeOH - H2O (3070) 1H NMR (400 MHz CDCl3) 196 (2H qn J 71 Hz CH2-3) 235 (2H t J
74 Hz CH2-2) 370 (2H t J 70 Hz CH2N) 764-766 (2H m H5rsquo and H6rsquo)
777-779 (2H m H4rsquo and H7rsquo) Spectral data in agreement with those
previously reported in the literature152259
NN-Dibenzyl-4-(1rsquo3rsquo-dioxoisoindolin-2rsquo-yl)butanamide 855
6
5
4
7
3N
21
4
3
21
O
O
O
N C26H24N2O3MW 41248
1
6 5
4
32
1
6
5 4
3
2
A
B
193
Guilaine F Blanc Experimental
A solution of acid 853 (10 g 43 mmol 10 eq) in thionyl chloride (407 mL 558
mmol 130 eq) was heated to reflux over 25 h The solvent was then removed
under reduced pressure The crude mixture was immediately diluted with dry
CH2Cl2 (6 mL) The solution was added drop-wise to a stirred solution of
dibenzylamine 854 (91 mL 47 mmol 11 eq) dry pyridine (38 mL 47 mmol
11 eq) and dry CH2Cl2 (25 mL) at 0 degC This stirred solution was allowed to warm
to rt over 15 min and was then acidified with dilute aqueous HCl (5 by volume)
Layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x)
The organic layer was dried (MgSO4) and the solvent was removed under reduced
pressure The amide 855 was obtained after recrystallisation in diethyl ether-
pentane (955) (vv) as a cream amorphous solid (1218 g 69)
mp 98-100 degC (ether-pentane) 1H NMR (400 MHz CDCl3) 203 (2H qn J 70 Hz CH2-3) 240 (2H t J
73 Hz CH2-2) 371 (2H t J 68 Hz CH2-4) 435 (2H s NCH2Ph) 453 (2H s
NCH2Ph) 705 (2H d J 70 Hz H2rdquo and H6rdquo or H2rdquorsquo and H6rdquorsquo) 715 (2H d J
68 Hz H2rdquo and H6rdquo or H2rdquorsquo and H6rdquorsquo) 718-727 (6H m H4rdquo H5rdquo H6rdquo and
H4rdquorsquo H5rdquorsquo and H6rdquorsquo) 763- 765 (2H m H5rsquo and H6rsquo) 775-777 (2H m H4rsquo
and H7rsquo) 13C NMR (100 MHz CDCl3)C 2442 (CH2) 3052 (CH2) 3756 (CH2)
4835 (CH2) 4990 (CH2) 12325 (CH) 12637 (CH) 12740 (CH) 12758 (CH)
12828 (CH) 12863 (CH) 12896 (CH) 13212 (C) 13392 (CH) 13643 (C)
13734 (C) 16845 (C) 17233 (C) IR νmax (NaCl)cm-1 3053 (CH sp2) 2937 (CH
sp3) 1651 (C=O amide) MS (EI) mz () 412 (M+ 12) 321 (M+ Bn 32) 216
(M+ Bn and PhCH=NH 47) 160 (PhthCH2+ 29) 106 (PhCH=NH2
+ 100) 91
(Bn+ 61) HRMS (EI) 4121786 (M+ C26H24N2O3 requires 4121787)
Microanalysis Theory C 7573 H 583 N 680 Results C 7538 H 605
N 685
194
Guilaine F Blanc Experimental
4-Amino-NN-dibenzylbutanamide 847
A
B
H2N4
3
21
O
N
1
6 5
4
32
1
6
5 4
3
2
C18H22N2OMW 28238
Amide 855 (500 g 121 mmol 10 eq) was heated at reflux with hydrazine
hydrate 856 (18 mL 370 mmol 305 eq) and ethanol (77 mL) for 2 h The
reaction mixture was then cooled to 0 degC A precipitate which appeared upon
cooling was removed by filtration The filtrates were concentrated under
reduced pressure to remove ethanol then re-dissolved in ethyl acetate and
washed with a sat NaHCO3(aq) The aqueous layer was extracted with ethyl
acetate (2 ) The combined organic layers were washed with brine (1 ) dried
(MgSO4) and the solvent was removed under reduced pressure The desired
amine 847 was obtained as a yellow oil (297 g 87) 1H NMR (400 MHz CDCl3) 183 (2H qn J 71 Hz CH2-3) 242 (2H t J
74 Hz CH2-2) 272 (2H t J 70 Hz CH2-4) 305 (2H br s NH2) 437 (2H s
NCH2Ph) 451 (2H s NCH2Ph) 705 (2H d J 69 Hz H2rsquo and H6rsquo or H2rdquo and
H6rdquo) 712 (2H d J 73 Hz H2rsquo and H6rsquoor H2rdquo and H6rdquo) 715-730 (6H m H3rsquo
H4rsquo H5rsquo and H3rdquo H4rdquo H5rdquo) 13C NMR (100 MHz CDCl3)C 2971 (CH2) 3190
(CH2) 4124 (CH2) 4821 (CH2) 4994 (CH2) 12639 (CH) 12742 (CH) 12766
(CH) 12819 (CH) 12864 (CH) 12897 (CH) 13648 (C) 13734 (C) 17349 (C)
IR νmax (NaCl)cm-1 3361 (NH) 1636 (C=O amide) 1495 (C=C) MS (EI) mz ()
282 (M+ 5) 239 [(CH3CONBn2)+ 43] 196 [(PhCH=NHBn)+ 9] 148 (32) 106
(PhCH=NH2+ 96) 91 (Bn+ 100) HRMS (EI) 2821735 (M+ C18H22N2O requires
2821732)
195
Guilaine F Blanc Experimental
NN-Dibenzyl-4-(benzylidenamino)butanamide 848
A
B
N4
3
21
O
N
1
6 5
4
32
1
6
5 4
3
2
C25H26N2OMW 37049
1
65
4
32
Benzaldehyde 812 (03 mL 3 mmol 12 eq) was added to a stirred suspension
of the amine 847 (737 mg 261 mmol 10 eq) and Na2SO4 (358 mg 252 mmol
10 eq) in dry CH2Cl2 (7 mL) under argon at rt After stirring overnight the
mixture was filtered and the filtrate washed with water (2 ) then brine (1 )
and then dried (MgSO4) and the solvent was removed under reduced pressure
Excess reagents were removed at 100 degC under reduced pressure to leave the
imine 848 (517 mg 54) as a yellow oil 1H NMR(400 MHz CDCl3) 206 (2H qn J 69 Hz CH2-3) 250 (2H t
J 73 Hz CH2-2) 361 (2H t J 65 Hz CH2-4) 437 (2H s NCH2Ph) 454 (2H s
NCH2Ph) 705 (2H d J 66 Hz H2rdquo and H6rdquo or H2rdquorsquo and H6rdquorsquo) 715 (2H d
J 66 Hz H2rdquo and H6rdquo or H2rdquorsquo and H6rdquorsquo) 718-734 (9H m H3rsquo H4rsquo H5rsquo and
H3rdquo H4rdquo H5rdquo and H3rdquorsquo H4rdquorsquo H5rdquorsquo) 757-759 (2H m H2rsquo and H6rsquo) 815-817
(1H br s CH=N)
Due to the relative instability of this compound we decided to carry on the next
step without more characterization
Methyl 2-aminoethanoate hydrochloride salt 860
H3N
O
OCl C3H8ClNO2
MW 12555
The reaction was carried out following the procedure described for compound
818 using thionyl chloride (04 mL 6 mmol 20 eq) glycine 858 (225 mg 300
mmol 10 eq) in MeOH (40 mL) Washing the crude product with hot hexane
left the hydrochloride salt of the amino ester 860 as an amorphous solid (366
mg 98)
196
Guilaine F Blanc Experimental
mp= 155-157 degC 1H NMR (400 MHz DMSO-d6) 374 (3H s OCH3) 384 (2H s CH2) 848 (3H
br s NH3) 13C NMR (100 MHz DMSO-d6)C 3943 (CH3) 5248 (CH2) 16806 (C)
IR νmax (NaCl)cm-1 3415 (NH) 1752 (C=O) MS (FAB) mz () 90 [(M+
ammonium cation) 14] 79 (100) HRMS (FAB) 900555 [(M+ ammonium cation)
C4H8NO2 requires 900554] NMR spectral data in broad agreement with those
previously reported in CDCl3 1H NMR and IR spectral data in broad agreement
with those previously reported in D2O260
Methyl 2(S)-aminopropanoate hydrochloride salt 861
H3N
O
OCl
Me C4H10ClNO2MW 13958
In a same way the reaction was carried out using thionyl chloride (39 mL 53
mmol 20 eq) and a solution of Lndashalanine 859 (237 g 266 mmol 10 eq) in
MeOH (32 mL) Washing the crude product with hot hexane provided the
hydrochloride salt of the amino ester 861 as an amorphous solid (340 g 92) 1H NMR (400 MHz DMSO-d6) 143 (3H d J 71 Hz CH3CH) 374 (3H s
OCH3) 405 (1H q J 72 Hz CHCH3) 874 (3H br s NH3) 13C NMR (100 MHz
DMSO-d6)C 1553 (CH3) 4763 (CH) 5263 (CH3) 17026 (C) IR νmax (ATR)
cm-1 3570 (NH) 2956 (CH sp3) 1741 (C=O ester) 1602 (NH) MS (CI+) mz ()
104 [(M+ ammonium cation) 100] HRMS (CI+) 1040709 [(M+ ammonium
cation) C4H10NO2 requires 1040712] NMR spectral data in broad agreement
with those previously reported in CDCl3261
Methyl 2(S)ndash(benzylidenamino)propanoate 864
N
O
O
Me
1
2
3
45
6
C11H13NO2MW 19123
197
Guilaine F Blanc Experimental
The reaction was carried out following the procedure described for compound
819 using triethylamine (10 mL 72 mmol 20 eq) benzaldehyde 812 (048
mL 47 mmol 13 eq) the amino ester 861 (500 mg 358 mmol 10 eq) and
Na2SO4 (307 mg 216 mmol 06 eq) in dry CH2Cl2 (11 mL) Excess reagents were
removed at 140 degC under reduced pressure to leave the imine 864 (132 mg
19) as a yellow oil 1H NMR (400 MHz CDCl3) 144 (3H d J 68 Hz CH3CH) 374 (3H s OCH3)
405 (1H q J 68 Hz CHCH3) 730-735 (3H m H3rsquo H4rsquo and H5rsquo) 768-
770 (2H m H2rsquo or H6rsquo) 822 (1H br s CH=N) 1H NMR spectral data in
agreement with those previously reported in the literature262
Nndashbenzylidenndash3ndashmethoxybutndash3ndashenndash2ndashamine 866
NO
Me
1
2
3
45
6
C12H15NOMW 18925
The reaction was carried out as described for compound 820 using a 132 M
solution of Cp2TiMe2 814 (14 mL 18 mmol 60 eq) and the imino ester 864
(586 mg 031 mmol 10 eq) The solvent was removed under reduced pressure
to yield the crude enol ether 866 as a yellow oil which was used directly in the
cyclisation reaction (21 mg 36) 1H NMR (400 MHz CDCl3) 158 (3H d J 68 Hz CH3CH) 373 (3H s OCH3)
408 (1H q J 68 Hz CHCH3) 415 (1H d J 23 Hz CHAHB=) 435 (1H d J 22
Hz CHAHB=) 755-756 (3H m H3rsquo H4rsquo and H5rsquo) 791-794 (2H m H2rsquo and
H6rsquo) 844 (1H s CH=N) 1H NMR spectral data in agreement with those
previously reported in the literature263
198
Guilaine F Blanc Experimental
125 Experimental to chapter 10
Benzyl 2(S)-amino-3-(4rsquo-hydroxyphenyl)propanoate hydrochloride salt 109
4
56
1
23
HONH3 C16H18ClNO3
MW 30777O
O
Cl
HA HB
Procedure A (S)-tyrosine 103 (100 g 552 mmol 10 eq) p-TsOH (105 g
552 mmol 10 eq) and p-TsCl (126 g 661 mmol 12 eq) were added to dry
benzyl alcohol (11 mL 106 mmol 19 eq) and the mixture was heated at 80 oC
for 15 h under argon Benzyl alcohol was removed by distillation The mixture
was diluted with CHCl3 (110 mL) Then 1 M NaHCO3 (aq) (110 mL) was added to
the mixture The mixture was shaken and the layers were separated The
organic layer was concentrated to about 50 mL and 75 M HCl in dioxane (1 mL)
was added to the solution A precipitate was formed which was recrystallised
from methanol-ether to give the ester 109 as an amorphous solid (127 mg
74)
Procedure B Following the procedure described by Viswanatha and Hruby193 a
mixture of (S)-tyrosine 103 (140 g 773 mmol 10 eq) conc HCl (4 mL) and
benzyl alcohol (40 mL 387 mmol 50 eq) was heated at 100 C for 15 min to give
a clear solution Benzene (20 mL) was added and the solution was heated at
100 C and water was removed azeotropically for 25 h Conc HCl (1 mL) was
added and heating was continued for another 05 h The mixture was cooled and
diluted with diethyl ether (50 mL) The mixture was extracted with 1 M HCl(aq)
(5 20 mL) and water (2 20 mL) The aqueous layer was washed with diethyl
ether (2 ) and the pH was brought to pH 9 with 2 M NH4OH(aq) The mixture was
left overnight The solid was filtered off washed with water (2 ) and dried
(MgSO4) The solid was stirred with acetone (100 mL) and filtered to give
tyrosine (10 mg) The filtrate was concentrated under reduced pressure to give
the ester 109 as a yellow gum which solidified (842 mg 40)
199
Guilaine F Blanc Experimental
Procedure C Acetyl chloride (30 mL 42 mmol 30 eq) was added to a stirred
solution of dry benzyl alcohol (50 mL 483 mmol 35 eq) at 0 C The solution
was stirred for 15 min at 0 C under argon and then (S)-tyrosine 103 (250 g
138 mmol 10 eq) was added portion-wise to the solution The resulting
solution was heated at reflux for 4 h before removing benzyl alcohol by
distillation The ester 109 was obtained as a cream solid (981 mg 23 )
mp decomposed above 300 degC 1H NMR (400 MHz Methanol-d4) 305-315 (2H m CH2CH) 427 (1H t J 70
Hz CHCH2) 521 (1H d J 118 Hz OCHAHBPh) 525 (1H d J 120 Hz
OCHAHBPh) 671 (2H d J 84 Hz H3rsquo and H5rsquo) 697 (2H d J 84 Hz H2rsquo and
H6rsquo) 731-739 (5H m Ph) 13C NMR (100 MHz Methanol-d4)C 3681 (CH2)
5540 (CH) 6924 (CH2) 11695 (CH) 12557 (C) 12969 (CH) 12982 (CH)
12998 (CH) 13173 (CH) 13619 (C) 15836 (C) 17021 (C) IR νmax (KBr)cm-1
3404 (NH) 3138 (OH) 1739 (C=O) MS (FAB) mz () 272 [(M+ ammonium
cation) 100] 93 (43) HRMS (FAB) 2721285 [(M+ ammonium cation)
C16H18NO3 requires 2721287] []D26 1612 (c 104 MeOH) 1H NMR spectral
data in broad agreement with those previously reported in a mixture CDCl3-
DMSO-d6193
Benzyl 2(S)-[N-(tert-butoxycarbonyl)amino]-3-(4rsquo-hydroxyphenyl)propanoate
1010
4
5
6
1
23
HOHN
O
O
C21H25NO5MW 37143
O
O
HA HB
Prodecure A A solution of Boc2O (373 mg 171 mmol 11 eq) in dioxane
(16 mL) was added to a solution of (S)-tyrosine benzyl ester 109 (421 mg
155 mmol 10 eq) and Et3N (035 mL 25 mmol 16 eq) in water (18 mL) at rt
After being stirred for 24 h the reaction was acidified with 10 HCl(aq) at 0 degC
and then extracted with ethyl acetate (3 ) The combined organic layers were
washed with 5 HCl(aq) (2 ) The ester 1010 was obtained as a brown oil (498
mg 87)
200
Guilaine F Blanc Experimental
1H NMR (400 MHz CDCl3) 125 (9H s tBu) 286-289 (2H m CH2CH) 443-
449 (1H m CHCH2) 496 (1H d J 123 Hz OCHAHBPh) 505 (1H d J 120 Hz
OCHAHBPh) 511 (1H d J 83 Hz NH) 660 (2H d J 84 Hz H3rsquo and H5rsquo) 675
(2H d J 82 Hz H2rsquo and H6rsquo) 715-724 (5H m Ph) 1H NMR spectral data in
agreement with those previously reported in the literature194
Procedure B A solution of Boc2O (338 mg 155 mmol 10 eq) in cyclohexane
(03 mL) was added at 10 degC to a solution of (S)-tyrosine benzyl ester 109 (421
mg 155 mmol 10 eq) in cyclohexane (070 mL) After 20 h at 20 degC the
organic layer was washed with 001 N HCl(aq) and sat NaHCO3(aq) The solvent was
removed under reduced pressure The ester 1010 was obtained as a brown oil
(497 mg 86) Data as above
2(S)-[N-(tert-butoxycarbonyl)amino]-3-(4rsquo-hydroxyphenyl)propanoic acid
1012
C14H19NO5MW 28130
4
56
1
23
HOHN
OH
O
O
O
Following the procedure described by Jung and Lazarova264 triethylamine (58
mL 42 mmol 15 eq) was added to a solution of (S)-tyrosine 103 (500 g 276
mmol 10 eq) in dioxane water (11)(100 mL) The reaction flask was cooled to
0 oC and Boc2O (660 g 302 mmol 11 eq) was added in one batch After 05 h
the mixture was allowed to warm to rt and stirred overnight The reaction
mixture was then concentrated and the residue was diluted with water The
aqueous layer was extracted with ethyl acetate (3 ) acidified to pH 1 with 1 M
HCl(aq) and back extracted with ethyl acetate (2 ) The combined organic
extracts were washed with brine (1 ) dried (MgSO4) and the solvent was
removed under reduced pressure The acid 1012 was obtained without further
purification as a white foam (776 g 100)
201
Guilaine F Blanc Experimental
1H NMR (400 MHz CDCl3) H 136 (9H s tBu) 293-301 (2H m CH2CH) 447-
452 (1H m CHCH2) 500 (1H d J 84 Hz NH) 587 (1H br s OH) 666 (2H
d J 81 Hz H3rsquo and H5rsquo) 698 (2H d J 82 Hz H2rsquo and H6rsquo) 1H NMR spectral
data in agreement with those previously reported in the literature264
2(S)-[N-(tert-butoxycarbonyl)amino]-3-(4rsquo-methoxyphenyl)propanoic acid
1013 and methyl 2(S)-[N-(tert-butoxycarbonyl)amino]-
3-(4rsquo-methoxyphenyl)propanoate 1015
4
56
1
23
MeOHN
OH
O
O
O
C15H21NO5MW 29533
MeOHN
OMe
O
O
O
C16H23NO5MW 30936
Iodomethane (17 mL 28 mmol 10 eq) K2CO3 (572 g 414 mmol 15 eq) N-
Boc-(S)-tyrosine 1012 (776 g 276 mmol 10 eq) and anhydrous DMF (20 mL)
were stirred under argon at rt overnight The reaction mixture was quenched
with water (10 mL) and extracted with CH2Cl2 (3 ) dried (MgSO4) and the
solvent was removed under reduced pressure The acid 1013 was obtained in a
8812 mixture of the acid 1013 and the ester 1015 as a yellow liquid (504 g
88 mass recovery) The mixture was used without further purification
Data on acid only 1H NMR (400 MHz CDCl3) 133 (9H s tBu) 285-297 (2H
m CH2CH) 361 (3H s OMe) 438-443 (1H m CHCH2) 510 (1H d J 74 Hz
NH) 671 (2H d J 82 Hz H3rsquo and H5rsquo) 686 (2H d J 82 Hz H2rsquo and H6rsquo) 1H
NMR spectral data in agreement with those previously reported in the
literature265
202
Guilaine F Blanc Experimental
Benzyl 2(S)-[N-(tert-butoxycarbonyl)amino]-3-(4rsquo-methoxyphenyl)
propanoate 1011 and benzyl 2(S)-[N-(tert-butoxycarbonyl)amino]-
3-(4rsquo-hydroxyphenyl) propanoate 1020
C22H27NO5MW 38545
4
5
6
1
23
MeOHN
O
O
O
OHO
HN
O
O
O
O
C21H25NO5MW 37143
HA HAHB HB
Procedure A Following the procedure described by Rosenberg et al198 sodium
hydride [80 in mineral oil] (256 g 854 mmol 24 eq) was added to a solution
of N-Boc-(S)-tyrosine 1012 (1004 g 3573 mmol 10 eq) in anhydrous DMF (146
mL) at 0 degC under argon After 1 h iodomethane (22 mL 36 mmol 10 eq) was
added and the reaction was stirred at 0 degC for 3 h Benzyl bromide (47 mL
39 mmol 11 eq) was added and the reaction was allowed to warm to rt and was
stirred for 2 h The reaction was quenched with acetic acid (22 mL) poured
into sat NaHCO3(aq) and extracted with ethyl acetate (3 ) The organic layer was
washed with brine (1 ) and dried (MgSO4) Then the solvent was removed under
reduced pressure Flash chromatography [SiO2 petroleum etherndashEt2O (1000ndash
7525)] gave a 964 inseparable mixture of the ether 1011 and the alcohol
1020 (848 g 84 mass recovery) as an orange oil
R [SiO2 petroleum etherndashEt2O (7030)] 028 1H NMR (400 MHz CDCl3) 147 (9H s tBu) 307 (2H m CH2CH) 379 (3H s
OMe) 461-466 (1H m CHCH2) 510 (1H br s NH) 513 (1H d J 119 Hz
OCHAHBPh) 522 (1H d J 122 Hz OCHAHBPh) 680 (2H d J 82 Hz H3rsquo and
H5rsquo) 699 (2H d J 82 Hz H2rsquo and H6rsquo) 729-742 (5H m Ph) 13C NMR (100
MHz CDCl3)C 2837 (CH3) 3739 (CH2) 5467 (CH) 5519 (CH3) 6706 (CH2)
7985 (C) 11398 (CH) 12786 (C) 12848 (CH) 12861 (CH) 13037 (CH)
13532 (C) 15518 (C) 15865 (C) 17187 (C) IR νmax (NaCl)cm-1 3370 (N-H)
1715 (C=O ester) 1612 (N-H) 1511 (C=C) MS (CI+) mz () 386 [(M+H)+ 12]
250 [(M+H)+ BnO2CH] 215 (100) HRMS (CI+) 3861964 [(M+H)+ C22H28NO5
203
Guilaine F Blanc Experimental
requires 3861967] []D24 175 (c 107 CHCl3)
1H NMR and MS spectral data
consistent with the literature198
Procedure B A solution of the 4159 mixture of N-Boc-O-methoxy-(S)-tyrosine
1013 and N-Boc-O-methoxy-(S)-tyrosine methyl ester 1015 (400 g 136 mmol
10 eq) BnOH (15 mL 15 mmol 11 eq) and DMAP (166 mg 136 mmol 01 eq)
in CH2Cl2 (21 mL) under argon was treated with a solution of DCC (310 g 150
mmol 11 eq) in CH2Cl2 (31 mL) The mixture was stirred at 25 degC for 45 min
then cooled to 0 degC The filtrate was washed with water (2 x) 10 AcOH A
precipitation was observed The precipitate was removed by filtration and
washed with cold CH2Cl2 The filtrate was washed with H2O (2 x) The organic
layer was dried with MgSO4 and evaporated under reduced pressure Flash
chromatography [cyclohexane ndash EtOAc (8020 ndash 7030)] gave the desired
compound 1011 (214 mg 4) as a uncolor oil RF [SiO2 cyclohexane ndash EtOAc
(7030)] 056 Data as above
1-Benzyl-3-(4rsquo-methylphenyl)triazene 1019
NHN
C14H15N3MW 22529
N
A mixture of crushed ice (5000 g) and conc HCl (28 mL) was added to p-
toluidine 1018 (1000 g 9333 mmol 10 eq) at 10 degC A solution of potassium
nitrite (929 g 109 mmol 117 eq) in water (30 mL) was slowly added with
continued stirring for 1 h until a positive starch-potassiun iodide test was
obtained and the mixture was stirred for an additional hour The mixture was
then brought to pH 68-72 at 0 degC with a cold solution of sat NaCO3(aq) The
solution was added slowly to a vigorously stirred mixture of Na2CO3 (3000 g)
35 benzylamine(aq) (60 mL) and crushed ice (2000 g) The reaction mixture was
kept at 10 degC during the addition and stirred for 4 h at rt The solution was
extracted with diethyl ether (3 ) The combined organic extracts were dried
(Na2SO4) and concentrated under reduced pressure to give the triazene 1019 as
a red solid (2100 g 100) which was sufficiently pure for the next step
204
Guilaine F Blanc Experimental
1H NMR (400 MHz CDCl3) 225 (3H s Me) 376 (1H s NH) 471 (2H s
CH2) 705 (2H d J 79 Hz Ar-H) 714-728 (7H m Ar-H) IR νmax (NaCl)cm-1
3220 (NH) 1643 (C=C) 1519 (NH) MS (EI) mz () 106 (C6H5CH=NH2+ 20) 91
(C6H5CH2+ 100) HRMS (EI) 2251267 (M+ C14H15N3 requires 2251266)
Compound reported in the literature without spectroscopic data provided266
Benzyl 2(S)-[N-allyl-N-(tert-butoxycarbonyl) amino]-3-(4rsquorsquo-
methoxyphenyl)propanoate 104
4
56
1
23
MeO
32
1
BocN
O
O
C25H31NO5MW 42552
HC HD
HA HB
Sodium hydride [80 in mineral oil] (506 mg 169 mmol 13 eq) was added
portion-wise to a solution of the amine 1011 and alcohol 1020 (499 g 130
mmol 10 eq) and allyl bromide (15 mL 17 mmol 13 eq) in anhydrous DMF (75
mL) at 0 oC under argon The reaction mixture was then allowed to warm to rt
and stirred for 55 h After this time the reaction mixture was carefully poured
into iced-water and extracted into ethyl acetate (2 ) The combined organics
were then washed with water (3 ) dried (MgSO4) and the solvent was removed
under reduced pressure Flash chromatography [SiO2 petroleum etherndashEt2O
(1000ndash8515)] gave the ester 104 (28 mg 51) as an oil
R [SiO2 petroleum etherndashEt2O (7030)] 033 1H NMR (400 MHz DMSO-d6 at 90 degC) 134 (9H s tBu) 305 (1H dd J 93
and 142 Hz CHAHB-3) 320 (1H dd J 58 and 140 Hz CHAHB-3) 341 (1H dd
J 62 and 156 Hz NCHCHD) 371-377 (4H m OCH3 and NCHCHD) 437-441 (1H
m CH-2) 490-515 (4H m =CH2 and OCH2Ph) 549-558 (1H m CH=) 682
(2H d J 89 Hz H3rsquo and H5rsquo) 709 (2H d J 89 Hz H2rsquo and H6rsquo) 728-734
(5H m Ph) 13C NMR (100 MHz DMSO-d6 at 90 degC)C 2795 (CH3) 3459 (CH2)
4999 (CH2) 5518 (CH) 6100 (CH3) 6606 (CH2) 6975 (CH2) 7960 (C) 11394
(CH) 12763 (CH) 12783 (CH)12821 (CH) 12989 (C) 13006 (CH) 13463
(CH) 13591 (C) 15420 (C) 15821 (C) 17041 (C) IR νmax (ATR)cm-1 1739
(C=O) 1693 (C=O) 1647 (C=C) 1246 (C-O ether) 1163 (C-O ester) MS (CI+) mz
205
Guilaine F Blanc Experimental
() 426 [(M+H)+ 77] 370 (100) 326 (91) HRMS 4262281 [(M+H)+ C25H31NO5
requires 4262280] []D26 2769 (c 14 CHCl3)
3-Methoxy-5-phenylpent-2(Z)-ene 1023
OMe C12H16OMW 17625
TiCl4 (27 mL 25 mmol 40 eq) was added slowly to a stirred solution of freshly
distilled THF (42 mL) at 0 degC under argon Freshly distilled and dry TMEDA
(74 mL 49 mmol 80 eq) was added drop-wise to the solution After 05 h at 0
degC Zinc (359 g 549 mmol 90 eq) (previously activated by washing several
times with 5 HCl(aq) H2O acetone Et2O and drying under vacuum) was added
to the mixture at 0 degC in many portions in such a manner that the temperature
remained at 0 degC Then PbCl2 (75 mg 027 mmol 44 meq) was added and the
resulting suspension was warmed to 25 degC A solution of methyl 3-phenyl
propionate 1022 (095 mL 61 mmol 10 eq) and 11-dibromoethane (12 mL
13 mmol 22 eq) in dry THF (16 mL) was added via an addition funnel over a
period of 10 min at 25 degC and stirring was continued for 38 h The reaction
mixture was then cooled to 0 degC and sat K2CO3(aq) (10 mL) was added After
stirring at 0 degC for an additional 15 min the mixture was poured into Et2O (40
mL) and then passed through a short column of basic alumina (pre-treated by
shaking with 6 weight of water) to filter off the solid formed during the
quench The layers were separated and the aqueous layer extracted with Et2O
the combined ethered extracts were dried (Na2SO4) and the solvent was removed
under reduced pressure The residue was treated with hexane and the insoluble
precipitate formed was filtered off by passing through a short column of basic
alumina eluting with hexane Removal of solvents under reduced pressure gave
the enol ether 1023 as an oil (624 mg 58) 1H NMR (400 MHz CDCl3) 166 (3H m CH3CH) 244-252 (2H m CH2) 278-
287 (2H m CH2) 365 (3H s OCH3) 467 (1H q J 68 Hz CHCH3) 724-738
(5H m Ar-H) 1H NMR spectral data in agreement with those previously reported
in the literature 267
206
Guilaine F Blanc Experimental
Benzyl 2(S)-[N-(tert-butoxycarbonyl)-N-(2rsquo-oxoethyl)amino]-3-(4rsquorsquo-
methoxyphenyl) propanoate 1024
4
56
23
MeO
32
1
BocN
O
O
OC24H29NO6MW 42749
HA HB
A suspension of K2OsO42H2O (30 mg 008 mmol 2 mol) in deionised water (15
mL) was added to a stirred solution of alkene 104 (171 g 402 mmol 10 eq) in
THF (11 mL) at rt Then NaIO4 (258 g 121 mmol 30 eq) in water (23 mL) was
added over 05 h After stirring at rt for a further 05 h the reaction was diluted
with Et2O (50 mL) and quenched with sat Na2S2O3(aq) (40 mL) The aqueous layer
was extracted with Et2O (3 ) and the combined organics were dried (MgSO4) and
the solvent was removed under reduced pressure Flash chromatography [SiO2
petroleum ether-Et2O (1000-3070)] gave the aldehyde 1024 (102 g 60) as
an oil
R [SiO2 petroleum etherndashEt2O (4060)] 058 1H NMR(400 MHz DMSO-d6 at 90 degC) 129 (9H s tBu) 302 (1H dd J 98
and 143 Hz CHAHB-3) 319 (1H dd J 56 and 143 Hz CHAHB-3) 370 (5H m
OCH3 and CH2N) 478-487 (1H br s H2) 508 (2H s OCH2Ph) 682 (2H d J
78 Hz H3rsquo and H5rsquo) 712 (2H d J 76 Hz H2rsquo and H6rsquo) 728-741 (5H m Ph)
912 (1H s CHO) 13C NMR (100 MHz DMSO-d6 at 90 degC)c 2773 (CH3) 3451
(CH2) 5520 (CH2) 5557 (CH) 6636 (CH3) 6974 (CH2) 8070 (C) 11406 (CH)
12732 (CH) 12777 (CH) 12798 (CH) 12829 (CH) 12998 (C) 13573 (C)
15449 (C) 15832 (C) 17039 (C) 19936 (CH) IR νmax (NaCl)cm-1 1735 (C=O
ester) 1698 (C=O aldehyde) 1513 (C=C) MS (CI+) mz () 428 [(M+H)+ 15] 372
[(M+H)+ (CH3)2C=CH2 100] 328 [(M+H)+ (CH3)2C=CH2 and CO2 29] HRMS (CI+)
4282070 [(M+H)+ C24H30NO6 requires 4282073] []D24 767 (c 23 CHCl3)
207
Guilaine F Blanc Experimental
Benzyl 2(S)-N-[2rsquo2rsquo-bis(phenylthio)ethylamino]-3-(4rsquorsquo-methoxyphenyl)
propanoate 1027
4
5
6
1
23
MeO
32
1 O
O
C31H31NO3S2MW 52971
HN 1
2PhS SPh
HCHA HB HD
BF3OEt2 (01 mL 055 mmol 11 eq) was added to a solution of aldehyde 1024
(200 mg 047 mmol 10 eq) thiophenol (01 mL 11 mmol 23 eq) and acetic
acid (040 mL) in dry toluene (1 mL) under argon After 4 h the reaction mixture
was diluted with CH2Cl2 (10 mL) and washed with water (3 ) dried (MgSO4) and
the solvent was removed under reduced pressure Flash chromatography [SiO2
hexane-ethyl acetate (1000-7030)] gave the thioacetal 1027 (50 mg 20) as
an oil
R [SiO2 hexane-ethyl acetate (6040)] 032 1H NMR (400 MHz CDCl3) 196 (1H br s NH) 271 (1H dd J 58 and
125 Hz CHAHB-3) 283 (2H d J 70 Hz CH2N) 289 (1H dd J 67 and 125 Hz
CHAHB-3) 343 (1H t J 68 Hz CH-2rsquo) 368 (3H s OCH3) 435 (1H t J 62 Hz
CH-2) 493 (1H d J 122 Hz OCHCHDPh) 497 (1H d J 122 Hz OCHCHDPh)
670 (2H d J 87 Hz H3rdquo and H5rdquo) 697 (2H d J 87 Hz H2rdquo and H6rdquo) 710-
736 (15H m 3 x Ph) 13C NMR (100 MHz CDCl3)C 3767 (CH2) 5045 (CH2)
5417 (CH3) 5729 (CH) 6195 (CH) 6545 (CH2) 11286 (CH)12666 (CH)
12678 (CH) 12714 (CH) 12720 (CH) 12737 (CH) 12781 (CH) 12913 (CH)
12917 (CH) 13151 (CH) 13182 (CH) 13244 (C) 13261 (C) 13447 (C)
15744 (C) 17292 (C) IR νmax (NaCl)cm-1 3442 (N-H stretching) 1732 (C=O)
1612 (NH bending) MS (CI+) mz () 530 [(M+H)+ 74] 422 [(M+H)+ HOCH2C6H5
100] 420 [(M+H)+ HSPh 58] 312 [(M+H)+ HOCH2C6H5 and HSPh 32] 286
[(M+H)+ CH2=C(SPh)2 34] 167 (63) HRMS (CI+) 5301813 [(M+H)+ C31H32NO3S2
requires 5301824] []D25 + 043 (c 07 CHCl3)
208
Guilaine F Blanc Experimental
Ethyl 2-[N-(tert-butoxycarbonylamino)]acetate 1041
O
HN
O
C9H17NO4MW 20324
O
O
The reaction was carried out according to procedure described for compound
1010 using triethylamine (60 mL 43 mmol 20 eq) and a stirred solution of
glycine ethyl ester hydrochloride 1028 (300 g 215 mmol 10 eq) in
dioxanewater (11) (69 mL) The carbamate 1041 was obtained without
further purification as an oil (437 g 100) 1H NMR (400 MHz DMSO-d6) H 120 (3H t J 70 Hz CH3CH2) 140 (9H s tBu)
367 (2H d J 60 Hz CH2N) 409 (2H q J 70 Hz CH2CH3) 657 (1H br s NH) 1H NMR spectral data in agreement with those previously reported in the
literature268269
Ethyl 2-[N-allyl-N-(tert-butoxycarbonyl)amino]acetate 1029
O12
N
O
O
O
C12H21NO4MW 24330
12
3
The reaction was carried out according to procedure described for compound
104 using sodium hydride [80 in mineral oil] (837 mg 277 mmol 13 eq)
carbamate 1041 (436 g 215 mmol 10 eq) and allyl bromide (24 mL 28
mmol 13 eq) in anhydrous DMF (119 mL) The ester 1029 was obtained (474
g 91) as a yellow liquid
R [SiO2 petroleum ether-Et2O (7030)] 048
1H NMR (400 MHz DMSO-d6 at 90 degC) 120 (3H t J 71 Hz CH3CH2)
139 (9H s tBu) 375-388 (4H m CH2-2 and CH2-1rsquo) 412 (2H q J 71 Hz
CH2CH3) 509 (1H d J 103 Hz CHAHB=) 513 (1H d J 174 Hz CHAHB=) 571
(1H m CH=) 1H NMR spectral data in agreement with those previously reported
in the literature270
209
Guilaine F Blanc Experimental
Ethyl 2-(p-toluenesulfonamido)acetate 1042
O
HN
S
OO
O1
65
43
2
C11H15NO4SMW 25731
Following the procedure described by Shipov et al203 triethylamine (20 mL
14 mmol 20 eq) was added to a cooled suspension of glycine ethyl ether
hydrochloride salt 1028 (100 g 716 mmol 10 eq) in dry CH2Cl2 (14 mL)
then p-TsCl (137 g 716 mmol 10 eq) was added portion-wise The reaction
mixture was stirred at 21 degC for 45 h under argon The precipitate was filtered
off and the filtrate was concentrated under reduced pressure The mixture was
dissolved in Et2O and the excess of triethylamine was removed by washing with 1
M HCl(aq) (2 ) then the aqueous layer was extracted with Et2O (3 ) The
combined organics were dried (MgSO4) and the solvent was removed under
reduced pressure The sulfonamide 1042 was obtained without further
purification as a yellow oil (148 g 80)
R [SiO2 petroleum etherndashethyl acetate (7030)] 036 1H NMR (400 MHz CDCl3) 111 (3H t J 72 Hz CH3CH2) 235 (3H s CH3Ar)
369 (2H d J 51 Hz CH2N) 401 (2H q J 72 Hz CH2CH3) 500 (1H br s NH)
724 (2H d J 81 Hz H3rsquo and H5rsquo) 768 (2H d J 83 Hz H2rsquo and H6rsquo) 13C NMR
(100 MHz CDCl3)C 1399 (CH3) 2155 (CH3) 4417 (CH2) 6192 (CH2) 12729
(CH) 12976 (CH) 13612 (C) 14384 (C) 16879 (C) IR νmax (ATR)cm-1 3221
(NH) 1732 (C=O ester) 1620 (NH) MS (EI) mz () 257 (M+ 18) 184
(TsNHCH2+ 100) 155 (CH3C6H4SO2
+ 94) 91 (CH3C6H4+ 84) HRMS (EI) 2570725
(M+ C11H15NO4S requires 2570722) Microanalysis Theory C 5136 H 584 N
545 Results C 5134 H 589 N 551
210
Guilaine F Blanc Experimental
Ethyl 2-(N-allyl-p-toluenesulfonamido)acetate 1030
O12
NS
OO
O1
65
43
2
C14H19NO4SMW 29737
12
3
The reaction was carried out following the procedure described for compound
1029 using sodium hydride [80 in mineral oil] (304 g 102 mmol 13 eq)
sulfonamide 1042 (2017 g 785 mmol 10 eq) and allyl bromide (88 mL 100
mmol 13 eq) in anhydrous DMF (436 mL) Flash chromatography [SiO2
petroleum etherndashethyl acetate (955ndash8020)] gave the ester 1030 (1452 g 63)
as an oil
R [SiO2 petroleum etherndashethyl acetate (7030)] 071 1H NMR(400 MHz CDCl3) 119 (3H t J 71 Hz CH3CH2) 242 (3H s CH3Ar)
390 (2H d J 64 Hz CH2-1rsquo) 400 (2H s CH2-2) 408 (2H q J 70 Hz
CH2CH3) 516 (1H d J 176 Hz CHAHB=) 518 (1H d J 109 Hz CHAHB=) 564-
574 (1H m CH=) 730 (2H d J 77 Hz H3rdquo and H5rdquo) 774 (2H d J 78 Hz
H2rdquo and H6rdquo) 13C NMR (100 MHz CDCl3)C 1404 (CH3) 2152 (CH3) 4700
(CH2) 5074 (CH2) 6120 (CH2) 11981 (CH2) 12737 (CH) 12958 (CH) 13230
(CH) 13689 (C) 14319 (C) 16885 (C) IR νmax (NaCl)cm-1 1739 (C=O ester)
1644 (C=C allyl) 1597 (C=C arom) MS (CI+) mz () 298 [(M+H)+ 24] 89 (100)
HRMS (CI+) 2981108 [(M+H)+ C14H20NO4S requires 2981113]
N-allyl-N-(2-ethoxyprop-2-en-1-yl)-p-toluenesulfonamide 1033
O21
NS
3
O
O1
65
43
2
12
3
C15H21NO3SMW 29540
Procedure A A 107 M solution of Cp2TiMe2 1021 (32 mL 34 mmol 30 eq) in
toluene-THF (11 by mass) was added to the ester 1030 (344 mg 116 mmol
10 eq) and sealed in a 10 mL microwave tube under argon The mixture was
211
Guilaine F Blanc Experimental
irradiated over 10 min under 100 W microwave power to raise the internal
temperature to 65 degC before cooling The resultant black solution was
concentrated under reduced pressure Flash chromatography [Al2O3 petroleum
etherndashCH2Cl2 (8020ndash6040)] gave the enol ether 1033 (71 mg 21) as a brown
oil
R [Al2O3 petroleum ether-CH2Cl2 (6040)] 053 1H NMR (400 MHz CDCl3)105 (3H t J 69 Hz CH3CH2) 234 (3H s CH3Ar)
350 (2H q J 70 Hz CH2CH3) 376-377 (4H m 2 x CH2N) 389 (1H d J 23
Hz CHAHB-3) 398 (1H d J 23 Hz CHAHB-3) 508 (1H d J 91 Hz CHCHD-3rdquo)
509 (1H d J 173 Hz CHCHD-3rdquo) 555-565 (1H m CH=) 719 (2H d J 81 Hz
H3rsquo and H5rsquo) 766 (1H d J 83 Hz H2rsquo and H6rsquo) 13C NMR (100 MHz CDCl3)C
1419 (CH3) 2145 (CH3) 4921 (CH2) 4981 (CH2) 6296 (CH2) 8461 (CH2)
11891 (CH2) 12761 (CH) 12905 (CH) 13286 (CH) 13778 (C) 14292 (C)
15728 (C) IR νmax (ATR)cm-1 2980 (CH sp3 and sp2) 1631 (C=C) 1599 (C=C
arom) 1155 (C-O ether)
Due to the relative instability of this compound we decided to carry onto the
next step without more characterization
Procedure B A 107 M solution of Cp2TiMe2 1021 (46 mL 50 mmol 30 eq) in
toluene-THF (11 by mass) was added to the ester 1030 (491 mg 165 mmol
10 eq) and the mixture stirred under argon at 65 degC in the dark for 24 h After
this time the mixture was diluted with petroleum ether and filtered The
filtrate was concentrated under reduced pressure Flash chromatography [Al2O3
petroleum etherndashethyl acetate (1000ndash5050)] then gave the enol ether 1033
(187 mg 38) as a yellow oil Data as above
N-allyl-N-(2-oxopropyl)-p-toluenesulfonamide 1043
321
NS
OO
O1
65
43
2
12
3
C13H17NO3SMW 26734
212
Guilaine F Blanc Experimental
Procedure C The reaction was carried out according to procedure A using a
107 M solution of Cp2TiMe2 1021 (32 mL 34 mmol 30 eq) in toluene-THF
(11 by mass) and the ester 1030 (344 mg 116 mmol 10 eq) The resultant
black solution was concentrated under reduced pressure 1 M HCl(aq) (10 mL) was
added to a solution of the crude mixture in THF (11 mL) The mixture was stirred
for 1 h at 21 degC After this time the reaction mixture was poured into water and
extracted into ethyl acetate (3 ) The combined organics were dried (MgSO4)
and the solvent was removed under reduced pressure Flash chromatography
[petroleum ether-Et2O (1000ndash8020)] gave the ketone 1043 (15 mg 5) as a
yellow oil
R [SiO2 petroleum ether-Et2O (7030)] 033 1H NMR (400 MHz CDCl3) 211 (3H s CH3CO) 237 (3H s CH3Ar) 374 (2H
d J 66 Hz CH2-1rdquo) 384 (2H s CH2-1) 507 (1H qd J 13 and 170 Hz
CHAHB=) 511 (1H qd J 11 and 101 Hz CHAHB=) 559 (1H ddt J 101 168
and 67 Hz CH=) 724 (2H d J 78 Hz H3rsquo and H5rsquo) 764 (2H d J 76 Hz H2rsquo
and H6rsquo) 13C NMR (100 MHz CDCl3)C 1984 (CH3) 2531 (CH3) 4979 (CH2)
5383 (CH2) 11864 (CH2) 12567 (CH) 12798 (CH) 13037 (CH) 13432 (C)
14197 (C) 20230 (C) IR νmax (NaCl)cm-1 1734 (C=O ketone) 1643 (C=C) MS
(CI+) mz () 268 [(M+H)+ 87] 157 (CH3C6H4SO2H2+ 39) 136 (55) 112
[(CH2=CHCH=NHCH2COCH3)+ 100] HRMS (CI+) 2681006 [(M+H)+ C13H18NO3S
requires 2681007]
Procedure D Grubbs 1st generation catalyst 1045 (50 mg 60 mol 30 mol)
was added to a stirred solution of enol ether 1033 (58 mg 020 mmol 10 eq)
in dry CH2Cl2 (1 mL) under argon The mixture was stirred at 50 degC for 6 h The
solvent was removed under reduced pressure The crude mixture was then
stirred with THF (2 mL) and 1 M HCl (5 mL) for 1 h The reaction was quenched
with water and the aqueous layer extracted with ethyl acetate The organic
layer was dried (MgSO4) and then concentrated under reduced pressure Flash
chromatography [SiO2 petroleum ether-ethyl acetate (1000-7030)] gave the
ketone 1043 (34 mg 65) as an oil Data as above
Procedure E Grubbs 2nd generation catalyst 1046 (11 mg 10 mol 5 mol)
was added to a stirred solution of enol ether 1033 (69 mg 023 mmol 10 eq)
213
Guilaine F Blanc Experimental
in dry CH2Cl2 (23 mL) under argon The mixture was stirred at 50 degC for 1 h The
solvent was removed under reduced pressure Flash chromatography [Al2O3
hexane-ethyl acetate (1000-8020)] gave the ketone 1043 (28 mg 46) as an
oil Data as above
N-(2-ethoxyprop-2-en-1-yl)-p-toluenesulfonamide 1044
O21
HN
S
3
O
O1
65
43
2
C12H17NO3SMW 25533
The reaction was carried out according to procedure A using a 107 M solution of
Cp2TiMe2 1021 (32 mL 34 mmol 30 eq) in toluene-THF (11 by mass) and the
ester 1030 (344 mg 116 mmol 10 eq) Flash chromatography [Al2O3
petroleum etherndashCH2Cl2 (8020ndash6040)] gave the enol ether 1044 (110 mg 37)
as a yellow oil 1H NMR(400 MHz CDCl3) 118 (3H t J 69 Hz CH2CH3) 242 (3H s ArCH3)
353 (2H q J 70 Hz OCH2) 359 (2H d J 63 Hz CH2) 384 (1H br s
CHAHB=) 398 (1H br s CHAHB=) 490 (1H br s NH) 728 (2H d J 81 Hz Ar)
774 (2H d J 82 Hz Ar)
N-(2-oxopropyl)-p-toluenesulfonamide 1047
321
HN
S
OO
O1
65
43
2
C10H13NO3SMW 22728
The reaction was carried out according to procedure D using Grubbs 1st
generation catalyst 1045 (50 mg 60 mol 30 mol) and a stirred solution of
enol ether 1033 (58 mg 020 mmol 10 eq) in dry CH2Cl2 (1 mL) Flash
chromatography [SiO2 petroleum ether-ethyl acetate (1000-7030)] gave the
ketone 1047 (15 mg 35) as an oil 1H NMR (400 MHz CDCl3) 215 (3H s CH3CO) 244 (3H s CH3Ar) 371 (2H
br s CH2N) 548-551 (1H m NH) 732 (2H d J 81 Hz H3rsquo and H5rsquo) 767
214
Guilaine F Blanc Experimental
(2H d J 81 Hz H2rsquo and H6rsquo) 1H NMR spectral data in agreement with those
previously reported in the literature271
Ethyl 2-[N-(2rsquo-oxoethyl)-p-toluenesulfonamido]acetate 1048
C13H17NO5SMW 29934O1
2
NS
OO
O1
65
43
2
12
O
The reaction was carried out according to procedure described for compound
1024 using K2OsO42H2O (50 mg 013 mmol 2 mol) in deionised water
(27 mL) a stirred solution of alkene 1030 (200 g 673 mmol 10 eq) in THF
(19 mL) and NaIO4 (432 g 202 mmol 30 eq) in water (39 mL)Flash
chromatography [SiO2 petroleum etherndashethyl acetate (1000-4060)] gave the
aldehyde 1048 (142 g 71) as a yellow oil
R [SiO2 petroleum etherndashethyl acetate (6040)] 041 1H NMR (400 MHz CDCl3) 121 (3H t J 72 Hz CH3CH2) 243 (3H s CH3Ar)
398 (2H s CH2-2) 408-414 (4H m CH2-1rsquo and CH2CH3) 733 (2H d J 81 Hz
H3rdquo and H5rdquo) 769 (2H d J 83 Hz H2rdquo and H6rdquo) 970 (1H s CHO) 13C NMR
(100 MHz CDCl3)C 1399 (CH3) 2103 (CH3) 4999 (CH2) 5740 (CH2) 6148
(CH2) 12760 (CH) 13029 (CH) 13558 (C) 14397 (C) 16848 (C) 19818 (CH)
IR νmax (ATR)cm-1 2983 (CH sp3) 1732 (C=O aldehyde and ester) 1597 (C=C
arom) MS (FAB) mz () 300 [(M+H)+ 100] HRMS (FAB) 3000905 [(M+H)+
C13H18NO5S requires 3000906]
Ethyl 2-N-[2rsquo2rsquo-bis(phenylthio)ethyl]-p-toluenesulfonamidoacetate 1049
O12
NS
OO
O1
65
43
2
1C25H27NO4S3MW 50168
2
SPhPhS
215
Guilaine F Blanc Experimental
The reaction was carried out according to procedure described for compound
1027 using BF3OEt2 (054 mL 431 mmol 11 eq) aldehyde 1048 (117 mg
392 mmol 10 eq) thiophenol (092 mL 900 mmol 23 eq) and acetic acid
(35 mL) in dry toluene (9 mL) Flash chromatography [SiO2 petroleum ether-
ethyl acetate (1000-6040)] gave the thioacetal 1049 (957 mg 49) as an oil
R [SiO2 petroleum ether-ethyl acetate (8020)] 049 1H NMR (400 MHz CDCl3) 112 (3H t J 71 Hz CH3CH2) 236 (3H s CH3Ar)
352 (2H d J 71 Hz CH2-1rsquo) 398 (2H q J 71 Hz CH2CH3) 437 (2H s CH2-
2) 482 (1H t J 72 Hz CH-2rsquo) 714 (2H d J 81 Hz H3rdquo and H5rdquo) 732-738
(8H m H2rdquo and H6rdquo and Ar-H) 749 (4H d J 73 Hz Ar-H) 13C NMR (100 MHz
CDCl3)C 1343 (CH3) 2099 (CH3) 5054 (CH2) 5181 (CH2) 5720 (CH) 6073
(CH2) 12693 (CH) 12746 (CH) 12857 (CH) 12883 (CH) 13199 (CH) 13289
(C) 13536 (C) 14299 (C) 16827 (C) IR νmax (ATR)cm-1 1737 (C=O ester)
1577 (C=C) MS (FAB) mz () 524 [(M+Na)+ 100] 392 (86) 237 (99) HRMS
(FAB) 5240999 [(M+Na)+ C25H27NO4S3Na requires 5241000]
Methyl 2(S)-amino-3-phenylpropanoate hydrochloride salt 1058
O
1 O2
2H3N
31
65
4
3
Cl
C10H14ClNO2MW 21568
HB
HA
Following the procedure described by Hvidt and Szarek213 (S)-phenylalanine
1051 (2100 g 127 mmol 10 eq) was added to a stirred solution of thionyl
chloride (110 mL 152 mmol 12 eq) in methanol (350 mL) and the resulting
mixture heated under reflux for 18 h The mixture was then evaporated under
reduced pressure affording in quantitative yield (2731 g) a crystalline product
1058 that was used without further purification 1H NMR (400 MHz D2O) 315 (1H dd J 76 and 139 Hz CHAHB-3) 327 (1H
dd J 58 and 139 Hz CHAHB-3) 376 (3H s OCH3) 435 (1H dd J 58 and
76 Hz CHN) 720-722 (2H m H2rsquo and H6rsquo) 730-737 (3H m H3rsquo H4rsquo and
H5rsquo) 1H NMR spectral data in agreement with those previously reported in the
literature213
216
Guilaine F Blanc Experimental
Methyl 2(S)-amino-3-phenylpropanoate 1059
O
1 O2
2H2N
31
65
4
3
C10H13NO2MW 17922
HBHA
Following the procedure described by Garner and Kaniskan214 a solution of (S)-
phenylalanine methyl ester hydrochloride salt 1058 (2731 g 1270 mmol) in
dry CH2Cl2 was shaken with concentrated aqueous ammonia solution (2 ) The
organic layer was dried (MgSO4) filtered and the solvent was removed under
reduced pressure to afford the free amine 1059 as a liquid (2149 g 95) 1H NMR (400 MHz CDCl3) 142 (2H br s NH2) 284 (1H dd J 78 and 134
Hz CHAHB-3) 307 (1H dd J 51 and 136 Hz CHAHB-3) 368-373 (4H m OCH3
and CHN) 717 (2H d J 76 Hz H2rsquo and H6rsquo) 721-731 (3H m H3rsquo H4rsquo and
H5rsquo) 13C NMR (100 MHz CDCl3)C 4110 (CH2) 5197 (CH) 5584 (CH3) 12682
(CH) 12856 (CH) 12926 (CH) 13723 (C) 17545 (C) IR νmax (ATR)cm-1 3383
(NH2) 3003 (CH sp2) 1734 (C=O ester) MS (FAB) mz () 180 [(M+H)+ 100]
HRMS (FAB) 1801027 [(M+H)+ C10H14NO2 requires 1801025] []D22 + 2885 (c
126 CHCl3)
Methyl 2(S)-(N-benzylidenamino)-3-phenylpropanoate 1052
O
1 O2
2N
31
65
4
3
C17H17NO2MW 26732HB
HA
Benzaldehyde (47 mL 47 mmol 10 eq) was added to a stirred mixture of free
amine 1059 (1001 g 5592 mmol 12 eq) in dry CH2Cl2 (280 mL) and MgSO4
The mixture was stirred at rt under argon for 20 h After filtration the solvent
was removed under reduced pressure and the crude product 1052 (1495 g
quant) was used in the next step without purification due to its instability
217
Guilaine F Blanc Experimental
1H NMR (400 MHz CDCl3) 315 (1H dd J 88 and 134 Hz CHAHB-3) 337
(1H dd J 51 and 136 Hz CHAHB-3) 373 (3H s OCH3) 417 (1H dd J 51 and
88 Hz CHN) 714-724 (5H m Ph) 736-740 (3H m H3rsquo H4rsquo and H5rsquo) 766-
769 (2H m H2rsquo and H6rsquo) 790 (1H s CH=N) 1H NMR spectral data in
agreement with those previously reported in the literature214
Methyl 2(S)-(N-benzylamino)-3-phenylpropanoate 1053
O
1 O2
2HN
3 1
65
4
3
C17H19NO2MW 26934HA HB
Following the procedure described by Garner and Kaniskan214 NaBH4 (318 g
841 mmol 15 eq) was added to a stirred solution of imine 1052 (1500 g 56
mmol 10 eq) in methanol (135 mL) at 0 degC The reaction mixture was allowed
to stir at 0 degC for 15 h at which point acetone was added and the mixture was
concentrated under reduced pressure The residue was dissolved in ethyl acetate
and washed with water (2 ) The organic layer was dried (MgSO4) and
concentrated under reduced pressure to yield the amine 1053 as an oil (862 g
57) 1H NMR (400 MHz CDCl3) 180 (1H br s NH) 295 (2H d J 71 Hz CH2CH)
353 (1H t J 68 Hz CHCH2) 362 (3H s OCH3) 363 (1H d J 131 Hz
NHCHAHBPh) 373 (1H d J 131 Hz NHCHAHBPh) 715 (2H d J 71 Hz H2rsquo and
H6rsquo) 719-728 (8H m Ph H3rsquo H4rsquo and H5rsquo) 1H NMR spectral data in
agreement with those previously reported in the literature214
3(S)4-Dibenzylmorpholin-2-one 1060
N
O
O
Ph
Ph
HaxHX
HY Heq
Heq
HB
HA
HC
Hax
C18H19NO2MW 28135
12
34
56
218
Guilaine F Blanc Experimental
A stirred solution of amine 1053 (309 mg 115 mmol 10 eq) triethylamine
(02 mL 14 mmol 12 eq) and 2-bromoethanol (01 mL 14 mmol 12 eq) in
dry toluene (24 mL) was heated under reflux under argon for 20 h After
cooling the mixture was filtered and the filtrate concentrated under reduced
pressure Flash chromatography [SiO2 petroleum ether-ethyl acetate (1000ndash
5050)] gave the morpholine 1060 (78 mg 24) as a yellow oil
R [SiO2 petroleum ether-ethyl acetate (8020)] 036 1H NMR (400 MHz CDCl3) 238 (1H ddd J 25 101 and 126 Hz CH-5ax)
272 (1H dt J 126 and 25 Hz CH-5eq) 311 (1H dd J 47 and 140 Hz CHAHB)
322 (1H dd J 47 and 140 Hz CHAHB) 331 (1H d J 131 Hz CHXHY)
360 (1H t J 47 Hz CHc) 375 (1H dt J 22 and 104 Hz CH-6ax) 396 (1H d
J 134 Hz CHXHY) 402 (1H dt J 107 and 28 Hz CH-6eq) 715-725 (10H m
Ar-H) 1H NMR spectral data in agreement with those previously reported in the
literature272
Methyl 2(S)-[N-(22rsquo-dimethoxyethylidenamino]-3-phenylpropanoate 1062
O
1 O2N
3
Ph
12MeO
OMe
C14H19NO4MW 26530
HAHB
Dimethoxyacetaldehyde [60 in water] (30 mL 20 mmol 11 eq) was added to
a stirred solution of amine 1059 (327 g 183 mmol 10 eq) in methanol (52
mL) The mixture was stirred at rt for 20 h After filtration excess
dimethoxyacetaldehyde was removed at 125 degC under reduced pressure to leave
the imine 1062 (326 g 73) as a yellow oil 1H NMR (400 MHz CDCl3) 308 (1H dd J 43 and 137 Hz CHAHB-3)
318 (3H s OCH3) 330-332 (4H m CO2CH3 and CHN) 372 (3H s OCH3)
406 (1H dd J 47 and 137 Hz CHAHB-3) 463 (1H d J 43 Hz CH-2rsquo) 712-
727 (6H m Ar-H and CH=N)
219
Guilaine F Blanc Experimental
Methyl 2(S)-[N-(2rsquo2rsquo-dimethoxyethylamino)]-3-phenylpropanoate 1063
O
1 O2
HN
3
Ph
1
C14H21NO4MW 267322MeO
OMe
HBHA
Procedure A The reaction was carried out according to the procedure described
for compound 1053 using the imine 1062 (871 mg 329 mmol 10 eq prepared
from 589 mg of amine 1059) methanol (8 mL) and sodium borohydride (187
mg 494 mmol 15 eq) Flash chromatography [SiO2 petroleum ether-ethyl
acetate (1000ndash5050)] gave the amine 1063 (54 mg 6) as a yellow oil
R [SiO2 petroleum ether-ethyl acetate (7030)] 028 1H NMR (400 MHz CDCl3) 171 (1H br s NH) 252 (1H dd J 51 and
119 Hz CHAHB-3) 267 (1H dd J 59 and 120 Hz CHAHB-3) 288 (2H d J
71 Hz CH2N) 323 (3H s OCH3) 324 (3H s OCH3) 346 (1H t J 71 Hz CH-
2rsquo) 347 (3H s CO2CH3) 433 (1H t J 54 Hz NCHCH2) 710-723 (5H m Ar-
H) 13C NMR (100 MHz CDCl3)C 3662 (CH2) 4821 (CH2) 5040 (CH3) 5201
(CH3) 5264 (CH3) 6193 (CH) 10267 (CH) 12562 (CH) 12734 (CH) 12815
(CH) 13638 (C) 17361 (C) IR νmax (ATR)cm-1 1734 (C=O) MS (CI+) mz ()
268 [(M+H)+ 100] 236 [MeOCH=CHNH2+CH(Bn)CO2Me 78] 208
[(MeO)2CHCH2NH2+CH=CHPh 52] 180 +[H3NCH(Bn)CO2Me] 78 HRMS (CI+)
2681539 [(M+H)+ C14H22NO4 requires 2681549] []D23 + 178 (c 132 CHCl3)
Procedure B 10 Palladium on carbon (120 mg) was added to a stirred solution
of imine 1062 (109 g 410 mmol 10 eq prepared from 108 g of amine
1059) in ethanol (37 mL) The atmosphere was changed to H2 and the reaction
was stirred at rt for 22 h The mixture was filtered and the solvent removed
under reduced pressure to yield the amine 1063 as a yellow oil (980 mg 90
over 2 steps) Data as above
220
Guilaine F Blanc Experimental
Methyl 2(S)-[N-benzyl-N-(2rsquo2rsquo-dimethoxyethyl)amino]-3-phenylpropanoate
1064
C21H27NO4MW 35744
O
1 O2N
3 Ph
12MeO
OMePh
Benzyl bromide (20 mL 18 mmol 15 eq) was added to a stirred solution of
amine 1063 (318 g 119 mmol 10 eq) and DIPEA (42 mL 24 mmol 20 eq) in
dry CH3CN (18 mL) under argon The mixture was stirred at 70 degC for 22 h The
mixture was then evaporated under reduced pressure The resulting mixture was
dissolved in water and the aqueous layer extracted with ethyl acetate (3 ) The
organics were washed with water (2 ) 01 N HCl (1 ) water (1 ) and then
dried (MgSO4) The solvent was removed under reduced pressure Flash
chromatography [SiO2 petroleum ether-ethyl acetate (1000ndash9010)] gave the
ester 1064 (323 g 76) as an oil
R [SiO2 petroleum ether-ethyl acetate (8020)] 053 1H NMR (400 MHz CDCl3) 268 (1H dd J 53 and 141 Hz CHAHB-3)
275 (1H dd J 48 and 141 Hz CHAHB-3) 284 (1H dd J 79 and 140 Hz
CHCHD-1rsquo) 302 (1H dd J 72 and 140 Hz CHCHD-1rsquo) 312 (3H s OCH3)
315 (3H s OCH3) 357 (3H s OCH3) 360 (1H d J 144 Hz NCHEHFPh)
370 (1H t J 76 Hz CH-2rsquo) 393 (1H d J 141 Hz NCHEHFPh) 407 (1H dd J
49 and 53 Hz NCHCH2) 703-716 (10H m Ar-H) 13C NMR (100 MHz
CDCl3)C 3597 (CH2) 5087 (CH3) 5279 (CH3) 5334 (CH3) 5397 (CH2) 5589
(CH2) 6455 (CH) 10479 (CH) 12597 (CH) 12667 (CH) 12787 (CH) 12797
(CH) 12848 (CH) 12910 (CH) 13819 (C) 13932 (C) 17287 (C) IR νmax
(ATR)cm-1 1732 (C=O ester) MS (CI+) mz () 358 [(M+H)+ 92] 326
[MeOCH+CH2N(Bn)CH(Bn)CO2Me 100] HRMS (CI+) 3582014 [(M+H)+ C21H28NO4
requires 3582018] []D23 2059 (c 118 CHCl3)
221
Guilaine F Blanc Experimental
Methyl 2(S)-[N-benzyl-N-2rsquo(RS)-methoxy-2rsquo-(phenylthio)ethylamino]-3-
phenylpropanoate 1065
O
1 O2N
3 Ph
12PhS
Ph
C26H29NO3SMW 43558
OMe O
1 O2N
3 Ph
12PhS
PhOMe
and
A mixture of acetal 1064 (200 mg 056 mmol 10 eq) and freshly distilled
thiophenol (013 mL 13 mmol 23 eq) was added to molten TBAB (55 mg
017 mmol 30 mol) at 130 degC and the whole mixture was stirred at 130 degC
under argon for 1 h After 1 h more thiophenol (013 mL 13 mmol 23 eq) was
added and the mixture was left to stir at 130 degC for 5 h Then the mixture was
diluted with CH2Cl2 and washed with water (2 ) The organic layer was dried
(MgSO4) and the solvent was removed under reduced pressure Flash
chromatography [SiO2 petroleum ether-ethyl acetate (1000ndash955)] gave a 11
mixture of epimeric acetals 1065 (161 mg 66) as an oil Data for (2S2rsquoR)-
1065 and (2S2rsquoS)-1065
R [SiO2 petroleum ether-ethyl acetate (9010)] 041 1H NMR (400 MHz CDCl3) H 280 (1Ha or b dd J 85 and 143 Hz CHAHB-3a or b)
285 (1Ha or b dd J 76 and 142 Hz CHAHB-3a or b) 291-303 (6H m CH2-1rsquo and
CHAHB-3 a and b) 324 (3Ha or b s OCH3a or b) 325 (3Ha or b s OCH3
a or b) 353 (3Ha
or b s CO2CH3a or b) 355 (3Ha or b s CO2CH3
a or b) 356 (1H a or b d J 139 Hz
NCHCHDPha or b) 364 (1H a or b t J 78 Hz CH-2rsquoa or b) 370 (1H a or b d J 147 Hz
NCHCHDPha or b) 374 (1H a or b t J 79 Hz CH-2rsquoa or b) 392 (1H a or b d J 144 Hz
NCHCHDPha or b) 397 (1H a or b d J 141 Hz NCHCHDPha or b) 426 (1H a or b dd J
38 and 83 Hz CHNa or b) 445 (1H a or b dd J 43 and 76 Hz CHNa or b) 697-
728 (30H m Ar-H a and b) 13C NMR (100 MHz CDCl3) C 3535 (CH2) 3538 (CH2)
5015 (CH3) 5498 (CH2) 5500 (CH2) 5516 (CH3) 5558 (CH2) 5566 (CH2)
6405 (CH3) 6448 (CH) 8924 (CH) 9121 (CH) 12516 (CH) 12518 (CH)
12585 (CH) 12587 (CH)12590 (CH) 12621 (CH) 12629 (CH) 12708 (CH)
12710 (CH) 12713 (CH) 12761 (CH) 12767 (CH) 12773 (CH) 12822 (CH)
12824 (CH) 13206 (CH) 13209 (CH) 13256 (C) 13263 (C) 13718 (C)
13732 (C) 13839 (C) 13859 (C) 17215 (C) 17224 (C) IR max (ATR)cm-1
2951 (CH sp2) 1733 (C=O ester) 1495 (C=C) MS (FAB) mz () 436 [(M+H)+ 13]
222
Guilaine F Blanc Experimental
326 [MeOCH+CH2N(Bn)CH(Bn)CO2Me 39] 282 [+CH2N(Bn)CH(Bn)CO2Me 100]
HRMS (FAB) 4361949 [(M+H)+ C26H30NO3S requires 4361946] []D22 9774 (c
36 CHCl3)
Lithium naphthalenide (LN) 1078
Li
Following the procedure described by Cohen and Weisenfeld273 to a flame-dried
flask which was continually purged with argon was added dry and degassed THF
(10 mL) and lithium ribbon ( 51 mg 74 mmol 10 eq) Naphthalene (738 mg
576 mmol 10 eq) was slowly added The dark green color of the radical anion
appeared within 10 min The mixture was stirred for 6 h after which it was
presumed that the LN 1078 had formed completely and a 058 M solution had
therefore been prepared
Lithium 1-(NN-dimethylamino)naphthalenide (LDMAN) 1079
Li
N
Following the procedure described by Cohen et al229 to a flame-dried flask
which was continually purged with argon was added dry and degassed THF
(10 mL) and lithium ribbon (40 mg 58 mmol 10 eq) The mixture was then
cooled to mdash55 degC 1-(NN-dimethylamino)naphthalene (08 mL 51 mmol 10
eq) was slowly added The dark green color of the radical anion appeared within
10 min The mixture was stirred for 35 h after which it was presumed that the
LDMAN 1079 had formed completely and a 05 M solution had therefore been
prepared
223
Guilaine F Blanc Experimental
Lithium 44rsquo-di-tert-butylbiphenylide (LDBB) 1080
Li
Following the procedure described by Cohen and Doubleday233 to a flame-dried
flask which was continually purged with argon was added dry and degassed THF
(64 mL) and lithium ribbon (23 mg 33 mmol ) The mixture was then cooled to
0 degC 44rsquo-Di-tert-butylbiphenyl (765 mg 288 mmol) was slowly added The
dark green color of the radical anion appeared within 10 min The mixture was
stirred for 5 h after which it was presumed that the LDBB 1080 had formed
completely and a 05 M solution had therefore been prepared
Methyl 2(S)-[N-benzyl-N-(2rsquo-oxoethyl)amino]-3-phenylpropanoate 1081
N 21 OMe
O
3 Ph
12H
PhO
C19H21NO3MW 31137
Trichloromethylsilane (014 mL 112 mmol 20 eq) and acetal 1064 (200 mg
056 mmol 10 eq) were added successively to a stirred solution of NaI (210 mg
140 mmol 25 eq) in dry CH3CN (22 mL) under argon at rt and the mixture
stirred for 1 h The reaction was then quenched with water and extracted with
CH2Cl2 The organics were washed with sat Na2S2O3(aq) (1 ) H2O (1 ) brine (1
) and then dried (Na2SO4) The solvent was removed under reduced pressure to
give the aldehyde 1081 (127 mg 73) without further purification 1H NMR (400 MHz CDCl3) H 286 (1H dd J 85 and 140 Hz CHAHB-3) 305
(1H dd J 71 and 139 Hz CHAHB-3) 329 (1H dd J 23 and 182 Hz CHCHD-1rsquo)
343 (1H d J 182 Hz CHCHD-1rsquo) 361-367 (5H m OCH3 CHN and NCHEHFPh)
379 (1H d J 136 Hz NCHEHFPh) 703-722 (10H m Ar-H) 924 (1H d J
20 Hz CHO) 13C NMR (100 MHz CDCl3) C 3621 (CH2) 5136 (CH3) 5733
224
Guilaine F Blanc Experimental
(CH2) 6035 (CH2) 6516 (CH) 12658 (CH) 12755 (CH) 12832 (CH) 12839
(CH) 12900 (CH) 12915 (CH) 13751 (C) 13777 (C) 17251 (C) 20280 (CH)
IR max (ATR)cm-1 1726 (C=O) 1269 (C-O ester) MS (CI+) mz () 312 [(M+H)+
100] HRMS (FAB) 3121598 [(M+H)+ C19H22NO3 requires 3121600] []D24
5180 (c 11 CHCl3)
Methyl 2(S)-benzamido-3-phenylpropanoate 1084
HN 2
1 OMe
O
31
1
O
65
4
32
C17H17NO3MW 28332
65
4
32
HBHA
Procedure A Following the procedure described by Nadia et al274 benzoyl
chloride (09 mL 77 mmol 10 eq) was added dropwise to a stirred solution of
amine 1059 (138 g 771 mmol 10 eq) 2 N K2CO3 (96 mL 193 mmol 25 eq)
in CHCl3 (154 mL) The mixture was heated under reflux for 3 h The reaction
was then quenched with water and the aqueous layer was extracted with CHCl3
(3 ) The combined organic layers were dried (Na2SO4) and the solvent was
removed under reduced pressure to give the amide 1084 (218 g 100) which
was used without further purification 1H NMR (400 MHz CDCl3)322 (1H dd J 56 and 139 Hz CHAHB-3) 329 (1H
dd J 58 and 139 Hz CHAHB-3) 376 (3H s OCH3) 509 (1H td J 58 and 76
Hz CHN) 659 (1H d J 73 Hz NH) 713-715 (2H m H2rsquorsquo and H6rdquo) 725-732
(3H m H3rsquorsquo H4rdquo and H5rdquo) 739-744 (2H m H2rsquo and H6rsquo) 748-753 (1H m
H4rsquo) 771-774 (2H m H3rsquo and H5rsquo) 1H NMR spectral data in agreement with
those previously reported in the literature274
Procedure B Titanocene dichloride (709 mg 285 mmol 30 eq) Mg (83 mg
34 mmol 36 eq) [pre-dried at 250 degC overnight] and freshly activated 4 Ǻ
molecular sieves (500 mg) were twice heated gently under reduced pressure for
about 1 min shaking the flask between heatings and then placed under Ar Dry
THF (1 mL) was added followed by freshly distilled P(OEt)3 (10 mL 57 mmol
225
Guilaine F Blanc Experimental
60 eq) After stirring for 3 h at rt a solution of dithiane 1089 (500 mg 095
mmol 10 eq) in dry THF (27 mL) was added to the mixture and stirred
overnight at rt The reaction was quenched by addition of 1 M NaOH and the
resulting insoluble materials were filtered off through Celite The filtrate was
extrated with Et2O (3 ) The combined organic layers were dried (K2CO3) The
solvent removed under reduced pressure Flash chromatography [SiO2
petroleum ether (100)] gave the amide 1084 (53 mg 20) as yellow oil 1H NMR (400 MHz CDCl3)323 ( 1H dd J 52 and 139 Hz CHAHB-3) 330
(1H dd J 51 and 134 Hz CHAHB-3) 377 (3H s OCH3) 506-511 (1H m
CHN) 672 (1H br s NH) 714-716 (2H m H2rsquorsquo and H6rdquo) 725-730 (3H m
H3rsquorsquo H4rdquo and H5rdquo) 741-744 (2H m H2rsquo and H6rsquo) 749-753 (1H m H4rsquo)
773-775 (2H m H3rsquo and H5rsquo)
Methyl 2(S)-(N-allylbenzamido)-3-phenylpropanoate 1085
NOMe
O
PhO
C20H21NO3MW 32339
Following the procedure described by Poulsen and Bornaghi238 benzoyl chloride
(43 mL 37 mmol 20 eq) was added to a stirred solution of amine 1084 (404
g 185 mmol 10 eq) triethylamine (52 mL 37 mmol 20 eq) in dry CH2Cl2 (84
mL) The mixture was stirred at rt under argon for 3 h The reaction mixture was
then diluted with CH2Cl2 and washed with 1 N HCl (1 ) brine (1 ) and the
organic layer was dried (MgSO4) The solvent was removed under reduced
pressure Flash chromatography [SiO2 petroleum ether-ethyl acetate (1000ndash
7030)] gave the amide 1085 (539 g 90) as an oil
R [SiO2 petroleum ether-ethyl acetate (8020)] 030 1H NMR (400 MHz DMSO-d6 at 90 degC) 323-337 (2H m NCHCH2) 365-384
(2H m NCH2CH) 371 (3H s OCH3) 452-456 (1H m NCHCH2) 502-507 (2H
m CH2=) 554-566 (1H m CH=) 715-743 (10H m Ar-H) 1H NMR spectral
data in agreement with those previously reported in the literature238
226
Guilaine F Blanc Experimental
Methyl 2(S)-(N-allylamino)-3-phenylpropanoate 1087
HN 21 OMe
O
3 Ph
C13H17NO2MW 21928
HBHA
Lithium hydroxide monohydrate (100 g 24 mmol 215 eq) was added to
activated 4 Aring molecular sieves (5 g) in anhydrous DMF (62 mL) and then the
suspension was vigorously stirred for 20 min The amine 1059 (200 g 112
mmol 10 eq) was added and the mixture was stirred for 45 min Allyl bromide
(116 mL 134 mmol 12 eq) was added to the suspension and then the mixture
was allowed to stir for 16 h under argon at rt After filtration the combined
filtrate was washed with water (2 ) and dried (Na2SO4) The solvent was
removed under reduced pressure Flash chromatography [SiO2 petroleum ether-
ethyl acetate (1000ndash5050)] gave the amine 1087 (115 g 47) as a yellow oil 1H NMR(400 MHz CDCl3) 162 (1H br s NH) 295 (2H d J 68 Hz
NCH2CH) 311 (1H tdd J 13 63 and 139 Hz CHAHB-3) 326 (1H tdd J 13
58 and 139 Hz CHAHB-3) 355 (1H apparent t J 68 Hz NCHCH2) 363 (3H s
OCH3) 506 (1H qd J 13 and 102 Hz CHAHB=) 511 (1H qd J 15 and 172
Hz CHAHB=) 580 (1H tdd J 60 102 and 172 Hz CH=) 716-730 (5H m Ar-
H) 1H NMR spectral data in agreement with those previously reported in the
literature275
Methyl 2(S)-[NN-bis(allyl)amino]-3-phenylpropanoate 1086
N 21 OMe
O
3 1
12
3
1
2
3
C16H21NO2MW 25934
65
4
32
In the same way the reaction was carried out using lithium hydroxide
monohydrate (100 g 238 mmol 215 eq) activated 4 Aring molecular sieves (5 g)
227
Guilaine F Blanc Experimental
in anhydrous DMF (62 mL) the amine 1059 (200 g 112 mmol 10 eq) and allyl
bromide (116 mL 134 mmol 12 eq) Flash chromatography [SiO2 petroleum
ether-ethyl acetate (1000ndash5050)] gave the amine 1086 (413 mg 14) as an
oil 1H NMR (400 MHz CDCl3) 280 (1H dd J 71 and 136 Hz CHAHB-3) 296
(1H dd J 78 and 136 Hz CHAHB-3) 299 (2H dd J 74 and 142 Hz 2 x
NCHCHD-1rsquo) 326-329 (2H ddd J 16 48 and 145 Hz 2 x NCHCHD-1rsquo) 351
(3H s OCH3) 362 (1H apparent t J 76 Hz NCHCH2) 497 (2H m 2 x
CHEHF=) 504 (2H qd J 16 and 172 Hz 2 x CHEHF=) 553-563 (2H m CH=)
706-709 (3H m H3rsquorsquo H4rdquo and H5rdquo) 713-716 (2H m H2rsquorsquo and H6rdquo) 1H NMR
spectral data in agreement with those previously reported in the literature276
Methyl 2(S)-[N-(2rsquo-oxoethyl)benzamido]-3-phenylpropanoate 1088
N 21 OMe
O
3
12
O
O
C19H19NO4MW 32536
The reaction was carried out according to the procedure described for compound
1024 using K2OsO42H2O (46 mg 012 mmol 2 mol) in deionised water
(24 mL) alkene 1085 (200 g 619 mmol 10 eq) in THF (17 mL) at rt and
NaIO4 (397 g 186 mmol 30 eq) in water (36 mL) Flash chromatography [SiO2
petroleum etherndashethyl acetate (7030-3070)] gave the aldehyde 1088 (1746 g
87) as a yellow oil
R [SiO2 petroleum ether-ethyl acetate (2080)] 041 1H NMR (400 MHz CDCl3) 290 (1H dd J 38 and 112 Hz CHAHB-3) 321
(1H dd J 36 and 139 Hz CHAHB-3) 378 (3H s OCH3) 395 (1H d J 172 Hz
NCHCHD-1rsquo) 429 (1H d J 172 Hz NCHCHD-1rsquo) 475 (1H m NCHCH2) 692-694
(4H m Ar-H) 727-738 (6H m Ar-H) 955 (1H br s CHO) 13C NMR (100 MHz CDCl3)C 3564 (CH2) 5164 (CH2) 5228 (CH) 5979 (CH3)
12599 (CH) 12680 (CH) 12789 (CH) 12831 (CH) 12855 (CH) 12938 (CH)
13363 (C) 13489 (C) 17004 (C) 17231 (C) 19716 (CH) IR max (ATR)cm-1
228
Guilaine F Blanc Experimental
1732 (C=O) 1639 (C=O) 1265 (C-O ester) MS (CI+) mz () 326 [(M+H)+ 100]
HRMS (CI+) 3261398 [(M+H)+ C19H20NO4 requires 3261392] []D23 6696
(c 22 CHCl3)
Methyl 2(S)-N-[2rsquo2rsquo-bis(phenylthio)ethyl]benzamido-3-phenylpropanoate
1089
N 21 OMe
O
3 Ph
12
O
SPhPhS
C31H29NO3S2MW 52770
The reaction was carried out according to the procedure described for compound
1027 using BF3OEt2 (074 mL 59 mmol 11 eq) aldehyde 1088 (175 g 537
mmol 10 eq) thiophenol (130 mL 124 mmol 23 eq) and glacial acetic acid
(47 mL) in dry toluene (122 mL) Flash chromatography [SiO2 petroleum ether-
ethyl acetate (1000-8020)] gave the thioacetal 1089 (116 g 41) as prisme
R [SiO2 petroleum ether-ethyl acetate (8020)] 044
mp 63-65 degC 1H NMR (400 MHz DMSO-d6 at 90 degC) 314 (1H dd J 88 and 139 Hz CHAHB-
3) 325 (1H dd J 61 and 142 Hz CHAHB-3) 341-353 (1H m NCHCHD-1rsquo)
362 (3H s OCH3) 367-374 (1H m NCHCHD-1rsquo) 445-449 (1H m NCHCH2)
482-488 (1H m NCH2CH) 701-745 (20H m Ar-H) 13C NMR (100 MHz DMSO-
d6 at 90 degCC 3499 (CH2) 5177 (CH3) 5180 (CH) 5549 (CH2) 5956 (CH)
12655 (CH) 12681 (CH) 12765 (CH) 12782 (CH) 12821 (CH) 12831 (CH)
12898 (CH) 12900 (CH) 12909 (CH) 12959 (CH) 13158 (CH) 13187 (CH)
13320 (C) 13389 (C) 13560 (C) 13717 (C) 16999 (C) 17001 (C) IR max
(ATR)cm-1 1735 (C=O ester) 1641 (C=O amide) MS (CI+) mz () 528 [(M+H)+
58] 418 [(M+H)+ PhSH 100] HRMS (CI+) 5281671 [(M+H)+ C31H30NO3S2 requires
5281667] Microanalysis Theory C 7059 H 550 N 266 Results C 7057
H 550 N 283 []D23 11739 (c 15 CHCl3)
229
Guilaine F Blanc Experimental
Bis(phenylthio)methylbenzene 1091
SPh
SPhC19H16S2
MW 30846
In a same way the reaction was carried out using BF3OEt2 (13 mL 104 mmol
11 eq) benzaldehyde 1090 (096 mL 94 mmol 10 eq) thiophenol (22 mL
22 mmol 23 eq) and glacial acetic acid (83 mL) in dry toluene (215 mL) Flash
chromatography [SiO2 petroleum ether-ethyl acetate (1000-955)] gave the
thioacetal 1091 (204 mg 70) as a solid
R [SiO2 petroleum ether-ethyl acetate (955)] 053 1H NMR (400 MHz CDCl3) 542 (1H s CH) 721-728 (9H m Ar-H) 732-737
(6H m Ar-H) 1H NMR spectral data in agreement with those previously reported
in the literature277
14-Diphenylbutan-2-one 1092
12
3
4O
C16H16OMW 22430
The reaction was carried out according to the procedure B described for
compound 1084 using titanocene dichloride (727 mg 292 mmol 30 eq) Mg
(87 mg 35 mmol 36 eq) and 4 Ǻ molecular sieves (515 mg) dry THF (49 mL)
and dry P(OEt)3 (10 mL 58 mmol 60 eq) and a solution of dithiane 1091 (300
mg 097 mmol 10 eq) in THF (3 mL) Removal of solvent under reduced
pressure gave the crude enol ether derivative The crude liquid was quickly
passed through a short column of silica [petroleum ether-ethyl acetate (1000-
955) to remove excess of P(OEt)3 The resulting crude was then dissolved in THF
(5 mL) and stirred with 1 M HCl (5 mL) for 1 h at rt Water was added and the
aqueous layer was extracted with EtOAc (3 ) The combined organics were then
dried (MgSO4) and removal of the solvent under reduced pressure gave a mixture
of the ketone 1092 and 3-phenylpropanoic acid Therefore a solution of this
mixture in THF (5 mL) was treated with 1 M NaOH (5 mL) and stirred for 1 h at
230
Guilaine F Blanc Experimental
rt The reaction was stopped by addition of water and the aqueous layer was
extracted with EtOAc (3 ) The organic layer was then dried (MgSO4) and the
solvent removed under reduced pressure to give the pure ketone 1092 (44 mg
40) as a yellow oil 1H NMR (400 MHz CDCl3) 269 (2H t J 69 Hz CH2-4) 279 (2H t J 69 Hz
CH2-3) 358 (2H s CH2-1) 706-724 (10H m Ar-H)1H NMR spectral data in
agreement with those previously reported in the literature278
Phenyl vinyl sulfide 1094
SC8H8S
MW 13621
The reaction was carried out according to the procedure B described for
compound 1084 using titanocene dichloride (709 mg 285 mmol 30 eq) Mg
(83 mg 34 mmol 36 eq) and 4 Ǻ molecular sieves (500 mg) dry THF (1 mL)
dry P(OEt)3 (10 mL 57 mmol 60 eq) and dithiane 1089 (500 mg 095 mmol
10 eq) in dry THF (27 mL) Flash chromatography [SiO2 petroleum ether (100)]
gave the sulfide 1094 (46 mg 70) as yellow oil
R [SiO2 petroleum ether (100)] 069 1H NMR (400 MHz CDCl3) 532 (1Hd J 166 Hz CHAHB=) 524 (1H d J 96
Hz CHAHB=) 654 (1H dd J 96 and 166 Hz CH=) 722-753 (5H m Ar-H) 1H
NMR spectral data in agreement with those previously reported in the
literature279
126 Experimental to chapter 11
Methyl 33-bis(phenylthio)propanoate 1122
PhS
PhS
O
O
C16H16O2S2MW 30443
Following the procedure described by Rahim et al115 BF3OEt2 (89 mL 71
mmol 20 eq) was added to a stirred solution of methyl acetal 1121 (50 mL
35 mmol 10 eq) and thiophenol (72 mL 71 mmol 20 eq) in CHCl3 (35 mL) at
231
Guilaine F Blanc Experimental
0degC under argon After 20 h at rt the reaction mixture was quenched by
addition of water and the aqueous layer was extracted with CHCl3 (3 ) The
organic layer was washed with water (2 ) and dried (Na2SO4) The solvent was
removed under reduced pressure The thioacetal 1122 was obtained as an oil
(947 g 88) and used without further purification 1H NMR (400 MHz CDCl3) 281 (2H d J 73 Hz CH2CH) 368 (3H s OCH3)
481 (1H t J 73 Hz CH2CH) 731-732 (6H m Ar-H) 748-750 (4H m Ar-H) 1H NMR spectral data in agreement with those previously reported in the
literature280
33-Bis(phenylthio)propan-1-ol 1123
PhS
PhS
OH C15H16OS2MW 27642
Following the procedure described by Rahim et al115 a solution of ester 1122
(814 g 267 mmol 10 eq) in dry THF (20 mL) was added to a suspension of
LiAlH4 (114 g 300 mmol 112 eq) in dry THF (30 mL) at 0 degC under argon
After being stirred overnight at rt the reaction was quenched by dropwise
addition of 1 M NaOH and the insoluble materials were filtered off through
Celite The filtrate was extracted with Et2O (3 ) The organics were dried
(MgSO4) and the solvent was removed under reduced pressure Flash
chromatography [SiO2 petroleum ether-ethyl acetate (1000-9010)] gave the
alcohol 1123 (828 g 80) as an oil
R [SiO2 petroleum ether-ethyl acetate (7030)] 056 1H NMR (400 MHz CDCl3) 170 (1H br s OH) 201 (2H td J 58 and 68Hz
CHCH2) 388 (2H t J 58 Hz CH2OH) 464 (1H t J 68 Hz CHCH2) 725-733
(6H m Ar-H) 746-749 (4H m Ar-H) 1H NMR spectral data in agreement with
those previously reported in the literature115
232
Guilaine F Blanc Experimental
3-(Phenylthio)acrylaldehyde 1128
O
1 H2
3
PhSC9H8OS
MW 16422
DMSO (48 mL) and triethylamine (65 mL 47 mmol 70 eq) were added to a
stirred solution of alcohol 1123 (184 g 667 mmol 10 eq) in dry DCM (51 mL)
at rt under argon After cooling to 0 degC sulfur trioxide pyridine (420 g 267
mmol 40 eq) was added in batches The reaction mixture was stirred overnight
at rt The mixture was then quenched with sat NaHCO3(aq) The aqueous layer
was extracted with CH2Cl2 (3 ) The organic layers were washed with water
(1 ) brine (1 ) and dried (MgSO4) The solvent was removed under reduced
pressure to give the αβ-unsaturated aldehyde 1128 as an EZ mixture (71)
(103 g 94) Due to the relative instability of this compound the crude mixture
was used in the next step without further purification
Data on E-isomer only from the crude mixture 1H NMR (400 MHz CDCl3)
593 (1H dd J 78 and 150 Hz CH-2) 720-731 (3H m Ph) 743-750 (2H m
Ph) 768 (1H d J 150 Hz CH-3) 943 (1H d J 78 Hz CHO)
3-(Phenylthio)acrylic acid 1130
O
1 OH2
3
S
C9H8O2SMW 18022
1
65
4
32
7 M KOH (19 mL) was added to a stirred solution of ester 1122 (500 mg 164
mmol 10 eq) in EtOH (31 mL) and the reaction was left to stir overnight at rt
The reaction mixture was then poured into water and the aqueous layer washed
with Et2O (3 ) The organic layer was discarded The aqueous layer was
acidified with 6 M HCl and extracted with Et2O (3 ) The organics were dried
(MgSO4) and flash chromatography [SiO2 petroleum ether-ethyl acetate (9010-
5050)] gave the acid 1130 (219 mg 74) as a powder and a 141 mixture of EZ
compounds
mp 104-106 degC
233
Guilaine F Blanc Experimental
R [SiO2 petroleum ether-ethyl acetate (6040)] 043
Data on E-isomer only 1H NMR (400 MHz CDCl3) 561 (1H d J 152 Hz CH-
2) 740-743 (3H m H3rsquo H4rsquo and H5rsquo) 748-750 (2H m H2rsquo and H6rsquo) 792
(1H d J 152 Hz CH-3)13C NMR (100 MHz CDCl3)C 11430 (CH) 12980 (CH)
12988 (CH) 12992 (C)13318 (CH) 15039 (CH) 17042 (C) IR max (ATR)cm-
1 3250 (OH) 2972 (CH sp2) 1705 (C=O) MS (CI+) mz () 181 [(M+H)+ 100]
HRMS (CI+) 1810327 [(M+H)+ C9H9SO2 requires 1810323] Microanalysis
Theory C 6000 H 445 Results C 6029 H 462 Commercial compound
reported in the literature without spectroscopic data provided281282
33-Bis(phenylthio)propyl 4rsquo-toluenesulfonate 1126 bis[33rsquo-bis(phenylthio)prop-1-yl ether 1131
OPhS
PhS
C22H22O3S3MW 43060
SO
OOPhS
PhS
SPh
SPh
C30H30OS4MW 53482
Procedure A A solution of alcohol 1123 (514 mg 186 mmol 10 eq) in dry
pyridine (043 mL) was added dropwise to a stirred solution of p-toluenesulfonyl
chloride (398 mg 209 mmol 112 eq) in dry pyridine (045 mL) at 0 degC under
argon The mixture was stirred for 16 h at rt under argon The mixture was then
diluted with water and extracted with Et2O (3 ) The combined organics were
washed with 1 M HCl (2 ) water (2 ) and brine (1 ) and then dried (Na2SO4)
The solvent was removed under reduced pressure to afford a 21 mixture of
tosylate and dimer 11261131 (428 mg) The crude mixture was used in the
next step without further purification due to the instability of the tosylate
1126 but characterization of tosylate 1126 and dimer 1131 were carried out
later on
Procedure B In a same way the reaction was carried out using alcohol 1123
(489 mg 177 mmol 10 eq) in dry pyridine (041 mL) and p-toluenesulfonyl
chloride (135 g 709 mmol 40 eq) in dry pyridine (15 mL) After 2 h at rt
234