ch402: synthetic chemistry i (organic) professor martin wills. synthetic approaches to complex...
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CH402: Synthetic Chemistry I (Organic) Professor Martin Wills.synthetic approaches to complex target organic molecules
Structure of course (7 lectures) (underlined/red text indicates the molecule on which the course will focus, and the examinable/workshop material), there is one handout and one set of notes on the course with links to references:
1) Introduction to strategy, disconnections, retrosynthesis, protecting groups and extreme targets which may include palytoxin, vitamin B12, brevitoxin, azadirachtin, vancomycin.2) Early classics of total synthesis in organic chemistry, which may include colchicine, morphine, strychnine, thienamycin and penicillin.3) Lessons learnt from the synthesis of small important organic molecules which may include hirsutene, periplanone B, epothilones and prostaglandins.4) Molecules with a high degree of functionality, which may include avermectin, erythromycin, amphotericin B, strychnine.5) Construction of highly complex structures which may include ginkgolide B, calicheamycin, taxol.6) The use of cycloadditions in complex molecule synthesis, which may include FR182877/abyssomicin C , estrone, platensimycin, progesterone, daphniphylline alkaloids.7) Enantioselective strategies which may include biotin a-arylpropionic acids, menthol, zaragozic acid, statins. 1
CH402: Synthetic Chemistry I (Organic), lectures 1-7; Professor Martin Wills.
synthetic approaches to complex target organic molecules
Recommended reading (not essential but if you want to learn more or check anything):
Classics in Total Synthesis; K. C. Nicolaou and E. J. Sorensen, Wiley-VCH 1996. Classics in Total Synthesis II, K. C. Nicolaou and E. J. Sorensen, VCH 2003. Molecules that changed the world, K. C. Nicolaou and T. Montagnon, Wiley-VCH, 2008. The Logic of Chemical Synthesis, E. J. Corey and X.-M. Cheng, Wiley-VCH, 1995. S. Warren and P. Wyatt, Organic Synthesis: The Disconnection Approach, Wiley, 2nd Edn 2008 and the associated workbook, 2nd Edition 2009. Catalysis in Asymmetric Synthesis’ by V. Caprio and J. M. J. Williams, Wiley, 2010 (2nd Edition). In addition, other annual reviews of progress frequently appear in review journals. For more detailed reviews of particular areas, you can search the web of knowledge or Scifinder Scholar for comprehensive literature surveys.
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CH402: Synthetic Chemistry I (Organic), lectures 1-7; Professor Martin Wills.
Specific requirements and structure of the course:
15 CATS is equivalent to around 150 study hours. There are 10 lectures of 1 h each, three workshops (1h, 2h, 2h) and a piece of assessed work which would be expected to take 15-20 hours of work. The remaining time is for self-study around the subject.
For the M. Wills section of the course, a number of key references will be provided on the seven molecules selected for detailed study. These seven molecules and the associated references represent the main material for the workshops and for the examinable material.
Key references will be provided for each of the seven targets in bold, and these papers should be treated as examinable material however - you do not have to learn the content by heart but should ensure that you understand the reasons for the choice of strategy and the main mechanisms, particularly with respect to the key steps indicated for each synthesis.
The assessed task will involve writing an essay about the analysis of a complex synthesis (which will not be one of the seven highlighted earlier). Further information about this will be distributed early in the course.
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Please note that not all reagents/solvents/conditions are given for each step. In most cases only the main reagent or reagents are shown.
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1) Introduction to strategy, disconnections, retrosynthesis, protecting groups and extreme targets which may include palytoxin, vitamin B12, brevetoxin, azadirachtin, vancomycin.
Recap: disconnections, synthons, FGIs and reagents.
Target
O
O OH
disconnection here
retrosynthetic arrow:
Synthons
O
O OH
Idealised fragments,which youwould buy if you could.
Actual reagents.
O
O O
These are what you actuallydo the reaction with
NH2
HO
NH2
HO O
+
NO2
O
R1
R2 R1
R2
H2 catalyst
R1
R2
OH
HR1
R2
OH
H
R1
R2
O
BrMgHR1
R2
O
Ph3PH
For the cis-alkene For the trans-alkene
R1 OR2
C O C N
'Easy' to form but lessstable - tend to do late insynthesis
C C C C
'Difficult to form but morestable - tend to do early insynthesis to establish C skeleton
R1 OR2
Br
R1 OR2
R1 ClR2
OH
O
O
But remember there are no ‘rules’ – the only limit is your imagination!
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Examples of ‘extreme targets’ which have been prepared by total synthesis.
N N
N N
Co
Me
Me
O
NH2
Me
NH2
OH
Me
MeCONH2
H
Vitamin B12
H2NOC
MeH2NOC
MeH
H2NOC
MeO
NH
CN
N
NOP
O O
Me
MeHO
OHH
Me
OO
Synthesised by Woodwardand Eschenmoser 1973.
O
O
O
O
O
O
O
OO
O O
O
O
H
H H HH H H
H
H
H
HO
H HH
HH
HBrevetoxin B:A marine neurotoxin
Synthesised by Nicolaou in 1995.
Azadiractin,insect antifeedant and growth disruptor Ley, 2007.
O
O
O
OH
H
O
HO HOH
O
O
H
OMeO O
O
Palytoxin is too bigto fit on this slide – see the next slide!.
Vancomycin,Antibiotic, Evans, 1999.
OO
NH
OHN
O
OO
HOH2N
O
HO
HO
OH
Cl
Cl
HN
NH
NHMeNH
O
O
OHO
O
O
NH2
O
OHOH
HO
HO
NH
HO2C
6
O
HO
HO OH
OH
OH
OH
OH
OH
H
OH
OO
Me
Me
Me
O
HO OH
MeOH
OH
OH
HO
NH
HO
OH
HO
OO
HN
OH
HOOH
O
O
OH
OHH
HO
HO
OH
OH
OHOH
OH
OH
OH
OH
O
HO
HO
OH
OHHO
HO
OH
OH
OO
Me
O
OHH2N
Palytoxin - toxic marinenatural product.Synthesised by Kishi in 1994.
"Synthesis of Palytoxin from Palytoxin Carboxylic-Acid". E. M. Suh and Y. Kishi, J. Am. Chem. Soc. 1994, 116 (24): 11205–11206. "Total Synthesis of Palytoxin Carboxylic-Acid and Palytoxin Amide". R. W. Armstrong, J. M. Beau, Y. Kishi et al. J. Am. Chem. Soc. 1989, 111, 7530–7533.
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Palytoxin – the power of protecting groups.
O
BMPO
PMBO OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
H
HO
THPO
OPMB
OO
Me
Me
OTBS
PPh3
I
O
PMBO
PMBO OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
HOTHP
OPMB
OO
Me
Me
OH
OTBS= OSiMe2tBu (sometimes called OTBDMS)OPMB=CH2C6H4p(OMe) (paramethoxybenzyl)OTHP=Otetrahydropyran.OBz= OCOPh (benzoyl)(in contrast OBn = OCH2Ph; benzyl).
O
PMBO
PMBO OPMB
OPMB
OPMB
OPMB
OPMB
OPMB
HTHPO
OPMB
OO
Me
Me
+
i) (COCl)2, DMSO, Et3Nii) nBuLi, THF, -78oC.iii) H2, Pd/C.iv) TBAF ((Bu)4NF), THF
Me
MeMe
O
BzO O O
MeOMe
OBz
OBz
BzO
O O
BzO O O
MeOMe
OBz
OBz
BzO
a similar sequenceof transformations.
(convert to PPh3)
A list of protecting groups follows in a couple of slides, along with removal methods.
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O
OO
O
O
O
O
O
O
H
H
H
H
O
OO
H
H
H
H
HH
H
O
O
H
H
O
OHOOHH
H
H
Halichondrin B - synthesis by Kishi, 1982.
Eribulin – an anticancer drug which arose from the related halichondrin synthesis:
OO
O
O
O
O
H
H
H
H
O
OO
H
H
H
H
MeOOHH2N
Eribulin-synthetic anticancer compound, approved in 2010.
(marketed asHalaven)
Works by binding to microtubules and hindering mitosis.
D. S. Kim, C. G. Dong, J. T. Kim, H. Guo, J. Huang, P. S. Tiseni and Y. Kishi, "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". J. Am. Chem. Soc. 2009, 131, 15636–15641.
Conclusion of total synthesis:T. D. Aicher, K. R. Buszek, F. G. Fang, C. J. Forsyth, S. Ho Jung, Y. Kishi, M. C. Matelich, P. M. Scola, D. M. Spero and S. K. Yoon, J. Am. Chem. Soc. 1992, 114, 3162-3164.
OTMS=OSi(Me)3
OTBS= OSi(Me)2tBu (also called OTBDMS)
OTPS=OSi(Ph)2tBu (also called OTBDPS)
OTIPS=)Si(iPr)3
Silyl group are added using R3SiCl + amine base, removed using fluoride e.g. HF or (Bu)4NF
(TBAF). TMS can be removed with mild acid.
OPMB=CH2C6H4p(OMe) (paramethoxybenzyl)
OBn = OCH2Ph (benzyl).
Above are added using ArCH2Br + base, Bn removed by H2/Pd and PMB by using DDQ
(dichlorodicyanoquinone).
OTHP=Otetrahydropyran; added using THPOH and acid, removed with H2O/acid.
OBz= OCOPh (benzoyl) and OAc (acetate): added using anhydride or acid chloride, removed
with H2O/acid.
NtBoc; add with Boc2O, remove with acid (CF3CO2H),
NZ = N(CO)OCH2Ph, add with chloride, remove by hydrogenation.
NFMoc; add via chloride, remove with base.
Commonly used protecting groups:
ORO
ROTHP =
O
OR2N
R2NtBoc = O
OR2N
R2NZ =
Ph
O
OR2N
R2NFMoc =
10
Vitamin B12 – strategic construction of large units. A very large target can soon be broken down into smaller ones if a convergent strategy is used.
N N
N N
Co
Me
Me
O
NH2
Me
CO2Me
H
MeMe
CO2MeH
Vitamin B12MeO2C
MeMeO2C
MeH
MeO2C
MeHO2C
CN
CN
In reverse - remove side chain(this means it goes in last in thesynthesis).
NH
N
Br
CO2Me
MeMeO2C
MeH
MeO2C
MeHO2C
N
HN
Me
CO2Me
H
MeMe
CO2MeH
O
S
O
O
Me
Position of disconnection - or where a bond will be formedin the synthetic direction.
HN MeMe
CO2MeHS
HN
Me
CO2Me
HO
O
Me
S
and
and
O
MeMe
HO2C
+
MeMe
MeO
O
Synthesised by Woodward and Eschenmoser, et al. 1973 (and over 100 students and researchers.
R. B. Woodward, Pure & Appl. Chem. 1973, 33, 145, A. Eschenmoser and C. E. Winter, Science 1977, 196, 1410. (and other references).
R B Woodward(Harvard)
Albert EschenmoserETH Zurich
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Brevetoxin B – a marine neurotoxin (‘red tide’ algae blooms)multiple coupling steps for ring construction – some examples.
O O
OTPS
H
H
BnO
H J
K
MeO2C
TPSO
HO O
OTPS
H
H
BnO
J
K
MeO2C
TPSO
OTPS=Si(tBu)Ph2
NaH, THFOO
OBn OTPS
OTPSMeO2C
O O
OTPS
H
H
BnO
H J
K
HOO
MeO2C
I
O O
OTPS
H
H
BnO
H J
K
OHO
H
MeO2C
I
Camphorsulfonic acid
H
OO
O
OOBn
OBn
H H
H
OHO
O
OOBn
OBn
H H
H
HO
ClCl
Cl
ClOC Et3N
then DMAPE F G
O
O
O
O
O
O
O
BnO
OBn
OH H H
H H H
H HH
H
O
O
O
OH H
H
(EtO)2(O)P iPr2NEtO
HO
O
H H
H A-G section
You’d be expect to know, or be able to work out, the mechanisms of the reactions.
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Brevetoxin B – multiple coupling steps for ring construction; synthesis completion.
O
O
O
O
O
O
O
OO
O OOTBS
H H HH H H
H
H
H
TBSO
H HH
HH
HO
O
O
O
O
O
O
OHO
O OOTBS
H H HH H H
H
H
H
TBSO
H HH
H
H
EtS
EtS
O
O
O
O
O
O
O
OHC
OTMS O
O OOTBS
H H HH H H
H
H
H
TBSO
H HH
H
H
EtSEtS
PPh3i) nBuLiii) acid
AgClO4 SiO2Ph3SnH, AIBN
Note what a variety of cyclisation methods can be used.
Professor K. C. Nicolaou, Scripps Research Institute(California).
Reference: ‘The Total Synthesis of Brevetoxin B: A Twelve-Year Odyssey in Organic Synthesis’ K. C. Nicolaou, Angew. Chem. Int. Ed. 1996, 35, 588-607.
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Vancomycin – aromatic ether coupling strategies.
Vancomycin,Antibiotic, Evans, 1999.
OO
NH
OHN
O
OO
HOH2N
O
HO
HO
OH
Cl
Cl
HN
NH
NHMeNH
O
O
OHO
O
O
NH2
O
OHOH
HO
HO
NH
HO2C
OO
NH
OHN
OHCl
Cl
HN
NH
NHMeNH
O
O
OHO
O
O
NH2
O
OHOH
HO
HO
NH
HO2C
OH
O
NH2
HN
OP
Cl
NH
O
O
O
OPOP
PO
PO
NH
HO2C
F
HO
O
O2N
HN
NH
NHMe
O
OPO
NH2
O
+
P=protecting group.
Vancomycin is a powerful antibiotic which inhibits the formation of cell walls by binding to terminal peptide chains.
Professor David Evans, Harvard.
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Vancomycin – aromatic ether coupling strategies.
FO
NH
OHN
O NO2
Cl
HN
NH
NHMeNH
O
O
OHO
O
O
NHP
O
OHOH
HO
HO
NH
MeHNOC
OHO
NH
HN
Cl
NH
O
O
O
OBnOBn
BnO
HO
NH
MeHNOC
F
HO
O
O2N
HN
NH
NHMe
O
OPO
NH2
O
+
CF3HN
NH
O
OO
HO
NH
MeHNOC
F
Cl
O2N
OMe
OBn
OMe
MeO
How could this be made?
F
CF3NH
Cl
NH
O
OO
OMeOMe
MeO
HO
NH
MeHNOC
NO2
OH
VOF3BF3.OEt2AgBF4CF3CO2H
thenNaBH(OAc)3
First step is reductive coupling
OH
CF3O
deprotect thenadd:
Two stages of aromatic ether formation.
Total Syntheses of Vancomycin and Eremomycin Aglycons, D. A. Evans, M. R. Wood, B. W. Trotter, T. I. Richardson, J. C. Barrow, J. L. Katz, Angew. Chem. Int. Ed. 1998, 19, 2700-2704.
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Azadirachtin – dealing with sensitive functionality. Selected for closer focus.
Azadirachtin,insect antifeedant and growth disruptor Ley, 2007.
OO
O
HO
HO
OHHMeO2C
HO
O
O
H
OOMe
O
O
O
OO
AcOH
MeO2C HOH
O CO2MeOH
H OO
O OH
O
OHO
TBSOH
MeO2C HO
MeO2C
OBn
H OO
O OBn OMe
Eliminate toalkene.
Deprotect OH
reduce
add side chain
Deprotect OHand replace with OAc
Prepared by S. V. Ley and Colleagues in 2007.
‘The Azadirachtin Story, by G. E. Veitch, A. Boyer and S. V. Ley, Angew. Chem. Int. Ed. 2008, 47, 9402-9429.
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Azadirachtin – dealing with sensitive functionality.
MsO
O O
OBnOMe
OPMB
HO O
OBn
H
OMeBr
Br
i) MeLi.LiBr.ii) iPrMgBr (CH2O)n
iii) Ms2OiPr2NEtO O
OBn
H
OBr
Br
i) DIBAL-Hii) MeOH, acid
mixture formed but separation not required.
O O
OBn
H
OTBSO
PMBOPMBO
MOMOi) CF3CO2H to remove TBS
ii) SO3.py to oxidise.iii) Ph3PCHBr2, tBuOKO OAc
OAc
AcO
AcO
AcO
Commercially available carboydrate derivative.
A key step - learn mechanism
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Azadirachtin – Decalin construction.
O
OTESO
TESOH
MeO2C HO
MeO2C
OBn
H
O
OO
O
HMeO2C H
O
MeO2C
OBn
H
Ph
O
OO
O
HMeO2C H
O
H
Ph
O
CN
O
OHO
PhMe2SiH
MeO2C H
OH
S
S
O
PhMe2SiH
MeO2C H
OMe
S
S
pTsOH/H2O
OPhMe2Si
CO2Me
HS
S
OOMeOMe
OMeO
Diels-Alder reaction
2.4:1 preference for this isomer.The selectivity is reversed if thesilane is not present.
O
OPhMe2Si
CO2Me
HS
S
OMeOMe
OTebbe reagent
OPhMe2Si
CO2Me
HS
S
OMeOMe
OH
HO HS
S
OMeOMe
OTBSPhMe2Si
CO2Me
Br
then F-
Key step tolearn andunderstand.
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Azadirachtin – synthesis completion.
O
OHO
TBSOH
MeO2C HO
MeO2C
OBn
H OO
O OBn OMe
O
OHO
TBSOH
MeO2C HO
MeO2C
OBn
H OO
OBn OMeepoxidise
Radicalcyclisation
O
OHO
TBSOH
MeO2C HO
MeO2C
OBn
H
.
OO
OBn OMe
O
MeS
S
O
OHO
HOH
MeO2C HO
MeO2C
OBn
H
.
OO
OBn OMe
OPMB
O
OTESO
TESOH
MeO2C HO
MeO2C
OBn
H O O
OBn OMeOPMB
O
OTESO
TESOH
MeO2C HO
MeO2C
OBn
H
MsOO O
OBn OMeOPMB
H
H
H H
All steps except the last one in this sequence are key material to study and understand.
NaH, [15-crown-5], 0oC
i) TBAF; removesTES groups.
ii) 185oC, orgold catalyst.
i) add TBSClii) DDQ, DCM
iii) CS2, basethen MeI.
Bu3SnH, AIBN,toluene, 100oC.
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2) Early classics of total synthesis in organic chemistry, which may include colchicine, morphine, strychnine, thienamycin and penicillin.
Colchicine,various biologicalproperties,
O
OMe
OMe
MeO
MeO
O
NH
Morphine,Analgesic,Gates 1952.
HO
ONMe
HH
HO
H
StrychnineToxic alkaloid.Woodward 1954.
N
N
OO
H
H
H
H
Penicillin VAntibiotic.Sheehan 1957.
N
S
OCO2H
HHHN
PhO
O
ThienamycinAntibiotic.
NO
S
CO2H
HHOH
NH2
Cephalosporin CAntibiotic.
N
S
OHO2C
HHHN
O OAc
HO2C
NH2
TropinonePrecursor to morecomplex alkaloids includingatropine, cocaine etcRobinson 1917.
MeN
O
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Tropinone A small but important alkaloid and precursor of other drug molecules.
Robinson 1917.MeN
O
NMe O OMeNH2
The power of basiccondensation reactions.
O
O
Try to draw the mechanism
An actual synthesis:
MeNH2
O
O
+ ?
+ OO2C
O2C
Ca2MeN
O
CO2H
HO2C
MeN
O
NaOH thenHCl
(-2 CO2)
NMe
OH
OH
CO2H
CO2H
NMe
OH
O
CO2H
CO2H
H
H
NMe O
CO2H
CO2H
H
Sir Robert Robinson. Nobel Prize 1947.
PhD Manchester 1910,Sydney 1912-1915,Manchester 1915-1920,Director of Research at the British Dyestuffs Corporation 1920-21,StAndrews 1921-1922,Manchester 1922-1928,London 1928-1930,Oxford 1930-1955.
Birch, A. J. (1993). "Investigating a Scientific Legend: the Tropinone Synthesis of Sir Robert Robinson, F.R.S". Notes and Records of the Royal Society of London, 1993, 47, 277–296.
Tropinone: A classic synthesis.
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Colchicine,
O
NH
MeO
MeO
OMe
OMe
O
OH
MeO
MeO
OMe
O
An early synthesis of colchicine (Eschenmoser et al 1959):
HO
HO
OH OOH
Purpurogallin (availablestarting material)
MeO
MeO
OH O
i) Me2SO4ii) H2 Pd/C
iii) LiAlH4iv) H3PO4
i) CO2MeEt3N
ii) MeI
MeO
MeO
OMe O
O
O
Cl
O O175oC
MeO
MeO
OMeO
H
ClO
O
MeO
MeO
OMe
CO2Me
CO2Me
H
Cl
i) H2SO4 thenCH2N2.
tBuOKtBuOHMeO
MeO
OMe
CO2Me
CO2Me
MeO
MeO
OMe
CO2Me
CO2Me
Many steps.
racemic
(step i) proceeds viainitial OH alkylation)
i) N bromosuccinamide,(PhCO2)2
ii) NH3, EtOH.iii) KOH, EtOH.iv) CH2N2 v) Ac2O
Features in MT course CH408
Colchicine; Deceptively simple but actually very challenging.
BBC Science news 12th Sept 2011: ‘The native British Autumn crocus, is recorded in early herbal guides as a treatment for inflammation. This is because it contains the potent chemical colchicine, which is known to have medicinal properties, including anti-cancer effects.’ (reporting on anew drug delivery method).
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Colchicine,
O
NH
MeO
MeO
OMe
OMe
O
O
MeO
MeO
OMe
OH
A more recent synthesis of colchicine (Graening and Schmalz, 2005):
MeO
MeO
OMe
DMSO, (CF3CO)2Othen Et3N.
enantiomer-ically pure.
i) MeI, K2SO4, ii) TBAF.iii) Zn(N3)2.py DIAD, PPh3 *
iv) PPh3, H2O.v) Ac2O, pyridine.
OTBS
* Mitsunobu reaction
(last steps are from Banwell synthesis)
OH
OH
OTBSMeO
MeO
OMe O
O
OTBS
i) L-selectride(H- source)
ii) TMSOf then K2CO3, MeOH.
MeO
MeO
OMe
O
O
OTBS
N2
[Rh2(OAc)4]reflux
I
MeO
MeO
OMe
OTBS
TMS
i) iPrMgClO
OOii) iBuOCOCl thenCH2N2.
I
MeO
MeO
OMe
O
TMS
Enantioselectivereduction using chemicalcatalyst.
I
OHMeO
MeO
OMe
O
2 steps.
Total synthesis of colchicine in comparison:By: Graening, Timm; Schmalz, Hans-Guenther , Angew Chem Int Ed. 2004, 43, 3230-3256.
Colchicine
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Penicillin VAntibiotic.Sheehan 1957.
N
S
OCO2H
HHHN
PhO
O
ThienamycinAntibiotic.
NO
S
CO2H
HHOH
NH2
Cephalosporin CAntibiotic.
N
S
OHO2C
HHHN
O OAc
HO2C
NH2
Penicillin Va synthesis that uses classicalcondensations and amide formations.
N
S
OCO2H
HHHN
PhO
OHN
S
OCO2H
HHH
NPhO
OOH
amide formation
HN
S
OCO2H
HH
N
OH
O
O
CHO
O
HN
OtBu
O
OH2N
HS
CO2H
N
S
OCO2H
HHHNR
O
[O]
penicillin core
Mechanistic challenge:
NO
HHHNR
O
cephalosporin core
S
OAc
CO2H
+
Synthesis of Penicillins and related antibiotics.
John S Sheehan
From Time Magazine, March 1957; ‘After nine years of dogged work, Chemist John C. Sheehan of M.I.T. announced last week that he had discovered a practical method of synthesizing penicillin V.’The synthesis would not compete with microbiological methods for Pencillin, but allows analogues to be made.
24
Morphine,Analgesic,Gates 1952.
HO
ONMe
HH
HO
H
Heroin,
AcO
ONMe
HH
AcO
H
Codeine
MeO
ONMe
HH
HO
H
Morphine,Analgesic,Trost, 2002.(an asymmetric synthesis)
HO
ONMe
HH
HO
H
MeO
ONHMe
H
HO
H
Cyclise NMe onto alkene
then removeOMe->OH
Morphine
MeO
O CN
H H
MeO
O CN
H
Br Pd-catalysedintramolecularHeck reaction.
Pd(OAc)2diphosphine
MeO
O
H
O
CO2MeBr
CO2Me
OCl3C
O
(racemic)
+MeO
OH
O
Br Palladium catalysedasymmetric allylation
Combination of Pd-catalysed asymmetricreactions and couplingreactions.
PPh2
NH
Ph2P
HN
Ph Ph
O O
Pd
Morphine and related alkaloids.
Professor Barry Trost (Stanford).
"Enantioselective Synthesis of (-)-Codeine and (-)-Morphine", Trost, B.M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542.
25
StrychnineToxic alkaloid.first by Woodward 1954.
N
N
OO
H
H
H
H
N
N
OO
H
H
H
H
HO2C CO2H
Ac2O, NaOAc, AcOHNH
HO
N
O
H
H
H
H
Wieland-Gumlich aldehyde.
NR2
N
OtBuHO
NR2 = NNMe
NMeO
NR2
N
OtBu
HHONR2
N
OtBu
HHO
NR2
HN
OtBu
HHO
HN
H
H
NR2
OtBu
OH
The synthesis here is by Overman 1995.
A
B
Strychnine – selected for closer analysis.
L Overman
S. D. Knight, L. E. Overman and G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293–9294 .
Key step here is the transformationOf A to B.
Shibasaki synthesis of strychnine
StrychnineShibasaki synthesis2002..
as before
NAc
HO
N
O
H
H
H
H
Strychnine
NAc
HO
N
OTIPS
H H
oxidationof alcohol
remove TIPSN
Ac
HO
N
OTIPS
H H
EtS NiCl2, NaBH4
N
OSEM
N
OPMB
H
EtSsteps
NO2
OSEM
HN
OPMB
H
EtS
EtS
O
Zn, MeOH
NH4Cl
NH2
OSEM
N
OPMB
H
H
EtS
EtS
O NH
OSEM
N
OPMB
H
EtS
EtS
NO2
OSEM
HO
OPMB
HO
NH2EtS
EtS
i) Tf2O
ii)
OH
OTIPS
OPMB
HO
I
CO2Me
CO2Me
HO O CO2Me
CO2Me
+
Asymmetric catalyst
DMTSF
(undefined reagent which suppliesequivalent of H+)
A
BC
D
E
T. Ohshira, Y. Xu, R. Takita, S. Shimizu, D. Zhong and M. Shibasaki, J. Am. Chem. Soc, 2002, 124, 14546-14547.
Key steps are from A to C (via B).
27
StrychnineSynthesis byVanderwal and Martin, 2011.longest linear sequence of six steps!Chem. Sci. 2011, 2, 649-651.
N
N
OO
H
H
H
H
HO2C CO2H
Ac2O, NaOAc, AcOHNH
HO
N
O
H
H
H
HWieland-Gumlich aldehyde.
(known process)
NH
O
N OH
H
TMS NaHMDS, NMPthen CuBr.SMe2
5-10% yield.
NH
O
NH
H
Br OH
TMS
iPrNEt2 69%NH
O
N
H
Pd(PPh3)4
O
OO
O
NH
O
N
KOtBu
THF, 0.02M 80oC
NH
NH N
O2N
NO2
81% based on pyridiniumsalt, 100% recovery of excesss.m.
Key step
D. B. C. Martin and C. D. Vanderwal, Chemical Science, 2011, 2, 649-651.
Strychnine synthesis by Vanderwal, 2011.
28
StrychnineApproach to closely related akuammicine by Andrade et al, 2010.
NH
HO
N
O
H
H
H
HWieland-Gumlich aldehyde.
(known process)
DIBAL-H, toluene
Strychnine
NHMeO2C
N
OH
H
H
HNHMeO2C
N
OTBS
H
NaBH3CNAcOH
NaOMe, MeOH(epimerises)
NH
CO2Me
NOTBS
I Pd(PPh3)4PPh3, Et3N
HNH
CO2Me
NBn
HOTBS
I
Br
iii)
K2CO3
ii) debenzylation
N
CO2Me
NBn i) Reduction ofthe C=O bond.
O
NH
CO2Me
NBn
O
Br
O
DBU
(base)
NH
NBn
O
Br
MeO OTMS
NH
NBn O
BrCl
NH
O
BnNH2
MgSO4
AgOTf
+
A
B C D
E
G. Sirasani, T. Paul, W. Dougherty Jr., S. Kassel and R. B Andrade, J. Org. Chem. 2010, 75, 3529-3532.
Strychnine synthesis by Andrade, 2010. Key steps are from A to C and from D to E.
29
3) Lessons learnt from the synthesis of small important organic molecules which may include hirsutene, periplanone B, epothilones and prostaglandins.
Hirsutene.
H
HH
Periplanone BPheromone
O
OO
Epothilone AAnti cancer1996/7.
O
O
HO
OOHO
N
S
Prostaglandins (E2 illustrated)Various biological functions.
CO2H
O
HO OH
OH
CH3
Grandisolmale cotton boll weevil pheromone
3030
Intramolecular epoxide opening reactions
The synthesis of Grandisol, the pheromone of the male cotton boll weevil, and closely-related compounds, has been achieved in a very concise synthesis using a key epoxide-opening step. The high level of ring strain provides a means for the synthesis of similarly strained targets:
O
mCPBA =
Cl
O
O O
H
O
O
4-exo-tet
CNO
CNO
base
NaOMe
CN
O
HHO
O
'steps'OH
CN
CH3Grandisol(racemic product is formed,but this is the correctdiastereoisomer)
OMe OMe
OMeOMe
I. Petschen, A. Parrilla, M. P. Bosch, C. Amela, A. A. Botar, F. Camps and A. Guerrero, Chem. Eur. J. 1999, 11, 3299-3309
31
Hirsutene – radical cyclisation approach by Curran.
Hirsutene.
H
HH HH
IH
HH
I
H
HHHH
I Radicalcyclisation
nBu3SnHAIBN
I
HH
I
OH
HH
HO
CO2H
HH
OTHP
H
OTHP
Br
OO
Li Naphthalenide(reduces bromide)
then CuBr.SMe2
i) sulphonic acidii) LiAlH4
(CF3SO2)2Opyridine.
nBu4N I
LiTMS
D. P. Curran and D. M. Rakiewicz, Tetrahedron 1985, 41, 3943-58.D. P. Curran and D. M. Rakiewicz, Donna M, J. Am. Chem. Soc. 1985, 107, 1448-9.
32
Periplanone B. – approach by Still.
Periplanone BPheromone - Still 1979.
O
OO
O
OOTBS
EEO
O
OOTBS
EEO
H2C SMe2
DMSO/THF
O
OH
EEO
ii) tBuOOH
TMSO
EEO
OTMSO
EEO
O
EEO
HO
EEO
O
EEO
Li
Et2O
KH, 18-C-6 TMSCl
mCPBAi)TBSCl, imidazole, DMF
OEE = OO
W. C. Still, J. Am. Chem. Soc. 1979, 101, 2493-2495. M. A. Adams, K. Nakanishi, W. C. Still, E. V. Arnold, J. Clardy, C. J. Persoons, J. Am. Chem. Soc. 1979, 101, 2495- 2498.
33
Prostaglandins – approach by Corey.
Prostaglandins (E2 illustrated)Various biological functions.
CO2H
O
HOOH
MeO
+
Cl CN
MeO
CN
ClCu(II)
MeO
O
MeO
OO
HO
OHO
OMe
KI3
HO
OMe
O
O
I
NaOH, H2O
mCPBAKOH, H2ODMSO
HO
O
O
O
P(O)(OMe)2
O
HO
O
O
O
N aH, DME
A classic synthetic approach:
THPO
O
OH
OTHP
CO2HPh3P
+ base
then oxidation.
E. J. Corey, N. M. Weinshenker, T. K. Schaaf J. Am. Chem. Soc. 1969, 91, 5675-5677. This process has been significantly developed by Corey since the initial report.
34
Epothilones - This to be the focus of Section 3.
Epothilone A R=HEpothilone B R=Me(a very extensive range now discovered andprepared by synthesis)Anti cancer O
O
OH
O OH O
N
S
R
In the biological synthesis, the compounds are produced by polyketide synthase multienzyme complexes which pass the growing chain from domain to domain until an intramolecular cyclisation completes the synthesis and releases the product from the enzyme. The epoxidation is the last step after this cyclisation. Epothilones can be prepared by cloning and expressing the genecluster in myxococcus xanthus.
O
OH
O OH O
N
S
REpothilone C R=HEpothilone D R=Me
Discussed in MT course for binding - metathesisAnd structural variation but not synthesis.
First isolated in early 1990s from soil bacterium Sorangium cellusum and found to possess antfungal activity. In 1993, they were found to possess antitumour activity in a screen run by MSD. Epothilone B was even more active than taxol and share the same binding site on tubulin. First synthesised in 1996-7. Can be prepared by fermentation processes. Tubulin is a polymeric, tube-shaped protein which for the ‘mititic spindle when cells divide – this controls the correct separation of DNA into the daughter cells. Like Taxol, epothilones bind to the tubulin in the microtubules and interfere with their operation, thus preventing mitosis. Like many anticancer drugs, epothilones are highly cytotoxic. More information on biological action in M. Tosin’s CH408 course.
35
Epothilones – synthetic strategies.
O
O
HO
OOHO
N
S
R
Strategies towards epothilones:epoxidation - late in syntheticdirection.
O
HO
OOHO
N
S
R
Make bond bymacrolactonisation
Make bond by metathesis
Create withaldol reaction.
Create withaldol reaction.
condensation?
Semisynthesis represents A viable approach to new analogues.The majority are made by derivatisation.Note the amide version too.
Key review: J. Mulzer, K.-H. Altmann, Höfle, R. Müller and K. Prantz, COMPTES RENDUS CHIMIE. 2008, 11, 1336-1368.
36
Epothilones – metathesis approach.
O
HO
OOHO
N
S
Epothilone A
OTBS=OSiMe2(tBu)(remove with Fluoride F-)
O
HO
OOHO
N
S
Epothilone C
DMDO
OO
O
(3:1 ratio)
HF/pyridine
O
HO
OTBSOO
N
S
(1.2:1 E:Z)
Grubbs metathesiscatalyst
O
HO
OTBSOO
N
S
EDCIDMAP
OH
HO
OTBSOO
OH
N
S
OH
OTBSOO
O+
2 eq. LDA
-78oC(aldol)
(3:2 with other trans isomer)
Nicoloau 1996 synthesis:
Key Step
37
Epothilones – alkyne metathesis approach.
O
HO
OOHO
N
S
Epothilone C
Furstner synthesis, 2001.
HF, Et2O
Lindlar catalystquinoline1 atm H2
O
HO
OOHO
N
S
O
HO
OOHO
N
S Mo-based (Schrock) metathesis catalyst.
HO
N
S
OH
HO
OOHO
DCC, DMAP, DCM, 81%
HO
OOO
i) Acid (hydrolyse acetal)ii) TBSOTfiii) Acid
iv) PDCO
LDA, THFOOO
EtO
OTBSOHO
(prepared by anasymmetric hydrogenation)
Key steps are the conversion of A to B, and B to C
B
C
A
38
Epothilones – Aldol approach.
O
HO
OOHO
N
S
Epothilone C
An early but ingenious intramolecular aldol reaction approach by Danishefsky:
O
TBSO
OOTBSOH
N
Si) Oxidation.ii) Deprotection
O
TBSO
OOTPSO
N
S i) KHMDSii) HF.py
iii) TBSOTfTBSO
OMeTPSO
BR2
9-BBN
O
I
O
N
S
OMe
PdCl2(dppf), CsCO3Ph3As
pTsOH
Key step is conversion of A to B.
A
B
Prof Samuel Danishefsky,Columbia University and the Memorial Sloan-Kettering Cancer Center (New York)
39
Epothilones – lactonisation approach.
O
HO
OOHO ZK-EPO (sagopilone).
A large scale industrial synthesis of asynthetic epothilone analogue now inclinical trials as anti-cancer drug.
N
S'i) Yamaguchi lactonisation'ii) HF-pyiii) DMDO (7:1)
OTBS
HO
OTBSOO
N
SO
OTBS
HO
OOO
N
S
OH
Deprotection ofacetal and oxidationto acid.
OOO
OTBS
ON
S
LDA, ZnCl2
ii) pTsOHiii) Swern oxidation.
OTBS
N
SPh3P
O
THPO
i) NaHMDS
(note-E:Z mixture isformed but unwantedisomer is isomerisedto required one)
Key step is the Aldol reaction from A to B.
A B
40
4) Molecules with a high degree of functionality, which may include avermectin, erythromycin, amphotericin B and strychnine (covered in part 2).
O
O
O
Me
Me
OH
OH
Me
Me
Me
OH
HO
H
Me
OH
Me
Erythromycinaglycone
(in the full molecule, twocarbohydrates are attached to OHs *)
*
*
StrychnineToxic alkaloid.Woodward 1954.
N
N
OO
H
H
H
H
Avermectin (B1a illustrated)Insecticides.1986,87..
O
O
O
O
O
O
OHH
OH
HO
O
MeO
OH
MeO
Amphtericin BAntifungal.1987.
O
HO OH HO
OH
HO OH
OH
O
OH
CO2H
O OOH
NH2HO
O
41
Avermectins - retrosynthesis.
Avermectin (B1a illustrated)Insecticides.
O
O
O
O
O
O
O
OHH
OH
HO
O
MeO
OH
MeO
H
OO
O
MeO
OH
MeO
OO
O
O
OH
H
O
O
OHH
OHO
First discovered when a scientist notice a healthy patch of grass on a golf course! Analysis of the sample produced a bacteria which produced the Avermectins. These act as insecticides and as treatment for internal and external parasites in livestock. Almost no toxicity to humans.
42
Avermectin – Hanessian route.
Synthesis by Hanessian (to aglycone):
O
O
O
O
HO
O
OHH
OH
H
O
CO2HOH
O
O
HO
OHH
OH
H
DCC, DMAP
O CO2Me
O
OTMSH
O
Completion requiresaddition of sugars anddouble bond rearrangement
O
SO2Ph OTBS
O
TBSO
H
Couple fragmentsthen deprotect.
TMS
O
OTBS
OH
PhO2S
TMSOH
O
OTBS
TBSO
OH
HH
H H
i) nBuLi to acetylene then add lactone.
ii) Pd/ BaSO4 H2.iii) BF3.Et2O.iv) TBAF.
O
OTBS
OH
HO
H
i) (PhS)2, PPh3ii) mCPBA.
+
O
OTBS
BnO
base, then SOCl2 then reductive eimination(Julia olefination)
Professor StephenHanessian (Univeristy ofMontreal).
S. Hanessian, A. Ugolini, D. Debé, P. J. Hodges and C. André, J. Am. Chem. Soc. 1986, 108, 2776-2778.
43
Amphotericin B – focus of this section. Key disconnections and approach.
Amphtericin BAntifungal.1987.
O
HO OH HO
OH
HO OH
OH
O
OH
CO2H
O OOH
NH2HO
O
OOP
NP2PO
X
P=protecting groupX=leaving group.
HO
OP PO
OP
PO OP
OMe
O
OP
CO2Me
O
O
PMeO
O
MeO
OH
PO
O
form alkenes here
44
HO
O OO
O OTBS
OMe
O
OTBS
CO2Me
O
O
PMeO
O
MeO
BnO
O O
H
O
OO O
OTBS
P
MeO
O
OMe
Both could be made by starting from each enantiomerof the sugar xylose, however the favoured method involved a Sharpless allylic epoxidation
i) Wadsworth-Emmons
ii) further conversions
+
OH
O PhOH
O PhO
OH
O PhO
OH
OPhO
Ring open epoxide thenoxidise to CHOthen PPh3P=CHCO2Methen reduce to alcohol
OPh
OH
OH
Steps
OPh
Ph2(But)SiOO
OH
RedAlOPh
HO OH OH
OPh
O O OTBS
O Ph
OH
HO
O Ph
OSi(tBu)Ph2
HO
O
K. C. Nicolaou, R. A. Daines, J. Uenishi, W. S. Li, D. P. Paphatjis and T. K. Chakraborty, J. Am. Chem. Soc. 1988, 110, 4672-4685. (the completion is described in the two papers which follow this).
Amphotericin B – focus of this section. Nicolaou approach.First step;- Sharpless asymmetric epoxidation.
Key step is the Wadsworth-Emmons reaction.
45
Amphotericin B completion of the synthesis.
O
HO OH HO
OH
HO OH
OH
O
OH
CO2H
O
OO
OTBSN3
AcO
X
P=protecting groupX=leaving group.
O
PO
O
O OO
O OTBS
OMe
O
OTBS
CO2MeO
O
P
MeO
O
MeO
O
PO
O
O OO
O OTBS
OMe
O
OTBS
CO2Me
O
DBU, LiCl or K2CO3.
i) Reduce C=O,deprotect
ii) add
NH
CCl3
OOH
NH2HO
iii) complete
HO
O OO
O OTBS
OMe
O
OTBS
CO2Me
O
O
PMeO
O
MeO
OH
PO
O
Couple fragments togetherusing DCC and DMAP.
Key step is the Intramolecular cyclisation reaction of A to B.
A
B
46
Amphotericin B; Carrerira synthesis of polyol structure:
O O
OH
O
OH
CO2Me
O
MeO
TBSO
OOBnOO O
N
HO
O
O
MeO
TBSO
OOBnO XN
O
XN=chiral auxiliary group
O O
N OHTBSO
OOBnO
HO
O
MeO
XN
O
(Bu3Sn)2O, tBuOCl.
i) LiOOHii) MeOH, EtOAc
iii) Mo(CO)6 MeCN/water
O O
OTBSO
OOBnO OtBu
i) LiAlH4, THFii) TEMPO, NaOCl
iii) HONH2.HCl, py
O O
OHO
OOBnO
OtBu
i) H2, Pd/C, MeOHii) TBSCl, Imidazole
O O
OO
OtBu
H
OOBnO+
Zn(OTf)2,
N-methyl ephedrine(chiral directing agent).
OOBnO
H
O
N2
(EtO)2(O)P CO2Et
K2CO3, MeOH
O O
OTBSO
OtBuOOOtBu
OTBSO
Enantiomers
A. M. Szpilman, D. M. Cereghette, N. R. Wurtz, J. M. Manthorpe and E. M. Carreira, Angew. Chem. Int.
Ed. 2008, 47, 4335-4338
The key step is conversion of A to B.
A
B
47
OH OH O OOH OH O O O OO OOH OH
Aspirational approach to polyol synthesis - how could this be done:
Answer - it can (Krische synthesis of (+)-Roxaticin (related to amphotericin B) from 2010:
Ph2P
Ph2P
IrOO
ClO2N
OMeOMe
Cl
ClOH OH
OAc
10 mol%
Cs2CO3, 110oC
OH OH
>99% ee with a 30:1preference for this isomer over the meso.
O OOH OHProtect the diolthen
oxidise alcohols.
Repeat twicewith S-enantiomerof chiral catalyst.
R enantiomerof catalyst.
OH OIr OH O
Ir
HH H
HOH O
Ir
HH OH OH +
Ir
H
OAc
OAc
Ir(abbreviated catalyst)
Ir
H
OAcIr
H- OAc
Amphotericin B; Krische iterative polyol synthesis:
48
O O O OO OOH OH
Next steps in the synthesis:
O O O OO OOHElimination
PMBO
Grubbs metathesiscatalyst
O O O OO OOH
PMBO
O O O OO O
PMBOHO
Ir catalyst againOAc
3 eq.
O O O OO O
OHO
O
Added in 3 stages.
(+) Mycotocin A
S. B. Han, A. Hassan, I. S. Kim and M. J. Krische, J. Am. Chem. Soc. 2010, 132, 15559-15561.
Amphotericin B; Krische iterative polyol synthesis:
Michael KrischeUniversity of Texas at Austin.
Key step is conversion of A to B.
AB
49
5) Construction of highly complex structures which may include ginkgolide B, calicheamycin, taxol.
OS
OH
ONH
O
HOO
OHN
MeO
OI
OMeOMe
O
OHO
MeO HO
O
O
NHCO2MeHO
H
MeSSS Calicheamicin - anticancer molecule
Nicolaou, 1992
Ginkgolide B1988
O
O
O
O
HO
O
HO H
O
HO
O H
H
O
O
OH
HO
O
O
Ph
O
Ph
NHBz
OH
OAcO
AcO
HTaxol - anti cancer molecule
Nicolaou, Holton 1994
Features in MT course, Including biosynthesis, Semisynthesis and binding.
Ginkgo tree inKew gardens.
50
Calicheamycin – intramolecular cyclisation. Calicheamicin - anticancer molecule -enediyne component.
RO
O
NHCO2MeHO
H
MeSSS
RO
O
NHCO2MeEt3SiO
H
BzO
O
O
O
NHCO2MeEt3SiO
H
O
O
O
ONphth
Et3SiO
OMs
O
MeO
DIBAL-H
NaBH4
PhCOCl
H
i) SiO2
O
O
NphthEt3SiO
O
MeOH
O
O
O
NH2
Et3SiO
O
MeOH
OO
O
NEt3SiO
O
MeOO
O
NOO
CO2Me
Et3SiO
SiMe3
Mo(CO)6, then K2CO3
Me3Si
COCl
COCl
i) Pyridine +
ii) SiO2iii) Ac2O
Nphth = N
O
O
KN(SiMe3)2(base)then MsCl/pyridine
pyridine
ii) MeNHNH2iii) (Cl2CO)3 pyridine.
Chemistry and Biology of Natural and Designed Enediynes, K.C. Nicolaou, A.L. Smith, E.W. Yue, Proc. Natl. Acad. Sci. USA 1993, 90, 5881-5888.
51
Ginkgolide B.
O
O
O
O
HO
O
HO H
O
HO
O H
H
O
O
O
MeO
O
O
O
OH
MeO
O
OMe
O
H
O
O
O
H
OH
O
O OH
MeO
O
TfO
MeO i) Pd coupling to
O
O
O
H
ii) (cHex)B)2H, iii) AcOH, H2O2.iv) 1N HCl.
i) (COCl)2ii) nBu3N, heat.
(via a [2+2]cycloaddition)
Ph3COOHNaOH
(Baeyer-Villiger)
severalsteps
CSA
(acid)
several steps
E J Corey (Harvard)
Alleviates asthma symptoms(and other medicinal properties)
E. J. Corey, M. C. Kang, M. C. Desai, A. K. Ghosh and I. N. HoupisJ. Am. Chem. Soc., 1988, 110, 649–651
52
Taxol – selected for close analysis.
TBSO
OTBS
OBn
O
O
H
O
N NHSO2Ar
AcO
CNCl
AcO CN
Cl
CO2Et
OH
HO
HO
O
OHO
OH
O
EtO2C
OO
OH
HO
EtO2C
OO
OCO2EtO
BPh
OO
OCO2EtO
BPh
O
O
OH
OH
CO2Et
PhB(OH)2 90oC
(Diels-Alder)+
(Endo TS)
130oC
OHHO
O O
O
O
EtO2CBPh
Features in MT course, Including biosynthesis, Semisynthesis and binding.
Nicolaou route: Key step is conversion of A to B.
‘The Conquest of Taxol’, K. C. Nicolaou and R. K. Guy, Angew. Chem. Int. Ed. 1995, 34, 2079-2090.
A
B
53
Taxol – Nicolaou route.
O
O
OH
HO
O
O
Ph
O
Ph
NHBz
OH
OAcO
AcO
H
OH
OBn
OO
O
HO
OH
Ph
BzN
OTES
O
O
O
OTES
HOO
O
AcO
HPh
HO
OAcO
OOBn
OO
O
O
OH
O
OTBS
OBn
HO
TBSO
OH
O
TBSOOTBS
OBn
O
O
H
O
N
TiCl3.DMEZn-Cu
McMurry Coupling
NHSO2Ar
i) nBuLi
(shapiro reaction)
Removal of silyl groups(use fluoride).
ii)
Key steps are conversion of A to B, andof C to D.
A
C DB
Taken from: ‘The Conquest of Taxol’, K. C. Nicolaou and R. K. Guy, Angew. Chem. Int. Ed. 1995, 34, 2079-2090.
O
O
OH
HO
O
O
Ph
O
Ph
NHBz
O
OAcO
AcO
HN Me
AcO
water soluble Taxol prodrugs.
O
O
OH
HO
O
O
Ph
O
Ph
NHBz
O
OAcO
AcO
HO
SO2
CO2Me
O
O
O
HO
O
O
Ph
O
Ph
NHBz
OH
OAcO
AcO
H
HN
SO2O
O
NEt2
NEt2
Bioactive fluorescent taxoid.
55
Taxol - Holton route.
O
O
OH
HO
O
O
Ph
O
Ph
NHBz
OH
OAcO
AcO
H
O
OTES
HOO
O
AcO
HPh
HO
OAcO
OTES
HO
O
OTES
O
O
H+
OTES
O
OH
H+
H
H
O OH
OTES
OH
OTES
O
O
Ph
BzN
OTES
O
R. A. Holton, H.-B. Kim, C. Somoza, F. Liang, R. J. Biediger, P.D. Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentle and J. W. Liu, J. Am. Chem. Soc. 1994, 116, 1599-1600.
Professor Robert Holton, Florida State University.
Key step is conversion of A to B.
A
B
56
Taxol - An approach to the CD ring by G Audran et al. 2008:
O
OTBS
OBnO
H
MeOOMe
H
O
OTBS
OHO
H
MeOOMe
H
PMB
i) BnBr, NaHii) DDQ
iii) TPAP(oxidation)
OMs
OTBS
O HO
H
MeOOMe
H
PMB
HO
DBU (base)
(with inversion)
OH
OTBS
OHO
H
MeO OMe
H
PMB HO
OH
OTBS
O
H
MeO OMe
H
PMB
OsO4, NMO
OTBS
O
H
MeO OMe
PMB
SeO2, TBHP
O O H
OH
HO
H
MeO OMe
O OO O
MeO
OMeOMe
O
O
O Ph3P OMe
KOtBu
CSA,MeOH
LiAlH4
P. Bremond, G. Audran and H. Monti, J. Org. Chem. 2008, 73, 6033-6036.
Key steps are conversion of A to B and C to D.
A
D
B
C
57
6) The use of cycloadditions in complex molecule synthesis, which may include FR182877, estrone, platensimycin, progesterone, daphniphyllum alkaloids, abyssomicin C.
O
O
O
HO
HO2C
H H
AcO
H
H
H
OH
H
H
Hexacyclinic acid-
O
O
O
H
HO
H
H
H
OH
H
H
FR 182877 Estronehormone1952
H H
HO
O
H
Progesteronehormone1952
H H
O
H
O
Platensimycininhibitor of fatty acidbiosyntheisis
HO2C
OH
NH
OH
O
O
O
Daphiphylium alkaloid
HN
O
O
O
H
Cholesterol biosynthesis and statins etc in MT course with discussion of biosynthesis.
58
Estrone – Vollhardt synthesis.
Estronehormone1952
H H
HO
O
H
H H
Me3Si
O
HMe3Si
H
Me3Si
O
Me3Si
H
Me3Si
O
Me3Si
H
O
SiMe3
SiMe3
CpCo(CO)2
K. Peter Vollhardt, Berkeley. K. Peter C. Vollhardt, Angew. Chem. Int.
Ed. 1984, 23, 539-556.
59
Progesterone – W. S. Johnson, 1971.
H H
H
O
Progesterone
H H
O
H
O
O aq. KOH
H H
H
O
O3
H H
H
O
aq K2CO3
O
OO
O
O
OH
H
Note this is a racemic synthesis.
W. S. Johnson, M. B. Gravestock and B. E. McCarry, "Acetylenic bond participation in biogenetic-like olefinic cyclizations. II. Synthesis of dl-progesterone". J. Am. Chem. Soc. 1971, 93, 4332–4.
William Summer Johnson (Stanford)
60
Estrone, progesterone - Pattenden approach.
H H
Me
MeMe
Another clever racemicbut stereoselective approach byPattenden:
isomericmixture denoted by
OH
Me
MeMe
O
Me
MeMe
OSePh
nBu3SnHAIBN, heat
.
Professor Gerry Pattenden,Nottingham.
A. Batsanov, L. Chen, G. B. Gill and G. Pattenden J. Chem. Soc., Perkin Trans. 1, 1996, 45-55.
61
Endiandric acids:K. C. Nicolaou’s research group achieved a direct synthesis of endiandric acid A in the laboratory. This was achieved by the reduction of the two alkyne groups in the molecule below by Lindlar catalyst (cis- alkenes are formed selectively) which then formed the product upon heating in toluene. A pretty impressive ‘one-pot’ reaction.
H H
MeO2C
HH
H
Ph
Endiandric acid A(methyl ester derivative)
MeO2C Ph
MeO2CPh
(not isolated)
H2 Lindlar catalyst(Pd/CaCO3, + Pb or quinine poison)
100oC
Toluene
K. C. Nicolaou, N. A. Petasis and R. E. Zipkin, J. Am. Chem. Soc. 1982, 104, 5560-5562.
6262
Further applications of Diels-Alder reactions - alkaloid synthesis:
NH
O
OBn Bn=CH2Ph
CHO
+
NH
CHO
O
OBn
P
O
nPr
O
MeOMeO
base(Wadsworth-Emmons)
NH
O
OBn
Diels-Alder
O
nPr
H2, Pd/C(removes CO2Bnand reduces alkene)
NH2
O
nPr H+ (catalytic)
N
H
HnPr
not isolated
NaBH4
(reduces C=NNH
H
H H
Pumiliotoxin C('poison arrow' toxin)
regio and stereo-controlled
R. Kartika and R. E. Taylor, Richard Chemtracts 2006, 19, 385-390.
63
Daphniphyllum alkaloids.
Daphiphylium alkaloid
HN
O
O
O
H
HN
HHO
O
i) NH3
ii) AcOH
CO2tBu
CHO
CO2tBu
CHO OH
MsCl, DBU
DIBAL-H
Swern oxidation
G. A. Wallace and C. H. Heathcock, "Further Studies of the Daphniphyllum Alkaloid Polycyclization Cascade," J. Org. Chem. 2001, 66, 450-454
64
FR182877 – selected for close analysis.
O OTMS
O
TESO
H
OTES
O
O
O
H
HO
H
H
H
OH
H
H
O OTMS
O
TESO
OTES
OtBuH
H
H
H
H
OtBu
O OTMS
O
TESO
OTES
OtBu
OOTMS
O
TESO
OTES
OtBu
OCO2Me
FR 182877i) Sulfonic acid.ii) TFA/DCM
iii) EDC/DMAP
i) KHMDS, PhSeBrii) mCPBA, DCM.Pd2dba3
H
O
NMe(OMe)
OTMS
TESO
OTES
OTES
AcO
i) Pd2(dba)3LiCl, iPr2NEtNMP
+ ii) LDA, MeCO2tBuiii) TBAFiii) MeOCOCl, pyridine.
Sorensen Approach – inspired by biosynthetic route:
Eric SorensenPrinceton University
D. A. Vosberg, C. D. Vandewall and E. J. Sorensen, . J. Am. Chem. Soc. 2002, 124, 4552-4553.
Key step is fromA to B.
A B
65
FR182877 – anticancerCompound, selected for close analysis.
O OTBS
O
Br
TBSO
H
OTBS
OEtH
H
H
H
H
O OTBS
O
Br
TBSO
OTBS
OEt
OOTBS
O
TBSO
OTBS
OEt
OH
(-) FR 182877
Steps
i) Ph2Se2O3ii) SO3 py TEA.I2, PPh3
then CsCO3
O OTBS
O
Br
TBSO
OTBS
OEt
H
H
H
H
O OTBS
O
Br
TBSO
OTBS
OEt
Diels-Alder
50oC, 6h.
H
H
E
B(OH)2
O
NMe(OMe)
OTMS
TBSO
OTBS
OTBS
i) Pd(PPh3)4
base
+ii) steps.
Br
Br
Evans Approach(to (-) enantiomer)
Different (Suzuki) coupling stepbetween fragments butsame cyclisation approach:
D. A. Evans and J. T. Starr, Angew. Chem. Int. Ed.. 2002, 41,1787-1790.
Key step is fromA to B.
A B
66
Abyssomicin C – selected for close analysis. Again a Diels-Alder approach by Sorensen. This compound inhibits growth of gram positive bacteria including MRSA and the vancomycin resistant strain. It blocks an early stage in the biosynthesis of tetrahydrofolate – a process important to bacteria but not humans.
O
O
O
OO
O
OH
O
i) Dess-Martin Periodinate (oxidant)
ii) Sc(OTf)3, DCM (elimination).OTBS
O
O
O
O
OTBS
OMe
OMe
OMe
O OTESOTBS
O OTESO
i) LDA, THF
ii) TBSOTf, base
iii) Swern oxidation:Me2S(O), (COCl)2, Et3N
LDA, toluene
(selective for OTES group)
+
Deprotonation to form the vinyllithium is proposed.
C. W. Zapf, B. A. Harrison, C. Drahl and S. J. Sorenson, Angew. Chem. Int. Ed.. 2005, 44,6533-6537.
Key step is fromA to B. A
B
67
Abyssomicin C – synthesis completion.
Abyssomicin CAntibacterial natural product.
O
O
O
O
OH
O
O
OH
O
OOO
pTsOH, LiCl,MeCN
O
O
O
O
OMe
O
O
LiClDMSO
O
O
O
O
OMeO
O
O
O
OMe
Diels-Aldercycloaddition
Toluene,100oC
H
O
O
O
O
OMe
Key step is fromA to B.
A
B
68
Abyssomicin C – synthesis by Nicolaou.
Abyssomicin CAntibacterial natural product.
O
OH
O
OOO
oxidation
ii) Grubbs metathesiscatalyst
ii) DDQ
O
OH
O
OHOOH
O
OTES
O
OHOOH i) HCl. MeOK
(remove TES)
O
OTES
O
O
PMBOO
i) tBuLi then
Approach depends on early synthesis of bicyclic part then coupling to aldehyde, and a metathesis:
K. C. Nicolaou and S. T. Harrison. J. Am. Chem. Soc. 2007, 129, 429-440.
Key step is fromA to B.
A
B
69
7) Enantioselective strategies which may include biotin, a-arylpropionic acids, menthol, zaragozic acid, statins (nb statins and zaragozic acids mentioned in MT course).
OH
L-menthol
Biotin
S
NHHN
H H
O
CO2H
Ibuprofen
CO2HLovastatin(Mevacor).....Chlesterol-lowering.
O
HO
HO
O
O
OO
O
HO2CHO2C
CO2HOH
Ph
O OH
AcO
70
A total synthesis of Biotin.
Biotin
S
NHHN
H H
O
CO2HS
NHN
H H
O
CO2H
Ph
OHH
S
NN
H H
O
Ph
OH
H
O
S
NNH
H H
O
Ph
OH
H
O EtO
S
NNH
H H
Ph
OH
O
S
NNH
H
Ph
O
O
S
NNH
H
Ph
O
O
S
ONH
H
O
OEtS
OH2N
HOEt
L-cysteinemehyl ester dimer
2
i) DIBAL,ii) BnNH(OH).HCl PhCH3
heat
Zn, AcOHthen
ClCO2Me,Na2CO3. Ba(OH)2
dioxane/H2O
3 steps
.
E. G. Baggiolini, H. L. Lee, G. Pizzolato, M. R. Uskoković, J. Am. Chem. Soc. 1982, 104, 6460.
71
a-Arylpropionic acids
Ibuprofen
CO2H
Ibuprofen
CO2HCO2H
Asymmetric hydrogenation:
Asymmetric hydrocyanation:
{Ru(DUPHOS)]+
H2
HCN
Rh/diphosphine
S
H H
OHH
note how the left hand structure is unambigous-link chiral centres through a normal bond (i.e. not a wedge or dash)
S
H H
OHConfusing
Several classes of asymmetric catalysts can do this.
72
Zaragozic acid synthesis – key asymmetric dihydroxylations.
OTMS
O
O
O
O
BnO2C
O
CO2BnOH
O
O
O
O
OSEM
OHHO
oxidationsesterifications
OH
O
O
O
O
OSEM
OH
O
O
O
O
OSEM
OH
HO
PMBO
O
O
O
OSEM
PMBO
MeO
PMBO
O
OSEM
PMBO
MeO
AD-mix
(performs anasymmetricdihydroxylation
Then use 2-methoxypropene and acid toform acetal.
DDQ, H2O OsO4, NMO
NMO=
N
O
O
Zaragozic acid A/Squalestatin S1Chlesterol-lowering.
OO
O
HO2CHO2C
CO2HOH
Ph
O OH
AcO
73
Zaragozic acid synthesis – continued.
Zaragozic acid A/Squalestatin S1Chlesterol-lowering.
OO
O
HO2CHO2C
CO2HOH
Ph
O OH
AcO
OOMeO2C
BnO2C
CO2MeOH
Ph
HO OH
OTBS
Ph
OTBS
O
O
O
O
O
BnO2C
OH
CO2Bn
OH
Ph
OTBSOTMS
O
O
O
O
BnO2C
HO
CO2Bn
S S
OTMS
O
O
O
O
BnO2C
O
CO2Bn
Ph
OTBS
S S
Li
i) 2% HCl/ MeOH(removes TMS)
ii) Hg(ClO4)2, CaCO3
1.8% HCl/MeOH
severalsteps.
Reference: a) K. C. Nicolaou. E. W. Yue, Y. Naniwa, F. DeRiccardis, A. Nadin, J. E. Leresche. S. LaGreca. Z. Yang, Angew. Chem. Int. Ed. 1994, 33, 2184. b) K. C. Nicolaou, A. Nadin, J. E. Leresche, S . LaCreca, T. Tsuri. E. W. Yue, Z. Yang, Angew. Chem. Int. Ed. 1994, 33. 2187.
7474
Menthol is prepared through an ene reaction: This uses a mild Lewis acid. The chirality of the product comes entirely from the single chiral centre of the starting material, itself made by an asymmetric isomerisation reaction.
OH OH
H2, Pd/C
O O
H
via
ZnBr2
ZnBr2(catalyst)
H
O
H
OZnBr2
L-menthol
Ph2P
PPh2
[Rh/S-BINAP]
RhNMe2 NMe2
Isomerisation (not a reduction!)
H
H+/H2O
This method was developed by Takasago, developed in collaboration with R. Noyori – BASF have a similar strategy. S.-I. Inoue, H. Takaya, K. Tani, S. Otsuka, T. Saito and R. Noyori, J. Am. Chem. Soc. 1990, 112, 4897.
75
Statins - selected for closer attention.
O
HO
H
R
O
O
H
O
O
HO
H
R
O
O
O
R
OH
HO
OHO
OH
OH
O
R
OHOH
OH
O
(CoA)S
OH
R=Me; Lovastatin (Mevacor)R=H; Mevastatin (Compactin)Chlesterol-lowering drugs
Simvastatin (Zocor)
The above compounds are natural products isolated by fermentation - they work by ring opening to the 3,5-dihydroxy acid, which inhibits fatty acid (and cholesterol) biosynthesis (see M. Tosin course CH404 for more information on this).
hydrolysis of ester.
Mevaldic acid hemithioacetal-intermediate in cholesterol biosynthesis
note relationshipto chlesterol-synthesis]intermediate shown on left
OH
OH
OOH
N
FOH
OH
OOH
N
N pFC6H4N
S
OO
OH
OH
O
N
OH
F
Ph
OPhHN
Fluvastatin (Lescol)
Rosuvastatin (Crestor)
Atorvastatin (Lipitor)
76
Synthetic approaches to statins; An early approach to compactin from M. Hirama and M. Uei.
O
O
O
OBn
O
O
OBn
P(O)(OMe)2O
OTBS
OMe
O
OTBS
POMe
OMe
O
O3 then
Me2S
OMe
O
O
OTBS
i)
ii) Ac2Oiii) Na/Hg
OH
MeO O
O
MeO O
Bakers' yeast
O
HO
HO
O
H
O
M. Hirama and M. Uei, J. Am. Chem. Soc. 1982, 104, 4251-4253.
77Hirama and Uei, J. Am. Chem. Soc. 1982, 104, 4251-4253.
O
HO
H
R
O
O
H
O
Last steps include i) deprotection of the OBn to OH, then oxidation, ii) deprotection iii) cyclisation to the lactone
O
OTBSH
H
O
O
OBn
O
OTBS
O
O
OBn
P(O)(OMe)2O
OTBS O
O
O
OBn
+ NaH
THF
reflux
chlorobenzene
O
OHH
H
R
O
SOCl2
O
H
H
R
O
Other isomers are formed andseparated by chromatography.
Key steps is fromA to B and B to C.
B CA
78
Synthetic approaches (+)-dihydrocompactinwhere remote stereocontrol is achieved.
O
H
H
OH
O
OTMS
OTMS OH
i) Al(OTf)3/ TfOHii) H2O, HCl
iii) K2CO3/MeOH
49% for 3 steps.9:1 mixture of isomers.
O
TMSO
O
TMSO
H
H
O
TMSO
H
+
OO
H
H
1 : 1 mixture formed
stereochemistrycontrolled atthis step.
bydeprotonation
by OTMSadding to C=O
T. Sammakia, D. J. Johns, G. Kim and M. A. Berliner, J. Am. Chem. Soc. 2005, 127, 6504-6505.
Key step is fromA to B.
A B
79
Synthetic approaches (+)-dihydrocompactin – completion of synthesis.
O
H
H
OH
OH
OH
H
H
O
OCPh3Br
O
O
H
H
HO
O
O
O
i) Ph3CCl, py
ii) L-selectride(reduce C=O).iii) BrCOCH2Br, py
py=pyridine
i) Add side chainii) ZnBr2 (remove Tr).iii) Dess-Martinperiodinate.
SmI2
(reductive coupling)
O
H
H
O
OBr
O
O
T. Sammakia, D. J. Johns, G. Kim and M. A. Berliner, J. Am. Chem. Soc. 2005, 127, 6504-6505.
Key step is fromA to B.
A B
80
Statins - An approach to a subunit involving organocatalysis and a metathesis.
OHH
OHOH
H
OH
Grubbs metathesis
DCM, reflux
OH
O
LiAlH4
OH
O
Br
OH
OSnBu3
Pd(PPh3)4
Br
O
O
steps
Br
AIBNnBu3SnH
(radical cyclisation)
O
O
O
onestep
O
O
OTMS
+
TMS
TMS TMS TMS
TMS TMS
TMS
NH
NMeO
Ph
J. Robichaud and F. Tremblay, Org. Lett. 2006, 8, 597-600.
Key step is fromA to B.
A B