Samarium(II) Iodide Mediated Cyclizations in Natural Product SynthesisThe Kagan Reagent Part II
An Evans Group Afternoon SeminarKeith Fandrick
Seminar outline:-Introduction and Background-Intramolecular Barbier Reaction-Intramolecular Reformatsky Reaction-Radical Alkene and Alkyne Cyclizations-Carbonyl-Alkene Reductive Cyclizations-Intramolecular Pinacol Couplings-Intramolecular Reductive Couplings of Carbonyls and Hydrazones-Total Synthetic endeavors utilizing mutiple SmI2 cyclizations
Primary ReferencesProcter, D. J. Chem. Rev. 2004, 3371.Krief, A. Chem. Rev. 1999, 745.Molander, G. Chem. Rev. 1996, 307.Molander, G. Chem. Rev. 1992, 29.Curran, D. R. Synlett 1992, 943. Rajapakse, H. Evans Group Seminar 1998
SmI2 Discovery and BackgroundIntroduction
-Samarium diiodide was first reported by Kagan in 1977. Kagan reported the preliminary deoxygenation of epoxides and sulfoxides, chemoselective reduction of aldehydes in the presence of ketones, dehalogenations, and couplings between ketones and alkyl halides. (Kagan, H. B. Nouv. J. Chim. 1977, 5. Kagan, H. B. J. Am. Chem. Soc. 1980, 2693)
-Samarium diiodide is the subject of >20 reviews and >850 publications.
-Samarium diiodide is commercially available as an anhydrous powder (5g, $185) or as a 0.1 M solution in THF (100mL, $32). (Aldrich catalog 2003-2004)
-Samarium diiodide can be prepared from Sm metal and CH2I2, ICH2CH2I, or I2.
-Reactions are generally performed with an excess of samarium diiodide, degassed reagents and solvents, and in dry THF containing an antioxidant.
-Catalytic amounts of SmI2 can be used with the addition of mischmetall (alloy of lanthanides [La 33%, Ce 50%, Nd 12%, Pr 4%, Sm and other lanthanides 1%] to regenerate SmI2. The use of catalytic amounts of Sm(II) and mischmetall is more cost effective. The alloy is unreactive to carbonyls and simple to use.
-The normal work-up usually requires acidic conditions. However, Rochelle's salt and potassium carbonate can be used for acid sensitive substrates. (Little D. J. Org. Chem. 1996, 3240)
-THF appears to be the proton source for the termination of radical cascades. If a second reduction with additional equivalent of SmI2 occurs the proton source is generally the alcoholic co-solvent. (Curran D. P. J. Am. Chem. Soc. 1988, 5046)
-Samarium diiodide chemoselectively reduces: organic halides, carbonyls, α-hetero-sustituted carbonyls, cyclopropyl ketones, epoxides, amine oxides, sulfoxides, phosphine oxides, sulfones, sulfonates, nitro, nitroso, and azo compounds, allyl acetates, and isoxazoles.
Krief, A. Chem. Rev. 1999, 745.
-2.25
-2
-1.75
-1.5
-1.25
-10 1 2 3 4 5 6 7
Equiv of HMPA relative to Samarium Diiodide
Oxi
datio
n Po
tent
ial
SmI2 Reduction Potential
-Samarium diiodide is a polyvalent single electron reducing agent.
-The reduction potential (Eo) of Sm+2/Sm+3
in water is -1.55 V compared to Nao/Na+1 of -2.77 V.
-The reduction potential of SmI2 can be increased by the addition of HMPA, and LiBror LiCl.
-The addition of transition metal increasesthe rate of several SmI2 reactions.(Kagan, H. B. Synlett 1996, 633)
-Changes in protic solvents can alterthe rates of SmI2 mediated reactions andin some cases alter the mechanism.
-Visible light increases the reduction potentialof SmI2. (Ogawa, A. J. Am. Chem. Soc. 1997, 2745)
Krief, A. Chem. Rev. 1999, 745.
UV-vis spectrum of SmI2 in THF
Effects on the Eo of SmI2 with HMPA
SmI2 Barbier Reaction Basic Mechanism
Sm
I
I
HMPA
HMPA
HMPA
HMPAOuter Sphere
ETR-I+ Sm
I
I
HMPA
HMPA
HMPA
HMPA+ R
+ Sm
I
I
HMPA
HMPA
HMPA
HMPA
Outer Sphere ETSm
I
I
HMPA
HMPA
HMPA
HMPA+ R
+-
Sm
R
I
HMPA
HMPA
HMPA
HMPASm
I
I
HMPA
HMPA
R
HMPAorR' R'
O
R' R'R
OSmInHMPAm
H+R' R'
R
OH
-Reduction of the ketone followed by substitution of alkyl-halide with ketyl-radical ruled out by Kagan, because the use of chiral alkyl-halides leads to racemic products.
-The replacemed of HMPA with LiBr predominately leads to the Pinacol product via inner sphere electron transport/reduction of the ketone via formation of SmBr2.
-Replacement of HMPA with HMDS leads to the formation of [Sm(HMDS)2]2, which has a redox potential inbetween SmI2 and [Sm(HMPA)6]I2. [Sm(HMDS)2]2 reacts faster with alkyl halides and ketones via change in mechanism towards an inner sphere ET process.
Molander, G. J. Am. Chem. Soc. 1987, 6556. Curran, D. P. Synlett 1992, 943.Flowers, R. A. Org. Lett. 1999, 2133.Flowers, R. A. J. Am. Chem. Soc. 2000, 7718.Flowers, R. A. J. Am. Chem. Soc. 2002, 6895. Flowers, R. A. J. Am. Chem. Soc. 2002, 14663.Flowers, R. A. J. Am. Chem. Soc. 2004, 6891.
Intramolecular SmI2 Barbier ReactionsBasic Mechanism
Me
Me O
Me
I
Me
Me O
Me Me
Me O
MeMe
Me O
Me
Me
Me O
Me
I2Sm
Me
Me
Me
OSmI2
Me
Me
Me
OH
Me
Me O
Me
SmI2
Me
Me
Me
OSmI2
Me
Me
Me
OH
SmI2
SmI2KSm
KC
SmI2
H+
H+
H+
Reactions performed with 2 equiv of SmI2 and 20 equiv of HMPA
SmI2 (M) A B C D0.010.030.050.07
64%42%27%20%
21%42%55%59%
11%11%13%15%
4%5%5%6%
A
B
C
Me
MeO
Me
D Curran, D. P. Tetrahedron 1997, 9023Krief, A. Chem. Rev. 1999, 745Molander, G. A. J. Org. Chem. 1991, 4112
H
Me
Intramolecular SmI2 Barbier ReactionsEunicellin and Muscone
O
O
I
Me
Me SmI2, THF-78 oC to rt
O
MeOH
O
AcO
AcO Me
OAc
OAcMeMeMe
CH2
Eunicellin
Hoffman, M. R. Tetrahedron 1997, 4331
88% Single Diastereomer
SmI2, HMPATHF
1) HgO, I2 PhH, hv, O oC 59%2) Bu3SnH-AIBN PhH, hv, 82%
O
Me
90% Single Diatereomer(+/-) Muscone
Suginome, H. Tetrahedron 1987, 3963
O
I
Me Me
OHH
H
MeMe
Intramolecular SmI2 Barbier ReactionsPolyoxypeptin A
NTs
I Me O
ORNTs
OHMe
ORNTs
MeOH
ORSmI2 +
R Yield A:BTBDPSTrH
76%45%75%
13:8731:6997:3
THF, HMPA
HNN
N
N
N
NH HN
O
Me
O
O
N
O
OMeO
OH
H
H
MeOH
Pr
H
iPrH
Me
HO
OH H
Me
H
OHO O
OH
Polyoxypeptin A
OSmI2O
H
N H
I
OSmI2O
H
H
Me
N
I
TsTs
Favored Disfavored
Hamada, Y. Tetrahedron Letters 2002, 4695Procter D. Chem. Rev. 2004, 3371
Hamada's Explanation
OO
Sm(III)(HMPA)n
N
I
Ts
H
O
Me
N
I
Ts
OP Sm(III)(HMPA)n
HH
Procter's Explanation
-Mechanism might proceed through a bis-radical stucture
A B
Intramolecular SmI2 Barbier CyclizationsSynthetic Studies Towards Variecolin
Molander, G. Org. Lett. 2001, 2257For increased reaction rates with NiI2 see: Kagan, H. Synlett 1996, 633For increasing reducing ability of SmI2 with visible light see: Ogawa A. J. Am. Chem. Soc. 1997, 2745
OMe
I
O
Cl+
SmI2, cat. NiI2THF, 72% OH
OMe
Cl
1:1 Mixture of diastereomers due to racemic starting
materials RuCl3, NaIO4MeCN, CCl4, H2O
65%
OCl
O
H
H
H
O
HO SmI2, NiI2hv, THF
H
Me
MeH
H
H
MeOHC
O
Me
Me
63%
Variecolin
Model of Intermediate A
A
OSmInTHFm
SmI2 Reformatsky reactionsBasic Mechanism
OBr
O
O
MePh
2 equiv SmI2THF, -78 oC
<15min
O
H
Me
O
Ph O
Ph MeOH
O
95%. Single DiastereomerMolander, G. A. J. Am. Chem. Soc. 1987, 6556
-Due to Sm(III)'s ionic radius, high coordination number, and high oxophilicity: SmI2 has been used succesfully as a chelation element to bring two reaction centers in proximity for the formation of large ring.
CHO
(CH2)nBr
CO2Me
(CH2)n
OH
CO2Me
(CH2)nO
OMe
OSmInTHFm (CH2)n
O
O
OMe
SmInTHFm
n Ring Size Yield6791213
89111415
68%70%74%82%82%
Inanaga, J. Tetrahedron Lett. 1991, 6371
O
Me
SmI2 Intramolecular Reformatsky reactions(+/-) Paeoniflorigenin and Paeoniflorin
O
O
OH OTIPS
H
Me
Cl
NC
Slow Additionof SmI2 (7 equiv)
THF, -45 oC10h
O
OTIPS
NC
HO
O
MeO
OH
HO
HOO
MeO
OH
O
HO
O
OHHO
HOHO
Paeoniflorin Paeoniflorigenin
Chem 3D w/ MM2 energy minimization
Corey, E. J. J. Am. Chem. Soc. 1993, 8871
93% Single Diastereomer
-Product of the cyclization is base sensitive. Retro-Aldol is observed upon treatment of product with Et3N.
O
SmI2 Intramolecular Reformatsky reactionsUridine Derivatives
Matsuda A. J. Org. Chem. 1997, 1368
O N
OTBSO
O
O
N
O
OEt
SmI2THF O N
OTBS
N
O
OEt
OOH
H
OBr
O N
OTBS
N
O
OEt
OH
OH
H2N
O
Uridine Derivatives
O
O
O
I3Sm
-Substrate is Base sensitive
-Uridine Derivatives have been shown to be potent antitumor agents bothin vitro and in vivo
Base
OTBS
Conditions Product Yieldsrt w/ Znrt0 oC-78 oC-78 oC w/ HMPA
A
C 22%A 71%A 75%A 90%A 76%, B 11%
O N
OTBSO
AcO
N
O
OEt
NH
N
O
OEt
B C
Product Distribution Plausible Transition State
SmI2 Intramolecular Reformatsky reactionsTaxol-Mukaiyama
Br
O
Me MeOTBS
OBn
OTBS
OBn
OPMB
Br
O
Me MeO
OBn
OTBS
OBn
OPMB
Me
O
Me MeO
OBn
OTBS
OBn
OPMB
Br
OBnO
TBSO
PMBO OBn
OHMe
Me
OBnO
TBSO
PMBO OBn
OHMe
Me
87% dr 65:35
Me
OBnO
TBSO
PMBO OBn
OHMe
Me
Me
70% dr 83:17
1) 1N HCl, THF2) (COCl)2, DMSO, Et3N CH2Cl2 94%
1) LHMDS, MeI, HMPA, THF 100%2) 1N HCl, THF 83%3) (COCl)2, DMSO, Et3N, CH2Cl2 95%
SmI2, THF, 0 oCSmI2, THF, 0 oC
Me
OAcOMe
OH
OOAc
HOBzOH
MeMe
O
O
Ph
NHBz
OHTaxol (paclitaxel)
Mukaiyama, T. Chem. Eur. J. 1999, 121
SmI2 Intramolecular Reformatsky reactionsTaxol-Mukaiyama
Me
O
Me MeO
OBn
OTBS
OBn
OPMB
Br
OBnO
TBSO
PMBO OBn
OHMe
Me
Me
70% dr 83:17
SmI2, THF, 0 oC
Me
OAcOMe
OH
OOAc
HOBzOH
MeMe
O
O
Ph
NHBz
OHTaxol (paclitaxel)
Mukaiyama, T. Chem. Eur. J. 1999, 121
OSmIII
OR
R
Me
Chem 3D Mimimized SmIII Enolate Chelate
Simplified Chair Transition State
-Preliminary modeling suggest reaction preceeds through E-enolate
*
Sm
Inoue, M. ACIEE 1998, 965Inoue, M. JOC 1999, 9416
SmI2 Intramolecular Reformatsky reactionsModel Studies Toward Ciguatoxin
O
O
O
O
OH
H HH H
OTBPS
OH
HH H H
OTBPS
O
O
O
O
O
OH
H HH H
OTBPS
O
HH H H
OTBPS
O
Br
O
O
O
O
OH
H HH H
HH H H
O
O
O OO
HH Me
H
OHMe
HH
H
HMe
OHFG H I
JK
LMF-M Ciguatoxin Model
Ciguatoxin
O
O
O
O
OH
H HH H
OTBPS
OAc
HH H H
OTBPS
O
SmI2, THF-78 oC
1) Ac2O, DMAP, 0 oC2) NaBH4, CH2Cl2/MeOH3) PhOC(S)Cl, DMAP, CH3CN, rt
66% over 5 steps
SingleDiastereomer
OO
O
HH
HH
H
HH
O
O
OO O
H H Me
H
OHMe
HH HHMe
OH
O
O
O
O
O
HHHH
OHHOHHHH
HO
Me
HO
A BDC E F
GH
I J KL M
PhO
S
Inoue, M. ACIEE 1998, 965Inoue, M. JOC 1999, 9416
SmI2 Intramolecular Reformatsky reactionsModel Studies Toward Ciguatoxin
O
O
O
O
OH
H HH H
OTBPS
OH
HH H H
OTBPS
O
O
O
O
O
OH
H HH H
OTBPS
O
HH H H
OTBPS
O
Br
SmI2, THF-78 oC
SingleDiastereomer
Sm
OSm
O
R
RH
Chem 3D Minimized Stucture ofthe SmIII Chelated Enolate Simplified Conformation
SmI2 Radical-Alkene and Alkyne CyclizationsBasic Mechanism
I R
RSmI2THF
R
R
RR
SmIII
R
R
R
R
SmIII
RR
OH
R'
R
R
R'
OH
SmI2
kc
kSm
R Equiv HMPA A/B ratioHHHHHMe
2.33.23.7570
08/9234/6650/5056/4452/480/100
Curran, D. Tetrahedron Lett. 1993, 1717.For a review on the mechanism of SmI2 reactions see: Curran, D. Synlett 1992, 943.For a review of coupling of organic halides and carbonyl compounds see: Krief, A. Chem. Rev. 1999, 745.
A
B
SmI2 Radical-Alkene and Alkyne CyclizationsSynthetic Utility of Intermediate Organo-Samarium Compounds
O
I
O
SmIII
2 equiv SmI2THF, HMPA
O
iPr
O
(iPrCO)2O
O
I
I2
O
SePh
O
SPhPhSeSePh
PhSSPh
O
OHMe
NEt2
Me
O
NEt2
O
SnBu3
Bu3SnI
O
NHPh
O
PhNCO
O
D
D2O
56%
70%
72%
65%
76%
82%65%
80%
Molander, G. Chem. Rev. 1996, 307Procter, D. J. Chem. Rev. 2004, 3371
SmI2 Radical-Alkene CyclizationsC-Glycoside Formation
Beau, J.-M. ACIEE 1994, 1383.For the use of 2-pyridine as a chelation point see: Yamamoto, H. JACS 2004, 4128.
O
OBnO
BnO SO2R
SiMe
Me
BnOSmI2
Conditions
O
OBnO
BnOBnO
O
OHBnO
BnO EtBnO
TBAFDMF
Conditions R Overall Yield B
B
A
N
THF/HMPA
THF
THF
78%
80%
37%
-Authors propose 2-pyridyl group lowers LUMO thus facilitates inital sulfone cleavage
-Possibility of 2-pyridyl group serving as a chelating point, thus facilitating inner sphereelectron transport process for inital sulfone cleavage.
O
BnOBnO
BnO
k1
k2
C
Protonation By THF
SiMe2
O
OBnO
BnOBnO
SiMe2
O
OBnO
BnOBnO
SiMe2Me
SmI2 Radical Carbonyl-Alkene CyclizationsBasic Mechanism
Molander, G. J. Org. Chem. 1995, 872.Curran, D. P. Synlett 1992, 943Rajapaksa, H. Group Seminar 6-1998
R
O 1) 2.2 equiv SmI2 2 equiv t-BuOH THF/HMPA2) H+
HO R
Me
HO R
Me
HO R
+ +
HOSmnTHFm
RH
OSmnTHFm
R
OSmnTHFm
R
R % isolated Yield of A and B % Yield C Reaction (diast ratio, A:B) TimeMei-Prt-BuPh
86 (>150:1)85 (23:1)78 (3:1)48 (1<150)
-34-
15 min30 min8 h2 h
A B C
-Carbonyl reduction by SmI2 is well documented
OSmIII
SmI2 Radical Carbonyl-Alkene CyclizationsBasic Mechanism, an Example of an Activated Alkene
Procter, D. J. Org. Lett. 2003, 4811
O
O
O
Me
Me
Me
Me
OH
H O
OH
Me
Me
OH
H O
OH
DBU, PhCH3, 69%
SmI2THF-MeOH +
63% 17%
O
O
OMe
Me
SmIII
O
OMe
MeOSmIII
O
Me
Me
O
OO
Me
Me
OSmIII
Transition States
A B C D
SmI2 Radical Carbonyl-Alkene CyclizationsBasic Mechanism, an Example of an Activated Alkene
Procter, D. J. Org. Lett. 2003, 4811
O
Me
O
O1el
O
Me
O
O
O
Me
O
O el OO
SmInTHFm
O
Me OH
O
OMe
H OH
OOSmIII
Me
HO
OSmIII
OSmIIIMe
HO
Oel
MeOH"efficient
protonation"
t-BuOHSlower Protonationallows cyclization
71%
64%Single Diastereomer
SmI2THF
el
SmI2
SmI2 SmI2
SmI2 Radical Carbonyl-Alkene CyclizationsBasic Mechanism, an Example of an Activated Alkene
Procter, D. J. Org. Lett. 2003, 4811
O
Me
O
O1el
O
Me
O
O
O
Me
O
O el OO
SmInTHFm
O
Me OH
O
OMe
H OH
OOSmIII
Me
HO
OSmIII
OSmIIIMe
HO
Oel
MeOH"efficient
protonation"
t-BuOHSlower Protonationallows cyclization
71%
64%Single Diastereomer
O
O
OO
H OH
O
70%
SmI2THF
SmI2THF
Supporting evidence for the anionic model
el
SmI2
SmI2 SmI2
SmI2 Radical Carbonyl-Alkyne CyclizationsIsocarbacyclin
Noyori, R. Tetrahedron 1990, 6689.Procter, D. Chem. Rev. 2004. 3371.
TBSO
HO
Me
OTBS
( )4
Reagents A (C6 dr) B (C5 dr) C DZn,TMSCl, 2,6 Lutidine, in THF, at refluxLi-Naphthalene, t-BuOH, in THF at -70 oCSmI2, t-BuOH, in THF at -70 oChv, Et3N, in CH3CN at rt
28% (ND mix)65% (ND mix)71% (9:1)60% (2:1)
51% (1:1)15% (1:2)-20% (ND)
-3%8%-
--8%-
ND denotes mixture was defined as an "epimeric mixture" at the defined stereocenter
HO
RRO
O
RRO
HO
RROR
RO
OH
2A B C D
Reagents
A
HO
CO2H( )4
MeOH
( )4
+ + +
Isocarbacyclin
OSmIII
HH
RTBSO
HH
RTBSO
SmIIIO
vs'
Plausible Transition States
C6
C5
SmI2 Radical Carbonyl-Alkene Cyclizations (-)-Patchoulenone
Banwell, M. G. New J. Chem. 2003, 50.
Me Me
Me
OBn
Me
O
Me
BnOHOMe
Me
Me
SmI2, PhSHTHF-HMPA 3 steps
Me
O
Me
MeMe
(-)-Patchoulenone
Me Me
Me
OBnO
Me
BnOHO
Me
Me
BnOHO
Me
MeTHF-HMPA
SmI2+
54%0%
39%71%
74%Single Diastereomer
Additive Yield B Yield CNonePhSH
B C
X-Ray Structure of A
A
Model Studies, effects of PhSH additive
-Prins, carbonyl-ene, and Paterno-Buchi reactions proved to be inferiormethods in the synthesis
OO
SmI2 Radical Carbonyl-Alkene Cyclizations trans-Fused Polytetrahydropyrans
O
OCO2Et
CHO
H
HO
H
H
OCO2Et
OH
H
H
SmI2MeOH-THF
O O OSmIII
O
EtOH
H H
H
O O OSmIII
O
EtOH
H H
H
O O OSmIII
O
EtOH
H H
H
SmI2
SmI2
-Issues with similtaneous binding of ketyl radical and conjugated ester, geometerical constraints?
-Alternated Possibilities
O O OSmIII
O
EtOH
H H
H
O O OSmIII
O
EtOH
H H
HProcter's Alternative Non-Chelation
Hori, N. Tetrahedron Lett. 1999, 2811Hori, N. Org. Lett. 1999, 1099Hori, N. Tetrahedron 2002, 1853Suzuki, K. Tetrahedron Lett. 2002, 8653
92%Single Diastereomer
SmI2 Radical Carbonyl-Alkene Cyclizations trans-Fused Polytetrahydropyrans
O
OCO2Et
H
H O
H
H
SmI2MeOH-THF
Hori, N. Tetrahedron Lett. 1999, 2811Hori, N. Org. Lett. 1999, 1099Hori, N. Tetrahedron 2002, 1853Suzuki, K. Tetrahedron Lett. 2002, 8653
CHO
O
O
OH
H
O O O
EtOH
H
H
O
H SmIII
O O
H
H
HO
H
SmIIIO
OEt
or
84%Single Diastereomer
Iterative Cyclizations produces Polytetrahydropyrans and Oxepanes
O
O
O
OR R R R
H H H H
CO2Et
OH
R= Me or H
O
O
O
OCO2Et
OH
H HH H
HH H H
-Cyclizations proceed in high yield (>80%) and with complete stereocontrol
SmI2 Radical Carbonyl-Alkene Cyclizations Natural Product Synthesis and Synthetic Studies
Also, the D and E ring of the A-F fragment of Yessotoxin. Suzuki, K. Org. Lett. 2002, 3943
CiguatoxinTakakura, H. ACIEE
2001, 1090
Brevetoxin BMatsuo, Tetrahedron Lett.
2000, 7673
Nakata, T. J. Am. Chem. Soc.2004, ASAP
GambierolKadota, I. JACS 2001, 6199Kadota, I. JACS 2001, 11893
O
SmI2 Radical Carbonyl-Alkene Cyclizations Synthetic Studies Toward Vinigrol
HOH
Me
Me
OMeO2C
CO2MeH
MeMe
OHI2Sm
SmI2, MeOHTHF, -78 oC
OHMe
OHH
MeO2C
Me
81%Single Diastereomer
HOH
Me
Me
OMeO2C
SmI2, MeOHTHF, -78 oC
HOH
Me
Me
HOMeO2C
81%
OH
H H
Me
Me
OH HO
MeHVinigrol
Matsuda, F. Synlett 1996, 1057
SmI2 Radical Carbonyl-Alkene Cyclizations Synthetic Studies Toward Vinigrol
HOH
Me
Me
OMeO2C
SmI2, MeOHTHF, -78 oC
HOH
Me
Me
HOMeO2C
81%
OH
H H
Me
Me
OH HO
MeHVinigrol
Matsuda, F. Synlett 1996, 1057
HOX
Me
Me
OMeO2C
SmI2, MeOHTHF, rt
HOX
Me
Me
OH
MeO2C
XHAc
Yield45%85%
O
MeMe
I2Sm
MeO2C
OHH
MeMe
HO
O
I2Sm H
CO2Me
Non-productive Productive
SmI2 Radical Carbonyl-Alkene Cyclizations (+/-) Hypnophilin
Me
MeMe O
OO
Me
MeMe O
OO
SmIII
Me
O
O
Me
Me
OSmIII
H
H Me
Me
OSmIII
H
H Me
H
Me
Me
OH
H
H Me
H
O
O
O
OSmI2
Solvent0 oC
pTSAacetone
Me
Me
H
H Me
H
OH
O
SolventTHF
THF/HMPATHF/DMPU
Pdt11%91%87%
epi-C11--
9%
Reduction18%9%4%
Yield of ketoneNA
63%69%
-Addition of D2O lead to no incorporation of deuteriumin products.
Me
Me
H
H MeOH
O
O
Hypnophilin
Curran, D. P. J. Am. Chem. Soc. 1988, 5064
C11
SmI2 Radical Carbonyl-Alkene Cyclizations (-)-C10-Desmethyl Arteannuim B
Me O Me
H
OHCH2CO2Me
CO2Me
SmI2THF-MeOH Me
H
O
O
O
(-)-C10-Desmethyl Arteannuim B
Lansbury, P. T. Tetrahedron Lett.
1992, 1029
O
H
HH
OO
R
Me
Me
R=Me or HArtemisinin
O
OSmIII
Me
Me
>95%Single Diastereomer
-α,β-unstaturated ester harder to reduce (Ep -2.45 V) than enone (Ep -2.2 V)
-Performing reaction at -78 oC leads to reduction of enone to allylic alcohol.
-Reaction required degassed solvents and slow separate addition of MeOH and SmI2.
-Inital product acid sensitive, utilizing Rochelle's salt and a medium of 10% potassium carbonate significantly inproved yields.
0 oC
O
OSmIII
Me
Me
SmI2
O
OSmIII
Me
Me
MeOH
Little, R. D. J. Org. Chem. 1996, 3240
SmI2 Radical Carbonyl-Alkene Cyclizations Mucocin
OHC
OEtO2C
CHO
OBnO
O
O
CHO
OBnO
O
HO
EtO2CSmI2
THF-MeOH-5 oC
87%Single Diastereomer
O
H
OI2SmO
EtO
O
H
OI2SmO
EtO
SmI2MeOH
H
H
H
H
O O
OO
Me
HO
OH OH
OHMe
Mucocin
-Survival of second aldehyde suggests inital SmI2 reduction is reversible
-Increasing reaction time or using larger amounts of SmI2 leads to Pinacol-type coupling and reduction products.
Nakata, T. ACIEE 2002, 4751Curran, D. P. Synlett 1992, 943
SmI2 Radical Carbonyl-Alkene CyclizationsUpial
Nagaoka, H. Tetrahedron Lett. 1993, 1504.Shibuya, K. J. Chem. Soc. Chem. Commun. 1991, 1545.Procter, G. Chem. Rev. 2004, 3371.
OCHO
OCHO
Me Me SmI2THF-HMPA, rt
Me Me
2:1 Mixture of olefin isomersO
OH76%Single Diastereomer
Me Me
O CHO
OUpial
3 steps
Proposed Mechanism
O
OCHO
Me Me
O
SmI2
OCHO
Me MeSmI2
OCHO
Me Me
SmIII
O
Me Me
SmIII
O
SmI2 Radical Carbonyl-Alkene Cyclizations Model Studies: Upial
Shibuya, K. J. Chem. Soc. Chem. Commun. 1991, 1545.Proctor, G. Chem. Rev. 2004, 3371.
Me Me
O CHO
OUpial
Supporting Evidence
O O
OCHO
O O
OCHO
SmI2THF-HMPA( )n ( )n
O
OH
n Yield123
55%73%76%
Without HMPA product yields were 5-10%
SmI2THF-HMPA
D2OOCHO
D
OCHO
D
+
51% 13%
SmI2 Intramolecular Pinacol Couplings Basic Mechanism, myo-Inositol
-Attractive alternative to TiCl3-Zn/Cu, Mg(Hg)-TiCl4, or Ytterbium pinacol couplings.
-Predominately gives cis-diol trans to α-substitution
OTIPS
OBn
BnO
BnO O
O
OTIPS
OBn
BnO
BnOO3, DMS
MeOH, Py
OH
OH
OTIPS
OBn
BnO
BnO OH
OH
OTIPS
OBn
BnO
BnOSmI2, THF
-78 oC +
>20 : 170% over 2 steps
TIPSO
OOOBn
BnOBnO
SmIII
TIPSO OO
OBnBnO
BnOSmIII
TIPSO
O
OOBn
BnOBnO
SmIII
SmI2
TIPSO
OSmIII
OSmIII
OBnBnO
BnO
H+
Kornienko, A. Tetrahedron Asymmetry 1998, 2783.Chiara, J. L. Terahedron Letters 1994, 1969.Chiara J. L. Tetrahedron Letters 1991, 1125.Guidot J. P. Tetrahedron Letters 1994, 6671.Molander, G. A. J. Am. Chem. Soc. 1989, 8236.dodong, U. K. J. Org. Chem. 1988, 2132.
OH
OH
OH
OH
HO
HO
myo-Inositol
CH2OH
HO H
H OH
HO H
H OH
CH2OHD-Iditol
or L-Iditol
OH
OH
SmI2 Intramolecular Pinacol Couplings Caryose and a Jojoba Bean Disacchride
O
BnO
O
Me
BnOBnO
O
BnO
O
Me
BnOBnO SmIII
SmI2tBuOH-THF
OH
BnO
OH
Me
BnOBnO
HO
OH
Me
HOHO
OH
CHO
Caryose
Adinolfi, M. Tetrahedron 1997, 11767
93:7 mixture of cis-Diols64% Yield
O
OBn
BnO
BnOOBnO
SmIIIO
O
OBn
OBn
BnO
BnO SmI2tBuOH-THF
OH
OH
BnO
OBn
OBn
BnO
Single Diastereomer40% with Oxidation
O
OOH
HO
OH
OH
OH
HO
OHOH
A Jojoba BeanDisaccharide
Kornienko, A. Carbohydrate Research 1998, 144.
SmI2 Intramolecular Pinacol CouplingsSynthetic Studies Toward Taxol
OO
MeMe
Me
MeMe
OMe
OMe
OHOH
OO
MeMe
Me
MeMe
OMe
OMe
OO
SmI2 (10 equiv)
63%
THF, rt
-Performing reaction at -78 oC leads to reduction
-Corresponding Pinacol with TiCl4/Zn produces pdt in 33% yield.
OHO
MeMe
OH
OHOH
Me
H OH
AcOOPh
OO
OH
Ph
O
Taxol
Swindell, C. S. J. Org. Chem. 1996, 1109.Swindell, C. S. Tetrahedron 1996, 2321.Arseniyadis, S. tetrahedron Lett. 1993, 1137.
SmI2 Intramolecular Pinacol CouplingsSynthetic Studies Toward Taxol
OO
MeMe
Me
MeMe
OMe
OMe
OHOH
OO
MeMe
Me
MeMe
OMe
OMe
OO
SmI2 (10 equiv)
63%
THF, rt
Sm
Swindell, C. S. J. Org. Chem. 1996, 1109.Swindell, C. S. Tetrahedron 1996, 2321.Arseniyadis, S. tetrahedron Lett. 1993, 1137.
Sm
Sm-Chelated Models Minimized Energies
0 ∆Ε = +9.8 Kcal
Minimized structures Utilizing Molecular Mechanics in Spartan 04',Ground State conformers and restricting carbonyl-carbonyl distance at 3.0 Å.
SmI2 Intramolecular Reductive Coupling of Carbonyl-HydrazonesBasic Mechanism, An Example
H
NPh2N
O
( )n
OH
NHNPh2
CH3
OH
H
NNPh2
( )n
( )nN
R
O
NPh2
SmIII
( )n
NR
O
NPh2
SmIII
( )n
1) SmI22) H+
H
NPh2N
OSmIII
( )n CH2
OH
H
NNPh2
( )n
1) SmI22) H+SmI2
A
Bn12
A : B>25 : 14.2 : 1
Yield72%ND
SmI2 Intramolecular Reductive Coupling of Carbonyl-HydrazonesBasic Mechanism, An Example
H
NPh2N
O
( )n
OH
NHNPh2
CH3
OH
H
NNPh2
( )n
( )nN
R
O
NPh2
SmIII
( )n
NR
O
NPh2
SmIII
( )n
1) SmI22) H+
H
NPh2N
OSmIII
( )n CH2
OH
H
NNPh2
( )n
1) SmI22) H+SmI2
A
Bn12
A : B>25 : 14.2 : 1
Yield72%ND
H
NPh2N
H
NPh2N
Br
SmI2THF-HMPA
No reaction
CH3
OH
H
NNPh2
NHNPh2
Additional Evidence
>25 : 1Yields from 75-93%
+
Fallis, A. G. J. Org. Chem. 1994, 6514.Inanaga J. Tetrahedron Lett. 1991, 3555.Fallis A. G. J. Am.. Chem.. Soc. 1994, 7447.
SmI2 Intramolecular Reductive Coupling of Carbonyl-OximesSynthesis of Trehazolin
Chiara, J. L Org. Lett. 1999, 1705.Giese, B. J. Org. Chem. 1998, 5877.Chiara, J. L. Synlett 1999, 1551.
Proposed Transition States
O
NH
OH
HO
HO N
OOH
OH
HOOH
OHTrehazolin
7 Steps
O
NOBn
O
O
OAcBnO
Me
Me
O
OOH
BnO OH
NH2
MeMe1) SmI2 (6 equiv)
THF-tBuOH2) H2O3) LiOH, H2O
98%
SmI2 Intramolecular Reductive Coupling of Carbonyl-OximesSynthesis of Trehazolin
O
NOBn
O
O
OAcBnO
Me
Me
O
OOH
BnO OAc
NHOBn
Me
Me
O
OOH
BnO OAc
NHAc
Me
Me
O
OOH
BnO OH
NH2
MeMe
SmI2 (3 equiv)
THF-tBuOH
1) SmI2 (6 equiv)THF-tBuOH2) H2O3) Ac2O, pyr
1) SmI2 (6 equiv)THF-tBuOH2) H2O3) LiOH, H2O
Chiara, J. L Org. Lett. 1999, 1705.Giese, B. J. Org. Chem. 1998, 5877.Chiara, J. L. Synlett 1999, 1551.
86%
99%
98%
SmI2 Intramolecular Reductive Couplingof Carbonyl-Oximes
Synthesis of Diazonamide A
Diazonamide A
25 %Mixture of Stereoisomers
-No reaction in the absence of HMPA Nicolaou, K. C. ACIEE 2001, 4705.Nicolaou, K. C. ACIEE 2003, 1753.
Cr(CO)3Cr(CO)3
SmI2 Intramolecular Reductive Arene-Cr(CO)3-Carbonyl CyclizationsSynthetic Studies Towards Pseudoterosin G and Helioporin E
Me
Me
Me
OMe
OMe
OMe
2.5 equiv SmI2THF-HMPA
Me
Me
Me
OMe
MeOH
51%
Me
Me
Me
OH
Me
O
Me
HOOH
OHMe
Me
Me
Me
Me
Me
O
O
Pseudoterosin GHelioporin E
Schmalz, H.-G. Tetrahedron Lett. 1996, 1947.Schmalz, H.-G. J. Org. Chem. 1995, 2383.Higa, T. Tetrahedron 1993, 811.Fenical, W. J. Org. Chem. 1990, 4916.
Cr(CO)3
Cr(CO)3
Cr(CO)3Cr(CO)3
SmI2 Intramolecular Reductive Arene-Cr(CO)3-Carbonyl Cyclizations Mechanism
Me
Me
Me
OMe
OMe
OMe
SmI2 Me
Me
Me
OMe
OMe
Me
SmIIIO
Me
Me
Me
OMe
OMe
OSmIII
MeH
SmI2
Me
Me
Me
OMe
OMe
OSmIII
MeH
H+
Cr(CO)3
Me
Me
Me
OMe
OMe
OSmIII
MeH
H1) -MeOH2) H2O
Cr(CO)3
Me
Me
Me
OMe
OHMe
Schmalz, H.-G. Tetrahedron Lett. 1996, 1947.Schmalz, H.-G. J. Org. Chem. 1995, 2383.
O
OBz
Carbonyl-Olefin Reductive Coupling/Intramolecular SmI2 Barbier CyclizationPhorbol Skeleton
OBz
O
CO2Me
OO
+O
O
OMeO
SmI2SmI2
t-BuOHTHF, rt
58% CO2MeOO
OHOBz
Single Diastereomer
1) NaOMe, MeOH THF, 85%2) I2, PPh3 Imidazole THF, 90%
OO
IO
O
SmI2NiI2 cat.
THF, rt, 1 h88%O
O
H
H
O
HO
H
Conditions Time YieldNo AdditveWith NiI2
5-7h1h
43-68%82-88%
Little D. Org. Lett. 2000, 2873For increased reaction rates with NiI2 see: Kagan, H. Synlett 1996, 633
Single Diastereomer
H
H
A
H
HO
OH H
Me
HOH
Me
MeH
OH
Me
O
Phorbol
O
OBz
Carbonyl-Olefin Reductive Coupling/Intramolecular SmI2 Barbier CyclizationPhorbol Skeleton
OBz
O
CO2Me
OO
+O
O
OMeO
SmI2SmI2
t-BuOHTHF, rt
58% CO2MeOO
OHOBz
Single Diastereomer
1) NaOMe, MeOH THF, 85%2) I2, PPh3 Imidazole THF, 90%
OO
IO
O
SmI2NiI2 cat.
THF, rt, 1 h88%O
O
H
H
O
HO
H
Conditions Time YieldNo AdditveWith NiI2
5-7h1h
43-68%82-88%
Little D. Org. Lett. 2000, 2873For increased reaction rates with NiI2 see: Kagan, H. Synlett 1996, 633
Single Diastereomer
H
H
A
Model of Intermediate A
OH
Reductive Carbonyl Conjugate and Pinacol CyclizationsGrayanotosin III
Shirahama, H. J. Org. Chem. 1994, 5532
O
HMe
OHOMe
O
O
HMe
OHOMe
OH
SmI2, HMPATHF, -78 oC
MM2 Minimized Structure of A
A86%
Single Diastereomer
H
HO
HOMe OH
H
MeOHHO
MeMe
Grayanotoxin III
Sm
SmIII
O
HMe
OO
OHMe
Me
OXOH
Reductive Carbonyl Conjugate and Pinacol CyclizationsGrayanotosin III
Kan, T. J. Org. Chem. 1994, 5532.Kan, T. J. Org. Chem. 1994, 5113.
H
HO
HOMe OH
H
MeOHHO
MeMe
Grayanotoxin III
MeOX
SPh
Me
Me
OH
OTBDMS
H
OX MeOX
HH
OH
TBDMSO
MeMe
SmI2HMPA/THF
Me
TBDMSO
H
OSmIII
H
R
SPh
78%Single Diasteromer
Plausible Transition States
-Both E and Z-allyl sulfides gave the same product in similar yields
SPh
Me
Me
OH
OR
H
OH
RO
MeMe
X
OH
H
OH
SmI2HMPA/THF
SmI2HMPA/THF
X= SPh SO2Ph
47%78%
R= Bn Ac TBDMS
83%86%91%
Model Studies
OSmIII
H
SPh
H
O
H
SPhTBDMSO
Me
Meor
H
H
OSmIII
H
SPhor
SmIII
x= MOM
OH
Reductive Carbonyl Conjugate and Pinacol CyclizationsGrayanotosin III
Kan, T. J. Org. Chem. 1994, 5532.Kan, T. Synlett, 1991, 391.
H
HO
HOMe OH
H
MeOHHO
MeMe
Grayanotoxin III
SmI2HMPA/THF
54%Single Diasteromer
OX MeOX
HHHO
MeMe
Me OX
O
OOX
H
HO
HOMe OX
H
MeOXHO
MeMe
X= MOM
OX MeOX
HHRO
MeMe
Me OX
O
OX= MOM OX
H
HO
HOMe OX
H
MeOXHO
MeMe
OX MeOX
HHRO
MeMe
Me OX
OH
HO
Model Studies
Conditions
Conditions R %A %B
A B
Titanium-pinacolSmI2, HMPA-THFSmI2, HMPA-THF
decompositionND 50%
NAMOMH
Sole prdND
OH
Reductive Carbonyl Conjugate and Pinacol CyclizationsGrayanotosin III
Kan, T. J. Org. Chem. 1994, 5532.Kan, T. Synlett, 1991, 391.
H
HO
HOMe OH
H
MeOHHO
MeMe
Grayanotoxin III
SmI2HMPA/THF
54%Single Diasteromer
OX MeOX
HHHO
MeMe
Me OMOM
O
OOX
H
HO
HOMe OX
H
MeOXHO
MeMe
X= MOM
Potential Stereochemical Model
OX MeOX
HHO
MeMe
Me OMOM
O
O
SmIII
SmIII
Sm
Sm
Concluding Remarks
Benifits of Samarium Diiodide Cyclizations
-Samarium diiodide shows great functional group tolerance.
-The redox potential of SmI2 can be altered by changes in: solvent, co-solvents, ligands, additives, light, and counter ions. This allows fine tuning of the one electron reduction so that relative rates of functional group reductions can be estimated and controlled. (For the reduction potential of several functional groups see: Fry, A. J. Synthetic Organic Electrochemistry, 2nd ed.; John Wiley and Sons: New York, 1989.)
-Samarium diiodide has been used succesfully in multiple total synthetic endeavors as a mild single electron chelating reducting agent.
-Due to samarium diiodide's large ionic radius, high coordination number, and high oxophilicity samarium diiodide has been used succesfully as a chelating element to bring two reacting centers in proximity to form large ring systems.
-Samarium diiodide has been shown to be a superior alternative to traditional methods for Barbier, Pinacol, Reformatsky, Carbonyl-Alkene, and Carbonyl-Alkyne cyclizations.
Drawbacks of Samarium Diiodide Cyclizations
-The uncertainity in the mechanism of the transformations limits the stereochemical predictive potential of the reagent.
