postdoc-hélène lebel (advisor : prof. eric n. jacobsen)
DESCRIPTION
KINETIC RESOLUTION OF 2,2-DISUBSTITUTED EPOXIDES APPLICATION TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A. Postdoc-Hélène Lebel (Advisor : Prof. Eric N. Jacobsen). January 1998-June 1999. Isolation and Biological Activities. •Isolated from Okinawan marine sponge Hippospongia sp. - PowerPoint PPT PresentationTRANSCRIPT
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KINETIC RESOLUTION OF 2,2-DISUBSTITUTED EPOXIDES KINETIC RESOLUTION OF 2,2-DISUBSTITUTED EPOXIDES APPLICATION TO THE TOTAL SYNTHESIS OF TAUROSPONGIN AAPPLICATION TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A
Postdoc-Hélène Lebel(Advisor : Prof. Eric N. Jacobsen)
January 1998-June 1999
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Isolation and Biological ActivitiesIsolation and Biological Activities
HO3S
HN
O OH O O
O O
Taurospongin A
13
Kobayashi and coworkers, J. Org. Chem. 1997, 62, 3831-3836.
•Isolated from Okinawan marine sponge Hippospongia sp.
•Inhibitory activity against DNA polymerase (IC50 = 7.0 µM) and HIV reverse transcriptase (IC50 = 6.5 µM).
•Weak inhibitory activity against c-erB-2 kinase (IC50 = 28 µg/mL).
•No cytotoxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cells (IC50 > 10 µg/mL).
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Proposed Synthetic ApproachProposed Synthetic Approach
HO3S
HN
O OH O O
O O 13
O OH O OPG
O
PGO
PGOO
3 7 9
3 7 9
3
Kinetic resolution of 2,2-disubstituted epoxides.
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Kinetic Resolution of Epoxides by Asymmetric Ring OpeningKinetic Resolution of Epoxides by Asymmetric Ring Opening
RO
NuX RO
R
OXNu
Cat*
Max y. : 50% Max y. : 50%
RO
+ +
•50% waste of the material: starting material has to be inexpensive.
•Easy separation of epoxide and product.
•Possibility of high ee for the recovered substrate, even with moderately selective systems.
Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5-26.Robinson, D.; Bull, S. D. Tetrahedron: Asymmetry 2003, 14, 1407-1446.
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Kinetic Resolution of Epoxides : Theoretical ConsiderationsKinetic Resolution of Epoxides : Theoretical Considerations
krel = ln[(1-c)(1-ee)]ln[(1-c)(1+ee)]
kf
ks=
Recovered Substrate Product
= ln[(1-c)(1+ee)]ln[(1-c)(1-ee)]
krelkf
ks=
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Kinetic Resolution of Epoxides : Chromium and Cobalt CatalystsKinetic Resolution of Epoxides : Chromium and Cobalt Catalysts
RO
(±)N N
HH
O OM
t-Bu
t-But-Bu
t-Bu
(S,S)-1 : M = Cr(N3)(S,S)-2 : M = Co(OAc)
RO
(±)
(S,S)-1 (0.5-2.0%)
TMSN3 (0.5 equiv) R
OTMSN3
40-49% y.89-98%ee
krel = 44-280
H2O (0.5 equiv)
Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 7420-7421.
(S,S)-2 (0.5-2.0%)R
OR
OH+ OH krel = 50 - >400
44-46% y.98-99%ee
38-50% y.86-98%ee
Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936-938.
Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315.
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Crystal Structure of (S,S)-(Salen)CrNCrystal Structure of (S,S)-(Salen)CrN33 complex complex
Karl B. Hansen
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Kinetic Resolution of 2,2-Disubstituted EpoxidesKinetic Resolution of 2,2-Disubstituted Epoxides
•Discrimination between a methyl and an alkyl group.
•Increase the global steric hindrance : deleterious for catalytic activity.
H
OMe
Me
OH
Me
OR
R
OMe
krel = >400
X X
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Solvent Conversion
0.5 equiv
0.5 equiv
0.5 equiv
2.0 equiv
TBME---
---
0%
0%
0%
0%
OR ee (epoxide)
OBn
OBn
2.0 equiv
2.0 equiv
TBME
TBME
0%
0%
---
------
---
---
---
2.0 equiv TBME 0% ---
2.0 equiv TBME 0% ---
OBn 0.5 equiv CoOAc (1.0 equiv) TBME 50% (40 h)(OAc)
0%
Entry
1
2
3
4
5
6
7
8
9
H2O
THF
M
OTBS
OTBS
OTBS
OTBS
CoOAc
CoOAc
CoOAc
CoOAc
CoOAc
CoOC(CF3)
OTBS CoOC(CF3)
OH CoOC(CF3)
Hydrolytic Kinetic Resolution of 2,2-Disubstituted EpoxidesHydrolytic Kinetic Resolution of 2,2-Disubstituted Epoxides
ROO
H2O (x equiv) / solvent RO
ROH
OH+
(R,R)-(Salen)M (2 mol%)X
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Kinetic Resolution of 2,2-Disubstituted EpoxidesKinetic Resolution of 2,2-Disubstituted EpoxidesR
OR'OH (x equiv) R
O
ROR
OH+
(R,R)-(Salen)M (2 mol%) X
PhOH (2.0 equiv)
PhOH (2.0 equiv)0%
0%
---
---PhOH (2.0 equiv)
PhOH (2.0 equiv)
0%
0%
---
---
n-Pr
R'OH (x equiv) Conv. ee (epoxide)
OBn
OBn
OBn
AcOH (0.5 equiv)
AcOH (0.5 equiv) +EtN(i-Pr)2 (0.5 equiv)
0% ---
AcOH (0.5 equiv)
(R,R)-CoOAc (0.01 equiv)+ (R,R)-CrN3 (0.01 equiv)(S,S)-CoOAc (0.01 equiv)+ (R,R)-CrN3 (0.01 equiv)
0% ---
(R,R)-CoOAc (0.01 equiv)+ (R,R)-CrN3 (0.01 equiv)OBn
OBn
AcOH (0.5 equiv)
AcOH (0.5 equiv)
AcOH (0.5 equiv)
15% (40 h)
0%
---
20% (40 h)
0% ---
Entry
1
23
4
5
6
7
8
9
10
0% ---
OTBS
OTBS
CoOAc
CoOC(CF3)
OH
OH
CoOAc
CoOC(CF3)
R M
CoOAc
CrN3
CoOAc
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TBSOO
TMSN3 (0.5 equiv) / TBME
TBSOO
TBSON3
OH
+(S,S)-(Salen)CrN3 (2 mol%) TBSO
OTMSN33 days
1 : 135-40% conv.
Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl Azidewith Trimethylsilyl Azide
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Proposed Catalytic Cycle for the (Salen)Cr(III) Catalyzed Proposed Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSNAsymmetric Ring Opening of Epoxides with TMSN33
N3
Cr
O
Cr
RO
RN3
RN3
OH
RN3
OTMS
Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924-10925.
TMSN3
HN3
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Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of 2,2-DisubstitutedRing Opening of 2,2-Disubstituted Epoxides with TMSNEpoxides with TMSN33
N3
Cr
O
Cr
RO
RN3
RN3
OH
R'
R'
R'
RN3
OTMSR'
TMSN3
HN3
X
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Kinetic Resolution of 2,2-Disubstituted Epoxides with Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl AzideTrimethylsilyl Azide
TBSOO
TMSN3 (0.5 equiv), ROH / TBME TBSOO
TBSON3
OH+
(S,S)-(Salen)CrN3 (2 mol%)
12 hours
Conversion
i-PrOH (1.0 equiv) 35%
45%
0%
i-PrOH (0.5 equiv)
MeOH (1.0 equiv)
ROH
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Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSNRing Opening of Epoxides with TMSN33 and 2-Propanol and 2-Propanol
N3
Cr
O
Cr
RO
RN3
RN3
OH
R'
R'
R'
RN3
OTMSR'
TMSN3 + i-PrOH
TMSN3
HN3
X
i-PrOTMS
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Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with HNwith HN3 3 Catalyzed by a (Salen)Cr(III) ComplexCatalyzed by a (Salen)Cr(III) Complex
RO
TMSN3, i-PrOH / TBME RO(R,R)-(Salen)CrN3 (2 mol%)
Entry Epoxide Reagents (equiv) Yield ee
1
2
3
4
OTBSO
OBnO
OPh
O
O5
0.55
0.55
0.60
0.55
0.50
42%
44%
44%
42%
46%
99%
95%
97%
99%
98%
Lebel, H.; Jacobsen, E. N. Tetrahedron Lett. 1999, 40, 7303-7306.
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Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with HNwith HN3 3 Catalyzed by a (Salen)Cr(III) ComplexCatalyzed by a (Salen)Cr(III) Complex
R1
R2O
TMSN3, i-PrOH / TBME R1
R2O
(Salen)CrN3 (2 mol%)+
R1
R2HON3 +
R1
R2N3
OH
external internal
Entry Epoxide Conv. ee (epoxide)
1
2
3
50%
35%
≤5%
36%
25%
---
Regio (ext:int)
PhO
O
O
1.5 : 1
1 : 3
---
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Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with HNwith HN3 3 Catalyzed by a (Salen)Cr(III) ComplexCatalyzed by a (Salen)Cr(III) Complex
RO
TMSN3, i-PrOH / TBME RO(R,R)-(Salen)CrN3 (2 mol%)
Entry Epoxide Reagents (eq) Yield ee
1
2
3
4
EtO2CO
t-BuO2CO
PhO
O
0.65
0.55
0.50
0.50
37%
46%
45% conv.(1 : 6, ext:int)
50% conv.(<1 : 10, ext:int)
74%
85%
41%
10%
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Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with HNwith HN3 3 Catalyzed by a (Salen)Cr(III) ComplexCatalyzed by a (Salen)Cr(III) Complex
TMSN3, i-PrOH / TBME
(R,R)-(Salen)CrN3 (2 mol%)R
TMS
O
RTMS
O
Entry Reagents (equiv) Yield ee (epoxide)
1
2
3
0.50
0.50
0.70a
50% conv.(1 : 2, ext:int)
48%
50% conv.(2 : 1, ext:int)
16%
45%
80%
No Reaction is observed with epoxides substituted by terminal alkyne.
Me
a 5 mol% of (R,R)-(Salen)CrN3 was used.
R
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Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols
O
TMSN3 (0.5 equiv), i-PrOH (0.5 equiv)
(R,R)-(Salen)CrN3 (2 mol%) / TBME
BnOO
BnO49% y. 88% ee
HO
BnON3
N3
BnOOH
+
46% y. 93% ee 4% y. 20% ee
Two reaction pathways:
-Highly selective terminal attack-Poorly selective internal attack
Variation of the ratio of regioisomers with conversion
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Proposed Cooperative MechanismProposed Cooperative Mechanism
•No reaction background in absence of catalyst.•Catalyst concentration did not affect the regioselectivity.•No erosion of the enantiomeric excess
Rate = kobs[catalyst]2[epoxide]-1[HN3]0
N3
Cr
O
N3
Cr+ N3
O CrCr
N3
Selective Pathway: bimetallic
Unselective Pathway: monometallic (????)
O
N3
Cr+ N3
O Cr N3
TerminalAttack
InternalAttack
Me
R
R Me
R Me
MeR
In the case of the desymmetrisation of meso epoxides:
HN3
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Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols
OR
HOR N3
N3
R OH
OR
OHR N3
N3
R OH
kterm
kterm
kint
kint
kterm S >>>> kint S > kterm R ~ kint R
R
S
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Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols
TMSN3, i-PrOH / TBME
(R,R)-(Salen)CrN3 (2 mol%)
RO
R
HON3
Entry Azido Alcohol Reagents (equiv) Yield ee
1
2
3
4
5
0.50
0.50
0.50
0.50
0.50
46%
47%
45%
44%
40%
93%
90%
92%
95%
99%
HO
BnON3
HO
TBSON3
HO
PhN3
HON3
HON3
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Kinetic Resolution of 2,2-Disubstituted Epoxides Kinetic Resolution of 2,2-Disubstituted Epoxides with Chromium Catalyst and TMSNwith Chromium Catalyst and TMSN33
TBSOO
TMSN3 (0.65 equiv)i-PrOH (0.65 equiv) / TBME TBSO
O(S,S)-(Salen)CrN3 (2 mol%)0 °C, 12 hours
37% yield (5.5 g)97% ee, krel = 14
(15 g, 69 mmol)
TBSOO
Absolute Stereochemistry
1. TBAF / THF2. NaH, BnBr / THF, DMF
BnOO
[α]D = +7.89 (c 3.40, CHCl3)
Lit: [α]D = +9.60 (c 2.95, CHCl3)
G ill, M.; Sm rdel, A. F. Tetrαhedron: Asym m etry 1990, 1, 453-464.
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Retrosynthetic AnalysisRetrosynthetic Analysis
HO3S
HN
O OH O O
O O 13
O OH O OPG
O
PGO
3 7 9
3 7 9
OPG
PGO 3
O OPG
7 9
OPG
PGO 3
O OH
9ROPGOO
3
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Synthesis of PrecursorsSynthesis of Precursors
TBSOO
H , BuLi (1.5 equiv)BF3•OEt2 (1.5 equiv) / THF
-78 °C to rt 81% y.
TBSO
OH
TBSO
OTES
TESOTf2,6-lutidine
CH2Cl2
97% y.
MeO
OO
1. (R)-BINAP-Ru(II)H2 (100 atm) / MeOH
2. TBSCl, Imidazole
MeO
OTBSO84% y. (2 steps)99% ee
Noyori and coworkers JACS 1988, 110, 629-631; Tet. Lett. 1991, 32, 4163-4166.
CH2Cl2
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Synthesis of Ketone by Alkylation of anSynthesis of Ketone by Alkylation of an in-situ Generated Weinreb Amidein-situ Generated Weinreb Amide
R OMe
ClMgO N(OMe)Me
R N(OMe)Me
O
R Ph
O
-MeOMgClOMeClMg
O N
PhR
Me
Me(MeO)NMgCl
RCO2Me
PhMgCl
NH
OOMeMe
H
HHO
H
Me 1. Me(MeO)NH•HCl (1.25 equiv) / THF
2. PhMgCl (8 equiv) / THF, -5 °C
NH
OPhMe
H
HHO
H
Me
Williams and coworkers Tet. Lett. 1995, 36, 5461-5464.
87% yield
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Synthesis of Propargylic KetoneSynthesis of Propargylic Ketone
TBSO
OTES
MeO
OTBSO
N
OTBSO
Me
MeOTBSO
OTES Li
t-BuLi / THF-78 °C
Me(MeO)NH2Cl, i-PrMgClTHF, int. temp. < -10 °C
TBSO
OTES
O OTBS72% y.
-10 °C to 60 °C
TBSO
OTES24%
1.0 equiv 1.0 equiv
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Diastereoselective Reduction of Diastereoselective Reduction of -Alkoxy Ketone-Alkoxy Ketone
O OPG
R
OH OPG
R
OOPG
M
H
"H" from the bottom face
Via:
Key issues:
•Need to differentiate both alcohols.
•Few examples with only modest stereoselectivities for 1,3-induction with chelating protecting group.
Alternative solution:
•Use chiral catalyst capable of overriding any inherent substrate bias.
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Asymmetric Transfer Hydrogenation of Asymmetric Transfer Hydrogenation of α,α,-Acetylenic Ketones-Acetylenic Ketones
R1R2
O
R1R2
OH
NH
RuNPh
Ph
Ts
0.5 mol%
Noyori and coworkers J. Am. Chem. Soc. 1997, 119, 8738-8739.
85-99% y.95-99% ee
NH
RuNPh
Ph
Ts
NH2
NHPh
Ph
Ts
+ [RuCl2(h6-p-cym ene)]2
i-PrOH
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Asymmetric Transfer Hydrogenation of Asymmetric Transfer Hydrogenation of α,α,-Acetylenic Ketones-Acetylenic Ketones
OTES
O OTBS
TBSO
OTES
OH OTBS
TBSO
OTES
O OTBS
TBSO
OTES
OH OTBS
NH
RuNPh
Ph
Ts
2 mol%
87% yield≥20:1 dr
Both diastereoisomers areseparable by flash chromatography.
NH
RuNPh
Ph
Ts
94% yield≥20:1 dr
TBSOi-PrOH
i-PrOH
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Synthesis of the Saturated DiolSynthesis of the Saturated Diol
TBSO
OTES OAc OTBS
TBSO
OTES
OH OTBS
1. Pd(OH)2, Et3N / EtOAc, H2
2. Ac2O, DMAP / Pyridine
HO
OH OAc OTBS
TBAF, HOAcTHF
92% y. (2 steps)
86% y.
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Taurine Coupling : First AttemptTaurine Coupling : First Attempt
HO
OH OAc OTBS
HO
OH OAc OTBSO
HN
OH OAc OHOHO3S
HN
OH OH OAcOHO3S
+
1. EtO2CCl, Et3N / THF
2.
Et3N / H2O, MeCN
Tempo, Aliquat 336, KBr, NaOCl H2O, CH2Cl2
78% y.
HO3SNH2
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Synthesis of Unsaturated Fatty Acid ChainSynthesis of Unsaturated Fatty Acid Chain
MeO2CHO2C
Br OTBS+
1. n-BuLi / THF, HMPA, -45 °C
2. p-TsOH (cat) / MeOH, reflux
OH
78% yield
MeO2C
CHO
PDC / CH2Cl2Celite, MS 4A
74% yield
1. (PhO)3P, I2
2. Ph3P / CH3CN, reflux
87% yield (2 steps)
IPh3P (CH2)15CH3HO (CH2)15CH3
O 13
HO
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Synthesis of Unsaturated Fatty Acid ChainSynthesis of Unsaturated Fatty Acid Chain
MeO2CH
O
IPh3P (CH2)15CH3 +
(2.0 equiv)NaHMDS (1.8 equiv) / THF
-20 °C to rt
O 13
MeO
72% yield (1 isomer, NMR)
O 13
HO
LiOH 1N / MeOH, THF83% yield
34% overall yield, 5 steps
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Esterification with the Unsaturated Fatty Acid ChainEsterification with the Unsaturated Fatty Acid Chain
HO
OH OAc OTBS
1. Tempo, Aliquat 336, KBr, NaOClH2O, CH2Cl2
2. Allyl bromide, i-Pr2NEt / CH2Cl2
81% yield (2 steps)
O
OH OAc OTBSO
1. HF•Pyr / Pyr, THF
2. DIC, i-Pr2NEt, DMAP HO
O 13
O
O OH O O
O O 13
75% yield (2 steps)
CH2Cl2
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Completion of the SynthesisCompletion of the Synthesis
O
O OH O O
O O
Taurospongin A
13
HO3S
HN
O OH O O
O O 13
1. Pd(PPh3)4, pyrrolidine / CH2Cl22. EtO2CCl, Et3N / THF
3.
Et3N / MeCN, H2O (1:1)
68% yield (3 steps)
HO3SNH2
MeO3S
HN
O OH O O
O O 13
CH2N2
[α]D = -3.0° (c 0.53, CHCl3)Lit: [α]D = -1.4° (c 0.78, CHCl3)
Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
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STEREOSELECTIVE CYCLOPROPANATION OF ALLYLIC ALCOHOLS: STEREOSELECTIVE CYCLOPROPANATION OF ALLYLIC ALCOHOLS: APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U-106305APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U-106305
Ph.D. Thesis-Hélène Lebel(Advisor : Prof. André B. Charette)
May 1993-December 1997
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OTi
O
OO
i-PrO Oi-Pr
PhPh Ph
Ph 1995
(ChristianBrochu)
Stereoselective Cyclopropanations: An OverviewStereoselective Cyclopropanations: An OverviewRelative Stereocontrol
Absolute Stereocontrol
"CH2"R2 R4
R1
R3 R3
R1
R4R2
OH OH
•Cyclic Substrates : Weinstein, Dauben, Denmark - Sylvie Prescott
•Acyclic Substrates : Pereyre, Molander - Hélène Lebel
"CH2"R2 OH
R1
R3 R3
R1
OHR2
•Chiral Auxiliary •Chiral Stoichiometric Ligand •Chiral Catalyst
1991(B. Côté, J.F. Marcoux, N. Turcotte)
OBnO
BnOBnO
OHO
R1
R2
R3
OB
O
Bu
CONMe2Me2NOC
1994
(Hélène Juteau)
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Stereoselective Cyclopropanations Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcoholsof Acyclic Chiral Allylic Alcohols
Anti Syn
"CH2" "CH2"R4R2
R1
R3
OH
R4R2
R1
R3
OH
R4R2
R1
R3
OH
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Stereoselective Cyclopropanations of Acyclic Chiral Allylic Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols : Literature Precedent (1994)Alcohols : Literature Precedent (1994)
OH OH
M. Pereyre J. Chem. Research. Synop. 1978, 179.
Zn-Cu, CH2I2Et2O, Reflux
RatioSyn/Anti
E = 57 : 43
Z = >99 : 1
"CH2" = IZnCH2I / Et2O
Ph R
OH
Ph R
OH
G. Molander J. Org. Chem. 1989, 54, 3525-3532. M. Lautens J. Org. Chem. 1992, 57, 798-800.
Sm(Hg), CH2I2THF, -78 °C to rt
"CH2" ISmCH2I / THF
R = Bu, 1 : 1.4R = Me, 1 : 6
=
R = i-Pr, 200 : 1
Me
N
N
MeO
OMeOH
Me
N
N
MeO
OMeOH
Schöllkopf et al. Liebigs Ann. Chem. 1991, 857 and Tetrahedron 1988, 44, 5293.
Et2Zn (2.5 equiv), CH2I2 (2.5 equiv)
Hexanes>98% de
"CH2" EtZnCH2I / Hexanes=
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Zinc ReagentsZinc Reagents
Intramolecular Hydrogen Bonding : Separation of both diastereomers by TLC
H. Mollendal Acta Chem. Scand. 1992, 46, 861. L. Joris J. Am. Chem. Soc. 1968, 90, 327.
Me Me
O
-polar (H-Bond)
H
Me Me
OH
+polar (no H-Bond)
Ph Me
OH
Ph Me
OHEt2Zn, CH2I2
CH2Cl2, 0 °C to rt
RatioSyn / AntiConversion
75% 6.6 : 1
3.2 : 1>98%
2.3 : 1
85%
Zinc reagent
2 1
5 5
10 5
2 4
5 10
EtZnCH2I + Et2Zn
95%
>98% 7.0 : 1
6.6 : 1
Et2Zn CH2I2
EtZnCH2I
EtZnCH2I
Zn(CH2I)2
Zn(CH2I)2
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Determination of the Relative StereochemistryDetermination of the Relative Stereochemistry
Ph O
OMeH
NO2Ph
Op-NO2Bz
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R1 R2
OH
R1 R2
OHEtZnCH2I (5 equiv)
CH2Cl2, -10 °C to rt
Stereoselective Cyclopropanations with Zinc Reagents :Stereoselective Cyclopropanations with Zinc Reagents :E-Disubstituted Chiral Allylic AlcoholsE-Disubstituted Chiral Allylic Alcohols
Allylic alcoholRatio
Syn / AntiYield
86% 7 : 1
87%
130 : 1
110 : 1
75% 6 : 1
97%
Ph Me
OH
Me Me
OH
Ph Et
OH
n-Pr Et
OH
Allylic alcoholRatio
Syn / AntiYield
98% 150 : 1
>200 : 1
97% >200 : 1
84%
Ph Bu
OH
Ph i-Pr
OH
Ph t-Bu
OH
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R1 R4
OH
R1 R4
OHEtZnCH2I (5 equiv)
CH2Cl2, -10 °C to rt
R2
R3
R2
R3
Stereoselective Cyclopropanations with Zinc Reagents :Stereoselective Cyclopropanations with Zinc Reagents :E-Disubstituted and Z-Trisubstituted Chiral Allylic AlcoholsE-Disubstituted and Z-Trisubstituted Chiral Allylic Alcohols
Charette, A. B., Lebel, H. J. Org. Chem. 1995, 60, 2966-67
OH
Me
Ph
Ph Et
OH
Me
Ph Me
OH
Me
96%
>200 : 1
>200 : 1
98%
Allylic alcohol
95%
YieldRatio
Syn / Anti
33 : 1
95% >200 : 1
Allylic alcohol YieldRatio
Syn / Anti
OH
Et
Ph
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Stereoselective Cyclopropanations of Chiral Allylic AlcoholsStereoselective Cyclopropanations of Chiral Allylic Alcohols
Zn(CH2I)2 IZnCH2I ZnI2
Zn(CH2I)2
EtZnCH2I
Et2Zn
Zn(CH2I)2 Et2Zn
IZnCH2I
EtZnI
2 EtZnCH2I
IZnCH2I ZnI2
IZnCH2I2
LewisAcid
Sterichindrance EtZnCH2I EtZnI
Diastereoselectivity = 1 : 1
Diastereoselectivity = 3 : 1
Diastereoselectivity = 7 : 1
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Stereoselective Cyclopropanations of Chiral Allylic AlcoholsStereoselective Cyclopropanations of Chiral Allylic Alcohols
Et2ZnCH2I2
EtH
Ph
H
OZnEtCH3
ZnICH2Et
Ph
H
OZnEtCH3
Ph
H
OHCH3
H H H
Et2Zn
+
EtZnCH2I
Ph
H H
OZnEtCH3
ZnIEt
Syn
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Stereoselective Cyclopropanations of Chiral Allylic AlcoholsStereoselective Cyclopropanations of Chiral Allylic Alcohols
Et2ZnCH2I2
Ph
CH3
HOZnEt
Ph
CH3
HOH
H H
Et2Zn
+
EtZnCH2IPh
H
OZnEtH
CH3
ZnEt
ICH2
EtH
Ph
H
OZnEtH
CH3
ZnEt
I
Anti
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R1 R4
OBn
R1 R4
OBnEtZnCH2I (5 equiv)
CH2Cl2, -10 °C to rt
R2
R3
R2
R3
+ R1 R4
OBnR2
R3Syn Anti
Stereoselective Cyclopropanations of Chiral Allylic EthersStereoselective Cyclopropanations of Chiral Allylic Ethers
Allylic etherRatio
Syn / AntiYield
94% 1 : 9 88%
1 : 2
1 : 2
98% 1 : 7
97%
Ph Me
OBn
Ph Me
OBn
Ph Et
OBn
n-Pr Et
OBn
Allylic etherRatio
Syn / AntiYield
15 : 1
82% 19 : 1
85%
Ph i-Pr
OBn
Me
OBnPh
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Stereoselective Cyclopropanations of Chiral Allylic EthersStereoselective Cyclopropanations of Chiral Allylic Ethers
R1 R4
OMe
R1 R4
OMeEtZnCH2I (5 equiv)
CH2Cl2, -10 °C to rt
R2
R3
R2
R3
+ R1 R4
OMeR2
R3Syn Anti
Allylic etherRatio
Syn / AntiYield
95% 1 : 2
3 : 193%
Ph Me
OMe
Ph Et
OMe
17 : 1
94% >20 : 1
80%
Ph i-Pr
OMe
Me
OMePh
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Stereoselective Cyclopropanations of Chiral Allylic EthersStereoselective Cyclopropanations of Chiral Allylic Ethers
Ph
OBn
CH3
HH
EtZnCH2I
Ph HCH3
OBnZn
Et
ICH2
Ph
OBn
CH3
HH
Anti
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Stereoselective Cyclopropanations Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcoholsof Acyclic Chiral Allylic Alcohols
Anti Syn
"CH2" "CH2"R4R2
R1
R3
OH
R4R2
R1
R3
OH
R4R2
R1
R3
OH
Chiral Ligand ????
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R2
R1
R3OH R2
R1
R3OH
OB
O
Me2NOC CONMe2
Bu
2 equiv Zn(CH2I)2 or Zn(CH2I)2•DME
1.1 equiv
Enantioselective Cyclopropanations of Allylic Alcohols : Enantioselective Cyclopropanations of Allylic Alcohols : Chiral DioxaborolaneChiral Dioxaborolane
Ph OHOH
Bu3Sn OHBu3Sn OH
95% yield94% ee
BnO
93% yield91% ee
I OHI OH
88% yield90% ee
73% yield90% ee
83% yield90% ee71% yield
83% ee
OH
85% yield94% ee
OH
OTIPS85% yield88% ee
Ph OH
96% yield85% ee
Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, 2651. Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60, 1081. Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943.
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Me
OH
Ph Me
OH
Ph Me
OH
Ph
+
Me
OH
Ph
+
MePh Me
OH
Ph+
320 : 48
520 : 1
anti-(S)
anti-(R)
syn-(S)
syn-(R)
OB
O
Me2NOC CONMe2
Bu
OH
(S)
(R)
Zn(CH2I)2
Enantioselective Cyclopropanations of Chiral Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral DioxaborolaneAllylic Alcohols : Chiral Dioxaborolane
No possibility for kinetic resolution : both enantiomers react at the same rate
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R1 R3
OH
R1 R3
OH
CH2Cl2, -10 °C
Zn(CH2I)2, 2.2 equiv., Ligand, 1.2 equiv.
R2 R2
Enantioselective Cyclopropanations of Chiral Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral DioxaborolaneAllylic Alcohols : Chiral Dioxaborolane
Allylic alcohols Ratio Syn / AntiYield
98%74% (80%)
<1 : 200 1 : 12
Ph Me
OH
Ph Me
OH
Ph Et
OH
n-Pr Et
OH
Chiral Ligand
R,RS,S
R,RS,S
R,RS,S
R,RS,S
Me
92%57% (60%)
<1 : 200 1 : 20
83%54% (59%)
1 : 281 : 12
84%54% (59%)
1 : 321 : 12
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Enantioselective Cyclopropanations of Chiral Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral DioxaborolaneAllylic Alcohols : Chiral Dioxaborolane
R1 R3
OH
R1 R3
OH
CH2Cl2, -10 °C
Zn(CH2I)2, 2.2 equiv., Ligand, 1.2 equiv.R2 R2
Allylic Alcohol Ratio Syn / AntiYield
Ph i-Pr
OH
Et
OH
Chiral Ligand
R,RS,S
R,RS,S
40% (63%)16% (37%)
1 : 1.81.6 : 1
30%20%
>20 : 1>20 : 1
Ph
Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845-8856.
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Enantioselective Cyclopropanations of Chiral Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral DioxaborolaneAllylic Alcohols : Chiral Dioxaborolane
OB
O
CONMe2Me2NOC
Bu O PhZn
CH2I
HO Ph
Me AntiH
HO Ph
H SynMe
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U-106305(or any of other 63 isomers)
NH
O
Novel cholesteryl ester transfer protein inhibitor
Kuo and coworkers, J. Am. Chem. Soc. 1995, 117, 10629-10634. (Upjohn)Isolation:
Biological Activity:
Structure and Biological Activity of U-106305Structure and Biological Activity of U-106305
High Density Lipoproteines(HDL)
Cholesterol
Cholesteryl ester transfer protein
Very Low and Low Density Lipoproteines
(VLDL and LDL)Cholesterol
•Decrease the concentration of cholesterol in HDL: increase of coronary risk.•Animals deficient in plasma cholesteryl ester transfer activity are resistant to atherosclerosis.•Human with a genetic deficiency of CETP have an apparent resistance to atherosclerosis.
P. Barter and K.-A. Rye Clinical and Experimental Pharmacology and Physiology 1994, 21, 663-672.
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MeHN
O
RO Me
ROOH
Retrosynthetic Analysis of U-106305Retrosynthetic Analysis of U-106305
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Retrosynthetic Analysis of U-106305Retrosynthetic Analysis of U-106305
HOOH
HOOH
HOOH
HOOH
HOOH
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Synthesis of theTricyclopropyldimethanolSynthesis of theTricyclopropyldimethanol
HOOBn
OB
O
Bu
Me2NOC CONMe2
HOOBn
HOOHZn(CH2I)2•DME (2.0)
CH2Cl2, 0-25 °C
OHHO
H2, Pd/C
1. PDC, CH2Cl2
2. (MeO)2P(O)CHCOOEt
(1.1)
quant. (ca. 91% ee)quant.
3. DIBAL-H, CH2Cl2, 99%
THF, 49% (EE/EZ: 7/1)
EtOH
OB
O
Bu
Me2NOC CONMe2
CH2Cl2, 0-25 °C
(2.2)
90%, ≥ 10 : 1
OHHO
Zn(CH2I)2•DME, (4.4)
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Synthesis of the PentaclopropyldimethanolSynthesis of the Pentaclopropyldimethanol
OHHO
HOH2CCH2OH
HOH2CCH2OH
11 étapes (14% rend. global)≥ 10 : 1
1. PDC, CH2Cl22. (MeO)2P(O)CHCOOEt
3. DIBAL-H, CH2Cl2, 99%THF, 41% (EE/EZ: 5/1)
OB
O
Bu
Me2NOC CONMe2
CH2Cl2, 0-25 °C
(2.2)
90%, ≥ 10 : 1
Zn(CH2I)2•DME, (4.4)
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Asymmetric Double CyclopropanationsAsymmetric Double Cyclopropanations
95%
85.74%
9%
0.24%
77.4
8.14
0.21
8.14
0.42
0.42
0.02
0.21
0.02
0.0006
0.00003
0.0012
0.01
0.0012
0.02
0.02
0.42
0.01
0.42
4.07
0.48 5
4.51
0.01
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RO Me
ROH
O
MeX
X = S, P, Si
RO CH2OH
Olefination
RO Me
Chemoselective Cyclopropanation+ Deoxygenation
Approach to 1,2-DicyclopropylalkenesApproach to 1,2-Dicyclopropylalkenes
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Approach to Approach to 1,2-Dicyclopropylalkenes1,2-Dicyclopropylalkenes
TIPSOH
O
HOOH
1. TIPSCl, NaH2. PDC, CH2Cl2
50%
TIPSO CH2OH
TIPSO CH2OH
1. NaHMDS / THF -78 °C(ETO)2(O)P CO2Et
2. DIBAL-H / CH2Cl248%
Zn(CH2I)2•DME (3.0 equiv)CH2Cl2, -10 °C
OB
O
Me2NOC
Bu
CONMe2
(1.2 equiv)
81%, >20 : 1 de; 9 : 1 (mono : bis)
R
Deoxygenation
X
NSPh
O
O
1. Bu3P, C6H6
2. Raney Ni, EtOH, -40 °C
,
Barrett Deoxygenation
~40%
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Approach to 1,2-DicyclopropylalkenesApproach to 1,2-Dicyclopropylalkenes
RO
RO
MeX+
OlefinationX = S, P, Si
H
O
•Ratio E : Z
•Possible decomposition or racemization of the cyclopropylmethyl carbanion
MeX MeXXMe
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Approach to 1,2-DicyclopropylalkenesApproach to 1,2-Dicyclopropylalkenes
RO
RO
Me OH
H
O
2.S
NSNa
Me SO2BT
Me+ S
M
S
N
S. Julia Olefination
O O
1. MsCl, Et3N
3. MCPBA, 0-25 °C
Base
S. Julia T.L. 1991,1175; BSCF 1993, 336 et 856. P. Kocienski Synthesis 1996, 285 et 652.
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Approach to 1,2-DicyclopropylalkenesApproach to 1,2-Dicyclopropylalkenes
1 : 1
TIPSOH
O
SO O
TIPSO
TIPSOS
N++
NaHMDS / THF
-60 ou -78 °C
25 °C
Solvant (M) Ratio (E : Z)
DMF (0.005 M) 3.8 : 1
Temp.
-60 °C
DMF (0.05 M) 3.5 : 1-60 °C
DME (0.05 M) -60 °C 2.4 : 1
Diglyme (0.05 M) -65 °C 1.8 : 1
THF (0.05 M) -78 °C 1.1 : 1
TMEDA (0.05 M) -40 °C 1 : 2.5
Dioxane (0.05 M) 1 : 4.0
Et2O (0.05 M)
CH2Cl2 (0.05 M)
Toluène (0.05 M)
-78 °C
-78 °C
-78 °C
1 : 7.7
1 : 9.8
1 : 10
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O M
OSR2
H
H
R1
O
NS
R1 H
O
R2 S
M
O OS
N
Non-Coordinating Solvent:Closed Transition State
OMSO2BTR2
H
H
R1H
SO2MR2
H
R1
BTO
R1
H H
R2
Coordinating Solvent:Opened Transition State
S
NM
O SO
LL
R2 H
R1H
O
HR2 H
SO2BT
OM
R1H
R2 H
SO2M
OBT
R1
R2
HR1
H
Solvent Effect in the S. Julia OlefinationSolvent Effect in the S. Julia Olefination
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TIPSO
HO
Me
H
O S
1. NaHMDS, THF DMF (0.005 M), -60 °C2. Bu4NF / THF
4.4 : 1
(E:Z)
S
N
O O
+
92%
1. PDC, CH2Cl2, 87%
HN
O
HN
OP(O)(OEt)2
(+)-U-106305
NaH, DME 80%
Synthetic: [α]D = +297°Nαturαl: [α]D = -270°
2.
Completion of the Synthesis of (+)-U-106305Completion of the Synthesis of (+)-U-106305
Charette, A. B.; Lebel, H.J. Am. Chem. Soc. 1996, 118, 10327-10328.
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Ph OH
OHBnO
84%>20 : 1 chemo21 : 1 enantio
OHTIPSO
85%8 : 1 chemo
>20 : 1 enantio
78% rdt8 : 1 chemo
>20 : 1 enantio
OH OHLigand, 1.2 equiv / CH2Cl2Zn(CH2I)2•DME (2-3 equiv)
R R
Chemoselective Cyclopropanation of DienolChemoselective Cyclopropanation of Dienol
Charette, A. B.; Juteau, H.; Lebel, H.; Deschenes, D. Tetrahedron Lett. 1996, 37, 7925-7928.
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Double Cyclopropanation of Dienes : Double Cyclopropanation of Dienes : Stereochemical Outcome ?Stereochemical Outcome ?
OHR
OH
Chiral Ligand / CH2Cl2
R
OHR
Stereochemistry???
Zn(CH2I)2
Zn(CH2I)2
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Double Cyclopropanation of DienesDouble Cyclopropanation of Dienes
OHCH2Cl2, -10 °C
OHBnO BnO
EtZnCH2I (5 éq)
ICH2ZnCH2I (5 éq)
>95%7 : 1
RZnCH2I
OH OHBnO BnOx xLigand, 1.2 éq
CH2Cl2, -10°C
Zn(CH2I)2•DME
OHBnO
Zn(CH2I)2•DME (8 éq)90%, 7 : 1
OHBnO
Zn(CH2I)2•DME (6 éq)93%, 7 : 1
3
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HOOH
HOOH
HOOH
TIPSOOH
TIPSO CO2Et
EtO2CCO2Et
1. PDC, CH2Cl22. (EtO)2P(O)CH2CH=CHCO2Et
T1/2 (C6D6) = 1 h
1. TBAF, THF2. PDC, CH2Cl23. (EtO)2P(O)CH2CH=CHCOOEt NaHMDS / THF, -78 °C
DIBALH / CH2Cl2-78 °C
55%
46%
53%
NaHMDS / THF, -78 °C
HOH2CCH2OH
AsymmetricAsymmetricTetracyclopropanationTetracyclopropanation
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EtO2CCO2Et 25 °C
180 °C
T1/2 (C6D6) = 1 heureEtO2C CO2Et
H H
25 °C 160 °C
Cope Divinylcyclopropane RearrangementCope Divinylcyclopropane Rearrangement
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Asymmetric TetracyclopropanationAsymmetric Tetracyclopropanation
HOH2CCH2OH
HOOH
HOOH
CH2Cl2, -10 °C
+
90%
Zn(CH2I)2•DME(6 + 3 + 3 equiv)
OB
O
CONMe2Me2NOC
Bu
2.4 éq
6
1