KINETIC RESOLUTION OF 2,2-DISUBSTITUTED EPOXIDES APPLICATION TO THE TOTAL SYNTHESIS OF TAUROSPONGIN ...
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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.

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Postdoc-Hélène Lebel (Advisor : Prof. Eric N. Jacobsen)

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Postdoc h l ne lebel advisor prof eric n jacobsen

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


Postdoc h l ne lebel advisor prof eric n jacobsen

Isolation and Biological Activities

•Isolated from Okinawan marine sponge Hippospongia sp.

•Inhibitory activity against DNA polymerase b (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).


Postdoc h l ne lebel advisor prof eric n jacobsen

Proposed Synthetic Approach

Kinetic resolution of 2,2-disubstituted epoxides.


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of Epoxides by Asymmetric Ring Opening

Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal.2001, 343, 5-26.

Robinson, D.; Bull, S. D. Tetrahedron: Asymmetry2003, 14, 1407-1446.


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of Epoxides : Theoretical Considerations

Recovered Substrate

Product


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of Epoxides : Chromium and Cobalt Catalysts


Postdoc h l ne lebel advisor prof eric n jacobsen

Crystal Structure of (S,S)-(Salen)CrN3 complex


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides


Postdoc h l ne lebel advisor prof eric n jacobsen

Hydrolytic Kinetic Resolution of 2,2-Disubstituted Epoxides


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl Azide


Postdoc h l ne lebel advisor prof eric n jacobsen

Proposed Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSN3


Postdoc h l ne lebel advisor prof eric n jacobsen

Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of 2,2-DisubstitutedEpoxides with TMSN3


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl Azide


Postdoc h l ne lebel advisor prof eric n jacobsen

Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSN3 and 2-Propanol


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex

Lebel, H.; Jacobsen, E. N. Tetrahedron Lett.1999, 40, 7303-7306.


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Proposed Cooperative Mechanism

•No reaction background in absence of catalyst.

•Catalyst concentration did not affect the regioselectivity.

•No erosion of the enantiomeric excess


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Kinetic Resolution of 2,2-Disubstituted Epoxides with Chromium Catalyst and TMSN3


Postdoc h l ne lebel advisor prof eric n jacobsen

Retrosynthetic Analysis


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of Precursors


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of Ketone by Alkylation of an

in-situ Generated Weinreb Amide


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of Propargylic Ketone


Postdoc h l ne lebel advisor prof eric n jacobsen

Diastereoselective Reduction of b-Alkoxy Ketone


Postdoc h l ne lebel advisor prof eric n jacobsen

Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones


Postdoc h l ne lebel advisor prof eric n jacobsen

Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of the Saturated Diol


Postdoc h l ne lebel advisor prof eric n jacobsen

Taurine Coupling : First Attempt


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of Unsaturated Fatty Acid Chain


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of Unsaturated Fatty Acid Chain


Postdoc h l ne lebel advisor prof eric n jacobsen

Esterification with the Unsaturated Fatty Acid Chain


Postdoc h l ne lebel advisor prof eric n jacobsen

Completion of the Synthesis

Lebel, H.; Jacobsen, E. N. J. Org. Chem.1998, 63, 9624.


Postdoc h l ne lebel advisor prof eric n jacobsen

STEREOSELECTIVE CYCLOPROPANATION OF ALLYLIC ALCOHOLS: APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U-106305

Ph.D. Thesis-Hélène Lebel

(Advisor : Prof. André B. Charette)

May 1993-December 1997


Stereoselective cyclopropanations an overview

Stereoselective Cyclopropanations: An Overview

Relative Stereocontrol

•Cyclic Substrates : Weinstein, Dauben, Denmark - Sylvie Prescott

•Acyclic Substrates : Pereyre, Molander - Hélène Lebel

Absolute Stereocontrol

•Chiral Auxiliary

•Chiral Catalyst

•Chiral Stoichiometric Ligand


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols : Literature Precedent (1994)


Postdoc h l ne lebel advisor prof eric n jacobsen

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.

Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Zinc Reagents


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Determination of the Relative Stereochemistry


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations with Zinc Reagents :

E-Disubstituted Chiral Allylic Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations with Zinc Reagents :

E-Disubstituted and Z-Trisubstituted Chiral Allylic Alcohols

Charette, A. B., Lebel, H. J. Org. Chem. 1995, 60, 2966-67


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Alcohols


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Ethers


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Ethers


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Chiral Allylic Ethers


Postdoc h l ne lebel advisor prof eric n jacobsen

Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols

Chiral Ligand ????


Postdoc h l ne lebel advisor prof eric n jacobsen

Enantioselective Cyclopropanations of Allylic Alcohols : Chiral Dioxaborolane

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.


Postdoc h l ne lebel advisor prof eric n jacobsen

Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane

No possibility for kinetic resolution : both enantiomers react at the same rate


Postdoc h l ne lebel advisor prof eric n jacobsen

Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane


Postdoc h l ne lebel advisor prof eric n jacobsen

Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane

Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron1999, 55, 8845-8856.


Postdoc h l ne lebel advisor prof eric n jacobsen

Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane


Postdoc h l ne lebel advisor prof eric n jacobsen

Structure and Biological Activity of U-106305

•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 Physiology1994, 21, 663-672.


Postdoc h l ne lebel advisor prof eric n jacobsen

Retrosynthetic Analysis of U-106305


Postdoc h l ne lebel advisor prof eric n jacobsen

Retrosynthetic Analysis of U-106305


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of theTricyclopropyldimethanol


Postdoc h l ne lebel advisor prof eric n jacobsen

Synthesis of the Pentaclopropyldimethanol


Postdoc h l ne lebel advisor prof eric n jacobsen

Asymmetric Double Cyclopropanations


Postdoc h l ne lebel advisor prof eric n jacobsen

Approach to 1,2-Dicyclopropylalkenes


Postdoc h l ne lebel advisor prof eric n jacobsen

Approach to

1,2-Dicyclopropylalkenes


Postdoc h l ne lebel advisor prof eric n jacobsen

Approach to 1,2-Dicyclopropylalkenes

•Ratio E : Z

•Possible decomposition or racemization of the cyclopropylmethyl carbanion


Postdoc h l ne lebel advisor prof eric n jacobsen

Approach to 1,2-Dicyclopropylalkenes


Postdoc h l ne lebel advisor prof eric n jacobsen

Approach to 1,2-Dicyclopropylalkenes

1 : 1


Postdoc h l ne lebel advisor prof eric n jacobsen

Solvent Effect in the S. Julia Olefination


Postdoc h l ne lebel advisor prof eric n jacobsen

Completion of the Synthesis of (+)-U-106305

Charette, A. B.; Lebel, H.

J. Am. Chem. Soc.1996, 118, 10327-10328.


Postdoc h l ne lebel advisor prof eric n jacobsen

Chemoselective Cyclopropanation of Dienol

Charette, A. B.; Juteau, H.; Lebel, H.; Deschenes, D. Tetrahedron Lett.1996, 37, 7925-7928.


Postdoc h l ne lebel advisor prof eric n jacobsen

Double Cyclopropanation of Dienes : Stereochemical Outcome ?


Postdoc h l ne lebel advisor prof eric n jacobsen

Double Cyclopropanation of Dienes


Postdoc h l ne lebel advisor prof eric n jacobsen

Asymmetric

Tetracyclopropanation


Postdoc h l ne lebel advisor prof eric n jacobsen

Cope Divinylcyclopropane Rearrangement


Postdoc h l ne lebel advisor prof eric n jacobsen

Asymmetric Tetracyclopropanation


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