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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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.

•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).


Proposed Synthetic Approach

Kinetic resolution of 2,2-disubstituted epoxides.


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.


Kinetic Resolution of Epoxides : Theoretical Considerations

Recovered Substrate

Product


Kinetic Resolution of Epoxides : Chromium and Cobalt Catalysts


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


Kinetic Resolution of 2,2-Disubstituted Epoxides


Hydrolytic Kinetic Resolution of 2,2-Disubstituted Epoxides


Kinetic Resolution of 2,2-Disubstituted Epoxides


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


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


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


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


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


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.


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


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


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


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


Proposed Cooperative Mechanism

•No reaction background in absence of catalyst.

•Catalyst concentration did not affect the regioselectivity.

•No erosion of the enantiomeric excess


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


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


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


Retrosynthetic Analysis


Synthesis of Precursors


Synthesis of Ketone by Alkylation of an

in-situ Generated Weinreb Amide


Synthesis of Propargylic Ketone


Diastereoselective Reduction of b-Alkoxy Ketone


Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones


Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones


Synthesis of the Saturated Diol


Taurine Coupling : First Attempt


Synthesis of Unsaturated Fatty Acid Chain


Synthesis of Unsaturated Fatty Acid Chain


Esterification with the Unsaturated Fatty Acid Chain


Completion of the Synthesis

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


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

Relative Stereocontrol

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

•Acyclic Substrates : Pereyre, Molander - Hélène Lebel

Absolute Stereocontrol

•Chiral Auxiliary

•Chiral Catalyst

•Chiral Stoichiometric Ligand


Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols


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


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


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


Stereoselective Cyclopropanations with Zinc Reagents :

E-Disubstituted Chiral Allylic Alcohols


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


Stereoselective Cyclopropanations of Chiral Allylic Alcohols


Stereoselective Cyclopropanations of Chiral Allylic Alcohols


Stereoselective Cyclopropanations of Chiral Allylic Alcohols


Stereoselective Cyclopropanations of Chiral Allylic Ethers


Stereoselective Cyclopropanations of Chiral Allylic Ethers


Stereoselective Cyclopropanations of Chiral Allylic Ethers


Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols

Chiral Ligand ????


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.


Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane

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


Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane


Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane

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


Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane


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.


Retrosynthetic Analysis of U-106305


Retrosynthetic Analysis of U-106305


Synthesis of theTricyclopropyldimethanol


Synthesis of the Pentaclopropyldimethanol


Asymmetric Double Cyclopropanations


Approach to 1,2-Dicyclopropylalkenes


Approach to

1,2-Dicyclopropylalkenes


Approach to 1,2-Dicyclopropylalkenes

•Ratio E : Z

•Possible decomposition or racemization of the cyclopropylmethyl carbanion


Approach to 1,2-Dicyclopropylalkenes


Approach to 1,2-Dicyclopropylalkenes

1 : 1


Solvent Effect in the S. Julia Olefination


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

Charette, A. B.; Lebel, H.

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


Chemoselective Cyclopropanation of Dienol

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


Double Cyclopropanation of Dienes : Stereochemical Outcome ?


Double Cyclopropanation of Dienes


Asymmetric

Tetracyclopropanation


Cope Divinylcyclopropane Rearrangement


Asymmetric Tetracyclopropanation


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