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 TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A

•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 TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A

Kinetic resolution of 2,2-disubstituted epoxides.


Kinetic Resolution of Epoxides by Asymmetric Ring Opening TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A

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 TO THE TOTAL SYNTHESIS OF TAUROSPONGIN A

Recovered Substrate

Product








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



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 HN Ring Opening of Epoxides with TMSN3 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 HN Ring Opening of Epoxides with TMSN3 Catalyzed by a (Salen)Cr(III) Complex


Kinetic Resolution of 2,2-Disubstituted Epoxides with HN Ring Opening of Epoxides with TMSN3 Catalyzed by a (Salen)Cr(III) Complex


Kinetic Resolution of 2,2-Disubstituted Epoxides with HN Ring Opening of Epoxides with TMSN3 Catalyzed by a (Salen)Cr(III) Complex



Proposed Cooperative Mechanism of Azido Alcohols

•No reaction background in absence of catalyst.

•Catalyst concentration did not affect the regioselectivity.

•No erosion of the enantiomeric excess





Retrosynthetic Analysis Chromium Catalyst and TMSN


Synthesis of Precursors Chromium Catalyst and TMSN


Synthesis of Ketone by Alkylation of an Chromium Catalyst and TMSN

in-situ Generated Weinreb Amide


Synthesis of Propargylic Ketone Chromium Catalyst and TMSN


Diastereoselective Reduction of Chromium Catalyst and TMSNb-Alkoxy Ketone


Asymmetric Transfer Hydrogenation of Chromium Catalyst and TMSNa,b-Acetylenic Ketones


Asymmetric Transfer Hydrogenation of Chromium Catalyst and TMSNa,b-Acetylenic Ketones


Synthesis of the Saturated Diol Chromium Catalyst and TMSN


Taurine Coupling : First Attempt Chromium Catalyst and TMSN


Synthesis of Unsaturated Fatty Acid Chain Chromium Catalyst and TMSN


Synthesis of Unsaturated Fatty Acid Chain Chromium Catalyst and TMSN



Completion of the Synthesis Chromium Catalyst and TMSN

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
Stereoselective Cyclopropanations: An Overview APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U-106305

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 : 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 : : Determination of the Relative Stereochemistry

E-Disubstituted Chiral Allylic Alcohols


Stereoselective Cyclopropanations with Zinc Reagents : : Determination of the Relative Stereochemistry

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 : Determination of the Relative Stereochemistry


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


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


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


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


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



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

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



Structure and Biological Activity of U-106305 Alcohols : Chiral Dioxaborolane

•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 Alcohols : Chiral Dioxaborolane


Retrosynthetic Analysis of U-106305 Alcohols : Chiral Dioxaborolane


Synthesis of theTricyclopropyldimethanol Alcohols : Chiral Dioxaborolane


Synthesis of the Pentaclopropyldimethanol Alcohols : Chiral Dioxaborolane


Asymmetric Double Cyclopropanations Alcohols : Chiral Dioxaborolane


Approach to 1,2-Dicyclopropylalkenes Alcohols : Chiral Dioxaborolane


Approach to Alcohols : Chiral Dioxaborolane

1,2-Dicyclopropylalkenes


Approach to 1,2-Dicyclopropylalkenes Alcohols : Chiral Dioxaborolane

•Ratio E : Z

•Possible decomposition or racemization of the cyclopropylmethyl carbanion


Approach to 1,2-Dicyclopropylalkenes Alcohols : Chiral Dioxaborolane


Approach to 1,2-Dicyclopropylalkenes Alcohols : Chiral Dioxaborolane

1 : 1


Solvent Effect in the S. Julia Olefination Alcohols : Chiral Dioxaborolane


Completion of the Synthesis of (+)-U-106305 Alcohols : Chiral Dioxaborolane

Charette, A. B.; Lebel, H.

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


Chemoselective Cyclopropanation of Dienol Alcohols : Chiral Dioxaborolane

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



Double Cyclopropanation of Dienes Alcohols : Chiral Dioxaborolane


Asymmetric Alcohols : Chiral Dioxaborolane

Tetracyclopropanation


Cope Divinylcyclopropane Rearrangement Alcohols : Chiral Dioxaborolane


Asymmetric Tetracyclopropanation Alcohols : Chiral Dioxaborolane


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