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(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
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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).
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Proposed Synthetic Approach
Kinetic resolution of 2,2-disubstituted epoxides.
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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: Asymmetry 2003, 14,
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Kinetic Resolution of Epoxides : Theoretical Considerations
Recovered Substrate Product
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Kinetic Resolution of Epoxides : Chromium and Cobalt Catalysts
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Crystal Structure of (S,S)-(Salen)CrN3 complex
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Kinetic Resolution of 2,2-Disubstituted Epoxides
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Hydrolytic Kinetic Resolution of 2,2-Disubstituted Epoxides
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Kinetic Resolution of 2,2-Disubstituted Epoxides
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Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl Azide
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Proposed Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSN3
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Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of 2,2-Disubstituted Epoxides with TMSN3
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Kinetic Resolution of 2,2-Disubstituted Epoxides with Trimethylsilyl Azide
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Catalytic Cycle for the (Salen)Cr(III) Catalyzed Asymmetric Ring Opening of Epoxides with TMSN3 and 2-Propanol
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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,
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Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex
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Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex
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Kinetic Resolution of 2,2-Disubstituted Epoxides with HN3 Catalyzed by a (Salen)Cr(III) Complex
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Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols
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Proposed Cooperative Mechanism
•No reaction background in absence of catalyst. •Catalyst concentration did not affect the regioselectivity. •No erosion of the enantiomeric excess
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Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols
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Kinetic Resolution of 2,2-Disubstituted Epoxides: Formation of Azido Alcohols
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Kinetic Resolution of 2,2-Disubstituted Epoxides with Chromium Catalyst and TMSN3
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Retrosynthetic Analysis
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Synthesis of Precursors
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Synthesis of Ketone by Alkylation of an
in-situ Generated Weinreb Amide
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Synthesis of Propargylic Ketone
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Diastereoselective Reduction of b-Alkoxy Ketone
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Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones
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Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones
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Synthesis of the Saturated Diol
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Taurine Coupling : First Attempt
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Synthesis of Unsaturated Fatty Acid Chain
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Synthesis of Unsaturated Fatty Acid Chain
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Esterification with the Unsaturated Fatty Acid Chain
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Completion of the Synthesis
Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
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Ph.D. Thesis-Hélène Lebel (Advisor : Prof. André B. Charette)
STEREOSELECTIVE CYCLOPROPANATION OF ALLYLIC ALCOHOLS: APPLICATION TO THE TOTAL SYNTHESIS OF (+)-U Ph.D. Thesis-Hélène Lebel (Advisor : Prof. André B. Charette) May 1993-December 1997
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Stereoselective Cyclopropanations: An Overview
Relative Stereocontrol •Cyclic Substrates : Weinstein, Dauben, Denmark - Sylvie Prescott •Acyclic Substrates : Pereyre, Molander - Hélène Lebel Absolute Stereocontrol •Chiral Auxiliary •Chiral Stoichiometric Ligand •Chiral Catalyst
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Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols
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Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols : Literature Precedent (1994)
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Zinc Reagents
Intramolecular Hydrogen Bonding : Separation of both diastereomers by TLC H. Mollendal Acta Chem. Scand. 1992, 46, L. Joris J. Am. Chem. Soc. 1968, 90, 327.
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols : Determination of the Relative Stereochemistry
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Stereoselective Cyclopropanations with Zinc Reagents :
E-Disubstituted Chiral Allylic Alcohols
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Stereoselective Cyclopropanations with Zinc Reagents :
E-Disubstituted and Z-Trisubstituted Chiral Allylic Alcohols Charette, A. B., Lebel, H. J. Org. Chem. 1995, 60,
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols
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Stereoselective Cyclopropanations of Chiral Allylic Alcohols
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Stereoselective Cyclopropanations of Chiral Allylic Ethers
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Stereoselective Cyclopropanations of Chiral Allylic Ethers
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Stereoselective Cyclopropanations of Chiral Allylic Ethers
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Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols
Chiral Ligand ????
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Enantioselective Cyclopropanations of Allylic Alcohols : Chiral Dioxaborolane
Charette, A. B.; Juteau, H. J. Am. Chem. Soc. 1994, 116, Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60, Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem. Soc. 1998, 120,
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Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane
No possibility for kinetic resolution : both enantiomers react at the same rate
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Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane
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Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane
Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55,
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Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane
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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 Physiology 1994, 21,
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Retrosynthetic Analysis of U-106305
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Retrosynthetic Analysis of U-106305
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Synthesis of theTricyclopropyldimethanol
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Synthesis of the Pentaclopropyldimethanol
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Asymmetric Double Cyclopropanations
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Approach to 1,2-Dicyclopropylalkenes
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1,2-Dicyclopropylalkenes
Approach to 1,2-Dicyclopropylalkenes
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Approach to 1,2-Dicyclopropylalkenes
•Ratio E : Z •Possible decomposition or racemization of the cyclopropylmethyl carbanion
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Approach to 1,2-Dicyclopropylalkenes
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Approach to 1,2-Dicyclopropylalkenes
1 : 1
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Solvent Effect in the S. Julia Olefination
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Completion of the Synthesis of (+)-U-106305
Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118,
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Chemoselective Cyclopropanation of Dienol
Charette, A. B.; Juteau, H.; Lebel, H.; Deschenes, D. Tetrahedron Lett. 1996, 37,
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Double Cyclopropanation of Dienes : Stereochemical Outcome ?
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Double Cyclopropanation of Dienes
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Tetracyclopropanation
Asymmetric Tetracyclopropanation
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Cope Divinylcyclopropane Rearrangement
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Asymmetric Tetracyclopropanation
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