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Postdoc-Hélène 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. 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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  1. 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

  2. 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).

  3. Proposed Synthetic Approach Kinetic resolution of 2,2-disubstituted epoxides.

  4. 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.

  5. Kinetic Resolution of Epoxides : Theoretical Considerations Recovered Substrate Product

  6. Kinetic Resolution of Epoxides : Chromium and Cobalt Catalysts

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

  8. Kinetic Resolution of 2,2-Disubstituted Epoxides

  9. Hydrolytic Kinetic Resolution of 2,2-Disubstituted Epoxides

  10. Kinetic Resolution of 2,2-Disubstituted Epoxides

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

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

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

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

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

  16. 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.

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

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

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

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

  21. Proposed Cooperative Mechanism •No reaction background in absence of catalyst. •Catalyst concentration did not affect the regioselectivity. •No erosion of the enantiomeric excess

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

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

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

  25. Retrosynthetic Analysis

  26. Synthesis of Precursors

  27. Synthesis of Ketone by Alkylation of an in-situ Generated Weinreb Amide

  28. Synthesis of Propargylic Ketone

  29. Diastereoselective Reduction of b-Alkoxy Ketone

  30. Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones

  31. Asymmetric Transfer Hydrogenation of a,b-Acetylenic Ketones

  32. Synthesis of the Saturated Diol

  33. Taurine Coupling : First Attempt

  34. Synthesis of Unsaturated Fatty Acid Chain

  35. Synthesis of Unsaturated Fatty Acid Chain

  36. Esterification with the Unsaturated Fatty Acid Chain

  37. Completion of the Synthesis Lebel, H.; Jacobsen, E. N. J. Org. Chem.1998, 63, 9624.

  38. 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

  39. 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

  40. Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols

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

  42. 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

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

  44. Stereoselective Cyclopropanations with Zinc Reagents : E-Disubstituted Chiral Allylic Alcohols

  45. 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

  46. Stereoselective Cyclopropanations of Chiral Allylic Alcohols

  47. Stereoselective Cyclopropanations of Chiral Allylic Alcohols

  48. Stereoselective Cyclopropanations of Chiral Allylic Alcohols

  49. Stereoselective Cyclopropanations of Chiral Allylic Ethers

  50. Stereoselective Cyclopropanations of Chiral Allylic Ethers

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