1. (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

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: Asymmetry 2003, 14,

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-Disubstituted Epoxides 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,

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. 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

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 Stoichiometric Ligand
•Chiral Catalyst

40. Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols

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

42. 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.

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,

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

51. Stereoselective Cyclopropanations of Chiral Allylic Ethers

52. Stereoselective Cyclopropanations of Acyclic Chiral Allylic Alcohols
Chiral Ligand ????

53. 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,

54. Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane
No possibility for kinetic resolution : both enantiomers react at the same rate

55. Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane

56. Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane
Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55,

57. Enantioselective Cyclopropanations of Chiral Allylic Alcohols : Chiral Dioxaborolane

58. 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,

59. Retrosynthetic Analysis of U-106305

60. Retrosynthetic Analysis of U-106305

61. Synthesis of theTricyclopropyldimethanol

62. Synthesis of the Pentaclopropyldimethanol

63. Asymmetric Double Cyclopropanations

64. Approach to 1,2-Dicyclopropylalkenes

65. 1,2-Dicyclopropylalkenes
Approach to
1,2-Dicyclopropylalkenes

66. Approach to 1,2-Dicyclopropylalkenes
•Ratio E : Z
•Possible decomposition or racemization of the cyclopropylmethyl carbanion

67. Approach to 1,2-Dicyclopropylalkenes

68. Approach to 1,2-Dicyclopropylalkenes
1 : 1

69. Solvent Effect in the S. Julia Olefination

70. Completion of the Synthesis of (+)-U-106305
Charette, A. B.; Lebel, H.
J. Am. Chem. Soc. 1996, 118,

71. Chemoselective Cyclopropanation of Dienol
Charette, A. B.; Juteau, H.; Lebel, H.; Deschenes, D. Tetrahedron Lett. 1996, 37,

72. Double Cyclopropanation of Dienes : Stereochemical Outcome ?

73. Double Cyclopropanation of Dienes

74. Tetracyclopropanation
Asymmetric
Tetracyclopropanation

75. Cope Divinylcyclopropane Rearrangement

76. Asymmetric Tetracyclopropanation