1. Vanadium-Catalyzed Selenide Oxidation with in situ [2,3] Sigmatropic Rearrangement: Scope and Asymmetric Applications Campbell Bourland February 6, 2002 1

2. List of Abbreviations e.e. d.e. TBHP CHP m-CPBA acac TBAF SOS ASOS enantiomeric excess (% major enantiomer - % minor enantiomer) diastereomeric excess (% major diastereomer - % minor diastereomer) tert-butyl hydroperoxide cumene hydroperoxide meta-chloroperbenzoic acid acetyl acetonate tetrabutyl ammoniumfluoride selenide oxidation with in situ [2,3] sigmatropic rearrangement asymmetric selenide oxidation in situ [2,3] sigmatropic rearrangement 2

3. Importance of Allylic Alcohols Rapamycin prostaglandins 3

4. Allylic Alcohols Useful as Precursors in Synthesis Henbest and Wilson’s Asymmetric Epoxdiation: Corey’s Asymmetric Epoxidation: Henbest, H. B.; Wilson, R. A. L. J. Chem. Soc. 1959, 1958. Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256. 4

5. Application of Selenides to Synthesis Selenoxide Syn-Elmination to form alkene: The SOS reaction: 5

6. Traditional Methods for Selenide Oxidation Wirth, T. Tetrahedron 1999, 55, 1. 6

7. Selenoxide vs. Sulfoxide 7 Reich, H. J. et. al. J. Am. Chem. Soc. 1983, 105, 2503.

8. Standard Protocol for Synthesis of the Allylic Selenides 70-90% 90-99% < 95% 8

9. Development of Vanadium-Catalyzed SOS Reaction 9

10. Utility of the Vanadium-Catazlyed SOS Reaction on (E)-Substrates Carter, R. G.; Bourland, T. C. J. Chem. Soc. Chemm. Commun. 2000, 2031. 10

11. Utility of the Vanadium-Catazlyed SOS Reaction on Tri-Substituted and (Z) Substrates 11

12. Effects of a Stereocenter on SOS Reaction 12

13. Conclusion from Racemic SOS Reaction Conditions optimized for racemic series of Vanadium-catalyzed SOS reaction. System works on a wide variety of substrates. Good yields, short reaction times. Stereocenter does not effect SOS reaction. 13

14. Fujita’s Asymmetric Oxidation of Sulfides with Salen-VO(acac) 2 Nokijima, K.; Kojima, M.; Fujita, J. Chem. Lett. 1986, 1433. 14

15. Bolm’s Ligand-Based for Asymmetric Oxidation of Sulfides Bolm, C.; Bienwald, F. Angew. Chem. Int. Ed. Engl. 1995, 34, 2640. 15

16. Two Chiral Events Occurring in SOS Reaction Oxidation of selenide to chiral selenoxide: Rearrangement of chiral selenoxide to alcohol: 16

17. Endo vs. Exo Pathways Endo pathway appears to be favored by calculations and experimental results Reich, H. J. et. al. J. Am. Chem. Soc. 1983, 105, 2503. 17

18. Davis’ Oxidation of Selenides oxaziridine Davis, F. A.; Reddy, T. R. J. Org. Chem. 1992, 57, 2599. 18

19. Davis’ Work in SOS Reaction Chiral induction from selenoxide to selenenate only 70-80% efficient. (Z)-Olefin geometry gives higher selectivity. Stereochemical outcome consistent with an endo transition state. Davis, F. A.; Reddy, T. R. J. Org. Chem. 1992, 57, 2599. 19

20. Vanadium-Catalyzed ASOS Reaction: Ligand-Based Approach 20

21. Selected Examples of Ligand-Based ASOS Reaction 21

22. Problems with Ligand-Based System L* = Chiral Schiff base ligand LB* = Chiral Auxiliary containing a Lewis Base 22

23. Auxiliary-Based System Used to Understand Ligand-Based Systems Auxiliary Approach: Ligand Approach: Evans, D. A.; et. al. J. Am. Chem. Soc. 1999, 121, 686. 23

24. Williams Use of Auxiliary for Asymmetric Oxidation of Sulfides Williams, J. M. J.; et. al. J. Chem. Soc. Perkin Trans. 1 1996, 331. 24

25. Examples of Auxiliaries Utilized in ASOS Reactions Reich, H. J.; Yelm, K. E. J. Org. Chem. 1991, 56, 5672 Fujita, K.; et. al. Synlett 1998, 987. Uemura, S.; et. al. J. Org. Chem. 1995, 60, 4114. Koizumi, N.; et. al. Tetrahedron 1997, 53, 12115 25 (t-BuOCl instead of m-CPBA)

26. Synthesis of Monodentate Auxiliaries Applied to Vanadium-Catalyzed ASOS Reaction 50-74% 61-73% 26

27. ASOS Reaction with Mondentate Auxiliaries 27

28. Results From Monodentate ASOS Reaction 28

29. Camphor Based Monodentate Oxazoles 29

30. Monodentate Auxillary with m-CPBA Only 4% d.e. 30

31. Williams Use of Auxiliary for Asymmetric Oxidation of Sulfides Williams, J. M. J.; et. al. J. Chem. Soc. Perkin Trans. 1 1996, 331. 31

32. Synthesis of Bidentate Auxiliary System 32

33. ASOS Reaction with Bidentate Auxiliary 33

34. Methylated Serine-based Auxillary ASOS Reaction 34

35. Bidentate Auxillary ASOS Reaction with Different Metal Catalysts 35

36. Threonine-Based Auxillary ASOS Reaction 36

37. Synthesis of Epimeric Selenides 37

38. Synthesis of Iso-Propyl Selenides 38

39. ASOS Reaction with Iso-propyl Selenides 39

40. Possible Explanation of Stereochemistry 40

41. Conclusion Racemic SOS reaction: Developed the first catalytic, metal-based method. Requires only 10 mol% VO(acac) 2 and applicable to a wide range of substrates. Vanadium-catalyzed, Auxiliary-Based ASOS reaction: Achieved up to 70% diastereomeric excess (d.e.) with an oxazole-based auxiliary. Laid the foundation for the development of a ligand- based ASOS reaction system. 41

42. Acknowledgements Committee Members Dr. Rich Carter Dr. Mitch Avery Dr. Dan Mattern Lab Group Wei Zhang David Weldon Melissa Gronemeyer Chrissy Castrichini Dr. and Mrs. Walter Bourland Rachel Graves The Graves Clan Stacy Jones Qun Zhu G-Flo and Big Serge Dr. Ismail Ahmed Dr. Linda Spargo The University of Mississippi 42