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

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

Importance of Allylic Alcohols Rapamycin prostaglandins 3

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, Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107,

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

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

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

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

Development of Vanadium-Catalyzed SOS Reaction 9

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

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

Effects of a Stereocenter on SOS Reaction 12

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

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

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

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

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,

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

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,

Vanadium-Catalyzed ASOS Reaction: Ligand-Based Approach 20

Selected Examples of Ligand-Based ASOS Reaction 21

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

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

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

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, Koizumi, N.; et. al. Tetrahedron 1997, 53, (t-BuOCl instead of m-CPBA)

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

ASOS Reaction with Mondentate Auxiliaries 27

Results From Monodentate ASOS Reaction 28

Camphor Based Monodentate Oxazoles 29

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

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

Synthesis of Bidentate Auxiliary System 32

ASOS Reaction with Bidentate Auxiliary 33

Methylated Serine-based Auxillary ASOS Reaction 34

Bidentate Auxillary ASOS Reaction with Different Metal Catalysts 35

Threonine-Based Auxillary ASOS Reaction 36

Synthesis of Epimeric Selenides 37

Synthesis of Iso-Propyl Selenides 38

ASOS Reaction with Iso-propyl Selenides 39

Possible Explanation of Stereochemistry 40

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

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