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INTRODUCTION

INTRODUCTION. In the past, a few d -oxygenated a,b -unsaturated compounds have been selected as substrates for research in the filed of Michael addition. One of the most studied substrates are derived from glyceraldehyde acetonide (Figure 1).

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INTRODUCTION

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  1. INTRODUCTION In the past, a few d-oxygenated a,b-unsaturated compounds have been selected as substrates for research in the filed of Michael addition. One of the most studied substrates are derived from glyceraldehyde acetonide (Figure 1). Figure 1. Examples of substrates with d-oxygen used for Michael addition

  2. PROBLEM Unfortunately, the electron donating nature of d-oxygen makes the b-carbon much less electrophilic (Figure 2). This makes these molecules as poor substrates for the Michael addition. Figure 2. d-Oxygenated a,b-unsaturated substrate with a less electrophilic b-carbon.

  3. SOLUTIONS A number of modified conditions have been studied in the past in order to make some of these poor substrates, such as d-oxygenated a,b-unsaturated ketone, work for the Michael additions (Figure 3). Figure 3. Conditions for poor substrates in Michael addition *PhLi gives 1,2-product as the major product.

  4. Figure 4. Modified conditions for Michael Addition with certain substrates. However, with d-oxygenated a,b-unsaturated ester as the substrates, only limited conditions had been applied successfully (Figure 4). Unfortunately, when phenyl lithium (PhLi) was used, NO conjugated product was obtained.

  5. GOALS Our goal is to find which condition(s) can be applied to the Michael addition with d-oxygenated a,b-unsaturated esters as the substrates.

  6. RESULTS I Table 1. Michael addition from PhMgBr

  7. UNEXPECTED RESULTS

  8. RESULTS II Table 1. Michael addition from PhLi

  9. STEREOSELECTIVITY OF MAJOR PRODUCT

  10. MECHANISM

  11. DISCUSSIONS • PhMgBr INSTEAD PhLi undergoes Michael Addition • CuBr.Me2S/Me2S or CuCN as an additive required • TMSCl is a MUST for this Michael Addition • TMEDA offered NO assistance at all • LiBr is NOT necessary for Michael Addition. But it IMPROVED distereoselectivity • HMPA, used in other substrates as reported, is NOT required

  12. ACKNOWLEDGEMENTS Dr. Victor J.Hruby Dr. Jon Rainier NIH and USPHS SELECTED REFERENCES • Taylor, R. J. K., Ed. Organocopper Reagents - A Practical Approach, Oxford University Press, 1994, 362pp. • Raczko, J. Stereoselective 1,4-addition of Grignard reagents to chiral g-alkoxy-a,b-unsaturated ketones, Tetrahedron: Asymmetry, 1997, 8(22), pp3821-3828. • Leonard, J., Mohialdin, S., Reed, D., Ryan, G and Swain, P. A., Stereoselective conjugate addition of organolithium and organocopper reagents to d-oxygenated a,b-unsaturated carbonyl systems derived from glyceraldehyde acetonide, Tetrahedron, 1995, 51(47), p12843-12858. • Costa, J. S., Dias, A. G., Anholeto, A. L., Monteiro, M. D.Patrocinio, V. L., and Costa, R. R., Syn-selective Michael addition of nitromethane derivatives to enolates derived from (R)-glyceraldehyde acetonide, J. Org. Chem., 1997, 62, pp4002-4006. • Yechezkel, T., Ghera, E., Ramesh, N. G., and Hassner A., Asymmetric synthesis of substituted cyclopentanes via Michael initiated ring closure reactions, Tetrahedron: Asymmtry, 1996, 7(8), pp2423-2436.

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