Our fine success in obtaining extraordinarily high asymmetric inductions (usually greater than 90% e.e. and in some cases greater than 98% e.e.) during nucleophilic Beta-addition to some enantiomerically pure Alpha,Beta-ethylenic sulfoxides prompts us to propose here three new aspects of this research area; each of these three topics involves asymmetric reactions of enantiomerically pure, unsaturated lactone sulfoxides. First, we propose to use enantiomerically pure 3-arylsulfinyl-2-pyrones in mild, Lewis acid-promoted, inverse electron demand Diels-Alder cycloadditions as an exciting and highly significant new way to prepare structurally complex, highly functionalized, stereochemically well-defined, and synthetically versatile cyclohexenes of high enantiomeric purity. A stunning initial discovery makes this project highly likely to succeed and to be a fundamental breakthrough in asymmetric organic synthesis. to illustrate the great potential of this asymmetric Diels-Alder reaction for very short and highly stereocontrolled syntheses of enantiomerically pure and physiologically active compounds, we propose to prepare natural anti-tumor (+)-crotepoxide. Second, we propose to use an enantiomerically pure unsaturated valerolactone sulfoxide in a highly stereocontrolled total synthesis of fragrant natural (-)-Beta-vetivone, a structurally challenging spiro(4.5)decane system. This process includes an effective and highly stereocontrolled method for preparing two adjacent tertiary and quaternary chiral carbon centers with excellent control of absolute stereochemistry. Third, we propose to use an enantiomerically pure butenolide sulfoxide in an extremely short, direct, and flexible asymmetric synthesis of natural and derivatized (3R)-A-factor, a very potent intracellular autoregulatory substance essential for streptomycin production and cell differentiation. The successful execution of these plans will represent a very significant demonstration of the great utility of enantiomerically pure unsaturated lactone sulfoxides in asymmetric synthetic methodology and in preparation of diverse physiologically active compounds of high enantiomeric purity.
|Greising, D M; Schwartz, Z; Posner, G H et al. (1997) A-ring analogues of 1, 25-(OH)2D3 with low affinity for the vitamin D receptor modulate chondrocytes via membrane effects that are dependent on cell maturation. J Cell Physiol 171:357-67|
|Boyan, B D; Posner, G H; Greising, D M et al. (1997) Hybrid structural analogues of 1,25-(OH)2D3 regulate chondrocyte proliferation and proteoglycan production as well as protein kinase C through a nongenomic pathway. J Cell Biochem 66:457-70|
|Yukihiro, S; Posner, G H; Guggino, S E (1994) Vitamin D3 analogs stimulate calcium currents in rat osteosarcoma cells. J Biol Chem 269:23889-93|
|Posner, G H; Nelson, T D; Guyton, K Z et al. (1992) New vitamin D3 derivatives with unexpected antiproliferative activity: 1-(hydroxymethyl)-25-hydroxyvitamin D3 homologs. J Med Chem 35:3280-7|