Synthesis of Carbocyclic and Heterocyclic Compounds (Chemistry)

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This research will lead to the development of new synthetic reactions and pathways to some important classes of biologically active alkaloids. It will in addition provide new routes to the important beta-lactams. The synthesis of several carbocyclic and heterocyclic ring systems will be studied with the objective of developing new methodology and applying it to selected targets in the natural product domain. A photochemically mediated cyclization of beta-ketoester enolates will be extended to a system designed to test the feasibility of this reaction in a nine-membered ring, where annulation would afford a tricyclic precursor to the adenylatecyclase inhibitor forskolin. A stannic chloride-mediated cyclization of olefinic beta-ketoesters will also be examined for asymmetric induction where the ester is derived from a chiral alcohol. Application of this technology to synthesis of diterpenes of the stemodane, stemarane, and aphidicolane group is projected. Finally, the cyclization of beta-ketoesters in the presence of manganese acetate will be investigated as a means for elaborating novel bridged frameworks. A route to the taxane family of diterpenoids, specifically taxusin, has been planned around this construct. In the heterocyclic area, a new synthesis of beta.lactams will be pursued that hinges on extrusion of nitrogen from the sulfoximine of a N-aminopyrazolinone with concomitant ring contraction. This methodology will be incorporated into a chiral synthesis of penicillins and other beta-lactam antibiotics. In an extension of work originally carried out by Ghosez, the use of hydrazones of alpha, beta-unsaturated aldehydes in the Diels-Adler reaction will be examined as a device for preparing perhydroisoquinolines. A chiral entry to the gelsemine class of alkaloids, specifically koumine, would be explored by this means.