The overall goal of this proposed program of research is the development of new tactics and strategies for the synthesis of alkaloid natural products and biologically active nitrogen containing compounds. Within this general context, a number of specific objectives have been established, and these may be divided into methodological studies and efforts directed toward the total syntheses of biologically active, nitrogen-containing natural products. On the methodological front, the principal goals are to: (1) develop new methods for the stereoselective synthesis of functionalized dienes; (2) explore further the utilization of cycloaddition reactions, especially Diels-Alder reactions involving heterodienes or vinylogous imides, for the construction of heterocyclic structural subunits found in alkaloids; and (3) expand the scope and synthetic utility of the inter- and intramolecular reactions of iminium salts with electron-rich nucleophilic partners, especially oxygenated furans. In the arena of total synthesis, we will: (1) continue development of intramolecular hetero Diels-Alder reactions in tandem with biomimetic chemistry for the syntheses of alkaloids of Strychnos, Ajmaline, and Sarpagine families including condylocarpine, akuammicine, strychnine, polyneuridine, quebrachidine and akuammidine; (2) exploit a novel and recently discovered sequence that entails nucleophilic addition to a 3,4-dihydrocarboline iminium salt followed by skeletal reorganization as a key step for the syntheses of indole alkaloids of the Aspidosperma (e.g., vindorosine) and perhaps Strychnos families; (3) design a convergent approach to manzamine A, a complex cytotoxic alkaloid, using a strategy that features an unusual intramolecular [4+2] cycloaddition of a vinylogous imide; and (4) develop a potentially general approach to alkaloids containing butyrolactone subunits using a novel condensation of oxygenated furans with iminium salts and demonstrate the efficacy of such methodology by its application to concise syntheses of the polycyclic Stemona alkaloid croomine and the Ergot alkaloids rugulovasines A and B and lysergic acid. Finally, we intend to prepare reasonable quantities of the targeted compounds and selected intermediates for submission to C. P. Starks, Inc., Eli Lilly, DuPont, Merck and Abbott Laboratories for biological evaluation.
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