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Alkaloid Synthesis Using N-Acylpyridinium Salts as Building Blocks: Progress Towards the Total Synthesis of (-)-FR901483 and Synthesis of Novel Polyheterocyclic Compounds
(2003-06-26) Gotchev, Dimitar Borissov; Daniel L. Comins, Committee Chair; Suzanne T. Purrington, Committee Member; Bruce Novak,, Committee Member; Binghe Wang, Committee Member
A study directed toward the total synthesis of the potent immunosuppressant (-)-FR901483 was examined. Three approaches to the tricyclic core of the targeted molecule were investigated, utilizing Grignard addition to an N-acylpyridinium salt and quaternary center formation as the key synthetic steps. In the first route, a pivotal keto-aldehyde intermediate was needed to study an intramolecular pinacol coupling approach to the backbone of the title compound. In the second and third generation synthetic designs, an intramolecular 6-exo-tet epoxide opening was envisioned as a means of generating the azabicyclo ring system of the target. Three novel polyheterocyclic ketones were synthesized in a flexible manner in search for an asymmetric epoxidation catalyst of unfunctionalized trans-alkenes. The targeted compounds were derived via a regiospecific alkylation of 5-hydroxy-2-methylpyridine, followed by functional group manipulation and nitrogen atom cyclization.