Efficient Synthesis of Macrolides via Palladium-Catalyzed Carbonylative Macrolactonizations and Divergent Synthesis of Monoterpene Indole Alkaloids

Yu Bai, Purdue University

Abstract

The first part of this thesis describes an efficient synthesis of THP/THF containing macrolides. Tetrahydropyran (THP) and tetrahydrofuran (THF)-containing macrolides are a diverse family of natural products with a broad range of biological activity, particularly anticancer activity. We here developed an efficient palladium-catalyzed alkoxycarbonylative macrolactonization to construct THP/THF containing macrolides with different ring sizes and substitutes. We also utilized this strategy to synthesize 9-demethylneopeltolide, which enabled us to validate not only its potent anticancer activity but also discover its new antimalarial activity. The second part of this thesis describes a total synthesis of (-) spinosyn A via carbonylative macrolactonization. Tetracyclic macrolide spinosyn A is the major component of spinosad, an organic insecticide widely used around the world with over $200 million sales per year. However, cross-resistance has been observed for spinosad, and the current biosynthesis cannot be used to make a large amount of analogs to target the observed resistance. So far the three known total syntheses from the groups of Evans, Paquette, and Roush, and one chemoenzymatic synthesis from Liu group are lengthy and not flexible for analog synthesis. We here developed an efficient and flexible approach toward (-)-spinosyn A, which would allow quick access of analogs with structural variations at the tetracyclic core. Our synthesis features an organocatalyzed IMDA reaction, gold(I) -catalyzed propargylic acetate rearrangement with simultaneous oxidative seleno elimination and TBS-deprotection to provide an alpha-iodoenone, and a palladium -catalyzed carbonylative Heck macrolactonization to building the 5,12-fused macrolactone ring system. The D-forosamine glycosylation was achieved using glycosyl orthoalkynylbenzoate as donor and Ph3PAuCl/AgOTf as promoter. The third part of this thesis describes a divergent synthesis of monoterpene indole alkaloids. Terpene indole alkaloids (TIAs) are one of the most prominent families, from which drug molecules like vinblastine, vincristine, yohimbine, ajmalicine, ajmaline, quinine, and camptothecin have been identified. Recently, monoterpene indole alkaloids with novel structural skeletons were isolated such as mersicarpine, leuconodines, leuconoxine, melodinine E, leuconolam, and rhazinilam. We here synthesized these natural products from a pivotal intermediate, which is derived from a Witkop-Winterfeldt oxidative indole cleavage followed by transannular cyclization. This strategy offers opportunities to create TIA analogs for anticancer drug discovery.

Degree

Ph.D.

Advisors

Dai, Purdue University.

Subject Area

Chemistry|Organic chemistry

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