Convergent Methods for Synthesizing Rings in the Context of Natural Product Synthesis: I. Development of a Tandem Stille-Oxa-Electrocyclization Reaction, and Progress Toward the Total Synthesis of Saudin. II. Development of the Direct Acyl-Alkylation of Arynes, and Its Application Toward the Total Synthesis of Amurensinine

Citation

Tambar, Uttam Krishan (2006) Convergent Methods for Synthesizing Rings in the Context of Natural Product Synthesis: I. Development of a Tandem Stille-Oxa-Electrocyclization Reaction, and Progress Toward the Total Synthesis of Saudin. II. Development of the Direct Acyl-Alkylation of Arynes, and Its Application Toward the Total Synthesis of Amurensinine. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/PMHT-S093. https://resolver.caltech.edu/CaltechETD:etd-12212005-185814

Abstract

Cyclic molecular structures are ubiquitous in chemistry. Efficient and convergent methods to synthesize these rings are of great importance, specifically in the context of natural product synthesis. The development of two methods for the synthesis of the core structures of the natural products saudin and amurensinine are described.

First, the development of the tandem Stille-oxa-electrocyclization will be discussed in the context of synthetic efforts with saudin. The labdane diterpenoid saudin was isolated in 1985 by Mossa and Cassady from the leaves of the Clutia richardiana (L.) family Euphorbiaceae. The natural product was found to induce hypoglycemia in mice and therefore could be an appealing lead structure for the development of new agents to treat diabetes. A diastereoselective tandem Stille-oxa-electrocyclization reaction has been developed, which provides access to the core structure of saudin in a rapid and convergent manner. Additionally, this new reaction has been extended to the convergent preparation of related polycyclic pyran systems. Progress has been made on the advancement of these complex pyran systems toward the synthesis of saudin.

Secondly, the development of the direct acyl-alkylation of arynes will be described in the context of the total synthesis of the isopavine natural product amurensinine. The isopavine alkaloids are promising lead structures for the treatment of neuronal disorders such as as Parkinson’s disease, Down’s syndrome, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s chorea. All members of this family of natural products contain a seven-membered benzannulated carbocycle. To address the challenge of synthesizing the isopavines, an efficient and mild acyl-alkylation of arynes has been developed. The method forms ortho-disubstituted aromatic products that would otherwise be difficult to synthesize. Additionally, the method is used to synthesize medium-sized benzannulated carbocycles, such as the seven-membered ring structure in the isopavine alkaloids, by the ring-expansion of cyclic beta-ketoesters. Overall, the transformation results in the formation of two new C–C bonds by the net insertion of an aryne into the alpha,beta C-C sigma-bond of a beta-ketoester. This reaction has been applied in the total synthesis of amurensinine.

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