Year of Publication

2006

Document Type

Dissertation

College

Arts and Sciences

Department

Chemistry

First Advisor

Robert B. Grossman

Abstract

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of compounds that reveal intriguing biological activities and interesting and challenging chemical structures. These products are claimed to possess antioxidant, antiviral, and antimitotic properties. Increasing interest is related to their function in the CNS as modulators of neurotransmitters associated to neuronal damaging and depression. All these features make PPAPs targets for synthesis. We decided to focus our own initial efforts in this area on the type A PPAP, nemorosone because we thought that its fairly simple structure relative to other PPAPs would present fewer hurdles as we developed our methodology.In the past decade many approaches to the synthesis of the bicyclo[3.3.1]nonane-2,4,9-trione structure of type A PPAPs have been reported, but only two total syntheses of any PPAP, garsubellin A by Shibasaki and Danishefsky, have been published recently, near the end of 2005. All approaches have relied on the ??,????-annulation of a three-carbon bridge onto a cyclohexanone, although the methods used to execute this annulation differ dramatically. The methods most often used to form the two new C–C bonds have involved classical carbonyl chemistry.We have developed a short and efficient synthetic approach to the bicyclo[3.3.1]nonane skeleton of the PPAPs that involves a novel three-carbon ??,????-annulation of a sterically hindered cyclic ??-keto ester with 3,3-diethoxypropyne. The alkynylation reaction permits the construction of the two contiguous quaternary centers of the PPAPs in reasonable yield and without complications from side reactions. We have also successfully applied a recently developed syn hydrosilylation to the very hindered product of this alkynylation reaction. Our methodology received positive feedback already, and we see this total synthesis of nemorone as an ideal platform for the implementation of new synthetic methodologies.

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