Title

An enantiospecific synthetic approach to the ansatrienin family of ansamycin antibiotics

Date of Award

1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

James Kallmerten

Keywords

Ansamycin, Antibiotics, Enantiospecific

Subject Categories

Organic Chemistry | Pharmacology

Abstract

Progress towards an enantiospecific synthetic route to the ansatrienin family of naturally-occurring ansamycin antibiotics is presented herein. Synthetic design was originally based on the Emmons-Horner coupling of C9-N and C1-C8 synthons of the target system. Construction of the C9-N intermediate was motivated by a novel strategy for intramolecular protection of the C13- hydroxyl group as part of a pyranosidic ring system with C17. The pyran ring system was efficiently generated through an asymmetric hetero-Diels Alder reaction, which additionally served to impart chirality to the system as well as dictate C14-C15 olefin geometry and set the stage for sigmatropic development of the C11-C13 contiguous stereocenters. Mukaiyama aldol technology was successfully employed as an alternative to the ester enolate Claisen rearrangement for generating relative stereochemistry at C11-C13. The C3 stereocenter was derived from R-(+)-malic acid, which was successfully employed to generate the C1-C8 intermediate. Failure to effect convergence via the originally intended Emmons-Horner protocol necessitated investigation of several alternative synthetic pathways to the target system. Linear extension of the C9-N intermediate via sequential Emmons-Horner olefinations to install the all- trans triene moiety, followed by an aldol condensation with ethyl acetate, served to complete the carbon skeleton, not accounting for C3-stereochemistry. Attempts to install the requisite stereochemistry at C3 via an asymmetric aldol were unsuccessful. Several synthetic approaches to the ansatrienin target system are described.

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