Date of Award

5-18-2007

Degree Type

Dissertation

Degree Name

Ph.D.

Degree Program

Chemistry

Department

Chemistry

Major Professor

Jursic, Branko

Second Advisor

Harmjanz, Michael

Third Advisor

Trudell, Mark

Abstract

Invasive fungal infections are prevalent and often deadly in immunocompromised patients. There continues to be a pressing need for the development of novel antifungal compounds since there are currently only 13 compounds licensed for the treatment of invasive fungal infections and antibiotic-resistant strains have been emerging. CAY-1 is an antifungal steroidal saponin which was isolated from the fruit of the cayenne pepper plant in 0.1% yield. In Vitro studies of CAY-1 have shown it to be an effective antifungal agent against sixteen pathogenic fungal strains and it showed no cytotoxicity toward mammalian cells up to 100 ìg/mL. The development of a practical synthesis of CAY-1 will potentially allow for further exploration of its medicinal utility and provide the opportunity to synthesize derivatives of CAY-1 which could be investigated in structure-activity relationship studies. To this end, methods for the preparation of they CAY-1 aglycone and pentasaccharide moieties have been investigated. Through this work, several partially protected stereoisomers of the CAY-1 aglycone have been prepared which can be used for the synthesis of saponin derivatives of CAY-1 for structure-activity relationship studies. Definitive characterization of one of these isomers, 3á-hydroxy-(22S, 25R)-5á-spirostan-2â-yl acetate, was achieved by X-ray crystallography. Furthermore, a quantitative inversion of the C-3 stereochemical configuration of this compound was achieved via an acetate group migration of the corresponding mesylate. The possibility of competition between the acetate migration and substitution mechanisms with various nucleophiles was explored. The results, however, indicate that this inversion only occurs via the acetate migration. Additionally, the CAY-1 pentasaccharide synthesis poses two significant challenges. First, these results demonstrate that the central 2, 3-branched portion can be synthesized efficiently from a partially protected glucopyranosyl acceptor since the C-2 and C-3 alcohols differ in their reactivity in glycosylation reactions. The second challenge is the ƒÀ-(1¨4) linkage to the galactosyl acceptor which significantly increases the complexity of the synthesis as compared to literature reported syntheses of other branched oligosaccharides. Nonetheless, this ƒÀ-(1¨4) linkage was achieved using a disarmed trichloroacetimidate glucosyl donor.

Rights

The University of New Orleans and its agents retain the non-exclusive license to archive and make accessible this dissertation or thesis in whole or in part in all forms of media, now or hereafter known. The author retains all other ownership rights to the copyright of the thesis or dissertation.

Share

COinS