Dissertation

Studies towards the identification of mycobacterial cell wall biosynthesis inhibitors and synthetic studies of buergerinin F, buergerinin G, and feigrisolide B

Han, Jeong-Seok

2003

Overview

This dissertation consists of four sections. The first section describes the synthesis of methyl 4a-carba-D-galactofuranosides. Oligosaccharides containing furanose moieties are important constituents of the cell wall of Mycobacterium tuberculosis, the intracellular causative bacterial pathogen of tuberculosis. A polysaccharide, arabinogalactan, attached to long chain lipids called mycolic acids, in combination with glycolipids found at the periphery of the cell wall envelope, provide a very efficient hydrophobic barrier that prevents the intrusion of drugs into the microorganism. Compounds that interfere with the biosynthesis of the arabinogalactan are therefore potential anti-tuberculosis agents. All arabinose and galactose residues of the arabinogalactan are found in the furanose form. Because furanose polysaccharides are critical for the survival of mycobacteria, the enzymes responsible for the biosynthesis of mycobacterial cell wall are very promising targets for drug action. A route for the synthesis of metabolically stable carbasugar analogs of galactofuranosides, was developed from D-galactose by using ring-closing metathesis as a key transformation. The second section, which is related to the first section in that it is focused on the identification of new anti-tuberculosis agents, details the synthesis of C-glycosidic glycopeptides. A series of C-arabinosyl glycopeptides was synthesized by solid-phase peptide synthesis. The Fmoc-protected arabinofuranoside building block was prepared from D-arabinose. The key transformations were Homer-Emmons olefination and catalytic asymmetric hydrogenation of resulting enamide ester. The synthesized dipeptides will be screened for their ability to inhibit arabinosyltransferases involved in mycobacterial cell wall assembly. The third section reports the synthesis of buergerinin F and buergerinin G, recently isolated from a plant Scrophularia buergeriana. The synthesis of buergerinin F and G was achieved from thymidine. We were able to establish the structures and absolute stereochemistry of these natural products. The final section addresses studies towards the synthesis of feigrisolide B, a seven-membered lactone isolated from fungi Streptomyces griseus . The synthetic study includes coupling reaction of two key intermediates and deoxygenation protocol developed in our group. Three more steps from the prepared intermediate would provide feigrisolide B.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biochemistry / Microbiology / Organic chemistry
• ISBN: 0496566695, 9780496566693