Semester

Fall

Date of Graduation

2007

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

George A O'Doherty

Abstract

The carbohydrate portion of the natural products plays a crucial role in biology, such as target binding, solubility, tissue targeting, and membrane transportation. The O'Doherty group use a de novo methodology to build the desired functionality and stereochemistry within each sugar, in contrast to the traditional approach using known sugar isomers as starting materials. Recently, we have developed a practical and highly diastereoselective palladium catalyzed glycosylation reaction to control the stereochemistry at the anomeric center. Continuing, our investigations on the utility of this strategy, we turned our attention to the syntheses of the bioactive carbohydrate-based natural product analogues. The targets we chose are mannopeptimycin-E, novobiocin, methymycin, ribofuranose-adenosine and coumarin glycosides. All of which we felt were amenable to medicinal SAR studies.;Mannopeptimicins are cyclic hexapeptides glycosylated with a disaccharide side chain, which possesses potent antibacterial activity against gram-positive bacteria with good activity against drug resistant (MDR) bacteria. An enantioselective syntheses of the manno-disaccharide fragments of mannopeptimycin-E and its nine analogues were been achieved in 7-10 steps and 35-40% overall yield via an iterative palladium-glycosylation strategy. Key to the success of this approach was the ease with which the C-4 isovalerate group was introduced, and the high diastereoselectivity of the palladium-catalyzed glycosylation and bis-dihydroxylation reactions.;Recently novobiocin was shown to inhibit Hsp90 protein, which is a promising target for development of cancer chemotherapeutics. We developed a practical 7-10 steps diastereoselective route for the syntheses of nine different analogues of three aglycones all in good yields. This route relies on an alternative pyranol palladium-catalyzed glycosylation reaction, diastereoselective dihydroxylation, regioselective carbamate installation strategy. Currently, the nine-novobiocin analogues are being tested against different cancer cell lines in Prof. Blagg's labs.;Methymycin is a 12-membered macrolactone, an important class of antibiotics used to treat infections caused by Gram-positive bacteria. We have developed divergent and highly enantioselective route to eight various amino/azido/dideoxy methymycin analogues. The key to the success of this method is the iterative use of the palladium-catalyzed glycosylation reaction, Luche reduction and Myers' reductive rearrangement. Currently, a small library of methymycin analogues was under testing on glycosyltransferase assays in Prof. Hung-Wen Liu labs.

Download

Share

COinS