Date of Award

8-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Alexander Wei

Committee Chair

Alexander Wei

Committee Member 1

Hilkka I. Kenttamaa

Committee Member 2

Chengde Mao

Committee Member 3

Christopher Uyeda

Abstract

Heparan sulfate (HS) and closely related heparin are comprised of alternating units of D-glucosamine and either D-glucuronic acid (D-GluA) or L-iduronic acid (L-IdoA), and support variable degrees of sulfation which can interact with a large number of proteins with diverse biological functions. HS oligosaccharides can be constructed from readily accessible D-GlcN and D-GlcA derivatives, but the inclusion of L-IdoA is less straightforward. To address this, our laboratory has developed alternative synthetic strategies for HS-like oligosaccharides to incorporate either D-GlcA or L-IdoA in a synthetically efficient manner by nucleophilic ring opening of 4-epoxypyranosides, which can be made from readily available D-hexoses in few steps. These are derived from 4-deoxypentenosides (4-DPs), unsaturated pyranosides that can be linked with other sugars, enabling us to investigate synthetic strategies involving post-glycosylative modifications. Terminal 4-DPs have been generated at a late stage from β-1,4-linked disaccharides, and also by stereoselective coupling of 4-DP thioglycoside donors with various acceptors. The 4’-enol ether can be modified by stereoselective epoxidation and ring opening by a dithiocarbamate auxiliary, which can be activated by copper(I) salts for carbon nucleophile addition with terminal L-ido configuration. We also explored stereoselective glycosylation of a novel glucosamine donor with a N-diphenylphosphinamido group.

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