Sulfated glucosamine libraries: Solution and solid -phase synthesis
Abstract
Orthogonally protected glucosamine derivatives were synthesized as building blocks for oligosaccharides related to heparan sulfate and 1,4-linked α-glucosamine sulfate. Heparin and heparan sulfate possess highly charged domains which are thought to be responsible for much of their biological activities, but the structure-function relationships for biologically active sequences is poorly defined. We propose to generate libraries of sulfated oligosaccharides by developing an orthogonal sulfation strategy based on a common intermediate. Each position can be selectively deprotected and sulfated in the presence of the remaining protecting groups, and subsequent deprotections can be performed in the presence of the sulfate esters. Optimized deprotections and sulfations were also performed with the orthogonally protected glucosamines loaded onto a solid support. The solid-phase approach improves the efficiency of the orthogonal sulfation strategy by simplifying the workup and purification of highly polar intermediates. The chemistry developed on resin-supported carbohydrate ligands may also be useful in the preparation of multivalent gold glyconanoparticles, to screen for high-affinity ligands for heparin-binding proteins or to inhibit cell-surface receptor dimerization. In the course of this synthetic work, a temperature-dependent reductive ring opening of p-methoxybenzylidene acetals was developed. The method proved to be general and highly regioselective, producing either the 4-O- or 6-O-PMB ethers in high yields using the same set of reagents. Reductive cleavage at 0°C resulted in the exclusive formation of 4-O-PMB ethers, whereas reaction at -78°C produced 6-O-PMB ethers. The latter condition was observed to be compatible with a variety of acid-sensitive functional groups.
Degree
Ph.D.
Advisors
Wei, Purdue University.
Subject Area
Organic chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.