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theses

This dissertation describes the total synthesis toward griseolic acid B and the direct glycosylation of nucleosides and peptides. The first part of this thesis focuses on the total synthesis of the nucleoside griseolic acid B and its derivatives. The griseolic acids were of particular interest since they contain the highly unusual and strained 1,5-dioxabicyclo[3.3.0]oct-3-ene acting as a mimetic of the ribose phosphate in cyclic nucleotides. Using griseolic acids as templates, more selective and therefore therapeutically useful agents potentially can be identified for the treatment of cardiovascular problems, sexual dysfunction and inflammation. However, the existing reported synthetic strategy to griseolic acid using cis-sulfoxide elimination makes it is almost impossible to synthesize large amounts of material for biologic studies. Thus, a more flexible and efficient access to griseolic acids and their analogues is desired. Our proposed retrosynthetic analysis of griseolic acid B makes use of conjugate addition reaction and a late-stage Vorbrüggen glycosylation. The challenges and successes of this synthesis are described in detail. More specifically, the route to 1,5-dioxabicyclo[3.3.0]oct-3-ene core integrates a stereoselective Michael addition reaction and the nucleobase is introduced by a facile and highly diastereoselective late-stage N-glycosylation. Unfortunately, the proposed last step, elimination of sulfonate confronts a disastrous roadblock. An alternative strategy is proposed for future work, which includes a palladium reduction of triflate to generate 1,5-dioxabicyclo[3.3.0]oct-3-ene core. In chapter III, we describe mild and general experimental conditions for the efficient O-glycosylation of nucleoside ribofuranose hydroxyls despite competition from more Lewis basic sites on the purine or pyrimidine nucleobase. Indium(III) triflate serves both to activate the glycosyl donor, either a thioglycoside or glycosyl trichloroacetimidate, and to promote the isomerization of ancillary donor, heterocycle-glycosylated, intermediates to the desired nucleoside disaccharide. The isolation and characterization of (O-4)- and (N-3)-2″,3″,4″,6″-tetra-acetyl-D-glucopyranosyl derivatives of uridine 2′,3′,5′-triacetate provides evidence for the susceptibility of these sites to unintended or temporary glycosylation. In chapter IV, we further demonstrate the efficient and elegant synthesis of N, O-glycopeptides by direct N, O-glycosylation of asparagine or serine/threonine containing peptides with glycosyl thio-glucoside utilizing a catalytic amount of copper triflate benzene complex in dichloroethane. The coupling method allows for the synthesis of the various N, O-glycopeptides from the primary amide or alcohol derivatives, which are effective biochemical probes for elucidation of the role of glycoproteins. Chapter V includes the experimental procedures for the preparation of all compounds, backed up by full analytical characterization. In addition, 1H- and 13C-NMR spectra are given.

ETD_7276

Ph.D.

Includes bibliographical references

by Yonglian Zhang

doi:10.7282/T3W09854

ETD doctoral

The author owns the copyright to this work.