Glycal assembly by in situ generation of glycosyl dithiocarbamates and a diversity-oriented approach towards the synthesis of heparin and heparan sulfate oligosaccharides

Panuwat Padungros, Purdue University

Abstract

Glycal assembly was introduced nearly twenty years ago as an alternative strategy for the synthesis of linear and branched carbohydrates, but its adoption has been limited by practical issues of coupling efficiency and yield. This barrier can be lifted by the in situ formation of glycosyl dithiocarbamate (DTC) intermediates in a one-pot coupling of glycal-derived donors and acceptors. α-Epoxyglycals (generated by stereoselective epoxidation) are treated with a mixture of diethylamine and CS 2 to produce β-glycosyl DTCs in quantitative yields, then activated with Cu(I) or Cu(II) triflate at low temperatures for direct coupling with glycal acceptors. The glycosyl coupling is highly β-selective and proceeds in good yields with unencumbered acceptors, despite the presence of a C2 hydroxyl on the donor. The glycosyl DTC intermediates can be further armed by in situ 2-O-benzoylation without resorting to chromatography, to enable the glycosylation of larger or sterically demanding acceptors in high overall yields. The efficiency of the modified glycal assembly method is illustrated with the expedient construction of a branched hexasaccharide comprised of β-1,2- and β-1,3-linkages, performed in 11 synthetic steps and just four chromatographic purifications. Heparan sulfate (HS) and closely related heparin are sulfated polysaccharides belonging to the glycosaminoglycan family. These are the most acidic biopolymer in nature, and can interact with a large number of proteins with diverse biological functions. HS and heparin are comprised of alternating units of D-glucosamine and either D-glucuronic (D-GluA) acid or L-iduronic acid (L-IdoA), and support variable degrees of sulfation. Heparin is already widely used as an antithrombotic agent, and specific sequences within HS or heparin are considered to have potential for treatment of atherosclerosis, inflammation, viral infections, and Alzheimer's disease, but in the most cases the precise molecular structure are unknown. With respect to synthesis, the variable sulfation patterns within HS can be addressed by an orthogonal deprotection/sulfation strategy. HS oligosaccharides can be constructed from readily accessible D-GlcN and D-Glc-A derivatives, but the inclusion of L-IdoA is more difficult. Most methods for preparing L-IdoA are lengthy and laborious, and IdoA has poor reactivity as a glycosyl donor, resulting in low coupling yields. This has encouraged us to develop alternative synthetic strategies for HS-like oligosaccharide that incorporate either D-GlcA or L-IdoA in a synthetically efficient manner. Recently, our laboratory has reported the novel synthetic method for preparing L-hexopyranosides by nucleophilic ring opening of 4-epoxypyranosides, which can be made from readily available D-hexoses in few steps. We use this method to develop a diversity-oriented approach towards the construction of Heparin and Heparan Sulfate Oligosaccharides. A terminal 4-deoxypentenoside can be generated at a late state from β-1,4-linked disaccharides, and can be converted into a terminal D-GlcA unit by stereoselective epoxidation followed by SN 2 ring opening reaction, or a terminal L-IdoA unit by syn addition

Degree

Ph.D.

Advisors

Wei, Purdue University.

Subject Area

Chemistry|Biochemistry

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