Adventures in Carbohydrate Chemistry: New Synthetic Technologies, Chemical Synthesis, Molecular Design, and Chemical Biology

Abstract

The field of carbohydrate chemistry has occupied the minds and hearts of many scientists for over a hundred years and, as we enter the twenty-first century, it continues to be both vigorous and challenging. Among the most exciting aspects of organic chemistry in the last few decades has been the interplay between the specialized subdisciplines of carbohydrate chemistry and total synthesis, each enabling and advancing the other in new directions and towards greater heights. In this review article we highlight our own adventures at the interface of these disciplines, which were driven for the most part by objectives in chemical synthesis and chemical biology. Specifically, we describe our interests and efforts to utilize carbohydrates as starting materials for total synthesis, to invent and develop new synthetic technologies for carbohydrate synthesis, to construct complex oligosaccharides in solution or on solid support, and to utilize carbohydrate templates as scaffolds for peptide mimetics and for molecular diversity construction. Finally, applications of the developed synthetic strategies and enabling technologies towards the solution of biologically significant problems are discussed.

Utilization of bench-stable and readily available nickel(II) triflate for access to 1,2-cis-2-aminoglycosides

“…These results are comparable to what was accomplished with use of the Ni(4-F-PhCN) 4 OTf 2 catalyst. 6b,c Next, we examined the efficacy of Ni(OTf) 2 to mediate stereoselective formation of GlcNα(1→4)GlcA disaccharides 16 and 17 (entries 4 and 5), which are an important subunit of the anticoagulant heparin oligosaccharides 2a and could not be prepared in high yield and α-selectivity with use of in-housed prepared Ni(4-F-PhCN) 4 (OTf) 2 . Accordingly, coupling of armed glucuronic acid acceptor 11 and disarmed acceptor 12 with glucosamine donor 5 to provide α-exclusive disaccharides 16 and 17 , respectively, in moderate to good yield.…”

“…Thus, the scalability of its production is of utmost importance. 2d,20 Safety could become a major issue during the scale-up process with C(2)-azido donors. Synthesis of these donors requires the use of the TfN 3 and when not handled properly can be highly explosive.…”

“…2 It is well known that preparation of 1,2- trans -glycosides can be conveniently accessed in high selectivity through anchimeric assistance by a neighboring C(2)-ester protecting group. 3 Unfortunately, no such facile technique exists for general formation of its 1,2- cis counterpart.…”

“…Amongst these methodologies, the two major categories utilize the non-assisting C(2)-azido or C(2,3)-oxazolidinone donors which rely on the substrate’s structural features and protecting groups to invoke a higher ratio of 1,2- cis -2-amino selectivity. 2a,d,g,5 …”

Regenerative Glycosylation under Nucleophilic Catalysis

“…The concept has some similarities with the two-step activation by Nicolaou 38-40 and Danishefsky 41-44 and preactivation strategy by Huang-Ye, 45-48 but differs in the catalytic conversion and continuous regeneration of the glycosyl donor. In the previous methods, the entire precursor (thioglycoside or glycal) is first converted into reactive intermediates (Br, F, OTf/NTf 2 or epoxide) and then acceptor is added.…”