Department of Pharmaceutical and Biomedical Sciences, University of Georgia, 250 West Green Street, Athens, Georgia 30602, United States.
Department of Chemistry, University of Georgia, 140 Cedar Street, Athens, Georgia 30602, United States.
J Am Chem Soc. 2021 Jan 13;143(1):17-34. doi: 10.1021/jacs.0c11106. Epub 2020 Dec 22.
Carbohydrate chemistry is an essential component of the glycosciences and is fundamental to their progress. This Perspective takes the position that carbohydrate chemistry, or glycochemistry, has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author's and other laboratories. The first of these potential inflexion points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the experimental evidence supports bimolecular S2-like mechanisms for typical glycosylation reactions over unimolecular ones involving stereoselective attack on naked glycosyl oxocarbenium ions. Similarly, it is argued that the experimental evidence does not support long-range stereodirecting participation of remote esters through bridged bicyclic dioxacarbenium ions in organic solution in the presence of typical counterions. Rational design and improvement of glycosylation reactions must take into account the roles of the counterion and of concentration. A second crossroads is that between mainstream organic chemistry and glycan synthesis. The case is made that the only real difference between glycan and organic synthesis is the formation of C-O rather than C-C bonds, with diastereocontrol, strategy, tactics, and elegance being of critical importance in both areas: mainstream organic chemists should feel comfortable taking this fork in the road, just as carbohydrate chemists should traveling in the opposite direction. A third crossroads is that between carbohydrate chemistry and medicinal chemistry, where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the past decade or so, but creativity, input, and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.
碳水化合物化学是糖科学的重要组成部分，也是其发展的基础。本文认为，碳水化合物化学或糖化学在向糖科学转变的道路上已经到达了三个十字路口，并通过作者和其他实验室的例子来说明这一点。这些潜在转折点中的第一个涉及糖苷化反应的机制和保护基团的作用。本文认为，实验证据支持典型糖苷化反应的双分子 S2 样机制，而不是涉及立体选择性攻击裸露糖基氧碳正离子的单分子机制。同样，本文认为，实验证据也不支持在典型抗衡离子存在下，通过桥联双环二氧碳正离子远程酯通过远程立体定向参与有机溶液中的糖苷化反应。糖苷化反应的合理设计和改进必须考虑抗衡离子和浓度的作用。第二个十字路口是主流有机化学和聚糖合成之间的关系。本文提出，聚糖合成和有机合成之间唯一真正的区别是形成 C-O 而不是 C-C 键，非对映选择性控制、策略、战术和优雅在这两个领域都至关重要：主流有机化学家应该感到舒适地在这条路上做出选择，就像碳水化合物化学家应该朝着相反的方向前进一样。第三个十字路口是碳水化合物化学和药物化学之间的关系，在这两个领域中，都有很多机会进行双向交流。在过去的十年左右，糖科学取得了巨大的进展，但需要来自各个领域的科学家的创造力、投入和创造力来应对仍然存在的许多复杂挑战，其中最重要的是开发更广泛和更通用的立体特异性糖苷化反应。
