Glycomimetics are structural mimics of naturally occurring carbohydrates and represent important therapeutic leads in several disease treatments. However, the structural and stereochemical complexity inherent to glycomimetics often challenges medicinal chemistry efforts and is incompatible with diversity-oriented synthesis approaches. Here, we describe a one-pot proline-catalyzed aldehyde α-functionalization/aldol reaction that produces an array of stereochemically well-defined glycomimetic building blocks containing fluoro, chloro, bromo, trifluoromethylthio and azodicarboxylate functional groups. Using density functional theory calculations, we demonstrate both steric and electrostatic interactions play key diastereodiscriminating roles in the dynamic kinetic resolution. The utility of this simple process for generating large and diverse libraries of glycomimetics is demonstrated in the rapid production of iminosugars, nucleoside analogues, carbasugars and carbohydrates from common intermediates.

糖模拟物是天然存在的碳水化合物的结构模拟物，代表了几种疾病治疗中的重要治疗线索。然而，糖模拟物固有的结构和立体化学复杂性常常挑战药物化学的努力，并且与面向多样性的合成方法不相容。在这里，我们描述了一种一锅式脯氨酸催化的醛 α-官能化/羟醛反应，该反应产生一系列立体化学明确定义的拟糖结构单元，其中包含氟、氯、溴、三氟甲硫基和偶氮二羧酸酯官能团。使用密度泛函理论计算，我们证明了空间相互作用和静电相互作用在动态动力学分辨率中起着关键的非对映体区分作用。