Abstract
AbstractGlycomimetics 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.
Funder
Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada
Publisher
Springer Science and Business Media LLC
Subject
Materials Chemistry,Biochemistry,Environmental Chemistry,General Chemistry
Reference61 articles.
1. Overend, W. G. Detection of carbohydrate structures on isolated subcellular organelles of rat liver by heterophile agglutinins. Nature 242, 71–71 (1973).
2. Ernst, B. & Magnani, J. L. From carbohydrate leads to glycomimetic drugs. Nat. Rev. Drug Discov. 8, 661–677 (2009).
3. Rojo, J., Sousa-Herves, A. & Mascaraque, A. in Comprehensive Medicinal Chemistry III (eds Chackalamannil, S., Rotella, D. & Ward, S. E.) 577–610 (Elsevier, 2017).
4. Zhang, Y. & Wang, F. Carbohydrate drugs: current status and development prospect. Drug Discov. Ther. 9, 79–87 (2015).
5. Magnani, J. L. & Ernst, B. Glycomimetic drugs-a new source of therapeutic opportunities. Discov. Med. 8, 247–252 (2009).
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