Tandem Organocatalytic α-Chlorination−Aldol Reactions: A Powerful Tool for Carbohydrate and Iminosugars Synthesis

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Dynamic Kinetic Resolution
De novo Synthesis of Carbohydrates
OGA Inhibition
Alzheimer’s Disease

Carbohydrates play a vital role in regulating biological events that range from cell recognition to pathogen/host adhesion. Not surprisingly, inhibitors of carbohydrate binding and cleaving processes, such as iminosugars, have been identified as leads in various therapeutic areas and several glycomimetic drugs have been approved for use in humans. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration within modern high-throughput screening technologies. Progress in glycomimetic research is often closely tied to advances in the de novo synthesis of unnatural carbohydrates, with much success being realized through the use of organocatalytic reactions. Our continued interest in the use of α-chloroaldehydes as building blocks for natural product synthesis led us to probe their organocatalytic aldol reactions with 2,2-dimethyl-1,3-dioxan-5-one. These efforts resulted in the discovery of a one-pot α-chlorination—aldol reaction that involves the dynamic kinetic resolution of an in situ generated α-chloroaldehyde. This process provides direct access to novel, enantiomerically-enriched building blocks (β-ketochlorohydrins) that are well-suited for the synthesis of carbohydrates and C-glycoconjugates. In this thesis, a unique synthetic strategy to convert a wide range of acetaldehyde derivatives into imino-C-nucleoside analogues in two or three straightforward transformations is described. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this a promising process for diversity-oriented synthesis and should enable drug discovery efforts. Finally, the synthesis of configurationally divergent iminocyclitols is presented. This study led to the identification of potent, selective and brain penetrant OGA inhibitors as lead candidates for the treatment of Alzheimer’s disease.

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Robert A. Britton
Thesis type: 
(Thesis) Ph.D.