Catalytic Nucleophilic Glyoxylation: Asymmetric Derivatizations and Aldol/Oxidati

描述（由申请人提供）：a-酮酯在有机合成中起重要作用，是许多生物活性天然产物的普遍亚结构。a-酮酯结构的引入在合成上具有挑战性，而产生这种功能的直接方法是非常可取的。本提案旨在开发实用的新催化反应，提供合成的乙醛酸盐阴离子等价物，以允许将该亚结构直接结合到亲电试剂中。提议的化学将利用硅基乙醛酸盐，一种独特的多功能连接试剂在约翰逊实验室开发，作为一个方便的亲核乙醛酸盐供体在氰化物催化添加到醛。提出了一种新的催化不对称加成/氧化反应级联的发展与乙酰乙酸酯和对亲电试剂。这个反应可以方便地得到富集对映体的a-酮酯。

DESCRIPTION (provided by applicant): a-Ketoesters play an important role in organic synthesis and are prevalent substructures of many biologically active natural products. The introduction of the a-ketoester structure is synthetically challenging and direct methods for the generation of this functionality are highly desirable. This proposal aims to develop practical new catalytic reactions that provide the synthetic equivalents of glyoxylate anions to allow the direct incorporation of this substructure into electrophiles. The proposed chemistry will utilize silyl glyoxylates, a unique versatile conjunctive reagent developed in the Johnson laboratory, to serve as a convenient nucleophilic glyoxylate donor in cyanide catalyzed additions to aldehydes. The development of a novel catalytic asymmetric addition/oxidation reaction cascade with acetoacetates and p-electrophiles is also proposed. This reaction will allow expedient access to enantioenriched a-ketoesters. PUBLIC HEALTH RELEVANCE: The synthesis of enantiopure biologically-relevant small molecules is an important area in the health sciences, as these compounds are used to probe structure-activity relationships in biological processes and can potentially serve as new chemotherapeutic agents. It is desirable to prepare these compounds as efficiently as possible and this grant aims to develop asymmetric reactions to incorporate the a-ketoester moiety. Chiral a-ketoesters are of particular interest due to their importance as intermediates in natural product synthesis and their roles in metabolic and biosynthetic pathways.