Development and Application of Disiloxanes as a New Class of Hard Anion-Binding Organocatalysts

描述（由申请人提供）：含氧、氮和硫的立体中心普遍存在于天然产物和许多最常用的单对映体药物化合物中。因此，碳杂原子键形成的催化不对称方法的发展具有高选择性和效率，同时具有低毒性和对空气和湿度的敏感性，这对于从合成和药物发现到商业药物制造的有机化学健康相关领域非常重要。不对称阴离子结合有机催化剂具有许多这些特征，它们在O， N或基于阴离子结合方面的应用可以为新的不对称转化提供入口。不幸的是，目前的催化剂设计依赖于酸性氢键来进行阴离子结合，并且会与坚硬的碱性阴离子进行去质子化和分解。本提案概述了一类新的手性二硅氧烷催化剂的开发和应用，以寻求解决这一限制。与目前的催化剂不同，二硅氧烷能够在没有氢键的情况下结合阴离子，这将使它们大大扩展了目前阴离子结合催化剂的范围。

DESCRIPTION (provided by applicant): Oxygen, nitrogen and sulfur-containing stereocenters are prevalent in natural products and many of the most prescribed single-enantiomer pharmaceutical compounds. As a result, the development of catalytic asymmetric methodologies for carbon-heteroatom bond formations that show high selectivity and efficiency accompanied by low toxicity and sensitivity to air and moisture are important to health-related areas of organic chemistry ranging from synthesis and drug discovery to manufacturing of commercial drugs. Asymmetric anion-binding organocatalysts possess many of these characteristics, and their application towards O, N, or S-based anion- binding could provide entry into new asymmetric transformations. Unfortunately, current catalyst designs rely on acidic hydrogen-bonds for anion-binding, and will undergo deprotonation and decomposition with hard, basic anions. This proposal outlines the development and application of a new class of chiral disiloxane catalysts that seek to address this limitation. Unlike current catalysts, disiloxanes ar able to bind anions without hydrogen-bonds, which would allow them to greatly expand the scope of current anion-binding catalysts. As these molecules have never been used as catalysts, initial studies will seek to understand the steric and electronic factors of achiral disiloxanes necessary for anion-binding catalysis. These features will be considered in the design and synthesis of chiral disiloxane catalysts, which will seek to utilize silicon-centered chirality for high stereoinduction. Upon synthesis of these new catalysts, their application for reactions involving hard oxygen, nitrogen and sulfur anions will be considered. Their use in the asymmetric hetero-Michael addition to �-unsaturated carbonyl compounds and nitro-olefins will produce motifs prevalent in biologically active molecules such as polyacetate and polyketide natural products, �mino alcohols and thiols, and 1,2- diamines. Extension of the methodology to allow activity biomimetic of hydrolase enzymes will allow desymmetrizations and resolutions that can deliver �ertiary �mino acids and a host of other important structures. Together, the stability, facile synthesis, and wide potential application of these new disiloxane catalysts towards biologically active structures will allow them to find great use in the development and production of a wide range of therapeutic drugs that can improve human health.