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

二硅氧烷作为新型硬阴离子结合有机催化剂的开发与应用

• 批准号: 9014424
• 负责人: Michael Joseph Ardolino
• 金额: $ 3.54万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014424
• 关键词: Acids; Address; Air; Alcohols; Alkenes; Amino Acids; Amino Alcohols; Anions; Area; Binding; Biomimetics; Carbon; Catalysis; Characteristics; Development; Diamines; Disease; Drug Design; Electronics; Enzymes; Glycols; Goals; Health; Human; Hydrogen Bonding; Hydrolase; Malignant Neoplasms; Medicine; Methodology; Methods; Modeling; Natural Products; Nitrogen; Organic Chemistry; Oxygen; Pharmaceutical Preparations; Pharmacologic Substance; Process; Production; Reaction; Research Project Grants; Resolution; Silicon; Siloxanes; Staging; Structure; Sulfhydryl Compounds; Sulfur; Therapeutic; Toxic effect; base; carbonyl compound; catalyst; deprotonation; design; drug discovery; drug production; enantiomer; fighting; improved; prevent; scaffold; small molecule

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.

描述（由申请人提供）：含氧、氮和硫的立构中心普遍存在于天然产物和许多最常用的单一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表明。高选择性和效率以及低毒性和对空气和水分的敏感性对于有机化学的健康相关领域（从合成和药物发现到商业药物的制造）非常重要。阴离子结合有机催化剂具有许多这些特性，并且它们在基于 O、N 或 S 的阴离子结合方面的应用可以提供新的不对称转化的途径，不幸的是，当前的催化剂设计依赖于酸性氢键进行阴离子结合，并且该提案概述了新型手性二硅氧烷催化剂的开发和应用，旨在解决与现有催化剂二硅氧烷不同的问题。它们能够在没有氢键的情况下结合阴离子，这将使它们能够极大地扩展当前阴离子结合催化剂的范围。 由于这些分子从未被用作催化剂，初步研究将寻求了解阴离子结合催化所需的非手性二硅氧烷的空间和电子因素，这些特征将在手性二硅氧烷催化剂的设计和合成中得到考虑，这将寻求利用硅中心手性进行高立体诱导，在合成这些新型催化剂时，将考虑它们在涉及硬氧、氮和硫阴离子的反应中的应用。 β-不饱和羰基化合物和硝基烯烃的杂迈克尔加成将产生生物活性分子中普遍存在的基序，例如聚乙酸酯和聚酮化合物天然产物、氨基醇和硫醇以及1,2-二胺，从而扩展该方法以允许活性。水解酶的仿生将允许去对称化和解析，从而提供叔氨基酸和许多其他重要结构。这些新型二硅氧烷催化剂的稳定性、合成简便性和对生物活性结构的广泛潜在应用将 使它们能够在开发和生产各种可以改善人类健康的治疗药物中发挥巨大作用。