A Reverse Polarity Stereoselective C-C Bond-Forming Strategy for Preparing Chiral Amines

制备手性胺的反极性立体选择性 C-C 键形成策略

• 批准号: 9975183
• 负责人: Steven Joseph Malcolmson
• 金额: $ 28.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975183
• 关键词: Amines; Amino Alcohols; Anions; Aziridines; Biological; Carbon; Chemicals; Complex; Coupling; Development; Diamines; Epoxy Compounds; Frequencies; Generations; Goals; Health; Human; Hybrids; Imines; Investigation; Lead; Medicine; Methods; Natural Products; Nature; Organic Chemistry; Organic Synthesis; Outcome; Pharmacologic Substance; Preparation; Production; Reaction; Reagent; Research; Site; Technology; Time; Work; amino group; chemical function; cost effective; design; improved; innovation; interest; novel; novel strategies; programs; scaffold

Project Abstract: The development of new methods for the efficient and stereoselective preparation of amine-containing chemical building blocks is a compelling objective in organic synthesis as a large number of biologically active compounds contain an amino group bound to a stereogenic carbon. The chemical functionality that may flank the amine in these compounds is vast, including a number of commonly-encountered motifs, such as amino alcohols and diamines; additionally, the amine-bearing stereogenic center may be tri- or tetrasubstituted. Despite their frequency in targets of biological importance, methods for the stereoselective synthesis of 1,3- diamines, 1,3-amino alcohols, and amino-containing tetrasubstituted stereogenic centers are sparse, with the mode of their generation often labor intensive and/or circuitous. Several scaffolds within these frameworks have only rarely been produced. The long-term goal of this research program is to design and develop novel stereoselective C–C bond-forming methods for preparing difficult-to-access but highly sought-after chiral amines. Our strategy employs a polarity reversal of an imine (umpolung): rather than act as an N-substituted carbon electrophile, we transform the reagent to an N-substituted carbon nucleophile—a 2-azaallyl anion— that may be combined stereoselectively with a number of electrophilic partners to furnish alpha-substituted chiral amines. In these investigations, we will focus on C–C bond formations with 2-azaallyl anions for: 1) the stereoselective synthesis of challenging 1,3-diamine and amino alcohol functionality, 2) the enantioselective preparation of homoallylic amines with N-containing tetrasubstituted stereogenic centers, and 3) stereoselective three component coupling reactions with a silyl-substituted 2-azaallyl anion as a double alpha- amino anion equivalent. The new methods developed under the aegis of this project provide innovative solutions to long-standing challenges in the preparation of chiral amines that will permit streamlined synthesis of several biologically important complex molecules. The new chemical space that will be garnered might enable exploration of novel medicinal leads that may lead to active pharmaceutical ingredients to improve human health.

项目摘要： 开发有效和立体选择胺的新方法的开发 化学构建块是有机合成的引人注目的目标，作为大量生物活性 化合物包含与立体碳结合的氨基群。可能侧面的化学功能 这些化合物中的胺很大，包括许多常见的图案，例如氨基 酒精和二胺；另外，含胺的立体源性中心可以是三或四位化的。 尽管它们在生物学重要性的靶标中发生频率，但立体选择性合成的方法为1,3-- 二氨基，1,3-氨基醇和含有氨基的四硫酸四含量的立体源性中心很少 他们这一代的模式通常是劳动密集型和/或circuit之以鼻。这些框架中的几个脚手架 很少生产。该研究计划的长期目标是设计和开发新颖 立体选择性C – C键形成方法，用于制备难以入门但备受追捧的手性 胺。我们的策略员工的极性逆转亚胺（Umpolung）：而不是充当N-取代的 碳电力，我们将试剂转换为N均取代的碳核凤凰（2-氮杂阴离子） 可以将其与许多亲电伴侣立体选择，以提供α-取代 手性胺。在这些调查中，我们将专注于2-氮杂阴离子的C-C键形成：1） 挑战的立体选择性合成1,3-二胺和氨基醇功能，2）对映选择性 用含有N的四碱立体源性中心的均方根胺制备，3） 立体选择性的三个成分耦合反应与甲硅烷基取代的2-氮杂阴离子作为双α- 氨基阴离子等效。根据该项目的宙斯盾开发的新方法提供了创新的 在制备手性胺的长期挑战的解决方案，这些胺将允许流线型合成 在几种具有生物学重要的复杂分子中。将获得的新化学空间可能 实现对新型医疗潜在客户的探索，这可能导致活性药物成分以改善 人类健康。