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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

基本信息

批准号：
10217180
负责人：
Steven Joseph Malcolmson
金额：
$ 28.47万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2023-07-31
项目状态：
已结题

项目摘要

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：高效、立体选择性制备含胺化合物新方法的开发化学结构单元是有机合成中一个引人注目的目标，因为大量的生物活性化合物含有与立体碳结合的氨基。可能侧翼的化学功能这些化合物中的胺含量很大，包括许多常见的基序，例如氨基醇和二胺；另外，带有胺的立体中心可以是三取代或四取代的。尽管它们经常出现在具有生物学重要性的靶标中，但立体选择性合成 1,3- 的方法二胺、1,3-氨基醇和含氨基的四取代立体中心很少，他们的生产方式通常是劳动密集型和/或迂回的。这些框架内的几个脚手架只很少生产。该研究计划的长期目标是设计和开发新颖的立体选择性 C-C 键形成方法，用于制备难以获得但备受追捧的手性化合物胺类。我们的策略采用亚胺的极性反转（umpolung）：而不是充当 N-取代碳亲电试剂，我们将试剂转化为 N-取代的碳亲核试剂——2-氮杂烯丙基阴离子—— 可以与许多亲电伙伴立体选择性地组合以提供α-取代手性胺。在这些研究中，我们将重点关注 2-氮杂烯丙基阴离子的 C-C 键形成：1) 具有挑战性的 1,3-二胺和氨基醇官能团的立体选择性合成，2) 对映选择性具有含氮四取代立体中心的高烯丙基胺的制备，以及3) 与甲硅烷基取代的 2-氮杂烯丙基阴离子作为双 α- 的立体选择性三组分偶联反应氨基阴离子当量。在该项目的支持下开发的新方法提供了创新解决手性胺制备中长期存在的挑战，从而简化合成几个生物学上重要的复杂分子。将获得的新化学空间可能能够探索可能导致活性药物成分改善的新药物线索人类健康。