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

项目摘要： 高效、立体选择性制备含胺化合物新方法的研究进展 在有机合成中，化学构件是一个引人注目的目标，因为它具有大量的生物活性 化合物含有与立体碳结合的氨基。可能位于侧翼的化学功能 这些化合物中的胺含量很大，包括一些常见的基序，如氨基 醇和二胺；此外，含胺的立体中心可以是三取代或四取代。 尽管它们在具有重要生物学意义的靶标中出现的频率很高，但立体选择性合成1，3-二氢呋喃的方法 二胺、1，3-氨基醇和含氨基的四取代立体中心是稀疏的， 他们的生成模式往往是劳动密集型和/或迂回的。这些框架内的几个脚手架 都很少被生产出来。这项研究计划的长期目标是设计和开发新的 立体选择性C-C成键方法制备难于获得但备受追捧的手性 胺。我们的策略采用了亚胺(Umpolung)的极性反转：而不是充当N-取代 碳亲核试剂，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- 它可以与许多亲电伙伴立体选择性地结合以提供α-取代 手性胺。在这些研究中，我们将重点研究2-氮杂烯丙基阴离子的C-C键形成：1) 挑战1，3-二胺和氨基醇官能度的立体选择性合成，2)对映体选择性 含氮四取代立体生成中心的高烯丙基胺的制备，以及3) 硅基取代的2-氮杂烯丙基阴离子作为双α-烯丙基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的 解决手性胺制备中长期存在的挑战，从而实现流线型合成 几个具有重要生物学意义的复杂分子。将获得的新的化学空间可能 能够探索可能导致活性药物成分的新药物线索以改进 人类健康。

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.