Chiral α,α-Disubstituted Amine Synthesis by Dynamic Kinetic Resolution

动态动力学分辨率合成手性α,α-二取代胺

• 批准号: 9381121
• 负责人: Joseph John Topczewski
• 金额: $ 35.94万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9381121
• 关键词: Amination; Amines; Azides; Biology; Carbidopa; Carbon; Chemicals; FDA approved; Family; Ketamine; Kinetics; Methods; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Property; Public Health; Resolution; Series; System; base; beta-site APP cleaving enzyme 1; inhibitor/antagonist; programs

Project Summary Chiral α,α-Disubstituted Amine Synthesis by Dynamic Kinetic Resolution Overview: This program targets a new paradigm in the synthesis of chiral α,α-disubstituted amines. This will be accomplished by enabling a dynamic kinetic resolution of allylic azides. This approach takes advantage of the innate properties of allylic azides and the allylic azide rearrangement. The proposed pathway is significant and unique because it would establish the chirality of these amines without directly forming a C-C or C-N bond. Instead, this approach brings additional functionality to the product while simultaneously establishing the chiral α,α-disubstituted center. The various phases of this proposal concern expanding upon preliminary results to a wide array of target systems. Three different approaches are provided to differentiate non-symmetric allylic systems and include using: i) conjugation, ii) proximity effects, and iii) sterics. Each of these approaches is capable of providing synthetically useful amines or amine surrogates. Many of the most common heterocycles, including those present in a series of BACE-1 inhibitors, are conceivably available by one of these approaches. Relevance to Public Health: Most pharmaceutical agents contain an amine or amine derivative. In many cases, the carbon to which the amine is bound is a stereocenter. The configuration of this center is essential to controlling the intended pharmacological effect. For simple amines, many efficient methods can establish the desired chirality. However, for highly substituted amines, this is not the case. Robust and general methods are lacking. BACE-1 inhibitors are an illustrative family. In the last several years, dozens of BACE-1 inhibitors have been disclosed from >10 major pharmaceutical companies. All contain this motif. In all cases, establishing this stereocenter was problematic. Supporting this program would simplify the syntheses of these chiral amines and make them available for applications in medicinal chemistry and chemical biology.

项目摘要 动态动力学拆分法合成手性α，α-二取代胺 概述：该计划的目标是手性α，α-二取代胺合成的新范例。这将是 这是通过使烯丙基叠氮化物能够动态动力学拆分来实现的。这种方法利用了 烯丙基叠氮化物的固有性质和烯丙基叠氮化物重排。拟议的途径意义重大， 这是独特的，因为它将建立这些胺的手性而不直接形成C-C或C-N键。 相反，这种方法为产品带来了额外的功能，同时建立了手性结构。 α，α-双取代中心。 这项建议的各个阶段涉及将初步成果扩大到一系列广泛的目标， 系统.提供了三种不同的方法来区分非对称烯丙型系统，包括 使用：i）共轭，ii）邻近效应，和iii）立体。这些方法中的每一种都能够提供 合成有用的胺或胺替代物。许多最常见的杂环，包括那些 存在于一系列BACE-1抑制剂中，可通过这些方法之一获得。 与公共卫生的相关性：大多数药剂含有胺或胺衍生物。在许多情况下， 与胺结合的碳是立构中心。该中心的配置对于 控制预期的药理作用。对于简单的胺，许多有效的方法可以建立 所需的手性。然而，对于高度取代的胺，情况并非如此。稳健和通用的方法是 缺乏BACE-1抑制剂是一个示例性家族。在过去的几年里，数十种BACE-1抑制剂已经 已被10家大型制药公司披露。都包含这个主题。在所有情况下，确定这一点 立体中心是有问题的。支持这一计划将简化这些手性胺的合成， 使其可用于药物化学和化学生物学。