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.

项目概要 动态动力学拆分合成手性 α,α-二取代胺 概述：该计划的目标是合成手性 α,α-二取代胺的新范例。 该方法利用了烯丙基叠氮化物的动态动力学拆分来实现。 烯丙基叠氮化物的固有特性和烯丙基叠氮化物重排是重要且重要的。 其独特之处在于它可以在不直接形成 C-C 或 C-N 键的情况下建立这些胺的手性。 相反，这种方法为产品带来了额外的功能，同时建立了手性 α,α-二取代中心。 该提案的各个阶段涉及将初步结果扩展到广泛的目标 提供了三种不同的方法来区分非对称烯丙基系统，包括 使用：i) 共轭，ii) 邻近效应，以及 iii) 空间位阻。 许多最常见的杂环，包括那些合成上有用的胺或胺替代物。 存在于一系列 BACE-1 抑制剂中的 BACE-1 抑制剂可以通过其中一种方法获得。 与公共卫生的相关性：大多数药剂在许多情况下都含有胺或胺衍生物。 与胺结合的碳是立体中心，该中心的构型对于该中心至关重要。 对于简单的胺，可以通过许多有效的方法来控制药理预期效果。 然而，对于高度取代的胺，情况并非如此。 BACE-1 抑制剂是一个典型的家族，在过去的几年里，已有数十种 BACE-1 抑制剂。 超过 10 家主要制药公司都披露了这一主题。 立体中心是有问题的。支持该计划将简化这些手性胺和的合成。 使它们可用于药物化学和化学生物学的应用。