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

项目摘要 动态动力学拆分合成手性α，α-二取代胺 概述：这个项目的目标是合成手性α，α-二取代胺的新范例。这将是 通过实现烯丙基叠氮化物的动态动力学拆分来实现。这种方法利用了 烯丙基叠氮化合物的先天性质和烯丙基叠氮化合物重排。所提出的途径具有重要意义 独一无二的是，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 α，α--被取代的中心。 该提案不同阶段涉及在初步成果的基础上扩大到广泛的目标 系统。提供了三种不同的方法来区分非对称的烯丙基体系，包括 使用：i)共轭，ii)邻近效应，以及iii)立体。这些方法中的每一个都能够提供 合成有用的胺或胺替代品。许多最常见的杂环，包括那些 存在于一系列BACE-1抑制剂中，可以通过这些方法中的一种获得。 与公众健康相关：大多数药剂都含有胺或胺的衍生物。在许多情况下， 胺结合的碳是一个立体中心。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 想要的手性。然而，对于高取代度的胺来说，情况并非如此。健壮而通用的方法有 缺乏。BACE-1抑制剂是一个具有说明性的家族。在过去的几年里，数十种BACE-1抑制剂已经 被10家主要制药公司披露。这一切都包含着这样的主题。在所有情况下，建立这一点 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和 使其可用于药物化学和化学生物学。

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.