Alpha-Tertiary Amines and Amino Acids via Rearrangement of Ureas

α-叔胺广泛存在于天然的和人工合成的生物活性分子中，为过去50年来许多合成策略的发展提供了动力。它们构成了一个令人惊讶的困难的合成挑战--特别是当必须以对映体选择性的方式合成季碳中心的时候。最方便的方法是将亲核试剂1，2加成到酮亚胺上，但这些物种缺乏反应性，再加上很难实现良好的立体选择性，因此鼓励人们探索构建第四元中心的替代方法。一种有效的替代方法利用容易获得的前体的重排，通常(但不总是)随着新的叔碳到氮键的形成(例如Curtius重排或Sigmatrotic重排)。另一种合成受阻胺的有用方法是由Clayden等人开发的锂化脲的重排反应。该项目的目的将是调查这一以前未报道的重新安排的范围、限制和适用性。本项目包括三个重要方面：第一部分是游离非天然氨基酸的合成。从乙烯基脲开始，对映选择性重排和进一步的转化将是获得氨基酸的新途径。第二部分将涉及重排的底物范围。将研究新的底物(腈/酸取代脲)以及新的非芳香族迁移基团。第三部分是未见文献报道的乙烯基脲对映体选择性氢化合成新的对映选择性重排反应的起始原料。

The wide occurrence of alpha-tertiary amines in naturally occurring and synthetic bioactive molecules has provided an impetus for the development of a number of synthetic strategies over the last 50 years. They pose a surprisingly difficult synthetic challenge - especially when the quaternary carbon centre has to be synthesised in an enantioselective way. The most convenient approach has been the 1,2 addition of nucleophiles to ketimines, but the lack of reactivity of these species coupled with difficulties of achieving good stereoselectivity has encouraged the exploration of alternative ways of constructing of the quaternary centre. A powerful alternative approach makes use of the rearrangement of readily available precursors, often (but not always) with formation of a new tertiary carbon to nitrogen bond (for example Curtius or sigmatropic rearrangement). Another useful method for synthesising hindered amines is the rearrangement of lithiated ureas that was developed by Clayden et al. The aim of the project will be to investigate the scope, limitations, and applicability of this previously unreported rearrangement. The project consists of three important aspects: Part I is the synthesis of free unnatural amino acids. Starting from vinylureas, enantioselective rearrangement and further transformations will be a new access to amino acids. Part II will deal with the scope of the substrates for the rearrangement. New substrates (nitrile/acid substituted ureas) will be investigated as well as the new non aromatic migrating groups. Part III is the literature unknown enantioselective hydrogenation of vinyl ureas to synthesise new starting material for the enantioselective rearrangement chemistry.