Alpha-Tertiary Amines and Amino Acids via Rearrangement of Ureas

在过去的50年里，α -叔胺广泛存在于天然存在的和合成的生物活性分子中，为许多合成策略的发展提供了动力。它们构成了一个非常困难的合成挑战——尤其是当季碳中心必须以对映选择性的方式合成时。最方便的方法是在酮胺上加入1,2亲核试剂，但这些物质缺乏反应性，加上难以达到良好的立体选择性，促使人们探索构建四元中心的替代方法。另一种强大的替代方法是利用现有前体的重排，通常（但并不总是）形成新的叔碳氮键（例如Curtius或sigropic重排）。另一种有用的合成受阻胺的方法是由Clayden等人开发的锂化脲的重排。该项目的目的是调查这种以前未报道的重排的范围、局限性和适用性。该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。从乙烯脲开始，对映体选择性重排和进一步的转化将是氨基酸的新途径。第二部分将讨论重排的底物范围。新的底物（腈/酸取代脲）和新的非芳香族迁移基团将被研究。第三部分是文献未知的乙烯基脲的对映选择性加氢合成新的对映选择性重排化学原料。

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.