Alpha-Tertiary Amines and Amino Acids via Rearrangement of Ureas

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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.