Late-Stage Alpha-Alkylation of Cyclic Amines

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Year 1: General skills training and lab rotationsYears 2-4: The aim of this project is to develop a novel platform for the late-stage alpha-alkylation of cyclic amines, via amine oxidation and subsequent iminium ion functionalisation. Within this challenging transformation there are three key objectives: optimisation of conditions for selective formation of the endo-iminium ion, development of compatible conditions to enable alkylation in a single synthetic sequence, and investigation into the scope and generality of this procedure in its application to complex molecules.The Polonovski-Potier reaction will be used as a basis for the selective formation of endo-iminium ions. It is well known that the required N-oxides can be easily synthesised using m-CPBA to oxidise the equivalent aliphatic amine. However, the regioselectivity of the C-H elimination step is essentially unknown. Therefore, extensive investigations into the optimization of reaction conditions for the selective formation of the endo-iminium ion in a wide array of cyclic amines will be undertaken, with a particular focus on the influence of temperature, solvent, and acetylating agent on selectivity. Compared to conventional strategies for iminium ion formation via direct sp3 C-H oxidation, the excellent chemoselectivity and high functional group tolerance exhibited by these methodologies means this platform will meet the criteria outlined previously for late-stage functionalisation.Subsequent alkylation of the in situ generated iminium ions will be inspired by the CAA and Zn CAA protocols developed by Gaunt, providing a suit of conditions for this transformation. Reaction conditions compatible with the C-H elimination step will first be developed to enable alkylation in a one-pot process. The influence of TMS-OTf equivalents, reaction concentration and order of addition will be investigated, as these proved successful during CAA optimization studies. After this, the substrate scope will be expanded to explore the selectivity of this protocol in more complicated systems, such as 2 or 3-substituted and bridged cyclic amines.Finally, the generality of this procedure for the alkylation of complex molecules will be investigated by applying this reaction to a broad range of common drug fragments, such as noscapine, flavoxate, N-Boc tritoqualine and N-Boc valbenazine.