Late-Stage Alpha-Alkylation of Cyclic Amines

1年级：一般技能培训和实验室轮转2-4年级：该项目的目的是通过胺氧化和随后的胺离子功能化，为环胺的后期-烷基化开发一个新的平台。在这一具有挑战性的转变中，有三个关键目标：优化选择性形成内铝离子的条件，开发相容条件以实现单一合成序列的烷基化，以及研究该过程在复杂分子应用中的范围和普遍性。Polonovski-Potier反应将被用作选择性形成内铝离子的基础。众所周知，使用m-CPBA可以很容易地合成所需的n -氧化物来氧化等效的脂肪胺。然而，C-H消除步骤的区域选择性基本上是未知的。因此，将对多种环胺选择性形成内-亚胺离子的反应条件进行广泛的优化研究，特别关注温度、溶剂和乙酰化剂对选择性的影响。与通过直接sp3 C-H氧化形成铝离子的传统策略相比，这些方法所表现出的优异的化学选择性和高官能团耐受性意味着该平台将满足先前概述的后期功能化标准。随后原位生成的铝离子的烷基化将受到Gaunt开发的CAA和Zn CAA协议的启发，为这种转化提供了一套条件。首先将开发与碳氢消除步骤相容的反应条件，以使烷基化在一锅过程中实现。将研究TMS-OTf当量、反应浓度和加成顺序的影响，因为这些在CAA优化研究中被证明是成功的。在此之后，底物范围将扩大，以探索该协议在更复杂的体系中的选择性，如2或3取代和桥接环胺。最后，将通过将该反应应用于广泛的常见药物片段，如诺斯卡平、黄硫酸盐、N-Boc三氯喹和N-Boc缬苯那嗪，来研究复杂分子烷基化过程的普遍性。

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.