Late-Stage Alpha-Alkylation of Cyclic Amines

环胺的后期α-烷基化

• 批准号: 2638405
• 金额: --
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2638405
• 关键词: Late; Stage; Alpha; Alkylation; Cyclic

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.

第一年：一般技能培训和实验室轮换第2-4年：该项目的目的是开发一个新的平台，用于环胺的后期α-烷基化，通过胺氧化和随后的亚胺离子官能化。在这一具有挑战性的转变有三个关键目标：优化的条件选择性形成的endo-iminium离子，开发兼容的条件，使烷基化在一个单一的合成序列，并调查的范围和一般性，这一程序在其应用复杂的molecules.The Polonovski-Potier反应将被用作基础的endo-iminium离子的选择性形成。众所周知，所需的N-氧化物可以容易地使用m-CPBA氧化等效的脂肪胺来合成。然而，C-H消除步骤的区域选择性基本上是未知的。因此，将进行广泛的调查，以优化反应条件的选择性形成的endo-iminium离子在广泛的环状胺，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氧化形成亚胺鎓离子的常规策略相比，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官能化的标准。为这种转变提供了一套条件。首先将开发与C-H消除步骤相容的反应条件，以使烷基化能够在一锅法中进行。将研究TMS-OTf当量、反应浓度和添加顺序的影响，因为这些在CAA优化研究期间被证明是成功的。在此之后，底物范围将扩大，以探索在更复杂的系统，如2或3-取代和桥接的环amines.Finally，该程序的一般性复杂分子的烷基化将通过将该反应应用于广泛的常见药物片段，如诺斯卡品，flavoxate，N-Boc tritoqualine和N-Boc valbenazine进行研究。