Catalytic Asymmetric Amine Synthesis using Ni/Photoredox Decarboxylations

项目总结/摘要 胺的不对称合成在有机化学中具有重要意义。胺是常见的 药物分子中的基序并赋予生物活性分子有用的性质（例如，溶解性， 氢键合）。用于胺的不对称合成的一般催化方法是非常需要的， 特别是当它们使用广泛可用的起始材料时。拟议的研究旨在 通过使用双催化剂由广泛可得羧酸和醇合成胺， Ni/光氧化还原策略和使用羟胺酯试剂作为胺源和氧化剂。光氧化还原 催化剂在温和的反应条件下通过脱羧提供有机自由基，而Ni 催化剂作为催化胺化试剂。目的1中的第一反应寻求将羧酸转化为 转化为手性胺。第二个反应将以醇-胺为目标 通过使用草酰氯进行转化以产生烷基辛酸酯，烷基辛酸酯经历脱羧以提供 光催化条件下的有机自由基。这种转换将补充经典方法， 醇到胺的转化（例如，SN 2、还原胺化、Mitsunobu反应），但将表现出优点 增加选择性和范围，减少化学计量的浪费，沿着， 将实现对映体选择性的机制。最后一点特别吸引人，因为非手性 醇原料可以通过立体会聚作用转化为对映体富集的胺 前手性自由基与手性Ni催化剂的反应。目标2旨在将反应条件推广到 用胺偶联配偶体和外源氧化剂代替预先生成的羟胺酯。这 修改将允许从商业供应商购买所有试剂，这将加快 将该方法引入有机合成。通过使用商业试剂的调整， 希望拟议的研究将影响药物合成，包括药物化学工作 其中偶联配偶体的商业可用性应能够实现快速药物库多样化，并且 过程化学应用，其中能够购买大量廉价的商业 试剂将促进在大规模应用中的采用。

PROJECT SUMMARY/ABSTRACT The asymmetric synthesis of amines is of critical importance in organic chemistry. Amines are common motifs in pharmaceutical molecules and impart useful properties on bioactive molecules (e.g., solubility, hydrogen bonding). General catalytic methods for the asymmetric synthesis of amines are highly desirable, particularly when they make use of widely available starting materials. The proposed research seeks to synthesize amines from widely available carboxylic acids and alcohols by employing a dual catalytic Ni/photoredox strategy and using hydroxylamine ester reagents as amine sources and oxidants. Photoredox catalysis provides access to organic radicals via decarboxylation under mild reaction conditions, while the Ni catalyst serves as a catalytic aminating reagent. The first reaction in Aim 1 seeks to convert carboxylic acids into chiral amines using the strategy described above. A second reaction will target an alcohol-to-amine conversion by using oxalyl chloride to generate alkyl oxalates that undergo decarboxylation to furnish an organic radical under photocatalytic conditions. This transformation will complement classical methods for alcohol-to-amine conversion (e.g., SN2, reductive amination, Mitsunobu reactions), but will exhibit advantages of increased selectivity and scope, reduced stoichiometric waste, along with a fundamentally distinct mechanism whereby enantioselectivity will be achieved. The final point is especially appealing because achiral alcohol starting materials may be transformed into enantioenriched amines through the stereoconvergent reaction of a prochiral radical with a chiral Ni catalyst. Aim 2 seeks to generalize the reaction conditions to replace pre-generated hydroxylamine esters with amine coupling partners and exogenous oxidants. This modification will allow for all of the reagents to be purchased from commercial vendors, which should expedite the incorporation of the method into organic synthesis. With the adaptation that utilizes commercial reagents, it is hoped that the proposed research will impact pharmaceutical synthesis, including medicinal chemistry efforts wherein commercial availability of coupling partners should enable rapid drug library diversification, and process chemistry applications in which the ability to purchase large amounts of inexpensive commercial reagents will facilitate adoption in large-scale applications.