Catalytic Asymmetric Amine Synthesis using Ni/Photoredox Decarboxylations

项目摘要/摘要 胺的不对称合成在有机化学中具有重要意义。胺是很常见的 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)。用于不对称合成胺的一般催化方法是非常可取的， 特别是当他们使用广泛可用的起始材料时。这项拟议的研究旨在 利用双重催化剂从广泛存在的羧酸和醇中合成胺 镍/光氧化还原策略，并使用羟胺酯试剂作为胺源和氧化剂。光氧化还原 催化提供了在温和的反应条件下通过脱羧基获得有机自由基的途径，而镍 催化剂用作催化胺化试剂。目标1中的第一个反应寻求将羧酸 使用上述策略转化为手性胺。第二个反应的目标是从酒精到胺 利用草酰氯生成烷基草酸盐的转化过程，这些烷基草酸盐经过脱羧基反应后提供 光催化条件下的有机自由基。这种转换将对传统方法进行补充 醇转胺(如Sn2、还原胺化、Mitsunobu反应)，但将显示出优势 提高了选择性和范围，减少了化学计量废物，同时从根本上讲 实现对映体选择性的机制。最后一点特别吸引人，因为 醇的起始原料可以通过立体聚合体转化为对映体富集胺 前手性自由基与手性镍催化剂的反应。目标2试图将反应条件推广到 用胺偶联伙伴和外源氧化剂取代预先生成的羟胺酯。这 改装将允许所有试剂从商业供应商那里购买，这应该会加快 将这种方法结合到有机合成中。随着利用商业试剂的改编，它 希望拟议的研究将影响药物合成，包括药物化学的努力 其中偶联伙伴的商业可用性应该能够使药物库迅速多样化，以及 过程化学的应用，其中能够购买大量廉价的商业 试剂将有助于在大规模应用中采用。

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.