Catalytic Asymmetric Amine Synthesis using Ni/Photoredox Decarboxylations

使用 Ni/光氧化还原脱羧催化不对称胺合成

• 批准号: 9925798
• 负责人: Scott D McCann
• 金额: $ 0.92万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-11 至 2020-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925798
• 关键词: Acids; Adoption; Alcohols; Amides; Amination; Amines; Amino Acids; Benzoic Acids; Biological; Biological Assay; Carboxylic Acids; Catalysis; Chemicals; Chemistry; Chlorides; Complement; Complex; Coupling; Decarboxylation; Disease; Esters; Exhibits; Human; Hydrogen Bonding; Hydroxylamine; Isopropanol; Libraries; Ligands; Methods; Modification; Optics; Organic Chemistry; Organic Synthesis; Oxalates; Oxalic Acids; Oxidants; Oxides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Prevention; Process; Property; Pyrrolidines; Quality of life; Reaction; Reagent; Research; Solubility; Solvents; Source; Stereoisomer; Structure; Testing; Vendor; base; catalyst; drug market; drug structure; functional group; piperidine; trait; wasting

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.

项目概要/摘要 胺的不对称合成在有机化学中至关重要。胺类很常见 药物分子中的基序并赋予生物活性分子有用的特性（例如溶解度、 氢键）。非常需要用于胺不对称合成的通用催化方法， 特别是当他们使用广泛可用的原材料时。拟议的研究旨在 通过使用双催化从广泛使用的羧酸和醇合成胺 Ni/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 催化作用可以在温和的反应条件下通过脱羧作用获得有机自由基，而 Ni 催化剂用作催化胺化试剂。目标 1 中的第一个反应旨在转化羧酸 使用上述策略转化为手性胺。第二个反应将针对醇到胺 通过使用草酰氯进行转化生成草酸烷基酯，该草酸烷基酯进行脱羧以提供 光催化条件下的有机自由基。这种转变将补充经典方法 醇到胺的转化（例如 SN2、还原胺化、Mitsunobu 反应），但会表现出优势 增加选择性和范围，减少化学计量浪费，以及根本上不同的 实现对映选择性的机制。最后一点特别有吸引力，因为非手性 醇原料可以通过立体会聚转化为对映体富集的胺 前手性自由基与手性镍催化剂的反应。目标 2 试图将反应条件概括为 用胺偶联剂和外源氧化剂取代预先生成的羟胺酯。这 修改后将允许从商业供应商购买所有试剂，这应该会加快 将该方法纳入有机合成中。通过使用商业试剂的改造， 希望拟议的研究能够影响药物合成，包括药物化学工作 其中偶联伙伴的商业可用性应能够实现药物库的快速多样化，并且 过程化学应用，其中能够购买大量廉价的商业产品 试剂将促进大规模应用的采用。