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.

项目摘要/摘要 胺的不对称合成在有机化学中至关重要。胺很常见 药物分子中的基序和对生物活性分子的有用特性（例如，溶性， 氢键）。胺不对称合成的一般催化方法是高度可取的， 特别是当他们使用广泛可用的起始材料时。拟议的研究试图 通过使用双重催化，从广泛可用的羧酸和醇中合成胺 Ni/Photoredox策略，并使用羟胺酯试剂作为胺源和氧化剂。 Photoredox 催化在轻度反应条件下通过脱羧提供了有机自由基的访问，而Ni 催化剂用作催化摩擦试剂。 AIM 1中的第一个反应试图转换羧酸 使用上述策略进入手性胺。第二个反应将针对酒精到胺 通过使用氯乙烯来产生脱羧基化以提供烷基化的烷基烷基化的转化 有机自由基在光催化条件下。这种转变将补充经典方法 酒精到胺的转化（例如，SN2，还原胺化，Mitsunobu反应），但会表现出优势 选择性和范围的提高，化学计量浪费减少，以及根本不同的 将实现对映选择性的机制。最后一点特别吸引人，因为Achiral 酒精的起始材料可以通过立体ver剂转化为富含对映的胺 攻击性自由基与手性NI催化剂的反应。 AIM 2试图将反应条件推广到 用胺偶联伴侣和外源氧化剂代替预先产生的羟胺酯。这 修改将允许所有试剂从商业供应商那里购买，这应该加快 该方法纳入有机合成。通过使用商业试剂的改编 希望拟议的研究将影响药物合成，包括药物化学工作 其中耦合伙伴的商业可用性应实现快速的药物图书馆多元化，而 工艺化学应用，其中购买大量廉价商业的能力 试剂将有助于在大规模应用中采用。