Development of a photoinduced, copper-catalyzed, enantioconvergent synthesis of unnatural amino acids

开发光诱导、铜催化、对映异构体合成非天然氨基酸

• 批准号: 9889808
• 负责人: Suzanne Marie Batiste
• 金额: $ 6.49万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889808
• 关键词: Acids; Address; Amines; Amino Acids; Carbon Dioxide; Complex; Copper; Coupling; Decarboxylation; Development; Diabetes Mellitus; Esters; Malignant Neoplasms; Mediating; Metals; Methodology; Methods; Oxidants; Pharmaceutical Chemistry; Pharmacologic Substance; Photochemistry; Phthalimides; Planet Earth; Preparation; Reaction; Research; Scheme; Source; Variant; catalyst; innovation; irradiation; novel therapeutics; therapeutic development; unnatural amino acids; wasting

ABSTRACT β,β-Disubstituted-α-amino acids and α-aminoboronic acids are two classes of unnatural α-amino acids that are present in pharmaceuticals used to treat conditions ranging from diabetes to cancer. There is considerable room for improvement on existing methods for the preparation of these two classes of unnatural amino acids, as they are largely dependent on diastereoselective synthesis with a stoichiometric amount of a chiral auxiliary. This proposal outlines a research plan to develop a new asymmetric, photoinduced, copper-catalyzed methodology to synthesize β,β-disubstituted-α-amino acids and α-aminoboronic acids from racemic of α-malonyl and α-boryl NHP esters, respectively. Here, the chiral copper catalyst in combination with blue-LED irradiation will mediate the decarboxylation of NHP esters and their subsequent enantioselective Csp3-N cross-coupling with phthalimide, efficiently used as the source of protected amine. The proposed reaction will not generate any stoichiometric waste, other than CO2, in the reaction itself, and will not require an exogenous precious metal photocatalyst to initiate the reaction. The utility of this method will be explored through the synthesis of an array of hindered unnatural α-amino acids and alkyl substituted α-aminoboronic acids, including new variants that have never been synthesized before.

摘要 β，β-二取代-α-氨基酸和α-氨基硼酸是两类非天然的α-氨基酸 存在于用于治疗从糖尿病到癌症的各种疾病的药物中。有相当大的空间 改进现有的制备这两类非天然氨基酸的方法，因为它们 在很大程度上依赖于化学计量的手性助剂的非对映选择性合成。这 提案概述了一项研究计划，以开发一种新的不对称、光诱导、铜催化的方法 由β，β-丙二酰基和α-硼基外消旋合成α-二取代α-氨基酸和α-氨基硼酸 分别为NHP酯类。在这里，手性铜催化剂与蓝光LED照射相结合将起到中介作用 NHP酯的脱羧基及其随后的对映选择性CSP3-N与邻苯二甲酰亚胺的交叉偶联， 有效地用作受保护的胺的来源。提议的反应不会产生任何化学计量比 反应本身会产生二氧化碳以外的废物，而且不需要外源贵金属光催化剂来 启动反应。这种方法的实用性将通过合成一组受阻的 非天然α-氨基酸和烷基取代α-氨基硼酸，包括从未出现过的新变体 之前合成的。