Innovative Tools for Chemical Synthesis: Cyclase-inspired Catalysis, Shuttle Catalysis , and Tandem Catalysis

化学合成的创新工具：环化酶催化、穿梭催化和串联催化

• 批准号: 10649303
• 负责人: Vy M Dong
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649303
• 关键词: Address; Amides; Amination; Amines; Amino Acids; Area; Attention; Biochemical; Carbon; Carboxylic Acids; Catalysis; Chemicals; Chemistry; Complex; Conscious; Coupling; Development; Discipline; Drug Industry; Esters; Face; Generations; Goals; Hydroxylamine; Industrialization; Lead; Metabolic; Methodology; Methods; Molecular Structure; Natural Products; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorus; Process; Property; Protocols documentation; Reaction; Reagent; Reducing Agents; Research; Research Personnel; Side; Therapeutic; Transition Elements; Work; Yang; amidation; base; catalyst; chemical synthesis; design; drug discovery; improved; innovation; insight; interest; multidisciplinary; nitroalkane; novel; programs; racemization; small molecule; tool; unnatural amino acids; wasting

Principle Investigator/Program Director (Last, first, middle): Dong, Vy, M Project Summary/Abstract The construction of amide bonds is a widely used chemical transformation across many disparate disciplines of chemistry and is one of the most frequently employed disconnections in the pharmaceutical industry. As such, efforts to improve and expand the synthetic utility of amide bond formation remain integral for multidisciplinary reaction development and drug discovery campaigns within academic and industrial sectors. The coupling of sterically hindered amino acids, such as therapeutically valuable α,α-disubstituted α-amino acids and derivatives thereof, represents an underdeveloped yet promising area for amide bond formation that can be improved. Although methods to construct difficult amide bonds are available, waste generated from either stoichiometric or super-stoichiometric reagent use as well as possible deleterious reaction byproducts produced using conventional approaches imposes the need to develop more sustainable protocols. Previous work from Xie and coworkers have shown that acyl radical peptide precursors can be generated under photoredox conditions via a P(V)/P(III) cycle, however is limited to nitroarene and nitroalkane coupling partners. Therefore, our goal is to broaden the scope of accessing sterically hindered amide bonds catalytically by employing an umpolung approach using a phosphorus catalyst to generate nucleophilic acyl radical amino acid partners to form hindered secondary and tertiary amide bonds with readily accessible, electrophilic hydroxylamine esters. If successful, this methodology could enable a more facile approach towards sterically hindered peptides that may be extended towards additional challenging amide structural motifs.

项目负责人/项目负责人（后、前、中）：Dong、Vy、M 项目概要/摘要 酰胺键的构建是跨许多不同学科广泛使用的化学转化 化学，是制药行业最常用的断线之一。像这样， 改善和扩大酰胺键形成的合成效用的努力仍然是多学科的组成部分 学术和工业领域的反应开发和药物发现活动。的耦合 位阻氨基酸，例如有治疗价值的α,α-二取代的α-氨基酸和衍生物 其中，代表了酰胺键形成的一个尚未开发但有前途的领域，可以改进。 尽管构建困难的酰胺键的方法是可用的，但化学计量或化学计量产生的废物 超化学计量试剂的使用以及可能产生的有害反应副产物 传统方法需要制定更可持续的协议。谢和之前的作品 同事们已经证明，酰基自由基肽前体可以在光氧化还原条件下通过 然而，P(V)/P(III) 循环仅限于硝基芳烃和硝基烷烃偶联伙伴。因此，我们的目标是 通过使用umpolung扩大催化访问空间位阻酰胺键的范围 使用磷催化剂生成亲核酰基氨基酸伴侣以形成位阻的方法 仲酰胺和叔酰胺与易于接近的亲电羟胺酯键合。如果成功的话， 这种方法可以为可延伸的空间位阻肽提供更简便的方法 面向其他具有挑战性的酰胺结构基序。