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.

首席调查员/项目总监(最后、第一、中间)：董，Vy，M 项目摘要/摘要 酰胺键的结构是一种广泛使用的化学转化，涉及许多不同的学科 化学，是制药业中最常使用的断开装置之一。因此， 改进和扩大酰胺键形成的综合效用的努力对多学科来说仍然是不可或缺的 学术和工业领域内的反应发展和药物发现运动。的耦合性 空间受阻氨基酸，例如具有治疗价值的α，α-二取代α-氨基酸及其衍生物 其中，代表了一个不发达但有希望形成酰胺键的领域，可以改进。 尽管有构建困难的酰胺键的方法可用，但从化学计量比或 超化学计量试剂的使用以及可能产生的有害反应副产物 传统方法要求制定更可持续的议定书。谢和他之前的工作 同事们已经证明，在光氧化还原条件下，酰基自由基肽前体可以通过 然而，P(V)/P(III)循环仅限于硝基芳烃和硝基烷烃偶联对。因此，我们的目标是 通过使用UPolung来扩大催化获得空间受阻的酰胺键的范围 一种利用磷催化剂生成亲核酰基氨基酸配对形成受阻的方法 仲胺和叔胺与易于接近的亲电羟胺酯键合。如果成功， 这种方法可以更方便地处理可能被扩展的空间受阻多肽 朝向更具挑战性的酰胺结构基序。