Innovation in Catalyst and Oxidative Amination Reaction Development for the Synthesis of Darobactin and Other Ribosomally Synthesized Post-translationally Modified Peptides (RiPPs)

用于合成 Darobactin 和其他核糖体合成的翻译后修饰肽 (RiPP) 的催化剂和氧化胺化反应开发的创新

• 批准号: 10469565
• 负责人: Simon B. Blakey
• 金额: $ 30.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469565
• 关键词: Acetates; Address; Alkenes; Amides; Amination; Amino Acids; Antibiotics; Binding; Bioinformatics; Biological; Catalysis; Chemicals; Chemistry; Code; Collaborations; Complex; Coupling; Development; Drug Targeting; Enzymes; Exhibits; Family; Gene Cluster; Generations; Hydrogen Bonding; Investigation; Membrane Proteins; Metals; Natural Products; Palladium; Parents; Peptides; Pharmacologic Substance; Reaction; Research; Rhodium; Ribosomes; Structure; System; Transition Elements; amidation; catalyst; crosslink; design; drug discovery; frontier; innovation; novel; pathogen; quorum sensing; tool

Project Summary In this proposal we have outlined a plan to develop a new family of planar chiral indenyl Co, Rh, and Ir catalysts that will be broadly applicable in the development of new oxidative amination reactions. This represents a significant innovation in catalysis. Catalyst development is presented in the context of allylic C-H functionalizations, which represent a contemporary frontier of group IX metal catalysis, in which C-H functionalization relies on the innate reactivity of the C-H bond, and does not require a Lewis basic directing group. Our preliminary results support the hypothesis that the rhodium catalysts described in this proposal will enable a significantly expanded pool of viable nucleophiles and alkene substrates when compared to prior state-of-the-art palladium catalyzed allylic C-H functionalization. Mechanistic studies demonstrate that the parent RhCp* platform provides products via a common allylic acetate intermediate, obtained via oxidatively induced reductive elimination. These mechanistic investigations provide hypothesis driven 2nd generation catalyst and reaction designs to control regio- and enantioselectivity. Preliminary results demonstrate that the new catalyst platform is broadly applicable for enantioselective catalysis beyond allylic C-H functionalization reactions. The full development of these reactions represents a particularly significant advance in the synthesis of non-canonical amino acids, peptides, and amide containing natural products and pharmaceuticals. The new reactions and catalysts are developed for the synthesis of emerging ribosomally synthesized posttranslationally modified peptide (RiPP) natural products, discovered through bioinformatic analysis, and presenting novel structural motifs. In the long term, the realization of the chemistry described in this proposal will provide powerful new tools for drug discovery chemists to invent new pharmaceuticals.

项目摘要 在该提案中，我们概述了开发平面手性吲哚钴，Rh， 和Ir催化剂，在开发新的氧化胺方面将有广泛的应用 反应。这代表着催化领域的一项重大创新。介绍了催化剂的发展概况 在代表集团当代前沿的烯丙基C-H官能化的背景下 金属催化，其中C-H官能化依赖于C-H键的固有反应性， 并且不需要Lewis Basic导演组。我们的初步结果支持这一假设 这项提案中描述的Rh催化剂将使显著扩大的 活性亲核试剂和烯烃底物与现有最先进的钯相比 催化的烯丙基C-H官能化。机制研究表明，亲本RHCP* 平台通过普通的烯丙基乙酸酯中间体提供产品，通过氧化获得 诱导还原消除。这些机械性的研究提供了假设驱动的第二个 生成催化剂和反应设计，以控制区域和对映体选择性。初步 结果表明，新型催化剂平台具有广泛的应用前景。 烯丙基C-H官能化反应以外的催化作用。这些反应的充分发展 代表了非正则氨基酸合成方面的一个特别重大的进步， 含有天然产物和药物的多肽和酰胺。新的反应和 开发了用于合成翻译后合成的新兴核糖体的催化剂 通过生物信息学分析发现的修饰多肽(RIPP)天然产物，以及 呈现出新颖的结构主题。从长远来看，实现 这一提议将为药物发现化学家发明新的 制药公司。