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: 10259785
• 负责人: Simon B. Blakey
• 金额: $ 30.5万
• 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/10259785
• 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; peptide structure; 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 在此提案中，我们概述了制定一个新的平面性手性indenenyl Co的计划。 和IR催化剂将广泛用于开发新的氧化胺化 反应。这代表了催化中的重大创新。提出了催化剂的开发 在烯丙基C-H功能化的背景下，它代表了当代的群体前沿 IX金属催化，其中C-H功能化依赖于C-H键的先天反应性， 并且不需要刘易斯基本指导小组。我们的初步结果支持假设 该提案中描述的铑催化剂将使能够显着扩大 与先前的最新钯相比 催化的烯丙基C-H功能化。机械研究表明，父rhcp* 平台通过氧化性获得的普通烯丙基乙酸中间体提供产品 诱导的还原消除。这些机械研究提供了假设驱动的第二个 生成催化剂和反应设计，以控制区域和对映选择性。初步的 结果表明，新的催化剂平台广泛适用于对映选择性 超出烯丙基C-H功能化反应的催化。这些反应的全面发展 在合成非规范氨基酸的合成方面是一个特别重要的进步， 肽和含有天然产物和药物的酰胺。新反应和 开发催化剂是为了合成新兴的核糖体合成后翻译后的合成 通过生物信息学分析发现的修饰肽（RIPP）天然产品， 提出新颖的结构图案。从长远来看，化学中描述的化学的实现 该建议将为药物发现化学家提供强大的新工具，以发明新的 药品。