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: 10688236
• 负责人: Simon B. Blakey
• 金额: $ 30.19万
• 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/10688236
• 关键词: Acetates; Address; Alkenes; Amides; Amination; Amino Acids; Antibiotics; Binding; Bioinformatics; Biological; Catalysis; Chemicals; Chemistry; Code; Collaborations; Complex; Coupling; Development; Electronics; 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; invention; novel; pathogen; peptide natural products; 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.

项目概要 在此提案中，我们概述了开发新的平面手性茚基 Co、Rh、 和Ir催化剂将广泛应用于新型氧化胺化的开发 反应。这代表了催化领域的重大创新。介绍了催化剂的开发 在烯丙基 C-H 官能化的背景下，代表了基团的当代前沿 IX 金属催化，其中 C-H 官能化依赖于 C-H 键的固有反应性， 并且不需要路易斯碱性指导基团。我们的初步结果支持假设 该提案中描述的铑催化剂将能够显着扩大 与现有最先进的钯相比，具有可行的亲核试剂和烯烃底物 催化烯丙基C-H官能化。机制研究表明母体 RhCp* 平台通过常见的乙酸烯丙酯中间体提供产品，该中间体通过氧化获得 诱导还原消除。这些机制研究提供了第二个假设驱动的 生成催化剂和反应设计以控制区域选择性和对映选择性。初步的 结果表明，新的催化剂平台广泛适用于对映选择性 超越烯丙基C-H官能化反应的催化作用。这些反应的充分发展 代表了非规范氨基酸合成方面的一个特别重大的进步， 肽和含有酰胺的天然产物和药物。新的反应和 开发催化剂用于合成新兴核糖体合成翻译后 通过生物信息分析发现的修饰肽（RiPP）天然产物，以及 呈现新颖的结构主题。从长远来看，实现中描述的化学反应 该提案将为药物发现化学家提供强大的新工具，以发明新的药物 药品。

项目成果

Enantioselective Aziridination of Unactivated Terminal Alkenes Using a Planar Chiral Rh(III) Indenyl Catalyst.

使用平面手性 Rh(III) 茚基催化剂对未活化末端烯烃进行对映选择性氮丙啶化。

• 发表时间: 2024-01-17
• 影响因子: 15
• 作者: Gross, Patrick;Im, Hoyoung;Laws 3rd, David;Park, Bohyun;Baik, Mu;Blakey, Simon B
• 通讯作者: Blakey, Simon B

Synthesis, stereochemical assignment, and enantioselective catalytic activity of late transition metal planar chiral complexes.

后过渡金属平面手性配合物的合成、立体化学分配和对映选择性催化活性。

• DOI: 10.1039/d3cs00325f
• 发表时间: 2023-08-09
• 期刊: Chemical Society reviews
• 影响因子: 46.2
• 作者: DAVID A. Laws;Christopher D. Poff;Ethan M Heyboer;S. Blakey
• 通讯作者: S. Blakey

Synthesis of Ribosomally Synthesized and Post-Translationally Modified Peptides Containing C-C Cross-Links.

含有 C-C 交联的核糖体合成和翻译后修饰肽的合成。

• DOI: 10.1021/acs.jnatprod.2c00508
• 发表时间: 2022-10-28
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Laws III, David;Plouch, Eleda V.;Blakey, Simon B.
• 通讯作者: Blakey, Simon B.