Supplement to Synthesis of Diverse Natural Products and Complex Heterocycles with Donor/Donor Carbenoids

用供体/供体类胡萝卜素合成多种天然产物和复杂杂环的补充

• 批准号: 10158974
• 负责人: Jared Thomas Shaw
• 金额: $ 4.04万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158974
• 关键词: Acute Disease; Address; Alkanes; Antibiotics; Architecture; Area; Award; Biological Phenomena; Biology; Carbon; Chemicals; Chemistry; Chronic Disease; Complex; Dangerousness; Data; Development; Electrons; Estrogen receptor positive; Exhibits; Future; Generations; Goals; Health; Hydrazones; Hydrogen; In Situ; Journals; Lead; Legal patent; Life; Literature; Medicine; Metabolic; Metals; Methodology; Methods; Mission; Natural Products; Nitrogen; Organic Chemistry; Organic Synthesis; Oxygen; Parents; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Process; Public Health; Reaction; Research; Rhodium; Science; Societies; Structure; Sulfur; System; Technology; Testing; Tetrahydroisoquinolines; Time; Translating; United States National Institutes of Health; Work; base; carbene; catalyst; chemical reaction; cycloaddition; diazo compound; disability; drug discovery; experimental study; functional group; high throughput screening; indoline; innovation; interest; molecular assembly/self assembly; next generation; novel; novel therapeutics; oxidation; parent grant; pharmacophore; small molecule

Project Summary/Abstract (from parent award GM124234) An urgent need exists for new methods to rapidly prepare complex organic molecules with the potential to become new drugs. There is a widening gap in both the accessibility of complex core structures that are difficult to exploit and in the availability of core structures that are not already the subject of numerous patents. This gap will be addressed by identifying new synthetic methods that achieve the dual goals of enabling efficient access to useful cores while also exploring previously inaccessible "chemical space." The long-term goal is to understand the reactivity of unstabilized carbenes and their immediate precursors. The objective of this application is to explore rhodium-catalyzed C–H insertion reactions of carbenes that are generated without the isolation of diazo compounds while also exploring new tandem cycloaddition/rearrangement processes. The central hypothesis is that appending two "donor" groups to a carbene precursor will open up new avenues of reactivity for organic chemistry. This hypothesis is supported by preliminary results regarding a) the unique ability of donor/donor carbenes to engage in highly enantioselective C–H insertion reactions and b) a remarkable cycloaddition/ rearrangement sequence that produces drug-like heterocyclic core structures absent from the patent literature! Small molecules comprise the vast majority of treatments for both acute and chronic diseases in both the developed and developing world. Research in this application will lay the groundwork to save lives and enable the next generation of pharmaceutical discovery by advancing three Specific Aims. 1) Synthesis of oxygen and sulfur heterocycles by catalytic C–H insertion. This aim will explore asymmetric carbene reactions under conditions that avoid isolation of dangerous intermediates, exhibit unprecedented functional group tolerance, and lead to core structures common to both drug discovery leads and natural products that modulate biological phenomena. 2) Assembly of densely-substituted indolines, indanes and tetrahydro-isoquinolines (THIQs) by catalytic C–H insertion. The insertion technology will become a platform for discovery in the assembly of nitrogen- and carbon-based polycyclic systems representing useful starting points for drug discovery. 3) Rapid construction of complex heterocycles from new one-pot dipolar cycloaddition-[1,5] shift sequence. Our one-pot system for the generation and immediate reaction of diazo intermediates will be used to construct complex spiro- heterocycles in a single step, yielding unexplored molecules for pharmaceutical and biomedical applications. The proposed approach is innovative because it is based on a new methodological platform that accesses previously inaccessible chemical reactivity. This research is significant because it will change the way synthetic chemists approach targets while at the same time opening up new vistas for discovery of useful molecules for medicine and other fields. Ultimately, the discoveries emerging from our research will represent a vertical step in the assembly of molecular architectures that will translate into new medicines to address our society's most pressing health challenges.

项目摘要/摘要（来自家长奖GM124234）

项目成果

Divergent Asymmetric Synthesis of Panowamycins, TM-135, and Veramycin F Using C-H Insertion with Donor/Donor Carbenes.

• DOI: 10.1002/anie.202203072
• 发表时间: 2022-06-20
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Bergstrom, Benjamin D.;Merrill, Amy T.;Fettinger, James C.;Tantillo, Dean J.;Shaw, Jared T.
• 通讯作者: Shaw, Jared T.

Deconvoluting Nonlinear Catalyst-Substrate Effects in the Intramolecular Dirhodium-Catalyzed C-H Insertion of Donor/Donor Carbenes Using Data Science Tools.

• DOI: 10.1021/acscatal.3c04256
• 发表时间: 2024-01-05
• 期刊: ACS CATALYSIS
• 影响因子: 12.9
• 作者: Souza, Lucas W.;Miller, Beck R.;Cammarota, Ryan C.;Lo, Anna;Lopez, Ixchel;Shiue, Yuan-Shin;Bergstrom, Benjamin D.;Dishman, Sarah N.;Fettinger, James C.;Sigman, Matthew S.;Shaw, Jared T.
• 通讯作者: Shaw, Jared T.

Transition Metal Catalyzed Insertion Reactions with Donor/Donor Carbenes.

• DOI: 10.1002/anie.202007001
• 发表时间: 2021-03-22
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Bergstrom BD;Nickerson LA;Shaw JT;Souza LW
• 通讯作者: Souza LW

Enantioselective Synthesis of Indolines, Benzodihydrothiophenes, and Indanes by C-H Insertion of Donor/Donor Carbenes.

• DOI: 10.1002/anie.201809344
• 发表时间: 2018-11-12
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Souza LW;Squitieri RA;Dimirjian CA;Hodur BM;Nickerson LA;Penrod CN;Cordova J;Fettinger JC;Shaw JT
• 通讯作者: Shaw JT