Selective C(sp3)-H Oxidations and Functionalizations with Tunable Metal Catalysts for Synthesis

使用可调金属催化剂进行选择性 C(sp3)-H 氧化和官能化合成

• 批准号: 9918921
• 负责人: Maria White
• 金额: $ 50.09万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918921
• 关键词: Alkylation; Amination; Biological; Carbon; Chemicals; Complex; Coupling; Development; Effectiveness; Foundations; Goals; Hydrocarbons; Hydrogen Bonding; Hydroxylation; Iron; Manganese; Mediating; Medicine; Metals; Methods; Molecular Structure; Natural Products; Nature; Nitrogen; Organic Synthesis; Oxides; Oxygen; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Reaction; Scientist; Site; Source; Structure; Sulfoxide; System; Therapeutic; Transition Elements; base; biological research; catalyst; drug candidate; drug discovery; functional group; metal complex; novel; oxidation; physical property; programs; scaffold; small molecule; tool

Project Summary The biological activity of organic molecules is strongly impacted by the oxygen, nitrogen and carbon functional groups on their hydrocarbon scaffolds. Classically, the practice of organic synthesis has focused on building these scaffolds while concurrently introducing this functionality. We hypothesized that, analogous to nature, a late stage oxidation strategy, i.e., direct introduction of oxidized functionality into C(sp3)-H bonds of molecule scaffolds, would provide opportunities to diversify molecular structures and streamline syntheses. Our preliminary studies using novel transition metal catalysts have validated late stage C-H oxidation as a powerful approach for streamlining synthetic sequences and directly diversifying natural products and other complex structures. Building on this strong foundation, we plan to discover new catalysts to expand the scope of C(sp3)-H functionalizations possible. These reactions will broaden the functionality that can be introduced, sites that can be accessed, and classes of natural products and medicinal compounds that can be derivatized and synthesized. The key to our approach is to develop transition metal catalysts that mediate C(sp3)-H bond cleavage and functionalization, enabling tunable control over reactivity, as well as site-, chemo-, and stereoselectivity. We have discovered and commercialized palladium/sulfoxide catalysts for allylic C-H functionalizations, iron catalysts for aliphatic C-H hydroxylations, and manganese catalysts for intramolecular C(sp3)-H aminations. These catalysts proceed with unprecedented levels of reactivity and tunable selectivities in complex molecule settings, without the need for directing groups. These reactions and the late stage derivatization approach have already begun to be utilized by pharmaceutical companies in drug discovery and metabolite identification. The major challenges in the application of this strategy as a comprehensive C(sp3)-H functionalization approach to enable drug discovery are the development of new intermolecular methods and the expanded capacity for site-, chemo-, and stereoselectivities. To overcome these challenges, we will develop 1) new palladium/sulfoxide complexes for catalyst-controlled asymmetric induction and complex fragment couplings; 2) new base metal complexes for aliphatic C-H hydroxylations that proceed with alternate catalyst-controlled, predictable site selectivities and increased tolerance of π-systems and nitrogen-containing compounds; and 3) new base metal complexes for intra- and intermolecular C-H amination and alkylations. Analogous to the impact of cross-coupling methods on C(sp2)-C(sp2) bond formation in drug discovery, these reactions will ultimately empower scientists to form C(sp3)-O, -N, and -C bonds from ubiquitous C(sp3)-H bonds in complex molecule scaffolds. This will reinvigorate efforts to explore natural products and other complex molecules as sources of medicines and biological research tools.

项目总结