An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis

用于立体选择性自由基生物催化的可进化金属酶平台

• 批准号: 10792280
• 负责人: Yang Yang
• 金额: $ 17万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10792280
• 关键词: Aromatic Compounds; Biochemical; Biochemistry; Catalysis; Computer Models; Data; Development; Engineering; Enzymes; Funding; Laboratories; Mediating; Metalloproteins; Methods; Nature; Nitrogen; Organic Chemistry; Organometallic Chemistry; Outcome; Oxidation-Reduction; Process; Property; Reaction; Science; Technology; Therapeutic; clinically significant; interdisciplinary approach; metalloenzyme; novel; parent grant; programs; small molecule

Project Summary Despite substantial advancements in small-molecule catalysis, general methods to control the stereoselectivity in radical-mediated transformations remain a formidable challenge facing synthetic chemists. On the other hand, enzymes are known for their ability to exert exquisite control over the stereochemical outcome of the reactions they catalyze. However, the catalytic repertoire of enzymes has been largely limited to their native biochemistry. Using an interdisciplinary approach combining ideas and technologies from organic chemistry, organometallic chemistry, biocatalysis, enzyme engineering and computational modeling, we will reprogram naturally occurring metalloenzymes to catalyze unnatural radical reactions with excellent stereoselectivity. Capitalizing on the innate redox property of metallocofactor present in a plethora of natural metalloproteins, we will develop metalloredox radical biocatalytic reactions with significant synthetic utility. First, we will develop new-to-nature metalloredox atom transfer radical addition reactions that proceed with excellent diastereo- and enantiocontrol. Second, we will advance stereoselective radical additions to aromatic compounds in a metalloenzyme-controlled fashion. Furthermore, enantioselective C-H functionalization reactions involving enzymatically formed nitrogen-centered radicals will be developed. All the three aims are supported by strong preliminary data gathered in our laboratory. Together, these novel metalloredox biocatalytic processes constitute a powerful toolbox for the rapid assembly of diverse bioactive small molecules that are highly valuable in biomedical sciences. Furthermore, the development of new-to-nature catalytic functions will dramatically broaden the biochemical landscape of metalloenzymes.

项目摘要 尽管在小分子催化方面取得了实质性进展，但控制立体选择性的一般方法 自由基介导的转化仍然是合成化学家面临的巨大挑战。另一方面，在一项研究中， 酶以其对反应的立体化学结果施加精确控制的能力而闻名 他们催化。然而，酶的催化库在很大程度上限于它们的天然生物化学。 采用跨学科的方法，结合有机化学的思想和技术，有机金属 化学，生物催化，酶工程和计算建模，我们将重新编程自然发生 金属酶催化非天然自由基反应具有优异的立体选择性。利用先天的 金属辅因子的氧化还原性质存在于过多的天然金属蛋白质，我们将开发金属氧化还原 自由基生物催化反应，具有重要的合成效用。首先，我们将开发新的自然金属氧化还原 原子转移自由基加成反应，进行良好的非对映体和对映体控制。二是 将以金属酶控制的方式促进对芳族化合物的立体选择性自由基加成。 此外，涉及酶促形成的氮中心的对映选择性C-H官能化反应也可以用于制备手性化合物。 激进分子将会发展。所有这三个目标都得到了我们实验室收集的强有力的初步数据的支持。 总之，这些新的金属氧化还原生物催化过程构成了快速组装的强大工具箱 在生物医学科学中具有高度价值的各种生物活性小分子。而且 新的自然催化功能的发展将大大拓宽生物化学景观， 金属酶