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

基本信息

批准号：
10650814
负责人：
Yang Yang
金额：
$ 36.59万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
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

项目摘要

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 metalloenzymatically 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.

项目概要尽管小分子催化取得了实质性进展，但控制立体选择性的通用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，酶以其对反应的立体化学结果进行精确控制的能力而闻名它们起到催化作用。然而，酶的催化能力很大程度上局限于其天然的生物化学。采用跨学科方法，结合有机化学、有机金属的思想和技术化学、生物催化、酶工程和计算模型，我们将重新编程自然发生的金属酶以优异的立体选择性催化非自然自由基反应。充分利用与生俱来的优势存在于大量天然金属蛋白中的金属辅因子的氧化还原特性，我们将开发金属氧化还原具有重要合成用途的自由基生物催化反应。首先，我们将开发新型金属氧化还原剂原子转移自由基加成反应以优异的非对映体和对映体控制进行。第二，我们将以金属酶控制的方式推进芳香族化合物的立体选择性自由基加成。此外，涉及金属酶促形成的氮-的对映选择性C-H官能化反应中心部首将得到发展。所有这三个目标都得到了我们收集的强有力的初步数据的支持。实验室。这些新颖的金属氧化还原生物催化过程共同构成了快速反应的强大工具箱。多种生物活性小分子的组装，这些小分子在生物医学科学中具有很高的价值。此外，新型催化功能的开发将极大地拓宽生物化学领域金属酶。