An Evolvable Metalloenzyme Platform for Stereoselective Radical Biocatalysis

项目摘要 尽管在小分子催化方面取得了实质性的进展，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一个巨大挑战。另一方面， 众所周知，酶能够精确地控制反应的立体化学结果。 它们会催化。然而，酶的催化反应在很大程度上局限于它们本身的生物化学。 采用跨学科的方法，结合有机化学、有机金属、 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 金属酶催化非自然自由基反应，具有良好的立体选择性。利用先天的优势 金属辅因子的氧化还原特性存在于大量的天然金属蛋白中，我们将开发金属氧化还原 具有显著合成效用的自由基生物催化反应。一是开发适应自然的金属氧化还原 原子转移自由基加成反应，具有出色的非对映和对映体控制。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反应。 此外，涉及金属酶促生成的氮的不对称C-H官能化反应也是非常重要的。 将发展以中心为中心的激进分子。所有这三个目标都得到了在我们的 实验室。综上所述，这些新的金属氧化还原生物催化过程构成了快速 在生物医学科学中具有极高价值的各种生物活性小分子的组装。此外， 新型催化功能的开发将极大地拓宽生物化学的版图 金属酶。

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.