Abstract:

Photocatalysis has the advantages of mild reaction conditions, renewability, and strong reactivity, but the poor selectivity limits its further application in asymmetric synthesis. Enzymatic catalysis shows unique advantages of high selectivity and specificity, but it leads to some defects such as limited reaction types and relatively narrow substrate scope. Photoenzymatic catalysis combines the advantages of high reactivity of photocatalysis with high selectivity of enzymatic catalysis, providing a novel synthesis model, that is more in line with the requirements of modern green organic synthesis. The term “photoenzyme reactions” narrowly refers to the synergistic catalysis involving photoenzymes, which can be classified into the following four categories: natural photoenzymactic reactions, artificial photoenzymatic reactions, photo-biocatalysis cascade reactions, and photo-induced promiscuous enzymatic reactions. However, natural photoenzymes are rarely found in nature, the stringent substrate scope further hinders their application. Artificial photoenzymes integrate photosensitizers into the scaffold of natural enzymes, which have been well summarized in previous reviews. Photo-biocatalysis cascade reactions by combining photochemical steps and enzymatic steps can realize some complex organic synthesis processes. Since the first report on NAD(P)H-dependent KREDs-catalyzed enantioselective radical dehalogenation of lactones, photosensitive cofactor-dependent unnatural photoenzymatic catalysis demonstrated its great potential in the field of organic synthesis, and continues to thrive to date, which has addressed many problems difficult to be achieved in traditional organic synthesis. Since 2023, research into the promiscuity of photoenzyme catalysis has witnessed continuous breakthroughs, reporting diverse novel types of photoenzyme catalytic reactions and mechanisms. The precise control over stereoselectivity and even regioselectivity directly addresses the longstanding challenges in the field of organic synthesis. While there have been many publications summarizing the related research, yet rarely focused on this rapidly evolving field. In this review, we summarize the recent and representative reports of photo-induced promiscuous enzymatic reactions, and classify them according to asymmetric dehalogenation, hydrogenation, intramolecular cyclization, intermolecular C—C/C—N/C—S cross-coupling reactions through free radical pathways, etc. These reactions exhibit different mechanisms due to different enzymes and substrates. For example, in the process of redox initiation, there are two types: single-electron reduction initiation and single-electron oxidation initiation. In the radical termination process, single-electron reduction termination and single-electron oxidation termination may be used. The diversity of mechanisms also makes it possible to develop more photoenzyme-catalyzed promiscuous reactions. In the future, new photoenzymatic methods will be promoted by rapidly developing technologies such as genetic engineering, synthetic biology, enzyme engineering, flow chemistry, and artificial intelligence, and more efficient and highly selective new-to-nature reactions will emerge, significantly expanding the application range of photoenzyme catalysis in the field of green asymmetric synthesis.

Key words: photoenzymatic catalysis, non-natural reactions, asymmetric synthesis, synthesis biology, promiscuous reactions

摘要：

光催化具有条件温和、可再生、反应性强等优点，然而由于自由基的高活性往往导致其选择性难以调控，限制了光催化在不对称有机合成中的广泛应用。酶催化虽具有高选择性和专一性的优势，但这也导致其存在反应类型单一和底物谱窄等缺陷。将反应性强的光催化与选择性高的酶催化相结合的光酶催化则可以提供一种全新的合成模式，实现优势互补，更加符合现代绿色有机合成的要求。狭义的光酶催化反应，也就是光酶协同反应一般包括以下四类：天然光酶反应，人工光酶反应，光催化与酶催化的偶联反应以及光酶催化混乱性反应。近年来，光酶催化的研究蓬勃发展，解决了许多传统有机合成中难以实现的问题，尤其是在不对称合成领域已占据重要地位。例如，脂肪酸光脱酸酶可以催化长链脂肪酸脱羧转化为相应烃类；结合光敏辅因子和蛋白骨架的人工光酶大大拓展了酶的应用范围，催化更多样化非天然有机化学品的生物合成；光催化剂催化光化学反应与酶催化反应的偶联方式可以实现一些复杂的有机合成过程；以及近年来一些含有光敏辅因子的氧化还原酶在光激发下催化新分子混乱性反应的功能。尽管已有许多文献对相关研究进行了总结，但是自2023年以来，光酶催化混乱性研究不断突破，涌现出许多全新的光酶催化反应类型和反应机理，立体选择性和区域选择性的精准调控更是满足了不对称合成的重大需求。对于这个飞速发展的领域，系统归纳其成果仍显得至关重要。因此本综述聚焦在光激发下光敏辅因子依赖型酶催化的混乱性反应最新研究成果，根据不同催化反应类型，分别介绍光酶通过自由基途径实现不对称脱卤、氢化、分子内环化、分子间C—C/C—N/C—S键交叉耦合等非天然反应。这些反应由于酶和底物的不同，展示了不同机理。例如在氧化还原起始过程中，包括单电子还原起始和单电子氧化起始两种类型；在自由基终止过程中，可能采用单电子还原终止和单电子氧化终止，而单电子还原终止方式中也存在氢原子转移和电子转移/质子转移耦合过程等不同情况。机理的多样性也为拓展更多的光酶催化混乱性反应提供了可能。在未来，新型的光酶催化方法将在快速发展的基因工程、合成生物学、酶工程，以及流动化学、人工智能等学科和技术的推动下，涌现出更多高效、高选择性的新分子新功能反应，显著拓展光酶催化方法在有机合成（尤其是绿色不对称合成）领域中的应用范围。

关键词: 光酶催化, 非天然反应, 不对称合成, 合成生物学, 混乱性反应