Photobiocatalysis—where light is used to expand the reactivity of an enzyme—has recently emerged as a powerful strategy to develop chemistries that are new to nature. These systems have shown potential in asymmetric radical reactions that have long eluded small-molecule catalysts¹. So far, unnatural photobiocatalytic reactions are limited to overall reductive and redox-neutral processes^{2,3,4,5,6,7,8,9}. Here we report photobiocatalytic asymmetric sp³–sp³ oxidative cross-coupling between organoboron reagents and amino acids. This reaction requires the cooperative use of engineered pyridoxal biocatalysts, photoredox catalysts and an oxidizing agent. We repurpose a family of pyridoxal-5′-phosphate-dependent enzymes, threonine aldolases^10,11,12, for the α-C–H functionalization of glycine and α-branched amino acid substrates by a radical mechanism, giving rise to a range of α-tri- and tetrasubstituted non-canonical amino acids ^13,14,15 possessing up to two contiguous stereocentres. Directed evolution of pyridoxal radical enzymes allowed primary and secondary radical precursors, including benzyl, allyl and alkylboron reagents, to be coupled in an enantio- and diastereocontrolled fashion. Cooperative photoredox–pyridoxal biocatalysis provides a platform for sp³–sp³ oxidative coupling¹⁶, permitting the stereoselective, intermolecular free-radical transformations that are unknown to chemistry or biology.

光生物催化——利用光来扩大酶的反应活性——最近已成为开发自然化学的强大策略。这些系统在不对称自由基反应中显示出潜力，而这些反应长期以来一直是小分子催化剂所无法实现的¹。到目前为止，非自然光生物催化反应仅限于整体还原和氧化还原中性过程^{2,3,4,5,6,7,8,9}。在这里，我们报道了有机硼试剂和氨基酸之间的光生物催化不对称sp ³ – sp ³氧化交叉偶联。该反应需要协同使用工程吡哆醛生物催化剂、光氧化还原催化剂和氧化剂。我们重新利用了吡哆醛-5′-磷酸依赖性酶家族苏氨酸醛缩酶^10,11,12，通过自由基机制对甘氨酸和 α-支链氨基酸底物进行 α-C-H 功能化，产生了一系列α-三取代和四取代的非规范氨基酸^13,14,15拥有最多两个连续的立构中心。吡哆醛自由基酶的定向进化允许初级和次级自由基前体，包括苄基、烯丙基和烷基硼试剂，以对映体和非对映体控制的方式偶联。协同光氧化还原-吡哆醛生物催化为sp ³ – sp ³氧化偶联¹⁶提供了一个平台，允许化学或生物学未知的立体选择性、分子间自由基转化。