Enzymatic metal hydride and hydrogen atom transfer reactions: recent developments for synthetic applications.

Metal-hydrogen (M-H) intermediates are central to many organometallic processes but only play a transient role in metalloenzyme mechanisms in Nature and cannot be used directly for synthetic purposes. However, recent advances have revealed that robust zinc and iron metalloproteins can be repurposed to access M-H intermediates for conversion of unsaturated organic moieties. This perspective surveys the developing field of M-H-driven biocatalysis, focusing on metal hydride and metal hydrogen atom transfer (MHAT) reactions. The ease with which M-H intermediates can be generated at enzyme metal centres is particularly striking, requiring only addition of simple organohydrosilane or borohydride co-substrates. We first explore how heterolytic enzyme M-H cleavage enables stereoselective ketone, alkene, and imine reductions, emulating classical nicotinamide adenine dinucleotide phosphate (NAD(P)H)-dependent oxidoreductase chemistry. We then survey remarkable reports of homolytic M-H cleavage as a route to radical hydrofunctionalisation, cyclisation, and hydrogenation of unactivated alkenes. Whilst mechanistically impressive, our perspective also shows that this new reactivity is scalable and evolvable for improved substrate scope and stereoselectivity. Finally, we discuss how emerging cobalt-based systems are opening pathways to new-to-nature catalysis, including Birch-like reductive dearomatisation. Collectively, these developments establish enzymatic M-H chemistry as a powerful, practical, and rapidly evolving platform for implementing biocatalysis in synthesis.