Scaffold-Based Functional Models of [Fe]-Hydrogenase (Hmd): Building the Bridge between Biological Structure and Molecular Function.

The well-known dinuclear [FeFe] and [NiFe] hydrogenase enzymes are redox-based proton reduction and H2 oxidation catalysts. In comparison, the structural and functional aspects of the mononuclear nonredox hydrogenase, known as [Fe]-hydrogenase or Hmd, have been less explored because of the relatively recent crystallographic elucidation of the enzyme active site. Additionally, the synthetic challenges posed by the highly substituted and asymmetric coordination environment of the iron guanylylpyridinol (FeGP) cofactor have hampered functional biomimetic modeling studies to a large extent. The active site contains an octahedral low-spin Fe(II) center with the following coordination motifs: a bidentate acyl-pyridone moiety (C,N) and cysteinyl-S in a facial arrangement; two cis carbonyl ligands; and a H2O/H2 binding site. In [Fe]-hydrogenase, heterolytic H2 activation putatively by the pendant pyridone/pyridonate-O base serving as a proton acceptor. Following H2 cleavage, an intermediate Fe-H species is thought to stereoselectively transfer a hydride to the substrate methenyl-H4MPT+, thus forming methylene-H4MPT. In the past decade, chemists, inspired by the elegant organometallic chemistry inherent to the FeGP cofactor, have synthesized a number of faithful structural models. However, functional systems are still relatively limited and often rely on abiological ligands or metal centers that obfuscate a direct correlation to nature's design.Our group has developed a bioinspired suite of synthetic analogues of Hmd to better understand the effects of structure on the stability and functionality of the Hmd active site, with a special emphasis on using a scaffold-based ligand design. This systematic approach has contributed to a deeper understanding of the unique ligand array of [Fe]-hydrogenase in nature and has ultimately resulted in the first functional synthetic models without the aid of abiological ligands. This Account reviews the reactivity of the functional anthracene-scaffolded synthetic models developed by our group in the context of current mechanistic understanding drawn from both protein crystallography and computational studies. Furthermore, we introduce a novel thermodynamic framework to place the reactivity of our model systems in context and provide an outlook on the future study of [Fe]-hydrogenase synthetic models through both a structural and functional lens.