COMMENTARY COMMENTARY Incorporating light atoms into synthetic analogues of FeMoco Daniel E. DeRoshaa and Patrick L. Hollanda,1 Nitrogen is an essential element for all life on Earth. atoms into cluster cores, Lee and coworkers (14) have However, the elemental form of dinitrogen (N2) is typ- described an iron–sulfur cubane featuring a core N ically inert, and must be converted to the more reac- atom, while Ohki and coworkers (9) have formed one tive and biologically accessible ammonia (NH3) before cluster with an O atom in the center. These are nota- incorporation into proteins, nucleic acids, and other ble synthetic achievements, but because these reac- biomolecules. In nature, the only enzymes capable tions involve self-assembly, rational design of more of the multielectron reduction of N2 to NH3 are nitro- biologically relevant clusters based on these results genases, whose complexity has captured the imagina- is challenging. Now, in PNAS, Xu et al. (15) report a tion of biochemists (1), synthetic chemists (2), and systematic method for incorporating nitrogen- and spectroscopists (3) alike. Their active sites are iron– oxygen-based core atoms into iron–tungsten–sulfur sulfur clusters that are produced through elaborate clusters, in a strategy that may be transferable to the biosynthetic pathways (4). One special aspect of the challenge of embedding a carbon donor into analogs nitrogenase active-site clusters is the presence of mo- of the FeMoco. lybdenum or vanadium heteroatoms in addition to The new clusters (Fig. 1) include complete cubanes iron: the cofactors are described as the iron–molybde- and incomplete cubanes that feature a single W atom, num cofactor (FeMoco) or the iron–vanadium cofactor a congener of the biologically relevant Mo. Their syn- (FeVco). Because of the unusual shape of these clus- theses are based on a previously developed strategy ters, and the desire to systematically understand the known as template-assisted assembly, which employs influence of the Mo/V atom on an iron–sulfur cluster, trisulfido metal complexes such as (Tp*)WS3 (Fig. 1) to chemists have long striven to synthesize simpler ana- direct assembly of additional Fe and S atoms into logs (5). These synthetic analogs are influential be- clusters (16). The (Tp*)WS3 template stays intact in cause they can demonstrate feasible mechanistic each synthesis and therefore leads to products with steps and can enable correlation of specific structural less structural rearrangement than observed using features with spectroscopic signatures. In a relevant self-assembly methods. In previous work, Holm and example, synthetic chemists have prepared eight- colleagues (17) have shown that adding iron halide metal clusters with topological similarity to the FeMoco salts and sodium thiolate to trisulfido metal complexes and FeVco (6–9). forms incomplete cubanes or complete cubanes, and However, a newer challenge for synthetic chemists that product selectivity is controlled by reaction stoi- is presented by the light atom in the center of the chiometry. The new approach advanced by Xu et al. FeMoco and FeVco, which has been identified as a (15) in PNAS employs the one-electron reductant, so- carbide (C4-) that has no precedent in biology (Fig. 1) dium benzophenone ketyl. The resulting heterometal- – – (10–12). The discovery of an interstitial carbon in the lic clusters incorporate a core halide ligand (Cl or Br ) cofactors raises fundamental questions about the in a binding site otherwise occupied by thiolate in bonding, reactivity, and role of a central carbide within previously reported clusters (X′ in Fig. 1). This seem- an iron–sulfur cluster, and about the mechanism ingly minor change opens the door to synthetic op- through which it is installed into the cluster. However, portunities, because core halides are easily replaced embedding a light atom like carbon into an iron–sulfur with other ligands—including those that feature light cluster is challenging. Tatsumi and coworkers have atoms—through metathesis reactions. The synthetic described a series of eight-iron–seven-sulfur clusters methods devised by Xu et al. (15) in PNAS may there- that feature light atoms such as N (7, 13), but these fore enable the synthesis of model compounds that ligands are in bridging sites in contrast to the core feature a more similar coordination sphere to the carbide of nitrogenase. Toward incorporating light FeMoco in nitrogenase. aDepartment of Chemistry, Yale University, New Haven, CT 06511 Author contributions: D.E.D. and P.L.H. wrote the paper. The authors declare no conflict of interest. Published under the PNAS license. See companion article on page 5089. 1To whom correspondence should be addressed. Email: [email protected]. Published online April 30, 2018. 5054–5056 | PNAS | May 15, 2018 | vol. 115 | no. 20 www.pnas.org/cgi/doi/10.1073/pnas.1805700115 Downloaded by guest on September 23, 2021 Fig. 1. Template-assisted synthesis of cubanes that feature a core halide ligand (X′) that can be replaced with light atoms. (Inset) The FeMoco active site of nitrogenase. Belt Fe atoms shown in red are thought to be sites of N2 binding and reduction. Structural features of interest for investigation using synthetic model systems are indicated with colored spheres. These include Fe, carbide, sulfide, and homocitrate-supported Mo. In demonstrating the utility of these new methods for installing Another important question raised by these results is whether light atoms, Xu et al. (15) exchange the core halide atom X′ for the synthetic methods developed by Xu et al. (15) are applicable – ligands that feature light atoms like N and O, such as azide (N3 ) to incorporating a carbon-based ligand to mimic the carbide in – and methoxide (OMe ). Two different strategies for core halide the FeMoco. Literature precedent demonstrates that a bridging substitution are disclosed: direct salt metathesis and oxidative iron carbene can form upon reaction of diazoalkane with a diiron metathesis (15). Their results demonstrate that while incomplete bridging halide complex, at least in one case (18). The use of diazo- cubane clusters undergo salt metathesis, complete cubanes are alkanes, for example trimethylsilyldiazomethane, may therefore afford inert under these conditions and oxidative metathesis must in- a bridging carbene ligand through oxidative metathesis with a com- stead be used (Fig. 1). At first this two-pronged approach may plete cubane. Even more biologically relevant would be substitution seem like a limitation of the synthetic method. However, the of bridging halide X′ with a methyl ligand, because biosynthesis of the ability to choose between the complementary strategies can carbide ligand in the FeMoco proceeds through methyl group transfer be useful for guiding reaction design. For example, if an oxo (O2-) from SAM (S-adenosyl methionine) (12). Addition of methyl anion to core atom were desired, then it would be appropriate to use oxi- an incomplete cubane may give rise to a bridging methyl ligand dative metathesis from the complete cubanes with addition of oxo through salt metathesis, or alternatively addition of methyl radical transfer reagents (for example, N2O). The design principles impli- could be used to install a carbon ligand through oxidative metathesis. cated by these findings should aid future investigators in pursuit of If a C donor can be installed, the next stage will be testing new iron–sulfur clusters featuring biologically relevant light atoms. whether these cubane-type iron–sulfur clusters are amenable to These heterometallic clusters are interesting examples of iron– assembly into higher nuclearity clusters. Previous work indicates sulfur clusters featuring light core atoms, but how similar are they that in the presence of a reductant, related all-sulfide clusters di- to the FeMoco of nitrogenase? One apparent difference is the merize to form edge-bridged (bis)cubanes (17). Addition of thio- presence of W in place of Mo. Another discrepancy is the coordi- late sources then causes rearrangement to form corner-sharing bis nation sphere at the group 6 metal; in contrast to homocitrate (cubanes) with the topology of the FeMoco. Will light atom frag- and histidine ligands in the FeMoco, the W atom in the new ments in the clusters reported by Xu et al. (15) stay intact upon compounds is coordinatively saturated and supported by the assembly to larger clusters? If so, what reactivity patterns are charac- tridentate Tp* ligand. A future avenue toward greater biological teristic of these synthetic FeMoco analogs? The ability to introduce a analogy would therefore be incorporating Mo instead of W as carbon into synthetic iron–sulfur clusters with the topology of the – the second transition metal. Unfortunately, use of [(Tp)MoS5] FeMocomaygiveinsightintotheinfluenceofthecarbideindini- as a template instead of (Tp*)WS3 leads to incorporation of sulfide trogen reduction, in addition to fundamental knowledge about the in the bridging site X′, where halides bind, deactivating the cluster electronic structure of the unusual cofactor. toward further transformations. However, other Mo templates are t known, and in particular the previously reported ( Bu3tach)MoS3 Acknowledgments t = ( Bu3tach 1,3,5-tritert-butyl-1,3,5-triazacyclohexane) (16) might The authors’ research is supported by the National Institutes of Health give analogous clusters featuring biologically relevant Mo. (Grant GM-065313). 1 Hu Y, Ribbe MW (2010) Decoding the nitrogenase mechanism: The homologue approach. Acc Chem Res 43:475–484. ˇ 2 Cori´cI, Holland PL (2016) Insight into the iron-molybdenum cofactor of nitrogenase from synthetic iron complexes with sulfur, carbon, and hydride ligands. JAm Chem Soc 138:7200–7211. 3 Kowalska J, DeBeer S (2015) The role of X-ray spectroscopy in understanding the geometric and electronic structure of nitrogenase. Biochim Biophys Acta 1853:1406–1415. DeRosha and Holland PNAS | May 15, 2018 | vol. 115 | no. 20 | 5055 Downloaded by guest on September 23, 2021 4 Ribbe MW, Hu Y, Hodgson KO, Hedman B (2014) Biosynthesis of nitrogenase metalloclusters.