Stepwise and Reversible Assembly of 2Fe–2S Rhombs to 8Fe–8S Clusters and Their Topological Interconversions

Among all enzymatic metallocofactors, those found in nitrogenases, the P- and L-/M-clusters, stand out for their structural complexity. They are assembled by proteins of the Nif gene cluster from Fe2S2 rhombs—the smallest building blocks in FeS cluster chemistry—through a sequence of reactions constructing a Fe8S8 precursor. This fundamental transformation is unknown in chemical synthesis, impeding our understanding of how enzymes selectively build such elaborate inorganic molecules. Here, we report the rational stepwise assembly of [Fe8S8]n+ (n=2,4,6) clusters from [Fe2S2]2+ rhombs, within an extensive cyclic synthetic network. We identify a [Fe8S8]4+ cluster of unique topology, for which we coin the term “interlocked” double-cubane (ildc). This topology is not unprecedented in enzymes, as the ildc is a molecular analogue of the K-cluster, a proposed biosynthetic precursor to both the P- and M-clusters. Its synthesis, along with the characterization of all related intermediates, offers key insights into the mechanisms governing the assembly of these cofactors, advancing our understanding of both enzymatic and synthetic FeS cluster construction.