CNS and CNP Iron(II) Mono-Iron Hydrogenase (Hmd) Mimics: Role of Deprotonated Methylene(acyl) and the <i>trans</i>-Acyl Site in H₂ Heterolysis

We report syntheses and H2 activation involving model complexes of mono-iron hydrogenase (Hmd) derived from acyl-containing pincer ligand precursors bearing thioether (CNSPre) or phosphine (CNPPre) donor sets. Both complexes feature pseudo-octahedral iron­(II) dicarbonyl units. While the CNS pincer adopts the expected mer-CNS (pincer) geometry, the CNP ligand unexpectedly adopts the fac-CNP coordination geometry. Both complexes exhibit surprisingly acidic methylene C–H bond (reversibly de/protonated by a bulky phenolate), which affords a putative dearomatized pyridinate-bound intermediate. Such base treatment of Fe-CNS also results in deligation of the thioether sulfur donor, generating an open coordination site trans from the acyl unit. In contrast, Fe-CNP maintains a CO ligand trans from the acyl site both in the parent and dearomatized complexes (the −PPh2 donor is cis to acyl). The dearomatized mer-Fe-CNS was competent for H2 activation (5 atm D2(g) plus phenolate as base), which is attributed to both the basic site on the ligand framework and the open coordination site trans to the acyl donor. In contrast, the dearomatized fac-Fe-CNP was not competent for H2 activation, which is ascribed to the blocked coordination site trans from acyl (occupied by CO ligand). These results highlight the importance of both (i) the open coordination site trans to the organometallic acyl donor and (ii) a pendant base in the enzyme active site

“Criss-Crossed” Dinucleating Behavior of an N4 Schiff Base Ligand: Formation of a μ‑OH,μ‑O₂ Dicobalt(III) Core via O₂ Activation

We report the synthesis and structural characterization of a dicobalt­(III) complex with a μ-OH,μ-O₂ core, namely μ-OH,μ-O₂-[Co­(enN4)]₂(X)₃ [<b>1­(ClO</b>_<b>4</b><b>)</b>_<b>3</b> and <b>1­(BF</b>_<b>4</b><b>)</b>_<b>3</b>]. The dinuclear core is cross-linked by two N4 Schiff base ligands that span each cobalt center. The formally Co^III–Co^III dimer is formed spontaneously upon exposure of the mononuclear Co­(II) complex to air and exhibits a ν­(O–O) value at 882 cm^–1 that shifts to 833 cm^–1 upon substitution with ¹⁸O₂. The CV of <b>1­(BF</b>_<b>4</b><b>)</b>_<b>3</b> exhibits a reversible {Co^III–Co^III}↔{Co^III–Co^IV} redox process, and we have investigated the oxidized {Co^III–Co^IV} species by EPR spectroscopy (<i>g</i> = 2.02, 2.06; <i>S</i> = 1/2 signal) and DFT calculations

“Criss-Crossed” Dinucleating Behavior of an N4 Schiff Base Ligand: Formation of a μ‑OH,μ‑O₂ Dicobalt(III) Core via O₂ Activation

We report the synthesis and structural characterization of a dicobalt­(III) complex with a μ-OH,μ-O₂ core, namely μ-OH,μ-O₂-[Co­(enN4)]₂(X)₃ [<b>1­(ClO</b>_<b>4</b><b>)</b>_<b>3</b> and <b>1­(BF</b>_<b>4</b><b>)</b>_<b>3</b>]. The dinuclear core is cross-linked by two N4 Schiff base ligands that span each cobalt center. The formally Co^III–Co^III dimer is formed spontaneously upon exposure of the mononuclear Co­(II) complex to air and exhibits a ν­(O–O) value at 882 cm^–1 that shifts to 833 cm^–1 upon substitution with ¹⁸O₂. The CV of <b>1­(BF</b>_<b>4</b><b>)</b>_<b>3</b> exhibits a reversible {Co^III–Co^III}↔{Co^III–Co^IV} redox process, and we have investigated the oxidized {Co^III–Co^IV} species by EPR spectroscopy (<i>g</i> = 2.02, 2.06; <i>S</i> = 1/2 signal) and DFT calculations

Engineered Chimeras Unveil Swappable Modular Features of Fatty Acid and Polyketide Synthase Acyl Carrier Proteins

The strategic redesign of microbial biosynthetic pathways is a compelling route to access molecules of diverse structure and function in a potentially environmentally sustainable fashion. The promise of this approach hinges on an improved understanding of acyl carrier proteins (ACPs), which serve as central hubs in biosynthetic pathways. These small, flexible proteins mediate the transport of molecular building blocks and intermediates to enzymatic partners that extend and tailor the growing natural products. Past combinatorial biosynthesis efforts have failed due to incompatible ACP–enzyme pairings. Herein, we report the design of chimeric ACPs with features of the actinorhodin polyketide synthase ACP (ACT) and of the Escherichia coli fatty acid synthase (FAS) ACP (AcpP). We evaluate the ability of the chimeric ACPs to interact with the E. coli FAS ketosynthase FabF, which represents an interaction essential to building the carbon backbone of the synthase molecular output. Given that AcpP interacts with FabF but ACT does not, we sought to exchange modular features of ACT with AcpP to confer functionality with FabF. The interactions of chimeric ACPs with FabF were interrogated using sedimentation velocity experiments, surface plasmon resonance analyses, mechanism-based cross-linking assays, and molecular dynamics simulations. Results suggest that the residues guiding AcpP–FabF compatibility and ACT–FabF incompatibility may reside in the loop I, α-helix II region. These findings can inform the development of strategic secondary element swaps that expand the enzyme compatibility of ACPs across systems and therefore represent a critical step toward the strategic engineering of “un-natural” natural products