Dinuclear nickel complexes modeling the structure and function of the acetyl CoA synthase active site

Abstract

A dinuclear nickel complex with methyl and thiolate ligands, Ni(dadt^Et)Ni(Me)(SDmp) (2), has been synthesized as a dinuclear Ni_d–Ni_p-site model of acetyl-CoA synthase (ACS) (dadt^Et is N,N′-diethyl-3,7-diazanonane-1,9-dithiolate; Dmp is 2,6-dimesitylphenyl). Complex 2 was prepared via 2 methods: (i) ligand substitution of a dinuclear Ni(II)–Ni(II) cation complex [Ni(dadt^Et) Ni(tmtu)₂] (OTf)₂(1) with MeMgBr and KSDmp (tmtu is tetramethylthiourea), (ii) methyl transfer from methylcobaloxime Co(dmgBF₂)₂(Me)(Py) (5) to a Ni(II)–Ni(0) complex such as [Ni(dadt^Et)Ni(cod)] (3), generated in situ from Ni(dadt^Et) and Ni(cod)₂, followed by addition of KSDmp (cod is 1,5-cyclooctadiene; dmgBF₂ is difluoroboryl-dimethylglyoximate). Method ii models the formation of Ni_p–Me species proposed as a plausible intermediate in ACS catalysis. The reaction of 2 with excess CO affords the acetylthioester CH₃C(O)SDmp (8) with concomitant formation of Ni(dadt^Et)Ni(CO)₂ (9) and Ni(CO)₄ plus Ni(dadt^Et). When complex 2 is treated with 1 equiv of CO in the presence of excess 1,5-cyclooctadiene, the formation of 9 and Ni(CO)₄ is considerably suppressed, and instead the dinuclear Ni(II)–Ni(0) complex is generated in situ, which further affords 2 upon successive treatment with Co(dmgBF₂)₂(Me)(Py) (5) and KSDmp. These results suggest that (i) ACS catalysis could include the Ni_d(II)–Ni_p(0) state as the active species, (ii) The Ni_d(II)–Ni_p(0) species could first react with methylcobalamin to afford Ni_d(II)–Ni_p(II)–Me, and (iii) CO insertion into the Ni_p–Me bond and the successive reductive elimination of acetyl-CoA occurs immediately when CoA is coordinated to the Ni_p site to form the active Ni_d(II)–Ni_p(0) species.