Synthesis and reactivity of acetyl coenzyme A synthase active site analogues

Acetyl coenzyme A synthase (ACS) produces acetyl coenzyme A (acetyl-CoA) by combining CH3 from a methylated corrinoid iron-sulfur protein (CH3-CoFeSP), CO from carbon monoxide dehydrogenase (COdH) and coenzyme A (CoA). Biologically unprecedented nickel-methyl, nickel-carbonyl, and acetyl-nickel intermediates are proposed to occur during catalysis. To probe the feasibility of Ni(II)Ni(I) or Ni(II)Ni(0) intermediates during catalysis, the synthesis of a dinucleating thiol macrocycle with asymmetric coordination sites was targeted. En route to this ligand, a series of mononuclear nickel thiol-based Schiff base complexes, N,N'-bis(3-methoxycarbonylthiosalicylidene)-R-diaminonickel(II) (Ni(3-MOC-tsalR)) where R = 1,2- diaminoethane (en), 1,3-diaminopropane (pr), 1,4-diaminobutane (but), 1,2-phenylenediamine (phen), and 4,5- dimethyl-1,2-phenylenediamine (dimph), were synthesized. The resultant square-planar complexes were characterized spectroscopically and crystallographically. Cyclic voltammetry studies of Ni(3-MOC-tsalR) (R = en, pr, but) showed one reversible cathodic wave, assigned as the Ni(II)/Ni(I) reduction. Studies of Ni(3-MOCtsalR) (R = phen, dimph) exhibited an irreversible cathodic peak assigned as a ligand reduction. Attempts to synthesize the asymmetric dinucleating thiol macrocycle using various starting diamines and starting materials at different temperatures and reaction times all failed to produce the desired product.;The tridentate ligand bis[2-(isopropylthio)ethyl]phenylphosphine (S iPrPSi Pr, (PhP(CH2CH2SPri) 2)) with two thioether donors has been used to investigate the mechanism of methyl transfer. Reaction of Si PrPSiPr with Ni(cod) 2 (cod = 1,5-cyclooctadiene) and two equivalents of triphenylphosphine (PPh3) generated (kappa2- Si PrPSiPr)Ni(PPh 3)2. The resultant tetrahedral complex was characterized spectroscopically and crystallographically. (kappa2- S iPrPSi Pr)Ni(PPh3)2 was found to decompose over time in solution to (kappa2-Si PrPS)2Ni. The alkyl transfer reactivity of (kappa 2- SiPrPS iPr)Ni(PPh3)2 was assayed through reactions with alkylcobaloximes, i.e., methyl, methyl-d3, ethyl, isopropyl and neopentyl. The reaction of methyl and methyl-d3 derivatives of RCo(dmgBF2)2py (dmgBF2 = (difluoroboryl)dimethylglyoximato, py = pyridine) with (kappa2 - SiPrPS iPr)Ni(PPh3)2 proceeded in quantitative spectroscopic yields forming the respective alkyl species, [(kappa2-SiPrPS iPr)Ni(PPh3)R]+ (R = Ch3 or CD3) and [Co(dmgBF2)2PPh 3]-. Reactions of (kappa2- S iPrPSi Pr)Ni(PPh3)2 with RCo(dmgBF2) 2py, where R = Ch3CH2 or CH(Ch3) 2, yielded ethylene and propylene, respectively, rather than the corresponding Ni-alkyl complex, implicating successful alkyl transfer followed by facile beta-hydrogen elimination for these nickel complexes. Kinetics data obtained for the transfer of alkyls (Ch3, Ch3CH2) to (kappa2- S iPrPSi Pr)Ni(PPh3)2 supports an SN2 mechanism similar to that found in the enzyme.