Synthesis and reactivity of acetyl coenzyme A synthase active site analogues
Date
2014
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
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 iPr PSi Pr , (PhP(CH2 CH2 SPri ) 2 )) with two thioether donors has been used to investigate the mechanism of methyl transfer. Reaction of Si Pr PSiPr with Ni(cod) 2 (cod = 1,5-cyclooctadiene) and two equivalents of triphenylphosphine (PPh3 ) generated (κ2 - Si Pr PSiPr )Ni(PPh 3 )2 . The resultant tetrahedral complex was characterized spectroscopically and crystallographically. (κ2 - S iPr PSi Pr )Ni(PPh3 )2 was found to decompose over time in solution to (κ2 -Si Pr PS)2 Ni. The alkyl transfer reactivity of (κ 2 - SiPr PS 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 )2 py (dmgBF2 = (difluoroboryl)dimethylglyoximato, py = pyridine) with (κ2 - SiPr PS iPr )Ni(PPh3 )2 proceeded in quantitative spectroscopic yields forming the respective alkyl species, [(κ2-SiPr PS iPr )Ni(PPh3 )R]+ (R = Ch3 or CD3 ) and [Co(dmgBF2 )2PPh 3 ]- . Reactions of (κ2 - S iPr PSi Pr )Ni(PPh3 )2 with RCo(dmgBF2 ) 2 py, where R = Ch3 CH2 or CH(Ch3 ) 2 , yielded ethylene and propylene, respectively, rather than the corresponding Ni-alkyl complex, implicating successful alkyl transfer followed by facile β-hydrogen elimination for these nickel complexes. Kinetics data obtained for the transfer of alkyls (Ch 3 , Ch3 CH2 ) to (κ2- S iPr PSi Pr )Ni(PPh3 )2 supports an SN 2 mechanism similar to that found in the enzyme.