Thiol conjugation

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

Enantioselectivities were found to change sharply depending upon the reaction conditions including catalyst structure, reaction temperature, solvent, and additives. Some representative examples of such selectivity dependence are listed in Scheme 7.42. The thiol adduct was formed with 79% ee (81% yield) when the reaction was catalyzed by the J ,J -DBFOX/Ph aqua nickel(II) complex at room temperature in dichloromethane. Reactions using either the anhydrous complex or the aqua complex with MS 4 A gave a racemic adduct, however, indicating that the aqua complex should be more favored than the anhydrous complex in thiol conjugate additions. Slow addition of thiophenol to the dichloromethane solution of 3-crotonoyl-2-oxazolidinone was ineffective for enantioselectivity. Enantioselectivity was dramatically lowered and reversed to -17% ee in the reaction at -78 °C. A similar tendency was observed in the reactions in diethyl ether and THF. For example, a satisfactory enantioselectivity (80% ee) was observed in the reaction in THF at room temperature, while the selectivity almost disappeared (7% ee) at 0°C. 

With the success in Lewis acid-catalyzed thiol conjugate addition reactions mentioned above, we further tried to apply the J ,J -DBFOX/Ph-nickel(II) aqua complex catalyst to the catalyzed asymmetric conjugate addition reactions of hydroxyl-amines [88, 89]. However, after some preliminary examinations, we found that... 

Tang, W. and Abbott, F.S. 1996. Characterization of thiol-conjugated metabolites of 2-propylpent-4-enoic acid (4-ene VPA), a toxic metabolite of valproic acid, by electrospray tandem mass spectrometry. J. Mass Spectrom. 31 926. 

Thiol conjugation Epoxides Glutathione S-transferases (glutathione or N-acetylcysteine) Glutathione or N-acetyl cysteine thioethers... 

Scheme 2.10 Thiol conjugate addition DCL templated by SJGST. (a) Blank DCL, (b) DCL after 10 minutes in the presence of SJGST, (c) DCL after equilibration and subsequent addition of the target, after 2 days, and (d) same system after 6 days. Adapted with permission from Reference 47. Copyright (2006) American Chemical Society.

Scheme 2.11 Thiol conjugate addition DCL templated by SJGST. Trace a) shows the blank DCL assembled in the absence of enzyme. Trace b) shows the templated DCL. Adapted with etc.

Carmichael NG, Fowler BA. Effects of separate and combined chronic mercuric chloride and sodium selenite administration in rats histologic, ultrastructural and x-ray microanalytical studies of liver and kidney. J Env Pathol Toxicol 1979 3 399-412. Aslamkhan AG, Han YH, Yang XP, et al.Human renal anion transporter 1 dependent uptake and toxicity of mercuric thiol conjugates in Madin-Darby canine kidney cells. Mol Pharmacol 2003 63(3) 590-6. 

AG Borel, FS Abbott. Identification of carbamoylated thiol conjugates as metabolites of the antineoplastic l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, in rats and humans. Drug Metab Dispos 21 889, 1993. 

Jiao D, Smith TJ, Yang CS, Pittman B, Desai D, Amin S, Chung F-L. Chemopreventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis. Carcinogenesis 1997 18 2143-2147. 

FIGURE 3.8 GSH conjugate metabolism formation of mercapturic acid, Ai-acetyl cysteine and thiol conjugates. 

Tang W, Miller RR. In vitro drug metabolism thiol conjugation. In Yan Z, Caldwell GW, editors. Methods in Pharmacology and Toxicology Optimization in Drug Discovery In Vitro Methods. Totowa, NJ Human Press Inc 2005. p 369-383. 

In order to confirm the GSH mediation of protein corona-capped AuNPs, the IR spectrum of the protein corona-capped AuNPs in the presence of GSH showed a new weak absorption signal at 2356 cm (line (ii) of Figure 5.20b), which was assigned to S-H vibration (Ding et al., 2009) indicating the thiol conjugation with the AuNPs surface. This peak was not present in protein corona-capped AuNPs not reacted with GSH (line (i) of Figure 5.20b). 

Zhang H, Lau WC, Hollenberg PF (2012) Formation of the thiol conjugates and active metabolite of clopidogrel by human liver microsomes. Mol Pharmacol 82 302-309... 

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