Thiols sulphenyl derivatives

The conversion of thiols to various sulphenyl derivatives has been utilized as a means of thiol protection as well as, in many cases, a route to disulphides. Sulphenyl derivatives considered in this section include S-sulphonates, sulphenyl iodides, symmetrical and unsymmetrical disulphides (as used for protection) and certain heavy-metal derivatives. A summary of the chemistry of certain sulphenyl derivatives appeared earlier [159]. 

The reversible protection of the thiol group by conversion to an unsymmetrical disulphide has been accomplished by the action of various sulphenyl derivatives on peptide- or protein-bound cysteine residues. Althou these derivatives are likely to be most useful when only one disu hide bond (or one or more thiol groups) are desired, recent experiments by several laboratories indicates the promise of these S-protective groups which include S-aryl [167], S-ethyl [13], and S-t-butyl mercapto groups [168]. 

The formation of unsymmetrical disulphides by the reaction of S-sulphonates with thiols is analogous to a number of other sulphenyl derivatives. In general terms the reaction may be represented as shown in eq. 7.14. A number of intermediates in addition to the sulphenyl iodides [92], sulphenyl thiocyanates [108] and sulphenyl sulfonates [175] have been utilized to advantage in the synthesis of unsymmetrical disulphides. These include the monodisulphide dioxides (RSO2—), studied in detail by Field and his colleagues [178], the disulphide monoxides (RSO—) [178, 179] and more recently the S-monothiocar-bonates (ROCS--) [180] and sulphenamides [186]. 

The photostimulated reactions of thiolate anions with 2-halo-2 -nitropropane derivatives yield both oc-nitrosulphides via an S l pathway and disulphides (equation 71a)282 284. In contrast with the case of the oxidative dimerisation products of the mono-enolates, the disulphides are formed via an ionic mechanism nucleophilic attack by the thiolate anion on the a-halogen and subsequent reaction of a second thiolate with the sulphenyl halide. As expected for such a process, disulphide formation is favoured (and thus a-nitrosulphide formation is disfavoured) the more nucleophilic the thiolate (i.e. derived from a less acidic thiol) and the easier the abstraction of the halo-substituent (i.e. I > Br > Cl). Use of the protic solvent methanol instead of the usual dipolar aprotic solvents for the reaction of equation 71a is detrimental to the yield of the S l substitution products exclusively disulphides are formed285 (equation 71b). Methanol solvation probably retards the dissociation of the radical anion intermediate in the SRN reaction, into radical and anion, and hence retards the chain reaction relative to the ionic reaction. The non-nucleophilic methylsulphinate ion gives only an S l reaction product with 2-bromo-2-nitropropane286. 

The A -unsaturated-5a-thiol (350) reacted with bromine or chlorine to give the 3j8-halogeno-2a,5a-epithio-derivative (353). ° It is suggested that a 5a-sulphenyl halide e.g. (351)] is first formed, and then attacks the olefinic bond to give the sulphonium ion (352), which suffers nucleophilic attack upon C(3) by halide ion. Lead tetra-acetate similarly afforded the 3j8-acetoxy-2a,5a-epithio-compound. 

The additions of thiols and sulphenyl chlorides to alkenylphosphonic derivatives to yield (2-alkylthioethyl)phosphonic compounds are reactions which have already been noted" Dialkyl (alkylthiomethyl)phosphonates yield a-chloro derivatives when treated with ncs in CCl/° the resultant dialkyl (l-alkylthio-l-chloromethyl)phosphonates undergo Friedel-Crafts arylation with benzene, alkylbenzenes or other activated aromatics in the presence of SnCl4 or TiCl/ yields are said to be good. 

It may be useful to inteTchange the reactivities of the peptide and the protein (or carrier) as described in Section 3.1. In that case it is convenient to prepare chloroacetyl (27), bromoacetyl (23, 28, 29), or /V-Boc-5-(3-nitro-2-pyridyl-sulphenyl)cysteinyl (30, 31) derivatives by N-tenninal acylation of the side-chain protected and resin-bound peptides. (It should be noted that thiol-containing or other reducing scavengers should be avoided during the final deprotection of these peptides.)... 

Although sulphenyl iodides are generally too reactive to be utilized for protective groups, the conversion of thiols to sulphenyl iodides by the action of iodine or iodine monochloride has been useful in certain situations [164, 165]. The reversible protection of a thiol group in lactic dehydrogenase was also accomplished [166] by treatment of the protein with mercury(ll) chloride. After chemical modification of a histidine residue the chloromercury group was removed by treatment with cysteine. The insoluble nature of these derivatives makes the heavy metal S-protective groups potentially less useful for smaller molecules. 

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