Unsymmetrical disulphides

The reagent is highly selective, as demonstrated by the inertness of several sensitive functionalities such as amino, hydroxyl, azo, hydrazo, phenol, sulphide, disulphide, sulphoxide, aldehyde moieties, and olefmic and acetylenic carbon-carbon bonds. The ability of the reagent to differentiate thiols may be used to prepare unsymmetrical disulphides. 

Ring opening reactions of benzisothiazolones have provided a new route to unsymmetrical disulphides <97JHC1463>. 

Unsymmetrical disulphides can be formed by the decomposition of a sulphenamide with a thiol . 

The cleavage of the N—S bond in N(thiosulphenyl)phthalimide with thiols yields an unsymmetrical trisulphide >. Unsymmetrical disulphides are also formed in the thiolate anion fracture of the C—S bond in ethyl thiocyanate in DMF small amounts, less than 10%, of the symmetrical disulphides are formed. ... 

Thiol-disulphide exchanges to form unsymmetrical disulphide bonds have been exploited extensively both in protein and peptide chemistry. King et aL (13) have used an aromatic thiol, the 4-dithiopyridyl group, as a cysteinyl-activating group to cross-link proteins via intermolecular disulphide bonds. Similarly, other aromatic thiols such as 2-thiopyridyl and nitropyridyl sulphenyl (Npys) have been used in peptide synthesis to form unsymmetrical disulphides. These and other similar methods can be applied to the ligation of unprotected peptides. 

Unsymmetrical disulphides are prepared by the reaction of thiols with sulphenyl compounds, a new synthesis of this type involving first the conversion of a thiol R SH into R SSC02R by its reaction with CISCO2R in MeOH at 0 °C, followed by room-temperature reaction of the intermediate with a second thiol R SH to give R SSR and HO CS -OR . Acetyl sulphenyl chlorides AcSCl similarly yield AcSSR with RSH, - though the product is susceptible to attack by the thiol, resulting in the formation of symmetrical disulphides. Acyl alkyl... 

Preparation.—Many examples of the incidental formation of disulphides have been discussed in preceding sections, but few of these have undergone development as potential preparative methods, since there is no shortage of routes to these compounds. However, routes to unsymmetrical disulphides in particular, and from a wider range of starting materials, continue to be developed. Recent papers are collected at the end of this section, with brief details of their contents, where continuing development of known methods is concerned. 

Aralkyl trimethylsilyl sulphides RSSiMej give disulphides with sulphenyl chlorides, and symmetrical diselenides are formed from the selenium analogues with Ij (PhSeSiMcj - PhSeSePh + MejSil). The formation of unsymmetrical disulphides from steroidal A -diene-S-thiones and 2-nitrobenzenesulphenyl chloride is in accordance with the concept of hard and soft acids and bases, the soft thione nucleophile reacting with the soft sulphenyl halide, but not with the hard sulphonyl chloride. The resulting A -trienyl 2-nitrophenyl disulphides participate in thiol-disulphide exchange (see next section). 

Finally, it has been noted that the attempted detritylation of open-chain unsymmetrical disulphides containing S-trityl groups using silver nitrate in pyridine led to extensive decomposition and neither the silver mercaptide nor thiol (after treatment of the reaction mixture with hydrogen sulphide) could be isolated [94]. Thus there is some question as to whether peptides containing preformed cystine residues and S-trityl or S-benz-hydryl cysteine can be deblocked with heavy metals without causing cleavage of the disulphide bond. 

The direct conversion of thioethers to unsymmetrical disulphides with thiocyanogen or sulphenyl thiocyanates has been studied in some detail. Early invest ations established that the S-trityl thioethers could be selectively oxidized in the presence of S-benzhydryl or S-benzyl thioethers [95] as well as in the presence of one or more disulfide bonds [100]. Molecules containing two 5-trityl thioethers can also be cyclized [104, 105] in good yield. The reaction of thiocyanogen with thiols... 

In contrast to the iodine-methanol procedure, the sulphenyl-thiocyanate method does not provide statistical mixtures of symmetrical and unsymmetrical disulphides. Thus the reaction of thiols or S-trityl thioethers with sulphenyl thiocyanates appears to be relatively specific and rapid (e.g., (31) from the S-trityl thioether). In situations when the reaction is slow (e.g., (31) from S-benzhydryl thioether with no acid catalysis) disproportionation of the sulphenyl thiocyanate seems to occur (as with the sulphenyl iodides) and symmetrical disulphide can be isolated. Thus as pointed out by Kamber [92] the iodine oxidation of thioethers appears useful in situations where the... 

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]. 

With Acids, Bases. The S-sulphonates appear to be relatively stable in the pH range 1-9 [160] although they are readily decomposed in O.lN-sodium hydroxide. According to Swan, S-sulphonates are relatively stable to N- or 6N-hydrochloric acid and are converted to thiol with hot dilute acid. These studies indicate that S-sulphonates are somewhat more stable than unsymmetrical disulphides and considerably more stable than the sulphenyl iodides or thiocyanates. 

The lability of unsymmetrical disulphides to acids and bases has previously been mentioned [91, 103]. Ciuffarin and Fava... 

The synthesis of oxytocin using the S-ethylmercapto group [13] indicated that the AT-t-amyloxycarbonyl group could be removed with trifluoroacetic acid without apparent acid-catalyzed disulphide interchange of the S-ethylmercapto group. Surprisingly the unsymmetrical disulphide was also stable to the action of 25% ammonia in methanol during the ammonolysis of (70). 

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]. 

A-Thioalkylphthalimides (215) are converted into A -alkylphthalimides by tris(dimethylamino)phosphine, providing a method of transformation of thiols into amines. Thiols react with such N-thioalkylphthalimides in a general procedure for the preparation of unsymmetrical disulphides a similar reaction with amines gives A -thio-iV -diamides. These reactions are outlined in Scheme 145. 

Thiols have been activated by conversion into thionitrites (213) with dinitrogen tetroxide. The latter react readily with other thiols, sulphinic acids, and amines as shown in Scheme 31, resulting in unsymmetrical disulphides (214), thiosulphonates (215), and N-nitrosamines (216) respectively. 

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