Fission of Disulfides

In peptides containing two cysteines a cyclic disulfide, such as the one found in oxytocin 

Both intrachain and interchain disulfide bridges are present in insulin (cf. Table 3, p. 7) and it is obvious that determination of the sequence of the two chains had to be preceded by their separation. 

There is an almost embarrassingly rich choice of methods by which disulfides can be cleaved, for instance in a smooth reaction with potassium cyanide 

A serius drawback of this otherwise simple and straightforward method of chain separation is the damage suffered by tyrosine and tryptophan side chains in the process. Oxidation of methionine residues to the corresponding sulfoxides also occurs, but it is reversible. In the presence of heavy metal impurities, however, irreversible oxidation to sulfones can take place 

These complicating factors do not render the performic acid method impractical, but they must be taken into account in the interpretation of the results of subsequent degradations. 

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By oxidative sulfitolysis. Originally this method was conceived as involving (i) fission of disulfide by sulfite to produce thiol and S-sulfo-cysteine, and (ii) oxidation of this thiol to disulfide which again reacts with sulfite as in (i). The over-all reaction is the conversion of disulfide to >S-sulfocysteine. On this basis the reactions can be formulated as in reaction (II). 

Figure 4-5. S—S fission of disulfides in an aqueous alkaline oxidizing medium. Reprinted with permission of the Journal of the Society of Cosmetic Chemists.

In oxidative decarboxyiation of pyruvate to acetyi-CoA, the enzyme-bound disulfide-containing coenzyme lipoic acid is also involved. The electron-rich enamine intermediate, instead of accepting a proton, is used to attack a sulfur in the lipoic acid moiety. This leads to fission of the S-S bond, and thereby effectively reduces the lipoic acid fragment. Regeneration of the TPP ylid via the reverse aldol-type... 

Isothiocanic esters are also readily accessible by acid fission of diaryl-ureas,1063 reaction of arylamines with iV,jV-diethylthiocarbamoyl chloride,812 and by treatment of iV-metalated amidophosphates with carbon disulfide.813... 

There must be few organic syntheses of any complexity that do not involve a reduction at some stage. Reduction is used in the sense of addition of hydrogen to an unsaturated group (such as a carbon-carbon double bond, a carbonyl group or an aromatic ring) or addition of hydrogen with concomitant fission of a bond between two atoms (such as the reduction of a disulfide to a thiol or of an alkyl halide to a hydrocarbon). 

With the very active W-6 or W-7 Raney Ni (alkaline), desulfurization occurs before ring fission and /V-mclhylanilinc is the only product, while with less active W-5 and degassed W-7 Raney Ni in the presence of alkali, ring fission takes place to some extent before desulfurization, which may lead to o-aminothiophenol (isolated in its oxidized form, 2,2 -diaminodiphenyl disulfide) and aniline, probably via the formyl derivative as the intermediate as shown in Scheme 13.13.148... 

The liquid phase photolysis of dimethyl disulfide (2537 A) has been reported to produce dimethyl sulfide and dimethyl trisulfide in equal quantities, and traces of CH4 and methyl tetrasulflde. Ethyl disulfide again gave mono, tri- and tetra-sulfides with a trace of ethyl mercaptan. All irradiations were prolonged, of the order 24-48 hours. It was claimed that C-S fission in the primary photolytic dissociation... 

The photolyses of 6,8-thioctic acid and 1,2-dithiolane (trimethylene disulfide) at 3650 A proceed via S-S fission with quantum yields of 0.4 and 0.6 respectively with decreasing wavelength the quantum yield increases and probably approaches unity. ... 

Photodecomposition of 1,2-benzisothiazole (17) affords the ring-opened disulfide 7.40 If the 3-position is blocked by substitution, then more interesting products may result. Photocycloaddition reactions of 3-phenyl-1,2-benzisothiazole (23) with alkenes afford excellent yields of 2,3-dihydro-1,4-benzothiazepins such as 24.41 With electron-rich alkynes, thiazabicyclohep-tadienes (25) are produced, but no reaction occurs with 2-butyne, 1-phenylpropyne, or dimethyl acetylenedicarboxylate.42 An analogous S—N bond fission occurs with 2-aryl-1,2-benzisothiazolinones.43... 

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