Reduction to thiols

The best preparative method for mercaptopyrimidines varies from position to position from thioureas and their equivalents. Thiones in any of the electrophilic positions are prepared by thiolysis of halo-pyrimidines, or commonly by thiation of pyrimidinones using phosphorus pentasulfide or, more recently, the superior Lawesson reagent 2,4-bis-/ -methoxyphenyl-l,3,2,4-dithiadiphosphetane 2,4-disulfide. Thiolysis in the 5-position requires a metal sulfide and a 5-bromide under vigorous conditions. Alternatively, pyrimidines substituted with strongly electron-donating substituents may be sulfonated, for example, by chlorosulfonic acid, in the 5-position with subsequent reduction to thiol. 

Sulphonic acids/sulphonates have been determined by conversion to the sulphonyl chlorides. One method of determining the latter has been by reduction to thiols, e.g. with Zn/HCl159 or by LiAlH/60, followed by GLC. 

Trisulfides are predicted to be converted rapidly to the corresponding disulfides with subsequent reduction to thiols (Moutiez et al., 1994), which are then metabolized via the various pathways described above for simple thiols. 

A number of substances contain a disulfide or polysulfide group, which is predicted to be biotransformed initially by reduction to thiols, which would then be metabolized as described above. Some substances were simple alkyl and aryl disulfides or polysulfides (Nos 564-579, 582-588, 1299, 1300, 1686, 1687 and 1693-1701), whereas alternative processes of elimination would be available for disulfides or polysulfides with additional functional groups (Nos 580 and 581). The Committee concluded that under the current conditions of use as flavouring agents, the combined intake of these substances would not saturate the metabolic pathways and combined intakes would not raise safety concerns. 

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

Sulfinic acids can be prepared by reduction of sulfonyl chlorides. Though mostly done on aromatic sulfonyl chlorides, the reaction has also been applied to alkyl compounds. Besides zinc, sodium sulfite, hydrazine, sodium sulfide, and other reducing agents have been used. For reduction of sulfonyl chlorides to thiols, see 19-57. 

See Wallace, O.B. Springer, D.M. Tetrahedron Lett., 1998, 39, 2693 for cleavage of thiol esters to thiols with NaSMe in methanol and Choi, J. Yoon, N.M. Synth. Commun., 1995, 25, 2655 for borohydride exchange resin-Pd(OAc)2 reductive cleavage of thiol esters to thiols. 

Reduction of Sulfonyl Halides and Sulfonic Acids to Thiols... 

HI, also give the reduction. Sulfonic acids have been reduced to thiols with a mixture... 

A variety of solvents was investigated for this reaction, as shown in Table 15.1. As inferred from Table 15.1, the hydrogenolysis performance is best in more polar solvents snch as acetonitrile, acetone, ethyl acetate, and acetic acid. Only in o-dichlorobenzene is the rate of reaction ranch lower than predicted by the dielectric constant. The presence of nonpolar solvents snch as hexane and the thiol product resulted in large amonnts of the disnlfide intermediate. It has been shown that the disnlfide is the intermediate in stoichiometric rednctions such as samarium diiodide reduction of alkyl thiocyanates to thiols (11) so it is reasonable to expect it as the... 

The platinum(II) catalyzed reduction of civ,civ,/rart.v-diaminedihalodihydroxoplatinum(IV) complexes by ascorbate has been reported to proceed via a long-lived platinum(IV)-ascorbate radical.518 Ascorbate reduction of complexes with halides in the axial sites has been reported to proceed via reductive attack on one of these halides.519 This group also showed that reduction by A sc2 occurred seven orders of magnitude more rapidly than reduction by I IAsc and that H2Asc is unreactive.519 Reduction by thiols and methionine is strongly dependent on pH because of a similar variation in reactivity of the protonated and unprotonated forms of the reductants.505,514... 

Thiol esters undergo smooth reduction to give aldehydes by the Fukuyama hydrosilylation procedure, which is an alternative way to transform carboxylic acids to aldehydes. Upon treatment with Et3SiH and 10% Pd/C, a thioester underwent smooth reduction to give an aldehyde.409,410 For example, to a stirred mixture of thioester and Pd/C in acetone may be added Et3SiH at room temperature under an Ar atmosphere. Stirring is continued until the hydrogenolysis is complete (0.5-1 h) (Scheme 4.117). 

In a comparative study of disulfide reducing agents, it was determined that use of the relatively strong reductants DTT and TCEP required only 3.25 and 2.75 mole equivalents per mole equivalent of antibody molecule to achieve the reduction of two interchain disulfide bonds between the heavy chains of a monoclonal IgG (Sun et al., 2005). This limited reduction strategy retains intact bispecific antibody molecules while providing discrete sites for conjugation to thiols. 

The following protocol for labeling proteins with 5-IAF is adapted from Gorman (1987). It is a bit unusual in that it involves reduction of disulfides with dithiothreitol (DTT) and immediate reaction with 5-IAF in excess without removal of excess reductant. The procedure can be changed to include a gel filtration step after disulfide reduction to remove excess DTT, but in any case, it should be optimized for each protein to be modified. An alternative to the use of DTT to produce sulfhydryls is thiolation with a compound that can generate free thiols upon reaction with a protein (Chapter 1, Section 4.1). 

For complete reduction of all disulfides in the presence of a denaturant, react for 16 hours at 0°C and 2 hours at room temperature. For partial reduction of disulfides, the reaction time may be reduced to 2 hours at 37°C, particularly for antibody thiol reduction, if only partial reduction of thiols in the hinge region is done. 

Disulfides can be reduced to two thiols (Fig. 5.14). The best example is the reduction of oxidized glutathione (GSSG) back to the reduced form (GSH) (Fig. 5.14), which is mediated by glutathione reductase. In addition, exchange can occur with other thiols mediated by protein disulfide isomerase. In principle, sulfenic acids can probably also be reduced back to thiols, but because of the reactivity of the sulfenic acid, this is not generally observed. 

Single phase reduction Here, Au3+ ions are reduced to Au(I) by the addition of thiols followed by the complete reduction to Au(0) by adding reducing agents such as sodium borohydride (NaBH4) [2].The reaction can be represented as,... 

An intriguing use of a quaternary ammonium salt in a two-phase reaction is to be found with the regeneration of 1 -benzyl-1,4-dihydronicotinamide by sodium dithionite in a biomimetic reduction of thiones to thiols [12], The use of sodium dithionite in the presence of sodium carbonate for the 1,4-reduction of the pyri-dinium salts to 1,4-dihydropyridines is well established but, as both the dithionite and the pyridinium salts are soluble in water and the dihydropyridine and the thione are insoluble in the aqueous phase and totally soluble in the organic phase, it is difficult to identify the role of the quaternary ammonium salt in the reduction cycle. It is clear, however, that in the presence of benzyltriethylammonium chloride, the pyridine system is involved in as many as ten reduction cycles during the complete conversion of the thione into the thiol. In the absence of the catalyst, the thione is recovered quantitatively from the reaction mixture. As yet, the procedure does not appear to have any synthetic utility. 

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