Formation of Cyclic Disulfides

The reaction has been extended to the synthesis of the analogous 3-alkylthio heterocycles (123) from the appropriate dithiobiurets (122).132 1-Substituted 2,4-dithiobiurets (125), unlike their monothio-biuret analogs (118), are unsuitable as precursors of 1,2,4-thiadiazoles, since in any oxidation the two thiol groups may be expected to react preferentially, resulting in the formation of cyclic disulfides (126). The formulation of such oxidation products as 1,2,4-thiadiazoles has indeed been discussed by Bambas1 however, the available evidence133 favors the cyclic disulfide structure.134... 

R = Et) yields, by the familiar Hugershoff cyclization,114 the substituted benzthiazole 128 and not the thiadiazolidine 129. In 1,5-dialkyl-aryl group suitable for benzthiazole formation, oxidation by iodine or bromine causes mainly S-dealkylation and subsequent formation of cyclic disulfides (126)137 in two cases, however, the formation of thiadiazolines (129 R = PhCH2, R = Me, R" = Me or Et and R = CH2=CHCH2, R=p-C6H4Me, R" = Me)137-138 as additional products in undisclosed yields, has been observed. 

Figure 19. Formation of cyclic disulfide derivative of 2-chlorovinyl arsonous acid using 3,4-dimercaptotoluene (16)...

In this reaction, 2 equiv of thiirane is consumed in the formation of each disulfide group. One equivalent of alkene is also formed. The proposed mechanism of formation of cyclic disulfides from thiirane is shown in Scheme 31. 

An alternative method for the formation of cyclic disulfide was invented by the reaction of S on alumina in two steps by making good use of solid support (Scheme 9) <92JOC2013>. 

An interesting synthetic approach to thietanes is the selective desulfurization of cyclic disulfides.The treatment of dithiolanes with a diethyl-aminophosphine results in a ring contraction to thietanes, (Eq. 19). This has been demonstrated with a-lipoic acid, a coenzyme with a dithiolane structure involved in the biological oxidation of pyruvic acid. The reaction is proposed to be initiated by the electrophilic attack of the phosphorus on the ring sulfur atom, resulting in the formation of an acyclic internal phosphonium salt, which by subsequent elimination of a phosphine sulfide, closes to the four-membered ring. °... 

Solid-phase chemistry was employed in the synthesis of cyclic disulfides. Scheme 12 shows a sequence of reactions that led to the formation of 1,2-dithiepane in 75% yield <2000TL9989>. 

There are currently four racemic PPIs available on the market omeprazole, lansoprazole, pantoprazole, and rabeprazole. (More recently, enantiomerically pure versions have also been studied and developed, e.g., S-omeprazole, marketed by AstraZeneca as esomeprazole see Chapter II-2.) Proton pump inhibitors share the same core structure, the substituted pyridylmethyl-sulfmyl-benzimidazole, but differ in terms of substituents on this core structure. The absolute requirements of the core structure for the activity of PPIs was not understood until it became clear that the active PPIs are derived from inactive prodrugs the prodrugs are transformed, in the acid-secreting parietal cells, by a unique cascade of chemical structural transformations leading to the active principle, a cyclic sulfenamide species. Inhibition of acid secretion in turn is then achieved by formation of covalent disulfide bonds with key cysteines of the (H+/K+)-ATPase. 

Formation of polycatenane network has recently been suggested by Endo et al. during the thermal polymerization of cyclic disulfides such as 1,2-dithi-ane, where involvement of the cyclic polymers in the polydisulfide formed is proved by mass spectrometry [268] (Scheme 55). The elastic properties of the corresponding polydisulfide is believed to come from the polycatenane network structure. 

A tin-directed cyclization technique was introduced for a selective formation of the monomer. This mild, template-driven ring closure gave a good yield of the desired monomer <86TL44i>. Thus, high yield preparations of cyclic disulfides, including 1,2-dithiolanes, 1,2-dithiane, 1,2-dithiepane, and up to 1,2-dithiacyclodecane, by this oxidative cyclization with bromine or iodine from the... 

Intramolecular reaction between two mercapto groups yields a cyclic disulfide and will be treated together with other problems of cyclization. Formation of intermolecular disulfide bridges connecting two identical chains requires merely dehydrogenation. 

A new easier approach to cyclic poly(aliphatic disulfide)s by catal3d ic transformation of thiiranes by (thiirane)W(CO)5 complexes has been studied (85,86). For this purpose, the new thiirane complexes such as W(CO)5(thiirane) (cl), W(CO)5(cis-dimethylthiirane) (c2), and W(CO)5(frans-dimethylthiirane) (c3) were prepared and characterized. It was found that cl, as W(CO)5(NCMe) (87) used earlier, transforms free thiirane (thiacyclopropane, ethylene sulfide) [420-12-2] (28) into a mixture of cyclic poly(disulfide)s (29), and ethylene, catalytically the compound (29a) was the major product ( 66%). Also, cis- and traras-dimethylthiirane were catalytically transformed hy c2 and c3 with the formation of small amounts of cyclic disulfides. The mechanism of these reactions has heen proposed. 

In the uterus, the production of 3, S -cyclic AMP is induced by the activation of the /7-adrenergic receptors and followed by inhibition of the electrical and mechanical activities. The action of oxytocin may be partly due to its ability to prevent the formation of cyclic AMP. The role of the reactive disulfide groups in the peptide receptors has already been discussed. The complexity of the receptor structure is pointed out by the observation that metals potentiate specifically the action of S-S polypeptides on the rat uterus, in such a way that it becomes very sensitive to vasopressin when the perfusion fluid contains a metal The order of metal potency is... 

Scheme 18 Synthesis of cyclic PSTY by the combination of reversible addition fragmentation chain transfer (RAFT) polymerization and the formation of a disulfide linkage...

The above method was adopted by Ballard [16] for the synthesis of the cyclic terpene gold(I) mercaptides and also by Fitch [19-22] during his studies. However, this common early route is not recommended when using expensive, or difficult to prepare mercaptan ligands, because of the use of the mercaptan as a sacrificial reductant with two molar equivalents required to effect the gold reduction. This formation of the disulfide as a by-product also means that careful separation of the desired product is required. 

Although a variety of oxidizing agents are available for this transformation it occurs so readily that thiols are slowly converted to disulfides by the oxygen m the air Dithiols give cyclic disulfides by intramolecular sulfur-sulfur bond formation An example of a cyclic disulfide is the coenzyme a lipoic acid The last step m the laboratory synthesis of a lipoic acid IS an iron(III) catalyzed oxidation of the dithiol shown... 

Dithiatopazine 73 serves as a sulfur-transfer reagent under thermal conditions. Tlius, heating 73 and diene 130 in toluene at 100°C formed a cyclic disulfide 131 (25%) and a tetrasulfide 132 (28%) with the formation of the alkene 118 (90%). Under similar conditions, the highly strained acetylene 133 was converted to the 1,2-dithiete 134 (65%) and the congested thiophene 135 (12%) (90JA3029). 

The cycloaddition of alkynes with the tributylphosphine-carbondisulfide adduct 131 results in the in situ formation of the ylides 132 which react with aldehydes to give the novel 2-arylidene or 2-alkylidene-l,3-dithioles 133 (Scheme 36) [132]. Concerning ylides C-substituted by sulfur we can also mention a publication on the behavior of various keto-stabilized ylides towards acyclic and cyclic a s-disulfides allowing the synthesis of substituted thiazoles, thiols, and dithiols [133]. 

The presence of two sulfhydryl groups in DTT and DTE, however, allows the formation of a favored cyclic disulfide during the course of target protein reduction (Figure 1.75). This drives the equilibrium toward the reduction of target disulfides. Therefore, complete reduction is possible with much lower concentrations of DTT or DTE than when using monothiol systems. 

Cyclic disulfides.1 Singlet sulfur is generated when 2,2 -dithiobenzoylbiphenyl is heated at 80-130° with formation of 9,10-diphenylphenanthrene (equation I). The S2 can be trapped by a Diels-AIder reaction with 1,3-dienes to form cyclic disulfides in 60-85% yield. 

Electrolytic reduction of H SO /HjSeO mixtures using aluminium electrodes results in the formation of a sulfur-selenium coating at the elwtrode Irradiation of a solution of SCg in carbon disulfide by sunhght for 1-2 hours at 20 °C results in the formation of various cyclic selenium sulfides The formation of Se Sg compounds is also initiated by refluxing the above solution . ... 

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