Cyclic sulfenamides

The anti-ulcer agents omeprazole, lanzoprazole, and pantoprazole have been introduced during the past decade for the treatment of peptic ulcers. Gastric acid secretion is efficiently reduced by prazole inhibition of H+K+-ATPase in the parietal cells of the gastrointestinal mucosa [75]. The prazoles themselves are not active inhibitors of the enzyme, but are transformed to cyclic sulfenamides in the intracellular acidic compartment of parietal cells [76]. The active inhibitors are permanent cations at pH < 4, with limited possibilities of leaving the parietal cells, and thus are retained and activated at the site of action. In the neutral body compartments the prazoles are stable, and only trace amounts are converted to the active drugs. (For a review on omeprazole, see Ref. [77].)... 

Ames and Kovacic [45] studied the electrochemistry of omeprazole, active metabolites and a bound enzyme model, with possible involvement of electron transfer in the antiulcer action of the drug. The active metabolites cyclic sulfenamide and sulfur radical entities, exhibited reduction potentials of 0.3 and 0.2 V, respectively. The value for the bound enzyme model was 0.7 V and that for omeprazole was >1.4 V. The results lend credence to the hypothesis that electron transfer comprises part of the mode of action in addition to H+/K+-ATPase inhibition. 

The addition of 70% HPF6 led to the production of crystals of this intermediate. Although too unstable to recrystallize, it was possible to obtain crystals for an X-ray investigation of a PF6 salt of an omeprazole analogue, revealing the cyclic sulfenamide structure of the intermediate (Fig. 2.8) [20]. 

Fig. 3.9 The acid-catalyzed rearrangement of the substituted benzimidazole pantoprazole (prodrug) to the cyclic sulfenamide (active principle) and its reaction with thiols.

The elusive nature of the cyclic sulfenamide is exemplified by its instability in aqueous weakly acidic or neutral solution. However, under conditions which resemble those of the parietal cell (e.g., 0.1 M HC1), the cyclic sulfenamide was fairly stable if, in addition, the concentrations were in the micromolar range. With isolated cyclic sulfenamides in hand, the study of the reaction of this species with thiols (e.g., mercaptoethanol) in different solvents and in different acidic solutions could easily be performed, and compared with similar reactions starting with the... 

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. 

A -Methyl pyrroloisothiazolones 34 (R =C02Me, NO2 R = H, Me) show downfield H NMR chemical shifts with respect to N-methylated open-chain or cyclic sulfenamides (see Sections 4.05.6.3.4 and 4.05.9.1.1). This behavior can be attributed to a strong deshielding effect caused by a partial positive charge on the N-atom, as depicted in the zwitterionic resonance structure 34a (Equation 4) <2003HCA2471>. 

The desulfurization of episulfides by d.v-oxaziridine (56) appears to be a general reaction affording the alkene, dimethylsulfur diimide (MeN=S=NMe), and azomethane (MeN=NMe) (80JOC1691). These latter products are formed via the intermediate thionitrosomethane (59) (Equation (8)) which was trapped with 2,3-butadiene to give the cyclic sulfenamide (60) in 22-33% yield. The alkenes are formed in good to excellent yield (80-90%) with retention of configuration. 

Yang J, Groen A, Lemeer S et al (2007) Reversible oxidation of the membrane distal domain of receptor PTPalpha is mediated by a cyclic sulfenamide. Biochemistry 46 709-719... 

Behaving like cyclic sulfenamides the 2,3-dihydro[l,2,4]thiadiazolo[4,3-a]benzimidazo-3-ones (111) react with amines suffering cleavage of the A, 5 -bond A -substituted benzimidazol-2-ylsul-fenamides (126) and the corresponding 1,3-disubstituted ureas are obtained (Equation (24)) <85JCS(P1)1007>. 

Scheme 14 Reactions of cyclic sulfenamides 97 with oxalyl chloride...

In vivo omeprazole is transformed into the active inhibitor, a cyclic sulfenamide (Figure 36.34), which forms disulfide bridges with the thiol groups of the enzyme and thus inactivates The high specificity in the action... 

Among a host of other phosphine-catalysed reactions in which the initial step is the formation of a reactive phosphoniobetaine intermediate by addition to a carbon-carbon double or triple bond are intramolecular cyclisations leading to benzobicyclo[4,3,0]-compounds, " cyclic ethers " and lactones,and a great many intermolecular reactions, e.g., a [3 -b 3]-annulation of modified t-butyl allylic carbonates and alkylidenemalonitriles to give cyclohexenes,phosphine- (and fluoride)- catalysed routes to 1,4-benzothiazepines from cyclic sulfenamides and alkynes, a [4- -3]-annu-lation of allylic carbonates with methyl coumalate to give functionalised bicyclo[3.2.2]nonadienes, the a-carbon addition of cyanide ion, generated in situ from cyanohydrins, to activated alkynes, and a stereoselective... 

A new stable sulfenylating reagent 3-phenylsulfenyl-2-GV-cyano-imino)thiazolidine 57 has been described. It reacts with amines or thiols to give sulfenamides or disulfides in excellent yields. a-Sulfenylation of carbonyl compounds also proceeds smoothly and if an optically active 4-diphenylmethyl substituent is attached to the thiazolidine ring (58), the cyclic (3-ketoester 59 can be sulfenylated in high yield with an ee of 96% to give the sulfide 60 <00SL32>. 

The condensation reaction of cyclic amidines with trichloromethylsulfenyl chloride yields sul-fenamides, which afford 5-arylimino-l,2,4-thiadiazolines on treatment with aromatic amines <84CHEC-I(6)463>. An example of this type of reaction starting from 2-amino-4-arylthiazoles (271) affords 3/f-thiazolo[2,3-c]-l,2,4-thiadiazoles (272), via the sulfenamide (270) (Scheme 60) <88IJC(B)501>. 

In a series of publications (75JOC2600, 70JOC1965, 73JOC3087), Potts and coworkers have reported that cyclic amidines (290) readily condense with trichloromethylsulfenyl chloride (329) to yield the sulfenamides (330 Scheme 119). Treatment of the latter compounds with aromatic amines in the presence of triethylamine results in cyclization, possibly via an intermediate such as (331), to produce bicyclic products of type (332). Heterocycles (290) which have been used successfully in this reaction include 2-amino-l,3,4-thiadiazoles, 3-aminopyridazines, 2-aminopyrimidines, 2-aminopyrazines, 2-aminopyridines, 3-aminoisoxazoles and 5-amino-1,2,4-thiadiazoles. The sulfenamide derivative (330) of 2-aminopyridine also was found to react with sodium sulfide and with diethyl malonate to produce (333) and (334) respectively. Attempts to hydrolyze (332) to (295) under acidic conditions failed. 

The addition of allylboronates (105) and (106) to aryl sulfenimines (104) to provide sulfenamides (107) has also been reported by Wuts and Jung (equation 23). High yields of (107) are obtained even though the reaction is slow (4 h to 3 d, refluxing toluene). The reaction rate is a function of the size of the boronate ligand (106 is slower than 105). The authors attribute the reaction sluggishness to a cyclic boro-nate transition state. 

There are four preparation methods for S-acyl sulfenamides 96 (1) RC(0)SX (X=Cl,Br,I)+R NH [20,284] (2) M(RCOS) (M=Na,K)+R NCl [78,229,262] (3) M(RCOS) (M=Na, K) + sodium hydroxylamine-0-sulfonate (see Scheme 13) [262] (4) addition reaction of RCOSH to activated N=N double bond [67]. The cyclic compounds 97, such as benzoisothiazolinones, have also been obtained by oxidizing the corresponding isothiazolthiones with KMn04 [198] or iso-propylethylenoxide [82] and by heating bis(o-aminobenzoyl) disulfide in acetic acid [64]. 

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