Thiophilic activators

Recently, a number of thiophilic activators that can activate thioglycosides of low reactivity at low temperature have been described. For example, thiophilic promoter systems, such as diphenylsulfoxide [87,99], S-(4-methoxyphenyl)benzenethiosulfinate... 

The strong interest in 1-thioaldoses and 1-thioglycosides (66,201) as a consequence of their recent use as anomeric protecting-groups, and concomitantly for glycosyl transfer with the help of thiophilic activators, led to... 

Pyruvated glycosyl donors (halides and trichloroacetimidates) are conveniently prepared from the corresponding alkyl or aryl 0- and S-glycosides or from 1-0 unprotected glycoses using standard methods [39d,41]. In addition, 1-thio-glycosides can be used directly as pyruvated glycosyl donors when adequate thiophilic activations are applied [39b, d]. 

Further elongations of the sugar chain should therefore be performed with trichloroacetimidates when pyruvated glycosyl donors are involved. Thus, disaccharide 15 is converted into imidate 17 and coupled to the thio-glycoside 18 (Scheme 4) [44]. Now, for the formed trisaccharide 19, thiophilic activation can be applied without any problems, since here a normal donor is involved. Coupling to acceptor 20 followed by deblocking furnishes the tetrasaccharide 21, which can be coupled to a protein via its aminopentyl aglycon. 

Since other thiophilic activation systems (DMTST [48], NIS-TfOH [60,61], PhSeOTf [62], NBS-Bu4NOTf or Ph2lOTf [63], MeSBr-AgOTf [64]) are also compatible with the acetonitrile assistance, the combined use of a thioglycoside donor and acetonitrile (or other nitrile solvents) became a powerful option for a-sialoside synthesis, being parallel with C3-appended donors. 

Figala V, Klemm K, Kohl B, et al. Acid activation of H -K -ATPase inhibiting 2-(2-Pyridylmethylsulphinyl) benzimidazoles isolation and characterization of the thiophilic active principle and its reactions. J Chem Soc Chem Commun 1986 125-127. 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

Scheme 5.1 Mechanism of thioglycoside activation (a) by thiophiles X1 such as /V-bromosuccinimicle (NBS), 11,12 methyl triflate,13 dimethyl(methylthio)sulfonium triflate (DMTST),14 phenylselenyl triflate (PhSeOTf),17,18 iV-iodosuccinimide/triflic acid (MS/TfOH),19 20 and iodonium di-sym-collidine perchlorate (IDCP)21 (b) by tris(4-bromophenyl)ammoniumyl hexachloroantimonate (TBPA,+)25 and (c) via anomeric sulfoxides.26 The stereochemical outcome of these glycosylations follows the same general trends as with many other glycosyl donor/promoter combinations (m-CPBA = mcta-chloroperbenzoic acid).

The proton pump inhibitors are lipophilic weak bases (pKa 4-5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H +, K+ ATPase, irreversibly inactivating the enzyme. 

Fluorine/iodine mixtures, which can be regarded as sources of both iodonium and fluoride ion, have been used to prepare glycosyl fluorides from the corresponding thioglycosides and gem-difluorides from some diaryl-1,3-dithio-lanes (Fig. 68) [161,162]. Activation of the carbon-sulfur bond towards nucleophilic attack by fluoride ion is achieved by complexation of the thiophilic iodonium species with the sulfur atoms. 

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