Tetracyclic sulfenamide

Proton pump inhibitors are prodrugs that require activation in an acid environment. After absorption into the systemic circulation, the prodrug diffuses into the parietal cells of the stomach and accumulates in the acidic secretory canaliculi. Here, it is activated by proton-catalyzed formation of a tetracyclic sulfenamide (Figure 36-2), trapping the drug so that it cannot diffuse back across the... 

An efficient methodology for the construction of pyrrolizidines and other polycyclic nitrogen heterocycles using a radical domino sequence has been revealed by Bowman and coworkers [46]. These authors employed sulfenamides as substrates, which easily form aminyl radicals by treatment with tributyltin hydride and AIBN. For instance, 3-101 smoothly underwent a twofold 5-exo-trig cyclization to give the tetracyclic pyrrolizidine product 3-105 in 90% yield (Scheme 3.26). As intermediates, the radicals 3-102 to 3-104 can be assumed. 

The key steps are (a) acid gradient-dependent accumulation of the prodrugs and (b) an add- or enzyme surfacecatalyzed conversion of the prodrugs to a sulfenic add and then to a tetracyclic, planar sulfenamide. A detailed mechanistic analysis of the chemistry behind the substituted benzimidazoles was published recently. Recent findings may suggest that the pump itself may play a role in its own inhibition in that perhaps the sulfenic acid is formed on the surface of the pump, and this is the reactive intermediate binding to the relevant cysteines. 

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