Ti-Salan catalyzed asymmetric sulfoxidation of pyridylmethylthiobenzimidazoles to optically pure proton pump inhibitors

•The new environmentally benign process for the synthesis of esomeperazole is reported.•The first asymmetric sulfoxidation of pyridylmethylthiobenzimidazoles on Ti-salan complexes.•The temperature dependence of enantioselectivity demonstrates isoinversion behavior.•The structure-reactivity relationships for the catalysts and the oxidation mechanism are discussed.

The asymmetric sulfoxidation of two pyridylmethylthiobenzimidazoles to anti-ulcer drugs of the PPI family (S)-omeprazole and (R)-lansoprazole with hydrogen peroxide, mediated by a series of chiral titanium(IV) salan complexes is reported. High sulfoxide yields (up to >95%) and enantioselectivities (up to 94% ee) have been achieved. The introduction of electron-withdrawing substituents leads to less active and less enantioselective catalysts. Like for the previously reported Ti-salalen catalyzed sulfoxidations, the temperature dependence of the sulfoxidation enantioselectivity in the presence of Ti-salan complexes is nonmonotonic, demonstrating isoinversion behavior with decreasing temperature. The oxidation is likely rate-limited by the formation of the active (presumably peroxotitanium(IV)) species, followed by a faster oxygen transfer to the substrate.

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