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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