Catalytic asymmetric oxidation of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide catalyzed by a titanium complex with (S,S)-N,N′-dibenzyl tartramide ligand

A chiral titanium complex, formed in situ from Ti(Oi-Pr)4, (S,S)-N,N′-dibenzyl tartramide and water was found to serve as an efficient catalyst for the asymmetric oxidations of 1H-benzimidazolyl pyridinylmethyl sulfides with cumene hydroperoxide (CHP) in the absence of a base. Several proton pump inhibitors (PPIs), such as esomeprazole, lansoprazole, rabeprazole and pantoprazole were obtained in high yield (up to 92%) and excellent enantiomeric excess (up to 96%).

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(S)-5-Methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzo[d]imidazole (esomeprazole)C17H19N3O3S95% ee[α]D25=-152.0 (c 0.1, CHCl3)Absolute configuration: (S)Source of chirality: (S,S)-N,N′-Dibenzyl tartramide

(S)-2-([3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole (lansoprazole)C16H14F3N3O2S94% ee[α]D25=-199.7 (c 1.0, acetone)Absolute configuration: (S)Source of chirality: (S,S)-N,N′-Dibenzyl tartramide

(S)-2-([4-(3-Methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo[d]imidazole (rabeprazole)C18H21N3O3S94% ee[α]D25=-135.0 (c 0.05, CHCl3)Absolute configuration: (S)Source of chirality: (S,S)-N,N′-Dibenzyl tartramide

(S)-6-(Difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo[d]imidazole (pantoprazole)C16H15F2N3O4S96% ee[α]D25=-95.5 (c 0.3, MeOH)Absolute configuration: (S)Source of chirality: (S,S)-N,N′-Dibenzyl tartramide