Mechanism of the Asymmetric Sulfoxidation in the Esomeprazole Process: Effects of the Imidazole Backbone for the Enantioselection

Abstract

Abstract:The asymmetric sulfoxidation reaction of imidazole-based prochiral sulfides was studied to explore the mechanistic details of the highly efficient esomeprazole process, which is one of the few industrial scale catalytic asymmetric procedures. The synthetic studies revealed that the smallest subunit governing the selectivity in the esomeprazole process is an imidazole ring. Thus, by using the esomeprazole procedure methyl imidazole sulfide could be oxidized as efficiently as its several functionalized derivatives, including pyrmetazol. However, alkylation of the imidazole nitrogen led to a major drop of the enantioselectivity. Our atmospheric pressure chemical ionization-mass spectrometry (APCI/MS) studies indicate that addition of small amounts of water to the reaction mixture facilitates the formation of mononuclear titanium species, which are the active catalytic intermediates of the selective oxidation reaction. One of the most important features of the esomeprazole procedure is that amine additives increase the enantioselectivity of the oxidation process. The NMR studies of the presumed reaction intermediates show that under catalytic conditions the amines are able to coordinate to titanium and dissociate the coordinated imidazole substrate. The density functional theory (DFT) modelling studies provided new insights in the mechanism of the asymmetric induction. It was found that the oxidation requires a lower activation energy if the imidazole sulfide precursor does not coordinate to titanium. Two possible reaction paths were explored for this out of sphere oxidation mechanism. The most important interaction governing the enantioselection is hydrogen bonding between the N À H of the imidazole ring and the chiral tartrate ligand on titanium. Furthermore, the oxidation reaction imposes an important structural constraint to the TS structure involving a linear arrangement of the peroxide oxygens and the sulfur atom. This constraint and the N coordination of imidazole leads to a very strained structure for the inner sphere mechanism of the oxidation, which leads to a much higher activation barrier than the corresponding out of sphere process, and therefore it is unlikely.

A Study of Factors Affecting Enantioselectivity in the Oxidation of Aryl Benzyl Sulfides in the Presence of Chiral Titanium Catalysts

“…[7,8] For many years, titanium catalyst chemistry in the oxidation of sulfides has focused mainly on the synthetic aspects, whereas mechanistic investigations have seldom been reported. [11][12][13] However, in 2009, three similar studies [6,14,15] on titanium-catalyzed enantioselective oxidation of sulfides were published, two of them [6,15] also considered theoretical aspects.…”

“…[6] It was pointed out that, in contrast to Sharpless-like catalysts, the active complex should contain a single titanium atom. Formation of a similar complex was reported to be favored by the addition of water, [6] which is absent in the Sharpless enantioselective epoxidation.…”

“…[6] It was pointed out that, in contrast to Sharpless-like catalysts, the active complex should contain a single titanium atom. Formation of a similar complex was reported to be favored by the addition of water, [6] which is absent in the Sharpless enantioselective epoxidation. When the investigation on the oxidation was extended to small molecules that are structurally related to the omeprazole sulfide, such as alkyl imidazolyl sulfides, high enantioselectivity (Ͼ94 % ee) was frequently observed.…”

“…[1][2][3] Some sulfoxides are very important on their own right, [4] for instance, the anti-ulcer agent (S)-omeprazole. [5,6] Indeed, this drug is nowadays one of the best-selling drugs, and it is produced on a multi-ton-per-year scale. [6] Among the various strategies that have been employed to produce optically active sulfoxides, [1][2][3] special interest has focused on the enantioselective oxidation of sulfides, [7,8] in a procedure that is also preferentially employed in the industrial synthesis of bioactive target molecules.…”

“…[5,6] Indeed, this drug is nowadays one of the best-selling drugs, and it is produced on a multi-ton-per-year scale. [6] Among the various strategies that have been employed to produce optically active sulfoxides, [1][2][3] special interest has focused on the enantioselective oxidation of sulfides, [7,8] in a procedure that is also preferentially employed in the industrial synthesis of bioactive target molecules. [7,8] Furthermore, in our previous work [9] we have shown that the enantioselective oxidation is a valuable strategy for preparing sulfoxides bearing carbanionic leaving groups; this approach opens a route to many other sulfoxides that are [ not easily produced by other methods, through a straightforward displacement reaction with Grignard reagents.…”