Asymmetric oxidation of the sulfide

Omeprazole can be made by reaction of a substituted diaminobenzene to make the benzoimidazole [38]. Alkylation of the thiol gives the sulfide which is then oxidized to the sulfoxide, omeprazole. The omeprazole can be separated into the two enantiomers. Preferably, asymmetric oxidation of the sulfide is done to selectively prepare the S enantiomer, esomeprazole. 

The same catalysts have been investigated for the asymmetric oxidation of dialkyl sulfides using PhIO as the oxidant in CH3CN perfluorooctane.[54] Although the conversions (>80%) and selectivities to sulfoxides (>90%) were generally good, and the more heavily fluorinated catalysts could be recycled 4 times with only small drops... 

An attractive route to chiral sulfoxides is based on asymmetric oxidation of unsymmetrical sulfides by means of chiral oxidizing reagents. The first asymmetric oxidation of sulfides with optically active pera-cids (eq. [1]) has been independently described in 1960 by two groups headed by Montanan (36) in Italy and by Balenovic (37) in... 

In contrast to asymmetric oxidation of unsymmetrical sulfides with chiral peracids, microbial oxidation usually gives much better results. Thus, optically active phenyl benzyl sulfoxide was prepared by oxidation of the parent sulfide via fermentation with Aspergillus niger, NRRL 337, with 18% optical purity (42). Similarly, asymmetric... 

The asymmetric oxidation of prochiral sulfides has become the method of choice for the synthesis of optically active sulfoxides. The first examples of a really efficient asymmetric oxidation of snlfides to sulfoxides were independently reported by Pitchen... 

Chiral sulfoxides have emerged as versatile building blocks and chiral auxiliaries in the asymmetric synthesis of pharmaceutical products. The asymmetric oxidation of prochiral sulfides with chiral metal complexes has become one of the most effective routes to obtain these chiral sulfoxides.We have recently developed a new heterogeneous catalytic system (WO3-30% H2O2) which efficiently catalyzes both the asymmetric oxidation of a variety of thioethers (1) and the kinetic resolution of racemic sulfoxides (3), when used in the presence of cinchona alkaloids such as hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether [(DHQD)2-PYR], Optically active sulfoxides (2) are produced in high yields and with good enantioselectivities (Figure 9.3). ... 

Asymmetric oxidation of prochiral sulfides is one of the most effective routes for the preparation of chiral sulfoxides. These latter molecules attract great interest, as they are useful synthons for some drugs. They can also be used as chiral auxiliaries due to their configurational stability. The oxidation can be performed by using complexes... 

The oxidation of sulfides to sulfoxides by TBHP in the presence of Mo and V catalysts has been extensively studied.230,256 A modified Sharpless reagent,243 i.e. Ti(OPr )4/2 diethyl tartrate/1 H20, was used for the asymmetric oxidation of prochiral sulfides to sulfoxides with enantiomeric excess greater than 90% (equation 82).160,257... 

In 1984 the Padua group described the asymmetric oxidation of some sulfides with I-butyl hydroperoxide in the presence of 1 mole equiv. of Ti(0-i-Pr)4 / (R,R)-DET (1 4) combination... 

Cotton etal. [14] described an asymmetric synthesis of esomeprazole. Esomeprazole, the (S)-enantiomer of omeprazole, was synthesized via asymmetric oxidation of prochiral sulfide 5-methoxy-2-[[(4-methoxy-3,5-dimethyl pyridin-2-yl)methyl]thio]-lH-benzimidazole 1. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide in the presence of (S,S)-diethyl tartarate (DET). The enan-tioselectivity was provided by preparing the titanium complex in the presence of sulfide 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of sulfide 1 in the presence of amine. An enantioselectivity of 94% ee was obtained using this method. 

The large-scale production of esomeprazole is now successfully achieved by asymmetric oxidation of the same sulfide intermediate as is used in the production of omeprazole (Scheme 2.5). Using the titanium-based catalyst originally developed by K. Barry Sharpless for allyl alcohol oxidation [56] and by H.B. Kagan for certain sulfide oxidations [57], a process was developed that could achieve initial enantiomeric excesses of about 94% [53]. During the production process, the optical purity is further enhanced by the preparation of esomeprazole magnesium salt, with subsequent re-crystallization. 

Using the clear homology of epoxidation of olefin and the oxidation of sulfide, Jacobsen and co-workers65 and Katsuki and co-workers66,67 applied their system developed for the asymmetric epoxidation of simple olefin to the asymmetric oxidation of prochiral sulfides. 

Oxidation by chiral oxaziridines. For more than a decade, Davis s group49,71 76 has been working on the stoichiometric asymmetric oxidation of prochiral sulfides. In a series of elegant and important papers, they have demonstrated that their approach is one of the best methods in the synthesis of chiral sulfoxides. This research has yielded four generations of chiral oxaziridines 41- 44 exhibiting different stereoselectivities as a result of their dissimilar active-site structures (Fig. 5). 

Chiral sulfoxides. The Sharpless reagent lor asymmetric epoxidation also effects asymmetric oxidation of prochiral sulfides to sulfoxides. The most satisfactory results are obtained for the stoichiometry Ti(0-(-Pr)4/L DET/H20/(CH,),C00H = 1 2 1 2 for I equiv. of sulfide. In the series of alkyl p-tolyl sulfides, the (R)-sulfoxide is obtained in 41-90% ee the enantioselectivity is highest when the alkyl group is methyl. Methyl phenyl sulfide is oxidized to the (R)-sulfoxide in 81% ee. Even optically active dialkyl sulfoxides can be prepared in 50-71% ee the enantioselectivity is highest for methyl octyl sulfoxide. 

The asymmetric oxidation reaction of prochiral poly(ester 0-sulfide)s to optically active poly(ester 0-sulfoxide)s can be accomplished with almost theoretical chemoselactivity and moderate to high enantioselectivity degrees. While the asymmetric oxidation of prochiral sulfides should not be a preparative method for chiral sulfoxides, we expect that the structure of the parent polymers might be specifically designed for the preparation of chiral thermotropic poly(ester 0-sulfoxi-de)s. 

Asymmetric oxidation of the prochiral sulfide (pyrmetazol), the penultimate intermediate in the manufacture of omeprazole (see Fig. 5). 

When (R)-binaphtol 3.7 (R = H) is used as a titanium ligand, the catalytic asymmetric oxidation of arylmethylsulfides by fe/7-BuOOH in the presence of water in CCI4 leads to (i )-sulfbxides [815, 947, 1514], In tins reaction, the initial oxidation of the sulfide into the chiral sulfoxide takes place with a moderate ee (= 50%). This step is fbllowed by further oxidation of the sulfoxides with kinetic resolution ( 1.6) [815, 1514]. To observe a high enantiomeric excess (> 90%), it is necessary to oxidize the minor (S)-enantiomer into the corresponding sulfone, and the chemical yield of the sulfoxide is in the 45 - 65% range. 

The asymmetric oxidation of sulfides represents a straightforward access to chiral sulfoxides that are useful compounds for asymmetric synthesis as chiral auxiliaries and also for the synthesis of biologically active molecules. Among the different methods to perform these reactions, titanium-mediated thioether oxidation is one of the most attractive. Indeed, Kagan ° and Modena independently showed that the use of chiral titanium complexes derived from Sharpless reagent allows the asymmetric oxidation of prochiral sulfides (Scheme 7.6). 

Various metallocene sulfoxides of quite high ee s are now available through the asymmetric oxidation of the corresponding sulfides by the Kagan reagent (Scheme... 

The catalytic asymmetric oxidation of prochiral sulfides by chemical means is a difficult task. While a number of workers have been active in this area during the past few years, few systems simultaneously show good induction of chirality and good catalytic activity. The most common catalysts involve transition-metal complexes (homogeneous or supported) as well as chiral electrodes. These approaches are described successively below. 

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