Asymmetric oxidation of prochiral sulfides

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). ... 

Table 9.4 Asymmetric oxidation of prochiral sulfides ArSR by aq. H2O2 catalyzed by W03-cinchona alkaloids at 0°C...

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... 

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. 

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. 

Table 8 Asymmetric oxidation of prochiral sulfides to sulfoxides using (—)-AT-(phenylsulfonyl)(3,3-di-...

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). 

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. 

Several approaches have been described for the preparation of optically active sulfoxides [5-7]. The three main routes to obtain these compounds are as follows (i) the asymmetric sulfoxidation of prochiral sulfides, (ii) nucleophilic substitution using a chiral sulfur precursor, and (iii) the kinetic resolution of racemic sulfoxides. The first of tiiese methods involves the use of various oxidants and catalysts and has been the most extensively employed. There are many examples in the scientific literature and reviews are available on this approach. In recent years, much attention has been focused on the synthesis of organic sulfoxides by emplo5dng conditions compatible with the green chemistry procedures [8-10]. For this reason, mild oxidants such as molecular oxygen or hydrogen peroxide are considered in combination with novel catalysts in order to develop a mild and environmentally friendly process. 

Flavoprotein oxidases do not catalyze directly the oxidation of prochiral sulfides, but these biocatalysts have been used in combination with other oxidative enzymes to perform asymmetric sulfoxidations. Thus, flavoprotein oxidases are able to generate hydrogen peroxide in situ as a byproduct, which will be used as an oxidant by, for example, peroxidases or peroxygenases. This cascade methodology enhances the operational stability of peroxidases when compared with the one-pot addition of hydrogen peroxide. The direct addition of peroxides often leads to rapid inactivation of the employed enzyme [18]. 

In addition to the enantioselective preparation of 1,3-dithiane 1 -oxides, our group has been concerned with the development of novel methods for the catalytic asymmetric oxidation of other prochiral sulfides our currently preferred system employs an enantiomerically pure sulfonylimine and commercially available hydrogen peroxide.70... 

Asymmetric Oxidation of Sulfides. Prochiral sulfides are oxidized by (camphorylsulfonyl)oxaziridine (1) to optically active sulfoxides. Over-oxidation to sulfones is not observed (eq 1 ). However, the best chiral A-sulfonyloxaziridines for the asymmetric oxidation of sulfides to sulfoxides are the (+)- and (Phenylsulfonyl )(3,3-dichlorocamphoryl )oxazi ridinesfi... 

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

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