Sulfoxidation, asymmetric

1 Asymmetric oxidation of sulfides and kinetic resolution of sulfoxides 

In the area of metal catalyzed asymmetric sulfoxidation there is still much room for improvement. The most successful examples involve titanium tartrates, but at the same time often require near stoichiometric quantities of catalysts [301, 302]. Recently, this methodology has been successfully used for the production of (S)-Omeprazole by AstraZeneca [303] (see Fig. 4.110). A modified Kagan-pro-cedure [302] was applied, using cumene hydroperoxide as the oxidant. Another example is the sulfoxidation of an aryl ethyl sulfide, which was in development by Astra Zeneca as a candidate drug for the treatment of schizophrenia. In this case the final ee could be improved from 60% to 80% by optimising the Ti tar-trate ratio [304]. 

From a practical viewpoint the recently discovered vanadium-based and iron-based asymmetric sulfoxidation with hydrogen peroxide is worth mentioning [305, 306]. For vanadium, in principle as little as 0.01 mol% of catalyst can be employed (Fig. 4.111). With tridentate Schiff-bases as ligands, formed from readily available salicylaldehydes and (S)-tert-leucinol, ees of 59-70% were obtained for thioanisole [305], 85% ee for 2-phenyl-l,3-dithiane [305] and 82-91% ee for tert-butyl disulfide [307]. For iron, similar results were obtained using 4 mol% of an iron catalyst, synthesized in situ from Fe(acac)3 and the same type of Schiff base ligands as in Fig. 4.111 (see Ref. [306] for details). 

Finally, but certainly not least, we note that the enzyme chloroperoxidase (CPO), catalyzes the highly enantioselective ( 98% ee) sulfoxidation of a range of substituted thioanisoles [308]. In contrast to the epoxidation of alkenes, where turnover frequencies were low (see above), in the case of sulfoxidation of thioa-nisole a turnover frequency of around 16 s-1 and a total turnover number of 125000 could be observed. A selection of data is represented in Fig. 4.112. Besides aryl alkyl sulfides, also dialkylsulfides could be oxidized with reasonable enantioselectivities [27]. 

Another class of peroxidases which can perform asymmetric sulfoxidations, and which have the advantage of inherently higher stabilities because of their non-heme nature, are the vanadium peroxidases. It was shown that vanadium bromoperoxidase from Ascophyllum nodosum mediates the production of (R)-methyl phenyl sulfoxide with a high 91% enantiomeric excess from the corresponding sulfide with H202 [38]. The turnover frequency of the reaction was found to be around 1 min-1. In addition this enzyme was found to catalyse the sulfoxidation of racemic, non-aromatic cyclic thioethers with high kinetic resolution [309]. 

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Asymmetric sulfoxidation catalyzed by a Vanadium-dependent bromoperoxidase... 

The oxidation of heteroatoms and, in particular, the conversion of sulfides to asymmetric sulfoxides has continued to be a highly active field in biocatalysis. In particular, the diverse biotransformations at sulfur have received the majority of attention in the area of enzyme-mediated heteroatom oxidation. This is particularly due to the versatile applicability of sulfoxides as chiral auxiliaries in a variety of transformations coupled with facile protocols for the ultimate removal [187]. 

Enantiomerically pure sulfoxides play an important role in asymmetric synthesis either as chiral building blocks or stereodirecting groups [156]. In the last years, metal- and enzyme-catalyzed asymmetric sulfoxidations have been developed for the preparation of optically active sulfoxides. Among the metal-catalyzed processes, the Kagan sulfoxidation [157] is the most efficient, in which the sulfide is enantioselectively oxidized by Ti(OzPr)4/tBuOOH in the presence of tartrate as chirality source. However, only alkyl aryl sulfides may be oxidized by this system in high enantiomeric excesses, and poor enantioselectivities were observed for dialkyl sulfides. 

Enzymes, in particular peroxidases, catalyze efficiently the enantioselective oxidation of alkyl aryl sulfides and also dialkyl sulfides, provided that the alkyl substituents are sterically differentiable by the enzyme. The peroxidases HRP, CPO, MP-11, and the mutants of HRP, e. g. F41L and F4IT, were successfully used as biocatalysts for the asymmetric sulfoxidation (Eq. 14). A selection of sulfides. 

SCHEME 101. Uncatalyzed asymmetric sulfoxidation with chiral hydroperoxides as oxidants... 

SCHEME 105. Asymmetric sulfoxidation using Kagan s or Modena s catalytic system... 

The results of the titanium-promoted asymmetric sulfoxidation of various sulfides using stoichiometric amounts of Ti(OPr-i)4/(R,R)-DET/hydroperoxide are shown in Table 27. 

In 2001, Scettri and coworkers could show that titanium-catalyzed asymmetric sulfoxidation with a tertiary furyl hydroperoxide 188a can be achieved under catalytic conditions by a modification of Uemura s approach employing (R)-BINOL as chiral ligand (equation 57). Under these conditions sulfoxides could be isolated in medium to good... 

SCHEME 110. Asymmetric sulfoxidation with various chiral metal catalysts... 

SCHEME 113. Ti/DET-catalyzed asymmetric sulfoxidation using a steroidal furyl hydroperoxide 191a as oxidant... 

A further catalytic method for asymmetric sulfoxidation of aryl alkyl sulfides was reported by Adam s group, who utilized secondary hydroperoxides 16a, 161 and 191b as oxidants and asymmetric inductors (Scheme 114) . This titanium-catalyzed oxidation reaction by (S)-l-phenylethyl hydroperoxide 16a at —20°C in CCI4 afforded good to high enantiomeric excesses for methyl phenyl and p-tolyl alkyl sulfides ee up to 80%). Detailed mechanistic studies showed that the enantioselectivity of the sulfide oxidation results from a combination of a rather low asymmetric induction in the sulfoxidation ee <20%) followed by a kinetic resolution of the sulfoxide by further oxidation to the sulfone... 

An overview of the obtained results of the titanium-catalyzed asymmetric sulfoxidation of various sulfides with different optically pure hydroperoxides as oxidant and asymmetric inductor is given in Table 29. 

TABLE 29. Results of the titanium-catalyzed asymmetric sulfoxidation with optically pure hydroperoxides (yields are given and ee values are given in brackets)... 

Katsuki reported that di-/r-oxo Ti(salen) complex 88 was an excellent catalyst for asymmetric sulfoxidation with UHP adduct as oxidant in methanol (ee 92-99%) . The same group found that 88 dissolved in MeOH rapidly dissociated into a monomeric Ti(salen) complex 89, which reacted with H2O2 to give rise to the corresponding peroxo species 90, active in the oxidation process " (equation 51). 

Hogan, P. J., Hopes, P. A., Moss, W. O., Rohinson, G. E. and Patel, I. Asymmetric Sulfoxidation of an Aryl Ethyl Sulfide Modification of Kagan Procedure to Provide a Viable Manufacturing Process. Org. Process Res. Dev. 2002, 6, 225-229. 

Asymmetric sulfoxidation of aryl methyl sulhdes wra hydrogen... 

ASYMMETRIC SULFOXIDATION OF ARYL METHYL SULFIDES WITH HYDROGEN PEROXIDE IN WATER... 

The procedure is very easy to reproduce and the asymmetric sulfoxidation may be applied to a relatively large range of aryl methyl sulfides (Table 9.7). Remarkable features are (i) easy isolation of the enantioenriched products from the catalyst by simple diethyl ether/water-SDS two phase separation (ii) use of green and... 

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