Thioethers, asymmetric oxidation

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). ... 

The asymmetric oxidation of thioethers as well as kinetic resolution of sulfoxides with 30% H2O2 catalyzed by a stable, recyclable and commercially avialable solid WO3 catalyst provides a simple and effective procedure for the preparation of chiral sulfoxides in good enantimeric purity. The procedure is very easy to perform. 

Diethyl tartrate is the best tartaric acid derivative for enantioselective oxidation of thioethers. This finding was established for the asymmetric oxidation of methyl p-tolyl sulfide with cumene hydroperoxide, that is, 96% ee (DET) 87% ee (diisopropyl tartrate) 62% ee (dimethyl tartrate) [24] and 1.5% ee (bis A, V-dimethy I tart rami de, r-BuOOH as the oxidant) [17]. 

Major interest has been expressed in the synthesis of chiral sulfoxides since the early 1980s, when it was discovered that chiral sulfoxides are efficient chiral auxiliaries that are able to bring about important asymmetric transformations [22]. Sulfoxides are also constituents of important drugs (e.g., omeprazole (Losec , Priso-lec )) [23]. There is a plethora of routes of access to enantioenriched sulfoxides, and many involve metal-catalyzed asymmetric oxidations [24]. Examples of ruthenium metal-based syntheses of sulfoxides are scarce, presumably due to the tendency of sulfur atoms to bind irreversibly to a ruthenium center. Schenk et al. reported a dia-stereoselective oxidation of Lewis acidic Ru-coordinated thioethers with dimethyl-dioxirane (DMD) (Scheme 10.16) [25[. Coordination of the prochiral thioether to the metal is followed by diastereoselective oxygen transfer from DMD in high yield. The... 

If the asymmetric oxidation is applied on racemic thioethers diastereomeric products result. In the case of an efficient kinetic resolution [20] both sulfide and sulfoxide can be obtained in optically active form. An elegant application of this principle was described by Gibson nee Thomas in the resolution of planar chiral racemic 9 [21]. 

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). 

Thioethers can be asymmetrically oxidized both by bacteria (e.g., Corynebacte-rium equi [1186], Rhodococcus equi [1187]) and fungi (e.g., Helminthosporium sp. [1188] and Mortierella isabellina [1189]). Even baker s yeast has this capacity [1190, 1191]. As shown in Scheme 2.158, a large variety of aryl-alkyl thioethers were... 

More recently, Kraus has reported the use of flavin-cyclodextrin conjugate catalyst 41 for the asymmetric oxidation of both aromatic and aliphatic methyl thioethers, using hydrogen peroxides in a phosphate buffer (Scheme 19.19) [120, 121]. 

The hydrogen peroxide-mediated oxidation of p-tolyl methyl sulfide with chiral iminium salt 20 (Figure 19.9), reported in 1993, gives a 32% ee [81]. The use of chiral flavinium salt catalysts afforded a 65% ee for the same transformation [119], More recently, Kraus has reported the use of flavin-cyclodextrin conjugate catalyst 41 for the asymmetric oxidation of both aromatic and aliphatic methyl thioethers, using hydrogen peroxides in a phosphate buffer (Scheme 19.19) [120, 121]. 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

Oxidation of divalent sulfur atoms in thioethers is a common biotransformation of sulfur-containing compounds [Eq. (9)]. Oxidation proceeds in two stages, first to the sulfoxide and then to the sulfone. Sulfoxides have increased polarity and are often observed as excreted metabolites, but they can also be reduced back to the sulfide. Formation of the sulfoxide creates an asymmetric center, and stereospecific oxidation can occur. Sulfones tend to be terminal metabolites no evidence for their reduction exists. 

Very recently, Fedin, Kim and colleagues synthesized a homochiral metalorganic polymeric material, [Zn2(bdc)(L-lac)(dmf)] (DMF) (36), by using a one-pot solvothermal reaction of Zn(NO3)2, L-lactic acid (L-H2lac) and 1,4-benzenedicarbox-ylic acid (H2bdc) in DMF [53]. This 3-D homochiral microporous framework exhibited permanent porosity and enantioselective host-guest sorption properties towards several substituted thioether oxides. Although 36 could catalyze the oxidation of thioethers to sulfoxides with size and chemoselectivity, no asymmetric induction was observed. 

Enantiomerically pure sulfoxides are important intermediates in organic synthesis (21) and quite a number of pharmaceuticals and other biologically active compounds harbor a chiral sulfoxide unit (22). With respect to oxidation catalysis, enantiomerically enriched sulfoxides can either be accessed by asymmetric sulfoxidation of prochiral thioethers (Scheme 7, path a), or by kinetic resolution of racemic sulfoxides (Scheme 7, path b). For the latter purpose, enantio-specific oxidation of one sulfoxide enantiomer to the sul-fone, followed by separation, is the method of choice. 

The material 6 showed a remarkable catalytic activity in the oxidation of thioethers 13 to sulfoxides 14 by urea hydroperoxide (UHP) or H O (Scheme 2). Although the conversion and selectivity (for 14 over 15, >90%) was reasonable with UHP for the substrates with smaller substituents, 13a and 13b, the ones with bulkier substrates 13c and 13d failed to produce any measurable conversion. The conversion increases to 100% by changing UHP with H O. The catalytic activity of 6 for selective sulfoxidation remains similar even after 30 cycles. Despite the fact that no asymmetric induction was found in the catalytic sulfoxidations, enantioen-riched sulfoxides were obtained by enantioselective sorption of the resulting racemic mixture by the chiral pores of 6, which occured simultaneously with the catalytic process. Thus, after catalytic oxidation of 13a, (5)-14a was preferentially absorbed by the pore of 6 leaving exactly equal amount of the excess ) -enantiomer in the solution phase (-20% ee). The combination of high catalytic activity and enantioselective sorption property of 6 provides a unique opportunity to device a one-step process to produce enantioenriched products. 

To get a greener process, Jackson and coworkers reported a study dedicated to the use of immobilised Schiff base ligands for asymmetric thioether oxidation (Scheme 7.9). The salen ligand derivative 13, linked to a Wang resin, formed an extremely robust titanium complex, which allows the system to be reused several times without erosion of conversion and enantioselectivity. No leaching of titanium was detected in the reaction solvent. 

Formation of symmetrically mixed sulfide radical cations, (R R"S SR R"), can be achieved most conveniently by one-electron oxidation of the corresponding mixed thioethers, R R"S [100]. Asymmetric (R 2SaSR"2) radical cations can be... 

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