Racemic sulfoxide resolution

Numerous reactions of racemic sulfoxides with chiral reagents have been accomplished2,12. These examples of kinetic resolution usually lead to sulfoxides of low enantiomeric purity, but there are some exceptions. 

In principle, it should be possible to selectively reduce one of the enantiomers in a racemic sulfoxide mixture that is, an asymmetric kinetic resolution via reduction should... 

Table 8.2 Kinetic resolution of racemic sulfoxides (R-SO-Me) with 1.

Since in principle the reactions of enantiomeric sulfoxides with a chiral reagent are expected to proceed at unequal rates, a possibility exists for obtaining chiral sulfoxides, especially when the reacting racemic sulfoxide is used in excess in relation to the chiral reagent. A typical example of such a kinetic resolution of a racemic sulfoxide is its reaction with a deficiency of chiral peracid, affording a mixture of optically active sulfoxide and achiral sulfone (62,63). However,... 

Recently, Juge and Kagan (68) reported that a more efficient kinetic resolution of racemic sulfoxides takes place in the Pummerer-type reaction with optically active a-phenylbutyric acid chloride 38 in the presence of N,A-dimethylaniline. In contrast to the asym-... 

As shown in Table 12,H202 and fBuOOH have been used frequently as oxygen donors in peroxidase-catalyzed sulfoxidations. Other achiral oxidants, e.g. iodo-sobenzene and peracids, are not accepted by enzymes and, therefore, only racemic sulfoxides were found (c.f. entries 34-36). Interestingly, racemic hydroperoxides oxidize sulfides to sulfoxides enantioselectively under CPO catalysis [68]. In this reaction, not only the sulfoxides but also the hydroperoxide and the corresponding alcohol were produced in optically active form by enzyme-catalyzed kinetic resolution (cf. Eq. 3 and Table 3 in Sect. 3.1). 

In the sulfoxidation, small to appreciable amounts of over oxidation with formation of undesired sulfone were observed, a result that implies that kinetic resolution may be involved in influencing the overall stereochemical result 105). This was shown to be the case. Indeed, some of the mutants are also excellent catalysts in the kinetic resolution of racemic sulfoxides such as 25 105). Directed evolution was then applied successfully to eliminate undesired sulfone formation, specifically, by going through a second cycle of epPCR 105). This is significant because it shows for the first time that an undesired side reaction can be eliminated by directed evolution. 

A solid-phase sulfur oxidation catalyst has been described in which the chiral ligand is structurally related to Schiff-base type compounds (see also below). A 72% ee was found using Ti(OPr-i)4, aqueous H2O2 and solid-supported hgand 91 . More recently, a heterogeneous catalytic system based on WO3, 30% H2O2 and cinchona alkaloids has been reported for the asymmetric oxidation of sulfides to sulfoxides and kinetic resolution of racemic sulfoxides. In this latter case 90% ee was obtained in the presence of 92 as chiral mediator. ... 

In general, sulfoximines are accessible by various routes, and most of them involve sulfur oxidation/imination sequences. For example, enantiopure 9 is commonly prepared starting from sulfide 10, which is oxidized with hydrogen peroxide (under acidic conditions) giving sulfoxide 11 (Scheme 2.1.1.1). Subsequent imina-tion of 11 with a mixture of sodium azide and sulfuric acid affords sulfoximine 9 as a racemate. Enantiomer resolution can then be achieved with camphorsul-fonic acid, leading to both enantiomers of 9 with high efficiency [15]. Alternatively, many sulfoximine syntheses start from enantiopure sulfoxides [16, 17], which can be stereospecifically iminated with 0-mesitylenesulfonylhydroxyl-amine (MSH) [18], as shown for the synthesis of sulfoximine (1 )-13 in Scheme 2.I.I.2. 

WO3-3O % H2O2-CINCHONA ALKALOIDS A NEW HETEROGENEOUS CATALYTIC SYSTEM FOR ASYMMETRIC OXIDATION OF SULFIDES AND KINETIC RESOLUTION OF RACEMIC SULFOXIDES... 

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). ... 

In 1973, Stewart and Doherty [9] resolved enantiomers of tryptophan on a column packed with BSA-succinoylaminoethyl-agarose in a discontinuous elution procedure. The mobile phase used was 0.1 M borate buffer (pH 9.2). The chromatograms of this classical research are shown in Figure 2. Several years later, this technique was applied for the chiral resolution of warfarin enantiomers [10]. In 1981, the enantiomers of tryptophan and warfarin racemates were resolved on various serum albumin CSPs [11,21,22]. The same method was used for the resolution of other drugs [12-14]. Allenmark et al. [23] studied the resolution of a series of active racemic sulfoxides on a BSA column using 0.08 M phosphate buffer (pH 5.8) as the eluting solvent. 

Resolution of Sulfoxides. Although it can be considered as the resolution of an unique type of carboxylic acid, some racemic sulfoxides containing carboxyhc acids have been resolved via diastereomeric crystalline complexes with brucine (eq 11). ... 

The biscinchona alkaloid ligands can also be used for the asymmetric oxidation of sulfides to sulfoxides with hydrogen peroxide as the oxidant in the presence of tungsten(VI) oxide, or layered double hydroxide (LDH) supported 0s04 as catalyst (Scheme 3.46) [375, 376]. The approach can also be used to affect a kinetic resolution of racemic sulfoxides by oxidation of one enantiomer to the sulfone (Scheme 3.47) [376]. 

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. 

Scheme 7. Chiral sulfoxides by enantioselective oxidation of prochiral thioethers, and by oxidative kinetic resolution of racemic sulfoxides.

The enzyme mutants used for the enantioselective sulfoxidation of the thioether 41 were also tested in the oxidative kinetic resolution of the racemic sulfoxide rac-42 (28). For example, the mutant shown in entry 2 of the Table in Scheme 19 gave 98.7 % ee of the /(-sulfoxide 42 after 43 % conversion... 

The kinetic resolution of a racemic sulfoxide during which one enantiomer is oxidized to yield an achiral sulfone is feasible but it has been shown to proceed with low selectivities. 

Uemura found that the addition of water was essential fca the catalysis in the BlNOL-Ti-catalyzed sulfoxidation. Furthermore, the kinetic resolution of racemic sulfoxides could also be catalyzed by a BINOL-Ti complex to give the optically pure sulfoxides in moderate chemical yields under very mild conditions (269). 

A selection of biocatalytic deoxygenation reactions is shovm in Figure 1.8. The reducing power of baker s yeast in an ethanol-water mixture and sodium hydroxide at 60° C has been found effective for the rapid and selective reduction of a series of N-oxides like aromatic and heteroaromatic N-oxide compounds [118]. DMSO reductase from Rhodobacter sphaeroides f sp. denitrificans catalyzed the (S)-enantioselective reduction of various sulfoxides and enabled the resolution of racemic sulfoxides for the synthesis of (R)-sulfoxides with >97% ee [119,120]. Purified dimethyl sulfoxide reductase from Rhodobacter capsulatus resolved a racemic mixture of methyl p-tolyl sulfoxide by catalyzing the reduction of (S)-methyl p-tolyl sulfoxide and gave enantio-merically pure (J )-methyl p-tolyl sulfoxide in 88% yield, while whole cells of E. coli,... 

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. 

Both PAMO and HAPMO are not only able to perform the desymmetrization of prochiral sulfides but they can also catalyze the kinetic resolution of racemic sulfoxides by oxidizing selectively one of the sulfoxide enanhomers to the sulfone, leaving... 

TABLE 6.3 Synthesis of Optically Active Sulfoxides by Kinetic Resolution of Racemic Sulfoxides Employing BVMOs... 

---