Kinetic resolution of racemic sulfoxide

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

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-... 

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. ... 

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). ... 

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.

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). 

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... 

Thakur VV, Sudalai A. WO3-30% H202-cinchona alkaloids a new heterogeneous catalytic system for the asymmetric oxidation of sulfides and the kinetic resolution of racemic sulfoxides. Tetrahedron Asymm. 2003 14 407-410. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Kinetic resolution of racemic 4-bromophenyl methyl sulfoxide. Ill... 

KINETIC RESOLUTION OF RACEMIC 4-BROMOPHENYL METHYL SULFOXIDE... 

Hoft reported about the kinetic resolution of THPO (16b) by acylation catalyzed by different lipases (equation 12) °. Using lipases from Pseudomonas fluorescens, only low ee values were obtained even at high conversions of the hydroperoxide (best result after 96 hours with lipase PS conversion of 83% and ee of 37%). Better results were achieved by the same authors using pancreatin as a catalyst. With this lipase an ee of 96% could be obtained but only at high conversions (85%), so that the enantiomerically enriched (5 )-16b was isolated in poor yields (<20%). Unfortunately, this procedure was limited to secondary hydroperoxides. With tertiary 1-methyl-1-phenylpropyl hydroperoxide (17a) or 1-cyclohexyl-1-phenylethyl hydroperoxide (17b) no reaction was observed. The kinetic resolution of racemic hydroperoxides can also be achieved by chloroperoxidase (CPO) or Coprinus peroxidase (CiP) catalyzed enantioselective sulfoxidation of prochiral sulfides 22 with a racemic mixmre of chiral hydroperoxides. In 1992, Wong and coworkers and later Hoft and coworkers in 1995 ° investigated the CPO-catalyzed sulfoxidation with several chiral racemic hydroperoxides while the CiP-catalyzed kinetic resolution of phenylethyl hydroperoxide 16a was reported by Adam and coworkers (equation 13). The results are summarized in Table 4. 

TABLE 4. Kinetic resolution of racemic hydroperoxides via CPO and CiP catalyzed enantioselec-tive sulfoxidation... 

KINETIC RESOLUTION OF RACEMIC SULEOXIDES (FIGURE 9.4) 9.3.2 SYNTHESIS OE (R)-(+)-PHENYL BENZYL SULFOXIDE... 

It should be noted that the related imine-oxaziridine couple E-F finds application in asymmetric sulfoxidation, which is discussed in Section 10.3. Similarly, chiral oxoammonium ions G enable catalytic stereoselective oxidation of alcohols and thus, e.g., kinetic resolution of racemates. Processes of this type are discussed in Section 10.4. Whereas perhydrates, e.g. of fluorinated ketones, have several applications in oxidation catalysis [5], e.g. for the preparation of epoxides from olefins, it seems that no application of chiral perhydrates in asymmetric synthesis has yet been found. Metal-free oxidation catalysis - achiral or chiral - has, nevertheless, become a very potent method in organic synthesis, and the field is developing rapidly [6]. 

Uemura et al. found that the combination Ti(OPr%/binaphthol/water in ratio 1 2 >10 acts as a catalyst for oxidation of aryl methyl sulfides into the corresponding sulfoxides by Bu OOH (see also Section 1.4.1) [159]. A mechanistic study showed that the titanium complex was a sulfoxidation catalyst (initial ee -50%) as well as a catalyst for the overoxidation into sulfones, with an enhancement of the ee of the residual sulfoxides (because the minor sulfoxide enantiomer is preferentially oxidized). In a subsequent paper, the authors reported the kinetic resolution of racemic aryl methyl sulfoxides by the same catalyst [160]. A stereoselectivity factor s of 2.6 was calculated for the kinetic resolution of racemic methyl p-tolyl sulfoxide. For example, methyl p-tolyl sulfoxide (<99% ee) could be recovered from oxidation at about 75% conversion. Using partially resolved l,l -binaphthol, a positive nonlinear effect was established. 

The use of (S,S)-l,2-bis- butyl-l,2-ethanediol (S,S)-30) in the titanium-catalyzed oxidation of various aryl methyl sulfides by cumene hydroperoxide afforded sulfoxides in ees up to 95% (Scheme 8.5) [68[. Interestingly, the authors observed that the ee of the sulfoxide increased with the reaction time, indicating a kinetic resolution of the sulfoxide product. A control experiment with racemic p-tolyl sulfoxide showed that the (i )-enantiomer is oxidized to sulfone three times faster than the (S)-enantiomer by the catalytic system employed. For this reason, the yields of the chiral sulfoxides are moderate and in the range of 40-50%. 

Scheme 19.39 Kinetic resolution of racemic methyl phenyl sulfoxide catalysed by Al(salalen).

The reaction of the enantiomerically pure sulfoxide anion (0.5 equiv) with a racemic bicyclic enone allows for the kinetic resolution of the enone15b. 

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. 

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

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