Sulfoxide enantiomers

Cyclodextrins, toroidal molecules composed of 6, 7 and 8 D-gJucose units, are now commercially available at reasonable cost. They form inclusion compounds with a variety of molecules and often differentially include sulfoxide enantiomers . This property has been used to partially resolve some benzyl alkyl, phenyl alkyl and p-tolyl alkyl sulfoxides. The enantiomeric purities after one inclusion process ranged from 1.1% for t-butyl p-tolyl sulfoxide to 14.5% for benzyl t-butyl sulfoxide. Repeating the process on methyl p-tolyl sulfoxide (10) increased its enantiomeric purity from 8.1 % to 11.4% four recrystallizations raised the value to 71.5%. The use of cyclodextrins in asymmetric oxidations is discussed in Section II.C.l and in the resolution of sulfinate esters in Section II.B.l. 

Figure 3. Effect of temperature on the magnitude of the chemical shift difference between isopropyl methyl sulfoxide enantiomers in the presence of (-)-TFPE in CCI4. Molar ratio of alcohol to sulfoxide to solvent is 2 1 5. Symbols are as in Figure 2. Reprinted with permission from Tetrahedron Lett. 1974,2295-2298.

This LSR-CSA technique (discussed in detail in ref. 76) has also been appUed to a series of sulfoxides. Nitroarylsulfoxides are also capable of a strong three-point interaction with fluoroalcohols 1, an ability that is responsible for a considerable difference in stability between the solvates. Mixtures of Id and 2,4-dinitrophenyl methyl sulfoxide are red, and the intensity of this color is inversely proportional to temperature, consistent with formation of tt-tt complexes. Crystallization of the racemic sulfoxide from carbon tetrachloride solutions of (/ )- d leaves mother liquor enriched in the (i )-sulfoxide enantiomer, that predicted by the usual solvation model (41), to form the more stable solvate. With this compound it is also apparent that the (/ , iS )-solvate may differ considerably from the predicted conformation, by population of 42. This additional interaction. 

DiTOX systems are amenable to stereoselective preparation for both sulfoxide enantiomers. 

Lanchote VL, Garcia FS, Dreossi SA, Takayanagui OM. Pharmacokinetic interaction between albendazole sulfoxide enantiomers and antiepileptic drugs in patients with neuro-cysticercosis. Ther Drug Monit 2002 24(3) 338 5. 

Our efforts were amply rewarded and a real breakthrough was achieved when, very unexpectedly, finding that the addition of a base had a tremendous impact on the transformation to the desired sulfoxide enantiomer [24]. We now knew that our sulfide could in fact be oxidized in an asymmetric fashion so we were on the right track Some facts for this crucial progress will be described in more detail below. 

A modified Sharpless reagent has been developed by Kagan [503, 814], Modena [502, 814] and their coworkers. This new catalyst is formed by mixing water, Ti(0/-Pr)4, and diethyltartrate in a ratio of 1/1/2. The modified catalyst promotes enantioselecfrve oxidation of arylalkylsulfides by fert-BuOOH, and chiral sulfoxides are produced with excellent enantiomeric excesses (> 90%). Lower selectivities are observed from dialkylsulfides. From (R,R) or (5 S)-diethyl tartrate, either sulfoxide enantiomer can be obtained. The use of cumene hydroperoxide as the oxidant may improve the enantioselectivity. Uemura and coworkers obtained similar results by replacing the tartrates in these complexes with binaph-thols [815],... 

The (S)-(-)-sulfoxide is predominantly produced (82 % S, 18 % R) from p-tolyl ethyl sulfide when cyclohexanone monooxygenase from Acinetobacter sp. NCIB 9871191 was used, whereas the the FAD-containing monooxygenase from hog liver micro-somes oxidizes p-tolyl ethyl sulfide to yield the (R)-(+)-sulfoxide enantiomer as the major product (95 % R, 5 % S) 15). 

Buronfosse, T, Moroni, R, Benoit, E., and Riviere, J. L. (1995), Stereoselective sulfoxidation of the pesticide methiocarb by flavin-containing monooxygenase and cytochrome P450-dependent monooxygenases of rat liver microsomes. Anticholinesterase activity of the two sulfoxide enantiomer. J. Biochem. Toxicol. 10, 179-189. 

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. 

Figure 10 Oxidative and reductive human biotransformations of sulindac in vivo. Racemic sulindac sulfoxide, a prodrug, is reversibly reduced to the active sulfide metabolite, which is reoxidized to either the R- or the S-sulfoxide enantiomer. The sulfoxides are also irreversibly oxidized to a sulfone metabolite. The reduction of the sulfoxides to sulfide is a nonmicrosomal process and therefore is not a confounding parameter in determining microsomal oxidation. (From Ref. 137.)...

A second, isolated example of construction of useful chiral azetidinones by the N-C4 bonding strategy utilizes the phenylsulfinylpropionamide 93a as starting material. Treatment of this compound with TMSOTf/TEA promoted a Pummerer rearrangement concerted with lactamization to 93b [43a]. Starting from the ( — )-sulfoxide enantiomer, obtained by HPLC resolution with a chiral stationary fase (cellulose tribenzoate), the 4/ -phenylthio enantiomer was obtained in 67% optical yield [43b]. Hydroxyethylation of this intermediate is described in Sect. 3.1. 

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. 

When the chiral center is tricoordinate, as is the case for sulfoxides sulfonium salts, and phosphines, then a phantom atom of atomic number zero is taken to occypy the lowest-priority site of a presumed tetrahedral atom. Application of the sequence rule in the usual manner allows the assignment of the R configuration to the benzyl phenyl sulfoxide enantiomer and the 5 configuration to the methylal-lylphenylphosphine enantiomer shown in Scheme 2.1. 

Louren90 CL, Batista JM, Furlan M, He Y, Nafie LA, Santana CS, Cass QB. Albendazole sulfoxide enantiomers preparative chiral separation and absolute stereochemistry. J. Ckroma-togr., A 2012 1230 61 5. 

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