Enantiomeric methyl sulfoxide

In the case of the condensation of benzyl methyl sulfoxide with bcnzaldchydc (40% yield), the diastereomeric ratio of four enantiomeric (S-sulfinyl alcohols after immediate workup is 41 19 8 32 . 

In 1926 Harrison et al. (20) described the first resolutions of 4 -amino-4-methyldiphenyl sulfoxide 7 and / -carboxyphenyl methyl sulfoxide 8 into the enantiomeric forms via formation and crystal-... 

An alternative route to enantiomeric methyl alkyl sulfoxides (95) is based on the reaction of aliphatic Grignard reagents with the dia-... 

Similar differentiation between enantiomers by means of NMR can also be achieved by the use of chiral lanthanide shift reagents (243). Tris-[3-(heptafluoropropylhydroxymethylene)-d-camphorato] -europium was used for the first time (244) for determining the enantiomeric content of benzyl methyl sulfoxide 34. The enantiomeric composition of the partially resolved methyl p-tolyl sulfoxide 41 was estimated using tris-[3-(r-butylhydroxymethylene)-c -camphorato]-europium (245). Another complex of europium, tris-[3-(trifluoro-methylhydroxymethylene)-c -camphorato] europium (TFMC), in contrast to those mentioned above, was effective in the differentiation of various enantiomeric mixtures of chiral sulfinates (107), thiosul-finates (35), and sulfinamides (246). 

Preparation of various enantiomerically pure sulfoxides by oxidation of sulfides seems feasible in the cases where asymmetric synthesis occurs with ee s in the range of 90% giving crystalline products which can usually be recrystallized up to 100% ee. Aryl methyl sulfides usually give excellent enantioselectivity during oxidation and are good candidates for the present procedure. For example, we have shown on a 10-mmol scale that optically pure (S)-(-)-methyl phenyl sulfoxide [a]p -146 (acetone, o 1) could be obtained in 76% yield after oxidation with cumene hydroperoxide followed by flash chromatographic purification on silica gel and recrystallizations at low temperature in a mixed solvent (ether-pentane). Similarly (S)-(-)-methyl o-methoxyphenyl sulfoxide, [a]p -339 (acetone, o 1.5 100% ee measured by HPLC), was obtained in 80% yield by recrystallizations from hexane. 

Oxidation of thioethers derived from the natural chirality pool , the readily available lactic acid and 3-hydroxybutyric acid, has been used in molar-scale preparation of enantiomerically pure sulfoxides methyl ( )-2-(phenylsulfinyl)acrylate and (K)-isopropenyl p-tolyl sulfoxide [107]. 

Enantiopure 2,2,5,5-tetramethyl-3,4-hexanediol was prepared by Yamanoi and Imamoto [46]. A combination of Ti(0-i-Pr)4 with this diol (1 2) gives a chiral catalyst for sulfide oxidation with cumyl hydroperoxide in the presence of 4A molecular sieves in toluene. At -20°C p-tolyl methyl sulfoxide (95% ee) was obtained in 42% yield together with 40% sulfone, A kinetic resolution increased, to some extent, the enantiomeric excess of the product, that is, at lower conversion (20% yield) the enantiopurity of the resulting sulfoxide was only 40% ee. This catalytic system is ineffective for the enantioselective oxidation of dialkyl sulfides. 

Andersen, K. K., Bujnicki, B., Drabowicz, J., Mikolajczyk, M., and O Brien, J. B. (1984) Synthesis of enantiomerically pure alkyl and aryl methyl sulfoxides from cholesteryl methanesulfinates, J. Org. Chem. 49, 4070-4072. 

Enantiomeric enriched a-thiosulfoxides 391 can be prepared by addition of a-thiomethyllithiums to p-tolyl sulfinate601. The deprotonation of p-tolyl (p-tolylsulfanyl)methyl sulfoxide (403) took place with w-BuLi at — 78 °C to afford the enantioenriched lithium derivative 404602. The addition to benzaldehyde followed by methylation of the hydroxy group and deprotection gave a-methoxyphenylacetaldehyde with 70% ee. This chiral formyl anion gave diastereoselectively Michael addition to a-substituted cyclopentenones603. The acylation of compound 404 followed by LAH reduction allowed the diastereoselective preparation of compounds 405 up to 99% de (Scheme 105)604. 

Some dialkyl sulfoxides (86) were also separated into enantiomers by complexation with 10b. n-Butyl methyl sulfoxide (86a) and methyl -propyl sulfoxide (86d) were easily separated with 10a to give enantiomerically pure (-i-)-86a and (-)-86d, respectively, in good yields. However, 86b and 86f were poorly separated with 10b, and 86c and 86e did not form complexes with 10b [32]. 

Posner et al. reported the first example of an asymmetric additive Pummerer rearrangement in their total synthesis of (-)-methyl jasmonate, a perfume essence.Enantiomerically pure sulfoxide 98 was treated with diehloroketene (generated in situ from dichloroacetyl chloride and triethylamine) to form a,y5-disubstituted sulphide 99. The mechanism is thought to involve a [3,3]-sigmatropic rearrangement of the doubly charged intermediate 100. 

The method has been recently improved, in collaboration with Fiisfero (Scheme 5) (36). In fact, lithium derivative of (6>naphthyl methyl sulfoxide 21 was found to provide much better stereocontrol in the condensation with A -PMP fluoroalkyl imines 15a,b,f. The resulting A -PMP naphthyl derivatives 22 were transformed into the enantiomeric (5)-P-fluoroalaninols 20 following an identical sequence of reactions, in high overall yields and stereoselectivity. Oxidation of the hydroxymethylene group, according to the method of Sharpless (37), extended the field of application of this strategy to the synthesis of enantiopure p-fluoro alanines 23. The wide scope of the NOP reaction is demonstrated by the fact that also naphthyl sulfoxides, like 22, can be successfully submitted to the reaction. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

An achiral reagent cannot distinguish between these two faces. In a complex with a chiral reagent, however, the two (phantom ligand) electron pairs are in different (enantiotopic) environments. The two complexes are therefore diastereomeric and are formed and react at different rates. Two reaction systems that have been used successfully for enantioselective formation of sulfoxides are illustrated below. In the first example, the Ti(0-i-Pr)4-f-BuOOH-diethyl tartrate reagent is chiral by virtue of the presence of the chiral tartrate ester in the reactive complex. With simple aryl methyl sulfides, up to 90% enantiomeric purity of the product is obtained. 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

The enantiomerically pure isobomeol allyl sulfoxide derivatives (17 ,2Y,3/ ,4S )-1,7,7-tri-methyl-3-[(S)- or -(/ )-2-propenylsulfmyl]bicyclo[2.2.1]heptan-2-ol are thermally more stable inversion of configuration at sulfur, S -> / , occurs at 135-145 °C. Their lithio derivatives give exclusively y-1,4-adducts with 2-cyclopentenone19. 

Cyclodextrins, toroidal molecules composed of 6, 7 and 8 D-glucose units, are now commercially available at reasonable cost. They form inclusion compounds with a variety of molecules and often differentially include sulfoxide enantiomers29,30. 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 r-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 sulfmate esters in Section II.B.l. 

The hydrolysis of seven alkyl arenesulfinylalkanoates by the bacterium Corynebacterium equi IFO 3730 studied by Ohta and coworkers34 are recent examples of kinetic resolutions which give sulfoxides of high enantiomeric purity and in reasonable yield. Compounds 16a, 16b and 16c were recovered in 30 to 43% yield and in 90 to 97% e.e. The S enantiomers underwent hydrolysis more rapidly than the R isomers. Sulfoxide 17 was isolated in 22% yield and 96% e.e., but sulfoxide 18 was completely metabolized. Esters other than methyl gave inferior results. The acids formed upon hydrolysis, although detected, were for the most part further metabolized by the bacterium. 

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