Sulfoxides optically pure

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. 

Recrystallization of a 1 1 molecular complex formed from several sulfoxides and (R)-( + )-2,2 -dihydroxy-l, l -binaphthyl (7) allowed resolution of the former22. Conversely, using the optically pure sulfoxide, it was possible to resolve racemic bis-naphthol 7. 

Preparation of the appropriate optically active sulfmate ester is initially required for reaction with a Grignard or other organometallic reagent. If the method is to produce homochiral sulfoxides, the precursor sulfmate ester must be optically pure. An exception to this statement occurs if the reaction yields a partially racemic sulfoxide which can be recrystallized to complete optical purity. 

Aryl- and alkyl-magnesium halides were the first reagents used to form sulfoxides from sulfinate ester 19 and related (— )-menthyl arenesulfinates (equations 564,665,758 and 866). Whereas optically pure esters produced the homochiral sulfoxides shown in equations (5), (6) and (7), the ester shown in equation (8) was an oily mixture of four diastereomers which led to formation of a meso sulfoxide and a d, l pair enriched in one enantiomer. A homochiral sulfoxide was obtained by fractional crystallization. 

Optically pure (S)-benzyl methyl sulfoxide 139 can be converted to the corresponding a-lithio-derivative, which upon reaction with acetone gave a diastereomeric mixture (15 1) of the /S-hydroxysulfoxide 140. This addition reaction gave preferentially the product in which the configuration of the original carbanion is maintained. By this reaction, an optically active epoxy compound 142 was prepared from the cyclohexanone adduct 141181. Johnson and Schroeck188,189 succeeded in obtaining optically active styrene oxide by recrystallization of the condensation product of (+ )-(S)-n-butyl methyl sulfoxide 143 with benzaldehyde. 

Sulfoxides without amino or carboxyl groups have also been resolved. Compound 3 was separated into enantiomers via salt formation between the phosphonic acid group and quinine . Separation of these diastereomeric salts was achieved by fractional crystallization from acetone. Upon passage through an acidic ion exchange column, each salt was converted to the free acid 3. Finally, the tetra-ammonium salt of each enantiomer of 3 was methylated with methyl iodide to give sulfoxide 4. The levorotatory enantiomer was shown to be completely optically pure by the use of chiral shift reagents and by comparison with a sample prepared by stereospecific synthesis (see Section II.B.l). The dextrorotatory enantiomer was found to be 70% optically pure. 

Molecules having only a sulfoxide function and no other acidic or basic site have been resolved through the intermediacy of metal complex formation. In 1934 Backer and Keuning resolved the cobalt complex of sulfoxide 5 using d-camphorsulfonic acid. More recently Cope and Caress applied the same technique to the resolution of ethyl p-tolyl sulfoxide (6). Sulfoxide 6 and optically active 1-phenylethylamine were used to form diastereomeric complexes i.e., (-1-)- and ( —)-trans-dichloro(ethyl p-tolyl sulfoxide) (1-phenylethylamine) platinum(II). Both enantiomers of 6 were obtained in optically pure form. Diastereomeric platinum complexes formed from racemic methyl phenyl (and three para-substituted phenyl) sulfoxides and d-N, N-dimethyl phenylglycine have been separated chromatographically on an analytical column L A nonaromatic example, cyclohexyl methyl sulfoxide, did not resolve. 

A major problem with the sulfoxide synthesis using menthyl sulfmates is its failure to produce optically pure dialkyl sulfoxides. The prerequisite menthyl alkanesulfinates are oils which have resisted separation into the individual epimers. The menthyl phenyl methanesulfmates are an exception the R epimer is crystalline . One solution to this problem, at least for preparing methyl alkyl sulfoxides, was achieved using cholesteryl methanesulfmates (27) . Both epimers were crystalline and could be separated by fractional crystallization, although in poor yield. Treatment of the epimers with n-propyl, n-butyl, isobutyl, p-tolyl and benzyl magnesium halides yielded the respective methyl alkyl sulfoxides (28) in greater than 95% e.e. and in 32 to 53% yields. 

No stereoselectivity was observed in the formation of a 1 1 diastereomeric mixture of 2-hydroxy-2-phenylethyl p-tolyl sulfoxide 145 from treatment of (R)-methyl p-tolyl sulfoxide 144 with lithium diethylamide . However, a considerable stereoselectivity was observed in the reaction of this carbanion with unsymmetrical, especially aromatic, ketones The carbanion derived from (R)-144 was found to add to N-benzylideneaniline stereoselectivity, affording only one diastereomer, i.e. (Rs,SJ-( + )-iV-phenyl-2-amino-2-phenyl p-tolyl sulfoxide, which upon treatment with Raney Ni afforded the corresponding optically pure amine . The reaction of the lithio-derivative of (-t-)-(S)-p-tolyl p-tolylthiomethyl sulfoxide 146 with benzaldehyde gave a mixture of 3 out of 4 possible isomers, i.e. (IS, 2S, 3R)-, (IS, 2R, 3R)- and (IS, 2S, 3S)-147 in a ratio of 55 30 15. Methylation of the diastereomeric mixture, reduction of the sulfinyl group and further hydrolysis gave (—)-(R)-2-methoxy-2-phenylacetaldehyde 148 in 70% e.e. This addition is considered to proceed through a six-membered cyclic transition state, formed by chelation with lithium, as shown below . ... 

Bicyclo-y-butyrolactones.1 The reaction of ketenes with chiral vinyl sulfoxides to obtain optically pure -y-arylsulfanylbutyrolactones (12,177) can be extended to a synthesis of bicyclic butyrolactones. Thus the arylsulfanyl group of 1 undergoes... 

Alkenyl p-tolyl sulfoxides.1 Various 1-alkynylmagnesium bromides react stereospecifically (with inversion) with 1 in ether/toluene to give chiral 1-alkynyl sulfoxides 2. Reduction of 2 with LiAlH4 (THF, - 90°) affords optically pure (E)-1-alkenyl p-tolyl sulfoxides (3). The corresponding (Z)-isomers are obtained by hydrogenation of 2 with the Wilkinson catalyst. 

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. 

SCHEME 114. Titanium-catalyzed enantioselective sulfoxidation with secondary, optically pure hydroperoxides... 

An overview of the obtained results of the titanium-catalyzed asymmetric sulfoxidation of various sulfides with different optically pure hydroperoxides as oxidant and asymmetric inductor is given in Table 29. 

TABLE 29. Results of the titanium-catalyzed asymmetric sulfoxidation with optically pure hydroperoxides (yields are given and ee values are given in brackets)... 

Another type of chiral alkene applied in 1,3-dipolar cycloadditions are vinyl groups attached to chiral phosphine oxides or sulfoxides. Brandi et al. (150,151) used chiral vinyl phosphine oxide derivatives as alkenes in 1,3-dipolar cycloadditions with chiral nitrones. This group also studied reactions of achiral nitrones with chiral vinyl phosphine oxide derivatives. Using this type of substrate, fair endo/exo-selectivities were obtained. In reactions involving optically pure vinyl phosphine oxides, diastereofacial selectivities of up to 42% de were obtained. Chiral vinyl... 

Carboxylation of lithiated vinylic sulfoxides is also highly stereoselective, as shown by a one-pot experiment leading from optically pure (if)- -alkenyl aryl sulfoxides to optically pure methyl 2-arylsulfinyl-2-alkenoates without EjZ isomerization63. 

Starting from optically active 1-chlorovinyl p-tolyl sulfoxide derived from 2-cyclohex-enone, the asymmetric synthesis of cyclopropane derivative (85) was realized (equation 23) . Addition reaction of lithium enolate of tert-butyl acetate to 83 gave the adduct (84) in 96% yield with over 99% ee. Treatment of the latter with i-PrMgCl in a similar way as described above afforded optically pure (15,6/ )-bicyclo[4.1.0]hept-2-ene (85) in 90% yield. 

It has been found that F-Teda BF4 (6) transforms chiral and optically pure ft-oxo sulfoxides into the corresponding a-fluoro-substituted compounds 30 without affecting the chiral sulfinyl group.106... 

A remarkably high diastereoselective excess was obtained in the addition of the anion of (S)-(-)-methyl 1-naphthyl sulfoxide to n-alkyl phenyl ketones. The sulfoxide was prepared in optically pure form by oxidation of the complex of methyl 1-naphthyl sulfide and 13-cyclodextrin with peracetic acid followed by crystallization. Desulfurization of the adducts provided enantiomerically pure tertiary alcohols (393]. 

A quite general method of access to optically pure sulfoxides is due to Andersen [96-98] a menthyl sulfinate ester is reacted with a Grignard reagent. Both enantiomers of menthyl p-toluenesulfinate are commercially available. A large-scale preparation of (-)-menthyl (S)-p-toluenesulfinate as well as that of (7 )-(+)-methyl p-tolyl sulfoxide is described [99] by Solladi et al. Other related approaches are presented and discussed in [86]. 

Chiral Sulfoxides in the Synthesis of Optically Pure Fluoro Substituted Compounds of Biological Interest ... 

Chiral a-methylene-y-lactones.1 (R)-( + )-Alkyl p-tolyl sulfoxides (2), readily obtainable in almost quantitative yield from (l),2 on lithiation (LiTMP) and reaction with lithium a-bromomethylacrylate (3) are converted into a-methylene-y-sulfinyl carboxylic acids (4), which can be separated by chromatography or crystallization. Reduction of optically pure 4 provides y-tolylthio acids [(S)-5], which on methylation and treatment with potassium f-butoxide are converted into (4R)-a-methylene-y-lactones (6), with inversion of chirality. 

Steroid synthesis. The sulfoxide (S)-( + )-2 has been used as a chiral synthon for ring D in steroid synthesis. The first step in a synthesis of 11-ketoequilenin (5)3 involves addition of 6-methoxy-2-naphthylmagnesium bromide followed by in situ methylation of the intermediate enolate ion to give 3 in greater than 98% optical purity. This product was converted into optically pure (S, S)-( + )-4, the racemate of which has been converted into( + )-l 1-kctoequilenin. 

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