(-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate

[1517-82-4]  · C17H26O2S  · (-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate  · (MW 294.50)

(agent used for the synthesis of chiral sulfoxides1,3)

Physical Data: [a]D = -202° (acetone, c = 2.0).

Preparative Method: obtained by reaction of (-)-menthol with p-toluenesulfinyl chloride. This esterification showed no particular stereoselectivity, giving an equal amount of the two sulfinate diastereomers.1 In order to avoid a chromatographic separation, it is possible to epimerize these sulfinate esters in acidic medium and displace the resulting equilibrium towards the less soluble isomer, (-)-menthyl (S)-p-toluenesulfinate, in 80% yield (eq 1).2 This procedure was later extended to large scale preparation.3

The absolute configuration of (-)-menthyl (S)-p-toluenesulfinate was established by correlation with (-)-menthyl p-iodobenzenesulfinate, known from X-ray diffraction analysis.4

Synthesis of Chiral Sulfoxides.

Alkyl Sulfoxides.

Any Grignard reagent reacts with (-)-menthyl (S)-p-toluenesulfinate and displaces the menthoxy group with complete inversion of configuration at sulfur (eq 2; R = Me,3,5 Et,5,6 n-C6H137).

It was also reported that using methyllithium instead of the methyl Grignard could give some racemization of methyl p-tolyl sulfoxide as a result of methyl group exchange via a methylene sulfine intermediate.8

(R)-4-Substituted cyclohexylmethyl p-tolyl sulfoxide (1)9 as well as (R)-4-hydroxybutyl p-tolyl sulfoxide (2)10 and (R)-3-butenyl p-tolyl sulfoxide (3)11 were also obtained by reaction of (-)-menthyl (S)-p-toluenesulfinate and the corresponding Grignard reagent.

Vinyl Sulfoxides.

A stereocontrolled preparation of (E)-1-alkenyl p-tolyl sulfoxide from (-)-menthyl-(S) p-toluenesulfinate was reported (eq 3).12a

One example was also reported showing the formation of an (E)-alkenyl sulfoxide in the reaction of a vinylic lithium compound on menthyl sulfinate (eq 4).12b

(+)-(S)-2-(p-Tolylsulfinyl)-2-cyclopentenone was also prepared by reaction of a vinyllithium derivative and menthyl sulfinate (eq 5).13

The preparation of optically pure (E)- and (Z)-1-alkenyl p-tolyl sulfoxides was described via stereoselective reduction of 1-alkynyl p-tolyl sulfoxides (eq 6).14

Alkynic sulfoxides have been made from trimethylsilylethynylmagnesium bromide and the resulting alkyne disilylated on silica gel (eq 7).15

Chiral vinyl sulfoxides can also be prepared by a Horner-Emmons reaction of carbonyl compounds with a-phosphoryl sulfoxides which are obtained from lithiated dimethyl methylphosphonate and (-)-menthyl (S)-p-toluenesulfinate (eq 8).16 However, this reaction applied to carbonyl compounds often gives a mixture of the (E) and (Z) isomers of the vinylic sulfoxide.

The reaction of a-phosphoryl sulfoxide with the dimethyl acetal of pyruvic aldehyde allowed the preparation of the corresponding vinylic sulfoxide as a 1:1 mixture of (E) and (Z) isomers which could be isomerized with Lithium Diisopropylamide to the lithiated (E) isomer, used for the asymmetric synthesis of a-tocopherol (eq 9).17

The Wittig reaction of an optically active sulfinylphosphonium ylide was reported to yield only the (E)-vinylic sulfoxides (eq 10).18

Diaryl Sulfoxides.

Optically active diaryl sulfoxides are prepared by reaction of an aryl Grignard with (-)-menthyl (S)-p-toluenesulfinate: 2,5-dimethoxyphenyl p-tolyl sulfoxide (4), a precursor of sulfinyl quinones,19 and 3-pyridyl p-tolyl sulfoxide (5), a precursor of sulfinyl dihydropyridines (studied as NADH model compounds)20 are two typical examples.

Sulfinyl Esters and Derivatives.

(R)-(+)-t-Butyl 2-(p-tolylsulfinyl)acetate is conveniently prepared by reaction of the magnesium enolate of t-butyl acetate (readily made with Bromomagnesium Diisopropylamide) with (-)-menthyl (S)-p-toluenesulfinate (eq 11).21

Substituted sulfinyl esters (6) have also been prepared by this reaction using the same base22a or lithium cyclohexyl(isopropyl)amide,22b which gives higher yields.

The anion of acetonitrile also reacts with (-)-menthyl (S)-p-toluenesulfinate to give the corresponding b-sulfinylacetonitrile (eq 12).23

Similarly, exo-metalation with LDA of the racemic 3-methyl-4,5-dihydroisoxazole and reaction with (-)-menthyl (S)-p-toluenesulfinate afforded the sulfinyl-4,5-dihydroisoxazole as a diastereomeric mixture;24 lithiated N,N-dimethylthioacetamide leads to the sulfinyl N,N-dimethylthioacetamide,25 and lithiated ethyl N-methoxyacetimidate leads to p-tolylsulfinylethyl-N-methoxyacetimidate (eq 13).26

b-Keto Sulfoxides.

Cyclic b-keto sulfoxides are readily obtained from the magnesium enolate of the ketone and (-)-menthyl (S)-p-toluenesulfinate27 as a mixture of diastereomers in which the major epimer has the sulfoxide group in the equatorial orientation (eq 14).

By condensation of the dianion of t-butyl acetoacetate and (-)-menthyl (S)-p-toluenesulfinate, the corresponding b-keto sulfoxide was obtained in high yield (eq 15) and shown to be an efficient precursor of both enantiomers of b-hydroxybutyric acid via selective reduction of the ketone carbonyl group.28 b,d-Diketo sulfoxides were prepared in a similar way from diketone dianions (eq 16).29

Imino Sulfoxides.

Metalated imines reacted with (-)-menthyl (S)-p-toluenesulfinate to yield the corresponding sulfinylimines as a diastereoisomeric mixture (eq 17).30

Similarly, exo-metalated cyclic imines afforded the sulfinylimines as an alkaloid precursor (eq 18).31


(S,S)-Bis(p-tolylsulfinyl)methane (7) is readily prepared from (-)-menthyl (S)-p-toluenesulfinate and (R)-methyl p-tolyl sulfoxide.32 (+) (S)-p-Tolylsulfinylmethyl t-butyl sulfone (8) was made from the t-butyl methyl sulfone anion and (-)-menthyl (S)-p-toluenesulfinate.33

Chiral N-benzylidene p-toluenesulfinamides were prepared by reaction of benzonitrile with an alkyllithium followed by addition of (-)-menthyl (S)-p-toluenesulfinate and converted into optically active amines and amino acids (eq 19).34

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Guy Solladié & Françoise Colobert

University Louis Pasteur, Strasbourg, France

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