[1519-39-7] · C8H10OS · (R)-(+)-Methyl p-Tolyl Sulfoxide · (MW 154.25)
Physical Data: [a]D +146° (acetone, c = 2), +192° (CHCl3, c = 1.2).
Preparative Methods: the most popular means of preparing this reagent is the nucleophilic displacement of (-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate with methyl Grignard with complete inversion of configuration at sulfur (eq 1).1
This reagent is also prepared by the reaction of Methylmagnesium Bromide with optically active (S)-N-sulfinyloxazolidinone, which is obtained by asymmetric synthesis2 from the oxazolidinone derived from (4R,5S)-norephedrine with a low diastereoselectivity (70:30) (eq 2).
Both enantiomers of methyl p-tolyl sulfoxide are also prepared from diacetyl D-glucose giving, with mesyl chloride, and according to the base used, the (S)-methyl sulfinate with diisopropylethylamine or the (R)-methyl sulfinate with pyridine, which are then transformed with p-tolylmagnesium bromide into the corresponding (S)- or (R)-methyl p-tolyl sulfoxide (eq 3).3
(R)-(+)-methyl p-tolyl sulfoxide is obtained by asymmetric oxidation of the corresponding sulfide with t-Butyl Hydroperoxide in the presence of a stoichiometric amount of a modified Sharpless reagent (Titanium Tetraisopropoxide)-(+)-(R,R)-diethyl tartrate-H2O in a ratio of 1:2:1) in 96% ee.4
(-)-a,a-Dichlorocamphorsulfonyloxaziridine (1) was shown to be a highly efficient reagent for the asymmetric oxidation of methyl p-tolyl sulfide, giving the corresponding (+)-(R)-sulfoxide in 95% ee.5
It was shown recently that chloroperoxidase-catalyzed oxidation of methyl p-tolyl sulfide, using Hydrogen Peroxide or t-BuOOH as the stoichiometric oxidant, afforded the corresponding (+)-(R)-sulfoxide in 99% ee.6
Optically active b-keto sulfoxides are very useful building blocks (eq 4) because they can be stereoselectively reduced to afford either diastereomer of the corresponding b-hydroxy sulfoxide under appropriate conditions (Diisobutylaluminum Hydride or Zinc Chloride/DIBAL)8 and thus give access to a wide variety of compounds: chiral carbinols7 by desulfurization with Raney Nickel or Lithium/ethylamine in the case of allylic alcohols;8b epoxides8a via cyclization of the derived sulfonium salt; butenolides7b by alkylation of the hydroxy sulfoxide; 1,2-diols via a Pummerer rearrangement followed by reduction of the intermediate.9
Numerous applications to total synthesis of natural products have been reported. In the case of the macrolide (R)-lasiodiplodin, the achiral ester (eq 5) was reacted with the (+)-(R)-methyl p-tolyl sulfoxide derived anion to give the corresponding b-keto sulfoxide, which was then reduced with DIBAL to give, after desulfurization, the seco-ester of (R)-lasiodiplodin (eq 5).10 This is an example showing that the chirality can be introduced at the end of the synthesis in the desired configuration.
In the synthesis of (S)-zearalenone11 and of a chiral spiroacetal, (2S,6R)-2-methyl-1,7-dioxaspiro[5.6]dodecane,12 the starting product was a functionalized b-keto sulfoxide resulting from the reaction of glutaric anhydride with lithiated (+)-(R)-methyl p-tolyl sulfoxide (eq 6).
It was also shown in the enantioselective synthesis of the macrolide patulolide A13 that the anion of methyl p-tolyl sulfoxide was more reactive towards the imidazolide, prepared from the hemi ethyl sebacate, than the ester group (eq 7).
In a similar way,9 lithiated (+)-(R)-methyl p-tolyl sulfoxide was able to react only with the methyl ester group in presence of a t-butyl ester, as shown in the case of t-butyl methyl octadioate (eq 8).
The enantioselective syntheses of yashabushiketol14 and gingerols15 showed the synthetic utility of chiral epoxides obtained from (R)-methyl p-tolyl sulfoxide (eq 9).
Methyl chloroacetate reacts with the anion of (R)-methyl p-tolyl sulfoxide to give the corresponding d-chloro-b-keto sulfoxide (eq 10), which can be easily transformed into the corresponding b-hydroxy sulfoxide which gives, in presence of a base, the optically active a-sulfinyl epoxides.16 As illustrated here, a-sulfinyl epoxides can be opened by cuprates, leading to chiral homoallylic alcohols.17
(R)-Methyl p-tolyl sulfoxide anion also reacts with b-keto esters to give the corresponding b,d-diketo sulfoxides,18 which are useful in the preparation of optically active 1,3-diols (eq 11).19
Difluoroalkyl sulfinylmethyl ketones have been prepared in enantiomerically pure form from (+)-(R)-methyl p-tolyl sulfoxide in high yield (eq 12).20 The ketone function was then reduced with complete diastereoselectivity.
The absolute configuration at C-32 in recently isolated triterpenoids was assigned by reduction of a b-keto sulfoxide (eq 13).21
A vinylic sulfoxide was prepared from (R)-methyl p-tolyl sulfoxide and benzophenone. Cyclopropanation of the double bond with Dimethylsulfoxonium Methylide gave a good diastereoselectivity (eq 14).22
3-Sulfinylpropionic acid was made from lithium 2-bromoacetate and (R)-methyl p-tolyl sulfoxide (eq 15).23
Sulfinyl dienes were made from a,b-unsaturated esters and methyl p-tolyl sulfoxide followed by enolization of the ketone group (eq 16).24
Although the carbanion of (R)-methyl p-tolyl sulfoxide reacted with aldehydes and ketones with a poor diastereoselectivity,25 it reacts with imines with a much higher stereoselectivity25 as long as the imine substituent is an aromatic ring.26 (R)-(+)-Tetrahydropalmatine was synthesized by addition of (R)-methyl p-tolyl sulfoxide carbanion to 3,4-dihydro-6,7-dimethoxyisoquinoline (eq 17).27
Guy Solladié & Françoise Colobert
University Louis Pasteur, Strasbourg, France