Sulfinates, chiral, racemization

Sharpless and Klunder22 are developing a new procedure for conversion of sulfonyl chlorides directly into menthyl sulflnate esters using trimethyl phosphite as a reducing agent (equation 2). This method, starting with sulfonyl chlorides rather than with the much less available sulfinyl chlorides, should allow access to an even wider range of sulfinate esters and, ultimately, to various chiral, non-racemic sulfoxides. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Chiral sulfinates are important intermediates that are widely applied in the synthesis of other classes of chiral organosulfur compounds and in their configurational correlations. Optically active sulfinates were first prepared in 1925 by Phillips (100) in two ways. The first consisted in the transesterification of racemic alkyl p-toluenesulfin-ates with chiral alcohols such as (-)-menthol and (-)-2-octanol yielding a mixture of two optically active sulfinates as shown in eq. [26]. The... 

A new and general approach to chiral aliphatic or aromatic sulfinates has been recently described by Mikofajczyk and Drabowicz (107). It consists of the asymmetric condensation of racemic sulfinyl chlorides at low temperature with achiral alcohols in the presence of chiral tertiary amines as asymmetric reagents. The optical purity (up to 45%) of the sulfinates formed is strongly dependent on the structure of all the reaction components. 

Another approach to chiral sulfinates was developed by Pirkle and Hoekstra (108) it is based on incomplete but stereoselective reaction of racemic sulfinates with chiral Grignard reagents. This kinetic resolution affords the unreacted sulfinates enriched in the (5 -enantiomers with optical purities in the 8-64% range. The chiral cyclic sulfinates 66 and 67 were first obtained by this method. 

In addition to sulfimides, the nitrogen analogs of sulfinates and sulfinamides are chiral and have been obtained as optically active compounds. For instance, the synthesis of diastereomeric menthyl p-toluenesulfinimidoates 90 mentioned above was effected by Cram and his collaborators (18,137) on two ways. The first comprised the reaction of racemic A -tosyl-p-tolueneiminosulfinyl chloride 92 with menthol, followed by separation of the diastereomers of 90, whereas in the second method the reaction of the ester (->45 with chloramine T was utilized. 

Hydrogen chloride was also found to catalyze the racemization of chiral sulfinates. Herbrandson and Dickerson (267) found that diastereomerically pure menthyl arenesulflnates undergo epimeriza-tion in nitrobenzene in the presence of hydrogen chloride and chloride ions. On the basis of kinetic studies they proposed a mecha-... 

It was found recently (283) that alcoholysis of chiral sulfinates proceeds at room temperature in the presence of strong acids with predominant inversion of configuration or racemization. The latter result is most probably due to the competitive symmetrical alkoxy-alkoxy exchanges in the starting and produced sulfinates. The reaction of (-i-iS-propargylp-toluenesulfinate (226) with isopropyl alcohol best illustrates these experiments. 

The sulfenate-sulfoxide and sulfinate-sulfone rearrangements are very reliable and proceed with complete syn stereoselectivity17, ls. The allenic sulfoxides can be used for the synthesis of chiral alkylallenes with retention of configuration (see Section 1.1.3.). The relative configuration at sulfur in the allenic sulfoxides is not important for further synthetic purposes and racemization at sulfur is often observed without affecting the allenic axial dissymmetry. 

Although the exact mechanism of the reaction is difficult to resolve, from our accumulated data we can propose a mechanism which explains the experimental results obtained and enables the prediction of the stereochemistry of the sulfinate formed, based on the steric volume of the amine. The experimental data clearly demonstrate that the diastereoselective formation of a sulfinate is base-dependent. Therefore, the proposed mechanism has to include the effect of the base on the stereocourse of the reaction. Some additional circumstances have to be taken into account (1) the reaction of sulfiny 1 chlorides with alcohols in the presence of bases does not proceed via a sulfine intermediate117 (2) Mislow has proved that the reaction of chiral alcohols with sulfinyl chlorides in the presence of a base is kinetically controlled814,83 and (3) on first inspection, one could imagine the extreme case where DAG, under the influence of the base, reacts with only one of the enantiomeric sulfinyl chlorides. However, this is not the case, because the same yield and ee are obtained when 1.2 or 2.0 equiv of MeSOCl are used. Accordingly, the first step of the process could be an equilibrium reaction involving the sulfinyl chloride and the base. The racemic sulfinamide formed would be the active sulfur species that interacts with the sugar derivative. 

Preparation of Chiral Sulfinates. Optically active sulfinates can be prepared by reaction of a symmetrical sulfite with t-Butylmagnesium Chloride in the presence of an optically active amino alcohol. The best enantioselectivity has been observed using quinine as the optically active amine (eq 2)3 An alternative approach to this new enantioselective asymmetric synthesis of alkyl t-butylsulfinates would be reaction of a racemic sulfinate with r-butylmagnesium chloride complexed by optically active alkaloids (eq 3). In this case, kinetic resolution of the racemic sulfinate leads to an optically active sulfinate and an optically active sulfoxide. 

The rearrangement of sulfinate esters to sulfones has also been investigated. Detailed understanding of the mechanism results from the acetolysis of chiral (asymmetric sulfur and carbon) p-phenylbenzhydryl p-toluenesulfinate (120)ul Fava found that (120) undergoes epimerization at sulfur with complete retention at carbon. Sulfone (121) was formed in 33% optical purity, together with a small amount of racemic acetate. It appears that epimerization at sulfur is due to return from the intimate ion pair whereas sulfone (121) can form from both intimate and solvent-separated ion pairs. 

Although sulfur is a chiral center because the molecule does not undergo inversion, rapid racemization occurs by formation of the sulfinate anion, making all attempts to prepare and study optically active 2-naphthalenesulfinic acid doomed to failure. (Remember that a racemic modification is a mixture of equal parts of enantiomers, and is therefore optically inactive) ... 

Oxidation of a chiral dithioate 94 with m-CPBA yielded an (E) and (Z) mixture of chiral sulfines 95, which underwent racemization on standing for 24 h via the enesulfenic acid intermediate 96 (Scheme 21) [26]. 

Around the time of Solladie s initial work on 3-ketosulfoxide reduction, Cinquini reported an enantioselective route to chiral amines by reduction of non-racemic N-alkylidene sulfinamides [36]. The A-alkylidene sulfinamide substrates were readily prepared in one pot by addition of alkyl or aryl Grignard reagents to a nonenolizable aromatic nitrile to yield an imino-Grignard intermediate which was allowed to react with (5 )-(-)-menthyl p-toluene sulfinate (Scheme 4.25). The resulting A-alkylidene sulfinamides were found to be enantiomerically pure and of (S) configuration. 

---