Chiral sulfinates

Ueno and coworkers49 have developed a procedure for the synthesis of chiral sulfinic acids. Treatment of (R)-( + )-23 with disulfide 24 and tributylphosphine in THF gave (S)-( — )-25. Compound 25 was oxidized with potassium permanganate to the sulfone, which was then reduced to the sulfinic acid, (S)-( — )-26, by treatment with sodium borohydride. Conversion of 26 or an analog to an ester would lead to diastereomers. If these epimers could be separated, then they would offer a path to homochiral sulfoxides with stereogenic carbon and sulfur atoms. 

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... 

During the past decade much attention was paid to the synthesis of chiral sulfinates with the sulfur atom as a sole center of chirality. A little earlier, Fava (105) had reported the asymmetric oxidation of methyl p-toluenesulfenate with (+)-monopercamphoric acid, yielding the corresponding sulfinate 65. The optical purity of the product was, however, very small (ca. 3%). 

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. 

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). 

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 carbanion generated by ot-proton abstraction of a 2-alkyloxazoline is capable of typical enolate chemistry. Thus, the carbanion was found to react with nitriles to give an enamine, with formate esters to give an aldehyde that can be trapped,with chiral sulfinate esters to give chiral sulfoxides,and with alkylating agents. A carbamate-protected aminomethyl chiral oxazoline was deprotonated and alkylated with diastereoselectivities up to 92% de. ... 

Direct lithiation of pyridazine 132 followed by trapping with chiral sulfinate esters produced chiral sulfoxides 133, analogous to the pyrimidine reaction covered in Section 6.2.2.2 <99JOC4512>. Queguiner and co-workers demonstrated that a second lithiation/trapping sequence can provide fully substimted pyridazines 134 with high diastereoselectivities. 

Zwanenburg and his group [105] have addressed the question of the tautomeric interconversion of aliphatic sulfines into vinyl sulfenic acids. They have synthesised dithioesters bearing an a asymmetric carbon centre. Oxidation with mCPBA did produce chiral sulfines, which did not racemise except when a phenyl group was attached to the a carbon. 

Chiral sulfinates, (CH3)3CS(0)0R. Alkyl f-butylsulfinates can be prepared by reaction of /-butylmagnesium chloride with dialkyl sulfites. If the reaction is carried out in the presence of an optically active amine, the products can be optically active. The highest enantioselectivity is observed with amino alcohols, in particular with (-)-quinine (1). 

Table 11. Synthesis of Chiral Sulfinates 55 and 56 from Sulfite 53 (Scheme 16)...

Moreover, N-sulfinyl oxazolidinones have been shown to be good intermediates for the synthesis of chiral sulfinate esters and sulfinamides with excellent ee. In all cases, the absolute configuration of the sulfoxide obtained is in agreement with the fact that nucleophilic displacement occurs with inversion of configuration at the sulfur center in the starting /V-sulfinyl oxazolidinone. 

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. 

Chiral sulfoxides are conveniently synthesised by Andersen s method (1962), in which a chiral sulfinate (4) is treated with a Grignard reagent. The reaction involves a sulfinyl group transfer and occurs with complete stereochemical inversion at the sulfur atom... 

There are several efficient methods available for the synthesis of homochiral sulfoxides [3], such as asymmetric oxidation, optical resolution (chemical or bio-catalytic) and nucleophilic substitution on chiral sulfinates (the Andersen synthesis). The asymmetric oxidation process, in particular, has received much attention recently. The first practical example of asymmetric oxidation based on a modified Sharpless epoxidation reagent was first reported by Kagan [4] and Modena [5] independently. With further improvement on the oxidant and the chiral ligand, chiral sulfoxides of >95% ee can be routinely prepared by these asymmetric oxidation methods. Nonetheless, of these methods, the Andersen synthesis [6] is still one of the most widely used and reliable synthetic route to homochiral sulfoxides. Clean inversion takes place at the stereogenic sulfur center of the sulfinate in the Andersen synthesis. Therefore, the key advantage of the Andersen approach is that the absolute configuration of the resulting sulfoxide is well defined provided the absolute stereochemistry of the sulfinate is known. 

Since we wanted to prepare a series of chiral acetylenic sulfoxides with different substituents on the aryl moiety, we needed access to the corresponding chiral sulfinates. Optically pure (-)-menthyl-p-toluenesulfinate (6 a) is commercially available but the other sulfinates (6b and 6c) are not. They were prepared according to an efficient procedure developed by Sharpless [9] from substituted benzenesulfonyl chlorides which are commercially available (Scheme 2). The sulfinates were formed as a mixture of diastereomers by in situ reduction of the... 

In order to obtain an insight into the diastereoselectivity in the Diels-Alder reaction of acetylenic sulfinates, chiral (+)-trans-2-phenylcyclohexanol [35] was used in place of cyclohexanol in the synthesis of the dienophile. A 1 1 dia-stereoisomeric mixture of acetylenic sulfinates 69 and 70 was obtained. After separation, each diastereoisomer was subjected to a Diels-Alder reaction with cyclopentadiene. Although the reaction once again occurred readily at room temperature, to our disappointment an inseparable mixture of diastereomeric adducts (3 2 by NMR) was obtained for each sulfinate. Apparently, a more spatially demanding chiral auxiliary needs to be incorporated into the dienophile in order to generate chiral sulfinates which cycloadd with prominent diastereoselectivity. 

The hetero-Diels-Alder reaction of chiral sulfines 24, bearing the relatively cheap (S)-proline as chiral auxiliary, with 2,3-dimethyl-l,3-butadiene (17) proceeds with low to moderate diastereoselectivity66. 

Another type of chiral sulfine 24 was prepared from an optically active sulfoximine [Eq. (20)].56... 

Some additional chiral sulfines prepared from (S)-proline have also been prepared and their reactions with 2,3-dimethylbutadiene studied.57 ( )-Sulfines of type 26 all reacted to afford mixtures of diastereomeric adducts [Eq. (21)]. 

For sulfoxides attached to a cycloalkenone, e.g., formation of 12 and 13, a detailed procedure which can also serve as a model for the reaction of other enolates with chiral sulfinates has been published3. Such compounds are not only useful as chiral dienophiles, but have found applications as chiral Michael acceptors and for other purposes6. A chiral quinone 14 was obtained by the same technique14. 

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]. 

Asymmetric Pummerer reactions with chiral sulfinates have been moderately successful but avoid pathway A, or more specifically, an achiral thionium ion, although... 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

C. ALLYLIC DERIVATIVES BEARING CHIRAL SULFINATE GROUPS... 

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