Stereogenic Sulfur Center

There are a number of important kinds of stereogenic centers besides asymmetric carbon atoms. One example is furnished by sulfoxides with nonidentical substituents on sulfur. Sulfoxides are pyramidal and maintain dieir configuration at room temperature. Unsymmetrical sulfoxides are therefore chiral and exist as enantiomers. Sulfonium salts with three nonidentical ligands are also chiral as a result of their pyramidal shape. Some examples of chiral derivatives of sulfur are given in Scheme 2.1. 

While the chemistry of alkyl and allylic sulfoxide anions is similar to that of phosphine oxides, phosphinates and sulfone stabilized anions (Sections 1.5.2.2.1 -2), the situation is further complicated by the additional stereogenic center at sulfur. Therefore in all cases, asymmetric induction may arise from the stereocenter at sulfur. 

A simplistic view of the mechanism is depicted in Scheme 3.5. The sulfoxide (I) is activated by triflic anhydride to generate a sulfonium salt (III). It was observed early on that the outcome of the glycosylation was not influenced by the configuration at the two variable stereogenic centers in the sulfoxide donor (i.e., anomeric carbon and sulfur).1 This was taken as evidence for the intermediacy of the oxycarbenium ion (V), which arises from rapid elimination of an alkylsulfenyl triflate(IV) from III. Reaction of V with a nucleophile then gives rise to a mixture of a- and P-glycosides (II). 

The stereochemical outcome of such cycloadditions may be altered by substituents attached to the nitrile oxide-olefin linker. Hassner and co-workers (75,240,253-255) and Kurth and co-workers (256) examined the influence of a stereogenic center a to the dipole in the cycloaddition of alkene-tethered nitrile oxides that feature a sulfur or oxygen atom within the connecting chain (Table 6.13). As expected, the diastereofacial selectivity is increased in the presence of fragments with increasing steric demand. Cycloadditions of thioethers show lower... 

Since the sulfur atom in sulfoxides is inherently a stereogenic center, the resultant products are a mixture of... 

The formation of an alkanethiol by reaction of an alkyl halide or alkyl /Moluenesulfonatc with thiourea occurs with inversion of configuration in the step in which the carbon-sulfur bond is formed. Thus, the formation of (R)-2-butanethiol requires (.S Kvcc-butyl /Moluenesulfonatc, which then reacts with thiourea by an SN2 pathway. The /Moluenesulfonatc is formed from the corresponding alcohol by a reaction that does not involve any of the bonds to the stereogenic center. Therefore, begin with (.S )-2-bulanol. 

Inversion of configuration at the stereogenic center is required. The nucleophile must therefore attack the stereogenic center, and acid-catalyzed hydrolysis should be chosen. Dilute sulfuric acid would be satisfactory. 

Sulfur is one atom further removed from the stereogenic center, and so C—O outranks C—C—S. 

The oxidation of a heteroatom such as sulfur can generate a new stereogenic center. This type of oxidation has presented special problems (see Section 9.7). 

AstraZeneca (formerly Astra) has launched the proton-pump inhibitor esomeprazole (19) (as Nexium) as a treatment for peptic ulcer, gastroesophageal reflux disease, duodenal ulcer, and esophagitis. Esomeprazole is the (S)-enantiomer of omeprazole and was developed as a result of its improved pharmokinetic profile and better potency after oral dosing than (f )-form of omeprazole or the racemate. The dosage is higher than would be expected for a simple chiral switch. The stereogenic center is at sulfur. Detailed accounts of the development of the process have been published.189190... 

Watanabe et al. examined a similar addition/trapping tandem involving vinylic sulfones [178]. Acceptable ee s were obtained when bidentate chelation was made possible, as was the case when benzimidazolyl moities were attached to the sulfur atom (the ligand was again a box derivative). Yet only one stereogenic center was created during the reaction. 

The configuration at sulfur only influences the stereochemical outcome in systems without a stereogenic center at C-l. 

AUyl Sulfoxide Rearrangements of Compounds Without a Stereogenic Center at C-l (Chirality Transfer from Sulfur)... 

Induction in the chirality transfer from C-l to C-3 overrides that of the chirality transfer from the sulfur atom to C-3. Therefore, the chirality at the heteroatom only has an impact on systems lacking a stereogenic center at C-l. The two diastereomeric transition states for the rearrangement of such chiral sulfoxides are designated as exo and endo"1. These lead to the different enantiomers of the allylic alcohol. Their energy difference, which depends mainly on the substitution of the double bond, determines the enantioselectivity of the process. 

It has long been known that a thiol and an alkene react in an atmosphere of oxygen at room temperature to give /i-hydroxy sulfoxides64, compounds with stereogenic centers at the ft-carbon and the sulfinyl sulfur. 

Treatment of cyclic ketones with [(-)-menthyl] (A)-4-methylbenzenesulfinate in the presence of diisopropylaminomagnesium bromide affords optically active a-sulfinylcycloalkanones 1 as diastereomeric mixtures. This reaction is accompanied by complete inversion of configuration at sulfur and generation of a new stereogenic center at the a-carbon atom71. 

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