Chiral sulfoxides from

Figure 1.55 Industrial scale chiral sulfoxides from titanium catalyzed as3fmmetric oxidations.

Chiral sulfoxides are useful intermediates in asymmetric synthesis. A number of methods for their preparation were developed in the last decade. An interesting displacement of dimethylphosphonylmethyl moiety, a carbon leaving group, from sulfur by Grignard reagents was used to obtain enantiomerically purep-tolyl sulfoxides.3 4 Optically pure methyl 4-bromophenyl sulfinate was subjected to a one-pot sequence yielding unsymmetrical dialkyl sulfoxides in 60-97% yield and >98% ee. A simple one-pot synthesis of chiral sulfoxides from norephedrine-derived... 

Remarkably, there is a noticeable lack of general methods for the asymmetric preparation of chiral sulfoxides from sulfides. The most satisfactory method would be a generally applicable enantioselective sulfoxidation reaction which would allow the preparation of sulfoxides from any prochiral sulfide with high ee s and in which the sulfoxide would be amenable to enantioselective preparation in both senses. 

The typical S-oxidation with BVMOs allows the formation of chiral sulfoxides from organic sulfides. This oxidation has received much interest in organic chemistry due to its use in the synthesis of enantiomerically enriched materials as chiral auxiliaries or directly as biologically active ingredients. This reaction has been studied extensively with CHMO from Adnetohacter showing high enantioselectivi-ties in the sulfoxidation of alkyl aryl sulfides, disulfides, dialkyl sulfides, and cychc and acyclic 1,3-dithioacetals [90]. CHMO also catalyzes the enantioselective oxida-hon of organic cyclic sulfites to sulfates [91]. 

Let us note that until now electrochemistry has not been able to yield chiral sulfoxides from the starting prochiral thioethers even though the use of chiral (chemically modified) electrodes was considered. 

As an alternative to menthyl sulfinates, Alcudia and coworkers [496] have prepared chiral sulfoxides from the sulfinate 1.137 derived from diacetone glucose 1.48. By varying the reaction conditions, either (R) or (5)-1.137 can be obtained so that the subsequent reactions with RMgX give, at will, rather ( )- or (fr)-1.136... 

Recombinant E. coli expressing the nitrobenzene dioxygenase from Cotncmonas sp. JS765 with amino acid substitutions at position 258 or 293 was used to increase the production of chiral sulfoxides from thioanisole, p-tolyl, Cl-thioanisole, and Br-thioanisole [44]. Chiral sulfoxides are mostly known as important precursors in the pharmaceuhcal industry [13]. For example, modafinil, marketed imder the name Provigil by Cephalon and prescribed for the treatment of imcontrollable sleepiness caused by narcolepsy or sleep apnea, has a chiral sulfoxide center [57, 58]. Esomeprazole, another chiral sulfoxide, is marketed by AstraZeneca imder the name Nexium as a proton pump inhibitor that reduces gastric acid secretion for treatment of gastroesophageal reflux disease [59]. 

Chiral chemical reagents can react with prochiral centers in achiral substances to give partially or completely enantiomerically pure product. An example of such processes is the preparation of enantiomerically enriched sulfoxides from achiral sulfides with the use of chiral oxidant. The reagent must preferential react with one of the two prochiral faces of the sulfide, that is, the enantiotopic electron pairs. 

With this encouraging result from the model system, a gram quantity of the racemic sulfoxide 40 was prepared by oxidation of benzoxathiin 16 with mCPBA and a small amount of chiral sulfoxide (A)-40 with 94% ee was isolated by subsequent chiral HPLC separation (Scheme 5.12). When chiral sulfoxide (S)-40 was treated with borane-dimethylsulfide, a clean reduction of the olefin and the sulfoxide was observed. More surprisingly, only the desired cis-diaryl dihydrobenzoxathiin 12 was observed in high yield and unchanged 94% ee. No trans-isomer or 16 was observed. With this proof of concept in hand, an efficient... 

The elimination of the chiral auxiliary from hydroxy sulfoxides by hydrogenolysis of the C-S bond with Ra-Ni did not give the expected desulfurized... 

In addition, it has been observed that iridum complexes generated in situ from (TrCl3-3H20] and chiral sulfoxides cause no asymmetric induction during hydrogenation (300). 

Scheme 18.5 Synthesis of the insect pheromone 12 from chiral sulfoxide 13 (pTol = p-tolyl) [23].

Two formal syntheses of (-)- [80] and (+)-kumausallene [81] followed this route and relied on the enantioselective preparation of the 2,6-dioxabicyclo[3.3.0]octane core 69 starting from diethyl tartrate or an appropriate chiral sulfoxide. In contrast, Evans et al. [82] used a distinct biomimetic approach in their enantioselective synthesis of the natural product (-)-62 (Scheme 18.23). 

The most important and widely used approach to chiral sulfoxides is the method developed by Andersen (5) based on the reaction between the diastereomerically pure (or strongly enriched in one dia-stereomer) menthyl arenesulfinates and Grignard reagents. The first stereospecific synthesis of optically active (+H7 )-ethyl p-tolyl sulfoxide 22 was accomplished in 1962 by Andersen (75) from (-)-(iS)-menthyl p-toluenesulfmate 45 and ethylmagnesium iodide. 

Recent studies on chiral sulfoximides, espcially in the laboratories of Cram, Johnson, Andersen, and Stirling, have been centered on the stereospecific interconversions between chiral sulfoxides, sulfimides, and sulfoximides, as well as on the construction of new stereochemical cycles. For the sake of brevity, only some selected results from these extensive studies are presented here to illustrate various stereospecific syntheses of chiral sulfoximides. 

The use of a chiral sulfoxide group as the stereoinducing element is at the center of Solladie s approach to the smaller fragment [44] and a C(8)-C(18) segment [44,45] of the larger fragment of lb (Scheme 27). jS-Ketosulfoxide 200 was obtained from S-ketoester 198 via carbonyl protection and condensation with chiral sulfoxide 199. Two completely diastereoselective reductions of 200... 

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