Sharpless/Kagan system

Three synthetic approaches were used to provide armodafinil during the process development by Cephalon/Novasep.34 Since the racemic modafinil is commercially available, the resolution via preferential crystallization of modafinic acid 6 was employed for phase I clinical trials and was subsequently replaced by large-scale chiral chromatography. Meanwhile, an economical enantioselective synthetic route was developed by using asymmetric oxidation catalyzed by a titanium (IV) isopropoxide and diethyl tartrate with cumene hydroperoxide (the Sharpless/Kagan system).363... 

Kagan and Pitchen ° and Modena and coworkers independently reported the oxidation of sulfides to sulfoxides using modified Sharpless epoxidation catalyst (titanium/diethyl tartrate). By 1987, Kagan had already reported a catalytic variation of the reaction and an improved catalytic system allows for the use of lower (10 mol%) loading of catalyst. For example, sulfide (5.143) undergoes sulfoxidation with good enantioselectivity. An alternative catalyst based on Ti(0 Pr)4 and BINOL is also effective for sulfoxidation, providing up to 96% ee. ... 

An enantioselective version of the reaction described in Protocol 4 has been recently investigated. The asymmetric oxidation of the sulfur centre was performed with the Kagan s modified Sharpless system [1.3 equiv of cumene hydroperoxide in the presence of a Ti(OPr )4/diethyl tartrate/H20 catalyst] and afforded the corresponding sulfinyl-substituted complexes with high enantiomeric purity (Scheme 6.8). 

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