Modified Kagan method

The first samples were obtained by resolution.191193 Because the last step in the synthesis of the racemate is the oxidation of the sulfide to the sulfoxide,194-198 this has been modified to provide the S-isomer (Scheme 31.15). This is achieved by the Kagan method, which is a variation of the Sharpless epoxidation (see Chapter 9).199 200... 

Similar to the evolution of omeprazole (Prilosec) to esomeprazole (Nexium), the switch from racemic modafinil to enantioenriched armodafinil utilized asymmetric oxidation of sulfide.35 Although several asymmetric oxidation methods to provide enantiopure sulfoxides have been developed, the modified Kagan system [(Ti(Oi-Pr)4/(5,5)-DET] was selected due to superior yields and optical purities (% ee).36b The Kagan method is very useful, but it is substrate dependant (Table 3). Several sulfide derivatives of modafinil were screened to determine a direction for optimization. It was found the sulfide amide 11 provided excellent optical purity and further optimization. 

Oxidation in the presence of chiral titanium tartrate (modified Sharpless method). Inspired by the Sharpless asymmetric epoxidation48 of allylic alcohols with hydroperoxides in the presence of chiral titanium complex [diethyl tartrate (DET) and Ti(0-i-Pr)4], Kagan and co-workers46 and Modena and co-workers47 developed almost at the same time two variations of this reaction leading to o.p. sulfoxides with high enantiomeric purity. 

Kaganer modified Dubinin s method in order to calculate the surface area within micropores. He assumed that the adsorption potential of the sites is distributed according to a Gaussian function such that... 

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. 

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