Modena reagent

The Sharpless epoxidation of allylic alcohols by hydroperoxides uses as mediator [45] or as catalyst [46] a chiral titanium complex obtained from the combination Ti(OPr )4/diethyl tartrate (DET) in 1 1 ratio. Kinetic resolution of P-hydroxysulfides was also observed, but without diastereoselectivity for the product P-hydroxysulfoxides [47]. We found that the Sharpless reagent deactivated by 1 equivalent of water allows the enantioselective oxidation of aryl methyl sulfides into sulfoxides to be performed with ee s up to 90% [4S-50]. The best reagent combination proved to be Ti(0Pr )4/DET/H20 = 1 2 1. Independently, Modena et al. obtained similar enantioselectivities with the combination Ti(OPr )4/DET in 1 4 ratio [51]. These two combinations are sometimes referred to as the Kagan reagent and the Modena reagent, respectively. They will be considered successively. 

Table 1.3 Some representative examples of sulfoxidation by TBHP in presence of the combination Ti(OiPr )4/(l ,i )-DET =1 4 ( Modena reagent ) ...

The Modena reagent is the basis of a new method for the resolution of chiral ketones [59]. Thus, ( )-menthone was transformed into 1,3-dithiolane (65) and oxidized using TBHP. The two 5-monooxides were separated, and the major one gave after cleavage (-)-menthone (93% ee). The Modena procedure is also very successful in the preparation of nonracemic 1,1 -binaphthyl-2,2 -dithiol (66a) [156,157]. Monooxidation of the dimethyl dithioether (66b) furnished an almost 1 1 mixture of diastereoisomeric sulfoxides (each with >98% ee). When the two sulfur atoms of (66) are connected by a carbon chain, such as in (66c) or (66d), the... 

Significant improvements in asymmetric oxidations were made by Modena and, especially, by Kagan, and their coworkers. Both groups used chiral peroxotitanium complexes patterned after the Sharpless reagent as the oxidants. 

Modena, G. Todesco, RE. J. Chem. Soc., 1962, 4920, and references cited therein. There are some reagents that oxidize sulfoxides in preference to sulfides, (e.g., NaMn04) see Henbest, H.B. Khan, S.A. Chem. Commun., 1968, 1036. 

The enantioselective chemical and enzymatic oxidations of sulfides [86, 94] have also received many interesting developments. High e.e. values have been obtained independently by Kagan [103,104] and Modena [105] via modified Sharpless reagents and by Davis s group [106], which used various chiral oxaziridines. 

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. 

A modified Sharpless reagent has been developed by Kagan [503, 814], Modena [502, 814] and their coworkers. This new catalyst is formed by mixing water, Ti(0/-Pr)4, and diethyltartrate in a ratio of 1/1/2. The modified catalyst promotes enantioselecfrve oxidation of arylalkylsulfides by fert-BuOOH, and chiral sulfoxides are produced with excellent enantiomeric excesses (> 90%). Lower selectivities are observed from dialkylsulfides. From (R,R) or (5 S)-diethyl tartrate, either sulfoxide enantiomer can be obtained. The use of cumene hydroperoxide as the oxidant may improve the enantioselectivity. Uemura and coworkers obtained similar results by replacing the tartrates in these complexes with binaph-thols [815],... 

Because of the availability of their Ti-electrons, alkenes and alkynes are sensitive to electrophilic addition. It is an intriguing question why, with certain reagents and under certain conditions, alkenes are more reactive than alkynes, whereas in other cases the reverse is true. This question has been addressed by Modena and coworkers. They consider protons and carbocations as reagents that react with alkenes at similar or lower rates than with alkynes. Addition of these reagents gives rise to open carbocations in a ratedetermining step. 

Rappoport has presented a detailed outline of the mechanisms of the reactions of vinyl halides with nucleophilic reagents. Modena et /. " have provided further evidence in support of a spectrum of transition states for elimination from activated vinyl halides induced by alkoxide bases. Cristol and Whittemore have shown that the stereoselectivity of elimination from vinyl halides is largely determined by the choice of basic reagent alkoxide bases encourage am/-elimination, whereas syn-elimination and alpha-elimination become dominant with lithium alkyls. 

The asymmetric oxidation of sulfides represents a straightforward access to chiral sulfoxides that are useful compounds for asymmetric synthesis as chiral auxiliaries and also for the synthesis of biologically active molecules. Among the different methods to perform these reactions, titanium-mediated thioether oxidation is one of the most attractive. Indeed, Kagan ° and Modena independently showed that the use of chiral titanium complexes derived from Sharpless reagent allows the asymmetric oxidation of prochiral sulfides (Scheme 7.6). 

Oxidation of sulfides has been performed by TBHP in anhydrous conditions with an excess of diethyl tartarate (4 equivalents) [59]. Modena used 1,2-dichloroethane or toluene as solvent at -20°C. Some examples are listed in Table 1.3. As with the Kagan reagent, a high ee (88%) is obtained for the sulfoxidation of methyl p-tolyl sulfide in 1,2-dichloroethane, but the ee drops to 64% in toluene. 

The Kagan reagent was used at Eli Lilly to resolve racemic thiazolidinone (60) (Scheme 1.16) [153]. At 60% and 80% completion, the ee s of recovered (-)-(60) were 67% and 94%, respectively. The Modena procedure (i.e. no added water in the reagent system) gave a much slower reaction, but the ee shows only a small decrease. 

Most applications of sulfide oxidations by alkyl hydroperoxides have involved titanium catalysis together with chiral ligands for enantioselective transformations. The groups of Kagan in Orsay [61] and Modena in Padova [62] reported independently on the use of chiral titanium complexes for the asymmetric sulfoxidation by the use of BuOOH as the oxidant. A modification of the Sharpless reagent with the use of Ti(0 Pr)4 and (J ,J )-diethyl tartrate (J ,J )-DET) afforded chiral sulfoxides with up to 90% ee (Eq. (8.17)). 

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