Enantioselective oxidations Sharpless reagent

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. 

The Orsay group found serendipitously that methyl p-tolyl sulfide was oxidized to methyl p-toly 1 sulfoxide with high enantiomeric purity (80-90% ee) when the Sharpless reagent was modified by addition of 1 mole equiv. of water [16,17]. The story of this discovery was described in a review [19], Sharpless conditions gave racemic sulfoxide and sulfone. Careful optimization of the stoichiometry of the titanium complex in the oxidation of p-tolyl sulfide led to the selection of Ti(0iPr)4/(7 ,7 )-DET/H20 (1 2 1) combination as the standard system [ 17]. In the beginning of their investigations, the standard conditions implied a stoichiometric amount of the chiral titanium complex with respect to the prochiral sulfide [16,17,20-23]. Later, proper conditions were found, which decreased the amount of the titanium complex without too much alteration of the enantioselectivity [24,25],... 

Chiral sulfoxides or selenoxides.1 This oxaziridine (1) is generally more effective than the modified Sharpless reagent of Kagan (13, 52) for enantioselective oxidation of alkyl aryl sulfides or selenides to the corresponding sulfoxides or selenoxides. The polar Cl groups of 1 improve both rate and the enantioselectivity. 

Chiral sulfoxides. The Sharpless reagent lor asymmetric epoxidation also effects asymmetric oxidation of prochiral sulfides to sulfoxides. The most satisfactory results are obtained for the stoichiometry Ti(0-(-Pr)4/L DET/H20/(CH,),C00H = 1 2 1 2 for I equiv. of sulfide. In the series of alkyl p-tolyl sulfides, the (R)-sulfoxide is obtained in 41-90% ee the enantioselectivity is highest when the alkyl group is methyl. Methyl phenyl sulfide is oxidized to the (R)-sulfoxide in 81% ee. Even optically active dialkyl sulfoxides can be prepared in 50-71% ee the enantioselectivity is highest for methyl octyl sulfoxide. 

Selenoxides derived from unsymmetrical selenides are chiral and stable toward pyramidal inversion at room or even higher temperatures. They are produced enantioselectively by the use of chiral oxidants such as the Sharpless reagent or camphor-derived oxaziridines or diastereoselectively with achiral oxidants when one of the selenide substituents is itself chiral (see Section 9). Racemic selenoxides have been resolved by chromatography over chiral adsorbents. Chiral selenoxides racemize readily in water, particularly under acid-catalyzed conditions, presumably via the intermediacy of achiral selenoxide hydrates (equation 2). 

Preparative Methods the title reagent can be prepared from commercially available (1,2-benzenedithiol and 1,3-dichloroacetone. After condensation of these reagents in the presence of DMAP, the resulting l,5-benzodithepan-3-one is enantioselectively oxidized to the (/f)-monosulfoxide by modified Sharpless oxidation [cumene hydroperoxide, Ti(0-t-Pr)4] in the presence of (-F)-diethyl tartrate as a chiral ligand. - Subsequent dry ozonation" of the (/f)-monosulfoxide affords (lf ,5f )-bis-sulfoxide 1, having >98% optical purity. Alternative use of (—)-diethyl tartrate in the modified Shaipless oxidation makes possible convenient access to enantiomeric (15,5S)-1. ... 

Optically active sulfoxides can also be prepared by asymmetric oxidation of sulfides. However, numerous papers have reported very low enantioselectivity." Only one report, " using a modified Sharpless reagent, H20/Ti(0Pr )4/diethyl tartrate/BuKX)H, described asymmetric oxidation of alkyl aryl sulfoxides with good enantiomeric excesses 75 to 95%. 

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],... 

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. 

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)). 

In 1980, Katsuki and Sharpless described the first really efficient asymmetric epoxidation of allylic alcohols with very high enantioselectivities (ee 90-95%), employing a combination of Ti(OPr-/)4-diethyl tartrate (DET) as chiral catalyst and TBHP as oxidant Stoichiometric conditions were originally described for this system, however the addition of molecular sieves (which trap water traces) to the reaction allows the epoxidation to proceed under catalytic conditions. The stereochemical course of the reaction may be predicted by the empirical rule shown in equations 40 and 41. With (—)-DET, the oxidant approaches the allylic alcohol from the top side of the plane, whereas the bottom side is open for the (-l-)-DET based reagent, giving rise to the opposite optically active epoxide. Various aspects of this reaction including the mechanism, theoretical investigations and synthetic applications of the epoxy alcohol products have been reviewed and details may be found in the specific literature . 

Because of this catalyst degradation, organometallic catalysts are currently the best synthetic reagents for enantioselective epoxidation of olefins. Chiral Mn(III)-salen complexes yield up to 99% ee for cw-disubstituted, tri- and tetra-substituted alkenes [62], but the best results require less desirable oxidants - iodosyl benzene or hypochlorite. Other catalysts accept a more limited substrate range the Sharpless-Katsuki titanium-tartrate ester [65] for allylic alcohols and the JuUa-Colonna epoxidation for a,P-unsaturated ketones [66]. 

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