Chiral oxidants Sharpless reagent

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. 

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. 

Chiral sulfoxides (12, 92). Kagan et al.3 have reviewed the asymmetric oxidation of sulfides by a water-modified Sharpless reagent. Optical yields are generally highest in the oxidation of aryl methyl sulfides (—75-90%). 

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). 

Sharpless reagent is the most popular of the chiral oxidants. It is a mixture of tetraisopropoxytitanium, diethyl (R,R)- or (5,5)-tartrate, water, and tert-butyl hydroperoxide in the molar ratio 1 2 1 1 [224],... 

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 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). 

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. 

Aryl vinyl selenides (3) are oxidized by (—)-(l) to selenoxide intermediates which undergo elimination to chiral allenic sulfones (eq 6). Somewhat better ee values were observed using the modified Sharpless reagent (up to 38% ee). As3mimetric oxidation of cyclohexyl selenides by oxaziridine (—)-(l) give axially chiral cyclohexylidene derivatives in up to 83% ee (eq 7). ... 

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)). 

The asymmetric oxidation of a variety of acyclic (89) and cyclic (90) substituted enol phosphates using commercially available Sharpless reagent (93), and a fructose derived chiral (94) as a catalyst, afforded the corresponding a-hydroxy ketones (91) and (92) in high enantioselectivily and good yields (Scheme 30). The influence of steric and electronic... 

Sharpless and Masumune have applied the AE reaction on chiral allylic alcohols to prepare all 8 of the L-hexoses. ° AE reaction on allylic alcohol 52 provides the epoxy alcohol 53 in 92% yield and in >95% ee. Base catalyze Payne rearrangement followed by ring opening with phenyl thiolate provides diol 54. Protection of the diol is followed by oxidation of the sulfide to the sulfoxide via m-CPBA, Pummerer rearrangement to give the gm-acetoxy sulfide intermediate and finally reduction using Dibal to yield the desired aldehyde 56. Homer-Emmons olefination followed by reduction sets up the second substrate for the AE reaction. The AE reaction on optically active 57 is reagent... 

Asymmetric epoxidation of olefins is an effective approach for the synthesis of enan-tiomerically enriched epoxides. A variety of efficient methods have been developed [1, 2], including Sharpless epoxidation of allylic alcohols [3, 4], metal-catalyzed epoxidation of unfunctionalized olefins [5-10], and nucleophilic epoxidation of electron-deficient olefins [11-14], Dioxiranes and oxazirdinium salts have been proven to be effective oxidation reagents [15-21], Chiral dioxiranes [22-28] and oxaziridinium salts [19] generated in situ with Oxone from ketones and iminium salts, respectively, have been extensively investigated in numerous laboratories and have been shown to be useful toward the asymmetric epoxidation of alkenes. In these epoxidation reactions, only a catalytic amount of ketone or iminium salt is required since they are regenerated upon epoxidation of alkenes (Scheme 1). 

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 . 

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