Sharpless method

The requirement for the presence of an adjacent alcohol group can be regarded as quite a severe limitation to the substrate range undergoing asymmetric epoxidation using the Katsuki-Sharpless method. To overcome this limitation new chiral metal complexes have been discovered which catalyse the epoxidation of nonfunctionalized alkenes. The work of Katsuki and Jacobsen in this area has been extremely important. Their development of chiral manganese (Ill)-salen complexes for asymmetric epoxidation of unfunctionalized olefins has been reviewed1881. 

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

Another regioselective addition to an epoxide was used as one step in a synthesis of the r-butyldiphenylsilyl ether (7) of verrucarinic acid from 5.3 The diol was converted into the optically active epoxy alcohol by the Sharpless method (10, 64-65) and then oxidized to the epoxy acid 6 by the new ruthenium-catalyzed oxidation of Sharpless et al. (this volume). This epoxy acid undergoes almost exclusive / -addition with trimethylaluminum to give the desired product 7. 

Equatorially positioned methyl-branched derivatives may be obtained by reductive cleavage of spiro epoxides [94], Thus the Peterson olefination of 188gives the exocyclic 3 -methylene function in 189. By means of a Sharpless epoxidation the allylic 4"-hydroxy group should determine the chirality of the resulting epoxide. However, the Sharpless method does not show any reaction neither in a monosaccharide model system nor in this trisaccharide precursor [95]. Amazingly, the classical epoxidation with m-chloroperbenzoic acid is employed to give exclusively the desired (3"R) epoxide 190 in excellent yield. These results may be associated with a sufficient chiral induction of the stereochemical information at C-l", C-4", and C-5". A subsequent reduction furnishes the original E-D-C trisaccharide sequence 191 of mithramycin [95, 96]. 

Dihydroxylation of olefins followed by oxidation with periodate leads to cyclization and the corresponding carbinolamine. This can then be reduced to the piperidine <2005JOC10182> (Scheme 12). The strategy was used in the synthesis of both the (2A,3i )-3-hydroxypipecolic acid 13 and (2 5, 3A)-3-hydroxypipecolic acid 14 from D-serine. Variations in this strategy toward both trans-isomers of the 3-hydroxypipecolic acid moiety are shown in Schemes 13 and 14. The initial stereochemistry was introduced using Sharpless method <2005JOC360>. 

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. 

Both chemical and enzymatic synthetic methods for the asymmetric oxidation of the carbon-carbon double bond have been developed [46], but the area of carbon-carbon double bond oxidations has been shaped by the breakthrough discovery of asymmetric epoxidation of allylic alcohols with the Katsuki-Sharpless method [47]. Catalytic asymmetric synthesis of epoxides from alkenes by Jacobsen... 

In the case of alkenes with polar functional groups, two-site attachment of the substrate to a chiral oxidant is possible and has allowed spectacular enantioselection. Thus, both the hydroperoxide anion based epoxidation of a,/ -unsaturated carbonyls and the epoxidation of allylic alcohols by the titanium(IV)-based Sharpless method exhibit very high enantioselectivity on a wide variety of substrates. 

Figure 2. Enantioselective epoxidation of allylic alcohols hy the Sharpless method...

As discussed in the preceeding section, the application of the Sharpless method to the epoxidation of homoallylic alcohols leads to epoxy alcohols with only 23-55% enantiomeric excess and of opposite steric course relative to that observed for allylic alcohols. The reason for the low enantioselection was considered to be due to steric congestion in the chain of the homoallylic alcohol as it folded to come into contact with the peroxygen. 

To date a number of useful methods have been developed to prepare nucleophilic selenium species other than the Sharpless method tl]. They involve... 

The step marked A is similar to the ene synthesis (15-23). The step marked B is a [2,3]-sigmatropic rearrangement (see 18-35). The reaction can also be accomplished with ferf-butyl hydroperoxide, if Se02 is present in catalytic amounts (the Sharpless method).The Se02 is the actual reagent the peroxide... 

Chiral epoxides and vicinal diols (employed as their corresponding cyclic sulfate or sulfite esters as reactive intermediates) are extensively employed high-value intermediates in the synthesis of chiral compounds because of their ability to react with a broad variety of nucleophiles (Figs. 11.2-1 and 11.2-2). In recent years, extensive efforts have been devoted to the development of chemo-catalytic methods for their production19, 10]. Thus, the Sharpless methods allowing for the asymmetric epoxida-... 

Diamides of tartaric acid with primary amines have been used as chiral ligands for titanium-and zirconium-catalyzed epoxidations of homoallylic alcohols by the Sharpless method (Section D.4.5.2.4.). Such diamides are conveniently obtained from dimethyl or diethyl tartrate by reaction with the corresponding amine38. The iV,A A, /V -tetrarnethyl diamide has been used for the formation of chiral dioxolanes (Section D.1.5.1.) and in the synthesis of chiral alkenes (Section D.l.6.1.5.). 

The seminal enantioselective allylic alcohols epoxidation realized by Katsuki and Sharpless [18] to which other similarly steroselective reactions soon followed (e.g., bishydroxyla-tion, cyclopropanation, lactonization and catalytic hydrogenation) have been invaluable for this purpose. One of the most significant applications, as far as drug synthesis is concerned, of the Sharpless method from the innumerable ones which have been found in the past 20 years is the routine preparation (Fig. 6) of antipodal pairs of known chirality of (3-blockers such as propranolol (5) [19]. 

Synthesis of Chiral Oxirans. The Katsuki and Sharpless method for... 

Full details have been given for the synthesis of a variety of a-diazo-esters (113) and of chiral oc-thio-esters (114). a,8-Epoxy-esters (115) can be obtained from the parent unsaturated esters either by using a new epoxidation reagent prepared from fluorine gas and aqueous acetonitrile or lithium t-butylhydroperoxide ( ). When this latter reagent is added to unsaturated esters derived from chiral alcohols, reasonable diastereoselection is observed but, as yet, not enough (up to 60%) to rival the Sharpless method. All four isomers of the useful epoxy-esters [(116) (2R,3S) isomer] have been obtained from the... 

Epoxidation of bishotnoaUyUc alcohols. The Sharpless method of epoxidation (5, 75-76) of these alcohols is highly stereoselective. Thus reaction of 1 with r-butyl hydroperoxide catalyzed with VO(acac)2 followed by treatment with acetic acid gives the tetrahydrofuranes 2 and 3 in the ratio 9 1. ... 

The second approach makes use of the Sharpless method, consisting in opening of the oxirane ring with selenophenol to 357. Oxidation of 357 to the unstable selenooxide (358) followed by refluxing in ethanol gives 281 in good yields. This method was used by David for the preparation of 3,4-unsaturated precursors of disaccharides. 

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