Sharpless asymmetric epoxidation Kinetic resolution using

Sharpless "asymmetric epoxidation" has been used in the enantioselective synthesis of several natural products, including the kinetic resolution of allylic alcohols [11] and the creation of ... 

Kinetic resolution (chapter 28) using the Sharpless asymmetric epoxidation with L-(+)-di-isopropyl tartrate (chapter 25) removed the unwanted enantiomer as the epoxide 62 and left the required enantiomer (—)-61 for transformation into (+)-grandisol 63. 

An alternative and more ingenious method gave all the stereochemical information required.13 The racemic dienol 94 was subjected to Sharpless asymmetric epoxidation (chapter 25), 15 This is another kinetic resolution run to about 50% completion. Using an excess of di-isopropyl tartrate (DIPT, 1.5 equivalents) one enantiomer of the alcohol (R)-94 remained (72% ee) and one enantiomer of one diastereoisomer of the epoxide 95 (>95% ee) was formed. Once again the unreacted starting material 94 has a lower ee than the enantioselectively formed product 95. 

There can be no doubt that the reliability of the Sharpless reaction amongst many different classes of allyl alcohol contributes to its success as a synthetic tool in asymmetric synthesis. Another remarkable attribute of the Sharpless asymmetric epoxidation is the very high level of discrimination between enantiomers of secondary allylic alcohols leading to the wide use of this system for the kinetic resolution of these substrates. The kinetic resolution (Figure 4.5) was first reported using stoichiometric amounts of titanium/tartrate, but catalytic amounts of titanium may also be employed. ... 

Kinetic resolution of secondary allylic alcohols by Sharpless asymmetric epoxidation using fert-butylhydroperoxide in the presence of a chiral titanium-tartrate catalyst has been widely used in the synthesis of chiral natural products. As an extension of this synthetic procedure, the kinetic resolution of a-(2-furfuryl)alkylamides with a modified Sharpless reagent has been used . Thus treatment of racemic A-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [( )-74] with fert-butylhydroperoxide, titanium isopropoxide [Ti(OPr-/)4], calcium hydride (CaHa), silica gel and L-(+)-diisopropyl tartrate [l-(+)-DIPT] gave (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)ethylamine [(S)-74] in high chemical yield and enantiomeric excess . Similarly prepared were the (S)-Al-p-toluenesulphonyl-a-(2-furfuryl)-n-propylamine and other homologues of (S)-74 using l-(+)-D1PT. When D-(—)-DIPT was used, the enantiomers were formed . ... 

The Sharpless asymmetric epoxidations (SAEs) have been used in many cases for the synthesis of enantiopure 5,6-dihydropyrones, both in the direct mode, the conversion of a prochiral olefin into an enantioenriched epoxide, and in the kinetic resolution mode, which involves the selective epoxidation of one of the enantiomers in a racemic olefin. For example, a very recent synthesis of a natural pyrone isolated... 

Sharpless epoxidation reactions are thoroughly discussed in Chapter 4. This section shows how this reaction is used in the asymmetric synthesis of PG side chains. Kinetic resolution of the allylic secondary alcohol ( )-82 allows the preparation of (R)-82 at about 50% yield with over 99% ee (Scheme 7-23).19... 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

The Sharpless epoxidation is sensitive to preexisting chirality in selected substrate positions, so epoxidation in the absence or presence of molecular sieves allows easy kinetic resolution of open-chain, flexible allylic alcohols (Scheme 26) (52, 61). The relative rates, kf/ks, range from 16 to 700. The lower side-chain units of prostaglandins can be prepared in high ee and in reasonable yields (62). A doubly allylic alcohol with a meso structure can be converted to highly enantiomerically pure monoepoxy alcohol by using double asymmetric induction in the kinetic resolution (Scheme 26) (63). A mathematical model has been proposed to estimate the degree of the selectivity enhancement. 

Chiral to side-chain units can also be obtained by various catalytic and stoichiometric asymmetric synthesis as well as by resolution (30). Scheme 14 shows the preparation of these side-chain units using kinetic resolution by the Sharpless epoxidation (31), amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde (32), lithium acetylide ad-... 

The original report32 of the titanium-catalyzed asymmetric epoxidation of allylic alcohols in 1980 has been followed by hundreds of applications, the majority of which use the initially reported conditions. In the decade since the introduction of this reaction numerous improvements have been made41. The most complete discussion of the preparative aspects of both the asymmetric epoxidation and the kinetic resolution was presented by the Sharpless group42. This paper details the effects of reagent stoichiometry and concentration, substrate concentration, aging of the catalyst and variation of oxidant, solvent and tartrate as well as workup procedures. What is particularly noteworthy in this presentation is that significant amounts of unpublished work are drawn upon to develop recommendations for successful reaction. 

Should the starting material 53 be enantiomerically pure Yes, as there is virtually no kinetic resolution. The asymmetric centre in 53 is evidently too far from the alkene that reacts by AE to have more than a minor effect on the stereoselectivity. Enantiomerically pure alcohol 53 was already available from asymmetric reduction (using CBS, see chapter 26) of the corresponding enone. Sharpless epoxidation does have limitations but it is supremely practical. 

We will see Sharpless epoxidation reactions in the Double Methods section towards the end of the chapter. Interestingly, Sharpless other famous asymmetric method - dihydroxylation - has not found widespread use in kinetic resolution. This is probably because the AD is just too powerful or, to be anthropomorphic, too wilful. In other words, it is not sensitive to the chirality of the substrate and charges ahead and reacts with both enantiomers. That is not to say there are not examples of kinetic resolution with dihydroxylation,19 but they are more rare. However, the dihydroxylation is even more useful and much more general than the kinetic resolution of allylic alcohols by asymmetric epoxidation and was discussed in Chapter 25. A slightly complicated case of kinetic resolution of alcohols by asymmetric dihydroxylation is in the Double Methods section. 

Scheme 8.8. Reactions of a chiral allylic alcohol under Sharpless epoxidation conditions (Ti(0-i-Pr)4, /-BuOOH) using the chiral tartrates given (DIPT = diisopropyltartrate). (a) The matched case, in which the preferred approach of the asymmetric catalyst and the diastereoselectivity of the substrate are the same, (b) The mismatched case, (cj An example of a Sharpless kinetic resolution (KR).

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