Sharpless kinetic asymmetric epoxidation

A noteworthy feature of the Sharpless Asymmetric Epoxidation (SAE) is that kinetic resolution of racemic mixtures of chiral secondary allylic alcohols can be achieved, because the chiral catalyst reacts much faster with one enantiomer than with the other. A mixture of resolved product and resolved starting material results which can usually be separated chromatographically. Unfortunately, for reasons that are not yet fully understood, the AD is much less effective at kinetic resolution than the SAE. 

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]. 

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 ... 

Asymmetric epoxidation of racemic unsaturated fluoro alcohols by the chiral Sharpless reagent can be exploited for kinetic resolution of enantiomers The recovered stereoisomer has 14-98% enantiomeric excess [55] (equation 50)... 

The epoxidation of alkenylsilanols parallels that of allylic alcohols in exhibiting good enantioselectivities339. Kinetic resolution of the alkenylsilanol 213 by the Sharpless asymmetric epoxidation has been accomplished, with the rate difference for the oxidation of the enantiomers of 213 being unusually high (>11)340. 

Kinetic resolution (not as good as Sharpless asymmetric epoxidation)... 

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. 

The Katsuki-Sharpless asymmetric epoxidation of racemic diol ( )-496 (obtained by allylation of ( )-crotonaldehyde) gives, after chromatographic separation, the erythro-epoxidc (+)-497 (33% yield, >95% ee). Its urethane undergoes assisted epoxide ring opening under acidic conditions, providing a 10 1 mixture of araZ mg-carbonate (+)-498 and the nZ 6>-stereomer. Carbonate hydrolysis and subsequent ozonolysis generates D-olivose (Scheme 13.114). Asymmetric epoxidation of the kinetically resolved dienol (—)-496 (72%) leads to (—)-497... 

The last and key step during the total synthesis of (-)-laulimalide by I. Paterson et al. was the Sharpless asymmetric epoxidation. The success of the total synthesis relied on the efficient kinetic differentiation of the Cis and C20 allylic alcohols during the epoxidation step. When the macrocyclic diol was oxidized in the presence of (+)-DIPT at -27 °C for 15h, only the C16-C17 epoxide was formed. 

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. 

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. 

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. 

Scheme 8.5. Proposed mechanism for the Sharpless asymmetric epoxidation reaction of allylic alcohols, shown here for a simple tran -allylic alcohol. For the AE reaction, Ra = Rb = H. When one (or occasionally both) of these substituents are alkyl groups, the Scheme pertains to the kinetic resolution sequence described in the next 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).

Applications of asymmetric epoxidation and kinetic resolution procedures The importance of the Sharpless AE and KR procedures is best measured by the speed with which they have become a part of the synthetic chemist s bag of tricks . Although a measure of their utility can be gleaned from examples given in sections... 

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