Sharpless epoxidation, racemic alcohols

Selective polymerization, enantiomers, 185 Semico rrin-copper complexes, 199 Sharpless epoxidation, racemic alcohols, 45 Side-chain units, prostaglandins, 310 Sigmatropic reactions, 222 Silanes, oxidative addition, 126 Silica gel, 285, 352... 

Contrary to the optical resolutions described in Sections 2.1.1.-2.1.3., which depend on the solubility or chromatographic properties ( Thermodynamic resolution ), the kinetic resolution rests on rate differences shown by the enantiomers when reacted with an optically active reagent. In the ideal case, only one enantiomer is converted into the envisaged product and the other enantiomer is unchanged. In this way, optical resolution is reduced to the more simple separation of two different reaction products. In practice, only two methods of kinetic resolution are reasonably general and reliable the Sharpless epoxidation of allylic alcohols and the enzymatic transesterification of racemic alcohols or carboxylic acids. 

RESOLUTION OF RACEMIC ALCOHOLS AND RELATED SUBSTRATES. Under certain conditions, enantiomers react at sufficiently different rates and they provide a chemical means to resolve racemates (Scheme 31) (64). The Sharpless epoxidation efficiently resolves allylic alcohols that have flex-le structures (64, 65). Homogeneous hydrogenation with (/ )- or (S)-... 

The kinetic resolution of racemic tertiary hydroperoxides via catalytic Sharpless epoxidation with various allylic alcohols was investigated (Eq. 6AA.3).9 The reaction of 1-cyclohexyl-1-phenylethyl hydroperoxide gave partially resolved hydroperoxide with up to 29% at about 50% conversion. 

Within limits, an increase in the steric bulk at the olefin terminus of allylic alcohols of the type R1 CH(OH)CH=CHR2 causes an increase in the rate of epoxidation of the more-reactive enantiomer, and a decrease in the rate for the less-reactive enantiomer, resulting in enhanced kinetic resolution334. However, complexes of diisopropyl tartrate and titanium tetra-terf-butoxide catalyse the kinetic resolution of racemic secondary allylic alcohols with low efficiency335. Double kinetic resolution techniques can show significant advantages over the simple Sharpless epoxidation techniques336. 

A considerable amount of work was required to optimize the leaving group and avoid racem-ization through a Payne rearrangement mechanism.12 Of course, the Sharpless epoxidation of allyl alcohols is well-known to access these 3-functionalized epoxides. 

Sharpless epoxidations are discussed in the plural because primary (Figures 3.35 and 3.38) and secondary allylic alcohols (Figure 3.39) are reacted in different ways. Primary allylic alcohols are reacted to completion. Secondary allylic alcohols—if they are racemic—are usually reacted only to 50% conversion (the reason for this will become clear shortly). The oxidation agent is always a hydroperoxide, usually tert-BuOOH. The chiral additive used is 6-12 mol% of an enantiomerically pure dialkyl ester of tartaric acid, usually the diethyl ester (diethyltar-... 

Racemic chiral secondary allylic alcohols can be subjected to a kinetic resolution by means of the Sharpless epoxidation (Figure 3.39). The reagent mixture reacts with both enantiomers of the allylic alcohol—they may be considered as a-substituted crotyl alcohols—with very different rates. The unreactive enantiomer is therefore isolated with enantiomer excesses close to ee = 100% in almost 50% yield at approximately 50% conversion. The other enantiomer is the reactive enantiomer. Its epoxidation proceeds much faster (i.e., almost quantitatively) at 50% conversion. The epoxide obtained can also be isolated and, due to its enantiomeric excess, used synthetically. 

Fig. 3.41. Mechanistic details of Sharpless epoxidations, part III epoxidations of chiral racemic secondary allylic alcohols in the presence of l-(+)-DET and their diastereo-selectivities. Transition state of the matched pair (top), transition states of the mismatched pair (bottom).

When racemic secondary allylic alcohols 3.17 are subjected to standard Sharpless epoxidation conditions, kinetic resolution takes place [127], By choosing (RJi)- or (5,5)-tartrate, either enantiomer of the epoxyalcohol can be obtained with a maximum yield of 50%, alongside the unreacted allylic alcohol. The ratio of epoxidation rates of the enantiomeric allylic alcohols is usually high enough to obtain both the epoxyalcohol and the unreacted allylic alcohols in high enantiomeric excesses. In some cases, the use of dicyclohexyl- instead of diisopropyl tartrate improves the enantioselectivity. Homoallylic alcohols are also epoxidized, but the selectivities are significantly lower [808]. 

Reaction D in Fig. 5 represents a very useful approach to a number of enantiomerically pure allylic alcohols by the Sharpless epoxidation procedure [32], In the reported example, the reaction carried out with t-BuOOH/Ti(OPr-i)4 on racemic ( )-l-cyclohexyl-2-butenol in the presence of (-l-)-diisopropyltartrate (DIPT) occurs almost exclusively on the (5)-enantiomer of the substrate, and affords a single epoxide. The unreacted (R)-alcohol can be isolated in 96% e.e. 

The Sharpless epoxidation serves as the predominant approach for the asymmetric epoxidation of allylic alcohols, which is catalyzed with L-(+)/D-(-)-diethyl tartrate and titanium tetraisopropoxide (Ti(O-f-Pr) ) using TBHP as the oxidant [9, 19]. Primary allylic alcohols are t5qjical substrates for Sharpless epoxidation, and the same system could be used to kinetically resolve racemic secondary allylic alcohols as well [116,117]. 

A recent study demonstrated that SMO can also catalyze the kinetic resolution of secondary phenyl allylic alcohols with excellent stereoselectivity [118]. Using the whole cells of recombinant E. coli expressing the SMO from Pseudomonas sp. LQ26, the kinetic resolution of racemic l-phenylprop-2-enol 5delded (IR, 2R)-phenyl glycidol with >99% ee and 98% de, and (R)-alcohol was recovered with >99% ee at 50% conversion for 2h (Scheme 13.13b) [118], which displayed an advantage over previously established chemistry methods, such as the Sharpless epoxidation and... 

Chemistry-based kinetic resolution methods, which make use of the preferential reaction of one enantiomer with a chiral reagent (e.g. hydroboration of racemic alkenes with diisopinocampheylborane) or an achiral reagent in the presence of an appropriate chiral catalyst (e.g. Sharpless epoxidation of racemic allylic alcohols with t-BuOOH in the presence of (2R,3R)- or (25,35)-diisopropyl tartrate and Ti(Oi-Pr)4) have not been exploited so far for the isolation of e.p. labeled substances. In contrast, biochemical methods have been widely used, particularly for the resolution of racemic a-[ " C]amino acids and various [ C]carboxylic acids. Such methods, including ... 

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

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]. 

In principle, any reaction with a racemate using a chiral reagent can be used to effect a kinetic resolution. Kagan (56) has recently given an analysis of the relationship between the extent of reaction and die enantiomeric excess that can be achieved, while Sharpless (57) has applied kinetic resolution successfully to racemic allyl alcohols using his titanium alkoxide tartrate epoxidation reaction. 

The combination of the preceding method of obtaining allyl alcohols with the Sharpless kinetic resolution (SKR) of secondary allyl alcohols allows conversion of the original racemic allyl alcohol into a pure enantiomer with a 100% theoretical yield. By this procedure, the glycidol obtained by the SKR epoxidation of the secondary allyl alcohol is converted into the corresponding mesylate and then treated with the Te ion, furnishing the allylic alcohol with the same configuration of the enantiomer in the SKR which... 

Sharpless Asymmetric Epoxidation This is a method of converting allylic alcohols to chiral epoxy alcohols with very high enantioselectivity (i.e., with preference for one enantiomer rather than formation of racemic mixture). It involves treating the allylic alcohol with tert-butyl hydroperoxide, titanium(IV) tetra isopropoxide [Ti(0—/Pr)4] and a specific stereoisomer of tartaric ester. For example,... 

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