Sharpless method, kinetic resolution

Various catalytic or stoichiometric asymmetric syntheses and resolutions offer excellent approaches to the chiral co-side chain. Among these methods, kinetic resolution by Sharpless epoxidation,14 amino alcohol-catalyzed organozinc alkylation of a vinylic aldehyde,15 lithium acetylide addition to an alkanal,16 reduction of the corresponding prochiral ketones,17 and BINAL-H reduction18 are all worth mentioning. 

The 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

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... 

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. 

The combination of the chemistry shown in Scheme 22,100 with the Sharpless kinetic resolution (SKR) of secondary allylic alcohols 46101 provides a method for the conversion of racemic allylic alcohols 46 into a single enantiomer with 100% theoretical yield.102 The reaction of sodium telluride with the mesylate 48 derived from 47 affords 46a. In this way, a single enantiomer of the allylic alcohol 46 is obtained in high yield (Scheme 23).102... 

Not all organic chemists can be Involved in such exciting projects as the launching of a new anti-AIDS drug. But the chemistry used in this project was invented by chemists in other institutions who had no idea that it would eventually be used to make Crixlvan. The Sharpless asymmetric epoxlda-tion, the catalytic asymmetric reduction, the stereoselective enolate alkylation, and the various methods tried out for the enantiomerically pure amino indanol (resolution, enzymatic kinetic resolution) were developed by organic chemists in research laboratories. Some of these famous chemists like Sharpless invented new methods, some made new compounds, some studied new types of molecules, but all built on the work of other chemists. 

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. 

Syntheses of relatively simple chiral drugs on an industrial scale are the domain of catalytic or enzymatic methods. In the case of the calcium antagonist diltiazem [113] Sharpless asymmetric dihydroxylation (AD-reaction) is employed which works particularly efficiently for cinnamic acid derivatives such as 48-1. In fact diol 48-2 is obtained with good optical enrichment and is then converted into the target compound via 6 routine steps. Alternatively diltiazem is prepared via classical optical resolution or via enzymatic kinetic resolution of suitable intermediates [113]. 

It should be emphasized that one major advantage of diastereoseleclive methods using allylic alcohols as substrates is their availability in cnantiomerically pure or enriched form (c.g., kinetic resolution by Sharpless oxidation, see Section D.4.5.). 

Synthesis of Chiral Oxirans. The recently introduced Katsuki-Sharpless reagent (titanium alkoxide with tartrate) has proved highly effective for the maiden introduction of chirality into prochiral allylic alcohols. An interesting development of this procedure has afforded the possibility of kinetic resolution of racemic allylic alcohols. The basis of the method involves the... 

Among the chemical methods, the catalytic epoxidation method proposed by Sharpless [84-87] and enantioselective hydrogenation using Noyori catalysts attract the most attention [88] for the kinetic resolution of drug enantiomers. 

Kinetic resolution is the achievement of partial or complete resolution by viitue of unequal rates of reaction of the enantiomers in a racemate with a chiral catalyst [5]. The method usually forms two products one enantiomer does not react with the chiral catalyst or else it reacts very slowly whilst the other enantiomer reacts with the aid of the chiral catalyst to form a new product which may or may not be chiral. As a result two different compounds now make up the mixture and can be separated by conventional chromatographic techniques. One of the most widely applied examples of this technique is the Sharpless Kinetic Resolution. This asymmetric epoxidation of ally lie alcohols was reported by Sharpless in 1980 catalysed by a titanium (IV) tartrate complex in the presence of a hydroperoxide [6] and has been employed in a number of kinetic resolutions [7]. This reaction shows remarkable... 

As we predicted in last year s Report, the Sharpless chiral epoxidation procedure for allylic alcohols is beginning to make its impact with the synthesis of several important synthetic intermediates and natural products. We highlight here just one application to the synthesis of a key building block (2) for methymycin synthesis. This epoxide was produced in 79% yield and in >95% e.e. (Scheme 4). Owing to the water solubility of (2) modified work-up conditions were also developed and discussed. This enantioselective epoxidation method has been applied to produce a remarkably high kinetic resolution procedure for... 

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... 

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