Allyl alcohols kinetic resolution with Sharpless epoxidation

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. 

The AE reaction has been applied to a large number of diverse allylic alcohols. Illustration of the synthetic utility of substrates with a primary alcohol is presented by substitution pattern on the olefin and will follow the format used in previous reviews by Sharpless but with more current examples. Epoxidation of substrates bearing a chiral secondary alcohol is presented in the context of a kinetic resolution or a match versus mismatch with the chiral ligand. Epoxidation of substrates bearing a tertiary alcohol is not presented, as this class of substrate reacts extremely slowly. 

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. 

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]. 

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... 

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 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. 

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. 

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. 

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. 

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]. 

Using a racemic allylic alcohol, one can take advantage of this rate differential to selectively epoxidize the more reactive 5 isomer in the presence of its antipode. This procedure is known as a Sharpless kinetic resolution (KR) [13,36]. The KR has very wide applicability for the preparation of both 1,2-anti epoxy alcohols and the unreacted allylic alcohol, often with very high enantioselectivities (note that the diastereomeric 1,2-syn series is not generally available by this technique). In general terms, carrying out the reaction to lower conversions will maximize the yield and... 

Representative examples are shown in Scheme 9. The Sharpless AE of geraniol (57) with (+)-diethyl tartrate (DET) gave a-epoxide 58 with 95% ee. In a double asymmetric induction, epoxidation of allylic alcohol 59 with (—)- and (+)-DET provided a- and P-epoxides, 60 and 61, in ratios of 40 1 and 1 14, respectively [23]. It is noteworthy that high asymmetric selectivity was induced even in the mismatched case. The Sharpless AE is also effective for the kinetic resolution of racemic allylic alcohols. In the reaction of 62 with 0.6 equiv. of t-BuOOH and... 

Kinetic resolution of another allylic alcohol in the Sharpless epoxidation was also employed in the synthesis of (Jl)-lO and fully oxygenated AB building block 35 (Scheme 6) [47]. Epoxidation of alcohol 34 [48] followed by LAH reduction and then oxidation with the Fetizon reagent [41,49] furnished hydroxyketone (Jl)-lO. Ketahzation of the carbonyl group and subsequent stereoselective benzyUc hydroxylation, using iodosobenzene in the presence of [ 5,10,15,20-tetrakis(pentafluorophenyl)-2 lH,23H-porphine ] iron(lll) chlo-... 

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 epoxidation of allylic alcohols by hydroperoxides uses as mediator [45] or as catalyst [46] a chiral titanium complex obtained from the combination Ti(OPr )4/diethyl tartrate (DET) in 1 1 ratio. Kinetic resolution of P-hydroxysulfides was also observed, but without diastereoselectivity for the product P-hydroxysulfoxides [47]. We found that the Sharpless reagent deactivated by 1 equivalent of water allows the enantioselective oxidation of aryl methyl sulfides into sulfoxides to be performed with ee s up to 90% [4S-50]. The best reagent combination proved to be Ti(0Pr )4/DET/H20 = 1 2 1. Independently, Modena et al. obtained similar enantioselectivities with the combination Ti(OPr )4/DET in 1 4 ratio [51]. These two combinations are sometimes referred to as the Kagan reagent and the Modena reagent, respectively. They will be considered successively. 

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... 

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