Racemization catalysts allylic alcohols

The catalyst is sensitive to pre-existing chirality in the substrate the expoxidation of racemic secondary allylic alcohols often proceeds tepidly with only one of the enantiomers ... 

With an increase of conversion, the enantiopurity of unreacted (S)-substrate increases and the diastereoselectivity of the product decreases. Using Ru-((S)-binap)(OAc)2, unreacted (S)-substrate was obtained in more than 99% ee and a 49 1 mixture of anti-product (37% ee (2R,iR)) at 76% conversion with a higher kR ks ratio of 16 1 [46]. In the case of a racemic cyclic allyl alcohol 24, high enantiopurity of the unreacted alcohol was obtained using Ru-binap catalyst with a high kR ks ratio of more than 70 1 [Eq. (16)] [46]. In these two cases, the transition state structure is considered to be different since the sense of dia-stereoface selection with the (S)- or the (R)-catalysts is opposite if a similar OH/ C=C bond spatial relationship is assumed. 

Heterogeneous copper catalysts prepared with the chemisorption-hydrolysis technique are effective systems for hydrogen transfer reactions, namely carbonyl reduction, alcohol dehydrogenation and racemization, and allylic alcohol isomerization. Practical concerns argue for the use of these catalysts for synthetic purposes because of their remarkable performance in terms of selectivity and productivity, which are basic features for the application of heterogeneous catalysts to fine chemicals synthesis. Moreover, in all these reactions the use of these materials allows a simple, safe, and clean protocol. 

The resolution of racemic secondary allyl alcohols can be performed in the presence of certain ruthenium chiral catalysts through enantioselective asymmetric hydrogenation [811, 881], Chiral poisoning also works in such kinetic resolutions. For example, hydrogenation of 2-cyclohexenol under ( )-binap-Ru catalysis in the presence of (II , 25)-ephedrine 1.61 (10 equiv) provides unreacted (J )-2-cydo-hexenol in 95% ee after 60% conversion [857],... 

Asymmetric epoxidation of racemic secondary allyl alcohols 3.17 takes place with kinetic resolution [127], The presence of a substituent on the same face as the reagent at transition state induces a decrease in rate due to steric hindrance. Therefore, according to the (Ry or (S)-absolute configuration of the substrate, the rate of epoxidation with a given catalyst will be different (Figure 7.33). The ratio of rates in a kinetic resolution depends upon the nature of the R substituent, the temperature, and the structure of the tartrate 2.69 (R = Me, Et, /-Pr). Cyclohexyl tartrates have been recommended for kinetic resolutions because bulkier esters give higher relative rate ratios [808]. A few examples of resolutions are shown in Fig-... 

Immobilized and reusable ruthenium catalyst 13 oxovanadium compounds 14 and 15 as catalysts for the racemization of allylic alcohols. 

The vanadium catalyst promotes the 1,3-transposition of the hydroxyl group of 54, and this tertiary alcohol (not suitable for the lipase) is converted into a new racemic secondary allylic alcohol rac-55. Just as this alcohol was produced, CAL-B catalyzed the enantioselective acylation of the (R)-enantiomer. In addition, the vanadium compound... 

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. 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

DKR requires two catalysts one for resolution and one for racemization. We and others have developed a novel strategy using enzyme as the resolution catalyst and metal as the racemization catalyst as shown in Scheme 1. The R-selecfive DKR can be achieved by combining a R-selective enzyme with a proper metal catalyst and its counterpart by the combination of the metal catalyst with a -selective enzyme. This strategy has been demonstrated to be applicable to the DKR of secondary alcohols, allylic esters, and primary amines. Among them, the DKR of secondary alcohols has been the most successful. 

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

When racemic 3-methyl-2-cyclohexenol is hydrogenated by the BINAP-Ru catalyst at 4 atm H2, trcms- and cis-3-methylcyclohexanol are produced in a 300 1 ratio (Scheme 33). The reaction with the (/ )-BINAP complex affords the saturated R,3R trans alcohol in 95% ee in 46% yield and unreacted S allylic alcohol in 80% ee with 54% recovery. 

The kinetic resolution of a variety of racemic epoxides has been performed using a chiral bicyclic diamine ligand (9).38 Using 5 mol % of catalyst, both epoxide and allylic alcohol can be obtained in up to 99% ee when the reaction is stopped shortly before or after 50% conversion is reached. 

Here we summarize some of our results obtained by exploiting the hydrogen transfer ability of heterogeneous copper catalysts and therefore their activity in the reduction of polyunsaturated compounds, racemization and dehydrogenation of unactivated secondary alcohols, and isomerization of allylic alcohols. 

To utilize these reactions, a few conditions must be met. A selective enzyme is crucial and the metal-organic catalyst must facilitate a fast racemization of the substrate. Last but not least the catalyst should not influence the enzyme in terms of selectivity and reactivity. In the ideal case the enzyme hydrolyzes one enantiomer of the allylic acetate, giving rise to the allylic alcohol, which itself is not susceptible to Pd-catalyzed racemization. 

The most famous asymmetric oxidation catalyst, Sharpless-Katsuki complex [Ti(0-iPr)4, t-BuOOH and ester of tartaric acid], used for the asymmetric epoxidation of allylic alcohols can also oxidize prochiral and racemic cyclobutanones 7.25 and 7.27 to enan-tiomerically enriched lactones 7.26 and 7.28, respectively. 

---