Racemization of allylic alcohols

Scheme 1.25 Vanadium-catalyzed racemization of allylic alcohol.

A similar lipase/ruthenium combination of an enzyme with an organometallic compound was employed to resolve racemates of allylic alcohols to allylic acetates of high optical purity and more than 80% yield in the presence of an acyl donor (Lee, 2000). 

Certain racemic allyl acetates can be enzymatically hydrolysed in the presence of an achiral Pd(II) complex, giving the allyl alcohol with high enantiomeric excess and in >50% yield (Scheme 5.47) [124]. The Pd( 11)-catalysed 1,3-acetate shift reported by Overman may be involved in the racemization of allyl acetates [125]. Racemization of allyl alcohol catalysed by oxo vanadium compound, VO(Si(CjH5)3), proceeds in a similar manner via allyl vanadate intermediate [126]. Use of Pd(0) complex leads to a conceptually similar but chemically different strategy, in which the racemization proceeds via a tr-allyl complex [127]. 

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

A novel approach was developed very recently by Kita et al. [15]. DKR of allylic alcohols was performed by combining a lipase-catalyzed acylation with a racemization through the formation of allyl vanadate intermediates. Excellent yields and enantioselectivities were obtained. An example is shown in Figure 4.4. A limitation with this approach for the substrates shown in Figure 4.4 is that the allylic alcohol must be equally disubstituted in the allylic position (R = R ) since C—C single bond rotation is required in the tertiary alkoxy intermediate. Alternatively, R or R can be H if the two allylic alcohols formed by migration of the hydroxyl group are enantiomers (e.g. cyclic allylic acetates). 

D KR of allylic alcohols can be also performed using ruthenium complexes for the racemization that occurs through hydrogen transfer reactions (vide infra) [16]. 

Stopping the reaction before completion. This method is very similar to the asymmetric syntheses discussed on page 132. A method has been developed to evaluate the enantiomeric ratio of kinetic resolution using only the extent of substrate conversion. An important application of this method is the resolution of racemic alkenes by treatment with optically active diisopinocampheylborane, since alkenes do not easily lend themselves to conversion to diastereomers if no other functional groups are present. Another example is the resolution of allylic alcohols such as (56 with one... 

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. 

Similarly,110 (lR,2S )-ephedrine is an effective poison in the kinetic resolution of allylic alcohols using racemic BINAP instead of the expensive (R)-BINAP. (/ )-2-cycIohexenoI can thus be obtained in >95% ee using a racemic... 

The three-step procedure described for the preparation of the illustrated crotylsilanes is initiated with the hydrosilation of rac-3-butyn-2-ol. This procedure is significantly improved with respect to the positional selectivity of the hydrosilation resulting in exclusive formation of the racemic (E)-vinylsilane, and as a result the present procedure is much more amenable to scale-up than those previously described in the literature.8 The enzymatic resolution of the racemic secondary allylic alcohol (vinylsilane) has also been reported using commercially available lipase extracts. The use of a Johnson ortho ester Claisen rearrangement affords the (E)-crotylsilanes 4 in nearly enantiomerically pure form. 

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. 

Table 14. Kinetic Resolution of Racemic Primary Allylic Alcohols via Sharplcss Epoxidation...

TABLE 18. Enantiomeric excesses obtained in the vanadium-catalyzed asymmetric epoxidation of allylic alcohols using enantiomeric pure ligand 140a and racemic as well as enantiomerically pure hydroperoxide 16a... 

The first example of chemoenzymatic DKR of allylic alcohol derivatives was reported by Williams et al. [37]. Cyclic allylic acetates were deracemized by combining a lipase-catalyzed hydrolysis with a racemization via transposition of the acetate group, catalyzed by a Pd(II) complex. Despite a limitation of the process, i.e. long reaction times (19 days), this work was a significant step forward in the combination of enzymes and metals in one pot Some years later, Kim et al. considerably improved the DKR of allylic acetates using a Pd(0) complex for the racemization, which occurs through Tt-allyl(palladium) intermediates. The transesterification is catalyzed by a lipase (Candida antarctica lipase B, CALB) using isopropanol as acyl acceptor (Scheme 5.19) [38]. 

The isomerization of cyclic allyl alcohols to produce ketones proceeds more cleanly [17]. Effective kinetic resolution of racemic cyclic allylic alcohols has been reported [18]. The isomerization of racemic 4-hydroxy-2-cyclopentanone (29) in the presence of 0.5 mol % of [Rh[(/ )-BlNAP](MeOH)2 + in THF proceeded with 5 1 enantiomeric discrimination at 0°C to give 1,3-cyclopentadione (31) via enol ketone 30, leaving the /(-starting allylic alcohol (91% ee and 27% recovery yield) at 72% conversion after 14 days (eq 3.12). (R)-4-Hydroxy-2-cy-clopentenone is a key building block for prostaglandin synthesis [19]. 

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. 

Preparatively more relevant is the use of chiral lithium amide bases, which have been successfully used both for enantioselective generation of allylic alcohols from meso-epoxides and for the related kinetic resolution of racemic epoxides [49, 50]. In many instances, chiral amide bases such as 58, 59, or 60 were used in stoichiometric or over-stoichiometric quantities, affording synthetically important allylic alcohols in good yields and enantiomeric excesses (Scheme 13.28) [49-54], Because of the scope of this review, approaches involving stoichiometric use of chiral bases will not be discussed in detail. 

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. 

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. 

Scheme 9. Kinetic resolution of racemic cyclic allyl alcohols (a) Rh[(R)-BINAP](MeOH)2 +, THF, 0°C, 14days.

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