Resolution, of racemic diols

Bis(phe nylthiomethyl)dihydropyran, CSA, CHCI3, 54-93% yield. This dihydropyran can be used for the resolution of racemic diols or for regio-selective protection, which is directed by the chirality of the dihyropyran. Other 2,2 -substituted bisdihydropyrans that can be cleaved by a variety of methods are available, and their use in synthesis has been reviewed. ... 

Whereas the chiral TEMPO analog 87 was used to resolve racemic secondary alcohols, the D-fructose-derived ketone 88 [137] proved useful for oxidative resolution of racemic diols (Table 10.13) [138, 139], Persulfate in the form of Oxone, Curox, etc., served as the final oxidizing agent, and the dioxirane generated from the ketone 88 is the chiral active species. Because of the relatively low conversions (except for unsubstituted dihydrobenzoin) at which the ee stated were achieved, the method currently seems to be of less practical value. Furthermore, typically 3 equiv. ketone 88 had to be employed [138, 139]. 

As summarized in Schemes 12.9 and 12.10, kinetic resolution of propargylic [21] and allylic [22] alcohols work equally well. The DMAP-ferrocene hybrid 21c was also used for kinetic resolution of racemic diols and for the desymmetrization of meso diols [20]. These two applications are discussed in Section 13.3. 

Resolution of Racemic Diols and Amino Alcohols via Diastereomeric Borate Complexes... 

The reaction can also be run using catalytic amounts of a tin reagent which results in acylation of the least hindered alcohol or monoacylation of symmetrical diols is also possible. The use of a chiral tin reagent gives modest levels of kinetic resolution of racemic diols. ... 

The application of the AE reaction to kinetic resolution of racemic allylic alcohols has been extensively used for the preparation of enantiomerically enriched alcohols and allyl epoxides. Allylic alcohol 48 was obtained via kinetic resolution of the racemic secondary alcohol and utilized in the synthesis of rhozoxin D. Epoxy alcohol 49 was obtained via kinetic resolution of the enantioenriched secondary allylic alcohol (93% ee). The product epoxy alcohol was a key intermediate in the synthesis of (-)-mitralactonine. Allylic alcohol 50 was prepared via kinetic resolution of the secondary alcohol and the product utilized in the synthesis of (+)-manoalide. The mono-tosylated 3-butene-1,2-diol is a useful C4 building block and was obtained in 45% yield and in 95% ee via kinetic resolution of the racemic starting material. 

One way of overcoming these problems is by kinetic resolution of racemic epoxides. Jacobsen has been very successful in applying chiral Co-salen catalysts, such as 21, in the kinetic resolution of terminal epoxides (Scheme 9.18) [83]. One enantiomer of the epoxide is converted into the corresponding diol, whereas the other enantiomer can be recovered intact, usually with excellent ee. The strategy works for a variety of epoxides, including vinylepoxides. The major limitation of this strategy is that the maximum theoretical yield is 50%. 

The importance of proper immobilization of enzymes can be shown in the kinetic resolution of racemic a-acetoxyamides. This group of compounds is an important class of chemicals since they can be readily transformed into a-amino acids [17], N-methylated amino acids, and tripeptide mimetics [18], amino alcohols [19], 1,2-diols [20], 1,2-diamines [21], and enantiopure l,4-dihydro-4-phenyl isoquinolinones [22]. 

Recently, Schaumann et al. 153,154 an(j Bienz et tf/.155,156 have developed dependable routes for the resolution of racemic functionalized organosilanes with Si-centered chirality using chiral auxiliaries, such as binaphthol (BINOL), 2-aminobutanol, and phenylethane-l,2-diol (Scheme 2). For instance, the successive reaction of BINOL with butyllithium and the chiral triorganochlorosilanes RPhMeSiCl (R = /-Pr, -Bu, /-Bu) affords the BINOL monosilyl ethers 9-11, which can be resolved into the pure enantiomers (A)-9-ll and (7 )-9-11, respectively. Reduction with LiAlFF produces the enantiomerically pure triorgano-H-silanes (A)- and (R)-RPhMeSiH (12, R = /-Pr 13, -Bu 14, /-Bu), respectively (Scheme 2). Tamao et al. have used chiral amines to prepare optically active organosilanes.157... 

In contrast to the asymmetrization of meso-epoxides, the kinetic resolution of racemic epoxides by whole fungal and bacterial cells has proven to be highly selective (see above). These biocatalysts supply both the unreacted epoxide enantiomer and the corresponding vidnal diol in high enantiomeric excess. This so-called classic kinetic resolution pattern of the biohydrolysis is often regarded as a major drawback since the theoretical chemical yield can never exceed 50% based on the racemic starting material. As a consequence, methods... 

Kinetic resolution of racemic terminal epoxide with water (HKR) is an attractive strategy for the synthesis of valuable enantiopure terminal epoxide and corresponding diol. Easy availability of terminal epoxides at cheaper price and water as sole reagent with a recoverable chiral catalyst makes this solvent free protocol very attractive for its commercial exploitation [53, 54]. Both terminal epoxides and respective diols in their chirally pure form have wider applications in academics and industry [48, 50]. For the efficient resolution the reaction rates of the two enantiomers must be unequal and the reaction must be stopped when only one enantiomer reacts to give a maximum of 50% product leaving behind the other enantiomer unreacted. 

Enantiopure epoxides and vicinal diols are important versatile chiral building blocks for pharmaceuticals (Hanson, 1991). Their preparation has much in common and they may also be converted into one another. These chirons may be obtained both by asymmetric synthesis and resolution of racemic mixtures. When planning a synthetic strategy both enzymic and non-enzymic methods have to be taken into account. In recent years there has been considerable advance in non-enzymic methods as mentioned in part 2.1.1. Formation of epoxides and vicinal diols from aromatics is important for the break down of benzene compounds in nature (See part 2.6.5). 

Catalytic oxidation is a possible means of kinetic resolution of racemic mixtures of alcohols (Scheme 10.19, Eq. 1) or of desymmetrization of meso-diols (Scheme 10.19, Eq. 2). 

This chapter covers the kinetic resolution of racemic alcohols by formation of esters and the kinetic resolution of racemic amines by formation of amides [1]. The desymmetrization of meso diols is discussed in Section 13.3. The acyl donors employed are usually either acid chlorides or acid anhydrides. In principle, acylation reactions of this type are equally suitable for resolving or desymmetrizing the acyl donor (e.g. a meso-anhydride or a prochiral ketene). Transformations of the latter type are discussed in Section 13.1, Desymmetrization and Kinetic Resolution of Cyclic Anhydrides, and Section 13.2, Additions to Prochiral Ketenes. 

High enantiomeric excess in organocatalytic desymmetrization of meso-diols using chiral phosphines as nucleophilic catalysts was achieved for the first time by Vedejs et al. (Scheme 13.21) [36a], In this approach selectivity factors up to 5.5 were achieved when the C2-symmetric phospholane 42a was employed (application of chiral phosphines in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). A later study compared the performance of the phos-pholanes 42b-d with that of the phosphabicyclooctanes 43a-c in the desymmetrization of meso-hydrobenzoin (Scheme 13.21) [36b], Improved enantioselectivity was observed for phospholanes 42b-d (86% for 42c) but reactions were usually slow. Currently the bicyclic compound 43a seems to be the best compromise between catalyst accessibility, reactivity, and enantioselectivity - the monobenzoate of hydrobenzoin has been obtained with a yield of 97% and up to 94% ee [36b]. 

The same group subsequently discovered that the loading of the chiral diamine catalyst can be reduced substantially if triethylamine is added in stoichiometric amounts as an achiral proton acceptor [37b]. As shown at the top of Scheme 13.23, as little as 0.5 mol% catalyst 45 was sufficient to achieve yields and ee comparable with the stoichiometric variant (application of the Oriyama catalysts 44 and 45 in the kinetic resolution of racemic secondary alcohols is discussed in Section 12.1). Oriyama et al. have also reported that 1,3-diols can efficiently be desymme-trized by use of catalysts 44 or 45. For best performance n-butyronitrile was used as solvent and 4-tert-butylbenzoyl chloride as acylating agent (Scheme 13.23, bottom) [38]. 

The peptide catalysts 53a-e incorporating a 4-pyrrolidinopyridine moiety were tested in the desymmetrization of cyclohexane meso-1,2- and meso-1,3-diols by Ka-wabata et al. (Scheme 13.26) [42]. As summarized in Scheme 13.26, enantiomeric excesses were up to 65% and chemical yields were in the range 40-77%. (Application of the Kawabata catalysts to the kinetic resolution of racemic alcohols is discussed in Section 12.1.)... 

Kinetic resolution of racemic alcohols by acylation Few steps from chiral diols... 

KINETIC RESOLUTION OF DIOLS 5.5.1. Desymmetrization of racemic diols... 

In an enzymatic resolution approach, chiral (+)-tra .s-diol (60) was prepared by the stereoselective acetylation of racemic diol with lipases from Candida cylindraceae and P. cepacia. Both enzymes catalyzed the acetylation of the undesired enantiomer of racemic diol to yield monoacetylated product and unreacted desired (+)-trans-diol (60). A reaction yield of 40% and an e.e. of >90% were obtained using each lipase [104],... 

Enantioselective C-H insertion is still a virgin area in dioxirane chemistry, but its feasibility has been demonstrated in the kinetic resolution of racemates and in the desymmetrization of meso 1,2-diols and their acetals. Moderately good enan-tioselectivity has been achieved by use of Shi s ketone 9 as the precursor to the dioxirane (Scheme4) [27, 28],... 

The hydrolytic kinetic resolution of racemic terminal epoxides using metal salen catalysts is one of the premier methods for the formation of enantioenriched oxiranes and/or 1,2-diols, e.g., <1997SCI936, 1998JOC6776, 2000AGE3604, 2002JA1307>. 

Optically active diols have been used for several asymmetric syntheses [67] and chiral resolutions [68]. In 1990, Kawashima and co-workers [69] reported the first example of direct optical resolution of racemic 2,2 -dihydroxy-l,l -binaphthyl (34) with (R,R)-29. In this procedure equimolar amounts of racemic 34 and (R,R)-29 were added in benzene and the mixture was heated to a homogeneous solution and then cooled to room temperature. After crystallization of the precipitate and treatment with hydrochloric acid, (R)-(+)-34 was obtained with an optical purity of 94% and in a yield of 86% based on the amount of enantiomer presents in the racemate (Scheme 23). 

Beller et al. [85] recently described the aerobic dihydroxylation of olefins catalyzed by osmium at basic pH, as mentioned above. When using the hydroquini-dine and hydroquinine bases, they were able to obtain reasonable enantioselectivities (54% ee to 96% ee) for a range of substrates. An alternative route towards enantiopure diols, is the kinetic resolution of racemic epoxides via enantioselec-tive hydrolysis catalyzed by a Co(III)salen acetate complex, developed by Jacob-... 

The 1,1-binaphthyl ring system is a key component of a number of chiral ligands that have been used as catalysts for asymmetric synthesis <1992S503>. Chemo- and stereoselective (. )-stannepin-catalyzed monobenzoylation of terminal 1,2-diols 312 afforded ( -enantiomer-enriched 2-benzoylated diols 313 in moderate selectivity. Only a trace of 1-benzoylated diols 314 was observed (Equation 55). Thus, the method was successfully applied to kinetic resolution of racemic 1-phenyl-1,2-ethanol using a chiral organotin catalyst <2000JOC996>. 

---