Resolution of Racemic Alcohols

In the case of the resolution of alcohols, lipases are used to prepare both enantiomers of 2-alkanols, phenylethanols and phenylpropanols, furylethanols, binaphthols and cyclo-pentene-l,3-diols. Both enantioselective acylations with irreversible acyl donors in organic solvents as well as enantioselective hydrolyses in aqueous buffer solutions are in use to achieve the resolutions. Immobilized lipases for process improvements have been prepared and are available. 

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Resolution of racemic alcohols by acylation (Table 6) is as popular as that by hydrolysis. Because of the simplicity of reactions ia nonaqueous media, acylation routes are often preferred. As ia hydrolytic reactions, selectivity of esterification may depend on the stmcture of the acylatiag agent. Whereas Candida glindracea Upase-catalyzed acylation of racemic-cx-methylhenzyl alcohol [98-85-1] (59) with butyric acid has an enantiomeric value E of 20, acylation with dodecanoic acid increases the E value to 46 (16). Not only acids but also anhydrides are used as acylatiag agents. Pseudomonasfl. Upase (PFL), for example, catalyzed acylation of a-phenethanol [98-85-1] (59) with acetic anhydride ia 42% yield and 92% selectivity (74). 

The advantage of this ketal is that unlike the THP group, only a single isomer is produced in the derivatization. Conditions used to hydrolyze the THP group can be used to hydrolyze this acetal. This group may also find applications in the resolution of racemic alcohols. 

Hydrogen transfer reactions are reversible, and recently this has been exploited extensively in racemization reactions in combination with kinetic resolutions of racemic alcohols. This resulted in dynamic kinetic resolutions, kinetic resolutions of 100% yield of the desired enantiopure compound [30]. The kinetic resolution is typically performed with an enzyme that converts one of the enantiomers of the racemic substrate and a hydrogen transfer catalyst that racemizes the remaining substrate (see also Scheme 20.31). Some 80 years after the first reports on transfer hydrogenations, these processes are well established in synthesis and are employed in ever-new fields of chemistry. 

Terao, Y., Tsuji, K., Murata, M., Achiwa, K., Nishio, T., Watanabe, N. and Seto, K., Eacile process for enzymatic resolution of racemic alcohols. Chem. Pharm. Bull, 1989,37,1653-1655. 

As already mentioned, the secondary alcohols that are obtained are optically active. It should be stressed that the reduction of ketones to carbinols by means of fermenting yeast is completely different from the method of resolution of racemic alcohols by treatment with living microorganisms (Pasteur). In the latter case one of the enantiomorphs is removed by oxidation during metabolism in the former it is produced by true asymmetric hydrogenation, without the intermediate formation of the inactive form, (Cf. Mayer and Levene and Walti. )... 

Kinetic optical resolution of racemic alcohols and carboxylic acids by enzymatic acyl transfer reactions has received enormous attention in recent years56. The enzymes generally employed are commercially available lipases and esterases, preferentially porcine liver esterase (PLE) or porcine pancreatic lipase (PPL). Lipases from microorganisms, such as Candida cylindracea, Rhizopus arrhizus or Chromobacterium viscosum, are also fairly common. A list of suitable enzymes is found in reference 57. Standard procedures are described in reference 58. Some examples of the resolution of racemic alcohols are given39. 

Esters are widespread in fruits and especially those with a relatively low molecular weight usually impart a characteristic fruity note to many foods, e.g. fermented beverages [49]. From the industrial viewpoint, esterases and lipases play an important role in synthetic chemistry, especially for stereoselective ester formations and kinetic resolutions of racemic alcohols [78]. These enzymes are very often easily available as cheap bulk reagents and usually remain active in organic reaction media. Therefore they are the preferred biocatalysts for the production of natural flavour esters, e.g. from short-chain aliphatic and terpenyl alcohols [7, 8], but also to provide enantiopure novel flavour and fragrance compounds for analytical and sensory evaluation purposes [12]. Enantioselectivity is an impor-... 

The application of enzymatic acylation for the resolution of racemic alcohols in organic solvent has shown to be an effective method to rapidly synthesize chiral alcohols. The racemic alcohols are treated with the lipase and acylating agent one enantiomer remains unconverted whereas the second enantiomer is esterified and easily separated by distillation (Scheme 7.2). Vinyl acetate or isopropenyl acetate are typical acylating agents, as the generated vinyl alcohol tautomerizes rapidly... 

Scheme 7.2 Resolution of racemic alcohols through enzymatic acylation.

Scheme 7.4 Resolution of racemic alcohol enzymatic acylation.

Scheme 7.8 Dynamic kinetic resolution of racemic alcohols by the combination of transition metal catalysis with enzymatic acylation.

RESOLUTION OF RACEMIC ALCOHOLS AND RELATED SUBSTRATES. Under certain conditions, enantiomers react at sufficiently different rates and they provide a chemical means to resolve racemates (Scheme 31) (64). The Sharpless epoxidation efficiently resolves allylic alcohols that have flex-le structures (64, 65). Homogeneous hydrogenation with (/ )- or (S)-... 

The acid esters of 1,2-dicarboxylic acids are conveniently prepared by heating the corresponding cyclic anhydride with one molar proportion of the alcohol (see the preparation of alkyl hydrogen phthalates from phthalic anhydride and their use in the resolution of racemic alcohols, Section 5.19). 

Phthalic anhydrides readily form hydrogen phthalate esters on reaction with alcohols the derivatives from 3-nitrophthalic anhydride are usually nicely crystalline compounds and are hence suitable for purposes of characterisation. Hydrogen phthalate esters are also useful in appropriate instances for the resolution of racemic alcohols (Section 5.19). 

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. 

The kinetic resolution of racemic alcohols is probably the most intensively studied aspect of organocatalysis, and its beginnings can be traced back to the 1930s [2, 3]. In these early attempts naturally occurring alkaloids such as (—)-brucine and (+)-quinidine were used as catalysts. Synthetic chiral tertiary amines also were introduced and examined, and enantiomeric excesses up to ca. 45% were achieved up to the early 1990s [4, 5]. 

Kinetic Resolution of Racemic Alcohols and Amines The Spivey-catalysts 22a-d and the Jeong-Kim-catalyst 22e ... 

Recent years have seen enormous advances in the field of catalytic asymmetric acylations. Most of the work has been devoted to the kinetic resolution of racemic alcohols. For this application the most efficient catalysts currently available are... 

In principle, oxidative kinetic resolution of racemic alcohols can be achieved by using chiral oxidation catalysts such as TEMPO derivatives or dioxiranes. The selectivity achieved by use of these methods is, however, less than that observed in acylation reactions (Section 12.1). 

Miller et al. achieved selective functionalization of the enantiotopic hydroxyl groups of meso-inositols. In particular, they were able to convert myo-inositol 49 to either mono-phosphorylated D-myo-inositol-l-phosphate 50 or D-myo-inositol-3-phosphate mt-50 in high yield and with excellent ee (98%) (Scheme 13.25) [40, 41], This remarkable result was achieved by using the pentapeptides 51 or 52 as catalyst. These catalysts were identified from peptide libraries by a combinatorial approach. The peptides 51 and 52 are highly selective and complementary low-molecular-weight kinase mimics. It is also interesting to note that the opposite enantioselectivity of catalysts 51 and 52 could hardly have been predicted on the basis of the type and sequence of the amino acids involved. (Application of the Miller peptide catalysts to the kinetic resolution of racemic alcohols is discussed in Section 12.1.)... 

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