Kinetic Resolution of Racemic Alcohols

Although kinetic resolution provides the desired enantiomer in 50% yield at most, this is a method of choice due to the simplicity of the experimental procedure. If both the enantiomers are required for structure-activity relationship studies, kinetic resoluhon of racemic alcohols is a convenient method to secure the enantiomers. A drawback of this method is time-consuming separation of the products of enzymatic reaction by chromatography. 

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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. 

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-... 

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

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.)... 

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

To demonstrate the synthetic application of this methodology, the authors subsequently demonstrated its use for the preparative kinetic resolutions of a series of 2° alcohols, Table 24, whereby 20 ml solutions of each racemic alcohol were passed through the bioreactor (3.3 h) and found to afford analogous results to those obtained during the initial optimization experiments. The authors successfully demonstrated the use of immobilized and lyophilized enzymes within a continuous flow reactor, presenting a synthetically viable approach to the kinetic resolution of racemic alcohols. 

Lipases have been extensively used for the kinetic resolution of racemic alcohols or carboxylic acids in organic solvents. Chiral alcohols are usually reacted with achiral activated esters (such as vinyl, isopropenyh and trichloroethyl esters) for shifting the equilibrium to the desired products and avoiding problems of reversibility. For the same reasons, chiral acids are often resolved by using acidolysis of esters. In both cases, the overall stereoselectivity is affected by the thermodynamic activity of water of water favors hydrolytic reactions leading to a decrease in the optical purity of the desired ester. Direct esterifications are therefore difficult to apply since water formed during the reaction may increase the o of the system, favors reversibiUty, and diminishes the overall stereoselectivity. 

Acyl Transfer Reactions. (6)-A7-benzoyloxazolidinones have been used as acyl transfer reagents to effect the kinetic resolution of racemic alcohols. The bromomagnesium alkoxides formed from phenyl n-alkyl alcohols selectively attack the exocyclic benzoyl moiety to afford recovered auxiliary and the derived (R)-benzoates in >90% ee and >90% yield (eq 47). The scope of this reaction seems to be limited to this class of substrates as selectivity drops with increasing the steric bulk of the alkyl group. 

Kinetic Resolution by Hydrolysis. Until very recently, kinetic resolution of racemic alcohols as ester derivatives was by far the most common type of asymmetric transformations involving lipases. There are number of examples involving acyclic secondary alcohols, such as the glyceraldehyde derivative in eq 1 and various related alkyl- and aryloxy substituted chloride and tosylate glycerol derivatives. - ... 

Hydrolytic enzymes have long been used for the kinetic resolution of racemic alcohols and carboxylic acids. In recent years, the corresponding transformation on Table 14,1 List of suppliers of enzymes referred in this chapter. 

Ichikawa, S., and Ikariya, T. (2004) High-efficiency and minimum-waste continuous kinetic resolution of racemic alcohols by using lipase in supercritical carbon dioxide. Chem. Commun. (Camb.j, 20, 2286-2287. 

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