Resolutions of amines

Lipases have also been widely applied for the resolution of racemic chiral amines. In principle, these reactions can be carried out in both the hydrolytic mode as well as under conditions favouring acylation. As amines are more nucleophilic than alcohols, it is necessary to use less reactive acyl donors in order to minimize the background reaction of non-enzyme catalysed acylation, and in this respect it appears that simple esters such as ethyl acetate are optimal. 

The influence of pure organic solvents or organic solvent/ionic liquid mixtures on the resolution of racemic phenylethylamine catalysed by CALB using various acyl donors was studied [16]. The results revealed that the choice of both acyl donor and reaction medium is crucial for generating products with high enantioselectivity. 

Similarly, trans-cycloalkane 1,2-diamines and boron containing amines and amides have been resolved very effectively (E 200) using CALB [18,19]. 

The resolution of amino acids was reported employing the ionic Hquid 1-ethyl-3-methylimidazolium acetate. Esters of various DL-amino acids were used and DL-phenylalanine methyl ester exhibited the highest ee ( 98%). An interestingly high ee (98.2%) was also found for the resolution in deuterium oxide (D2O) as opposed to ordinary water and it was suggested that this was caused by protein stabihzation by the DjO [20]. 

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Kinetic resolution of racemic allylic acetates has been accomplished via asymmetric dihydroxylation (p. 1051), and 2-oxoimidazolidine-4-carboxy-lates have been developed as new chiral auxiliaries for the kinetic resolution of amines. Reactions catalyzed by enzymes can be utilized for this kind of resolution. ... 

Reduction, carboxyl groups, 56,83 Reduction of a,0-unsaturated p-toluene-sulfonyl-hydrazones to alkenes, 59,42 Reductive alkylation, 56,52 Reductive cleavage, 56, 101 Resolution of amines, 55,80, 83 Rexyn 201,55,4 Rhodium(III) oxide, 57, 1 Ring contraction, 56, 107 Ring expansion of cycloalkanones to cycloalkenones, 59, 113... 

Aral S, Bellemin-Laponaz S, Fu GC (2001) Kinetic resolution of amines by a nonenzymatic acylation catalyst. Angew Chem Int Ed 40 234-236... 

Dynamic Kinetic Resolution of Amines Involving Biocatalysis and In Situ Free-radical-mediated Racemization... 

Gastaldi, S., Escoubet, S., Vanthuyne, N., Gil, G. and Bertrand, M.P., Dynamic kinetic resolution of amines involving biocatalysis and in situ free radical mediated racemization. Org. Lett., 2007, 9, 837-839. 

Scheme 6.6 BASF process for enzymatic resolution of amines.

Scheme 6.7 Easy-on/easy-off resolution of amines with penicillin G amidase.

Enzymatic kinetic resolution of amines Faber K (2000) Biotransformations in organic chemistry, 4th edn. Springer, Berlin Heidelberg New York, Sect. 3.1.3... 

Both (R)- and (S)-amino transferase are available forthe synthesis of enantiomerically pure amines from racemic amines. Degrees of conversion were at or close to 50% for resolutions, and enantioselectivities customarily reached > 99% e.e. for the amine product from both resolutions or syntheses from ketones (Stirling, 1992 Matcham, 1996). The donor for resolutions of amine racemates was usually pyruvate whereas either isopropylamine or 2-aminobutane served as donors for reduction of ketones. The products range from i- and D-amino acids such as i-aminobutyric acid (see Section 7.2.2.6) and i-phosphinothricin (see Section 7.4.2) to amines such as (S)-MOIPA (see Section 7.4.2). 

Catalytic kinetic resolution of amines has been a typical domain of enzymatic transformations. Attempts to use low-molecular-weight catalysts have notoriously been frustrated by the rapid uncatalyzed background reaction of the amine substrate with the acyl donor [40]. The first solution to this problem was recently developed by Fu, who used the planar chiral catalyst 21d and O-acyl azlactone 40 as the acyl donor (Scheme 12.19) [41]. In this process, the acyl transfer from the azlactone 40 to the nucleophilic catalyst 21d is rapid relative to both direct transfer to the substrate and to the transfer from the acylated catalyst to the substrate amine. Under these conditions, which implies use of low reaction temperatures, selectivity factors as high as 27 were achieved (Scheme 12.19) [41]. 

It is especially worth noting that a method for non-enzymatic resolution of amines by acylation has also been developed. It is hoped that selectivity factors and ease of operation achieved in the kinetic resolution of alcohols will soon by possible with amines also. 

For a stoichiometric kinetic resolution of amines, using preformed N-acyl derivatives of ferrocenyl DMAP derivatives see Y. Ie, G. C. Fu,... 

Toda, F., Mori, K., Stein, Z., and Goldberg, I. (1989) Optical Resolution of Amine N-Oxides by Diastereoisomeric Complex Formation with Optically Active Host Compound, Tetrahedron Lett., 30, 1841-1844. 

For GC, the two most useful chiral reagents are /V-trifluoroacetyl-L-prolyl chloride (TCP) and menthyl chloroformate (MCF). TCP is used for the resolution of amines and MCF for alcohols. At best the reagents are 99% optically pure, but they can be as little as 90% pure. 

L-Tartaric acid is an abundant constituent of many fruits such as grapes and bananas and exhibits a slightly astringent and refreshing sour taste. It is one of the main acids found in wine. It is added to other foods to give a sour taste and is normally used with other acids such as citric acid and malic acid as an additive in soft drinks, candies, and so on. It is produced by acid hydrolysis of calcium tartrate, which is prepared from potassium tartrate obtained as a by-product during wine production. Optically active tartaric acid is used for the chiral resolution of amines and also as an asymmetric catalyst. 

In general the hydrolysis of amides is performed as a kinetic resolution and not as a dynamic kinetic resolution. It is applied industrially [96] but in most cases the industrial kinetic resolution of amines, as performed for instance by BASF, is an acylation of racemic amines [38], rather than the hydrolysis of racemic amides. For the acylation of amines many different acyl donors [27] and enzymes can be used, including lipases (or a review see [97]). 

Fig. 9.18 Lipase-catalyzed resolution of amines BASF process.

Kraml, C.M., Zhou, D., Byrne, N., and McCoimeU, O. 2005. Enhanced chromatographic resolution of amine enantiomers as carhohenzyloxy derivatives in high-performance liquid chromatography and supercritical fluid chromatography. Journal of Chromatography A, 1100 108-15. 

The racemic acid can be resolved by crystallization of the salt of (+ )-l with cinchonine. The optically pure acids are useful for resolution of amines. Reduction of the corresponding methyl esters provides a particularly useful route to (S)-( -)- and (R)-( + )-binaphthol (9, 169-170). ... 

Resolution of Amines. Amines react with (R)- or (S)-NEI to form the corresponding urea diastereomers which can be separated in a manner analogous to the alcohols in eq 1. Secondary amines thus resolved can be recovered from the diastereomers by hydrolysis, as in the synthesis of chiral nonracemic lactams, or by decomposition in refluxing alcohols, as demonstrated by the resolution of several amine drugs. ... 

It appears, then, that isocyanate and isothiocyanate CDAs are useful in LC resolutions of amines. Several of these agents are commercially available, and many others can be readOy prepared from a variety of commercially available optically active primary amines. The stereochemical stability of these CDAs is excellent, their reaction with amines is rapid and convenient, and the derivatives are readily and sensitively detected. These reagents are likely, therefore, to enjoy continued popularity. 

Camphanic add chloride, (11), described above in the resolution of amines, has also been used in the derivatization and separation of hydroxyl compounds. The bronchodilator proxyphylline was resolved after derivatization with [11] using RP LC in a study of the optical purity of synthetic samples of the enantiomers (150). 

Barksdale, J.M. Clark, C.R. Synthesis and liquid chromatographic evaluation of some chiral derivatizing agents for resolution of amine enantiomers. Anal. Chem. 1984, 56 (6), 958-961. 

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