Kinetic Resolution of Racemic Amines

Chiral amines are valuable synthons that dominate agrochemicals and pharmaceutical drug pipelines. Current methods for the preparation of amines are largely based upon resolution, and this is an excellent example of an industrial success. BASF makes a range of chiral amines by acylating racemic amines with proprietary esters, whereby one enantiomer is acylated to the amide, which can be easily separated from the unreacted amine [7]. For example, the resolution of racemic 15 in 

The enzymatic KR is based on the reaction between the most favored enantiomer of a racemic amine and a suitable acyl donor in an organic solvent. The acylation of amines can also be considered as an aminolysis process, the examples for the KR on primary amines being more common in the literature than the resolution of secondary amines. From fhe hydrolases toolbox, lipases seem to be the most suitable enzymes due to the fact that they scarcely ever hydrolyze an amide bond [184,185], and, therefore, the reaction is practically irreversible. CAL-B has usually shown the best activity and selectivity for fhe resolution of racemic amines [186,187]. 

Structures of common non-activated esters for the kinetic resolution of racemic primary amines through acylation reactions and schematic representation of the isolation and purification procedure. 

Lipase-catalyzed kinetic resolution of a-methylbenzylamine using lipases in organic solvents. 

Lipase atalyzed kinetic resolution of 3,3-dimethyl-2-butanamine using isopropyl methoxyacetate in diethyl ether. 

Ethyl methoxyacetate (EtOMeOAc) has also been employed successfully for the resolution of racemic amines such as l-aryl-2-fluoroethylamines [192], l-phenylbut-3-en-l-amine [193], or 1-arylallylamines [194]. The use of this acyl donor improves the results for sterically hindered aminoalkylpyridines with respect to the ones obtained with EtOAc in some cases (Table 9.4) [195]. Significantly, the kinetic and stereoselectivity values of the reactions dramatically decrease with bulkier alkyl substituents. 

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Figure 5.19 Recycling experiments in the kinetic resolution of racemic amine using the sol-gel CaLB immobilizate prepared with 18-crown-6 as an additive. (Reproduced from ref. 30, with permission.)... 

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 lipase catalyzes the kinetic resolution of racemic amines, e.g. 1-phenyl-ethylamine (Fig. 19-21)[11. Products are intermediates for pharmaceuticals and pesticides. They can also be used as chiral synthons in asymmetric synthesis. As acylating agent ethylmethoxyacetate is used, because the reaction rate is more than 100 times faster than that with butyl acetate. Probably an enhanced carbonyl activity induced by the electronegative a-substituents accounts for the activating effect of the methoxy group. The lipase is immobilized on polyacrylate. The lowered activity caused by use of in organic solvent (tert-methylbutylether = MTBE) can be increased... 

Isatin as a strategic motif for asymmetric catalysis 13CAC2131. Nonenzymatic acylative kinetic resolution of racemic amines and related compounds 12EJ01471. 

Scheme 4.10 Enzymatic kinetic resolution of racemic amines.

Atropisomerization of the C-amide bond can be suppressed by introducing a bulky f-butyl group in the naphthalene by an S Ar reaction. Addition of crystals of (+)-l 15/116 to f-BuLi in cold toluene provides with good ee s the naphthalene derivatives 117/118 of undetermined absolute configuration. Kinetic resolutions of racemic amines were also performed using the provisional chiral molecular conformation derived from chiral crystals [94]. Despite the attractive features of these examples, planning of absolute asymmetric S Ar transformation remains a difficult task since only about 10% of achiral substrates crystallize in a chiral fashion. 

G., Nagy, J., Urge, L, Darvas, F., and Poppe, L. (2010) Synthesis and lipase catalysed kinetic resolution of racemic amines. Stud. Univ. Babes-Bolyai, Ser. Chem., 45, 289-296. 

Truppo, M.D., N.J. Turner, and J.D. Rozzell, Efficient kinetic resolution of racemic amines using a transaminase in combination with an amino acid oxidase. Chem. Commun., 2009(16) 2127-2129. 

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