Amine dynamic resolution

Dynamic Resolution of Chiral Amine Pharmaceuticals Turning Waste Isomers into Useful Product... 

I 13 Dynamic Resolution of Chiral Amine Pharmaceuticals Turning Waste Isomers into Useful Product Table 13.3 Enantiomer ratios at different stages of the (IS, 4S)-sertraline mandelate process. 

Fortunately, our racemization work had established the ability of trimethyla-mine to produce acceptable rates of racemization in the absence of toluene. The use of two equivalents of the amine supplied the answer and provided the last factor for establishing a successful, large-scale enzymatic dynamic resolution. In the laboratory, this combination produced >99% conversion to (R)-l of 97.6% eep after 22.1 hours, more than adequate for our objectives. 

In addition to the use of enzyme and transition metal combinations for the dynamic resolution of alcohols, there has been a brief report of the use of amines as substrates. In 1996, Reetz and Schimossek reported the combination of palladium on carbon with an immobilized lipase (from Candida antarctica) in the dynamic... 

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

In contrast to the facile in-situ racemization of sec-alcohols via Ru-catalysts (Schemes 3.14 and 3.17), which allows dynamic resolution, the isomerization of ot-chiral amines requires more drastic conditions. Hydrogen transfer catalyzed by Pd [283, 284], Ru [285, 286] Ni, or Co [287] is slow and requires elevated temperatures close to 100°C, which still requires the spatial separation of (metal-catalyzed) racemization from the lipase aminolysis [288]. 

Scheme 3.23 Lipase-catalyzed dynamic resolution of amines via ester aminolysis...

As there was an amine handle for the formation of diastereomeric salts, classical resolution of to obtain CP-465,022 was also an option (Scheme 23). With the ability to thermally racemize the wrong antipode, one could envision a dynamic resolution (or, asymmetric transformation). In the presence of the appropriate chiral acid, there would be an equilibrium of the enantiomers of CP-392,110 in solution, with only the desired antipode CP-465,022 crystallizing out as the insoluble diastereomeric salt. Pfizer has developed a number of other atropisomers, and this sort of dynamic resolution has been worked out for one of those candidates. 

Transaminases are important enzymes in the synthesis of chiral amines, amino acids, and amino alcohols, hi this chapter the properties of transaminases, the reaction mechanisms, and their selectivity and substrate specificity are presented. The synthesis of chiral building blocks for pharmaceutically relevant substances and fine chemicals with transaminases as biocatalysts is discussed. Enzymatic asymmetric synthesis and dynamic resolution are discussed using transaminases. Protein engineering by directed evolution as well as rational design of transaminases under process condition is presented to develop efficient bioprocesses. 

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

Scheme 7.19 Dynamic kinetic resolution of primary amines.

The procedure constitutes the first known example of a chemoenzymatic dynamic kinetic resolution of a secondary amine. The operational simplicity of the procedure is exemplified by the mild conditions, air-stable reagents and low catalyst loading. 

Stirling, M., Blacker J. and Page M.I., Chemoenzymatic dynamic kinetic resolution of secondary amines. Tetrahedron Lett., 2007, 48, 1247. 

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