Chiral amines equilibrium shift

The resolution of chiral amines via lipase-catalyzed enantioselective acylation is now a major industrial process, but interest in adopting ionic liquid reaction media has been surprisingly scant. Interestingly, acids could be used as the acyl donor (Figure 10.15) rather than the usual activated ester in a range ofionic liquids. CaLB was employed as the biocatalyst, and water was removed to shift the equilibrium toward the product [130, 131]. The highest rates were found in [BMMIm][TfO], [EMIm][TfO], and [EMIm][BF4]. 

The enzyme class which has received the most increase in attention in industrial and synthetic applications since 2000 is (o-transaminases, in which a suitable inexpensive amino-donor 16 is used to convert a C=0 group of a prochiral substrate 15 into chiral amine 17. In order to shift the equilibrium to the desired amine product, the keto by-product 18 is usually converted in a second irreversible enzymatic step into an iimocent side product 19 (Scheme 15.3). 

Orthogonal cascades have been used to date for the removal of by-products in order to shift equilibrium. An excellent example of an orthogonal cascade is based on using alanine as an amino donor for the co-transaminase-catalyzed synthesis of chiral amines [49]. 

Equilibrium shift by spontaneously tautomerization of the ketone by-product. The prochiral ketone (a) and the chosen amino donor (b) are leading to the chiral amine by tautomerization of the ketone byproduct (c) to (d). 

A drawback of using lactate dehydrogenase as a biocatalyst to remove pyruvate from the reaction equilibrium is the need for the NADH cofactor. Another possibility to eliminate the coproduct is the application of a p5uruvate decarboxylase (Scheme 29.6b). A cofactor is not required, and the resulting products of pyruvate decarboxylation, acetaldehyde, and CO are highly volatile, shifting the equilibrium toward the product [68]. Several pyruvate decarboxylases from yeast and bacteria are commercially available and are active at the same pH value as the transaminase required for the asymmetric synthesis of chiral amines. 

This extraction process for product removal and shifting of the equilibrium is the method of choice to obtain high yields of chiral amines, but is not suitable for the production of amino acids due to their zwitterionic character, only allowing poor partition into the membrane. 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

The equilibrium of the enzyme acylation reaction can be shifted towards the synthesis of the amide by precipitation of the acylated product formed (Fig. 6). The racemic ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate 3 is an insoluble liquid, whereas the (R)-phenylacetamide 10 is an insoluble solid. The racemic ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate 3 was added to dilute hydrochloric acid. The pH of the reaction medium was then adjusted to 6. Phenylacetic acid (2 equiv.) was added and the pH of the medium was readjusted to 6. Soluble PGA (50 units/100 mg of racemic amine) was added, and the reaction was stirred at room temperature. After completion of the reaction, the pH of the reaction mixture was adjusted to 4. Filtration of the reaction mixture gave (R)-amide 10 in quantitative yield. Chiral HPLC analysis of this isolated amide showed the absence of (S)-amide. The pH of the filtrate was raised to 8, and the filtrate was extracted with ethyl acetate to obtain (S)-amine 11 (yield 90%) (Fig. 6). The chiral HPLC analysis indicated an R S ratio of 2 98. 

NMR analysis revealed that this material exists as a complex mixture of amide rotamers as well as diastereomers due to the new chiral center created by the protonated amine. Shown in Scheme 5.18 are the major and minor diastereomers, la and lb, with rotation indicated about the amide linkage. The stereochemistry of the major diastereomer, la, was determined based on the observed NOEs shown with the structure, hi characterizing this compound, it was observed that the dynamic equilibrium of diastereomers was significantly affected by solvent polarity. A crystalline perchlorate salt was obtained, and the single-crystal X-ray of this salt revealed that the piperidine ring is positioned directly over the aryl ring which results in a significant upfield shift of the axial protons. 

Similarly, enzyme modification is required to increase throughput and to reduce enzyme usage in the reaction. High temperature was used successfully to increase the rate of reaction and simultaneously allow removal of acetone from the reaction to shift equilibrium by the development of a thermostable enzyme capable of activity at >55 °C. Another major problem could be poor selectivity of the enzyme resulting in low chiral purity of the product amine. This requires modification of the enzyme and... 

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