Enzymatic synthesis chiral amine

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

The synthesis of a-branched amines caught our attention, as these compounds exhibit parhcular biological activity. In several of our ongoing projects involving the synthesis of biologically achve compounds, we required the asymmetric synthesis of a-branched chiral amines. a-Branched amines can be prepared by various routes, all performed in an asymmetric fashion. Currently, enzymatic and chemical separation of racemic a-branched amines and also diastereoselective methods still play a major role on an industrial scale [25]. However, due to poor separation by the latter methods and for economic reasons, catalytic approaches will be favored. 

The enantioselective reductive amination of ketoacid substrates has been dem onstrated and provides amino acids that are beyond the scope of this review [6]. Enzymatic based reductive amination is now possible and allows nonamino acid chiral amine synthesis, however, this field of study is also beyond the scope of this material [7]. Finally, much of the material discussed here also appeared in a recent review of ours on the general subject of chiral amine synthesis. 

Optically active amines are important intermediates and chiral auxiliaries in the technical synthesis of agrochemicals and pharmaceuticals. BASF, one of the world s leading producers of chiral amines, developed a process based on the enzymatic resolution of racemic amines 49 with Burkholderia plantarii lipase immobilized on polyacrylate (Scheme 16) [75,76]. Methoxyacetic acid estars are particularly well suited for the stereospecific enzymatic differentiation, giving both the free amine (S)-49 and the acylated product R)-50 in high ee. The reaction stops at 50% conversion and the selectivity factor was calculated to be as high as 500. A plug-flow or batch reactor can be used for the enzymatic reaction and the residence time is in the range of 5-7 h. The more important amine (R)-49 can be liberated with the aid of base and is subsequently purified by distil-... 

Fig.1. (A) Structure of Omapatrilat (1), an anti hypertensive drug. (B) Enzymatic synthesis of chiral syn-thon for Omapatrilat (1) Reductive amination of sodium 2-keto-6-hydroxyhexanoic acid (3) to (5)-6-hy-droxynorleucine (2) by glutamate dehydrogenase.

Chiral amine compounds with high optical purities can be difficult to prepare by many types of traditional catalysts. One well-known enzymatic synthesis of chiral amines involves TAs [6,47]. The to-TA transfers an amine group from an amino donor onto the ketone moiety of the amino acceptor (Figure 7.6). The most popular example, which won the presidential green chemistry award in 2010, has been the development of an co-TA by Merck and Codexis for an (R)-selective TA to synthesize sitagliptin (Januvia ) [48]. 

Enzymatic Synthesis of Chiral Amines using (O-Transamlnases, Amine Oxidases, and the Berberlne Bridge Enzyme... 

Chiral amines have been attracting attention as an important composition, particularly for pharmaceutical products. The organic synthetic methods of optically active amine compounds have been developed through the traditional resolution of racemic amines with the formation of diastereomer salts using an optically active mandelic acid or tartaric acid. Enzymatic synthesis has mainly used lipase and S- or R-stereoselective amine transaminase (AT) [29-31] (Figure 19.7). Turner et al. successfully synthesized chiral (R)- and (S)-amines by kinetic resolution using a combination of stereoselective AT and d- or L-amino acid oxidase (AAOx) [32] (Figure 19.7). However, the theoretical yield of the products has been limited to 50% in the kinetic resolution. 

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 simple primary-tertiary diamine salts can be successfully applied in the aldol reactions of a-hydroxyketones with good activity and excellent stereoselectivity. Notably, the catalyst enabled the reaction of dihydroxyacetone (DHA), a versatile C3-building block in the chemical and enzymatic synthesis of carbonhydrates. By employing either free or protected DHA, syn- or anh-diols could be selectively formed with excellent enantioselectivity (Scheme 5.7). Since enantiomers of diamine 26 and 29 are readily available, this class of chiral primary amine catalysts thus functionally mimics four types of DHA aldolases in nature [17b]. Later, simple chiral primary-tertiary diamine 27 derived from amino acid was also found to be a viable catalyst for the iyn-selective aldol reactions of hydroxyacetone and free DHA (Scheme 5.7) [18]. 

The typical technologies used for the preparation of amines have also been used for the synthesis of optically pure (R)- or (S)-l-aminoindane. For example, resolution approaches include the diastereoisomeric salt formation of racemic A-bcnzyl- l -aminoindane with (,S )-mandclic acid41 or (R,R) tartaric acid,42 which resulted in, after hydrogenation, (R)-l-aminoindane with >99% ee. Also, resolutions that use enzymatic acylation concepts have been described.43 44 The maximum theoretic yield of 50% is a clear limitation of these methods. Asymmetric synthetic approaches to chiral 1-aminoindanes have been described, including enantioselective hydrosilylation of l-indanoxime45 46 and hydroboration of indene 47 However, ee values were low to moderate. 

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