Chiral amines deracemization

Recently Turner and coworkers have sought to extend the deracemization method beyond a-amino acids to encompass chiral amines. Chiral amines are increasingly important building blocks for pharmaceutical compounds that are either in clinical development or currently licensed for use as drugs (Figure 5.7). At the outset of this work, it was known that type II monoamine oxidases were able to catalyze the oxidation of simple amines to imines in an analogous fashion to amino acid oxidases. However, monoamine oxidases generally possess narrow substrate specificity and moreover have been only documented to catalyze the oxidation of simple, nonchiral... 

Subsequently Turner and coworkers were able to show that the Asn336Ser variant possessed broad substrate specificity, with the ability to oxidize a wide range of chiral amines of interest [19]. They also discovered a second mutation, Ile246Met, which conferred enhanced activity toward chiral secondary amines as exemplified by the deracemization of racemic 1-methyltetrahydroisoquinoline (MTQ) (9) (Figure 5.9)[20j. 

In order to be able to apply this deracemization method to a wide range of chiral amines, it was essential to identify monoamine oxidase enzymes possessing both... 

Use of a chiral proton source, a chiral base or base/chiral ligand complex circumvents the problem of incorporation and removal of a chiral auxiliary. Simpkins and coworkers opened the possibility of enantioselective protonation as a method for the asymmetric syntheses of 1-substituted tetrahydroisoquinolines [77]. Using the chiral amine 98 as a proton source, deracemization of 97 proceeded in up to 93 7 er, alleviating the requirement for a chiral auxiliary (Scheme 28). 

Employing co-TAs gives access to chiral amines via three different types of transformation, namely (i) kinetic resolution (KR) by means of enantioselective deamination, (ii) asymmetric amination, and (iii) deracemization which represents... 

Amine oxidases (AOs) can be used to synthesize primary, secondary and tertiary amines. Deracemization of chiral amines can be achieved by an enantioselective oxidation by an AO followed by a reduction using a nonselective reducing agent (Figure 7.12) [47d,76]. There are two types of AOs Type 1 (Cu/TOPA dependent, CAOs, EC.1.4.3.6) and Type 11 (Flavin dependent, EC 1.4.3.4). This chapter will solely focus on the flavin dependent monoamine oxidases. 

The synthesis of chiral amines using co-TA can be performed by three different pathways (Scheme 2.2) [19] (i) kinetic resolution of amines by oxidative deamination, (ii) stereoselective synthesis via amination of prochiral ketones, and (iii) deracemization combining (i) kinetic resolution and (ii) stereoselective synthesis [19]. 

The asymmetric amination of ketones is by far the most preferred approach for the preparahon of chiral amines using co-TAs. However, alternative methodologies may be considered if the carbonyl precursor is unstable or the synthesis of the racemic amine is easier to provide better results in economic and/or yield terms. Using racemic amines deracemization strategies allow the preparation of the desired amines in enantiopme form and a theoretical 100% yield [84- ]. This can be achieved by the combination of two stereocomplementary w-TAs. In the first step, the enantioselec-tive deamination of the racemic amine affords enantiopure untouched amine (50%) and the corresponding ketone (50%). In the second step, an enantiocomplementary -TA catalyzes the asymmetric amination of the ketone, leading to the optical pure amine in 100% theoretical yield (Scheme 2.18). 

Similar to AAOs, MAO can also be employed either in the stereoinversion starting from an enantiopure amine or in the deracemization starting from the racemate vide supra) [18]. Both approaches have been proven to be remarkably efficient for chiral amine synthesis, in particular for cyclic secondary and tertiary structures. Conversely, for acyclic imine intermediates, a competing hydrolysis reaction toward the carbonyl compound is often observed, thus leading to a diminished product yield. This spontaneous hydrolysis was recently exploited for the deracemization cascade reaction combining an (S)-selective MAO with an (R)-selective co-TA (Scheme 2.44) [149]. 

Asymmetric synthesis of amines is a synthetically important research area due to the broad range of applications of chiral amines in fhe field of pharmaceuticals [134]. Amine oxidases are a versatile class of catalysts, which turned out to be very suitable for the preparation of chiral amines by means of desymmetrization or deracemization reactions. With respect to the latter, a racemic amine is enantioselectively oxidized by the amine oxidase, and simultaneously the in situ-formed imines or iminium ions, respectively, are reduced in a nonenantioselective chemical reduction process (with typically a borohydride) back to the racemic amine [135]. The key catalyst for such a... 

TABLE 29.2 A Variety of Chiral Amines and Amino Alcohols Produced with Asymmetric Synthesis (AS) and Dynamic Kinetic Resolution (DKR)/Deracemization (DE)... 

Figure 14.6 Enzymatic deracemization concepts for production of chiral alcohols, amines and amino acids...

In order to extend the approach to include deracemization of chiral secondary amines, this group carried out directed evolution on the monoamine oxidase (MAO) enzyme MAO-N (Scheme 2.32). A new variant was identified with improved catalytic properties towards a cyclic secondary amine 64, the substrate used in the evolution experiments. This new variant had a single point mutation, lle246Met, and was found to have improved catalytic properties towards a number of other cyclic secondary amines. The new variant was used in the deracemization of rac-64 yielding (R)-64 in high yield and enantiomeric excess [34]. 

The term deracemization covers reactions in which two enantiomers are inter-converted by a stereoinversion process such that a racemate can be transformed to a non-racemic mixture without any net change in the composition of the molecule. Deracemization reactions usually involve a redox process, for example, the interconversion of chiral secondary alcohols via the ketone or alternatively the interconversion of amino acids/amines via the corresponding imine (Scheme 4.37). 

Scheme 4.46 One-pot, two-step deracemization of a-chiral primary amines.

Deracemization of chiral primary, secondary, and tertiary (S)-amines by MAOs in combination with a nonselective reducing agent. 

Deracemizations of chiral secondary amines employing the variant MAO-N D3 in combination with ammonia borane complex (a) 1-methyl-tetrahydroisoquinoline (20 mM) (b) 2-phenylpyrrolidine (100 mM). 

The s)mthesis of all kinds of amino acids has been studied extensively in the last decades. Due to enhanced enzymatic and pharmacodynamic stability, as well as their diverse structures and biochemical properties, amino acids were maintained as chiral building blocks in numerous peptidomimetics, in single-enantiomer drugs, and also in various fields of agriculture [79,80]. Due to the wide substrate specificity of transaminases, these enzymes are suitable as biocatalysts for the amination of keto acids or deracemization of racemic amines to produce enantiopure amino acids [2,54,81]. 

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