Amino acid enantiopure

Another approach for the synthesis of enantiopure amino acids or amino alcohols is the enantioselective enzyme-catalyzed hydrolysis of hydantoins. As discussed above, hydantoins are very easily racemized in weak alkaline solutions via keto enol tautomerism. Sugai et al. have reported the DKR of the hydantoin prepared from DL-phenylalanine. DKR took place smoothly by the use of D-hydantoinase at a pH of 9 employing a borate buffer (Figure 4.17) [42]. 

In this context, also mentionable are several publications by the groups of Dlaz-de-Villegas [242], Guarna [243], Kunz [244] and Waldmann [245], which describe the formation of six-membered azaheterocycles via treatment of an imine with an appropriate substituted diene. For instance, as described by Waldmann and coworkers, reaction of the enantiopure amino acid-derived imines 2-452 with Danishefsky s diene 2-453 in the presence of equimolar amounts of a Lewis acid provided diastereomeric enaminones 2-456 and 2-457 (Scheme 2.105) [245a]. 

Several other practical syntheses of enantiopure amino acid derivatives have been accomplished recently from substrate 35 (Chart 10.6). The Imperiali group has used two techniques following PTC alkylations that occurred with modest enantioselectivity (50-53% ee). The first involved fractional recrystallization followed by subsequent deprotection/reprotection to give 39 (>99% ee). In the second method, enzymatic hydrolysis of the amino acid methyl ester with alkaline protease and then nitrogen acylation gave 40 (99% ee) [16]. Several other publications that deal with related purification techniques have appeared [17-19]. 

Scheme 84 Synthesis of 3,5-tra s-(+)-(3fl,5K)-3-carbomethoxycarbapenam starting from an enantiopure amino acid...

Initially, we examined the reaction of aldehyde 11 and z-Pr2Zn in the presence of the 20 naturally occurring enantiopure amino acids [82]. L-Alanine induced the production of (S)-5-pyrimidyl alkanol 12 with 90% yield and 92% ee. In contrast, D-alanine gave (R)-12 with 90% ee. These reproducible results clearly show that the configuration of alanine determined the configuration of the produced 5-pyrimidyl alkanol. In the case of all 20 amino acids, their chirality is recognized and highly enantiomerically enriched pyrimidyl alkanol 12 was obtained. 

The mechanism of the polyleucine-catalyzed epoxidation is still under investigation [74]. Kinetic studies indicate that the reaction proceeds via the reversible addition of chalcone to a polyleucine-bound hydroperoxide [75]. Recent discussions have included studies of asymmetric amplification polyleucine derived from non-enantiopure amino acid shows highly amplified epoxide enantiomeric excess, and the results fit a mathematical model requiring the active catalyst to have five terminal homochiral residues, as rationalized by molecular modeling studies [76]. 

The more recent work on this area deals predominantly with the asymmetric induction in aza Diels-Alder reactions in order to develop a novel powerful tool for the stereoselective synthesis of biologically active compounds. Thus, Wald-mann et al. demonstrated the utility of chiral imines derived from enantiopure amino acids by obtaining the cycloadduct 3-3 in very good diastereoselectivity from imine 3-1 and Brassard s diene 3-2 (Fig. 3-1) [181]. 

DSM developed a slightly different approach towards enantiopure amino acids. Instead of performing the Strecker synthesis with a complete hydrolysis of the nitrile to the acid it is stopped at the amide stage. Then a stereoselective amino acid amidase from Pseudomonas putida is employed for the enantioselective second hydrolysis step [83], yielding enantiopure amino acids [34, 77, 78]. Although the reaction is a kinetic resolution and thus the yields are never higher than 50% this approach is overall more efficient. No acylation step is necessary and the atom efficiency is thus much higher. A drawback is that the racemisation has to be performed via the Schiff s base of the D-amide (Scheme 6.23). 

Lipases are of remarkable practical interest since they have been used in numerous biocatalytic applications, such as kinetic resolution of alcohols and carboxyl esters (both in water and in non-aqueous media) [1], regioselective acylations of poly-hydroxylated compounds, and the preparation of enantiopure amino acids and amides [2, 3]. Moreover, lipases are stable in organic solvents, do not require cofactors, possess broad substrate specificity, and exhibit, in general, a high enantioselectivity. All these features have contributed to make hpases the class of enzyme with the highest number of biocatalytic applications carried out in neat organic solvents. 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

The roots for the activity in the field of preparation of enantiopure amino acids in the Leibniz-Institut fur Organische Katalyse an der Universitat Rostock e.V. (formerly known as Bereich Komplexkatalyse which was a part of the Zentral-institut fur Organische Chemie der Akademie der Wissenschaften der DDR ) were planted at the end of the 1960s by Horst Pracejus, who was its director at that time (Fig. 1). In the 1950s Pracejus had previously worked on asymmetric catalysis and published outstanding results on the reaction of nucleophiles with ke-tenes catalyzed by chiral bases and developed a fundamental understanding of the mechanism of such enantioselective processes controlled by opposed entropic and enthalpic parts of the free activation enthalpy [1],... 

Scheme 25. Synthesis of enantiopure amino acids via photolysis of chromium carbene complexes.

U. E. Rusbandi, C. Lo, M. Skander, A. Ivanova, M. Creus, N. Humbert, T. R. Ward, Second generation artificial hydrogenases based on the biotin-avidin technology improving activity, stability and selectivity by introduction of enantiopure amino acid spacers, Adv. Synth. Catal., 2007, 349, 1923-1930. 

Biocatalysts are not always immobilized on membranes in bioreactors, though. As enzymes are macromolecules and often differ greatly in size from reactants they can be separated by size exclusion membrane filtration with ultra- or nano-filtration. This is used on an industrial scale in one type of enzyme membrane reactor for the production of enantiopure amino acids by kinetic racemic resolution of chemically derived racemic amino acids. The most prominent example is the production of L-methionine on a scale of 400 t/y (Liese et al, 2006). The advantage of this method over immobilization of the catalyst is that the enzymes are not altered in activity or selectivity as they remain solubilized. This principle can be applied to all macromolecular catalysts which can be separated from the other reactants by means of filtration. So far, only enzymes have been used to a significant extent. 

Several methods are used for the synthesis of amino acids. A mqjor problem with any synthesis is preparing enantiopure products. Most of the syntheses shown here give racemic amino acids, but methods are known that produce amino acids highly enriched in one enantiomer (see Chapter 9). Enantioselective synthetic methods will not be discussed. A method used quite often to obtain an enantiopure amino acid prepares the racemic compound, followed by isolation of the 1-amino acid by resolution, as described in Chapter 9, Section 9.8. 

As pointed out previously, all of the amino acids prepared in this section are racemic. To obtain an enantiopure amino acid requires separation of the enantiomers via resolution. As discussed in Chapter 9 (Section 9.2), the physical properties of enantiomers are identical except for specific rotation. Because separation methods rely on differences in physical properties, this is a problem. It is overcome if the racemic amino acid mixture reacts with a reagent that has a stereogenic center. The resulting product will be a mixture of diastereomers, which have different physical properties and may be separated. 

A second chemical reaction is required to remove the first reagent and release the enantiopure amino acid. This process is called optical resolution (see Chapter 9, Section 9.8). Chemicals obtained from nature as a single enantiomer are used most often as the reactive agent, but they must have a functional group that is able to react with one of the functional groups in a racemic molecule. 

Brucine is used in a similar manner and the carboxyl unit of the amino acid is coordinated to the tertiary amine unit in brucine rather than the poorly basic amide nitrogen. Selective crystallization of these salts leads to their separation, and basic hydrolysis leads to an enantiopure amino acid. It is now possible to separate many racemic mixtures into their enantiomeric components by using high-pressure liquid chromatography (HPLC) fitted with a column that contains a chiral compound bound to an adsorbent (known as chiral HPLC columns). Such columns have been developed by William H. Pirkle (United States 1934-). The chiral HPLC column is prepared by coating a chiral chemical compound on an inert material when a solution of the racemic mixture passes through this column, one enantiomer is adsorbed to the column material better than the other. These are sometimes called Pirkle columns. 

Scheme 11.12 Synthesis of enantiopure amino acids by cascade reactions, including amino acid dehydrogenase-catalyzed reactions.

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]. 

Only a few examples are known in which amino acids are produced by (catalytic) asymmetric synthesis. The asymmetric hydrogenation of dehydroamino acids, previously developed by Monsanto for L-phenylalanine, is today only used for the production of l-DOPA [11]. Many other asymmetric routes for the synthesis of enantiopure amino acids... 

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