D-tert-leucine

Finally in this sechon, a novel approach has been developed for the enzyme-catalyzed synthesis of D-tert-leucine 55 from the corresponding racemate (Scheme... 

Another example is provided by D-tert-leucine (9) (Scheme 2.13), where an asymmetric approach cannot be used. This unnatural amino acid is prepared by a resolution method.31,32... 

Fig. 14 Kinetic resolution of or-fcrf-leucine catalyzed by L-leucine dehydrogenase (L-LeuDH) for the preparation of D-tert-leucine with simultaneous NAD+ regeneration using NADH oxidase (Nox) from Lactobacillus brevis...

Another example for the regeneration of NAD+ is represented by the LeuDH catalyzed preparation of D-tert-leucine [89]. Starting from DL-tert-leucine, the L-enantiomer was oxidized to trimethylpyruvate while D-tert-leucine remained as the desired product. The consumed cofactor NAD+ can be regenerated by use of NADH oxidase (Nox) from L. brevis (Fig. 14). 

A highly diastereoselective acetate aldol reaction that uses an L-tert-leucine-derived N-acetyl thiazolidinethione auxiliary 125 and dichlorophenylborane has been reported <04OL23>. Thiazolidinethione reagent 127, pseudoenantiomeric to 125, is also found to be effective in diastereoselective asymmetric aldol reactions, thus obviating the expensive D-tert-leucine <04OL3139>. Asymmetric aldol additions of A-propionyl thiazolidinethione... 

Hummel, W., Kuzxi, M., and Geueke, B. (2003) An efficient and selective enzymatic oxidation system for the synthesis of enantiomerically pure D-tert-leucine. Org. Lett., 5, 3649-3650. 

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

Owing to its structural simplicity, the synthesis of 33 proceeded in three steps on a multi-gram scale (74% overall yield on 5 g-scale). Using catalyst 33 it could be also proved that the multi-gram synthesis of industrial interesting unnatural amino acids (e.g., D-tert-leucine) is possible under biphasic conditions with only 0.5 mol% of 33 (Scheme 30.8). Aqueous KCN was used as a cheap and safer cyanide source, and this as well as the shortened reaction time and higher reaction temperature made this procedure more convenient for industrial application. 

FIGURE 3.2 Densitograms obtained in the quantitative determination of TLC-separated enantiomers of ferf-leucine (a) L-terf-leucine, (b) L-fe/t-leucine+0.1%D-tert-leucine, (c) L-tert-leucine + 1 % D-tert-leucine, and (d) external reference standard. Layer, Chiralplate mobile phase, methanol/water (10 80) detection, dip in 0.3% ninhydrin solution in acetone quantification, scanning at 520 nm. (Reprinted from Guenther, K. and Moeller, K., in Handbook of Thin Layer Chromatography, 3rd edn., Sherma, J. and Fried, B., Eds., Marcel Dekker, Inc., New York, NY, 2003, pp. 471-533. With permission.)... 

While the production of D-amino acids is well established the preparation of L-amino acids is difficult due to the limited selectivity and narrow substrate spectrum of L-hydantoinases. This can be circumvented by employing rather un-selective hydantoinases in combination with very enantioselective L-carbamoyl-ases and carbamoyl racemases [90]. Furthermore, a D-hydantoinase has been genetically modified and converted into a L-hydantoinase. This enzyme can be used on a 100-kg scale for the production of L-tert-leucine [34]. Finally, the fact that the X-ray structure of an L-hydantoinase is known gives hope that side-directed mutagenesis will lead to improved L-hydantoinases [91]. 

Kragl, U. VasicRacki, D. Wandrey, C. Continuous production of L-tert-leucine in series of two enzyme membrane reactors— modelling and computer simulation. Bioprocess Eng. 1996, 14 (6), 291-297. 

A typical example for an efficient transamination process is the production of l-alanine, l-25, which is carried out in a continuous manner starting from pyruvate, 24, and L-glutamate, l-22, with a high space-time yield of 4.8kg/(L-d) (Fig. 13) [28], In addition, several non-proteinogenic a-amino acids, e.g., L-phosphinothri-cine, L-homophenylalanine, and L-tert-leucine have been also produced via transamination. 

Other examples of the nse of transaminases to synthesize unnatural amino acids have also been described in the literature, including L-tert-lencine (r-Tle) (9), L-2-amino-4-(hydroxymethylphos-phinyl)butanoic acid (phosphinothricin) and L-thienylalanines. Not all unnatural amino acids can be accessed by this technology. Althongh it works well for L-tert-leucine, D-tert-lencine remains elnsive. 

Leucine dehydrogenase is the enzyme used as the biocatalyst in the process commercialized by Degussa to produce L-tert-leucine (9). Similar to phenylalanine dH, leucine dH has been used to prepare numerous unnatural amino acids because of its broad substrate specificity. For example, cloned, thermostable alanine dH has been used with a coupling enzyme system to prepare D-amino acids. - ... 

Figure 22 Remission-location curves (a) L-rerf-leucine (Degussa) (b) h-tert-Ltu + 0.1% D-tert-Lew, (c) L tert-Leu + 1% D-/crr-Leu (d) external reference sample. Conditions eluent C A. = 540 nm.

D-Threonine-L-tert-leucine-derived bifunctional phosphine catalyzes highly enan-tioselective [3+2] annulation of maleimides with allenes, allowing the synthesis of optically active, functionalized bicyclic cyclopentenes containing two tertiary stereogenic centers (Scheme 6.30) [34],... 

L-fert-leucine and APIs containing i-feit-ieucine ( -tert-leucine (b) teiaprevir (c) boceprevir (d) atazanavir (e) faldaprevir (f) asunaprevir (g) vedroprevir (h) BB-83698. 

FIGURE 1.19 X-ray crystal structures of selector-selectand complexes (ion-pairs) (a) O-9-(P-chloro-fert-butylcarbamoyl)quinine with iV-(3,5-dinitrobenzoyl)-(5)-leucine, (b) tbe pseudoenantiomeric complex of 0-9-( 3-cbloro-tert-butylcarbamoyl)quinidine with N-(3,5-dinitrobenzoyl)-(i )-leucine, (c) 0-9-( 3-cbloro-terf-butylcarbamoyl)quinine with N-(3,5-dinitrobenzoyl)-(5)-alanyl-(5)-alanine, and (d) comparison of tbe complexes of (a) and (c). Most hydrogens have been omitted for the purpose of clarity. (Reprinted from C. Czerwenka et al., Anal. Chem., 74 5658 (2002). With permission.)... 

A further method to induce chirality in the pyridoxamine-mediated transamination reactions was developed by Kuzuhara et al. [13]. They synthesized optically resolved pyridinophanes (21, 22) having a nonbranched ansa chain" between the 2 - and 5 -positions of pyridoxamine. With the five-carbon chain in 21 and 22, the two isomers do not interconvert readily. In the presence of zinc(n) in organic solvents such as methanol, tert-butanol, acetonitrile, and nitromethane, they observed stereoselective transamination between pyridinophanes and keto acids. The highest ee%s are 95 % for d-and L-leucine by reaction of the corresponding a-keto acid with (S)- and (R)- 22, respectively. On the basis of kinetic analysis of the transamination reactions, Kuzuhara et al. originally proposed a mechanism for the asymmetric induction through kinetically controlled stereoselective protonation to the carboanion attached to an octahedral Zn(n) chelate intermediate. However, they subsequently raised some questions about this proposal [14]. 

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