L-terf-Leucine

The Chemical Development Drug Evaluation branch of Johnson Johnson Pharmaceutical Research Development LLC in Raritan, USA, performed the exothermic reaction of methyl chloroformate with amines to methyl carbamates [34]. Owing to large heat release, hot spots occur. For the reaction of N-methoxycarbonyl-L-terf-leucine with methyl chloroformate to the amino acid derivative, it is even observed at laboratory scale. 

Coupling of pyrazinecarboxylic acid (33) and L-cyclohexylglycine methyl ester (34) with a subsequent saponification afforded 35 in excellent yield (Scheme 15.9). Subsequent coupling with L-terf-leucine methyl ester 36 and saponification furnished the required optically pure acid 37. The Orm group was able to significantly increase both the atom and step economy as well as the overall yield (74% vs 11% over four steps) of acid 37 compared to the already known synthesis routes. 

A valuable synthetic approach toward enantiomerically pure nonnatural a-amino acids is based on enz5nnatic reductive amination of a-keto acids [103]. The most prominent industrial example in this field is the synthesis of L-terf-leucine, which has... 

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.)... 

Figure 14 Total turnover number (ttn) as a function of the ratio of substrate/coenzyme concentration and coenzyme retention for the enzymatic synthesis of L-terf-leucine. The data points are experimental values (compare Table 5). Feed concentrations 2-oxo-3,3-dimethylbutanoic acid (A) 500 mmol/L, (B) 900 mmol/L, (C) 500 mmol/L NAD (A) 0.06 mmol/L, (B) 0.2 mmol/L, (C) 0.2 mmol/L. UF, ultrafiltration NF, nanofiltration R, retention.

Methyl iV-[(2S)-2- 2-(feif-Butoxycarbonyl)-l-[(3- (2S)-2-[4-(rerf-butyldiinethylsiloxy)benzyl]-l-(terf-butyldimethylsi]yl)-4-oxoazetidm-3-yl)propionyl)aminoacetyllhydrazino)-3-phenylpropionyll-L-leucinate (107) [154]... 

Because of its bulky, inflexible, and hydrophobic side chain, terf-leucine (2-amino-3,3-dimethylbutanoic acid, Tie) is an important amino acid used as template or catalyst compound in asymmetric synthesis and in peptidic medicinal compounds. L-Tle has attracted much attention as a key component of newly emerged drugs or as building block of ligands, catalysts, and auxiliaries for asymmetric synthesis. It is synthesized in ton-scale by reductive amination of trimethylpyruvic acid by means of LeuDH from Bacillus stearothermophilus with very high yield and excellent optical purity [153]. NADH, which is consumed during the reaction, can be regenerated by FDH from C. boidinii (Fig. 35). 

The reaction of N-(terf-butoxycarbonyl)leucinal 2-41 a by Danishefsky et al. with l-methoxy-3-trimethylsilyloxy-l,3-butadiene 2-10 gave the pyrones 2-42 and 2-43 with an induced diastereoselectivity of 9 1 in favour of the syn-com-pound in the presence of Eu(hfc)3 [96]. Later Garner [97] used a N-Boc-serine derived aldehyde 2-41 b and Danishefsky s diene 2-10. In both cases a chelation-control forming a complex between the nitrogen and the oxygen could explain the obtained selectivity. In the presence of HMPA chelation is minimized to give a higher extent of the anfi-product 2-43 (Fig. 2-12) [97]. 

The straightforward synthesis of difluorostatine (7,11) is shown in Scheme 3. A Reformatsky reaction (72) of terf-butyloxycarbonyl-L-leucinal 4 with ethylbromodifluoroacetate in the presence of activated zinc dust afforded the diastereomeric adduct 6. After hydrolysis of the ester, the resulting acid was used in the preparation of peptide XI which was separated from its epimer. Oxidation under Swem condition (73) of the carbinol gave the corresponding ketones as an epimeric mixture at the center which is adjacent to the carbonyl. This mixture of two compounds could be separated to give the desired isomer Xm. 

A soln. of carbobenzoxy-L-proline p-nitrophenylester and tert-huiy leucinate in methylene chloride allowed to stand 48 hrs. at room temp. ferf-butyl carbobenzoxyprolyl-L-leucinate. Y 96%.—terf-Butyl esters are particularly useful in peptide synthesis, because the ester group can be removed by acid catalysis (s. Synth. Meth. 15, 12) and thus side reactions encountered in alkaline hydrolysis avoided. Other advantages arise from the stability of amino acid and peptide tert-butyl esters as free bases, particularly in allowing their storage. F. use, prepn., and hydrolysis of tert-butyl esters s. G. W. Anderson and F. M. Callahan, Am. Soc. 82, 3359 (1960) peptides from p-nitrophenyl esters s. a. J. Meienhofer and V. du Vigneaud, Am. Soc. 83, 142 (1961) B. Liberek, Chem. Ind. 1961,987. 

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