P-dipeptide synthesis

Scheme 7.31 Lipases in P-dipeptide synthesis in organic solvents.

Many reports confirm notable reductions in reaction times when carrying out reactions under micro flow conditions. Concerning p-dipeptide synthesis, for example, a comparison between batch and micro-reactor processing was made for the reaction of Dmab-P-alanine and Fmoc-i-P-homophenylalanine [158]. While the micro reactor gave a 100% yield in 20 min, only about 5% was reached with the batch method. Even after 400 h, only 70% conversion was achieved. 

Eledroosmotic flow (EOF) conditions were applied and yielded only 10% conversion with constant reactant movement [9]. The use of stopped-flow techniques, which periodically push and mix the flow, led to a 50% increase in yield. A change in the coupling agent from l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) to dicyclohexylcarbodiimide (DCC) for reasons of limited solubility resulted in a 93% yield of the dipeptide. Batch P-dipeptide synthesis using EDCI gave a yield of 50% [6]. 

A reduction in reaction time by virtue of the improved transport properties in eledroosmotic-driven microreadors was demonstrated for the P-dipeptide synthesis using pentafluorophenyl O-activation. Fmoc-P-alanine was preactivated by introducing the pentafluorophenyl fundion as ester group [9]. Dmab-P-alanine and the pentafluorophenyl ester of Fmoc-P-alanine readed, and the synthesis of the corres-... 

Champagne, J.-M., Coste, J., and Jouin, P. (1993) Synthesis of mixed phosphonate diester analogues of dipeptides using BOP or PyBOP reagents. Tetrahedron Lett. 

From all known CRC, carnosine first appeared in muscle maturation. Its transformation into N-acetylcamosine (heart), anserine or ophidine (skeletal muscles) depends on specific en2ymes, thus the amount, to which these compounds are accumulated within the muscle, depends on functional activity of muscle [17]. In brain, besides carnosine, homocamosine is also present, which is synthesized by the same enzyme camosyne synthase having similar affinity to both P-alanine and y-aminobutyric acid. Thus, the ratio between carnosine and its homolog in different regions of brain is defined by the accessibility of substrates for dipeptide synthesis. In whole, tissue specificity in distribution and accumulation of different CRC allows to suggest correlation between the biological features of CRC and functional specificity of different excitable tissues [18]. 

Jonsson, A. A., Adlercreutz, P., and Mattiasson, B., Effects of subzero temperatures on the kinetics of protease catalyzed dipeptide synthesis in organic media, Biotechnol. Bioeng., 46, 429 36, 1995. 

Barros, R.J., Wehtje, E., and Adlercreutz, P. (1999) Enhancement of immobilized protease catalyzed dipeptide synthesis by the presence of insoluble protonated nucleophile. Enzyme Microb. Technol., 24 (8-9), 480-488. 

Reproduced with permission from Machuca E, Rojas Y, Juarlsti E Synthesis and evaluation of (S)-prolhe-contalnlng a. p-dipeptides as organocatalysts In solvent-free asymmetric aldol reactions under ball-milling conditions. Asian J Org Chem 2015 4 46-53. Copyright (2015), Wiley. 

Hernandez J, Juaristi E. Green synthesis of a,p- and p,p-dipeptides under solvent-free conditions. J Org Ghem 2010 75 7107-11. 

Kino K, Nakazawa Y, Yagasaki M (2008) Dipeptide Synthesis by L-amino Acid Ligase from Ralstonia Solanacearum. Biochem. biophys res. comm. 371 p. 536-40. 

Prolyl aminopeptidases (PAP) are exopeptidases that hydrolytically cleave off an N-terminal Pro from peptides. The enzymes belong to the a/p hydrolase fold proteins. A PAP from Streptomyces thermoluteus carrying the active site nucleophile mutation S144C was used as a catalyst for the synthesis of proline-containing peptides. Dipeptide synthesis was obtained with an amino acid methyl or benzyl ester as the acyl donor and prolyl-OBz as the nucleophile [21]. Under alkaline conditions, cycli-zation and polymerization of prolyl-OBz was observed. 

Kuhn, D., Durrschmidt, P., Mansfeld, J., Ulbrich-Hofmann, R. (2002). Boilysin and ther-molysin in dipeptide synthesis a comparative study. Biotechnol. Appl. Biochem., 36, 71-76. 

In the first publication describing the preparative use of an enzymatic reaction in ionic liquids, Erbeldinger et al. reported the use of the protease thermolysin for the synthesis of the dipeptide Z-aspartame (Entry 6) [34]. The reaction rates were comparable to those found in conventional organic solvents such as ethyl acetate. Additionally, the enzyme stability was increased in the ionic liquid. The ionic liquid was recycled several times after the removal of non-converted substrates by extraction with water and product precipitation. Recycling of the enzyme has not been reported. It should be noted, however, that according to the log P concept described in the previous section, ethyl acetate - with a value of 0.68 - may interfere with the pro-... 

The cis P-lactams 57 are shown to act as cholesterol absorption inhibitors <96BMCL1947> and 58, an analogue of the dipeptide Phe-Gly methyl ester, is a protease inhibitor <96BMCL983>. A straightforward synthesis of proclavaminic acid 59, a biosynthetic precursor of clavulanic acid, is reported <96TA2277>. 

Organic synthesis 19 [OS 19] Dipeptide from Fmoc-L-y homo-p-chlorophenylalanine... 

OS 16] ]R 5] ]P 13] Using continuous flow in an electroosmotic-driven micro reactor gave a quantitative yield of the dipeptide in only 20 min (600 V for Dmab-/ -alanine 700 V for the Fmoc ester) [5, 88]. Batch synthesis under the same conditions gave only a 40-50% yield [5] (46% in [5]), needing 24 h. 

OS 25] [R 4] [P 17] For dipeptide formation from the pentafluorophenyl ester of (J )-2-phenylbutyric acid and (S)-a-methylbenzylamine an extent of racemization of 4.2% was found [86]. At higher concentration (0.5 instead of 0.1 M), a higher degree of racemization was found (7.8%). This experiment also served to demonstrate monitoring of the racemization of a simple carboxylic acid used in peptide synthesis. 

Friedrichsen, G., P. Jakobsen, M. Taub, and M. Begtrup. Application of enzymatically stable dipeptides for enhancement of intestinal permeability. Synthesis and in vitro... 

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