Application Research of 2-Phenylglycine and its derivatives

Introduction

Optically active D-amino acids are widely used in the pharmaceutical industry as intermediates for the synthesis of semisynthetic antibiotics and pesticides. Among them, the demand for D-2-phenylglycine for the synthesis of drugs such as aspoxicillin, cefbuperazone, and cefpiramide has been increasing. The efficiency of various procedures for the production of D-2-phenylglycine have been studied, such as the production from its keto-analogue by D-amino acid aminotransferase and from D,L-2-phenylglycine (Fgiure 1) using isoelectrically trapped penicillin G acylase. The D-amino acid aminotransferase system has a low reaction rate and D-2-phenylglycine is transformed from 2-oxo-2-phenylacetic acid with a molar yield of 2%.The conversion system using penicillin G acylase requires a multicompartment electrolyzer with an isoelectric membrane to prevent the reverse process the hydrolysis of 4-hydroxyphenylacetyl-L-phenylglycine. These procedures therefore need to be improved.[1]

Enantioselective N-acetylation of 2-phenylglycine

The demand for D-2-phenylglycine used to synthesize semisynthetic antibiotics and pesticides is increasing. We have isolated a Chryseobacterium sp. that selectively transformed the L-form of racemic D,L-2-phenylglycine to (2S)-2-acetylamide-2-phenylacetic acid with a molar yield of 50% and an enantiomer excess of >99.5% under optimal culture conditions, consequently resulting in 99% pure D-2-phenylglycine remaining in the culture. The enantioselective N-acetylation was catalyzed by an acetyl-CoA-dependent N-acetyltransferase whose synthesis was induced by L-2-phenylglycine. The enzyme differed from previously reported bacterial arylamine N-acetyltransferases in molecular mass and substrate specificity. The relative activity ratio of the enzyme with the substrates L-2-phenylglycine, D-2-phenylglycine, 2-(2-chlorophenyl)glycine, and 5-aminosalicylic acid (a good substrate of arylamine N-acetyltransferase) was 100:0:56.9:5.49, respectively. The biotransformation by the N-acetyltransferase-producing bacterium reported here could constitute a new preparative route for the enzymatic resolution of D,L-2-phenylglycine.[1]

Design, Synthesis and Bioassay of 2-Phenylglycine Derivatives as Potential Pesticide Candidates

Plant diseases can seriously affect the growth of food crops and economic crops. To date, pesticides are still among the most effective methods to prevent and control plant diseases worldwide. Consequently, to develop potential pesticide molecules, a series of novel 2-phenylglycine derivatives containing 1,3,4-oxadiazole-2-thioethers were designed and synthesized. The bioassay results revealed that G 19 exhibited great in vitro antifungal activity against Thanatephorus cucumeris with an EC 50 value of 32.4 μg/mL, and in vivo antifungal activity against T. cucumeris on rice leaves at a concentration of 200.0 μg/mL (66.9 %) which was close that of azoxystrobin (73.2 %). Compounds G 24 (80.2 %), G 25 (89.4 %), and G 27 (83.3 %) exhibited impressive in vivo inactivation activity against tobacco mosaic virus (TMV) at a concentration of 500.0 μg/mL, which was comparable to that of ningnanmycin (96.3 %) and markedly higher than that of ribavirin (55.6 %). The antibacterial activity of G 16 (63.1 %), G 26 (89.9 %), G 27 (78.0 %), and G 28 (68.0 %) against Xoo at a concentration of 50.0 μg/mL was higher than that of thiadiazole copper (18.0 %) and bismerthiazol (38.9 %). Preliminary mechanism studies on the antifungal activity against T. cucumeris demonstrated that G 19 can affect the growth of mycelia by disrupting the integrity of the cell membrane and altering the permeability of the cell. These studies revealed that the amino acid derivatives containing a 1,3,4-oxadiazole moiety exhibited certain antifungal, antibacterial, and anti-TMV activities, and these derivatives can be further modified and developed as potential pesticide molecules.[2]

Synthesis of Unprotected 2-Arylglycines

The transamination of α-keto acids with 2-phenylglycine is an effective methodology for directly synthesizing unprotected α-amino acids. However, the synthesis of 2-arylglycines by transamination is problematic because the corresponding products, 2-arylglycines, transaminate the starting arylglyoxylic acids. Herein, we demonstrate the use of commercially available l-2-(2-chlorophenyl)glycine as the nitrogen source in the transamination of arylglyoxylic acids, producing the corresponding 2-arylglycines without interference from the undesired self-transamination process.[3]

One-pot, two-step synthesis of unnatural α-amino acids

This study reported the nor-AZADO-catalyzed exhaustive aerobic oxidations of 1,2-diols to α-keto acids. Combining oxidation with transamination using dl-2-phenylglycine led to the synthesis of free α-amino acids (AAs) in one pot. This method enables the rapid and flexible preparation of a variety of valuable unnatural AAs, such as fluorescent AAs, photoactivatable AAs, and other functional AAs for bioorthogonal reactions.[4]

References

[1] Takenaka S, Honma Y, Yoshida K, Yoshida K. Enantioselective N-acetylation of 2-phenylglycine by an unusual N-acetyltransferase from Chryseobacterium sp. Biotechnol Lett. 2013;35(7):1053-1059. doi:10.1007/s10529-013-1172-z

[2] Zhang H, Zhao C, Zheng H, Chen X, Chen B, Wu Z. Design, Synthesis and Bioassay of 2-Phenylglycine Derivatives as Potential Pesticide Candidates. Chem Biodivers. 2023;20(1):e202200957. doi:10.1002/cbdv.202200957

[3] Inada H, Shibuya M, Yamamoto Y. Synthesis of Unprotected 2-Arylglycines by Transamination of Arylglyoxylic Acids with 2-(2-Chlorophenyl)glycine. J Org Chem. 2020;85(17):11047-11059. doi:10.1021/acs.joc.0c01302

[4] Inada H, Furukawa K, Shibuya M, Yamamoto Y. One-pot, two-step synthesis of unnatural α-amino acids involving the exhaustive aerobic oxidation of 1,2-diols. Chem Commun (Camb). 2019;55(100):15105-15108. doi:10.1039/c9cc07889d

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