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1.4.3.1.2.2.1 Preparation Using Penicillin G Acylase

DOI: 10.1055/sos-SD-214-00231

Hall, M.; Faber, K.; Tasnádi, G.Science of Synthesis: Biocatalysis in Organic Synthesis, (20151313.

As an alternative to acylase I, penicillin G acylase (PGA) can also be applied for the hydrolysis of N-acyl amino acids. Penicillin acylases (EC 3.5.1.11) cleave the acyl moiety of penicillins to yield 6-aminopenicillanic acid. Among them, penicillin G acylase, which hydrolyzes the phenylacetyl group from penicillin G, has been extensively studied[‌66‌] and used in the synthesis of semisynthetic penicillin antibiotics[‌67‌,‌68‌] and in peptide synthesis representing a mild protecting group manipulating tool,[‌20‌,‌69‌] as well as in various biocatalytic reactions.[‌70‌] As can be delineated from its natural substrate (PenG), penicillin G acylase is highly specific for phenylacetic acid, and only small groups, such as hydroxy or amino groups, are allowed at the 2-position of the acyl moiety, while the penicillin-recognizing subsite is highly specific for S-amino acids but also discriminates other chiral primary amines.[‌71‌] α-Amino acids are good substrates,[‌72‌‌75‌] but, interestingly, a number of N-phenylacetyl β-amino acids[‌76‌‌80‌] and esters,[‌81‌] and even γ-amino acids[‌82‌] have been resolved with penicillin G acylase. It seems that the carboxylic acid function is not essential for substrate acceptance; this has been demonstrated by the enantioselective hydrolysis of N-phenylacetyl aminophosphonic and aminophosphonous acids.[‌83‌,‌84‌] The enzyme is commercially available, also in an immobilized form. Scheme 7 shows examples of the enantioselective hydrolysis of N-phenylacetyl β-amino acids 13. It is important to mention that penicillin G acylase is highly S-selective toward α-amino acid derivatives, but is less faithful with β-analogues, as the priority of the substituents can occasionally change depending on the substitution pattern, leading to an apparent R selectivity.

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