Penicillin amidase-catalysed transfer of low specific acyl moiety. Synthesis of 7-benzoxazolonylacetamido desacetoxycephalosporanic acid.
The methyl ester of 2-benzoxazolon-3-yl-acetic acid was used as an acyl donor in the penicillin amidase-catalysed transfer reaction to 7-aminodesacetoxycephalosporanic acid. The synthesis of 7-(2-benzoxazolon-3-yl-acetamido)-desacetoxycephalosporanic acid was carried out as a kinetically controlled reaction. A characteristic feature of this system is that the benzoxazolone derivatives are very low specific substrates for penicillin amidase (the kcat/Km values for their hydrolysis were shown to be 10(5)-fold lower compared to the corresponding values for phenylacetyl derivatives). Nevertheless, penicillin amidase proved to be an effective catalyst for the synthesis of these new cephem derivatives (50% yield for 6 h). The reason is the observed unusually high value for the transferase-hydrolase activity ratio. The determined value for (k3'/k3)app = 120,000 implies that in this case of low specific acyl moiety, penicillin amidase acts more like a transferase than a hydrolase. The maximum yield has been increased up to 70% by lowering the reaction temperature and stepwise feeding of the reaction medium with the acyl component. The results obtained extend the potential of the penicillin amidase as a catalyst for the synthesis of a new group of biologically active cephem derivatives.
Institute of Organic Chemistry, Bulgarian Academy of Sciences, Sofia.
N
N
Stambolieva
Z
Z
Mincheva
B
B
Galunsky
V
V
Kalcheva
D000215:Acylation; D002219:Carbamates / Q000378:metabolism*; D002511:Cephalosporins / Q000378:metabolism*; D007700:Kinetics; D010399:Penicillin Amidase / Q000378:metabolism*
D002219:Carbamates; D002511:Cephalosporins; C077255:7-(2-benzoxazolon-3-ylacetamido)desacetoxycephalosporanic acid; D010399:Penicillin Amidase