A New Approach to Semisynthetic Penicillins by the Mixed Anhydride Method

An improvement of the efficiency of organic chemical synthesis was attempted by the imitation of natural reactions. Phosphorylated amino acid derivatives and the rupture of thus obtained »high energy phosphates« was used for aminoacylations of 6-11minopenicillanic acid (6-APA). Namely, the energy-rich mixed anhydrides, formed from adenosine triphosphate (ATP) and amino acids were shown to be the most efficient biosynthetic aminoacylating agents for the formation of the terminal 3'-0-aminoacyl-adenosine of the transfer ribonucleic acids. To our knowledge only a French patent1 superficially described mixed anhydrides as acylating agents in the semisynthetic approach to penicillins. In our quest for a new method for the preparation of semisynthetic p-lactam antibiotics the aminoacylation of methyl 6-aminopenicillanate by mixed high-energy phosphates was shown to be an efficient one. A mixed anhydride such as N-phthaloylglycyldibenzylphosphate anhydride was prepared from phthaloylglycyl chloride and the silver salt ·Of dribenzylphosphate2 according to the Sheehan and Frank method3• It exhibited signals at -i: 2.02---:2.36 (4H, m, Pht protons), 2.63 (10 H, s, Ph protons), 4.77 and 4.91 (2 X 2H, 2 X s, 2 X OCH2) and 5.57 (2H, s, N-CH2) in the 1H NMR spectrum and absorptions at Vmax 1792, 1773, 1720, 735, 713, and 697 cm-1 in the IR spectrum.