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Computational study on formation of 15-membered azalactone by double reductive amination using molecular mechanics and density functional theory calculations

The Journal of Antibioticsvolume 71pages549556 (2018) | Download Citation


Formation of 15-membered azalactone by double reductive amination was analyzed using molecular mechanics and density functional theory calculations for simplified model compounds. As a result, the following aspects were clarified. When methylamine attacks a linear bis-aldehyde in the first step, there are possibilities that two regioisomers are formed. However, one of them exhibited remarkably stable energy level compared with the other. The stable isomer indicated a short distance between a methylamine moiety and an unreacted aldehyde. This short distance, about 2.3 Å, could be explained by hydrogen bonding, which implied relatively easy cyclization in the second step. Moreover, this cyclization process was supposed to be exothermic according to comparison of energy levels before and after cyclization.

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We thank Mr. H. Yamaguchi, Dr. T. Kikkoji, and Mr. Y. Sasaki for encouragement and valuable supports. We are grateful to Professor D. Uemura, Professor K. Tadano, and Associate Professor Y. Sakamoto for supervision about macrolactonization for a medium to large sized ring system. We also thank Ms. K. Yasufuku and Mr. I. Kobayashi for direction in intellectual properties and IP administration. We sincerely appreciate very kind supports by Dr. K. Ohta and Mrs. M. Kasuya, Conflex Corporation.

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Author notes

    • Tomoaki Miura

    Present address: Department of Intellectual Property, Meiji Seika Pharma Co., Ltd., Yokohama, Japan

    • Kenichi Kanemoto

    Present address: Technical Department Production Division, Meiji Seika Pharma Co., Ltd., Tokyo, Japan

    • Keiichi Ajito

    Present address: Department of Project Planning & Management, Meiji Seika Pharma Co., Ltd., Tokyo, Japan


  1. School of Pharmacy, Showa University, Shinagawa, Tokyo, Japan

    • Hiroaki Gouda
  2. Conflex Corporation, Minato, Tokyo, Japan

    • Naofumi Nakayama
  3. Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan

    • Tomoaki Miura
    • , Kenichi Kanemoto
    •  & Keiichi Ajito


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Correspondence to Keiichi Ajito.

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