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Computation-Assisted Disconnection Approach for the Synthesis of Neoantimycins, 15-Membered Macrocyclic Depsipeptides

[ Vol. 14 , Issue. 2 ]

Author(s):

Shuhei Yamakoshi, Masako Okamoto, Hiroaki Sawamoto, Yuuki Arai, Eiji Kawanishi, Michiko Sasaki and Kei Takeda*   Pages 299 - 308 ( 10 )

Abstract:


Objective: The objective of this study was to provide experimental chemists with useful guidance for proper choice of a reasonable cyclization precursor in macrolactonization in which there are several options in disconnection analysis.

Method: A combination of DFT calculations and MD simulations was used to achieve the aim. In the former method, (1) structures having a local minimum energy near the macrocyclic structure are located by DFT calculations starting from coordinates generated by breaking the corresponding ester C–O bonds (2) among the structures obtained, the one with the shortest distance between the carbon and oxygen atoms and the carboxylic carbon atom is selected as the most likely candidate for macrolactonization. The latter approach involves that (1) global minimum structures for the possible macrocyclization precursors are located by molecular mechanics calculations (2) each of the structures is subjected to MD simulations and a structure maintaining the shortest distances between the two reacting centers during the simulations is selected as a reasonable cyclization precursor.

Results: The utility of the computation-assisted disconnection approach was verified by the synthesis of prunustatin A, whose synthesis has already been reported by us, and demonstrated by the application to the synthesis of neoantimycin, a 15-membered macrocyclic depsipeptide.

Conclusion: It was demonstrated that the approach provides useful guidance for designing synthetic strategies for synthetic chemists because of the relatively high speed and simplicity of the calculations involved.

Keywords:

Neoantimycin, Prunustatin A, Macrocyclization, DFT calculation, MD simulation.

Affiliation:

Department of Synthetic Organic Chemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Chemistry Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Chemistry Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Research Unit B, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Research Unit B, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Department of Synthetic Organic Chemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Department of Synthetic Organic Chemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553

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