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Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation‐Inhibitory Activity
Author(s) -
Nomura Yusaku,
Thuaud Frédéric,
Sekine Daisuke,
Ito Akihiro,
Maeda Satoko,
Koshino Hiroyuki,
Hashizume Daisuke,
Muranaka Atsuya,
Cruchter Thomas,
Uchiyama Masanobu,
Ichikawa Satoshi,
Matsuda Akira,
Yoshida Minoru,
Hirai Go,
Sodeoka Mikiko
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201901093
Subject(s) - chemistry , circular dichroism , stereochemistry , diastereomer , chirality (physics) , intramolecular force , stereoselectivity , diborane , catalysis , boron , organic chemistry , chiral symmetry breaking , physics , quantum mechanics , nambu–jona lasinio model , quark
A synthetic methodology to access all possible stereoisomers of spectomycin A1 (SMA1) and A2 (SMA2) has been established through late‐stage diversification. The key reaction for the construction of all four diastereomers is an intramolecular cyclization based on the umpolung of π‐allyl palladium species with bis(pinacolato)diborane (B 2 (pin) 2 ). Silyl group assisted direct benzylic oxidation of each isomer enabled construction of the fragile β‐hydroxytetralone skeleton to provide the SMAs. The relative and absolute stereochemistry of SMA2 was also determined, and the absolute stereochemistry of SMA1 was extrapolated based on the optical rotation of SMA2. The axial chirality of SMAs is discussed based on circular dichroism spectra and DFT calculations, and it is concluded that the M isomer is predominant in solution. Biochemical assessment of all isomers in vitro revealed that the C9 hydroxyl group and dimeric structure were both important for protein SUMOylation‐inhibitory activity.