Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity

Yusaku Nomura, Frédéric Thuaud, Daisuke Sekine, Akihiro Ito, Satoko Maeda, Hiroyuki Koshino, Daisuke Hashizume, Atsuya Muranaka, Thomas Cruchter, Masanobu Uchiyama, Satoshi Ichikawa, Akira Matsuda, Minoru Yoshida, Go Hirai, Mikiko Sodeoka

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Abstract

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 (B2(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.

Original languageEnglish
Pages (from-to)8387-8392
Number of pages6
JournalChemistry - A European Journal
Volume25
Issue number35
DOIs
Publication statusPublished - Jun 21 2019

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All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry

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