|
|||||
|
|
Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity |
|
| Authors: | Dr Yusaku Nomura Dr Frédéric Thuaud Dr Daisuke Sekine Prof?Dr Akihiro Ito Satoko Maeda Dr Hiroyuki Koshino Dr Daisuke Hashizume Dr Atsuya Muranaka Dr Thomas Cruchter Prof?Dr Masanobu Uchiyama Prof?Dr Satoshi Ichikawa Prof?Dr Akira Matsuda Prof?Dr Minoru Yoshida Prof?Dr Go Hirai Prof?Dr Mikiko Sodeoka |
| Institution: | 1. RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198 Japan
Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812 Japan These two authors contributed equally to this work.;2. RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198 Japan These two authors contributed equally to this work.;3. RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198 Japan;4. RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198 Japan School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392 Japan;5. RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198 Japan;6. RIKEN Center for Emergent Matter Science, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198 Japan;7. Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo, 060-0812 Japan |
| 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. |
| Keywords: | diastereoselectivity natural products spectomycins stereochemistry total synthesis |