Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation‐Inhibitory Activity. Issue 35 (20th May 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Chemistry. Volume 25:Issue 35(2019)
• Page Start: 8387
• Page End: 8392
• Publication Date: 2019-05-20
• Subjects: diastereoselectivity -- natural products -- spectomycins -- stereochemistry -- total synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201901093
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Ring systems : All stereoisomers of monomeric spectomycins (spectomycin A1 and A2) have been synthesized (see figure). The relative and absolute stereochemistry of the natural products have also been determined. Spectomycin B1 (a spectomycin A2 dimer) is a potent inhibitor of protein SUMOylation, but the monomeric spectomycins are all weaker inhibitors; thus, the dimeric structure is important for biological activity.