Scalable total synthesis of (+)-aniduquinolone A and its acid-catalyzed rearrangement to aflaquinolones

• DOI: 10.1038/s42004-022-00655-x
• Publication Date: 2022-03-17T11:04:45Z
• Authors: Feng-Wei Guo; Xiao-Feng Mou; Yong Qu; Mei-Yan Wei; Guang-Ying Chen; Chang-Yun Wang; Yu-Cheng Gu; Chang-Lun Shao
• Keywords: Chemistry; QD1-999; 01 natural sciences; Article; 3. Good health; 0104 chemical sciences

AbstractThe strong antibacterial, antiviral and anticancer activities demonstrated by quinolones make them promising lead structures and important synthetic targets for drug discovery. Here, we report, to the best of our knowledge, the first scalable total synthesis of antiviral (+)-aniduquinolone A, possessing a 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one skeleton. This synthetic strategy explores E-stereoselective Horner–Wadsworth–Emmons (HWE) olefination as the key step to assemble isopropenyl substituted tetrahydrofuran onto the 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one core, which is built by highly diastereoselective intramolecular aldol reaction. Moreover, two sets of stereoisomers of aniduquinolone A with substantially overlapping NMR data were synthesized completely and assigned unambiguously by comprehensive analysis of both their spectroscopic and X-ray diffraction data. Unexpectedly, aflaquinolones A, C, and D that feature different 2,4-dimethyl cyclohexanone moieties were transformed successfully from (+)-aniduquinolone A by treating with TFA. The methodology delineated herein can be applied broadly to the synthesis of natural alkaloids containing the core structure of 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one.