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

Abstract

The 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.

Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo

“…Natural products with structural diversity and unique biological activities have always been developed as new therapeutic agents or as a source of inspiration to exploit new therapeutic agents for different diseases. − Arf1, a small guanosine triphosphate-binding protein in a variety of malignant tumors, is associated with tumor progression and metastasis . Growing evidence supports that Arf1 can be used as an effective therapeutic target for tumor therapy, , which was corroborated in current findings that Arf1-mediated lipid metabolism sustained cancer cells, and its ablation (synergistic effect with PD-1 blockage) induced antitumor immune responses in mice …”

Highly efficient and scalable total syntheses and stereochemical assignment of potent anti-inflammatory pesimquinolones I and J

“…Our retrosynthetic analysis divides 1 into three fragments ( 9 , 13 and 14 ). Pesimquinolone I ( 1 ) could be prepared through an intramolecular aldol reaction 31 of benzophenone 8 . We speculated that aryne chemistry 32 could provide straightforward access to the desired benzophenone 8 .…”

Targeted isolation of antitubercular cycloheptapeptides and an unusual pyrroloindoline-containing new analog, asperpyrroindotide A, using LC–MS/MS-based molecular networking

“…In our previous research, a series of bioactive natural products were isolated from marine-derived fungi, and some active compounds have been synthesized (Guo et al 2022 ; Jia et al 2015 ; Shao et al 2011 , 2013 ; Xu et al 2021 ) including the discovery of cyclohexadepsipeptides chrysogeamides A–G (Hou et al 2019a ), cycloheptapeptides asperversiamides A–C ( 1 – 3 ) (Hou et al 2019b ) and asperheptatides A–D ( 4 – 7 ) (Chao et al 2021 ) in coral-derived fungi (Fig. 1 ) guided by LC–MS/MS-based molecular networking.…”