Coniochaetones are chromone derivatives bearing a fused cyclopentanoid ring, originally isolated from the coprophilous fungus Coniochaeta saccardoi. In terms of biological activity, coniochaetone A displays potent cytotoxicity and activity against Chromobacterium violaceum. In our previous work, we accomplished the syntheses of tetrahydroxanthone natural products bearing a fused cyclohexane ring, including diversonol, kibdelone C, ascherxanthone A, and rugulotrosin A. Among these, the synthesis of rugulotrosin A featured a Knoevenagel condensation/6π-electronic cyclization cascade followed by an aromatization process. Our initial synthetic plan targeted the pivotal intermediate 17 via a palladium-catalyzed carbonylative cross-coupling of 18 and 19. However, this approach was plagued by regioselectivity issues at the 1,3-dicarbonyl nucleophile: C-attack furnished the desired tricarbonyl 17, whereas O-attack gave benzoic enol ester 24. Although 24 could, in principle, be converted to 17 via a Fries-type rearrangement, this transformation proved unsuccessful in our hands, with 24 predominating. Consequently, we revised our strategy toward 17 using a Roskamp reaction/Dieckmann condensation sequence. Unfortunately, under Lewis acid conditions, the Roskamp protocol exclusively delivered the 1,2-aryl migration product 27 rather than the desired 1,2-hydride shift adduct. We therefore turned to Ramachary’s reductive Knoevenagel condensation/cyclization, which efficiently constructed the tricyclic core framework. The subsequent installation of the benzylic oxidation state proved challenging, as most oxidizing conditions led to decomposition of the substrate. After extensive screening, we successfully introduced a tert-butylperoxy group at the benzylic position under the conditions of palladium on activated carbon (Pd/C), tert-butyl hydroperoxide (TBHP), and potassium carbonate (K₂CO₃). This intermediate was then converted to ketone 30 via Kornblum-DeLaMare rearrangement. Final deprotection of the methyl ether delivered coniochaetone A (1). Reduction of the C-1 carbonyl group in 1 afforded coniochaetone B (2), and subsequent selective methylation of the secondary alcohol furnished coniochaetone C (3) under mild conditions of silver oxide (Ag₂O) and methyl iodide (MeI). Following the establishment of this efficient route, we successfully achieved the gram-scale synthesis of coniochaetones, laying the foundation for further biological activity studies.

Key words: coniochaetones, condensation, benzylic oxidation, gram-scale synthesis