Close the ring to break the cycle: tandem quinolone-alkyne-cyclisation gives access to tricyclic pyrrolo[1,2-a]quinolin-5-ones with potent anti-protozoal activity

Abstract

We describe a tandem reaction leading to tricyclic pyrrolo[1,2-a]quinolin-5-ones with unique selectivity against the liver stage of the malaria parasite.

Synthesis of bacterial 2-alkyl-4(1H)-quinolone derivatives

“…2-Alkyl-4(1H)-quinolone N-oxides 3 are important metabolites of P. aeruginosa with diverse anti-microbial and anti-protozoal activities. 13,23,[46][47][48] In 1956, Cornforth and James were the first to isolate AQNOs 3 from culture supernatants of P. aeruginosa and characterize their structures. 8 They also reported the first synthesis of HQNO 3a by O-ethoxycarbonyl protection of 2-heptyl-4(1H)-quinolone and N-oxidation using peroxybenzoic acid.…”

Synthesis of 4-Quinolone N-Oxides via Controlled Partial Hydrogenation of 2-Nitrobenzoyl Enamines

“…The second approach extends the Conrad-Limpach synthesis of AQs with three additional steps (O-protection/N-oxidation/O-deprotection) to finally give AQNOs. Due to its inefficiency, the former approach has fallen out of favour, while the latter has been the preferred one in virtually all studies of AQNOs ever since [9,10,11,12,13]. Although there have been attempts for its optimization and refinement [10], this oxidative approach is still far from ideal and is not well suited for preparation of functionalized analogs.…”

Synthetic approach to 2-alkyl-4-quinolones and 2-alkyl-4-quinolone-3-carboxamides based on common β-keto amide precursors

“…Despite the variety of synthetic approaches to the construction and functionalization of the 4-quinolone ring system, most of the recent studies related to microbial 2-alkyl-4-quinolones relied on variations of the age-old Conrad-Limpach and Camps methods for the construction of the heterocyclic quinolone core [26,36,[52][53][54][55]. These methods usually give poor overall yields of the target quinolone products and require rather harsh conditions during the ring-forming step, such as prolonged heating in Ph 2 O (270 °C) or in dioxane/NaOH (110 °C), respectively.…”