Synthesis of Azafluorenone Antimicrobial Agents

Abstract

The azafluorenones constitute a growing class of alkaloids. 1 Representative natural products of this class include compounds 1-5 as shown. Onychine (1) was active against C. albicans B311 with a MIC of 3.12 µg per milliliter. 2 In addition, compound 1 also exhibited antimicrobial activity against S. aureus NCTC 8530, B. subtilis IFO 3007, Escherichia coli IFO 3545, and Saccharomyces cereVisiae IFO 0203 in the range 50 to >100 µg per milliliter. 3 Polyfothine (2) shows DNA-damaging activity. 4 Isoursuline (5) exhibited antimalarial activity against Plasmodium falciparum at micromolar concentrations. 5 Both compounds 1 and 2 have been synthesized by Koyama using an acid-catalyzed rearrangement of the oxime O-allyl ether of an indanone. 6 Compound 1 has also been synthesized by way of intramolecular Friedel-Crafts reactions and organometallic coupling reactions. 7,8 Of particular note is the novel boronic acid coupling developed by Snieckus and co-workers. 9

Synthesis of Azalurenone Alkaloids by Pd- mediated Intramolecular Oxidative Cyclisation Protocol

“…Scheme 2.2: LDA mediated synthesis. Kraus et al 4 devised a three step protocol for the formation of azafluorenone 2.14 via nucleophilic attack of 3-lithio-4-methylpyridine 2.10 on suitably substituted 2bromobenzaldehyde 2.11 followed by successive steps of MnO2 oxidation of resulting alcohols 2.12 and the Heck cyclization of keto compounds 2.13 to afford 2.14 in 53% yield (Scheme 2.3). In the extension, we aimed to explore the intramolecular oxidative Heck cyclization in synthesizing azafluorenone.…”

Facile Synthesis of Onychines

“…The residue was subjected to flash column chromatography on silica gel (MeOH/CH 2 Cl 2 1:3) to afford 5 as a white powder; yield: 188 mg (44%, 0.88 mmol); mp 100.5-101.2 °C. 5H-indeno[1, 2-b] pyridin-5-one (Onychine, 1Aa); [8][9][10][11][12] Typical Procedure A solution of ethyl 4-methyl-2-phenylpyridine-3-carboxylate (4Aa; 33.2 mg, 0.14 mmol) in polyphosphoric acid (1 mL) was heated at 220 °C for 1 h. After the pH value of the mixture was adjusted to 8, the mixture was extracted with CH 2 Cl 2 (3 × 15 mL). The combined organic M. Arita et al…”

“…When O-crotyloxime derived from 1, 3-indanedione was treated under basic conditions, 1Aa is synthesized in a single step, which involves the rearrangement of the crotyl group followed by intramolecular condensation forming a pyridine ring (Method c). 10 Onychine (1Aa) is also obtained by forming a C-C bond between the pyridine ring and the substituent; palladium-catalyzed intramolecular cross-coupling of 3-(2-bromobenzoyl)-4-methylpyridine (Method d) 11 and intramolecular Friedel-Crafts acylation of ethyl 4methyl-2-phenylnicotinate (Method e) 12 have been reported. Thus, while several routes to obtain onychine have been established, the difficulty in obtaining the starting materials limits the synthesis of versatile substituted onychines.…”

Contemporary development in sequential Knoevenagel, Michael addition multicomponent reaction for the synthesis of 4-Aryl-5-oxo-5H-indeno[1,2-b]pyridine-3-carbonitrile

“…Among this class, indenopyridine, containing natural alkaloids (Fig. 2) such as onychine (A), polyfothine (B), isoursuline (C), and cyathocaline (D), has great privilege in medicinal chemistry [29][30][31][32][33][34].…”