Collective Total Synthesis of 4‐Azafluorenone Alkaloids

Abstract

4-Azafluorenones are typically obtained by acid-mediated cyclization of 2-arylnicotinates. However, this approach fails to give 5-oxygenated 4-azafluorenones due to lactonization of 2-(2-alkoxy)phenylnicotinate intermediates. Herein, we report two modifications of established approaches to 4-azafluorenone synthesis that, either in combination or by themselves, enable the flexible preparation of 4-azafluorenones with diverse oxygenation patterns in the benzenoid ring. Undesired lactonization was circumvented via tert-butyl hydroperoxide (TBHP)mediated radical cyclization of 2-aryl-3-(hydroxymeth-yl)pyridines. In the absence of suitable protecting groups for phenolic intermediates, bromide substituents were regioselectively introduced as latent hydroxy groups and later converted under palladium catalysis. We present the first total syntheses of five 4-azafluorenone alkaloids muniranine, darienine, 5,8dimethoxy-7-hydroxyonychine, 5,6,7,8-tetramethoxyonychine, and 6,8-dihydroxy-7-methoxyonychine in addition to new total syntheses of six 4-azafluorenone alkaloids and one related pyridocoumarin alkaloid.

Construction of the 4-Azafluorenone Core in a Single Operation and Synthesis of Onychine

“…The spectral data obtained for 1 ( 1 H and 13 C NMR tabulated below) are in agreement with that reported in literature. 4…”

“…If we narrow our focus to onychine ( 1 ), the simplest and earliest isolated member of the azafluorenone family, we may view the natural product as an instructive model that has been a proving ground of distinct synthetic approaches to the core structure. Synthetic efforts directed toward 1 and related natural products have been recently reviewed …”

“…3 Representative alkaloids that possess this tricyclic fused system include onychine (1), polyfothine (2), and cyathocaline (3), and these and related metabolites possess biological activities including antimalarial and cytotoxicity (Figure 1). 4 Extensive synthetic exploration of azafluorenone derivatives has revealed enhanced antiproliferative characteristics or other properties as compared to the natural products. 5 As examples, synthetic derivatives 4 and 5 offer improved anticancer activity as compared to the natural azafluorenone variants and are lead compounds for development and potential clinical application.…”

“…Synthetic efforts directed toward 1 and related natural products have been recently reviewed. 4 Our interest in azafluorenes and azafluorenones, as well as in the de novo synthesis of pyridine structures, primed us toward a retrosynthesis that identified the substructure of ninhydrin (8) embedded within the target molecule (Scheme 1: Retrosynthesis). 14,15 Given the long and rich history of ninhydrin 16 derivatives, and the commodity status of the parent ninhydrin (8), we envisioned that a synthesis proceeding from this starting material would be direct and relatively versatile for incorporation of substituents on the pyridine nucleus.…”

“…Representative alkaloids that possess this tricyclic fused system include onychine ( 1 ), polyfothine ( 2 ), and cyathocaline ( 3 ), and these and related metabolites possess biological activities including antimalarial and cytotoxicity (Figure ). Extensive synthetic exploration of azafluorenone derivatives has revealed enhanced antiproliferative characteristics or other properties as compared to the natural products . As examples, synthetic derivatives 4 and 5 offer improved anticancer activity as compared to the natural azafluorenone variants and are lead compounds for development and potential clinical application. , Interest in the 4-azafluorenone core has not been restricted to medicinal chemists; the fundamental photophysical properties have also attracted significant attention. , With improved aqueous solubility compared to the parent carbocyclic fluorenone core, azafluorenones have been studied and advanced as fluorescent probes, and in other light-emitting and imaging applications. − …”