Studies Directed towards the Synthesis of the Acridone Family of Natural Products: Total Synthesis of Acronycines and Atalaphyllidines

Abstract

A modular and flexible three-step synthetic strategy has been developed for the synthesis of acridone natural products of biological significance. The tetracyclic core of acridone derivatives has been achieved efficiently in high yield from commercially available anthranilic acid and phenol derivatives via condensation reaction, followed by regioselective annulation. Acridone alkaloids acronycine and noracronycine are synthesized in improved overall yields in fewer steps than the previously reported approaches. The method has further been used for the synthesis of atalaphyllidine and 5-hydroxynoracronycine in excellent yields for the first time. Moreover, the synthetic utility of the present strategy has been showcased by the synthesis of oxa and thia analogues of acronycine alkaloid.

Arynes in Natural Product Synthesis

“…However, the major limitation on [4+2] aryne cycloaddition is that most reaction under this category requires cyclic dienes most commonly furans [23]. Acronycine (3,12-dihydro-6-methoxy-3,3,12-trimethyl-7H-pyrano[2,3-c]acridin-7-one) is a naturally occurring alkaloid [24]. Acronycine (4), an anticancer acridone alkaloid [25], was synthesized by Watanabe and co-workers using the intermolecular forms of benzyne.…”

“…Fluoroarene ( 22) was processed with nBuLi to produce aryne, which was then linked with methylmagnesium chloride (23). The presently formed aryne magnesium compound is then gone through the third addition aldehyde gives benzylic alcohol as diastereomers a( 23) and b (24). These diastereomers a and b are then converted to a lactone (25).…”

K2CO3-Catalyzed Dual C–C-Coupled Cyclization to 3-Amino-4-benzoylbiphenyls and In Situ I2-Catalyzed C–N Bond Forming Annulation: A Metal-Free Synthesis of Arylacridones

“…Acridone alkaloids and compounds are also found as an anti-HIV, antifungal, antitumor, inhibiting the proliferation of breast cancer and many other activities . As a consequence, a substantial number of synthetic methods have been developed to construct acridones, such as photocatalytic or molecular oxygen promoted oxidation of acridines and acridinium ion, DDQ-induced reaction between isatoic anhydride with lithium enolate of 2-cyclohexen-1-one, intramolecular C–C bond forming cyclization through C–H activation of N-aryl substituted acids, , intramolecular nucleophilic substitution of 2-amino-2-halobenzophenones, , esters, aldehydes, ketones, and anthranils, carbonyl insertion of diaryl amine, Cu-salt-mediated intramolecular C–N bond formation and C–C bond cleavage of 2-aminobenzophenon, and few other methods . Arynes are also used as a smart synthon for the construction of functionalized acridones .…”