Visible-Light-Induced Radical Cascade Cyclization: Synthesis of the ABCD Ring Cores of Camptothecins

Abstract

A new strategy for constructing indolizino[1,2-b]quinolin-9(11H)-ones (ring cores of camptothecins) from readily available isocyanoarenes and N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones has been developed through a visible-light-induced radical cascade cyclization process. The reaction proceeds under mild conditions with fair to excellent yields. The easy introduction of substituents for both reactants and the broad functional group tolerance of the reaction make it a straightforward route to the cores of the marketed camptothecins and their derivatives.

Visible‐Light‐Induced Radical Cascade Cyclization: Synthesis of (20S)‐Camptothecin, SN‐38 and Irinotecan

“…Standard conditions: 1c (40.1 mg, 0.1 mmol), isonitriles (0.2 mmol), K 2 CO 3 (13.8 mg, 0.1 mmol), Ru(bpy) 3 (PF 6 ) 2 (1.8 mg, 2 mol%), NEt 3 (5.1 mg, 50 mol%), CH 3 CN (1.5 mL), irradiation with a 7 W blue LED under nitrogen atmosphere at rt for 24 h. the success of our previous work, [13] a two-step synthesis of SN-38 with 1c and 2b is also feasible. Firstly, a photoreaction of 1c and 2b composed (S)-4,11-diethyl-4-hydroxy-9-methoxy-1,12-dihydro-14H-pyrano [3',4':6,7]indolizino [1,2-b]quinoline-3,14(4H)-dione (3l) in 82% yield, and then demethylation of 3l was completed with 40% HBr in a sealed tube at 110 o C to afford SN-38 in 86% yield (Scheme 3, II).…”

“…[13] 1, 140.0, 120.1, 120.0, 100.1, 86.8, 73.0, 44.6, 13.6, 12.6 118.3, 116.6, 100.5, 87.5, 72.5, 71.9, 66.5, 44.7, 31.7, 13.6, 12.6, 7.8. [13] 1, 140.0, 120.1, 120.0, 100.1, 86.8, 73.0, 44.6, 13.6, 12.6 118.3, 116.6, 100.5, 87.5, 72.5, 71.9, 66.5, 44.7, 31.7, 13.6, 12.6, 7.8.…”

“…[13] Yellow liquid, 2.5 g (9.5 mm Hg, 69 o C). [13] White solid, 5.0 g, 72% yield. 1 1-Chloro-4-isocyanobenzene (2g).…”

“…1 1-Chloro-4-isocyanobenzene (2g). [13] White solid, 4.1 g, 85% yield. [13] White solid, 5.0 g, 72% yield.…”

“…[13] It was an improvement based on Curran's first report of the cascade cyclization between isocyanoarenes and N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones (Scheme 1, I). [13] It was an improvement based on Curran's first report of the cascade cyclization between isocyanoarenes and N-(alkyl-2-yn-1-yl)pyridin-2(1H)-ones (Scheme 1, I).…”