We report a visible‐light‐mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals, leading to valuable 1,4‐dicarbonyl compounds. The process capitalizes upon the excited‐state reactivity of 4‐acyl‐1,4‐dihydropyridines that, upon visible‐light absorption, can trigger the generation of acyl radicals. By means of a chiral amine catalyst, iminium ion activation of enals ensures a stereoselective radical trap. We also demonstrate how the combination of this acylation process with a second catalyst‐controlled bond‐forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3‐substituted 1,4‐dicarbonyl products.
We report herein a visible light‐mediated C−H hydroxyalkylation of quinolines and isoquinolines that proceeds via a radical path. The process exploits the excited‐state reactivity of 4‐acyl‐1,4‐dihydropyridines, which can readily generate acyl radicals upon blue light absorption. By avoiding the need for external oxidants, this radical‐generating strategy enables a departure from the classical, oxidative Minisci‐type pattern and unlocks a unique reactivity, leading to hydroxyalkylated heteroarenes. Mechanistic investigations provide evidence that a radical‐mediated spin‐center shift is the key step of the process. The method's mild reaction conditions and high functional group tolerance accounted for the late‐stage functionalization of active pharmaceutical ingredients and natural products.
A series of optically pure (R)- and (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives was designed and synthesized as novel anthramycin analogues in a three-step, one-pot procedure, and tested for their antiproliferative activity on nine following cell lines: MV-4-11, UMUC-3, MDA-MB-231, MCF7, LoVo, HT-29, A-549, A2780 and BALB/3T3. The key structural features responsible for exhibition of cytotoxic effect were determined: the (S)-configuration of chiral center and the presence of hydrophobic 4-biphenyl substituent in the side chain. Introduction of bromine atom into the 8 position (8g) or substitution of dilactam ring with benzyl group (8m) further improved the activity and selectivity of investigated compounds. Among others, compound 8g exhibited selective cytotoxic effect against MV-4-11 (IC = 8.7 μM) and HT-29 (IC = 17.8 μM) cell lines, while 8m showed noticeable anticancer activity against MV-4-11 (IC = 10.8 μM) and LoVo (IC = 11.0 μM) cell lines. The cell cycle arrest in G/S checkpoint and apoptosis associated with overproduction of reactive oxygen species was also observed for 8e and 8m.
We report av isible-light-mediated organocatalytic strategy for the enantioselective acyl radical conjugate addition to enals,l eading to valuable 1,4-dicarbonyl compounds.T he process capitalizes upon the excited-state reactivity of 4-acyl-1,4-dihydropyridines that, upon visible-light absorption, can trigger the generation of acyl radicals.B ym eans of ac hiral amine catalyst, iminium ion activation of enals ensures as tereoselective radical trap.W ea lso demonstrate howt he combination of this acylation process with as econd catalystcontrolled bond-forming event allows to selectively access the full matrix of all possible stereoisomers of the resulting 2,3substituted 1,4-dicarbonyl products.
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