Catalytic Enantioselective Synthesis of Conformationally Stable C(sp2)−C(sp3) Naphthocoumarin Atropisomers

Cabua, M. Chiara;Moi, Davide

;Cocco, Emanuele;Onnis, Valentina;Podda, Enrico;Aitken, David J.;Carlone, Armando;Luisi, Renzo;Tuveri, Enrica;Parsons, Drew F.;Secci, Francesco

2026-01-01

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Abstract

A straightforward atroposelective access to enantiomerically enriched 2-hydroxy-3-(2-oxochroman-4-yi)naphthalene-1,4-diones (with yields ranging from 32% to 87% and enantiomeric excesses up to 99%) is described. Using an organocatalytic approach, 2-hydroxynaphthoquinone reacts with a 3-coumarin-3-carboxylic acid through a tandem 1,4-addition/decarboxylation process initiated by a thiourea-functionalized cinchona alkaloid, which efficiently controls the stereochemistry of a newly forged stereocenter, while simultaneously directing the formation of a configurationally stable C(sp2)−C(sp3) synclinal atropisomer. The methodology has been explored across a broad substrate scope, and the results are supported by detailed nuclear magnetic resonance (NMR) analyses, single-crystal X-ray diffraction, and density functional theory (DFT) calculations.