Solvent-Controlled Remote Chemodivergent Synthesis of γ,δ-/γ-Functionalization of 2H-Chromen-2-ones via Cascade 1,6-Conjugate Additions.

We have developed an efficient solvent-controlled remote chemodivergent synthesis of functionalized coumarins via cascade 1,6-conjugate addition reactions of 3-cyano-4-alkenyl-2H-chromen-2-ones with α-bromomalonates. In CH2Cl2, a 1,6-addition/cyclopropanation pathway affords coumarin scaffolds bearing a polysubstituted cyclopropane motif in high yields (up to 90% yields) with excellent diastereoselectivity (in all cases >25:1 dr), whereas in EtOAc, a 1,6-addition/cyclization/ring-opening pathway delivers (Z)-γ-substituted 3-cyano-4-styrylcoumarins with excellent stereoselectivity. The synthetic utility of this protocol is demonstrated through scale-up reactions and downstream transformations of the products. Molecular docking studies suggest that the resulting coumarin scaffolds possess potential antitumor activity.