Synthesis of condensed chiral pyranopyran derivatives with antiproliferative activity using domino Knoevenagel-IMHDA sequences

Abstract

We explored a domino Knoevenagel-intramolecular hetero-Diels-Alder (IMHDA) sequence, in which chiral pentaheterocyclic frameworks containing a pyrano[4,3-b]pyran unit condensed with a pyrone/pyridone and a tetrahydroquinoline/chroman subunit were synthesized. Substituted 2H-chromenes or 3,6-dihydro-2H-pyrans bearing an o-(formylaryl)-ether or -amine moiety were used as substrates, along with 4-hydroxypyrone, -pyridone, -coumarin and 2-quinolone derivatives as active methylene reagents, to assemble chiral condensed ring systems in a domino sequence. In the IMHDA cyclization step, two competing heterodiene subunits consisting of an α,β-unsaturated ketone or an ester/lactam carbonyl afforded regioisomeric condensed coumarin or chromone rings, respectively. Both heterodienes can undergo cyclization with an endo or exo transition state, resulting in two pairs of diastereomers. Up to four possible isomers were isolated in the cyclisation reactions and their structures elucidated using 2D NMR, chiroptical methods, and two single-crystal X-ray diffraction structures. The regio- and diastereoselectivity of the cyclisation was investigated in terms of temperature, solvent and the structures of the substrate and reagent. Simplified substrates were prepared from 5,6-dihydro-2H-pyran derivatives, the reactions of which took place with complete regio- and stereoselectivity, providing a single product with good yields. Some of the products exhibited antiproliferative activity against human cancer cell lines with IC₅₀ values down to 5.7 µM.