Organocatalytic synthesis of chiral benzopyrans

Benzopyrans, or chromenes, are widespread in nature and are considered to be a privileged scaffold in medicinal chemistry. Herein, we report the first organocatalyzed asymmetric synthesis of chiral benzopyrans. The benzopyran unit is constructed through a domino reaction involving an oxa-Michael attack of salicylic aldehyde derivatives onto α,β-unsaturated aldehydes, activated through iminium-ion formation with the organocatalyst, followed by an intramolecular aldol reaction and subsequent elimination of water. This overall reaction sequence provides benzopyrans with aromatic C-2 substituents in up to 60% yield and 60% enantioselectivity, while C-2 aliphatic analogues can be obtained in 90% enantiomeric excess, but with only 20% yield. The role of additives, as well as the possible racemization of the benzopyran, was also investigated. © 2006 Elsevier Ltd. All rights reserved.