Homochiral AB segments for (+)- and (–)-pillaromycinone were prepared in 11 steps from 2-acetylfuran. The synthesis featured an intramolecular Diels–Alder reaction of a 2,5-disubstituted furan and a hydroxyl-directed homogeneous hydrogenation of the tetrasubstituted alkene double bond of two enones. The CD segment was attached by a modified Staunton–Weinreb annulation to produce the desired homochiral