Design and development of first synthetic approach to the functionalized tetracyclic framework of structurally novel seco-tetracenomycin natural products saccharothrixones A–C has been reported. A thermal dehydro Diels-Alder reaction of an arenyne-alkyne unit has been utilized as the key synthetic step. This strategy has been extended for the generation of a small library of diversely functionalized tetracyclic systems of seco-tetracenomycins. An approach for the synthesis of poly-hydroxyl tetracyclic system has also been described. This report represents the first synthetic approach to the tetracenomycin natural products saccharothrixones A–C. © 2018 Elsevier Ltd