Wrightiadione contains a unique tetracyclic isoflavone moiety and has been shown to exhibit a broad range of biological activities. An efficient and straightforward synthetic method for generating the molecular complexity of wrightiadione was developed through three-step tandem dehydrogenation/oxidation/oxidative cyclization reactions with a Pd/Cu catalytic system. This unprecedented one-pot route utilizes a broad range of substrates, providing a convenient and powerful synthetic tool for accessing naturally occurring tetracyclic isoflavone wrightiadione and its nitrogen-containing derivatives.