Automated Reactivity Prediction of Complex Molecules and Its Application to Total Synthesis of Ageliferin

Predicting the reactivity of complex molecules and planning reliable synthetic routes have long been challenges in natural product synthesis. We have addressed these challenges by using automated reactivity prediction using ConfoTS, an integrated program based on ACCeL, and have completed the total synthesis of ageliferin. The optimal substrate equipped with a d-tartrate scaffold for the dearomative Diels-Alder reaction of the hymenidin unit was designed through automated evaluation of the energy barriers for various virtual substrates. The highly functionalized six-membered framework was stereoselectively constructed by the cycloaddition of the designed substrate, leading to the synthesis of ageliferin in 15 steps from a known tetrahydropyridazine.