Polycyclic ring systems represent the most common structural features of drug molecules and natural products. Chemical synthesis of complex polycyclic molecules with multiple stereogenic centers, especially quaternary carbon stereocenters, has been a significant challenge in the field of total synthesis. Due to the low reactivities of the substrates and congested chemical environments, the efficient establishment of polycyclic rings and enantioselective construction of quaternary carbon stereocenters are still ongoing challenges. In our laboratory, we are devoted to developing new methodologies and strategies for the total syntheses of bioactive polycyclic natural products and the exploration of their biological potentials. The photoenolization/Diels-Alder (PEDA) reaction has been recognized as a powerful strategy to increase synthetic efficiency and address the aforementioned issues. Over the past several years, our group systematically reinvestigated this reaction in terms of its reactivity and stereoselectivity and developed a unique dinuclear metal-promoted reaction process for constructing fused or spiro polycyclic rings bearing quaternary carbon stereocenters. During the course of this investigation, we have come to realize how to rationally design the synthetic route based on the PEDA reaction and successfully implement the synthetic projects.In this Account, we summarize our endeavors and journeys in the development and application of the PEDA reaction to the total synthesis of topologically complex natural products in order to draw attention to its broad utility and encourage further uptake. In the first part, we provide the details on the investigation of the PEDA reaction to address the issues of reactivity, diastereoselectivity, and enantioselectivity. An enantioselective PEDA reaction involving Ti(Oi-Pr)4 and TADDOL-type ligands was developed. This reaction enables the sterically bulky dienophiles to interact with the transient photoenolized hydroxy-o-quinodimethanes, delivering a wide range of polycyclic rings with single or vicinal quaternary carbon stereocenters in good yields with excellent enantioselectivities. In the second part, we showcase the synthetic potential of PEDA reaction in total synthesis of natural products. The fused tricyclic ring systems, bearing gem-dimethyl groups or quaternary carbon stereocenters located at the ring junction, were efficiently constructed by Ti(Oi-Pr)4-promoted PEDA reactions, which enabled the syntheses of three different types of natural products, including aromatic polyketides (anthrabenzoxocinones, fasamycins/naphthacemycins, and benastatins), meroterpenoid (oncocalyxone B), and halenaquinones (xestoquinone, adociaquinones A and B). To access structurally more complex triterpenoids, namely, perovskones and hydrangenones, the asymmetric PEDA reaction was developed to build a tricyclic ring along with three contiguous quaternary carbon stereocenters. The asymmetric PEDA reaction was also applied to achieve the total synthesis of aryltetralin lactone lignans. Furthermore, an intramolecular PEDA reaction provides a new pathway for the rapid construction of highly congested hydrophenanthrene with a quaternary carbon stereocenter, facilitating the total synthesis of five hasubanan alkaloids. We anticipate that the development of the PEDA reaction will inspire future innovations and progressions in asymmetric photo reactions, and its synthetic potential will be expanded by further applications in the total synthesis of complex natural and drug molecules.
