Currently, the frontier challenges in total synthesis pertain to increasing the synthetic efficiency and enabling the divergent synthesis of a number of natural products. Bioinspired synthesis has been well recognized as an effective approach to increasing synthetic efficiency. Especially, when bioinspired synthesis was applied at late-stage skeletal diversification to generate various natural products with distinct carbon skeletons, it held special promise for achieving both goals. In our laboratory, bioinspired synthesis has served as one of two long-standing principles for facilitating the efficient synthesis of natural products. In this Account, we summarize our endeavors and journeys in the bioinspired synthesis of natural products. We categorize our work into three parts based on the imitation of biosynthetic reactions and processes.(1) To mimic the key cyclization steps. Inspired by the biosynthetic process that formed the core skeleton, we developed new synthetic methods to enable the rapid and efficient construction of the core skeletons of the targeted molecules, ultimately leading to their concise total synthesis, for example, seven-step total synthesis of lamellarins D and H featuring three bioinspired oxidative coupling reactions, seven-step total synthesis of clavicipitic acid highlighted by a C-H activation/aminocyclization cascade reaction, eight-step total synthesis of phalarine via a bioinspired oxidative coupling, seven-step total synthesis of alpha-cyclopiazonic acid, and ten-step total synthesis of speradine C through a bioinspired cascade cyclization reaction initiated by the benzylic carbocation of indole. (2) To mimic the revised biosynthetic pathway proposed by us. In some cases, the proposed biosynthetic processes may be flawed, as they contradict some basic principles of chemistry. Thus, an alternative biosynthetic process must be proposed and investigated. We showcase the total synthesis of euphorikanin A through a bioinspired benzilic acid-type rearrangement and bipolarolides A and B via a bioinspired Prins reaction/ether formation cascade cyclization. (3) To mimic the skeletal diversification process. Nature usually synthesizes a multitude of products from a key common intermediate in a divergent manner. Biogenic skeletal diversification to generate various natural products with distinct carbon skeletons has also drawn our attention. Compared with single-target-oriented synthesis, skeletal-diversity-oriented synthesis of natural products remains underexplored due to its high synthetic challenges. We showcased the divergent total syntheses of ten pallavicinia diterpenoids with three distinct skeletons and six grayanane diterpenoids with three distinct skeletons, which were achieved with unprecedented ease and high efficiency by imitation of the proposed biogenic skeletal diversification process. These two successful projects can serve as inspiration for the application of the bioinspired skeletal diversification strategy to other skeletally diverse natural products.
