In the past five years, our group has achieved a series of complex and biologically important natural product total syntheses, which makes those natural product synthetically accessible. The chemistry developed during our total synthesis campaign has not only helped us to deal with various challenges encountered in the syntheses of the selected target molecules, but has also opened up new avenues for synthesizing other natural products and their derivatives, which will likely result in molecules with improved biological functions and tool compounds to enable elucidation of their mechanism of actions or potential cellular targets. Our syntheses have propelled the art of total synthesis of complex natural products (see Z. Yang, “The Journey of Schinortriterpenoid Total Syntheses” Acc. Chem. Res. 2019, 52, 480−491, and Z. Yang, “Navigating the Pauson−Khand Reaction in Total Syntheses of Complex Natural Products” Acc. Chem. Res. 2021, 54, 556−568).
Currently, our group is focusing on the precise synthesis of natural products by application of free radical reaction as a key step. Through the comprehensive use of photochemistry, quantum chemistry and artificial intelligence, we now build up an intelligent chemical synthesis platform, which can understand the principle and mechanism of free radical reaction from the molecular level, and seek new ways of molecular activation and reaction control strategy.
This journey has made us ponder what we should do in the future to improve these synthetic methods and what the next steps should be. Obviously, the synthetic efficiency needs to be significantly improved; this includes decreasing the total number of synthetic steps, developing more convergent strategies, and reducing the overall time and resources invested, and the waste generated. Thus, new enabling synthetic capabilities and strategies are needed to achieve these goals. To this end, we will use theoretical calculation to design new transition metal catalysts, organic small molecular catalysts, photocatalysts, multi-functional catalysts. We will also explore the machine-assisted high- throughput screening technology to realize the visible light-mediated precise construction of the core structures of complex natural products.
For the long-term development of therapies centered on these medicinally important natural products or their derivatives, we will use machine learning to optimize synthetic routes and methods to achieve intelligence-driven artificial intelligence drug design and precise synthesis to create the chemistry more flexible and efficient. The developed chemistry can be used to make 1) new synthetic analogues to improve their on-target potency and selectivity, and to optimize the ADMET pharmacokinetics and pharmacology, 2) and chemical probe molecules to elucidate their modes of action and help us to understand the related biological and disease processes. We have started on an adventurous and enjoyable voyage to reach an ideal synthesis.