Biomimetic Synthesis of Natural Products: A Journey To Learn, To Mimic, and To Be Better

ConspectusTotal synthesis of natural products has been one of the most exciting and dynamic areas in synthetic organic chemistry. Nowadays, the major challenge in this field is not whether a given target of interest can be synthesized but how to make it with commendable efficiency and practicality. To meet this grand challenge, a wise way is to learn from Mother Nature who is recognized for her superb capability of forging complicated and sometimes beyond-imagination molecules in her own delicate way. Indeed, since Sir Robert Robinson published his groundbreaking synthesis of tropinone in 1917, biomimetic synthesis of natural products, a process of imitating nature's way to make molecules, has evolved into one of the most popular research directions in organic synthesis.Our group has been engaging in biomimetic synthesis of natural products in the past decade. During this time, we have come to realize that the successful implementation of a biomimetic synthesis entails the orchestrated combination of bioinspiration and rational design. On the one hand, we prefer to utilize some elegant bioinspired transformations (e.g., Diels–Alder dimerization, 6π-electrocyclization, and [2 + 2]-photocycloaddition) as the key steps of our synthesis, which enable rapid construction of the core skeletons of the chased targets with high efficiency; on the other hand, various powerful reactions (e.g., dyotropic rearrangement of β-lactone, tandem aldol condensation/Grob fragmentation reaction, and organocatalytic asymmetric Mukaiyama–Michael addition) are rationally designed by us, which allow for facile access to the requisite precursors for attempting biomimetic transformations. In some cases, the proposed biomimetic transformation may fail to give a satisfactory result in practice, and thus we opt to develop creative tactics (e.g., hydrogen atom transfer-triggered vinyl cyclobutane ring opening/oxygen insertion/cyclization cascade) that can meet the challenge. Guided by this synthesis concept, we have achieved the total syntheses of multiple families of natural products of great importance in both chemistry and biology, representatives of which include xanthanolides, cytochalasans, and plakortin-type polyketides. Of note, most of these targets could be accessed in a concise, efficient, and scalable manner, which paves the way for further exploration of their biological functions and medicinal potential. Moreover, owing to their biomimetic nature, our syntheses provide valuable information for deciphering the underlying biosynthetic pathways of the chased targets, which could not be attained by other synthetic modes.