Total Syntheses of Highly Oxidized Natural Products†

Comprehensive Summary Natural products with high oxidation states and complex chemical skeletons exhibit diverse bioactivities due to their unique interactions with biological targets. The high oxidation state is characterized by the presence of multiple oxygen‐containing functional groups such as hydroxyl groups, carbonyl groups, and epoxides that are usually tough to construct selectively. In recent years, thanks to the development of efficient strategies and sophisticated methodologies, significant advancements have been made in the total syntheses of highly oxidized natural products (HONPs). In this review, we highlight recent examples of HONPs focusing on tetrodotoxin (TTX) and its derivatives, steroidal alkaloids, sesquiterpenes, and diterpenoids since 2019. Key Scientists In 2005, the Yang group applied the thioureas as ligands in the Pauson−Khand reaction for total synthesis of triterpene natural products. The methodological advances have achieved total syntheses of a series of topologically complex natural products with diverse structural features in the following years. In 2009, the Baran group established a pioneering “two‐phase” approach for the total synthesis of highly oxidized terpenes, an innovative strategy has since inspired numerous advancements in the field. In 2011, Xu and Theodorakis achieved the total synthesis of (−)‐jiadifenolide, a highly oxidized sesquiterpene from Illicium . In 2012, the Li group applied 6π electrocyclization for total synthesis of natural products containing aromatic rings. In 2014, the Inoue group introduced the α‐alkoxy bridgehead radical, facilitating a unified total synthesis of ryanodane diterpenoids. In subsequent years, radical‐based convergent strategies were employed for assembling HONPs. The Li group developed the type ΙΙ 5+2 reaction, which can be efficiently applied in the total synthesis of HONPs featuring bridged ring systems. The Reisman group presented the oxidation pattern analysis that guided their synthetic designs for the synthesis of complex, highly oxidized ryanodane and isoryanodane diterpenes. In 2017, the Gao group reported a photoenolization/Diels‐Alder (PEDA) reaction for constructing related polycyclic rings with elevated oxidation states. In 2018, the Ding group developed an unprecedented oxidative dearomatization‐induced (ODI) 5+2 cycloaddition/pinacol‐ type 1,2‐acyl migration cascade to assemble the highly oxygenated bicyclo3.2.1octane ring system, which was subsequently applied to the synthesis of highly oxidized grayanane diterpenoids. In the same year, the Gui group explored “bioinspired” strategic transformations that enabled the rapid construction of core framework of steroid and terpenoid natural products. In 2020, the Luo group successfully synthesized several HONPs, including (−)‐batrachotoxinin, (−)‐zygadenine, and grayanane diterpenoids, employing elegant strategies. In 2021, the Zhang group developed site‐specific photochemical desaturation and late‐stage skeletal reorganization strategies, enabling the divergent total synthesis of Illicium sesquiterpenes. In 2022, the Jia group achieved the first total synthesis of (−)‐principinol C, subsequently accomplished six highly oxidized grayanane diterpenoids. More recently, the Trauner group reported a concise synthesis of tetrodotoxin, employing a particularly elegant strategy.