Total Synthesis of Natural Products with Bridged Bicyclo[m.n.1] Ring Systems via Type II [5 + 2] Cycloaddition

Abstract

Conspectus Natural products containing bridged ring systems are widely identified and show significant biological activity. The development of efficient synthesis reactions and strategies to construct bridged ring systems is a long-standing but very significant challenge in organic chemistry. In 2014, our group developed a unique type II [5 + 2] cycloaddition reaction that provides a facile and direct methodology for constructing highly functionalized bridged bicyclo[4.3.1], bicyclo[4.4.1], bicyclo[5.4.1], bicyclo[6.4.1], and other bicyclo­[m.n.1] systems containing a strained bridgehead double bond. In this Account, we summarize the methodology development and report the results of application of our unique strategy for the total synthesis of several natural products with bridged ring systems (i.e., cyclocitrinol, cerorubenic acid-III, and vinigrol) during the past 5 years in our laboratory. In the first part, we introduce the logic behind the design and discovery of type II [5 + 2] cycloadditions. The substrates can be easily synthesized by a modular approach, followed by base-promoted group elimination under heat to form an oxidopyrylium ylide, which can undergo cycloaddition under relatively mild conditions with a variety of double bonds to generate bridged bicyclo­[m.n.1] frameworks in high yield. The diastereocontrol and unique endo selectivity of this methodology are favorable for further application to the synthesis of complex natural products. In the second part, we highlight our endeavors in the total synthesis of several different types of molecules bearing bridged ring systems using our methodology. The bridged bicyclo[4.4.1] system is the core structure of two different types of natural products, cyclocitrinol and cerorubenic acid-III, that can be efficiently constructed by type II [5 + 2] cycloadditions. The development of suitable strategies and methods for site-selective cleavage of the C–O bond of the oxa-[3.2.1] ring system in the products of type II [5 + 2] cycloadditions is also discussed and highlighted during the syntheses. Moreover, the bridged bicyclo[5.3.1] system is the core structure of vinigrol, which can be constructed through a novel ring contraction sequence of the bicyclo[5.4.1] system formed by a type II [5 + 2] cycloaddition. By combining with a ring contraction cascade, we believe that type II [5 + 2] cycloadditions have the potential to be used as a unified approach to constructing natural products containing bridged bicyclo­[m.n.1] frameworks.

Asymmetric Total Synthesis of Phomarol

“…Third, whether the type I [5 + 2] cycloaddition of our proposed precursor with several sensitive functional groups could occur under mild instead of harsh conditions was also unknown. In our previous total syntheses, all of the types I and II [5 + 2] cycloadditions without any activating group proceeded under harsh conditions (such as at high temperature) 25,26,52 without any activating group.…”

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

“…Cycloaddition reaction have been demonstrated to be reliable strategy for the quick access to the complex ring structures. [5] In recent years, the transition metalcatalyzed cycloaddition reactions have been widely promoted and studied. Compared with the traditional cycloaddition methods, such as the Diels-Alder reaction, the transition metal-catalyzed cycloaddition reactions provide better synthetic expediencies and more abundant heterocycles.…”

Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions

“…Particularly, there have been no reports of type II IMDA reactions being used to make bicyclo[5.2.2], bicyclo [4.2.2], and bicyclo[3.2.2] ring systems. In addition, other type II intramolecular cycloadditions 22 , 23 (including innovative Davies-[4+3] 24 , remarkable Wender-[4+4] 25 , and our [5+2] 26 , 27 ) are unknown for the synthesis of bicyclo[m.n.2] ring systems. Currently, few intramolecular cycloaddition reactions are available for the direct and efficient synthesis of various bicyclo[m.n.2] ring systems.…”