Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts

Abstract

The polycyclic furanobutenolide-derived cembranoid and norcembranoid natural products are a family of congested, stereochemically complex, and extensively oxygenated polycyclic diterpenes and norditerpenes. Although the elegant architectures and biological activity profiles of these natural products have captured the attention of chemists since the isolation of the first members of the family in the 1990s, the de novo synthesis of only a single polycyclic furanobutenolide-derived cembranoid and norcembranoid has been accomplished. This article will begin with a brief discussion of the proposed biosyntheses and biosynthetic connections among the polycyclic furanobutenolide-derived cembranoids and norcembranoids followed by a comprehensive review of the synthetic efforts toward each member of the natural product family, including biomimetic, semisynthetic, and de novo synthetic strategies. This body of knowledge has been gathered in order to provide insight into the reactivity and constraints of these compact and highly oxygenated polycyclic structures, as well as to offer guidance for future synthetic endeavors.

Biosynthetic Interrelationships within Polycyclic Cembranoids Isolated from Corals: Conjecture, Biomimetic Synthesis and Reality

“…The aristocratic nature, combined with the unusual fusion of rings with complex oxy‐substitution patterns and stereochemistry in the polycyclic structures 8 – 14 have enticed and seduced a number of synthetic chemists to take up the challenge of their synthesis in the lab. A recent review has summarised a variety of synthetic approaches that have been made towards members of the polycyclic structures 8 – 14 , especially towards bielschowsksin 8 and ineleganolide 12 . In this Perspective we focus on speculations that have been made, by us and others, over the past decade on the most likely biosynthesis pathways to the aforementioned polycycles and some of their relatives, and then summarise the progress that has been made to vindicate some of these speculations in the lab., i.e.…”

“…It is also reported to exhibit cytotoxicity against non‐small lung cancer cells and renal cancer cells. Its challenging structure and interesting biological properties have combined to make bielschowskysin one of the most revered targets amongst synthetic chemists in recent years …”

A Kinetic Dearomatization Strategy for an Expedient Biomimetic Route to the Bielschowskysin Skeleton

“…Given the significance of exo-enol ethers as key biosynthetic precursors to several other complex natural products (e.g.,v errilin, plumarellide,o rm andapamate), [2] we anticipate that the kinetic dearomatization strategy reported herein will be applicable to the synthesis of al arge number of molecules in this class.F inally,t his study suggests that the fourth 7S,8S epoxide diastereomer should be the biosynthetic precursor to 1;h owever, both isolation and preparation of this stereoisomer still remain elusive. [15,28]…”

Rhodium‐Catalyzed [4+2+1] Cycloaddition of In Situ Generated Ene/Yne‐Ene‐Allenes and CO

“…Seven-membered carbocyclic rings are privileged skeletons widely found in natural products [1] with biological and medicinal significances (for example,c olchicine,g uanacastepene,i ngenol). However,t he synthesis of seven-membered carbocycles is still posing challenges [2] to chemists due to the facts that 1) only limited number of reactions and strategies are available;a nd 2) many molecules with seven-membered carbocycles have different substitution patterns and stereocenters,w hich could be difficult or impossible to achieve by the previously reported methods and strategies for sevenmembered ring synthesis.T herefore,d eveloping new reactions to access seven-membered carbocycles,w hich could either expand or complement previous reactions,i sa n important frontier in reaction development.…”