Catalytic Asymmetric Inverse‐Electron‐Demand Diels–Alder Reactions of 2‐Pyrones with Indenes: Total Syntheses of Cephanolides A and B

Abstract

An inverse‐electron‐demand Diels–Alder (IEDDA) reaction could complement the conventional normal‐electron‐demand Diels–Alder reaction in the synthesis of six‐membered carbocycles. However, catalytic asymmetric all‐carbon‐based IEDDA reactions are underdeveloped. Herein, we disclosed a copper‐catalyzed asymmetric IEDDA reaction using electron‐deficient 3‐carboalkoxyl‐2‐pyrones and electronically unbiased indenes as reactants. This method enables the rapid and enantioselective construction of a wide range of hexahydrofluorenyl bridged‐lactone scaffolds. Using this method, asymmetric total syntheses of cephanolides A and B were accomplished.

Recent Advances in the Total Synthesis of Cephalotane-Type Norditerpenoids from Cephalotaxus sinensis

“…These syntheses have divergent biomimetic strategies, which provide a flexible method reference for the biogenic synthesis of cephalotaxus diterpenoids and structure related derivatives. Inspired by Hu's synthesis strategy 30 for fortalphinoid A and cephinoid H, Yang 31 accomplished the third racemic total synthesis of cephanolide B via tandem Pauson-Khand reaction and oxidative aromatization catalyzed by Cobalt.…”

“…Three years after the molecular discovery, Gao [29] achieved the first asymmetric total synthesis of cephanolides A and B featured a convergent strategy, developed an intramolecular Prins cyclization to construct the central hexahydrofluorenol skeleton (A-B-C ring), and a sequence of transformations, such as Friedel-Crafts cyclization to forge the cage-like skeleton. The second asymmetric total synthesis of cephanolides A and B was accomplished by Cai [30] via a copper-catalyzed asymmetric inverse-electron-demand Diels-Alder reaction using electrondeficient 3-carboalkoxyl-2-pyrones and electronically unbiased indene as reactants.…”

“…A novel [4 + 2] cycloaddition reaction using coppercatalyzed asymmetric inverse-electron-demand Diels-Alder reaction (IEDDA) to obtain the enantioselective hexahydrofluorenyl bridged-lactone scaffolds was exploited by Cai [30] . Based on this method, other asymmetric total syntheses of cephanolides A and B were accomplished.…”

Enantioselective construction of cis-hydroindole scaffolds via an asymmetric inverse-electron-demand Diels–Alder reaction: application to the formal total synthesis of (+)-minovincine

“…Due to the hemi-aromatic and adjustable electronic properties, electron-deficient 2-pyrone has become a favored diene component in the IEDDA reaction with a wide range of applications in aromatic compounds and complex natural product synthesis. 19,20 Particularly, the Cai group demonstrated the enantioselective IEDDA reaction of 3-carboalkoxyl-2-pyrone with electron-rich dienophiles, such as 2,2-dimethyl-1,3-dioxole, 20 g silyl cyclohexadienol 20 i and 1-naphthyl acetylenes, 20 j affording the products in high yield, excellent ee, and high dr. In spite of the above achievements, catalytic asymmetric synthesis of cis -hydroindoles via the enantioselective IEDDA reaction of 2-pyrones with cyclic enamines is still in its infancy so far.…”

Construction of Tetracyclic Core Skeleton of Cephalotaxus Diterpenoids through Diastereoselective Pauson‐Khand Reaction

“…[11] Cai and coworkers achieved the asymmetric total synthesis of cephanolides A and B from an enantioselective inverse-demand Diels-Alder Reactions developed in their lab. [12] Very recently, Yang, Zhang, and coworkers accomplished total synthesis of cephanolide B through a gentle intramolecular Pauson-Khand reaction/6π-electrocyclization/aromatization cascade. [13] Stimulated by the keen interest in Cephalotaxus diterpenoids, we carried out a synthetic study on three members of this family, 3-deoxyfortalpinoid F, fortalpinoid A, and cephinoid H. It is noteworthy that there is a common tetracyclic core skeleton existing in Cephalotaxus diterpenoids (Figure 1).…”