Total synthesis of the Daphniphyllum alkaloid daphenylline

Abstract

The Daphniphyllum alkaloids are a large class of natural products isolated from a genus of evergreen plants widely used in Chinese herbal medicine. They display a remarkable range of biological activities, including anticancer, antioxidant, and vasorelaxation properties as well as elevation of nerve growth factor. Daphenylline is a structurally unique member among the predominately aliphatic Daphniphyllum alkaloids, and contains a tetrasubstituted arene moiety mounted on a sterically compact hexacyclic scaffold. Herein, we describe the first total synthesis of daphenylline. A gold-catalysed 6-exo-dig cyclization reaction and a subsequent intramolecular Michael addition reaction, inspired by Dixon's seminal work, were exploited to construct the bridged 6,6,5-tricyclic motif of the natural product at an early stage, and the aromatic moiety was forged through a photoinduced olefin isomerization/6π-electrocyclization cascade followed by an oxidative aromatization process.

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

“…A 6π-electrocyclization23 (path a) and a Heck-type annulation242526272829 (path b) were envisioned as two alternatives to forge the carbazole motif. The former draws on our recent syntheses of tubingensin A and daphenylline3031, while the latter relies on activation of the indole C2–H bond by palladium. Correspondingly, triene ( 7 ) and indosespene ester ( 8 ) are considered as the key intermediates for the two strategies.…”

Total Syntheses of (+)‐Sarcophytin, (+)‐Chatancin, (−)‐3‐Oxochatancin, and (−)‐Pavidolide B: A Divergent Approach

“…[9] The latter compound in turn should be accessible from the bicyclic enone 10 and Grignard reagent 11 through aH elquist annulation. [14] Upon further exposure to aqueous HF,t he second Mukaiyama Michael addition, followed by elimination proceeded smoothly to give the requisite cis- [6,6] bicyclic diketone 10 in 84 %y ield. [13] Our synthesis began with construction of the common intermediate 9 (Scheme 2).…”

Total Syntheses of Daphenylline, Daphnipaxianine A, and Himalenine D

“…[11] Theb iogenesis of Daphniphyllum alkaloids offers important information for developing synthetic routes to these molecules; [1a] for example, Heathcock and co-workers developed an elegant biomimetic polycyclization cascade. [4] During our previous synthesis of daphenylline (1, Figure 1), [6,12] we were intrigued by abiosynthetic hypothesis for the formation of this alkaloid from acharacteristic calyciphylline Atype [1c] Daphniphyllum alkaloid, daphenilongeranin C [13] (2), proposed by Hao and coworkers,w ho isolated 1. [14] Am inor modification of their proposal is illustrated in Figure 1.…”

“…[14] Am inor modification of their proposal is illustrated in Figure 1. Upon activation by acid, 2 could undergo Wagner-Meerwein-type ring expansion to arrive at hydroxycarboxylic acid 3;the strain of the congested spiro ring system may provide adriving force.Dehydration of 3 would generate diene 4.F urther decarboxylation followed by aromatization may give 1.This hypothesis builds alinkage between 1 and as eries of Daphniphyllum alkaloids from the calyciphylline As ubfamily sharing a6 -6-5-7-5-5-hexacyclic core, [1b,c] which inspired us to exploit this relationship from as ynthetic perspective.D aphnipaxianine A [15] (5,F igure 2) and himalenine D [16] (6)are two oxygenated calyciphylline A type alkaloids isolated by the groups of Hao and Yue, respectively;t hey have not been synthesized to our knowledge.Herein, we report the total syntheses of 1, 5,a nd 6.…”