An Asymmetric Pathway to Dendrobine by a Transition‐Metal‐Catalyzed Cascade Process

Abstract

An asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one-pot, sequential palladium-catalyzed enyne cycloisomerization and rhodium-catalyzed diene-assisted pyrrolidine formation by allylic CH activation. The developed transition-metal-catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late-stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall.

Azomethine Ylide Cycloaddition Approach toward Dendrobine: Synthesis of 5-Deoxymubironine C

“…1 H NMR (400 MHz, CDCl 3 ): δ 11.22 (bs, 1H), 5.39 (s, 1H), 4.97 (t, J = 4.9 Hz, 1H), 4.00 (m, 2H), 3.87 (m, 2H), 3.12 (q, J = 8. 4 20 = +5.2 (c = 1.0, CHCl 3 ). 13.…”

“…R f : 0.24 (30% EtOAc in pentane, stains with KMnO 4 ). 1 20 = +112 (c = 0.80, CHCl 3 ). Synthesis of Methyl (2a 1 S,4S,5S,5aS,7aS)-4-Isopropyl-2a 1methyl-2a 1 ,3,4,5,5a,6,7,7a-octahydroindeno[7,1-cd]isoxazole-5-carboxylate (18).…”

“…The broad bioactivity of 1 , its biogenetic kinship with the picrotoxanes, and its stereochemically crowded skeleton have made it the subject of numerous total − and formal − syntheses which have dissected the molecule in a variety of manners (Scheme a). Though thoughtful in strategy and inspiring in execution, many approaches require late-stage redox manipulation and/or incremental functional group interconversion.…”

A Metathetic Approach to [5/5/6] Aza-Tricyclic Core of Dendrobine, Kopsanone, and Lycopalhine A Type of Alkaloids

“…Dendrobine (1), a tetracyclic pyrrolidine alkaloid isolated from the Dendrobium nobile plant, shows analgesic and antipyretic activity. 1 Dendrine (4) and mubironine C (5) are structurally related alkaloids to dendrobine (1), originated from similar orchid species. 2 Kopsinidines 6-8 and kopsanone (2) are monoterpenoid alkaloids isolated from Kopsia officinalis plant that exhibits anti-inflammatory, antirheumatic, and cholinergic effects.…”

“…Recently, Chen and co-workers have disclosed the [5/5/6] aza-tricyclic Kende intermediate towards asymmetric synthesis of dendrobine in seven steps in 15% overall yield (Scheme 1a). 5 In 2018, Williams and Trauner have reported the synthesis of 5-deoxymubironine C in eight steps in 7% overall yield (Scheme 1b). 6 Here, we have developed a simple and stereoselective metathesis strategy to synthesize [5/5/6] pyrrolidine azatricyclic core, which produced more than 50% overall yield in a stereoselective manner (Scheme 1c).…”