Total Synthesis of Bioactive Canthine Alkaloid Cordatanine Comprising in Situ Double Oxidative Aromatization of Tetrahydrocarbazole

Abstract

Starting from tryptamine and methoxymaleic anhydride, concise and efficient total synthesis of cordatanine has been accomplished via regioselective reduction of methoxymaleimide, acid-catalyzed intramolecular cyclization of the formed lactamol, in situ stepwise oxidations leading to aromatization, and intramolecular cyclization with the exchange of N-regioselectivity. An attempted synthesis of regioisomeric natural product zanthochilone has been described in brief with reversal of reduction selectivity.

Recent Advances in the Synthesis of β-Carboline Alkaloids

“…Finally, oxidation of the hydroxy group in alcohols 129-131 was achieved using MnO2 on Celite ® , and aldehydes 16, 132, 133 were isolated in good yields. The synthesis of alkaloids 17-21 was then performed from these building blocks (16,132,133), which were reacted with indoles (134)(135)(136)(137) to afford secondary alcohols and then oxidized with active MnO2 to provide the first total synthesis of trigonostemines A (17) and B (18), carried out in 7 steps. At the same time, this pathway represents a new synthetic method for the preparation of pityriacitrin (20).…”

“…The practical total synthesis of canthine derivative cordatanine ( 40 ) has also been accomplished ( Scheme 26 ) [ 137 ] starting from tryptamine ( 108 ) and methoxymaleic anhydride ( 226 ), and by subsequent regioselective reduction of methoxymaleimide intermediate 227 into hydroxy derivative 228 . Acid-catalyzed intramolecular dehydrative cyclization of 228 furnished compound 229 .…”

“…The subsequent cycloamination was also successfully applied for the synthesis of carbolines including harmicine 39, where its tetracyclic structure was built up in only one step from tryptamine (108) and 1,4-butanediol (224), in the presence of trifluoroacetic acid and Ru-catalyst (225). One-step synthesis of racemic harmicine(39).The practical total synthesis of canthine derivative cordatanine (40) has also been accomplished (Scheme 26)[137] starting from tryptamine (108) and methoxymaleic anhydride (226), and by subsequent regioselective reduction of methoxymaleimide intermediate 227 into hydroxy derivative 228. Acid-catalyzed intramolecular dehydrative cyclization of 228 furnished compound 229.…”

Post‐Pictet‐Spengler Cyclization (PPSC): A Strategy to Synthesize Polycyclic β‐Carboline‐Derived Natural Products and Biologically Active N‐Heterocycles

“…Cordatanine ( 175 ), a Canthine alkaloid isolated from “ Drymaria cordata ” was synthesized via chemoselective reduction of methoxymaleimide 171 followed by Pictet‐Spengler reaction (Scheme , Route a) . Initially, tryptamine was reacted with methoxymaleic anhydride ( 170 ) in o ‐dichlorobenzene to produce 171 , which underwent chemoselective carbonyl reduction in the presence of sodium borohydride at −10 °C to yield intermediate 172 .…”

First Total Synthesis of (±)-Rhodoconferimide

“…26,27 (+)-Rhodoconferimide exhibits a 15-fold more potent free radical scavenging activity compared to the well-known synthetic antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT) (Figure 1). 26 In continuation of our studies on the total synthesis of recently isolated structurally interesting and biologically important natural products; [28][29][30] we herein report the first total synthesis of (±)-rhodoconferimide from the readily available precursors vanillin and dimethyl maleate.…”