Gram Scale Total Synthesis of 2‐Hydroxy‐3‐methylcarbazole, Pyrano[3,2‐a]carbazole and Prenylcarbazole Alkaloids

Abstract

Naturally occurring carbazole alkaloids including 2‐hydroxy‐3‐methylcarbazole, pyrano[3,2‐a]carbazole alkaloids (girinimbine and murrayacine) and prenylcarbazole alkaloids (mukoenine‐A and heptaphylline) have been synthesized on gram scale. The key compound in these syntheses is 9‐benzyl‐2‐methoxy‐3‐methylcarbazole, which was prepared by an efficient Au‐catalyzed cyclization reaction of readily available methoxypropadiene and indole‐2‐carbaldehyde. Girinimbine and murrayacine were synthesized by a concise PhB(OH)2‐mediated intermolecular cyclization with 3‐methylbut‐2‐enal. Palladium‐catalyzed allylation/Claisen rearrangement proved to be the best route to mukoenine‐A and heptaphylline.

First Total Synthesis of the Cytotoxic Carbazole Alkaloid Excavatine‐A and Regioselective Annulation to Pyrano[2,3‐a]carbazoles and [1,4]Oxazepino[2,3,4‐jk]carbazoles

“…Given that pyrano[2,3‐ a ]carbazoles 6a – c could not be converted into excavatine‐A ( 1 ), we devised an alternative approach by introduction of the prenyl side chain at the 8‐hydroxycarbazole 8a through O ‐allylation and subsequent Claisen rearrangement (Scheme ) . Palladium(0)‐catalyzed coupling of 8a and 1,1‐dimethylallyl methyl carbonate provided the required tert ‐prenyl ether 28 .…”

Transition Metal‐Catalyzed Benzannulation towards Naturally Occurring Carbazole Alkaloids

“…In 2013, we further applied this protocol to the general synthesis of isomukonidine, clausine L, mukonidine, glycosinine, mukonal, and clausine V . To further demonstrating the great potential for its application as a general approach for the synthesis carbazole alkaloids, we realized the gram scales synthesis of 7‐methoxy‐O‐methylmukonal, clausine‐O, clausine‐K, clausine‐H, 7‐methoxymukonal, methyl 2‐hydroxy‐7‐methoxy‐9H‐carbazole‐3‐carboxylate, 2‐hydroxy‐3‐methylcarbazole, pyrano[3,2‐ a ]carbazole alkaloids (girinimbine and murrayacine) and prenylcarbazole alkaloids (mukoenine‐A and heptaphylline) . Here, we describe the total synthesis of these carbazole alkaloids in detail to show the beauty of our newly developed methodologies.…”

“…According to the retrosynthetic analysis presented in Scheme , the construction of the pyran ring and the installation of the prenyl group are the keys for the synthesis of these target pyrano[3, 2‐a]carbazole alkaloids (girinimbine and murrayacine) and prenylcarbazole alkaloids (mukoenine‐A and heptaphylline), in addition to the carbazole skeleton formation. The strategies employed here to build the six‐membered oxacycle in girinimbine and murrayacine involve Knoevenagel condensation of 9‐benzyl‐3‐methyl‐2‐hydroxycarbazole 13 b with α,β‐unsaturated aldehydes, followed by 6π ‐electrocyclization.…”

“…9‐Benzyl‐2‐methoxy‐3‐methylcarbazole 15 was finally generated by treatment of 7 b with n ‐BuLi followed by methylation with methyl iodide. With such a sequence, methylated carbazole 15 was synthesized in five steps with 78 % overall yield from 6 b (Scheme ) …”

“…Then mukoenine‐A could be afforded in high yield by the subsequent Claisen rearrangement of 18 . Considering the fact that the oxidant DDQ is sensitive to hydroxyl group, heptaphylline was synthesized by the oxidation of 18 with DDQ and subsequent Claisen rearrangement in refluxing toluene (Scheme ) …”