Total Synthesis of Phenanthroindolizidine Alkaloids by Combining Iodoaminocyclization with Free Radical Cyclization

Abstract

A concise and modular synthesis of phenanthroindolizidine alkaloids was achieved by combining iodoaminocylization with a free radical cyclization approach. The route described allowed the preparation of (±)-tylophorine, (±)-antofine, and (±)-deoxypergularinine in six steps. When commercially available l-prolinol was used as a chiral building block, (S)-(+)-tylophorine was also synthesized in 49% yield and >99% ee over five linear steps.

Total Synthesis of Phenanthropiperidine Alkaloids by Sequential Alkylation of N,N‐Dibenzylaminoacetonitrile

“…( E )‐2,3‐bis(3,4‐dimethoxyphenyl)acrylic acid, 6 a . From an adapted procedure reported in the literature [19c] . An oven‐dried two‐necked 250‐mL round bottom flask, equipped with a reflux condenser and connected to an argon inlet tube, was successively charged with 9.80 g (49.95 mmol, 1.0 equiv.)…”

Progress in Total Syntheses of Anti‐malignant Pleural Mesothelioma Compounds

“…In 2016, Opatz and coworkers reported the total synthesis of phenanthroindolizidine alkaloids including ( S )‐tylophorine, via a free‐radical cyclization in 49% overall yield over five linear steps (Scheme ) . 2,3‐Diphenylacylic acid 113 was prepared via condensation of commercially available veratraldehyde 112 and homoveratric acid 111.…”

Rapid entry to phenanthroindolizidine alkaloids via an acid-catalysed acyliminium ion-electrocyclization cascade

“…11,12 Specific highlighted synthetic advancements include the first total asymmetric synthesis of antofine using a chiral phase transfer catalyst (13 steps). 13 More recently an iterative Suzuki-Miyaura coupling strategy (9 steps), 14 and an enantioselective iodoamino-radical cyclization (6 steps), 15 have been documented. A large-scale synthetic route to racemic phenanthroindolizidines (7 steps), 16 and a rapid approach to seco-analogs via a palladium/indium aminochlorocarbonylation Friedel-Crafts strategy (5 steps) 17 are also notable advances.…”