Asymmetric [3+2] Annulation Approach to 3-Pyrrolines: Concise Total Syntheses of (−)-Supinidine, (−)-Isoretronecanol, and (+)-Elacomine

• Published in: Angewandte Chemie International Edition 2015-11, Vol.54 (46), p.13706-13710
• Main Authors: Chogii, Isaac, Njardarson, Jon T.
• Format: Article
• Language: English
• Subjects: annulation; Asymmetry; Chemical reactions; Compatibility; Cyclization; Effectiveness; heterocycles; Imines; Indoles - chemical synthesis; Indoles - chemistry; Molecular Structure; Nucleophiles; Organic chemistry; Precursors; Pyrroles - chemistry; Pyrrolizidine Alkaloids - chemical synthesis; Pyrrolizidine Alkaloids - chemistry; reaction mechanisms; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Stereoisomerism; synthetic methods; total synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201506559

An asymmetric [3+2] annulation reaction to form 3‐pyrroline products is reported. Upon treatment with lithium diisopropylamide, readily available ethyl 4‐bromocrotonate is deprotonated and trapped with Ellman imines selectively at the α‐position to yield enantiopure 3‐pyrroline products. This new method is compatible with aryl, alkyl, and vinyl imines. The efficacy of the method is showcased by short asymmetric total syntheses of (−)‐supinidine, (−)‐isoretronecanol, and (+)‐elacomine. This novel annulation approach also works for an aldehyde, thus providing access to a 2,5‐dihydrofuran product in a single step from simple precursors. By modifying the structure of the carbanion nucleophile, an asymmetric vinylogous aza‐Darzens reaction can be realized. Caught in a trap: In the title reaction deprotonated ethyl 4‐bromocrotonate is selectively trapped with Ellman imines, at the α‐position, to yield enantiopure 3‐pyrroline products. The efficacy of the method is showcased by short asymmetric total syntheses of (−)‐supinidine, (−)‐isoretronecanol, and (+)‐elacomine (see scheme).