Applications and Limitations of the I2‑Mediated Carbamate Annulation for the Synthesis of Piperidines: Five- versus Six-Membered Ring Formation

• Published in: Journal of organic chemistry 2013-10, Vol.78 (19), p.9791-9802
• Main Authors: Corkran, Hilary M, Munneke, Stefan, Dangerfield, Emma M, Stocker, Bridget L, Timmer, Mattie S. M
• Format: Article
• Language: English
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemistry; Carbamates - chemistry; Cyclization; Fucose - chemistry; Imino Pyranoses - chemistry; Molecular Structure; Piperidines - chemical synthesis; Piperidines - chemistry; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo401512h

A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d-galactose as starting materials, the transformations into the piperidines 1-deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy-d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis.