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

Abstract

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.

Synthesis of d-Fagomine and Its Seven- and Eight-Membered Higher-Ring Analogues, and the Formal Synthesis of (+)-Australine from l-Xylose-Derived Chiron

“…23 Its analytical data are in complete agreement with those of previous reports. 24 The synthesis of seven-membered iminoalditol 2 was also initiated from L-xylose-derived olefin 6. Phthalimido compound 15 was synthesized from 6 under Mitsunobu conditions.…”

Diastereoselective Carbamate Annulation for the Synthesis of 2,5‐Dideoxy‐2,5‐iminoglycitols

“…Although the carbamate annulation of alkenylamine 8 a proceeded smoothly, the attempted annulation of 8 b gave a complex mixture of products, despite full‐conversion of starting material, as observed by TLC. Purification of these products proved difficult and we reasoned that a mixture of pyrrolidines, piperidines, and O‐cyclised products formed, as previously observed when developing our PGF‐syntheses of piperidines from aldoses ,. Thus, the annulation mixture of 8 b was subjected to base hydrolysis, which gave a mixture of iminosugars in which DMDP ( 10 ) could be identified as the major product, but in a much lower yield over the two steps (16%) as compared to the 4,5‐ cis product 4 , which was isolated in 98% yield from the analogues 2 S isomer 8 a .…”

“…Our interest in iminosugars was sparked by a desire to develop efficient syntheses for these compounds that limit the use of protecting groups. To date, a protecting‐group‐free (PGF) approach has been successfully applied to the syntheses of mono‐hydroxymethyl substituted pyrrolidines (e. g., 1,4‐dideoxy‐1,4‐imino‐ d ‐xylitol, 3 ) with high over‐all yield and stereoselectivity, and also for the syntheses of piperidines (e. g., DGJ, 2 ), and deoxygenated derivatives …”

“…Key in these synthetic strategies was the use of a PGF Vasella‐reductive amination reaction and an I 2 ‐mediated carbamate annulation . However, for the synthesis of piperidines, avoiding protecting groups was challenging and on occasion, mixtures of products were formed …”

Preparation of 1,6-di-deoxy-d-galacto and 1,6-di-deoxy-l-altro nojirimycin derivatives by aminocyclization of a 1,5-dicarbonyl derivative

“…Different approaches have been explored in the past years to address this challenge. Some works reported the syntheses of 1-deoxynojirimycin and its isomers employing as starting materials substrates from the chiral pool such as carbohydrates [23][24][25] or amino acids [26,27]. Other strategies started instead from different open chain precursors and were based on chemoenzymatic [28,29] or asymmetric reactions such as dihydroxylation [30], aldol reaction coupled with a reductive amination [31] or aminohydroxylation [32] transformations.…”