Modulation of Cis-Trans Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines

Abstract

2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in nearly 500 currently available structures, and present in at least 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate using NMR studies and modelling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives that the amide cis-trans equilibrium is affected by intramolecular hydrogen bonding between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the cis- or trans-amide conformation; thereby compounds with a tailored conformational ratio were prepared as proven by NMR studies. Analysis of the available X-ray data of a variety of the published N-acyl-piperidine containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that the reported directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures.

2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in nearly 500 currently available structures, and present in at least 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate using NMR studies and modelling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives that the amide cis-trans equilibrium is affected by intramolecular hydrogen bonding between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the cis- or trans-amide conformation; thereby compounds with a tailored conformational ratio were prepared as proven by NMR studies. Analysis of the available X-ray data of a variety of the published N-acyl-piperidine containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that the reported directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures.

2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in nearly 500 currently available structures, and present in at least 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate using NMR studies and modelling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives that the amide cis-trans equilibrium is affected by intramolecular hydrogen bonding between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the cis- or trans-amide conformation; thereby compounds with a tailored conformational ratio were prepared as proven by NMR studies. Analysis of the available X-ray data of a variety of the published N-acyl-piperidine containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that the reported directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures.