title: Modulation of 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 approximately 500 currently available structures, and present in nearly 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 density functional theory modeling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures.
authors.affiliation: †Department of Chemistry, Imperial College London, London SW7 2AZ, U.K.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lanyon-Hogg
authors.affiliation: †Department of Chemistry, Imperial College London, London SW7 2AZ, U.K.
authors.forename: Markus
authors.initials: M
authors.lastname: Ritzefeld
authors.affiliation: †Department of Chemistry, Imperial College London, London SW7 2AZ, U.K.
authors.forename: Naoko
authors.initials: N
authors.lastname: Masumoto
authors.affiliation: ‡National Heart and Lung Institute, Imperial College London, London SW7 2AZ, U.K.
authors.forename: Anthony I
authors.initials: AI
authors.lastname: Magee
authors.affiliation: †Department of Chemistry, Imperial College London, London SW7 2AZ, U.K.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Rzepa
authors.affiliation: †Department of Chemistry, Imperial College London, London SW7 2AZ, U.K.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
mesh_terms: D000577:Amides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D011789:Quantum Theory; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D000577:Amides; D011725:Pyridines; D013876:Thiophenes