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.
Highlights
The 2-substituted N-acyl-piperidine motif is present in a wide range of molecular architectures,[1] including those of biologically active compounds.[2]
Restricted rotation about the amide bond affects the chemical space sampled by the acyl substituent and can have an impact on molecular properties; the pharmacological influence of restricted rotation and atropisomerism is increasingly recognized in drug discovery.[3]
The 2-substituted N-acyl-piperidine motif can be found in a range of known molecular architectures and biologically active compounds
Summary
The 2-substituted N-acyl-piperidine motif is present in a wide range of molecular architectures,[1] including those of biologically active compounds.[2]. Low-temperature selective NOE assignment of rotamers, in combination with density functional theory (DFT) modeling, indicated the existence of a non-covalent interaction (NCI) between the ortho position of a 2-phenyl Nacyl-piperidine and the amide carbonyl, altering the amide conformation. These tools were used for de novo design and analysis of 5-acyl-6,7-dihydrothieno[3,2-c]pyridines with manipulated conformational preferences. Strategies for directing conformation are of interest in larger peptideand peptoid-based architectures
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