Bridged bicyclic amino acids have high potential applicability as self-organized, conformationally constrained synthetic building blocks that do not require assistance from hydrogen bond formation. We systematically investigated the intrinsic conformational propensities of dipeptides of bridged bicyclic β-amino acids by means of accelerated molecular dynamics simulation and density functional theory (DFT) calculations in methanol, chloroform, and water. While the main-chain conformation, represented by φ and θ values, is fixed by the nature of the bicyclic ring structure, rotation of the C-terminal carbonyl group (ψ) is also restricted, converging to one or two minima. In endo-type dipeptides, in which the two N- and C-terminal amides are spatially close to each other, the C-terminal amide plane is placed horizontally. In exo-type dipeptides, in which the two amides are on opposite sides of the ring plane, the C-terminal carbonyl group can take two types of positions: either parallel/antiparallel with the N-terminal carbonyl or beneath the bicyclic ring, forcing the amide NHMe moiety to lie outside of the ring. We also examined the cis-trans preference of model bicyclic amides. Although the parent amides exhibit cis-trans equilibrium without any preference, addition of a methyl group on one of the bridgehead positions tips the equilibrium towards trans.
Keywords: DFT calculation; amide cis-trans equilibrium; bicyclic β-amino acid; conformation; molecular dynamics simulation; proline.
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