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We introduce a design principle to stabilize helically chiral structures from an achiral tetrasubstituted [2.2]paracyclophane by integrating it into a macrocycle. The [2.2]paracyclophane introduces a three-dimensional perturbation into a nearly planar macrocyclic oligothio-phene. The resulting helical structure is stabilized by two bulky substituents installed on the [2.2]paracyclophane unit. The increased enantiomerization barrier enabled the separation of both enantiomers. The synthesis of the target helical macrocycle 1 involves a sequence of halogenation and cross-coupling steps and a high-dilution strategy to close the macrocycle. Substituents tuning the energy of the enantiomerization process can be introduced in the last steps of the synthesis. The chiral target compound 1 was fully characterized by NMR spectroscopy and mass spectrometry. The absolute configurations of the isolated enantiomers were assigned by comparing the data of circular dichroism spectroscopy with TD-DFT calculations. The enantiomerization dynamics was studied by dynamic HPLC, variable temperature 2D exchange spectroscopy and supported by quantum-chemical calculations.
PMID: 30632363 [PubMed - as supplied by publisher]