Chiral Induction in Quinoline-Derived Oligoamide Foldamers: Assignment of Helical Handedness and Role of Steric Effects

Abstract

Chiral groups attached to the end of quinoline-derived oligoamide foldamers give rise to chiral helical induction in solution. Using various chiral groups, diastereomeric excesses ranging from 9% to 83% could be measured by NMR and circular dichroism. Despite these relatively weak values and the fact that diastereomeric helices coexist and interconvert in solution, the right-handed or left-handed helical sense favored by the terminal chiral group could be determined unambiguously using X-ray crystallography. Assignment of chiral induction was performed in an original way using the strong tendency of racemates to cocrystallize, and taking advantage of slow helix inversion rates, which allowed one to establish that the stereomers observed in the crystals do correspond to the major stereomers in solution. The sense of chiral helical induction was rationalized on the basis of sterics. Upon assigning an Rs or Ss chirality to the stereogenic center using a nomenclature where the four substituents are ranked according to decreasing sizes, it is observed that Rs chirality always favors left-handed helicity and Ss chirality favors right-handed helicity (P). X-ray structures shed some light on the role of sterics in the mechanism of chiral induction. The preferred conformation at the stereocenter is apparently one where the bulkiest group should preferentially point away from the helix, the second largest group should be aligned with the helix backbone, and the smallest should point to the helix.