Resolution and Determination of the Absolute Configuration of a Twisted Bis-Lactam Analogue of Tröger’s Base: A Comparative Spectroscopic and Computational Study

The first reported twisted bis-lactam,
a racemic Tröger’s
base (TB) analogue (2), was resolved into its enantiomers
on a chiral stationary phase HPLC column. The absolute configuration
of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated
vibrational circular dichroism (VCD) and electronic circular dichroism
(ECD) spectra. The absolute configuration of (−)-2 was determined by comparing experimental and calculated electronic
circular dichroism (ECD) spectra. The corresponding theoretical spectra
were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G­(d,p) level of theory.
The absolute configuration of (+)-2 was also determined
to (R,R)-2 by anomalous
X-ray diffraction (AXRD) in a chiral space group P212121 using Cu-irradiation resulting
in a very low Flack parameter of −0.06(3), despite the heaviest
element being an oxygen atom, thus unambiguously confirming the results
from the spectroscopic studies. We conclude that, for the Tröger’s
base (TB) analogue (2), we may rank the reliability of
the individual methods for AC determination as AXRD ≫ VCD >
ECD, while the synergy of all three methods provides very strong confidence
in the assigned ACs of (+)-(R,R)-2 and (−)-(S,S)-2.