Molecular Recognition and Cocrystallization of Methylated and Halogenated Fragments of Danicalipin A by Enantiopure Alleno-Acetylenic Cage Receptors

Enantiopure (P)4- and (M)4-configured
alleno-acetylenic cage (AAC) receptors offer
a highly defined interior for the complexation and structure elucidation
of small molecule fragments of the stereochemically complex chlorosulfolipid
danicalipin A. Solution (NMR), solid state (X-ray), and theoretical
investigations of the formed host–guest complexes provide insight
into the conformational preferences of 14 achiral and chiral derivatives
of the danicalipin A chlorohydrin core in a confined, mostly hydrophobic
environment, extending previously reported studies in polar solvents.
The conserved binding mode of the guests permits deciphering the effect
of functional group replacements on Gibbs binding energies ΔG. A strong contribution of conformational energies toward
the binding affinities is revealed, which explains why the denser
packing of larger apolar domains of the guests does not necessarily
lead to higher association. Enantioselective binding of chiral guests,
with energetic differences ΔΔG293 K up to 0.7 kcal mol–1 between diastereoisomeric
complexes, is explained by hydrogen- and halogen-bonding, as well
as dispersion interactions. Calorimetric studies (ITC) show that the
stronger binding of one enantiomer is accompanied by an increased
gain in enthalpy ΔH but at the cost of a larger
entropic penalty TΔS stemming
from tighter binding.