Aza-Crown Macrocycles as Chiral Solvating Agents for Mandelic Acid Derivatives

A series of new chiral macrocycles containing the trans-1,2-diaminocyclohexane (DACH) subunit and arene- and
oligoethylene
glycol-derived spacers has been prepared in enantiomerically pure
form. Four of the macrocycles have been characterized by X-ray crystallography,
which reveals a consistent mode of intramolecular N–H···N
hydrogen bonding and conformational variations about the N-benzylic bonds. Most of the macrocycles were found to differentiate
the enantiomers of mandelic acid (MA) by 1H NMR spectroscopy
in CDCl3; within the series of macrocycles tested, enantiodiscrimination
was promoted by (i) a meta-linkage geometry about
the arene spacer, (ii) the presence of naphthalene- rather than phenylene-derived
arene spacers, and (iii) increasing length of the oligoethylene glycol
bridge. 1H NMR titrations were performed with optically
pure MA samples, and the data were fitted to a simultaneous 1:1 and
2:1 binding model, yielding estimates of 2:1 binding constants between
some of the macrocycles and MA enantiomers. In several cases, NOESY
spectra of the MA:macrocycle complexes show differential intramolecular
correlations between protons adjacent to the amine and carboxylic
acid groups of the macrocycles and MA enantiomers, respectively, thus
demonstrating geometric differences between the diastereomeric intermolecular
complexes. The three most effective macrocycles were employed as chiral
solvating agents (CSAs) to determine the enantiomeric excess (ee)
of 18 MA samples over a wide ee range and with very high accuracy
(1% absolute error).