CHIRAL SEPARATION OF 4,4-DISUBSTITUTED PIPERIDINYL SUBSTANCE P ANTAGONISTS

Abstract

The chiral separation of fourteen Substance P antagonists, substituted at a benzylic carbon to generate a chiral centre, was investigated using Chiracel OD-H and Chiralpak AD stationary phases. The nature of an N-substituent, distant from the chiral centre, was found to modulate separation selectivity. Aromatic substitution on the benzyl group also affected separation selectivity, but to a lesser degree. Some complementary character between Chiracel OD-H and Chiralpak AD was seen, but selection of the optimal phase did not appear predictable. The effect of temperature was also unanticipated, with some compounds showing the expected decrease of separation selectivity with temperature, whereas, an example of an improvement in separation selectivity with temperature to give an entropically controlled separation was also observed. This serves to highlight the complex nature of enantioselective interactions using chiral polymers and suggests that, given an unknown compound in this series, adequate separation conditions are difficult to predict.

ACKNOWLEDGMENT

The authors wish to thank Christophe Derrien and Paloma Fernandez-Diaz for their technical assistance, and Peter Hunt for modelling aromatic electron densities.