Chiral separation of 4,4-disubstituted piperidinyl substance P antagonists

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