Stereoselective Synthesis 0f (3S)- and (3R)-3-Hydroxy-3-(2,6-Dimethyl-4-Hydroxyphenyl)Propanoic Acid and its Incorporation into a Cyclic Enkephalin Analogue

Abstract

2’,6’-dimethyl substitution of the Tyr1 residue of opioid agonist peptides and deletion of the N-terminal amino group have been shown to represent a general structural modification to convert opioid peptide agonists into antagonists [1]. This conversion required the syntheses of opioid peptide analogues containing 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) in place of Tyr1. The cyclic enkephalin analogue Dhp-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2 is a potent µ opioid antagonist and a less potent δ and κ antagonist [2]. An analogue of this peptide with β-methylated Dhp, (3S)-3-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(3S)-Mdp], in place of Dhp showed increased antagonist activity at all three receptors, whereas an analogue containing β-isopropyl-substituted Dhp [(3R)-Idp] turned out to be a mixed κ agonist/µ antagonist [3]. To further investigate the SAR at the β position of Dhp in the cyclic analogue, we examined the effect of substituting β-hydroxylated Dhp on the opioid activity profile. This required the development of stereoselective syntheses of (3S)- and (3R)-3-hydroxy-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(3S)-and (3R)-Hdp].