Synthesis and bioassay of LHRH‐antagonists with N‐Ac‐d‐O‐phenyltyrosine and N‐Ac‐d‐3‐(2‐dibenzofuranyl)alanine in position 1

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Abstract
N‐Ac‐d‐O‐phenyltyrosine was synthesized via the corresponding azlactone. Resolution of the dl methyl esters was achieved by Subtilisin Carlsberg. Treatment with palladium(II) acetate in trifluoroacetic acid converted N‐Ac‐d‐O‐phenyltyrosine into N‐Ac‐d‐3‐(2‐dibenzofuranyl)alanine. These two amino acids were incorporated instead of N‐Ac‐d‐2‐Nal into position 1 of the LHRH‐antagonist (N‐Ac‐d‐2‐Nal1, d‐pClPhe2, d‐3‐Pal3, c‐PzACAla5, d‐PiCLyS6, ILys8,d‐Ala10)‐LHRH. The more rigid N‐Ac‐d‐3‐(2‐dibenzofuranyl)alanine was structurally more effective than N‐Ac‐d‐O‐phenyltyrosine; the AOAs for the corresponding analogs were 82 and 38%, respectively, at 0.5 μg. Replacement of c‐PzACAla in position 5 by O‐phenyltyrosine significantly decreased potency.