No abstract

Three novel peptide analogues containing a residue of the hindered amino acid dibenzylglycine (Dbg) were prepared. Although [Glp6, Dbg7]‐substance P‐(6–11) possessed no substance P agonist or antagonist activity, [Dbg4, Leu5]‐enkephalinamide was 8.4 times as potent as [Leu5]‐enkephalinamide in isolated tissue assays for opioid activity, and proved highly δ‐selective (300‐fold). [N,N‐Di‐allyl Tyr1, Dbg4, Leu5]‐enkephalinamide was a moderately potent opioid antagonist, but showed little μ or δ selectivity. Dbg residues were incorporated using 2‐trifluoromethyl‐4,4‐dibenzyl‐oxazolin‐5‐one. Problems were experienced in coupling even dipeptides to peptides containing amino‐terminal Dbg, and the ‘encapsulation’ of any dialkylglycine residue at the centre of a tripeptide before further coupling offered the best synthetic strategy for future work in such analogues.

A short route for the preparation of 2‐trifluoromethyl‐4,4‐dialkyloxazolin‐5‐ones (Tdo's), useful reagents for the addition of dialkylglycine residues to the N‐terminus of peptides, was examined. 2‐Trifluoromethyl‐oxazolin‐5(4H)‐one proved too unstable for a general substrate for alkylation, but 2‐trifluoromethyl‐4‐alkyl‐oxazolin‐5(2H)‐ones, readily available from protein amino acids, could be alkylated to Tdo's in the presence of mild base using active alkyl halides. 2‐Trifluoromethyl‐4,4‐dibenzyl‐oxazolin‐5‐one, prepared in this way as a stable crystalline solid, coupled well with protein amino acid esters or amides, confirming the utility of reagents of this type. Of a number of alkylations examined, only in the case of 2‐trifluoromethyl‐4‐isobutyl‐oxazolin‐5(2H)‐one using isobutenyl iodide was the isomeric 2‐trifluoromethyl‐2‐isobutenyl‐4‐isobutyl‐oxazolin‐5‐one observed at all; in this case, it predominated. Ammonolysis of Tdo's gave Tfa‐dialkylglycine amides, N‐deprotection of which using NaBH4 unexpectedly gave 2‐trifluoromethyl‐4,4‐dialkylimidazol‐5‐ones. The partition coefficients (P) of a series of N‐acetyldialkylglycinamides were measured. Comparison with the values obtained for similar derivatives of the corresponding protein amino acids showed a close correlation between the increasing hydrophobicity of the second side chain of the dialkylglycine derivative and the log P values obtained.

A short route for the preparation of 2-trifluoromethyl4,4-dialkyloxazolin-5ones (Tdo's), useful reagents for the addition of dialkylglycine residues t o the Nterminus of peptides, was examined. 2-Trifluoromethyl-oxazolin-5(4H)-one proved too unstable for a general substrate for alkylation, but 2-trifluoromethyl-4-alkyl-oxazolin-5(2H)-ones, readily available from protein amino acids, could be alkylated t o Tdo's in the presence of mild base using active alkyl halides. 2-Trifluoromethyl-4,4-dibenzyl-oxazolin-5-one, prepared in this way as a stablecrystalline solid, coupled well with protein amino acid esters or amides, confirming the utility of reagents of this type. Of a number of alkylations examined, only in the case of 2-trifluoromethyl-4-isobutyl-oxazolin-5(2H)-one using isobutenyl iodide was the isomeric 2-trifluoromethyl-2-isobutenyl-4-isobutyloxazolin-5-one observed at all; in this case, it predominated. Ammonolysis of Tdo's gave Tfa-dialkylglycine amides, N-deprotection of which using NaBH4 unexpectedly gave 2-trifluoromethyl-4,4-dialkylimidazol-5-0nes. The partition coefficients (P) of a series of N-acetyldialkylglycinamides were measured. Comparison with the values obtained for similar derivatives of the corresponding protein amino acids showed a close correlation between the increasing hydrophobicity of the second side chain of the dialkylglycine derivative and the log €' values obtained.In a detailed investigation of the preparation of peptides containing ap-di-n-propylglycine (I), it was found that this hindered residue is difficult to incorporate by normal coupling methods. However, it can be efficiently introduced using 2-trifluoromethyl-4,4-di~z-propyloxazolin-5-one, indicating that 2-trifluoromethyl-4,4-dialkyl-oxazolin-5-ones (Tdo's) are likely t o be generally useful reagents for preparing peptides containing dialkylglycine residues. As a short route to Tdo's, we have ?Reference 1 refers to Parts 1 and 2 ; Part 1 reviews the background to the work described here.

Three novel peptide analogues containing a residue of the hindered amino acid dibenzylglycine (Dbg) were prepared. Although [Glp6, Dbg7] -substance P-(6-11) possessed n o substance P agonist or antagonist activity, [Dbg4, Leu5]enkephalinamide was 8.4 times as potent as [Leu'] -enkephalinamide in isolated tissue assays for opioid activity, and proved highly 6-selective (-300-fold).[N, N-Di-ally1 Tyr' , Db$, Leu'] -enkephalinamide was a moderately potent opioid antagonist, but showed little /* or 6 selectivity. Dbg residues were incorporated using 2-trifluorornethy1-4,4-dibenzyl-oxazolin-S-one. Problems were experienced in coupling even dipeptides t o peptides containing amino-terminal Dbg, and the 'encapsulation' of any dialkylglycine residue at the centre of a tripeptide before further coupling offered the best synthetic strategy for future work in such analogues.