Synthesis and Opiate Activity of Pseudo-Tetrapeptides Containing Chiral Piperazin-2-one and Piperazine Derivatives.

Abstract

Enantiomeric piperazin-2-one derivatives, N,N'-ethylene-bridged alanylphenylalanines (1a or 1b), were synthesized using (S)- or (R)-alanine and phenylalanine as starting materials, and were inserted into the second and third positions of enantiomeric pseudo-tetrapeptides (P1a- or P1b-OEt). The corresponding piperazine derivatives (1a- or 1b-sRed) obtained by selective BH3 reduction of the amide carbonyl groups of 1a or 1b were similarly inserted into the same positions of tetrapeptides (P1a- and P1b-sRed). Enantiomeric N,N'-ethylene-bridged tyrosyltyrosine derivatives (2a or 2b) obtained from (S)- or (R)-tyrosine were also inserted into the first and second positions of two pairs of enantiomeric tetrapeptides (P2a- and P2b-OEt or P'2a- and P'2b-OEt). The opiate activities of the eight peptides thus obtained were studied by use of the mouse vas deferens and the guinea pig ilcum assays in order to elucidate the structure-activity relationships of these peptides, especially with respect to stereochemistry.

Mastering chiral substituted 2-oxopiperazines

“…Yamashita et al 46,47 have developed a simple way to obtain chiral 1,3-disubstituted 2-oxopiperazines by acid-catalyzed lactamization of easily accessible 3,6-diaza-1,8-octanedioic acids of general structure 19, linear N,N 0 -ethylene-bridged bis-a-amino acids, in turn prepared by reacting two enantiomerically pure amino acids 17 and 18, and 1,2-dibromoethane (Scheme 1).…”

“…Acid-promoted cyclization of 19 proceeded with concomitant esterification to give piperazinones 20, which have been eventually used to obtain constrained mimics of Met-and Leu-Enkephalin, 46 biologically relevant pseudotetrapeptides 47 and dermorphin analogues. 48 The use of two different amino acids furnished a mixture of 2-oxopiperazines which could be separated by chromatography.…”

“…46,47 Thus, the development of convenient and easy methods for generating such compounds from two different amino acids represents a major aim with regard to the synthesis of chiral piperazinones.…”

New efficient enantioselective synthesis of 2-oxopiperazines: a practical access to chiral 3-substituted 2-oxopiperazines

“…Amongst all of the useful azalactams, 1,3,4-trisubstituted-2-oxopiperazines, which possess two stereogenic centres, one intracyclic (C 3 ) and one extracyclic ðC 0 1 Þ, are of particular interest as medicinal chemistry tools. Many syntheses of diastereomerically pure 1,3,4-trisubstituted-2-oxopiperazine have been reported, such as the lactamization of linear N,N 0 -bispeptides, [9][10][11] N 4 -C 5 bond formation 12 or N 1 -C 6 bond formation. 13 However, in these methods, the whole synthesis has to be repeated if access to diastereomers is desired.…”

Selective BH3-Reduction of Amide Carbonyl Groups of Lithium Salts of N-t-Butoxycarbonyl (S)-O-Benzyl Tyrosyl (S)-Proline and N,N′-Ethylene-Bridged Dipeptides

“…These amino alcohols 6 are obtained by the reduction of amide and carboxylic acid groups of the parent dipeptides. Recently, we inserted a chiral piperazine derivative 7 obtained by selective BH 3 reduction of the tertiary amide carbonyl group of the lithium salt of a piperazin-2-one derivative 7 ( N -benzyloxycarbonyl N, N' -ethylene-bridged alanyl-phenylalanine) and the parent piperazin-2-one derivative 7 as the units in the second and third positions of shorter dermorphin analogs (tetrapeptides). As a result, it was found in the guinea pig ileum and the mouse vas deferens assays of these analogs that the replacement of the piperazin-2-one ring with the piperazine ring influenced the activities of these analogs.…”