Design, Synthesis, NMR-Solution and X-Ray Crystal Structure ofN-Acyl-γ-dipeptide Amides That Form aβII′-Type Turn

Abstract

Conformational analysis of g-amino acids with substituents in the 2-position reveals that an N-acyl-gdipeptide amide built of two enantiomeric residues of unlike configuration will form a 14-membered H-bonded ring, i.e., a g-peptidic turn (Figs. 1 ± 3). The diastereoselective preparation of the required building blocks was achieved by alkylation of the doubly lithiated N-Boc-protected 4-aminoalkanoates, which, in turn, are readily available from the corresponding (R)-or (S)-a-amino acids (Scheme 1). Coupling two such g-amino acid derivatives gave N-acetyl and N-[(tert-butoxy)carbonyl] (Boc) dipeptide methyl amides (1 and 10, resp.; Fig. 2, Scheme 2); both formed crystals suitable for X-ray analysis, which confirmed the turn structures in the solid state ( Fig. 4 and Table 4). NMR Analysis of the acetyl derivative 1 in CD 3 OH, with full chemical-shift and coupling assignments, and, including a 300-ms ROESY measurement, revealed that the predicted turn structure is also present in solution ( Fig. 5 and Tables 1 ± 3). The results described here are yet another piece of evidence for the fact that more stable secondary structures are formed with a decreasing number of residues, and with increasing degree of predictability, as we go from a-to b-to g-peptides. Implications of the superimposable geometries of the actual turn segments (with amide bonds flanked by two quasi-equatorial substituents) in a-, b-, and g-peptidic turns are discussed.

Design and Synthesis of γ‐Dipeptide Derivatives with Submicromolar Affinities for Human Somatostatin Receptors

“…In a previous paper we have shown that simple N ‐acyl‐γ‐dipeptide amides that resemble a βII′ turn of an α‐peptide can be designed to form a turn structure in solution (NMR) and in the solid state (X‐ray) 1. 2 To see whether such a turn could also be used to mimic a peptide, the biological activity of which rests upon a turn structure carrying functionalized side chains, we have now synthesized compounds 1 a – g (Scheme ), with the side chain of tryptophan in the γ 2 position of the first and of lysine in the γ 4 position of the second γ‐amino acid, and have tested their affinities for the human somatostatin receptors hsst 1–5 3–6…”

“…The synthesis of γ‐dipeptide derivatives 1 commenced with the N ‐Boc‐γ‐lactams 2 and 3 (Boc= tert ‐butoxycarbonyl), readily available from the corresponding commercial ( R )‐Ala and ( S )‐Lys acids by known procedures 1. 7 Ring opening (with the Lys derivative after change of side‐chain protection, → 4 ), and esterification with Me 3 Si(CH 2 ) 2 OH provided the ( R )‐Boc‐γ 4 ‐hhAla and Boc‐γ 4 ‐hhLys(Bn 2 ) esters, which were doubly deprotonated and alkylated with 1‐mesitylenesulfonyl‐3‐bromomethylindole and MeI to give the unlike γ 2,4 ‐amino acid derivatives 5 and 7 , respectively.…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…Reduction of the azide and hydrolysis of the lactam affords (S,S)-a-methyl pregabalin (S,S)-(173) [143]. Alkylation, under a range of conditions, of the enolates of methyl N-protected g-amino esters (174) affords the syn-2,4-disubstituted products (175), through 1,3-asymmetric induction (Scheme 14.49) [144,145].…”

Homologs of Amino Acids and Explorations into the Worlds of β‐ and γ‐Peptides

“…In the six years of research on peptides consisting of homologated proteinogenic amino acids we [54][55][56][57][58][59] and others [60][61][62][63][64] have embarked for a trip into an entirely new world, in which almost everything we know about a-peptides had to be disregarded. The homologous peptides form secondary structures, such as helices and turns, with as few as two to six residues [10,12,21,42,58], whereas α-peptides require more than ten residues for helix and turn formation under the same conditions (MeOH solution, NMR detection); parallel [6,21,64] and antiparallel [21,42,58] sheets and stacks (of cyclic ßpeptides [8,22,36,45]) are found in solution and in the solid state ( Figure 6).…”

“…The homologous peptides form secondary structures, such as helices and turns, with as few as two to six residues [10,12,21,42,58], whereas α-peptides require more than ten residues for helix and turn formation under the same conditions (MeOH solution, NMR detection); parallel [6,21,64] and antiparallel [21,42,58] sheets and stacks (of cyclic ßpeptides [8,22,36,45]) are found in solution and in the solid state ( Figure 6). All of these secondary structures can be designed by choosing the "right" substitution pattern (constitution) and (relative and absolute) configuration of the residues in the ß-and γ-peptidic chains, and MD calculations (GROMOS96 program, including solvent) furnish all the experimentally determined structures within a couple of nanoseconds ("in silico") [18,31,38].…”