Synthesis of Z‐Protected Aib‐ and Phe(2Me)‐Containing Pentapeptides and Their Crystal Structures

Abstract

A series of pentapeptide derivatives containing alpha,alpha-disubstituted alpha-amino acids have been prepared by a combination of the 'azirine/oxazolone method' and segment condensations. X-Ray crystal-structure determinations of the molecular structures confirmed the presence of helical conformations stabilized by beta-turns of type III or III'. Pentapeptides containing (R)-Phe(2Me) form a right-handed helix, whereas those containing (S)-Phe(2Me) adopt a left-handed helical structure.

Synthesis of Cyclopentapeptides with Three to Five Aib Units

“…-The synthesis of the pentapeptides Z-Gly-AibAcb-Aib-Gly-OMe (4a, Acb = 1-aminocyclobutanecarboxylic acid) and Z-Gly-AibPro-Aib-Aib-N(Me)Ph (4b) have been described recently [12]. They were deprotected in the usual way: saponification of 4a with LiOH.H 2 O in THF/H 2 O/MeOH gave the peptide acid Z-Gly-Aib-Acb-Aib-Gly-OH (5a, 96%), and subsequent hydrogenolysis, either with H 2 /Pd/C in MeOH or with HCO 2 NH 4 /Pd/C in MeOH, led to H-Gly-Aib-Acb-Aib-Gly-OH (6a) in quantitative and 95% yield, respectively.…”

“…They were deprotected in the usual way: saponification of 4a with LiOH.H 2 O in THF/H 2 O/MeOH gave the peptide acid Z-Gly-Aib-Acb-Aib-Gly-OH (5a, 96%), and subsequent hydrogenolysis, either with H 2 /Pd/C in MeOH or with HCO 2 NH 4 /Pd/C in MeOH, led to H-Gly-Aib-Acb-Aib-Gly-OH (6a) in quantitative and 95% yield, respectively. Selective hydrolysis of 4b with 3N HCl in THF/H 2 O at room temperature yielded Z-Gly-Aib-Pro-Aib-Aib-OH (5b, 70%) [12]. The latter was deprotected at the N-terminus to give H-Gly-Aib-Pro-Aib-Aib- OH (6b) quantitatively (H 2 /Pd/C) and in 67% yield (HCO 2 NH 4 /Pd/C), respectively.…”

Helical screw‐sense preferences of peptides based on chiral, Cα‐tetrasubstituted α‐amino acids

“…The available structural information on the conformational preferences of (αMe)Phe points to a close similarity to the screw‐sense bias shown by (αMe)Leu. The occurrence of 66 (αMe)Phe residues is documented in 42 X‐ray diffraction structures of linear derivatives and peptides . Only one example of the fully extended and one of the semi ‐extended conformations were reported .…”

Synthesis and Solid State Conformation of Tetrapeptide Amides Containing two Aib and two (αMe)Phe Residues – Use of Enantiomerically Pure 2‐Benzyl‐2‐methyl‐2H‐azirin‐3‐amines as (αMe)Phe‐Synthons

“…Thus, the preparation of racemic synthons for Iva [60] and (αMe)Phe [61] was elaborated in our group and their convenient use in peptide synthesis has been demonstrated. [20,21,30,32,[62][63][64][65] Furthermore, analogous optically active 3-amino-2H-azirines of type 1 -3 (Fig. 1) bearing a chiral substituent at the amino group were obtained after chromatographic separation of the corresponding diastereomeric mixtures.…”