Solution‐Phase Synthesis of Aib‐Containing Cyclic Hexapeptides

Abstract

The 18-membered Aib-containing cyclohexapeptides, cyclo(-Gly-Aib-Aib-Gly-Aib-Phe-) (22), cyclo(-Gly-Aib-Phe(2Me)-Gly-Aib-Aib-) (24a), cyclo(-Gly-Phe(2Me)-Aib-Gly-Aib-Aib-) (24b), and cyclo(-Gly-Phe(2Me)-Aib-Gly-Aib-Phe-) (25), have efficiently been synthesized by solution-phase techniques. The linear precursors 1a-1d were prepared by combining the 'azirine/oxazolone method' for incorporation of alpha,alpha-disubstituted alpha-amino acids (Aib, Phe(2Me)) into the peptide chains by classical peptide coupling methods for segment condensations. Deprotection of the amino and carboxy termini of 1a-1d, followed by cyclization with DEPC as the coupling reagent, gave the above-mentioned cyclic hexapeptides 22, 24a, 24b, and 25 in good yields (26-57%). The solid-state conformations of the linear hexapeptides 1d, 16 and 27, and of the cyclohexapeptides 22 and 25 have been established by X-ray crystallography.

Synthesis of Macrocyclic Lactones via Ring Transformation of 4‐(ω‐Hydroxyalkyl)‐1,3‐oxazol‐5(4H)‐ones

“…These results extend the use of 1,3‐oxazol‐5(4 H )‐ones as reactive building blocks and intermediates in organic synthesis. Intramolecular reactions with a nucleophilic group attached to the amino acid residue at C(2) are the key step in the preparation of cyclopeptides and cyclodepsipeptides containing α , α ‐disubstituted α ‐amino acids, in which the 1,3‐oxazol‐5(4 H )‐ones are formed as intermediates. On the other hand, the ‘direct amide cyclization’ of 2‐acylamino acid N , N ‐dimethylamides of type 21 with a ω ‐amino‐ or ω ‐hydroxyalkyl substituent in the α ‐position leads to lactams and lactones, respectively, via an intermediate 1,3‐oxazol‐5(4 H )‐one bearing the nucleophile‐containing side chain at C(4).…”

“…This reaction, called ‘direct amide cyclization’, has been used extensively for the synthesis of Aib‐containing cyclodepsipeptides . The same concept, under different reaction conditions, proved to be successful for the preparation of Aib‐containing cyclopeptides .…”

Synthesis of Cyclohexapeptides Containing Pro and Aib Residues

“…This result was very surprising since we have previously successfully cyclized several Aib-containing hexapeptides at an Aib/Gly site in good yields (45-57%) [5] [13]. We assume that the Pro residue at position 5 of the sequence makes the peptide more rigid, thereby completely preventing cyclization.…”

“…Since we have successfully cyclized hexapeptides containing several Aib residues and one or two Gly residues [5], the aim of this work was to investigate the cyclization tendencies of hexapeptides containing Aib and Pro residues. Pro is believed to prefer turn-forming cis-peptide bonds, which should facilitate the ring closure.…”

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 .…”