Synthesis of Cyclohexapeptides Containing Pro and Aib Residues.

Abstract

Cyclization reactions on hexapeptides containing several alpha-aminoisobutyric acid (= 2-amino-2-methylpropanoic acid; Aib) residues and the turn-promoting glycine (Gly) and proline (Pro) residues were investigated. Eight linear hexapeptides were synthesized, and their cyclization was attempted with various coupling reagents. The macrolactamization step proved to be difficult since only three hexapeptides could be cyclized. Two of these latter peptides were the linear precursors of the same cyclic hexapeptide, cyclo(Aib-Aib-Phe-Pro-Aib-Gly) (1). Surprisingly, they gave 1 in almost the same yield. Thus, 1 was obtained in 35% yield upon ring closure at the Phe/Pro site by using DEPBT as the coupling reagent, whereas the cyclization at the Aib/Phe site led to 1 in 28 and 34% yield by using PyAOP and DEPC, respectively (DEPBT = 3-[(diethoxyphosphoryl)oxy]-1,2,3-benzotriazin-4(3H)-one, PyAOP = (1H-7-azabenzotriazol-1-yloxy)tripyrroli-din-1-ylphosphonium hexafluorophosphate, DEPC = diethyl phosphorocyanidate). Another cyclic hexapeptide, cyclo(Aib-Aib-Gly-Aib-Pro-Gly) (2) was prepared in 34% yield when DEPC was used in the cyclization step. The solid-state conformation of 1 was established by X-ray crystallography. 2 Cyclization reactions on hexapeptides containing several Aib residues and the turn promoting Gly and Pro residues were investigated. Eight linear hexapeptides were synthesized and their cyclization was attempted using various coupling reagents. The macrolactamization step proved to be difficult since only three of these hexapeptides could be cyclized. Two of these peptides were the linear precursors of the same cyclic hexapeptide, cyclo(Pro-Aib-Gly-Aib-AibPhe) (1). Surprisingly, they gave 1 in almost the same yield. Thus, 1 was obtained in 35% yield upon ring closure at the Phe/Pro site using DEPBT as the coupling reagent, whereas the cyclization at the Aib/Phe site led to 1 in 28 and 34% yield by using PyAOP and DEPC, respectively. Another cyclic hexapeptide, cyclo(GlyAib-Pro-Gly-Aib-Aib) (2) was prepared in 34% yield when DEPC was used in the cyclization step. The solid-state conformation of 1 was established by X-ray crystallography.3

New 21‐ and 24‐atom Aib‐containing cyclopeptides

“…Next, the macrolactamisation ability of the organophosphorus reagent DEPC [35] was tested. This reagent showed high efficiency during the cyclisation of Aib-containing penta-and hexapeptides [12][13][14]18]. However, the cyclisation step leading to cyclic octapeptide 1 resulted only in a complex mixture of products.…”

“…We are interested in the design and synthesis of cyclic peptides containing C(2)-tetrasubstituted αamino acids in order to achieve a greater degree of conformational rigidity in a cyclopeptide structure. Our previous successful synthesis of cyclic hexapeptides containing several Aib residues [12][13][14] prompted us to investigate the cyclisation tendencies of longer Aib-containing peptides. The cyclisation of peptides consisting of more than seven amino acid residues is generally considered easier to accomplish in comparison with the cyclisation of small linear peptides (three to six amino acids) [15].…”

“…We have started our investigation with the synthesis and cyclisation of octapeptides, since there are, to the best of our knowledge, no literature reports about the synthesis, conformational analysis or isolation of cyclooctapeptides containing Aib residues. Having in mind that the cyclisation of hexapeptides bearing Leu-Aib-Phe or Gly-Aib-Aib tripeptide sequences, or alternating Aib and proteinogenic amino acid residues, resulted in conformations that were highly favourable for the cyclisation [12][13][14], we decided to incorporate such sequences also in our longer chains. The present work reports on the synthesis of two cyclic octapeptides cyclo(Leu-Aib-Phe-Aib-Gly-Aib-Phe-Aib) (1) and cyclo(Gly-Aib-Aib-Val-Aib-Leu-Aib-Phe) (2), and a cycloheptapeptide cyclo(Gly-Aib-Val-Aib-Leu-Aib-Phe) (3) (Figure 1).…”

“…H, 3 NH); 5.05 (br. s, PhCH 2 O); 4.32-4.30, 4.05-3.92, 3.79-3.31 (3m, 3 H α of Leu, Val and Phe); 2.97-2.94 (m, H β of Phe); 1.99-1.97 (m, H β of Val); 1.62-1.48 (m, 2 H β and H γ of Leu); 1.38, 1.35, 1.34, 1.30 (4s, 4 Me of 2 Aib and tBu); 0.90-0.79 (m, 2 Me of Leu, 2 Me of Val) 13. C-NMR (CDCl 3 ): 174.3, 173.8, 171.6, 171.1, 170.2 (5s, 4 CO (amide) and CO (ester)); 156.7 (s, CO(urethane)); 137.3, 136.7 (2s, 2 arom.…”

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

“…A wellknown example is alamethicin, [1][2][3][4][5] a membrane-channel forming peptaibol [6][7][8][9][10][11][12][13] with antibiotic activities. We have shown that the 'azirine/oxazolone method' [14][15][16][17][18] is a convenient approach for the synthesis of Aib-containing oligopeptides [15,[19][20][21][22][23][24] and peptaibols. [25][26][27][28][29][30][31][32] In addition to Aib, peptaibols may also contain the chiral α,α-disubstituted α-amino acid isovaline (Iva).…”