The Efficient Preparation of Di- and Tripeptides by CouplingN-(Cbz- or Fmoc-α-aminoacyl)benzotriazoles with Unprotected Amino Acids

Abstract

N-(Cbz-or Fmoc-a-aminoacyl)benzotriazoles 2 and Nprotected peptidoylbenzotriazoles 6 are coupled in aqueous acetonitrile solution with free amino acids or dipeptides to prepare: (i) 22 chirally pure dipeptides 5a-v (in an average yield of 82%) from N-(Cbz-or Fmoc-a-aminoacyl)benzotriazoles 2 and unprotected amino acids, (ii) five chiral tripeptides 7a-e (in an average yield of 75%) from N-protected peptidoylbenzotriazoles 6 and unprotected amino acids, (iii) one chiral tripeptide 7g (62%) from N-(Cbz-or Fmoc-a-aminoacyl)benzotriazole 2a and the free dipeptide 8. In all, N-(Cbz-or Fmoc-a-aminoacyl)benzotriazole derivatives of 17 of the 20 naturally occurring amino acids were used, including those containing the following unprotected side chain functionalities: alcoholic -OH (Ser), indole -NH (Trp), imidazole -NH, phenolic -OH (Tyr), -CONH 2 (Gln, Asn), -SH (Cys), -CO 2 H (Glu, Asp), and -S-S (Cystine). Support for the complete retention of chirality was obtained by parallel experiments involving D-Ala, L-Ala, and DL-Ala for the preparation of di-and tripeptides. This and other evidence for chiral integrity was supported by NMR and HPLC analyses.

A convenient synthesis of chiral 1,2,4-oxadiazoles from N-protected (α-aminoacyl)benzotriazoles

“…26b Efficient preparations of functionalized N-(Z or Fmoc-α-aminoacyl)benzotriazoles derived from Tyr, Trp, Met, Cys, and Gln were followed by advantageous coupling with unprotected amino acids (L-Ala, DL-Ala, L-Phe, DL-Phe). 27 We herein demonstrate facile reactions for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles derived from chiral α-amino acids utilizing N-(Boc, Z, and Fmoc-α-aminoacyl)benzotriazoles. We also report the preparation of 3,5-substituted-1,2,4-oxadiazoles utilizing Nacylbenzotriazoles in order to show the general applicability of the method.…”

“…28 We have now made N-protected diastereomers of peptidolylbenzotriazoles 10a-f from 1a,b,e,f and amino acid 8a-d. The extent of racemization during 1,2,4-oxadiazole ring-formation was then checked by NMR and HPLC of products 11a-f from reactions of 10a-f with 2a (Scheme 5).…”

A Facile Synthesis of C-terminal Neoglycopeptides: Incorporation of Urea Moiety between Sugars and Peptides Employing Curtius Rearrangement

“…Fmoc-peptide acids (Katritzky et al, 2006) were prepared by the reaction of Fmoc-amino acid with freshly prepared Bis-TMS-amino acid (Tantry et al, 2002). They were converted to corresponding acid azides via mixed anhydride.…”

Efficient preparation of azodye-labeled aminoxy acids and peptides

“…23 Melting points were determined on a capillary point apparatus equipped with a digital thermometer and are uncorrected. NMR spectra were recorded in acetone-d 6, CDCl 3 or DMSO-d 6 with TMS for 1 H (300 MHz) and 13 C (75 MHz) as an internal reference. Elemental analyses were performed on a Carlo Erba-1106 instrument.…”

“…10a-c Aminoxy peptides also feature strong intramolecular hydrogen bonds between adjacent residues in peptidomimetic foldamers 11 and may provide useful labels. N-Acylbenzotriazoles are easily prepared, non-hygroscopic, chirally stable analogs of acid halides that are relatively insensitive to water, 12,13 and are therefore advantageous for N-, O-, C-, or S-acylation; [12][13][14][15][16][17][18] especially where the corresponding acid chlorides are unstable or difficult to prepare. 19,20 We previously acylated amino acids and amines with N-(4-arylazobenzoyl)-1H-benzotriazoles 21 and we recently synthesized azodye-labeled peptides in good yields by a milder procedure than published methods.…”