Elsevier

Tetrahedron

Volume 65, Issue 25, 20 June 2009, Pages 4923-4929
Tetrahedron

Convenient synthesis of C-terminal di- and tri-peptide amides from N-protected dipeptidoylbenzotriazoles

https://doi.org/10.1016/j.tet.2009.02.070Get rights and content

Abstract

N-Protected dipeptidoylbenzotriazoles react with aqueous ammonia to give dipeptide primary amides (77–98%) and with N-unprotected α-amino amides to afford tripeptide primary amides (82–86%).

Introduction

Naturally occurring peptides are essential for many cellular functions.1, 1(a), 1(b) Peptides modified at the C-terminus are substrates or inhibitors for a variety of proteolytic enzymes.2 The incorporation of a primary amide at the C-terminus is common modification:3 around 50% of biologically active peptides contain such functionality.4, 4(a), 4(b) Peptidyl α-carboxamides are especially widely distributed in animals and elicit vital physiological effects:1a examples include oxytocin,5 lutenizing hormone releasing hormone (LHRH),6 neurokinins,7 and vasopressin and gastrine.8

Peptidyl α-carboxamides are also found within protease inhibitors. For example, the pseudo pentapeptide l-682,679 (1) is a highly potent and selective inhibitor of HIV-1 protease (IC50=0.42 nM, Fig. 1) (11) and l-685,458 (2) is a potent inhibitor of γ-secretase (IC50=17 nM) of potential therapeutic benefit in the treatment of Alzheimer's disease and other neurological disorders (Fig. 1).9, 9(a), 9(b), 9(c) Cathepsin L (EC 3.4.22.16) is an example of the papain-like cysteine proteases, which are ubiquitously distributed in the lysosomes of cells with prominent roles in nonspecific intracellular protein breakdown,10 and physiologically important extra-cellular functions.11

Recently, an Nω-nitroarginine-containing dipeptide amide [l-ArgNO2-l-Lys-NH2 (ll) (3)] and [d-Lys-d-ArgNO2-NH2 (dd) (4)] (Fig. 2)12 showed a remarkable selectivity (hundreds- to thousands-fold) for inhibition of the neuronal isozyme of nitric oxide synthase (nNOS) over two other isozymes.13, 13(a), 13(b) This nNOS selectivity has implications in the potential treatment of strokes,14 migraine headaches,15 and Alzheimer's disease.16 Moreover, l-Leu-x-amides (where x is any amino acid residue) support growth of a leucine auxotroph as well as the free peptide.17

N-Acylbenzotriazoles are neutral efficient coupling reagents for N-acylation,18, 18(a), 18(b), 18(c), 18(d) C-acylation,19, 19(a), 19(b), 19(c) and O-acylation.20, 20(a), 20(b) N-(Aminoacyl)benzotriazoles prepared from N-protected α-amino acids were successfully utilized for synthesis of di-, tri-, and tetrapeptides.21, 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h) As part of the synthetic strategy for the modification of peptides at the C-terminus, we now report the synthesis of C-terminal protected dipeptides 10al, (10a+10a′),22 (10e+10e′) and tripeptide amides 13a,b and (13a+13a′) by treating N-protected dipeptidoylbenzotriazoles 9al, (9a+9a′), and (9e+9e′) with aqueous ammonia or with unprotected α-amino carboxamides 12a,b, respectively.

Section snippets

Synthesis of N-protected dipeptidoylbenzotriazoles

Treating Cbz-protected amino acids 5ae and (5b′) with 4 equiv of benzotriazole and 1 equiv of SOCl2 in THF or CH2Cl2 at 20 °C for 2 h, following the published procedure,21(a), 21(c) gave N-(Cbz-α-aminoacyl)benzotriazoles 6ae and (6b′) in 78–95% (Scheme 1). Peptide coupling was achieved by the reaction of 6ae and (6b′) with unprotected amino acids 7ag and (7a′) in aqueous acetonitrile in the presence of Et3N for 10–40 min.21b After washing with 6 M HCl, the resulting dipeptides 8al, (8a+8a′), and

Summary

In summary, we have developed a convenient and efficient approach for a broad range of chirally pure dipeptide primary amides (average yield 88%), by treating the corresponding N-protected dipeptidoylbenzotriazoles with aqueous ammonia. The approach was extended to the preparation of tripeptide primary amides (average yield 83%) by using some of the same substrates with N-unprotected α-amino amides. These results, coupled with the simplicity of isolation and purification procedures, make this

General

All mps are uncorrected. NMR spectra were recorded on a Varian Gemini (300 MHz) spectrometer in DMSO-d6 with TMS for 1H (300 MHz) and 13C (75 MHz) as an internal reference. IR spectra were recorded on a Unicam SP-1200 infrared spectrophotometer using KBr Wafer technique. N-Cbz-amino acids and amino acids were purchased from Fluka (Buchs, Switzerland) and Acros (Suwanee, GA, USA), were used without further purification. Elemental analyses were performed on a Carlo Erba-1106 instrument. Optical

Acknowledgements

The authors gratefully acknowledge Professor Alan R. Katritzky for his generous help by allowing us to implement this work in his labs and also for his valuable suggestions.

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