Elsevier

Tetrahedron Letters

Volume 54, Issue 1, 2 January 2013, Pages 72-79
Tetrahedron Letters

Bis(amino amides) derived from natural amino acids as chiral receptors for N-protected dicarboxylic amino acids

https://doi.org/10.1016/j.tetlet.2012.10.099Get rights and content

Abstract

A family of bis(amino amides) derived from natural amino acids has been synthesized and tested for the NMR enantiodiscrimination, as chiral receptors, of some N-protected dicarboxylic amino acids. The influence of the amino acid side chain is an important parameter to obtain good enantiodiscrimination. The binding between bis(amino amides) and N-protected dicarboxylic amino acids has been thoroughly studied by ESI-MS and NMR spectroscopic methods as well as by molecular modeling.

Introduction

Selective receptors for chiral molecules have many technological, industrial, biomedical, and environmental applications.1 Thus, artificial chiral receptors for carboxylic acids are important as many relevant biomolecules contain this functionality. Dicarboxylates, implicated in different biomolecular processes, are particularly important targets in this regard.2

Some polyamine receptors are able to interact with dicarboxylic acids in both organic solvents and aqueous media.3 Although most dicarboxylic acids present in biological systems are chiral, only a few enantioselective receptors for chiral dicarboxylic acids have been described.4 Peptidomimetic structures have been designed for multiple purposes, including their use as chiral receptors, and we have been recently involved in the preparation and study of pseudopeptides with the general structure 4.5 In this context, some of those compounds have shown to be efficient chiral shift agents (CSAs) for the enantiodifferentiation of mandelic acid and some related guests, including relevant aryl propionic acids.6 Futhermore, in the literature several host compounds with bisamide functionalities have been developed and studied as CSAs,7 for amines,7(a), 7(b) derivatized amino acids,7(c), 7(d) and carboxylic acids.7(e), 7(f), 4(q)

Taking this into account, we considered the synthesis of new bis(amino amides) derived from natural amino acids, with the general structure 4 as effective chiral solvating agents for N-protected dicarboxylic amino acids. An aliphatic spacer with five methylene groups was selected for our study after some molecular modeling in order to develop the appropriate ditopic receptor, and several starting amino acids were considered.

Section snippets

Results and discussion

Open-chain pseudopeptides 4 derived from l-phenylalanine, l-tryptophan, and l-proline, were prepared from the corresponding N-Cbz protected amino acid through the initial formation of their activated N-hydroxysuccinimide esters (2), coupling with 1,5-pentanediamine, and final N-deprotection, following reported procedures (Scheme 1).8 Overall yields, after the final deprotection step, were in the range of 80%. These chiral bis(amino amides) were fully characterized by 1H NMR, 13C NMR, IR,

Conclusions

In conclusion, we have synthesized a new family of CSAs based on bis(amino amide) ligands derived from natural amino acids and demonstrated that they are good receptors for N-protected dicarboxylic amino acids. The formation of diastereomeric complexes is fast and quantitative, being possible the analysis in situ using NMR spectrometry. A multidisciplinary study using mass spectrometry, NMR, and molecular modeling, has allowed us to identify the structural factors responsible for the

Materials and reagents

All reagents were used as purchased from commercial suppliers without further purification. Chiral α-amino amides were synthesized as previously described7 while all the N-protected amino acids were commercially available. The NMR spectroscopic experiments were carried out on a 500 or 300 MHz for 1H and 13C NMR, respectively. The chemical shifts are reported in ppm using trimethylsilane (TMS) as a reference. FTIR spectra were acquired with a MIRacle single-reflection ATR diamond/ZnSe accessory.

General procedure for the preparation of N-hydroxysuccinimide esters of amino acids7

Acknowledgments

Financial support from Ministerio de Ciencia y Tecnología (CTQ2011-28903-C02-01), Fundación Caixa Castelló-Bancaixa (P1-1B-2009-58), and Generalitat Valenciana PROMETEO 2012/020 is acknowledged. N.C. thanks Bancaixa for a fellowship. The authors are grateful to the Serveis Centrals d’Instrumentació Científica (SCIC) of the Universitat Jaume I for the spectroscopic facilities.

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