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Synlett 2004(9): 1449-1471  
DOI: 10.1055/s-2004-829540
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© Georg Thieme Verlag Stuttgart · New York

Design, Synthesis, Conformational Analysis and Application of Azabicyclo­alkane Amino Acids as Constrained Dipeptide Mimics

Laura Belvisia, Lino Colombob, Leonardo Manzonic, Donatella Potenzaa, Carlo Scolastico*a
a Università degli Studi di Milano, Dipartimento di Chimica Organica e Industriale and Centro Interdisciplinare Studi bio-molecolari e applicazioni Industriali CISI, Via Venezian 21, 20133 Milano, Italy
Fax: +39(02)50314072; e-Mail: carlo.scolastico@unimi.it;
b Università di Pavia, Dipartimento di Chimica Farmaceutica, Via Taramelli 12, 27100 Pavia, Italy
c CNR, Istituto di Scienze e Tecnologie Molecolari (ISTM), Via Venezian 21, 20133 Milano, Italy
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Publication History

Received 26 November 2003
Publication Date:
29 June 2004 (online)

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Abstract

In the field of peptidomimetics, major efforts have been focused on the design and synthesis of conformationally constrained compounds that mimic or induce reverse-turn motifs of peptides and proteins which are thought to play important roles in recognition and biological activity. In this regard, a particularly attractive class of compounds are the azabicyclo[X.Y.0]alkane dipeptide mimics. We present our efforts on the design, synthesis, and conformational analysis of a series of rigid surrogates of dipeptide units for applications within constrained peptide analogues, for employment as inputs for combinatorial science and biological applications. Several general and versatile synthetic approaches have been conceived to deliver a variety of enantiomerically pure azabicycloalkanes. All of these methodologies rely on the construction of a 5-, 6-, or 7-membered lactam on a preformed proline based nucleus. Different strategies were adopted to perform the key cyclization step: a) radical addition to an olefinic double bond, b) alkylation of a malonate enolate, c) ring-closing metathesis (RCM), and d) lactam bond formation.

  • 1 Introduction

  • 2 Synthesis of Azabicyclo[X.Y.0]alkane Amino Acids

  • 2.1 Radical Approach

  • 2.1.1 Synthesis of Cyclization Precursors

  • 2.2 Non-Radical Approaches

  • 2.2.1 Synthesis of 5,5-, 6,5- and 7,5-Fused Bicyclic Lactams via Horner-Emmons Olefination and Lactam Bond Formation

  • 2.2.2 Hydrophobic Appendages at C-3 Position via Malonate Alkylation or RCM

  • 2.2.3 Spiro and Trinuclear Dipeptide Mimics via Lactam Bond Formation or RCM

  • 2.2.4 Heteroatomic Side-Chain Functionalization via Lactam Bond Formation or RCM

  • 3 Conformational Analysis of Azabicycloalkane Amino ­Acids

  • 3.1 Molecular Modeling

  • 3.2 Discussion of 1H NMR and IR Data

  • 4 Incorporation of Azabicycloalkane Amino Acids into ­Bioactive Peptides

  • 4.1 Thrombin Inhibitors

  • 4.2 ανβ3-Integrin Ligands

Key words

peptidomimetic - peptide secondary structure - azabicycloalkane amino acids - biological activity - conformational analysis

24

Steward, J. J. P. MOPAC Version 60, F. J. Seiler Research Laboratory U. S. Air Force Academy CO 80840, QCPE 455.

34

The following activating agents were used in different conditions of temperature and solvent: DCC CIP/HOAt HATU EDC/HOAt DPPA and PyBop.

54

Molecular mechanics calculations were performed within the framework of MacroModel [12c] version 55 using the MacroModel implementation of the Amber all-atom force field [77] (denoted AMBER*). The torsional space of each molecule was randomly varied with the usage-directed Monte Carlo conformational search of Chang Guida and Still. [50] Ring-closure bonds were defined in the six- and seven-membered rings of the 6,5- and 7,5-fused bicyclic lactams, respectively. Amide bonds were included among the rotatable bonds. For each search at least 2000 starting structures for each variable torsion angle were generated and minimized until the gradient was less than 0.05 kJ/Åmol using the truncated Newton-Raphson method [78] implemented in MacroModel. Duplicate conformations and those with an energy greater than 6 kcal/mol above the global minimum were discarded. The nature of the stationary points individuated was tested by computing the eigenvalues of the second-derivative matrix.

56

Values of the Cα i -Cα ι + 3 distance (dα) of less than 7 Å were used to define the presence of a reverse-turn. The range 0±30° for the virtual torsion angle β (C i -Cα i+1 -Cα i+2 -N i+3 ) was taken to indicate a tight reverse-turn. [55] Assignment of a low-energy conformation to a particular turn type was made where possible on the basis of the ideal φ and ψ torsion angles (±30°) reported by Rose et al. [49] With regard to the intramolecular hydrogen bond parameters it was assumed that a hydrogen bond is formed when the distance between the acceptor and the hydrogen of the donor is smaller than 25 Å, the N-H···O bond angle is greater than 120°, and the H···O=C angle is greater than 90°.

58

The percentage of β-turn hydrogen bond resulting from Monte Carlo/Stochastic Dynamics (MC/SD) [79] simulations in GB/SA chloroform or water of dipeptide and tetrapeptide analogues of the indolizidinone ring system is generally lower than the corresponding value calculated by the MC/EM protocol. A better agreement between the two computational approaches is observed for the benzyl-substituted dipeptide mimic 59x and its longer derivatives. [59] It should be also noted that MC/SD simulations of some bicyclic systems showed convergence problems. NMR and IR spectroscopic studies of sequences of different length will play an important part in assessing the β-turn inducing potential of the bicyclic mimics.

60

Previous data [59] suggest that δNH < 62 ppm for a completely non-hydrogen-bonded peptide amide or carbamate proton.

62

The amide I region of the IR spectrum is predominately due to the C=O stretching vibration; 35y, 37y, 40y, and 42y have three different types of carbonyls: a secondary amide, a tertiary amide, and a carbamate. On the basis of model compounds, [80] they are known to give rise to three distinct absorbances: at 1680-1675 cm- 1 for the free secondary amide, at 1665 cm- 1 for the free tertiary amide of the 6,5-fused bicyclic lactam, and at 1730 cm- 1 for the free carbamate. Hydrogen bonding to the carbonyl shifts the band to lower frequency by 20-30 cm- 1.