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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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Received 26 November 2003
Publikationsdatum:
29. Juni 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

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