Design, Synthesis, and Applications of 3-Aza-6,8-Dioxabicyclo[3.2.1]Octane-Based Scaffolds for Peptidomimetic Chemistry

Abstract

During the last three decades numerous peptides have been introduced in the treatment of several diseases, though, due to their low bioavailability, non-peptide compounds have been preferred for the generation of new therapeutic agents presenting a peptide as lead candidate. Thus, much effort has been devoted towards the development of isosteres capable to mimic either backbone or side chain structures, in order to improve biological stability and potency, and to reduce the complexity of the lead peptide. Such process has taken advantage of the synthesis of compounds using combinatorial library methodologies, which have achieved a major role in drug discovery, and recently, diversity-oriented synthesis has gained interest from many organic and medicinal chemists. Our group has focused on the development of a new class of bicyclic molecular scaffolds named BTAa (Bicycles from Tartaric acid and Amino acids), having a 3-aza-6,8-dioxa-bicyclo[3.2.1]octane as core structure, and amino acid side chain functionalities on ­stereodefined positions. These molecules are good templates for peptidomimetic design, and examples varying substituents, ­stereochemistry and ring-size have been reported using different synthetic strategies. Moreover, scaffolds derived from amino ketones and sugar derivatives (BTKa) have been synthesised on solid phase, thus exploring new methodologies for the generation of focused libraries of peptidomimetics. These compounds have been applied as dipeptide isosteres by the introduction in a cyclic oligopeptide chymotripsin inhibitor, and it has been demonstrated that BTAa scaffolds having the carboxylic group in 7-endo position can be considered as mimetics of β-turns in cyclic and linear peptides. New synthetic methodologies for proline-like bicyclic scaffolds have been developed for the production of different species of reverse-turn inducers, and BTAa scaffolds as γ/δ-amino acids have been used as monomers for the synthesis of oligomeric structures.

• 1 Introduction

• 2 3-Aza-6,8-dioxabicyclo[3.2.1]octane-Based Scaffolds

• 2.1 Formal COOH Shift

• 2.2 BTKa and 7-endo-BTKa

• 2.3 [4.2.1]- and [5.2.1]-Sized Scaffolds

• 2.4 Towards Polycyclic Scaffolds

• 2.5 Chemical Stability

• 2.6 Structural Features

• 3 Bicyclic Scaffolds for Combinatorial Chemistry

• 3.1 Ketone on Resin

• 3.2 Sugar Moiety on Resin

• 3.3 Amine on Resin

• 3.4 Parallel Synthesis of Amides

• 4 Bicyclic Scaffolds in Foldamer Design

• 5 Bicyclic Scaffolds as Reverse-Turn Inducers

• 5.1 BTAa as Reverse-Turn Mimetics in Cyclic Peptides

• 5.2 BTAa as Reverse-Turn Mimetics in Linear Model Peptides

• 5.3 Model Peptides for BGS Scaffolds as Proline Mimetics

• 6 Concluding Remarks

Key words

peptidomimetics - solid-phase synthesis - peptides - conformational analysis - combinatorial chemistry

References and Notes

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30

TBDMS-protected 3-amino-1,2-propanediol was obtained in high purity and yield after a two-step process involving reaction of benzylamine with TBDMS-protected glycidol in the presence of LiNTf₂, and subsequent hydrogenation of the benzylic group.

34

Crystallographic data (excluding structure factors) for the structure 110 in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 286087. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].