The Development of a Modular Synthesis of Teraryl-Based α-Helix Mimetics as Potential Inhibitors of Protein–Protein Interactions

Dedicated to Professor Manfred T. Reetz on the occasion of his 70th birthday.

Abstract

In this account we describe the evolution of our successful efforts to develop a modular synthesis of teraryl-based α-helix mimetics as potential inhibitors of protein–protein interactions. At the center of our convergent synthetic route are 2-substituted 4-iodophenyl triflates as core fragments, which by consecutive Suzuki couplings with 5-substituted pyridin-3-ylboronic acids are converted into the desired teraryl compounds. With our strategy it should be possible to synthesize all 5670 variants of the teraryl α-helix mimetics using a set of 2 × 18 building blocks featuring the side chains of the 18 proteinogenic amino acids that are of relevance for protein–protein interactions.

1 Introduction and Concept

1.1 Protein–Protein Interactions

1.2 α-Helix Mimetics

1.3 Linear Synthesis of α-Helix Mimetics

2 Modular Synthetic Route to Teraryls

2.1 Core Fragments

2.2 Pyridinylboronic Acids

3 Conclusion and Outlook

Key words

cross-coupling - Grignard reactions - inhibitors - peptides - pyridines

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