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Synlett 2014; 25(09): 1202-1214
DOI: 10.1055/s-0033-1340740
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© Georg Thieme Verlag Stuttgart · New York

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

Melanie Trobe
a   Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria   Fax: +43(316)87332402   Email: breinbauer@tugraz.at
,
Martin Peters
a   Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria   Fax: +43(316)87332402   Email: breinbauer@tugraz.at
b   Fraunhofer Project Group Electrochemical Energy Storage, Fraunhofer Institute of Chemical Technology ICT, Parkring 6, 85748 Garching b. München, Germany
,
Sebastian H. Grimm
a   Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria   Fax: +43(316)87332402   Email: breinbauer@tugraz.at
,
Rolf Breinbauer*
a   Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, 8010 Graz, Austria   Fax: +43(316)87332402   Email: breinbauer@tugraz.at
› Author Affiliations
Further Information

Publication History

Received: 24 November 2013

Accepted after revision: 08 January 2014

Publication Date:
02 April 2014 (online)

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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