Late-Stage Functionalization by Chan–Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors |
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| Authors: | Henry Robinson Steven A Oatley James E Rowedder Pawel Slade Dr Simon J F Macdonald Dr Stephen P Argent Prof?Dr Jonathan D Hirst Thomas McInally Prof?Dr Christopher J Moody |
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| Institution: | 1. School of Chemistry, GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham, Jubilee Campus, Triumph Road, Nottingham, NG7 2TU UK;2. School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD UK;3. Medicinal Science & Technology, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY UK |
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| Abstract: | A late-stage functionalization of the aromatic ring in amino acid derivatives is described. The key step is a copper-catalysed diversification of a boronate ester by amination (Chan–Lam reaction) that can be carried out on a complex β-aryl-β-amino acid scaffold. This not only considerably extends the substrate scope of amination partners, but also delivers an array of potent and selective integrin inhibitors as potential treatment agents of idiopathic pulmonary fibrosis (IPF). This versatile chemical strategy, which is amenable to high-throughput-array protocols, allows the installation of pharmaceutically valuable heteroaromatic fragments at a late stage by direct coupling to NH heterocycles, leading to compounds with drug-like attributes. It thus constitutes a useful addition to the medicinal chemist's repertoire. |
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| Keywords: | β-amino acids C?N coupling integrin antagonists late-stage functionalization medicinal chemistry |
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