Synthesis of a β-strand mimetic based on a pyridine scaffold |
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Authors: | David Blomberg Jan Kihlberg |
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Affiliation: | a Organic Chemistry, Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden b AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden |
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Abstract: | A synthetic route to a 2,4-disubstituted pyridine as a potential β-strand mimetic has been developed and applied in the synthesis of a tripeptidomimetic of Leu-Gly-Gly. The pyridine scaffold replaces the central glycine, and is substituted with analogues of leucine and glycine in positions 4 and 2, respectively. 2-Fluoro-4-iodopyridine was chosen as the functionalized scaffold and was substituted with protected leucinal in position 4 via a Grignard exchange reaction using iso-propyl magnesium chloride. The glycine moiety was introduced in position 2 via a nucleophilic aromatic substitution reaction (SNAr) facilitated by microwave irradiation. The synthetic sequence involved 12 steps with an overall yield of 7%. |
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Keywords: | β-Strand mimetic 2-Aminopyridine Grignard exchange reaction Nucleophilic aromatic substitution |
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