An Improved Procedure for the Synthesis of Enaminones - Dimer Building Blocks in β-Strand Mimetics

Andreas Larsson; Sara Spjut; Jan Kihlberg; Fredrik Almqvist

doi:10.1055/s-2005-872094

PAPER

An Improved Procedure for the Synthesis of Enaminones - Dimer Building Blocks in β-Strand Mimetics

Andreas Larsson^a, Sara Spjut^a, Jan Kihlberg*^a,b, Fredrik Almqvist*^a
^a Department of Chemistry, Organic Chemistry, Umeå University, 901 87 Umeå, Sweden
^b Medicinal Chemistry, AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden
Fax: +46(90)138885; e-Mail: jan.kihlberg@chem.umu.se; e-Mail: fredrik.almqvist@chem.umu.se;

Abstract

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Abstract

@-Tides have been shown to have the same characteristics as a peptide in the β-strand conformation and to have the ability to self-associate into dimeric β-sheets. Aza-cyclohexaenaminones, obtained by condensation of a protected azacyclohexa-3,5-dione and amino acid esters, are the key building-blocks in the synthesis of @-tides. An improved three-step synthetic sequence to these enaminones has been developed that takes advantage of microwave-assisted chemistry in two of the steps to enhance the reaction rates. It was also found that the enaminone building blocks can be obtained by direct condensation of the aza-cyclohexa-3,5-dione with amino acid esters, without prior activation of the diketone. Multivariate design was used to optimize this microwave-assisted condensation, resulting in a short reaction time (300 s) and high yields (67-94%).

Key words

enaminones - β-strand mimetics - microwave-assisted synthesis - multivariate design - optimization

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References

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