Efficient One-Pot Access to Trisubstituted 2-Benzazepin-3-ones as Constrained Pseudopeptide Analogues and Privileged Scaffolds

摘要

Background: Benzazepines received great attention in the field of medicinal chemistrysince this scaffold has been recognized to belong to the important family of privileged templates.More specifically, the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) is used as a corestructure in a variety of constrained therapeutic peptide (turn) mimetics.Most of the synthetic approachestowards this template have focused on cyclizations which form the central 7-memberedazepine ring.Objective: Previous investigations in our group allowed an expansion of the substitution patternsin the 4-amino-benzazepin-3-one scaffold by introduction of methyl substituents at positions 4 and5 of the azepinone ring system, but also to 1-aryl substituted compounds. These were the onlytrisubstituted analogues obtained to date. To introduce an additional point of diversification andconformational constraint useful for peptide mimicry, one can use bifunctional substrates in theUgi reaction as reported in the present manuscript.Method: The 1-carboxamido-substituted Aba scaffold has been synthesized via the Ugi-3CR reactionstarting from N-Phth-protected 2-formyl-L-Phe-OH with a set of amine and isocyanide derivatives.The most suited reaction conditions were applied, involving preformation of the imine inMeOH (0.1 M) in the presence of anhydrous Na2SO4 during 2 hours at room temperature, followedby the addition of an equimolar quantity of isocyanide prior to heating the reaction mixture at80 °C for 20 hours, using sealed vial reaction conditions.Results: The substituted Aba scaffolds were isolated in moderate yields (and diastereomeric ratio).This is due to the requirement for a double N-phthaloyl protection of the bifunctional buildingblock, which prevents the use of an excess of amine reagent to drive the reaction conversion tocompletion, and some starting substrate always remains. Despite the moderate yields, the methodologyis efficient since it only requires a limited number of synthetic steps in a final one-pot reaction.In most cases, the diastereomers could be separated by preparative RP-HPLC or via silica gelcolumn chromatography. This is interesting from a medicinal chemistry point of view, since accessis provided to the individual diastereomers.Conclusion: We have developed an efficient and useful one-pot strategy to access 1-substituted 4-aminobenzazepinone (Aba) derivatives via the Ugi-3CR reaction. To the best of our knowledge,these scaffolds are only accessible through the presented methodology. The obtained structuralcomplexity, as well as the substitution versatility of these trisubstituted scaffolds, will allow theiruse in various biological applications.