Background: Benzazepines received great attention in the field of medicinal chemistry
since 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 core
structure in a variety of constrained therapeutic peptide (turn) mimetics.Most of the synthetic approaches
towards this template have focused on cyclizations which form the central 7-membered
Objective: Previous investigations in our group allowed an expansion of the substitution patterns
in the 4-amino-benzazepin-3-one scaffold by introduction of methyl substituents at positions 4 and
5 of the azepinone ring system, but also to 1-aryl substituted compounds. These were the only
trisubstituted analogues obtained to date. To introduce an additional point of diversification and
conformational constraint useful for peptide mimicry, one can use bifunctional substrates in the
Ugi reaction as reported in the present manuscript.
Method: The 1-carboxamido-substituted Aba scaffold has been synthesized via the Ugi-3CR reaction
starting 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 in
MeOH (0.1 M) in the presence of anhydrous Na2SO4 during 2 hours at room temperature, followed
by the addition of an equimolar quantity of isocyanide prior to heating the reaction mixture at
80 °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 building
block, which prevents the use of an excess of amine reagent to drive the reaction conversion to
completion, and some starting substrate always remains. Despite the moderate yields, the methodology
is 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 gel
column chromatography. This is interesting from a medicinal chemistry point of view, since access
is 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 structural
complexity, as well as the substitution versatility of these trisubstituted scaffolds, will allow their
use in various biological applications.