In a phenotypic screening campaign, the development of novel and modular synthetic procedures for the synthesis of compound collections with stereochemical and skeletal diversity is considered one of the most important elements. In this context, biomacromolecules possess large three-dimensional environments with defined binding surfaces; as such, they interact only with molecules that have complementary three-dimensional structures. In this context, a tandem diastereoselctive and modular protocol for the construction of a range of diverse collections of chromenopyrroles employing build/couple/pair one-pot combination of Ugi-4CR, nucleophilic acyl substitution, decarboxylation, [3+2]-cycloaddition and 1,3-sigmatropic rearrangement cascade using a variety of readily available carboxylic acids, amines, isocynaide and alkenes, is described. Our methodology features a novel method for intramolecular azomethine ylide generation followed by <i>in situ</i> intramolecular [3+2]-cycloaddition. This process generates in a diastereoselective manner, two new chiral carbon-carbon bonds and more than six points of diversity. Furthermore, this tandem process was also expanded toward the synthesis of asymmetric chromenopyrroles using amino acids as chiral auxiliary. Moreover, post-pairing reactions were carried out to increase the diversity of our pilot compound collections.

Unprecedented one-pot diasteroselective/asymmetric route for the access of diverse collections of chromeno[4,3-a]pyrrole scaffolds

255th National Meeting (2018)

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