Pyrrolidine and piperidine based chiral spiro and fused scaffolds via build/couple/pair approach

Abstract

A versatile stereoselective diversity oriented synthetic pathway to the possible spiro and fused diverse heterocyclic small molecules is described. The strategy involved the “build–couple–pair” approach involving an S_NAr, Michael addition and Mannich reaction on chiral acyl bicyclic lactams 2a/b, followed by a cyclization onto the inbuilt scaffold electrophile, thereby leading to asymmetric fused and spirocyclic nitrogen heterocycles. A “post-pair” phase has been incorporated to generate more polar compounds. We used Principal Component Analysis (PCA) and polar moment of inertia to evaluate the shape-space diversity of our scaffolds with respect to a commercial database and observed extraordinary diversity within the scaffold network. We further calculated the polar surface area (PSA) of our molecules which is an indicator for drug cell permeability.