Heterocyclic Merging of Stereochemically Diverse Chiral Piperazines and Morpholines with Indazoles

Chemistry. 2023 Oct 2;29(55):e202301888. doi: 10.1002/chem.202301888. Epub 2023 Aug 29.


We report a heterocyclic merging approach to construct novel indazolo-piperazines and indazolo-morpholines. Starting from chiral diamines and amino alcohols, novel regiochemically (1,3 and 1,4) and stereochemically diverse (relative and absolute) cohorts of indazolo-piperazines and indazolo-morpholines were obtained within six or seven steps. The key transformations involved are a Smiles rearrangement to generate the indazole core structure and a late-stage Michael addition to build the piperazine and morpholine heterocycles. We further explored additional vector diversity by incorporating substitutions on the indazole aromatic ring, generating a total of 20 unique, enantiomerically pure heterocyclic scaffolds.

Keywords: chiral morpholines; chiral piperazines; fused heterocycles; indazoles; scaffold merging.