1-Oxa-2,6-Diazaspiro[3.3]heptane as a New Potential Piperazine Bioisostere – Flow-Assisted Preparation and Derivatisation by Strain-Release of Azabicyclo[1.1.0]butanes

The development of novel strained spiro heterocycles (SSHs) as bioisosteres for aromatic or non-strained aliphatic rings is highly sought after for improving drug design. Their high molecular rigidity and predictable vectorization can enhance drug-likeness, target selectivity and clinical success. Towards this goal, 1-oxa-2,6-diazaspiro[3.3]heptane (ODASE) is reported as a novel potential SSH-bioisostere. We demonstrate through theoretical studies the potential of this strained spiro heterocycle to act as a bioisostere for piperazine. We have developed its synthesis from the highly strained azabicyclo[1.1.0]butyl intermediate through a robust and mild flow technology-assisted two-step protocol. Its tolerance and stability towards medicinally relevant N-functionalisation protocols are studied, as well as its mild reduction to the C3-aminoalkylazetidinol motif found in the anti-cancer drug cobimetinib.