A set of novel SO2-containing azabicyclo[3.n.1]alkanes has been synthesized by the double-Mannich annulation of of the corresponding monocyclic S-ketones. These compounds have been rationally designed as 3D-shaped, conformationally restricted SO2-containing building blocks for drug discovery.

The synthesis of multifunctional spirocycles was achieved from common cyclic carboxylic acids (cyclobutane carboxylate, cyclopentane carboxylate, l-proline, etc.). The whole sequence included only two chemical steps-synthesis of azetidinones, and reduction into azetidines. The obtained spirocyclic amino acids were incorporated into a structure of the known anesthetic drug Bupivacaine. The obtained analogues were more active and less toxic than the original drug. We believe that this discovery will lead to a wide use of spirocyclic building blocks in drug discovery in the near future.

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