Synthesis of Multifunctional Spirocyclic Azetidines and Their Application in Drug Discovery

Abstract

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.

Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

“…Three of the synthesized spiro-β-lactams and their respective yields are presented in Scheme 5. [20] The conventional Staudinger reaction was also applied in the synthesis of four peptidomimetic spiroβ-lactams 24 (Scheme 6). [21] The molecules were obtained from the reaction between ketenes, generated from serine and threonine-derived morpholine derivatives 22 and aromatic imines 23.…”

“…The same research group extended the scope of the previous work by incorporating 5‐ to 7‐membered carbocyclic and heterocyclic rings into the spirocyclic structure, obtaining seventeen spiro‐β‐lactams 21 in yields ranging from 14% to 89%. Three of the synthesized spiro‐β‐lactams and their respective yields are presented in Scheme 5 [20] …”

Synthesis of 2,2‐Disubstituted Spirocyclic Pyrrolidines by Intramolecular Dieckmann Condensation

“…Since then, spirocyclic building blocks have been playing an important role in medicinal chemistry . In this context, we recently developed novel spirocyclic 3,3‐disubstituted pyrrolidines for drug design (Figure B) . Herein, we extend these studies to a new generation of spirocyclic 2,2‐disubstituted pyrrolidines (Figure C).…”

Strain‐Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones

“…[5] Despite these attractive features, there is a limited range of approaches available for the synthesis of spiro-azetidines. [6] Current strategies often involve lengthy syntheses of tethered cyclic molecules before invoking a further ring-closing step, typically through alkylation, [7] cycloaddition, [8] metal-catalyzed cyclization onto alkenes or alkynes, [9] or ring-closing metathesis reactions. [10] Another limitation is the difficulty in forming highly functionalized spiro-azetidines that would be amenable to additional structural diversification.…”