Diastereoselective Spirocyclization: Entry to Spirocyclic Diketopiperazines

We report a novel approach to access spirocyclic compounds containing a diketopiperazine (DKP) motif fused on a pyrrolidine ring. The shared spirocyclic carbon is at the ketone oxidation state, bearing two carbon-nitrogen bonds, one of which is introduced stereoselectively during the cyclization event. The reaction proceeds through an acid-catalyzed cyclization of a pendent chiral aminoamide unit onto a 2,3-dehydroproline amide moiety with up to >98:2 diastereoselectivity. We have demonstrated the generality of this methodology and its applicability to access chemically diverse DKP-containing structures. The extent of stereoinduction and how it varies according to the bulkiness of the substituent on the pendent aminoamide is demonstrated through a diverse substrate set. This methodology gives access to an underexplored spirocyclic diketopiperazine motif that may be useful in identifying new bioactive molecules.