We report an operationally simple approach to access spirocyclic compounds containing diketopiperazines unit fused with a proline ring. The shared spirocyclic carbon between the two rings is at ketone oxidation state and it carries two carbon-nitrogen bonds. The reaction proceeds through an acid catalyzed cyclization of a chiral pendent aminoamide unit onto N-protected 2,3-dehydroproline amide, with good diastereoselectivity. Spirocyclic compounds are of great interest since they offer a unique three dimensionality that can be utilized to target orthogonally position binding vectors and to improve physicochemical properties of a drug candidate by increasing sp3 character. In this presentation, we will talk about the mechanistic understanding of this specific ring cyclization event, as well as the applicability of general synthetic utility of this method to access chemically diverse DKP structures.

Diastereoselective spirocyclization; entry to diketopiperazines (DKP) containing spirocyclic compounds

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ACS Fall 2022

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