Modular, Automated Synthesis of Spirocyclic Tetrahydronaphthyridines from Primary Alkylamines

Alex Cresswell, Qiao Cao, Josh Tibbetts, Gail Wrigley, Adam Smalley

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1 Citation (SciVal)

Abstract

Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8- naphthyridines (“1,8-THNs”), in addition to their regioisomeric 1,6 THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular SNAr N arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C–N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer’s MC4R antagonist PF-07258669.
Original languageEnglish
Article number215
JournalCommunications Chemistry
Volume6
Issue number1
Early online date4 Oct 2023
DOIs
Publication statusE-pub ahead of print - 4 Oct 2023

Bibliographical note

Funding Information:
This work was supported by the Engineering and Physical Sciences Research Council (EP/X026566/1). A.J.C. thanks the Royal Society for a University Research Fellowship (UF150533), the University of Bath for a Global Doctoral Scholarship (Q.C.) and both AstraZeneca and UCB for generous financial support. The authors gratefully acknowledge the technical staff within Chemistry at the University of Bath for technical support and assistance in this work, including the Material and Chemical Characterisation Facility (MC²) ( https://doi.org/10.15125/mx6j-3r54 ). We also acknowledge Dr Michelle Garnsey at Pfizer for helpful discussions.

Publisher Copyright:
© 2023, Springer Nature Limited.

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