Modular, Automated Synthesis of Spirocyclic Tetrahydronaphthyridines from Primary Alkylamines

Qiao Cao; Josh Tibbetts; Gail L. Wrigley; Adam P. Smalley; Alexander J. Cresswell

doi:10.1038/s42004-023-01012-2

Modular, Automated Synthesis of Spirocyclic Tetrahydronaphthyridines from Primary Alkylamines

Qiao Cao, Josh Tibbetts, Gail L. Wrigley, Adam P. Smalley, Alexander J. Cresswell^*

^*Corresponding author for this work

Chemistry

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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 language	English
Article number	215
Number of pages	7
Journal	Communications Chemistry
Volume	6
DOIs	https://doi.org/10.1038/s42004-023-01012-2
Publication status	Published - 4 Oct 2023

Bibliographical note

Acknowledgments:
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.

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title = "Modular, Automated Synthesis of Spirocyclic Tetrahydronaphthyridines from Primary Alkylamines",

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{\textquoteright}s MC4R antagonist PF-07258669.",

author = "Qiao Cao and Josh Tibbetts and Wrigley, {Gail L.} and Smalley, {Adam P.} and Cresswell, {Alexander J.}",

note = "Acknowledgments: 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.",

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AU - Cresswell, Alexander J.

N1 - Acknowledgments: 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.

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N2 - 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.

AB - 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.

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DO - 10.1038/s42004-023-01012-2

M3 - Article

SN - 2399-3669

VL - 6

JO - Communications Chemistry

JF - Communications Chemistry

M1 - 215

ER -

Modular, Automated Synthesis of Spirocyclic Tetrahydronaphthyridines from Primary Alkylamines

Abstract

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