Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

Joseph C. Abell; Christian P. Bold; Laia Vicens; Tom Jentsch; Noelia Velasco; Jasper L. Tyler; Robert N. Straker; Adam Noble; Varinder K. Aggarwal

doi:10.1021/acs.orglett.2c04095

Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

Joseph C. Abell, Christian P. Bold, Laia Vicens, Tom Jentsch, Noelia Velasco, Jasper L. Tyler, Robert N. Straker, Adam Noble, Varinder K. Aggarwal^*

^*Corresponding author for this work

Research output: Contribution to journal › Letter (Academic Journal) › peer-review

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Abstract

The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1′-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

Original language	English
Pages (from-to)	400-404
Number of pages	5
Journal	Organic Letters
Volume	25
Issue number	2
Early online date	10 Jan 2023
DOIs	https://doi.org/10.1021/acs.orglett.2c04095
Publication status	E-pub ahead of print - 10 Jan 2023

Bibliographical note

Funding Information:
J.C.A. and J.L.T. thank the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. C.P.B. thanks the Swiss National Science Foundation for a Postdoc Mobility Fellowship (P500PN_202691). L.V. thanks the Spanish Ministry of Science, Innovation and Universities for a Ph.D. grant (FPU16/04231) and a mobility fellowship (EST19/00778). The authors thank N. E. Pridmore (University of Bristol) for X-ray analysis.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

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@article{fa57561f4b9b46b89ef6a95e5d272dd0,

title = "Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines",

abstract = "The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1′-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.",

author = "Abell, {Joseph C.} and Bold, {Christian P.} and Laia Vicens and Tom Jentsch and Noelia Velasco and Tyler, {Jasper L.} and Straker, {Robert N.} and Adam Noble and Aggarwal, {Varinder K.}",

note = "Funding Information: J.C.A. and J.L.T. thank the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. C.P.B. thanks the Swiss National Science Foundation for a Postdoc Mobility Fellowship (P500PN_202691). L.V. thanks the Spanish Ministry of Science, Innovation and Universities for a Ph.D. grant (FPU16/04231) and a mobility fellowship (EST19/00778). The authors thank N. E. Pridmore (University of Bristol) for X-ray analysis. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

year = "2023",

month = jan,

day = "10",

doi = "10.1021/acs.orglett.2c04095",

language = "English",

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journal = "Organic Letters",

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TY - JOUR

T1 - Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

AU - Abell, Joseph C.

AU - Bold, Christian P.

AU - Vicens, Laia

AU - Jentsch, Tom

AU - Velasco, Noelia

AU - Tyler, Jasper L.

AU - Straker, Robert N.

AU - Noble, Adam

AU - Aggarwal, Varinder K.

N1 - Funding Information: J.C.A. and J.L.T. thank the Bristol Chemical Synthesis Centre for Doctoral Training and the EPSRC (EP/G036764/1) for funding. C.P.B. thanks the Swiss National Science Foundation for a Postdoc Mobility Fellowship (P500PN_202691). L.V. thanks the Spanish Ministry of Science, Innovation and Universities for a Ph.D. grant (FPU16/04231) and a mobility fellowship (EST19/00778). The authors thank N. E. Pridmore (University of Bristol) for X-ray analysis. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/1/10

Y1 - 2023/1/10

N2 - The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1′-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

AB - The identification of the beneficial pharmacokinetic properties of aza-spirocycles has led to the routine incorporation of these highly rigid and three-dimensional structures in pharmaceuticals. Herein, we report an operationally simple synthesis of spirocyclic dihydropyridines via an electrophile-induced dearomative semi-pinacol rearrangement of 4-(1′-hydroxycyclobutyl)pyridines. The various points for diversification of the spirocyclization precursors, as well as the synthetic utility of the amine and ketone functionalities in the products, provide the potential to rapidly assemble medicinally relevant spirocycles.

U2 - 10.1021/acs.orglett.2c04095

DO - 10.1021/acs.orglett.2c04095

M3 - Letter (Academic Journal)

C2 - 36626565

SN - 1523-7060

VL - 25

SP - 400

EP - 404

JO - Organic Letters

JF - Organic Letters

IS - 2

ER -

Synthesis of Dihydropyridine Spirocycles by Semi-Pinacol-Driven Dearomatization of Pyridines

Abstract

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