Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates

S. Paul Jones, James D. Firth, Mary C. Wheldon, Masakazu Atobe, Roderick E. Hubbard, David C. Blakemore, Claudia De Fusco, Simon C.C. Lucas, Stephen D. Roughley, Lewis R. Vidler, Maria Ann Whatton, Alison J.A. Woolford, Gail L. Wrigley, Peter O'Brien*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we report the synthesis of piperidine-based 3D fragment building blocks - 20 regio- and diastereoisomers of methyl substituted pipecolinates using simple and general synthetic methods. cis-Piperidines, accessed through a pyridine hydrogenation were transformed into their trans-diastereoisomers using conformational control and unified reaction conditions. Additionally, diastereoselective lithiation/trapping was utilised to access trans-piperidines. Analysis of a virtual library of fragments derived from the 20 cis- and trans-disubstituted piperidines showed that it consisted of 3D molecules with suitable molecular properties to be used in fragment-based drug discovery programs.

Original languageEnglish
Pages (from-to)1614-1620
JournalRSC Medicinal Chemistry
Issue number12
Early online date11 Oct 2022
Publication statusPublished - 1 Dec 2022

Bibliographical note

Funding Information:
We are grateful to AstraZeneca, Astex Pharmaceuticals, Lilly, Pfizer and Vernalis for supporting this venture. When this research was carried out, CDF was employed by AstraZeneca and LRV and MAW were employed by Lilly. MA is currently employed by Modulus Discovery. This project was funded by the EPSRC (MCW), BBSRC (BB/N008332/1) (JDF), University of York (SPJ), Asahi Kasei (MA) and The Royal Society (Industry Fellowship, INF\R1\191028) (POB). We thank Biovia for supplying Pipeline Pilot software.

Publisher Copyright:
© The Royal Society of Chemistry 2022

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