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.
Bibliographical noteFunding 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.
© The Royal Society of Chemistry 2022