Piperidine-based building blocks have found extensive application in medicinal chemistry.1-2 The piperidine substructure is also present in a variety of biologically active natural products,3 synthetic pharmaceuticals, and agrochemicals.4
Figure 1 gives examples of piperidine-derived natural alkaloids: calvine 1 and (-)-sparteine, the substructure of 2. The latter is used as an antiarrhythmic agent and an optically active ligand for Pd (II) complexes for enantioselective oxidation of benzyl alcohol derivatives.5 Presently, there are over 100 piperidine-based commercially available drugs possessing a broad spectrum of activities, e.g., antibacterial, anesthetic (exemplified by Ropivacaine 3 in Fig. 1), anti-allergic (Loratadine 4 in Fig. 1), cardiovascular, antipsychotic, and antiasthmatic.6
Essential features of substituted piperidines and related saturated heterocycles are ‘3D shape’ structures, a limited number of rotatable bonds, and chirality. These features allow the engineering of additional protein-ligand interactions not accessible to a flat aromatic ring.7
Figure 1. Examples of natural products and marketed drugs containing the piperidine cycle
Representative structures of functionalized piperidines available from Life Chemicals are presented below. The full data-set of the C-substituted piperidines can be obtained upon request at firstname.lastname@example.org.
- For recent works, see: (a) Weng, Q.; Che, J.; Zhang, Z. et al. J. Med. Chem. 2019, 62, 3268–3285. (b) Addie, M. et al. J. Med. Chem. 2013, 56, 2059. (c) Hirschhauser, C.; Parker, J. S.; Perry, M. W. D.; Haddow, M. F.; Gallagher, T. Org. Lett. 2012, 14, 4846–4849.
- For piperidine-based covalent inhibitors, see: Butler, C. R.; Beck, E. M.; Harris, A. et al. J. Med. Chem. 2017, 60, 9860–9873.
- (a) Chen, Q.-B.; Gao, J.; Zou, G.-A.; Xin, X.-L.; Aisa, H. A. J. Nat. Prod. 2018, 81, 1474–1482. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
- McAteer, C. H.; Balasubramanian, M.; Murugan, R. In Comprehensive Heterocyclic Chemistry III, Eds. Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Pergamon, Oxford, 2008. Vol. 7, p. 309.
- Mueller, J. A.; Cowell, A.; Chandler, B. D.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 14817.
- The information source: www.drugbank.ca (accessed in May 2019).
- Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752.