C-Substituted Pyrrolidines from Life Chemicals Inspiring Your Drug Discovery Endeavour!

Pyrrolidines are an important class of heterocycles found in numerous natural products,¹ bioactive molecules,² organocatalysts,³ and building blocks in organic synthesis.⁴ There are over 60 FDA approved pyrrolidine-based drugs.⁵ Antihypertensive agent Captopril 1 (Figure 1) is an example of the pyrrolidine derived marketed drugs. Pyrrolidine has found its use as a core scaffold in advanced pharmaceutical research compounds and clinical candidates, e.g., Factor Xa inhibitor 2,⁶ NK3 receptor antagonists 3,⁷ and DPP-IV inhibitors 4⁸ shown in Fig. 1. Synthesis of combinatorial libraries of functionalized pyrrolidines for HTS-based drug discovery was recently reported.⁹

Figure 1. Examples of advanced pharmaceutical compounds containing the pyrrolidine substructure

Given the importance of the pyrrolidine substructure, Life Chemicals offers a rich structural variety of pyrrolidine-based building blocks and screening compounds for synthetic and drug discovery projects.

The full set of the title structures can be provided upon request at orders@lifechemicals.com. Please, see the representative set of available C-functionalized pyrrolidines below.

References:

1.  (a) Fukuda, Е.; Sudoh, Y.; Tsuchiya, Y.; Okuda, T.; Igarashi, Y. J. Nat. Prod., 2014, 77, 813–817. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626. (c) Cheng, Y.; Huang, Z. T.; Wang, M. X. Curr. Org. Chem. 2004, 8, 325–351.
2. (a) Alvarez- Ibarra, C.; Csaky, A. G.; Lopez de Silanes, G. A.; Quiroga, M. L. J. Org. Chem. 1997, 62, 479–484. (b) Bianco, A.; Maggini, M.; Scorrano, G.; Toniolo, C.; Marconi, G.; Villani, C.; Prato, M. J. Am. Chem. Soc. 1996, 118, 4072–4080.
3.  (a) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
4. (a) Fujieda, H.; Maeda, K.; Kato, N. Org. Process Res. Dev. 2019, 23, 69–77. (b) Campello, H. R.; Parker, J.; Perry, M.; Ryberg, P.; Gallagher, T. Org. Lett., 2016, 18, 4124–4127. (c) Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580–591. (d) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–3712. (e) Pearson, W. H. Pure Appl. Chem. 2002, 74, 1339–1347.
5. www.drugbank.ca; accessed in March 2019.
6. Anselm, L.; Banner, D. W.; Benz, J.; Groebke Zbinden, K.; Himber, J.; Hilpert, H.; Huber, W.; Kuhn, B.; Mary, J.-L.; Otteneder, M. B.; Panday, N.; Ricklin, F.; Stahl, M.; Thomi, S.; Haap, W. Bioorg. Med. Chem. Lett. 2010, 20, 5313–5319.
7. Jablonski, P.; Kawasaki, K.; Knust, H.; Limberg, A.; Nettekoven, M.; Ratni, H.; Riemer, C.; Wu, X. PCT Int. Appl. O2009019163; Chem. Abstr. 2007, 147, 118261.
8. Backes, B. J.; Longenecker, K.; Hamilton, G. L. et al. Bioorg. Med. Chem. Lett. 2007, 17, 2005–2012.
9. For combinatorial syntheses of pyrrolidine-based screening compounds, see: (a) Baumann, M.; Baxendale, I. R.; Kuratli, C.; Ley, S. V.; Martin, R. I.; Schneider. J. ACS Comb. Sci. 2011, 13, 405–413. (b) Kumar, A.; Gupta, G.; Srivastava, S. J. Comb. Chem. 2010, 12, 458–462.