Morpholines and their homologs are highly represented among small molecules that are biologically and therapeutically relevant, including many natural products.1-2 For example, polygonapholine 13 (used as a tonic drug) and chenolin C 24, shown in Figure 1, are morpholine-derived natural alkaloids.
The morpholine moiety has found widespread use in medicinal chemistry, for the morpholine is a weaker base than, e.g., piperidine, which often demonstrates more attractive physicochemical properties.1a Nowadays, there are around 20 commercially available drugs containing the morpholine fragment.5 Model structures of appetite suppressive drug Phendimetrazine 3 and antidepressant Reboxetine 4 are depicted in Figure 1.
Furthermore, morpholine scaffolds have widely been utilized in the agrochemical industry for their antibacterial and antifungal properties.6 They have also been applied as chiral auxiliaries in asymmetric synthesis.7
Figure 1. Examples of natural products and marketed drugs containing the morpholine unit
A representative set of C-substituted morpholines available from Life Chemicals is provided below. The full catalog of the morpholine derivatives can be obtained upon request at firstname.lastname@example.org.
- For reviews, see: (a) Andrs, M.; Korabecny, J.; Jun, D.; Hodny, Z.; Bartek, J.; Kuca, K. J. Med. Chem. 2015, 58, 41–71. (b) Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641. (c) Aitken, R. A.; Aitken, K. M. In Comprehensive Heterocyclic Chemistry III, Eds. Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K. Pergamon, Oxford, 2008. Vol. 8, p. 461.
- Matralis, A. N.; Kourounakis, A. P. ACS Med. Chem. Lett. 2019, 10, 98–104.
- Lin, C.; Huang, P.; Lu, C.; Wu, R.; Hu, W.; Wang, J. Tetrahedron 1997, 53, 2025.
- Bobzin, S. C.; Faulkner, D. J. J. Org. Chem. 1991, 56, 4403.
- www.drugbank.ca (accessed in April 2019)
- Dieckmann, H.; Strockmaier, M.; Kreuzig, R.; Bahadir, M. Fesenius’ J. Anal. Chem. 1993, 345, 784.
- For examples, see: (a) Enders, D.; Meyer, O.; Raabe, G.; Runsink, J. Synthesis 1994, 66. (b) Dave, R.; Sasaki, N. A. Org. Lett. 2004, 6, 15.