Expand your building block collection with our C-Substituted Morpholines

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 orders@lifechemicals.com.

References

1. 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.
2. Matralis, A. N.; Kourounakis, A. P. ACS Med. Chem. Lett. 2019, 10, 98–104.
3. Lin, C.; Huang, P.; Lu, C.; Wu, R.; Hu, W.; Wang, J. Tetrahedron 1997, 53, 2025.
4. Bobzin, S. C.; Faulkner, D. J. J. Org. Chem. 1991, 56, 4403.
5. www.drugbank.ca (accessed in April 2019)
6. Dieckmann, H.; Strockmaier, M.; Kreuzig, R.; Bahadir, M. Fesenius’ J. Anal. Chem. 1993, 345, 784.
7. 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.