Total Synthesis of Pyrrole Imidazole Alkaloids enabled by a Unique Chemoselective Oxidation
The Axinellamines, Massadines, and Palau’amine are complex marine natural products
belonging to the oroidin family isolated from sponge agelas oroides. Their complex structures,
varying modes of functionalities, and biological activities have made them attractive targets for
total synthesis. Although isolated in 1993, Palau’amine was not synthesized until seven years
later due to the incorrect structure being reported. Revision of the structure, as well as the
development of a unique chemoselective oxidation enabled the total synthesis of this natural
product as well as the Axinellamines and Massadines. The approach taken by many groups
towards the total syntheses of these natural products was to build a common core. The direct
oxidation created by Baran and coworkers bridged the gap between building a core and total
synthesis. Baran’s chemoselective oxidation provided a direct route from the guanidine moiety to
the hemiaminal functionality present in these complex structures. Before the syntheses of these
pyrrole imidazole alkaloids, the chemistry of building a core was approached in ways that would
already have a pre-oxidized carbon installed to access the hemiaminal without the use of a direct
oxidation step. Baran’s unique chemoselective oxidation took a direct approach and is the first
for this kind of chemistry. The unique selectivity this oxidation delivered is highlighted by the
installation of the hydroxyl despite the many functionalities present in these complex structures.
1. Baran, P. S., et al. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.
2. Baran, P. S., et al. Angew. Chem. Int. Ed. 2010, 49, 1095-1098.
3. Ferreira-Pereira, A., et al. J. Nat. Prod. 2011, 74, 279–282
4. Rasapalli, S., et al. Org. Biomol. Chem. 2013, 11, 4133-4137
5. Chen, C., et al. Chem. Commun. 2014, 50, 8628-8639
6. Quinn, R. J., et al. J. Org. Chem. 1999, 64, 731-735.
7. Baran, P. S., et al. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.
8. Carreira, E. M., et al. J. Am. Chem. Soc. 2000, 122, 8793-8794.
9. Lovely, C. J., et al. Org. Lett. 2007, 9, 3861-3864.
10. Baran, P. S., et al. Angew. Chem. Int. Ed. 2008, 47, 3581-3583.
11. Hampson, N. A.; Lee, J. B. J. Chem. Soc. C, 1970, 815-817
12. Lee, J. B. et al. Tetrahedron. 1972, 29, 751-752.
13. Fusetani, N., et al. Org. Lett. 2003, 5, 2255-2257.
14. Kock, M.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6721-6724.
15. Baran, P. S., et al. Angew. Chem. Int. Ed. 2008, 49, 16490-16491.
16. Scheuer, P. J., et al. J. Am. Chem. Soc. 1993, 115, 3376-3377.
17. Scheuer, P. J., et al. J. Org. Chem. 1998, 63, 3281-3286.
18. Kock, M., et al. Angew. Chem. Int. Ed. 2007, 46, 2320 –2324.
19. Romo, D., et al. Org. Lett. 2001, 3, 1535-1538.
20. Overman, L. E., et al. Tetrahedron. 2004, 60, 9559-9568.
21. Baran, P. S., et al. Chem. Soc. Rev., 2011, 40, 1976–1991
22. Namba, K., et al. Nature Commun. 2015, 6, 1-9.