Stephen Chamberland

Boston College Undergraduate Research Summary

 

Total Synthesis of Luotonin A and Studies Toward the Total Synthesis of Louisianin C

While I was an undergraduate student researcher in the T. Ross Kelly group at Boston College, I completed a Scholar of the College Senior Thesis project.  In only four months, I successfully completed the seven-step total synthesis of the cytotoxic alkaloid luotonin A (Scheme 1).1,2  Luotonin A possesses a structure reminiscent of camptothecin, analogs of which are currently utilized as chemotherapeutic agents.3  The mechanism of action of camptothecin involves stabilization of the human DNA topoisomerase I-DNA covalent binary complex.4,5  This binding event leads to double-stranded DNA cleavage and, ultimately, to cell death.6,7  Recent studies suggest that luotonin A inhibits both topoisomerases I and II through sequence specific p,p or hydrogen bonding interactions involving the quinazolinone (D and E ring) portion of the molecule.8,9  The key step in this synthesis involved Friedländer condensation of diketone 1 with 2-aminobenzaldehyde to provide luotonin A in 36% yield.


                The remainder of my Scholar of the College research efforts were directed toward the total synthesis of Louisianin C (Scheme 2), a 3,4,5-trisubstituted pyridine containing natural product exhibiting anti-angiogenic activity.10  In this synthetic effort, I demonstrated that diisopropyl isonicotinamide 2 could undergo ortho-lithiation by deuterium quenching experiments.  In subsequent efforts, however, I was not able to attach the desired allylic electrophile to this anion.  The remainder of the initially proposed synthetic approach appears below in Scheme 2.  The Kelly group recently completed the total synthesis of Louisianin C using a slightly different approach.11 


References

(1)     Kelly, T. R.; Chamberland, S.; Silva, R. A. Tetrahedron Lett. 1999, 40, 2723-2724.

(2)     Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997, 46, 541-546.

(3)     Slichenmyer, W. J.; Rowinsky, E. K.; Donehower, R. C.; Kaufmann, S. H. J. Nat. Cancer Inst. 1993, 85, 271.

(4)     Hutchinson, C. R. Tetrahedron 1981, 37, 1047.

(5)     Hertzberg, R. P.; Caranfa, M. J.; Holden, K. G.; Jakas, D. R.; Gallagher, G.; Mattern, M. R.; Mong, S.-M.; Bartus, J. O.; Johnson, R. K.; Kingsbury, W. D. J. Med. Chem. 1989, 32, 715.

(6)     Hsiang, Y.-H.; Lihou, M. G.; Liu, L. F. J. Biol. Chem. 1985, 260, 14873.

(7)     Kohn, K. W.; Pommier, Y. Ann. N. Y. Acad. Sci. 2000, 922, 11.

(8)     Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M. J. Am. Chem. Soc. 2003, 125, 13628-13629.

(9)     Cagir, A.; Jones, S. H.; Eisenhauer, B. M.; Gao, R.; Hecht, S. M. Bioorg. Med. Chem. Lett 2004, 14, 2051-2054.

(10)   Sunazuka, T.; Zhi-Ming, T.; Harigaya, Y.; Takamatsu, S.; Hayashi, M.; Komiyama, K.; Omura, S. J. Antibiot. 1995, 48, 1090-1094.

(11)   Beierle, J. M.; Osimboni, E. B.; Metallinos, C.; Zhao, Y.; Kelly, T. R. J. Org. Chem. 2003, 68, 4970-4972.