1. Synthesis of a Thiourea Inhibitor
of Varicella Zoster Virus (VZV)
CHM 402 Talk
Connor Holt
Sydney Cox
Dr. David Goode
1 May 2015

2. Varicella Zoster Virus
• Virus that causes chicken pox and
shingles
• As of 2004, only four available
treatments
– Inhibits the viral DNA polymerase
needed to replicate the viral
genome
– Prone to resistance
• Discovery of thiourea-inhibitors of
VZV
– Dr. Visalli analyzes these
compounds and their effects on
VZV
• Isoxazole derivative currently being
synthesized & tested
M. J. D. Grandi et al. Bioorg. Med. Chem. Lett, 14, 2004, 4157-4160.
Image from http://journals.cambridge.org/fulltext_content/ERM/ERM7_15/S146239940500966Xsup003.htm

3. Portal Protein
http://viralzone.expasy.org/all_by_protein/3944.html
Goode, D. Chemistry Department, Mercer University, Macon, GA. Personal Communication, April 2015.

4. Retrosynthesis

5. Isoxazole Retrosynthesis

6. What’s the issue?
• The [3+2] cycloaddition with phenylacetylene can result in
two regioisomers

7. What Did We Observe?
Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-6.
Liu, K.; Shelton, B.; Howe, R. J. Org. Chem. 1980, 45, 3916-18.
Sun, R.; Li, Y.; Xiong, L.; Liu, Y.; Wang, Q. Journal of Agricultural and Food Chemistry 2011, 59, 4851–4859.

8. At first, we didn’t know which isomer this NMR spectra represented.
300 MHz
DMSO

9. Regioselective Method
• Used this method to compare NMR spectrums
Wang, J. et al. Synlett, 2013, 24, 79-84.

10. 300 MHz
DMSO
How were the two isomers ultimately distinguished?

11. Nuclear Overhauser Effect (NOE)
Lv, W.; Liu, J.; Lu, D.; Flockhart, D. A.; Cushman, M. Journal of Medicinal Chemistry 2013, 56, 4611–4618.
What does it do?
NOE vs. J Coupling

12. NOE
• the vinyl proton!
Correct Isomer Wrong Isomer

13. Correct Isomer
Wrong Isomer
HH
H
H
H

14. What’s Next?
• Reduce nitro to the amine
Chen, H.; Nilson, C.; Choudhury, A.; Sorgi, K. ARKIVOC. 2008, 14, 1-6.

15. Another Regioselective Method
*very low yielding, reaction was dirty and required a column
*decided to try and trap the enolate and lower temperature
Vitale, P.; Tacconelli, S.; Perrone, M.; Malerba, P.; Simone, L.; Scilimati, A.; Lavecchia, A.; Dovizio, M.; Marcantoni, E.; Bruno, A.; Patrigani, P. J. Med. Chem. 2013, 4277-4299.

16. Trapping the Enolate
*may have synthesized the aromatized version instead
What we know:
1. NMR (60 MHz) gives little info about structure
2. Rf value of correct isomer matches main product spot
3. No indication of TMS protected product
Vitale, P.; Tacconelli, S.; Perrone, M.; Malerba, P.; Simone, L.; Scilimati, A.; Lavecchia, A.; Dovizio, M.; Marcantoni, E.; Bruno, A.; Patrigani, P. J. Med. Chem. 2013, 4277-429
Bruss, H.; Schuster, H.; Martinez, R.; Kaiser, M.; Antonchick, A.; Waldmann, H. Beilstein J. Org. Chem. 2014, 10, 194-208.

17. Proposed Mechanism

18. For the Future
• Optimize isoxazole synthesis
• Figure out which isomer is actually active
against VZV
• Synthesize other derivatives

19. Acknowledgements
• Mercer University
• The Chemistry Department
• Dr. Goode
• Sydney Cox

20. Questions?