1. Synthesis of Essential
Intermediate
4H-Seleno[3,2-b]pyrrole
Jacob Curry

2. Synthesis Aim
Figure 1: 4H-Seleno[3,2-b]pyrrole

3. Figure 2: 4H-Seleno[3,2-b]pyrrole
compared with
[4,5]selenotryptophan.

4. Background
Proteins and amino acids—what’s so
important?
• Form and function
• Mutations in sequence
Figure 3: Arabinose
binding protein.
Image from
http://chemistry.umeche.maine.ed
u/

5. X-Ray Crystallography and NMR
• Accurately shows
structural themes for
observed molecules
• NMR
o Not crystal-based
o No size restriction
Figure 4: X-ray crystallography
method.
Image from http://projectcrystal.org/

6. The Phase Problem and
MAD
• The images developed by X-ray
crystallography have scattering issues.
• Inclusion of a heavy atom/metal eliminates
the problem and helps elucidate protein
structure.
• Multi-wavelength Anomalous Dispersion
o Scattering of electron-rich metalloid atoms
o Thus, phase may be determined by a single species

7. Methods
• Paulmier-Phillips Protocol vs. Boles-Silks-
Hatch Method
• Why?
o Cost-efficient, reaction timeline
o Stable product
o Direct 77Se insertion
• Mass spectroscopy, NMR
• Past experiences

8. Paulmier-Phillips Scheme
Figure 5: Paulmier-Phillips scheme.
21
34

9. Boles-Silks-Hatch
Scheme
Figure 6: Boles/Silks/Hatch scheme for
the synthesis of 4H-seleno[3,2-b]pyrrole.
21
3
4
Product % Yield Mass (g)
2 98.8 % 1.446
3 47.6% 0.632
4 In
progress
/

10. Step 1: Bromination
Product % Yield Mass (g)
2 98.8 % 1.446

11. Step 2: Transmetallation
Product % Yield Mass (g)
3 47.6 % 0.632

12. Step 3: Annulation
Product % Yield Mass (g)
4 In prog. /

13. Overall…
• Each step of the scheme has been verified
and has produced in good yield
• Efficiently developing and purifying this
product in a favorable yield is essential to the
synthesis of [4,5]selenotryptophan
• Artificial amino acids/analogs
o Determine protein form and function
o Protein-based drugs/treatments

14. Future Work
• Scale up the reactions
• Continued purification
• Reach conclusion of this scheme: 4H-
Seleno[3,2-b]pyrrole
• Do scheme with tellurium (Te)
• Follow this up with synthesis of final analog
[4,5]selenotryptophan

15. Lignin Peroxidase
• Peroxidases break
down lignin
• Contains a catalytic
tryptophan domain,
Trp 171
• Gain an
understanding of the
enzyme and its
mechanism
Figure 7: Lignin peroxidase.

16. References
• Hatch, Duane M. et al. Methods for the Synthesis of Heavy-Atom Derivatized Amino
Acids: Useful Probes for X-Ray Crystallography, Vibrational, and NMR Spectroscopy of
Proteins. Current Organic Chemistry, 2004, 8, 47-64. Print.
• Hatch, Duane. Novel Synthesis, Purification, and Characterization of Labeled and
Unlabeled (6,7) Selena-L-Tryptophan and It’s Potential Use in the Elucidation of Protein
Structure and Function. Tenn. Tech. Univ. 2003. pp. 4-8, 19-70. Print.
• Hatch, Duane. Towards a Concise Annulation Method for the Synthesis of Selenolo[2,3-
b] and [3,2-b]pyrrole and Further Enzymatic Elaboration to Labeled and Unlabeled
[6,7]SeTrp and [4,5]SeTrp. Print.
• Nelson, D., & Cox, M. Lehninger Principles of Biochemistry (6th ed.). New York: W.H.
Freeman and Company, 2013. 15, 89, 143, 576, 906-907. Print.
• Pecorino, L. (2012). Apoptosis: Molecular Mechanisms of Apoptosis. In Molecular
Biology of Cancer (3rd ed.). Oxford: Oxford University Press.
• Pecorino, L. (2012). DNA structure and stability: Mutations versus repair. In Molecular
Biology of Cancer (3rd ed.). Oxford: Oxford University Press.
• Read, R. (2008, April 22). Overview of macromolecular X-ray crystallography. Retrieved
April 18, 2015, from http://www-
structmed.cimr.cam.ac.uk/Course/Overview/Overview.html.

17. Thanks
• Duane Hatch, Ph.D.
• Ryan Agh
• Daniel Gilani
• Belmont University
o College of Sciences and Mathematics
o Department of Chemistry and Physics
• Los Alamos National Laboratories,
Bioscience Division
• Department of Energy VFP