Optimizing the Synthesis of a Selenium-Containing Tryptophan Analog Precursor
Noah DeBlanco, Duane M. Hatch Ph.D. § Department of Chemistry and Physics, Belmont University, Nashville, TN, 37212
Synthesis
Abstract
Protein structure determination is essential when diving
into the etiology of certain diseases. The analysis of
these protein structures can be challenging, but using xray crystallography combined with heavy atom
containing amino acids can help provide better
structural information. Our amino acid of interest
is tryptophan due to its low natural abundance in most
proteins.
Results
1. Form 2-iodomethyl-1,3-dioxolane using 2-bromomethyl-1,3-dioxolane to yield a more
reactive reagent through reflux (Figure 3) in acetone (Finkelstein Reaction).
Finkelstein Reaction Scheme
Na I
85% yield
Figure 5:
iodomethyl-1,3dioxolane NMR
53% yield
NaBr
Br
Figure 1: selenophen[2,3-b]pyrrole
Selenophene pyrrole (Figure 1), a tryptophan analog
precursor containing selenium, must be synthesized
before the selenotryptophan (Figure 7) can be realized.
Previous attempts towards the synthesis of the
selenophene pyrrole resulted in undesirable yields over
too many steps. Therefore, improving techniques,
increasing yields, and finding a more direct route
would have a significant impact on the possible
commercial availability of this heavy atom analog.
I
2. Tosyl selenide: Using n-tosyl pyrrole, n-butyllithium, and selenium in THF at -50°C
(Metalation Reaction). Followed by flash column chromatography with 20:80 ethyl
acetate:hexanes (Figure 4)
Metalation Reaction Scheme
Se
Se
Ts
Figure 6: selenophen[2,3b]pyrrole NMR
Ts
Future Goals
Finding the most optimal way to maximize yield and
efficiency in synthesizing selenophene pyrrole was the
primary focus of this research. The tosyl selenide was
realized, which will allow multiple Lewis-acids to be
tested for the ring closing (annulation) reaction that is
necessary to produce the selenium-containing bicyclic
ring structure (Figure 1) needed for the tryptophan analog
(Figure 7).
Background
Due to the phase problem of x-ray crystallography
(Figure 2), the use of amino acid analogs containing
heavy metal atoms is an efficient way to recognize the
structure of a protein. The problem is reduced because of
the greater electron density being measured.
Figure 7: [6,7]SeTrp
References
1. Moroder, L, Musiol, H‐J. Amino acid chalcogen analogues as tools in peptide and protein
research. J Pep Sci. 2020; 26:e3232. https://doi.org/10.1002/psc.3232(Accessed March 16,
2021).
2. Hatch, Duane. Tenn. Tech. Univ. 2003. pp. 4-8, 19-70.
3. Cowtan, Kevin, Phase Problem in Xray Crystallography, and its Solution. Encyclopedia of
Life Sciences. 2001. http://people.bu.edu/mfk/restricted566/phaseproblem.pdf (Accessed March
17, 2021).
Acknowledgments
Figure 3: Reflux for Finkelstein Reaction
Figure 2: Phase determination from diffraction data.
(www.creative-biostructure.com/phase-determination-87.htm)
Figure 4: Flash column chromatography and TLC
analysis of the fractions after Metalation Reaction
Belmont University Department of Chemistry and Physics
Dr. Duane Hatch, Bishoy Sami
SURFS 2023