Discipline: Chemistry and Chemical Sciences
Subcategory: Cancer Research
Israt Jahan - Tuskegee University
δ-Lactams constitute an important class of compounds in synthetic chemistry and biology. They are known to possess a broad range of significant pharmacological properties and often found in essential building blocks of a variety of biologically intriguing natural products and their structural motif can be incorporated in the design and synthesis of novel biologically active molecules such as compounds that are similar in structure to Panepoxydone, which is a potential treatment of triple-negative breast cancer.1
There have also been several methods detailing the enantioselective synthesis of δ-Lactams through ring closing metathesis reactions of enantiomerically pure precursors,9 nitrilase catalyzed ring expansion of aziridines,10 and the use of organophosphorus reagents as organocatalysts.11 However, the synthesis of amino acid condensed δ-Lactams utilizing a stereoselective approach is surprisingly rare. Therefore, there is a need for additional straightforward methods capable of preparing enantiomerically enriched δ-Lactams.
We have recently demonstrated that at ambient temperature, triacetic acid lactone reacts with amines to produce 4-amino-2-pyrones. If the temperature raised to 1000 C, 4-hydroxy-2-pyridones are generated with a remarkable chemoselectivity. Hence, we wanted to employ this condensation strategy to prepare δ-Lactams in a stereoselective manner.12
Five amino acids (Alanine, valine, histidine, asparagine, glycine) and o-phosphoethanolamine have been used for the purpose of converting TAL into a lactam. The product distribution is temperature dependent with the amide being formed at higher temperatures. Amino acids have not been screened for this condensation. Therefore, we could potentially generate either the amide or the vinyl amine. From these, only Histidine, Asparagine and O-Phosphoethanolamine show product formation. O-Phosphoethanolamine is particularly intriguing due to the multiple products condensation routes via oxygen or nitrogen, that are possible. The screening also presents the potential for stereodefined products as the amino acids employed are single enantiomers.
In a 25mL round bottom flask 1:1.5 ratio of TAL and amino acids were added. 4.00 mL of water was added, a reflux condenser attached, and the reaction vessel was sealed with a rubber septum and flushed with nitrogen gas. The reaction was refluxed for 24-hours on an oil bath. After 24-hours, the reaction mixture was filtered and washed with distilled water. Differential solubility in ethyl acetate allowed the oil and solid fractions to be isolated. 1H-NMR was conducted using either deuterium oxide or CDCl3 as a solvent. All spectra were collected on a Bruker Avance 400 MHz NMR spectrometer.
The presence of crude condensation product was revealed by 1H NMR spectroscopic analysis.
Currently we are working on the purification of the product. Our future research will be focused on the adsorption of the purified product over nanoparticles and targeted delivery of the product into different cancer cell lines.
1. Collignon, J., Lousberg, L., Schroeder, H., & Jerusalem, G. (2016). Breast Cancer (Dove Med Press), 8, 93-107.
2. Fiorelli, C.; Savoia, D. J. Org. Chem. 2007, 72, 6022–6028.
3. Vervisch, K.; D’hooghe, M.; Rutjes, F. P. J. T.; De Kimpe, N. Org. Lett. 2012, 14,106–109.
4. Albrecht, A.; Morana, F.; Fraile, A.; Jørgensen, K. A. Chem. Eur. J. 2012, 18,10348–10354.
5. Kraus, G. A., Wanninayake, U. K., & Bottoms, J. (2016). Tetrahedron Letters, 57(11), 1293-1295.
Funder Acknowledgement(s): This research was funded by in part O. Abdalla, Department of Chemistry, Tuskegee University, awarded by NIH/NCI U54 CA118623 MSM/TU/UABCCC Partnership.
Faculty Advisor: Albert E. Russell, firstname.lastname@example.org
Role: I did all the synthesis and characterization of the product.