• Home Page

• Synthesis Mechanism and FMO Explanation

• 1H-NMR

• Experimental

• Leading Question

• References

• About Us

INITIAL REFERENCES

Spiderman used the web to find 3 references pertaining to epimerization

Hussar, D. A.; Niebergall, P. J.; Sugita, E. T.; Doluisio, J. T. J. Pharm. Pharmac. 1968, 20, 539-546.

Kajita, R.; Goto, T.; Lee, S. H.; Oe, T. Chem. Res. Toxical. 2013, 26, 1926-1936.

Garg, A.; Khosla, C.; Cane, D. E. J. Am. Chem. Soc. 2013, 135, 16324-16327.

ARTICLE 1 SUMMARY:

Tetracyclines are a class of antibiotics that can undergo epimerization reactions to create molecules that differ significantly in configuration, altering properties such as effectiveness of in vitro antbiotic activity. In a solvent with a pH range from 2-6, using varying conditions of temperature and buffer strength, tetracyclines are likely to undergo epimerization. Spontaneous epimerization of stock medications such as tetracycline can cause a loss in potency, or even worse, result in medical ailments such as kidney damage. Therefore, research in tetracycline manipulation is important to prevent medication exposure to conditions that could result in this transition. When calcium or copper was introduced, no effect or degradation was seen, respectively. Only when in a solution with a pKa around 4.0 was the epimerization kinetically favored over complete degradation of the molecule. In more basic solutions, multiple deprotonations of the tetracycline resulted in loss of chemical potency. On the other hand, in a slightly acidic solution, the most basic hydroxyl group would be protonated, subsequently resulting in a stereochemical shift of the alcohol to its cis-form.

ADDITIONAL REFERENCES

Spiderman got tangled up in the first article and wanted to find out more about it, so he found 3 separate articles that used it as a citation.

 

Tetracycline derivative concentrations in a 1.5 pH phosphate solution were monitored through a nonlinear regression based off of first-order epimerizations of the compounds. Rate constants were obtained for first-order tetracycline epimerization, as well as tetracycline degradation. The tetracycline epimerization allowed for the quantification of the kinetic rate of transformed, non-degraded products. It was found that tetracycline epimerization could occur at a pH as low as 1.5, showing that the range of acidity was lower than initially reported (pH=4.0).

It was known from the previous article that tetracycline epimerizes in certain solutions with certain buffers. By using NMR tests, it was determined that one of the solutions that tetracycline hydrochloride undergoes a quick epimerization is pyridine. Since variable temperatures were used during each epimerization reaction, temperature dependence of the reaction was also gauged by its effect on the equilibrium constant.

Standard reaction conditions allowing the epimerization of tetracycline to occur were used from article 1 above. Since a slight variance was found between the dimethylamino resonance structure of tetracycline and its C-4 epimer, NMR was used to differentiate between the two. In previous spectrophotometric methods, the tetracycline would have had to been acidified first. Fortunately, this was not necessary when using NMR, and the possibility of anhydro formation upon acidification was eliminated.

University of Michigan Chem 215/216 HH Winter 2014. Nicholas Carducci's Structured Study Group. HTML Project of Callie Chappell, James Lawniczak, Aiman Faruqi, and Ryan Gentil