XtalFluor-E: Selective Fluorination Reagent

XtalFluor-E (diethylamino difluorosulfunium tetrafluoroborate) appears as one of deoxyfluorinating reagents that improve the weakness of DAST. Different from DAST which is liquid reagents, XtalFluor-E is a solid reagent so it's more stable. 

The mechanism of deoxyfluorination with XtalFluor-E is similar to DAST. The reaction also involves the dialkylaminodifluorosulfane intermediate. However, the difference is, when using XtalFluor-E, it release tetrafluoroboric acid and the reaction also fluoride starved so the side reactions often occur such as the formation of ether compound. For example, see the scheme below. 

Therefore, the reaction with XtalFluor-E usually involves additive such as Et3N.3HF (triethylamine trihydrofluoride) as the source of exogenous fluoride (see the table below). However, the order of the addition of Et3N.3HF should be noted. The yield will be better if the addition of this additive is done with the reagent (XtalFluor-E) before the addition of the substrate. If it is done after the addition of substrate and reagent, then the yield will not be improved because the deoxyfluorination has occurred instantaneously already. That's why the addition of Et3N.3HF after that will be less meaning.   

The addition of strong base might be improving the yield as it will work for the deprotonation. The work from previous table shown also explained that the addition of DBU as non-nucleophile strong base improved the yield of the reaction and reducing the side reactions. Although the yield was improved, the reaction rates were slower than when using Et3N.3HF.

All the data and explanation is refered to this reference:

Heureux, A. L., Beaulieu, F., Bennett, C., Bill, D. R., Clayton, S., Mirmehrabi, M., … Couturier, M. (2010). Aminodifluorosulfinium Salts : Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling †,‡, 3401–3411. https://doi.org/10.1021/jo100504x

DAST: The First Deoxyfluorination Reagent

Reported by a chemist at Dupont in 1975, DAST (Dietylaminosulfur trifluoride) became a stable to gaseous SF4 (Wen-Li Hua, Xiang-Go Hu, & Hunter, 2017) . This gaseous reagent, SF4, is extremely toxic and corrosive. Hence, DAST appeared as an alternative in liquid form. The excellence of DAST than SF4, DAST is easier to be handled as it doesn't require much higher temperatures.

Nevertheless, it was soon found that DAST also has some weaknesses. If it undergoes heating, it can decompose and produce SF4 as we already knew that this substance is toxic and corrosive. If it undergoes further heating, it can explode into undefined gases and black char (Heureux, et al., 2010). 

Then, Deoxofluor was developed. From differential scanning calorimetry (DSC), Deoxofluor has the same decomposition temperature with DAST, yet it degrades slower so it is considered safe.

Do you know? Soon after DAST and Deoxofluor conducted in larger scale, it is found to be unsafe. The preparation process was problematic. First, the purification of the crude using vacuum distillation is dangerous as they are explosive. Secondly, after the manufacturing, the shipping regulation is very strict. Thirdly, these reagent is also not stable in color. Fourthly, during the use, both may generate free HF which is very volatile, highly toxic, extremely corrosive to the skin and other tissues including bones (Heureux, et al., 2010).

Nonetheless,  DAST remains the most popular deoxyfluorination reagent because of its availability and general scope (Nielsen, Ugaz, Li & Doyle, 2015). Deoxyfluorination is a reaction of introducing fluorine atom into a molecule through the substitution of alcohol functional group. The reaction with DAST proceeds with inversion. It goes with SN2 reaction as the alcohol functional group is a poor leaving group, the alcohol then is converted into weaker base by being attached with the electrophilic sulfur atom. Then, the nucleophile, the fluorine atom with negative charge, attacks from the backside of the carbon atom which is the electrophile. It attacks from the backside since the leaving group which is attached with the electrophile blocks the approach of the nucleophile from the frontside. That's why it simply goes with inversion through SN2 reaction.

In deoxyfluorination, DAST also has limitation. It may produce side products. If the substrate has double bond, it may undergo elimination. And if the substrate has carbonyl group, it may be difluorinated. Therefore, several new reagents has been developed to improve the selectivity.  

Reference:

Heureux, A. L., Beaulieu, F., Bennett, C., Bill, D. R., Clayton, S., Mirmehrabi, M., … Couturier, M. (2010). Aminodifluorosulfinium Salts : Selective Fluorination Reagents with Enhanced Thermal Stability and Ease of Handling †,‡, 3401–3411. https://doi.org/10.1021/jo100504x

Nielsen, M. K., Ugaz, C. R., Li, W., & Doyle, A. G. (2015). PyFluor: A Low-Cost, Stable, and Selective Deoxy fl uorination Reagent, 9571–9574. https://doi.org/10.1021/jacs.5b06307

Wen-Li Hua, Xiang-Guo Hu, L. H. (2017). Recent Developments in the Deoxyfluorination of Alcohols and Phenols : New Reagents , Mechanistic Insights , and Applications, 4917–4930. https://doi.org/10.1055/s-0036-1590881

A Prospective Fluorinated Drugs

[Picture Source: ThoughtCo]

Twenty percents of marketed drugs are fluorinated because fluorine atom can completely change the biological properties, for example, 5-Fluorouracil. Before being introduced by the fluorine atom, the uracil is transformed into DNA by Thymidylate synthase that is not desired in cancer case. By introducing the fluorine atom, the uracil now acts as antimetabolite that inhibits the thymidylate synthase so indirectly inhibit the carcinogenesis also. That's how fluorine atom can completely change the biological properties of natural uracil (Berger, Pittman, & Wyatt, 2009).

Another example is Fludcortisone. Cortisone itself is a steroid that prevents the release of a substance that causes inflammation in the body so it possesses glucocorticoid activity. After being introduced with fluorine atom, the activity exceeded by factor 10 than the parent hormones (cortisone), therefore it possess a remarkable glucocorticoid activity. 

So, how come fluorine atom can completely change biological properties of a compound? What kind of atom is it? 

Fluorine atom as expected in the periodic table of elements possesses ultimate electronegativity and oxidation potential. Talking about the amount, fluorine atom is available abundantly even more significant than other halogens on Earth's crust as it is the 13th most common element on Earth's crust. Compare to other halogens, Fluorine atom also has extraordinary high hydration energy so therefore it behaves as a very poor nucleophile in aqueous solution. Another feature of fluorine atom that makes it different from others is the C-F bond, it is one of the strongest chemical bonds as its biological formation/cleavage will be quiet difficult to generate under normal condition. 

Fluorine atom can give effect to organic compound properties not only due to its electronegativity, but also other properties it possesses such as lipophilicity, size, and electrostatic interaction. Those properties can dramatically influence the chemical reaction. Do you know, even a single fluorine atom is able to change a biological property of a natural product. 

Last but not least, after the fluorination, the fluorine atom can change the acidity or basicity of a parent compound so this can strongly influence binding affinity pharmacokinetic properties and bioavailability of a drug candidate. 

As a powerful functional group, the number fluorinated drugs is expected to increase in the future. How come? Atorvastatin Lipitor became the most profitable drug until 2011. Another example, Fluticasone propionate, the annual sales became more than 5 billion dollars.

You can read all the development of fluorinated drugs from a paper written by Wang et al (2013).

That's all the post I wrote. Thank you for visiting. I apologize if there is a mistake. 

Reference:

Berger, S. H., Pittman, D. L., & Wyatt, M. D. (2009). chemotherapy, 76(6), 697–706. https://doi.org/10.1016/j.bcp.2008.05.019.Uracil

Wang, J., Sánchez-Roselló, M., Aceña, J. L., Del Pozo, C., Sorochinsky, A. E., Fustero, S., … Liu, H. (2014). Fluorine in pharmaceutical industry: Fluorine-containing drugs introduced to the market in the last decade (2001-2011). Chemical Reviews, 114(4), 2432–2506. https://doi.org/10.1021/cr4002879