Fluorine arguably retains the most unique physiochemical properties of elements employed in synthetic organic chemistry. The small covalent radius of fluorine (C-F, F radius = 1.47 Å) along with its high electronegativity contribute to the atom’s unique characteristics – handling, stability, and incorporation of the element into small molecules is challenging using traditional synthetic techniques.114 Interestingly, naturally occurring fluorinated molecules are rare (fluoroacetic acid is one example)115 and have no known biological activity, but a number of important pharmaceutical agents contain at least one fluorine atom. Collectively, fluorine substituents impart numerous chemical properties to their molecules, including lipophilicity, metabolic stability, and bioavailability.
Marketed by Hoffmann-LaRoche beginning in 1957, the antineoplastic compound 5-fluorouracil was the earliest reported fluorinated pharmaceutical agent (Figure 23).116 It effects its anticancer activity by inhibiting thymidylate synthase, which in turn prevents the cellular synthesis of thymidine. This simple addition of fluorine to the nucleobase uracil significantly enhanced its desirable biological properties, and can be considered the grandfather of the modern interest seen in fluorine medicinal chemistry. Fluoxetine (Prozac, an antidepressant), fulvestrant (an anticancer agent), and the combination therapy efavirenz (an antiviral agent) are three other drugs, spanning a range of diseases and mechanisms of action, benefitting from the addition of the fluorine atom.
Prozac is one of the more well-known antidepressants, and was a blockbuster for Eli Lilly, with sales approaching $1B annually at its peak. The inclusion of a trifluoromethyl group in the para-position of the phenolic ring increases the potency for inhibiting serotonin uptake sixfold compared to the non-fluorinated parent compound.117
Efavirenz, an antiretroviral cocktail from Gilead and Bristol-Myers-Squibb, includes two structurally diverse fluorinated compounds. Structure-activity relationship studies showed the presence of the trifluoromethyl group in efavirenz improved drug potency by lowering the pKa of the cyclic carbamate; this carbamate makes a key hydrogen bond contact with the HIV-1 protein. The trifluoromethyl group also acts to improve allosteric binding to HIV-1, altering the enzyme’s conformation and inhibiting its activity.
114 O'Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
115 Vartiainen, T.; Kauranen, P. Anal. Chim. Acta 1984, 157, 91.
116 Heidelberger, C.; Chaudhuri, N. K.; Danneberg, P.; Mooren, D.; Griesbach, L.; Duschinsky, R.; Schnitzer, R. J.; Pleven, E.;
Scheiner, J. Nature 1957, 179, 663.
117 Wong, D. T.; Bymaster, F. P.; Engleman, E. A. Life Sci. 1995, 57, 411.
Figure 23. Diverse, Fluorine-Containing Parmaceutical Agents
β-Fluoroamines are a unique class of fluorinated compounds118 that display remarkable CNS-penetrant properties (Figure 24). The most illustrious pharmaceutical agent with such a scaffold is arguably sofosbuvir, which is an RNA polymerase inhibitor responsible for recent high cure rates of the hepatitis C virus.119 In addition to the success of sofosbuvir, there are recent examples of BACE and PIM kinase inhibitors which are clinical candidates containing β-fluoroamines for use in treatment of Alzheimer’s dementia and leukemia. Furthermore, β-fluoroamines exhibit decreased amine basicity and enhanced binding interactions similar to the fluorinated motifs discussed earlier.120 Understandably, the β-fluoroamine motif is a desirable functionality when targeting a wide array of disease states; notably, it improves biological efficacy in compounds with widely differing mechanisms of action. Despite this, from a synthetic standpoint there is a lack of direct methods to access both chiral, racemic or chiral, non-racemic β-fluoroamines.
While the number of enantioselective fluorination reactions has grown tremendously in the recent literature, the majority of the transformations still require rigorous setup conditions, prefunctionalized substrates and specially tuned catalysts to deliver the fluorine atom in an enantioselective manner in order to construct β- fluoroamines. Recently developed in our group is a chiral proton-catalyzed direct aza-Henry reaction between α- fluoronitroalkanes and readily accessible imines. These adducts provide access to β-fluoro-β-nitroamines in good
118 Percy, J. M. Sci. Synth. 2005, 34, 379.
119 Clark, J. L.; Hollecker, L.; Mason, J. C.; Stuyver, L. J.; Tharnish, P. M.; Lostia, S.; McBrayer, T. R.; Schinazi, R. F.; Watanabe, K.
A.; Otto, M. J.; Furman, P. A.; Stec, W. J.; Patterson, S. E.; Pankiewicz, K. W. J. Med. Chem. 2005, 48, 5504.
120 Morgenthaler, M.; Schweizer, E.; Hoffmann-Roder, A.; Benini, F.; Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.; Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Muller, K. ChemMedChem 2007, 2, 1100.
Figure 24. Some β-Fluoroamine-Containing Pharmaceutical Agents
synthetic yield and high enantioselectivity. Subsequent stannane-mediated radical denitration of the aza-Henry adduct affords the β-fluoroamine motif in good yield via synthetically practical procedures (Scheme 51).121 While these β-fluoroamines are inherently valuable by themselves, the ability to transform them into biologically relevant compounds would be especially noteworthy. β-Fluoroamines are known to have dramatic influences on blood-brain barrier penetrant small molecules. With the multitude of data on the pharmaceutical benefits of fluorine, and the specific effect fluorine has on blood-brain barrier penetrance, we wondered what effect adding a fluorine atom β to the amine would have on the properties of morphine.
In order for morphine to be active, it must cross the blood-brain barrier to access opioid receptors. To interact with these receptors, the amine must be protonated. However, the molecule must be the free base to transverse the blood-brain barrier. We hypothesized that a fluorinated morphine molecule would be more lipophilic than its parent molecule, thereby helping to facilitate the transversing of the blood-brain barrier. The amine should still be basic enough to be reversibly protonated at physiological pH, however, and therefore be active once inside the blood-brain barrier. In other words, we thought that fluorinated morphine may have increased beneficial properties.
We established the goal to synthesize four molecules related to morphine. The first target was a stereoenriched fluorinated intermediate within Rice’s route to morphine, which could eventually be carried through toward a complete chemical synthesis of fluorinated morphine. Since Rice’s route is arguably the most efficient route in the literature, we reasoned that intercepting the route could also lead to a concise synthesis of a fluorinated morphine. We also targeted fluorinated norcoclaurine and fluorinated reticuline in order to submit them to the biosynthetic opioid pathway in yeast with hopes to probe the promiscuity of the enzymatic machinery and produce fluorinated opioid derivatives. If it becomes possible to produce them via fermentation instead of chemical
121 Vara, B.A.; Johnston, J.N. Manuscript Submitted.