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Patricia Van Arnum was executive editor of Pharmaceutical Technology.
Fluorinated molecules play an important role as pharmaceutical compounds. Recent advances seek to overcome the challenges of selective and late-stage insertion of fluorine into small molecules.
Fluorine-based compounds play an important role in pharmaceuticals. It is estimated that up to 20% of pharmaceuticals on the market or in clinical development contain a fluorine atom, and 30% of key blockbuster drugs contain fluorine (1). Given the importance of fluorine-based molecules in drug development, chemists must overcome challenges associated with fluorination of small molecules.
Polyketide synthase pathways
Researchers at the University of California at Berkeley and Stanford University in California reported on their elucidation of engineered polyketide synthase pathways as a means to produce organofluorines (2). The researchers engineered two changes into Escherichia colibacteria that had previously been engineered to make polyketides (2, 3). In their work, the researchers showed that a pathway for producing fluoroacetate can be used as a source of fluorinated building blocks for introducing fluorine into natural-product scaffolds. Specifically, they constructed pathways involving two polyketide synthase systems and showed that fluoroacetate can be used to incorporate fluorine into the polyketide backbone in vitro. The researchers further showed that fluorine can be inserted site-selectively and introduced into polyketide products in vivo. The researchers asserted that their work shows the potential of producing complex fluorinated natural products using synthetic biology (2, 3).
Catalytic enantioselective cyclization
Researchers at the University of North Carolina at Chapel Hill reported on their work involving catalytic enantioselective cyclization and C3-fluorination of polyene (4, 5). The researchers reported that xylyl-phanephos) Pt
in combination with XeF
mediates the consecutive diastereoselectivecation-olefin cyclization/fluorination of polyene substrates (5). The researchers reported that isolated yields were typically in the range of 60-69%, and enantioselectivities reached as high as 87%. The researchers noted that the data were consistent with a stereoretentive fluorination of a P
Pt-alkyl cation intermediate (5). The researchers detailed a [Pt]-catalyzed method for first cyclizing polyenes and then selectively fluorinating at the C3 position using XeF
. The addition of TMS-OMe to scrub adventitious HF provided a procedure that gave isolated yields as high as 80% and enantioselectivities up to 87% (4, 5). The researchers proposed a mechanism by which the substrate undergoes a [Pt]-initiated cascade cyclization to generate an intermediate [Pt]-alkyl, which is observed as the catalytic resting state. This compound reacted with XeF
faster than ß-H elimination to give the desired fluorinated product with a stereochemistry that is retentive at the original C3-Pt position (4, 5).
Tobias Ritter, a professor of chemistry in the Department of Chemistry and Chemical Biology at Harvard University in Cambridge, Massachusetts, and his team, recently reported on their work involving palladium(III)-catalyzed fluorination of arylboronic acid derivatives. The researchers noted that developing practical carbon−fluorine bond-forming reactions to provide aryl fluorides is challenging. The researchers reported on a palladium-catalyzed fluorination of arylboronic acid derivatives, which allowed for an operationally simple, multigram-scale synthesis of functionalized aryl fluorides (6). The researchers proposed that the reaction mechanism involved a single-electron-transfer pathway involving a palladium (III) intermediate that was isolated and characterized. According to the researchers, the kinetic studies suggested a mechanism distinct from other known arene fluorination reactions without forming organopalladium species and offers an advantage over other metal-catalyzed or -mediated arene fluorination reactions. The researchers noted the reaction does not produce side products from protodemetalation, a common problem in synthesizing aryl fluorides (6), but the reaction had certain drawbacks, such as the inability to fluorinate heterocycles and form constitutional isomers for some electron-poor substrates (6).
Carbon-fluorine bond formation is an active area of research by Ritter and his group. Carbon-fluorine bond formation is a challenging chemical transformation, particularly for functional group-tolerant, late-stage fluorination of arenes (7). The researchers’ approach uses high-valent transition metal fluorides by means of oxidation of aryl transition metal complexes with electrophilic fluorination reagents (7). The group’s long-term goal is to develop new methods for the synthesis of small-molecule tracers for positron emission tomography (PET), an imaging method to study biological processes in vivo. PET with the isotope 18F is currently limited by the absence of general chemistry that can introduce fluorine into molecules at a late stage, and carbon-fluorine bond formation using high-valent transition metal fluorides via oxidation of aryl transition metal complexes with electrophilic fluorination reagents is one approach to resolve that challenge (7-9).
Ritter and his team also developed an approach for silver-catalyzed late-stage fluorination using a cross-coupling reaction that attached fluorine atoms onto aromatic substituents. The reaction used silver oxide to catalyze the fluorination of aryl tin compounds with the electrophilic fluorinating reagent N-chloromethyl-N-fluorotriethylenediammonium hexafluorophosphate. The researchers asserted that the reaction was the first example of silver catalysis for carbon-heteroatom bond formation by cross-coupling chemistry (9, 10).
Carbon-fluorine bond formation by transition-metal catalysis is difficult. Typically, transition metal-catalyzed fluorination reactions for synthesizing functionalized arenes use palladium as the metal in the catalyst (9, 10). A key benefit of the silver-catalyzed fluorination reaction is the variety of functional groups that can be tolerated and breadth of substrates used. The researchers applied the cross-coupling reaction to fluorinate polypeptides, polyketides, and alkaloids and showed tolerance by various functional groups, including vinyl ethers, dienones, alcohols, allylic alcohols, ethers, esters, and oxetanes (9, 10).
G.K. Surya Prakash, professor of chemistry at the University of Southern California (USC) and director of the USC Loker Hydrocarbon Research Institute, and his team reported on their work in using fluoroform (CF3H) in the direct nucleophilic trifluoromethylation of silicon, boron, sulfur, and carbon centers (11). Fluoroform is a byproduct of the manufacture of polytetrafluoroethylene (Teflon), refrigerants, polyvinylidene fluoride, and other products. Although fluoroform has little practical use, the trifluoromethyl (-CF3) functionality is important for pharmaceuticals (11). The researchers elucidated the conditions needed to convert fluoroform into useful reagents, including the silicon-based Ruppert-Prakash reagent for efficient (-CF3) transfer. Fluoroform with elemental sulfur was also converted to trifluoromethanesulfonic acid, a widely used superacid, according to a Dec. 7, 2012 USC press release. Specifically, the researchers reported on a direct trifluoromethylation protocol using close to stoichiometric amounts of CF3H in common organic solvents, such as tetrahydrofuran, diethyl ether, and toluene. The researchers reported that the approach can be applied to a variety of silicon, boron, and sulfur-based electrophiles as well as carbon-based electrophiles.
Researchers at the RIKEN Advanced Science Institute in Wako, Japan reported on their work on the copper-catalyzed trifluoromethylation of allylsilanes (12). Trifluoromethylation of allylsilane derivatives was achieved using CuI and Togni’s reagents under mild conditions. Specifically, the researchers developed a synthesis technique that selectively and efficiently combined fluorine and amino acids into the same organic molecule, according to a Sept. 28, 2012 RIKEN Advanced Science Institute press release. The starting materials were alpha-keto esters that contained a carbonyl group and an ester group. The first reaction involved the substitution of a hydrogen atom, on the carbon atom adjacent to the carbonyl group, for a fluorine atom, resulting in two enantiomers for which a palladium-based catalyst was used to preferentially produce one of the enantiomers, thereby making the reaction enantioselective. The carbonyl group of the fluorinated alpha-keto ester was then transformed to a hydroxyl group with two possible stereoisomers, for which one stereoisomer could be preferentially produced by using different reagents. The technique not only introduced fluorine, but two stereogenic centers to the molecule. Forming two stereogenic centers created the possibility of four different stereoisomers, which were subsequently isolated in separate reaction sequences. The researchers’ future interests involve widening the fluorination reaction to other starting materials, according to the release.
1. D. O’Hagan, J. Fluorine Chem. 131 (11), 1071-10801 (2010.
2. M.C.Y. Chang et al., Science 341 (6150) 1089-1094 (2013).
3. R.F. Service, Science 341 (6150) 1052-1053 (2013).
4. M.R. Gagné, “Group Research Highlights: Catalytic Enantioselective Cyclisation (University of North Carolina, Chapel Hill, NC ), www.chem.unc.edu/people/faculty/gagne/?display=research_display&show=all, accessed Sept. 20, 2013.
5. N.A. Cochrane , H. Nguyen and M.R. Gagné, J. Am. Chem. Soc. 135 (2) 628-631 (2013).
6. T. Ritter et al., J. Am. Chem. Soc. online, DOI: 10.1021/ja405919z, Sept. 16, 2013.
7. Ritter Group, “Research: Functional Group-Tolerant Late-Stage Carbon-Fluorine Bond Formation (Harvard University, Cambridge, MA), www.chem.harvard.edu/groups/ritter/research.html, accessed Sept. 20, 2013.
8. T. Ritter et al., Science 334 (6056) 639-642 (2010).
9. P. Van Arnum, Pharm. Technol. 34 (12) 40-42 (2010).
10. T. Pingping, T Furuya and T. Ritter ,J. Am. Chem. Soc. 132 (34) 12150-12154 (2010).
11. G.K. Surya Prakash, et al., Science 338 (6112) 1324-1327 (2012).
12. M. Sodeoka et al., Angew. Chem. Int. Ed. Engl. 51 (19) 4577-4580 (2012).