Selective Light-Driven Chemoenzymatic Trifluoromethylation

Research Article Cite This: ACS Catal. 2018, 8, 2225−2229

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Selective Light-Driven Chemoenzymatic Trifluoromethylation/ Hydroxylation of Substituted Arenes Victor Sosa, Marya Melkie, Carolina Sulca, Jennifer Li, Lawrence Tang, Jeffrey Li, Justin Faris, Bridget Foley, Tam Banh, Mallory Kato, and Lionel E. Cheruzel* Department of Chemistry, San José State University, One Washington Square, San José, California 95192-0101, United States S Supporting Information *

ABSTRACT: The merging of photoredox trifluoromethylation with hybrid P450 BM3 variants has enabled the selective lightdriven functionalization of several arenes. This approach capitalizes on the unique photochemical properties of the Ru(II)diimine photosensitizer to initiate single electron transfer events. Under photoredox conditions, a CF3 radical promoted by the d6 metal complex can add to arenes. In the hybrid P450 BM3 enzymes, the covalently attached Ru(II)-diimine photosensitizer provides the necessary electrons to perform, upon visible light activation, P450 oxyfunctionalizations on the trifluoromethylated substrates. KEYWORDS: chemoenzymatic process, light-driven biocatalysis, trifluoromethylation/hydroxylation, Ru(II)-diimine photosensitizer, electron transfer

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their mutational tolerance, they have been particularly suitable for optimization by protein engineering.11 With the recent advancement of photoredox trifluoromethylation,12 we sought to merge this approach with the hybrid P450 BM3 enzymes in order to perform selective chemoenzymatic trifluoromethylation/hydroxylation upon visible light irradiation. The introduction of trifluoromethyl groups has surged in pharmaceuticals owing to their beneficial properties13 and is expected to keep increasing with the advancement of synthetic methodology. Selected examples of recently approved FDA drugs are shown in Figure 1, highlighting the diverse scaffolds bearing trifluoromethyl (CF3) groups. Pioneering work by Fasan and Arnold demonstrated the combination of P450-catalyzed oxygenation with deoxyfluorination to achieve selective fluorinated organic compounds.14 Hartwig and Zhao merged an organometallic catalyst with the P450 BM3 enzyme to perform selective epoxidation of the cross-metathesis product.15 Recently, the Fasan group established a chemo-biocatalytic approach for producing trifluor-

hemoenzymatic approaches offer the advantages of combining the potential of chemocatalysis with biocatalysts selectivity and evolvability.1 Recent advances in C−H bond activation have resulted in the expansion of the organic reaction toolbox and opened new avenues for the diversification of building blocks and late-stage functionalization of various compounds.2 Among the strategies employed for C−H functionalization, visible light photoredox catalysis has emerged as a new and innovative approach.3 Among photosensitizers of choice, d6 metal complexes,3 such as Ru(II)-diimine, and more recently organic photosensitizers4 have been shown to possess suitable excited-state photochemical properties to initiate radical processes. The Ru(II)-diimine complexes have also been used in the study of long-range electron transfer in modified metalloproteins5 and have found applications in the light-driven activation of various enzymatic reactions.6 Our laboratory has developed hybrid P450 enzymes containing a covalently attached Ru(II)-diimine photosensitizer able to deliver the necessary electrons to P450 BM3 heme domain enzymes7 and harness their synthetic potential8 upon visible light excitation. Cytochrome P450s are heme thiolate enzymes that catalyze a breadth of chemical reactions9 such as regio- and stereoselective C−H oxyfunctionalization, O-dealkylation, heteroatom oxidation, and noncanonical reactions.10 Due to © 2018 American Chemical Society

Received: December 5, 2017 Revised: January 28, 2018 Published: January 31, 2018 2225

DOI: 10.1021/acscatal.7b04160 ACS Catal. 2018, 8, 2225−2229

Research Article

ACS Catalysis

Table 1. Summary of the Compounds Selectively Functionalized Using the Light-Driven Chemoenzymatic Approach

Figure 1. Selected examples of approved FDA drugs containing trifluoromethyl groups.

omethyl-substituted cyclopropanes using engineered myoglobin variants.16 Herein, we focus on substituted arenes that could be trifluoromethylated using photoredox catalysis and subsequently selectively functionalized by the light-driven hybrid enzymes according to Scheme 1. Using the combined lightdriven approaches, eight compounds (see Table 1) were selectively functionalized with moderate to good yields by three novel hybrid enzymes. The hybrid enzymes, F87V-Ru, A82F-Ru, and D52-Ru, were generated as previously reported7a,17 and feature a Ru(bpy)2PhenA (Ru) photosensitizer (bpy = 2,2′-bipyridine and PhenA = 5-acetamido-1,10-phenanthroline) covalently attached to the non-native single cysteine L407C. The covalent attachment of the photosensitizer at this position led previously to high photocatalytic activity and initial reaction rates in the hydroxylation of long chain fatty acid substrates.7c Subsequent characterizations revealed that the photosensitizer is ideally located where the redox partner is thought to bind and that the photogenerated reductive species has the appropriate driving force for fast electron delivery using highly conserved amino acid residues.7b The F87V18 and the “gatekeeper” F87V/ A82F19 mutations are known to enable the oxyfunctionalization of several aromatic compounds. The D52-Ru mutant was identified via a directed evolution approach, recently initiated in our laboratory, focusing on light-driven benzylic hydroxylation using the chromogenic 1-benzyl-4-nitrophenyl ether substrate. 17 This evolved mutant (R167L/K224N/S383N/ L407C/D434A) displays enhanced photocatalytic activity toward propylbenzene (3-fold) and naphthalene (10-fold) compared to the sL407C-Ru parent (see Figure S1).

a

The asterisks represent the various sites of trifluoromethylation. Determined HPLC yield over two reaction steps. cWith 400 μM substrate, 2 μM hybrid enzyme, and 100 mM sodium diethyldithiocarbamate. b

Under Stephenson photoredox conditions using trifluoroacetic anhydride and pyridine N-oxide,12a all compounds listed in Table 1 could be trifluoromethylated in good yields. Often a mixture of isomers is produced with the exception of 7ethoxycoumarin (entry 7), which was quantitatively converted to the 3-CF3 analogue. The compounds were thoroughly characterized by 1H, 13C, and 19F NMR as well as gas chromatography−mass spectrometry (GC/MS; see Figures S2−S13). In most cases, the isomers could be separated by reversed-phase high-performance liquid chromatography (HPLC) to unambiguously confirm the position of trifluoromethylation and hence the substrate selectivity of the hybrid enzymes. All trifluoromethylated compounds were subjected to the hybrid enzymes under the light-driven reaction conditions.7a,17 The products were characterized by HPLC and GC/MS after silylation of the alcohol moiety. Starting with diphenylmethane (entry 1, Table 1), the photoredox trifluoromethylation yielded a mixture of three isomers (1a−c) that could be further separated into the ortho

Scheme 1. Merging of the Photoredox and Hybrid Enzymes for the Light-Driven Trifluoromethylation/Hydroxylation of Substituted Arenes Taking Advantage of the Photochemical Properties of Ru(II)-Polypyridyl Complexes

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DOI: 10.1021/acscatal.7b04160 ACS Catal. 2018, 8, 2225−2229

Research Article

ACS Catalysis

Figure 2. GC chromatograms of the products obtained from the light-driven chemoenzymatic reactions. (A) Example of selective hydroxylation by the F87V-Ru enzyme with the trifluoromethylated diphenylmethane mixture (1a−c) as well as with the separated meta-substituted isomer (1b) and ortho/para-substituted isomer mixture (1a,c). The retention times for 2a and 2b match those of authentic standards (black traces). Products obtained with the various hybrid enzymes D52-Ru (blue), F87V-Ru (red), and A82F-Ru (black) with trifluoromethylated indane, 3a,b (B); propylbenzene, 5a−c (C), and bromopropylbenzene, 8a,b (D).

respectively) when compared to authentic standards. The D52Ru mutant shows preference for the para and meta position as no ortho product (6a) could be detected. The A82F-Ru mutant, however, shows preference for the ortho/meta positions as no 4-CF3-1-phenylpropanol product (6c) was observed (see Figure 2C). Interestingly, for the F87V-Ru, the hydroxylation occurs predominantly at the least favored β position on the propyl chain based on the mass fragmentation pattern observed after silylation of the 7b product (see Figure S16). While some engineered P450 BM3 mutants have shown such unique regioselectivity,22 the F87V mutant displayed only 20% selectivity for the β position of propylbenzene.18a The presence of the CF3 group at the meta position in 5b promotes the regioselectivity of hydroxylation at this position predominantly. Recent reports by Sherman23 and Bell24 elegantly demonstrated the directing role of anchors and ester functionality on substrates to mediate selective P450 hydroxylation. We expanded the scope of the light-driven reactions to probe the functional group tolerance (with 8, 13, and 15, entries 4, 6, and 7, respectively), trifluoromethylation selectivity (15, entry 7), and heteroarene functionalization (17, entry 8) as well as the various reactions catalyzed by P450 enzymes including direct arene hydroxylation (11, entry 5), O-dealkylation (13 and 15, entries 6 and 7, respectively), and heteroatom oxyfunctionalization (17, entry 8). Trifluoromethylation of bromopropylbenzene (entry 4) yields a 65:35 mixture of 8a and 8b, respectively, with the CF3 group adjacent to the electron-withdrawing group on the arene of 8a. Hydroxylation was noted with all three hybrid enzymes, as shown in Figure 2D, albeit with different regioselectivities. The two isomers were separated by reversed-phase HPLC (Figures S6 and S7) and individually submitted to the enzymatic hydroxylation conditions to confirm the isomer preference. All mutants selectively hydroxylated the major product 8a (Figure S17). The D52-

and para isomers (1a and 1c, respectively) and the meta isomer (1b). When the mixture of 1a−c was submitted to the lightdriven enzymatic reactions, hydroxylated products were observed with the three hybrid enzymes. As shown in Figure 2A for F87V-Ru, only the ortho-substituted (1a) and metasubstituted (1b) isomers are hydroxylated to the corresponding 2a and 2b products, respectively, based on mass fragmentation and comparison with authentic standards. Furthermore, compound 1a is preferentially hydroxylated over the para isomer, 1c, for the A82F-Ru and F87V-Ru mutants, whereas the D52-Ru mutant shows negligible activity (see Figure S14). The meta-substituted isomer (1b) is hydroxylated to 2b by all three variants with a 93% ee noted for the F87V-Ru. We wanted to further investigate the isomer selectivity as well as the hydroxylation regioselectivity of the hybrid enzymes using the trifluoromethylated compounds listed in Table 1. The trifluoromethylation of indane yielded a mixture of two isomers, 3a and 3b, in a 60:40 ratio, respectively (see Figure S4). The mixture was subjected to the hybrid enzymes, and hydroxylation was found to occur at the benzylic position with all enzymes (see Figure S15). Substrate selectivity was achieved by varying the hybrid enzyme variant as shown in Figure 2B. The D52-Ru and F87V-Ru mutants hydroxylated both CF3 isomers to the 4a,b products. A82F-Ru, on the other hand, selectively hydroxylated only one of the two isomers to yield primarily 5-CF3-1-indanol (4a) with a 62% ee. The wild-type P450 BM3 enzyme displays minimal stereoselectivity in indane hydroxylation (16% ee), which could be enhanced using decoy molecules (50% ee)20 or directed evolution (60−99% ee).21 Upon trifluoromethylation of propylbenzene, three products (5a−c) were obtained in equal amount with a slight preference for the meta position (see Figure S5). Different hydroxylated products were obtained depending on the hybrid enzymes and the position of the CF3 substituents (see Figure S16). Using the evolved variant, two hydroxylated products were observed and identified as the 3- and 4-CF3-phenyl-1-propanol (6b and 6c, 2227

DOI: 10.1021/acscatal.7b04160 ACS Catal. 2018, 8, 2225−2229

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Ru variant hydroxylated at the benzylic position to form 9a, whereas the F87V-Ru and A82F-Ru mutants yielded hydroxylation at the β position of the propyl chain in 10a. Naphthalene (entry 5) was primarily trifluoromethylated in high yield at position 1 (11a), as shown in Figure S8, and could solely be hydroxylated to 12 by the evolved variant, D52-Ru (Figure S18), which showed enhanced activity toward naphthalene. The traditional substrates to probe O-dealkylation of P450 enzymes have involved the chromogenic p-nitrophenoxy or fluorogenic ethoxycoumarin derivatives. The 1-octyl-4-nitrophenyl ether compound was previously used to evolve P450 BM3 variants toward short alkane functionalization.25 Its trifluoromethylation yielded, after purification, a major compound (13, Figure S9) with the CF3 group adjacent to the electron-withdrawing nitro group rather than the electrondonating alkoxy substituent. The trifluoromethylated substrate 13 could then be dealkylated by the D52-Ru mutant to yield the yellow chromophore 3-CF3-4-nitrophenolate, 14, displaying a 20 nm blue shift in absorbance maximum compared to the well-known nitrophenolate analogue (see Figure S19). Interestingly, trifluoromethylation of the 7-ethoxycoumarin yielded solely the 3-CF3-7-ethoxycoumarin product (15, entry 7). The 1H, 13C, and 19F NMR spectra in Figure S10 confirm that compound 15 is an isomer of the commercially available 4CF3-7-ethoxycoumarin used to probe the activity of human P450 isoforms.26 Despite low activity noted with all current hybrid enzyme mutants, the 3-CF3-7-ethoxycoumarin, 16, formed displays fluorescence emission shifted compared to the 4-CF3- and 7-hydroxycoumarin counterparts (see Figure S20). Heteroarene functionalization was probed with quinoline (entry 8). Under the trifluoromethylation conditions, two isomers were obtained, which could be separated, revealing that trifluoromethylation occurred primarily at the 5 and 8 positions in compounds 17a and 17b, respectively (Figures S11 and S12). The F87V-Ru mutant produced only one oxidized compound, in 78% yield, from the mixture of isomers (see Figure S21). From the mixture or the two trifluoromethylated quinolines individually, only the 5-CF3-quinoline (17a) is being converted to its N-oxide analogue, which matches an authentic sample prepared independently by meta-chloroperoxybenzoic acid oxidation27 (see Figure S21). The presence of CF3 at the 5 position in 17a promotes N-oxidation versus hydroxylation previously reported for quinoline.28 In conclusion, this light-driven chemoenzymatic approach enables the selective trifluoromethylation/hydroxylation of substituted arenes by capitalizing on the photochemical properties of Ru(II)-diimine photosensitizers and hybrid P450 BM3 enzymes. This system also benefits from the selectivity of the P450 BM3 mutants to differentiate between the trifluoromethylated isomers and produce regio- and stereoselective products. Further engineering of the hybrid enzymes could alleviate the need to purify the mixture of trifluoromethylated products and yield highly selective hydroxylation of desired isomers “on demand”. This methodology could thus find applications in late-stage functionalization of target compounds3b,29 and toward the tailored diversification of lead compounds.30

Research Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.7b04160. Synthetic details and general procedures; characterization data including 1H, 19F, and 13C NMR spectra; HPLC and GC/MS chromatograms (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lionel E. Cheruzel: 0000-0003-0283-6816 Author Contributions

L.C. and M.K. designed the experiments, analyzed the data, and wrote the manuscript. V.S. and M.M. performed the key experiments. All authors contributed significantly to the work presented in this paper. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation through Grant No. 1509924 (L.C.). M.M. acknowledges financial support from National Institute of General Medical Sciences of the National Institutes of Health under Award No. R25GM071381. C.S. acknowledges financial support from CSU-LSAMP, funded through the National Science Foundation under Grant No. HRD-1302873 and the Chancellor’s Office of the California State University.

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