Preorganized Cyclic α,α-Disubstituted α-Amino Acids Bearing

Note pubs.acs.org/joc

Preorganized Cyclic α,α-Disubstituted α‑Amino Acids Bearing Functionalized Side Chains That Act as Peptide-Helix Inducers Hiroyuki Kobayashi,†,‡ Takashi Misawa,† Kenji Matsuno,‡ and Yosuke Demizu*,† †

Division of Organic Chemistry, National Institute of Health Sciences, Tokyo 158-8501, Japan Department of Chemistry and Life Science, Kogakuin University, 2665-1 Nakano, Hachioji, Tokyo 192-0015, Japan

‡

S Supporting Information *

ABSTRACT: Preorganized cyclic α,α-disubstituted α-amino acids (dAA) bearing functionalized side chains that acted as peptide-helix inducers, which could be used for solid-phase peptide synthesis, were designed and synthesized. Furthermore, a helical octapeptide with the following amino acid sequence was prepared, and its preferred conformation was analyzed based on its CD spectra: Ac-X1EYSAX2KA-NH2 (11: X1 = ApiC4N3, X2 = Ac6c). The side-chain azido functional group of peptide 11 was efficiently converted to various 1,2,3-triazole groups via Huisgen 1,3-dipolar cycloaddition reactions involving different types of alkynes. The new cyclic dAA derivatives, which combine the advantages of conformational preorganization and side-chain functional groups, should prove to be a useful tool for the further development of biologically active peptides.

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elical structures in proteins are one of the most important secondary structures in living systems because they act as mediators of protein−protein and protein−DNA interactions. In order to express these functions in oligopeptide units, it is important to design peptide molecules that can form similar helical structures as in proteins. Thus, the strategy of peptidehelix stabilization has been established to be effective at enhancing bioactivities. As mimics of helix-stabilized peptides, several types of helical oligomers so-called “foldamers”, α-,1 β-,2 and γ-peptide foldamers,3 aromatic amide foldamers,4 urea-type foldamers,5 have been reported. These foldamers are generally constructed using rigidly locked molecules, and regarding αpeptide foldamers, α,α-disubstituted α-amino acids (dAA) are often utilized as the peptide-helix promotors. To date, various types of achiral, chiral, acyclic, and cyclic dAA have been developed,1 and we recently developed two types of cationic cyclic dAA, both of which are 4-aminopiperidine-4-carboxylic acid (Api) derivatives, ApiC2NH2 as a lysine mimic and ApiC2Gu as an arginine mimic (Figure 1).6 Furthermore, ApiC2NH2 and ApiC2Gu residues were incorporated into the nonhelical nonaarginine, and the relationship between their preferred secondary structures and cell permeabilities was investigated. The result showed that the peptides (Arg-Arg-dAA) 3 containing ApiC2NH2 or ApiC2Gu were able to form stabilized helices and to possess higher cell penetrating ability than the © 2017 American Chemical Society

Figure 1. Chemical structures of the cationic cyclic dAA Api, ApiC2NH2, and ApiC2Gu.

nonaarginine. Thus, side-chain functionalized Api derivatives7 could be useful helical promoters and might enhance the biological activities of oligopeptides. In this Note, we designed and synthesized preorganized Api derivatives with various functionalized (peptide-helix-inducing) side chains, which could be used for solid-phase peptide synthesis (SPPS). The three main advantages of using Api as a skeleton are as follows: (1) Api is an achiral amino acid and is easy to synthesize in large quantities; (2) Api contains a piperidine moiety; therefore, a variety of functional groups can be easily attached to its side chain; and (3) cyclic dAA can be Received: August 2, 2017 Published: September 15, 2017 10722

DOI: 10.1021/acs.joc.7b01946 J. Org. Chem. 2017, 82, 10722−10726

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The Journal of Organic Chemistry

Then, peptides Ac-X1EYSAX2KA-NH2 10 (X1 = ApiC2CO2H, X = Ac6c) and 11 (X1 = ApiC4N3, X2 = Ac6c), which contained proteinogenic hydrophobic (Ala), hydrophilic (Ser), acidic (Glu), and basic (Lys) amino acids, as well as dAA, were synthesized using microwave-assisted solid-phase methods. The sequence was selected to prove that the “click reaction” would proceed smoothly despite the presence of some reactive functional groups on the sequence. The peptide AcAEYSAAKA-NH 2 (9), which was solely composed of proteinogenic amino acid residues, was also prepared as a control (Figure 2). “Click reactions” between the side-chain azido group of peptide 11 and three types of alkynes were performed (Scheme 2).9 The reactions of 11 (on resin)10 with the alkynes proceeded smoothly to give the corresponding triazoles 12− 14 (Scheme 2a). Furthermore, the reaction of the unprotected peptide 11, which contained several natural amino acids with reactive functional groups, also proceeded to afford peptide 13 in only 30 min (Scheme 2b). Next, we assessed the CD spectra of the peptides in PBS buffer to analyze their preferred secondary structures (Figure 3). The spectrum of peptide 9 displayed negative maxima at 197 nm, indicating that 9 formed random structures in PBS buffer (Figure 3a). On the other hand, the spectra of peptides 10 and 11, which contained cyclic dAA, displayed negative maxima at around 208 and 225 nm, indicating that 10 and 11 formed right-handed (P) helical structures (Figure 3b).11 Based on the R ratios (θ225/θ208) of peptides 10 and 11, it was considered that the dominant conformations of them were 310helices (R = 0.45 for 10, 0.43 for 11), respectively.11b,c Thus, the insertion of cyclic dAA residues into short peptide sequences could be a useful technique for stabilizing helical structures.1,6,12 Furthermore, the spectrum of peptide 13 after the “click reaction” showed similar helical patterns to that of 11 before the reaction, indicating that the side-chain triazole group did not affect the secondary structure of the peptide (Figure 3c).13 In summary, we designed and synthesized preorganized cyclic dAA that contained side-chain functional groups (peptide-helix inducers), which can be used for general SPPS.

introduced into peptide sequences more efficiently than acyclic dAA. The designed Api derivatives were introduced into peptides to prepare helical octapeptides with the following sequence via SPPS: Ac-X1EYSAX2KA-NH2 (X1, X2 = dAA). Furthermore, the side-chain azido group on the peptide was converted to various 1,2,3-triazole groups via Huisgen 1,3dipolar cycloaddition reactions involving alkynes (“click reactions”). The preferred conformations of the peptides before and after the “click reactions” were analyzed based on their CD spectra in phosphate-buffered saline (PBS) buffer. Scheme 1 shows the synthetic route for the Fmoc-protected dAA, which contained different functionalized side chains. The

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Scheme 1. Synthesis of Fmoc-Protected Api Derivatives 2−8

starting Fmoc-Api(Boc)-OH (1) was synthesized according to the method described in a previous report.8 The designed Fmoc-protected dAA (2−8) were synthesized via a Boc deprotection on the piperidine ring under acidic conditions, followed by a coupling with the corresponding carboxylic acids. Mimetics of Lys (2),6 Arg (3),6 Leu (4), Phe (5), Ser (6), Asp/ Glu (7), and an azido-containing Api derivative (8) that could be subjected to postmodification were prepared.

Figure 2. Synthesized peptides 9−11. 10723

DOI: 10.1021/acs.joc.7b01946 J. Org. Chem. 2017, 82, 10722−10726

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The Journal of Organic Chemistry Scheme 2. “Click Reaction” of the Side-Chain Azido Group of Peptide 11

Figure 3. The 190−260 nm regions of the CD spectra of (a) 9, (b) 10 and 11, and (c) 11 and 13 (peptide concentration: 0.1 mM in PBS buffer).

structure, and thus, the side-chain modification of the azido group of peptide 11 to a triazole group did not affect the secondary structure of the peptide. This strategy could also be useful for the side-chain to side-chain cross-linking by introducing an amino acid residue with the side-chain alkyne in the intramolecular sequence to produce stabilized helical peptides. Thus, the preorganized cyclic dAA described in this study are expected to be invaluable for designing foldamer scaffolds, new peptide-based drugs,14 and materials.

The model octapeptides Ac-AEYSAAKA-NH2 (9), AcX1EYSAX2KA-NH2 10 (X1 = ApiC2CO2H, X2 = Ac6c), and 11 (X1 = ApiC4N3, X2 = Ac6c) were synthesized using microwaveassisted SPPS, and their preferred secondary structures were analyzed based on their CD spectra in PBS buffer. Peptide 9 formed random structures, whereas peptides 10 and 11 formed stable helical structures, as expected. It was demonstrated that the insertion of Api derivatives into short peptide sequences is useful for inducing a helical structure. Postmodification of the helical peptide 11 via “click reactions” was also demonstrated. Three types of alkynes with maleimide, polyethylene glycol (PEG), and sterically bulky moieties, respectively, were used for these reactions. The reactions proceeded smoothly, even with the peptide on resin, and the desired products were obtained after excision. Furthermore, peptide 13, which was produced by one of these reactions, also predominantly folded into a helical

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EXPERIMENTAL SECTION

General. 1H and 13C NMR spectra were recorded at 400 and 100 MHz in CDCl3 with tetramethylsilane used as an internal standard. FT-IR spectra were recorded at 1 cm1 resolution, with an average of 128 scans used for the solution (CDCl3) method and a 0.1 mm path length for NaCl cells. High-resolution mass spectra were recorded with 10724

DOI: 10.1021/acs.joc.7b01946 J. Org. Chem. 2017, 82, 10722−10726

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The Journal of Organic Chemistry

NMR (400 MHz, CDCl3) δ 7.76 (2H, d, J = 7.6 Hz), 7.57 (2H, d, J = 7.6 Hz), 7.40 (2H, t, J = 7.6 Hz), 7.30 (2H, d, J = 7.6 Hz), 5.14 (1H, br), 4.48 (2H, br), 4.20 (1H, t, J = 6.4 Hz), 4.13 (1H, d, J = 14.4 Hz), 3.63 (1H, br), 3.30 (2H, t, J = 6.4 Hz), 3.26 (1H, br), 3.12 (2H, br), 2.34 (2H, t, J = 6.4 Hz), 2.14 (2H, br), 1.99 (1H, br), 1.40 (1H, br), 1.74−1.61 (4H, m); 13C NMR(100 MHz, CDCl3) δ 175.9, 171.0, 155.9, 143.6, 143.5, 141.4, 127.8, 127.1, 124.9, 120.1, 66.9, 57.5, 51.2, 47.2, 41.3, 37.1, 32.6, 32.5, 32.0, 28.5, 22.3; [HR-ESI(+)-TOF]: m/z calcd for C26H30N5O5 [M + H]+ 492.2249: found 492.2250. Synthesis and Purification of Peptides 9−11. Peptides 9−11 were synthesized using microwave-assisted solid-phase methods on NovaPEG Rink amide resin according to standard Fmoc chemistry techniques. Microwave irradiation (MARS6; CEM corporation) was performed for coupling and Fmoc deprotection using open reaction vessels monitoring the internal reaction mixture temperature. The following describes a representative coupling and deprotection cycle at a 25 μmol scale. First, 65 mg NovaPEG Rink amide resin (loading: 0.5 mmol/g) was soaked for 1 h in CH2Cl2. After the resin had been washed with N,N-dimethylformamide (DMF), Fmoc-amino acid (4 equiv) and HATU (4 equiv) dissolved in 1.5 mL N-methyl-2pyrrolidone (NMP) were added to the resin. Then, N,Ndiisopropylethylamine (8 equiv) and HOAt (1.0 mL, 0.1 M solution in NMP) were added to the above mixture and coupled for 8 min at 60 °C. Deprotection was carried out using 2 mL of 20% piperidine in DMF (2 mL) for 6 min at 80 °C. After the peptide synthesis, the resin was suspended in cleavage cocktail (1.9 mL trifluoroacetic acid [TFA], 50 μL water, and 50 μL triisopropylsilane [TIPS]; final concentration: 95% TFA, 2.5% water, and 2.5% TIPS) for 3 h at room temperature. The TFA solution was evaporated to a small volume under a stream of N2 and dripped into cold ether to precipitate the peptides. The dried crude peptides were dissolved in 1.3 mL of 50% acetonitrile in water and then purified by reversed-phase high-performance liquid chromatography (HPLC) using a Discovery BIO Wide Pore C18 column (25 cm × 21.2 mm). After being purified, the peptide solutions were lyophilized. Peptide purity was assessed using analytical HPLC and a Discovery BIO wide pore C18 column (25 cm x 4.6 mm), and the peptides were characterized by liquid chromatography ion trap time-of-flight (LCMS-IT-TOF) mass spectrometry. On-Resin Click Reactions. After peptide elongation, the relevant alkyne (3.0 equiv), CuSO4 (0.5 equiv), and sodium ascorbate (0.5 equiv) in DMF/H2O (2 mL/0.1 mL) were added to the resin, and the mixture was reacted for 24−72 h at room temperature under shaking. The cleavage of peptides 12−14 from the resin and their subsequent purification were carried out in accordance with the above-mentioned method. Click Reactions Involving Peptide 11. A mixture of peptide 11, the relevant alkyne (3.0 equiv), CuSO4 (0.5 equiv), and sodium ascorbate (0.5 equiv) in DMF/H2O (0.5 mL/0.05 mL) was stirred for 30 min at room temperature. The mixture was purified in accordance with the above-mentioned method. HR-MS Data of Peptides 9−14. Peptide 9. 4.3 mg (20% isolated yield); HRMS (ESI+) calcd for C37H59N10O13 [M + H]+ 851.4258; found: 851.4251. Peptide 10. 4.6 mg (17% isolated yield); HRMS (ESI+) calcd for C48H75N11O16 [M + 2H]2+ 530.7691; found: 530.7686. Peptide 11. 4.5 mg (17% isolated yield); HRMS (ESI+) calcd for C49H78N14O14 [M + 2H]2+ 543.2905; found: 543.2915. Peptide 12. 5.2 mg (17% isolated yield); HRMS (ESI+) calcd for C56H83N15O16 [M + 2H]2+ 610.8066; found: 610.8065. Peptide 13. 5.4 mg (16% isolated yield); HRMS (ESI+) calcd for C58H94N14O18 [M + 2H]2+ 637.3430; found: 637.3427. Peptide 14. 5.1 mg (15% isolated yield); HRMS (ESI+) calcd for C69H102N14O16 [M + 2H]2+ 691.3794; found: 691.3791.

LCMS-IT-TOF spectrometer. CD spectra were recorded using a 1.0 mm path length cell. PBS buffer was used as a solvent. Synthesis of Cyclic α,α-Disubstituted α-Amino Acids 4−8. Fmoc-Api-OH (1) was prepared using the reported method.8 Compound 1 (300 mg, 0.75 mmol) was dissolved in 4 M HCl in 1,4-dioxane (1 mL) and stirred for 3 h. The solution was concentrated in vacuo to give a crude amine, which was used for the next reaction without further purification. A solution of the above amine in CH2Cl2 (5 mL) was treated with carboxylic acid (2.2 mmol), diisopropylethylamine (DIPEA) (0.76 mL, 4.5 mmol), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC) (514 mg, 2.7 mmol), and 1-hydroxybenzotriazole (HOBt) (362 mg, 2.7 mmol), and the reaction mixture was stirred for 1 h at room temperature. The mixture was concentrated in vacuo, and the resultant solid was dissolved with AcOEt. The organic layer was washed with 3% aqueous HCl and brine, before being dried over Na2SO4. The solvent was then removed, and the residue was purified by column chromatography on silica gel (0 → 1% MeOH in CH2Cl2) to give the Fmoc-protected amino acids 4−8 as amorphous. 4-([{(9H-Fluoren-9-yl)methoxy}carbonyl]amino)-1-(4methylpentanoyl)piperidine-4-carboxylic acid (4). 175 mg (52%); Amorphous; IR (CDCl3, cm1) 3435, 2960, 1730, 1635; 1H NMR (400 MHz, CDCl3) δ 7.74 (2H, d, J = 7.2 Hz), 7.56 (2H, d, J = 7.2 Hz), 7.38 (2H, t, J = 7.2 Hz), 7.29 (2H, t, J = 7.2 Hz), 5.21 (1H, br), 4.45 (2H, br), 4.18 (1H, t, J = 6.4 Hz), 4.13 (1H, br), 3.65 (1H, br), 3.26 (1H, br), 3.12 (1H, br), 2.20 (2H, d, J = 6.8 Hz), 2.13−2.03 (3H, m), 1.98 (1H, br), 1.89 (1H, br), 0.95 (6H, d, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ: 176.1, 171.5, 155.8, 143.6, 143.5, 141.2, 128.9, 128.1, 127.7, 127.0, 125.2, 124.9, 120.0, 66.8, 57.4, 47.1, 41.8, 37.1, 32.7, 25.8, 22.6, 22.5; [HR-ESI(+)-TOF]: m/z calcd for C26H31N2O5 [M + H]+ 451.2235: found 451.2230. 4-([{(9H-Fluoren-9-yl)methoxy}carbonyl]amino)-1-(3phenylpropanoyl)piperidine-4-carboxylic acid (5). 250 mg (67%); Amorphous; IR (CDCl3, cm1) 3435, 3030, 1730, 1635; 1H NMR (400 MHz, CDCl3) δ 7.74 (2H, d, J = 7.6 Hz), 7.55 (2H, d, J = 7.2 Hz), 7.38 (2H, t, J = 7.6 Hz), 7.31−7.27 (5H, m), 7.19 (2H, d, J = 7.2 Hz), 5.12 (1H, br), 4.44 (2H, br), 4.17 (1H, t, J = 6.4 Hz), 4.12 (1H, d, J = 14.0 Hz), 3.54 (1H, br), 3.13 (2H, br), 2.95 (2H, t, J = 7.6 Hz), 2.60 (2H, t, J = 7.2 Hz), 1.94 (2H, br), 1.86 (2H, br); 13C NMR (100 MHz, CDCl3) δ 176.4, 171.1, 155.9, 143.6, 143.5, 141.3, 141.0, 128.6, 128.4, 127.8, 127.1, 127.0, 126.3, 124.9, 120.0, 66.8, 57.4, 47.1, 41.4, 37.3, 34.9, 32.5, 31.8, 31.5; [HR-ESI(+)-TOF]: m/z calcd for C30H31N2O5 [M + H]+ 499.2235: found 499.2257. 4-([{(9H-Fluoren-9-yl)methoxy}carbonyl]amino)-1-{3-(tertbutoxy)propanoyl}piperidine-4-carboxylic acid (6). 256 mg (69%); Amorphous; IR (CDCl3, cm1) 3435, 2977, 1717, 1627; 1H NMR (400 MHz, CDCl3) δ 7.74 (2H, d, J = 7.6 Hz), 7.56 (2H, d, J = 7.2 Hz), 7.38 (2H, t, J = 7.6 Hz), 7.29 (2H, t, J = 7.6 Hz), 5.19 (1H, br), 4.44 (2H, br), 4.18 (1H, t, J = 6.4 Hz), 4.14 (1H, br), 3.72 (1H, br), 3.66 (2H, t, J = 7.2 Hz), 3.26 (1H, br), 3.09 (1H, br), 2.63−2.51 (2H, m), 2.12 (2H, br), 1.97 (1H, br), 1.91 (1H, br), 1.18 (9H, s); 13C NMR(100 MHz, CDCl3) δ 176.2, 170.4, 155.9, 143.6, 141.3, 127.8, 127.1, 124.9, 120.0, 73.3, 66.8, 58.5, 57.6, 47.2, 41.6, 37.1, 34.2, 32.5, 32.2, 27.5; [HR-ESI(+)-TOF]: m/z calcd for C28H35N2O6 [M + H]+ 495.2497: found 495.2498. 4-([{(9H-Fluoren-9-yl)methoxy}carbonyl]amino)-1-{4-(tert-butoxy)-4-oxobutanoyl}piperidine-4-carboxylic acid (7). 219 mg (56%); Amorphous; IR (CDCl3, cm1) 3435, 2982, 1723, 1645; 1H NMR (400 MHz, CDCl3) δ 7.74 (2H, d, J = 7.6 Hz), 7.55 (2H, d, J = 7.2 Hz), 7.38 (2H, t, J = 7.6 Hz), 7.29 (2H, d, J = 7.6 Hz), 5.27 (1H, br), 4.44 (2H, br), 4.18 (1H, t, J = 6.4 Hz), 4.11 (1H, d, J = 13.6 Hz), 3.66 (1H, br), 3.27 (1H, br), 3.11 (1H, br), 2.56 (4H, s), 2.13 (2H, br), 1.97 (1H, br), 1.90 (1H, br), 1.44 (9H, s); 13C NMR(100 MHz, CDCl3) δ 176.2, 172.5, 170.1, 156.0, 143.6, 143.5, 141.4, 127.8, 127.1, 124.9, 120.0, 80.6, 66.8, 57.5, 47.2, 41.1, 37.3, 32.5, 31.9, 30.4, 28.1, 27.9; [HR-ESI(+)-TOF]: m/z calcd for C29H35N2O7 [M + H]+ 523.2446: found 523.2447. 4-([{(9H-Fluoren-9-yl)methoxy}carbonyl]amino)-1-(5azidopentanoyl)piperidine-4-carboxylic acid (8). 225 mg (61%); Amorphous; IR (CDCl3, cm1) 3435, 2954, 2100, 1729, 1635; 1H

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01946. 10725

DOI: 10.1021/acs.joc.7b01946 J. Org. Chem. 2017, 82, 10722−10726

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The Journal of Organic Chemistry

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Information about the 1H NMR and 13C NMR spectra of compounds 2−8 and the HPLC data of peptides 9−14 (PDF)

Nagano, M.; Suemune, H.; Tanaka, M. J. Org. Chem. 2014, 79, 9125− 9140. (10) Erdmann, R. S.; Wennemers, H. J. Am. Chem. Soc. 2010, 132, 13957−13959. (11) (a) Comprehensive Chiroptical Spectroscopy; Berova, N., Polavarapu, P. L, Nakanishi, K., Woody, R. W., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2012; Vol. 2, Chapters 14 and 15. (b) Pengo, P.; Pasquato, L.; Moro, S.; Brigo, A.; Fogolari, F.; Broxterman, Q. B.; Kaptein, B.; Scrimin, P. Angew. Chem., Int. Ed. 2003, 42, 3388−3392. (c) Toniolo, C.; Polese, A.; Formaggio, F.; Crisma, M.; Kamphuis, J. J. Am. Chem. Soc. 1996, 118, 2744−2745. (12) (a) Tsuchiya, K.; Numata, K. Chem. Commun. 2017, 53, 7318− 7321. (b) Mondal, S.; Adler-Abramovich, L.; Lampel, A.; Bram, Y.; Lipstman, S.; Gazit, E. Nat. Commun. 2015, 6, 8615. (c) Demizu, Y.; Doi, M.; Kurihara, M.; Okuda, H.; Nagano, M.; Suemune, H.; Tanaka, M. Org. Biomol. Chem. 2011, 9, 3303−3312. (13) The CD spectra of peptide 12 is shown in the Supporting Information. The peptide 14 was difficult to dissolve in PBS buffer because of its hydrophobicity. (14) (a) Gopalakrishnan, R.; Frolov, A. I.; Knerr, L.; Drury, W. J.; Valeur, E. J. Med. Chem. 2016, 59, 9599−9621. (b) Demizu, Y.; Ohoka, N.; Nagakubo, T.; Yamashita, H.; Misawa, T.; Okuhira, K.; Naito, M.; Kurihara, M. Bioorg. Med. Chem. Lett. 2016, 26, 2655−2658. (c) Yamashita, H.; Kato, T.; Oba, M.; Misawa, T.; Hattori, T.; Ohoka, N.; Tanaka, M.; Naito, M.; Kurihara, M.; Demizu, Y. Sci. Rep. 2016, 6, 33003. (d) Nagakubo, T.; Demizu, Y.; Kanda, Y.; Misawa, T.; Shoda, T.; Okuhira, K.; Sekino, Y.; Naito, M.; Kurihara, M. Bioconjugate Chem. 2014, 25, 1921−1924.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +81-3-3700-1141. Fax: +813-3707-6950. ORCID

Yosuke Demizu: 0000-0001-7521-4861 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported, in part, by JSPS KAKENHI grant numbers 26460169 and 17k08385 (Y.D.) and by a grant from the Takeda Science Foundation (Y.D.).

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REFERENCES

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DOI: 10.1021/acs.joc.7b01946 J. Org. Chem. 2017, 82, 10722−10726