Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of

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Cite This: J. Am. Chem. Soc. 2018, 140, 3514−3517

Diastereo- and Enantioselective Formal [3 + 2] Cycloaddition of Cyclopropyl Ketones and Alkenes via Ti-Catalyzed Radical Redox Relay Wei Hao,† Johannes H. Harenberg,†,‡ Xiangyu Wu,† Samantha N. MacMillan,† and Song Lin*,†,§ †

Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States Department Chemie, Ludwig-Maximilians-Universität München, Munich, 81377, Germany § Atkinson Center for a Sustainable Future, Cornell University, Ithaca, New York 14853, United States ‡

S Supporting Information *

Scheme 1. [3 + 2] Cycloaddition via Ti-Catalyzed Radical Redox Relay and Its Related Literature Precedents

ABSTRACT: We report a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and radical-acceptor alkenes to form polysubstituted cyclopentane derivatives. Catalyzed by a chiral Ti(salen) complex, the cycloaddition occurs via a radical redox-relay mechanism and constructs two C−C bonds and two contiguous stereogenic centers with generally excellent diastereo- and enantioselectivity.

O

wing to the high reactivity and unique selectivity of organic radicals, the discovery of new reactions mediated by these open-shell intermediates continues to provide solutions to challenging synthetic problems in traditional twoelectron chemistry.1 In this context, new catalyst-controlled stereoselective reactions involving free radical intermediates remain highly desirable.2 Since early reports of the use of Lewis acids, transition metals, and organocatalysts,3 innovative catalytic strategies that regulate the absolute stereochemistry of radical addition reactions have provided powerful synthetic methods and accelerated understanding of open-shell reaction pathways.4 Because they can adopt multiple continuous oxidation states, Ti complexes are highly versatile catalysts for redox radical organic transformations.5 Although chiral Ti complexes can engage radical pathways to catalyze enantioselective C−C formation,6 such reactions have been primarily limited to pinacol-type couplings,7 Barbier reactions,8 and ring-opening functionalizations of epoxides.9 Recently, we disclosed a new strategy in which a TiIII catalyst triggers a series of tandem radical redox processes leading to the [3 + 2] cycloaddition of N-acylaziridines and alkenes to furnish substituted pyrrolidine products (Scheme 1A).10 This approach exploits several unique characteristics of Ti, including the oxophilicity of TiIV, the capability of TiIII to induce bond weakening,11 and the biradical character of TiIV azaenolates.12 Although it resembles dual-catalytic photoredox chemistry,13 our strategy is distinct in that it integrates a redox mediator and a substrate-activating cocatalyst into one molecular scaffold,14 thereby allowing us to control reactivity and stereoselectivity by tuning the structure of a single ligand. We hypothesized that this radical redox-relay strategy could be applied to the [3 + 2] cycloaddition of cyclopropyl ketonesstructural analogues of N-acylaziridinesand alkenes (Scheme 1C) to produce highly © 2018 American Chemical Society

substituted cyclopentanes. These carbocyclic structures are ubiquitous in bioactive compounds and frequently used as analogs to pyrrolidines in medicinal chemistry studies.15 To date, the intermolecular cycloaddition strategy for enantioenriched cyclopentanes has been largely limited to the use of donor−acceptor-type cyclopropanes. These substrates readily undergo ring opening in the presence of a catalyst to form 1,3-dipolar intermediates before alkene addition (Scheme 1B).16 Yoon et al.17 reported an elegant combination of photoredox chemistry and chiral Lewis acid catalysis to expand the scope of the [3 + 2] cycloaddition (see Scheme 1C). Despite its excellent enantioselectivity, the reaction generally Received: December 27, 2017 Published: February 21, 2018 3514

DOI: 10.1021/jacs.7b13710 J. Am. Chem. Soc. 2018, 140, 3514−3517

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Journal of the American Chemical Society

were obtained using catalyst 7 with 1,3-diaminopropane as the ligand backbone (entry 5). The cycloaddition was equally efficient and marginally less enantioselective when Mn was replaced with Zn (entry 6). The loading of Et3N·HCl could be reduced to 50 mol % with marginal decrease in yield (entry 7). In theory, the overall redox-neutral transformation requires only a catalytic amount of reductant to activate the catalyst. Decreasing the loading of Mn to 20 mol %, however, led to substantially lower product yield (entry 8). The interplay between 3, Mn, and Et3N·HCl in initiating and maintaining the radical redox catalytic cycle is intriguing,19 and mechanistic understanding of such a process is currently underway. Finally, replacing ethyl acetate with tetrahydrofuran or acetonitrile as the solvent led to diminished stereoselectivity (entries 9, 10). We then explored the substrate scope of the radical [3 + 2] cycloaddition under the trans selective conditions using catalyst 3 (Scheme 2). A variety of styrene derivatives proved to be excellent coupling partners, yielding the corresponding products (2, 8−15) in high dr and ee. Functional groups such as pinacolborate (9) and N-heterocycles (14, 15) were compatible. We noted that reactions using electron-deficient styrenes (e.g., 9, 10) were less enantioselective and required lower temperatures to reach high levels of ee. Cycloadduct 16 with an N-methylimidazol-2-yl group was isolated in high yield, good dr, and excellent ee from the corresponding heterocyclic substrate. 3-Vinyl-3-deoxyestrone was converted to 17 nearly as a single stereoisomer. We obtained crystal structures of 2 and 17 and determined their absolute and relative stereochemistries. Stereochemical assignments for structurally similar products were made by analogy. 1,1-Disubstituted alkenes were also suitable substrates. Products 18−20, each with a quaternary stereogenic centers, were isolated in high stereochemical purity. Ethyl 2-phenyl acrylate was also converted to 21 in 9:1 dr and 80% ee. In all cases, the aryl substituent from the alkene substrate adopted a trans relationship with the benzoyl group in the major diastereomeric product.20 Both isoprene and acrylamide underwent the desired transformation to furnish products 22 and 23, respectively, in moderate to high dr and excellent ee. Electron-deficient alkenes were also investigated as radical acceptors in the [3 + 2] cycloaddition. Acrylates (24, 25), phenyl vinyl sulfone (26), and vinyl pinacolborane (27) underwent the radical cascade to yield the corresponding products in nearly complete diastereoselectivity favoring the configuration in which the electron-withdrawing substituent is placed trans to the benzoyl group. Achieving high enantioselectivity was challenging with these alkenes under the standard conditions. Lowering the temperature, however, improved selectivity with the expense of longer reaction times. 1Phenylstyrene was also converted to the desired product (28) in moderate ee. We hypothesize that, in these cases, the greater stability of the carbon-centered radicals resulting from the first C−C bond formation might alter the position of the selectivitydetermining transition state on the reaction coordinate, thus influencing enantioinduction by the chiral catalyst. Mechanistic studies of the origin of enantioselectivity and its dependence on the electronic properties of the alkene are underway. Methyl 2,2-dimethylcyclopropyl ketone was converted to cycloadduct 29 in synthetically useful dr, albeit with low ee. 2Phenylcyclopropyl phenyl ketone reacted to furnish 30 in 2:1 dr with respect to the stereochemistry at position 4; both diastereomers were formed in high ee.

required high loadings of the chiral Lewis acid and was primarily demonstrated for electron-neutral and -rich alkenes. We studied radical [3 + 2] cycloaddition using 2,2dimethylcyclopropyl phenyl ketone (1) and styrene as substrates. In principle, the coordination of TiIII to the carbonyl group in 1 would trigger radical relay from the metal center to the quaternary carbon, leading to the homolytic cleavage of a C−C bond in the cyclopropane to form a carbon-centered radical tethered to a TiIV enolate. Similar to the mechanism of our previous aziridine-alkene reaction,10 this intermediate would engage styrene in a stepwise radical cycloaddition to furnish cyclopentane 2, during which TiIV would regain an electron from the reactant assembly and return to TiIII, achieving catalytic turnover. A survey of reaction parameters revealed that salensupported complex 3 bearing phenylene-1,2-diamine and 3adamantyl-5-methyl salicylaldehyde was the optimal catalyst (Table 1, entry 1). With Mn as the reductant and Et3N·HCl18 Table 1. Reaction Optimizationa

entry

variation from the standard conditions

yield (%)b

trans/ cisb

ee (%)c

1 2 3 4 5 6 7 8 9 10

None 4 instead of 3 5 instead of 3 6 instead of 3 in MeCN 7 instead of 3 in MeCN Zn instead of Mn 50 mol % Et3N·HCl 20 mol % Mnf THF instead of EtOAc MeCN instead of EtOAc

98 96 94 66 84 95 80 31 63 34

>19:1 3:1 14:1 1:3.2 1:2.4 >19:1 >19:1 >19:1 4:1 1.4:1

97 84 69 −d −d 90 −e −e 81 73

a

Reactions were carried out on 0.05 mmol scale. Preactivation of the catalyst was conducted for each reaction by mixing the TiIV catalyst precursor, reductant, and Et3N·HCI in the solvent for 10 min prior to addition of the substrates. See Supporting Information for detailed procedure. bDetermined with 1H NMR. cDetermined with HPLC. d Not applicable. eNot determined. fPreactivation of catalyst for 1 h.

as an additive in ethyl acetate at room temperature, the reaction delivered a nearly quantitative yield of cycloadduct 2 in the trans configuration effectively as a single stereoisomer (>19:1 dr, 97% ee). Altering the salicylaldehyde (4) or the diamine backbone (5) on the ligand substantially decreased both diastereo- and enantioselectivity (entries 2, 3). Half-titanocene CpTiCl3 (6), an effective catalyst in our previous aziridine cycloaddition reactions, was also competent. Notably, the cis isomer was the major product in a 3:1 dr with acetonitrile as the solvent (entry 4). As such, both diastereomeric products could be obtained by changing the catalyst identity. Similar results 3515

DOI: 10.1021/jacs.7b13710 J. Am. Chem. Soc. 2018, 140, 3514−3517

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Journal of the American Chemical Society Scheme 2. Substrate Scope of Ti-Catalyzed [3 + 2] Cycloadditionsa

a

Reactions conducted on 0.1 mmol scale with 1 equiv of cyclopropyl ketone, 1.2 equiv of alkene, 10 mol % 3, 1.5 equiv of Mn, 1.5 equiv of Et3N·HCl in EtOAc at 22 °C for 12 h. Isolated yields reported. bWith 5 mol % 3. cAt−25 °C for 48 h. dOn 1.0 mmol scale with 2.5 mol % 3 and 1.05 equiv of alkene for 60 h. eAt−35 °C for 50 h. fAt 0 °C for 48 h.

expect this radical redox catalysis to provide solutions to other challenging synthetic problems.

We also demonstrated the scalability of the reaction. On a 1 mmol scale with only 2.5 mol % catalyst 3, product 15 was obtained in 83% yield, complete trans selectivity, and 92% ee.21 The Lewis acid catalyzed 1,3-dipolar cycloaddition of donor−acceptor cyclopropanes with 2π coupling partners has been reported.22 Compared with our system, this canonical two-electron mode of activation is usually applied to different cyclopropane derivatives and dipolarophiles, giving rise to different product structures. To further support the radical intermediacy in our Ti-catalyzed cycloaddition, we conducted a spin trapping experiment using 5,5-dimethyl-pyrroline N-oxide (DMPO) and observed the formation of persistent nitroxide radical adduct 31 with ESR spectroscopy and mass spectrometry (see Scheme 3 and Supporting Information (SI)).

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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/jacs.7b13710. Experimental procedures and characterization data (PDF) Crystallographic data for compound 2 (deposited in the Cambridge Structural Database: CCDC1589640) (CIF) Crystallographic data for compound 17 (deposited in the Cambridge Structural Database: CCDC1589641) (CIF)

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Scheme 3. Spin Trapping Experiment

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Song Lin: 0000-0002-8880-6476 Notes

The authors declare no competing financial interest.

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In summary, we developed a stereoselective formal [3 + 2] cycloaddition of cyclopropyl ketones and alkenes using our previous reported radical redox relay strategy. With a Ti catalyst supported by a salen ligand, the reaction yielded highly substituted cyclopentanes in generally excellent diastereo- and enantioselectivity from readily accessible starting materials. We

ACKNOWLEDGMENTS This study made use of the Cornell Center for Materials Research Shared Facilities (DMR-1120296), the NMR facility (CHE-1531632) supported by the NSF, and the ESR facility supported by the NIGMS (P41GM103521). We thank Juno 3516

DOI: 10.1021/jacs.7b13710 J. Am. Chem. Soc. 2018, 140, 3514−3517

Communication

Journal of the American Chemical Society

(11) Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 6440−6443. (12) Studies describing the biradical character of structurally analogous TiIV enolates: (a) Beaumont, S.; Ilardi, E. A.; Monroe, L. R.; Zakarian, A. J. Am. Chem. Soc. 2010, 132, 1482−1483. (b) Cież, D.; Pałasz, A.; Trzewik, B. Eur. J. Org. Chem. 2016, 2016, 1476−1493. (c) Gu, Z.; Herrmann, A. T.; Zakarian, A. Angew. Chem., Int. Ed. 2011, 50, 7136−7139. (d) Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem. Soc. 2012, 134, 6976−6979. (e) Mabe, P. J.; Zakarian, A. Org. Lett. 2014, 16, 516−519. (f) Alvarado, J.; Herrmann, A. T.; Zakarian, A. J. Org. Chem. 2014, 79, 6206−6220. (13) For representative recent reviews, see: (a) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035−10074. (b) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 1−18. (14) Chiral catalysts integrating both the photoredox and enantioselective catalysts in the same molecular scaffold have recently developed. For a review, see: Zhang, L.; Meggers, E. Acc. Chem. Res. 2017, 50, 320−330. (15) For examples, see: (a) Defauw, J. M.; Murphy, M. M.; Jagdmann, E., Jr.; Hu, H.; Lampe, J. W.; Hollinshead, S. P.; Mitchell, T. J.; Crane, H. M.; Heerding, J. N.; Mendoza, J. S.; Davis, J. E.; Darges, J. W.; Hubbard, F. R.; Hall, S. E. J. Med. Chem. 1996, 39, 5215−5227. (b) Hanessian, S.; Yun, H.; Hou, Y.; Yang, G.; Bayrakdarian, M.; Therrien, E.; Moitessier, N.; Roggo, S.; Veenstra, S.; TintelnotBlomley, M.; Rondeau, J.-M.; Ostermeier, C.; Strauss, A.; Ramage, P.; Paganetti, P.; Neumann, U.; Betschart, C. J. Med. Chem. 2005, 48, 5175−5190. (16) (a) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50, 6167−6170. (b) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc. 2013, 135, 7851−7854. (c) Hashimoto, T.; Kawamata, Y.; Maruoka, K. Nat. Chem. 2014, 6, 702−705. (17) (a) Amador, A. G.; Sherbrook, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2016, 138, 4722−4725. For a closely related, racemic intramolecular [3 + 2] cycloaddition, see: (b) Lu, Z.; Shen, M.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 1162−1164. (18) ESR data suggested that Et3N·HCl promotes the reduction of TiIV to TiIII. See SI. Analogous pyridinium salts have been shown to stabilize TiIII catalysts in epoxide ring opening: (a) Gansäuer, A.; Behlendorf, M.; von Laufenberg, D.; Fleckhaus, A.; Kube, C.; Sadasivam, D. V.; Flowers, R. A., II Angew. Chem., Int. Ed. 2012, 51, 4739−4742. (b) Gansäuer, A.; Kube, C.; Daasbjerg, K.; Sure, R.; Grimme, S.; Fianu, G. D.; Sadasivam, D. V.; Flowers, R. A., II J. Am. Chem. Soc. 2014, 136, 1663−1671. (c) Gansäuer, A.; von Laufenberg, D.; Kube, C.; Dahmen, T.; Michelmann, A.; Behlendorf, M.; Sure, R.; Seddiqzai, M.; Grimme, S.; Sadasivam, D. V.; Fianu, G. D.; Flowers, R. A., II Chem. - Eur. J. 2015, 21, 280−289. (19) For mechanistic studies of related TiIII-catalyzed epoxide ring opening reactions, see ref 18. (20) The relative stereochemistry of products 18−22 was determined using 2D NMR. See SI. (21) The lower enantioselectivity likely arose from the decreased catalyst loading. Under the standard conditions in Table 1, using 2.5 mol% 3 instead of 10 mol% gave the product in 91% ee. This concentration dependence of reaction ee is currently under investigation. (22) (a) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122−3123. (b) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S. J. Am. Chem. Soc. 2010, 132, 9688−9692. Also see ref 15.

Siu for experimental assistance, Dr. Geoffrey Coates for kindly sharing salen ligands, Dr. Ivan Keresztes for help with NMR spectral analysis, and Dr. Boris Dzikovski for assistance with ESR data acquisition and analysis.

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REFERENCES

(1) (a) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis; WileyVCH: Weinhein, 2001. (b) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692−12714. (c) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58−102. (d) Ischay, M. A.; Yoon, T. P. Eur. J. Org. Chem. 2012, 2012, 3359−3372. (e) Crossley, S. W. M.; Martinez, R. M.; Obradors, C.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912−9000. (2) (a) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263−3296. (b) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical Reactions; Wiley-VCH: Weinheim, 1996. (3) For early examples, see: (a) Kameyama, M.; Kamigata, N.; Kobayashi, M. J. Org. Chem. 1987, 52, 3312−3316. (b) Groves, J. T.; Viski, P. J. Am. Chem. Soc. 1989, 111, 8537−8538. (c) Mok, P. L. H.; Roberts, B. P. J. Chem. Soc., Chem. Commun. 1991, 150−152. (d) Larrow, J. F.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 12129−12130. (e) Sibi, M.; Ji, J.; Wu, J. H.; Gürtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996, 118, 9200−9201. (f) Haque, M. B.; Roberts, B. P. Tetrahedron Lett. 1996, 37, 9123−9126. (g) Hamachi, K.; Irie, R.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4979−4982. (4) For representative recent examples, see: (a) Capacci, A. G.; Malinowski, J. T.; McAlpine, N. J.; Kuhne, J.; MacMillan, D. W. C. Nat. Chem. 2017, 9, 1073−1077. (b) Miller, Z. D.; Lee, B. J.; Yoon, T. P. Angew. Chem., Int. Ed. 2017, 56, 11891−11895. (c) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681−684. (d) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre, P. Nature 2016, 532, 218−222. (e) Huang, X.; Quinn, T. R.; Harms, K.; Webster, R. D.; Zhang, L.; Wiest, O.; Meggers, E. J. Am. Chem. Soc. 2017, 139, 9120−9123. (f) Chen, B.; Fang, C.; Liu, P.; Ready, J. M. Angew. Chem., Int. Ed. 2017, 56, 8780− 8784. (g) Zhang, W.; Wang, F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G. Science 2016, 353, 1014−1018. (h) Jiang, H.; Lang, K.; Lu, H.; Wojtas, L.; Zhang, X. P. J. Am. Chem. Soc. 2017, 139, 9164−9167. (i) Milan, M.; Bietti, M.; Costas, M. ACS Cent. Sci. 2017, 3, 196−204. (5) For recent reviews, see: (a) Davis-Gilbert, Z. W.; Tonks, I. A. Dalton Trans. 2017, 46, 11522−11528. (b) Cuerva, J. M.; Juan, J. C.; Justicia, J.; Oller-Lòpez, J. L.; Oltra, J. E. Top. Curr. Chem. 2006, 264, 63−91. (c) Streuff, J. Chem. Rec. 2014, 14, 1100−1113. (d) Gansäuer, A.; Hildebrandt, S.; Vogelsang, E.; Flowers, R. A., II Dalton Trans. 2016, 45, 448−452. (6) (a) Gansäuer, A.; Justicia, J.; Fan, C.-A.; Worgull, D.; Piestert, F. Top. Curr. Chem. 2007, 279, 25−52. (b) Streuff, J.; Gansäuer, A. Angew. Chem., Int. Ed. 2015, 54, 14232−14242. (7) For representative examples, see: (a) Bensari, A.; Renaud, J.-L.; Riant, O. Org. Lett. 2001, 3, 3863−3865. (b) Chatterjee, A.; Bennur, T. H.; Joshi, N. N. J. Org. Chem. 2003, 68, 5668−5671. (c) Li, Y.-G.; Tian, Q.-S.; Zhao, J.; Feng, Y.; Li, M. J.; You, T. P. Tetrahedron: Asymmetry 2004, 15, 1707−1710. For a mechanistically related carbonyl-nitrile reductive coupling, see: (d) Streuff, J.; Feurer, M.; Bichovski, P.; Frey, G.; Gellrich, U. Angew. Chem., Int. Ed. 2012, 51, 8661−8664. (8) For an examples, see: Estévez, R. E.; Justicia, J.; Bazdi, B.; Fuentes, N.; Paradas, M.; Choquesillo-Lazarte, D.; García-Ruiz, J. M.; Robles, R.; Gansäuer, A.; Cuerva, J. M.; Oltra, J. E. Chem. - Eur. J. 2009, 15, 2774−2791. (9) For representative examples, see: (a) Gansäuer, A.; Bluhm, H.; Lauterbach, T. Adv. Synth. Catal. 2001, 343, 785−787. (b) Gansäuer, A.; Shi, L.; Otte, M. J. Am. Chem. Soc. 2010, 132, 11858−11859. (c) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 3237−3240. (10) Hao, W.; Wu, X.; Sun, J. Z.; Siu, J. C.; MacMillan, S. N.; Lin, S. J. Am. Chem. Soc. 2017, 139, 12141−12144. For a review on a similar strategy for epoxide cycloaddition reactions, see ref 5d. 3517

DOI: 10.1021/jacs.7b13710 J. Am. Chem. Soc. 2018, 140, 3514−3517