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PHOTOCATALYSIS

Asymmetric copper-catalyzed C-Ncross-couplings induced byvisible lightQuirin M. Kainz, Carson D. Matier, Agnieszka Bartoszewicz, Susan L. Zultanski,Jonas C. Peters,* Gregory C. Fu*

Despite a well-developed and growing body of work in copper catalysis, the potentialof copper to serve as a photocatalyst remains underexplored. Here we describe aphotoinduced copper-catalyzed method for coupling readily available racemictertiary alkyl chloride electrophiles with amines to generate fully substitutedstereocenters with high enantioselectivity. The reaction proceeds at –40°C underexcitation by a blue light-emitting diode and benefits from the use of a single,Earth-abundant transition metal acting as both the photocatalyst and the source ofasymmetric induction. An enantioconvergent mechanism transforms the racemicstarting material into a single product enantiomer.

Photochemistry can furnish reactive inter-mediates that would otherwise be difficultto access under synthetically useful condi-tions. Its application in organic synthesishas therefore expanded rapidly during the

past decades (1), most recently in the context of

enantioselective photoredox catalysis with tran-sition metals (2–4). With several recent note-worthy exceptions, each of which involves thea-functionalization of carbonyl compounds bya chiral iridium catalyst (5–7), the metal-catalyzedmethods require two catalysts, (i) a transitionmetalcomplex that undergoes photoexcitation and servesas a site for redox chemistry and (ii) a separatechiral catalyst that effects enantioselective bondformation. Transition metal–free photoredox ca-talysis has also been reported (8, 9).

We have been interested in photocatalyticapproaches to the construction of C-N bonds(10), given the high value of amines in fieldsranging from biology to chemistry to materialsscience (11). Whereas initial efforts to develop tran-sition metal–catalyzed C-N cross-coupling reac-tions focused on the use of aryl and alkenyl halidesas the electrophilic coupling partner (12, 13),during the past few years, alkyl halides that arenot suitable substrates for classic SN2 reactionshave emerged as useful coupling partners underthe combined action of light and copper catalysis(14, 15). To date, progress has not yet been reportedin the development of an asymmetric variantof these reactions, and the use of copper as aphotoredox catalyst (16) is uncommon in compar-ison with the use of preciousmetals such as iridiumand ruthenium. Here we describe a copper-catalyzed enantioconvergent cross-coupling ofracemic tertiary alkyl halides that is induced byvisible light, a process that lies at the intersectionof several important dimensions of modern chem-ical catalysis (Fig. 1A).Although considerable advances have recently

been reported in the development of enantiocon-vergent cross-couplings of racemic secondary alkylelectrophiles with carbon nucleophiles to formC-C bonds (17–19), no highly effective methodshave yet been described for tertiary alkyl halides,which require differentiation of three distinct car-bon substituents by the catalyst in order to deliverhigh enantioselectivity. In the field of asymmetricsynthesis as a whole, highly stereoselective reac-tions involving tertiary electrophiles are relativelyuncommon, despite the fact that fully substitutedcarbons are a commonmotif in organicmolecules(20). We anticipated that the radical mechanismthat we have postulated for C-X bond cleavage inthe presence of copper and light (vide infra) (14, 15)

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Division of Chemistry and Chemical Engineering, CaliforniaInstitute of Technology (Caltech), Pasadena, CA 91125, USA.*Corresponding author. E-mail: jpeters@caltech.edu (J.C.P.);gcfu@caltech.edu (G.C.F.)

Fig. 1. A photocatalytic approach to the asymmetricsynthesisofamines. (A) Asymmetric copper-catalyzedC-N cross-couplings induced by visible light (cat., cata-lyst; hn, light energy; Ph, phenyl). (B) Outline of astrategy for the enantioconvergent cross-coupling of aracemic tertiary alkyl halide via a radical intermediate.

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might enable us to surmount this challenge, be-cause a single, comparatively stable tertiary radicalcould be formed from a racemic mixture of elec-trophiles (Fig. 1B).Another issue was whether common chiral

ligands such as phosphines would even bind tocopper, much less induce high enantioselectivityin the C-N bond–forming process, in the presenceof a much more abundant nucleophilic couplingpartner. Previously described methods for photo-induced copper-catalyzed N-alkylation used CuIas a precatalyst with no added ligand (14, 15).As a model coupling process, we examined

the reaction of carbazole—a heterocycle that oc-curs in bioactive molecules, including N-tert-alkyl–substituted compounds (21, 22)—with ana-halocarbonyl compound, representing a classof electrophiles that has not previously been usedin photoinduced copper-catalyzed cross-couplings.Upon investigating a range of reaction parame-

ters, we discovered that irradiation of the cross-coupling partners at –40°C for 16 hours in thepresence of CuCl, a chiral phosphine (L*), and aBrønsted base provides the desired product in 95%yield and 95% enantiomeric excess (ee) (Fig. 2A,entry 1). In contrast to our earlier studies of photo-induced copper-catalyzedN-alkylations, this processoperates under visible light from a blue light-emitting diode (rather than under an ultravioletsource) and at relatively low catalyst loading [1.0mole percent (mol %) rather than 10 mol %]. Acatalyst loading of 0.25 mol % led to only amodest loss in yield and no erosion in ee (entry 2,~300 turnovers; previously, the highest turnovernumber for a photoinduced copper-catalyzed N-alkylation was about nine) (14, 15).Control experiments established that copper

(Fig. 2A, entry 3; the alkyl halide is recovered quan-titatively) and light (entry 4) are necessary to ac-hieve C-Nbond formation under these conditions.

Furthermore, essentially no C-N coupling (<1%)occurs when the tertiary alkyl chloride, carbazole,and lithium tert-butoxide (LiOt-Bu) are heated at80°C in toluene for 16 hours. Our concern that aphosphine (L*)might not bind effectively to copperin the presence of a stoichiometric quantity of thenucleophile appears to be unfounded, as evidencedby our observation of high enantiomeric excess inthe C-N coupling (entry 1) and of an enhanced ratein the presence of the ligand [ligand-acceleratedcatalysis (23); entry 1 versus entry 5]. From a prac-tical point of view, it is worth noting that CuCl andthe chiral phosphine are commercially availableand that theprocess is nothighlymoisture-sensitive(entry 6).We examined the scope of this photoinduced

copper-catalyzed method for enantioconvergentN-alkylation by racemic tertiary alkyl halides(Fig. 2B). For couplings of carbazole with N-acylindoline–derived electrophiles, good to excellent

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Fig. 2. Asymmetric copper-catalyzed C-N cross-couplings induced by visible light. (A) Effect of changes in the reaction parameters.Yields were determinedthrough analysis by proton nuclearmagnetic resonance (1H NMR) spectroscopy with the aid of an internal standard. (B) Scope of the reaction with respect to theelectrophile. Yields were determined by isolation after chromatographic purification. (C) Scope of the reaction with respect to the nucleophile. Yields weredetermined by isolation after chromatographic purification. Et, ethyl group; Bn, benzyl group; Me, methyl group; t-Bu, tert-butyl group.

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yields and enantioselectivities occur with a rangeof substituents in the a position of the electro-phile (entries 1 to 6). In the case of a,a-dialkyl–substituted electrophiles (entries 5 and 6), thecatalyst selectively discriminates between twoalkyl groups, including a methyl and an isobutylgroup (entry 6), to furnish high ee.The introduction of an electron-donating or

an electron-withdrawing substituent onto the in-doline does not compromise the efficiency of thecross-coupling (Fig. 2B, entries 7 and 8). If desired,N-acylindolines can be transformed into primaryalcohols or carboxylic acids (24). A variety of othera-haloamides are also suitable electrophilic cross-coupling partners (entries 9 to 11), including aWeinreb amide (entry 11), which is important insynthesis because it serves as a useful precursor toketones (25).To gain additional insight into the compatibility

of various functional groups with these conditionsfor enantioconvergent C-N cross-couplings of ter-tiary alkyl halides, we examined the impact ofadditives (1.0 equivalent) on the course of thecoupling process shown in Fig. 2B, entry 1. Wedetermined that adding an unactivated secondaryalkyl bromide (cyclohexyl bromide), a ketone(2-nonanone), a secondary alcohol (5-nonanol),an ester (methyl octanoate), an alkene (cis- or trans-5-decene), an alkyne (5-decyne), or a nitrile (valer-onitrile) has no adverse impact on the yield or en-antioselectivity, and these additives canbe recoveredintact at the end of the cross-coupling, whereasadding a primary amine (3-phenylpropylamine)or an aldehyde (octanal) impedes N-alkylation.With respect to the nucleophilic coupling part-

ner, substituted carbazoles are also suitable sub-

strates (Fig. 2C, entries 1 to 5); the enantioconvergentC-N cross-coupling can be conducted on a gramscale with a similar outcome (entry 1 resulted in1.29 g of product, 94% yield, and 94% ee). Indolescan also be used as nucleophiles in these photo-induced copper-catalyzed couplings, delivering thedesired product with good yield and enantiose-lectivity (entries 6 to 9). Because indoles are com-mon subunits in bioactive compounds (26), andnatural products with a tertiaryN-alkyl substituentare known (27, 28), these represent a useful ad-dition to the limited families of nitrogen nucleo-philes that are compatible with metal-catalyzedC-N alkylations with alkyl halides (14, 15).Because we are able to obtain the cross-coupling

product in high yield and ee when using only 1.2equivalents of a racemic electrophile, it is evidentthat both enantiomers of the electrophile can betransformed under the reaction conditions into aparticular enantiomer of the product (enantio-convergence), although not necessarily at identi-cal rates [kinetic resolution (29)]. To gain insightinto whether a kinetic resolution was occurring,we measured the ee of the unreacted tertiary al-kyl halide at the end of the cross-coupling shownin Fig. 2B, entry 1. Our observation that the re-covered electrophile is racemic suggests eitherthat the enantiomeric substrates are reacting atessentially identical rates (no kinetic resolution)or that in situ racemization of the electrophile isoccurring. Through the use of enantiopure alkylhalides, we established that virtually no racemi-zation takes place under the reaction conditions(Fig. 3A). These couplings with enantiopure elec-trophiles further establish that the chiral ligandvery effectively controls the absolute configuration

of the product, regardless of the stereochemistryof the starting electrophile, and that C-Cl bondcleavage is essentially irreversible.An outline of a possible mechanism for photo-

induced copper-catalyzed C-N couplings of alkylhalides is illustrated in Fig. 3B (14, 15). Irradi-ation of a copper-nucleophile complex (A) couldlead to an excited-state adduct (B) that wouldthen engage in electron transfer with the alkylhalide (R-X) to generate an alkyl radical; next,bond formation between the nucleophile and theradical (Nu-R) could occur through an inner-sphere pathway involving a copper-nucleophilecomplex (C). In contrast to most asymmetric pho-toredox reactions catalyzed by transition metals(2–4), a singlemetal (copper) appears to be respon-sible for both the photochemistry and the en-antioselective bond-forming process. The bindingof the nucleophile to copper in situ to form acopper complex that can serve as a photoreduc-tant is important in this outline.We have synthesized and crystallographically

characterized a copper complex that includes thechiral phosphine and the carbazolide nucleophile,(L*)2Cu(carbazolide) (1) (Fig. 3C). The three li-gands are arranged in a trigonal planar geometryaround copper. When complex 1 (1.0 mol %) isused in place of CuCl and L* under our standardreaction conditions, the yield and the ee of the C-Ncross-coupling product are essentially unchanged[92% yield, 94% ee; compare with Fig. 2A, entry1 (95% yield, 95% ee)]. Furthermore, irradiationof complex 1 in the presence of a stoichiometricamount of a racemic tertiary alkyl halide leads toC-N bond formation in good yield and with en-antioselectivity that is comparable to the catalyzed

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Fig. 3. Mechanistic studies. (A) Investigation of kinetic resolution. (B) Outline of a possible pathway for photoinduced copper-catalyzed C-N cross-couplings of alkyl halides. For simplicity, all copper complexes are illustrated as neutral species, and all processes are depicted as being irreversible; X maybe serving as an inner- or an outer-sphere ligand [Ln denotes additional ligand(s) coordinated to copper]. (C) Synthesis and structural characterization of (L*)2Cu(carbazolide) (thermal ellipsoids are drawn at 50%probability, and H atoms are omitted for clarity). (D) Stoichiometric cross-coupling reaction with isolated(L*)2Cu(carbazolide).

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process [(Fig. 3D; compare with Fig. 2A, entry1 (95% ee)]; no coupling occurs in the absence oflight. Collectively, these observations are consist-entwith the suggestion that complex 1, or a copper-carbazolide-L* species that can be derived fromcomplex 1, is a plausible intermediate in thecatalytic cycle.Whereas enantioconvergent metal-catalyzed

cross-couplings of racemic secondary alkyl hal-ides have recently emerged as powerful tools forC-Cbond construction, therehas been little progressin corresponding C-heteroatom bond–forming pro-cesses or in the use of tertiary alkyl halides ascoupling partners. We have established that, withthe aid of visible light, a copper-based chiral catalystderived from commercially available componentscan achieve enantioconvergent C-N cross-couplingreactions of racemic tertiary alkyl chlorides withgood to excellent enantioselectivity. In contrastto nearly all metal-catalyzed asymmetric photo-redox methods described to date, which use sep-arate catalysts to effect redox chemistry and bondformation, in this method a single catalyst is re-sponsible for the photochemistry and for the en-antioselective bond construction. This work standsat a previously unexplored intersection of asym-metric synthesis, catalysis with Earth-abundantmetals, photoinduced processes, and cross-couplingreactions of alkyl electrophiles, each of which rep-resents an important current theme in chemicalsynthesis.We anticipate that our observations com-prise the initial advances in a fertile area ofasymmetric catalysis: the enantioconvergentsynthesis of secondary and tertiary C-heteroatombonds through photoinduced transition metal–catalyzed couplings of alkyl halides.

REFERENCES AND NOTES

1. A. Albini, M. Fagnoni, Photochemically-Generated Intermediatesin Synthesis (Wiley, 2013).

2. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 113,5322–5363 (2013).

3. R. Brimioulle, D. Lenhart, M. M. Maturi, T. Bach, Angew. Chem.Int. Ed. 54, 3872–3890 (2015).

4. D. M. Schultz, T. P. Yoon, Science 343, 1239176(2014).

5. H. Huo et al., Nature 515, 100–103 (2014).6. H. Huo, C. Wang, K. Harms, E. Meggers, J. Am. Chem. Soc. 137,

9551–9554 (2015).7. C. Wang et al., Chemistry 21, 7355–7359 (2015).8. A. Bauer, F. Westkämper, S. Grimme, T. Bach, Nature 436,

1139–1140 (2005).9. D. A. Nicewicz, T. M. Nguyen, ACS Catal. 4, 355–360

(2014).10. S. E. Creutz, K. J. Lotito, G. C. Fu, J. C. Peters, Science 338,

647–651 (2012).11. S. A. Lawrence, Amines: Synthesis, Properties and Applications

(Cambridge Univ. Press, 2004).12. L. Jiang, S. L. Buchwald, in Metal-Catalyzed Cross-Coupling

Reactions, A. de Meijere, F. Diederich, Eds. (vol. 2, Wiley–VCH,2004), pp. 699–760.

13. J. F. Hartwig, S. Shekhar, Q. Shen, F. Barrios-Landeros, inChemistry of Anilines, Z. Rappoport, Ed. (vol. 1, Wiley, 2007),pp. 455–536.

14. A. C. Bissember, R. J. Lundgren, S. E. Creutz, J. C. Peters,G. C. Fu, Angew. Chem. Int. Ed. 52, 5129–5133 (2013).

15. H.-Q. Do, S. Bachman, A. C. Bissember, J. C. Peters, G. C. Fu,J. Am. Chem. Soc. 136, 2162–2167 (2014).

16. S. Paria, O. Reiser, ChemCatChem 6, 2477–2483(2014).

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18. Y. Liang, G. C. Fu, . J. Am. Chem. Soc. 137, 9523–9526(2015).

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20. K. W. Quasdorf, L. E. Overman, Nature 516, 181–191(2014).

21. C. Schuster et al., J. Org. Chem. 80, 5666–5673(2015).

22. A. W. Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 112,3193–3328 (2012).

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24. P. M. Lundin, G. C. Fu, J. Am. Chem. Soc. 132, 11027–11029(2010).

25. S. Balasubramaniam, I. S. Aidhen, Synthesis 2008, 3707–3738(2008).

26. G. W. Gribble, Ed., Heterocyclic Scaffolds II: Reactions andApplications of Indoles (Springer, 2010).

27. R. Vallakati, J. A. May, J. Am. Chem. Soc. 134, 6936–6939(2012).

28. E. K. Schmitt et al., Angew. Chem. Int. Ed. 50, 5889–5891(2011).

29. H. Pellissier, in Separation of Enantiomers, M. Todd, Ed. (Wiley–VCH, 2014), pp. 75–122.

ACKNOWLEDGMENTS

Support has been provided by NIH (National Institute ofGeneral Medical Sciences, grant R01–GM109194), the Gordon

and Betty Moore Foundation, the Alexander von HumboldtFoundation (fellowship for Q.M.K.), and the Bengt LundqvistMemorial Foundation of the Swedish Chemical Society(fellowship for A.B.). We thank J. M. Ahn, L. M. Henling(Caltech X-Ray Crystallography Facility), M. W. Johnson,N. D. Schley, M. Shahgholi (Caltech Mass Spectrometry Facility),M. K. Takase (Caltech X-Ray Crystallography Facility), N. Torian(Caltech Mass Spectrometry Facility), D. G. VanderVelde(Caltech NMR Facility), and S. C. Virgil (Caltech Centerfor Catalysis and Chemical Synthesis) for assistance andhelpful discussions. Experimental procedures and characterizationdata are provided in the supplementary materials. Metricalparameters for the structures of compounds 1 to 4 areavailable free of charge from the Cambridge CrystallographicData Centre under accession numbers CCDC 1435979, 1435978,1435977, and 1435980.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/351/6274/681/suppl/DC1Materials and MethodsSupplementary TextFigs. S1 to S5Tables S1 to S23References (30–37)Spectral Data

10 November 2015; accepted 7 January 201610.1126/science.aad8313

PLANT IMMUNITY

Using decoys to expand therecognition specificity of a plantdisease resistance proteinSang Hee Kim,* Dong Qi,† Tom Ashfield, Matthew Helm, Roger W. Innes‡

Maintaining high crop yields in an environmentally sustainable manner requires thedevelopment of disease-resistant crop varieties. We describe a method to engineerdisease resistance in plants by means of an endogenous disease resistance gene fromArabidopsis thaliana named RPS5, which encodes a nucleotide-binding leucine-rich repeat(NLR) protein. RPS5 is normally activated when a second host protein, PBS1, is cleavedby the pathogen-secreted protease AvrPphB. We show that the AvrPphB cleavage sitewithin PBS1 can be substituted with cleavage sites for other pathogen proteases, whichthen enables RPS5 to be activated by these proteases, thereby conferring resistance tonew pathogens.This “decoy” approach may be applicable to other NLR proteins and shouldenable engineering of resistance in plants to diseases for which we currently lack robustgenetic resistance.

Intracellular receptors belonging to thenucleotide-binding leucine-rich repeat (NLR)family play central roles in both the humanand plant innate immune systems (1, 2). Inplants, their primary function is in pathogen

detection, and this often involves the recognitionof pathogen-derived virulence factors known aseffector proteins. After detection of effector pro-teins, NLRs become activated, leading to the in-

duction of numerous defense responses, includinga localized cell death response termed the hy-persensitive response (HR) that serves to preventspread of infection. NLR proteins are highly spe-cific with regard to the pathogen effectors thateach can detect, with a single NLR protein capa-ble of detecting only a limited number of effec-tors. Research on plant NLRs conducted over thepast 20 years has focused on understanding themechanistic basis of this specificity, with a long-term goal of being able to create new specific-ities. The ability to engineer novel specificitieswould enable the production of crop plants withgenetically based resistance to diseases that cur-rently must be controlled by environmentallydamaging, and expensive, pesticides.

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Department of Biology, Indiana University, Bloomington, IN47405, USA.*Present address: Division of Plant Sciences, University ofMissouri, Columbia, MO 65211, USA. †Present address: Center forResearch and Technology, Altria Group, Richmond, VA 23219, USA.‡Corresponding author. E-mail: rinnes@indiana.edu

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Asymmetric copper-catalyzed C-N cross-couplings induced by visible lightQuirin M. Kainz, Carson D. Matier, Agnieszka Bartoszewicz, Susan L. Zultanski, Jonas C. Peters and Gregory C. Fu

DOI: 10.1126/science.aad8313 (6274), 681-684.351Science 

, this issue p. 681; see also p. 666Sciencecouples alkyl chlorides to indoles and carbazoles with a high degree of enantioselectivity.Earth-abundant copper (see the Perspective by Greaney). Through coordination to a chiral ligand, the copper center

now report a blue light-driven C-N bond-forming reaction catalyzed byet al.metals such as ruthenium or iridium. Kainz proven to be versatile catalysts for organic reactions. For the most part, however, these catalysts have contained rare

havetend to absorb. Over the past decade, the field has undergone a renaissance as compounds that absorb visible light Organic photochemistry has traditionally relied on excitation in the ultraviolet, where carbon-based compounds

Copper's light touch forges C-N bonds

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