Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Chiral Brønsted acid-controlled intermolecular asymmetric [2 + 2] photocycloadditions


Control over the stereochemistry of excited-state photoreactions remains a significant challenge in organic synthesis. Recently, it has become recognized that the photophysical properties of simple organic substrates can be altered upon coordination to Lewis acid catalysts, and that these changes can be exploited in the design of highly enantioselective catalytic photoreactions. Chromophore activation strategies, wherein simple organic substrates are activated towards photoexcitation upon binding to a Lewis acid catalyst, rank among the most successful asymmetric photoreactions. Herein, we show that chiral Brønsted acids can also catalyze asymmetric excited-state photoreactions by chromophore activation. This principle is demonstrated in the context of a highly enantio- and diastereoselective [2+2] photocycloaddition catalyzed by a chiral phosphoramide organocatalyst. Notably, the cyclobutane products arising from this method feature a trans-cis stereochemistry that is complementary to other enantioselective catalytic [2+2] photocycloadditions reported to date.


A defining characteristic of modern synthetic chemistry is the capacity to conduct complexity-building organic reactions with high levels of stereocontrol. The strategies available to dictate the stereochemical outcome of photochemical reactions, however, remain significantly underdeveloped compared to other classes of organic reactions1,2,3,4,5,6,7,8. The difficulty of conducting asymmetric photochemical reactions has often been attributed to the very short lifetimes and high reactivities associated with electronically excited compounds; these features challenge the ability of catalysts to intercept and modulate the behavior of organic excited states. In the past few years, highly enantioselective photoreactions have increasingly exploited chiral Lewis acids, either as catalysts or as co-catalysts. The insight that the same privileged classes of chiral Lewis acid structures that have been so enabling in ground-state asymmetric synthesis can also be applied to enantioselective photochemistry has increased the pace of discovery in this area. There are two general mechanisms by which chiral Lewis acids can influence the enantioselectivity of excited-state photoreactions. First, Bach pioneered the chromophore activation strategy in which chiral Lewis acids are used to attenuate the singlet excited-state energy of α,β-unsaturated carbonyl compounds (Fig. 1a)9,10. As the absorption of the catalyst-bound substrate occurs more strongly at longer wavelengths than the free substrate, the activated substrate may be selectively excited by a judicious choice of irradiation wavelength. Second, our group has developed a mechanistically distinctive strategy that we have termed “triplet activation.” In this approach, chiral Lewis acid coordination lowers the triplet energy of α,β-unsaturated carbonyls, allowing for their selective activation by a triplet sensitizer over unbound substrate molecules (Fig. 1b)11,12,13. Although fundamentally distinct, both strategies use chiral Lewis acids to modify the excited-state properties of the substrate and preferentially activate the catalyst-bound complex, thereby minimizing racemic background reactivity.

Fig. 1: Asymmetric acid-catalyzed photoreactions.
figure 1

a Intramolecular [2 + 2] photocycloadditions via Lewis acid-catalyzed chromophore activation; LA = Lewis acid. b Intermolecular [2 + 2] photocycloadditions via Lewis acid-catalyzed triplet activation. c Intermolecular [2 + 2] photocycloadditions via Bronsted acid-catalyzed chromophore activation. HA = Brønsted acid.

In the first decade of the twenty-first century, secondary amine and Brønsted acid organocatalysis emerged as an alternative approach to chiral Lewis acid catalysis for a wide range of asymmetric ground-state transformations14,15,16,17. Remarkably, these catalysts could control many of the same classes of asymmetric transformations as better-studied chiral Lewis acids, often enabling the use of functionalized substrates that would not be compatible with strongly Lewis acidic catalyst structures. One might reasonably wonder if organocatalysts might prove equally versatile in asymmetric photochemistry. Very recently, Takagi and Tabuchi18 demonstrated that chiral phosphoric acids are effective stoichiometric templates for asymmetric [2 + 2] photocycloaddition reactions of quinolones, although this interaction had little effect on the photophysical properties of the substrate. Pioneering studies by Melchiorre and colleagues19,20 have demonstrated that secondary amine organocatalysts can activate prochiral enals by chromophore activation: the iminium intermediates absorb at longer wavelengths than the free enal substrates and the excited states have been utilized in a variety of useful organic transformations. Very recently, Bach and colleagues21,22 demonstrated the first example of triplet activation by secondary amine organocatalysis, demonstrating that the vinyl iminium intermediate undergoes energy transfer faster than the free parent enal and can be the key intermediate in an enantioselective [2 + 2] photocycloaddition. The ability of Brønsted acid catalysts to engage in chromophore and triplet activation mechanisms, however, has been underexplored. Although hydrogen bonding and Brønsted acid catalysts have been studied extensively as chiral sensitizers for asymmetric photoreactions23,24,25, their ability to alter the photophysical properties of organic substrates has not been significantly exploited. In an isolated example, Sivaguru and colleagues26,27 described an enantioselective intramolecular [2 + 2] cycloaddition using a chiral thiourea catalyst that could activate a coumarin substrate through both static and dynamic complex formation. Our group also recently reported the first example of triplet activation in a racemic [2 + 2] photocycloaddition reaction in which the addition of p-TsOH as a co-catalyst was demonstrated to increase the rate of triplet energy transfer from a Ru(II) photocatalyst to 2-acyl imidazole 1, which subsequently underwent a [2 + 2] photocycloaddition28.

In this work, we report a highly enantio- and diastereoselective excited-state [2 + 2] cycloaddition catalyzed by a 1,1′-Bi-2-naphthol (BINOL)-derived phosphoramide Brønsted acid catalyst. A combination of spectroscopic and computational studies indicate that this catalyst operates via the principle of chromophore activation (Fig. 1c).


Reaction development

The discovery of this chiral organocatalytic photoreaction occurred serendipitously during our studies to further develop the p-TsOH/photocatalytic [2 + 2] cycloaddition method into an asymmetric reaction by the use of a chiral Brønsted acid. We began by screening BINOL-derived Brønsted acid co-catalysts, as they constitute a privileged catalyst class in thermal asymmetric transformations (Fig. 2)29. When 1 and styrene were irradiated in the presence of 1 mol% [Ir(Fppy)2(dtbbpy)]PF6 and 20 mol% acid catalyst AC-1, the cycloadduct was obtained in 37% ee in a 1:2 ratio of transcis to transtrans diastereomers (entry 1). We observed a reversal in the diastereoselectivity at −78 °C and a concomitant increase in enantioselectivity (81% ee, entry 2). The more acidic N-triflyl phosphoramide AC-2 led to a further increase in enantioselectivity (entry 3), consistent with a stronger substrate–catalyst interaction30. Finally, replacing the phenyl groups on the catalyst with 4-trifluoromethylphenyl groups (AC-3) led to the optimal catalyst, affording the cycloadduct in 7:1 d.r. and 95% ee (entry 4).

Fig. 2: Optimization studies.
figure 2

aYields and diastereomer ratios determined by 1H NMR spectroscopy. bEnantiomeric excess of the major diastereomer determined by chiral HPLC. cRatio of transcis isomer to transtrans isomer. dConducted at room temperature. eConducted in the dark.

To our surprise, control experiments omitting the photocatalyst from the reaction gave nearly identical yield and selectivity (entry 5). This indicates that AC-3 is not only responsible for the selectivity of the reaction but also activates the substrate towards photoexcitation. In the absence of both catalysts, the racemic product was still formed in low yield, indicative of a slow direct photoreaction that is outcompeted by the acid-catalyzed reaction (entry 6). Notably, in this control experiment, the transtrans diastereomer is favored in a 2:1 ratio, indicating that the diastereoselectivity of the acid-catalyzed reaction (entry 5) is a product of catalyst control. Chalcone was also tested as a substrate and gave diminished yields of product with no ee, suggesting that a sufficiently basic functionality capable of interacting with the Brønsted acid catalyst is required (entry 8). The transcis diastereoselectivity of the major product is notable: direct excitation and triplet-sensitized reactions of acyclic enones with alkenes typically favor formation of the transtrans isomer31,32,33,34. Indeed, the direct photoreaction conducted in the absence of the chiral Brønsted acid (entry 6) favors the transtrans diastereomer and thus we conclude that the observed diastereoselectivity is imposed by the acid catalyst. This method constitutes the first enantioselective photocycloaddition that selectively accesses a simple monocyclic diarylcyclobutane with 1,2-cis diastereoselectivity.

Reaction scope

We evaluated the scope of the reaction under optimized reaction conditions (Fig. 3). A variety of α,β-unsaturated carbonyl compounds with electronically varied β-aryl substituents (29) were accommodated, producing the corresponding cycloadducts in high yields and selectivities. Substrates with substituents at the ortho position (3, 7) reacted slower than corresponding substrates with meta or para substitution but were formed in higher diastereoselectivity. A thienyl substrate (11) reacted efficiently. Finally, as this reaction does not require a conventional photocatalyst, substrates with oxidation or reduction potentials within the range of common transition metal photocatalysts are tolerated35, including nitroarenes (12) and aryl iodides (13). The alkene acceptor scope also includes substitution at each position of the arene acceptor (1517) and an array of electron-withdrawing (1819) and -donating (2021) substituents. Notably, a p-alkoxy-substituted styrene (20) was tolerated under these conditions, whereas the same alkene undergoes rapid polymerization using our previous Lewis acid-catalyzed methods11. Various functional groups including protected alcohols (2223), a photolabile azide (24), and a protected amine (25) were all tolerated. Heterocycles were also readily transformed including benzofuran- and indole-substituted alkenes (2829). Substituted and unsubstituted dienes (3031) were competent substrates. Any substrate that features alternate binding sites for the chiral catalyst, however, generally affords low reactivity (32). Intriguingly, two aliphatic exocyclic alkenes (3435) gave moderate yields and good ee to afford medicinally interesting spirocyclic products36. Cycloadditions between two densely functionalized reaction partners also provided high enantioselectivity (36) and cleavage of the imidazolyl group to a methyl ester occurred with no significant loss of stereochemical fidelity (Fig. 4).

Fig. 3: Scope studies.
figure 3

Reactions conducted using 1 equiv 2-acyl imidazole, 10 equiv alkene, 20 mol% AC-3 in toluene, irradiating for 14 h with a Kessil H150 LED unless otherwise noted. Yields represent the isolated yield of both diastereomers. Enantiomeric excess of the major diastereomer determined by chiral HPLC. aConducted for 24 h. bConducted with 40 mol% acid catalyst AC-3. cConducted in CH2Cl2.

Fig. 4: Auxiliary cleavage.
figure 4

The imidazolyl group of the cycloadduct is readily cleaved in good yield with retention of enantioselectivity.

Mechanistic studies

An intriguing outcome of our optimization study was the unexpected observation that AC-3 catalyzes this reaction without a separate triplet sensitizer. We therefore elected to investigate its role in greater detail. Neither 1 nor AC-3 absorbs appreciably in the visible region (Fig. 5a), and as the emission of the light source does not overlap with the absorption of the acid catalyst, direct excitation of the acid catalyst is not feasible. We therefore conclude that the Brønsted acid is not a conventional triplet photosensitizer in this reaction. The substrate, on the other hand, absorbs weakly at wavelengths >400 nm, accounting for the slow background reaction in the absence of catalyst (Fig. 2, entry 6). Upon combining colorless solutions of the acid and substrate, the mixture became noticeably yellow, corresponding to a red shift in absorption that increased with added acid catalyst. The emission of the light source overlapped well with bound but poorly with unbound substrate, consistent with relatively minimal contribution from the racemic background reaction.

Fig. 5: Mechanistic studies.
figure 5

a Ultraviolet-visible spectra of 1 and AC-3 in CH2Cl2. b X-ray crystal structure of acid-bound substrate. c Binding depiction of acid-bound substrate. d HOMO(π) and LUMO(π*) of 1 and 1H+AC-4.

We next performed nuclear magnetic resonance (NMR) titration experiments with 1 and AC-3 in toluene-d8 and calculated an association constant of Ka = 7.5 × 106 (Supplementary Fig. 5). We also isolated the substrate-acid complex from diethyl ether and determined its structure using X-ray crystallography (Fig. 5b, c). Key features of the interaction included an apparent hydrogen bond between the protonated imidazolium on the substrate and the phosphoramide oxygen on the catalyst. This interaction differs significantly from the typical chelating interactions of acyl imidazoles with chiral Lewis acid catalysts, including the chiral-at-metal Rh catalysts Meggers and colleagues37,38 have utilized in analogous asymmetric [2 + 2] photocycloaddition reactions. Further, the orientation of the substrate alkene relative to the π-surface of the biaryl catalyst renders the top face of the enone more accessible for cycloaddition, which is consistent with the experimentally observed absolute configuration of the cycloadduct. Although both the substrate and acid catalyst are white solids, the isolated crystals were yellow, indicating that the complex absorbs visible light. Together, these results are suggestive that the crystal structure could be similar to the catalytically active complex in solution.

Based on these data, we considered two possible modes of substrate activation within the acid–substrate complex. First, we considered a chromophore activation mechanism in which protonation of the substrate lowers the relative energy of its first singlet excited state, thus making direct excitation by visible light achievable. This hypothesis is consistent with the red-shifted absorption of enones in sulfuric acid solution39,40. Second, we considered that the chiral catalyst and enone substrate might form an electron donor–acceptor complex41,42,43,44,45. In this scenario, a new intermolecular transition between the highest-occupied molecular orbital (HOMO) of the electron-rich phosphoramide donor and the lowest-unoccupied molecular orbital (LUMO) of the electron-deficient imidazolium acceptor could be lower in energy than the intramolecular transitions on either individual species. To distinguish between these mechanisms, we examined the influence of various acid catalysts on the yield of the photocycloaddition (Fig. 6). If the electron donor–acceptor mechanism were operative, acid catalysts lacking the π-conjugation of AC-3 would not form photochemically active complexes; however, a variety of acids increased the reaction rate, with similar apparent reaction rates using AC-3 and AC-4. Therefore, the bathochromic shift in the absorption of the substrate is likely an intrinsic property of the protonated substrate and not the result of a specific donor–acceptor interaction.

Fig. 6: Effect of structurally diverse Brønsted acids on the cycloaddition.
figure 6

Yields and diastereomer ratios determined by 1H NMR spectroscopy.

To understand the origin of this effect, we conducted density functional theory (DFT) and time-dependent DFT (TDDFT) calculations (Fig. 5d). Unsurprisingly, the HOMO and LUMO of 1 were found to be fully delocalized across the molecule with a HOMO–LUMO gap of 6.65 eV. The π-conjugation in the HOMO can be divided into an imidazolium and a cinnamoyl part. After protonation (1H+–AC-4), the HOMO becomes significantly more localized and is dominated by the cinnamoyl part (see Supplementary Information for details). This demixing of the two π-components upon protonation weakens the electrostatic impact of the proton on the HOMO energy, resulting in a relatively moderate shift of −0.36 eV. In contrast, the LUMO maintains delocalization across both π-domains and the LUMO energy shifts by −0.91 eV upon protonation. Consequently, the HOMO–LUMO gap is reduced from 6.65 to 6.10 eV, enabling excitation by visible light. TDDFT/Tamm–Dancoff approximation calculation and natural transition orbital analysis revealed the excitation from HOMO to LUMO (π → π* transition) in 1 and 1H+–AC-4 to be most important, and the excitation energies of 4.40 and 4.01 eV, respectively, were in good agreement with experimental observations.

Given this combination of synthetic, spectroscopic, and computational evidence, we propose that the BINOL-derived acid acts as a dual-purpose catalyst, altering the absorption spectrum of the substrate and providing a stereodifferentiating environment for the cycloaddition. The red-shifted absorption of the bound substrate enables selective excitation of the catalyst-bound complex and minimal competition from direct racemic background photocycloaddition. The resulting excited-state substrate is preorganized relative to the chiral environment defined by the Brønsted acid catalyst and styrene approaches at the accessible face of the enone, yielding highly enantioenriched product.

We have developed a highly enantioselective [2 + 2] photocycloaddition catalyzed by a BINOL phosphoramide organocatalyst. We believe that these results are significant for a variety of reasons. First, the stereocontrol offered by this reaction is high and the access it provides to the transcis diastereomer of diarylcyclobutanes distinguishes it synthetically from previous reports of asymmetric [2 + 2] photocycloadditions. Thus, although highly enantioselective catalysis of excited-state reactions is a relatively new capability in synthetic chemistry, the level of comprehensive control these methods collectively provide are beginning to approach the sophistication available in more conventional asymmetric reactions. More importantly, this study demonstrates that chiral Brønsted acids can activate enones by altering the absorption properties of the substrate. The extension of the concept of chromophore activation to chiral Brønsted acid-catalyzed photoreactions adds a distinctive approach to the strategic toolbox available for the design of stereocontrolled organic photoreactions.



Photochemical reactions were carried out with a Kessil H150-Blue lamp. Diastereomer ratios for reactions were determined by 1H NMR analysis of unpurified reaction mixtures vs. a phenanthrene internal standard. 1H and 13C NMR data were obtained using a Bruker Avance-500 spectrometer with a DCH cryoprobe and are referenced to tetramethylsilane (0.0 p.p.m.) and CDCl3 (77.0 p.p.m.), respectively. 19F and 31P NMR data were obtained using Bruker Avance-400 spectrometer. NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sext = sextet, sept = septet, m = multiplet), coupling constant(s) in Hz, integration. NMR spectra were obtained at 298 K unless otherwise noted. Fourier-transform infrared spectra were obtained using a Bruker Tensor 27 spectrometer and are reported in terms of frequency of absorption (cm−1). Melting points were obtained using a Stanford Research Systems DigiMelt MPA160 melting point apparatus and are uncorrected. Mass spectrometry was performed with a Thermo Q ExactiveTM Plus using electrospray ionization-time of flight. Enantiomeric excesses were determined by chiral high-performance liquid chromatography (HPLC) of isolated materials using a Waters e2695 separations module with 2998 PDA detector and Daicel CHIRALPAK® columns, and HPLC grade i-PrOH and hexanes. Traces were acquired using Empower 3® software. Optical rotations were measured using a Rudolf Research Autopol III polarimeter at room temperature in CH2Cl2. Ultraviolet-visible absorption spectra were acquired using a Varian Cary® 50 UV-visible spectrophotometer. For the preparation of catalysts and substrates, see Supplementary Methods. For mechanistic experiments, see Supplementary Figs. 16; for crystallographic data, see Supplementary Figs. 712; and for computational data, see Supplementary Figs. 13 and 14.

General photoreaction procedure

An oven-dried Schlenk tube was charged with acyl imidazole (0.4 mmol, 1.0 equiv), styrene (4.0 mmol, 10.0 equiv.), (R)-AC-3 (0.08 mmol, 0.2 equiv.), and 8 mL toluene. The Schlenk tube was sealed with a glass stopper and degassed via freeze–pump–thaw technique (3 × 5 min). This was then cooled to −78 °C and irradiated with a Kessil H150-Blue lamp for 14 h. The reaction mixture was then diluted 2–3× with CH2Cl2 before addition of 2 mL sat. aq. NaHCO3. The mixture was vigorously stirred for 1 min, the organic layer separated, and the aqueous layer extracted with CH2Cl2 (2 × 4 mL). The combined organics were dried over Na2SO4, concentrated, and analyzed by 1H NMR vs. internal standard (phenanthrene), to determine conversion and diastereomeric ratio. The crude mixture was then purified via flash column chromatography using Et2O/pentanes as the eluent, giving an isolated mixture of separable diastereomers. The major diastereomer of each mixture was characterized.

Data availability

All data generated in this study are provided in the Supplementary Information files. The X-ray crystallographic coordinates for compound 18 and for the 1AC-3 salt have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers CCDC-2022776 and CCDC-2022777, respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via


  1. 1.

    Rau, H. Asymmetric photochemistry in solution. Chem. Rev. 83, 535–547 (1983).

    CAS  Article  Google Scholar 

  2. 2.

    Inoue, Y. Asymmetric photochemical reactions in solution. Chem. Rev. 92, 741–770 (1992).

    CAS  Article  Google Scholar 

  3. 3.

    Inoue, Y. & Ramamurthy, V. Chiral Photochemistry. Molecular and Supramolecular Photochemistry Vol. 11 (Marcel Dekker, 2004).

  4. 4.

    Brimioulle, R., Lenhart, D., Maturi, M. M. & Bach, T. Enantioselective catalysis of photochemical reactions. Angew. Chem. Int. Ed. 54, 3872–3890 (2015).

    CAS  Article  Google Scholar 

  5. 5.

    Zou, Y.-Q., Hörmann, F. M. & Bach, T. Iminium and enamine catalysis in enantioselective photochemical reactions. Chem. Soc. Rev. 47, 278–290 (2018).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Sherbrook, E. M. & Yoon, T. P. in Specialist Periodical Reports: Photochemistry (eds Albini, A. & Protti, S.) Vol. 46, 432−448 (Royal Society of Chemistry, 2019).

  7. 7.

    Prentice, C., Morrisson, J., Smith, A. D. & Zysman-Colman, E. Recent developments in enantioselective photocatalysis. Beilstein J. Org. Chem. 16, 2363–2441 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Rigotti, T. & Alemán, J. Visible light photocatalysis – from racemic to asymmetric activation strategies. Chem. Commun. 56, 11169–11190 (2020).

    CAS  Article  Google Scholar 

  9. 9.

    Brimioulle, R. & Bach, T. Enantioselective Lewis acid catalysis of intramolecular enone [2+2] photocycloaddition reactions. Science 342, 840–843 (2013).

    ADS  CAS  PubMed  Article  Google Scholar 

  10. 10.

    Brenninger, C., Jolliffe, J. D. & Bach, T. Chromophore activation of α,β-unsaturated carbonyl compounds and its application to enantioselective photochemical reactions. Angew. Chem. Int. Ed. 57, 14338–14349 (2018).

    CAS  Article  Google Scholar 

  11. 11.

    Blum, T. R., Miller, Z. D., Bates, D. M., Guzei, I. A. & Yoon, T. P. Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer. Science 354, 1391–1395 (2016).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Miller, Z. D., Lee, B. J. & Yoon, T. P. Enantioselective crossed photocycloadditions of styrenic olefins by Lewis acid catalyzed triplet sensitization. Angew. Chem. Int. Ed. 56, 11891–11895 (2017).

    CAS  Article  Google Scholar 

  13. 13.

    Daub, M. E. et al. Enantioselective [2+2] cycloadditions of cinnamate esters: generalizing Lewis acid catalysis of triplet energy transfer. J. Am. Chem. Soc. 141, 9543–9547 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Erkkilä, A., Majander, I. & Pihko, P. M. Iminium catalysis. Chem. Rev. 107, 5416–5470 (2007).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Mukherjee, S., Yang, J. W., Hoffmann, S. & List, B. Asymmetric enamine catalysis. Chem. Rev. 107, 5471–5569 (2007).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Doyle, A. G. & Jacobsen, E. N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 107, 5713–5743 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Akiyama, T. Stronger Brønsted acids. Chem. Rev. 107, 5744–5758 (2007).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Takagi, R. & Tabuchi, C. Enantioselective intramolecular [2+2] photocycloaddition using phosphoric acid as a chiral template. Org. Biomol. Chem. 18, 9261–9267 (2020).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Silvi, M., Verrier, C., Rey, Y. P., Buzzetti, L. & Melchiorre, P. Visible-light excitation of iminium ions enables the enantioselective catalytic β-alkylation of enals. Nat. Chem. 9, 868–873 (2017).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Verrier, C. et al. Direct stereoselective installation of alkyl fragments at the β-carbon of enals via excited iminium ion catalysis. ACS Catal. 8, 1062–1066 (2018).

    CAS  Article  Google Scholar 

  21. 21.

    Hörmann, F. M., Chung, T. S., Rodriguez, E., Jakob, M. & Bach, T. Evidence for triplet sensitization in the visible‐light‐induced [2+2] photocycloaddition of eniminium ions. Angew. Chem. Int. Ed. 57, 827–831 (2018).

    Article  CAS  Google Scholar 

  22. 22.

    Hörmann, F. M. et al. Triplet energy transfer from ruthenium complexes to chiral eniminium ions: enantioselective synthesis of cyclobutanecarbaldehydes by [2+2] photocycloaddition. Angew. Chem. Int. Ed. 59, 9659–9668 (2020).

    Article  CAS  Google Scholar 

  23. 23.

    Bibal, B., Mongin, C. & Bassani, D. M. Template effects and supramolecular control of photoreactions in solution. Chem. Soc. Rev. 43, 4179–4198 (2014).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Ramamurthy, V. & Sivaguru, J. Supramolecular photochemistry as a potential synthetic tool: photocycloaddition. Chem. Rev. 116, 9914–9993 (2016).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Burg, F. & Bach, T. Lactam hydrogen bonds as control elements in enantioselective transition-metal-catalyzed and photochemical reactions. J. Org. Chem. 84, 8815–8836 (2019).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Vallavoju, N., Selvakumar, S., Jockusch, S., Sibi, M. P. & Sivaguru, J. Enantioselective organo-photocatalysis mediated by atropisomeric thiourea derivatives. Angew. Chem. Int. Ed. 53, 5604–5608 (2014).

    CAS  Article  Google Scholar 

  27. 27.

    Vallavoju, N. et al. Organophotocatalysis: insights into the mechanistic aspects of thiourea-mediated intermolecular [2+2] photocycloadditions. Angew. Chem. Int. Ed. 55, 5446–5451 (2016).

    CAS  Article  Google Scholar 

  28. 28.

    Sherbrook, E. M., Jung, H., Cho, D., Baik, M.-H. & Yoon, T. P. Brønsted acid catalysis of photosensitized cycloadditions. Chem. Sci. 11, 856–861 (2020).

    CAS  Article  Google Scholar 

  29. 29.

    Parmar, D., Sugiono, E., Raja, S. & Rueping, M. Complete field guide to asymmetric BINOL-phosphate derived Brønsted acid and metal catalysis: history and classification by mode of activation; Brønsted acidity, hydrogen bonding, ion pairing, and metal phosphates. Chem. Rev. 114, 9047–9153 (2014).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Nakashima, D. & Yamamoto, H. Design of chiral N-triflyl phosphoramide as a strong chiral Bronsted acid and its application to asymmetric Diels–Alder reaction. J. Am. Chem. Soc. 128, 9626–9627 (2006).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Du, J., Skubi, K. L., Schultz, D. M. & Yoon, T. P. A dual-catalysis approach to enantioselective [2+2] photocycloadditions using visible light. Science 344, 392–396 (2014).

    ADS  CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Lei, T. et al. General and efficient intermolecular [2+2] photodimerization of chalcones and cinnamic acid derivatives in solution through visible-light catalysis. Angew. Chem. Int. Ed. 56, 15407–15410 (2017).

    CAS  Article  Google Scholar 

  33. 33.

    Li, R. et al. Photocatalytic regio- and stereo-selective [2+2] cycloaddition of styrene derivatives using a heterogeneous organic photocatalyst. ACS Catal. 7, 3097–3101 (2017).

    CAS  Article  Google Scholar 

  34. 34.

    Fan, X., Lei, T., Chen, B., Tung, C.-H. & Wu, L.-Z. Photocatalytic C–C bond activation of oxime ester for acyl radical generation and application. Org. Lett. 21, 4153–4158 (2019).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Nguyen, J. D., D’Amato, E. M., Narayanam, J. M. & Stephenson, C. R. Engaging unactivated alkyl, alkenyl and aryl iodides in visible-light-mediated free radical reactions. Nat. Chem. 4, 854–859 (2012).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Carreira, E. M. & Fessard, T. C. Four-membered ring-containing spirocycles: synthetic strategies and opportunities. Chem. Rev. 114, 8257–8322 (2014).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Huang, X. et al. Direct visible-light-excited asymmetric Lewis acid catalysis of intermolecular [2+2] photocycloadditions. J. Am. Chem. Soc. 139, 9120–9123 (2017).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Jung, H. et al. Understanding the mechanism of direct visible-light-acitivated [2+2] cycloadditions mediated by Rh and Ir photocatalysts: combined computational and spectroscopic studies. Chem. Sci. 12, 9673–9681 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Zalewski, R. I. & Dunn, G. E. Protonation of conjugated carbonyl groups in sulfuric acid solutions. I. Adaptation of the amide acidity function HA for protonation of the carbonyl group in non-Hammett bases. Can. J. Chem. 46, 2469–2470 (1968).

    CAS  Article  Google Scholar 

  40. 40.

    Zalewski, R. I. & Dunn, G. E. Protonation of conjugated carbonyl groups in sulfuric acid solutions. II. Protonation and basicity of α,β-unsaturated alicyclic ketones. Can. J. Chem. 47, 2263–2270 (1969).

    CAS  Article  Google Scholar 

  41. 41.

    Mulliken, R. S. Molecular compounds and their spectra. J. Am. Chem. Soc. 74, 811–824 (1952).

    CAS  Article  Google Scholar 

  42. 42.

    Rosokha, S. V. & Kochi, J. K. Fresh look at electron-transfer mechanisms via the donor-acceptor bindings in the critical encounter complex. Acc. Chem. Res. 41, 641–653 (2008).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Lima, C. G., Lima, T. M., Duarte, M., Jurberg, I. D. & Paixão, M. W. Organic synthesis enabled by light-irradiation of EDA complexes: theoretical background and synthetic applications. ACS Catal. 6, 1389–1407 (2016).

    CAS  Article  Google Scholar 

  44. 44.

    Arceo, E., Jurberg, I. D., Álvarez-Fernández, A. & Melchiorre, P. Photochemical activity of a key donor-acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes. Nat. Chem. 5, 750–756 (2013).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Bahamonde, A. & Melchiorre, P. Mechanism of the stereoselective α-alkylation of aldehydes driven by the photochemical activity of enamines. J. Am. Chem. Soc. 138, 8019–8030 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references


Funding for this research project was provided by the NIH (GM127545). M.J.G. thanks the NSF for a graduate research fellowship (DGE-1747503) and the Wisconsin Alumni Research Foundation for additional support. M.-H.B. acknowledges support from the Institute for Basic Science (IBS-R10-A1) in Korea. NMR and MS facilities at UW–Madison are funded by the NIH (1S10 OD020022-1) and a generous gift from the Paul J. and Margaret M. Bender Fund. X-ray facilities were funded in part by the NSF (CHE-1919350).

Author information




E.M.S. and M.J.G. performed the experimental work for this study. B.P. performed DFT calculations. I.A.G. conducted all the X-ray crystallographic analyses. M.-H.B. and T.P.Y. supervised the research. All co-authors participated in the preparation of the manuscript.

Corresponding authors

Correspondence to Mu-Hyun Baik or Tehshik P. Yoon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sherbrook, E.M., Genzink, M.J., Park, B. et al. Chiral Brønsted acid-controlled intermolecular asymmetric [2 + 2] photocycloadditions. Nat Commun 12, 5735 (2021).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI:


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing