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Intercepting fleeting cyclic allenes with asymmetric nickel catalysis

Abstract

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity1. The considerable ring strain (30–50 kilocalories per mole)2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, catalytic asymmetric variants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding the types of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

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Fig. 1: Historical context of strained cyclic intermediates and current reaction design.
Fig. 2: Scope of benzotriazinones and cyclic allenes in the racemic annulation reaction.
Fig. 3: Optimization and scope of the asymmetric annulation.
Fig. 4: Computational study of the asymmetric annulation reaction mechanism.

Data availability

Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under CCDC 1987661. The authors declare that all other data supporting the findings of this study are available within the paper and its Supplementary Information files.

References

  1. 1.

    Wenk, H. H., Winkler, M. & Sander, W. One century of aryne chemistry. Angew. Chem. Int. Ed. 42, 502–528 (2003).

    CAS  Article  Google Scholar 

  2. 2.

    Liebman, J. F. & Greenberg, A. A survey of strained organic molecules. Chem. Rev. 76, 311–365 (1976).

    CAS  Article  Google Scholar 

  3. 3.

    Angus, R. O., Jr, Schmidt, M. W. & Johnson, R. P. Small-ring cyclic cumulenes: theoretical studies of the structure and barrier to inversion of cyclic allenes. J. Am. Chem. Soc. 107, 532–537 (1985).

    CAS  Article  Google Scholar 

  4. 4.

    Pellissier, H. & Santelli, M. The use of arynes in organic synthesis. Tetrahedron 59, 701–730 (2003).

    CAS  Article  Google Scholar 

  5. 5.

    Dockendorff, C., Sahli, S., Olsen, M., Milhau, L. & Lautens, M. Synthesis of dihydronaphthalenes via aryne-Diels–Alder reactions: scope and diastereoselectivity. J. Am. Chem. Soc. 127, 15028–15029 (2005).

    CAS  Article  Google Scholar 

  6. 6.

    Picazo, E. et al. Arynes and cyclic alkynes as synthetic building blocks for stereodefined quaternary centers. J. Am. Chem. Soc. 140, 7605–7610 (2018).

    CAS  Article  Google Scholar 

  7. 7.

    Stoermer, R. & Kahlert, B. Ueber das 1-Brom-cumaron. Ber. Dtsch. Chem. Ges. 35, 1633–1640 (1902).

    CAS  Article  Google Scholar 

  8. 8.

    Roberts, J. D., Simmons, H. E., Carlsmith, L. A. & Vaughan, C. W. Rearrangement in the reaction of chlorobenzene-1-C14 with potassium amide. J. Am. Chem. Soc. 75, 3290–3291 (1953).

    CAS  Article  Google Scholar 

  9. 9.

    Wittig, G. Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen. Naturwissenschaften 30, 696–703 (1942).

    ADS  CAS  Article  Google Scholar 

  10. 10.

    Wittig, G. & Pohmer, L. Intermediäre Bildung von Dehydrobenzol (Cyclohexa-dienin). Angew. Chem. 67, 348 (1955).

    CAS  Article  Google Scholar 

  11. 11.

    Scardiglia, F. & Roberts, J. D. Evidence for cyclohexyne as an intermediate in the coupling of phenyllithium with 1-chlorocyclohexene. Tetrahedron 1, 343–344 (1957).

    CAS  Article  Google Scholar 

  12. 12.

    Wittig, G. & Fritze, P. On the intermediate occurrence of 1,2-cyclohexadiene. Angew. Chem. Int. Edn Engl. 5, 846 (1966).

    Article  Google Scholar 

  13. 13.

    Berry, R. S., Clardy, J. & Schafer, M. E. Benzyne. J. Am. Chem. Soc. 86, 2738–2739 (1964).

    CAS  Article  Google Scholar 

  14. 14.

    Diau, E. W.-G., Casanova, J., Roberts, J. D. & Zewail, A. H. Femtosecond observation of benzyne intermediates in a molecular beam: Bergman rearrangement in the isolated molecule. Proc. Nat. Acad. Sci. 97, 1376–1379 (2000).

    ADS  CAS  Article  Google Scholar 

  15. 15.

    Dubrovskiy, A. V., Markina, N. A. & Larock, R. C. Use of benzynes for the synthesis of heterocycles. Org. Biomol. Chem. 11, 191–218 (2013).

    CAS  Article  Google Scholar 

  16. 16.

    Chen, S. et al. Preparation of substituted 2,2-bipyrimidinyl compounds and analogs thereof, and methods using the same. International patent W02019222238 A2 (2019).

  17. 17.

    Mauger, C. C. & Mignani, G. A. An efficient and safe procedure for the large-scale Pd-catalyzed hydrazonation of aromatic chlorides using Buchwald technology. Org. Process Res. Dev. 8, 1065–1071 (2004).

    CAS  Article  Google Scholar 

  18. 18.

    Takikawa, H., Nishii, A., Sakai, T. & Suzuki, K. Aryne-based strategy in the total synthesis of naturally occurring polycyclic compounds. Chem. Soc. Rev. 47, 8030–8056 (2018).

    CAS  Article  Google Scholar 

  19. 19.

    Tadross, P. M. & Stoltz, B. M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 112, 3550–3577 (2012).

    CAS  Article  Google Scholar 

  20. 20.

    Gampe, C. M. & Carreira, E. M. Arynes and cyclohexyne in natural product synthesis. Angew. Chem. Int. Ed. 51, 3766–3778 (2012).

    CAS  Article  Google Scholar 

  21. 21.

    Schleth, F., Vettiger, T., Rommel, M. & Tobler, H. Process for the preparation of pyrazole carboxylic acid amides. International patent WO2011131544 A1 (2011).

  22. 22.

    Lin, J. B., Shah, T. J., Goetz, A. E., Garg, N. K. & Houk, K. N. Conjugated trimeric scaffolds accessible from indolyne cyclotrimerizations: synthesis, structures, and electronic properties. J. Am. Chem. Soc. 139, 10447–10455 (2017).

    CAS  Article  Google Scholar 

  23. 23.

    Caeiro, J., Peña, D., Cobas, A., Pérez, D. & Guitián, E. Asymmetric catalysis in the [2+2+2] cycloaddition of arynes and alkynes: enantioselective synthesis of a pentahelicene. Adv. Synth. Catal. 348, 2466–2474 (2006).

    CAS  Article  Google Scholar 

  24. 24.

    Yubuta, A. et al. Enantioselective synthesis of triple helicenes by cross-cyclotrimerization of a helicenyl aryne and alkynes via dynamic kinetic resolution. J. Am. Chem. Soc. 142, 10025–10033 (2020).

    CAS  Article  Google Scholar 

  25. 25.

    Li, L., Li, Y., Fu, N., Zhang, L. & Luo, S. Catalytic asymmetric electrochemical α-arylation of cyclic β-ketocarbonyls with anodic benzyne intermediates. Angew. Chem. Int. Ed. 59, 14347–14351 (2020).

    CAS  Article  Google Scholar 

  26. 26.

    Quintana, I., Peña, D., Pérez, D. & Guitián, E. Generation and reactivity of 1,2-cyclohexadiene under mild reaction conditions. Eur. J. Org. Chem. 2009, 5519–5524 (2009).

    Article  Google Scholar 

  27. 27.

    Barber, J. S. et al. Diels–Alder cycloadditions of strained azacyclic allenes. Nat. Chem. 10, 953–960 (2018).

    CAS  Article  Google Scholar 

  28. 28.

    Lofstrand, V. A. & West, F. G. Efficient trapping of 1,2-cyclohexadienes with 1,3-dipoles. Chemistry 22, 10763–10767 (2016).

    CAS  Article  Google Scholar 

  29. 29.

    Barber, J. S. et al. Nitrone cycloadditions of 1,2-cyclohexadiene. J. Am. Chem. Soc. 138, 2512–2515 (2016).

    CAS  Article  Google Scholar 

  30. 30.

    Yamano, M. M. et al. Cycloadditions of oxacyclic allenes and a catalytic asymmetric entryway to enantioenriched cyclic allenes. Angew. Chem. Int. Ed. 58, 5653–5657 (2019).

    CAS  Article  Google Scholar 

  31. 31.

    Lofstrand, V. A., McIntosh, K. C., Almehmadi, Y. A. & West, F. G. Strain-activated Diels–Alder trapping of 1,2-cyclohexadienes: intramolecular capture by pendent furans. Org. Lett. 21, 6231–6234 (2019).

    CAS  Article  Google Scholar 

  32. 32.

    Pellissier, H. Dynamic kinetic resolution. Tetrahedron 59, 8291–8327 (2003).

    CAS  Article  Google Scholar 

  33. 33.

    Balci, M. & Jones, W. M. Chirality as a probe for the structure of 1,2-cycloheptadiene and 1,2-cyclohexadiene. J. Am. Chem. Soc. 102, 7607–7608 (1980).

    CAS  Article  Google Scholar 

  34. 34.

    Dhokale, R. A. & Mhaske, S. B. Transition-metal-catalyzed reactions involving arynes. Synthesis 50, 1–16 (2018).

    CAS  Article  Google Scholar 

  35. 35.

    Chattopadhyay, B. & Gevorgyan, V. Transition-metal-catalyzed denitrogenative transannulation: converting triazoles into other heterocyclic systems. Angew. Chem. Int. Ed. 51, 862–872 (2012).

    CAS  Article  Google Scholar 

  36. 36.

    Thorat, V. H., Upadhyay, N. S., Murakami, M. & Cheng, C.-H. Nickel-catalyzed denitrogenative annulation of 1,2,3-benzotriazin-4-(3H)-ones with benzynes for construction of phenanthridinone scaffolds. Adv. Synth. Catal. 360, 284–289 (2018).

    CAS  Article  Google Scholar 

  37. 37.

    Wang, N., Zheng, S.-C., Zhang, L.-L., Guo, Z. & Liu, X.-Y. Nickel(0)-catalyzed denitrogenative transannulation of benzotriazinones with alkynes: mechanistic insights of chemical reactivity and regio- and enantioselectivity from density functional theory and experiment. ACS Catal. 6, 3496–3505 (2016).

    CAS  Article  Google Scholar 

  38. 38.

    Yamauchi, M., Morimoto, M., Miura, T. & Murakami, M. Enantioselective synthesis of 3,4-dihydroisoquinolin-1(2H)-ones by nickel-catalyzed denitrogenative annulation of 1,2,3-benzotriazin-4(3H)-ones with allenes. J. Am. Chem. Soc. 132, 54–55 (2010).

    CAS  Article  Google Scholar 

  39. 39.

    Jin, Z. & Yao, G. Amaryllidaceae and sceletium alkaloids. Nat. Prod. Rep. 36, 1462–1488 (2019).

    CAS  Article  Google Scholar 

  40. 40.

    Miura, T., Yamauchi, M., Kosaka, A. & Murakami, M. Nickel-catalyzed regio- and enantioselective annulation reactions of 1,2,3,4-benzothiatriazine-1,1(2H)-dioxides with allenes. Angew. Chem. Int. Ed. 49, 4955–4957 (2010).

    CAS  Article  Google Scholar 

  41. 41.

    Feng, M., Tang, B., Wang, N., Xiu, H.-X. & Jiang, X. Ligand controlled regiodivergent C1 insertion on arynes for construction of phenanthridinone and acridone alkaloids. Angew. Chem. Int. Ed. 54, 14960–14964 (2015).

    CAS  Article  Google Scholar 

  42. 42.

    Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful to the NIH-NIGMS (R01 GM123299 and R01 GM132432 for N.K.G., and T32 GM067555 for A.V.K.), the NSF (CHE-1764328 for K.N.H., DGE-1144087 for M.M.Y. and B.J.S., and DGE-1650604 for A.V.K.), the Trueblood family (for N.K.G.), and the Swiss National Science Foundation for an Early Mobility Postdoctoral Fellowship (M.G.). These studies were supported by shared instrumentation grants from the NSF (CHE-1048804) and the NIH NCRR (S10RR025631). Calculations were performed on the Hoffman2 cluster and the UCLA Institute of Digital Research and Education (IDRE) at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (OCI-1053575).

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Authors

Contributions

M.M.Y., A.V.K., M.G. and B.J.S. designed and performed experiments and analysed experimental data. Q.S., B.L. and S.C. designed, performed, and analysed computational data. K.N.H. and N.K.G. directed the investigations and prepared the manuscript with contributions from all authors; all authors contributed to discussions.

Corresponding authors

Correspondence to K. N. Houk or Neil K. Garg.

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Competing interests

The authors declare no competing interests.

Extended data figures and tables

Extended Data Fig. 1 Proposed catalytic cycle.

Computational studies support a mechanism involving activation of the benzotriazinone by the Ni catalyst, migratory insertion across one olefin of the cyclic allene, isomerization to a Ni π-allyl complex, and enantioselective outer-sphere attack to provide the observed phenanthridinone.

Supplementary information

Supplementary Information

This file contains: General Procedures; Reaction Optimization Data; Single Crystal X-Ray Diffraction Data; Supercritical Fluid Chromatography Data; 1H and 13C NMR Spectral Data; Computational Methods; Detailed Computational Mechanistic Analysis, Atomic Coordinates for all Structures Studied Computationally and Supplementary References.

Supplementary Data

This file contains the CheckCIF and CIF file for Compound 69 CCDC reference 1987661.

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Yamano, M.M., Kelleghan, A.V., Shao, Q. et al. Intercepting fleeting cyclic allenes with asymmetric nickel catalysis. Nature 586, 242–247 (2020). https://doi.org/10.1038/s41586-020-2701-2

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