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Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block

Nature volume 547, pages 196–200 (2017)Cite this article

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Abstract

The stereoselective oxidation of hydrocarbons is one of the most notable advances in synthetic chemistry over the past fifty years1,2,3. Inspired by nature, enantioselective dihydroxylations, epoxidations and other oxidations of unsaturated hydrocarbons have been developed. More recently, the catalytic enantioselective allylic carbon–hydrogen oxidation of alkenes has streamlined the production of pharmaceuticals, natural products, fine chemicals and other functional materials4,5,6,7. Allylic functionalization provides a direct path to chiral building blocks with a newly formed stereocentre from petrochemical feedstocks while preserving the olefin functionality as a handle for further chemical elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic carbon–hydrogen oxidation of simple alkenes with cyclic or terminal double bonds8,9,10,11,12,13,14,15,16. However, a general and selective allylic oxidation using the more common internal alkenes remains elusive. Here we report the enantioselective, regioselective and E/Z-selective allylic oxidation of unactivated internal alkenes via a catalytic hetero-ene reaction with a chalcogen-based oxidant. Our method enables non-symmetric internal alkenes to be selectively converted into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the resulting multifunctional chiral building blocks highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be used in the synthesis of complex target molecules.

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Figure 1: Catalytic enantioselective oxidation of unactivated terminal and internal alkenes.
Figure 2: Substrate scope of the catalytic enantioselective and regioselective allylic oxidation of internal unactivated alkenes.
Figure 3: Multiple synthetic derivitizations of the synthetically versatile product of the catalytic enantioselective and regioselective allylic oxidation of internal alkenes.
Figure 4: Mechanistic studies of the catalytic enantioselective allylic oxidation of internal alkenes.

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References

  1. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis I–III (Springer, 1999)

  2. Ojima, I. (ed.) Catalytic Asymmetric Synthesis 3rd edn (John Wiley & Sons, 2010)

  3. Bonini, C. & Righi, G. A critical outlook and comparison of enantioselective oxidation methodologies of olefins. Tetrahedron 58, 4981–5021 (2002)

    Article  CAS  Google Scholar 

  4. Page, P. C. B . & McCarthy, T. J. in Comprehensive Organic Synthesis (eds Trost, B. M . & Fleming, I ) 83–117 (Pergamon, 1991)

  5. Grennberg, H. & Bäckvall, J.-E. in Transition Metals for Organic Synthesis (eds Beller, M. & Bolm, C. ) 243–265 (Wiley-VCH, 2008)

  6. Liu, G. & Wu, Y. in C–H Activation (eds Yu, J.-Q. & Shi, Z. ) 195–209 (Springer, 2010)

  7. Andrus, M. B. in Stereoselective Synthesis 3: Stereoselective Pericyclic Reactions, Cross Coupling, and C–H and C–X Activation (ed. Evans, P. A. ) Ch. 11 (Georg Thieme, 2011)

  8. Johannsen, M. & Jørgensen, K. A. Allylic amination. Chem. Rev. 98, 1689–1708 (1998)

    Article  CAS  Google Scholar 

  9. Zalatan, D. N. & Bois, J. D. in C–H Activation (eds Yu, J.-Q. & Shi, Z. ) 347–378 (Springer, 2010)

  10. Collet, F., Lescot, C. & Dauban, P. Catalytic C–H amination: the stereoselectivity issue. Chem. Soc. Rev. 40, 1926–1936 (2011)

    Article  CAS  Google Scholar 

  11. Covell, D. J. & White, M. C. A chiral Lewis acid strategy for enantioselective allylic C–H oxidation. Angew. Chem. Int. Ed. 47, 6448–6451 (2008)

    Article  CAS  Google Scholar 

  12. Ramirez, T. A., Zhao, B. & Shi, Y. Recent advances in transition metal-catalyzed sp3 C–H amination adjacent to double bonds and carbonyl groups. Chem. Soc. Rev. 41, 931–942 (2012)

    Article  CAS  Google Scholar 

  13. Andrus, M. B. & Zhou, Z. Highly enantioselective copper−bisoxazoline-catalyzed allylic oxidation of cyclic olefins with tert-butyl p-nitroperbenzoate. J. Am. Chem. Soc. 124, 8806–8807 (2002)

    Article  CAS  Google Scholar 

  14. Eames, J. & Watkinson, M. Catalytic allylic oxidation of alkenes using an asymmetric Kharasch–Sosnovsky reaction. Angew. Chem. Int. Ed. 40, 3567–3571 (2001)

    Article  CAS  Google Scholar 

  15. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008)

    Article  CAS  ADS  Google Scholar 

  16. Trost, B. M., Donckele, E. J., Thaisrivongs, D. A., Osipov, M. & Masters, J. T. A new class of non-C2-symmetric ligands for oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. J. Am. Chem. Soc. 137, 2776–2784 (2015)

    Article  CAS  Google Scholar 

  17. Sharpless, K. B. & Lauer, R. F. Selenium dioxide oxidation of olefins. Evidence for the intermediacy of allylseleninic acids. J. Am. Chem. Soc. 94, 7154–7155 (1972)

    Article  CAS  Google Scholar 

  18. Schonberger, N. & Kresze, G. Chemistry of sulfur diimides. 6. Ene reactions and [2+2] cycloadditions of N,N′-ditosyl sulfur diimide and N-sulfinyl-para-toluenesulfonamide. Liebigs Ann. Chem. 1725–1731 (1975)

  19. Sharpless, K. B., Hori, T., Truesdale, L. K. & Dietrich, C. O. Allylic amination of olefins and acetylenes by imido selenium compounds. J. Am. Chem. Soc. 98, 269–271 (1976)

    Article  CAS  Google Scholar 

  20. Sharpless, K. B. & Hori, T. Allylic amination of olefins and acetylenes by imido sulfur compounds. J. Org. Chem. 41, 176–177 (1976)

    Article  CAS  Google Scholar 

  21. Hori, T., Singer, S. P. & Sharpless, K. B. Allylic deuteration and tritiation of olefins with N-sulfinylsulfonamides. J. Org. Chem. 43, 1456–1459 (1978)

    Article  CAS  Google Scholar 

  22. Whitesell, J. K. & Carpenter, J. F. Absolute stereochemical control in allylic oxidation via ene reactions of N-sulfinylcarbamates. J. Am. Chem. Soc. 109, 2839–2840 (1987)

    Article  CAS  Google Scholar 

  23. Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013)

    Article  CAS  Google Scholar 

  24. Sharma, A. & Hartwig, J. F. Enantioselective functionalization of allylic C–H bonds following a strategy of functionalization and diversification. J. Am. Chem. Soc. 135, 17983–17989 (2013)

    Article  CAS  Google Scholar 

  25. Lauer, A. M., Mahmud, F. & Wu, J. Cu(I)-catalyzed, α-selective, allylic alkylation reactions between phosphorothioate esters and organomagnesium reagents. J. Am. Chem. Soc. 133, 9119–9123 (2011)

    Article  CAS  Google Scholar 

  26. Ishibashi, H., Ishihara, K. & Yamamoto, H. Chiral proton donor reagents: tin tetrachloride-coordinated optically active binaphthol derivatives. Chem. Rec. 2, 177–188 (2002)

    Article  CAS  Google Scholar 

  27. Surendra, K. & Corey, E. J. Highly enantioselective proton-initiated polycyclization of polyenes. J. Am. Chem. Soc. 134, 11992–11994 (2012)

    Article  CAS  Google Scholar 

  28. Yamamoto, H. & Futatsugi, K. “Designer acids”: combined acid catalysis for asymmetric synthesis. Angew. Chem. Int. Ed. 44, 1924–1942 (2005)

    Article  CAS  Google Scholar 

  29. Huang, Y., Unni, A. K., Thadani, A. N. & Rawal, V. H. Hydrogen bonding: Single enantiomers from a chiral-alcohol catalyst. Nature 424, 146 (2003)

    Article  CAS  ADS  Google Scholar 

  30. Johnston, J. N., Muchalski, H. & Troyer, T. L. To protonate or alkylate? Stereoselective Brønsted acid catalysis of C–C bond formation using diazoalkanes. Angew. Chem. Int. Ed. 49, 2290–2298 (2010)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  32. Taylor, M. S. & Jacobsen, E. N. Asymmetric catalysis by chiral hydrogen-bond donors. Angew. Chem. Int. Ed. 45, 1520–1543 (2006)

    Article  CAS  Google Scholar 

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Acknowledgements

Financial support was provided by the W. W. Caruth Jr Endowed Scholarship, the Robert A. Welch Foundation (Grant I-1748), the National Institutes of Health (R01GM102604), the National Science Foundation CAREER Award (1150875), and the Sloan Research Fellowship. We thank V. Lynch for X-ray structural analysis.

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Authors and Affiliations

  1. Department of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9038, Texas, USA

    Liela Bayeh, Phong Q. Le & Uttam K. Tambar

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  1. Liela Bayeh
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Contributions

L.B., P.Q.L. and U.K.T. conceived the work and designed the experiments. L.B. and P.Q.L. performed the laboratory experiments. U.K.T. oversaw the project. All authors analysed the data and wrote the manuscript.

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Correspondence to Uttam K. Tambar.

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The authors declare no competing financial interests.

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Extended data figures and tables

Extended Data Figure 1 Development of an enantioselective and regioselective allylic oxidation of internal unactivated alkenes via an ene reaction.

a, Our approach to generating one allylic oxidation product from unactivated internal alkenes and chalcogen-based oxidants. Sulfurimide reagent 3d was chosen for several reasons. First, compared to diimide oxidants 3b and 3c, sulfurimide 3d is considerably less electrophilic and therefore less reactive in thermal hetero-ene reactions, affording greater opportunity for a catalyst-controlled process. Second, the ene adducts generated between internal olefins and oxidants 3a–3c undergo spontaneous [2,3]-rearrangements, which preclude the ability to diversify the resulting oxidation products. Lastly, the presence of distinct nitrogen and oxygen moieties on the central sulfur atom in the allylic oxidation product provides an opportunity for further chemistry to access synthetically diverse products via C–N and C–O bond formation (see Fig. 1b). b, Optimization of the enantioselective allylic oxidation of cis-5-decene. Reaction conditions: cis-5-decene (1 equiv.), sulfurimide reagent 3d (1.5 equiv.), solvent (0.13 M). Yields were determined by 1H NMR using 1,4-dimethoxybenzene as an internal standard. a0.5 equiv. trifluoroacetic acid added to reaction. b10-mmol scale. cIsolated yield. d>20:1 initial d.r. (5a:5b). At −70 °C, reagent 3d did not undergo a background thermal ene reaction with cis-5-decene 4 in the absence of a catalyst (entry 1). Achiral Lewis acids such as TiCl4, SnCl4 and SbCl5 catalysed the ene reaction at −70 °C in CH2Cl2 to furnish the allylic oxidation product 5 in low yields (entries 2–4). Although coordination of BINOL to titanium and tin provided ene-adduct 5 in low enantiomeric excess (entries 5 and 6), the antimony–BINOL complex gave the oxidized product in considerably higher enantiomeric excess with enhanced yield (entry 7). Addition of 50 mol% trifluoroacetic acid (TFA) improved the efficiency of the reaction (entry 8). Examination of several solvents revealed the beneficial effects of CH2Cl2 on the yield of the reaction (entry 8) and of PhMe on the enantioselectivity of the reaction (entry 9). In concert, these two solvents improved the stereoselectivity of the transformation, which was performed on a 10-mmol scale with commercially available (R)-BINOL (entry 10). On the basis of the observed effect of the aromatic solvent on the stereoselectivity of the reaction, we evaluated a series of aryl-substituted BINOL-based diols. Co-catalyst 6 was deemed optimal for this process (see Supplementary Information), with slightly improved enantioselectivity (entry 11). Although the ene adduct was formed as a >20:1 mixture of epimers at sulfur (5a and 5b), which indicates that this process is also highly diastereoselective at −78 °C, this mixture equilibrated over several hours at ambient temperature to a 4:1 mixture of epimers.

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Bayeh, L., Le, P. & Tambar, U. Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block. Nature 547, 196–200 (2017). https://doi.org/10.1038/nature22805

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