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Catalytic reductive desymmetrization of malonic esters

Nature Chemistry volume 13, pages 634–642 (2021)Cite this article

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Abstract

Desymmetrization of fully substituted carbons with a pair of enantiotopic functional groups is a practical strategy for the synthesis of quaternary stereocentres, as it divides the tasks of enantioselection and C−C bond formation. The use of disubstituted malonic esters as the substrate of desymmetrization is particularly attractive, given their easy and modular preparation, as well as the high synthetic values of the chiral monoester products. Here, we report that a dinuclear zinc complex with a tetradentate ligand can selectively hydrosilylate one of the carbonyls of malonic esters to give α-quaternary β-hydroxyesters, providing a promising alternative to the desymmetric hydrolysis using carboxylesterases. The asymmetric reduction features excellent enantiocontrol that can differentiate sterically similar substituents and high chemoselectivity towards the diester motif of substrates. Together with the versatile preparation of malonic ester substrates and post-reduction derivatization, the desymmetric reduction has enabled the synthesis of a diverse array of quaternary stereocentres with distinct structural features.

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Fig. 1: Quaternary stereocentres via desymmetrization of malonic esters.
Fig. 2: Zinc-catalysed desymmetric hydrosilylation of malonic esters.
Fig. 3: Application of the reductive desymmetrization.
Fig. 4: Kinetic study and proposed hydride transfer transition states.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for 50a reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2025159. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.

References

  1. Quasdorf, K. W. & Overman, L. E. Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516, 181–191 (2014).

    Article  CAS  Google Scholar 

  2. Trost, B. M. & Jiang, C. Catalytic enantioselective construction of all-carbon quaternary stereocenters. Synthesis 369-396 (2006).

  3. Corey, E. J. & Guzman-Perez, A. The catalytic enantioselective construction of molecules with quaternary carbon stereocenters. Angew. Chem. Int. Ed. 37, 388–401 (1998).

    Article  Google Scholar 

  4. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  Google Scholar 

  5. Lovering, F. Escape from flatland 2: complexity and promiscuity. MedChemComm 4, 515–519 (2013).

    Article  CAS  Google Scholar 

  6. Das, J. P. & Marek, I. Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems. Chem. Commun. 47, 4593–4623 (2011).

    Article  CAS  Google Scholar 

  7. Feng, J., Holmes, M. & Krische, M. J. Acyclic quaternary carbon stereocenters via enantioselective transition metal catalysis. Chem. Rev. 117, 12564–12580 (2017).

    Article  CAS  Google Scholar 

  8. Wendlandt, A. E., Vangal, P. & Jacobsen, E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018).

    Article  CAS  Google Scholar 

  9. Braun, M. & Kotter, W. Titanium(iv)-catalyzed dynamic kinetic asymmetric transformation of alcohols, silyl ethers, and acetals under carbon allylation. Angew. Chem. Int. Ed. 43, 514–517 (2004).

    Article  CAS  Google Scholar 

  10. Zhao, W., Wang, Z., Chu, B. & Sun, J. Enantioselective formation of all‐carbon quaternary stereocenters from indoles and tertiary alcohols bearing a directing group. Angew. Chem. Int. Ed. 54, 1910–1913 (2015).

    Article  CAS  Google Scholar 

  11. Zeng, X.-P., Cao, Z.-Y., Wang, Y.-H., Zhou, F. & Zhou, J. Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem. Rev. 116, 7330–7396 (2016).

    Article  CAS  Google Scholar 

  12. Petersen, K. S. Nonenzymatic enantioselective synthesis of all-carbon quaternary centers through desymmetrization. Tetrahedron Lett. 56, 6523–6535 (2015).

    Article  CAS  Google Scholar 

  13. de María, P. D., García-Burgos, C. A., Bargeman, G. & van Gemert, R. W. Pig liver esterase (PLE) as biocatalyst in organic synthesis: from nature to cloning and to practical applications. Synthesis 1439-1452 (2007).

  14. García-Urdiales, E., Alfonso, I. & Gotor, V. Enantioselective enzymatic desymmetrizations in organic synthesis. Chem. Rev. 105, 313–354 (2005).

    Article  Google Scholar 

  15. Toone, E. J., Werth, M. J. & Jones, J. B. Enzymes in organic synthesis. 47. Active-site model for interpreting and predicting the specificity of pig liver esterase. J. Am. Chem. Soc. 112, 4946–4952 (1990).

    Article  CAS  Google Scholar 

  16. Provencher, L. & Jones, J. B. A concluding specification of the dimensions of the active site model of pig liver esterase. J. Org. Chem. 59, 2729–2732 (1994).

    Article  CAS  Google Scholar 

  17. Björkling, F. et al. Enzyme catalysed hydrolysis of dialkylated propanedioic acid diesters, chain length dependent reversal of enantioselectivity. Tetrahedron 41, 1347–1352 (1985).

    Article  Google Scholar 

  18. Musidlowska, A., Lange, S. & Bornscheuer, U. T. By overexpression in the yeast Pichia pastoris to enhanced enantioselectivity: new aspects in the application of pig liver esterase. Angew. Chem. Int. Ed. 40, 2851–2853 (2001).

    Article  CAS  Google Scholar 

  19. Smith, M. E. et al. Investigation of the cosolvent effect on six isoenzymes of PLE in the enantioselective hydrolysis of selected α,α-disubstituted malonate esters. ChemCatChem 4, 472–475 (2012).

    Article  CAS  Google Scholar 

  20. Wilent, J. & Petersen, K. S. Enantioselective desymmetrization of diesters. J. Org. Chem. 79, 2303–2307 (2014).

    Article  CAS  Google Scholar 

  21. Karad, S. N., Panchal, H., Clarke, C., Lewis, W. & Lam, H. W. Enantioselective synthesis of chiral cyclopent-2-enones by nickel-catalyzed desymmetrization of malonate esters. Angew. Chem. Int. Ed. 57, 9122–9125 (2018).

    Article  CAS  Google Scholar 

  22. Selmani, A. & Darses, S. Enantioenriched 1-tetralones via rhodium-catalyzed arylative cascade desymmetrization/acylation of alkynylmalonates. Org. Lett. 21, 8122–8126 (2019).

    Article  CAS  Google Scholar 

  23. Marciniec, B. (ed.) Hydrosilylation: A Comprehensive Review on Recent Advances (Springer, 2009).

  24. Rendler, S. & Oestreich, M. in Modern Reduction Methods (eds Andersson, P. G. & Munslow, I. J.) 183–207 (Wiley, 2008).

  25. Díez-González, S. & Nolan, S. P. Transition metal-catalyzed hydrosilylation of carbonyl compounds and imines. A review. Org. Prep. Proced. Int. 39, 523–559 (2007).

    Article  Google Scholar 

  26. Uvarov, V. M. & de Vekki, D. A. Recent progress in the development of catalytic systems for homogenous asymmetric hydrosilylation of ketones. J. Organomet. Chem. 923, 121415 (2020).

    Article  CAS  Google Scholar 

  27. Mimoun, H., de Saint Laumer, J. Y., Giannini, L., Scopelliti, R. & Floriani, C. Enantioselective reduction of ketones by polymethylhydrosiloxane in the presence of chiral zinc catalysts. J. Am. Chem. Soc. 121, 6158–6166 (1999).

    Article  CAS  Google Scholar 

  28. Mimoun, H. Selective reduction of carbonyl compounds by polymethylhydrosiloxane in the presence of metal hydride catalysts. J. Org. Chem. 64, 2582–2589 (1999).

    Article  CAS  Google Scholar 

  29. Das, S., Möller, K., Junge, K. & Beller, M. Zinc-catalyzed chemoselective reduction of esters to alcohols. Chem. Eur. J. 17, 7414–7417 (2011).

    Article  CAS  Google Scholar 

  30. Enthaler, S. & Wu, X.-F. (eds) Zinc Catalysis: Applications in Organic Synthesis (Wiley, 2015).

  31. Enthaler, S. Rise of the zinc age in homogeneous catalysis? ACS Catal. 3, 150–158 (2013).

    Article  CAS  Google Scholar 

  32. Wu, X. & Neumann, H. Zinc-catalyzed organic synthesis: C–C, C–N, C–O bond formation reactions. Adv. Synth. Catal. 354, 3141–3160 (2012).

    Article  CAS  Google Scholar 

  33. Trost, B. M., Hung, C.-I. & Mata, G. Dinuclear metal‐prophenol catalysts: development and synthetic applications. Angew. Chem. Int. Ed. 59, 4240–4261 (2020).

    Article  CAS  Google Scholar 

  34. Trost, B. M. & Mino, T. Desymmetrization of meso 1,3- and 1,4-diols with a dinuclear zinc asymmetric catalyst. J. Am. Chem. Soc. 125, 2410–2411 (2003).

    Article  CAS  Google Scholar 

  35. Liu, Y., Han, S.-J., Liu, W.-B. & Stoltz, B. M. Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules. Acc. Chem. Res. 48, 740–751 (2015).

    Article  CAS  Google Scholar 

  36. Yang, Y., Cho, I., Qi, X., Liu, P. & Arnold, F. H. An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp3)–H bonds. Nat. Chem. 11, 987–993 (2019).

    Article  CAS  Google Scholar 

  37. Zhang, F.-H., Zhang, F.-J., Li, M.-L., Xie, J.-H. & Zhou, Q.-L. Enantioselective hydrogenation of dialkyl ketones. Nat. Catal. 3, 621–627 (2020).

    Article  CAS  Google Scholar 

  38. Walsh, P. J. & Kozlowski, M. C. in Fundamentals of Asymmetric Catalysis 297–329 (University Science Books, 2009).

  39. Ushio, H. & Mikami, K. Asymmetric reduction of ortho-multisubstituted benzophenones catalyzed by diamine–Zn–diol complexes. Tetrahedron Lett. 46, 2903–2906 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the University of Hong Kong for a start-up fund. We acknowledge funding support from the Laboratory for Synthetic Chemistry and Chemical Biology under the Health@InnoHK Program launched by the Innovation and Technology Commission, the Government of HKSAR. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. C.-M. Che and P. Chiu are acknowledged for their kind support and sharing of chemicals. K.-H. Low, J. Yip and B. Yan are acknowledged for X-ray crystallography, mass spectroscopy and NMR spectroscopy, respectively. We also thank L. Wu for helpful discussion.

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Authors and Affiliations

  1. State Key Laboratory of Synthetic Chemistry, Department of Chemistry, The University of Hong Kong, Hong Kong, China

    Pengwei Xu & Zhongxing Huang

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  1. Pengwei Xu
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  2. Zhongxing Huang
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Contributions

Z.H. conceived and designed the project. P.X. and Z.H. carried out the experiments, analysed the data and wrote the manuscript.

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Correspondence to Zhongxing Huang.

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Peer review information Nature Chemistry thanks Marcin Kwit and the other, anonymous, reviewers(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1 and 2, experimental procedures, product characterization data and mechanistic studies.

Supplementary Data

Crystallographic data for compound 50a; CCDC reference 2025159.

Source data

Source Data Fig. 2c

Statistical Source Data.

Source Data Fig. 4a

Statistical Source Data.

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Xu, P., Huang, Z. Catalytic reductive desymmetrization of malonic esters. Nat. Chem. 13, 634–642 (2021). https://doi.org/10.1038/s41557-021-00715-0

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