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Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction

Nature Chemistry volume 10, pages 888–894 (2018)Cite this article

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Abstract

The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon–carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities. Parts per million (ppm) levels of catalyst loadings can be routinely used and provide fast and quantitative product formation in high enantiopurity. In situ spectroscopic studies and acidity measurements suggest a silylium ion based, asymmetric counteranion-directed Lewis acid catalysis mechanism.

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Fig. 1: Representative examples of tertiary aldol-containing natural products and catalytic asymmetric routes to these moieties.
Fig. 2: Reactivity comparison of DSI C-1 and IDPi C-2 in the Mukaiyama aldol reaction of ketone as electrophile under identical reaction conditions.
Fig. 3: Mukaiyama aldol reaction of ketones on a preparative scale with catalyst loadings between 0.9 and 25 ppm.
Fig. 4: Study of the reaction mechanism.

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Acknowledgements

Support from the Max Planck Society, the Deutsche Forschungsgemeinschaft (Leibniz Award to B.L. and Cluster of Excellence RESOLV, EXC 1069) and the European Research Council (Advanced Grant ‘C–H Acids for Organic Synthesis, CHAOS’) is acknowledged. The authors thank J.L. Kennemur for her suggestions during the preparation of this manuscript, P. Gupta for his assistance on the preparation of artwork, the technicians of our group, and the members of our NMR, MS and HPLC departments for their excellent service. The work of K.K. and I.L. was supported by grant IUT20-14 from the Estonian Ministry of Education and Research. This paper is dedicated to Prof. T. Mukaiyama in celebration of his 90th birthday (Sotsuju).

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Authors and Affiliations

  1. Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany

    Han Yong Bae, Denis Höfler, Philip S. J. Kaib, Pinar Kasaplar, Chandra Kanta De, Arno Döhring, Sunggi Lee & Benjamin List

  2. University of Tartu, Institute of Chemistry, Tartu, Estonia

    Karl Kaupmees & Ivo Leito

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Contributions

H.Y.B. developed the reaction and investigated the substrate scope, derivatizations of the aldol products, and implemented in situ FT-IR study. D.H. first observed the high activity of IDPi catalysts in the described reaction. The IDPi catalysts were developed by H.Y.B., P.S.J.K. and B.L. H.Y.B., P.S.J.K., P.K. and S.L. synthesized the IDPi catalysts used in this study. H.Y.B., C.K.D. and A.D. investigated large-scale and low-catalyst loading experiments. K.K. and I.L. measured pKa values of acid catalysts. B.L. designed and oversaw the project. H.Y.B. and B.L. wrote the manuscript.

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Correspondence to Benjamin List.

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Bae, H.Y., Höfler, D., Kaib, P.S.J. et al. Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon–carbon bond forming reaction. Nature Chem 10, 888–894 (2018). https://doi.org/10.1038/s41557-018-0065-0

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