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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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).
The authors declare no competing interests.
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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