Approaching Parts-Per-Billion Levels in Challenging Asymmetric Organocatalysis

Since its establishment as a field at the beginning of this century, organocatalysis has significantly advanced chemical synthesis in academia and industry. However, a common view suggesting that organocatalysts are generally less active than metalbased catalysts and enzymes still occasionally persists.

In the first part of this presentation, we will discuss our recent findings on biomimetic enantioselective reactions regarding efficient "direct" introduction of (thio)ester enolate equivalents via chiral Brønsted base catalysis. In the light of both mechanistic and environmental approaches, we developed different hydrogen bonding promoted asymmetric reactions that those are, decarboxylative aldol reaction of malonic acid half thioester with aldehyde which is inspired by polyketide biosynthesis,[1] rate-accelerated Michael addition reaction of malonate with nitroolefin “on water” due to the hydrophobic amplification effect,[2] and Mannich reaction of highly reactive thioester enolate precursor dithiomalonate with N-Boc imine/α-amido sulfone.[3] The low catalytic activity, which is regarded as an intrinsic limitation of organocatalyst, could be addressed by taking advantage of nature's solution.

In the second part, as an “in-direct” approach, we will demonstrate a new class of chiral catalysts which enable the highly challenging enantioselective Mukaiyama aldol reaction of ketones in the presence of extremely low catalyst loading (down to 0.00009 mol%: 0.9 parts-per-millions). The developed highly acidic (pKa = 4.5 in acetonitrile) imidodiphosphorimidate catalysts were employed as potent catalysts for the Mukaiyama aldol reaction of commercially available silyl ketene acetals with ketones, via Lewis acid catalysis. Previously developed chiral disulfonimides (pKa = 8.4 in acetonitrile), which proved to be efficient catalysts of the Mukaiyama aldol reaction of aldehyde failed to achieve the desired transformation.[4,5]

References

[1] H. Y. Bae, J. H. Sim, J. W. Lee, B. List, C. E. Song, Angew. Chem. Int. Ed. 2013, 52, 12143.

[2] H. Y. Bae, C. E. Song, ACS Catal. 2015, 5, 3613.

[3] H. Y. Bae, M. J. Kim, J. H. Sim, C. E. Song, Angew. Chem. Int. Ed. 2016, 55, 10825.

[4] H. Y. Bae, B. List, Chem.-Eur. J. 2018, 24, 13767.

[5] H. Y. Bae, D. Höfler, P. S. J. Kaib, P. Kasaplar, C. K. De, A. Döhring, S. Lee, K. Kaupmees, I. Leito, B. List, Nat. Chem. 2018, 10, 888. 

20181012_화학과 특별세미나_배한용박사.pdf