Professor Ken Houk’s group collaboration featured in Science

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The Houk group with Bin Tan’s group at the Southern University of Science and Technology (SUSTech) discover first asymmetric four-component Ugi Reaction.

The team reports a major breakthrough in the field of asymmetric catalysis in their paper “Asymmetric phosphoric acid-catalyzed four-component Ugi reaction” published in the September 14, 2018 issue of the journal Science

The Ugi four-component reaction was discovered by Estonian-born German chemist Ivar Ugi in 1959. It is one of the most prominent multi-component reactions (MCRs) in organic chemistry. It transforms a mixture of 4 different molecules, an isocyanide, an aldehyde (or ketone), an amine, and a carboxylic acid into a complicated peptide-like structure in one pot, with water as the only by-product. 


Figure 1. Chiral phosphoric acid (CPA)-catalyzed asymmetric four-component Ugi reaction, and a DFT-computed transition structure that controls the absolute stereochemistry. Credit: Science.

The Ugi reaction is widely used in the synthesis of heterocycles, frequent components of drugs and natural. It is well-suited for building large molecular libraries in drug discovery. The only deficiency of the Ugi reaction and related MCRs is that the absolute stereochemistry – which of the mirror image products is formed – could not be controlled. Until now! The Tan discovery shows how to control the stereochemistry and Houk’s calculations show why this works. 

Yu%2CPeiyuanAfter years of tedious work, the Tan group at SUSTech found that chiral phosphoric acids (CPAs) derived from SPINOL can catalyze the Ugi four-component reaction with high enantioselectivity (up to 99% ee). Computational modeling by UCLA alum Dr. Peiyuan Yu (Ph.D. ’17, Houk group) (pictured right) showed how the multi-step reaction occurs, and why only one mirror image of the product is formed. The complex of the CPA and the carboxylic acid plays a profound role in the reaction processes, and the Yu-Houk quantum mechanical simulation of the reaction pathway showed exactly how this works. 

The authors foresee multiple uses of this asymmetric four-component Ugi protocol for the synthesis of chiral peptides, natural products, and drug candidates.

To learn more about the Houk group’s research, visit the group’s website.