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.
After 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.