Research progress on enantiomeric divergent synthesis of Shanghai Institute of Organic Chemistry

[ Instrument R&D of Instrument Network ] The preparation of a pair of enantiomers of chiral molecules is the basic task of asymmetric synthesis, which is of great significance to medicinal chemistry and materials science. In a general asymmetric synthesis reaction, different enantiomers of the product can be obtained by changing the absolute configuration of chiral sources (such as chiral substrates, prosthetic groups, reagents, catalysts/ligands, etc.). However, some chiral source molecules in nature only exist in the form of a single enantiomer, and it is difficult to prepare target products with different absolute configurations through the asymmetric synthesis reaction controlled by such chiral source molecules.

In addition, the reaction time can also be used to control important macro variables of the asymmetric synthesis reaction output. The kinetic resolution reaction is to use the difference in reaction rate between a pair of enantiomers in the racemic substrate molecule and the chiral catalyst to achieve a single enantiomer of the target product and substrate molecule by precisely controlling the reaction time. Enrichment of the body. But in the general kinetic resolution reaction, the absolute configuration of the product molecule is still determined by the absolute configuration of the chiral catalyst. To obtain different enantiomers of product molecules, chiral catalysts with different absolute configurations still need to be used.

Recently, the team of You Shuli, a researcher at the State Key Laboratory of Metal Organic Chemistry at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, discovered a unique "enantiomeric divergent synthesis of reaction duration-dependent" when studying the asymmetric allylic dearomatization reaction catalyzed by iridium. "Phenomenon: Without changing the absolute configuration of the chiral source in the reaction system, a pair of enantiomers of the target product molecule can be obtained with high enantioselectivity only by adjusting the reaction duration.

This study found that 6-hydroxyisoquinoline 1a and racemic allyl carbonate (rac)-2a can be catalyzed by iridium complexes derived from chiral phosphoramidite ligand (S)-L1 in methanol The asymmetric allyl substitution reaction produces chiral allylamine derivative 3aa. If the reaction time is controlled to 10 hours, the (R) configuration target product can be obtained with 98% ee; if the reaction time is shortened to 6 minutes, the (S) configuration target product can be obtained with 94% ee. The real-time monitoring of the ee value of 3aa of allylamine in the reaction system clearly shows that with the extension of the reaction time, the absolute configuration of the target product is reversed, and the high enantioselectivity can be respectively selected at 6 minutes and 10 hours. The target products of (S) and (R) configurations are obtained. In other words, this kind of reaction can produce chiral allyl groups with important application value in organic synthesis by adjusting the reaction time without changing the absolute configuration of the chiral catalyst. Different enantiomers of amine molecules. Nucleophilic reagents suitable for this type of reaction include a series of 6-hydroxyisoquinoline, 8-hydroxyisoquinoline and a variety of aromatic amine derivatives.

The mechanism study shows that there are two kinetic resolution effects of chiral iridium catalyst on allyl carbonate and allylamine under the reaction conditions. In the presence of (S)-L1-derived iridium catalyst, (S) configuration allyl carbonate has higher activity and can react with 6-hydroxyisoquinoline quickly to generate (S) configuration allylamine ( The reaction rate constant is k1S) but the product is not stable under the reaction conditions. It can react with the solvent methanol under the same iridium catalyst to form the corresponding allyl methyl ether, and at the same time release 6-hydroxyisoquinoline (reaction rate constant Is k2S). The (R) configuration allyl carbonate with lower activity gradually reacts with 6-hydroxyisoquinoline and slowly accumulates the (R) configuration allylamine (the reaction rate constant is k1R). The product is very stable under reaction conditions and is not easy to undergo etherification with methanol (the reaction rate constant is k2R). When the reaction rates of the two kinetic resolution systems match each other, the enrichment of allylamine enantiomers with opposite absolute configurations can be observed at different reaction durations.

"Enantiomeric divergent synthesis dependent on reaction time" is a new reaction phenomenon in asymmetric synthesis. Its discovery and reaction mechanism research enrich the connotation of asymmetric catalytic reaction and provide a new method for the efficient preparation of different enantiomers of chiral molecules. way.

Related results were published in Nature Chemistry. The research was supported by the Ministry of Science and Technology, National Natural Science Foundation of China, Chinese Academy of Sciences, Shanghai Science and Technology Commission and Tencent Foundation.