Super acid mimicase catalyzed to achieve asymmetric and efficient identification of methyl and ethyl groups

On May 4, 2022, Nature Online published the research results of professor Benjamin List team of the Max Planck Coal Research Institute in Germany and the team of Professor Cheng Guijuan of the University of Chinese of Hong Kong( Shenzhen) entitled “Organocatalytic stereoselective cyanosilylation of small ketones”.

By designing and using an organic superacid IDPi catalyst with an enzyme-like cavity structure, the research group successfully achieved asymmetric silicon cyanidation reaction of 2-butanone, with an enantiomer excess of up to 96%. Theoretical calculations reveal the reaction mechanism and chiral recognition mechanism. The corresponding authors of the paper are Professor Benjamin List and Professor Cheng Guijuan; the first author is Dr. Zhou Hui.

According to the “lock-key” catalytic model, enzyme catalysis can achieve chemical conversion efficiently and three-dimensionally, so it has the irreplaceable and unique advantages of other catalysts. Due to the similar electrical and spatial hindrances of the two substituents, dialkylone is difficult to identify by chiral catalysts, so its precise asymmetric induction reaction has been difficult to solve. Among them, the asymmetric reaction in which 2-butanone is involved is often distinguished by the fact that the methyl and ethyl groups are too similar, and often only the enzyme catalyst has the ability to distinguish them. Inspired by the asymmetric hydrogenation of 2-butanone catalyzed by the imitation enzyme of the metal iridium complex of academician Zhou Qilin (Nat. Catal. 2020, 3, 621), Recently, the research group of Professor Benjamin List of the Max Planck Coal Research Institute in Germany designed and used an organic superacid IDPi catalyst with a mimicase cavernous cavity structure, and successfully achieved asymmetric silicon cyanidation reaction of 2-butanone, with enantiomer excesses as high as 96%.

Figure 1: Study background and reaction design (Image: Nature)

In the past hundred years, asymmetric silicon cyanidation reactions have been widely studied and have become relatively mature. However, due to the similarity of methyl and ethyl groups in 2-butanone, it is difficult to study asymmetric reactions. In the few successful examples available, functionally modified enzymatic catalysts can give up to 87% enantiomer excess values, while both metal catalysts and organic small molecule catalysts thiourea give only 11% enantiomer excesses. Under the guidance of the idea of silicon positive ion asymmetry counter-anion-guided catalysis, the List research group successfully solved this problem by using the developed iminobiphosphinoimide (IDPi), which achieved unprecedented fine identification of the enantiosity through the chiral microenvironment of the confined space of its binding site (Figure 1).

Figure 2: Substrate expansion and product application (partial) (Image source: Nature)

In the specific reaction study process, both fatty ketones and aromatic ketones can give the target product with good enantioselectivity and efficiency, and the corresponding products have been shown to have high application potential in drug synthesis and pesticide research (Figure 2). In terms of mechanism studies, NMR studies captured the formation of enol silicone ethers in the initial stages of the reaction, and confirmed the guess that enol silicon ethers were used as reaction intermediates through control experiments.

Professor Cheng Guijuan’s research group of Chinese University of Hong Kong, Shenzhen proposed a new mechanism of isomurocyanic acid as an active reaction intermediate through density functional theory calculation. Calculations found that the catalyst IDPi reacted with TMSCN to form an active catalyst for silylation and released isocyanic acid. It is worth mentioning that the generation of isothydrocyanic acid is easier than hydrocyanic acid, and its reactivity is higher, and isothydrocyanic acid is dynamically balanced with hydrocyanic acid under the action of the catalyst. The silicon-based catalyst activates the raw ketones to form an oxygen-carbon-induced ion-pair intermediate, which is attacked by isothydrocyanic acid, generates the target product, silylated cyanol, and regenerates the catalyst. In addition, calculations show that the enol silicone intermediate is a kinetic product that can be converted to a thermodynamically more stable cyanosilatation product (Figure 3a). Detailed control experiments and NMR studies also provide a factual basis for the elaboration of the mechanism. Structural analysis showed that IDPi formed a compact structure with an embedding rate of up to 73.4%, and its central skeleton and substituents formed a narrow, asymmetrical reaction pocket, distinguishing the transition structure that generated two enantiomer products (Figure 3b). Calculations show that the substituent of the catalyst can regulate the shape, size, embedding volume and steric hindrance distribution of the catalyst reaction pockets, thereby forming different chiral pockets to specifically identify different types of substrates such as fatty ketones and aromatic ketones.

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Figure 3: Theoretical computing research (Image source: Nature)

(Source: Science Network)

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