CHEMICAL SCIENCE

Bifunctional catalyst for cross-assembly confinement by non-covalent action


Professor Yingyang Yang’s team from Hong Kong Chinese University and Professor Huang Guowei of King Abdullah University of Science and Technology in Saudi Arabia published a new study titled “Cross-assembly confined bifunctional catalysis via non-covalent interactions for asymmetric halogenation” in the journal Chem.

The research group used non-covalent interaction to assemble bifunctional catalysts with the formation of achiral Lewis bases and chiral phosphoric acid. By changing the achiral Lewis base catalyst, the catalyst pocket can be finely tuned, avoiding the lengthy synthesis step of traditional chiral bifunctional catalysts, thereby improving the efficiency of asymmetric reaction optimization. This strategy was used to achieve highly enantioselective half-frequency narol reshoot and intramolecular etherization initiated by brominium ions.

The corresponding authors of the paper are Zheng Tianyu, Huang Guowei, Yang Yingyang; The first authors are Zheng Tianyu and Chen Rui.

Chiral bifunctional catalysts can provide a confined environment to achieve highly enantioselective reactions. However, lengthy synthesis steps are often required to introduce different substituents to modulate the confined microenvironment, which reduces the efficiency of the optimized reaction. Chiral phosphoric acid is the most versatile bifunctional catalyst for asymmetric reactions, and many highly enantioselective reactions can be achieved by modifying substituents of chiral phosphoric acid. However, synthesizing different chiral phosphoric acids often requires the early introduction of different substituents, which means that a large number of parallel synthesis is required, reducing efficiency.

Yingyang Yang’s research team has been working on asymmetric halogenation reactions (Nature Catalysis 2020, 3, 993-1001; Chem 2020, 6, 919-932; J. Am. Chem. Soc. 2021, 143, 12745-12754;J. Am. Chem. Soc. 2014, 136, 5627-5630;J. Am. Chem. Soc. 2013, 135, 1232-1235;J. Am. Chem. Soc. 2011, 133, 9164-9167;J. Am. Chem. Soc. 2010, 132, 15474-15476)。 Asymmetric halogenated reactions usually require chiral bifunctional catalysts, such as chiral phosphoric acid. However, modifying chiral phosphoric acid catalysts usually requires a lot of time and is inefficient, and sometimes even requires special large-site halide blocking reagents to achieve highly enantioselective halogenation reactions. Through recent studies of non-covalent effects in catalytic reactions (ACS Catal. 2019, 9, 8083-8092;ACS Catal. 2021, 11, 3498-3506;), the team envisages that chiral bifunctional catalysts can be constructed by non-covalent interaction to assemble chiral phosphoric acid and non-chiral Lewis base catalysts to improve the optimal efficiency of asymmetric halogenated reactions (Figure 1).

Figure 1: Non-covalently assembled chiral bifunctional catalyst for asymmetric halogenated reactions.

In order to verify this hypothesis, the half-frequency acol rebeat triggered by the bromide ion was selected as the template reaction, and Yang Yingyang’s group and Huang Guowei’s group cooperated to verify cyclopropylthione as a non-covalent donor through density functional theory calculations and two-dimensional nuclear magnetic experiments, and when mixed with N-bromosuccinimide (NBS) and chiral phosphoric acid, a C1-symmetrical chiral complex can be formed by the action of nonclassical hydrogen bonding, and the active site of this catalysis is more limited than that of chiral phosphoric acid alone (Figure 2).

Figure 2: Catalytic mode assembled by non-covalent action.

By changing different achiral Lewis base catalysts, cyclopropylselenone is utilizedA4andCPA-1, a 97% e.e. rearrangement product can be obtained2a。 By changing the achiral Lewis base and using aminopyridine to adjust the size of the catalytic pocket, the system can also be applied to asymmetric brominated intramolecular etherification reactions. Bromofuran4aIt has a diastereoselectivity of 97.5:2.5 and is proposed as an intermediate assembled by non-classical hydrogen bonds by density functional theory calculationsSB2is thermodynamically sound (Figure 3).

Figure 3: Optimization of reaction by altering an achiric Lewis base catalyst.

The developed asymmetric brominated intramolecular etherification reaction can be applied to the total synthesis of natural products and the synthesis of pharmaceutical intermediates (Figure 4).

Figure 4: Synthesis of natural products and pharmaceutical intermediates.

In this study, different asymmetric halogenation reactions were realized by mainly screening the asymmetric Lewis base catalyst by assembling chiral phosphoric acid and achiral Lewis base to form a new bifunctional catalytic system by using non-covalent action. This study provides a new idea for the design of chiral bifunctional catalysts. (Source: Science Network)

Related paper information:https://doi.org/10.1016/j.chempr.2023.01.016



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