Shanghai Institute of Organic Sciences, Chinese Academy of Sciences achieved a new breakthrough in the migration dioxidation of endoolefins

On April 27, 2023, researcher Guosheng Liu from the Institute of Organic Chemistry, Chinese Academy of Sciences, and the team of Professor Lin Zhenyang of the Hong Kong University of Science and Technology published a research result entitled “Regio- and enantioselective remote dioxygenation of internal alkenes” in the journal Nature Chemistry. Palladium-catalyzed migration dioxidation of endoolefins was realized for the first time, and the reaction had excellent regional and stereoselectivity, among which the introduction of functional groups at the pyridine C-6 position of the pyridine-oxazolin ligand (Pyox) was the key to regulating the chemistry and regional selectivity of the reaction. This reaction exhibits excellent enantioselectivity and regional selectivity for simple endoolefins and various functional group-substituted endoolefins, providing a new method for the efficient synthesis of 1,n-diol compounds.

Postdoctoral fellow Xiaonan Li and Postdoctoral Fellow of HKUST Zhilong Yang are co-first authors of the paper, Professor Guosheng Liu and Professor Zhenyang Lin are co-corresponding authors of the paper, and Shanghai Institute of Organic Chemistry is the first unit.

Optically active 1,N-diol is an important class of organic compounds, widely found in natural products and drug fragments, and is an important synthetic. Direct enantioselective oxidation of endoolefins is the most efficient method for synthesizing such compounds, especially transition metal-catalyzed asymmetric reactions provide chemists with a powerful tool for synthesizing optical pure alcohols. However, due to steric hindrance, transition metal-catalyzed endoolefins tend to have lower reactivity, and their enantioselective functionalization is extremely challenging, not to mention asymmetric endoolefins, whose regional selectivity is more difficult to control.

The functionalization reaction of transition metal catalyzed endoolefins is generally coordinated by metal and double π bonds, activated olefins are attacked by nucleophiles, nucleophilic metallization reaction occurs, asymmetric inactive olefins due to the steric hindrance on both sides of the double bond, the electrical phase is not much difference (for example: methyl and ethyl groups in 2-pentene), its regional selectivity is difficult to control, so the formed alkyl metal intermediates are functionally grouped to obtain low-selectivity regional isomers. In these reactions, nucleophilic metallization is often irreversible, while functionalization of alkyl metal species is often the decisive step of the reaction. Current reports on regional selective functionalization of endoolefins mainly focus on endoolefins with guided functional groups or polarized olefin double bonds.

Figure 1: Intermolecular functional grouping of endoolefins.

In recent years, Liu Guosheng’s research group at the Shanghai Institute of Organic Chemistry has been working on the asymmetric bifunctional grouping of terminal olefins, and found that the introduction of a major block group in the pyridine C-6 position in the Pyox ligand can increase the electrophilicity of palladium catalysts to activate olefins. Thus, intermolecular asymmetric dioxidation and oxycarbonylation reactions based on Pd(IV)-based inactive teloene were developed (Nat. Catal. 2021, 4, 172;Angew. Chem. Int. Ed. 2021,60, 14881)。 On this basis, they explored the asymmetric transport double oxidation reaction of endoolefins, designed and synthesized a novel pyroxazolin ligand, and realized the asymmetric migration double oxidation reaction of high region selection of endoolefins for the first time. DFT calculations show that pyroxazolin ligands are very important in the reaction to reduce the oxpalladination reaction energy barrier, making it a reversible process; Through the difference of allyl carbon-hydrogen bonds on both sides of the carbon-carbon double bond, the process of first palladium-hydrogen migration anti-insertion becomes a determining step of regional selectivity. They achieved a simple asymmetric migration dioxidation reaction of inactivated endoolefins with Pd(OAc)2 as catalyst and PhI(OAc)2 as oxidant, which is also suitable for various functional group-substituted endoolefins, and reacts with high regional selectivity and enantioselectivity to obtain α-addition bicarboxylate compounds (up to regio: 50:1, 95% e.e.). In addition, the enolefins containing chiral centers can also carry out the reaction smoothly, and complex endoolefins containing drug molecules and natural product fragments are also suitable for this reaction.


Figure 2: Palladium-catalyzed asymmetric migration dioxidation of endoolefins.

Figure 3: Palladium-catalyzed substrate expansion for asymmetric migration dioxidation of endoolefins.

Therefore, this reaction provides an efficient way to convert from cheap and readily available olefins to 1,n-diol compounds. (Source: Science Network)

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