Phosphonocarboxylation of Various Alkenes via Photoredox Catalysis

Phosphonyl and carboxyl groups are valuable functional groups, however, their simultaneous incorporation via catalytic difunctionalization of alkenes has not been realized yet. Here we report the phosphonocarboxylation of alkenes with CO2 via visible-light photoredox catalysis.

Aug 23, 2019
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With the increasing natural resources and environmental crisis, it is highly desirable to develop green and sustainable synthetic methods. Carbon dioxide (CO2) has been regarded as a ubiquitous, green and recyclable one carbon (C1) feedstock in organic synthesis. Although the thermodynamic stability and kinetic inertness of CO2 introduces daunting challenges, a wide range of transformation using this gaseous reagent has been developed to fix CO2 with organic compounds. Notably, catalytic carboxylation of unsaturated compounds with CO2, leading to synthetically and biologically important carboxylic acids, has attracted much attention of chemists.

Photocatalysis has emerged as a powerful tool in organic synthesis, chemists have been mimicking nature's ability for long time to harness light in organic transformations and transform CO2 to generate value-added products. Besides, difunctionalization of alkenes are a powerful strategy in organic synthesis for generation of highly functionalized skeletons. However, the visible-light-mediated difunctionalization of alkenes with CO2 is still scarce and yet underdeveloped with limited examples reported by Martin (Angew. Chem. Int. Ed. 201756, 10915-10919), Wu (Angew. Chem. Int. Ed. 201857, 17220-17224) and Our group (Angew. Chem. Int. Ed. 201756, 15416-15420), independently. Moreover, photocatalytic difunctionalization of the electron-rich alkenes, such as enamine and enol derivatives, which could deliver more intriguing molecules, with CO2 has not been reported yet.

Phosphorus-containing carboxylic acids are highly valuable compounds and widely exist in natural products, materials and pharmaceuticals. However, synthetic methods for such important compounds are extremely limited to de novo synthesis. We surmised that the simultaneous incorporation of both phosphonyl and carboxyl groups via selective difunctionalization of enamides and other alkenes would serve as an ideal route to deliver important β-phosphono carboxylic acids, including β-phosphono α-amino acids.

The research group led by Prof. Da-Gang Yu at Sichuan University has devoted massive efforts to the area of visible-light-driven carbon dioxide utilization. For example, we developed the visible-light-driven difluoroalkylation and alkylation of allylamines to synthesize oxazolinones (Org. Lett., 2017, 20, 190-193; Org. Lett., 2018, 20, 3049-3052), the thiocarboxylation of olefins with unique regioselectivity (Angew. Chem. Int. Ed. 201756, 15416-15420), the hydrocarboxylation of enamides/imines to generate α-amino acids (Angew. Chem. Int. Ed. 201857, 13897-15901), and carboxylation of C-N bonds in the tetraalkyl ammonium salts with CO2 (J. Am. Chem. Soc., 2018, 140, 17338-17342). In our recent paper published in Nature Communications, we described our latest progresses on this topic. For the first time, the simultaneous incorporation of phosphonyl and carboxyl into organic molecules via photocatalytic difunctionalization of alkenes with CO2 has been realized, delivering a diverse array of β-phosphono carboxylic acids, including structurally complex unnatural α-amino acids. The desired reaction takes place in a rather precise manner, overriding several potential side pathways, showing exceedingly high chemo- and regio-selectivities as well as wide substrate scope. Moreover, this strategy also represents a rare example of redox-neutral difunctionalization of alkenes with H-P(O) compounds. 

Taken together, our study published in Nature Communications would provide an efficient method for accessing important and potentially bioactive β-phosphono carboxylic acids, including β-phosphono α-amino acids. We are currently working on seeking potential applications of these new molecules and their derivatives in drug design and discovery. Hopefully, the structurally novel and diverse molecules could truly contribute to the fighting with neurodegenerative diseases.

Da-Gang Yu

Professor, Sichuan University

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