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. 2017, 56, 10915-10919), Wu (Angew. Chem. Int. Ed. 2018, 57, 17220-17224) and Our group (Angew. Chem. Int. Ed. 2017, 56, 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. 2017, 56, 15416-15420), the hydrocarboxylation of enamides/imines to generate α-amino acids (Angew. Chem. Int. Ed. 2018, 57, 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.