Cross-coupling to form unprotected carboaryl compounds

Recently, Niu Dawen’s research group of Sichuan University has developed a nickel-catalyzed cross-coupling method to generate carbaryl glycosides by using stable and readily available allyl glycosyl sulfone and aryl halide. On January 17, 2023, Beijing time, the research results were published in the journal Nature Synthesis under the title “Direct synthesis of unprotected aryl C-glycosides by photoredox Ni-catalysed cross-coupling”.

Glycosides refer to carbohydrate compounds formed by linking the upper groups of sugar to different atoms, such as oxyglycosides, nitrogenosides and carbosides. For carbosides, although their content in nature is less, the carbon-carbon bonds of the carboside terminal groups have stronger resistance to enzymatic hydrolysis and chemical hydrolysis, which makes the carbosides have good enzyme stability and druggability. Among them, carboaryl glycosides are an important class of carboside compounds, and their structure is that glycoheterococcus is directly connected to aromatic carbon atoms. These compounds exhibit a wide range of biological functions, including anticancer, antiviral, and antidiabetic activity, and are therefore widely used in pharmaceutical science and biological research (Figure 1). For example, the most commonly prescribed antidiabetic drugs for type II diabetes are carboarylins. Therefore, the efficient synthesis of carbarylside methods is of great value.

Figure 1: Representative carboarynosides.

However, glycosyl units contain a large number of free hydroxyl groups and stereocentric centers (including stereocenters of glycosidic bonds), making the preparation of carboaryl glycosides a challenge. The existing methods for preparing carboarynoside compounds have two major types of defects, one is that it requires upper protection and deprotection of hydroxyl groups, and requires multi-step reactions to obtain products; Second, the stereocentric center of the glycosidic bond cannot be efficiently controlled, and the mixed configuration is obtained instead of a single configuration.

Figure 2: Design of the reaction of cross-coupling of allyl sulfone donor and aryl halide to prepare carbaryl glycosides.

Niu Dawen’s research group of Sichuan University has long been engaged in research in the field of glycochemistry ( Recently, the research group developed a nickel-catalyzed cross-coupling method to generate carbaryl glycosides from stable and readily available allyl glycosyl sulfone and aryl halide. Among them, allyl glycosyl sulfone is a glycosyl donor developed by this group and has been used to synthesize oxyglycosides and sulfur glycosides (JACS, 2021, 11919; Nature Chemistry, 2022, 686)。 In this work, the research group proposed to use the combination of sodium p-tolyl sulfinate and allyl glycosyl sulfone as the equivalent of glycan anions, and couple with aryl halides under nickel-catalyzed conditions to generate carbaryl glycosides (Figure 2). This reaction has the following advantages: first, due to the good stability of allyl glycosyl sulfone and good functional group compatibility of sugar radicals, no protective radicals are required on the glycan donor; Second, the reaction is carried out in a highly stereoselective manner, which can generate 1,2-trans carbaryl glycosides; Third, for sugar units with different stereoscopic and electronic characteristics, high reaction yield and high stereoselectivity are achieved. These advantages enable rapid and modular synthesis of carboarynosides.

To demonstrate the synthetic application potential of this method, the researchers used the method to synthesize ASGPR inhibitors and some drug derivatives. In addition, this method was successfully applied to four glittoids (Figure 3). The researchers used flow chemistry to synthesize dapagliflozin on a scale larger than grams, demonstrating the potential for large-scale production.

Figure 3: Application of carbarylside synthesis method.

Finally, using DFT theoretical calculations, the researchers have an in-depth understanding of the reaction mechanism and explain the reasons for the high stereoselectivity of the reaction. The researchers found that unprotected glycan units can further reduce activation energy and improve reaction efficiency due to their smaller structural size compared to protected glycation units. (Source: Science Network)

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