The same group reported a direct synthesis of unprotected aryl C-glycosides by photoredox/nickel-catalyzed cross-coupling of bench-stable allyl glycosyl sulfones with aryl halides (Scheme 9).[20] The developed protocol features a wide scope of aryl halides and allyl glycosyl sulfones, delivering desired products in moderate-to-good yields with high 1,2-trans selectivities. A great functional group tolerance was observed in aryl halide coupling partners, though a limitation of scope was observed in the reaction of aryl iodides bearing a bulky, ortho -isopropyl group. Notably, protic hydrogen atoms, such as those in free hydroxyls (75p ) and secondary amides. (75m ), and potentially chelating alkyl sulfide groups (75n ) were compatible with the reaction. Moreover, various heterocycles were accommodated. It was found that electron-rich aryl iodides gave slightly higher yields than electron-deficient ones. Aryl chlorides (75o ) survived in the reaction, though aryl bromides and iodides are reactive in the developed method. Diverse glycosyl donors were examined in the reaction. Remarkably, the selectivity profiles of the developed method appeared quite insensitive to the identity of glycosyl donors and the 1,2-trans aryl C-glycosides were generated preferentially or exclusively in all examined examples. For example, C-pentopyranosides, such as xylopyranoside (75af ), lyxoside (75ah ), and arabinoside (75ak ), were obtained in good yields and with moderate-to-excellent diastereoselectivity. Aryl C-furanosides were also conveniently prepared with acceptable selectivity by the method. Additionally, the method was successfully applied to the synthesis of complex drug-sugar conjugates (75an, 75ao ) and glycopeptide (75ap ), affording desired products in good yields and with excellent 1,2-trans selectivity. Finally, the synthetic applicability of the developed protocol was further highlighted by the rapid synthesis of enzyme inhibitors (Scheme 10-B, 75aq ) and active pharmaceutical ingredients of commercial drugs (Scheme 10-B, 75ar–75au ). Of note, Niu’s approach worked well in the synthesis of dapagliflozin under continuous flow conditions, allowing over 1 gram of dapagliflozin (75as ) preparation in their reaction setup.
Preliminary mechanistic investigations suggest the following: 1) the glycosyl radical is generated during the reaction; 2) the formation of glycosyl radicals is triggered by the initial generation of a tolyl sulfonyl radical, which subsequently adds to the terminal alkene group of allyl glycosyl sulfones; 3) the aryl-Ni(II) complex is likely generated during the process.
Scheme 10 Plausible mechanism and synthetic application of Niu’s method