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