In 2022, the Li group presented a chemoselective and diastereoselective
method that enables the synthesis of aryl C-nucleotides by
nickel-catalyzed cross-coupling of furanosyl acetates with aryl iodides
(Scheme 19). [28] The method enabled
chemoselective coupling of multihalogenated aryl iodide with furanosyl
acetate (139a ), presumably owing to the higher oxidative
addition rate of low-valent nickel to aryl iodide than other aryl
halides in the examined solvent. The authors found that electron-rich
(139b ), electron-neutral (139c ), and electron-poor
aryl iodides (139d ) all coupled with equal levels of
efficiency. Moreover, medicinally relevant heterocycles were also
effective coupling partners in the reaction, affording the corresponding
products in synthetically useful yields (139e–139g ).
Limitations in scope were observed in reactions using
para-dimethylaminophenyl iodide and aryl iodides bearing ketone
moieties. Notably, exclusive 1,2-trans selectivity was observed when
D-ribofuranosides were used as coupling partners, which could be
attributed to the steric hindrance at the α-face of D-ribofuranose
produced by substituents in C2 and C3. Moreover, other glycosyl
acetates, such as mannofuranosyl acetate and three pyranosyl acetates,
were also examined and furnished the desired aryl C-glycosides in
moderate yields and with good 1,2-trans selectivities
(139h–139j ), with one exception that benzyl-protected
D-glucosyl acetate affords product with modest β-selectivity
(139k ). To showcase the synthetic utility of this strategy, a
series of late-stage functionalizations with the resulting aryl bromide
was successfully realized (139la–139le , Scheme 19-A, bottom).
Furthermore, a concise synthetic route of the IMPDH (inosine
5‘-monophosphate dehydrogenase) inhibitor was developed using the
developed method. Remarkably, the reaction was successfully incorporated
in the synthesis of BRDP-Hep (142 , Scheme 19-B), designed
analogs of ADP-Hep (ADP-β-D-manno-heptose). BRDP-Hep showed better
effects than the naturally occurring ADP-Hep on both the activation of
NF-κB signaling and the phosphorylation induction of TIFA
(TRAF-interacting protein with the forkhead-associated domain).
Scheme 19 Aryl C-nucleoside analog synthesis enabled by
nickel-catalyzed cross-coupling of furanosyl acetates with aryl iodides