Journal of the American Chemical Society
Communication
general, controllable, and selective catalytic strategy for C-2
functionalization of carbohydrates using readily available 1-
halosugars.16
The mechanistic hypothesis of the proposed transformation
is outlined in Figure 2. We envisioned that photoexcited
24 W blue light-emitting diodes (LED) in the presence of
Pd(PPh3)4 (5.00 mol %), N,N-diisopropylethylamine (DIPEA,
2.00 equiv) in isopropyl acetate (i-PrOAc, 0.05 M) at room
temperature for 20 h, we observed a 94% yield of α-only
product 2a with >20:1 C-2 selectivity (Table S1, entry 1). The
Pd(PPh3)4 catalyst was shown to be critical for the desired
reactivity because replacing it with PPh3 or Pd(PPh3)Cl2, led
to no reaction or a significantly lower yield and selectivity
(entries 2 and 3). We recognized that the relative rates of the
intramolecular 1,2-SCS and the intermolecular hydrogen atom
transfer must be controlled to achieve high levels of
regioselectivity. It was envisioned that the unique inner-sphere
coordination interaction between the Pd catalyst and alkyl
radical could stabilize and modulate the reactivity of radical
intermediates, thus minimizing the premature C-1 reduc-
tion.1e,20 Indeed, the use of other common Ru-, Ir-, and
organic-based photoredox catalysts, where inner-sphere coor-
dination is not feasible, proved to be ineffective and afforded
the product with low yields and selectivity (entries 4−6).
Reactions in acetonitrile were sluggish and were accompanied
by the erosion of the regioselectivity (entry 7). Control
experiments showed that DIPEA, an oxygen-free environment,
and light were all essential for the desired reactivity (entries 8−
10).
With the optimized conditions in hand, we next examined
the scope of the reaction. In general, a wide range of α-
bromosugars afforded the desired 2-deoxy sugars in up to 95%
yield with >20:1 regioselectivity (Table 1A).21 α-Glucosyl
bromides with different ester protecting groups such as acetyl,
benzoyl, or pivaloyl worked well (2a−2c). Other α-
bromosugars, including those derived from acetylated L-fucose,
D-xylose, and D-galactose, were also viable substrates (2d−
2f).22 Substrates with benzyl-, methyl-, and the acid-sensitive
tert-butyldimethylsilyl-protected C-6 hydroxyl groups were
well tolerated, affording the desired products 2g−2i in 72−
91% yields with >20:1 C-2 selectivity. A free C-6 hydroxyl
group, which is useful for further functionalization and often
serves as a glycosyl acceptor, reacted smoothly and gave
product 2j in 72% yield. A fused ring structure also proved to
be compatible with the reaction conditions (2k). The structure
of the migratory ester group has little effect on the reaction
efficiency because C-2 esters substituted with alkyl, aryl, or
heteroaryl groups underwent excited-state Pd-catalyzed 1,2-
SCS smoothly, forming the corresponding products 2l−2q in
74−90% yields. A melibiose derivative gave the desired 2-
deoxy-disaccharide 2r in 89% yield. Notably, the reaction
affords the α-2-deoxyglycosides exclusively, and the corre-
sponding β-isomers were not observed.
The synthetic utility of this process is further highlighted by
its amenability to (i) a late-stage modification of functionally
dense natural product- and drug-conjugated sugar derivatives
and (ii) the synthesis of deuterated 2-deoxy sugars (Table 1).
For example, α-Bromoglucose derivatives of oleanolic acid,
Indomethacin, Probenecid, Bezafibrate, Febuxostat, Zaltopro-
fen, Ibuprofen, and Adapalene reacted and afforded the desired
products 2s−2z in good yields and excellent levels of
regioselectivity, demonstrating that the method can be used
in the preparation of pharmaceutically relevant compounds.
Furthermore, deuterium-labeled sugars are versatile probes for
the study of biological processes such as metabolic and
biosynthetic pathways,23 and useful chiral building blocks for
the synthesis of chiral deuterated precursors of bioactive
molecules.24 Using d8-THF as the solvent and Cs2CO3 as the
Figure 2. Proposed catalytic cycle for the excited-state Pd-catalyzed
C-2 functionalization of carbohydrates.
palladium catalyst [Pd(0)]* undergoes radical oxidative
addition with 1-halo sugar 1, generating the hybrid 1-
glycosyl-Pd-X complexes IIa and IIb.2b,3 The glycosyl radical
IIa favors the B2,5 boat conformation (IIIa) because of the
hyperconjugation between the singly occupied molecular
orbital (SOMO) and σ*C−O orbital of the C-2−OAc
group.17 Such an interaction is more pronounced in glycosyl
radicals because the lone pair electron of the endocyclic-O (ηO,
anomeric interaction) raises the SOMO energy level. Such an
extended anomeric interaction weakens the C-2−OAc bond
and promotes the 1,2-SCS through a concerted [2,3]-acyloxy
rearrangement with a cyclic five-membered ring transition state
IIIb,11b,17a forming the deoxypyranosan-2-yl radical IVa that
18
4
prefers the C1 chair conformation. Although the anomeric
radical is more stable than the secondary alkyl radical, the
molecular stability gained from the formation of an anomeric
C−O bond in IVa drives the desired 1,2-SCS.19 Under visible-
light irradiation, the intermediate IVa is in equilibrium with
alkyl-Pd(II)X complex IVb, which allows access to both open-
and closed-shell reactivities. We anticipate that these hybrid Pd
species can engage in a wide range of cross-coupling reactions
through processes such as (i) transmetalation followed by
reductive elimination or (ii) radical coupling or atom/group
transfer followed by reduction of Pd(I)X to furnish the desired
C-2 functionalized carbohydrate 2 and regenerate Pd(0)
catalyst, completing the catalytic cycle.
With this hypothesis in mind, we started our investigations
using readily available α-glucosyl bromide (1a) as a model
substrate. Initial experiments showed that upon exposing 1a to
1729
J. Am. Chem. Soc. 2021, 143, 1728−1734