Organic Letters
Letter
Recently, nitrogen-centered radicals (NCRs) have aroused
growing concern in synthetic chemistry because NCRs could
be used as key intermediates for effective construction of C−N
bonds.22 On the basis of the considerable synthetic potential of
glycals for preparation of 2-amino-2-deoxyglycosides, we
proposed that it would be an ideal strategy if the N−F
reagents were converted to nitrogen-centered radicals23 and
added to glycal at the C2 position, followed by glycosylation
with acceptors at the C1 position. Herein, we reported the
nitrogen-centered radical cascade regioselective amination of
glycal and anomeric specific glycosylation (Scheme 1c).24
As shown in Scheme 2, we hypothesized that nitrogen-
centered benzenesulfonimide radical A, generated from NFSI
Table 1. Optimization of the Amidoglycosylation
Condition
a
b
entry
NFSI (equiv)
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.2
1.2
1.2
DCE
DCE
DCM
THF
MeNO2
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
rt
50
50
50
50
50
50
50
50
50
50
22
38
<5
<5
16
<5
56
67
75
62
72
Scheme 2. Proposed TEMPO-Catalyzed Radical Cascade
Amidoglycosylation of Glycal
c
10
11
d
a
Reactions were performed with 1 (0.25 mmol), 2 (0.3 mmol),
TEMPO (0.05 mmol), and NFSI in solvent (1.0 mL) for 3 h under an
b
argon atmosphere. Isolated yields were determined by silica gel
c
column chromatography. The reaction was conducted with TEMPO
d
(0.025 mmol). The reaction was conducted with TEMPO (0.075
mmol).
highest yield (entries 10 and 11). To demonstrate the
practicability of this method, the reaction was conducted on
a 2 g scale and a 64% yield was achieved.
by reduction with TEMPO, might regioselectively electrophili-
cally add the alkenyl of glycal to give radical D. Radical D
would then be oxidized by TEMPO+ B to afford oxocarbenium
E and recycle the catalyst TEMPO.25 We considered that the
steric hindrance of benzenesulfonimide and/or the neighbor-
ing effects of the sulfonyl group would direct the glycosylation
in a 1,2-trans manner to furnish anomerically specific product
F.
With the optimized reaction conditions established, various
glycal donors were examined to explore the scope of the NCR-
mediated amidoglycosylation (Scheme 3). In addition to the
benzyl ether, the methyl ether, benzylidene, diisopropylidene,
allyl ether, and silyl ether were also suitable protecting groups
and the corresponding disaccharides 4−8, respectively, were
afforded in good yields as well as excellent selectivities (β:α >
20:1 or β only). When the D-galactals masked by benzyl ether
or methyl ether, the substrates were also well tolerated and
afforded products in moderate to good yields (9 and 10). The
acyl groups, such as benzoyl and pivalic groups, were also
evaluated by installation at the C6 position of D-galactals, and
the corresponding products 11 and 12 were harvested in good
yields and selectivities. We found when the glycal was fully
protected with acetyl groups, although excellent anomeric
selectivities remained, an only 37% yield of product 13 was
isolated. The low yield was due to the lower HOMO energies
of the double bond.27 TheL-rhamnals were also subjected for
the amidoglycosylation. The related disaccharides 14 and 15
were also harvested in good yields. These results demonstrated
that the nitrogen-centered radical was a practical protocol for
the preparation of β-selective 2-amino-2-deoxyglycosides using
glycals as glycosylation donors.
The scope of acceptors for amidoglycosylation was also
evaluated (Scheme 4). Different monosaccharide acceptors
with primary alcohols were subjected for radical glycosylation.
Products 16−21 were obtained in good yields and excellent
anomeric selectivities. Different types of protective groups like
benzyl, diisopropylidene, benzoyl, pivaloyl, and allyl are
applicable to showcase the generality of this amidoglycosyla-
tion. The acceptors with secondary alcohols were then
conducted for the glycosylation, but we found that the yields
were obviously decreased (30% for 22 and 42% for 23). We
Our initial investigation of the amidoglycosylation involving
NCR was conducted between tri-O-benzyl-D-glucal 1 and
diisopropylidene-D-galactose 2. After treatment with NFSI and
a catalytic amount of TEMPO in DCE at room temperature,
glycosylation product 3 was obtained in 22% yield (Table 1,
entry 1). NMR analysis showed that acceptor 2 was β-
selectively coupled with glucal 1 as we proposed. We noticed
that glycal 1 was not completely consumed. To accelerate the
reaction and increase the yield, the reaction temperature was
increased to 50 °C. The glycosylation was slightly improved
with a 38% yield (entry 2). Screening the solvents, such as
DCM, THF, MeNO2, and toluene (entries 3−6, respectively),
identified MeCN as the optimal solvent with 56% yield (entry
7). Meanwhile, a byproduct was also isolated from the reaction
mixture as a result of Ferrier rearrangement (see the
mechanism of Ferrier rearrangement,26 C3 elimination resulted
from HF formation in the reaction. However, attempts to
neutralize the HF with a base (NaHCO3, Na2CO3, Na3PO4,
etc.) did not significantly suppress the Ferrier rearrangement.
Instead, we found that decreasing the amount of NFSI
considerably decreased the amount of the Ferrier rearrange-
ment byproduct and glycosylation product 2 was afforded in a
75% yield (Table 1, entries 8 and 9). The amount of catalyst
TEMPO was also evaluated, and 0.2 equiv of TEMPO gave the
1223
Org. Lett. 2021, 23, 1222−1227
Shang, Wenbin
