A protecting group-free approach for synthesizingC-glycosides through glycosyl dithiocarbamates

Article abstract of DOI:10.1039/d1ob00311a

The first protection/deprotection-free process for radicalC-glycosylation has been achieved through one-step preparable glycosyl dithiocarbamates (GDTCs). The Giese-type reaction and radical allylation of unprotected GDTCs were successfully performed to obtain the corresponding α-C-glycosides stereoselectively under mild reaction conditions.

Full text of DOI:10.1039/d1ob00311a

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A protecting group–free approach for synthesizing
C-glycosides through glycosyl dithiocarbamates†
Cite this: Org. Biomol. Chem., 2021,
19, 3134
Gefei Li, Masato Noguchi, Genki Arisaka, Yuuki Tanaka and Shin-ichiro Shoda
*
Received 19th February 2021,
Accepted 17th March 2021
DOI: 10.1039/d1ob00311a
rsc.li/obc
The first protection/deprotection-free process for radical
On the other hand, radical approaches are considered
C-glycosylation has been achieved through one-step preparable promising for the protection-free synthesis of C-glycosides,
glycosyl dithiocarbamates (GDTCs). The Giese-type reaction and because radical reactions can generally be performed in the
radical allylation of unprotected GDTCs were successfully per- presence of hydroxy groups. Despite enormous investigations
formed to obtain the corresponding α-C-glycosides stereoselec- on C-glycosylation through radical species,8 so far there have
tively under mild reaction conditions.
been no reports on C-glycosylation without protection. One of
the most decisive reasons is the fact that a simple method for
the preparation of unprotected glycosyl radical precursors has
not been established.
Shortening of a synthetic pathway is of critical importance in
organic synthesis.1 In particular, the development of a simple
and economical route that does not involve protection and de-
protection of the hydroxy groups has become one of the most
challenging topics in glyco-process chemistry.2
C-Glycosides, sugars whose exocyclic oxygen is replaced by
carbon, are essentially stable to the action of both acids and
bases and resist enzymatic hydrolysis.3 These sugar mimetics
show potent antiviral and anti-tumour activities, and have
attracted growing attention in pharmaceutical and biological
research.4 C-Linked α-galactosylceramides possess higher anti-
cancer activities than the corresponding O-galactosides due to
their increased bioavailabilities.5 C-Alkyl glycosides have been
of interest as novel biosurfactants that can be derived from
renewable feedstock.6
In the previous work, we reported a direct method for the
preparation of glycosyl dithiocarbamates (GDTCs) from free
sugars without using protecting groups, based on the concept
of “direct anomeric activation” using 2-chloro-1,3-dimethyl-
imidazolinium chloride (DMC).9 These results prompted us to
design a new C-glycosylating route that necessitates no protec-
tion/deprotection steps. Here we propose a novel protection-
free protocol for the construction of C-glycosidic bonds based
on the addition reaction of glycosyl radicals generated from
unprotected GDTCs (Fig. 1, upper). To the best of our knowl-
edge, this is the first protection-free synthesis of C-glycosides
through glycosyl radical species.10
We first screened H-sources to optimise the yield of
C-glycosylation by using methyl acrylate (MA) as the glycosyl
acceptor (Table 1). The reaction of β-D-glucopyranosyl di-
There have been so many reports on C-glycoside synthesis7
by anionic approaches,7e–h cationic approaches7i–m and tran-
sition metal-mediated approaches,7n–p using various kinds of
glycosyl donors such as glycosyl halides, 1,2-anhydro sugars
and glycals. The C–C bond forming reactions based on these
approaches must be carried out under strictly anhydrous con-
ditions and require protection of the hydroxy groups, which
has become a significant synthetic barrier for organic chemists
(Fig. 1, lower).
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku
University, 6-6-07, Aoba, Aoba-ku, Sendai, 980-8579 Japan.
E-mail: shinichiro.shoda.a6@tohoku.ac.jp
†Electronic supplementary information (ESI) available: General information,
experimental data, characterization details, NMR spectra and ESI-MS data of pro-
ducts. See DOI: 10.1039/d1ob00311a
Fig. 1 The newly proposed manufacturing process of C-glycosides
through glycosyl dithiocarbamates (GDTCs) (upper). Conventional
approach for the synthesis of C-glycosides (lower).
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Table 1 Comparative results of radical C-glycosylation under different
conditionsa
Table 2 Protecting group–free synthesis of C-glycosides using glyco-
syl dithiocarbamatesa
Entry Product
1
Solvent
Time (h) Yield/%b (α/β)
Yield of
C-glycoside
2 (%) (α/β)
MA
(equiv.)
H-Source
(equiv.)
Time
(h)
Yield of
3 (%)
2-Propanol
5
3
2
70 (α only)
40 (α only)
65 (α only)
Entry
1
5
5
5
5
None
8
—
—
29
28
65
2
1,4-Dioxane
DMF
2
Bu3SnH (2)
Bu3SnH (2)
H3PO2 (5)
Et3N (5.5)
H3PO2 (2)
Et3N (2.5)
H3PO2 (5)
Et3N (5.5)
1.5
1.5
3
70 (α only)
72 (α only)
35 (α only)
3b
4
3c
5
6
5
8
3
25 (α only)
36 (α only)
40
61
20
4
2-Propanol
2
68 (α only)
a All the reactions were carried out in 2-propanol under argon. The
yield (equiv.) and α/β ratio were determined by NMR analysis. b H2O
(50 μL) was added to the reaction mixture.
5
6
2-Propanol
Ethanol
2
4
72 (60/40)
75 (α only)
methyldithiocarbamate 1 with an excess amount of MA in the
presence of 2,2′-azobisisobutyronitrile (AIBN) did not take
place (entry 1). When the reaction was carried out in the pres-
ence of tributyltin hydride (Bu3SnH) as a H-source under the
standard Giese conditions, the addition product of glucopyra-
nosyl propanoate 2 was obtained in 70% yield along with the
formation of 1,5-anhydro-D-glucitol 3 (29%) (entry 2). The reac-
tion also took place smoothly in an aqueous 2-propanol solu-
tion (entry 3).
The use of a greener H-source, phosphinic acid–triethyl-
amine (H3PO2–Et3N) system,11 led to the formation of pro-
panoate 2 in a lower yield, affording glucitol 3 as the main
product (entry 4). In order to avoid the formation of glucitol 3,
we performed the reaction with a decreased equivalent of
H3PO2 (entry 5) and an increased amount of MA (entry 6).
However, the yields of propanoate 2 remained quite low, indi-
cating that hydrogen abstraction by the glycosyl radical predo-
minates under the AIBN–H3PO2–Et3N conditions.
7d
DMF
48
63 (α only)
a Experimental data: see the ESI.† b Determined by NMR analysis.
c Compound 6 was isolated after acetylation. d 10.0 equiv. of MA was
employed.
enables an interaction with the non-bonding electron pair on
the ring oxygen.8b In the case of using xylose-type GDTC as the
glycosyl donor, an anomeric mixture of MA-C-Xyl 8 (α/β = 60/
40) was obtained in 72% yield (entry 5). Matsuda et al.
reported that a radical addition could occur via a transition
1
state having a C4-like conformation, leading to the formation
of a β-type C-glycoside.12 The formation of the β-anomer in
C-xylosylation may be attributed to the conformational change
of the xylopyranose ring which lacks the hydroxymethyl moiety
at the C-5 position.
Upon expanding this methodology to disaccharides, MA-C-
α-melibioside 9 and MA-C-α-chitobioside 10 were successfully
prepared (entries 6 and 7) starting from the corresponding
GDTCs. Since the use of 2.0 equivalents of Bu3SnH resulted in
incomplete conversion of chitobiosyl DTC, we had to carry out
the reaction for a longer time (48 h) using a large excess of
Bu3SnH (6.0 equiv.) and MA (10.0 equiv.).
Next, we focused our attention on the synthesis of allyl
C-glycosides which are important precursors for complex
C-glycosides13 (Table 3). When β-D-glucopyranosyl dimethyl-
dithiocarbamate 1 was treated with allyltributyltin (3.0 equiv.)
in the presence of AIBN (0.5 equiv.) in 2-propanol at 75 °C, a
mixture of allyl C-glucoside 11 and 1,5-anhydro-D-glucitol 3
was obtained (11/3 = 7/8) (entry 1). We hypothesized that the
formation of glucitol 3 was caused by hydrogen atom abstrac-
tion from 2-propanol,14 and we performed the reaction with
other solvents such as ethanol, acetonitrile and 1,4-dioxane.
With the optimised reaction conditions in hand, we contin-
ued our investigation by applying this radical addition reaction
to various alkenes using the AIBN–Bu3SnH system (Table 2).
The glucosyl radical derived from dithiocarbamate 1 was
smoothly added to acrylonitrile (AN), affording AN-C-α-Glc 4 in
70% yield (entry 1). The reaction with styrene (St) gave the
corresponding α-C-glucoside 5 in a moderate yield (entry 2).
When a hydrophilic alkene, acrylamide (AA), was used as a gly-
cosyl acceptor in DMF, the corresponding AA-C-α-Glc 6 was
produced in a stereo-selective manner (entry 3).
We further investigated C-glycosylation by using various
GDTCs as glycosyl donors. The reaction of the mannose-type
GDTC with MA occurred smoothly under Giese conditions,
giving rise to the corresponding MA-C-α-Man 7 (entry 4). The
observed high α-selectivity in C-glucosylation and
C-mannosylation can be explained by the fact that the anome-
ric radical preferentially adopts the axial orientation which
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Table 3 Radical reaction of allyltributyltin with glucosyl dithiocarbamate derivatives
Substrate
(concentration)
Allyltributyltin
equiv.a
C-Glycosideb
yield (%) (α/β)
Byproductb
yield (%)
Entry
1
AIBN equiv.
0.5
Solvent
Time (h)
21
1 (0.05 M)
1 (0.05 M)
1 (0.05 M)
1 (0.05 M)
1 (0.05 M)
1 (0.05 M)
12 (0.05 M)
12 (0.25 M)
16 (0.1 M)
3.0
5.0
5.0
5.0
10.0
15.0
5.0
5.0
8.0
2-Propanol
11
3
40
3
50
3
40
3
43
3
35
35 (α only)
11
50 (α only)
11
50 (α only)
11
57 (α only)
11
65 (α only)
11
60 (α only)
13
15 (6/1)
13
60 (4/1)
17
2
3
4
5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
0.5
0.3
0.5
Ethanol
4
Acetonitrile
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
6
4
2
1.5
4
3
40
14
15
14
10
18
15
15
70
15
20
19
20
Toluene
24
24
Toluene
55 (α only)
a The equivalents of allyltributyltin and AIBN were relative to the substrate. b The yield and α/β ratio were determined by 1H NMR analysis
Among these solvents, 1,4-dioxane gave the best result with
Table 4 Protection-free synthesis of allyl C-glycosides through glyco-
syl dithiocarbamatesa
regard to the yield of C-glucoside 11 (entry 4). We also found
that the yield was affected by the amount of allyltributyltin,
taking the maximum value around 10 equivalents (entries 5
and 6).
In an effort to emphasize the superiority of the present pro-
tection-free C-glycosylation over the conventional method of
using protecting groups, two kinds of GDTC derivatives (12
and 16), the hydroxy groups of which are protected with acetyl
groups and benzyl groups, respectively, were subjected to the
radical conditions. In the case of using acetate 12, although
the formation of the 1,5-anhydro product was obviously sup-
pressed, the desired acetylated allyl C-glycoside 13 was
obtained in only 15% yield (entry 7). The low yield of
C-glycoside 13 was mainly due to the formation of 2-allyl-2-
deoxy derivative 15,15,16 as the result of a 1,2-migration of the
acetoxy group.17 At a higher concentration of acetate 12, the
intermolecular addition of the glycosyl radical species to
allyltributyltin predominated over the 1,2-migration, affording
a mixture with a higher proportion of acetylated C-glucoside
13 (entry 8). The α/β ratio of the resulting acetate 13 was 4:1.
On the other hand, the benzylated substrate 16 stereoselec-
tively yielded the α-product 17 in a moderate yield along with
the 1,5-anhydro derivative 18 and 3,4,6-tri-O-benzyl-glucal 19
Time
(h)
Yieldb
(%)
Entry Product
1
Solvent
3
3
3
1,4-Dioxane
67
65
70
2
3
1,4-Dioxane
Ethanol
4
9
Ethanol/DMF
(1/1)
63
a Experimental data: see the ESI.† b Determined by NMR analysis.
as elimination by-products.18 These results clearly indicated anosyl DTC and mannopyranosyl DTC with allyltributyltin
that the present protection-free processes have several decisive gave the corresponding allyl α-C-glycosides (20 and 21) in
advantages over the methods of using protected glycosyl 67% and 65%, respectively (entries 1 and 2). The challen-
radical precursors.
ging disaccharides, melibiosyl DTC and chitobiosyl DTC,
The protection-free anomeric C-allylation was then were treated under the same radical allylation conditions,
applied to other sugars (Table 4). The reaction of galactopyr- affording allyl C-α-melibioside 22 and allyl C-α-chitobioside
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In conclusion,
a
convenient protecting group–free
C-glycosylating process has been developed through unpro-
tected glycosyl dithiocarbamates (GDTCs). This protocol pro-
vides us with α-C-glycosides under mild conditions without
the tedious processes of protection and deprotection of the
hydroxy groups. The vital point of this methodology is that the
DMC-mediated one-step preparation of unprotected GDTCs
occupies the key position in the whole synthetic process,
which allowed the application of the first protection-free
addition reaction of unprotected glycosyl radicals to various
alkenes. More importantly, the present process is effective for
the C-glycosylation of oligosaccharides, which will be of con-
siderable value in the design of glycomaterials. Further appli-
cations to glycopolymer synthesis and the elucidation of a
detailed reaction mechanism are now in progress.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
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