Iterative α-Glycosylation Strategy for 2-Deoxy- and 2,6-Dideoxysugars: Application to the One-Pot Synthesis of Deoxysugar-Containing Oligosaccharides

Article abstract of DOI:10.1002/ejoc.201400006

This paper describes the development of an iterative and α-selective glycosylation method for 2-deoxyglycosyl and 2,6-dideoxythioglycoside donors based on the DMF modulation concept. We used NMR spectroscopy to probe the 2-deoxyglycosyl imidinium intermediate and elucidated the conditions to decrease the formation of glycal and thus to increase the reaction yields. Further elaboration of the glycosylation method opened the gate for an iterative one-pot synthesis of 2-deoxy- and 2,6-dideoxyglycoside-containing oligosaccharides. An iterative glycosylation method is established for highly reactive 2-deoxyglycosyl donors on the basis of the DMF modulation concept. This method is effective for 2-deoxy- and 2,6-dideoxythioglycosyl donors, and it opens the gate for the one-pot synthesis of deoxysugar-containing oligosaccharides; NIS = N-iodosuccinimide. Tf = trifluoromethylsulfonyl, NAP = 2-naphthylmethyl, STol = p-tolylthio, Bz = benzoyl.

Full text of DOI:10.1002/ejoc.201400006

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400006
Iterative α-Glycosylation Strategy for 2-Deoxy- and 2,6-Dideoxysugars:
Application to the One-Pot Synthesis of Deoxysugar-Containing
Oligosaccharides
Jiun-Han Chen,[a] Jyh-Herng Ruei,[a] and Kwok-Kong Tony Mong*[a]
Keywords: Carbohydrates / Oligosaccharides / Glycosylation
This paper describes the development of an iterative and α-
selective glycosylation method for 2-deoxyglycosyl and 2,6-
dideoxythioglycoside donors based on the DMF modulation
concept. We used NMR spectroscopy to probe the 2-deoxy-
glycosyl imidinium intermediate and elucidated the condi-
tions to decrease the formation of glycal and thus to increase
the reaction yields. Further elaboration of the glycosylation
method opened the gate for an iterative one-pot synthesis
of 2-deoxy- and 2,6-dideoxyglycoside-containing oligosac-
charides.
nors.[14] It is reasoned that 2-deoxyglycosyl donors are more
reactive than their non-deoxy counterparts, as inferred from
the highest reactivity value (RRV = 1000000) of 2-deoxy-
thioglucoside relative to that of thioglucoside (RRV = 2000)
Introduction
2-Deoxyglycosides and 2-deoxysugar-containing oligo-
saccharides are common in natural glycosylated products,[1]
including landomycins,[2] olivomycins,[3] vancomycin,[4] and
anthracyclines.[5] Removal or modification of the deoxy-
sugar component of these compounds affects their bioacti-
vities. A point in case is the deconjugation of anthracyclines
and digitalis glycosides.[6] Such structure–activity relation-
ships inspire organic chemists to optimize the medicinal
properties of natural products and therapeutic agents
through modification with simple deoxyglycoside or 2-de-
oxysugar-containing oligosaccharides.[7–9]
and 2-azido-2-deoxythioglucoside (RRV
= 200, Fig-
ure 1).[15] Whether or not the DMF-modulated glycosyl-
ation is useful for 2-deoxyglycosyl donors is questionable.
Given the wide distribution of deoxysugars in natural glyc-
osylated products and their utility in lead optimizations, it
is desired to apply the DMF-modulated glycosylation to
simplify the synthesis of 2-deoxysugar-containing oligosac-
charides.
The simplest way to assemble an oligosaccharide is
through one-pot glycosylation.[10] Previous one-pot glyc-
osylation methods have been mainly developed for glycosyl
substrates that bear a hydroxy or amino function at the C2
position, although these methods are generally impractical
for 2-deoxysugars. The lack of a C2 substituent renders 2-
deoxyglycosyl donors highly susceptible to elimination, and
stereochemical control in glycosylation is difficult.[11] In the
past, only a few one-pot glycosylation methods were investi-
gated for the synthesis of 2-deoxysugar-containing oligosac-
charides.[12] In most instances, 2-deoxysugar-containing oli-
gosaccharides are often prepared through a stepwise glyc-
osylation approach, which is time consuming and inef-
ficient.[13]
Figure 1. Comparison of the relative reactivity values (RRVs) of
protected 2-deoxythioglucoside, thioglucoside, and 2-azido-2-de-
oxythioglucoside.
We recently reported on the use of formamide as a mod- Results and Discussion
ulator for glycosylation with C2-substituted glycosyl do-
In formamide-modulated glycosylation, a glycosyl donor
is activated and converted into α/β-glycosyl imidinium ad-
ducts in the presence of a formamide nucleophile. As the
β-imidinium adduct is more reactive than the α-imidinium
adduct, the former adduct would react predominately with
the acceptor to give the glycosylation product with good α
selectivity. As the key to the modulated glycosylation is the
[a] Applied Chemistry Department, National Chiao Tung
University of Taiwan,
1001, Ta Hsueh Road, Hsinchu, Taiwan, R.O.C.
E-mail: tmong@mail.nctu.edu.tw
http://www.ac.nctu.edu.tw/members/teacher.php
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400006.
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J.-H. Chen, J.-H. Ruei, K.-K. T. Mong
1
SHORT COMMUNICATION
glycosyl imidinium adduct, we elucidated the conditions for correlation between the anomer H and 13C signals (refer
the formation of the glycosyl imidinium adduct from a 2- to the NMR spectra in the Supporting Information). How-
deoxyglycosyl donor (Table 1).
ever, we were unable to detect the β-anomer of 3, which
may be attributed to its scarcity.
Based on the reaction conditions explored in the NMR
spectroscopy study, we validated the DMF-modulated glyc-
osylation with 2-deoxythioglucosyl donors 1 and 4 and 2-
deoxythiogalactosyl donors 5 and 6 (Scheme 1, Table 2).
Table 1. Result of the activation of thioglucoside 1 under different
reaction conditions.
Entry
DMF [equiv.]
T [°C]
Ratio[a] [%]
2
3
1
2
3
4
5
4.0
8.0
4.0
4.0
4.0
0
0
–10
–20
–40
100
100
100
50
n.d.
n.d.
n.d.
50
Յ5
95
[a] The 3/2 ratio was determined by comparing the integral of their
1
anomeric signals in the H NMR spectra; n.d.: not determined.
Thus, a mixture of 2-deoxythioglucoside 1 and DMF in
CDCl3 was treated with N-iodosuccinimide (NIS) and (tri-
methylsilyl)trifluoromethanesulfonate (TMSOTf).[16] The
resulting mixture was then analyzed by NMR spectroscopy.
At a reaction temperature of 0 °C, only elimination product
glucal 2 was formed, irrespective of the amount of DMF
added (4.0 or 8.0 equiv. with respect to 1; Table 1, entries 1
and 2). Upon reducing the reaction temperature to below
–10 °C, desired 2-deoxyglucosyl imidinium adduct 3 grad-
ually emerged, and the formation of glucal 2 was reduced
(Table 1, entries 3–5). Complete suppression of the forma-
Scheme 1. Validation of the DMF-modulated glycosylation method
with 2-deoxythioglycosyl donors 1, 4, 5, and 6; PG = protecting
group, Bz = benzoyl.
Under the DMF modulation conditions, the glycosyl-
tion of glucal came at –40 °C and below (Table 1, entry 5). ation of primary galactosyl acceptor 7 with 2-deoxythiogal-
The chemical identity and the α-anomeric configuration of actosyl donor 5 at –40 °C afforded disaccharide 9 in a high
imidinium adduct 3 were determined by the chemical shifts 91% yield with an excellent 25:1 α/β ratio (Table 2, entry 1).
of the anomeric proton (H-1), H-2eq, and H-2ax at δ = 6.28, Repeating the reaction with the conventional procedure de-
2.58, and 1.97 ppm, respectively (Figure 2).[14,17] Additional creased the reaction yield to 75% owing to the galactal for-
evidence was obtained from the chemical shift of the anom- mation (Table 2, entry 2). The glycosylation of 7 with 2-
eric carbon atom at δ = 107 ppm (1JC,H = 180 Hz) and the deoxythioglucosyl donor 4 in the presence of DMF
1
Figure 2. H NMR of 2-deoxyglucosyl imidinium adduct 3 at –40 °C.
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Iterative α-Glycosylation Strategy for Deoxysugars
Table 2. Validation of the DMF-modulated glycosylation method
with 2-deoxythioglycoside donors 1, 4, 5, and 6.
Encouraged by the results of the validation, we applied
the DMF modulation to the glycosylation of thioglycosyl
acceptors. The resulting glycosylation products would di-
rectly be used as glycosyl donors without modification,
which would thus pave the way for iterative α-glycosylation.
Accordingly, thioglycoside acceptors 15–19 and 2-deoxy-
thioglycoside acceptors 20–24 were prepared for glycosyl-
ation with 2-deoxythioglycosyl donors 1 and 5 (Scheme 2).
To broaden the scope of the investigation, 2,6-dideoxythiog-
lycosyl donors, that is, thioolivoside 13 and thioolioside 14,
were included. Notably, these 2,6-dideoxyglycoside motifs
occur frequently in natural products. Table 3 summarizes
the results of this glycosylation study.
In the glycosylation with 2-deoxythioglycosyl donors 1
and 5, a reaction temperature of –40 °C was applied for the
activation of the donor and the coupling with the acceptor
(conditions A, Scheme 2, a). In contrast, in the glycosyl-
ation with the 2,6-dideoxythioglycosyl donors, a lower reac-
tion temperature of –70 °C was needed to avoid the glycal
formation in the donor activation, and the temperature for
coupling of the acceptor was kept below Յ–50 °C (condi-
tions B, Scheme 2, b). For particular glycosylations, an ad-
ditional amount of DMF (4.0 or 8.0 equiv.) was added to
improve the α selectivity.
Entry
Donor,
acceptor
DMF
[equiv.]
Time
[h]
Product, yield
[%] (α/β[a]
)
1
2
3
4
5
6
7
8
9
5, 7
5, 7
4, 7
4, 7
4, 7
1, 8
1, 8
6, 8
6, 8
4
0[b]
12[c]
4
3.0
3.0
12.0
4.0
4.0
10
10
8.5
3.5
9, 91 (25:1)
9, 75 (19:1)
10, 95 (7:1)
10, 93 (4:1)
10, 80 (1:1)
11, 81 (32:1)
11, 50 (3.5:1)
12, 82 (11:1)
12, 72 (8:1)
0[b]
4
0[b]
4
0[b]
[a] The α/β ratios were determined by HPLC analysis; the HPLC
chromatograms are given in the Supporting Information. [b] A con-
ventional glycosylation procedure was applied in the absence of a
DMF modulator. [c] An additional 8.0 equiv. of DMF was added
to the mixture after the activation of the donor. Thus, the overall
amount of DMF added was 12 equiv.
(4.0 equiv.) produced desired disaccharide 10 in a high 93%
yield but with a moderate α/β ratio of 4:1 (Table 2, entry 4).
The selectivity was improved by adding an additional
amount of DMF (8.0 equiv.) after the donor activation
(Table 2, entry 3). In comparison, no selectivity was ob-
served in the absence of the DMF modulation (Table 2, en-
The glycosylation of thioglycosyl acceptors 15–22 with
try 5). Other than galactosyl acceptor 7, the DMF modula- 2-deoxythioglycosyl donors 1 and 5 went smoothly, and di-
tion procedure was effective for the glycosylation of gluc- saccharide thioglycosides 25–33 were obtained in high 70–
osyl acceptor 8 with 2-deoxythioglucosyl donor 1 and 2- 90% yield with α/β ratios spanning from 8:1 to Ͼ20:1
deoxythiogalactosyl donor 6 (Table 2, entries 6–9).
(Table 3, entries 1–9). No significant thio-transfer side reac-
Scheme 2. (a) Iterative α-glycosylation with 2-deoxythioglycosyl donors 1 and 5. (b) Iterative α-glycosylation with 2,6-dideoxythioglycosyl
donors 13 and 14. (c) Thioglycoside acceptors 15–19 and 2-deoxythioglycosyl acceptors 20–24; NAP = 2-naphthylmethyl.
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J.-H. Chen, J.-H. Ruei, K.-K. T. Mong
SHORT COMMUNICATION
Table 3. Glycosylation of thioglycosyl acceptors with 2-deoxythio-
glycosyl donors 1 and 5 and 2,6-dideoxy-thioglycosyl donors 13
and 14.
Entry
Donor,
acceptor
DMF
[equiv.]
Time
[h]
Product, yield
[%] (α/β[a]
)
1
2
3
4
5
6
7
8
1, 15[b]
1, 16[b]
1, 17[b]
1, 18[b]
1, 19[b]
1, 20[b]
5, 21[b]
5, 22[b]
5, 15[b]
13, 16[c]
13, 20[c]
14, 16[c]
14, 23[c]
14, 24[c]
12
4
4
4
12
4
7
25, 89 (8:1)
18
24
27
20
18
18
18
20
30
24
20
18
36
26, 90 (15:1[d]
27, 77 (11:1[d]
)
)
28, 73 (9:1[d]
)
29, 75 (Ͼ20:1[d]
30, 70 (8:1[d]
31, 74 (12:1[d]
)
)
)
4
)
12
12
12
12
12
8
32, 81 (Ͼ20:1[d]
9
33, 75 (11:1[d]
34, 80 (12:1[d]
)
)
10
11
12
13
14
35, 55 (α-only[e])
36, 65 (16:1[d]
37, 65 (α-only[e])
38, 81 (Ͼ20:1[d]
)
12
)
[a] The α/β ratios of 26–34, 36, and 38 were determined by HPLC
analysis (mighty gel 2.5–40 mm with hexane/CH2Cl2/EtOAc elu-
Scheme 3. Iterative one-pot α-glycosylation for the synthesis of 2-
deoxysugar-containing oligosaccharide 40.
1
tion at 0.8 mLmin–1), and the ratio of 25 was based on H NMR
spectroscopy. [b] Conditions A were used. [c] Conditions B were
used. [d] HPLC chromatograms are given in the Supporting Infor-
mation. [e] The α-anomer was isolated, and the β-anomer was not ture was brought to –70 °C; at which point disaccharide
detected.
38 was undertaken the second modulated glycosylation to
couple with thioglucosyl acceptor 16. As such, target 41
was obtained in 59% yield as a single isolable isomer.
tion occurred under the glycosylation conditions.[18] The α
selectivity was lower for primary glycosyl acceptor 15 than
for secondary acceptor 16 (Table 3, entries 1 and 2). A sim-
ilar trend was observed in glycosylations with 2-azido-2-
deoxyglycosyl donors.[14b]
The glycosylation of thioglycosyl acceptors 16, 20, 23,
and 24 with 2,6-dideoxythioglycosyl donors 13 and 14 fur-
nished expected disaccharide thioglycosides 34–38 in 55–
81% yield with high to excellent α selectivity (Table 3, en-
tries 10–14). Disaccharide 38 is commonly found in olivo-
mycins[19] and chromomycins.[20]
After examining the substrate scope of the glycosylation
method, we proceeded to the one-pot synthesis of 2-deoxy-
sugar-containing oligosaccharides. In this regard, protected
tetrasaccharide glycoside 40 and trisaccharide thioglycoside
41 were selected as our models (Schemes 3 and 4).
The synthesis of 40 required 2-deoxythioglucosyl build-
ing block 1, 2-deoxythioglucosyl building block 20, and re-
ducing end disaccharide building block 39 (Scheme 3).
Thus, 2-deoxythioglucoside 1 was coupled with 2-deoxy-
thioglucoside 20 using the DMF-modulated glycosylation
method to furnish disaccharide intermediate 30. The inter-
mediate 30 and the regenerated DMF underwent a second
modulated glycosylation to react with disaccharide 39
affording desired tetrasaccharide 40 in 45% yield.
The one-pot synthesis of trisaccharide target 41 was chal-
lenging, because both 2,6-dideoxythioglycoside building
blocks 14 and 24 invoked are prone to undergo glycal for-
mation. Our synthesis commenced with the coupling of
thioolioside acceptor 24 with thioolioside donor 14 by
Scheme 4. Iterative one-pot α-glycosylation for the synthesis of 2-
deoxysugar-containing oligosaccharide 41.
Conclusions
We developed a simple α-selective glycosylation method
for 2-deoxy- and 2,6-dideoxythioglycoside donors based on
the DMF modulation concept. Further application of this
method to oligosaccharide synthesis was demonstrated. As
a number of natural products are glycosylated with deoxy-
sugars, the DMF-modulated glycosylation method should
prove useful for their preparation.
Supporting Information (see footnote on the first page of this arti-
cle): Preparation or references for the preparation of glycosyl sub-
strates 1, 4–6, 8, 13–24, and 39; DMF-modulated glycosylation
protocols for 2-deoxythioglycosyl donors; and NMR spectroscopic
using
DMF-modulated
glycosylation
procedure B
(Scheme 2, b). The reaction produced disaccharide thio-
glycoside 38 and regenerated the DMF (Scheme 4). After
the first glycosylation was complete, the reaction tempera- data.
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Iterative α-Glycosylation Strategy for Deoxysugars
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Published Online: February 7, 2014
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