Efficient Synthesis of α-Glycosyl Chlorides Using 2-Chloro-1,3-dimethylimidazolinium Chloride: A Convenient Protocol for Quick One-Pot Glycosylation

Article abstract of DOI:10.1002/ejoc.201800360

A mild and convenient method for the synthesis of α-glycosyl chlorides in high 80–96 % yields within 15–30 min using 2-chloro-1,3-dimethylimidazolinium chloride (DMC) is disclosed. The method has a wide substrate scope and is compatible with labile OH protecting groups, including benzyl, acetyl, benzoyl, isopropylidene, benzylidene, TBDMS (tert-butyldimethylsilyl), and TBDPS (tert-butyldiphenylsilyl) groups. The excellent α selectivity obtained in this reaction is attributed to in-situ isomerization of β-glycosyl chlorides to the more stable α-glycosyl chlorides, as demonstrated by ¹H NMR spectroscopic studies. Disarmed sugars with OBz or OAc groups at C-2 were chlorinated at a faster rate but ismomerized (β→α) at a slower rate than armed sugars with an OBn group at C-2. More importantly, the method enables highly desirable one-pot glycosylation reactions to take place, thus allowing efficient syntheses of disaccharides and simple O-glycosylated sugars in high overall yields without the need for separation or purification of the α-glycosyl chloride donors. This method will be especially useful for direct glycosylation reactions using glycosyl chloride donors that are unstable upon separation and purification.

Full text of DOI:10.1002/ejoc.201800360

A Journal of
Accepted Article
Title: Efficient synthesis of ꢀ-glycosyl chlorides using 2-chloro-1,3-
dimethylimidazolinium chloride: A convenient protocol for quick
one-pot glycosylation
Authors: Madhu Tatina, Duc Thinh Khong, and Zaher M. A. Judeh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800360
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800360
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10.1002/ejoc.201800360
European Journal of Organic Chemistry
FULL PAPER
Efficient synthesis of -glycosyl chlorides using 2-chloro-1,3-
dimethylimidazolinium chloride: A convenient protocol for quick
one-pot glycosylation
Madhu Babu Tatina,[a] Duc Thinh Khong,[a] Zaher M. A. Judeh*[a]
chlorinating reagent should have wide substrate scope,
show tolerance to labile sugar protecting groups,
demonstrate convenience to avoid strict chlorination
conditions, reduce reaction times and allow for easy
separation of the products.
Abstract: A mild and convenient method for the synthesis of -
glycosyl chlorides in high 80-96% yields within 15-30 min using
2-chloro-1,3-dimethylimidazolinium chloride (DMC) is disclosed.
The method has a wide substrate scope and is compatible with
labile hydroxyl protecting groups including benzyl, acetyl,
benzoyl, isopropylidene, benzylidene, TBDMS and TBDPS silyl
ether. The excellent  selectivity obtained in this reaction is
attributed to in-situ isomerization of -glycosyl chlorides to the
more stable -glycosyl chlorides as proven 1H NMR studies.
Disarmed sugars with OBz or OAc at C2 were chlorinated at a
Over the past years, we have been interested in developing
simple approaches for the synthesis of phenylethanoid
glycosides.9 Our strategy required us to in-situ generate
glycosyl donors to undergo one-pot glycosylation without
donors separation or switching of reaction solvents to avoid
multistep reactions and tedious purifications. This became
faster rate but ismomerized (
) at a slower rate in
even more imperative since some
-glycosyl chlorides
comparison to armed sugars with OBz at C2. More important,
the method enables the highly desired one-pot glycosylation
thus allowing for the efficient syntheses of disaccharides and
simple O-glycosylated sugars in high overall yields without the
need for separation or purification of the -glycosyl chloride
donors. This method will be especially useful for the direct
glycosylation using glycosyl chloride donors that are unstable
upon separation and purification.
decompose during purification using silica gel column
chromatography or during storage.4,7 For this purpose, we
re-investigated the synthesis of
-glycosyl chlorides
anticipating developing a simple synthetic approach that
tolerates typical sugar protecting groups and at the same
time enables direct one-pot glycosylation. One-pot
glycosylation10 represents a quick and simple process for
obtaining oligosaccharides and is therefore highly desirable.
It reduces the number of synthetic steps, avoids tedious
purification and solves potential degradation problems of
some glycosyl chloride donors. For example, Mong and co-
Introduction
Glycosyl halides (chlorides, bromides, iodides and
fluorides) are important donors used for the synthesis of O-,
C- and N-glycosides.1 Excellent progress has been made in
workers developed
glycosylation protocol that required separation of the
glycosyl chlorides and solvent switch before the
a two-step, one-pot chlorination-
a
synthesizing
-glycosyl chlorides using several methods
glycosylation reaction.4 Nishida and co-workers reported
successful one-pot bromination-glycosylation between the
in-situ generated glycosyl bromides and various acceptors.
However, the reaction required the use of 3 mol equiv. of
both the acceptor as well as the catalyst with respect to the
glycosyl bromide donors and also needed long times of 22-
96 h for completion.11
including metal halides (SnCl4 and TiCl4),2 PPh3/CCl4,3
DMF/trichlorotriazine,4 oxalyl chloride,5 triphosgene,6
PPh3/hexachloroacetone7 and others.8 Ideally, the
[a]
School of Chemical and Biomedical Engineering,
Nanyang Technological University,
62 Nanyang Drive, N1.2–B1-14,
Singapore 637459
Herein, we wish to report a simple method for the synthesis
Tel.: +65-6790-6738;
Fax: +65-6794-7553;
of a wide range of
-glycosyl chlorides using commercially
E-mail: zaher@ntu.edu.sg
available chlorinating
agent 2-chloro-1,3-
dimethylimidazolinium chloride (DMC) and demonstrate the
practicality of this method in direct one-pot glycosylation of
selected sugars.
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.201800360
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Results and Discussion
Table 1. Optimization of chlorination of per-O-benzylated glucose
DMC is a versatile dehydrating reagent used in several
organic transformations including esterification, amination,
oxidation, reduction and conversion of alcohols to
chlorides.12 In carbohydrate chemistry, and specifically
concerning the anomeric center, DMC was used for several
selective transformations such as acetylation,13 azidation,14
synthesis of triazoles and oxazoline,15 synthesis of 1,6-
anhydro sugars16 and thio glycosylation.17 To examine the
a]
1a using DMC to synthesize

-glycosyl chloride 2a [
.
OBn
OBn
O
Cl
O
OH
N
DMC, base
solvent, rt
Cl
Cl
BnO
OBn
N
BnO
OBn
OBn
OBn
DMC
2a
1a
Yield [%]
(only )[b]
N.R.
Entry
Solvent
Base
Time
usefulness of DMC in the preparation of
chlorides from sugars, we initially screened the chlorination
of 2,3,4,6-tetra-O-benzyl -glucopyranose 1a as a model
-glycosyl
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
CH3CN
THF
s-Collidine
Et3N
24 h
15 min
30 min
24 h
89
70
D
DBU
substrate using s-collidine as a base in dichloromethane
(DCM) (Table 1, entry 1). These reaction conditions were
intentionally chosen to ensure compatibility with the
planned one-pot glycosylation conditions to avoid
Pyridine
NaH
40
N.R.
24 h
Et3N
24 h
65
N.R.
Et3N
24 h
isolation/purification of the
switching and interference of the by-products. However,
under these conditions, the desired -glycosyl chloride 2a
-glycosyl chlorides, solvent
N.R.
DMF
Et3N
24 h
[a] DMC (0.1 mmol) was added to a solution of tetra-O-benzylated glucose 1a
(0.1 mmol) and base (0.1 mmol) in 1.5 ml of the solvent. [b] Isolated yields
after column chromatography purification. [c] N.R. = no reaction.

was not detected even after 24 h (Table 1, entry 1). We
then screened several bases including Et3N, DBU, pyridine
and NaH (Table 1, entry 2-5). Et3N gave the highest yield of
To examine the scope of this chlorination reaction, we prepared
various substrates including tetra-O-benzylated 1b, tetra-O-
acetylated 1c-1f, partially silylated 2,4-O-TBDPS (t-butyl
diphenylsilyl ether) 1g, 2,4-O-acetylated-3-O-TBDMS (t-butyl
dimethylsilyl ether) 1h, 4,6-O-benzylidene-2,3-di-O-benzylated
1i, diisopropylidene 1j and tetra-O-benzoylated 1k sugars
(Table 2). In all the cases, the chlorination reactions of 1a-j
proceeded successfully to give high 80-96% yield of glycosyl
chlorides 2a-k within 15-30 min at room temperature without
special precautions (Table 2). In the case of tetra-O-benzylated
glucose 1a and tetra-O-benzylated mannose 1b (armed sugars),
the glycosyl chlorides 2a and 2b were obtained in ca 90% yield
in just 15 min with complete  selectivity (Table 2, entries 1-2).
Tetra-O-acylated glucose, mannose, galactose and rhamnose
1c-1f (disarmed sugars) took double the reaction time (30 min)
to give the corresponding glycosyl chlorides 2c-2f in slightly
lower 82-85% yields and with complete  selectivity with the
exception of 1e which gave 2e in  ratio of 3:1 (Table 2, entry
3-6).18a We noted that reaction of 1c-1f with DMC was very quick
as indicated by TLC (within 5 minutes) but longer reaction times
of 30 minutes were employed to convert the -anomers to their
corresponding -anomers (see discussion under mechanism
later). Effectively, the reaction can be stopped at 5 minutes to
89% of
-glycosyl chloride 2a in just 15 min while DBU
gave 2a in lower 70% yield after 30 min (Table 1, entries 2
and 3, respectively). However, the chlorination using
pyridine was sluggish (40% yield after 24 h) and NaH failed
to give any product possibly due to its insolubility in DCM
(Table 1, entries 4 and 5, respectively). Attempts to further
increase the yield of 2a by replacing DCM with CH3CN,
THF or DMF were not fruitful since either lower yields or no
products were obtained (Table 1, entries 6-8). The reason
why no products were obtained with THF and DMF is not
known. In fact, 1H NMR spectra of the crude reaction
mixture did not show any change in all the substrates used
in the reaction. In all the cases, glycosyl chloride 2a was
obtained exclusively with
 selectivity. With the optimized
reaction conditions in our hands (Table 1, entry 2), we
proceeded to examine the scope and limitation of this
reaction. It is important to note that these conditions are
classic for glycosylation reactions.
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10.1002/ejoc.201800360
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Entry
1
Glycosyl
substrate 1[a]
Glycosyl
chloride
Time
(min)
Yield [%]
obtain the -glycosyl chlorides. Chlorination of sugars containing
acid-labile protecting groups such as TBDPS 1g, TBDMS 1h
and cyclic acetals 1i and 1j also proceeded smoothly to give the
corresponding glycosyl chlorides 2g-j, respectively, in good to
excellent yields (Table 2, entries 7-10). In the case of the
partially silylated 2,4-di-O-TBDPS rhamnose 1g, we obtained
excellent 88% yield of 2g with exclusive  selectivity (Table 2,
entry 7). Rhamnose sugar with TBDMS and Ac moieties reacted
smothly under to yield the correspong glycosyl chloride 2h
(Table 2, entry 8). -Glycosyl chloride 2g was unstable during
column chromatography purification using silica gel and quickly
hydrolysed to give back the starting material 1g whereas
compound 2h exhibits good stability during purification. On the
other hand, 4,6-O-benzylidene-2,3-di-O-benzylated glucose 1i
gave the glycosyl chloride 2h in 80% yield within 20 min with
selectivity ratio of 3:1 (Table 2, entry 9). The exact reason for
the formation of the -isomer is not very clear and may be due to
the disarming nature of benzylidenes moiety.18b Diisopropylidene
mannofuranose 1j gave 95% yield of -glycosyl chloride 2j with
[b]
2
(

)
15
15
30
89
(
(
only)
2
3
90
only)
85
(only)
4
5
30
30
85
( only)
82 (3:1)
complete
 selectivity within 30 min (Table 2, entry 9).
Interestingly, tetra-O-benzoylated glucose 1k gave 96% of
glycosyl chloride 2k with : ratio of 1:10. From TLC, we noted
that formation of the glycosyl chloride was very quick (5-10 min)
but the reaction was continued for 30 minutes to attempt to
convert -glycosyl chloride 2k to its -anomer. This did not
happen to a great extent as in the cases of 2c-2f because OBz
is less electron withdrawing group than OAc. Longer reaction
times and purification over silica gel increased the ratio of -
glycosyl chlorides on the account of their -anomers. The :
selectivity ratios will be reasoned during our discussion on the
mechanism of the DMC-mediated chlorination below.
6
7
30
20
85
( only)
88c
O
Cl
OR
( only)
RO
OH
2g
8
30
20
30
80
( only)
O
Cl
OBn
9
80
O
H
Ph
(3:1)
O
OBn
2i
10
95
( only)
Table 2. Scope of the DMC-mediated chlorination of glycosyl substrates
1 to give glycosyl chlorides 2.[a]
11
30
96
(1:10)
O
OH
O
Cl
DMC, Et3N
DCM, rt
RO
RO
[a] DMC (0.1 mmol) was added to a solution of glycosyl substrate 1 (0.1 mmol)
and Et3N (0.1 mmol) in 1.5 ml of the DCM. [b] Isolated yields after column
chromatography purification. [c] Estimated using 1H NMR spectrum of the
crude product.
1
2
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To gain an understanding of the mechanism of the DMC-
mediated chlorination, we used 1H NMR to monitor the progress
of chlorination of tetra-O-benzylated glucose 1a (having no
neighbouring group participation (NGP)) and tetra-O-acetylated
glucose 1c (showing NGP) as model substrates (Table 3,
Figure. 1). When DMC was mixed with a solution of 1a and Et3N
show similar mechanism to the -I anomer with no NGP and
give -glycosyl chlorides through intermediates -VI and -VII.
This is because attack from the position is blocked due to
steric effects.
Table 3. 1H NMR study of the formation of - and -glycosyl chlorides.[a]
1
in CDCl3 and the H NMR spectrum quickly measured (Ca after
5 min), two new sets of signals in ca 1.1:1 ratio corresponding to
-glycosyl chloride 2a (= 6.01, d, J = 7.8 Hz, H-1) and -
glycosyl chloride 2a (= 5.13, d, J = 3.6 Hz, H-1) were identified
at 59% overall conversion (Figure. 1, Table 3, entry 1. Scheme
1).18a When the spectrum of the same sample was measured
after 30 min and then 45 min, the : selectivity ratios were
found to be 1:0.2 and 1:0.08, respectively, at ~95% conversion.
Entry
Reactant
Product

Conv.
~ 5 min

Conv.
30 min

Conv.
45 min
OBn
1
2
(1.1:1)
~ 59%
 (1:0.08
~ 95%
O
OH
~ 95%
BnO
OBn
OBn
1a
1
However, when we repeated the same H NMR study with 1c,
(1:10.4)
~ 96%

~ 96%
(1:7
~ 96%
the ratio of -glycosyl chloride to -glycosyl chlorides after 5 min
was found to be 1:10.4 after ~96% conversion while the ratio
after 30 min and then 45 min was 1:8.4 and 1:7, respectively
(Table 3, entry 2). Even after 15 h, the ratio was found to be
1:4.4 (Scheme 1). However, as indicated in Table 2, entry 3,
when 2c was isolated after 30 min, it was found to be pure -
glycosyl chloride with no sign of its -anomer indicating quicker
isomerization on silica gel during purification. Based on these
[a] Measured using 1H NMR after reaction for a specific time.
observations and the literature reports,14-17
a
plausible
mechanism for DMC chlorination is shown in scheme 1 for
substrates without (e.g. 1a) and with (e.g. 1c) NGP. Abstraction
of the OH protons of the substrates using Et3N is followed by
nucleophilic attack on the chloro imine carbon of DMC (Scheme
1). In the case where there is no NGP (R’= CH2, Bn, TBDPS),
intermediate -II which is formed from -I anomer undergoes
SN2 attack by Cl- to form the -glycosyl chlorides. Similarly, the
-I anomer should give the -glycosyl chlorides through SN2
attack on intermediate -II (Scheme 1). Based on the anomeric
effect concept, -glycosyl chlorides are more stable than -
glycosyl chlorides.19 Therefore, the initially formed -glycosyl
chlorides will isomerize through SN2 attack by Cl- (possibly from
Et3N.HCl) to -glycosyl chlorides.11,20 The presence of Et3N.HCl
was confirmed from the 1H NMR studies since the signal at
11.26 ppm corresponded to the proton of Et3N.HCl. Where
there is NGP (R’ = Ac or Bz) at C2, intramolecular attack of the
carbonyl group of intermediate -III, which is obtained from -I
anomer, gives -IV which upon SN2 attack by Cl- gives the -
glycosyl chlorides that isomerize to the more stable -glycosyl
chlorides (Scheme 1). The -I anomer with NGP is predicted to
Figure 1. Progress of chlorination of tetra-O-benzyl--D-glucopyranosyl
hemiacetal 1a at different time interval using 1H NMR.
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10.1002/ejoc.201800360
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Without NGP:
10 as acceptors gave disaccharides 6-7 and simple O-
OR
OR
OR
Cl
N
N
glycosylated product 8 in 60-72% overall yield with 
N
O
O
O
RO
RO
RO
RO
RO
RO
O
+
O
N
selectivity as shown in Scheme 2. The glycosylation products
seem to favours selectivity as judged from their  ratios.21
We noted that one-pot reaction between 1c and 10 did not
proceed probably due to the disarming effect of the OAc
moieties. However, when AgOTf was replaced by Ag2O, the
orthoester 11 was obtained in % yield.
OR'
OR'
OR'

-I
Cl
Cl
Cl


-glycosyl chloride
-II
Cl
SN
2
inversion
OR
OR
OR
Cl
O
O
O
N
RO
RO
RO
RO
RO
RO
+
Cl
Cl
N
OR'
OR'
OR'

-glycosyl chloride
OH
O
Cl

-I
 II
-
N
N
Cl
R' = Bn, -CH2, TBDPS
With NGP:
General reaction:
OR
OR
OR
N
N
OR
OR
O
O
i. DMC (1 eq), Et3N
(2 eq), DCM, rt, 15 min
O
Cl
RO
RO
RO
RO
O

RO
RO
-I
+ DMC
Cl
O
OH
OR
O
OR1
OR
O
O
O
O
Cl
O
ii. R1OH (0.8 eq),
AgOTf (1.5 - 2 eq),
- 60 oC, 20-60 min
O
R'


-IV
-III
R'
RO
RO
R'

-glycosyl chloride
OR
OR
R'= Me, Ph
SN2
5 8
-
inversion
Donors:
O
OR
O
OR
O
OR
SN2
OBn
BnO
OBn
inversion
O
O
O
O
O
O
RO
RO
RO
RO
RO
RO

-I
+ DMC
Cl
Cl
N
O
O
OH
BnO
BnO
BnO
BnO
O
O
O
OH
Cl
OH
O
O
BnO
1a
O
R'
 VII
-
R'
 VI
R'
-glycosyl chloride
N
1b


-glycosyl chloride
-
Cl
1i
R'= Me, Ph
Acceptors: R1
OH
O
Scheme 1. Plausible mechanism for DMC-mediated chlorination for the
BnO
BnO
HOBn
formation of - and -glycosyl chlorides.
BnO
OMe
10
9
 
:
Products: (Yield,
ratio)
BnO
OBn
This isomerization process and conversion of -glycosyl
chlorides to -glycosyl chlorides are clearly supported by our 1H
NMR studies (Figure 1, Scheme 1). As mentioned before, the
: ratio and the rate of isomerization depended on the reaction
time and purification process. As time progress, -glycosyl
chlorides are converted to their -anomers during the reaction
and this process seems to be faster during purification over
silica gel column. It is also obvious that the rate of isomerization
is substrate dependant as demonstrated by1H NMR studies and
when comparing the : selectivity ratios in Table 1).
OBn
O
O
BnO
BnO
BnO
BnO
O
O
BnO
BnO
BnO
O
O
BnO
BnO
BnO
BnO
OMe
O
O
OMe
6
5, 62 %,
, 64 %,
=3:2

O

=1:5
O
OAc
OBn
O
O
AcO
O
BnO
O
BnO
BnO
AcO
O
OBn
O
BnO
O
OBn
BnO
Ph
OMe
7

8, 76 %

O
, 75 %
, 60 %
=1:10
=3:4
11
Scheme 2. Direct one-pot chlorination-glycosylation reaction.
We attempted a simple one-pot glycosylation protocol by in-situ
generating the glycosyl chloride donors according to the
optimum conditions in Table 2, cooling the reaction mixture to -
60 C followed by addition of sugar acceptors and AgOTf
(Scheme 2). Consequently, one-pot glycosylation between
glycosyl chloride 2a (generated in-situ from tetra-O-benzylated
glucose 1a) and -1-methoxy-2,3,4-O-tribenzyl glucose acceptor
9 gave disaccharide 5 in 62% yield in α:β ratio of 1:5 within 1 h
(Scheme 2). Similarly, one-pot glycosylation between per-O-
benzylated glucose 1a, per-O-benzylated mannose 1b and
diisopropylidene mannofuranose 1i as glycosyl chloride donors
with -1-methoxy-2,3,4-O-tribenzyl glucose 9 and benzyl alcohol
Conclusions
We have developed a simple and highly efficient method for the
synthesis of -glycosyl chlorides in very high 80-96% yields and
short 15-30 min reaction times using commercially available
DMC. Under the reaction conditions employed, -glycosyl
chlorides isomerized to the more stable -glycosyl chlorides as
proven by the 1H NMR studies. Disarmed sugars were
chlorinated at a faster rate but isomerized at a slower rate in
comparison to armed sugars. The method conveniently enabled
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10.1002/ejoc.201800360
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efficient one-pot glycosylation to give the products in high overall
yields within 1 h. Attempts at one-pot N- and S-glycosylation
using this protocol are under examination in our laboratory.
column chromatography hexane:ethyl acetate gradient gave the
pure glycosylated product 5-8.
1.3 One-pot glycosylation using disarmed sugar 1c: DMC
(0.2 mmol, 34 mg) was added to a stirred solution of 1c (0.2
mmol, 70 mg) and triethylamine (0.4 mmol, 56 µl) in
dichloromethane (3 mL) at room temperature and the mixture
stirred for 15-30 min (TLC). After complete consumption of
the 1c, benzyl alcohol (0.8 eq. 0.16 mmol, 17 µl) and silver oxide
(1 eq., 0.2 mmol, 47 mg) were added and the reaction mixture
was stirred for another 8h at 40 oC. The reaction mixture was
then diluted with DCM (15 mL) and filtered through a small pad
of celite. The filtrates were then concentrated to give the crude
product which upon purification using column chromatography
4:1 hexane:ethyl acetate gave the orthoester 11 as syrup (66 mg.
75% Yield).
Experimental Section
1. General experimental methods
Chemical reagents were purchased from Sigma-Aldrich or Alfa
Aesar and used as received without further purification. 1H NMR
spectra were recorded at 300 MHz on a Bruker Avance DPX
300. Unless stated otherwise, data refer to solutions in CDCl3
with TMS as an internal reference. 13C NMR spectra were
recorded at 75.47 MHz on a Bruker Avance DPX 300. IR spectra
were recorded using Bruker MPA FT-NIR. HRMS were recorded
using a Qstar XL MS/MS system. Analytical TLC was performed
using Merck 60 F254 precoated silica gel plates (0.2 mm
thickness) and visualized using UV radiation (254 nm) or stained
ceric ammonium nitrate in 30% H2SO4 solution. Flash
chromatography was performed using Merck silica gel 60 (60-
120 mesh).
1.4 NMR studies
In a NMR tube, sugar 1c or 1i (0.1 mmol) was dissolved in
CDCl3 (540 µl) and Et3N (16 µl, 0.1 mmol) was added. The
solution was shaken by inverting the NMR tube several times
and then the 1H NMR spectrum was recorded. DMC (17 mg, 0.1
mmol) was then added to the reaction mixture, the tube shaken
by inverting it several times and both the 1H and 13C NMR
spectra were recorded (ca 5 min). The spectra were recorded
few times after a specific time (See Table 3). The :ratios were
calculated from the integral values of the anomeric protons (H1)
1.1 General procedure for chlorination using DMC: DMC (1
eq.) was added to a stirred solution of sugars (1a-k, 0.5 mmol)
and triethylamine (1 eq.) in DCM (3 mL) in glass vials at room
temperature and the mixture was stirred for 15-30 min (TLC).
After complete consumption of the sugar, the reaction mixture
was diluted with DCM (10 mL) and washed with water (3 X 15
mL). The organic layer was dried over MgSO4, filtered and the
solvent removed under vacuum to give the crude glycosyl
chlorides. Purification of the crude glycosyl chlorides using silica
gel column chromatography using hexane:ethyl acetate (75:25)
as eluent provided the pure glycosyl chlorides 2a-k. Note that 2g
was unstable on silica gel.
1
of the - and -glycosyl chlorides. Please see the complete H
NMR and 13C NMR spectra of this experiment in the SI.
Acknowledgements
We thank Nanyang Technological University for financial help
(RG 142/16).
1.2 General procedure for one-pot glycosylation with armed
sugars: DMC (0.2 mmol) was added to a stirred solution of
sugars 1a, 1b, 1i (0.2 mmol) and triethylamine (0.4 mmol) in
dichloromethane (3 mL) at room temperature and the mixture
stirred for 15-30 min (TLC). After complete consumption of the
sugars 1a, 1b, 1i, the reaction mixture was cooled to -60 oC then
the acceptors 9 or 10 (0.8 eq.) were added followed by addition
of silver triflate (0.4 mmol). After complete consumption of the
glycosyl chloride (TLC), the reaction mixture was quenched with
Et3N (0.4 mmol), diluted with DCM (15 mL) and filtered through a
small pad of celite. The filtrates were then concentrated to give
the crude glycosylated products which upon purification using
Keywords:
glycosyl
chlorides
•
2-Chloro-1,3-
dimethylimidazolinium chloride • one pot glycosylation • Koenigs-
knorr glycosylation • Armed/disarmed sugars
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Glycosyl chlorides; glycosylation
Madhu Babu Tatina,[a] Duc Thinh
Khong,[a] Zaher M. A. Judeh*[a]
Page No. – Page No.
Efficient synthesis of -glycosyl
chlorides using 2-chloro-1,3-
dimethylimidazolinium chloride: A
convenient protocol for quick one-pot
glycosylation
A convenient method for the synthesis of -glycosyl chloride donors in high 80-96%
yields within 15-30 min using 2-chloro-1,3-dimethylimidazolinium chloride has been
developed. The method enables quick and direct one-pot glycosylation in high
overall yields.
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