Straightforward synthesis of protected 2-hydroxyglycals by chlorination-dehydrochlorination of carbohydrate hemiacetals

Article abstract of DOI:10.1016/j.carres.2020.108086

A straightforward and scalable method for the synthesis of protected 2-hydroxyglycals is described. The approach is based on the chlorination of carbohydrate-derived hemiacetals, followed by an elimination reaction to establish the glycal moiety. 1,2-dehy

Full text of DOI:10.1016/j.carres.2020.108086

Journal Pre-proof
Straightforward synthesis of protected 2-hydroxyglycals by chlorination-
dehydrochlorination of carbohydrate hemiacetals
Jan Choutka, Michal Kratochvíl, Jakub Zýka, Radek Pohl, Kamil Parkan
PII:
S0008-6215(20)30222-6
DOI:
https://doi.org/10.1016/j.carres.2020.108086
CAR 108086
Reference:
To appear in: Carbohydrate Research
Received Date: 9 April 2020
Revised Date: 18 June 2020
Accepted Date: 18 June 2020
Please cite this article as: J. Choutka, M. Kratochvíl, J. Zýka, R. Pohl, K. Parkan, Straightforward
synthesis of protected 2-hydroxyglycals by chlorination-dehydrochlorination of carbohydrate
hemiacetals, Carbohydrate Research (2020), doi: https://doi.org/10.1016/j.carres.2020.108086.
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Straightforward synthesis of protected 2-hydroxyglycals by chlorination-dehydrochlorination of
carbohydrate hemiacetals
Jan Choutka,†,a Michal Kratochvíl,†,a Jakub Zýka,a Radek Pohlb and Kamil Parkan*,a
a
Department of Chemistry of Natural Compounds, University of Chemistry and Technology, Prague,
Technická 5, 166 28, Prague, Czech Republic
b
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Gilead Sciences &
IOCB Research Centre, Flemingovo nám. 2, 166 10, Prague, Czech Republic
† These authors contributed equally to this work.
* Corresponding author: parkank@vscht.cz
Abstract:
A straightforward and scalable method for the synthesis of protected 2-hydroxyglycals is described. The
approach is based on the chlorination of carbohydrate-derived hemiacetals, followed by an elimination
reaction to establish the glycal moiety. 1,2-dehydrochlorination reactions were studied on a range of glycosyl
chlorides to provide suitable reaction conditions for this transformation. Benzyl ether, isopropylidene and
benzylidene protecting groups, as well as interglycosidic linkage, were found to be compatible with this
protocol. The described method is operationally simple and allows for the quick preparation of 2-
hydroxyglycals with other than ester protecting groups, providing a feasible alternative to existing methods.
Keywords:
Glycals
2-Hydroxyglycals
Dehydrochlorination
Glycosyl chlorides
Carbohydrates
1. Introduction
Glycals are 1,2-unsaturated cyclic enol ether derivatives of carbohydrates. These compounds, formally
classified as derivatives of 1,4- or 1,5-anhydro alditols, are an important class of intermediates in natural
product synthesis, mainly due to the presence of the enol ether double bond and the broad possibilities of its
derivatization. [1,2]
Among glycals, compounds containing an oxygen atom at C-2 (derivatives of 2-hydroxyglycals) have gained
considerable attention owing to their closer resemblance to the native carbohydrate scaffold. Acetyl-protected
2-hydroxyglycals have been studied extensively for their Ferrier rearrangement [3,4], which is widely used in
1

carbohydrate chemistry. However, other common protecting groups such as ether or acetal groups have been
introduced, providing higher stability towards a wider range of reaction conditions. On 2-hydroxyglycals
protected with other than acyl protecting groups, multiple types of transformations have been described. These
include the addition of sulfur [5] and carbon [6–8] radicals, cyclopropanation [9] (in some cases followed by
ring expansion to septanosides) [10–12], epoxidation [13], ring-opening arylation with arylboronic acids [14],
as well as an attempt at C-1 lithiation [15].
The preparation of 2-hydroxyglycals bearing ester protecting groups can most conveniently be carried out by
an anomeric bromination of peracetylated carbohydrates with HBr followed by dehydrobromination by a base.
[16,17] This method is well established and generally straightforward, but it requires the presence of an
anomeric acyl group and is furthermore limited to substrates with acid-stable protecting groups.
Figure 1. General methods for the synthesis of protected 2-hydroxyglycals.
Therefore, alternative methods are needed to account for these limitations and to provide a synthetic approach
to 2-hydroxyglycals with acid-sensitive protection. In the past, several such methods emerged, as outlined in
Figure 1. The more general approaches include syn-elimination reactions of glycosyl sulfoxides [18] and
selenoxides [19]. Although these methods work well, the starting thio- and selenoglycosides are not always
readily available. Moreover, these approaches are limited by the inherent syn-periplanar stereochemical
2

requirements which narrow the range of utilizable substrates to 1,2-trans derivatives only. Another published
method [20] uses an oxidative addition of Pd(0) species to in situ generated glycosyl mesylates followed by
spontaneous β-hydride elimination of the anomeric palladium intermediate. Besides that, the synthesis of 2-
benzyloxyglucal 3a has been reported via bromolysis of a corresponding pentenyl glycoside [9] or
halogenation of 1-O-acetyl-2,3,4,6-tetra-O-benzyl-D-glucopyranose [21,22]. However, none of these reports
demonstrated the compatibility with acid-labile protection.
Herein, we provide a simple way of converting reducing carbohydrates to variously protected 2-
hydroxyglycals by a two-stage chlorination-dehydrochlorination protocol. The described method is applicable
to both 1,2-cis and 1,2-trans glycosyl chlorides and is carried out under aprotic conditions, allowing for the
use of acid-sensitive protecting groups and thus providing an approach to previously undescribed products.
Additionally, improved synthetic pathways to several partially protected carbohydrate-derived hemiacetals are
described.
2. Results and discussion
2.1.Preparation of substrates
In order to develop the proposed methodology, a variety of hemiacetal substrates have been synthesized.
2,3,4,6-tetra-O-benzyl-
D
-glucopyranose 1a [23], 2,3,4,6-tetra-O-benzyl-
D
-galactopyranose 1b [24] and
2,3-di-O-benzyl-4,6-O-benzylidene-D-glucopyranose 1c [25] have been synthesized following literature
procedures.
Regarding the synthesis of 2,3:4,6-di-O-isopropylidene-
D
-mannopyranose 1d, some conflicting evidence can
-mannose is the diisopropylidene D-
be found in the literature. A thermodynamic product of acetonation of
D
mannofuranose 1k [26]; however several reports describe direct kinetic acetonation to the pyranose 1d. In our
experience, these methods result in an inseparable mixture of pyranose and furanose diacetonides 1d and 1k,
and isolation via the recrystallization of the anomeric acetate 5 is needed to obtain the pure pyranose 1d, as
described in the original report by Gelas and Horton [27]. (Scheme 1)
The 2,3:4,6-di-O-isopropylidene-D-glucopyranose 1e and -galactopyranose 1f are currently only available
through the hydrogenolysis of their benzyl glycosides [28,29]. Nevertheless, this reaction is complicated by
over-reduction to the corresponding 2,3:4,6-di-O-isopropylidene alditols. Herein, we used an aprotic
deallylation of the known allyl glucoside 7 [30] and galactoside 9 [31] by allylic rearrangement and
ozonolysis. (Scheme 2)
To test the compatibility of the presented method with an interglycosidic linkage, the hepta-O-benzyl lactose
1g was synthesized. Existing synthetic approaches to this compound involve peracetylated lactosyl bromide
[32–36], lactose peracetate [37,38], lactosucrose [39] or octa-O-benzyl lactose [40] as key intermediates. We
3

developed an alternative approach based on the use of piperidine as a temporary anomeric protecting group of
lactose, as revealed in Scheme 3.
Next, 2,3,5-tri-O-benzyl aldopentofuranoses with D-ribo (1h [41]), D-arabino (1i [42]) and D-xylo (1j [43])
configuration have been prepared by the hydrolysis of their methyl glycosides. Additionally, at the time of the
writing of this manuscript compounds 1a, 1b, 1h, 1i and 1k are also available from commercial suppliers.
Scheme 1. Synthesis of 2,3:4,6-di-O-isopropylidene-D-mannopyranose 1d. [27]
Scheme 2. Synthesis of diisopropylidene derivatives 1e and 1f.
Scheme 3. Synthesis of hepta-O-benzyl lactose 1g via its N-piperidine derivative 11.
2.2.Chlorination-Dehydrochlorination
Having the partially protected hemiacetals in hand, we considered the possibilities of converting the anomeric
hydroxyl to a suitable leaving group. This type of transformation is well documented in carbohydrate
chemistry, with sulfonate esters or halogens being a common choice. We decided to use anomeric chlorides,
as they can be obtained from hemiacetals by several known methods under aprotic or mildly protic conditions.
Notably, chlorination with Vilsmeier reagent [44,45], diphenyl chlorophosphate [46], 2-chloro-1,3-
dimethylimidazolinium chloride (DMC) [47], a mixture of pyridine and triphosgene [48], as well as the Appel
reaction [49–51] were described.
4

Base-promoted 1,2-dehydrochlorination reactions of glycosyl chlorides were previously described on
perbenzylated lactosyl and maltosyl chlorides [12] and also reported a number of times as an unwanted side
reaction in minor amounts [52–58]. Other than that, this important transformation was to this date not
systematically studied with respect to reaction conditions, substrate configuration and protecting group
compatibility.
To address this problem, 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl chloride 2a was prepared by chlorination with
Vilsmeier reagent and purified by column chromatography. The chloride 2a was then used for a screening of
multiple bases and solvents as summarized in Table 1. Three of the evaluated bases were found to be effective
in promoting the dehydrochlorination of 2a and gave the glycal 3a in excellent yields. The use of NaH in
DMF at room temperature provided glycal 3a in 91% yield in the reaction mixture, as determined by 1H NMR
with an internal standard (Table 1, entry 3). Switching to acetonitrile led to a yield of 85% after 16 h of
reaction at room temperature (Table 1, entry 2); however, raising the temperature to 50 °C increased the yield
to 99% with a shortened reaction time of 2 h (Table 1, entry 1). NaH also provided excellent results in THF
(96%, Table 1, entry 4), but reflux temperature and increased amounts of NaH (10 equivalents instead of 5)
were required. We also found that elimination by t-BuOK in THF at room temperature resulted in 98% yield
of 3a (Table 1, entry 5), making it a promising candidate for this transformation.
Finally, several tertiary amine bases were evaluated under several conditions (Table 1, entries 6 - 14) with
DBU being the only efficient of them. DBU provided a good result in acetonitrile (90%, Table 1, entry 6) but
was less effective in other solvents (Table 1, entries 7 - 9). Experiments with weaker amine bases such as
DABCO, DIPEA or DMAP led to low or no conversions of the chloride 2a and did not provide the
elimination product in any measurable amount.
Table 1. Screening of elimination conditions.[a]
Entry Base (eq.)
Solvent
T [°C][b] Time [h] NMR conversion NMR yield
[%][c]
[%][c]
1
2
3
4
NaH (5)
NaH (5)
NaH (5)
NaH (10)
MeCN
MeCN
DMF
50
rt
2
100
99
16
2
100
100
100
85
91
96
rt
THF
80
16
t-BuOK
(2.5)
5
THF
rt
2
100
98
6
DBU (4)
MeCN
rt
16
100
90
5

CH2Cl2/MeCN
(1:1)
7
DBU (4)
rt
16
100
73
8
DBU (4)
DBU (4)
CH2Cl2
DMF
50
rt
24
16
24
24
24
24
24
100
85
23
7
62
57
0
9
10
11
12
13
14
DABCO (4) CH2Cl2
DIPEA (4) DMF
DIPEA (4) CH2Cl2
DMAP (4) DMF
DMAP (4) CH2Cl2
50
rt
0
50
rt
5
0
0
0
50
0
0
[a] All reactions carried out with 100 mg (179 µmol) of 2a. [b] Oil bath temperature,
except for rt. [c] Corresponds to a calculated mass determined by 1H NMR of the reaction
mixture after work-up using 1,3,5-trimethoxybenzene as an internal standard.
With several promising conditions for the β-elimination of glycosyl chlorides identified, the versatility of
these conditions was tested on a wider range of substrates. In some cases, t-BuOK was found to provide
significant amounts of byproducts arising from SN2 processes, as pictured in Scheme 4. Notably, the reaction
of benzyl protected α-
D
-galactopyranosyl chloride 2b led to the formation of the desired elimination product
-mannofuranosyl chloride
3b in 43% yield together with 46% of tert-butyl β-glycoside 12. The reaction of α-
D
2k provided the SN2 product 13 in a very clean fashion in quantitative yield. These results suggest that with t-
BuOK, the relative rates of elimination and nucleophilic substitution can vary significantly across different
glycosyl chlorides and the outcome of the reaction is strongly substrate-dependent.
We have also discovered that DBU, albeit successful in the elimination of chloride 2a, was not effective in
promoting dehydrochlorination on other substrates and was found to be more sensitive to the configuration on
C-1 relative to C-2. This effect can be seen on the
D-mannopyranose diacetonide 1d (Scheme 5). The
chlorination of this substrate with a triphosgene/pyridine mixture leads to the 2:1:1 ratio of the α-chloride α-
2d, β-chloride β-2d and the glycal product 3d, which is formed spontaneously during the chlorination. This
mixture of chlorination products, upon treatment with DBU in acetonitrile, converts to an equimolar mixture
of α-2d and 3d and the reaction does not proceed further even with longer reaction time or higher
temperature. This shows that only the intermediate chloride with β-configuration β-2d underwent elimination
under the given conditions.
Overall, NaH was found to be the most potent base for this transformation; however, other factors such as the
reaction solvent and temperature were identified to be important as well. The most consistent results and best
yields were obtained using acetonitrile as a solvent at 50 °C.
6

Scheme 4. Competition between SN2 and β-elimination pathways on selected glycosyl chlorides.
Scheme 5. Chlorination/elimination of 1d with DBU.
2.3.Substrate scope
To test the generality of the aforementioned process, the partially protected sugar hemiacetals 1a-k were
subjected to a two-stage protocol consisting of chlorination and subsequent elimination under the conditions
established earlier. The results of this endeavor are summarized in Table 2.
Several known chlorination methods were tested first to obtain the best results. Initially, the Vilsmeier
reagent[44] was used for chlorinations, but it was found to give inferior results in this protocol, as seen in
Table 2, entries 1 and 2. Moreover, this chlorination method was problematic on 2,3:4,6-di-O-isopropylidene-
D
-mannopyranose 1d, as the treatment of this substrate with the Vilsmeier reagent provided a mixture of the
expected 2,3:4,6-di-O-isopropylidene- -mannopyranosyl chloride 2d with the 2,3:5,6-di-O-isopropylidene-D-
D
mannofuranosyl chloride 2k in the 1:20 ratio. This rearrangement to a five-membered ring is likely catalyzed
by a hydrogen chloride, which is generated in the solution during the chlorination. A similar result was
reported on the same substrate under Appel conditions [59]. Thus, our investigations turned to the use a
combination of pyridine and triphosgene in the 3:1 ratio as described originally by Mobashery [60] and later
adapted by Norris [48]. With this system, no rearrangements were observed, and the reaction proceeded
cleanly under aprotic conditions.
7

Nevertheless, the use of pyridine proved problematic on more reactive furanose substrates 1h, 1i and 1j,
where significant amounts of anomeric pyridinium salts were recovered from the reaction mixture after
chlorination. These pyridinium products arise from the displacement of the anomeric chlorine atom with
pyridine and were observed on substrates that show high electrophilicity on the anomeric center. In these
cases, the problem was overcome by the use of less nucleophilic 2,6-lutidine, which facilitated the
chlorination of these substrates effectively. On the other hand, 2,6-lutidine showed little or no reactivity on the
less reactive substrates, indicating that the use of pyridine or lutidine should be considered complementary.
The scope of this method was then explored with the emphasis on acid-sensitive substrates, as these are not
easily accessible by current methods. The 2-benzyloxy glycals 3a and 3b derived from D-glucose and D-
galactose were obtained in 85% and 71%, respectively, providing two-step one-chromatography approach to
these important substrates from commercially available materials.
Benzylidene protecting group was found to be compatible as well, even though a lower yield of 54% and a
somewhat more sluggish reaction was observed in the case of glucal 3c. Another acetal group, isopropylidene,
was generally well tolerated, although some differences in reaction yields were observed between differently
configured hemiacetals. The 2,3:4,6-di-O-isopropylidene-
diisopropylidene -mannose 1d and the elimination protocol employing NaH in acetonitrile, as seen in Table
2, entry 4. The same glycal was obtained from diisopropylidene -glucopyranose 1e, although elimination
with t-BuOK provided better yield than NaH in this case (78%, Table 2, entry 5). All things considered, our
results provide a relatively straightforward approach from -mannose or -glucose to glucal 3d, which is
currently only available in acceptable yield via the selenoxide method [19]. 2,3:4,6-di-O-isopropylidene-
D-glucal 3d was obtained in 74% yield upon using
D
D
D
D
D
-
galactal 3f can be accessed by this protocol as well, albeit in a moderate yield of 37% after elimination with
NaH (Table 2, entry 6). Despite lower yield, this synthetic approach to galactal 3f is valuable, as no other
approach to this compound was described to this day, and according to our experience, the galactal 3f is not
accessible by the selenoxide elimination (see Supplementary material, S2.3.). Importantly, interglycosidic
linkage is tolerated in this protocol, as demonstrated on the transformation of hemiacetal 1g to 2-benzyloxy
lactal 3g in 68% yield (Table 2, entry 7). This transformation was already reported earlier under very similar
conditions. [12]
The effort to extend this chlorination-dehydrochlorination methodology to furanose hemiacetals has only met
with limited success. The chlorination of pentofuranoses 1h, 1i and 1j required the use of 2,6-lutidine instead
of pyridine for the reasons mentioned above. Although the furanosyl chlorides 2h, 2i and 2j could be obtained
using this approach, their elimination was successful only in the case of ribosyl chloride 2h, giving 2-
benzyloxy-
protected
under the elimination conditions. Similarly, the elimination of
complete decomposition to an unidentified mixture of products. Furthermore, the chlorination of
D
-ribal 3h in 75% yield after elimination with t-BuOK. The same product was also obtained from
-arabinose 1i, but only in negligible yields of 4 - 8% (Table 2, entry 9) due to a major degradation
-xylofuranosyl chloride 2j resulted in
D
D
8

diisopropylidene
D-mannofuranose 1k proceeded smoothly with triphosgene/pyridine to give the
corresponding α-chloride 2k, as reported earlier. This chloride, however, proved to be particularly resilient to
1,2-dehydrochlorination reactions. The treatment with NaH in acetonitrile led to double aldol condensation
with acetonitrile yielding an unstable N-glycoside product 14.[61] The reaction with t-BuOK resulted in a
clean SN2 reaction to give tert-butyl-β-D-mannofuranoside 13 (Scheme 4). Further attempts to use other
elimination conditions from Table 1 or more forcing conditions did not provide the desired glycal either.
To put our observations into the stereochemical context, the chlorination reactions resulted in most cases in
the formation of glycosyl chlorides with α-configuration. However, in the case of chlorides 2f, 2h and 2j,
major amounts of the β-isomer were observed. It is worth noting that the observed anomeric ratio for
chlorides 2d and 2f is influenced by a partial elimination which takes place under the chlorination conditions
(Table 2, entries 4 and 6). For this reason, the true stereochemical preference of the reaction could not be
determined in these cases.
The anomeric configuration of the glycosyl chlorides did not seem to have a major influence on the success of
the elimination reactions, as seen in Table 2, entries 4 and 8. In these cases, the intermediate chlorides 2d and
2h have mainly 1,2-trans configuration, which would be generally considered less favorable for elimination.
Yet, the elimination proceeded in favorable overall yields of 74% and 75%. This observation suggests that
1,2-dehydrochlorination reactions of glycosyl chlorides with NaH or t-BuOK do not necessarily rely on a
bimolecular mechanism and unlike with DBU, the relative configuration on C-1 and C-2 is not critical. Other
factors, such as the stability of the chloride or susceptibility to substitution reactions or other unwanted
processes, seem to be more important.
Table 2. Scope of the chlorination-dehydrochlorination of partially protected hemiacetals.[a]
Chlorination
method
Elimination
method
Isolated yield
over 2 steps [%]
Chloride α/β
Entry
1
Substrate
Product
ratio
A
C
A
C
D
D
D
D
85
64
71
61
2a
α only
2b
α only
2
3
2c
α only
A
D
54
9

2d
4
5
6
A
D
74
α/β/3d
2:1:1
A
A
D
E
36
78
2e
α only
A
A
2f
α/β/3f
1:1.5:1
E[d]
36
68
2g
α only
7
A
D
B
B
D
E
24
75
2h
α/β
1:7
8
9
O
B
B
D
E
8
4
2i
α/β
1:0.2
OH
OBn
BnO
1i BnO
B
B
A
D
E
ND[b]
ND[b]
2j
α/β
1:1.3
10
-
-
D
ND[78]
2k
α only
11
A
E
ND[c]
[a] All reactions were carried out with 2 mmol of a substrate 1a-k. Isolated yields over 2 steps after column chromatography are given.
Conditions: A: triphosgene/pyridine, THF, rt, 1 h; B: triphosgene/2,6-lutidine, THF, rt, 1 h; C: Vilsmeier reagent, CH2Cl2, 0 ˚C, 30 min
[44] ; D: 60% NaH, MeCN, 50 ˚C, 2 h; E: t-BuOK, THF, rt, 2 h. [b] Decomposition. [c] SN2 reaction was observed (see Scheme 4).
[d] Elimination was carried out for 30 min at 0 ˚C and then for 30 min at rt; ND = not determined
3. Conclusion
In this paper, base-promoted dehydrochlorination reactions of glycosyl chlorides have been explored and
suitable conditions for the preparation of a variety of protected 2-hydroxyglycals have been identified. The
presented synthetic approach is particularly advantageous in the cases where the partially protected hemiacetal
substrates with a free anomeric hydroxyl group are readily available. For this reason, improved synthetic
access to several known hemiacetal substrates from unprotected sugars has been developed.
This method is carried out as a two-step one-chromatography protocol and it relies on chlorination of the
anomeric position of carbohydrates and subsequent 1,2-dehydrochlorination to establish the glycal double
10

bond. The aprotic conditions of this protocol enable the use of acid-sensitive substrates and protecting groups.
Moreover, it provides a concise approach to several important 2-benzyloxy glycals.
Under the identified elimination conditions (method D or E), both 1,2-cis and 1,2-trans glycosyl chlorides
have been found to undergo 1,2-dehydrochlorination. However, differences in yields (4 - 85%) were observed
through differently configured substrates and some substrates even proved entirely resilient or unstable under
the reaction conditions.
4. Experimental section
General considerations, experimental procedures for the preparation of substrates, other experimental details,
and copies of 1H and 13C NMR spectra are included in the Supplementary material.
Method A (triphosgene/pyridine) [48]
:
Triphosgene (1 mmol, 0.5 eq.) was added to a solution of substrate 1 (2 mmol, 1 eq.) in anhydrous THF (10
mL) under Ar atmosphere. The solution was cooled to 0 °C and pyridine (3.2 mmol, 1.6 eq.) was added
dropwise. The formation of a white precipitate (pyridinium chloride) was observed immediately during the
addition. The reaction was stirred at room temperature for 1 h and then filtered. The filtrate was concentrated
under reduced pressure, dissolved in EtOAc (100 mL) and washed with H2O (2 × 100 mL). The organic layer
was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting oil was
kept under high vacuum for 1 h.
Method B (triphosgene/2,6-lutidine)
The same as Method A, except that 2,6-lutidine (3.2 mmol, 1.6 eq.) was used instead of pyridine.
Method C (Vilsmeier reagent) [44]
:
Oxalyl chloride (3 mmol, 1.5 eq.) was added dropwise to the solution of the substrate 1 (2 mmol, 1 eq.) and
DMF (3.4 mmol, 1.7 eq.) in CH2Cl2 (15 mL) under Ar atmosphere at 0 °C. An exothermic reaction with gas
evolution was observed. The reaction mixture was allowed to warm to room temperature and stirred for 30
min. Then, the mixture was poured into ice water and diluted with CH2Cl2 (100 mL). The organic phase was
washed with chilled H2O (150 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The resulting oil was kept under high vacuum for 1 h.
Method D (NaH in MeCN):
The crude glycosyl chloride 2 obtained with chlorination Method A, B or C was dissolved in anhydrous
MeCN (15 mL) and NaH (10 mmol, 5 eq. relative to substrate 1, 60% in mineral oil) was added. The
heterogeneous mixture was stirred at 50 °C for 2 h. After the elimination was finished, MeOH (5 mL) was
11

added slowly at 0 °C and the solvents were evaporated under reduced pressure. The residue was dissolved in
EtOAc (100 mL) and washed with H2O (100 mL). The aqueous phase was separated and washed with EtOAc
(100 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel.
Method E (t-BuOK in THF):
The crude glycosyl chloride 2 obtained with chlorination Method A, B or C was dissolved in anhydrous THF
(20 mL) and t-BuOK (5 mmol, 2.5 eq. relative to substrate 1) was added. The reaction mixture was stirred for
2 h at room temperature and then quenched with H2O (5 mL). The reaction mixture was extracted between
EtOAc (100 mL) and H2O (100 mL). The aqueous phase was then washed with EtOAc (2 × 100 mL), the
combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography on silica gel.
Practical considerations:
1. In general, when running chlorination reactions of sugar hemiacetals to form glycosyl chlorides, TLC is
not an entirely reliable method to track the conversion of the reaction. Frequently, the starting material
would display on the TLC plate, when in fact the reaction is fully completed. This is likely due to a reverse
hydrolytic reaction happening on the silica gel plate. For reliable determination of the reaction conversion,
1H NMR is more suitable.
2. In the Mobashery chlorination protocol involving triphosgene/pyridine mixture, it is recommended to add
pyridine relatively slowly, dropwise, to avoid creating local excess of pyridine. If pyridine is added
rapidly, there is a higher risk of secondary nucleophilic substitution and formation of anomeric pyridinium
salts on some substrates.
4.1.1,5-Anhydro-2,3,4,6-tetra-O-benzyl-D-arabino-hex-1-enitol (3a):
Methods A and D: Following Method A, substrate 1a (1.1 g, 2 mmol) was reacted with triphosgene (297 mg,
1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method D, the crude chloride 2a was reacted with
NaH (400.0 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 891 mg (85%).
Methods C and D: Following Method C, substrate 1a (1.1 g, 2 mmol) was reacted with oxalyl chloride (257
µL, 3 mmol) and N,N-dimethylformamide (263 µL, 3.4 mmol). Then, following Method D, the crude chloride
2a was reacted with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 665 mg (64%).
Isolation: The product 3a was purified by column chromatography on silica gel (Hexane/EtOAc 10:1) and
obtained in the form of a colorless oil which solidified upon standing. The characterization data were
consistent with the literature. [9,19]
12

Rf = 0.52 (Hexane/EtOAc 5:1); m.p. 64 - 66 °C (acetone); [α
]
= - 4.6 (c = 0.3 in CHCl3); H NMR (401
D
20
1
MHz, Chloroform-d): δ = 7.41 – 7.19 (m, 20H; Ar-H), 6.32 (s, 1H; H-1), 4.77 – 4.69 (m, 4H; CHPh), 4.62 (d,
Jgem = 11.5 Hz, 1H; CHPh), 4.60 (d, Jgem = 11.7 Hz, 1H; CHPh), 4.56 – 4.54 (m, 2H; CHPh), 4.27 (d, J3,4 = 4.7
Hz, 1H; H-3), 4.13 – 4.07 (m, 1H; H-5), 3.91 (dd, J4,5 = 6.7 Hz, J4,3 = 4.7 Hz, 1H; H-4), 3.78 (dd, Jgem = 10.6
Hz, J6a,5 = 6.0 Hz, 1H; H-6a), 3.69 (dd, Jgem = 10.6 Hz, J6b,5 = 3.5 Hz, 1H; H-6b); 13C NMR (101 MHz,
Chloroform-d): δ = 139.0 (C-2), 138.5 (Ar-Cipso), 138.2 (Ar-Cipso), 138.1 (Ar-Cipso), 137.3 (Ar-Cipso), 128.6,
128.6, 128.5, 128.5, 128.1, 128.0, 127.98, 127.96 (Ar-C), 127.91 (C-1), 127.85, 127.77, 127.74, 127.70 (Ar-
C), 76.4 (C-5), 75.7 (C-3), 74.4 (C-4), 73.6 (CH2Ph), 73.0 (CH2Ph), 72.4 (CH2Ph), 71.2 (CH2Ph), 68.4 (C-6);
IR (CHCl3): ṽ = 3090, 3067, 3032, 2910, 2869, 1670, 1605, 1587, 1497, 1454, 1159, 1100, 1071, 1028, 911,
698, 467 cm-1; MS (ESI): m/z = 545.2 [M+Na]+; HRMS (ESI): m/z calcd for C34H34O5Na: 545.2299 [M+Na]+;
found 545.2294.
4.2. 1,5-Anhydro-2,3,4,6-tetra-O-benzyl-D-lyxo-hex-1-enitol (3b):
Methods A and D: Following Method A, substrate 1b (1.1 g, 2 mmol) was reacted with triphosgene (297 mg,
1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method D, the crude chloride 2b was reacted with
NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 743 mg (71%).
Methods C and D: Following Method C, substrate 1b (1.1 g, 2 mmol) was reacted with oxalyl chloride (257
µL, 3 mmol) and N,N-dimethylformamide (263 µL, 3.4 mmol). Then, following Method D, the crude chloride
2b was reacted with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 638 mg (61%).
Isolation: The product 3b was purified by column chromatography on silica gel (Hexane/EtOAc 10:1) and
obtained in the form of a colorless oil which solidified upon standing. The characterization data were
consistent with the literature. [8]
1
Rf = 0.37 (Hexane/EtOAc 8:1); [α]20 = - 44.7 (c = 0.3 in CHCl3); H NMR (401 MHz, Chloroform-d): δ =
D
7.37 – 7.27 (m, 20H; Ar-H), 6.19 (d, J1,3 = 1.0 Hz, 1H; H-1), 4.84 (d, Jgem = 12.0 Hz, 1H; CHPh), 4.79 (d, Jgem
= 12.0 Hz, 1H; CHPh), 4.78 (d, Jgem = 12.0 Hz, 1H; CHPh), 4.73 (d, Jgem = 11.3 Hz, 1H; CHPh), 4.63 (d, Jgem
= 11.3 Hz, 1H; CHPh), 4.62 (d, Jgem = 12.0 Hz, 1H; CHPh), 4.55 (d, Jgem = 12.0 Hz, 1H; CHPh), 4.45 (d, Jgem
= 12.0 Hz, 1H; CHPh), 4.25 (dd, J3,4 = 4.2 Hz, J3,1 = 1.0 Hz, 1H; H-3), 4.24 – 4.20 (m, 1H; H-5), 3.96 – 3.89
(m, 2H; H-4, H-6a), 3.71 (dd, Jgem = 10.9 Hz, J6b,5 = 3.4 Hz, 1H; H-6b); 13C NMR (101 MHz, Chloroform-d):
δ = 138.92 (Ar-Cipso), 138.85 (C-2), 138.4 (Ar-Cipso), 138.2 (Ar-Cipso), 137.4 (Ar-Cipso), 128.53, 128.48, 128.4,
128.09, 128.01, 127.95, 127.94, 127.85, 127.73, 127.70, 127.6 (Ar-C), 127.0 (C-1), 75.3 (C-5), 73.7 (CH2Ph),
73.5 (CH2Ph), 73.3 (C-4), 72.7 (CH2Ph), 71.9 (C-3), 71.5 (CH2Ph), 67.8 (C-6); IR (CHCl3): ṽ = 3090, 3067,
2923, 2871, 1604, 1588, 1497, 1454, 1149, 1101, 1028, 913, 698, 459; MS (ESI): m/z = 545.2 [M+Na]+;
HRMS (ESI): m/z calcd for C34H34O5Na: 545.2299 [M+Na]+; found 545.2296.
13

4.3. 1,5-Anhydro-2,3-di-O-benzyl-4,6-O-benzylidene-D-arabino-hex-1-enitol (3c):
Methods A and D: Following Method A, substrate 1c (897 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method D, the crude chloride 2c was reacted
with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 467 mg (54%).
Isolation: The product 3c was purified by column chromatography on silica gel (Hexane/EtOAc 10:1) and
obtained in the form of a white solid. The characterization data were consistent with the literature. [19] Rf =
0.32 (Hexane/EtOAc 10:1); m.p. not determined (decomposition at 220 °C); [α]20 = - 34.1 (c = 0.2 in
D
CHCl3); 1H NMR (401 MHz, Chloroform-d): δ = 7.54 (dd, J = 7.7, 2.1 Hz, 2H; Ar-H), 7.46 – 7.25 (m, 13H;
Ar-H), 6.32 (d, J1,3 = 1.0 Hz, 1H; H-1), 5.61 (s, 1H; CHPh), 4.92 (d, Jgem = 12.0 Hz, 1H; CHaCHbPh), 4.88 (d,
Jgem = 12.0 Hz, 1H; CHaCHbPh), 4.76 (d, Jgem = 11.4 Hz, 1H; CHaCHbPh), 4.73 (d, Jgem = 11.4 Hz, 1H;
CHaCHbPh), 4.53 (dd, J3,4 = 7.4 Hz, J3,1 = 1.0 Hz, 1H; H-3), 4.38 (dd, Jgem = 9.6 Hz, J6a,5 = 4.3 Hz, 1H; H-6a),
4.11 (dd, J4,5 = 9.9 Hz, J4,3 = 7.4 Hz, 1H; H-4), 3.89 – 3.74 (m, 2H; H-6b, H-5); 13C NMR (101 MHz,
Chloroform-d): δ = 139.7 (C-2), 138.6 (Ar-Cipso), 137.3 (Ar-Cipso), 137.1 (Ar-Cipso), 129.4 (C-1), 129.1 (Ar-C),
128.6 (Ar-C), 128.4 (Ar-C), 128.3 (Ar-C), 128.1 (Ar-C), 128.0 (Ar-C), 127.7 (Ar-C), 127.7 (Ar-C), 126.2 (Ar-
C), 101.1 (CHPh), 80.0 (C-4), 74.9 (C-3), 73.5 (CH2Ph), 71.5 (CH2Ph), 69.2 (C-5), 68.5 (C-6); IR (CHCl3): ṽ
= 3091, 3068, 2933, 2871, 1659, 1606, 1586, 1497, 1466, 1454, 1375, 1342, 1165, 1149, 1095, 1075, 1066,
1028, 995, 915, 698, 467 cm-1; MS (ESI): m/z = 453.2 [M+Na]+; HRMS (ESI): m/z calcd for C27H26O5Na:
453.1671 [M+Na]+; found 453.1673.
4.4. 1,5-Anhydro-2,3:4,6-di-O-isopropylidene-D-arabino-hex-1-enitol (3d):
From 1d:
Methods A and D: Following Method A, substrate 1d (521 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method D, the crude chloride 2d was reacted
with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 359 mg (74%).
From 1e:
Methods A and D: Following Method A, substrate 1e (521 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method D, the crude chloride 2e was reacted
with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 175 mg (36%).
Methods A and E: Following Method A, substrate 1e (521 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method E, the crude chloride 2e was reacted
with t-BuOK (561 mg, 5 mmol). Isolated yield 379 mg (78%).
Isolation: The product 3d was purified by column chromatography on silica gel (Hexane/EtOAc 15:1) and
obtained in the form of a colorless oil. The characterization data were consistent with the literature. [19] Rf =
1
0.59 (Hexane/EtOAc 5:1); [α]20 = + 62.0 (c = 0.5 in CHCl3); H NMR (401 MHz, Chloroform-d): δ = 6.22
D
14

(d, J1,3 = 1.8 Hz, 1H; H-1), 4.59 (dd, J3,4 = 7.4 Hz, J3,1 = 1.8 Hz, 1H; H-3), 4.00 (dd, Jgem = 11.0 Hz, J6a,5 = 5.6
Hz, 1H; H-6a), 3.90 (dd, J4,5 = 10.5 Hz, J4,3 = 7.4 Hz, 1H; H-4), 3.85 (dd, Jgem = 11.0 Hz, J6b,5 = 10.5 Hz, 1H;
H-6b), 3.59 (td, J5,4 = J5,6b = 10.5 Hz, J5,6a = 5.6 Hz, 1H; H-5), 1.55 (s, 3H; C(CH3)2), 1.49 (s, 3H; C(CH3)2),
1.46 (s, 3H; C(CH3)2), 1.45 (s, 3H; C(CH3)2); 13C NMR (101 MHz, Chloroform-d): δ = 134.3 (C-2), 122.3 (C-
1), 113.4 (C(CH3)2),99.8 (C(CH3)2), 73.8 (C-3), 71.3 (C-4), 67.4 (C-5), 62.1 (C-6), 29.0 (C(CH3)2), 26.9
(C(CH3)2), 25.5 (C(CH3)2), 19.2 (C(CH3)2); IR (CHCl3): ṽ = 2992, 2940, 2901, 1802, 1736, 1706, 1460, 1383,
1375, 1347, 1318, 1267, 1232, 1217, 1201, 1165, 1123, 1104, 1083, 1053, 1007, 967, 936, 914, 851, 796, 762,
752, 680, 663, 601, 560, 524, 506, 483, 468 cm-1; MS (APCI): m/z = 243.1 [M+H]+; HRMS (ESI): m/z calcd
for C12H18O5Na: 265.1046 [M+Na]+; found 265.1047.
4.5. 1,5-Anhydro-2,3:4,6-di-O-isopropylidene-D-lyxo-hex-1-enitol (3f):
Methods A and E: Following Method A, substrate 1f (521 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following modified Method E, the crude chloride 2f was
reacted with t-BuOK (561 mg, 5 mmol) for 30 min at 0 ˚C and then for 30 min at room temperature. Isolated
yield 176 mg (36%).
Isolation: The product 3f was purified by column chromatography on silica gel Hexane/EtOAc 15:1 + 1%
Et3N) and obtained in the form of a colorless oil. Rf = 0.47 (Hexane/EtOAc 2:1); [α]20 = + 65.4 (c = 0.3 in
D
acetone); 1H NMR (401 MHz, Acetone-d6): δ = 6.23 (d, J1,3 = 2.3 Hz, 1H; H-1), 4.67 (ddd, J3,4 = 4.3 Hz, J3,1
2.3 Hz, J3,5 = 0.8 Hz, 1H; H-3), 4.49 (dd, J4,3 = 4.3 Hz, J4,5 = 1.6 Hz, 1H; H-4), 4.15 (dd, Jgem = 12.6 Hz, J6a,5
=
=
1.7 Hz, 1H; H-6a), 3.83 (dd, Jgem = 12.6 Hz, J6b,5 = 2.0 Hz, 1H; H-6b), 3.64 (dddd, J5,6b = 2.0 Hz, J5,6a = 1.7
Hz, J5,4 = 1.6 Hz, J5,3 = 0.8 Hz, 1H; H-5), 1.48 (s, 3H; C(CH3)2), 1.43 (s, 3H; C(CH3)2), 1.37 (s, 3H; C(CH3)2),
1.30 (s, 3H; C(CH3)2); 13C NMR (101 MHz, Acetone-d6): δ = 133.69 (C-2), 122.30 (C-1), 112.52 (C(CH3)2),
98.88 (C(CH3)2), 71.70 (C-3), 66.30 (C-5), 64.03 (C-4), 63.52 (C-6), 29.58 (C(CH3)2), 26.40 (C(CH3)2), 26.20
(C(CH3)2), 18.99 (C(CH3)2); IR (CHCl3): ṽ = 2990, 2939, 2905, 2867, 1614, 1458, 1382, 1374, 1333, 1233,
1146, 1086, 1041, 1028, 854, 516 cm-1; MS (ESI): m/z = 265.1 [M+Na]+; HRMS (ESI): m/z calcd for
C12H18O5Na: 265.1043 [M+Na]+; found 265.1046.
4.6. 1,5-Anhydro-2,3,6-tri-O-benzyl-4-O-(2′,3′,4′,6′-tetra-O-benzyl-β-
enitol (3g):
D-galactopyranosyl)-D-arabino-hex-1-
Methods A and D: Following Method A, substrate 1g (1.95 g, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and pyridine (258 µL, 3.2 mmol). Then, following Method D, the crude chloride 2g was reacted
with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 1.3 g (68%).
Isolation: The product 3g was purified by column chromatography on silica gel Hexane/EtOAc 5:1) and
obtained in the form of a colorless oil. The characterization data were consistent with the literature. [12,62] Rf
= 0.23 (Hexane/EtOAc 10:1); [α]20D = - 8.2 (c = 0.2 in CHCl3); 1H NMR (401 MHz, Chloroform-d): δ = 7.36
15

– 7.21 (m, 35H; Ar-H), 6.28 (d, J1,3 = 1.3 Hz, 1H; H-1), 4.95 (d, Jgem = 11.6 Hz, 1H; CH2Ph), 4.85 (d, Jgem
=
10.7 Hz, 1H; CH2Ph), 4.76 (d, Jgem = 11.9 Hz, 1H; CH2Ph), 4.74 – 4.63 (m, 6H; CH2Ph), 4.61 (d, Jgem = 11.6
Hz, 1H; CH2Ph), 4.51 (d, Jgem = 12.1 Hz, 1H; CH2Ph); 4.49 (d, J1',2' = 7.7 Hz, 1H; H-1'), 4.45 (d, Jgem = 12.1
Hz, 1H; CH2Ph), 4.39 (d, Jgem = 11.7 Hz, 1H; CH2Ph), 4.34 (d, Jgem = 11.7 Hz, 1H; CH2Ph), 4.34 – 4.29 (m,
1H; H-5), 4.28 (dd, J3,4 = 3.2 Hz, J3,1 = 1.3 Hz, 1H; H-3), 4.19 (dd, J4,3 = 3.2 Hz, J4,5 = 3.5 Hz, 1H; H-4), 3.88
(d, J = 2.9 Hz, 1H; H-4'), 3.83 (dd, J6a,6b = 10.6 Hz, J6a,5 = 7.1 Hz, 1H; H-6a), 3.79 (dd, J2',3' = 9.8 Hz, J2',1'
=
7.7 Hz, 1H; H-2'), 3.62 (dd, J6b,6a = 10.6 Hz, J6b,5 = 4.2 Hz, 1H; H-6b), 3.57 – 3.43 (m, 4H; H-3', H-5', H-6'a,
13
H-6'b); C NMR (101 MHz, Chloroform-d): δ = 138.8, 138.7, 138.3, 137.9 (Ar-Cipso), 137.8 (C-2), 137.5
(Ar-Cipso), 128.6, 128.5, 128.5, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.2, 128.1 (Ar-C), 128.0 (C-1),
128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.7, 127.7, 127.5 (Ar-C), 103.2 (C-1'), 82.3 (C-3'), 79.3 (C-2'),
75.3 (CHPh), 75.0 (C-5), 74.8 (CHPh), 73.9 (C-3), 73.7 (C-4), 73.7 (CHPh), 73.6 (C-4'), 73.5 (C-5'), 73.3
(CHPh), 73.2 (CHPh), 70.0 (CHPh), 71.2 (CHPh), 68.8 (C-6'), 67.9 (C-6); IR (CHCl3): ṽ = 3090, 3067, 3033,
1605, 1586, 1497, 1454, 1158, 1093, 1076, 1076, 1028, 983, 912, 699, 461 cm-1; MS (ESI): m/z = 977.4
[M+Na]+; HRMS (ESI): m/z calcd for C61H62O10Na: 977.4235 [M+Na]+; found 977.4237.
4.7. 1,4-Anhydro-2,3,5-tri-O-benzyl-D-erythro-pent-1-enitol (3h):
From 1h:
Methods B and D: Following Method B, substrate 1h (841 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and 2,6-lutidine (371 µL, 3.2 mmol). Then, following Method D, the crude chloride 2h was
reacted with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 192 mg (24%).
Methods B and E: Following Method B, substrate 1h (841 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and 2,6-lutidine (371 µL, 3.2 mmol). Then, following Method E, the crude chloride 2h was
reacted with t-BuOK (561 mg, 5 mmol). Isolated yield 602 mg (75%).
From 1i:
Methods B and D: Following Method B, substrate 1h (841 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and 2,6-lutidine (371 µL, 3.2 mmol). Then, following Method D, the crude chloride 2h was
reacted with NaH (400 mg, 10 mmol, 60% suspension in mineral oil). Isolated yield 66 mg (8%).
Methods B and E: Following Method B, substrate 1h (841 mg, 2 mmol) was reacted with triphosgene (297
mg, 1 mmol) and 2,6-lutidine (371 µL, 3.2 mmol). Then, following Method E, the crude chloride 2h was
reacted with t-BuOK (561 mg, 5 mmol). Isolated yield 32 mg (4%).
Isolation: The product 3h was purified by column chromatography on silica gel (Hexane/EtOAc 15:1 + 1%
Et3N) and obtained in the form of a colorless oil. The characterization data were consistent with the literature.
[20] Rf = 0.43 (Hexane/EtOAc 6:1); [α]20D = + 59.3 (c = 0.2 in CHCl3); 1H NMR (401 MHz, Chloroform-d):
δ = 7.39 – 7.27 (m, 15H; Ar-H), 6.19 (d, J1,3 = 0.8 Hz, 1H; H-1), 4.79 (d, Jgem = 11.4 Hz, 1H; CH2Ph), 4.73 (d,
16

J
gem = 11.4 Hz, 1H; CH2Ph), 4.71 (d, Jgem = 12.0 Hz, 1H; CH2Ph), 4.67 (dd, J3,4 = 3.3 Hz, J3,1 = 0.8 Hz, 1H; H-
3), 4.58 (d, Jgem = 12.1 Hz, 1H; CH2Ph), 4.54 (d, Jgem = 12.2 Hz, 1H; CH2Ph), 4.52 (ddd, J4,5a = 6.2 Hz, J4,5b
=
5.8 Hz, J4,3 = 3.3 Hz, 1H; H-4), 3.56 (dd, Jgem = 10.2 Hz, J5a,4 = 6.2 Hz, 1H; H-5a), 3.42 (dd, Jgem = 10.2 Hz,
13
J5b,4 = 5.8 Hz, 1H; H-5b); C NMR (101 MHz, DMSO-d6): δ = 140.84 (C-2), 138.38 (Ar-Cipso), 138.13 (Ar-
Cipso), 136.85 (Ar-Cipso), 128.38, 128.29, 128.22, 127.91, 127.67, 127.62, 127.57, 127.54, 127.44 (Ar-C),
127.28 (C-1), 82.62 (C-4), 80.74 (C-3), 72.32 (CH2Ph), 71.74 (CH2Ph), 69.64 (C-5), 69.38 (CH2Ph); IR
(CHCl3): ṽ = 3113, 3090, 3067, 3033, 2931, 2867, 1667, 1606, 1587, 1497, 1454, 1364, 1310, 1289, 1157,
1099, 1073, 1028, 912, 853, 699 cm-1; MS (ESI): m/z = 425.2 [M+Na]+; HRMS (ESI): m/z calcd for
C26H26O4Na: 425.1722 [M+Na]+; found 425.1723.
Acknowledgments
This work was supported by financial support from specific university research (MSMT No. 21-SVV/2019).
We also appreciate the support from Gilead Sciences, Inc., provided under the program “Molecules for Life”
at the Gilead Sciences & IOCB Prague Research Centre.
Dedication
Dedicated to the memory of Prof. Jitka Moravcová.
Supplementary Material
Supplementary Material containing additional experimental data can be found at the online version of this
article.
References and notes
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23

Highlights
•
2-Hydroxyglycals were synthesized via chlorination-dehydrochlorination of carbohydrate
hemiacetals.
•
•
•
•
Simple synthetic protocol, gram-scale amounts.
Aprotic conditions were utilized, allowing for the use of acid-sensitive substrates.
Both 1,2-cis and 1,2-trans glycosyl chlorides provide 2-hydroxyglycals after elimination.
Piperidine was used as a temporary anomeric protecting group of lactose.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: