A metal free mild and green approach for tandem opening of 4,6-O-benzylidene acetals to their corresponding 6-O-acetyl derivatives: Application in the synthesis of a trisaccharide using one-pot glycosylation reactions

Article abstract of DOI:10.1016/j.carres.2019.03.002

An efficient and high yielding reaction for tandem opening of 4,6-O-benzylidene derivatives (gluco, galacto, manno, 2-phthalimido-2-deoxy glucosides) to their corresponding 6-O-acetyl derivatives has been established under metal free condition using 60% solution of aqueous acetic acid (v/v). The reaction is equally pertinent for large scale synthesis and also for disaccharide glycosides. Its application for the construction of a building block towards synthesis of a trisaccharide part related to Pseudomonas aeruginosa utilizing one-pot glycosylation reactions has also been described.

Full text of DOI:10.1016/j.carres.2019.03.002

Accepted Manuscript
A metal free mild and green approach for tandem opening of 4,6-O-benzylidene
acetals to their corresponding 6-O-acetyl derivatives: Application in the synthesis of a
trisaccharide using one-pot glycosylation reactions
Mana Mohan Mukherjee, Nabamita Basu, Shantanu Nandi, Rina Ghosh
PII:
S0008-6215(19)30033-3
https://doi.org/10.1016/j.carres.2019.03.002
CAR 7684
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 19 January 2019
Revised Date: 4 March 2019
Accepted Date: 4 March 2019
Please cite this article as: M.M. Mukherjee, N. Basu, S. Nandi, R. Ghosh, A metal free mild and green
approach for tandem opening of 4,6-O-benzylidene acetals to their corresponding 6-O-acetyl derivatives:
Application in the synthesis of a trisaccharide using one-pot glycosylation reactions, Carbohydrate
Research (2019), doi: https://doi.org/10.1016/j.carres.2019.03.002.
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ACCEPTED MANUSCRIPT
A metal free mild and green approach for
regioselective tandem opening of 4,6-O-benzylidene
acetals to their corresponding 6-O-acetyl derivatives:
Application in the synthesis of a trisaccharide using
one-pot glycosylation reactions
Mana Mohan Mukherjee, Nabamita Basu, Shantanu Nandi and Rina Ghosh
A highly regioselective tandem opening of mono- and di-saccharide based 4,6-O-benzylidene
derivatives under metal free condition has been developed towards their corresponding 6-O-
acetyl derivatives in excellent yields using 60 % solution of aqueous acetic acid (v/v). Its
application for the construction of a block building towards synthesis of a trisaccharide related to
Pseudomonas aeruginosa has also been described.

ACCEPTED MANUSCRIPT
A metal free mild and green approach for tandem opening of 4,6-O-
benzylidene acetals to their corresponding 6-O-acetyl derivatives:
Application in the synthesis of a trisaccharide using one-pot glycosylation
reactions
Mana Mohan Mukherjee,a,c Nabamita Basu,b Shantanu Nandia and Rina Ghosha*
aDepartment of Chemistry, Jadavpur University, Jadavpur, Kolkata, 700032, West Bengal,
India.
b Department of Chemistry, Nabagram Hiralal Paul College, Konnagar, Hoogly, West Bengal
- 712246, India.
c Currently at Section on Carbohydrate Chemistry, Laboratory of Bioorganic Chemistry,
NIDDK, National Institutes of Health, Bethesda, MD, USA.
E-mail: ghoshrina@yahoo.com; rina.ghosh@jadavpuruniversity.in
Abstract
An efficient and high yielding reaction for tandem opening of 4,6-O-benzylidene derivatives
(gluco, galacto, manno, 2-phthalimido-2-deoxy glucosides) to their corresponding 6-O-acetyl
derivatives has been established under metal free condition using 60 % solution of aqueous
acetic acid (v/v). The reaction is equally pertinent for large scale synthesis and also for
disaccharide glycosides. Its application for the construction of a building block towards
synthesis of a trisaccharide part related to Pseudomonas aeruginosa utilizing one-pot
glycosylation reactions has also been described.
Keywords
Opening of 4,6-O-Benzylidene acetals; 6-O-Acetyl derivatives; Carbohydrate; One-pot
Glycosylation; Trisaccharide
1

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1. Introduction
It is well accepted that carbohydrates in general play immense importance in living
processes; in addition the monosaccharides are also considered to be inexpensive chiral pools
for the synthesis of many optically pure biologically significant target compounds [1].
Towards the synthesis of value added intermediates and building blocks, monosaccharides
require efficient protecting group manipulations under mild and environmentally sustainable
conditions, and it remains a permanent challenge in organic synthesis utilizing carbohydrates
[2]. Because of their easy preparation and to a wide range of chemical tolerance, the 4,6-O-
benzylidene acetals are widely used protecting groups of sugars [3]. Reductive opening of the
carbohydrate 4,6-O-benzylidene acetals, producing benzyl ether at either the C-4 or C-6
position, have been explored in literature previously [4]. A relatively less frequent
investigation has been performed on selective cleavage of 4,6-O-benzylidene acetals under
oxidative condition towards formation of the corresponding 4-O-benzoyl or 6-O-benzoyl
derivatives [5]. We report herein a green tandem route for the opening of 4,6-O-benzylidene
acetals towards their 6-O-acetyl derivative with the 4-hydroxy group free; so far literature
report on this ground is still unknown. Simple treatment with 60 % aqueous solution of acetic
acid (v/v) without use of any metal source was sufficient for this purpose. This type of
selective opening is of immense importance as the resulting product can be used as glycosyl
acceptor, or suitable protection of the remaining 4-hydroxy group can lead us to orthogonally
protected glycosyl donor. The effect of strong electron withdrawing properties of remote
substituent, particularly those at C-6, has been known for a while. There have been numbers
of reports describing long-range 6-O-acyl or carbonate group assisted synthesis of α-
glycosides and also in opposition of the idea of remote participation [6]. The assistance of
such substituent on 1,2-cis glycosylation was accredited to shielding (steric or electronic) of
2

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the top face of the ring, blocking the β face of oxocarbenium ion and thereby favouring
nucleophilic attack at the anomeric carbon from the opposite face [7].
2. Results and Discussion
In our synthetic endeavour on glycoscience, specially during synthesis of glycoconjugate
related to the strain of E. coli O120, in order to prepare suitable glycosyl donor or acceptor,
we needed to open the 4,6-O-benzylidene ring [8] to prepare the corresponding 4,6-di
hydroxy compound, and we came across a serendipitous observation during this process.
Thus, when phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside (1a,
Table 1, Fig. 1) was subjected to 4,6-O-benzylidene ring opening reaction using traditional
procedure of 80% aqueous acetic acid (v/v) at 80 oC [9]; to ensure a complete conversion, the
allowed reaction time exposure was 8 hours, which was much higher than the usual reaction
time. To our surprise the newly formed spot found on the TLC was at much higher Rf than the
1
expected one. The H NMR spectrum showed one sharp singlet peak corresponding to 3
hydrogens at 2.12 ppm (s, 3H, COCH3), 2 hydrogen multiplate at 4.32-4.56 (m, 2H, H6, H6')
and 1 hydrogen broad singlet at 2.56 (brs, 1H, OH), and peaks at 20.9 (CH3) and 171.4 (C=O)
Table 1
Standardisation of reaction condition.
1a→1b
Entry
% of aqueous Temperature Time Isolated
acetic acid (v/v)
(oC)
80
80
80
80
100
80
80
rt
(h) Yield (%)
1
2
3
4
5
6
7
8
9
80
80
80
80
80
60
60
60
60
40
8
67
74
80
78
54
87
85
--a
--a
63
12
16
20
16
16
20
16
72
20
rt
80
10
a No desired product was formed.
3

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ppm in the 13C NMR spectrum led us to the presumption for the formation of the
corresponding phenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-glucopyranoside derivative
(1b) in 67% yield. After few trial reactions (Table 1, Fig. 1) the best result was obtained
when the reaction was carried out with 60% aqueous acetic acid (v/v) for 16 hours (87%)
(Table 1, entry 6).
Starting Materials
OBn
O
O
O
O
O
BnO
Ph
O
O
Ph
Ph
O
Ph
O
O
O
O
SPh
OBn
STol
STol
OBn
BnO
HO
BnO
2a
OH
1a
3a
4a
SPh
Ph
Ph
O
Ph
O
O
O
O
O
Ph
O
O
O
O
BzO
O
O
O
BzO
STol
SPh
OMe
SPh
BnO
5a
BnO
OMe
BnO
6a
OBn
OBn
8a
7a
Ph
Ph
O
Ph
O
O
O
O
O
O
O
Ph
O
O
OAll
O
BzO
OMP
OAll
NPhth
12a
STol
BnO
BzO
BzO
NPhth
11a
OBn
9a
OBz
10a
O
O
O
Ph
BnO
O
O
BnO
BnO
O
Ph
O
O
BnO
SPh
OBn
BnO
BnO
O
OBn
O
SPh
BnO
14a
13a
OBn
Products
OBn
O
AcO
HO
BnO
AcO
HO
BnO
O
AcO
HO
HO
AcO
HO
BnO
SPh
O
O
STol
STol
OBn
OBn
1b
2b
OH
3b
SPh
4b
OAc
OAc
HO
OAc
HO
AcO
HO
HO
O
O
O
BzO
SPh
O
STol
BnO
SPh
OMe
BnO
BzO
BnO
5b
OBn
7b
OBn
OMe
6b
8b
OAc
OAc
OAc
HO
HO
HO
AcO
HO
O
O
O
O
OAll
OMP
OAll
NPhth
BzO
BnO
STol
OBz
BzO
BzO
NPhth
11b
OBn
9b
12b
10b
OAc
O
OAc
BnO
O
HO
O
O
BnO
BnO
HO
SPh
OBn
BnO
BnO
BnO
OBn
O
O
14b
SPh
13b
BnO
OBn
4

ACCEPTED MANUSCRIPT
Fig. 1. Starting materials and products.
Table 2
Opening of 4,6-O-benzylidene acetalsa.
Entry Starting Product
Material
Isolated
Yield (%)
87 (81)
83
82 (78)
84
Entry Starting Product Isolated
Material
Yield (%)
88 (84)
83
1
2
3
4
5
6
7
8
9
1a
2a
3a
4a
5a
6a
7a
1b
2b
3b
4b
5b
6b
7b
8a
9a
8b
9b
10
11
12
13
14
82
84
10a
11a
12a
13a
14a
10b
11b
12b
13b
14b
78
87
85
80
76b
72b
a All reactions were carried out with 60% of aqueous acetic acid (v/v) at 80 oC for 16 hours;
b Reaction was performed under similar condition for 20 hours.
To corroborate with our presumption towards formation of 6-OAc, 4-OH derivative, we
thought to carry out the reaction with phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-α-D-
mannopyranoside (2a, Fig. 1) under previously standardized condition, then characterizing
the product (spectral analysis) and comparing that with the literature reported characterization
data, it was confirmed that the corresponding product formed was phenyl 6-O-acetyl-2,3-di-
O-benzyl-1-thio-α-D-mannopyranoside 2b [10] (Table 2, entry 2, Fig. 1).Under this
standardized condition a number of 4,6-O-benzylideneted derivatives were subjected towards
selective opening of the benzylidene ring. Various 4,6-O-benzylidene derived thioglycosides
underwent smooth conversion towards their corresponding 6-O-acetyl derivatives. Thus, p-
methylphenyl 4,6-O-benzylidene-1-thio-β-D-glucopyranoside (3a) produced p-methylphenyl
6-O-acetyl-1-thio-β-D-glucopyranoside 3b [11] in 82% yield, p-methylphenyl 2,3-di-O-
benzyl-4,6-O-benzylidene-1-thio-β-D-glucopyranoside 4a yielded 84% of p-methylphenyl 6-
O-acetyl-2,3-di-O-benzyl-1-thio-β-D-glucopyranoside 4b, whereas its galactoside analogue
5

ACCEPTED MANUSCRIPT
6a furnished 87% of the desired product 6b [11] (Table 2, entries 3, 4 and 6, Fig. 1). Phenyl
2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-galactopyranoside
7a
generated
the
corresponding product phenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-galactopyranoside 7b
[12] in 85% yield (Table 2, entry 7, Fig. 1). 4,6-O-Benzylidene ring opening of phenyl 3-O-
benzyl-4,6-O-benzylidene-2-O-methyl-1-thio-β-D-galactopyranoside 8a and p-methylphenyl
2,3-di-O-benzoyl-4,6-O-benzylidene-1-thio-β-D-galactopyranoside 10a produced their
corresponding 6-O-acetyl derivatives 8b and 10b in 88% and 82% respective yields (Table 2,
entries 8 and 10, Fig. 1). Large scale ramifications (5 mmol scale) with the substrates 1a, 3a
and 8a furnished the corresponding products 1b, 3b and 8b in 81%, 78% and 84% respective
yield (Table 2, entries 1, 3 and 8, Fig. 1), which is almost comparable with the pilot reactions
and hence in this process can be used for the preparation of suitable substrate in preparative
scale too.
Along with the S-glycosides various 4,6-O-benzylidenated O-glycosides of glucose and
galactose substrates were exemplified under this ring opening reaction condition. Methyl 2,3-
di-O-benzoyl-4,6-O-benzylidene-α-D-glucopyranoside 5a generated the corresponding
methyl-6-O-acetyl-2,3-di-O-benzoyl-α-D-glucopyranoside 5b [13] in 78% yield and p-
methoxyphenyl 2,3-di-O-benzyl-4,6-O-benzylidene-β-D-galactopyranoside 9a yielded 83%
of p-methoxyphenyl 6-O-acetyl-2,3-di-O-benzyl-β-D-galactopyranoside 9b (Table 2, entries
5 and 9, Fig. 1). Allyl 3-O-benzoyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-
glucopyranoside 11a was converted to allyl 6-O-acetyl-3-O-benzoyl-2-deoxy-2-phthalimido-
β-D-glucopyranoside 11b in 84% yield whereas the reaction akin to its galactose analogue
12a produced 80% of 12b (Table 2, entries 11 and 12, Fig. 1).Then 4',6'-O-benzylidene
derivatives of disaccharide glycosides like cellobiose and maltose were subjected to this ring
opening reaction. For these disaccharide derivatives required time for the selective removal
of 4',6'-O-benzylidene ring was little higher than that of the monosaccharides. After 20 hours
6

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phenyl 6-O-acetyl-2,3-di-O-benzyl-β-D-glucopyranosyl (1→4)-2,3,6-tri-O-benzyl-1-thio-α-
D-glucopyranoside 13b and phenyl 6-O-acetyl-2,3-di-O-benzyl-β-D-glucopyranosyl(1→4)-
2,3,6-tri-O-benzyl-1-thio-β-D-glucopyranoside 14b were obtained in 76% and 72% yields,
respectively (Table 2, entries 13 and 14, Fig. 1).
To understand the mechanistic pathway a few controlled experiments were also undertaken.
To check the remote possibility of formation of the 6-acetate from an intermediate diol in
60% aqueous acetic acid, three other reactions were carried out under the standardized
reaction condition, including phenyl 2,3-di-O-benzyl-1-thio-β-D-glucopyranoside, glycerol
and erythritol, but in no case a primary O-acetylation product could be identified even after
24 hours (unpublished results). Thus, probably the following mechanistic pathway may be
operative. The reaction is initiated by protonation on C-6 oxygen of the 4,6-O-benzylidene
acetal generating a C-6 OH and an oxonium ion intermediate at C-4. Consecutive attack at
the electrophilic carbon of the oxonium ion by the acetate anion followed by subsequent
transfer of the acetate to the C-6 position, and then hydrolysis finally affords the 6-OAc
product.
After successful conversion of numbers of 4,6-O-benzylidene derivatives towards their
corresponding 6-O-acetyl,4-hydroxyl derivatives we turned our attention for the application
of this process to synthesise a suitable glycosyl acceptor and for its utilization in the synthesis
of a trisaccharide via one-pot sequential glycosylation reactions. For this purpose the
synthesis of the trisaccharide derivative (Fig. 2) related to the pentasaccharide repeating unit
present in the outer core of Pseudomonas aeruginosa was chosen [14]. P. aeruginosa is an
opportunistic pathogen which is the major cause of various infections in natural defense or
immuno-compromised human body. It induces eye, ear, respiratory system, intra-abdominal,
bloodstream, urinary tract, skin and soft tissue infections. P. aeruginosa mostly causes the
infection after hospitalization of a patient. It can grow on a broad spectrum of nutrients and
7

ACCEPTED MANUSCRIPT
survives in hospital drains, sinks and even in disinfectant solutions. It causes cornea
infections (keratitis) to patients who have suffered from corneal injury caused by contact
lenses. It is also the main cause of hospital-acquired pneumonia in mechanically ventilated
patients such as cystic fibrosis, burn, AIDS or cancer affected individuals [15].
P. aeruginosa is inherently resistant to a large number of antibiotics and has the ability to
acquire resistance from the host immune system or other antibiotics by biofilm formation
[16]. Due to its high growth factor and resistance towards antibiotics, P. aeruginosa
infections are extremely difficult to control and have a very high mortality rate. During the
past decade, search for vaccines against P. aeruginosa has led to prolonged research on
conjugate vaccine comprising of proteins and/or carbohydrates or DNA vaccines [17] that
could work as ammunitions for protection of the patients.
OTCA
OBz
O
OBn
OBn
O
BnO
OH
BnO
OBz
O
16
BnO
BnO
O
O
BnO
BnO
STol
17
BnO
OBn
BnO
OBn
O
OH
AcO
15
O
O
OMP
NPhth
AcO
OMP
18
NPhth
Fig. 2. Retrosynthetic analysis of target trisaccharide 15.
To synthesize the fully protected trisaccharide repeating unit 15 presents in the outer core of
P. aeruginosa, as its β-p-methoxyphenyl glycoside, a one-pot sequential glycosylation
strategy was envisioned. Retrosynthetic analysis of 15 led us to three building blocks likely
2-O-benzoyl-3,4-di-O-benzyl-L-rhamnosyl trichloroacetimidate 16 [8g] as glycosyl donor, p-
methylphenyl 2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside 17 as orthogonally protected
thioglycoside acceptor and p-methoxyphenyl3-O-acetyl-6-O-benzyl-2-deoxy-2-phthalimido-
β-D-galactopyranoside18 [18], as the reducing end acceptor (Fig. 2).
8

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The monomeric building blocks 16 and 18 were synthesized according to the literature
reported procedures. The synthesis of 17 was performed starting from commercially available
D-glucose (Scheme 1). D-glucose was converted to p-methylphenyl 4,6-O-benzylidene-thio-
β-D-glucopyranoside 3a according to a literature reported process [3c]. Compound 3a was
subjected to acetic acid mediated 4,6-O-benzylidene ring opening reaction under our
standardized reaction condition to produce p-methylphenyl 6-O-acetyl-1-thio-β-D-
glucopyranoside 3b [11] followed by benzylation of the three hydroxy groups in the presence
of 6-O-acetyl group using benzyl 2,2,2-trichloroacetimidate [19], TMSOTf in dry THF,
which furnished p-methylphenyl 6-O-acetyl-2,3-4-tri-O-benzyl-1-thio-β-D-glucopyranoside
19 [20] in 87% yield over 2 steps. Zemplén deacetylation of compound 18 generated our
desired thioglycoside acceptor 17 [21] in almost quantitative yield (Scheme 1). Comparing its
spectral data with the corresponding reported data, and then crystal structure analysis of
compound 17 (CCDC No. 1584216) confirmed the formation of the desired product side by
side also indirectly the structure of 3b (Fig. 1), the product of the present 4,6-O-
debenzylidenation ring opening reaction of 3a.
Ref 3c
O
HO
AcO
HO
OH
O
Ph
O
a
O
D-Glucose
STol
STol
OH
OH
3a
3b
b
OH
AcO
BnO
BnO
O
O
BnO
BnO
c
STol
OBn
STol
OBn
17
19
Reagents and conditions:
a) 60% (v/v) aq. Acetic acid, 16 h, 78%;
b) Benzyl trichloroacetimidate, TMSOTf, THF,
4 Å MS, rt, 81%; c) NaOMe, MeOH, 94%.
ORTEP diagram
of compound 17
(CCDC NO 1584216)
Scheme 1. Synthesis of glucose based building block 17.
9

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After having the present set of donor and acceptors in hand we applied a one-pot
glycosylation technique to prepare the targeted trisaccharide. Glucose based orthogonal
acceptor 17 was glycosylated with rhamnopyranosyl trichloroacetimidate donor 16 (-60 oC to
room temperature) using 10 mol% of FeCl3 [8f]. After complete consumption of the starting
materials (checked by TLC), the second acceptor 18 followed by a thioglycoside activator, N-
phenylthio-ε-caprolactum [22], were added into the same reaction vessel. The reaction
o
mixture was then allowed to reach 0 C, and 1 equivalent Tf2O was added; TLC after 10
minutes showed complete consumption of starting materials with formation of a new
prominent spot. After usual work-up the desired trisaccharide 15 was isolated in 67% yield
(Scheme 2).
NH
OBz
O
OBn
OBn
O
OBn
HO
AcO
CCl3
O
OMP
O
O
BnO
18
NPhth
O
BnO
BnO
BnO
OBz
OH
16
BnO
OBn
O
O
15
b
a
O
BnO
STol
OMP
BnO
AcO
NPhth
Reagents and conditions:
a) FeCl3, THF, -60 oC to rt
BnO
17
67%
b) N-phenylthiocaprolactum, Tf2O, 0 oC
Scheme 2. Synthesis of trisaccharide 15 via one-pot sequential glycosylation reactions.
The formation of the trisaccharide derivative 15 was confirmed by NMR spectroscopic
1
techniques (1H-, 13C-, H-13C coupled, COSY, HSQC) and also by HRMS analysis.
Compound 15 showed anomeric proton signals, listed from the non-reducing end at δ 6.07 (d,
8.0 Hz), 5.12 (d, 3.0 Hz) and 4.75-4.79 (m), respectively, and the corresponding anomeric
carbons at δ 97.6 (173.5 Hz), 92.8 (169.7 Hz) and 98.1 (170.9 Hz). The observed NMR
spectral data indicate the presence of one β-linked galactosamine, one α-linked
glucopyranose and one α-linked rhamnopyranose residue in 15.
10

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3. Conclusion
In summery we have developed an efficient and green 4,6-O-benzylidene tandem ring
opening procedure towards its 6-O-acetyl, 4-hydroxy derivative modulated by 60% aqueous
acetic acid (v/v). We have utilized this process towards the construction of a building block
for the synthesis of a trisaccharide adopting one-pot sequential glycosylation reactions.
Advantages of the present 4,6-O-benzylidene acetal tandem ring opening protocol lies in its
high yield, operational simplicity, exclusive selectivity towards formation of 6-acetate, and
applicability both in case of mono and disaccharides, and also for preparative scale.
Precluding the use of any metal salt but of environmentally benign acid makes this tandem
4,6-O-benzylidene acetal opening methodology toward the corresponding 6-acetate, a green
one. Ramification of this procedure towards the total synthesis of other oligosaccharides is
underway for future publications.
4. Experimental
4.1. General procedure
All reactions were performed in flamed-dried flasks fitted with rubber septa under a positive
pressure of argon, unless otherwise stated. THF was refluxed with metalic sodium and
distilled before use and stored over 4Å molecular sieves. Traces of water in the starting
materials were removed by co-evaporation with toluene. Flash column chromatography was
performed employing Silica Gel 60 Sorbent (40-63 µm, 230-400 mesh). Thin-layer
chromatography (analytical and preparative) was performed using Merck silica gel plates
(60-F254) to monitor the reactions and visualised under UV (254 nm) and/or by charring with
5% ethanolic solution of sulfuric acid. NMR spectra were recorded on a Bruker DPX-300
(300 MHz) and a Bruker DPX-500 (500 MHz), spectrometer at ambient temperature in
CDCl3 and assigned using 2D-methods (COSY, HSQC). Optical rotations were measured
11

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using Jasco P-1020 digital polarimeter. High Resolution Mass Spectra (HRMS) were
measured in a QTOF I (quadrupole-hexapole-TOF) mass spectrometer with an orthogonal Z-
spray-electrospray interface on Micro (YA-263) mass spectrometer (Manchester, UK).
4.2. General Experimental procedure
Starting material (0.5 mmol) was treated with 60% (v/v) aqueous acetic acid (25 mL, 125 mL
for 5 mmol) at 80 °C for required time (checked by TLC). This was diluted with ethyl acetate
(EA) and washed subsequently with water (500 mL), NaHCO3 solution (200 mL). The
organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum to furnish
crude product. Purification of the crude product by silica gel column chromatography yielded
the corresponding 6-O-acetyl derivative.
4.3. Phenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-glucopyranoside (1b):
Pure product was isolated as white solid following elution of the column with 33% EA/PE.;
Yield 213 mg, 87% (Starting from 270 mg, 0.5 mmol; 1.97 g, 81%, starting from 2.7 g, 5
mmol).; Mp: (EA/PE) 80-82 oC. [α]25D =-34.3 (c 1.13, CHCl3). 1H-NMR (300 MHz, CDCl3):
δ 2.12 (s, 3H, COCH3), 2.56 (brs, 1H, OH), 3.46-3.53 (m, 4H, H2, H3, H4, H5), 4.32-4.56 (m,
2H, H6, H6'), 4.70 (d, 1H, J = 9.2 Hz, H1), 4.76 (d, 1H, J = 10.3 Hz, BnH), 4.78 (d, 1H, J =
11.3 Hz, BnH), 4.95 (d, 1H, J = 11.3 Hz, BnH), 4.97 (d, 1H, J = 10.2 Hz, BnH), 7.28-7.46
(m, 13H, ArH), 7.57-7.60 (m, 2H, ArH). 13C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3), 63.5,
70.0, 75.4, 75.6, 80.6, 85.9, 87.7 (C1), 127.7, 127.9, 128.0, 128.1, 128.3, 128.5, 128.7, 128.9,
132.1, 133.6, 137.9, 138.3, 171.4 (C=O). HRMS (ESI-TOF): Calculated for C28H30O6SNa
(M+Na) 517.1661 found 517.1674.
4.4. Phenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-α-D-mannopyranoside (2b):10
Pure product was isolated as colourless syrup following elution of the column with 33%
EA/PE.; Yield 205 mg, 83% (Starting from 270 mg, 0.5 mmol). [α]25 = +27.6 (c 1.05,
D
12

ACCEPTED MANUSCRIPT
1
CHCl3), lit10 [α]20 = +27.0 (c 1.00, CHCl3). H-NMR (300 MHz, CDCl3): δ 2.08 (s, 3H,
D
COCH3), 3.71 (dd, 1H, J = 3.1, 9.4 Hz, H3), 4.01-4.07 (m, 2H, H2, H4), 4.28-4.33 (m, 1H,
'
H5), 4.34-4.51 (m, 2H, H6, H6 ), 4.55-4.63 (m, 3H, BnH), 4.72 (d, 1H, J = 12.2 Hz, BnH),
5.65 (s, 1H, H1), 7.30-7.41 (m, 13H, ArH), 7.47-7.51 (m, 2H, ArH). 13C-NMR (75 MHz,
CDCl3): δ 20.8 (COCH3), 63.6, 66.8, 71.6, 71.9, 71.96, 75.5, 79.4, 85.7 (C1), 127.6, 127.9,
127.94, 128.0, 128.1, 128.4, 128.6, 129.1, 131.6, 133.9, 137.7, 171.2 (C=O). HRMS (ESI-
TOF): Calculated for C28H30O6SNa (M+Na) 517.1661 found 517.1658.
4.5. p-Methylphenyl 6-O-acetyl-1-thio-β-D-glucopyranoside (3b):11
Pure product was isolated as white solid following elution of the column with 75% EA/PE.;
Yield 135 mg, 82% (Starting from 187 mg, 0.5 mmol; 1.28 g, 78%, starting from 1.87 g, 5
o
mmol). Mp (EA/PE) 102-104 C, lit11 Mp 104 °C. [α]25D =+50.4 (c 1.08, CHCl3), lit11 [α]20
D
1
=+53.2 (c 0.92, CHCl3). H-NMR (300 MHz, CDCl3): δ 2.08 (s, 3H, COCH3), 2.32 (s, 3H,
CH3), 3.36-3.42 (m, 2H, H2, H3), 3.49-3.57 (m, 2H, H4, H5), 3.94 (brs, 3H, OH), 4.26-4.41
'
(m, 2H, H6, H6 ), 4.50 (d, 1H, J = 9.5 Hz, H1), 7.07-7.09 (d, 2H, J = 7.9 Hz, ArH), 7.41-7.43
13
(d, 2H, J = 7.9 Hz, ArH). C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3), 21.1 (CH3), 63.7,
69.9, 72.0, 77.6, 87.9 (C1), 128.5, 129.7, 132.4, 132.9, 138.1, 171.7 (C=O). HRMS (ESI-
TOF): Calculated for C15H20O6SNa (M+Na) 351.0879 found 351.0872.
4.6. p-Methylphenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-glucopyranoside (4b):
Pure product was isolated as white solid following elution of the column with 30% EA/PE.;
Yield 213 mg, 84% (Starting from 277 mg, 0.5 mmol). Mp (EA/PE) 84-86 oC. [α]25D =-28.5
1
(c 1.01, CHCl3). H-NMR (300 MHz, CDCl3): δ 2.11 (s, 3H, COCH3), 2.35 (s, 3H, CH3),
3.42-3.53 (m, 4H, H2, H3, H4, H5), 4.30-4.39 (m, 2H, H6, H6'), 4.61 (d, 1H, J = 9.4 Hz, H1),
4.74 (d, 1H, J = 10.2 Hz, BnH), 4.76 (d, 1H, J = 11.3 Hz, BnH), 4.92 (d, 1H, J = 11.1 Hz,
BnH), 4.95 (d, 1H, J = 10.2 Hz, BnH), 7.01-7.12 (d, 2H, J = 7.8 Hz, ArH), 7.30-7.49 (m,
12H, ArH). 13C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3), 21.2 (CH3), 63.5, 70.0, 75.4, 75.6,
13

ACCEPTED MANUSCRIPT
77.6, 80.5, 85.9, 87.9 (C1), 127.9, 128.0, 128.1, 128.3, 128.5, 128.7, 129.7, 129.8, 132.8,
137.9, 138.0, 138.4, 171.5 (C=O). HRMS (ESI-TOF): Calculated for C29H32O6SNa (M+Na)
531.1818 found 531.1814.
4.7. Methyl 6-O-acetyl-2,3-di-O-benzoyl-α-D-glucopyranoside (5b):13
Pure product was isolated as colourless syrup following elution of the column with 35%
EA/PE.; Yield 173 mg, 78% (Starting from 245 mg, 0.5 mmol). [α]25 =+237.5 (c 1.07,
D
1
CHCl3), lit13 [α]20 =+232 (c 1.2, CHCl3). H-NMR (300 MHz, CDCl3): δ 2.17 (s, 3H,
D
COCH3), 3.45 (s, 3H, OCH3), 3.83 (app t, 1H, J = 9.3, 9.7 Hz, H4), 4.01 (m, 1H, H5), 4.42
'
(dd, 1H, J = 2.1, 12.3 Hz, H6), 4.53 (dd, 1H, J = 4.4, 12.3 Hz, H6 ), 5.14 (d, 1H, J = 3.6 Hz,
H1), 5.27 (dd, 1H, J = 3.6, 10.2 Hz, H2), 5.77 (app t, 1H, J = 9.3, 9.9 Hz, H3), 7.36-7.41 (m,
13
4H, ArH), 7.49-7.55 (m, 2H, ArH), 7.98-8.00 (m, 4H, ArH). C-NMR (75 MHz, CDCl3): δ
20.9 (COCH3), 55.4 (OCH3), 63.0, 69.5, 69.8, 71.4, 73.9, 97.1 (C1), 128.4, 129.1, 129.2,
129.8, 129.9, 133.4, 165.9 (C=O), 167.3 (C=O), 171.4 (C=O). HRMS (ESI-TOF): Calculated
for C23H24O9Na (M+Na) 467.1318 found 467.1316.
4.8. p-Methylphenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-galactopyranoside (6b):11
Pure product was isolated as white solid following elution of the column with 35% EA/PE.;
Yield 220 mg, 87% (Starting from 277 mg, 0.5 mmol). Mp (EA/PE) 126-128 oC, lit11 Mp 128
°C. [α]25D =+12.3 (c 1.01, CHCl3).1H-NMR (300 MHz, CDCl3): δ 2.10 (s, 3H, COCH3), 2.36
(s, 3H, CH3), 3.58-3.66 (m 2H, H3, H5), 3.73 (t, 1H, J = 9.1 Hz, H2), 4.00 (d, 1H, J = 2.5 Hz,
'
H4), 4.35-4.40 (m, 2H, H6, H6 ), 4.58 (d, 1H, J = 9.7 Hz, H1), 4.74 (bs, 2H, BnH), 4.78 (d,
1H, J = 12.2 Hz, BnH), 4.89 (d, 1H, J = 10.3 Hz, BnH), 7.12-7.14 (d, 2H, J = 7.9 Hz, ArH),
7.33-7.42 (m, 8H, ArH), 7.44-7.48 (dd, 2H, J = 1.7, 8.2 Hz, ArH), 7.50-7.52 (d, 2H, J = 8.1
13
Hz, ArH). C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3), 21.1 (CH3), 63.4, 66.7, 72.4, 75.6,
75.8, 76.9, 82.4, 87.9 (C1), 127.8, 127.9, 128.1, 128.3, 128.4, 128.6, 129.6, 129.9, 132.6,
14

ACCEPTED MANUSCRIPT
137.6, 137.7, 138.2 170.8 (C=O). HRMS (ESI-TOF): Calculated for C29H32O6SNa (M+Na)
531.1818 found 531.1823.
4.9. Phenyl 6-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-galactopyranoside (7b):12
Pure product was isolated as white solid following elution of the column with 35% EA/PE.;
o
Yield 210 mg, 85% (Starting from 270 mg, 0.5 mmol). Mp (EA/PE) 132-134 C, lit12 Mp
135-137 °C. [α]25D =+10.4 (c 1.04, CHCl3), lit12 [α]20D =+8.1 (c 1.00, CHCl3). 1H-NMR (500
MHz, CDCl3): δ 2.00 (s, 3H, COCH3), 2.39 (brs, 1H, OH), 3.52 (dd, 1H, J = 3.5, 9.5 Hz, H5),
3.57 (t, 1H, J = 6.5 Hz, H3), 3.67 (t, 1H, J = 9.5 Hz, H3), 3.92 (brs, 1H, H4), 4.25-4.32 (m,
'
2H, H6, H6 ), 4.55 (d, 1H, J = 10.0 Hz, H1), 4.65 (bs, 2H, BnH), 4.68 (d, 1H, J = 10.5 Hz,
BnH), 4.78 (d, 1H, J = 10.5 Hz, BnH), 7.19-7.30 (m, 11H, ArH), 7.33-7.36 (d, 2H, J = 7.0
Hz, ArH), 7.52 (d, 2H, J = 6.5 Hz, ArH). 13C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3), 63.5,
66.7, 72.4, 75.7, 75.8, 76.9, 82.3, 87.7 (C1), 127.5, 127.9, 128.1, 128.3, 128.4, 128.6, 128.9,
131.9, 133.8, 137.5, 138.1, 171.8 (C=O). HRMS (ESI-TOF): Calculated for C28H30O6SNa
(M+Na) 517.1661 found 517.1664.
4.10. Phenyl 6-O-acetyl-3-O-benzyl-2-O-methyl-1-thio-β-D-galactopyranoside (8b): Pure
product was isolated as colourless syrup following elution of the column with 30% EA/PE.;
Yield 184 mg, 88% (Starting from 232 mg, 0.5 mmol; 1.75 g, 84%, starting from 2.3 g, 5
mmol). [α]25D =+48.1 (c 1.07, CHCl3). 1H-NMR (300 MHz, CDCl3): δ 2.07 (s, 3H, COCH3),
2.52 (brs, 1H, OH), 3.42-3.53 (m, 2H, H3, H5), 3.61-3.64 (m, s, 4H, H2, OCH3), 3.99 (bs, 1H,
'
H4), 4.31-4.40 (m, 2H, H6, H6 ), 4.53 (d, 1H, J = 9.1 Hz, H1), 4.70-4.78 (m, 2H, BnH), 7.28-
13
7.39 (m, 8H, ArH), 7.58-7.61 (m, 2H, ArH). C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3),
61.3 (OCH3), 63.5, 66.8, 72.4, 75.7, 77.3, 82.2, 87.4 (C1), 127.4, 127.9, 128.1, 128.5, 128.6,
128.8, 131.9, 133.8, 137.6, 138.3, 170.8 (C=O). HRMS (ESI-TOF): Calculated for
C22H26O6SNa (M+Na) 441.1348 found 441.1344.
4.11. p-Methoxylphenyl 6-O-acetyl-2,3-di-O-benzyl-β-D-galactopyranoside (9b):
15

ACCEPTED MANUSCRIPT
Pure product was isolated as white solid following elution of the column with 35% EA/PE.;
Yield 210 mg, 83% (Starting from 277 mg, 0.5 mmol). Mp (EA/PE) 96-98 oC. [α]25D =+12.9
1
(c 1.02, CHCl3). H-NMR (300 MHz, CDCl3): δ 2.11 (s, 3H, COCH3), 2.62 (bs, 1H, OH),
3.60-3.64 (m, 1H, H5), 3.74 (app t, 1H, J = 5.4 Hz, H3), 3.81 (s, 3H, OCH3), 3.94 (t, 1H, J =
'
8.5 Hz, H2), 4.01 (m, 1H, H4), 4.38-4.43 (m, 2H, H6, H6 ), 4.79-4.88 (m, 4H, BnH), 5.06 (d,
1H, J = 10.8 Hz, H1), 6.84-6.87 (d, 2H, J = 8.5 Hz, ArH), 7.05-7.08 (d, 2H, J = 8.6 Hz, ArH),
13
7.28-7.48 (m, 10H, ArH). C-NMR (75 MHz, CDCl3): δ 20.9 (COCH3), 55.7 (OCH3), 63.1,
66.6, 72.1, 72.8, 75.4, 77.3, 78.5, 80.4, 102.9 (C1), 114.5, 118.7, 127.8, 127.9, 128.1, 128.2,
128.4, 128.6, 137.7, 138.4, 151.5, 155.4, 170.8 (C=O). HRMS (ESI-TOF): Calculated for
C29H32O8Na (M+Na) 531.1995 found 531.1987.
4.12. p-Methylphenyl 6-O-acetyl-2,3-di-O-benzoyl-1-thio-β-D-galactopyranoside (10b):
Pure product was isolated as white foam following elution of the column with 33% EA/PE.;
1
Yield 222 mg, 82% (Starting from 291 mg, 0.5 mmol). [α]25D =+44.5 (c 1.07, CHCl3). H-
NMR (300 MHz, CDCl3): δ 2.10 (s, 3H, COCH3), 2.34 (s, 3H, CH3), 3.94 (m, 1H, H5), 4.30
'
(m, 1H, H4), 4.38-4.40 (m, 2H, H6, H6 ), 4.85 (d, 1H, J = 9.9 Hz, H1), 5.30 (m, 1H, H3), 5.71
(t, 1H, J = 9.8 Hz, H2), 7.01-7.02 (d, 2H, J = 7.1 Hz, ArH), 7.30-7.53 (m, 8H, ArH), 7.90-
8.10 (m, 4H, ArH). 13C-NMR (75 MHz, CDCl3): δ 20.8 (COCH3), 21.2 (CH3), 62.6, 67.4,
67.8, 75.3, 76.0, 86.9 (C1), 128.4, 128.5, 128.9, 129.5, 129.7, 129.8, 129.9, 133.2, 133.5,
138.5, 165.3 (C=O), 165.4 (C=O), 170.8 (C=O). HRMS (ESI-TOF): Calculated for
C29H28O8SNa (M+Na) 559.1403 found 559.1415.
4.13. Allyl 6-O-acetyl-3-O-benzoyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (11b):
Pure product was isolated as white foam following elution of the column with 40% EA/PE.;
Yield 208 mg, 84% (Starting from 270.5 mg, 0.5 mmol). [α]25D =+66.6 (c 1.76, CHCl3). 1H-
NMR (300 MHz, CDCl3): δ 2.12 (s, 3H, COCH3), 3.58 (bs, 1H, OH), 3.80-3.85 (m, 2H, H4,
'
H5), 4.08 (m, 1H, AllH), 4.30 (m, 1H, AllH), 4.42-4.51 (m, 3H, H2, H6, H6 ), 5.03-5.17 (m,
16

ACCEPTED MANUSCRIPT
2H, AllH), 5.48 (d, 1H, J = 8.4 Hz, H1), 5.74 (m, 1H, AllH), 5.93 (m, 1H, H3), 7.26-7.31 (m,
13
2H, ArH), 7.46 (m, 1H, ArH), 7.61-7.65 (m, 2H, ArH), 7.76-7.84 (m, 4H, ArH). C-NMR
(75 MHz, CDCl3): δ 20.9 (COCH3), 54.5, 63.3, 70.2, 74.1, 74.2, 97.2 (C1), 117.7, 123.5,
128.4, 128.8, 129.8, 131.4, 133.5, 134.2, 166.9 (C=O), 167.9×2 (C=O), 171.5 (C=O).
HRMS (ESI-TOF): Calculated for C26H25NO9Na (M+Na) 518.1427 found 518.1419.
4.14. Allyl 6-O-acetyl-3-O-benzoyl-2-deoxy-2-phthalimido-β-D-galactopyranoside (12b):
Pure product was isolated as colourless syrup following elution of the column with 40%
EA/PE.; Yield 198 mg, 80% (Starting from 270.5 mg, 0.5 mmol). [α]25 =+79.1 (c 1.74,
D
CHCl3). 1H-NMR (300 MHz, CDCl3): δ 2.09 (s, 3H, COCH3), 2.53 (bs, 1H, OH), 3.99 (app t,
1H, J = 6.1, 6.2 Hz,AllH), 4.07 (m, 1H, AllH), 4.26-4.33 (m, 2H, H4, H5), 4.37-4.40 (m, 2H,
'
H6, H6 ), 4.82 (dt, 1H, J = 2.4, 8.7 Hz, H2), 5.04-5.17 (m, 2H, AllH), 5.42 (d, 1H, J = 8.4 Hz,
H1), 5.74 (m, 1H, AllH), 5.82 (dd, 1H, J = 2.8, 11.3 Hz, H3), 7.32-7.37 (m, 2H, ArH), 7.50
(m, 1H, ArH), 7.64-7.67 (m, 2H, ArH), 7.77-7.79 (m, 2H, ArH), 7.88-7.91 (m, 2H, ArH).
13C-NMR (75 MHz, CDCl3): δ 20.8 (COCH3), 51.2, 60.4, 62.6, 66.6, 69.9, 71.3, 72.2, 73.6,
77.3, 97.4 (C1), 117.7, 123.5, 128.5, 128.9, 129.6, 129.8, 131.4, 133.4, 133.5, 134.2, 165.4
(C=O), 167.9×2 (C=O), 170.9 (C=O). HRMS (ESI-TOF): Calculated for C26H25NO9Na
(M+Na) 518.1427 found 518.1436.
4.15. Phenyl 6-O-acetyl-2,3-di-O-benzyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-1-
thio-β-D-glucopyranoside(13b):
Pure product was isolated as colourless syrup following elution of the column with 20%
EA/PE.; Yield 352 mg, 76% (Starting from 486 mg, 0.5 mmol). [α]25 =-20.6 (c 1.28,
D
1
CHCl3). H-NMR (300 MHz, CDCl3): δ 2.06 (s, 3H, COCH3), 2.63 (bs, 1H, OH), 3.36-3.45
(m, 2H), 3.55-3.63 (m, 2H), 3.73-3.86 (m, 5H), 3.97-4.11 (m, 2H), 4.39 (dd, 1H, J = 3.9, 12.3
Hz, H6'/H6), 4.49-4.61 (m, 5H, 4×BnH, H6/H6'), 4.68-4.74 (m, 2H, BnH), 4.85-4.96 (m, 4H,
'
BnH), 5.63 (d, 1H, J = 3.6 Hz, H1 ), 7.14-7.37 (m, 28H, ArH), 7.59-7.62 (m, 2H, ArH). 13C-
17

ACCEPTED MANUSCRIPT
NMR (75 MHz, CDCl3): δ 21.0 (COCH3), 63.3, 69.2, 70.1, 70.6, 73.0, 73.4, 73.6, 74.4, 75.4,
'
75.6, 78.9, 79.1, 81.0, 81.1, 86.8, 87.5 (C1), 97.1 (C1 ), 126.6, 126.9, 127.4, 127.7, 127.8,
128.0, 128.1, 128.4, 128.5, 128.7, 129.1, 132.2, 133.8, 137.9, 138.4, 138.6, 138.7, 171.8
(C=O). HRMS (ESI-TOF): Calculated for C55H58SO11Na (M+Na) 949.3598 found 949.3583.
4.16. Phenyl 6-O-acetyl-2,3-di-O-benzyl-β-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-1-
thio-β-D-glucopyranoside(14b):
Pure product was isolated as colourless syrup following elution of the column with 20%
EA/PE.; Yield 333 mg, 72% (Starting from 486 mg, 0.5 mmol). [α]25 =-46.8 (c 1.07,
D
1
CHCl3). H-NMR (300 MHz, CDCl3): δ 1.98 (s, 3H, COCH3), 2.61 (bs, 1H, OH), 3.22 (m,
1H), 3.30-3.39 (m, 3H), 3.43-3.50 (m, 2H), 3.63 (app t, 1H, J = 8.6, 8.8 Hz), 3.78 (m, 1H),
3.89 (m, 1H), 4.04 (app t, 1H, J = 9.3, 9.4 Hz), 4.14 (m, 1H), 4.37-4.48 (m, 2H), 4.52 (d, 1H,
'
J = 6.9 Hz, H1), 4.60-4.90 (m, 9H), 5.10 (d, 1H, J = 10.8 Hz, H1 ), 7.24-7.32 (m, 28H, ArH),
7.55-7.58 (m, 2H, ArH). 13C-NMR (75 MHz, CDCl3): δ 20.8 (COCH3), 63.1, 69.2, 70.1,
'
73.3, 73.6, 74.9, 75.3, 75.4, 77.2, 79.2, 80.1, 82.2, 83.9, 84.9, 87.5 (C1), 102.6 (C1 ), 127.4,
127.5, 127.6, 127.7, 127.8, 127.89, 127.9, 128.1, 128.2, 128.3, 128.36, 128.4, 128.5, 128.8,
132.1, 133.7, 138.2, 138.3, 138.5, 139.1, 171.4 (C=O). HRMS (ESI-TOF): Calculated for
C55H58SO11Na (M+Na) 949.3598 found 949.3589.
4.17. p-Methylphenyl 6-O-acetyl-2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (19):20
2 g of compound 3a was converted to compound 3b according to general procedure described
previously and the acetic acid along with the water was co evaporated with tolueneunder
vacuum and proceeded to next step reaction. It was dissolved in dry THF (10 mL), 4 Å
molecular sieves (MS), benzyl 2,2,2-trichloroacetimidate (25.5 mmol, 4.74 mL) was added a
catalytic amount of TMSOTf (1.27 mmol, 0.35 mL). The mixture was stirred at room
temperature for 12 hours and then diluted with saturated NaHCO3 solution (200 mL) and
followed by water (200 mL). The organic layer was separated, and the water layer was
18

ACCEPTED MANUSCRIPT
washed with EA (2×20 mL). The combined organic layers were dried over MgSO4, filtered,
and then concentrated. The residue was purified by column chromatography 20% PE/EA to
give pure product 19 as colorless syrup in 81% yield (2.8 g). [α]25 =-21.3 (c 1.5, CHCl3),
D
lit20 [α]25 =-18 (c 0.9, CHCl3).1H (300 MHz, CDCl3): δ 2.06 (s, 3H, COCH3), 2.34 (s, 3H,
D
'
CH3), 3.45-3.53 (m, 3H, H2, H3, H4), 3.70 (m, 1H, H5), 4.22 (m, 1H, H6), 4.37 (m, 1H, H6 ),
4.56-4.61 (m, 2H, BnH), 4.74 (d, 1H, J = 10.2 Hz, H1), 4.83-4.87 (m, 2H, BnH), 4.88-4.95
13
(m, 2H, BnH), 7.09-7.12 (d, 2H, J = 9.0 Hz, ArH), 7.25-7.48 (m, 17H, ArH). C-NMR (75
MHz, CDCl3): δ 21.1 (CH3), 21.3 (COCH3), 63.5, 75.3, 75.6, 76.0, 77.1, 77.7, 81.1, 86.9,
88.0 (C1), 128.0, 128.1, 128.2, 128.3, 128.4, 128.6, 128.70, 128.73, 129.8, 129.9, 132.9,
137.8, 138.1, 138.2, 138.5, 170.8 (C=O).
4.18. p-Methylphenyl 2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside (17):21
To a solution of 19 (2 g, 3.34 mmol) in dry MeOH (27 mL) 1 M methanolic NaOMe (3 mL)
solution was added, and the reaction mixture was stirred for 3 hours at room temperature. The
solvent was removed under pressure and the crude mixture was diluted with EA (20 mL), and
subsequently washed with brine solution (100 mL), and washings were concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel with
25% EA/PE to give white solid and crystallized from EA/PE to produce needle shaped
o
crystals.; Yield 1.74 g, 94%. Mp 96-98 C (EA/PE), lit21 Mp 97-98 °C. [α]25D =+6.8 (c 1.05,
1
CHCl3), lit21 [α]24 =+6.5 (c 1.00, CHCl3). H-NMR (300 MHz, CDCl3): δ 1.75 (brs, 1H,
D
OH), 2.37 (s, 3H, CH3), 3.39 (m, 1H, H5), 3.48 (app t, 1H, J = 9.1, 9.3 Hz, H2), 3.58 (t, 1H, J
'
= 9.2 Hz, H4), 3.68-3.77 (m, 2H, H3, H6), 3.90 (dd, 1H, J = 2.4, 11.9 Hz, H6 ), 4.65-4.69 (d,
2H, J = 10.1 Hz, BnH), 4.79 (d, 1H, J = 10.3 Hz, H1), 4.86-4.97 (m, 4H, BnH), 7.13-7.16 (d,
13
2H, J = 7.9 Hz, ArH), 7.29-7.46 (m, 17H, ArH). C-NMR (75 MHz, CDCl3): δ 21.3 (CH3),
62.3, 75.3, 75.7, 76.0, 77.8, 79.5, 81.3, 86.7, 88.0 (C1), 127.9, 128.0, 128.07, 128.13, 128.2,
19

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128.4, 128.61, 128.64, 128.7, 129.7, 130.0, 132.8, 138.0, 138.15, 138.19, 138.5. HRMS (ESI-
TOF): Calculated for C34H36SO5Na (M+Na) 579.2181 found 579.2183.
4.19. p-Methoxyphenyl2-O-benzoyl-3,4-di-O-benzyl-α-L-rhamnopyranosyl-(1→6)-2,3,4-
tri-O-benzyl-β-D-glucopyranosyl-(1→4)-3-O-acetyl-6-O-benzyl-2-deoxy-2-phthalimido-
β-D-galactopyranoside (15):
A mixture of 16 (128 mg, 0.21 mmol), 17 (100.0 mg, 0.18 mmol) and flame activated 4Å
molecular sieves were stirred in dry THF (20 mL) for 40 minutes at room temperature under
argon atmosphere. The mixture was cooled to -60 ºC, and FeCl3 (3.4 mg, 0.02 mmol) was
added, and the reaction mixture was allowed to achieve room temperature. After 45 minutes
complete consumption of both the starting materials was observed (Checked by
TLC).Acceptor 18 (88.6 mg, 0.16 mmol) and N-phenylthio-ε-caprolactum (39.8 mg, 0.18
mmol) were then added to the same vessel. After the addition reaction vessel was placed in a
0 °C cold bath and 1 equivalent of triflic anhydride (0.03 mL, 0.18 mmol) was added to it.
The second step of the reaction was completed within 10 minutes (indicated by TLC). The
reaction mixture was quenched by Et3N and then filtered through celite bed. The bed was
washed with EA(3×15 mL). The combined filtrate and washings was washed subsequently
with saturated sodium thiosulphate, aqueous NaHCO3 (2x50 mL) and water (2x50 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated to furnish a syrupy
compound. The crude product was purified by flash column chromatography (eluent: PE/EA,
2:1) to afford the desired compound 15 in 67% yield (170 mg) as white foam.
[α]27D =+98.3 (c 1.0, CHCl3). 1H (500 MHz, CDCl3): δ 1.30 (d, 3H, J = 6.0 Hz, CH3), 1.81 (s,
3H, COCH3), 3.00 (t, 1H, J = 9.0 Hz), 3.11-3.18 (m, 2H, BnH), 3.24 (d, 1H, J = 11.0 Hz,
ʹ
ʹʹ
BnH), 3.31 (dd, 1H, J = 3.5, 10.0 Hz, H2 ), 3.51 (t, 1H, J = 9.5 Hz, H4 ), 3.60-3.64 (m, 6H,
ʹ
ʹ
ʹ
ʹʹ
OCH3, H3 , H5 , H6 ), 3.70 (m, 1H, H5 ), 4.12 (d, 1H, J = 11.5 Hz, BnH), 4.19 (dd, 1H, J = 3.5,
ʹʹ
9.5 Hz, H3 ), 4.27 (t, 1H, J = 6.0 Hz), 4.49-4.56 (m, 3H, BnH), 4.59-4.72 (m, 5H, H6, H6a,
20

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ʹʹ
BnH), 4.75-4.79 (m, 3H, H1 , H3, H5), 4.81-4.85 (app t, 1H, J = 9.0, 11.5 Hz, H2), 4.92 (d,
ʹ
1H, J = 11.0 Hz, BnH), 4.97 (d, 1H, J = 11.0 Hz, BnH), 5.12 (d, 1H, J = 3.0 Hz, H1 ), 5.70
ʹʹ
(brs, 1H, H2 ), 5.76 (d, 1H, J = 2.0 Hz, H4), 6.07 (d, 1H, J = 8.0 Hz, H1), 6.57-6.59 (d, 2H, J =
9.5 Hz), 6.83 (brs, 2H, ArH), 6.86-6.88 (d, 2H, J = 9.0 Hz, ArH), 7.13-7.40 (m, 34H, ArH),
7.54 (t, 1H, J = 9.0 Hz, ArH), 7.63-7.73 (m, 2H, ArH), 8.05-8.06 (d, 2H, ArH). 13C (125
MHz, CDCl3): δ 18.2 (CH3), 20.5 (COCH3), 52.9 (C3), 55.4 (C2), 65.0 (C4), 65.9 (PhCH2),
"
'
"
'
67.6 (C5 ), 68.7 (C6 , PhCH2), 69.7 (C2 ), 70.2 (C5 ), 71.3 (PhCH2), 71.8 (C2), 72.9, 73.6
'
"
'
"
(PhCH2), 73.7 (C6), 74.5 (PhCH2), 75.5 (PhCH2), 77.2 (C4 ), 77.8 (C3 ), 79.3 (C2 ), 80.3 (C4 ),
'
"
'
81.2 (C3 ), 92.8 (C1 ), 97.6 (C1), 98.1 (C1 ), 114.3, 118.6, 127.4, 127.6, 127.8, 127.9, 128.0,
128.1, 128.2, 128.21, 128.23, 128.3, 128.4, 130.0, 130.1, 133.0, 133.8, 138.0, 138.2, 138.3,
138.5, 138.6, 150.9, 155.3, 165.9 (C=O), 170.6 (C=O). HRMS (ESI-TOF) Calcd for
C84H83NO19Na [M+Na]+ 1432.5457, found 1432.5449.
Acknowledgements
MMM is thankful to UGC, India for a fellowship (SRF), and RG acknowledges the research
support obtained from CSIR, India (Scheme Nos. 02/0186/14/EMR-II and
02(0313)/17/EMR-II). DST-FIST and UGC-CAS, India are also acknowledged for
instrumental supports to the Department of Chemistry, Jadavpur University.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http//
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Highlights
•
•
•
•
•
•
Metal-free green protocol
Regioselective tandem opening of sugar 4,6-O-benzylidene acetals
Regioselective formation of sugar 6-O-acetyl derivative from 4,6-O-benzylidene acetal
Standardized condition uses only 60% aqueous acetic acid at 60 °C
Application towards synthesis of a glycosyl acceptor
Towards one-pot glycosylation reactions for a trisaccharide synthesis