Picoloyl protecting group in synthesis: Focus on a highly chemoselective catalytic removal

Article abstract of DOI:10.1039/d0ob00803f

The picoloyl ester (Pico) has proven to be a versatile protecting group in carbohydrate chemistry. It can be used for the purpose of stereocontrolling glycosylations via an H-bond-mediated Aglycone Delivery (HAD) method. It can also be used as a temporary protecting group that can be efficiently introduced and chemoselectively cleaved in the presence of practically all other common protecting groups used in synthesis. Herein, we will describe a new method for rapid, catalytic, and highly chemoselective removal of the picoloyl group using inexpensive copper(ii) or iron(iii) salts. This journal is

Full text of DOI:10.1039/d0ob00803f

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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00803F
Picoloyl Protecting Group in Synthesis: Focus on a Highly
Chemoselective Catalytic Removal
Scott A. Geringer, Michael P. Mannino, Mithila D. Bandara, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University Boulevard, St. Louis,
MO 63121, USA; e-mail: demchenkoa@umsl.edu
Dedicated to the memory of Bert Fraser-Reid (1934-2020) who was among the first to recognize the effect of protecting groups in
carbohydrate chemistry “Protecting groups do more than protect”
ABSTRACT: The picoloyl ester (Pico) has proven to be a versatile protecting group in carbohydrate chemistry. It can be used
for the purpose of stereocontrolling glycosylations via an H-bond-mediated Aglycone Delivery (HAD) method. It can also be
used as a temporary protecting group that can be efficiently introduced and chemoselectively cleaved in the presence of
practically all other common protecting group used in synthesis. Herein, we will describe a new method for rapid, catalytic,
and highly chemoselective removal of picoloyl group using inexpensive copper(II) or iron(III) salts.
Introduction
Recently, our group16-25 and others26-36 have done extensive
studies on the use of the picoloyl (Pico) protecting group. In
particular, the Pico group assisted H-bond-mediated
Aglycone Delivery (HAD) glycosylation reaction provided
high facial α- or β-stereoselectivity that was always syn in
respect to the Pico group. The stereoselectivity was only
one advantage of using the Pico protecting group. The Pico
group can be cleaved in traditional Zemplén conditions37
using sodium methoxide in methanol.23 It was also found
that Pico could be selectively cleaved off in the presence of
The chemical synthesis of glycans is a difficult task that
typically involves manipulation of a variety of protecting
groups to obtain selectively protected building blocks.1-4 As
once stated by Fraser-Reid, “protecting groups do more
5
than protect:” they are also known to control all types of
selectivity: regio-, stereo-, and chemoselectivity in
glycosylation. Protecting groups may also have a powerful
effect on the building block reactivity in glycosylation.6
During the synthesis of carbohydrates and other complex
biomolecules, protecting groups often need to be
chemoselectively removed over other protecting and
functional groups present in the molecule. Some reaction
conditions used for chemoselective protecting group
removal are harsh or rely on using toxic reagents. Others
lead to only marginal chemoselectivity and hence require
careful refinement of reaction conditions to avoid
undesired removal of other protecting groups. Dedicated
studies in this area led to the discovery of a few sets of
orthogonal protecting group. Orthogonal combinations
practically all other known protecting groups using zinc(II)
18, 20, 23
acetate27 or copper(II) acetate.17,
This reaction,
however, is slow with reported times of 16 h,17,
and
21
typically requires stoichiometric amount of Cu(OAc)2 (1-1.3
equiv). Reported herein are new reaction conditions that
allow for entirely chemoselective removal of Pico using
catalytic (30 mol %) ferric chloride or Cu(OAc)2. The
developed conditions are directly compatible with all other
protecting groups used in orthogonal glycan synthesis.
Results and Discussion
identified
by
Boons:
levulinoyl
(Lev),
acetyl,
After preliminary screening of potential reagents, we
discovered that iron(III) chloride provides a much faster
removal of Pico under the same reaction conditions to those
previously reported for Cu(OAc)2. We have purposefully
chosen compounds equipped with Pico at the C-4 position
that was particularly resistant towards removal in our
previous studies.17, 21 Thus, deprotection of 4-Pico in a series
of linear and branched glycans required excess Cu(OAc)2
and prolonged reaction time (16 h). Deprotection of
thioglycoside 116 equipped with 4-Pico group with Cu(OAc)2
(1.3 equiv) in MeOH-DCM (1/9) was more rapid, but still
required 3 h to complete (Table 1, entry 1). As a result, the
deprotected derivative 2 was obtained in 99% yield.
Performing the reaction with FeCl3 (1.3 equiv) under
similar reaction conditions afforded compound 2 in 99%
yield in 3.5 h (entry 2).
fluorenylmethoxycarbonyl (Fmoc), tert-butyldiphenylsilyl
(TBDPS);7 Fmoc, naphthyl, Lev, and allyloxycarbonyl
(Alloc);8 Schmidt: Fmoc, phenoxyacetyl, Lev, Alloc;9
Seeberger: naphthyl, Lev, Fmoc, 2-(azidomethyl)benzoyl;10-
13
14
and others13,
offer excellent flexibility for selective
liberation of particular hydroxyl groups. These protecting
group strategies are commonly employed in glycan
assembly using reactions in solution and on solid
supports.15 Nevertheless, identifying other stable and
selectively removable protecting groups that can be
selectively removed under mild and/or unique reaction
conditions is always a desirable direction of research in the
field of polyfunctional compound synthesis and
modification. In particular, new protecting groups that
would easily fit into existing schemes and orthogonal
combinations are of particular interest.

Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00803F
Table 1. Optimization of the Pico group removal under
catalytic conditions
reaction conditions with other temporary protecting
groups. Removing the 6-Pico group in benzoylated
thioglycoside 9 was rapid and chemoselective with either
catalyst. The desired 6-OH derivative 10 was obtained in
93-99% yield in 10-15 min (Scheme 1). This result
demonstrates that Pico can be chemoselectively removed in
the presence of benzoyl groups. Deprotection of the 3-Pico
group in benzylidene-protected thiomannoside 1118 was
also rapid and efficient. 3-OH derivative 12 was rapidly
produced (10-30 min) in the presence of either catalyst. The
yields for the formation of 12 were also excellent (92-99%),
which confirms compatibility of the acid-labile benzylidene
acetal group with the developed reaction conditions. The
removal of 4-Pico in glucosamine derivative 13 was also
very efficient, and the resulting 4-OH derivative 14 was
obtained in 99% yield in 1.5-4 h). This result indicated the
efficiency of the developed method in application to
aminosugars and compatibility of the phthlalimido group
with these reaction conditions.
OBn
O
OBn
O
Catalyst (mol %)
PicoO
BnO
HO
BnO
SEt
SEt
MeOH/DCM
(ratio, v/v), rt
BnO
BnO
1
2
Entry
Catalyst, solvent, time
yield
1
2
3
4
5
6
7
8
9
Cu(OAc)2 (130), MeOH/DCM (1/9), 3 h
FeCl3 (130), MeOH/DCM (1/9), 3.5 h
FeCl3 (30), MeOH/DCM (1/9), 48 h
FeCl3 (30), MeOH/DCM (1/1), 18 h
FeCl3 (30), MeOH/DCM (9/1), 5 h
FeCl3 (30), MeOH (neat), 5 h
FeCl3 (15), MeOH/DCM (9/1), 10 h
FeCl3 (5), MeOH/DCM (9/1), 28 h
Cu(OAc)2 (30), MeOH/DCM (9/1), 1.5 h
99%
98%
75%
87%
91%
89%
99%
92%
99%
After recording these promising results, we endeavored to
optimizing the reaction condition to determine whether
substoichiometric amounts of metal salts would be
sufficient for driving the Pico deprotection to completion.
We first found that upon reducing the amount of FeCl3 to 30
mol %, the reaction still occurred. However, this reaction
was significantly slower, and required 48 h to obtain
compound 2 in 75% yield (entry 3). In a further attempt to
refine the reaction conditions, we investigated the effect of
the solvent. Increasing the amount of MeOH in respect to
DCM gave us the desired outcome. Thus, deprotection in
MeOH-DCM (1/1) produced compound 2 in 87% in 18 h
(entry 4). Furthermore, deprotection in MeOH-DCM (9/1)
afforded compound 2 in 91% yield in 5 h (entry 5). Using
neat methanol showed no further improvement (entry 6).
Reactions using even lower amounts of FeCl3, 15 and even 5
mol %, could still be driven to completion, but required
longer reaction time, 10 and 28 h, respectively (entries 7
and 8). Nevertheless, compound 2 was obtained in excellent
yields of 99% and 92%, respectively. We also wanted to see
how well Cu(OAc)2 worked under these new reaction
conditions. As depicted in entry 9, this reaction was even
faster, and compound 2 was produced in 99% yield in only
1.5 h. It should be noted that the reaction did not proceed
when performed in the presence of methanol, without the
addition of a catalyst.
The method also proved successful in chemoselective
removal of the 4-Pico group in acetylated sialic acid
derivative 15.32 4-OH Sialoside 16 was rapidly produced in
the presence of FeCl3 in 95% yield in 50 min. A similar
reaction in the presence of copper(II) acetate was even
faster (20 min), but this translated in a somewhat lower
yield of compound 16 (73%). Deprotection of 6-Pico with
FeCl3 in differentially protected thioglycoside 1738 was very
rapid (15 min) affording 6-OH derivative 18 in 97% yield.
This result indicated excellent compatibility of the Fmoc
group that is commonly used as a temporary protecting
group in iterative oligosaccharide synthesis. The removal
of 4-Pico in compound 19 was somewhat slow with FeCl3,
but the desired 4-OH derivative 20 was smoothly produced
in an excellent yield (99%). This result ultimately confirms
the compatibility of p-methoxybenzyl group with the
developed reaction conditions. The 4-Pico group removal in
19 in the presence of copper(II) acetate was significantly
faster (20 min), but the yield of product 20 was somewhat
lower (85%).
We also wanted to evaluate whether these reaction
conditions are capable of concomitant removal of multiple
Pico groups. When 4,6-di-Pico derivative 21 was treated
with 30 mol % of iron(III) chloride the desired diol 22 was
produced in 99% yield. This reaction required 24 h to go to
completion. As in a number of previous cases deprotection
in the presence of copper(II) acetate was much more rapid
(10 min) without affecting the efficiency: diol 22 was
produced in 99% yield. Even tri-Pico compound 2323 could
be efficiently deprotected using only 30 mol % of either
catalyst. As a result, triol 24 was isolated in 83-91% yield in
15-45 min.
From these optimizations, we carried out subsequent
deprotection reactions using 30 mol % of the catalyst in
MeOH-DCM (9/1). First, we wanted to investigate other
regioisomers of 1 wherein Pico was present at C-2, C-3, and
25
C-6 positions, compounds 3, 5,24, and 7,16 respectively
(Scheme 1). Interestingly, removing Pico from the C-2
position in 3 with FeCl3 was very sluggish, which resulted in
a much longer and incomplete reaction giving compound 4
in only71% yield after 3 days. We are unsure of the rationale
for this result that seems to stand out from the general
trend. In contrast, a similar reaction in the presence
Cu(OAc)2 rapidly produced 2-OH derivative 4 in 91% yield
in 2 h. Deprotection of 3-Pico in 5 with FeCl3 afforded 3-OH
derivative 6 in 91% yield in 5 h. The removal of 6-Pico in 7
was very rapid and efficient in the presence of either
catalyst, and 6-OH derivative 8 was obtained in 99% in 10-
20 min.
Scheme 1. Broadening the scope of the chemoselective
Pico cleavage using Fe(III) or Cu(II) catalysts
Following the success of our preliminary trials, we moved
on to investigating the compatibility of the developed

Page 3 of 9
Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00803F
FeCl3 or Cu(OAc)2
(30 mol %)
established reaction conditions. This outcome ultimately
proves the complexation mode of metal salts that leads to
swift deprotection of Pico groups.
O
O
PicoO
HO
MeOH/DCM (9/1)
Scheme 2. Proposed mechanism of picoloyl cleavage
OBn
O
OBn
O
OR
O
BnO
BnO
BnO
BnO
BnO
SEt
O
RO
SEt
SEt
N
BnO
O
RO
BnO
3
4
5
6
: R=Pico
: R=H, 71%, 72 h (Fe)
91%, 2 h (Cu)
: R=Pico
: R=H, 91%, 5 h (Fe)
O
7
8
: R=Pico
: R=H, 99%, 20 min (Fe)
99%, 10 min (Cu)
A
O
HO
OBn
OBn
OR
Cl
Cl
FeCl3
Ph
O
E
O
O
O
+
Cl
O
BzO
RO
Fe
O
SEt
SEt
RO
BzO
BnO
O
N
N
BzO
PhthN
: R=Pico
: R=H, 99%, 4 h (Fe)
99%, 1.5 h (Cu)
O
SEt
OCH3
9
11
12
13
14
: R=Pico
10
: R=Pico
O
: R=H, 99%, 15 min (Fe)
93%, 10 min (Cu)
: R=H, 92%, 30 min (Fe)
99%, 10 min (Cu)
B
Cl
Cl
Cl
Fe
HOCH3
AcO
O
OAc
BnO
OR
CO2Me
SPh
OpMB
O
N
O
Cl
O
AcO
AcHN
O
Cl
RO
BnO
O
Cl
SEt
H
O
SEt
FmocO
Fe
D
O
BnO
BzO
H3C
RO
N
O
15
: R=Pico
17
18
O
: R=Pico
19
20
: R=Pico
16
: R=H, 95%, 50 min (Fe)
73%, 20 min (Cu)
O
H3C
: R=H, 97%, 15 min (Fe)
: R=H, 99%, 16 h (Fe)
85%, 20 min (Cu)
H
C
OR
O
RO
RO
OBn
O
OBn
O
OBn
O
0.3 equiv FeCl3
9:1 CH2Cl2:MeOH
RO
BnO
SEt
RO
BnO
BnO
NR
SEt
O
SEt
O
O
O
BnO
SEt
BnO
BnO
21
22
23
: R=Pico
: R=Pico
: R=H, 99%, 24 h (Fe)
99%, 10 min (Cu)
24
: R=H, 91%, 45 min (Fe)
83%, 15 min (Cu)
or
30
29
N
N
OBn
O
PhthN
Ph
O
Conclusions
BnO
O
O
OTBS
RO
O
The Pico group can be used as an effective temporary
protecting group . The Pico group can be cleaved using
traditional Zemplén conditions using sodium methoxide in
methanol, and its stability is similar to that of benzoyl ester
group. In contrast to previous reports dealing with the
chemoselective removal of the Pico group in the presence of
other esters that employed stoichiometric reagents, this
study demonstrated that the Pico group can be removed in
a catalytic manner using 30 mol% of iron(III) chloride or
copper(II) acetate. These conditions are also capable of
chemoselective removal of even multiple Pico groups.
Reactions performed with Cu(OAc)2 were generally faster,
but on a number of occasions FeCl3-catalyzed reactions
provided better yields. The developed conditions are
directly compatible with all other protecting groups used in
other orthogonal protection schemes. Hence, it is to be
expected that the Pico group can directly supplement the
arsenal of existing orthogonal group combinations used for
glycan synthesis.
25
26
: R=Pico
: R=H, 98%, 25 min (Fe)
OBn
BnO
BnO
BnO
OR
OBn
O
OBn
OBn
O
O
BnO
OBn
BnO
O
O
O
O
OBn
BzO
PhthN
BzO
27
28
: R=Pico
: R=H, 99%, 2 h (Fe)
Finally, we also investigated the removal of the Pico group
from oligosaccharides. When 3’-Pico protected disaccharide
25 was treated with FeCl3 compound 26 was efficiently
produced in 98% yield in 25 min. This result signified
compatibility of the developed conditions with tert-
butyldimethylsilyl (TBS), benzylidene, and phthalimido
groups, all in one platform. Lacto-N-tetraose 27,39,
a
40
common core human milk tetrasaccharide, equipped with
6’-Pico group could also be efficiently deprotected with
FeCl3 to afford compound 28 in 99% in 2 h.
Mechanistically, we hypothesize that when a picoloylated
derivative A is used, iron(III) chloride (or copper(II)
acetate) coordinate between both the carbonyl oxygen and
the nitrogen atoms of the Pico group as shown in Scheme 2
for intermediate B. This pulls electron density away from
the carbonyl carbon allowing for a nucleophile to attack, in
our case methanol via tetrahedral intermediate C. The
subsequent proton exchange leads to intermediate D, and
Experimental Section
General. Column chromatography was performed on silica
gel 60 (70-230 mesh), reactions were monitored by TLC on
Kieselgel 60 F254. The compounds were detected by
examination under UV light and by charring with 10%
sulfuric acid in methanol. Solvents were removed under
reduced pressure at <40 °C. Optical rotations were
measured at ‘Jasco P-2000’ polarimeter. Unless noted
the
tetrahedral
intermediate
collapse
the
transesterification products, unprotected alcohol E and
methyl picolinate. Iron(III) chloride is released and is
available for the next catalytic cycle. To reinforce this
reaction mechanism, we also investigated whether other
positional isomers of the Pico group could be removed
accordingly. For this purpose we obtained 3-niconoyl and 3-
O-iso-niconoyl protected compounds 29 and 30 (Scheme
2).24, 25 No deprotection took place even in 24 h under the
1
otherwise, H NMR spectra were recorded in CDCl3 at 300,
13C NMR spectra were recorded in CDCl3 at 75 MHz.
Accurate mass spectrometry determinations were
performed using Agilent 6230 ESI TOF LCMS.
Synthesis of Picoloyl Containing Compounds

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General procedure for the Pico group introduction. Picolinic
acid (2-3 equiv per OH), 1-ethyl-3-(3-
Ethyl
3,6-di-O-benzyl-2-deoxDyO-2I:-1p0h.10th39a/lDi0mOiBd0o0-840-3OF -
picoloyl-1-thio-β-D-glucopyranoside (13). The title
compound was prepared from ethyl 3,6-di-O-benzyl-2-
dimethylaminopropyl)carbodiimide (EDC, 2-3 equiv per
OH), and 4-dimethylaminopyridine (DMAP, 0.2-0.5 equiv
per OH) were added to a solution of a starting material
containing at least one OH group in CH2Cl2, and the resulting
mixture was stirred under argon for 16 h at rt. After that,
the reaction mixture was diluted with CH2Cl2 and washed
with water (twice). The organic phase was separated, dried
with magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by column
chromatography on silica gel (ethyl acetate - hexane
gradient elution) to give the corresponding compound
containing one or more Pico groups.
deoxy-2-phthalimido-1-thio-β-D-glucopyranoside43
(14,
1.20 g, 1.88 mmol) in CH2Cl2 (50 mL), picolinic acid (0.46 g,
3.76 mmol), EDC (0.58 g, 3.76 mmol), and DMAP (0.045 g,
0.37 mmol) in accordance with the general procedure as a
white amorphous solid in 85% yield (0.86 g, 1.62 mmol).
Analytical data for 13: Rf = 0.2 (ethyl acetate/hexane, 1/1,
v/v); [α]D24 +59.4 (c = 1.0, CHCl3);1H NMR (300 MHz, CDCl3):
δ 8.77 (d, 1H, aromatic), 8.08 (d, 1H, aromatic), 7.88–7.76
(m, 2H, aromatic), 7.74–7.62 (m, 3H, aromatic), 7.53–7.45
(m, 1H, aromatic), 7.29–7.12 (m, 6H, aromatic), 6.93 (m, 2H,
aromatic), 6.85–6.74 (m, 3H, aromatic), 5.52 (dd, 1H, H-4),
5.35 (d, J1,2 = 10.6 Hz, 1H, H-1), 4.74 (dd, 1H, H-3), 4.57 (d, 2J
= 12.1 Hz, 1H, CHPh), 4.51 (s, 2H, CH2Ph), 4.45–4.33 (m, 2H,
H-2, CHPh), 4.06 (m, J5,6a = J5,6b = 4.4 Hz, 1H, H-5), 3.71 (dd,
2H, H-6a, 6b), 2.68 (m, 2H, SCH2CH3), 1.19 (t, J = 7.4 Hz, 3H,
SCH2CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 168.1, 167.5,
164.3, 150.1, 147.6, 138.0, 137.7, 137.2, 134.1, 134.0, 131.7,
128.3 (x2), 128.1 (x4), 127.8 (x2), 127.6, 127.5, 127.3,
125.8, 123.7, 123.5, 81.3, 77.9, 77.6, 74.4, 74.1, 73.6, 69.8,
54.9, 24.2, 15.1 ppm; HRMS [M+Na]+ calcd for
C36H34N2O7SNa 661.1984 found 661.1993.
Ethyl
3,4,6-tri-O-benzyl-2-O-picoloyl-1-thio-β-D-
glucopyranoside (3). The title compound was prepared
from ethyl 3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside41
(4, 34.6 mg, 0.07 mmol) in CH2Cl2 (2.0 mL), picolinic acid
(26.0 mg, 0.21 mmol), EDC (40.3 mg, 0.21 mmol), and DMAP
(4.3 mg, 0.03 mmol) in accordance with the general
procedure as a white amorphous solid in 87% yield (36.3
mg, 0.60 mmol). Analytical data for 3: Rf = 0.50 (ethyl
1
acetate/toluene, 1/1, v/v); [α]D23 +22.3 (c = 1.0, CHCl3); H
NMR (300 MHz, CDCl3): δ 8.77 (d, 1H, aromatic), 8.12 (d, 1H,
aromatic), 7.83 (m, 1H, aromatic), 7.48 (m, 1H, aromatic),
7.40–7.24 (m, 8H, aromatic), 7.24–7.15 (m, 2H, aromatic),
7.15–7.05 (m, 5H, aromatic), 5.38 (dd, J2,3 = 9.6 Hz, 1H, H-2),
Ethyl
2,3-di-O-benzyl-4-O-p-methoxybenzyl-6-O-
picoloyl-1-thio-β-D-glucopyranoside (19). NaH (60% in
mineral oil, 703.4 mg 17.60 mmol) was added portionwise
to a solution of ethyl 4,6-O-p-methoxybenzylidene-1-thio-β-
D-glucopyranoside44 (31, 3.0 g, 8.79 mmol) in
dimethylformamide (25 mL), and the resulting mixture was
cooled to 0 °C. Benzyl bromide (4.5 g, 26.37 mmol) was
added dropwise, a second batch of NaH (60% in mineral oil,
703.4 mg, 17.60 mmol) was then added portionwise, and
the resulting mixture was stirred under argon for 5 h. After
that, the reaction mixture was poured into ice water (50
mL) and stirred for 30 min. The aqueous phase was
extracted with ethyl acetate/ diethyl ether (1/1, v/v, 3 x 75
mL). The combined organic extract (~225 mL) was washed
with cold water (3 x 30 mL). The organic phase was
separated, dried with magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (ethyl
acetate – hexane gradient elution) to give ethyl 2,3-di-O-
benzyl-4,6-O-p-methoxybenzylidene-1-thio-β-D-
2
2
4.82 (d, J = 10.6, 1H, CHPh), 4.75 (m, J = 11.0 Hz, 2H, 2 x
CHPh) 4.67 (d, J1,2 = 9.6 Hz, 1H, H-1) 4.68–4.51 (m, 3H, 3 x
CHPh), 3.97 (dd, J3,4 = 9.1 Hz, 1H, H-3), 3.77 (dd, J4,5 = 9.6 Hz,
1H, H-4), 3.76 (m, 1H, H-6a), 3.75 (m, J6a,6b = 4.6 Hz, 1H, H-
6b), 3.57 (dd, J5,6a = J5,6b = 9.1 Hz, 1H, H-5), 2.85–2.62 (m, 2H,
SCH2CH3), 1.24 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13C NMR (75
MHz, CDCl3): δ 164.3, 150.0, 147.8, 138.3, 138.1, 138.0,
137.2, 128.6 (x 2), 128.4, 128.3, 128.1, 127.9, 127.8, 127.7,
127.2, 126.0, 84.4, 83.4, 79.6 (x2), 78.1 (x2), 75.6 (x2), 75.3
(x2), 73.6 (x2), 73.4 (x2), 69.0 (x2), 24.1, 15.1 ppm; HRMS
[M+Na]+ calcd for C35H37NO6SNa 622.2236 found 622.2244.
Ethyl
glucopyranoside (9). The title compound was prepared
from ethyl 2,3,4-tri-O-benzoyl-1-thio-β-D-
2,3,4-tri-O-benzoyl-6-O-picoloyl-1-thio-β-D-
glucopyranoside42 (10, 4.65 g, 8.66 mmol) in CH2Cl2 (100
mL), picolinic acid (2.15 g, 17.32 mmol), EDC (3.32 g, 17.32
mmol), and DMAP (0.21 g, 1.73 mmol) in accordance with
the general procedure as a white amorphous solid in 99%
yield (5.56 g, 8.65 mmol). Analytical data for 9: Rf = 0.30
glucopyranoside (32, 4.42 g, 8.46 mmol) in 96% yield.
Selected analytical data for 32: Rf
= 0.65 (ethyl
24
acetate/hexane, 2/3, v/v); 1H NMR (300 MHz, CDCl3): δ 7.47
(ethyl acetate/ hexane, 1/1, v/v); [α]D +16.2 (c = 1.0,
– 7.18 (m, 12H, aromatic), 6.95 – 6.85 (m, 2H, aromatic),
CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.71 (m, 1H, aromatic),
8.10 (m, 1H, aromatic), 8.00–7.92 (m, 2H, aromatic), 7.92–
7.85 (m, 2H, aromatic), 7.85–7.76 (m, 3H, aromatic), 7.55–
7.23 (m, 10H, aromatic), 5.93 (dd, J3,4 = 9.5 Hz, 1H, H-3), 5.66
(dd, J4,5 = 9.8 Hz, 1H, H-4), 5.58 (dd, J2,3 = 9.7 Hz, 1H, H-2),
4.87 (dd, J1,2 = 10.0 Hz, 1H, H-1), 4.68 (dd, 1H, H-6a), 4.62
2
5.54 (s, 1H, CHPh), 4.85 (dd, J = 11.3 Hz, 2H, CH2Ph), 4.84
(dd, 2J = 10.2 Hz, 2H, CH2Ph), 4.56 (d, J1,2 = 9.8 Hz, 1H, H-1),
4.33 (dd, J3,4 = 10.4, 1H, H-3), 3.81 (s, 3H, OCH3), 3.80 – 3.64
(m, 3H, H-4, 6a, 6b), 3.50-3.39 (m, 2H, H-2, 5), 2.76 (m, 2H,
SCH2CH3), 1.32 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm.
(dd, J6a,6b = 12.2 Hz, 1H, H-6b), 4.27 (dd, J5,6a = 3.4 Hz, J5,6b
=
A mixture containing compound 32 (4.42 g, 8.46 mmol),
molecular sieves (4Å, 3.0 g) in dimethylformamide (20 mL)
was stirred under argon for 1 h at rt. The resulting mixture
was cooled to 0 °C, sodium cyanoborohydride (2.66 g, 42.3
mmol) was added followed by slow dropwise addition of
trifluoroacetic acid (9.65 g, 84.6 mmol), the reaction
mixture was allowed to warm to ambient temperature and
stirred for 16 h at rt. After that, the solids were filtered off
5.5 Hz, 1H, H-5), 2.86–2.65 (m, 2H, SCH2CH3), 1.23 (t, J = 7.4
Hz, 3H, SCH2CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 165.9,
165.4 (x2), 164.7, 150.2, 147.6, 137.2, 133.7, 133.5 (x2),
130.1 (x2), 130.0 (x2), 129.9 (x2), 129.2, 128.9, 128.8, 128.6
(x4), 128.5 (x2), 127.2, 125.5, 84.1, 76.2, 74.2, 70.7, 69.9,
64.4, 24.6, 15.1 ppm; HRMS [M+Na]+ calcd for C35H31NO9SNa
664.1617 found 664.1626.

Page 5 of 9
Organic & Biomolecular Chemistry
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through a pad of Celite and rinsed successively with DCM.
The combined filtrate (~150 mL) was washed with sat. aq.
NaHCO3 (3 x 40 mL). The layers were separated, and the
aqueous phase was extracted with dichloromethane (2 x
150 mL). The combined organic phase was dried with
magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column
chromatography on silica gel (ethyl acetate - hexane
gradient elution) to give ethyl 2,3-di-O-benzyl-4-O-p-
methoxybenzyl-1-thio-β-D-glucopyranoside 20 in 79%
yield (3.51 g, 6.68 mmol). Analytical data for 20: Rf = 0.45
= 4.3 Hz, J5,6b = 4.4 Hz, 1H, H-5), 3.97D(dOdI:,1J03.,140=399/D.10HOBz0, 018H0,3HF -
3), 3.61 (dd, J2,3 = 8.9 Hz, 1H, H-2), 2.89 – 2.65 (m, 2H,
SCH2CH3), 1.29 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13C NMR (75
MHz, CDCl3): δ 164.6, 164.3, 150.1, 150.0, 147.7, 147.4,
137.9, 137.8, 137.2, 137.1, 128.6 (x3), 128.4 (x2), 128.2
(x2), 128.1 (x2), 127.8, 127.3, 127.1, 125.9, 125.6, 85.4, 83.7,
81.7, 75.9, 75.8, 75.5, 71.9, 64.3, 25.2, 15.3 ppm; HRMS
[M+Na]+ calcd for C34H34N2O7SNa 637.1984 found 637.1988.
Ethyl
2-O-benzyl-3,4,6-tri-O-picoloyl-1-thio-α-D-
mannopyranoside (23). p-Toluenesulfonic acid (3.1 mg,
0.016 mmol) and ethanethiol (12.3 mg, 0.198 mmol) were
added to a solution of ethyl 2-O-benzyl-4,6-O-benzylidene-
3-picoloyl-1-thio-α-D-mannopyranoside18 (33, 16.6 mg,
0.033 mmol) in DCM (0.5 mL), and the resulting solution
was stirred under argon for 2 h at rt. The reaction mixture
was then neutralized with triethylamine, the volatiles were
removed under reduced pressure, and the residue
containing ethyl 2-O-benzyl-1-thio-α-D-mannopyranoside
(34) was dried in vacuo for 2 h. The title compound was
then obtained from crude 34 (0.033 mmol) in
dichloromethane (0.5 mL), picolinic acid (24.6 mg, 0.198
mmol), EDC (38.0 mg, 0.198 mmol), and DMAP (0.81 mg,
0.007 mmol) in accordance with the general procedure as a
white amorphous solid in 86% yield (17.7 mg, 0.028 mmol).
Analytical data for 23: Rf = 0.4 (acetone/toluene, 1/1, v/v);
25
(ethyl acetate/hexane, 3/2, v/v); [α]D -32.5 (c = 1.86,
CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.50 – 7.19 (m, 12H,
2
aromatic), 6.87 (d, 2H, aromatic), 4.85 (dd, J = 9.4 Hz, 2H,
CH2Ph), 4.83 (dd, 2J = 10.2 Hz, 2H, CH2Ph), 4.50 (s, 2H,
CH2Ph), 4.48 (d, J1,2 = 9.7 Hz, 1H, H-1), 3.80 (s, 3H, OCH3),
3.71 (d, 1H, H-6a), 3.70 (d, 1H, H-6b), 3.62 (dd, J4,5 = 9.1 Hz,
1H, H-4), 3.51 (dd, J3,4 = 8.6 Hz, 1H, H-3), 3.44 (dd, J5,6a = J5,6b
= 4.8 Hz, 1H, H-5), 3.40 (dd, J2,3 = 9.0 Hz, 1H, H-2), 2.87 – 2.62
(m, 2H, SCH2CH3), 1.32 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm; 13
C
NMR (75 MHz, CDCl3): δ 159.5, 138.7, 138.1, 130.0, 129.6,
128.8, 128.6 (x2), 128.2, 128.1 (x2), 114.0, 86.2, 85.3, 81.4,
77.9, 75.7, 75.6, 73.5, 72.5, 70.6, 55.5, 25.3, 15.4 ppm; HRMS
[M+Na]+ calcd for C30H36O6SNa 547.2125 found 547.2131.
Compound 19 was prepared from 20 (1.48 g, 2.83 mmol) in
CH2Cl2 (50 mL), picolinic acid (0.701 g, 5.65 mmol), EDC
(1.08 g, 5.65 mmol), and DMAP (0.069 g, 0.57 mmol) in
21
1
[α]D +52.5 (c = 2.0, CHCl3); H NMR (300 MHz, CDCl3): δ
8.70 (d, 3H, aromatic), 8.17 – 7.95 (m, 3H, aromatic), 7.84 –
7.66 (m, 3H, aromatic), 7.51 – 7.38 (m, 3H, aromatic), 7.38 –
7.25 (m, 2H, aromatic), 7.25 – 7.10 (m, 3H, aromatic), 6.17
(dd, J4,5 = 10.0 Hz, 1H, H-4), 5.70 (dd, J3,4 = 10.0 Hz, 1H, H-3),
5.51 (dd, 1H, H-1), 4.87 (dd, 1H, H-5), 4.68 (dd, 2J = 12.0 Hz,
2H, CH2Ph), 4.67-4.64 (m, 2H, H-6a, 6b), 4.27 (dd, J2,3 = 1.5
Hz, 1H, H-2), 2.84 – 2.47 (m, 2H, SCH2CH3), 1.29 (t, J = 7.4 Hz,
3H, SCH2CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 164.5, 164.0,
163.7, 150.2, 150.1 (x2), 147.6, 147.1, 147.0, 137.5, 137.2
(x2), 137.1, 128.4 (x2), 127.9 (x3), 127.3, 127.1, 126.9,
125.7, 125.6, 125.4, 82.0, 77.1, 73.1, 72.8, 68.8, 68.3, 64.0,
25.4, 14.9 ppm; HRMS [M+Na]+ calcd for C33H31N3O8SNa
652.1724 found 652.1738.
accordance with the general procedure as
a white
amorphous solid in 97% yield (1.72 g, 2.74 mmol).
Analytical data for 19: Rf = 0.55 (acetone/ hexane, 1/1, v/v);
24
1
[α]D -27.6 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ
8.78 – 8.69 (m, 1H, aromatic), 7.98 (m, 1H, aromatic), 7.78
(m, 1H, aromatic), 7.46 (m, 1H, aromatic), 7.41 – 7.24 (m,
5H, aromatic), 7.18 – 7.02 (m, 7H, aromatic), 6.77 – 6.66 (m,
2H, aromatic), 5.37 (dd, J4,5 = 9.7 Hz, 1H, H-4), 4.84 (dd, 2J =
10.2 Hz, 2H, CH2Ph), 4.73 (dd, 2J = 11.2 Hz, 2H, CH2Ph), 4.55
(d, J1,2 = 9.8 Hz, 1H, H-1), 4.39 (dd, 2H, H-6a, 6b), 3.90 (dd,
J3,4 = 9.1 Hz, 1H, H-3), 3.82 (dd, 1H, H-5), 3.73 (s, 3H, OCH3),
2
3.60 (dd, J = 4.4 Hz, 2H, CH2Ph), 3.56 (dd, J2,3 = 8.9 Hz, 1H,
H-2), 2.89 – 2.69 (m, 2H, SCH2CH3), 1.34 (t, J = 7.4 Hz, 3H,
SCH2CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 164.3, 159.1,
145.0, 147.7, 138.1, 138.0, 137.1, 130.1, 129.5 (x2), 128.6
(x4), 128.3 (x2), 128.1 (x3), 127.7, 127.1, 125.7, 113.7, 85.3,
83.8, 81.8, 77.4, 75.8, 75.6, 73.3, 72.5, 69.5, 55.3 (x2), 25.2,
15.4 ppm; HRMS [M+Na]+ calcd for C36H39NO7SNa 652.2345
found 652.2347.
Selective Deprotection of the Pico group
General procedure for Pico removal. Iron(III) chloride
(0.017 mmol) or copper(II) acetate (0.017 mmol) was
added to a solution of a Pico derivative (0.051 mmol) in
MeOH-DCM (1.0 mL, 1.0/1, v/v), and the resulting mixture
was stirred under argon at rt. Upon completion (see the
reaction time listed in Scheme 1), the volatiles were
removed under reduced pressure. The residue was diluted
with DCM (~5 mL) and washed with sat. aq. NaHCO3 (5 mL)
and water (2 x 5 mL). The organic phase was separated,
dried using magnesium sulfate, filtered and concentrated
under reduced pressure. The residue was purified by
column chromatography on silica gel (ethyl acetate –
hexane gradient elution) to give the corresponding
deprotected derivative in yields listed in Scheme 1.
Ethyl
2,3-di-O-benzyl-4,6-di-O-picoloyl-1-thio-β-D-
glucopyranoside (21). The title compound was prepared
from ethyl 2,3-di-O-benzyl-1-thio-β-D-glucopyranoside45
(22, 237.3 mg, 0.59 mmol) in CH2Cl2 (10 mL), picolinic acid
(364.0 mg, 2.90 mmol), EDC (555.9 mg, 2.90 mmol), and
DMAP (36.1 mg, 0.30 mmol) in accordance with the general
procedure as a white amorphous solid in 86% yield (311.1
mg, 0.51 mmol). Analytical data for 21: Rf
= 0.30
(acetone/hexane, 1/3, v/v); [α]D24 -6.40 (c = 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): δ 8.77 – 8.64 (m, 2H, aromatic), 8.15
– 8.06 (m, 1H, aromatic), 8.06 – 7.98 (m, 1H, aromatic), 7.86
– 7.74 (m, 2H, aromatic), 7.52 – 7.29 (m, 7H, aromatic), 7.08
(s, 5H, aromatic), 5.52 (dd, J4,5 = 9.8 Hz, 1H, H-4), 4.85 (dd, 2J
= 10.2 Hz, 2H, CH2Ph), 4.76 (dd, 2J = 11.2 Hz, 2H, CH2Ph),4.61
(d, J1,2 = 9.8 Hz, 1H, H-1), 4.56 (d, 2H, H-6a, 6b), 4.06 (dd, J5,6a
Ethyl
(2). The title compound was obtained from ethyl 2,3,6-tri-
O-benzyl-4-O-picoloyl-1-thio-β-D-glucopyranoside16
(1,
2,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside
29.1 mg, 0.052 mmol) and iron(III) trichloride (2.5 mg,
0.016 mmol) in methanol (0.9 mL) and dichloromethane
(0.1 mL) in accordance with the general procedure as a
colorless syrup in 5 h in 91% yield (23.3 mg, 0.047 mmol).

Organic & Biomolecular Chemistry
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Alternatively, the title compound was obtained from
thioglycoside 1 (29.6 mg, 0.049 mmol) and copper(II)
acetate (3.0 mg, 0.015 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 1.5 h in 99% yield (24.8
mg, 0.048 mmol). Analytical data for 2 was in accordance
with that reported previously.46
the general procedure as a colorlessDsyOrI:u1p0.i1n03390/Dm0OinB0in088083F%
yield (22.2 mg, 0.055 mmol). Alternatively, the title
compound was obtained from 11 (14.6 mg, 0.029 mmol)
and copper(II) acetate (1.8 mg, 0.0087 mmol) in methanol
(0.45 mL) and dichloromethane (0.05 mL) in accordance
with the general procedure as a colorless syrup in 10 min in
93% yield (25.1 mg, 0.047 mmol). Analytical data for 12
was essentially the same as reported previously.49
Ethyl
3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside
(4). The title compound was obtained from precursor 3
(29.0 mg, 0.048 mmol) and iron(III) trichloride (2.4 mg,
0.015 mmol) in methanol (0.9 mL) and dichloromethane
(0.1 mL) in accordance with the general procedure as a
colorless syrup in 48 h in 71% yield (17.0 mg, 0.034 mmol).
Alternatively, the title compound was obtained from
thioglycoside 3 (33.1 mg, 0.055 mmol) and copper(II)
acetate (3.3 mg, 0.017 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 2 h in 91% yield (15.2 mg,
0.03 mmol). Analytical data for 4 was in accordance with
that reported previously.41
Ethyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-
D-glucopyranoside (14).
The title compound was
obtained from compound 13 (29.9 mg, 0.047 mmol) and
iron(III) trichloride (2.3 mg, 0.014 mmol) in methanol (0.9
mL) and dichloromethane (0.1 mL) in accordance with the
general procedure as a colorless syrup in 5 h in 99% yield
(25.2 mg, 0.047 mmol). Alternatively, the title compound
was obtained from thioglycoside 13 (36.4 mg, 0.057 mmol)
and copper(II) acetate (1.8 mg, 0.017 mmol) in methanol
(0.9 mL) and dichloromethane (0.1 mL) in accordance with
the general procedure as a colorless syrup in 1.5 h in 99%
yield (30.0 mg, 0.056 mmol). Analytical data for 14 was
essentially the same as reported previously.43
Ethyl
2,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside
(6). The title compound was obtained from ethyl 2,4,6-tri-
Methyl (phenyl 5-acetamido-7,8,9-tri-O-acetyl-3,5-
dideoxy-2-thio-D-glycero-α-D-galacto-non-2-
25
O-benzyl-3-O-picoloyl-1-thio-β-D-glucopyranoside24,
(5,
9.5 mg, 0.017 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 91% yield (8.1 mg, 0.016
mmol). Analytical data for 6 was in accordance with that
reported previously.47
ulopyranosid)onate (16). The title compound was
obtained from methyl (phenyl 5-acetamido-7,8,9-tri-O-
acetyl-3,5-dideoxy-4-O-picoloyl-2-thio-D-glycero-α-D-
galacto-non-2-ulopyranosid)onate32 (15, 22.9 mg, 0.035
mmol) and iron(III) trichloride (1.7 mg, 0.01 mmol) in
methanol (0.9 mL) and dichloromethane (0.1 mL) in
accordance with the general procedure as a colorless syrup
in 50 min in 95% yield (17.9 mg, 0.033 mmol). Alternatively,
the title compound was obtained from thioglycoside 15
(26.8 mg, 0.041 mmol) and copper(II) acetate (2.5 mg,
0.012 mmol) in methanol (0.9 mL) and dichloromethane
(0.1 mL) in accordance with the general procedure as a
colorless syrup in 20 min in 73% yield (16.2 mg, 0.030
mmol). Analytical data for 16: Rf = 0.40 (methanol/
dichloromethane, 1/9, v/v); [α]D25 +25.3 (c = 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): δ 7.53 – 7.46 (m, 2H, aromatic), 7.43
– 7.29 (m, 3H, aromatic), 5.99 (d, J = 8.4 Hz, 1H, NH), 5.32
(dd, J7,8 = 7.3 Hz, 1H, H-7), 5.27 (dt, J8,9a = 5.0 Hz, J8,9b = 2.4 Hz
1H, H-8), 4.39 (dd, J9a,9b = 12.6 Hz, 1H, H-9a), 4.26 (dd, 1H,
H-9b), 3.90 (dd, J6,7 = 10.4 Hz, 1H, H-6), 3.86 (s, 1H, 4-OH),
3.64 (dd, J4,5 = 10.6, 1H, H-4), 3.57 (s, 3H, OCH3), 3.50 (dd, J5,6
= 8.5 Hz, 1H, H-5), 2.89 (dd, J3eq,3ax = 13.0, J3eq,4 = 4.4 Hz, 1H,
H-3eq), 2.15, 2.06, 2.03, 1.96 (4 s, 12H, NCOCH3, 3 x OCOCH3),
1.86 (dd, J3ax,4 =11.4 Hz, 1H, H-3ax) ppm; 13C NMR (75 MHz,
CDCl3): δ 172.4 (x2), 170.9 (x2), 170.5 (x2), 170.3 (x2),
168.3 (x2), 136.5 (x3), 130.0, 129.0 (x4), 88.0, 74.1, 70.1,
69.2, 68.1, 62.1, 52.8 (x3), 41.4, 29.5, 23.7, 21.2 (x2), 21.0
(x3) ppm; HRMS [M+Na]+ calcd for C24H31NO11SNa
564.1510 found 564.1521.
Ethyl
2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside
(8). The title compound was obtained from 2,3,4-tri-O-
benzyl-6-O-picoloyl-1-thio-β-D-glucopyranoside16 (7, 35.4
mg, 0.055 mmol) and iron(III) trichloride (2.7 mg, 0.016
mmol) in methanol (0.9 mL) and dichloromethane (0.1 mL)
in accordance with the general procedure as a colorless
syrup in 20 min in 98% yield (28.8 mg, 0.054 mmol).
Alternatively, the title compound was obtained from
thioglycoside 7 (18.1 mg, 0.03 mmol) and copper(II) acetate
(1.8 mg, 0.009 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 10 min in 99% yield (15.2
mg, 0.03 mmol). Analytical data for 8 was in accordance
with that reported previously.48
Ethyl 2,3,4-tri-O-benzoyl-1-thio-β-D-glucopyranoside
(10). The title compound was obtained from substrate 9
(31.9 mg, 0.050 mmol) and iron(III) trichloride (2.4 mg,
0.015 mmol) in methanol (0.9 mL) and dichloromethane
(0.10 mL) in accordance with the general procedure as a
colorless syrup in 15 min in 96% yield (25.7 mg, 0.0048
mmol). Alternatively, the title compound was obtained from
thioglycoside 9 (32.3 mg, 0.050 mmol) and copper(II)
acetate (3.0 mg, 0.015 mmol) in methanol (0.9 mL) and
dichloromethane (0.10 mL) in accordance with the general
procedure as a colorless syrup in 10 min in 93% yield (25.1
mg, 0.047 mmol). Analytical data for 10 was essentially the
same as reported previously.42
Ethyl
2-O-benzoyl-4-O-benzyl-3-O-(9-
fluorenylmethoxycarbonyl)-1-thio-β-D-
galactopyranoside (18).
The title compound was
obtained from ethyl 2-O-benzoyl-4-O-benzyl-3-O-(9-
fluorenylmethoxycarbonyl)-6-O-picoloyl-1-thio-β-D-
galactopyranoside38 (17, 31.2 mg, 0.042 mmol) and
iron(III) trichloride (2.0 mg, 0.013 mmol) in methanol (0.9
mL) and dichloromethane (0.1 mL) in accordance with the
general procedure as a colorless syrup in 15 min in 91%
Ethyl
2-O-benzyl-4,6-O-benzylidene-1-thio-α-D-
mannopyranoside (12). The title compound was obtained
from ethyl 2-O-benzyl-4,6-O-benzylidene-3-O-picoloyl-1-
thio-α-D-mannopyranoside18 (11, 31.7 mg, 0.062 mmol)
and iron(III) trichloride (3.0 mg, 0.019 mmol) in methanol
(0.9 mL) and dichloromethane (0.1 mL) in accordance with

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yield (25.2 mg, 0.047 mmol). Analytical data for 18: Rf = 0.45
HRMS [M+Na]+ calcd for C15H22OD5SONI:a10.3103379./1D008O0B00f8o0u3nFd
337.1120.
25
(ethyl acetate/hexane, 1/1, v/v); [α]D +25.7 (c = 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.05 (d, 2H, aromatic),
7.69 (dd, 2H, aromatic), 7.59 – 7.22 (m, 12H, aromatic), 7.19
– 7.04 (m, 2H, aromatic), 5.76 (dd, J2,3 = 10.0 Hz, 1H, H-2),
tert-Butyldimethylsilyl
O-(2-O-benzyl-4,6-O-
benzylidene-β-D-mannopyranosyl)-(1→4)-3,6-di-O-
benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside
(26). The title compound was obtained from tert-
butyldimethylsilyl O-(2-O-benzyl-4,6-O-benzylidene-3-O-
picoloyl-β-D-mannopyranosyl)-(1→4)-3,6-di-O-benzyl-2-
deoxy-2-phthalimido-β-D-glucopyranoside23 (25, 29.0 mg,
0.028 mmol) and iron(III) trichloride (1.3 mg, 0.083 mmol)
in methanol (0.9 mL) and dichloromethane (0.1 mL) in
accordance with the general procedure as a colorless syrup
in 25 min in 91% yield (25.5 mg, 0.027 mmol). Analytical
data for 26 was essentially the same as reported
previously.23
2
5.07 (dd, J3,4 = 2.8 Hz, 1H, H-3), 4.68 (dd, J = 11.6 Hz, 2H,
CH2Ph), 4.60 (d, J1,2 = 9.9 Hz, 1H, H-1), 4.34 (dd, 1H, H-6a),
4.24 (dd, J6a,6b = 10.3 Hz, 1H, H-6b),4.08 (dd, J5,6a = 7.9 Hz, J5,6b
= 7.1 Hz, 1H, H-5), 4.04 (dd, J4,5 = 5 Hz, 1H, H-4), 3.86 (dd, J =
11.1, 6.8 Hz, 1H, Fmoc), 3.67 (m, 1H, Fmoc), 3.56 (m, 1H,
Fmoc), 2.88 – 2.60 (m, 2H, SCH2CH3), 1.23 (t, J = 7.3 Hz, 3H,
SCH2CH3) ppm; 13C NMR (75 MHz, CDCl3): δ 165.5, 154.7,
143.4, 142.9, 141.4, 141.3, 137.6, 133.5, 130.1 (x2), 129.6,
128.8 (x3), 128.7 (x3), 128.6 (x2), 128.4, 128.1 (x2), 127.3
(x2), 125.4, 125.1, 120.2, 84.0, 79.3, 79.1, 75.0, 73.5, 70.4,
62.0, 46.6, 24.1, 15.0 ppm; HRMS [M+Na]+ calcd for
C37H36O8SNa 663.2029 found 663.2027
Benzyl
O-(2-O-benzoyl-3,4,6-tri-O-benzyl-β-D-
galactopyranosyl)-(1→3)-O-(4,6-di-O-benzyl-2-deoxy-
2-phthalimido-β-D-glucopyranosyl)-(1→3)-O-(2-O-
benzoyl-4-O-benzyl-β-D-galactopyranosyl)-(1→4)-
2,3,6-tri-O-benzyl-β-D-glucopyranoside (28). The title
compound was obtained from benzyl O-(2-O-benzoyl-3,4,6-
tri-O-benzyl-β-D-galactopyranosyl)-(1→3)-O-(4,6-di-O-
benzyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl)-
(1→3)-O-(2-O-benzoyl-4-O-benzyl-6-O-picoloyl-β-D-
galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-D-
Ethyl 2,3-di-O-benzyl-4-O-p-methoxybenyl-1-thio-β-D-
glucopyranoside (20). The title compound was obtained
from compound 19 (32.8 mg, 0.052 mmol) and iron(III)
trichloride (2.5 mg, 0.015 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 16 h in 99% yield (28.5
mg, 0.054 mmol). Alternatively, the title compound was
obtained from 19 (29.4 mg, 0.047 mmol) and copper(II)
acetate (2.8 mg, 0.014 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 15 min in 85% yield (20.8
mg, 0.040 mmol).
glucopyranoside39 (27, 9.9 mg, 0.0049 mmol) and iron(III)
trichloride (2.3 mg, 0.0015 mmol) in methanol (0.9 mL) and
dichloromethane (0.1 mL) in accordance with the general
procedure as a colorless syrup in 45 min in 99% yield (9.3
mg, 0.0049 mmol). Analytical data for 28 was essentially the
same as reported previously.39
Ethyl 2,3-di-O-benzyl-1-thio-β-D-glucopyranoside (22).
The title compound was obtained from 21 (57.0 mg, 0.093
mmol) and iron(III) trichloride (4.5 mg, 0.028 mmol) in
methanol (1.8 mL) and dichloromethane (0.2 mL) in
accordance with the general procedure as a colorless syrup
in 24 h in 99% yield (37.2 mg, 0.092 mmol). Alternatively,
the title compound was obtained from thioglycoside 21
(30.4 mg, 0.049 mmol) and copper(II) acetate (3.0 mg,
0.015 mmol) in methanol (0.9 mL) and dichloromethane
(0.1 mL) in accordance with the general procedure as a
colorless syrup in 10 min in 99% yield (20.3 mg, 0.048
mmol). Analytical data for 22 was essentially the same as
reported previously.45
Attempted deprotection of Pico regioisomers
Iron(III) chloride (1.3 mg, 0.0008 mmol) was added to a
solution of ethyl 2,4,6-tri-O-benzyl-3-O-nicotinoyl-1-thio-β-
25
D-glucopyranoside24,
(29, 14.8 mg, 0.026 mmol) in
methanol (0.9 mL) and dichloromethane (0.1 mL), and the
resulting mixture was stirred under argon at rt. No reaction
took place after 24 h.
Iron(III) chloride (1.5 mg, 0.0009 mmol) was added to a
solution of ethyl 2,4,6-tri-O-benzyl-3-O-iso-nicotinoyl-1-
thio-β-D-glucopyranoside24, 25 (30, 17.3 mg, 0.031 mmol) in
methanol (0.9 mL) and dichloromethane (0.1 mL), and the
resulting mixture was stirred under argon at rt. No reaction
took place after 24 h.
Ethyl 2-O-benzyl-1-thio-α-D-mannopyranoside (24).
The title compound was obtained from 23 (36.5 mg, 0.058
mmol) and iron(III) trichloride (2.8 mg, 0.017 mmol) in
methanol (0.9 mL) and dichloromethane (0.1 mL) in
accordance with the general procedure as a colorless syrup
in 45 min in 91% yield (16.6 mg, 0.052 mmol). Alternatively,
the title compound was obtained from 23 (37.3 mg, 0.059
mmol) and copper(II) acetate (3.6 mg, 0.018 mmol) in
methanol (0.9 mL) and dichloromethane (0.1 mL) in
accordance with the general procedure as a colorless syrup
in 15 min in 83% yield (15.5 mg, 0.049 mmol). Analytical
ASSOCIATED CONTENT
Supporting Information. Spectral data for all new and
selected known compounds. This material is available free of
charge via the Internet at
.
AUTHOR INFORMATION
Corresponding Author
*E-mail: demchenkoa@umsl.edu
21
data for 24: Rf = 0.50 (acetone/toluene, 1/1, v/v); [α]D
+103.1 (c = 1.0, CHCl3); 1H NMR (300 MHz, MeOD): δ 7.49 –
7.22 (m, 5H, aromatic), 5.32 (s, 1H, H-1), 4.68 (dd, 2J = 11.9,
2H, CH2Ph), 3.97 – 3.60 (m, 6H, H-2, 3, 4, 5, 6a, 6b), 2.76 –
2.48 (m, 2H, SCH2CH3), 1.23 (t, J = 7.4 Hz, 3H, SCH2CH3) ppm;
13C NMR (75 MHz, MeOD): δ 139.7 (x2), 129.5 (x2), 129.3,
128.9, 83.1, 81.5, 75.1, 73.8, 73.3, 69.4, 62.9, 26.0, 15.4 ppm;
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by awards from the NSF (CHE-
1058112) and NIGMS (GM111835). We thank Dr. Rensheng
Luo (UM – St. Louis) for aquiring spectral data using 600 MHz

Organic & Biomolecular Chemistry
Page 8 of 9
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DOI: 10.1039/D0OB00803F
23. S. G. Pistorio, S. A. Geringer, K. J. Stine and A. V. Demchenko, J.
Org. Chem., 2019, 84, 6576-6588.
24. M. P. Mannino and A. V. Demchenko, Chem. Eur. J., 2020, 26,
2927-2937.
25. M. P. Mannino and A. V. Demchenko, Chem. Eur. J., 2020, 26,
2938-2946.
26. V. Prasad, E. T. Birzin, C. T. McVaugh, R. D. van Rijn, S. P.
Rohrer, G. Chicchi, D. J. Underwood, E. R. Thornton, A. B. Smith
III and R. Hirschmann, J. Med. Chem., 2003, 46, 1858-1869.
27. J. Y. Baek, Y.-J. Shin, H. B. Jeon and K. S. Kim, Tetrahedron Lett.,
2005, 46, 5143-5147.
28. J.-H. Ruei, P. Venukumar, A. B. Ingle and K.-K. T. Mong, Chem.
Commun., 2015, 51, 5394-5397.
29. S. Xiang, M. Hoang Kle, J. He, Y. J. Tan and X. W. Liu, Angew.
Chem. Int. Ed., 2015, 54, 604-607.
30. Y. L. Lu, B. Ghosh and K. T. Mong, Chem. Eur. J., 2017, 23, 6905-
6918.
31. Y. F. Wu and Y. F. Tsai, Org. Lett., 2017, 19, 4171-4174.
32. S. Escopy, S. A. Geringer and C. De Meo, Org. Lett., 2017, 19,
2638-2641.
33. M. Shadrick, C. Yu, S. Geringer, S. Ritter, A. Behm, A. Cox, M.
Lohman and C. De Meo, New J. Chem., 2018, 42, 14138-14141.
34. B. Jones, A. Behm, M. Shadrick, S. A. Geringer, S. Escopy, M.
Lohman and C. De Meo, J. Org. Chem., 2019, 84, 15052-15062.
35. A. Dubey, A. Tiwari and P. K. Mandal, Carbohydr. Res., 2019, 487,
107887.
36. P. Shit, A. Gucchait and A. K. Misra, Tetrahedron, 2019, 75,
130697.
37. G. Zemplén and E. Pacsu, Ber. Dtsch. Chem. Ges., 1929, 62, 1613-
1614.
38. M. D. Bandara, K. J. Stine and A. V. Demchenko, Carbohydr. Res.,
2019, 483, 107743.
39. M. D. Bandara, K. J. Stine and A. V. Demchenko, J. Org. Chem.,
2019, 84, 16192-16198.
40. M. D. Bandara, K. J. Stine and A. V. Demchenko, Carbohydr. Res. ,
2019, 486, 107824.
41. M. J. L. Thijssen, K. M. Halkes, J. P. Kamerling and J. F. G.
Vliegenthart, Bioorg. Med. Chem., 1994, 2, 1309-1317.
42. G. H. Veeneman and J. H. van Boom, Tetrahedron Lett., 1990, 31,
275-278.
43. P. Nagorny, B. Fasching, X. Li, G. Chen, B. Aussedat and S. J.
Danishefsky, J. Am. Chem. Soc., 2009, 131, 5792-5799.
44. M. Mende, M. Nieger and S. Brase, Chemi. Eur. J., 2017, 23, 12283-
12296.
45. P. J. Garegg, I. Kvarnstrom, A. Niklasson, G. Niklasson and S. C. T.
Svensson, J. Carbohydr. Chem., 1993, 12, 933-953.
46. S. Koto, T. Uchida and S. Zen, Bull. Chem. Soc. Jpn., 1973, 46,
2520-2523.
NMR spectrometer that was purchased thanks to the NSF
(award CHE-0959360).
REFERENCES
1. M. Jager and A. J. Minnaard, Chem. Commun., 2016, 52, 656-664.
2. S. S. Kulkarni, C. C. Wang, N. M. Sabbavarapu, A. R. Podilapu, P.
H. Liao and S. C. Hung, Chem. Rev., 2018, 118, 8025-8104.
3.
A. G. Volbeda, G. A. van der Marel and J. D. C. Codée, in
Protecting Groups – Strategies and Applications in Carbohydrate
Chemistry, ed. S. Vidal, Wiley-VCH, Weinheim, 2019, pp. 1-28.
T. Wang and A. V. Demchenko, Org. Biomol. Chem., 2019, 17,
4934-4950.
B. Fraser-Reid, K. N. Jayaprakash, J. C. López, A. M. Gómez and C.
Uriel, in ACS Symp. Ser. (Frontiers in Modern Carbohydrate
Chemistry) ed. A. V. Demchenko, Oxford Univ. Press, 2007, vol.
960, pp. 91-117.
4.
5.
6.
M. D. Bandara, J. P. Yasomanee and A. V. Demchenko, in Selective
Glycosylations: Synthetic Methods and Catalysts, ed. C. S. Bennett,
Wiley, 2017, pp. 29-58.
7.
8.
A. Prabhu, A. Venot and G. J. Boons, Org. Lett., 2003, 5, 4975-
4978.
Z. Wang, Z. S. Chinoy, S. G. Ambre, W. Peng, R. McBride, R. P. de
Vries, J. Glushka, J. C. Paulson and G. J. Boons, Science, 2013, 341,
379-383.
9.
S. D. Markad and R. R. Schmidt, Eur. J. Org. Chem., 2009, 5002-
5011.
10. P. H. Seeberger, Acc. Chem. Res., 2015, 48, 1450-1463.
11. D. Senf, C. Ruprecht, G. H. M. deꢀKruijff, S. O. Simonetti, F.
Schuhmacher, P. H. Seeberger and F. Pfrengle, Chem. Eur. J., 2017,
23, 3197-3205.
12. M. Guberman and P. H. Seeberger, J. Am. Chem. Soc., 2019, 141,
5581-5592.
13. F. Pfrengle and P. H. Seeberger, in Protecting Groups – Strategies
and Applications in Carbohydrate Chemistry, ed. S. Vidal, Wiley-
VCH, Weinheim, 2019, pp. 451-472.
14. K. Ágoston, H. Streicher and P. Fügedi, Tetrahedron: Asymmetry,
2016, 27, 707-728.
15. M. Panza, S. G. Pistorio, K. J. Stine and A. V. Demchenko, Chem.
Rev., 2018, 118, 8105−8150.
16. J. P. Yasomanee and A. V. Demchenko, J. Am. Chem. Soc., 2012,
134, 20097-20102.
17. J. P. Yasomanee and A. V. Demchenko, Angew. Chem. Int. Ed.,
2014, 53, 10453–10456.
18. S. G. Pistorio, J. P. Yasomanee and A. V. Demchenko, Org. Lett.,
2014, 16, 716-719.
19. J. P. Yasomanee and A. V. Demchenko, Chem. Eur. J., 2015, 21,
6572-6581.
20. A. K. Kayastha, X. G. Jia, J. P. Yasomanee and A. V. Demchenko,
Org. Lett., 2015, 17, 4448-4451.
21. M. P. Mannino, J. P. Yasomanee, A. V. Demchenko and V. Patteti,
in Carbohydrate Chemistry: Proven Synthetic Methods, eds. P.
Murphy and P. Vogel, CRC Press, Boca Raton - London - New
York, 2017, vol. 4, pp. 3-10.
47. M. J. L. Thijssen, M. H. G. Bijkerk, J. P. Kamerling and J. F. G.
Vliegenthart, Carbohydr. Res., 1998, 306, 111-125.
48. A. K. Ray and N. Roy, Carbohydr. Res., 1990, 196, 95-100.
49. S. Cherif, J.-M. Clavel and C. Monneret, J. Carbohydr. Chem.,
2002, 21, 123-130.
22. M. P. Mannino, J. P. Yasomanee and A. V. Demchenko, Carbohydr.
Res., 2018, 470, 1-7.

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Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00803F
FeCl3 or Cu(OAc)2
O
O
O
HO
(30 mol %)
O
N
MeOH/DCM (9/1)
OR
OR
91-99%
R - other protecting groups
ethers: benzyl, pMB, TBS
esters: acetyl, benzoyl, Fmoc
also benzylidene, phthalimido
Picoloyl
(Pico)
Tested for Glc, GlcN, Gal, Man, NANA and glycans
up to tetrasaccharide. Also works for multiple picoloyls
9