Glycosyl nitrates in synthesis: Streamlined access to glucopyranose building blocks differentiated at C-2

Article abstract of DOI:10.1039/c8ob00477c

In an attempt to refine a CAN-mediated synthesis of 1,3,4,6-tetra-O-acetyl-α-d-glucopyranose (2-OH glucose) we unexpectedly discovered that this reaction proceeds via the intermediacy of glycosyl nitrates. Improved mechanistic understanding of this reaction led to the development of a more versatile synthesis of 2-OH glucose from a variety of precursors. Also demonstrated is the conversion of 2-OH glucose into a variety of building blocks differentially protected at C-2, a position that is generally hard to protect regioselectively in the glucopyranose series.

Full text of DOI:10.1039/c8ob00477c

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Glycosyl nitrates in synthesis: streamlined access to glucopyranose building blocks
differentiated at Cꢀ2
Tinghua Wang, Swati S. Nigudkar, Jagodige P. Yasomanee, Nigam P. Rath, Keith J. Stine, and
Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis
One University Boulevard, St. Louis, Missouri 63121, USA
Abstract
In an attempt to refine a CANꢀmediated synthesis of 1,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀglucopyranose
(2ꢀOH glucose) we unexpectedly discovered that this reaction proceeds via the intermediacy of
glycosyl nitrates. Improved mechanistic understanding of this reaction led to the development of
a more versatile synthesis of 2ꢀOH glucose from a variety of precursors. Also demonstrated is the
conversion of 2ꢀOH glucose into a variety of building blocks differentially protected at Cꢀ2, a
position that it generally hard to protect regioselectively in the glucopyranose series.
Keywords: synthesis, mechanism, regioselectivity, protecting groups, glycosylation
Introduction
Poor accessibility to monosaccharide building blocks hampers development of all methods for
oligosaccharide synthesis. In particular, the development of automation platforms for
oligosaccharide assembly is affected. As Seeberger, the developer of the first oligosaccharide
synthesizer, notes "differentially protected monosaccharide building blocks is currently the
bottleneck for chemical synthesis".1 Indeed, most benchꢀtime is dedicated to making building
blocks. Since a large glycosyl donor excess is still needed for the automated solid phase
1

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synthesis, researchers experience significant setbacks having to make and remake building
blocks. Things are further complicated by the large variety of carbohydrate structures and
sequences. “Unlike the synthesis of peptides and oligonucleotides, there are no universal
building blocks or methods for the synthesis of all glycans.”2
DꢀGlucose, the predominant monosaccharide in plant polysaccharides and bacterial glycans,
is also one of the major components of the mammalian glycome.3 Building blocks of the Dꢀgluco
series are often first compounds tested in practically all new glycosylation reactions and
applications. Every synthetic glycoscience lab makes glucose building blocks. Paradoxically,
glucose 1 remains the hardest sugar for selective protection due to its trans-trans-trans
allꢀequatorial 2,3,4ꢀtriol arrangement (Scheme 1). Methods for selective protection of different
positions of glucose exist, but many suffer from relaxed regioselectivity and/or require multiple
steps with tedious separations of isomers.4ꢀ6 Even excellent concepts including tinꢀmediated
alkylation,7ꢀ10 phaseꢀtransfer reactions,11ꢀ13 TMSꢀmediated regioselective protection in
oneꢀpot,14,15 etc.16 all suffer from a limited scope and/or fair selectivity.
The Cꢀ2 is the most important position in synthesis because protecting groups at Cꢀ2 have a
profound effect on stereoselectivity of glycosylation. The Cꢀ2 can be either alkylated or acylated
for the synthesis of either 1,2ꢀcis or 1,2ꢀtransꢀlinked glycosides, respectively. For instance, a vast
majority of all syntheses of αꢀ (1,2ꢀcis) glucosides use 2ꢀOꢀbenzylated donors.17,18 Paradoxically,
Cꢀ2 is the most difficult position to benzylate selectively. A few approaches are known, but all
provide fair selectivity. Regioselectivity suffers during the phaseꢀtransfer differentiation of 2ꢀ vs.
3ꢀOH,13 whereas stereoselectivity suffers during glycalꢀbased syntheses that often lead to
mixtures of Glc/Man isomers.19ꢀ21 Hung’s excellent method for the oneꢀpot regioselective
protection provides no access to 2ꢀbenzyl derivatives at all.22
In addition to selective protections, acyl group migration or other selective deprotection
techniques have proven to be useful reaction pathways to access partially substituted building
blocks for oligosaccharide synthesis.23ꢀ25 A few approaches to employ such rearrangements to
obtain 2ꢀhydroxyl sugars have been developed, but many have limitations and their scope
remains narrow. The classical Helferich’s threeꢀstep inꢀsitu conversion of glucose 1 to
1,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀglucopyranose 2 depicted in Scheme 1 is in practice very elaborate. It
requires strict control of the reaction temperature and reactant addition order, but still provides a
2

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low yield of 27%.26 Somewhat more straightforward procedures have been developed for the
synthesis of 2ꢀOH galactose27 and mannose28 derivatives, but these approaches do not work for
the synthesis of 2ꢀOH glucose 2. Our reinvestigation of the synthesis of 2ꢀOH glucose led to the
discovery of a scalable oneꢀstep protocol with cerium(IV) ammonium nitrate (CAN). This
procedure afforded compound 2 in 51% isolated yield in one step from acetobromoglucose 3 and
was crossꢀvalidated via the Proven Methods book series.29
Since both Helferich’s and our CANꢀmediated reaction provide a mixture of regioisomers,
2ꢀOH 2 and its 1ꢀOH counterpart 4, the reaction was thought to proceed via the intermediacy of
an acyloxonium ion. Nevertheless, both the reaction mechanism and the modes to enhance the
2ꢀOH selectivity remain largely unknown. The lack of regiocontrol hampers the yields of these
reactions. In addition, 2ꢀOH glucose 2 can be purified by crystallization only because the
chromatographic purification is impractical due to the propensity of product 2 to rapidly
isomerize into its more stable hemiacetal counterpart 4. Reported herein is our first attempt to
understand the driving forces of this reaction and its expansion to other substrates and targets.
Scheme 1. Previous methods for the synthesis of 2ꢀOH glucose 2
Results and Discussion
The benchmark experiment for the synthesis of 2ꢀOH glucose 2 was performed under the
previously established reaction conditions. CAN (1.6 equiv) was added to a stirring solution of
330 in nitromethane and the reaction mixture was stirred for 18 h at room temperature. After
that, the mixture was quenched with water, extracted with CH2Cl2, the extract was neutralized,
dried, and concentrated. The product was purified by crystallization from diethyl ether to afford
white crystalline compound 2 in 51% yield. It is noteworthy that stoichiometric amount of
water (as a source of a proton) is needed to ensure that this reaction proceeds to completion. This
3

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requirement is supported by the fact that no reaction occurred in the presence of molecular sieves
in anhydrous nitromethane. The addition of a large excess of water helps to accelerate the
reaction, but it also significantly diminishes the regioselectivity towards the formation of 2ꢀOH
isomer 2.
Our attempts to improve the CANꢀmediated reaction rates and the yield of product 2
began with the investigation of various precursors shown in Figure 1. The reaction with glucose
pentaꢀacetate 5 was very sluggish, and only a trace amount of the desired product 2 was observed.
The addition of BF3ꢀOEt2 helped to accelerate this reaction, but also diminished the
regioselectivity of product 2 vs. hemiacetal 4. The outcome of the reaction with Sꢀethyl
glycoside 631 was similar to that of the reaction with bromide 3 and 2ꢀOH glucose 2 was isolated
in 52% yield. Accordingly, benzoylated compounds 7ꢀ932,33 were investigated as starting
materials. However, no reactions occurred under the standard CANꢀmediated activation
conditions. Attempts to investigate building blocks bearing benzylidene protecting group failed
because acetals are readily removed in the presence of CAN.
Figure 1. Preliminary investigation of other precursors 5, 6 for the synthesis of 2 and 7ꢀ9 for
the attempted synthesis of 2ꢀOH glucose tetraꢀbenzoate
Results of this preliminary study showed that only reactions with acetylated bromide 3
and thioglycoside 6 as precursors provide acceptable yields for the formation of 2 (around 50%).
Still, these reactions are rather sluggish and require at least 16ꢀ18 h to complete. This is possibly
in part due to a fairly low solubility of CAN in nitromethane, the reaction solvent used in all
preliminary experiments. Hence, as the next step forward we screened other solvents that may
provide a more suitable environment for reactions with CAN. Indeed, acetonitrile, DMF and
DMSO, all accelerated the reaction with glycosyl bromide precursor 3 (14 h, 5 h, and 1 h,
respectively). However, only reactions in acetonitrile maintained the regioselectivity of product 2
4

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vs. 4, similar to that achieved in reactions in nitromethane. With this incremental success, we
added acetonitrile in future experiments. Interestingly, nitromethane was the only solvent in this
series that worked well with Sꢀethyl glycoside 6 precursor.
The most commonly proposed mechanism of cerium(IV)ꢀmediated organic reactions
involves generation of the radicalꢀcation species along with the reduction of Ce(IV) to Ce(III)
with subsequent regeneration of Ce(IV) in the presence of an oxidant specifically added for this
purpose.34 To investigate whether the CANꢀmediated formation of 2ꢀOH glucose 2 follows this
radicalꢀregenerative pathway, we investigated whether catalytic amounts of CAN would be
sufficient to convert precursors 3 and 6 to the desired product. As a result of this experiment, we
determined that compound 3 indeed can be converted to 2ꢀOH glucose 2 in the presence of
subꢀstoichiometric amounts of CAN (range investigated 10ꢀ90 mol %) in acetonitrile. The
optimal balance between the reaction time, yield of 2, and regioselectivity of 2ꢀOH/1ꢀOH was
achieved in the presence of 0.5 equiv of CAN. This reaction allowed us to maintain the same
selectivity of product 2 (2/4 = 4/1) as that achieved with stoichiometric amount of CAN. We also
noted that typical reactions of bromide 3 were accompanied by the formation of foulꢀsmelling
brownꢀred fumes, which were determined to be bromine by a standard test reaction with AgNO3
solution. Bromine that was produced by the oxidation of bromide 3, along with the reduction of
Ce(IV) to Ce(III), can act as the coꢀoxidant to regenerate Ce(IV) from Ce(III) and thus sustain
the catalytic cycle of the reaction.
In strong contrast, the conversion of thioglycoside 6 to the 2ꢀOH derivative 2 was
incomplete in the presence of catalytic amounts of CAN, but could be driven to completion by
adding at least stoichiometric CAN. This reaction was accompanied by the formation of a white
precipitate that was determined to be (NH4)2[Ce(III)(NO3)5]·2H2O 10 by Xꢀray crystallography
(Figure 2). Based on the preliminary inꢀsitu NMR studies (see the SI), we believe that the
thioglycoside activation proceeds via the oxidation with CAN, which requires quantitative CAN.
The reaction originated from bromide 3 performed in the presence of added ethanethiol also
produced salt 10, and required stoichiometric CAN to go to completion. A reaction of ethane
thiol alone with CAN in acetonitrile also produced 10 and the NMR showed a strong shift of the
methylene signal in comparison with ethanethiol (see the SI).
Alongside, phenyl
2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀ
D
ꢀglucopyranoside 1135 was investigated providing comparable
5

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results (see the SI). Based on the chemical shifts recorded, we believe that thiols are oxidized to
the corresponding sulfonic acids, which requires stoichiometric CAN. For this reason, catalytic
amounts of CAN are insufficient to drive the conversion of Sꢀethyl glycoside 6 into 2ꢀOH
glucose 2 to completion.
Figure 2. Crystal Structure of (NH4)2[Ce(III)(NO3)5]·2H2O 10
Having determined the involvement of CAN and the beneficial role of acetonitrile in
accelerating the reaction of bromide 3, we turned our attention to identifying more effective
modes for accelerating the rates of the formation of 2ꢀOH glucose 2. For this reason, we chose a
more reactive glycosyl iodide 1236 as the starting material. Indeed, the reaction of iodide 12 in
the presence of 0.5 equiv of CAN in acetonitrile was much faster (3 h), but it also led to a
reduced regioselectivity for the formation of 2 vs. 4 (2/4 = 2/1). Intriguingly, an additional spot,
right underneath the spot corresponding to the starting material 12, was observed by TLC during
the reaction. This additional compound was not present in the final reaction mixture, which was
indicative of the presence of a quasiꢀstable reaction intermediate en route to the products. All
initial attempts to isolate this additional compound/intermediate from the prematurely quenched
reaction mixtures by column chromatography have failed. Persistent inꢀsitu tracking of reaction
mixtures with NMR, gave us a hypothesis that this additional compound might have been
glycosyl nitrate 13 (Scheme 2). This elusive intermediate was reported previously,37 but we
needed the additional proof to support this hypothesis. On the basis of this discovery, reactions
6

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initiated from bromide 3 were reinvestigated and the same intermediate 13 was detected by NMR
(Scheme 2a). The formation of nitrate 13 was previously overlooked because this compound has
the same retention factor (Rf) as that of bromide 3. Based on this evidence, we concluded that the
synthesis of 2 with CAN undergoes the pathway via the intermediacy of reactive glycosyl nitrate
13 that gets hydrolyzed into 2ꢀOH 2 (and its 1ꢀOH counterpart 4).
Scheme 2. The discovery of glycosyl nitrate intermediate 13
OAc
O
OAc
O
AcO
AcO
OAc
O
CAN
AcO
AcO
AcO
AcO
HO
OAc
ONO2
MeCN
2
AcO
AcO
13
LG
OAc
O
12: LG = I
3: LG = Br
AcO
AcO
OH
AcO
4
Since the synthesis of 2ꢀOH glucose 2 was found to proceed via glycosyl nitrate
intermediate 13, we investigated other nitrate salt reagents with the general idea of investigating
their applicability to the synthesis of glycosyl nitrates and, by extension, compound 2. Among
screened common ammonium, potassium, silver(I), copper(II), magnesium(II), lead(II),
barium(II), and ferric nitrates, only AgNO3 provided the enhancement of the regioselectivity
towards 2ꢀOH product over the original procedure with CAN. Thus, the highest ratio of 2 to 4
(5/1) was obtained from bromide 3 in the presence of 50 mol % of AgNO3. This approach
allowed us to obtain nitrate 13 by the reaction of bromide 3 with stoichiometric AgNO3 in the
presence of molecular sieves in dry acetonitrile (Scheme 3). As a result, nitrate 13 was obtained
in a pure crystalline form in 77% yield and its structure was confirmed by spectroscopic and
crystallographic techniques. It should be noted that AgNO3 (in combination with γꢀcollidine in
7

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benzene) was previously used for the synthesis of nitrate 13.37
8

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Scheme 3. Synthesis of acetylated and benzoylated glucosyl nitrates 13 and 14
OAc
O
OAc
O
AgNO3, 3Å MS
AcO
AcO
AcO
AcO
ONO2
dry MeCN, 5 min
77%
AcO
AcO
Br
3
13
OBz
O
OBz
O
AgNO3, 3Å MS
BzO
BzO
BzO
BzO
ONO2
dry MeCN, 5 min
91%
BzO
BzO
Br
7
14
The proton NMR spectrum of 13, partially depicted in Scheme 2c, is consistent with the
previously recorded reaction mixtures resulting from halides 3 and 12 and CAN (Scheme 2a and
b). Xꢀray crystal structure of nitrate 13 is depicted in Figure 3. In a similar fashion,
benzoylated glycosyl nitrate 14 was synthesized by reaction of bromide 7 with stoichiometric
AgNO3 in the presence of molecular sieves in dry acetonitrile (Scheme 3). As a result, nitrate 14
was obtained in a pure crystalline form in 91% yield and its structure was confirmed by
spectroscopic and crystallographic techniques. Xꢀray crystal structure of nitrate 14 is depicted
in Figure 3.
Figure 3. XꢀRay structures of acetylated nitrate 13 and its benzoylated counterpart 14
When the crystalline glycosyl nitrate 13 was reꢀdissolved in acetonitrile, 2ꢀOH derivative
2 was readily formed in 6 h in the absence of any additional reagents. Even better
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regioselectivity (2/4 = 6/1) was recorded in this reaction. A preparativeꢀscale (3ꢀ5 g) synthesis
followed by the purification by crystallization from ether gave 2ꢀOH glucose 2 in 75% yield.
Based on the experimental evidence obtained by the inꢀsitu reaction monitoring by NMR and
eventually the isolation and characterization of the reaction intermediate, we propose the
following mechanism of this reaction. Silver(I)ꢀassisted bromide leaving group departure leads to
the formation of the glycosyl nitrate. This may proceed via the intermediacy of oxacarbenium
and acyloxonium intermediates. However, this could also proceed via a concerted displacement
via a sixꢀmembered intermediate A shown in Scheme 4. While we do not yet have sufficient
experimental evidence to unambiguously prove this Waldenꢀlike inversion pathway,38 this
hypothesis is supported by previous observations. As shown by many since the pioneering work
by Isbell,39 the displacement of αꢀbromides under KoenigsꢀKnorr conditions40 can proceed via
the SN2ꢀlike mechanism. We believe that the complete βꢀselectivity obtained in the synthesis of
glycosyl nitrates is also due to the occurrence of Walden inversion, not the participatory effect of
the 2ꢀOꢀacetyl substituent. The glycosyl nitrate intermediate can readily dissociate to form the
acyloxonium ion intermediate B. The latter is then attacked by the molecule of water to form the
tetrahedral intermediate C upon the loss of the proton. This hydrate intermediate C is too
unstable to be isolated, but if essentially the same transformation in performed in the presence of
methanol and molecular sieves a stable methyl 1,2ꢀorthoacetate is formed instead. Since the Oꢀ2
oxygen in C is more basic than its anomeric counterpart the protonation is preferentially
occurring at Cꢀ2 leading to the 2ꢀOH glucose as the kinetic product. The alternative pathway via
the protonation of Oꢀ1 is slower, but it can be favored in the presence of a large excess of water.
In these cases, decreased regioselectivity towards the formation of the 2ꢀOH product is observed.
Scheme 4. A plausible reaction mechanism for the synthesis of 2ꢀOH with silver nitrate
10

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It has become common knowledge that aqueous acidic conditions promote isomerization
of 2ꢀOH glucose 2 into hemiacetal 4. However, when compounds 2 and 4 were treated
individually with AgNO3 or with HNO3 in acetonitrile no product interchange was detected. This
implies that these reaction conditions do not promote the isomerization of 2ꢀOH glucose 2 into
its thermodynamically more stable 1ꢀOH counterpart. Besides, bromide 3 is very stable in
acetonitrile and no hydrolysis would occur without adding nitrate reagents. Bromide 3 would
slowly hydrolyze in the presence of silver(I) oxide producing hemiacetal 4, but not 2ꢀOH glucose
2. Similarly, the methyl orthoester would remain stable under the reaction conditions, but
would slowly decompose into a mixture of a hemiacetal and methyl glycoside, but not 2ꢀOH
glucose, in the acidic medium. Based on these experiments, we conclude that the formation of
nitrate 13 is fundamental to the high regioselectivity obtained for the formation of 2ꢀOH glucose
2.
Having achieved certain success in the synthesis of 2ꢀOH glucose 2, we turned our
attention towards further modification of this regioselectively protected intermediate.
Benzylation of 2ꢀOH glucose 2 with benzyl triflate41 or 2,2,2ꢀtrichloroacetimidate42ꢀ45 was
previously established. Other reagents including the Dudley reagent46,47 and benzyl
Nꢀaryltrifluoroacetimidate48 may also be suitable for this purpose. Therefore, herein we
predominantly investigated esterꢀtype protecting groups. This study included the comparative
investigation of conventional stepwise approaches and more streamlined oneꢀpot
conversionꢀprotection reactions. Levulinoyl group was introduced by using levulinic acid in the
presence of EDC coupling reagent and DMAP. A sequential twoꢀstep conversion of bromide 3 in
the presence of CAN with the subsequent treatment with LevOH/EDC/DMAP afforded
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2ꢀOꢀlevulinoyl derivative 15 in 63% yield (entry 1, Table 1). When essentially the same sequence
was performed in the presence of AgNO3 instead of CAN, product 15 was obtained in 71% yield
(entry 2). The direct conversion of nitrate 13 into 2ꢀOꢀlevulinoyl tetraacetate 15 in the presence
of LevOH/EDC/DMAP produced the product in 85% yield (entry 3). Picoloyl group was
introduced in a similar fashion using picolinic acid, EDC and DMAP. Reactions of bromide 3
with CAN, bromide 3 with AgNO3, and nitrate 13 followed by esterification with
PicoOH/EDC/DMAP afforded 2ꢀOꢀpicoloyl tetraacetate 16 in 49%, 51% and 67% yield,
respectively (Entries 4ꢀ6). Along similar lines, we have also investigated the introduction of
trifluoromethanesulfonyl ester, a possible intermediate for the synthesis of mannosamine and its
derivatives. Mannosamine is a common component of bacterial glycans49ꢀ51 and a biosynthetic
precursor of sialic acids.52ꢀ54 Reactions of bromide 3 with CAN, bromide 3 with AgNO3, and
nitrate 13 followed by sulfonylation with triflic anhydride in the presence of pyridine afforded
2ꢀOꢀtrifluoromethanesulfonyl tetraacetate 17 in 54%, 52% and 67% overꢀall yield, respectively
(Entries 7ꢀ9). Benzoylated glucosyl nitrate 14 could also be converted into 2ꢀOꢀtriflyl
tetrabenzoate 18 in 54% yield (entry 10).
Table 1. The synthesis of selectively 2ꢀOꢀesterified derivatives 15ꢀ18
Entry
Starting Material
Additive
CAN (0.5 equiv)
AgNO3 (0.5 equiv)
none
Conditions
Product
15
Yield
63%
71%
85%
49%
51%
67%
1
2
3
4
5
6
A
A
A
B
B
B
3
3
15
13
3
15
CAN (0.5 equiv)
AgNO3 (0.5 equiv)
none
16
3
16
13
16
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7
8
CAN (0.5 equiv)
AgNO3 (0.5 equiv)
none
C
C
C
C
54%
52%
67%
54%
3
3
17
17
17
18
9
13
14
10
none
Conclusions
Reported herein is an improved method for the synthesis of 2ꢀOH glucose, which is an
important synthon for production of differentially protected building blocks of Dꢀglucose. It
was discovered that the synthesis of 2ꢀOH glucose proceeds via the intermediacy of glycosyl
nitrates. Glycosyl nitrates of the 2ꢀaminosugars have been investigated quite extensively as
intermediates of the azidonitration reaction of glycals.55 Glycosyl nitrates of neutral,
perꢀoxygenated sugar series, are much more rare, and their utility in synthesis remains practically
unexplored beyond a few isolated examples.56ꢀ58 Esterification of Cꢀ2 hydroxyl group could be
performed without the isolation of the 2ꢀOH glucose intermediate. This, along with the
previously established methods for 2ꢀOꢀbenzylations under acidic or neutral conditions, offers a
convenient route for the synthesis of important intermediates and building blocks for
oligosaccharide synthesis.
Experimental
General. The reactions were performed using commercial reagents. The ACS grade solvents
used for reactions were purified and dried in accordance with standard procedures. Cerium(IV)
ammonium nitrate (CAN) was dried for 6 h under reduced pressure. CH2Cl2 was distilled from
CaH2 directly prior to application. Molecular sieves (3 Å) used for reactions, were crushed and
activated in vacuo at 390 °C for 8 h in the first instance and then for 2ꢀ3 h at 390 °C directly
prior to application. Reactions were monitored by TLC on Kieselgel 60 F254 (EM Science). The
compounds were detected by examination under UV light and by charring with 10% sulfuric acid
in methanol. Column chromatography was performed on silica gel 60 (70ꢀ230 mesh). Solvents
o
were removed under reduced pressure at <40 C. Optical rotations were measured with a Jasco
13
Pꢀ2000 polarimeter. 1H NMR spectra were recorded at 300 MHz and C NMR spectra were
1
recorded at 75 MHz. The H chemical shifts are referenced to the signal of the residual CHCl3
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13
(δH = 7.26 ppm) for solutions in CDCl3. The C chemical shifts are referenced to the central
signal of CDCl3 (δC = 77.23 ppm) for solutions in CDCl3. HRMS were recorded with a JEOL
MStation (JMSꢀ700) Mass Spectrometer.
General procedure for the synthesis of 1,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀglucopyranose (2) with
CAN (Method 1). CAN (33.3 mg, 0.061 mmol) was added to a solution of bromide 3 (50 mg,
0.121 mmol) in acetonitrile (1.0 mL) and water (2.2 ꢁL), and the resulting reaction mixture was
stirred for 16ꢀ20 h at rt. After that, the volatiles were removed under reduced pressure. The
residue was dissolved in CH2Cl2 (~10 mL) and washed with water (5 mL), 10% aq. Na2S2O3 (5
mL), and water (3 × 5 mL). The organic layer was separated, dried over MgSO4, and
concentrated in vacuo. The residue was crystallized from dry diethyl ether to afford the title
compound as colorless crystals. Analytical data for 2: Rf = 0.40 (ethyl acetate/hexanes, 1/1,
v/v); m. p. 98ꢀ99 °C (diethyl ether); [α]D23 +115.0 (c = 1, CHCl3); Lit. data:26 m. p. 98–100 ˚C,
1
[α]D +141 (c = 3.2, CHCl3); H n.m.r.: δ, 2.03, 2.06, 2.08, 2.18 (4 s, 12H, 4 x COCH3), 2.66 (d,
1H, J2,OH = 8.2 Hz, OH), 3.88 (ddd, 1H, J2,3 = 9.8 Hz, Hꢀ2), 3.98ꢀ4.04 (m, 1H, J5,6a = 2.5 Hz, J5,6b
= 4.3 Hz, Hꢀ5), 4.05 (dd, 1H, J6a,6b = 12.6 Hz, Hꢀ6a), 4.25 (dd, 1H, Hꢀ6b), 5.07 (dd, 1H, J4,5 = 9.8
13
Hz, Hꢀ4), 5.25 (dd, 1H, J3,4 = 9.8 Hz, Hꢀ3), 6.22 (d, 1H, J1,2 = 3.8 Hz, Hꢀ1) ppm; C n.m.r.: δ,
20.7, 20.8, 20.9, 21.1, 61.7, 67.6, 69.7, 69.8, 73.2, 91.4, 169.4, 169.7, 170.9, 171.5 ppm;
HRꢀFAB MS [M+Na]+ calcd for C14H20O10Na 371.0954, found 371.0970.
General procedure for the synthesis of 1,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀglucopyranose (2) with
AgNO3 (Method 2). AgNO3 (10.3 mg, 0.061 mmol) was added to a solution of bromide 3 (50
mg, 0.121 mmol) in acetonitrile (1.0 mL) and water (2.2 ꢁL), and the resulting reaction mixture
was stirred for 16ꢀ20 h at rt. After that, the volatiles were removed under reduced pressure. The
residue was dissolved in CH2Cl2 (~10 mL) and washed with water (5 mL), 10% aq. Na2S2O3 (5
mL), and water (3 × 5 mL). The organic layer was separated, dried over MgSO4, and
concentrated in vacuo. The residue was crystallized from dry diethyl ether to afford the title
compound as colorless crystals.
General procedure for the synthesis of 1,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀglucopyranose (2) from
14

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nitrate 13 (Method 3). Compound 13 (50 mg, 0.127 mmol) was dissolved in acetonitrile (1.0
mL) and water (2.2 ꢁL) and the reaction mixture was stirred for 6 h at rt. After that, the volatiles
were removed under reduced pressure. The residue was dissolved in CH2Cl2 (~10 mL) and
washed with water (5 mL), sat. aq. NaHCO3 (5 mL), and water (3 × 5 mL). The organic layer
was separated, dried over MgSO4, and concentrated in vacuo. The residue was crystallized from
dry diethyl ether to afford the title compound as colorless crystals.
2,3,4,6ꢀTetraꢀOꢀacetylꢀβꢀDꢀglucopyranosyl nitrate (13). AgNO3 (2.2 g, 12.9 mmol) was added
to a solution of bromide 3 (5.0 g, 12.2 mmol) in dry acetonitrile (30 mL) and the resulting
mixture was stirred for 5 min at rt. After that, the solids were filtered off through a pad of Celite
and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2
(~250 mL) and washed with water (50 mL), 1% aq. NaOH (50 mL), and water (3 × 50 mL).
The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was
crystallized from dry diethyl ether (~40 mL) to afford the title compound (3.68 g, 77% yield) as
22
colorless crystals. Analytical data for 13: Rf = 0.75 (ethyl acetate/hexanes, 1/1, v/v); [α]D ꢀ4.3
(c = 1, CHCl3); Lit. data:37 m. p. 96–97 ˚C, [α]D ꢀ4 (c 0.4, acetonitrile), ꢀ8 (c 1.0, carbon
1
tetrachloride); H n.m.r.: δ, 2.02, 2.04, 2.07, 2.09 (4 s, 12H, 4 × COCH3), 3.87ꢀ3.93 (m, 1H,
J5,6a = 2.3 Hz, J5,6b = 4.6 Hz, Hꢀ5), 4.14 (dd, 1H, J6a,6b = 12.5 Hz, Hꢀ6a), 4.29 (dd, 1H, Hꢀ6b),
5.13 (m, 2H, J2,3 = 8.4 Hz, J4,5 = 9.2 Hz, Hꢀ2, 4), 5.30 (dd, 1H, J3,4 = 9.2 Hz, Hꢀ3), 5.80 (d, 1H,
13
J1,2 = 8.4 Hz, Hꢀ1) ppm; C n.m.r.: δ, 20.5, 20.6, 20.7, 21.0, 61.2, 67.3, 67.8, 72.6, 72.8, 96.9,
168.9, 169.3, 170.1, 170.6 ppm; HRꢀFAB MS [M+Na]+ calcd for C14H19NO12Na 416.0805,
found 416.0785.
Preparativeꢀscale synthesis of 1,3,4,6ꢀTetraꢀOꢀacetylꢀαꢀDꢀglucopyranose (2) from nitrate 13.
Nitrate 13 (3.68 g, 9.36 mmol) was dissolved in acetonitrile (35 mL) and water (0.15 mL), and
the resulting reaction mixture was stirred for 6 h at rt. After that, the volatiles were removed
under reduced pressure. The residue was dissolved in CH2Cl2 (~100 mL) and washed with water
(30 mL), 10% aq. Na2S2O3 (30 mL), and water (3 × 10 mL). The organic layer was separated,
dried over MgSO4, and concentrated in vacuo. The residue was crystallized from dry diethyl
ether (~30 mL) to afford the title compound (2.44 g, 75% yield) as colorless crystals.
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2,3,4,6ꢀTetraꢀOꢀbenzoylꢀβꢀDꢀglucopyranosyl nitrate (14). AgNO3 (0.27 g, 1.60 mmol) was
added to a solution of bromide 7 (1.00 g, 1.52 mmol) in dry acetonitrile (10 mL) and the reaction
mixture was stirred for 5 min at rt. After that, the solids were filtered off through a pad of Celite
and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2
(~75 mL) and was washed with water (30 mL), 1% aq. NaOH (30 mL), and water (3 × 30 mL).
The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was
crystallized from dry diethyl ether (~10 mL) to afford the title compound (0.88 g, 91% yield) as
22
colorless crystals. Analytical data for 14: Rf = 0.60 (ethyl acetate/hexanes, 3/7, v/v); [α]D
+46.8 (c = 1, CHCl3); m. p. 94.6–96.0 ˚C; 1H n.m.r.: δ, 4.38 (m, 1H, J5,6a = 5.3 Hz, J5,6b = 3.0 Hz,
Hꢀ5), 4.50 (dd, 1H, J6a,6b = 12.3 Hz, Hꢀ6a), 4.66 (dd, 1H, Hꢀ6b), 5.66 (dd, 1H, J2,3 = 9.3Hz, Hꢀ2),
5.73 (dd, 1H, J4,5 = 9.3 Hz, Hꢀ4), 6.01 (dd, 1H, J3,4 = 9.3 Hz, Hꢀ3), 6.15 (d, 1H, J1,2 = 8.2 Hz,
13
Hꢀ1), 7.27ꢀ7.61 (m, 12H, aromatic), 7.80ꢀ8.07 (m, 8H, aromatic) ppm; C n.m.r.: δ, 62.6, 68.5,
68.7, 72.7, 73.5, 97.4, 128.4 (×2), 128.5 (×2), 128.6 (×2), 128.7 (×6), 129.9 (×4), 130.1 (×
2), 130.2 (×2), 133.4, 133.7, 133.8, 133.9, 164.8, 165.1, 165.7, 166.2 ppm; HRꢀFAB MS
[M+Na]+ calcd for C34H27NO12Na calcd: 664.1431, found 664.1425.
1,3,4,6ꢀTetraꢀOꢀacetylꢀ2ꢀOꢀlevulinoylꢀαꢀDꢀglucopyranose (15). From bromide 3 (Methods
1 and 2). CAN (33.3 mg, 0.061 mmol, Method 1) or AgNO3 (10.3 mg, 0.061 mmol, Method 2)
was added to a solution of bromide 3 (50 mg, 0.121 mmol) in acetonitrile (1.0 mL) and water
(2.2 ꢁL), and the resulting reaction mixture was stirred for 16ꢀ20 h at rt. After that, the volatiles
were removed under reduced pressure. The residue was dissolved in CH2Cl2 (~10 mL) and
washed with water (5 mL), 10% aq. Na2S2O3 (5 mL), and water (3 × 5 mL). The organic layer
was separated, dried over MgSO4, and concentrated in vacuo. Crude residues obtained by
Method 1 or 2 were dissolved in dry CH2Cl2 (1.0 mL) and levulinic acid (24.9 mg, 0.214 mmol),
EDC (55.0 mg, 0.287 mmol) and DMAP (3.5 mg, 0.029 mmol) were added. The resulting
reaction mixture was stirred under argon for 1 h at rt. After that, the reaction mixture was diluted
with CH2Cl2 (~50 mL) and washed with water (10 mL), sat. aq. NaHCO3 (10 mL), and water (3
× 10 mL). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (ethyl acetateꢀtoluene gradient
16

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elution) to afford the title compound in 63% (from 3 by Method 1) or 71% (from 3 by Method 2),
respectively, as a clear syrup. From nitrate 13 (Method 3). Nitrate 13 (50 mg, 0.127 mmol)
was dissolved in acetonitrile (1.0 mL) and water (2.2 ꢁL), and the resulting reaction mixture was
stirred for 6 h at rt. After that, the volatiles were removed under reduced pressure. The residue
was dissolved in CH2Cl2 (~10 mL) and washed with water (5 mL), sat. aq. NaHCO3 (5 mL), and
water (2 × 5 mL). The organic layer was separated, dried over MgSO4, and concentrated in
vacuo. Crude residue was dissolved in dry CH2Cl2 (1.0 mL) and levulinic acid (24.9 mg, 0.214
mmol), EDC (55.0 mg, 0.287 mmol) and DMAP (3.5 mg, 0.029 mmol) were added. The
resulting reaction mixture was stirred under argon for 1 h at rt. After that, the reaction mixture
was diluted with CH2Cl2 (~50 mL) and washed with water (10 mL), sat. aq. NaHCO3 (10 mL),
and water (3 × 10 mL). The organic layer was separated, dried over MgSO4, and concentrated
in vacuo. The residue was purified by column chromatography on silica gel (ethyl
acetateꢀtoluene gradient elution) to afford the title compound in 85% yield as a clear syrup.
Analytical data for 15: Rf = 0.25 (ethyl acetate/hexanes, 1/1, v/v); [α]D22 +76.4 (c = 1, CHCl3);
1H n.m.r.: δ, 2.00, 2.03, 2.04, 2.11, 2.14 (5 s, 15H, 5 x COCH3), 2.29ꢀ2.80 (m, 4H, CH2CH2),
3.99ꢀ4.12 (m, 2H, J5,6b = 4.4 Hz, J6a,6b = 12.7 Hz, Hꢀ5, Hꢀ6a), 4.22 (dd, 1H, Hꢀ6b), 5.01ꢀ5.14 (m,
2H, J2,3 = 9.8 Hz, Hꢀ2, 4), 5.44 (dd, 1H, J3,4 = 9.8 Hz, Hꢀ3), 6.26 (d, 1H, J1,2 = 3.7 Hz, Hꢀ1) ppm;
13C n.m.r.: δ, 20.6, 20.7 (x 2), 20.9, 27.6, 29.7, 37.6, 61.5, 67.8, 69.3, 69.6, 69.8, 89.0, 168.8,
169.4, 170.4, 170.6, 171.5, 206.0 ppm; HRꢀFAB MS [M+Na]+ calcd for C19H26O12Na 469.1322,
found 469.1298.
1,3,4,6ꢀTetraꢀOꢀacetylꢀ2ꢀOꢀpicoloylꢀαꢀDꢀglucopyranose (16). From bromide 3 (Method 1
or 2) or nitrate 13 (Method 3). Crude residues obtained from bromide 3 or nitrate 13, as
described for the synthesis of 15, were dissolved in dry CH2Cl2 (1.0 mL) and picolinic acid (26.5
mg, 0.214 mmol), EDC (55.0 mg, 0.287 mmol), and DMAP (3.5 mg, 0.029 mmol) were added.
The resulting reaction mixture was stirred under argon for 1 h at rt. After that, the reaction
mixture was diluted with CH2Cl2 (~50 mL) and washed with water (10 mL), sat. aq. NaHCO3 (10
mL), and water (3 × 10 mL). The organic layer was separated, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl
acetateꢀtoluene gradient elution) to afford the title compound in 49% (from 3 by Method 1), 51%
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(from 3 by Method 2), or 67% (from 13 by Method 3) yield, respectively, as a white foam.
22
Analytical data for 16: Rf = 0.20 (ethyl acetate/hexanes, 1/1, v/v); [α]D +104.0 (c = 1,
1
CHCl3); H n.m.r.: δ, 1.94, 2.03, 2.08, 2.14 (4 s, 12H, 4 × COCH3), 4.03ꢀ4.21 (m, 2H, J5,6b
=
3.8 Hz, J6a,6b = 12.3 Hz, Hꢀ5, 6a), 4.28 (dd, 1H, Hꢀ6b), 5.21 (dd, 1H, J4,5 = 9.8 Hz, Hꢀ4), 5.36 (dd,
1H, J2,3 = 10.3 Hz, Hꢀ2), 5.67 (dd, 1H, J3,4 = 9.8 Hz, Hꢀ3), 6.46 (d, 1H, J1,2 = 3.7 Hz, Hꢀ1),
7.46ꢀ8.73 (m, 4H, aromatic) ppm; 13C n.m.r.: δ, 20.6, 20.7, 20.8, 20.9, 61.4, 67.7, 69.8, 69.9, 70.4,
89.0, 125.3, 127.4, 137.2, 146.6, 150.4, 163.5, 168.7, 169.4, 170.2, 170.7 ppm; HRꢀFAB MS
[M+Na]+ calcd for C20H23NO11Na 476.1169, found 476.1125.
1,3,4,6ꢀTetraꢀOꢀacetylꢀ2ꢀOꢀtrifluoromethanesulfonylꢀαꢀ
D
ꢀglucopyranose (17).
From
bromide 3 (Method 1 or 2) or nitrate 13 (Method 3). Crude residues obtained from bromide 3
or nitrate 13, as described for the synthesis of 15, were dissolved in pyridine (1.0 mL) and
CH2Cl2 (0.1 mL) and triflic anhydride (36 ꢁL, 0.214 mmol) was added dropwise under argon at
0 °C. The resulting reaction mixture was stirred for 1 h at 0 °C rt. After that, the volatiles were
removed under reduced pressure, and the residue was coꢀevaporated with toluene. The residue
was diluted with CH2Cl2 (~50 mL) and washed with water (10 mL), sat. aq. NaHCO3 (10 mL),
and water (3 × 10 mL). The organic layer was separated, dried over MgSO4, and concentrated
in vacuo. The residue was purified by column chromatography on silica gel (ethyl
acetateꢀtoluene gradient elution) to afford the title compound in 54% (from 3 by Method 1), 52%
(from 3 by Method 2), or 67% (from 13) yield, respectively, as a white foam. Analytical data for
17 was in accordance with that reported previously.59 HRꢀFAB MS [M+Na]+ calcd for
C15H19F3O10SNa 503.0447, found 503.0460.
1,3,4,6ꢀTetraꢀOꢀbenzoylꢀ2ꢀOꢀtrifluoromethanesulfonylꢀαꢀDꢀglucopyranose (18). Nitrate 14
(811 mg, 1.26 mmol) was dissolved in acetonitrile (8.0 mL) and water (23 ꢁL) and the resulting
mixture was stirred for 24 h at rt. After that, the volatiles were removed under reduced pressure.
The residue was dissolved in CH2Cl2 (~100 mL) and washed with water (30 mL), sat. aq.
NaHCO3 (30 mL), and water (3 × 30 mL). The organic layer was separated, dried over MgSO4,
and concentrated in vacuo. Crude residue was dissolved in pyridine (10 mL) and CH2Cl2 (1.0 mL)
and triflic anhydride (0.32 mL, 1.90 mmol) was added dropwise under argon at 0 °C. The
18

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resulting reaction mixture was stirred for 1 h at 0 °C. After that, the volatiles were removed
under reduced pressure, and the residue was coꢀevaporated with toluene. The residue was diluted
with CH2Cl2 (~100 mL) and washed with water (30 mL), sat. aq. NaHCO3 (30 mL), and water (3
× 30 mL). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (ethyl acetateꢀhexanes gradient
elution) to afford the title compound in 54% yield as a white amorphous solid. Analytical data
22
1
for 18: Rf = 0.50 (ethyl acetate/hexanes, 3/7, v/v); [α]D +60.7 (c = 1, CHCl3); H n.m.r.: δ,
4.40ꢀ4.50 (m, 1H, Hꢀ6a), 4.65ꢀ4.52 (m, 2H, Hꢀ5, 6b), 5.29 (dd, 1H, J2,3 = 10.0 Hz, Hꢀ2), 5.76 (dd,
1H, J4,5 = 9.9 Hz, Hꢀ4), 6.25 (dd, 1H, J3,4 = 9.9 Hz, Hꢀ3), 6.82 (d, 1H, J1,2 = 3.8 Hz, Hꢀ1),
7.31ꢀ7.75 (m, 12H, aromatic), 7.88ꢀ8,04 (m, 6H, aromatic), 8.14ꢀ8.22 (m, 2H, aromatic) ppm;
13C n.m.r.: δ, 62.0, 68.7, 69.5, 70.4, 80.2, 89.1, 118.3 (q), 128.1, 128.2, 128.3, 128.5 (×2), 128.6
(×2), 129.1 (×2), 129.4, 129.9 (×2), 130.0 (×4), 130.3 (×2), 130.4 (×2), 133.9 (×2), 134.5
(×2), 164.0, 165.1, 165.5, 166.1 ppm; HRꢀFAB MS [M+Na]+ calcd for C35H27F3O12SNa
751.1073, found 751.1064.
Xꢀray Structure Determination
Crystals of appropriate dimension were obtained by slow evaporation. Single crystals of
appropriate dimensions were mounted on MiTeGen cryoloops in random orientations.
Preliminary examination and data collection were performed using a Bruker X8 Kappa Apex II
Charge Coupled Device (CCD) Detector system single crystal XꢀRay diffractometer equipped
with an Oxford Cryostream LT device. All data were collected using graphite monochromated
Mo Kα radiation (λ= 0.71073 Å) from a fine focus sealed tube XꢀRay source. Preliminary unit
cell constants were determined with a set of 36 narrow frame scans. Typical data sets consist of
combinations of ϖ and φ scan frames with typical scan width of 0.5° and counting time of 15
seconds/frame at a crystal to detector distance of 4.0 cm. The collected frames were integrated
using an orientation matrix determined from the narrow frame scans. Apex II and SAINT
software packages (Bruker Analytical X-Ray, Madison, WI, 2010) were used for data collection
and data integration. Analysis of the integrated data did not show any decay. Final cell constants
were determined by global refinement of reflections harvested from the complete data set.
Collected data were corrected for systematic errors using SADABS (Bruker Analytical X-Ray,
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Madison, WI, 2010) based on the Laue symmetry using equivalent reflections.
Crystal data and intensity data collection parameters are listed in Tables 1Sꢀ6S for compound 10,
7Sꢀ13S for compound 13, and 14Sꢀ20S for compound 14. Structure solution and refinement were
carried out using the SHELXTLꢀ PLUS software package.60 The structures were solved by
direct methods and refined successfully with full matrix leastꢀsquares refinements by minimizing
Σw(Fo2ꢀFc2)2. The nonꢀhydrogen atoms were refined anisotropically to convergence. All
hydrogen atoms were treated using appropriate riding model (AFIX m3). The final residual
values and structure refinement parameters are listed in Table 1S for compound 10, 7S for
compound 13, 14S for compound 14. Absolute structure determinations were carried out using
Parson’s method61 for compounds 13 and 14. Twin data reduction and twin refinement (HKLF 5)
refinement was carried out for compound 10. Disordered water molecules could not be modeled
for compound 14 and squeezed data (PlatonꢀSqueeze) was used for the final refinement. As the
crystals for compound 14 were weakly diffracting we shipped the crystals for synchrotron data
collection at ALS. However, no data set could be collected with the crystals as the crystals had
decomposed in shipping, even under dry ice.
Complete listings of positional and isotropic displacement coefficients for hydrogen atoms,
anisotropic displacement coefficients for the nonꢀhydrogen atoms are listed as supplementary
material (Tables 2S, 4S and 5S for compound 10; 8S, 10S and 11S for compound 13; 15S, 17S
and 18S for compound 14). Bond lengths [Å] and angles [°] as well as torsion angles [°] are
listed as supplementary material (Tables 3S and 6S for compound 10; 9S and 12S for compound
13; 16S and 19S for compound 14).
ASSOCIATED CONTENT
1
13
Supporting Information. H and C NMR spectra for all new compounds have been supplied as
the Supporting Information. Table of calculated and observed Xꢀray structure factors for
compounds 10, 13, and 14 are available in electronic format. This material is available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
20

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* Alexei V. Demchenko. Eꢀmail: demchenkoa@umsl.edu
Author Contributions
The manuscript was written through contributions of all authors. / All authors have given
approval to the final version of the manuscript.
Funding Sources
This work was supported by grants from the National Institute of General Medical Sciences
(GM111835 and GM120673).
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