Selective Acetylation of Non-anomeric Groups of per- O-Trimethylsilylated Sugars

Article abstract of DOI:10.1021/acs.joc.0c02813

Selective modification of the hydroxyl groups of sugars has been a long-standing challenge due to their proximate relative reactivity. Herein, we report a TMSOTf-catalyzed selective acetylation of the non-anomeric hydroxyl groups of several per-O-TMS-protected sugar substrates while leaving their anomeric group unaffected. In addition to standing versatile by itself, the anomeric O-TMS group left intact can be functionalized to afford key sugar precursors such as imidate donors, which could otherwise be synthesized via a stepwise anomeric deprotection-functionalization procedure.

Full text of DOI:10.1021/acs.joc.0c02813

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Selective Acetylation of Non-anomeric Groups of
per‑O‑Trimethylsilylated Sugars
Welday Desta Weldu and Cheng-Chung Wang*
Cite This: J. Org. Chem. 2021, 86, 5336−5344
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ABSTRACT: Selective modification of the hydroxyl groups of
sugars has been a long-standing challenge due to their proximate
relative reactivity. Herein, we report a TMSOTf-catalyzed selective
acetylation of the non-anomeric hydroxyl groups of several per-O-
TMS-protected sugar substrates while leaving their anomeric group
unaffected. In addition to standing versatile by itself, the anomeric
O-TMS group left intact can be functionalized to afford key sugar
precursors such as imidate donors, which could otherwise be
synthesized via a stepwise anomeric deprotection-functionalization
procedure.
part from the obvious roles of carbohydrates as energy
precursors for such kinds of adjustments.7 The majority of per-
Asources and structural components, their involvement in acetylation reactions are carried out using excess acetic
anhydride (Ac2O) as an acetylating agent in the presence of
pyridine8 or its derivatives like 4-(dimethylamino)pyridine9,10
as catalysts, though plenty of other protocols are also
available.11 In order to address the issue of regioselectivity in
acetylations, a number of attempts have been made over the
past several years involving reactions by both chemical12−16
and enzymatic17,18 methods. However, these reactions utilize
building blocks where the anomeric hydroxyl functionality is
either already protected or free but is one of the target groups
in the acetylation process. In the meantime, when the
anomeric center is required to undergo base-mediated
nucleophilic reactions such as during the preparation of
imidate donors and tert-butyldimethylsilyl functionalized
acceptors,19,20 anomeric deprotection is needed, leading to
the incessant protecting group manipulation procedure.
Ascribed to their role as temporary masking agents and
enhancing the solubility of sugar building blocks,3 per-O-
trimethylsilylated (per-O-TMS-protected) sugarswith a
different anomeric substituent such as thiotoluene (STol),
thiophenyl (SPh), or methoxy (OMe) groupshave been
used as transient precursors in numerous carbohydrate
synthetic protocols. Hung and co-workers used per-O-silylated
sugars to construct various orthogonally protected carbohy-
drate building blocks via a regioselective sequential one-pot
molecular recognition events attributed to their prevalence at
the surface of cells1 has long been the focus of scientific
curiosity questing to decipher the mechanism of their
functions. Although the most ubiquitous in nature, accessing
carbohydrates of interest in pure form and adequate quantity
for biological evaluation has been almost formidable mainly
due to their structural complexity and diversity.2 In this regard,
synthesis has become one of the most reliable ways of
obtaining the target molecules of biological values. Never-
theless, the multifunctionality of carbohydrates also poses
invincible difficulties during synthesis. The hydroxyl groups
that are not required to make subsequent reaction should be
masked with appropriate protecting groups which can easily be
removed when needed. Meanwhile, this circuitous protection-
deprotection process during the preparation of carbohydrate
building blocks remains a tedious task in organic synthesis
demanding innovative strategies.3,4
In the customary practice, the installation of carbohydrate
protecting groups often begins with the modification of the
anomeric hydroxyl group owing to the unique reactivity
features rendered by its hemiacetal functionality.5 As the
anomeric center is also the site of glycosidic linkage formation
in subsequent glycosylation reactions, its alteration should be
made prudently based on the synthetic design. In this case, if
the building block of interest is a glycosyl donor, the anomeric
center should be equipped with a leaving group, whereas, if an
acceptor is needed for glycosylations other than 1,1′-glycosidic
linkage formation, the anomeric hydroxyl moiety should be
masked with a protecting group compatible with ensuing
reaction conditions.6 Because of their ease of preparation and
good stability, per-acetylated sugars are commonly used as
Received: November 25, 2020
Published: February 26, 2021
https://dx.doi.org/10.1021/acs.joc.0c02813
© 2021 American Chemical Society
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protection procedure under trimethylsilyl trifluoromethanesul-
fonate (TMSOTf) catalysis.21−23 Beau’s group also followed a
similar approach but under different catalytic conditions,24,25
showing the indispensable role of TMS-protected sugars as
starting materials for multiple transformations. Likewise, fully
O-silylated (i.e., including the anomeric center) sugars have
been widely applied in different sugar derivatizations where the
anomeric O-TMS is mainly the reaction site. For instance,
Gervay-Hague’s group used this strategy to obtain per-O-
silylated glycosyl iodides which were employed in subsequent
transformations,26−28 while Wang and co-workers followed a
similar approach for microwave-assisted synthesis of 1,6-
anhydrosugars via intramolecular anomeric protection and to
obtain orthogonally protected thioglycoside donors.29,30 On
the other hand, regioselective modifications of per-O-TMS-
protected sugars without affecting the anomeric O-TMS group
have also been reported.31,32 However, further manipulations
through the ordinary protection-deprotection pathways are
inevitable in order to access 1-O-TMS glycosyl precursors
which can either be directly used in ensuing glycosylation
reactions or be transformed into other leaving groups such as
imidates.
Over the past several years, a plethora of reports have shown
the synthetic versatility of 1-O-TMS-equipped sugars in which
they have been employed as either glycosyl donors or
acceptors in the construction of various carbohydrate
scaffolds.33−41 Unfortunately, the preparation of these building
blocks from per-acetylated starting materials through the step-
uneconomic anomeric deprotection-silylation procedures
requiring high energy and time for workup and purifica-
tionhas limited their synthetic utility. On the other hand, 1-
O-TMS per-acetyl sugars can still be synthesized in two steps
(anomeric deacetylation to obtain a hemiacetal and silylation)
from commercially available per-acetyl precursors. However,
per-acetyl sugars are more expensive and may not be
commercially available compared to the free sugar starting
materials. Moreover, the silylation of a free anomeric hydroxyl
group needs tremendous effort to optimize the conditions for
the stereoselective formation of the new bond.42 Herein, we
report an expeditious synthesis of per-acetylated 1-O-TMS
containing sugars through TMSOTf-catalyzed acetylation of
the non-anomeric hydroxyl groups of per-O-TMS-protected
carbohydrates while leaving their 1-O-TMS group intact with
the retention of its precedent stereochemistry. Thus, our
established methodology can be applied to speed up chemical
glycosylation by alleviating the cumbersome protection-
deprotection challenges.
Table 1. Optimization of Selective Acetylation Condition
yield (%)
entry
Ac2O (equiv)
TMSOTf (equiv)
time (h)
3
4
a
1
2
3
4
10
10
6
0.4
0.4
0.2
0.2
20
4
1
86
55
2
a
35
91
88
4
2
a
No product isolated.
HMBC correlations (Figure S1). Encouraged by the
unprecedented formation of 1-O-TMS-equipped product 3,
we intended to optimize the acetylation reaction condition so
as to obtain an improved yield. Gratifyingly, sagacious
reduction of the Ac2O and TMSOTf equivalences to 6 and
0.2, respectively, and quenching the reaction after 1 h gave 3 in
an excellent yield (91%) with a trace amount of 4 (2%) (Table
1, entry 3). Further decrement of Ac2O to 4 equiv did not
significantly alter the yield of 3 but took longer reaction time,
and thus, 6 equiv of Ac2O and 0.2 equiv of TMSOTf were
taken as the optimum conditions for further acetylation
attempts.
Our finding reveals that the non-anomeric hydroxyl groups
of per-O-TMS sugar 2 are acetylated, leaving the anomeric O-
TMS group unaffected. On the other hand, Gervay-Hague
observed that the anomeric O-TMS group of N-acetamido-
protected sugar analogue of 2 was acetylated next to the
primary O-TMS (6-O-TMS) group, thereby obtaining 1,6-di-
O-acetylated species, while the 3- and 4-O-TMS groups
remained intact.12
With this discovery and the optimized selective acetylation
condition at our disposal, we investigated the viability of the
methodology in other per-O-TMS-protected amino-sugars
prepared in accordance with reported silylation and N-
functionalization procedures.43 To this end, commercially
available D-glucosamine (1), D-galactosamine (5), and D-
mannosamine (6) hydrochloride monosaccharides were used
to prepare per-O-TMS substrates 7, 8, and 9, respectively.
These easily accessed per-O-silylated sugars were subsequently
subjected to our established selective acetylation condition,
and the results are shown in Table 2. To our delight, the
respective 1-O-TMS acetylated products 10−12 (Table 2,
entries 1−3) were obtained in good yields within 1 h reaction
time, proving that the anomeric O-TMS group is still the least
reactive regardless of the type and the conformation of the
amino substituent at C-2. Likewise, the use of benzoic
anhydride (Bz2O) as an acylating agent could also provide
per-benzoylated 1-O-TMS product 13 in a moderate yield after
a longer reaction time despite the low reactivity of the bulky
Bz2O (Table 2, entry 4).44,45 On the other hand, treatment of
the per-O-TMS substrate 2 with acetyl chloride (AcCl) did not
form any acetylated product, likely due the inertness of AcCl
toward activation by the TMSOTf catalyst (Scheme S1).
Our early premise regarding the observed difference in the
acetylation order of the TMS-masked hydroxyl groups of the
sugar substrates 2, 7, and 8 targeted at the presence of the
amino substituent at C-2. Accordingly, we asserted that the
pre-installed electron withdrawing C-2 substituents, namely,
the trichloroacetamido (TCANH) and the azido (N3) groups,
We commenced our investigation with the synthesis of a
per-O-silylated amino sugar derivative of commercially
available D-glucosamine hydrochloride (1) based on our
reported method in two steps.43 The resulting compound 2
was then treated with various equivalents of Ac2O under
TMSOTf catalysis as shown in Table 1. The formation of the
fully acetylated compound 4 as the sole product required 20 h
under treatment of substrate 2 with 10 equiv of Ac2O and 0.4
equiv of TMSOTf (added in two portions), resulting in 86%
yield (Table 1, entry 1). Close scrutiny of the reaction progress
by thin layer chromatography (TLC) under the same reaction
condition showed the full consumption of the starting material
and the formation of two major spots after stirring for 4 h.
Neutralizing the reaction mixture with triethyl amine (Et3N),
followed by workup, gave compounds 3 (35%) and 4 (55%)
(Table 1, entry 2) as verified with three bonds separated
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Table 2. Selective Acetylation of Amino Sugar Substrates 2,
7−9 with Pre-installed C-2 Substituent
Table 3. Selective Acetylation of Sugar Substrates 19−23
without Pre-installed C-2 Substituent
a
b
Yield of β-isomer of 12 was determined from NMR. Condition:
Bz2O (6 equiv), TMSOTf (0.3 equiv), 4 h.
in addition to the endocyclic oxygen atom, were playing a role
in attenuating the nucleophilicity of the oxygen moiety at the
anomeric O-TMS group, thereby rendering it the least reactive
in the acetylation process. In order to vindicate this
presumption, we investigated the acetylation of per-O-TMS-
protected sugars without a pre-installed substituent at C-2.
Thus, we first tested our protocol in a per-O-TMS-protected
derivative of D-glucose (14) and was then extended to other
analogous sugar substrates. Accordingly, we prepared the
respective per-O-TMS-protected sugars from commercially
available 14, D-galactose (15), D-mannose (16), L-fucose (17),
and the disaccharide lactose (18) based on a procedure from
the literature.46 Then, the resulting per-O-TMS-protected
products 19−23 were subjected to our developed acetylation
condition. Astonishingly, the respective per-acetylated sugars
24−28 (Table 3, entries 1−5) were obtained in good to
moderate yields in which the non-anomeric hydroxyl groups
were acetylated, while leaving the anomeric O-TMS group
intact. These results indicate that the oxygen atom in the
anomeric O-TMS group is still the least reactive, even
compared to the axial groups in the per-O-TMS substrates
20−23 which are typically considered less reactive for steric
reasons. To this effect, the yield of 25 (Table 3, entry 2) is
particularly the lowest presumably due to the poor reactivity of
the 4-O-TMS group of 20. On the other hand, previous works
utilizing different acetylation conditions revealed that the
anomeric O-TMS group of both per-O-silylated monosacchar-
ides and disaccharides was among the first groups to undergo
the silyl exchange reaction.12,13,16 Meanwhile, the attainment
of per-acetylated 1-O-TMS lactose 28 (Table 3, entry 5) shows
that our established acetylation protocol can effectively
differentiate the slight reactivity variations in multi-hydroxy-
lated sugars.
hydroxyl groups are considered the most reactive due to less
steric congestion. Likewise, excluding the anomeric hydroxyl
group because of its unique reactivity features, the secondary
hydroxyl groups are usually differentiated based on their spatial
orientation as either axial or equatorial where the former is
usually deemed less reactive due to stereoelectronic
factors.47−50 Therefore, we presumed that the order of the
reactivity of each O-TMS group in our TMSOTf-catalyzed
acetylation reaction is an extrapolation of the order of the
reactivity of the respective hydroxyl groups. In order to
substantiate this preposition, we decided to probe the order of
acetylation of each O-TMS group of 2 by treating a limited
amount of the acetylating agent. To this end, 2 was treated
with 1.5 equiv of Ac2O and 0.2 equiv of TMSOTf. To the
contrary of our assumption where the less sterically hindered
primary 6-O-TMS group was perceived as the most reactive,
the 3-O-TMS group was acetylated first, providing 29 in 56%
yield, together with 3,6-di-O-acetylated compound 30 as a
minor product (Scheme 1). Although not clear as to why this
difference occurred, the 6-O-TMS group was reported to be
the first to be acetylated under Gervay-Hague’s slightly basic
condition.12 Meanwhile, treatment of 8 with 1.5 equiv of Ac2O
resulted in a mixture of inseparable products, making it difficult
to identify each product formed, and thus, the use of 2.0 equiv
of Ac2O afforded the 1,3-di-O-TMS containing product 31 in
30% yield, along with the 1-O-TMS product 11 in 42%.
Similarly, treatment of 20 with 3.0 equiv of Ac2O gave majorly
the 1-O-TMS product 25, together with the partially acetylated
products 32 and 33 in 13% and 8% yields, respectively
(Scheme 1). With these results of selective acetylation
reactions in hand, we proposed the plausible mechanism of
our method as shown in Scheme 2 for the acetylation of
substrate 2.
The exploitation of the marginal nucleophilicity differences
in the hydroxyl groups of glycopyranose sugars has been a
common strategy to separately modify each group using a
variety of reaction conditions; it is well-recognized that the
electron density around a nucleophile is influenced by its
inductive and steric environments. Accordingly, the primary
As depicted in Scheme 2, the TMSOTf catalyst first activates
the acetylating agent (Ac2O), resulting in the formation of
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a subsequent cascade of acetylation reactions with the
remaining O-TMS groups.
Scheme 1. Selective Acetylation Reactions of 2, 8, and 20
Myriads of research outputs have shown the synthetic
versatility of 1-O-TMS-equipped sugar substrates which are
employed as both glycosyl donors and acceptors such as in the
synthesis of O-alkylated glycosides and 1,1′-disaccharides
including trehalose.33,37,39−41 On the other hand, the
acquisition of the per-acetylated 1-O-TMS sugars in such
short steps and with no sophisticated workup or purification
procedures can provide a unique opportunity for the
expeditious synthesis of carbohydrate building blocks of
interest. Moreover, the possibility of modifying the 1-O-TMS
group under either basic or acidic conditions is another
captivating feature of our methodology as demonstrated for
product 3 as a representative example (Scheme 3). In this
Scheme 3. Preparation of Versatile Carbohydrate
Precursors from 1-O-TMS Sugars
Scheme 2. Plausible Mechanism of TMSOTf-Catalyzed
Selective Acetylation
regard, with the use of 1-O-TMS precursor 3, imidate donors
can easily be prepared which could otherwise be synthesized
through the commonly employed time-consuming anomeric
deprotection of fully acetylated sugars such as 4.51 In the
meantime, imidate donor 36 was synthesized in a single step
from the reaction of 1-O-TMS sugar 3 and trichloroacetonitrile
(Cl3CCN) in DCM utilizing tetrabutylammonium fluoride
(TBAF) to cleave the TMS group in situ. Likewise, the same
sugar building block 3 was used to prepare p-methoxyphenyl
(MP)-protected sugar 37 which is usually synthesized from
fully acetylated precursor 4 under triflic acid-mediated
reaction.52 In our case, the mixture of 3 and p-methoxyphenol
(p-MeOPhOH) in DCM was treated with BF3·OEt2 to afford
37 in a good yield. Interestingly, Scheme 3 is a manifestation
that the easily accessible 1-O-TMS group can serve the
purpose of a free hydroxyl or an anomeric acetyl group
provided that suitable reaction conditions are used and, thus,
can also be used to prepare thioglycosides.53
It is to be noted from Scheme 3 that the ability of 1-O-TMS
substrates to react as either nucleophiles or electrophiles has an
extraordinary consequence in determining the stereochemistry
of the final products. In this respect, with the driving force of
F−Si bond formation, the TBAF-mediated reaction of 3
cleaves the O−Si bond,54 generating intermediate 38 which
consists of a negatively charged oxygen nucleophile that attacks
the electrophilic center of Cl3CCN to give tetrabutylammo-
nium ion-stabilized intermediate 39. Therefore, the stereo-
chemistry at C-1 of 3 is also retained in the imidate donor 36,
providing only a single isomer (Scheme 4a). On the other
hand, under the Lewis acid BF3·OEt2-mediated condition, the
O-TMS group of 3 is activated to form complex 40, thereby
serving as a leaving group to generate the incipient
oxocarbenium intermediate 41 which has been detected via
cold-ion infrared spectroscopy.55 The suitably placed sub-
adduct 34 which, then, initially reacts with the most
nucleophilic O-TMS group of 2, yielding intermediate 35.
Subsequent bond cleavage and rearrangement in 35 gives the
partially acetylated sugar 29, regenerating the catalyst to
resume the reaction cycle, and successive reactions of the
remaining O-TMS groups of 29 based on the order of their
reactivity afford the final per-acetylated 1-O-TMS desired
product 3.
Although convenient to separately modify using hemiacetal
chemistry, the anomeric hydroxyl group when considered
alone is less reactive as a nucleophile since its lone pair
electrons are tightly held by the hemiacetal environment.5
Therefore, we postulate that the proximity of the anomeric
group to the electron withdrawing endocyclic oxygen (i.e., its
hemiacetal functionality) plays a prominent role in enfeebling
the nucleophilicity of the 1-O-TMS moiety by withholding its
lone pair of electrons, hence making it remain unaffected until
the other groups are acetylated. Furthermore, steric congestion
of the 1-O-TMS group due to 1,2-cis interaction may be
considered as an additional factor contributing to its low
reactivity with the exception of mannose derivatives such as 21
which gave a good selectivity irrespective of such steric
influence. Unlike Gervay-Hague’s condition that proceeds
through prior cleavage of the most electrophilic TMS group by
an acetate anion,13 there is no co-reagent in our protocol that
can cleave the TMS group before reaction with the acetylating
agent. Thus, the most nucleophilic O-TMS group is believed to
attack the activated acetylating agent like 34, thereby leading to
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completion by TLC, the reaction mixture was filtered, the residue was
washed with ethyl acetate (EA), and the filtrate was concentrated to
get the respective O-silylated desired free amino products. To the
suspension of each silylated product in dichloromethane/pyridine (7/
3, 0.2 M solution) under a N2 atmosphere was then added
trichloroacetyl chloride (1.1 equiv) at 0 °C under a N2 atmosphere.
After stirring for 2 h, the reaction mixture was concentrated in rota
and was filtered with a Celite pad by washing it with EA/hexane (1/
10). The filtrate was then evaporated in vacuo. Resilylation of partially
cleaved TMS groups using HMDS (2.5 equiv) and TMSOTf (0.1
equiv) and direct rota after checking completion of reaction (roughly
30 min) furnished the desired N-functionalized per-O-TMS products
2, 8, and 9, respectively.
Scheme 4. Proposed Mechanism of Imidate Formation (a)
and p-Methoxyphenyl Installation (b) Reactions of
Substrate 3
After silylating glucosamine hydrochloride 1 (2.5 g) with HMDS as
described above, it was subjected to the following azide transfer
reaction. To a cooled (in ice bath) suspension of the O-silylated
product in DCM (0.5 M solution) was added 4-dimethylaminopyr-
idine (3.0 equiv), followed by direct addition of TfN3 which was
prepared separately from reaction of NaN3 (4 equiv) and Tf2O (1.2
equiv) in a mixture of water and DCM (1:2, 0.2 M solution). After
stirring for 12 h at rt, the reaction mixture was quenched with glycine
(1.5 equiv) and filtered by washing the residue with hexane. The
filtrate was concentrated in vacuo and resilylated as already mentioned
above to get the desired per-O-trimethylsilylated azido product 7.
General Procedure for Silylation of Non-amino Sugars.26,46
To a stirring solution of the free sugars 14−18 (2.5 g each) in
dimethylformamide (DMF, 0.2 M solution) was added triethyl amine
(Et3N, 1.1 equiv for each free hydroxyl group). This content was
placed in an ice bath, and trimethylsilyl chloride (TMSCl, 1.1 equiv
for each free hydroxyl group) was added. After stirring the reaction
mixture at rt for 4 h for the monosaccharides and 8 h for the
disaccharide, it was diluted with hexane and crushed ice was added.
The organic layer was separated, and the aqueous layer was washed
one more time with hexane. The combined organic layers were
washed three times with water, dried over MgSO4, and concentered in
vacuo to get the desired per-O-silylated products 19−23.26,46
General Procedure for the Synthesis of 1-O-TMS Products.
A solution of each per-O-silylated sugars 2, 8, and 9 (1.0 g, 1.63
mmol) in DCM (8.2 mL, 0.2 M solution) was placed in an ice bath, to
which were successively added Ac2O (1.0 mL, 9.80 mmol) and
TMSOTf (61 μL, 0.33 mmol). To a suspension of 7 (1.0 g, 2.03
mmol) in DCM (10 mL, 0.2 M solution) in an ice bath were
sequentially added Ac2O (1.2 mL, 9.80 mmol) and TMSOTf (76 μL,
0.41 mmol). Similarly, each solution of 19−21 (1.0 g, 1.85 mmol) in
DCM (9 mL, 0.2 M) was treated with Ac2O (1.1 mL, 11.1 mmol) and
TMSOTf (68 μL, 0.37 mmol). Suspensions of 22 (1.0 g, 2.21 mmol)
in DCM (11.1 mL) and 23 (1.0 g, 1.09 mmol) in DCM (5.5 mL)
were, respectively, treated with Ac2O (1.0 mL, 9.95 mmol) and
TMSOTf (81 μL, 0.44 mmol) and Ac2O (1.2 mL, 11.45 mmol) and
TMSOTf (41 μL, 0.22 mmol). The ice bath was then removed, and
after stirring each reaction mixture for 1 h at rt, it was diluted with
DCM and neutralized with Et3N. Then, saturated NaHCO3 solution
was added and the organic layer separated. The organic layer was
further washed with saturated NaHCO3 solution twice, concentrated
in vacuo, and purified by flash column chromatography using EtOAc/
Hexane as eluent to obtain the respective per-acetylated 1-O-TMS
products 3, 10−13, and 24−28.
stituent at C-2 of 41 instigates the well-known neighboring
group participation to give the five-membered ring oxazoli-
nium intermediate56 42 which dictates the stereochemistry of
the resulting product 37. Consequently, nucleophilic attack by
p-MeOPhOH on the open β-face of 42 with concomitant loss
of proton (H+) yields 37 with inversion of stereochemistry
relative to that of 3 (Scheme 4b).
In conclusion, we have developed an expeditious protocol
that enables accessing a versatile class of sugar precursors
which can significantly abate the main bottleneck of
carbohydrate synthesis: notably prolonged reaction time due
to the protection-deprotection manipulation of protecting
groups. Thus, our methodology can remarkably speed up
chemical glycosylation in conjunction with other proven
strategies such as orthogonal protection.7,57
EXPERIMENTAL SECTION
■
General Information. All reagents obtained from commercial
sources were used without further purification. All reactions were
carried out under a nitrogen atmosphere and in flame-dried glassware.
All solvents were purified and dried from a sealed purification system
equipped with activated Al2O3. Flash column chromatography was
conducted using Silica Gel Geduran Si 60 (0.040−0.063 mm, E.
Merck). TLC was performed on precoated glass plates of Silica Gel 60
F254 (0.25 mm, E. Merck), and detection was executed either by
spraying with a solution of Ce(SO4)2, (NH4)2MoO4, and H2SO4 in
water and subsequently heating on a hot plate or UV light (254 nm).
1H NMR, 13C NMR, DEPT, HSQC, and HMBC spectra were
recorded by Bruker AV400, Av500, or N600 MHz. 1H and 13C
chemical shifts are in ppm designated relative to Me4Si using the
CDCl3 lock signal at δ 7.24 and 77.23, respectively. Multiplicities are
reported by using the following symbols: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet. Coupling constant (J) values are
stated in hertz. Mass spectra were analyzed by a Waters Premier XE
instrument using a TOF mass analyzer with ESI mode. Structural
assignments were made with additional information from selective
1D-TOCSY experiments. Specific rotations were measured on a Jasco
P-2000 digital polarimeter using a 50 mm cell at 589 nm and are
reported in 10−1·deg·cm2·g−1 at ambient temperature; the sample
concentrations are in g·dL−1. IR spectra were analyzed with a
PerkinElmer Paragon 1000 FT-IR spectrometer. Melting points were
determined with an MP-2D melting apparatus.
General Procedure for Silylation and N-Functionalization of
Amino Sugars.43 To a stirring solution of the free amino sugar
hydrochlorides 1, 5, or 6 (2.5 g each) in 50 mL of acetonitrile
(CH3CN) was added hexamethyldisilazane (HMDS, 2.5 equiv) at
room temperature (rt) under a N2 atmosphere, and the mixture was
allowed to stir for 3 h at the same temperature. After checking its
General Procedure for Selective Acetylation Reactions of 2,
8, and 20. To each 0.2 M DCM solution of 2 (1.0 g, 1.63 mmol), 8
(1.0 g, 1.63 mmol), and 20 (1.0 g, 1.85 mmol) in an ice bath were,
respectively, added Ac2O (0.24 mL, 2.45 mmol; 0.33 mL, 3.3 mmol;
0.54 mL, 5.55 mmol), and TMSOTf (0.2 equiv each). After removing
the ice bath and stirring each reaction mixture for 15−30 min at rt, it
was diluted with DCM and neutralized with Et3N. Then, saturated
NaHCO3 solution was added and the organic layer separated. The
organic layer was further washed with saturated NaHCO3 solution
twice, concentrated in vacuo, and purified by flash column
chromatography using EA/Hexane or EtOAc/Toluene as eluent to
obtain the respective partially acetylated products 29−33.
5340
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J. Org. Chem. 2021, 86, 5336−5344

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Trimethylsilyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroacetamido-
α-D-glucopyranoside (3). TLC: EtOAc/Hexane = 1:3, Rf = 0.3.
Colorless syrup (Yield: 775 mg, 91%). [α]3D0 +71.9° (c 1.3, CH2Cl2).
7.87 (m, 4H, ArH), 7.53 (m, 1H, ArH), 7.50−7.45 (m, 2H, ArH),
7.40 (m, 2H, ArH), 7.33 (m, 4H, ArH), 7.13 (d, J = 8.6 Hz, 1H, NH),
5.80 (t, J = 10.3 Hz, 1H, H-3), 5.68 (t, J = 9.4 Hz, 1H, H-4), 5.42 (d, J
= 3.0 Hz, 1H, H-1), 4.56−4.37 (m, 4H, H-2, H-5, H-6), 0.23 (s, 9H,
CH3) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 167.4, 166.4, 165.4,
162.1 (all CO), 133.8, 133.7, 133.3, 130.1, 130.0, 130.0 (all CH),
129.8, 129.0, 128.8 (all C), 128.6, 128.6 (CH), 92.2 (C), 91.8 (C-1),
71.4, 69.2, 68.4 (all CH), 63.3 (CH2), 55.6 (CH), 0.1 (CH3) ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C32H32NO9NaSiCl3
730.0804; found 730.0801.
IR (CH2Cl2) v 3425, 2959, 1747, 1721, 1515, 1224, 1049, 848 cm−1.
̅
1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 9.0 Hz, 1H, NH), 5.29 (t,
J = 9.7 Hz, 1H, H-3), 5.24 (d, J = 3.4 Hz, 1H, H-1), 5.08 (t, J = 9.7
Hz, 1H, H-4), 4.22 (dd, J = 11.6, 4.4 Hz, 1H, H-6a), 4.13 (ddd, J =
10.5, 9.1, 3.5 Hz, 1H, H-2), 4.08−4.00 (m, 2H, H-5, H-6b), 2.06 (s,
3H, CH3), 2.00 (s, 3H, CH3), 1.98 (s, 3H, CH3), 0.16 (s, 9H, CH3)
ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 171.4, 170.6, 169.5, 161.9
(all CO), 92.3 (CCl3), 91.6 (C-1), 70.8, 68.2, 68.0 (all CH), 62.3
(CH2), 55.0 (CH), 20.8, 20.8, 20.7 (all CH3), −0.1 (CH3) ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H26NO9NaSiCl3
544.0335; found 544.0328.
Trimethylsilyl 2,3,4,6-Tetra-O-acetyl-α-D-glucopyranoside (24).58
TLC: EtOAc/Hexane = 1:2, Rf = 0.3. Colorless syrup (Yield: 607 mg,
78%). [α]2D7 +107.3° (c 1.1, CH2Cl2). IR (CH2Cl2) v 2958, 1745,
̅
1367, 1219, 1040, 847 cm−1. 1H NMR (500 MHz, CDCl3) δ 5.45 (t, J
= 9.7 Hz, 1H, H-3), 5.34 (d, J = 3.2 Hz, 1H, H-1), 5.00 (t, J = 9.7 Hz,
1H, H-4), 4.77 (dd, J = 10.1, 3.4 Hz, 1H, H-2), 4.22 (dd, J = 12.4, 4.9
Hz, 1H, H-6a), 4.11 (m, 1H, H-5), 4.00 (dd, J = 12.2, 2.2 Hz, 1H, H-
6b), 2.04 (s, 3H, CH3), 2.00 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.97 (s,
3H, CH3), 0.12 (s, 9H, CH3) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 170.9, 170.4, 170.3, 169.8 (all CO), 90.5 (C-1), 72.0,
70.3, 68.9, 67.2 (all CH), 62.3 (CH2), 20.9, 20.9, 20.9, 20.8 (all CH3),
−0.1 (CH3) ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H28O10NaSi 443.1344; found 443.1349.
Trimethylsilyl 3,4,6-Tri-O-acetyl-2-azido-2-deoxy-α-D-glucopyra-
noside (10). TLC: EtOAc/Hexane = 1:3, Rf = 0.3. Colorless syrup
(Yield: 703 mg, 86%). [α]3D0 +160.7° (c 1.4, CH2Cl2). IR (CH2Cl2) v
̅
2951, 2108, 1750, 1224, 1048, 848 cm−1. 1H NMR (400 MHz,
CDCl3) δ 5.46 (t, J = 9.6 Hz, 1H, H-3), 5.26 (d, J = 3.2 Hz, 1H, H-1),
4.98 (t, J = 9.8 Hz, 1H, H-4), 4.24 (dd, J = 12.1, 4.8 Hz, 1H, H-6a),
4.11 (m, 1H, H-5), 3.99 (dd, J = 12.2, 2.0 Hz, 1H, H-6b), 3.14 (dd, J
= 10.5, 3.1 Hz, H-2), 2.04 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.00 (s,
3H, CH3), 0.19 (s, 9H, CH3) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 170.7, 170.3, 169.9 (all CO), 93.0 (C-1), 70.3, 68.9, 67.6
(all CH), 62.3 (CH2), 61.7 (CH), 20.9, 20.9, 20.8 (all CH3), −0.1
(CH3) ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H25N3O8NaSi 426.1303; found 426.1298.
Trimethylsilyl 2,3,4,6-Tetra-O-acetyl-α-D-galactopyranoside
(25).42 TLC: EtOAc/Hexane = 1:2, Rf = 0.4. White solid (Yield:
506 mg, 65%). Mp = 116−118 °C. [α]2D8 +124.8° (c 1.1, CH2Cl2). IR
(CH2Cl2) v 2960, 1746, 1371, 1223, 1061, 847 cm−1. 1H NMR (500
̅
MHz, CDCl3) δ 5.40−5.38 (m, 2H, H-1, H-4), 5.30 (dd, J = 10.7, 3.2
Hz, 1H, H-3), 5.01 (dd, J = 10.8, 3.3 Hz, 1H, H-2), 4.30 (m, 1H, H-
5), 4.05−3.99 (m, 2H, H-6), 2.08 (s, 3H, CH3), 2.01 (s, 3H, CH3),
1.99 (s, 3H, CH3), 1.94 (s, 3H, CH3), 0.11 (s, 9H, CH3) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 170.6, 170.5, 170.4, 170.3 (all
Trimethylsilyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroacetamido-
α-D-galactopyranoside (11). TLC: EtOAc/Hexane = 1:3, Rf = 0.3.
Sticky solid (Yield: 733 mg, 86%). [α]3D0 +89.0° (c 1.0, CH2Cl2). IR
(CH2Cl2) v 3422, 3340, 2960, 1750, 1719, 1518, 1372, 1226, 1079,
̅
1
848 cm−1. H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 9.3 Hz, 1H,
NH), 5.38 (d, J = 2.9 Hz, 1H, H-4), 5.29 (d, J = 3.5 Hz, 1H, H-1),
5.25 (dd, J = 11.1, 3.2 Hz, 1H, H-3), 4.40 (m, 1H, H-2), 4.27 (t, J =
6.5 Hz, 1H, H-5), 4.10−4.02 (m, 2H, H-6), 2.14 (s, 3H, CH3), 2.02
(s, 3H, CH3), 1.97 (s, 3H, CH3), 0.17 (s, 9H, CH3) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 171.0, 170.6, 170.4, 162.1 (all CO),
92.5 (CCl3), 92.3 (C-1), 68.4, 67.5, 67.1 (all CH), 62.2 (CH2), 50.9
(CH), 20.9, 20.8, 20.8 (all CH3), −0.1 (CH3) ppm. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H26NO9NaSiCl3 544.0335; found
544.0327.
CO), 90.9 (C-1), 69.2, 68.4, 67.8, 66.2 (all CH), 62.1 (CH2), 20.9,
20.8, 20.8, 20.8 (all CH3), −0.2 (CH3) ppm. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C17H28O10NaSi 443.1344; found 443.1344.
Trimethylsilyl 2,3,4,6-Tetra-O-acetyl-α-D-mannopyranoside
(26).59 TLC: EtOAc/Hexane = 1:2, Rf = 0.4. Colorless syrup
(Yield: 591 mg, 76%). [α]2D8 +39.1° (c 1.1, CH2Cl2). IR (CH2Cl2) v
̅
1
2960, 1745, 1368, 1218, 1143, 1075, 1048, 875, 847 cm−1. H NMR
(500 MHz, CDCl3) δ 5.39 (dd, J = 10.1, 2.7 Hz, 1H, H-3), 5.22 (t, J =
10.0 Hz, 1H, H-4), 5.09 (m, 2H, H-1, H-2), 4.22 (dd, J = 12.0, 5.3
Hz, 1H, H-6a), 4.08−4.01 (m, 2H, H-5, H-6a), 2.11 (s, 3H, CH3),
2.04 (s, 3H, CH3), 2.00 (s, 3H, CH3), 1.95 (s, 3H, CH3), 0.15 (s, 9H,
CH3) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 170.8, 170.4, 170.1,
169.9 (all CO), 90.7 (C-1), 71.3, 69.0, 68.5, 66.5 (all CH), 62.8
(CH2), 21.1, 20.9 (CH3), −0.1 (CH3) ppm. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C17H28O10NaSi 443.1344; found 443.1341.
Trimethylsilyl 2,3,4-Tri-O-acetyl-α-L-fucopyranoside (27). TLC:
EtOAc/Hexane = 1:2, Rf = 0.5. Pale yellow syrup (Yield: 591 mg,
Trimethylsilyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroacetamido-
α/β-D-mannopyranoside (12). Yield: 596 mg, 70%, α:β = 8:1. 12-
α: TLC: EtOAc/Hexane = 1:2, Rf = 0.4. White solid, mp = 120−121
°C. [α]2D6 +33.2° (c 1.0, CH2Cl2). IR (CH2Cl2) v 3361, 2958, 2922,
̅
2851, 1738, 1703, 1519, 1367, 1226, 1048, 844 cm−1. 1H NMR (500
MHz, CDCl3) δ 6.82 (d, J = 9.4 Hz, 1H, NH), 5.42 (dd, J = 10.1, 4.1
Hz, 1H, H-3), 5.17−5.13 (m, 2H, H-1, H-4), 4.44 (m, 1H, H-2), 4.19
(dd, J = 12.1, 4.4 Hz, 1H, H-6a), 4.12−4.05 (m, 2H, H-5, H-6b), 2.06
(s, 3H, CH3), 2.03 (s, 3H, CH3), 1.97 (s, 3H, CH3), 0.20 (s, 9H,
CH3) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ 170.7, 170.3, 169.9,
163.3 (all CO), 93.2 (C-1), 92.5 (CCl3), 69.4, 68.2, 65.7 (all CH),
62.4 (CH2), 53.9 (CH), 20.9 (CH3), −0.1 (CH3) ppm. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C17H26NO9NaSiCl3 544.0335; found
544.0341. 12-β: TLC: EtOAc/Hexane = 1:2, Rf = 0.3. Sticky solid.
76%). [α]2D8 −135.4° (c 1.1, CH2Cl2). IR (CH2Cl2) v 2960, 1746,
̅
1370, 1250, 1222, 1060, 982, 803 cm−1. 1H NMR (500 MHz, CDCl3)
δ 5.35−5.31 (m, 2H, H-1, H-3), 5.25 (d, J = 3.2 Hz, 1H, H-4), 5.02
(dd, J = 10.7, 3.3 Hz, 1H, H-2), 4.25 (q, J = 6.6 Hz, 1H, H-5), 2.12 (s,
3H, CH3), 2.02 (s, 3H, CH3), 1.95 (s, 3H, CH3), 1.08 (d, J = 6.6 Hz,
3H, H-6), 0.11 (s, 9H, CH3) ppm. 13C{1H} NMR (125 MHz,
CDCl3) δ 170.9, 170.6, 170.5 (all CO), 91.0 (C-1), 71.5, 69.3, 68.3,
64.3 (all CH), 21.0, 20.9, 20.9, 16.1 (all CH3), −0.1 (CH3) ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H26O8NaSi
385.1289; found 385.1288.
[α]2D7 −9.0° (c 0.7, CH2Cl2). IR (CH2Cl2) v 3416, 2957, 2924, 2852,
̅
1748, 1727, 1513, 1371, 1227, 1057, 847 cm−1. 1H NMR (600 MHz,
CDCl3) δ 6.92 (d, J = 7.9 Hz, 1H, NH), 5.09−5.02 (m, 3H, H-1, H-3,
H-4), 4.49 (m, 1H, H-2), 4.18−4.11 (m, 2H, H-6), 3.68 (m, 1H, H-
5), 2.06 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.00 (s, 3H, CH3), 0.14 (s,
9H, CH3) ppm. 13C{1H} NMR (150 MHz, CDCl3) δ 170.7, 170.7,
169.9, 163.2 (all CO), 93.8 (C-1), 92.7 (CCl3), 72.8, 71.9, 65.8 (all
CH), 62.5 (CH2), 54.4 (CH), 20.9, 20.9 (CH3), −0.2 (CH3) ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H26NO9NaSiCl3
544.0335; found 544.0339.
Trimethylsilyl 2,3,6-Tri-O-acetyl-4-O-(2′,3′,4′,6′-tetra-O-acetyl-α-
D-galactopyranosyl)-α-D-glucopyranoside (28). TLC: EtOAc/Hex-
ane = 1:1, Rf = 0.3. Colorless syrup (Yield: 591 mg, 76%). [α]D28
+58.4° (c 1.0, CH2Cl2). IR (CH2Cl2) v 2958, 1747, 1370, 1220, 1051,
̅
847 cm−1. 1H NMR (400 MHz, CDCl3) δ 5.45 (t, J = 9.6 Hz, 1H, H-
3), 5.32 (d, J = 3.0 Hz, 1H, H-4′), 5.26 (d, J = 3.4 Hz, 1H, H-1), 5.09
(dd, J = 10.4, 8.0 Hz, 1H, H-2′), 4.92 (dd, J = 10.4, 3.5 Hz, 1H, H-3′),
4.70 (dd, J = 10.1, 3.4 Hz, 1H, H-2), 4.45 (d, J = 7.9 Hz, 1H, H-1′),
4.35 (dd, J = 11.8, 1.7 Hz, 1H, H-6a), 4.14−4.01 (m, 4H, H-5, H-6b,
H-6′), 3.84 (t, J = 6.9 Hz, 1H, H-5′), 3.68 (t, J = 9.5 Hz, 1H, H-4),
2.13 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.02 (s, 3H,
Trimethylsilyl 3,4,6-Tri-O-benzoyl-2-deoxy-2-trichloroacetami-
do-α-D-glucopyranoside (13). TLC: EtOAc/Hexane = 1:3, Rf =
0.5. White foam (Yield: 555 mg, 46%). [α]2D7 +23.6° (c 1.3, CH2Cl2).
IR (CH2Cl2) v 34423, 3064, 2958, 1722, 1515, 1267, 1105, 1095, 846,
̅
709 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.03 (m, 2H, ArH), 7.93−
5341
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J. Org. Chem. 2021, 86, 5336−5344

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
CH3), 2.00 (s, 3H, CH3), 1.94 (s, 3H, CH3), 0.12 (s, 9H, CH3) ppm.
Trichloroacetimidoyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroace-
tamido-α-D-glucopyranoside (36).51 To a suspension of 3 (100
mg, 0.19 mmol) in DCM (2.0 mL, 0.1 M solution) were successively
added trichloroacetonitrile (0.2 mL, 1.9 mmol) and TBAF (l M
solution in THF; 2 mL, 1.9 mmol). After stirring for 3 h at rt, the
reaction mixture was diluted with DCM and saturated NaHCO3 was
added. The organic layer was separated and washed with saturated
NaHCO3 one more time, dried over MgSO4, filtered, and
concentrated in vacuo. Purification using flash column chromatog-
raphy with EtOAc/Hexane (1/2) afforded 36 as a white solid (88 mg,
78%). Mp = 152−154 °C. [α]D30 +56.6° (c 1.1, CH2Cl2). (Literature:
13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 170.5, 170.4, 170.3,
169.8, 169.4 (all CO), 101.5 (C-1′), 90.4 (C-1), 77.0, 72.3, 71.3,
70.8, 70.2, 69.4, 68.1, 66.8 (all CH), 62.4, 61.0 (both CH2), 21.2,
21.0, 20.9, 20.8, 20.7 (CH3), −0.0 (CH3) ppm. HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C29H44O18NaSi 731.2189; found 731.2181.
Trimethylsilyl 3-O-Acetyl-4,6-bis-O-trimethylsilyl-2-deoxy-2-tri-
chloroacetamido-α-D-glucopyranoside (29). TLC: EtOAc/Hexane
= 1:6, Rf = 0.7. Colorless syrup (Yield: 532 mg, 56%). [α]2D7 +68.3° (c
1.4, CH2Cl2). IR (CH2Cl2) v 3425, 2958, 1748, 1721, 1513, 1250,
̅
1
1229, 1145, 1054, 839, 751 cm−1. H NMR (500 MHz, CDCl3) δ
mp = 160−161 °C; [α]D +75° (c 1, CHCl3).51 IR (CH2Cl2) v 3414,
6.89 (d, J = 9.0 Hz, 1H, NH), 5.22−5.18 (m, 2H, H-1, H-3), 3.99 (m,
1H, H-2), 3.81 (t, J = 9.0 Hz, 1H, H-4), 3.76−3.67 (m, 3H, H-5, H-
6), 2.05 (s, 3H, CH3), 0.14 (s, 9H, CH3), 0.10 (m, 18H, CH3) ppm.
13C{1H} NMR (125 MHz, CDCl3) δ 171.5, 162.0 (all CO), 92.5
̅
1
3339, 2957, 1722, 1680, 1518, 1224, 1040, 823, 797 cm−1. H NMR
(400 MHz, CDCl3) δ 8.81 (s, 1 H, CNH), 6.98 (d, J = 8.5 Hz, 1H,
NH), 6.47 (d, J = 3.6 Hz, 1H, H-l), 5.41 (t, J = 10.3, 1H, H-3), 5.27
(t, J = 10.0 Hz, 1H, H-4), 4.42 (m, 1H, H-2), 4.27 (dd, J = 12.8, 4.4
Hz, 1H, H-6a), 4.15−4.09 (m, 2H, H-5, H-6b), 2.07 (s, 3H, CH3),
2.05 (s, 3H, CH3), 2.04 (s, 3H, CH3) ppm. 13C{1H} NMR (100
MHz, CDCl3) δ 171.7, 170.8, 169.3, 162.3 (all CO), 160.2 (C
NH), 93.9 (C-1), 91.9, 90.7 (both CCl3), 70.7, 70.3, 67.1 (all CH),
61.5 (CH2), 54.1 (CH), 20.9, 20.8, 20.7 (all CH3) ppm. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C16H18N2O9NaCl6 614.9036; found
614.9034.
(C), 91.7 (C-1), 73.8, 72.8, 68.9 (all CH), 61.4 (CH2), 55.5 (CH),
21.3 (CH3), 0.5, 0.0, −0.2 (all CH3) ppm. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C19H38NO7NaSi3Cl3 604.0914; found 604.0923.
Trimethylsilyl 3,6-Di-O-acetyl-4-O-trimethylsilyl-2-deoxy-2-tri-
chloroacetamido-α-D-glucopyranoside (30). TLC: EtOAc/Hexane
= 1:3, Rf = 0.4. Colorless syrup (Yield: 180 mg, 20%). [α]2D7 +67.7° (c
1.4, CH2Cl2). IR (CH2Cl2) v 3423, 2959, 1745, 1720, 1514, 1252,
̅
1223, 1057, 841, 752 cm−1. 1H NMR (400 MHz, CDCl3) δ 6.88 (d, J
= 8.8 Hz, 1H, NH), 5.23−5.19 (m, 2H, H-1, H-3), 4.27 (m, 1H, H-
6a), 4.15 (dd, J = 12.0, 4.6 Hz, 1H, H-6b), 4.03 (m, 1H, H-2), 3.94
(m, 1H, H-5), 3.79 (t, J = 9.1 Hz, 1H, H-4), 2.08 (s, 3H, CH3), 2.05
(s, 3H, CH3), 0.15 (s, 9H, CH3), 0.09 (s, 9H, CH3) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ 171.5, 170.9, 162.0 (all CO), 92.4 (C),
91.7 (C-1), 73.4, 70.2, 69.4 (all CH), 63.0 (CH2), 55.4 (CH), 21.3,
21.0 (CH3), 0.5, −0.0, (CH3) ppm. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C18H32NO8NaSi2Cl3 574.0624; found 574.0625.
Trimethylsilyl 4,6-Di-O-acetyl-3-O-trimethylsilyl-2-deoxy-2-tri-
chloroacetamido-α-D-galactopyranoside (31). TLC: EtOAc/Hex-
ane = 1:4, Rf = 0.4. Colorless syrup (Yield: 270 mg, 30%). [α]D24
p-Methoxyphenyl 3,4,6-Tri-O-acetyl-2-deoxy-2-trichloroaceta-
mido-β-D-glucopyranoside (37).52 To a cooled (in ice bath)
suspension of 3 (100 mg, 0.19 mmol) and p-methoxyphenol (47.2
mg, 0.38 mmol) in DCM (2.0 mL, 0.1 M solution) was added BF3·
OEt2 (44 μL, 0.42 mmol). After stirring for 4 h at rt, the reaction
mixture was concentrated in vacuo and purified using flash column
chromatography with EtOAc/Hexane (1/1) to get 37 as a white
powder (85 mg, 80%). Mp = 187−188 °C. [α]3D0 −11.2° (c 1.1,
CH2Cl2). (Literature: mp = 176−177 °C; [α]D −10° (c 1, CHCl3).52
IR (CH2Cl2) v 3332, 2958, 1746, 1530, 1507, 1368, 1214, 1040, 823
̅
cm−1. 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J = 8.9 Hz, 1H, NH),
6.94 (m, 2H, ArH), 6.76 (m, 2H, ArH), 5.41 (t, J = 10.1 Hz, 1H, H-
3), 5.14 (t, J = 9.6 Hz, 1H, H-4), 5.06 (d, J = 8.1 Hz, 1H, H-1), 4.28
(dd, J = 12.2, 5.3 Hz, 1H, H-6a), 4.24−4.14 (m, 2H, H-2, H-6b), 3.82
(m, 1H, H-5), 3.74 (s, 3H, OCH3), 2.07 (s, 3H, CH3), 2.02 (s, 3H,
CH3), 1.99 (s, 3H, CH3) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ
171.1, 170.8, 169.5, 162.3 (all CO), 156.2, 151.2 (both ArC),
119.3, 114.8 (both ArCH), 100.6 (C-1), 92.4 (CCl3), 72.3, 71.6, 68.6
(all CH), 62.3 (CH2), 56.2 (CH), 55.8 (OCH3), 20.9, 20.8 (both
CH3) ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C21H24NO10NaCl3 578.0358; found 578.0348.
+82.4° (c 1.1, CH2Cl2). IR (CH2Cl2) v 3424, 2958, 1746, 1727, 1511,
̅
1
1440, 1370, 1251, 1223, 1117, 1065, 843, 755 cm−1. H NMR (500
MHz, CDCl3) δ 6.59 (d, J = 9.0 Hz, 1H, NH), 5.28 (d, J = 3.4 Hz,
1H, H-1), 5.23 (m, 1H, H-4), 4.20 (m, 2H, H-2, H-5), 4.11 (dd, J =
11.5, 4.8 Hz, 1H, H-6a), 4.00 (dd, J = 11.5, 7.7 Hz, 1H, H-6b), 3.93
(dd, J = 10.3, 3.4 Hz, 1H, H-3), 2.12 (s, 3H, CH3), 2.02 (s, 3H, CH3),
0.16 (s, 9H, CH3), 0.09 (s, 9H, CH3) ppm. 13C{1H} NMR (125
MHz, CDCl3) δ 170.7, 170.6, 161.9 (all CO), 92.8 (C), 92.3 (C-1),
70.0, 67.7, 67.4 (all CH), 63.0 (CH2), 53.2 (CH), 21.0, 20.9 (CH3),
0.1, −0.1, (CH3) ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C15H26O8NaSi 574.0624; found 574.0627.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02813.
Trimethylsilyl 2,3,6-Tetra-O-acetyl-4-O-trimethylsilyl-α-D-galac-
topyranoside (32). TLC: EtOAc/Toluene = 1:10, Rf = 0.4. Colorless
syrup (Yield: 108 mg, 13%). [α]2D5 +109.6° (c 1.3, CH2Cl2). IR
■
sı
(CH2Cl2) v 2959, 1745, 1371, 1249, 1225, 1161, 1066, 996, 875, 842,
̅
754 cm−1. 1H NMR (400 MHz, CDCl3) δ 5.39 (d, J = 3.3 Hz, 1H, H-
1), 5.22 (dd, J = 10.7, 2.8 Hz, 1H, H-3), 5.08 (dd, J = 10.7, 3.4 Hz,
1H, H-2), 4.1 (m, 3H, H-4, H-5, H-6a), 4.01 (dd, J = 13.6, 9.0 Hz,
1H, H-6b), 2.06 (s, 3H, CH3), 2.02 (s, 3H, CH3), 2.01 (s, 3H, CH3),
0.10 (m, 18H, CH3) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ
170.6, 170.5 (all CO), 91.0 (C-1), 70.3, 69.5, 69.5, 68.0 (all CH),
63.0 (CH2), 21.4, 21.0, 21.0 (CH3), 0.4, −0.1, (CH3) ppm. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H26O8NaSi 473.1634;
found 473.1640.
All NMR spectroscopic data for compounds 3, 10−13,
24−33, 36, and 37 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Cheng-Chung Wang − Institute of Chemistry and Sustainable
Chemical Science and Technology (SCST), Taiwan
International Graduate Program (TIGP), Academia Sinica,
Taipei 115, Taiwan; orcid.org/0000-0002-2562-0658;
Email: wangcc7280@gate.sinica.edu.tw
Trimethylsilyl 2,4,6-Tetra-O-acetyl-3-O-trimethylsilyl-α-D-galac-
topyranoside (33). TLC: EtOAc/Toluene = 1:10, Rf = 0.3. Colorless
syrup (Yield: 67 mg, 8%).[α]2D5 +116.7° (c 1.4, CH2Cl2). IR (CH2Cl2)
1
v 2959, 1746, 1371, 1250, 1225, 1157, 1122, 883, 843, 754 cm−1. H
̅
NMR (400 MHz, CDCl3) δ 5.39 (d, J = 3.4 Hz, 1H, H-1), 5.22 (m,
1H, H-4), 4.78 (dd, J = 9.9, 3.4 Hz, 1H, H-2), 4.25 (m, 1H, H-5),
4.08 (m, 2H, H-3, H-6a), 3.99 (dd, J = 11.3, 7.6 Hz, 1H, H-6b), 2.07
(s, 3H, CH3), 2.02 (m, 6H, CH3), 0.11 (s, 9H, CH3), 0.08 (m, 9H,
CH3) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 170.6 (all
CO), 91.1 (C-1), 72.6, 71.0, 66.6 (all CH), 62.9 (CH2), 21.1, 20.9
(CH3), 0.1, −0.1, (CH3) ppm. HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C15H26O8NaSi 473.1634; found 473.1634.
Author
Welday Desta Weldu − Institute of Chemistry and Sustainable
Chemical Science and Technology (SCST), Taiwan
International Graduate Program (TIGP), Academia Sinica,
Taipei 115, Taiwan; Department of Applied Chemistry,
National Yang Ming Chiao Tung University, Hsinchu 300,
Taiwan
5342
https://dx.doi.org/10.1021/acs.joc.0c02813
J. Org. Chem. 2021, 86, 5336−5344

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02813
(19) Palmacci, E. R.; Seeberger, P. H. Toward the Modular
Synthesis of Glycosaminoglycans: Synthesis of Hyaluronic Acid
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Academia Sinica (MOST 108-3114-Y-001-
002; AS-SUMMIT-109) and the Ministry of Science and
Technology (MOST 108-2113-M-001-019-; MOST 109-2113-
M-001-005-) for their financial support.
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