Synthesis of Sterically Congested Carbamates of Carbohydrates through Organic Base Catalysis

Article abstract of DOI:10.1055/s-0037-1612425

4,6-O-Benzylidene acetal protected α-methoxy D-glucose and D-glucosamine are useful building blocks for the syntheses of carbohydrate derivatives and functional molecular assemblies. In this research, we have developed a general method for the preparation of C-3 carbamate derivatives of densely functionalized glucose and glucosamine with isocyanates using organic bases as catalysts. Without a suitable catalyst, the C-3 hydroxy group of the glucosamine derivative could not be converted into the corresponding carbamates when treated with isocyanates. Several organic bases were screened as the catalysts for the reactions, and we discovered that 5.0 molpercent of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was an effective catalyst for the carbamoylation reaction. A library of both alkyl and aryl carbamate derivatives of the two sterically congested carbohydrates have been effectively synthesized using the current method.

Full text of DOI:10.1055/s-0037-1612425

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
A
en
A. Chen et al.
Paper
Synthesis
Synthesis of Sterically Congested Carbamates of Carbohydrates
through Organic Base Catalysis
Anji Chen
RNCO
O
O
Ph
Ph
Dan Wang
O
O
MeCN, DBU (5 mol%)
O
O
Lalith P. Samankumara
HO
O
R'
O
R'
Guijun Wang*
0
0
0
0-0
0
0
1-
7
4
7
3-0
0
0
4
OMe
OMe
R' = NHAc, OBz, R = aryl, alkyl
NH
R
Department of Chemistry and Biochemistry, Old Dominion University,
Norfolk, VA 23529, USA
g1wang@odu.edu
Received: 10.01.2019
Accepted after revision: 12.03.2019
Published online: 16.04.2019
been used as a convenient reagent for the carbonylation of
amino alcohols to form carbamates.14–16 Ethyl 1H-imidaz-
ole-1-carboxylate derived from CDI has been shown to se-
lectively acylate indoles and oxazolidinones to form N-aryl
carbamates.17 CDI has also been used in Lossen’s rearrange-
ment of various hydroxamic acids to the corresponding iso-
cyanate intermediates, which were then converted into car-
bamates.18 The trichloroacetamide group has been convert-
ed into isocyanate in situ, followed by treatment with
alcohols to afford the corresponding carbamates.19 Trifluo-
roacetamide intermediates have been converted into cyclic
carbamate oxazinanones as well.20 Recently, carbon dioxide
has been used as a carbonylation source under different
conditions for the synthesis of carbamates.21–23 1,8-Diazabi-
cyclo[5.4.0]undec-7-ene (DBU) is a versatile reagent that is
useful for many synthetic applications.24 Besides being an
organic base, DBU also functions as a nucleophile and has
been used as a nucleophilic catalyst for reactions of amines
with CO2 or carbonates to form various carbamate deriva-
tives.22,23,25
The structures of several commonly used organic bases
are shown in Figure 1. These include 4-(dimethylami-
no)pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Among
these three organic bases, DBU is the strongest organic base
and it has a lower nucleophilicity than DABCO. The nucleo-
philicity order of these three bases is DMAP < DBU < DAB-
CO; the basicity order is different: DABCO < DMAP < DBU.26
These organic bases have been used for the synthesis of N-
aryl carbamates from amines and carbonates, and it was
found that DBU is moderately effective, but DMAP and DAB-
CO were unable to catalyze the carbamate formation.27 Both
DBU and DABCO have been utilized as organocatalysts for
the synthesis of polyurethane.28,29 Other amidine and guan-
idine derivatives such as 1,5-diazabicyclo[4.3.0]non-5-ene
DOI: 10.1055/s-0037-1612425; Art ID: ss-2019-z0013-op
Abstract 4,6-O-Benzylidene acetal protected -methoxy D-glucose
and D-glucosamine are useful building blocks for the syntheses of car-
bohydrate derivatives and functional molecular assemblies. In this re-
search, we have developed a general method for the preparation of C-3
carbamate derivatives of densely functionalized glucose and glucos-
amine with isocyanates using organic bases as catalysts. Without a suit-
able catalyst, the C-3 hydroxy group of the glucosamine derivative
could not be converted into the corresponding carbamates when treat-
ed with isocyanates. Several organic bases were screened as the cata-
lysts for the reactions, and we discovered that 5.0 mol% of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) was an effective catalyst for the
carbamoylation reaction. A library of both alkyl and aryl carbamate de-
rivatives of the two sterically congested carbohydrates have been effec-
tively synthesized using the current method.
Key words carbamates, isocyanates, glucosamine, glucose, organo-
catalysis
Carbamates or urethanes make up an important class of
compounds in pharmaceutics and for the preparation of
polymeric materials.1 Organic carbamates are essential
functional groups of many biologically active compounds
and pharmaceutics and they are also important synthetic
intermediates.2–7 Cyclic carbamates, such as oxazolidinones
formed by glucosamine derivatives, have shown great ap-
plications in glycosylation reactions for carbohydrate syn-
thesis.8,9 The synthesis of carbamates typically involves re-
actions of alcohols with isocyanates or isocyanate precur-
sors by using certain catalysts. Many methods have been
developed using carboxylic acids or their derivatives as pre-
cursors through Hoffman or Curtius rearrangement reac-
tions, to produce isocyanate intermediates in situ, and fol-
lowed by addition of alcohols to form urethanes.10–12 In re-
cent years, precursors such as ureas have also been used to
prepare these carbamates.13 Carbonyldiimidazole (CDI) has
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

B
A. Chen et al.
Paper
Synthesis
(DBN) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) have
been shown to be effective organocatalysts for the synthe-
sis of polyurethanes.29
hydroxy group of the glucose derivatives is more sterically
hindered and less reactive in comparison to the 2-hydroxy
group. For the acylation or carbamoylation of the 3-hydroxy
group of the sugar derivative, more vigorous reaction con-
ditions are typically required.
O
N
N
N
N
Because of the potential applications of carbamate de-
rivatives as self-assembled functional materials and as use-
ful synthetic intermediates for multistep synthesis and bio-
logically active compounds, we are interested in developing
general procedures that are effective for the introduction of
the carbamate functional group to densely protected glu-
cose and glucosamine derivatives. As shown in Scheme 1,
we used the N-acetyl-D-glucosamine derivative 6 as the
starting material to study its functionalization to afford 3-
carbamate derivative 7. To show the generality of the meth-
od, we also used a 2-benzoate glucose derivative 8 as the
starting material to prepare the 3-carbamate derivative 9.
To synthesize a variety of different carbamate deriva-
tives of the highly functionalized monosugars with general
structures of 7 and 9, we studied the effectiveness of a few
common organic bases as catalysts. Several alcohols were
initially used as the substrates for the preparation of their
corresponding carbamates with phenyl isocyanate in aceto-
nitrile and by using DBU and DABCO as the catalysts. The
structures of the alcohols and the screening results are in-
cluded in the Supporting Information (SI; Table S1). Three
alcohols were initially used as the substrates for the test re-
action: triethylene glycol, decane-1,10-diol, and tert-butyl
alcohol. As shown in the SI (Table S1), both DBU and DABCO
(5 mol%) were effective at catalyzing the reactions to full
conversion in 2 hours; the corresponding dicarbamates
N
N
N
N
N
N
N
N
DMAP
DABCO
DBU
DBN
CDI
Figure 1 Structures of organic bases and reagents useful for carba-
mate formation
The preparation of carbamates from non-hindered alco-
hols and isocyanates is usually straightforward; in general,
stirring the isocyanates and alcohols together with trime-
thylamine is sufficient to produce the carbamates in good
yields. For hindered alcohols, such as tert-butyl alcohol and
secondary isocyanates, the reactions typically have poor
conversions and require higher temperatures or the use of
organic bases or tin complexes as catalysts. In the course of
the synthesis and study of monosaccharide-based self-as-
sembling materials, we found that various carbamate deriv-
atives are effective low-molecular-weight gelators.30 As
shown in Scheme 1, the 3-hydroxy groups of glucose or glu-
cosamine derivatives are not as readily acylated or derivat-
ized as the 2-hydroxy groups. When compound 1 is used as
the starting material, esterification typically leads to the
formation of 2-ester 2, 2,3-diester 3, and a small amount of
3-ester, with the 2-acyl derivative as the major product.31,32
When isocyanate (1 equiv) is used as the reagent, the 2-car-
bamate 4 is obtained as the major product along with a
small amount of dicarbamate 5.30 This indicates that the 3-
O
O
O
O
O
O
HO
O
RCOCl, pyridine
O
R
O
R
O
OMe
OMe
O
6
O
R
O
4
5
O
2
O
2
3
1
HO
3
OH
RNCO
OMe
O
O
O
O
O
1
O
O
HO
O
O
O
OMe
OMe
O
O
NH
NH
NH
R
4
R
R
5
major product
O
O
O
Ph
Ph
Ph
O
Ph
O
O
O
O
O
O
O
O
O
O
HO
HO
O
NH
O
O
NH
O
OMe
OMe
OMe
OMe
O
O
NH
O
O
NH
Ph
R
R
6
7
8
9
Scheme 1 Selective acylation of 4,6-O-benzylidene methyl -D-glucopyranoside and the structures of the targeted 3-carbamate sugar derivatives 7
and 9 and their precursors
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

C
A. Chen et al.
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Synthesis
were obtained in excellent yields (~90%). We also tested the
reaction of the tertiary alcohol tert-butyl alcohol with phe-
nyl isocyanate, and the reactions also gave good yields.
When phenyl isocyanate was changed to 4-methoxyphenyl
isocyanate, the reactions required a longer time and the
yields were also lower for both catalysts, DABCO giving 76%
yield and DBU only giving 52% yield. For the reactions of
benzyl alcohol with the secondary cyclohexyl isocyanate,
good yields of the cyclohexyl carbamates were obtained
when DBU (10 mol%) was used as the catalyst. The encour-
aging results for tert-butyl alcohol and cyclohexyl isocya-
nate when using DBU or DABCO indicated that similar con-
ditions could be applied to sterically hindered sugar alco-
hols such as compounds 6 and 8.
Several different reaction conditions were tested when
using the N-acetyl glucosamine derivative 6 (Table 1). The
full list of reactions screened for aliphatic isocyanates and
phenyl isocyanate are shown in the SI (Tables S2 and S3). A
few key entries are included in Table 1. Alkyl isocyanates
were tested first in the presence of several different bases
as the catalysts. For hexyl isocyanate, without catalyst or in
the presence of either K2CO3 or DMAP at room temperature,
no product formation resulted; when DBU (0.30 equiv) was
used, the starting material was fully converted and the de-
sired carbamate was obtained in 81% isolated yield. The
lower isolated yield was possibly due to difficulties in re-
moving the urea byproduct, and DBU may also affect prod-
uct extraction into the organic phase. For benzyl isocyanate,
the use of DMAP could only improve the conversion to 30%
at higher temperature. For heptyl isocyanate, at room tem-
perature in acetonitrile, none of the following bases afford-
ed any product formation: triethylamine, DMAP, NMI, and
K2CO3. When DMAP was used at 60 °C for 24 hours, only
25% conversion to carbamate 7 resulted. Only DBU was ef-
fective in catalyzing the reaction to full conversion and af-
forded the heptyl carbamate in 87% isolated yield.
Table 1 Optimization of the Reaction Conditions for the Preparation
of Carbamate Derivatives 7a
O
Ph
O
Ph
O
O
O
O
RNCO, cat.
MeCN
O
HO
NH
O
NH
OMe
OMe
O
NH
O
R
6
7
Entry Cat.
(equiv)b
R
RNCO
(equiv)
Temp,
timec
Conversion
(%)d
1
2
DMAP (0.10)
DBU (0.30)
DMAP (0.20)
NMI (0.20)
DBU (0.30)
DMAP (0.15)
NMI (0.10)
DBN (0.10)
DBU (0.30)
DBU (0.05)
DBU (0.02)
Bn
1.5
1.5
1.5
1.5
2.0
1.5
1.1
1.5
1.1
1.1
1.1
60 °C, 18 h
r.t., 2 h
30
Bn
83
3
heptyl
heptyl
heptyl
Ph
60 °C, 24 h
r.t., 12 h
r.t., 2 h
31 (25)e
NRf
4
5
87
6
r.t., 5 h
100 (77)
29 (20)
60
7
Ph
50 °C, 12 h
r.t., 12 h
r.t., 1 h
8
Ph
9
Ph
100
10
11
Ph
r.t., 1 h
100 (90)
100 (93)
Ph
r.t., 1 h
a Reaction conditions: 6 (75 mg, 0.232 mmol, 1 equiv), RNCO (1.0–2.0
equiv), cat. (0.02–0.30 equiv), anhyd MeCN (3 mL).
b DMAP = 4-(dimethylamino)pyridine; NMI = 1-methylimidazole; DBN = 1,5-
diazabicyclo[4.3.0]non-5-ene; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene;
DABCO = 1,4-diazabicyclo[2.2.2]octane.
c The reaction mixture was stirred at elevated temperature only after no re-
action occurred at r.t. for 12 h.
d Conversion determined by 1H NMR spectroscopy.
e Isolated yield given in parentheses.
f NR = no reaction.
addition makes a big difference to the effectiveness of the
carbamate synthesis. If DBU was added together with the
alcohol and isocyanate, the reaction did not proceed to give
full conversion with one equivalent PhNCO. The sugar alco-
hol 6 was added first followed by acetonitrile as the solvent
and DBU (20 mol%) as the catalyst, and the mixture was
stirred for 15–30 minutes. Then the phenyl isocyanate was
added in two batches of 0.5 equivalent; this led to about
77% of the starting material being converted into the carba-
mate; adding one more equivalent of PhNCO afforded full
conversion and an isolated yield of 81%. However, if the DBU
catalyst was added later, after mixing of the isocyanate and
alcohol for 15 minutes, typically the reaction with one
equivalent of aryl isocyanate occurs readily within 1 hour to
afford the desired carbamates in full conversion and more
than 90% isolated yield. The optimum amount of DBU cata-
lyst was also tested: 0.3, 0.2, 0.1, 0.05, and 0.02 equivalents
of DBU were all effective in catalyzing the reaction to full
conversion within 1 hour. The carbamate products were ob-
tained in over 90% isolated yields when using 5.0 and 2.0
mol% of DBU, but further reduction of DBU to 1 mol% was
As shown in Table 1 and in the SI (Table S3), phenyl iso-
cyanate was significantly more reactive compared to the al-
kyl isocyanates. Without catalyst at r.t. and in the presence
of DMAP (0.15 equiv) as catalyst in THF, no product was ob-
tained. However, the use of DMAP as catalyst in acetonitrile
led to full conversion in 5 hours. Several other organic bases
besides DMAP were also screened. NMI only led to 20% con-
version at 50 °C overnight; DABCO and hexamethylenete-
tramine (HMTA) were not effective either, leading to com-
plex mixtures. DBN afforded better conversion; the use of
DBN (0.10 equiv) at r.t. for 12 hours led to 60% conversion to
the product. When DBU was used as the catalyst, the reac-
tion afforded clean conversion to the desired product, simi-
lar to the alkyl carbamate synthesis.
Therefore, DBU was chosen as the main catalyst to be
optimized for the reaction to synthesize sugar carbamate
derivatives. Interestingly, we found that the order of reagent
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

D
A. Chen et al.
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Synthesis
O
Ph
N
O
Ph
Ph
O
O
Ph
O
O
O
O
H
O
N
HO
O
+
HO+
N
NH
O
C
OMe
NH
N–
OMe
NH
OMe
C
O–
Ph
O
O
C
O
6
O
N
O
O
O
Ph
Ph
Ph
H
N+
O
O
O
O
N
O
+
H
+
N–
N
C
NH
C
NH
OMe
OMe
N
Ph
N
O
O
O
O
7a
Scheme 2 Proposed mechanism of the reaction
not effective. On the basis of these findings, DBU (5.0 mol%)
was selected as the catalyst for the synthesis of other carba-
mates.
(2 equiv) were used. The reason that the catalyst did not
perform well with this substrate is probably due to the
presence of the electron-withdrawing nitro group, which
increases the electrophilicity of the isocyanate and makes it
more reactive towards nucleophilic attack. The DBU cata-
lyst probably acted more like a nucleophile and formed a
stable complex with the isocyanate, which deactivates the
catalyst. The presence of the 2-NHAc also affected the reac-
tion significantly. Aliphatic isocyanates usually react slower
than aryl isocyanates due to both steric and electronic fac-
The different reaction outcomes due to the order of re-
agent addition could possibly be rationalized. DBU is a
strong base and when it is added first with the alcohol, it
may deprotonate (or partially deprotonate) the 3-OH group
and the 2-NHAc group. The deprotonation of the 3-OH
should lead to product formation. On the other hand,
deprotonation of NHAc or forming a hydrogen bond with
the amide will hinder the reaction. Another possible reason
is that DBU forms complexes with the isocyanates through
nucleophilic attack; if the nucleophilic adduct is too stable,
this will also hinder the formation of product. It has been
shown that DBU can function both as a base and as a nucle-
ophilic catalyst for carbamate synthesis; DBU can form a
cyclic adduct with two equivalents of BnNCO.28,29 However,
if DBU is added later, it is more likely that it will function
mainly as a base and not as a nucleophile (Scheme 2). The
sugar alcohol 6 will react with the isocyanate first and form
an unstable and reversible intermediate, so that adding
DBU at this stage will accelerate the proton transfer of the
intermediate leading to product formation. Since the inter-
mediate is more acidic, DBU will function mostly as a base,
and the amide will not interfere with the reaction. Further
studies are necessary to confirm this hypothesis.
Using the optimized conditions and DBU as the catalyst,
we synthesized a library of sugar carbamate derivatives as
shown in Table 2. The majority of aryl isocyanates were
converted smoothly into the desired product when 1.1
equivalents of the isocyanates were used (entries 1–3 and
5), except for 4-nitrophenyl isocyanate (entry 4). For this
compound, only 35% conversion was observed when DBU
(5 mol%) was used and after stirring for 1 hour; the addition
of an extra 1 equivalent of isocyanate did not improve the
conversion. However, the reaction proceeded in 78% con-
version when DBU (10 mol%) and 4-nitrophenyl isocyanate
Table 2 Synthesis of 3-O-Carbamates 7 of Glucosamine Derivativesa
O
O
O
O
O
O
RNCO
O
HO
NH
OMe
O
DBU (5 mol%)
MeCN
NH
OMe
O
NH
O
R
6
7
Entry DBU
R
RNCO
(equiv)
Product Conver-
sion (%)b
Yield
(%)
(equiv)
1
2
0.05
0.05
0.05
0.10
0.05
0.05
0.05
0.05
0.05
Ph
1.1
1.1
1.5
2.0
1.1
1.1
2.1
2.1
2.1
2.5
7a
7b
7c
7d
7e
7f
100
100
100
78
90
89
91
71
87
89
87
89
86
86
4-MeOC6H4
4-BrC6H4
4-O2NC6H4
2-Naph
Bn
3
4
5
100
100
100
100
100
100
6
7
pentyl
hexyl
7g
7h
7i
8
9
heptyl
Cy
c
10
–
7j
a Reaction conditions: 6 (1 equiv), RNCO, DBU, MeCN.
b Conversion determined by 1H NMR spectroscopy.
c DABCO (0.40 equiv) used instead of DBU.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

E
A. Chen et al.
Paper
Synthesis
tors. Benzyl isocyanate (1.1 equiv) and linear alkyl isocya-
nates (2.0 equiv) reacted smoothly with the sugar deriva-
tive 6 when using 5.0 mol% DBU as the catalyst. The second-
ary cyclohexyl isocyanate was very sluggish under the same
conditions; DBU (5 mol%) with CyNCO (1 equiv) at room
temperature gave only 33% conversion, and no further con-
version was observed with additional catalyst and isocya-
nate at higher temperature. DABCO, on the other hand, pro-
duced satisfactory results, leading to the corresponding car-
bamate in 86% isolated yield (entry 10).
To test the generality of the method, the glucose-de-
rived benzoate 8 was subjected to similar reaction condi-
tions using DBU (5 mol%) as catalyst. Unlike the reactions of
glucosamine derivative 6, the reactions with the 2-benzoyl
glucose derivative 8 proceeded smoothly to the corre-
sponding carbamate derivatives in excellent yields. As
shown in Table 3, DBU (5.0 mol%) was sufficient for catalyz-
ing the reaction, and typically the reactions with the isocy-
anates (1.1 equiv) occurred readily in 1–2 hours at room
temperature to afford the desired carbamates in full conver-
sion and more than 90% isolated yield. Both aromatic and
aliphatic isocyanates were converted smoothly into the de-
sired carbamates, including cyclohexyl isocyanate and 4-ni-
trophenyl isocyanate. The reactivity difference in the two
sugar derivatives is interesting and this is useful for further
selectively functionalization on different sugars.
In an attempt to account for the reactivity differences
between the two sugar alcohols, we carried out a molecular
modeling study for the structures of the two compounds by
using Chem3D. The energy-minimized conformations of
compounds 6 and 8 are shown in Figure 2. In compound 6,
the amide NH group forms an intramolecular hydrogen
bond with the anomeric oxygen with an estimated bond
length of 2.33 Å; this leads to a more rigid steric environ-
ment for the formation of alkyl carbamates at the 3-posi-
tion. The amide NH may also participate in hydrogen bond-
ing with DBU and isocyanate. The 3-hydroxy group in com-
pound 6 also forms a hydrogen bond with the 4-oxygen,
with a bond length of 2.45 Å; the estimated pKa value of
compound 6 is 12.6. In comparison, the 3-OH of the glucose
derivative 8 forms a stronger hydrogen bond with the car-
bonyl group of the 2-benzonate with a bond length of 1.89
Å, and a pKa value of 12.4, which is slightly more acidic than
that of compound 6. The difference in the acidity and hy-
drogen bonding patterns in the two molecules could ac-
count for their reactivity differences with isocyanates. The
glucosamine derivative 6 was more sluggish in the reac-
tions with isocyanates due to the reduced nucleophilicity of
the 3-hydroxy group and the 2-NHAc group interfering
with the reaction.
Table 3 Synthesis of 3-Carbamates of Benzoate-Protected Glucose
Derivatives 9a
O
O
O
O
O
O
R
RNCO
HO
O
Figure 2 The energy-minimized structures of compounds 6 (a) and 8
(b)
O
O
O
DBU (5 mol%)
MeCN, r.t.
1–2 h
O
O
OMe
OMe
NH
8
9
The facile synthesis of 3-O-carbamates from the 2-O-
benzoate of glucose derivative 8 allows us to access a class
of useful hydrogelators and organogelators. The 2-benzoate
can be selectively removed in the presence of the carba-
mate with sodium methoxide and methanol, leading to the
mono-3-carbamate glucose derivatives. As a proof of the
method, we selected compounds 9a, 9g, and 9i and treated
them with NaOMe in methanol (Scheme 3). The benzoyl
group was removed selectively to afford the corresponding
3-carbamate derivatives 10 and 11. The 3-pentyl and 3-
heptyl carbamate derivatives 11a and 11b were previously
found to be effective gelators,32 and they were synthesized
by reacting the diol 1 with pentyl and heptyl isocyanate, re-
spectively, in a one-pot reaction, as the minor products.
Due to the lengthy chromatography required for the isola-
tion of the 2-O-carbamate and 3-O-carbamate products, the
one-pot method was only suitable for compound screening,
but not for scaling up the 3-carbamates to practical quanti-
ties. In contrast, the current method affords products 11a
and 11b in excellent yields in two steps, as shown in
100% conversion for all RNCO listed based on 1H NMR spectra
Entry
R
Product
Yield (%)
1b
2
Ph
9a
9a
9b
9c
9d
9e
9f
0
90
85
86
85
84
87
87
87
89
90
Ph
3
4-MeOC6H4
4-BrC6H4
4-O2NC6H4
2-Naph
Bn
4
5
6
7
8c
9
pentyl
hexyl
9g
9h
9i
10
11
heptyl
Cy
9j
a Reaction conditions: 8 (1 equiv), RNCO (1.1 equiv), DBU (0.05 equiv),
MeCN, r.t., 1–2 h.
b No DBU used.
c RNCO (2.1 equiv) used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

F
A. Chen et al.
Paper
Synthesis
Scheme 3. Since 3-O-carbamate 9 can be synthesized in
high yields and the deprotection reaction also proceeds in
quantitative conversion to the 3-O-carbamate 10 as the
only product, this method can be used for the effective syn-
thesis of carbohydrate derivatives containing 2-hydroxy-3-
O-carbamate functional groups in higher yields with more
straightforward purifications.
prepared from 1,6-diisocyanatohexane have shown appli-
cations as organogelators as well.35,36 We therefore expect
that the sugar based bis-urethanes will also have interest-
ing material properties.
We have synthesized a library of sterically congested
carbamate derivatives from protected glucose and glucos-
amine. These sugar derivatives contain a 4,6-O-benzylidene
acetal protective group and the 2-position is acetylated or
benzoylated and only the 3-OH is unfunctionalized. The
syntheses of the carbamates were carried out by using DBU
(5.0 mol%) as the organocatalyst. For the glucose group, the
corresponding carbamates were obtained effectively in
about one hour in quantitative conversions; dimeric carba-
mates were also synthesized in excellent isolated yields.
The method is useful since only a catalytic amount of DBU
was used and the reaction can tolerate steric hindrance in
the substrates. When the N-acetyl-D-glucosamine deriva-
tive is used as the substrate, typically two equivalents of al-
kyl isocyanate were required for full conversion into the
corresponding carbamates. We also showed that the benzo-
ate protective group at the C-2 position could be removed
selectively to afford the 3-carbamate derivatives in excel-
lent yields. The self-assembling properties of these carbam-
oyl carbohydrates are currently being investigated and will
be reported in due course. A carbamate function introduced
at a specific position on carbohydrates could affect the out-
come of glycosylation reactions and has applications in car-
bohydrate synthesis. The synthesis of these sugar deriva-
tives by a feasible and practical method provides an easy
access to regioselective functionalization of glucose or glu-
cosamine derivatives. In addition, the method developed
O
O
O
O
O
R
O
R
O
O
NaOMe
MeOH
O
O
O
OH
O
OMe
OMe
NH
NH
r.t., 6 h
87%
9
10, R = Ph
11a, R =
92%
95%
11b, R =
Scheme 3 Debenzoylation reaction to synthesize the 3-carbamate de-
rivatives
To expand the scope of the carbamate syntheses, bis-
isocyanates were used to react with the corresponding glu-
cose 2-O-benzoate 8 to synthesize several dimeric carba-
mates. As shown in Scheme 4, for both an alkyl and an aryl
isocyanate, the reactions proceeded in excellent yields to
produce the corresponding dimeric carbamates 12 and 13.
This can be expected because of the excellent conversion
obtained for the monomeric carbamates. This type of bis-
urethanes have shown numerous applications, for instance,
4,4′-methylenebis(p-phenyl isocyanate) and 1,6-diisocy-
anatohexane have been used for the preparation of thermo-
plastic medical polyurethanes,33,34 and the bis-carbamates
OMe
O
O
Ph
O
OBz
O
O
HO
O
O
OCNZNCO
(0.5 equiv)
O
O
O
O
OMe
H
N
O
O
8
NH
BzO
MeO
DBU (5 mol%)
MeCN, r.t., 1 h
O
O
Ph
12, 84%
Z =
OMe
OBz
O
Ph
O
O
O
H
O
O
N
O
N
O
H
O
O
BzO
Ph
MeO
13, 81%
Z =
Scheme 4 Synthesis of dimeric carbamate glucose derivatives 12 and 13
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

G
A. Chen et al.
Paper
Synthesis
should be applicable to other sterically hindered systems
and more complex compounds that require mild carbamoy-
lation conditions.
Yield: 97 mg (89%); Rf = 0.3 (60% EtOAc/hexanes); white solid; mp
238.0–240.0 °C.
1H NMR (400 MHz, DMSO-d6):  = 9.45 (s, 1 H, NHAr), 8.00 (d, J = 9.4
Hz, 1 H, NHAc), 7.40–7.29 (m, 7 H), 6.86–6.80 (m, 2 H), 5.65 (s, 1 H),
5.15 (t, J = 9.9 Hz, 1 H, H-3), 4.69 (d, J = 3.5 Hz, 1 H, H-1), 4.28–4.19 (m,
2 H, H-6a, H-2), 3.89–3.73 (m, 3 H, H-6b, H-4, H-5), 3.69 (s, 3 H,
ArOCH3), 3.38 (s, 3 H, OCH3), 1.81 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 169.6, 154.8, 153.1, 137.3, 132.0,
128.9, 128.0, 126.0, 119.8, 113.9, 100.4, 98.9 (C-1), 79.2 (C-4), 69.6 (C-
3), 67.8 (C-6), 62.7 (C-5), 55.1 (ArOCH3), 55.0 (OCH3), 51.7 (C-2), 22.3.
Reagents and solvents were used as received from the suppliers. All
purifications were conducted by flash chromatography using 230–
400 mesh silica gel obtained from Natland International Corporation.
1H NMR and proton-decoupled 13C NMR spectra were obtained on
Bruker 400 MHz spectrometers of samples in DMSO-d6 or CDCl3. The
chemical shifts were reported by using CDCl3/DMSO-d6 as internal
standard at  = 7.26/2.50 (1H NMR) and at  = 77.00/39.50 (13C NMR),
respectively. 2D NMR experiments (HSQC, COSY) were also conducted
on a 400 MHz Bruker NMR spectrometer to assist the 1H and 13C sig-
nal assignment. Melting point measurements were carried out by us-
ing a Fisher Jones melting point apparatus. The molecular mass was
measured by using LCMS on an Agilent 6120B Single Quad Mass spec-
trometer and LC1260 system with ESI in positive ionization mode.
Screening reactions for triethylene glycol, decane-1,10-diol, tert-bu-
tyl alcohol, and benzyl alcohol with isocyanates and the 1H and 13C
NMR spectra of all intermediates and final products are provided in
the Supporting Information (SI).
LC-MS (ESI+): m/z [M + H]+ calcd for C24H29N2O8: 473.2; found: 473.2.
Methyl 2-Acetamido-4,6-O-benzylidene-3-O-(4-bromophenylcar-
bamoyl)-2-deoxy--D-glucopyranoside (7c)
4-Bromophenyl isocyanate (46 mg, 0.232 mmol, 1 equiv) was added
first. The 1H NMR spectrum showed only 70% conversion after 1 h
stirring. Then more 4-bromophenyl isocyanate (23 mg, 0.116 mmol,
0.5 equiv) was added and the mixture was stirred for another 1 h at
r.t. The 1H NMR spectrum showed full conversion.
Yield: 109 mg (91%); Rf = 0.4 (60% EtOAc/hexanes); white solid, mp
235.0–237.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.48–7.42 (m, 2 H), 7.35–7.28 (m, 5 H),
7.13 (d, J = 8.9 Hz, 2 H), 6.86 (s, 1 H, NHAr), 6.10 (d, J = 9.4 Hz, 1 H,
NHAc), 5.54 (s, 1 H, PhCH), 5.26 (t, J = 10.0 Hz, H-3), 4.75 (d, J = 3.6 Hz,
1 H, H-1), 4.45–4.37 (m, 1 H, H-2), 4.32 (dd, J = 10.3, 4.7 Hz, 1 H, H-6a),
3.98–3.90 (m, 1 H, H-5), 3.38 (t, J = 10.3 Hz, 1 H, H-6b), 3.75 (t, J = 10.0
Hz, 1 H, H-4), 3.44 (s, 3 H, OCH3), 1.94 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.5, 153.1, 136.8, 136.6, 131.9,
129.2, 128.3, 126.3, 120.2, 116.1, 102.0 (PhCH), 99.2 (C-1), 79.2 (C-4),
71.4 (C-3), 68.9 (C-6), 62.9 (C-5), 55.5 (OCH3), 52.7 (C-2), 23.2.
Carbamate Derivatives 7; General Procedure
Compound 6 (75 mg, 0.232 mmol, 1 equiv) and anhyd MeCN (3 mL)
were added to a 50 mL round-bottom flask, followed by the appropri-
ate isocyanate. The reaction mixture was stirred for 15 min at r.t., af-
ter which DBU (5.0 mol%; 0.05 mL of a 1 mL stock solution in anhyd
MeCN containing 1 equiv DBU) was added to the reaction mixture.
1
The mixture was stirred at r.t. for 1 h, after which the H NMR spec-
trum showed full conversion. The mixture was concentrated using a
rotavap under vacuum and the residue was treated with H2O (5.0 mL)
and extracted with EtOAc (3 × 20 mL). The combined organic phase
was dried over anhyd Na2SO4. The solvent was removed using a ro-
tavap to afford the crude product, which was purified by flash chro-
matography (silica gel, 100% hexanes to 60% EtOAc/hexanes). All com-
pounds 7a–j were synthesized by the same method unless otherwise
noted.
LC-MS (ESI+): m/z [M + H]+ calcd for C23H26N2O7Br: 521.1; found:
521.0.
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(4-nitro-
phenylcarbamoyl)--D-glucopyranoside (7d)
4-Nitrophenyl isocyanate (38 mg, 0.232 mmol, 1 equiv) was added
first. Then DBU (0.023 mmol, 0.1 equiv) was added to the mixture.
The 1H NMR spectrum showed only 50% conversion after 1 h stirring.
More 4-nitrophenyl isocyanate (38 mg, 0.232 mmol, 1 equiv) was
then added and the mixture was stirred for another 1 h at r.t. The 1H
NMR spectrum showed 78% conversion.
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(phenylcar-
bamoyl)--D-glucopyranoside (7a)
Phenyl isocyanate (0.028 mL, 0.255 mmol, 1.1 equiv) was used.
Yield: 90 mg (90%); Rf = 0.3 (60% EtOAc/hexanes); white solid; mp
241.0–243.0 °C.
Yield: 80 mg (71%); Rf = 0.25 (60% EtOAc/hexanes); yellow solid; mp
241.0–243.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.50–7.46 (m, 2 H), 7.35–7.30 (m, 3 H),
7.29–7.21 (m, 4 H), 7.07–6.99 (m, 1 H), 6.87 (s, 1 H, NHPh), 6.19 (d, J =
9.4 Hz, 1 H, NHAc), 5.57 (s, 1 H), 5.32 (t, J = 10.0 Hz, 1 H, H-3), 4.79 (d,
J = 3.6 Hz, 1 H, H-1), 4.47–4.40 (m, 1 H, H-2), 4.34 (dd, J = 10.2, 4.7 Hz,
1 H, H-6a), 4.01–3.93 (m, 1 H, H-5), 3.84 (t, J = 10.2 Hz, 1 H, H-6b), 3.78
(t, J = 10.2 Hz, 1 H, H-4), 3.46 (s, 3 H), 1.97 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.6, 153.3, 137.5, 136.8, 129.2,
128.9, 128.2, 126.3, 123.5, 118.7, 101.9, 99.2 (C-1), 79.3 (C-4), 71.1 (C-
3), 69.0 (C-6), 63.0 (C-5), 55.4 (OCH3), 52.9 (C-2), 23.2.
1H NMR (400 MHz, CDCl3):  = 8.02 (d, J = 9.2 Hz, 2 H), 7.95 (s, 1 H,
NHAr), 7.46–7.40 (m, 2 H), 7.33 (d, J = 9.2 Hz, 2 H), 7.28–7.23 (m, 3 H),
6.25 (d, J = 9.6 Hz, 1 H, NHAc), 5.54 (s, 1 H, PhCH), 5.29 (t, J = 10.1 Hz, 1
H, H-3), 4.76 (d, J = 3.6 Hz, 1 H, H-1), 4.50–4.43 (m, 1 H, H-2), 4.34 (dd,
J = 10.3, 4.8 Hz, 1 H, H-6a), 4.00–3.92 (m, 1 H, H-5), 3.86–3.75 (m, 2 H,
H-6b, H-4), 3.46 (s, 3 H, OCH3), 1.95 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.6, 152.8, 143.8, 142.9, 136.6,
129.4, 128.3, 126.3, 124.8, 117.6, 102.1 (PhCH), 99.2 (C-1), 79.3 (C-4),
71.9 (C-3), 68.9 (C-6), 62.9 (C-5), 55.5 (OCH3), 52.5 (C-2), 23.2.
LC-MS (ESI+): m/z [M + H]+ calcd for C23H27N2O7: 443.2; found: 443.2.
LC-MS (ESI+): m/z [M + H]+ calcd for C23H26N3O9: 488.2; found: 488.2.
Methyl2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(4-methoxy-
phenylcarbamoyl)--D-glucopyranoside (7b)
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(1-naphth-
ylcarbamoyl)--D-glucopyranoside (7e)
4-Methoxyphenyl isocyanate (0.029 mL, 0.255 mmol, 1.1 equiv) was
used.
1-Naphthyl isocyanate (0.036 mL, 0.255 mmol, 1.1 equiv) was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

H
A. Chen et al.
Paper
Synthesis
Yield: 99 mg (87%); Rf = 0.3 (60% EtOAc/hexanes); white solid; mp
Yield: 93 mg (89%); Rf = 0.3 (60% EtOAc/hexanes); white solid; mp
263.0–265.0 °C.
204.0–206.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.88–7.65 (m, 4 H), 7.52–7.42 (m, 5 H),
7.38–7.32 (m, 3 H), 7.02 (s, 1 H, NHAr), 6.04 (d, J = 9.4 Hz, 1 H, NHAc),
5.57 (s, 1 H, PhCH), 5.34 (t, J = 10.1 Hz, H-3), 4.78 (d, J = 3.6 Hz, 1 H, H-
1), 4.47–4.38 (m, 1 H, H-2), 4.32 (dd, J = 10.1, 4.7 Hz, 1 H, H-6a), 3.98–
3.90 (m, 1 H, H-5), 3.86–3.74 (m, 2 H, H-6b, H-4), 3.43 (s, 3 H, OCH3),
1.95 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.48–7.44 (m, 2 H), 7.37–7.32 (m, 3 H),
6.05 (d, J = 8.9 Hz, 1 H, NH), 5.52 (s, 1 H), 5.17 (t, J = 10.1 Hz, 1 H, H-3),
4.80–4.72 (m, 2 H, NH, H-1), 4.32–4.21 (m, 2 H, H-6a, H-2), 3.92–3.84
(m, 1 H, H-5), 3.78 (t, J = 10.2 Hz, 1 H, H-6b), 3.66 (t, J = 9.5 Hz, 1 H, H-
4), 3.39 (s, 3 H, OCH3), 3.20–3.05 (m, 2 H, NHCH2), 1.97 (s, 3 H), 1.49–
1.40 (m, 2 H), 1.31–1.20 (m, 6 H), 0.86 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.4, 154.5, 137.0, 134.1, 132.1,
129.1, 128.6, 128.3, 126.4, 126.3, 126.1, 125.6, 120.7, 101.7 (PhCH),
99.2 (C-1), 79.2 (C-4), 71.6 (C-3), 69.0 (C-6), 63.0 (C-5), 55.4 (OCH3),
52.9 (C-2), 23.3.
13C NMR (100 MHz, CDCl3):  = 170.2, 156.5, 137.1, 129.1, 128.2,
126.3, 101.6, 99.1 (C-1), 79.3 (C-4), 70.6 (C-3), 69.0 (C-6), 62.9 (C-5),
55.3 (OCH3), 53.2 (C-2), 41.1 (NHCH2CH2), 31.4, 29.8 (NHCH2CH2),
26.3, 23.2, 22.5, 14.0.
LC-MS (ESI+): m/z [M + H]+ calcd for C27H29N2O7: 493.2; found: 493.2.
LC-MS (ESI+): m/z [M + H]+ calcd for C23H35N2O7: 451.2; found: 451.2.
Methyl 2-Acetamido-3-O-(benzylcarbamoyl)-4,6-O-benzylidene-
2-deoxy--D-glucopyranoside (7f)
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(heptylcar-
bamoyl)--D-glucopyranoside (7i)
Benzyl isocyanate (0.032 mL, 0.255 mmol, 1.1 equiv) was added.
Heptyl isocyanate (0.040 mL, 0.255 mmol, 1.1 equiv) was added first.
The 1H NMR spectrum showed 60% conversion after 1 h, so that more
heptyl isocyanate (0.036 mL, 0.232 mmol, 1 equiv) was added and the
mixture was stirred for another 1 h at r.t. The 1H NMR spectrum
showed 100% conversion.
Yield: 94 mg (89%); Rf = 0.3 (60% EtOAc/hexanes); white solid; mp
244.0–246.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.50–7.43 (m, 2 H), 7.38–7.33 (m, 3 H),
7.25–7.19 (m, 5 H), 6.00 (d, J = 9.0 Hz, 1 H, NHAc), 5.52 (s, 1 H), 5.22 (t,
J = 10.1 Hz, 1 H, H-3), 5.16 (t, J = 5.9 Hz, 1 H, PhCH2NH), 4.74 (d, J = 3.5
Hz, 1 H, H-1), 4.41–4.24 (m, 4 H, PhCH2NH, H-2, H-6a), 3.94–3.85 (m, 1
H, H-5), 3.78 (t, J = 10.2 Hz, 1 H, H-6b), 3.68 (t, J = 9.5 Hz, 1 H, H-4),
3.40 (s, 3 H, OCH3), 1.89 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.2, 156.6, 138.2, 137.1, 129.1,
128.6, 128.2, 127.4, 127.2, 126.3, 101.7, 99.1 (C-1), 79.3 (C-4), 71.0 (C-
3), 68.9 (C-6), 62.9 (C-5), 55.3 (OCH3), 53.0 (C-2), 45.0 (PhCH2NH),
23.1.
Yield: 93 mg (86%); Rf = 0.4 (60% EtOAc/hexane); white solid; mp
194.0–196.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.48–7.44 (m, 2 H), 7.37–7.32 (m, 3 H),
6.05 (d, J = 9.0 Hz, 1 H, NHAc), 5.52 (s, 1 H), 5.17 (t, J = 10.0 Hz, 1 H, H-
3), 4.81–4.72 (m, 2 H, H-1, CH2NH), 4.32–4.21 (m, 2 H, H-2, H-6a),
3.92–3.84 (m, 1 H, H-5), 3.78 (t, J = 10.2 Hz, 1 H, H-6b), 3.66 (t, J = 9.5
Hz, 1 H, H-4), 3.40 (s, 3 H, OCH3), 3.22–3.04 (m, 2 H, CH2NH), 1.97 (s, 3
H), 1.50–1.40 (m, 2 H), 1.33–1.17 (m, 8 H), 0.86 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.2, 156.5, 137.1, 129.1, 128.2,
126.3, 101.6, 99.1 (C-1), 79.3 (C-4), 70.6 (C-3), 69.0 (C-6), 62.9 (C-5),
55.3 (OCH3), 53.2 (C-2), 41.1 (CH2NH), 31.7, 29.8, 28.9, 26.6, 23.2, 22.6,
14.0.
LC-MS (ESI+): m/z [M + H]+ calcd for C24H29N2O7: 457.2; found: 457.2.
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(pentylcar-
bamoyl)--D-glucopyranoside (7g)
LC-MS (ESI+): m/z [M + H]+ calcd for C24H37N2O7: 465.2; found: 465.2.
Pentyl isocyanate (0.033 mL, 0.255 mmol, 1.1 equiv) was added first.
The 1H NMR spectrum showed only 40% conversion after 1 h stirring.
More pentyl isocyanate (0.030 mL, 0.232 mmol, 1 equiv) was then
added and the mixture was stirred for another 1 h at r.t., after which
the 1H NMR spectrum showed 100% conversion.
Methyl 2-Acetamido-4,6-O-benzylidene-3-O-(cyclohexylcarbam-
oyl)-2-deoxy--D-glucopyranoside (7j)
Cyclohexyl isocyanate (0.045 mL, 0.348 mmol, 1.5 equiv) was added
first, followed by DABCO (10.4 mg, 0.093 mmol, 0.4 equiv). The reac-
tion mixture was stirred for 1 h at r.t., after which the 1H NMR spec-
trum showed 0% conversion. The reaction mixture was then refluxed
Yield: 88 mg (87%); Rf = 0.3 (60% EtOAc/hexanes); white solid; mp
222.0–224.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.50–7.43 (m, 2 H), 7.38–7.31 (m, 3 H),
6.05 (d, J = 8.9 Hz, 1 H, NHAc), 5.52 (s, 1 H), 5.17 (t, J = 10.0 Hz, 1 H, H-
3), 4.85–4.70 (m, 2 H, H-1, CH2NH), 4.33–4.20 (m, 2 H, H-2, H-6a),
3.93–3.83 (m, 1 H, H-5), 3.78 (t, J = 10.2 Hz, 1 H, H-6b), 3.66 (t, J = 9.5
Hz, 1 H, H-4), 3.39 (s, 3 H, OCH3), 3.22–3.05 (m, 2 H, CH2NH), 1.97 (s, 3
H), 1.51–1.39 (m, 2 H), 1.34–1.17 (m, 4 H), 0.87 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 170.2, 156.5, 137.1, 129.1, 128.2,
126.3, 101.6, 99.1 (C-1), 79.3 (C-4), 70.6 (C-3), 69.0 (C-6), 62.9 (C-5),
55.3 (OCH3), 53.2 (C-2), 41.1 (CH2NH), 29.5, 28.8, 23.2, 22.3, 13.9.
1
for 20 h, after which the H NMR spectrum showed 78% conversion.
Additional cyclohexyl isocyanate (0.030 mL, 0.232 mmol, 1.0 equiv)
was then added and the mixture was refluxed for another 5 h; this
time the 1H NMR spectrum showed 94% conversion.
Yield: 89 mg (86%); Rf = 0.4 (60% EtOAc/hexanes); white solid; mp
236.0–238.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.49–7.43 (m, 2 H), 7.38–7.32 (m, 3 H),
6.06 (d, J = 8.6 Hz, 1 H, NHAc), 5.52 (s, 1 H), 5.16 (t, J = 10.0 Hz, 1 H, H-
3), 4.78–4.66 (m, 2 H, H-1, CyNH), 4.31–4.21 (m, 2 H, H-2, H-6a), 3.92–
3.84 (m, 1 H, H-5), 3.78 (t, J = 10.2 Hz, 1 H, H-6b), 3.65 (t, J = 9.2 Hz, 1
H, H-4), 3.47–3.36 (m, 4 H, CH in cyclohexyl, OCH3), 1.97 (s, 3 H),
1.94–1.02 (m, 10 H).
13C NMR (100 MHz, CDCl3):  = 170.2, 155.6, 137.1, 129.1, 128.2,
126.3, 101.6, 99.1 (C-1), 79.3 (C-4), 70.4 (C-3), 69.0 (C-6), 62.9 (C-5),
55.3 (OCH3), 53.2 (C-2), 50.0 (CH in cyclohexyl), 33.2, 32.9, 25.4, 24.7,
24.6, 23.3.
LC-MS (ESI+): m/z [M + H]+ calcd for C22H33N2O7: 437.2; found: 437.2.
Methyl 2-Acetamido-4,6-O-benzylidene-2-deoxy-3-O-(hexylcar-
bamoyl)--D-glucopyranoside (7h)
Hexyl isocyanate (0.038 mL, 0.255 mmol, 1.1 equiv) was added first.
The 1H NMR spectrum showed 53% conversion after 1 h stirring, and
more hexyl isocyanate (0.030 mL, 0.232 mmol, 1 equiv) was then
added to the mixture, which was stirred for another 1 h at r.t. The 1H
NMR spectrum showed 100% conversion.
LC-MS (ESI+): m/z [M + H]+ calcd for C23H33N2O7: 449.2; found: 449.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

I
A. Chen et al.
Paper
Synthesis
Carbamates 9 from Protected Glucose 8; General Procedure
1H NMR (400 MHz, CDCl3):  = 8.08–8.04 (m, 2 H), 7.57–7.52 (m, 1 H),
7.46–7.37 (m, 4 H), 7.32–7.26 (m, 5 H), 7.12–7.06 (m, 2 H), 6.60 (s, 1
H, NH), 5.75 (t, J = 9.4 Hz, 1 H, H-3), 5.55 (s, 1 H, PhCH), 5.15–5.10 (m,
2 H, H-1, H-2), 4.36 (dd, J = 10.3, 4.8 Hz, 1 H, H-6a), 4.08–4.01 (m, 1 H,
H-5), 3.85 (t, J = 10.3 Hz, 1 H, H-6b), 3.78 (t, J = 9.4 Hz, 1 H, H-4), 3.43
(s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  = 166.2, 152.1, 136.7, 136.6, 133.6,
131.8, 130.0, 129.2, 129.0, 128.5, 128.2, 126.3, 120.3, 116.0, 101.9
(PhCH), 97.9 (C-1), 79.3 (C-4), 72.6 (C-2), 70.4 (C-3), 68.9 (C-6), 62.6
(C-5), 55.6 (OCH3).
Compound 8 (45 mg or 75 mg, 1 equiv) and anhyd MeCN (3 mL) were
added to a 50 mL round-bottom flask, followed by the appropriate
isocyanate (1.1 equiv). The mixture was stirred for 15 min at r.t., then
DBU (5.0 mol%; 0.05 mL of a 1 mL stock solution in anhyd MeCN con-
taining 1 equiv DBU) was added to the reaction mixture. The resulting
1
mixture was stirred at r.t. for 1 h, after which the H NMR spectrum
showed full conversion. The mixture was concentrated using a ro-
tavap under vacuum and the residue was treated with H2O (5.0 mL)
and extracted with EtOAc (3 × 20 mL). The combined organic phase
was dried over anhyd Na2SO4. The solvent was removed using a ro-
tavap to afford the crude product, which was purified by flash chro-
matography (silica gel, 100% hexanes to 60% EtOAc/hexanes). All com-
pounds 9a–j were synthesized by the same method unless otherwise
noted.
LC-MS (ESI+): m/z [M + H]+ calcd for C28H27BrNO8Br: 584.1; found:
584.1.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(4-nitrophenylcarba-
moyl)--D-glucopyranoside (9d)
Compound 8 (75 mg, 0.202 mmol, 1 equiv) and 4-nitrophenyl isocya-
nate (36 mg, 0.222 mmol, 1.1 equiv) were used.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(phenylcarbamoyl)-
-D-glucopyranoside (9a)
Yield: 94 mg (85%); Rf = 0.25 (25% EtOAc/hexanes); off-white solid;
mp 111.0–113.0 °C.
Compound 8 (45 mg, 0.116 mmol, 1 equiv) and phenyl isocyanate
(0.016 mL, 0.128 mmol, 1.1 equiv) were used.
1H NMR (400 MHz, CDCl3):  = 8.08–8.00 (m, 4 H), 7.58–7.51 (m, 1 H),
7.44–7.37 (m, 4 H), 7.31–7.27 (m, 2 H), 7.24–7.18 (m, 3 H), 7.03 (s, 1
H, NH), 5.78 (t, J = 9.7 Hz, 1 H, H-3), 5.55 (s, 1 H, PhCH), 5.20–5.13 (m,
2 H, H-2, H-1), 4.38 (dd, J = 10.4, 4.8 Hz, 1 H, H-6a), 4.12–4.04 (m, 1 H,
H-5), 3.91–3.79 (m, 2 H, H-6b, H-4), 3.46 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  = 166.1, 151.6, 143.3, 143.0, 136.5,
133.7, 130.0, 129.3, 128.9, 128.6, 128.3, 126.3, 124.8, 117.8, 102.1
(PhCH), 97.9 (C-1), 79.3 (C-4), 72.4 (C-2), 70.9 (C-3), 68.9 (C-6), 62.5
(C-5), 55.6 (OCH3).
Yield: 52 mg (90%); Rf = 0.2 (20% EtOAc/hexanes); white solid; mp
156.0–158.0 °C.
1H NMR (400 MHz, CDCl3):  = 8.10–8.04 (m, 2 H), 7.56–7.44 (m, 3 H),
7.42–7.27 (m, 7 H), 7.25–7.20 (m, 2 H), 7.05–6.98 (m, 1 H), 6.56 (s, 1
H, NHAr), 5.77 (t, J = 9.8 Hz, 1 H, H-3), 5.56 (s, 1 H, PhCH), 5.17–5.08
(m, 2 H, H-1, H-2), 4.36 (dd, J = 10.3, 4.9 Hz, 1 H, H-6a), 4.09–4.00 (m,
1 H, H-5), 3.84 (t, J = 10.3 Hz, 1 H, H-6b), 3.78 (t, J = 9.8 Hz, 1 H, H-4),
3.42 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  = 166.2, 152.3, 137.5, 136.9, 133.5,
130.1, 129.1, 128.9, 128.5, 128.2, 126.3, 123.5, 118.8, 101.8 (PhCH),
97.9 (C-1), 79.3 (C-4), 72.8 (C-2), 70.1 (C-3), 68.9 (C-6), 62.6 (C-5),
55.5 (OCH3).
LC-MS (ESI+): m/z [M + H]+ calcd for C28H27N2O10: 551.2; found: 551.2.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(1-naphthylcarbam-
oyl)--D-glucopyranoside (9e)
LC-MS (ESI+): m/z [M + H]+ calcd for C28H28NO8: 506.2; found: 506.2.
Compound 8 (75 mg, 0.202 mmol, 1 equiv) and 1-naphthyl isocyanate
(0.033 mL, 0.222 mmol, 1.1 equiv) were added.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(4-methoxyphenyl-
carbamoyl)--D-glucopyranoside (9b)
Yield: 94 mg (84%); Rf = 0.5 (25% EtOAc/hexanes); white solid; mp
93.0–95.0 °C.
Compound 8 (45 mg, 0.116 mmol, 1 equiv) and 4-methoxyphenyl iso-
cyanate (0.017 mL, 0.128 mmol, 1.1 equiv) were used.
1H NMR (400 MHz, CDCl3):  = 8.14–8.09 (m, 2 H), 7.82–7.78 (m, 1 H),
7.69–7.62 (m, 3 H), 7.54–7.49 (m, 3 H), 7.42–7.33 (m, 7 H), 7.26–7.22
(m, 1 H), 6.83 (s, 1 H, NH), 5.83 (t, J = 9.6 Hz, 1 H, H-3), 5.59 (s, 1 H,
PhCH), 5.18–5.11 (m, 2 H, H-1, H-2), 4.36 (dd, J = 10.2, 4.8 Hz, 1 H, H-
6a), 4.10–4.01 (m, 1 H, H-5), 3.89–3.76 (m, 2 H, H-6b, H-4), 3.43 (s, 3 H,
OCH3).
13C NMR (100 MHz, CDCl3):  = 166.2, 153.5, 137.0, 134.0, 133.5,
132.2, 130.1, 129.14, 129.07, 128.5, 128.2, 126.3, 126.1, 125.9, 125.6,
120.7, 101.7 (PhCH), 97.9 (C-1), 79.3 (C-4), 72.7 (C-2), 70.5 (C-3), 68.9
(C-6), 62.6 (C-5), 55.5 (OCH3).
Yield: 53 mg (85%); Rf = 0.3 (25% EtOAc/hexanes); white solid; mp
192.0–194.0 °C.
1H NMR (400 MHz, CDCl3):  = 8.10–8.05 (m, 2 H), 7.57–7.51 (m, 1 H),
7.50–7.45 (m, 2 H), 7.44–7.38 (m, 2 H), 7.37–7.32 (m, 3 H), 7.16 (d, J =
8.8 Hz, 2 H), 6.80–6.75 (m, 2 H), 6.40 (s, 1 H, NHAr), 5.75 (t, J = 9.8 Hz,
1 H, H-3), 5.56 (s, 1 H, PhCH), 5.14 (d, J = 3.7 Hz, 1 H, H-1), 5.12–5.07
(m, 1 H, H-2), 4.35 (dd, J = 10.2, 4.8 Hz, 1 H, H-6a), 4.07–3.99 (m, 1 H,
H-5), 3.87–3.73 (m, 5 H, H-6b, H-4, ArOCH3), 3.42 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  = 166.2, 156.1, 152.7, 136.9, 133.5,
130.6, 130.1, 129.2, 129.1, 128.5, 128.2, 126.3, 120.9, 114.1, 101.8
(PhCH), 97.9 (C-1), 79.4 (C-4), 72.8 (C-2), 70.1 (C-3), 69.0 (C-6), 62.6
(C-5), 55.50 (OCH3), 55.47 (ArOCH3).
LC-MS (ESI+): m/z [M + H]+ calcd for C32H30NO8: 556.2; found: 556.2.
Methyl 2-O-Benzoyl-3-O-(benzylcarbamoyl)-4,6-O-benzylidene--
D-glucopyranoside (9f)
LC-MS (ESI+): m/z [M + H]+ calcd for C29H30NO9: 536.2; found: 536.2.
Compound 8 (75 mg, 0.202 mmol, 1 equiv) and benzyl isocyanate
(0.030 mL, 0.222 mmol, 1.1 equiv) were used.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(4-bromophenylcar-
bamoyl)--D-glucopyranoside (9c)
Yield: 91 mg (87%); Rf = 0.6 (40% EtOAc/hexanes); white solid; mp
62.0–64.0 °C.
Compound 8 (75 mg, 0.202 mmol, 1 equiv) and 4-bromophenyl isocy-
anate (44 mg, 0.222 mmol, 1.1 equiv) were used.
1H NMR (400 MHz, CDCl3):  = 8.14–8.07 (m, 2 H), 7.63–7.57 (m, 1 H),
7.53–7.43 (m, 4 H), 7.40–7.35 (m, 3 H), 7.17–7.10 (m, 1 H), 7.09–7.00
(m, 4 H), 5.73 (t, J = 9.8 Hz, 1 H, H-3), 5.55 (s, 1 H, PhCH), 5.13–5.03
Yield: 101 mg (86%); Rf = 0.5 (25% EtOAc/hexanes); white solid; mp
100.0–102.0 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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A. Chen et al.
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Synthesis
(m, 2 H, H-1, H-2), 4.92 (t, J = 5.6 Hz, 1 H, NH), 4.37–4.21 (m, 3 H, H-6a,
PhCH2), 4.06–3.97 (m, 1 H, H-5), 3.81 (t, J = 10.3 Hz, 1 H, H-6b), 3.72 (t,
J = 9.8 Hz, 1 H, H-4), 3.41 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  = 166.1, 155.5, 138.3, 137.1, 133.4,
130.1, 129.3, 129.1, 128.5, 128.4, 128.2, 127.22, 127.18, 126.3, 101.7
(PhCH), 97.9 (C-1), 79.5 (C-4), 72.7 (C-2), 70.0 (C-3), 69.0 (C-6), 62.5
(C-5), 55.5 (OCH3), 45.0 (PhCH2).
2), 4.65–4.58 (m, 1 H, NH), 4.33 (dd, J = 10.2, 4.8 Hz, 1 H, H-6a), 4.05–
3.96 (m, 1 H, H-5), 3.81 (t, J = 10.2 Hz, 1 H, H-6b), 3.71 (t, J = 9.7 Hz, 1
H, H-4), 3.40 (s, 3 H, OCH3), 3.08–2.95 (m, 2 H, NHCH2), 1.31–1.16 (m,
4 H), 1.13–1.03 (m, 6 H), 0.83 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.2, 155.3, 137.0, 133.4, 130.1,
129.3, 129.0, 128.4, 128.2, 126.3, 101.7 (PhCH), 97.9 (C-1), 79.4 (C-4),
72.9 (C-2), 69.6 (C-3), 68.9 (C-6), 62.6 (C-5), 55.4 (OCH3), 41.0
(NHCH2), 31.6, 29.7, 28.8, 26.5, 22.5, 14.0.
LC-MS (ESI+): m/z [M + H]+ calcd for C29H30NO8: 520.2; found: 520.2.
LC-MS (ESI+): m/z [M + H]+ calcd for C29H38NO8: 528.3; found: 528.3.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(pentylcarbamoyl)--
D-glucopyranoside (9g)
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(cyclohexylcarbam-
oyl)--D-glucopyranoside (9j)
Compound 8 (45 mg, 0.116 mmol, 1 equiv) and pentyl isocyanate
(0.017 mL, 0.128 mmol, 1.1 equiv) were added first. The 1H NMR
spectrum showed 55% conversion after 1 h stirring. Additional pentyl
isocyanate (0.015 mL, 0.116 mmol, 1 equiv) was added and the mix-
ture was stirred for another 1 h at r.t., at which time the 1H NMR spec-
trum showed 100% conversion.
Compound 8 (75 mg, 0.202 mmol, 1 equiv) and cyclohexyl isocyanate
(0.029 mL, 0.222 mmol, 1.1 equiv) were added.
Yield: 93 mg (90%); Rf = 0.5 (25% EtOAc/hexanes); white solid; mp
82.0–84.0 °C.
1H NMR (400 MHz, CDCl3):  = 8.11–8.07 (m, 2 H), 7.59–7.54 (m, 1 H),
7.51–7.41 (m, 4 H), 7.38–7.32 (m, 3 H), 5.66 (t, J = 9.8 Hz, 1 H, H-3),
5.54 (s, 1 H, PhCH), 5.10 (d, J = 3.7 Hz, 1 H, H-1), 5.08–5.00 (m, 1 H, H-
2), 4.55–4.45 (m, 1 H, NHCH), 4.33 (dd, J = 10.3, 4.8 Hz, 1 H, H-6a),
4.04–3.96 (m, 1 H, H-5), 3.81 (t, J = 10.3 Hz, 1 H, H-6b), 3.70 (t, J = 9.8
Hz, 1 H, H-4), 3.44–3.33 (m, 4 H, OCH3, NHCH), 1.89–1.77 (m, 1 H),
1.57–1.42 (m, 3 H), 1.34–1.11 (m, 3 H), 1.10–0.96 (m, 2 H), 0.91–0.77
(m, 1 H).
13C NMR (100 MHz, CDCl3):  = 166.2, 154.5, 137.1, 133.4, 130.1,
129.3, 129.0, 128.4, 128.2, 126.3, 101.7 (PhCH), 98.0 (C-1), 79.5 (C-4),
72.9 (C-2), 69.5 (C-3), 69.0 (C-6), 62.6 (C-5), 55.4 (OCH3), 49.8 (NHCH),
33.0, 25.4, 24.6, 24.5.
Yield: 49 mg (87%); Rf = 0.3 (20% EtOAc/hexanes); colorless solid; mp
75.0–77.0 °C.
1H NMR (400 MHz, CDCl3):  = 8.12–8.06 (m, 2 H), 7.60–7.54 (m, 1 H),
7.51–7.42 (m, 4 H), 7.39–7.33 (m, 3 H), 5.66 (t, J = 9.8 Hz, 1 H, H-3),
5.54 (s, 1 H, PhCH), 5.09 (d, J = 3.6 Hz, 1 H, H-1), 5.07–5.00 (m, 1 H, H-
2), 4.58 (s, 1 H, NHCH2), 4.33 (dd, J = 10.3, 4.8 Hz, 1 H, H-6a), 4.05–3.96
(m, 1 H, H-5), 3.81 (t, J = 10.3 Hz, 1 H, H-6b), 3.70 (t, J = 9.8 Hz, 1 H, H-
4), 3.40 (s, 3 H, OCH3), 3.11–2.98 (m, 2 H, NHCH2), 1.34–1.24 (m, 2 H),
1.21–1.06 (m, 4 H), 0.75 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 166.2, 155.3, 137.0, 133.4, 130.1,
129.3, 129.0, 128.4, 128.2, 126.3, 101.7 (PhCH), 97.9 (C-1), 79.5 (C-4),
72.9 (C-2), 69.6 (C-3), 68.9 (C-6), 62.6 (C-5), 55.4 (OCH3), 41.0
(NHCH2), 29.4, 28.6, 22.1, 13.8.
LC-MS (ESI+): m/z [M + H]+ calcd for C28H34NO8: 512.2; found: 512.2.
LC-MS (ESI+): m/z [M + H]+ calcd for C27H34NO8: 500.2; found: 500.2.
Compounds 10 and 11; General Procedure
In a scintillation vial, compound 9 (1 equiv) was dissolved in anhyd
MeOH; addition of NaOMe (0.5 equiv) followed. The reaction mixture
was stirred at r.t. for 6 h. The 1H NMR spectrum showed full conver-
sion. Solvent was removed by a rotavap to afford the crude product,
which was purified by column chromatography (silica gel, hex-
anes/EtOAc, 9:1 to hexanes/EtOAc/MeOH, 70:30:1); this afforded the
desired product as a white solid.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(hexylcarbamoyl)--
D-glucopyranoside (9h)
Compound 8 (45 mg, 0.116 mmol, 1 equiv) and hexyl isocyanate
(0.019 mL, 0.128 mmol, 1.1 equiv) were added.
Yield: 52 mg (87%); wax-like solid; Rf = 0.35 (20% EtOAc/hexanes).
1H NMR (400 MHz, CDCl3):  = 8.11–8.06 (m, 2 H), 7.60–7.54 (m, 1 H),
7.52–7.42 (m, 4 H), 7.39–7.32 (m, 3 H), 5.67 (t, J = 9.7 Hz, 1 H, H-3),
5.54 (s, 1 H, PhCH), 5.09 (d, J = 3.6 Hz, 1 H, H-1), 5.07–5.01 (m, 1 H, H-
2), 4.58 (s, 1 H, NHCH2), 4.33 (dd, J = 10.2, 4.8 Hz, 1 H, H-6a), 4.04–3.96
(m, 1 H, H-5), 3.81 (t, J = 10.3 Hz, 1 H, H-6b), 3.70 (t, J = 9.7 Hz, 1 H, H-
4), 3.40 (s, 3 H, OCH3), 3.11–2.96 (m, 2 H, NHCH2), 1.35–1.23 (m, 2 H),
1.20–1.03 (m, 6 H), 0.79 (t, J = 6.8 Hz, 3 H).
Methyl 4,6-O-Benzylidene-3-O-(phenylcarbamoyl)--D-glucopyra-
noside (10)
Compound 9a (20 mg, 0.040 mmol, 1 equiv) and NaOMe (1.1 mg,
0.020 mmol, 0.5 equiv) were added.
Yield: 13 mg (87%); Rf = 0.5 (5% MeOH/DCM); white solid; mp 215.0–
13C NMR (100 MHz, CDCl3):  = 166.2, 155.3, 137.1, 133.4, 130.1,
129.3, 129.0, 128.4, 128.2, 126.3, 101.7 (PhCH), 97.9 (C-1), 79.5 (C-4),
72.9 (C-2), 69.6 (C-3), 69.0 (C-6), 62.6 (C-5), 55.4 (OCH3), 41.0
(NHCH2), 31.3, 29.7, 26.2, 22.4, 13.9.
217.0 °C.
1H NMR (400 MHz, CDCl3):  = 7.49–7.44 (m, 2 H), 7.39–7.28 (m, 7 H),
7.09–7.03 (m,1 H), 6.68 (s, 1 H), 5.51 (s, 1 H), 5.27 (t, J = 9.6 Hz, 1 H),
4.83 (d, J = 3.8 Hz, 1 H), 4.35–4.29 (m, 1 H), 3.95–3.87 (m, 1 H), 3.81–
3.67 (m, 2 H), 3.63 (t, J = 9.6 Hz, 1 H), 3.49 (s, 3 H), 2.56–2.50 (m, 1 H).
LC-MS (ESI+): m/z [M + H]+ calcd for C28H36NO8: 514.2; found: 514.2.
13C NMR (100 MHz, CDCl3):  = 155.4, 137.6, 137.0, 129.1, 129.0,
128.3, 126.3, 123.7, 118.9, 101.7, 100.3, 78.7, 73.6, 72.2, 69.0, 62.8,
55.6.
Methyl 2-O-Benzoyl-4,6-O-benzylidene-3-O-(heptylcarbamoyl)--
D-glucopyranoside (9i)
Compound 8 (75 mg, 0.202 mmol, 1 equiv) and heptyl isocyanate
LC-MS (ESI+): m/z [M + H]+ calcd for C21H24NO7: 402.2; found: 402.2.
(0.036 mL, 0.222 mmol, 1.1 equiv) were added.
Methyl 4,6-O-Benzylidene-3-O-(pentylcarbamoyl)--D-glucopyra-
Yield: 95 mg (89%); wax-like solid; Rf = 0.6 (25% EtOAc/hexanes).
noside (11a)
1H NMR (400 MHz, CDCl3):  = 8.11–8.06 (m, 2 H), 7.59–7.54 (m, 1 H),
7.50–7.42 (m, 4 H), 7.37–7.31 (m, 3 H), 5.66 (t, J = 9.7 Hz, 1 H, H-3),
5.54 (s, 1 H, PhCH), 5.10 (d, J = 3.6 Hz, 1 H, H-1), 5.07–5.01 (m, 1 H, H-
Compound 9g (50 mg, 0.100 mmol, 1 equiv) and NaOMe (2.7 mg,
0.050 mmol, 0.5 equiv) were added.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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A. Chen et al.
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Synthesis
Yield: 35 mg (92%); Rf = 0.45 (5% MeOH/DCM); white solid; mp
186.0–188.0 °C.
Funding Information
We are grateful for financial support from a Boehringer Ingelheim Sci-
ence Advancement grant and the National Science Foundation (grant
1H NMR (400 MHz, CDCl3):  = 7.49–7.44 (m, 2 H), 7.37–7.33 (m, 3 H),
5.50 (s, 1 H), 5.15 (t, J = 9.7 Hz, 1 H), 4.83–4.72 (m, 2 H), 4.33–4.26 (m,
1 H), 3.92–3.83 (m, 1 H), 3.75 (t, J = 10.3 Hz, 1 H), 3.69–3.61 (m, 1 H),
3.56 (t, J = 9.7 Hz, 1 H), 3.46 (s, 3 H), 3.22–3.12 (m, 2 H), 2.90–2.79 (m,
1 H), 1.54–1.43 (m, 2 H), 1.35–1.21 (m, 4 H), 0.87 (t, J = 6.5 Hz, 3 H).
CHE 1808609).
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Supporting Information
Methyl 4,6-O-Benzylidene-3-O-(heptylcarbamoyl)--D-glucopyra-
Supporting information for this article is available online at
noside (11b)
https://doi.org/10.1055/s-0037-1612425.
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Compound 9i (50 mg, 0.095 mmol, 1 equiv) and NaOMe (2.6 mg,
0.048 mmol, 0.5 equiv) were added.
References
Yield: 38 mg (95%); Rf = 0.5 (5% MeOH/DCM); white solid; mp 180.0–
182.0 °C.
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(4) Ghosh, A. K.; Brindisi, M. J. Med. Chem. 2015, 58, 2895.
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(7) Zappia, G.; Menendez, P.; Delle Monache, G.; Misiti, D.; Nevola,
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(8) Manabe, S.; Ishii, K.; Ito, Y. Eur. J. Org. Chem. 2011, 497.
(9) Kancharla, P. K.; Navuluri, C.; Crich, D. Angew. Chem. Int. Ed.
2012, 51, 11105.
1H NMR (400 MHz, CDCl3):  = 7.49–7.43 (m, 2 H), 7.38–7.32 (m, 3 H),
5.49 (s, 1 H), 5.15 (t, J = 9.7 Hz, 1 H), 4.82–4.72 (m, 2 H), 4.33–4.26 (m,
1 H), 3.91–3.83 (m, 1 H), 3.75 (t, J = 10.2 Hz, 1 H), 3.70–3.62 (m, 1 H),
3.56 (t, J = 9.7 Hz, 1 H), 3.46 (s, 3 H), 3.22–3.11 (m, 2 H), 2.82 (d, J = 8.5
Hz, 1 H), 1.52–1.40 (m, 2 H), 1.35–1.17 (m, 8 H), 0.86 (t, J = 6.9 Hz, 3
H).
Dicarbamate Compound 12
Compound 8 (90 mg, 0.232 mmol, 1 equiv) and 4,4′-methylenediphe-
nyl diisocyanate (29 mg, 0.116 mmol, 0.5 equiv) were stirred under
the reaction conditions.
Yield: 100 mg (84%); Rf = 0.5 (40% EtOAc/hexanes); off-white solid;
mp 150.0–152.0 °C.
(10) Wang, G.; Hollingsworth, R. I. Tetrahedron: Asymmetry 2000, 11,
4429.
1H NMR (400 MHz, CDCl3):  = 8.09–8.02 (m, 4 H), 7.54–7.43 (m, 6 H),
7.40–7.35 (m, 4 H), 7.33–7.28 (m, 6 H), 7.14 (d, J = 8.4 Hz, 4 H), 6.97
(d, J = 8.4 Hz, 4 H), 6.51 (s, 2 H), 5.76 (t, J = 9.8 Hz, 2 H, H-3), 5.55 (s, 2
H, PhCH), 5.15–5.07 (m, 4 H, H-1, H-2), 4.38–4.32 (m, 2 H, H-6a), 4.07–
3.99 (m, 2 H, H-5), 3.87–3.73 (m, 6 H, H-6b, CH2, H-4), 3.42 (s, 6 H,
OCH3).
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S. E. RSC Adv. 2014, 4, 13012.
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463.
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M.; Gaware, V.; Varghese, S.; Harel, D.; Kurhade, S. Org. Lett.
2012, 14, 2814.
13C NMR (100 MHz, CDCl3):  = 166.2, 152.3, 136.9, 136.3, 135.6,
133.5, 130.0, 129.2, 129.1, 128.5, 128.2, 126.2, 119.1, 101.8 (PhCH),
97.9 (C-1), 79.3 (C-4), 72.7 (C-2), 70.1 (C-3), 68.9 (C-6), 62.6 (C-5),
55.5 (OCH3), 40.5 (CH2).
LC-MS (ESI+): m/z [M + H]+ calcd for C57H55N2O16: 1023.4; found:
1023.4.
(17) Heller, S. T.; Schultz, E. E.; Sarpong, R. Angew. Chem. Int. Ed.
2012, 51, 8304.
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C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org. Lett. 2009,
11, 5622.
Dicarbamate Compound 13
Compound 8 (90 mg, 0.232 mmol, 1 equiv) and 1,6-diisocyanatohex-
ane (0.019 mL, 0.116 mmol, 0.5 equiv) were added.
(19) Nishikawa, T.; Urabe, D.; Tomita, M.; Tsujimoto, T.; Iwabuchi, T.;
Isobe, M. Org. Lett. 2006, 8, 3263.
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W. Angew. Chem. Int. Ed. 2015, 54, 11686.
Yield: 88 mg (81%); Rf = 0.5 (40% EtOAc/hexanes); white solid; mp
118.0–120.0 °C.
1H NMR (400 MHz, CDCl3):  = 8.11–8.04 (m, 4 H), 7.59–7.52 (m, 2 H),
7.47–7.35 (m, 8 H), 7.32–7.27 (m, 6 H), 5.66 (t, J = 9.5 Hz, 2 H, H-3),
5.49 (s, 2 H, PhCH), 5.14–5.06 (m, 4 H, H-2, H-1), 4.64–4.51 (m, 2 H,
NH), 4.36–4.29 (m, 2 H, H-6a), 4.06–3.97 (m, 2 H, H-5), 3.84 (t, J = 10.2
Hz, 2 H, H-6b), 3.74 (t, J = 9.5 Hz, 2 H, H-4), 3.41 (s, 6 H, OCH3), 2.95–
2.78 (m, 2 H), 2.69–2.53 (m, 2 H), 1.13–0.79 (m, 8 H).
13C NMR (100 MHz, CDCl3):  = 166.1, 155.3, 137.0, 133.4, 130.1,
129.3, 129.1, 128.5, 128.2, 126.3, 101.8 (PhCH), 97.9 (C-1), 79.4 (C-4),
72.7 (C-2), 69.5 (C-3), 68.9 (C-6), 62.6 (C-5), 55.4 (OCH3), 40.6, 28.8,
25.9.
LC-MS (ESI+): m/z [M + H]+ calcd for C50H57N2O16: 941.4; found: 941.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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A. Chen et al.
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