Direct Coupling of Amides and Urea to Glycosyl Halides Using Silver Triflate

Article abstract of DOI:10.1002/ejoc.201600350

We herein report the coupling of various amides and ureas to glycosyl halides in the presence of silver triflate at room temperature. A 1:1 mixture of α/β diastereomers was obtained when alkyl/heteroaryl amides and substituted ureas were added to gluco an

Full text of DOI:10.1002/ejoc.201600350

DOI: 10.1002/ejoc.201600350
Communication
Carbohydrate Synthesis
Direct Coupling of Amides and Urea to Glycosyl Halides Using
Silver Triflate
Luz M. Rosado,[a][‡] Terence J. Meyerhoefer,[a][‡] Saqib M. Bett,[a] Saba. Ilyas,[a]
Lubabalo. Bululu,[a] Carla A. Martin,[a] Troy W. Joseph,[b] and Michael De Castro*[a]
Abstract: We herein report the coupling of various amides and of the reaction was also explored. When the acetyl-protected
ureas to glycosyl halides in the presence of silver triflate at glucuronamide was employed in the reaction, the ꢀ anomer of
room temperature. A 1:1 mixture of α/ꢀ diastereomers was ob- the corresponding pseudodissacharide was obtained as the ma-
tained when alkyl/heteroaryl amides and substituted ureas jor isomer in good yields at room temperature. The newly syn-
were added to gluco and galacto haloglycosides. The effect of thesized compounds were subjected to viability studies using
temperature, halogen, protecting group of the sugar and sub- HeLa cancer cells. The results obtained are also discussed in this
stituent of the amide in the overall yields and stereoselectivity study.
Introduction
Glycosylamides and glycosylureas are a very important class of
compounds in carbohydrate chemistry. Thiophene-containing
glycosylamides (I) (Figure 1) are known to inhibit growth and
proliferation in bovine aortic endothelial cells and are currently
under development as a potential angiogenic inhibitor.[1] Glyc-
osylamide (II) and the glycosylurea (III) (Figure 1) are potent
inhibitors of glycogen phosphorylase and as such both com-
pounds show promise as chemotherapeutics for the treatment
Figure 1. Biologically active glycosylamides/ureas.
of type II diabetes.[2] Glycosylamides have also been employed
as glycosyl donors. For example glycosylamide (IV) (Figure 1)
can undergo glycosylation reactions with a variety of alcohols
and amines in high yields under mild neutral conditions at
room temperature.[3]
ligation with diphenylphosphanyl-phenyl ethers and α-glycosyl
Glycosylamines and glycosyl azides are common precursors
azides.[8]
used in the chemical synthesis of glycosylamides and glycosyl-
A handful of very useful methods exist for the chemical syn-
ureas. The reaction of glycosylamines with carboxylic acids and
thesis of glycosylureas. A traditional approach involves the acid-
activated aspartic acids residues of protected peptides have
catalyzed condensations of glucose with urea.[9]Other methods
been used towards the synthesis of N-glycolipids,[4] and N-
includes the coupling of isocyanates with nucleophilic
glycopeptides, respectively.[5] Glycosyl azides have also been
amines,[10] and the use of
D-glucal trichloroacetamides as start-
employed as starting materials in the preparation of ꢀ-glycosyl-
ing materials.[11] While the methods mentioned above are very
robust, the direct coupling of amides or ureas to sugars remains
unexplored. Advantages to such an approach include: access to
a large pool of commercially available amides/ureas as well as
the minimization of steps involved in the chemical synthesis of
the final compounds.
amides.[6]
Other methods includes the reaction of acyl glycosyl isothio-
cyanates with carboxylic acids catalyzed by trimethylamine.[7]
In the case of the less abundant α-glycosylamides a standard
procedure for its preparation employs a traceless Staudinger
Khane and co-workers reported the prepration of glycosyl-
acetamides via the direct addition of trimethylsilylacetamide to
a thiophenyl glycoside donor.[12] Glycosylamides have also been
prepared via the reaction of 1-hydroxy glycosyl donors and tri-
methylsilylacetamide in the presence of triflouromethane sulf-
onic anhydride and diphenyl sulfoxide.[13] Other donors such
as trichloroacetimidates and trifluoroacetimidates[14] have been
used in the glycosylation of asparagine towards the synthesis
[a] Chemistry Department, Farmingdale State College-SUNY,
2350 Broadhollow Rd., Farmingdale, NY 11735, USA
E-mail: michael.decastro@farmingdale.edu
http://www.farmingdale.edu/faculty/michael-decastro/index.shtml
[b] Touro College, School of Health and Sciences,
1700 Union Blvd., Bay Shore, NY 11706, USA
[‡] Both authors contributed equally to this project.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600350.
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of N-glycopeptides. Our laboratory recently published the prep- Table 1) and ꢀ-gluco (2a′) (Entry 1, Table 1) in a 1:1 ratio of the
aration of 2-deoxy-2-iodo-glycosylamides via the addition of sil- known glycosylacetamide.[19] The same results were obtained
ylated amides and urea to D-glucal in the presence of N-iodo- when the reaction was conducted at 0 °C. When trifluorotri-
succinimide.[15] We failed to substitute the iodine at the C-2 methylsilylacetamide was employed in the reaction multiple
position with a hydroxyl group using a mixture of silver triflate spots were detected upon TLC analysis and its use was discon-
in acetonitrile and water when having a secondary amide at tinued. Identical results were obtained when N,N′-bis(trimethyl-
the anomeric center. This motivated us to explore an alternative silyl)urea and 1-(trimethylsilyl)-2-pyrrolidinone were employed.
route using glycosyl halides as starting material instead. We The known glycoimidazole[20] (2b′) (Entry 2, Table 1) and glyco-
hypothesize that the presence of chlorine at the anomeric cen- benzotriazole[21] (2c′) (Entry 3, Table 1) were synthesized using
ter of a benzyl-protected glucose 1 (Scheme 1) will undergo the corresponding silylated heterocycles: 1-(trimethylsilyl)-
nucleophilic substitution with amide/urea and silylated amides imizadole and 1-(trimethylsilyl)-1H-benzotriazole, respectively.
in the presence of silver triflate (AgTOf) (Scheme 1).
The ꢀ-isomer was obtained exclusively as indicated by the large
coupling constants (2b′, J1–2 = 7.0 Hz) and (2c′, J1–2 = 10.0 Hz),
respectively.[22] Encouraged by these results we decided to ex-
plore the coupling of primary amides and urea to precursor 1
(Scheme 2). This time the glycosyl halide 1 (1.0 equiv.) was
mixed with the amide/urea (3.0 equiv.) in freshly distilled aceto-
nitrile. This was followed by the addition of a mixture of AgOTf
(1.5 equiv.) in dry acetonitrile. After 1 hour complete disappear-
ance of the starting material was observed using TLC analysis.
The reaction was worked up and purified using flash column
chromatography and the results summarized in (Table 2).
Scheme 1. Proposed glycosylation reaction.
The reaction of glycosyl halides with an alcohol acceptor in
the presence of silver or mercury salts is one of the oldest meth-
ods for the preparation of a new glycosidic bond.[16,17] However,
the direct coupling of amides and ureas to glycosyl halides re-
mains a relatively unexplored area in carbohydrate chemistry.
This could be in part due to the poor nucleophilicity displayed
by such functional group.
Table 1. Diastereomeric ratios of N-glycosides.
We are pleased to report our findings in the coupling of aryl
and heteroaryl amides to glucose and galactose having chlorine
at the anomeric center in the presence of AgOTf. The addition
of a secondary amide as well as silylated amides and hetero-
cycles to the glucose derivative was also explored. The effect
of the protecting group of the sugar, substituent of the amide
as well as reaction temperature and nature of the halogen in
the overall yields and stereoselectivity is also discussed. When
the acetyl-protected glucuronamide was used as the acceptor,
a series of pseudodisaccharides having an amide linkage were
synthesized with excellent yields and stereoselectivity. The new
compounds were used in cytotoxic studies using HeLa cancer
cell and the results are also discussed in this report.
[a] Determined by integration of the anomeric protons in the 1H-NMR spec-
trum. [b] Represents product recovered following extractive workup and sub-
sequent chromatographic purification using (SiO2).
Results and Discussion
Our studies began with the reaction of glycosyl halide 1[18] with
trimethylsilylacetamide (Entry 1, Table 1) in the presence of
AgOTf and dry acetonitrile (Scheme 1). Hence, trimethylsilyl-
acetamide (3.0 equiv.) was mixed in dry acetonitrile (3.0 mL).
Silver triflate (1.5 equiv.) was pre-mixed in dry acetonitrile and
added dropwise to the reaction flask at room temperature. The
reaction was mixed for 10 min at room temperature. The mix-
ture of the glycosyl halide 1 (1.0 equiv.) in freshly distilled aceto-
nitrile (2.0 mL) was subsequently added to the reaction flask. A
gray precipitate, presumably corresponding to silver chloride,
was immediately observed upon addition of the sugar. After 1
Scheme 2. Direct coupling of amides and urea to glycosyl halides.
With the exception of the known glycosylbenzamide (3c, 3c′)
hour complete disappearance of the starting material was de- (Entry 6, Table 2)[23] a 1:1 ratio of the α/ꢀ isomer was always
tected using TLC analysis. NMR analysis of the crude mixture isolated. When urea was employed in the reaction, the ꢀ ano-
indicated the presence of both the α-gluco (2a) (Entry 1, mer 3d′ (Entry 8, Table 2) was obtained as a single isomer albeit
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Table 2. Diastereomeric ratios of glucose derived glycosylamide/urea.
ylcarbamate, trifluoroacetamide and bromoacetamide did not
react at all and starting material was always recovered (results
not shown). Similar results were obtained when the galactose
glycosyl halide was used as starting material (Table 3,
Scheme 3).
Table 3. Diastereomeric ratios of galactose derived glycosylamide/urea.
[a] Determined by integration of the anomeric protons in the 1H-NMR spec-
trum. [b] Represents product recovered following extractive workup and sub-
sequent chromatographic purification using (SiO2).
[a] Determined by integration of the anomeric protons in the 1H-NMR spec-
trum. [b] Represents product recovered following extractive workup and sub-
sequent chromatographic purification using (SiO2).
in low yields.[24]That was not the case with phenyl urea[25] (3b,
3b′) (Entry 5, Table 2) where a mixture was obtained. The ꢀ-
linked pseudodisaccharide was obtained as the major isomer
Scheme 3. Direct coupling of amides and urea to galactose glycosyl halide.
We hypothesized that the addition reaction may take place
with glucuronamide (3f′, J1–2 = 8.5 Hz)[26] (Entry 10, Table 2) following the mechanism depicted in (Scheme 4). An SN-1 type
and with secondary amides (3g′) (Entry 11,Table 2). It should addition of the amide to the anomeric center will explain the
be mentioned that traces of the α-linked pseudodisaccharide formation of both anomers (Scheme 4). Since triflic acid is gen-
was detected after careful analysis of 1H-NMR spectroscopy. erated under our reaction conditions we began to contemplate
Amides having electron-withdrawing substituents such as benz- the possibility of anomerization of the newly installed amides
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(Scheme 5). Although remote, since we have an excess of the
amide that can potentially quenched any acid generated in our
reaction, we decided to rule out such posibility by conducting
the following experiment. Glycosylacetamide 2a′ (Entry 7,
Table 2) was diluted in dry acetonitrile and 0.1 % equivalent by
weight of triflic acid was added to the reaction mixture at room
temperature. After two hours TLC analysis did not show the
formation of the α-anomer 2a and the starting material 2a′ was
isolated (Scheme 5).
Scheme 4. Proposed mechanism for the addition of amides to the glycosyl
halide.
Figure 2. A. Representative data for the glucose series. B. Representative data
for the galactose series.
We decided to explore the addition reaction using the acetyl-
protected glucose bromide and chloride. The glycosyl bromide
and glycosyl chloride proved to be very labile and multiple
spots were obtained upon TLC analysis.[27] In both cases TLC
analysis suggested the formation of the hydrolyzed product as
the major by-product of the reaction. One can hypothesize that
the electron-withdrawing nature of the acetyl protecting group
may not help stabilize the formation of the carbocation at the
C-1 position. This coupled with the poor nucleophilicity of the
amides and ureas will explain the addition of the hydroxyl
HeLa cells were grown in 6 well plates to 80 % confluence in
DMEM medium with 10 %FBS. Cells were treated for 24 h with
various glucose/galactose analogues at 100 μM, 10 μM, respec-
tively. After 24 h the media was collected and the cells were
washed with PBS. Media and trypsinized cells were spun down
at 2000 rpm. The pellet was resuspended in 1 mL of PBS.
10 μL of cells were mixed with 10 μL of Trypan Blue. Viable
group to the anomeric center. We did not detect the formation and dead cell counts were determined using a hemocytomer.
of the ortho ester of the acetyl-protected sugar using LCMs For the glucose-based compounds the best results were ob-
analysis. Dichloromethane and propionitrile were evaluated as tained with the glycosylbenzotriazole analog 2c′ (Figure 3)
possible solvents in our glycosylation studies and were used (86 %, 100 μM) (Figure 2, A).
under the same reaction conditions. For both solvents, the iso-
lated product yields were much lower and it required longer
reaction times. This may be due in part to the poor solubility
of AgOTf displayed with both solvents.
Such activity does not come as a surprise since this com-
pound is known to inhibit cell growth in cancer cells.[29] The α-
anomer of the glycosylacetamide 2a (69 % at 100 μ
(67 % at 100 μ ) performed much better than the ꢀ-anomer
) and 3a′ (55 % at 100 μ ) (Figure 2, A). A
M
) and 3a
M
The newly synthesized glycosylamides and glycosylureas, 3d′ (43 % at 100 μ
M
M
both the glucose and galactose series, were subjected to viabil- 10 % increase is observed when the dimethyl urea is fused to
ity studies using HeLa cancer cell lines. We also included in this the carbohydrate such as the case with compound A (Figure 2)
study a series of previously synthesized carbohydrate-based (77 % at 100 μ
heterocyclic compounds such as the dimethyl-substituted N- is observed with compound (3d′) (16 % at 100 μ
glycooxazoline (A).[28] The most representative data is shown in Table 1) vs. compound (3a′) (55 % at 100 μ
) (Figure 2, A). It
(Figure 2, A) for the glucose series and (Figure 2, B) for the seems the methyl groups may play a role in the overall activity
M
) (Figure 2, A). Interestingly a decrease in activity
M
) (Entry 8,
M
galactose series.
of the compound. Moreover the presence of a nitrogen at the
Scheme 5. Acid-catalyzed anomerization of the newly installed amides.
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obtained when dry acetonitrile was used in the reaction. The
dimethyl urea and acetamide containing glucose analogs show
promising anticancer properties. The same can be said about
the dimethyl urea and benzamide galactose analogs. The opti-
mization and mode of action of these compounds is currently
under investigation and the results will be disclosed in future
publications.
Experimental Section
General: Column chromatography was performed on silica gel 60
(EM Science, 70–230 mesh). Reactions were monitored by thin-layer
chromatography (TLC) on Kieselgel 60 F254 (EM Science), and the
compounds were detected by examination under UV light and by
charring with 10 % sulfuric acid in MeOH. Solvents were removed
Figure 3. Biologically active glucose-based glycosylamides/ureas.
axial position of compounds A, 2a, 3a may also be advanta-
geous to the glucose analogs. The glucose analogs showed a
under reduced pressure at <40 °C. Acetonitrile was distilled from
1
greater potency than the galactose analogs. The galactose- CaH2 and stored over molecular sieves (3 Å). H NMR and 13C NMR
spectra were recorded with Varian spectrometers (models Inova 300
and 500) equipped with Sun workstations and a 400 MHz JEOL
spectrometer. 1H NMR spectra were recorded in [D6]acetone and
referenced to residual CH3COCH3 at 2.0 ppm and 13C NMR spectra
referenced to the peak at δ = 205 ppm. Assignments were made
by standard gCOSY and gHSQC. High-resolution mass spectra were
obtained on a Bruker model Ultraflex MALDI-TOF mass spectrome-
based glycosylamides/ureas were only effective at 100 μ
centrations while substantial activity was observed for the gluc-
ose analogs at 10 μ concentrations. The most representative
data for these compounds (Figure 4) are shown in (Figure 2, B).
The best results were obtained with the ꢀ-glycosylurea 5a′
M con-
M
(70 % at 100 μ
M
) along with the glycosylbenzamide 5b′ (65 %
at 100 μ ) (Figure 2, B). The mode of action for the compounds
M
ter. 2,3,4,6-tri-O-benzyl-D-glucopyranoside, 2,3,4,6-tri-O-benzyl-D-
A, 2a, 3a, 5a′, 5b′ is currently underway and the results will be
disclosed in future publications.
galactopyranoside, thionyl chloride and dry dimethylformamide
(DMF) were purchased from Sigma–Aldrich. (Trimethylsilyl)acet-
amide, 1-(trimethylsilyl)imizadole, 1-(trimethylsilyl)-1H-benzotria-
zole, benzamide, dimethylurea, acetamide, phenylurea, thiophene-
2-carboxiamide, azetidinone and silver triflate were also purchased
from Sigma–Aldrich.
Representative Procedure for the Preparation of N-Glycosides:
(Trimethylsilyl)acetamide (0.21 g,1.61 mmol) was diluted in dry
acetonitrile (5.0 mL) followed by the addition of a solution of silver
triflate (AgOTf) (0.20 g, 0.806 mmol) in dry acetonitrile (1.0 mL). The
reaction was stirred for 10 min at room temperature. A solution of
2,3,4,6-tri-O-benzyl-α-D-glucopyranosyl chloride (0.3 g, 0.54 mmol)
in dry acetonitrile (1.0 mL) was added dropwise to the reaction
mixture over 2 min period. A gray precipitate was observed immedi-
ately after the addition of the silver salt. After 2 h complete disap-
pearance of the starting material was detected using TLC analysis.
The reaction was quenched with deionized water and the mixture
was diluted in dichloromethane (DCM) (50 mL). The crude mixture
was washed with deionized water (3 × 100 mL). The organic layer
was dried with MgSO4 and the solvent was removed in vacuo.
Figure 4. Biologically active galactose-based glycosylamides/ureas.
Representative Procedure for the Preparation of Glycosyl-
amides/Ureas: Benzamide (0.48 g,1.61 mmol) was diluted in dry
acetonitrile (5.0 mL) followed by the addition of 2,3,4,6-tri-O-benzyl-
Conclusions
α-D-glucopyranosyl chloride (0.3 g,0.54 mmol). A solution of silver
We herein report the facile synthesis of various glycosylamides
and glycosylureas by coupling electron rich amides and ureas
to glycosyl halides in the presence of silver triflate and aceto-
nitrile at room temperature. The ꢀ-linked pseudodissacharide
was obtained as the major product when the acetyl-protected
glucuronamide was used as the acceptor under the same reac-
tion conditions. Sluggish results were obtained when the
triflate (AgOTf) (0.21 g,0.80 mmol) in dry acetonitrile (1.0 mL) was
added dropwise to the reaction mixture over 2 min. A gray precipi-
tate was observed immediately after the addition of the silver salt.
The mixture was stirred at room temperature and after 2 h com-
plete disappearance of the starting material was detected using TLC
analysis. The reaction was quenched with deionized water and the
mixture was diluted in dichloromethane (DCM) (50 mL). The crude
acetyl-protected glycosyl halide was employed as starting ma- mixture was washed with deionized water (3 × 100 mL). The organic
layer was dried with MgSO4 and the solvent was removed in vacuo.
terial. The addition reaction did not take place at all when elec-
tron deficient amides were used in the reaction. We did not
observed any improvements in the stereoselectivity and yields
Representative Procedure for the Preparation of the Pseudo-
dissacharide: 2,3,4,6-Tri-O-benzyl-α-D-glucopyranosyl chloride
when the reaction was conducted at 0 °C. The best yields were (0.3 g,0.54 mmol) was diluted in dry acetonitrile (5.0 mL) followed
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by the addition of the acceptor glucuronamide (0.38 g, 1.1 mmol).
The reaction was mixed at room temperature and a solution of
silver triflate (AgOTf) (0.21 g,0.80 mmol) in dry acetonitrile (1.0 mL)
was added dropwise to the reaction mixture. A gray precipitate was
7.21 (m, 20 H, Ar), 5.38 (d, J1–2 = 10.0 Hz, 1 H, 1-H), 4.97–4.47 (m, 8
H, OCH2Ph), 4.09 (t, J3–2 = 12, J3–4 = 8.0 Hz, 1 H, 3-H), 3.82–3.78 (m,
2 H, 2-H, 4-H), 3.69–3.51 (m, 3 H, 5-H, 6-H), 2.97 (t, J = 4.0 Hz,
CH2CH2N), 2.90 (t, J = 4.5 Hz, CH2CH2N) ppm. 13C NMR (125 MHz,
observed immediately after the addition of the silver salt. The mix- [D6]acetone): δ = 167.50, 139.20, 138.82, 138.45, 128.51, 128.21,
ture was stirred at room temperature and after 2 h complete disap- 127.78, 127.31, 126.49, 82.65, 79.04, 77.75, 77.26, 75.98, 74.88, 74.56,
pearance of the donor was detected using TLC analysis. The reac-
tion was quenched with deionized water and the mixture was di-
luted in dichloromethane (DCM) (50 mL). The crude mixture was
washed with deionized water (3 × 100 mL). The organic layer was
dried with MgSO4 and the solvent was removed in vacuo.
73.55, 72.98, 72.47, 69.17, 65.46, 42.18, 37.29, 34.39 ppm. HR-MALDI-
ToF/MS: m/z calcd. for C37H39NO6 593.2777, found 594.2853 [M +
H]+.
N-(2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl)dimethylurea
(5a): The crude mixture (0.35 g) was purified using flash silica gel
N-(2,3,4,6-Tetra-O-benzyl-α-
(3a): The crude mixture (0.41 g) was purified using flash silica gel
D
-glucopyranosyl)dimethylurea
column chromatography (hexane/ethyl acetate, 6:1 then 3:1 v/v), to
give a clear oil (0.13 g, 78 %) Rf = 0.34. H NMR (500 MHz, [D6]ace-
1
column chromatography (hexane/ethyl acetate, 6:1 then 3:1 v/v), to tone): δ = 7.52 (t, J = 3.5, J = 6.5 Hz, 2 H, Ar), 7.44–7.32 (m, 18 H,
give a clear oil (0.135 g, 84 %) Rf = 0.35. 1H NMR (500 MHz, [D6]ace- Ar), 6.55 (dd, JNH-1 = 9.5 Hz, 1 H, NH), 5.17 (t, J1-NH = 3, J1–2 = 2.5 Hz,
tone): δ = 7.23–7.09 (m, 20 H, Ar), 7.93 (d, JNH-1 = 7.5 Hz, 1 H, NH),
5.95 (dd, J1–2 = 3.5, J1-NH = 5.5 Hz,1 H,1-H), 4.81 (d, J = 10 Hz, 1 H,
OCH2Ph), 4.65 (dd, J = 10, J = 10 Hz, 2 H,OCH2Ph), 4.54–4.38 (m, 5
H,OCH2Ph), 3.81 (t, J2–3 = 9.5, J2–1 = 9.0 Hz, 1 H, 2-H), 3.79–3.61 (m,
1 H, 1-H), 5.02–4.83 (m, 5 H, O CH2 Ph), 4.70–4.57 (m, 3 H, O CH2Ph),
4.20 (s, J = 0.0 Hz, 1 H, H3), 3.89–3.74 (m, 4 H, 2-H, 5-H,6-H), 3.63
(dd, J = 9.0, J = 5.0 Hz, 1 H, 4-H), 2.94 (m, 6 H, CH3) ppm. 13C NMR
(125 MHz, [D6]acetone): δ = 157.30, 139.58, 139.42, 138.68, 128.23,
3 H, 5-H, 6-H), 3.52 (t, J3–2 = 9.0, J3–4 = 6.0 Hz, 1 H, 3-H), 3.43 (t, J4– 127.63, 127.45, 127.33, 127.13, 83.76, 82.08, 78.63, 74.76, 72.88,
= 9.5, J4–3 = 8.5 Hz, 1 H, 4-H), 2.78 (s, 6 H, CH3) ppm. 13C NMR
72.29, 68.60, 35.48 ppm. HR-MALDI-ToF/MS: m/z calcd. for
5
(125 MHz, [D6]acetone): δ = 157.44, 139.46, 138.92, 138.49, 128.44,
128.36, 128.26, 128.15, 127.55, 127.23, 127.16, 81.74, 78.64, 78.00,
76.24, 74.75, 72.94, 70.74, 69.25, 35.56 ppm. HR-MALDI-ToF/MS: m/z
calcd. for C37H42N2O6 610.3043, found 611.3121[M + H]+.
C37H42N2O6 610.3043, found 611.3121[M + H]+.
N-(2,3,4,6-Tetra-O-benzyl-ꢀ-D-galactopyranosyl)dimethylurea
(5a′): The crude mixture (0.35 g) was purified using flash silica gel
column chromatography (hexane/ethyl acetate, 6:1 then 3:1 v/v), to
1
N-(2,3,4,6-Tetra-O-benzyl-ꢀ-
D
-glucopyranosyl)dimethylurea
give a clear oil (0.13 g, 78 %) Rf = 0.30. H NMR (500 MHz, [D6]ace-
(3a′): The crude mixture (0.41 g) was purified using flash silica gel
tone): δ = 7.47 (t, J = 1.5, J = 7 Hz, 2 H, Ar), 7.41–7.27 (m, 18 H, Ar),
column chromatography (hexane/ethyl acetate, 6:1 then 3:1 v/v), to 6.52 (d, JNH-1 = 10.0 Hz, 1 H, NH), 5.13 (dd, J1-NH = 8.5, J1–2 = 9.5 Hz,
give a clear oil (0.135 g, 84 %) Rf = 0.29. 1H NMR (500 MHz, [D6]ace- 1 H, 1-H), 4.96 (d, J = 11 Hz, 1 H, OCH2Ph), 4.89 (t, J = 8, J = 4 Hz,
tone): δ = 7.42–7.27 (m, 20 H, Ar), 6.46 (d, JNH-1 = 10.0 Hz, 1 H, NH),
2 H, OCH2Ph), 4.80 (d, J = 12.0 Hz, 1-H, OCH2Ph), 4.64–4.51 (m, 4 H,
5.13 (dd, J1-NH = 9.5, J1–2 = 9.0 Hz,1 H,1-H), 4.92 (dd, J = 10, J = OCH2Ph), 4.14 (dd, J = 10, J = 9.5 Hz, 1-H, 3-H), 3.84–3.79 (m, 3-H,
10 Hz, 2 H, OCH2Ph), 4.85 (dd, J = 10, J = 10 Hz, 3 H,OCH2Ph), 4.68 2-H,5-H, 6-H), 3.71 (dd, J = 9.5, J = 6.0 Hz, 1-H, 6-H), 3.58 (dd, J =
(d, J = 10 Hz, 1 H,OCH2Ph), 4.57 (dd, J = 10, J = 10 Hz, 2 H,OCH2Ph), 9.5, J = 6.0 Hz, 1-H, 4-H), 2.90 (s, 6 H, CH3) ppm. 13C NMR (125 MHz,
3.79 (t, J3–4 = 7.5, J3–2 = 7.0 Hz, 1 H, 3-H), 3.75–3.71 (m, 3 H, 5-H, 6-
H), 3.62 (t, J4–5 = 9.5, J4–3 = 9.0 Hz, 1 H, 4-H), 3.54 (t, J2–3 = 9.5, J2–1
= 9.0 Hz, 1 H, 2-H), 2.92 (s, 6 H, CH3) ppm. 13C NMR (125 MHz,
[D6]acetone): δ = 157.44, 139.23, 138.71, 138.49, 128.15, 127.86,
127.39, 127.27, 85.93, 81.81, 81.62, 78.10, 76.01, 75.07, 72.91, 69.02,
35.39 ppm. HR-MALDI-ToF/MS: m/z calcd. for C37H42N2O6 610.3043,
found 611.3121[M + H]+.
[D6]acetone): δ = 157.35, 139.65, 139.49, 138.76, 129.12, 128.51,
127.37, 126.67, 83.81, 82.21, 78.73, 74.99, 74.21, 72.94, 72.36, 68.63,
35.57 ppm. HR-MALDI-ToF/MS: m/z calcd. for C37H42N2O6 610.3043,
found 611.3121[M + H]+.
Acetyl 6-N-(2,3,4,6-Tetra-O-benzyl-ꢀ-
D-glucopyranosyl)-2,3,4-
tri-O-acetyl-α- -amidogalactopyranoside (5f′): The crude mix-
D
ture (0.75 g) was purified using flash silica gel column chromatogra-
phy (hexane/ethyl acetate, 6:1 then 1:1 v/v), to give a clear oil
Acetyl 6-N-(2,3,4,6-Tetra-O-benzyl-ꢀ-
tri-O-acetyl-α-
ture (0.89 g) was purified using flash silica gel column chromatogra- (d, JNH-1 = 10.0 Hz, 1 H, NH), 7.48–7.27 (m, 20 H, Ar), 6.37 (d, J1–2
D-glucopyranosyl)-2,3,4-
D
-amidoglucuronopyranoside (3f′): The crude mix- (0.35 g, 75 %) Rf = 0.34. 1H NMR (500 MHz, [D6]acetone): δ = 7.89
=
phy (hexane/ethyl acetate, 6:1, 1:1 v/v then ethyl acetate), to give a
white powder (0.32 g, 68 %) Rf = 0.20. H NMR (500 MHz, [D6]ace-
4.0 Hz, 1 H, 1-H), 5.74 (dd, J1-NH = 9.5, J1–2 = 8.5 Hz, 1 H, H′-1), 5.52
(dd, J3–4 = 8.0, J4–5 = 7.5 Hz, 1 H, 3-H), 5.43 (dd, J3–2 = 9.5, J3–4
1
=
tone): δ = 7.96 (d, JNH-1 = 10.0 Hz, 1 H, NH), 7.41–7.27 (m, 20 H, Ar),
6.37 (d, J1–2 = 4.5 Hz, 1 H, 1-H), 5.74 (dd, J1-NH = 9.5, J1–2 = 8.5 Hz,
9.0 Hz, 1 H, 4-H), 5.10 (dd, J2–3 = 9.5, J2–1 = 8.0 Hz, 1 H, 2-H), 4.96–
4.78 (m, 4 H, OCH2Ph), 4.69–4.42 (m, 5 H, OCH2Ph, 6-H), 4.40 (dd,
1 H, H′-1), 5.52 (dd, J3–4 = 8.5, J4–5 = 7.5 Hz, 1 H, 3-H), 5.10 (dd, J2– J5–6 = 8.5, J5–4 = 8.0 Hz, 5-H), 4.18 (dd, J2–3 = 8.5, J2–1 = 8.0 Hz, 1 H,
= 9.5, J2–1 = 8.0 Hz, 1 H, 2-H), 4.94–4.79 (m, 6 H, OCH2Ph), 4.67–
H′-2), 3.91–3.81 (m, 2 H, H′-3, H′-6), 3.71 (dd, J4–5 = 8.0, J4–3
=
3
4.55 (m, 4 H, OCH2Ph, 6-H), 4.53 (dd, J5–6 = 9.3, J5–4 = 8.0 Hz, 5-H),
4.42 (dd, J4–5 = 7.5, J4–3 = 8.0 Hz, 4-H), 3.91–3.81 (m, 4 H, H′-2, H′-
7.5 Hz,1 H, H′-4), 3.59 (dd, J5–6 = 8.5, J5–4 = 7.5 Hz, 1 H, H′-5), 2.09–
1.96 (m, 12 H, CH3) ppm. 13C NMR (125 MHz, [D6]acetone): δ =
3, H′-4, H′-6), 3.68 (dd, J5–6 = 8.5, J5–4 = 7.5 Hz, 1 H, H′-5), 2.09–1.96 170.03, 169.53, 168.65, 167.13, 139.35, 138.85, 138.49, 128.23,
(m, 12 H, CH3) ppm. 13C NMR (125 MHz, [D6]acetone): δ = 188.78,
169.58, 169.33, 168.84, 168.80, 167.32, 139.38, 138.97, 138.91,
138.20, 128.36, 128.19, 127.79, 127.59, 127.50, 127.36, 88.56, 81.85,
127.36, 127.29, 88.47, 88.45, 79.08, 78.45, 74.81, 74.63, 74.47, 72.91,
72.33, 72.24, 72.03, 70.03, 69.08, 68.93, 68.83, 67.95, 59.67, 19.97,
19.89, 19.76, 19.69, 19.54, 13.65 ppm. HR-MALDI-ToF/MS: m/z calcd.
78.28, 77.62, 74.95, 74.69, 74.37, 74.28, 73.05, 72.33, 71.94, 70.98, for C48H53NO15 883.9321, found 884.3483 [M + H]+.
69.26, 68.94, 68.82, 19.93, 19.77, 19.70, 19.58 ppm. HR-MALDI-ToF/
MS: m/z calcd. for C48H53NO15 883.9321, found 884.3483[M + H]+.
Acknowledgments
N-(2,3,4,6-Tetra-O-benzyl-ꢀ- -glucopyranosyl)azetidinone (3g′):
D
The authors would like to thank John Kubin M. S, Chemistry
Department-Farmingdale State College and the Farmingdale-
The crude mixture (0.11 g) was purified using flash silica gel column
chromatography (hexane/ethyl acetate, 3:1 v/v), to give a clear oil
(0.082 g, 72 %) Rf = 0.39. 1H NMR (500 MHz, [D6]acetone): δ = 7.36– CSTEP program for financial support. The authors also want to
Eur. J. Org. Chem. 2016, 2778–2784
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Communication
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Received: March 21, 2016
Published Online: May 23, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim