Rapid transformation of D-mannose into orthogonally protected D-glucosamine and D-galactosamine thioglycosides

Article abstract of DOI:10.1021/jo200342v

An expedient protocol for synthesis of orthogonally protected 2-azido-2-deoxy-d-glucosamine and 2-azido-2-deoxy-d-galactosamine donors from d-mannose is described. Readily available phenyl β-d-thiomannoside is rapidly transformed into d-GlcN₃ thioglycosides via a highly regioselective 3-O-acylation followed by 4,6-O-benzylidenation and azide displacement of C2-OTf, which is further converted into d-GalN₃ thioglycosides through Lattrell-Dax inversion of the C4 hydroxy group and its Boc protection. The reaction sequence may be completed in 2 days and involves simple workups and minimal column chromatography.

Full text of DOI:10.1021/jo200342v

NOTE
pubs.acs.org/joc
Rapid Transformation of D-Mannose into Orthogonally Protected
D-Glucosamine and D-Galactosamine Thioglycosides
Madhu Emmadi and Suvarn S. Kulkarni*
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
S Supporting Information
b
ABSTRACT: An expedient protocol for synthesis of orthogonally
protected 2-azido-2-deoxy-D-glucosamine and 2-azido-2-deoxy-D-
galactosamine donors from D-mannose is described. Readily available
phenyl β-D-thiomannoside is rapidly transformed into D-GlcN3
thioglycosides via a highly regioselective 3-O-acylation followed by
4,6-O-benzylidenation and azide displacement of C2-OTf, which is
further converted into D-GalN3 thioglycosides through LattrellꢀDax
inversion of the C4 hydroxy group and its Boc protection. The
reaction sequence may be completed in 2 days and involves simple workups and minimal column chromatography.
arbohydrates are involved in a plethora of important biolo-
gical processes, such as viral and bacterial infections, cell
C
growth and proliferation, cellꢀcell communication, and immune
response.1,2 2-Amino-2-deoxysugars are ubiquitous in the most
important classes of glycoconjugates and oligosaccharides. In
particular, N-acetylated and N-sulfonated derivatives of D-glucos-
amine (D-GlcNH2) and D-galactosamine (D-GalNH2) form key
structural components of biologically important O-glycoproteins,
blood group antigens, N-glycoproteins, GPI anchors, glycosphin-
golipids, lipopolysaccharides, and antifreeze glycoproteins.
Owing to their biological importance and the difficulties
associated with their procurement in acceptable purity and
amounts from natural sources, the glycosamine-containing oli-
gosaccharides and glycoconjugates have received immense atten-
tion from the synthetic chemists.3ꢀ5 The challenging target
molecules often contain branched structures with various sugars
joined to the aminosugars at their 3-O, 4-O, as well as 6-O
positions. The aminosugars are in turn connected at the reducing
end with other glycosides or conjugates in a 1,2-cis or more
frequently 1,2-trans manner. Of these, the installation of 1,2-trans
linkages could be achieved by taking advantage of the neighbor-
ing group participation of the C2 functionality. On the other
hand, a nonparticipating C2 azido group on the 2-azido-2-
deoxyglycopyranosyl donor is often used to direct the formation
of a more challenging 1,2-cis linkage. The azide functionality is
stable under generally employed glycosylation conditions as well
as protecting group manipulations, and it could be conveniently
transformed into the requisite -NH2 or -NHAc groups upon
reduction or treatment with thioacetic acid, respectively. Con-
sequently, several routes have been devised for the synthesis of
appropriately protected 2-azido-2-deoxy-D-glucopyranose (D-
GlcN3) 1 and 2-azido-2-deoxy-D-galactopyranose (D-GalN3) 2
donors (Figure 1) starting from either a glycosamine or by
stereoselective introduction of an azido group at the C2 position
of 1,6-anhydrosugar derivatives, glycals, or hexopyranoses.
Figure 1. Regioselectively protected D-glucosamine and D-galactosa-
mine donors.
The common methods of preparation for both (D-GlcN3 1)
and (D-GalN3 2) derivatives include (1) Paulsen’s azide opening
of either 1,6,2,3-anhydro-manno6/talo7 configured Cernꢁy
ꢀ
epoxides8,9 or the 2-deoxy-2-iodo-1,6-anhydrosugars10 via tran-
ꢀ
siently formed Cernꢁy epoxides and (2) Lemieux’s azido-
nitration11 or azidoselenation12 and one-pot azidochlorination13
of glycals. Danishefsky’s sulfamidoglycosylation14 and Gin’s
acetamidoglycosylation15 protocols give direct access to the
GlcNAc and GalNAc containing glycosides starting from glycals.
The D-GlcN3 derivatives have been also accessed by (1) azide
displacement of the O2 triflate derivative of β-manno-
pyranoside,16ꢀ20 1,6-anhydro-β-mannopyranosides,21 and their
cyclic sulfates22 and (2) direct conversion of glucosamine
derivatives by diazo transfer using TfN323 or imidazole-1-sulfonyl
azide hydrochloride24 or through 2-deoxy-2-hydrazinogluco-
pyranose.25 Although the diazotransfer procedure is also applic-
able to GalNH2, it is seldom26 carried out because of its high cost.
Instead, C4 epimerization of the easily available 2-acetamido-2-
deoxyglucopyranose (D-GlcNAc)27 or 2-pthalamido-2-deoxyglu-
copyranose derivatives (D-GlcNPhth)28,29 is a preferred route.
Syntheses of D-GalNH2 starting from L-lyxose30 or D-tagatose31
have been also reported. Recently, a procedure for amination of
Received: February 25, 2011
Published: April 21, 2011
r
2011 American Chemical Society
4703
dx.doi.org/10.1021/jo200342v J. Org. Chem. 2011, 76, 4703–4709
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Rapid and Efficient Transformation of β-D-Thio-
mannoside 3 into D-GlcN3 Thioglycoside Donors
Scheme 2. Conversion of D-GalN3 Derivatives into Regiose-
lectively Protected D-GalN3 Thioglycoside Donors
C2 of a β-galactopyranoside with retention of configuration
by double inversion process, involving azide displacement of
O2-imidazylate is reported.32 In spite of the mammoth efforts, a
short, efficient, and practical synthesis of orthogonally protected
D-GlcN3 and more importantly D-GalN3 donors is elusive.
In the context of our ongoing project on the synthesis of
mucin core oligosaccharides we require a ready access to large
quantities of regioselectively protected D-GlcN3 and D-GalN3
donors. Herein, we describe an expeditious and convenient route
for the preparation of orthogonally substituted D-GlcN3 and D-
GalN3 donors from a readily available and inexpensive starting
material derived from D-mannose.
van Boom and co-workers first observed that the C2-OTf
group of a methyl β-D-mannoside undergoes a facile nucleophilic
displacement by azide anions to afford the 2-azido-2-deoxyglu-
cose compound in excellent yields, whereas the corresponding R-
anomers do not react easily.16 On the basis of this pioneering
approach, a few reports on the conversion of β-D-mannoside to
D-glucosamine building blocks have been published. Since the
alkyl β-O-mannosides were difficult to prepare and to convert
into glycosyl donors, Pavliak and Kovꢁac employed 1,3,4,6-tetra-
O-acetyl-β-D-mannopyranoside.17 However, difficulties resulted
as there were no methods to obtain the starting material
efficiently.18 To circumvent this problem, Pozsgay reported
two methods using easily accessible β-D-thiomannopyrano-
side.19,20 These improved methods still involve lengthy routes
to obtain selectively protected D-GlcN3 donors.
We envisioned that the readily available phenyl 1-thio-β-D-
mannopyranoside 333 could be regioselectively protected in a few
steps such that all the hydroxyls are differentiated. A C2 inversion
by azide displacement of 2-OTf followed by C4 epimerization
would give a facile access to orthogonally protected D-GlcN3 and
D-GalN3 donors, respectively.
A simple and straightforward preparation of regioselectively
protected D-GlcN3 donors, involving regioselective 3-O-acyla-
tion of mannoside 3, as a key step, is shown in Scheme 1.
Recently, a regioselective protection of various hexopyranosides
catalyzed by dimethyltin dichloride (Me2SnCl2) is reported,34
wherein the regioselectivity of monobenzoylation is conceived as
an intrinsic character of the sugar dependent on the relative
disposition of the free hydroxyl groups and also on the stereo-
chemistry of the anomeric function. For example, the R and β
isomers of methyl glucopyranoside have been shown to afford
exclusively the 2-O- or 6-O-benzoylated products, respectively,
whereas methyl R-mannopyranoside exhibited a preference for
3-O-acylation. Intriguingly, no studies have been reported for the
β-mannosides as well as any thioglycosides. We tested this
reaction on β thiomannoside 3 and found that it works very
well to afford the corresponding 3-O-acylated products in
excellent yields. Thus, compound 3 was treated successively
with 0.05 equiv of Me2SnCl2, DIPEA (2 equiv), and 1.1 equiv of
acetyl chloride or benzoyl chloride in THF/H2O (19:1) at rt for
2.5 h to afford the corresponding 3-O-acetate or 3-O-benzoate
mannosides 4a and 4b, in very good isolated yields (90% and
92%), respectively. Compound 4a, upon treatment with ben-
zaldehyde dimethyl acetal (1.3 equiv) in the presence of 10-
camphorsulfonic acid (0.25 equiv) in CH3CN at ambient
temperature, rapidly afforded the 4,6-O-benzylidene acetal 5a
(90%), which upon triflation at O2 followed by nucleophilic
displacement of the triflyloxy group by NaN3 furnished the
desired D-GlcN3 building block 6a in 82% yield over two steps.
Under identical conditions, 4,6-O-bezylidenation of 4b instantly
generated 2-OH compound 5b (90%), which upon similar
triflation followed by azide displacement of C2 triflyloxy group
furnished 6b (85%, two steps). Since each reaction was essen-
tially completed within a short time and no side products were
encountered, it was realized that the crude products could be
carried forward as such until the last step. Accordingly, the
overall four-step sequence could be carried out on a 2 g scale in a
day without any intermittent purification to obtain compound
6b (1.6 g) in 44% overall yield after a single chromatographic
purification.
With the successful preparation of selectively protected D-
GlcN3 building blocks we proceeded further to obtain the
corresponding D-GalN3 derivatives. Scheme 2 outlines the pre-
paration of orthogonally substituted D-GalN3 building blocks.
Hydrolysis of the 4,6-O-benzylidene acetal of 6a followed by
selective TBDPS protection of the primary hydroxyl group of the
so formed diol cleanly afforded the 4-OH compound 7a (81%, two
steps). It should be noted that switching the solvent from DMF35
to acetonitrile resulted in remarkable acceleration of this reaction.
The reaction was completed in only 10 min, and the use of
acetonitrile in place of DMF also expedited the workup procedure.
In a similar manner, benzoate 6b was rapidly transformed into the
4-hydroxy derivative 7b in excellent yield. With the requisite 4-OH
D-GlcN3 derivatives 7a and 7b in hand, the stage was set for C4
inversion. Of the various conditions attempted for the C4
epimerization of D-GlcN3, the LattrellꢀDax reaction36,37 involving
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The Journal of Organic Chemistry
NOTE
Scheme 3. Preparation of Orthogonally Protected D-GlcN3
and D-GalN3 Thioglycoside Donors
out in 2 days and is also amenable to scale-up. Most of the
reactions are performed at rt or in an ice bath and do not require
any special apparatus. The protocol is expected to accommodate
various other acyl groups as well as substituted benzylidene
acetals to further expand the scope. This method should find a
wide application in synthesis of glycosamine-containing complex
carbohydrates.
’ EXPERIMENTAL SECTION
General Methods. All reactions were conducted under a dry
nitrogen atmosphere. Solvents (CH2Cl2 >99%, THF 99.5%, acetonitrile
99.8%, DMF 99.5%) were purchased in capped bottles and dried under
sodium or CaH2. All other solvents and reagents were used without
further purification. All glassware was oven-dried before use. TLC was
performed on precoated aluminum plates of silica gel 60 F254 (0.25 mm,
E. Merck). Developed TLC plates were visualized under a short-wave
UV lamp and by heating plates that were dipped in ammonium
molybdate/cerium(IV) sulfate solution. Silica gel column chromatogra-
phy was performed using silica gel (100ꢀ200 mesh) and employed a
solvent polarity correlated with TLC mobility. NMR experiments were
conducted on 400 MHz instrument using CDCl3 (D, 99.8%) or
(CD3)2CO (D, 99.9%) as solvents. Chemical shifts are relative to the
deuterated solvent peaks and are in parts per million (ppm). Hꢀ H
COSY was used to confirm proton assignments. Mass spectra were
acquired in the ESI mode. Melting points were determined by capillary
apparatus. Specific rotation experiments were measured at 589 nm (Na)
and 25 °C. IR spectra were recorded on an FT-IR spectrometer using
CsCl plates.
triflate displacement by nitrite ion under mild conditions worked
the best. Accordingly, triflation of 7a (Tf2O, Py, CH2Cl2, 10 min)
followed by nucleophilic displacement of the formed 4-triflyloxy
group with 3 equiv of tetrabutylammonium nitrite (TBANO2) in
CH3CN at rt for 1 h cleanly afforded the desired D-GalN3
derivative 8a in 73% yield over two steps. In similar fashion,
3-OBz derivative7bunderwenta facile C4 epimerizationtodeliver
8b in good yield (77%). No side products were obtained. Our
results are in agreement with the observations made by
Konradsson29 and Ramstr€om38 in the D-gluco and other related
systems, wherein the success of such nucleophilic displacements
has been attributed to the presence of a neighboring equatorial
ester group. The four-step sequence involving two brief workups
and subsequent passing through silica gel column could be
executed in a day in 58% overall yield.
Scheme 3 delineates protection of the free 4-OH groups of D-
GlcN3 and D-GlcN3 building blocks to construct orthogonally
protected building blocks. The D-GlcN3 4-OH compounds 7a
and 7b and D-GalN3 derivatives 8a and 8b, individually, upon
treatment with Boc anhydride in the presence of cat. DMAP in
pyridine and CH2Cl2 at rt instantly provided the fully protected
building blocks 9a, 9b, 10a, and 10b in 91%, 91%, 90%, and 90%
yields, respectively.
In conclusion, we have established a straightforward route to
transform β-D-thiomannosides into selectively protected 2-azi-
do-2-deoxyglucose and 2-azido-2-deoxygalactose thioglycoside
donors. All the building blocks are new compounds which have
been characterized thoroughly using NMR and other spectro-
scopic methods (see the Supporting Information). The protect-
ing groups employed, Boc, TBDPS, Ac (or Bz), and N3, being
stable and orthogonal to each other, could be selectively depro-
tected, in any order, during chain elongation, allowing access to
diverse building blocks for glycoside assembly. The amenability
of the benzylidene acetals to their regioselective O4 or O6
reductive opening imparts extra flexibility to this class of donors,
as demonstrated by Hung and co-workers in their efficient one-
pot protection approach extended to 2-azidothioglucosides39
and very recently to anomeric acetates.40
Thioglycosides have always been among the choicest of stable
donors owing to their ease in handling and ability to be
transformed into other types of donors.41,42 Our method allows
a rapid access to versatile thioglycoside donors. All the reactions
are simple and clean and involve routine workup and minimal
column chromatography. With the individual reaction time
ranging from 5 min to 2 h, the entire sequence could be carried
1
1
Phenyl 3-O-Acetyl-1-thio-β-D-mannopyranoside (4a).
Me2SnCl2 (0.08 g, 0.37 mmol) and DIPEA (2.5 mL, 15.05 mmol) were
added sequentially to a stirred solution of phenyl 1-thio-β-D-mannopyr-
anoside 333 (2.0 g, 7.52 mmol) in THF/H2O (48 mL, 19:1). After 5 min,
AcCl (0.6 mL, 8.28 mmol) was added, and the solution was stirred at rt
for 2.5 h. After total consumption of the starting material, the reaction
was quenched with 3% HCl (40 mL) and extracted against EtOAc
(80 mL), and the aqueous layer was separated and washed with EtOAc
(80 mL ꢁ 2). The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (7:3 ethyl acetate/petroleum ether) to
obtain 4a as a white foam (2.12 g, 90%): [R]25 ꢀ100.2 (c 0.92,
D
CHCl3); IR (CHCl3) ν 3398, 3019, 2975, 1736, 1522, 1219, 1047, 772,
669 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.42ꢀ7.39 (m, 2H, ArH),
7.23ꢀ7.19 (m, 3H, ArH), 4.94 (s, 1H, H-1), 4.83 (dd, J = 10.0, 3.0 Hz
1H, H-3), 4.30 (d, J = 3.0 Hz, 1H, H-2), 4.25 (t, J = 10.0 Hz, 1H, H-4),
3.93 (bs, 2H, H-6), 3.37ꢀ3.35 (m, 1H, H-5), 2.14 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3) δ 171.4, 134.2, 131.0, 129.2, 127.6, 87.3, 80.3,
76.7, 71.0, 63.6, 61.2, 21.2; HRMS calcd for C14H18O6S [M þ Na]þ
337.0722, found 337.0711.
Phenyl 3-O-Benzoyl-1-thio-β-D-mannopyranoside (4b).
Me2SnCl2 (0.08 mg, 0.37 mmol) and DIPEA (2.6 mL, 15.13 mmol)
were added sequentially to a stirred solution of 3 (2.0 g, 7.56 mmol) in
THF/H2O (48 mL, 19:1). After 5 min, BzCl (0.95 mL, 8.32 mmol) was
added, and the solution was stirred at rt for 2.5 h. After total consump-
tion of the starting material, the reaction was quenched with 3% HCl
(40 mL) and extracted against EtOAc (80 mL), and the aqueous layer
was separated and washed with EtOAc (80 mL ꢁ 2). The combined
organic layers were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel (1:1
ethyl acetate/petroleum ether) to obtain compound 4b as a white solid
(2.6 g, 92%): [R]25D ꢀ40.0 (c 0.56, CHCl3); mp 158.5 °C; IR (CHCl3)
1
ν 3434, 3019, 1720, 1523, 1217, 928, 770, 669 cmꢀ1; H NMR (400
MHz, (CD3)2CO) δ 8.08 (d, J = 7.0 Hz, 2H, ArH), 7.62 (t, J = 7.5 Hz,
1H, ArH), 7.52ꢀ7.48 (m, 4H, ArH), 7.31 (t, J = 7.5 Hz, 2H, ArH), 7.23
4705
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NOTE
(t, J = 7.5 Hz, 1H, ArH), 5.27 (s, 1H, H-1), 5.10 (dd, J = 9.8, 3.3 Hz, 1H,
H-3), 4.43 (d, J = 3.3 Hz, 1H, H-2), 4.21 (t, J = 9.8 Hz, 1H, H-4), 3.92
(dd, J = 12.0, 2.5 Hz, 1H, H-6a), 3.81 (dd, J = 12.0, 5.1 Hz, 1H, H-6b),
3.60ꢀ3.56 (m, 1H, H-5); 13C NMR (100 MHz, (CD3)2CO) δ 166.7,
137.0, 133.8, 131.3, 130.5, 130.3, 129.8, 129.2, 127.3, 87.7, 82.0, 79.0,
71.4, 65.3, 62.5; HRMS calcd for C19H20O6S [M þ Na]þ 399.0878,
found 399.0880.
111 °C; IR (CHCl3) ν 3067, 2881, 2112, 1754, 1479,1370, 1217, 1100,
909, 739, 650 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.59ꢀ7.55 (m, 2H,
ArH), 7.42ꢀ7.33 (m, 8H, ArH), 5.48 (s, 1H, benzylidene), 5.24 (t, J =
10.0 Hz, 1H, H-3), 4.61 (d, J = 10.0 Hz, 1H, H-1), 4.39 (dd, J = 11.2, 4.4
Hz, 1H, H-6eq), 3.78 (t, J = 10.0 Hz, 1H, H-4), 3.55ꢀ4.52 (m, 2H, H-6a,
H-5), 3.41 (t, J = 10.0 Hz, 1H, H-2), 2.11 (s, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 169.7, 136.8, 134.0, 130.7, 129.39, 129.33, 129.03,
128.4, 126.2, 101.6, 87.1, 78.4, 73.1, 70.8, 68.5, 63.7, 20.9; HRMS calcd
for C21H21O5SN3 [M þ Na]þ 450.1100, found 450.1079.
Phenyl 3-O-Acetyl-4,6-O-benzylidene-1-thio-β-D-manno-
pyranoside (5a). 10-Camphorsulfonic acid (0.1 g, 0.46 mmol) was
added to a solution of 4a (0.578 g, 1.84 mmol) in acetonitrile (7 mL). To
this solution was added benzaldehyde dimethyl acetal (0.33 mL, 2.2
mmol) dropwise under N2 atmosphere and the mixture allowed to stir at
rt. After 10 min, the reaction was quenched with Et3N, solvents were
evaporated on rotor, and the residue was chromatographed on silica gel
(3:7 ethyl acetate/petroleum ether) to afford desired product 5a as a
white solid (0.66 g, 90%): [R]25D ꢀ69.6 (c 0.21, CHCl3); mp 203 °C; IR
(CHCl3) ν 3020, 2925, 1740, 1523, 1217, 771, 669 cmꢀ1; 1H NMR (400
MHz, (CD3)2CO) δ 7.49ꢀ7.44 (m, 4H, ArH), 7.37ꢀ7.30 (m, 5H,
ArH), 7.26ꢀ7.22 (m, 1H, ArH), 5.65 (s, 1H, benzylidene), 5.35 (s, 1H,
H-1), 5.07 (dd, J = 10.0, 3.3 Hz 1H, H-3), 5.00 (dd, J = 5.7, 0.8 Hz, OH;
exchangeable by D2O), 4.43ꢀ4.38 (m, 1H, H-2), 4.27 (dd, J = 10.0, 5.0
Hz, 1H, H-6eq), 4.19 (t, J = 10.0 Hz, 1H, H-4), 3.84 (t, J = 10.0 Hz, 1H,
H-6ax), 3.69 (dt, J = 10.0, 5.0 Hz, 1H, H-5), 2.03 (s, 3H, CH3); 13C
NMR (100 MHz, (CD3)2CO) δ 170.8, 138.9, 136.7, 130.4, 129.8, 129.6,
128.8, 127.5, 127.2, 102.4, 88.46, 76.3, 74.3, 71.9, 71.4, 69.0, 20.9; HRMS
calcd for C21H22O6S [M þ Na]þ 425.1035, found 425.1026.
Phenyl 2-Azido-2-deoxy-3-O-benzoyl-4,6-O-benzylidene-
1-thio-β-D-glucopyranoside (6b). Trifluoromethanesulfonic an-
hydride (0.24 mL, 1.42 mmol) was added dropwise at 0 °C to a stirred
solution of 5b (0.33 g, 0.71 mmol) in CH2Cl2 (6 mL). After 2 min,
pyridine (0.12 mL, 1.42 mmol) was added to the stirred solution at the
same temperature. After 10 min, the reaction mixture was diluted with
CH2Cl2 (30 mL) and washed successively with aq. NaHCO3 (10 mL)
and water (10 mL). The separated organic layer was dried over Na2SO4
and concentrated in vacuo. The crude product was used for the next step
without purification.
The crude product which was obtained in the above step was
dissolved in DMF (2.5 mL), and to this NaN3 (0.09 mg, 1.42 mmol)
was added. This reaction mixture was stirred at rt for 1 h, and then the
reaction mixture was diluted with EtOAc (40 mL) and washed with
water. The separated aqueous layer was washed with EtOAc (40 mL ꢁ 2).
The combined organic layers were dried over Na2SO4 and concentrated
in vacuo. The desired product was purified by column chromatography
on silica gel (1:9 ethyl acetate/petroleum ether) as eluent to obtain 6b as
a white solid (0.3 g, 85%): [R]25D ꢀ75.5 (c 0.81, CHCl3); mp 118 °C;
IR (CHCl3) ν 3020, 2114, 1732, 1521, 1261, 1220, 1101, 928, 765,
669 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 2H, ArH),
7.62ꢀ7.56 (m, 3H, ArH), 7.40ꢀ7.27 (m, 10H, ArH), 5.50 (t, J = 9.6 Hz,
1H, H-3), 5.47 (s, 1H, benzylidene), 4.69 (d, J = 9.6 Hz, 1H, H-1), 4.39
(dd, J = 9.6, 5.0 Hz 1H, H-6eq), 3.80 (t, J = 9.6 Hz, 1H, H-6ax), 3.71
(t, J = 9.6 Hz, 1H, H-4), 3.63 (dt, J = 9.6, 4.4 Hz 1H, H-5), 3.58 (t, J = 9.6
Hz, 1H, H-2); 13C NMR (100 MHz, CDCl3) δ 165.4, 136.7, 133.8,
133.5, 130.8, 130.0, 129.4, 129.3, 129.1, 128.9, 128.5, 128.3, 126.2, 101.5,
87.3, 78.5, 73.6, 70.9, 68.5, 64.1; HRMS calcd for C26H23O5SN3 [Mþ Na]þ
512.1256, found 512.1264.
Phenyl 3-O-Acetyl-2-azido-2-deoxy-6-O-tert-butyldiphe-
nylsilyl-1-thio-β-D-glucopyranoside (7a). Compound 6a (90 mg,
0.21 mmol) was dissolved in 80% AcOH (4.5 mL) and kept for reflux at
85 °C for 90 min. Toluene (5 mL) was added, and the reaction mixture
was concentrated in vacuo and subsequently coevaporated with toluene
(3 ꢁ 5 mL). The crude product which was obtained after the removal of
solvents was dissolved in CH3CN (1.5 mL), and imidazole (40 mg,
0.526 mmol) was added. To this stirred solution was added TBDPSCl
(65 μL, 0.252 mmol). After 10 min, the reaction mixture was concen-
trated in vacuo, and the crude product was purified by column
chromatography using silica gel (1:9 ethyl acetate/petroleum ether) to
afford product 7a as a pale yellow viscous liquid (98 mg, 81%): [R]25
D ꢀ30.2 (c 0.3, CHCl3); IR (CHCl3) ν 3446, 3019, 2976, 2113, 1746,
1521, 1426, 1391, 1219, 1046, 928, 767, 669, 625 cmꢀ1; 1H NMR (400
MHz, CDCl3) δ 7.73ꢀ7.68 (m, 4H, ArH), 7.59ꢀ7.57 (m, 2H, ArH),
7.45ꢀ7.35 (m, 6H, ArH), 7.34ꢀ7.24 (m, 3H, ArH), 4.86 (t, J = 9.6 Hz,
1H, H-3), 4.42 (d, J = 9.6 Hz, 1H, H-1), 3.87 (d, J = 4.0 Hz, 2H, H-6),
3.63 (t, J = 9.6 Hz, 1H, H-4), 3.37ꢀ3.33 (m, 1H, H-5), 3.27 (t, J = 9.6 Hz,
1H, H-2), 2.08 (s, 3H, CH3), 1.0 (s, 9H, (CH3)3CSi); 13C NMR (100
MHz, CDCl3) δ 171.5, 135.9, 135.8, 135.7, 133.6, 133.0, 132.9 131.1,
130.0, 129.2, 128.6, 128.3, 128.0, 86.0, 79.8, 76.9, 69.9, 63.8, 62.7, 26.9,
21.1, 19.4; HRMS calcd for C30H35O5SN3Si [M þ Na]þ 600.1964,
found 600.1978.
Phenyl 3-O-Benzoyl-4,6-O-bezylidene-1-thio-β-D-manno-
pyranoside (5b). 10-Camphorsulfonic acid (0.08 g, 0.345 mmol) was
added to a solution of 4b (0.52 g, 1.38 mmol) in acetonitrile (7 mL). To
this solution was added benzaldehyde dimethyl acetal (0.25 mL, 1.65
mmol) dropwise under N2 atmosphere and the mixture allowed to stir at
rt. After 10 min, the reaction was quenched with Et3N, solvents were
evaporated on rotor, and the residue was chromatographed on silica gel
(2:8 ethyl acetate/petroleum ether) to afford desired product 5b as a
white solid (0.576 g, 90%): [R]25D ꢀ57.0 (c 0.25, CHCl3); mp 193 °C;
IR (CHCl3) ν 3019, 1719, 1522, 1216, 767, 669 cmꢀ1; 1H NMR (400
MHz, (CD3)2CO) δ 8.08 (d, J = 7.2 Hz, 2H, ArH), 7.62 (t, J = 7.5 Hz,
1H, ArH), 7.52ꢀ7.41 (m, 6H, ArH), 7.35ꢀ7.23 (m, 6H, ArH), 5.72 (s,
1H, benzylidene), 5.46 (s, 1H, H-1), 5.40 (dd, J = 10.0, 3.3 Hz 1H, H-3),
4.58 (d, J = 3.3 Hz, 1H, H-2), 4.39 (t, J = 10.0 Hz, 1H, H-4), 4.31 (dd, J =
10.0, 5.0 Hz, 1H, H-6eq), 3.90 (t, J = 10.0 Hz, 1H, H-6ax), 3.79 (dt, J =
10.0, 5.0 Hz, 1H, H-5); 13C NMR (100 MHz, (CD3)2CO) δ 166.3,
138.9, 136.8, 134.0, 131.0 (2C), 130.5, 129.9, 129.6, 129.3, 128.8, 127.5,
127.1, 102.3, 88.67, 76.5, 75.0, 72.0, 71.6, 69.1; HRMS calcd for
C26H24O6S [M þ Na]þ 487.1191, found 487.1171.
Phenyl 3-O-Acetyl-2-azido-2-deoxy-4,6-O-bezylidene-1-
thio-β-D-glucopyranoside (6a). Trifluoromethanesulfonic anhy-
dride (0.53 mL, 3.12 mmol) was added dropwise at 0 °C to a stirred
solution of 5a (0.63 g, 1.56 mmol) in CH2Cl2 (9 mL). After 2 min,
pyridine (0.25 mL, 3.12 mmol) was added to this stirred solution at the
same temperature. After 10 min, the reaction mixture was diluted with
CH2Cl2 (40 mL) and washed successively with aq NaHCO3 (10 mL)
and water (10 mL). The separated organic layer was dried over Na2SO4
and concentrated in vacuo. The crude product was used for the next step
without purification.
The crude product which was obtained in the above step was
dissolved in DMF (3.5 mL), and to this NaN3 (0.2 g, 3.12 mmol) was
added. This reaction mixture was stirred at rt for 1 h, and then the
reaction mixture was diluted with EtOAc (40 mL) and washed with
water. The separated aqueous layer was washed with EtOAc (40 mL ꢁ 2).
The combined organic layers were dried over Na2SO4 and concentrated
in vacuo. The crude product was purified by column chromatography on
silica gel by using 1:9 ethyl acetate/ petroleum ether as eluent to obtain
6a as a white solid (0.61 g, 82%): [R]25D ꢀ106.5 (c 0.62, CHCl3); mp
Phenyl 2-Azido-2-deoxy-3-O-benzoyl-6-O-tert-butyldi-
phenylsilyl-1-thio-β-D-glucopyranoside (7b). Compound 6b
(0.1 g, 0.24 mmol) was dissolved in 80% AcOH (5 mL) and kept for
4706
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The Journal of Organic Chemistry
NOTE
reflux at 90 °C for 90 min. Toluene (5 mL) was added, and the reaction
mixture was concentrated in vacuo and subsequently coevaporated with
toluene (3 ꢁ 5 mL). The crude product which was obtained after the
removal of solvents was dissolved in CH3CN (1 mL), and imidazole (35
mg, 0.51 mmol) was added. To this stirred solution was added TBDPSCl
(65 μL, 0.245 mmol). After 15 min, the reaction mixture was concen-
trated in vacuo, and the desired product was purified by column
chromatography on silica gel by using 1:9 ethyl acetate/petroleum ether
as eluent to afford the product 7b as a white foam (103 mg, 81%):
[R]25D þ5.5 (c 0.98, CHCl3); IR (CHCl3) ν 3444, 3018, 2976, 2114,
1712, 1520, 1426, 1392, 1219, 1042, 928, 764, 669, 625 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 8.07 (d, J = 7.2 Hz, 2H, ArH), 7.71 (t, J = 7.6 Hz,
4H, ArH), 7.63ꢀ7.28 (m, 14H, ArH), 5.17 (t, J= 9.6 Hz, 1H, H-3), 4.58 (d,
J=9.6 Hz, 1H, H-1), 3.99 (d, J = 4.0 Hz, 2H, H-6), 3.85 (t, J = 9.6 Hz, 1H,
The combined organic layers were dried over Na2SO4 and concentrated
in vacuo. The desired product was purified by column chromatography
(1:9 ethyl acetate/petroleum ether) to obtain 8b as a white foam (0.29 g,
77%): [R]25D þ36.6 (c 0.61, CHCl3); IR (CHCl3) ν 3464, 3019, 2931,
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 6.8 Hz, 2H, ArH),
7.76ꢀ7.55 (m, 7H, ArH), 7.47ꢀ7.36 (m, 8H, ArH), 7.33ꢀ7.24 (m,
3H, ArH), 4.98 (dd, J = 10.0, 2.8 Hz, 1H, H-3), 4.55 (d, J = 10.0 Hz, 1H,
H-1), 4.44 (d, J = 2.8 Hz, 1H, H-4), 4.05ꢀ3.93 (m, 3H, H-6a, 6b & H-2),
3.60 (t, J = 4.0 Hz, 1H, H-5), 3.33 (bs, 1H, OH) 1.06 (s, 9H,
(CH3)3CSi); 13C NMR (100 MHz, CDCl3) δ 165.9, 135.8, 135.7,
133.7, 133.5, 132.5, 132.2, 131.5, 130.24, 130.21 130.1, 129.4, 129.2,
128.6, 128.5, 128.12, 128.09, 86.8, 77.5, 76.6, 68.2, 64.9, 59.7, 26.9, 19.2;
HRMS calcd for C35H37O5SN3Si [M þ Na]þ 662.2121, found
662.2112.
Phenyl 3-O-Acetyl-2-azido-2-deoxy-6-O-tert-butyldiphe-
nylsilyl-4-O-tert-butyloxycarbonyl-1-thio-β-D-glucopyrano-
side (9a). Boc2O (40 μL, 0.17 mmol) and DMAP (2 mg, 0.017 mmol)
were added sequentially to a clear solution of 7a (33 mg, 0.057 mmol) in
CH2Cl2 (0.5 mL), and to this stirred solution was added pyridine
(15 μL, 0.17 mmol). After 15 min, reaction was quenched with MeOH,
diluted with CH2Cl2 (30 mL), and washed successively with NaHCO3
(10 mL) and brine (10 mL). The separated organic layer was dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (1:12 ethyl acetate/petroleum
ether) to obtain the desired product as a colorless viscous liquid 9a (34.5
mg, 91%): [R]25D ꢀ23.1 (c 0.15, CHCl3); IR (CHCl3) ν 3020, 2932,
2114, 1756, 1524, 1275, 1258, 1216, 1112, 1045, 762, 669, 613,
505 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.78ꢀ7.75 (m, 2H, ArH),
7.69ꢀ7.66 (m, 2H, ArH), 7.64ꢀ7.61 (m, 2H, ArH), 7.44ꢀ7.24 (m, 9H,
ArH), 5.12 (t, J = 10.0 Hz, 1H, H-3), 4.99 (t, J = 10.0 Hz, 1H, H-4), 4.49
(d, J = 10.0 Hz, 1H, H-1), 3.84 (d, J = 2.8 Hz, 2H, H-6), 3.56 (td, J = 4.0,
10.0 Hz, 1H, H-5), 3.45 (t, J = 10.0 Hz, 1H, H-2), 2.08 (s, 3H), 1.43
(s, 9H, (CH3)3CO) 1.05 (s, 9H, (CH3)3CSi); 13C NMR (100 MHz,
CDCl3) δ 170.0, 152.4, 135.8, 135.7, 134.9, 134.1, 133.2, 132.9, 130.7,
129.9, 129.8, 129.3, 128.8, 127.9, 86.0, 83.0, 78.6, 75.3, 70.5, 62.8, 62.2,
27.7, 26.8, 20.9, 19.4; HRMS calcd for C35H43O7SN3Si [M þ Na]þ
700.2489, found 700.2474.
2115, 1721, 1602, 1428, 1268, 1216, 1113, 929, 770, 669, 622, 505 cmꢀ1
;
H-4), 3.54ꢀ3.49 (m, 2H, H-2 and H-5), 1.07 (s, 9H, (CH3)3CSi); 13
C
NMR (100 MHz, CDCl3) δ 167.1, 135.8, 135.7, 133.8, 133.5, 133.06,
133.0, 131.3, 130.1, 130.0, 129.2, 129.1, 128.7, 128.5, 127.9, 86.2, 80.0,
78.5, 69.9, 63.7, 63.1, 26.9, 19.4; HRMS calcd for C35H37O5SN3Si [M þ
Na]þ 662.2121, found 662.2136.
Phenyl 3-O-Acetyl-2-azido-2-deoxy-6-O-tert-butyldiphe-
nylsilyl-1-thio-β-D-galactopyranoside (8a). Trifluoromethane-
sulfonic anhydride (0.1 mL, 0.54 mmol) was added dropwise at 0 °C
to a stirred solution of 7a (0.16 g, 0.27 mmol) in CH2Cl2 (2 mL). After 2
min, pyridine (50 μL, 0.54 mmol) was added to this stirred solution at
the same temperature. After 10 min, the reaction mixture was diluted
with CH2Cl2 (30 mL) and washed successively with 1 M HCl (10 mL),
aq NaHCO3 (10 mL), and water (10 mL). The separated organic layer
was dried over Na2SO4 and concentrated, and this crude product was
used for the next step without purification.
The crude product which was obtained after solvent removal was
dissolved in acetonitrile (1.5 mL), TBANO2 (0.23 mg, 0.81 mmol) was
added, and this reaction was stirred at rt. After 1 h, the reaction mixture
was diluted with EtOAc and washed with water. The separated aqueous
layer was washed with EtOAc (30 mL ꢁ 2). The combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel (1:9 ethyl
acetate/petroleum ether) to obtain 8a as a pale yellow viscous liquid
(0.114 g, 73%): [R]25 þ11.4 (c 0.12, CHCl3); IR (CHCl3) ν 3455,
D
3019, 2932, 2115, 1748, 1523, 1427, 1364, 1217, 928, 770, 669,
623 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.76ꢀ7.74 (m, 2H, ArH),
7.69ꢀ7.66 (m, 2H, ArH), 7.64ꢀ7.61 (m, 2H, ArH), 7.46ꢀ7.37 (m, 6H,
ArH), 7.30ꢀ7.24 (m, 3H, ArH), 4.77 (dd, J = 10.0, 2.8 Hz, 1H, H-3),
4.47 (d, J = 10.0 Hz, 1H, H-1), 4.28 (d, J = 2.8 Hz, 1H, H-4), 4.02 (dd, J =
11.2, 4.0 Hz, 1H, H-6a), 3.92 (dd, J = 11.2, 4.0 Hz, 1H, H-6b), 3.85 (t, J =
10.0 Hz, 1H, H-2), 3.51 (t, J = 4.0 Hz, 1H, H-5), 2.16 (s, 3H, CH3), 1.07
(s, 9H, (CH3)3CSi); 13C NMR (100 MHz, CDCl3) δ 170.3, 135.8,
135.6, 133.5, 132.4, 132.0, 131.2, 130.26, 130.23, 129.23, 128.5, 128.1,
128.0, 86.5, 77.5, 75.8, 68.4, 65.1, 59.2, 26.8, 21.1, 19.2; HRMS calcd for
C30H35O5SN3Si [M þ Na]þ 600.1964, found 600.1980.
Phenyl 2-Azido-2-deoxy-3-O-benzoyl-6-O-tert-butyldi-
phenylsilyl-4-O-tert-butyloxycarbonyl-1-thio-β-D-glucopyr-
anoside (9b). Boc2O (0.23 mL, 0.98 mmol) and DMAP (0.012 g, 0.03
mmol) were added sequentially to a clear solution of 7b (0.21 g, 0.33
mmol) in CH2Cl2 (2 mL), and to this stirred solution was added
pyridine (80 μL, 0.98 mmol). After 15 min, the reaction was quenched
with MeOH, diluted with CH2Cl2 (40 mL), and washed successively
with NaHCO3 (10 mL) and brine (10 mL). The separated organic layer
was dried over Na2SO4 and concentrated in vacuo. The crude product
was purified by column chromatography on silica gel (1:12 ethyl
acetate/petroleum ether) to obtain desired product 9b as a white foam
(0.223 g, 91%): [R]25 ꢀ26.0 (c 0.73, CHCl3); IR (CHCl3) ν 3019,
Phenyl 2-Azido-2-deoxy-3-O-benzoyl-6-O-tert-butyldi-
phenylsilyl-1-thio-β-D-galactopyranoside (8b). Trifluoro-
methanesulfonic anhydride (0.2 mL, 1.18 mmol) was added dropwise
at 0 °C to a stirred solution of 7b (0.38 g, 0.59 mmol) in CH2Cl2 (5 mL).
After 2 min, pyridine (0.1 mL, 1.18 mmol) was added to this stirred
solution at the same temperature. After 10 min, the reaction mixture was
diluted with CH2Cl2 (40 mL) and washed successively with 1 M HCl
(10 mL), aq NaHCO3 (10 mL), and water (10 mL). The separated
organic layer was dried over Na2SO4 and concentrated, and this crude
product was used for the next step without purification.
The crude product which was obtained after solvent removal was
dissolved in acetonitrile (4 mL),to this was added TBANO2 (0.51 mg,
1.17 mmol), and the reaction mixture was stirred at rt. After 1 h, the
reaction mixture was diluted with EtOAc (40 mL) and washed with
water. The separated aqueous layer was washed with EtOAc (40 mL ꢁ 2).
D
2976, 2114, 1750, 1523, 1427, 1219, 1046, 928, 759, 625, 505 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 8.08 (d, J = 6.8 Hz, 2H, ArH), 7.76ꢀ7.55
(m, 7H, ArH), 7.47ꢀ7.36 (m, 8H, ArH), 7.33ꢀ7.24 (m, 3H, ArH), 5.36
(t, J = 10.0 Hz, 1H, H-3), 5.15 (t, J = 10.0 Hz, 1H, H-4), 4.61 (d, J = 10.0
Hz, 1H, H-1), 3.87 (d, J = 2.8 Hz, 2H, H-6), 3.63 (td, J = 4.0, 10.0 Hz, 1H,
H-5), 3.59 (t, J = 10.0 Hz, 1H, H-2), 1.21 (s, 9H, (CH3)3CO), 1.07
(s, 9H, (CH3)3CSi); 13C NMR (100 MHz, CDCl3) δ 165.7, 152.2,
135.8, 135.7, 134.9, 133.8, 133.5, 133.2, 133.0, 131.1, 130.2, 129.89,
129.83, 129.3, 128.7, 128.5, 127.92, 127.90, 86.4, 82.9, 78.7, 75.5, 70.4,
63.2, 62.3, 27.5, 26.8, 19.4; HRMS calcd for C40H45O7SN3Si [M þ
Na]þ 762.2645, found 762.2657.
Phenyl 3-O-Acetyl-2-azido-2-deoxy-6-O-tert-butyldiphenyl-
silyl-4-O-tert-butyloxycarbonyl-1-thio-β-D-galactopyranoside
(10a). Boc2O (52 μL, 0.22 mmol) and DMAP (0.003 g, 0.02 mmol)
4707
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The Journal of Organic Chemistry
NOTE
were added sequentially to a clear solution of 8a (0.043 g, 0.074 mmol)
in CH2Cl2 (0.5 mL), and to this stirred solution was added pyridine (20
μL, 0.22 mmol). After 15 min, the reaction was quenched with MeOH,
diluted with CH2Cl2 (30 mL), and washed successively with NaHCO3
(10 mL) and brine (10 mL). The separated organic layer was dried over
Na2SO4 and concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (1:12 ethyl acetate/petroleum
ether) to obtain product 10a as a colorless viscous liquid (45 mg, 90%):
[R]25D þ10.0 (c 0.3, CHCl3); IR (CHCl3) ν 3019, 2929, 2115, 1750,
1520, 1273, 1254, 1214, 1114, 1043, 762, 669, 613, 505 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.76ꢀ7.61 (m, 4H, ArH), 7.58ꢀ7.52 (m, 2H,
ArH), 7.45ꢀ7.35 (m, 6H, ArH), 7.30ꢀ7.26 (m, 3H, ArH), 5.35 (d, J =
2.8 Hz, 1H, H-4), 4.89 (dd, J = 10.0, 2.8 Hz, 1H, H-3), 4.49 (d, J = 10.0
Hz, 1H, H-1), 3.80ꢀ3.71 (m, 4H, H-2, H-5, 6a and 6b), 2.06 (s, 3H,
CH3), 1.47 (s, 9H, (CH3)3CO), 1.01 (s, 9H, (CH3)3CSi); 13C NMR
(100 MHz, CDCl3) δ 169.9, 153.2, 135.78, 135.72, 133.7, 133.1, 133.0,
132.8, 132.1, 130.0, 129.2, 129.1, 128.2, 127.9, 87.2, 82.6, 77.2, 73.6, 69.1,
61.5, 59.8, 27.8, 26.8, 20.9, 19.28; HRMS calcd for C35H43O7SN3Si
[M þ Na]þ 700.2489, found 700.2463.
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nylsilyl-4-O-t-butyloxy carbonyl-1-thio-β-D-galactopyrano-
side (10b). Boc2O (0.18 mL, 0.76 mmol) and DMAP (0.01 g, 0.076
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obtain product 10b as a white foam (0.17 g, 90%): [R]25D þ51.0 (c 0.6,
CHCl3); IR (CHCl3) ν 3019, 2932, 2116, 1746, 1523, 1286, 1218, 1142,
1112, 910, 772, 669, 504 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J
= 6.8 Hz, 2H, ArH), 7.72ꢀ7.61 (m, 7H, ArH), 7.44ꢀ7.34 (m, 8H, ArH),
7.31ꢀ7.28 (m, 3H, ArH), 5.50 (d, J = 3.2 Hz, 1H, H-4), 5.16 (dd, J =
10.0, 3.2 Hz, 1H, H-3), 4.58 (d, J = 10.0 Hz, 1H, H-1), 3.94 (t, J = 10.0
Hz, 1H, H-2), 3.81- 3.78 (m, 3H, H-5, H-6a and 6b), 1.30 (s, 9H,
(CH3)3CO); 1.02 (s, 9H, (CH3)3CSi); 13C NMR (100 MHz, CDCl3) δ
165.4, 152.8, 135.7, 134.9, 133.5, 133.1, 132.8, 132.2, 130.1, 130.0,
129.99, 129.81, 129.3, 129.2, 128.4, 128.2, 127.98, 127.95, 87.3, 82.7,
77.2, 74.1, 69.4, 61.7, 60.4, 27.6, 26.8, 19.2; HRMS calcd for C40H45O7S-
N3Si [M þ Na]þ 762.2645, found 762.2651.
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’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
all new compounds and 1Hꢀ H COSY for compound 8a. This
1
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’ ACKNOWLEDGMENT
::
This work was supported by the Department of Science and
Technology (Grant No. SR/S1/OC-40/2009) and Council of
Scientific and Industrial Research (Grant No. 01(2376)/10/
EMR-II). M.E. thanks CSIR-New Delhi for a fellowship. We
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