A novel glycosyl donor for synthesis of 2-acetamido-4-amino-2,4,6-trideoxy- α-d-galactopyranosides

Article abstract of DOI:10.1016/j.carres.2010.08.017

2-Azido-4-benzylamino-4-N-,3-O-carbonyl-2,4,6-trideoxy-d-galactopyranosyl trichloroacetimidate (14) was conveniently prepared in six steps by regioselective introduction of an N-benzyl carbamate at O-3 of 6-deoxy-d-glucal 6, followed by mesylation at O-4.

Full text of DOI:10.1016/j.carres.2010.08.017

Carbohydrate Research 345 (2010) 2323–2327
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
A novel glycosyl donor for synthesis of
2-acetamido-4-amino-2,4,6-trideoxy-a-D-galactopyranosides
⇑
Ithayavani Iynkkaran, David R. Bundle
Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Gunning-Lemieux Chemistry Centre, Edmonton, AB, Canada T6G 2G2
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2010
Received in revised form 24 August 2010
Accepted 25 August 2010
Available online 29 September 2010
2-Azido-4-benzylamino-4-N-,3-O-carbonyl-2,4,6-trideoxy-D-galactopyranosyl trichloroacetimidate (14)
was conveniently prepared in six steps by regioselective introduction of an N-benzyl carbamate at O-3
of 6-deoxy- -glucal 6, followed by mesylation at O-4. Intramolecular displacement of the leaving group
D
afforded oxazolidinone 11. Azidonitration of the bicyclic glycal 11 gave the glycosyl nitrate anomers 12 in
good yield and stereoselectivity. Hydrolysis of the anomeric nitrates under aqueous conditions gave the
pyranose 13, which was easily converted into the imidate 14. Glycosylation of cyclohexanol by 14 gave
Keywords:
3,4-Oxazolidinone 6-deoxyglucal
Azidonitration
glycosides 16a and 16b in a ratio of 4:1.
Ó 2010 Elsevier Ltd. All rights reserved.
Differentiated 2,4-diamino groups
Glycosyl trichloroacetimidate
a-Glycosylation
1. Introduction
2. Results and discussion
Retrosynthetic analysis identified tri-O-acetyl-D-glucal as start-
2-Acetamido-4-amino-2,4,6-trideoxy-
D-galactopyranose is
a
constituent of a number of Gram-positive and Gram-negative bac-
terial polysaccharides either as an
- or b-pyranose.1,2 Its occur-
rence as an -pyranose residue in the repeating unit of the
ing point for the synthesis of the diamino-trideoxyhexose. This
would require the introduction and regioselective differentiation
of amino groups at C-2 and C-4 and the relatively straight forward
task of C-6 deoxygenation (Scheme 1). With an appropriately pro-
a
a
capsular polysaccharides of Streptococcus pneumoniae type 1,3,4
Streptococcus mitis,5 and Bacteroides fragilis6,7 is notable since the
4-amino functionality is an essential element in the zwitterionic
motif that endows these polysaccharides with unique T-cells-acti-
vating properties, via MHC-II presentation.8,9
tected
D-glucal derivative, reduction introduces the C-6 deoxy
functionality, while an intramolecular nucleophilic cyclization
can be employed to install a 4-amino group. Finally, azidonitration
of the glycal provides a non-participating azido group at C-2 to
A variety of approaches have been used to synthesize methyl 2-
facilitate a-glycosylation reactions. This approach was realized
via the following synthetic transformations.
acetamido-4-amino-2,4,6-trideoxy-
D
-galactopyranoside.10–14
However, methyl glycosides especially possessing the 2-acetam-
ido-2-deoxy function are not well suited for further manipulation
to create glycosyl donors. Approaches that address this require-
ment have been described by the groups of van Boom15 and van
der Marel.16 Our group has also reported the synthesis of this res-
idue by manipulation at the disaccharide stage.17
As part of our efforts to synthesize repeating unit sequences of
the S. pneumoniae type 1 zwitterionic polysaccharide, we have
developed a concise synthesis of a novel 4-amino-2-azido-2,4,6-
Deoxygenation at C-6 was conveniently achieved on a large
scale by a two-step displacement reduction sequence (Scheme 2).
Deacetylation of 1, followed by selective tosylation of 2, provides
the known derivative 3.18 Reaction of 3 with LiI in THF afforded
the 6-deoxy-6-iodo derivative 419 followed by reductive removal
of the iodide using Bu3SnH and AIBN to give 519 in 85% yield over
the displacement and reduction steps.18,20,21 This sequence was
preferred to reduction of 3,4-di-O-acetyl-6-O-p-toluenesulfonyl-
D
-glucal (3)18 with LiAlH4, NaBH4 or DIBAL, all of which afforded
6-deoxy- -glucal (6) in only modest yields. Diacetate 5 was transe-
sterified to obtain 6-deoxy-
-glucal (6).19
trideoxy-
D
-galactopyranosyl donor 14 that is well suited to a ster-
D
eoselective
a-glycosylation.
D
Attempts to introduce the amino functionality at C-4 of 6 by SN2
substitution of a sulfonate ester were unsuccessful. Selective pro-
tection of the C-3 hydroxyl group by TBDMSCl gave the hindered
3-O-TBDMS derivative 722 (Scheme 2). Mesylate 822 could be ob-
tained in good yield, but inversion of configuration at C-4 by azide
⇑
Corresponding author. Tel.: +1 780 492 8808; fax: +1 780 492 7705.
E-mail address: dave.bundle@ualberta.ca (D.R. Bundle).
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.08.017

2324
I. Iynkkaran, D. R. Bundle / Carbohydrate Research 345 (2010) 2323–2327
R
NR
N
Intramolecular
cyclization
Azidonitration
O
O
O
O
O
MsO
O
O
O
OH
O
N3
NHR
I
OAc
O
Deoxygenation
O
O
HO
HO
HO
HO
AcO
AcO
Scheme 1. Retrosynthesis of a suitably protected 4-amino-2-azido-2,4,6-trideoxyhexose.
the target amino alcohol late in the synthesis (Fig. 1).27,28 Carba-
mate derivatives are readily formed under neutral conditions, the
carbamate anion easily generated, and treatment with a stronger
base hydrolyzes the oxazolidinone ring.26,28,29
OTs
O
OAc
O
OH
a
c
b
O
AcO
AcO
AcO
AcO
HO
HO
1
3
2
The C-3 hydroxyl group of compound 9 was converted into a
substituted carbamate by condensation of compound 9 with ben-
zyl isocyanate to give benzylcarbamate 10 in excellent yield
(Scheme 3). Treatment of compound 10 with t-BuOK generated
the potassium salt of the N-benzylcarbamate anion which cyclized
in situ to afford the N-benzyloxazolidinone 11.27 It was subse-
quently realized that the synthesis of 11 was accomplished most
efficiently by avoiding the protection and deprotection of the C-3
hydroxyl by a TBDMS group, since the C-3 hydroxyl group of 6
could be regioselectively protected with benzylisocyanate in good
yield (Scheme 4). The free hydroxyl group at C-4 of 15 was then
activated for an intramolecular cyclization reaction by conversion
to mesylate 10 under carefully monitored conditions.
I
O
O
AcO
AcO
AcO
AcO
d
f
5
4
O
7
HO
HO
O
HO
e
g
TBDMSO
6
O
MsO
TBDMSO
8
Scheme 2. Reagents: (a) NaOMe, MeOH, 92%; (b) TsCl, Py, then Ac2O, Py, 77% (over
two-steps); (c) LiI, THF; (d) AIBN, Bu3SnH, 85% (over two-steps); (e) NaOMe, MeOH,
90%; (f) TBDMSCl, DMF, Imidazole, 90%; (g) MsCl, Py, 86%.
The stereoselective azidonitration of glycals to the correspond-
ing 2-azido-2-deoxyglycosyl nitrates is significantly influenced by
the configuration at C-4 such that galactals yield predominately
the 2-azido-2-deoxy-galactopyranose product with very little of
the corresponding talo derivative.30 As expected the reaction of
was unsuccessful. Leaving groups such as triflate and tosylate also
failed to provide the desired product. Even when the bulky TBDMS
group was removed by treating 8 with TBAF, azide displacement of
the mesylate failed.
We chose to introduce the 4-amino group by exploiting dis-
placement by a neighboring carbamate group. Cyclic carbamates
(oxazolidinones) bridging a vicinal amino alcohol such as C-2 and
oxazolidinone protected 6-deoxy-D-galactose 11 with ceric ammo-
nium nitrate (CAN) and sodium azide resulted in the formation of
the glycosyl nitrate anomers 12 with excellent stereoselectivity.
Conventional conditions for the removal of the anomeric nitrates
by halide ions,30 thiophenoxide ion,31 sulfide ions, and acetolysis30
gave very poor yields and, in some cases, decomposition occurred.
It was found that the treatment of the anomeric azidonitrates 12 in
acetonitrile and water gave the desired pyranose 13 in good yield
(Scheme 3).
Reaction of hemiacetal 13 with trichloroacetonitrile and K2CO3
in dichloromethane gave trichloroacetimidate 14, which could be
obtained in excellent yield as an anomeric mixture (a/b 3:2) with-
out the need for chromatographic purification (Scheme 3). The
effectiveness of this glycosyl donor was accessed by reaction with
cyclohexanol. In the presence of the trimethylsilyl triflate, as
C-3 of 2-amino-2-deoxy-D-hexopyranoses have been used as pro-
tecting groups in glucosamine and galactosamine chemistry.23–25
For the synthesis of a 4-amino-4-deoxy-hexose, intramolecular
delivery of a temporarily tethered nitrogen nucleophile in SN2
fashion to an electrophilic site is a convenient way to simulta-
neously introduce and protect the 4-amino function with excellent
control over the regiochemistry and stereochemistry of the amino
group, while minimizing the extent of side reactions.26 In addition,
because the resulting cyclic intermediate simultaneously protects
both the amino and the alcohol groups, it can be converted into
O
O
NBn
X
NHBn
X
Base
HO
BnNCO
O
O
X
O
Base, H2O
HO
NHBn
O
NBn
Figure 1. Synthesis of an oxazolidinone ring by an attack of a tethered, internal nucleophile on an electrophilic intermediate, and subsequent aqueous hydrolysis to expose
the latent amino group.

I. Iynkkaran, D. R. Bundle / Carbohydrate Research 345 (2010) 2323–2327
2325
O
O
O
a
b
MsO
MsO
HO
MsO
O
TBDMSO
O
9
8
NHBn
10
Bn
Bn
N
N
O
O
c
d
O
O
O
O
ONO2
N3
11
12
Bn
Bn
N
N
O
O
O
O
e
f
O
O
OH
O
CCl3
N3
N3
14
13
NH
α : β
α : β
2 : 1
3 : 2
Scheme 3. Reagents: (a) TBAF, THF, 87%; (b) BnNCO, DCM, 90%; (c) t-BuOK, THF, 95%; (d) NaN3, CAN; (e) H2O, MeCN, 78% (over two-steps); (f) Cl3CCN, DCM, K2CO3, 100%.
O
O
O
a
b
HO
MsO
O
HO
HO
O
O
O
NHBn
NHBn
6
15
10
Bn
N
Bn
Bn
N
N
O
O
O
O
O
c
O
+
O
O
O
O
O
CCl3
N3
N3
N3
O
NH
16α
16β
14
Scheme 4. Reagents and conditions: (a) BnNCO, DCM, 85%; (b) MsCl, Py, 0 °C, 87%; (c) cyclohexanol, TMSOTf, À10 °C to 0 °C, 70%, (
a/b = 4:1).
promoter 14 reacted with cyclohexanol to give the 2,4,6-trideoxy-
galactopyranoside 16 as an /b mixture (4:1) in 70% yield
(Scheme 4). The potential of imidate 14 as a valuable and readily
prepared building block for assembly of larger oligosaccharide
structures has been confirmed by its use in the synthesis of the tri-
visualized under UV light, and/or by treatment with 5% H2SO4 in
EtOH followed by heating. Organic solvents were removed under
vacuum at <40 °C. Medium-pressure chromatography was con-
ducted using silica gel (230–400 mesh, Silicycle, Montreal) at flow
a
rates of 5–10 mL minÀ1 1H NMR spectra were recorded at 500 or
.
saccharide repeating unit
a
-
D
-FucpN2AcN4-(1?4)-
a
-
D
-GalpA-
600 MHz, and chemical shifts, reported in d (ppm), were referenced
to internal residual protonated solvent signals or to external ace-
tone (0.1% ext. acetone at d 2.225 ppm) in the case of D2O. 13C
NMR was recorded at 125 MHz, and chemical shifts are referenced
to internal CDCl3 (d 77.23) or external acetone (d 31.07).
(1?3)- -GalpA-(1?OMe of the S. pneumoniae type 1 polysaccha-
D
ride (manuscript in preparation).
3. Experimental
3.2. 3-O-(tert-Butyldimethylsilyl)-6-deoxy-
D-glucal (7)
3.1. General methods
To a solution of 6-deoxy-
D
-glucal19 (6, 2.10 g, 16.2 mmol) and
All chemical reagents were of analytical grade and used as ob-
tained from commercial sources unless otherwise indicated. Sol-
vents used in water-sensitive reactions were purified by
successive passage through columns of alumina and copper under
nitrogen. Unless otherwise noted, reactions were carried out at
room temperature, and water-sensitive reactions were performed
under an atmosphere of argon. Molecular sieves were flame dried
and then allowed to cool to room temperature under argon before
use. Reactions were monitored by analytical thin-layer chromatog-
raphy (TLC) performed on Silica Gel 60-F254 (E. Merck). Plates were
imidazole (1.65 g, 24.2 mmol, 1.5 equiv) in dry DMF (12 mL) was
added TBDMSCl (4.88 mL, 17.76 mmol, 1.1 equiv) dropwise at
0 °C. The resulting mixture was stirred for 6 h at room tempera-
ture. The reaction mixture was cooled to 0 °C and quenched with
MeOH, and the solvent was evaporated under reduced pressure.
The residue was dissolved in DCM (25 mL) and washed with an
equal volume of water and brine. The organic extract was dried
over Na2SO4, filtered, and concentrated. Column chromatography
on silica gel using 10:1 hexanes–EtOAc afforded the monosilyl

2326
I. Iynkkaran, D. R. Bundle / Carbohydrate Research 345 (2010) 2323–2327
derivative 7 (3.55 g, 90%) as a white solid. 1H NMR (600 MHz,
CDCl3): d 6.26 (dd, 1H, J1,2 = 6.0 Hz, J1,3 = 1.1 Hz, H-1), 4.63 (ddd,
1H, J1,2 = 6.1 Hz, J2,3 = 2.2 Hz, J2,4 = 1.1 Hz, H-2), 4.25–4.19 (m, 1H,
H-3), 3.91 (dq, J4,5 = 8.9 Hz, J5,6 = 6.5 Hz, H-5), 3.47 (app t, 1H,
J3,4 = 7.8 Hz, J4,5 = 7.9 Hz, H-4), 1.39 (d, 3H, J5,6 = 6.5 Hz, H-6 CH3),
0.92 (s, 9H, C(CH3)3), 0.13 (s, 6H, SiCH3). 13C NMR (125 MHz,
CDCl3): d 143.6, 103.4, 74.9, 74.3, 70.5, 25.8, 18.1, 17.2, À4.3,
À4.5. HRESIMS: calcd for C12H24O3SiNa (M+Na): 267.1387, found
267.1385. Anal. Calcd for C12H24O3Si: C, 58.97; H, 9.90. Found: C,
55.83; H, 9.72.
J4,5 = 8.4 Hz, H-4), 4.36 (d, 2H, J = 6.0 Hz, PhCH2), 4.12 (q, 1H,
J4,5 = 10.1 Hz, J5,6 = 6.4 Hz, H-5), 3.01 (s, 3H, CH3SO2), 1.41 (d, 3H,
J5,6 = 6.4 Hz, H-6 CH3). 13C NMR (125 MHz, CDCl3): d 155.6, 146.0,
138.0, 128.7, 127.7, 127.5, 99.0, 79.3, 72.7, 69.2, 45.2, 38.8, 16.8.
HRESIMS: calcd for
364.0824.
C15H19NO6SNa (M+Na): 364.0825, found
3.6. 4-Benzylamino-4-N-,3-O-carbonyl-4,6-dideoxy-D-galactal
(11)
The carbamate derivative 10 (0.34 g, 1.0 mmol) was dissolved in
dry THF (15 mL) and treated with t-BuOK (0.13 g, 0.12 mmol,
1.2 equiv) in portions. The reaction mixture was stirred at room
temperature for 20 h. The reaction mixture was quenched with
satd aq NH4Cl; then it was diluted with EtOAc (10 mL). The organic
phase was washed with water (25 mL) and brine (25 mL), dried
over MgSO4, filtered, and concentrated. Chromatography on silica
gel (4:1 hexanes–EtOAc) yielded oxazolidinone derivative 11
3.3. 3-O-(tert-Butyldimethylsilyl)-6-deoxy-4-O-mesyl-D-glucal
(8)
MsCl (2.25 mL, 19.7 mmol, 1.5 equiv) was added to a solution of
silyl derivative 722 (3.20 g, 13.1 mmol) in a mixture of dry DCM and
dry pyridine (4:1, v/v, 20 mL) at 0 °C. The reaction mixture was
warmed to room temperature while being stirred for 2.5 h. The
solution was diluted with DCM (20 mL) and washed with an equal
volume of water and brine. The organic extract was dried over
Na2SO4, filtered, and concentrated. Chromatography on silica gel
(0.23 g, 95%) as a white solid. [
(498 MHz, CDCl3): 7.56–7.24 (m, 5H, ArH), 6.56 (d, 1H,
a]
69.0 (c 0.2, CH2Cl2); 1H NMR
D
d
J1,2 = 6.2 Hz, H-1), 5.03 (dd, 1H, J1,2 = 6.2 Hz, J2,3 = 3.7 Hz, H-2),
4.93–4.88 (d, 1H, Jgem = 15.8 Hz, PhCH2), 4.87 (dd, 1H,
J2,3 = 3.7 Hz, J3,4 = 7.8 Hz, H-3), 4.22 (d, 1H, Jgem = 15.8 Hz, PhCH2),
4.15 (dq, 1H, J4,5 = 3.5 Hz, J5,6 = 6.9 Hz, H-5), 3.82 (dd, 1H,
J3,4 = 7.9 Hz, J4,5 = 3.5 Hz, H-4), 1.35 (d, 3H, J5,6 = 6.4 Hz, H-6 CH3).
13C NMR (125 MHz, CDCl3): d 159.1, 147.6, 135.6, 128.9, 128.0,
127.9, 99.0, 70.5, 67.2, 55.3, 47.8, 15.2. HRESIMS: calcd for
with 9:1 hexanes–EtOAc as eluent gave 822 (3.63 g, 86%). [
a]
D
À33.1 (c 0.9, CH2Cl2); 1H NMR (600 MHz, CDCl3): d 6.33 (dd, 1H,
J1,2 = 6.2 Hz, J1,3 = 1.2 Hz, H-1), 4.72 (dd, 1H, J1,2 = 6.2 Hz,
J2,3 = 3.1 Hz, H-2), 4.58 (dd, 1H, J3,4 = 5.5 Hz, J4,5 = 7.1 Hz, H-4),
4.41–4.36 (m, 1H, H-3), 4.20–4.15 (m, 1H, H-5), 3.09 (s, 3H,
CH3SO2), 1.45 (d, 3H, J5,6 = 6.5 Hz, H-6 CH3), 0.93–0.89 (s, 9H,
C(CH3)3), 0.13 (s, 3H, SiCH3), 0.13 (s, 3H, SiCH3). 13C NMR
(125 MHz, CDCl3): d 143.7, 102.1, 82.1, 72.6, 66.5, 39.0, 25.8,
C
C
14H16NO3Na (M+Na): 246.1125, found 246.1125. Anal. Calcd for
14H16NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.22; H, 6.58;
18.0, 16.9, À4.3, À4.4. HRESIMS: calcd for
C
13H26O5SSiNa
N, 5.61.
(M+Na): 345.1162, found 345.1162. Anal. Calcd for C13H26O5SiS:
C, 48.42; H, 8.13; S, 9.94. Found: C, 48.63; H, 8.18; S, 9.51.
3.7. 2-Azido-4-benzylamino-4-N-,3-O-carbonyl-2,4,6-trideoxy-
a/b-D-galactopyranose (13)
3.4. 6-Deoxy-4-O-mesyl-D-glucal (9)
A mixture of cerium(IV) ammonium nitrate (2.35 g, 4.29 mmol,
3 equiv) and NaN3 (0.14 g, 2.14 mmol, 1.5 equiv) was added to a
solution of the oxazolidinone derivative of 6-deoxy- -galactal
A solution of silyl ether 822 (2.70 g, 8.38 mmol) in dry THF
(20 mL) was treated with TBAF (1.0 M in THF, 2.63 mL, 10.1 mmol,
1.2 equiv) at 0 °C. The reaction mixture was warmed to room tem-
perature and stirred at this temperature for 3 h. The solution was
then diluted with EtOAc (20 mL), washed with equal volume of
water and brine, then dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by column chromatography (6:4
hexanes–EtOAc) to afford the title compound 9 (1.52 g, 87%) as a
D
(0.35 g, 1.43 mmol) 11 in dry MeCN (7 mL) at À15 °C under argon.
The resulting suspension was vigorously stirred at this tempera-
ture until TLC analysis (3:2 hexanes–EtOAc) indicated a complete
consumption of starting material. After the reaction was complete,
the mixture was diluted with EtOAc and concentrated. The residue
was redissolved in Et2O, filtered through Celite, and concentrated
under reduced pressure. The resulting residue was dissolved in
MeCN (5 mL), and H2O (2 mL) was added to this solution. The reac-
tion mixture was stirred at room temperature for 16 h and then
MeCN was evaporated. The residue dissolved in EtOAc (7 mL)
was washed with an equal volume of water and brine, and then
the solution was dried over Na2SO4, filtered, and concentrated. Col-
umn chromatography on silica gel using 3:2 hexanes–EtOAc affor-
white solid. [
6.36 (d, 1H, J1,2 = 6.9 Hz, H-1), 4.77 (dd, 1H, J1,2 = 6.0 Hz,
a]
18.5 (c 0.45, CH2Cl2); 1H NMR (600 MHz, CDCl3):
D
d
J2,3 = 2.3 Hz, H-2), 4.48 (m, 2H, H-4, H-3), 3.99 (dq, 1H,
J4,5 = 10.1 Hz, J5,6 = 6.4 Hz, H-5), 3.20 (s, 3H, CH3SO2), 2.43 (s, 1H,
2-OH), 1.43 (d, 3H, J5,6 = 6.4 Hz, H-6 CH3). 13C NMR (125 MHz,
CDCl3): d 145.0, 102.4, 84.0, 72.5, 68.2, 38.8, 17.1. HRESIMS: calcd
for C7H12O5SNa (M+Na): 231.0298, found 231.0289. Anal. Calcd for
C7H12O5S: C, 40.38; H, 5.81; S, 15.40. Found: C, 40.54; H, 5.85; S,
15.54.
ded the azido derivative 13 (
a mixture of anomers. 1H NMR (600 MHz, CDCl3): d 7.35 (m, 5H,
ArH), 7.27–7.21 (m, 5H, ArH), anomer: 5.41 (app t, J1,2 = 4.6 Hz,
a/b 2:1, 0.33 g, 78% over two-steps) as
a
3.5. 3-O-(N-Benzyl)-carbamoyl-6-deoxy-4-O-mesyl-
D
-glucal (10)
J1,OH = 4.6 Hz, H-1), 5.04 (d, 1H, Jgem = 15.6 Hz, PhCH2), 4.63 (dd,
1H, J2,3 = 4.7 Hz, J3,4 = 8.4 Hz, H-3), 4.32 (dq, 1H, J4,5 = 2.4 Hz,
J5,6 = 6.2 Hz, H-5), 4.18 (d, 1H, Jgem = 15.6 Hz, PhCH2), 4.11 (app t,
1H, J1,2 = 4.5 Hz, J2,3 = 4.5 Hz, H-2) 3.55 (dd, 1H, J3,4 = 8.3 Hz,
J4,5 = 2.5 Hz, H-4), 3.20 (d, 1H, J = 4.9 Hz, 1-OH), 1.30 (d, 3H,
J5,6 = 6.7 Hz, H-6 CH3). b Anomer: 4.97 (d, 1H, Jgem = 15.9 Hz,
PhCH2), 4.73 (app t, J1,2 = 6.5 Hz, J1,OH = 6.5 Hz, H-1), 4.36 (app t,
1H, J2,3 = 7.5 Hz, J3,4 = 7.5 Hz, H-3), 4.32 (d, 1H, Jgem = 16.0 Hz,
PhCH2), 4.11 (dq, 1H, J4,5 = 2.5 Hz, J5,6 = 7.2 Hz, H-5), 3.77 – 3.63
(m, 2H, H-2, H-4), 3.44 (d, 1H, J = 6.4 Hz, 1-OH), 1.39 (d, 3H,
J5,6 = 7.4 Hz, H-6 CH3). 13C NMR (125 MHz, CDCl3, from HMQC): d
A solution of mesylate 9 (1.05 g, 5.05 mmol) in DCM (12 mL)
was treated with benzylisocyanate (1.00 mL, 7.57 mmol, 1.5 equiv)
in the presence of TEA (1.3 mL, 12.6 mmol, 2.5 equiv) at room tem-
perature for 16 h. The solvent was concentrated under reduced
pressure. The residue was subjected to silica gel column chroma-
tography using 3:1 hexanes–EtOAc as eluent to obtain the carba-
mate 10 as a white crystalline solid (1.48 g, 90%). [
a]
66.9 (c
D
0.33, CH2Cl2); 1H NMR (498 MHz, CDCl3): d 7.39–7.24 (m, 5H,
ArH), 6.41 (dd, 1H, J1,2 = 6.0 Hz, J2,3 = 1.3 Hz, H-1), 5.43 (ddd, 1H,
J = 6.5 Hz, J = 2.9 Hz, J = 1.6 Hz, H-3), 5.23 (s, 1H, OCONHBn), 4.81
(dd, 1H, J1,2 = 6.1 Hz, J2,3 = 2.9 Hz, H-2), 4.68 (dd, 1H, J3,4 = 6.7 Hz,
129.0, 129.0, 128.2, 128.0, 127.8, 127.7, 127.6,
a anomer: d 158.6,
135.4, 90.3, 72.3, 65.0, 57.9, 55.1, 49.3, 17.6. b Anomer: d 159.5,

I. Iynkkaran, D. R. Bundle / Carbohydrate Research 345 (2010) 2323–2327
2327
135.1, 95.7, 74.8, 69.1, 64.5, 56.8, 49.1, 17.7. HRESIMS: calcd for
14H16N4O4Na (M+Na): 327.1064, found 327.1062.
ature in the presence of powdered 4 Å molecular sieves for
30 min before being cooled to À10 °C. TMSOTf (7.6 L, 0.01 mmol,
C
l
0.5 equiv) was then added, and the reaction mixture was stirred for
a further 1 h at À10 °C; then it was allowed to warm to 0 °C, at
which point the reaction was completed. The reaction was
quenched by addition of TEA and stirred for an additional
20 min, after which the mixture was diluted, filtered through Cel-
ite, and concentrated. Chromatography of the residue on silica gel
with a stepped gradient of 15–20% EtOAc in hexanes afforded com-
3.8. 2-Azido-4-benzylamino-4-N-,3-O-carbonyl-2,4,6-trideoxy-
,b- -galactopyranosyl trichloroacetimidate (14)
a
D
A mixture of
a and b 6-deoxy-galactopyranoses 13 a,b (2.0 g,
6.6 mmol) was dissolved in freshly distilled DCM (15 mL). CCl3CN
(4.75 mL, 32.9 mmol, 5 equiv) and K2CO3 (2.73 g, 19.7 mmol,
3 equiv) were added to the resulting solution, and the mixture
was vigorously stirred at room temperature under argon. After
14 h, the mixture was concentrated. The residue was dissolved in
freshly distilled DCM (10 mL) and filtered through a microfilter
to remove inorganic salts. The filtrate was concentrated under re-
pound 16 as colorless syrup (a/b 4:1, 0.02 g, 70%). a Anomer: [a]
D
16.2 (c 0.3, CH2Cl2); 1H NMR (600 MHz, CDCl3): d 7.39–7.21 (m, 5H,
ArH), 5.15 (d, 1H, J1,2 = 3.6 Hz, H-1), 4.98 (d, 1H, Jgem = 15.6 Hz,
PhCH2), 4.58 (dd, 1H, J2,3 = 8.0 Hz, J3,4 = 5.8 Hz, H-3), 4.28–4.24
(qd, 1H, J4,5 = 2.2 Hz, J5,6 = 6.9 Hz, H-5), 4.25–4.19 (d, 1H,
Jgem = 15.7 Hz, PhCH2), 3.88 (dd, 1H, J1,2 = 4.4 Hz, J2,3 = 5.7 Hz, H-
2), 3.65 (m, 1H, OCH(CH2)5), 3.58 (d, 1H, J3,4 = 8.0 Hz, J4,5 = 2.3 Hz,
H-4), 2.03–1.79 (m, 4H, OCH(CH2)2(CH2)3), 1.77–1.64 (m, 6H,
OCH(CH2)2(CH2)3), 1.55 (d, 3H, J5,6 = 6.9 Hz, H-6 CH3). 13C NMR
(125 MHz, CDCl3): d 158.8, 135.6, 128.9, 128.0, 127.7, 94.7, 76.5,
72.3, 70.3, 64.3, 57.9, 55.9, 49.2, 35.6, 33.4, 31.5, 25.5, 24.1, 23.7,
17.5. HRESIMS: calcd for C20H26N4O4Na (M+Na): 409.1846, found
409.1845.
duced pressure to afford imidate 14 as an
a
,b anomeric mixture (
a/
b 3:2, 2.94 g, 100%). 1H NMR (600 MHz, CDCl3):
a
anomer: d 8.76 (s,
1H, NHCOCl3), 7.48–7.31 (m, 5H, ArH), 6.42 (d, J1,2 = 4.6 Hz, H-1),
5.06 (d, 1H, Jgem = 15.4 Hz, PhCH2), 4.69 (dd, 1H, J2,3 = 4.8 Hz,
J3,4 = 8.4 Hz, H-3), 4.40 (app t, 1H, J1,2 = 4.5 Hz, J2,3 = 4.5 Hz, H-2),
4.38 (qd, 1H, J4,5 = 2.5 Hz, J5,6 = 7.0 Hz, H-5), 4.15 (d, 1H,
Jgem = 15.4 Hz, PhCH2), 3.62 (dd, 1H, J3,4 = 8.4 Hz, J4,5 = 2.4 Hz, H-
4), 1.34 (d, 3H, J5,6 = 6.8 Hz, H-6 CH3). b Anomer: d 8.72 (s, 1H,
NHCOCl3), 7.28–7.22 (m, 5H, ArH), 5.87 (d, 1H, J1,2 = 7.2 Hz, H-1),
4.95 (d, 1H, Jgem = 15.3 Hz, PhCH2), 4.45 (dd, 1H, J2,3 = 7.5 Hz,
J3,4 = 8.7 Hz, H-3), 4.21 (d, 1H, Jgem = 15.3 Hz, PhCH2), 4.09 (app t,
1H, J1,2 = 7.3 Hz, J2,3 = 7.3 Hz, H-2), 4.05 (qd, 1H, J4,5 = 3.8 Hz,
J5,6 = 7.2 Hz, H-5), 3.81 (dd, 1H, J3,4 = 8.7 Hz, J4,5 = 3.8 Hz, H-4),
1.43 (d, 3H, J5,6 = 7.2 Hz, H-6 CH3). 13C NMR (125 MHz, CDCl3, from
References
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a anomer: 160.5,
157.9, 135.3, 93.9, 72.0, 67.4, 56.7, 54.5, 49.3, 17.3. b Anomer: d
161.0, 158.4, 134.7, 96.4, 73.5, 69.8, 62.1, 55.3, 48.8, 17.7. HRE-
SIMS: calcd for
470.0161.
C16H16Cl3N5O4Na (M+Na): 470.0160, found
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A solution of 6-deoxy-
D
-glucal (6)19 (0.06 g, 0.46 mmol) in DCM
(2 mL) was treated with benzylisocyanate (0.07 mL, 0.55 mmol,
1.2 equiv) in the presence of TEA (0.07 mL, 0.69 mmol, 1.5 equiv)
at 0 °C for 6 h. The solvent was removed under reduced pressure.
The residue was subjected to silica gel column chromatography
using 3:1 hexanes–EtOAc as eluent to obtain the monocarbamate
15 as a white crystalline solid (0.10 g, 85%). [
a]
À14.2 (c 0.8,
D
CH2Cl2); 1H NMR (600 MHz, CDCl3): d 7.42–7.27 (m, 5H, ArH),
6.43 (dd, 1H, J1,2 = 6.2 Hz, J1,3 = 1.4 Hz, H-1), 5.15 (ddd, 1H,
J1,3 = 1.8 Hz, J2,3 = 2.5 Hz, J3,4 = 6.7 Hz, H-3), 4.65 (dd, 1H,
J1,2 = 6.1 Hz, J2,3 = 2.4 Hz, H-2), 4.37 (d, 2H, J = 6.0 Hz, PhCH2), 4.34
(s, 1H, OCONHBn) 3.88 (dq, 1H, J4,5 = 9.7 Hz, J5,6 = 6.4 Hz, H-5),
3.59 (ddd, 1H, J3,4 = 6.8 Hz, J4,5 = 8.6 Hz, J4,4OH = 1.2 Hz, H-4), 1.41
(d, 3H, J5,6 = 6.4 Hz, H-6 CH3). 13C NMR (125 MHz, CDCl3): d
158.0, 146.7, 137.8, 128.8, 128.7, 127.5, 99.0, 75.2, 74.9, 73.3,
45.3, 17.2. HRESIMS: calcd for C14H17NO4Na (M+Na): 286.1050,
found 286.1053. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N,
5.32. Found: C, 63.88; H, 6.48; N, 5.41.
3.10. Cyclohexyl 2-azido-4-benzylamino-4-N-,3-O-carbonyl-
2,4,6-trideoxy-a-D-galactopyranoside (16)
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Cyclohexanol (0.07 mL, 0.7 mmol, 10 equiv) and imidate 14
(0.03 g, 0.07 mmol) were dissolved in freshly distilled DCM
(2 mL), and the mixture was stirred under argon at room temper-