A short stereoselective synthesis of the protected uracil 3′-epi-polyoxin C

Article abstract of DOI:10.1016/j.tetasy.2011.02.004

A short synthetic approach to the protected uracil 3′-epi-polyoxin C 20 has been developed. The stereoselective [3,3]-sigmatropic rearrangement of the corresponding 7-thiocyanato-α-d-xylo-hept-5-enfuranose 6 was employed as the key step to construct the C-5 stereocentre in 5-isothiocyanato-α-d- gluco-hept-6-enfuranose 8 and the formal synthesis of uracil 3′-epi-polyoxin C has been accomplished for the first time. This synthesis provides a facile method for multigram scale preparation and thus is useful for the research into the polyoxins' structure-activity relationship and to search for more potent and effective anticandidal agents.

Full text of DOI:10.1016/j.tetasy.2011.02.004

Tetrahedron: Asymmetry 22 (2011) 207–214
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A short stereoselective synthesis of the protected uracil 30-epi-polyoxin C
⇑
Jozef Gonda , Miroslava Martinková, Andrea Baur
Institute of Chemical Sciences, Department of Organic Chemistry, P.J. Šafárik University, Moyzesova 11, Sk-040 01 Košice, Slovak Republic
a r t i c l e i n f o
a b s t r a c t
A short synthetic approach to the protected uracil 30-epi-polyoxin C 20 has been developed. The
Article history:
Received 6 December 2010
Accepted 2 February 2011
Available online 1 March 2011
stereoselective [3,3]-sigmatropic rearrangement of the corresponding 7-thiocyanato-
a-D-xylo-hept-5-
enfuranose 6 was employed as the key step to construct the C-5 stereocentre in 5-isothiocyanato-
a-D-
gluco-hept-6-enfuranose 8 and the formal synthesis of uracil 30-epi-polyoxin C has been accomplished
for the first time. This synthesis provides a facile method for multigram scale preparation and thus is
useful for the research into the polyoxins’ structure–activity relationship and to search for more potent
and effective anticandidal agents.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
thiocyanates (Scheme 1) leading to the protected uracil 30-epi-
polyoxin C. Analogous methodology was previously used for the
Polyoxins are
a
class of pyrimidine nucleoside peptide
stereoselective synthesis of thymine polyoxin C13 and polyoxamic
acid.14
antibiotics that were first isolated from Streptomyces cacao var
aoensis.1 Polyoxins and closely related compounds, such as the
nikkomycins display significant activity against phytopathogenic
fungi2 and are ineffective against other microorganisms, plants or
animals.3 Since 1970, with the first published synthesis4 of the su-
gar component of the nucleoside portion of the polyoxins, the syn-
thesis of polyoxin C,5 polyoxin L,6 polyoxin J,7 and/or fragments of
the polyoxins8 have been undertaken by various groups. Amongst
them, polyoxin C constitutes as a basic amino acid nucleoside
common to most members of polyoxin and nikkomycin dipeptides
and is a valuable intermediate for the synthesis of these analogues.
O
NH2
(S)
NH
(S)
O
OH
NH2
(S)
HOOC
1
4
3
N
2
O
H
(S)
O
HOOC
OH
HO
xylo-
3'
H
HO
OH
uracil polyoxin C, (3'S)
uracil 3'-epi-polyoxin C (3'R)
D
-Ribose is frequently used in the preparation of the core structure
[3,3]-sigmatropic
rearrangement
S
C
N
N
C
S
of polyoxin C due to its characteristic structural feature and the key
step involved in the construction of a C-5 stereocentre with an
amine functionality. The different biological activities of the poly-
oxins and nikkomycins compared to the enzyme chitin synthase in
Candida albicans suggested that analogues of the polyoxins could
be more effective as anticandidal agents. In this regard, some
attention has been paid to the synthesis of structural analogues
of the polyoxins,9,10 but so far there has been only one report11
concerning the preparation of the diastereoisomers of polyoxins
and nikkomycins.
O
O
O
(R)
O
H
H
oxidation
O
RO
O
RO
Scheme 1. Retrosynthetic route to 30-epi-polyoxin C.
2. Results and discussion
As shown in Scheme 2, our synthesis began with the reduction
of esters16 2 and 3 using a standard procedure with diisobutylalu-
minum hydride in CH2Cl2, which resulted in the formation of allylic
alcohols 4 (90%) and 5 (94%). Thiocyanates 6 and 7 were prepared
by the nucleophilic displacement of the O-mesyl group in the cor-
responding mesylates derived from allylic alcohols 2 and 3, by
thiocyanate (KSCN, in acetonitrile).
Over the course of our ongoing research program directed to-
wards the use of the aza-Claisen rearrangement of allylic thiocya-
nates, we have described the synthesis of natural products and
analogues possessing an amino acid pattern.12 This paper concerns
a simple approach to the stereoselective introduction of a nitrogen
atom at C-5 of D-glucose via aza-Claisen rearrangements of allylic
With allylic thiocyanates 6 and 7 in hand, we then performed
the thermal aza-Claisen rearrangement, which was carried out at
⇑
Corresponding author. Tel.: +421 55 6228332; fax: +421 55 6222124.
E-mail addresses: jgonda@upjs.sk, jozef.gonda@upjs.sk (J. Gonda).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.004

208
J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
OH
EtOOC
1. MsCl, Et3N,
O
O
CH2Cl2
DIBALH
O
O
0 °C to rt
CH2Cl2
-13 °C
O
RO
2. KSCN, CH3CN
rt
O
RO
2, R = Bn
4, R = Bn, 90 %
3, R = TIPS
5, R = TIPS, 94 %
SCN
NCS
NCS
O
O
O
O
5
7
O
4
O
1
Δ or MW
6
H
2
3
H
+
O
Table 1
O
RO
O
RO
RO
6, R = Bn, 82 %
9, R = Bn
8, R = Bn
10, R = TIPS
7, R = TIPS, 85 %
11, R = TIPS
Scheme 2.
90 °C in heptane under a nitrogen atmosphere to give the isothio-
cyanates 8 and 9 in 77% yield and 10 and 11 in 71% yield, as an eas-
ily separable mixtures of diastereoisomers (8:9 = 70:30 ratio,
10:11 = 76:24, determined by 1H NMR spectroscopy, Table 1).
Table 1
[3,3]-Sigmatropic rearrangement of thiocyanates 6 and 7
Entry Thiocyanate Conditions
Time Ratioa 8:9 Yieldb
(h)
(10:11)
(%)
1
2
3
4
5
6
8
9
6
D
, 90 °C, heptane
24
3
3
75:25
90:10
87:13
92:8
77
55
53
43
60
45
71
60
62
55
56
MW, 70 °C, o-xylene
MW, 80 °C, o-xylene
MW, 70 °C, hexane
MW, 90 °C, cyclohexane
MW, 40 °C, CH2Cl2
1
0.5
2.5
24
1
1
1
3
94:6
88:12
76:24
90:10
88:12
90:10
75:25
7
D, 90 °C, heptane
MW, 70 °C, o-xylene
MW, 70 °C, hexane
MW, 90 °C, cyclohexane
MW, 40 °C, CH2Cl2
10
11
12
a
Determined by 1H NMR. Ratio in the crude reaction mixtures.
Isolated combined yields.
b
A remarkable acceleration of the thermal [3,3]-sigmatropic
Figure 1. ORTEP structure of 10 showing crystallographic numbering.
rearrangement of 6 and 7 from 24 h (entries 1 and 8) to 0.5–1 h
(Table 1, entries 5 and 11) with good stereoselectivity was ob-
served using microwave irradiation conditions15 in cyclohexane
at 90 °C (Table 1). The reaction was performed in closed vessels
in a focused microwave reactor (CEM Discover), with control of
the power and temperature by an infrared sensor. It has been re-
ported16 that an Overman rearrangement of trichloro- and trifluo-
roacetimidates, derived from the allylic alcohol 4, proceeds
without stereoselectivity and takes place an inseparable mixture
of diastereoisomers.
was required for continuation of the synthesis of 30-epi-polyoxin
C (Scheme 3).
In order to rationalise the observed stereoselectivity of the rear-
rangement, high-level density functional theory (DFT) calculations,
which include electron correlation effects, were carried out. The
solvent effects were also taken into account, in order to obtain a
more realistic model of the reaction.
Two transition structures were located using the JAGUAR 7.7. pro-
gram.21 The B3LYP/6-31G(d,p) (vacuum) geometry of the transition
states TS1 and TS2 is given in Figure 2 along with the bond
distances. Single-point energy calculations of the solution phase
transition states at the B3LYP/cc-pVTZ(cyclohexane)//B3LYP/6-
31G(d,p) (vacuum) were performed. From the calculations, for
the pathway 6?TS1?8, the activation energy was found to be
1.95 kcal/mol lower than for the pathway 6?TS2?9 using a
standard Poisson-Boltzmann continuum solvation model as
implemented in JAGUAR 7.7.21 The nature of vacuum B3LYP transi-
tion states was verified with frequency calculations, yielding only
one large imaginary frequency. Harmonic zero-point energy
corrections at B3LYP/6-31G(d,p) obtained from the frequency
The configuration of the newly introduced stereocentre at C-5
in 10 was established by an X-ray diffraction analysis as (R) (Fig. 1).
In our subsequent strategy, the conversion of isothiocyanate 8
into the protected amine was necessary. The reaction of 8 with
CH3ONa in methanol at 0 °C gave thiourethane 12 in 94% yield.
The treatment of 12 with mesitylnitrile oxide in acetonitrile affor-
ded urethane20 14 in 92% yield (Scheme 3).
In order to correlate the stereochemistry of isothiocyanate 8
with 10 at C-5, a sample of compound 10 was converted into car-
bamate 13 and subsequent reaction with benzyl bromide/NaH fur-
nished 14. A comparison of the 1H and 13C NMR data of 14 with the
compound prepared from 8 demonstrated that the stereochemis-
try at C-5 in 14 was as expected as the (R)-configuration, which

J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
209
NHCSOCH3
O
NHCOOCH3
O
MNO,
MeOH,
NaOMe
CH3CN,
O
O
8
H
H
0 °C, 10 min
94%
rt, 92%
O
BnO
O
BnO
12
14
NaH,
BnBr
NHCOOCH3
O
NHCOOCH3
O
1. MeOH, NaOMe
2. MNO, CH3CN
TBAF,
THF
O
O
10
H
H
O
O
TIPSO
HO
15
13
Scheme 3.
Figure 2. Transition structures for the rearrangement 6?8 + 9. Relative energies of transition states (in kcal/mol) are shown in parentheses and bond distances (in Å).
calculations of the vacuum transition states were applied to the
transition state energies.
Thus, the predicted diastereomeric ratio of 8:9 at 90 °C was
93.7:6.3. This result is in very good agreement with the experimen-
tal data (8:9 = 94:6; Table 1, entry 5).
anomers were separated by column chromatography and fully
characterized, the synthesis was continued with the mixture of
these compounds. Finally, nucleoside formation was carried out
according to Vorbruggen’s procedure17 by treatment of compounds
19 with silylated uracil in the presence of trimethylsilyl trifluoro-
methanesulfonate to furnish 20 in 64% yield (Scheme 4).
The oxidative cleavage of the vinyl group in 14 was achieved
using catalytic amounts of RuCl3 in the presence of an excess of
NaIO4 (CH3CN/CCl4/H2O = 2:2:3) to afford amino acid 16 in 74%
yield. Compound 16 was converted into the corresponding methyl
ester 17 by treatment with CH3I/K2CO3 in DMF in 90% yield
(Scheme 4).
3. Conclusion
A stereoselective synthetic approach to the protected form of
uracil 30-epi-polyoxin C 20 has been accomplished from the known
Exposure of compound 17 to Amberlite IR 120 H+ resulted in the
cleavage of the 1,2-O-isopropylidene group and the corresponding
lactol 18 was isolated as an inseparable mixture of anomers. The
resulting furanose 18 was subsequently treated with acetic anhy-
dride in dry pyridine and DMAP as a catalyst to produce diacetates
a-D-glucofuranose 2. The stereoselective [3,3]-sigmatropic rear-
rangement of the corresponding thiocyanate 6 was employed as
the key step to construct the C-5 stereocentre and the uracil 30-
epi-polyoxin C 20 has been synthesized for the first time. Signifi-
cantly, the synthesis provides a facile method for multigram scale
preparation and will be convenient for research of the polyoxins’
19a and 19b as a mixture of anomers in 74% yield. Although these

210
J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
NHCOOCH3
NHCOOCH3
O
NaIO4, RuCl3,
CH3CN/CCl4/H2O
(2 : 2 : 3), rt
CH3I, K2CO3,
DMF, rt, 1 h
O
HOOC
O
H3COOC
O
14
H
H
O
O
BnO
BnO
16
17
NHCOOCH3
O
Amberlite IR 120H+,
dioxan/H2O (1:1),
65 °C, 18.5 h
Ac2O, pyridine, DMAP,
15 min 0 °C, 45 min rt,
74%
H3COOC
OH
H
OH
BnO
18
O
NHCOOCH3
O
NH
H3COOCNH
O,O-bis(trimethylsilyl) uracil,
N
O
H3COOC
OAc
TMSOTf, 1,2-dichloroethane
O
H
H3COOC
H
OAc
reflux, 3 h, 64%
BnO
BnO
OAc
19α, 19β
20
Scheme 4.
structure–activity relationship and to search for more potent and
effective anticandidal agents.
4.1.1. (E)-3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-
xylo-hept-5-enfuranose 4
a-D-
Diisobutylaluminum hydride (29.5 mL of a 1.2 M toluene solu-
tion) was added dropwise to solution of ester (3.40 g,
a
2
4. Experimental
4.1. General
9.76 mmol) in dry CH2Cl2 (44 mL) which was pre-cooled to
ꢀ13 °C. The resulting mixture was stirred at the same temperature
for 50 min and then quenched with methanol (2 mL). The mixture
was warmed to room temperature and poured into 30% aq K/Na
tartrate (145 mL). After being stirred for 30 min, the mixture was
then extracted with CH2Cl2 (3 ꢁ 70 mL). The combined organic lay-
ers were dried over Na2SO4, after which the solvent was removed
under reduced pressure, and the residue was purified by chroma-
tography on silica gel (2:1 hexane/ethyl acetate) to afford 2.70 g
All commercial reagents were used in the highest available pur-
ity from Aldrich, Fluka, Merck or Acros Organics without further
purification. Solvents were dried and purified before use according
to standard procedures. For flash column chromatography on silica
gel, Kieselgel 60 (0.040–0.063 mm, 230–400 mesh, Merck) was
used. Solvents for flash chromatography (hexane, ethyl acetate,
methanol, dichloromethane) were distilled before using. Thin layer
chromatography was run on Merck silica gel 60 F254 analytical
plates; detection was carried out with either ultraviolet light
(254 nm), or spraying with a solution of phosphomolybdic acid,
potassium permanganate basic solution, a solution of concentrated
H2SO4, with subsequent heating. 1H NMR and 13C NMR spectra
were recorded in CDCl3 at ambient temperature on a Varian Mer-
cury Plus 400 FT NMR spectrometer (400.13 MHz for 1H and
100.6 MHz for 13C) using TMS as internal reference. For 1H d are gi-
ven in parts per million (ppm) relative to TMS (d = 0.0) and for 13C
relative to CDCl3 (d = 77.0). The multiplicity of the 13C NMR signals
concerning the 13C–1H coupling was determined by the DEPT
method. Chemical shifts (in ppm) and coupling constants (in Hertz)
were obtained by first-order analysis; assignments were derived
from COSY and H/C correlation spectra. Infrared (IR) spectra were
measured with a Nicolet Avatar 330 FT-IR spectrometer as KBr pel-
(90%) of allylic alcohol 4 as a colourless oil: ½a D25
¼ ꢀ59:3 (c 0.54,
ꢂ
CHCl3). dH (CDCl3, 400 MHz): 7.36–7.27 (m, 5H, Ph), 6.01 (dtd,
J6,5 = 15.7 Hz, J7,6 = 5.1 Hz, J7,6 = 5.0 Hz, J7,CH3 = 0.6 Hz, 1H, H6),
5.95 (d, J2,1 = 3.8 Hz, 1H, H1), 5.88 (tdd, J6,5 = 15.7 Hz, J5,4 = 7.1 Hz,
J7,5 = 1.4 Hz, J7,5 = 1.4 Hz, 1H, H5), 4.67–4.63 (m, 3H, H2, H4, CH2Ph),
4.53 (d, JH,H = 12.2 Hz, 1H, CH2Ph), 4.17 (m, 2H, H7), 3.87 (d,
J4,3 = 3.1 Hz, 1H, H3), 1.50 (s, 3H, CH3), 1.32 (s, 3H, CH3). dC (CDCl3,
100 MHz): 137.5 (Ci), 134.1 (CH), 128.4 (2 ꢁ CHPh), 127.9 (CHPh),
127.6 (2 ꢁ CHPh), 125.0 (CH), 111.5 (C), 104.8 (CH), 83.4 (CH),
82.9 (CH), 80.6 (CH), 72.2 (CH2), 62.9 (CH2), 26.7 (CH3), 26.2
(CH3). Anal. Calcd for C17H22O5: C, 66.65; H, 7.24. Found: C,
66.78; H, 7.06.
4.1.2. (E)-5,6-Dideoxy-1,2-O-isopropylidene-3-O-triizopropyl-
silyl-a-D-xylo-hept-5-enfuranose 5
According to the same procedure described for the preparation
of 4, ester 3 (1.65 g, 3.98 mmol) and diisobutylaluminum hydride
(12 mL of a 1.2 M toluene solution) afforded after flash chromatog-
raphy on silica gel (5:1 hexane/ethyl acetate) 1.40 g (94%) of allylic
lets and expressed in
sured on a P3002 Krüss polarimeter and reported as follows: [
m
values (cmꢀ1). Optical rotations were mea-
D (c
a]
in grams per 100 mL, solvent). Melting points were recorded on a
Kofler hot block and are uncorrected. Microwave reactions were
carried out on the focused microwave system (CEM Discover).
The temperature content of the vessel was monitored using a cal-
ibrated infrared sensor mounted under the vessel. At the end of all
reactions the contents of vessel were cooled rapidly using a stream
of compressed air. Small quantities of reagents (lL) were measured
with appropriate syringes (Hamilton). All reactions were per-
formed under an atmosphere of nitrogen unless otherwise noted.
alcohol 5 as a colourless oil: ½a D25
¼ ꢀ22:2 (c 0.45, CHCl3). dH
ꢂ
(CDCl3, 400 MHz): 6.01 (ddd, J6,5 = 15.7 Hz, J7,6 = 5.2 Hz,
J7,6 = 5.2 Hz, 1H, H6), 5.93 (d, J2,1 = 3.7 Hz, 1H, H1), 5.88 (tdd,
J6,5 = 15.7 Hz, J5,4 = 7.6 Hz, J7,5 = 1.4 Hz, J7,5 = 1.4 Hz, 1H, H5), 4.62
(dd, J5,4 = 7.6 Hz, J4,3 = 2.7 Hz, 1H, H4), 4.47 (d, J2,1 = 3.7 Hz, 1H,
H2), 4.25 (d, J4,3 = 2.7 Hz, 1H, H3), 4.18–4.15 (m, 2H, H7), 1.51 (s,
3H, CH3), 1.33 (s, 3H, CH3), 1.11–1.09 (m, 21H, 3 ꢁ CH, 6 ꢁ CH3).
dC (CDCl3, 100 MHz): 134.2 (CH), 126.1 (CH), 111.5 (C), 104.7

J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
211
(CH), 86.0 (CH), 81.7 (CH), 78.1 (CH), 63.1 (CH2), 26.9 (CH3), 26.3
(CH3), 17.9 (6 ꢁ CH3), 12.2 (3 ꢁ CH). Anal. Calcd for C19H36O5Si:
C, 61.25; H, 9.74. Found: C, 61.31; H, 9.69.
ethyl acetate) gave 1.30 g (53%) of isothiocyanate 8 and 0.44 g
(18%) of 9.
Diastereoisomer 8: colourless oil; ½a D25
¼ ꢀ39:4 (c 0.66, CHCl3).
ꢂ
dH (CDCl3, 400 MHz): 7.41–7.31 (m, 5H, Ph), 5.97 (ddd,
J7trans,6 = 17.0 Hz, J7cis,6 = 10.3 Hz, J6,5 = 5.1 Hz, 1H, H6), 5.92 (d,
J2,1 = 3.7 Hz, 1H, H1), 5.46 (ddd, J7trans,6 = 17.0 Hz, J7trans,5 = 1.5 Hz,
4.1.3. (E)-3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-7-
thiocyanato-a-D-xylo-hept-5-enfuranose 6
At first, Et3N (1.82 mL, 13.07 mmol) was added to a solution of
alcohol 4 (2.67 g, 8.716 mmol) in dry CH2Cl2 (30 mL) pre-cooled to
0 °C, followed by the dropwise addition of methanesulfonyl chlo-
ride (0.809 mL, 10.46 mmol). After stirring at 0 °C for 15 min and
then at room temperature for 1.5 h, the solvent was removed un-
der reduced pressure. The residue was diluted with Et2O (50 mL),
after which the salts were removed by filtration and washed with
diethyl ether. Evaporation of the solvent at reduced pressure
afforded a crude mesylate that was used in the subsequent reac-
tion directly without further purification. To a solution of crude
mesylate in dry acetonitrile (30 mL) was added KSCN (1.27 g,
13.07 mmol). After being stirred for 2.5 h at room temperature,
the solvent was evaporated under reduced pressure. The residue
was diluted with diethyl ether (50 mL), after which the salts were
filtered off, the solvent was removed, and the residue was chro-
matographed on silica gel (5:1 hexane/ethyl acetate) to afford
J7trans,7cis = 0.6 Hz, 1H, H7trans), 5.31 (ddd, J7cis,6 = 10.3 Hz, J7cis,5 =
1.5 Hz, J7trans,7cis = 0.6 Hz, 1H, H7cis), 4.71 (d, JH,H = 11.2 Hz, 1H,
CH2Ph), 4.66 (d, JH,H = 11.2 Hz, 1H, CH2Ph), 4.63 (d, J2,1 = 3.7 Hz,
1H, H2), 4.62–4.59 (m, 1H, H5), 4.15–4.12 (m, 2H, H3, H4), 1.49 (s,
3H, CH3), 1.32 (s, 3H, CH3). dC (CDCl3, 100 MHz): 136.9 (Ci), 134.8
(NCS), 132.9 (CH), 128.6 (2 ꢁ CHPh), 128.2 (CHPh), 128.1 (2 ꢁ CHPh),
117.6 (CH2), 112.2 (C), 105.5 (CH), 82.1 (CH), 81.6 (CH), 81.3 (CH),
72.6 (CH2), 57.2 (CH), 26.9 (CH3), 26.3 (CH3). Anal. Calcd for
C
18H21NO4S: C, 62.23; H, 6.09; N, 4.03. Found: C, 62.08; H, 6.22;
N, 4.21.
Diastereoisomer 9: colourless crystals; mp 29–31 °C;
½
a 2D5
ꢂ
¼ ꢀ87:8 (c 0.30, CHCl3). dH (CDCl3, 400 MHz): 7.39–7.28 (m,
5H, Ph), 5.98 (d, J2,1 = 3.8 Hz, 1H, H1), 5.64 (ddd, J7trans,6 = 16.9 Hz,
J7cis,6 = 10.2 Hz, J6,5 = 5.5 Hz, 1H, H6), 5.46 (ddd, J7trans,6 = 16.9 Hz,
J7trans,5 = 1.3 Hz, J7trans,7cis = 1.0 Hz, 1H, H7trans), 5.27 (ddd, J7cis,6
=
10.2 Hz, J7cis,5 = 1.3 Hz, J7trans,7cis = 1.0 Hz, 1H, H7cis), 4.67 (d,
JH,H = 11.6, 1H, CH2Ph), 4.64 (d, J2,1 = 3.8 Hz, 1H, H2), 4.63 (m, 1H,
H5), 4.43 (d, JH,H = 11.6 Hz, 1H, CH2Ph), 4.11 (dd, J5,4 = 8.9 Hz,
J4,3 = 3.3 Hz, 1H, H4), 3.87 (d, J4,3 = 3.3 Hz, 1H, H3), 1.50 (s, 3H,
CH3), 1.33 (s, 3H, CH3). dC (100 MHz, CDCl3): 136.7 (Ci), 134.9
(NCS), 130.9 (CH), 128.6 (2 ꢁ CHPh), 128.2 (CHPh), 127.8 (2 ꢁ CHPh),
119.1 (CH2), 112.1 (C), 105.1 (CH), 81.9 (CH), 81.6 (CH), 81.3 (CH),
71.9 (CH2), 59.0 (CH), 26.8 (CH3), 26.3 (CH3). Anal. Calcd for
2.49 g (82%) of thiocyanate 6 as a colourless oil: ½a D25
¼ ꢀ45:6 (c
ꢂ
0.24, CHCl3). dH (CDCl3, 400 MHz): 7.37–7.28 (m, 5H, Ph), 5.99–
5.96 (m, 3H, H1, H5, H6), 4.68 (dd, J5,4 = 5.1 Hz, J4,3 = 3.1 Hz, 1H,
H4), 4.66 (d, JH,H = 12.1 Hz, 1H, CH2Ph), 4.63 (d, J2,1 = 3.8 Hz, 1H,
H2), 4.57 (d, JH,H = 12.1 Hz, 1H, CH2Ph), 3.92 (d, J4,3 = 3.1 Hz, 1H,
H3), 3.66 (m, 1H, H7), 3.58 (m, 1H, H7), 1.50 (s, 3H, CH3), 1.32 (s,
3H, CH3). dC (CDCl3, 100 MHz): 137.3 (Ci), 131.3 (CH), 128.5
(2 ꢁ CHPh), 127.9 (CHPh), 127.7 (2 ꢁ CHPh), 126.6 (CH), 111.7
(SCN), 111.6 (C), 104.9 (CH), 83.1 (CH), 82.8 (CH), 79.8 (CH),
72.2 (CH2), 35.7 (CH2), 26.6 (CH3), 26.2 (CH3). Anal. Calcd for
C18H21NO4S: C, 62.23; H, 6.09; N, 4.03. Found: C, 62.38; H, 6.20;
N, 4.15.
C18H21NO4S: C, 62.23; H, 6.09; N, 4.03. Found: C, 62.04; H, 6.18;
4.1.6. 5,6,7-Trideoxy-1,2-O-isopropylidene-3-O-triisopropyl-
N, 3.90.
silyl-5-isothiocyanato-
5,6,7-trideoxy-1,2-O-isopropylidene-3-O-triisopropylsilyl-5-
isothiocyanato-b- -ido-hepto-6-enfuranose 11
a-D-gluco-hepto-6-enfuranose 10 and
4.1.4. (E)-5,6,7-Trideoxy-1,2-O-isopropylidene-3-O-triisopropyl-
L
silyl-7-thiocyanato-
a
-
D
-xylo-hept-5-enfuranose 7
Microwave-assisted synthesis: Using the same procedure as de-
scribed for the preparation of isothiocyanates 8 and 9, compound
7 (0.25 g, 0.604 mmol) was converted into the corresponding iso-
thiocyanates 10 and 11 (see Table 1).
Using the same procedure as described for the preparation of
compound 6, alcohol 5 (1.30 g, 3.49 mmol) was converted into
crystalline thiocyanate 7 (1.05 g, 73%, 11:1 hexane/ethyl acetate);
mp 59–60 °C. ½a 2D5
ꢂ
¼ ꢀ61:3 (c 0.44, CHCl3). dH (CDCl3, 400 MHz):
Conventional method: According to the same procedure de-
scribed for the preparation of isothiocyanates 8 and 9, thiocyanate
7 (0.60 g, 1.45 mmol) was converted into the corresponding iso-
thiocyanates 10 (0.38 g, 63%) and 11 (79 mg, 13%), (35:0.5 hex-
ane/ethyl acetate, see Table 1).
5.96 (m, 2H, H5, H6), 5.93 (d, J2,1 = 3.6 Hz, 1H, H1), 4.64 (m, 1H,
H4), 4.46 (d, J2,1 = 3.6 Hz, 1H, H2), 4.29 (d, J4,3 = 2.5 Hz, 1H, H3),
3.64–3.63 (m, 2H, H7), 1.51 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.09–
1.06 (m, 21H, 3 ꢁ CH, 6 ꢁ CH3). dC (CDCl3, 100 MHz): 132.1 (CH),
126.5 (CH), 111.8 (C), 111.7 (SCN), 104.7 (CH), 85.9 (CH), 81.0
(CH), 78.0 (CH), 35.8 (CH2), 26.9 (CH3), 26.3 (CH3), 18.0 (6 ꢁ CH3),
12.3 (3 ꢁ CH). Anal. Calcd for C20H35NO4SSi: C, 58.07; H, 8.53; N,
3.39. Found: C, 58.15; H, 8.45; N, 3.46.
Diastereoisomer 10: white crystals; mp 69–70 °C; ½a D25
¼ þ47:0
ꢂ
(c 0.55, CHCl3); IR (KBr) m
max (cmꢀ1) 2960, 2940, 2866, 2036, 1084,
1024. dH (CDCl3, 400 MHz): 6.04 (ddd, J7trans,6 = 16.9 Hz,
J7cis,6 = 10.3 Hz, J6,5 = 5.0 Hz, 1H, H6), 5.88 (d, J2,1 = 3.5 Hz, H1), 1H,
5.48 (dd, J7trans,6 = 16.9 Hz, J7trans,5 = 1.5 Hz, 1H, H7trans), 5.34 (dd,
J7cis,6 = 10.3 Hz, J7cis,5 = 1.3 Hz, 1H, H7cis), 4.52–4.47 (m, 2H, H5,
H3), 4.45 (d, J2,1 = 3.5 Hz, 1H, H2), 4.05 (dd, J5,4 = 9.6 Hz,
J4,3 = 2.6 Hz, 1H, H4), 1.49 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.20–
1.12 (m, 21H, 3 ꢁ CH, 6 ꢁ CH3). dC (CDCl3, 100 MHz): 134.3 (NCS),
133.4 (CH), 117.3 (CH2), 112.3 (C), 105.2 (CH), 84.8 (CH), 82.9
(CH), 75.8 (CH), 56.8 (CH), 26.9 (CH3), 26.3 (CH3), 18.1 (6 ꢁ CH3),
12.7 (3 ꢁ CH). Anal. Calcd for C20H35NO4SSi: C, 58.07; H, 8.53; N,
3.39. Found: C, 58.13; H, 8.61; N, 3.46.
4.1.5. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-iso-
thiocyanato-a-D-gluco-hept-6-enfuranose 8 and 3-O-benzyl-
5,6,7-trideoxy-1,2-O-isopropylidene-5-isothiocyanato-bL-ido-
hept-6-enfuranose 9
Microwave-assisted synthesis: Thiocyanate 6 (0.25 g, 72 mmol)
was weighed in a 10-mL glass pressure microwave tube equipped
with a magnetic stirrer bar. The corresponding solvent (4 mL, see
Table 1) was added and the tube was closed with a silicon septum
after which the reaction mixture was subjected to microwave irra-
diation (for temperatures and reaction times see Table 1). Removal
of the solvent and chromatography on silica gel (7:1 hexane/ethyl
acetate) afforded isothiocyanates 8 and 9 (for the yields see
Table 1).
Diastereoisomer 11: colourless oil; ½a D25
¼ ꢀ49:7 (c 0.68, CHCl3).
ꢂ
dH (CDCl3, 400 MHz): 5.97 (d, J2,1 = 3.7 Hz, 1H, H1), 5.85 (ddd,
J7trans,6 = 16.9 Hz, J7cis,6 = 10.3 Hz, J6,5 = 4.9 Hz, 1H, H6), 5.56
(dd, J7trans,6 = 16.9 Hz, J7trans,5 = 1.5 Hz, 1H, H7trans), 5.38 (dd,
J7cis,6 = 10.3 Hz, J7trans,5 = 1.2 Hz, 1H, H7cis), 4.61 (dddd, J5,4 = 8.3 Hz,
J6,5 = 4.9 Hz, J7trans,5 = 1.5 Hz, J7trans,5 = 1.2 Hz, 1H, H5), 4.48
(d, J2,1 = 3.7 Hz, 1H, H2), 4.32 (d, J4,3 = 3.0 Hz, 1H, H3), 4.07 (dd,
J5,4 = 8.3 Hz, J4,3 = 3.0 Hz, 1H, H4), 1.49 (s, 3H, CH3), 1.32 (s, 3H,
Conventional method:
7.05 mmol) in dry heptane (15.9 mL) was heated at 90 °C. Evapora-
tion of the solvent and chromatography on silica gel (7:1 hexane/
A solution of thiocyanate 6 (2.45 g,

212
J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
CH3), 1.11–1.09 (m, 21H, 3 ꢁ CH, 6 ꢁ CH3). dC (CDCl3, 100 MHz):
134.6 (NCS), 131.1 (CH), 118.8 (CH2), 112.2 (C), 104.8 (CH), 85.3
(CH), 83.0 (CH), 76.3 (CH), 58.8 (CH), 26.9 (CH3), 26.4 (CH3), 18.0
(6 ꢁ CH3), 12.8 (3 ꢁ CH). Anal. Calcd for C20H35NO4SSi: C, 58.07;
H, 8.53; N, 3.39. Found: C, 57.97; H, 8.61; N, 3.29.
4.1.9. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-
(methoxycarbonylamino)- -gluco-hept-6-enfuranose 14
a-D
To a solution of thiocarbamate 12 (1.25 g, 3.29 mmol) in dry
acetonitrile (29 mL) was added mesitylnitrile oxide (0.58 g,
3.62 mmol) and the resulting mixture was stirred at room temper-
ature. After 3.5 h, the reaction mixture did not contain any starting
material 5, the solvent was evaporated under reduced pressure and
the residue was purified by column chromatography on silica gel
(hexane/ethyl acetate, 3:1) to afford 1.10 g (92%) of carbamate 14
as a colourless oil.
4.1.7. 3-O-Benzyl-5,6,7-trideoxy-1,2-O-isopropylidene-5-
(methoxythiocarbonylamino)-a-D-gluco-hept-6-enfuranose 12
To a solution of isothiocyanate 8 (1.25 g, 3.60 mmol) in dry
methanol (32.4 mL) was added sodium methoxide (0.214 g,
3.96 mmol) at 0 °C. The reaction mixture was stirred for 10 min
at 0 °C and then for a further 2.5 h at room temperature. The sol-
vent was removed and the residue was partitioned between CH2Cl2
(40 mL) and water (15 mL). The aqueous layer was then extracted
with further portions of CH2Cl2 (2 ꢁ 20 mL). The combined organic
layers were dried over Na2SO4, after which the solvent was evapo-
rated in vacuo and the residue was purified by flash chromatogra-
phy on silica gel (5:1 hexane/ethyl acetate) to give 1.28 g (94%) of
Synthesis of 14 from 15: To a solution of alcohol 15 (50 mg,
0.183 mmol) in dry THF (1 mL), pre-cooled to 0 °C, was added so-
dium hydride (8.8 mg, 0.22 mmol, 60% dispersion in mineral oil,
freed of oil with anhydrous THF). The resulting mixture was stirred
for 10 min at 0 °C, after which benzyl bromide (0.026 mL,
0.22 mmol) and tetrabutylammonium iodide (8.1 mg, 0.022 mmol)
were added at the same temperature. The mixture was allowed to
cool to room temperature and stirring was continued for another
1.5 h. The mixture was then partitioned between Et2O (5 mL) and
ice water (0.4 mL). The aqueous phase was extracted with an addi-
tional portion of Et2O (5 mL), and the combined organic layers
were dried over Na2SO4, the solvent was evaporated and the resi-
due was subjected to flash chromatography on silica gel (3:1 hex-
ane/ethyl acetate) to afford 51 mg (77%) of compound 14 as a
thiocarbamate 12 as a colourless oil: ½a D25
¼ þ22:4 (c 0.21, CHCl3).
ꢂ
dH (CDCl3, 400 MHz): 7.57 (br d, J5,NH = 7.6 Hz, 1H, NH), 7.41–7.31
(m, 5H, Ph), 5.96 (d, J2,1 = 3.8 Hz, 1H, H1), 5.68 (ddd, J7trans,6
=
17.2 Hz, J7cis,6 = 10.4 Hz, J6,5 = 5.5 Hz, 5H, H6), 5.44–5.40 (m, 1H,
H5), 5.30 (ddd, J7trans,6 = 17.2 Hz, J7trans,5 = 1.5 Hz, J7trans,7cis = 1.3 Hz,
1H, H7trans), 5.21 (ddd, J7cis,6 = 10.4 Hz, J7trans,5 = 1.5 Hz, J7trans,7cis
=
colourless oil: ½a D25
¼ þ44:2 (c 0.33, CHCl3). dH (CDCl3, 400 MHz):
ꢂ
1.3 Hz, 1H, H7cis), 4.68 (d, JH,H = 11.4 Hz, 1H, CH2Ph), 4.58 (d,
J2,1 = 3.8 Hz, 1H, H2), 4.49 (d, JH,H = 11.4 Hz, 1H, CH2Ph), 4.28 (dd,
J5,4 = 4.9 Hz, J4,3 = 3.3 Hz, 1H, H4), 4.04 (d, J4,3 = 3.3 Hz, 1H, H3),
3.94 (s, 3H, OCH3), 1.49 (s, 3H, CH3), 1.32 (s, 3H, CH3). dC (CDCl3,
100 MHz): 191.3 (C@S), 136.3 (Ci), 132.7 (CH), 128.7 (2 ꢁ CHPh),
128.4 (CHPh), 128.1 (2 ꢁ CHPh), 117.5 (CH2), 111.7 (C), 104.8 (CH),
83.0 (CH), 81.3 (CH), 79.2 (CH), 72.2 (CH2), 57.0 (OCH3), 54.6
(CH), 26.7 (CH3), 26.1 (CH3). Anal. Calcd for C19H25NO5S: C,
60.14; H, 6.64; N, 3.69. Found: C, 60.35; H, 6.87; N, 3.51.
7.40–7.31 (m, 5H, Ph), 5.96 (d, J2,1 = 3.9 Hz, 1H, H1), 5.77 (ddd,
J7trans,6 = 17.1 Hz, J7cis,6 = 10.4 Hz, J7cis,6 = 5.5 Hz, 1H, H6), 5.71 (m,
1H, NH), 5.29 (ddd, J7trans,6 = 17.1 Hz, J7trans,5 = 1.2 Hz, J7trans,7cis
=
1.2 Hz, 1H, H7trans), 5.16 (ddd, J7cis,6 = 10.4 Hz, J7cis,5 = 1.2 Hz,
J7trans,7cis = 1.2 Hz, 1H, H7cis), 4.75 (m, 1H, H5), 4.65 (d, JH,H = 11.5 Hz,
1H, CH2Ph), 4.57 (d, J2,1 = 3.9 Hz, 1H, H2), 4.47 (d, JH,H = 11.5 Hz, 1H,
CH2Ph), 4.19 (m, 1H, H4), 3.99 (d, J4,3 = 3.3 Hz, 1H, H3), 3.64 (s, 3H,
OCH3), 1.48 (s, 3H, CH3), 1.32 (s, 3H, CH3). dH (CDCl3, 100 MHz):
156.7 (C@O), 136.6 (Ci), 134.9 (CH), 128.6 (2 ꢁ CHPh), 128.3 (CHPh),
128.1 (2 ꢁ CHPh), 116.5 (CH2), 111.6 (C), 104.9 (CH), 82.8 (CH), 81.5
(CH), 79.8 (CH), 72.2 (CH2), 52.8 (CH), 52.0 (OCH3), 26.7 (CH3), 26.2
(CH3). Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found:
C, 62.68; H, 6.81; N, 3.70.
4.1.8. 5,6,7-Trideoxy-1,2-O-isopropylidene-3-O-triisopropyl-
silyl-5-(methoxycarbonylamino)-a-D-gluco-hept-6-enfuranose
13
To a solution of isothiocyanate 10 (0.20 g, 0.484 mmol) in dry
methanol (4.9 mL) was added sodium methoxide (28.6 mg,
0.53 mmol) at room temperature. After 6.5 h, no starting material
was detected (TLC) in the reaction mixture. The solvent was evap-
orated in vacuo and the residue was partitioned between CH2Cl2
(10 mL) and water (2 mL). The water phase was extracted with fur-
ther portions of CH2Cl2 (2 ꢁ 5 mL). The combined organic layers
were dried over Na2SO4, after which the solvent was evaporated
and the residue was purified through a short column of silica gel
(11:1 hexane/ethyl acetate) to give 0.174 g (81%) of thiocarbamate
as a colourless oil, which was used immediately in the next step to
avoid problems connected with its possible instability. To a solu-
tion of thiocarbamate (0.17 g, 0.381 mmol) in dry acetonitrile
(3.4 mL) was added mesitylnitrile oxide (68 mg, 0.42 mmol). The
reaction mixture was stirred for 3 h at room temperature. Evapora-
tion of the solvent under reduced pressure gave a residue, which
was purified by column chromatography on silica gel (9:1 hex-
ane/ethyl acetate) to afford 0.147 g (90%) of crystalline carbamate
4.1.10. 5,6,7-Trideoxy-1,2-O-isopropylidene-5-(methoxy-
carbonylamino)-a-D-gluco-hept-6-enfuranose 15
To a solution of compound 13 (0.10 g, 0.233 mmol) in dry THF
(2.30 mL) was added a 1 M solution of Bu4NF in THF (0.23 mL,
0.233 mmol) at 0 °C. The resulting mixture was stirred for a further
10 min at 0 °C and then for 30 min at room temperature. The sol-
vent was removed and the residue was partitioned between ethyl
acetate (5 mL) and water (1 mL). The aqueous phase was extracted
with further portions of ethyl acetate (2 ꢁ 5 mL). The combined or-
ganic layers were dried over Na2SO4, the solvent was evaporated,
and the residue was purified by flash chromatography on silica
gel (2:1 hexane/ethyl acetate) to afford 55 mg (86.5%) of com-
pound 15 as a colourless oil: ½a D25
¼ þ147:3 (c 0.28, CHCl3). dH
ꢂ
(CDCl3, 400 MHz): 6.10 (ddd, J7trans,6 = 17.4 Hz, J7cis,6 = 10.6 Hz,
J6,5 = 5.0 Hz, 1H, H6), 5.95 (d, J2,1 = 3.6 Hz, 1H, H1), 5.34 (ddd,
J7trans,6 = 17.4 Hz, J7trans,5 = 1.8 Hz, J7trans,7cis = 0.6 Hz, 1H, H7trans),
5.30 (ddd, J7cis,6 = 10.6 Hz, J7cis,5 = 1.7 Hz, J7trans,7cis = 0.6 Hz, 1H,
H7cis), 4.90 (d, J5,NH = 8.1 Hz, 1H, NH), 4.63 (br s, 1H, OH), 4.56 (d,
J2,1 = 3.6 Hz, 1H, H2), 4.44 (ddddd J5,4 = 10.1 Hz, J5,NH = 8.1 Hz,
J6,5 = 5.0 Hz, J7trans,5 = 1.8 Hz, J7cis,5 = 1.7 Hz, 1H, H5), 4.13 (m, 1H,
H3), 3.86 (dd, J5,4 = 10.1 Hz, J4,3 = 2.0 Hz, 1H, H4), 3.73 (s, 3H,
OCH3), 1.48 (s, 3H, CH3), 1.31 (s, 3H, CH3). dC (CDCl3, 100 MHz):
158.0 (C@O), 135.0 (CH), 116.7 (CH2), 111.5 (C), 105.1 (CH), 84.3
(CH), 83.0 (CH), 74.1 (CH), 53.0 (OCH3), 50.8 (CH), 26.8 (CH3),
26.1 (CH3). Anal. Calcd for C12H19NO6: C, 52.74; H, 7.01; N, 5.13.
Found: C, 52.89; H, 7.20; N, 5.27.
13: mp 77–78 °C; ½a D25
¼ þ1:5 (c 0.20, CHCl3). dH (CDCl3, 400 MHz):
ꢂ
5.97–5.89 (m, 2H, H1, H6), 5.67 (m, 1H, NH), 5.32 (d,
J7trans,6 = 17.2 Hz, 1H, H7trans), 5.22 (m, 1H, H7cis), 4.68 (m, 1H, H5),
4.43 (m, 2H, H2, H3), 4.14 (m, 1H, H4), 3.65 (s, 3H, OCH3), 1.48 (s,
3H, CH3), 1.31 (s, 3H, CH3), 1.16–1.08 (m, 21H, 6 ꢁ CH3, 3 ꢁ CH).
dC (CDCl3, 100 MHz): 156.6 (C@O), 135.3 (CH), 116.6 (CH2), 111.7
(C), 104.5 (CH), 85.1 (CH), 80.9 (CH), 77.6 (CH), 52.8 (CH), 52.0
(OCH3), 26.8 (CH3), 26.3 (CH3), 18.0 (6 ꢁ CH3), 12.8 (3 ꢁ CH). Anal.
Calcd for C21H39NO6Si: C, 58.71; H, 9.15; N, 3.26. Found: C, 58.57;
H, 9.27; N, 3.37.

J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
213
4.1.11. Methyl 3-O-benzyl-5-deoxy-1,2-O-isopropylidene-5-
(methoxycarbonylamino)- -gluco-hexofuranuronate 17
77.7 (CH), 77.4 (CH), 73.1 (CH2), 54.4 (CH), 52.5 (OCH3), 52.3
(OCH3), 20.9 (CH3), 20.4 (CH3). Anal. Calcd for C20H25NO10: C,
54.67; H, 5.73; N, 3.19. Found: C, 54.51; H, 5.59; N, 3.29.
a
-D
To a suspension of carbamate 14 (1.05 g, 2.89 mmol) in CCl4/
CH3CN/H2O (29 mL, 2:2:3) were successively added NaIO4
(3.09 g, 14.45 mmol) and ruthenium trichloride hydrate (29 mg,
0.14 mmol). After 6 h, no starting compound was detected (TLC)
in the reaction mixture, which was then extracted with CH2Cl2
(2 ꢁ 30 mL). The combined organic layers were dried over Na2SO4,
after which the solvent was evaporated in vacuo, and the residue
was purified through a short column of silica gel (95:5 CH2Cl2/
CH3OH) to afford 0.82 g (74%) of carboxylic acid 16 as a colourless
oil, which was used immediately in the subsequent reaction.
To a solution of acid 16 (0.80 g, 2.10 mmol) in dry DMF (28 mL)
were successively added K2CO3 (0.319 g, 2.307 mmol) and CH3I
(0.196 mL, 3.146 mmol) at room temperature. After the starting
material was completely consumed (1 h, judged by TLC), the reac-
tion was stopped, poured into ice water (28 mL) and extracted with
diethyl ether (2 ꢁ 50 mL). The combined organic layers were dried
over Na2SO4, after which the solvent was removed, and the residue
was subjected to flash chromatography on silica gel (3:1 hexane/
ethyl acetate) to yield 0.75 g (90%) of ester 17 as a colourless oil;
Anomer 19b: ½a 2D5
¼ ꢀ34:7 (c 0.11, CHCl3). dH (CDCl3, 400 MHz):
ꢂ
7.39–7.29 (m, 5H, Ph), 6.18 (s, 1H, H1), 5.65 (br d, J5,NH = 9.3 Hz, 1H,
NH), 5.24 (s, 1H, H2), 4.99 (m, 2H, H4, H5), 4.75 (d, JH,H = 11.6 Hz,
1H, CH2Ph), 4.49 (d, JH,H = 11.6 Hz, 1H, CH2Ph), 4.17 (d,
J4,3 = 5.3 Hz, 1H, H3), 3.68 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.13
(s, 3H, CH3CO), 2.06 (s, 3H, CH3CO). dC (CDCl3, 100 MHz): 170.3
(C@O), 169.7 (C@O), 169.3 (C@O), 157.1 (C@O), 136.3 (Ci), 128.6
(3 ꢁ CHPh), 128.3 (CHPh), 128.1 (CHPh), 99.2 (CH), 82.1 (CH), 81.4
(CH), 78.1 (CH), 72.6 (CH2), 53.7 (CH), 52.3 (2 ꢁ OCH3), 20.8
(2 ꢁ CH3). Anal. Calcd for C20H25NO10: C, 54.67; H, 5.73; N, 3.19.
Found: C, 54.79; H, 5.55; N, 3.07.
4.1.13. Methyl 20-O-acetyl-30-O-benzyl-10,50-dideoxy-10-[3,4-
dihydro-2,4-dioxo-1(2H)-pyrimidinyl]-50-(methoxycarbonyl-
amino)-b-D-gluco-hexofuranuronate 20
A mixture of uracil (94 mg, 0.839 mmol), 1,1,1,3,3,3-hexameth-
yldisilazane (2.51 mL, 12.04 mmol) and trimethylsilyl chloride
(0.27 mL, 2.11 mmol) was stirred at reflux. After 6 h, the mixture
was allowed to cool to room temperature and concentrated. To a
½
a 2D5
ꢂ
¼ ꢀ33:4 (c 0.25, CHCl3). dH (CDCl3, 400 MHz): 7.40–7.31 (m,
5H, Ph), 5.96 (d, J2,1 = 3.8 Hz, 1H, H1), 5.70 (br d, J5,NH = 9.4 Hz,
1H, NH), 4.97 (dd, J5,NH = 9.4 Hz, J5,4 = 6.4 Hz, 1H, H5), 4.64 (dd,
J5,4 = 6.6 Hz, J4,3 = 3.7 Hz, 1H, H4), 4.62 (d, JH,H = 11.4 Hz, 1H,
CH2Ph), 4.58 (d, J2,1 = 3.8 Hz, 1H, H2), 4.46 (d, JH,H = 11.4 Hz, 1H,
CH2Ph), 4.05 (d, J4,3 = 3.7 Hz, 1H, H3), 3.67 (s, 3H, OCH3), 3.66 (s,
3H, OCH3), 1.50 (s, 3H, CH3), 1.33 (s, 3H, CH3). dH (CDCl3,
100 MHz): 170.6 (C@O), 157.0 (C@O), 136.3 (Ci), 128.6 (2 ꢁ CHPh),
128.3 (3 ꢁ CHPh), 112.0 (C), 105.1 (CH), 82.9 (CH), 81.8 (CH), 78.0
(CH), 72.4 (CH2), 53.5 (CH), 52.4 (2 ꢁ OCH3), 26.9 (CH3), 26.3
(CH3). Anal. Calcd for C19H25NO8: C, 57.71; H, 6.37; N, 3.54. Found:
C, 57.59; H, 6.19; N, 3.33.
solution of the mixture of acetates 19a, 19b (80 mg, 0.182 mmol)
in dry 1,2-dichloroethane (1.3 mL) was added the above-prepared
bis(trimethylsilyl) uracil dissolved in 1,2-dichloroethane (2.6 mL),
followed by the dropwise addition of TMSOTf (0.198 mL,
1.094 mmol) at room temperature. The resulting mixture was stir-
red at reflux for 3 h, then quenched with 7% aq solution of NaHCO3
(3 mL) and extracted with CH2Cl2 (2 ꢁ 15 mL). The combined or-
ganic layers were dried over Na2SO4, the solvent was evaporated,
and the residue was purified by flash chromatography on silica
gel (1:2 hexane/ethyl acetate) to give 57 mg (64%) of crystalline
compound 20: mp 60–62 °C; ½a D25
¼ þ22:2 (c 0.16, CHCl3); IR
ꢂ
(KBr) mmax (cmꢀ1) 3064, 2956, 1694, 1229, 1050. dH (CDCl3,
400 MHz): 8.79 (br s, 1H, NH), 7.58 (d, J6,5 = 8.2 Hz, 1H, H6),
4.1.12. Methyl 1,2-di-O-acetyl-3-O-benzyl-5-deoxy-5-(methoxy-
carbonylamino)-a-D-gluco-hexofuranuronate 19a and its b-
anomer 19b
Ester 17 (0.70 g, 1.77 mmol) was dissolved in 1,4-dioxane
(14 mL) and the resulting solution was diluted with water
(14 mL). Next, Amberlite IR-120 (H+) (6.9 g) was added and the
mixture was stirred at 65 °C. After 18.5 h, no starting material
was detected (TLC), and the reaction was stopped and allowed to
cool to room temperature. Insoluble materials were removed by
filtration, the solvent was evaporated and the residue was purified
through a short column of silica gel (1:2 hexane/ethyl acetate) to
afford 0.38 g (60%) of lactol 18 as an inseparable mixture of ano-
mers. To a solution of 18 (0.19 g, 0.535 mmol) in pyridine (4 mL)
were added DMAP (13 mg, 0.105 mmol) and acetic anhydride
(0.15 mL, 1.587 mmol) at 0 °C. The reaction mixture was stirred
for a further 15 min at 0 °C and then for 45 min at room tempera-
ture. The stirring solution was poured into ice water (5 mL) and ex-
tracted with diethyl ether (2 ꢁ 12 mL). The combined organic
layers were dried over Na2SO4, after which the solvent was evapo-
rated in vacuo, and the residue was subjected to flash chromatog-
raphy on silica gel (3:1 hexane/ethyl acetate) to afford 90 mg (38%)
Table 2
Crystal data and structure refinement parameters for compounds 10
10
Empirical formula
Formula weight
Temperature, T (K)
Wavelength, k (Å)
Crystal system
C20H35NO4SSi
413.65
293(2)
0.71073
Orthorhombic
P212121
Space group
Unit cell dimensions
a (Å)
b (Å)
9.4548 (3)
12.4226 (4) b = 90 (6)°
20.7169 (6)
2433.27 (13)
4
1.129
0.204
896
c (Å)
V (Å3)
Z
qcalcd (g/cm3)
Absorption coefficient (mmꢀ1
F(0 0 0)
)
Crystal size (mm)
Theta (°) range for data collection
Index ranges
0.5 ꢁ 0.150 ꢁ 0.065
2.71–25.00
of 19
a
and 85 mg (36%) of 19b as colourless oils.
¼ þ204:1 (c 0.17, CHCl3). dH (CDCl3,
11 6 h 6 11
Anomer 19
a:
½ ꢂ
a 2D5
ꢀ14 6 k 6 14
400 MHz): 7.39–7.31 (m, 3H, Ph), 7.25–7.23 (m, 2H, Ph), 6.42 (d,
J2,1 = 4.6 Hz, 1H, H1), 5.51 (br d, J5,NH = 10.0 Hz, 1H, NH), 5.20 (m,
1H, H2), 5.02 (dd, J4,3 = 7.1 Hz, J5,4 = 4.1 Hz, 1H, H4), 4.93 (dd,
J5,NH = 10.0 Hz, J5,4 = 4.1 Hz, 1H, H5), 4.57 (d, JH,H = 11.7 Hz, 1H,
CH2Ph), 4.46 (d, JH,H = 11.7 Hz, 1H, CH2Ph), 4.43 (dd, J4,3 = 7.1 Hz,
J3,2 = 6.0 Hz, 1H, H3), 3.71 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 2.06
(s, 3H, CH3CO), 2.02 (s, 3H, CH3CO). dC (CDCl3, 100 MHz): 169.9
(C@O), 169.5 (C@O), 169.2 (C@O), 157.2 (C@O), 136.4 (Ci), 128.5
(2 ꢁ CHPh), 128.3 (CHPh), 128.0 (2 ꢁ CHPh), 93.5 (CH), 80.0 (CH),
ꢀ24 6 l 6 24
Independent reflections (Rint
Absorption correction
Max. and min. transmission
Refinement method
)
4292 (0.0637)
Semi-empirical from equivalents
1.0000 and 0.878
Full-matrix least-squares on F2
4292/0/252
Data/restraints/parameters
Goodness-of-fit on F2
0.893
Final R indices [I>2
r
(I)]
R1 = 0.0340, wR2 = 0.0628
R1 = 0.0804, wR2 = 0.0685
0.153 and ꢀ0.195
R indices (all data)
Largest diff. peak and hole (eÅꢀ3
)

214
J. Gonda et al. / Tetrahedron: Asymmetry 22 (2011) 207–214
Muzzerelli, R. A. A., Ed.; Pergamon Press: Oxford, 1977; pp 5–44; (d) Isono, K. J.
0
0
0
7.37–7.28 (m, 5H, Ph), 6.07 (d, J2 ,1 = 1.9 Hz, 1H, H1 ), 5.63 (m, 2H,
H5, NH), 5.19 (m, 1H, H2 ), 5.05 (m, 1H, H5 ), 4.69 (d, JH,H = 11.4 Hz,
1H, CH2Ph), 4.55 (d, JH,H = 11.4 Hz, 1H, CH2Ph), 4.51 (m, 1H, H4 ),
Antibiot. 1988, 41, 1711–1739.
0
0
3. Misato, M.; Kakiki, K. In Antifungal Compounds; Siegel, M., Sisler, H. D., Eds.;
Dekker: New York, 1977; p 277.
0
0
0
0
0
0
4. Naka, T.; Hashizume, T.; Nishimuta, T. Tetrahedron Lett. 1971, 12, 95–98.
5. (a) Damodaran, N. P.; Jones, G. H.; Moffatt, J. G. J. Am. Chem. Soc. 1971, 93, 3812–
3813; (b) Ohrui, H.; Kuzuhara, H.; Emoto, S. Tetrahedron Lett. 1971, 12, 4267–
4270; (c) Akita, H.; Uchida, K.; Chen, C.-Y. Heterocycles 1997, 46, 87–90; (d)
Dondoni, A.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. Tetrahedron Lett.
1994, 35, 9439–9442; (e) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55,
3853–3857; (f) Garner, P.; Park, J. M. J. Org. Chem. 1990, 55, 3772–3776; (g)
Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265–
276; (h) Auberson, Y.; Vogel, P. Tetrahedron Lett. 1990, 46, 7019–7032; (i) Akita,
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Thomas, E. J.; Wilson, P. D. J. Chem. Soc., Perkin Trans. 1 1999, 3305–3310.
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4.05 (dd, J4 ,3 = 3.9 Hz, J3 ,2 = 0.8 Hz, 1H, H3 ), 3.70 (s, 3H, OCH3),
3.66 (s, 3H, OCH3), 2.15 (s, 3H, CH3CO). dC (CDCl3, 100 MHz):
169.9 (C@O), 169.6 (C@O), 162.7 (C@O), 156.6 (C@O), 149.9
(C@O), 139.7 (CH), 135.6 (Ci), 128.7 (5 ꢁ CHPh), 102.5 (CH), 88.3
(C0H), 80.3 (C0H), 80.2 (C0H), 79.1 (C0H), 72.4 (CH2), 52.9 (C0H),
52.8 (2 ꢁ OCH3), 20.8 (CH3). Anal. Calcd for C22H25N3O10: C,
53.77; H, 5.13; N, 8.55. Found: C, 53.55; H, 5.26; N, 8.39.
4.2. X-ray crystallography
7. (a) Kuzuhara, H.; Ohrui, H.; Emoto, S. Tetrahedron Lett. 1973, 5055–5058; (b)
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2979–2984; (f) Gethin, D. M.; Simpkins, N. Tetrahedron 1997, 53, 14417–14436;
(g) Ghosh, A. K.; Wang, Y. J. Org. Chem. 1998, 63, 6735–6738.
9. (a) Krainer, E.; Becker, J. M.; Naider, F. J. Med. Chem. 1991, 34, 174–180; (b)
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Garciá-López, M.-T.; DelasHeras, F. G.; Méndez-Castrillón, P. P. Synthesis 1987,
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5589.
Single crystals of 10 suitable for an X-ray diffraction were ob-
tained from a mixture of Et2O and hexane by slow evaporation at
room temperature. The intensities were collected at 293(2) K on
a Oxford Diffraction XCalibur2 CCD diffractometer using MoK
a
radiation (k = 0.71073 Å). Selected crystallographic and other rele-
vant data for the compound 10 are listed in Table 2. The structure
was solved by direct methods.18 All non-hydrogen atoms were re-
fined anisotropically by full-matrix least-squares calculations
based on F2.18 All hydrogen atoms were included in calculated
19
positions as riding atoms, with SHELXL9718 defaults. PLATON pro-
gramme was used for structure analysis and molecular and crystal
structure drawings preparation.
Complete crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre,
CCDC No. CCDC 738029. These data can be obtained free of charge
from the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: +44-1223-336033;
e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
11. Luo, Y.-C.; Zhang, H.-H.; Liu, Y.-Z.; Cheng, R.-L.; Xu, P.-F. Tetrahedron:
Asymmetry 2009, 20, 1174–1180.
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Gonda, J.; Martinková, M.; Raschmanová, J.; Balentová, E. Tetrahedron:
Asymmetry 2006, 17, 1875–1882; (c) Martinková, M.; Gonda, J.;
Raschmanová, J. Molecules 2006, 11, 564–573; (d) Martinková, M.; Gonda, J.;
Acknowledgements
The present work was supported by the Grant Agency
(Nos. 1/0100/09 and 1/0281/08) of the Ministry of Education,
Slovak Republic. NMR measurements provided by the Slovak
State Programme Project No. 2003SP200280203 are gratefully
acknowledged.
ˇ
Raschmanová, J.; Vojtícková, M. Tetrahedron 2007, 63, 10603–10607.
13. Chen, A.; Savage, I.; Thomas, E. J.; Wilson, P. D. Tetrahedron Lett. 1993, 34, 6769–
6772.
14. Savage, I.; Thomas, E. J. J. Chem. Soc., Chem. Commun. 1989, 717–719.
15. (a) Gonda, J.; Martinková, M.; Zadrošová, A.; Šoteková, M.; Raschmanová, J.;
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Conka, P.; Gajdošíková, E.; Kappe, C. O. Tetrahedron Lett. 2007, 48, 6912–6915;
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(b) Gajdošíková, E.; Martinková, M.; Gonda, J.; Conka, P. Molecules 2008, 13,
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