Reactions of per-O-acetylglucosyl isothiocyanate with carbon bases. A new method for the stereocontrolled syntheses of nucleosides and glucosylaminothiophenes

Article abstract of DOI:10.1016/S0957-4166(98)00243-2

Reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate 5 with diethyl malonate in a basic medium gave the corresponding glucopyranosyl thioamide without significant deacetylation. This thioamide in solution presents Z-anti as the sole configuration. Reactions of 5 with carbanions which have an ethoxycarbonyl group are a way to prepare anomerically pure N- nucleoside derivatives of pyrrole and tetrahydropyridine. Reactions of 5 with carbanions stabilized by one cyano group are used to prepare glucosylamino thiophenes with only the β-configuration. Some other stereochemical aspects of the prepared compounds are discussed.

Full text of DOI:10.1016/S0957-4166(98)00243-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2517–2532
Reactions of per-O-acetylglucosyl isothiocyanate with carbon
bases. A new method for the stereocontrolled syntheses of
nucleosides and glucosylaminothiophenes
José Fuentes,∗ José L. Molina and M. Angeles Pradera
Dpto de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 29 May 1998; accepted 16 June 1998
Abstract
Reaction of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylisothiocyanate 5 with diethyl malonate in a basic medium
gave the corresponding glucopyranosyl thioamide without significant deacetylation. This thioamide in solution
presents Z-anti as the sole configuration. Reactions of 5 with carbanions which have an ethoxycarbonyl group
are a way to prepare anomerically pure N-nucleoside derivatives of pyrrole and tetrahydropyridine. Reactions of
5 with carbanions stabilized by one cyano group are used to prepare glucosylamino thiophenes with only the
β-configuration. Some other stereochemical aspects of the prepared compounds are discussed. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Sugar isothiocyanates are versatile starting materials in the syntheses of several types of glycoconju-
gates of biological interest.1 Of the sugar isothiocyanates, the glycosyl ones are the most useful, which
has prompted the development of both preparation procedures1–5 and synthetic applications.1,6–9 At the
same time, the nucleosides and aminothiophenes are interesting chemotherapeutic tools in the treatment
of various infectious diseases,10 which has originated an increasing demand for new compounds, and
considerable effort is being directed towards the syntheses of nucleoside analogues. In the framework of
a program aimed at the development of sugar isothiocyanate chemistry, in this paper we report on the re-
actions of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate,11 as an example of easily available
glycosyl isothiocyanate, and different carbon bases. We also explore the use of the corresponding adducts
in the preparation of pyrrole and pyridine nucleoside derivatives and of glycosylaminothiophenes. Many
reactions of sugar isothiocyanates with N-, O- and S-nucleophiles have been studied;1,12 however, the
data on reactions with carbon bases are very scarce and limited to enamines as nucleophiles.7,12
∗
Corresponding author. E-mail: jfuentes@cica.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00243-2

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J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
Fig. 1. Conformational stereoisomers by rotation around the C10–N bond of 6
2. Results and discussion
Commercially available diethyl malonate, ethyl cyanoacetate, phenylthioacetonitrile, cyanoacetamide
and malonodinitrile, and the newly synthesized phenacyl and acetonyl derivatives of diethyl malonate
1–3 and of malonodinitrile 4 were used to generate carbanions to study their reactions with 2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosyl isothiocyanate 5. Compounds 1–4 were prepared by alkylation of diethyl
malonate or malonodinitrile with the corresponding α-haloketone in the presence of sodium hydride
1
under a nitrogen atmosphere. The structures 1–4 were supported by IR, H- and 13C-NMR, and mass
spectroscopic data (see Experimental).
2.1. Reactions of the glucosyl isothiocyanate 5 with carbanions having two ester groups
Reaction of the isothiocyanate 5 with diethyl malonate in a basic medium produced the N-
glucosylthioamide 6 (Fig. 1), whose analytical and spectroscopic (Table 1 and Experimental) data were
in agreement with the proposed structure. The hydrogen bond between the NH and an ethoxycarbonyl
group, shown in Fig. 1, was evident from the chemical shift of NH (9.55 ppm, close to that for other
strongly chelated amino groups6), and from the existence of two different resonances in the 13C-NMR
spectrum at 165 (CO chelated) and 164 ppm (CO free) for the ethoxycarbonyl groups.
The sugar amides and thioamides can exist in four configurational and conformational stereoisomers
(Fig. 2), and because of the important biological role of many glycoconjugates with an amido function,
such as glycopeptides, glycolipids, calicheamicins,13 and istamycins,14 it is very interesting to know the
exact stereochemistry of any amidosugar. This can be a way to rationalize the role of these compounds
in molecular recognition or enzyme inhibition phenomena. The aforementioned equilibrium has been
evaluated for several types of amidosugar derivative15 and the Z-anti as sole conformer or mixtures of Z-
anti and Z-syn conformers have been described as predominant stereoisomers. The recent observation16
that the value (9–11 Hz) for the 3JH,H between the NH and the vicinal CH sugar proton (H-1 or H-2) is
compatible with both the antiperiplanar and synperiplanar arrangements of NH and CH has demonstrated

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2519
Table 1
Selected NMR data (δ, ppm; J, Hz) for compounds 6–14, 18–22, and 25,26 in CDCl3
a possible controversy in the published results, and new experiments have been carried out on both 2-
amido-2-deoxy sugars16 and glycosylamides.17 In the case of the thioamido derivative 6, the presence of
1
a sole stereoisomer was evident from the H- and 13C-NMR spectra which showed only one signal set.
The above-discussed hydrogen bond is compatible with the Z-anti 6a and Z-syn 6b stereoisomers (Fig. 1)
and rules out the E-anti and E-syn configurations. To distinguish between 6a and 6b the indicated NOE
experiments were carried out. From these, the 1,3-syn-axial disposition between NH and C20–H was
evident, and consequently the Z-anti stereoisomer is the only possible one.
Treatment of the glucosyl isothiocyanate 5 with the diethyl phenacyl (acetonyl) malonates 1–3
and sodium hydride gave the glucosyl thioamide derivatives 7–9 respectively. The NMR spectra of
compounds 7 and 8 had single sets of signals, the data being very close to those for 6, and supporting
the same structure and stereochemistry. In these two cases, the chemical shift for the NH resonance was
≈11.2 ppm, corroborating the presence of a strong hydrogen bond. Compounds 7 and 8 were stable in
solution in chloroform even after 10 days, and no formation of cyclic structures in the aglycon moiety
were observed. This is probably due to the conjugation between the carbonyl and phenyl groups of the
phenacyl radical. In the case of the reaction 5+3, the 1H-NMR data of the final product demonstrated the
1
structure 9; however the H- and 13C-NMR spectra showed the existence of an equilibrium between 9
and the two (5R,5S) hemiaminalic structures 10. The ratio of 9:10 at room temperature was 1.1:10 and
did not change over time. The two diastereomers 10 were in a 1:1 ratio, which is consistent with the
nonstereogenic character of C-2 and C-3 in the aglycon moiety of 9. With increasing temperature, the
proportion of 9 in the equilibrium increased, the ratio of 9:10 reaching 1:4 at 50°C. Selected spectroscopic
data of 10 are included in Table 1.

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J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
Fig. 2. Stereochemical equilibrium for the amide moiety of sugar amides (X=O) and thioamides (X=S)
Cyclodehydration of 7 and 8 with acetic anhydride and phosphoric acid gave the N-nucleoside
derivatives of pyrroline-5-thione 11 and 12. The resonance of the C_S group of 11 and 12 appeared
at ≈165 ppm, a value very different to that for the starting materials, and close to that reported for related
1
azolinethiones.18 The 13C resonances at ≈141 (C-2) and 116 (C-3) ppm and the H resonance at 6.22
ppm supported the presence of the double bond in the aglycon moiety.
When the same treatment with acetic anhydride and phosphoric acid was carried out on 9, the N-
1
glucosyl pyridine derivative 13 was obtained in 65% yield after purification. The H- and 13C-NMR
spectra of 13 showed a sole signal set, and no signals attributable to the other diasteromeric structure
were observed. In contrast to 11 and 12, the C_S group of 13 resonated at 196.7 ppm; the signals for
the C_CH group appeared at 152.9 (C-5), 105.1 (C-6) and 6.49 (_CH) ppm. This latter resonance was
a double doublet showing allylic couplings (2.2 and 1.7 Hz) with the protons on C-4. The resonance
of the ketone C_O was observed at 199.6 and there was no signal for NH. A possible mechanism to
explain the formation of the N-nucleoside analogue 13 is depicted in Scheme 1. The enolic form 9b,

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2521
which can be acetylated, undergoes internal addition, followed by dehydration (if acetylated elimination
of AcOH) to give 14. This intermediate is an enamine analogue with strong nucleophilic character at the
β-carbon (C-5). Consequently it can react at this position with an acetyl cation to give 13, after loss of
a proton. A possible structure 16 for the intermediate was considered, but the spectroscopic data and the
existence of only one stereoisomer for 13 ruled out this formula. Related six-membered cyclizations of
γ-oxothioureas have been described.19
Scheme 1. Possible mechanism for the formation of 13
2.2. Reactions of the isothiocyanate 5 with carbanions having one cyano group
When the carbanion from ethyl cyanoacetate reacted with the glucosyl isothiocyanate 5, a non-
isolatable salt (17) was formed (Scheme 2); which by reaction with phenacyl bromide gave the S-
phenacyl derivative 18 in high yield, and no cyclization to a thiophene derivative was observed. The
1
phenacyl group of 18 was evident from the IR band at 1684 cm−1 (C_O) and from the H resonances
at 4.96 and 4.63 ppm (AB system for CH2, JAB 17.1 Hz) and 13C resonances at 191.8 (C_O) and 42.7
ppm (CH2).20 The cyano group resonated at 117.3 ppm and its IR C^N bond appeared at 2212 cm−1
;
there were no signals for a C_S group. The chemical shift for the resonance of the NH (10.32 ppm)
demonstrated a strong hydrogen bond between this proton and the carbonyl of the ester group. The
existence of this H-bond supported the E configuration assigned to the C_C double bond.
In the case of the reaction of 5 with phenylthioacetonitrile, and afterwards with phenacyl chloride, the
S-phenacyl derivative 19 and the glucosylamino thiophene 20 were obtained after chromatography. The
structural data of 19 closely resembled those of 18 (see Table 1 and Experimental), except the resonance
for NH, which appeared at 7.10 ppm and corresponds to a weakly chelated amino proton. This fact
is indicative of Z configuration of the C_C double bond, with a hydrogen bond between the cis NH
and C^N groups. Dilution studies confirmed the intramolecular chelated structure. Compound 20 (see
structure discussion together with 21 and 22) with a thiophene structure arises from the nucleophilic
addition of the methylene of the phenacyl group onto the cyano group of the E stereoisomer of 19.
When cyanoacetamide and malonodinitrile were used to generate the carbanions, the glucosylamino-
thiophenes 21 and 22 were isolated. The IR spectra of 20–22 revealed the presence of the NH2 stretching

2522
J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
Scheme 2. Reaction of compound 5 with cyanoderivatives
band at 3424–3322 cm−1 and, in the case of 22, a C^N absorption at 2212 cm−1. The 1H-NMR spectra
showed broad signals for the NH2 groups and a doublet for the NH at 6.54 ppm for 20 (nonchelated
structure), 8.66 ppm for 21 (hydrogen bond between NH and CO groups) and 6.77 ppm (weak hydrogen
bond between NH and C^N). In contrast with what happened with 18 and 19, in the three cases 20–22,
the H-1 of the sugar ring resonated at higher field than H-2, H-3 and H-4. No signals for a C_S group
were observed.
Some reactions between benzoyl isothiocyanate and methylene active reagents have been studied21
and a structure related to 17 has been proposed as an intermediate.
The reaction of 5 with a dicyano derivative has also been studied. Thus, when 5 was added on the
carbanion proceeding from phenacylmalonodinitrile 4, and the resulting salt 23 was S-alkylated with
phenacyl bromide, the diasteromeric mixture (C-3 epimers) of glucosyliminothiophenes 25 and 26 was
obtained. This mixture could be resolved chromatographically, and 25 (major) and 26 (minor) were
isolated as pure products, although the configuration of C-3 could not be assigned. Compounds 25 and
26 are formed (Scheme 3) by nucleophilic addition of the methylene of the S-alkyl group of 24 on each
one of the cyano groups. The 1H-NMR spectra (Table 1 and Experimental) of 25 and 26 had no signals for
NH, and H-1 of the sugar ring resonated as a doublet. The chemical shifts for the resonances of C-1 of the
sugar ring and C_N (C-2 of the thiophene ring) were close to those described for related glucosylimino
derivatives.22 The resonances for the C–CH2 group appeared at ≈42.5 ppm and the chemical shifts for
the resonances of the NH2 were ≈8.4 ppm, a value at a remarkably lower field than those for the same
protons in 20–22; this suggests a possible seven-membered ring hydrogen bond with the carbonyl of
phenacyl group.
As with other aldimines,22 the glucosylimines 25 and 26 probably prefer the conformation indicated in
the Scheme 3, because this is stabilized by a π-→σ* delocalization of the π electrons of the C_N bond
in the σ* orbital of the C1–O bond in the pyranosyl ring.
Conventional deacetylation of compounds 6, 11, 12, 18 and 22 gave the glucosyl thioamide 27, the N-
nucleosides 28 and 29, and the glucosylaminothiophenes 30–31. The deacetylation of the phenylthio- and

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2523
Scheme 3. Reaction of compound 5 with phenacyl malonodinitrile
carbamoylderivatives 19–21 was also tried but in these three cases decomposition took place, and it was
not possible to isolate the corresponding deacetylated derivative. Compounds 27–31 were characterized
by their NMR data (see Experimental). Compound 27 showed a strongly chelated structure (δNH 10.6
ppm). During the treatment with sodium methoxide of the N-nucleosides 11 and 12, saponification of
an ethoxycarbonyl group and then decarboxylation took place, and in this way 28 and 29 had only one
ethoxycarbonyl group. Compound 29 was isolated whereas 28 was only spectroscopically detected. In the
case of compound 18, under deacylation conditions, the cyclization took place and the aminothiophene
derivative 30, with the same structure as 31, was obtained.

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J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
In conclusion, a glycosyl isothiocyanate, the 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate
5, can react with methylene active compounds, in a basic medium, without significant deacylation. These
reactions open ways to prepare glycosylthioamides, nucleoside analogues of different heterocycles, and
glycosylamino heterocycles. In all cases, the anomeric configuration is fixed by the C-10 configuration of
the glucosyl isothiocyanate. In cases of the glucosylamino derivatives, the anomerization described for
other free and O-protected glycosyl amines did not take place.23,24
3. Experimental
3.1. General
Melting points are uncorrected. Optical rotations were measured for solutions in dichloromethane.
1
FTIR spectra were recorded for KBr discs or thin films. H-NMR (500 and 300 MHz) and 13C-
NMR (125.7 and 75.4 MHz) spectra were obtained for solutions in CDCl3, (CD3)2SO or MeOH-d4.
Assignments were confirmed by homonuclear 2D COSY and heteronuclear 2D correlated experiments.
FAB-mass spectra were recorded with a Kratos MS-80RFA instrument with a resolution of 1000 (10%
valley definition). Ions were produced by a beam of xenon atoms (6–7 kV) using a matrix consisting
of thioglycerol or 3-nitrobenzyl alcohol and NaI as salt. HREIMS (70 eV), HRCIMS (150 eV) and
HRDCIMS (150 eV) experiments were performed with a Micromass AutoSpecQ instrument with a
resolution of 10 000 (5% valley definition). Isobutane was used as the reactive gas (500 mA, 8 kV).
TLC was performed on silica gel HF254, with detection by UV light or charring with H2SO4. Silica gel
60 (Merck, 230–400 mesh) was used for preparative chromatography.
3.2. General procedure for the preparation of 1–4
To a stirred solution of diethyl malonate (6.59 mmol) for 1–3 or malononitrile for 4 (6.59 mmol) in
v mL of dry DMF over molecular sieves and under nitrogen, 9.88 mmol of NaH (as a suspension in
mineral oil) are added. After 5 min, the corresponding α-haloketone (6.59 mmol) was added dropwise as
a solution in 1.5 mL of dry DMF over molecular sieves and under nitrogen (for 1–3) or added directly as
a solid (in the case of 4) onto the carbanion. The corresponding mixture was stirred at 30°C for 30 min,
then diluted with ether (for 1–3) or dichloromethane (for 4), washed with water, dried (MgSO4), filtered
and evaporated to dryness.
3.2.1. Diethyl phenacylmalonate 1
v=1 mL. Column chromatography (ether:hexane=1:4) of the residue gave an oil (1.08 g, 59%); IR νmax
3063, 2984, 2934, 1732, 1690, 1451, 1368, 1267, 1155 and 1031 cm−1; 1H-NMR (500 MHz, CDCl3):
δ 8.01–7.27 (m, 5H, Ph), 4.29–4.20 (m, 2H, CH2CH3), 4.06 (t, 1H, JHC,CH =7.1, HC), 3.64 (d, 2H,
2
CH2COPh), 1.30 (t, 6H, 3JH,H=7.1, 2CH2CH3) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 196.5 (COPh),
169.0 (2C, 2CO2Et), 136.4–128.1 (6C, Ph), 61.7 (2C, 2CH2CH3), 47.1 (HC), 37.7 (CH2COPh), 13.9
(2C, 2CH2CH3) ppm; HREIMS m/z obsd 278.1152, calcd for C15H18O5 278.1154.
3.2.2. Diethyl p-chlorophenacylmalonate 2
v=2 mL. Column chromatography (ether:hexane=1:4) of the residue gave an oil (1.65 g, 80%); IR νmax
3094, 2984, 2936, 1738, 1690, 1454, 1368, 1275, 1179 and 1032 cm−1; 1H-NMR (300 MHz, CDCl3):
δ 7.96–7.42 (m, 4H, Ph), 4.27, 4.26 (each q, each 2H, 3JH,H=7.1, 2CH2CH3), 4.07 (t, 1H, JHC,CH =7.1,
2

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2525
HC), 3.61 (d, 2H, CH2COPh), 1.31 (t, 6H, 2CH2CH3) ppm; 13C-NMR (75.4 MHz, CDCl3): δ 195.3
(COPh), 168.8 (2C, 2CO2Et), 140.3–128.9 (6C, Ph), 61.7 (2C, 2CH2CH3), 47.0 (HC), 36.7 (CH2COPh),
13.9 (2C, 2CH2CH3) ppm; HREIMS m/z obsd 312.0780, calcd for C15H17O5Cl 312.0765.
3.2.3. Diethyl acetonylmalonate 3
v=1 mL. Column chromatography (ether:hexane=1:4) of the residue gave an oil (0.60 g, 42%); IR
1
νmax 2986, 2940, 1738, 1458, 1366, 1271, 1159 and 1024 cm−1; H-NMR (300 MHz, CDCl3): δ 4.20
3
(q, 4H, JH,H=7.1, 2CH2CH3), 3.85 (t, 1H, JHC,CH =7.1, HC), 3.06 (d, 2H, CH2COCH3), 2.21 (s, 3H,
2
CH2COCH3), 1.27 (t, 6H, 2CH2CH3) ppm; 13C-NMR (75.4 MHz, CDCl3): δ 204.8 (COCH3), 168.7
(2C, 2CO2Et), 61.6 (2C, 2CH2CH3), 46.8 (HC), 41.9 (CH2COPh), 29.6 (COCH3), 13.9 (2C, 2CH2CH3)
ppm; HREIMS m/z obsd 216.1004, calcd for C10H16O5 216.0998.
3.2.4. Phenacyl malonodinitrile 4
v=2 mL. Column chromatography (dichloromethane) of the residue gave a white solid (0.79 g, 65%)
which gradually becomes brown at room temperature. This brown impurity could be removed by further
column chromatography (ether:hexane=1:1); IR νmax 3054, 2907, 1732, 2255, 1682, 1589, 1447, 1358
1
and 1217 cm−1; H-NMR (300 MHz, CDCl3): δ 8.03–7.56 (m, 5H, Ph), 4.48 (t, 1H, JHC,CH =6.8,
2
HC), 3.84 (d, 2H, CH2) ppm; 13C-NMR (75.4 MHz, CDCl3): δ 192.2 (COPh), 134.7–128.0 (6C, Ph),
112.3 (2C, 2CN), 39.4 (CH2COPh), 17.6 (HC) ppm; HREIMS m/z obsd 184.0635, calcd for C11H8ON2
184.0637.
3.3. Diethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl-aminothiocarbonyl malonate 6
To a stirred solution of 511 (0.50 mg, 1.28 mmol) in dry DMF (4 mL) under argon at 40°C, diethyl
malonate (0.19 mL, 1.28 mmol) and KOH (1.28 mmol) were added. The mixture was stirred for 1 h at
40°C, then diluted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated
to dryness. The resulting product was purified by recrystallization (ether:hexane). 6 was obtained as a
crystalline solid (0.43 mg, 61%) which had mp 101–102°C (ether:hexane); [α] +52 (c 1.0); IR νmax
3308, 2982, 2942, 1750, 1537, 1420, 1370, 1225 and 1040 cm−1; 1H-NMR (500 MHz, CDCl3): δ 9.55
(d, 1H, JNH,1=8.1, NH), 5.75 (dd, 1H, J1,2=9.5, H-1), 5.35 (t, 1H, J2,3=J3,4=9.5, H-3), 5.21 (t, 1H, H-
2), 5.12 (t, 1H, J4,5=9.5, H-4), 4.97 (s, 1H, CH), 4.31–4.21 (m, 5H, H-6a and 2CH2CH3), 4.11 (dd,
1H, J5,6b=2.1, J6a,6b=12.5, H-6b), 3.86 (ddd, 1H, J5,6a=4.5, H-5), 2.09, 2.08, 2.04, 2.03 (each s, each
3
3H, 4Ac), 1.31, 1.28 (each t, each 3H, JH,H=7.1, 2CH2CH3) ppm; 13C-NMR (125.7 MHz, CDCl3):
δ 193.7 (C_S), 170.5, 170.4, 169.7, 169.3 (4COCH3), 165.0, 164.0 (2CO2Et), 81.7 (C-1), 73.7 (C-5),
72.4 (C-3), 69.8 (C-2), 68.0 (C-4), 66.2 (CH), 62.8, 62.7 (2CH2CH3), 61.4 (C-6), 20.5, 20.2 (2COCH3),
20.4 (2C, 2COCH3), 13.8 and 13.6 (2CH2CH3) ppm; FABMS m/z 572 (100, [M+Na]+·). Anal. calcd for
C22H31O13NS: C, 48.08; H, 5.69; N, 2.55; S, 5.83. Found: C, 47.94; H, 5.60; N, 2.66; S, 5.66.
3.4. General procedure for the preparation of 7–10
To a stirred solution of 0.26 mmol 1 for 7, 2 for 8, or 3 for 9 and 10 in v mL of dry DMF over
molecular sieves and under nitrogen, 0.31 mmol of NaH (as a suspension in mineral oil) was added. After
5 min, 0.26 mmol of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate 5 was added dropwise as
a solution in 0.75 mL of dry DMF over molecular sieves and under nitrogen onto the carbanion. The
mixture was stirred at 30°C for t min, then diluted with ether, washed with water, dried (MgSO4), filtered
and evaporated to dryness.

2526
J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
3.4.1. N-(20,30,40,60-Tetra-O-acetyl-β-D-glucopyranosyl)-2,2-diethoxycarbonyl-4-phenyl-4-oxo-
thiobutanamide 7
Column chromatography (ether:hexane=1:1 and 3:1) of the residue gave a white amorphous solid
(69 mg, 40%) which had [α] +39 (c 1.0); IR νmax 3214, 3030, 2980, 2942, 1751, 1688, 1537, 1452,
1370, 1225 and 1042 cm−1; 1H-NMR (0300 MHz, CDCl3): δ 11.21 (d, 1H, JNH,1 =8.2, NH), 7.98–7.27
0
0
0
0
0
0
(m, 5H, Ph), 5.83 (t, 1H, J1 ,2 =8.2, H-1 ), 5.37–5.30 (m, 2H, H-2 , 3 ), 5.15 (m, 1H, H-4 ), 4.70 (d, 1H,
J
3a,3b=18.6, C-3a), 4.33–4.20 (m, 5H, H-60a and 2CH2CH3), 4.29 (d, 1H, C-3b), 4.09 (dd, 1H, J5 ,6 b=2.3,
0 0
J6 a,6 b=12.4, H-60b), 3.83 (ddd, 1H, J4,5=10.0, J5 ,6 a=4.6, H-5), 2.09, 2.06 (each s, each 3H, 2Ac), 2.03
0
0
0
0
3
(s, 6H, 2Ac), 1.22, 1.19 (each t, each 3H, JH,H=7.1, 2CH2CH3) ppm; 13C-NMR (75.4 MHz, CDCl3):
δ 199.9 (C-4), 196.5 (C-1), 170.6, 170.0, 169.9, 169.4 (4COCH3), 168.0, 166.2 (2CO2Et), 135.9–128.1
(6C, Ph), 81.9 (C-10), 73.9 (C-50), 73.0, 69.9 (C-20, 30), 68.3 (C-40), 65.4 (C-2), 63.0, 62.9 (2CH2CH3),
61.6 (C-60), 47.1 (C-3), 20.6, 20.4 (2COCH3), 20.5 (2C, 2COCH3), 13.6, 13.5 (2CH2CH3) ppm; FABMS
m/z 690 (100, [M+Na]+·). Anal. calcd for C30H37O14NS: C, 53.97; H, 5.59; N, 2.10; S, 4.80. Found: C,
53.97; H, 5.51; N, 2.21; S, 5.18.
3.4.2. N-(20,30,40,60-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(4-chlorophenyl)-2,2-diethoxycarbonyl-
4-oxo-2-thiobutanamide 8
Column chromatography (ether:hexane=1:1 and 3:1) of the residue gave a white amorphous solid
(108 mg, 59%) which had [α] +45 (c 1.0); IR νmax 3206, 3041, 2984, 2942, 1755, 1684, 1539, 1368,
1
1225 and 1038 cm−1; H-NMR (300 MHz, CDCl3): δ 11.15 0(d, 01H, JNH,1 =8.2, NH), 7.93–7.40 (m,
0
0
0
0
0
0
0
0
4H, Ar), 5.82 (t, 1H, J1 ,2 =8.2, H-1 ), 5.37–5.27 (m, 2H, H-2 , 3 ), 5.15 (t, 1H, J3 ,4 =J4 ,5 =10.0, H-
40), 4.66, 4.25 (each d, each 1H, J3a,3b=18.6, H-3a, 3b), 4.24 (dd, 1H, J5 ,6 a=4.6, J6 a,6 b=12.4, H-60a),
0
0
0
0
4.24 (q, 4H, JH,H=7.1, 2CH2CH3), 4.09 (dd, 1H, J5 ,6 b=2.3, H-60b), 3.83 (ddd, 1H, H-50), 2.09, 2.07
(each s, each 3H, 2Ac), 2.04 (s, 6H, 2Ac), 1.23, 1.20 (each t, each 3H, 2CH2CH3) ppm; 13C-NMR (75.4
MHz, CDCl3): δ 199.6 (C-4), 195.4 (C-1), 170.5, 169.4 (2COCH3), 169.9 (2C, 2COCH3), 167.8, 166.0
(2CO2Et), 140.0–128.9 (6C, Ar), 81.9 (C-10), 73.8 (C-50), 72.9, 70.4 (C-20, 30), 68.2 (C-40), 65.3 (C-2),
63.0, 62.9 (2CH2CH3), 61.6 (C-60), 46.9 (C-3), 20.6, 20.4 (2COCH3), 20.5 (2C, 2COCH3), 13.5 and
13.4 (2CH2CH3) ppm; FABMS m/z 724 (100, [M+Na]+·). Anal. calcd for C30H36O14NSCl: C, 51.32; H,
5.17; N, 1.99; S, 4.57. Found: C, 51.21; H, 4.99; N, 2.05; S, 4.58.
3
0
0
3.4.3. N-(20,30,40,60-Tetra-O-acetyl-β-D-glucopyranosyl)-2,2-diethoxycarbonyl-4-oxothiopentanamide
(9) and 2(R,S)-4,4-diethoxycarbonyl-2-hydroxy-2-methyl-1-(20 ,30,40,60-tetra-O-acetyl-β-D-gluco-
pyranosyl)-5-thioxopyrrolidine 10
Column chromatography (ether:hexane=3:1) of the residue gave a white amorphous solid 9+10 (58
mg, 37%).
Compound 9: 1H-NMR (500 MHz, CDCl3): δ 10.80 (d,01H, JNH,1 =7.7, NH), 5.78 (dd, 1H, J1 ,2 =9.5,
0
0
0
H-10), 5.39 (t, 1H, J2 ,3 =J3 ,4 =9.5, H-3 ), 5.24 (t, 1H, H-2 ), 5.12 (t, 1H, J4 ,5 =9.5, H-4 ), 4.30–4.18 (m,
4H, H-60a, 60b and CH2CH3), 3.86–3.83 (m, 1H, H-50), 2.95–2.75 (m, 2H, H-3a, 3b), 2.09, 2.06, 2.02,
1.92 (each s, each 3H, 4Ac), 1.73 (s, 1H, CH3COCH2), 1.26 (t, 6H, 3JH,H=7.10, 2CH2CH3) ppm.
0
0
0
0
0
0
0
0
Compound 10: 1H-NMR (500 MHz, CDCl3): δ 6.38 (d, 1H, J1 ,2 =9.5, H-1 ), 5.35, 5.33 (each t, each
0
0
0
0
0
0
0
0
0
0
0
0
0
1H, J2 ,3 =J3 ,4 =9.5, H-2 , 3 ), 5.15 (t, 1H, J4 ,5 =9.5, H-4 ), 4.30–4.18 (m, 4H, H-6 a, 6 b and CH2CH3),
3.81 (dt, 1H, J5 ,6 a=J5 ,6 b=3.3, H-50), 2.81–2.76 (m, 2H, H-3a, 3b), 2.07, 2.04, 2.01, 1.98 (each s, each
0
0
0
0
3
3H, 4Ac), 1.62 (s, 1H, CH3COCH2), 1.29 (t, 6H, JH,H=7.1, 2CH2CH3) ppm; 13C-NMR (125.7 MHz,
CDCl3) δ 199.7, 195.8 (2CS), 171.9–166.0 (12C, 4CO2Et and 8COCH3), 84.2, 83.7 (2C-10), 75.6, 74.9
(2C-50), 73.0, 71.9 (2C-20), 72.3, 70.4 (2C-30), 67.9, 67.6 (2C-40), 96.7, 95.2 (2C-2), 70.9, 70.2 (2C-4),
63.0–60.9 (2C-60 and 4CH2CH3), 46.7, 44.9 (2C-3), 27.3, 25.0 (2CH3), 20.7–20.2 (8C, 8COCH3), 13.8,

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2527
13.7 (4C, 4CH2CH3) ppm; FABMS m/z 628 (100, [M+Na]+·). HRFABMS m/z obsd 628.1665, calcd for
C25H35O14NSNa 628.1676. Anal. calcd for C25H35O14NS: C, 49.58; H, 5.83; N, 2.31; S, 5.29. Found:
C, 48.91; H, 5.47; N, 2.45; S, 5.25.
3.5. General procedure for the preparation of 11–13
The starting material (7 for 11, 8 for 12 or 9 for 13, 0.34 mmol) was dissolved in 3.4 mL of acetic
anhydride and 0.17 mL of melted anhydrous H3PO4. The mixture was stirred at r.t. for t hours and
then poured into ice–water, extracted with ether, washed with saturated aqueous NaHCO3 and water,
dried (MgSO4) and concentrated. The residue was taken up in 96% ethanol and treated with basic resin
Amberlist IR-45(OH), filtered and evaporated. The residue was purified by column chromatography
(ether:hexane=3:1).
3.5.1. 4,4-Diethoxycarbonyl-2-phenyl-1-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosyl)-5-thioxo-
2-pyrroline 11
White and amorphous solid (168 mg, 76%); t=12 h; [α] −7 (c 0.9); IR νmax 3067, 2980, 1750, 1653,
1447, 1371, 1225 and 1040 cm−1; 1H-NMR (500 MHz, CDCl3): δ 7.52–7.39 (m, 5H, Ph), 6.22 (s, 1H,
0
0
0
0
0
0
0
0
0
0
0
H-3), 5.32 (t, 1H, J2 ,3 =J3 ,4 =8.9, H-3 ), 5.23 (dd, 1H, J1 ,2 =8.6, H-2 ), 5.20 (t, 1H, J4 ,5 =8.9, H-4 ),
4.77 (d, 1H, H-10), 4.32–4.24 (m, 5H, H-60a and 2CH2CH3), 4.20 (dd, 1H, J5 ,6 b=2.2, J6 a,6 b=12.3,
0
0
0
0
H-60b), 3.86 (ddd, 1H, J5 ,6 a=5.1, H-50), 2.09, 2.05, 2.01, 1.97 (each s, each 3H, 4Ac), 1.29, 1.28 (each
0
0
t, each 3H, JH,H=7.0, 2CH2CH3) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 170.7, 170.3, 169.3, 168.9
3
(4COCH3), 166.3 (C-5), 165.3, 165.2 (2CO2Et), 142.4 (C-2), 132.1–126.4 (6C, Ph), 115.0 (C-3), 92.0
(C-10), 76.9 (C-4), 73.7 (C-50), 73.5 (C-30), 71.4 (C-20), 68.4 (C-40), 62.9, 62.8 (2CH2CH3), 62.1 (C-60),
20.7 (COCH3), 20.5 (3C, 3COCH3), 13.9 and 13.8 (2CH2CH3) ppm; FABMS m/z 672 (100, [M+Na]+·).
Anal. calcd for C30H35O13NS: C, 55.46; H, 5.43; N, 2.16; S, 4.94. Found: C, 55.43; H, 5.20; N, 2.17; S,
5.08.
3.5.2. 2-(4-Chlorophenyl)-4,4-diethoxycarbonyl-1-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosyl)-5-
thioxo-2-pyrroline 12
White and amorphous solid (156 mg, 67%); t=10 h; [α] +54 (c 0.7); IR νmax 3075, 2980, 1753, 1655,
1437, 1371, 1225 and 1040 cm−1; 1H-NMR (300 MHz, CDCl3): δ 7.042–7.40 (m, 4H, Ar), 6.22 (s,01H, H-
0
0
0
0
0
0
0
0
0
3), 5.32 (t, 1H, J2 ,3 =J3 ,4 =9.3, H-3 ), 5.22 (dd, 1H, J1 ,2 =8.4, H-2 ), 5.19 (t, 1H, J4 ,5 =9.3, H-4 ), 4.77
(d, 1H, H-10), 4.32–4.24 (m, 4H, H-60a), 4.29 (q, 4H, 3JH,H=7.1, 2CH2CH3), 4.20 (dd, 1H, J5 ,6 b=2.4,
0
0
J
6 a,6 b=12.4, H-60b), 3.86 (ddd, 1H, J5 ,6 a=4.6, H-50), 2.09, 2.05, 2.01, 1.97 (each s, each 3H, 4Ac),
0 0 0 0
1.29, 1.28 (each t, each 3H, 2CH2CH3) ppm; 13C-NMR (125.7 MHz, DMSO-d6): δ 170.0, 169.6, 169.3,
168.6 (4COCH3), 164.8, 164.8 (2CO2Et), 164.7 (C-5), 140.3 (C-2), 134.5–128.1 (6C, Ar), 116.4 (C-3),
91.3 (C-10), 76.7 (C-4), 72.5 (C-50), 72.3 (C-30), 71.2 (C-20), 68.0 (C-40), 62.5, 62.4 (2CH2CH3), 61.8
(C-60), 20.5, 20.4 (2COCH3), 20.3 (2C, 2COCH3), 13.7, 13.6 (2CH2CH3) ppm; FABMS m/z 706 (100,
[M+Na]+·). Anal. calcd for C30H34O13NSCl: C, 52.67; H, 5.01; N, 2.05; S, 4.69. Found: C, 52.49; H,
4.94; N, 2.40; S, 4.59.
3.5.3. 5-Acetyl-3,3-diethoxycarbonyl-1,2,3,4-tetrahydro-1-(20 ,30,40,60-tetra-O-acetyl-β-D-gluco-
pyranosyl)-2-thioxopyridine 13
Amorphous solid (139 mg, 65%); t=7 h; [α] −20 (c 0.4); IR νmax 2978, 1753, 1690, 1605, 1439,
1
0
1371, 1223, 1098 and 1040 cm−1; H-NMR (500 MHz, CDCl3): δ 6.60 (d, 1H, J1 ,2 =9.6, H-1 ), 6.49
0
0
0
0
0
0
0
0
0
0
(dd, 1H, H-6), 5.66 (t, 1H, J2 ,3 =9.6, H-2 ), 5.42 (t, 1H, J3 ,4 =9.6, H-3 ), 5.25 (t, 1H, J4 ,5 =9.6, H-

2528
J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
40), 4.39 (dd, J5 ,6 a=3.7, J6 a,6 b=12.7, H-60a), 4.33–4.21 (m, 4H, 2CH2CH3), 4.17 (dd, 1H, J5 ,6 b=2.0,
H-60b), 3.93 (ddd, 1H, H-50), 4.03 (dd, 1H, J4a,4b=19.1, J4a,6=1.7, H-4a), 3.75 (dd, 1H, J4b,6=2.2, H-
4b), 2.33 (s, 3H, _CCOCH3), 2.13, 2.08, 2.04, 1.94 (each s, each 3H, 4Ac), 1.30, 1.29 (each t, each
0
0
0
0
0
0
3H, JH,H=7.1, 2CH2CH3) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 199.6 (_CCOCH3), 196.7 (C-2),
3
170.1, 169.6 (2COCH3), 169.3 (2C, 2COCH3), 166.4, 165.8 (2CO2Et), 152.9 (C-5), 105.1 (C-6), 83.1
(C-10), 74.8 (C-50), 72.8 (C-30), 69.9 (C-3), 67.2 (C-20), 66.9 (C-40), 62.8, 62.7 (2CH2CH3), 61.1 (C-60),
36.6 (C-4), 32.1 (_CCOCH3), 20.4, 20.0 (2COCH3), 20.3 (2C, 2COCH3), 13.7, 13.6 (2CH2CH3) ppm;
FABMS m/z 652 (100, [M+Na]+·). Anal. calcd for C27H35O14NS: C, 51.50; H, 5.60; N, 2.22; S, 5.09.
Found: C, 50.29; H, 5.71; N, 2.64; S, 5.47.
3.6. General procedure for the reaction of 5 with cyanocarbanions
To a stirred solution of 0.26 mmol of ethyl cyanoacetate for 18, phenylthioacetonitrile for 19 and 20,
cyanoacetamide for 21, malononitrile for 22, or 4 for 25 and 26 in 0.75 mL of dry DMF at 30°C and under
nitrogen, 0.33 mmol of NaH (as a suspension in mineral oil) was added. After 5 min, 5 (0.26 mmol) was
dropped, as a solution in 0.75 mL of dry DMF under nitrogen onto the carbanion. The mixture was stirred
at 30°C for t1 min, then 0.26 mmol of phenacyl bromide was added and stirred for t2 min. The mixture
was poured into saturated aqueous NH4Cl, extracted with ether (except for the case of 21, which was
extracted with dichloromethane), washed with water, dried (MgSO4), filtered and evaporated to dryness.
3.6.1. (E)-Ethyl 2-cyano-3-phenacylthio-3-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosylamino)
acrylate 18
t1=t2=10 min. Column chromatography (ether:hexane=3:1) of the residue gave an amorphous solid
(150 mg, 93%); [α] +15 (c 1.0); IR νmax 3192, 3063, 2982, 2212, (CN), 1770, 1684 (CO of phenacyl),
1582, 1439, 1370, 1260, 1084 and 1032 cm−1; 1H-NMR (500 MHz, CDCl3): δ 10.32 (d, 1H, J0NH,1 =7.8,
0
0
0
0
0
0
0
0
NH), 7.98–7.50 (m, 5H, Ph), 5.59 (dd, 1H, J1 ,2 =9.4, H-1 ), 5.35 (t, 1H, J2 ,3 =J3 ,4 =9.4, H-3 ), 5.21 (t,
1H, H-20), 5.09 (t, 1H, J4 ,5 =9.4, H-4 ), 4.96, 4.63 (each d, each 1H, JH,H=17.1, CH2COPh), 4.23 (dd,
0
2
0
0
1H, J5 ,6 a=4.8, J6 a,6 b=12.4, H-60a), 4.23 (q, 2H, 3JH,H=7.1, CH2CH3), 4.08 (dd, 1H, J5 ,6 b=2.2, H-60b),
3.85 (ddd, 1H, H-50), 2.09, 2.06 (each s, each 3H, 2Ac), 2.04 (s, 6H, 2Ac), 1.30 (t, 3H, CH2CH3) ppm;
13C-NMR (125.7 MHz, CDCl3): δ 191.8 (COPh), 170.5, 169.9, 169.8, 169.7, 169.3, 166.3 (4COCH3,
CO2Et and C-3), 134.8–128.4 (6C, Ph), 117.3 (CN), 82.8 (C-10), 81.5 (C-2), 73.3 (C-50), 72.7 (C-30),
69.9 (C-20), 68.1 (C-40), 61.5 (2C, C-60 and CH2CH3), 42.7 (CH2COPh), 20.6, 20.4 (2COCH3), 20.5 (2C,
2COCH3), 14.1 (CH2CH3) ppm; FABMS m/z 643 (100, [M+Na]+·). Anal. calcd for C28H32O12N2S: C,
54.19; H, 5.20; N, 4.51. Found: C, 54.63; H, 5.79; N, 4.47.
0
0
0
0
0
0
3.6.2. (Z)-3-Phenacylthio-2-phenylthio-3-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosylamino)
acrylonitrile 19 and 3-amino-2-benzoyl-4-phenylthio-5-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosyl-
amino)thiophene 20
t1=t2=30 min. Column chromatography (ether:hexane=2:1) of the residue gave 19 (56 mg, 33%) and
20 (29 mg, 17%).
19: [α] −4 (c 0.3); IR νmax 3312, 3059, 2953, 2195 (CN), 1746, 1709 (CO of phenacyl), 1549, 1452,
1
1371, 1227 and 1036 cm−1; H-NMR (500 MHz, CDCl3): δ 8.04–7.08 (m, 11H, NH and 2Ph), 5.42
0
0
0
0
0
0
0
0
0
(dd, 1H, JNH,1 =8.3, J1 ,2 =9.4, H-1 ), 5.32 (t, 1H, J2 ,3 =J3 ,4 =9.4, H-3 ), 5.04, 5.00 (each t, each 1H,
0
0
2
0
0
0
0
J4 ,5 =9.4, H-2 , 4 ), 4.96, 4.48 (each d, each 1H, JH,H=16.9, CH2COPh), 4.22 (dd, 1H, J5 ,6 a=4.8,
0
0
0
0
J
6 a,6 b=12.4, H-60a), 4.04 (dd, 1H, J5 ,6 b=2.2, H-60b), 3.79 (ddd, 1H, H-50), 2.04, 2.02, 2.01, 1.78 (each
s, each 3H, 4Ac) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 192.3 (COPh), 170.7, 170.6, 170.4, 169.7,

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2529
169.3 (C-3 and 4COCH3), 134.8–125.7 (12C, 2Ph), 119.2 (CN), 83.3 (C-10), 79.2 (C-2), 73.0 (C-50),
72.4 (C-30), 69.9 (C-20), 68.2 (C-40), 61.5 (C-60), 42.0 (CH2COPh), 20.5, 20.4, 20.0, 19.9 (4COCH3)
ppm; FABMS m/z 679 (100, [M+Na]+·). Anal. calcd for C31H33O10N2S2: C, 56.61; H, 5.06; N, 4.26; S,
9.75. Found: C, 56.30; H, 5.02; N, 4.20; S, 9.40.
20: [α] −11 (c 0.7); IR νmax 3322 (NH), 3057, 2918, 2851, 1748, 1460, 1371, 1227 and 1036 cm−1
;
1H-NMR (500 MHz, CDCl3): δ 7.76–7.06 (m, 10H, 2Ph), 6.54 (d, 1H, JNH,1 =9.5, NH), 5.29 (t, 1H,
0
0
0
0
0
0
0
0
0
0
0
0
0
J2 ,3 =J3 ,4 =9.5, H-3 ), 5.01 (t, 1H, J4 ,5 =9.5, H-4 ), 4.99 (t, 1H, J1 ,2 =9.5, H-2 ), 4.65 (t, 1H, H-1 ),
4.21 (dd, 1H, J5 ,6 a=5.5, J6 a,6 b=12.4, H-60a), 4.08 (dd, 1H, J5 ,6 b=2.3, H-60b), 3.79 (ddd, 1H, H-50),
2.02, 2.00, 1.88, 1.68 (each s, each 3H, 4Ac) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 186.1 (COPh),
170.8, 170.5, 169.8, 169.4 (4COCH3), 162.7, 157.8 (2C, thiophene ring), 140.1–125.7 (12C, 2Ph), 97.8,
95.1 (2C, thiophene ring), 84.9 (C-10), 73.1 (C-50), 72.1 (C-30), 70.4 (C-20), 68.3 (C-40), 61.6 (C-60),
20.4 (2C, 2COCH3), 20.3, 19.9 (2COCH3) ppm; HREIMS m/z obsd 656.1510, calcd for C31H32O10N2S2
656.1498.
0
0
0
0
0
0
3.6.3. 3-Amino-2-benzoyl-4-carbamoyl-5-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosylamino)
thiophene 21
t1=15 min, t2=30 min. Column chromatography (dichloromethane:methanol=40:1) of the residue gave
21 (71 mg, 46%) as an amorphous solid which had [α] −58 (c 0.7); IR νmax 3443 (NH), 3287, 3061,
1
2951, 1753, 1657, 1466, 1371, 1225 and 1036 cm−1; H-NMR (500 MHz, CDCl3): δ 8.66 (d, 1H,
0
0
0
0
0
0
JNH,1 =9.5, NH), 7.69–7.45 (m, 5H, Ph), 5.75 (s, 2H, NH2), 5.33 (t, 1H, 0J2 ,3 =J3 ,4 =9.5, H-3 ), 5.12
J
0
0
0
0
0
0
0
0
(t, 1H, J1 ,2 =9.5, H-2 ), 5.05 (t, 1H, J4 ,5 =9.5, H-4 ), 4.66 (t, 1H, H-1 ), 4.19 (dd, 1H, J5 ,6 a=5.4,
6 a,6 b=12.4, H-60a), 4.09 (dd, 1H, J5 ,6 b=2.2, H-60b), 3.78 (ddd, 1H, H-50), 2.07, 2.04, 2.03, 1.87 (each
0 0 0 0
s, each 3H, 4Ac) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 187.1 (COPh), 170.4, 170.2, 169.9, 169.3
(4COCH3), 164.9, 155.9 (2C, thiophene ring), 141.2–127.2 (6C, Ph), 103.2, 98.8 (2C, thiophene ring),
84.5 (C-10), 73.2 (C-50), 72.4 (C-30), 70.6 (C-20), 68.2 (C-40), 61.6 (C-60), 20.5, 20.3 (2COCH3), 20.4
(2C, 2COCH3) ppm; FABMS m/z 614 (100, [M+Na]+·). Anal. calcd for C26H29O11N3S: C, 52.79; H,
4.94; N, 7.10; S, 5.42. Found: C, 52.64; H, 5.10; N, 6.96; S, 5.84.
3.6.4. 3-Amino-2-benzoyl-4-cyano-5-(20 ,30,40,60-tetra-O-acetyl-β-D-glucopyranosylamino)thiophene
22
t1=15 min, t2=10 min. Column chromatography (ether:hexane=6:1) of the residue gave 22 (136 mg,
91%) as an amorphous solid which had [α] −103 (c 0.5); IR νmax 3424 (NH), 3302, 3055, 2951, 2212
1
(CN), 1753, 1597, 1478, 1371, 1221 and 1040 cm−1; H-NMR (500 MHz, CDCl3): δ 7.70–7.43 (m,
0
0
0
0
0
5H, Ph), 7.10–6.85 (bs, 2H, NH2), 6.77 (d, 1H, JNH,1=9.5, NH), 5.34 (t, 1H, J2 ,3 =J3 ,4 =9.5, H-3 ),
0
0
0
0
0
0
0
0
0
5.07 (t, 1H, J4 ,5 =9.5, H-4 ), 5.03 (t, 1H, J1 ,2 =9.5, H-2 ), 4.77 (t, 1H, H-1 ), 4.24 (dd, 1H, J5 ,6 a=5.2,
J
6 a,6 b=12.5, H-60a), 4.12 (dd, 1H, J5 ,6 b=2.1, H-60b), 3.84 (ddd, 1H, H-50), 2.11, 2.04, 2.03, 1.91 (each
0 0 0 0
s, each 3H, 4Ac) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 186.5 (COPh), 171.4, 170.4, 169.8, 169.3
(4COCH3), 164.5, 157.8 (2C, thiophene ring), 140.1–127.1 (6C, Ph), 112.6 (CN), 97.0 (1C, thiophene
ring), 84.4 (C-10), 82.2 (1C, thiophene ring), 73.0 (C-50), 72.1 (C-30), 70.9 (C-20), 67.9 (C-40), 61.5 (C-
60), 20.6, 20.4 (2COCH3), 20.5 (2C, 2COCH3) ppm; FABMS m/z 596 (100, [M+Na]+·). Anal. calcd for
C26H27O10N3S: C, 54.44; H, 4.74; N, 7.33; S, 5.59. Found: C, 54.04; H, 4.95; N, 7.29.
3.6.5. 3R(S) and 3S(R)-4-Amino-5-benzoyl-3-cyano-2,3-dihydro-3-phenacyl-2-(20 ,30,40,60-tetra-O-
acetyl-β-D-glucopyranosylimino)thiophene 25 and 26
t1=t2=20 min. Column chromatography (ether:hexane=2:1 and 4:1) of the residue gave 25 (22 mg,
12%) and 26 (40 mg, 22%).

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J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
25: [α] −135 (c 0.6); IR νmax 3395 (NH), 3283, 3063, 2955, 2208 (CN), 1751, 1684, 1613, 1481,
1
1371, 1227 and 1040 cm−1; H-NMR (500 MHz, CDCl3): δ 8.41 (bs, 2H, NH2), 8.06–7.26 (m, 10H,
0
0
0
0
0
0
0
0
0
0
0
2Ph), 5.32 (t, 1H, J2 ,3 =J3 ,4 =9.5, H-3 ), 5.15 (t, 1H, J1 ,2 =9.5, H-2 ), 5.08 (t, 1H, J4 ,5 =9.5, H-4 ),
4.88 (d, 1H, H-10), 4.20 (dd, 1H, J5 ,6 a=5.7, J6 a,6 b=12.3, H-60a), 4.18 (d, 1H, 2JH,H=18.6, CHHCOPh),
0
0
0
0
4.10 (dd, 1H, J5 ,6 b=2.2, H-60b), 3.88 (d, 1H, CHHCOPh), 3.82 (ddd, 1H, H-50), 2.04 (s, 6H, 2Ac),
2.03, 1.79 (each s, each 3H, 2Ac) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 195.5 (CH2COPh), 189.3
(COPh), 170.5, 170.1, 170.0, 169.5 (4COCH3), 165.4, 162.6, 153.5 (3C, thiophene ring), 140.0–127.0
(12C, 2Ph), 115.5 (CN), 97.3 (1C, thiophene ring), 89.2 (C-10), 74.1 (C-50), 72.8 (C-30), 71.2 (C-20), 68.5
(C-40), 62.1 (C-60), 48.5 (CH2Ph), 20.8, 20.6, 20.5, 20.4 (4COCH3) ppm; HREIMS m/z obsd 691.1857,
calcd for C34H33O11N3S 691.1836.
0
0
26: [α] +89.2 (c 0.7); IR νmax 3368 (NH), 3298, 3059, 2957, 2185 (CN), 1759, 1694, 1620, 1481,
1
1371, 1229 and 1036 cm−1; H-NMR (500 MHz, CDCl3): δ 8.36 (bs, 2H, NH2), 8.04–7.26 (m, 10H,
0
0
0
0
0
0
0
0
0
0
0
2Ph), 5.31 (t, 1H, J2 ,3 =J3 ,4 =9.5, H-3 ), 5.20 (t, 1H, J1 ,2 =9.5, H-2 ), 5.12 (t, 1H, J4 ,5 =9.5, H-4 ),
4.71 (d, 1H, H-10), 4.25 (dd, 1H, J5 ,6 a=5.1, J6 a,6 b=12.6, H-60a), 4.24 (d, 1H, 2JH,H=18.4, CHHCOPh),
0
0
0
0
4.15 (dd, 1H, J5 ,6 b=2.2, H-60b), 3.82 (ddd, 1H, H-50), 3.81 (d, 1H, CHHCOPh), 2.03, 2.01, 2.00, 1.99
(each s, each 3H, 4Ac) ppm; 13C-NMR (125.7 MHz, CDCl3): δ 194.4 (CH2COPh), 189.0 (COPh), 170.8,
170.2, 169.5, 169.4 (4COCH3), 166.7, 162.6, 153.6 (3C, thiophene ring), 139.8–126.9 (12C, 2Ph), 115.0
(CN), 95.5 (1C, thiophene ring), 90.5 (C-10), 73.7 (C-50), 73.0 (C-30), 71.7 (C-20), 68.2 (C-40), 61.9 (C-
60), 48.1 (CH2Ph), 20.9, 20.7 (2COCH3), 20.6 (2C, 2COCH3) ppm; HREIMS m/z obsd 691.1872, calcd
for C34H33O11N3S 691.1836.
0
0
3.7. General deacetylation method
The acetylated product (0.48 mmol) was dissolved in 6 mL of anhydrous methanol at r.t. and 1.0 mmol
of NaOMe was added with stirring to the solution. The process was controlled by TLC (ether:hexane=6:1
and dichloromethane:methanol=4:1) until total deacylation of the starting material. After t min, the
reaction mixture was neutralized with acid resin Amberlite IR-120(H), filtered and the solvent evaporated
under reduced pressure. The following products were prepared in this manner.
3.7.1. Diethyl β-D-glucopyranosylaminothiocarbonyl malonate 27
t=15 min. In this case, the ratio NaOMe/6, was three times that of the general method. 13C-NMR (75.4
MHz, DMSO-d6): δ 194.3 (CS), 164.9 (2C, 2CO2Et), 83.6 (C-10), 79.0 (C-50), 77.5 (C-30), 72.4 (C-20),
69.7 (C-40), 64.8 (CH), 61.6 (2C, 2CH2), 60.5 (C-60) ppm; FABMS m/z 404 (100, [M+Na]+·). HRCIMS
m/z obsd 381.1060, calcd for C14H23O9NS+H 381.1094.
3.7.2. 4-Ethoxycarbonyl-1-(β-D-glucopyranosyl-2-phenyl-5-mercapto-2-pyrrole 28
t=15 min. This compound was not isolated pure. 13C-NMR (125.7 MHz, MeOH-d4): δ 166.6–162.4
(C-5, CO2Et), 135.4–126.7 (6C, Ph), 122.2 (C-4), 109.2 (C-2), 89.0 (C-10), 85.4 (C-3), 79.3 (C-50), 78.9
(C-30), 74.8 (C-20), 71.6 (C-40), 62.7 (C-60), 61.1 (COCH2CH3), 14.8 (COCH2CH3) ppm; FABMS m/z
432 (100, [M+Na]+·). HRDCIMS m/z obsd 410.1292, calcd for C19H23O7NS+H 410.1273.
3.7.3. 2-Chlorophenyl-4-ethoxycarbonyl-1-(β-D-glucopyranosyl)-5-mercapto-pyrrole 29
t=20 min. 13C-NMR (125.7 MHz, MeOH-d4): δ 166.5, 164.0 (C-5, CO2Et), 134.2–126.3 (6C, Ph),
122.5 (C-4), 109.2 (C-2), 88.9 (C-10), 85.4 (C-3), 79.4, 78.9 (C-30, 50), 74.7 (C-20), 71.5 (C-40), 62.6,
61.1 (C-60, COCH2CH3), 14.8 (COCH2CH3) ppm; FABMS m/z 443 (100, M+·). HRDCIMS m/z obsd
444.0891, calcd for C19H22O7NSCl+H 444.0884.

J. Fuentes et al. / Tetrahedron: Asymmetry 9 (1998) 2517–2532
2531
3.7.4. 3-Amino-2-benzoyl-4-ethoxycarbonyl-5-(β-D-glucopyranosylamino)thiophene 30
t=10 min. 13C-NMR (75.4 MHz, MeOH-d4): δ 187.5 (COPh), 171.1 (CO2Et), 166.1, 159.8 (2C,
thiophene ring), 142.7–128.1 (6C, Ph), 98.3, 97.0 (2C, thiophene ring), 87.4 (C-10), 79.4 (C-50), 78.5
(C-30), 74.5 (C-20), 71.1 (C-40), 62.3 (C-60), 61.8 (CH2CH3), 14.6 (CH2CH3) ppm; FABMS m/z 475
(100, [M+Na]+·). HRDCIMS m/z obsd 453.1340, calcd for C20H23O8N2S+H 453.1331.
3.7.5. 3-Amino-2-benzoyl-4-cyano-5-(β-D-glucopyranosylamino)thiophene 31
t=15 min. 13C-NMR (75.4 MHz, MeOH-d4): δ 187.4 (COPh), 166.8, 159.6 (2C, thiophene ring),
142.2–128.1 (6C, Ph), 114.1 (CN), 96.9 (1C, thiophene ring), 87.6 (C-10), 80.6 (1C, thiophene ring),
79.1, 78.7 (C-30, 50), 73.8 (C-20), 71.0 (C-40), 62.3 (C-60) ppm; FABMS m/z 428 (100, [M+Na]+·).
HRDCIMS m/z obsd 406.1088, calcd for C18H19O6N3S+H 406.1073.
Acknowledgements
We thank the Dirección General de Investigación Científica y Técnica of Spain for financial support
(grant number PB 94/1440 C02-01) and the Fundación Cámara of the University of Seville for a grant to
José L. Molina.
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