Nitrogen versus sulfur acylation in sugar thioureas: Regioselectivity and conformational consequences

Article abstract of DOI:10.1016/S0957-4166(00)00054-9

The influence of steric and electronic effects in the regioselectivity of base-catalysed acetylation reactions of sugar thioureas and the structural and conformational properties of the resulting products have been investigated. Bulky alkyl substituents f

Full text of DOI:10.1016/S0957-4166(00)00054-9

Tetrahedron: Asymmetry 11 (2000) 1331±1341
Nitrogen versus sulfur acylation in sugar thioureas:
regioselectivity and conformational consequences
M. Isabel Garcõa-Moreno,a Juan M. Benito,a Carmen Ortiz Melleta,* and
Jose M. Garcõa Fernandezb,*
a
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Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Sevilla, E-41071 Sevilla, Spain
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Instituto de Investigaciones Quõmicas, CSIC, Americo Vespucio s/n, Isla de la Cartuja, E-41092 Sevilla, Spain
b
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Received 20 January 2000; accepted 7 February 2000
Abstract
The in¯uence of steric and electronic e€ects in the regioselectivity of base-catalysed acetylation reactions
of sugar thioureas and the structural and conformational properties of the resulting products have been
investigated. Bulky alkyl substituents favoured S-acetylation, whereas aryl substituents directed acylation
at nitrogen. The conformational properties of both the S- and N-acetyl compounds are governed by the
...
existence of a strong six-membered NH OˆC intramolecular hydrogen bond that locks the pseudoamide
bonds in a rigid con®gurational arrangement. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Sugar thioureas1,2 ®gure prominently in neoglycoconjugate synthetic strategies,3 including
neoglycoproteins,4 glycodendrimers,5±11 glycoclusters12±17 and pseudooligosaccharides.18±20 Most
of the NMR studies of this class of compounds are concerned with the partial double-bond
character of the pseudoamide N±C(ˆS) bonds, arising from the contribution of zwitterionic
resonance structures (N+ˆC±S^) to the ground state of thioureas.21 This electronic property
results in an approximately planar thiourea framework and rotational kinetic parameters in the
range of the chemical shift time scale. In the particular case of deoxythioureido sugars, the
coexistence of several hydrogen bond acceptor centres together with the thiourea NH proton
donors exerts a dramatic in¯uence on the relative rotameric populations and on the correspond-
ing rotational barrier heights.22,23 Broad NMR signals are obtained even at temperatures well
above room temperature, which seriously hamper NMR structural analysis.
An immediate improvement of the NMR spectral resolution should result if the thiourea seg-
ment could be anchored in a precise con®gurational arrangement. Moreover, we have recently
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00054-9

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1332
reported that the imposition of conformational constraints at the thiourea grouping may have
crucial consequences on the secondary structure and molecular recognition properties of carbo-
hydrate derived thioureas.24,25 In this context, we became interested in studying the regioselec-
tivity of base-catalysed acetylation reactions of deoxythioureido sugars, taking into account that
introduction of an acyl group either at nitrogen or at sulfur must strongly favour six-membered
intramolecular hydrogen-bonded patterns, possibly providing con®gurational integrity at the
pseudoamide bonds. The structure of the acetylation products as a function of the primary or
secondary carbon atom location of the thioureido group and the nature of the substituents is
reported.
2. Results and discussion
The 5-deoxy-5-thioureido-d-xylofuranose and 5-deoxy-5-thioureido-l-idofuranose acetonide
derivatives 1±3 and 4±6, respectively, were chosen as model compounds for our study. They
represent particularly challenging problems due to the exocyclic location of the thiourea group,
which complicates the corresponding conformational equilibria. Furthermore, compounds 1±6
have been used as synthetic precursors of azasugar-type glycosidase inhibitors.26,27 They were
prepared in virtually quantitative yield by the coupling reaction of 5-amino-5-deoxy-1,2-O-iso-
propylidene-a-d-xylofuranose28 or 5-amino-5-deoxy-1,2-O-isopropylidene-b-l-idofuranose,29
respectively, with methyl, phenyl and 2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl isothiocyanate.30
1
In both series, the H and 13C NMR spectra exhibited a pronounced line broadening even at
323 K in chloroform-d or methanol-d4 solutions, especially at the H-5 and C-5 region, indicative
of relatively slow chemical exchange processes between the (Z)- and (E)-rotamers about the
corresponding N±C(ˆS) bond. Dynamic NMR data have shown that the contribution of the
(E)-rotamer to the con®gurational equilibrium of deoxythioureido sugars is related to the existence
of a seven-membered intramolecular hydrogen bond analogous to that characteristic of peptide
g-turns (C7 conformation).18,22±25 This folding arrangement, which would engage the furanoid
oxygen atom O-5 in the case of 1±3 and O-4 or O-6 in the case of 4±6 (Fig. 1), brings about a 2
kcal mol^1 increase in the activation free energy (ÁG) for rotation, being responsible for the
unusually high coalescence temperatures.
Upon treatment with acetic anhydride in pyridine, the d-xylofuranose derivatives 1±3 under-
went, predominantly, acetylation at nitrogen yet the outcome of the reaction was strongly
dependent on the nature of the N0-substituent. Thus, the N0-methylthioureido sugar 1 yielded a
mixture of the N- and N0-acetyl thioureas 7 and 8 in 1:2 relative proportion, whereas the

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M. I. Garcõa-Moreno et al. / Tetrahedron: Asymmetry 11 (2000) 1331±1341
1333
...
Figure 1. Seven-membered hydrogen-bonded structures of 5-deoxy-5-thioureido sugars; I, NH O-4 hydrogen bond in
...
pentofuranose derivatives; II and III, NH O-4 and NH O-6 hydrogen bonds in hexofuranose derivatives
...
N0-phenylthioureido sugar 2 led, regiospeci®cally, to the N0-acetyl derivative 9. Under identical
reaction conditions, the (1!5)-thiourea-tethered pseudodisaccharide 3 was acetylated mainly at
the non-anomeric nitrogen atom to give 10. A minor proportion of the isomeric S-acetyl iso-
thiourea 11 was also isolated (Scheme 1).
Scheme 1. Regioselectivity of the acetylation reaction of compounds 1±3 and structure of the resulting products; (i) 1:1
Ac2O:pyridine
For the 5-deoxy-5-thioureido-l-idofuranose homologues 4±6, the secondary carbon atom location
of the thiourea functionality prevented acetylation at the C-5-linked nitrogen atom, probably due
to steric hindrance. In the case of the N0-methylthioureido derivative 4 the acetylation reaction
proceeded predominantly at the sulfur atom to give 13, together with a small proportion of the
N0-acetyl-N0-methylthioureido sugar 12. Acetylation of the N0-phenyl and N0-glucopyranosyl
derivatives 5 and 6 occurred completely regioselectively at the N0- and S-atoms, respectively, to
give 14 and 15 as the sole reaction products (Scheme 2). In the latter case, addition of N,N-
dimethylaminopyridine as base catalyst was advantageous in order to increase the yield of the
acetylation product.

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M. I. Garcõa-Moreno et al. / Tetrahedron: Asymmetry 11 (2000) 1331±1341
1334
Scheme 2. Regioselectivity of the acetylation reaction of compounds 4±6 and structure of the resulting products; (i) 1:1
Ac2O:pyridine; (ii) 1:1 Ac2O:pyridine, 0.1 equiv. DMAP
In stark contrast to that observed for the deoxythioreido sugar precursors 1±6, all the products
of acetylation at nitrogen exhibited well resolved 1H and 13C NMR spectra at room temperature.
The very strong deshielding observed for the remaining NH or N0H proton (11.9±11.6 ppm) is
characteristic of strong hydrogen bonding, in agreement with its engagement in a six-membered
intramolecular hydrogen bond that anchors the con®guration with both carbon substituents in cis
relationship with respect to the thiocarbonyl sulfur atom. The location of the (E)-oriented acyl
group was unequivocally induced from the pseudoamide proton 3JH,H relationships.
The isothiourea proton of the S-acetyl derivatives 11, 13 and 15 resonated at 8.6±8.4 ppm in
chloroform-d solution. Since thiourea protons typically resonate at 7.0±6.0 ppm, these data also
...
suggest the existence of NH OˆC(S) intramolecular hydrogen bonding. Further evidence was
obtained from the corresponding chemical shift temperature coecient values (ÁdNH/ÁT<0.001
ppm K^1), which were consistent with observed values for the N- or N0-acetylated derivatives 7±
10, 12 and 14 and with previously reported data for intramolecularly hydrogen bonded thiourea
protons.22,25 In the case of compound 13, the splitting pattern of the methyl signal, a doublet,
indicated that the isothiourea group was attached to the carbohydrate moiety through the
double-bonded nitrogen atom. The chemical shift di€erence for the methyl resonances in 13 (3.15
ppm) and its positional isomer 12 (3.68 ppm) is in accordance with that expected for (E)- and (Z)-
dispositions with respect to the sulfur atom,22,25 respectively, supporting the proposed six-mem-
bered hydrogen-bonded structures. Nevertheless, the NMR spectra recorded at 303 K displayed
signi®cant line broadening for the resonances of C-4, C-5 and C-6 as well as for the correspond-
ing protons, indicative of relatively slow rotational processes about the NˆC bond. Fast
exchange was achieved at 313 K.

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M. I. Garcõa-Moreno et al. / Tetrahedron: Asymmetry 11 (2000) 1331±1341
1335
1
The H NMR spectra of the glucopyranosylisothioureido derivatives 11 and 15 indicated a
vicinal relationship for the NH proton and protons at C-5, pointing to a glycosylimino structure.
The down®eld chemical shift of the anomeric proton (6.10±6.09 ppm) was indicative of close
proximity to the sulfur atom, supporting the (Z)-con®guration at the CˆN bond and the anti
disposition between H-10 and the N0-lone pair. This scenario is analogous to that encountered at
the anomeric region of glycosylthioureas.1,2 Actually, the alternative (E)-con®guration would
bring the bulky saccharide residues into 1,3-parallel disposition, an unfavourable arrangement.
Accordingly, rotation about the CˆN bond was prevented for 11 and 15, resulting in well-
resolved 1H and 13C NMR spectra at room temperature.
The ensemble of results can be explained in terms of the steric and electronic e€ects of the
nitrogen substituents at the thiourea functionality. As a general rule, N-acylation is strongly dis-
favoured for thiourea nitrogen atoms attached to bulky alkyl substituents (e.g., the l-idofuranose
template in 4±6 or the d-glucopyranosyl substituent in 3 and 6). In contrast, aryl groups direct
acylation at nitrogen (e.g., 2 and 5), probably by increasing the acidity of the corresponding N0H
proton due to delocalization of the N0-lone pair into the aromatic ring. Likewise, in S-acetyl
isothioureas the preferred tautomeric form seems to be determined by the electronic e€ects of the
substituents at the amidine system. Thus, the electron-attracting glucopyranosyl residue in the
pseudodisaccharides 11 and 15 is located at the more electronegative imine-type nitrogen,
whereas the furanoid residue occupies this position in 13, with the methyl group (+I e€ect) at the
amine-type terminus.
In any case, acetylation of the thiourea group in deoxythioureido sugars resulted in a remark-
able simpli®cation of the conformational equilibria by favouring six-membered intramolecular
hydrogen-bonded folding patterns. Further application of this reaction as a tool to control the
secondary structures and molecular recognition properties of sugar thiourea-based pseudooligo-
saccharides and receptors will be reported in due course.
3. Experimental
Optical rotations were measured at room temperature in 1 cm or 1 dm tubes. IR spectra were
1
recorded on an FT-IR instrument. H (and 13C) NMR spectra were recorded at 500 (125.7) and
300 (75.5) MHz. In the FABMS spectra, the primary beam consisted on Xe atoms with a
maximum energy of 8 keV. The samples were dissolved in m-nitrobenzyl alcohol and the positive
ions were separated and accelerated over a potential of 7 keV. NaI was added as cationizing
agent. In the CIMS spectra, isobutane was used as the reactive gas (500 mA, 8 kV). TLC was
performed with E. Merck precoated TLC plates, silica gel 30F-245, with visualization by UV
light and by charring with 10% sulfuric acid. Microanalyses were performed by the Instituto
de Investigaciones Quõmicas (Sevilla, Spain). Methyl and phenyl isothiocyanates used were
commercial grade.
3.1. General procedure for the preparation of 5-deoxy-1,2-O-isopropylidene-5-thioureido-ꢀ-d-
xylofuranose 1±3 and ꢁ-l-idofuranose derivatives 4±6
To solutions of 5-amino-1,2-O-isopropylidene-5-deoxy-a-d-xylofuranose28 or 5-amino-1,2-O-
isopropylidene-5-deoxy-b-l-idofuranose29 (1.91 mmol) in pyridine (15 mL) were added methyl,
phenyl and 2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl isothiocyanate30 (2.10 mol). The reaction

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M. I. Garcõa-Moreno et al. / Tetrahedron: Asymmetry 11 (2000) 1331±1341
1336
mixtures were stirred at room temperature until total consumption of the starting amino sugar
(TLC), concentrated and puri®ed by column chromatography with the eluent indicated in each case.
3.2. 5-Deoxy-1,2-O-isopropylidene-5-(N0-methylthioureido)-ꢀ-d-xylofuranose 1
Reaction time: 2.5 h. Yield: 0.5 g (99%); [ꢀ]D=+17.8 (c 0.9, MeOH); Rf 0.26 (20:1
CH2Cl2:MeOH); UV (MeOH): 240 nm ("mM 15.02); IR (KBr) 3376, 3266, 2986, 2917, 1551, 1371,
1217 and 1007 cm^1; ꢂH (300 MHz, CD3OD, 313 K) 1.28, 1.43 (6H, 2s, Me2C), 2.94 (3H, bs, NMe),
3.56 (1H, dd, J4,5b 6.5, J5a,5b 14.0, H-5b), 3.95 (1H, m, H-5a), 4.07 (1H, d, J2,3 0, J3,4 2.7, H-3),
4.28 (1H, td, J4,5a 6.5, H-4), 4.49 (1H, d, J1,2 3.7, H-2), 5.87 (1H, d, H-1); ꢂC (75.5 MHz, CD3OD,
313 K) 26.3, 26.9 (CMe2), 30.9 (MeN), 43.9 (C-5), 75.5 (C-3), 80.6 (C-4), 86.7 (C-2), 106.1 (C-1),
112.7 (CMe2), 184.2 (CˆS), FABMS: m/z 285 (100, [M+Na]+), 263 (80, [M+H]+). Anal. calcd for
C10H18O4N2S: C, 45.78; H, 6.90; N, 10.68. Found: C, 45.72; H, 6.96; N, 10.68.
3.3. 5-Deoxy-1,2-O-isopropylidene-5-(N0-phenylthioureido)-ꢀ-d-xylofuranose 2
Reaction time: 2.5 h. Yield: 0.61 g (98%); [ꢀ]D=+3.9 (c 0.9, CH2Cl2); Rf 0.73 (20:1
CH2Cl2:MeOH); UV (CH2Cl2): 262 nm ("mM 14.34); IR (KBr) 3306, 2986, 2936, 1543, 1497,
1375, 1215 and 1013 cm^1; ꢂH (300 MHz, CDCl3, 313 K) 1.28, 1.44 (6H, 2s, Me2C), 3.68 (1H, dt,
J4,5b=JNH,5b 4.7, J5a,5b 14.9, H-5b), 4.12 (1H, ddd, J3,4 3.1, J4,5a 7.7, H-4), 4.21 (1H, d, J2,3 0, H-
3), 4.26 (1H, dd, H-5a), 4.53 (1H, d, J1,2 3.6, H-2), 5.84 (1H, d, H-1), 6.44 (1H, m, NH), 7.49±7.13
(5H, m, Ph), 8.06, (1H, s, NH); ꢂC (75.5 MHz, CDCl3, 313 K) 26.4, 26.8 (CMe2), 42.9 (C-5), 74.1
(C-3), 79.3 (C-4), 84.9 (C-2), 104.4 (C-1), 111.5 (CMe2), 125.2 (C-2, 6 Ph), 127.8 (C-4 Ph), 131.3
(C-3,5 Ph), 135.5 (C-1 Ph), 182.5 (CˆS); FABMS: m/z 347 (100, [M+Na]+), 325 (80, [M+H]+).
Anal. calcd for C15H20O4N2S: C, 55.54; H, 6.21; N, 8.63. Found: C, 55.68; H, 6.22; N, 8.49.
3.4. 5-Deoxy-1,2-O-isopropylidene-5-[N0-(2,3,4,6-tetra-O-acetyl-ꢁ-d-glucopyranosyl)thioureido]-
ꢀ-d-xylofuranose 3
Reaction time: 4 h. Yield: 0.78 g (71%); [ꢀ]D=+15.5 (c 0.9, CH2Cl2); Rf 0.28 (2:1 EtOAc:
petroleum ether); UV (CH2Cl2): 250 nm ("mM 8.16); IR (KBr) 3362, 2949, 1751, 1545, 1375, 1219
and 1036 cm^1; ꢂH (500 MHz, CDCl3, 313 K): 1.33, 1.48 (6H, 2s, Me2C), 2.02, 2.04, 2.07, 2.09
(12H, 4s, 4 Ac), 3.65 (1H, m, H-5b), 3.84 (1H, ddd, J5 ,6 a 4.8, J4 ,5 10.1, J5 ,6 b 2.0, H-50), 4.10 (1H,
0
0
0
0
0
0
m, H-5a), 4.12 (1H, dd, J6 a,6 b 12.4, H-60b), 4.18 (1H, d, J2,3 0, J3,4 2.4, H-3), 4.20 (1H, td,
J4,5a=J4,5b 7.2, H-4), 4.30 (1H, dd, H-60a), 4.55 (1H, d, J1,2 3.6, H-2), 4.97 (1H, t, J1 ,2 =J2 ,3 9.5,
0
0
0
0
0
0
H-20), 5.06 (1H, dd, J3 ,4 9.5, H-40), 5.33 (1H, t, H-30), 5.66 (1H, bt, H-10), 5.93 (1H, d, H-1), 6.90
(2H, bs, 2 NH); ꢂC (125.7 MHz, CDCl3) 20.3±20.5 (MeCO), 26.0, 26.5 (CMe2), 42.5 (C-5), 61.8
(C-60), 68.5 (C-40), 69.8 (C-20), 72.9 (C-50), 73.3 (C-30), 74.4 (C-3), 79.0 (C-4), 82.8 (C-10), 85.2 (C-
2), 104.5 (C-1), 111.9 (CMe2), 171.2±169.0 (CO), 184.2 (CˆS); FABMS: m/z 601 (100, [M+Na]+),
579 (60, [M+H]+). Anal. calcd for C23H34O13N2S: C, 47.74; H, 5.92; N, 4.84. Found: C, 47.66; H,
5.66; N, 4.82.
0
0
3.5. 5-Deoxy-1,2-O-isopropylidene-5-(N0-methylthioureido)-ꢁ-l-idofuranose 4
Reaction time: 7 h. Yield: 0.48 g (87%); [ꢀ]D=^19.5 (c 1.1, MeOH); Rf 0.27 (20:1
CH2Cl2:MeOH); UV (MeOH): 240 nm ("mM 9.1); IR (KBr) 3376, 2926, 1572, 1377, 1215, 1071

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M. I. Garcõa-Moreno et al. / Tetrahedron: Asymmetry 11 (2000) 1331±1341
1337
and 1007 cm^1; ꢂH (300 MHz, CD3OD, 313 K) 1.30, 1.45 (6H, 2s, Me2C), 2.97 (3H, s, MeNH), 3.73
(2H, d, J5,6 4.4, H-6a, H-6b), 4.13 (1H, d, J2,3 0, J3,4 2.7, H-3), 4.30 (1H, dd, J4,5 8.0, H-4), 4.49
(1H, d, J1,2 3.8, H-2), 4.58 (1H, m, H-5), 5.89 (1H, d, H-1); ꢂC (75.5 MHz, CD3OD, 313 K) 26.3,
26.9 (CMe2), 33.0 (MeN), 56.5 (C-5), 62.5 (C-6), 75.6 (C-3), 81.0 (C-4), 86.8 (C-2), 105.8 (C-1),
112.6 (CMe2), 182.5 (CˆS); FABMS: m/z 315 (100, [M+Na]+). Anal. calcd for C10H20O5N2S: C,
47.19; H, 6.90; N, 9.58; S, 10.79. Found: C, 45.20; H, 6.72; N, 9.53; S, 11.07.
3.6. 5-Deoxy-5-(N0-phenylthioureido)-1,2-O-isopropylidene-ꢁ-l-idofuranose 5
Reaction time: 6 h. Yield: 0.61 g (90%); [ꢀ]D=+14.6 (c 0.69, MeOH); Rf 0.24 (20:1
CH2Cl2:MeOH); UV (MeOH): 250 nm ("mM 14.4); IR (KBr) 3428, 2959, 2848, 1657 and 1021 cm^1;
ꢂH (300 MHz, CD3OD, 313 K) 1.29, 1.44 (6H, 2s, Me2C), 3.72 (1H, dd, J5,6b 5.2, J6a,6b 11.1, H-6b),
3.79 (1H, dd, J5,6a 3.9, H-6a), 4.15 (1H, d, J2,3 0, J3,4 2.8, H-3), 4.37 (1H, dd, J4,5 7.0, H-4), 4.50
(1H, d, J1,2 3.7, H-2), 4.77 (1H, m, H-5), 5.96 (1H, d, H-1), 7.45±7.15 (5H, m, Ph); ꢂC (75.5 MHz,
CD3OD, 313 K) 26.4, 27.0 (CMe2), 56.6 (C-5), 62.4 (C-6), 75.8 (C-3), 80.6 (C-4), 86.9 (C-2), 105.9
(C-1), 112.8 (CMe2), 125.3, 126.7, 130.2, 139.6, (6C, Ph),182.0 (CˆS); FABMS: m/z 377 (100,
[M+Na]+). Anal. calcd for C16H22O5N2S: C, 54.22; H, 6.26; N, 7.90; S, 9.05. Found: C, 54.24; H,
6.40; N, 7.89; S, 9.05.
3.7. 5-Deoxy-5-[N0-(2,3,4,6-tetra-O-acetyl-ꢁ-d-glucopyranosyl)thioureido]-1,2-O-isopropylidene-
ꢁ-l-idofuranose 6
Reaction time: 24 h. Yield: 1.07 g (93%); [ꢀ]D=^2.6 (c 0.76, CH2Cl2); Rf 0.22 (20:1
CH2Cl2:MeOH); UV (MeOH): 248 nm ("mM 14.5); IR (KBr) 3428, 2951, 1760, 1553, 1236 and
1037 cm^1; ꢂH (300 MHz, CD3OD, 313 K) 1.97, 2.00 (6 H), 2.02 (4 Ac), 1.28, 1.44, (6H, 2 s, CMe2),
3.74 (2H, m, H-6a, H-6b), 3.88 (1H, ddd, J5 ,6 b 2,4, J5 ,6 a 4.5, J4 ,5 9.4, H-50), 4.09 (1H, dd, J6 a,6 b
12.3, H-60b), 4.14 (1H, d, J2,3 0, J3,4 2.9, H-3), 4.27 (1H, dd, H-60a), 4.33 (1H, bd, H-4), 4.48 (1H,
0
0
0
0
0
0
0
0
d, J1,2 3.8, H-2), 4.65 (1H, m, H-5), 4.98 (1H, dd, J1 ,2 7.8, J2 ,3 9.4, H-20), 5.02 (1H, t, J3 ,4 9.4 H-
40), 5.31 (1H, t, H-30), 5.87 (1H, d, H-1), 5.88 (1H, d, H-10); ꢂC (75.5 MHz, CD3OD, 313 K) 20.5
(MeCO), 26.3, 27.0 (CMe2), 56.5 (C-5), 61.8 (C-6), 63.1 (C-60), 69.7 (C-40), 71.9 (C-20), 74.4 (C-50),
74.8 (C-30), 75.6 (C-3), 80.4 (C-4), 83.5 (C-10), 86.9 (C-2), 105.9 (C-1), 112.6 (CMe2), 171.3, 171.5,
171.6, 172.3 (CO), 185.3 (CˆS); FABMS: m/z 631 (100%, [M+Na]+). Anal. calcd for C24H36O14N2S:
C, 47.36; H, 5.97; N, 4.60; S, 5.27. Found: C, 47.01; H, 5.90; N, 4.33; S, 5.00.
0
0
0
0
0
0
3.8. General procedure for acetylation of the 5-deoxy-5-thioureido sugars 1±6
Acetylation of the N,N0-disubstituted thioureas 1±6 (0.5 mmol) was e€ected conventionally by
treatment with 1:1 Ac2O:pyridine (4 mL) at room temperature for 24 h, followed by puri®cation
by column chromatography with the eluent indicated in each case. For compound 6, addition of a
catalylic amount of N,N-dimethylaminopyridine (0.1 mmol) to the reaction mixture was found
advantageous.
3.9. 3-O-Acetyl-5-(N-acetyl-N0-methylthioureido)-5-deoxy-1,2-O-isopropylidene-ꢀ-d-xylofuranose 7
Yield: 48 mg (27%); [ꢀ]D=^38.0 (c 1.0, CH2Cl2); Rf 0.49 (20:1 CH2Cl2:MeOH); UV (CH2Cl2):
271 nm ("mM 9.31); IR (KBr) 3173, 2988, 2936, 1746, 1672, 1547, 1377, 1225 and 1030 cm^1;

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1338
ꢂH (300 MHz, CDCl3) 1.29, 1.48 (6H, 2s, Me2C), 2.12 (3H, s, OAc), 2.49 (3H, s, NAc), 3.14 (3H,
d, JMe,NH 4.5, MeN), 3.80 (1H, dd, J4,5b 8.3, J5a,5b 15.6, H-5b), 4.51 (1H, d, J2,3 0, J1,2 3.8, H-2),
4.73 (1H, dt, J3,4=J4,5a 3.0, H-4), 5.17 (1H, dd, H-5a), 5.28 (1H, d, H-3), 5.90 (1H, d, H-1), 11.30
(1H, d, NH); ꢂC (75.5 MHz, CDCl3) 20.7 (MeCOO), 26.0, 26.4 (CMe2), 26.6 (MeCON), 33.2
(MeN), 48.9 (C-5), 77.0 (C-3), 78.4 (C-4), 83.3 (C-2), 104.4 (C-1), 112.2 (CMe2), 167.4 (CO ester),
175.5 (CO amide), 184.7 (CˆS); CIMS: m/z 347 (100, [M+H]+). Anal. calcd for C14H22O6N2S: C,
48.54; H, 6.40; N, 8.08. Found: C, 48.26; H, 6.90; N, 7.76.
3.10. 3-O-Acetyl-5-(N0-acetyl-N0-methylthioureido)-5-deoxy-1,2-O-isopropylidene-ꢀ-d-xylofuran-
ose 8
Yield: 88 mg (50%); [ꢀ]D=+8.0 (c 1.0, CH2Cl2); Rf 0.64 (20:1 CH2Cl2:MeOH); UV (CH2Cl2):
273 nm ("mM 20.32); IR (KBr) 3154, 2988, 2930, 1748, 1674, 1539, 1373, 1221 and 1026 cm^1; ꢂH
(300 MHz, CDCl3) 1.30, 1.50 (6H, 2s, Me2C), 2.10 (3H, s, OAc), 2.37 (3H, s, NAc), 3.34 (1H,
ddd, JNH,5b 5.0, J4,5b 7.0, J5a,5b 14.1, H-5b), 3.69 (3H, s, MeN), 4.05 (1H, dt, J4,5a=JNH,5a 5.5, H-
5a), 4.52 (1H, d, J2,3 0, J1,2 3.8, H-2), 4.62 (1H, ddd, J3,4 3.1, H-4), 5.20 (1H, d, H-3), 5.92 (1H, d,
H-1), 11.60 (1H, s, NH); ꢂC (75.5 MHz, CDCl3) 20.6 (MeCOO), 26.1, 26.6 (CMe2), 29.6
(MeCON), 38.5 (MeN), 44.9 (C-5), 75.9 (C-3), 76.6 (C-4), 83.6 (C-2), 104.7 (C-1), 112.1 (CMe2),
169.6 (CO ester), 174.8 (CO amide), 184.7 (CˆS); CIMS: m/z 347 (100, [M+H]+). Anal. calcd for
C14H22O6N2S: C, 48.54; H, 6.40; N, 8.08. Found: C, 48.42; H, 6.40; N, 7.81.
3.11. 3-O-Acetyl-5-(N0-acetyl-N0-phenylthioureido)-5-deoxy-1,2-O-isopropylidene-ꢀ-d-xylofuranose
9
Yield: 0.19 g (91%); [ꢀ]D=^3.3 (c 1.0, CH2Cl2); Rf 0.60 (1:1 EtOAc:petroleum ether); UV
(CH2Cl2): 229 nm ("mM 11.45); IR (KBr) 3165, 2988, 2938, 1748, 1674, 1537, 1373, 1260, 1051
and 698 cm^1; ꢂH (300 MHz, CDCl3) 1.30, 1.51 (6H, 2s, Me2C), 2.11 (3H, s, OAc), 2.33 (3H, s,
NAc), 3.88 (1H, ddd, JNH,5b 1.8, J4,5b 6.9, J5a,5b 13.9, H-5b), 4.06 (1H, dt, J4,5a=JNH,5a 5.5, H-5a),
4.54 (1H, d, J2,3 0, J1,2 3.8, H-2), 4.64 (1H, ddd, J3,4 3.0, H-4), 5.22 (1H, d, H-3), 5.95 (1H, d, H-
1), 7.43±7.16 (5H, m, Ph), 11.77 (1H, dd, NH); ꢂC (75.5 MHz, CDCl3) 20.4 (MeCOO), 25.8, 26.3
(CMe2), 27.5 (MeCON), 44.3 (C-5), 75.6 (C-3), 76.2 (C-4), 83.2 (C-2), 104.3 (C-1), 111.7 (CMe2),
127.8±129.2 (C-2 to C-6 Ph), 141.8 (C-1 Ph), 169.4 (CO ester), 174.4 (CO amide), 184.1 (CˆS);
CIMS: m/z 409 (40%, [M+H]+). Anal. calcd for C19H24O6N2S: C, 55.87; H, 5.92; N, 6.86.
Found: C, 55.71; H, 5.60; N, 6.52.
3.12. 3-O-Acetyl-5-[N-acetyl-N0-(2,3,4,6-tetra-O-acetyl-ꢁ-d-glucopyranosyl)thioureido]-5-deoxy-
1,2-O-isopropylidene-ꢀ-d-xylofuranose 10
Yield: 0.14 mg (50%); [ꢀ]D=^18.8 (c 1.0, CH2Cl2); Rf 0.65 (30:1 CH2Cl2:MeOH); UV
(CH2Cl2): 278 nm ("mM 10.67); IR (KBr) 2988, 2924, 1757, 1686, 1534, 1375, 1221 and 1045 cm^1;
ꢂH (500 MHz, CDCl3) 1.27, 1.46 (6H, 2s, Me2C), 1.99±2.11 (OAc), 2.50 (3H, s, NAc), 3.74 (1H,
dd, J4,5b 7.9, J5a,5b 14.9, H-5b), 3.81 (1H, ddd, J5 ,6 b 2.2, J5,6a 4.5, J4,5 9.5, H-50), 4.08 (1H, dd,
0
0
J6 a,6 b 12.5, H-6b0), 4.27 (1H, dd, H-6a0), 4.49 (1H, d, J2,3 0, J1,2 3.8, H-2), 4.70 (1H, ddd, J4,5a 1.8,
0
0
J3,4 3.1, H-4), 5.03 (1H, dd, H-5a), 5.08 (1H, t, J1 ,2 =J2 ,3 9.5, H-20), 5.13 (1H, dd, J3 ,4 9.5, H-40),
0
0
0
0
0
0
5.26 (1H, d, H-3), 5.30 (1H, t, H-30), 5.78 (1H, t, J1 ,N H 8.1, H-10), 5.89 (1H, d, H-1), 11.71 (1H, d,
N0H); ꢂC (125.7 MHz, CDCl3) 20.5±20.7 (MeCOO), 26.0, 26.4 (CMe2), 26.7 (MeCON), 49.5 (C-5),
0
0

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M. I. Garcõa-Moreno et al. / Tetrahedron: Asymmetry 11 (2000) 1331±1341
1339
61.5 (C-60), 68.1 (C-40), 70.2 (C-20), 73.0 (C-50), 73.5 (C-30), 77.1 (C-3), 78.1 (C-4), 83.1 (C-10), 83.2
(C-2), 104.5 (C-1), 112.3 (CMe2), 169.3±170.6 (CO ester), 175.5 (CO amide), 186.5 (CˆS);
FABMS: m/z 685 (90, [M+Na]+). Anal. calcd for C27H38O15N2S: C, 48.94; H, 5.78; N, 4.23.
Found: C, 49.03; H, 6.19; N, 4.41.
3.13. 3-O-Acetyl-5-[S-acetyl-3-(2,3,4,6-tetra-O-acetyl-ꢁ-d-glucopyranosyl)-1-isothioureido]-5-deoxy-
1,2-O-isopropylidene-ꢀ-d-xylofuranose31 11
Yield: 44 mg (13%); [ꢀ]D=+78.0 (c 1.0, CH2Cl2); Rf 0.60 (30:1 CH2Cl2:MeOH); UV (CH2Cl2):
275 nm ("mM 8.31); IR (KBr) 3320, 2980, 2938, 1751, 1526, 1373, 1227 and 1038 cm^1; ꢂH (500
MHz, CDCl3) 1.31, 1.50 (6H, 2s, Me2C), 1.98±2.17 (15H, 5s, OAc), 2.40 (3H, s, SAc), 3.73 (1H,
ddd, JNH,5b 4.6, J4,5b 9.1, J5a,5b 14.0, H-5b), 3.85 (1H, ddd, J5 ,6 b 2.2, J5 ,6 a 6.2, J4 ,5 9.6, H-50),
0
0
0
0
0
0
3.92 (1H, ddd, J4,5a 3.6, JNH,5a 6.1, H-5a), 4.07 (1H, dd, J6 a,6 b 12.5, H-60b), 4.35 (1H, dd, H-60a),
4.58 (1H, d, J2,3 0, J1,2 3.8, H-2), 4.62 (1H, ddd, J3,4 3.0, H-4), 5.08 (1H, t, J1 ,2 =J2 ,3 9.6, H-20),
0
0
0
0
0
0
5.10 (1H, dd, J3 ,4 9.5, H-40), 5.23 (1H, d, H-3), 5.25 (1H, t, H-30), 5.97 (1H, d, H-1), 6.10 (1H, d,
H-10), 8.40 (1H, dd, NH); ꢂC (125.7 MHz, CDCl3) 20.5±20.7 (MeCOO), 24.1 (MeCOS), 26.1, 26.5
(CMe2), 45.3 (C-5), 62.2 (C-60), 67.7 (C-40), 67.8 (C-20), 73.8 (C-50), 74.6 (C-30), 75.8 (C-3), 76.3
(C-4), 80.2 (C-10), 83.6 (C-2), 104.6 (C-1), 112.3 (CMe2), 170.0±169.3 (CO ester), 170.6 (CˆN),
182.5 (CO thioester). Anal. calcd for C27H38O15N2S: C, 48.94; H, 5.78; N, 4.23. Found: C, 49.02;
H, 6.11; N, 4.19.
0
0
3.14. 3,6-Di-O-acetyl-5-(N0 -acetyl-N0 -methylthioureido)-5-deoxy-1,2-O-isopropylidene-ꢁ-l-
idouranose 12
Yield: 51 mg (24%); [ꢀ]D=^20.6 (c 1.0, CH2Cl2); Rf 0.42 (1:1 EtOAc:petroleum ether); UV
(CH2Cl2): 274 nm ("mM 11.5); IR (KBr) 3133, 1748, 1674, 1522, 1373, 1225 and 1026 cm^1; ꢂH
(300 MHz, CDCl3) 1.29, 1.50 (6H, 2s, Me2C), 2.05, 2.12 (6H, 2s, OAc), 2.37 (3H, s, NAc), 3.68
(3H, s, MeN), 4.23 (1H, dd, J5,6b 5.6, J6a,6b 12.3, H-6b), 4.27 (1H, dd, J5,6a 5.8, H-6a), 4.47 (1H, d,
J2,3 0, J1,2 3.8, H-2), 4.52 (1H, t, J3,4=J4,5 3.4, H-4), 5.07 (1H, m, H-5), 5.26 (1H, d, H-3), 5.96
(1H, d, H-1), 11.80 (1H, d, J5,NH 7.6, NH); ꢂC (75.5 MHz, CDCl3) 20.7 (MeCO), 26.1, 26.6
(CMe2), 38.6 (MeN), 53.9 (C-5), 62.5 (C-6), 76.5 (C-4), 76.7 (C-3), 83.4 (C-2), 104.6 (C-1), 112.2
(CMe2), 169.4, 170.5 (CO ester), 174.8 (CO amide), 183.9 (CˆS); FABMS: m/z 441 (100,
[M+Na]+). Anal. calcd for C17H26O8N2S: C, 48.79; H, 6.26; N, 6.69. Found: C, 49.01; H, 6.14; N,
6.68.
3.15. 3,6-Di-O-acetyl-5-(S-acetyl-1-methyl-3-isothioureido)-5-deoxy-1,2-O-isopropylidene-ꢁ-l-
idofuranose31 13
Yield: 136 mg (65%); [ꢀ]D=^53.0 (c 1.0, CH2Cl2); Rf 0.30 (1:1 EtOAc:petroleum ether); UV
(CH2Cl2): 272 nm ("mM 7.8); ꢂH (300 MHz, CDCl3) 1.31, 1.48 (6H, 2s, Me2C), 2.02±2.20 (9H, 3s,
Ac), 3.15 (3H, d, JMe,NH 4.8, MeN), 4.30 (1H, dd, J5,6b 5.8, J6a,6b 11.3, H-6b), 4.62 (2H, m, H-5,
H-6a), 4.50 (1H, m, H-4), 4.56 (1H, d, J2,3 0, J1,2 3.7, H-2), 5.22 (1H, d, J3,4 2.4, H-3), 5.89 (1H, d,
H-1), 8.60 (1H, m, NH); ꢂC (75.5 MHz, CDCl3) 20.7 (MeCO), 26.3, 26.5 (CMe2), 33.2 (MeN),
54.0 (C-5), 61.0 (C-6), 74.8 (C-3), 76.6 (C-4), 83.7 (C-2), 103.6 (C-1), 112.6 (CMe2), 169.1±170.5
(CO ester), 183.9 (CO thioester); FABMS: m/z 441 (100, [M+Na]+). Anal. calcd for
C17H26O8N2S: C, 48.79; H, 6.26; N, 6.69. Found: C, 48.49; H, 6.33; N, 6.69.

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1340
3.16. 3,6-Di-O-acetyl-5-(N0-acetyl-N0-phenylthioureido)-5-deoxy-1,2-O-isopropylidene-ꢁ-l-idofuranose
14
Yield: 193 mg (80%); [ꢀ]D=^4.0 (c 0.6, CH2Cl2); Rf 0.42 (1:2 EtOAc:petroleum ether); UV
(CH2Cl2): 277 nm ("mM 10.3); IR (KBr) 3476, 2990, 1748, 1682, 1530, 1406, 1232 and 1029, 731
and 694 cm^1; ꢂH (300 MHz, CDCl3) 1.32, 1.53 (6H, 2s, Me2C), 1.93, 2.07 (6H, 2s, OAc), 2.11
(3H, s, NAc), 4.30 (2H, d, J5,6 5.4, H-6a, H-6b), 4.52 (1H, d, J2,3 0, J1,2 3.7, H-2), 4.59 (1H, t,
J3,4=J4,5 3.7, H-4), 5.03 (1H, dtd, J5,NH 7.6, H-5), 5.30 (1H, d, H-3), 6.03 (1H, d, H-1), 7.10±7.50
(5H, m, Ph), 11.90 (1H, d, NH); ꢂC (75.5 MHz, CDCl3) 20.7, 20.9 (MeCO), 26.2, 26.7 (CMe2),
38.6 (MeN), 53.5 (C-5), 62.5 (C-6), 76.8 (C-4), 77.3 (C-3), 83.5 (C-2), 104.6 (C-1), 112.3 (CMe2),
128.8, 129.3, 129.4, 142.1 (Ph), 169.6, 170.5 (CO ester), 174.6 (CO amide), 183.6 (CˆS); FABMS:
m/z 503 (100, [M+Na]+). Anal. calcd for C22H28O8N2S: C, 54.99; H, 5.87; N, 5.83; S, 6.67. Found:
C, 54.76; H, 5.81; N, 5.63; S, 6.58.
3.17. 3,6-Di-O-acetyl-5-[S-acetyl-3-(2,3,4,6-tetra-O-acetyl-ꢁ-d-glucopyranosyl)-1-isothioureido]-
5-deoxy-1,2-O-isopropylidene-ꢁ-l-idofuranose31 15
Yield: 172 mg (47%); [ꢀ]D=+64.5 (c 1.1, CH2Cl2); Rf 0.35 (1:2 EtOAc:petroleum ether); UV
(CH2Cl2): 277 nm ("mM 13.5); IR (KBr) 3293, 2999, 1760, 1428, 1371, 1236 and 1053 cm^1; ꢂH
(500 MHz, CDCl3) 1.32, 1.49 (6H, 2s, Me2C), 1.97±2.08 (OAc), 2.39 (3H, s, SAc), 3.78 (1H, dd,
J5 ,6 b 2.2, J6 a,6 b 12.4, H-60b), 3.82 (1H, ddd, J5 ,6 a 3.6, J4 ,5 9.5, H-50), 4.02 (1H, dd, J5,6b 4.3,
0
0
0
0
0
0
0
0
J6a,6b 11.8, H-6b), 4.12 (1H, t, J3 ,4 9.5, H-40), 4.58 (1H, d, J2,3 0, J1,2 3.8, H-2), 4.61 (1H, dd, J5,6a
4.3, H-6a), 4.64 (1H, dd, J3,4 3.0, J4,5 9.1, H-4), 4.81 (2H, m, H-5, H-6a0), 5.24 (2H, m, H-20, H-30),
5.28 (1H, d, H-3), 6.03 (1H, m, H-10), 6.09 (1H, d, H-1), 8.51 (1H, m, NH); ꢂC (125.7 MHz,
CDCl3) 20.5±21.0 (MeCOO), 23.9 (MeCOS), 26.0, 26.2 (CMe2), 54.6 (C-5), 61.4 (C-6), 62.7 (C-
60), 68.4 (C-40), 74.4 (C-20), 74.9 (C-30), 75.6 (C-50), 77.6 (C-3), 76.8 (C-4), 79.8 (C-10), 83.5 (C-2),
104.3 (C-1), 112.1 (CMe2), 169.0±171.1 (CO ester), 171.2 (CˆN), 182.3 (CO thioester). Anal.
calcd for C30H42O17N2S: C, 49.04; H, 5.76; N, 3.81; S, 4.36. Found: C, 49.00; H, 5.74; N, 3.81; S,
4.14.
0
0
Acknowledgements
Support from DGICyT (grant no. PB 97/0747) is acknowledged. M.I.G.-M. thanks the
Fundacion Camara for a doctoral fellowship.
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