Stereocontrolled synthesis of thiohydantoin spironucleosides from sugar spiroacetals

Article abstract of DOI:10.1016/j.tet.2005.09.128

5-Epithiohydantocidin, N-alkyl and N-glycosylthiohydantoin spironucleosides are prepared from glycosylaminoesters and from furanoid and pyranoid methyl isothiocyanatoulosonates. The aminoesters and the isothiocyanates are obtained, in a stereocontrolled m

Full text of DOI:10.1016/j.tet.2005.09.128

Tetrahedron 62 (2006) 97–111
Stereocontrolled synthesis of thiohydantoin spironucleosides from
sugar spiroacetals
*
´
Jose Fuentes, Bader A. B. Salameh, M. Angeles Pradera, Francisco J. Fernandez de Cordoba
´
´
´
and Consolacion Gasch
´
´
Departamento de Quımica Organica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 13 July 2005; revised 23 September 2005; accepted 29 September 2005
Available online 26 October 2005
Dedicated to Professor J. Plumet on the occasion of his 60th birthday
Abstract—5-Epithiohydantocidin, N-alkyl and N-glycosylthiohydantoin spironucleosides are prepared from glycosylaminoesters and from
furanoid and pyranoid methyl isothiocyanatoulosonates. The aminoesters and the isothiocyanates are obtained, in a stereocontrolled manner,
from sugar spiroacetals through a high-yielding sequence involving ring opening with trimethyl azide, formation of an ester group, reduction
of the azide, and, in the case of isothiocyanates, reaction with thiophosgene.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper, we report the full data on a synthetic procedure
to prepare furanoid and pyranoid spirothiohydantoins using
methyl isothiocyanatoulosonates (11, 18) and methyl
aminoulosonates (9, 10, and 17) as key intermediates. We
have previously shown7f that ketofuranosyl isothiocyanates
are transient intermediates in the preparation of spironucleo-
sides of 1,3-O,N five member heterocycles.
The chemistry of spironucleosides, a type of nucleoside in
which the anomeric carbon belongs simultaneously to the
sugar ring and to the nitrogenated heterocyclic moiety,1 has
received considerable development in the last decade. This
interest is due to the isolation from culture broths of
Streptomices hygroscopicus of (C)-hydantocidin (1), the
first natural spironucleoside.2 The (C)-hydantocidin shows
low toxicity for mammals and has herbicidal and plant
growth-regulatory activities, which have been related to its
inhibitory activity of adenylsuccinate synthase.3 Other
spiro-anulated compounds4 also have biological interest
due to their activity as inhibitors of glycogen phosphorilase
and a-amylase.5 Syntheses of (C)-hydantocidin have been
reported,6 and starting from 1993 many syntheses of
hydantocidin analogues and related carbocyclic derivatives
have been described.1b,7
2. Results and discussion
The starting materials to prepare the pyranoid and furanoid
2-isothiocyanatoulosonic esters 11 and 18 (Scheme 1) were
the b-azido-1-trimethyl ethers 3 and 13, respectively, which
we have previously reported,7f and were obtained by
reaction of trimethylsilyl azide with the corresponding
spiroacetal11 2 or 12 in freshly distilled acetonitrile, under
stringently anhydrous conditions. Desilylation of 3 with a
catalytic amount of TBAF (tetrabutyl ammonium fluoride).
3H2O produced 4 in high yield. Swern12 oxidation of 4
afforded the azido aldehyde 5, whose NMR data showed the
signals for 5 and additional signals corresponding to a
hydrate as is described for related aldehydes.13 Further
oxidation (NaClO2) of 5 followed by treatment with
diazomethane gave the 3-O-benzylazido ester 7. Treatment
of 4 with ruthenium chloride-sodium metaperiodate
produced simultaneous oxidation of the formyl and benzyl
groups with formation of the 3-O-benzoyl ulosonic acid
derivative 6, which was not isolated, and in situ converted
(reaction with CH2N2) into the methyl 3-O-benzoyl azido
Recently, we reported our preliminary results on the
preparation of pyranoid and furanoid isothiocyanatouloso-
nates, a new type of sugar isothiocyanate which is used for
the stereocontrolled preparation of thiohydantoin spironu-
cleosides.8 Some data on related ulosononitriles9 and
furanoid ulosonoisothiocyanates10 have been reported later.
Keywords: Spironucleosides; Thiohydantoins; Thioureas; Isothiocyanates.
*
Corresponding author. Tel.: C34 954557150; fax: C34 954624960.;
e-mail: jfuentes@us.es
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.128

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J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
Scheme 1. Preparation of new glycosyl aminoulosonates and glycosyl isothiocyanatoulosonates from sugar spiroacetals. Reagents and conditions: (i) TMSN3,
TMSOTf, CH3CN, 0 8C; (ii) TBFA.3H2O, THF, rt; (iii) DMSO, CH2Cl2, K70 8C; (iv) RuCl3$H2O, NaIO4, CH3CN, H2O, CCl4, rt; (v) NaClO2, (CH3)2C]
CH–CH3, NaH2PO4$2H2O, tBuOH, H2O, 0 8C; (vi) CH2N2, Et2O, MeOH, 0 8C; (vii) H2/C–Pd, MeOH, rt; (viii) CSCl2, CHCl3, H2O, CaCO3, rt.
ester 8. Catalytic hydrogenation of 7 and 8 gave the
glycosylaminoester anomeric mixtures 9 and 10, respect-
ively, in good yields. The anomeric ratio for 9 was 1:9 (a:b,
CDCl3, rt, equilibrium), whereas in the case of 10 the ratio
of the two anomers was 2:5 (same conditions), although the
anomeric (C-2) configuration of each anomer for 10 was not
determined. The anomeric mixture 9 was used only in route
A (Scheme 2) for the synthesis of spirothiohydantoins.
Compound 10 was also transformed, by reaction with
thiophosgene in basic medium, into an anomeric mixture
(a:b 16:1) of glycosyl isothiocyanates, from which only the
a anomer 11 was isolated. This compound was used in route
B of spirothiohydantoins (Scheme 2).
In a similar way, the reaction of 13 with TBAF$ 3H2O gave
the known6b 1-O-unprotected furanosyl azide 14, which by
oxidation with ruthenium chloride–sodium metaperiodate
(/15), followed by estherification with CH2N2, produced
the methyl ulosonate 16. Catalytic hydrogenation of 16
yielded the anomeric mixture (a:b ratio 6:1) of aminoesters
17 in virtually quantitative yield. Reaction of 17 with
thiophosgene in the presence of CaCO3 gave, after column
chromatography, the a (65%) and b (20%) isothiocyanato
ulosonates 18a and 18b as isolated products.
Table 1 shows selected spectroscopic data for the structural
assignments of compounds 4–5, 7–11, and 16–18. Thus the

J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
99
Scheme 2. Preparation of 5-epithiohydantocidin, N-alkyl and N-glycosylthiohydantoin spironucleosides from glycosylaminoesters (route A) and from methyl
isothiocyanatoulosonates (route B).
IR spectra of the azido derivatives 4–5, 7, 8, and 16 had
absorption for the N3 group at 2116–2128 cmK1. The NMR
spectra of 4 showed no signals for a SiMe3 group, and the
OH was evident from the IR absorption at 3497 cmK1 and
from the interchangeable (D2O) double doublet at 2.12 ppm
in the 1H NMR spectrum. The hydrated form of 5 appeared
in the 1H NMR spectrum in a 1:4 ratio with respect to the free
aldehyde, the chemical shift for the resonance of H-1 of the
hydrate being 5.22 ppm. The carbonyl groups of the b-azido
ulosonic esters 7, 8 and 16, resonated at 165.4–166.7 ppm
(Table 1) as is reported14 for related azido esters. The signal
for the resonance of the anomeric carbon in 4, 5, 7, and 8 was
close to 91 ppm, as is described for glycopyranosyl azides;15
the same carbon for the furanoid derivative 16 resonated at
100.5 ppm. The b configuration for the major compound in
the anomeric mixture 9 is proposed according to the order of
formation, and the anomeric ratio is given in the equilibrium
(NMR measurements). In the 6:1 anomeric mixture 17 the
major compound was the a anomer. The anomeric
configuration being supported on the order of formation,
and on the differences of chemical shifts of H-3 and C-3 for
the two anomers (H-3 is relatively deshielded in the a
anomer whereas C-3 is relatively shielded in the same
anomer), which is in agreement with reported data for
related compounds.16 The isothiocyanato group of 11, 18a
and 18b was evident from the corresponding IR absorptions
Table 1. Selected spectroscopic data (n cmK1, d ppm, J Hz) for compound 3–5, 7–11, and 16–18a
b
Compound
nN3b/nNCS
d C-1
d C-2
d C-3
d NCS
4
5
7
2118
2122
2126
2128
—
64.9
91.7
90.9
91.1
90.3
86.1
85.4
87.7
100.5
93.6
95.1
97.7
76.2
74.6
76.7
70.8
77.2
72.2
72.9
86.9
81.7
84.4
88.8
—
—
—
—
—
—
145.1
—
—
192.5
166.7
165.8
171.4
170.9
165.0
165.4
169.9
166.0
164.9
8
9c
10c
11
16
17c
18a
18b
—
2002
2116
—
2018
2016
144.9
145.1
a NMR data are obtained in CDCl3.
b KBr discs.
c Data for the major anomer.

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J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
Table 2. Synthesis of thiohydantoin spironucleosides
Entry
Starting aminoester or isothiocyanatoulo-
sonate (anomeric ratio)
Route
A
Product (s)
Yield (%)
1
9 (a:b 1:9)
65 (20a) 31
(20b)
2
3
10 (5:2)
10 (5:2)
A
A
70
76 (22a) 9
(22b)
4
10 (5:2)
A
81
5
11 (only a anomer)
B
72
6
17 (a:b 6:1)
A
79
7
17 (a:b 6:1)
A
83
8
9
18 (a:b 13:4)
B
B
74 (27a) 20
(27b)
18 (a:b 13:4)
64 (28a) 21
(28b)

J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
101
Table 2 (continued)
Entry
Starting aminoester or isothiocyanatoulo-
sonate (anomeric ratio)
Route
B
Product (s)
Yield (%)
10
11
12
18 (a:b 13:4)
60 (29a) 17
(29b)
18 (a:b 13:4)
B
A
73 (30a) 21
(30b)
19 (1:5)
94
13
19 (1:5)
A
94
at 2000–2018 cmK1, and from the 13C resonances at roughly
145 ppm, characteristic of glycosyl isothiocyanates.17 The
vicinal coupling constants between the protons of the
pyranoid ring of 11 were indicative of C2 conformation,
0
slightly distorted by the dioxolane ring (the value of J5,6 , for
96% yield the resoluble mixture of spirothiohydantoins 20
(Scheme 2, route A and Table 2, entry 1). This reaction was
low-yielding under milder conditions, probably due to the
stabilization by hydrogen bondings between the amino
group and the oxygen atoms on C-1 and C-3 in the starting
aminoester. The reaction involves the formation of an
intermediate thiourea which spontaneously cyclates to the
thiohydantoin.20
5
example, was 6.9 Hz). The anomeric configuration (the NCS
group is in a position) of this compound was deduced from
its transformation into the spiranic compound 24 and from
3
the NMR data of 24 (see below). The JHH values for the
protons of the furanoid ring of 18b were very close to that for
the b-D-psicofuranosyl azide.6b The anomeric carbon in 18a
resonated at higher field (95.1 ppm) than the same carbon in
18b (97.7 ppm), as in related pairs of anomers.14b,16a,18 This
assignment of the anomeric configurations were confirmed
by the NMR data of 27–30 (see below).
The IR spectra of 20a and 20b had the signal for the
carbonyl group (nCZO) at 1765 cmK1, and the C]S and
C]O groups resonated (Table 3) at roughly 184 and
169.5 ppm, respectively, in accord with that described for
related spirohydantoins.21 The 3JHH values between protons
of the pyranose ring were indicative of the C1 confor-
4
mation. The anomeric configuration is based on the value of
the JCH between C-4 and H-10 (Fig. 1), which was in the
The glycosylamines 9, 10 and 17, together with described19
methyl 2-aminohept-2-ulofuranosonate 19 were used in the
route A to prepare spirothiohydantoins (Scheme 2). Both
anomers of 19 had been reported as isolated products. In our
first attempt to prepare spirothiohydantoins from 19, pure a
and b anomers were used; but, due to the anomeric
equilibrium under the reaction conditions, in both cases
the same spirothiohydantoin was obtained, consequently,
the anomeric mixture 19 aCb was used in subsequent
reactions. A related cyclization using phenylisocyanate as
sole heterocumulene has been reported.16a
3
range18,21 for antiperiplanar nuclei in 20a (6.8 Hz) and in
the range for gauche nuclei in 20b (2.6 Hz). Additionally,
the resonance for H-1 (NH) of 20b was at lower field than
that for 20a, as in spirohydantoins of other pyranoid
sugars.21
The a configuration of 21 was deduced from the value
(5.9 Hz) of the coupling constant between H-10 and C-4,
indicative of anti relationship between the corresponding
nuclei.
Treatment of the anomeric mixture of aminoesters 9 with
phenyl isothiocyanate in DMF at 85 8C for 23 h resulted in
Similarly, the reaction of 10 with 2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl isothiocyanate22 and with 2,3,5-tri-O-

102
J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
benzoyl-b-D-ribofuranosyl isothiocyanate23 gave the N-gly-
cosyl spirothiohydantoins 22a, 22b (entry 3) and 23 (entry
4).
The treatment of the ulofuranosonic aminoester 17 with the
same glycosyl isothiocyanates gave, in high yield, the
furanoid spirothiohydantoins 25 and 26 only as a anomers
(Table 2, entries 6 and 7). Selected structural data, including
representative diaxial 3JH,H values of pyranoids derivatives,
of 22, 23, 25 and 26 are shown in Table 3. The anomeric
configurations were supported on HMBC24 and carbon-
proton coupled experiments in a similar way to that above
commented for 20.
Figure 1. Relationship between H-10 and C-4 in C-5 epimers of pyranoid
spirothiohydantoins.
moiety and C-4 of 31–32 practically coincide with those for
the a anomers 25, 26, 27a, 28a, 29a, and 30a, we propose
that in both cases the same spatial relationship exists, that is,
31 and 32 have b anomeric configuration.
The last spirothiohydantoins prepared through route A were
31 and 32, which were obtained, in almost quantitative
yield, by reaction of the sugar aminoester anomeric
mixture19 19 (see above) with 2,3,4,6-tetra-O-acetyl-b-D-
glucopyranosyl isothiocyanate22 and with 2,3,5-tri-O-
benzoyl-b-D-ribofuranosyl isothiocyanate23 respectively,
under mild conditions (Table 2, entries 12 and 13). As the
configuration of C-4 and C-3 in 31 and 32 are the contrary to
those for 25–28, and the spectroscopic data for the hydration
Compounds 22–26, 31 and 32 had a glycosyl radical on N-8,
consequently their structures are simultaneously those of N-
and spiro-nucleoside.
The route B (Scheme 2) to prepare thiohydantoin
spironucleosides is the reaction of methyl isothiocyanatou-
losonates with ammonia, alkyl, and aryl amines.
Table 3. Selected NMR data (d ppm, J Hz) for spironucleosides 20–35 at 500 MHz in CDCl3
Compounda
d H-1 (NH)
d H-10
J9,10
d C-2 (C]S)
d C-4 (C]O)
d C-5
d C-10
20a
20b
21(a)
22a
22b
23(a)
24(a)
33(a)
34(a)b
7.06
9.09
8.04–7.18
7.65
8.24
8.13–7.26
7.52
8.72
3.70
4.10
5.67
5.52
5.79
5.52
5.65
5.75
3.95
7.1
7.9
7.4
7.8
6.9
7.8
7.4
9.7
10.1
183.6
184.9
182.8
182.1
183.5
181.2
183.2
182.1
185.6
169.4
169.5
168.7
167.1
166.7
168.2
168.9
166.7
172.0
86.6
87.1
85.6
84.4
84.5
84.8
85.5
84.5
88.0
77.7
77.0
71.2
71.1
68.4
71.2
71.1
71.5
70.3
—
Compounda
d H-6
d H-4
J3,4
d C-7
d C-9
d C-5
d C-4
25(a)
26(a)
27a
27b
28a
28b
29a
29b
30a
30b
31b
32b
35a
7.38
8.13–7.34
8.09–7.43
7.49
7.41
7.43
7.27
7.32
8.09–7.31
7.76
7.34
4.88
4.63
4.88
4.93
4.83
4.92–4.87
4.82
4.92–4.85
4.99
5.00
6.0
6.0
6.1
6.4
6.0
—
181.6
181.2
181.2
180.8
183.5
183.3
183.2
183.1
182.8
182.7
181.6
181.4
185.0
170.5
169.9
171.2
168.1
170.9
168.0
171.0
168.2
170.4
167.5
170.5
170.6
167.8
91.5
92.1
94.7
95.8
92.8
93.8
92.4
93.6
93.0
94.1
89.7
90.2
95.5
80.2
80.6
80.7
86.2
80.7
86.1
80.6
86.1
80.9
86.3
80.0
80.1
74.6
6.0
—
6.1
6.1
5.9
5.9
4.8
4.84
4.89
4.32
7.31
—
In MeOH-d4.
a In the second part of the table (furanoid derivatives) the numbering of formulas changes, but homologous nuclei are in the same column as in the first part.
b In D2O.

J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
103
Thus, the treatment of the pyranoid isothiocyanate 11 with
4-methoxyaniline, in DMF at 85 8C, produced (Table 2,
entry 5) the spirothiohydantoin 24, whose spectroscopic
data (Table 3) supported the indicated structure. The
coupling constant (5.8 Hz) between C-4 and H-10 con-
firmed18 the a configuration not only for 24, but also for the
starting isothiocyanate 11.
methoxide of 35 produced the 5-epithiohydantocidin 36a,
together with its b anomer 36b (a:b anomeric ratio 6:1,
global yield 85%). Related spiroepimerizations have been
reported.7f,26 The spectroscopic data of 36a and 36b
coincide with those previously reported16c for the same
compounds prepared through an iminophosphorane
intermediate.
Reactions of a mixture of the anomers 18a and 18b with
ammonia, methylamine, dodecylamine, and aniline, gave
the corresponding thioureido derivative, which spon-
taneously cyclates, in the reaction medium, and under
mild conditions, to afford the corresponding spironucleo-
sides (27–30) in high yields (Table 2, entries 8–11). In all
cases, mixtures of spiroanomers were obtained, which could
be resolved. Table 3 shows selected spectroscopic data for
these compounds. The most significant differences between
the NMR data for the a and the b anomers are the chemical
shifts of H-2, C-4, and C-5, which resonated at lower field in
the minor b anomers, than in the major a anomers. The
difference in the chemical shift of H-2 has been previously
reported,16b and has been used to define the anomeric
configuration of thiohydantocidin.16c The d values for C-2
and C-3 are virtually identical in all the a anomers, and
differ by 2 ppm in the b anomers. The coupling constants
between H-2 and CH2OBz are higher in the a anomers than
in the b anomers. These data further confirmed the anomeric
configurations of 18a and 18b.
3. Conclusion
Glycosylaminoesters and 2-deoxy-2-isothiocyanato-hex-2-
ulofura(pyra)nosonates —a new class of glycosyl isothio-
cyanate- are easily and stereoselectively prepared from sugar
spiroacetals. Both types of compound can be transformed
under mild conditions and in high yields, into glycosylspir-
othiohydantoins, including 5-epithiohydantocidin. The tar-
get compounds are spironucleosides, and in the case of
N-glycosyl derivatives are simultaneously N-nucleosides.
4. Experimental
4.1. General methods
Unless otherwise noted, starting materials were obtained for
commercial suppliers and used without purification. All
manipulations of air-sensitive compounds were carried out
in an inert atmosphere under recirculation of nitrogen or
argon. The following reaction solvents were distilled under
nitrogen immediately before use: THF and Et2O from Na/
benzophenone; CH2Cl2 from CaH2; toluene from Na; and
MeOH from Mg. Et2O and petroleum ether for column
chromatography were also distilled under nitrogen from Na/
benzophenone before use. TLC were performed on silica gel
HF254, with visualization by UV light or charring with 10%
H2SO4 (EtOH) or 1% Ce(SO4)2. 4H2O-5% ammonium
molybdate-6% H2SO4. Silica gel 60 (Merck, 70–230 or
230–400 mesh) was used for preparative chromatography.
With the goal of having O-unprotected spirothiohydantoins,
the deprotections of 22a and 27a have been carried out
(Scheme 3).
The isopropylidene group of 22a was removed with DDQ25
in acetonitrile:water 9:1 at 45 8C, obtaining 33, which was
O-debenzoylated by treatment with sodium methoxide in
methanol. No measurable anomerization14a was observed,
and the O-unprotected N- and spironucleoside 34 was
obtained in 85% yield after preparative HPLC.
In the case of 27a the acetal group was removed (/35) in
91% yield, by treatment with TFA:H2O 2:3 as reported for
its C-7 oxo analogue.16b The O-debenzoylation with sodium
A Perkin-Elmer model 141 MC polarimeter, tubes of 1 cm,
and solutions in CH2Cl2, unless other stated, at 589 nm,
were used for measurements of specific rotations. IR were
Scheme 3. Total deprotection of spirohydantoins 22a and 27a. Reagents and conditions: (i) DDQ, CH3CN:H2O 9:1, 45 8C, 36 h, 83%; (ii) NaOMe 1M, MeOH,
91% (36aC36b), 85% (34); (iii) TFA:H2O 2:3, rt., 1 h, 91%.

104
J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
recorded for KBr discs or films on a Bomen Michelson MB
120 FTIR spectrophotometer.
DMSO (0.17 mL, 2.4 mmol) in CH2Cl2 (2 mL) was added.
The mixture was stirred for 5 min, and a solution of 4
(100 mg, 0.3 mmol) in CH2Cl2 (1.5 mL) was then added
dropwise. After 30 min, Et3N (0.42 mL, 3 mmol) was
added. The mixture was stirred at K70 8C for another
5 min, and then raised to room temperature slowly. A
solution of saturated NaHCO3 (2 mL) was added and the
mixture was extracted with AcOEt (3!4 mL), dried
(MgSO4), evaporated, and purified by column chromatog-
raphy (Et2O/petroleum ether 1:2). Yield: 0.091 g, 92%
(amorphous solid). IR: nmax 2984, 2122 (N3), 1576, 1417,
1117 and 1101 cmK1. 1H NMR (500 MHz, CDCl3, d ppm, J
Hz): d 9.28 (s, 1H, H-1), 7.36–7.30 (m, 5H, Ar), 4.77 (s, 2H,
CH2Ph), 4.40 (dd, 1H, J4,5Z6.5 Hz, H-4), 4.31 (ddd, 1H, H-
5), 4.24 (dd, 1H, J5,6aZ2.5 Hz, J6a,6bZ13.1 Hz, H-6a), 4.12
(dd, 1H, J5,6Z1.1 Hz, H-6b), 3.91 (d, 1H, J3,4Z5.7 Hz, H-
3), 1.48, 1.35 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, d ppm): d 192.5 (C-1), 137.5–127.7
(Ar), 109.9 (CCH3), 90.9 (C-2), 74.6 (C-3), 73.9 (C-4,
CH2Ph), 72.4 (C-5), 62.4 (C-6), 27.0, 25.3 (2CH3).
HRFABMS m/z calcd. for C16H21N3O6Na ([MCH2OC
Na]C): 374.1328, found: 374.1331.
Mass spectra (EI, CI and FAB) were recorded with a Kratos
MS-80RFA or a Micromass AutoSpecQ instrument with a
resolution of 1000 or 60000 (10% valley resolution). For the
FAB spectra ions were produced by a beam of xenon atoms
(6–7 keV), using 3-nitrobenzyl alcohol or thioglycerol as
matrix and NaI as salt.
A Waters 2690 instrument, with a PDA 996 detector, and
a mBondpack C18 column (7,8!300 mm) was used for
HPLC.
NMR experiments were recorded on a Bruker AMX 500
(500.13 MHz for 1H and 125.75 MHz for 13C) or on a
1
Bruker AMX300 (300.5 MHz for H and 75.50 MHz for
13C). Sample concentrations were typically in the range
10–15 mg per 0.5 mL of CDCl3. Chemical shifts are given
in parts per million, and tetramethylsilane was the internal
standard. 2D COSY, HMQC, TOCSY, HMBC and 1D
NOESY experiments were carried out to assist in NMR
signal assignments.
1H NMR data for the hydrate of 5. (500 MHz, CDCl3, d
ppm, J Hz) d 7.35–7.30 (m, 5H, Ar), 5.22 (s, 1H, H-1), 4.93
(d, 1H, JH,HZ11.5 Hz, CHHPh), 4.67 (d, 1H, CHHPh),
4.40 (dd, 1H, J4,5Z5.8 Hz, H-4), 4.30 (m, 1H, H-5), 4.20
(dd, 1H, J5,6aZ1.5 Hz, J6a,6bZ13.4 Hz, H-6a), 4.13 (dd,
1H, J5,6bZ3.0 Hz, H-6b), 3.92 (d, 1H, J3,4Z7.3 Hz, H-3),
1.52, 1.38 (2CH3).
Compounds 211, 1211 and 1919 were prepared according to
the described literature procedures. Compounds 3 and 13
were prepared as we described in a previous work.7f
2
4.2. 2-Azido-3-O-benzyl-2-deoxy-4,5-O-isopropylidene-
b-D-fructopyranose (4) and 2-azido-6-O-benzyl-2-deoxy-
3,4-O-isopropylidene-b-D-psicofuranose (14)
To a solution of 3 (for 4) or 13 (for 14) (100 mg, 0.25 mmol)
a catalytic amount of TBAF$3H2O in THF (3 mL) was
added. The mixture was stirred at room temperature for 2 h,
evaporated, and purified by column chromatography (Et2O/
petroleum ether 1:5).
4.4. Methyl (3-O-benzyl-2-deoxy-4,5-O-isopropylidene-
b-D-arabino-hex-2-ulopyranosyl)onate azide (7)
To a solution of 5 (100 mg, 0.3 mmol) and 2-methylbut-2-
ene (0.32 mL, 3 mmol) in 2-methylpropan-2-ol (2 mL) at
0 8C, another solution of NaClO2 (81 mg, 0.9 mmol) and
NaH2PO4.2H2O (140 mg, 0.9 mmol) in H2O (1 mL) was
added. The mixture was stirred at room temperature for 2 h,
evaporated to half, extracted with Et2O (3!8 mL), washed
with HCl (2%, 20 mL) and then with brine, dried (MgSO4),
and evaporated to dryness. The residue was dissolved in
Et2O:MeOH (5 mL) and stirred at 0 8C with a solution of
CH2N2 in Et2O (5 mL) for 20 min, then evaporated and
purified by column chromatography (Et2O/petroleum ether
2:1). Yield: 0.089 g, 82% (amorphous solid). [a]2D4 K106 (c
2.0). IR: nmax. 2988, 2953, 2126(N3), 1755, 1381, 1244,
Data for 4. Yield: 0.072 g, 88% (syrup). [a]2D7 K158 (c 1.0).
IR: nmax 3497, 3032, 2986, 2934, 2880, 2118 (N3), 1458,
1
1375, 1248, 1221, 1115, 1078 and 1022 cmK1. H RMN
(500 MHz, CDCl3, d ppm, J Hz): d 7.38–7.26 (m, 5H, Ar),
2
4.92 (d, 1H, JH,HZ11.7 Hz, CHHPh), 4.68 (d, 1H,
CHHPh), 4.38 (dd, 1H, J4,5Z5.89 Hz, J3,4Z7.2 Hz, H-4),
4.28 (dt, 1H, J5,6aZJ5,6bZ1.9 Hz, H-5), 4.14 (m, 2H, H-6a,
H-6b), 3.88 (dd, 1H, J1a,1bZ11.7 Hz, J1a,OHZ6.3 Hz,
H-1a), 3.81 (dd, 1H, J1b,OHZ7.9 Hz, H-1b), 3.65 (d, 1H,
H-3), 2.12 (dd, OH), 1.50, 1.39 (each s, each 3H, 2CH3). 13C
NMR (125.7 MHz, CDCl3, d ppm, J Hz): d 128.6–127.4
(Ar), 109.1 (CCH3), 91.7 (C-2), 76.5 (C-4), 76.2 (C-3), 73.2
(C-5), 73.0 (CH2Bn), 64.9 (C-1), 61.6 (C-6), 27.8, 26.0
(2CH3). HREIMS m/z calcd for C16H21O5N3 ([M]C):
335.1481, found: 335.1483.
1
1121 and 1074 cmK1. H NMR (300 MHz, CDCl3, d ppm,
2
J Hz): d 7.33–7.27 (m, 5H, Ar), 4.84 (d, 1H, JH,H
Z
11.8 Hz, CHHPh), 4.69 (d, 1H, CHHPh), 4.37 (dd, 1H, H-4),
4.30 (ddd, 1H, J4,5Z6.0 Hz, J5,6aZ2.5 Hz, J5,6bZ1.8 Hz,
H-5), 4.16 (m, 2H, H-6a, H-6b), 4.01 (d, 1H, J3,4Z6.8 Hz,
H-3), 3.75 (s, 3H, OCH3), 1.52, 1.37 (each s, each 3H,
2CH3). 13C NMR (75 MHz, CDCl3, d ppm): d 166.7 (C-1),
137.3–127.7 (Ar), 109.4 (CCH3), 91.1 (C-2), 76.7 (C-3),
75.8 (C-4), 73.5 (CH2Ph), 72.6 (C-5), 63.0 (C-6), 53.2
(OCH3), 27.5, 25.8 (2CH3). HRFABMS m/z calcd for
C17H21O6N3Na ([MCNa]C): 386.1, found 386.1331. Anal.
Calcd for C17H21O6N3: C, 56.19; H, 5.83; N, 11.56. Found:
C, 56.29; H, 5.88; N, 11.65.
Data for 14. Yield: 0.088 g (92%). The spectroscopic data
for 14 were coincident with those reported6b for the same
compound prepared in a different way.
4.3. 2-Azido-3-O-benzyl-1-dehydro-2-deoxy-4,5-O-iso-
propylidene-b-D-fructopyranose (5)
To a cold solution (K70 8C) of oxalyl chloride (0.1 mL,
1.2 mmol) in CH2Cl2 (1 mL), under argon, a solution of

J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
105
4.5. General procedure for the oxidation of 4 and 14 with
RuO4. Preparation of compounds 8 and 16
NMR (500 MHz, CDCl3, d ppm J Hz): d 7.33–7.27 (m, 5H,
Ar), 4.85 (d, 1H, JH,HZ11.7 Hz, CHHPh), 4.65 (d, 1H,
2
CHHPh), 4.39 (dd, 1H, J5,6aZ2.9 Hz, J6a,6bZ13.1 Hz,
H-6a), 4.30 (t, 1H, H-4), 4.23 (dd, 1H, J4,5Z6.4 Hz, H-5),
3.98 (d, 1H, J3,4Z7.1 Hz, H-3), 3.97 (d, 1H, H-6b), 3.70
(s, 3H, OCH3), 2.17 (bs, 2H, NH2), 1.54, 1.38 (each s, each
3H, 2CH3). 13C NMR (125.7 MHz, CDCl3, d ppm): d 171.4
(C-1), 137.8–127.7 (Ar), 108.9 (CCH3), 86.1 (C-2), 77.2
(C-3), 77.0 (C-4), 73.4 (C-5), 72.9 (CH2Ph), 59.8 (C-6), 52.8
(OCH3), 27.9, 26.2 (2CH3). HRFABMS m/z calcd for
C17H23O6NNa ([MCNa]C): 360.1423, found: 360.1423.
To a stirred solution of 4 (for 8) or 14 (for 16) (335 mg,
1.0 mmol), CH3CN (5.4 mL), CCl4 (5.4 mL), H2O (8 mL)
and NaIO4 (1.12 g, 5.2 mmol) RuCl3. H2O (0.12 g,
0.52 mmol) was added. The mixture was stirred vigorously
for 15 min at room temperature, diluted with buffer AcOH/
AcOK (1 M; pHZ4), filtered over Celite, extracted with
CH2Cl2 (20 mL), dried (MgSO4), and evaporated to
dryness. The residue was dissolved in Et2O:MeOH 1:1
(15 mL) and stirred at 0 8C with a solution of CH2N2 in Et2O
for 20 min, evaporated, and purified by column chromato-
graphy (Et2O/petroleum ether 1:6).
4.6.2. Methyl (3-O-benzoyl-2-deoxy-4,5-O-isopropyl-
idene-a,b-D-arabino-hex-2-ulopyranosyl)onate amine
(10). xZ0.113 g. Diastereoisomers in C-2 ratio 5:2
(configuration not determinated). Column chromatography:
Et2O/petroleum ether 2:3. Yield: 0.074 g, 70% (syrup).
HRCIMS: m/z calcd for ([MCH]C): 352.1396, found:
352.1399. IR: nmax. 3412, 3309, 2986, 1743, 1734, 1437,
4.5.1. Methyl (3-O-benzoyl-2-deoxy-4,5-O-isopropyl-
idene-b-D-arabino-hex-2-ulopyranosyl)onate azide (8).
Yield: 0.170 g, 45% (syrup). [a]2D5 K95 (c 0.9). IR: nmax
2988, 2948, 2128(N3), 1755, 1732, 1385, 1223, 1076 and
1101 cmK1.1H NMR (300 MHz, CDCl3, d ppm, J Hz): d
8.06–7.42 (m, 5H, Ar), 5.69 (d, 1H, J3,4Z7.3 Hz, H-3), 4.44
(dd, 1H, J4,5Z5.6 Hz, H-4), 4.35 (m, 2H, H-5, H-6a), 4.24
(dd, 1H, J5,6bZ2.8 Hz, J6a,6bZ13.5 Hz, H-6b), 3.79 (s, 3H,
OCH3), 1.61, 1.39 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, d ppm): d 165.8, 164.9 (C-1, C]O),
133.5–127.8 (Ar), 110.2 (CCH3), 90.3 (C-2), 73.5 (C-4),
72.7 (C-5), 70.8 (C-3), 62.9 (C-6), 53.6 (OCH3), 27.3, 26.0
(2CH3). HRCIMS m/z calcd for C17H20O7N3 ([MCH]C):
378.1301, found: 378.1304.
1249, 1119 and 1099 cmK1
.
NMR data for the major anomer. 1H NMR (500 MHz,
CDCl3, d ppm, J Hz): d 8.03–7.41 (m, 5H, Ar), 5.66 (d, 1H,
J3,4Z7.7 Hz, H-3), 4.42 (dd, 1H, J5,6aZ2.9 Hz, H-6a), 4.39
(dd, 1H, J4,5Z5.5 Hz, H-4), 4.30 (dd, 1H, H-5), 4.13 (d, 1H,
J6a,6bZ13.2 Hz, H-6b), 3.74 (s, 3H, OCH3), 2.11 (bs, 2H,
NH2), 1.65, 1.37 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, (ppm): (170.9 (C-1), 164.7 (COPh),
133.3–128.3 (Ar), 109.6 (CCH3), 85.4 (C-2), 74.3 (C-4),
73.3 (C-5), 72.2 (C-3), 59.9 (C-6), 53.26 (OCH3), 27.6, 26.2
(2CH3).
4.5.2. Methyl (6-O-benzoyl-2-deoxy-3,4-O-isopropyl-
idene-b-D-ribo-hex-2-ulofuranosyl)onate azide (16).
Yield: 0.170 g, 45% (syrup). [a]2D5 K104 (c 0.85). IR:
nmax 2990, 2116(N3), 1763, 1724, 1453, 1375, 1273, 1107
and 1070 cmK1. 1H NMR: (500 MHz, CDCl3, d ppm, J Hz):
d 8.09–7.43 (m, 5H, Ar), 4.89 (dd, 1H, J4,5Z1.5 Hz, H-4),
4.82 (dt, 1H, H-5), 4.70 (d, 1H, J3,4Z5.8 Hz, H-3), 4.55 (dd,
1H, J5,6aZ6.0 Hz, J6a,6bZ11.8 Hz, H-6a), 4.48 (dd, 1H,
J5,6bZ6.1 Hz, H-6b), 3.89 (s, 3H, OCH3), 1.48, 1.32 (each s,
each 3H, 2CH3). 13C NMR (125.7 MHz, CDCl3, d ppm): d
166.0, 165.4 (C-1, C]O), 133.2–128.1 (Ar), 114.3 (CCH3),
100.5 (C-2), 86.9 (C-3), 85.7 (C-5), 81.9 (C-4), 63.9 (C-6),
53.1 (OCH3), 26.0, 25.1 (2CH3). HRFABMS m/z calcd for
C17H19O7N3Na ([MCNa]C): 400.1121, found: 400.1124.
Anal. Calcd for C17H19O7N3: C, 54.11; H, 5.08; N, 11.14.
Found: C, 54.32; H, 5.09; N, 11.14.
NMR data for the minor anomer. 1H NMR (500 MHz,
CDCl3, ( ppm, J Hz): ( 8.03–7.40 (m, 5H, Ar), 5.37 (d, 1H,
J3,4Z7.1 Hz, H-3), 4.84 (t, 1H, J4,5Z6.1 Hz, H-4), 4.33 (dd,
1H, H-5), 4.20 (dd, 1H, J5,6aZ2.0 Hz, J6a,6bZ13.7 Hz,
H-6a), 3.88 (dd, 1H, J5,6bZ3.1 Hz, H-6b), 3.78 (s, 3H,
OCH3), 2.38 Method, 2H, NH2), 1.62, 1.57 (each s, each 3H,
2CH3). 13C NMR (125.7 MHz, CDCl3, (ppm): (167.6 (C-1),
165.2 (COPh), 133.3–128.3 (Ar), 109.3 (CCH3), 87.6 (C-2),
74.7 (C-4), 73.5 (C-3), 72.8 (C-5), 63.1 (C-6), 52.4 (OCH3),
27.7, 26.0 (2CH3).
4.6.3. Methyl (6-O-benzoyl-2-deoxy-3,4-O-isopropyl-
idene-a,b-D-ribo-hex-2-ulofuranosyl)onate amine (17).
xZ0.113 g. Diastereoisomers in C-2 ratio (a:b) 6:1.
Column chromatography: Et2O/petroleum ether 1:2.
Yield: 0.10 g, 95% (syrup). IR: nmax 3422, 3343, 2988,
1734, 1720, 1655, 1383, 1273 and 1097 cmK1. HRCIMS
m/z calcd for C17H22O7N1([MCH]C): 352.1396, found:
352.1398. Anal. Calcd for C17H21O7N: C, 58.11; H, 6.02; N,
3.99, found C, 57.94; H, 6.06; N, 3.82.
4.6. General procedure for the reduction of azides 7, 8
and 16. Preparation of amines 9, 10 and 17
A solution of the corresponding azide 7 (for 9), 8 (for 10) or
16 (for 17) (x mg, 0.3 mmol) in MeOH (10 mL) was stirred
at room temperature in the presence of Pd-C 10% (20 mg)
and hydrogen (balloon pressure) for 1 h. The mixture was
filtered over Celite, evaporated, and purified by column
chromatography.
NMR data for the a anomer. 1H NMR (500 MHz, CDCl3, d
ppm, J Hz): d 8.05–7.46 (m, 5H, Ar), 5.02 (d, 1H, J3,4
Z
6.1 Hz, H-3), 4.85 (dd, 1H, J4,5Z3.4 Hz, H-4), 4.45 (td, 1H,
J5,6aZJ5,6bZ5.7 Hz, H-5), 4.34 (m, 2H, H-6a, H-6b), 3.73
(s, 3H, OCH3), 2.56 (bs, 2H, NH2), 1.59, 1.38 (each s, each
3H, 2CH3). 13C NMR (125.7 MHz, CDCl3, d ppm): d 169.9
(C-1), 166.1 (COPh), 133.1–128.3 (Ar), 113.8 (CCH3), 93.6
(C-2), 82.4 (C-4), 81.8 (C-5), 81.7 (C-3), 64.2 (C-6), 52.7
(OCH3), 26.8, 25.2 (2CH3).
4.6.1. Methyl (3-O-benzyl-2-deoxy-4,5-O-isopropyl-
idene-a,b-D-arabino-hex-2-ulopyranosyl)onate amine
(9). xZ0.109 g. Relationship of diastereoisomers in C-2
ratio (a:b) 1:9. Column chromatography: Et2O/petroleum
ether 1:6. Yield: 0.10 g, 99% (syrup). IR: nmax. 3395, 3335,
1
2984, 1743, 1433, 1381, 1249, 1167 and 1068 cmK1. H

106
J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
1
NMR data for the b anomer. 1H NMR (500 MHz, CDCl3, d
ppm, J Hz): d 8.05–7.42 (m, 5H, Ar), 4.89 (dd, 1H, J4,5
0.034 g, 20%. [a]2D5 K115 (c 0.5). H NMR (500 MHz,
Z
CDCl3, d ppm, J Hz): d 8.09–7.45 (m, 5H, Ar), 4.98 (d, 1H,
J3,4Z5.8 Hz, H-3), 4.94 (dd, 1H, J4,5Z1.3 Hz, H-4), 4.81
(td, 1H, H-5), 4.55 (dd, 1H, J5,6aZ6.1 Hz, H-6a), 4.50 (dd,
1H, J5,6bZ5.6 Hz, J6a,6bZ12.0 Hz, H-6b), 3.92 (s, 3H,
OCH3), 1.47, 1.33 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, d ppm): d 165.9 (C]O), 164.9 (C-1),
145.1 (NCS), 133.2–128.4 (Ar), 114.6 (CCH3), 97.7 (C-2),
88.8 (C-3), 85.8 (C-5), 81.8 (C-4), 63.5 (C-6), 53.4 (OCH3),
25.8, 25.0 (2CH3). HRCIMS m/z calcd for C18H20O7NS
([MCH]C): 394.0961, found: 394.0971.
1.9 Hz, H-4), 4.71 (td, 1H, J5,6aZJ5,6bZ6.4 Hz, H-5), 4.61
(d, 1H, J3,4Z6.1 Hz, H-3), 4.56 (ddd, 2H, J6a,6bZ11.4 Hz,
H-6a, H-6b), 3.83 (s, 3H, OCH3), 1.48, 1.32 (each s, each
3H, 2CH3). 13C NMR (125.7 MHz, CDCl3, d ppm): d 170.9
(C-1), 166.1 (COPh), 133.0–128.0 (Ar), 113.9 (CCH3), 96.2
(C-2), 88.4 (C-3), 84.7 (C-5), 82.7 (C-4), 65.3 (C-6), 52.6
(OCH3), 26.2, 25.1 (2CH3).
4.7. General procedure for the preparation of the
isothiocyanatoulosonates 11, 18a, and 18b
4.8. General procedures for the reactions of the glyco-
sylaminoesters 9, 10, 17, and 19 (aCb) with alkyl or aryl
isothiocyanates (Route A). Preparation of the hydanto-
cidin-related spironucleosides 20a, 20b, 21, 22a, 22b, 23,
25, 26, 31, and 32†
To a mixture of a solution of the glycosylaminoester 10 (for
11) or 17 (for 18a and 18b) (150 mg, 0.43 mmol) in CH2Cl2
(3 mL), and CaCO3 (300 mg, 3.0 mmol) in H2O (0.75 mL),
was added CSCl2 (120 ml, 1.5 mmol). The mixture was
stirred vigorously at room temperature for 3 days, diluted
with CH2Cl2 (30 mL), washed with water and then brine,
dried (MgSO4), and evaporated to dryness. The residue was
purified by column chromatography.
Method I (used for the preparation of compounds 20a and
20b). A solution of 9 (100 mg, 0.3 mmol) in DMF was
stirred with phenylisothiocyanate (53 mL, 0.45 mmol) at
85 8C for 23 h. The solvent was evaporated and the residue
was purified by column chromathography.
4.7.1. Methyl (2-deoxy-3-O-benzoyl-4,5-O-isopropyl-
idene-a-D-arabino-hex-2-ulopyranosyl)onate isothiocya-
nate (11). The residue was a 16:1 mixture of anomers.
Column chromatography: Et2O/petroleum ether 1:6.Yield:
0.135 g, 80% (syrup). [a]2D6 C79 (c 1.0). IR: nmax. 2986,
Method II (used for the preparation of compounds 21, 22a,
22b, 23, 25, 26, 31, and 32). A solution of the aminoester 10
(for 21, 22a, 22b and 23), 17 (for 25 and 26), or 19(aCb)
(for 31 and 32) (0.3 mmol) in THF (2 mL) was stirred at
40 8C with phenylisothiocyanate (for 21), 2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosylisothiocyanate (for 22a, 22b, 25,
and 31) or 2,3,5-tri-O-benzoyl-b-D-ribofuranosylisothiocya-
nate (for 23, 26, and 32) (0.33 mmol). After t days, the
solvent was evaporated and the residue was purified by
column chromatography.
2002 (NCS), 1740, 1736, 1314, 1261, 1103 and 1070 cmK1
.
1H NMR (500 MHz, CDCl3, d ppm, J Hz): d 7.98–7.43 (m,
5H, Ar), 5.70 (d, 1H, J3,4Z4.4 Hz, H-3), 4.50 (dd, 1H,
J4,5Z6.1 Hz, H-4), 4.43 (dd, 1H, H-5), 4.15 (d, 1H, J5,6a
Z
5.4 Hz, H-6a), 4.04 (dd, 1H, J6a,6bZ12.6 Hz, J5,6bZ6.9 Hz,
H-6b), 377 (s, 3H, OCH3), 1.61, 1.37 (each s, each 3H,
2CH3). 13C NMR (125.7 MHz, CDCl3, (ppm): (165.0 (C-1),
164 (C]O), 145.1 (NCS), 133.8–127.6 (Ar), 110.7 (CCH3),
87.7 (C-2), 72.9 (C-4), 71.3 (C-3), 69.3 (C-5), 63.6 (C-6),
53.6 (OCH3), 27.3, 25.6 (2CH3). HRFABM m/z calcd for
([MCNa]C): 416.0780, found: 416.0772. Anal. Calcd for
C18H19O7NS: C, 54.95; H, 4.87; N, 3.56. Found: C, 54.91;
H, 4.89; N, 3.59.
4.8.1. (5R,8R,9R,10S)-10-Benzyloxy-8,9-dimethylmethyl-
enedioxy-4-oxo-3-phenyl-2-thioxo-6-oxa-1,3-diazaspiro-
[4.5]decane (20a). Method I. Column chromatography:
Et2O/petroleum ether 1:4. Yield: 0.086 g, 65% (amorphous
solid). [a]2D2 K84 (c 0.5). IR: nmax 2986, 2916, 1765, 1726,
1402, 1159 and 1030 cmK1. 1H NMR (500 MHz, CDCl3, a
ppm, J Hz): ( 7.47–7.22 (m, 10H, Ar), 7.06 (bs, 1H, NH),
4.7.2. Methyl (2-deoxy-6-O-benzoyl-3,4-O-isopropyl-
idene-a-D-ribo-hex-2-ulofuranosyl)onate isothiocyanate
(18a). Column chromatography: Et2O/petroleum ether
1:9. Yield: 0.110 g, 65% (syrup). [a]2D8 K62 (c 0.86). IR:
nmax. 2986, 2018 (NCS), 1757, 1724, 1601, 1271 and
2
4.91 (d, 1H, JH,HZ11.8 Hz, CHHPh), 4.73 (d, 1H,
CHHPh), 4.72 (t, 1H, H-9), 4.59 (dd, 1H, J7a,8Z3.2 Hz,
J7a,7bZ13.5 Hz, H-7a), 4.39 (ddd, 1H, J8,9Z5.6 Hz, H-8),
4.16 (dd, 1H, J7b,8Z2.2 Hz, H-7b), 3.70 (d, 1H, J9,10
Z
1
1099 cmK1. H NMR (500 MHz, CDCl3, d ppm, J Hz): d
7.1 Hz, H-10), 1.54, 1.41 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, (ppm): (183.6 (C-2), 169.4 (C-4),
136.9–128.2 (Ar), 109.7 (CCH3), 86.6 (C-5), 77.7 (C-10),
76.8 (C-9), 73.3 (CH2Ph), 72.9 (C-8), 63.0 (C-7), 27.9, 25.9
(2CH3). HRFABMS m/z calcd for C23H24O5N2SNa ([MC
Na]C): 463.1304, found: 463.1293.
8.05–7.45 (m, 5H, Ar), 5.07 (d, 1H, J3,4Z6.8 Hz, H-3), 4.84
(dd, 1H, J4,5Z3.1 Hz, H-4), 4.68 (dd, 1H, H-5), 4.58 (dd,
1H, J5,6aZ3.8 Hz, J6a,6bZ12.2 Hz, H-6a), 4.49 (dd, 1H,
J5,6bZ4.2 Hz, H-6b), 3.80 (s, 3H, OCH3), 1.71, 1.40 (each s,
each 3H, 2CH3). 13C NMR (125.7 MHz, CDCl3, d ppm): d
166.0 (C-1), 165.9 (C]O), 144.9 (NCS), 133.5–128.1 (Ar),
117.3 (CCH3), 95.1 (C-2), 84.4 (C-3), 82.6 (C-5), 80.9
(C-4), 63.5 (C-6), 53.8 (OCH3), 26.1, 25.3 (2CH3).
HRCIMS m/z calcd for C18H20O7NS ([MCH]C):
394.0961, found: 394.0959. Anal. Calcd for C18H19O7NS:
C, 54.95; H, 4.87; N, 3.56. Found: C, 55.10; H, 4.76; N,
3.60.
4.8.2. (5S,8R,9R,10S)-10-Benzyloxy-8,9-dimethylmethyl-
enedioxy-4-oxo-3-phenyl-2-thioxo-6-oxa-1,3-diazaspiro-
[4.5]decane (20b). Method I. Column chromatography:
Et2O/petroleum ether 1:4. Yield: 0.041 g, 31% (amorphous
† For nomenclature of the spironucleosides we have followed the IUPAC
rules for spiro compounds (see rule B-10.1 in IUPAC Nomenclature of
organic Chemistry, Edition of 1979, Pergamon Press). Alternatively, the
second part of the rule 2-Carb-35.3 of Nomenclature of Carbohydrates,
recomendations 1996 (Carbohydr. Res. 1997, 297,1) would be used.
4.7.3. Methyl (2-deoxy-6-O-benzoyl-3,4-O-isopropyl-
idene-b-D-ribo-hex-2-ulofuranosyl)onate isothiocyanate
(18b). Column chromatography: Et2O/Hex 1:9. Yield:

J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
107
1
solid). [a]2D6 K110 (c 1.1). IR: nmax. 2986, 1768, 1591, 1406,
1107 and 1022 cmK1. 1H NMR (500 MHz, CDCl3, d ppm, J
Hz): d 9.09 (bs, 1H, NH), 7.47–7.15 (m, 10H, Ar), 4.93 (d,
2942, 1957, 1953, 1499, 1375, 1223 and 1099 cmK1. H
NMR (500 MHz, CDCl3, d ppm, J Hz): d 8.24 (bs, 1H, NH),
8.05–7.40 (m, 5H, Ar), 5.94 (t, 1H, H-20), 5.80 (d, 1H,
2
0
0
0
1H, CHHPh), 4.60 (d, 1H, JH,HZ10.0 Hz, CHHPh), 4.43
(dd, 1H, J9,10Z7.9 Hz, J8,9Z5.5 Hz, H-9), 4.30 (dd, 1H,
J7a,8Z1.6 Hz, H-7a), 4.28 (m, 1H, H-8), 4.13 (dd, 1H,
J2 ,3 Z9.3 Hz, H-1 ), 5.79 (d, 1H, J9,10Z6.9 Hz, H-10), 5.23
0
0
0
0
0
(t, 1H, J2 ,3 Z9.3 Hz, H-3 ), 5.16 (t, 1H, J3 ,4 Z9.8 Hz,
H-40), 4.39 (m, 2H, H-8, H-9), 4.33 (dd, 1H, J7a,8Z2.1 Hz,
0
0
J7a,7bZ10.9 Hz, J7b,8Z3.2 Hz, H-7b), 4.10 (d, 1H, J9,10
Z
J7a,7bZ13.8 Hz, H-7a), 4.21 (d, 1H, J6 a,6 bZ12.3 Hz,
7.9 Hz, H-10), 1.54, 1.38 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, (ppm): (184.9 (C-2), 169.5 (C-4),
137.1–127.6 (Ar), 109.9 (CCH3), 87.1 (C-5), 77.0 (C-10),
76.0 (C-9), 73.5 (CH2Ph), 72.5 (C-8), 63.2 (C-7), 27.8, 25.9
(2CH3). HRFABMS m/z calcd for C23H24O5N2SNa ([MC
Na]C): 463.1304, found 463.1292.
H-60a), 4.16 (dd, 1H, J5 ,6 bZ3.0 Hz, H-60b), 4.07 (dd, 1H,
J7b,8Z3.2 Hz, H-7b), 3.77 (m, 1H, H-50), 2.08, 2.01, 1.95,
1.67, 1.38 and 1.27 (each s, each 3H, 6CH3). 13C NMR
(125.7 MHz, CDCl3, d ppm): d 183.5 (C-2), 170.8, 170.1,
169.2, 168.9, 166.7, 164.0 (6C]O0), 133.4–128.4 (Ar),
111.1 (CCH3), 84.5 (C-5), 81.2 (C-1 ), 74.4*, 74.2* (C-9,
C50), 73.4 (C-30), 71.9 (C-8),068.4 (C-10), 67.7 (C-40), 67.4
(C-20), 62.9 (C-7), 61.5 (C-6 ), 27.2, 25.9, 20.7, 20.5 (2C),
19.2 (6CH3). HRCIMS m/z calcd for C31H37O15N2S ([MC
H]C): 709.1915, found: 709.1910.
0
0
4.8.3. (5R,8R,9R,10S)-10-Benzoyloxy-8,9-dimethyl-
methylenedioxy-4-oxo-3-phenyl-2-thioxo-6-oxa-1,3-di-
azaspiro[4.5]decane (21). Method II. tZ3 days. Column
chromatography: Et2O/Hex 1:5. Yield: 0.095 g, 70%
(amorphous solid). [a]2D0 K77 (c 1.1). IR: nmax. 3291,
4.8.6. (5R,8R,9R,10S)-10-Benzoyloxy-8,9-dimethyl-
methylenedioxy-4-oxo-2-thioxo-3-(20,30,50-tri-O-benzoyl-
b-D-ribofuranosyl)-6-oxa-1,3-diazaspiro[4.5]decane
(23). Method II. tZ5 days. Column chromatography: Et2O/
petroleum ether 1:3. Yield: 0.20 g, 81% (amorphous solid).
[a]2D7 K31 (c 0.9). IR: nmax 2991, 1730, 1599, 1489, 1379,
2986, 1755, 1732, 1593, 1491, 1252 and 1103 cmK1
.
1H NMR (500 MHz, CDCl3, d ppm, J Hz): d 8.04–7.18
(m, 11H, Ar, NH), 5.67 (d, 1H, J9,10Z7.4 Hz, H-10), 4.88
(dd, 1H, J8,9Z5.9 Hz, H-9), 4.65 (dd, 1H, J7a,8Z2.9 Hz,
H-7a), 4.50 (m, 1H, H-8), 4.34 (d, 1H, J7a,7bZ13.6 Hz,
H-7b), 1.67, 142 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, d ppm): d 182.8 (C-2), 168.7 (C-4),
165.5 (C]O), 133.8–128.1 (Ar), 110.3 (CCH3), 85.6 (C-5),
73.7 (C-9), 72.9 (C-8), 71.2 (C-10), 63.4 (C-7), 27.6, 25.9
(2CH3). HRCIMS m/z calcd for C23H22O6N2S ([MCH]C):
455.1277, found: 455.1264.
1265, 1105 cmK1 1H NMR (500 MHz, CDCl3, d ppm,
.
0
0
J Hz): d 8.13–7.26 (m, 21H, Ar, NH), 6.41 (d, 1H, J1 ,2
0
Z
2.4 Hz, H-10), 6.26 (dd, 1H, J2 ,3 Z6.3 Hz, H-2 ), 6.22 (t,
0
0
0
0
0
1H, J3 ,4 Z6.6 Hz, H-3 ), 5.52 (d, 1H, J9,10Z7.8 Hz, H-10),
4.88 (dd, 1H, J4 ,5 aZ3.0 Hz, J5 a,5 bZ11.8 Hz, H-50a), 4.64
0
0
0
0
(dd, 1H, H-40), 4.63 (dd, 1H, J7b,8Z2.7 Hz, H-7b), 4.61 (dd,
1H, J4 ,5 bZ3.8 Hz, H-50b), 4.60 (dd, 1H, J8,9Z5.8 Hz,
H-9), 4.38 (m, 1H, H-8), 4.31 (d, 1H, J7a,7bZ13.6 Hz,
H-7a), 1.62, 1.40 (each s, each 3H, 2CH3). 13C NMR
(75 MHz, CDCl3, d ppm): d 181.2 (C-2), 168.2, 166.1,
165.6, 165.1, 165.0 (5C]O), 133.6–128.0 (Ar), 110.1
(CCH3), 86.2 (C-10), 84.8 (C-5), 78.9 (C-40), 73.7 (C-9),
72.9 (C-8), 72.5 (C-20), 71.2 (C-10), 70.3 (C-30), 63.2 (C-7),
62.6 (C-50), 27.6, 25.9 (2CH3). Anal. Calcd for
C43H38N2O13S: C, 62.77; H, 4.65; N, 3.40. Found: C,
62.74; H, 4.82; N, 3.21.
0
0
4.8.4. (5R,8R,9R,10S)-10-Benzoyloxy-8,9-dimethyl-
methylenedioxy-4-oxo-3-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-2-thioxo-6-oxa-1,3-diazaspiro[4.5]-
decane (22a). Method II. tZ4 days. Column chromato-
graphy: Et2O/petroleum ether 1:1. Yield: 0.161 g, 76%
(amorphous solid). [a]2D4 K46 (c 0.9). IR: nmax 2986, 2942,
1
1957, 1953, 1499, 1375, 1223 and 1099 cmK1. H NMR
(500 MHz, CDCl3, d ppm, J Hz): d 7.97–7.37 (m, 5H, Ar),
0
0
0
7.65 (bs, 1H, NH), 5.970(t, 1H, J2 ,3 Z9.4 Hz, H-2 ), 5.77 (d,
0
0
1H, J1 ,2 Z9.6 Hz, H-1 ), 5.52 (d, 1H, J9,10Z7.8 Hz, H-10),
0
0
0
0
0
5.33 (t, 1H, J3 ,4 Z9.3 Hz, H-3 ), 5.24 (t, 1H, J4 ,5 Z9.6 Hz,
H-40), 4.88 (dd, 1H, J8,9Z5.5 Hz, H-9), 4.56 (dd, 1H,
J7a,8Z2.9 Hz, H-7a), 4.42 (m, 1H, H-8), 4.31 (d, 1H,
J7a,7bZ13.7 Hz, H-7b), 4.20 (m, 2H, H-60a, H-60b), 3.76 (dt,
4.8.7. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-9-oxo-8-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-7-thioxo-1-oxa-6,8-diazaspiro[4.4]-
nonane (25). Method II. tZ5 days. Column chromato-
graphy: Et2O/petroleum ether 2:3. Yield: 0.168 g, 79%
(amorphous solid). [a]2D5 K36 (c 1.2). IR: nmax 2988, 2936,
1H, J5 ,6 aZJ5 ,6 bZ3.3 Hz, H-50), 2.04, 2.03, 2.02, 1.97,
1.61, 1.38 (each s, each 3H, 6CH3). 13C NMR (125.7 MHz,
CDCl3, d ppm): d 182.1 (C-2), 170.5, 169.9, 169.4, 169.3,
165.6 (5C]O), 167.1 (C-4),0 133.7–128.4 (Ar), 110.1
(CCH3), 84.4 (C-5), 81.0 (C-1 ), 74.4 (C-50), 74.1 (C-9),
73.2 (C8, C30), 71.1 (C-10), 68.0 (C-40), 67.1 (C-20), 63.0
(C-7), 61.7 (C-60), 27.8, 26.0, 20.5, 20.4, 20.3 (6CH3).
HRCIMS m/z calcd for C31H37O15N2S ([MCH]C):
709.1915, found: 709.1916. Anal. Calcd for
C31H36O15N2S: C, 52.54; H, 5.12; N, 3.95. Found: C,
52.62; H, 5.23; N, 4.00.
0
0
0
0
1755, 1491, 1273, 1215 and 1097 cmK1 1H NMR
.
(300 MHz, CDCl3, d ppm, J Hz): d 8.09–7.42 (m, 5H,
0
0
0
Ar), 7,38 (bs, 1H, NH), 5.92 (t, 1H, J2 ,3 Z9.5 Hz, H-2 ),
0
0
0
0
5.82 (d, 1H, J1 ,2 Z9.5 Hz,0 H-1 ), 5.30 (t, 1H, H-3 ), 5.19
0
0
(t, 1H, J3 ,4 Z9.8 Hz, H-4 ), 4.94 (dd, 1H, J2,3Z1.6 Hz,
H-3), 4.88 (d, 1H, J3,4Z6.0 Hz, H-4), 4.56 (m, 2H, H-2,
2
CHHOBz), 4.48 (dd, 1H, JH,HZ13.3 Hz, J2,HZ8.6 Hz,
CHHOBz), 4.19 (m, 2H, H-60a, H-60b), 3.83 (ddd, 1H,
J5 ,6 aZ2.8 Hz, J5 ,6 bZ4.4 Hz, H-50), 2.09, 2.04, 2.01, 1.90,
1.60, 1.40 (each s, each 3H, 6CH3). 13C NMR (75 MHz,
CDCl3, d ppm): d 181.6 (C-7), 170.5, 170.0, 169.2, 169.1,
168.7, 165.9 (6C]O), 133.1–128.3 (Ar), 114.5 (CCH3),
91.5 (C-5)0, 82.8 (C-2), 82.6 (C-3), 80.9 (C-10), 80.2 (C-4),
74.6 (C-5 ), 73.2 (C-30), 67.7 (C-40), 66.9 (C-20), 64.1
(CH2OBz), 61.5 (C-60), 26.5, 24.7, 20.6, 20.4 (for 2C), 20.1
0
0
0
0
4.8.5. (5S,8R,9R,10S)-10-Benzoyloxy-8,9-dimethyl-
methylenedioxy-4-oxo-3-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-2-thioxo-6-oxa-1,3-diazaspiro[4.5]-
decane (22b). Method II. tZ4 days. Column chromato-
graphy: Et2O/petroleum ether 1:1. Yield: 0.019 g, 9%
(amorphous solid). [a]2D2 K83 (c 0.6). IR: nmax 2986,

108
J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
(6CH3). Anal. Calcd for C31H36O15N2S C, 52.54; H, 5.12;
N, 3.95. Found: C, 52.38; H, 5.44; N, 3.99.
H-500a), 3.96 (m, 1H, H-500b), 1.56, 1.46, 1.40, 1.38 (each s,
each 3H, 4CH3). 13C NMR (125.7 MHz, CDCl3, (ppm):
181.4 (C-7), 170.6 (C-9), 166.1, 165.2, 165.1 (3C]O),
133.5–128.3 (Ar), 114.1, 109.5 (2CCH3), 90.2 (C-5), 86.2
(C-1000), 80.1 (C-3CC-4), 79.4 (C-2), 79.020 (C-40), 720.7
(C-4 ), 71.8 (C-20), 71.2 (C-30), 66.9 (C-5 ), 63.4 (C-5 ),
26.8, 25.8, 25.1, 24.2 (4CH3). HRCIMS m/z calcd for
C40H41O13N2S ([MCH]C): 789.2329, found: 789.2329.
Anal. Calcd for C40H40O13N2S: C, 60.90; H, 5.11; N, 3.55.
Found: C, 60.84; H, 4.98; N, 3.47.
4.8.8. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-9-oxo-7-thioxo-8-(20,30,50-tri-O-benzoyl-
b-D-ribofuranosyl)-1-oxa-6,8-diazaspiro[4.4]nonane
(26). Method II. tZ5 days. Column chromatography: Et2O/
petroleum ether 1:3. Yield: 0.205 g, 83% (amorphous solid).
[a]2D7 K47 (c 1.0). IR: nmax 2996, 1773, 1724, 1601, 1269
and 1099 cmK1.1H NMR (500 MHz, CDCl3, ( ppm, J Hz):
0
0
8.13–7.34 (m, 21H, Ar, NH), 6.48 (d, 1H, J1 ,2 Z3.0 Hz,
H-10), 6.28 (dd, 1H, J2 ,3 Z6.2 Hz, H-2 ), 6.20 (t, 1H,
4.9. General procedures for the reactions of the isothio-
cyanatoulosonates 11, 18a, and 18b with ammonia,
alkyl, aryl, and glycosyl amines (Route B). Preparation
of the hydantocidin-related spironucleosides 24, 27a,
27b, 29a, 28a, 28b, 29a, 29b, 30a, and 30b
0
0
0
0
0
0
0
0
0
0
J3 ,4 Z6.5 Hz, H-3 ), 4.89 (dd, 1H, J4 ,5 aZ3.6 Hz, J5 a,5 b
Z
12.2 Hz, H-50a), 4.75 (dd, 1H, J2,3Z2.4 Hz, H-3), 4.65 (ddd,
1H, J4 ,5 bZ4.7 Hz, H-40), 4.63 (d, 1H, J3,4Z6.0 Hz, H-4),
4.57 (td, 1H, J2,CH2Z6.0 Hz, H-2), 4.53 (dd, 1H, H-50b),
4.53 (m, 2H, CH2OBz), 1.58, 1.33 (each s, each 3H, 2CH3).
13C NMR (125.7 MHz, CDCl3, (ppm): (181.2 (C-7), 169.9
(C-9), 166.1, 166.0, 165.0 (4C]O),0 133.5–128.3 (Ar),
114.6 (CCH3), 92.1 (C-5), 86.4 (C-1 ), 83.1 (C-2), 82.2
(C-3), 80.6 (C-4), 79.6 (C-40), 72.6 (C-20), 70.6 (C-30), 64.1
(CH2OBz), 62.9 (C-50), 26.6, 24.8 (2CH3). HRCIMS m/z
calcd for C43H39O13N2S ([MCH]C): 823.217, found:
823.2173. Anal. Calcd for C43H38O13N2S: C, 62.77; H,
4.65; N, 3.40. Found: C, 62.52; H, 4.64; N, 3.94.
0
0
Method III (starting from free amines; used for the
preparation of compounds 24, 27a, 27b, 29a, 29b, 30a,
and 30b). A solution of the isothiocyanatoulosonate 11 (for
24) or a mixture 6.5:2 of 18a and 18b (for 27a, 27b, 29a,
29b, 30a, and 30b) (90 mg, 0.23 mmol) in THF (3 mL) was
stirred with NH3 (for 27a and 27b), dodecylamine (for 29a
and 29b) or aniline (for 30a and 30b) (x mmol) at T 8C for t
min. The solvent was evaporated and the residue was
purified by column chromatography.
4.8.9. (2R,3S,4S,5S,400R)-2-(200,200-Dimethyl-100,300-dioxo-
lan-400-yl)-3,4-dimethylmethylenedioxy-9-oxo-8-(20,30,
40,60-tetra-O-acetyl-b-D-glucopyranosyl)-7-thioxo-1-oxa-
6,8-dizaspiro[4.4]nonane (31). Method II. tZ5 days.
Column chromatography: Et2O/petroleum ether 1:6 [a]D25
C31 (c 1.0). Yield: 0.190 g, 94% (amorphous solid). IR:
nmax. 2985, 2942,1757, 1753, 1491, 1377,1227, 1223, 1098
Method IV (starting from amines as ammonium salts; used
for the preparation of compounds 28a and 28b). To a
solution of a mixture 6.5:2 of the isothiocyanatoulosonates
18a and 18b (90 mg, 0.23 mmol), a solution of CH3NH2.
HCl (17 mg, 0.25 mmol) and NaHCO3 (21 mg, 0.25 mmol)
in H2O (0.2 mL) was added. The mixtue was stirred for
10 min at room temperature, concentrated to half, diluted
with CH2Cl2 (15 mL), washed with brine, dried (MgSO4),
and evaporated to dryness. The residue was purified by
column chromatography.
and 1068 cmK1. 1H NMR (500 MHz, CDCl3, ( ppm, J Hz):
0
0
0
7.34 (bs, 1H, NH), 5.82 (d, 1H, J1 ,2 Z9.2 Hz, H-1 ), 5.71
0
0
0
0
0
(t, 1H, J2 ,3 Z9.2 Hz, H-2 ), 5.34 (t,01H, J3 ,4 Z9.4 Hz, H-
30), 5.16 (t, 1H, J4 ,5 Z9.8 Hz, H-4 ), 4.99 (m, 1H, H-3),
4.84 (d, 1H, J3,4Z5.9 Hz, H-4), 4.33 (m, 2H, H-2, H-400),
4.22 (m, 2H, H-60a, H-60b), 4.05 (m, 2H, H-500a, H-500b),
0
0
4.9.1. (5R,8R,9R,10S)-10-Benzoyloxy-8,9-dimethyl-
methylenedioxy-3-p-methoxyphenyl-4-oxo-2-thioxo-6-
oxa-1,3-diazaspiro[4.5]decane (24). Method III. xZ
31 mg, 0.25 mmol. TZ40 8C. tZ2 h. Column chromato-
graphy: Et2O/petroleum ether 1:4. Yield: 0.08 g, 72%. [a]D22
K88 (c 1.3). IR: nmax 3291, 2984, 1755, 1732, 1599, 1489,
1379, 1252 and 1105 cmK1. 1H NMR (300 MHz, CDCl3, d
ppm, J Hz): d 8.04–6.93 (m, 9H, Ar), 7.52 (bs, 1H, NH),
3.82 (dt, 1H, J5 ,6 aZJ5 ,6 bZ3.6 Hz, H-50), 2.10, 2.04, 2.02,
1.97, 1.54, 1.44, 1.39, 1.36 (each s, each 3H, 8CH3). 13C
NMR (75 MHz, CDCl3, (ppm): (181.6 (C-7),170.5, 170.1,
169.8, 169.5, 169.3 (5C]O), 113.9, 109.5 (2CCH3), 89.7
(C-5), 81.2 (C-10), 80.0 0(0C-3CC-4), 079.0 (C-2), 74.6 (C-50),
72.7*, 72.6* (C-30, C-4 ), 68.1 (C-2 ), 67.8 (C-40), 66.6 (C-
500), 61.6 (C-60), 26.8, 25.8, 25.0, 24.3, 20.6, 20.5, 20.4
(8CH3). Anal. Calcd for C28H38O15N2S1: C, 49.85; H, 5.68;
N, 4.15, found: C, 49.28; H, 5.63; N, 4.18.
0
0
0
0
5.65 (d, 1H, J9,10Z7.4 Hz, H-10), 4.88 (dd, 1H, J8,9
Z
5.8 Hz, H-9), 4.65 (dd, 1H, J7a,7bZ13.6 Hz, J7a,8Z2.9 Hz,
H-7a), 4.49 (m, 1H, H-8), 4.33 (dd, 1H, J7b,8!1, H-7b),
3.82 (s, 3H, OCH3), 1.66, 1.42 (each s, each 3H, 2CH3). 13
C
4.8.10. (2R,3S,4S,5S,400R)-2-(200,200-Dimethyl-100,300-dioxo-
lan-400-yl)-3,4-dimethylmethylenedioxy-9-oxo-7-thioxo-
8-(20,30,50-tri-O-benzoyl-b-D-ribofuranosyl)-1-oxa-6,8-
diazaspiro[4.4]nonane (32). Method II. tZ4 days. Column
chromatography: Et2O/petroleum ether 1:3. Yield: 0.177 g,
75% (amorphous solid). [a]2D6 C18 (c 1.1). IR: nmax 2988,
NMR (75 MHz, CDCl3, d ppm): d 183.2 (C-2), 168.9 (C-4),
165.4 (C]O), 160.0–114.3 (Ar), 110.3 (CCH3), 85.5 (C-5),
73.7 (C-9), 72.8 (C-8), 71.1 (C-10), 63.3 (C-7), 55.3
(OCH3), 27.5, 25.8 (2CH3). HRCIMS m/z calcd for
C24H24O7N2S ([MCH]C): 485.1383, found: 485.1377.
1
2930, 1730, 1719, 1489, 1269, 1099 and 1068 cmK1. H
NMR (500 MHz, CDCl3, ( ppm, J Hz): ( 8.08–7.31 (m, 15H,
0
4.9.2. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-9-oxo-7-thioxo-1-oxa-6,8-diazaspiro-
[4.4]nonane (27a). Method III. xZ5 min bubbling NH3.
TZ room temperature. tZ15 min. Column chromato-
graphy: Et2O/petroleum ether 1:2. Yield: 0.064 g, 74%
(amorphous solid). [a]2D5 K68 (c 1.2). IR nmax. 3288, 2992,
0
0
Ar), 7.31 (s, 1H, NH), 6.43 (d, 1H, J1 ,2 Z4.0 Hz, H-1 ),
0
0
0
0
0
6.32 (dd, 1H, J2 ,3 Z6.3 Hz, H-2 ), 6.02 (t, 1H, J3 ,4
Z
6.3 Hz, H-30), 5.02 (dd, 1H, J2,3Z3.3 Hz, J3,4Z5.9 Hz,
H-3), 4.89 (d, 1H, H-4), 4.76 (dd, 1H, J4 ,5 aZ3.8, J5 a,5 b
0
0
0
0
Z
Z
11.3 Hz, H-50a), 4.67 (ddd, 1H, H-40), 4.64 (dd, 1H, J4 ,5 b
0
0
1
5.4 Hz, H-50b), 4.34 (m, 2H, H-2, H-400), 4.08 (m, 1H,
2944, 1771, 1717, 1507, 1385, 1275 and 1099 cmK1. H

J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
109
NMR (500 MHz, CDCl3, d ppm, J Hz): d 8.76 (bs, 1H, NH),
8.09–7.43 (m, 6H, ArCNH), 4.92 (dd, 1H, J2,3Z2.5 Hz,
H-3), 4.88 (d, 1H, J3,4Z6.1 Hz, H-4), 4.60 (td, 1H, H-2),
4.9.6. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-8-dodecyl-9-oxo-7-thioxo-1-oxa-6,8-di-
azaspiro[4.4]nonane (29a). Method III. xZ0.047 mg,
10.25 mmol. TZ room temperature. tZ30 min. Column
chromatography: Et2O/petroleum ether 1:9–1:5 gradient.
Yield: 0.075 g, 60% (syrup). [a]2D5 K64 (c 0.9). IR: nmax
4.55 (dd, 1H, J2,CH2aZ5.6 Hz, CH2a), 4.50 (dd, 1H, 2JH,H
Z
11.7 Hz, J2,CH2bZ6.5 Hz, CH2b), 1.61, 1.38 (each s, each
3H, 2CH3). 13C NMR (125.7 MHz, CDCl3, d ppm): d 181.2
(C-7), 171.2 (C-9), 166.1 (C]O), 133.4–127.6 (Ar), 114.9
(CCH3), 94.7 (C-5), 82.8 (C-2), 82.2 (C-3), 80.7 (C-4), 64.3
(CH2OBz), 26.6, 24.8 (2CH3). Anal. Calcd for
C17H18N2O6S: C, 53.96; H, 4.79; N, 7.40. Found: C,
53.67; H, 5.19; N, 7.01.
1
2924, 2853, 1751, 1724, 1474, 1273 and 1101 cmK1. H
NMR (300 MHz, CDCl3, (ppm, J Hz): (8.09–7.42 (m,
5H, Ar), 7.27 Method, 1H, NH), 4.92 (dd, 1H, J2,3Z2.0 Hz,
H-3), 4.82 (d, 1H, J3,4Z6.0 Hz, H-4), 4.60–4.48 (m, 3H,
3
H-2, CH2OBz), 3.76 (t, 2H, JH,HZ7.5 Hz, NCH2), 1.65–
3
1.25 (m, 26H, (CH2)10, 2CH3), 0.87 (t, 3H, JH,HZ6.3 Hz,
CH3). 13C NMR (75 MHz, CDCl3, (ppm): (183.2 (C-7),
171.0 (C-9), 165.9 (C]O), 133.1–128.3 (Ar), 114.6
(CCH3), 92.4 (C-5), 82.4 (C-2), 82.3 (C-3), 80.6 (C-4),
64.2 (CH2OBz), 41.2 (NCH2), 31.7, 29.4 (for 2C), 29.3,
29.23, 29.1, 28.9, 27.4, 26.5 (for 2C), 24.7, 22.5 ((CH2)10,
2CH3), 13.9 (CH3). Anal. Calcd for C29H42O6N2S: C, 63.71;
H, 7.74; N, 5.12, found C, 63.68; H, 7.84; N, 5.14.
4.9.3. (2R,3R,4R,5S)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-9-oxo-7-thioxo-1-oxa-6,8-diazaspiro-
[4.4]nonane (27b). Method III. xZ5 min bubbling NH3.
TZ room temperature. tZ15 min. Column chromato-
graphy: Et2O/petroleum ether 1:2. Yield: 0.017 g, 20%
(amorphous solid). [a]2D5 K160 (c 0.6). IR: nmax. 3229, 2928,
1777, 1717, 1593, 1379, 1265, 1103 cmK1 1H NMR
.
(500 MHz, CDCl3, (ppm, J Hz): (8.42 (bs, 1H, NH), 8.03–
7.49 (m, 5H, Ar), 7.48 Method, 1H, NH), 4.93 (d, 1H, J3,4
Z
4.9.7. (2R,3R,4R,5S)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-8-dodecyl-9-oxo-7-thioxo-1-oxa-6,8-di-
azaspiro[4.4]nonane (29b). Method III. xZ0.047 mg,
10.25 mmol. TZ room temperature. tZ30 min. Column
chromatography: Et2O/petroleum ether 1:9–1:5 gradient.
Yield: 0.021 g, 17% (syrup). [a]2D6 K102 (c 1.0). IR: nmax.
3295, 2926, 2855, 1763, 1723, 1599, 1489, 1273 and
6.4 Hz, H-4), 4.90 (dd, 1H, J2,3Z2.0 Hz, H-3), 4.88 (m, 1H,
2
H-2), 4.63 (dd, 1H, JH,HZ12.4 Hz, J2,CH2aZ4.3 Hz,
CH2a), 4.47 (dd,1H, J2,CH2bZ3.3 Hz, CH2b), 1.62, 1.35
(each s, each 3H, 2CH3). 13C NMR (125.7 MHz, CDCl3,
(ppm): (180.8 (C-7), 168.1 (C-9), 166.0 (C]O), 133.8–
128.4 (Ar), 116.5 (CCH3), 95.8 (C-5), 86.2 (C-4), 83.4 (C-
2), 81.3 (C-3), 64.7 (CH2OBz), 25.0, 24.9 (2CH3). HREIMS
m/z calcd for C17H18O6N2S ([M]C): 378.0886, found:
378.0889.
1
1101 cmK1. H NMR (300 MHz, CDCl3, ( ppm, J Hz):
8.07–7.48 (m, 5H, Ar), 7.32 (bs, 1H, NH), 4.92–4.85 (m,
3H, H-2, H-3, H-4), 4.62 (dd, 1H, J2,HZ3.9 Hz, CHHOBz),
2
4.48 (dd, 1H, J2,HZ3.1 Hz, JH,HZ12.3 Hz, CHHOBz),
3.77 (m, 2H, NCH2), 1.63–0.85 (m, 26H, (CH2)10, 2CH3),
4.9.4. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-8-methyl-9-oxo-7-thioxo-1-oxa-6,8-di-
azaspiro[4.4]nonane (28a). Method IV. Column
chromatography: Et2O/petroleum ether 1:9. Yield:
0.057 g, 64%. [a]D26 K82 (c 1.1). IR: nmax. 2988, 2942,
3
0.88 (t, 3H, JH,HZ6.5 Hz, CH3). 13C NMR (125.7 MHz,
CDCl3, (ppm): (183.1 (C-7), 168.2 (C-9), 165.9 (C]O),
133.7–128.3 (Ar), 116.5 (CCH3), 93.6 (C-5), 86.1 (C-4),
83.0*, 81.3* (C-2, C-3), 64.7 (CH2OBz), 41.3 (NCH2), 31.8,
29.5 (for 2C), 29.4, 29.37, 29.2, 29.1, 27.5, 26.5, 25.1, 24.9,
22.6 ((CH2)10, 2CH3), 14.0 (t, 3H, CH3). HRCIMS m/z
Calcd for C29H43N2O6S ([MCH]C): 547.2842, found:
547.2835.
1
1757, 1717, 1489, 1375, 1275 and 1099 cmK1. H NMR
(300 MHz, CDCl3, (ppm, J Hz): (8.09–7.43 (m, 5H, Ar),
7.41 (sb, 1H, NH), 4.92 (dd, 1H, J2,3Z1.8 Hz, H-3), 4.83 (d,
1H, J3,4Z6.0 Hz, H-4), 4.60–4.48 (m, 3H, H-2, CH2OBz),
3.23 (s, 3H, NCH3), 1.68, 1.37 (each s, each 3H, 2CH3).
13C NMR (125.7 MHz, CDCl3, (ppm): (183.5 (C-7), 170.9
(C-9), 166.0 (C]O), 133.1–128.3 (Ar), 114.7 (CCH3), 92.8
(C-5), 82.5 (C-2), 82.2 (C-3), 80.7 (C-4), 64.3 (CH2OBz),
27.3, 26.5, 24.7 (3CH3). HRCIMS m/z calcd for
C18H21O6N2S ([MCH]C): 393.1120, found: 393.1114.
4.9.8. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-9-oxo-8-phenyl-7-thioxo-1-oxa-6,8-di-
azaspiro[4.4]nonane (30a). Method III. xZ23 ml,
0.25 mmol. TZ40 8C. tZ3 h. Column chromatography:
toluene/AcOEt 100:1–50:1 gradient. Yield: 0.076 g, 73%
(amorphous solid). [a]2D4 K73 (c 1.0). IR: nmax. 2987, 1763,
1719, 1497, 1452, 1230 and 1071 cmK1 1H NMR
.
4.9.5. (2R,3R,4R,5S)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-8-methyl-9-oxo-7-thioxo-1-oxa-6,8-di-
azaspiro[4.4]nonane (28b). Method IV. Column
chromatography: Et2O/petroleum ether 1:9.Yield: 0.019 g,
21% (amorphous solid). [a]2D4 K132 (c 1.1). IR: nmax 3308,
2982, 2941, 1763, 1724, 1489, 1275 and 1097 cmK1.1H
NMR (500 MHz, CDCl3, ( ppm, J Hz): ( 8.05–7.49 (m, 5H,
Ar), 7.43 (bs, 1H, NH), 4.92–4.87 (m, 3H, H-2, H-3, H-4),
4.63 (dd, 1H, J2,HZ4.3 Hz, CHHOBz), 4.46 (dd, 1H,
2JH,HZ12.4 Hz, J2,HZ3.2 Hz, CHHOBz), 3.23 (s, 3H,
NCH3), 1.64, 1.34 (each s, each 3H, 2CH3). 13C NMR
(125.7 MHz, CDCl3, (ppm): (183.3 (C-7), 168.0 (C-9),
165.9 (C]O), 133.7–128.3 (Ar), 116.4 (CCH3), 93.8 (C-5),
86.1 (C-4), 83.1*, 81.3* (C-2, C-3), 64.7 (CH2OBz), 27.4,
25.1, 24.9 (3CH3). HRCIMS m/z calcd for C18H21O6N2S
([MCH]C): 393.1120, found: 393.1122.
(500 MHz, CDCl3, d ppm, J Hz): d 8.09–7.31 (m, 11H,
Ar, NH), 4.99 (d, 1H, J3,4Z6.1 Hz, H-4), 4.97 (dd, 1H,
J2,3Z2.3 Hz, H-3), 4.65 (td, 1H, H-2), 4.58 (dd, 1H, J2,H
Z
Z
C
2
5.7 Hz, CHHOBz), 4.54 (dd, 1H, J2,HZ6.5 Hz, JH,H
11.8 Hz, CHHOBz), 1.65, 1.42 (each s, each 3H, 2CH3). 13
NMR (125.7 MHz, CDCl3, d ppm): d 182.8 (C-7), 170.4
(C-9), 166.0 (C]O), 133.2–127.9 (Ar), 114.9 (CCH3), 93.0
(C-5), 82.8 (C-2), 82.4 (C-3), 80.9 (C-4), 64.3 (CH2OBz),
26.6, 24.8 (2CH3). Anal. Calcd for C23H22O6N2S: C, 60.78;
H, 4.88; N, 6.16. Found: C, 60.85; H, 5.01; N, 6.11.
4.9.9. (2R,3R,4R,5S)-2-Benzoyloxymethyl-3,4-dimethyl-
methylenedioxy-9-oxo-8-phenyl-7-thioxo-1-oxa-6,8-di-
azaspiro[4.4]nonane (30b). Method III. xZ23 ml,
0.25 mmol. TZ40 8C. tZ3 h. Column chromatography:

110
J. Fuentes et al. / Tetrahedron 62 (2006) 97–111
Toluene: AcOEt 100:1–50:1 gradient. Yield: 0.022 g, 21%
(amorphous solid). [a]2D4 K138 (c 0.9). IR: nmax. 3291, 2936,
4.12. Preparation of 34 and 36(aCb)
1775, 1593, 1489, 1271 and 1103 cmK1 1H NMR
.
´
To a solution of 33 (for 34) o 35 [for 36(aCb)] (x mg,
0.15 mmol) in MeOH (1 mL), another solution of NaMeO
1 M in MeOH (1 mL) was added. The solution was stirred
for 1 h at room temperature, neutralized with Dowexw,
filtered, and concentrated to dryness. The residue was
purified by HPLC (reversed-phase).
(500 MHz, CDCl3, (ppm, J Hz): (8.06–7.30 (m, 10H, Ar),
7.76 (bs, 1H, NH), 5.00 (d, 1H, J3,4Z6.1 Hz, H-4), 4.93 (m,
2H, H-2, H-3), 4.66 (dd, 1H, J2,HZ3.9 Hz, 2JH,HZ12.3 Hz,
CHHOBz), 4.51 (dd, 1H, J2,HZ2.9 Hz, CHHOBz), 1.61,
1.36 (each s, each 3H, 2CH3). 13C NMR: (125.7 MHz,
CDCl3, (ppm): (182.7 (C-7), 167.5 (C-9), 166.0 (C]O),
133.7–128.2 (Ar), 116.7 (CCH3), 94.1 (C-5), 86.3 (C-4),
83.1*, 81.2* (C-2, C-3), 64.6 (CH2OBz), 25.1, 25.0 (2CH3).
HRCIMS m/z calcd for C23H23O6N2S ([MCH]C):
455.1277, found: 455.1272.
4.12.1. (5R,8R,9R,10S)-4-Oxo-8,9,10-trihydroxy-3-(b-D-
glucopyranosyl)-2-thioxo-6-oxa-1,3-diazaspiro[4.5]-
decane (34). xZ100 mg. HPLC: MeOH/H2O 70: 1. Yield
0.037 g, 85%. [a]D22 K32 (c 0.5, MeOH). IR: nmax. 3308,
2893, 1763, 1491, 1379, 1103, 1071 cmK1 1H NMR
.
0
0
500 MHz, D2O, d ppm, J Hz): d 5.66 (d, 1H, J1 ,2
Z
2
9.6 Hz, H-10), 4.39 (dd, 1H, JH,HZ13.0 Hz, J7a,8!1,
H-7a), 4.34 (t, 1H, J2 ,3 Z9.4 Hz, H-2 ), 4.28 (dd, 1H,
J8,9Z3.3 Hz, H-9), 4.05 (m, 1H, H-8), 3.95 (d, 1H, J9,10
4.10. (5R,8R,9R,10S)-10-Benzoyloxy-8,9-dihydroxy-4-
oxo-3-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosyl)-2-
thioxo-6-oxa-1,3-diazaspiro[4.5]decane (33)
0
0
0
Z
10.1 Hz, H-10), 3.87 (dd, 1H, J7b,8Z2.0 Hz, H-7b), 3.83
2
To a solution of 22a (100 mg, 0.14 mmol) in CH3CN: H2O
9:1 (3 mL), DDQ (7.5 mg, 0.033 mmol) was added. The
mixture was stirred at 45 8C for 36 h. The solution was
concentrated to dryness and the residue was purified by
column chromatography (Et2O). Yield: 0.078 g, 83%
(amorphous solid). [a]2D5 K29 (c 0.1). IR: nmax 2945,
0
0
(dd, 1H, J5 ,6 aZ1.7 Hz, H-6a), 3.69 (dd, JH,HZ12.5 Hz,
J5 ,6 bZ4.4 Hz, H-60b), 3.49 (m, 3H, H-30, H-40, H-50). 13C
NMR (125.7 MHz, D2O, d ppm): d 185.6 (C-7), 172.0 (C-9),
88.0 (C-5), 84.2 (C-10), 79.8, 77.8, 70.5, 70.3 (C-30, C-40,
C-50, C-10), 69.3, 69.2 (C-8, C-20), 67.7 (C-7), 61.6 (C-60).
HRFABMS calcd for C13H21N2O10S: 397.0917, found:
397.0891.
0
0
1
1755, 1732, 1599, 1489, 1377, 1240 and 1103 cmK1. H
NMR (500 MHz, CDCl3, d ppm, J Hz): d 8.72 (bs, 1H, NH),
0
0
0
7.89–7.32 (m, 5H, Ar), 5.98 (t, 1H, J2 ,3 Z9.3 Hz, H-2 ),
4.12.2. (2R,3R,4R,5R and S)-2-Hydroxymethyl-3,4-dihy-
droxy-9-oxo-7-thioxo-1-oxa-6,8-diazaspiro[4.4]nonane
(36 aCb). xZ50 mg. HPLC: AcOEt/MeOH 10:1. Dia-
stereoisomers in C-5 ratio (R:S): 6:1. Yield: 29 mg, 87%.
The spectroscopic data were coincident with those
reported16c in the literature.
0
0
0
5.80 (d, 1H, J1 ,2 Z9.5 Hz, H-1 ), 5.75 (d, 1H, J9,10
Z
0
0
0
9.7 Hz, H-10), 5.31 (t, 1H, J3 ,4 Z9.5 Hz, H-3 ), 5.26 (t, 1H,
H-40), 4.71 (dd, 1H, J8,9Z2.9 Hz, H-9), 4.54 (d, 1H, J7a,7b
Z
12.7 Hz, H-7a), 4.35 (dd, 1H, J5 ,6 aZ4.2 Hz, H-60a), 4.24
0
0
0
0
0
0
(m, 1H, H-8), 4.18 (dd, 1H, J5 ,6 bZ2.3 Hz, J6 a,6 b
Z
Z
12.5 Hz, H-60b), 4.14 (d, 1H, H-7b), 3.78 (dt, 1H, J4 ,5
0
0
9.6 Hz, H-50), 2.05, 2.04, 2.03, 1.94 (each s, each 3H,
4CH3), 1.68 (bs, 2H, 2OH). 13C NMR (75 MHz, CDCl3, d
ppm): d 182.1 (C-2), 170.6, 169.9, 169.4, 169.3, 167.04,
166.7 (6C]O), 134.0–0127.8 (Ar), 84.5 (C-5), 80.9 (C-1 ),
74.3 (C-50), 73.0 (C-3 ), 71.5 (C-10), 68.9*, 68.8* (C-8,
C-9), 67.8 (C-40), 67.2 (C-20), 65.8 (C-7), 61.7 (C-60), 20.5,
20.4 (parta 2C), 20.1 (4CH3). HRCIMS m/z calcd for
C28H33O15N2S ([MCH]C): 669.1602, found: 669.1594.
Acknowledgements
´
We thank the Direccion General de Ensen˜anza Superior e
´
´
Investigacion Cientıfica of Spain and the Junta de Andalucia
for the financial support (grant numbers PB97/0730,
BQU2001-3740, CTQ2004-1178 with FEDER partici-
pation, and FQM-134), and Agencia Espan˜ola de
´
Cooperacion Internacional for the award of a fellowship
to B.A.B.S. This work is part of the European Programme
COST D13, action number D13/0001/98.
4.11. (2R,3R,4R,5R)-2-Benzoyloxymethyl-3,4-dihydroxy-
9-oxo-7-thioxo-1-oxa-6,8-diazaspiro[4.4]nonane (35)
A solution of 27a (55 mg, 0.145 mmol) in TFA:H2O 2:3
(5 mL) was stirred at room temperature for 1 h. The solution
was concentrated to dryness and the residual amount of acid
was eliminated by repeated evaporations with toluene. The
residue was purified by column chromatography (EtOAc/
petroleum ether 1:2). Yield: 0.045 g, 91%. [a]2D0 K14 (c 1.0,
MeOH). IR: nmax. 3237, 2926, 1765, 1717, 1599, 1505,
1379, 1279 and 1103 cmK1. 1H NMR (500 MHz, MeOD, d
References and notes
´
´
1. (a) Fernandez-Bolan˜os, J.; Blasco Lopez, A.; Fuentes Mota, J.
Carbohydr. Res. 1990, 199, 239–242. (b) Gimisis, T.;
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Chem. 2002, 67, 1302–1307.
ppm, J Hz): d 8.11–7.45 (m, 5H, Ar), 4.49 (dd, 1H, 2JH,H
Z
13.4 Hz, J2,HZ5.0 Hz, CHHOBz), 4.40 (m, 2H, H-2,
CHHOBz), 4.34 (dd, 1H, J2,3Z3.8 Hz, H-3), 4.32 (d, 1H,
J3,4Z4.8 Hz, H-4). 13C NMR (125.7 MHz, MeOD, d ppm):
d 185.0 (C-7), 174.9, 167.8 (2C]O), 134.4–129.6 (Ar),
95.5 (C-5), 83.7 (C-2), 74.6*, 73.2* (C-3, C-4), 65.4
(CH2OBz). HRFABMS m/z calcd for C14H14N2O6SNa
([MCNa]C): 361.0470, found: 361.0478.
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´
13. Dondoni, A.; Scherrmann, M. C.; Marra, A.; Delepine, J. L.
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´
4. (a) Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P.
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T. D.; Platt, F. M.; Tsitsanou, K. E.; Zographos, S. E.;
Oikonomakos, N. G.; Fleet, G. W. J. Tetrahedron: Asymmetry
1996, 7, 157–170. (b) Brandstetter, T. W.; delaFuente, C.;
Kim, Y.-h.; Cooper, R. I.; Watkin, D. J.; Oikonomakos, N. G.;
Jonson, L. N.; Fleet, G. W. J. Tetrahedron 1996, 52,
10711–10720. (c) See also 7d.
´
Curr. Pharm. Des. 2003, 9, 1177–1189. (b) Somsak, L.;
´
Kovacs, L.; Toth, M.; Szilagyi, L.; Gyorgydeak, Z.; Dinya, Z.;
´
´
´
¨
´
Docsa, T.; Toth, B.; Gergely, P. J. Med. Chem. 2001, 44,
2843–2848. (c) Bichard, C. J. F.; Mitchel, E. P.; Wormald,
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