Isothiocyanato derivatives of sugars in the stereoselective synthesis of spironucleosides and spiro-C-glycosides

Article abstract of DOI:10.1016/S0957-4166(01)00223-3

A stereocontrolled synthesis of pyranoid and furanoid spironucleosides and spiro-C-glycosides (D-ribo and D-arabino configurations) of oxazolidines, oxazolines and perhydrooxazines via isothiocyanato sugar derivatives is reported. The intermediate isothio

Full text of DOI:10.1016/S0957-4166(01)00223-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1267–1277
Isothiocyanato derivatives of sugars in the stereoselective
synthesis of spironucleosides and spiro-C-glycosides†
Consolacio´n Gasch, M. Angeles Pradera, Bader A. B. Salameh, Jose´ L. Molina and Jose´ Fuentes*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 23 March 2001; accepted 11 May 2001
Abstract—A stereocontrolled synthesis of pyranoid and furanoid spironucleosides and spiro-C-glycosides (D-ribo and D-arabino
configurations) of oxazolidines, oxazolines and perhydrooxazines via isothiocyanato sugar derivatives is reported. The intermedi-
ate isothiocyanates are prepared from sugar spiroketals by stereoselective opening of the acetal ring with trimethylsilyl N- and
C-nucleophiles, and later formation of the isothiocyanato group. © 2001 Elsevier Science Ltd. All rights reserved.
zolidine derivatives.11 The most suitable starting materi-
als to prepare deoxy-isothiocyanato sugars (sugar
1. Introduction
isothiocyanates with the NCS group situated on a
non-glycosidic position) are amino sugars. These are
obtained by degradation of a natural polysaccharide, as
The term spironucleoside was introduced in 1990 to
designate a class of spiranic sugar derivatives in which
the anomeric carbon belongs to both the sugar ring and
to a heterocyclic base.1 Data on this type of compound
were reported before 1990 but, as far as we are aware,
without using the term spironucleoside. Of the different
classes of nucleosides, the spironucleosides are probably
the least well known. However, the isolation from
Streptomyces hygroscopicus, in 1991, of (+)-hydanto-
cidin,2 the first natural spironucleoside, and later3 the
discovery of its potent herbicidal and regulatory plant
growth activities and its low mammalian toxicity, have
resulted in great interest in the chemistry of spironu-
cleosides. The structure of (+)-hydantocidin, a furanoid
spironucleoside of hydantoin, was completely estab-
lished through its synthesis.4,5 In the last eight years,
other syntheses of hydantocidin,6 spirofuranoid deriva-
tives of different heterocycles,7 pyranoid analogues of
hydantocidin,8 and carbocyclic derivatives9 have been
reported.
in the case of D-glucosamine, by reaction of a monosac-
charide with ammonia or an ammonium salt, as in the
case of glycosylamines, or by introducing the amino
group through an azido derivative which is frequently
obtained from reaction of a sulfonyloxysugar with
sodium azide.13 Glycosyl isothiocyanates can also be
obtained by reaction of a protected glycosyl halide with
an inorganic thiocyanate.10
Silylated nucleophiles are well-known reactants which
have been used for carbonꢀcarbon and car-
bonꢀheteroatom bond formation by reactions with
aldehydes, ketones and acetals,14 although there are
only a few examples of reactions with sugar spiro-
acetals.15 Herein, we report the preparation of different
spironucleosides and spiro-C-glycosides of five- and
six-membered heterocycles, through transient or stable
isothiocyanato (and in one case isocyanato) sugar
derivatives. These isothiocyanato sugars were obtained
by opening of the spiranic dioxolane ring of the
monosaccacharide spiroketals 1 and 2, using nitrogen-
containing trimethylsilyl derivatives as nucleophiles.
Sugar isothiocyanates are versatile synthetic intermedi-
ates, which have been widely used in the preparation of
heteroaryl derivatives of carbohydrates including N-
and C-nucleosides.10,11 However, their use in the prepa-
ration of spironucleosides is very scarce and, to the best
of our knowledge, limited to oxazolidine1,12 and imida-
2. Results and discussion
* Corresponding author.
Dedicated to Professor Joachim Thiem on the occasion of his
60th birthday.
†
Reaction of the b-
D-ribohexulofuranose (psicofuranose)
spiroketal16 1 with trimethylsilyl isothiocyanate in the
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00223-3

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C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
lution of these anomers, so 7 was directly used in the
next step of the synthesis. Thus, desilylation of 7 with
tetrabutylammonium fluoride, and reaction with thio-
carbonyl diimidazole, produced the corresponding a-
presence of trimethylsilyl triflate gave the O-protected
thioxo-oxazolidine spironucleoside 3 in unexpectedly
low yield (Scheme 1). This was formed from the corre-
sponding transient b-D-ribohexulofuranosyl isothio-
and
b-psicofuranosyl
isothiocyanate,
which
cyanate. Similarly, attempts at N-glycosylation of 1
with trimethylsilyl isocyanate in the presence of a Lewis
acid gave mixtures of the b-(4) and a-(5) oxospironu-
cleosides which could be separated. The best results, a
22% yield of 4 and a 5% yield of 5, were obtained when
trimethylsilyl triflate was used as the Lewis acid in
dichloromethane as solvent with equimolar amounts of
the Lewis acid and the nucleophilic reagent. These
results are parallel to that described5 for a related
glycosidation.
spontaneously cyclized to the a-(8) and b-(3) spirooxa-
zolidines. These nucleosides were isolated in ca. 5:1
ratio. Treatment of
8
with triethylamine in
dichloromethane produced an equilibrium mixture of
both anomers (a:b ratio 1:5), from which 8 (15%) and 3
(80%) were isolated.
The structures of compounds 3, 4, 6, 7 and 8 were
1
confirmed by IR, H and 13C NMR spectroscopic data
(see Table 1 and Section 4). For 5, only IR and HRMS
data could be obtained. Compounds 3 and 8 showed
the 13C resonance for the CꢁS group at roughly 189
ppm in accord with that described for five-membered
cyclic thiocarbamates.18,19 The IR band for CꢁO of 4
and 5 appeared20 at 1755 cm−1 and that for the azido
group of 6 at 2118 cm−1 (see Ref. 5). The amino groups
of the mixture of anomers 7 presented the IR absorp-
As the yield for the glycosidation of 1 with TMSNCS
was low, to obtain 3 we followed the sequence indicated
in Scheme 1. The reaction of 1 with trimethylsilyl azide
in acetonitrile to obtain 2-azido-6-O-benzyl-2-deoxy-
3,4-O-isopropylidene a- and b-D-psicofuranoses has
been reported previously.5 We observed that when the
reaction was carried out at 0°C under stringently anhy-
drous conditions (see Section 4), the corresponding
trimethylsilyl ether 6 was obtained in high yield, and
only as the b-anomer. Data for related trimethylsilyl
ethers have been reported.17 Hydrogenation of 6 at
room temperature for 2 h gave 7 as a pair of anomers
quantitatively (a:b ratio 3:2). Partial silyl deprotection
was observed during attempts at chromatographic reso-
1
tion at 3311 cm−1 and the H resonance at 2.24 ppm.
The Me3Si-group of the same compounds was evident
from the NMR signals at 0.08 and 0.14 ppm (1H), and
−0.7 and −0.5 ppm (13C). The anomeric configuration
of 6 was shown to be b because treatment with tetra-
butylammonium fluoride gave the corresponding desily-
lated b-psicofuranosyl azide.5 Moreover, the chemical
Scheme 1. Reagents and conditions: (i) TMSNCS, TMSOTf, −20°C, 1 h, 10%; (ii) TMSNCO, TMSOTf, −20°C, 2 h, 22% for 4
and 5% for 5; (iii) 1. TMSN3, 0°C, 5 min; 2. TMSOTf, 0°C, 5 min, 90%; (iv) H2/Pd–C, rt, 2 h, 80%; (v) 1. Bu4NF·3H2O, rt, 1
h; 2. Im2CS, rt, 3 h, 63% for 8, 16% for 3; (vi) Et3N, CH2Cl2, rt, 3 h, 80%; (vii) TMSCN, TMSOTf, −20°C, 2 h7b (viii) 1. LiAlH4,
Et2O, 0°C, 30 min and then rt, 2 h; 2. Cl2CS, rt, 6 h, 39% for 11, 36% for 12; (ix) Et3N, 80°C, 40 min, 85% for 13, 96% for 14;
(x) TMSCH2CN, TMSOTf, −20°C, 1 h, 23% for 15, 5% for 16.

C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
1269
a,b
Table 1. Relevant NMR data for compounds 3, 4, 6, 8, 11–16, 21–28, and 29 in CDCl3
l (ppm)
JH,H (Hz)
C(1)H
C(1%)H
C(3)H
C(1)
C(2)
C(3)
CꢁX
1,1%
3,4
3
4
6
8
4.88
4.66
4.46
4.23
4.61
4.80
4.38
4.55
4.57
4.75
4.51
4.48
4.54
4.56
3.60
3.68
3.46
3.76
3.64
3.52
3.51
75.8
71.3
65.2
81.2
48.7
46.5
71.1
72.1
72.0
71.3
65.2
63.0
67.7
80.4
65.3
72.5
72.3
100.1
97.5
100.6
99.5
83.3
86.5
76.7
77.3
110.1
68.7
92.4
92.3
85.8
90.9
79.2
68.8
100.9
84.8
82.4
85.2
83.7
85.7
83.1
84.0
82.4
85.5
85.4
75.7
75.6
77.0
75.8
76.1
74.6
77.5
189.1
157.5
–
11.1
10.5
–
5.8
5.8
5.9
5.9
6.6
6.1
6.3
6.3
5.9
5.9
7.1
6.0
6.8
5.3
7.2
5.3
7.3
3.95
4.58
3.84
3.75
4.31
4.33
4.50
4.47
3.90
3.85
4.33
3.77
3.69
4.26
4.19
4.18
4.19
3.78
3.76
188.9
132.7
132.7
186.5
186.7
167.7
169.3
–
10.8
14.3
14.6
11.5
11.2
10.7
10.8
10.8
10.8
–
11
12
13
14
15
16
21
29c
22
24
25
27
28
–
–
3.54
4.47
189.7
–
186.0
169.1
–
11.9
–
3.94
4.08
3.79
3.94
4.24
5.3
a For comparison of the NMR data the compounds are numbered as
The nomenclature as spiranic heterocycles is included in Section 4.
b For the NMR frequency see Section 4.
D-psicose or D-fructose derivatives (see 3 in Scheme 1 and 24 in Scheme 3).
c 29 is the a-anomer of 21, its NMR data were obtained from a mixture 21+29 (see Section 4).
1
shifts and the coupling constants for the H resonances
of 6 and those for the non-silylated CH2OH derivative5
are practically identical. There are no antecedents for
13C resonances. In all the described nucleophilic ring
openings of sugar spiroketals with trimethylsilyl nuc-
leophiles,15 the b-anomer was the major product. The
anomeric configurations of 3, 4, 5, 7 and 8 are sup-
ported by NOE experiments performed on 3 and 8, and
on the major (b) and minor (a) components of the
mixture 7 (Fig. 1).
and 12. Treatment of 11 and 12 with triethylamine
produced the intramolecular cycloaddition, giving the
spiro-C-glycosides 13 and 14, respectively, in high
yields. Chromatographic and MS analysis showed a
small amount (less than 3%) of the intermolecular
addition product.
The structures 11–14 were based on analytical and
spectroscopic data (Table 1 and Section 4). Thus, the
IR spectra of the isothiocyanates 11 and 12 showed the
absorption for the NCS group at 2201 and 2106 cm−1,
respectively, and the carbon atom of the same group
resonated at 132.7 ppm, in agreement with reported10
data for related isothiocyanates. The CꢁS group of the
spirothiocarbamates 13 and 14 resonated at roughly
The trans-fused bicyclic sugar thiocarbamates can act
as sugar isothiocyanates. A thiocarbamate–isothio-
cyanate equilibrium has been studied18 for solutions of
such compounds in various solvents. In the reaction of
8 with triethylamine, formation of neither the isothio-
cyanate 18 nor the isothiocyanate decomposition prod-
ucts was observed. Taking this fact into account, we
propose, as a route for the transformation 8 to 3, the
direct anomerization through the partially O-protected
open chain form 17, shown in Scheme 2. Attack of the
hydroxyl group on the Re face of the imino group, to
give the b-anomer 3, is more favorable than attack on
the Si face which leads to the a-anomer 8, because in
the latter the associated dipoles to the CꢁN and C(3)O
bonds are roughly parallel. Open chain structures, simi-
lar to 17, have been proposed for anomeric equilibria of
N-substituted glycosylamines.21
With the aim of preparing spiro-C-glycosides of five-
and six-membered rings, we synthesized the isothio-
cyanatomethyl derivatives 11 and 12, which were pre-
pared from the described7b psicofuranosyl cyanides 9
and 10.22 Reduction7b with lithium aluminum hydride,
followed by treatment of the resulting syrup with thio-
phosgene, gave the corresponding isothiocyanates 11
Figure 1. NOE effects of 3, 7a, 7b, and 8.

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C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
Scheme 2. Mechanism of the anomerization of 8.
186.6 ppm, a value very close to that reported19 for
oxazine-2-thiones with non-spiranic structure. Com-
pounds 13 and 14 showed H NMR resonances for the
NH group. Table 1 shows that the spiranic carbon
(C(2) using the numbering indicated in Table 1) res-
onates at lower field in the spironucleosides 3, 4, and 8
than in the spiro-C-glycosides 13 and 14.
product 15. In the second case, the key intermediate is
the nitrile 20, without loss of the isopropylidene group.
Compound 20 by internal cyclization can produce the
minor product 16.
1
To prepare 6+5 and 6+6 spironucleosides and spiro-C-
glycosides, we started from the fructopyranose spiroke-
tal derivative 216 (Scheme 3). The N-glycosylation of 2
with trimethylsilyl azide, in the same conditions
described above for the preparation of 6, gave with
high stereoselectivity the expected fructopyranosyl
azides 21 (b) and 29 (a) as a 9:1 b:a anomeric mixture.
From this mixture, 21 could be isolated after chro-
matography. (The NMR data for 29 were measured
from the spectra of the mixture; see Section 4.) Hydro-
genation of 21 for 2 h at room temperature produced,
in almost quantitative yield, the b-fructopyran-
osylamine 22. On treatment with tetrabutylammonium
fluoride followed by thiocarbonyldiimidazole, 22 was
converted to the pyranosyl isothiocyanate 23, which
spontaneously cyclized to give the spironucleoside 24,
in 75% overall yield from 21.
In the reaction of 1 with (trimethylsilyl)acetonitrile,
using the conditions mentioned above for the other silyl
derivatives, the spironucleosides 15, and the spiro-C-
glycoside 16 (minor product), were isolated. Compound
15 has been described previously7b although its 13C
NMR data were not reported. The molecular formula
and the spectroscopic data (w CꢀN 1649 cm−1 and l
CꢀN 169.3 ppm) of the minor product suggest that the
probable structure is 16. Nucleophilic attack of
(trimethylsilyl)acetonitrile on the anomeric carbon
(Scheme 1) can take place from the nitrogen atom
(N-attack) or the methylenic carbon (C-attack). In the
first case, the heterocumulene intermediate 19 is
formed, which by internal cycloaddition gives the major
Scheme 3. Reagents and conditions: (i) 1. TMSN3, 0°C, 5 min; 2. TMSOTf, 0°C, 5 min, 85%; (ii) H2/Pd–C, rt, 2 h, 90%; (iii) 1.
Bu4NF·3H2O, rt, 1 h; 2. Im2CS, rt, 3 h, 83%; (iv) 1. TMSCN, −20°C, 5 min; 2. TMSOTf, 0°C, 5 min; 3. Bu4NF·3H2O, rt, 8 h,
55%; (v) 1. LiAlH4, 0°C, 30 min; 2. Im2CS; (vi) Et3N, rt, 10 h, 60% from 25; (vii) TMSCH2CN, TMSOTf, −20°C, 1 h, 75%.

C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
1271
The reaction of 2 with (trimethylsilyl)acetonitrile under
the same conditions yielded the b-spironucleoside 28
(75%). The CꢁN band of 28 in the IR spectrum was
seen at 1663 cm−1 as in the case of 15. The CꢁN group
The IR spectrum of compound 21 contained the band
for the azido group at 2114 cm−1, close to that for 6,
whereas in the spectrum of 22, the NH group was seen
at 3286 cm−1. The trimethylsilyl groups of 21 and 22
1
1
resonated at 169.1 ppm and there were H (2.05, 1.56
were evident from the corresponding H (0.13 and 0.11
and 1.40 ppm) and 13C (28.2, 26.2, and 14.4 ppm)
NMR resonances for three methyl groups (Me2C and
CH3-Cꢁ). The mechanism that we propose for the
formation of 28 is the same as that proposed for the
formation of 15 (Scheme 3, N-attack). In this case no
side product resulting from C-attack was isolated.
ppm, respectively) and 13C (−0.5 and −0.4 ppm, respec-
tively) NMR resonances. The chemical shift for the
resonance of the CꢁS group of 24 was 189.7 ppm,
confirming19 the oxazolidine-2-thione structure. The b
anomeric configuration of 24 was supported by the
observed NOE effects between C(3)H and C(1a)H
(numbering as sugar derivative, Fig. 2), C(4)H and the
NH proton. The vicinal coupling constants for the
protons of the sugar ring of 24 and the NOE for
C(3)H–NH supported the slightly distorted chair con-
formation depicted in Fig. 2. The distortion in the
C(3)–C(4) region (numbering of the sugar structure),
probably due to condensation with the dioxolane ring,
is evident from the values of J3,4 and J4,5 (5.3 and 6.9
Hz, respectively). The b configuration of 24 supports
the same configuration for 21 and 22.
3. Conclusion
The reaction of sugar spiroketals with trimethylsilyl N-
and C-nucleophiles, followed by suitable methods to
introduce the NꢁCꢁS group, is a convenient stereoselec-
tive route to prepare spironucleosides and spiro-C-gly-
cosides of 1,3-O,N-heterocycles.
C-Glycosylation of 2 with trimethylsilyl cyanide in the
presence of trimethylsilyl triflate, followed by desilyl-
ation with tetrabutylammonium fluoride, gave the b-
fructopyranosyl cyanide 25. Lithium aluminum hydride
reduction of 25, followed by reaction with thiocarbonyl
diimidazole, produced the transient isothiocyanate 26,
which cyclized to the spiro-C-fructopyranoside 27 upon
treatment with triethylamine.
4. Experimental
4.1. General methods
Melting points are uncorrected. Optical rotations were
measured for solutions in CH2Cl2. FTIR spectra were
recorded as KBr discs or thin films. H NMR (500 or
1
300 MHz) and 13C NMR (125.7 or 75.4 MHz) spectra
were obtained for solutions in CDCl3. Chemical shifts
are given in ppm, and the spectra were calibrated on
CDCl3 signals. When this was not possible, TMS was
used as an internal reference. Assignments were confir-
med by homonuclear 2D COSY and heteronuclear 2D
correlated experiments. Mass spectra (EI and FAB)
were recorded with a Kratos MS-80RFA or a Micro-
mass AutoSpecQ instrument with a resolution of 1000
or 10,000 (10% valley definition). For the FAB spectra,
ions were produced by a beam of xenon atoms (6–7
keV), using 3-nitrobenzyl alcohol and thioglycerol as
matrix and NaI as salt. TLC was performed on silica-
gel HF254, with detection by UV light or charring with
H2SO4. Silica-gel 60 (Merck, 70–230 and 230–400 mesh)
was used for preparative chromatography.
The IR spectrum of 25 had absorptions for the OH
group at 3298 cm−1 and contained no band for the CꢂN
group in accord with that described for other glycosyl
cyanides.23 The presence of the CꢂN group was con-
firmed by the 13C resonance at 116.8 ppm, and the
glycosyl cyanide structure was supported by this and
also by the chemical shift of the anomeric carbon (65.3
ppm); both signals are in agreement with reported
data23 for glycopyranosyl cyanides. In the case of 27,
1
there was an IR band at 3269 cm−1 (NH), a H broad
resonance at 8.18 ppm (NH), and a 13C resonance at
186.0 ppm (CꢁS). The latter value is very close to that
for the six-membered cyclic thiocarbamates 13 and 14,
and to that described19 for other perhydrooxazine-2-
thiones. The anomeric configuration of 25 and 27 is
supported by the fact that 25 is the only product
obtained in the glycosylation of 2 and by the NOE
experiment for 27 shown in Fig. 2. As in the case of 24,
the pyranose ring presented a slightly distorted chair
conformation.
4.2. Preparation of compounds 3, 4, 5 and 16
To a solution of 1 (100 mg, 0.29 mmol) in freshly
distilled CH2Cl2 (2 mL) under argon and at tempera-
ture T, TMSNCS (121 mL, 0.86 mmol) for 3, TMSNCO
(86 mL, 0.86 mmol) for 4 and 5, or TMSCH2CN (156
mL, 1.14 mmol) for 15 and 16, and then TMSOTf (82
mL, 0.43 mmol) were added. The resulting solution was
kept at temperature T for t h (monitoring the reaction
by TLC; ether/petroleum ether 2:1), then poured into a
saturated aqueous solution of ammonium chloride,
extracted with CH2Cl2, washed with water, dried
(MgSO4), and concentrated. Purification of the result-
ing products was performed by column chromatogra-
phy as indicated in each case.
Figure 2. NOE effects of 24 and 27.

1272
C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
4.2.1. (2R,3R,4R,5R)-6-Aza-2-benzyloxymethyl-3,4-di-
methylmethylenedioxy-1,8-dioxaspiro[4.4]nonan-7-thione
3. T=−20°C, t=1 h. Column chromatography (ether/
petroleum ether 1:2) of the residue gave 3 as a colorless
syrup. Yield 10%; [h]2D6=−119 (c 0.9); IR wmax 3370,
3028, 2930, 1462, 1375, 1262, 1211, 1082, and 1026
HREIMS m/z obsd. 333.1576, calcd for C18H23NO5
333.1576.
Compound 16: [h]D26=−77 (c 0.9); IR wmax 3445, 3060,
1
2976, 1649, 1460, 1373, 1250, 1209, and 1063 cm−1; H
NMR (300 MHz): l 7.40–7.26 (m, 5H, Ph), 4.81 (dd,
1
2
cm−1; H NMR (500 MHz): l 8.20 (s, 1H, H-6), 7.46–
1H, J2,3=1.2, J3,4=5.9, H-3), 4.60 (d, 1H, JH,H=12.0,
7.26 (m, 5H, Ph), 4.88 (d, 1H, J9a,9b=11.1, H-9a), 4.80
CHHPh), 4.56 (d, 1H, H-4), 4.51 (d, 1H, CHHPh),
2
(d, 1H, J2,3=0.0, J3,4=5.8, H-3), 4.63 (d, 1H, JH,H
=
4.47 (d, 1H,
J6a,6b=10.8, H-6a), 4.33 (dt, 1H,
11.2, CHHPh), 4.61 (d, 1H, H-4), 4.57 (d, 1H,
J2,CHHOBn=J2,CHHOBn=7.2, H-2), 4.19 (d, 1H, H-6b),
CHHPh), 4.46 (d, 1H, H-9b), 4.31 (sa, 1H, H-2), 3.75,
3.60 (m, 2H, CH2OBn), 2.44 (s, 2H, H-11a, 11b), 1.46,
1.33, 1.29, and 1.28 (each s, each 3H, 4CH3) ppm; 13C
NMR (75.4 MHz): l 169.3 (C-10), 138.8–127.6 (6C,
Ph), 112.6, 109.6 (2CCH3), 85.4 (C-4), 83.8 (C-2), 83.4
(C-3), 73.3 (CH2 of Bn), 71.3 (C-6), 70.6 (CH2OBn),
2
3.56 (each dd, each 1H, JH,H=10.6, J2,H=1.3, J2,H
=
1.8, respectively, CH2OBn), 1.42, and 1.31 (each s, each
3H, 2CH3) ppm; 13C NMR (125.7 MHz): l 189.1 (C-7),
135.3–128.3 (6C, Ph), 112.4 (CCH3), 100.1 (C-5), 84.8
(C-4), 83.7 (C-2), 82.0 (C-3), 74.2 (CH2 from Bn), 75.8
68.7 (C-5), 40.3 (C-11), 29.2, 29.8, 26.3, and 25.0
+
’
(C-9), 70.9 (CH2OBn), 25.7 and 24.2 (2CH3) ppm;
(4CH3) ppm; FABMS m/z 414 (100, [M+Na] );
+
’
FABMS m/z 374 (100, [M+Na] ); HREIMS m/z obsd.
HREIMS m/z obsd. 391.1993, calcd for C21H29NO6
351.1137, calcd for C17H21NO5S 351.1140.
391.1995.
4.2.2. (2R,3R,4R,5R)-6-Aza-2-benzyloxymethyl-3,4-di-
4.3. 2-Azido-6-O-benzyl-2-deoxy-3,4-O-isopropylidene-
1-O-trimethylsilyl-b-D-psicofuranose 6
methylmethylenedioxy-1,8-dioxaspiro[4.4]nonan-7-one
4
and
(2R,3R,4R,5S)-6-aza-2-benzyloxymethyl-3,4-di-
methylmethylenedioxy-1,8-dioxaspiro[4.4]nonan-7-one 5.
T=−20°C, t=2 h. Column chromatography (ether/
petroleum ether 1:2) of the residue gave 4 (22%) and 5
(5%) as colorless syrups.
To a solution of 1 (100 mg, 0.29 mmol) in freshly
distilled acetonitrile (3 mL) at 0°C, under argon in the
presence of activated 4 A molecular sieves, TMSN3 (75
,
mL, 0.57 mmol) was added. The solution was stirred for
5 min, then TMSOTf (25 mL, 0.15 mmol) was added
dropwise, and the stirring was continued at 0°C for a
further 5 min. The mixture was neutralized with Et3N,
diluted with Et2O, filtered through Celite and concen-
trated. Column chromatography (ether/petroleum ether
1:12) gave 6 as colorless syrup; yield 90%; [h]3D0=−87 (c
1.0); IR wmax 3053, 2986, 2118 (N3), 1454, 1375, 1249,
Compound 4: [h]D27=−79 (c 0.8); IR wmax 3389, 3060,
1
2982, 1755, 1458, 1377, 1263, 1078, and 1028 cm−1; H
NMR (500 MHz): l 7.41−7.26 (m, 5H, Ph), 6.57 (s, 1H,
H-6), 4.80 (d, 1H, J3,4=5.8, H-4), 4.66 (d, 1H, J9a,9b
=
10.5, H-9a), 4.65 (d, 1H, 2JH,H=11.5, CHHPh), 4.62 (d,
1H, J2,3=0.0, H-3), 4.51 (d, 1H, CHHPh), 4.28 (s, 1H,
H-2), 4.23 (d, 1H, H-9b), 3.71, 3.55 (each d, each 1H,
2JH,H=10.6, CH2OBn), 1.43 and 1.31 (each s, each 3H,
2CH3) ppm; 13C NMR (125.7 MHz): l 157.5 (C-7),
135.9–128.2 (6C, Ph), 112.4 (CCH3), 97.5 (C-5), 85.7
(C-3), 83.7 (C-2), 82.4 (C-4), 74.2 (CH2 of Bn), 71.3
1
1070 and 1022 cm−1; H NMR (500 MHz): l 7.36–7.28
(m, 5H, Ph), 4.79 (dd, 1H, J3,4=5.9, J4,5=1.7, H-4),
4.59 (s, 2H, CH2Ph), 4.42 (ddd, 1H, J5,6a=5.9, J5,6b
=
7.4, H-5), 4.38 (d, 1H, H-3), 3.95 (m, 2H, H-1a, H-1b),
3.63 (m, 2H, H-6a, H-6b), 1.49, 1.31 (each s, each 3H,
2CH3), 0.17 (s, 9H, Si(CH3)3) ppm; 13C NMR (125.7
MHz): l 137.8–127.6 (6C, Ph), 113.2 (CCH3), 100.6
(C-2), 85.7 (C-5), 85.2 (C-3), 82.8 (C-4), 73.5 (CH2Ph),
(C-9), 71.1 (CH2OBn), 26.1 and 24.5 (2CH3) ppm;
+
’
FABMS m/z 358 (100, [M+Na] ); HREIMS m/z obsd.
335.1363, calcd for C17H21NO6 335.1369.
70.2 (C-6), 65.2 (C-1), 26.4, 25.1 (2CH3), −0.7
Compound 5: IR wmax 3389, 3060, 2982, 1755, 1458,
+
’
(Si(CH3)3) ppm; FABMS m/z 430 (100, [M+Na] );
1377, 1263, 1078, and 1028 cm−1; FABMS m/z 358
HRFABMS m/z obsd. 430.17769, calcd for
C19H29NaN3O5Si 430.17742.
+
’
(100, [M+Na] ); HREIMS m/z obsd. 335.1349, calcd
para C17H21NO6 335.1369.
4.2.3. (2R,3R,4R,5R)-6-Aza-2-benzyloxymethyl-3,4-di-
methylmethylenedioxy-7-methyl-1,8-dioxa-spiro[4.4]non-
6-ene 15 and (2R,3R,4R,5R)-2-benzyloxymethyl-8,8-
dimethyl-3,4-dimethylmethylenedioxy-10-imino-1,7,9-tri-
oxaspiro[4.6]undecane 16. T=−20°C, t=1 h. Column
chromatography (ether/petroleum ether 1:2) of the
residue gave 15 (23%) and 16 (5%) as colorless syrups.
4.4. 2-Amino-6-O-benzyl-2-deoxy-3,4-O-isopropylidene-
1-O-trimethylsilyl-D-psicofuranose 7 (a+b)
A mixture of the azide 6 (100 mg, 0.25 mmol) and 10%
Pd–C in MeOH (7 mL) was hydrogenated under a
slightly positive pressure of hydrogen (balloon) at rt for
2 h, then diluted with MeOH, filtered through Celite
and concentrated to give the corresponding amine 7.
The crude product thus obtained was used without
purification for the next step. To obtain samples for
NMR characterization flash column chromatography
(ether/petroleum ether 1:2 as eluent) was used. Yield
80%; the NMR data were obtained from the mixture of
7b and 7a (2:3 ratio).
1
The IR and H NMR data of 15 were consistent with
reported data.7a 13C NMR (125.7 MHz): l 167.7 (C-7),
136.8–127.5 (6C, Ph), 112.6, 110.1 (CCH3, C-5), 85.5
(C-4), 83.9 (C-2), 83.4 (C-3), 73.7 (CH2 from Bn), 72.0
(C-9), 70.9 (CH2OBn), 26.4, 25.1 (2CH3), and 14.2
+
’
(ꢁC-CH3) ppm; FABMS m/z 356 (100, [M+Na] );

C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
1273
1
Compound 7b: H NMR (500 MHz): l 7.33–7.25 (m,
5H, Ph), 4.60–4.54 (m, 3H, H-4, CH2Ph), 4.46 (d, 1H,
4.6. Preparation of the isothiocyanates 11 and 12
J
3,4=6.4, H-3), 4.21 (m, 1H, H-5), 3.57 (d, 1H, J1a,1b
=
A solution of the starting nitrile22 (160 mg, 0.50 mmol)
9 for 11 or 10 for 12 in Et2O (5.4 mL) was cooled to
0°C, then LiAlH4 (38 mg, 1.00 mmol) was added and
the resulting mixture was stirred at 0°C for 30 min and
then at rt for 2 h (the process was monitored by TLC,
ether/petroleum ether 2:1). The mixture was treated
with K2CO3 (1 M, 0.26 mL) which effected the forma-
tion of a grey precipitate that was removed by filtration
through Celite. The organic layer was washed with
brine and dried on MgSO4. Evaporation of the solvent
gave the expected product as a colorless syrup which
was dissolved in CH2Cl2 (9 mL) and treated with
CaCO3 (126 mg, 1.26 mmol), water (9 mL) and thio-
phosgene (62 mL, 0.63 mmol). The heterogeneous mix-
ture was stirred vigorously for 6 h (the process was
monitored by TLC, ether/petroleum ether 2:1). The
mixture was filtered and the organic layer of the filtrate
was separated, washed with water and dried (MgSO4).
The solvent was then evaporated. The residue was
purified by column chromatography (ether/petroleum
ether 1:2).
10.2, H-1a), 3.54 (d, 2H, J5,6=5.1, 2H-6), 3.50 (d, 1H,
H-1b), 2.24 (bs, 2H, NH2), 1.57, 1.36 (each s, each 3H,
2CH3), 0.08 (s, 9H, Si(CH3)3) ppm; 13C NMR (125.7
MHz): l 138.0–127.6 (6C, Ph), 113.6 (CCH3), 94.4
(C-2), 82.4 (C-4), 81.9 (C-3), 81.4 (C-5), 73.6 (CH2Ph),
71.2 (C-6), 67.4 (C-1), 27.0, 25.3 (2CH3), −0.7
(Si(CH3)3) ppm.
1
Compound 7a: H NMR (500 MHz): l 7.33–7.25 (m,
5H, Ph), 4.83 (dd, 1H, J4,5=2.0, H-4), 4.60–4.54 (m,
2H, CH2Ph), 4.50 (d, 1H, J3,4=6.3, H-3), 4.23 (m, 1H,
H-5), 3.79 (d, 1H, J1a,1b=10.4, H-1a), 3.69 (d, 1H,
H-1b), 3.67 (dd, 1H, J5,6a=3.3, J6a,6b=10.2, H-6a), 3.59
(dd, 1H, J5,6b=3.5, H-6a), 2.24 (bs, 2H, NH2), 1.48,
1.30 (each s, each 3H, 2CH3), 0.14 (s, 9H, Si(CH3)3)
ppm; 13C NMR (125.7 MHz): l 137.4–127.6 (6C, Ph),
112.4 (CCH3), 95.7 (C-2), 86.9 (C-3), 83.5 (C-5), 82.8
(C-4), 73.4 (CH2Ph), 71.8 (C-6), 65.7 (C-1), 26.3, 24.9
(2CH3), −0.5 (Si(CH3)3) ppm; FABMS for 7 (a+b) m/z
+
’
382 (100, [M+H] ); HRCIMS m/z obsd. 382.20492,
calcd for C19H32NO5Si 382.20498.
4.6.1. 6-O-Benzyl-2-deoxy-3,4-O-isopropylidene-2-iso-
4.5. (2R,3R,4R,5S)-6-Aza-2-benzyloxymethyl-3,4-
dimethylmethylenedioxy-1,8-dioxaspiro[4.4]nonan-7-
thione 8 and (2R,3R,4R,5R)-6-aza-2-benzyloxymethyl-
3,4-dimethylmethylenedioxy-1,8-dioxaspiro[4.4]nonan-7-
thione 3
thiocyanatomethyl-b-D-psicofuranose 11. Yield 39%
from 9; [h]2D5=−43 (c 1.0); IR wmax 3680–3450, 3063,
2976, 2201 (NCS), 2083 (NCS), 1454, 1387, 1262, 1078,
1
and 1030 cm−1; H NMR (300 MHz): l 7.35–7.26 (m,
5H, Ph), 4.76 (dd, 1H, J3%,4%=6.6, J4%,5%=3.7, H-4), 4.59
(s, 2H, CH2Ph), 4.27 (m, 1H, H-5), 3.84 (d, 1H, J1a,1b
=
To a solution of crude 7 (100 mg, 0.26 mmol) in
CH2Cl2 (3 mL), a catalytic amount of TBAF·3H2O was
added. The mixture was stirred at rt for 1 h, then
washed with brine, water and further brine, dried
(MgSO4), and concentrated to dryness. The resulting
residue was taken up into CH2Cl2 (3 mL) and 1,1%-thio-
carbonyldiimidazole (160 mg, 0.89 mmol) was added.
After 3 h at rt the solvent was evaporated. Column
chromatography (ether/petroleum ether 3:1) of the
residue gave 8 (50% from 6) as an amorphous solid and
3 (13% from 6).
14.3, H-1a), 3.83–3.74 (m, 1H, CHHNCS), 3.77 (d, 1H,
H-1b), 3.67–3.61 (m, 1H, CHHNCS), 3.66–3.54 (m,
2H, H-6a, 6b), 3.58 (d, 1H, H-3), 1.56 and 1.35 (each
s, each 3H, 2CH3) ppm; 13C NMR (75.4 MHz): l
137.7–127.7 (6C, Ph), 132.7 (NCS), 114.4 (CCH3), 85.7
(C-3), 83.4, 83.3 (C-2, 5), 82.9 (C-4), 73.6 (CH2 from
Bn), 70.8 (C-6), 62.6 (CH2NCS), 48.7 (C-1), 26.1 and
+
’
24.6 (2CH3) ppm; FABMS m/z 388 (100, [M+Na] );
HREIMS m/z obsd. 365.1286, calcd for C18H23O5NS
365.1297. Anal. calcd for C18H23NO5S: C, 59.16; H,
6.34; N, 3.83. Found: C, 59.08; H, 6.43; N, 3.65%.
Compound 8: [h]D27=−128 (c 0.9); IR wmax 3283, 3030,
1
2926, 1464, 1375, 1267, 1219, 1070, and 1041 cm−1; H
4.6.2. 6-O-Benzyl-2-deoxy-3,4-O-isopropylidene-2-iso-
NMR (500 MHz): l 7.43–7.02 (m, 5H, Ph), 7.20 (s, 1H,
H-6), 4.78 (dd, 1H, J2,3=0.9, J3,4=5.9, H-3), 4.58 (d,
1H, J9a,9b=10.8, H-9a), 4.55 (d, 1H, H-4), 4.47 (m, 2H,
CH2Ph), 4.33 (d, 1H, H-9b), 4.31 (sa, 1H, H-2), 3.61
thiocyanatomethyl-a-D-psicofuranose 12. Yield 36%
from 10; [h]2D5=+5 (c 0.8); IR wmax 3451, 3030, 2987,
2199 (NCS), 2106 (NCS), 1449, 1375, 1256, 1211, and
1
1078 cm−1; H NMR (500 MHz): l 7.37–7.30 (m, 5H,
2
(dd, 1H, JH,H=10.3, J2,H=2.0, CHHOBn), 3.52 (dd,
Ph), 4.93 (dd, 1H, J3%,4%=6.1, J4%,5%=5.0, H-4), 4.75 (d,
1H, H-3), 4.61, 4.54 (each d, each 1H, 2JH,H=11.8,
CH2Ph), 4.19 (m, 1H, H-5), 3.77 (dd, 1H, J5,6a=2.7,
1H, 10.3, J2,H=2.0, CHHOBn), 1.53, and 1.37 (each s,
each 3H, 2CH3) ppm; 13C NMR (125.7 MHz): l 188.9
(C-7), 136.7–128.7 (6C, Ph), 113.3 (CCH3), 99.5 (C-5),
83.7 (C-4), 82.1 (C-3), 81.7 (C-2), 81.2 (C-9), 74.0
J
6a,6b=10.5, H-6a), 3.75 (d, 1H, J1a,1b=14.6, H-1a),
3.71 (d, 1H, 2JH,H=11.6, CHHNCS), 3.69 (d, 1H,
H-1b), 3.63 (dd, 1H, J5,6b=2.1, H-6b), 3.60 (d, 1H,
CHHNCS), 1.54 and 1.34 (each s, each 3H, 2CH3)
ppm; 13C NMR (125.7 MHz): l 136.8–127.9 (6C, Ph),
132.7 (NCS), 113.7 (CCH3), 86.5 (C-2), 84.6 (C-5), 83.1
(C-3), 81.6 (C-4), 73.8 (CH2 of Bn), 69.9 (C-6), 65.9
(CH2Ph), 71.5 (CH2OBn), 26.3 and 24.2 (2CH3) ppm;
+
’
CIMS m/z 352 (100, [M+H] ); HRCIMS m/z obsd.
352.12200, calcd for C17H22NO5S 352.12187. Anal.
calcd for C17H21NO5S: C, 58.10; H, 6.02; N, 3.98.
Found: C, 58.26; H, 6.20; N, 3.91%.
(CH2NCS), 46.5 (C-1), 27.0 and 25.1 (2CH3) ppm;
FABMS m/z 388 (100, [M+Na] ); HREIMS m/z obsd.
365.1274, calcd for C18H23NO5S 365.1297.
+
’
Treatment of 8 (100 mg, 28 mmol) with Et3N (1 mL) in
CH2Cl2 (4 mL) at rt for 3 h gave 3 (80%) and 8 (15%).

1274
C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
4.7. Cyclization of the isothiocyanates 11 and 12
Compound 21: [h]D29=−126 (c 0.9); IR wmax 3032, 2986,
1
2114 (N3), 1458, 1384, 1253, 1093 and 1022 cm−1; H
To a solution of the corresponding isothiocyanate (65
mg, 0.18 mmol), 11 for 13 and 12 for 14, in DMF (1
mL), triethylamine (20 mL, 0.14 mmol) was added. The
reaction mixture was heated to 80°C for 40 min and
then evaporated to dryness to give the product indi-
cated in each case. The reaction was monitored by TLC
(ether/petroleum ether 2:1).
NMR (500 MHz): l 7.35–7.26 (m, 5H, Ph), 4.89 (d, 1H,
2JH,H=11.9, CHHPh), 4.66 (d, 1H, CHHPh), 4.36 (t,
1H, J3,4=J4,5=7.1, H-4), 4.27 (ddd, 1H, J5,6a=1.3,
J5,6b=2.8, H-5), 4.12 (dd, 1H, J6a,6b=13.6, H-6a), 4.07
(dd, 1H, H-6b), 3.90 (d, 1H, J1a,1b=10.8, H-1a), 3.78
(d, 1H, H-1b), 3.60 (d, 1H, H-3), 1.49, 1.37 (each s,
each 3H, 2CH3), and 0.13 (s, 9H, Si(CH3)3) ppm; 13C
NMR (125.7 MHz): l 137.9–127.6 (6C, Ph), 109.1
(CCH3), 92.4 (C-2), 76.6 (C-4), 75.7 (C-3), 73.3
(CH2Ph), 73.2 (C-5), 65.2 (C-1), 61.9 (C-6), 27.8, 26.0
4.7.1. (2R,3R,4R,5R)-9-Aza-2-benzyloxymethyl-3,4-di-
methylmethylenedioxy-1,7-dioxaspiro[4.5]decane-8-thione
13. Column chromatography (ether/petroleum ether
1:2) of the residue gave 13 as a white solid. Yield 85%;
[h]2D5=−22 (c 1.1); IR wmax 3266, 3063, 2988, 1580, 1458,
(2CH3), and −0.5 (Si(CH3)3) ppm; FABMS m/z 430
+
’
(60, [M+Na] ); HRFABMS m/z obsd. 430.17771,
calcd for C19H29N3O5NaSi 430.17742.
1
1377, 1265, 1204, 1159, and 1078 cm−1; H NMR (500
1
NMR data for 29 (from the mixture): H NMR (500
MHz): l 7.88 (bs, 1H, H-9), 7.39–7.26 (m, 5H, Ph), 4.88
2
MHz): l 7.35–7.26 (m, 5H, Ph), 4.75 (m, 2H, CH2Ph),
4.37–4.35 (m, 2H, H-4, H-5), 4.10 (m, 2H, H-6a and
H-6b), 3.85 (d, 1H, J1a,1b=10.6, H-1a), 3.76 (d, 1H,
H-1b), 3.678 (d, 1H, J3,4=6.0, H-3), 1.49, 1.37 (each s,
each 3H, 2CH3), and 0.13 (s, 9H, Si(CH3)3) ppm; 13C
NMR (125.7 MHz): l 136.7–128.1 (6C, Ph), 109.8
(CCH3), 92.3 (C-2), 78.6 (C-4), 75.6 (C-3), 73.7
(CH2Ph), 71.4 (C-5), 63.0 (C-1), 64.2 (C-6), 27.2, 25.2
(2CH3), and −0.7 (Si(CH3)3) ppm.
(dd, 1H, J2,3=2.2, J3,4=6.3, H-3), 4.56 (d, 1H, JH,H
=
11.8, CHHPh), 4.51 (d, 1H, H-4), 4.50 (d, CHHPh),
4.36 (m, 1H, H-2), 4.31 (d, 1H, J6a,6b=11.5, H-6a), 4.26
4
2
(dd, 1H, J6b,10a=2.2, H-6b), 3.62 (dd, 1H, JH,H=10.4,
2,H=2.8, CHHOBn), 3.57 (dd, 1H, 2,H=2.8,
J
J
CHHOBn), 3.44 (m, 1H, J10a,10b=12.8, H-10a), 3.35 (d,
1H, H-10b), 1.51 and 1.33 (each s, each 3H, 2CH3)
ppm; 13C NMR (125.7 MHz): l 186.5 (C-8), 137.2–
127.8 (6C, Ph), 114.0 (CCH3), 84.0 (C-4), 83.2 (C-2),
82.9 (C-3), 73.7 (CH2 from Bn), 71.1 (C-6), 70.8
(CH2OBn), 65.8 (C-5), 49.2 (C-10), 25.9, and 25.4
4.9. 2-Amino-3-O-benzyl-2-deoxy-4,5-O-isopropylidene-
1-O-trimethylsilyl-b-D-fructopyranose 22
+
’
(2CH3) ppm; FABMS m/z 388 (100, [M+Na] ). Anal.
calcd for C18H23NO5S: C, 59.16; H, 6.34; N, 3.83.
Found: C, 58.95; H, 6.36; N, 4.12%.
Compound 22 was prepared and purified following the
procedure described for 7. Yield 90%; d.e. 80%; IR wmax
3286, 3034, 2978, 1449, 1370, 1248, 1069 and 1028
cm−1; H NMR (500 MHz): l 7.34–7.27 (m, 5H, Ph),
4.7.2. (2R,3R,4R,5S)-9-Aza-2-benzyloxymethyl-3,4-di-
methylmethylenedioxy-1,7-dioxaspiro[4.5]decane-8-thione
14. Column chromatography (ether/petroleum ether
1:2) of the residue gave 14 as a white solid. Yield 96%;
[h]2D2 −4 (c 0.7); IR wmax 3306, 3063, 2986, 1543, 1458,
1
4.90 (d, 1H, 2JH,H=11.6, CHHPh), 4.62 (d, 1H,
CHHPh), 4.35 (t, 1H, J3,4=J4,5=6.8, H-4), 4.30 (dd,
1H, J5,6a=2.8, J6a,6b=13.3, H-6a), 4.21 (dd, 1H, H-5),
3.98 (d, 1H, H-6b), 3.54 (m, 2H, H-1a, H-1b), 3.46 (d,
1H, H-3), 1.53, 1.36 (each s, each 3H, 2CH3), and 0.11
(s, 9H, Si(CH3)3) ppm; 13C NMR (125.7 MHz): l
138.3–127.7 (6C, Ph), 108.5 (CCH3), 85.8 (C-2), 77.0
(C-3), 74.0 (C-5), 73.3 (C-4), 73.0 (CH2Ph), 67.7 (C-1),
59.0 (C-6), 27.9, 26.2 (2CH3), and –0.4 (Si(CH3)3) ppm;
1
1377, 1260, 1173, 1080, and 1038 cm−1; H NMR (500
MHz): l 7.56 (bs, 1H, H-9), 7.37–7.28 (m, 5H, Ph), 4.89
2
(dd, 1H, J2,3=2.1, J3,4=6.3, H-3), 4.57 (d, 1H, JH,H
=
11.7, CHHPh), 4.48 (d, 1H, H-4), 4.48 (d, CHHPh),
4
4.33 (m, 1H, H-2), 4.33 (dd, 1H, J6a,6b=11.2, J6a,10b
=
4
2.1, H-6a), 4.19 (dd, 1H, J6b,10a=1.0, H-6b), 3.60 (dd,
1H, JH,H=10.6, J2,H=2.7, CHHOBn), 3.56–3.53 (m,
+
’
EIMS m/z 382 (60, [M+H] ); HREIMS m/z obsd.
2
382.20428, calcd for C19H32NO5Si 382.20498.
1H, H-10a), 3.55 (dd, 1H, J2,H=3.0, CHHOBn), 3.23
(m, 1H, H-10b), 1.49 and 1.33 (each s, each 3H, 2CH3)
ppm; 13C NMR (125.7 MHz,): l 186.7 (C-8), 137.1–
127.8 (6C, Ph), 113.7 (CCH3), 83.3 (C-2), 82.9 (C-3),
82.4 (C-4), 77.3 (C-5), 73.8 (CH2 from Bn), 72.1 (C-6),
4.10. (5R,8R,9R,10S)-1-Aza-10-benzyloxy-8,9-dimethyl-
methylenedioxy-3,6-dioxaspiro[4.5]decan-2-thione 24
Prepared following the procedure described for 8.
Column chromatography (ether/petroleum ether 1:1)
gave 24 as an amorphous solid. Yield 75% (from 21);
[h]2D4=−78 (c 1.0); IR wmax 3160, 3034, 2982, 2932, 1462,
70.9 (CH2OBn), 47.2 (C-10), 26.1 and 24.5 (2CH3)
+
’
ppm; FABMS m/z 388 (100, [M+Na] ); HRFABMS
m/z obsd. 388.1197, calcd for C18H23NO5NaS 388.1195.
1
1381, 1231, 1021, 1088 and 1005 cm−1; H NMR (500
4.8. 2-Azido-3-O-benzyl-2-deoxy-4,5-O-isopropylidene-
MHz): l 7.39–7.26 (m, 5H, Ph), 4.77, 4.69 (each d, each
1H, JH,H=11.8, CH2Ph), 4.47 (s, 2H, H-4a, 4b), 4.44
(dd, 1H, J8,9=6.9, J9,10=5.3, H-9), 4.24 (ddd, 1H,
J7a,8=2.1, J7b,8=0.9, H-8), 4.04 (dd, 1H, J7a,7b=13.3,
2
1-O-trimethylsilyl-b-
O-benzyl-2-deoxy-4,5-O-isopropylidene-1-O-trimethyl-
silyl-a- -fructopyranose 29
D
-fructopyranose 21 and 2-azido-3-
D
H-7a), 3.90 (bd, 1H, H-7b), 3.76 (d, 1H, H-10), 1.48
and 1.34 (each s, each 3H, 2CH3) ppm; 13C NMR
(125.7 MHz): l 189.7 (C-2), 136.7–128.1 (6C, Ph), 110.0
(CCH3), 90.9 (C-5), 80.4 (C-4), 75.8 (C-10), 73.7 (CH2
from Bn), 72.7 (C-9), 72.1 (C-8), 63.3 (C-7), 26.6 and
Prepared following the procedure described for 6. Ratio
21:29 (9:1). Column chromatography (ether/petroleum
ether 1:15) gave 21 (85%) as a pure colorless syrup and
a mixture of 21+29 (10%).

C. Gasch et al. / Tetrahedron: Asymmetry 12 (2001) 1267–1277
1275
+
’
24.9 (2CH3) ppm; FABMS m/z 374 (100, [M+Na] );
13.8, H-2a), 3.85 (dd, 1H, H-2b), 3.52 (d, 1H, H-5),
3.41 (m, 2H, H-11a and H-11b), 1.53 and 1.36 (each s,
each 3H, 2CH3) ppm; 13C NMR (125.7 MHz): l 186.0
(C-9), 136.6–127.9 (6C, Ph), 109.6 (CCH3), 74.6 (C-5),
73.7 (CH2Ph), 73.4 (C-4), 72.7 (C-3), 72.5 (C-7), 68.8
HREIMS m/z obsd. 351.1130, calcd for C17H21NO5S
351.1140. Anal. calcd for C17H21NO5S: C, 58.10; H,
6.02; N, 3.98. Found: C, 58.10; H, 6.03; N, 3.94%.
4.11. 3-O-Benzyl-2-cyano-2-deoxy-4,5-O-isopropylidene-
(C-6), 61.5 (C-2), 41.6 (C-11), 27.1 and 25.3 (2CH3)
ppm; EIMS m/z 365 (10, [M] ); HREIMS m/z obsd.
+
’
b-D
-fructopyranose 25
365.12972, calcd for C18H23NO5S 365.12969. Anal.
calcd for C18H23NO5S: C, 59.16; H, 6.34; N, 3.83.
Found: C, 59.48; H, 6.26; N, 3.64%
A solution of 2 (100 mg, 0.29 mmol) and TMSCN (11
mL, 0.86 mmol) in CH2Cl2 (2.5 mL) was stirred at
,
−20°C under argon in the presence of 4 A molecular
sieves. After stirring the mixture for 5 min, TMSTfO
(52 mL, 0.29 mmol) was added and the stirring was
maintained for 2 h. The mixture was neutralized with
Et3N, diluted with Et2O, filtered through Celite and
concentrated. The residue was dissolved in CH2Cl2 (3
mL), and a catalytic amount of TBAF·3H2O was
added. The mixture was kept at rt for 8 h, then washed
with water and brine, dried (MgSO4), and concentrated
to dryness. The residue was purified by column chro-
matography (ether/petroleum ether 1:5). Yield (55%);
[h]3D0=−88 (c 1.5); IR wmax 3298, 3033, 2986, 2143, 1451,
4.13. (5R,8R,9R,10S)-1-Aza-10-benzyloxy-8,9-dimethyl-
methylenedioxy-2-methyl-3,6-dioxaspiro[4.5]dec-1-ene 28
Prepared following the procedure described for 15.
T=−20°C, t=2 h. Column chromatography (ether/
petroleum ether 1:1). Yield 75%; [h]=−77 (c 0.8); IR
wmax 3028, 2982, 1663, 1452, 1379, 1246, 1217, 1119,
1
and 1082 cm−1; H NMR (500 MHz): l 7.36–7.26 (m,
5H, Ph), 4.95 (d, 1H, J4a,4b=12.2, CHHPh), 4.69 (d,
1H, CHHPh), 4.53 (dd, 1H, J8,9=5.8, J9,10=7.3, H-9),
4.37 (dd, 1H, J7a,7b=13.3, J7a, 8=2.8, H-7a), 4.30 (dd,
1
2
1426, 1373, 1217, 1107, 1071, and 1020 cm−1; H NMR
1H, J7b,8=0, H-8), 4.08 (d, 1H, JH,H=9.4, H-4a), 3.99
(500 MHz): l 7.36–7.70 (m, 5H, Ph), 4.94 (d, 1H,
2JH,H=11.8, CHHPh), 4.70 (d, 1H, CHHPh), 4.42 (dd,
1H, J3,4=7.2, J4,5=5.7, H-4), 4.32 (d, 1H, J6a,6b=14.1,
H-6a), 4.30 (dd, 1H, J5,6b=2.6, H-5), 4.12 (dd, 1H,
H-6b), 3.94 (d, 1H, J1a,1b=11.9, H-1a), 3.79 (d, 1H,
H-1b), 3.64 (d, 1H, H-3), 1.61 (bs, 1H. HO), 1.48 and
1.39 (each s, each 3H, 2CH3) ppm; 13C NMR (125.7
MHz): l 137.2–128.0 (6C, Ph), 115.3 (CN), 109.8
(CCH3), 76.9 (C-4), 74.4 (C-3), 72.9 (2C, C-5 and
CH2Ph), 64.8 (C-1), 64.2 (C-6), 27.8 and 26.0 (2CH3)
ppm; 13C NMR (125.7 MHz, Me2CO-d6): l 139.0–128.5
(6C, Ph), 116.8 (CN), 110.2 (CCH3), 79.2 (C-2), 77.7
(C-4), 76.1 (C-3), 74.0 (CH2Ph), 73.9 (C-5), 73.9 (C-5),
(d, 1H, H-7b), 3.94 (d, 1H, H-4b), 3.51 (d, 1H, H-10),
2.05 (s, 3H, ꢁC-CH3), 1.56 and 1.40 (each s, each 3H,
2CH3) ppm; 13C NMR (125.7 MHz): l 169.1 (C-2),
137.9–127.6 (6C, Ph), 108.8 (CCH3), 100.9 (C-5), 78.1
(C-9), 77.5 (C-10), 74.5 (CH2 of Bn), 74.1 (C-8), 72.3
(C-4), 60.9 (C-7), 28.2, 26.2 (2CH3) and 14.4 (ꢁC-CH3)
+
’
ppm; FABMS m/z 356 (100, [M+Na] ); HRFABMS
m/z obsd. 334.1645, calcd for C18H24N O5 334.1654.
Acknowledgements
65.3 (C-1), 64.9 (C-6), 28.1 and 26.3 (2CH3) ppm;
We thank the Direccio´n General de Ensen˜anza Supe-
rior e Investigacio´n Cient´ıfica of Spain and the Junta de
Andalucia for financial support (grant numbers PB97/
0730 and FQM-134), and Fundacio´n Ca´mara and
Agencia Espan˜ola de Cooperacio´n Internacional for the
award of fellowships to J.L.M. and B.A.B.S., respec-
tively. This work is part of the European Programme
COST D13, action number D13/0001/98.
+
’
IEMS m/z 342 (100, [M+Na] ); HREIMS m/z obsd.
320.1500, calcd for C17H22NO5 320.1498.
4.12. (3R,4R,5S,6R)-10-Aza-5-benzyloxy-3,4-dimethyl-
methylenedioxy-1,8-dioxaspiro[5.5]undecan-9-thione 27
A solution of 25 (100 mg, 0.51 mmol) in diethyl ether (3
mL) was cooled to 0°C, then LiAlH4 (24 mg, 0.62
mmol) was added and the resulting mixture was stirred
for 30 min at 0°C, allowed to warm to rt and stirred for
a further 2 h. Treatment with K2CO3 (1 M, 0.16 mL)
gave a grey precipitate that was removed by filtration
through Celite. The organic layer was washed with
brine, dried over MgSO4 and concentrated. The residue
was dissolved in CH2Cl2 (3 mL), and 1,1%-thiocar-
bonyldiimidazole (160 mg, 0.89 mmol) and Et3N (0.5
mL) were added. After stirring for 10 h at rt the solvent
was evaporated and the residue was purified by column
chromatography (ether/petroleum ether 3:1) to give 27
as an amorphous solid (60%); [h]2D9=+29 (c 1.4); IR
wmax 3269, 3034, 2980, 1460, 1373, 1287, 1244, 1070 and
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