Expeditious synthesis of sulfoazetidine spiro-C-glycosides from ketose acetals

Article abstract of DOI:10.1016/j.tet.2005.10.038

Pyranoid and furanoid spiro-N-mesyl azetidines, a new type of water-soluble spiro-C-nucleoside, have been prepared from easily available sugar spiroacetals (or glycosyl cyanides). The synthetic pathway involves opening of the acetalic ring with trimethyls

Full text of DOI:10.1016/j.tet.2005.10.038

Tetrahedron 62 (2006) 915–921
Expeditious synthesis of sulfoazetidine spiro-C-glycosides
from ketose acetals
´
Francisco J. Sayago, M. Angeles Pradera, Consolacion Gasch and Jose Fuentes
*
´
´
´
´
´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Sevilla, Apartado 553, E-41071 Sevilla, Spain
Received 6 September 2005; revised 13 October 2005; accepted 13 October 2005
Available online 8 November 2005
Abstract—Pyranoid and furanoid spiro-N-mesyl azetidines, a new type of water-soluble spiro-C-nucleoside, have been prepared from easily
available sugar spiroacetals (or glycosyl cyanides). The synthetic pathway involves opening of the acetalic ring with trimethylsilylcyanide,
reduction, formation of an N,O-dimesylate, cyclization with sodium hydride in anhydrous DMF, and O-deprotection.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
(TBAF)12 was also attempted, but decomposition took place
and the yield was very low. Reduction of 2 with lithium–
aluminium hydride gave the non-isolated 1,3-aminohydroxy
derivative, which was directly transformed into the sulfo-
amidoester 4 by reaction with mesyl chloride at rt. Basic
treatment (NaH) of 4 in anhydrous DMF produced the
spirosulfonamide 5. Simultaneous removals of the isopro-
pylidene and benzyl groups afforded the water-soluble
sulfoazetidine spiro-C-nucleoside 6 in 40% overall yield
from 1 (six steps).
The azetidine ring is an important target of synthetic organic
chemistry due to the significant pharmaceutical activities of
this four-membered heterocycle. Thus, the b-lactams are
well-known antibiotics,1 and take part in the structure of
anticancer drugs;2 and dihydroazetidines have been recently
reported as probiotics.3 N-Tosylazetidines have been used
as masked dipoles in heterocyclization reactions.4 The data
on carbohydrate derivatives with azetidine rings are scarce;
they are mainly on fused azetidines,5 and in one case on
alditol–azetidines biologically active as glycosidase inhibi-
tors.6 We have not found antecedents either on spiro-
azetidine sugar derivatives or on sugar N-sulfoazetidines. In
this communication, we report the preparation of the water-
soluble N-sulfospirosugarazetidines 6, 12, and 24, as
representative examples of azetidine spiro-C-glycosides.7
The starting materials are the easily available pyranoid (1, 7,
and 13) and furanoid (18) sugarspiroacetals with b-D-ribo
(1, 18) and b-D-arabino (7, 13) configurations. The synthetic
pathway involves a cyclization step to form the azetidine
ring based on reported8–10 preparations of simple mono-
cyclic azetidines from 1,3 aminoalcohols.
The 13C NMR spectrum of 2 presented a signal at 118.9 ppm
for the cyano group, and the b-configuration for this
compound was based on NOE experiments performed on
4. The two mesyl groups of 4 resonated at 2.99, 2.97 (1H),
40.5 and 37.6 (13C) ppm and its 2D-NOESY spctrum
showed strong NOE contacts between the CH2NHMs and
H-3 of the sugar ring confirming b configuration for this
group, and consequently for the C^N group of 2. The
signal for the resonance of the spiro carbon atom of 5
appeared at 72.0 ppm. The 13C NMR spectrum of 6 showed
the resonance for C-4 (anomeric carbon in the sugar ring) at
76.4 ppm, this being the sugar carbon atom resonating at
lowest field, as in related O-unprotected pyranoid spiro-C-
glycosides of different five-membered heterocycles.13,14
The resonances for the mesyl group of 6 appeared at 2.93
(CH3) and 33.9 (CH3) ppm.
2. Results and discussion
Treatment of the diisopropylidene acetal 111 with trimethyl-
silyl cyanide, followed by O-desilylation with SiO2 gave the
b-D-ribohexulopyranosyl cyanide 2 in 81% yield (Scheme 1).
The standard desilylation with tetrabutylammonium fluoride
To obtain the arabino-spirosulfoazetidine 12 we have
started (Scheme 1) from two differently O-protected
D-fructose derivatives, the tri-O-benzyl spiroacetal 715 and
the 4,5-O-isopropylidenefructopyranosyl cyanide 14, which
was easily prepared14 from the spiroacetal 13.16 The overall
yield was better in the case of 7. The opening of the
spiroacetal ring of 7 to obtain 8 was performed with
Keywords: Azetidines; Glycosides; Spirosugars.
*
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.2005.10.038

916
F. J. Sayago et al. / Tetrahedron 62 (2006) 915–921
6
O
O
CN
NH2
OH
O
2
3
O
R4O
R3O
R4O
R3O
5
4
R4O
R3O
OH
1
iii
O
i
ii or vii
R1
R1
R1
R2
R2
R2
2, 8, 14
1, 7, 13
3, 9, 15
O5
6
1
2
O
O
NHMs
OMs
7
R4O
R3O
N Ms
N Ms
R4O
R3O
4
iv
R4O
R3O
v
vi
8
9
3
R1
R1
R1
R2
R2
R2
4, 10, 16
6, 12
5, 11, 17
Compound
R1
H
R2
OBn
R3 R4 Anomers
CMe2
1
2
3
β
H
H
OBn
OBn
OBn
OBn
OH
H
CMe2
β
CMe2
β
H
CMe2
4
β
H
CMe2
5
−
H
H
H
6
7
−
β
OBn
OBn
OBn
OBn
OBn
OH
OBn
OBn
OBn
OBn
OBn
Bn Bn
Bn Bn
Bn Bn
Bn Bn
Bn Bn
H
8
α:β
α:β
α:β
−
H
9
H
H
10
11
12
13
14
15
16
17
H
H
H
−
H
CMe2
β
H
H
CMe2
CMe2
CMe2
CMe2
β
β
H
β
H
−
Scheme 1. Reagents and conditions: (i) TMSCN, TfOTMS, CH2Cl2, K20 8C, 2.5 h; (ii) SiO2, CH2Cl2, rt, 24 h; (iii) LiAlH4, Et2O, rt, 2.5 h; (iv) ClMs/Py, rt,
12 h; (v) NaH, DMF, 2.5 h; (vi) H2, Pd/C; MeOH, AcOH, rt, 12 h; (vii) TBAF, CH2Cl2, rt, 0.5 h.
trimethylsilyl cyanide, but in this case, the use of TBAF was
possible. Product 8 was a mixture of anomers (a/b ratio
1:3); the attack of the TMSCN took place preferably by the
less hindered pathway to give the b anomer. The mixture
was directly used in the next steps, as in both cases the same
spiroazetidine is obtained. The 13C NMR spectrum of 8
showed signals at 117.9 (a-anomer) and 116.2 ppm
(b-anomer) for the C^N group. The treatment of 8 and
14 with lithium–aluminium hydride (/ 9, 15) followed by
reaction with mesyl chloride gave the pair of anomers 10 (b)
and 10a (a), as isolated products, and 16, respectively.
With the aim of preparing furanoid spiroazetidines we have
started with the furanosyl cyanide 19, which was easily
prepared17 from the furanoid spiroacetal 18.18 When the
same reactions (Scheme 2) were performed on 19, the sulfon-
amide spiro-C-glycoside 24 was obtained in 37% overall yield
from 19. In this case, the removal of the isopropylidene group
was performed with MeOH/HCl (89% yield) and the
O-debenzoylation with H2/Pd/C in AcOEt (quantitative).
The key step is the cyclization (Scheme 3) by internal
nucleophilic displacement of the mesyloxy group, to afford
the spiroazetidine (5, 11, 17, and 23). A preparation of
N-mesylaminoglycosides through non-isolated N-mesyl-
aziridines obtained by a related cyclization, has been
recently communicated.19
Cyclization of 10 and 16 (/ 11, 17) followed by
O-deprotection gave the target spiroazetidine 12 in high
yield. The NMR data of 12 supported the proposed
structure, being also C-4 the ring carbon atom whose
resonance appeared at lowest field (75.7 ppm). The values
of the coupling constants J7,8 and J8,9 (3.0 and 8.5 Hz,
respectively) were indicative of gauche and antiperiplanar
relationships, respectively, between the corresponding
protons, and consequently the pyranoid ring of 12 is in
the 1C4 (numbering of the sugar ring) conformation in
methanol (see Fig. 1).
In conclusion, we have developed a high yielding six-step
synthesis of water-soluble pyranoid and furanoid spiro-C-
glycosides derived of N-sulfoazetidines. The key step is the
formation of the azetidine ring, which is promoted by NaH.
The stereochemistry is defined by the starting sugar
derivative and the reactions are experimentally easy.
3. Experimental
Ms
N
H8
H7
O
3.1. General methods
OH
OH
HO
H9
A Perkin-Elmer Model 141 MC polarimeter, 1-cm tubes, at
589 nm, was used for measurement of specific rotations.
Figure 1. Conformation of compound 12.

F. J. Sayago et al. / Tetrahedron 62 (2006) 915–921
917
NH2
OH
NHMs
OMs
CN
O
O
O
O
O
OH
O
i
ii
iii
BnO
BnO
BnO
BnO
O
O
O
O
O
O
O
O
20
19
21
18
Ms
Ms
O
O
Ms
O
N
N
N
vi
v
iv
BnO
BnO
HO
HO
OH
OH
HO
O
O
22
23
24
Scheme 2. Reagents and conditions: (i) Ref. 17; (ii) LiAlH4, Et2O, rt, 2.5 h; (iii) MsCl/Py, rt, 12 h; (iv) NaH, DMF, 2.5 h; (v) MeOH, HCl; (vi) H2, Pd/C,
AcOEt, rt, 3 h.
δ
O
δ
O
δ
O
NHMs
OMs
O
N
S O
NaH
DMF
N-Ms
R
R
R
OMs
5, 11, 17, 23
4, 10, 16, 21
Scheme 3. Key step in the formation of the azetidine ring of 5, 11, 17, and 23.
IR spectra were recorded for KBr discs on a Bomen
Michelson MB-120 FTIR spectrophotometer. Mass spectra
(CI, and FAB) were recorded with or a Micromass
AutoSpecQ instrument with a resolution of 1000 or
60,000 (10% valley definition). For the FAB spectra, ions
were produced by a beam of xenon atoms (6–7 K eV), using
3-nitrobenzyl alcohol or 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. NMR experiments were
recorded on Bruker AMX or Avance AV 500 spectrometers
(500.13 MHz for 1H and 125.75 MHz for 13C). Sample
concentrations were typically in the range 10–15 mg per
0.6 mL of solvent. Chemical shifts are given in ppm, using
TBAF$3H2O for 8. The mixture was stirred at rt, 24 h for 2,
and 1 h for 8, then washed with water and brine, dried
(MgSO4), and concentrated to dryness. The residue was
purified by column chromatography using Et2O:hexane 1/1
as eluent.
3.2.1. 3-O-Benzyl-2-cyano-2-deoxy-4,5-O-isopropyl-
idene-b-D-psicopyranose 2. Colorless syrup. Yield 81%;
[a]2D9 K111 (c 0.6, CH2Cl2); CIMS m/z 319 [(MCH)C]; IR
2984, 2911, 2114, 1740, 1678, 1651, 1561, 1516, 1456,
1
1395, 1262, 1100, 864, 801 cmK1. H NMR (500 MHz,
CDCl3) d 7.40–7.36 (m, 5H, Ph),4.86, 4.71 (each d, each
1H, JgemZ12 Hz, CH2Ph), 4.57 (dd, 1H, J3,4Z3.5 Hz,
J4,5Z7.5 Hz, H-4), 4.31 (ddd, 1H, J5,6aZ1.5 Hz, J5,6b
2.5 Hz, H-5), 3.99 (m, 4H, H-3, H-1a, H-1b, H-6a), 3.83 (dd,
Z
1
the residual protonated solvent signal as reference. H and
13C assignments were confirmed by 2D conventional COSY
and HSQC experiments, 2D NOESY experiments were
carried out on a 5 mm inverse detection probe operating at
303 K, by using the double-pulsed field gradient spin-echo
technique (DPFGSE-NOE).20 A mixing time of 400 ms, a
recycle delay of 2 s, and 1024 transients per spectrum, were
used in all cases. Selective inversions were performed by
using Gaussian-shaped soft pulses (50 ms).
1H, J6a,6bZ13 Hz, H-6b), 1.55, 1.36 (each s, each 3H,
C(CH3)2) ppm; 13C NMR (125.7 MHz, CDCl3)
d
136.3–128.6 (Ar), 118.9 (C^N), 110.7 (C(CH3)2), 75.9
(C-2), 74.1 (C-3), 73.9 (CH2Ph), 72.3 (C-5), 71.1 (C-4), 64.8
(C-6), 64.5 (C-1), 26.1, 25.0 (C(CH3)2) ppm; HRCIMS m/z
obsd 320.1488, calcd for C17H22NO5 320.1498.
3.2.2. 3,4,5-Tri-O-benzyl-2-cyano-2-deoxy-a,b-D-fructo-
furanose 8. Colorless syrup. Yield 85%; a/b (1:3); CIMS:
m/z 459 [(MCH)C]; IR 3030, 2917, 2874, 2114, 1740,
1699, 1651, 1516, 1456, 1397, 1262, 1092, 868, 739,
3.2. General procedure for the preparation of
compounds 2 and 8
671 cmK1 13C NMR for a anomer (125.7 MHz, CDCl3) d
;
138.0–127.7 (Ar), 117.9 (CN), 75.2 (C-4*), 74.7 (C-2), 73.7
(CH2Ph), 72.8 (C-3), 71.9 (C-5*), 71.5, 71.4 (2 CH2Ph),
64.5 (C-6), 62.3 (C-1) ppm. For b anomer (125.7 MHz,
CDCl3) d 130.0–127.7 (Ar), 116.2 (CN), 80.5 (C-4*), 80.1
(C-2), 75.5 (CH2Ph), 73.3 (C-3), 72.7 (C-5*), 72.5, 72.0
(2 CH2Ph), 65.8 (C-6), 64.7 (C-1) ppm; HRCIMS m/z obsd
460.2132, calcd for C28H30NO5 460.2124. Anal. Calcd for
C28H29NO5: C, 73.18; H, 6.36; N, 3.05. Found: C, 72.76; H,
6.28; N, 3.10.
A solution of 1 or 7 (2.85 mmol) in CH2Cl2 (13.0 mL) was
˚
stirred at K20 8C under argon and 4 A molecular sieve.
TMSCN (1200 mL, 8.81 mmol), and TMSOTf (847 mL,
4.4 mmol) were added and the stirring was maintained for
2 h. The mixture was neutralized with Et3N (694 mL),
diluted with Et2O, washed with water, dried (MgSO4), and
concentrated to dryness. The residue was solved in CH2Cl2
(20.0 mL), and silica gel 60 (Merck, 70–230 and 230–400
mesh) (15.0 g) was added, for 2, and a catalytic amount of

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F. J. Sayago et al. / Tetrahedron 62 (2006) 915–921
3.3. General procedure for the preparation of
compounds 4, 10, 16, and 21
obsd 642.1806, calcd for C30H37NO9NaS2 642.1807. Anal.
Calcd for C30H37NO9S2: C, 58.14; H, 6.02; N, 2.26; S,
10.35. Found: C, 57.76; H, 5.98; N, 2.40; S, 10.11%. Data
for 10. Yield 50%; [a]2D4 K34 (c 1, CH2Cl2); FABMS: m/z
642 [(MCNa)C]; IR 3117, 2963, 2874, 1740, 1678, 1645,
A solution of 2, 8, or 14 (1.69 mmol) in diethyl ether
(18 mL) was cooled to 0 8C, then LiAlH4 (334 mg,
8.63 mmol) was added and the resulting mixture was stirred
3 h at rt. Treatment with K2CO3 1 M (0.87 mL) gave a white
precipitate that was removed by filtration through Celite.
The organic layer was washed with brine, dried on MgSO4
and concentrated. The residue was dissolved in pyridine
(6.5 mL) under argon, and a solution of mesyl chloride
(1.1 mL) was dropped. The mixture was stirred at rt for 24 h.
The solution was poured into ice-water and extracted with
CH2Cl2, the organic layer was separated, washed with 1 M
sulphuric acid, saturated aqueous sodium hydrogen-
carbonate, and water, dried (MgSO4), filtered and eva-
porated to dryness. The residue was purified by column
chromatography as indicated in each case.
1626, 1561, 1516, 1456, 1397, 1092, 1024, 870, 801 cmK1
;
1H NMR (500 MHz, CDCl3) d 7.36–7.26 (m, 15H, Ph),
4.85–4.57 (m, 7H, 3 CH2Ph, NH), 4.52 (d, 1H, J1a,1b
11.5 Hz, H-1a), 4.36 (d, 1H, H-1b), 4.04 (d, 1H, J3,4
Z
Z
7.5 Hz, H-3), 3.92 (dd, 1H, J5,6aZ4.5 Hz, J6a,6bZ13 Hz,
H-6a), 3.84 (m, 1H, H-5), 3.82 (m, 1H, H-4), 3.65 (d, 1H,
H-6b), 3.51 (dd, 1H, JNH;CH Z5 Hz, JgemZ14 Hz,
2
HCHNH), 3.34 (dd, 1H, JNH;CH Z7:5 Hz, HCHNH), 2.98,
2
2.96 (each s, each 3H, CH3SO2) ppm; 13C NMR
(125.7 MHz, CDCl3) d 137.8–127.8 (Ar), 77.8 (C-4), 77.2
(C-2), 75.3 (CH2Ph), 75.1 (C-3), 72.4 (CH2Ph), 72.3 (C-5),
71.7 (CH2Ph), 69.4 (C-1), 61.6 (C-6), 41.4 (CH2NH), 40.6,
37.9 (2 CH3SO2) ppm; HRFABMS m/z obsd 642.1793,
calcd for C30H37NO9NaS2 642.1807.
3.3.1. 3-O-Benzyl-2-deoxy-4,5-O-isopropylidene-1-O-
mesyl-2-mesylaminomethyl-b-D-psicopyranose 4. Col-
umn chromatography (AcOEt/hexane 1:1) of the residue
gave 4 as a amorphous solid. Yield 80%; [a]3D1 K23 (c 0.9,
CH2Cl2); CIMS m/z 480 [(MCH)C]; IR 3422, 3119, 2963,
1773, 1699, 1649, 1557, 1520, 1458, 1398, 1262, 1090,
1032, 872, 801 cmK1; 1H NMR (500 MHz, CDCl3) d 7.40–
7.30 (m, 5H, Ph), 5.09 (d, 1H, J1a,1bZ12 Hz, H-1a), 4.76,
4.64 (each d, each 1H, JgemZ11.5 Hz, CH2Ph), 4.57 (dd,
1H, JNH;CH Z9 Hz, JNH;CH Z4:5 Hz, NH), 4.52 (dd, 1H,
3.3.3. 3-O-Benzyl-2-deoxy-4,5-O-isopropylidene-1-O-
mesyl-2-mesylaminomethyl-b-D-fructopyranose 16. Col-
umn chromatography (CH2Cl2/MeOH 60:1) of the residue
gave 16 as amorphous solid. Yield 66%; [a]3D1 K10 (c 0.9,
CH2Cl2); CIMS m/z 480 [(MCH)C]; IR 3422, 3119, 2963,
1740, 1678, 1651, 1618, 1561, 1516, 1456, 1397, 1262,
1092, 870, 802 cmK1; 1H NMR (500 MHz, CDCl3) d 7.39–
7.32 (m, 5H, Ph), 4.81 (d, 1H, JgemZ11.5 Hz, CH2Ph), 4.66
(dd, 1H, JNH;CH Z6 Hz, JNH;CH Z7 Hz, NH), 4.57 (d, 1H,
2a
2b
2a
2b
J3,4Z3.5 Hz, J4,5Z6 Hz, H-4), 4.33 (d, 1H, H-1b), 4.23 (m,
1H, H-5), 3.99 (d, 1H, H-3), 3.75 (dd, 1H, J5,6aZ5.5 Hz,
J6a,6bZ13 Hz, H-6a), 3.66 (dd, 1H, J5,6bZ7 Hz, H-6b), 3.44
(dd, 1H, JgemZ13 Hz, HCHNH), 3.38 (dd, 1H, HCHNH),
2.99, 2.97 (each s, each 3H, CH3SO2–), 1.58, 1.33 (each s,
each 3H, C(CH3)2) ppm; 13C NMR (125.7 MHz, CDCl3) d
137.3–128.3 (Ar), 110.5 (C(CH3)2), 75.2 (C-2), 72.6 (C-3),
72.4 (CH2Ph), 71.8 (C-5), 71.2 (C-4), 67.7 (C-1), 62.0 (C-6),
45.2 (CH2NH), 40.5, 37.6 (2 CH3SO2), 27.3, 25.3
(C(CH3)2) ppm; HRCIMS m/z obsd 480.1381, calcd for
C19H30NO9S2 480.1362. Anal. Calcd for C19H29NO9S2: C,
47.59; H, 6.10; N, 2.92; S, 13.37. Found: C, 47.25; H, 5.96;
N, 2.90; S, 12.95%.
CH2Ph), 4.47 (dd, 1H, J3,4Z5.5 Hz, J4,5Z7 Hz, H-4), 4.35
(d, 1H, J1a,1bZ10.5 Hz, H-1a), 4.31 (m, 1H, H-5), 4.26 (d,
1H, H-1b), 3.94 (dd, 1H, J5,6aZ3 Hz, J6a,6bZ13 Hz, H-6a),
3.82 (d, 1H, H-3), 3.81 (dd, 1H, J5,6bZ3 Hz, H-6b), 3.52
(dd, 1H, JgemZ14 Hz, HCHNH), 3.20 (dd, 1H, HCHNH),
3.00, 2.95 (each s, each 3H, CH3SO2–), 1.52, 1.37 (each s,
each 3H, C(CH3)2) ppm; 13C NMR (125.7 MHz, CDCl3) d
137.1–128.3 (Ar), 109.9 (C(CH3)2), 76.3 (C-2), 74.6 (C-3),
74.1 (C-4), 73.7 (CH2Ph), 72.3 (C-5), 69.6 (C-1), 62.4 (C-6),
42.3 (CH2NH), 40.7, 37.7 (2 CH3SO2–), 26.9, 25.0
(C(CH3)2) ppm; HRCIMS m/z obsd 480.1346, calcd for
C19H30NO9S2 480.1362.
3.3.2. Tri-O-benzyl-2-deoxy-1-O-mesyl-2-mesylamino-
methyl-a-D-fructopyranose 10a and tri-O-benzyl-2-
deoxy-1-O-mesyl-2-mesylaminomethyl-b-D-fructo-
pyranose 10. Column chromatography (AcOEt/hexane 1:1)
of the residue gave 10 and 10a as amorphous solids. Data for
10a. Yield 16%; [a]D26 K29 (c 0.94, CH2Cl2); FABMS: m/z
642 [(MCNa)C]; IR 3117, 2963, 2874, 1740, 1678, 1645,
3.3.4. 6-O-Benzyl-2-deoxy-3,4-O-isopropylidene-1-O-
mesyl-2-mesylaminomethyl-b-D-psicofuranose 21. Col-
umn chromatography (Et2O/hexane 4:1) of the residue gave
21 as amorphous solid. Yield 66%. [a]3D1 C8 (c 0.9,
CH2Cl2); CIMS m/z 480 [(MCH)C]; IR 3121, 2963, 2868,
1740, 1651, 1561, 1518, 1456, 1395, 1358, 1262, 1092, 868,
1
802, 669 cmK1; H NMR (500 MHz, CDCl3) d 7.38–7.32
1626, 1561, 1516, 1456, 1397, 1092, 1024, 870, 801 cmK1
;
(m, 5H, Ph), 5.75 (dd, 1H, JNH;CH Z8:5 Hz,
2a
1H NMR (500 MHz, CDCl3) d 7.36–7.28 (m, 15H, Ph),
4.87–4.56 (m, 6H, 3 CH2Ph), 4.53 (d, 1H, J1a,1bZ11.5 Hz,
H-1a), 4.46 (dd, 1H, JNH;CH Z7:5 Hz, JNH;CH Z5 Hz,
JNH;CH Z3:5 Hz, NH), 4.94 (dd, 1H, J3,4Z6.5 Hz, J4,5Z
2b
5.5 Hz, H-4), 4.79 (d, 1H, H-3), 4.60, 4.56 (each d, each 1H,
JgemZ11.5 Hz, CH2Ph), 4.37, 4.31 (each d, each 1H,
J1a,1bZ10.5 Hz, H-1a, H-1b), 4.14 (m, 1H, H-5), 3.74 (dd,
1H, J5,6aZ2.5 Hz, J6a,6bZ10.5 Hz, H-6a), 3.60 (dd, 1H,
J5,6bZ2.5 Hz, H-6b), 3.38 (dd, 1H, JgemZ13 Hz, HCHNH),
3.32 (dd, 1H, HCHNH), 3.06, 2. 74 (each s, each 3H,
2a
2b
NH), 4.23 (d, 1H, H-1b), 4.17 (d, 1H, J3,4Z8.5 Hz, H-3),
3.88 (dd, 1H, J5,6aZ4 Hz, J6a,6bZ13 Hz, H-6a), 3.82
(m, 1H, H-5), 3.77 (dd, 1H, J4,5Z3 Hz, H-4), 3.65 (d, 1H,
H-6b), 3.42 (dd, 1H, JgemZ13 Hz, HCHNH), 3.32 (dd, 1H,
HCHNH), 2.96, 2.86 (each s, each 3H, CH3SO2) ppm; 13C
NMR (125.7 MHz, CDCl3) d 149.5–123.9 (Ar), 78.2 (C-4),
77.9 (C-2), 75.5 (CH2Ph), 74.5 (C-3), 72.6 (C-5), 72.1
(CH2Ph), 71.8 (CH2Ph), 66.5 (C-1), 62.2 (C-6), 44.8
(CH2NH), 40.6, 37.7 (2 CH3SO2) ppm; HRFABMS m/z
CH3SO2–), 1.52, 1.33 (each s, each 3H, C(CH3)2) ppm; 13
C
NMR (125.7 MHz, CDCl3) d 136.9–128.3 (Ar), 114.2
(C(CH3)2), 84.6 (C-5), 83.6 (C-3), 81.6 (C-4), 73.9
(CH2Ph), 69.6 (C-6), 69.0 (C-1), 47.2 (CH2NH), 40.2,
37.6 (2 CH3SO2), 27.2, 25.3 (C(CH3)2) ppm. Anal. Calcd

F. J. Sayago et al. / Tetrahedron 62 (2006) 915–921
919
for C19H29NO9S2: C, 47.59; H, 6.10; N, 2.92; S, 13.37.
Found: C, 47.38; H, 6.12; N, 2.91; S, 13.25%.
Column chromatography (Et2O/hexane 2:1) of the residue
gave 17 as amorphous solid. Yield 64%; [a]2D9 K44 (c 0.9,
CH2Cl2); FABMS m/z 406 [(MCNa)C]; IR 3117, 2963,
2878, 1699, 1645, 1559, 1516, 1464, 1397, 1339, 1262,
3.4. General procedure for the preparation of
compounds 5, 11, 17, and 22
1092, 1022, 870, 801, 685 cmK1 1H NMR (500 MHz,
;
CDCl3) d 7.37–7.30 (m, 5H, Ph), 4.93, 4.66 (each d, each
1H, JgemZ11.5 Hz, CH2Ph), 4.26 (t, 1H, J7,8ZJ8,9Z6 Hz,
H-8), 4.20 (m, 1H, H-7), 4.02 (d, 1H, J3a,3bZ8.5 Hz, H-3a),
To a stirred solution of the corresponding -N and
O-mesylated compound 4, 10, 16, or 21 (0.15 mmol) in
DMF (3.6 mL) at rt, sodium hydride (60 mg, 1.50 mmol)
was added for compounds 11, 17, and 22. For compound 5,
the sodium hydride was added in three portions (20 mg at 0,
5, and 10 h of reaction). The reaction mixture was stirred at
rt. When monitoring of the reaction by TLC (AcOEt/hexane
1:1) indicated that all starting material had been consumed,
the mixture was poured into ice-water and extracted with
CH2Cl2. The organic layer was separated, washed with
water, dried (MgSO4), filtered, and evaporated to dryness.
The residue was purified by column chromatography
(AcOEt/hexane 1:1).
4.01 (d, 1H, J1a,1bZ9 Hz, H-1a), 3.96 (dd, 1H, J6a,6b
Z
13.5 Hz, J6a,7Z2 Hz, H-6a), 3.83 (m, 3H, H-1b, H-3b,
H-6b), 3.66 (d, 1H, H-9), 2.73 (s, 3H, CH3SO2–), 1.51, 1.36
(each s, each 3H, C(CH3)2) ppm; 13C NMR (125.7 MHz,
CDCl3) d 137.4–128.30 (Ar), 110.0 (C(CH3)2), 76.5 (C-9),
75.0 (C-8), 73.5 (CH2Ph), 72.4 (C-4), 72.3 (C-7), 62.0 (C-6),
59.6 (C-3), 55.7 (C-1), 35.2 (CH3SO2-), 27.7, 25.8 (2
(C(CH3)2) ppm; HRFABMS m/z obsd 406.1314, calcd for
C18H25NO6NaS 406.1300.
3.4.4.
(6R,7S,8R)-2-Aza-6-benzyloxymethyl-7,8-
(dimethylmethylenedioxy)-2-N-mesyl-5-oxaspiro[3.4]-
octane 22. Column chromatography (Et2O/hexane 2:1) of
the residue gave 22 as amorphous solid. Yield 63%; [a]D31
K76 (c 0.8, CH2Cl2); FABMS m/z 406 [(MCNa)C]; IR
3117, 2940, 2866, 1846, 1740, 1699, 1651, 1626, 1561,
3.4.1. (7R,8R,9R)-2-Aza-9-benzyloxy-7,8-(dimethyl-
methylenedioxy)-2-N-mesyl-5-oxaspiro[3.5]nonane 5.
Column chromatography (AcOEt/hexane 1:1) of the residue
gave 5 as amorphous solid. Yield 54%; [a]3D1 K31 (c 0.96,
CH2Cl2); FABMS m/z 406 [(MCNa)C]; IR 3119, 2959,
2880, 1740, 1678, 1651, 1626, 1516, 1464, 1397, 1335,
1262, 1092, 856, 799 cmK1; 1H NMR (500 MHz, CDCl3) d
1516, 1456, 1395, 1339, 1273, 1092, 1026, 872, 797 cmK1
;
1H NMR (500 MHz, CDCl3) d 7.41–7.28 (m, 5H, Ph), 4.81
(dd, 1H, J6,7Z0.5 Hz, J7,8Z6 Hz, H-7), 4.75 (d, 1H, H-8),
4.53, 4.43 (each d, each 1H, JgemZ11.5 Hz, CH2Ph), 4.25
(m, 2H, H-6, H-3a), 3.95 (d, 1H, J3a,3bZ9 Hz, H-3b), 3.86
(d, 1H, J1a,1bZ9 Hz, H-1a), 3.69 (d, 1H, H-1b), 3.55, 3.51
7.37–7.35 (m, 5H, Ph), 4.88, 4.65 (each d, each 1H, Jgem
11.5 Hz, CH2Ph), 4.55 (dd, 1H, J7,8Z5.5 Hz, J8,9Z3 Hz,
H-8), 4.38 (d, 1H, J3a,3bZ9 Hz, H-1a), 4.22 (dt, 1H, J6a,7
Z
Z
5.5 Hz, J6b,7Z8 Hz, H-7), 3.99 (d, 1H, J1a,1bZ9 Hz, H-3a),
3.95 (d, 1H, H-1b), 3.77 (d, 1H, H-3b), 3.73 (dd, 1H,
J6a,6bZ12 Hz, H-6a), 3.51 (d, 1H, H-9), 3.49 (dd, 1H,
H-6b), 2.75 (s, 3H, CH3SO2), 1.50, 1.35 (each s, each
3H,) ppm; 13C NMR (125.7 MHz, CDCl3) d 137.0–128.5
(Ar), 110.6 (C(CH3)2), 73.1 (C-9), 72.0 (C-4), 71.7 (C-7),
71.6 (C-8), 71.5 (CH2Ph), 62.5 (C-6), 58.9 (C-3), 56.1 (C-1),
34.7 (CH3SO2–), 28.1, 25.9 (C(CH3)2) ppm; HRFABMS m/
z obsd 406.1304, calcd for C18H25NO6NaS 406.1300. Anal.
Calcd for C18H25NO6S: C, 56.38; H, 6.57; N, 3.65; S, 8.36.
Found: C, 55.94; H, 6.45; N, 3.65; S, 8.21%.
(each dd, each 1H, JgemZ10 Hz, J
Z2:5 Hz, HCHOBn,
6;CH2
HCHOBn), 2.88 (s, 3H, CH3SO2), 1.45, 1.38 (each s, each
3H, C(CH3)2) ppm; 13C NMR (125.7 MHz, CDCl3) d
137.1–128.2 (Ar), 112.8 (C(CH3)2), 85.7 (C-8), 83.9
(C-6), 83.3 (C-7), 81.0 (C-4), 74.1 (CH2Ph), 71.7
(CH2OBn), 63.7 (C-1), 57.2 (C-3), 36.2 (CH3SO2), 26.5,
25.2 (C(CH3)2) ppm; HRFABMS m/z obsd 406.1305, calcd
for C18H25NO6NaS 406.1300. Anal. Calcd for
C18H25NO6S: C, 56.38; H, 6.57; N, 3.65; S 8.36. Found:
C, 56.18; H, 6.42; N, 3.67; S, 8.34.
3.5. General procedure for the preparation of
compounds 6 and 12
3.4.2. (7R,8R,9S)-2-Aza-7,8,9-tribenzyloxy-2-N-mesyl-5-
oxaspiro[3.5]nonane 11. Column chromatography (Et2O/
hexane 4:1) of the residue gave 11 as amorphous solid.
Yield 76%; [a]3D1 K28 (c 1.0, CH2Cl2); FABMS m/e 546
[(MCNa)C]; IR 3117, 2961, 2874, 1740, 1699, 1651, 1626,
To a solution of the corresponding O-protected compound 5,
11 or 17 (0.14 mmol) in dry methanol (3.7 mL), acetic acid
(370 mL) and C/Pd (122 mg) were added. The reaction
mixture was stirred at rt, under hydrogen for 12 h, and
controlled by TLC (AcOEt/MeOH 15:1) until total
consumption of the starting material. The mixture was
diluted with methanol (25 mL) and neutralized with basic
resin Amberlite IR-400(OHK), filtered, and evaporated to
dryness. The residue was purified by column chromato-
graphy (AcOEt/MeOH 15:1).
1
1561, 1506, 1456, 1397, 1262, 1092, 799, 669 cmK1; H
NMR (500 MHz, CDCl3) d 7.35–7.38 (m, 15H, Ph), 4.79–
4.57 (m, 6H, CH2Ph), 4.05 (d, 1H, J3a,3bZ9.5 Hz, H-3a),
4.01 (d, 1H, J1a,1bZ9 Hz, H-1a), 3.90–3.85 (m, 2H, H-6a,
H-7), 3.88 (d, 1H, H-3b), 3.85 (d, 1H, J8,9Z6 Hz, H-9), 3.75
(d, 1H, H-1b), 3.70 (dd, 1H, J7,8Z2 Hz, H-8), 3.58 (dd, 1H,
J6a,6bZ11 Hz, J6b,7Z2 Hz, H-6b), 2.76 (s, 3H, CH3SO2)
ppm; 13C NMR (125.7 MHz, CDCl3) d 138.0–127.9 (Ar),
76.6 (C-9), 76.0 (C-8), 74.5 (CH2Ph), 73.5 (C-4), 72.8
(CH2Ph), 72.2 (C-7), 71.7 (CH2Ph), 61.4 (C-6), 58.7 (C-3),
56.8 (C-1), 35.4 (CH3SO2) ppm; HRFABMS m/z obsd
546.1901, calcd for C29H33NO6NaS 546.1926.
3.5.1. (7R,8R,9R)-2-Aza-7,8,9-trihydroxy-2-N-mesyl-5-
oxaspiro[3.5]nonane 6. Amorphous solid. Yield 93%;
[a]3D0 C4 (c 1.2, MeOH); CIMS m/z 254 [(MCH)C]; IR
3420, 3121, 2963, 1740, 1699, 1651, 1626, 1539, 1516,
1
3.4.3. (7R,8R,9S)-2-Aza-9-benzyloxy-7,8-(dimethyl-
methylenedioxy)-2-N-mesyl-5-oxaspiro[3.5]nonane 17.
1456, 1397, 1262, 1092, 1028, 870, 801, 685 cmK1; H
NMR (500 MHz, MeOD) d 4.28 (d, 1H, J3a,3bZ9.5 Hz, H-

920
F. J. Sayago et al. / Tetrahedron 62 (2006) 915–921
1a), 4.05 (d, 1H, J1a,1bZ9.0 Hz, H-3a), 3.94 (t, 1H, J6a,7
Z
d 4.31 (dt, 1H, J3a,3bZ9.0 Hz, J1a,3aZJ1b,3aZ1.0 Hz, H-3a),
4.03 (m, 2H, H-7, H-8), 3.96 (dd, 1H, J1a,1bZ9.0 Hz, H-1a),
3.88 (dt, 1H, J1a,1bZ9.0 Hz, J1b,3bZ1.0 Hz, H-1b), 3.87 (m,
1H, H-6), 3.80 (dd, 1H, H-3b), 3.66 (dd, 1H, JgemZ12 Hz,
J6;CH Z3 Hz, HCHOH), 3.54 (dd, 1H, J6;CH Z4 Hz,
J7,9Z2.5 Hz, H-7), 3.78 (d, 1H, H-1b), 3.68 (d, 1H, H-3b),
3.65 (m, 2H, H-6a, H-8), 3.55 (d, 1H, J6a,6bZ8.5 Hz, H-6b),
3.45 (d, 1H, H-9), 2.93 (m, 3H, CH3SO2) ppm; 13C NMR
(125.7 MHz, MeOD) d 76.4 (C-4), 73.6 (C-7), 71.5 (C-9),
68.5 (C-8), 63.3 (C-6), 59.1 (C-3), 57.5 (C-1), 33.9
(CH3SO2 ppm; HRCIMS m/z obsd 254.0703, calcd for
C8H16NO6S 254.0698.
2
2
HCHOH), 2.94 (s, 3H, CH3SO2) ppm; 13C NMR
(125.7 MHz, MeOD) d 85.6 (C-6), 79.8 (C-4), 75.7 (C-7),
72.4 (C-8), 62.9 (CH2OH), 61.6 (C-1), 59.2 (C-3), 34.3
(CH3SO2) ppm; HRCIMS m/z obsd 254.0708, calcd for
C8H16NO6S 254.0698.
3.5.2. (7R,8R,9S)-2-Aza-7,8,9-trihydroxy-2-N-mesyl-5-
oxaspiro[3.5]nonane 12. Amorphous solid. Yield 93%
(from 11), 92% (from 17). [a]2D9 K47 (c 0.9, MeOH); CIMS
m/z 254 [(MCH)C]; IR 3422, 2963, 1834, 1740, 1651,
Acknowledgements
1561, 1516, 1456, 1397, 1262, 1092, 1024, 870, 796 cmK1
;
1H NMR (500 MHz, MeOD) d 4.13 (dd, 1H, J3a,3bZ9.5 Hz,
J1a,3aZ1.0 Hz, H-3a), 4.10 (dd, 1H, J1a,1bZ9.0 Hz, H-1a),
3.83 (m, 1H, H-7), 3.79 (dd, 1H, J1b,3bZ1.0 Hz, H-3b), 3.77
(dd, 1H, H-1b), 3.72 (m, 2H, H-6a, H-9), 3.60 (dd, 1H,
´
We thank the Secretarıa de Estado de Universidades e
Investigacion of Spain and the Junta de Andalucia for
´
financial support (grant numbers BQU2001-3740, CTQ
2004-1178 with FEDER participation, and FQM-134), and
´
the Ministerio de Educacion y Cultura, for the award of a
fellowships to F.J.S.
J6a,6bZ12.5 Hz, J6a,7Z2.5 Hz, H-6b), 3.52 (dd, 1H, J7,8
Z
C
3.0 Hz, J8,9Z8.5 Hz, H-8), 2.94 (s, 3H, CH3SO2) ppm; 13
NMR (125.7 MHz, MeOD) d 75.7 (C-4), 72.3 (C-8), 70.7
(C-9), 68.9 (C-7), 65.8 (C-6), 59.5 (C-3), 56.1 (C-1), 34.2
(CH3SO2) ppm; HRCIMS m/z obsd 254.0710, calcd for
C8H16NO6S 254.0698.
References and notes
3.5.3.
(6R,7S,8R)-2-aza-6-benzyloxymethyl-7,8-di-
hydroxy-2-N-mesyl-5-oxaspiro[3.4]octane 23. To a
solution of 22 (0.45 mmol) in methanol (12.0 mL),
concentrated hydrochloric acid (946 mL) was added. The
reaction mixture was stirred at rt for 12 h. The process was
controlled by TLC (CH2Cl2/MeOH, 15:1 as eluent). The
solution was neutralized with NaHCO3, filtered, and the
solvent was evaporated under reduced pressure. The residue
was purified by column chromatography (CH2Cl2/MeOH,
30:1) as eluent to give 23 as amorphous solid. Yield 89%.
[a]2D9 K5 (c 0.9, CH2Cl2); CIMS m/z 344 [(MCH)C]; IR
3447, 3030, 2924, 2870, 1653, 1507, 1456, 1404, 1339,
1. (a) For a recent reference, see as example: Venkateson, A. M.;
Agarwal, A.; Abe, T.; Ushirogochi, H.; Yamamura, I.;
Kumogai, T.; Petersen; Peter, J.; Weis, W.; Lenoy, E.;
Yang, Y.; Shlaes, D. M.; Ryan, J. L.; Mansour, T. S. Bioorg.
Med. Chem. 2004, 12, 5807–5817. (b) Tuta, E.; Wittigens, A.;
´
Maffii, G.; Blanchi, G. In Gallo, V., Santamarıa, L., Eds.;
Research Progress in Organic, Biological and Medicinal
Chemistry; North-Holland: Amsterdan, 1964; Vol. 1, p 477.
2. Barbaro, G.; Battaglia, A.; Di Giuseppe, F.; Giorgianni, P.;
Guerrini, A.; Bertucci, C.; Geremia, S. Tetrahedron:
Asymmetry 1999, 10, 2765–2773.
1092, 1026, 874, 756, 712 cmK1 1H NMR (500 MHz,
;
3. Ozone, F.; Inoue, Y.; Shiraishi, A.; Hamashima, H.;
Masuda, K.; Shiojima, K.; Sasatsu, M. J. Microbiol. Meth.
2002, 50, 91–95.
MeOD) d 7.35–7.25 (m, 5H, Ph), 4.53 (s, 2H, CH2Ph), 4.30
(d, 1H, J3a,3bZ9 Hz, H-3a), 4.05 (m, 2H, H-7, H-8), 3.99
(m, 1H, H-6), 3.90 (dd, 1H, J1a,1bZ9 Hz, J1a,3bZ1 Hz,
H-1a), 3.86 (d, 1H, H-1b), 3.80 (dd, 1H, H-3b), 3.60 (dd,
4. Ungureanu, I.; Klotz, Ph.; Schoenfelder, A.; Mann, A.
Tetrahedron Lett. 2001, 42, 6087–6091.
1H, JgemZ10.5 Hz, J6,CH Z3.0 Hz), 3.53 (dd, 1H,
2
5. See as examples: (a)
Furman, B.; Thu¨rmer, Z. K.;
J6;CH Z4 Hz, HCHOH), 2.92 (s, 3H, CH3SO2) ppm; 13C
2
Lysek, R. L.; Voelter, W.; Chmielewski, M. Angew. Chem.,
Int. Ed. 1999, 38, 1121–1123. (b) Obika, S.; Andoh, J.;
Onoda, M.; Nakagawa, O.; Hiroto, A.; Sugimoto, T.;
Imanishi, T. Tetrahedron Lett. 2003, 44, 5267–5270.
6. Eniade, A.; Martin, O. R. Carbohydr. Res. 2002, 337,
273–277.
NMR (125.7 MHz, MeOD) d 139.5–128.7 (Ar), 84.3 (C-6),
80.0 (C-4), 75.6 (C-7*), 74.5 (CH2Ph), 72.9 (C-8*), 71.4
(CH2OH), 61.8 (C-1), 59.2 (C-3), 34.3 (CH3SO2) ppm;
HRCIMS m/z obsd 344.1164, calcd for C15H22NO6S
344.1168.
7. For the term spironucleoside, see: Gasch, C.; Pradera, M. A.;
Salameh, B. A. B.; Molina, J. L.; Fuentes, J. Tetrahedron:
Asymmetry 2001, 12, 1267–1277.
3.5.4.
(6R,7S,8R)-2-Aza-7,8-dihydroxy-6-hydroxy-
methyl-2-N-mesyl-5-oxaspiro[3.4]octane 24. To a solu-
tion of 23 (0.397 mmol) in AcOEt (27.0 mL), C/Pd (27 mg)
was added. The reaction mixture was stirred at rt, under
hydrogen for 1.5 h, and controlled by TLC (AcOEt/MeOH
15:1 as eluent), until total consumption of the starting
material, filtered through Celite and concentrated. The
residue was purified by column chromatography (AcOEt/
MeOH 15:1) to give 24 as amorphous solid. Yield 99%.
[a]2D9 C6 (c 0.9, MeOH); CIMS m/z 254 [(MCH)C];
IR 3422, 3121, 2963, 1740, 1694, 1645, 1551, 1464, 1397,
1262, 1092, 1024, 801 cmK1; 1H NMR (500 MHz, MeOD)
´
´
8. Barluenga, J.; Fernandez-Marı, F.; Viado, A. L.; Aguilar, E.;
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