Thioanhydro sugars. Part IX: Enantiospecific synthesis of a polyhydroxythio lane, key intermediate for the preparation of glycosidase inhibitors bearing inner thiosulfonium salt

Article abstract of DOI:10.1016/S0957-4166(02)00368-3

(2R,3R,4S)-3,4-Dihydroxy-2-[(R)-1,2-dihydroxyethyl]thiolane (1,4-anhydro-4-thio-D-mannitol), 1 has been prepared from methyl 4,6-O-benzylidene-α-D-altropyranoside 2 in seven steps, the latter being readily available from commercial methyl α-D-glucopyranos

Full text of DOI:10.1016/S0957-4166(02)00368-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1417–1421
Thioanhydro sugars. Part 9: Enantiospecific synthesis of a
polyhydroxythiolane, key intermediate for the preparation of
glycosidase inhibitors bearing inner thiosulfonium salt†
Isidoro Izquierdo,* Mar´ıa T. Plaza, Rafael Asenjo and Antonio Ram´ırez
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 17 June 2002; accepted 5 July 2002
Abstract—(2R,3R,4S)-3,4-Dihydroxy-2-[(R)-1,2-dihydroxyethyl]thiolane (1,4-anhydro-4-thio-
from methyl 4,6-O-benzylidene-a- -altropyranoside 2 in seven steps, the latter being readily available from commercial methyl
a- -glucopyranoside. © 2002 Elsevier Science Ltd. All rights reserved.
D-mannitol), 1 has been prepared
D
D
1. Introduction
groups have reported, on the stereospecific synthesis of
polyhydroxythiolanes5 and thioanalogues of cas-
tanospermine,6 These works mostly followed the isola-
tion of the potent sucrase inhibitors salacinol7 and
kotalanol,8 which bear a sulfonium salt-containing het-
erocycle in their skeletons, from Salacia reticulata
Wight (Celastaceae), an antidiabetic treatment in popu-
lar Indian Ayurvedic traditional medicine.
In relation to the general interest of our group on the
use of simple sugar derivatives as starting chiral tem-
plates for the stereospecific synthesis of complex
molecules with biological activity (glycosidase
inhibitors, pheromones, toxins, etc.), we have reported
on the enantiospecific synthesis of compounds bearing
the polyhydroxythiane,1,2 thiolane3 and other related
moieties,4 some of them being used as key intermediates
for the stereocontrolled synthesis of a thioanalogue of
swainsonine.3c
The retrosynthetic analysis shown below, clearly indi-
cated that (2R,3R,4S)-3,4-dihydroxy-2-[(R)-1,2-dihy-
droxyethyl]thiolane (1,4-anhydro-4-thio- -mannitol) 1
D
could be an excellent chiral key intermediate for build-
ing-up in a stereocontrolled manner the skeleton of
the showed target molecules (the stereochemistry of
Despite the lack of reported work in the literature on
these types of substances, over the last 2 years, different
* Corresponding author. E-mail: isidoro@platon.ugr.es
† For Part VIII, see Ref. 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00368-3

1418
I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1417–1421
thioswainsonine totally matches that of 1, only being
necessary a chain-lengthening at the hydroxymethyl
group followed by cyclisation.3c In the case of salacinol
and kotalanol, structurally related stereoisomers could
be prepared for future SAR analyses. Accordingly, we
report herein on the enantiospecific synthesis of 1 from
corresponding 2,3-di-O-methanesulfonyl derivative 3 in
80% yield. Compound 3 was easily transformed (80–
83% yield) into methyl 2,3-di-O-methanesulfonyl-a-D-
altropyranoside 4, by removal of the 4,6-O-benzyli-
dene group, and subsequently allowed to react under
the thio-Mitsunobu reaction conditions10 to afford,
fast and regioselectively at C(6), methyl 6-S-acetyl-
a suitably protected derivative of methyl a-
D-altropy-
ranoside, easily prepared from commercially available
2,3-di-O-methanesulfonyl-6-thio-a-
5.
D-altropyranoside
methyl a-
D
-glucopyranoside.
The structure of 5 was determined on the basis of its
analytical and spectroscopic data (see Tables 1 and 2
for the 1H and 13C NMR spectra), where marked
upfield shifts were seen for H(6,6%) and C(6) with
respect to their positions in 4, indicating that an O“S
interchange had occurred.
2. Results and discussion
According to Scheme 1 below, treatment of methyl
4,6-O-benzylidene-a- with
-altropyranoside9
methanesulfonyl chloride in dichloromethane gave the
D
2
Scheme 1. Reagents and conditions: (a)MsCl/Et3N/CH2Cl2; (b) AcOH/H2O or I2/MeOH; (c) Ph3P/DEAD/AcSH.
Table 1. 1H NMR chemical shifts (l) and J (Hz) values for compound 1, 3–7, 9, and 11
Compound H-1
H-1%
H-2
H-3
H-4
H-5
H-6
H-6%
OMe
OMs
1a
3b
4c
2.89t,
1,2=9.7,
J1,1%=9.7
2.82dd,
4.16ddd,
4.25t
3.35dd,
3.87ddd
3.60dd,
3.40dd,
J5,6%=6.0
–
–
J
J1%,2=6.7
J2,3=3.1
J
J
3,4=3.7,
4,5=9.7
J
5,6=2.8,
J6,6%=11.6
4.36dd,
4.83s
–
4.88d,
2,3=3.0
5.02t
4.03dd,
4.24dt
3.79t,
J5,6%=10.4
3.44s
3.39s
3.14s, 2.99s
3.22s, 3.16s
J
J
J
3,4=3.2,
4,5=9.8
J5,6=5.3,
J6,6%=10.4
4.82s
–
–
4.81d,
2,3=3.5
4.96dd,
J3,4=5.8
3.91–3.74m 4.08ddd,
J=3.6,
3.91–3.74m
J
J=6.7,
J=8.4
5d
4.75bs
4.71d,
4.81dd,
4.91t,
3,4=3.7
4.06bquin
3.78ddd,
4,5=9.5
3.30dd,
3.25dd,
J5,6%=3.9
3.40s
3.14s, 3.12s
J
J
1,2=1.4,
2,3=3.8
J
J
J5,6=5.3,
J6,6%=14.6
2.81dd,
6e
7f
–
–
4.66dd,
2,3=3.0
4.69dd,
2,3=4.4
3.33dd,
3,4=4.7
4.86t,
3,4=3.8
4.24bt
4.04m
2.58d,
J6,6%=12.3
2.94dd,
J5,6%=9.8,
J6,6%=13.8
2.84d
3.27s
3.35s
2.82s
J
1,2=6.9
4.73d,
1,2=2.3
J
J
J5,6=4.5
3.74ddd,
3.97dt,
3.21dd
3.28s, 3.21s
J
J
J
J4,5=9.4,
J5,6=2.8
J4,OH=6.6
9g
4.65d,
1,2=6.6
–
4.22m
3.47t,
2,3=4.0
4.44dd,
3.95m
3.05dd,
J
3.54s
–
–
J
J
J
J
3,4=4.4,
4,5=2.9
5,6=4.7,
J6,6%=12.6
5.29–5.21m 4.40dd,
5,6=2.4,
J6,6%=12.5
11h
3.13–3.05m
5.29–5.21m 5.70t,
2,3=3.6
3.83dd,
4.00dd,
J5,6%=5.6
–
J
J
J
3,4=4.0,
4,5=10.7
J
a MeOH-d4 (sugar numbering).
b Signal for PhCH at 5.63s.
c Me2CO-d6, signal for OH-4 at 4.70d (J 6.7 Hz).
d Signal for MeCOS and HO-4 at 2.40s and 3.69d (J 6.2 Hz), respectively.
e Signal for OH-4 at 4.48d (J 4.6 Hz).
f DMSO-d6.
g Signals for HO-2,4 at 2.92bs and 2.40dd.
h Signals (sugar numbering) for OAc at 2.10s, 2.08s, 2.02s, and 1.99s.

I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1417–1421
Table 2. 13C NMR chemical shifts (l) for compound 1, 3–7, 9, and 11
1419
Compound
C-1
C-2
C-3
C-4
C-5
C-6
OMe
OMs
Others
1
3
4
5
6
7
9
11
33.42
99.05
99.68
98.72
98.73
97.59
103.10
30.72
73.37
74.79
49.60
77.49
56.01
64.83
64.99*
75.09
65.44b
75.87
70.33*
65.79
68.97
62.34
30.77
29.83
39.80
30.26
63.70
–
–
–
75.20*
77.81*
76.11*
76.81
73.65*
76.81*
75.21*
48.51
73.23*
71.17*
67.06*
76.32
58.10
55.50
55.87
56.32
55.10
57.52
–
38.60, 38.18
38.30, 38.16
38.53, 38.21
37.71
37.88, 37.57
–
PhCH, 102.32
–
AcS, 198.52, 30.63
–
–
–
76.35a
67.66
75.32a
50.40
67.66b
76.47
74.69*
71.69*
44.46
–
AcO, 170.02, 170.01, 20.77, 20.74,
20.65
*
,a,b Interchangeable assignments.
Treatment of 5 with sodium methoxide (see Scheme 2)
effected clean removal of the S-acyl group producing a
mercaptide anion, which promoted an intramolecular
and regioselective nucleophilic attack at C(3) to afford
methyl
2-O-methanesulfonyl-3,6-thioanhydro-a-D-
mannopyranoside 6, according to its chiroptical, ana-
lytical and spectroscopic data (see Tables 1 and 2).
When the reaction was scaled up to multigrams, the
corresponding S-deacylation product 7 could be iso-
lated in minute quantity. The structure of 6 was also
confirmed by desulfuration with Raney-nickel in reflux-
ing ethanol, that surprisingly afforded the unexpected
Scheme 3. Reagents and conditions: (a) 70% TFAA/H2O; (b)
NaBH4/MeOH; (c) Ac2O/Pyr/DMAP.
methyl 2,3,6-trideoxy-a-
-erythro-hexopyranoside 8,11
D
3. Experimental
3.1. General
where not only C(3,6)-desulfuration, but also deoxy-
genation at C(2), had occurred. On the other hand, in
order to complete the synthesis of 1 (see Scheme 3),
compound 6 was 2-O-demesylated by treatment with
LiAlH4 in anhydrous refluxing 1,2-dimethoxyethane
(DME) to 9.
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. Solutions were dried
over MgSO4 before concentration under reduced pres-
1
sure. The H and 13C NMR spectra were recorded with
Hydrolysis of 9 gave the intermediate aldehyde 10
(which was not investigated), which was subsequently
reduced with sodium borohydride to 1, whose structure
was determined on the basis of its analytical and spec-
troscopic data, as well as those of its peracetylated
derivative 11.
Bruker AMX-300, AM-300, and ARX-400 spectrome-
ters for solutions in CDCl3 (internal Me4Si). IR spectra
were recorded with a Perkin–Elmer 782 instrument and
mass spectra with a Micromass Mod. Platform II and
Autospec-Q mass spectrometers. Optical rotations were
measured for solutions in CHCl3 (1 dm tube) with a
Scheme 2.

1420
I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1417–1421
Jasco DIP-370 polarimeter. TLC was performed on
precoated silica gel 60 F254 aluminium sheets and detec-
tion by charring with H2SO4 Column chromatography
was performed on silica gel (Merck, 7734). The non-
crystalline compounds, for which elemental analyses
were not obtained were shown to be homogeneous by
chromatography and characterised by NMR and
HRMS.
10.5 mmol). After 10 min, thioacetic acid (0.85 g, 11.2
mmol) and compound 4 (2.45 g, 7 mmol) were added,
and after 10 min the mixture allowed to reach rt and
then left for 4 h. TLC (ether/hexane/ethanol, 6:0.5:0.2)
then revealed a less polar product. The solvent was
evaporated and the residue purified by silica gel chro-
matography (ether/hexane, 6:1“ether/hexane/ethanol,
6:1:0.2) to afford syrupy 5 (2.32 g, 81%): [h]2D3=+32 (c
1.1); w
3523 (OH) and 1696 cm−1 (AcS). For NMR
film
max
3.2. Methyl 4,6-O-benzylidene-2,3-di-O-methanesulfonyl-
a-D-altropyranoside, 3
data, see Tables 1 and 2. Mass spectrum (LSIMS): m/z:
431.0111 [M++Na] for C11H20O10NaS3 431.0116 (devia-
tion 1.3 ppm).
To a stirred and cooled (ice-water) solution of methyl
4,6-O-benzylidene-a-
-altropyranoside9 2 (3.95 g, 14
D
3.5. Methyl 2-O-methanesulfonyl-3,6-thioanhydro-a-D-
mmol) and triethylamine (6.5 mL, 46.2 mmol) in dry
dichloromethane (70 mL) a solution of methanesulfonyl
chloride (2.4 mL, 30.8 mmol) in the same solvent (40
mL) was added dropwise and the reaction mixture
allowed to warm to rt and then left for 1 h. TLC
(ether/hexane/ethanol, 6:0.5:0.2) then revealed the pres-
ence of a less polar product. The mixture was filtered
and the filtrate treated with ethanol (5 mL), washed
with brine, water, then concentrated to a solid foam
mannopyranoside, 6
To a stirred solution of 5 (2.59 g, 6.35 mmol) in dry
methanol (40 mL), 1 M methanolic sodium methoxide
(10 mL) was added dropwise and the mixture main-
tained at room temperature for 5 h. TLC (ether/hexane/
ethanol, 6:1:0.1) then showed the presence of a slightly
more polar product. The mixture was neutralised
(AcOH) and concentrated. Column chromatography
(ether/hexane/ethanol, 6:1:0.1“ether/ethanol 5:2) of
the residue afforded first crystalline 6 (1.53 g, 90%): mp
178–179°C (from ether/hexane); [h]2D5=+113 (c 0.8). For
NMR data, see Tables 1 and 2. Anal. calcd for
C8H14O6S2: C, 35.54; H, 5.22; S, 23.72. Found: C,
35.80; H, 5.71; S, 23.30%.
that was recrystallised from ethanol to afford pure 3
KBr
(4.91 g, 80%): mp 162–164°C; [h]2D2=+44 (c 1.1); w
max
3034, 3019, 703, and 684 cm−1 (aromatic). For NMR
data, see Tables 1 and 2. Anal. calcd for C16H28O10S2:
C, 43.82; H, 5.06; S, 14.63. Found: C, 43.80; H, 5.47; S,
15.10.
3.3. Methyl 2,3-di-O-methanesulfonyl-a-
D
-altropyran-
Eluted second was crystalline methyl 6-deoxy-2,3-di-O-
oside, 4
methanesulfonyl-6-thio-a- -altropyranoside (7, 133
D
mg): mp 115–117°C (from ether/ethanol); [h]2D5=+142
3516 and 3507 cm−1 (SH and
KBr
max
(a) A suspension of compound 3 (440 mg, 1 mmol) in
aqueous 70% acetic acid (12 mL) was vigorously stirred
at rt until a homogeneous solution was obtained. TLC
(ether/hexane/ethanol, 6:1:0.1), then showed a slower-
running product. The mixture was concentrated and
repeatedly co-distilled with toluene–ethanol to remove
water and acetic acid. The residue was crystallised from
(c 0.5, ethyl acetate); w
OH). For NMR data, see Tables 1 and 2. Anal. calcd
for C9H18O9S3: C, 29.50; H, 4.95; S, 26.25. Found: C,
29.87; H, 5.20; S, 26.65%.
3.6. Methyl 2,3,6-trideoxy-a-
D
-erythrohexopyranoside,
8
ethanol/hexane to give 4 (290 mg, 83%): mp 176–178°C;
[h]2D7=+50 (c 1.2, acetone); w
3566 cm−1 (OH). For
To a solution of 6 (160 mg, 0.6 mmol) in ethanol (10
mL) Raney-nickel (1 g, Fluka) was added and the
mixture heated under reflux for 1 h. TLC (ethyl acetate/
hexane 3:1) then revealed the presence of a slightly less
polar product. The catalyst was filtered off, washed
with ethanol and the filtrate and washings concentrated
to a residue that was submitted to chromatography
(ethyl acetate/hexane 2:1) to yield 8 (30 mg, 21%) as a
colourless syrup: [h]2D3=+150 (c 0.5) (lit.11b [h]D20=+154
(c 1). NMR data were in accordance with those found
in the literature.11
KBr
max
NMR data, see Tables 1 and 2. Anal. calcd for
C9H18O10S2: C, 30.85; H, 5.18; S, 18.30. Found: C,
31.22; H, 5.58; S, 17.96%.
(b) To a well stirred solution of iodine (1.9 g) in
methanol (190 mL) compound 3 (3.8 g, 8.7 mmol) was
added and the mixture heated under reflux for 30 min.
TLC (ether/hexane/ethanol, 6:1:0.1) then showed the
presence of 4. Saturated aqueous sodium thiosulfate
solution was added to reduce iodine and then concen-
trated to a residue that was extracted with ethyl acetate
(3×100 mL). The solvent was removed and the residue
purified by chromatography (ether–ethanol 10:1“5:1)
to afford crystalline 4 (2.43 g, 80%).
3.7. Methyl 3,6-thioanhydro-a-D-mannopyranoside, 9
To a stirred suspension of LiAlH4 (220 mg, 5.8 mmol)
in anhydrous refluxing DME (10 mL) was added drop-
wise a solution of 6 (610 mg, 2.26 mmol) in the same
solvent (20 mL) under argon and the refluxing contin-
ued for 3 h. TLC (ethyl acetate) then showed the
presence of a more polar product. Ethyl acetate satu-
rated with an aqueous solution of potassium bisulfate
was cautiously added, the mixture was filtered through
3.4. Methyl 6-S-acetyl-2,3-di-O-methanesulfonyl-6-thio-
a-
D
-altropyranoside, 5
To
a
stirred and cooled (ice-water) solution of
triphenylphosphine (2.8 g, 10.5 mmol) in dry THF (20
mL) was added diethyl azodicarboxylate (DEAD, 1.9 g,

I. Izquierdo et al. / Tetrahedron: Asymmetry 13 (2002) 1417–1421
1421
Acknowledgements
a Celite pad, and the filtrate concentrated to a
residue that was supported on silica gel, then chro-
matographed (ether“ether/ methanol, 20:1) to give
first starting material 6 (45 mg) and then syrupy 9
(320 mg, 80%); [h]2D3=+66 (c 0.5). For NMR data,
see Tables 1 and 2. Mass spectrum (LSIMS): m/z:
215.0352 [M++Na] for C7H12O4NaS 215.0354 (devia-
tion 0.7 ppm).
The authors are deeply grateful to Ministerio de Edu-
cacio´n y Cultura (Spain) for financial support (Project
PB98-1357).
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ethyl]thiolane (1,4-anhydro-4-thio-D-mannitol), 1
M.-D. Carbohydr. Res. 1993, 242, 109–118.
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trifluoroacetic acid (5 mL) was heated at 60°C for 4
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10). The mixture was concentrated and repeatedly co-
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