Direct stereoselective synthesis of β-thiomannosides

Article abstract of DOI:10.1021/jo9914667

A highly diastereoselective synthesis of β-thiomannopyranosides is described in which S-phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-thia- α-D-mannopyranoside S-oxide is treated with triflic anhydride and 2,6-di- tert-butyl-4-methylpyridine in CH₂Cl₂ at -78 °C leading to the formation of an intermediate α-mannosyl triflate. Addition of primary, secondary, or tertiary thiols then leads to the β-thiomannosides, by an S(N)2-like displacement, in good yield and with excellent stereoselectivity. Deprotection is achieved either by Birch reduction or by Zemplen deacetylation, of the acetyl protected aglycons, followed by hydrogenolysis over Pearlman's catalyst. The assignment of configuration of the β- thiomannopyranosides is discussed in terms of the chemical shift of the mannose H5 resonance and the ¹J(CH) of the mannose anomeric carbon.

Full text of DOI:10.1021/jo9914667

J . Org. Chem. 2000, 65, 801-805
801
Dir ect Ster eoselective Syn th esis of â-Th iom a n n osid es
David Crich* and Hongmei Li
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Received September 15, 1999
A highly diastereoselective synthesis of â-thiomannopyranosides is described in which S-phenyl
2,3-di-O-benzyl-4,6-O-benzylidene-1-deoxy-1-thia-R-D-mannopyranoside S-oxide is treated with triflic
anhydride and 2,6-di-tert-butyl-4-methylpyridine in CH2Cl2 at -78 °C leading to the formation of
an intermediate R-mannosyl triflate. Addition of primary, secondary, or tertiary thiols then leads
to the â-thiomannosides, by an SN2-like displacement, in good yield and with excellent stereose-
lectivity. Deprotection is achieved either by Birch reduction or by Zemplen deacetylation, of the
acetyl protected aglycons, followed by hydrogenolysis over Pearlman’s catalyst. The assignment of
configuration of the â-thiomannopyranosides is discussed in terms of the chemical shift of the
1
mannose H5 resonance and the J CH of the mannose anomeric carbon.
In tr od u ction
to activate the thioglycoside or sulfoxide so rapidly, then
it would seem likely they might compete effectively with
the triflate 3 for capture of the thiol introduced as
nucleophile. Moreover, early experiments by the Vernon
and Overend groups showed that while displacement of
halide from 2,3,4,6-tetra-O-methylglucopyranosyl chlo-
ride and 2,3,4,6-tetra-O-acetylglucopyranosyl bromide by
thiolates was bimolecular and led cleanly to the â-thio-
glucosides, the corresponding reactions in the mannose
series did not depend on thiolate concentration and gave
complex reaction mixtures.17,18 Finally, although thiogly-
cosides are most commonly thought of in terms of
convenient, shelf-stable glycosyl donors,19 they also have
significant potential as competitive inhibitors of oligosac-
charide processing enzymes, which renders methods for
their diastereoselective synthesis all the more impor-
tant.20,21
Recently, we have shown how Kahne’s sulfoxide gly-
cosylation method1-3 can be adapted to permit the direct
formation of the elusive â-mannopyranosides.4-9 In this
method, a mannosyl sulfoxide (1),10-12 or the correspond-
ing thiomannoside (2),11,13 is activated at -78 °C with
triflic anhydride or benzenesulfenyl triflate, respectively,
with formation of an R-mannosyl triflate 3.14,15 Subse-
quent addition of an alcohol, primary, secondary, or
tertiary, provokes an SN2-like displacement resulting,
overall, in the formation of the â-mannoside 4 in a highly
stereoselective manner. A priori replacement of the
alcohol as nucleophile by a thiol should lead to the
formation of â-thiomannosides and, given the enhanced
nucleophilicity of thiols over alcohols, do so with even
greater â-selectivity. However, this extension of the
original method is not necessarily as trivial as it appears
at first sight. Activation of the sulfoxide 1 with triflic
anhydride must lead to the formation of highly electro-
philic sulfenic and/or sulfinic acid derivatives.15,16 One
of these, benzenesulfenyl triflate, was demonstrated to
react quantitatively with 1 or 2 within in a matter of
minutes at -78 °C, fortuitously, with formation of the
key triflate intermediate 3.11,13,14 If such species are able
(1) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J . Am. Chem.
Soc. 1989, 111, 6881.
(2) Yan, L.; Kahne, D. J . Am. Chem. Soc. 1996, 118, 9239.
(3) Liang, R.; Yan, L.; Loebach, J .; Ge, M.; Uozumi, Y.; Sekanina,
K.; Horan, N.; Gildersleeve, J .; Thompson, C.; Smith, A.; Biswas, K.;
Still, W. C.; Kahne, D. Science 1996, 274, 1520.
(4) Barresi, F.; Hindsgaul, O. In Modern Methods in Carbohydrate
Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood Academic
Publishers: Amsterdam, 1996; p 251.
(5) Hodosi, G.; Kova´c, P. J . Am. Chem. Soc. 1997, 119, 2335.
(6) Ito, Y.; Ohnishi, Y.; Ogawa, T.; Nakahara, Y. Synlett 1998, 1102.
(7) Ohtake, H.; Iimori, T.; Ikegami, S. Synlett 1998, 1420.
(8) Toshima, K.; Kasumi, K.; Matsumura, S. Synlett 1998, 643.
(9) Ziegler, T.; Lemanski, G. Angew. Chem., Int. Ed. Engl. 1998,
37, 3129.
Resu lts a n d Discu ssion
Activation of the sulfoxide 1,22 in the presence of 2,6-
di-(tert-butyl)-4-methylpyridine (DTBMP), with triflic
anhydride at -78 °C followed by addition of 2 equiv of
octane thiol (5) and gradual warming to 0 °C gave, after
extraction and chromatography over silica gel, the â-thio-
(10) Crich, D.; Sun, S. J . Org. Chem. 1997, 62, 1198.
(11) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
(12) Crich, D.; Mataka, J .; Sun, S.; Lam, K.-C.; Rheingold, A. R.;
Wink, D. J . J . Chem. Soc., Chem. Commun. 1998, 2763.
(13) Crich, D.; Sun, S. J . Am. Chem. Soc. 1998, 120, 435.
(14) Crich, D.; Sun, S. J . Am. Chem. Soc. 1997, 119, 11217.
(15) Gildersleeve, J .; Pascal, R. A.; Kahne, D. J . Am. Chem. Soc.
1998, 120, 5961.
(17) Rhind-Tutt, A. J .; Vernon, C. A. J . Chem. Soc. 1960, 4637.
(18) Capon, B.; Collins, P. M.; Levy, A. A.; Overend, W. G. J . Chem.
Soc. 1964, 3242.
(19) Garegg, P. J . Adv. Carbohydr. Chem. Biochem. 1997, 52, 179.
(20) Driguez, H. In Topics in Current Chemistry: Glycoscience;
Driguez, H., Thiem, J ., Eds.; Springer: Berlin, 1997; Vol. 187, p 85.
(21) This last concept is beautifully illustrated by a recent crystal
structure of a thioglycoside bound to the active site of an endogluca-
nase: Sulzenbacher, G.; Driguez, H.; Henrissat, B.; Schulein, M.;
Davies, G. J . Biochemistry 1996, 35, 15280.
(16) Gildersleeve, J .; Smith, A.; Sakurai, D.; Raghavan, S.; Kahne,
D. J . Am. Chem. Soc. 1999, 121, 6176.
10.1021/jo9914667 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/16/2000

802 J . Org. Chem., Vol. 65, No. 3, 2000
Ta ble 1. Syn th esis of â-Th iom a n n osid es
Crich and Li
Ta ble 2. Dia gn ostic NMR Da ta a
entry
acceptor
product
% yield
anomeric
1J C,H
substance configuration
solvent
δ H1 δ H5
(Hz)
1
2
3
4
5
5
6
10
14
18
7
8
11
15
19
74
77
69
61
63
7
8
â
â
â
â
â
â
â
R
R
CDCl3
CDCl3
CDCl3
CDCl3
4.62
4.73
4.73
4.52
4.71
4.69
4.80
5.51
5.35
3.40
3.43
3.38
3.25
3.37
3.22
3.25
4.30
4.25
150.4
149.3
153.7
153.7
151.6
151.2
149.5
166.8
165.7
11a
15a
19a
21
22
2
CDCl3
MeOH-d4
MeOH-d4
CDCl3
mannoside (7) in 74% isolated yield (Table 1, entry 1).
Importantly, there was no indication of competing forma-
tion of the R-anomer in this reaction. Replacement of
octane thiol by tert-butyl thiol (6) also gave an excellent
yield of the corresponding, pure â-thiomannoside (8)
(Table 1, entry 2). Our concerns about potential side
reactions with byproducts from the activation were
evidently unfounded, and we therefore turned to the
synthesis, and application, of more appropriate primary
and secondary carbohydrate-based thiols as nucleophiles.
20
CDCl3
a
Data for the mannose system
which, on exposure to potassium thioacetate in DMF,
afforded the glucothioacetate 17. Treatment of 17 with
hydrazine hydrate led to the thiol 18, which was coupled
with 1, by the standard protocol, giving 19 in 63% yield
(Table 1).
Mitsunobu23,24 coupling of methyl 2,3,4-tri-O-acetyl-R-
D-glucopyranoside with thioacetic acid gave the thiol
ester 9 in 79% yield, which, on exposure to hydrazine
hydrate, provided the primary thiol 10 in 71% yield.
Coupling of this thiol with sulfoxide 1, following activa-
tion by Tf2O, provided the disaccharide 11 in 69% yield
(Table 1).
In none of the above coupling reactions were we able
to find evidence for the formation of the R-anomers in
the 1H and 13C NMR spectra of the crude reaction
mixtures, within the limits of detection, as determined
by the absence of the characteristic downfield anomeric
protons of authentic R-thiomannosides (Table 2). The
coupling reactions were therefore very highly â-selective.
The yields, while less than perfect, are good and sufficient
for most practical purposes; several unidentified byprod-
ucts made up the mass balance.
A similar Mitsunobu reaction/selective deacetylation
sequence applied to the glucoside 1225 provided the
galacto-thioacetate 13 and the thiol 14. Coupling of 14
with the sulfoxide 1 by the standard protocol afforded
the â-thiomannoside 15 in 61% yield (Table 1).
The assignment of anomeric stereochemistry in the
mannose series can be problematic owing to the similar-
3
ity between the J H1,H2 coupling constants in the R- and
â-series. Evidently, for the â-anomer the stereochemistry
may be established unambiguously by the observation
of nuclear Overhauser interactions between the anomeric
hydrogen and H3 and H5.26 Indeed, noesy spectroscopy
was used to confirm the configurations of 11, 15, 21 and
22. The accepted method in the field, however, relies on
the magnitude of the 1J C,H coupling between the anomeric
carbon and its attached proton. In the O-glycosides, the
R-anomer has a numeric value of around 173 Hz, while
in the â-series 163 Hz is typical.27 In addition, we have
noted that in the 4,6-O-benzylidene-protected â-manno-
sides the mannose H5 occurs as an unusually upfield
multiplet consistently resonating between δ 3.1 and 3.3
in CDCl3 solution.11 In the case of the â-thiomannosides
prepared here we again observed the mannose H5 to
resonate somewhat upfield in the region δ 3.25-3.43, in
CDCl3, as opposed to δ 4.25-4.35 the chemical shift of
H5 in the authentic R-thiomannosides 2 and 20 (Table
Reaction of 12 with triphenylphosphine and iodine in
the presence of imidazole provided the galactoiodide 16,
(22) Sulfoxide 1 is a single diastereomer at sulfur,11 most likely with
configuration SR.12 The highly diastereoselective oxidation of the
thioglycoside precursor is likely to be a consequence of the exo-anomeric
effect which, in the â-series with the axial C-S bond, projects the pro-S
lone pair underneath the pyranose ring and so renders it sterically
inaccessible.12 On the basis of the extensive work of Kahne with mixed
diastereomeric sulfoxides in the â-series, it is unlikely that the
configuration at sulfur is of consequence in the ensuing chemistry.1-3
(23) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119.
(26) The 1H NMR spectra of all of the various thioglycosides
presented here were sufficiently well-resolved as to enable full assign-
ments to be made by the usual methods.
(24) Hughes, D. L. Org. React. 1992, 42, 335.
(25) Garegg, P. J .; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97.
(27) Bock, K.; Pedersen, C. J . Chem. Soc., Perkin Trans. 2 1974,
293.

Direct Stereoselective Synthesis of â-Thiomannosides
J . Org. Chem., Vol. 65, No. 3, 2000 803
1
give 9 (0.329 g, 0.87 mmol, 79%): [R]D ) +80.8° (c, 5.5); H
2). We suggest that, provided the pyranose is locked in
NMR δ 1.92 (s, 3 H), 1.98 (s, 3 H), 2.00 (s, 3 H), 2.27 (s, 3 H),
2.99 (dd, J ) 14.2, 6.9 Hz, 1 H), 3.12 (dd, J ) 14.2, 3.0 Hz, 1
H), 3.32 (s, 3 H), 3.84 (ddd, J ) 9.9, 6.9, 3.0 Hz, 1 H), 4.70-
4.83 (m, 2 H), 4.86 (t, J ) 9.6 Hz, 1 H), 5.35 (t, J ) 9.6 Hz, 1
H); 13C NMR δ 20.7, 30.0, 30.4, 55.4, 68.2, 70.0, 70.9, 96.6,
169.9, 170.0, 170.1, 194.6. Anal. Calcd. for C15H22O9S‚
0.5H2O: C, 46.51; H, 5.98. Found: C, 46.55; H, 5.93.
4
the C1-chair system by the 4,6-O-benzylidene group, an
Meth yl 2,3,4-Tr i-O-a cetyl-6-th io-R-D-glu cop yr a n osid e
(10). 9 (0.329 g, 0.87 mmol) was dissolved in DMF (10 mL) at
room temperature, and N2H4‚H2O (0.019 g, 1.54 mmol, 1.77
equiv) was added slowly. After 5-10 min, CH3CO2H (0.0945
g, 1.54 mmol, 1.77 equiv) was added dropwise. After consump-
tion of the starting material (∼20 min), the reaction mixture
was diluted with ethyl acetate and washed with water, and
the water phase was extracted with ethyl acetate. The
combined organic phase was washed with water and brine,
dried (MgSO4), filtered, and concentrated. The crude product
was purified by flash chromatography on silica gel (eluent:
EtOAc/hexane 1/1) to give 10 as a glass (0.2098 g, 0.62 mmol,
H5 resonance in this region will be sufficient and
diagnostic for the â-thiomannosides. However, we also
investigated the J C,H coupling constants and find that,
1
as with the O-glycosides, the numerical value is around
10-15 Hz smaller in the â- than in the R-series (Table
2). Both the R- and â-1J C,H coupling constants are
somewhat smaller than in the corresponding O-glycosides
but a change of this nature is not unexpected given the
replacement of the C-O by a C-S bond.28
Finally, deprotection of selected thioglycosides was
explored. The simple S-alkyl substances 7 and 8 proved
somewhat resistant to hydrogenolysis at ambient tem-
perature and pressure over both Pd/C and Pd(OH)2, and
the use of more forcing conditions led to competing
degradation. These compounds were therefore depro-
tected, following the example of Pinto and co-workers,29
by Birch reduction, which gave 21 and 22 in excellent
yield. A further example (19) was first exposed to
catalytic sodium methoxide in methanol (Zemplen deacety-
lation), which provided 23 in 56% yield, followed by
hydrogenolysis over Pearlman’s catalyst leading to the
isolation of 24 in 43% yield.
1
72%): [R]D ) +128.2° (c, 3.1); H NMR δ 1.74 (t, J ) 8.4 Hz,
1 H), 2.00 (s, 3 H), 2.04 (s, 3 H), 2.07 (s, 3 H),2.58-2.70 (m, 2
H), 3.45 (s, 3 H), 3.87 (m, 1 H), 4.87 (dd, J ) 10.2, 3.7 Hz, 1
H), 4.94 (d, J ) 3.7 Hz, 1 H), 4.99 (t, J ) 9.6 Hz, 1 H), 5.47 (t,
J ) 9.8 Hz, 1 H); 13C NMR δ 20.8, 26.1, 55.5, 69.6, 70.1, 71.0,
71.3, 96.6, 169.9, 170.1, 170.2. Anal. Calcd for C13H20O8S: C,
46.42; H, 5.99. Found: C, 46.10; H, 6.05.
Meth yl 2,3-Di-O-a cetyl-4-a cetylth io-6-O-ben zyl-R-D-ga -
la ctop yr a n osid e (13). The yellowish syrup 13 was prepared
1
similarly to 9 in 54% yield: [R]D ) +71.7° (c, 1.3); H NMR δ
1.94 (s, 3 H), 2.07 (s, 3 H), 2.34 (s, 3 H), 3.39 (s, 3 H), 3.45-
3.67 (m, 2 H), 4.25-4.50 (m, 3 H), 4.56 (d, J ) 12.1 Hz, 1 H),
4.88-5.05 (m, 2 H), 5.51 (dd, J ) 10.0, 4.3 Hz, 1 H), 7.20-
7.50 (m, 5 H); 13C NMR δ 20.9, 21.0, 30.9, 47.4, 55.4, 67.9,
68.2, 69.8, 70.1, 73.5, 97.3, 127.7, 127.8, 128.5, 138.0, 169.9,
170.5, 194.0. Anal. Calcd for C20H26O8S: C, 56.33; H, 6.14.
Found: C, 56.13; H, 6.18.
Meth yl 2,3-Di-O-a cetyl-6-O-ben zyl-4-th io-R-D-ga la cto-
p yr a n osid e (14). The preparation of 14 followed that of 10
and gave a 71% yield: [R]D ) +128.3° (c, 2.0); 1H NMR δ 1.49
(d, J ) 8.5 Hz, 1 H), 2.09 (s, 6 H), 3.37 (s, 3 H), 3.58-3.78 (m,
3 H), 4.32 (m, 1 H), 4.52 (d, J ) 12.0 Hz, 1 H), 4.60 (d, J )
12.0 Hz, 1 H), 4.96 (d, J ) 3.7 Hz, 1 H), 5.19 (dd, J ) 10.6, 3.7
Hz, 1 H), 5.31 (dd, J ) 10.6, 4.5 Hz, 1 H), 7.20-7.42 (m, 5 H);
13C NMR δ 20.6, 20.7, 42.4, 55.1, 67.5, 68.3, 69.3, 70.0, 73.3,
97.0, 127.5, 127.6, 128.3, 137.8, 169.8, 170.1. Anal. Calcd for
Exp er im en ta l Section
C
18H24O7S: C, 56.24; H, 6.29. Found: C, 56.09; H, 6.35.
Meth yl 2,3-Di-O-a cetyl-6-O-ben zyl-4-iod o-R-D-ga la cto-
Unless otherwise stated, 1H and 13C NMR spectra were
recorded as CDCl3 solutions and have chemical shifts (δ)
downfield from tetramethylsilane. Specific rotations are for
CHCl3 solutions unless otherwise stated. All solvents were
dried and distilled by standard methods. All reactions were
conducted under an atmosphere of dry N2 or Ar. Microanalyses
were carried out by Midwest Microlabs, Indianapolis.
p yr a n osid e (16). 12 (1.725 g, 4.68 mmol), I2 (3.563 g, 14.04
mmol, 3.0 equiv), PPh3 (4.960 g, 18.72 mmol, 4.0 equiv), and
imidazole (1.287 g, 18.72 mmol, 4.0 equiv) were added into
THF (80 mL) at room temperature, and the ensuing mixture
was stirred at 80 °C overnight. When the starting material
disappeared, the reaction mixture was cooled to room tem-
perature, diluted with toluene, and washed successively with
saturated NaHCO3, 5% sodium thiosulfate, and water. The
water phase was extracted with ethyl acetate, and the
combined organic phase was washed with water and brine,
dried (MgSO4), filtered, and concentrated. The crude product
was purified by flash chromatography on silica gel (eluent:
EtOAc/hexane 1/1) to give 16 as a white solid (2.014 g, 4.21
mmol, 90%): mp 44-46 °C; [R]D ) +118.8° (c, 1.7); 1H NMR δ
2.08 (s, 3 H), 2.10 (s, 3 H), 3.39 (s, 3 H), 3.42-3.70 (m, 3 H),
4.49-4.63 (m, 3 H), 4.77 (dd, J ) 4.1, 1.4 Hz, 1 H), 4.95 (d, J
) 3.8 Hz, 1 H), 5.18 (dd, J ) 10.4, 3.8 Hz, 1 H), 7.24-7.40 (m,
5 H); 13C NMR δ 21.0, 21.1, 37.4, 55.5, 66.9, 68.5, 70.8, 73.8,
74.0, 97.3, 127.9, 128.0, 128.6, 137.9, 170.0, 170.3. Anal. Calcd
for C18H23O7I: C, 45.20; H, 4.85. Found: C, 44.96; H, 4.82.
Met h yl 2,3-Di-O-a cet yl-4-a cet ylt h io-6-O-b en zyl-R-D-
glu cop yr a n osid e (17). 16 (1.478 g, 3.09 mmol) and potassium
thioacetate (1.44 g, 12.4 mmol, 4.0 equiv) were dissolved in
DMF (45 mL) at room temperature, and the reaction mixture
was stirred at 90 °C for 2 h. After the starting material was
consumed, the reaction mixture was cooled to room temper-
ature, diluted with ethyl acetate, and washed with water. The
Meth yl
2,3,4-Tr i-O-a cetyl-6-a cetylth io-R-D-glu cop y-
r a n osid e (9). Methyl 2,3,4-tri-O-acetyl-R-D-glucpyranoside
(0.357 g, 1.11 mmol) and PPh3 (0.443 g, 1.67 mmol, 1.5 equiv)
were dissolved in THF (20 mL) at room temperature, and
DEAD (0.200 g, 0.18 mL, 1.67 mmol, 1.5 equiv) was added
dropwise. After 10 min, thioacetic acid (0.177 g, 0.17 mL, 2.22
mmol, 2.0 equiv) was added slowly, following which the
reaction mixture was stirred overnight at room temperature.
After consumption of the starting material, the reaction
mixture was diluted with ethyl acetate and washed with
saturated NaHCO3 and water, and the water phase was
extracted with ethyl acetate. The combined organic phase was
washed with water and then brine, dried (MgSO4), filtered,
and concentrated. The crude product was purified by flash
chromatography on silica gel (eluent: EtOAc/hexane 1/1) to
(28) J uaristi, E.; Cuevas, G. The Anomeric Effect; CRC: Boca Raton,
1995.
(29) Metha, S.; J ordan, K. L.; Weimar, T.; Kreis, U. C.; Batchelor,
R. J .; Einstein, F. W. B.; Pinto, B. M. Tetrahedron: Asymmetry 1994,
5, 2367.

804 J . Org. Chem., Vol. 65, No. 3, 2000
Crich and Li
water phase was extracted with ethyl acetate, and the
combined organic phase was washed with water and brine,
dried (MgSO4), filtered, and concentrated. The crude product
was purified by flash chromatography on silica gel (eluent:
EtOAc/hexane 1/3-1/2) to give 17 (0.870 g, 2.04 mmol, 66%)
128.9, 129.1, 137.8, 138.2, 138.6, 170.1, 170.2, 170.4. Anal.
Calcd for C40H46O13S: C, 62.65; H, 6.05. Found: C, 62.62; H,
6.09.
Meth yl 2,3-d i-O-a cetyl-6-O-ben zyl-4-S-(2,3-d i-O-ben zyl-
4,6-O-b en zylid en e-â-D-m a n n op yr a n osyl)-4-t h io-R-D-ga -
la ctop yr a n osid e (15): yield 61%; glass; [R]D ) +32.6°, (c, 0.3);
1H NMR δ 1.91 (s, 3 H), 2.10 (s, 3 H), 3.24 (m, 1 H), 3.40 (s, 3
H), 3.59 (dd, J ) 9.7, 3.0 Hz, 2 H), 3.71 (dd, J ) 10.5, 4.3 Hz,
1 H), 3.80 (m, 2 H), 3.99 (d, J ) 2.6 Hz, 1 H), 4.12 (dd, J )
10.5, 4.9 Hz, 1 H), 4.22 (t, J ) 9.5 Hz, 1 H), 4.34 (m, 1 H), 4.52
(m, 1 H), 4.52 (d, J ) 12.1 Hz, 1 H), 4.59 (d, J ) 12.1 Hz, 1 H),
4.70 (d, J ) 12.4 Hz, 1 H), 4.83 (d, J ) 10.9 Hz, 1 H), 4.86 (d,
J ) 12.4 Hz, 1 H) 4.98 (d, J ) 3.8 Hz, 1 H), 5.03 (d, J ) 10.9
Hz, 1 H), 5.19 (dd, J ) 10.6, 3.8 Hz, 1 H), 5.44 (dd, J ) 10.6,
4.1 Hz, 1 H), 5.59 (s, 1 H), 7.18-7.52 (m, 20 H); 13C NMR δ
21.0, 21.1, 48.9, 55.4, 68.4, 69.2, 69.7, 70.9, 71.3, 72.3, 73.3,
73.5, 76.3, 77.4, 78.8, 78.9, 79.6, 86.5, 97.2, 101.6, 126.2, 127.6,
127.8, 127.9, 128.0, 128.6, 128.7, 129.1, 137.6, 138.0, 138.4,
169.9, 170.6. Anal. Calcd for C45H50O12S‚1.5H2O: C, 64.19; H,
6.34. Found: C, 64.22; H, 6.08.
Meth yl 2,3-d i-O-a cetyl-6-O-ben zyl-4-S-(2,3-d i-O-ben zyl-
4,6-O-b en zylid en e-â-D-m a n n op yr a n osyl)-4-t h io-R-D-glu -
cop yr a n osid e (19): 63% yield; [R]D ) +4.1° (c, 0.5); 1H NMR
δ 1.99 (s, 3 H), 2.08 (s, 3 H), 3.03 (t, J ) 10.7 Hz, 1 H), 3.39 (s,
3 H), 3.30-3.52 (m, 1 H), 3.74 (dd, J ) 9.9, 3.0 Hz, 1 H), 3.78-
3.92 (m, 3 H), 3.93 (d, J ) 2.2 Hz, 1 H), 4.04 (dd, J ) 10.7, 3.7
Hz, 1 H), 4.11-4.28 (m, 2 H), 4.54 (d, J ) 12.0 Hz, 1 H), 4.60
(d, J ) 12.0 Hz, 1 H), 4.73 (m, 2 H), 4.80-5.00 (m, 5 H), 5.47
(t, J ) 10.7 Hz, 1 H), 5.59 (s, 1 H), 7.19-7.58 (m, 20 H); 13C
NMR δ 20.9, 45.6, 55.4, 67.7, 68.5, 69.3, 70.5, 71.7, 72.3, 73.5,
73.6, 75.7, 78.4, 78.6, 80.4, 83.4, 97.2, 101.6, 126.2, 127.6, 127.7,
127.9, 128.2, 128.3, 128.5, 129.1, 137.6, 137.9, 138.3, 170.3,
170.5. Anal. Calcd for C45H50O12S‚0.5H2O: C, 65.60; H, 6.24.
Found: C, 65.47; H, 6.13.
S-Octyl 1-Th io-R-D-m a n n op yr a n osid e (21). Thioglycoside
7 (40.7 mg) was dissolved in THF (2 mL), and liquid ammonia
(7 mL) was condensed into the flask. Sodium (∼30 mg) was
then added until a persistent blue color was obtained. Solid
NH4Cl (∼0.1 g) was then added, and the solvents were allowed
to evaporate under air. The crude reaction mixture was
purified by chromatography on silica gel (eluent: EtOAc/
hexane 1/1 then CHCl3/MeOH 12/1) to give the title compound
(18 mg, 83%) as a colorless oil: [R]D ) -43.5° (c, 0.17, MeOH);
1H NMR δ (MeOH-d4) 0.88 (t, J ) 6.6 Hz, 3 H), 1.20-1.48 (m,
10 H), 1.62 (m, 2 H), 2.70 (td, J ) 7.3, 3.3 Hz, 2 H), 3.22 (m,
1 H), 3.45 (dd, J ) 9.4, 3.3 Hz, 1 H), 3.56 (t, J ) 9.5 Hz, 1 H),
3.69 (dd, J ) 11.9, 5.5 Hz, 1H), 3.80-3.95 (m, 2 H), 4.69 (s, 1
H); 13C NMR δ (MeOH-d4) 14.6, 23.9, 30.1, 30.5 (2 C’s), 31.3,
32.3, 33.2, 63.1, 68.5, 74.2, 76.5, 82.5, 86.4; FABHRMS m/z
331.1556 (calcd for C14H28O5SNa 331.1555, M+ + Na).
S-ter t-Bu tyl 1-Th io-â-D-m a n n op yr a n osid e (22). Depro-
tection of 8 with Na in liquid NH3 analogously to the procedure
described above for 21 gave 22 in 80% yield as a colorless oil:
[R]D ) -79.0° (c, 0.3, MeOH); 1H NMR (MeOH-d4) δ 1.36 (s, 9
H), 3.25 (m, 1 H), 3.50 (dd, J ) 9.4, 3.3 Hz, 1 H), 3.58 (t, J )
9.4 Hz, 1 H), 3.68 (dd, J ) 11.9, 5.3 Hz, 1 H), 3.75-3.90 (m, 2
H), 4.80 (d, J ) 0.8 Hz, 1 H); 13C NMR (MeOH-d4) δ 32.2, 63.1,
68.4, 72.5, 75.2, 76.6, 82.1, 83.7; FABHRMS m/z 275.0931
(calcd for C10H20O5SNa 275.0929, M+ + Na).
Meth yl 6-O-Ben zyl-4-S-(2,3-d i-O-ben zyl-4,6-O-ben zyli-
d en e-â-D-m a n n op yr a n osyl)-4-t h io-R-D-glu cop yr a n osid e
(23). Diacetate 19 (200 mg) was dissolved in freshly distilled
MeOH (20 mL) and transferred to a solution of sodium (0.5
mg) in dry MeOH (10 mL). The resulting reaction mixture was
stirred at room temperature until TLC indicated completion,
after which Dowex 50 cation-exchange resin was added to
neutralize the solution to pH 7. The reaction mixture was then
filtered, evaporated, and purified by chromatography on silica
gel (eluent: EtOAc/hexane 3/1) to give the title compound as
an oil (101.3 mg, 57%): [R]D ) +35.8° (c, 0.9); 1H NMR (CDCl3)
δ 2.27 (d, J ) 7.2 Hz, 1 H), 2.94 (t, J ) 10.4 Hz, 1 H), 3.34 (m,
1 H), 3.42 (s, 3 H), 3.59 (dd, J ) 9.8, 3.0 Hz, 2 H), 3.62-3.75
(m, 3 H), 3.79 (d, J ) 2.0 Hz, 1 H), 3.83-3.94 (m, 2 H), 4.16-
4.34 (m, 2 H), 4.37 (d, J ) 12.1 Hz, 1 H), 4.54 (s, 1 H), 4.62-
4.78 (m, 4 H), 4.85 (d, J ) 3.6 Hz, 1 H), 4.91 (d, J ) 12.2 Hz,
1
as a yellowish syrup: [R]D ) +114.8° (c, 3.2); H NMR δ 1.99
(s, 3 H), 2.05 (s, 3 H), 2.27 (s, 3 H), 3.45 (s, 3 H), 3.64 (m, 2 H),
3.75 (t, J ) 11.1 Hz, 1 H), 3.92-4.03 (m, 1 H), 4.54 (AB quartet,
J ) 13.4, 12.3 Hz, 2 H), 4.91 (dd, J ) 9.9, 3.6 Hz, 1 H), 4.99
(d, J ) 3.6 Hz, 1 H), 5.46 (dd, J ) 11.1, 9.9 Hz, 1 H), 7.21-
7.42 (m, 5 H); 13C NMR δ 20.7, 20.8, 30.7, 44.3, 55.4, 68.8,
69.5, 69.7, 72.3, 73.6, 97.0, 127.7, 127.8, 128.4, 138.0, 170.0,
170.2, 192.9. Anal. Calcd for C20H26O8S: C, 56.33; H, 6.14.
Found: C, 56.19; H, 6.22.
Meth yl 2,3-Di-O-a cetyl-6-O-ben zyl-4-th io-R-D-glu cop y-
r a n osid e (18). The preparation of 18 followed that of 10 and
gave a 65% yield: [R]D ) +94.2° (c, 1.6); 1H NMR δ 1.37 (d, J
) 8.5 Hz, 1 H), 2.05 (s, 3 H), 2.08 (s, 3 H), 3.08 (dd, J ) 20.1,
10.4 Hz, 1 H), 3.39 (s, 3 H), 3.76 (dd, J ) 11.2, 1.8 Hz, 2 H),
3.92 (m, 1 H), 4.53 (d, J ) 12.1 Hz, 1 H), 4.66 (d, J ) 12.1 Hz,
1 H), 4.85 (dd, J ) 10.0, 3.6 Hz, 1 H), 4.97 (d, J ) 3.6 Hz, 1
H), 5.28 (t, J ) 10.4 Hz, 1 H), 7.22-7.40 (m, 5 H); 13C NMR δ
20.7, 40.6, 55.5, 69.2, 72.2, 73.1, 73.8, 97.4, 128.0, 128.6, 138.1,
170.4. Anal. Calcd for C18H24O7S: C, 56.24; H, 6.29. Found:
C, 56.45; H, 6.39.
Gen er a l P r oced u r e for Cou p lin g Rea ction s. Sulfoxide
and DTBMP (2.0 equiv) were dissolved in CH2Cl2 (0.02-0.04
M in 1), and Tf2O (1.1 equiv) was added dropwise at -78 °C.
After the mixture was stirred for 10-20 min, a CH2Cl2 solution
of the thiol acceptor (2.0 equiv) was added slowly. The reaction
mixture was then stirred for a further 2 h at -78 °C, then the
temperature was increased to 0 °C over 1-2 h, and stirring
was continued at 0 °C for another 0.5 h before the reaction
was quenched with saturated NaHCO3. The reaction mixture
was diluted with ethyl acetate and washed with water, the
aqueous phase was extracted with ethyl acetate, and the
organic phases were combined and washed with water and
brine, dried (MgSO4), concentrated, and purified by flash
chromatography on silica gel.
S-Octyl 2,3-O-ben zyl-4,6-O-ben zylid en e-1-th io-â-D-m a n -
n op yr a n osid e (7): yield 74%; yellowish syrup; [R]D ) -43.7°
(c, 0.8); 1H NMR δ 0.88 (t, J ) 6.9 Hz, 3 H), 1.20-1.44 (m, 10
H), 1.58 (m, 2 H), 2.67 (t, J ) 7.3 Hz, 2 H), 3.40 (m, 1 H), 3.72
(dd, J ) 9.9, 3.2 Hz, 1 H), 3.91 (t, J ) 10.4 Hz, 1 H), 4.00 (d,
J ) 3.2 Hz, 1 H), 4.27 (m, 2 H), 4.62 (s, 1 H), 4.72 (d, J ) 12.4
Hz, 1 H), 4.78-4.95 (m, 2 H), 5.02 (d, J ) 11.3 Hz, 1 H), 5.63
(s, 1 H), 7.20-7.60 (m, 15 H); 13C NMR δ 14.3, 22.9, 29.0, 29.4,
30.2, 32.0, 32.1, 68.7, 72.1, 73.2, 75.9, 78.8, 79.0, 80.0, 86.5,
101.6, 126.3, 127.8, 127.9, 128.3, 128.4, 128.6, 128.8, 129.1,
137.8, 138.3, 138.6. Anal. Calcd for C35H44O5S: C, 72.88; H,
7.69. Found: C, 72.77; H, 7.74.
S-ter t-Bu tyl 2,3-O-ben zyl-4,6-O-ben zylid en e-1-th io-â-D-
m a n n op yr a n osid e (8): yield 77%; yellowish syrup; [R]D
)
-48.6° (c, 4.1); 1H NMR δ 1.36 (s, 9 H), 3.43 (m, 1 H), 3.76
(dd, J ) 9.8, 3.1 Hz, 1 H), 3.90 (t, J ) 10.3 Hz, 1 H), 4.01(d, J
) 2.1 Hz, 1 H), 4.18-4.32 (m, 2 H), 4.68-4.78 (m, 2 H), 4.80
(d, J ) 11.1 Hz, 1 H), 4.86 (d, J ) 12.5 Hz, 1 H), 5.01 (d, J )
11.1 Hz, 1 H), 5.62 (s, 1 H), 7.25-7.55(m, 15 H); 13C NMR δ
31.8, 43.5, 68.8, 71.9, 73.1, 76.1, 79.0, 80.0, 80.2, 83.7, 101.6,
126.3, 127.7, 127.8, 128.3, 128.4, 128.6, 128.7, 129.1, 129.4,
129.5, 131.8, 135.6, 137.8, 138.4, 138.7. Anal. Calcd for
C31H36O5S‚H2O: C, 69.12; H, 7.11. Found: C, 69.11; H, 6.80.
Meth yl 2,3,4-tr i-O-a cetyl-6-S-(2,3-d i-O-ben zyl-4,6-O-ben
zylid en e-â-D-m a n n op yr a n osyl)-6-t h io-R-D-glu cop yr a n o-
1
sid e (11): yield 69%; glass; [R]D ) +32.0° (c, 0.6); H NMR δ
2.00 (s, 3 H), 2.02 (s, 3 H), 2.08 (s, 3 H), 2.72-2.82 (m, 2 H),
3.35 (s, 3 H), 3.31-3.47 (m, 1 H), 3.71 (dd, J ) 9.8, 3.0 Hz, 1
H), 3.84-3.96 (m, 2 H), 3.98 (d, J ) 2.6 Hz, 1 H), 4.20-4.34
(m, 2 H), 4.71 (m, 2 H), 4.77 (d, J ) 11.2 Hz, 1 H), 4.83-4.98
(m, 4 H), 5.02 (d, J ) 11.2 Hz, 1 H), 5.43 (t, J ) 9.4 Hz, 1 H),
5.62 (s, 1 H), 7.21-7.56 (m, 15 H); 13C NMR δ 20.9, 21.0, 32.8,
55.6, 68.6, 69.9, 70.2, 71.2, 72.1, 72.2, 73.5, 75.9, 78.7, 79.0,
80.1, 87.0, 96.7, 101.7, 126.3, 127.9, 128.0, 128.3, 128.4, 128.6,

Direct Stereoselective Synthesis of â-Thiomannosides
J . Org. Chem., Vol. 65, No. 3, 2000 805
1 H), 4.99 (d, J ) 11.1 Hz, 1 H), 5.59 (s, 1 H), 7.20-7.54 (m,
20 H); 13C NMR (CDCl3) δ 51.0, 52.4, 55.8, 68.2, 69.5, 70.2,
71.8, 73.1 (2 C’s), 73.7 (2 C’s), 76.0, 78.5, 80.0, 87.0, 99.6, 101.6,
126.2, 127.8, 128.0, 128.1, 128.4, 128.6, 129.1, 137.5, 137.7,
138.2, 138.5. Anal. Calcd for C41H46O10S‚0.75H2O: C, 66.10;
H, 6.43. Found: C, 66.06; H, 6.35.
3.96 (dd, J ) 11.8, 1.8 Hz, 1 H), 4.66 (d, J ) 3.6 Hz, 1 H), 4.77
(s, 1 H); 13C NMR (CD3OD) δ 55.8, 63.1, 63.3, 68.5, 72.4, 73.6,
74.5, 74.8, 76.4, 82.9, 84.1, 101.4, 102.7. Anal. Calcd for
C13H24O10S: C, 41.93; H, 6.50. Found: C, 41.61; H, 6.73.
Ack n ow led gm en t. We thank the NIH (GM 57335)
for support of this work and the University of Illinois
at Urbana Champaign mass spectrometry laboratory for
FABHRMS.
Meth yl 4-S-(â-D-Ma n n op yr a n osyl)-4-th io-R-D-glu cop y-
r a n osid e (24). Compound 23 (63 mg) was dissolved in
anhydrous EtOH (20 mL), treated with Pd(OH)2 (60 mg), and
stirred under H2 at atmospheric pressure for 2 days. Filtration
and concentration gave disaccharide 24 as a colorless oil (13.8
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for 21 and 22. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
mg, 43%): [R]D ) +43.2 (c 0.4, MeOH); H NMR (MeOH-d4,
400 MHz) δ 2.75 (t, J ) 10.8 Hz, 1 H), 3.20 (m, 1 H), 3.34 (s,
3 H), 3.40 (td, J ) 9.5, 3.5 Hz, 2 H), 3.47 (d, J ) 9.6 Hz, 1 H),
3.50-3.65 (m, 3 H), 3.79 (m, 2 H), 3.89 (d, J ) 3.2 Hz, 1 H),
J O9914667