Synthesis of positional thiol analogs of β-D-galactopyranose

Article abstract of DOI:10.1002/ejoc.200700364

Approaches toward the synthesis of thio-β-D-galactose derivatives are described. These compounds were prepared from the parent carbohydrates: D-galactose, methyl β-D-galactoside and methyl β-D-glucoside, respectively. It was found that not only the strategies of protecting group introduction and selective deprotection, but also the choices of solvent and nucleophilic reagent concentration were crucial to allow the efficient introduction of sulfur at different positions of the galactose ring. The effects from the solvent, the nucleophilic reagent concentration, and the protecting group patterns have been investigated. The results clearly show that ester protecting groups play highly important roles for the synthesis of thio-containing carbohydrates, requiring nonpolar solvents to suppress the neighboring group participation. For the Lattrell-Dax (nitrite-mediated) inversion reaction, employed in the synthetic route to the 2-thio-β-D- galactoside, intramolecular nucleophilic attack, as well as stronger stereospecific ester activation, are necessary to overcome hindrance from 4,6-O-benzylidene protection. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700364

FULL PAPER
DOI: 10.1002/ejoc.200700364
Synthesis of Positional Thiol Analogs of β- -Galactopyranose
D
Zhichao Pei,[a] Hai Dong,[a] Rémi Caraballo,[a] and Olof Ramström*[a]
Keywords: Thiosaccharides / Galactose / Lattrell–Dax / Inversion
Approaches toward the synthesis of thio-β-
atives are described. These compounds were prepared from
the parent carbohydrates: -galactose, methyl β-
side and methyl β- -glucoside, respectively. It was found that
not only the strategies of protecting group introduction and
selective deprotection, but also the choices of solvent and nu-
cleophilic reagent concentration were crucial to allow the ef-
ficient introduction of sulfur at different positions of the ga-
lactose ring. The effects from the solvent, the nucleophilic
reagent concentration, and the protecting group patterns
have been investigated. The results clearly show that ester
D
-galactose deriv-
protecting groups play highly important roles for the synthe-
sis of thio-containing carbohydrates, requiring nonpolar sol-
D
D
-galacto- vents to suppress the neighboring group participation. For
the Lattrell–Dax (nitrite-mediated) inversion reaction, em-
ployed in the synthetic route to the 2-thio-β- -galactoside,
D
D
intramolecular nucleophilic attack, as well as stronger
stereospecific ester activation, are necessary to overcome
hindrance from 4,6-O-benzylidene protection.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
since the galactose motif is ubiquitous in bioactive carbo-
hydrate structures. For example, in an early study, the bind-
ing of a series of alkyl or aryl 1-thio-β--galactopyran-
osides to β--galactosidase from E. coli was investigated.[12]
The results indicated that the S-linked structures function
as efficient competitive inhibitors, not being degraded by
the enzyme. Moreover, galectins constitute a family of
structurally related β-galactoside-binding proteins of in-
creasing importance in for example cancer processes.[3]
Efficient synthetic protocols to thio-β--galactopyran-
oside derivatives are thus of high interest, since these struc-
tures can serve as acceptors in the synthesis of bioactive
Introduction
Interactions between carbohydrates and proteins are in-
creasingly being recognized as crucial in many biological
processes, and form the main device for a variety of cellular
events such as adhesion, communication, proliferation, and
cell death. In addition, carbohydrate recognition is involved
in important disorders in, for example, infectious diseases
and cancer.[1–6] To thoroughly understand and control these
interactions, and to be able to develop new therapies and
drugs, well-defined carbohydrate ligands need to be synthe-
sized. Thioglycosides, where the glycosidic oxygen atom is
replaced with sulfur are often the glycosyl donors of choice
for the synthesis of thio-oligosaccharides. Investigations of
protein-thio-oligosaccharide binding indicate that thiolink-
ages offer a higher degree of flexibility between glycols units
and possess more conformers than their natural O-linked
ligands.[7] This effect is also shown for the related glycosyl-
disulfides, resulting in the coverage of larger conformational
space in the binding site due to the increased flexibility and
extended length of the disulfide bond compared to natural
O-glycosides.[8,9] Furthermore, S-linked oligosaccharides
also have an additional benefit over their C-linked counter-
parts when used as enzyme inhibitors: the interglycosidic
sulfur atom may act as a hydrogen-bond acceptor which, as
in the natural substrate, could play an important role in
binding of the ligand.[10,11]
Thio-β--galactopyranosides are in this sense especially
important compounds for the study of biological processes,
[a] Department of Chemistry, Royal Institute of Technology,
Teknikringen 30, 10044 Stockholm, Sweden
Fax: +46-8-7912333
E-mail: ramstrom@kth.se
Figure 1. Thio-β--galactopyranosides targeted.
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Z. Pei, H. Dong, R. Caraballo, O. Ramström
FULL PAPER
thio-oligosaccharides. Syntheses of different thiosacchar- the inversion of the equatorial hydroxy group at C-2 proved
ides have also been developed by several research groups especially sensitive, and 4,6-O-benzylidene protection re-
for the use as biological probes, potential protein or enzyme sulted in low conversions. Consequently, the ester protect-
inhibitors.[13,14] However, a systematic investigation of the ing strategy is essential for the synthesis of sulfur-contain-
synthesis of the positional thio-β--galactose derivatives ing carbohydrates when Lattrell–Dax epimerization proto-
has not been performed. This issue has been addressed in cols are employed. However, due to neighboring group par-
this study, where a full range of thio-β--galactose deriva- ticipation of ester functionalities in triflate-activated carbo-
tives has been synthesized (Figure 1). The effects of the nu- hydrates, where 5- or 6-membered acyloxonium intermedi-
cleophile, the solvent, and the protecting pattern have ates may form during thiolation, the solvent also plays im-
furthermore been investigated.
portant roles.[17]
Compound 1 can easily be synthesized following stan-
dard coupling methods at the anomeric center. Two main
strategies for the synthesis of 1 have been developed from
the corresponding glycosyl bromide 7, both of which in few
Results and Discussion
steps using either thioacetate or thiourea coupling.[18,19]
A
drawback of the first, two-phase method (pathway b in
Scheme 1),[13] is that hydrolysis of 7 generated the byprod-
uct in the aqueous phase, thus decreasing the yields. In the
alternative thiourea approach (pathways d-e-f in
Scheme 1),[19] the advantage was to avoid byproduct forma-
tion, and obtain compound 10, which can be used for 1-S
glycosylation protocols. The overall yield was, however, not
improved. A more direct solution to the problem is pre-
sented as the new, modified pathway c-f in Scheme 1. Treat-
ment of the glycosyl bromide directly with tetrabutylammo-
nium thioacetate in dry toluene or potassium thioacetate in
dry acetone, afforded the thioglycoside in high yield (59%
over three steps).
Compound 5 can also be easily produced due to the ease
of functionalization of the primary 6-OH group compared
to the secondary hydroxy groups. Synthesis of compound 5
was reported by Wachter and Branchaud, however devoid
of any analytical data.[20] The synthetic route of compound
5 is outlined in Scheme 2. Tosylation of 11 with tosyl chlo-
ride, subsequent acetylation, displacement with thioacetate,
and final deprotection afforded compound 5 in good yield.
It has previously been shown, for other carbohydrate deriv-
atives, that this strategy can be simplified to circumvent the
non-acetylated intermediate 13 in the reaction sequence.[21]
Regioselectivity is a well-known problem in carbohydrate
chemistry due to several hydroxy groups of similar reactiv-
ity. Therefore, strategies of protecting group introduction
and selective deprotection are essential in carbohydrates
synthesis. The most common hydroxy groups protecting
groups are esters, ethers, and acetals, where especially, ace-
tyl, benzoyl, benzyl and benzylidene groups are frequently
used. However, for sulfur-containing carbohydrates, the
benzyl ether group is less attractive because of deprotection
difficulties by common reduction protocols.[15] Organic sul-
fur compounds are very poisonous to metal hydrogenation
catalysts, consequently hampering the deprotection. Thus,
the ester and benzylidene protecting groups remain the
more prevalently used for the synthesis of sulfur-containing
carbohydrates. Selective protection protocols can further-
more be used to generate a variety of structures by hydroxy
epimerization strategies. For example, epimerization of
carbohydrate structures to the corresponding epi/hydroxy
stereoisomer by the Lattrell–Dax (nitrite-mediate) inversion
reaction is an efficient means to generate compounds with
inverse configuration. Enhanced control of this reaction can
also be achieved by stereospecific ester activation,[16] where
neighboring ester groups are important for the inversion
reactivity. Furthermore, the protecting group pattern during
Scheme 1. Synthesis of 1-thio-β--galactopyranose (1); (a) HOAc-HBr, CH2Cl2, room temp., overnight, 70%; (b) HSAc, 1  Na2CO3,
CH2Cl2, TBAHSO4, room temp., 2 h, 55%; (c) i: TBASAc, toluene, room temp., 2 h; or ii: KSAc, acetone, room temp., 2 h, 88%; (d)
thiourea, DMF or acetone, 60 °C, 4 h, 69%; (e) ethanolamine, acetone, 60 °C, 2 h, 81%; (f) NaOMe, MeOH, room temp., 2 h, 95%.
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Thiol Analogs of β--Galactopyranose
Attempts to apply this strategy in the present case however tassium thioacetate in DMF failed to produce a non-acety-
proved less successful. Treatment of compound 12 with po- lated intermediate.
Efficient synthetic routes to 2 have not been coherently
reported in the literature. When designing a viable synthesis
to this compound, we opted for an inversion strategy.
Methyl β--galactoside was preferably chosen as starting
material due to the low cost, and for this reason, a suitable
methyl taloside derivative, where the hydroxy group in the
2-position was free and all other positions were protected,
was necessary for the synthesis of the 2-S galactose deriva-
tives. In this case, the inversion of the equatorial OH at C-
2 in the galactose derivative initially had to be performed.
As mentioned above, an efficient route to OH inversion in
carbohydrate chemistry involves the triflation of a given hy-
droxy group, followed by inversion with nitrite (Lattrell–
Dax reaction).[16,22–27] However, an investigation of the lit-
Scheme 2. Synthesis of methyl 6-thio-β--galactopyranoside (5); (a)
erature revealed surprisingly few examples of the inversion
TsCl, pyridine, 0 °C to room temp., 2 h, 72%; (b) i: Ac2O, pyridine,
of the equatorial OH at C-2, using this or other methods.
Interestingly, a literature report for the inversion of an
DMAP, room temp., 3 h; ii: KSAc, DMF, 60 °C, 2 h, 68%; (c) Na-
OMe, MeOH, room temp., 2 h, 93%.
Scheme 3. Synthesis of 2-thio-β--galactopyranoside (2); (a) PhCH(OMe)2, TsOH, DMF, room temp., 16 h, 70%; (b) i: Bu2SnO, dry
MeOH, reflux, 2 h; ii: Ac2O, DMF, room temp., 2 h, 72%; (c) Tf2O, pyridine, CH2Cl2, –30 to 0 °C, 2 h; (d) TBANO2, toluene, 50 °C,
2 h; (e) PhCONCO, CH2Cl2, –30 to 0 °C, 3 h, 60%; (f) NaH, THF, 0 °C to room temp., 3 h; (g) NaOH, THF, room temp., 12 h, then
80 °C, 3 h, 82% for 2 steps; (h) TBASAc, toluene, room temp., 2 h, 68%; (j) i: NaOMe, MeOH, 2 h; ii: CHCl3, HCl, H2O, room temp.,
87%.
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Z. Pei, H. Dong, R. Caraballo, O. Ramström
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equatorial OH at C-2 in the methyl α--glucoside derivative, the 4,6-O-benzylidene group for the inversion reaction in
where the 2-OH was free and the other hydroxy groups pro- the galactose derivative compared to glucose derivative. In
tected following a 4,6-O-benzylidene/3-OBz protecting an attempt to overcome the effects from the 4,6-O-benzyl-
strategy, showed that the reaction was performed at 80 °C idene group, the 4-OH and 6-OH groups in compound 24
for 6 hours.[23] In addition, our previous study for inversion were instead protected with benzoyl groups. However, sub-
of an equatorial OH at C-2 in methyl β--glucoside deriva- sequent thiolation with thioacetate in DMF or toluene af-
tives, where the same protecting group strategy was used, forded the 2,3-elimination product as a major component,
indicated that the reaction could only be performed at and only traces of inversion product. Nonetheless, an intra-
50 °C for 6 h.[16] Clearly, this suggested that the inversion molecular relatively strong nucleophilic reagent can over-
of an equatorial OH at C-2 is considerably more difficult come the hindrance from the 4,6-O-benzylidene group to
compared to the common inversion reactions. In these stud- afford the inversion product (entry 4 in Scheme 4). Further-
ies, the 4,6-O-benzylidene functionality was prevalently more, the results could also imply a potentially stronger ac-
used because of the selective and simultaneous protection tivation effect from the benzoylcarbamate moiety compared
of two hydroxy groups.
to an ester group (entry 5 in Scheme 4).
Consequently, our preliminary efforts toward the synthe-
sis of 2 were to try to obtain the key intermediate talose
derivative 21 (pathway a-b-c-d in Scheme 3). The 4,6-O-
benzylidenegalactoside derivative treated with tin dioxide,
followed by benzoyl chloride or acetic anhydride, selectively
rendered the key galactoside derivative, where the 2-OH
was free and all other hydroxy groups protected using a 4,6-
O-benzylidene/3-OBz or 3-OAc protecting strategy. The key
talose derivative could then be obtained from the key com-
pound through the Lattrell–Dax inversion reaction.
Introduction of a triflate at C-2 in 21 followed by the
SN2 reaction with KSAc provided the desired 23, which
should be easily deprotected to afford 2 (pathway c-h-j in
Scheme 3). Unfortunately, treatment of galactose derivative
16 with KNO2 failed to afford the inversion talose deriva-
tive 21. This is likely to be due to steric hindrance from
the 4,6-O-benzylidene group in the key intermediate of this
synthetic route. In an attempt to overcome this problem,
the strategy shown at pathway e-c-f-g in Scheme 3 was in-
stead tested. The intramolecular benzoylcarbamate O-cycli-
zation has been investigated to illustrate that it was an ef-
ficient means to overcome the steric hindrance problem for
the inversion reaction.[26] Treatment of 14 with benzoyl iso-
cyanate gave 17, where the selective carbamoylation was
performed at C-3 in 14. Treatment of 17 with triflic anhy-
dride then afforded the cyclization substrate 18. Treatment
of 18 with sodium hydride, and subsequent hydrolysis under
more vigorous basic conditions gave inversion product 20.
Finally, product 2 was successfully synthesized according to
the synthetic route a-e-c-f-g-b-c-h-j in Scheme 3.
To further study the effects of the protecting group
pattern as well as the configuration pattern in the inversion
of the equatorial 2-OH in β--galactose derivatives, several
different inversion routes were probed (Scheme 4). As can
be seen, galactose derivative 24, where the 2-OH was free
and the other hydroxy groups protected using a 4,6-O-
benzylidene/3-OBz protection strategy, failed to undergo
the inversion reaction (entry 1 in Scheme 4), whereas the
inversion reaction for the analog glucose derivative 26 was
successful (entry 2 in Scheme 4). As a comparison, the in-
Scheme 4. Inversions at C-2; (a) TBANO2, CH3CN, or KNO2,
DMF, 50 °C; (b) i: NaH, THF, 0 °C to room temp., 3 h; ii: NaOH,
THF, room temp. to 80 °C; iii: Bu2SnO, MeOH, reflux; iv: Ac2O,
DMF, room temp.
Previous report also suggest that a 4,6-O-benzylidene
version reaction of an alternative galactose derivative 16, protection pattern plays a very important role in the synthe-
using 3-OAc instead of 3-OBz, was tested (entry 3 in sis of the 3-thio-β--galactose derivatives, with the key step
Scheme 4), however also failing to furnish the inversion involving the conversion of the 3-OTf gulose derivative to
product. The results suggest that the steric hindrance from the corresponding galactose derivatives.[27,28] In addition,
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Thiol Analogs of β--Galactopyranose
Scheme 5. Synthesis of methyl 3-thio-β--galactopyranoside (3); (a) i: Bu2SnO, MeOH, reflux, 2 h; ii: BnBr, TBAI, benzene, reflux, 2 h,
70%; (b) Ac2O, pyridine, DMAP, room temp., 3 h, 92%; (c) Pd(OH)2, H2, MeOH, room temp., overnight, 95%; (d) Tf2O, pyridine,
CH2Cl2, –30 to 0 °C, 2 h; (e) TBANO2, CH2Cl2, 50 °C, 2 h, 62%; (f) TBASAc, toluene, room temp., 4 h, 78%; (g) NaOMe, MeOH, room
temp., 2 h, 86%; (h) KSAc, DMF, room temp.
recent reports demonstrated that tetrabutylammonium Scheme 5. Key intermediate 3-OH gulose derivative 33 was
thioacetate is a useful nucleophile in the successful synthesis prepared from the corresponding 3-OTf galactose derivative
of 3-thiogalactose derivatives when esters were used as pro- 32, obtained in 4 steps from methyl β--galactoside (route
tecting groups.[29,30] Our initial strategy for the synthesis of via a-b-c-d-e in Scheme 5). Introduction of a triflate group
the 3-thiogalactose derivative 3 is shown in Scheme 5.
at C-3 in 33 followed by the SN2 reaction with 40 equiv. of
The methyl guloside derivative 33, where the hydroxy TBASAc in toluene at room temperature provided the de-
group in the 3-position was free and the other positions sired compound 35. With this strategy, the byproduct 3-
were protected with acetyl groups, was essential for the syn- thiogulose derivative 36 was competitively formed in only
thesis of the 3-thiogalactose derivative. Compound 33 was 4% yield (pathway f in Scheme 5). Final deprotection of
also easily obtained in five steps according to the designed compound 35 under Zemplén conditions afforded com-
synthetic strategy. However, treatment of 33 with triflic an- pound 3.
hydride, and subsequent thiolation with KSAc in DMF in-
Synthesis of compound 4 was reported by Maradufu and
stead afforded side product 31, which was generated via the Perlin, using displacement of the corresponding brosylated
neighboring ester group participation followed by hydroly- glucose derivative and devoid of analytical data for the tar-
sis. Our previous study indicated that the efficient stereose- get compound.[31] In our preliminary study, the key inter-
lective synthesis of 3-thiogalactose derivative from the cor- mediate methyl β--glucoside derivative 40, where the hy-
responding 3-OTf gulose derivatives, where ester protecting droxy group in the 4-position was free and the other posi-
groups were used, were highly dependent on the solvent and tions were protected with benzoyl groups, was obtained in
the nucleophile concentration.[17] In this study, it could be three steps from methyl β--glucoside (pathway a-b-c in
proposed that the choice of the solvent and the nucleophile Scheme 6).[32] Initially, methyl β--glucoside (37) was selec-
concentration controlled the product formation. Neigh- tively converted into the corresponding 6-TIPS (triisopro-
boring group participation could be attenuated by per- pylsilyl) derivative 38 by standard imidazole-activated treat-
forming the reactions at high nucleophile concentration in ment with TIPSCl in DMF in the presence of imidazole.
toluene. The overall synthetic route for 3 is displayed in Subsequent benzoylation of all other positions afforded 39,
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Scheme 6. Synthesis of methyl 4-thio-β--galactopyranoside (4); (a) TIPSCl, DMF, imidazole, room temp., 1 h; (b) BzBr, DMF, room
temp., 2 h, 80% for 2 steps; (c) TBAF, THF, 0 °C, 1 h, 85%; (d) Tf2O, pyridine, CH2Cl2, –30 to 0 °C, 2 h; (e) TBASAc, toluene, room
temp., 4 h, 76%; (f) NaOMe, MeOH, room temp., 2 h, 86%; (g) KSAc, DMF, room temp.; (h) i: Bu2SnO, MeOH, reflux, 2 h; ii: BzCl,
toluene, 0 °C to room temp., 6 h, 75%.
which yielded the key intermediate 4-OH glucoside deriva- solvents are efficient to suppress the neighboring group par-
tive 40 through benzoyl group migration during the fluo- ticipation when esters are used as protecting groups in thiol-
ride-induced deprotection. More recently, a very convenient ation of carbohydrates. The influences on the nitrite-medi-
route to obtain the key intermediate methyl 4-OH glucoside ate inversion reaction of 2-OTf galactose derivatives as well
derivative 40 was however developed, based on a one-pot as glucose derivatives with different protecting patterns
organotin-mediated multiprotection procedure (pathway h have been investigated. It was found that although the in-
in Scheme 6).[33,34] Our initial strategy included the intro- version of 2-OTf-galactose derivatives was more difficult to
duction of a triflate at C-4 in compound 40 to afford gluco- perform compared to 2-OTf-glucose derivatives due to the
side 41, followed by inversion with potassium thioacetate steric hindrance from the 4,6-O-benzylidene, the stronger
in DMF to yield the desired C-4 inverted compound 42. nucleophilic attack, as well as stronger stereospecific ester
Unfortunately, attempted thiolation of compound 41 with activation can conquer the hindrance to afford the desired
potassium thioacetate in DMF afforded a reaction mixture inversion product. In addition, 2-OTf galactose derivatives,
(pathway g in Scheme 6). It was assumed that the problem using ester protecting groups instead of the 4,6-O-benzyl-
was caused by formation of the six-membered acyloxonium idene, was found to be an efficient means for the inversion
ring arising from the 6-OBz group in the polar solvents. To due to the less hindrance from the ester groups.
suppress this neighboring group participation, thiolation of
compound 41 with tetrabutylammonium thioacetate in tol-
uene was instead used, in this case, affording the C-4 in-
Experimental Section
verted compound 42 (pathway e in Scheme 5). Subsequent
General: All commercially available starting materials and solvents
deprotection of galactoside 42 yielded compound 4 in good
were reagent grade and used without further purification. Chemical
yield.
reactions were monitored with thin-layer chromatography using
precoated silica gel 60 (0.25 mm thickness) plates (Macherey–
Nagel). Flash column chromatography was performed on silica gel
Conclusions
60 (SDS 0.040–0.063 mm). Optical rotations were measured with
a Perkin–Elmer 343 polarimeter at the sodium D line at ambient
A range of thio-β--galactose derivatives have been suc-
temperature. 1H and 13C-NMR spectra were recorded with a
cessfully synthesized by using the strategies of different pro-
Bruker Avance 400 instrument or a Bruker DMX 500 instrument
tecting group patterns and selective deprotection, as well as
at 298 K in CDCl3 or D2O, using the residual signals from CHCl3
the choices of solvent and nucleophilic reagent concentra-
tion. The results indicate that ester protecting groups play a
highly important role for the synthesis of sulfur-containing
carbohydrates, where the inversion of triflated hydroxy
(1H: δ = 7.25 ppm; 13C: δ = 77.0 ppm), and from H2O (1H: δ =
4.70 ppm) as internal standard. 1H peak assignments were made
by first order analysis of the spectra, supported by standard 1H-1H
correlation spectroscopy (COSY). 13C peak assignments were made
groups has to be performed with nitrite anion. Non-polar by first order analysis of the spectra, supported by standard 1H-
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Thiol Analogs of β--Galactopyranose
13C correlation spectroscopy (HMQC). Elemental analyses were
performed by Analytische Laboratorien, Lindlar, Germany. HRMS
was carried out by Instrumentstationen, Kemicentrum, Lund Uni-
versity, Sweden.
DMF (15 mL), and the solution was heated to 70 °C. Then potas-
sium thioacetate (2.70 g, 23.7 mmol) was added in portions. The
reaction mixture was stirred at 70 °C for 18 h. When TLC indicated
that the starting material had disappeared, the reaction mixture
was diluted with water, then extracted with ethyl acetate and the
combined organic phase was washed with water and then brine,
dried with Na2SO4, and concentrated. Purification of the residue
by flash column chromatography (hexane/ethyl acetate, 2:1) af-
General Synthesis of Triflate Derivatives: To a solution of the suit-
ably O-protected methyl β--glycoside derivative, carrying an un-
protected OH at C-2, C-3 or C-4 (0.94 mmol), in CH2Cl2 (5 mL)
was added pyridine (0.65 mL) at –20 °C. Trifluoromethanesulfonic
anhydride (1.88 mol) in CH2Cl2 (2 mL) was added dropwise, and
the mixture was stirred while allowing to warm from –20 °C to
10 °C over 2 h. The resulting mixture was subsequently diluted with
CH2Cl2 and washed with 1  HCl, aqueous NaHCO3, water, and
brine. The organic phase was dried with Na2SO4 and concentrated
in vacuo at low temperature. The residue was used directly in the
next step without further purification.
1
forded 1.1 g of product (58%). H NMR (CDCl3, 400 MHz): δ =
5.34 (dd, J3,4 = 3.40, J4,5 = 0.88 Hz, 1 H, 4-H), 5.11 (dd, J2,3
10.45, J1,2 = 7.93 Hz, 1 H, 2-H), 4.92 (dd, J2,3 = 10.45, J3,4
=
=
3.40 Hz, 1 H, 3-H), 4.29 (d, J1,2 = 7.93 Hz, 1 H, 1-H), 3.62 (m,
J5,6a = 6.99, J5,6e = 6.99 Hz, 1 H, 5-H), 3.45 (s, 3 H, OCH3), 3.05
(m, J6a,6e = 13.85 Hz, 1 H, 6a-H), 3.00 (m, 1 H, 6e-H), 2.33 (s, 3
H, SCOCH3), 2.15 (s, 3 H, OCOCH3), 2.04 (s, 3 H, OCOCH3),
1.96 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3, 125 MHz): δ =
195.1 (CO), 170.8 (CO), 170.5 (CO), 169.9 (CO), 102.4 (C-1), 72.5
(C-5), 71.5 (C-3), 69.2 (C-2), 68.4 (C-4), 57.4 (OCH3), 30.9 (CH3
SAc), 29.0 (C-6), 21.2 (CH3 OAc), 21.1 (CH3 OAc), 21.0 (CH3
OAc) ppm. [α]2D2 = +40.0 (c = 0.9, CHCl3).
General Inversion of Triflate Derivatives: TBANO2 or KNO2
(5 equiv.) was added to a solution of the above triflate residue in
dry toluene (CH3CN, CH2Cl2 or DMF). After stirring at 0 to 50 °C
for 1–6 h, the mixture was diluted with CH2Cl2 and washed with
water, then brine. The organic phase was dried with Na2SO4 and
concentrated in vacuo. Purification of the residue by flash column
chromatography afforded the inversion compounds.
Methyl 6-Thio-β-D-galactopyranoside (5): Prepared from compound
13 according to the general ester deprotection procedure (0.87 g,
93%). Overall yield from compound 11: 46% over 4 steps. 1H
NMR (D2O, 500 MHz): δ = 4.28 (d, J1,2 = 7.98 Hz, 1 H, 1-H), 3.92
(d, J3,4 = 3.25 Hz, 1 H, 4-H), 3.89 (t, J5,6 = 6.95 Hz, 1 H, 5-H),
3.63 (dd, J2,3 = 10.05 Hz, 1 H, 3-H), 3.50 (s, 3 H, OCH3), 3.45 (dd,
1 H, 2-H), 2.96 (d, 2 H, 6-H) ppm. 13C NMR (D2O, 125 MHz): δ
= 104.2 (C-1), 73.3, 73.2 (C-5, C-3), 70.9 (C-2), 69.8 (C-4), 57.7
(OCH3), 38.5 (C-6) ppm. [α]2D2 = –50.2 (c = 0.5, H2O).
General Procedure for the Synthesis of Thiolacetate Derivatives:
TBASAc or KSAc (1–40 equiv.) was added to a solution of the
protected triflate residue in dry toluene or dry DMF, respectively.
After stirring at room temperature for 2–4 h, the mixture was di-
luted with ethyl acetate and washed with brine. The organic phase
was dried with Na2SO4 and concentrated in vacuo. Purification of
the residue by flash column chromatography afforded the thiolacet-
ate derivative.
Methyl 3-O-Acetyl-4,6-O-(phenylmethanediyl)-β-D-talopyranoside
(21): Compound 20 (56.5 mg, 0.2 mmol) and dibutyltin oxide
(55 mg, 0.22 mmol) were dissolved in methanol (3 mL), and re-
fluxed for two hours. After evaporation of the solvent, the residue
was dried under vacuum, and then dissolved in toluene (3 mL). A
solution of acetic anhydride (20 mg, 0.2 mmol) in anhydrous tolu-
ene (1 mL) was added dropwise, and then allowed to react at room
temp. for 2 h. The resulting mixture was directly purified by flash
column chromatography (hexane/ethyl acetate, 6:4), affording
General Method for Single or Multiple Regioselective Acylation via
the Respective Stannylene Intermediates: Methyl β--galactoside de-
rivatives and dibutyltin oxide (2–4 equiv.) were dissolved in meth-
anol, and refluxed for two hours. After evaporation of the solvent,
the residue was dried under vacuum, and then dissolved in toluene.
A solution of benzoyl chloride or acetic anhydride (1–3 equiv.) in
anhydrous toluene was added dropwise, and then allowed to react
at 90 °C for 2 h. The resulting mixture was directly purified by flash
column chromatography, affording the selectively protected deriva-
tive.
1
47 mg of compound 21 (72%). H NMR (CDCl3, 400 MHz): δ =
7.43–7.49 (m, 2 H, CHPh), 7.31–7.36 (m, 3 H, CHPh), 5.46 (s, 1 H,
Ph-CH-), 4.84 (t, J3,2 = 3.3, J3,4 = 3.3 Hz, 1 H, 3-H), 4.40 (dd, J6a,5
= 1.5, J6a,6b = 12.6 Hz, 1 H, 6a-H), 4.36 (d, J1,2 = 0.8 Hz, 1 H, 1-
H), 4.05–4.11 (m, 1 H, 6b-H), 3.90–3.96 (m, 1 H, 2-H), 3.59 (s, 3
H, OCH3), 3.42–3.46 (m, 1 H, 5-H), 3.34 (d, JOH,2 = 11.3 Hz, 1 H,
OH), 2.15 (s, 3 H, OCOCH3) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 170.6 (CO), 137.0, 129.2, 128.2, 126.1 (Cph), 101.5 (C-1), 73.7
(C-4), 70.6 (C-3), 69.1 (C-6), 68.7 (C-2), 66.6 (C-5), 57.2 (CH3
OMe), 21.0 (CH3 OAc) ppm. [α]2D2 = +24.5 (c = 1.0, CHCl3).
HRMS: calcd. for C16H20O7 [M + Na+]: 347.1107; found 347.1113.
General Deprotection of Carbohydrates Derivatives Protected with
Ester: The protected methyl β--glycoside derivative was dissolved
in methanol at room temp., and sodium methoxide (1.1 equiv.) in
methanol was added dropwise. The reaction mixture was stirred at
room temp. for 2 h under nitrogen protection and monitored with
TLC. After consumption of the starting material, the solvent was
removed under vacuum. Purification of the residue by flash column
chromatography afforded the deprotection product.
Methyl 2,3,5-Tri-O-acetyl-6-S-acetyl-6-thio-β-
D-galactopyranoside
Methyl 2-S-Acetyl-3-O-acetyl-4,6-O-(phenylmethanediyl)-2-thio-β-
(13): Methyl β--galactopyranoside (0.97 g, 5 mmol) was dissolved
in dry pyridine (4 mL) at 0 °C, and tosyl chloride (1.05 g, 5.5 mmol,
1.1 equiv.) in dry pyridine (2 mL) was added slowly. The reaction
mixture was warmed to room temperature and stirred overnight
under nitrogen atmosphere. After consumption of the starting ma-
terial, pyridine (10 mL) and acetic anhydride (5 mL) were added
in the reaction mixture. The reaction mixture was stirred at room
temperature overnight. When TLC indicated that the starting mate-
rial had disappeared, the reaction mixture was diluted with water,
then extracted with ethyl acetate, and the combined organic phase
was washed with 2  HCl, water and then brine, dried with
Na2SO4, and concentrated. The crude product was dissolved in dry
D-galactopyranoside (23): Triflation of compound 21 was per-
formed according to the general triflation procedure yielding com-
pound 22. Compound 22 was then directly dissolved in dry toluene,
then TBASAc (318 mg, 1 mmol) was added to the solution. After
stirring at room temperature for 2 h, the mixture was diluted with
ethyl acetate and washed with brine. The organic phase was dried
with Na2SO4 and concentrated in vacuo. Purification of the residue
by flash column chromatography (hexane/ethyl acetate, 2:1) af-
forded 38 mg of compound 23 (68%). 1H NMR (CDCl3,
400 MHz): δ = 7.49–7.56 (m, 2 H, CHPh), 7.31–7.41 (m, 3 H,
CHPh), 5.54 (s, 1 H, Ph-CH-), 5.17 (dd, J3,2 = 11.8, J3,4 = 3.5 Hz,
1 H, 3-H), 4.66 (d, J1,2 = 8.8 Hz, 1 H, 1-H), 4.34 (dd, J6a,5 = 1.5,
Eur. J. Org. Chem. 2007, 4927–4934
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4933

Z. Pei, H. Dong, R. Caraballo, O. Ramström
FULL PAPER
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J6a,6b = 12.3 Hz, 1 H, 6a-H), 4.29 (br. d, 1 H, 4-H), 4.08 (dd, J6b,5
= 1.8 Hz, 1 H, 6b- H), 3.87 (dd, 1 H, 2-H), 3.51 (s, 3 H, OCH3),
3.44–3.55 (m, 1 H, 5-H), 2.33 (s, 3 H, SCOCH3) 2.07 (s, 3 H, OC-
OCH3) ppm. 13C NMR (CDCl3, 125 MHz): δ = 193.7 (CO SAc),
170.6 (CO OAc), 137.6, 129.0, 128.2, 126.4 (CPh), 101.5 (C-1), 100.9
(Ph-CH), 72.9 (C-4), 70.3 (C-3), 69.2 (C-6), 66.3 (C-5), 57.8 (CH3
OMe), 45.5 (C-2), 30.8 (CH3 SAc), 20.8 (CH3 OAc) ppm. [α]2D2
=
+38.2 (c = 1.0, CHCl3). HRMS: calcd. for C18H22O7S [M + Na+]:
405.0984; found 405.0992.
Methyl 2-Thio-β-D-galactopyranoside (2): Prepared from compound
23 according to the general ester deprotection procedure followed
by acid treatment (18 mg, 87%). Overall yield from compound 11:
1
15% over 9 steps. H NMR (D2O, 400 MHz): δ = 4.49 (d, J1,2
=
8.8 Hz, 1 H, 1-H), 3.86–3.89 (m, 1 H, 4-H), 3.82 (dd, J3,2 = 11.0,
J3,4 = 3.5 Hz, 1 H, 3-H), 3.73 (dd, J6a,6b = 11.7, J6a,5 = 7.9 Hz, 1
H, 6a-H), 3.68 (dd, J6b,5 = 4.4 Hz, 1 H, 6b-H), 3.56 (dd, 1 H, 5-H),
3.53 (s, 3 H, OCH3), 2.70 (dd, 1 H, 2-H) ppm. 13C NMR (D2O,
125 MHz): δ = 102.8 (C-1), 74.9 (C-5), 69.6 (C-3), 68.2 (C-4), 61.1
(C-6), 57.0 (CH3 OMe), 55.3 (C-2) ppm. [α]2D2 = +58.6 (c = 0.5,
H2O). HRMS: calcd. for C7H14O5S [M + Na+]: 233.0460; found
233.0467.
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3309.
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6955.
Methyl 3-Thio-β-D-galactopyranoside (3): Prepared from 76 mg of
compound 35 according to the general ester deprotection pro-
cedure (36 mg, 86%). Overall yield from compound 11: 25% over
8 steps. 1H NMR (D2O, 500 MHz): δ = 4.28 (d, J1,2 = 7.6 Hz, 1
H, 1-H), 4.09 (d, J4,3 = 2.8 Hz, 1 H, 4-H), 3.62–3.71 (m, 3 H, 5-H,
6-H), 3.48 (s, 3 H, OCH3), 3.42 (dd, J2,3 = 11.5 Hz, 1 H, 2-H), 3.05
(dd, 1 H, 3-H) ppm. 13C NMR (D2O, 125 MHz): δ = 105.0 (C-1),
77.4 (C-5), 68.6 (C-2), 67.0 (C-4), 61.2 (C-6), 58.6 (C-3), 57.1 (CH3
OMe) ppm. [α]2D2 = +72.6 (c = 0.5, H2O). C7H14O5S + 1/2 H2O:
calcd. C 38.35, H 6.90, S 14.62; found C 37.87, H 6.83, S 14.43.
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Methyl 4-Thio-β-D-galactopyranoside (4): Prepared from 115 mg of
compound 42 according to the general ester deprotection pro-
cedure (37 mg, 86%). Overall yield from compound 37: 49% over
4 steps. 1H NMR (D2O, 500 MHz): δ = 4.19 (d, J1,2 = 8.5 Hz, 1
H, 1-H), 3.76–3.94 (m, J3,4 = 3.25 Hz, 4 H, 3-H, 5-H, 6-H), 3.45
(s, 3 H, OCH3), 3.35–3.42 (m, 1 H, 4-H), 3.18 (dd, J2,1 = 8.5, J2,3
= 8.9 Hz, 1 H, 2-H) ppm. 13C NMR (D2O, 125 MHz): δ = 104.1
(C-1), 74.9 (C-5), 72.2 (C-3), 71.8 (C-2), 62.7 (C-4), 62.0 (C-6), 57.3
(CH3 OMe) ppm. [α]2D2 = –10.2 (c = 0.5, H2O). C7H14O5S + 1/2
H2O: calcd. C 38.35, H 6.90, S 14.62; found C 38.35, H 7.00, S
14.46.
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Acknowledgments
This study was supported by the Swedish Research Council, the
Swedish Foundation for International Cooperation in Research
and Higher Education, and the Carl Trygger Foundation.
[34] H. Dong, Z. Pei, S. Byström, O. Ramström, J. Org. Chem.
2007, 72, 1499–1502.
Received: April 23, 2007
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Published Online: July 30, 2007
4934
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4927–4934