In(III) triflate-mediated solvent-free synthesis and activation of thioglycosides by ball milling and structural analysis of long chain alkyl thioglycosides by TEM and quantum chemical methods

Article abstract of DOI:10.1021/jo5001753

Conventional solution-phase synthesis of thioglycosides from glycosyl acetates and thiols in the presence of In(III) triflate as reported for benzyl thioglucoside failed when applied to the synthesis of phenolic and alkyl thioglycosides. But, it was achieved in high efficiency and diastereospecificity with ease by solvent-free grinding in a ball mill. The acetates in turn were also obtained by the homogenization of free sugars with stoichiometric amounts of acetic anhydride and catalytic In(OTf)₃ in the mill as neat products. Per-O-benzylated thioglycosides on grinding with an acceptor sugar in the presence of In(OTf)₃ yield the corresponding O-glycosides efficiently. The latter in the case of a difficult secondary alcohol was nearly exclusive (>98%) in 1,2-cis-selectivity. In contrast, the conventional methods for this purpose require use of a coreagent such as NIS along with the Lewis acid to help generate the electrophilic species that actually is responsible for the activation of the thioglycoside donor in situ. The distinctly different self-assembling features of the peracetylated octadecyl 1-thio-α- and β-d-galactopyranosides observed by TEM could be rationalized by molecular modeling.

Full text of DOI:10.1021/jo5001753

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Article
In(III) triflate-mediated solvent-free synthesis and activation of
thioglycosides by ball milling and structural analysis of long chain
alkyl thioglycosides by TEM and quantum chemical methods
Vajinder Kumar, Nikhil Taxak, Ramnivas Jangir, Prasad V. Bharatam, and KP Ravindranathan Kartha
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5001753 • Publication Date (Web): 26 Mar 2014
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In(III) triflateꢀmediated solventꢀfree synthesis and activation of thioglycosides
by ball milling and structural analysis of long chain alkyl thioglycosides by
TEM and quantum chemical methods
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Vajinder Kumar, Nikil Taxak, Ramnivas Jangir, Prasad V. Bharatam and
K.P. Ravindranathan Kartha*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research, S.A.S. Nagar, Punjab 160062, India.
rkartha@niper.ac.in
ABSTRACT: Conventional solutionꢀphase synthesis of thioglycosides from glycosyl acetates
and thiols in the presence of In(III) triflate as reported for benzyl thioglucoside failed when
applied to the synthesis of phenolic and alkyl thioglycosides, But, it was achieved in high
efficiency and diastereospecificity with ease by solventꢀfree grinding in a ball mill. The acetates
in turn were also obtained by the homogenization of free sugars with stoichiometric amounts of
acetic anhydride and catalytic In(OTf)3 in the mill as neat products. PerꢀOꢀbenzylated
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thioglycosides on grinding with an acceptor sugar in the presence of In(OTf)3 yield the
corresponding Oꢀglycosides efficiently. The latter in the case of a difficult secondary alcohol was
nearly exclusive (>98%) in 1,2ꢀcisꢀselectivity. In contrast, the conventional methods for this
purpose require use of a coꢀreagent such as NIS along with the Lewis acid to help generate the
electrophilic species that actually is responsible for the activation of the thioglycoside donor in
situ. The distinctly different selfꢀassembling features of the peracetylated octadecyl 1ꢀthioꢀαꢀ and
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βꢀDꢀgalactopyranosides observed by TEM could be rationalized by molecular modelling.
INTRODUCTION
The excellent potential that In(III) triflate holds for promoting various carbohydrate
reactions became evident from the highly efficient acyl transfer reactions as well as the
formation and hydrolysis of cyclic acetals of various carbohydrates reported some time ago.1 A
case of thioglycosylation reaction noted involved treatment of the glycosyl acetate 1 with benzyl
mercaptan at 50 °C in dichloroethane to form the desired 1,2ꢀtransꢀlinked benzyl 1ꢀthioꢀ
glycoside 2 in 2 h in virtually quantitative yield (Scheme 1, Path A). On the basis of the latter
observation and from a need for synthesizing multiꢀgram quantities of the phenyl thioꢀβꢀ
galactoside derivative 5 in the context of an ongoing work, we recently tried to extend the above
reaction to thiophenol as an acceptor for reaction with perꢀOꢀacetylated βꢀ ꢀgalactose 4 (For
Dꢀ
D
structures see Scheme 2 to follow later). It was disappointing to see that while at room
Scheme 1. Comparison of In(OTf)3–mediated reaction of a glycosyl acetate with BnSH/PhSH
under conventional and mechanochemical conditions.
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temperature virtually no reaction took place, it was found to be accompanied by degradation
products at 50 °C in dichloroethane as a result of which the yields were drastically affected
unlike in the preparation of 2. The latter reaction, when repeated using acetate 1 in place of 4
was also proved unsuccessful (Scheme 1, Path A). This led us to think of the reaction in solid
state instead. Our own observations in this regard as well as those in the literature showed that
the chemical reactivity and selectivity exhibited by many solid state reactions are often better
than their corresponding solutionꢀphase counterpart.2 As an alternative therefore, the reaction
was held under solventꢀfree conditions mechanochemically using a planetary ball mill (Scheme
2) and the results were indeed very interesting. Under the optimized conditions the acetate 4
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Scheme 2. In(OTf)3–Mediated mechanochemical activation of galactosyl acetate for
thioglycosylation.
reacted with thiophenol effectively, giving the desired phenyl thioglycoside 5 in 84% yield in 90
min. The details on the optimization of the reaction conditions as well as a comparison of the
current method with that of a set of important conventional thioglycosylation methods are as
under.
RESULTS AND DISCUSSION
Homogenization of galactosyl acetate 4 with mercaptophenol in the presence of In(OTf)3 (25
mol%) for 1.5 h in the ball mill resulted in the complete disappearance of 4 from the reaction
mixture as ascertained by TLC (EtOAcꢀHexanes, 1:1, entry 1, Table 1). A new compound with
Rf value marginally higher than that of the acetate 4, and unlike 4 detectable under the UV
detection lamp, had been formed instead. The solids were therefore subjected to an aqueous
workup and the crude product so obtained was purified on a short column of silica (eluent,
EtOAcꢀHexanes, 2:8). Spectroscopic analysis showed the crystalline product obtained to be the
desired phenyl thiogalactoside 5.3,4 The requirement of In(OTf)3 was subsequently optimized by
experiments as tabulated in Table 1. It was found that performing the reaction using 25 mol% of
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Table 1. Optimization of reaction conditions for the In(OTf)3ꢀmediated solventꢀfree
mechanochemical thiogalactosylation.a
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Entry In(OTf)3
Time
(h)
Yield of 5
Remarks
No
(mol
equiv)
0.25
1
1.5
2.5
84
78
Complete consumption of 4; only the βꢀ
glycoside (5) was formed
2
0.25
Some αꢀglycoside was also formed along
with 5 but separated efficiently on silica
gel chromatographically
3
4
5
6
0.15
0.15
0.10
0.05
2.0
45
65
ꢀꢀ
50% of 4 had been consumed; only the βꢀ
glycoside (5) was formed
10.0
10.0
10.0
70% of 4 had been consumed; only the βꢀ
glycoside (5) was formed
Only 20% of 4 had been consumed
(TLC); attempt to isolate 5 was not made
No reaction was observed
ꢀꢀ
a 1 mmol (390.5 mg) of 4 was ground in an SS bowl containing SS balls along with thiophenol (3 mmol) and In(OTf)3.3,4
the metal triflate was sufficient for satisfactory results. At lower levels of the metal triflate and at
shorter reaction times, it was found that the 1,2ꢀtransꢀlinked thioglycoside was the only product
formed. Longer periods of grinding beyond the completion of reaction led essentially to the
anomerization product (1,2ꢀcisꢀlinked glycoside corresponding to 5).
In accordance with a general Lewis acidꢀcatalyzed reaction, In(OTf)3 can be considered
to activate the glycosyl acetate 4 as shown in Scheme 3. Coordination of the metal center in the
catalyst with the carbonyl oxygen of the anomeric acetyl group can render the acyl group
departure possible, with the assistance of the lone pair of electrons on ring oxygen (Oꢀ5) as
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represented in the structure 4a. This must lead to the successive formation of ion pairs 4b and 4c.
Nucleophilic attack of the thiol can then result in the formation of the desired thioglycoside 5
stereospecifically. The formation of the thioglycoside (5) must also lead to the release of the
metal salt suggesting that, in principle, the reaction must be catalytic in In(III) although in
practice it was observed (see above) that 0.25 mol equiv of the salt was needed for the reaction to
proceed in a reasonably short period of grinding.
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Alternatively, the thiol activation by the metal triflate as represented in equation 1
(Scheme 3) if considered shall also culminate in the satisfactory formation of 5 upon reaction of
the metallated thiol derivative A2, formed as an activated intermediate, on the cyclic
oxocarbonium ion 4c described earlier. However, circumstantial evidence suggests that the
former mechanism is operative. It was observed that on terminating the reaction upon complete
consumption of the glycosyl acetate leaves the thioglycoside formed stereospecifically. But on
continued grinding for long periods beyond the completion of the reaction, acidꢀcatalyzed
anomerization product could also be obtained.
Scheme 3. Indium triflateꢀassisted thioglycosylation of galactose pentaacetate 4.
A comparison of the current method for the preparation of 1,2ꢀtransꢀlinked 1ꢀ
thioglycosides with the classical method that makes use of the more reactive glycosyl βꢀacetate
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preferably has been presented in Table 2 below. Thus, while the BF3·Et2Oꢀpromoted
thioglycoside preparation reported by Ferrier and Furneaux, which is still used quite extensively,
typically takes nearly 1.5 to 2 days for completion of the reaction (entries 1, 3 and 4, Table 2),
the current method allows it in 1.5 h with better efficiency (entry 9, Table 2; see also later). The
current method is also more effective than the wellꢀaccepted modified method later introduced
by Pozsgay and Jennings (entries 2 and 5, Table 2). Again, while the current procedure is
solventꢀfree, the iodineꢀpromoted reactions (entries 6 – 8, Table 2), though are faster, of wide
acceptance and of equal efficiency (product yield) as the current method, require use of the
poisonous solvent, MeCN to be best successful. Clearly, the method reported herein is thus
superior in many respects.
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Table 2. A comparison of the reported thioglycosylation methods with the current method.
Method
Transformation
Entry
Lit refa
Thiol
Promoter
(mol%)
Solvent
Time (h)
Yield (%)
reagent
1
2
R = OAc → R = SPh
R = OAc → R = SMe
PhSH
BF3·Et2O
(300)
CHCl3
43
5
69
84
5(a)
5(b)
TMSꢀ
SMe
BF3·Et2O
(60)
CH2Cl2
3
4
R = OAc → R = SEt
R = OAc → R = SBn
EtSH
BF3·Et2O (22)
BF3·Et2O (20)
CHCl3
CHCl3
35
46
83
70
5(a)
5(a)
BnSH
5
R = OAc → R = SMe
TMSꢀ
SMe
TMSOTf (60)
CH2Cl2
48
93
5(b)
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R = OAc → R = SPh
R = OAc → R = SEt
TMSꢀ
SPh
I2 (120)
I2 (120)
MeCN
MeCN
2 min
2 min
80
85
5(c)
5(c)
TMSꢀ
SEt
8
9
R = OAc → R = SEt
R = OAc → R = SPh
EtSH
PhSH
I2 (120)
MeCN
None
5 min
1.5
80
86
5(c)
ꢀ
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In(OTf)3 (25)
a A 3ꢀ50% (w/v, based on the sugar substrate) solution in the desired solvent is employed for the reaction
Under the conditions optimized for 4 when the glucosamine derivative 1 was allowed to react
with thiophenol the reaction took place effectively and the corresponding βꢀthioglycoside 36 was
obtained in 86% yield as colorless solid by crystallization (entry 1, Table 3; Scheme 1, Path B).
Extending the reaction to αꢀDꢀglucose pentaacetate (6) also gave the desired 1,2ꢀtransꢀlinked
thioglycoside 7 in good yield (entry 2, Table 3).3,7 pꢀNitrothiophenol (phenyl ring bearing an
electron withdrawing substituent) and pꢀthiocresol (phenyl ring bearing an electron donating
substituent) were also evaluated as acceptors for the thioglycosylation reaction. The desired
respective thioglycosides 83 and 93 were also obtained stereospecifically in excellent yields on
60ꢀ90 min of grinding (entries 3ꢀ4, Table 3). The solutionꢀphase method employing the relatively
more toxic MoO2Cl2 is not only comparatively more sluggish but also requires the more reactive
glycosyl βꢀacetate for the above reactions.10b In the context of another ongoing work in our
laboratory, we needed 1ꢀthioꢀβꢀDꢀgalactopyranosides having long chain alkyl residues on the
sulfur. Therefore the preparation of the desired galactosides 108 and 119 was also attempted
under the above optimized reaction condition to successful completion (entries 5ꢀ6, Table 3).
Table 3. Indium triflateꢀmediated mechanochemical thioglycosylation of glycosyl acetates.a
Entry
1
Substrate
Product
Time (h)
1.5
Yield (%)
86
3
1
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8 X = NO2
9 X = Me
3
4
5
6
1.5
90
84
3
1.0
3.5
3.5
Compound 3
70ꢀ80b
10 n = 17
11 n = 13
a A mixture of the perꢀOꢀacetylated monosaccharides (1 mmol), thiophenol (2.2 mmol) and In(OTf)3 (0.25 mmol) was ground in
an SS bowl containing SS balls using a planetary ball mill; b 7–8% of the αꢀanomer corresponding to 10/11 were also isolated.
As the preparation of the perꢀOꢀacetylated monosaccharides can also be carried out in
quantitative yields in the presence of indium triflate,1 the acetylation step was also carried out in
the ball mill. Thus, anhydrous Dꢀgalactose (12) was mixed in an SS bowl with acetic anhydride
in the ball mill for about half an hour in the presence of In(OTf)3 (2ꢀ5 mg/g sugar, that is, ≤0.16
mol%) and the clear acetylation product was subjected to an alkaline aqueous workup. The solids
obtained were dried and after putting back into the milling bowl were ground with thiophenol
and the catalyst as described above (entry 1a, Table 4). The product was then obtained in a yield
of 78% after a quick column chromatographic purification.3,4,10 The reaction was then repeated
on a preparative scale with 5 g of the hexose (12) as the starting material and the glycoside 4 was
obtained in 85% yield as crystals on crystallization of the crude product obtained after the
aqueous workup (entry 1b, Table 4). It has been consistently observed that solventꢀfree reactions
in the ball mill work with higher efficiency when conducted on multiꢀgram quantities as
better/more effective mixing can be achieved in such cases.3 With this successful reaction, the
method was extended to a range of other sugars (pentoses, entries 2ꢀ3, Table 4; hexoses, entries
4ꢀ5, Table 4; deoxyhexose, entry 6, Table 4; and disaccharides, entries 7ꢀ8, Table 4) to evaluate
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the general applicability of the reaction. It was found that the respective phenylthioglycosides
were obtained efficiently in all the cases (Table 4). As must be expected,
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8
Table 4. Indium triflateꢀmediated mechanochemical thioglycosylation of sugarsa
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Entry
1a
Substrate
Product
(Lit reference)
5
Yield (%)
D
D
ꢀGalactose (12)
on 1 g scale
ꢀGalactose (12)
on 5 g scale
78
85
1b
5
2
3
D
ꢀXylose (13)
ꢀArabinose (15)
ꢀGlucose (17)
74
68
14
L
16
7
4
5
D
77
88
D
ꢀMannose (18)
19
6
L
ꢀRhamnose (20)
74
21
23
7
8
D
ꢀLactose (22)
64
65
67
D
ꢀMaltose (24)
25
9b
DꢀGalactose (12)
4B
a A mixture of the monosaccharides/disaccharides (1 mmol), Ac2O (1.1 mol equiv per OH group) and In(OTf)3 (2ꢀ5 mg/g sugar)
was ground in an SS bowl containing SS balls using a planetary ball mill for 30 min and the product after aqueous workup was
directly subjected to the thioglycosylation as in Table 3; [b] The sugar was subjected to perꢀOꢀbenzoylation by treatment with
Bz2O (instead of Ac2O) before subjecting to thioglycosylation as in other cases.
the perꢀOꢀbenzoylated Dꢀgalactose (structure not shown), prepared from Dꢀgalactose (12) by dryꢀ
grinding with benzoic anhydride in the presence of In(OTf)3, also underwent facile solventꢀfree
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thioglycosylation upon grinding with thiophenol in the presence of the metal triflate to afford the
5
6
respective thioglycoside 4B in good yield (entry 9, Table 4).
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Based on the above results and the proven catalytic efficiency (as a Lewis acid) of
In(OTf)3, including its ability to cause anomerization of thioglycosides as has been observed
above, the Oꢀglycosylation using an “armed“ thioglycoside (26) was performed in the absence of
a coꢀpromoter such as NIS which was proven impossible by the conventional procedure (Path A,
Scheme 4). Thus, when the benzylated thiogalactoside 26 and the acetonide 27 were ground at
500 rpm in the presence of In(OTf)3, complete consumption of the acceptor 27 occurred in a
relatively short period of 1.5 h (Scheme 4, Path B) and the desired disaccharide product 27 was
formed in excellent yield. As could be expected from the nonꢀparticipatory group located on Oꢀ2
of the donor substrate, the product was a mixture of 1,2ꢀcisꢀ/transꢀlinked glycosides (28 α/β, as
typical of these reactions)17,18 obtained in a ratio of 1:9. During the process of monitoring the
progress of the above reactions in the ball mill, it was noted that the initial chromatograms (TLC)
showed the nearꢀexclusive presence of the βꢀglycoside (28β) in the reaction mixture, although at
the end of the 1.5 h reaction the ratio of 28α: 28β was 1:9. Most interestingly the α/β ratio for 28
could be altered effectively by controlling the conditions of grinding (for details see Table 5).
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27, R = H
No products
Path A
O
OR
O
BnO
BnO
OBn
O
O
SPh
O
BnO
26
O
27, R = H
28, R = Bn4Galpꢀ ꢀ/ ꢀ
100%
Path A: Conventional ꢀ In(OTf)3 (up to 100 mol%), Et2O, 25 °C, up to 48 h
Path B: Mechanochemical ꢀ In(OTf)3 (25 mol%), Ball mill, 500 rpm, 1.5 h
Scheme 4. In(III) triflateꢀmediated disaccharide synthesis.
Table 5. In(III) triflateꢀpromoted solventꢀfree armed thioglycosideꢀactivation.
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
In(OTf)3
(mmol)
Grinding
speed
(rpm)
Time
(h)
Consumption
of 26 (%)
Combined yield
(%)
α:β
1
2
3
4
5
6
0.25
0.25
0.25
0.25
0.25
0.25
450
450
500
550
550
550
1
60
65
51
55
neat βꢀ
βꢀ, ≥95
1 : 9
1.5
1.5
100
100
100
100
61
0.75
1.0
66
1 : 9
40ꢀ45
40ꢀ45
2 : 3
1.25
5 : 3
7
8
0.25
0.25
500
500
1
2
50
40
64
1 : 4
100
1 : 1.2
The In(OTf)3ꢀmediated glycosylation therefore was also tried at lower speeds of mixing in the
ball mill. Thus, at 450 rpm at the end of a 1 h mixing period in the planetary ball mill the only
glycoside product detected by TLC was 28β, though 40% of the starting materials were still left
(entry 1, Table 5). Continuing grinding for another 30 min could bring only marginal
improvement in the consumption of the donor (entry 2, Table 5). However, by then the formation
of 28α had been started. In another experiment when mixing was allowed for 30 min at 500 rpm,
following an initial 1.5 h at 450 rpm, complete consumption of the thioglycoside occurred (entry
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not shown in the Table). Therefore another reaction at 500 rpm was carried out with 1.5 h as the
mixing period. Again, the reaction was found to be complete but 10% of 28α was also obtained
along with the major βꢀproduct (28β, entry 3, Table 5) which at 550 rpm (entry 4, Table 5) was
found obtainable in a shorter time of 0.75 h of grinding. Under the latter conditions while with a
grinding time of 1 h the ratio of 28α:28β isolated was found to be 2:3 (entry 5, Table 5), it was
found to be 5:3 (entry 6, Table 5) for a grinding period of 1.25 h. Thus, a clear qualitative
difference in the onset as well as rate of anomerization was visible as a function of grinding
speed. Considering the significance of this observation, a detailed investigation on these factors
is currently being pursued in our laboratory.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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36
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The partially acetylated glucose derivative 29,19 in which a possibility for acyl migration
existed, was also examined as a typical acceptor for the above glycosylation. At 500 rpm when
the glycosylation was allowed to take place in the ball mill for 1 h, at which time approximately
50% of the starting materials had been consumed, the disaccharide 30 was obtained in 40% yield
with α:β = 1:4. No acetyl migration was observed. And at the end of a 2 h reaction, during which
the complete consumption of the starting materials had taken place, the disaccharides 30α and
30β were obtained in a ratio of 1:1.2. The combined yield of the disaccharide was 64%. A small
amount of 2,3,4,6ꢀtetraꢀOꢀbenzyl galactopyranose was also obtained as a byꢀproduct. The
reaction was subsequently extended to a difficult secondary alcohol case, the diol substrate 31 to
obtain the monoꢀ and diꢀOꢀglycosylated products 32 and 33 in excellent yields (80ꢀ83%) in
which the αꢀlinked disaccharide was present in excess of 98%. On purification, 32α and 33α
(required in connection with our work on synthetic polyvalent protein inhibitors) were obtained
pure.
In the case of armed thioglycosides, for example 26, it would seem possible that the
nucleophilicity of sulfur is sufficient enough to allow the lone pair of electrons on the atom to
complex with the metal center in In(III) triflate to give rise to an activated intermediate 34 which
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after the departure of the modified aglycone moiety, a process that can be reasoned possible by
the assistance of the Oꢀ5ꢀlone pair of electrons, forms the oxocarbenium ion intermediate 35 that
upon further reaction with an acceptor alcohol yields the desired glycosides in the conventional
manner (Scheme 5). The fact that disarmed thioglycosides, example 4, does not smoothly react
in the same manner lends support to this hypothesis as does the lower reactivity of the pꢀ
nitrophenyl 2,3,4,6ꢀtetraꢀOꢀbenzylꢀ1ꢀthioꢀβꢀDꢀgalactcoside towards the same reaction. A clear
10
11
12
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20
21
22
23
24
25
26
27
28
29
30
31
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35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Possible mechanism of activation of an armed thioglycoside by In(III) triflate.
advantage of the indium triflateꢀpromoted solventꢀfree method of thioglycosylation was thus
evident from a comparison of the observations noted in Schemes 1 & 4 and Table 1 (Entry 1).
However, as a comparison of the current method with the conventional solutionꢀphase
protocol must also be worthwhile and in context, the preparation of the disaccharide 28 from
compounds 26 and 27 described above (see Scheme 4) was also performed in the conventional
manner in solutionꢀphase (Table 6). In the absence of a coꢀpromoter (NIS) in anhydrous ether no
disaccharide formation was observed even on continuing the reaction up to 2 days at room
temperature (entries 1ꢀ3, Table 6) and in spite of using the metal triflate up to a level of 1 mol
equiv. However, when the same reaction was carried out in the presence of added NIS it
proceeded almost instantly giving rise to the expected disaccharide 28 in less than 2 min at rt.
Although the reaction was neat, chromatographic isolation led to pure 28 in a yield of 68%
(probably losing some product on the surface of silica) with the anomeric ratio of α:β = 3:2
(Entry 4, Table 6). Under the same conditions, the reaction carried out in acetonitrile or
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dichloromethane led to poorer yields of the product (Entries 5 and 6, Table 6). In ether, the
glycosylation was effective with the use of the metal triflate catalyst up to a level of 5 mol%
(Entries 7ꢀ10, Table 6). The results thus, amply demonstrate that In(III) triflate can indeed serve
9
Table 6. Conventional In(III) triflateꢀpromoted solutionꢀphase synthesis of disaccharide 28.[a]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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Entry
In(OTf)3
(mol equiv) (mol equiv)
NIS
Solvent
Time
(min)
2 d
Yield,
(%)
Nil
α : β
1
2
0.25
0.5
ꢀꢀ
ꢀꢀ
ꢀꢀ
1
1
1
1
1
1
1
Et2O
Et2O
ꢀꢀ
2 d
2 d
Nil
Nil
ꢀꢀ
3
1.0
Et2O
ꢀꢀ
4
0.25
0.25
0.25
0.20
0.15
0.10
0.05
Et2O
2
68
3 : 2
1 : 1
3 : 2
7 : 3
7 : 3
7 : 3
7 : 3
5
CH3CN
CH2Cl2
Et2O
5ꢀ10
30
48
6
33
7
2ꢀ5
65ꢀ75
65ꢀ75
65ꢀ75
65ꢀ75
8
Et2O
2ꢀ5
9
Et2O
10ꢀ15
20ꢀ25
10
Et2O
a The reaction was carried out by treating compounds 26 (1 mmol) and 27 (1 mmol) in the solvent (1 ml/100 mg sugar
derivative) specified in the Table 5.
as an efficient Lewis acid catalyst in generating the activating species20 (the iodonium species)
when used with NIS in order to activate thioglycosides for Oꢀglycosylation reactions. Compared
to many of the other catalysts of this class such as AgOTf,21 TfOH/TMSOTf,22 etc., In(OTf)3
holds distinct practical advantages in terms of its sensitivity to light, air, moisture, etc. and/or
greenness and therefore, must find wide acceptance in future.
Further, in the course of the preparation of the alkyl thioglycosides 10 and 11, we noticed that
considerable degree of foaming occurred during the aqueous workup particularly when the
organic solvent for extraction was shaken vigorously, as a consequence of which back extraction
proved essential for securing complete recovery of the product present. Also, the foaming was
considerably more prominent when dichloromethane was used in place of EtOAc for extraction.
While the above observations were not surprising given the known surfactantꢀlike properties of
long chain alkyl glycosides as well as the poorer solubility of methylene chloride (compared to
that of EtOAc) in water, it was certainly surprising that a qualitative difference in the foaming
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characteristic was observed during the processing of the αꢀ and βꢀthioglycosides. Intrigued by
this, the above glycosides were subjected to analysis by TEM as well as quantum chemical
studies and the results are summarized below.
9
Table 7. Transmission electron microscopic analysis of octadecyl 1ꢀthiogalactopyranosides 10 (α
& β) and 36 (α & β).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
Compound structure
TEM images
A solution of 10β in hexane containing traces of
CH2Cl2 was used for TEM. Magnification:
X1700. Particle diameter: 325 nm to 650 nm.
1
2
3
A solution of 10α in hexane containing traces of
CH2Cl2 was used for TEM. Magnification:
X7800 (Left), X19000 (Right). Particle length:
500 nm to 1500 nm.
A solution of 36β in hexane containing traces of
H2O was used for TEM. Magnification: X330
(Left), X1700 (Right). Particle length: 335 nm
to 1 ꢁ
4
A solution of 36α in hexane containing traces of
H2O was used for TEM. Magnification: X9600
(Left), X29000 (Right). Particle diameter: 96
nm to 258 nm
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A solution of 36β in MeOH containing traces of
H2O was used for TEM. Magnification: X420
(Left), X1700 (Right).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A solution of 36α in MeOH containing traces of
H2O was used for TEM. Magnification: X420
(Left), X1700 (Right).
Study of the literature shows that carbohydrateꢀbased surfactants have been studied
widely with respect to their surface active properties and liquid crystalline behavior.23 In the
former, the glycosides used for the studies have been otherwise unprotected. Also, till now the
aggregation behaviour of these surfactants has been investigated as a function of the alkyl chain
length, nature of the head group and its geometry.24 Observations we made during the
preparation of the αꢀ and βꢀ anomers of 10 and 11 seemed to suggest that it could also be
dependent upon the stereochemistry at the anomeric center. TEM imaging showed that the selfꢀ
assembly of octadecyl 2,3,4,6ꢀtetraacetylꢀαꢀ and βꢀthiogalactosides (10α and 10β) possessed
distinct organizational patterns. Not unexpectedly though, it was also dependent upon the nature
of the solvent used for the study (Table 7). Thus when a solution of the anomers 10α and 10β in
hexane containing traces of methylene chloride was used for loading the sample onto the copper
grid for TEM, while the βꢀanomer assembled into spherical particles the αꢀanomer organized to
give ellipsoid particles (entries 1 and 2, Table 7). Most interestingly, upon deprotection of the
acetyl groups on 10 α/β (to give 36α/β) a reversal of the organizational patterns obtained was
observed (entries 3 and 4, Table 7). Thus, while 36β gave rise to longitudinal pattern, spherical
particles were produced in the case of the corresponding αꢀanomer. Further, upon changing the
solvent system for the sample preparation from hexane to MeOH, the former organized into
particles possessing morphological features akin to polygons whereas the αꢀanomer seemed to
retain the spherical pattern, though it was rather irregular in nature. Therefore, in an attempt to
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rationalize these behavioral differences obtained above, semiꢀempirical calculations on these
molecules were carried out.
7
8
9
Electronic structure, interaction analysis and rationalization of the TEM morphological
features.25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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59
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In order to understand the structural details of the protected αꢀ and βꢀthiogalactosides
(10α and 10β) and to determine the distinct intermolecular and intramolecular interactions
present in them, their structures were optimized employing the dispersionꢀcorrected semiꢀ
empirical quantum chemical method, PM3ꢀD using Gaussian09 package. The optimized 3D
structures of the monomers of these thioglycosides obtained are shown in Fig. 1 (for the details
of the methodology, see supporting information, S1). Two predominant intramolecular hydrogen
bonding interactions (Fig. 1) were observed in 10α as compared to one (only) intramolecular
hydrogen bonding interaction observed in the βꢀanomer (10β). Several intramolecular van der
Waals contacts are noticeable in the βꢀanomer (10β) giving rise to the ‘δꢀshaped’ geometry,
which are absent in the αꢀanomer. The monomeric structure 10β was observed to be
comparatively more stable than 10α by 2.42 kcal/mol (Table 8). To confirm this fact, B3LYP/3ꢀ
21G single point energy calculations were carried out, which showed that 10β is more stable than
10α by ~7 kcal/mol. To examine the selfꢀassembling character of these molecules, dimeric
structures were constructed from the optimized geometries of the monomers and were optimized
using the PM3ꢀD method. The optimized 3D geometries of the dimers are also shown in Fig. 1. It
is clear from Fig. 1 that 10α and 10β exhibit distinct intermolecular interactions; 10α is driven by
the hydrogen bonding forces arising from the galactose moiety, while 10β is driven by the
hydrophobic interactions.
Table 8. The relative and stabilization energies of thiogalactosides, 10α and 10β and their dimers
and tetramers, calculated using PM3ꢀD method.
Thioglycoside
Relative Energy
(kcal/mol)
Formulae
Dimerization Energya
(kcal/mol)
2.42
0.00
ꢀ
ꢀ
ꢀ
10α
10β
ꢀ
45.82
EDꢀ10αꢀ2E10α
ꢀ28.75
Dꢀ10α
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0.00
81.02
0.00
EDꢀ10β– 2E10β
ETꢀ10α– 2EDꢀ10α
ETꢀ10β– 2EDꢀ10β
ꢀ69.73
ꢀ81.18
ꢀ70.55
Dꢀ10β
Tꢀ10α
Tꢀ10β
a Dimerization energies were calculated by subtracting the summation of energies of monomers and dimers from the
energies of the dimers and tetramers respectively, as given in the formulae.
9
10
11
12
13
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16
17
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19
20
21
22
23
24
25
26
27
28
29
30
31
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33
34
35
36
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53
54
55
56
57
58
59
60
2.54
2.64
2.48
10α
10β
2.44
2.73
2.51
1.90
Dꢀ10α
Dꢀ10β
Tꢀ10α
Tꢀ10β
TEMꢀ10α
TEMꢀ10β
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Figure 1. Optimized geometries of 10α and 10β in their monomeric, dimeric and tetrameric arrangements by PM3ꢀ
D method. The selfꢀassembly of the thioglycosides are shown in the form of dimer and tetramer structures showing
distinct interactions and arrangement. The corresponding TEM images of the respective thioglycosides are also
shown. All the distances indicating intermolecular and intramolecular interactions are given in Å. Colour code:
carbon, sky blue; oxygen, red; hydrogen, grey; sulfur, yellow.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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26
27
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29
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38
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47
48
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50
51
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53
54
55
56
57
58
59
60
There are two different intermolecular interactions in the structure Dꢀ10α, namely Hꢀ
bond interaction between the anomeric hydrogen of one monomer and the ester oxygen atom of
the other [(C1)HꢀꢀꢀO(CO)ꢀC6] and the acetyl (methyl) hydrogen atom of one monomer and the
carbonyl oxygen atom of the other [C6ꢀOꢀC(O)ꢀCHꢀꢀꢀO=CꢀOꢀC4]. The Hꢀbond distances were
observed to be 2.44 Å and 2.73 Å respectively for these interactions. These intermolecular
interactions provide a twisted Lꢀshaped geometry to Dꢀ10α. On the other hand, the dimeric
structure of 10β, represented as Dꢀ10β (‘δꢀshaped’) in Fig. 1, is observed to possess a head group
containing the sugar portions and the tail containing side chains. This orientation of Dꢀ10β is due
to two important intermolecular Hꢀbonding interactions and hydrophobic interactions. The Hꢀ
bonding interactions are (i) [C4ꢀOꢀC=OꢀꢀꢀHꢀCH2ꢀC(O)ꢀOꢀC3, 1.90 Å], and (ii) [C6ꢀOꢀC(O)ꢀCHꢀ
ꢀꢀO (sugar ring), 2.51 Å], as shown in Fig. 1. The strong hydrophobic interactions observed due
to dispersion effects result in the spiralꢀshaped orientation of the side chains in Dꢀ10β. These
interactions stabilize the dimeric structure Dꢀ10α and Dꢀ10β in which Dꢀ10β was observed to be
more stable (by ~46 kcal/mol) than Dꢀ10α. The higher stability of Dꢀ10β can be inferred owing
to the presence of many intramolecular and intermolecular hydrophobic interactions. However,
the hydrophobic interactions are less pronounced in Dꢀ10α. Also, the energy gain due to the
dimer formation in Dꢀ10α and Dꢀ10β respectively is 28.75 kcal/mol and 69.73 kcal/mol
respectively (Table 8). This indicates a higher stability of dimer Dꢀ10β as compared to Dꢀ10α.
The stabilization energies of both the dimers, Dꢀ10α and Dꢀ10β suggest the clear possibility of
selfꢀassembling character in them.
The optimized geometries of the dimeric structures were further utilized to construct the
tetrameric structures, Tꢀ10α and Tꢀ10β. Tꢀ10α was found to adopt an irregular linear
arrangement, showing the sideꢀchains in parallel orientation with each other, controlled mostly
by van der Waals contacts. This indicated the presence of predominant hydrophobic interactions,
contributing substantially to the stability of the tetrameric structure Tꢀ10α and hence, to the selfꢀ
assembling property. This arrangement could also be considered to corroborate the TEM image
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of 10α showing an organized pattern of rectangular/ellipsoidal sheets (Fig. 1 and supporting
information Figure S1). Tꢀ10β on the other hand adopts a spherical (globular) pattern, where the
sugar portion of the dimers are oriented inwards (forming the head), while the long alkyl side
chains are oriented outwardly (forming the tail). These tetramers can be extended further to the
octameric structures where a more precise spherical arrangement, like a micelle, can be observed
(as shown in supporting information Figure S2). This also is in line with the spherical pattern
observed in the TEM images of 10β.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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Hence, the relative stabilization energies, different intramolecular, intermolecular
interactions, hydrophobic, van der Waals interactions and different arrangements of the
geometries arising from these interactions confirm the selfꢀassembling property and the relative
stabilities of these thiogalactosides. Thus, a relation between the polymeric arrangement of these
thiogalactosides and their TEM analytical data could be identified using the dispersionꢀcorrected
semiꢀempirical quantum chemical methods. The selfꢀassembling nature of these molecules could
be judged to be due to the energy gain on thermodynamic grounds, along with the electrostatic
factors, as well as hydrophobic forces.
CONCLUSION
In conclusion, we have demonstrated that In(OTf)3 can be profitably employed in the
formation and activation of thioglycosides under solventꢀfree conditions and without the aid of
an additional coꢀpromoter as in the conventional methods. The In(OTf)3ꢀpromoted Oꢀ
glycosylation in solutionꢀphase was, however, ineffective in the absence of added NIS. Using
NIS as a coꢀreagent the Oꢀglycosylation was also facile and effective in ether although the
desired stereoselectivity was poorer compared to the solventꢀfree reaction. Further work
exploring wider applications of the solventꢀfree methodology is in progress in our laboratory.
The distinct morphological features observed in the transmission electron micrographs of
thiogalactosides 10α and 10β clearly suggest their selfꢀassembly properties that must be
distinctly different from each other. Optimization of their structures by semiꢀempirical quantum
chemical methods has revealed the clearly distinguishing features of their association up to the
size of tetrameric units and are thus supportive of the differently organized structures obtained on
TEM imaging.
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GENERAL EXPERIMENTAL METHODS
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All the reagents used were as purchased without further purification. Solvents used for reactions
were dried according to standard methods. Reactions were monitored by TLC, which was
performed with 0.2 mm preꢀcoated silica gel 60 F254 aluminum sheets. Compounds were
detected by dipping the TLC plates in an ethanolic solution of sulphuric acid (5%, v/v) and
heating them. Melting points were determined on a melting point apparatus. Specific rotations
were recorded on a digital Polarimeter at room temperature (approximately 20ꢀ25 °C). NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
spectra were recorded on 400 MHz spectrometer. H NMR and 13C NMR spectra were
referenced using either residual solvent signals, or tetramethylsilane in the respective deuterated
solvents. Wherever necessary 1Hꢀ1H COSY and 1Hꢀ13C HMQC spectra were used additionally to
confirm the NMR peak assignments. Splitting patterns are described as singlet (s), doublet (d),
triplet (t), quartet (q), and broad (br); the value of chemical shifts (δ) are given in ppm and
coupling constants (J) are reported in Hertz (Hz). Mass spectra were recorded on a MALDI
TOF/TOF or HRMS (TOF) spectrometer.
General procedure for the thioglycosylation of perꢀOꢀacylated monosaccharides by
planetary ball mill
The glycosyl acetate (1/3/6, 0.391 g, 1 mmol), thiophenol (0.250 g, 2.2 mmol) and
In(OTf)3 (0.141g, 0.25 mmol) were allowed to mix in a stainless steel (SS) jar (capacity, 50 mL)
containing SS balls (10 numbers, 10 mm o.d.) for 1.5 h (or until the reaction was complete: TLC,
EtOAc:Hexanes, 1:1) in a planetary ball mill (Retsch PMꢀ100, Retsch GmbH & Co. KG,
Germany) at 550 rpm. [For reactions on a scale of 15 g or more of the glycosyl acetate, 2.0 mol
equiv of the thiol were mixed in the SS jar (125 ml capacity) using SS balls (6 numbers, 20 mm
o.d.) for about 80ꢀ90 min]. EtOAc followed by water were then added to the mixture, the organic
layer was separated and washed successively with aq Na2CO3 solution (10%, w/v) and water,
dried (Na2SO4), and concentrated under reduced pressure to afford the respective crude
thioglycoside that was purified by column chromatography on silica using EtOAcꢀHexanes (2:3)
as eluent. In the case of preparations on multiꢀgram scale the products where they are crystalline
could be isolated by crystallization from diethyl etherꢀnꢀHex to obtain analytically pure product.
The spectral data were in accordance with the expected structure and in agreement with the
literature values (3,6 7,3,7 8, 93, 108 and 119).
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General procedure for the thioglycosylation starting from free sugars by planetary ball
mill
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The desired free sugar, 12/13/15/17/18/20/22/24 (1 g), acetic anhydride (1.1 mol equiv
per –OH group; typically 2.9 ml/g of hexose or 2.2 ml/g of a disaccharide made of hexose units)
and In(OTf)3 (catalytic, 0.1ꢀ0.2 mol%; typically 5 mg/g sugar)26 were allowed to mix in a
stainless steel (SS) jar (capacity, 50 mL) containing SS balls (10 numbers, 10 mm o.d.) for 30
min (or until the reaction was complete: TLC, EtOAc:Hexanes, 1:1) at 550 rpm as described
above. The mixture was added to crushed ice and after stirring well the precipitated perꢀOꢀ
acetylated sugar was separated by filtration at the pump and was washed successively with cold
aq Na2CO3 solution (10%, w/v) and water and was dried. The dried product was transferred back
to the milling bowl and after adding thiophenol (typically, 1.35 g in the case of a hexose) and
In(OTf)3 (typically, 0.78 g, 25 mol% in the case of a hexose) was milled for 1.5 h. The product
(5/3,4,10 14/11 16/12 7/3,6,7 19/6 21/13 23/14 25/15 4B,16 respectively) was isolated and purified as
described above. The details are given in Table 4.
Phenyl 3,4,6ꢀtetraꢀOꢀacetylꢀ2ꢀdeoxy 2ꢀphthaliimidoꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (3):
Yield 86% (0.45 g); White solid; mp 136.1 °C; [α]D25 +61.4 (c 1.0 in CHCl3), (lit +70.5 c 1.5 in
1
CHCl3); IR νmax (KBr, cmꢀ1): 2929, 1750, 1427, 1369, 1222, 1082, 1054, 917, 749; H NMR
(400MHz, CDCl3): δ 7.88ꢀ7.86 (m, 2H, 1&4PhꢀH thali) 7.79ꢀ7.76 (m, 2H, 2&3PhꢀH thali), 7.43ꢀ
7.41 (m, 2H, 2&6 PhꢀH), 7.31ꢀ7.25 (m, 3H, 3,4&5 PhꢀH), 5.80 (t, J = 9.4 Hz, 1H, Hꢀ3), 5.73 (d,
J = 10.6 Hz, 1H, Hꢀ1), 5.15 (t, J = 9.8 Hz, 1H, Hꢀ4), 4.37 (d, J = 10.4 Hz, 1H, Hꢀ2), 4.30 (dd,
1H, Hꢀ6a), 4.21 (dd, 1H, Hꢀ6b), 3.93ꢀ3.89 (m, 1H, Hꢀ5), 2.11, 2.03, 1.85 (3s, 9H, 3xCOCH3);
13C{1H} NMR (100MHz, CDCl3): δ 170.7ꢀ169.4 (4C), 134.5, 134.4, 133.3, 128.9, 128.5, 83.1,
75.8, 71.7, 68.7, 62.2, 53.5, 29.7, 20.8, 20.6, 20.4; MS (MALDIꢀTOF) for C6H25NO9S,
calculated m/z 527.125, found 550.126 [M+Na]+.
Phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (5):
25
Yield 84% (0.37 g); White solid; mp 64ꢀ65 °C; [α]D +4.8 (c 1 in CHCl3), (lit +4.2 c 1 in
CHCl3); IR νmax (KBr, cmꢀ1): 2929, 1750, 1369, 1222, 1082, 1054, 917, 749; 1H NMR (400MHz,
CDCl3): δ 7.54ꢀ7.51 (m, 2H, 2&6 PhꢀH), 7.33ꢀ7.28 (m, 3H, 3,4&5 PhꢀH), 5.42 (d, J = 2.4 Hz,
1H, Hꢀ4), 5.25 (t, J = 9.9 Hz, 1H, Hꢀ2), 5.06 (dd, J1 = 3.3 Hz, J2 = 9.9 Hz, 1H, Hꢀ3), 4.73 (d, J=
9.9 Hz, 1H, Hꢀ1), 4.23ꢀ4.10 (m, 2H, Hꢀ6a, Hꢀ6b), 3.95 (t, J = 8.4 Hz, 1H, Hꢀ5), 2.13, 2.12, 2.05,
13
1.98 (4s, 12H, 4xCOCH3); C{1H} NMR (100MHz, CDCl3): δ 170.4ꢀ169.5 (4C), 132.5, 129.1,
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128.2, 127.9, 90.5, 74.4, 72.0, 69.1, 61.6, 20.8, 20.7, 20.6, 20.5; MS (MALDIꢀTOF) for
C20H24O9S, calculated m/z 440.114, found 463.586 [M+Na]+, 479.590 [M+K]+.
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Phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀglucopyranoside (7):
Yield 84% (0.35 g); White solid; mp 120ꢀ121 °C; [α]D25 ꢀ19.2 (c 1 in CHCl3); IR νmax (KBr, cmꢀ
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1): 2949, 2891, 1744, 1372, 1255, 1226, 1089, 1043; H NMR (400MHz, CDCl3): δ 7.52ꢀ7.48
(m, 2H, 2,6ꢀPhꢀH), 7.33ꢀ7.29 (m, 3H, 3,4,5ꢀPhꢀH), 5.22 (t, J = 9.6 Hz, 1H, Hꢀ3), 5.04 (t, J =
10.0 Hz, 1H, Hꢀ2), 4.97 (t, J = 9.1 Hz, 1H, Hꢀ4), 4.70 (d, J = 10.1 Hz, 1H, Hꢀ1), 4.24ꢀ4.16 (m,
2H, Hꢀ6a, Hꢀ6b), 3.75ꢀ3.70 (m, 1H, Hꢀ5), 2.09, 2.08, 2.02, 1.99 (3s, 12H, 4xCOCH3); C NMR
(100MHz, CDCl3): δ 170.7, 169.9, 169.8, 133.6, 128.9, 128.4, 85.7, 76.0, 74.0, 69.9, 68.3, 62.2,
20.8, 20.6; MS (MALDIꢀTOF) for C20H24O9S, calculated m/z 440.114, found 463.470 [M+Na]+,
479.460 [M+K]+.
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4ꢀNitrophenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (8):
Yield 90% (0.44 g); White solid; mp 145ꢀ146 °C; [α]D25 ꢀ6.3 (c 1 in CHCl3); IR νmax (KBr, cmꢀ
1
1): 2928, 1750, 1368, 1340, 1223, 1083, 1057; H NMR (400 MHz, CDCl3): δ 8.20ꢀ8.15 (m, 2H,
3,5ꢀPhꢀH), 7.63ꢀ7.59 (m, 2H, 2,6ꢀPhꢀH), 5.48 (d, J = 3.2 Hz, 1H, Hꢀ4), 5.30 (t, J = 9.9 Hz, 1H,
Hꢀ2), 5.10 (dd, J1 = 3.2, J2 = 9.9, 1H, Hꢀ3), 4.88 (d, J = 9.9 Hz, 1H, Hꢀ1), 4.23ꢀ4.11 (m, 2H, Hꢀ
13
6a, Hꢀ6b), 4.05 (bt, J = 6.2 Hz, 1H, Hꢀ5), 2.16, 2.08, 2.07, 1.98 (4s, 12H, 4xCOCH3); C{1H}
NMR (100MHz, CDCl3): δ 170.3, 170.0, 169.9, 169.4, 146.9, 144.1, 130.4, 126.4, 124.5, 124.0,
84.8, 74.8, 71.7, 67.1, 66.7, 61.7, 20.7, 20.6, 20.6, 20.5; MS (MALDIꢀTOF) for C20H23NO11S,
calculated m/z 485.102, found 508.112 [M+Na]+, 524.013 [M+K]+.
4ꢀMethylphenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (9):
25
Yield 84% (0.38 g); White solid; mp 111ꢀ112 °C; [α]D +4.8 (c 1 in CHCl3), (lit.+4.2 c1 in
1
CHCl3); IR νmax (KBr, cmꢀ1): 2971, 2938, 1750, 1369, 1224, 1083, 1055; H NMR (400 MHz,
CDCl3): δ 7.43 (d, J = 8.1 Hz, 2H, 2,6ꢀPhꢀH), 7.15 (d, J = 7.9 Hz, 2H, 3,5ꢀPhꢀH), 5.42 (d, J = 3.3
Hz, 1H, Hꢀ4), 5.22 (t, J = 9.9 Hz, 1H, Hꢀ2), 5.04 (dd, J1 = 3.2 Hz, J2 = 9.9 Hz, 1H, Hꢀ3), 4.67
(d, J = 9.8 Hz, 1H, Hꢀ1), 4.22ꢀ4.07 (m, 2H, Hꢀ6a, Hꢀ6b), 3.93 (t, J = 6.4 Hz, 1H, Hꢀ5), 2.34 (s,
3H, CH3), 2.11, 2.10, 2.04, 1.97 (4s, 12H, 4xCOCH3); 13C{1H} NMR (100MHz, CDCl3): δ
170.4, 170.2, 170.1, 169.5, 138.5, 133.1, 129.7, 128.6, 87.0, 74.4, 72.1, 67.3, 67.2, 61.6, 21.2,
20.9, 20.7, 20.6; MS (MALDIꢀTOF) for C21H26O9S, calculated m/z 454.130, found 477.119
[M+Na]+, 493.096 [M+K]+.
Octadecyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀαꢀDꢀgalactopyranoside (10α):
Yield 7ꢀ8% (0.034 g); White amorphous solid; mp 52.7 °C; [α]D25 +115.9 (c 1 in CHCl3); IR νmax
1
(KBr, cmꢀ1): 2944, 2834, 1748, 1369, 1225, 1020; H NMR (400 MHz, CDCl3): δ 5.72 (d, J =
5.2 Hz, 1H, Hꢀ1), 5.45 (bd J = 2.3 Hz, 1H, Hꢀ4), 5.26ꢀ5.22 (m, J1 = 5.2 Hz, J2 = 3.0 Hz, 2H, Hꢀ
2, Hꢀ3), 4.59 (bt, J = 7.1Hz, 1H, Hꢀ6), 4.11ꢀ4.09 (m, 2H, Hꢀ6, Hꢀ5), 2.70ꢀ2.67 (m, 2H, CH2),
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2.14, 2.07, 2.04, 1.99 (4s, 12H, 4xCOCH3), 1.60ꢀ1.58 (m, 2H, CH2), 1.41ꢀ1.19 (m, 28H,
14xCH2), 0.89 (m, 2H, CH2); 13C{1H} NMR (100 MHz, CDCl3): δ 170.3ꢀ169.9 (4C), 82.1, 68.2,
68.0, 66.4, 61.8, 31.9, 29.8, 29.7, 29.6, 29.4, 29.3 28.9, 22.7, 20.8, 20.7, 14.1; MS (ESI HRMS)
for C32H56O9SNa, calculated m/z 639.3543, found 639.3546 [M+Na]+.
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Octadecyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (10β):
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Yield 66% (0.46 g); White amorphous solid; mp 58 °C; [α]D25 ꢀ15.29 (c 1 in CHCl3); IR νmax
1
(KBr, cmꢀ1): 2944, 2834, 1748, 1369, 1225, 1020; H NMR (400 MHz, CDCl3): δ 5.43 (d, J =
3.1 Hz, 1H, Hꢀ4), 5.23 (t, J = 9.9 Hz, 1H, Hꢀ2), 5.06 (dd, J1 = 3.3Hz, J2 = 9.9Hz, 1H, Hꢀ3), 4.47
(d, J = 9.9Hz, 1H, Hꢀ1), 4.16ꢀ4.11 (m, 2H, Hꢀ6a, Hꢀ6b), 3.92 (bt, 1H, Hꢀ5), 2.70ꢀ2.67 (m, 2H,
CH2), 2.15, 2.07, 2.04, 1.98 (4s, 12H, 4xCOCH3), 1.60ꢀ1.58 (m, 2H, CH2), 1.39ꢀ1.18 (m, 28H,
14xCH2), 0.89 (m, 2H, CH2); 13C{1H} NMR (100 MHz, CDCl3): δ 170.4ꢀ169.6 (4C), 84.2, 74.3,
71.9, 67.3, 61.5, 31.9, 29.7, 29.7, 29.6, 29.2, 28.8, 22.7, 20.6, 14.1; MS (ESI HRMSꢀTOF) for
C32H56O9SNa, calculated m/z 639.3543, found 639.3544 [M+Na]+.
Tetradecyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀαꢀDꢀgalactopyranoside (11α):
Yield 7ꢀ8% (0.030 g); Oil; [α]D25 +52.0 (c 1 in CHCl3); IR νmax (KBr, cmꢀ1): 2943, 2827, 1737,
1
1366, 1225, 1010; H NMR (400 MHz, CDCl3): δ 5.73 (d, J = 5.2 Hz, 1H, Hꢀ1), 5.46 (bd J =
2.3 Hz, 1H, Hꢀ4), 5.27ꢀ5.23 (m, J1 = 5.2 Hz, J2 = 3.0 Hz, 2H, Hꢀ2, Hꢀ3), 4.60 (t, J = 7.1Hz, 1H,
Hꢀ6), 4.12ꢀ4.10 (m, 2H, Hꢀ6, Hꢀ5), 2.59ꢀ2.46 (m, 2H, CH2), 2.15, 2.08, 2.05, 2.00 (4s, 12H,
13
4xCOCH3), 1.59ꢀ1.57 (m, 2H, CH2), 1.34ꢀ1.23 (m, 24H, 12xCH2), 0.90 (m, 2H, CH2); C{1H}
NMR (100 MHz, CDCl3): δ 170.4ꢀ169.9 (4C), 82.2, 68.2, 68.0, 66.4, 61.9, 31.9, 29.8, 29.7, 29.6,
29.5, 28.9, 22.7, 20.8, 20.7, 14.1; MS (ESI HRMSꢀTOF) for C28H48O9SNa, calculated m/z
583.2917, found 583.2917 [M+Na]+.
Tetradecyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside (11β):
Yield 65% (0.37 g); Oil; [α]D25 ꢀ11.9 (c 1 in CHCl3); IR νmax (KBr, cmꢀ1): 2966, 2834, 1749,
1366, 1220, 1025; 1H NMR (400 MHz, CDCl3): δ 5.42 (d, J = 2.9 Hz, 1H, Hꢀ4), 5.22 (t, J = 9.9
Hz, 1H, Hꢀ2), 5.03 (dd, J1 = 3.3 Hz, J2 = 9.9Hz, 1H, Hꢀ3), 4.46 (d, J = 9.9 Hz, 1H, Hꢀ1), 4.14ꢀ
4.10 (m, 2H, Hꢀ6a, Hꢀ6b), 3.93 (bt, 1H, Hꢀ5), 2.69ꢀ2.66 (m, 2H, CH2), 2.15, 2.07, 2.04, 1.98 (4s,
12H, 4xCOCH3), 1.59ꢀ1.57 (m, 2H, CH2), 1.37ꢀ1.24 (m, 24H, 12xCH2), 0.86 (m, 2H, CH2); 13C
NMR (100 MHz, CDCl3): δ 170.3, 170.2, 170.1, 169.9 (4C), 84.2, 74.3, 71.9, 67.3, 61.4, 31.9,
29.7, 29.6, 29.5, 29.3, 28.9, 22.6, 20.8, 14.1; MS (ESI HRMSꢀTOF) for C28H48O9SNa, calculated
m/z 583.2917, found 583.2917 [M+Na]+.
Phenyl 2,3,4ꢀtriꢀOꢀacetylꢀ1ꢀthioꢀβꢀDꢀxylopyranoside (14):
Yield 74% (0.24 g); White solid; mp 76ꢀ77 °C; [α]D25 ꢀ55.6 (c 1 in CHCl3); 1H NMR (400 MHz,
CDCl3): δ 7.51ꢀ7.48 (m, 2H), 7.34ꢀ7.31 (m, 3H), 5.19 (t, J1 = 8.2 Hz, 1H), 4.98ꢀ4.82 (m, 2H),
4.83 (d, J = 8.3 Hz, 1H, Hꢀ1), 4.29 (dd, J1 = 11.8 Hz, J2 = 4.9 Hz, 1H), 3.45 (dd, J1 = 12.0 Hz, J2
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4
5
6
13
169.8, 169.3, 132.7, 132.2, 129.0, 128.2, 86.3, 72.0, 69.8, 68.4, 65.2, 20.8, 20.7; M.W.
(C17H20O7S) 368.04; ESIꢀMS m/z 391.09 [M+Na]+.
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Phenyl 2,3,4ꢀtriꢀOꢀacetylꢀ1ꢀthioꢀβꢀLꢀarabinopyranoside (16):
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25
Yield 68% (0.22 g); Oil, [α]D ꢀ59.7 (c 1 in CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.49ꢀ7.46
(m, 2 H) 7.34ꢀ7.27 (m, 3H), 5.30ꢀ5.20 (m, 2H), 5.10 (dd, J1 = 8.4 Hz, J2 = 3.4 Hz, 1H), 4.82 (d, J
= 7.8 Hz, 1H), 4.17 (dd, J1 = 12.7 Hz, J2 = 4.2 Hz, 1H), 3.68 (dd, J1 = 12.7 Hz, J2 = 2.0 Hz, 1H),
2.13 (s, 6H, 2xCOCH3), 2.06 (s, 3H, COCH3); 13C{1H} NMR (100 MHz, CDCl3): δ 170.3,
169.9, 169.5, 133.3, 132.2, 129.1, 128.6, 86.9, 70.9, 68.5, 67.5, 65.3, 20.9, 20.8, 20.7; M.W.
(C17H20O7S) 368.03; ESIꢀMS m/z 391.07 [M+Na]+.
Phenyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀ1ꢀthioꢀαꢀDꢀmannopyranoside (19):
Yield 88% (0.38 g); Oily liquid, [α]D25 = +84.9 (c 2 in CH2Cl2); 1H NMR (400 MHz, CDCl3): δ
7.51ꢀ7.49 (m, 2H), 7.36ꢀ7.31 (m, 3H), 5.53ꢀ5.51 (m, 2H), 5.38ꢀ5.32 (m, 2H), 4.58ꢀ4.55 (m, 1H),
4.33 (dd, J1 = 12.24 Hz, J2 = 6.0 Hz, 1H), 4.10 (dd, J1 = 12.4 Hz, J2 = 2.3 Hz, 1H), 2.17ꢀ2.04 (4s,
12H, 4xCOCH3); 13C{1H} NMR (100MHz, CDCl3): δ 170.5, 169.9, 169.8, 169.7, 132.6, 132.1,
129.2, 128.1, 85.7, 70.9, 69.5, 69.4, 66.4, 62.4, 20.9, 20.7, 20.7, 20.6; M.W. (C20H24O9S) 440.11;
ESIꢀMS m/z 463 [M+Na]+.
Phenyl 2,3,4ꢀtriꢀOꢀacetylꢀ1ꢀthioꢀαꢀLꢀrhamnopyranoside (21):
°
25
1
Yield 74% (0.28 g); Colorless solid; mp 116ꢀ118 C; [α]D ꢀ105.8 (c 1 in CHCl3); H NMR
(CDCl3, 400 MHz): δ 7.49ꢀ7.46 (m, 2H, PhꢀH) 7.34ꢀ7.27 (m, 3H, PhꢀH), 5.50 (dd, 1H, J1 = 1.6
Hz, J2 = 3.3 Hz, Hꢀ2), 5.41 (d, J1 = 1.6 Hz ,1H, Hꢀl), 5.29 (dd, 1H, J1 = 10.0 Hz, J2 = 3.3 Hz, Hꢀ
3), 5.17 (t, 1H, J1 = 9.8 Hz, Hꢀ4), 4.39ꢀ4.32 (m, 1H, Hꢀ5), 2.20, 2.09, 2.01 (3s, 9H,COCH3), 1.25
(d, 3H, J1 = 6.2 Hz, CH3); 13C{1H} NMR (100MHz, CDC13): δ 170.1 (2xCOCH3), 169.9
(COCH3), 133.3, 131.8, 129.2, 127.9, 85.7, 71.3, 71.1, 69.4, 67.8, 20.9, 20.9, 20.7 (CHSCO),
17.3 (Cꢀ6); M.W. (C18H22O7S) 383.45, ESIꢀMS m/z 405.10 [M+Na]+.
Phenyl 2,3,6ꢀtriꢀOꢀacetylꢀ4ꢀOꢀ(2’,3’,4’,6’ꢀtetraꢀOꢀacetylꢀβꢀDꢀgalactopyranosyl)ꢀ1ꢀthioꢀβꢀDꢀ
glucopyranoside (23):
°
25
1
Yield 64% (0.47 g); White solid; mp 89ꢀ90 C; [α]D ꢀ21.7 (c 1 in CHCl3); H NMR (400MHz,
CDCl3): δ 7.49ꢀ7.46 (m, 2H), 7.34ꢀ7.27 (m, 3H), 5.35 (d, J1 = 3.2 Hz, 1H, Hꢀ4’), 5.22 (t, J = 9.1
Hz, 1H, Hꢀ3), 5.11 (dd, J1 = 10.4 Hz, J2 = 7.8 Hz, 1H, Hꢀ2’), 4.95 (dd, J1 = 10.4 Hz, J2 = 3.1 Hz,
Hꢀ3’), 4.90 (t, J1 = 9.5 Hz, 1H, Hꢀ2), 4.68 (d, J1 = 10.1 Hz, 1H, Hꢀ1), 4.54 (dd, 1H, J1 = 1.8 Hz, J2
= 11.9 Hz, Hꢀ6), 4.47 (d, 1H, J1 = 7.8, Hꢀ1’), 4.15ꢀ4.05 (m, 3H, 2xHꢀ6’, Hꢀ6), 3.88ꢀ3.85 (m, 1H,
Hꢀ5’), 3.78ꢀ3.73 (m, 1H, Hꢀ4), 3.67ꢀ3.63 (m, 1H, Hꢀ5), 2.17, 2.15, 2.13,2.10, 2.09,1.98, 1.97 (7s,
21H, COCH3); 13C{1H} NMR (100MHz, CDCl3): δ 170.3, 170.3, 170.1, 170.1, 169.7, 169.1,
169.0, 133.1, 131.8, 128.9, 128.3, 101.0, 85.5, 76.7, 76.1, 73.8, 71.0, 70.7, 69.1, 66.6, 62.1, 60.8,
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Phenyl
2,3,6ꢀtriꢀOꢀacetylꢀ4ꢀOꢀ(2’,3’,4’,6’ꢀtetraꢀOꢀacetylꢀαꢀDꢀglucopyranosyl)ꢀ1ꢀthioꢀβꢀDꢀ
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glucopyranoside (25):
Yield 65% (0.48 g); White solid; mp 89ꢀ90 °C; [α]D25 +42.2 (c 1 in CHCl3); 1H NMR (400 MHz,
CDCl3): δ 7.50ꢀ7.48 (m, 2H), 7.35ꢀ7.31 (m, 3H), 5.41 (d, J = 4.0 Hz, 1H), 5.36 (t, J = 9.8 Hz,
1H), 5.30 (t, J = 7.0 Hz, 1H), 5.06 (t, J = 9.9 Hz, 1H), 4.86 (dd, J1 = 4.0 Hz, J2 = 10.5 Hz, Hꢀ1),
4.84 (t, J = 8.9 Hz, 1H), 4.75 (d, J = 10.1, 1H), 4.55 (dd, J1 = 2.4 Hz, J2 = 12.1 Hz, 1H), 4.27ꢀ
4.21 (m, 2H), 4.06 (dd, J1 = 12.4 Hz, J2 = 2.2 Hz, 1H), 3.98ꢀ3.93 (m, 2H), 3.76ꢀ3.71 (m, 1H),
2.14 (s, 3H, COCH3), 2.12, 2.08, 2.06, 2.05, 2.01, 1.99 (7s, 21H, COCH3); 13C{1H} NMR
(100MHz, CDCl3): δ 170.6, 170.4, 170.2, 170.0, 169.6, 169.5, 133.4, 131.3, 129.2, 128.9, 128.5,
95.6, 85.1, 76.5, 76.1, 72.4, 70.7, 70.0, 69.3, 68.5, 68.0, 62.8, 61.9, 20.9, 20.8, 20.7, 20.6, 20.5;
M.W. (C32H40O17S) 728.19; ESIꢀMS m/z 751.21 [M+Na]+.
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Phenyl 2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranoside (4B):
25
Yield 67% (0.43 g); White solid; mp 81.3 °C; [α]D +81.7 (c 1 in CHCl3), (lit. +81.5 c 1 in
CHCl3); IR νmax (neat, cmꢀ1): 2926, 1728, 1601, 1266, 1094, 1069, 1026, 749, 707; 1H NMR (400
MHz, CDCl3): δ 8.05ꢀ7.22 (m, 25H, PhꢀH), 6.02 (bd, J = 2.9 Hz, 1H, Hꢀ4), 5.77 (t, J = 9.9 Hz,
1H, Hꢀ2), 5.61 (dd, J1 = 3.2 Hz, J2 = 9.9 Hz, 1H, Hꢀ3), 5.05 (d, J = 9.9 Hz, 1H, Hꢀ1), 4.69ꢀ4.64
(m, 1H, Hꢀ5), 4.48ꢀ4.39 (m, 2H, Hꢀ6); 13C{1H} NMR (100 MHz, CDCl3): δ 166.1, 165.5, 165.4,
165.2, 134.0, 133.6, 133.4, 133.3, 131.2, 130.0, 129.8, 129.8, 128.9, 128.7, 128.6, 128.5, 128.4,
128.3, 85.9, 76.7, 75.1, 73.0, 68.3, 67.8, 62.5; MS (MALDIꢀTOF) for C40H32O10S, calculated m/z
688.05, found m/z 726.987 [M+K]+ 711.013 [M+Na]+.
,
General procedure for the activation of thioglycosides under solventꢀfree conditions
A mixture of the desired benzylated phenyl thioglycoside (for 26, 0.632 g, 1 mmol), the acceptor
alcohol (for 27, 0.310 g, 1.2 mmol) and In(OTf)3 (0.141 g, 0.25 mmol) were allowed to mix in a
stainless steel (SS) jar (capacity, 50 mL) containing SS balls (10 numbers, 10 mm o.d.) for 90
min (or until the reaction was complete: TLC, EtOAc:Hexanes, 1:1) at 500 rpm. The mixture
was taken up in EtOAc and was transferred to a separatory funnel containing crushed ice. The
organic layer was washed successively with cold aq Na2CO3 solution (10%, w/v) and water and
after drying (Na2SO4) was concentrated to dryness under reduced pressure to afford the
respective crude disaccharide that was purified by column chromatography on silica using
EtOAcꢀHexanes (1:4) as eluent.
General procedure for the activation of thioglycosides in solutionꢀphase
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To a solution of the desired benzylated phenyl thioglycoside (for 26, 0.632 g, 1 mmol) and the
acceptor alcohol 27, (0.260 g, 1 mmol) was added NIS (0.225 g, 1 mmol) followed by In(OTf)3
(0.030 g, 0.05 mmol) and the mixture was allowed to stir at rt for 5ꢀ10 min (or until the reaction
was complete: TLC, EtOAc:Hexanes, 1:1). The mixture was diluted with EtOAc and was
transferred to a separatory funnel containing crushed ice. The organic layer was washed
successively with cold aq Na2CO3 solution (10%, w/v) and water and after drying (Na2SO4) was
concentrated to dryness under reduced pressure to afford the respective crude disaccharide that
was purified by column chromatography on silica using EtOAcꢀHexanes (1:4) as eluent.
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1:2,3:4ꢀDiꢀO-isopropylideneꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀDꢀgalactopyranosyl)ꢀαꢀDꢀ
galactopyranose (28α):
Yield 7% (0.045 g); Oil; [ α]D25 +51.0 (c 2 in CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.4ꢀ7.2 (m,
20H), 5.51 (d, J = 5.0 Hz, 1H, Hꢀ1’), 5.00 (d, J = 3.6 Hz, 1H, Hꢀ1), 4.92 (d, J = 11.4 Hz, 1H,
CH2Ph), 4.82 (d, J = 11.7 Hz, 1H, CH2Ph), 4.74ꢀ4.71 (m, 3H, CH2Ph), 4.58ꢀ4.55 (m, 2H, PhꢀH,
Hꢀ3), 4.48ꢀ4.38 (q, J = 11.8 Hz, 2H, CH2Ph), 4.32ꢀ4.28 (m, 2H, Hꢀ4 and Hꢀ2) 4.06ꢀ3.93 (m, 5H,
Hꢀ2, Hꢀ3, Hꢀ4, Hꢀ5, Hꢀ5’), 3.80ꢀ3.70 (m, 2H, Hꢀ6’), 3.58ꢀ3.49 (m, 2H, Hꢀ6); 13C{1H} NMR (100
MHz, CDCl3): δ 139.3, 139.0, 138.8, 128.3, 128.3, 128.2, 127.6, 109.2, 108.6, 97.6, 96.4, 92.0,
79.0, 76.8, 74.8, 73.4, 73.1, 72.7, 70.9, 70.7, 70.6, 69.2, 68.7, 66.4, 30.2, 29.7, 29.6, 29.4; MS
(MALDIꢀTOF) for C46H54O11Na, calculated m/z 782.366, found 821.330 [M+K]+ 805.356
,
[M+Na]+.
1:2,3:4ꢀDiꢀO-isopropylideneꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀβꢀDꢀgalactopyranosyl)ꢀαꢀDꢀ
galactopyranose (28β):
1
Yield 54% (0.42 g); Oil; [ α]D25 ꢀ107.4 (c 1 in CHCl3); H NMR (400 MHz, CDCl3): δ 7.5ꢀ7.2
(m, 20H), 5.58 (d, 1H, Hꢀ1’), 5.06 (d, 1H, CH2Ph), 4.94 (d, 1H, CH2Ph), 4.81ꢀ4.70 (m, 3H,
CH2Ph), 4.62 (d, 1H, CH2Ph), 4.58 (d, 1H, Hꢀ3’), 4.46ꢀ4.39 (m, 3H, CH2Ph, Hꢀ1), 4.33 (dd, 1H,
Hꢀ2’), 4.23 (dd, 1H, Hꢀ4’), 4.14 (dd, 1H, Hꢀ6a’), 4.10ꢀ4.08 (m, 1H, Hꢀ5’), 3.90ꢀ3.89 (m, 1H, Hꢀ
4), 3.85 (dd, 1H, Hꢀ2), 3.72 (dd, 1H, Hꢀ6b’), 3.62ꢀ3.57 (m, 2H, Hꢀ5, Hꢀ3), 3.54ꢀ3.50 (m, 2H, Hꢀ
13
6a, Hꢀ6b), 1.50 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.32 (s, 3H, CH3); C{1H}
NMR (100 MHz, CDCl3): δ 139.2, 138.6, 139.9, 128.6, 128.4, 128.3, 128.1, 127.9, 127.8, 127.5,
109.3, 108.6, 104.7, 96.4, 81.9, 79.1, 76.7, 74.7, 74.5, 73.5, 73.3, 73.1, 71.5, 70.8, 70.5, 69.6,
68.6, 67.4, 29.7, 29.4, 26.0, 25.9, 25.1, 24.4. MS (MALDIꢀTOF) for C46H54O11Na, calculated m/z
782.366, found 805.356 [M+Na]+, 821.330 [M+K]+.
Methyl 2,3,4ꢀtriꢀOꢀacetylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀα/βꢀDꢀgalactopyranosyl)ꢀαꢀDꢀglucoꢀ
pyranoside (30α/β):
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Yield 64% (0.54 g); Oil; H NMR (400 MHz, CDCl3, for 30β): δ 7.41ꢀ7.27 (m, 20H, PhꢀH of
benzyl), 5.48 (t, 1H, Hꢀ3), 5.07 (t, 1H, Hꢀ4), 4.97ꢀ4.85 (m, 3H, CH2Ph, Hꢀ1), 4.84ꢀ4.79 (m, 3H,
CH2Ph, Hꢀ1’,Hꢀ2), 4.77 (d, 1H, CH2Ph), 4.70 (d, 1H, CH2Ph), 4.59 (d, 1H, CH2Ph), 4.45 (d, 1H,
CH2Ph), 4.40 (d, 1H, CH2Ph), 4.07 (bdd, 1H, Hꢀ6a), 4.01ꢀ3.90 (m, 4H, Hꢀ5, Hꢀ6b, Hꢀ2’, Hꢀ4’),
3.77ꢀ3.73 (q, 1H, Hꢀ3), 3.51ꢀ3.47 (m, 3H, Hꢀ5’, Hꢀ6a’, Hꢀ6b’), 3.31 (s, 3H, OCH3), 2.06, 2.05,
2.03 (s, 9H, 3xCOCH3); 13C{1H} NMR (100 MHz, CDCl3): δ 170.1, 169.8, 138.8, 138.7, 138.0,
128.5, 128.4, 128.3, 128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 127.6, 127.5, 127.4, 97.7 (Cꢀ1β),
96.5, 78.6, 75.1, 75.0, 74.7, 73.4, 73.1, 72.9, 71.0, 70.4, 69.6, 69.2, 69.1, 67.9, 66.2, 55.2, 20.8,
20.7, 20.7; MS (MALDIꢀTOF) for C48H58O11Na, calculated m/z 842.351, found 881.315
[M+K]+, 865.346 [M+Na]+.
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2ꢀOꢀ( 2,3,4,6ꢀTetraꢀOꢀbenzylꢀαꢀDꢀgalactopyranosyl) diethyl tartrate (32):
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Yield 36% (0.26 g); Oil; racemate; H NMR (CDCl3, 400 MHz): δ 7.44ꢀ7.22 (m, 20H, PhꢀH),
5.35 (d, J1 = 3.6 Hz, 1H, Hꢀ1), 4.93 (d, 2H, CH2Ph), 4.84 (d, 1H, CH2Ph), 4.73ꢀ4.65 (m, 4H,
CH2Ph, CꢀH of diethyl tartrate), 4.55 (d, 2H, CH2Ph), 4.45 (d, 2H, CH2Ph), 4.38 (d, 2H, CH2Ph),
4.25ꢀ4.21 (m, 3H, COOCH2), 4.10 (dd, J1 = 3.6 Hz, J1 = 10.1 Hz, 1H, Hꢀ2), 4.02ꢀ3.94 (m, 1H,
COOCH2), 3.89 (m, 1H, Hꢀ4), 3.84 (dd, J1 = 2.7 Hz, J1 = 10.1 Hz, 1H, Hꢀ3), 3.68 (bt, 1H, Hꢀ5),
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3.53 (t, 1H, Hꢀ6a), 3.46 (t, 1H, Hꢀ6b), 1.29 (t, 3H, CH3), 1.18 (t, 3H, CH3); C{1H} NMR (100
MHz, CDCl3): δ 171.1, 168.4, 138.8, 138.6, 138.2, 137.9, 128.4, 128.3, 128.2, 128.2, 127.9,
127.8, 127.7, 127.6, 127.60, 127.5, 95.3, 78.0, 77.4, 77.3, 77.1, 76.8, 75.9, 74.9, 74.8, 74.2, 73.5,
73.4, 72.5, 72.4, 70.1, 68.4, 61.9, 61.6, 14.2, 14.1; MS (ESI HRMSꢀTOF) C42H48O11Na,
calculated m/z 751.3094 [M+Na]+, found m/z 751.3094 [M+Na]+.
2,3ꢀDiꢀOꢀ( 2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀDꢀgalactopyranosyl) diethyl tartrate (33):
1
Yield 47% (0.57 g); Oil; racemate; H NMR (CDCl3, 400 MHz): δ 7.49ꢀ7.23 (m, 20H), 5.31 (d,
J1 = 3.4 Hz, 1H, Hꢀ1), 4.98 (t, 2H, CH2Ph), 4.86ꢀ4.80 (m, 3H, CH2Ph, CꢀH of diethyl tartrate),
4.72 (d, 1H, CH2Ph), 4.59 (d, 1H, CH2Ph), 4.49 (d, 1H, CH2Ph), 4.43 (d, 1H, CH2Ph), 4.28ꢀ4.23
(dd, 1H, COOCH2), 4.19 (dd, J1 = 3.4 Hz, J2 = 10.1 Hz, 1H, Hꢀ2), 4.13ꢀ4.08 (m, 1H, COOCH3),
4.04ꢀ4.01 (m, 2H, Hꢀ3, Hꢀ4), 3.97ꢀ3.92 (bm, 1H, Hꢀ5), 3.61ꢀ3.54 (m, 2H, Hꢀ6a, Hꢀ6b), 1.23 (t,
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3H, CH3); C{1H} NMR (100 MHz, CDCl3): δ 168.4, 139.2, 138.8, 138.7, 138.5, 138.1, 138.0,
128.5, 128.4, 128.3, 128.22, 128.21, 128.2, 128.1, 128.1, 127.9, 127.8, 127.6, 127.5, 127.4,
127.3, 127.3, 96.3, 78.8, 75.8, 75.2, 74.8, 74.6, 74.0, 73.7, 73.6, 73.4 73.1, 71.8, 70.1, 68.5, 61.6,
61.3, 14.2; MS (ESI HRMSꢀTOF) C76H82O16Na, calculated m/z 1273.5501 [M+Na]+, found m/z
1273.5500 [M+Na]+.
Computational Details: The monomeric geometries were optimized using the dispersionꢀ
corrected semiꢀempirical PM3ꢀD method,27 using the G09 package.28 All the other geometries
were optimized using PM3ꢀD method. This method has been reported to be helpful, reliable and
applicable in the optimization studies of large molecules, and save considerable computing time.
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PM3ꢀD method incorporates dispersion effects, used to model hydrophobic and dispersion
interactions, at reduced computational expense. The detailed studies using PM3ꢀD method
provides insights into the structural details of dimers, polymeric structures and supramolecular
systems. Initially, the geometry optimizations of monomers, 10α and 10β, were computed. These
optimized geometries were employed for the dimerꢀconstruction and thereafter, the dimers were
optimized. The dimerization energies were also calculated for both the anomers. The optimized
geometries of dimers were utilized for the construction of the tetramers, and further optimized.
The optimized tetrameric geometries of 10α and 10β provide a clear depiction of the
arrangement, which was correlated with TEM analysis. The energy and geometric parameters
used in the discussion are based on PM3ꢀD method unless otherwise specifically mentioned.
Single point calculations were carried out on the two monomers of 10α and 10β using B3LYP/3ꢀ
21G method.29
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ACKNOWLEDGEMENTS
Vajinder Kumar sincerely acknowledges the award of a Research Fellowship by CSIRꢀUGC,
New Delhi, India. NT thanks Department of Science and Technology (DST), New Delhi for
DSTꢀInspire Fellowship. NT also thanks Mr. Chaitanya Jaladanki for his timely help and
suggestions.
SUPPORTING INFORMATION AVAILABLE: Experimental procedures, compound
characterization data, and computational details are available free of charge via the Internet at
http://pubs.acs.org.
REFERENCES:
(1) a) Giri, S. K.; Verma, M.; Kartha, K. P. R. J. Carbohydr. Chem. 2008, 27, 464. b)
Mattison, A. L.; Michel, A. K.; Colinger, M. J. Carbohydrate Res. 2012, 347, 142. c)
Bizir, N. P.; Atkins, S. R.; Helland, L. C.; Colvin, S. F.; Twitschell, J. R.; Cloniger, M. J.
Carbohydrate Res. 2008, 343, 1814.
(2) a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025. b) Mugunthan, G.; Kartha, K. P. R.
Trends Carbohydr. Res. 2009, 1, 1. c) Wang, G. W. Chem. Soc. Rev. 2013, 42, 7668. d)
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