In(III) triflate-catalyzed detritylation and glycosylation by solvent-free ball milling

Article abstract of DOI:10.1016/j.carres.2014.08.002

A highly efficient In(III) triflate-assisted method for the detritylation of O-trityl derivatives of carbohydrates, phenols, and alcohols using solvent-free mechanochemical method is described. In the case of carbohydrates, further reaction in the presence of an acceptor sugar leads to highly efficient glycosylation in the same pot resulting in the formation of the desired glycoside-product in very high yields. The method was applied successfully to the synthesis of a combinatorial library of galactose-based (1,6)-linked cyclohexa-, hepta-, and octasaccharides on gram scale.

Full text of DOI:10.1016/j.carres.2014.08.002

Carbohydrate Research 397 (2014) 18–26
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
In(III) triflate-catalyzed detritylation and glycosylation
by solvent-free ball milling
⇑
Vajinder Kumar, Narender Yadav, K. P. Ravindranathan Kartha
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2014
Received in revised form 1 August 2014
Accepted 2 August 2014
Available online 10 August 2014
A highly efficient In(III) triflate-assisted method for the detritylation of O-trityl derivatives of carbohy-
drates, phenols, and alcohols using solvent-free mechanochemical method is described. In the case of car-
bohydrates, further reaction in the presence of an acceptor sugar leads to highly efficient glycosylation in
the same pot resulting in the formation of the desired glycoside-product in very high yields. The method
was applied successfully to the synthesis of a combinatorial library of galactose-based (1,6)-linked cyclo-
hexa-, hepta-, and octasaccharides on gram scale.
Keywords:
Detritylation
Ó 2014 Elsevier Ltd. All rights reserved.
Glycosylation
Solvent-free mechanochemistry
Ball milling
Indium triflate
1. Introduction
(1), it was observed that detritylation occurred prior to the activa-
tion of the thioglycoside residue (Scheme 1) as a result of which
In the recent years In(III) triflate has found wide acceptance as a
Lewis acid over a broad range of organic reactions.1–14 Acylation of
alcohols, phenols, and amines catalyzed by this metal salt was
reported by Frost and co-workers in 1999.1 The excellent catalytic
efficiency observed in these reactions, it appears, not only
prompted them to take a stock of the literature on the applications
of In(III) salts (the triflate and the halides) soon afterward2 but also
led them to find new applications of the catalyst, alone3 and in com-
bination with other metal catalysts.4 The fact that the applications
of indium salts known until that period were not very many can be
seen from the published reviews of that time.5,6 However,
applications of In(III) halides in organic reactions such as transeste-
rification (by InI3),7 rearrangement of epoxides (by InCl3),8 etc were
already recognized.6 Some of the applications of this triflate salt
that have been noted since include intramolecular Diels–Alder
reactions,9 tetrahydropyranylation (and detetrahydropyranylation)
of alcohols,10 ring opening of aziridines,11 conversion of aldehydes
to acylals/acetals,12,13 and in various reactions of carbohydrates.14
More recently we had found that it is an efficient catalyst not only
for the preparation of thioglycosides but also for the activation of
armed thioglycosides for O-glycosylations under solvent-free mech-
anochemical conditions.15 In one of the latter class of reactions in
which the thioglycoside employed had a trityl protection present
not only that the expected (1,6)-linked disaccharide derived from
1 and 2 was obtained but also several possible oligomeric products
originating from 1 were isolated as a mixture. Upon carrying out the
reaction for short durations of grinding, however, only 3 was
observed in the isolated product. This led us to consider exploring
the possibility of exploiting this observation for its development
into a feasible method for detritylation. In view of the increasing
importance of solvent-free mechanochemical reactions in the con-
text of green chemistry, as well, this work was considered reward-
ing.16 Thus, its potential for preparing oligosaccharide library was
also investigated and the results are reported hereunder.
2. Results and discussion
The per-O-acetylated methyl 6-O-trityl-glucoside 4 was chosen
as the model substrate for the optimization of the reaction condi-
tions. In(OTf)3 at a level of 25 mol% was used and the reaction was
carried out mechanochemically in a ball mill under solvent-free
conditions. The results are tabulated in Table 1. At In(OTf)3 concen-
trations less than 25 mol% the reaction did not go to completion
even at 550 rpm in the planetary ball mill. In the planetary ball mill
the best results were obtained when the reaction was carried out
for 3.5 h at 550 rpm using 25 mol% of In(OTf)3. When reactions
were carried out in a vibratory ball mill the same results could
be achieved in 15 min at 30 Hz using In(OTf)3 at 25 mol% level.
⇑
Corresponding author. Fax: +91 172 2214692.
E-mail address: rkartha@niper.ac.in (K.P.R. Kartha).
http://dx.doi.org/10.1016/j.carres.2014.08.002
0008-6215/Ó 2014 Elsevier Ltd. All rights reserved.

V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
19
OTr
O
As excellent results were obtained in the above case, the reac-
tion was also carried out in the conventional manner in solution-
phase for comparison. A range of solvents, halogenated (CH2Cl2),
polar protic (MeOH), and polar non-protic (MeCN, THF) as often
employed in the literature methods were chosen for the study
and the observations are summarized in Table 2. In neat MeOH,
it was observed that, formation of a mixture of compounds with
polarity much higher than that of the desired 5 accompanied
(entry 1, Table 2). This was attributable to the possible Lewis acid
[In(OTf)3]-catalyzed transacetylation (random), MeOH serving as
the acyl acceptor. (It may be recalled that transesterification cata-
lyzed by InI3 in alcohol is known.7) Further, it was observed that
although no appreciable (or none at all) reaction took place in neat
solvents such as CH2Cl2, THF, or MeCN (entries 2, 3, and 6, Table 2),
in the presence of MeOH as a co-solvent detritylation did proceed
significantly better such that in a mixture of CH2Cl2/MeOH, 8:2 or
MeCN/MeOH 9:1 (entries 5 and 9, Table 2) it was complete in 6 h
and 30 min, respectively, though acetyl migration accompanied
in both cases. This has indeed been a limitation of majority of
the methods reported in the literature (see below). It is also not
surprising that, compared to the mechanochemical solvent-free
conditions; the acyl migration is facile in solution-phase particu-
larly under acidic conditions. Our observations on the acetyl migra-
OH
O
BnO
BnO
SPh
BnO
BnO
SPh
OBn
OBn
1
In(OTf)3 (25 mol%)
3
O
PM 100
550 rpm
OH
O
Di- to oligomeric
products from
O
O
1 1 2
/ and
O
2
Scheme 1. Attempted activation of an armed thioglycoside bearing
protecting group for O-glycosylation.
a trityl
Table 1
Standardization of the reaction conditions for solvent-free mechanochemical det-
ritylation
OTr
OH
O
AcO
AcO
In(OTf)3 (25 mol%)
Aqueous work-up
O
AcO
TrOH
+
AcO
AcO
4
AcO
OMe
OMe
5
Entry
Ball milling conditionsa,b
Remarks
(yield of 5, %)
tion
frequently
encountered
during
the
process
of
Ball mill
No. of balls
(size, mm)
Speed
(rpm)
Time
(h)
chromatographic purification of such partially protected sugar
derivatives as 5 on silica are also consistent with this inference.
Clearly the advantage of the mechanochemical method is evident.
It was also noted during the monitoring of these reactions by
TLC that the major by-product obtained in the reactions where
1
2
3
4
5
6
Planetary
Planetary
Vibratory
Vibratory
Vibratory
Vibratory
10 (10)
10 (10)
2 (10)
5 (3)
10 (3)
20 (3)
550
450
30 Hz
30 Hz
30 Hz
30 Hz
3.5
>6
0.25
0.5
<0.25
<0.25
Neat (>95)
Incomplete (70%)
Neat (>95)
Neat (>95)
Neat (>95)
MeOH was
a co-solvent was a compound moving faster
Neat (>95)
(Rf = 0.89, EtOAc/Hex, 0.5:9.5) than the expected by-product,
namely, TrOH (Rf = 0.28, EtOAc/Hex, 0.5:9.5) which was also pres-
ent in the reaction mixture but as a minor by-product. It was felt
that perhaps MeOH present in the reaction mixture acted as an
acceptor for the tritylium cation released from the sugar upon tri-
tyl deprotection and therefore leading to the formation of methyl
trityl ether. The observations on the Rf values obtained for the
by-products are in accordance with this. In order to confirm this
speculation the faster moving non-carbohydrate by-product was
isolated by chromatography and was subjected to structure eluci-
dation by NMR and MS analyses. The analytical data obtained for
the compound were indeed in agreement in all respects with that
a
A mixture of 4 (1 mmol) and In(OTf)3 (25 mol%) was ground in the mill under
the conditions shown in table.
b
At 10 or 20 mol% of the triflate the reaction did not go to completion for up to
4 h of reaction at 550 rpm in the planetary ball mill.
Importantly, in none of the cases were any acyl-migratory (O-4 to
O-6 migration) by-products detected which often is the case in the
conventional method using aqueous HOAc. Formation of the 6-O-
acetate (another by-product arising out of acetolytic cleavage of
the trityl ether) typical of the latter method is also not encountered
under the conditions of the current methodology.
Table 2
a
Observations on the solution-phase detritylation of 4 using In(OTf)3
Entry Solvent system
Time (h)
1
Comments
Observationsb
1
2
3
4
5
6
7
8
9
MeOH
Separate reactions using 5, 15, 25, and
50 mol% In(OTf)3 were performed
Separate reactions using 5, 15, 25, and
50 mol% In(OTf)3 were performed
Separate reactions using 5, 15, 25, and
50 mol% In(OTf)3 were performed
Reaction was performed using 25 mol%
In(OTf)3
Reaction was performed using 25 mol%
In(OTf)3. Complete reaction occurred
Reaction was performed using 25 mol%
In(OTf)3
Reaction was performed using 25 mol%
In(OTf)3
Reaction was performed using 25 mol%
In(OTf)3
Reaction was performed using 25 mol%
In(OTf)3
Degradation of the starting material leading to a mixture of
products occurred
No reaction occurred
MeCN
Up to 24
Up to 24
6
CH2Cl2
Deprotection up to 10–15%, 20%, 60%, and 80%, respectively, was
observed. Acetyl migration-product accompanied in each case
Deprotection up to 90% was observed. Acetyl migration product
accompanied
CH2Cl2–MeOH (9:1)
CH2Cl2–MeOH (8:2)
THF
6
Acetyl migration product accompanied
Up to 24
Up to 24
Up to 24
30 min
No reaction occurred
THF–MeOH (9:1)
THF–MeOH (8:2)
MeCN–MeOH (9:1)
Deprotection up to 30% was observed. Acetyl migration product
accompanied
Deprotection up to 40% was observed. Acetyl migration product
accompanied
Complete reaction occurred. Acetyl migration product accompanied
a
A mixture of 4 (1 mmol) and In(OTf)3 was taken up in the solvent system specified in the Table and was stirred at rt and the reaction was monitored by TLC.
Product(s) arising from acetyl migration, wherever observed, had been to an extent of 5–10% of the detritylated product which however increased on continuing the
b
reaction beyond the required time period or leaving the material in solution.

20
V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
Table 3
Comparison of solvent-free mechanochemical detritylation of 4 using various metal triflatesa and other indium salts
Entry
Triflate
Time
Inference
1
2
3
4
5
6
7
8
9
Sc(OTf)3
Sm(OTf)3
Mg(OTf)2
Zn(OTf)2
Cu(OTf)2
Al(OTf)3
In(OTf)3
TBAOTf
InBr3
Up to 115 min
Up to 115 min
Up to 115 min
Up to 115 min
Up to 30 min
15 min
Compound 4/5 = 2:3 was obtained indicating 60% completion. Traces of acetyl migration product formed
Compound 4/5 = 7:3 was obtained indicating 30% conversion
Compound 4/5 = 8:2 was obtained indicating 20% conversion
Compound 4/5 = 5.5:4.5 was obtained indicating 55% conversion
Compound 4/5 = 2:3 was obtained indicating 60% conversion
Compound 4/5 = 0:100 was obtained indicating 100% conversion. Yield, >95%
Compound 4/5 = 0:100 was obtained indicating 100% conversion. Yield, >95%
Compound 4/5 = 1:1 was obtained indicating 50% conversion
Compound 4/5 = 3:2 was obtained indicating 40% conversion
Compound 4/5 = 0:100 was obtained indicating 100% conversion. Yield, >95%
No reaction
15 min
Up to 45 min
Up to 45 min
45 min
Up to 45 min
Up to 45 min
10
11
12
InCl3
InF3
In(ClO4)3
Compound 4/5 = 1:9 was obtained indicating 90% conversion
a
A mixture of 4 (1 mmol) and Mx(OTf)y (25 mol%) was ground in a SS bowl using SS balls (2, 10 mm) in a vibratory ball mill at 30 Hz.
of MeOTr. Thus, the 1H NMR spectrum of the compound showed a
singlet at 3.12 ppm and a set of three multiplets between 7.26 and
7.53 ppm with 1:5 proton ratio, overall in accordance with OCH3/
(C6H5)3C. The observations on the formation of MeOTr in the trityl
deprotections described above also lend support to the proposed
mechanism of the reaction (see later).
In the light of the foregoing observations the In(OTf)3-mediated
detritylation could be rationalized as shown in Scheme 2. The
interaction of the lone pair of electrons on the trityl ether-oxygen
in the derivative 27 with In(III) can be considered to culminate in
the formation of the metallated salt 28 initially and thereafter to
the tritylium alcoholate 29. The latter during the aqueous work-
up gets quenched with water to yield the deprotected alcohol.
The by-product trityl alcohol expected thereupon could indeed
be isolated in an actual experiment. Further, when the trityl depro-
tection was attempted in the presence of an equivalent quantity of
18-crown-6, with which the metal center is expected to coordi-
nate, the reaction was extremely sluggish and only small traces
of the detritylated product were seen formed in the first half-hour
period of the reaction. Complete reaction took place in the control
experiment held in the absence of the crown ether, thus demon-
strating the definite role of the metal center. Moreover, the isola-
tion of MeOTr as a by-product from the detritylation reactions in
the conventional manner in which MeOH was a co-solvent also
lends support to the above contention.
As the detritylation reactions reported above were found to take
place neat, a subsequent reaction of the hydroxyl group so gener-
ated with an activated glycosyl donor that could be introduced
subsequently must in principle be possible. In order to validate this
point, an armed thioglycoside donor 31 was added to the milling
bowl on completion of detritylation of 4 and the grinding was con-
tinued for 2 h (Scheme 3). Examination of the reaction mixture
revealed formation of the disaccharide product. After a quick aque-
ous work-up and purification of the product by chromatography on
A comparative study on the applicability of other metal triflates
used in various organic transformations with that of In(III) triflate
was subsequently held and the results are summarized in Table 3.
Among the various metal triflates examined only Al(OTf)3 and
In(OTf)3 were found suitable and were equally effective. The
organic triflate, TBAOTf was also found not suitable for the
purpose. Hence In(OTf)3 which is marginally cheaper and less sen-
sitive to air and moisture compared to Al(OTf)3 was chosen as the
reagent of choice for further investigations. Among the other
indium salts evaluated were the halides (InBr3, InCl3, and InF3)
and the perchlorate [In(ClO4)3] (entries 9–12, Table 3). The results
showed that among these, the chloride, though compared to the
triflate the reaction took slightly longer time for completion, was
effective for the purpose. Thus, although In(OTf)3 was proved
advantageous for the solvent-free mechanochemical de-O-trityla-
tion, these experiments do suggest that the catalytic activity is
not unique to In(OTf)3; and that there could be other metal salts
(Lewis acids) other than those investigated in this work that may
also prove effective for the purpose.
A comparison of the current method with those reported in the
literature for de-O-tritylation was then made (Table 4). Most of the
cases, as can be seen from the table, suffer from one or the other
draw backs such as low tolerance to acid-sensitive groups and
by-product formation arising therefrom as well as due to acyl
migrations in cases where neighboring acyl groups are present,
requirement of reflux temperatures/anhydrous conditions, long
reaction times, etc. The present method seemed to be free from
most such limitations. In view of this, the work was extended to
a set of other substrates as well.
silica 32 was obtained in 64% yield as a mixture of
a- and
b-anomers in the ratio 1:1.2. To examine the stereochemical out-
come of the glycosylation reaction during its initial stages, the
reaction mixture after 1 h of grinding was subjected to aqueous
workup. Chromatographic analysis of the mixture revealed that
approximately 45% of the starting materials had been consumed
in that time. The disaccharide 32 was obtained in 40% isolated
Thus, trityl derivatives of carbohydrates bearing (i) neighboring
acyl substituent other than acetyl (6), (ii) acid-sensitive acetonide
(acetal) group (8), (iii) ether protection (10), (iv) ester protection in
an amino acid (12), and (v) a thioglycoside residue (on a mono-/
disaccharide, 14/16) as shown in Figure 1 were chosen for the
study. In all cases the trityl deprotection could be successfully per-
formed in excellent yields. The 50-O-tritylated/dimethoxytritylated
nucleosides (18 and 20, respectively, Fig. 1) also underwent the
desired reaction under the optimized conditions very effectively.
The trityl derivatives of non-carbohydrate substrates such as tyro-
yield and was a 1:4 mixture of
the end of the 2 h reaction, during which complete consumption
of the starting materials had taken place, the disaccharides 32
and 32b obtained were in the ratio 1:1.2, the combined yield of
the disaccharides being 64%. This was clearly suggestive of the
in situ anomerization of the inter-glycosidic linkage in the disac-
charide catalyzed by the metal triflate.
Based upon the above results our next attempt was to subject
the 6-O-trityl-protected phenyl thioglucoside 14 to grinding in
the ball mill in the presence of In(OTf)3 and examine the scope of
the reaction for generating a library of 1,6-linked galacto-oligosac-
charides of varying degree of oligomerization. Thus, compound 14
was homogenized in the ball mill at 550 rpm in the presence of
a- and b-anomers. However, at
a
sine and a-naphthol (phenolic oxygen-centered, 21 and 23) as well
as cyclopentanol (25, Fig. 1) also could be detritylated equally
successfully.

V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
21
Table 4
A comparison of the current method with the methods reported in the literature
Entry Reaction conditions
Comments
Lit.
17
Reagent
BCl3
Temp
(°C)
Solvent used
CH2Cl2
Time (h)
0.5
1
ꢀ30
Use of halogenated solvent and highly reactive reagent requiring strictly
anhydrous conditions
2
3
4
CuSO4
CBr4
CBr4-Photo-irradiation
Reflux Benzene
Reflux MeOH
5
1–5
8
Use of carcinogenic solvent and requirement of reflux temperature
Use of halogenated reagent and requirement of reflux conditions
Use of halogenated reagent, requirement of anhydrous conditions, and
relatively long reaction time
18
19
20
rt
Anhydrous MeOH
5
6
7
CAN
Ce(OTf)4
R2AlCl (10–20 equiv)
rt
rt
rt
MeCN
MeCN
Toluene, hexane and
CH2Cl2
9
2
0.1
Use of hazardous solvent and relatively long reaction time
Use of hazardous solvent
Use of halogenated solvent and aggressive reagent requiring strictly
anhydrous conditions
21
22
23
8
HCOOH
rt
Diethyl ether
0.75
Cleavage of acid-sensitive groups such as acetonide and hence cases of
poor yields
24
9
10
InBr3
I2/MeOH
Reflux MeCN–H2O
60 MeOH
3
6
Use of hazardous solvent and requirement of reflux conditions
Deprotection of acid-sensitive protecting groups such as acetonide, 4-
MeO-Bn, and TBDMS and hence cases of poor yields
Use of carcinogenic solvent, requirement of reflux temp, and very long
reaction time
Use of halogenated solvent; poor solubility of reagent in such solvents,
hence requirement of co-solvent
Use of halogenated reagent and solvent
25
26
11
12
MgBr2
ZnBr2
Reflux Benzene
7 days
0.1
27
28
29
rt
CH2Cl2, H2O or MeOH
13
14
IBr
TFA
rt
rt
CH2Cl2–MeOH (9:1)
i-BuOH–TFA
0.05
0.05–0.5
Cleavage of glycosidic bonds/other acid-sensitive groups and hence cases 30
of low yields
15
TESOTf or TMSOTf
rt
CH2Cl2
0.05–1
Highly corrosive reagent; use of halogenated solvent; cleavage of
glycosidic bonds and hence cases of low yields
Cases of low yields
31
16
17
Yb(OTf)3
HClO4 supported on
silica
rt
rt
THF
MeOH
4
2
32
Cleavage of acid-sensitive protecting groups and hence cases of low yields 33
18
19
20
Nafion-H
rt
rt
rt
MeOH
10
Requirement of relatively long reaction time; acetonide deprotection; low 34
yields
NaHSO4 supported on
Silica
HBr/AcOH
CH2Cl2–MeOH (9:1)
CH2Cl2
2–2.5
Use of halogenated solvent
35
A few min
Use of corrosive reagent; cleavage of acid sensitive groups possible, and
hence cases of low yields
36
21
22
AcOH
In(OTf)3
Reflux AcOH
2
0.25
By-product formation and hence cases of low yields
Solvent-free; relatively short reaction time; high yield
37
—
Ball
mill
None
In(OTf)3 (Scheme 4). The product mixture obtained after the aque-
ous workup was purified by GPC on HW-40S matrix. The fractions
collected were analyzed by MALDI-TOF-MS (Fig. 2). The molecular
mass of the largest oligomer (eluted first) matched well with that
of an octasaccharide unit that had lost one molecule of water and
thus corresponded precisely to a cyclic octasaccharide of structure
39 (Fig. 3). The first six daughter ions derived from the parent com-
pound (39, see Table 5) as seen in the spectra (Fig. 2) when analyzed
it revealed that they corresponded well with those with successive
loss of 1–6 units of benzyl groups from the parent molecular ion
([M+NaꢀnBn]+, n being the number of benzyl group(s) lost and is
equal to a number between 1 and 6). Similar was the case for the
oligosaccharides 35–38, all being in complete agreement with their
respective cyclic structures as shown in Figure 3. As cyclodextrins
are well known to form aggregates in solutions,38 it was felt inter-
esting to look for the structures of any possible aggregates formed
by these modified (benzylated) analogs by TEM. Thus, when the
cyclooctamer 39 as a representative member was examined by
TEM, the images obtained were indeed confirmative of aggregation
to yield cyclic structures (Fig. 4A). The confirmation of the forma-
tion of cyclic aggregates was obtained from the HAADF-STEM
images recorded on the sample (Fig. 4B). The contrasting images
that can be seen in Figure 4A and B clearly demonstrate the cyclic
structure for the aggregates formed.
both the compounds as drawn in Figure 3. In all the six cases (that
is, compounds 33–39) concluding the structural assignment with
the assignment of the configuration of the inter-glycosidic linkages
was proved impossible from the NMR spectroscopic data. This was
because of the fact that, although the compounds were homoge-
neous with respect to their respective molecular weights,39 they
were mixtures of isomeric compounds arising out of the differ-
ences in the anomeric configuration between the pairs of adjacent
sugar units. As each of the inter-glycosidic linkage has two possible
configurations and each additional glycosidic bond when added
gives rise to increasing number of possible isomers, it is not sur-
prising that the NMR spectra of these compounds were extremely
complex. Thus, although we could scale up the reaction success-
fully and apply on gram scale to produce significant quantities of
compounds 33–39, all were proved to be mixtures of anomers (a
combinatorial library) by NMR spectroscopy.
In conclusion, solvent-free mechanochemical method catalyzed
by In(OTf)3 has been found to be highly effective for the
de-O-tritylation of trityl ethers of carbohydrates, amino acids, alicy-
clic alcohols, and phenols. Unlike in some of the solution-phase reac-
tions known in the literature no by-products arising out of acetyl
migration, over acetylation, etc. were encountered in the solvent-
free method presented here. The method works with better effi-
ciency when carried out on preparative scale. The reaction could
be extended successfully to generate a combinatorial library of
cyclicoligosaccharides on gram scale. However, in the case ofthe lat-
ter although they are homogeneous with respect to their size, the
limitation is that they are mixtures of anomers.
In contrast, the disaccharide 33 and the trisaccharide 34 were,
as to be expected, not in the cyclized form. In these two cases their
respective molecular ion mass as well as those of the derived
daughter ions all corresponded well with the linear structures for

22
V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
OR
BnO
O
OR
OR
OR
O
O
O
BzO
BzO
O
FmocHN
CO2Me
95%
BnO
OBz
BzO
O
BnO
OMe
98%
O
12 R = Tr
6
R = Tr
R = H
10 R = Tr
13
R = H
98%
7
11
R = H
8
R = Tr
9 R = H
93%
HO
BzO
BzO
OR
O
BnO
BnO
OH
O
N
O
SPh
OR
O
HN
BnO
R = Tr
R = H
OR
18 R = Tr
19 R = H
R = DMTr
BzO
94%
93%
14
O
97%
15
20
BnO
BnO
O
O
OR
OR
SPh
OR
BnO
R = Tr
R = H
16
17
95%
25
23 R = Tr
24 R = H
R = Tr
96%
95%
FmocHN
CO2Me
26 R = H
21
22
R = Tr
R = H
96%
Figure 1. Structures of tritylated compounds subjected to mechanochemical solvent-free detritylation.
In(OTf)3,
18-Crown-6
3. Experimental
3.1. General
Only traces
of 30 was
formed
R
Tr
O
27
All the reagents were used as purchased without further
purification. Solvents used for reactions were dried according to
standard methods. Reactions were performed employing either a
planetary ball mill (PM 100, Retsch Gmbh, Germany) using stain-
less steel (SS) jar (capacity, 50 mL) containing SS balls (10 num-
bers, 10 mm o.d.) or a mixer mill (MM 400, Retsch Gmbh,
Germany) using SS jar (capacity, 10 mL) containing SS balls (20
numbers, 3 mm o.d.). Reactions were monitored by TLC, which
was performed with 0.2 mm pre-coated silica gel 60 F254 alumi-
num sheets. Compounds were detected by dipping the TLC plates
in ethanolic solution of sulfuric acid (5% v/v) and thereafter heating
them. Melting points were determined on a melting point appara-
tus. Specific rotations were recorded on a digital Polarimeter at
room temperature (approximately 20–25 °C). NMR spectra were
recorded on 400 MHz spectrometer. 1H NMR and 13C NMR spectra
were referenced using either residual solvent signals, or tetrameth-
ylsilane in the respective deuterated solvents. 1H–1H COSY and
1H–13C HMQC were used to confirm the NMR peak assignment.
Splitting patterns are described as singlet (s), doublet (d), triplet
(t), quartet (q), and broad (br); the values of chemical shifts (d)
are given in ppm and coupling constants (J) are reported in Hertz
(Hz). Mass spectra were recorded on MALDI-TOF/TOF and
HRMS-TOF Spectrometers.
In(OTf)3
δ-
In(OTf)3
In(OTf)
3 CPh3
via
R
O
R
O
δ+
28
Tr
H2O (aq. workup)
R
OH
30
R
O CPh3
29
TrOH
Scheme 2. Possible mechanism for the In(OTf)3-mediated detritylation.
OTr
O
AcO
AcO
AcO
OMe
4
(i) In(OTf)3 (25 mol%), Ball
mill (2 h, 550 rpm, PM-100)
(ii) In(OTf)3 (5 mol%), Ball mill
(2 h, 500 rpm, PM-100)
BnO
OBn
O
3.2. General procedure for the solvent-free detritylation
SPh
BnO
BnO
BnO
OBn
O
Method A—using a planetary ball mill: The tritylated compound
(1 mmol; typically 563 mg for 4) and In(OTf)3 (141 mg, 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 3.5 h (TLC,
EtOAc:Hex, 1:1 for 4) in a planetary ball mill (PM-100) at
550 rpm. EtOAc was added to the reaction mixture and the solu-
tion was transferred to a separatory funnel (50 ml ꢁ 3). It was then
washed successively with aq Na2CO3 solution (10%, w/v, 50 ml ꢁ 2)
and water (50 ml), dried (Na2SO4), and concentrated under
reduced pressure to afford the respective crude de-O-tritylated
BnO
31
O
BnO
AcO
O
AcO
AcO
OMe
32
(
64%; a-/b- = 1/1.2
)
Scheme 3. One-pot detritylation and glycosylation by solvent-free mechanochem-
ical method.

V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
23
BnO
BnO
(capacity, 50 mL) containing SS balls (10 numbers, 10 mm o.d.)
for 2 h in a planetary ball mill (PM-100) at 550 rpm. The desired
glycosyl donor (1 mmol, typically, 633 mg for 31) and In(OTf)3
(30 mg, .053 mmol) were then added to the same pot and the
grinding was continued for another 2 h. EtOAc was then added to
the reaction mixture. The solution was then washed successively
with aq Na2CO3 solution (10%, w/v) and water, dried (Na2SO4),
and was concentrated under reduced pressure to afford the corre-
sponding crude disaccharide that was purified by column chroma-
tography on silica using EtOAc–Hex as the eluent. Yield, 540 mg,
OTr
O
SPh
BnO
14
(i) In(OTf)3 (25 mol%), Ball
mill (4 h, 550 rpm, PM-100)
BnO
O
BnO
BnO
O
O
64%, for 32 (a/b = 1:1.2) from 4 and 31. The spectral data were in
accordance with the expected structure and in agreement with
the literature values.
H
O
OH
+
BnO
n
BnO
BnO
n
35 n = 4; 36 n = 5;
37 38
33
n = 2
n = 6;
39 n = 8
n = 7;
34 n = 3
3.4. General procedure for the solvent-free one-pot
detritylation and cyclooligomerization: preparation of
compounds 33–39
Scheme 4. Indium triflate-mediated solvent-free mechanochemical synthesis of
oligomeric 1,6-linked galacto-oligosaccharides.
The tritylated compound (2.55 mmol; typically 2 g for 14) and
In(OTf)3 (360 mg, 0.64 mmol) were ground in a SS jar (capacity,
50 mL) containing SS balls (10 numbers, 10 mm o.d.) for 4 h in a
planetary ball mill (PM-100) at 550 rpm. The reaction mixture that
was then taken up in EtOAc was then washed successively with aq
Na2CO3 solution (10%, w/v) and water in a separatory funnel. It was
then dried (Na2SO4), and was concentrated under reduced pressure
to afford the corresponding crude cyclooligomeric products that
were purified by GPC (Gel Permeation Chromatography) on
HW-40S resin using CH2Cl2–MeOH (1:1) as the eluent [(i) Using a
chromatographic equipment: Column, 100 cm (h) ꢁ 2.5 cm (d);
flow rate, 12.5 ml/min; fraction size 300 drops on Spectrum/Chrom
CF-2 fraction collector from Spectrum Chromatography, Houston
USA; or (ii) Manual: Column, 150 cm (h) ꢁ 3.0 cm (d); flow rate
1.0 ml/min by gravity; fraction size 6 ml]. The characterization of
compounds (33–39) was done by MALDI-TOF/TOF (Tabulated in
Table 5) and TEM imaging. Yield, calculated on the basis of the
monomer unit: 39, 76 mg, 7%; 38, 83 mg, 8%; 37, 127 mg, 12%;
36, 178 mg, 16%; 35, 161 mg, 15%; 34, 127 mg, 12%; and 33,
144 mg, 13% (total, 83%).
product. The crude product was purified by flash chromatography
to free it from the by-product, TrOH (yield, 305 mg, 95.2%, for 5
from 4). It was crystallized from diethyl ether-n-Hex to obtain ana-
lytically pure product. The spectral data were in accordance with
the expected structure and in agreement with the literature values.
Method B—using a vibratory ball mill: The tritylated compound
(1 mmol; typically 563 mg for 4) and In(OTf)3 (141 mg, 0.25 mmol)
were allowed to mix in a SS jar (capacity, 10 mL) containing SS
balls (20 numbers, 3 mm o.d.) for 15 min (TLC, EtOAc/Hex, 1:1 in
the case of 4) in a vibratory ball mill (MM-400) at 30 Hz. The
workup and isolation of the product were carried out as described
in Method A above. Yield, 308 mg, 96.2% for 5 from 4.
3.3. General procedure for the solvent-free one-pot
detritylation and glycosylation
The tritylated compound (1 mmol; typically 563 mg for 4) and
In(OTf)3 (141 mg, 0.25 mmol) were allowed to mix in a SS jar
Cyclooctasaccharide 39
Cycloheptasaccharide 38
Cyclohexasaccharide 37
Cyclopentasaccharide 36
Cyclotetrasaccharide 35
Figure 2. MALDI-TOF-MS spectra of the cyclooligosaccharide fractions (compounds 35–39) obtained on chromatographic separation of the product mixture by GPC.

24
V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
BnO
OH
BnO
BnO
OBn
OBn
O
OBn
O
O
O
HO
O
O
O
O
OH
OH
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
34
BnO
O
33
O
O
OBn
O
BnO
O
O
OBn
OBn
OBn
O
O
OBn
O
BnO
OBn
BnO
BnO
BnO
O
BnO
O
O
BnO
BnO
BnO
OBn
OBn
O
O
O
BnO
OBn
BnO
OBn
BnO
O
BnO
36
37
35
BnO
O
BnO
OBn
OBn
OBn
BnO
OBn
OBn
O
O
O
O
OBn
BnO
BnO
OBn
OBn
BnO
O
OBn
O
BnO
BnO
O
O
O
O
O
BnO
O
OBn
OBn
OBn
O
O
OBn
OBn
O
O
O
O
BnO
BnO
O
O
OBn
O
OBn
39
O
BnO
BnO
BnO
OBn
BnO
OBn
BnO
BnO
BnO
BnO
O
O
O
OBn
O
OBn
BnO
BnO
BnO
BnO
38
O
O
O
BnO
BnO
BnO
OBn
OBn
O
O
O
O
OBn
OBn
OBn
OBn
O
OBn
OBn
BnO
BnO
OBn
OBn
OBn
BnO
BnO
OBn
O
OBn
BnO
O
O
O
O
O
O
O
O
BnO
OBn
Figure 3. Structures of the oligosaccharides obtained on mechanochemical solvent-free reaction of 14 in the presence of In(OTf)3 and the transmission electron micrograph
obtained for compound 39.
Table 5
Comparison of the MW of some daughter ions formed from 33 to 39 on MALDI-TOF-MS and its correlation with loss of increasing number of Bn protecting groups in the respective
molecule*
Entry ?
1
2
3
4
5
6
7
Fragment(s) lost ?
1ꢁ Bn
2ꢁ Bn
3ꢁ Bn
4ꢁ Bn
5ꢁ Bn
6ꢁ Bn
7ꢁ Bn
DP = 8 (Cyclic)
DP = 7 (Cyclic)
DP = 6 (Cyclic)
DP = 5 (Cyclic)
DP = 4 (Cyclic)
DP = 3 (Linear)
DP = 2 (Linear)
MW+Na+ 3483.1
C
F
C
F
C
F
C
F
C
F
C
F
C
F
3391.9
3393.6
2959.4
2960.5
2526.1
2527.6
2094.4
2094.1
1661.9
1660.4
1247.3
1245.5
814.9
3300.8
3303.3
2868.3
2871.2
2435.8
2438.4
2003.3
2003.3
1570.8
1571.0
1156.2
1155.5
723.7
3209.4
3212.1
2777.2
2780.1
2344.6
2348.2
1912.1
1913.4
1479.6
1482.0
1065.1
1067.5
632.6
3118.3
3122.9
2686.0
2689.8
2252.9
2258.0
1821.0
1824.3
1388.5
1391.9
974.0
3027.4
3032.5
2594.9
2600.7
2162.4
2166.8
1729.9
1734.4
1297.5
1301.8
2936.3
MW = 3050.5
MW = 2618.0
MW = 2185.5
MW = 1753.0
MW = 1337.5
MW = 906.2
2503.8
2510.5
2071.3
2077.7
1638.7
1644.0
2412.6
2420.3
1980.2
1987.5
1547.6
1553.9
978.4
813.4
725.4
635.4
*
Molecular weight (MW) up to the first decimal point only is shown; C, calculated; F, found; DP, degree of polymerization.
3.5. Characterization of compounds
4.97 (d, 1H, J1,2 = 3.6 Hz, H-1), 4.89–4.85 (dd, 1H, J1,2 = 3.6 Hz,
J2,3 = 10.2 Hz, H-2), 3.80–3.69 (m, 2H), 3.63–3.57 (dd, 1H, H-5), 3.41
(s, 3H, –OCH3), 2.10 (s, 3H, –COCH3), 2.08 (s, 3H, COCH3), 2.02 (s, 3H,
–COCH3); 13C{1H} NMR (100 MHz, CDCl3) d 171.1–170.6, 97.3, 71.5,
70.3, 69.8, 69.4, 61.5, 55.9, 21.2; MS (MALDI-TOF) for C13H20O9, calcd
m/z 320.292, found 343.074 (M+Na)+, 359.047 (M+K)+.
3.5.1. Methyl 2,3,4-tri-O-acetyl-a-D
-glucopyranoside (5)29
Yield 96% (0.31 g). Colorless solid: mp 111 °C; [a]D
20 +148.8 (c 1,
CHCl3); 1H NMR (400 MHz, CDCl3) d 5.57–5.50 (t, 1H, J2,3 = 9.8 Hz,
J3,4 = 9.7 Hz, H-3), 5.06–4.99 (t, 1H, J3,4 = 9.8 Hz, J4,5 = 9.7 Hz, H-4),

V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
25
3.5.6. Phenyl 2,3,4-tri-O-benzyl-1-thio-b-
D
-galactopyranoside
(15)33
20
Yield 97% (0.53 g). Colorless solid: mp 88 °C; [
a]
ꢀ9.4 (c 1,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.58–7.22 (m, 20H, Ph–H),
5.01 (d, J = 11.6 Hz, Ph–CH2), 4.86 (d, J = 10.3 Hz, Ph–CH2), 4.80–
4.75 (m, Ph–CH2, H-1), 4.69 (d, Ph–CH2), 4.00 (t, J = 9.4 Hz, H-3),
3.88–3.83 (m, H-2, H-4), 3.65–3.62 (dd, J1 = 9.2 Hz, J2 = 2.3 Hz, 1H,
H-6), 3.58–3.51 (m, H-5), 3.48–3.65 (br t, H-6); 13C{1H} NMR
(100 MHz, CDCl3) d 138.5, 138.3, 133.9, 131.6, 128.9, 128.5,
128.4, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 127.2, 87.7,
84.3, 78.8, 77.5, 75.7, 74.2, 73.3, 73.1, 62.3; MS (MALDI-TOF) for
C
33H34O5S, calcd m/z 542.212, found 565.202 [M+Na]+, 581.176
Figure 4. Transmission electron micrograph obtained for the cyclooctamer 39. (A)
TEM image obtained for 39. A 3 mM solution of 39 in Hex–CH2Cl2 was used for
loading the sample on to the grid for imaging by TEM. Magnification: X6500.
Aggregates having ring structures formed can be seen. Inner diameter of the marked
ring: ꢂ263 nm and the thickness of the outer rim: ꢂ50 nm. Rings of other sizes can
also be seen. (B) HAADF-STEM image obtained for compound 39. The arrows point
to the aggregates having ring structures formed. Rings of other dimensions can also
be seen.
[M+K]+.
3.5.7. Phenyl 6-O-(20,30,40-tri-O-benzoyl-b-
D-glucopyranosyl)-
2,3,4-tri-O-benzyl-1-thio-b-
D
-galactopyranoside (17)29
20
Yield 95% (0.96 g). Colorless solid: mp 73 °C; [
a
]
D
ꢀ1.7 (c 0.5,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.95–7.27 (m, 35H, Ph–H),
5.90 (t, 1H, H-30), 5.47 (t, 2H, H-20, H-40), 5.05 (d, 1H, Ph–CH2),
4.88 (d, 1H, J = 5.0 Hz, 1H, H-10), 4.79–4.70 (m, 3H, Ph–CH2),
4.63–4.55 (m, 3H, Ph–CH2, H-1), 4.01–3.96 (m, 1H, H-6a), 3.92–
3.85 (m, 3H, H-2, H-5, H-6b), 3.79–3.75 (m, 1H, H-6a0), 3.68–3.60
(m, 2H, H-50, H-6b0), 3.51–3.44 (m, 2H, H-3, H-4); 13C{1H} NMR
(100 MHz, CDCl3) d 166.1, 165.8, 138.7, 138.2, 138.1, 133.7,
133.4, 131.9, 129.9, 129.7, 129.0, 128.9, 128.5, 128.4, 128.3,
128.2, 127.8, 127.7, 127.6, 127.5, 100.7 (C-10), 87.6 (C-1), 83.9,
76.7, 75.7, 74.6, 74.4 (C-50), 73.3, 72.7 (C-30), 72.6, 72.0 (C-40),
72.0, 69.5 (C-20), 67.7 (C-6), 61.1 (C-60); MS (MALDI-TOF) for
3.5.2. 1,2,3,4-Tetra-O-benzoyl-D
-glucopyranose (7)29
Yield 98% (0.58 g). Colorless solid: mp 81–84 °C; [a]
20 +43.3 (c
D
0.5, CHCl3); 1H NMR (400 MHz, CDCl3) d 8.17–8.18 (m, 2H, ArH),
8.06–7.87 (m, 16H, ArH), 7.57–7.27 (m, 22H, ArH), 6.87 (d, 1H,
J1,2 = 3.6 Hz, H-1 for a-product), 6.39 (t, 1H, J = 10.0 Hz, H-4 for a-
product), 6.27 (d, 1H, J1,2 = 8.2 Hz, H-1 for b-product), 6.08 (t, 1H,
J = 9.6 Hz, H-4 for b-product), 5.85 (dd, 1H, J1,2 = 8.2 Hz and
C
60H56O13S, calcd m/z 1016.344, found 1039.333 (M+Na)+,
J2,3 = 9.6 Hz, H-2 for b-product), 5.71–5.61 (m, 3H, H-3, H-2 for
product and H-3 for b-product), 4.28–4.25 (m, 1H, H-5 for -prod-
uct), 4.05–4.00 (m, 1H, H-5 for b-product), 3.94–3.70 (m, 4H, H-6a
and H-6b for both and b-product; MS (MALDI-TOF) for
34H28O10, calcd m/z 596.580, found 619.193 (M+Na)+, 635.167
(M+K)+.
a-
1055.3079 (M+K)+.
a
3.5.8. Uridine (19)29
a-
Yield 96% (0.22 g). Colorless solid: mp 168 °C; 1H NMR
(400 MHz, CD3OD) d 8.02 (d, J = 8.1 Hz, 1H, H–C–N), 5.91 (d,
J = 4.5, 1H, H-1), 5.71 (d, J = 8.1 Hz, 1H, H–C–C), 4.59 (s, 1H, N–H),
4.18–4.14 (m, 2H, H-3, H-4), 4.02–4.00 (m, 1H, H-2), 3.86 (dd,
J1 = 2.7, J2 = 9.5, 1H, H-5a), 3.75 (dd, J1 = 3.1, J2 = 9.1, 1H, H-5b).
C
3.5.3. 1,2:3,4-Di-O-isopropylidene-a-D
-galactopyranose (9)29
20
Yield 93% (0.24 g). Syrup: [a]
ꢀ49.3 (c 1, CHCl3); 1H NMR
D
(400 MHz, CDCl3) d 5.58 (d, 1H, J1,2 = 5.0 Hz, H-1), 4.60–4.57 (dd,
1H, J3,4 = 2.4 Hz, J2,3 = 7.9 Hz, H-3), 4.34–4.31 (m, 1H, J2,3 = 7.9 Hz,
H-2), 4.28–4.26 (dd, 1H, J4,5 = 1.5 Hz, J3,4 = 2.4 Hz, H-4), 3.90–3.83
(m, 2H, H-5, H-6), 3.77–3.72 (m, 1H, H-6), 1.54, 1.46, 1.34 (3s,
12H, CH3); 13C{1H} NMR (100 MHz, CDCl3) d 96.9, 71.8, 71.5,
71.2, 68.0, 63.1, 26.8, 26.5, 25.6, 25.1; MS (MALDI-TOF) for
3.5.9. Fmoc-
Yield 96% (0.40 g). Colorless solid: mp 93 °C; [
L
-Tyr-OMe (22)41
a]
20 +34.7 (c 0.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.76 (d, 2H), 7.56 (d, 1H), 7.39
(t, 1H), 7.31 (t, 2H), 7.30–7.22 (m, 2H), 6.93 (d, 2H), 6.73 (d, 2H),
5.27 (br d, 1H, N–H), 5.17 (s, 1H, OH), 4.65–4.60 (m, 1H, C–H),
4.46–4.40 (m, 1H, C–H of methylene), 4.37–4.33 (m, 1H, C–H of
methylene), 4.22–4.18 (m, 1H, C–H proton of Fmoc), 3.72 (s, 3H),
3.09–2.98 (m, 2H, benzylic protons).
C
12H20O6, calcd m/z 260.126, found 283.115 (M+Na)+, 299.089
(M+K)+.
3.5.4. Methyl 2,3,4-tri-O-benzyl-
a
D
-
D
20
-galactopyranoside (11)29
Yield 98% (0.46 g). Syrup: [
(400 MHz, CDCl3)
a]
+28.5 (c 1, CHCl3); 1H NMR
3.5.10. 1-Napthol (24)
Yield 95% (0.270 g from 2 mmol). Colorless solid: mp 95 °C; 1H
NMR (400 MHz, CDCl3) d 8.23 (br m, 1H, Ph–H), 7.87 (br m, 1H, Ph–
H), 7.54–7.48 (m, 3H, Ph–H), 7.37–7.33 (m, 1H, Ph–H), 6.85–6.80
(m, 1H, Ph–H), 5.34 (m, 1H, O–H).
d
7.36–7.14 (m, 15H, Ph–H), 5.00 (d,
J = 10.8 Hz, 1H, Ph–CH2), 4.89–4.84 (t, J = 11.6 Hz, 2H, Ph–CH2),
4.83–4.78 (m, Ph–CH2), 4.65 (d, J = 11.4 Hz, 1H, Ph–CH2), 4.57 (d,
J = 3.5 Hz, 1H, H-1), 4.02 (t, J = 9.2 Hz, 1H, H-4), 3.78–3.62 (m, 3H,
H-5, H-6a, H-6b), 3.57–3.48 (m, 2H, H-2, H-3), 3.36 (s, 3H, OC-H);
13C{1H} NMR (100 MHz, CDCl3) d 138.7, 138.1, 129.0, 128.9,
128.7, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 126.9, 98.2, 81.9, 79.9, 77.4, 76.7, 75.3, 74.9, 70.6, 61.9,
55.21; MS (MALDI-TOF) for C28H32O6, calcd m/z 464.219, found
487.209 (M+Na)+, 503.183 (M+K)+.
3.5.11. Cyclopentanol (26)
Yield 96% (0.41 g from 5 mmol). Colorless liquid; 1H NMR
(400 MHz, CDCl3) d 4.24–4.20 (br m, 1H, O–H), 3.04 (s, 1H, C–H),
1.73–1.61 (m, 4H, methylene protons), 1.56–1.43 (m, 4H, methy-
lene protons).
3.5.5. Fmoc-
Yield 95% (0.32 g). Colorless solid: mp 115 °C; [
L
-Ser-OMe (13)40
3.5.12. Methyl 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-benzyl-
b- -galactopyranosyl)- -gluco-pyranoside (32
/b)15
Yield 64% (0.53 g). Oil: 1H NMR (400 MHz, CDCl3, for 32b) d
7.41–7.27 (m, 20H, Ph–H of benzyl), 5.48 (t, 1H, H-3), 5.07 (t, 1H,
H-4), 4.97–4.85 (m, 3H, CH2Ph, H-1), 4.84–4.79 (m, 3H, CH2Ph,
H-10, H-2), 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 (br dd, 1H,
a/
20
a]
D
+7.0 (c 1,
D
a
-D
a
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.67 (d, 2H, Ph–H), 7.53 (br
s, 2H, Ph–H), 7.43 (t, 2H, Ph–H), 7.35 (t, 2H, Ph–H), 5.77 (br s, 1H,
N-H), 4.45–4.40 (br m, 3H, CH (Fmoc), COO–CH2), 4.25 (t, J = 6.8,
1H, C-H), 4.02 (br d, 1H, alpha methylene proton), 4.94 (br d, 1H,
beta methylene proton).

26
V. Kumar et al. / Carbohydrate Research 397 (2014) 18–26
H-6a), 4.01–3.90 (m, 4H, H-5, H-6b, H-20, H-40), 3.77–3.73 (q, 1H,
H-3), 3.51–3.47 (m, 3H, H-50, H-6a0, H-6b0), 3.31 (s, 3H, OCH3),
2.06, 2.05, 2.03 (s, 9H, 3ꢁ COCH3); 13C{1H} NMR (100 MHz, CDCl3)
d 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 (C-1b),
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 (MALDI-TOF) for
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Acknowledgments
Vajinder Kumar and Narender Yadav sincerely thank CSIR-UGC-
NET, New Delhi and NIPER SAS Nagar, respectively, for the award of
Research Fellowships. The authors are thankful to the reviewer
who asked for additional detritylation experiments: (i) using indiu-
m(III) salts other than the triflate and (ii) solution-phase reactions
in MeCN–MeOH and THF–MeOH.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2014.08.
002.
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based on the mass spectral data. For example, from Table S1 (see Supporting
information) that lists all the peaks observed in the MALDI-TOF/TOF spectra of
the oligomers 37–39, it can be seen that no oligomer contains peaks of mass
(m/z) greater than its molecular mass.
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