Application of ball milling technology to carbohydrate reactions: I. Regioselective primary hydroxyl protection of hexosides and nucleoside by planetary ball milling

Article abstract of DOI:10.1080/07328300802218713

Dry ball milling of hexosides with trityl chloride in the presence of DABCO or Na2CO3 has been found to result in their complete conversion to the respective 6-O-trityl ethers. Further wet grinding of the reaction mixture with Ac2O in the presence of DMAP led to the respective fully protected hexosides in good to excellent yields after isolation. It has been found to be an effective one-pot two-step synthesis under solvent-free condition. The speed of homogenization has been shown to highly influence the rate and outcome of the reaction, and commercially available planetary ball mill has been proved to be very convenient for carrying out the reaction under standardized and reproducible conditions.

Full text of DOI:10.1080/07328300802218713

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Application of Ball Milling Technology to
Carbohydrate Reactions: I. Regioselective
Primary Hydroxyl Protection of Hexosides
and Nucleoside by Planetary Ball Milling
Premanand Ramrao Patil a & K. P. Ravindranathan Kartha a
a National Institute of Pharmaceutical Education and Research, Department
of Medicinal Chemistry, Punjab, India
Published online: 24 Jul 2008.
To cite this article: Premanand Ramrao Patil & K. P. Ravindranathan Kartha (2008): Application of Ball
Milling Technology to Carbohydrate Reactions: I. Regioselective Primary Hydroxyl Protection of Hexosides and
Nucleoside by Planetary Ball Milling , Journal of Carbohydrate Chemistry, 27:5, 279-293
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Journal of Carbohydrate Chemistry, 27:279–293, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300802218713
Application of Ball Milling
Technology to
Carbohydrate Reactions:
I. Regioselective Primary
Hydroxyl Protection of
Hexosides and Nucleoside
by Planetary Ball Milling‡
Premanand Ramrao Patil and K. P. Ravindranathan Kartha
National Institute of Pharmaceutical Education and Research, Department of
Medicinal Chemistry, Punjab, India
Dry ball milling of hexosides with trityl chloride in the presence of DABCO or Na2CO3 has
been found to result in their complete conversion to the respective 6-O-trityl ethers.
Further wet grinding of the reaction mixture with Ac2O in the presence of DMAP led to
the respective fully protected hexosides in good to excellent yields after isolation. It has
been found to be an effective one-pot two-step synthesis under solvent-free condition.
The speed of homogenization has been shown to highly influence the rate and outcome of
the reaction, and commercially available planetary ball mill has been proved to be very
convenient for carrying out the reaction under standardized and reproducible conditions.
Keywords Trityl ethers, Regioselective reactions, Ball mill, Solvent-free synthesis,
Mechanochemical reactions
INTRODUCTION
Complexity in the structures of biologically important carbohydrates and their
derivatives makes their synthesis a challenging and difficult task that involves
Received March 3, 2008; accepted May 20, 2008.
‡Presented at the CARBO XXI Conference, Annual Meeting of the Association of Carbo-
hydrate Chemists & Technologists, India, November 26–29, 2006, New Delhi, India.
Address correspondence to K. P. Ravindranathan Kartha, National Institute of Pharma-
ceutical Education and Research, Department of Medicinal Chemistry, S.A.S. Nagar,
Punjab, India. E-mail: rkartha@niper.ac.in
279

P. R. Patil and K. P. R. Kartha
280
multi-step processes requiring selective functional group manipulations.
Selective protection of the primary hydroxyl group in hexosides and nucleosides
by bulky acid-labile groups such as trityl (Tr), t-butyldimethylsilyl (TBDMS), t-
butyldiphenylsilyl (TBDPS), etc., is very widely applied in synthetic oligosacchar-
ide and nucleoside chemistry.[1] The classical approach for this reaction involves
treatment ofthe respective glycoside ornucleoside with the desiredorganichalide
in pyridine, which serves both as the solvent and catalyst for the reaction.[1,2]
Alternatively, use of dimethylaminopyridine (DMAP) either alone or in combi-
nation with Et3 N,[3] imidazole,[4] 2,4,6-collidine,[5] DBU,[6] 2,6-lutidine,[7] etc.,
as catalyst in a suitable solvent such as DMF,[3–5] DCM,[6–7] or MeCN[8] is also
recommended. Some of these instances involve use of some of the more expensive
reagents such as TBDMS triflate[7] and N-trityl pyridinumfluoroborate[8] as the
respective donor reagents. In addition, solid phase tritylation[5] and tritylation
in molten salts,[9] as well as one involving the use of the TMS derivative of both
the alcohol to be silylated and trityl alcohol in the presence of TMSOTf,[10] have
also been reported. Thus, the O-tritylation reactions most often require environ-
mentally unfriendly solvents such as pyridine and DMF or expensive catalysts/
reagents such as DMAP, trityl triflate, N-trityl pyridinumfluoroborate, etc.
Hence, solvent-free synthesis proves more environmentally benign and economi-
cally feasibleandisextremely importantinthecontextofthefactthatwaste mini-
mization has become an essential part of the regulatory issues associated withthe
chemical industry worldwide. In this context, ball milling, a mechanochemical
technology scarcely used in synthetic organic chemistry, seemed particularly
attractive.[11] In this report we describe results of our recent work on the regiose-
lective etherification of hexosides and nucleoside by planetary ball milling. (In
planetary ball milling the grinding jar rotates about its own axis as well as
around the common axis of the sun wheel in the opposite direction. This results
in high pulverization energy and efficient mixing.)
RESULTS AND DISCUSSION
For the synthesis of the a- and b-(1,6)-linked galacto- and gluco-oligosacchar-
ides in progress in our laboratory, multigram quantities of the corresponding
chemoselectively protected monosaccharide building blocks 15a–15c, 17, 19,
21, and 23, obtainable from 1, 16, 18, 20, and 22, respectively via, the corre-
sponding 6-O-substituted ethers, were required. Toward this end and with a
view to reducing the use of harmful and high-boiling liquids such as pyridine
and DMF, the reaction of methyl a-D-glucopyranoside (1) with trityl chloride
(2) under solvent-free conditions was investigated. For the reaction conditions
to be reproducible, use of a commercially available ball mill was considered
desirable instead of the grinding/mixing carried out manually using a
mortar and pestle. A planetary ball mill wherein the conditions of grinding/
mixing can be electronically controlled/preset as desired seemed to be able to

Application of Ball Milling Technology to Carbohydrate Reactions I
281
serve the purpose. Indeed, when a mixture of the glucoside (1, 1 mmol), trityl
chloride (2, 1.25 mmol), and DABCO (3, 1.25 mmol) was allowed to mix at
500 rpm overnight chromatographically, pure 6-O-trityl derivative 4[12] was
obtained as crystalline solid in 67% of isolated yield (Sch. 1). It was identical
with authentic 4 prepared by a literature procedure,[3a] and was further
characterized as its triacetate 15a.[13]
Optimization of the reaction condition with respect to the concentration of
2 and 3 (with 2:3 at 0.5:1, 1:1, 1.25:1.25, 2.5:1.25, 1.25:2.5, 2.5:2.5, and 3.75:2.5
mol ratio, respectively, per mol of the glucoside 1 at 500 rpm for 15 h) was then
carried out and the best results were obtained when 2.5 mol each of 2 and 3 per
mol of compound 1 were used for the reaction. Under these conditions complete
consumption of 1 was indicated by TLC (eluent, CH2Cl2:MeOH, 8:2) and
isolation of the product by column chromatography (silica gel; eluent,
EtOAc:n-Hex, 4:1) afforded the desired crystalline 6-O-trityl ether 4 in 80%
yield. Alternatively, as it had been possible in most of the cases studied, the
product could also be obtained from the crude mixture directly by crystalliza-
tion. Choice of organic solvents was limited in the case of unprotected carbo-
hydrates and nucleosides because of solubility difficulties and avoidance of
organic solvents as an aim of current regulatory concern and compliance.
The reaction described above constitutes the first example of the application
of solvent-free regioselective tritylation in synthetic carbohydrate chemistry.
Application of DABCO, a relatively cheap base, as a catalyst for the reaction
described above is also new.
As the speed of milling was expected to influence the dynamic impact
energy produced during the process, the effect of this variable on the outcome
of the reaction was studied. Thus, in separate experiments compounds 1,
2, and 3 (mol ratio, 1:2.5:2.5, respectively) were homogenized in the mill
at different speeds (Table 1) and the yield of the purified product obtained
was estimated. Indeed, the speed of operation was found to have a direct
bearing on the rate of the reaction and the product yield, both being increased
with increasing speed. Thus, while at 100 rpm no product formation was
observed for a period of 24 h, significant yields were obtained by increasing it
to 400 rpm for 15 to 24 h, and at a setting of 600 rpm complete disappearance
of the starting material was observed in only 3 h. The effect of speed of
milling on the reaction time and the product yield is clearly evident from
Table 1.
It was observed that the reactions at 500 rpm and above resulted in the for-
mation of an intermediate molten mass (visible on observation of the reaction
mixture before completion of the reaction), which eventually turned into solids
on completion of the reaction. Similar observations in other solid/solid organic
reactions have been reported previously.[14] Other organic/inorganic bases as
possible alternatives to DABCO for the reaction were then investigated and the
results are summarized in Table 2.

P. R. Patil and K. P. R. Kartha
282
Table 1: Effect of milling speed on the regioselective tritylation of
methyl a-D-glucopyranoside (1).a
Isolated
yield (%)
Entry
rpm
Time (h)
1
2
3
4
5
6
7
8
100
200
300
300
400
400
500
600
24
24
15
24
15
0
21
32
39
55
58
80
87
24
15
3 (15)b
aThe reaction was carried out with 1 mmol of the glucoside 1 at 1:2:3 in
the ratio 1:2.5:2.5.
bThe reaction was complete in 3 h but the product was isolated after 15 h
in the mill.
Table 2: Effect of base on the regioselective tritylation of 1a.
Isolated
Entry
Base
Time (h)
yieldd (%)
1
2
3
None
NaOH
KOH
Na2CO3
Na2CO3
Na2CO3
K2CO3
Cs2CO3
Ag2CO3
DMAP
24
15
15
15
6
0
0
25
71
92
93
64
35
73
0
4
5b
6c
7
2
15
15
15
24
15
8
9
10
11
Imidazole
62
aReactions were carried out with 1 mmol of the glucoside 1 at
1:2:Base in the ratio 1:2.5:2.5 at 500 rpm.
bReaction was carried out with 15 g (77.2 mmol) of the glucoside 1 at
1:2:Base in the ratio 1:2.5:2.5 at 500 rpm.
cReaction was carried out with 15 g (77.2 mmol) of the glucoside 1 at
1:2:Base in the ratio 1:2.5:2.5 at 600 rpm.
dThe remaining was the unreacted starting material except in entries
5 and 6 where no starting material was detected.

Application of Ball Milling Technology to Carbohydrate Reactions I
283
Thus, among the common inorganic bases studied, anhydrous Na2CO3 and
Ag2CO3 were found to be effective for the reaction (Table 2, entries 4 and 8,
respectively), although they were not as efficient as DABCO. While the ineffi-
ciency of strongly basic alkali metal hydroxides for the reaction (entries 2
and 3, Table 2) could presumably be attributed to the strong nucleophilic char-
acter of the hydroxide ion, leading to the hydrolysis of the halide reagent 2,
the failure with DMAP was somewhat surprising yet reasonable as seen by
the possibility for the formation of a stable pyridinium salt by reaction with
2. Indeed, when a mixture of DMAP and 2 was ground under solvent-free
conditions in the ball mill (2 h, 500 rpm), the respective pyridinium salt was
obtained in quantitative yield.[15] Another interesting feature of this reaction
noticed was that the reactions were significantly more efficient, both in
terms of the yield and the reaction time, when carried out in multigram quan-
tities of the substrate. Thus, the 6-O-tritylation of 1 in the presence of Na2CO3
when carried out at a 15 g scale went to completion in 6 h at 500 rpm and in 2 h
at 600 rpm (entries 5 and 6, respectively, Table 2). Further, as evident from
these experiments (entries 5 and 6, Table 2), in large-scale preparations
Na2CO3, a greener (as well as cheaper) substitute for DABCO, was consistently
seen to be as efficient as DABCO.
Among the other substrates subjected to the tritylation reaction in the mill
were the partially protected diacetonides 5 and 7, a native hexose 10, and the
nucleoside 12. Compound 5, although bearing a primary hydroxyl group, but
being sticky in nature in the mill, gave the tritylated product 6[16] in only 59%
yield (5 h, 500 rpm). As was to be expected, the acetonide 7 bearing a relatively
hindered secondary hydroxyl group on C-3 was virtually unreactive to tritylation
in the ball mill. In sharp contrast, cyclopentanol (8) yielded the expected trityl
ether 9[17] in 96% isolated yield in 5 h at 500 rpm. Further, while D-galactose
(10) did not give any appreciable yield of the desired 6-O-trityl derivative (11)
at 500 rpm for 24 h, the reaction proceeded well at 600 rpm and the regioselec-
tively substituted 6-O-trityl-D-galactose (11,[18] characterized unambiguously
as its corresponding anomeric tetra-O-acetates by NMR) was obtained in reason-
able yield (47%) in 15 h. Likewise, uridine (12) was converted to its 50-O-trityl
derivative 13[9,19] and 50-O-dimethoxytrityl derivative 14,[20] both highly
valuable building blocks in nucleotide synthesis, in 43% and 44% yield, respect-
ively, by grinding it with 2/DMTCl (2.5 mol equiv), respectively, in the presence
of DABCO (2.5 mol equiv) for 15 h at 600 rpm without having to use any

P. R. Patil and K. P. R. Kartha
284
solvent or phase transfer catalyst.[9] It may be recalled that similar reactions
under microwave irradiation were also characterized by low yields as well as
undesired depurination.[9] Also, these reactions in ionic liquids, in spite of their
relatively high solubilizing power toward the nucleoside, have been reported to
proceed over long reaction times with low yields of the desired 50-O-DMT
derivative.[9]
As the overall objective was to obtain chemoselectively protected monosac-
charide building blocks, conversion of the trityl ether 4 to its tri-O-acetate 15a
in the same pot was highly desirable. Hence, upon completion of the tritylation
reaction as described above, DMAP (1 mol equiv) and Ac2O (1.5 mol equiv per
OH group) were added to the reaction mixture, which was wet-milled for
30 min at 500 rpm, whereby complete transformation of 4 into a faster-moving
compound with Rf ¼ 0.41 (TLC, eluent, EtOAc:n-Hex, 1:3; compound 4 was
immobile in this eluent system) took place, which upon aqueous workup and
chromatography (silica gel, eluent, EtOAc:n-Hex, 1:9) yielded (71%) a crystalline
compound identical to authentic 15a (entry 1, Table 3). In spite of the presence of
DABCO in the reaction mixture, the acetylation did not go to completion without
the added DMAP. It is also to be noted that if the fully protected derivatives such
as 15a are the desired compound (by successive one-pot tritylation followed by
acetylation), the use of Na2CO3 in the tritylation step is not recommended
because of the possible formation of CO2 in the acetylation step. The reaction
was then successfully scaled up to 5 g without affecting the yield. Encouraged
by these results, the reaction of 1 with TBDPSCl (a liquid at rt) and TBDMSCl
(a sticky solid at rt) in the presence of DABCO was investigated. The expected
products in these reactions were compounds 15b and 15c after the O-acetylation
of the respective initially formed 6-O-substituted product. Thus, as noted before,
while the reaction of 1 with TrCl (2) took 15 h for completion at 500 rpm, that with
TBDPSCl was complete in 6 h and 15b[17] was isolated in 72% yield after the sub-
sequent one-pot acetylation. The reaction with TBDMSCl was, however, not
complete in 15 h at 500 rpm (increasing the milling speed to 600 rpm also did
not enable completion of this reaction) and the yield of the respective acetylated
product 15c[18] obtained was only 49% (82% based on the isolated methyl tetra-
O-acetyl-a-D-glucopyranoside derived from the unreacted 1). The inefficiency
observed in the reaction of 1 with TBDMSCl could be attributed to the formation
of a highly sticky mass in the ball mill, which indeed prevented the mixture from
getting mixed effectively. It may be pointed out that in the latter case the balls
used in the mill were found to be glued to each other and to the wall, making
their effective movement virtually impossible (unlike in the other two cases).
´
˚
Incorporation of molecular sieves (powder, 4A) resulted in a marginally
improved isolated yield of 15c (being increased to 55% only). The procedure
was then successfully extended to other gluco- and galacto-configured monosac-
charide glycosides to obtain the corresponding O-acetylated 6-O-trityl ethers
17, 19, 21, and 23 from 16, 18, 20, and 22, respectively (entries 4–7, Table 3).

Table 3: One-pot two-step synthesis of variously protected carbohydrates by ball milling.a
Product after steps
Time
(step i, h)
Yield
(%)
Sr. no.
Substrate sugar
Methyl glucoside 1
i & ii
1b
2
Tri-O-acetyl-6-O-trityl glucoside 15a[13]
Tri-O-acetyl-6-O-t-butyldiphenylsilyl
glucoside 15b[21]
15
6
71
72
Methyl glucoside 1
3
Methyl glucoside 1
Tri-O-acetyl-6-O-t-butyldimethylsilyl
glucoside 15c[22]
15
49 (82)c
4
5
6
7
Methyl galactoside 16
Tri-O-acetyl-6-O- trityl galactoside 17[23]
Tri-O-acetyl-6-O-trityl galactoside 19
Tri-O-acetyl-6-O-trityl 1-thio-galactoside 21
Di-O-acetyl-6-O-trityl 1-thio-glucoside 23
15
15
15
15
80
85
2-(Trimethylsilyl)ethyl galactoside 18
Phenyl 1-thio-galactoside 20
Methyl 1-thio-glucoside 22
82
39 (91)c
aReactions were carried out with substrate (1 mmol):RCl:3 in the ratio 1:2.5:2.5 for (i) and substrate:DMAP:Ac2O in the ratio 1:1:1.5 per–OH group for (ii).
bThe reaction was scaled up to 5-g scale without affecting the yield.
cYield based on the recovered starting material in the O-acetylated form.

P. R. Patil and K. P. R. Kartha
286
The glucosamine derivative 22, in which a highly sticky mass was found to be
formed during the milling, again, gave poor yield of the product 23 (only 39%,
entry 7, Table 3).
CONCLUSION
A commercially available planetary ball mill was successfully used for the
regioselective 6-O-tritylation/silylation of various monosaccharides or their
derivatives under solvent-free conditions by dry grinding. The reactions could
be carried out on preparative scale with high efficiency in the presence of
Na2CO3 as catalyst. Successive acetylation by wet grinding was found to be an
efficient one-pot two-step protocol for the preparation of the corresponding
fully protected carbohydrate derivatives useful in the synthesis of building
blocks for oligosaccharide synthesis. As standardized and reproducible
conditions for homogenizations have been made possible by the choice of
commercially available equipment, clear observations on the effect of speed
and duration of homogenization on the rate and the yield of the reaction have
been made possible in the present study. Ball milling technology when applied
to reactions such as those reported here can lead to significant reduction in
the use of hazardous solvents such as pyridine and DMF. Application of ball
milling technology to other carbohydrate reactions is currently under way in
our laboratory.
EXPERIMENTAL
Melting points were recorded on Mettler DSC 851 or capillary melting point
apparatus and are uncorrected. Specific rotations were obtained on AUTOPOL
IV polarimeter at 208C. IR spectra were recorded on Nicolet FT-IR Impact 410
instrument either as neat or KBr pellets. NMR spectra were recorded on
300 MHz Bruker FT-NMR (Avance DPX300) spectrometer at 300 MHz for the
1H and at 75.47 MHz for the 13C nucleus. Chemical shifts are reported in ppm
from TMS as the internal standard. Mass spectra were obtained on an ultraflex
TOF/TOF MALDI mass spectrometer, which is equipped with a reflector and

Application of Ball Milling Technology to Carbohydrate Reactions I
287
controlled by the Flexcontrol1.4 software package. In MALDI-TOF MS
reflector mode, ions generated by a pulsed UV laser beam (nitrogen laser
l ¼ 337 nm, 20 Hz) were accelerated to a kinetic energy of 25 kV. TLC was
performed on 0.2 mm Merck precoated silica gel 60 F254 aluminum sheets. All
chromatographic purifications were carried out using silica gel 60 (60–120
mesh). All reagent chemicals were purchased from Aldrich Chemical Co
(Milwaukee, WI, USA).
General Procedure for the O-tritylation/silylation Using
Planetary Ball Mill
The substrate (1/5/8/10/12, 1 mmol), trityl chloride (2, 2.5 mmol) and
DABCO (3, 2.5 mmol) were allowed to mix in a stainless steel [SS; material
number, 1.4034, hardness, 48–52 HRC and composition (%), Fe (82.925), Cr
(14.5), Mn (1), Si (1), C (0.5), P (0.045) and S (0.03)] jar (capacity, 50 mL) containing
SS balls (10 numbers, 10 mm o.d.) for the desired period of time (as judged by TLC,
see Tables 1–3) in a planetary ball mill (Retsch PM-100; Retsch GmbH & Co. KG,
Germany) at the desired rpm (usually 500/600, see also Tables 1–3). The mixture
was then purified on a silica gel column [eluent, EtOAc:n-Hex, 1:9 (to remove the
by-products derived from excess 2) and 4:1 successively] to yield the respective
O-tritylated derivative, which was crystallized from EtOAc (or EtOAc-n-Hex) to
obtain analytically pure product (4/6/9/13/14). Alternatively, as it had been
possible in most of the cases studied, the product could also be obtained from
the crude mixturedirectlyby crystallization. Thespectraldata werein accordance
with the expected structure and in agreement with literature values.
Methyl 6-O-trityl a-D-glucopyrnoside[12] (4)
This was prepared by the general procedure described above in 80% yield
on 1-mmol scale reactions in the presence of DABCO at 500 rpm and 92–
93% yield on 77-mmol scale reactions in the presence of Na2CO3 at 500/
600 rpm, respectively, as white solid; NMR spectra were identical to those
described.[12a] mp 1408C (from EtOAc) (lit.[2a] 1388C). MALDI-TOF MS
C26H28O6 [M]þ calcd. m/z 436.189, found m/z 475.805 (M þ Kþ, 98%),
459.814 (M þ Naþ, 95%) and 243.537 (Trþ, 100%).
1,2:3,4-Di-O-isopropylidene-6-O-trityl-a-D-galactoyrnose[16]
(6)
Prepared by the general procedure described above, this compound was
purified by chromatography on a silica gel column using EtOAc:n-Hex ¼ 1:9.
Yield 59%; mp 77–788C (lit.[16a] 80–828C); NMR spectra were identical
to those described.[16b] MALDI-TOF MS C31H34O6 [M]þ calcd. m/z 502.236,

P. R. Patil and K. P. R. Kartha
288
found m/z 541.657 (M þ Kþ, 57%), 525.679 (M þ Naþ, 28%) and 243.419
(Trþ, 100%).
Cyclopentyl Trityl Ether[17] (9)
Prepared by the general procedure described above, this compound was
purified by chromatography on a silica gel column using EtOAc:n-Hex, 0.5:
9.5 as the eluent. Yield 96%, syrup; nmax (neat)/cm21 3032, 3057, 2955, 2868,
1490, 1448, 1047, and 705; dH (CDCl3) 7.47 (d, 6H, J 7.4, ArH), 7.28–7.17
(m, 9H, ArH), 4.01 (m, 1H, Cyclopent), 1.58 (m, 2H, Cyclopent), and 1.45–
1.28 (m, 6H, Cyclopent); MALDI-TOF MS C24H24O [M]þ calcd. m/z 328.183,
found m/z 351.621 (M þ Naþ, 58%) and 243.631 (Trþ, 100%).
50-O-Trityluridne[19] (13)
Prepared by the general procedure described above, this compound was
purified by chromatography on a silica gel column using EtOAc:n-Hex ¼ 9:1.
Yield 43%; mp 207–2088C (lit.[2c] 2008C); NMR spectral data were identical to
those described.[19] MALDI-TOF MS C28H26N2O6 [M]þ calcd. m/z 486.179,
found m/z 525.729 (M þ Kþ, 4%), 509.746 (M þ Naþ, 28%) and 243.489
(Trþ, 100%).
50-O-(4,40-Dimethoxytrityl)uridne[20] (14)
This was prepared by the general procedure described above, and purified by
chromatography on a silica gel column using EtOAc:n-Hex ¼ 9:1. Yield 44%; mp
111–1128C (lit.[20a] 123–1248C);NMR spectral datawereidenticaltothosedescri-
bed.[20b] MALDI-TOF MS C30H30N2O8 [M]þ calcd. m/z 546.200 found m/z
585.172 (M þ Kþ, 0.02%), 569.191 (M þ Naþ, 0.02%), 546.195 (Mþ, 0.004%),
and 303.155 (DMTþ, 100%).
General Procedure for the O-tritylation/silylation Followed
by the Per-O-acetylation in One Pot Using Planetary
Ball Mill
The substrate (1/16/18/20/22, 1 mmol), trityl- (or the desired silyl-)
chloride (2, 2.5 mmol), and DABCO (3, 2.5 mmol) were allowed to mix in an
SS jar (capacity, 50 mL) containing SS balls (10 numbers, 10 mm o.d) for the
desired period of time (as judged by TLC, see Table 3) in a planetary ball mill
at 500/600 rpm. To the crude O-tritylated product thus obtained DMAP
(1 mmol) and Ac2O (1.5 mol equiv per OH group to be acetylated) were added
and the homogenization was continued for 30 min at 500 rpm. The resulting
material was then taken up in CH2Cl2 and was subjected to an aq. workup

Application of Ball Milling Technology to Carbohydrate Reactions I
289
in a separatory funnel [successive washing with: i, cold dil aq HCl (20 mL ꢀ 2);
ii, aq 10% NaHCO3 (20 mL ꢀ 2); and iii, 50 mL water]. The organic solution
was then dried (Na2SO4), separated by filtration at the pump, and concentrated
to dryness under reduced pressure. The residue was purified on a silica gel
column (eluent, EtOAc:n-Hex, 1:9) to yield the respective fully protected carbo-
hydrates (15a/15b/15c/17/19/21/23) (see Table 3). Spectral data were in
accordance with the expected structure and in agreement with literature
values.
Methyl 2,3,4-tri-O-acetyl-6-O-trityl-a-D-glucopyranoside[13]
(15a)
This was prepared by the general procedure described above and isolated
as colorless crystals. Yield 72%; mp 1368C (lit.[2a] 1368C); NMR spectra were
identical to those described.[13a] MALDI-TOF MS C32H34O9 [M]þ calcd. m/z
562.220, found m/z 601.961 (M þ Kþ, 98%), 585.949 (M þ Naþ, 94%), and
243.590 (Trþ, 100%).
Methyl 2,3,4-tri-O-acetyl-6-O-tert-Butyldiphenylsilyl-a-D-
glucopyranoside[21] (15b)
Compound 15b was prepared by the general procedure described above in
71% yield as colorless solid; mp 82–838C; NMR spectral data were identical to
those described.[21a] MALDI-TOF MS C29H38O9Si [M]þ calcd. m/z 558.229,
found m/z 597.809 (M þ Kþ, 95%) and 581.822 (M þ Naþ, 100%).
Methyl 2,3,4-tri-O-acetyl-6-O-tert-butyldimethyllsilyl-a-D-
glucopyranoside[22] (15c)
This was prepared by the general procedure described above in an isolated
yield of 49% as syrup; [a]D ¼ þ110.3 (1 in CHCl3) (lit.[22a] þ124); NMR spectral
data were identical to those described.[22b] MALDI-TOF MS C19H34O9Si [M]þ
calcd. m/z 434.197, found m/z 473.667 (M þ Kþ, 20%), 457.692 (M þ Na2,
35%) and 403.648 (M-OCHþ3 , 100%).
Methyl 2,3,4-tri-O-acetyl-6-O-trityl-b-D-
galactopyranoside[23] (17)
Compound 17 was prepared by the general procedure described above in
80% yield as colorless solid, mp 68–698C (lit.[23a] 143–1458C); [a]D ¼ –45.5
(lit.[23a] –52.7); NMR spectra were identical to those described.[23b] MALDI-
TOF MS C32H34O9 [M]þ calcd. m/z 562.220, found m/z 601.838 (M þ Kþ,
43%), 585.851 (M þ Naþ, 49%), and 243.501 (Trþ, 100%).

P. R. Patil and K. P. R. Kartha
290
2-(Trimethylsilyl)ethyl 2,3,4-tri-O-acetyl-6-O-trityl-b-D-
galactopyranoside (19)
Compound 19 was prepared by the general procedure described above in
85% yield as white solid; mp 68–698C; [a]D ¼ –41.9 (C 1 in CHCl3); nmax
(KBr)/cm21 3033, 2952, 2890, 1754, 1449, 1368, 1249, 1221, 1079, and 707;
dH (CDCl3) 7.37 (d, 6H, J 7.0 Hz, ArH), 7.32–7.24 (m, 9H, ArH), 5.55 (d, 1H,
J3,4 2.2 Hz, H-4), 5.13 (dd, 1H, J1,2 7.6 Hz and J2,3 10.2 Hz, H-2), 5.06 (dd,
1H, H-3), 4.45 (d, 1H, H-1), 3.97 (m, 1H, OCH2), 3.79 (t, 1H, H-5), 3.52
(m, 1H, OCH2), 3.39 (dd, 1H, J5,6a 5.5 Hz and J6a,6b 8.6 Hz, H-6a), 3.10
(t, 1H, H-6b), 2.04, 1.99, 1.89 (3s, 9H, 3 ꢀ COCH3), 0.94 (m, 2H, SiCH2), and
0.00 (s, 9H, Si(CH3)3); MALDI-TOF MS C36H44O9Si [M]þ calcd. m/z 648.275,
found m/z 687.311 (M þ Kþ, 46%), 671.321 (M þ Naþ, 73%) and 243.175
(Trþ, 100%).
Phenyl 2,3,4-tri-O-acetyl-6-O-trityl-1-thio-b-D-
galactopyranoside (21)
Compound 21 was prepared by the general procedure described above in
82% yield as a white solid; mp 1388C; [a]D ¼ –10.2 (C 1 in CHCl3); nmax
(KBr)/cm21 2925, 2876, 2854, 1752, 1440, 1368, 1265, 1252, 1217, 1082,
1057, and 706; dH (CDCl3) 7.50 (m, 2H, ArH) 7.39 (m, 6H, ArH), 7.31–7.20
(m, 12H, ArH), 5.48 (d, 1H, J3,4 3.0 Hz, H-4), 5.19 (t, 1H, J2,3 9.9 Hz, H-2),
5.02 (dd, 1H, H-3), 4.71 (d, 1H, H-1), 3.72 (t, 1H, H-5), 3.43 (dd, 1H, J5,6a
6.2 Hz and J6a,6b 9.4 Hz H-6a), 3.08 (dd, 1H, H-6b), 2.08, 1.96, and 1.90 (3s,
9H, 3 ꢀ COCH3); MALDI-TOF MS C37H36O8S [M]þ calcd. m/z 640.213,
found m/z 679.905 (M þ Kþ, 48%), 663.901 (M þ Naþ, 46%) and 243.507 (Trþ,
100%).
Methyl 3,4-di-O-acetyl-6-O-trityl-2-deoxy-2-phthalimido-1-
thio-b-D-glucopyranoside (23)
Compound 13 was prepared by the general procedure described above in
39% yield as colorless solid; mp 83–848C; [a]D ¼ þ57.8 (C 1 in CHCl3); nmax
(KBr)/cm21 2929, 1747, 1718, 1383, 1233, 1093, 1038, and 715; dH (CDCl3)
7.87 (m, 2H, ArH), 7.74 (m, 2H, ArH), 7.47 (d, 6H, J 8.0 Hz, ArH), 7.33–7.21
(m, 9H, ArH), 5.82 (t, 1H, J2,3 9.4 Hz, H-3), 5.37 (d, 1H, J1,2 9.8 Hz, H-1),
5.28 (t, 1H, H-2), 4.49 (t, 1H, J3,4 9.4 Hz and J4,5 10.4 Hz, H-4), 3.82 (m, 1H,
H-5), 3.31 (d, 1H, J6a,6b 10.5 Hz, H-6a), 3.14 (dd, 1H, J5,6b 4.0 Hz and J6a,6b
10.2 Hz H-6a), 2.25 (s, 3H, SCH3), 1.85 and 1.74 (2s, 6H, 2 ꢀ COCH3);
MALDI-TOF MS C38H35NO8S [M]þ calcd. m/z 665.208, found m/z 704.209
(M þ Kþ, 63%), 688.225 (M þ Naþ, 100%), and 243.122 (Trþ, 92%).

Application of Ball Milling Technology to Carbohydrate Reactions I
291
ACKNOWLEDGMENT
Premanand Ramrao Patil would like to thank NIPER for a research fellowship.
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