Rapid carbohydrate protecting group manipulations assisted by microwave dielectric heating

Article abstract of DOI:10.1081/CAR-100105712

The protocols for oligosaccharide synthesis are often tedious due to extended synthetic routes and reaction times. We herein describe methods assisted by microwave dielectric heating, which enable very short reaction times and high yields for the introduction and removal of eleven of the most commonly used protecting groups in carbohydrate syntheses. Several examples are reported, where solid supported reagents in combination with microwave dielectric heating have been used. This results in both faster and easier synthesis and purification.

Full text of DOI:10.1081/CAR-100105712

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RAPID CARBOHYDRATE PROTECTING GROUP
MANIPULATIONS ASSISTED BY MICROWAVE DIELECTRIC
HEATING
Eva Söderberg a , Jacob Westman b & Stefan Oscarson* a
a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
Stockholm, S-106 91, Sweden
b Personal Chemistry, Hamnesplanaden 5, Uppsala, S-753 19, Sweden
Version of record first published: 16 Aug 2006.
To cite this article: Eva Söderberg , Jacob Westman & Stefan Oscarson* (2001): RAPID CARBOHYDRATE PROTECTING
GROUP MANIPULATIONS ASSISTED BY MICROWAVE DIELECTRIC HEATING, Journal of Carbohydrate Chemistry, 20:5, 397-410
To link to this article: http://dx.doi.org/10.1081/CAR-100105712
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J. CARBOHYDRATE CHEMISTRY, 20(5), 397–410 (2001)
RAPID CARBOHYDRATE PROTECTING GROUP
MANIPULATIONS ASSISTED BY MICROWAVE
DIELECTRIC HEATING
Eva Söderberg,1 Jacob Westman,2 and Stefan Oscarson1,*
1Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, S-106 91 Stockholm, Sweden
2Personal Chemistry, Hamnesplanaden 5, S-753 19 Uppsala, Sweden
ABSTRACT
The protocols for oligosaccharide synthesis are often tedious due to extended
synthetic routes and reaction times. We herein describe methods assisted by
microwave dielectric heating, which enable very short reaction times and high
yields for the introduction and removal of eleven of the most commonly used
protecting groups in carbohydrate syntheses. Several examples are reported,
where solid supported reagents in combination with microwave dielectric heat-
ing have been used. This results in both faster and easier synthesis and purifi-
cation.
INTRODUCTION
The methods needed to produce complex oligosaccharides are often tedious
and complex, irrespective of whether they involve synthesis or isolation from nat-
ural sources. However, since carbohydrates play an important role in a vast array
of biological processes, and there are advantages of carbohydrate-based drugs such
as low toxicity and immunogenicity, the interest in carbohydrates as drug candi-
dates is still high.1 In the development of new chemical entities today, there is a
need for faster and simpler methods for organic synthesis in general and for car-
bohydrate synthesis in particular. Since 1986 microwave irradiation has become an
increasingly popular method for accelerating synthetic transformation in the labo-
ratory.2 This technology offers a clean, effective and convenient method of heat-
397
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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SODERBERG, WESTMAN, AND OSCARSON
398
ing, which often results in higher yields and almost always shorter reaction times.
Some of the applications that have been published lately include palladium assisted
cross-coupling chemistry,3 cyclisation reactions4 and multi-component reactions.5
Carbohydrate chemistry assisted by microwave dielectric heating has so far been
described in a very limited number of publications.6 There has been a small num-
ber of publications dealing with protecting group chemistry but so far most of these
publications are reports of deprotection of different protecting groups using solvent
free techniques.7 We herein describe methods for fast and high yielding protection
and deprotection of hydroxyl functionalities assisted by microwave dielectric heat-
ing. In several cases a comparison is made with results obtained with conventional
methods described in the literature.
RESULTS AND DISCUSSION
Eleven common protecting groups were chosen representing acyl-, alkyl-,
silyl-, and acetal derivatives. As carbohydrate model compounds the monosaccha-
rides 1,2;5,6-di-O-isopropylidene-ꢀ-D-glucopyranose (1) and methyl ꢀ-D-glu-
copyranoside (3) were selected. In this study a Smithsynthesizer from Personal
Chemistry was used. This microwave-based synthesizer has a single mode cavity
with temperature regulation and pressure control, which means, that temperature
runaway and explosion risk are avoided. It should be noticed that the reaction con-
dition is not expressed by the power generated from the magnetron as for most mi-
crowave-assisted reactions published. All the data on the introduction of the vari-
ous protecting groups are summarized in Table 1. The yields are all isolated yields
after silica gel chromatography. However, most of the reactions were “one-spot”
TLC-reactions, and a simple washing procedure (or in the case of solid-supported
reagents a simple filtration) gave products in very high yields and sufficiently pure
to be used in subsequent reactions.
Acylations (Table 1, Entries 1–10, Schemes 1 and 2)
Compound 1 was acylated with acetyl chloride, chloroacetyl chloride, pival-
oyl chloride and benzoyl chloride together either with a conventional base,
pyridine, or with N,N-(diisopropyl)aminoethylpolystyrene (PS-DIEA) or N-
(methylpolystyrene)-4-(methylamino)pyridine (PS-DMAP) to give the 3-O- pro-
tected compounds 1a-1d in good yields in less than 20 minutes. The use of solid
supported reagent in these reactions resulted in a slightly slower reaction but still
fast compared to conventional methods. Of special interest are the entries regard-
ing the formations of pivaloyl esters (Entries 5–8). Due to the steric bulk of the pi-
valoyl group, these are often very slow reactions using conventional methods.
However, utilizing microwave heating pivaloate formation (even multiple, Entry
8) are in the same time range as acetate or benzoate formation.
With compound 1 as starting material a byproduct was formed in about 25%
yield during benzoylation and pivaloylation with pyridine as base. This was shown

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Table 1. Protection
Convent. Methods
Temp. Time/Yield Ratio Time/Yield/Temp.
Product
Reagent
AcCl
AcCl
AcCl
Base
(°C)
(min)/(%)
1:2a
(min)/(%)/(°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1a
1a
1a
1b
Pyridine
PS-DIEA
PS-DMAP
Pyridine
Pyridine
PS-DIEA
PS-DMAP
pyridine
Pyridine
PS-DMAP
NaH
NaH
NaH
KOH
Ag2O
KOH
NaH
170
165
180
100
170
160
180
160
170
170
190
190
180
150
190
160
180
200
180
190
180
170
12/80
20/66
15/85
8/95
15/85
20/79
15/88
10/68
10/96
15/89
1/88
1/95
1/96
2/98
20/68
5/90
n.d./81/609
—
—
—
ClAcCl
1c ꢁ 2c PivCl
3:1
3:1
n.d./77/609
—
1c
1c
3a
PivCl
PivCl
PivCl
300/88/rt19
2160/82/rt11
10/95/rtb,10
—
1d ꢁ 2d BzCl
1d
1e
1f
1f
1f
1f
1g
1h
1i ꢁ 2i
1i ꢁ 2i
1j
3b
3c
BzCl
AllBr
BnCl
BnBr
BnCl
BnBr
720/87/rt12
—
120/82/5013
300/82/reflux14
5640/90/rt15
120/94/rt16
300/29/rtb,17
120/90/rtb,18
11520/65/rt19
—
pMBnBr
oNO2BnBr
2/94
ButMe2SiCl Imidazole
10/94
15/83
5/93
10/70
5/83
3:1
3:1
ButMe2SiCl PS-DMAP
BSA
BSA
PhCHBr2
—
—
—
—
PS-DMAP
a Determined by NMR.
b Not the same reagents.
to be 6-O-benzoyl(pivaloyl)-1,2;3,5-di-O-isopropylidene-ꢀ-D-glucopyranose (2c
and 2d) obtained through a 5,6 to 3,5-acetal migration prior to acylation. Acetal
migration was not observed for the acetylation and chloroacetylation reactions, in-
dicating that acetylation is too rapid to allow for the acetal rearrangement. This mi-
gration, which has been observed earlier under Koenigs-Knorr and halogenation
conditions,8 is probably catalyzed by the formed pyridinium chloride, since irradi-
ation of 1 in pyridine with no acyl chloride added showed no migration. Further-
more, the use of a solid supported base, when the pyridinium chloride formed is
bound to the resin and not free in solution, prevented the migration.
Alkylations (Table 1, Entries 11–17, Scheme 1)
With a strong base very short reaction times were needed and excellent yields
of products were obtained. Also with a weak base an acceptable yield of product
was obtained in about 20 minutes (Entry 15). Most interesting is that the short re-
action time permits the use of a strong base even with base-labile starting materi-
als. For example, nitrophenyl groups in the reagent or in the saccharide to be pro-

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SODERBERG, WESTMAN, AND OSCARSON
400
Scheme 1.
tected most often excludes the use of sodium hydride as base, however, employing
microwave heating a very high yield of an o-nitrobenzyl protected derivative was
obtained (Entry 17).
Silylation (Table 1, Entries 18–21, Schemes 1 and 2)
Tert-Butyldimethylsilyl chloride with pyridine or PS-DMAP was employed
for the introduction of TBDMS groups, and for trimethylsilylation N,O-bis-
(trimethylsilyl)-acetamide (BSA) was used, a reagent which does not require any
additional base. Once more, short reaction times and high yields were observed.
Additionally, silylation with sterically hindered silyl reagents is the most applica-
ble field for microwave heating resulting in reaction rate enhancements of up to
around 700 times as compared to conventional methods (Entry 19). Here, too, ac-
etal migration was observed in compound 1, but this time the use of a solid sup-
ported base did not prevent this side reaction (Entries 18 and 19).
Acetal Formation (Table 1, Entry 22, Scheme 2)
The method developed by Garegg et al.22 to form benzylidene acetals by us-
ing benzal bromide in pyridine under refluxing condition for several hours was
Scheme 2.

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401
Table 2. Deprotection
Starting
Material
Temp.
(°C)
Time/Yield
(min)/(%)
Product
Reagent
Et3N
KCN
Et3N
Bu4NBr/KF
K10 Clay
K10 Clay
K10 Clay
Poly-PPTS
1
2
3
4
5
6
7
8
1d
1d
4
1i
1i
1
1
1
150
120
150
180
150
150
150
150
15/71
3/67
15/78
2/61
4/85
3/91
2/89
2/94
4a
1
glucose
glucose
4b
4
3c
3
modified. Compound 3 was treated with benzal bromide and PS-DMAP in
MeCN to form the 4,6-O-benzylidene derivative 3c in 83% yield after 5 min at
170° C.
Deprotection
For deprotection studies mild condition methods were chosen to see if the ex-
tended reaction times often connected with such methods could be shortened by the
use of microwave heating. Some solid supported reagents were also tested here.
The results are summarized in Table 2.
Deacylation (Table 2, Entries 1–3, Schemes 1 and 3)
The methods described by Tsuzuki et al.23 and Mori et al.24 were tried. Com-
pound 1d and ethyl 2,3-di-O-benzoyl-4,6-O-benzylidene-1-thio-ꢂ-D-glucopyra-
noside (4)25 were heated at 150 °C for 15 min in a mixture of triethylamine/
MeOH/water 1:5:1 to give compound 1 in 71 % yield and compound 4a in 78%
yield. Deacylation of compound 1d was also achieved using KCN in EtOH/H2O26
and heating for 3 min at 120 °C to give 1 in 67% yield.
Scheme 3.

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SODERBERG, WESTMAN, AND OSCARSON
402
Desilylation and Deacetalation (Table 2, Entries 4–8, Schemes 1–3)
There are a number of methods for deprotection of silyl groups under both
acidic and basic conditions.27 For basic conditions, compound 1i was treated with
Bu4NBr and KF for 2 min at 180 °C to give compound 1 in 61% yield. Montmo-
rillonite K 10 Clay in MeOH/water 1:1 was used for slightly acidic conditions. This
reagent also cleaves acetals and 4,4ꢃ-dimethoxytrityl protecting groups.28 Com-
pounds 1i and 1 were treated with K 10 Clay in MeOH/H2O at 150 °C for 4 min
and 3 min, respectively, to give glucose in high yields (85% and 91%, respec-
tively). This can be compared to the original conditions (75 °C for 72 h, 77% yield)
for deprotection of compound 1 to glucose.29 Similarily, compound 4 was treated
with K 10 Clay in MeOH/H2O for 2 min at 150 °C to give compound 4b in 89%
yield. Since polymer supported reagents worked out well for the acylation reaction,
we treated compound 3c with polymer supported PPTS (poly(4-vinylpyridinium p-
toluenesulfonate)) in EtOH/H2O at 150 °C for 2 min to give methyl ꢀ-D-glucopy-
ranoside (3) in 94% yield.
CONCLUSIONS
Microwave-heating has been shown to be a most useful method to assist pro-
tecting group manipulation reactions on saccharides. Short reaction times and large
rate enhancements as compared to conventional methods are observed, notably in
reactions using mild reagents or involving steric hindrance. Yields are comparable
or better than when using conventional methods, and sometimes much higher in re-
actions where the short reaction time prevents decomposition. The short reaction
times in combination with the easy performance and work-up, especially when us-
ing solid-supported reagents, make the method most attractive and also suitable for
automation.
EXPERIMENTAL
General Methods. The microwave assisted reactions were performed in a
Smithsynthesizer, a single mode microwave cavity, from Personal Chemistry.
NMR spectra were recorded in CDCl3 with Me4Si as internal standard at 25 °C, us-
ing a Varian Mercury 300 instrument at 300 MHz (1H)/75 MHz (13C). All NMR
spectra recorded were in agreement with the postulated structures and only selected
data are reported. TLC was performed on silica gel 60 F254 (Merck) and the prod-
ucts were detected by visualization under 254 nm light and charring with 8%
H2SO4 (aq). The samples were purified by flash chromatography on Silica Gel
(0.0404–0.063 mm, Amicon) eluted with toluene/EtOAc 4:1–1:1, unless otherwise
stated. Optical rotations were recorded at room temperature with a Perkin-Elmer
241 polarimeter using a 10 cm, 1 mL cell. All starting reagents were of the best
grade available (Aldrich or Lancaster) and were used without purification. The

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403
solid supported reagents were from Argonaut technologies or Aldrich. CAU-
TION: These reactions are not recommended to be carried out in a multimode
domestic microwave oven due to nonuniform irradiation and no temperature
control (risk of explosion and thermal runaway). Also observe that the reactions
are run in a closed vessel (screwcap with a septum) and that in several cases the
pressure during the reaction is between 5–10 bar.
3-O-Acetyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1a). Method
A: 1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1) (100 mg, 0.38 mmol) was
dissolved in MeCN (2 mL). Acetyl chloride (55 ꢄL, 0.77 mmol) and pyridine (93
ꢄL, 1.15 mmol) were added to the solution. The sample was irradiated for 12 min
at 170 °C. The mixture was diluted with MeOH, concentrated and purified to give
1a (93 mg, 0.31 mmol, 80%).
Method B: To a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL), acetyl
chloride (55 ꢄL, 0.77 mmol) and N,N-(diisopropyl)aminoethylpolystyrene (PS-
DIEA) (300 mg, 1.15 mmol) were added. The sample was irradiated for 20 min at
165 °C. The mixture was then filtered, concentrated and purified to give 1a (77 mg,
0.25 mmol, 66%).
Method C: To a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL), acetyl
chloride (83 ꢄL, 1.15 mmol) and N-(methylpolystyrene)-4-(methylamino)pyridine
(PS-DMAP) (402 mg, 1.54 mmol) were added. The sample was irradiated for 15
min at 180 °C and worked up and purified as described for Method B to give 1a
(99 mg, 0.32 mmol, 85%). 1a: [ꢀ]D ꢅ33° (c 1.0, CHCl3). (lit. ref. [ꢀ]D ꢅ31°).10
3-O-Chloroacetyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1b).
To compound 1 (100 mg, 0.38 mmol) in MeCN (2 mL), chloroacetyl chloride (60
ꢀL, 0.77 mmol) and pyridine (60 ꢄL, 0.77 mmol) were added. Irradiation of the
sample was performed for 8 min at 100 °C. The mixture was diluted with MeOH,
concentrated and purified to give 1b (123 mg, 0.36 mmol, 95%): [ꢀ]D ꢅ32° (c 1.0,
CHCl3). (lit. ref. [ꢀ]D ꢅ33°).31
3-O-Pivaloyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1c) and 6-
O-Pivaloyl-1,2:3,5-di-O-isopropylidene-ꢀ-D-glucofuranose (2c). Method A:
Pivaloyl chloride (95 ꢄL, 0.77 mmol) and pyridine (93 ꢄL, 1.15 mmol) were added
to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL). The sample was irradi-
ated for 15 min at 170° C. The mixture was diluted with MeOH, concentrated and
purified to give 1cꢁ2c (3:1, 112 mg, 0.32 mmol, 85%).
Method B: Pivaloyl chloride (95 ꢄL, 0.77 mmol) and PS-DIEA (300 mg, 1.15
mmol) were added to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL). The
sample was irradiated for 20 min at 160 °C. The mixture was filtered, concentrated
and purified to give 1c (105 mg, 0.30 mmol, 79%).
Method C: Pivaloyl chloride (141 ꢄL, 1,15 mmol) and PS-DMAP (402 mg,
1.54 mmol) were added to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL).
The sample was irradiated for 15 min at 180 °C. The mixture was filtered, concen-
trated and purified to give 1c (116 mg, 0.34 mmol, 88%). 1c: [ꢀ]D ꢅ26° (c 1.0,

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SODERBERG, WESTMAN, AND OSCARSON
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CHCl3). 13C NMR (CDCl3) ꢆ 67.9 (C-6), 72.6, 76.0, 80.5, 83.5 (C-2,-5), 105.33
(C-1), 109.4, 112.4 ((CH3)2COO), 176.9 (COO, ester). (lit. ref. 13C NMR (CDCl3)
ꢆ 105.2 (C1), 109.2, 112.2 ((CH3)2COO), 176.6 (COO, ester).9
3-O-Benzoyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1d) and 6-
O-Benzoyl-1,2:3,5-di-O-isopropylidene-ꢀ-D-glucofuranose (2d). Method A:
Compound 1 (100 mg, 0.38 mmol) was dissolved in MeCN (2 mL). Benzoyl chlo-
ride (89 ꢄL, 0.77 mmol) and pyridine (124 ꢄL, 1.54 mmol) were added to the so-
lution. The sample was irradiated for 10 min at 170 °C. The mixture was diluted
with MeOH, concentrated and purified to give 1dꢁ2d (3:1, 134 mg, 0.37 mmol,
95%).
Method C: Benzoyl chloride (89 ꢄL, 0.77 mmol) and PS-DMAP (1040 mg,
1.54 mmol) were added to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL).
The sample was irradiated for 15 min at 170 °C. The mixture was filtered, concen-
trated and purified to give 1d (124 mg, 0.34 mmol, 89%). 1d: [ꢀ]D ꢅ50° (c 1.0,
CHCl3). (lit. ref. [ꢀ]D ꢅ49.7°, EtOH).10
3-O-Allyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1e). Allyl
bromide (49 ꢄL, 0.58 mmol) and sodium hydride (23 mg, 0.58 mmol) were added
to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL). Irradiation of the sample
was performed for 1 min at 190 °C. The mixture was diluted with MeOH, concen-
trated and purified to give 1e (101 mg, 0.33 mmol, 88%): [ꢀ]D ꢅ24° (c 1.0,
CHCl3). (lit. ref. [ꢀ]D ꢅ28.8°).32
3-O-Benzyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose
(1f).
Method A: Compound 1 (100 mg, 0.38 mmol) was dissolved in MeCN (2 mL) and
benzyl chloride (133 ꢄL, 1.15 mmol) and potassium hydroxide (107 mg, 1.92
mmol) were added to the solution. The sample was irradiated for 2 min at 150 °C.
Purification gave 1f (132 mg, 0.38 mmol, 98%).
Method B: To a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL), benzyl
chloride (66 ꢄL, 0.58 mmol) and sodium hydride (23 mg, 0.58 mmol) were added.
The sample was irradiated for 1 min at 190 °C. Methanol was added to quench the
reaction. Purification gave 1f (128 mg, 0.36 mmol, 95%).
Method C: Benzyl bromide (114 ꢄL, 0.96 mmol) and silver oxide (89 mg,
1.15 mmol) were added to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL).
The sample was irradiated for 20 min at 190 °C. The mixture was diluted with
MeOH, filtered, concentrated and purified to give 1f (91 mg, 0.26 mmol, 68%).
Method D: To a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL), benzyl
bromide (69 ꢄL, 0.58 mmol) and sodium hydride (23 mg, 0.58 mmol) were added.
Irradiation of the sample was performed for 1 min at 180 °C. The mixture was di-
luted with MeOH, concentrated and purified to give 1f (129 mg, 0.37 mmol, 96%).
1f: [ꢀ]D ꢅ26° (c 1.0, CHCl3). (lit. ref. [ꢀ]D ꢅ26.4°).13
3-O-p-Methoxybenzyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose
(1g). Compound 1 (100 mg, 0.38 mmol) was dissolved in MeCN (2 mL). p-

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Methoxybenzyl chloride (130 ꢄL, 0.96 mmol) and potassium hydroxide (64 mg,
1.15 mmol) were added to the solution. The sample was irradiated for 5 min at 160
°C. Purification gave 1g (132 mg, 0.35 mmol, 90%): [ꢀ]D ꢅ27° (c 1.0, CHCl3). (lit.
ref. [ꢀ]D ꢅ17°).33
3-O-o-Nitrobenzyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1h).
o-Nitrobenzyl bromide (166 mg, 0.77 mmol) and sodium hydride (31 mg, 0.77
mmol) were added to a solution of 1 (100 mg, 0.38 mmol) in MeCN (2 mL). The
sample was irradiated for 2 min at 180 °C. The mixture was quenched with MeOH,
concentrated and purified to give 1h (143 mg, 0.36 mmol, 94%): [ꢀ]Dꢅ38° (c 1.0,
CHCl3); 1H NMR (CDCl3) ꢆ 1.33, 1.34, 1.43, 1.51 (s, 12H, CH3), 4.00–4.03 (m,
1H, H-6), 4.10–4.17 (m, 3H, H-3, H-4, H-6), 4.33–4.40 (m, 1H, H-5), 4.66–4.68
(d, 1H, H-2), 4.98–5.03 (d, 1H, CH2 benzyl), 5.12–5.17 (d, 1H, CH2 benzyl),
5.92–5.93 (d, 1H, J1,2 ꢇ 3.57 Hz, H-1), 7.43–8.10 (m, 4H, aromatic H); 13C NMR
(CDCl3) ꢆ 25.6, 26.5, 27.1 (CH3), 67.8 (C-6), 68.9 (C-5), 72.5 (CH2-Bn), 81.4 (C-
4), 82.4 (C-3), 82.6 (C-2), 105.4 (C-1), 109.3, 112.1 ((CH3)2COO), 124.8, 128.3,
128.9, 133.8, 134.5 147.2 (aromatic C).
Anal. Calcd for C19H25NO8 (395.40): C, 57.71; H, 6.37; N, 3.54. Found: C,
57.92; H, 6.28; N; 3.69.
3-O-tert-Butyldimethylsilyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofura-
nose (1i) and 6-O-tert-Butyldimethylsilyl-1,2:3,5-di-O-isopropylidene-ꢀ-D-
glucofuranose (2i). Method A: tert-Butyldimethylsilyl chloride (116 mg, 0.77
mmol) and imidazole (52 mg, 0.77 mmol) were added to a solution of 1 (100 mg,
0.38 mmol) in DMF (2 mL). The sample was irradiated for 10 min at 200 °C. The
mixture was diluted with toluene and extracted with water. The organic layer was
dried (MgSO4), filtered and concentrated. Purification gave 1iꢁ2i (3:1, 136 mg,
0.36 mmol, 94%).
Method B: tert-Butyldimethyl silyl chloride (116 mg, 0.77 mmol) and PS-
DMAP (780 mg, 1.15 mmol) were added to a solution of 1 (100 mg, 0.38 mmol)
in DMF (2 mL). The sample was irradiated for 15 min at 180 °C. The mixture
was filtered, concentrated and purified to give 1iꢁ2i (3:1, 120 mg, 0.32 mmol,
83%).
3-O-Trimethylsilyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose (1j).
N,O-Bis-(trimethylsilyl)acetamide (BSA) (285 ꢄL, 1.15 mmol) was added to a so-
lution of 1 (100 mg, 0.38 mmol) in DMF (2 mL). The sample was irradiated for 15
min at 190 °C. The mixture was worked up as described above in method A. Pu-
rification gave 1j (119 mg, 0.36 mmol, 93%). [ꢀ]D ꢅ18° (c 1.0, CHCl3). (lit. ref.
[ꢀ]D ꢅ16.9°).34
Methyl 2,3,4,6-Tetra-O-pivaloyl-ꢀ-D-glucopyranoside (3a). To a solu-
tion of methyl ꢀ-D-glucopyranoside (3) (100 mg, 0.51 mmol) in MeCN (2 mL), pi-
valoyl chloride (282 ꢄL, 2.31 mmol) and pyridine (248 ꢄL, 3.07 mmol) were
added. The sample was irradiated for 10 min at 160 °C, whereafter the mixture was

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SODERBERG, WESTMAN, AND OSCARSON
406
diluted with MeOH, concentrated and purified to give 3a (185 mg, 0.35 mmol,
68%): [ꢀ]D ꢁ105° (c 1.0, CHCl3). (lit. ref. [ꢀ]D ꢁ102°).11
Methyl 2,3,4,6-Tetra-O-trimethylsilyl-ꢀ-D-glucopyranoside (3b). To a
solution of 3 (100 mg, 0.51 mmol) in DMF (2 mL), BSA (1018 ꢄL, 4.12 mmol)
was added. The sample was irradiated for 10 min at 180 °C. Purification gave 3b
(89 mg, 0.27 mmol, 70%): [ꢀ]D ꢁ80° (c 1.0, CHCl3). (lit. ref. [ꢀ]D ꢁ79.7°).35
Methyl 4,6-O-Benzylidene-ꢀ-D-glucopyranoside (3c). Benzal bromide
(166 ꢄL, 1.0 mmol) and PS-DMAP (1044 mg, 1.54 mmol) were added to a solu-
tion of compound 2 (100 mg, 0.51 mmol) in MeCN (2 mL). The sample was irra-
diated for 5 min at 170° C. Purification gave 3c (121 mg, 0.43 mmol, 83%): [ꢀ]D
ꢁ89° (c 1.0, CHCl3). (lit. ref. [ꢀ]D ꢁ105°).36
Ethyl 4,6-O-Benzylidene-1-thio-ꢁ-D-glucopyranoside (4a). Ethyl 2,3-
di-O-benzoyl-4,6-O-benzylidene-1-thio-ꢂ-D-glucopyranoside (4) (100 mg, 0.19
mmol) was treated with Et3N/MeOH/H2O 1:5:1 (2 mL) and irradiated at 150 °C
for 15 min,. The mixture was concentrated and purified (toluene/EtOAc 1:1)
to give 4a (47 mg, 0.15 mmol, 78%): [ꢀ]D ꢅ61° (c 1.0, CHCl3). (lit. ref.
[ꢀ]D ꢅ65°).37
Ethyl 2,3-Di-O-benzoyl-1-thio-ꢁ-D-glucopyranoside (4b). Compound 4
(50 mg, 0.10 mmol) was treated with Montmorillonite K 10 Clay (50 mg) in
MeOH/H2O 1:1 (2 mL) and irradiated for 2 min at 150° C. The mixture was fil-
tered, concentrated and purified (toluene/EtOAc 1:1) to give 4b (37 mg, 0.08
mmol, 89%): [ꢀ]D ꢁ63° (c 1.0, CHCl3). (lit. ref. [ꢀ]Dꢁ87.6°).38
Deacylation of 3-O-Benzoyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofura-
nose (1d). Compound 1d (55 mg, 0.15 mmol) was treated with Et3N/MeOH/H2O
1:5:1 (2 mL), and irradiated for 15 min at 150 °C or with KCN (10 mg, 0.15 mmol)
in 2 mL EtOH/H2O 1:1 and irradiated for 3 min at 120 °C. The mixtures were con-
centrated and purified to give compound 1 (28 mg, 0.11 mmol, 71%), respectively,
(26 mg, 0.10 mmol, 67%).
Desilylation of 3-O-tert-Butyldimethylsilyl-1,2:5,6-di-O-isopropylidene-
ꢀ-D-glucofuranose (1i). To a solution of 1i (55 mg, 0.147 mmol) in MeCN (2
mL), Bu4NBr (95 mg, 0.29 mmol), potassium fluoride (17 mg, 0.29 mmol) and
H2O (0.1 mL) were added. The sample was irradiated for 2 min at 180 °C. Purifi-
cation (toluene/EtOAc 1:1) gave 1 (23 mg, 0.09 mmol, 61%).
Deprotection of 1,2:5,6-Di-O-isopropylidene-ꢀ-D-glucofuranose (1) and
3-O-tert-Butyldimethylsilyl-1,2:5,6-di-O-isopropylidene-ꢀ-D-glucofuranose
(1i). Compound 1 (100 mg, 0.38 mmol) and compound 1i (100 mg, 0.26 mmol)
were treated with Montmorillonite K 10 Clay (200 mg) in MeOH/H2O 1:1 (2 mL)
and irradiated for 3 and 4 min, respectively, at 150° C. The mixtures were filtered,
concentrated and purified (EtOAc:H2O: EtOH:AcOH; 20:3:3:2) to give glucose

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407
from compound 1 (63 mg, 0.35 mmol, 91%) and from compound 1i (40 mg, 0.22
mmol, 85%).
Deacetalation of Methyl 4,6-O-Benzylidene-ꢀ-D-glucopyranoside (3c).
Compound 3c (100 mg, 0.35 mmol) was treated with poly-4-vinylpyridinium p-
toluenesulfonate (200 mg) in EtOH/H2O 1:1 (2 mL) at 150 °C for 2 min. The mix-
ture was filtered, concentrated and purified (EtOAc:H2O:EtOH:AcOH; 20:3:3:2)
to give compound 3 (64 mg, 0.33 mmol, 94%).
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Received October 10, 2000
Accepted February 26, 2001

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