Reiterative intramolecular glycosylation supported by a rigid spacer

Article abstract of DOI:10.1002/1099-0690(200301)2003:1<128::AID-EJOC128>3.0.CO;2-S

This paper describes a synthesis of trisaccharide 1 by reiterative intramolecular glycosidation with 5-(bromomethyl)-2-methylbenzoic acid (5a) as starting material for the generation of a rigid spacer. Intramolecular glycosidation of donor-acceptor-tethered compound 24 yielded disaccharide 25. Transesterification of 25 afforded 26, which generated a new linking centre for the next spacer. Repetition of the previous cycle on 26 yielded trisaccharide 1, which again presents an extension point for the synthesis of higher saccharides. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/1099-0690(200301)2003:1<128::AID-EJOC128>3.0.CO;2-S

FULL PAPER
Reiterative Intramolecular Glycosylation Supported by a Rigid Spacer
Soumendu Paul,[a] Matthias Müller,[a] and Richard R. Schmidt*[a]
Keywords: Carbohydrates / Glycosidation / Macrocycles / Oligosaccharides / Spacers
This paper describes a synthesis of trisaccharide 1 by reiter- new linking centre for the next spacer. Repetition of the pre-
ative intramolecular glycosidation with 5-(bromomethyl)-2-
vious cycle on 26 yielded trisaccharide 1, which again pre-
methylbenzoic acid (5a) as starting material for the genera- sents an extension point for the synthesis of higher sacchar-
tion of
a
rigid spacer. Intramolecular glycosidation of
ides.
donor−acceptor-tethered compound 24 yielded disaccharide
25. Transesterification of 25 afforded 26, which generated a
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2003)
Introduction
Thanks to the prominent role of carbohydrates in bio-
logy,[1] glycoside bond formation is an area of intense activ-
ity in contemporary research in organic chemistry. The im-
portance of carbohydrates in biology stems from Nature’s
ability to effect glycosylation with absolute stereoselectivity,
a feature which in many cases is still only a desire in chem-
ists’ repertoire of methodology. In recent years, intramolec-
ular glycosylation[2] has emerged as a powerful tool for ster-
eoselective construction of glycosidic linkages. The various
approaches to intramolecular glycosylation[2,3] include the
spacer-mediated linkages of donor and acceptor through
nonreacting centres,[2,3Ϫ5] and among these we have devised
the rigid spacer-mediated concept,[2,6Ϫ10] which offers the
advantages of good yields and a high degree of anomeric
stereocontrol. To allow for reiterative glycosylation by this
approach, we envisioned the use of unsymmetrical rigid
spacers.[9] Scheme 1 depicts a general outline for reiterative
glycosylation by this approach. As shown for A, an accep-
tor with two selectively accessible hydroxy groups is re-
quired. Selective attachment of the rigid spacer by one
handle to one of the hydroxy groups of A affords B. Then,
tethering of the donor, which also has two selectively ac-
cessible hydroxy groups, to the other handle of the rigid
spacer yields C. Glycosidation (Ǟ D) and ring-opening of
the spacerϪdisaccharide macrocycle to liberate 1 equiv. of
A concludes this conceptual approach.
Scheme 1. Reiterative intramolecular oligosaccharide synthesis, R
increasing with each cycle
Y ϭ CO2tBu, R ϭ Me) was used to provide the desired
rigid spacer. The 2-methyl group of 5a was introduced to
reduce the conformational space in favour of the reacting
centres (Scheme 2, b). A [3-(bromomethyl)phenyl]silyl rigid
spacer 5b (5: Y ϭ SiiPr2Cl, R ϭ H) was also investigated.
Results and Discussion
Compound 2a[9] reacted smoothly with spacer 5a under
standard base-catalysed conditions, to yield 6 in 65% yield
with NaH as base and DMF as solvent (Scheme 3). To
achieve the desired (1Ǟ4)-glycosidic linkage, and also to
facilitate spacer linkage to acceptor 3, so as to yield a 14-
membered macrocycle,[2,7] it was necessary to replace the
methoxyphenylmethyl (MPM) group. Hence, 6 was treated
with DDQ/dichloromethane to yield the deprotected com-
pound, which was treated without purification with levul-
inic acid in the presence of DCC/DMAP to furnish the 4-
As our first attempt, we describe the synthesis of trisac-
charide 1 (Scheme 2), which we selected as a target for our
synthetic endeavours. As indicated in Scheme 2, 1 can be
assembled from known building blocks 2,[9,11,12] 3,[13] and
4.[14] tert-Butyl 5-(bromomethyl)-2-methylbenzoate (5a) (5:
[a]
Fachbereich Chemie, University of Konstanz,
Postfach M 725, 78457 Konstanz, Germany
Fax: (internat.) ϩ 49-(0)7531/88-3135
E-mail: Richard.Schmidt@uni-konstanz.de
128
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0128 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 128Ϫ137

Reiterative Intramolecular Glycosylation Supported by a Rigid Spacer
FULL PAPER
Scheme 2. (a) Retrosynthesis of target molecule 1; (b) preferred
conformers of 5a; R ϭ Bn; R1 ϭ Bn, Me; R4 ϭ MPM, H; R6 ϭ
PhCHOMe; RS ϭ rigid spacer
O-levulinoyl derivative 7 in 84% yield. Removal of the tert-
butyl group of 7 with TFA in dichloromethane yielded acid
8, which, when treated with 3 under standard esterification
conditions (DCC/DMAP), furnished ester 9 in 50% yield.
To set the stage for the generation of a 14-membered mac-
rocycle for glycosylation, the levulinoyl group of 9 was re-
moved with hydrazinium acetate in dichloromethane to
yield donorϪacceptor-tethered compound 10. Glycosyl-
ation of 10 under N-iodosuccinimide/triflic acid (NIS/
TfOH) mediated conditions afforded the disaccharide 11 in
71% yield. The reaction proceeded stereoselectively to yield
the β anomer. This result was unexpected, because 3-(β)-
donor/5,4--threo-acceptor tethering with a rigid m-xylylene
spacer had produced the Glcα(1Ϫ4)Glc linkage.[2,4Ϫ7] To
generate an anchoring point for further glycosylation, 11
was untethered by transesterification with sodium methox-
ide in methanol, to provide 12 in quantitative yield. The 3Ј-
hydroxy group of 12 was able to serve as the centre for the
next spacer linkage.
Scheme 3. Synthesis of disaccharide 12 with a 3-(methoxycarbonyl)-
benzyl spacer
move the methoxyphenylmethyl (MPM) group to provide
Encouraged by the results achieved with the 3-(methoxy- 16 in 87% yield. Glycosidation of 16 under NIS/TfOH-me-
carbonyl)benzyl spacer 5, we decided to explore the efficacy diated conditions gave a 1:1 mixture of 17α and 17β in an
of using a 3-silylbenzyl spacer in intramolecular glycosid- overall yield of 90%, whereas glycosidation under methyl
ation (Scheme 4). The 3-O-unprotected glucoside 3,[13] triflate mediated conditions yielded the α anomer 17α in
when treated with m-bromobenzyl bromide in the presence 70% yield. The silyl tethers of compounds 17α and 17β were
of NaH in DMF, furnished 3-bromobenzyl derivative 13 in cleaved by tetrabutylammonium fluoride (TBAF) in tetra-
90% yield. Compound 13, on treatment with diisopropylsi- hydrofuran to furnish 19α and 19β in 91% and 93% yields,
lyl dichloride in the presence of tert-butyllithium in THF at respectively. The benzylidene ring of 17β was cleaved with
Ϫ100 °C, furnished silyl chloride derivative 14. Next, 14 ethanethiol and p-toluenesulfonic acid (PTSA) to afford
was treated with acceptor 2b[11] under standard basic condi- 18β in 86% yield.
tions (NaH, DMF) to yield the spacer-linked compound
With the success of the methods described above behind
15. In the light of our previous success, glycosylation us, we chose to reflect on the suitability of either of the
through the intermediacy of a 14-membered macrocycle two methods for the synthesis of target molecule 1. Close
was an obvious choice, so 15 was treated with DDQ to re- evaluation revealed the 3-(bromomethyl)benzoyl spacer 5a
Eur. J. Org. Chem. 2003, 128Ϫ137
129

S. Paul, M. Müller, R. R. Schmidt
FULL PAPER
Scheme 4. Synthesis of disaccharides 19 with a 3-silylbenzyl spacer
to be better suited with regard both to its ease of synthesis glycosylation, 25 was transesterified with sodium methoxide
and to the stereoselectivity of the glycosylation reaction. in methanol to yield 3Ј-O-unprotected disaccharide 26
The target molecule 1 was synthesised by the sequence of (90%). The spacer 5a was now linked to the 3Ј-hydroxy
reactions outlined in Scheme 5. Acceptor 2c[12] was trans- group of 26 under standard basic conditions (NaH, DMF).
formed into compound 20 (70%) via the dibutylstannylene Much to our surprise, however, this reaction proceeded with
acetal (Bu2SnO/toluene) and subsequent treatment with a concomitant hydrolysis of the tert-butyl ester group to
spacer 5a. The 4-hydroxy group of 20, which was destined furnish benzoic acid derivative 27 in 75% yield. This, which
to act as an acceptor in the glycosylation reaction, was pro- to the best of our knowledge has not previously been re-
tected as the levulinoyl ester 21 under standard conditions ported, constitutes a novel method for base-assisted cleav-
(DCC/DMAP). The tert-butyl ester group of 21 was cleaved age of the tert-butyl ester group.[15] Esterification of 27 with
with trifluoroacetic acid in dichloromethane to yield the donor 4[14] under standard conditions yielded
acid 22. Esterification of 22 with 3 (DCC/DMAP) afforded donorϪacceptor-tethered intermediate 28 (70%). Since, in
23 (75%), the levulinoyl group of which was removed by our earlier glycosylations (Schemes 3 and 4), the nucleoph-
the action of hydrazinium acetate to yield donorϪacceptor- ile (i.e., the hydroxy group of the glycosyl acceptor) had
tethered 24 (65%). Glycosylation of 24 under NIS/TfOH been unprotected and not part of a rigid ring system, we
conditions furnished the disaccharide 25 in 73% yield; it conjectured that it would be of interest to investigate glycos-
was also gratifying to observe that the reaction had pro- ylation with an acceptor in which the reactive centre was
ceeded selectively to yield the β anomer. To enable further part of an acid-sensitive ring. We therefore decided to use
130
Eur. J. Org. Chem. 2003, 128Ϫ137

Reiterative Intramolecular Glycosylation Supported by a Rigid Spacer
FULL PAPER
Scheme 5. Synthesis of target molecule 1
28 directly for glycosylation, without cleavage of the benzyl- It needs to be mentioned, however, that longer reaction
idene acetal ring. Iodine in methanol, previously reported times resulted in the cleavage both of the newly formed gly-
for the cleavage of acetals,[3,16] seemed to be a good reagent cosidic linkage as well as of the α-methoxybenzyl group.
for glycosylation of 28; we surmised that iodine, being a Transesterification of 29 with sodium methoxide in meth-
soft atom, would coordinate to the softer sulfur atom at the anol yielded the target molecule 1 in 90% yield. Compound
anomeric centre, in preference to the oxygen of the acetal 1, by virtue of its 6ЈЈ-hydroxy group, presents an extension
ring. Thus, a carbocation would be generated at the anom- point for further synthesis.
eric carbon atom, which might invite an attack from the
secondary oxygen atom of the benzylidene ring (4Ј-O of 28)
in preference to the primary oxygen atom (i.e. 6Ј-O of 28),
furnishing a fourteen-membered ring, due to its proximity
to the anomeric centre, and bring about glycosylation. This
Conclusion
In conclusion, we have successfully demonstrated the util-
hypothesis worked in practice; 28, when treated with a 5% ity of the rigid spacer-based intramolecular glycosidation
(w/v) solution of iodine in methanol, reacted smoothly at method in the stereoselective construction of glycosidic
room temperature to yield 29 (α anomer only) in 83% yield. linkages for the synthesis of higher saccharides by reiterat-
Eur. J. Org. Chem. 2003, 128Ϫ137
131

S. Paul, M. Müller, R. R. Schmidt
FULL PAPER
a colourless oil (1.00 g; 65%). Rf ϭ 0.58. [α]D ϭ ϩ39 (c ϭ 1.00,
CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ 1.58 (s, 9 H), 2.56 (s, 3
H, ArCH3), 3.54Ϫ3.82 (m, 8 H, 2-H, 4-H, 5-H, 6ϪH2, OCH3),
4.05 (dd, J3,4 ϭ J3,2 ϭ 9.2 Hz, 1 H, 3-H), 4.38Ϫ4.87 (m, 11 H, 1-
H, 10 ArCHH), 5.03 (d, J ϭ 10.9 Hz, 1 H), 6.79 (d, J ϭ 8.6 Hz, 2
H, Ar), 7.02 (d, J ϭ 8.6 Hz, 2 H, Ar), 7.17Ϫ7.44 (d, J ϭ 1.8 Hz, 1
H, Ar) ppm. FAB MS: m/z ϭ 797 [Mϩ ϩ Naϩ]. C48H54O9 (774.9):
calcd. C 74.40, H 7.02; found C 73.83, H 6.99.
ive glycosylation. Without anchimeric assistance α- and β-
linkages were stereoselectively generated.
Experimental Section
General: All air- and/or water-sensitive reactions were carried out
under argon in dry solvents under anhydrous conditions. Reactions
were monitored by TLC on Merck silica gel coated plastic sheets
(60 F254) with UV light as visualising agent and 5% (NH4)2MoO4/
0.1% Ce(SO4)2 in 10% H2SO4 and heat as developing agents. Baker
silica gel (particle size 0.040Ϫ0.063 mm) was used for flash chroma-
tography. NMR spectra were recorded with Bruker DRX 600
(600 MHz) and AC 250 (250 MHz) instruments and calibrated with
tetramethylsilane as internal standard. Optical rotations were re-
corded with a PerkinϪElmer 241 MC polarimeter in a 1-dm cell
at 22 °C. FAB mass spectra were recorded with a Finnigan MAT
312/AMD 5000 spectrometer with a 3-nitrobenzyl alcohol matrix.
MALDI mass spectra were recorded with a Kratos compact spec-
trometer with a 2,5-dihydroxybenzoic acid matrix.
tert-Butyl 5-(Benzyl 2,3-di-O-benzyl-4-O-levulinoyl-α-D-glucopyr-
anosid-6-yloxy-methyl)-2-methylbenzoate (7): Water (5 mL) and
DDQ (152 mg, 0.67 mmol) were added to a solution of 6 (470 mg,
0.61 mmol) in dichloromethane, and the reaction mixture was
stirred at room temp. for a period of 5 h. It was then washed with
sodium bicarbonate solution (10 mL) and water (10 mL), and the
organic phase was dried with sodium sulfate and evaporated in
vacuo. The residue was taken up in dichloromethane (50 mL), and
DCC (629 mg, 3.05 mmol), levulinic acid (709 mg, 6.10 mmol) and
DMAP (0.02 g) were added. The reaction mixture was stirred for
a period of 20 h and then filtered, and the organic phase was con-
centrated in vacuo to yield the crude compound, which was puri-
fied by flash chromatography (petroleum ether/ethyl acetate, 4:1)
to yield pure 7 as a colourless oil (386 mg, 84%). Rf ϭ 0.44. [α]D ϭ
tert-Butyl 5-(Bromomethyl)-2-methylbenzoate (5a): Hydrogen
bromide in acetic acid (33%, 13 mL) was added to a mixture of 2-
methylbenzoic acid (4.08 g, 30.0 mmol), paraformaldehyde (2.50 g,
83.0 mmol) and O-phosphoric acid (85%, 7.0 mmol), and the mix-
ture was stirred for a period of 3 h at 115 °C. The system was
allowed to cool and poured into ice-cold water (500 mL), and the
precipitated solid material was filtered off and purified by flash
chromatography (petroleum ether/ethyl acetate, 4:1) to yield pure
5-(bromomethyl)-2-methylbenzoic acid (4.26 g, 62%) as colourless
crystals. TLC (petroleum ether/ethyl acetate, 3:1): Rf ϭ 0.34; m.p.
120Ϫ122 °C. 1H NMR (250 MHz, CDCl3): δ ϭ 2.66 (s, 3 H, CH3),
4.51 (s, 2 H, ArCH2Br), 7.27 (d, J ϭ 7.8 Hz, 1 H, 3-H), 7.49 (dd,
J ϭ 7.8, J ϭ 2.0 Hz, 1 H, 4-H), 8.10 (d, J ϭ 2.0 Hz, 1 H, 6-H)
ppm. EI MS: m/z ϭ 230 [Mϩ], 149 [M Ϫ Br]ϩ. C9H9BrO2 (229.1):
calcd. C 47.19, H 3.96; found C 47.53, H 4.24. This compound
(4.58 g, 20.0 mmol) was dissolved in dichloromethane (200 mL)
and cyclohexane (200 mL), and tert-butyl trichloroacetimidate[17]
(8.74 g, 40.0 mmol) in cyclohexane (20 mL) was added, followed by
the dropwise addition of boron trifluorideϪdiethyl ether (0.63 mL,
5.0 mmol). The mixture was stirred for a period of 1 h at room
temp and washed with sodium bicarbonate solution (100 mL), the
organic phase was dried with sodium sulfate, and the solvent was
evaporated in vacuo. The residue was purified by flash chromato-
graphy (petroleum ether/ethyl acetate, 97:3) to yield pure 5a as a
colourless oil. TLC (petroleum ether/ethyl acetate, 9:1): Rf ϭ 0.47.
1H NMR (250 MHz, CDCl3): δ ϭ 1.60 [br. s, 9 H, C(CH3)3], 2.56
(s, 3 H, CH3), 4.49 (s, 2 H, ArCH2Br), 7.18 (d, J ϭ 7.9 Hz, 1 H,
3-H), 7.39 (dd, J ϭ 7.9, J ϭ 2.0 Hz, 1 H, 4-H), 7.82 (d, J ϭ 2.0 Hz,
1 H, 6-H) ppm. EI MS: m/z ϭ 286 [Mϩ], 205 [M Ϫ Br]ϩ.
C13H17BrO2 (285.2): calcd. C 54.75, H 6.01; found C 54.87, H 5.97.
1
ϩ19 (c ϭ 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 1.58 [s,
9 H, C(CH3)3], 2.11 (s, 3 H, COCH3), 2.28Ϫ2.63 (m, 7 H,
CCH2CH2C, ArCH3), 3.45Ϫ3.60 (m, 3 H, 2-H, 6-H2), 3.90 (m, 1
H, 5-H), 3.99 (dd, J3,2 ϭ J2,3 ϭ 9.5 Hz, 1 H, 3-H), 4.47Ϫ4.68 (m,
7 H, 7 ArCHH), 4.83 (d, J1,2 ϭ 3.6 Hz, 1 H, 1-H), 4.90 (d, J ϭ
11.6 Hz, 1 H, ArCHH), 5.07 (dd, J4,3 ϭ J4,5 ϭ 10.1 Hz, 1 H, 4-H),
7.16Ϫ7.43 (m, 17 H, Ar), 7.74 (d, J ϭ 1.8 Hz, 1 H, Ar) ppm. FAB
MS: m/z ϭ 775 [Mϩ ϩ Naϩ]. C45H52O10 (752.9): calcd. C 71.79,
H 6.96; found C 71.35, H 7.02.
5-(Benzyl
2,3-di-O-benzyl-4-O-levulinoyl-α-D-glucopyranosid-6-
yloxymethyl)-2-methylbenzoic Acid (8): Trifluoroacetic acid (5 mL)
was added to a solution of 7 (0.33 g, 0.44 mmol) in dichlorome-
thane (30 mL) and the reaction mixture was stirred for 5 h at room
temp. Toluene (30 mL) was added, and the solvent was evaporated
in vacuo to yield crude 8, which was purified by flash chromato-
graphy (toluene/ethyl acetate, 1:1) to furnish pure 8 as a crystalline
compound, which was recrystallised from petroleum ether/ethyl
acetate. TLC (toluene/ethyl acetate, 1:1): Rf ϭ 0.27; m.p. 84 °C.
1
[α]D ϭ ϩ36 (c ϭ 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ
2.12 (s, 3 H, COCH3), 2.28Ϫ2.68 (m, 7 H, CCH2CH2C, ArCH3),
3.48Ϫ3.60 (m, 3 H, 2-H, 6-H2), 3.88 (m, 1 H, 5-H), 3.99 (dd, J3,4 ϭ
J3,2 ϭ 9.4 Hz, 1 H, 3-H), 4.50Ϫ4.71 (m, 7 H, 7 ArCHH), 4.83 (d,
J
1,2 ϭ 3.6 Hz, 1 H, 1-H), 4.90 (d, J ϭ 11.6 Hz, 1 H, ArCHH), 5.08
(dd, J4,3 ϭ J4,5 ϭ 10.1 Hz, 1 H, 4-H), 7.22Ϫ7.49 (m, 17 H, Ar),
7.97 (d, J ϭ 1.8 Hz, 1 H, Ar) ppm. C41H44O10 (696.8): calcd. C
70.67, H 6.36; found C 70.63, H 6.46.
Spacer-Linked Monosaccharide؊Monosaccharide 9: DCC (0.223 g,
1.08 mmol) and a catalytic amount of DMAP (0.02 g) were added
to a solution of 8 (0.502 g, 0.72 mmol) and 3 (0.346 mg, 0.86 mmol)
in dichloromethane (30 mL). The reaction mixture was stirred for
tert-Butyl 5-[Benzyl 2,3-di-O-benzyl-4-O-(4-methoxybenzyl)-α-
D-
glucopyranosid-6-yloxymethyl]-2-methylbenzoate (6): NaH (96 mg,
4.00 mmol) and 2a[9] (1.14 g, 2.0 mmol) were added to a solution 20 h at room temp., by which time the reaction had reached com-
of 5 (856 mg; 3.00 mmol) in DMF (20 mL). The mixture was stirred
at room temp. for 20 h, by which time the reaction had proceeded
to completion. The reaction mixture was diluted with MeOH
(10 mL) and ethyl acetate (100 mL) and washed with brine
(100 mL). The aqueous phase was reextracted with ethyl acetate
(3ϫ50 mL); the combined organic extract was washed with water
and brine, dried with sodium sulfate and concentrated in vacuo to
yield the crude compound as an oil, which was purified by flash
chromatography (petroleum ether/ethyl acetate, 5:1) to provide 6 as
pletion. The reaction mixture was filtered, and the solvent was re-
moved in vacuo. The crude compound thus obtained was purified
by flash chromatography (petroleum ether/ethyl acetate, 3:1) to
yield pure 9 as a colourless foam (370 mg, 50%). TLC (petroleum
ether/ethyl acetate, 3:1): Rf ϭ 0.32. [α]D ϭ ϩ15 (c ϭ 1.0, CHCl3).
1H NMR (600 MHz, CDCl3): δ ϭ 1.34 (t, J ϭ 7.4 Hz, 3 H,
SCH2CH3), 2.05 (s,
3 H, COCH3), 2.22Ϫ2.67 (m, 7 H,
CCH2CH2C, ArCH3), 2.76Ϫ2.83 (m, 2 H, SCH2CH3), 3.45 (dd,
J6,6 ϭ 10.8, J6,5 ϭ 4.6 Hz, 1 H, 6a-H), 3.52 (m, 2 H, 2a-H, 6a-H),
132
Eur. J. Org. Chem. 2003, 128Ϫ137

Reiterative Intramolecular Glycosylation Supported by a Rigid Spacer
FULL PAPER
3.58 (m, 1 H, 5a-H), 3.64 (dd, J2,1 ϭ J2,3 ϭ 9.2 Hz, 1 H, 2b-H), reaction had proceeded to completion. The reaction mixture was
3.73Ϫ3.79 (m, 2 H, 4b-H, 6b-H), 3.85 (m, 1 H, 5a-H), 3.97 (dd, neutralised with ion-exchange resin (Amberlite IR-120, Hϩ), the
J3,2 ϭ J3,4 ϭ 9.4 Hz, 1 H, 3a-H), 4.38 (m, 5 H, 1b-H, 4 ArCHH), mixture was filtered, and the solvent was evaporated in vacuo. The
4.43Ϫ4.53 (m, 4 H, 4 ArCHH), 4.60Ϫ4.69 (m, 5 H, 1b-H, 4
crude compound was purified by flash chromatography (petroleum
ArCHH), 4.81 (d, J1,2 ϭ 3.6 Hz, 1 H, 1a-H), 4.86 (d, J ϭ 11.7 Hz, ether/ethyl acetate, 3:1) to yield pure 12 (0.083 g, 87%) as a colour-
1 H, ArCHH), 5.09 (dd, J4,3 ϭ J4,5 ϭ 9.7 Hz, 1 H, 4a-H), 5.48 (s, less oil. TLC (toluene/ethyl acetate, 3:1): Rf ϭ 0.54. [α]D ϭ ϩ4 (c ϭ
1 H, PhCH), 5.62 (dd, J3,4 ϭ J3,2 ϭ 9.2 Hz, 1 H, 3b-H), 7.14Ϫ7.39
1.0, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 2.56 (s, ArCH3),
(m, 27 H, Ar), 7.76 (s, 1 H, Ar) ppm. MALDI MS: m/z ϭ 1103 3.07 (m, 1 H, 5b-H), 3.20 (dd, J2,1 ϭ J2,3 ϭ 7.8 Hz, 1 H, 2b-H),
[MNaϩ], 1119 [MKϩ]. C63H68O14S (1081.3): calcd. C 69.98, H 6.34;
found C 69.53, H 6.31.
3.37Ϫ3.45 (m, 3 H, 6a-H, 4b-H, 6b-H) 3.50Ϫ3.54 (m, 2 H, 2a-H,
3b-H), 3.68 (m, 1 H, 5a-H), 3.82Ϫ3.84 (m, 4 H, 6a-H, OCH3), 3.90
(m, 2 H, 3a-H, 4a-H), 4.13 (dd, J5,6 ϭ 4.8, J6,6 ϭ 10.2 Hz, 1 H, 6b-
H), 4.30 (2 H, 1b-H, ArCHH), 4.54 (d, J ϭ 12.0 Hz, 1 H, ArCHH),
4.57Ϫ4.60 (m, 2 H, 2 ArCHH), 4.68Ϫ4.83 (m, 6 H, 1a-H, 5
ArCHH), 4.92 (d, J ϭ 10.2 Hz, 1 H, ArCHH), 5.42 (s, 1 H, PhCH),
7.20Ϫ7.50 (m, 27 H, Ar), 7.82 (s, 1 H, Ar) ppm. MALDI MS: m/
z ϭ 975 [MNaϩ], 991 [MKϩ].
Spacer-Linked Monosaccharide؊Monosaccharide 10: Hydrazinium
acetate (0.028 g, 0.30 mmol) was added to a solution of 9 (0.342 g,
0.30 mmol) in dichloromethane (10 mL) and MeOH (1 mL), fol-
lowed by pyridine (1 mL). The mixture was stirred for 2 h at room
temp and then filtered, and the solvent was removed in vacuo. The
crude compound thus obtained was flash chromatographed to yield
pure 10 (0.192 g, 65%). TLC (petroleum ether/ethyl acetate, 2:1): Ethyl 2-O-Benzyl-4,6-O-benzylidene-3-O-(3-bromobenzyl)-1-thio-β-
Rf ϭ 0.38. [α]D ϭ ϩ5 (c ϭ 0.5, CHCl3). 1H NMR (250 MHz,
D-glucopyranoside (13): m-Bromobenzyl bromide (7.50 g,
CDCl3): δ ϭ 1.34 (t, J ϭ 7.4 Hz, 3 H, SCH2CH3), 2.50 (s, 3 H, 30.0 mmol) was added in portions to a suspension of 3[13] (10.1 g,
ArCH3), 2.76Ϫ2.83 (m, 2 H, SCH2CH3), 3.50 (dd, J6,6 ϭ 9.6, J6,5 ϭ 25.0 mmol) and sodium hydride (0.72 g, 30.0 mmol) in dry DMF
3.6 Hz, 1 H, 6a-H), 3.55Ϫ3.88 (m, 9 H, 2a-H, 3a-H, 4a-H, 5a-H,
6a-H, 2b-H, 4b-H, 5b-H, 6b-H), 4.38 (dd, J6,5 ϭ 4.8, J6,6
(150 mL). The reaction mixture was stirred for a period of 3 h at
room temp and then quenched by MeOH, and the solvent was
ϭ
10.3 Hz, 1 H, 6b-H), 4.50Ϫ4.75 (m, 9 H, 1b-H, 8 ArCHH), 4.83 evaporated in vacuo. The residue was taken up in ethyl acetate
(d, J1,2 ϭ 3.6 Hz, 1 H, 1a-H), 4.87 (d, J ϭ 10.7 Hz, 1 H, ArCHH), (250 mL) and washed with water (2ϫ50 mL) and brine (50 mL),
5.02 (d, J ϭ 11.4 Hz, 1 H, ArCHH), 5.49 (s, 1 H, PhCH), 5.63 (dd, and the aqueous phase was reextracted with ethyl acetate (50 mL).
1H, J3,4 ϭ J3,2 ϭ 9.0 Hz, 3b-H), 7.14Ϫ7.42 (m, 27 H, Ar), 7.72 (d,
The combined organic extracts were dried with sodium sulfate, and
the solvent was evaporated in vacuo. The crude compound was
J ϭ 1.8 Hz, 1 H, Ar) ppm. MALDI MS: m/z ϭ 1005 [MNaϩ], 1021
[MKϩ]. C58H62O12S (983.2): calcd. C 70.86, H 6.36; found C 70.52, purified by flash chromatography (petroleum ether/ethyl acetate,
H 6.35.
10:1) to yield pure 13 as a colourless oil (15.4 g, 90%). TLC (tolu-
ene/ethyl acetate, 9:1): Rf ϭ 0.57. [α]D ϭ Ϫ31 (c ϭ 1.0, CHCl3). 1H
NMR (250 MHz, CDCl3): δ ϭ 1.32 (t, J ϭ 7.4 Hz, 3 H,
SCH2CH3), 2.74Ϫ2.82 (m, 2 H, SCH2CH3), 3.42Ϫ3.50 (m, 2 H, 2-
H, 5-H), 3.66Ϫ3.82 (m, 3 H, 3-H, 4-H, 5-H), 4.36 (dd, J6,6 ϭ 10.4,
J6,5 ϭ 5.0 Hz, 1 H, 6 H), 4.56 (d, J1,2 ϭ 9.8 Hz, 1 H, 1-H),
4.71Ϫ4.96 (m, 4 H, 4 ArCHH), 5.57 (s, 1 H, PhCH), 7.10Ϫ7.50
(m, 14 H, Ar), 7.50 (m, 4 H, Ar) ppm. MALDI MS: m/z ϭ 596
[MNaϩ]. C29H31BrO5S (571.5): calcd. C 60.94, H 5.47; found C
61.00, H 5.41.
Benzyl 6,3Ј-O-(2-Methyl-5-methylene-benzoyl)-(2-O-benzyl-4,6-O-
benzylidene-β-D-glucopyranosyl)-(1؊4)-2,3-di-O-benzyl-α-D-gluco-
pyranoside (11): N-Iodosuccinimide (0.090 g, 0.40 mmol) and a
catalytic amount of trifluoromethanesulfonic acid (4 µm) were ad-
ded to a solution of 10 (0.195 g, 0.20 mmol) in dichloromethane,
and the reaction mixture was stirred for a period of 30 min. The
reaction mixture was then washed with sodium bicarbonate solu-
tion (10 mL) and sodium thiosulfate solution (10 mL). The aque-
ous phase was reextracted with dichloromethane (50 mL), the com-
bined organic extracts were washed with water and brine and dried
with sodium sulfate, and the solvent was removed in vacuo to yield
Ethyl 2-O-Benzyl-4,5-O-benzylidene-3-O-[3-(chlorodiisopropylsilyl)-
benzyl]-1-thio-β-D-glucopyranoside (14): A solution of 13 (1.71 g,
the crude product, which was purified by flash chromatography 3.0 mmol) in dry THF (15 mL) was cooled to Ϫ100 °C. tert-Butylli-
(petroleum ether/ethyl acetate, 4:1) to yield pure 11 (131 mg, 71%).
TLC (petroleum ether/ethyl acetate, 2:1): Rf ϭ 0.42. [α]D ϭ ϩ5 (c ϭ
thium (1.6 mol/L in hexane, 3.75 mL, 6.0 mmol) was added drop-
wise over a period of 1 h at Ϫ100 °C, after which dichlorodiisopro-
1.0, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 2.63 (s, 3 H, pylsilane (1.62 mL, 9.0 mL) was added. The temperature was now
ArCH3), 3.42 (d, J1,2 ϭ 2.2 Hz, 1 H, 2b-H), 3.55Ϫ3.58 (m, 2 H,
2a-H, 4a-H), 3.63 (dd, J5,6 ϭ 6.0, J6,6 ϭ 10.2 Hz, 1 H, 6a-H), 3.80
gradually raised to Ϫ50 °C and the mixture was stirred at that
temperature for a period of 1 h, after which it was gradually
(dd, 1 H, J5,6 ϭ 10.8, J6,6 ϭ 10.8 Hz, 6b-H), 3.86 (d, J6,6 ϭ 10.2 Hz, warmed to room temp. and the solvent was evaporated in vacuo.
1 H, 6a-H), 4.12 (dd, J5,6 ϭ 5.4, J5,4 ϭ 9.6 Hz, 1 H, 5a-H), 4.22 The excess dichlorodiisopropylsilane (b.p. 66 °C at 27 mbar) was
(dd, J5,6 ϭ 10.8 Hz, J5,4 ϭ 10.2 Hz, 1 H, 5b-H), 4.34 (dd, J3,4
ϭ
removed by the application of high vacuum to provide pure 14 as
J3,2 ϭ 7.8 Hz, 1 H, 3a-H), 4.42 (dd, J6,5 ϭ 5.4, J6,6 ϭ 10.8 Hz, 1 an oil, which was immediately used in the next step.
H, 6b-H), 4.51Ϫ4.55 (m, 8 H, 4b-H, 7Ј-H, 6 ArCHH), 4.80 (d, J ϭ
Ethyl
benzyl-4-O-(4-methoxybenzyl)-α-
pylsilylbenzyl}-1-thio-β-
2-O-Benzyl-4,6-O-benzylidene-3-O-{3-[methyl
2,3-di-O-
15.6 Hz, 1 H, 7Ј-H), 4.86Ϫ4.89 (m, 3 H, 1a-H, 2 ArCHH), 5.33 (d,
J3,4 ϭ 7.2 Hz, 1 H, 3b-H), 5.54 (s, 1 H, PhCH), 5.56 (br. s, 1 H,
1b-H), 7.15Ϫ7.26 (m, 23 H, Ar), 7.50 (m, 4 H, Ar), 8.15 (s, 1 H,
Ar) ppm. C56H56O12 (924.9): calcd. C 73.03, H 6.13; found C 73.01,
H 6.54.
D
-glucopyranosid-6-yloxy]diisopro-
D
-glucopyranoside (15): Sodium hydride
(0.10 g, 4.20 mmol) was added to a solution of 2b[11] (1.79 g,
3.60 mmol) in DMF (10 mL), followed by the dropwise addition of
a solution of 14 (192 g, 3.0 mmol). The reaction mixture was stirred
for a period of 20 h and then quenched with MeOH, and the solv-
Benzyl
O-(2-O-Benzyl-4,6-O-benzylidene-β-D-glucopyranosyl)-
(1؊4)-2,3-di-O-benzyl-6-O-(3-methoxycarbonyl-4-methylbenzyl)-α- ent was evaporated in vacuo. The residue was taken up in ethyl
D
-glucopyranoside (12): Sodium methoxide solution (1 mmol/mL in
acetate (50 mL) and washed with water (20 mL) and brine (20 mL),
and the organic extract was dried with sodium sulfate and concen-
trated in vacuo. The crude compound was purified by flash chro-
matography (petroleum ether/ethyl acetate, 9:1) to yield pure 15 as
MeOH, 0.5 mL, 5 mmol) was added to a solution of 11 (0.090 g,
0.10 mmol) in dichloromethane (5 mL), and the reaction mixture
was stirred for a period of 2 h at room temp., by which time the
Eur. J. Org. Chem. 2003, 128Ϫ137
133

S. Paul, M. Müller, R. R. Schmidt
FULL PAPER
a colourless oil (2.01 g, 61%). TLC (toluene/ethyl acetate, 6:1): Rf ϭ
triethylamine, diluted with dichloromethane (20 mL) and washed
1
0.75. [α]D ϭ Ϫ22 (c ϭ 1.0, CHCl3). H NMR (600 MHz, CDCl3): with water (10 mL) and brine (10 mL). The aqueous phase was
δ ϭ 0.93, 0.99 [2m, 12 H, 2 CH(CH3)2], 1.16 [m, 2 H, 2 CH(CH3)2], reextracted with CH2Cl2 (30 mL), the combined organic extracts
1.32 (t, J ϭ 7.4 Hz, 3 H, SCH2CH3), 2.72Ϫ2.77 (m, 2 H, CH2CH3), were dried with sodium sulfate, and the solvent was evaporated in
3.33 (s, 3 H, OCH3), 3.43Ϫ3.47 (m, 2 H, 2b-H, 5b-H), 3.50Ϫ3.52
(m, 2 H, 2a-H, 4a-H), 3.65 (m, 1 H, 5a-H), 3.70 (dd, J4,3 ϭ J4,5
9.3 Hz, 1 H, 4b-H), 3.76Ϫ3.86 (m, 6 H, 6a-H, 3b-H, 6b-H, OCH3),
3.90 (dd, J6,6 ϭ 10.8, J6,6 Ͻ 1.0 Hz, 1 H, 6a-H), 3.98 (dd, J3,4
vacuo. The residue was purified by flash chromatography (toluene/
ethyl acetate, 29:1) to yield pure 17β as a colourless foam (0.129 g,
70%). 17α: TLC (toluene/ethyl acetate, 9:1): Rf ϭ 0.38. [α]D ϭ Ϫ14
(c ϭ 0.5, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 1.01 [m, 3 H,
ϭ
ϭ
J3,2 ϭ 9.3 Hz, 1 H, 3a-H), 4.35 (dd, J6,6 ϭ 10.4, J6,5 ϭ 5.0 Hz, 1 CH(CH3)2), 1.05 [m, 3 H, CH(CH3)2], 1.11 [m, 3 H, CH(CH3)2],
H, 6b-H), 4.55 (m, 2 H, 2 ArCHH), 4.61 (d, J1,2 ϭ 3.3 Hz, 1 H, 1.14 [m, 3 H, CH(CH3)2], 1.21 [m, 2 H, 2 CH(CH3)2], 3.32 (ddd,
1a-H), 4.65 (d, J ϭ 12.5 Hz, 1 H, ArCHH), 4.62Ϫ4.66 (m, 2 H, 2
ArCHH), 4.73 (d, J ϭ 12.0 Hz, 1 H, ArCHH), 4.76Ϫ4.86 (m, 2 H,
J5,6 ϭ 4.7 Hz, J6,6 ϭ 10 Hz, J4,5 ϭ 9.7 Hz, 1 H, 5b-H), 3.45 (m, 4
H, 4a-H, OCH3), 3.51 (dd, J2,3 ϭ 9.4, J2,1 ϭ 3.5 Hz, 1 H, 2a-H),
2 ArCHH), 4.94Ϫ497 (m, 2 H, 2 ArCHH), 5.56 (s, 1 H, PhCH), 3.56 (dd, J6,6 ϭ J6,5 ϭ 10.3 Hz, 1 H, 6b-H), 3.62 (dd, J6,6 ϭ 10.3,
6.78 (d, J ϭ 8.5 Hz, 2 H, Ar), 7.12 (d, J ϭ 8.5 Hz, 2 H, Ar),
J6,5 ϭ 8.2 Hz, 1 H, 6a-H), 3.88 (dd, J5,6 ϭ 8.2, J5,4 ϭ 10.6 Hz, 1
7.25Ϫ7.46 (m, 20 H, Ar) ppm. MALDI MS: m/z ϭ 1121 [MNaϩ], H, 5a-H), 4.03 (dd, J3,2 ϭ J3,4 ϭ 9.1 Hz, 1 H, 3a-H), 4.07 (dd,
1161 [MKϩ]. C64H76O11SSi (1098.4): calcd. C 69.98, H 6.97; found J6,6 ϭ 10.6, J6,5 ϭ 4.7 Hz, 1 H, 6b-H), 4.19 (dd, 1 H, J6,6 ϭ 10.3,
C 70.08, H 7.33.
J6,5 Ͻ 1.0 Hz, 6a-H), 4.34 (dd, J3,4 ϭ J3,2 ϭ 9.7 Hz, 1 H, 3b-H),
4.54Ϫ4.58 (m, 3 H, 1a-H, 2 ArCHH), 4.66Ϫ4.74 (m, 3 H, 3
ArCHH), 4.85Ϫ4.91 (m, 2 H, 2 ArCHH), 5.01 (d, J ϭ 11.0 Hz, 1
H, ArCHH), 5.35 (s, 1 H, PhCH), 5.38 (d, J1,2 ϭ 2.9 Hz, 1 H, 1b-
H), 7.20Ϫ7.32 (m, 22 H, Ar), 7.50 (m, 1 H, Ar), 7.72 (m, 1 H, Ar)
ppm. FAB MS: m/z ϭ 939 [MNaϩ]. C54H64O11 (918.2): calcd. C
70.64, H 7.03; found C 70.17, H 6.90. 17β: TLC (toluene/ethyl acet-
Ethyl
2-O-Benzyl-4,6-O-benzylidene-3-O-{3-[methyl
2,3-di-O-
benzyl-α-
D-glucopyranosid-6-yloxy]-diisopropylsilylbenzyl}-1-thio-β-
D-glucopyranoside (16): Compound 15 (1.10 g, 1.0 mmol) was taken
up in CH2Cl2 (30 mL) and water (5 mL), and DDQ (272 mg,
1.20 mmol) was added. The reaction mixture was stirred for a
period of 20 h at room temp, after which it was diluted to 50 mL,
washed with sodium bicarbonate solution (2ϫ10 mL) and water
(10 mL), and dried with sodium sulfate. The solvent was removed
in vacuo. The crude compound was purified by flash chromato-
graphy (toluene/ethyl acetate, 19:1) to yield pure 16 as a colourless
oil (851 mg, 87%). TLC (toluene/ethyl acetate, 9:1): Rf ϭ 0.38.
[α]D ϭ Ϫ9 (c ϭ 0.8, CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ
0.92, 0.99 [2 m, 12 H, 2 CH(CH3)2], 1.18 [m, 2 H, 2 CH(CH3)2],
1.29 (t, J ϭ 7.4 Hz, 3 H, SCH2CH3), 2.71Ϫ2.75 (m, 2 H,
SCH2CH3), 3.34 (s, 3 H, OCH3), 3.42Ϫ3.47 (m, 3 H, 2a-H, 2b-H,
5b-H), 3.53 (ddd, J4,3 ϭ J4,5 ϭ 9.1, J4,OH ϭ 2.0 Hz, 1 H, 4a-H),
3.62 (m, 1 H, 5a-H), 3.70 (dd, J4,3 ϭ J4,5 ϭ 9.4 Hz, 1 H, 4b-H),
1
ate, 9:1): Rf ϭ 0.50. H NMR (600 MHz, CDCl3): δ ϭ 0.95 [m, 3
H, CH(CH3)2], 1.01 [m, 6 H, CH(CH3)2], 1.09 [m, 3 H, CH(CH3)2],
1.15 [m, 2 H, 2 CH(CH3)2], 3.34 (dd, J4,3 ϭ 8.2 Hz, 10 Hz, J4,5
9.7 Hz, 1 H, 4a-H), 3.35 (s, OCH3), 3.51 (dd, J2,3 ϭ 9.1, J2,1
ϭ
ϭ
3.5 Hz, 1 H, 2a-H), 3.54 (dd, J2,1 ϭ 2.1, J2,1 Ͻ 1.0 Hz, 1 H, 2b-H),
3.60 (dd, J6,6 ϭ J6,5 ϭ 10.3 Hz, 1 H, 6b-H), 3.73Ϫ3.80 (m, 2 H,
5a-H, 6a-H), 3.84 (dd, J3,4 ϭ 7.3, J3,2 Ͻ 1.0 Hz, 1 H, 3b-H), 3.88
(dd, J6,6 ϭ 10.3, J6,5 Ͻ 1.0 Hz, 1 H, 6a-H), 3.97 (dd, J5,6 ϭ 5.0 Hz,
J5,4 ϭ 10.3 Hz, 5b-H), 4.07 (dd, J3,4 ϭ J3,2 ϭ 8.8 Hz, 1 H, 3a-H),
4.18Ϫ4.20 (m, 2 H, 6b-H, ArCHH), 4.31 (d, J ϭ 11.6 Hz, 1 H,
ArCHH), 4.40 (dd, J4,5 ϭ 10.6, J4,3 ϭ 7.3 Hz, 1 H, 4b-H),4.45 (d,
J ϭ 13.8 Hz, 1 H, 8Ј-H), 4.49 (d, J ϭ 12.0 Hz, 1 H, ArCHH), 4.64
(d, J1,2 ϭ 3.5 Hz, 1 H, 1a-H), 4.72 (d, J ϭ 12.0 Hz, 1 H, ArCHH),
4.88 (d, J ϭ 10.3 Hz, 1 H, ArCHH), 5.01 (d, J ϭ 10.3 Hz, 1 H,
3.75 (dd, J6,6 ϭ 10.9, J6,5 ϭ 5.3 Hz, 1 H, 6a-H), 3.90 (dd, J6,6
10.9, J6,5 ϭ 3.8 Hz, 1 H, 6a-H), 4.32 (dd, J6,6 ϭ 10.6, J6,5 ϭ 5.0 Hz,
1 H, 6b-H), 4.55 (d, J1,2 ϭ 9.7 Hz, 1 H, 1b-H), 4.59 (d, J1,2
ϭ
ϭ
ArCHH), 5.11 (d, J ϭ 12.0 Hz, 1 H, 8Ј-H), 5.22 (br. s, 1 H, J1,2
Ͻ
3.5 Hz, 1 H, 1a-H), 4.63 (d, J ϭ 12.0 Hz, 1 H, ArCHH), 4.72Ϫ4.80
(m, 4 H, 4 ArCHH), 4.84 (d, J ϭ 10.3 Hz, 1 H, ArCHH),
4.93Ϫ4.97 (m, 2 H, 2 ArCHH), 5.55 (s, 1 H, PhCH), 7.24Ϫ7.35 (m,
24 H, Ar) ppm. MALDI MS: m/z ϭ 1101 [MNaϩ], 1118 [MKϩ].
C56H68O11SSi (978.0): calcd. C 68.75, H 7.01; found C 68.68, H
7.19.
1.0 Hz, 1b-H), 5.48 (s, 1 H, PhCH), 7.12Ϫ7.37 (m, 23 H, Ar), 7.46
(s, 1 H, Ar).
Methyl
6,3Ј-O-[-3-(Diisopropylsilyl)benzyl]-(2-O-benzyl-β-
D-gluco-
pyranosyl)-(1؊4)-2,3-di-O-benzyl-α-D-glucopyranoside (18β): Ethane-
thiol (222 µL, 3.0 mmol) and p-toluenesulfonic acid (0.010 g) were
added to a solution of 17β (0.55 g, 0.6 mmol) in dichloromethane
(30 mL). The reaction mixture was stirred at room temp. for a period
Methyl
benzylidene-α-
pyranoside (17α) and Methyl 6,3Ј-O-[-3-(Diisopropylsilyl)benzyl]- the solvent was evaporated in vacuo. The crude compound was puri-
6,3Ј-O-[-3-(Diisopropylsilyl)benzyl]-(2-O-benzyl-4,6-O-
D
-glucopyranosyl)-(1؊4)-2,3-di-O-benzyl-α-D-gluco- of 5 h. The reaction mixture was neutralised with triethylamine and
(2-O-benzyl-4,6-O-benzylidene-β-
D
-glucopyranosyl)-(1؊4)-2,3-di-
fied by flash chromatography (toluene/ethyl acetate, 2:1) to yield the
pure compound as an oil (0.43 g, 86%). TLC (toluene/ethyl acetate,
1:1): Rf ϭ 0.34. [α]D ϭ ϩ26 (c ϭ 0.5, CHCl3). 1H NMR (600 MHz,
CDCl3): δ ϭ 0.90 [m, 3 H, CH(CH3)2], 0.98 [m, 3 H, CH(CH3)2],
1.01 [m, 3 H, CH(CH3)2], 1.11 [m, 3 H, CH(CH3)2], 1.28 (m, 2 H, 2
O-benzyl-α- -glucopyranoside (17β). a) With NIS: Compound 16
D
(0.196 g, 0.20 mmol) was taken up in dry dichloromethane (20 mL),
and to this solution were added NIS (0.090 g, 0.40 mmol) and a
catalytic amount of trifluoromethanesulfonic acid (4 µL). The reac-
tion mixture was stirred at room temp. for a period of 30 min and CH(CH3)2], 2.59 (br. s, 1 H, 4b-OH), 2.69 (br. s, 1 H, 6b-OH), 3.32
was then washed with sodium bicarbonate solution (10 mL) and
sodium thiosulfate (10 mL). The aqueous phase was reextracted
(dd, J4,3 ϭ 8.5, J4,5 ϭ 9.9 Hz, 1 H, 4a-H), 3.40 (s, 3 H, OCH3), 3.43
(br. s, J2,3 ϭ J2,1 ϭ 1.5 Hz, 1 H, 2b-H), 3.55 (m, 2 H, 2a-H, 2b-H),
with dichloromethane (20 mL), the organic extracts were combined 3.64 (ddd, J3,4 ϭ 6.2, J3,2 Ͻ 1.0, J3,1 Ͻ 1.0 Hz, 1 H, 3b-H) 3.68Ϫ3.72
and dried with sodium sulfate, and the solvent was removed in
vacuo. The crude compound was purified by flash chromatography
(petroleum ether/ethyl acetate, 13:1 to 9:1) to yield the two anomers
(m, 3 H, 6a-H, 5b-H, 6b-H), 3.79 (dd, J5,6 ϭ 6.6, J5,4 ϭ 10.1 Hz, 1
H, 5a-H), 3.85 (dd, J6,6 ϭ 10.3, J6,5 Ͻ 1.0 Hz, 1 H, 6a-H), 4.09 (m,
2 H, 2 ArCHH), 4.20 (dd, J3,4 ϭ J3,2 ϭ 9.0 Hz, 1 H, 3a-H), 4.25 (bt,
17α (0.083 g, 45%), and 17β (0.083 g, 45%). b) With MeOTf: 1 H, 4b-H), 4.41 (d, J ϭ 13.8 Hz, 1 H, ArCHH), 4.56 (d, J ϭ
Methyl triflate (88 µL, 0.80 mmol) was added to a solution of 16 12.0 Hz, 1 H, ArCHH), 4.66 (m, 2 H, 1a-H, ArCHH), 4.74 (d, J ϭ
(0.196 g, 0.20 mmol) in dry dichloromethane (20 mL). After 2 h of
10.6 Hz, 1 H, ArCHH), 4.86 (d, J1,2 ϭ 10.6 Hz, 1 H, ArCHH), 5.04
stirring at room temp., the reaction mixture was neutralised with (br. s, J1,2 Ͻ 1.0, J1,3 Ͻ 1.0 Hz, 1 H, 1b-H), 5.12 (d, J ϭ 13.8 Hz, 1
134
Eur. J. Org. Chem. 2003, 128Ϫ137

Reiterative Intramolecular Glycosylation Supported by a Rigid Spacer
FULL PAPER
H, 8Ј-H), 7.00 (m, 2 H, Ar), 7.20Ϫ7.36 (m, 16 H, Ar) ppm. FAB 7.15Ϫ7.73 (m, 12 H, Ar), 7.72 (d, J ϭ 1.80 Hz, 1 H, Ar) ppm.
MS: m/z ϭ 859 [MNaϩ]. C47H60O10Si (830.1): calcd. C 68.01, H 7.29;
MALDI MS: m/z ϭ 601 [MNaϩ]. C34H42O8 (578.6): calcd. C 70.58,
found C 67.79, H 7.22.
H 7.26; found C 70.71, H 7.31.
Methyl
pylsilyl)benzyl]-α-
O-{2-O-Benzyl-4,6-O-benzylidene-3-O-[3-(hydroxydiisopro-
-glucopyranosyl}-(1؊4)-2,3-di-O-benzyl-α-D-
tert-Butyl 5-[Methyl 2,3-di-O-benzyl-4-O-levulinoyl-α-D-glucopyrano-
D
sid-6-yl-oxymethyl]-2-methylbenzoate (21): Levulinic acid (5.07 g,
43.65 mmol), DCC (9.06 g, 44 mmol), and DMAP (0.100 g) were ad-
ded to a solution of 20 (4.70 g, 0.61 mmol) in dichloromethane, and
the reaction mixture was stirred for a period of 24 h, by which time
the reaction mixture had acquired a deep brown color. The reaction
mixture was filtered and the solvent was evaporated. The residue was
purified by flash chromatography (petroleum ether/ethyl acetate, 3:2)
to yield pure 21 as an oil (4.38 g, 75%); TLC (petroleum ether/ethyl
acetate, 3:2). [α]D ϭ Ϫ6.2 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 1.58 [s, 9 H, C(CH3)3], 2.11 (s, 3 H, COCH3), 2.28Ϫ2.52
(m, 4 H, CCH2CH2C), 2.61 (s, 3 H, ArCH3), 3.38 (s, 3 H, OCH3),
3.45Ϫ3.54 (m, 2 H, 6-H2), 3.57 (m, 1 H, 2-H), 3.81 (m, 1 H, 5-H),
3.92 (m, 1 H, 3-H), 4.47 (m, 1 H, ArCHH), 4.60 (d, J ϭ 3.9 Hz, 1
H, 1-H), 4.64 (m, 1 H, ArCHH), 4.76 (m, 1 H, ArCHH), 4.78 (m, 1
H, ArCHH), 4.86 (m, 1 H, ArCHH), 4.88 (m, 1 H, ArCHH), 5.03
(m, 1 H, 4-H), 7.15Ϫ7.73 (m, 12 H, Ar), 7.72 (d, J ϭ 1.8 Hz, 1 H,
Ar) ppm. FAB MS: m/z ϭ 699 [MNaϩ], 714 [MKϩ]. C39H48O10
(676.3): calcd. C 69.23, H 7.1; found C 69.47, H 7.56.
glucopyranoside (19α): Tetrabutylammonium fluoride solution (1 mol/
L in THF, 120 µL, 0.12 mmol) was added to a solution of 17α
(0.092 g, 0.10 mmol) in tetrahydrofuran (25 mL) and the mixture was
stirred for a period of 2 h at room temp. The solvent was then re-
moved in vacuo, and the crude product was purified by flash chroma-
tography to yield 19α (0.085 g, 91%) as a colourless oil. TLC (toluene/
ethyl acetate, 4:1): Rf ϭ 0.18. [α]D ϭ Ϫ10 (c ϭ 1.0, CHCl3). 1H NMR
(600 MHz, CDCl3): δ ϭ 0.90 [m, 6 H, CH(CH3)2], 0.99 [m, 6 H,
CH(CH3)2], 1.12 [m, 2 H, 2 CH(CH3)2], 1.71 (s, 1 H, OH), 1.83 (t,
J ϭ 6.2 Hz, 1 H, OH), 3.37 (s, 3 H, OCH3), 3.52Ϫ3.54 (m, 2 H, 2a-
H, 2b-H), 3.62 (dd, J4,3 ϭ J4,5 ϭ 9.4 Hz, 1 H, 4b-H), 3.69 (dd, J6,5 ϭ
J6,6 ϭ 10.3 Hz, 1 H, 6b-H), 3.80Ϫ3.85 (m, 3 H, 5a-H, 6a-H, 5b-H),
3.96 (dd, J4,3 ϭ J4,5 ϭ 9.2 Hz, 1 H, 4a-H), 4.03 (dd, J3,2 ϭ J3,4
ϭ
9.4 Hz, 1 H, 3b-H), 4.09 (dd, J3,2 ϭ J3,4 ϭ 9.2 Hz, 1 H, 3a-H), 4.30
(dd, J6,6 ϭ 10.1, J6,5 ϭ 4.8 Hz, 1 H, 6b-H), 4.52Ϫ4.56 (m, 3 H, 1a-
H, 2 ArCHH), 4.66 (d, J ϭ 12.0 Hz, 1 H, ArCHH), 4.73Ϫ4.79 (m,
3 H, 3 ArCHH), 4.92 (d, J ϭ 10.9 Hz, 1 H, ArCHH), 4.99 (d, J ϭ
11.8 Hz, 1 H, ArCHH), 5.54 (s, 1 H, PhCH), 5.71 (d, J1,2 ϭ 3.9 Hz,
1 H, 1b-H), 7.16Ϫ7.48 (m, 24 H, Ar) ppm. FAB MS: m/z ϭ 957
[MNaϩ]. C54H66O12Si (935.2): calcd. C 69.35, H 7.11; found C 69.14,
H 6.97.
5-[Methyl 2,3-di-O-benzyl-4-O-levulinoyl-α-D-glucopyranosid-6-yloxy-
methyl]-2-methylbenzoic Acid (22): Trifluoroacetic acid was added to
a solution of 21 (3 g, 4.43 mmol) in dichloromethane, and the reac-
tion mixture was stirred for a period of 4 h. Toluene (20 mL) was
added, and the solvent was evaporated in vacuo to yield the crude
compound, which was purified by flash chromatography (petroleum
ether/ethyl acetate, 1:1) to yield pure 22 (2.75 g, 90%) as an oil. TLC
(petroleum ether/ethyl acetate, 1:1): Rf ϭ 0.15. [α]D ϭ Ϫ7.05 (c ϭ 1.0,
Methyl
pylsilyl)benzyl]-β-
O-{2-O-Benzyl-4,6-O-benzylidene-3-O-[3-(hydroxydiisopro-
-glucopyranosyl}-(1؊4)-2,3-di-O-benzyl-α-D-
D
glucopyranoside (19β): Tetrabutylammonium fluoride solution (1 mol/
L in tetrahydrofuran, 120 µL, 0.12 mmol) was added to a solution of
17β (0.092 g, 0.10 mmol) in tetrahydrofuran and the mixture was
stirred for 2 h at room temp., after which the solvent was removed in
vacuo and the residue was purified by flash chromatography (toluene/
ethyl acetate, 4:1) to yield pure 19β (0.087 g, 93%) as a colourless oil.
TLC (toluene/ethyl acetate, 4:1), Rf ϭ 0.18. [α]D ϭ Ϫ5 (c ϭ 1.0,
CHCl3). 1H NMR (600 MHz, CDCl3): δ ϭ 0.90 [m, 6 H, CH(CH3)2],
0.99 [m, 6 H, CH(CH3)2], 1.12 [m, 2 H, 2 CH(CH3)2], 1.58 (s, 1 H,
OH), 1.75 (br. s, 1 H, OH), 3.32Ϫ3.36 (m, 4 H, 5b-H, OCH3),
3.40Ϫ3.50 (m, 4 H, 2a-H, 5a-H, 2b-H, 6b-H), 3.61Ϫ3.66 (m, 2 H,
4b-H, 6a-H), 3.75Ϫ3.85 (m, 4 H, 3a-H, 4a-H, 3b-H, 6a-H), 4.15 (dd,
J6,6 ϭ 10.5, J6,5 ϭ 5.0 Hz, 1 H, 6b-H), 4.52 (d, J1,2 ϭ 3.7 Hz, 1 H,
1a-H), 4.60Ϫ4.63 (m, 2 H, 1b-H, ArCHH), 4.75Ϫ4.81 (m, 4 H, 4
ArCHH), 4.86 (d, J ϭ 11.2 Hz, 1 H, ArCHH), 4.91Ϫ4.92 (m, 2 H,
2 ArCHH), 5.49 (s, 1 H, PhCH), 7.24Ϫ7.46 (m, 24 H) ppm. FAB
MS: m/z ϭ 957 [MNaϩ]. C54H66O12Si (935.2): calcd. C 69.35, H 7.11;
found C 68.88, H 7.12.
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 2.11 (s, 3 H, COCH3),
2.28Ϫ2.52 (m, 4 H, CCH2CH2C), 2.61 (s, 3 H, ArCH3), 3.38 (s, 3 H,
OCH3), 3.45Ϫ3.54 (m, 2 H, 6-H2), 3.57 (m, 1 H, 2-H), 3.81 (m, 1 H,
5-H), 3.92 (m, 1 H, 3-H), 4.47 (m, 1 H, ArCHH), 4.60 (d, J ϭ 3.88
Hz, 1 H), 4.64 (m, 1 H, ArCHH), 4.76 (m, 1 H, ArCHH), 4.78 (m,
1 H, ArCHH), 4.86 (m, 1 H, ArCHH), 4.88 (m, 2 H, 2 ArCHH),
5.03 (m, 1 H, 4-H), 7.15Ϫ7.73 (m, 12 H, Ar), 7.72 (d, J ϭ 1.8 Hz, 1
H, Ar) ppm. MALDI MS: m/z ϭ 643 [MNaϩ], C35H40O10 (620.4):
calcd. C 67.74, H 6.45; found C 67.74, H 6.52.
Spacer-Linked Monosaccharide-Monosaccharide 23: DCC (3.09 g,
15 mmol) and a catalytic amount of DMAP (0.02 g) were added to
a solution of 22 (2.00 g, 3.22 mmol) and 3[13] (1.24 g, 3 mmol) in
dichloromethane (50 mL). The reaction mixture was stirred for a
period of 20 h at room temp and was then filtered, and the solvent
was removed in vacuo. The crude compound was purified by flash
chromatography (petroleum ether/ethyl acetate, 3:1) to yield pure 23
as colourless foam (2.42 g, 75%). TLC (petroleum ether/ethyl acetate,
3:2). [α]D ϭ Ϫ10.53 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz, CDCl3):
δ ϭ 1.34 (t, J ϭ 7.4 Hz, 3 H, SCH2CH3), 2.05 (s, 3 H, OCH3),
2.22Ϫ2.56 (m, 4 H, CCH2CH2C), 2.61 (s, 3 H, ArCH3), 2.7Ϫ2.83
(m, 2 H, SCH2CH3), 3.38 (s, 3 H, OCH3), 3.45 (m, 1 H, 6a-H), 3.54
tert-Butyl 5-[Methyl 2,3-di-O-benzyl-α-D-glucopyranosid-6-yloxyme-
thyl]-2-methylbenzoate (20): Compound 2c[12] (6.5 g, 18 mmol) was
taken up in toluene (60 mL), dibutyltin oxide (4.5 g, 18 mmol) was
added, and the solution was heated under reflux for 5 h in a
DeanϪStark apparatus. The solution was concentrated to a volume
of 10 mL, to which 5 (4.25 g, 18 mmol), and TBAI (7.4 g, 20 mmol)
were added, and was then heated under reflux for another 6 h. The
solvent was now removed in vacuo, and the residue was purified by
flash chromatography (petroleum ether/ethyl acetate, 2:1) to yield
pure 20 as an oil (7.03 g, 70%). TLC (petroleum ether/ethyl acetate,
3:2): Rf ϭ 0.41. [α]D ϭ Ϫ4.7 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 1.58 [s, 9 H, C(CH3)3], 2.61 (s, 3 H, ArCH3), 3.38 (s, 3
H, OCH3), 3.45Ϫ3.54 (m, 2 H, 6-H2), 3.57 (m, 1 H, 2-H), 3.83 (m,
1 H, 5-H), 3.92 (m, 2 H, 3-H, 4-H), 4.47 (m, 1 H, ArCHH), 4.60 (d,
J ϭ 3.92 Hz, 1 H, 1-H), 4.64 (m, 1 H, ArCHH), 4.78 (m, 1 H,
(m, 2 H, 6a-H, 2a-H), 3.61 (m, 1 H, 5-H), 3.64 (dd, J2,1 ϭ J2,3
ϭ
9.2 Hz, 1 H, 2b-H) 3.73Ϫ3.79 (m, 2 H, 4b-H, 6b-H), 3.85 (m, 1 H,
5a-H), 3.92 (m, 1 H, 3a-H), 4.40Ϫ4.49 (m, 5 H, 4 ArCHH, 1b-H),
4.50Ϫ4.58 (m, 4 H, 4 ArCHH), 4.60 d, J ϭ 3.9 Hz, 1 H, 1a-H), 5.48
(s, 1 H, PhCH), 7.12Ϫ7.37 (m, 23 H, Ar), 7.75 (s, 1 H, Ar) ppm.
MALDI MS: m/z ϭ 1025 [MNaϩ]. C57H62O14S (1002.9): calcd. C
68.26, H 6.38; found C 68.50, H 6.74.
Spacer-Linked Monosaccharide-Monosaccharide 24: Hydrazinium
acetate (0.074 g, 0.80 mmol) was added to a solution of 23 (0.80 g,
ArCHH), 4.86 (m, 1 H, ArCHH), 4.88 (m, 2 H, 2 ArCHH), 0.79 mmol) in dichloromethane and MeOH (2 mL), followed by pyr-
Eur. J. Org. Chem. 2003, 128Ϫ137 135

S. Paul, M. Müller, R. R. Schmidt
FULL PAPER
idine (1 mL). The mixture was stirred for 2 h at room temp and was Methyl
O-[2-O-Benzyl-3-O-(3-hydroxycarbonyl-4-methylbenzyl)-
then filtered, and the solvent was removed in vacuo to yield the crude 4,6-O-benzylidene-β-
compound, which was purified by flash chromatography to provide (3-methoxycarbonyl-4-methyl)benzyl]-α-
D
-glucopyranosyl]-(1؊4)-[2,3-di-O-benzyl-6-O-
-glucopyranoside (27): NaH
D
pure 24 as colourless foam (0.470 g, 65%). TLC (petroleum ether/ (32 mg, 1.368 mmol) was added to a solution of 26 (200 mg,
ethyl acetate, 3:2): Rf ϭ 0.43. [α]D ϭ Ϫ8.0 (c ϭ 1.0, CHCl3). 1H 0.228 mmol) in DMF and the mixture was stirred for 15 min. Com-
NMR (250 MHz, CDCl3): δ ϭ 1.34 (t, J ϭ 7.4 Hz, 3 H, SCH2CH3), pound 5 (195 mg, 0.684 mmol) was added, and the reaction mixture
2.56 (s, 3 H, ArCH3), 2.7Ϫ2.83 (m, 2 H, SCH2CH3), 3.38 (s, 3 H,
was stirred for a period of 3 h. It was then quenched by the addition
OCH3), 3.45 (m, 1 H, 6a-H), 3.54 (m, 3 H, 2a-H, 4a-H, 6a-H), 3.62 of MeOH (5 mL), and the solvent was evaporated in vacuo. The res-
(m, 1 H, 5b-H), 3.64 (m, 1 H) 3.73Ϫ3.79 (m, 3 H, 4b-H, 6b-H2), 3.81
(m, 1 H, 5a-H), 3.92 (m, 1 H, 3a-H), 4.40Ϫ4.49 (m, 5 H, 4 ArCHH,
1b-H), 4.50Ϫ4.58 (m, 4 H, 4 ArCHH), 4.60 (d, J ϭ 3.9 Hz, 1 H, 1a-
H), 5.48 (s, 1 H, PhCH), 5.63 (m, 1 H, 3b-H) 7.15Ϫ7.37 (m, 23 H,
Ar), 7.75 (s, 1 H, Ar) ppm. MALDI MS: m/z ϭ 929 [MNaϩ].
C52H58O12S (906.6): calcd. C 68.87, H 6.40; found C 69.05, H 6.77.
idue was taken in water and acidified, which yielded a white precipit-
ate. The aqueous solution was extracted with ethyl acetate
(3ϫ50 mL). The organic extracts were combined and the solvent was
evaporated in vacuo to yield the crude compound, which was purified
by flash chromatography (petroleum ether/ethyl acetate, 1:4) to yield
pure 27 (0.172 g, 75%). TLC (petroleum ether/ethyl acetate, 3:2): Rf ϭ
1
0.27. [α]D ϭ Ϫ11 (c ϭ 1.0, CHCl3). H NMR (250 MHz, CDCl3):
δ ϭ 2.59 (s, 3 H, ArCH3), 2.61 (s, 3 H, ArCH3), 3.26 (m, 1 H, 5b-
H), 3.28 (m, 1 H, 2b-H), 3.38 (s, 3 H, OCH3), 3.42Ϫ3.56 (m, 5 H,
6a-H, 2a-H, 3b-H, 4b-H, 6b-H), 3.65 (s, 3 H), 3.68 (m, 1 H, 5a-H),
3.70Ϫ3.92 (m, 3 H, 6a-H, 3a-H, 4a-H), 4.13Ϫ4.30 (m, 2 H, 1b-H,
1ArCHH), 4.55 (d, J1,2 ϭ 3.9 Hz, 1 H, 1a-H), 4.6Ϫ4.95 (m, 9 H, 9
ArCHH), 5.48 (s, 1 H, PhCH), 7.15Ϫ7.50 (m, 25 H, Ar), 7.76 (s, 1
H, Ar) ppm. MALDI MS: m/z ϭ 1047 [MNaϩ]. C60H64O15 (1024.8):
calcd. C 70.37, H 5.76; found C 70.71, H 5.98.
Methyl
benzylidene-β-
6,3Ј-O-(2-Methyl-5-methylenebenzoyl)-2-O-benzyl-4,6-O-
-glucopyranosyl-(1؊4)-2,3-di-O-benzyl-α- -gluco-
D
D
pyranoside (25): N-Iodosuccinimide (0.124 g, 0.55 mmol), followed by
a catalytic amount of triflic acid (6 µL), were added to a solution of
24 (0.25 g, 0.275 mmol) in dichloromethane (20 mL). The reaction
mixture was stirred at room temp. for a period of 10 min and was
then washed with sodium bicarbonate solution (30 mL) and sodium
thiosulfate solution (30 mL). The aqueous phase was reextracted with
dichloromethane (50 mL), the organic extracts were combined,
washed with water and brine and dried with sodium sulfate, and the
solvent was removed in vacuo. The crude compound obtained was
purified by flash chromatography (petroleum ether/ethyl acetate, 4:1)
to yield pure 25 (0.170 g, 73%) as a colourless foam. TLC (petroleum
ether/ethyl acetate, 3:2): Rf ϭ 0.48. [α]D ϭ Ϫ7.5 (c ϭ 1.0, CHCl3).
1H NMR (600 MHz, CDCl3): δ ϭ 2.56 (s, 3 H, ArCH3), 3.35 (d,
J ϭ 2.2 Hz, 1 H, 2b-H), 3.43 (s, 3 H, OCH3), 3.44Ϫ3.49 (m, 2 H,
2a-H, 4a-H), 3.50 (dd, J6,6 ϭ 10.3, J6,5 ϭ 6.0 Hz, 1 H, 6a-H), 3.77
Spacer-Linked Monosaccharide؊Disaccharide 28: Compound 4[14]
(48 mg, 0.099 mmol) and DCC (101 mg, 0.495 mmol) were added to
a solution of 27 (100 mg, 0.99 mmol) in dichloromethane, followed
by a catalytic amount of DMAP (0.020 g). The reaction mixture was
stirred for a period of 10 h and then filtered, and the solvent was
removed in vacuo to yield the crude compound, which was purified
by flash chromatography (petroleum ether/ethyl acetate, 2:1) to give
pure 28 (0.103 g, 70%). TLC (petroleum ether/ethyl acetate, 3:2): Rf ϭ
0.56. [α]D ϭ Ϫ12.56 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz, CDCl3):
δ ϭ 1.34 (t, J ϭ 7.4 Hz, 3 H, SCH2CH3), 2.60 (s, 3 H, ArCH3), 2.61
(s, 3 H, ArCH3), 2.7Ϫ2.83 (m, 2 H, SCH2CH3), 3.20Ϫ3.35 (m, 2 H,
2b-H, 5b-H), 3.38 (s, 3 H, OCH3), 3.42Ϫ3.56 (m, 8 H, 6a-H, 2a-H,
3b-H, 4b-H, 6b-H, 2c-H, 4c-H, 5c-H), 3.65 (m, 4 H, 5a-H, CO-
OCH3), 3.70Ϫ3.92 (m, 3 H, 6a-H, 3a-H, 4a-H), 4.12Ϫ4.22 (m,1 H,
3c-H), 4.30Ϫ4.42 (m, 3 H, 6a-H, 1b-H, ArCHH), 4.43Ϫ4.49 (m, 2
H, 6a-H), 4.50Ϫ4.52 (m, 2 H, 2 ArCHH), 4.53Ϫ4.68 (m, 6 H, 1a-H,
1c-H, 4 ArCHH), 4.70Ϫ5.0 (m, 10 H, 10 ArCHH), 5.50 (s, 1 H,
PhCH) 7.15Ϫ7.37 (m, 40 H, Ar), 7.78, (s, 1 H, Ar) ppm. MALDI
MS: m/z ϭ 1524 [MNaϩ], 1539.8 [MKϩ]. C89H96O19S (1500.8): calcd.
C 71.20, H 6.40; found C 71.27, H 6.59.
(dd, J6,6 ϭ 10.8, J6,5 ϭ 6.2 Hz, 1 H, 6b-H), 3.86 (dd, 1 H, J6,6
ϭ
10.2 Hz, 6a-H), 3.98 (m, 1 H, 5a-H), 4.16 (m, 2 H, 3a-H, 5b-H), 4.35
(dd, 1 H, J6,6 ϭ 10.8, J6,5 ϭ 6.2 Hz, 1 H, 6b-H), 4.54 (d, J1,2 ϭ 4.0
Hz, 1 H, 1a-H), 4.61 (m, 1 H, 4b-H), 4.68 (m, 2 H, 2 ArCHH), 4.77
(m, 2 H, 2 ArCHH), 4.82 (m, 2 H, 2 ArCHH), 5.01 (m, 2 H, 2
ArCHH), 5.28 (d, J3,4 ϭ 6.8 Hz, 1 H, 3b-H), 5.56 (s, 1 H, PhCH),
5.66 (br. s, 1 H, 1b-H), 7.15Ϫ7.45 (m, 23 H, Ar), 8.09 (s, 1 H, Ar)
ppm. MALDI MS: m/z ϭ 867 [MNaϩ]. C50H52O12 (844.9): calcd. C
71.09, H 6.16; found C 71.30, H 6.27.
Methyl
(1؊4)-2,3-di-O-benzyl-6-O-(3-methoxycarbonyl-4-methylbenzyl)-α-
-glucopyranoside (26): Sodium methoxide in MeOH (0.50 mmol)
was added to a solution of 25 (400 mg, 0.473 mmol) in dichlorome- α-
thane (20 mL) and the reaction mixture was stirred at room temp. glucopyranosyl]-(1؊4)-2,3-di-O-benzyl-6-O-(3-methoxycarbonyl-4-
O-(2-O-Benzyl-4,6-O-benzylidene-β-D-glucopyranosyl)-
D
Methyl 3Ј,6ЈЈ-O-[2-Methyl-5-(methylenebenzoyl)-2,3,4-tri-O-benzyl-
D
-glucopyranosyl]-(1؊4)-[2-O-benzyl-6-O-methoxybenzyl-β-D-
for 2 h. The mixture was now neutralised with ion-exchange resin methylbenzyl)-α-D-glucopyranoside (29): Compound 28 (20 mg,
(IR-120Hϩ) and filtered, and the solvent was removed in vacuo. The 0.013 mmol) was added to a solution of iodine in MeOH (5% w/v),
crude compound was purified by flash chromatography (petroleum and the reaction mixture was stirred at room temp. for a period of
ether/ethyl acetate, 4:1) to yield pure 26 (0.375 g, 90%) as a colourless 0.5 h. Sodium thiosulfate solution was now added until the reaction
oil. TLC (petroleum ether/ethyl acetate, 3:2): Rf ϭ 0.48. [α]D ϭ Ϫ8.7 was iodine-free, and the solvent was removed in vacuo. The residue
1
(c ϭ 1.0, CHCl3). H NMR (250 MHz): δ ϭ 2.61 (s, 3 H, ArCH3),
was taken in dichloromethane (20 mL) and washed with water. The
3.10 (m, 1 H, 5b-H), 3.22 (m, 1 H, 2b-H), 3.38 (s, 3 H, OCH3), aqueous phase was reextracted with dichloromethane (2ϫ30 mL).
3.42Ϫ3.56 (m, 5 H, 6a-H, 2a-H, 3b-H, 4b-H, 6b-H), 3.68 (m, 1 H,
5a-H), 3.80 (s, 3 H, COOCH3), 3.82Ϫ3.84 (m, 2 H, 6a-H), 3.90 (m,
The organic extracts were combined, dried with sodium sulfate and
concentrated to yield the crude compound, which was purified by
2 H, 3a-H, 4a-H), 4.13 (dd, J6,6 ϭ 10.2, J5,6 ϭ 4.6 Hz, 1 H, 6b-H), PLC (preparative thin layer chromatography) to yield pure 29 as a
4.24Ϫ4.30 (m, 2 H, 1b-H, ArCHH), 4.54 (d, J ϭ 3.9 Hz, 1 H, 1a- colourless foam (16 mg, 83%). TLC (petroleum ether/ethyl acetate,
H), 4.60 (m, 1 H, ArCHH), 4.70 (s, 1 H, ArCHH), 4.75 (m, 2 H, 2 3:2): Rf ϭ 0.42. [α]D ϭ Ϫ9.10 (c ϭ 1.0, CHCl3). 1H NMR (250 MHz,
ArCHH), 4.80 (m, 1 H, ArCHH), 4.82 (m, 1 H, ArCHH), 4.90 (s, 1
CDCl3): δ ϭ 2.60 (s, 3 H, ArCH3), 2.61 (s, 3 H, ArCH3), 3.1Ϫ3.2
H, ArCHH), 5.48 (s, 1 H, PhCH), 7.3Ϫ7.6 (m, 23 H, Ar), 7.80 (s, 1 (m, 2 H, 2b-H, 5b-H), 3.33 (s, 3 H, OCH3), 3.37 (s, 3 H, OCH3),
H, Ar) ppm. MALDI MS: m/z ϭ 875 [Mϩ], 898 [MNaϩ]. C51H56O13
(876.7): calcd. C 69.86, H 6.39; found C 69.95, H 6.63.
3.42Ϫ3.60 (m, 8 H, 6a-H, 2a-H, 2b-H, 4b-H, 6b-H, 2c-H, 4c-H, 5c-
H), 3.65 (m, 4 H, 5a-H, COOCH3), 3.80Ϫ3.98 (m, 4 H, 6a-H, 3a-H,
136
Eur. J. Org. Chem. 2003, 128Ϫ137

Reiterative Intramolecular Glycosylation Supported by a Rigid Spacer
4a-H, 3b-H), 4.12Ϫ4.22 (m, 1 H, 3c-H), 4.30 (m, 1 H, ArCHH), 4.39 7.22Ϫ7.45 (m, 40 H, Ar), 7.79 (s, 1 H, Ar). C89H98O21 (1502.9): calcd.
FULL PAPER
(d, J1,2 ϭ 7.8 Hz, 1 H, 1b-H), 4.43Ϫ4.49 (m, 2 H, 6c-H), 4.51 (s, 1
H, ArCHH), 4.57 (d, J1,2 ϭ 3.9 Hz, 1 H, 1a-H), 4.61 (s, 1 H,
C 71.10, H 6.52; found C 71.16, H 6.59.
ArCHH), 4.62 (m, 2 H, ArCHH), 4.65 (m, 3 H, 3 ArCHH), 4.72 (m, Acknowledgments
1 H, ArCHH), 4.76 (d, J ϭ 11.2 Hz, 1 H, ArCHH), 4.78Ϫ4.83 (m,
2 H, 2 ArCHH), 4.85Ϫ4.91 (m, 2 H, 2 ArCHH), 4.93 (m, 1 H,
ArCHH), 4.97 (br. s, 1 H, ArCHH), 5.10 (br. s, 1 H, ArCHH), 5.47
(s, 1 H, PhCH), 7.15Ϫ7.42 (m, 40 H, Ar), 7.78 (s, 1 H, Ar).
C88H94O20 (1470.9): calcd. C 71.83, H 6.39; found C 71.91, H 6.58.
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We are grateful to Anke
Friemel for her help in recording the NMR spectra.
[1]
A. Varki, Glycobiology 1993, 3, 97.
[2]
K.-H. Jung, M. Müller, R. R. Schmidt, Chem. Rev. 2000, 100,
4423Ϫ4442; and references therein.
M. Alani, D. J. Chambers, I. Cumpstey, A. J. Fairbanks, A. J.
[3]
Methyl
benzyl-3-O-3-(methoxycarbonyl-4-methylbenzyl)-6-O-(methoxy-
phenyl-methyl)-β- -glucopyranosyl]-(1؊4)-2,3-di-O-benzyl-6-O-(3-
methoxycarbonyl-4-methylbenzyl)-α- -glucopyranoside (1): Sodium
O-(2,3,4-Tri-O-benzyl-α-D-glucopyranosyl)-(1؊4)-[2-O-
Redgrave, C. M. P. Seward, Chem. Eur. J. 2002, 8, 2608Ϫ2621;
and references therein.
T. Ziegler, R. Lau, Tetrahedron Lett. 1995, 36, 1417Ϫ1420.
S. Valverde, A. M. Gomez, A. Hernandez, B. Herradon, J. C.
D
[4]
D
[5]
methoxide in MeOH (0.5 mmol) was added to a solution of 29
(10 mg, 0.007 mmol) in dichloromethane, and the solution was stirred
for a period of 2 h at room temp. Next, the reaction mixture was
neutralised by the addition of ion-exchange resin (Amberlite IR
120Hϩ) and filtered, and the solvent was evaporated in vacuo. The
crude compound was purified by PLC (preparative thin layer chro-
matography) to yield pure 1 (9 mg, 90%). TLC (petroleum ether/ethyl
Lopez, J. Chem. Soc., Chem. Commun. 1995, 2005Ϫ2006.
[6]
U. Huchel, R. R. Schmidt, Tetrahedron Lett. 1999, 38,
7693Ϫ7694.
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M. Müller. Ph.D. Thesis, University of Konstanz, 2001.
A. A.-H. Abdel Rahman, E. S. H. El Ashry, R. R. Schmidt,
[10]
1
acetate, 3:2): Rf ϭ 0.42. [α]D ϭ Ϫ9.42 (c ϭ 0.5, CHCl3). H NMR
Carbohydr. Res. 2002, 337, 195Ϫ206.
A. Chaudhary, G. Dorman, G. D. Prestwich, Tetrahedron Lett.
(600 MHz, CDCl3): δ ϭ 2.51 (s, 3 H, ArCH3), 2.53 (s, 3 H, ArCH3),
3.14Ϫ3.16 (m, 1 H, 5b-H), 3.33 (s, 3 H, OCH3), 3.34 (m, 1 H, 2b-
H), 3.37 (s, 3 H, OCH3), 3.42Ϫ3.46 (m, 3 H, 6b-H, 6a-H, 4c-H),
3.50Ϫ3.52 (m, 3 H, 2a-H, 2c-H, 3b-H), 3.55Ϫ3.56 (m, 2 H, 5a-H,
4b-H), 3.58 (m, 1 H, 6c-H), 3.65 (s, 3 H, COOCH3), 3.67 (s, 3 H,
COOCH3), 3.81 (m, 2 H, 6a-H, 3a-H), 3.88Ϫ3.91 (m, 2 H, 4a-H, 5c-
H), 4.01 (t, J ϭ 4.0 Hz, 1 H, 3c-H) 4.18Ϫ4.25 (m, 2 H, 6b-H,
ArCHH), 4.39 (d, J1,2 ϭ 7.73 Hz, 1 H, 1b-H), 4.42 (m, 1 H,
ArCHH), 4.44Ϫ4.48 (dd, 1 H, J5,6 ϭ 5.3, J6,6 ϭ 9.6 Hz, 6-H), 4.55
(m, 1 H, ArCHH), 4.57 (d, J1,2 ϭ 4.3 Hz, 1 H, 1c-H), 4.58 (d, J1,2 ϭ
3.9 Hz, 1 H, 1a-H), 4.61Ϫ4.63 (m, 1 H, ArCHH), 4.68Ϫ4.72 (m, 2
H, 2 ArCHH), 4.76Ϫ4.81 (m, 5 H, 5 ArCHH), 4.86Ϫ4.90 (m, 3 H,
3 ArCHH), 4.97 (d, J ϭ 8.2 Hz, 1 H, ArCHH), 5.47 (s, 1 H, PhCH),
[11]
1994, 35, 7521Ϫ7524.
[12]
Compound 2c was synthesised from methyl 2,3-di-O-benzyl-4,6-
O-benzylidene-α--glycopyranoside[11] by simple acetal cleavage.
P. J. Garegg, J. Kvarnström, A. Niklasson, G. Niklasson, S. C.
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A. K. Ray, N. Roy, Carbohydr. Res. 1990, 196, 95Ϫ100.
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S. Paul, R. R. Schmidt, Synlett, 2002, 1107Ϫ1108.
W. A. Szarek, A. Zamojski, K. N. Tiwari, E. R. Ison, Tetrahedron
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Lett. 1986, 27, 3827Ϫ3830.
A. Armstrong, I. Brackenbridge, R. F. Jackson, J. M. Kirk, Tet-
[17]
rahedron Lett. 1988, 29, 2483Ϫ2486.
Received May 23, 2002
[O02276]
Eur. J. Org. Chem. 2003, 128Ϫ137
137