Polymer-supported synthesis of a branched trisaccharide of the type IA Group B Streptococcus capsular polysaccharide: 3-Iodo-4-methoxybenzyl as a new O-protecting group

Article abstract of DOI:10.1016/S0040-4020(00)00612-8

The synthesis of a key branched trisaccharide (1), of the type IA Group B Streptococcus capsular polysaccharide is described. The monomethyl ether of polyethylene glycol (MeO-(CH₂CH₂O)(n)-H, MPEG) and dioxyxylene [p-(O)CH₂-C₆H₄-CH₂(O)-, DOX] have been used as the polymer-support/linker combination. Attempts to use the p-methoxybenzyl (PMB) protecting group under glycosylation conditions involving N-iodosuccinimide/silver trifuoromethanesulfonate promotion resulted in iodination to form the 3-iodo-4-methoxybenzyl (IPMB) derivative. Subsequently IPMB chloride was independently synthesized and used to introduce this new protecting group. The levulinoyl and the IPMB protecting groups have been used in an orthogonal manner to create 3,4-branching on a galactopyranosyl residue. Due to the enhanced acid stability of the IPMB group over the PMB group, the former group was critical to the success of the synthesis. The final trisaccharide and its intermediates were cleaved from the MPEG polymer-support by scandium(III)trifluoromethanesulfonate and acetic anhydride. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00612-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6415±6425
Polymer-Supported Synthesis of a Branched Trisaccharide of the
Type IA Group B Streptococcus Capsular Polysaccharide:
3-Iodo-4-methoxybenzyl as a New O-Protecting Group
*
Seema Mehta and Dennis M. Whit®eld
National Research Council, Ottawa, 100 Sussex Drive, Ontario, Canada K1A 0R6
Received 19 May 2000; accepted 5 July 2000
AbstractÐThe synthesis of a key branched trisaccharide (1), of the type IA Group B Streptococcus capsular polysaccharide is described.
The monomethyl ether of polyethylene glycol (MeO±(CH2CH2O)n±H, MPEG) and dioxyxylene [p-(O)CH2±C6H4±CH2(O)±, DOX] have
been used as the polymer-support/linker combination. Attempts to use the p-methoxybenzyl (PMB) protecting group under glycosylation
conditions involving N-iodosuccinimide/silver trifuoromethanesulfonate promotion resulted in iodination to form the 3-iodo-4-methoxy-
benzyl (IPMB) derivative. Subsequently IPMB chloride was independently synthesized and used to introduce this new protecting group. The
levulinoyl and the IPMB protecting groups have been used in an orthogonal manner to create 3,4-branching on a galactopyranosyl residue.
Due to the enhanced acid stability of the IPMB group over the PMB group, the former group was critical to the success of the synthesis. The
®nal trisaccharide and its intermediates were cleaved from the MPEG polymer-support by scandium(III)tri¯uoromethanesulfonate and acetic
anhydride. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
tion-phase synthesis. The attractiveness of this method is the
ease and the speed of isolation and puri®cation of the
polymer-bound product by its precipitation from the solu-
tion. Thus, contaminants and excess reagents are removed
without tedious and expensive chromatographic puri®ca-
tion. Stimulated by the versatility of the combination of
MPEG polymer-support and the dioxyxylene [p-(O)CH2±
C6H4±CH2(O)±, DOX] linker,5 we have adopted this
approach. The combination [(MPEG)(DOX)OH] has a
benzylic ether bond between the polymer and the linker,
and one free benzylic hydroxyl for linkage with the growing
oligosaccharide chain. We have recently described the
novel use of scandium(III)tri¯uoromethanesulfonate
(Sc(OTf)3) and acetic anhydride (Ac2O), for the cleavage
of oligosaccharides bound to PEG via the DOX linker.6
The popularity of combinatorial chemistry, and the prospect
of automated oligosaccharide synthesis has led to consider-
able development in the areas of polymer-supported,1,2 and
solid-phase oligosaccharide synthesis.3 Our interest is to
develop ef®cient and effective methods for the rapid
assembly of higher order oligosaccharides by polymer-
supported methods. Polymer-supported synthesis on the
monomethyl ether of polyethylene glycol (MeO±
(CH2CH2O)n±H, MPEG) is a powerful tool in organic
synthesis.4 In addition to providing the advantages of
solid-phase synthesis, the solubility of MPEG in reaction
solvents enables reactions to be performed in a homogenous
phase, and to conserve the stereochemical control of solu-
Figure 1. Structure of a single repeat unit of type 1A Group B Streptococcus capsular polysaccharide.
Keywords: oligosaccharides; polymer-supported; protecting groups.
* Corresponding author. Tel.: 1613-993-5265; fax: 1613-952-9092; e-mail: dennis.whit®eld@nrc.ca
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00612-8

6416
S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
polysaccharide (Fig. 2). This requires a galactose building
block which can be separately extended at O-3 and O-4. Our
®rst generation building blocks used the acid cleavable
isopropylidene ketal protecting group. However, complica-
tions from an acyl transfer side reaction and poor O-3/O-4
regioselectivity has led to a search for second generation
building blocks.8 The original formulation of (MPEG)-
(DOX) used O-benzyl as permanent protecting groups and
O-acyl as base cleavable protecting groups for chain exten-
sion.5 If O-acyl are used for stereochemical control by
neighboring group participation then protecting groups
cleavable in the presence of acyl and benzyl are required.
To date phenylboronate diesters9 and ketals8 have been
shown to ful®ll these criteria. Recently, the combination
of O-levulinoyl (Lev) and O-[9-¯uorenylmethoxycarbonyl]
(Fmoc) protecting groups has been introduced for this
purpose with (MPEG) supported oligosaccharides.10 In
this work we introduce the use of the 3-iodo-4-methoxy-
benzyl (IPMB) group as a new O-protecting group in
combination with Lev to achieve the required selectivity.
Figure 2. Target branched trisaccharide 1.
Results and Discussion
Our strategy was to synthesize a galactopyranosyl building
block with persistent benzoyl groups as protecting groups at
the O-2 and O-6 positions, and temporary protecting groups
at the O-3 and O-4 branching positions. Our initial efforts
were focussed on p-methoxybenzyl11 and acetyl groups as
the cleavable protecting groups. Treatment of the tetraol 212
with dibutyltin oxide afforded the 3,4-O-dibutylstannylene
intermediate 3 (Fig. 3).13 This was reacted with p-methoxy-
benzyl chloride in the presence of cesium ¯uoride14 to
Figure 3. 4-O-Acetyl (6) and 4-O-Levulinoyl (11) building blocks.
As a part of the process towards the development of
vaccines against Group B Streptococcus bacteria (Fig. 1),
we are involved in a program to synthesize fragments of the
serotype speci®c capsular polysaccharides.7 We now
describe the polymer-supported synthesis of a key branched
trisaccharide 1 of type 1A Group B Streptococcus capsular
Scheme 1.

S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
6417
dimethyl(thiomethyl)-sulfonium tri¯uoromethanesulfonate
(DMTST),19 and the non-iodinated compound 12 was
obtained (Scheme 1). For additional proof of structure,
and in order to determine the position of iodination,
compounds 10, 12, and 13, were cleaved from the polymer
support by treatment with scandium(III)tri¯uoromethane-
sulfonate (Sc(OTf)3) and acetic anhydride (Ac2O) to afford
14, 15 and 16, respectively (Scheme 2).6 It is interesting to
note that the iodinated-PMB group (IPMB) in 10 and 13 was
stable under cleavage conditions. However, the PMB group
in 12 was cleaved at room temperature, and the free
hydroxyl group at the 3-position was acetylated during
treatment with Sc(OTf)3/Ac2O,20 to afford 15.
Scheme 2.
produce selectively the 3-O-p-methoxybenzyl product 4.15
Selective benzoylation of the O-2 and O-6 with benzoic
anhydride and pyridine did afford the 2,6-di-O-benzoate
compound 5 in a 50% yield. Also isolated were the 6-O-
benzoate, 4,6-di-O-benzoate and 2,4,6-tri-O-benzoate
compounds. These compounds were debenzoylated and
retreated. Acetylation of 5 afforded the target galactose
building block 6 (Fig. 3).
Complete assignment of the 1H and 13C NMR signals of the
ring, as well as the protecting groups, was accomplished by
routine COSY and C±H correlation NMR experiments. The
chemical shift of the iodinated carbon atom (C-3 of the
IPMB aromatic system) was found to be 85.6 ppm, and
was in correspondence with literature values.21 The position
of iodine substitution was further con®rmed by TOCSY and
HMBC NMR experiments, in particular, HMBC cross-
peaks between C-3 and H-2, and C-3 and H-5 of the
IPMB aromatic system.
For the synthesis of the trisaccharide MPEG of 5000
molecular weight, was used as the polymer-support with
the DOX linker.5 The ®rst coupling of (MPEG)(DOX)OH
7 with the phenyl thiogalactopyranoside derivative 6 was
affected under NIS/silver tri¯uoromethanesulfonate
(AgOTf)16 promotion at 0±58C (Scheme 1). According to
our earlier investigations, these conditions were the most
suitable to avoid the detrimental migration of the benzoyl
protecting group at the 2-position of the galactose derivative
to the hydroxyl group on the DOX linker.8 The attempted
selective deacetylation at the 4-position of the polymer-
bound compound 8, in the presence of the 2,6-di-O-benzoyl
protecting groups was problematic. Typically, the selective
removal of acetate protecting groups in the presence of
benzoate protecting groups is accomplished using 3% HCl
in MeOH.17 However, under these conditions, the simul-
taneous hydrolysis of the 6-benzoate in compound 8 was
observed, and, instead of the desired alcohol 9, the 4,6-diol
10 was isolated (Scheme 1). At this point, an alternative
building block was contemplated and the acetyl group at
the 4-position was replaced with a Lev group. The alcohol
5 was transformed into compound 11 by reaction with
levulinic acid in the presence of 1,3-dicyclohexylcarbodi-
imide (DCC) and 4-dimethylaminopyridine (DMAP)
(Fig. 3). Compound 11 was coupled to the polymer-support
under NIS/AgOTf promotion16 (Scheme 1). Interestingly,
depending upon the time of the glycosylation reaction,
two different products were isolated. With reaction times
of 0.5 h, the expected polymer-bound product 12 was
obtained. However, longer reaction times produced a
mixture of two compounds. When the reaction was allowed
to proceed for 4 h, a single product 13, was obtained. To our
surprise, under the glycosylation conditions, the 4-methox-
benzyl (PMB) protecting group of 12 was iodinated to
produce compound 13. A similar observation of iodination
of PMB has been reported but the product was not charac-
terized.18 Compounds 12 and 13 had very similar NMR
spectra, but were differentiated on the basis of the chemical
shifts of the aromatic protons of the 4-methoxybenzyl
group. As a control experiment, the glycosylation of 7
with 11 was repeated with a non-iodinating promoter,
Our attention was next focussed on building block 13.
Selective delevulinoylation of the polymer-bound
compound 13 was achieved with a 2% hydrazine hydrate
solution in pyridine/acetic acid,22 to afford 18. Glycosyl-
ation of 18 with trichloroacetimidate donor 1723 was
performed with TESOTf as promoter,24 to afford the
polymer-bound disaccharide 19 (Scheme 3). Two glycosyl-
ations were required for the complete reaction of the
polymer-bound galactopyranosyl derivative. It is note-
worthy that similar glycosylations of the non-iodinated
analog 20 were not as ef®cient. Disaccharide 19 was cleaved
from the polymer with Sc(OTf)3/Ac2O, and characterized as
21. The removal of the 3-iodo-4-methoxy benzyl group
(IPMB) from 19 was attempted under oxidative conditions,
using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ),11a,11b
Scheme 3.

6418
S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
Scheme 4.
as well as cerium(IV) ammonium nitrate (CAN).25
However, these conditions were not amenable to our
substrates linked to the MPEG polymer-support. We
attribute these dif®culties to the complexation of the
reagents to the PEG support as reported for a number of
reagents.26 Further experimentation is necessary to clarify
these issues especially in light of the recent report of the
successful cleavage of a PEG bound N-PMB group using
CAN.27 The IPMB was removed under acidic conditions, by
the treatment of 19 with 10% TFA in dichloromethane,28 for
24 h (Scheme 4). It is noteworthy that compared to the
IPMB group in 19, the PMB group in the non-iodinated
analog 22 was removed with greater ease; the PMB group
required 10% TFA treatment for only 12 h. Thus, the acid
stability of the IPMB is higher than that of the PMB group.
It should be noted that sugar linkages have been reported to
be stable in 50% TFA during glycopeptide synthesis.29 Also,
the polymer bound product is precipitated from the 10%
TFA solution and is therefore never concentrated in the
presence of TFA. Compound 23 was cleaved from the
polymer-support with Sc(OTf)3/Ac2O, and characterized
as 24.
Scheme 6.
trisaccharide 26 (Scheme 5). Cleavage of the trisaccharide
from the polymer-support, mediated by Sc(OTf)3/Ac2O,
afforded the target trisaccharide 1. The H and 13C NMR
1
spectra of 1 were completely assigned and are fully
consistent with the expected regiochemistry and stereo-
chemistry of the 3,4-branching.
In order to probe the orthogonality of the Lev/IPMB protect-
ing group pair, the selective removal of the IPMB group, in
the presence of the Lev group was attempted. Treatment of
the polymer-bound galactose derivative 13 with 10% TFA
in CH2Cl2 for 24 h afforded the alcohol 27 (Scheme 6). The
Lev group was unaffected under these conditions and the
esters did not migrate. Subsequent glycosylation of 27 with
phenyl thioglycoside 25,30 under NIS/tri¯uoromethane-
sulfonic acid (TfOH) promotion,16 afforded the polymer-
bound disaccharide 28, which was cleaved from MPEG
with Sc(OTf)3/Ac2O, and characterized as the free
disaccharide 29.
Two sequential glycosylations of 23 with the phenyl
thioglycoside 25,30 with NIS/AgOTf, afforded the desired
The need for acid cleavable protecting groups, particularly,
differentially cleavable protecting groups, is well recog-
nized.31 Recent reports on the use of aminated benzyl ethers
and p-hydroxybenzyl derived protecting groups are indica-
tive of the desire for selectively removable hydroxyl group
protection, for solution, as well as, solid-phase synthesis.32
Figure 4. 4-O-Levulinoyl and 3-O-(3-iodo-4-methoxybenzyl) (34) building
block.
Scheme 5.

S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
6419
Scheme 7.
Our observed differences in the properties of the PMB and
IPMB ether protecting groups prompted us to investigate the
use of IPMB as a novel O-protecting group. We describe
here the attachment of IPMB group. 3-Iodo-4-methoxy-
benzyl chloride 30 was synthesized in a manner analogous
to that of the 2-iodo compound (Fig. 4).33 Reaction of
chloromethyl methyl ether in glacial acetic acid, with
o-iodoanisole for 60 h afforded 30. Treatment of the diol
3134 with dibutyltin oxide, followed by cesium ¯uoride
and 3-iodo-4-methoxybenzyl chloride 30 provided 33,
which was levulinoylated at the 4-position to afford 34.
As a control experiment, 34 was coupled to the polymer-
support 7 under DMTST promotion ((Scheme 7)). The
isolation of polymer-bound substrate 13, further con®rmed
the position of iodination to be the 3-position of the PMB
group.
gel 60 (230±400 mesh) was used. Detection was effected by
examination under UV light and by charring with 5%
sulfuric acid in water. All starting materials were dried over-
night in vacuo (1023 mmHg) over KOH or P2O5 prior to use,
and the solvents were distilled from appropriate drying
agents. Solutions were concentrated at 1 mmHg pressure
in a rotary evaporator. Optical rotations were measured
(lˆ589 nm) at room temperature in a 10 cm£1 mL cell.
1
The H and 13C NMR spectra were recorded in deuterio-
chloroform solution at 500.1 or 600.2 MHz and 125.8 or
1
150.9 MHz, respectively. H NMR spectra in CDCl3 were
referenced to residual CHCl3 at 7.24 ppm, and 13C NMR
spectra to the central peak of CDCl3 at 77.0 ppm. Assign-
ments were made by standard 1H±1H-COSY and
1H-coupled 13C±1H-COSY experiments. 1H chemical shifts
are reported to two decimal places and 13C shifts to one. In
the case of closely separated resonances an additional ®gure
is added to show that they are separately identi®able. For
polymer bound samples the MPEG methylenes were
saturated and quantitation was made by comparing integrals
to the terminal methyl of the MPEG. Assignments were
made by comparison to the spectra of building blocks and
cleaved compounds. Advantage was also taken of gradient-
enhanced 1D-selective TOCSY and NOESY experiments.
Typically 256 transients were used for TOCSY spectra with
mixing times from 20 to 150 ms and 4k transients for
NOESY spectra with mixing times of 200 to 500 ms.
In conclusion, this work has described the synthesis of a key
branched trisaccharide (1), of the type IA Group B Strepto-
coccus capsular polysaccharide, by the polymer-supported
method, with MPEG and DOX as the polymer-support/
linker combination. The IPMB group has been introduced
as a new protecting group. The Lev and the IPMB protecting
groups are amenable to selective cleavage, and have been
used in an orthogonal manner to produce 3,4-branching on
the galactopyranosyl residue. The enhanced acid stability of
the IPMB group over the PMB group provides a more
¯exible handle for the use of both these protecting groups
on the PEG polymer support, and for more general synthetic
applications.
The mass spectral analysis was done on a forward mass
spectrometer. Fast atom bombardment (FAB) MS was
performed using Xenon atom at 6 kV as source. Thio-
glycerol or a mixture of glycerol and thioglycerol were
used as FAB matrix. Typically 10±15 full range, low
resolution MS scans were averaged to yield a low resolution
mass spectrum. For high resolution MS, the electric sector
was scanned over the range of interest. Typically poly-
ethylene glycol or polypropylene glycol was used as an
internal mass standard and between 75 and 150 scans
were averaged. MALDI MS Spectra were taken on a
Experimental
Materials and general methods
TLC was performed on Merck Silica gel 60 F254 plates and
preparative silica gel chromatography on Merck Silica gel
60 (70±230 mesh). For ¯ash chromatography Merck Silica

6420
S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
Voyager-De STR Biochemistry Workstation, from
PerSeptive Biosystems, Framingham, MA, USA. 2,5-
Dihydroxybenzoic acid was used as MALDI matrix.
Microanalyses were performed by Ms. A. Webb from the
analytical services of this department.
(100%) to afford ¯uffy white crystals. Mp 165.28C;
[a]D20ˆ197.38 (c 1.2, CH2Cl2); 13C NMR (CDCl3): d 21.0
(COCH3), 55.1 (OCH3), 62.9 (C-6), 66.3 (C-4), 69.3 (C-2),
70.7 (CH2C6H4), 74.8 (C-5), 76.7 (C-3), 87.0 (C-1), 113.6
(C3-PMB, C5-PMB), 127.7±133.3 (Ar), 159.2 (C4-PMB),
165.2, 166.1 (2COC6H5), 170.4 (COCH3); 1H NMR
(CDCl3): d 2.22 (3H, s, COCH3), 3.71 (1H, dd, H-3), 3.72
(3H, s, OCH3), 4.04 (1H, m, H-5), 4.36 (1H, d, Jˆ12.5 Hz,
CHHC6H5), 4.46 (1H, dd, J5,6aˆ4.9 Hz, J6a,6bˆ11.2 Hz,
H-6a), 4.53 (1H, dd, J5,6bˆ8.0 Hz, J6a,6bˆ11.2 Hz, H-6b),
4.60 (1H, d, Jˆ12.5 Hz, CHHC6H5), 4.82 (1H, d,
J1,2ˆ10.3 Hz, H-1), 5.45 (1H, t, J1,212,3ˆ20.0 Hz, H-2),
5.67 (1H, d, Jˆ2.8 Hz, H-4), 6.61 (2H, d, Jˆ8.5 Hz,
PMB), 7.03 (2H, d, Jˆ8.5 Hz, PMB), 7.06±8.07 (15H,
Ar); Anal. Calcd for C36H34O9S: C, 67.28; H, 5.33, Found
C, 67.58; H, 5.24.
(MPEG) general work-up procedure
Typically (MPEG) bound substrates were worked up by
precipitation, by adding tert-butyl methyl ether (TBME)
(10±20 volumes) to the reaction mixtures. The polymer
was ®ltered, rinsed with TBME, and reprecipitated from
absolute ethanol (about 50 mL per g). The white precipitate
was collected by ®ltration, rinsed with ethanol then Et2O,
and taken up in CH2Cl2 and ®ltered. The ®ltrate was evapo-
rated and dried in vacuo to afford the polymer-bound
product. Throughout the experimental this procedure will
be referred to as standard work up.
(MPEG)(DOX)yl 2,6-di-O-benzoyl-4-O-acetyl-3-O-(3-
iodo-4-methoxybenzyl)-b-d-galactopyranoside (8). (MPEG)-
(DOX)OH 7 (300 mg, 0.06 mmol) and glycosyl donor 6
(60 mg, 0.09 mmol) were dried over drierite/CaCl2 over-
night, under vacuum. CH2Cl2 (3.0 mL) was added under
argon and the reaction ¯ask was cooled to 08C. N-Iodo-
succinimide (NIS) (141 mg, 0.6 mmol) was added, followed
by silver tri¯uoromethanesulfonate (AgOTf) (23 mg,
0.09 mmol). The reaction was monitored by TLC for the
exhaustion of 6. The reaction mixture was stirred for 4 h
after the colorization of the reaction mixture, and was
quenched with diisopropylethylamine (DIPEA). Then
Phenyl 2,6-di-O-benzoyl-3-O-(4-methoxybenzyl)-1-thio-
b-d-galactopyranoside (5). Phenyl 1-thio-b-d-galacto-
pyranoside 212 (7.4 g, 27.1 mmol) and dibutyltin oxide
(6.8 g, 27.3 mmol) were re¯uxed in methanol (1.0 L) for
4 h. The solvent was evaporated and the crude stannylene
derivative 3 was dried overnight. It was dissolved in N,N-
dimethylformamide (135 mL), and treated with cesium
¯uoride (5.0 g, 33.0 mmol) and 4-methoxybenzyl chloride
(12.0 mL, 81.3 mmol). After 48 h at 308C, the reaction was
concentrated and co-distilled with toluene. The residue was
chromatographed with hexane/ethyl acetate/methanol
(4:4:1) as eluant to yield phenyl 3-O-(4-methoxybenzyl)-
1-thio-b-d-galactopyranoside15 4 as a white solid (7.0 g,
66%). Triol 4 (1.6 g, 4.1 mmol) was treated with pyridine
(30 mL) and benzoic anhydride (2.6 g, 11.5 mmol). The
reaction mixture was stirred under argon for 10 days,
quenched with methanol and concentrated. The residue
was chromatographed with hexane/ethyl acetate (2:1) as
eluant. The title compound 5 was obtained as a white
solid (1.2 g, 50%). Also isolated were the 2,4,6-tri-O-
benzoylated, 4,6-di-O-benzoylated and the 6-O-benzoylated
compounds. [a]D20ˆ1168.08 (c 0.5, CH2Cl2); 13C NMR
(CDCl3): d 55.0 (OCH3), 64.1 (C-6), 66.5 (C-4), 69.4
(C-2), 71.3 (CH2C6H4), 76.1 (C-5), 78.5 (C-3), 86.7 (C-1),
113.8 (C3-PMB, C5-PMB), 127.4±133.1 (Ar), 159.4
1
standard work up afforded product 8 (290 mg, 97%). H
NMR (CDCl3): d 2.24 (3H, s, COCH3), 3.38 (3H, s,
OCH3), 3.95 (1H, t, H-5), 4.26 (1H, d, Jˆ12.4 Hz,
CHHC6H5), 4.47 (1H, dd, J5,6aˆ6.3 Hz, J6a,6bˆ11.3 Hz, H-
6a), 4.5±4.6 (2H, m, CH2C6H4-DOX), 4.56 (1H, d,
J1,2ˆ8.0 Hz, H-1), 4.61 (1H, dd, J5,6bˆ6.9 Hz, J6a,6b
ˆ
11.3 Hz, H-6b), 4.64 (1H, d, Jˆ12.7 Hz, CHHC6H4-
DOX), 4.84 (1H, d, Jˆ12.7 Hz, CHHC6H4-DOX), 5.46
(1H, dd, J1,2ˆ8.0 Hz, J2,3ˆ9.9 Hz, H-2), 5.60 (1H, d,
Jˆ3.1 Hz, H-4), 6.43 (1H, d, Jˆ8.5 Hz, H5-IPMB), 7.04
(1H, d, H6-IPMB), 7.10 (4H, s, DOX), 7.40±7.50 (5H, m,
Bz, H2-IPMB), 7.56±7.65 (2H, m, Bz), 7.91 (2H, d, Bz),
8.08 (2H, d, Bz).
Phenyl 2,6-di-O-benzoyl-4-O-levulinoyl-3-O-(4-methoxy-
benzyl)-1-thio-b-d-galactopyranoside (11). Alcohol 5
(450 mg, 0.75 mmol) was dissolved in anhydrous tetra-
hydrofuran (THF) (11 mL) and cooled to 08C. A solution
of levulinic acid (0.17 mL, 1.66 mmol) in THF (2 mL) was
added, followed by 1,3-dicyclohexylcarbodiimide (DCC)
(332 mg, 1.6 mmol) and 4-dimethylaminopyridine
(DMAP) (10 mg). The reaction was stirred overnight
under argon, quenched with methanol, and ®ltered through
celite and the ®ltrate evaporated. The residue was puri®ed
by column chromatography with hexane/ethyl acetate
(2.5:2) as eluant. The title compound 11 was obtained as a
white solid (500 mg, 95%). The product was crystallized
from hexane/ethyl acetate to afford white crystals. Mp
121.48C; [a]2D0ˆ172.98 (c 0.5, CH2Cl2); 13C NMR
(CDCl3): d 28.1, 38.1 (Lev), 55.1 (OCH3), 63.0 (C-6),
66.5 (C-4), 69.3 (C-2), 70.6 (CH2C6H4), 74.9 (C-5), 76.5
(C-3), 86.7 (C-1), 113.6 (C3-PMB,C5-PMB), 127.7±133.2
(Ar), 159.2 (C4-PMB), 165.2, 166.1 (2COC6H5), 172.1
(CH3COCH2CH2CO), 206.2 (CH3COCH2CH2CO); 1H
1
(C4-PMB), 165.3, 166.4 (2COC6H5); H NMR (CDCl3): d
3.70 (1H, dd, J2,3ˆ9.3 Hz, J3,4ˆ2.0 Hz, H-3), 3.73 (3H, s,
OCH3), 3.92 (1H, m, H-5), 4.14 (1H, bs, H-4), 4.49 (1H, d,
Jˆ12.2 Hz, CHHC6H5), 4.60 (1H, d, Jˆ12.2 Hz,
CHHC6H5), 4.64 (1H, dd, J5,6aˆ7.8 Hz, J6a,6bˆ11.2 Hz,
H-6a), 4.72 (1H, dd, J5,6bˆ2.9 Hz, J6a,6bˆ11.2 Hz, H-6b),
4.77 (1H, d, J1,2ˆ10.3 Hz, H-1), 5.51 (1H, t, J1,212,3
ˆ
19.5 Hz, H-2), 6.68 (2H, d, Jˆ8.8 Hz, PMB), 7.06±8.08
(17H, Ar); Anal. Calcd for C34H32O8S: C, 67.98; H, 5.37,
Found C, 68.03; H, 5.51.
Phenyl
benzyl)-1-thio-b-d-galactopyranoside (6). Alcohol
4-O-acetyl-2,6-di-O-benzoyl-3-O-(4-methoxy-
5
(100 mg, 0.17 mmol) was treated with pyridine (3 mL)
and acetic anhydride (Ac2O) (3 mL). The reaction was stir-
red overnight and concentrated. The residue was puri®ed by
column chromatography with hexane/ethyl acetate (3:2) as
eluant. The title compound 6 was obtained as a white solid
(101 mg, 94%). The product was crystallized from ethanol

S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
6421
NMR (CDCl3): d 2.20 (3H, s, COCH3), 2.67±2.87 (4H, m,
CH3COCH2CH2), 3.70 (1H, m, J2,3ˆ9.7 Hz, J3,4ˆ3.2 Hz, H-
3), 3.72 (3H, s, OCH3), 4.05 (1H, m, H-5), 4.33 (1H, d,
Jˆ12.2 Hz, CHHC6H5), 4.48 (1H, dd, J5,6aˆ4.9 Hz,
J6a,6bˆ11.5 Hz, H-6a), 4.56 (1H, d, Jˆ12.2 Hz,
CHHC6H5), 4.55 (1H, dd, J5,6bˆ7.6 Hz, J6a,6bˆ11.5 Hz,
H-6b), 4.79 (1H, d, J1,2ˆ10.1 Hz, H-1), 5.42 (1H, t,
J1,212,3ˆ19.6 Hz, H-2), 5.66 (1H, d, Jˆ3.0 Hz, H-4), 6.61
(2H, d, Jˆ8.5 Hz, PMB), 7.02 (2H, d, Jˆ8.5 Hz, PMB),
7.08±8.06 (15H, Ar); HRMS (FAB) calcd for
C39H38O10SNa: 721.2083, Found m/z: 721.2127
(M1Na1); Anal. Calcd for C39H38O10S: C, 67.03; H, 5.48,
Found C, 67.19; H, 5.84.
a-O-Acetyl-DOXyl 4,6-di-O-acetyl-2-O-benzoyl-3-O-(3-
iodo-4-methoxybenzyl)-b-d-galactopyranoside (14). The
polymer-bound galactopyranoside 8 (60 mg, 0.01 mmol)
was dissolved in Ac2O (0.5 mL) with heat. Sc(OTf)3
(3 mg, 0.06 mmol) was added and the reaction was stirred
under argon for 2 h. The reaction mixture was cooled to 08C,
excess TBME was added and the mixture was stirred for
15 min in order to precipitate the polymer. The precipitate
was ®ltered, the ®ltrate was concentrated and puri®ed by
preparative TLC with hexane/ethyl acetate (1:1) as eluant
to yield the title compound 14 (2 mg, 40%). The precipi-
tated polymer was dissolved in CH2Cl2, the solution was
concentrated and NMR was performed in order to con®rm
the complete cleavage of the sugar from the polymer. 14
[a]D20ˆ12.18 (c 0.1, CH2Cl2); 13C NMR (CDCl3): d 20.8,
20.9, 21.0 (3COCH3), 56.2 (OCH3), 61.9 (C-6), 65.87 (C-4),
65.92 (CH2C6H4-DOX), 69.9 (CH2C6H4-DOX), 70.6
(CH2C6H3), 70.96 (C-2), 71.01 (C-5), 76.3 (C-3), 85.6
(C3-IPMB), 99.5 (C-1), 110.7 (C5-IPMB), 128.0±136.8
(Ar), 129.9 (C6-IPMB), 131.4 (C1-IPMB), 138.9 (C2-
IPMB), 157.7 (C4-IPMB), 165.1 (COC6H5), 170.5
(COCH3); 1H NMR (CDCl3): 2.10, 2.12, 2.21 (9H, 3s,
3COCH3), 3.60 (1H, dd, J2,3ˆ10.3 Hz, J3,4ˆ3.4 Hz, H-3),
3.76 (3H, s, OCH3), 3.83 (1H, t, H-5), 4.23±4.28 (3H, m,
CHHC6H3-IPMB, H-6a, H-6b), 4.52±4.56 (2H, m, H-1,
CHHC6H3-IPMB), 4.64 (1H, d, Jˆ12.7 Hz, CHHC6H4-
DOX), 4.87 (1H, d, Jˆ12.7 Hz, CHHC6H4-DOX), 5.03
(2H, s, CH2C6H4-DOX), 5.44 (1H, t, J1,212,3ˆ17.6 Hz,
H-2), 5.53 (1H, d, Jˆ2.9 Hz, H-4), 6.44 (1H, d, Jˆ8.3 Hz,
H5-IPMB), 7.05 (1H, d, Jˆ8.3 Hz, H6-IPMB), 7.16 (4H,
dd, DOX), 7.45±7.48 (2H, t, Bz), 7.53 (1H, s, H2-IPMB),
7.61 (1H, t, Bz), 7.92 (2H, d, Bz); HRMS (FAB) calcd for
C35H37O12I: 799.1227, Found m/z: 799.1243 (M1Na1).
(MPEG)(DOX)yl 2,6-di-O-benzoyl-4-O-levulinoyl-3-O-
(4-methoxybenzyl)-b-d-galactopyranoside (12). A mix-
ture of (MPEG)(DOX)OH 7 (100 mg, 0.02 mmol) and
glycosyl donor 11 (20 mg, 0.03 mmol) was dried over
drierite/CaCl2, under vacuum overnight. CH2Cl2 (1.5 mL)
was added under argon and the reaction ¯ask was cooled to
08C. Dimethyl(methylthio)sulfonium tri¯ate (DMTST)
(39 mg, 0.15 mmol) was added. After 5 min the reaction
was warmed to room temperature and stirred for 30 min.
At this point, TLC indicated exhaustion of 11. The reaction
was cooled to 08C and quenched with DIPEA. Then stan-
dard work up afforded the polymer bound compound 12
1
(90 mg, 90%). H NMR (CDCl3): 2.17 (3H, s, COCH3),
2.71±2.84 (4H, m, CH3COCH2CH2), 3.37 (3H, s, OCH3),
3.59 (H-3), 3.94 (1H, t, H-5), 4.41 (1H, dd, H-6a), 4.48 (1H,
d, H-1), 4.82 (1H, d, CHHC6H4-DOX), 5.42 (1H, t, H-2),
5.59 (1H, d, H-4), 6.58 (2H, d, PMB), 6.99 (2H, d, PMB),
7.07 (4H, m, DOX), 7.43±7.49 (4H, m, Bz), 7.58±7.60 (2H,
m, Bz), 7.90 (2H, d, Bz), 8.07 (2H, d, Bz).
(MPEG)(DOX)yl 2,6-di-O-benzoyl-4-O-levulinoyl-3-O-
(3-iodo-4-methoxybenzyl)-b-d-galactopyranoside (13).
(1) Prepared from phenyl 2,6-di-O-benzoyl-4-O-levuli-
noyl-3-O-(4-methoxybenzyl)-1-thio-b-d-galactopyranoside
11 under AgOTf promotion. Compound 13 was prepared
from (MPEG)(DOX)OH 7 (300 mg, 0.06 mmol) and glyco-
syl donor 11 (60 mg, 0.09 mmol) with NIS (141 mg,
0.6 mmol) and AgOTf (23 mg, 0.09 mmol) as for compound
8 above. The polymer-bound product 13 was obtained
(290 mg, 97%).
a-O-Acetyl-DOXyl
3-O-acetyl-2,6-di-O-benzoyl-4-O-
levulinoyl-b-d-galactopyranoside (15). The polymer-
bound galactopyranoside 12 (50 mg, 0.01 mmol), was
dissolved in CH2Cl2 (0.5 mL). Ac2O (0.5 mL) was added
and the reaction was cooled to 08C. Sc(OTf)3 (3 mg,
0.06 mmol) was added and the reaction was stirred under
argon for 2 h. Excess TBME was added and the mixture was
stirred for 15 min in order to precipitate the polymer. The
precipitate was ®ltered, the ®ltrate was concentrated and
column chromatographed with hexane/ethyl acetate (1:1)
as eluant. The title compound 15 was obtained (4 mg,
52%). The precipitated polymer was dissolved in CH2Cl2,
the solution was concentrated and NMR was performed
in order to con®rm the complete cleavage of the sugar
from the polymer 15. [a]2D0ˆ22.28 (c 0.2, CH2Cl2); 13C
(2) Prepared from ethyl 2,6-di-O-benzoyl-4-O-levulinoyl-3-
O-(3-iodo-4-methoxybenzyl)-1-thio-b-d-galactopyranoside
34 under DMTST promotion. (MPEG)(DOX)OH 7 (150 mg,
0.03 mmol) and glycosyl donor 34 (40 mg, 0.05 mmol)
were dried over drierite/CaCl2 overnight in vacuo. CH2Cl2
(2.0 mL) was added under argon. DMTST (65 mg,
0.25 mmol) was added at 08C. After 5 min the reaction
was warmed to room temperature and stirred for 30 min.
At this point, TLC indicated exhaustion of 34. The reaction
was cooled to 08C and quenched with DIPEA. Then stan-
dard work up afforded the polymer bound compound 13
(90 mg, 90%). 1H NMR (CDCl3): d 2.19 (3H, s,
CH3COCH2CH2), 2.71±2.85 (4H, m, CH3COCH2CH2),
3.39 (3H, s, OCH3), 3.95 (1H, t, H-5), 4.63 (1H, d, H-1),
5.44 (1H, t, H-2), 5.61 (1H, d, H-4), 6.45 (1H, d, H5-IPMB),
7.04 (1H, d, H6-IPMB), 7.10 (4H, s, DOX), 7.45±7.50 (4H,
m, Bz), 7.52 (1H, s, H2-IPMB), 7.61 (2H, t, Bz), 7.93 (2H,
d, Bz), 8.09 (2H, d, Bz).
NMR (CDCl3):
d
20.5, 21.0 (2COCH3) 27.9
(CH3COCH2CH2CO), 29.7 (CH3COCH2CH2CO), 37.9
(CH3COCH2CH2CO), 61.7 (C-6), 65.9 (CH2C6H4-DOX),
67.4 (C-2), 69.5 (C-4), 70.1 (CH2C6H4-DOX), 70.8 (C-3),
71.0 (C-5), 99.5 (C-1), 128.0±136.6 (Ar), 165.1, 166.0
(2COC6H5),
170.2,
170.8
(2COCH3),
172.0
(CH3COCH2CH2CO), 206.0 (CH3COCH2CH2CO); 1H
NMR (CDCl3): d 1.90, 2.07, 2.17 (9H, 3s, 3COCH3),
2.72±2.78 (4H, m, CH3COCH2CH2), 4.06 (1H, t,
J4,515,6ˆ13.3 Hz, H-5), 4.35 (1H, dd, J5,6aˆ6.9 Hz,
J6a,6bˆ11.5 Hz, H-6a), 4.59 (1H, dd, J5,6bˆ6.9 Hz,
J6a,6bˆ11.5 Hz, H-6b), 4.62 (1H, d, CHHC6H4-DOX), 4.63
(1H, d, J1,2ˆ7.8 Hz, H-1), 4.86 (1H, d, CHHC6H4-DOX),
5.00 (2H, s, CH2C6H4-DOX), 5.17 (1H, dd, J2,3ˆ10.2 Hz,

6422
S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
J3,4ˆ3.4 Hz, H-3), 5.54 (2H, m, J2,313,4ˆ18.3 Hz, H-2, H-4),
7.11 (4H, dd, DOX), 7.42±7.46 (4H, m, Bz), 7.55±7.60 (2H,
q, Bz), 7.95 (2H, d, Bz), 8.02 (2H, d, Bz); HRMS (FAB)
calcd for C43H44O13Na: 791.2679, Found m/z: 791.2702
(M1Na1).
acetimidate 1723 (187 mg, 0.39 mmol) and galactopyrano-
side 18 (620 mg, 0.13 mmol) was dried over drierite/CaCl2
overnight under vacuum. Anhydrous CH2Cl2 (6 mL) was
added. It was cooled to 2408C and treated with TESOTf
(29 mL, 0.13 mmol). The reaction mixture was stirred for
1 h at 2108C and then for 1 h at 08C, quenched with DIPEA
(two drops). The standard work up afforded the polymer
bound disaccharide 19 (610 mg, 98%). The above procedure
was repeated to afford the polymer bound disaccharide 19
a-O-Acetyl-DOXyl 2,6-di-O-benzoyl-4-O-levulinoyl-3-
O-(3-iodo-4-methoxybenzyl)-b-d-galactopyranoside (16).
Galactopyranoside 13 (200 mg, 0.04 mmol) was dissolved
in CH2Cl2 (2 mL) and Ac2O (2 mL) was added. Sc(OTf)3
(15 mg, 0.3 mmol) was added and the reaction mixture was
stirred under argon for 3 h. The reaction was cooled to 08C
and treated with excess TBME (100 mL) in order to preci-
pitate the polymer. The polymer was ®ltered off. The ®ltrate
was concentrated and puri®ed by column chromatography
with hexane/ethyl acetate (2.5:2) as eluant, to afford the title
compound 16 (20 mg, 50%). The precipitated polymer was
dissolved in CH2Cl2, the solution was concentrated and
NMR was performed in order to con®rm the complete
cleavage of the sugar from the polymer. 16 [a]2D0ˆ115.58
(c 0.3, CH2Cl2); 13C NMR (CDCl3): d 21.0 (COCH3-DOX),
28.2 (CH3COCH2CH2CO), 29.7 (CH3COCH2CH2CO), 38.2
(CH3COCH2CH2CO), 56.2 (OCH3), 62.4 (C-6), 65.9
(CH2C6H4-DOX), 66.2 (C-4), 69.8 (CH2C6H3), 70.1
(CH2C6H4), 71.0 (C-2), 71.1 (C-5), 76.4 (C-3), 85.6 (C3-
IPMB), 99.3 (C-1), 110.6 (C5-IPMB), 128.0±136.8 (Ar),
129.6 (C6-IPMB), 131.4 (C1-IPMB), 139.0 (C2-IPMB),
157.7 (C4-IPMB), 165.1, 166.2 (2COC6H5), 170.8
(COCH3-DOX), 172.2 (CH3COCH2CH2CO), 206.2
1
(600 mg, 97%). H NMR (CDCl3): d 1.92, 2.03, 2.0, 1.92
(12H, 4s, 4COCH3), 3.36 (s, 3H, OCH3), 4.77 (1H, d,
CHHC6H4-DOX), 4.89 (1H, d, H-1II), 4.98±5.03 (2H, m,
H-2II, H-4II), 5.23 (1H, t, H-3II), 5.42 (1H, t,
J1,212,3ˆ17.9 Hz, H-2I), 6.59 (1H, d, Jˆ8.3 Hz, aromatic,
H5-IPMB), 7.92 (2H, d, Bz); 8.03 (2H, d, Bz).
a-O-Acetyl-DOXyl 2,6-di-O-benzoyl-3-O-(3-iodo-4-meth-
oxybenzyl)-4-O-(2,3,4,6-tetra-O-acetyl-a-d-glucopyra-
nosyl)-b-d-galactopyranoside (21). The polymer bound
disaccharide 19 (70 mg, 0.014 mmol) was treated with
Sc(OTf)3 (6 mg, 0.01 mmol) in CH2Cl2 (1 mL) and Ac2O
(1 mL) as for compound 16 above. The residue was puri®ed
by column chromatography with hexane/ethyl acetate (1:1)
as eluant. The title compound 21 was obtained (10 mg,
71%). [a]2D0ˆ225.08 (c 0.1, CHCl3); 13C NMR (CDCl3):
d 20.6, 20.7 (COCH3), 56.3 (OCH3), 61.8 (C-6II), 63.9
(C-6I), 66.0 (CH2C6H4-DOX), 68.6 (C-4II), 69.1
(CH2C6H5), 71.2 (C-2I), 71.4 (C-2II), 71.7 (C-5II,
CH2C6H5), 72.2 (C-5I), 72.6 (C-3II), 72.8 (C-4I), 79.6
(C-3I), 99.1 (C-1I), 100.7 (C-1II), 110.8±138.7 (aromatic),
165.0±173.0 (COCH3, COC6H5); 1H NMR (CDCl3): d 1.99,
2.00, 2.02, 2.06, 2.17, (15H, 5s, 5COCH3), 3.55±3.58 (2H,
m, H-5II, H-3I), 3.75 (1H, t, J 5,6a15,6bˆ11.8 Hz, H-5I), 3.78
(3H, s, OCH3), 4.02 (1H, dd, J6a,6bˆ12.1 Hz, H-6aII), 4.07±
4.12 (2H, m, H-4I, H-6aII), 4.41±4.47 (4H, m, H-1I, H-6aI,
CH2C6H5), 4.60 (1H, d, Jˆ13.0 Hz, CHHC6H4-DOX), 4.63
(1H, dd, J5,6aˆ5.3 Hz, J6a,6bˆ11.7 Hz, H-6aI), 4.79 (1H, d,
Jˆ13.0 Hz, CHHC6H4-DOX), 4.89 (1H, d, J1,2ˆ7.9 Hz,
H-1II), 4.98 (2H, s, CH2C6H4-DOX), 5.02±5.07 (2H, m,
H-4II, H-2II), 5.23 (1H, t, J2,313,4ˆ19.2 Hz, H-3II), 5.42
(1H, t, J1,212,3ˆ17.8 Hz, H-2I), 6.59 (1H, d, Jˆ8.4 Hz,
H5-IPMB), 7.05±7.12 (5H, m, DOX, H6-IPMB), 7.42±
7.50 (4H, m, Bz), 7.56±7.59 (3H, m, Bz, H2-IPMB), 7.91
(2H, d, Jˆ7.7 Hz, Bz), 8.03 (2H, d, Jˆ7.7 Hz, Bz); HRMS
(FAB) calcd for C52H55O20INa: 1149.2228, Found m/z:
1149.2275 (M1Na1).
1
(CH3COCH2CH2CO); H NMR (CDCl3): d 2.10 (3H, s,
COCH3-DOX), 2.20 (3H, s, COCH3-Lev), 2.72±2.90 (4H,
m, CH3COCH2CH2CO), 3.62 (1H, dd, J2,3ˆ10.1 Hz,
J3,4ˆ3.2 Hz, H-3), 3.76 (3H, s, OCH3), 3.96 (1H, t,
J4,515,6ˆ13.2 Hz, H-5), 4.24 (1H, d, CHHC6H5), 4.43 (1H,
dd, J5,6aˆ6.3 Hz, J6a,6bˆ11.2 Hz, H-6a), 4.52 (1H, d,
CHHC6H5), 4.53 (1H, d, J1,2ˆ7.8 Hz, H-1), 4.64 (2H, m,
CH2C6H4-DOX, H-6b), 5.02 (2H, s, CH2C6H4-DOX), 5.44
(1H, t, J1,212,3ˆ18.0 Hz, H-2), 5.62 (1H, brd, H-4), 6.45
(1H, d, Jˆ8.3 Hz, H5-IPMB), 7.04 (1H, d, Jˆ8.3 Hz, H6-
IPMB), 7.12 (4H, dd, DOX), 7.48 (4H, m, Bz), 7.52 (1H, s,
H2-IPMB), 7.61 (2H, t, Bz), 7.93 (2H, brd, Bz), 8.08 (2H, d,
Bz); HRMS (FAB) calcd for C43H43O13INa: 917.1646,
Found m/z: 917.1636 (M1Na1); Anal. Calcd for
C43H43O13I: C, 57.73; H, 4.84, Found C, 57.49; H, 4.91.
(MPEG)(DOX)yl 2,6-di-O-benzoyl-3-O-(3-iodo-4-methoxy-
benzyl)-b-d-galactopyranoside (18). Galactopyranoside
13 (700 mg, 0.14 mmol) was treated with a 4:1 solution of
pyridine/acetic acid, containing 2% hydrazine hydrate
(7 mL). The solution was stirred for 0.5 h, cooled to 08C,
and quenched with excess TBME (500 mL). The reaction
was vigorously stirred for 15 min in order to precipitate the
polymer. The polymer was ®ltered and dissolved in hot
absolute ethanol (500 mL) and left in the freezer overnight.
The white precipitate was collected by ®ltration, rinsed with
Et2O (2£10 mL) and dried in vacuo to afford the title
(MPEG)(DOX)yl
2,6-di-O-benzoyl-4-(2,3,4,6-tetra-O-
acetyl-b-d-glucopyranosyl)-b-d-galactopyranoside (23).
Disaccharide 19 (600 mg, 0.12 mmol) was treated with a
10% TFA solution in CH2Cl2 (10 mL) for 24 h. The reaction
was cooled to 08C, quenched with TBME (350 mL), and
stirred vigorously for 20 min. in order to precipitate the
polymer. The precipitate was ®ltered and washed well
with Et2O. It was recrystallized in ethanol, overnight. The
white precipitate was ®ltered, rinsed with Et2O (2£30 mL),
collected in CH2Cl2 and dried in vacuo to afford the title
compound 23 (580 mg, 97%). Compound 23 was charac-
terised as the cleaved compound 24.
1
compound 18 (630 mg, 90%). H NMR (CDCl3): d 3.38
(3H, s, OCH3), 4.09 (1H, d, H-4), 4.46 (1H, d, H-1), 5.54
(1H, t, H-2), 6.50 (1H, d, H5-IPMB).
(MPEG)(DOX)yl 2,6-di-O-benzoyl-3-O-(3-iodo-4-methoxy-
benzyl)-4-(2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl)-
b-d-galactopyranoside (19). A mixture of the trichloro-
a-O-Acetyl-DOXyl 3-O-acetyl-2,6-di-O-benzoyl-4-(2,3,4,
6-tetra-O-acetyl-b-d-glucopyranosyl)-b-d-galactopyra-
noside (24). Disaccharide 23 (50 mg, 0.01 mmol) was

S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
6423
treated with Sc(OTf)3 (3 mg) in Ac2O (1 mL) as for
compound 14. The residue was puri®ed by preparative
thin layer chromatography with hexane/ethyl acetate (2:3)
as eluant. The title compound 24 was obtained (4 mg, 60%).
13C NMR (CDCl3): d 20.57, 20.60, 20.63, 20.7, 20.8, 21.0
(6COCH3), 61.7 (C-6II), 63.7 (C-6I), 66.0 (CH2C6H4-DOX),
68.4 (C-4II), 69.5 (CH2C6H4-DOX), 69.6 (C-2I), 71.4
(C-2II), 71.8 (C-5II), 72.2 (C-5I), 72.5 (C-3II), 73.2 (C-3I),
74.2 (C-4I), 99.0 (C-1I), 101.3 (C-1II), 128.1±140.8
(aromatic), 165.0±173.0 (COCH3, COC6H5); 1H NMR
(CDCl3): d1.98, 2.01, 2.02, 2.06, 2.21 (18H, 5s,
J5,6aˆ3.9 Hz, J6a,6bˆ11.7 Hz, H-6bI), 4.32 (H-2III), 4.34
(H-4I), 4.35 (H-1I), 4.45 (H-6aII), 4.51 (H-6bIII), 4.52 (1H,
d, CHHC6H4-DOX), 4.64 (H-6bII), 4.66 (1H, d, CHHC6H4-
DOX), 4.97 (2H, s, CH2C6H4-DOX), 5.05 (H-2II), 5.13 (H-
4II), 5.16 (H-1II), 5.20 (H-4III), 5.24 (H-2I), 5.47 (1H, t,
J2,313,4ˆ18.6 Hz, H-3II), 5.49 (1H, d, J1,2ˆ8.3 Hz, H-1III),
5.68 (1H, t, J2,313,4ˆ19.5 Hz, H-3III), 6.95 (4H, m, DOX),
7.20±8.10 (14H, aromatic). MS (MALDI) calcd for
C64H67NO28Na: 1320.37, Found m/z: 1320.66 (M1Na1)
and MS (FAB) calcd for C64H67NO28K: 1336.35, Found
m/z: 1336.1 (M1K1), m/z 1118.1 (M-DOX1).
6COCH3), 3.59 (1H, m, H-5II), 3.90 (1H, t, J5,6a15,6b
ˆ
11.2 Hz, H-5I), 3.97 (1H, dd, J5,6aˆ2.3 Hz, J6a,6bˆ12.2 Hz,
H-6aII), 4.08 (1H, dd, J5,6aˆ4.5 Hz, J6a,6bˆ12.2 Hz, H-6bII),
4.23 (1H, t, J3,414,5ˆ2.6 Hz, H-4I), 4.46 (1H, dd,
J5,6aˆ6.8 Hz, J6a,6bˆ11.6 Hz, H-6aI), 4.55 (1H, d,
J1,2ˆ7.9 Hz, H-1I), 4.59 (1H, d, J1,2ˆ8.0 Hz, H-1II), 4.62
(1H, d, Jˆ12.7 Hz, CHHC6H4-DOX), 4.65 (1H, dd,
J5,6bˆ5.2 Hz, J6a,6bˆ11.6 Hz, H-6bI), 4.81 (1H, d,
Jˆ12.7 Hz, CHHC6H4-DOX), 4.99 (2H, s, CH2C6H4-
DOX), 5.03±5.08 (3H, m, H-3I, H-2II, H-4II), 5.23 (1H, t,
J2,313,4ˆ19.2 Hz, H-3II), 5.44 (1H, t, J1,2ˆ7.9 Hz,
J2,3ˆ10.0 Hz, H-2I), 7.07±7.12 (4H, m, DOX), 7.41±7.47
(4H, m, Bz), 7.57 (2H, t, Bz), 7.92 (2H, d, Jˆ7.3 Hz, Bz),
8.03 (2H, d, Jˆ7.3 Hz, Bz); HRMS (FAB) calcd for
C46H50O20Na: 945.2792, Found m/z: 945.2745 (M1Na1).
(MPEG)(DOX)yl 2,6-di-O-benzoyl-4-O-levulinoyl-3-O-
(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-b-d-gluco-
pyranosyl)-b-d-galactopyranoside (28). A mixture of 2530
(60 mg, 0.12 mmol) and 27 (300 mg, 0.06 mmol, prepared
from 13 as for 23) was dried over P2O5 under vacuum over-
night. Anhydrous CH2Cl2 (3 mL) was added. The reaction
mixture was treated with NIS (67 mg, 0.3 mmol) and tri¯ic
acid (3.0 mL, 0.036 mmol). The reaction mixture was stirred
for 2 h at room temperature and quenched with DIPEA (two
drops). Then standard work up afforded the polymer bound
disaccharide 28 (290 mg, 97%). Compound 28 was
characterized as the cleaved compound 29.
a-O-Acetyl-DOXyl 2,6-di-O-benzoyl-4-O-levulinoyl-3-
O-(3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-b-d-gluco-
pyranosyl)-b-d-galactopyranoside (29). Polymer-bound
disaccharide 28 (270 mg, 0.06 mmol) was treated with
Sc(OTf)3 (15 mg, 0.3 mmol) in CH2Cl2 and Ac2O as for
compound 16 above. The residue was puri®ed by column
chromatography with hexane/ethyl acetate (1:1) as eluant.
The title compound 29 was obtained (10 mg, 16%). 13C
NMR (CDCl3): d 20.4, 20.6, 21.0 (3COCH3), 28.1
(CH3COCH2CH2CO), 29.8 (CH3COCH2CH2CO), 38.2
(CH3COCH2CH2CO), 54.4 (C-2II), 61.5 (C-6II), 62.7
(C-6I), 65.9 (CH2C6H4-DOX), 68.8 (C-4II), 69.4
(CH2C6H4-DOX), 69.7 (C-4I), 70.2 (C-3II), 70.8 (C-2I),
71.5 (C-5I), 71.8 (C-5II), 77.2 (C-3I), 98.4 (C-1II), 98.8
(C-1I), 128.0±133.7 (aromatic), 165.0±173.0 (COCH3,
(MPEG)(DOX)yl
2,6-di-O-benzoyl-4-(2,3,4,6-tetra-O-
acetyl-b-d-glucopyranosyl)-3-(3,4,6-tri-O-acetyl-2-deoxy-
2-phthalimido-b-d-glucopyranosyl)-b-d-galactopyrano-
side (26). A mixture of phenyl (3,4,6-tri-O-acetyl-2-deoxy-
2-phthalimido)-1-thio-b-d-glucopyranoside 2530 (125 mg,
0.24 mmol) and disaccharide 23 (600 mg, 0.12 mmol) was
dried over P2O5 overnight under vacuum. Anhydrous
CH2Cl2 (6 mL) was added. The reaction mixture was cooled
to 08C and treated with NIS (270 mg, 1.2 mmol) and AgOTf
(62 mg, 0.24 mmol). The reaction mixture was stirred for
1 h at 08C and quenched with DIPEA (two drops). Then
standard work up afforded the polymer bound trisaccharide
26 (575 mg, 89%). The above procedure was repeated to
afford the polymer bound trisaccharide 26 (550 mg, 86%).
Compound 26 was characterized as the cleaved compound
1.
1
COC6H5); H NMR (CDCl3): d 1.70, 2.0, 2.06, 2.23, 2.26
(15H, 5s, 5COCH3), 2.78 (CH3COCH2CH2CO), 3.78 (1H,
m, H-5II), 3.96 (2H, m, H-3I, H-5I), 4.12 (1H, H-6aII), 4.22
(1H, H-2I), 4.30 (1H, H-6bII), 4.41 (1H, H-1I), 4.44±4.58
(2H, H-6aI, H-6bI, CHHC6H4-DOX), 4.72 (1H, d,
CHHC6H4-DOX), 4.98 (2H, s, CH2C6H4-DOX), 5.13
(H-4II), 5.31 (H-2I), 5.43 (1H, d, J1,2ˆ8.3 Hz, H-1II), 5.61
(H-4I), 5.68 (1H, t, J2,313,4ˆ19.5 Hz, H-3II), 6.96 (4H, m,
DOX), 7.28±8.18 (14H, aromatic). MS(MALDI-TOF)
calcd for C55H55NO21Na: 1089.03, Found m/z: 1088.42
(M1Na1).
a-O-Acetyl-DOXyl 2,6-di-O-benzoyl-4-(2,3,4,6-tetra-O-
acetyl-b-d-glucopyranosyl)-3-(3,4,6-tri-O-acetyl-2-deoxy-
2-phthalimido-b-d-glucopyranosyl)-b-d-galactopyrano-
side (1). Trisaccharide 26 (550 mg, 0.1 mmol) was treated
with Sc(OTf)3 (25 mg, 0.05 mmol) in CH2Cl2 (1 mL) and
Ac2O (1 mL) as for compound 16 above. The residue was
puri®ed by column chromatography with hexane/ethyl
acetate (1:1) as eluant. The title compound 1 was obtained
(14 mg, 13%). [a]D20ˆ12.08 (c 0.2, CH2Cl2); 13C NMR
(CDCl3): d 20.03±20.73 (COCH3), 54.4 (C-2III), 61.5
(C-6I), 61.6 (C-6III), 63.8 (C-6II), 65.7 (CH2C6H4-DOX),
68.4 (C-4III), 68.7 (CH2C6H4-DOX), 68.7 (C-4II), 69.9
(C-3III), 70.6 (C-2I), 71.4 (C-2II), 71.4 (C-5III), 71.3 (C-5II),
71.9 (C-5I), 72.9 (C-3II), 73.9 (C-4I), 79.6 (C-3I), 98.6
(C-1I), 99.02 (C-1III), 99.7 (C-1II), 128.0±133.7 (aromatic),
165.0±173.0 (COCH3, COC6H5); 1H NMR (CDCl3): d 1.80,
1.90, 2.02, 2.06, 2.09, 2.15 (24H, 6s, 8COCH3), 3.80 (H-5II),
3.81 (H-5I), 3.85 (H-5III), 3.92 (1H, dd, J2,3ˆ10.3 Hz, H-3I),
4.09 (H-6aIII), 4.13 (1H, dd, H-6aI), 4.20 (1H, dd,
3-Iodo-4-methoxybenzyl chloride (30). Chloromethyl
methyl ether (2.0 mL, 0.027 mmol) was dissolved in glacial
acetic acid (35 mL) and treated with o-iodoanisole (1.5 mL,
0.012 mmol). The reaction mixture was stirred at 558C for
60 h. The mixture was poured over ice, extracted into
CH2Cl2 and washed with water. The organic extract was
dried over sodium sulphate, ®ltered and concentrated. The
residue was puri®ed by column chromatography with
hexane/ethyl acetate (5:1) as eluant to afford the title
compound 30 (2.5 g, 74%). The product was recrystallized
from hexane/ethyl acetate to afford needle shaped crystals;

6424
S. Mehta, D. M. Whit®eld / Tetrahedron 56 (2000) 6415±6425
mp 47.38C. 13C NMR (CDCl3): d 45.0 (CH2), 56.4 (OCH3),
85.9 (C-3), 110.7 (C-5), 130.0 (C-6), 131.6 (C-1), 139.7
(C-2), 158.2 (C-4); 1H NMR (CDCl3): d 3.89 (3H, s,
OCH3), 4.52 (2H, s, CH2), 6.81 (1H, d, Jˆ8.3 Hz, H-5),
7.34 (1H, d, Jˆ8.3 Hz, H-6), 7.81 (1H, s, H-2); Anal.
Calcd for C8H8OClI: C, 34.00; H, 2.85, Found C, 34.22;
H, 2.91.
Jˆ12.2 Hz, CHHC6H3), 4.40 (1H, dd, J5,6aˆ5.9 Hz,
J6a,6bˆ11.2 Hz, H-6a), 4.54 (1H, d, Jˆ12.2 Hz,
CHHC6H3), 4.58 (1H, dd, J5,6bˆ6.8 Hz, J6a,6bˆ11.2 Hz, H-
6b), 4.61 (1H, d, J1,2ˆ10.3 Hz, H-1), 5.41 (1H, t,
J1,212,3ˆ19.5 Hz, H-2), 5.68 (1H, d, J3,414,5ˆ2.9 Hz, H-4),
6.47 (1H, d, Jˆ8.3 Hz, H5-IPMB), 7.05 (1H, dd, Jˆ8.3 Hz,
Jˆ2.0 Hz, H6-IPMB), 7.47 (4H, m, Bz), 7.54 (1H, d,
Jˆ2.0 Hz, H2-IPMB), 7.59 (2H, m, Bz), 7.98 (2H, d, Bz),
8.06 (2H, d, Bz).; HRMS (FAB) calcd for C35H37O10ISNa:
799.1050, Found m/z: 799.1066 (M1Na1); Anal. Calcd for
C35H37O10IS: C, 54.13; H, 4.80, Found C, 54.47; H, 4.86.
Ethyl 2,6-di-O-benzoyl-3-O-(3-iodo-4-methoxybenzyl)-1-
thio-b-d-galactopyranoside (33). A mixture of 3134
(200 mg, 0.42 mmol) and dibutyltin oxide (104 mg,
0.42 mmol) were re¯uxed in toluene (20 mL) for 7 h. The
solvent was evaporated and the crude stannylene derivative
32 was dried in vacuo. It was dissolved in dry N,N-dimethyl-
formamide (2.0 mL), and treated with cesium ¯uoride
(76 mg, 0.42 mmol) and 3-iodo-4-methoxybenzyl chloride
30 (356 mg, 1.26 mmol). The reaction was stirred at 558C
for 7 h, cooled to room temperature, quenched with excess
methanol, and concentrated. The residue was chromato-
graphed with hexane/ethyl acetate (2:1) as eluant. The
title compound 33 was obtained as a white solid (170 mg,
60%). [a]2D0ˆ130.18 (c 0.8, CH2Cl2); 13C NMR (CDCl3): d
14.9 (SCH2CH3), 24.0 (SCH2CH3), 56.2 (OCH3), 63.6
(C-6), 66.6 (C-4), 69.5 (C-2), 70.6 (CH2C6H3), 76.0 (C-5),
79.2 (C-3), 83.6 (C-1), 85.7 (C3-IPMB), 110.7 (C5-IPMB),
128.4±133.1 (Ar), 139.0 (C2-IPMB), 157.9 (C4-IPMB),
Acknowledgements
We thank E. Eichler for measuring melting points, K. Chan
for measuring FAB MS spectra, D. Krajcarski for measuring
MALDI MS and A. Webb for performing microanalysis.
This is NRC paper 42428.
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Ethyl
2,6-di-O-benzoyl-4-O-levulinoyl-3-O-(3-iodo-4-
methoxybenzyl)-b-d-thio-galactopyranoside (34). Com-
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THF (4 mL) and cooled to 08C. A solution of levulinic acid
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(2:1) as eluant. The title compound 34 was obtained as a
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28.1 (CH3COCH2CH2CO), 29.8 (CH3COCH2CH2CO), 38.2
(CH3COCH2CH2CO), 56.2 (OCH3), 62.5 (C-6), 66.6 (C-4),
69.2 (C-2), 70.1 (CH2C6H3), 74.8 (C-5), 77.5 (C-3), 84.0 (C-1),
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165.2, 166.2 (2COC6H5), 172.2 (CH3COCH2CH2CO),
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