Solid-phase carbohydrate synthesis via on-bead protecting group chemistry

Article abstract of DOI:10.1016/j.tet.2007.03.051

Di- and tri-saccharides were synthesized on a solid phase. The procedure started with a non-protected sugar linked via either cysteine or glutamine to a polystyrene resin. Selective dimethoxytritylation chemistry and subsequent steps yielded a resin-bound acceptor that could be glycosylated to yield β1,6-linked disaccharides. Reiteration of the procedure produced the trisaccharide.

Full text of DOI:10.1016/j.tet.2007.03.051

Tetrahedron 63 (2007) 4290–4296
Solid-phase carbohydrate synthesis via on-bead protecting
group chemistry
*
Hilbert M. Branderhorst, Rob M. J. Liskamp and Roland J. Pieters
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University,
PO Box 80082, 3508 TB, Utrecht, The Netherlands
Received 13 November 2006; revised 22 February 2007; accepted 8 March 2007
Available online 13 March 2007
Abstract—Di- and tri-saccharides were synthesized on a solid phase. The procedure started with a non-protected sugar linked via either cys-
teine or glutamine to a polystyrene resin. Selective dimethoxytritylation chemistry and subsequent steps yielded a resin-bound acceptor that
could be glycosylated to yield b1,6-linked disaccharides. Reiteration of the procedure produced the trisaccharide.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Such selective chemistry would have to be sequence inde-
pendent, and based on an excess of reagent to push reactions
to completion. If these procedures prove to be simple and
compatible with automation, many complex sugars, includ-
ing branched ones, can be made from a few building blocks
by reiteration of the steps. To take the first step toward this
distant goal, we started with the well-studied selective C-6
chemistry, based on the bulky 4,4-dimethoxytrityl (DMT)
protecting group that selectively reacts with primary hy-
droxyl groups even when applied in excess. The DMT group
was chosen for the mild cleavage conditions (1% dichloro
acetic acid in CH2Cl2) and the visible color release by the
DMT-cation that can be used for verification.
The difficulties in synthesizing complex synthetic carbo-
hydrates limit our understanding of their roles in biological
systems and also limit carbohydrate-based drug develop-
ment. Carbohydrates are nevertheless emerging as a class
of compounds, which play crucial roles in major diseases
such as (avian) flu,1 AIDS,2 and cancer.3 The shift of the syn-
thesis of oligomeric nucleotides and peptides to the solid
phase, and subsequent automation, has led to major steps
forward in their ease of preparation and application in bio-
logy. For carbohydrates, a universal solid-phase synthetic
method is more difficult but would have a great scientific
impact. Solid-phase synthesis of carbohydrates was first re-
ported in 19714 and since then much progress was made.5
The recent automation of the process represents a milestone.6
All published strategies in common are based on a two-step
protocol, which includes an on-bead glycosylation step and
an on-bead deprotection step. This means that strategically
protected carbohydrate donors are used for Glycosylation,
which, after coupling, can selectively be deprotected at the
desired position to afford a new glycosyl acceptor for further
elaboration. Although connecting the building blocks one
by one is a rapid procedure, the synthesis of all the desired
building blocks is a major effort to be customized for each
desired target carbohydrate. In response to this, we opted to
explore the use of resin-bound unprotected sugars to be se-
lectively converted to acceptors by on-bead selective chem-
istry commonly used in solution (Scheme 1). In principle, a
single carbohydrate can thus be elaborated into several di-
saccharides depending on the protecting chemistry used.
OAc
selective
protection
chemistry
AcO
AcO
O
OH
LG
HO
HO
OH
PGO
PGO
C3
C6
AcO
O
O
glycosylate, then
deacetylate
HO
C4
PGO
OH
selective
protection
chemistry
HO
HO
O
O
HO
PGO
glycosylate, then
deacetylate
C3
C6
etc.
O
PGO
C4
PGO
Scheme 1. General solid-phase synthesis of carbohydrates including a selec-
tive on-bead protection step followed by glycosylation and deprotection and
reiteration. A selective C6 protection step is exemplarily shown as used in
this paper.
As a linker, the trifunctional amino acid cysteine (1) was
chosen. Its sulfur atom can be linked to the sugar anomeric
center.7 After all synthetic procedures, this thioglycosidic
Keywords: Carbohydrates; Solid-phase synthesis; Glycosylation.
* Corresponding author. Tel.: +31 30 2536944; fax: +31 30 2536655;
e-mail: r.j.pieters@uu.nl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.051

H. M. Branderhorst et al. / Tetrahedron 63 (2007) 4290–4296
4291
linkage can selectively be cleaved with N-bromosuccinimide
(NBS) and a variety of nucleophiles.8 The cleavage con-
ditions we used involved DAST (diethylaminosulfur tri-
fluoride), which yielded the anomeric fluorides that can be
further functionalized (Scheme 2). Another attractive feature
of the cysteine linker is its amino group that was Fmoc pro-
tected, and thus a useful tool for determination of the loading
upon deprotection. Furthermore, the carboxylic acid func-
tion of cysteine was used for coupling the construct to an
amine functionalized polystyrene resin.
using anilinium p-toluenesulfinate as a scavenger yield-
ing 3.
The amino acid 3 was coupled to an aminomethylated poly-
styrene resin using the HATU coupling reagent and DIPEA
(Scheme 4). By Fmoc deprotection analysis, a resin loading
of 0.70 mmol/g was determined. The Fmoc group was
cleaved by 20% piperidine in NMP and the free amine was
subsequently acetylated with acetic anhydride. The carbohy-
drate was deacetylated using 5% N2H4 in DMF to yield resin
4. To verify its identity and evaluate the DAST/NBS cleav-
age method, the carbohydrate was fully benzoylated with
Bz-Cl in pyridine. Subsequent treatment of the resin with
NBS (5 equiv) and DAST (5 equiv) for 10 min afforded
the desired anomeric fluoride (Scheme 2).
OBz
O
OBz
O
BzO
BzO
BzO
BzO
DAST, NBS
S
F
OBz
OBz
AcHN
H
N
Introduction of the DMT group was achieved by treating
resin 4 with 10 equiv of DMT-Cl in pyridine. The remaining
hydroxyl functions of resin 5 were capped with Bz-Cl in pyr-
idine followed by cleavage of the DMT group with 1% DCA
in CH2Cl2 to yield resin 6. To verify the identity of this resin,
part of it resin was acetylated (Ac2O) and cleaved (DAST/
NBS) to afford the desired monoacetylated glycosyl fluo-
ride. This confirmation set the stage for the glycosylation re-
action of 6 for which galactose donor 7 (5 equiv) was used in
the presence of TMSOTf (0.3 equiv) as a promoter. The pro-
cedure was run twice and was followed by NBS/DAST
cleavage of the products from the resin. Product analysis re-
vealed that indeed the desired disaccharide 8 was obtained,
but also the peracetylated glycosyl fluoride 9. The reaction
was run several times and the ratio of 8:9 varied widely be-
tween 1/1 to 9/1. The formation of 9 can be explained by an
unwanted aglycon transfer mechanism, as has been noticed
O
Scheme 2. Cleavage conditions used for the cysteine bound carbohydrates
from the resin by DAST and NBS.
2. Results and discussion
2.1. S-Linked galactoside acceptor route
The S-linked amino acid 3 was synthesized starting from
commercially available Fmoc-Cys[S-trityl]-OH 1 (Scheme
3). Its carboxylic acid group was first protected as the allyl
ester by allyl bromide and K2CO3 as the base. The trityl
group was removed under acidic conditions and the acetyl-
ated carbohydrate was introduced by the action of SnCl4
as described.9 The allyl ester was removed by Pd(PPh3)4
OAc
AcO
AcO
O
TrtS
HS
S
OAc
c , d
a , b
OH
OH
O
FmocHN
FmocHN
FmocHN
O
O
O
1
3
2
Scheme 3. Synthesis of amino acid 5; reagents and conditions: (a) allyl bromide, K2CO3, DMF, 2 h, rt; (b) TFA, TES, CH2Cl2, 2 h, rt, 64% over two steps;
(c) galactose penta-acetate, SnCl4, CH2Cl2; and (d) Pd(PPh3)4, anilinium p-toluenesulfinate, quantitative over two steps.
MeO
OH
O
HO
HO
O
HO
HO
O
OMe
O
f,g
S
e
a-d
H2N
S
OH
H
N
OH
H
N
AcHN
AcHN
O
4
5
OAc
O
AcO
AcO
OAc
O
OH
O
AcO
AcO
BzO
BzO
OAc
O
AcO
7
AcO
AcO
O
S
+
O
NH
CCl3
AcO BzO
OBz
H
N
O
F
AcHN
OAc
BzO
F
O
h,i
OBz
6
8
9
Scheme 4. Reaction conditions: (a) 3, HATU, DIPEA; (b) piperidine, NMP; (c) Ac2O, pyridine; (d) N2H4, DMF; (e) DMT-Cl, pyridine; (f) Bz-Cl, pyridine;
(g) 1% dichloro acetic acid, CH2Cl2; (h) 7, TMSOTf, CH2Cl2; and (i) DAST, NBS.

4292
H. M. Branderhorst et al. / Tetrahedron 63 (2007) 4290–4296
OH
OH
unfortunately also the aglycon transfer product 9. In both
cases 9 was obtained in the range of 40–80%.
BzO
BzO
BzO
BzO
O
O
S
S
OBz
OBn
2.2. N-Linked galactoside acceptor route
H
N
H
N
In order to avoid the aglycon transfer, a more stable glyco-
sidic linkage was used based on an anomeric glutamine
linked to the resin. While this modification no longer allows
anomeric manipulation/conjugation of the synthesized car-
bohydrate, the glycopeptides that result from this pathway
are highly versatile and useful building blocks. Firstly, build-
ing block 1211 was coupled to a Rink-amide linker of a poly-
styrene resin (Scheme 5). The attached glyco-amino acid is
cleavable at the glutamine carboxy function by TFA. The
coupling of 12 to the resin was performed by HATU and
DIPEA. The subsequent reaction was a piperidine-mediated
Fmoc cleavage. A loading of 0.48 mmol/g was determined at
this stage. The liberated amine was capped with benzoyl
chloride and the acetates were removed by 5% N2H4 in
DMF. Selective tritylation of the primary hydroxyls was
found to work best using 5 equiv of DMT-Cl in pyridine as
a solvent. As before, the remaining hydroxyl functions
were benzoylated, and the primary hydroxyl was liberated
to yield resin 13. Glycosylation of this acceptor with donor
7 (5 equiv) and TMSOTf (0.3 equiv) as a promoter yielded
the expected disaccharide 15a, which was isolated by silica
chromatography. The product was obtained in ca. 25% yield
(i.e., 86% per reaction step). Since ortho ester formation is
a possible side reaction, the glycosylation was repeated
with pivaloyl protected donor 14, which is less prone to ortho
ester formation. Again the desired disaccharide (15b) was
obtained after HPLC purification in a slightly higher overall
yield of 30% (i.e., 88% per reaction step). Using this strategy
the procedure was reiterated for the synthesis of a trisaccha-
ride. The resin-bound disaccharide was subjected to NaOMe
deacylation followed by the selective C-6 chemistry reaction
11
10
O
O
Figure 1. Modified acceptors containing an aryl thioglycosidic linkage to
the solid phase.
before for reactions in solution.10 It is believed to result from
the relatively high nucleophilicity of the sulfur atom that can
to some extent outcompete the free OH of the acceptor.
Modifications of the glycosylation conditions could not
prevent the formation of 9. Furthermore the use of the anal-
ogous perbenzylated donor did not yield any product.
In solution, the unwanted aglycon transfer was suppressed
by changing from an anomeric thioalkyl group to a thioaryl
group.10a Furthermore, changing the protecting group pat-
tern was also shown to suppress the transfer.10b To this
end, two new resin-bound acceptors 10 and 11 were prepared
as shown in Figure 1. The first modification was the intro-
duction of an arylthio linkage as in 10. In 11, an additional
modification was made. Replacing the participating benzoyl
group for a non-participating benzyl group was expected to
disfavor the aglycon transfer reaction. Both resins were
prepared from the commercially available 3-[4-(trityl-
mercapto)phenyl]propionyl aminomethyl functionalized
polystyrene resin, starting with removal of its trityl group.
Subsequent glycosylation with the appropriate glycosyl
donors and deacetylation followed by the C-6 chemistry pro-
tocol of Scheme 4, yielded the two acceptor resins 10 and 11.
The glycosylation of these resins with 7 as before, followed
by NBS/DAST cleavage yielded the disaccharide 8 but
AcO
AcO
OAc
O
BzO
BzO
OH
O
H
N
H
OPiv
O
PivO
PivO
O
N
O
OAc
OBz
a-e,c,f
PivO
NH
CCl3
O
OH
14
NH-RINK-
FmocNH
BzHN
O
O
13
12
h,j,e,c,f,h,i
g/h, i
OPiv
O
RO OR
PivO
PivO
O
O
RO
O
BzO
PivO
RO
BzO
O
O
H
N
BzO
O
BzO
O
BzO
OBz
BzO
O
H
N
O
BzO
OBz
NH2
BzHN
O
NH2
15 a: R = OAc
15 b: R = OPiv
16
BzNH
O
Scheme 5. Reaction conditions: (a) Rink-polystyrene resin, HATU, DIPEA, DMF; (b) piperidine, NMP; (c) Bz-Cl, pyridine; (d) N2H2, DMF; (e) DMT-Cl,
pyridine; (f) 1% dichloro acetic acid, CH2Cl2; (g) 7, TMSOTf, CH2Cl2, 0 ꢀC; (h) 14, TMSOTf, CH2Cl2, 0 ꢀC; (i) TFA, H2O (95/5); and (j) NaOMe, MeOH.

H. M. Branderhorst et al. / Tetrahedron 63 (2007) 4290–4296
4293
sequence and, after glycosylation with 14 the desired trisac-
charide 16, was isolated after cleavage from the resin and
straightforward HPLC purification.
254 nm. Preparative HPLC runs were performed on a Gilson
HPLC workstation. 1H NMR (300 MHz) and 13C NMR
(75 MHz) were performed on a Varian G-300 spectrometer
1
and H NMR (500 MHz) and 13C NMR (125 MHz) were
recorded on a Varian INOVA-500 spectrometer. Chemical
shifts are given in parts per million relative to TMS (1H,
0.00 ppm) and CDCl3 (13C, 77.0 ppm). Assignments of the
NMR spectra of 15 and 16 were made on the basis of their
HSQC, HMBC, and TOCSY spectra.
3. Conclusions
The solid-phase synthesis of b1,6-linked galactosides
proved possible with a resin-bound unprotected sugar as
the starting point. Selective resin compatible protection
chemistry involving the C6 primary hydroxyl yielded accep-
tors that could be glycosylated. The synthesis greatly
benefited in the practical sense, from being performed on-
resin, as it requires only washing steps. Glycosylation thus
led to disaccharides, and finally a trisaccharide preparation
demonstrated that reiteration of the procedure was possible.
The synthesis with cysteine as the linking moiety connecting
the sugar to the resin suffered from unwanted aglycon trans-
fer, even when remedies that had been effective in solution
were not able to fully prevent the transfer. Recently reported
insights suggest that the use of two methyl groups flanking
the sulfur on the aromatic ring would be sufficient to prevent
the transfer.10c When glutamic acid was used to link the
sugar, stable glycopeptidic products were obtained from
the applied reaction sequence that could be cleaved from
the resin via the amino acid’s carboxyl group. The work in-
dicates that protecting group chemistry can be performed
on-resin and has the potential for the synthesis of a wide va-
riety of oligosaccharides from a limited set of glycosyl donor
molecules. To make this chemistry applicable it needs to be
extended to selectively produce other acceptors on-bead. As
such the versatile 4,6-O-benzylidene group was successfully
generated on-bead using an excess of reagents (not shown),
although reproducibility needs to be improved. In conclu-
sion, the presented work is an initial step in the exploration
of on-bead carbohydrate synthesis that goes beyond glyco-
sylation and deprotection steps, and may ultimately reduce
the labor involved in the building block synthesis.
4.1.1. Fmoc-Cys-OAllyl (2). To a solution of Fmoc-
Cys[Trt]-OH (5.86 g, 10 mmol) and K2CO3 (1.38 g,
10 mmol) in dry DMF (50 mL) was added allyl bromide
(1.74 mL, 20 mmol). TLC showed complete conversion af-
ter 2 h. The mixture was concentrated in vacuo and then
taken up in EtOAc (100 mL). The organic solution was
washed with 1 M KHSO4 (50 mL). The organic phase was
dried over Na2SO4, filtered, and concentrated. Column chro-
matography on silica gel (hex/EtOAc 7/1/2/1) yielded
Fmoc-Cys[Trt]-OAllyl as a white foam. 1H NMR spectrum
is consistent with Ref. 12: (300 MHz, CDCl3): 7.76–7.19
(23H, m, CHarom), 5.92–5.81 (1H, m, OCH2CHCH2), 5.33
(1H, d, Fmoc NH, J¼0.9 Hz), 5.27–5.23 (2H, m,
OCH2CHCH2), 4.62 (2H, d, OCH2CHCH2), 4.42–4.35
(3H, m, Fmoc CH2, CHa), 4.23 (1H, t, Fmoc CH, J¼6.9 Hz),
and 2.66 (2H, m, CH2b). To a solution of Fmoc-Cys[Trt]-
OAllyl (z9 mmol) and TES (7.26 mL, 45 mmol) in
CH2Cl2 (100 mL) was added TFA (3.35 mL, 45 mmol)
dropwise over 5 min and the mixture was stirred for addi-
tional 2 h. TLC (hex/EtOAc 3/1) showed completion of
the reaction. The mixture was concentrated in vacuo and
co-evaporation with toluene, ethanol, and CH2Cl2 yielded
crude 2. Silica gel chromatography (CH2Cl2/hex 4/1/9/1)
yielded the product as a white amorphous solid (2.45 g, 64%
1
over two steps). H NMR spectrum was consistent with
Ref. 13: (300 MHz, CDCl3): 7.77–7.32 (8H, m, Ph), 5.97–
5.88 (1H, m, OCH2CHCH2), 5.71 (1H, br d, Fmoc NH,
J¼7.4 Hz), 5.39–5.27 (2H, m, OCH2CHCH2), 4.71–4.63
(3H, m, OCH2CHCH2 and CHa), 4.44 (2H, d, Fmoc CH2,
J¼1.1 Hz), 4.23 (1H, t, Fmoc CH, J¼6.9 Hz), 3.05–2.99
(2H, m, CH2b), and 1.37 (1H, t, SH, J¼8.8 Hz). 13C NMR
(75.5 MHz, CDCl3): 141.3, 127.8, 127.1, 125.1, and 120.0
(Ph), 131.2 (OCH2CHCH2), 119.4 (OCH2CHCH2), 67.1
(OCH2CHCH2), 66.5 (Fmoc CH2), 55.2 (Ca), 47.1 (Fmoc
CH), and 27.2 (CH2b).
4. Experimental section
4.1. General remarks
Unless stated otherwise, chemicals were obtained from
commercial sources and used without further purification.
All solvents were purchased from Biosolve (Valkenswaard,
The Netherlands) and were stored over molecular sieves
(4 A). Pyridine was purchased from Acros (Geel, Belgium)
˚
and stored over molecular sieves (4 A). Both aminomethyl
polystyrene resin and Rink-amide functionalized amino-
methyl polystyrene resin were obtained from Rapp
€
Polymere (Tubingen, Germany). 3-[4-(Tritylmercapto)phe-
nyl]propionyl aminomethyl functionalized polystyrene resin
4.1.2. Fmoc-Cys[Gal(OAc)4]-OH (3). To a solution of 2
(950 mg, 2.48 mmol) and b-D-galactose penta-acetate
(1.93 g, 4.95 mmol) in dry CH2Cl2 (40 mL) was added drop-
wise SnCl4 (0.42 mL, 3.72 mmol). Immediately a yellow
colour appeared. The mixture was stirred for 4 h. TLC
(hex/EtOAc 1/1) indicated the complete conversion of 2 to
a single product. The mixture was diluted with CH2Cl2
(100 mL) and washed with 5% NaHCO3 solution (75 mL).
The organic phase was dried over Na2SO4, filtered, and con-
centrated in vacuo. Column chromatography on silica gel
was used to purify Fmoc-Cys[Gal(OAc)4]-OAllyl but the
excess of galactose penta-acetate could not completely be
˚
€
was obtained from Novabiochem (Laufelfingen, Switzer-
land). A solution of Ac2O (4.72 mL), DIPEA (2.18 mL), and
HOBT (230 mg) in NMP (100 mL) was used as the capping
mixture. TLC was performed on Merck precoated Silica 60
plates. Spots were visualized by UV light and by 10% H2SO4
in MeOH. Analytical HPLC runs were performed on a
Shimadzu automated HPLC system equipped with an evap-
orative light scattering detector (PL-ELS 1000, Polymer
Laboratories) and a UV/VIS detector operating at 220 and
1
removed. H NMR spectrum was consistent with Ref. 14
(300 MHz, CDCl3): 7.76 –7.27 (8H, m, Ph), 5.99 (1H, br
d, Fmoc NH, J¼7.8 Hz), 5.95–5.84 (1H, m, OCH2CHCH2),
5.37 (1H, d, H-4, J3,4¼3.9 Hz), 5.34–5.18 (3H, m,
OCH2CHCH2 and H-2), 5.01 (1H, dd, H-3, J2,3¼10.2 Hz,

4294
H. M. Branderhorst et al. / Tetrahedron 63 (2007) 4290–4296
J3,4¼3.3 Hz), 4.66 (2H, d, OCH2CHCH2), 4.60–4.54 (1H,
m, CHa), 4.45 (1H, d, H-1, J1,2¼9.9 Hz), 4.39–4.34 (2H,
m, Fmoc CH2), 4.25 (1H, t, Fmoc CH, J¼6.6 Hz), 4.05
(2H, d, 2H-6, J5,6¼6.3 Hz), 3.76 (1H, t, H-5, J5,6¼6.3 Hz),
3.29 (1H, dd, CHHb, J¼3.9 Hz, J¼14.7 Hz), 3.06 (1H, dd,
CHHb, J¼6.9 Hz, J¼14.1 Hz), 2.12, 2.06, 2.00, and 1.93
(4ꢁ3H, 4ꢁs, OC(O)CH3). 13C NMR (75.5 MHz, CDCl3):
170.3, 169.9, and 169.7 (OC(O)CH3), 155.9 (OC(O)NH),
141.3, 127.7, 127.1, 125.0, and 120.0 (Ph), 131.3
(OCH2CHCH2), 118.9 (OCH2CHCH2), 83.5 (C-1), 71.5,
66.8, 66.7, and 66.3 (C-2, C-3, C-4, and C-5), 67.0
(OCH2CHCH2), 66.3 (Fmoc CH2), 61.5 (C-6), 55.2
(CHa), 47.0 (Fmoc CH), 31.8 (CH2b), and 20.5
(C(O)CH3). A solution of the crude Fmoc-Cys[Gal(OAc)4]-
OAllyl (z2.48 mmol) and anilinium p-toluenesulfinate
(0.68 g, 2.73 mmol) was stirred in dry THF (40 mL) under
an argon atmosphere. Pd(PPh3)4 (80 mg, 0.07 mmol) was
added under argon. After stirring for 2 h, TLC indicated
100% conversion. The bright yellow mixture was concen-
trated in vacuo, dissolved in CH2Cl2 (100 mL), and washed
twice with 1 M HCl (50 mL). The organic phase was dried
over Na2SO4, filtered, and concentrated. The product was
isolated by column chromatography on silica gel (hex/
EtOAc 1/1/EtOAc/MeOH 1/1) as a yellow foam (1.656 g,
99% over two steps). The NMR spectrum of the product was
consistent with Ref. 9: (300 MHz, CDCl3): 7.75–7.35 (8H,
m, Ph), 6.11 (1H, br d, Fmoc NH, J¼7.50 Hz), 5.38 (1H,
d, H-4, J3,4¼2.7 Hz), 5.20 (1H, t, H-2, J¼9.9 Hz), 5.02
(1H, dd, H-3, J2,3¼9.9 Hz, J3,4¼3.3 Hz), 4.56–4.47 (3H,
m, Fmoc CH2 and H-1), 4.36 (1H, m, CHa), 4.23 (1H, t,
Fmoc CH, J¼6.30 Hz), 4.12 (1H, dd, H-6a, J¼7.2 Hz,
J¼11.4 Hz), 4.02 (1H, dd, H-6b, J¼6.3 Hz, J¼11.4 Hz),
3.29 (1H, dd, CHHb, J¼4.2 Hz, J¼14.7 Hz), 3.10 (1H, dd,
CHHb, J¼6.0 Hz, J¼14.1 Hz), 2.12, 2.04, 1.99 and 1.93
(4ꢁ3H, 4ꢁs, C(O)CH3). 13C NMR (75.5 MHz, CDCl3):
170.8, 170.2 170.0, and 169.8 (C(O)CH3), 141.2, 127.7,
127.1, 124.8, and 119.9 (Ph), 84.3 (C-1), 74.3, 71.5, 67.1,
and 66.9 (C-2, C-3, C-4, and C-5), 66.8 (Fmoc CH2), 61.5
(C-6), 53.9 (CHa), 46.9 (Fmoc CH), 31.8 (CH2b), and
20.7 and 20.5 (OC(O)CH3).
washing with CH2Cl2 (6ꢁ2 min) and Et2O (2ꢁ2 min). The
resin was dried under high vacuum.
4.4. General procedure for solid-phase glycosylations
(procedure C)
In a flask the resin (100–300 mg) was combined with the
glycosyl donor (5 equiv). An appropriate volume of dry
CH2Cl2 was added and the mixture was kept under an N2
atmosphere and cooled to 0 ꢀC. After 30 min TMSOTf
(0.3 equiv) was added. The mixture was slowly stirred at
0 ꢀC for 1 h followed by 1 h at rt. A drop of Et3N was added
to neutralize the mixture after which the resin was trans-
ferred to a solid-phase tube and washed five times with
CH2Cl2. The glycosylation procedure was subsequently
repeated.
4.5. General procedure for cleavage of the thioglycosides
from the resin by DAST/NBS (procedure D)
The resin was swollen in an appropriate amount of CH2Cl2
and DAST (5 equiv) was added followed by NBS (5 equiv).
N2 was bubbled through the mixture and after 30 min the
mixture was filtered and the resin was washed with
CH2Cl2 (4ꢁ2 min). The filtrate was concentrated to afford
the crude anomeric fluorides, which were purified by silica
gel column chromatography.
4.6. General procedure for cleavage of the Rink linker
(procedure E)
The resin was shaken in a mixture of 95% TFA and 5% H2O
for 2 h. The resin was filtered off and washed with CH2Cl2
(5ꢁ). The filtrate was concentrated to obtain the crude prod-
ucts, which were purified by silica gel column chromato-
graphy followed by HPLC.
4.6.1. Resin (4). A mixture of 3 (775 mg, 1.15 mmol), HATU
(437 mg, 1.15 mmol), and DIPEA (0.38 mL, 2.30 mmol) in
dry NMP (10 mL) was added to aminomethylated polysty-
rene resin (500 mg, 0.58 mmol NH2). The mixture was
shaken for 20 h and the resin was filtered, washed with
NMPand CH2Cl2 (3ꢁ10 mL, 2 mineach). TheKaiser test in-
dicated the reaction to be complete. The remaining amines
were capped with capping reagent (10 mL) for 1 h. After a
washing procedure with NMP and CH2Cl2 (both 3ꢁ10 mL,
2 min each, i.e., general washing procedure) the Fmoc group
was cleaved by treatment with 20% piperidine in NMP
(3ꢁ10 mL, each 20 min). After a general NMP/CH2Cl2
washing a Kaiser test showed the presence of free amines,
which were acetylated twice (1.5 h each) by a mixture of pyr-
idine (7.5 mL) and Ac2O (5 mL). After washing no free
amines were present as shown by the Kaiser test. Hydroxyl
deprotection was performed according to procedure A.
4.2. General procedure for solid-phase sugar
deacetylation (procedure A)
The resin was treated with 5% N2H4$H2O in DMF
(4ꢁ30 min) and subsequently washed with DMF and
CH2Cl2 (each 4ꢁ2 min).
4.3. General protocol for solid-phase C6-OH acceptor
synthesis (procedure B)
The resin containing an unprotected galactose moiety was
washed with an appropriate volume of pyridine (3ꢁ2 min).
A solution of 4,4-dimethoxytrityl chloride (5–10 equiv) in
dry pyridine was added to the resin and N2 was bubbled
through the mixture for 4 h. Then the resin was washed
with CH2Cl2 (6ꢁ2 min). The resin was swollen again in pyr-
idine and benzoyl chloride (10 equiv per OH) was added
slowly. N2 was bubbled through the mixture for 1 h followed
by a washing step with CH2Cl2 (4ꢁ2 min). The benzoylation
step was repeated. The resin was treated several times with
a 1% dichloro acetic acid solution in CH2Cl2 (2 min each)
until no color release was observed. This was followed by
4.6.2. Resin (6). Resin 4 was treated according to the proce-
dure B to yield resin 6.
4.6.3. Resin (10). In a solid-phase reaction tube com-
mercially available 3-[4-(tritylmercapto)phenyl]propionyl
aminomethyl functionalized polystyrene resin (1.00 g,
0.80 mmol) was treated several times (5 min each) with a 1/1
mixture of CH2Cl2 and TFA until the release of the yellow

H. M. Branderhorst et al. / Tetrahedron 63 (2007) 4290–4296
4295
trityl cation had ceased. The resin was washed with CH2Cl2
(6ꢁ) and Et2O (2ꢁ) and dried for 2 h. In a flask the resin
was combined with peracetylated galactopyranose (1.72 g,
4.40 mmol), CH2Cl2 (5 mL) was added followed by
BF3$Et2O (0.56 mL, 4.40 mmol). The reaction mixture
was stirred for 20 h. Then the resin was filtered off and
washed with CH2Cl2 (4ꢁ2 min) and Et2O (2ꢁ2 min). The
glycosylation procedure was repeated to guarantee a full
loading of the resin. The resin was subjected to the deacety-
lation procedure A. A 50-mg sample was benzoylated and
cleaved from the resin to indicate a loading of 0.8 mmol/g.
Finally procedure B was followed.
was washed with NMP (4ꢁ10 mL, 2 min each) and CH2Cl2
(4ꢁ10 mL, 2 min each). Kaiser test indicated the reaction to
be complete. To the resin was added a mixture of 12 (1.09 g,
1.56 mmol), HATU (593 mg, 1.556 mmol), and DIPEA
(515 mL, 3.12 mmol) in dry NMP (10 mL). The resin was
shaken for 20 h and the resin was filtered and washed with
NMP (4ꢁ10 mL, 2 min each), CH2Cl2 (4ꢁ10 mL, 2 min
each), and Et2O (2ꢁ10 mL, 2 min each). Standard Fmoc
analysis revealed a loading of 0.48 mmol/g. Although the
Kaiser test revealed a complete coupling, a capping reaction
(10 mL capping solution) was performed for 1 h. The Fmoc
group was cleaved by piperidine as described above. The
resin was swollen in dry pyridine (10 mL) and benzoyl chlo-
ride (0.91 mL, 7.8 mmol) was added. N2 was bubbled
through the mixture for 1 h followed by washing with
CH2Cl2 (6ꢁ10 mL, 2 min each) and Et2O (2ꢁ10 mL,
2 min each). Hydroxyl deprotection was performed accord-
ing to procedure A, selective protecting group chemistry was
performed according to procedure B.
4.6.4. Resin (11). Detritylation was performed as described
for the synthesis of resin 10. The 3-[4-(tritylmercapto)phe-
nyl]propionyl aminomethyl functionalized polystyrene resin
(0.44 mmol) was combined with donor 3,4,6-tri-O-acetyl-
2-O-benzyl-a/b-D-galactopyranosyl
trichloroacetimidate
(476 mg, 0.88 mmol, for synthesis see Supplementary data).
To this CH2Cl2 (15 mL) was added and the reaction mixture
was cooled to 0 ꢀC under an N2 atmosphere. After 30 min
TMSOTf (17 mL, 0.09 mmol) was added and the mixturewas
stirred slowly for 3 h. Then the mixture was warmed to rt and
stirred additionally for 20 h. The resin was transferred to a
solid-phase reaction vessel and washed with CH2Cl2 (4ꢁ)
and Et2O (2ꢁ). The glycosylation procedure was repeated
to guarantee a full loading of the resin. The resin was sub-
jected to the deacetylation procedure A. A 50-mg sample
was benzoylated and cleaved from the resin to indicate a
loading of 0.5 mmol/g. Finally procedure B was followed.
4.6.8. O-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-
(1/6)-(2,3,4-tri-O-benzoyl-N-(carboxamido N-benzoyl-
L-glutam-5-oyl)-b-D-galactopyranosylamine) (15a). Gly-
cosylation of resin 13 with 7 according to procedure C, fol-
lowed by cleavage from the resin by procedure E yielded
15a (white solid) (16.4 mg, 25%): nmax (KBr)¼3500–3100
(br), 2924, 1734, 1262, 1070, and 711 cmꢂ1 1H NMR
.
(500 MHz, CDCl3): 8.10–7.23 (22H, m, Ph, NH2), 6.74
(1H, br t, C(O)NHC-1), 5.92 (1H, dd, H-4, J3,4¼3.0 Hz),
5.73 (1H, dd, H-3, J2,3¼10.0 Hz, J3,4¼3.5 Hz), 5.67 (1H, t,
H-2, J1,2¼9.0 Hz), 5.61 (1H, t, H-1, J1,2¼8.5 Hz), 5.36
(1H, s, NHBz), 5.32 (1H, d, H-40, J3,4¼3.0 Hz), 5.17 (1H,
4.6.5. Fluoro O-(2,3,4,6-tetra-O-acetyl-b-D-galactopyra-
nosyl)-(1/6)-2,3,4-tri-O-benzoyl-a/b-D-galactopyrano-
side (8). Either resin 6, or 10 or 11 (100–300 mg) was
glycosylated according to procedure C and the product
was cleaved from the resin according to procedure D, to
yield monosaccharide 9 (clear glass) and the disaccharide
8 (white foam). Compound 8 (a/b¼1/1): 1H NMR
(500 MHz, CDCl3): 8.08–7.27 (15H, m, Ph), 6.07 (0.5H,
d, H-1a, JH,F¼53 Hz), 5.98–5.84 (2H, m, H-2 and H-4),
5.70–5.58 (1H, 2ꢁm, H-3), 5.63 and 5.53 (0.5H, 2ꢁd,
H-1b, JH,F¼51.8 Hz, J1,2¼6.4 Hz), 5.36 (1H, s, H-40), 5.20
dd, H-20, J2 ,3 ¼10.5 Hz, J1 ,2 ¼8.0 Hz), 4.99 (1H, dd,
0
0
0
0
H-30, J2 ,3 ¼10.0 Hz, J3 ,4 ¼3.0 Hz), 4.58 (1H, d, H-1 ,
0
0
0
0
0
0
0
J1 ,2 ¼8.0 Hz), 4.65–4.61 (1H, m, CHa), 4.26 (1H, t, H-5,
J5,6¼6.0 Hz), 4.08–3.83 (4H, m, H-50, 2ꢁH-60 and 2ꢁH-6),
2.59–2.51 and 2.42–2.27 (2ꢁ1H, 2ꢁm, CH2g), 2.10–1.94
(2H, m, CH2b), 2.13, 2.06, 1.98, and 1.97 (4ꢁ3H, 4ꢁs,
C(O)CH3). 13C NMR (125.5 MHz, CDCl3): 170.7, 170.5,
170.3, and 169.3 (C(O)CH3), (C(O)NHC-1), 133.3–128.3
(Ph), 100.9 (C-10), 78.9 (C-1), 75.5 (C-5), 71.5 (C-3), 70.8
(C-2), 70.8 (C-30), 70.6 (C-50), 68.0 (C-4), 68.2 (C-20), 66.3
(H-60), 66.7 (C-40), 60.7 (H-6), 52.7 (Ca), 32.7 (CH2g),
21.4, 20.5, and 20.3 (C(O)CH3). HRMS for C53H55N3O20
(M, 1053,338) M+H found 1054.295, calcd 1054.347.
(1H, t, H-20, J2 ,3 ¼9.8 Hz), 5.02 (1H, d, H-30,
0
0
0
0
0
J2 ,3 ¼10.3 Hz), 4.58–4.52 (1H, m, H-1 ), 4.65 and 4.30
(1H, 2ꢁbr s, H-5), 4.09–3.83 (5H, m, H-50, 2ꢁH-6, and
2ꢁH-60), 2.15, 2.07, 2.01, and 1.99 (4ꢁ3H, 4ꢁs,
C(O)CH3). 13C NMR (75.0 MHz, CDCl3): 170.2, 170.1,
and 169.6 (C(O)CH3), 165.4, 165.2, and 165.1 (C(O)Ph),
133.8–128.3 (Ph), 101.5 (C-10), 73.4, 73.3, 70.7, 69.9,
69.6, 68.5, 67.6, 66.9, 66.8, and 61.1 (C-2, C-20, C-3, C-30,
C-4, C-40, C-5, C-50, C-6, and C-60), and 20.6 (C(O)CH3).
4.6.9. O-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyranosyl)-
(1/6)-(2,3,4-tri-O-benzoyl-N-(carboxamido N-benzoyl-
L-glutam-5-oyl)-b-D-galactopyranosylamine) (15b). Gly-
cosylation of resin 13 with 14 according to procedure C,
followed by cleavage from the resin by procedure E yielded
15b (white solid) (21.8 mg, 30%): nmax (KBr)¼3500–2800
4.6.6. Fluoro 2,3,4,6 tetra-O-acetyl-b-D-galactopyrano-
side (9). Compound 9 (only b isomer): H NMR spectrum
(br), 1730, 1684, 1533, 1451, 1267, 1107, and 709 cmꢂ1
.
1
1H NMR (500 MHz, CDCl3): 8.10–7.22 (22H, m, Ph, NH2),
6.85 (1H, br t, (CO)NHC-1), 5.90 (1H, dd, H-4, J3,4¼3.5 Hz,
J4,5¼1.0 Hz), 5.72 (1H, dd, H-3, J2,3¼10.0 Hz, J3,4¼3.5 Hz),
5.67 (1H, dd, H-2, J1,2¼8.5 Hz, J2,3¼10.0 Hz), 5.64 (1H, s,
is consistent with Ref. 15: (300 MHz, CDCl3): 5.42 (1H, s,
H-4), 5.36–5.29 (1H, m, H-2), 5.25 (1H, dd, J1,2¼7.2 Hz,
JH,F¼49.2 Hz), 5.05 (1H, d, H-3, J¼4.5 Hz), 4.21 (2H, d,
2ꢁH-6, J¼3.9 Hz), 4.06 (1H, t, H-5, J¼3.6 Hz), 2.18,
2.11, 2.07, and 2.01 (4ꢁ3H, 4ꢁs, C(O)CH3).
NHBz), 5.61 (1H, t, H-1, J1,2¼8.5 Hz), 5.35 (1H, d, H-40,
0
0
0
0
0
0
0
J3 ,4 ¼3.5 Hz), 5.19 (1H, dd, H-2 , J1 ,2 ¼8.0 Hz, J2 ,3
¼
10.5 Hz), 5.09 (1H, dd, H-30, J2 ,3 ¼10.5 Hz, J3 ,4 ¼3.5 Hz),
0
0
0
0
4.62 (1H, d, H-10, J1 ,2 ¼8.0 Hz), 4.61 (1H, m, CHa), 4.26–
4.23 (1H, m, H-5), 4.01–3.89 (4H, m, H-50, H-6a, and
2ꢁH-60), 3.76 (1H, dd, H-6b, J¼7.0 Hz, J¼11.0 Hz),
0
0
4.6.7. Resin (13). Fmoc loaded Rink aminomethyl polysty-
rene resin (1.00 g, 0.78 mmol NHFmoc) was treated with
20% piperidine in NMP (3ꢁ10 mL, 15 min each). The resin

4296
H. M. Branderhorst et al. / Tetrahedron 63 (2007) 4290–4296
2.56–2.50 and 2.42–2.37 (2ꢁ1H, 2ꢁm, CH2g), 2.12–2.05
and 2.00–1.94 (2ꢁ1H, 2ꢁm, CH2b), 1.24, 1.16, 1.10, and
1.10 (4ꢁ9H, 4ꢁs, C(O)C(CH3)3). 13C NMR (125.5 MHz,
CDCl3): 177.9, 177.5, 177.0, and 176.8 (C(O)C(CH3)3),
167.9, 165.4, 165.3, 165.2, and 165.1 (C(O)Ph), 165.2
(C(O)NHC-1),130.0–128.3 (Ph), 100.9 (C-10), 79.0 (C-1),
75.2 (C-5), 71.0 (C-30), 71.0 (C-50), 70.8 (C-3), 70.8 (C-2),
68.7 (C-4), 68.6 (C-20), 67.6 (C-60), 66.8 (C-40), 61.0 (C-6),
52.5 (Ca), 38.7, 38.8, and 39.1 (C(O)C(CH3)3), 32.8
(CH2g), 27.1 (CH2b), 27.2, 27.1, and 27.1 (C(O)C(CH3)3).
HRMS for C65H79N3O20 (M, 1221.526) M+H found
1222.538, calcd 1222.534.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.03.051.
References and notes
1. (a) Stevens, J.; Blixt, O.; Tumpey, T. M.; Taubenberger, J. K.;
Paulson, J. C.; Wilson, I. A. Science 2006, 312, 404–410; (b)
Kiefel, M. J.; von Itzstein, M. Chem. Rev. 2002, 102, 471–
490.
2. Wang, L.-X. Curr. Opin. Drug Discov. Devel. 2006, 9, 194–
206.
4.6.10. O-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyrano-
syl)-(1/6)-O-(2,3,4-tri-O-benzoyl-b-D-galactopyrano-
syl)-(1/6)-(2,3,4-tri-O-benzoyl-N-(carbamoyl N-
benzoyl-L-glutam-5-oyl)-b-D-galactopyranosylamine)
(16). Glycosylation of resin 13 with 14 according to proce-
dure C. The resin (208 mg) was subsequently treated with
a 1% NaOMe solution in 20% MeOH/dioxane (6ꢁ5 mL,
20 min each). The resin was then washed with CH2Cl2
(6ꢁ5 mL, 2 min each) and Et2O (2ꢁ5 mL, 2 min each). Se-
lective protecting group chemistry was performed according
to procedure B followed by glycosylation with 14 according
to procedure C. Finally, cleavage from the resin was per-
formed by procedure E and purification by HPLC to yield
16 (white solid) (1.9 mg, 2%, non-optimized): nmax (KBr)¼
3500–3100 (br), 2965, 2929, 1734, 1281, 1107, and
3. Ragupathi, G.; Koide, F.; Livingston, P. O.; Cho, Y. S.; Endo,
A.; Wan, Q.; Spassova, M. K.; Keding, S. J.; Allen, J.;
Ouerfelli, O.; Wilson, R. M.; Danishefsky, S. J. J. Am. Chem.
Soc. 2006, 128, 2715–2725.
4. Frechet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492–
496.
5. (a) Seeberger, P. H.; Haase, W.-C. Chem. Rev. 2000, 100, 4349–
4393; (b) Jonke, S.; Liu, K.-G.; Schmidt, R. R. Chem.—Eur. J.
2006, 12, 1274–1290; (c) Boons, G.-J.; Zhu, T. Chem.—Eur. J.
2001, 7, 2382–2389; (d) Mogemark, M.; Elofsson, M.;
Kihlberg, J. J. Org. Chem. 2003, 68, 7281–7288; (e)
Danishefsky, S. J.; McClure, K. F.; Randolph, J. T.; Ruggeri,
R. B. Science 1993, 260, 1307–1309; (f) Nicolaou, K. C.;
Watanabe, N.; Li, J.; Pastor, J.; Winssinger, N. Angew.
Chem., Int. Ed. 1998, 37, 1559–1561; (g) Wu, J.; Guo, Z.
J. Org. Chem. 2006, 71, 7067–7070.
1
710 cmꢂ1. H NMR (500 MHz, CDCl3): 8.08–7.22 (37H,
m, Ph, NH2), 6.81 (1H, s, C(O)NH), 5.94 (1H, dd, H-4,
J3,4¼3.0 Hz, J4,5¼1.0 Hz), 5.82 (1H, dd, H-40, J3 ,4 ¼3.0 Hz,
6. Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001,
291, 1523–1527.
0
0
0
0
0
0
0
0
0
J4 ,5 ¼0.5 Hz), 5.67 (1H, dd, H-2 , J1 ,2 ¼8.0 Hz, J2 ,3
¼
7. For other solid-phase carbohydrate synthesis approaches based
on a thioglycoside linkers, see: (a) Rademann, J.; Schmidt,
R. R. J. Org. Chem. 1997, 62, 3650–3653; (b) Rademann, J.;
Geyer, A.; Schmidt, R. R. Angew. Chem., Int. Ed. 1998, 37,
1241–1245; (c) Chiu, S.-H. L.; Anderson, L. Carbohydr. Res.
1976, 50, 227–238; (d) Yan, L.; Taylor, C. M.; Goodnow, R.;
Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953–6954; (e)
Liang, R.; Yan, L.; Loebach, J.; Ge, M.; Uozumi, Y.;
Sekanina, K.; Horan, N.; Gildersleeve, J.; Thompson, C.;
Smith, A.; Biswas, K.; Still, W. C.; Kahne, D. Science 1996,
274, 1520–1522.
10.5 Hz), 5.66 (1H, dd, H-30, J2 ,3 ¼11.00 Hz, J3 ,4 ¼3.5 Hz),
0
0
0
0
5.61 (1H, t, H-2, J1,2¼8.5 Hz), 5.56–5.53 (3H, m, H-1, NH,
H-3), 5.30 (1H, d, H-400, J3 ,4 ¼3.5 Hz), 5.11 (1H, dd, H-2 ,
00
00 00
00
00 00
00 00
00 00
J1 ,2 ¼8.0 Hz, J2 ,3 ¼10.5 Hz), 5.02 (1H, dd, H-3 , J2 ,3
¼
0
00 00
0
0
10.5 Hz, J3 ,4 ¼3.5 Hz), 4.90 (1H, d, H-1 , J1 ,2 ¼7.5 Hz),
4.61–4.57 (1H, m, CHa), 4.28 (1H, d, H-100, J1 ,2 ¼7.5 Hz),
00 00
4.19 (1H, t, H-5, J5,6¼6.0 Hz), 4.04–4.00 (3H, m, H-500, H-
6a, and H-6a0), 3.89–3.77 (5H, m, H-50, H-6b, H-6b0, and
2ꢁH-600), 2.56–2.50 and 2.39–2.34 (2ꢁ1H, 2ꢁm, CH2g),
2.17–2.10 and 2.05–1.97 (2ꢁ1H, 2ꢁm, CH2b), 1.22, 1.11,
1.09, and 1.08 (4ꢁ9H, 4ꢁs, C(O)C(CH3)3). 13C NMR
(125.5 MHz, CDCl3): 177.8, 177.3, 176.9, and 176.6
(C(O)C(CH3)3), 167.7, 165.3, and 165.1 (C(O)Ph), 133.8–
127.3 (Ph), 101.0 (C-100), 100.5 (C-10), 79.1 (C-1), 75.0
(C-5), 72.9 (C-50), 71.7 (C-3), 71.6 (C-30), 70.9 (C-300),
70.8 (C-500), 70.5 (C-2), 69.6 (C-20), 68.7 (C-200), 68.4 (C-
4), 68.3 (C-40), 67.4 (C-6), 66.6 (C-400), 66.4 (C-60), 60.7
(C-600), 52.6 (Ca), 38.7, 38.8, and 39.1 (C(O)C(CH3)3),
32.7 (CH2g), 27.1 (CH2b), 27.1, and 27.0 (C(O)C(CH3)3).
HRMS for C92H101N3O28 (M, 1695.657) M+Na found
1718.638, calcd 1718.647.
8. Opatz, T.; Kallus, C.; Wunberg, T.; Kunz, H. Tetrahedron 2004,
60, 8613–8626.
9. Elofsson, M.; Walse, B.; Kihlberg, J. Tetrahedron Lett. 1991,
32, 7613–7616.
ꢀ
10. (a) Codee, J. D. C.; Stubba, B.; Schiattarella, M.; Overkleeft,
H. S.; van Boeckel, C. A. A.; van Boom, J. H.; van der
Marel, G. A. J. Am. Chem. Soc. 2005, 127, 3767–3773; (b)
Zhu, T.; Boons, G.-J. Carbohydr. Res. 2000, 329, 709–715;
(c) Li, Z.; Gildersleeve, J. C. J. Am. Chem. Soc. 2006, 128,
11612–11619.
11. van Ameijde, J.; Albeda, H. B.; Liskamp, R. M. J. J. Chem.
Soc., Perkin Trans. 1 2002, 1042–1049.
Acknowledgements
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13. Dauty, E.; Remy, J.-S.; Blessing, T.; Behr, J.-P. J. Am. Chem.
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14. Thayer, D. A.; Yu, H. N.; Galan, M. C.; Wong, C.-H. Angew.
Chem., Int. Ed. 2005, 44, 4596–4599.
The Utrecht Institute for Pharmaceutical Sciences and the
Royal Netherlands Academy of Arts and Sciences
(KNAW) are gratefully acknowledged for support. We thank
Dr. Johan Kemmink, Dr. Hans Ippel, and Maarten van Dijk
for spectroscopic measurements.
15. Hall, L. D.; Manville, J. F.; Bhacca, N. S. Can. J. Chem. 1969,
47, 1–17.