Solid phase syntheses of oligomannosides and of a lactosamine containing milk trisaccharide using a benzoate linker

Article abstract of DOI:10.1055/s-2001-18441

Galactose and mannose building blocks 9 and 12 were designed for the solid phase synthesis of oligosaccharides (SPOS). Both compounds were employed after condensation with benzoic acid function containing resin 10 in SPOS of human milk trisaccharide 1 and

Full text of DOI:10.1055/s-2001-18441

PAPER
2263
Solid Phase Syntheses of Oligomannosides and of a Lactosamine Containing
Milk Trisaccharide Using a Benzoate Linker
Solid
Phase Syntheses
a
of
O
ligom
a
t
nnosid
t
es and
h
of
a
Lactosa
i
C
a
ontaining
M
s
ilk Trisaccharid
G
e
rathwohl,a Richard R. Schmidt*b
a
Alchemia Pty. Ltd., 3 Hi-Tech Court, Brisbane Technology Park, Eight Mile Plains 4113, Qld, Australia.
b
Fachbereich Chemie, Universität Konstanz, Fach M 725, 78457 Konstanz, Germany
Fax +49(7531)883135; E-mail: richard.schmidt@uni-konstanz.de
Received 25 July 2001
GPI-anchors.35 Therefore, in the retrosynthetic analysis
polymer-bound target molecules 5 and 6-n were discon-
nected into the corresponding O-glycosyl trichloroacetim-
idates 7, 8,20 and 11 as glycosyl donors, and into primary
Abstract: Galactose and mannose building blocks 9 and 12 were
designed for the solid phase synthesis of oligosaccharides (SPOS).
Both compounds were employed after condensation with benzoic
acid function containing resin 10 in SPOS of human milk trisaccha-
ride 1 and oligomannosides 2–4 ( -(1 2)-linked hexamer). Thus, alcohol residues 9 and 12 which were directly attached to
the polymeric benzoic acid support 1032 via simple con-
in this approach a special linker development was not required and
with the temporary protective groups phenoxyacetyl (PA) and 9-
densation reactions.
fluorenylmethoxycarbonyl (Fmoc) as part of compounds 7–12 the
Two galactose building blocks 7 and 9 were prepared
starting from known derivative 13,36 bearing two free hy-
droxy functions in the C2 and C3 position (Scheme 2).
Regioselective introduction of the Fmoc group to the
more reactive O3 position of building block 13 was
achieved by using FmocCl in MeCN together with a cata-
lytic amount of DMAP and pyridine (1 equiv). After con-
version of 95% of the starting material, compound 14 was
isolated in 67% yield. Unreacted 13 was separated (28%)
and recycled. Installation of the benzoyl group to the re-
maining 2-hydroxy group of 14 was successful by using
benzoyl chloride in a mixture of CH2Cl2/pyridine ( 15).
Under these conditions, no loss of the Fmoc group was
observed. Subsequent 1-O-desilylation of derivative 15
using an excess of HF pyridine complex37 in pyridine at
0 °C furnished compound 16. As described previously,20
the trichloroacetimidoyl moiety was introduced to com-
pound 16 by treatment with CCl3CN in the presence of
NaH at 0 °C leading to galactosyl donor 7 (1H NMR:
= 6.85, J1,2 = 3.4 Hz, 1-H, containing only trace
amounts of anomer) in 86% yield.20 Fully protected
compound 18 was obtained starting from known 1336 by a
highly regioselective introduction of the phenoxyacetyl
(PA) group ( 17) at low temperature in 92% yield and
subsequent treatment with benzoyl cyanide and Et3N in
MeCN. Derivative 18 was converted into primary alcohol
9 via regioselective opening38 of the 4,6-O-benzylidene
group under reductive reaction conditions (BH3 THF, 10
equiv and 1 M dibutyl boron triflate, 1.0 equiv) in high
yield (90%).
strategy offers the additional advantage of having the anomeric cen-
tre at the reducing end available for further manipulations.
Key words: solid-phase synthesis, Fmoc-protected hydroxy
groups, glycosidations, trichloroacetimidates, oligosaccharides.
Oligosaccharides in their functions as cell surface carbo-
hydrates and soluble glycoforms play an important role in
nature.1–3 Although research in this field is still in its in-
fancy, today there is already striking evidence that glyco-
conjugates are involved in several important processes,
for instance, cellular differentiation and recognition, sig-
nal transduction pathways and certain disease states.4,5 In
spite of the achievements in the chemical synthesis of oli-
gosaccharides based on the development of highly reac-
tive sugar donors,6,7 glycosylation strategies and
advanced protective group chemistry in recent years,8–10
one of the future tasks is to combine this knowledge with
the advantages of the solid phase synthesis and support
glycobiology studies with a variety of well defined oli-
gosaccharides and glycoconjugates. Therefore, we decid-
ed to focus our research on the synthesis of biologically
important structures occuring as parts of N-glycans, GPI-
anchors and human milk oligosaccharides, both in
solution11–14 and a on solid phase.15–22
Since in SPOS23 quite a few different linker systems were
developed,15,17–22,24–31,42 we use in our strategy a commer-
cially available resin already bearing benzoic acid func-
tions as the linker moiety.32 Furthermore, we describe
herein the application of recently reported O-Fmoc
protected20 O-glycosyl trichloroacetimidates as glycosyl
donors6,7 to the solid phase synthesis of target oligosac-
charides 1-4 (Scheme 1); these compounds occur in na-
ture as part of human milk oligosaccharides33, high
mannose-type N-glycans and glycolipids,34 and within
3,6-Di-O-benzyl glucosamine derivative 1939 was pre-
pared from D-glucosamine in five steps, using a strategy
based on a dibutyltin oxide assisted regioselective benzy-
lation of the 3- and 6-O-positions (Scheme 3).39,40 Thus,
the Fmoc group was introduced to the 4-O-position of
compound 19 using FmocCl with a catalytic amount of
DMAP in pyridine at r.t. 1-O-Desilylation of derivative 20
using an excess of HF pyridine complex37 in THF fur-
nished compound 21, which was subsequently trans-
Synthesis 2001, No. 15, 12 11 2001. Article Identifier:
1437-210X,E;2001,0,15,2263,2272,ftx,en;T06501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2264
M. Grathwohl, R. R. Schmidt
PAPER
O
H
BnO
BnO
OBn
O
OAc
aO
OBn
AcO
BnO
2 (n = 1)
3 (n = 3)
4 (n = 5)
O
n
b
OTDS
O
O
c
O
AcO
HO
O
BnO
OBz
O
NPhth
BnO
BnO
O
O
O
1
Ph
O
O
O
Fmoc
BnO
BnO
BnO
OBn
O
O
OBn
O
BzO
O
n
OTDS
O
O
FmocO
6-n
(n = 1 - 5)
O
BnO
OBz
NPhth
O
O
O
O
OBn
5
O
BnO
O
Ph
Ph
O
OH
O
OFmoc
OBn
O
10
O
O
FmocO
HO
BnO
12
O
OBn
BzO
OH
O
O
NH
CCl3
7
OTDS
PAO
OFmoc
O
BnO
BnO
BnO
OBz
OBn
O
9
FmocO
BnO
O
CCl3
NH
O
NPhth
11
CCl3
NH
8
Scheme 1
formed into -glycosyl trichloroacetimidate 820 in the The 1-O-TDS group proved to be stable under these con-
presence of NaH (0.1 equiv) in CCl3CN as solvent in 97% ditions.43 Glycosylation with donor 7 under the same con-
yield; only the -isomer was obtained (1H NMR: = 6.41, ditions furnished fully protected trisaccharide resin 5.
J
1,2 = 8.4 Hz, 1-H).
Completion of the reaction at each step was monitored by
TLC and MALDI-TOF after analytical cleavage of a
small resin sample (2–4 mg). The mass spectra indicated
that the 2-O-benzoyl group was retained. Therefore, after
preparative cleavage21 from the resin 5 we performed an
additional O-acetylation step affording human milk
trisaccharide 1 (1H NMR: = 4.54, d, J1,2 = 7.5 Hz, 1a-H;
C-1a: = 96.80) in 61% overall yield from 22 (92% per
step).
The first galactose residue, primary alcohol 9, was at-
tached to the solid support 10 via a condensation reaction
with N,N’-diisopropyl carbodiimide (DIC)41 and a catalyt-
ic amount of DMAP in CH2Cl2 (Scheme 4). The remain-
ing carboxylate functions were transformed into the
methyl ester. Loading of resin 22 was determined to be
0.05 mmol/g after recycling and purification of starting
material 9. Resin 22 was swollen in THF and PA-cleavage
reaction with a 8 M solution of MeNH2 in EtOH was re- The reiterative solid phase cycle for the construction of
peated until the generated UV spot of the washing solu- the biologically important -(1 2) linked mannoside
tions completely disappeared, thus leading to polymer oligomers34,35 starts with the synthesis of appropriate
bound acceptor 23. An independent PA-cleavage experi- mannose building blocks 11 and 12 (Scheme 5). Since it
ment in solution with compound 18, applying the condi- is known that O-(2-O-acetyl-3,4,6-tri-O-benzyl- -D-man-
tions described above proved the stability of Bz in 2- nopyranosyl) trichloroacetimidate44 was already success-
position of the galactose residue.43
fully applied to the synthesis of -mannosides in
solution11,45 and on solid phase,15,21 we decided to evaluate
the usefulness of the corresponding 2-O-Fmoc protected
donor 11 for SPOS.
Glycosylation of resin 23 with donor 8 under standard sol-
id phase glycosylation conditions (0.3 equiv TMSOTf, 3.0
equiv donor) at low temperature followed by removal of
the Fmoc group22 afforded disaccharide acceptor resin 24.
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Syntheses of Oligomannosides and of a Lactosamine Containing Milk Trisaccharide
2265
Ph
10
9
O
O
O
1) DMAP,
CH2Cl2,
DIC
2) MeOH,
CH2Cl2
OTDS
HO
OH
pyridine,
FmocCl, pyridine,
DMAP, MeCN
13
PACl,
-15°C
(67%)
(92%)
22
23
Ph
MeNH2, THF/EtOH
Ph
95% conversion
O
O
O
O
1) 8, TMSOTf,
CH2Cl2, -20°C
2) Et3N/CH2Cl2
(4:1)
O
O
OTDS
OTDS
FmocO
PAO
O
OH
OH
14
15
16
BzCl, CH2Cl2/pyridine (2:1), (95%)
HF·pyridine, pridine, 0°C, (95%)
OBn
O
BzCN, MeCN,
Et3N, (93%)
17
18
OBn
O
O
OTDS
O
HO
BnO
OBz
0.1 equiv NaH,
NPhth
24
BH3·THF,
Bu2BOTf
(86%)
CH2Cl2/CCl3CN
(1:1), 0°C
(90%)
Ph
1) 7, TMSOTf, CH2Cl2, -20°C (→ 5)
2) NaOMe, CH2Cl2/MeOH (9:1)
3) Ac2O/Py
61% overall yield from 22
(6 steps, 92% per step)
O
O
OH
BnO
PAO
O
O
FmocO
OTDS
OBn
OAc
aO
OBn
O
BzO
OBz
O
NH
CCl3
AcO
7
9
b
OTDS
O
O
c
O
AcO
BnO
OBz
NPhth
O
1
Scheme 2
O
Ph
Scheme 4
Known precursor 2546 was treated with FmocCl and a cat-
alytic amount of DMAP in pyridine to furnish fully pro-
tected 26 in excellent yield. Deallylation47 was performed determined to be 0.20 mmol/g twice, via recycling of un-
with Wilkinson catalyst in a two-step sequence. Hydroly- consumed starting material after treatment with Et3N22
sis of the enol ether with iodine afforded 27, which was and purification, as well as via preparative cleavage of al-
subsequently transformed into the trichloroacetimidate 11 lyl 3,4-di-O-benzyl- -D-mannopyranoside48 from resin
at 0 °C in 93% yield. Primary alcohol 12 was synthesized 30. Removal of the Fmoc group by treatment of resin 30
in two steps from known 28.11 Introduction of the Fmoc with Et3N22 furnished acceptor resin 31. The maximum
group as described above furnished 29 in 95% yield. Sub-
sequent removal of the 6-O-TBDPS group with excess
HF pyridine complex37 in THF afforded compound 12.
D-Mannose
Ref 11
Primary alcohol 12 was subsequently attached to the car-
boxylic acid resin 10 as described above to furnish resin
30 (Scheme 6). In this approach loading of resin 30 was
Ref 47
OH
O
OH
O
BnO
BnO
BnO
SPDBTO
BnO
BnO
OBn
O
O
O
HO
BnO
25
26
27
FmocCl, DMAP, pyridine, (94%)
1) (Ph3P)3RhCl, 2) I2, (82%)
OTDS
FmocCl, DMAP,
pyridine, (95%)
28
29
NPhth
19
20
21
FmocCl, DMAP, pyridine, (82%)
HF·pyridine, THF, (92%)
NaH,
CCl3CN,
0°C
(93%)
HF·pyridine,
THF
(93%)
NaH,
Cl3CCN
(97%)
OFmoc
OFmoc
HO
BnO
BnO
BnO
O
O
BnO
OBn
O
BnO
FmocO
BnO
O
O
NH
CCl3
12
O
CCl3
11
NPhth
NH
8
Scheme 3
Scheme 5
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

2266
M. Grathwohl, R. R. Schmidt
PAPER
1) DMAP, DIC 2) MeOH (→ 30)
10 + 12
CH2Cl2,
Et3N (4:1)
OH
n = 5
O
O
O
OBn
CH2Cl2/MeOH (9:1)
NaOMe
BnO
O
31
OH
O
BnO
BnO
n = 3
O
H
f
BnO
BnO
BnO
O
OH
O
BnO
BnO
BnO
BnO
n
O
O
BnO
BnO
BnO
d
n = 1
O
e
32-n
O
O
O
O
BnO
BnO
BnO
OH
O
BnO
BnO
BnO
BnO
BnO
BnO
O
OBn
O
O
c
b
d
BnO
O
O
O
BnO
BnO
BnO
O
O
O
CH2Cl2,
NEt3 (4:1)
BnO
BnO
BnO
HO
BnO
BnO
11, TMSOTf,
CH2Cl2
O
b
c
a
O
Fmoc
BnO
BnO
O
O
2
HO
BnO
BnO
OAll
O
O
BnO
BnO
BnO
O
a
BnO
b
n
86% overall yield
(3 steps, 95% per step)
O
6-n
OAll
3
O
O
HO
BnO
BnO
O
48% overall yield
(7 steps, 90% per step)
O
a
OBn
O
19% overall yield
(11 steps, 86% per step)
BnO
O
OAll
4
Scheme 6
(Kratos) instrument in the positive mode using 2,5-dihydroxyben-
zoic acid in dioxane as matrix. Microanalyses were performed in the
unit of Microanalysis at the Fachbereich Chemie, Universität Kon-
stanz.
chain distance for a six membered ring of six bonds be-
tween acceptor hydroxyl function and position of linkage
as pointed out in resin 31 proved to be very useful in the
glycosylation reaction with donor 11 performed under
standard conditions at r.t. as described above. Repetition
of the glycosylation ( 6-n) and deprotection ( 32-n)
sequence in a cyclic manner (n = 1 to 5) furnished the cor-
responding oligomannosides 2 to 4 up to the hexameric
stage with high stereoselectivity and in excellent overall
yields.
O-(2-O-Benzoyl-4,6-O-benzylidene-3-O-(9-fluorenyl-methoxy-
carbonyl)- -D-galactopyranosyl) trichloroacetimidate (7)
Compound 16 (78 mg, 131 mol) was dissolved in CH2Cl2 (2 mL).
The solution was stirred at 0 °C after the addition of Cl3CCN (2 mL)
and NaH (0.5 mg) for 1.5 h. The crude reaction mixture was ad-
sorbed onto silica gel and the residue was purified by a flash chro-
matography through a short plug of silica (toluene–acetone, 10:1) to
furnish compound 7 (83 mg, 112 mol, 86%) as a white foam (con-
taining only trace amounts of -anomer).
In summary, we present highly efficient synthetic routes
for the SPOS via a simple ester-type linkage. The new
Fmoc bearing building blocks were successfully applied
to the solid phase synthesis of human milk trisaccharide 1
and oligomannosides 2 to 4. The target molecules were
isolated as anomerically pure derivatives in high overall
yields; they permit additional elongation at their reducing
end. Investigations on further suitable building blocks for
the synthesis of more complex, branched glycostructures
are currently underway.
Rf (toluene–acetone, 5:1) = 0.70.
[ ]D = +81.3 (c = 1.0, CHCl3).
1H NMR (600 MHz, CDCl3): = 4.06 (s, 1 H, 5-H), 4.10 (d, 1 H,
J
gem = 12.9 Hz, 6-H), 4.17 (t, 1 H, 3J = 7.5 Hz, 9-H), 4.34–4.40 (m,
3 H, 6´-H, CH2O (Fmoc)), 4.65 (d, 1 H, J = 3.5 Hz, 4-H), 5.49 (dd,
1 H, J2,3 = 10.6 Hz, J3,4 = 3.5 Hz, 3-H), 5.58 (s, 1 H, CHPh), 5.89
(dd, 1 H, J1,2 = 3.4 Hz, J2,3 = 10.6 Hz, 2-H), 6.85 (d, 1 H, J1,2 = 3.4
Hz, 1-H), 7.04–8.00 (m, 18 H, Ar), 8.55 (s, 1 H, NH).
13C NMR (150.9 MHz, CDCl3): = 46.5 (1 C, C-9), 64.9 (1 C, C-
5), 67.5 (1 C, C-2), 68.8 (1 C, C-6), 70.3 (1 C, CH2O (Fmoc)), 72.2
(1 C, C-3), 73.4 (1 C, C-4), 94.6 (1 C, C-1), 101.0 (1 C, CHPh).
Solvents were purified and dried in the usual way. All reactions
were performed with anhyd solvents and under argon unless other-
wise stated. TLC’s were performed on plastic plates Silica Gel 60
Anal. Calcd for C37H30Cl3NO9 (738.99): C, 60.14; H, 4.09; N, 1.90.
Found: C, 60.17; H, 4.13; N, 1.82.
F
254. Detection was achieved by treatment with a solution of 20 g
ammonium molybdate and 0.4 g Ce (IV) sulfate in 400 mL 10%
H2SO4 or with 15% H2SO4 and heating at 150 °C. Flash chromatog-
raphy was carried out on silica gel (Baker 30–60 m). Adsorption
of reaction crudes were performed using silica gel (Baker 60–200
m). Petroleum ether (PE) was used with the boiling range 35–
70 °C; toluene, CH2Cl2, MeOH and EtOAc were distilled. Optical
rotations were determined at 21 °C with a Perkin-Elmer 241/MC
polarimeter (1 dm cell). NMR spectra were recorded with Bruker
AC 250 and 600 DRX instruments, with tetramethylsilane as inter-
nal standard. MS spectra were recorded with a MALDI-kompakt
O-(3,6-Di-O-benzyl-2-desoxy-4-O-(9-fluorenylmethoxy-
carbonyl)-2-N-phthalimido- -D-glucopyranosyl) trichloro-
acetimidate (8)
Compound 21 (115 mg, 0.161 mmol) was dissolved in Cl3CCN (3
mL). The solution was stirred after the addition of NaH (0.5 mg) for
15 min. The crude reaction mixture was adsorbed onto silica gel and
the residue was purified by a flash chromatography through a short
plug of silica (toluene–acetone, 10:1) to furnish compound 8 (133
mg, 0.155 mmol, 97%) as a white foam.
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Syntheses of Oligomannosides and of a Lactosamine Containing Milk Trisaccharide
2267
Rf (toluene–acetone, 5:1) = 0.73.
[ ]D = +70.1 (c = 2.0, CHCl3).
Anal Calcd for: C44H40Cl3NO8 (817.15): C, 64.67; H, 4.93; N, 1.71.
Found: C, 64.50; H, 4.84; N, 1.57.
1H NMR (250 MHz, CDCl3): = 3.69, 3.74 (m, 2 H, 6-H, 6´-H),
4.00 (dt, 1 H, J4,5 = 10.0 Hz, J5,6 = 3.7 Hz, 5-H), 4.12 (t, 1 H, 3J = 7.0
Hz, 9-H), 4.29–4.66 (m, 4 H, 2 CH2Ph), 4.32, 4.38 (m, 2 H, CH2O
(Fmoc)), 4.51 (m, 1 H, 2-H), 4.59 (m, 1 H, 3-H), 5.10 (dd, 1 H,
Allyl 3,4-di-O-benzyl-2-O-(9-fluorenylmethoxy-carbonyl)- -D-
mannopyranoside (12)
To a solution of compound 29 (388 mg, 0.45 mmol) in THF (6 mL)
was added an excess of HF pyridine complex (2 mL). After stirring
for 9 h the reaction solution was diluted with EtOAc (10 mL) and
neutralized by treatment with solid CaCO3 and H2O (0.1 mL). The
mixture was filtered through MgSO4 and concentrated in vacuo.
Flash chromatography (toluene–acetone, 20:1) of the residue fur-
nished 12 (261 mg, 0.42 mmol, 93%) as a white foam.
J3,4 = 8.6 Hz, J4,5 = 10.0 Hz, 4-H), 6.41 (d, 1 H, J1,2 = 8.4 Hz, 1-H),
6.82–7.77 (m, 22 H, Ar), 8.58 (s, 1 H, NH).
13C NMR (150.9 MHz, CDCl3): = 47.07 (1 C, C-9), 54.75 (1 C, C-
2), 69.26 (1 C, C-6), 70.36 (1 C, CH2O (Fmoc)), 74.39 (1 C, C-5),
74.52 (2 C, 2 CH2Ph), 76.89 (1 C, C-3), 76.90 (1 C, C-4), 94.22 (1
C, C-1).
Rf (toluene–acetone, 20:1) = 0.11
[ ]D = +13.2 (c = 2.0, CHCl3).
1H NMR (600 MHz, CDCl3): = 1.92 (t, 1 H, 3J = 5.9 Hz, 7.0 Hz,
OH), 3.75 (m, 1 H, 5-H), 3.82, 3.87 (m, 2 H, 6-H, 6´-H), 3.93 (t, 1
H, 3J = 9.6 Hz, 4-H), 4.00 (dd, 1 H, 3J = 6.1 Hz, 2J = 12.8 Hz, OCH-
aCH=CH2), 4.06 (dd, 1 H, J2,3 = 12.4 Hz, J3,4 = 3.1 Hz, 3-H), 4.18
Anal. Calcd for C45H37Cl3N2O9 (856.15): C, 63.13; H, 4.36; N,3.27.
Found: C, 63.23; H, 4.31; N, 3.01.
Thexyldimethylsilyl 2-O-benzoyl-4-O-benzyl-3-O-phenoxy-
acetyl- -D-galactopyranoside (9)
To a cooled solution of compound 18 (2.00 g, 3.08 mmol) in CH2Cl2
(20 mL) at 0 °C were added dropwise 1M BH3 THF (31 mL, 10.0
equiv) and 1 M dibutyl boron triflate (3.1 mL, 1.0 equiv) under ar-
gon. After stirring for 6 h the reaction mixture was treated with Et3N
(4 mL), quenched by carefully addition of MeOH (~ 10 mL) and
concentrated in vacuo. Flash chromatography (toluene–acetone,
20:1) of the residue gave compound 9 (1.80 g, 2.77 mmol, 90%) as
a slightly yellowish oil.
3
2
(dd, 1 H, J = 5.2 Hz, J = 12.8 Hz, OCHbCH=CH2), 4.25 (t, 1 H,
3J = 7.5 Hz, 9-H), 4.32 (dd, 1 H, J = 7.9 Hz, J = 10.1 Hz, CHaO
(Fmoc)), 4.47 (dd, 1 H, J = 7.3 Hz, J = 10.3 Hz, CHbO (Fmoc)),
4.61 (d, 1 H, J = 11.3 Hz, CHHPh), 4.69 (d, 1 H, J = 10.9 Hz,
CHHPh), 4.77 (d, 1 H, 2J = 11.3 Hz, CHHPh), 4.96 (d, 1 H,
2J = 10.9 Hz, CHHPh), 4.97 (d, 1 H, J1,2 = 1.7 Hz, 1-H), 5.21–5.30
(m, 3 H, 2-H, OCH2CH=CH2), 5.85–5.92 (m, 1 H, OCH2CH=CH2),
7.20–7.78 (m, 18 H, Ar).
3
2
3
2
2
2
TLC Rf (toluene–acetone, 5:1) = 0.49.
13C NMR (150.9 MHz, CDCl3): = 46.6 (1 C, C-9), 62.2 (1 C, C-
6), 68.4 (1 C, OCH2CH=CH2), 70.3 (1 C, CH2O (Fmoc)), 71.8 (1 C,
CH2Ph), 72.0 (1 C, C-5), 72.7 (1 C, C-2), 74.3 (1 C, C-4),75.4 (1 C,
CH2Ph), 78.2 (1 C, C-3), 96.8 (1 C, C-1).
[ ]D = +4.0 (c = 4.0, CHCl3).
1H NMR (250 MHz, CDCl3): = 0.04, 0.14 (2s, 6 H, 2 SiCH3),
0.69–0.72 (m, 12 H, 4 CH3), 1.44–1.52 (m, 1 H, CH(CH3)2), 3.53–
3.66 (m, 2 H, 6-H, 6´-H), 3.79–3.85 (m, 1 H, 5-H), 3.95 (d, 1 H,
3J = 2.8 Hz, 4-H), 4.36 (d, 1 H, 2J = 16.4 Hz, PhOCHa), 4.44 (d, 1
MALDI–MS, m/z calcd for: [MNa+], 645.7; [MK+], 661.8. Found:
[MNa+], 645.1; [MK+], 661.1.
2
2
H, J = 16.4 Hz, PhOCHb), 4.56 (d, 1 H, J = 12.0 Hz, CHHPh),
4.74 (d, 2J = 12.0 Hz, 1 H, CHHPh), 4.84 (d, 1 H, J1,2 = 7.5 Hz, 1-
H), 5.28 (dd, 1 H, J2,3 = 10.5 Hz, J3,4 = 3.1 Hz, 3-H), 5.62 (dd, 1 H,
Anal Calcd for C38H38O8 (622.70): C, 73.29; H, 6.15. Found: C,
73.23; H, 6.12.
J
1,2 = 7.5 Hz, J2,3 = 10.5 Hz, 2-H), 6.66–8.03 (m, 15 H, Ar).
Thexyldimethylsilyl 4,6-O-benzylidene-3-O-(9-fluorenyl-
methoxycarbonyl)- -D-galactopyranoside (14)
13C NMR (150.9 MHz, DMSO): = 58.80 (1 C, C-6), 63.94 (1 C,
PhOCH2), 71.96 (1 C, C-2), 73.41 (1 C, C-3), 74.15 (2 C, C-4, C-5),
74.29 (1 C, CH2Ph), 94.97 (1 C, C-1).
To a cooled solution of compound 1336 (7.06 g, 17.2 mmol) in
MeCN (300 mL) under argon were added at –15 °C pyridine (1.4
mL, 1.0 equiv) and DMAP (21 mg, 0.01 equiv). After addition of
FmocCl (18.2 g, 4.0 equiv), the reaction mixture was allowed to
warm up and stirring was continued for 2 h at r.t. The crude reaction
solution was quenched by addition of MeOH (50 mL), adsorbed
onto silica gel and evaporated in vacuo. Flash chromatography (tol-
uene–acetone, 30:1) of the residue afforded pure starting material
13 (1.95 g, 4.8 mmol, 28%) as well as the desired compound 14
(7.29 g, 11.5 mmol, 67%; 95% of conversion) as a white foam.
MALDI-MS, m/z calcd for: [MNa+], 673.8; [MK+], 689.9. Found:
[MNa+], 673.5; [MK+], 689.4.
Anal. Calcd for C36H46O9Si (650.83): C, 66.44; H, 7.12. Found: C,
66.76; H, 7.05.
O-(3,4,6-tri-O-Benzyl-2-O-(9-fluorenylmethoxy-carbonyl)-
/ -D-mannopyranosyl) trichloroacetimidate (11)
Compound 27 (100 mg, 0.15 mmol) was dissolved in Cl3CCN (2
mL). The solution was stirred at 0 °C after the addition of NaH (0.5
mg) for 30 min. The crude reaction mixture was adsorbed onto silica
gel and the residue was purified by flash chromatography through a
short plug of silica gel (toluene–acetone, 20:1) to furnish compound
11 (114 mg, 0.14 mmol, 93%) as a white foam ( / = 8:1).
Rf (toluene–acetone, 5:1) = 0.83.
[ ]D = +39.4 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): = 0.14, 0.17 (2s, 6 H, 2 SiCH3),
0.80–0.85 (4s, 12 H, 4 CH3), 1.52–1.66 (m, 1 H, CH(CH3)2), 2.18
(bs, 1 H, OH), 3.42 (m, 1 H, 5-H), 3.90–4.02 (m, 2 H, 2-H, 6-H),
4.19–4.24 (m, 2 H, 6´-H, 9-H), 4.33–4.4.37 (m, 3 H, 4-H, CH2O
(Fmoc)), 4.57 (d, 1 H, J1,2 = 7.5 Hz, 1-H), 4.65 (dd, 1 H, J2,3 = 10.3
Hz, J3,4 = 3.7 Hz, 3-H), 5.44 (s, 1 H, CHPh), 7.14–7.69 (m, 13 H,
Ar).
13C NMR (150.9 MHz, CDCl3): = 46.6 (1 C, C-9), 66.3 (1 C, C-
5), 69.2 (1 C, C-6), 70.1 (1 C, CH2O (Fmoc)), 70.5 (1 C, C-2), 73.2
(1 C, C-4), 77.1 (1 C, C-3), 98.0 (1 C, C-1), 100.9 (1 C, CHPh).
Rf (toluene–acetone, 5:1) = 0.80 ( ), 0.71 ( ).
[ ]D = +19.3 (c = 2.0, CHCl3).
1H NMR (11- , 250 MHz, CDCl3): = 3.76 (dd, 1 H, J5,6 = 1.5 Hz,
J6,6´ = 11.1 Hz, 6-H), 3.88 (dd, 1 H, J5,6´ = 3.9 Hz, J6,6´ = 11.3 Hz, 6´-
H), 4.01–4.18 (m, 3 H, 3-H, 4-H, 5-H), 4.29 (t, 1 H, 3J = 7.3 Hz, 9-
H), 4.33–4.95 (m, 8 H, CH2O (Fmoc), 3 CH2Ph), 5.34 (dd, 1 H,
J1,2 = 1.9 Hz, J2,3 = 2.6 Hz, 2-H), 6.45 (d, 1 H, J1,2 = 1.9 Hz, 1-H),
7.15–7.80 (m, 23 H, Ar), 8.71 (s, 1 H, NH).
MALDI–MS, m/z calcd for: [MNa+], 656.8; [(M–PhCH)Na+],
567.8. Found: [MNa+], 656.6; [(M–PhCH)Na+], 568.2.
MALDI-MS, m/z calcd for: [MK+], 856.2; [(M–Cl3CCN)Na+],
695.7. Found: [MK+], 856.2; [(M–Cl3CCN)Na+], 695.7.
Anal Calcd for C36H44O8Si 0.5H2O (641.82): C, 67.37; H, 7.07.
Found: C, 67.38; H, 7.26.
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

2268
M. Grathwohl, R. R. Schmidt
PAPER
Thexyldimethylsilyl 2-O-benzoyl-4,6-O-benzylidene-3-O-
(9-fluorenylmethoxycarbonyl)- -D-galactopyranoside (15)
To a cooled solution of compound 14 (0.33 g, 0.52 mmol) in
CH2Cl2–pyridine (2:1, 6 mL) under argon was added at 0 °C ben-
zoyl chloride (100 l, 1.5 equiv). After stirring for 12 h at r.t. the re-
action mixture was diluted with EtOAc (10 mL), neutralized by sat.
NH4Cl and extracted with H2O (20 mL) and sat. NaCl (20 mL). The
combined organic layers were dried with MgSO4 and concentrated
in vacuo. The residue was purified by flash chromatography (tolu-
ene, pure) to furnish 15 (364 mg, 0.49 mmol, 95%) as a white foam.
TLC
was purified by flash chromatography (toluene–acetone, 20:1) to
give 17 (8.31 g, 15.27 mmol, 92%) as a white foam.
Rf (toluene–acetone, 5:1) = 0.63.
[ ]D = +59.2 (c = 2.0, CHCl3).
1H NMR (250 MHz, CDCl3): = 0.20, 0.24 (2s, 6 H, 2 SiCH3),
0.89–0.93 (m, 12 H, 4 CH3), 1.61–1.73 (m, 1 H, CH(CH3)2), 2.16 (d,
1 H, JH,OH = 2.2 Hz, OH), 3.50 (s, 1 H, 5-H), 3.95 (ddd, 1 H,
J
H,OH = 2.2 Hz, J1,2 = 7.5 Hz, J2,3 = 10.2 Hz, 2-H), 4.04 (dd, 1 H,
J5,6 = 1.7 Hz, J6,6´ = 10.7 Hz, 6-H), 4.27 (d, 1 H, 2J = 12.4 Hz, 6´-H),
4.43 (d, 1 H, 3J = 3.6 Hz, 4-H), 4.63 (d, 1 H, J1,2 = 7.5 Hz, 1-H), 4.70
(bs, 2 H, PhOCH2), 4.95 (dd, 1 H, J2,3 = 10.2 Hz, J3,4 = 3.7 Hz, 3-H),
5.48 (s, 1 H, CHPh), 6.86–7.50 (m, 10 H, Ar).
Rf (toluene–acetone, 20:1) = 0.52.
[ ]D = +45.4 (c = 2.0, CHCl3).
MALDI–MS, m/z calcd for: [MNa+], 567.7; [MK+], 583.8. Found:
1H NMR (250 MHz, CDCl3): = 0.11, 0.21 (2s, 6 H, 2 SiCH3),
0.72–0.75 (m, 12 H, 4 CH3), 1.53 (sp, 3J = 6.8 Hz, 1 H, CH(CH3)2),
3.58 (m, 1 H, 5-H), 4.09–4.16 (m, 2 H, 6-H, 9-H), 4.27 (s, 1 H, 6´-
[MNa+], 568.3 [MK+], 584.1.
Anal. Calcd for: C29H40O8Si (544.71): C, 63.94; H, 7.40. Found: C,
63.94; H, 7.20.
3
H), 4.30 (d, 1 H, J = 0.9 Hz, CHaO (Fmoc)), 4.34 (dd, 1 H, 3J = 1.2
Hz, 2J = 12.4 Hz, CHbO (Fmoc)), 4.50 (m, 1 H, 4-H), 4.94 (d, 1 H,
Thexyldimethylsilyl 2-O-benzoyl-4,6-O-benzylidene-3-O-
phenoxyacetyl- -D-galactopyranoside (18)
J1,2 = 7.6 Hz, 1-H), 5.01 (dd, 1 H, J2,3 = 10.5 Hz, J3,4 = 3.7 Hz, 3-H),
5.57 (s, 1 H, CHPh), 5.72 (dd, 1 H, J1,2 = 7.6 Hz, J2,3 = 10.5 Hz, 2-
H), 6.98–8.06 (m, 18 H, Ar).
Et3N (1.7 mL, 1.1 equiv) and benzoyl cyanide (2.16 g, 1.5 equiv)
were added under argon to a solution of compound 17 (6.00 g, 11.00
mmol) in MeCN (90 mL). After stirring for 2.5 h the reaction solu-
tion was treated with MeOH (40 mL) and concentrated in vacuo.
The residue was purified by flash chromatography (toluene–ace-
tone, 20:1) to give 18 (6.64 g, 10.23 mmol, 93%) as a beige, amor-
phous solid.
MALDI–MS, m/z calcd for: [MNa+], 759.9; [MK+], 776.0. Found:
[MNa+], 759.8; [MK+], 775.8.
Anal calcd for C43H48O9Si (736.92): C, 70.08; H, 6.57. Found: C,
70.21; H, 6.58.
2-O-Benzoyl-4,6-O-benzylidene-3-O-(9-fluorenylmethoxy-
carbonyl)- / -D-galactopyranose (16)
Rf (toluene–acetone, 5:1) = 0.66.
[ ]D = +47.0 (c = 3.0, CHCl3).
To a cooled solution of compound 15 (290 mg, 0.39 mmol) in pyri-
dine (10 mL) was added an excess of HF pyridine complex (1 mL)
at 0 °C. After stirring for 3.5 h at 0 °C the reaction solution was di-
luted with EtOAc (10 mL) and neutralized by treatment with solid
CaCO3 and H2O (0.1 mL). The mixture was filtered on MgSO4 and
concentrated in vacuo by co-distillation with toluene to dryness.
Flash chromatography (toluene–acetone, 20:1) of the residue af-
forded compound 16 (220 mg, 0.37 mmol, 95%) as a white foam ( /
= 4.5:1).
1H NMR (250 MHz, CDCl3): = 0.10, 0.20 (2s, 6 H, 2 SiCH3),
0.71–0.74 (m, 12 H, 4 CH3), 1.52 (sp, 3J = 6.8 Hz, 1 H, CH(CH3)2),
3.58 (s, 1 H, 5-H), 4.10 (dd, 1 H, J5,6 = 1.2 Hz, J6,6´ = 10.7 Hz, 6-H),
4.32 (dd, 1 H, J5,6 = 1.2 Hz, J6,6´ = 12.3 Hz, 6´-H), 4.47 (s, 1 H, 4-
H), 4.49 (d, 1 H, 2J = 16.5 Hz, PhOCHa), 4.62 (d, 1 H, 2J = 16.5 Hz,
PhOCHb), 4.93 (d, 1 H, J1,2 = 7.6 Hz, 1-H), 5.25 (dd, 1 H, J2,3 = 10.4
Hz, J3,4 = 3.7 Hz, 3-H), 5.53 (s, 1 H, CHPh), 5.65 (dd, 1 H, J1,2 = 7.6
Hz, J2,3 = 10.5 Hz, 2-H), 6.69–8.03 (m, 15 H, Ar).
MALDI–MS, m/z calcd for: [MNa+], 671.8; [MK+], 687.9. Found:
Rf (toluene–acetone, 20:1) = 0.55 ( ), 0.47 ( ).
[ ]D = +82.5 (c = 1.5, CHCl3).
[MNa+], 671.2; [MK+], 687.3.
3
1H NMR (16- , 250 MHz, CDCl3): = 2.87 (d, 1 H, J = 3.2 Hz,
Anal. Calcd for C36H44O9Si (648.81): C, 66.64; H, 6.84. Found: C,
66.43; H, 6.50.
OH), 4.11 (s, 1 H, 5-H), 4.16 (m, 1 H, 6-H), 4.20 (t, 1 H, 3J = 7.4
Hz, 9-H), 4.29–4.39 (m, 3 H, 6´-H, CH2O (Fmoc)), 4.59 (d, J = 3.3
Hz, 4-H), 5.51 (dd, J2,3 = 10.7 Hz, J3,4 = 3.4 Hz, 1 H, 3-H), 5.59 (s,
1 H, CHPh), 5.67 (dd, 1 H, J1,2 = 3.3 Hz, J2,3 = 10.7 Hz, 1 H, 2-H),
5.81 (t, 1 H, J1,2 = 3.3 Hz, 1-H), 7.05–8.08 (m, 18 H, Ar).
Thexyldimethylsilyl 3,6-di-O-benzyl-2-desoxy-4-O-(9-fluor-
enylmethoxycarbonyl)-2-N-phthalimido- -D-gluco-pyrano-
side (20)
DMAP (2 mg, 0.01 equiv) and FmocCl (0.38 g, 1.1 equiv) were
added under argon to a solution of compound 1939 (0.84 g, 1.33
mmol) in pyridine (6 mL). After stirring for 2 h the mixture was
concentrated in vacuo and coevaporated twice with toluene. Flash
chromatography (toluene toluene–EtOAc, 30:1) afforded com-
pound 20 (0.93 g, 1.09 mmol, 82%) as a white foam.
13C NMR (16- , 150.9 MHz, CDCl3): = 46.47 (1 C, C-9), 62.27 (1
C, C-5), 69.0 (1 C, C-2), 69.18 (1 C, C-6), 70.23 (1 C,
CH2O(Fmoc)), 71.86 (1 C, C-3), 73.84 (1 C, C-4), 91.2 (1 C, C-1),
100.8 (1 C, CHPh).
MALDI–MS, m/z calcd for: [MNa+], 617.; [MK+], 633.7. Found:
[MNa+], 617.7; [MK+], 633.6.
Rf (toluene–acetone, 20:1) = 0.51.
Anal. Calcd for C35H30O9 0.05H2O (603.62): C, 69.64; H, 5.18.
Found: C, 69.85; H, 5.16.
[ ]D = +38.6 (c = 2.0, CHCl3).
1H NMR (250 MHz, CDCl3): = –0.04, 0.12 (2 s, 6 H, 2 SiCH3),
0.56–0.62 (m, 12 H, 4 CH3), 1.31–1.42 (m, 1 H, CH(CH3)2), 3.67
(m, 2 H, 6-H, 6´-H), 3.82 (m, 1 H, 5-H), 4.14 (t, 1 H, 3J = 7.1 Hz, 9-
H), 4.18 (dd, 1 H, J1,2 = 8.1 Hz, J2,3 = 10.9 Hz, 2-H), 4.28–4.63 (m,
4 H, 2 CH2Ph), 4.30–4.38 (m, 2 H, CH2O (Fmoc)), 4.46 (dd, 1 H,
J2,3 = 10.9 Hz, J3,4 = 8.8 Hz, 3-H), 4.95 (dd, 1 H, J3,4 = 8.8 Hz,
Thexyldimethylsilyl 4,6-O-benzylidene-3-O-phenoxyacetyl-
-D-galactopyranoside (17)
To a cooled solution of compound 1337 (6.81 g, 16.6 mmol) in py-
ridine (70 mL) at –15 °C was added dropwise phenoxyacetyl chlo-
ride (2.5 mL, 1.1 equiv) under argon. After stirring for 2 h at –15 °C,
the solution was diluted with EtOAc (200 mL) and extracted with
H2O (100 mL) and sat. NaCl (100 mL). The combined organic lay-
ers were dried with MgSO4 and concentrated in vacuo. The residue
J4,5 = 9.9 Hz, 4-H), 5.35 (d, 1 H, J1,2 = 8.1 Hz, 1-H), 6.85–7.76 (m,
22 H, Ar).
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Syntheses of Oligomannosides and of a Lactosamine Containing Milk Trisaccharide
2269
13C NMR (150.9 MHz, CDCl3): = 46.6 (1 C, C-9), 57.4 (1 C, C-
2), 69.8 (1 C, C-6), 69.9 (1 C, CH2O (Fmoc)), 73.0 (1 C, C-5), 73.9
(2 C, 2 CH2Ph), 76.5 (1 C, C-3), 77.3 (1 C, C-4), 93.4 (1 C, C-1).
Anal. Calcd for C45H44O8 (712.83): C, 75.82; H, 6.22. Found: C,
75.98; H, 6.34.
3,4,6-Tri-O-benzyl-2-O-(9-fluorenylmethoxycarbonyl)- / -D-
mannopyranose (27)
MALDI–MS, m/z calcd for: [MNa+], 877.1; [MK+], 893.2. Found:
[MNa+], 877.4; [MK+], 893.4.
To a hot solution (95 °C) of compound 26 (0.35 g, 0.49 mmol) in a
mixture of toluene–EtOH–H2O (20:10:1, 15.5 mL) was added
Wilkinson catalyst (tris(triphenyl phosphine) rhodium-(I)-chloride,
96 mg, 0.2 equiv) and the solution was refluxed for 15 h. The solid
was filtered on silica, washed with toluene (2 20 mL), concentrat-
ed in vacuo and coevaporated twice with toluene–EtOH (5:1). The
crude residue was dissolved in THF–H2O (4:1, 5 mL) and treated
with iodine (0.25 g, 2.0 equiv) for 30 min. The reaction mixture was
diluted with EtOAc (30 mL) and extrated with Na2S2O3 (sat. solu-
tion, 3 20 mL) and H2O (3 20 mL). The combined organic layers
were filtered through MgSO4, silica and activated carbon. Flash
chromatography (toluene–acetone, 20:1) after removal of the sol-
vents in vacuo afforded compound 27 (0.27 g, 0.40 mmol, 82%) as
a white foam ( / , 6:1).
Anal. Calcd for C51H55NO9Si (854.07): C, 71.72; H, 6.49; N, 1.64.
Found; C, 71.55; H, 6.28; N, 1.35.
3,6-Di-O-benzyl-2-desoxy-4-O-(9-fluorenylmethoxycarbonyl)-
2-N-phthalimido- / -D-glucopyranose (21)
To a solution of compound 20 (296 mg, 0.35 mmol) in THF (3 mL)
was added an excess of HF pyridine complex (1 mL, ~100 equiv).
After stirring for 2.5 d the reaction solution was diluted with EtOAc
(5 mL) and neutralized by treatment with solid CaCO3 and H2O (0.1
mL). The mixture was filtered through MgSO4 and concentrated in
vacuo. Flash chromatography (toluene–acetone, 10:1) of the residue
furnished 21 (227 mg, 0.32 mmol, 92%) as a white foam ( / = 1:8).
Rf (toluene–acetone 10:1) = 0.16 ( ).
[ ]D = +62.3 (c = 2.0, CHCl3).
Rf (toluene–acetone, 5:1) = 0.42.
[ ]D = +14.6 (c = 1.5, CHCl3).
1H NMR (21- , 250 MHz, CDCl3): = 3.65, 3.67 (2s, 2 H, 6-H, 6´-
H), 3.88 (dt, 1 H, J4,5 = 10.1 Hz, J5,6 = 4.4 Hz, 5-H), 4.14 (t, 1 H,
3J = 7.0 Hz, 9-H), 4.16 (dd, 1 H, J1,2 = 8.6 Hz, J2,3 = 10.6 Hz, 2-H),
4.28 (d, 1 H, Jgem = 12.3 Hz, CHHPh), 4.32–4.54 (m, 5 H, 3-H,
CH2Ph, CH2O (Fmoc)), 4.59 (d, 1 H, Jgem = 12.0 Hz, CHHPh), 5.00
(dd, 1 H, J3,4 = 9.0 Hz, J4,5 = 9.9 Hz, 4-H), 5.37 (d, 1 H, J1,2 = 8.5
Hz, 1-H), 6.84–7.77 (m, 22 H, Ar).
1H NMR (250 MHz, CDCl3): = 3.43 (bs, 1 H, OH), 3.68–3.86 (m,
3 H, 5-H, 6-H, 6´-H), 4.08 (dd, 1 H, J2,3 = 2.9 Hz, J3,4 = 9.2 Hz, 3-
H), 4.08–4.14 (m, 1 H, 4-H), 4.22–4.34 (m, 2 H, 9-H, CHaO
3
2
(Fmoc)), 4.44 (dd, 1 H, J = 6.7 Hz, J = 9.4 Hz, CHbO (Fmoc)),
4.51–4.93 (m, 6 H, 3 CH2Ph), 5.24 (dd, 1 H, J1,2 = 1.4 Hz, J2,3 = 2.9
Hz, 2-H ), 5.32 (m, 1 H, 2-H ), 5.36 (bs, 1 H, 1-H ), 7.16–7.78 (m,
23 H, Ar).
MALDI–MS, m/z calcd for: [MNa+], 734.8; [MK+], 750.9. Found:
[MNa+], 734.5; [MK+], 750.5.
MALDI-MS, m/z calcd for: [MNa+], 695.7. Found: [MNa+], 695.4.
Anal Calcd for C43H37NO9 (711.76): C, 72.56; H, 5.24; N, 1.98.
Found: C, 72.44; H, 5.43; N, 1.83.
Anal. Calcd for C42H40O8 (672.76): C, 74.98; H, 5.99. Found: C,
74.73; H, 5.87.
Allyl 3,4,6-tri-O-benzyl-2-O-(9-fluorenylmethoxycarbonyl)-
-D-mannopyranoside (26)
Allyl 3,4-di-O-benzyl-6-O-tert-butyldiphenylsilyl-2-O-(9-fluor-
enylmethoxycarbonyl)- -D-mannopyranoside (29)
DMAP (6 mg, 0.01 equiv) and FmocCl (5.22 g, 4.0 equiv) were
added under argon to a solution of compound 2546 (2.60 g, 5.05
mmol) in pyridine (30 mL). After stirring for 30 min the solid was
filtered off, washed with toluene (2 30 mL) concentrated in vacuo
and coevaporated twice with toluene. Flash chromatography (tolu-
ene) furnished 26 (3.38 g, 4.75 mmol, 94%) as a yellow oil.
DMAP (2.2 mg, 0.01 equiv) and FmocCl (1.85 g, 4.0 equiv) were
added under argon to a solution of compound 2811 (1.14 g, 1.78
mmol) in pyridine (20 mL). After stirring for 1 h the mixture was
concentrated in vacuo and coevaporated twice with toluene. Flash
chromatography (toluene–PE, 3:1) afforded 29 (1.45 g, 1.69 mmol,
95%) as a white foam.
Rf (toluene–acetone, 10:1) = 0.76.
Rf (toluene–acetone, 20:1) = 0.72.
[ ]D = +9.7 (c = 1.5, CHCl3).
1H NMR (600 MHz, CDCl3): = 3.77 (dd, 1 H, J5,6 = 1.2 Hz,
[ ]D = +8.8 (c = 2.0, CHCl3).
1H NMR (250 MHz, CDCl3): = 1.10 (s, 9 H, C(CH3)3), 3.76–3.80
(m, 1 H, 5-H), 3.92–4.27 (m, 7 H, 3-H, 4-H, 6-H, 6´-H, 9-H,
OCH2CH=CH2), 4.32 (m, 1 H, CHaO (Fmoc)), 4.46 (dd, 1 H,
3J = 6.9 Hz, 2J = 9.8 Hz, CHbO (Fmoc)), 4.61 (d, 1 H, 2J = 11.3 Hz,
CHHPh), 4.64 (d, 1 H, 2J = 10.7 Hz, CHHPh), 4.79 (d, 1 H,
2J = 11.3 Hz, CHHPh), 4.94 (d, 1 H, 2J = 10.7 Hz, CHHPh), 5.01 (d,
1 H, J1,2 = 1.6 Hz, 1-H), 5.20 (dd, 1 H, J1,2 = 1.6 Hz, J2,3 = 11.5 Hz,
2-H), 5.23–5.30 (m, 2 H, OCH2CH=CH2), 5.80–5.94 (m, 1 H,
OCH2CH=CH2), 7.14–7.80 (m, 28 H, Ar).
J
6,6´ = 10.6 Hz, 6-H), 3.85 (dd, 1 H, J5,6´ = 4.8 Hz, J6,6´ = 10.7 Hz, 6´-
H), 3.89 (m, 1 H, 5-H), 3.99 (t, 1 H, 3J = 9.6 Hz, 4-H), 4.04 (dd, 1
H, 3J = 6.2 Hz, 2J = 12.8 Hz, OCHaCH=CH2), 4.07 (dd, 1 H,
J2,3 = 9.3 Hz, J3,4 = 9.1 Hz, 3-H), 4.22 (dd, 1 H, 3J = 5.2 Hz,
2J = 12.8 Hz, OCHbCH=CH2), 4.28 (t, 1 H, 3J = 7.5 Hz, 9-H), 4.34
(dd, 1 H, 3J = 8.0 Hz, 2J = 10.3 Hz, CHaO (Fmoc)), 4.46 (dd, 1 H,
3J = 7.3 Hz, 2J = 10.2 Hz, CHbO (Fmoc)), 4.57 (t, 2 H, 2J = 11.1 Hz,
12.5 Hz, CH2Ph), 4.62 (d, 1 H, 2J = 11.3 Hz, CHHPh), 4.73 (d, 1 H,
2J = 12.1 Hz, CHHPh), 4.79 (d, 1 H, 2J = 11.3 Hz, CHHPh), 4.92 (d,
1 H, 2J = 10.7 Hz, CHHPh), 5.05 (s, 1 H, J1,2 < 1.0 Hz, 1-H), 5.21–
5.32 (m, 3 H, 2-H, OCH2CH=CH2), 5.89–5.94 (m, 1 H,
OCH2CH=CH2), 7.18–7.79 (m, 23 H, Ar).
MALDI-MS, m/z calcd for: [MNa+], 884.3; [MK+], 900.2. Found:
[MNa+], 884.3; [MK+], 900.4. Anal. Calcd for C54H56O8Si (861.31):
C, 75.32; H, 6.55. Found: C, 75.45; H, 6.51.
13C NMR (150.9 MHz, CDCl3): = 46.60 (1 C, C-9), 68.15 (1 C,
OCH2CH=CH2), 68.97 (1 C, C-6), 70.24 (1 C, CH2O (Fmoc)),
71.62 (1 C, C-5), 71.85 (1 C, CH2Ph), 72.69 (1 C, C-2), 73.45 (1 C,
CH2Ph), 74.40 (1 C, C-4), 75.31 (1 C, CH2Ph), 78.27 (1 C, C-3),
96.64 (1 C, C-1).
General Procedure for the Loading (Procedure A)
Carboxypolystyrene resin 10 (100–200 mesh, 1% cross-linked, ini-
tial loading 1.24 mmol/g)32 was swollen in a CH2Cl2 solution (10
mL/g resin) containing the appropriate primary alcohol. DMAP (0.2
equiv) and DIC (5.0 equiv) were added subsequently and the result-
ing suspension was shaken for 3 d. The solid phase reaction was
quenched by direct addition of MeOH (1 mL/g resin) and shaking
was continued for 1 d. The reaction solution was rinsed off and the
MALDI-MS, m/z calcd for: [MNa+], 735.8; [MK+], 751.9 Found:
[MNa+], 735.4; [MK+],
751.5.
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

2270
M. Grathwohl, R. R. Schmidt
PAPER
Thexyldimethylsilyl (2,3-di-O-acetyl-4,6-O-benzylidene- -D-
galactopyranosyl)-(1 4)-(3,6-di-O-benzyl-2-desoxy-2-N-
phthalimido- -D-glucopyranosyl)-(1 3)-6-O-acetyl-2-O-
benzoyl-4-O-benzyl- -D-galactopyranoside (1)
Resin 5 (4.9 mol) was treated as described in procedure D. After
removal of the solvents in vacuo the crude cleavage residue was
treated with Ac2O (1 mL) and pyridine (1 mL) for 12 h. The result-
ing mixture was concentrated in vacuo and coevaporated twice with
toluene. The residue was purified by flash chromatography (tolu-
ene–acetone, 20:1) to furnish 1 (4.1 mg, 61% overall yield based on
resin 22) as an amorphous solid.
resin washed alternately with THF (3 15 mL/g resin) and CH2Cl2
(3 15 mL/g resin) and dried under high vacuum.
General Procedure for Fmoc-Deprotection (Procedure B)
Fmoc-Cleavage was performed on solid phase according to the pro-
cedure previously described.22
General Procedure for the Solid-Phase Glycosylation
(Procedure C)
Dry acceptor-loaded resin was directly swollen in a CH2Cl2 solution
(15 mL/g resin) containing the appropriate donor (3.0 equiv) under
argon. After 10 min under agitation, a freshly prepared 0.5 M TM-
SOTf solution in CH2Cl2 (0.3 equiv) was added and shaking was
continued for 30 min. The resin was filtered off, washed alternately
with THF (3 15 mL/g resin) and CH2Cl2 (3 15 mL/g resin) and
dried under high vacuum.
Rf (toluene–acetone, 5:1) = 0.40.
[ ]D = –13.0 (c = 0.2, CHCl3).
1H NMR (600 MHz, CDCl3): = –0.01 (s, 3 H, SiCH3), 0.07 (s, 3
H, SiCH3), 0.52–0.56 (m, 12 H, 4 CH3), 1.48–1.54 (m, 1 H,
CH(CH3)2), 1.91 (s, 3 H, COCH3), 2.04 (s, 3 H, COCH3), 2.05 (s, 3
H, COCH3), 3.21 (s, 1 H, 5c-H), 3.60 (m, 1 H, 5a-H), 3.61 (m, 1 H,
5b-H), 3.85 (m, 2 H, 6b-H, 6´b-H), 3.86 (m, 1 H, 3a-H), 3.88 (m, 1
H, 6c-H), 3.96 (d, 1 H, 3J = 3.7 Hz, 4a-H), 3.97 (m, 1 H, 6a-H), 4.11
(m, 1 H, 4b-H), 4.17 (m, 1 H, 6´a-H), 4.22 (m, 2 H, 2b-H, 6´c-H),
4.25 (d, 1 H, 3J = 3.2 Hz, 4c-H), 4.29 (m, 1 H, 3b-H), 4.41 (d, 1 H,
2J = 12.2 Hz, CHHPh), 4.54 (d, 1 H, J1,2 = 7.5 Hz, 1a-H), 4.55 (d,
2J = 11.8 Hz, 1 H, ), 4.64 (d, 1 H, 2J = 11.6 Hz, CHHPh), 4.67 (d, 1
H, J1,2 = 7.8 Hz, 1c-H), 4.72-4.77 (m, 1 H, CHHPh), 4.82 (dd, 1 H,
General Procedure for Cleavage (Procedure D)
Cleavage was performed according to the procedure previously de-
scribed.21
Resin 5
Resin 24 was glycosylated with 7 according to procedure C, at
–20 °C.
2
Resins 6-n
J2,3 = 10.4 Hz, J3,4 = 3.7 Hz, 3c-H), 4.93 (d, 1 H, J = 12.2 Hz,
CHHPh), 5.06 (d, 1 H, 2J = 11.8 Hz, CHHPh), 5.25 (d, 1 H,
Resins 32-n and resin 31 were glycosylated with 11 according to
procedure C.
J1,2 = 8.4 Hz, 1b-H), 5.26 (m, 1 H, 2a-H), 5.36 (m, 1 H, 2c-H), 5.41
(s, 1 H, CHPh), 6.68–8.05 (m, 25 H, Ph).
Resin 22
13C NMR (150.9 MHz, CDCl3): 56.40 (1 C, C-2b), 63.88 (1 C, C-
6a), 66.61 (1 C, C-5c), 68.67 (1 C, C-6b), 68.97 (1 C, C-6c), 69.71
(1 C, C-2c), 72.50 (1 C, C-3c), 72.78 (1 C, C-5a), 73.66 (1 C, C-4c),
73.68 (1 C, C-2a), 75.1 (1 C, C-5b), 76.04 (1 C, C-4a), 77.16 (1 C,
C-3b), 78.69 (1 C, C-4b), 80.67 (1 C, C-3a), 96.80 (1 C, C-1a),
100.13 (1 C, C-1b), 100.84 (1 C, C-1c), 101.44 (1 C, CHPh).
Resin 10 was loaded with the primary alcohol 9 (0.05 equiv) accord-
ing to procedure A. Loading of resin 22 was determined to be 0.05
mmol/g by recovering of starting material 9 after purification (as
described above).
Resin 23
MALDI-MS, m/z calcd for: [MNa+], 1387.5. Found: [MNa+],
1387.7.
To a suspension of resin 22 in THF (4 mL/g resin) was added
MeNH2 (8 M solution in EtOH, 4mL/g resin). The resin was filtered
off after 15 min and the procedure repeated, until the UV spot of the
washing solution completely disappeared. Finally, the resin was
washed alternately with THF (3 15 mL/g resin) and CH2Cl2 (3
15 mL/g resin) and dried under high vacuum.
Anal. Calcd for C75H85NO21Si (1364.56): C, 66.01; H, 6.28; N, 1.03.
Found: C, 66.32; H, 6.29; N, 1.00.
Allyl (3,4,6-tri-O-benzyl- -D-mannopyranosyl)-(1 2)-3,4-di-O-
benzyl- -D-mannopyranoside (2)
Resin 6-1 (9.8 mol) was treated as described in procedure D. The
residue was purified by flash chromatography (toluene–EtOAc,
10:1) to afford 2 (7.0 mg, 86% overall yield based on resin 30) as a
colorless oil.
Resin 24
Resin 23 was glycosylated with 8 according to procedure C, but at
–20 °C. Subsequently it was treated according to procedure B yield-
ing resin 24.
Rf (toluene–acetone, 5:1)= 0.37.
[ ]D = +11.2 (c = 0.5, CHCl3).
1H NMR (600 MHz, CDCl3): = 1.94 (bs, 1 H, 6a-OH), 2.39 (s, 1
H, 2b-OH), 3.61 (m, 1 H, 5a-H), 3.69 (d, 1 H, J5,6 = 3.3 Hz, 6b-H),
3.73 (m, 1 H, 6a-H), 3.74 (bs, 1 H, 6´b-H), 3.78 (m, 2 H, 4b-H,
OCHaCH=CH2), 3.79 (m, 1 H, 6´a-H), 3.80 (m, 1 H, 4aH), 3.87 (m,
1 H, 3b-H), 3.88 (m, 1 H, 5b-H), 3.94 (dd, 1 H, J2,3 = 2.7 Hz,
Resin 30
Resin 10 was loaded with the primary alcohol 12 (0.22 equiv) ac-
cording to Procedure A. Loading of resin 30 was determined to be
0.20 mmol/g by treatment of the combined filtrates with Et3N (1 mL
per 4 mL of filtrate) for 4 h and was recovered by preparative cleav-
age (using procedure D) of allyl-3,4-di-O-benzyl- -D-
mannopyranoside48 after purification.
J
3,4 = 9.4 Hz, 3a-H), 4.01 (d, 1 H, J = 5.2 Hz, OCHbCH=CH2), 4.03
Resin 31
(s, 1 H, 2a-H), 4.12 (s, 1 H, 2b-H), 4.49 (d, 1 H, 2J = 10.7 Hz, CHH-
Ph), 4.52 (d, 1 H, 2J = 12.1 Hz, CHHPh), 4.61 (d, 1 H, 2J = 12.1 Hz,
CHHPh), 4.62 (d, 1 H, 2J = 10.8 Hz, CHHPh), 4.65–4.74 (m, 4 H, 2
CH2Ph), 4.83 (d, 1 H, 2J = 10.7 Hz, CHHPh), 4.88 (d, 1 H, 2J = 10.8
Hz, CHHPh), 4.90 (d, 1 H, J1,2 = 1.4 Hz, 1a-H), 5.11 (m, 1 H,
OCH2CH=CHaH), 5.11 (d, J1,2 < 1.0 Hz, 1 H, 1b-H), 5.17 (dd, 1 H,
Fmoc-cleavage of the resin bound monosaccharide (resin 30) was
achieved subsequently according to procedure B yielding resin 31.
Resins 32-n
The Fmoc groups of resins 6-n were deprotected according to pro-
cedure B.
2J = 10.8 Hz, J = 1.1 Hz, OCH2CH=CHHb), 5.75–5.84 (m, 1 H,
3
OCH2CH=CH2), 7.18–7.39 (m, 25 H, Ar).
13C NMR (150.9 MHz, CDCl3): = 62.51 (1 C, C-6a), 68.49 (1 C,
OCH2CH=CH2), 68.79 (1 C, C-2b), 69.50 (1 C, C-6b), 72.04 (1 C,
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Solid Phase Syntheses of Oligomannosides and of a Lactosamine Containing Milk Trisaccharide
2271
C-5b), 72.30 (1 C, C-5a), 72.57 (1 C, CH2Ph), 72.63 (1 C, CH2Ph),
73.85 (1 C, CH2Ph), 74.70 (1 C, C-4b), 74.94 (1 C, C-4a), 75.41 (1
C, C-2a), 75.69 (2 C, 2 CH2Ph), 79.97 (1 C, C-3a), 80.14 (1 C, C-
3b), 98.51 (1 C, C-1a), 101.53 (1 C, C-1b).
1H NMR (600 MHz, CDCl3): = 1.99–2.07 (m, 1 H, 6a-OH), 2.37
(bs, 1 H, 2f-OH), 3.38 (d, 1 H, 2J = 12.2 Hz, 6e-H), 3.43–3.47 (m, 2
H, 6b-H, 6c-H), 3.49 (m, 1 H, 5a-H), 3.50 (m, 1 H, 6´e-H), 3.52–
3.63 (m, 8 H, 6a-H, 4b-H, 6´b-H, 6´c-H, 6d-H, 6´d-H, 6f-H, 6´f-H),
3.64–3.71 (m, 5 H, OCHaCH=CH2, 4a-H, 4c-H, 4d-H, 6´a-H), 3.75
(m, 1 H, 3b-H), 3.77 (m, 1 H, 3a-H), 3.78 (m, 1 H, 4f-H), 3.79 (m,
1 H, 5b-H), 3.81 (m, 3 H, 4e-H, 3f-H, 5f-H), 3.82 (m, 2 H, 3c-H, 3d-
H), 3.87–3.88 (m, 4 H, 5c-H, 5d-H, 3e-H, 5e-H), 3.90 (m, 2 H,
OCHbCH=CH2, 2a-H), 4.02–4.07 (m, 9 H, 2 CH2Ph, 2b-H, 2c-H,
2d-H, 2e-H, 2f-H), 4.20–4.31 (m, 8 H, 4 CH2Ph), 4.35–4.78 (m, 6
H, 3 CH2Ph), 4.88 (d, 1 H, J1,2 < 1.0 Hz, 1a-H), 5.10 (d, 1 H,
2J = 10.5 Hz, OCH2CH=CHaH), 5.04 (d, 1 H, J1,2 < 1.0 Hz, 1f-H),
5.08 (s, 1 H, OCH2CH=CHHb), 5.14 (d, 1 H, J1,2 = 1.3 Hz, 1e-H),
5.16 (d, 2 H, J1,2 < 1.0 Hz, 1c-H, 1d-H), 5.19 (d, 1 H, J1,2 = 1.2 Hz,
1b-H), 5.64–5.70 (m, 1 H, OCH2CH=CH2), 7.00–7.31 (m, 85 H,
Ar).
MALDI-MS, m/z calcd for: [MNa+], 856.0. Found: [MNa+], 856.1.
Anal. Calcd for C50H56O11 (832.99): C, 75.34; H, 7.29. Found: C,
75.28; H, 7.21.
Allyl (3,4,6-tri-O-benzyl- -D-mannopyranosyl)-(1 2)-(3,4,6-
tri-O-benzyl- -D-mannopyranosyl)-(1 2)-(3,4,6-tri-O-benzyl-
-D-mannopyranosyl)-(1 2)-3,4-di-O-benzyl- -D-manno-
pyranoside (3)
Resin 6-3 (52 mol) was treated as described in procedure D. The
residue was purified by flash chromatography (toluene–acetone,
40:1) to afford 3 (42 mg, 48% overall yield based on resin 30) as a
white foam.
13C NMR (150.9 MHz, CDCl3): = 62.22 (1 C, C-6a), 67.99 (1 C,
OCH2CH=CH2), 68.48 (2 C, C-2e, C-2f), 68.76 (1 C, C-6e), 69.35
(1 C, C-6b), 69.45 (1 C, C-6d), 69.70 (2 C, C-6c, C-6f), 71.58 (1 C,
C-5f), 71.65 (1 C, CH2Ph), 71.74 (1 C, C-5a), 71.86 (1 C, CH2Ph),
72.04 (1 C, CH2Ph), 72.09 (1 C, C-5b), 72.29 (1 C, C-5e), 72.38 (2
C, C-5c, C-5d), 73.19 (3 C, 3 CH2Ph), 73.29 (2 C, 2 CH2Ph), 74.30
(1 C, C-4e), 74.62 (1 C, C-4a), 74.96 (3 C, C-4c, C-4d, C-4f), 75.01
(1 C, C-4b), 75.12 (1 C, C-2d), 75.82 (1 C, C-2a), 76.14 (2 C, C-2b,
C-2c), 76.79 (3 C, 3 CH2Ph), 77.00 (3 C, 3 CH2Ph), 77.21 (3 C, 3
CH2Ph), 78.83 (1 C, C-3b), 79.14 (1 C, C-3a), 79.35 (2 C, C-3c, C-
3d), 79.65 (1 C, C-3e), 80.05 (1 C, C-3f), 98.06 (1 C, C-1a), 100.93
(1 C, C-1e), 101.02 (1 C, C-1f), 101.19 (2 C, C-1c, C-1d), 101.36 (1
C, C-1b).
Rf (toluene/acetone, 5:1) = 0.68.
[ ]D = +18.9 (c = 1.0, CHCl3).
1H NMR (600 MHz, CDCl3): = 1.95 (bs, 1 H, 6a-OH), 2.32 (s, 1
H, 2d-OH), 3.42 (d, 1 H, J6,6´ = 9.6 Hz, 6c-H), 3.49 (m, 1 H, 5a-H),
3.53 (dd, 1 H, J5,6 = 4.0 Hz, J6,6´ = 10.6 Hz, 6b-H), 3.53 (m, 1 H, 6´c-
H), 3.60 (m, 1 H, 4b-H), 3.61 (m, 1 H, 6a-H), 3.62 (m, 2 H, 6d-H,
6´d-H), 3.63 (m, 1 H, 6´b-H), 3.65 (m, 1 H, 4a-H), 3.67 (m, 1 H,
OCHaCH=CH2), 3.68 (m, 1 H, 6´a-H), 3.77 (m, 1 H, 3b-H), 3.78 (m,
3 H, 3a-H, 5b-H, 4d-H), 3.80 (m, 1 H, 4c-H), 3.81 (m, 1 H, 3d-H),
3.84 (m, 1 H, 5d-H), 3.85 (m, 2 H, 3c-H) 5c-H), 3.90 (m, 1 H, 2a-
H), 3.91 (m, 1 H, OCHbCH=CH2), 4.01 (t, 1 H, 3J = 2.4 Hz, 2b-H),
4.05 (m, 1 H, 2c-H), 4.06 (m, 1 H, 2d-H), 4.10 (d, 1 H, 2J = 12.2 Hz,
CHHPh), 4.72 (d, 2J = 12.2 Hz, 1 H, CHHPh), 4.32–4.54 (m, 16 H,
8 CH2Ph), 4.73–4.76 (m, 4 H, 2 CH2Ph), 4.86 (d, 1 H, J1,2 < 1.0 Hz,
MALDI-MS, m/z calcd for: [MNa+], 2586.0. Found: [MNa+],
2586.7.
1a-H), 5.01 (d, 2J = 10.4 Hz, 1 H, OCH2CH=CHaH), 5.06 (d, J1,2
<
Anal. Calcd for C158H168O3 (2563.01): C, 74.04; H, 6.61. Found: C,
74.13: H, 6.71.
1.0 Hz, 1 H, 1d-H), 5.05–5.09 (m, 1 H, OCH2CH=CHHb), 5.13 (d,
1 H, J1,2 = 1.3 Hz, 1b-H), 5.15 (d, 1 H, J1,2 = 1.3 Hz, 1c-H), 5.68–
5.72 (m, 1 H, OCH2CH=CH2), 6.98–7.24 (m, 55 H, Ar).
Acknowledgement
13C NMR (150.9 MHz, CDCl3): = 62.21 (1 C, C-6a), 67.99 (1 C,
OCH2CH=CH2), 68.49 (1 C, C-2d), 68.79 (1 C, C-6c), 69.50 (1 C,
C-6b), 69.65 (1 C, C-6d), 71.60 (1 C, CH2Ph), 71.74 (1 C, C-5d),
71.80 (1 C, C-5a), 72.07 (1 C, CH2Ph), 72.20 (1 C, CH2Ph), 72.30
(1 C, C-5b), 72.35 (1 C, C-5c), 73.25 (1 C, CH2Ph), 73.31 (1 C,
CH2Ph), 74.30 (1 C, C-4c), 74.62 (1 C, CH2Ph), 74.84 (1 C, C-4a),
74.94 (1 C, C-4d), 75.08 (1 C, C-4b), 75.14 (1 C, C-2c), 75.38 (1 C,
C-2b), 75.52 (1 C, C-2a), 76.79 (1 C, CH2Ph), 77.00 (C, CH2Ph),
77.21 (2 C, 2 CH2Ph), 78.82 (1 C, C-3b), 79.17 (1 C, C-3a), 79.41
(1 C, C-3c), 80.09 (1 C, C-3d), 98.05 (1 C, C-1a), 100.93 (1 C, C-
1c), 100.98 (2 C, C-1b, C-1d).
We thank the European Community (Grant N° FAIR-CT97-3142),
the Bundesministerium für Bildung und Forschung (Grant N° 0311
229) and the Deutsche Forschungsgemeinschaft for financial sup-
port of this work. The help of Dr. A. Geyer and A. Friemel in struc-
tural assignments is gratefully acknowledged.
References
(1) Varki, A. Glycobiology 1993, 3, 97.
(2) Dwek, R. A. Chem. Rev. 1996, 96, 683.
(3) Sharon, N.; Lis, H. In Glycosciences - Status and
Perspectives, Gabius J., Gabius S.; Chapman and Hall:
Weinheim, 1997, 133.
(4) Van den Steen, P.; Rudd, P. M.; Dwek, R. A.; Opdenakker,
G. Crit. Rev. Biochem./Mol. Biol. 1998, 33, 151.
(5) Hakamori, S. Adv. Cancer Res. 1989, 52, 257.
(6) (a) Schmidt, R. R. Angew. Chem. 1986, 98, 213.
(b) Schmidt, R. R. Angew. Chem. Int. Ed. Engl. 1986, 25,
212.
MALDI-MS, m/z calcd for: [MNa+], 1721.0. Found: [MNa+],
1720.4.
Anal. Calcd for C104H112O21 (1697.99): C, 73.56; H, 6.65. Found: C,
73.96; H, 6.72.
Allyl (3,4,6-tri-O-benzyl- -D-mannopyranosyl)-(1 2)-(3,4,6-
tri-O-benzyl- -D-mannopyranosyl)-(1 2)-(3,4,6-tri-O-benzyl-
-D-mannopyranosyl)-(1 2)-(3,4,6-tri-O-benzyl- -D-manno-
pyranosyl)-(1 2)-(3,4,6-tri-O-benzyl- -D-mannopyranosyl)-
(1 2)-3,4-di-O-benzyl- -D-mannopyranoside (4)
Resin 6-5 (78 mol) was treated as described in procedure D. The
residue was purified by flash chromatography (toluene–acetone,
40:1) to afford 4 (38 mg, 19% overall yield based on resin 30) as a
white, amorphous solid.
(7) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem. Biochem.
1994, 50, 21.
(8) Schmidt, R. R. In Carbohydrates – Synthetic Methods and
Applications in Medicinal Chemistry; Ogura, H.; Hasegawa,
A.; Suami, T., Eds.; Kodansha: Tokyo, 1992, 68.
(9) Ogawa, T. Chem. Soc. Rev. 1994, 397.
(10) Barresi, F.; Hindsgaul, O. In Modern Synthetic Methods;
Ernst, B.; Leumann, C., Eds.; Verlag Chemie: Weinheim,
Basel, 1995, 283.
Rf (toluene–acetone, 5:1) = 0.67.
[ ]D = +26.3 (c = 1.0, CHCl3).
Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York

2272
M. Grathwohl, R. R. Schmidt
PAPER
(11) (a) Mayer, T. G.; Kratzer, B.; Schmidt, R. R. Angew. Chem.
1994, 106, 2289. (b) Mayer, T. G.; Kratzer, B.; Schmidt, R.
R. Angew. Chem. Int. Ed. Engl. 1994, 33, 2177. (c) Mayer,
T. G. Dissertation; Universität Konstanz: Germany, 1996,
and references cited therein.
(31) Selenium based linker: (a) Nicolaou, K. C.; Mitchell, H. J.;
Fylaktakidou, K. C.; Suzuki, H.; Rodríguez, R. M. Angew.
Chem. 2000, 112, 1131. (b) Nicolaou, K. C.; Mitchell, H. J.;
Fylaktakidou, K. C.; Suzuki, H.; Rodríguez, R. M. Angew.
Chem. Int. Ed. 2000, 39, 1089.
(12) Aly, M. R. E.; Ibrahim, E.-S. I.; El-Ashry, E.-S. H.; Schmidt,
R. R. Eur. J. Org. Chem. 2000, 319; and references cited
therein.
(13) Chiesa, M. V.; Schmidt, R. R. Eur. J. Org. Chem. 2000,
3541; and references cited therein.
(14) Knuhr, P.; Castro-Palomino, J.; Grathwohl, M.; Schmidt, R.
R. Eur. J. Org. Chem. 2001, submitted, and references cited
therein.
(15) Rademann, J.; Schmidt, R. R. J. Org. Chem. 1997, 62, 3650.
(16) Heckel, A.; Mross, E.; Jung, K. H.; Rademann, J.; Schmidt,
R. R. Synlett 1998, 171.
(32) Resin 10 is commercially available from Novabiochem,
Switzerland; http://www.nova.ch.
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(25) Silyl ether type linker: (a) Danishefsky, S. J.; McClure, K.
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(43) At higher reaction temperatures and higher Lewis acid
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Synthesis 2001, No. 15, 2263–2272 ISSN 0039-7881 © Thieme Stuttgart · New York