Synthesis of DIvalent 2,2′-linked mannose derivatives by homodimerization

Article abstract of DOI:10.1055/s-0028-1083283

Several studies have implicated (1 → 2)-linked mannans as biologically relevant compounds. Recently, there has been a growing interest in the synthesis of multivalent carbohydrate assemblies due to their ability to target multiple receptors simultaneously. In the present work, a protective group strategy, based on the methodology originally developed by Crich, has been utilized for the homodimerization of olefinic carbohydrates, allowing a highly diastereoselective synthesis of some divalent structures. Furthermore, it is shown that divalent donors may undergo coupling reactions without losses in stereoselectivity or efficiency. The strategies described may potentially be applied to the synthesis of diverse neoglycoconjugates and oligosaccharides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083283

PAPER
567
Synthesis of Divalent 2,2¢-Linked Mannose Derivatives by Homodimerization
D
ivalent 2, 2
¢
-L
i
inked
l
Manno
i
se Deri
p
vatives S. Ekholm,a Monika Poláková,a,b Agnieszka J. Pawłowicz,a Reko Leino*a
a
Laboratory of Organic Chemistry, Åbo Akademi University, 20500 Åbo, Finland
Fax +358(2)2154866; E-mail: reko.leino@abo.fi
Institute of Chemistry, Centre for Glycomics, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovakia
b
Received 22 September 2008
Several methods for the synthesis of divalent molecules
have been reported previously.8–10 One of the most prom-
ising routes is based on cross-coupling olefin metathesis.
While having great potential in general, several problems
Abstract: Several studies have implicated (1→2)-linked mannans
as biologically relevant compounds. Recently, there has been a
growing interest in the synthesis of multivalent carbohydrate as-
semblies due to their ability to target multiple receptors simulta-
neously. In the present work, a protective group strategy, based on have limited the use of cross-coupling metathesis in car-
the methodology originally developed by Crich, has been utilized
bohydrate chemistry. In many cases, the issues are related
for the homodimerization of olefinic carbohydrates, allowing a
to the formation of undesired dimers, poor diastereoselec-
highly diastereoselective synthesis of some divalent structures. Fur-
tivities and the fact that, in contrast to ring-closing olefin
thermore, it is shown that divalent donors may undergo coupling re-
metathesis, the cross-coupling reaction is not driven by an
actions without losses in stereoselectivity or efficiency. The
strategies described may potentially be applied to the synthesis of
increase in entropy.11,12
diverse neoglycoconjugates and oligosaccharides.
In the present work, we have specifically targeted the
Key words: carbohydrates, divalent molecules, diastereoselective
synthesis, homodimerization, (1→2)-linked mannans
preparation of homodimerization products of mannose
monomers and dimers, which could potentially result in
biologically relevant oligo/dimeric structures, whilst
avoiding many of the problems associated with olefin
cross-coupling metathesis mentioned above. Attempts
were likewise made to influence the diastereoselectivity
of the homodimerization by selecting suitable protecting
group strategies. As mentioned, in the mannoside case,
(1→2)-linkages between the monosaccharide units have
been shown to be of significance in stimulating biological
activities.1,2 Accordingly, as a starting point for the
present study, the most reasonable position for the con-
necting linker to be prepared was between the 2- and the
2¢-positions of the mannosides. To our knowledge, such
2,2¢-linked divalent sugar moieties have not been reported
previously in the literature. Here, we present the prepara-
tion of several divalent 2,2¢-linked mannoside homo-
dimerization products, which were obtained in good
yields and high diastereoselectivities from building
blocks containing a terminal olefin. The subsequent
deprotection of the metathesis products obtained provided
complex divalent carbohydrate structures of potential bi-
ological relevance.
In several studies, (1→2)-linked mannans have been
found to be of significant importance for the stimulation
of biological responses and for functioning as inhibitors of
certain diseases and infections (Figure 1).1,2 Man-
a(1→2)Man oligomannosides have been shown to bind to
specific areas of cyanovirin-N and are considered to be
promising structures for the development of anti-HIV
vaccines.3 Manb(1→2)Man oligosaccharides have been
shown to stimulate macrophages to produce TNF-a, and
inhibit Candida albicans adhesion to endothelial cells.4–6
In both cases, a polymerization degree of two to seven has
been found to be sufficient for obtaining biological activ-
ity.1,3 Recently, several studies have indicated that multi-
valent assemblies in some cases increase the biological
activity of carbohydrates by targeting multiple receptors
simultaneously.7 Divalent molecules can be considered as
the simplest model systems for multivalent compounds
and to be ideal structures for exploring the minimal struc-
tural requirements for such binding.
For the preparation of monomeric and olefinic carbohy-
drate compounds a protective group strategy, developed
earlier by Crich et al., was successfully utilized.13 The es-
sential features of the methodology, relevant in the
present work, involves the utilization of 4,6-O-ben-
zylidene acetal and 3-O-benzyl protection of the mannose
starting material, followed by allylation of the 2-posi-
tion.14 Accordingly, several 2-O-allyl protected mannose
building blocks were prepared as illustrated in Scheme 1.
OH
HO
HO
HO
O
OH
HO
HO
HO
O
O
HO
HO
HO
O
HO
HO
HO
O
O
O
n
n
O
HO
HO
HO
O
HO
HO
HO
O
OH
OH
Figure 1 a-Linked mannan (left) and b-linked mannan (right)
Glycosylation of 1,2,3,4,6-penta-O-acetyl-D-mannopyra-
nose (1), using boron trifluoride–diethyl ether complex
(BF3·OEt2) as the promoter, with benzyl alcohol and
thiophenol, provided the corresponding benzyl (2) and
SYNTHESIS 2009, No. 4, pp 0567–0576
Advanced online publication: 27.01.2009
DOI: 10.1055/s-0028-1083283; Art ID: P10308SS
x
x
.
x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

568
F. S. Ekholm et al.
PAPER
OAc
OAc
O
by reacting the acceptors 15–17 with sodium hydride and
allylbromide in N,N-dimethylformamide (DMF), accord-
ing to procedures reported earlier for similar reactions.19
The homodimerization reactions of compounds 19–21
were carried out according to procedures reported by Das
and Roy.20 In all cases, brownish oils were first obtained,
suggesting the presence of ruthenium by-products. The re-
moval of such species has been the focus of several earlier
studies; suggested methods include the use of activated
carbon followed by flash chromatography on silica gel,
triphenylphosphine oxide bound on polymer support and
isocyanide.21–23 For the present work, the method using
activated carbon was slightly modified to provide color-
less oils or white solids after purification. It should be not-
ed that during the purification procedure, small amounts
of the desired products were likely absorbed and hence
lost during the process, thus reducing the isolated yields.
Nevertheless, good to excellent yields were obtained for
the dimerization products 22–24 (Scheme 2). In previous-
ly described reactions, the presence of sulfur-containing
substrates have been reported to decrease the yields by
poisoning the catalyst.10 In the present work, however,
such effects were not observed. Generally, E/Z ratios
ranging from 1:1 to 6:1 have been reported for homo-
dimerization reactions.10,21,24 In the present work, by
utilization of the protective group strategy described,
highly stereoselective E/Z ratios of 10:1 to 20:1 were ob-
tained. In the light of literature precedence, these findings
can be considered promising and may prove to be useful
in future exploration of diastereoselective cross-coupling
metathesis reactions in carbohydrate chemistry. In previ-
ous examples reporting similar diastereoselectivities, the
starting molecules have been tethered prior to the cross-
coupling olefin metathesis.25
AcO
AcO
AcO
AcO
AcO
AcO
O
iii
NH
CCl3
OH
4
5
O
iv
ii
OH
O
OAc
OAc
O
HO
HO
HO
AcO
AcO
AcO
AcO
AcO
AcO
i
O
v
OAc
1
R
R
2: R = OBn, 79%
3: R = SPh, 95%
6: R = OCyc, 69%
7 : R = OBn, 91%
8 : R = SPh, 96%
9 : R = OCyc, 91%
10: R = OMe
vi
OH
O
OH
O
Ph
O
Ph
vii
O
O
Ph
O
O
viii
O
O
O
BnO
BnO
HO
R
R
R
15: R = OBn, 75%
16: R = SPh, 85%
17: R = OCyc, 84%
18: R = OMe, 89%
11: R = OBn, 56%
12: R = SPh, 51%
13: R = OCyc, 57%
14: R = OMe, 52%
19: R = OBn, 100%
20: R = SPh, 100%
21: R = OCyc, 100%
Scheme 1 Synthesis of terminal olefins 19–21. Reagents and con-
ditions: (i) BF3·OEt2, corresponding alcohol, CH2Cl2, 20–48 h; (ii)
hydrazine acetate, DMF, 55 °C, 2 h, 100 %; (iii) DBU, CCl3CN,
CH2Cl2, 1.5 h, 72 %; (iv) cyclohexanol, BF3·OEt2, CH2Cl2, 22 h; (v)
NaOMe, MeOH, 24–48 h; (vi) PTSA, C6H5OCH(OMe)2, DMF,
60 °C, 2 h, 200 mbar; (vii) (1) Bu2SnO, toluene, 120 °C, 3 h; (2) TBA-
Br, CsF, BnBr, 120 °C, 3 h; (viii) NaH, allylbromide, DMF, 1–3 h.
thiophenyl (3) 2,3,4,6-tetra-O-acetyl-a-D-mannopyrano-
sides in good to excellent yields. With cyclohexanol, how-
ever, only 5% of the glycosylated product was obtained,
thus suggesting that an alternative synthetic route should
be devised. Accordingly, the cyclohexyl glycoside 6 was
prepared by utilizing the corresponding imidate15 donor 5,
which was prepared by selective deacetylation of the ano-
meric acetyl group in 1, followed by reaction with 1,8-di-
azabicyclo[5.4.0]undec-7-ene
(DBU)
and
trichloroacetonitrile.16 The coupling reaction between cy-
clohexanol and 5 was first attempted with trimethylsilyl
trifluoromethanesulfonate (TMSOTf) as the promoter,
but this resulted in poor yields (22%). Switching to
BF3·OEt2, however, led to a significant increase in the
yield (69%). Compounds 2, 3 and 6 were then deacetylat-
ed under Zemplén conditions, thereby providing the cor-
responding benzyl (7), thiophenyl (8) and cyclohexyl (9)
a-D-mannopyranosides in excellent yields.17 Next, the
glycosides 7–10 were converted into the corresponding
4,6-O-benzylidene-protected mannosides by using ben-
zaldehyde dimethyl acetal and p-toluenesulfonic acid
(PTSA) under reduced pressure in order to remove meth-
anol from the reaction mixture.13,18 The reaction proceed-
ed in moderate yields with the undesired dibenzylidene-
protected substrates formed as side products. Selective
benzylation of the 3-position was achieved by refluxing
compounds 11–14 in toluene with dibutyltin oxide
(Bu2SnO) followed by addition of benzyl bromide. The
corresponding acceptors 15–18 were obtained in yields
ranging from 75–89%, in accordance with the previously
reported results by Crich and co-workers.13 The 2-O-allyl
derivatives 19–21, required for the cross-coupling meta-
thesis reactions, were then prepared in quantitative yields
R1
R
BnO
O
R2
HO
HO
O
O
O
Ph
HO
O
O
i
ii
19–21
O
O
O
O
Ph
O
HO
HO
HO
O
R2
BnO
R1
25: R1= OH, R2 = H or
R2 = OH, R1 = H, 70%
26: R1 = OCyc, R2 = H, 70%
R
22: R = OBn, 95%, E/Z = 20:1
23: R = SPh, 74%, E/Z = 20:1
24: R = OCyc, 75%, E/Z = 10:1
Scheme 2 Synthesis of homodimerization products 25 and 26.
Reagents and conditions: (i) Grubbs I catalyst, CH2Cl2, 40 °C, 6 h; (ii)
H2 (1.4 bar), Pd/C, MeOH–EtOAc (9:1), 18 h.
Here, the stereoselectively formed double bond in the
metathesis reaction can potentially be subjected to several
types of further modifications including hydrolysis and
1,2-cis-dihydroxylation. It appears possible that the com-
bination of a 4,6-O-benzylidene acetal protecting group,
together with sterically congested or electron-rich substi-
tuents at the anomeric position, contribute to the high dia-
Synthesis 2009, No. 4, 567–576 © Thieme Stuttgart · New York

PAPER
Divalent 2,2¢-Linked Mannose Derivatives
569
BnO
stereoselectivities observed in the cross-metathesis
reaction. The results further suggest that electron-rich
groups at the anomeric position may have a larger impact
than sterically crowded ones. For the preparation of fully
deprotected analogues, the homodimerization products 22
and 24 were subjected to hydrogenolysis. Here, it was ob-
served that high hydrogen pressures (4 bar) resulted in de-
creased yields, probably due to decomposition of the 2,2¢-
linker. By lowering the pressure to 1.4 bar, the fully
deprotected compounds were obtained in good yields.
O
BnO
BnO
BnO
BnO
i, ii
O
O
BnO
RO
ref. 30
AcO
29
Ph
O
O
NH
CCl3
O
O
BnO
OMe
30: R = H
31: R = All
iii
iv
BnO
O
BnO
BnO
O
OBn
O
BnO
OBn
O
OBn
OH
O
O
O
BnO
O
O
HO
HO
HO
Ph
O
O
O
O
O
32
Ph
Ph
O
BnO
O
BnO
BnO
O
O
HO
HO
HO
O
O
OMe
O
O
OMe
OH
Ph
O
O
v
i
ii
23
27
28
HO
O
HO
O
HO
HO
O
O
Ph
O
O
HO
HO
HO
O
HO
HO
OH
O
O
O
O
O
O
O
BnO
Ph
O
HO
HO
HO
HO
O
HO
HO
HO
O
33
O
O
O
OMe
BnO
OH
OMe
OBn
Scheme 4 Synthesis of 33. Reagents and conditions: (i) 18,
TMSOTf, –10 °C, 0.5 h, 80%; (ii) MeOH–THF (3:1), NaOMe, 18 h,
98% (2 steps)30; (iii) NaH, allylbromide, DMF, 3 h, 80%; (iv) Grubbs
I catalyst, CH2Cl2, 40 °C, 6 h, 61%; (v) H2 (1.4 bar), Pd/C, MeOH–
EtOAc (9:1), 70%.
Scheme 3 Synthesis of 28. Reagents and conditions: (i) (1) 23,
TTBP, BSP, TF2O, –60 °C, 0.5 h; (2) 15, –78 °C, 2 h, 70%; (ii) H2
(1.4 bar), Pd/C, MeOH–EtOAc (9:1), 50%.
The synthesis of 1,4-bis[2-O-b-D-mannopyranosyl-
(1→2)-D-mannopyranose]butane (28) was accomplished
by coupling 2.3 equivalents of benzyl glycoside acceptors
with the divalent donor 23 (Scheme 3). For the synthesis
of b-linked mannosides, several methods have been re-
ported previously.13,26,27 The methodology developed by
Crich and co-workers has proven to be successful in sim-
ilar coupling reactions. The key features of this method
are the use 4,6-O-benzylidene acetal protecting group in
combination with a 2-O-propargyl group.13,14,20 In the
present case, the olefinic 2-O-butenyl linker could be ex-
pected to display similar properties to the 2-O-propargyl
group, thus directing the stereochemical outcome of the
glycosidation reaction in a similar fashion. Furthermore, a
coupling procedure using 1-benzenesulfinyl piperidine
(BSP)/ 2,4,6-tri-tert-butylpyrimidine (TTBP) and triflic
anhydride (TF2O) at –78 °C, was reported by Crich to be
a powerful tool for creating b-linkages between manno-
side units.28 The aforementioned concepts were success-
fully utilized in the present work for the synthesis of the
divalent b-linked disaccharide 27. To our knowledge, this
is the first example of a synthesis of b-linked mannosides
where several leaving groups are simultaneously activat-
ed in a coupling reaction. The formation of a b-linkage
was confirmed by measuring the 1JC¢,H¢ coupling constant
by NMR. A value of 155.2 Hz was obtained, thereby indi-
cating that only the b-anomer had been formed (1JC,H was
168.5 Hz). Furthermore, decreases in yield were not ob-
served, which suggests that similar strategies could also
be utilized for the synthesis of larger structures. Hydro-
genolysis of 27 according to earlier procedures resulted in
the fully deprotected substrate 28 in moderate yield.
For the preparation of methyl 2-O-allyl-3,4,6-tri-O-ben-
zyl-b-D-glucopyranosyl-(1→2)-3-O-benzyl-4,6-O-ben-
zylidene-a-D-mannopyranoside (31), a strategy utilizing
the imidate donor 2929 and acceptor 18 was selected
(Scheme 4) to provide, after the coupling reaction and
deacetylation, the disaccharide 30 with a free 2¢-hydroxy
group.30 Employing methods described previously, the
disaccharide 30 was converted into the corresponding 2¢-
O-allyl ether derivative in 80% yield. The slightly lower
yield, in comparison with the allylation of monosaccha-
rides, may be explained by steric hindrance. Next, the ho-
modimerization of 31 was carried out as described earlier,
providing compound 32 in moderate yields and high dia-
stereoselectivity, suggesting that large substituents at the
anomeric position have an impact on the diastereoselec-
tive outcome of the homodimerization reaction. The
slightly lower yield is possibly due to severe steric hin-
drance in this molecule. Hydrogenolysis of 32 gave 1,4-
bis[methyl-a-D-mannopyranosyl-(2→1)-2-O-b-D-gluco-
pyranosyl]butane in good yield.
To conclude, a protective group strategy allowing highly
diastereoselective homodimerization reactions of carbo-
hydrates has been utilized. The key features of this strate-
gy involve the use of electron-rich substituents at the
anomeric position in combination with a 4,6-O-ben-
zylidene acetal. Furthermore, it has been shown that sev-
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570
F. S. Ekholm et al.
PAPER
washed with sat. NaHCO3 (100 mL). The organic phase was sepa-
rated and 1 M NaOH (100 mL) was added. Stirring was continued
for 1 h, then the organic phase was separated and washed with sat.
NaHCO3 (100 mL) and 1 M NaOH (100 mL). The organic phase
was dried with anhydrous MgSO4, filtered and concentrated to give
3.
eral leaving groups can be activated and coupled
simultaneously without losses in selectivity or yield. Fu-
ture work in this area may be directed towards expanding
the scope of these strategies into the field of oligosaccha-
ride synthesis and cross-coupling olefin metathesis reac-
tions. Modified strategies might prove to be powerful
tools for the synthesis of diverse neoglycoconjugates.31 In
the present work, several divalent carbohydrate deriva-
tives were prepared. These compounds may potentially
show biological activities and could be screened, for ex-
ample, against C. albicans or cyanovirin-N.
Yield: 11.92 g (95%); yellowish oil; Rf = 0.49 (hexane–EtOAc,
1:1).
1H NMR (600 MHz, CDCl3): d = 7.50–5.30 (m, 5 H, ArH), 5.50 (dd,
J1,2 = 1.6 Hz, J2,3 = 3.2 Hz, 1 H, H-2), 5.50 (d, 1 H, H-1), 5.33 (dd,
J4,5 = 9.8 Hz, J3,4 = 9.9 Hz, 1 H, H-4), 5.32 (dd, 1 H, H-3), 4.55
(ddd, J5,6a = 2.3 Hz, J5,6b = 5.9 Hz, 1 H, H-5), 4.31 (dd, J6a,6b = –12.3
Hz, 1 H, H-6b), 4.11 (dd, 1 H, H-6a), 2.16, 2.08, 2.06, 2.02 (s, 12 H,
4 × OCCH3).
13C NMR (150 MHz, CDCl3): d = 170.6, 169.9, 169.8 (OCCH3),
132.1–129.2 (Ar), 85.7 (C-1), 70.9 (C-2), 69.5 (C-5), 69.4 (C-3),
66.4 (C-4), 62.4 (C-6), 20.9, 20.7 (OCCH3).
HRMS: m/z [M + Na]+ calcd for C20H24O9SNa: 463.1033; found:
463.1039.
HRMS: m/z [M + K]+ calcd for C20H24O9SK: 479.0798; found:
479.0791.
1
The H and 13C NMR spectra as well as the COSY, HSQC and
HMBC experiments were recorded at 25 °C with a Bruker AV 600
MHz spectrometer. Chemical shifts (d) are reported downfield from
TMS with residual CHCl3 or MeOH as internal reference. HRMS
were recorded using either a Bruker Micro Q-TOF with ESI (elec-
trospray ionization) operated in the positive mode, or a Fison Zab-
SpecOaTOF with EI (electron impact) ionization operated in the
positive mode. Optical rotations were measured with a Perkin–Elm-
er 241 polarimeter equipped with a Na-lamp (589 nm). TLC was
performed on aluminum sheets precoated with silica gel 60 F254
(Merck). Spots were visualized by UV followed by charring with
1:10 H2SO4/MeOH and burning with a heat gun. Preparative TLC
was performed on aluminum sheets precoated with silica gel 60 F254
(0.5 cm). Spots were visualized according to the earlier procedure.
Flash chromatography was carried out on silica gel 60 (0.040–0.060
mm, Merck) with different solvent systems based on differences in
structure. LC-MS analyses were carried out using an Agilent 1100
series LC/MSD Trap SL instrument equipped with an ESI source,
operated in the positive mode. HPLC purifications were performed
on an Agilent 1100 series liquid chromatographic system. Reaction
solvents were dried and distilled under argon before use. All reac-
tions containing sensitive reagents were carried out under an argon
atmosphere. Compounds 1 and 10 were obtained from commercial
sources. Compounds 3–5, 8, 11, 12, 15 and 16 have previously been
reported in the literature, however, to our knowledge, fully charac-
terized NMR data for these compounds are presented here for the
first time.13,32–34
2,3,4,6-Tetra-O-acetyl-D-mannopyranose (4)33
To a solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose (1.87
g, 4.78 mmol) in DMF (28 mL), was added hydrazine acetate (1.12
equiv). The reaction mixture was stirred at 55 °C for 2 h, then
cooled to r.t., diluted with EtOAc (80 mL) and extracted with sat.
NaHCO3 (60 mL). The resulting mixture was filtered through Celite
and the organic layer was separated. The organic layer was washed
with brine (50 mL) and H2O (2 × 50 mL), dried with anhydrous
MgSO4, filtered and concentrated to give 4.
Yield: 1.67 g (100% total; 86% a, 14% b); yellowish oil; Rf = 0.37
(hexane–EtOAc, 1:1).
1H NMR (600 MHz, CDCl3): d (a-anomer) = 5.43 (dd, J2,3 = 3.4 Hz,
J3,4 = 10.1 Hz, 1 H, H-3), 5.31 (dd, J4,5 = 10.1 Hz, 1 H, H-4), 5.29
(dd, J1,2 = 1.9 Hz, 1 H, H-2), 5.26 (d, 1 H, H-1), 4.27 (dd, J5,6b = 5.2
Hz, J6a,6b = –12.2 Hz, 1 H, H-6b), 4.24 (ddd, J5,6a = 2.3 Hz, 1 H, H-
5), 4.15 (dd, 1 H, H-6a), 2.17, 2.11, 2.06, 2.01 (s, 12 H, 4 × OCCH3).
13C NMR (150 MHz, CDCl3): d (a-anomer) = 170.7, 170.1, 169.9,
169.8 (OCCH3), 92.3 (C-1), 69.9 (C-2), 68.7 (C-3, C-5), 66.1 (C-4),
62.6 (C-6), 20.9, 20.8, 20.7 (OCCH3).
Benzyl 2,3,4,6-Tetra-O-acetyl-a-D-mannopyranoside (2)30
To a stirred solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose
(4.5 g, 12.73 mmol) and 4 Å MS (1 g) in CH2Cl2 (40 mL), was add-
ed BnOH (4 equiv). The reaction mixture was stirred for 20 min,
then cooled with an ice bath and BF3·OEt2 (8 equiv) was added
dropwise. The resulting mixture was stirred for 15 min, then
brought to r.t. and stirring was continued for 48 h. The reaction mix-
ture was diluted with CH2Cl2 (100 mL) and poured into ice-cold
H2O (200 mL) with stirring. The organic phase was separated and
washed with sat. NaHCO3 (100 mL), H2O (100 mL) and brine (100
mL). The organic phase was dried with anhydrous MgSO4, filtered
and concentrated. The crude product was purified by flash chroma-
tography (hexane–EtOAc, 3:1) to give 2.
HRMS: m/z [M + Na]+ calcd for C14H20O10Na: 371.0949; found:
371.0942.
2,3,4,6-Tetra-O-acetyl-a-D-mannopyranose Trichloroacetimi-
date (5)33
To a solution of 4 (1.7 g, 4.78 mmol) in CH2Cl2 (25 mL), was added
DBU (0.13 equiv) and CCl3CN (1.17 equiv) at 0 °C. The reaction
mixture was brought to r.t. and stirring was continued for 1.5 h. The
reaction mixture was diluted with CH2Cl2 (30 mL), washed with
brine (30 mL), dried with anhydrous Na2SO4, filtered and concen-
trated. The crude product was purified by flash chromatography
(hexane–EtOAc, 2:1 + 0.1% Et3N) to give 5.
Yield: 4.4 g (79%); colorless oil.
Yield: 2.0 g (72%); yellowish oil; Rf = 0.58 (hexane–EtOAc, 1:1).
Phenyl 2,3,4,6-Tetra-O-acetyl-1-thio-a-D-mannopyranoside
(3)13
1H NMR (600 MHz, CDCl3): d = 8.79 (s, 1 H, NH), 6.29 (d,
J1,2 = 2.0 Hz, 1 H, H-1), 5.48 (dd, J2,3 = 3.2 Hz, 1 H, H-2), 5.41 (dd,
J3,4 = 10.1 Hz, 1 H, H-3), 5.40 (dd, J4,5 = 10.0 Hz, 1 H, H-4), 4.28
(dd, J5,6b = 5.0 Hz, J6a,6b = –12.4 Hz, 1 H, H-6b), 4.19 (ddd,
J5,6a = 2.4 Hz, 1 H, H-5), 4.17 (dd, 1 H, H-6a), 2.20, 2.10, 2.07, 2.01
(s, 12 H, OCCH3).
To a stirred solution of 1,2,3,4,6-penta-O-acetyl-D-mannopyranose
(11.17 g, 28.61 mmol) and 4 Å MS (1 g) in CH2Cl2 (200 mL), was
added thiophenol (1.5 equiv). The reaction mixture was stirred for
20 min, then cooled with an ice bath and BF3·OEt2 (5 equiv) was
added dropwise. The resulting mixture was stirred for 15 min, then
brought to r.t. and stirring was continued for 20 h. The reaction mix-
ture was diluted with CH2Cl2 (100 mL) and poured into ice-cold
H2O (150 mL) with stirring. The organic phase was separated and
13C NMR (150 MHz, CDCl3): d = 170.6, 169.8, 169.7, 169.6
(OCCH3), 159.8 (CNH), 94.5 (C-1), 77.2–76.8 (CCl3, overlapped
Synthesis 2009, No. 4, 567–576 © Thieme Stuttgart · New York

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Divalent 2,2¢-Linked Mannose Derivatives
571
with CDCl3), 71.2 (C-5), 68.8 (C-3), 67.8 (C-2), 65.4 (C-4), 62.0
(C-6), 20.8, 20.7, 20.7, 20.6 (OCCH3).
Yield: 0.23 g (91%); white foam; Rf = 0.42 (CH2Cl2–MeOH, 4:1);
[a]D23 +93.5 (c 1, MeOH).
HRMS: m/z [M + Na]+ calcd for C16H20Cl3NO10Na: 514.0045;
found: 514.0029.
1H NMR (600 MHz, CD3OD): d = 4.89 (d, J1,2 = 1.8 Hz, 1 H, H-1),
3.80 (dd, J5,6a = 2.2 Hz, J6a,6b = –11.8 Hz, 1 H, H-6a), 3.73 (dd,
J2,3 = 3.4 Hz, 1 H, H-2), 3.70 (dd, J5,6b = 5.6 Hz, 1 H, H-6b), 3.70
(dd, J3,4 = 9.2 Hz, H-3), 3.70–3.62 (m, 1 H, OCHC5H10), 3.60 (ddd,
J4,5 = 9.3 Hz, 1 H, H-5), 3.60 (dd, 1 H, H-4), 1.93–1.70 (m, 4 H,
OCHC5H10), 1.58–1.2 (m, 6 H, OCHC5H10).
13C NMR (150 MHz, CD3OD): d = 99.4 (C-1), 75.8 (OCHC5H10),
74.7 (C-5), 72.8 (C-2), 72.7 (C-3), 68.8 (C-4), 63.0 (C-6), 34.5,
32.4, 26.9, 25.1, 24.9 (OCHC5H10).
Cyclohexyl 2,3,4,6-Tetra-O-acetyl-a-D-mannopyranoside (6)
To a solution of 5 (0.84 g, 1.70 mmol) in CH2Cl2 (10 mL) and 4 Å
MS (0.4 g), was added cyclohexanol (5.4 equiv). The reaction mix-
ture was stirred for 30 min, cooled on an ice bath and BF3·OEt2 (10.9
equiv) was added dropwise. The reaction mixture was brought to r.t.
and stirring was continued for 21.5 h. The reaction was neutralized
with Et3N, filtered and concentrated. The crude product was puri-
fied by flash chromatography (hexane–EtOAc, 4:1→3:1) to give 6.
HRMS: m/z [M + Na]+ calcd for C12H22O6Na: 285.1314; found:
285.1321.
Yield: 0.5 g (69%); colorless oil; Rf = 0.62 (hexane–EtOAc, 1:1);
[a]D23 +32.5 (c 1, CH2Cl2).
Synthesis of 4,6-O-Benzylidene-a-D-mannopyranosides; Gener-
al Procedure
1H NMR (600 MHz, CDCl3): d = 5.38 (dd, J2,3 = 3.5 Hz, J3,4 = 10.0
Hz, 1 H, H-3), 5.27 (dd, J4,5 = 10.2 Hz, 1 H, H-4), 5.19 (dd,
J1,2 = 1.8 Hz, 1 H, H-2), 4.96 (d, 1 H, H-1), 4.26 (dd, J5,6b = 5.5 Hz,
J6a,6b = –12.2 Hz, 1 H, H-6b), 4.12 (dd, J5,6a = 2.3 Hz, 1 H, H-6a),
4.08 (ddd, 1 H, H-5), 3.64–3.55 (m, 1 H, OCHC5H10), 2.16, 2.10,
2.05, 1.99 (s, 12 H, OCCH3), 1.90–1.71 (m, 4 H, OCHC5H10), 1.55–
1.23 (m, 6 H, OCHC5H10).
13C NMR (150 MHz, CDCl3): d = 170.7, 170.2, 170.0, 169.8
(OCCH3), 95.9 (C-1), 76.8 (OCHC5H10), 70.3 (C-2), 69.2 (C-3),
68.4 (C-5), 66.4 (C-4), 62.6 (C-6), 33.2, 31.4, 25.5, 24.1, 23.8
(OCHC5H10), 21.0, 20.8 (OCCH3).
To a solution of the corresponding deacetylated compound in DMF
(1 mL/40 mg deacetylated compound) was added PTSA (10 mol%)
and benzaldehyde dimethyl acetal (1 equiv). The reaction mixture
was stirred at 60 °C and 200 mbar for 2 h, concentrated and the res-
idue was dissolved in EtOAc (15 mL). The organic phase was
washed with sat. NaHCO3 (10 mL) and H2O (2 × 10 mL) and the
combined aqueous phase was extracted with EtOAc (2 × 15 mL).
The combined organic phase was washed with brine (15 mL), dried
with anhydrous MgSO4, filtered and concentrated. The crude prod-
uct was purified by flash chromatography (CH2Cl2–MeOH,
1:0→5:1) to give the corresponding 4,6-O-benzylidene-a-D-man-
nopyranoside.
HRMS: m/z [M]+ calcd for C20H31O10: 431.1917; found: 431.1886.
Benzyl 4,6-O-Benzylidene-a-D-mannopyranoside (11)32
Synthesized from 7 (0.37 g, 1.4 mmol) according to the general pro-
cedure for the synthesis of 4,6-O-benzylidene-a-D-mannopyrano-
sides.
Deacetylation; General Procedure
To a solution of the acetylated compound in MeOH (1 mL/100 mg
of acetylated compound), was added 5.4 M NaOMe (0.5 equiv per
acetyl group). The reaction mixture was stirred for 24–48 h, neutral-
ized with DOWEX 50 (H+ form), filtered and concentrated. The
crude product was purified by flash chromatography (CH2Cl2–
MeOH, 1:0→5:1) to give the corresponding deacetylated com-
pound.
Yield: 0.27 g (56%); white solid; Rf = 0.06 (CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.50–7.32 (m, 10 H, ArH), 5.58
(s, 1 H, CHPh), 4.98 (d, J1,2 = 1.5 Hz, 1 H, H-1), 4.75 and 4.54 (2 ×
d, J = –11.9 Hz, 2 × 1 H, CH2Ph), 4.27 (dd, J5,6a = 5.0 Hz, J6a,6b
=
Benzyl a-D-Mannopyranoside (7)30,34
Synthesized from 2 (0.7 g, 1.60 mmol) according to the general pro-
cedure for deacetylation, to give 7 with analytical data in agreement
with those previously reported.
–10.4 Hz, 1 H, H-6a), 4.15 (ddd, J3,3-OH = 0.4 Hz, J2,3 = 3.5 Hz,
J3,4 = 9.6 Hz, 1 H, H-3), 4.11 (ddd, J2,2-OH = 1.2 Hz, 1 H, H-2), 3.95
(dd, J4,5 = 9.5 Hz, 1 H, H-4), 3.90 (ddd, J5,6b = 10.3 Hz, 1 H, H-5),
3.84 (dd, 1 H, H-6b), 2.59 (d, 1 H, 3-OH), 2.56 (d, 1 H, 2-OH).
Yield: 0.39 g (91%); white crystals.
13C NMR (150 MHz, CDCl3): d = 137.2–126.2 (Ar), 102.3 (CHPh),
99.3 (C-1), 78.9 (C-4), 71.0 (C-2), 69.5 (CH2Ph), 68.8 (C-6), 68.7
(C-3), 63.2 (C-5).
HRMS: m/z [M + Na]+ calcd for C20H22O6Na: 381.1309; found:
381.1316.
Phenyl 1-Thio-a-D-mannopyranoside (8)13
Synthesized from 3 (11.92 g, 27.10 mmol) according to the general
procedure for deacetylation.
Yield: 7.10 g (96%); yellowish oil; Rf = 0.29 (MeOH–CHCl3, 1:5).
Phenyl 4,6-O-Benzylidene-1-thio-a-D-mannopyranoside (12)13
Synthesized from 8 (7.09 g, 26.1 mmol) according to the general
procedure for synthesis of 4,6-O-benzylidene-a-D-mannopyrano-
sides, to give compound 12 with analytical data in agreement with
those previously reported.
1H NMR (600 MHz, CD3OD): d = 7.53–7.25 (m, 5 H, ArH), 5.42
(dd, J1,2 = 1.6 Hz, 1 H, H-1), 4.08 (dd, J2,3 = 3.3 Hz, 1 H, H-2), 4.03
(ddd, J5,6a = 2.4 Hz, J5,6b = 5.6 Hz, J4,5 = 9.8 Hz, 1 H, H-5), 3.81 (dd,
J6a,6b = –12.0 Hz, 1 H, H-6a), 3.76 (dd, 1 H, H-6b), 3.72 (dd,
J3,4 = 9.5 Hz, 1 H, H-4), 3.68 (dd, 1 H, H-3).
Yield: 4.80 g (51%); white solid.
13C NMR (150 MHz, CD3OD): d = 136.0–128.6 (Ar), 90.6 (C-1),
75.7 (C-5), 73.8 (C-2), 73.2 (C-3), 68.8 (C-4), 62.7 (C-6).
Cyclohexyl 4,6-O-Benzylidene-a-D-mannopyranoside (13)
Synthesized from 9 (0.073 g, 0.28 mmol) according to the general
procedure for synthesis of 4,6-O-benzylidene-a-D-mannopyrano-
sides.
HRMS: m/z [M + Na]+ calcd for C12H16O5SNa: 295.0611; found:
295.0603.
HRMS: m/z [M + K]+ calcd for C12H16O9SK: 311.0350; found:
Yield: 0.057 g (57%); colorless oil; Rf = 0.06 (CHCl3); [a]D23 +70.5
(c 1, CH2Cl2).
1H NMR (600 MHz, CDCl3): d = 7.51–7.36 (m, 5 H, ArH), 5.58 (s,
1 H, CHPh), 5.03 (d, J1,2 = 1.5 Hz, 1 H, H-1), 4.27 (dd, J5,6a = 4.8
Hz, J6a,6b = –10.4 Hz, 1 H, H-6a), 4.13 (ddd, J3,3-OH = 3.4 Hz,
311.0348.
Cyclohexyl a-D-Mannopyranoside (9)
Synthesized from 6 (0.41 g, 0.96 mmol) according to the general
procedure for deacetylation.
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572
F. S. Ekholm et al.
PAPER
J2,3 = 3.5 Hz, J3,4 = 9.5 Hz, 1 H, H-3), 4.02 (ddd, J2,2-OH = 2.4 Hz,
1 H, H-2), 3.93 (dd, J4,5 = 8.9 Hz, 1 H, H-4), 3.92 (ddd, J5,6b = 10.1
Hz, 1 H, H-5), 3.82 (dd, 1 H, H-6b), 3.67–3.58 (m, 1 H,
OCHC5H10), 2.57 (d, 1 H, 2-OH), 2.54 (d, 1 H, 3-OH), 1.95–1.80
(m, 2 H, OCHC5H10), 1.78–1.68 (m, 2 H, OCHC5H10), 1.56–1.18
(m, 6 H, OCHC5H10).
13C NMR (150 MHz, CDCl3): d = 137.3–126.2 (Ar), 102.2 (CHPh),
98.0 (C-1), 79.2 (C-4), 75.3 (OCHC5H10), 71.6 (C-2), 68.9 (C-6),
68.8 (C-3), 63.0 (C-5), 33.4, 31.3, 25.6, 24.0, 23.8 (OCHC5H10).
J = –11.8 Hz, 2 × 1 H, CH2Ph), 4.34 (ddd, J5,6a = 4.9 Hz, J4,5 = 9.6
Hz, J5,6b = 10.2 Hz, 1 H, H-5), 4.29 (ddd, J2,2-OH = 1.4 Hz, J2,3 = 3.4
Hz, 1 H, H-2), 4.21 (dd, J6a,6b = –10.4 Hz, 1 H, H-6a), 4.18 (dd,
J3,4 = 9.6 Hz, 1 H, H-4), 3.97 (dd, 1 H, H-3), 3.86 (dd, 1 H, H-6b),
2.82 (d, 1 H, 2-OH).
13C NMR (150 MHz, CDCl3): d = 137.7–126.1 (Ar), 101.6 (CHPh),
87.8 (C-1), 79.0 (C-4), 75.7 (C-3), 73.2 (CH2Ph), 71.4 (C-2), 68.5
(C-6), 64.6 (C-5).
HRMS: m/z [M + Na]+ calcd for C26H26O5SNa: 473.1393; found:
473.1403.
HRMS: m/z [M + Na]+ calcd for C19H26O6Na: 373.1622; found:
373.1632.
Cyclohexyl 3-O-Benzyl-4,6-O-benzylidene-a-D-mannopyrano-
side (17)
Synthesized from 13 (0.13 g, 0.37 mmol) according to the general
procedure for synthesis of 3-O-benzyl-4,6-O-benzylidene-a-D-
mannopyranosides.
Methyl 4,6-O-Benzylidene-a-D-mannopyranoside (14)32
Synthesized from methyl a-D-mannopyranoside (3.0 g, 15.5 mmol)
according to the general procedure for synthesis of 4,6-O-ben-
zylidene-a-D-mannopyranosides, to give compound 14 with analyt-
ical data in agreement with those previously reported.
Yield: 0.14 g (84%); colorless oil; Rf = 0.64 (hexane–EtOAc, 1:1);
[a]D23 +49.5 (c 1, CH2Cl2).
Yield: 2.27 g (52%); colorless oil.
1H NMR (600 MHz, CDCl3): d = 7.52–7.30 (m, 10 H, ArH), 5.62
Synthesis of 3-O-Benzyl-4,6-O-benzylidene-a-D-mannopyrano-
sides; General Procedure
(s, 1 H, CHPh), 5.03 (d, J1,2 = 1.5 Hz, 1 H, H-1), 4.88 and 4.73 (2 ×
d, J = –11.7 Hz, 2 × 1 H, CH2Ph), 4.27 (dd, J5,6a = 4.9 Hz, J6a,6b
=
To a solution of the corresponding 4,6-O-benzylidene-a-D-man-
nopyranoside in toluene (4 mL/100 mg starting material), was add-
ed Bu2SnO (1 equiv). The reaction mixture was refluxed for 3 h,
cooled to r.t. then TBABr (1.05 equiv), CsF (1.02 equiv) and BnBr
(1.04 equiv) were added. The resulting mixture was refluxed for 3
h, cooled to r.t., diluted with EtOAc (40 mL) and sat. NaHCO3 (30
mL) and filtered through Celite. The organic phase was separated
and the aqueous phase was extracted with EtOAc (3 × 30 mL). The
combined organic phase was washed with H2O (40 mL), brine (30
mL), dried with anhydrous Na2SO4, filtered and concentrated. The
crude product was purified by flash chromatography (hexane–
EtOAc, 4:1) to give the corresponding 3-O-benzyl-4,6-O-ben-
zylidene-a-D-mannopyranoside.
–10.4 Hz, 1 H, H-6a), 4.10 (dd, J3,4 = 9.6 Hz, J4,5 = 9.7 Hz, 1 H, H-
4), 4.04 (ddd, J2,2-OH = 1.4 Hz, J2,3 = 3.4 Hz, 1 H, H-2), 3.97 (dd,
1 H, H-3), 3.93 (ddd, J5,6b = 10.4 Hz, 1 H, H-5), 3.85 (dd, 1 H, H-
6b), 3.65–3.55 (m, 1 H, OCHC5H10), 2.63 (d, 1 H, 2-OH), 1.86–
1.71 (m, 4 H, OCHC5H10), 1.58–1.23 (m, 6 H, OCHC5H10).
13C NMR (150 MHz, CDCl3): d = 138.1–126.0 (Ar), 101.5 (CHPh),
97.8 (C-1), 79.1 (C-4), 75.8 (C-3), 75.2 (OCHC5H10), 73.1 (CH2Ph),
70.6 (C-2), 68.9 (C-6), 63.3 (C-5), 33.4, 31.3, 25.6, 24.1, 23.8
(OCHC5H10).
HRMS: m/z [M]+ calcd for C26H32O6: 440.2198; found: 440.2199.
Methyl 3-O-Benzyl-4,6-O-benzylidene-a-D-mannopyranoside
(18)32
Synthesized from 14 (0.10 g, 0.35 mmol) according to the general
procedure for synthesis of 3-O-benzyl-4,6-O-benzylidene-a-D-
mannopyranosides, to give 18 with analytical data in agreement
with those previously reported.
Benzyl 3-O-Benzyl-4,6-O-benzylidene-a-D-mannopyranoside
(15)32
Synthesized from 11 (0.64 g, 1.77 mmol) according to the general
procedure for synthesis of 3-O-benzyl-4,6-O-benzylidene-a-D-
mannopyranosides.
Yield: 0.12 g (89%); colorless oil.
Yield: 0.65 g (75%); colorless oil; Rf = 0.55 (hexane–EtOAc, 1:1);
[a]D23 +55.9 (c 1, CH2Cl2).
Synthesis of 2-O-Allyl-3-O-benzyl-4,6-O-benzylidene-a-D-man-
nopyranosides; General Procedure
1H NMR (600 MHz, CDCl3): d = 7.51–7.28 (m, 15 H, ArH), 5.63
(s, 1 H, CHPh), 4.97 (d, J1,2 = 1.5 Hz, 1 H, H-1), 4.86 and 4.72 (2 ×
d, J = –11.8 Hz, 2 × 1 H, CH2Pha), 4.71 and 4.52 (2 × d, J = –11.8
Hz, 2 × 1 H, CH2Phb), 4.27 (dd, J5,6a = 4.9 Hz, J6a,6b = –10.3 Hz,
1 H, H-6a), 4.12 (dd, J4,5 = 9.5 Hz, J3,4 = 9.6 Hz, 1 H, H-4), 4.11
(ddd, J2,2-OH = 1.4 Hz, J2,3 = 3.5 Hz, 1 H, H-2), 3.98 (dd, 1 H, H-3),
3.91 (ddd, J5,6b = 10.5 Hz, 1 H, H-5), 3.87 (dd, 1 H, H-6b), 2.65 (d,
1 H, 2-OH).
13C NMR (150 MHz, CDCl3): d = 138.0–126.0 (Ar), 101.6 (CHPh),
99.2 (C-1), 78.9 (C-4), 75.7 (C-3), 73.1 (CH2Pha), 70.1 (C-2), 69.4
(CH2Phb), 68.9 (C-6), 63.5 (C-5).
HRMS: m/z [M + Na]+ calcd for C27H28O6Na: 471.1778; found:
471.1765.
To a solution of the corresponding 3-O-benzyl-4,6-O-benzylidene-
a-D-mannopyranoside in DMF (2 mL/100 mg starting material),
was added NaH (1.9 equiv) at 0 °C. The reaction mixture was
stirred for 15 min, then brought to r.t., stirred for 10 min then allyl-
bromide (1.5 equiv) was added. The resulting mixture was stirred
for 1–3 h, quenched with MeOH (0.4 mL/mmol starting material),
diluted with CH2Cl2 (30 mL) and washed with sat. NaHCO3 (30
mL). The organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (3 × 30 mL). The combined organic phase
was washed with brine (30 mL), dried with anhydrous Na2SO4, fil-
tered and concentrated. The crude product was purified by flash
chromatography (hexane–EtOAc, 8:1) to give the corresponding 2-
O-allyl-3-O-benzyl-4,6-O-benzylidene-a-D-mannopyranoside.
Phenyl 3-O-Benzyl-4,6-O-benzylidene-1-thio-a-D-mannopyra-
noside (16)13
Synthesized from 12 (2.59 g, 7.20 mmol) according to the general
procedure for synthesis of 3-O-benzyl-4,6-O-benzylidene-a-D-
mannopyranosides.
Benzyl 2-O-Allyl-3-O-benzyl-4,6-O-benzylidene-a-D-mannopy-
ranoside (19)33
Synthesized from 15 (0.18 g, 0.39 mmol) according to the general
procedure for synthesis of 2-O-allyl-3-O-benzyl-4,6-O-ben-
zylidene-a-D-mannopyranosides.
Yield: 2.90 g (85%); colorless oil; Rf = 0.65 (hexane–EtOAc, 1:1).
Yield: 0.21 g (100%); white crystals; Rf = 0.84 (hexane–EtOAc,
1:1); [a]D23 +66.6 (c 1, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.52–7.28 (m, 15 H, Ph), 5.63 (s,
1 H, CHPh), 5.60 (d, J1,2 = 1.2 Hz, 1 H, H-1), 4.90 and 4.75 (2 × d,
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Divalent 2,2¢-Linked Mannose Derivatives
573
1H NMR (600 MHz, CDCl3): d = 7.50–7.27 (m, 15 H, ArH), 5.90
[dddd, JCH2a,CH = 6.0 Hz, JCH2b,CH = 6.2 Hz, JCH,CH2(cis) = 10.3 Hz,
JCH,CH2(trans) = 17.2 Hz, 1 H, CH2CHCH2], 5.63 (s, 1 H, CHPh), 5.26
[dddd, JCH2a,CH2(trans) = –1.5 Hz, JCH2b,CH2(trans) = –1.5 Hz,
JCH2(trans),CH2(cis) = –1.7 Hz, 1 H, CH2CHCH2(trans)], 5.17 [dddd,
JCH2a,CH2(cis) = –1.1 Hz, JCH2b,CH2(cis) = –1.2 Hz, 1 H, CH2CHCH2(cis)],
4.90 (d, J1,2 = 1.7 Hz, 1 H, H-1), 4.87 and 4.70 (2 × d, J = –12.1 Hz,
2 × 1 H, CH2Pha), 4.72 and 4.49 (2 × d, J = –11.9 Hz, 2 × 1 H,
CH2Phb), 4.25 (dddd, JCH2a,CH2b = –12.9 Hz, 1 H, CH2bCHCH2),
4.24 (dd, J5,6a = 4.7 Hz, J6a,6b = –10.2 Hz, 1 H, H-6a), 4.21 (dd,
J4,5 = 9.2 Hz, J3,4 = 10.0 Hz, 1 H, H-4), 4.15 (dddd, 1 H,
CH2aCHCH2), 4.01 (dd, J2,3 = 3.2 Hz, 1 H, H-3), 3.88 (dd,
J5,6b = 10.4 Hz, 1 H, H-6b), 3.85 (ddd, 1 H, H-5), 3.82 (dd, 1 H, H-2).
CH2aCHCH2), 4.24 (dd, J5,6a = 4.8 Hz, J6a,6b = –10.2 Hz, 1 H, H-6a),
4.18 (dd, J4,5 = 9.2 Hz, J3,4 = 10.0 Hz, 1 H, H-4), 4.17 (dddd, 1 H,
CH2bCH=CH2), 3.99 (dd, J2,3 = 3.2 Hz, 1 H, H-3), 3.87 (ddd,
J5,6b = 10.5 Hz, 1 H, H-5), 3.85 (dd, 1 H, H-6b), 3.74 (dd, 1 H, H-2),
3.61–3.53 (m, 1 H, OCHC5H10), 1.89–1.65 (m, 4 H, OCHC5H10),
1.58–1.20 (m, 6 H, OCHC5H10).
13C NMR (150 MHz, CDCl3): d = 138.8–126.0 (Ar), 135.0
(CH2CHCH2), 117.6 (CH2CHCH2), 101.3 (CHPh), 97.5 (C-1), 79.4
(C-4), 78.2 (C-2), 76.5 (C-3), 75.1 (OCHC5H10), 73.2 (CH2Ph), 73.1
(CH2CHCH2), 68.9 (C-6), 64.2 (C-5), 33.3, 31.3, 25.6, 24.0, 23.8
(OCHC5H10).
HRMS: m/z [M + H]+ calcd for C29H38O6: 481.2585; found:
481.2574.
HRMS: m/z [M + Na]+ calcd for C29H37O6Na: 503.2404; found:
503.2386.
13C NMR (150 MHz, CDCl3): d = 138.7–126.0 (Ar), 134.8
(CH2CHCH2), 117.8 (CH2CHCH2), 101.4 (CHPh), 98.9 (C-1), 79.2
(C-4), 76.6 (C-2), 76.3 (C-3), 73.3 (CH2Pha), 73.1 (CH2CHCH2),
69.3 (CH2Phb), 68.8 (C-6), 64.4 (C-5).
HRMS: m/z [M + K]+ calcd for C29H37O6K: 519.2143; found:
519.2120.
HRMS: m/z [M + Na]+ calcd for C30H32O6Na: 511.2091; found:
511.2103.
Homodimerization of Olefins; General Procedure
To a solution of the terminal olefin in CH2Cl2 (1 mL/100 mg of ole-
fin), was added Grubbs I catalyst (10 mol%). The reaction mixture
was refluxed for 6 h, cooled to r.t. and concentrated. The crude
product was purified by flash chromatography (hexane–EtOAc,
8:1→1:1) to give a brownish oil. The resulting product was diluted
with CH2Cl2 (10 mL) and activated carbon (10 weight%) was add-
ed. The resulting mixture was stirred for 19.5 h, filtered through
Celite, purified by flash chromatography (hexanes–EtOAc,
3:1→1:1)) and concentrated to give the corresponding divalent
compound.
Phenyl 2-O-Allyl-3-O-benzyl-4,6-O-benzylidene-1-thio-a-D-
mannopyranoside (20)13
Synthesized from 16 (0.16 g, 0.35 mmol) according to the general
procedure for synthesis of 2-O-allyl-3-O-benzyl-4,6-O-ben-
zylidene-a-D-mannopyranosides.
Yield: 0.18 g (100%); colorless oil; Rf = 0.93 (hexane–EtOAc, 1:1);
[a]D23 +145.2 (c 1, CHCl3).
1H NMR (600 MHz, CDCl3): d = 7.52–7.27 (m, 15 H, ArH), 5.92
[dddd, JCH2a,CH = 5.8 Hz, JCH2b,CH = 5.9 Hz, JCH,CH2(cis) = 10.3 Hz,
JCH,CH2(trans) = 17.2 Hz, 1 H, CH2CHCH2], 5.64 (s, 1 H, CHPh), 5.53
(d, J1,2 = 1.5 Hz, 1 H, H-1), 5.29 [dddd, JCH2a,CH2(trans) = –1.5 Hz,
JCH2b,CH2(trans) = –1.5 Hz, JCH2(trans),CH2(cis) = –1.7 Hz, 1 H,
1,4-Bis(benzyl-3-O-benzyl-4,6-O-benzylidene-2-O-a-D-man-
nopyranosyl)but-2-ene (22)
CH2CHCH2(trans)],
5.20
[dddd,
JCH2a,CH2(cis) = –1.2
Hz,
Synthesized from 19 (0.13 g, 0.26 mmol) according to the general
procedure for homodimerization of olefins.
JCH2b,CH2(cis) = –1.2 Hz, 1 H, CH2CHCH2(cis)], 4.88 and 4.73 (2 × d,
J = –12.2 Hz, 2 × 1 H, CH2Ph), 4.29 (ddd, J5,6a = 4.8 Hz, J4,5 = 9.5
Hz, J5,6b = 10.0 Hz, 1 H, H-5), 4.26 (dd, J3,4 = 9.9 Hz, 1 H, H-4),
Yield: 0.12 g (95%); white foam; Rf = 0.81 (hexane–EtOAc, 1:1);
E/Z = 20:1.
4.22 (dd, J6a,6b = –10.3 Hz, 1 H, H-6a), 4.20 (dddd, JCH2a,CH2b
=
1H NMR (600 MHz, CDCl3): d (E-isomer) = 7.50–7.23 (m, 30 H,
ArH), 5.79–5.78 (m, 2 H, OCH2CHCHCH2O), 5.61 (s, 2 H, CHPh),
4.89 (d, J1,2 = 1.7 Hz, 2 H, H-1), 4.85 and 4.68 (2 × d, J = –12.1 Hz,
2 × 2 H, CH2Pha), 4.70 and 4.47 (2 × d, J = –11.9 Hz, 2 × 2 H,
CH2Phb), 4.26–4.24 (m, 2 H, 0.5 × OCH2CHCHCH2O), 4.22 (dd,
J5,6a = 4.8 Hz, J6a,6b = –10.2 Hz, 2 H, H-6a), 4.19 (dd, J4,5 = 9.3 Hz,
–12.2 Hz, 1 H, CH2aCHCH2), 4.18 (dddd, 1 H, CH2bCHCH2), 3.99
(dd, J2,3 = 3.2 Hz, 1 H, H-2), 3.96 (dd, 1 H, H-3), 3.88 (dd, 1 H, H-
6b).
13C NMR (150 MHz, CDCl3): d = 138.4–126.1 (Ar), 134.5
(CH2CHCH2), 118.0 (CH2CHCH2), 101.5 (CHPh), 87.3 (C-1), 79.1
(C-4), 78.1 (C-2), 76.1 (C-3), 73.2 (CH2Ph), 72.6 (CH2CHCH2),
68.5 (C-6), 65.4 (C-5).
J3,4 = 10.0 Hz, 2 H, H-4), 4.13–4.10 (m, 2 H, 0.5
OCH2CHCHCH2O), 4.00 (dd, J2,3 = 3.2 Hz, 2 H, H-3), 3.86 (dd,
×
HRMS: m/z [M + Na]+ calcd for C29H30O5SNa: 513.1706; found:
J5,6b = 10.5 Hz, 2 H, H-6b), 3.84 (ddd, 2 H, H-5), 3.78 (dd, 2 H, H-
513.1740.
2).
HRMS: m/z [M + K]+ calcd for C29H30O5SK: 529.1446; found:
529.1478.
13C NMR (150 MHz, CDCl3): d (E-isomer) = 138.5–126.1 (Ar),
129.8 (OCH2CHCHCH2O), 101.7 (CHPh), 99.1 (C-1), 79.5 (C-4),
77.0 (C-2), 76.5 (C-3), 73.6 (CH2Pha), 72.5 (OCH2CHCHCH2O),
69.5 (CH2Phb), 69.0 (C-6), 64.7 (C-5).
HRMS: m/z [M + Na]+ calcd for C58H60O12Na: 971.3977; found:
971.3988.
Cyclohexyl 2-O-Allyl-3-O-benzyl-4,6-O-benzylidene-a-D-man-
nopyranoside (21)
Synthesized from 17 (0.02 g, 0.05 mmol) according to the general
procedure for synthesis of 2-O-allyl-3-O-benzyl-4,6-O-ben-
zylidene-a-D-mannopyranosides.
HRMS: m/z [M + K]+ calcd for C58H60O12K: 987.3716; found:
987.3726.
Yield: 0.02 g (100%); colorless oil; Rf = 0.82 (hexane–EtOAc, 1:1);
[a]D23 +48.3 (c 0.1, CHCl3).
1,4-Bis(phenyl-3-O-benzyl-4,6-O-benzylidene-1-thio-2-O-a-D-
mannopyranosyl)but-2-ene (23)
Synthesized from 20 (135 mg, 0.28 mmol) according to the general
procedure for homodimerization of olefins.
1H NMR (600 MHz, CDCl3): d = 7.51–7.27 (m, 10 H, ArH), 5.94
[dddd, JCH2a,CH = 5.5 Hz, JCH2b,CH = 6.3 Hz, JCH,CH2(cis) = 10.3 Hz,
JCH,CH2(trans) = 17.2 Hz, 1 H, CH2CHCH2], 5.63 (s, 1 H, CHPh), 5.29
[dddd, JCH2a,CH2(trans) = –1.6 Hz, JCH2b,CH2(trans) = –1.6 Hz,
JCH2(trans),CH2(cis) = –1.7 Hz, 1 H, CH2CHCH2(trans)], 5.20 [dddd,
JCH2b,CH2(cis) = –1.1 Hz, JCH2a,CH2(cis) = –1.3 Hz, 1 H, CH2CHCH2(cis)],
4.95 (d, J1,2 = 1.7 Hz, 1 H, H-1), 4.88 and 4.71 (2 × d, J = –12.1 Hz,
2 × 1 H, CH2Ph), 4.30 (dddd, JCH2a,CH2b = –13.0 Hz, 1 H,
Yield: 98 mg (75%); white foam; Rf = 0.89 (hexane–EtOAc, 1:1);
E/Z = 20:1.
1H NMR (600 MHz, CDCl3): d (E-isomer) = 7.51–7.27 (m, 30 H,
ArH), 5.83–5.82 (m, 2 H, OCH2CHCHCH2O), 5.61 (s, 2 H, CHPh),
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574
F. S. Ekholm et al.
PAPER
5.51 (d, J1,2 = 1.3 Hz, 2 H, H-1), 4.87 and 4.70 (2 × d, J = –12.1 Hz,
2 × 2 H, CH2Ph), 4.28 (ddd, J5,6a = 5.1 Hz, J4,5 = 9.4 Hz, J5,6b = 10.2
HRMS: m/z [M + Na]+ calcd for C16H30O12Na: 437.1629; found:
437.1608.
Hz, 2 H, H-5), 4.24 (dd, J3,4 = 9.7 Hz, 2 H, H-4), 4.20 (dd, J6a,6b
=
–10.4 Hz, 2 H, H-6a), 4.20–4.12 (m, 4 H, OCH2CHCHCH2O), 3.95
(dd, J2,3 = 3.1 Hz, 2 H, H-2), 3.94 (dd, 2 H, H-3), 3.86 (dd, 2 H, H-
6b).
13C NMR (150 MHz, CDCl3): d (E-isomer) = 137.6–126.1 (Ar),
129.6 (OCH2CHCHCH2O), 101.5 (CHPh), 87.3 (C-1), 79.1 (C-4),
78.7 (C-2), 76.2 (C-3), 73.2 (CH2Ph), 71.6 (OCH2CHCHCH2O),
68.5 (C-6), 65.3 (C-5).
HRMS: m/z [M + Na]+ calcd for C56H56O10S2Na: 975.3207; found:
975.3219.
HRMS: m/z [M + K]+ calcd for C56H56O10S2K: 991.2946; found:
991.2943.
1,4-Bis(cyclohexyl-2-O-a-D-mannopyranosyl)butane (26)
Synthesized from 24 (38 mg, 0.04 mmol) according to the general
procedure for hydrogenolysis and purified by HPLC (Hypersil
BDS-C18 column; 5 mm, 4 × 125 mm; MeCN–H2O, 10% for 1 min,
MeCN–H2O, 10%→50% over 19 min; 0.5 mL/min).
Yield: 17 mg (70%); colorless oil; [a]D23 +24.3 (c 0.3, MeOH).
1H NMR (600 MHz, CD3OD): d = 5.01 (d, J1,2 = 1.7 Hz, 2 H, H-1),
3.81 (dd, J5,6a = 2.3 Hz, J6a,6b = –11.7 Hz, 2 H, H-6a), 3.74 (dd,
J2,3 = 3.5 Hz, J3,4 = 9.4 Hz, 2 H, H-3), 3.70–3.65 (m, 2 H,
OCHC5H10), 3.66 (dd, J5,6b = 5.9 Hz, 2 H, H-6b), 3.64–3.58 (m,
4 H, OCH2CH2CH2CH2O), 3.57 (ddd, J4,5 = 9.6 Hz, 2 H, H-5), 3.56
(dd, 2 H, H-4), 3.46 (dd, 2 H, H-2), 1.95–1.70 (m, 8 H, OCHC5H10),
1.70–1.60 (m, 4 H, OCH2CH2CH2CH2O), 1.56–1.00 (m, 12 H,
OCHC5H10).
13C NMR (150 MHz, CD3OD): d = 96.9 (C-1), 81.1 (C-2), 76.1
(OCHC5H10), 74.9 (C-5), 72.6 (C-3), 72.3 (OCH2CH2CH2CH2O),
69.3 (C-4), 63.2 (C-6), 34.5, 32.6 (OCHC5H10), 27.6
(OCH2CH2CH2CH2O), 26.9, 25.2, 25.0 (OCHC5H10).
1,4-Bis(cyclohexyl-3-O-benzyl-4,6-O-benzylidene-2-O-a-D-
mannopyranosyl)but-2-ene (24)
Synthesized from 21 (20 mg, 0.041 mmol) according to the general
procedure for homodimerization of olefins.
Yield: 15 mg (75%); white foam; Rf = 0.35 (hexane–EtOAc, 1:1);
E/Z = 10:1.
HRMS: m/z [M + Na]+ calcd for C28H50O12Na: 601.3194; found:
601.3194.
1H NMR (600 MHz, CDCl3): d (E-isomer) = 7.50–7.23 (m, 20 H,
ArH), 5.86–5.84 (m, 2 H, OCH2CHCHCH2O), 5.62 (s, 2 H, CHPh),
4.94 (d, J1,2 = 1.7 Hz, 2 H, H-1), 4.87 and 4.70 (2 × d, J = –12.2 Hz,
2 × 2 H, CH2Ph), 4.33–4.30 (m, 2 H, 0.5 × OCH2CHCHCH2O),
4.23 (dd, J5,6a = 4.8 Hz, J6a,6b = –10.1 Hz, 2 H, H-6a), 4.17 (dd,
J4,5 = 9.3 Hz, J3,4 = 10.0 Hz, 2 H, H-4), 4.18–4.15 (m, 2 H, 0.5 ×
OCH2CHCHCH2O), 3.98 (dd, J2,3 = 3.2 Hz, 2 H, H-3), 3.87 (ddd,
J5,6b = 10.4 Hz, 2 H, H-5), 3.84 (dd, 2 H, H-6b), 3.72 (dd, 2 H, H-2),
3.60–3.54 (m, 2 H, OCHC5H10), 1.85–1.19 (m, 20 H, OCHC5H10).
13C NMR (150 MHz, CDCl3): d (E-isomer) = 138.8–126.0 (Ar),
129.9 (OCH2CHCHCH2O), 101.3 (CHPh), 97.5 (C-1), 79.4 (C-4),
77.7 (C-2), 76.6 (C-3), 75.2 (OCHC5H10), 73.3 (CH2Ph), 72.2
(OCH2CHCHCH2O), 68.9 (C-6), 64.2 (C-5), 33.3, 31.4, 31.0, 24.1,
23.8 (OCHC5H10).
1,4-Bis[benzyl-3-O-benzyl-4,6-O-benzylidene-a-D-mannopyra-
nosyl-(2→1)-3-O-benzyl-4,6-O-benzylidene-2-O-b-D-mannopy-
ranosyl]but-2-ene (27)
To a stirred mixture of 23 (74 mg, 0.8 mmol) and 4 Å MS (0.2 g) in
CH2Cl2 (2.1 mL), were added BSP (2.4 equiv), TTBP (3 equiv) and
Tf2O (2.6 equiv) at –60 °C (dry ice/acetone). The reaction mixture
was stirred for 30 min, cooled to –78 °C and 15 (2.3 equiv) in
CH2Cl2 (2.0 mL) was added. The resulting mixture was stirred for 2
h, quenched by triethyl phosphite (0.1 mL) and stirred for 1 h. The
reaction mixture was brought to r.t. and diluted with CH2Cl2 (20
mL) and sat. NaHCO3 (20 mL). The aqueous phase was extracted
with CH2Cl2 (2 × 20 mL) and the combined organic phase was dried
with anhydrous Na2SO4, filtered and concentrated. The crude prod-
uct was purified by preparative TLC (EtOAc–hexane, 1:1). The
spots containing product were scraped off, diluted with EtOAc (20
mL), stirred for 2 h, filtered and concentrated to give 27.
HRMS: m/z [M + Na]+ calcd for C56H68O12Na: 955.4603; found:
955.4607.
HRMS: m/z [M + K]+ calcd for C56H68O12K: 971.4342; found:
971.4340.
Yield: 88 mg (70%); colorless oil; Rf = 0.10 (hexane–EtOAc, 1:1).
1H NMR (600 MHz, CDCl3): d (E-isomer) = 7.50–7.21 (m, 50 H,
ArH), 6.02–5.96 (m, 2 H, OCH2CHCHCH2O), 5.57 (s, 2 H,
CHPha), 5.50 (s, 2 H, CHPhb), 4.89 (d, J1,2 = 1.6 Hz, 2 H, H-1), 4.76
and 4.71 (2 × d, J = –10.5 Hz, 2 × 2 H, CH2Pha), 4.72 (s, 4 H,
CH2Phb), 4.68 and 4.46 (2 × d, J = –12.0 Hz, 2 × 2 H, CH2Phc),
4.53–4.49 (m, 2 H, 0.5 × OCH2CHCHCH2O), 4.52 (d, J1¢,2¢ = 0.7
Hz, 2 H, H-1¢), 4.34–4.30 (m, 2 H, 0.5 × OCH2CHCHCH2O), 4.20
(dd, J2,3 = 3.3 Hz, 2 H, H-2), 4.19 (dd, J5,6a = 4.8 Hz, J6a,6b = –10.1
Hz, 2 H, H-6a), 4.18 (dd, J5¢,6a¢ = 4.9 Hz, J6a¢,6b¢ = –10.2 Hz, 2 H, H-
6a¢), 4.15 (dd, J4¢,5¢ = 9.3 Hz, J3¢,4¢ = 9.9 Hz, 2 H, H-4¢), 4.12 (dd,
J4,5 = 9.3 Hz, J3,4 = 10.0 Hz, 2 H, H-4), 3.99 (dd, 2 H, H-3), 3.86
(dd, J2¢,3¢ = 3.2 Hz, 2 H, H-2¢), 3.84 (ddd, J5,6b = 10.3 Hz, 2 H, H-5),
3.79 (dd, 2 H, H-6b), 3.78 (dd, J5¢,6b¢ = 10.1 Hz, 2 H, H-6b¢), 3.53
(dd, 2 H, H-3¢), 3.21 (ddd, 2 H, H-5¢).
13C NMR (150 MHz, CDCl3): d (E-isomer) = 138.8–126.0 (Ar),
130.2 (OCH2CHCHCH2O), 101.5 (CHPha), 101.3 (CHPhb), 100.7
(1JC¢,H¢ = 155.2 Hz, C-1¢), 97.7 (1JC,H = 168.5 Hz, C-1), 78.6 (C-4),
78.4 (C-4¢), 77.2 (C-3¢), 77.1 (C-2¢), 75.2 (C-2), 74.3 (C-3), 73.6
(OCH2CHCHCH2O), 72.2 (CH2Pha), 71.6 (CH2Phb), 69.3
(CH2Phc), 68.8 (C-6, C-6¢), 68.5 (C-5¢), 67.6 (C-5) .
Hydrogenolysis; General Procedure
To a solution of the corresponding protected mannoside in MeOH–
EtOAc (9:1; 1 mL/10 mg starting material) was added Pd/C (10%
Pd, 2.5 equiv by mass). The reaction mixture was stirred in a reactor
under H2 (1.4 bar) overnight, then filtered through Celite and con-
centrated to give the corresponding fully deprotected mannoside.
1,4-Bis(2-O-D-mannopyranose)butane (25)
Synthesized from 22 (16 mg, 0.023 mmol) according to the general
procedure for hydrogenolysis and purified by HPLC (Zorbax
SB-Aq column; 5 mm, 4.6 × 250 mm; MeCN–H2O, 1% for 2 min,
MeCN–H2O, 1%→40% over 19 min; 0.5 mL/min).
Yield: 7 mg (70%); colorless oil; aa/ab/bb = 5:1:1.
1H NMR (600 MHz, CD3OD): d (aa-anomer) = 5.18 (d, J1,2 = 1.7
Hz, 2 H, H-1), 3.81 (dd, J5,6a = 2.4 Hz, J6a,6b = –11.7 Hz, 2 H, H-6a),
3.79 (dd, J2,3 = 3.5 Hz, J3,4 = 9.6 Hz, 2 H, H-3), 3.70 (ddd, J5,6b = 5.9
Hz, J4,5 = 9.7 Hz, 2 H, H-5), 3.68 (dd, 2 H, H-6b), 3.64–3.59 (m,
4 H, OCH2CH2CH2CH2O), 3.58 (dd, 2 H, H-4), 3.50 (dd, 2 H, H-2),
1.70–1.66 (m, 4 H, OCH2CH2CH2CH2O).
13C NMR (150 MHz, CD3OD): d (aa-anomer) = 93.2 (C-1), 81.3
(C-2), 74.2 (C-5), 72.4 (OCH2CH2CH2CH2O, C-3), 69.3 (C-4), 63.2
(C-6), 27.7 (OCH2CH2CH2CH2O).
HRMS: m/z [M + Na]+ calcd for C98H100O22Na: 1651.6598; found:
1651.6665.
Synthesis 2009, No. 4, 567–576 © Thieme Stuttgart · New York

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Divalent 2,2¢-Linked Mannose Derivatives
575
1,4-Bis[2-O-b-D-mannopyranosyl-(1→2)-D-mannopyra-
nose]butane (28)
Synthesized from 25 (20 mg, 0.012 mmol) according to the hydro-
genolysis general procedure and purified by HPLC (Zorbax SB-Aq
column; 5 mm, 4.6 × 250 mm; MeCN–H2O, 1% for 5 min, then
MeCN–H2O, 1%→40% over 19 min; 0.5 mL/min).
1,4-Bis[methyl-3-O-benzyl-4,6-O-benzylidene-a-D-mannopyra-
nosyl-(2→1)-3,4,6-tri-O-benzyl-2-O-b-D-glucopyranosyl]but-2-
ene (32)
Synthesized from 31 (0.11 g, 0.13 mmol) according to the general
procedure for homodimerization of olefins.
Yield: 66 mg (61%); white foam; Rf = 0.10 (hexane–EtOAc, 1:1);
E/Z = 20:1.
Yield: 5 mg (50%); colorless oil; aa/ab/bb = 8:2:1.
1H NMR (600 MHz, CD3OD): d (aa-anomer) = 5.18 (d, J1,2 = 1.8
Hz, 2 H, H-1), 4.64 (d, J1¢,2¢ = 0.8 Hz, 2 H, H-1¢), 3.94 (dd, J2,3 = 3.2
Hz, 2 H, H-2), 3.91–3.86 (m, 2 H, 0.5 × OCH2CH2CH2CH2O), 3.87
(dd, J5¢,6a¢ = 2.3 Hz, J6a¢,6b¢ = –12.0 Hz, 2 H, H-6a¢), 3.82–3.80 (m,
2 H, H-6a), 3.78 (dd, J3,4 = 9.6 Hz, 2 H, H-3), 3.77–3.73 (m, 2 H,
0.5 × OCH2CH2CH2CH2O), 3.73–3.67 (m, 8 H, H-2¢, H-3¢, H-6b¢,
H-6b), 3.65 (dd, J4,5 = 10.1 Hz, 2 H, H-4), 3.53 (dd, J4¢,5¢ = 8.8 Hz,
1H NMR (600 MHz, CDCl3): d (E-isomer) = 7.46–7.12 (m, 50 H,
ArH), 5.94–5.93 (m, 2 H, OCH2CHCHCH2O), 5.52 (s, 2 H, CHPh),
4.93 and 4.74 (2 × d, J = –11.0 Hz, 2 × 2 H, CH2Pha), 4.83 and 4.62
(2 × d, J = –12.6 Hz, 2 × 2 H, CH2Phb), 4.78 and 4.49 (2 × d, J =
–10.7 Hz, 2 × 2 H, CH2Phc), 4.77 (d, J1,2 = 1.7 Hz, 2 H, H-1), 4.57–
4.53 (m, 2 H, 0.5 × OCH2CHCHCH2O), 4.47 (s, 4 H, CH2Phd), 4.37
(d,
J1¢,2¢ = 7.8 Hz, 2 H, H-1¢), 4.22–4.18 (m, 2 H, 0.5 ×
J
3¢,4¢ = 9.5 Hz, 2 H, H-4¢), 3.50–3.45 (m, 2 H, H-5), 3.21 (ddd,
OCH2CHCHCH2O), 4.20 (dd, J2,3 = 3.6 Hz, 2 H, H-2), 4.20 (dd,
J5,6a = 4.8 Hz, J6a,6b = –10.3 Hz, 2 H, H-6a), 4.06 (dd, J4,5 = 9.4 Hz,
J3,4 = 10.1 Hz, 2 H, H-4), 3.89 (dd, 2 H, H-3), 3.72 (ddd, J5,6b = 10.3
Hz, 2 H, H-5), 3.71 (dd, J5¢,6a¢ = 1.5 Hz, J6a¢,6b¢ = –10.5 Hz, 2 H, H-
6a¢), 3.68 (dd, 2 H, H-6b), 3.62 (dd, J5¢,6b¢ = 5.4 Hz, 2 H, H-6b¢),
3.57 (dd, J3¢,4¢ = 8.9 Hz, J2¢,3¢ = 9.2 Hz, 2 H, H-3¢), 3.49 (dd,
J = J5¢,6b¢ = 5.8 Hz, 2 H, H-5¢), 1.80–1.60 (m, 4 H,
OCH2CH2CH2CH2O).
13C NMR (150 MHz, CD3OD): d (aa-anomer) = 101.4 (C-1¢), 93.7
(C-1), 81.0 (C-2¢), 80.6 (C-2), 78.8 (C-5¢), 75.3 (C-5), 75.1
(OCH2CH2CH2CH2O), 74.3 (C-3¢), 71.6 (C-3), 69.5 (C-4), 68.8 (C-
4¢), 62.9 (C-6, C-6¢), 27.6 (OCH2CH2CH2CH2O).
HRMS: m/z [M + Na]+ calcd for C28H50O22Na: 761.2686; found:
761.2688.
J
4¢,5¢ = 9.4 Hz, 2 H, H-4¢), 3.48 (ddd, 2 H, H-5¢), 3.46 (dd, 2 H, H-
2¢), 3.30 (s, 6 H, OCH3).
13C NMR (150 MHz, CDCl3): d (E-isomer) = 138.0–126.0 (Ar),
130.3 (OCH2CHCHCH2O), 103.0 (C-1¢), 101.4 (CHPh), 99.8 (C-
1), 84.6 (C-3¢), 81.8 (C-2¢), 78.2 (C-4), 77.7 (CH2Phc, C-4¢), 75.1
(CH2Pha, C-2), 75.0 (C-5¢), 73.6 (C-3), 73.5 (CH2Phd), 73.0
(OCH2CHCHCH2O), 70.8 (CH2Phb), 69.8 (C-6¢), 69.1 (C-6), 64.0
(C-5), 54.9 (OCH3).
Methyl 2-O-Allyl-3,4,6-tri-O-benzyl-b-D-glucopyranosyl-
(1→2)-3-O-benzyl-4,6-O-benzylidene-a-D-mannopyranoside
(31)
Synthesized from 3030 (0.14 g, 0.17 mmol) according to the general
procedure for synthesis of 2-O-allyl-3-O-benzyl-4,6-O-ben-
zylidene-a-D-mannopyranosides.
HRMS: m/z [M + H2O]+ calcd for C100H110O23: 1678.7432; found:
1678.7440.
Yield: 0.12 g (80%); white foam; Rf = 0.80 (hexane–EtOAc, 1:1);
[a]D23 –12.7 (c 1, CHCl3).
1,4-Bis[methyl-a-D-mannopyranosyl-(2→1)-2-O-b-D-gluco-
pyranosyl]butane (33)
1H NMR (600 MHz, CDCl3): d = 7.51–7.16 (m, 25 H, ArH), 6.00
[dddd, JCH2a,CH = 6.2 Hz, JCH2b,CH = 6.2 Hz, JCH,CH2(cis) = 10.3 Hz,
JCH,CH2(trans) = 17.2 Hz, 1 H, CH2CHCH2], 5.60 (s, 1 H, CHPh), 5.32
[dddd, JCH2b,CH2(trans) = –1.4 Hz, JCH2a,CH2(trans) = –1.5 Hz,
JCH2(cis),CH2(trans) = –1.9 Hz, 1 H, CH2CHCH2(trans)], 5.19 [dddd,
JCH2b,CH2(cis) = –1.0 Hz, JCH2a,CH2(cis) = –1.1 Hz, 1 H, CH2CHCH2(cis)],
4.95 and 4.80 (2 × d, J = –10.9 Hz, 2 × 1 H, CH2Pha), 4.84 and 4.63
(2 × d, J = –12.6 Hz, 2 × 1 H, CH2Phb), 4.82 and 4.53 (2 × d, J =
–10.8 Hz, 2 × 1 H, CH2Phc), 4.79 (d, J1,2 = 1.6 Hz, 1 H, H-1), 4.51
(dddd, JCH2a,CH2b = –11.7 Hz, 1 H, CH2aCH=CH2), 4.47 (s, 2 H,
CH2Phd), 4.40 (d, J1¢,2¢ = 7.8 Hz, 1 H, H-1¢), 4.27 (dd, J5,6a = 5.2 Hz,
J6a,6b = –10.6 Hz, 1 H, H-6a), 4.21 (dddd, 1 H, CH2bCHCH2), 4.21
(dd, J2,3 = 3.5 Hz, 1 H, H-2), 4.10 (dd, J4,5 = 9.2 Hz, J3,4 = 10.1 Hz,
1 H, H-4), 3.91 (dd, 1 H, H-3), 3.76 (ddd, J5,6b = 10.2 Hz, 1 H, H-5),
3.76 (dd, 1 H, H-6b), 3.72 (dd, J5¢,6a¢ = 1.8 Hz, J6a¢,6b¢ = –10.6 Hz,
1 H, H-6a¢), 3.63 (dd, J5¢,6b¢ = 5.4 Hz, 1 H, H-6b¢), 3.61 (dd,
Synthesized from 32 (24 mg, 0.014 mmol) according to the general
procedure for hydrogenolysis and purified by HPLC (Zorbax
SB-Aq column; 5 mm, 4.6 × 250 mm; MeCN–H2O, 1% for 5 min,
then MeCN–H2O, 1%→40% over 19 min; 0.5 mL/min).
Yield: 8 mg (70%); colorless oil; [a]D23 –1.5 (c 0.1, MeOH).
1H NMR (600 MHz, CD3OD): d = 4.79 (d, J1,2 = 1.7 Hz, 2 H, H-1),
4.40 (d, J1¢,2¢ = 7.8 Hz, 2 H, H-1¢), 3.97 (dd, J2,3 = 3.5 Hz, 2 H, H-2),
3.97–3.93 (m, 2 H, 0.5 × OCH2CH2CH2CH2O), 3.87 (dd, J5,6a = 2.2
Hz, J6a,6b = –11.8 Hz, 2 H, H-6a), 3.84 (dd, J5¢,6a¢ = 2.4 Hz, J6a¢,6b¢
=
–12.0 Hz, 2 H, H-6a¢), 3.70 (dd, J3,4 = 9.5 Hz, 2 H, H-3), 3.68–3.63
(m, 2 H, 0.5 × OCH2CH2CH2CH2O), 3.64 (dd, J5,6b = 6.1 Hz, 2 H,
H-6b), 3.64 (dd, J5¢,6b¢ = 6.0 Hz, 2 H, H-6b¢), 3.50 (ddd, J4,5 = 8.9
Hz, 2 H, H-5), 3.50 (dd, 2 H, H-4), 3.41 (s, 6 H, OCH3), 3.37 (dd,
J
3¢,4¢ = 9.1 Hz, J2¢,3¢ = 9.2 Hz, 2 H, H-3¢), 3.30 (dd, J4¢,5¢ = 9.8 Hz,
2 H, H-4¢), 3.26 (ddd, 2 H, H-5¢), 3.04 (dd, 2 H, H-2¢), 1.75–1.62
(m, 4 H, OCH2CH2CH2CH2O).
J3¢,4¢ = 8.5 Hz, J2¢,3¢ = 9.2 Hz, 1 H, H-3¢), 3.51 (dd, J4¢,5¢ = 8.8 Hz,
1 H, H-4¢), 3.50 (ddd, 1 H, H-5¢), 3.47 (dd, 1 H, H-2¢), 3.35 (s, 3 H,
OCH3).
13C NMR (150 MHz, CD3OD): d = 103.6 (C-1¢), 100.3 (C-1), 82.9
(C-2¢), 79.4 (C-2), 77.9 (C-5¢), 77.5 (C-3¢), 74.9 (C-5), 74.0
(OCH2CH2CH2CH2O), 71.7 (C-3), 71.4 (C-4¢), 69.6 (C-4), 63.4 (C-
6), 62.6 (C-6¢), 55.4 (OCH3), 27.8 (OCH2CH2CH2CH2O).
HRMS: m/z [M + Na]+ calcd for C30H54O22Na: 789.2999; found:
789.2996.
13C NMR (150 MHz, CDCl3): d = 138.6–126.1 (Ar), 135.1
(CH2CHCH2), 117.7 (CH2CHCH2), 103.0 (C-1¢), 101.5 (CHPh),
99.8 (C-1), 84.8 (C-3¢), 81.5 (C-2¢), 78.3 (C-4), 75.8 (H-4¢), 75.6
(CH2Pha), 75.3 (C-2), 75.1 (CH2Phc, H-5¢), 73.9 (CH2CHCH2), 73.7
(C-3), 73.5 (CH2Phd), 70.7 (CH2Phb), 69.7 (C-6¢), 69.1 (C-6), 63.9
(C-5), 54.9 (OCH3).
HRMS: [M + Na]+ calcd for C51H56O11Na: 867.3715; found:
867.3696.
Acknowledgment
The authors would like to thank the Academy of Finland (projects
# 121335 and 122126 for Reko Leino and Johannes Savolainen) and
TEKES (the Finnish Funding Agency for Technology and Innova-
tion, project 40134/06 for Reko Leino and Johannes Savolainen) for
financial support. The authors thank Markku Reunanen for the
HRMS analyses, Jari Sinkkonen and Mattias U. Roslund for their
HRMS: [M + K]+ calcd for C51H56O11K: 883.3454; found:
883.3445.
Synthesis 2009, No. 4, 567–576 © Thieme Stuttgart · New York

576
F. S. Ekholm et al.
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