Ready access to a branched Man5 oligosaccharide based on regioselective glycosylations of a mannose-tetraol with n-pentenyl orthoesters

Article abstract of DOI:10.1039/c2ob26432c

A branched Man₅ oligosaccharide has been synthesized by sequential regioselective glycosylations on a mannose-tetraol with n-pentenyl orthoester glycosyl-donors promoted by NIS/BF₃·Et ₂O, in CH₂Cl₂. An extended n-pentenyl chain was incorporated into the tetraol acceptor to facilitate (a) the solubility of the starting tetraol in CH₂Cl₂, and (b) future manipulations at the reducing end of the Man₅ oligosaccharide. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26432c

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PAPER
Ready access to a branched Man5 oligosaccharide based on regioselective
glycosylations of a mannose-tetraol with n-pentenyl orthoesters†‡
Clara Uriel,a Ana M. Gómez,*a J. Cristóbal López*a and Bert Fraser-Reidb
Received 21st July 2012, Accepted 24th August 2012
DOI: 10.1039/c2ob26432c
A branched Man5 oligosaccharide has been synthesized by sequential regioselective glycosylations on a
mannose-tetraol with n-pentenyl orthoester glycosyl-donors promoted by NIS/BF3·Et2O, in CH2Cl2. An
extended n-pentenyl chain was incorporated into the tetraol acceptor to facilitate (a) the solubility of the
starting tetraol in CH2Cl2, and (b) future manipulations at the reducing end of the Man5 oligosaccharide.
other groups which present the opportunity for linking the
glycan to a protein or a solid support to give a number of desi-
Introduction
High-mannose oligosaccharides are, ubiquitous, biologically impor-
tant molecules. They are known to participate in quality control and
intracellular transportation of glycoproteins.1 Furthermore, they
cover the surface of many pathogenic microorganisms and are the
targets of the immune system cells, including macrophages and
dendritic cells, through their mannose receptors, as well as of
soluble circulating proteins such as collectins.2 High-mannose
oligosaccharides belong to the N-linked family of carbohydrates,
which are conjugated to glycoproteins via an N-acetyl-glucosamine
unit to the amide group of an asparagine residue on the polypeptide
backbone. Chemically, they are characterized by the presence of a
variable number of mannose residues linked to the common core
Manα(1–6)[Manα(1–3)]Manβ(1–4)GlcNAcb(1–4)GlcNAc. Func-
tionally, these mannose oligosaccharides have been investigated as
recognition moieties in drug delivery,3 in targeting antigens to den-
dritic cells4,5 and in carbohydrate-based vaccines.6
rable biological tools. Consequently, synthetic efforts have been
devoted to the total synthesis of high mannose glycans of the
gp12013,14 as well as to the preparation of an assortment of
partial structures that exhibit affinity to human antibody 2G12
with potential immunogenic applications.15
Our group has been involved in recent years in exploring the
potential of n-pentenyl orthoesters (NPOEs) in the design of syn-
thetic strategies towards complex oligosaccharides.16 One aspect
appealing to us has been the advantages associated with regio-
chemically-driven methodologies, which might minimize the
number of protection–deprotection steps involved in standard
oligosaccharide synthesis.17 In this paper, we wish to describe
the effective application of sequential, regioselective, NPOE gly-
cosylations on a mannose-tetraol to target a branched penta-
saccharide moiety incorporated into HIV glycoprotein gp120.
The discovery of a broadly neutralizing human antibody
2G12,7 which was able to recognize oligomannose epitope
Man9GlcNAc2 (1, Fig. 1) present on the gp120 receptor-binding
glycoprotein of the HIV-1 virus,8 has given the confidence that
the glycan shield defense of the virus can be breached, and that
these structures under the right circumstances can act as potential
targets for vaccine development.9–12 In this context, early studies
seemed to indicate that the N-acetylglucosamine residues in
gp120 are not essential for specific binding of the mannan
moiety to target systems, and that they might be replaced with
Results and discussion
Synthetic strategy
In previous studies, we have found that NPOEs displayed an
excellent regioselectivity in glycosylations in CH2Cl2 of some
18
aInstituto de Química Orgánica General (IQOG-CSIC), Juan de la
Cierva 3, 28006 Madrid, Spain. E-mail: jc.lopez@csic.es;
Fax: +34 91 5644853; Tel: +34 91 5622900 Ext 320
bNatural Products and Glycotechnology Research Institute Inc., (NPG),
595F, Weathersfield Road, Pittsboro, NC, USA, 27312.
E-mail: dglucose@aol.com; Fax: +1 9195427111; Tel: +1 9195427111
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra of all compounds. See DOI: 10.1039/c2ob26432c
‡In memoriam of Professor Kostas Antonakis
Fig. 1 Structure of Man9GlcNAc2, 1.
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Table 1 Glycosylation of mannose tetraol 9 with NPOE 8
Orthoester
Entry (equiv.)
Yield
(%)
Reaction conditions (equiv.)
i
(2)
(2)
(4)
CH2Cl2/dioxane NIS (2)/BF3·OEt2,
−30 °C to r.t., overnighta
Dioxane NIS(1 + 1)/BF3·OEt2b r.t.,
10 min + 20 min
—
36
35
74
ii
iii
iv
Dioxane NIS(2 + 2)/Yb(OTf)3b r.t.,
10 min + 20 min
c
(1 + 1 + 1 + 1)c Dioxane NIS(1 + 1 + 1 + 1)/Yb(OTf)3
r.t., 90 min
Fig. 2 Regioselective glycosylation with NPOEs.
a NIS added in one portion. b NIS added in two portions. c Orthoester
and NIS added in several portions over 90 min.
glycosylation experiments. However, the use of CH2Cl2–dioxane
(1 : 1.3) as a solvent did not result in the formation of disacchar-
ide 10 (Table 1, entry i). Conversely, when dioxane was used as
a solvent, the reaction of tetraol 9 with NPOE 8, mediated by
either NIS/BF3·Et2O or NIS/Yb(OTf)3,26 led to the formation of
disaccharide 10 (Table 1, entries ii–iv). In the first case, the step-
wise addition27 of NIS (1 equiv. + 1 equiv.) allowed us to obtain
disaccharide 10 in 36% yield by reaction with NPOE 8 (2 equiv.,
Table 1, entry ii). The glycosylation of tetraol 9 with 4 equiv. of
donor 8 could produce a 35% or a 74% yield of disaccharide 10
by switching from a 2 + 2 equiv. addition of NIS to a stepwise
1 + 1 + 1 + 1 addition of NIS and 8, all together, to the reaction
mixture (Table 1, entries iii and iv). However, the fact that 4
equiv. of NPOE were required to obtain disaccharide 10 in good
yield made us search for alternative anomeric substituents in the
tetraol.
Scheme 1 Projected synthesis of Man5 unit 6, from tetraol 7.
mannose-derived diols (2, 3, Fig. 2)19 and triols (4, 5, Fig. 2).20
The same diols, when confronted with a phenyl 2,3,4,6-tetra-O-
benzyl 1-thio-mannopyranoside donor, displayed opposite
regioselectivity.19 Mannose-derived triols 4 and 5 also under-
went regioselective glycosylation with NPOEs whereas the use
of phenyl 2,3,4,6-tetra-O-benzyl 1-thio-mannoside as a donor
gave rise to complex reaction mixtures containing several sac-
charides (Fig. 2)20
Synthesis and glycosylation of tetraols based on
“chain extended” NPGs
Our previous success with regioselective NPOE glycosylations
of polyols in CH2Cl2 made us consider a second generation of
tetraol acceptors based on n-pentenyl glycosides (NPGs) with
enhanced lipophilicity that could facilitate their solubility in that
solvent. Our experience with “chain extended” NPGs28 led us to
consider tetraols 13 as acceptor candidates. The modified n-pen-
tenyl chain in these derivatives could, in principle, be derivatized
or oxidatively removed as needed in future endeavors. Accord-
ingly, cross-metathesis29–31 of NPG 11, readily formed by acid-
mediated rearrangement of 8,32 with pentenyl silyl ether 14a, or
with hexenyl ethers 14b,c (1st generation Grubbs catalyst, bis
(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride,33
CH2Cl2, reflux, 12 h) followed by saponification (NaOMe/
MeOH) led to tetraols 13a–c (E/Z mixtures, E very major
isomer), respectively, in good overall yields (Table 2).34
In this manuscript we describe a concise approach to the 3,6-
branched Man5 saccharide, 6, component of the
Man9GlcNAc2,21–25 from an unprotected tetraol acceptor 7, and
entirely based on NPOE-mediated regioselective glycosyl coup-
lings. In our strategy, the anomeric substituent of the unprotected
tetraol 7 (Scheme 1) might play a dual role as (i) a solubility
enhancer to facilitate its reaction in common glycosylation sol-
vents and (ii) a leaving group for future manipulations, including
glycosylation.
Glycosylation of thioglycosidic tetraol acceptors
For our initial experiments we selected phenyl 1-thiomannopyra-
noside 9 as the tetraol acceptor and NPOE 8 as the glycosyl
donor (Table 1). Since compound 9 showed low solubility in
CH2Cl2, CH2Cl2–dioxane mixtures were initially used in the
Glycosylation of tetraols 13 with NPOE 8 was then studied,
and our results are displayed in Table 3. Normally, a mixture of
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di- (15) and trisaccharides (16) was obtained, and better yields
of the corresponding derivatives occurred when benzyl substi-
tuted tetraol 13c was used as the glycosyl acceptor, when com-
pared to silyl derivative 13b (Table 3, compare entries i, ii with
entries iii, iv). The use of 1.2 equiv. of NPOE 8 led to acceptable
yields of disaccharide 15c (Table 3, entry iii, 46%), whereas
excess (4.0 equiv.) of NPOE donor led to acceptable yields of
3,6-trisaccharide 16c (Table 3, entry iv, 38%). In contrast,
attempted glycosylation of 13a with 3.0 equiv. of NPOE 8 led to
trisaccharide 17, with the anomeric tether modified, as the major
compound. The formation of the halo-furanosyl moiety in 17 is
undoubtedly due to a NIS-triggered 5-exo-trig cyclization of the
terminal OTBDPS group onto the olefin.35 The related isomeric
6-exo-trig cyclization in derivatives 13b and 13c was not
observed.
Regioselective synthesis of Man5 derivative 24
Based on these results, pentasaccharide 21 has been efficiently
assembled as shown in Scheme 2. Thus, disaccharide 15c was
glycosylated with NPOE 18, to give trisaccharide 19 in 63%
yield. The latter upon saponification unveiled heptaol 20, which
could be doubly-glycosylated with NPOE 18, to give pentasac-
charide 21 in 44% yield. In this reaction, tetrasaccharide 22 was
also isolated in 38% yield. The latter could be transformed into
21 by glycosylation with 2.0 equiv. of 18 (52% yield).
Table 2 Synthesis of tetraols based on “chain extended” NPGs 13a–c
The effectiveness of this approach lies on the regioselectivity
displayed in the glycosylation of mannose polyols with NPOEs.
Thus, for regioselectivity purposes, heptaol trisaccharide 20
could be viewed as a 2,3,4,6-mannose-tetraol, a 2,4-mannose-
diol, and a 2-OH mannoside, and from our previous studies and
the results displayed in Table 3, the regioselective glycosylation
at positions 3 and 6 of the mannose tetraol residue could have
been expected.
The anomeric pentenyl residue in pentasaccharide 23,
obtained by acetylation of 21, was efficiently transformed into
n-pentenyl pentasaccharide 24, by cross-metathesis in the
presence of ethylene (94% yield).36 The n-pentenyl moiety in 24
could in principle be: oxidatively hydrolyzed,37 transformed into
a variety of anomeric spacers,38–43 used as a handle for multi-
valent presentations,44–47 or used as a leaving group in further
synthetic transformations.48
Entry
Olefin (4 equiv.)
Products
Yields (%)
i
a) 90
b) 95
ii
a) 79
b) 80
iii
a) 60
b) 75
Table 3 Glycosylation of tetraols 13a–c
Entry
8
Tetraol
Reaction conditions
Disaccharide (yield)
Trisaccharide (yield)
i
(1.2 equiv.)
(3.0 equiv.)
(1.2 equiv.)
(4.0 equiv.)
(3.0 equiv.)
13b
13b
13c
13c
13a
NIS (1.2 equiv.) Yb(OTf)3, 10 °C, 1 h
NIS (1.2 equiv.) BF3·OEt2, 0 °C, 10 min
NIS (1.2 equiv.) BF3·OEt2, −5 °C, 10 min
NIS (4.0 equiv.) BF3·OEt2, 0 °C, 10 min
NIS (4.5 equiv.) BF3·OEt2, −25 °C, 10 min
15b (13%)
15b (39%)
15c (46%)
15c (11%)
16b (0%)
16b (36%)
16c (10%)
16c (38%)
ii
iii
iv
v
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Scheme 2 Regioselective synthesis of Man5 derivative 24.
Anhydrous magnesium sulphate was used for drying solutions.
Phenyl 1-thio-α-D-mannopyranoside 9,49 1-O-tert-butyldiphenyl-
silyl-4-penten-1-ol 14a,50 1-O-tert-butyldiphenylsilyl-5-hexen-1-
ol 14b,51 1-O-benzyl-5-hexen-1-ol 14c,52 n-pentenyl glycoside
1153 and NPOEs 8 and 1818 were prepared as previously
described.
Conclusions
A regioselective approach based on NPOE-regioselective glyco-
sylations that allows the preparation of a Man5 saccharide from a
starting mannose tetraol has been implemented. Only one depro-
tection step was required throughout the synthetic sequence.
Additionally, the overall process requires only one single NPOE,
8, as the starting material since NPOE 18 and the starting tetraol
13c were prepared from 8. An extended n-pentenyl chain was
incorporated to the anomeric position of tetraols 13 for solubility
purposes, and to facilitate further synthetic transformations.
General procedure for glycosylation with NPOEs. A dry
mixture of the corresponding NPOE and the appropriate acceptor
in toluene (5 mL) was azeotroped to dryness and subsequently
kept overnight under high vacuum. This mixture was then dis-
solved in the suitable dry solvent (5 mL mmol−1), the solution
cooled to the appropriate temperature, and NIS was added. After
stirring for 5 min, the corresponding acid was added. The
mixture was stirred for the indicated time, and the reaction was
quenched by addition of aqueous Na2S2O3 (10%) and NaHCO3
(satd). The layers were separated, the aqueous phase was
extracted with CH2Cl2 and the combined organic layers were
washed with saturated aqueous NaCl. The resultant organic
phase was dried, filtered and concentrated. The residue was
purified by flash silica gel column chromatography.
Experimental section
General methods
1H NMR and 13C NMR spectra were obtained for solutions in
CDCl3 using either a 300, 400 or a 500 MHz spectrometer.
Optical rotations were determined for solutions in chloroform
at 25 °C. Column chromatography was performed on silica gel
(230–400 mesh). TLC was conducted in precoated Kiesel gel 60
F254 (Merck). Detection was first by UV light (254 nm) then
charring with a 1/20/4 solution of sulfuric acid/acetic acid/H2O.
All solvents were purified by distillation over drying agents or
by elution through a PURE SOLV purification system. Reactions
requiring anhydrous conditions were performed under argon.
General procedure for the cross-metathesis (CM) reaction.
The n-pentenyl glycoside 11 (1 mmol) and the appropriate olefin
14a–c (4 mmol) were dissolved in dry CH2Cl2. Argon was
bubbled through the solution for 10 min and then 1st generation
Grubbs catalyst (5% mol) was added. The reaction mixture was
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1
refluxed for 12 h after which time air was bubbled through the
solution. The solvent was evaporated in vacuo and the residue
was filtered through a FLORISIL pad and then purified by flash
silica gel column chromatography.
gum. H-NMR (300 MHz, CDCl3) δ: 0.97 (s, 9H), 1.49–1.61
(m, 2H), 1.62–1.74 (m, 2H), 1.96–2.10 (m, 4H), 4.32–4.44 (m,
2H), 4.61 (dd, J = 11.7, 2.2 Hz, 1H), 5.00 (d, J = 1.9 Hz, 1H),
5.28–5.34 (m, 2H), 5.62 (dd, J = 3.2, 1.9 Hz, 1H), 5.85 (dd, J =
10.1, 3.3 Hz, 1H), 6.03 (dd, J = 10.1, 9.8 Hz, 1H), 7.15–8.03
(m, 30 H).13C-NMR (75 MHz, CDCl3) δ: 19.4, 27.0 (×3), 28.9,
29.2, 29.3, 32.6, 63.1, 63.4, 67.2, 68.3, 69.0, 70.3, 70.8, 97.8,
127.7 (×4), 128.4 (×2), 128.6 (×4), 128.7 (×2), 129.1, 129.3,
129.4, 129.5, 129.6 (×2), 129.8 (×4), 129.9 (×2), 130.0, 131.0,
133.2, 133.3, 133.5 (×3), 134.2, 135.7 (×4), 165.5, 165.6 (2),
General procedure for debenzoylation. The corresponding
benzoylated glycoside was dissolved in MeOH : THF (1 : 1)
(20 mL mmol−1) and then treated with a solution of NaOMe
(0.1 M) in MeOH. The reaction mixture was stirred until TLC
showed complete disappearance of the starting material. The
reaction was then neutralized by addition of acidic Amberlite
IR-120, filtered off, and concentrated. The residue was purified
by flash silica gel column chromatography.
166.3. ESI-HRMS: [M
+
H]+ m/z calcd 961.3983 for
C58H61O11Si, found 961.3958; [M + NH4]+ m/z calcd 978.4248
for C58H64O11SiN, found 978.4178; anal. calcd for C58H60O11Si
(961,17): C, 72.48; H, 6.29; O, 18.31; Si, 2.92. Found: C, 72.51;
H, 6.32.
Phenyl 6-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-1-
thio-α-D-mannopyranoside (10). Following the general pro-
cedure for glycosylation, the 1,2-orthoester 8 (number of equiva-
lents shown in Table 1) and the acceptor 9 were dissolved in dry
CH2Cl2 or dioxane (see Table 1), the solution was cooled to the
appropriate temperature, then NIS (number of equivalents shown
in Table 1) and BF3·Et2O (0.3 equiv.) or Yb(OTf)3 (0.3 equiv.)
were added. After TLC analysis indicated full disappearance of
the starting material, the reaction was quenched and the residue
was purified by flash chromatography (EtOAc). 1H-NMR
(300 MHz, CDCl3) δ: 3.84 (m, 1H), 3.89 (dd, J = 11.8, 1.6 Hz,
1H), 4.10 (t, J = 9.4 Hz, 1H), 4.23 (dd, J = 11.8, 3.6 Hz, 1H),
4.23–4.28 (m, 1H), 4.30–4.36 (m, 1H), 4.48 (dd, J = 11.7,
4.2 Hz, 1H), 4.52–4.56 (m, 1H), 4.69 (dd, J = 11.7, 2.3 Hz, 1H),
5.27 (d, J = 1.7 Hz, 1H), 5.60 (d, J = 1.3 Hz, 1H), 5.78 (dd, J =
3.3, 1.8 Hz, 1H), 5.91 (dd, J = 10.1, 3.4 Hz, 1H), 6.12 (t, J =
10.0 Hz, 1H), 7.20–8.10 (m, 25H). 13C-NMR (75 MHz, CDCl3)
δ: 63.0, 66.9, 67.2, 67.9, 69.0, 70.7 (×2), 72.6, 72.8 (×2), 88.6,
98.1, 127.7, 128.5 (×2), 128.6 (×2), 128.7 (×3), 128.8 (×2),
129.1, 129.2, 129.3 (×3), 129.4, 130.0 (×3), 130.1 (×3), 131.8
(×3), 133.3, 133.6, 133.7 (×2), 134.2, 165.7, 165.8, 166.1,
166.5. ESI-HRMS: [M + NH4]+ m/z calcd 868.2639 for
C46H46O14SN, found 868.2634; [2M + NH4]+ m/z calcd
1718.4934 for C92H88O28S2N, found 1719.4962; anal. calcd for
C46H42O14S (850.88): C, 64.93; H, 4.98; O, 26.32; S, 3.77.
Found: C, 64.77; H, 4.75. The structure of the disaccharide 10
was determined by acylation and 1H NMR analysis of the newly
8-O-tert-Butyldiphenylsilyl-4-(Z,E)-octenyl-α-D-manno-pyranoside
(13a). This compound was prepared from 12a (1.36 g,
1.4 mmol) following the general procedure for debenzoylation.
The residue was purified by flash chromatography (EtOAc) to
1
give 13a (720 mg, 95%) as a colorless oil; H-NMR (300 MHz,
CDCl3) δ: 1.05 (s, 9H), 1.49–1.66 (m, 4H), 1.94–2.11 (m, 4H),
3.26–4.03 (m, 10H), 4.79 (bs, 1H), 5.30–5.42 (m, 2H),
7.30–7.71 (m, 10H). 13C-NMR (75 MHz, CDCl3) δ: 19.3, 27.0
(×3), 28.9, 29.1, 29.4, 32.5, 61.0, 63.4, 66.2, 67.4, 71.1, 72.3,
100.2, 127.7 (×4), 129.6 (×2), 130.6 (×2), 134.1 (×2), 135.6
(×4). ESI-HRMS: [M + H]+ m/z calcd 545.2934 for C30H45O7Si
545.2824; [M + NH4]+ m/z calcd 562.3200 for C30H48O7SiN
562.3099. Anal. calcd for C30H44O7Si (544.75): C, 66.14; H,
8.14; O, 20.56; Si, 5.16. Found: C, 66.25; H, 8.30.
[9-O-tert-Butyldiphenylsilyl-4-(Z,E)-nonenyl]-2,3,4,6-tetra-O-
benzoyl-α-D-mannopyranoside (12b). n-Pentenyl glycoside 11
(664 mg, 1 mmol), 1-O-tert-butyldiphenylsilyl-5-hexen-1-ol 14b
(1.35 g, 4 mmol) and bis(tricyclohexylphosphine)benzylidine
ruthenium(IV) dichloride (41 mg, 0.05 mmol) were reacted
according to the general method for the CM reaction. The
residue was purified by flash silica gel column chromatography
(hexane/EtOAc, 9/1) to give 12b (770 mg, 79%) as a syrup;
1H-NMR (300 MHz, CDCl3) δ: 0.79–0.92 (m, 1H), 1.04 (s, 9H),
1.22–1.30 (m, 1H), 1.39–1.49 (m, 2H), 1.51–1.61 (m, 2H),
1.72–1.81 (m, 2H), 1.94–2.02 (m, 2H), 2.06–2.18 (m, 2H),
3.53–3.62 (m, 1H), 3.63–3.68 (m, 2H), 3.83 (dt, J = 9.1, 6.5 Hz,
1H), 4.39–4.45 (m, 1H), 4.48 (dd, J = 12.0, 4.5 Hz, 1H), 4.69
(dd, J = 12.0, 2.3 Hz, 1H), 5.08 (d, J = 1.7 Hz, 1H), 5.34–5.51
(m, 2H), 5.69 (dd, J = 3.3, 1.8 Hz, 1H), 5.92 (dd, J = 9.0,
3.3 Hz, 1H), 7.29–8.11 (m, 30H). ESI-HRMS: [M + NH4]+ m/z
calcd 992.4405 for C59H66O11SiN, found 992.4676; [M + H]+
m/z calcd 975.4139 for C59H66O11SiN, found 975.4436. Anal.
calcd for C59H62O11Si (974.40): C, 72.67; H, 6.41; O, 18.05; Si,
2.88. Found: C, 72.72; H, 6.58.
1
downshifted protons. H-NMR (300 MHz, CDCl3) δ: 2.00 (s,
3H), 2.06 (s, 3H), 2.12 (s, 3H), 3.64 (dd, J = 11.2, 2.4 Hz, 1H),
3.65–3.74 (m, 1H), 3.94 (dd, J = 11.2, 5.2 Hz, 1H), 4.29–4.35
(m, 1H), 4.37 (dd, J = 12.0, 4.2 Hz, 1H), 4.53 (ddd, J = 9.9, 5.2,
2.2 Hz, 1H), 4.61 (dd, J = 12.0, 2.4 Hz, 1H), 5.06 (d, J =
1.7 Hz, 1H), 5.30 (dd, J = 9.9, 3.2 Hz, 1H, H-3), 5.45 (t, J =
10.1 Hz, 1H, H-4), 5.46 (d, J = 1.7 Hz, 1H), 5.49 (dd, J = 3.2,
1.8 Hz, 1H, H-2), 5.72 (dd, J = 3.3, 1.7 Hz, 1H), 5.85 (dd, J =
10.1, 3.3 Hz, 1H), 6.07 (t, J = 10.0 Hz, 1H), 7.14–8.06
(m, 25H).
8-O-tert-Butyldiphenylsilyl-4-(Z,E)-octenyl-2,3,4,6-tetra-O-
benzoyl-α-D-mannopyranoside (12a). n-Pentenyl glycoside 11
(1.33 g, 2 mmol), 1-O-tert-butyldiphenylsilyl-4-penten-1-ol 14a
(2.6 g, 8 mmol) and bis(tricyclohexylphosphine)benzylidine
ruthenium(IV) dichloride (82 mg, 0.1 mmol) were reacted
according to the general method for the CM reaction. The
residue was purified by flash silica gel column chromatography
(hexane/EtOAc, 8/2) to give 12a (1.82 g, 90%) as a colorless
[9-O-tert-Butyldiphenylsilyl-4-(Z,E)-nonenyl]-l-α-D-manno-
pyranoside (13b). This compound was prepared from 12b
(720 mg, 0.748 mmol) following the general procedure for
debenzoylation. After stirring (2 h), the reaction was neutralized,
filtered, and concentrated. The residue was purified by flash
chromatography (EtOAc) to give 13b (237 mg, 80%); 13C-NMR
(75 MHz, CDCl3) δ: 19.3, 25.8, 27.0 (×3), 29.1, 29.4, 32.2,
32.4, 61.0, 63.9, 66.2, 67.4, 71.2, 71.8, 72.3, 100.1, 127.7 (×4),
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Glycosylation reaction of tetraol 13b with NPOE 8
129.3, 129.6 (×2), 131.1, 134.2 (×2), 135.7 (×4). API-ES
positive: 581.9 [M + Na]+. Anal. calcd for C31H46O7Si
(558.7782): C, 66.63; H, 8.30; O, 20.04; Si, 5.03. Found: C,
66.80; H, 8.41.
Reaction with Yb(OTf)3. To a stirred solution of tetraol 13b
(56 mg, 0.1 mmol) and NPOE 8 (79 mg, 0.12 mmol) in anhy-
drous CH2Cl2 (4 mL), at 10 °C, were added NIS (26.9 mg,
0.12 mmol) and Yb(OTf)3 (74 mg, 0.12 mmol). Work-up as
mentioned in the general procedure of glycosylation was fol-
lowed by column chromatography ((hexane/EtOAc, 7/3 to 1/1
and finally EtOAc) to give disaccharide 15b (14 mg, 13%).
9-O-Benzyl-4-(Z,E)-nonenyl-2,3,4,6-tetra-O-benzoyl-α-D-
mannopyranoside (12c). n-Pentenyl glycoside 11 (2.8 g,
4.2 mmol), 1-O-benzyl-5-hexen-1-ol 14c (1.6 g, 8.4 mmol) and
bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride
(172 mg, 0.21 mmol) were reacted according to the general
method for the CM reaction. The residue was purified by flash
silica gel column chromatography (hexane/EtOAc, 9/1) to give
Reaction with BF3·Et2O. To a stirred solution of tetraol 13b
(56 mg, 0.1 mmol) and NPOE 8 (79 mg, 0.12 mmol) in anhy-
drous CH2Cl2 (4 mL), at 0 °C, were added NIS (26.9 mg,
0.12 mmol) and BF3·Et2O (3.8 μL, 0.03 mmol). Work-up as
mentioned in the general procedure of glycosylation was fol-
lowed by column chromatography (hexane:EtOAc 7 : 3 to 1 : 1
and finally AcOEt) to give trisaccharide 16b (62 mg, 36%) fol-
lowed by disaccharide 15b (14 mg, 13%).
1
12c (2.32 g, 67%). H-NMR (300 MHz, CDCl3) δ: 1.40–1.51
(m, 2H), 1.58–1.68 (m, 2H), 1.75–1.82 (m, 2H), 1.99–2.08 (m,
2H), 2.10–2.23 (m, 2H), 3.45–3.50 (m, 2H), 3.54–3.63 (m, 1H),
3.79–3.89 (m, 1H), 4.40–4.52 (m, 4H), 4.68–4.72 (m, 1H), 5.09
(bs, 1H), 5.36–5.48 (m, 2H), 5.70 (dd, J = 1.8, 3.1 Hz, 1H), 5.93
(dd, J = 3.2, 10.1 Hz, 1H), 6.12 (t, J = 10.1 Hz, 1H);13C-NMR
(75 MHz, CDCl3) δ: 26.0, 28.9, 29.0, 29.1, 32.3, 62.8, 66.8,
67.0, 68.7, 70.0, 70.2, 70.5, 72.7, 97.6 (C1), 127.3, 127.5 (×2),
128.1 (×2), 128.2 (×2), 128.3 (×4), 128.5 (×2), 129.2, 129.6
(×3), 129.7 (2), 129.8 (×2), 131.0, 132.9, 133.0, 133.3 (×2),
138.6, 165.3, 165.4 (×2), 166.0. ESI-HRMS: [M + NH4]+ m/z
calcd 844.3696 for C50H55O11N, found 844.3601; [M + H]+ m/z
calcd 827.3431 for C50H51O11, found 827.3279. Anal. calcd for
C50H50O11 (826.92): C, 72.62; H, 6.09; O, 21.28. Found: C,
72.80; H, 6.22.
[9-O-tert-Butyldiphenylsilyl-4-(Z,E)-nonenyl]6-O-(2,3,4,6-tetra-
O-benzoyl-α-D-mannopyranosyl)-α-D-manno-pyranoside (15b).
1H-NMR (500 MHz, CDCl3) δ: 1.04 (s, 9H), 1.24–1.31 (m, 2H),
1.36–1.43 (m, 2H), 1.51–1.58 (m, 2H), 1.62–1.68 (m, 2H),
1.91–1.98 (m, 2H), 2.00–2.09 (m, 2H), 3.43–3.48 (m, 1H), 3.64
(t, J = 6.4 Hz, 2H), 3.69–3.75 (m, 2H), 3.77–3.81 (m, 1H),
3.82–3.86 (m, 1H), 3.90–3.98 (m, 2H), 4.16 (dd, J = 11.6,
4.2 Hz, 1H), 4.48 (dd, J = 12.1, 4.2 Hz, 1H), 4.57–4.60 (m, 1H),
4.71 (dd, J = 12.1, 2.7 Hz, 1H), 4.86 (bs, 1H), 5.32 (bs, 1H),
5.33–5.41 (m, 2H), 5.76 (bs, 1H), 5.93 (dd, J = 10.1, 3.4 Hz,
1H), 6.13 (t, J = 10.1 Hz, 1H), 7.23–8.11 (m, 30H); 13C-NMR
(75 MHz, CDCl3) δ: 18.2, 27.0 (×3), 29.3, 29.5, 31.1, 32.2,
32.4, 63.0, 64.0, 66.8, 67.0, 67.6, 68.1, 69.0, 70.2, 70.8, 71.1,
71.4, 72.4, 97.8, 100.0, 127.7 (×4), 128.5 (×2), 128.6 (×3),
128.7 (×2), 129.1 (×2), 129.4, 129.5, 129.6 (×2), 129.9 (×3),
130.0 (×2), 131.1, 133.2, 133.4, 133.6, 133.7, 135.7 (×2), 165.6,
165.7, 165.8, 166.4. ESI-HRMS: [M + NH4]+ m/z calcd
1154.4933 for C65H76O16SiN, found 1155.6382; [M + H]+ m/z
calcd 1137.4667 for C65H73O16Si, found 1138.2563. Anal. calcd
for C65H72O16Si (1137.3431): C, 68.64; H, 6.38; O, 22.51; Si,
2.47. Found: C, 68.89; H, 6.55.
[9-O-Benzyl-4-(Z,E)-nonenyl]-α-D-mannopyranoside
(13c).
This compound was prepared from 12c (2 g, 2.42 mmol) follow-
ing the general procedure for debenzoylation. The residue was
purified by flash chromatography (AcOEt) to give 13c (892 mg,
90%) as a colorless oil: 1H-NMR (300 MHz, CDCl3) δ:
1.35–1.46 (m, 2H), 1.56–1.67 (m, 4H), 1.95–2.09 (m, 4H),
3.33–3.97 (m, 10H), 4.49 (m, 2H), 4.79 (bs, 1H), 5.33–5.40 (m,
2H), 7.23–7.36 (m, 5H); 13C-NMR (75 MHz, CDCl3) δ: 25.9,
28.9, 29.1 (×2), 32.2, 60.7, 65.9, 67.1, 70.1, 70.9, 71.5, 72.1,
72.7, 99.9, 127.3, 127.5 (×2), 128.2 (×2), 129.3, 130.7, 138.5.
ESI-HRMS: [M + NH4]+ m/z calcd 428.2648 for C22H38O7N,
found 428.2576; [M + H]+ m/z calcd 411.2382 for C22H35O7,
found 411.2309. Anal. calcd for C22H34O7 (410.50): C, 64.37;
H, 8.35; O, 27.28. Found: C, 64.55; H, 8.40.
[9-O-tert-Butyldiphenylsilyl-4-(Z,E)-nonenyl]3,6-di-O-(2,3,4,6-
tetra-O-benzoyl-α-D-mannopyranosyl)-α-D-manno-pyranoside
(16b). 1H-NMR (500 MHz, CDCl3) δ: 1.02 (s, 9H), 1.31–1.43
(m, 2H), 1.48–1.65 (m, 4H), 1.90–2.06 (m, 4H), 3.32–3.40 (m,
2H), 3.62 (t, J = 6.4 Hz, 2H), 3.63–3.72 (m, 2H), 3.80–3.86 (m,
1H), 3.95 (d, J = 11.9 Hz, 1H), 3.99 (dd, J = 9.3, 2.9 Hz, 1H),
4.19 (dd, J = 11.6, 4.1 Hz, 1H), 4.22–4.27 (m, 2H), 4.52 (d, J =
12.0 Hz, 1H), 4.53 (d, J = 12.2 Hz, 1H), 4.56–4.63 (m, 1H),
4.67–4.76 (m, 3H), 4.88–4.94 (m, 1H), 5.29–5.41 (m, 2H), 5.42
(d, J = 1.5 Hz, 1H), 5.80 (dd, J = 3.3, 1.7 Hz, 1H), 5.87 (dd, J =
3.0, 1.7 Hz, 1H), 5.99 (dd, J = 9.7, 3.6 Hz, 1H), 6.02 (dd, J =
10.6, 3.3 Hz, 1H), 6.13 (t, J = 10.6 Hz, 1H), 6.15 (t, J = 9.7 Hz,
1H), 7.22–8.14 (m, 50H); 13C-NMR (75 MHz, CDCl3) δ: 19.4,
25.9, 32.2, 32.4, 63.1, 63.5, 64.0, 65.6, 66.8, 67.1, 67.2, 67.7,
69.0, 69.6, 70.1, 70.4, 70.5, 70.7, 71.0, 71.7, 83.2, 98.0, 99.9,
100.2, 127.7 (×4), 128.4 (×5), 128.5 (×4), 128.6 (×6), 128.7
(×4), 129.1, 129.2, 129.3, 129.4, 129.5 (×2), 129.6 (×4), 129.9
(×4), 130.0 (×8), 130.1 (×4), 131.1, 133.2 (×2), 133.3, 133.4,
133.5 (×2), 133.6, 133.7, 134.3, 135.7, 165.5, 165.6 (×2), 165.7
Glycosylation reaction of tetraol 13a with NPOE 8. According
to the general method for glycosylation NPOE 8 (199 mg,
0.3 mmol) and tetraol 13a (55.5 mg, 0.1 mmol) were dissolved
in CH2Cl2 (5 mL), and allowed to react for 15 min at −25 °C
with NIS (101 mg, 0.45 mmol) and BF3·Et2O (3.8 μL,
0.03 mmol). Purification by column chromatography (hexane/
EtOAc, 7/3) afforded trisaccharide 17 (66 mg, 41%) as a mixture
1
of diastereomers. Selected peaks for 17: H-NMR (500 MHz,
CDCl3) δ: 3.73 (m, 1 H, CH-furanyl), 4.10 (m, 1 H, CH-I).
13C-NMR (75 MHz, CDCl3) δ: 42.9, 43.0 (CH-I), 82.3, 82.4
(CH-Ofuranyl). ESI-HRMS: [M + NH4]+ m/z calcd 1606.4142
for C82H81O25IN, found 1606.4237; [M + H]+ m/z calcd
1589.3877 for C82H78O25I, found 1589.3831. Anal. calcd for
C82H77IO25 (1588.37): C, 61.97; H, 4.88; I, 7.98; O, 25.17.
Found: C, 61.88; H, 4.92.
8366 | Org. Biomol. Chem., 2012, 10, 8361–8370
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(×2), 165.8, 166.4, 166.5. ESI-HRMS: [M + H]+ m/z calcd
1715.6244 for C99H99O25Si, found 1717.1258. Anal. calcd for
C99H98O25Si (1715.9079): C, 69.30; H, 5.76; O, 23.31; Si, 1.64.
Found: C, 69.55; H, 5.86. The structure of the disaccharide 16b
was determined by acylation and 1H NMR analysis of the newly
downshifted protons: 1H-NMR (300 MHz, CDCl3) 1H-NMR
(500 MHz, CDCl3) δ: 1.02(s, 9H), 1.33–1.41 (m, 2H),
1.48–1.55 (m, 2H), 1.64–1.72 (m, 2H), 1.91–1.96 (m, 2H),
2.03–2.12 (m, 2H), 2.26 (s, 3H), 2.31 (s, 3H), 3.50 (dt, J = 9.6,
6.4 Hz, 1H), 3.61 (t, J = 6.5 Hz, 2H), 3.69 (dd, J = 9.0, 4.2 Hz,
1H), 3.81 (dt, J = 9.6, 6.8 Hz, 1H), 3.98–4.04 (m, 2H), 4.37 (dd,
J = 9.8, 3.5 Hz, 1H, H-3), 4.49 (dd, J = 12.2, 4.4 Hz, 1H), 4.52
(dd, J = 12.2, 3.6 Hz, 1H), 4.55–4.61 (m, 2H), 4.67 (dd, J =
12.2, 2.6 Hz, 1H), 4.71 (dd, J = 12.2, 2.5 Hz, 1H), 4.86 (d, J =
1.6 Hz, 1H), 5.15 (d, J = 1.8 Hz, 1H), 5.36 (d, J = 1.9 Hz, 1H),
5.38–5.41 (m, 2H), 5.43 (dd, J = 3.5, 1.6 Hz, 1H, H-2), 5.44 (t,
J = 9.8 Hz, 1H, H-4), 5.52 (dd, J = 3.6, 1.8 Hz, 1H), 5.75 (dd,
J = 3.3, 1.9 Hz, 1H), 5.81 (dd, J = 10.2, 3.2 Hz, 1H), 5.94 (dd,
J = 10.2, 3.3 Hz, 1H), 6.13 (t, J = 10.2 Hz, 1 H), 6.18 (t, J =
10.2 Hz, 1 H), 7.23–8.15 (m, 50 H).
4.44–4.47 (m, 2H), 4.52 (dd, J = 11.8, 3.9 Hz, 1H), 4.55–4.63
(m, 1H), 4.67–4.76 (m, 2H), 4.88–4.94 (m, 1H), 5.33–5.44 (m,
4H), 5.79 (dd, J = 3.2, 1.7 Hz, 1H), 5.86 (dd, J = 3.1, 1.8 Hz,
1H), 6.00 (dd, J = 9.7, 3.5 Hz, 1H), 6.02 (dd, J = 9.6, 3.4 Hz,
1H), 6.10–6.18 (m, 2H), 7.22–8.15 (m, 45H). 13C-NMR
(75 MHz, CDCl3) δ: 26.1, 29.3, 32.4, 63.0, 63.4, 65.8, 66.8,
66.9, 67.0, 67.5, 68.9, 69.5, 70.2, 70.4, 70.5, 70.6 (×2), 70.8,
71.7, 72.9 (×2), 82.9, 97.7, 99.9, 100.0, 127.5 (×3), 127.7 (×3),
128.3 (×3), 128.4 (×7), 128.5 (×3), 128.6 (×3), 128.9, 129.1 (2),
129.2, 129.3, 129.4, 129.6, 129.8 (×6), 129.9 (×9), 130.0 (3),
130.8, 133.1 (×2), 133.2, 133.3, 133.4 (×2), 133.5 (×2), 138.7,
165.4, 165.5, 165.6, 165.7 (×2), 165.9, 166.3, 166.4.
ESI-HRMS: [M + NH4]+ m/z calcd 1584.5801 for C90H90O25N,
found 1584.5727; [M
+
H]+ m/z calcd 1567.5536 for
C90H87O25, found 1567.5433. Anal. calcd for C90H86O25
(1567.6308): C, 68.96; H, 5.53; O, 25.52; found: C, 68.63;
H, 5.77.
[9-O-Benzyl-4-(Z,E)-nonenyl]6-O-(2,3,4,6-tetra-O-benzoyl-α-D-
mannopyranosyl)-3-O-(2-O-benzoyl-3,4,6-tri-O-benzyl-α-D-manno-
pyranosyl)-α-D-mannopyranoside (19). Following the general
procedure for glycosylation the NPOE 18 (311 mg, 0.5 mmol)
and disaccharide 15c (200 mg, 0.2 mmol) were dissolved in
CH2Cl2 (10 mL), and treated for 15 min with NIS (112 mg,
0.5 mmol) and BF3·Et2O (2.5 μL, 0.02 mmol) at −25 °C. After
work-up and column chromatography (hexane/EtOAc, 8/2 to
EtOAc), trisaccharide 19 (130 mg, 43%, 63% corrected) and
recovered disaccharide 15c (64 mg, 32%) were obtained. For 19:
1H-NMR (400 MHz, CDCl3) δ: 1.25–1.37 (m, 2H), 1.46–1.54
(m, 2H), 1.55–1.65 (m, 2H), 1.86–1.93 (m, 2H), 1.94–2.05 (m,
2H), 3.31–3.35 (m, 1H), 3.35 (t, J = 6.6 Hz, 2H), 3.56 (dd, J =
9.9, 7.4 Hz, 1H), 3.65–3.74 (m, 2H), 3.75–3.83 (m, 3H), 3.86
(dd, J = 11.0, 1.7 Hz, 1H), 3.92 (t, J = 9.6 Hz, 1H), 4.00 (dd, J
= 11.0, 8.0 Hz, 1H), 4.09 (m, 2H), 4.24–4.30 (m, 1H), 4.38 (t, J
= 8.0 Hz, 1H), 4.40–4.45 (m, 2H), 4.46 (d, J = 12.0 Hz, 1H),
4.49–4.52 (m, 1H), 4.54 (d, J = 12.0 Hz, 1H), 4.55 (d, J =
11.2 Hz, 1H), 4.57 (d, J = 1.5 Hz, 1H), 4.62 (dd, J = 12.1,
2.5 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.79 (d, J = 11.1 Hz,
1H), 5.15 (d, J = 1.9 Hz, 1H), 5.16 (d, J = 2.0 Hz, 1H),
5.28–5.39 (m, 2H), 5.55 (dd, J = 3.2, 2.0 Hz, 1H), 5.68 (dd, J =
3.2, 1.9 Hz, 1H), 5.88 (dd, J = 10.1, 3.2 Hz, 1H), 6.06 (t, J =
10.1 Hz, 1H), 7.09–8.07 (m, 45H); 13C-NMR (75 MHz, CDCl3)
δ: 26.0, 29.1, 29.2, 29.3, 32.3, 62.8, 65.9, 66.9, 67.1, 67.2, 69.2,
69.5, 69.8, 69.9, 70.3, 70.6, 71.2, 71.8, 72.0, 72.8, 73.5, 74.6,
74.8, 78.1, 82.3, 97.5, 99.0, 100.3, 127.4, 127.5 (×2), 127.6,
127.7, 127.8, 127.9 (×3), 128.1 (×3), 128.2, 128.3 (×7), 128.4
(×6), 128.5 (×2), 129.0, 129.1, 129.3, 129.6 (×2), 129.7 (×6),
129.8 (×4), 129.9 (×2), 130.6, 132.9, 133.0, 133.2, 133.8 (×2),
137.4, 137.7, 138.0, 138.6, 165.2, 165.3, 165.7, 166.2.
ESI-HRMS: [M + Na]+ m/z calcd 1547.5978 for C90H92O22Na,
found 1548.6020. Anal. calcd for C90H92O22 (1525.6803): C,
70.85; H, 6.08; O, 23.07; found: C, 70.45; H, 6.33. The structure
of the disaccharide 19 was determined by acylation and 1H
NMR analysis of the newly downshifted protons 1H-NMR
(400 MHz, CDCl3) δ: 1.33–1.44 (m, 2H), 1.51–1.61 (m, 2H),
1.62–1.72 (m, 2H), 1.92–2.00 (m, 2H), 2.02–2.09 (m, 2H), 2.10
(s, 3H), 2.20 (s, 3H), 3.41 (t, J = 6.6 Hz, 2H), 3.43–3.48 (m,
1H), 3.64–3.69 (m, 1 H), 3.71–3.79 (m, 2H), 3.81–3.84 (m, 1H),
3.87 (dd, J = 10.6, 3.0 Hz, 1H), 3.90–3.96 (m, 2H), 4.01 (dd,
Glycosylation reaction of tetraol 13c with NPOE 8. In two
different experiments, and following the general procedure for
glycosylation, NPOE 8 (80 mg, 0.12 mmol and 265 mg,
0.4 mmol, respectively) and tetraol 13c (41 mg, 0.12 mmol) in
CH2Cl2 (3 mL) were reacted with NIS (26.9 mg, 0.12 mmol and
89.6 mg, 0.4 mmol, respectively) and BF3·Et2O (1.5 μL,
0.012 mmol) at −5 °C. After work-up and column chromato-
graphy (hexane/EtOAc, 7/3 to 1/1 and finally EtOAc), trisacchar-
ide 16c (15 mg, 10% and 60 mg, 38%, respectively) and
disaccharide 15c (46 mg, 46% and 11 mg, 11%, respectively)
were obtained.
[9-O-Benzyl-4-(Z,E)-nonenyl]6-O-(2,3,4,6-tetra-O-benzoyl-α-D-
mannopyranosyl)-α-D-mannopyranoside
(15c). 1H-NMR
(300 MHz, CDCl3) δ: 1.28–1.36 (m, 2H), 1.48–1.60 (m, 4H),
1.87–1.92 (m, 2H), 1.94–2.01 (m, 2H), 3.33–3.38 (m, 1H), 3.37
(t, J = 6.6 Hz, 2H), 3.65 (td, J = 6.6, 9.6 Hz, 1H), 3.73 (ddd, J =
1.5, 3.9, 9.6 Hz, 1H), 3.80 (dd, J = 3.3, 9.6 Hz, 1H), 3.83 (dd, J
= 1.7, 12.0 Hz, 1H), 3.89 (dd, J = 1.4, 3.3 Hz, 1H), 3.94 (t, J =
9.6 Hz, 1H), 4.11 (dd, J = 4.2, 11.3 Hz, 1H), 4.37–4.43 (m, 3H),
4.52 (m, 1H), 4.65 (dd, J = 2.5, 12.2 Hz, 1H), 4.79 (d, J =
1.2 Hz, 1H), 5.21 (d, J = 1.8 Hz, 1H), 5.29–5.32 (m, 2H), 5.69
(dd, J = 1.8, 3.3 Hz, 1H), 5.84 (dd, J = 3.2, 10.2 Hz, 1H), 6.07
(t, J = 10.2 Hz, 1H), 7.16–7.52 (m, 15H), 7.74–8.04 (m, 8H).
13C-NMR (75 MHz, CDCl3) δ: 26.0, 29.1, 29.2, 32.3, 62.8,
66.5, 66.7, 67.3, 67.6, 68.7, 70.2, 70.3, 70.5, 70.9, 71.2, 72.3,
72.8, 97.5, 99.9, 127.4, 127.6 (×4), 128.2 (×4), 128.3 (×4),
128.4 (×4), 128.5 (×4), 129.5, 129.7 (×3), 129.8, 130.6, 132.9,
133.2, 133.3, 133.4, 138.5, 165.4, 165.5, 165.7, 166.2.
ESI-HRMS: [M + Na]+ m/z calcd 1011.3779 for C56H60O16Na,
found 1011.3785; anal. calcd for C56H60O16 (989.0660): C,
68.00; H, 6.11; O, 25.88. Found: C, 68.35; H, 6.25.
[9-O-Benzyl-4-(Z,E)-nonenyl]3,6-di-O-(2,3,4,6-tetra-O-benzoyl-
α-D-mannopyranosyl)-α-D-mannopyranoside
(16c). 1H-NMR
(400 MHz, CDCl3) δ: 1.34–1.44 (m, 2H), 1.54–1.66 (m, 4H),
1.92–2.09 (m, 4H), 3.33–3.46 (m, 3H), 3.64–3.75 (m, 1H),
3.81–3.87 (m, 1H), 4.00 (dd, J = 9.3, 3.1 Hz, 1H), 3.92–3.97
(m, 1H), 4.20 (dd, J = 11.9, 4.4 Hz, 1H), 4.22–4.27 (m, 2H),
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J = 9.5, 3.1 Hz, 1H), 4.15 (t, J = 9.6 Hz, 1H), 4.23 (dd, J = 10.0,
3.2 Hz, 1H, H-3), 4.43–4.52 (m, 4H), 4.54 (d, J = 11.3 Hz, 1H),
4.59 (d, J = 11.4 Hz, 1H), 4.67–4.71 (m, 1H), 4.72 (d, J = 12.0
Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.82 (d, J = 1.8 Hz, 1H),
4.85 (d, J = 11.1 Hz, 1H), 5.13 (d, J = 2.0 Hz, 1H), 5.14 (d, J =
1.7 Hz, 1H), 5.21 (dd, J = 3.3, 1.8 Hz, 1H, H-2), 5.34–5.42 (m,
3H, H-4), 5.44 (dd, J = 2.0, 1.7 Hz, 1H), 5.74 (dd, J = 3.3,
1.8 Hz, 1H), 5.92 (dd, J = 10.1, 3.3 Hz, 1H), 6.12 (t, J =
10.1 Hz, 1H), 7.17–8.13 (m, 45H). 13C-NMR (75 MHz, CDCl3)
δ: 21.0, 21.1, 26.2, 29.3, 29.4 (×2), 32.5, 62.9, 66.8, 66.9, 67.9,
68.0, 68.7, 69.0, 69.3, 69.6, 70.1, 70.4 (×2), 71.7, 71.8, 72.5,
72.9, 73.5, 74.0, 75.0, 76.1, 77.7, 97.2, 97.6, 100.5, 127.5 (×2),
127.6 (×4), 127.7 (×2), 128.0 (×2), 128.1 (×2), 128.3 (×3),
128.4 (×5), 128.5 (×5), 128.6 (×4), 128.7 (×2), 129.1, 129.3,
129.4, 129.6 (×2), 129.8 (×3), 129.9 (×3), 130.0 (×2), 131.0,
133.2 (×2), 133.3, 133.5, 133.6, 138.0, 138.6, 138.7, 138.8,
165.3, 165.4, 165.6, 165.9, 166.3, 170.2, 170.7.
128.2 (×3), 128.3 (×4), 128.4 (×3), 128.5 (×10), 128.6 (×7),
128.7 (×5), 129.7, 130.0, 130.1, 130.8, 133.2, 133.3, 137.6,
137.7, 138.0 (×2), 138.2 (×2), 138.3, 138.4, 138.5, 138.8, 165.8,
166.0. ESI-HRMS: [M + NH4]+ m/z calcd 2094.9511 for
C
123H140O29N, found 2096.5679. Anal. calcd for C123H136O29
(2078.38): C, 69.33; H, 6.80; O, 23.87. Found: C, 69.66; H,
6.95. The structure of the pentasaccharide 21 was confirmed by
acylation and 1H NMR analysis of the newly downshifted
1
protons: H-NMR (500 MHz, CDCl3, selected signals) δ: 5.11
(dd, J = 3.5, 1.7 Hz, 1H, H-2), 5.13 (dd, J = 3.3, 1.9 Hz, 1H,
H-2), 5.21 (dd, J = 3.6, 1.6 Hz, 1H, H-2), 5.22 (t, J = 10.0 Hz,
1H, H-4), 5.38 (t, J = 10.6 Hz, 1H, H-4). For 22: 1H-NMR
(400 MHz, CDCl3) δ: 1.39–1.46 (m, 2H), 1.56–1.64 (m, 4H),
1.97–2.07 (m, 4H), 3.26–3.34 (m, 1H), 3.46 (t, J = 6.6 Hz, 2H),
3.47–3.51 (m, 1H), 3.56–3.64 (m, 6H), 3.73–3.89 (m, 7H),
3.90–3.97 (m, 3H), 3.99–4.09 (m, 5H), 4.12 (dd, J = 10.1,
3.2 Hz, 1H), 4.15 (t, J = 10.2 Hz, 1H), 4.45 (d, J = 11.2 Hz,
1H), 4.46 (d, J = 11.8 Hz, 1H), 4.48–4.54 (m, 5H), 4.56 (d, J =
11.5 Hz, 1H), 4.66 (m, 2H), 4.67 (d, J = 12.0 Hz, 1H), 4.76 (d, J
= 11.3 Hz, 1H), 4.78 (d, J = 11.2 Hz, 1H), 4.84 (bs, 1H), 4.85
(d, J = 10.6 Hz, 1H), 4.98 (bs, 1H), 5.09 (bs, 1H), 5.40 (m, 2H),
5.70 (dd, J = 3.0, 1.9 Hz, 1H), 7.10–8.10 (m, 40H). 13C-NMR
(75 MHz, CDCl3) δ: 26.3, 29.3, 29.5, 29.6, 32.6, 65.4, 65.8,
67.0, 67.4, 68.0, 69.0, 69.3, 69.4 (×2), 69.6, 69.9, 70.5 (×2),
70.6, 70.9, 71.2, 71.7 (×2), 71.9, 72.2, 72.5, 73.1, 73.6, 73.8,
74.5, 74.9, 75.0, 75.5, 78.4, 80.1, 82.2, 97.8, 99.7, 100.8, 101.3,
127.7 (×3), 127.8 (×2), 127.9 (×3), 128.0, 128.1 (×4), 128.2
(×2), 128.3 (×5), 128.5 (×5), 128.6 (×6), 128.7 (×4), 129.8,
130.1, 130.2 (×2), 130.9, 133.4, 137.6, 138.0, 138.1, 138.3,
138.4, 138.5, 138.8, 166.2. ESI-HRMS: [M + Na]+ m/z calcd
1563.6866 for C89H104O23Na, found 1564.8234. Anal. calcd for
C89H104O23 (1541.76): C, 69.33; H, 6.80; O, 23.87. Found: C,
69.66; H, 6.95.
[9-O-Benzyl-4-(Z,E)-nonenyl]-6-O-(-α-D-mannopyranosyl)-3-
O-(3,4,6-tri-O-benzyl-α-D-mannopyranosyl)-α-D-mannopyrano-
side (20). This compound was prepared from 19 (130 mg,
0.085 mmol) following the general procedure for debenzoyla-
tion. The residue was purified by flash chromatography (CH2Cl2/
MeOH 9/1) to give 20 (73 mg, 86%). 1H-NMR (400 MHz,
CDCl3) δ: 1.26–1.67 (m, 6H), 1.84–2.06 (m, 4H), 3.10–3.28 (m,
2H), 3.38–3.67 (m, 5H), 3.68–4.08 (m, 8H), 4.22–4.41 (m, 3H),
4.46–4.79 (m, 8H), 4.87 (bs, 1H), 5.18–5.25 (m, 2H), 5.26–5.42
(m, 2H), 7.01–7.44 (m, 20H). 13C-NMR (75 MHz, CDCl3) δ :
26.2, 29.2, 29.4, 32.5, 61.4, 65.4, 66.7, 67.3, 68.7, 69.4, 70.4,
70.6, 71.3, 71.5, 71.7, 72.3, 72.9, 73.0, 73.5, 74.1, 75.0, 77.3,
79.4, 100.0, 100.2, 101.7, 127.6 (×2), 127.7 (×2), 127.8 (×2),
128.0 (×2), 128.1 (×4), 128.4 (×4), 128.5 (×4), 129.7, 130.7,
137.7, 138.0, 138.5, 138.7. ESI-HRMS: [M + Na]+ m/z calcd
1027.4667 for C55H72O17Na, found 1027.4663. Anal. calcd for
C55H72O17 (1005.15): C, 65.72; H, 7.22; O, 27.06. Found: C,
65.55; H, 7.35.
Glycosylation reaction of tetrasaccharide 22 with NPOE
18. Following the general procedure for glycosylation, the
NPOE 18 (16 mg, 0.026 mmol) and tetrasaccharide 22 (20 mg,
0.0129 mmol) were dissolved in CH2Cl2 (3 mL), and treated
with NIS (5.8 mg, 0.026 mmol) and BF3·Et2O (0.3 μL,
0.0026 mmol) at −15 °C. After work-up and column chromato-
graphy (hexane/EtOAc, 1/1), pentasaccharide 21 (14 mg, 52%)
was obtained.
Glycosylation reaction of heptaol trisaccharide 20 with NPOE
18. Following the general procedure for glycosylation, the
NPOE 18 (163 mg, 0.26 mmol) and heptaol trisaccharide 20
(44 mg, 0.044 mmol) were dissolved in CH2Cl2 (7 mL), and
treated with NIS (58 mg, 0.26 mmol) and BF3·Et2O (0.6 μL,
0.0044 mmol) at −15 °C. After work-up and column chromato-
graphy (hexane/EtOAc, 8/2 to EtOAc), pentasaccharide 21
(40 mg, 44%) and tetrasaccharide 22 (26 mg, 38%) were
Acetylation followed by CM with ethylene of pentasaccharide
21. Pentasaccharide 21 (12.5 mg) was acetylated following
usual conditions (Ac2O, pyr) to give acetylated derivative 23.
Argon was then bubbled through a solution of 23 (14 mg,
0.006 mmol) in CH2Cl2 (2 mL) and subsequently treated with
Grubbs’ catalyst (1 mg, 0.0012 mmol). The reaction mixture
was purged with ethylene and stirred (rt, 12 h). The residue was
filtered through a Florisil pad and purified by flash chromato-
graphy (hexane/EtOAc, 7/3) to afford n-pentenyl pentasacchar-
ide 24 (12 mg, 94%). Foam. [α]D = +22.9 (c 1.0, CHCl3).
1H-NMR (400 MHz) δ: 1.55–1.65 (m, 2H), 1.99 (s, 3H),
2.02–2.11 (m, 2H), 2.09 (s, 3H), 2.12 (s, 3H), 2.16 (s, 3H), 3.35
(dt, J = 9.7, 6.3 Hz, 1H), 3.46–3.51 (m, 1H), 3.59–3.81 (m,
11H), 3.83 (dd, J = 9.5, 3.3 Hz, 1H), 3.87–3.95 (m, 5H), 4.00
(dd, J = 9.5, 3.0 Hz, 1H), 4.06–4.20 (m, 5H), 4.40–4.48
(m, 3H), 4.50–4.89 (m, 20H), 4.91–4.99 (m, 2H), 4.97 (d,
1
obtained. For 21: H-NMR (500 MHz, CDCl3) δ: 1.15–1.22 (m,
2H), 1.29–1.37 (m, 2H), 1.49–1.55 (m, 2H), 1.86–1.98 (m, 4H),
3.22–3.27 (m, 1H), 3.37 (t, J = 6.6 Hz, 2H), 3.44–3.58 (m, 7H),
3.64–3.91 (m, 13H), 3.94–4.09 (m, 5H), 4.15 (m, 1H),
4.18–4.22 (m, 1H), 4.37–4.52 (m, 12H), 4.57 (d, J = 11.4 Hz,
1H), 4.59–4.62 (m, 2H), 4.64 (d, J = 12.1 Hz, 1H), 4.69–4.79
(m, 8H), 4.91 (bs, 1H), 5.02 (bs, 1H), 5.14 (bs, 1H), 5.25–5.35
(m, 2H), 5.54 (bs, 1H), 5.67 (bs, 1H), 7.07–7.99 (60H).
13C-NMR (75 MHz, CDCl3) δ: 26.2, 29.2, 29.4, 29.5, 32.5,
65.5, 65.8, 66.1, 66.9, 67.2, 68.7, 69.0, 69.1, 69.2, 69.7 (×2),
69.9, 70.4, 70.8, 71.0, 71.6 (×2), 71.7, 72.0 (×2), 72.2, 72.9,
73.0, 73.4, 73.7 (×2), 74.4, 74.7, 74.8, 74.9, 75.0, 75.4, 78.3,
78.4, 80.1, 81.8, 81.9, 97.6, 98.9, 100.3, 100.7, 101.4, 127.6
(×4), 127.7 (×6), 127.8 (×2), 127.9 (×4), 128.0 (×6), 128.1 (×4),
8368 | Org. Biomol. Chem., 2012, 10, 8361–8370
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J = 1.8 Hz, 1H), 5.06 (d, J = 1.9 Hz, 1H), 5.07 (d, J = 2.0 Hz,
1H), 5.11 (dd, J = 3.4, 1.7 Hz, 1H), 5.12 (dd, J = 3.3, 1.6 Hz,
1H), 5.20 (t, J = 10.0 Hz, 1H), 5.21 (dd, J = 3.4, 1.7 Hz, 1H),
5.37 (t, J = 10.0 Hz, 1H), 5.41 (dd, J = 3.0, 2.0 Hz, 1H), 5.66
(dd, J = 3.0, 1.9 Hz, 1H), 5.72 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H),
7.11–8.07 (m, 55H). 13C-NMR (75 MHz) δ: 20.9, 21.9 (×2),
21.1, 21.2, 28.5, 30.3, 65.8, 66.5, 67.6, 67.7, 68.1, 68.5, 68.7,
69.0, 69.2 (×2), 69.3, 69.6, 69.7, 71.4, 71.7 (×2), 71.9 (×2),
72.0, 72.2, 72.7, 73.5 (×3), 73.9, 74.0, 74.3, 75.0, 75.1, 75.3,
75.8, 76.4, 77.4 (×2), 78.5, 97.1, 97.2, 98.1, 100.4 (×2), 115.2,
127.5 (×4), 127.6 (×5), 127.7 (×4), 127.8 (×4), 127.9 (×4),
128.0 (×3), 128.1 (×5), 128.2 (×3), 128.3 (×5), 128.4 (×6),
128.5 (×10), 130.0, 130.1, 133.2, 133.3, 138.0, 138.1, 138.2,
138.3, 138.6 (×2), 138.7 (×2), 165.7, 165.8, 169.8, 170.0, 170.5,
170.6 (×2). ESI-HRMS: [M + NH4]+ m/z calcd 2142.8995 for
C122H136O33N, found 2143.8892. Anal. calcd for C122H132O33
(2124.86): C, 68.91; H, 6.26; O, 24.83. Found: C, 68.76;
H, 6.63.
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Acknowledgements
14 J. R. Merritt, E. Naisang and B. Fraser-Reid, J. Org. Chem., 1994, 59,
4443–4449.
This research has been supported with funds from the Ministerio
de Ciencia e Innovación and Comunidad de Madrid grants
CTQ2009-10343 and S2009/PPQ-1752, respectively. BFR
thanks the National Science Foundation, grant CHE 0717702.
We also thank Ms Marina Rodríguez (IQOG) for skillful techni-
cal support.
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