Synthesis of β-(1→2)-Linked 6-Deoxy- l -altropyranose Oligosaccharides via Gold(I)-Catalyzed Glycosylation of an ortho-Hexynylbenzoate Donor

Article abstract of DOI:10.1021/acs.joc.7b00057

The β-(1→2)-linked 6-deoxy-l-altropyranose di- to pentasaccharides 2-5, relevant to the O-antigen of the infectious Yersinia enterocolitica O:3, were synthesized for the first time. The challenging 1,2-cis-altropyranosyl linkage was assembled effectively via glycosylation with 2-O-benzyl-3,4-di-O-benzoyl-6-deoxy-l-altropyranosyl ortho-hexynylbenzoate (7) under the catalysis of PPh₃AuNTf₂. NMR and molecular modeling studies showed that the pentasaccharide (5) adopted a left-handed helical conformation.

Full text of DOI:10.1021/acs.joc.7b00057

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Article
Synthesis of #-(1-2)-Linked 6-Deoxy-L-altropyranose Oligosaccharides
via Gold(I)-Catalyzed Glycosylation of a ortho-Hexynylbenzoate Donor
Zhengnan Shen, Hani Mobarak, Wei Li, Göran Widmalm, and Biao Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00057 • Publication Date (Web): 23 Feb 2017
Downloaded from http://pubs.acs.org on February 24, 2017
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Synthesis of βꢀ(1→2)ꢀLinked 6ꢀDeoxyꢀ ꢀaltropyranose
L
5
Oligosaccharides via Gold(I)ꢀCatalyzed Glycosylation of a
6
7
8
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orthoꢀHexynylbenzoate Donor
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Zhengnan Shen,†,‡ Hani Mobarak,§ Wei Li,‡ Göran Widmalm,§* and Biao Yu‡*
†School of Physical Science and Technology, ShanghaiTech University, 100 Haike
Road, Shanghai 201210 (China)
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032 (China)
§Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
Sꢀ106 91 Stockholm (Sweden)
Eꢀmail: byu@sioc.ac.cn
Goran.Widmalm@su.se
Table of Contents
Abstract
The βꢀ(1→2)ꢀlinked 6ꢀdeoxyꢀ
Lꢀaltropyranose diꢀ to pentaꢀsaccharides 2–5, relevant to
the Oꢀantigen of the infectious Yersinia enterocolitica O:3, were synthesized for the
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first time. The challenging 1,2ꢀcisꢀaltropyranosyl linkage was assembled effectively
5
6
via glycosylation with 2ꢀOꢀbenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀLꢀaltropyranosyl
7
8
9
orthoꢀhexynylbenzoate (7) under the catalysis of PPh3AuNTf2. NMR and molecular
modeling studies showed that the pentasaccharide (5) adopted a leftꢀhanded helical
conformation.
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Introduction
Yersinia enterocolitica, a coccobacillus widely spread in nature, can survive below 0
οC or above 40 οC in both invertebrates and vertebrates.1 The Serotypes O:3, O:8, and
O:9 are human pathogens that cause various intestinal and gastric infections.2
ο
Particularly, their tolerance to grow at 5 C makes them lifeꢀthreatening in the
transfusion of contaminated blood.3 In view of the important role of
lipopolysaccharides (LPSs) in the invasion of bacteria to their host,4 the structural
analysis of Y. enterocolitica LPSs was conducted in the early 1970s, and a rare sugar
6ꢀdeoxyꢀL
ꢀaltropyranose was isolated as one of the major components.5 Further
studies disclosed that 6ꢀdeoxyꢀ
LꢀAltp assembled via a βꢀ(1→2)ꢀglycosidic linkage to
form a homopolysaccharide in the Oꢀantigen of Y. enterocolitica O:3.6 It is of great
interest to synthesize a series of the 6ꢀdeoxyꢀLꢀAltp oligosaccharides (Figure 1) in
order to study their potential biological functions in the bacteriaꢀhost interaction.
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FIGURE 1. The synthetic 6ꢀdeoxyꢀβꢀ
L
ꢀAltp-containing oligosaccharides 1–5 relevant
to the Oꢀantigen of Y. enterocolitica O:3 and the proposed βꢀselective glycosylation.
Relevant to the synthesis of βꢀglycosidic linkages in mannosides and rhamnosides, the
construction of the equatorial 1,2ꢀcisꢀβꢀlinkages in 6ꢀdeoxyꢀβꢀLꢀAltp (the C3ꢀepimer
of rhamnose) represents a synthetic challenge because of the αꢀfavored anomeric and
steric effects as well as the incapable of neighboring participation from a
transꢀoriented acyl group at O2.7 Crich et al. have developed an effective βꢀselective
mannosylation protocol8 with substrates tethered with 4,6ꢀOꢀbenzylidene group that
provides the torsional and electron withdrawing effects to favor the SN2ꢀlike
glycosylation via an intimate αꢀintermediate.9 This protocol cannot be applied to the
direct βꢀrhamnosylation due to the lack of an exoꢀcyclic hydroxymethyl group on
rhamnosyl donors. Nevertheless, several methods for βꢀselective rhamnosylation have
been developed employing donors equipped with a variety of protecting and leaving
groups associated with varied glycosylation conditions.10 However, to the best of our
knowledge, the stereoselective βꢀglycosylation of 6ꢀdeoxyꢀLꢀAltp has not been
reported.
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Recently, we discovered that glycosylation with both mannosyl and rhamnosyl
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6
orthoꢀalkynylbenzoate donors could provide good βꢀselectivity under the catalysis of
7
8
F
F
PPh3AuBAr4 (BAr4 = tetrakis[3,5ꢀbisꢀ(trifluoromethyl)phenyl]borate) complex.11,12
9
The βꢀstereoselective glycosylation could be attributed to favorable
a
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1ꢀαꢀglycosyloxyꢀisochromenyliumꢀ4ꢀgold(I) intermediate (e.g., I) that subsequently is
displaced by nucleophilic substitution via an SN2ꢀlike pathway.11 As a consequence,
we envisioned orthoꢀhexynylbenzoate donor 7 (Figure 1) installed with a
nonꢀparticipating benzyl group at O2 of 6ꢀdeoxyꢀLꢀAltp as a choice to construct the
desired glycosidic βꢀ(1→2)ꢀlinkage. In addition, two benzoyl groups were installed at
O3 and O4 that might enhance the βꢀselectivity via a putative remote participation
(via intermediate II),7d,11b,13 while the 2ꢀOꢀbenzyl group serves as a temporary
protecting group at the position where glycan elongation will take place. Herein, we
report the synthesis of 6ꢀdeoxyꢀβꢀLꢀAltp-containing monoꢀ to pentasaccharides 1–5
employing the gold(I)ꢀcatalyzed iterative glycosylation with orthoꢀhexynylbenzoate
donor 7 and 1H NMR analysis of the synthetic oligosaccharides.
Results and Discussion
Our
synthesis
commenced
with
the
preparation
of
methyl
2,4ꢀdiꢀOꢀacetylꢀ6ꢀdeoxyꢀαꢀ
LꢀAltp 8 from Lꢀrhamnose (6 steps and 40% overall
yield) employing modifications of literature transformations (Scheme 1).14a Treatment
of 8 with a catalytic amount of MeONa in MeOH led to triol 9 (99%),6b which was
then subjected to a regioselective isopropylidene protection of the cisꢀoriented 3ꢀOH
and 4ꢀOH groups in the presence of (CH3)2C(OMe)2 and CSA (camphorsulfonic acid)
at rt. The residue was directly used in the benzylation of the axial 2ꢀOH with BnBr
and NaH in DMF, and the subsequent acidic hydrolysis of the isopropylidene group
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provided diol 10 in an excellent 93% yield (3 steps from 9). Benzoylation of the two
free hydroxyl groups on 10 under the conditions of BzCl and Et3N in a catalytic
amount of DMAP provided 11 (90%).
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SCHEME 1. Preparation of 6ꢀdeoxyꢀ
L
ꢀAltp acceptor 6 and donor 7.
OMe
OH
MeONa, MeOH,
rt, 99%
OH
O
6 steps, 40%
O
AcO
HO
HO
L-rhamnose
OH
OAc
8
a) (CH3)2C(OMe)2, CSA, acetone, rt;
b) BnBr, NaH (60%), DMF, rt;
c) AcOH (80%, aq.), rt, 93%
OMe
OMe
OH
O
OH
O
HO
HO
OBn
OH
10
9
OMe
HCl (5 N), AcOH,
OBz
O
BzCl, DMAP, Et3N,
CH2Cl2, rt, 90%
SrCl2 6H O, 80 oC, 80%
•
2
BzO
OBn
nBu
11
nBu
OH
OBz
O
BzO
OBz
O
COOH
O
OBn
( / = 2.1:1)
BzO
DMAP, EDCI,
CH2Cl2, rt, 97%
O
12
OBn
7 ( / = 3.2:1)
Ag2O, MeI, CH2Cl2, 4Å MS, rt, 88%
OBz
O
Pd/C (5%), H2,
MeOH, rt, 83%
OBz
O
OMe
OMe
BzO
BzO
OH
OBn
13
6
The subsequent cleavage of the anomeric methyl group on 11 turned out to be
difficult, wherein the acidic conditions with AcOH, HCl, or H2SO4 at various
temperatures failed to give the desired hemiacetal (See SI). Fortunately, addition of a
catalytic amount of SrCl2•6H2O to a mixture of aqueous HCl (5 N) and AcOH at 80
οC succeeded in hydrolyzing the methyl glycoside to afford hemiacetal 12 in 80%
yield (β/α = 2.1:1).15 Condensation of 12 with orthoꢀhexynylbenzoic acid in the
presence of DMAP and EDCI in CH2Cl2 provided the desired 6ꢀdeoxyꢀLꢀAltp donor 7
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in an excellent 97% yield (β/α = 3.2:1). Furthermore, we capped hemiacetal 12 with a
βꢀlinked methyl group to provide 13 in 88% yield upon treatment with MeI and Ag2O
7
8
in CH2Cl2 at rt, wherein only a trace of the corresponding αꢀLꢀconfigured epimer 11
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was isolated. This excellent βꢀselectivity could be attributed to the greater proportion
of the βꢀOH at equilibrium on 12 as well as the significantly increased rate of
equilibrium in the presence of Ag2O prior to Oꢀmethylation.16 Moreover, a
presumable intramolecular hydrogen bonding of βꢀOH to O2 could make it a better
nucleophile than the αꢀOH and therefore enhance the βꢀselectivity.16a,16b The resulting
13 was then subjected to the Pd/Cꢀpromoted hydrogenolysis in MeOH to selectively
remove the benzyl group at O2, giving smoothly glycosyl acceptor 6 in 83% yield.
With the 6ꢀdeoxyꢀLꢀAltp donor 7 and acceptor 6 at hand, we examined the
gold(I)ꢀcatalyzed glycosylation with different counter anions (of the gold(I) catalyst),
solvents, and temperatures. As depicted in Table 1, all the condensations of 7 (1.2
equiv.) with 6 (1.0 equiv.) under the activation of gold(I) species (0.12 equiv.) led to
the desired disaccharide 14β with good βꢀselectivity (from a β/α ratio of 7.3:1 to β
only). The βꢀconfiguration was confirmed by the correlation observed between the
synꢀdiaxial H1’ and H5’ in a NOESY spectrum. Lowering the temperature from 0 οC
(entry 1) to ꢀ42 οC (entry 4) increased the β/α ratio from 7.3:1 to 15.2:1, but the yield
dropped from 97% to 72%. The βꢀselectivity could also be improved by replacing the
–
–
F
counter anion NTf2 with the previously optimized BAr4 , used for βꢀmannosylation
and βꢀrhamnosylation,11 leading to a βꢀonly selectivity in CH2Cl2 at ꢀ20 οC (entry 3);
however, the reaction became sluggish and the yield dropped to 34%. Replacement of
ο
the solvent CH2Cl2 with PhCl in the presence of PPh3AuNTf2 at ꢀ42 C decreased the
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βꢀselectivity but improved the yield from 72% (entry 4) to 99% (entry 5).
–
F
5
6
Interestingly, PhCl strongly weakened the effect of counter anion BAr4 , and
7
8
ο
therefore gave a yield of 90% and β/α ratio of 10.0:1 at ꢀ42 C (entry 6), that was
9
–
similar to those with NTf2 (entries 2 and 5). Nevertheless, the most efficient and
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convenient glycosylation could be attained under the catalysis of PPh3AuNTf2 in
CH2Cl2 at ꢀ20 οC (entry 2), leading to disaccharide 14β in gram scale in a short time,
excellent yield (98%), and high βꢀselectivity (β/α = 9.9:1).
TABLE 1. Examination of the βꢀselective glycosylation of 6ꢀdeoxyꢀ
LꢀAltp donor 7
with acceptor 6.
Temp. (οC)
Ratio (β:α)
7.3:1a
Entry Au(I) catalyst Solvent
Time (h) Yield (%)
1
2
3
4
5
6
PPh3AuNTf2 CH2Cl2
0
2
2
97
98
34
72
99
90
PPh3AuNTf2 CH2Cl2
ꢀ20
ꢀ20
ꢀ42
ꢀ42
ꢀ42
9.9:1b
F
PPh3AuBAr4
CH2Cl2
8
β onlya
15.2:1a
9.2:1a
PPh3AuNTf2 CH2Cl2
8
PPh3AuNTf2
PhCl
8
F
PPh3AuBAr4
PhCl
14
10.0:1a
aDetermined by 1H NMR; bDetermined by column isolation.
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TABLE 2. Attempts at removal of the benzyl group on disaccharide 14β (and
tetrasaccharide 18β) via hydrogenolysis.
7
8
9
10
11
12
13
14
15
16
17
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Entry Substrate
Solvent
H2 (atm) Time (h)
Yield
16%
1
2
MeOH
1
1
48
48
48
52
48
48
6
14β
14β
14β
14β
18β
18β
18β
18β
18β
MeOH/EtOAc
21%
3a
4
MeOH/EtOAc
1
12%
MeOH/AcOH (5:1)
MeOH/AcOH (5:1)
MeOH/AcOH (2:1)
MeOH/THF
1
91%
5
1
26%
6
1
52%
7
50
50
50
No reaction
9%
8
MeOH/AcOH (10:1)
MeOH/AcOH (5:1)
24
24
9b
Complex mixture
aPd(OH)2/C (15%) was used. bat 50 oC.
Difficulty was encountered in the subsequent cleavage of the 2ꢀOꢀbenzyl group on
disaccharide 14β (Table 2). Due to the increased steric hindrance from the added
sugar residue, hydrogenolysis of the 2ꢀOꢀbenzyl group turned out to be very sluggish
with Pd/C (entries 1 and 2) or Pd(OH)2/C (entry 3) in neutral solvent (cf., 13→6).
Delightfully, replacing the solvent with an acidic mixture of MeOH/AcOH (5:1) was
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able to remove smoothly the benzyl group to give alcohol 15 in 91% yield in gram
scale (entry 4).
7
8
9
Applying the optimized glycosylation conditions (PPh3AuNTf2 and 4Å MS in
CH2Cl2 at ꢀ20 οC) to the condensation of disaccharide alcohol 15 with
orthoꢀhexynylbenzoate donor 7 provided the desired trisaccharide 16β in excellent
yield (97%) and βꢀselectivity (β/α = 9.6:1) (Scheme 2). Although the Pd/Cꢀpromoted
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18
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hydrogenolysis of the terminal benzyl group on 16β was only partially successful
even in the MeOH/AcOH (5:1) mixture, we isolated the desired trisaccharide alcohol
17 in an acceptable 45% yield and recovered the remaining 16β.
SCHEME 2. Synthesis of 6ꢀdeoxyꢀ ꢀAltp trisaccharide 16β.
L
The same procedures were employed in the synthesis of tetraꢀ (18β) and
pentasaccharide (20β) (Scheme 3). Thus, treatment of trisaccharide alcohol 17 with
ο
donor 7 in the catalysis of PPh3AuNTf2 in CH2Cl2 at ꢀ20 C led to tetrasaccharides
18β/18α in comparably excellent yield (94%) but a decreased β/α ratio of 6.8:1 (cf.,
6+7→14β and 15+7→16β). The subsequent removal of the terminal benzyl group on
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tetrasaccharide 18β in a MeOH/AcOH (5:1) mixture via hydrogenolysis under 1ꢀatm
H2 at rt, unsurprisingly, only gave the desired alcohol 19 in a poor 26% yield (Table 2,
entry 5). Increasing the ratio of AcOH/MeOH from 1:5 to 1:2 improved the yield to
an acceptable 52% (entry 6). Conducting the reaction at 50ꢀatm H2 or higher
temperature was not able to offer a better result (entries 7ꢀ9). Nevertheless,
tetrasaccharide alcohol 19 was able to be coupled with donor 7 under the conditions
10
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12
13
14
15
16
17
18
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ο
of PPh3AuNTf2 in CH2Cl2 at ꢀ20 C, providing pentasaccharides 20β/20α in 91%
yield and a β/α ratio of 2.5:1. The poorer βꢀselectivity in the preparation of tetraꢀ and
pentasaccharide could be related to the weakened nucleophilicity of the terminal
2ꢀOH on 17 and 19 due to their great bulkiness and multiple electronꢀwithdrawing
benzoyl groups.11 Even so, the βꢀ(1→2)ꢀlinked tetraꢀ and pentasaccharide 18β and
20β, respectively, were still obtained in satisfactory yields.
SCHEME 3. Synthesis of 6ꢀdeoxyꢀ
20β.
LꢀAltp tetrasaccharide 18β and pentasaccharide
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The last stage of the synthesis involved the full cleavage of the benzoyl and benzyl
5
6
groups (Scheme 4). Thus, treatment of compounds 6, 15, 17, and 19 with MeONa in
7
8
MeOH removed the benzoyl
groups
and furnished the
desired
9
6ꢀdeoxyꢀβꢀ ꢀAltp-containing monoꢀ to tetrasaccharides 1ꢀ4 in 81% to 99% yields. On
L
10
11
12
13
14
15
16
17
18
19
20
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the other hand, removing the benzoyl groups on pentasaccharide 20β before
hydrogenolysis was able to extricate the hindered terminal 2ꢀOꢀbenzyl group and
therefore made the subsequent debenzylation smooth and highly efficient, furnishing
pentasaccharide 5 in 86% yield (two steps).
SCHEME 4. Global deprotection in the synthesis of 6ꢀdeoxyꢀβꢀLꢀAltp-containing
monoꢀ to pentasaccharides 1–5.
1
The H and 13C NMR chemical shifts of compounds 1–5, compiled in Table 3, were
assigned using 1D and 2D NMR experiments suitable for carbohydrates.17 The
1
pyranoid sugar residues are present in the C4 chair conformation based on vicinal
3JHH coupling constants (Table 3) where JH2,H3 ≈ 4 Hz and JH3,H4 ≈ 3 Hz are consistent
with a synclinal arrangement between protons and JH4,H5 ≈ 10 Hz arises from an
antiperiplanar arrangement. The βꢀconfiguration of the 6ꢀdeoxyꢀLꢀAltp sugar residues
1
were determined based on the magnitude of the anomeric JCH coupling constants
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being 160–165 Hz.18 Chemical shift differences between sugar residues in an oligoꢀ or
polysaccharide compared to their constituent monosaccharides carry structural
information and can be predicted employing computerized approaches, such as
GODESS19 and CASPER.20 The monosaccharide chemical shift displacements take
place as a result of various substitution effects, glycosylation or from steric influences
between residues, notable in particular in diꢀ and trisaccharides.21
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1
TABLE 3. H and 13C NMR chemical shifts (ppm) and coupling constants (Hz) of
compounds 1–5 in D2O at 37 ºC.
Compound
A
1
2
3
4
5
6
OMe
4.81 (1.06)
3.98
(4.12)
77.97
4.15
(3.23)
70.65
3.60
(9.63)
70.72
3.84
(6.27)
70.85 17.90 57.85
1.31 3.53
100.48 [160]
5.08 (0.82)
4.07
(3.99)
77.45
4.08
(3.20)
70.98
3.55
(9.84)
70.60
3.80
(6.26)
70.72 17.90
1.30
B
100.37 [163]
5.25 (0.93)
4.06
(3.91)
77.24
4.03
(3.16)
71.01
3.53
(9.99)
70.68
3.86
(6.24)
70.59 17.85
1.29
C
D
E
5
100.09 [164]
5.29 (0.98)
4.02
(3.92)
78.20
4.10
(3.24)
70.82
3.55
(9.89)
70.60
3.87
(6.28)
70.59 17.85
1.30
99.89 [165]
5.16 (1.22)
3.92
(4.01)
71.49
4.03
(3.30)
71.11
3.57
(9.63)
70.53
3.88
(6.29)
70.78 18.10
1.30
100.43 [165]
4.80 (1.06)
3.98
(4.14)
77.82
4.13
(3.20)
70.66
3.58
(9.64)
70.74
3.84
(6.26)
70.81 17.89 57.84
1.31 3.53
A
B
C
100.49 [160]
5.08 (0.96)
4.08
(3.91)
77.16
4.03
(3.07)
71.02
3.52
(9.86)
70.62
3.79
(6.22)
70.65 17.88
1.29
4
100.23 [163]
5.24 (1.01)
4.03
(3.89)
78.13
4.10
(3.19)
70.83
3.55
(9.93)
70.58
3.87
(6.24)
70.59 17.81
1.29
99.94 [165]
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5.16 (1.20)
3.92
(3.96)
71.47
4.03
(3.24)
71.10
3.57
(9.62)
70.53
3.87
(6.30)
70.78 18.09
1.30
D
A
B
C
A
B
A
100.38 [165]
4.80 (1.09)
3.98
(4.16)
77.81
4.09
(3.28)
70.71
3.55
(9.58)
70.77
3.83
(6.26)
70.74 17.87 57.83
1.29 3.53
100.34 [160]
5.06 (1.00)
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4.06
(3.95)
77.98
4.10
(3.27)
70.80
3.54
(9.92)
70.52
3.81
(6.26)
70.71 17.85
1.29
3
100.18 [163]
5.12 (1.22)
3.92
(3.98)
71.47
4.03
(3.29)
71.11
3.56
(9.60)
70.51
3.87
(6.30)
70.76 18.05
1.30
100.42 [164]
4.83 (1.31)
3.98
(4.48)
78.58
4.19
(3.24)
70.17
3.62
(9.21)
70.74
3.86
(6.38)
71.12 17.94 57.59
1.30 3.52
100.09 [162]
4.97 (1.21)
2
1
3.93
(4.08)
71.26
4.02
(3.29)
71.07
3.56
(9.52)
70.48
3.83
(6.31)
70.86 18.11
1.29
100.40 [163]
4.76 (1.65)
3.87
(4.70)
70.91
4.01
(3.33)
70.88
3.61
(8.77)
70.86
3.86
(6.39)
71.44 18.14 57.52
1.31 3.52
100.53 [161]
In the βꢀ(1→2)ꢀlinked 6ꢀdeoxyꢀ
L
ꢀAltp oligosaccharides synthesized herein
1
glycosylation effects are pronounced in H NMR spectra for the anomeric protons
1
(Figure 2). The Oꢀmethyl monosaccharide glycoside 1 has the lowest anomeric H
NMR chemical shift compared to other residues in larger oligosaccharides. For
compounds 3–5, an essentially nonꢀchanging chemical shift at δH ~4.80 in residue A is
evident. In disaccharide 2 the anomeric proton of the terminal residue B is displaced
downfield towards a higher chemical shift, an effect that also occurs in trisaccharide 3,
where the terminal residue is denoted C. Notably, at the trisaccharide level and
onwards the chemical shift of H1 in B, δH 5.06, only changes marginally in larger
oligosaccharides, suggesting that this part of the oligosaccharides is not further
perturbed once the length of the oligosaccharide increases. Similar to residue B, for
larger oligosaccharides the terminal residue in tetrasaccharide 4 and in
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pentasaccharide 5, residues D and E, respectively, both occur at δH 5.16, thus
implying that similar structural environments are present among residues at the
terminal end when the length of the oligosaccharide reaches a certain point. In
tetrasaccharide 4 the anomeric proton of residue C is shifted further downfield to 5.24
ppm whereas in pentasaccharide 5 the corresponding chemical shift is hardly altered,
now at 5.25 ppm. However, in the latter saccharide the chemical shift of the anomeric
proton of the penultimate residue D is shifted even further downfield to δH 5.29. The
chemical shift of this resonance, which is similar to that of the anomeric proton of the
adjacent residue C, indicates that the structural environment of residue D closely
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resembles that in the βꢀ(1→2)ꢀlinked 6ꢀdeoxyꢀLꢀAltpꢀcontaining polysaccharide of Y.
enterocolitica O:3, since only a small chemical shift difference is present between the
anomeric protons of these residues.
1
FIGURE 2. The anomeric region of H NMR spectra of compounds 1–5 in D2O at
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37 °C with sugar residues labeled A–E starting from the reducing end of the
oligosaccharides.
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As the substitution pattern in the oligosaccharides contains βꢀ(1→2)ꢀlinkages some
sugar residues are destined to become proximate to each other.22 A molecular model
of pentasaccharide 5 was made using the CarbBuilder program23 and is presented in
Figure 3. The resulting structure of pentasaccharide 5 is a leftꢀhanded helix and this
3D structural arrangement may then form a highly specific epitope in the
polysaccharide when present as an antigen in the bacterium.
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FIGURE
3.
Molecular
model
of
pentasaccharide
5,
6ꢀdeoxyꢀβꢀ
LꢀAltpꢀ(1→2)ꢀ[6ꢀdeoxyꢀβꢀ
LꢀAltpꢀ(1→2)]3ꢀ6ꢀdeoxyꢀβꢀLꢀAltpꢀOMe, made
by the computer program CarbBuilder and visualized using the PyMOL Molecular
Graphics System, version 1.8.4 Schrödinger, LLC. Sugar residues are labeled A – E
and the anomeric proton of residue D, which has the lowest 1H NMR chemical shift in
the pentasaccharide, is colored orange.
Interestingly, by noting that altrose is the C3ꢀepimer of mannose the 3D structure of
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the βꢀ(1→2)ꢀlinked 6ꢀdeoxyꢀLꢀAltpꢀcontaining oligosaccharides may be compared to
5
6
7
8
9
the 3D structure of βꢀ(1→2)ꢀlinked oligomannosides found in the cell wall of
Candida albicans. Oligosaccharides having βꢀ(1→2)ꢀlinked manosyl residues have
been synthesized, including a reducing tetrasaccharide,24 an octasaccharide with a
hexyl group at the reducing end25 and as propyl oligomannosides with up to six sugar
residues.26 These oligomannosides, including one with protecting groups,25 have been
described as having irregular, compact and/or contorted helical structures with
approximately three residues per turn. Furthermore, βꢀ(1→2)ꢀlinked oligomannosides
bind to a monoclonal antibody in a helical conformation similar to that observed in
absence of the protein, i.e., free in solution.27 Notably, in the series of propyl
glycosides the triꢀ, tetraꢀ, and pentasaccharides show the exact same order of 1H NMR
chemical shifts of their anomeric protons, labeled A–E as herein, as those of the
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6ꢀdeoxyꢀLꢀAltpꢀcontaining oligosaccharides, i.e., for the trisaccharide the chemical
shift increases in the order A–C, for the tetrasaccharide δH1D < δH1C and for the
pentasaccharide δH1E < δH1C < δH1D. The conformational state at the glycosidic
βꢀ(1→2)ꢀlinkages deduced from the modeling and molecular simulation studies in
conjunction with NMR spectroscopy experiments24,26,27 can thus be described as an
exoꢀanomeric synꢀconformation.28 Given these facts, a molecular model of
βꢀ
the exoꢀanomeric synꢀconformation was generated at the glycosidic linkages, forming
rightꢀhanded helix essentially the mirror image of that from
6ꢀdeoxyꢀβꢀ ꢀAltpꢀ(1→2)ꢀ[6ꢀdeoxyꢀβꢀ ꢀAltpꢀ(1→2)]3ꢀ6ꢀdeoxyꢀβꢀ ꢀAltpꢀOMe
DꢀManpꢀ(1→2)ꢀ[βꢀDꢀManp]3ꢀβꢀDꢀManpꢀOMe was built by CarbBuilder, in which
a
L
L
L
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presented in Figure 3. Although the above analysis for the conformation of a
5
6
7
pentasaccharide corresponding to the Oꢀantigen of Y. enterocolitica O:3 is based on
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1
only a H NMR chemical shift comparison and a pragmatic generation of the 3D
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structure of this oligomer, we judge it to be a reasonable model and description of its
overall shape.
Conclusion
In summary, we have developed an efficient approach to the assembly of
βꢀ(1→2)ꢀlinked 6ꢀdeoxyꢀ
represent models of the Oꢀantigen of Yersinia enterocolitica O:3. The synthesis
employs an iterative gold(I)ꢀcatalyzed glycosylation approach with
2ꢀOꢀbenzylꢀ3,4ꢀOꢀbenzyolꢀ6ꢀdeoxyꢀ ꢀaltropyranosyl orthoꢀhexynylbenzoate (7) as
Lꢀaltropyranosideꢀcontaining oligosaccharides, which
L
donor, which leads to excellent coupling yields and satisfactory βꢀselectivity. The
synthetic monoꢀ to pentasaccharides 1–5 were analyzed by NMR spectroscopy and
molecular modeling of the pentasaccharide (5) shows that it adopts a leftꢀhanded
helical structure; this may represent a 3D structural arrangement of a highly specific
epitope in the bacterial lipopolysaccharide. Further studies on the 3D structure of
these oligomers related to the lipopolysaccharide from Y. enterocolitica O:3 are
underway and the results will be reported in due course.
Experimental Section
General Information. All reactions were carried out under nitrogen or argon
atmosphere with anhydrous solvents in flameꢀdried glassware, unless otherwise noted.
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All glycosylation reactions were performed in the presence of 4Å molecular sieves,
which were flameꢀdried immediately before use in the reaction under high vacuum.
Glycosylation solvents were dried using a solvent purification system and used
directly without further drying. The chemicals used were reagent grade as supplied,
except where noted. Analytical thinꢀlayer chromatography was performed using silica
gel 60 F254 glass plates. Compound spots were visualized by UV light (254 nm) and
by heating with a solution of 10% H2SO4 in ethanol. Flash column chromatography
was performed on silica gel. NMR chemical shifts were referenced using Me4Si (0
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ppm), residual CHCl3 (1H NMR
δ
= 7.26 ppm, 13C NMR
δ
= 77.16 ppm) for
1
compounds 6–20. Peak and coupling constant assignments are based on H NMR,
COSY, HSQC, and NOESY spectral data. Splitting patterns were indicated as nr (not
resolved), s (singlet), d (doublet), t (triplet), q (quartet), and br (broad resonance) for
1H NMR data. Highꢀresolution mass spectra were recorded on an ESIꢀTOF mass
spectrometer. Optical rotations were measured on a polarimeter using either CHCl3 or
CH3OH as solvent.
1H, 13C, and 2D NMR spectra for resonance assignments of compounds 1–5 in D2O
ο
1
solution were carried out at 37 C on an NMR spectrometer operating at a H
frequency of 600 MHz. The chemical shifts are reported in ppm using internal sodium
3ꢀtrimethylsilylꢀ(2,2,3,3ꢀ2H4)ꢀpropanoate (TSP, δH 0.00) or external 1,4ꢀdioxane in
D2O (
δ
C 67.40) as references. 1H NMR chemical shifts and coupling constants of 1–5
1
were refined iteratively from H NMR spectra by totalꢀlineshape analysis using the
PERCH NMR spinꢀsimulation software.29 For 13C NMR spectra of compounds 1–5 an
exponential lineꢀbroadening factor of only 0.1 Hz was applied to the FID prior to FT,
such that peaks from nuclei with similar chemical shifts were resolved.
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General Procedure for the Gold(I)ꢀCatalyzed Glycosylation with
orthoꢀhexynylbenzoate Donor 7.
9
To a solution of donor 7 (1.2 equiv.) and the acceptor (1.0 equiv.) in dry CH2Cl2 was
added freshly activated 4Å molecular sieves (weight equaled the combined weight of
the donor and acceptor). The mixture was stirred at the indicated temperature for 20
min under Ar. Ph3PAuNTf2 (0.12 equiv.) or a combination of Ph3PAuCl (0.12 equiv.)
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F
and AgBAr4 (0.028 M in Et2O, 0.12 equiv.) was added. The stirring was continued at
the same temperature until TLC showed complete conversion of the acceptor. The
reaction was quenched by the addition of Ph3P (0.15 equiv.). The resulting mixture was
filtered through a pad of Celite and the filtrate was concentrated. The residue was
purified by silica gel column chromatography to provide the coupled glycosides.
General Debenzylation Procedure. To a solution of the benzylated compound in
MeOH or a combination of MeOH/AcOH was added Pd/C, and the suspension was
stirred under H2. After complete consumption of the benzylated compound (TLC), the
suspension was filtered through a pad of Celite and the filtrate was concentrated. The
resulting residue was purified by column chromatography to provide the desired
alcohol.
General Saponification Procedure. To a solution of the ester in MeOH was added
MeONa, and the mixture was stirred at rt. After complete consumption of the ester
(TLC), the mixture was concentrated. The resulting residue was purified by column
chromatography to provide the desired alcohol.
Methyl
6ꢀdeoxyꢀαꢀLꢀaltropyranoside
(9).
To
a
solution
of
2,4ꢀdiꢀOꢀacetylꢀ6ꢀdeoxyꢀαꢀ
L
ꢀAltp 811a (46 g, 175 mmol) in MeOH (400 mL) was
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added MeONa (9.5 g, 17.5 mmol) at rt. After stirring at rt for 12 h, the solution was
evaporated in vacuo to give a residue, which was purified by silica gel column
chromatography (CH2Cl2/MeOH, 10:1) to afford compound 9 (31 g, 99%) as a white
9
solid: [α]D28 = ꢀ49.8 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 4.63 (nr, 1H), 3.95
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(dd, J = 4.1, 2.0 Hz, 1H), 3.89 (d, J = 3.8 Hz, 1H), 3.75 (dq, J = 9.3, 6.3 Hz, 1H), 3.50
(dd, J = 9.3, 3.5 Hz, 1H), 3.43 (s, 3H), 1.35 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
CDCl3)
δ 101.1, 70.9, 69.7, 69.5, 65.4, 55.8, 17.7; HRMS (ESI) calcd for C7H14O5Na
[M + Na]+ 201.0733, found 201.0726.
Methyl 2ꢀOꢀBenzylꢀ6ꢀdeoxyꢀαꢀLꢀaltropyranoside (10). To a solution of 9 (30 g, 168
mmol) in acetone (1 L) was added (CH3)2C(OMe)2 (207 mL, 1.68 mol) and
camphorsulfonic acid (3.9 g, 16.8 mmol) at rt. After stirring for 1 h, Et3N was added
to quench the reaction. The mixture was concentrated in vacuo. The residue was used
directly for the next step without further purification.
ο
The residue was dissolved in dry DMF (600 mL), and stirred at 0 C for 15 min.
NaH (60% in mineral oil, 21 g, 504 mmol) and benzyl bromide (40 mL, 336 mmol)
were slowly added under Ar. The mixture was allowed to stir at rt for 12h until TLC
showed complete conversion of the starting materials. The mixture was quenched
with MeOH, and then diluted with CH2Cl2, washed with saturated aq. NH4Cl, dried
over Na2SO4, and concentrated. The residue was used directly for the next step
without further purification.
The residue above was dissolved in AcOH (80% aq. 400 mL). After stirring at 100
οC for 6 h, the mixture was evaporated in vacuo to give a residue, which was purified
by silica gel column chromatography (petroleum ether/EtOAc, 4:1) to afford 10 (42 g,
1
93% over 3 steps) as a colorless syrup: [α]D28 = ꢀ40.1 (c 1.5, CHCl3); H NMR (500
MHz, CDCl3)
δ
7.36–7.28 (m, 5H), 4.70 (d, J = 1.4 Hz, 1H), 4.61 (s, 2H), 3.98–3.94
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(m, 1H), 3.72–3.66 (m, 2H), 3.54–3.49 (m, 1H), 3.38 (s, 3H), 3.29 (d, J = 10.0 Hz,
1H), 2.53 (d, J = 10.2 Hz, 1H), 1.36 (d, J = 6.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
7
8
δ
137.6, 128.6, 128.1, 127.8, 99.4, 75.6, 72.3, 69.9, 68.9, 64.6, 55.4, 17.8; HRMS
9
(ESI) calcd for C14H20O5Na [M + Na]+ 291.1203, found 291.1203.
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Methyl 2ꢀOꢀBenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀαꢀLꢀaltropyranoside (11). To a
solution of 10 (40.0 g, 149 mmol) in dry CH2Cl2/Et3N (200 mL/207 mL) were added
ο
DMAP (1.8 g, 14.9 mmol) and BzCl (43 mL, 373 mmol) at 0 C. After stirring
overnight, the mixture was diluted with CH2Cl2, and was then washed with water and
brine, respectively. The organic layer was dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel column chromatography
28
(petroleum ether/EtOAc, 5:1) to afford 11 (63.9 g, 90%) as a colorless syrup: [α]D
=
1
ꢀ81.5 (c 4.7, CHCl3); H NMR (500 MHz, CDCl3)
δ 8.07 (d, J = 7.9 Hz, 2H),
7.96–7.95 (m, 2H), 7.60–7.57 (m, 1H), 7.55–7.51 (m, 1H), 7.47–7.42 (m, 4H),
7.39–7.35 (m, 4H), 7.33–7.29 (m, 1H), 5.80–5.79 (m, 1H), 5.45 (dd, J = 9.0, 3.3 Hz,
1H), 4.87 (d, J = 11.9 Hz, 1H), 4.78–4.74 (m, 2H), 4.52 (dq, J = 8.6, 6.4 Hz, 1H), 3.88
(dd, J = 4.1, 1.8 Hz, 1H), 3.47 (s, 3H), 1.39 (d, J = 6.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3)
δ 165.7, 165.5, 137.5, 133.19, 133.17, 130.1, 129.9, 129.8, 129.7, 128.5,
128.44, 128.41, 128.1, 128.0, 100.1, 75.3, 72.7, 71.2, 68.1, 63.3, 55.5, 17.6; HRMS
(ESI) calcd for C28H28O7Na [M + Na]+ 499.1727, found 499.1728.
2ꢀOꢀBenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀ
Lꢀaltropyranose (12).
A
solution of
compound 11 (7.1 g, 14.9 mmol), HCl (5 N aq., 6.3 mL), and SrCl2•6H2O (400 mg,
ο
1.5 mmol) in AcOH (150 mL) was stirred at 80 C for 8 h. The mixture was diluted
with EtOAc, and washed with water, saturated aq. NaHCO3, and brine, respectively.
The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel column chromatography (petroleum ether/EtOAc, 5:1) to
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provide hemiacetal 12 (5.6 g, 81%, b/a = 2.1:1) as a colorless syrup: 1H NMR (500
MHz, CDCl3) d 8.05–8.00 (m, 2H), 7.93–7.89 (m, 2H), 7.59–7.28 (m, 11H),
5.95–5.94 (m, 0.68H), 5.82–5.81 (m, 0.32H), 5.41 (dd, J = 8.9, 3.3 Hz, 0.32H), 5.30
(dd, J = 10.0, 3.1 Hz, 0.68H), 5.26 (d, J = 5.3 Hz, 0.32H), 5.18 (d, J = 12.2 Hz,
0.68H), 5.00 (d, J = 11.6 Hz, 0.68H), 4.85 (d, J = 11.9 Hz, 0.32H), 4.74 (d, J = 12.0
Hz, 0.32H), 4.70 (d, J = 11.6 Hz, 0.68H), 4.67–4.62 (m, 0.32H), 4.30 (dq, J = 9.8, 6.2
Hz, 0.68H), 3.87 (dd, J = 4.3, 1.9 Hz, 0.32H), 3.77 (dd, J = 3.4, 1.6 Hz, 0.68H), 3.73
(d, J = 12.3 Hz, 0.68H), 3.17 (d, J = 5.7 Hz, 0.32H), 1.35–1.33 (m, 3H); 13C NMR
(125 Hz, CDCl3) d 165.6, 165.5, 165.4, 165.2, 137.4, 136.7, 133.6, 133.3, 133.23,
133.15, 129.8, 129.7, 129.6, 129.5, 129.3, 128.7, 128.6, 128.47, 128.45, 128.44,
128.41, 128.40, 128.35, 128.0, 127.9, 93.4, 92.0, 75.7, 75.6, 73.2, 72.7, 71.2, 70.9,
68.4, 68.3, 67.9, 63.7, 18.0, 17.4; HRMS (ESI) calcd for C27H26O7Na [M + Na]+
485.1571, found 485.1576.
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Methyl 2ꢀOꢀBenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀβꢀLꢀaltropyranoside (13). To a
solution of hemiacetal 12 (923 mg, 2.0 mmol) in dry CH2Cl2 (20 mL) were added
Ag2O (1.06 g, 4.6 mmol), 4Å MS (1.0 g), and MeI (335 ꢀL, 4.6 mmol) at rt under Ar.
The mixture was stirred until TLC showed the complete conversion of the hemiacetal.
After being quenched with MeOH (1 mL), the mixture was filtered through Celite. The
filtrate was concentrated and the residue was purified by silica gel column
chromatography (petroleum ether/EtOAc, 10:1) to provide 13 (839 mg, 88%) as a
white foam: [α]D22 = ꢀ3.2 (c 0.6, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 8.00–7.99 (m,
2H), 7.92–7.90 (m, 2H), 7.61–7.58 (m, 1H), 7.54–7.51 (m, 1H), 7.47–7.44 (m, 4H),
7.38–7.34 (m, 4H), 7.31–7.27 (m, 1H), 5.82 (dd, J = 5.0, 3.2 Hz, 1H), 5.43 (dd, J =
8.5, 3.2 Hz, 1H), 4.91–4.82 (m, 3H), 4.23 (dq, J = 8.5, 6.4 Hz, 1H), 3.89 (dd, J = 5.0,
1.7 Hz, 1H), 3.60 (s, 3H), 1.42 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ
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165.5, 165.2, 137.9, 133.5, 133.3, 129.7, 129.7, 128.6, 128.5, 128.4, 128.1, 127.9,
100.5, 74.6, 73.5, 71.8, 69.6, 69.0, 57.1, 18.3; HRMS (ESI) calcd for C28H28O7Na [M
+ Na]+ 499.1727, found 499.1729.
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Methyl 3,4ꢀDiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀβꢀLꢀaltropyranoside (6). Compound 13 (3.7 g,
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7.8 mmol) was subjected to the general debenzylation procedure with Pd/C (5%, 3.4
g) in MeOH (80 mL). The purification by silica gel column chromatography
(petroleum ether/EtOAc, 4:1) provided 6 (2.5 g, 83%) as a white foam: [α]D28 = ꢀ13.5
(c 3.9, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 8.01–8.00 (m, 2H), 7.93–7.91 (m, 2H),
7.58–7.55 (m, 1H), 7.52–7.49 (m, 1H), 7.58–7.55 (m, 2H), 7.52–7.49 (m, 2H), 5.79
(dd, J = 5.6, 3.2 Hz, 1H), 5.45 (dd, J = 7.7, 3.2 Hz, 1H), 4.90 (d, J = 2.0 Hz, 1H),
4.32–4.19 (m, 1H), 4.14–4.11 (m, 1H), 3.59 (s, 3H), 2.79 (d, J = 5.1 Hz, 1H), 1.42 (d,
J = 6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 165.4, 133.4, 133.2, 129.72, 129.68,
129.63, 129.61, 128.5, 128.4, 100.0, 71.5, 69.9, 69.8, 68.9, 56.6, 18.4; HRMS (ESI)
calcd for C21H22O7Na [M + Na]+ 409.1258, found 409.1267.
2ꢀOꢀBenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀβꢀLꢀaltropyranosyl orthoꢀhexynylbenzoate
(7). To a solution of hemiacetal 12 (4.6 g, 9.9 mmol), orthoꢀhexynylbenzoic acid (2.0
g, 11.9 mmol), and DMAP (605 mg, 5.0 mmol) in dry CH2Cl2 (50 mL) was added
EDCI (2.3 g, 11.9 mmol) at rt. After stirring for 6 h, the mixture was diluted with
CH2Cl2, and was then washed with saturated aq. NaHCO3, water, and brine,
respectively. The organic layer was dried over Na2SO4, filtered, and concentrated.
The residue was purified by silica gel column chromatography (petroleum
ether/EtOAc, 10:1) to provide donor 7 (6.2 g, 97%, β/α = 3.2:1) as a colorless syrup:
1H NMR (500 MHz, CDCl3)
δ 8.03–8.91 (m, 5.74H), 7.75–7.73 (m, 0.26H),
7.61–7.27 (m, 12.74H), 7.00–6.97 (m, 0.26H), 6.50–6.50 (m, 0.74H), 6.45 (s, 0.26H),
5.95 (dd, J = 5.4, 3.1 Hz, 0.74H), 5.86–5.85 (m, 0.26H), 5.54–5.49 (m, 1H),
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4.92–4.84 (m, 2H), 4.75–4.70 (m, 0.26H), 4.47–4.42 (m, 0.74H), 4.1 (dd, J = 5.5, 1.9
Hz, 0.74H), 4.06 (dd, J = 3.3, 1.3 Hz, 0.26H), 2.48 (t, J = 7.2 Hz, 1.48H), 2.41 (t, J =
7
8
7.1 Hz, 0.52H), 1.65–1.37 (m, 7H), 0.94–0.90 (m, 3H);13C NMR (125 Hz, CDCl3)
δ
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165.6, 165.5, 165.38, 165.37, 164.5, 164.2, 137.4, 137.2, 134.7, 134.5, 133.6, 133.4,
133.28, 133.25, 132.3, 131.8, 131.2, 130.7, 130.6, 130.3, 129.94, 129.89, 129.80,
129.77, 129.69, 129.65, 129.6, 129.5, 128.7, 128.53, 128.50, 128.4, 128.3, 128.2,
128.1, 128.0, 127.2, 126.9, 125.6, 125.1, 97.1, 96.9, 92.6, 92.1, 79.2, 79.1, 74.5, 73.9,
73.4, 72.9, 71.5, 71.0, 70.6, 68.5, 67.9, 65.1, 30.8, 30.7, 22.19, 22.15, 19.7, 19.6, 18.5,
17.8, 13.78, 13.76; HRMS (ESI) calcd for C40H38O8Na [M + Na]+ 669.2459, found
669.2455.
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Methyl
3,4ꢀDiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀ2ꢀOꢀ(2ꢀOꢀbenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀβꢀ
ranosyl)ꢀβꢀ ꢀaltropyranoside (14β) and
3,4ꢀDiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀ2ꢀOꢀ(2ꢀOꢀbenzylꢀ3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀαꢀ
ranosyl)ꢀβꢀ ꢀaltropyranoside (14α). The general glycosylation procedure was used
Lꢀaltropy
L
Methyl
Lꢀaltropy
L
with donor 7 (2.72 g, 4.2 mmol), acceptor 6 (1.35 g, 3.5 mmol), and Ph3PAuNTf2 (311
ο
mg, 0.42 mmol) in CH2Cl2 (60 mL) at ꢀ20 C. The purification by silica gel column
chromatography (petroleum ether/EtOAc, 10:1) afforded the disaccharide 14β (2.58 g,
89%) and its αꢀanomer 14α (261 mg, 9%), both as white foams.
ο
14β: [α]D28 = ꢀ4.4 (c 4.5, CHCl3); mp = 87−90 C; 1H NMR (500 MHz, CDCl3)
δ
8.10–8.09 (m, 2H), 8.04–8.02 (m, 2H), 7.93–7.90 (m, 4H), 7.65–7.59 (m, 4H),
7.53–7.45(m, 6H), 7.43–7.4 (m, 2H), 7.37–7.33 (m, 4H), 7.32–7.29 (m, 1H), 6.00–5.98
(m, 1H), 5.84–5.82 (m, 1H), 5.52–5.50 (m, 2H), 5.45 (dd, J = 9.6, 3.2 Hz, 1H), 5.12 (d,
J = 12.4 Hz, 1H), 5.01–4.94 (m, 2H), 4.39 (d, J = 4.4 Hz, 1H), 4.28–4.23 (m, 2H), 4.07
(d, J = 4.2 Hz, 1H), 3.53 (s, 3H), 1.43 (d, J = 6.3 Hz, 3H), 1.39 (d, J = 6.3 Hz, 3H); 13C
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NMR (125 MHz, CDCl3)
δ 165.4, 165.03, 164.97, 164.9, 138.3, 133.5, 133.4, 133.1,
5
6
7
8
129.8, 129.74, 129.69, 128.7, 128.5, 128.41, 128.37, 128.1, 127.6, 100.6, 100.0, 74.7,
73.9, 73.63, 73.61, 71.3, 71.0, 70.4, 69.6, 69.5, 69.4, 57.1, 18.2, 18.1; HRMS (ESI)
calcd for C48H46O13Na [M + Na]+ 853.2831, found 853.2833 .
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14α: [α]D28 = ꢀ25.6 (c 9.6, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 8.26 (dd, J = 8.1,
1.4 Hz, 2H), 7.98 (dd, J = 8.2, 1.3 Hz, 2H), 7.95–7.90 (m, 4H), 7.56–7.30 (m, 16H),
7.25–7.21 (m, 1H), 5.86–5.84 (m, 1H), 5.76 (dd, J = 6.1, 3.2 Hz, 1H), 5.40 (dd, J =
9.7, 3.2 Hz, 1H), 5.35 (dd, J = 7.3, 3.2 Hz, 1H), 5.13 (nr, 1H), 5.02 (d, J = 2.2 Hz, 1H),
4.84 (dq, J = 9.6, 6.4 Hz, 1H), 4.71 (dd, J = 60.6, 11.7 Hz, 2H), 4.30–4.26 (m, 2H),
3.92 (dd, J = 3.8, 1.2 Hz, 1H), 3.61 (s, 3H), 1.39 (d, J = 6.5 Hz, 3H), 1.30 (d, J = 6.4
Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 165.7, 165.6, 165.4, 165.1, 137.2, 133.5,
133.3, 133.04, 133.00, 130.6, 130.0, 129.83, 129.77, 129.6, 129.5, 128.6, 128.52,
128.47, 128.34, 128.30, 128.0, 127.9, 100.4, 98.8, 76.2, 73.3, 72.9, 72.0, 71.3, 70.1,
68.1, 67.4, 63.2, 56.7, 18.6, 17.5; HRMS (ESI) calcd for C48H50O13N [M + NH4]+
848.3277, found 848.3273.
Methyl
3,4ꢀDiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀ2ꢀOꢀ(3,4ꢀdiꢀOꢀbenzoylꢀ6ꢀdeoxyꢀβꢀLꢀaltropyranosyl)ꢀβꢀL
ꢀaltropyranoside (15). Disaccharide 14β (3.7 g, 7.8 mmol) was subjected to general
debenzylation procedure with Pd/C (10%, 8.3 g) in MeOH/AcOH (100 mL/20 mL).
The purification by silica gel column chromatography (petroleum ether/EtOAc, 4:1)
1
provided 15 (2.90 g, 91%) as a white foam: [α]D28 = +29.4 (c 1.6, CHCl3); H NMR
(500 MHz, CDCl3)
δ 8.05–8.03 (m, 2H), 8.01–7.99 (m, 2H), 7.97–7.95 (m, 2H),
7.92–7.90 (m, 2H), 7.64–7.61 (m, 1H), 7.57–7.47 (m, 5H), 7.43–7.34 (m, 6H),
5.98–5.91 (m, 1H), 5.93 (dd, J = 4.4, 3.2 Hz, 1H), 5.83 (dd, J = 7.0, 3.1 Hz, 1H), 5.53
(dd, J = 6.0, 3.1 Hz, 1H), 5.38–5.35 (m, 2H), 4.91 (d, J = 1.4 Hz, 1H), 4.32–4.29 (m,
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2H), 4.26–4.23 (m, 2H), 3.58 (s, 3H), 3.19 (d, J = 6.3 Hz, 1H), 1.57 (d, J = 6.7 Hz,
13
3H), 1.40 (d, J = 6.3 Hz, 3H); C NMR (125 MHz, CDCl3)
δ 165.54, 165.47, 165.3,
7
8
9
165.1, 133.7, 133.32, 133.27, 133.2, 129.89, 129.85, 129.82, 129.81, 129.77, 129.60,
129.59, 128.7, 128.49, 128.48, 128.46, 101.5, 99.8, 75.6, 72.1, 71.5, 71.1, 69.8, 69.6,
69.3, 68.5, 57.1, 19.4, 18.1; HRMS (ESI) calcd for C41H40O13Na [M + Na]+ 758.2807,
found 758.2803.
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Trisaccharides 16β and 16α. The general glycosylation procedure was used with
donor 7 (3.04 g, 4.7 mmol), acceptor 15 (2.90 g, 3.9 mmol), and Ph3PAuNTf2 (348 mg,
ο
0.47 mmol) in CH2Cl2 (200 mL) at ꢀ20 C. The purification by silica gel column
chromatography (petroleum ether/EtOAc, 10:1) afforded the coupled trisaccharide 16β
(2.85 g, 88%) and its αꢀanomer 16α (217 mg, 9%) as both white foams.
16β: [α]D28 = +33.1 (c 1.8, CHCl3); mp = 112−114 οC; 1H NMR (500 MHz, CDCl3)
δ
8.11–8.09 (m, 2H), 8.03–8.01 (m, 2H), 7.91–7.89 (m, 4H), 7.87–7.85 (m, 2H),
7.75–7.73 (m, 2H), 7.64–7.58 (m, 4H), 7.51–7.40 (m, 8H), 7.35–7.27 (m, 10H),
7.17–7.13 (m, 1H), 6.00–5.99 (m, 1H), 5.94–5.93 (m, 1H), 5.78 (dd, J = 4.5, 3.0 Hz,
1H), 5.53 (dd, J = 9.7, 3.2 Hz, 1H), 5.50–5.43 (m, 2H), 5.43 (d, J = 1.3 Hz, 1H), 5.18
(d, J = 12.2 Hz, 1H), 5.10 (dd, J = 9.4, 3.0 Hz, 1H), 5.00 (d, J = 12.2 Hz, 1H), 4.86 (d,
J = 1.2 Hz, 1H), 4.43 (d, J = 4.3 Hz, 1H), 4.38 (d, J = 4.4 Hz, 1H), 4.31–4.26 (m, 2H),
4.23 (dq, J = 9.7, 6.2 Hz, 1H), 4.11 (dq, J = 9.3, 6.2 Hz, 1H), 3.52 (s, 3H), 1.42 (d, J =
6.3 Hz, 3H), 1.38 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H); 13C NMR (125 MHz,
cdcl3)
δ 165.4, 165.2, 165.0, 164.9, 164.8, 164.4, 138.7, 133.5, 133.4, 133.04, 133.01,
132.97, 132.8, 130.3, 130.1, 130.0, 129.9, 129.82, 129.79, 129.77, 129.76, 129.6,
128.7, 128.6, 128.37, 128.36, 128.34, 128.31, 128.2, 127.4, 101.1, 100.5, 98.8, 74.8,
74.7, 74.4, 72.6, 71.6, 71.0, 70.9, 70.3, 69.7, 69.6, 69.1, 69.0, 57.3, 18.4, 18.1, 17.8;
HRMS (ESI) calcd for C68H64O19Na [M + Na]+ 1207.3934, found 1207.3937.
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16α: [α]D28 = ꢀ26.3 (c 0.4, CHCl3); H NMR (500 MHz, CDCl3)
δ 8.32–8.30 (m,
5
6
7
8
2H), 8.18–8.16 (m, 2H), 8.11–8.09 (m, 2H), 8.04–8.02 (m, 2H), 7.87–7.85 (m, 2H),
7.66–7.60 (m, 2H), 7.55–7.30 (m, 17H), 7.27–7.19 (m, 6H), 5.96–5.94 (m, 1H),
5.89–5.87 (m, 1H), 5.67–5.66 (m, 1H), 5.51 (dd, J = 10.1, 3.2 Hz, 1H), 5.37 (d, J =
1.4 Hz, 1H), 5.23 (dd, J = 9.8, 3.2 Hz, 1H), 5.18 (dd, J = 10.0, 3.2 Hz, 1H), 5.15–5.12
(m, 2H), 4.93 (d, J = 11.7 Hz, 1H), 4.83–4.79 (m, 2H), 4.37 (dd, J = 3.8, 1.3 Hz, 1H),
4.27–4.21 (m, 2H), 4.07 (dq, J = 9.6, 6.2 Hz, 1H), 4.00 (d, J = 3.3 Hz, 1H), 3.49 (s,
3H), 1.38 (d, J = 6.3 Hz, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.15 (d, J = 6.2 Hz, 3H); 13C
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NMR (125 MHz, CDCl3)
δ 166.2, 166.1, 165.3, 165.0, 163.8, 137.5, 133.6, 133.5,
133.2, 132.83, 132.78, 132.7, 130.7, 130.6, 130.4, 130.2, 130.0, 129.9, 129.84, 129.82,
129.79, 129.73, 129.69, 129.6, 128.8, 128.73, 128.67, 128.5, 128.4, 128.24, 128.21,
128.12, 128.06, 100.7, 100.2, 97.5, 76.7, 76.3, 73.1, 72.5, 71.34, 71.31, 71.2, 70.3,
69.29, 69.26, 68.41, 67.39, 63.3, 56.9, 18.2, 18.1; HRMS (ESI) calcd for C68H64O19Na
[M + Na]+ 1207.3934, found 1207.3947.
Trisaccharide 17. Compound 16β (1.8 g, 1.5 mmol) was subjected to the general
debenzylation procedure with Pd/C (10%, 4.8 g) in MeOH/AcOH (30 mL/6 mL). The
purification by silica gel column chromatography (petroleum ether/EtOAc, 4:1)
recovered 16β (711 mg, 40%) and provided the desired 17 (739 mg, 45%) as a white
1
foam: [α]D28 = +31.2 (c 0.3, CHCl3); H NMR (500 MHz, CDCl3)
δ 8.05–8.00 (m,
4H), 7.98–7.89 (m, 6H), 7.82–7.80 (m, 2H), 7.62–7.58 (m, 2H), 7.52–7.44 (m, 8H),
7.36–7.29 (m, 8H), 5.96 (dd, J = 4.4, 3.2 Hz, 1H), 5.93–5.90 (m, 2H), 5.55 (dd, J =
7.2, 3.1 Hz, 1H), 5.45–5.40 (m, 3H), 5.26 (dd, J = 9.5, 3.1 Hz, 1H), 4.86 (d, J = 1.1
Hz, 1H), 4.48–4.46 (m, 1H), 4.40 (dd, J = 4.5, 1.3 Hz, 1H), 4.35–4.28 (m, 2H), 4.24
(dq, J = 9.3, 6.3 Hz, 1H), 4.17 (dq, J = 9.5, 6.3 Hz, 1H), 3.50 (s, 3H), 3.18 (d, J = 5.6
Hz, 1H), 1.53 (d, J = 6.6 Hz, 3H), 1.42 (d, J = 6.3 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H);
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13C NMR (125 MHz, CDCl3)
δ 165.48, 165.46, 165.2, 165.0, 164.92, 164.87, 133.52,
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6
7
8
133.50, 133.2, 133.1, 132.9, 130.2, 130.1, 129.91, 129.89, 129.86, 129.8, 129.73,
128.69, 128.66, 128.5, 128.4, 128.3, 101.2, 100.4, 99.0, 75.1, 73.5, 72.0, 71.1, 70.5,
70.2, 70.00, 69.99, 69.8, 69.2, 68.6, 57.3, 19.1, 18.3, 18.0; HRMS (ESI) calcd for
C61H58O19Na [M + Na]+ 1117.3465, found 1117.3464.
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16
17
18
19
20
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23
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Tetrasaccharides 18β and 18α. The general glycosylation procedure was used with
donor 7 (291 mg, 0.45 mmol), acceptor 17 (410 mg, 0.37 mmol), and Ph3PAuNTf2 (33
ο
mg, 0.045 mmol) in CH2Cl2 (20 mL) at ꢀ20 C. The purification by silica gel column
chromatography (petroleum ether/EtOAc, 5:1) afforded the coupled glycoside 18β
(472 mg, 82%) and its αꢀanomer 18α (69 mg, 12%) as both white foams.
18β: [α]D28 = +23.5 (c 1.8, CHCl3); mp = 133−136 οC; 1H NMR (500 MHz, CDCl3)
δ
8.06–7.99 (m, 8H), 7.87–7.85 (m, 4H), 7.78–7.75 (m, 4H), 7.67–7.58 (m, 4H),
7.51–7.41 (m, 10H), 7.33–7.22 (m, 14H), 7.10–7.07 (m, 1H), 6.15–6.14 (m, 1H),
6.02–5.99 (m, 2H), 5.73 (dd, J = 4.3, 3.0 Hz, 1H), 5.61–5.58 (m, 2H), 5.51 (dd, J =
9.9, 3.2 Hz, 1H), 5.45 (nr, 1H), 5.36 (nr, 1H), 5.24–5.20 (m, 2H), 5.14 (dd, J = 9.6,
3.0 Hz, 1H), 5.08 (d, J = 12.4 Hz, 1H), 4.88 (nr, 1H), 4.65 (d, J = 3.9 Hz, 1H), 4.57
(dq, J = 9.7, 6.2 Hz, 1H), 4.49 (d, J = 4.3 Hz, 1H), 4.35 (d, J = 3.8 Hz, 1H), 4.26 (dd,
J = 11.1, 5.3 Hz, 2H), 4.15 (dq, J = 9.6, 6.2 Hz, 1H), 4.04 (dq, J = 9.5, 6.3 Hz, 1H),
3.54 (s, 3H), 1.40 (d, J = 6.2 Hz, 6H), 1.06 (d, J = 6.2 Hz, 3H), 0.72 (d, J = 6.3 Hz,
3H); 13C NMR (125 MHz, CDCl3)
δ 165.38, 165.37, 165.02, 164.97, 164.9, 164.8,
164.7, 164.3, 138.8, 133.6, 133.3, 133.1, 132.9, 132.84, 132.81, 132.7, 130.34, 130.25,
130.2, 130.1, 130.0, 129.94, 129.87, 129.82, 129.80, 129.77, 129.7, 129.6, 128.7,
128.6, 128.4, 128.33, 128.29, 128.26, 128.2, 127.3, 101.6, 100.4, 99.4, 99.0, 75.5,
75.0, 74.3, 73.4, 73.2, 71.9, 71.4, 71.2, 71.1, 71.0, 70.7, 70.3, 69.7, 69.01, 68.97, 68.8,
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68.7, 57.3, 18.3, 18.1, 18.0, 17.4; HRMS (ESI) calcd for C88H82O25Na [M + Na]+
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6
1561.5037, found 1561.5033.
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8
1
18α: [α]D28 = +0.4 (c 0.5, CHCl3); H NMR (500 MHz, CDCl3)
δ 8.33–8.30 (m,
9
2H), 8.23 (dd, J = 8.2, 1.4 Hz, 2H), 8.13–8.11 (m, 2H), 7.93–7.91 (m, 2H), 7.89–7.87
(m, 2H), 7.84–7.82 (m, 2H), 7.79–7.77 (m, 2H), 7.68–7.61 (m, 1H), 7.57–7.49 (m,
7H), 7.51–7.41 (m, 5H), 7.44–7.34 (m, 4H), 7.35–7.20 (m, 13H), 7.16–7.10 (m, 1H),
6.00–5.99 (m, 1H), 5.96–5.95 (m, 1H), 5.85–5.84 (m, 1H), 5.78 (dd, J = 5.3, 3.0 Hz,
1H), 5.50 (dd, J = 10.2, 3.1 Hz, 1H), 5.43 (d, J = 1.1 Hz, 1H), 5.38 (d, J = 1.4 Hz, 1H),
5.30 (dd, J = 9.9, 3.2 Hz, 1H), 5.24 (dd, J = 10.1, 3.0 Hz, 1H), 5.18–5.12 (m, 3H),
4.93 (d, J = 11.7 Hz, 1H), 4.88 (d, J = 1.4 Hz, 1H), 4.82 (d, J = 11.7 Hz, 1H), 4.60 (d,
J = 3.8 Hz, 1H), 4.49 (dd, J = 5.3, 1.4 Hz, 1H), 4.33 (d, J = 4.0 Hz, 1H), 4.28 (dq, J =
9.9, 6.2 Hz, 1H), 4.12 (dq, J = 8.4, 6.4 Hz, 1H), 4.05 (dq, J = 9.6, 5.9 Hz, 1H), 4.00 (d,
J = 3.3 Hz, 1H), 3.53 (s, 3H), 1.40 (d, J = 6.2 Hz, 3H), 1.33 (d, J = 6.2 Hz, 3H), 1.15
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60
(d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.4 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 166.24,
166.22, 165.3, 165.0, 164.9, 164.7, 164.6, 163.4, 137.7, 133.5, 133.4, 133.0, 132.9,
132.8, 132.7, 132.6, 130.73, 130.69, 130.66, 130.3, 130.23, 130.19, 129.9, 129.84,
129.76, 129.72, 129.70, 129.62, 129.57, 128.70, 128.66, 128.6, 128.40, 128.38,
128.30, 128.26, 128.10, 128.07, 127.9, 101.6, 100.7, 97.4, 97.3, 72.9, 72.5, 71.7,
71.53, 71.45, 71.43, 71.41, 70.8, 70.1, 69.72, 69.67, 69.6, 68.9, 67.9, 67.4, 67.3, 63.2,
57.1, 18.26, 18.25, 18.2, 18.0; HRMS (ESI) calcd for C88H82O25Na [M + Na]+
1561.5037, found 1561.5045.
Tetrasaccharide 19. Tetrasaccharide 18β (380 mg, 0.25 mmol) was subjected to the
general debenzylation procedure with Pd/C (10%, 788 mg) in MeOH/AcOH (30
mL/15 mL). The purification by silica gel column chromatography (petroleum
ether/EtOAc, 4:1) recovered 18β (152 mg, 39%) and provided the desired 19 (185 mg,
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