Cascade in Situ Phosphorylation and One-Pot Glycosylation for Rapid Synthesis of Heptose-Containing Oligosaccharides

Article abstract of DOI:10.1021/acs.joc.0c01828

We report a one-pot glycosylation strategy for achieving rapid syntheses of heptose (Hep)-containing oligosaccharides. The reported procedure was designed to incorporate an in situ phosphorylation step into an orthogonal one-pot glycosylation. Hep-contain

Full text of DOI:10.1021/acs.joc.0c01828

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Article
Cascade In Situ Phosphorylation and One-Pot Glycosylation for
Rapid Synthesis of Heptose-Containing Oligosaccharides
Kwok-Kong Tony Mong,* Kuang-Chun Cheng,‡ I-Chen Lu,‡ Chia-Wei Pan, Yi-Fang Wang,
and Li-Ching Shen
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ABSTRACT: We report a one-pot glycosylation strategy for
achieving rapid syntheses of heptose (Hep)-containing oligosac-
charides. The reported procedure was designed to incorporate an
in situ phosphorylation step into an orthogonal one-pot
glycosylation. Hep-containing oligosaccharides were assembled
directly from building blocks with minimal effort expended on
manipulation of protecting and aglycone leaving groups. The utility
of our one-pot procedure was illustrated by synthesizing partial
core oligosaccharide structure present in the lipopolysaccharide of Ralstonia solanacearum.
tion,29−33 and preactivation one-pot glycosylation meth-
ods.34−36
INTRODUCTION
■
A unique feature of bacterial inner core oligosaccharides is the
presence of higher carbon sugars.1,2 Typical examples include
L-/D-glycero-D-manno-heptopyranoses (L,D- or D,D-Hep), 3-
deoxy-D-manno-oct-2-ulosonic acid (Kdo), and D-glycero-D-
talo-oct-2-ulosonic acid (Ko).3 Because the higher carbon
sugars are absent in mammalian glycans, the bacterial inner
core oligosaccharides and related structures are potential
antigen candidates for development of vaccines and diagnostic
agents.4−7 Structurally defined core oligosaccharide samples
are required for immunological studies, and an efficient
glycosylation method for higher carbon sugars is therefore
highly desired.
In the syntheses of heparin-based idraparinux32 and SSEA-4
hexasaccharide,33 glycosyl phosphates have been used as
donors for glycosylation of thioglycosyl acceptors (Figure
1a). Such phosphate donors have to be prepared from
thioglycoside precursors in separate reactions. We realized
that if the conditions for phosphorylation are compatible with
those for phosphate activation, these reaction steps could, in
theory, be merged to give a cascade one-pot procedure (Figure
1b). Such a protocol would enable the coupling of two
thioglycosyl building blocks with no concern regarding
differences between their reactivities and no need to prepare
the phosphate building block in a separate reaction.
Despite the advances in glycosylation methods for synthesis
of mammalian glycans, synthesizing a bacterial inner core
oligosaccharide target remains a nontrivial and challenging
task.8−14 A major challenge in the synthesis is the unavailability
of Hep sugars, which have to be prepared from mono-
saccharide precursors15,16 or by de novo synthesis from achiral
compounds.17 In most cases, the acquired Hep sugars have to
be further modified prior to glycosylation. Such lengthy
processes constitute a barrier for development of new
glycosylation methods. As a consequence, the bacterial inner
core oligosaccharides are still prepared by the less effective
stepwise glycosylation.5,18−23
RESULTS AND DISCUSSION
■
At first, the feasibility of the proposed cascade one-pot reaction
was investigated by performing a model study with
thiomannosyl building blocks 1 and 2 and methyl mannoside
acceptor 3 (Scheme 1a). Building block 2 was derived from a
known thiomannoside via standard protecting group manipu-
lation, while building blocks 1 and 3 were known
compounds.37,38
In the model cascade one-pot reaction, thiomannoside 1
(1.2 equiv) was phosphorylated by treatment with dibutyl
phosphate (1.3 equiv), N-iodosuccinimide (NIS; 1.2 equiv),
Because of the biological relevance and potential utility of
inner-core oligosaccharides, a straightforward one-pot glyco-
sylation method that involves (i) minimal protecting group
modification, (ii) a single type of glycosylation building block,
and (iii) no iterative adjustments of the reaction temperature is
needed. However, such prerequisites are difficult to achieve
with classical reactivity-based,24−28 orthogonal glycosyla-
Special Issue: A New Era of Discovery in Carbohy-
drate Chemistry
Received: July 30, 2020
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glycosylation by iterative treatment with reducing-end acceptor
3 (0.8 equiv) and a supplementary dose of NIS (0.8 equiv).
The acid byproduct produced in the first glycosylation also
participated in activation of the NIS promoter; therefore, no
supplementary dose of TMSOTf was required in the second
glycosylation. After glycosylation for an additional 1.5 h, the
desired trisaccharide 4 was obtained in 55% yield over one
phosphorylation and two glycosylation steps.
After validation of the cascade one-pot procedure, its
applicability to Hep building blocks was examined. In this
regard, the non-natural trisaccharide 5 was employed as the
synthetic target, which could be assembled from L,D-Hep
thioglycoside donor 6, L,D-Hep thioglycoside acceptor 7, and
reducing-end glucosyl acceptor 8 (Scheme 2a). Acceptor 8 is a
known compound and is derived from methyl α-glucoside.40
L,D-Hep thioglycoside 6 was synthesized from a known
thiomannoside 9 (Scheme 2b).41 Dibutyltin oxide (Bu2SnO)
mediated benzylation of 9 afforded a 3-O-Bn-protected
thiomannoside, which was subsequently alkylated with 2-
naphthylmetyhyl bromide to give 2-O-Nap-3-O-Bn-protected
thiomannoside 10. The structure of 10 was confirmed by 1D
and 2D NMR spectroscopy with the anomeric proton and
carbon signals found at 5.43 and 87.8 ppm, respectively (see
2D NMR spectra in the SI). Reductive cleavage of 10 with
borane (BH3)−THF and TMSOTf afforded thiomannoside
intermediate 11.42 Iodoxybenzoic acid (IBx) oxidation of 11
followed by methoxymethyl (MOM) Wittig olefination and
acid hydrolysis furnished the 1,7-dialdo substrate 12. L-Proline
(L-Pro)-catalyzed aminoxylation of 12 allowed the procure-
ment of the key 6-(anilinyl)oxy-L,D-Hep substrate with nearly
perfect L-glycero selectivity.16 Cleavage of the N−O bond at the
6-(anilinyl)oxy-substituted substrate was performed with
nitrosobenzene (PhNO) as the cleaving agent;43 this was
found to be more effective than the commonly used
CuSO4.16,44 As such, L,D-Hep diol 13 was obtained from 12
in 40% overall yield over three steps. The structure of diol 13
was supported by the 2D NMR spectroscopy; whereas, the
correlation signals between the hydroxyl protons and the
protons at C6 and C7 positions were clearly identified in the
COSY spectrum (SI). Further elaboration of diol 13 gave the
designated L,D-Hep building block 6 over three steps, which
included the (i) acetonide protection at the C6 and C7
hydroxyls, (ii) cleavage of the Nap protecting group at C2, and
(iii) reprotection of the C2 hydroxyl with benzoyl chloride
(BzCl).
Figure 1. (a) Preparation of phosphate donor for one-pot reaction.
(b) Cascade in situ phosphorylation and one-pot glycosylation
procedure.
Scheme 1. (a) Mannosyl Building Blocks 1−3. (b)
Validation of the Cascade Phosphorylation and One-Pot
Glycosylation Procedure
The L,D-Hep building block 7 was prepared from Hep
thioglycoside 15 (Scheme 2c).16 Benzylation of the C6 and C7
hydroxyls of 15 and subsequent removal of the isopropylidene
group afforded Hep 2,3-diol 16. Conversion of diol 16 to the
designated building block 7 involved orthogonal ester
formation and acid hydrolysis. The structure of building
block 7 was characterized with 1D and 2D NMR spectroscopy.
The proton signals at C6 and C7 positions were clearly
identified at 4.20, 3.74, and 3.53 ppm in the COSY and HSQC
spectra (SI).
With building blocks 6−8 in hand, we tackled the synthesis
of trisaccharide 5 (Scheme 3). The L,D-Hep donor 6 was
phosphorylated at −20 °C under NIS-promoted conditions to
give a phosphate intermediate. Subsequent treatment of the
adduct with L,D-Hep acceptor 7 and a stoichiometric amount
of TMSOTf initiated the first glycosylation, which proceeded
well at −20 °C to give an L,D-Hep disaccharide intermediate.
After completion of the first glycosylation (ca. 3 h), the
and a catalytic amount of trimethylsilyl trifluoromethanesulfo-
nate (TMSOTf; 0.2 equiv) according to the procedure
reported in the literature (Scheme 1b).32,33,39 The phosphor-
ylation worked well at 0 °C to give a phosphate adduct, which
was detected by TLC. Next, thiomannoside acceptor 2 (1
equiv) and TMSOTf (1.5 equiv) were added to the reaction
mixture to trigger the first glycosylation. Glycosylation of 2
with the phosphate adduct was complete within 1.5 h, and a
disaccharide thioglycoside was obtained cleanly. Without
isolation, the thioglycoside was subjected to a second
B
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Scheme 2. (a) L,D-Hep-Containing Trisaccharide 5 and Its
Constituent Building Blocks 6−8. (b) Preparation of L,D-
Hep Building Block 6. (c) Preparation of L,D-Hep Building
Block 7
Scheme 3. One-Pot Synthesis of L,D-Hep-Containing
Trisaccharide 5 Using the Cascade in Situ Phosphorylation
and One-Pot Glycosylation
2
was clearly indicated by the heteronuclear JC1−P coupling
constant of 5.5 Hz. The α-anomeric configuration of the
1
phosphate group was supported by the JC1−H1 coupling
constant of 175.1 Hz. The exclusive formation of the α-anomer
is attributed to the Bz group at C2 position, which directs the
formation of 1,2-trans glycosidic bond. As the Hep phosphate
in Scheme 3 has the same stereodirecting group at C2, it is
presumably an α-anomer without the need for NMR
characterization.
Furthermore, one may question if the phosphate leaving
group generated from the first glycosylation would engage with
the oxacarbenium ion in the second glycosylation to form a
phosphate intermediate. In practice, but no such a phosphate
intermediate was observed in the one-pot reactions of Schemes
1 and 3. However, we do not exclude the possibility because
the phosphate intermediate when formed might be immedi-
ately activated by an acid byproduct, which is also produced in
the glycosylation. To ensure the complete activation of a
possible phosphate intermediate, we applied a stoichiometric
amount of TMSOTf and NIS in subsequent cascade one-pot
reaction (see Scheme 4b).
The rapid synthesis of trisaccharide 5 motivated us to apply
the cascade one-pot procedure for procurement of a bacterial
inner core oligosaccharide. To this aim, the branched
tetrasaccharide 17 was chosen as the synthetic target, which
is the partial structure of the inner-core structure of the
lipopolysaccharide (LPS) of Ralstonia solanacearum Toudk-2
(Figure 2).45 Tetrasaccharide 17 consists of two L-rhamnose
(Rha) units, which are attached to the 2- and 3-hydroxyls of a
branching Hep residue and which is in turn connected to a
reducing-end Hep at the C3 position. All the glycosidic bonds
in the target have a 1,2-trans α-configuration.
reducing-end acceptor 8 and a supplementary dose of NIS
were added to the mixture. As was the case in the cascade one-
pot reaction shown in Scheme 1, no supplementary dose of
TMSOTf was needed to initiate the second glycosylation. The
target trisaccharide 5 was obtained in 45% yield over three
steps.
The key to the cascade phosphorylation and one-pot
glycosylation method is the in situ preparation of a phosphate
intermediate. To confirm the presence of the intermediate, the
mannosyl phosphate in Scheme 1 was isolated for NMR
characterization. The presence of the phosphate leaving group
Disconnection of target 17 gives known thiorhamnosyl
donor 18,46 L,D-Hep thioglycosyl acceptor 16, and reducing-
end L,D-Hep acceptor 19. The L,D-Hep thioglycosyl acceptor
C
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Scheme 4. (a) Preparation of L,D-Hep Building Block 19 from Methyl Mannoside 20. (b) One-Pot Synthesis of Partial Core
Tetrasaccharide 17 of R. solanacearum LPS via the Cascade Phosphorylation and One-Pot Glycosylation Method
16 was an advanced intermediate and was prepared as shown
in Scheme 2c. The L,D-Hep acceptor 19 was derived from
available methyl α-mannoside 20.47 Thus, IBx oxidation of 20
followed by MOM-Wittig olefination and acid hydrolysis
obtained the Hep-1,7-dialdo intermediate 2l (Scheme 4a).
Subsequent L-Pro-catalyzed aminoxylation of 21 followed by
reduction and N−O bond cleavage furnished Hep-1,7-diol
22.48 Conversion of 22 to the desired Hep acceptor 19 was
achieved by (i) benzylation of the C6 and C7 hydroxyls, (ii)
deprotection of the isopropylidene acetal at C2 and C3, and
(iii) orthoester formation and then acid hydrolysis. Similar to
Hep building block 7 in Scheme 2c, Hep building block 19 was
characterized with 1D and 2D NMR spectroscopy. From the
COSY NMR spectrum, the correlation signal between the C3
hydroxyl and the proton at C3 position of the Hep scaffold was
clearly identified in the COSY spectrum (see the SI).
Having prepared building blocks 16, 18, and 19, we
investigated the one-pot synthesis of tetrasaccharide 17
(Scheme 4b). First, thiorhamnoside 18 (2.2 equiv) was
Figure 2. Inner core oligosaccharide of R. solanacearum LPS, partial
core tetrasaccharide structure 17, and building blocks 16, 18, and 19.
phosphorylated under NIS-promoted conditions to give a
Rha phosphate intermediate. The Rha phosphate was in α-
1
anomeric configuration as indicated by the JC1−H1 coupling
2
constant of 174.4 Hz and JC1−P coupling constant of 5.3 Hz
D
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(SI). Next, the branching Hep building block 16 (1 equiv) and
a supplementary dose of TMSOTf (1.5 equiv) were added to
trigger the first glycosylation, whereas two glycosidic bonds
would be formed at the C2 and C3 hydroxyls of 16. Despite
the close proximity of these hydroxyl groups, the double
glycosylation took place swiftly to give the desired trisaccharide
product. Gladly, no undesired anomer or monoglycosylated
product was detected in the reaction mixture. After completion
of the first glycosylation (ca. 1.5 h), the reducing-end Hep
acceptor 19 (0.8 equiv), a supplementary dose of NIS (0.9
equiv), and TMSOTf (0.8 equiv) were added to initiate the
second glycosylation. With no adjustment of the reaction
temperature, the glycosylation worked well to give the desired
tetrasaccharide 23 as a single isomer in 42% yield over three
steps.
The α-configurations of the glycosidic bonds in tetrasac-
2
charide 23 are supported by the JC−H coupling constants
(167.0−171.2 ppm) at the anomeric centers (Figure 3).49 The
Figure 4. Partial HMBC correlation spectrum of inner core
tetrasaccharide 17.
an in situ phosphorylation step with an orthogonal one-pot
reaction. The new procedure streamlines the classical
orthogonal one-pot glycosylation and also avoids loss of the
phosphate intermediate during purification. The utility of the
method was shown by a one-pot synthesis of mannosyl
trisaccharide 4, Hep-containing trisaccharide 5, and the
protected inner-core tetrasaccharide structure 23 from the
LPS of Ralstonia solanacearum. We believe that this new one-
pot glycosylation procedure provides a valuable tool for rapid
synthesis of heptose-containing oligosaccharides.
Figure 3. Partial nondecoupling 13C NMR spectrum of protected
tetrasaccharide 23.
α-selectivity of isopropylidene-protected L-Rha donor 18 is
attributed to the conformation restrained isopropylidene group
at C2 and C3 positions. This has been reported in various
glycosylation settings.50,51 The α-selectivity of the trisaccharide
intermediate is likely related to the presence of two Rha
residues, which shield the β-face of the heptose from attack of
the acceptor. Global deprotection of 23 was accomplished by
(i) hydrolytic removal of the acetal and ester protecting groups
and (ii) Pd-catalyzed hydrogenolysis. As such, inner core
tetrasaccharide 17 was obtained from known mannoside
building block 20 in 6.4% yield over 14 linear steps. To the
best of our knowledge, this is the first example of a one-pot
synthesis of a Hep-containing inner core oligosaccharide.
Tetrasaccharide 17 was characterized with 1D and 2D NMR
spectroscopy. The anomeric proton and carbon signals of the
sugar residues could be clearly assigned on the base of the
COSY, HSQC, and HMBC correlation studies (see 2D spectra
in the SI). A unique feature of the 1H NMR spectrum of 17 is
the relative downfield shift of H2′ (at 4.13 ppm) and H3′ (at
∼3.92 ppm) proton signals of the branching Hep unit (SI).
This should be attributed to the substitution of the rhamnose
at the C2′ and C3′ positions. The glycosidic linkages between
the rhamnose and the Hep were confirmed by the HMBC
correlation signals between the anomeric protons of the
rhamnose substituents (H1′′ and H1′′′) and the C2′ and C3′
carbons of the Hep residue (Figure 4).
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reagents were of
commercial grade and used as received. All moisture-sensitive
reactions were performed under nitrogen atmosphere. DCM used
in the glycosylation reactions was predried with an aluminum oxide-
based solvent drying system before used. Progress of the reaction was
monitored by TLC analysis with detection by UV (254 nm) and
where applicable by spraying with an acidified solution of p-
anisaldehyde in EtOH or with a solution of (NH4)6Mo7O24·4H2O
and (NH4)4Ce(SO4)4·2H2O in 10% sulfuric acid (aq) followed by
charring with a hot gun. The heat source for reactions requiring
heating is an oil bath, and the temperature reported is the oil bath
temperature. Column chromatography was carried out using silica gel
(0.040−0.063 or 0.063−0.200 mm) from Silicycle. 1H and 13C
spectra were recorded on a Varian 400 or 600 MHz in CDCl3 or D2O.
Chemical shifts (δ) are reported in ppm relative to tetramethylsilane
as internal standard or the residual signal of the deuterated solvent.
Coupling constants (J) are measured in hertz. NMR peak assignments
were made using COSY and HSQC experiments, where applicable.
Preparation of Building Blocks 1−3. Preparation of Tolyl 2-O-
Benzoyl-3-O-benzyl-4,6-O-benzylidene-1-thio-α-D-mannopyrano-
side 1. Thiomannopyranoside 1 is a known compound prepared as a
colorless glassy solid (12.3 g, 39% over six steps) from D-mannose
(10.0 g, 55 mmol) following the literature procedures.37
Preparation of Tolyl 2-O-Benzoyl-4,6-O-benzylidene-1-thio-α-D-
mannopyranoside 2. To a mixture of known thiomannoside 9 (4.0 g,
10.7 mmol)37 in CH3CN (36 mL) were added CSA (0.25 g, 1.1
mmol) and PhC(OMe)3 (2.9 mL, 16.1 mmol). The reaction mixture
was stirred at rt for 1 h, and then the reaction was quenched with
Et3N. The solvent was removed by a rotary evaporator, and the
resulting syrup was absorbed in 40 mL of EtOAc to which was added
2 N HCl(aq) (8.0 mL). The EtOAc/HCl(aq) mixture was stirred
CONCLUSION
■
In summary, we have developed a cascade phosphorylation and
one-pot glycosylation procedure for the synthesis of heptose-
containing oligosaccharides The cascade procedure combines
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vigorously at rt for 10 min, and then the mixture was diluted with
EtOAc (40 mL). The combined EtOAc solution was washed with satd
NaHCO3 (40 mL) and brine (40 mL), dried (over MgSO4), and
filtered, and the filtrate was concentrated for column chromatography
purification (elution: hexanes/EtOAc, 6:1) to give thiomannoside 2
as a colorless glassy solid (4.4 g, 86% over two steps). Analytical data
ca. 4 h, the mixture was cooled to rt followed by addition of CsF (5.0
g, 32.7 mmol), BnBr (4.0 mL, 33.7 mmol), and Bu4NBr (11.0 g, 34.0
mmol). The reaction mixture was stirred at 100 °C for an additional 3
h then cooled to rt. The mixture was filtered over Celite to remove
the salts, and the filtrate was concentrated by a rotary evaporator to
give an oily syrup, which was absorbed in 150 mL of DCM. The
DCM solution was washed with H2O (100 mL) and brine (100 mL),
dried (over MgSO4), filtered, and concentrated for column
chromatography purification (elution: hexanes/EtOAc, 4:1) to obtain
thiomannoside 9a (13.2 g, 92%) as a white glassy substance.
Analytical data for thiomannoside 9a: Rf = 0.38 (hexanes/EtOAc,
2:1); [α]D25 = +195.9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.52−7.49 (m, 2H, ArH), 7.40−7.29 (m, 10H, ArH), 7.10 (d, J = 8.0
Hz, 2H, ArH), 5.60 (s, 1H), 5.50 (s, 1H, H-1), 4.87 (d, J = 11.6 Hz,
1H), 4.72 (d, J = 12.0 Hz, 1H), 4.34 (td, J = 9.6, 4.8 Hz, 1H, H-5),
4.24−4.23 (m, 1H, H-2), 4.22−4.14 (m, 2H, H-4, H-6a), 3.95 (dd, J
= 9.6, 3.2 Hz, 1H, H-3), 3.83 (t, J = 10.2 Hz, 1H, H-6b), 2.95−2.94
(m, 1H), 2.31 (s, 3H, SCH3); 13C{1H} NMR (100 MHz, CDCl3) δ
138.2, 137.9, 137.6, 132.5, 130.1, 129.6, 129.1, 128.7, 128.4, 128.2,
128.1, 126.3, 101.8 (CHPh), 88.4 (CH, C-1), 79.2 (CH, C-4), 75.9
(CH, C-3), 73.4 (CH2Ar), 71.5 (CH, C-2), 68.7 (CH2, C-6), 64.7
(CH, C-5), 21.3 (SCH3); HRMS (ESI-TOF) (m/z) [M + Na]+ calcd
for C27H28O5SNa 487.1550, found 487.1565.
25
for 2: Rf = 0.34 (hexanes/EtOAc, 4:1); [α]D = +113.48 (c 0.022
1
CHCl3); H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.3 Hz, 2H,
ArH), 7.60−7.52 (m, 3H, ArH), 7.45 (t, J = 7.7 Hz, 2H, ArH), 7.38
(d, J = 7.3 Hz, 5H, ArH), 7.12 (d, J = 7.9 Hz, 2H, ArH), 5.69 (d, J =
2.5 Hz, 1H, H-2), 5.65 (s, 1H, benzylidene-CH), 5.53 (s, 1H, H-1),
4.47−4.40 (m, 1H, H-5), 4.35−4.30 (m, 1H, H-3), 4.27 (dd, J = 10.4,
4.9 Hz, 1H, H-6b), 4.10 (t, J = 9.6 Hz, 1H, H-4), 3.87 (t, J = 10.3 Hz,
1H, H-6a), 2.71 (d, J = 4.0 Hz, 1H, OH), 2.32 (s, 3H, SCH3);
13C{1H} NMR (100 MHz, CDCl3) δ 165.8 (CO), 138.3, 137.0,
133.4, 132.7, 130.0, 129.9, 129.8, 129.4, 129.3, 129.2, 128.4, 128.3,
126.3, 102.2 (benzylidene-CH), 87.3 (C-1), 79.5, 74.1 (C-2), 68.5,
67.9, 64.5, 21.1 (SCH3); HRMS (ESI-TOF) (m/z) [M + H]+ calcd
for C27H27O6S 479.1523, found 479.1521.
Preparation of Methyl 2,3,4-Tri-O-benzyl-α-D-mannopyranoside
3. Methyl mannopyranoside 3 is a known compound prepared as a
white amorphous solid (5.4 g, 58% over three steps) from methyl α-D-
mannoside (4 g, 20 mmol) following the literature procedures.38
One-Pot Synthesis of Methyl 3-O-Benzyl-4,6-O-benzylidene-2-O-
benzoyl-α-D-mannopyranosyl-(1,3)-4,6-O-benzylidene-2-O-benzo-
yl-α-D-mannopyranosyl-(1,6)-2,3,4-tri-O-benzyl-α-D-mannopyra-
noside 4. To a mixture of thiomannoside 1 (130 mg, 0.23 mmol),
activated 4 Å MS (0.43 g), and dibutylphosphate (49.6 μL, 0.25
mmol) in DCM (4.6 mL) were added NIS (51.7 mg, 0.23 mmol) and
TMSOTf (8.33 μL, 0.046 mmol) at −20 °C. After the mixture was
stirred at −20 °C for 2 h, thiomannoside acceptor 2 (91 mg, 0.19
mmol) and TMSOTf (52.5 μL, 0.29 mmol) were added, and the
resulting mixture was stirred at 0 °C for 1.5 h. Then the reducing-end
acceptor 3 (71 mg, 0.152 mmol) and NIS (34.2 mg, 0.152 mmol)
were added. The mixture was stirred at 0 °C for an additional 1.5 h.
The reaction was quenched with Et3N (50 μL) and MS was removed
by filtration. The filtrate was diluted with DCM (12 mL) and then
washed with satd Na2S2O3 (15 mL), satd NaHCO3 (15 mL), and
brine (15 mL). The organic phase was dried (over MgSO4), filtered,
and concentrated for column chromatography purification (elution:
hexanes/EtOAc, 4:1) to give 4 as a light-yellow oily liquid (95 mg,
55% over three steps). Analytical data for 4: Rf = 0.26 (hexanes/
Preparation of Tolyl 3-O-Benzyl-4,6-O-benzylidene-2-O-(2-
naphthylmethyl)-1-thio-α-D-mannopyranoside 10. To a solution
of thiomannoside 9a and NapBr in DMF (112 mL) was added NaH
(1.7 g, 42.2 mmol) at 0 °C. After being stirred at 0 °C for 30 min, the
reaction mixture was stirred at rt for an additional 2.5 h. The reaction
was quenched by addition of satd NH4Cl (10 mL) then diluted with
DCM (120 mL). The DCM solution was washed with H2O (90 mL)
and brine (100 mL), dried (over MgSO4), filtered, and concentrated
for column chromatography purification (elution: hexanes/EtOAc,
6:1) to give thiomannoside 10 as an oily syrup (15.8 g, 81% over two
steps). Analytical data for thiomannoside 10: Rf = 0.48 (hexanes/
25
1
EtOAc, 4:1); [α]D = +66.7 (c 1.8, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.82−7.75 (m, 4H, ArH), 7.53−7.46 (m, 5H, ArH), 7.41−
7.27 (m, 8H, ArH), 7.21−7.18 (m, 2H, ArH), 7.01 (d, J = 8.0 Hz, 2H,
ArH), 5.66 (s, 1H), 5.43 (d, J = 1.6 Hz, 1H, H-1), 4.86−4.82 (m,
3H), 4.64 (d, J = 12.4 Hz, 1H), 4.38−4.28 (m, 2H, H-4,H-5), 4.27−
4.21 (m, 1H, H-6a), 4.07 (s, 1H, H-2), 4.01−3.98 (m, 1H, H-3), 3.89
(t, J = 9.8 Hz, 1H, H-6b), 2.29 (s, 3H, SCH3); 13C{1H} NMR (100
MHz, CDCl3) δ 138.6, 138.1, 137.8, 135.3, 133.4, 133.3, 132.5, 130.1,
130.0, 129.0, 128.53, 128.45, 128.4, 128.1, 127.9, 127.8, 127.2, 126.31,
126.28, 126.2, 101.7 (benzylidene-CH), 87.8 (C-1), 79.4 (C-4), 78.1
(CH, C-2), 76.4 (C-3), 73.4 (CH2Ar), 73.3 (CH2Ar), 68.7 (C-6),
65.7 (C-5), 21.3 (SCH3); HRMS (ESI-TOF) (m/z) [M + Na]+ calcd
for C38H36O5SNa 627.2176, found 627.2190.
25
1
EtOAc, 4:1); [α]D = −35.4 (c 2.6, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 7.5 Hz, 2H, ArH), 8.05 (d, J = 7.5 Hz, 2H,
ArH), 7.63−7.52 (m, 3H, ArH), 7.46 (dd, J = 15.8, 7.2 Hz, 9H, ArH),
7.35 (d, J = 7.6 Hz, 3H, ArH), 7.32 (s, 5H, ArH), 7.30 (d, J = 3.2 Hz,
5H, ArH), 7.28 (s, 2H, ArH), 7.24 (s, 4H, ArH), 7.16 (d, J = 3.3 Hz,
2H, ArH), 7.10 (d, J = 1.9 Hz, 3H, ArH), 5.70 (s, 1H, H-2″), 5.64 (s,
1H, H-2), 5.59 (s, 2H, H-1″, H-2′), 5.37 (s, 1H, H-1), 5.05 (s, 1H, H-
1′), 4.97 (d, J = 11.1 Hz, 1H), 4.73 (s, 2H), 4.70 (s, 1H), 4.62−453
(m, 4H), 4.49−4.44 (m, 2H), 4.32−4.21 (m, 3H), 4.11 (t, J = 10 Hz,
1H), 4.04 (dd, J = 9.6, 4.5 Hz, 2H), 3.97 (dd, J = 9.6, 2.9 Hz, 1H),
3.91−3.86 (m, 3H), 3.84−3.77 (m, 5H), 3.32 (s, 3H, OCH3);
13C{1H} NMR (100 MHz, CDCl3) δ 165.4 (CO), 165.3 (CO),
Preparation of Tolyl 3,4-Di-O-benzyl-2-O-(2-naphthylmethyl)-1-
thio-α-D-mannopyranoside 11. To a solution of the foregoing
thiomannoside 10 (14.6 g, 24.1 mmol) in DCM (80 mL) were added
BH3·THF (1 M in THF, 120.5 mL, 120.5 mmol) and TMSOTf (0.66
mL, 3.6 mmol) at 0 °C. After the mixture was stirred at 0 °C for 30
min, the reaction temperature was raised to rt and the stirring was
continued for additional 3 h. The reaction was then quenched with
Et3N (1 mL) followed by cautious addition of methanol (20 mL) to
quench the excess borane reagent. The mixture was concentrated by a
rotary evaporator, and the crude product was purified by column
chromatography (elution: hexanes/EtOAc, 4:1) to give thiomanno-
side 11 (13.6 g, 93%) as an amorphous substance. Analytical data for
thiomannoside 11: Rf = 0.25 (hexane/EtOAc, 4:1); [α]D25 = +48.9 (c
138.31, 138.26, 138.2, 137.9, 137.5, 137.1, 133.3, 133.1, 129.8, 129.7,
129.6, 128.70, 128.66, 128.5, 128.32, 128.28, 128.2, 128.1, 128.04,
128.03, 127.95, 127.91, 127.85, 127.77, 127.61, 127.56, 127.5, 127.4,
127.35, 126.3, 125.9, 101.6 (C-1″), 101.2, 99.6 (C-1), 98.8, 98.3 (C-
1′), 80.2, 79.3, 78.4, 74.9, 74.7, 74.1, 73.9, 72.6, 71.9, 71.6, 70.8, 70.0,
68.7, 68.6, 67.1, 64.5, 63.6, 54.7 (OCH3); HRMS (ESI−TOF) (m/z)
[M + Na]+ calcd for C75H74O18Na, 1285.4767, found, 1285.4717.
Preparation of Building Block 6. Preparation of Tolyl 3-O-
Benzyl-4,6-O-benzylidene-1-thio-α-D-mannopyranoside 9a.
1
0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 7.84−7.80 (m, 1H,
ArH), 7.78−7.74 (m, 3H, ArH), 7.50−7.45 (m, 3H, ArH), 7.36−7.23
(m, 10H, ArH), 7.21 (d, J = 8.4 Hz, 2H, ArH), 7.03 (d, J = 8.0 Hz,
2H, ArH), 5.43 (d, J = 1.2 Hz, 1H, H-1), 4.97 (d, J = 10.8 Hz, 1H),
4.83 (s, 2H), 4.69−4.60 (m, 3H), 4.15−4.11 (m, 1H, H-5), 4.07 (d, J
= 9.2 Hz, 1H, H-4), 4.03−4.02 (m, 1H, H-2), 3.90 (dd, J = 9.2, 3.2
Hz, 1H, H-3), 3.82 (s, 2H, H-6a, H-6b), 2.30 (s, 3H, SCH3), 1.88 (br,
1H, OH); 13C{1H} NMR (100 MHz, CDCl3) δ 138.5, 138.3, 138.2,
135.5, 133.4, 133.3, 132.70, 131.7, 130.2, 130.1, 128.73, 128.65, 128.5,
128.4, 128.3, 128.1, 128.01, 127.99, 127.94, 127.91, 127.8, 127.0,
To a solution of thiomannoside 9 (12.0 g, 32.1 mmol)37 in toluene
(236 mL) was added Bu2SnO (8.1 g, 32.7 mmol). The reaction
mixture was stirred under reflux with a Dean−Stark apparatus. After
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25
126.4, 126.21, 126.18, 86.7 (CH, C-1), 80.3 (CH, C-3), 76.5 (CH, C-
2), 75.5 (CH2Ar), 75.1 (CH, H-4), 73.4 (CH, C-5), 72.7 (CH2Ar),
72.5 (CH2Ar), 62.5 (CH2, C-6), 21.3 (SCH3); HRMS (ESI-TOF)
(m/z) [M + Na]+ calcd for C38H38O5SNa 629.2332, found 629.2326.
Preparation of Tolyl 3,4-Di-O-benzyl-6-deoxy-2-O-(2-naphthyl-
methyl)-1-thio-α-D-manno-hept-1,7-dialdo-pyranoside 12. To a
solution of thiomannoside 11 (13.7 g, 22.6 mmol) in DMSO (113
mL) was added IBx (9.5 g, 33.9 mmol). The reaction mixture was
stirred at 60 °C for 4 h. After the oxidation was complete, the mixture
was cooled to rt followed by addition of a brine solution (60 mL).
The resulting heterogeneous mixture was filtered to remove the
insoluble IBx byproduct. The filtrate was then diluted with DCM
(120 mL) and washed with brine (2 × 50 mL). The organic phase
was dried (over MgSO4), filtered, and concentrated by a rotary
evaporator to give the crude aldehyde product for the Wittig
olefination.
Analytical data for 13: Rf = 0.25 (hexanes/EtOAc, 1:1); [α]D
=
1
+56.3 (c 0.71, CHCl3); H NMR (400 MHz, CDCl3) δ 7.83−7.81
(m, 1H, ArH), 7.79−7.75 (m, 3H, ArH), 7.50−7.47 (m, 3H, ArH),
7.33−7.27 (m, 10H, ArH), 7.17 (d, J = 8.0 Hz, 2H, ArH), 7.05 (d, J =
8.0 Hz, 2H, ArH), 5.45 (d, J = 1.2 Hz, 1H, H-1), 4.98 (d, J = 10.8 Hz,
1H), 4.84 (s, 2H), 4.73 (d, J = 10.8 Hz, 1H), 4.66 (d, J = 12.0 Hz,
1H), 4.61 (d, J = 12.0 Hz, 1H), 4.24 (t, J = 9.4 Hz, 1H, H-4), 4.04 (d,
J = 10.0 Hz, 1H, H-5), 4.01−4.00 (m,1H, H-2), 3.97 (br, 1H, H-6),
3.89 (dd, J = 9.2, 3.2 Hz, 1H, H-3), 3.57−3.52 (m, 2H, H-7a, H-7b),
2.43 (d, J = 9.6 Hz, 1H, OH), 2.30 (s, 3H, SCH3), 1.91 (d, J = 6.0 Hz,
1H, OH); 13C{1H} NMR (100 MHz, CDCl3) δ 138.5, 138.4, 138.3,
135.4, 133.4, 133.3, 132.5, 130.2, 129.6, 128.7, 128.5, 128.3, 128.1,
128.01, 127.99, 127.96, 127.91, 127.0, 126.4, 126.2, 126.1, 86.6 (C-1),
80.2 (C-3), 76.2 (C-2), 75.6 (CH2Ar), 74.6 (C-4), 74.0 (C-5), 72.8
(CH2Ar), 72.53 (CH2Ar), 69.4 (CH, C-6), 65.2 (CH2, C-7), 21.3
(SCH3); HRMS (ESI-TOF) (m/z) [M + Na]+ calcd for
C39H40O6SNa 659.2438, found 659.2429.
Preparation of Tolyl 3,4-Di-O-benzyl-6,7-O-isopropylidene-2-O-
(2-naphthylmethyl)-L-glycero-1-thio-α-D-manno-heptopyranoside
14. To a solution of L,D-Hep diol 13 (1.5 g, 2.4 mmol) in acetone (24
mL) were added 2,2- dimethoxypropane (0.6 mL, 4.8 mmol) and
pTSA (5 mg, 0.24 mmol). The reaction mixture was stirred at rt for 4
h. The reaction was quenched by addition of Et3N (35 μL), and the
acetone was removed by a rotary evaporator. The concentrated
residue was absorbed in 30 mL of EtOAc solution, which was washed
with H2O (20 mL) and brine (20 mL), dried (over MgSO4), and
filtered. The filtrate was concentrated for chromatography purification
To a suspension of CH3OCH2PPh3Cl salt (23.2 g, 67.8 mmol) in
THF (63 mL) was added NaHMDS (2 M in THF, 31.7 mL, 63.3
mmol) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 h.
Meanwhile, the foregoing aldehyde was absorbed in 50 mL of THF
and the solution was transferred to the ylide solution by a syringe.
The resulting mixture was stirred at 0 °C overnight and then diluted
with EtOAc (100 mL), which was washed with H2O (80 mL) and
brine (100 mL). The organic phase was dried (over MgSO4) and
filtered. The filtrate was concentrated for column chromatography
purification (elution: hexanes/EtOAc, 6:1) to give an enol ether as a
pair of cis- and trans-isomers (8.2 g, 57% over two steps) (Rf = 0.38
and 0.43 for hexanes/EtOAc, 4:1). To the foregoing enol ether
isomers (8.2 g, 12.9 mmol) in acetone (129 mL) was added 2 N
HCl(aq) (3.2 mL) at rt. After the mixture was stirred at rt for 30 min,
satd Na2CO3 (15 mL) was added to neutralize the solution. Then the
mixture was diluted with EtOAc (100 mL) then washed with H2O
(60 mL) and brine (80 mL). After drying over MgSO4, the EtOAc
solution was filtered and subsequently concentrated for column
chromatography purification (elution: hexanes/EtOAc, 4:1) to give
Hep-1,7-dialdo substrate 12 (5.1 g, 51% from 11 over three steps) as
a colorless glassy substance. Analytical data for 12: Rf = 0.48
(elution: hexanes/EtOAc, 6:1) to obtain L,D-Hep 14 (1.6 g, 98%).
25
Analytical data for 14: Rf = 0.58 (hexanes/EtOAc, 1:1); [α]D
=
+48.7 (c 1.2, CHCl3); 1H NMR (400 MHz CDCl3) δ 7.81−7.79 (m,
1H, ArH), 7.76−7.72 (m, 3H, ArH), 7.49−7.43 (m, 3H, ArH), 7.32−
7.28 (m, 10H, ArH), 7.25 (d, J = 8.4 Hz, 2H, ArH), 7.03 (d, J = 8.0
Hz, 2H, ArH), 5.59 (s, 1H, H-1), 4.99 (d, J = 10.8 Hz, 1H), 4.83 (d, J
= 12.4 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 4.67 (d, J = 10.8 Hz, 1H),
4.62 (s, 2H), 4.49−4.48 (m, 1H, H-6), 4.15 (t, J = 9.6 Hz, 1H, H-4),
4.04−4.01 (m, 2H, H-2, H-5), 3.93−3.89 (m, 2H, H-3, H-7a), 3.81 (t,
J = 7.6 Hz, 1H, H-7b), 2.29 (s, 3H, SCH3), 1.44 (s, 3H), 1.38 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 138.6, 138.4, 137.9, 135.6,
25
1
(hexanes/EtOAc, 4:1); [α]D = +44.8 (c 0.58, CHCl3); H NMR
(400 MHz, CDCl3) δ 5.57 (t, J = 2.4 Hz, 1H, CHO), 7.82−7.73 (m,
4H, ArH), 7.49−7.45 (m, 3H, ArH), 7.32−7.26 (m, 10H, ArH), 7.20
(d, J = 8.0 Hz, 2H, ArH), 7.03 (d, J = 8.0 Hz, 2H, ArH), 5.42 (d, J =
1.6 Hz, 1H, H-1), 4.97 (d, J = 10.8 Hz, 1H), 4.84 (d, J = 12.4 Hz,
1H), 4.78 (d, J = 12.4 Hz, 1H), 4.61−4.56 (m, 4H, H-5), 4.05 (dd, J
= 2.8, 2.0 Hz, 1H, H-2), 3.89 (dd, J = 9.2, 2.8 Hz, 1H, H-3), 3.82 (t, J
= 9.4 Hz, 1H, H-4), 2.77 (ddd, J = 16.0, 4.0, 2.0 Hz, 1H, H-6a), 2.59
(ddd, J = 16.4, 8.4, 2.8 Hz, 1H, H-6b), 2.29 (s, 3H, SCH3); 13C{1H}
NMR (100 MHz, CDCl3) δ 200.5 (CHO), 138.13, 138.09, 138.02,
135.3, 133.4, 133.3, 132.2, 130.2, 130.1, 128.7, 128.5, 128.4, 128.14,
128.08, 128.07, 128.02, 128.00, 127.9, 127.1, 126.4, 126.21, 126.15,
86.5 (CH, C-1), 80.3 (CH, C-3), 78.0 (CH, C-4), 76.3 (CH, C-2),
75.4 (CH2Ar), 72.5 (CH2Ar), 72.3 (CH2Ar), 68.5 (CH, C-5), 46.0
(CH2, C-6), 21.3 (SCH3); HRMS (ESI-TOF) (m/z) [M + Na]+
calcd for C39H38O5SNa 641.2332, found 641.2329.
133.4, 133.2, 132.5, 130.2, 123.0, 128.6, 128.3, 128.1, 128.0, 127.9,
127.84, 127.83, 126.7, 126.2, 126.1, 126.0, 109.2, 86.1 (CH, C-1),
80.3 (CH, C-3), 76.3 (CH, C-2), 76.2 (CH, C-4), 75.5 (CH2Ar), 74.9
(CH, C-6), 72.3 (CH, C-5), 72.2 (CH2Ar), 72.0 (CH2Ar), 65.8
(CH2, C-7), 26.5 (CH3), 26.1 (CH3), 21.3 (SCH3); HRMS (ESI-
TOF) (m/z) [M + Na]+ calcd for C42H44O6SNa 699.2751, found
699.2753.
Preparation of Tolyl 3,4-Di-O-benzyl-6,7-O-isopropylidene-
L-glycero-1-thio-α-D-manno-heptopyranoside 14a.
To a solution of L,D-Hep thioglycoside 14 (1.5 g, 2.2 mmol) in DCM
(19.4 mL) and MeOH (2.2 mL) was added DDQ (0.98 g, 4.4 mmol)
in three equal portions over 1.5 h. The reaction mixture was stirred at
rt for 2 h and then quenched with satd Na2S2O3 (6 mL). The mixture
was diluted with DCM (12 mL) followed by washing with H2O (10
mL) and brine (20 mL), dried (over MgSO4), and filtered. The
filtrate was concentrated for column chromatography purification
(elution: hexanes/EtOAc, 4:1) to give L,D-Hep thioglycoside 14a
(0.87 g, 74%). Analytical data for 14a: Rf = 0.40 (hexanes/EtOAc,
2:1); [α]D25 = +169.0 (c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.38−7.31 (m, 12H, ArH), 7.10 (d, J = 8.0 Hz, 2H, ArH), 5.59 (s,
1H, H-1), 4.91 (d, J = 10.8 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 4.70
(d, J = 11.6 Hz, 1H), 4.68 (d, J = 10.8 Hz, 1H), 4.44 (td, J = 7.2, 2.4
Hz, 1H, H-6), 4.23−4.22 (m, 1H, H-2), 4.02 (dd, J = 9.6, 2.8 Hz, 1H,
H-5), 3.98 (t, J = 9.0 Hz, 1H, H-4), 3.89 (dd, J = 8.4, 3.2 Hz, 1H, H-
3), 3.81 (dd, J = 7.86, 7.0 Hz, 1H, H-7a), 3.63 (t, J = 7.6 Hz, 1H, H-
7b), 2.73−2.69 (m, 1H, OH), 2.31 (s, 3H, SCH3), 1.38 (s, 3H), 1.35
Preparation of Tolyl 3,4-Di-O-benzyl-2-O-(2-naphthylmethyl)-L-
glycero-1-thio-α-D-manno-heptopyranoside 13. To a solution of
L,D-Hep 1,7-dialdo substrate 12 (5.8 g, 9.4 mmol) in CH3CN (31
mL) were added L-proline (0.32 g, 2.8 mmol) and PhNO (3.0 g, 28.2
mmol). The reaction mixture was stirred at −20 °C for 2 d. Then
NaBH4 (0.78 g, 20.7 mmol) in ethanol (10 mL) was added, and the
mixture was stirred at 0 °C for 1 h. The reaction was quenched with
satd NH4Cl (5 mL). The heterogeneous mixture was diluted with
EtOAc (50 mL), which was then washed with H2O (40 mL) and
brine (40 mL), dried over MgSO4, and filtered. And the filtrate was
concentrated to give the crude 6-(anilinyl)oxy-L,D-Hep intermediate,
which was directly used as a substrate in the next reaction.
To a solution of crude 6-(anilinyl)oxy-L,D-Hep intermediate in
DCM (31 mL) was added PhNO (2.0 g, 18.8 mmol). The reaction
mixture was stirred at rt for 1 d then concentrated for column
chromatography purification (elution: hexanes/EtOAc, 2:1) to give
L,D-Hep diol 13 as a light-brown syrup (2.3 g, 40% over three steps).
G
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(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 138.4, 138.0, 137.8,
132.3, 130.1, 129.6, 128.8, 128.6, 128.22, 128.18, 128.10, 128.0, 109.3,
87.5 (CH, C-1), 80.4 (CH, C-3), 75.7 (CH, C-4), 75.6 (CH2Ar), 74.2
(CH, C-6), 72.2 (CH2Ar), 71.0 (CH, C-5), 69.8 (CH, C-2), 65.3
(CH2, C-7), 26.4 (CH3), 26.0 (CH3), 21.3 (SCH3); HRMS (ESI-
TOF) (m/z) [M + Na]+ calcd for C31H36O6SNa 559.2125, found
559.2138.
Preparation of Tolyl 2-O-Benzoyl-3,4-di-O-benzyl-6,7-O-isopro-
pylidene-L-glycero-1-thio-α-D-manno-heptopyranoside 6. To a
solution of L,D-Hep thioglycoside 14a in pyridine (8.6 mL) were
added BzCl (0.2 mL, 1.7 mmol) and DMAP (50 mg, 0.43 mmol).
The reaction mixture was stirred at 70 °C overnight then diluted with
EtOAc (20 mL) and washed with 1 N HCl(aq) (3 × 15 mL) and brine
(15 mL), dried (over MgSO4), and filtered. The filtrate was
concentrated for column chromatography purification (elution:
(CH2Ar), 73.0 (C-3), 72.5 (C-2), 72.4 (C-5), 71.4 (C-7), 21.3
(SCH3); HRMS (ESI-TOF) (m/z) [M + Na]+ calcd for
C35H38O6SNa 609.2281, found 609.2286.
Preparation of Tolyl 2-O-Benzoyl-4,6,7-tri-O-benzyl-L-glycero-1-
thio-α-D-manno-heptopyranoside 7. To a solution of L,D-Hep diol
16 (0.32 g, 0.55 mmol) in CH3CN (5.5 mL) were added CSA (26
mg, 0.11 mmol) and PhC(OMe)3 (0.28 mL, 1.6 mmol). The reaction
mixture was stirred at rt for 1 h, and then the reaction was quenched
with addition of Et3N. The solvent was removed by a rotary
evaporator. The residue was absorbed in an EtOAc solution (3 mL),
which was mixed with 2 N HCl(aq) (2.7 mL). The resulting mixture
was stirred vigorously at rt for 30 min and then diluted with EtOAc
(10 mL). The EtOAc solution was washed with satd NaHCO3 (10
mL) and brine (10 mL), dried (over MgSO4), and filtered. The
filtrate was concentrated for column chromatography purification
(elution: hexanes/EtOAc, 4:1) to give L,D-Hep building block 7 (0.3
hexanes/EtOAc, 6:1) to yield L,D-Hep building block 6 (0.5 g,
25
25
91%). Analytical data for 6: Rf = 0.45 (hexanes/EtOAc, 4:1); [α]D
=
g, 78%). Analytical data for 7: Rf = 0.45 (hexanes/EtOAc, 2:1); [α]D
1
+92.5 (c 0.67, CHCl3); H NMR (400 MHz, CDCl3) δ 8.10 (d, J =
7.2 Hz, 2H, ArH), 7.57 (t, J = 7.4 Hz, 1H, ArH), 7.44 (t, J = 7.8 Hz,
2H, ArH), 7.35−7.23 (m, 12H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH),
5.84−5.83 (m, 1H, H-2), 5.59 (d, J = 1.6 Hz, 1H, H-1), 4.95 (d, J =
10.8 Hz, 1H), 4.81 (d, J = 11.6 Hz, 1H), 4.69 (d, J = 10.8 Hz, 1H),
4.61 (d, J = 11.6 Hz, 1H), 4.54 (td, J = 6.8, 2.8 Hz, 1H, H-6), 4.18−
4.10 (m, 2H, H-4, H-5), 4.06 (dd, J = 8.6, 3.0 Hz, 1H, H-3), 3.94 (t, J
= 7.6 Hz, 1H, H-7a), 3.81 (t, J = 7.2 Hz, 1H, H-7b), 2.31 (s, 3H,
SCH3), 1.42 (s, 3H), 1.39 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.7(CO), 138.5, 138.3, 137.9, 133.4, 132.7, 130.2,
130.11, 130.07, 129.6, 128.59, 128.56, 128.54, 128.3, 128.2, 127.9,
109.3, 86.6 (CH, C-1), 78.7 (CH, C-3), 75.9 (CH, C-5), 75.7
(CH2Ar), 74.5 (CH, C-6), 71.9 (CH, C-4), 71.8 (CH2Ar), 70.6 (CH,
C-2), 65.5 (CH2, C-7), 26.4 (CH3), 25.9 (CH3), 21.3 (SCH3);
HRMS (ESI-TOF) (m/z) [M + Na]+ calcd for C38H40O7SNa
663.2387, found 663.2393.
= +100.0 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (dd, J
= 8.4, 1.2 Hz, 2H, ArH), 7.55 (t, J = 7.4 Hz, 1H, ArH), 7.40−7.26 (m,
19H, ArH), 7.04 (d, J = 8.0 Hz, 2H, ArH), 5.67 (d, J = 1.6 Hz, 1H, H-
1), 5.60 (dd, J = 3.2, 1.6 Hz, 1H, H-2), 4.94 (d, J = 11.6 Hz, 1H), 4.77
(d, J = 11.2 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 11.2 Hz,
1H), 4.47 (d, J = 14.0 Hz, 1H), 4.41 (d, J = 11.6 Hz, 1H), 4.30−4.23
(m, 2H, H-5, H-3), 4.20 (t, J = 5.2 Hz, 1H, H-6), 4.14 (t, J = 9.4 Hz,
1H, H-4), 3.74 (dd, J = 10.0, 6.8 Hz, 1H, H-7a), 3.53 (dd, J = 10.0,
4.8 Hz, 1H H-7b), 2.30 (s, 3H, SCH3), 2.23−2.22 (m, 1H, OH);
13C{1H} NMR (100 MHz, CDCl3) δ 166.3 (CO), 139.0, 138.4,
138.3, 137.8, 133.5, 132.0, 130.1, 129.96, 129.76, 128.7, 128.62,
128.58, 128.56, 128.1, 128.0, 127.8, 127.7, 86.1 (C-1), 76.0 (C-4),
75.7 (C-6), 74.9 (CH2Ar), 74.5 (C-2), 73.6 (CH2Ar), 73.0 (CH2Ar),
72.8 (C-5), 71.8 (C-3), 71.2 (C-7), 21.3 (SCH3); HRMS (ESI-TOF)
(m/z) [M + Na]+ calcd for C42H42O7SNa 713.2543, found 713.2551.
One-Pot Synthesis of Methyl 2-O-Benzoyl-3,4-di-O-benzyl-6,7-O-
isopropylidene-L-glycero-α-D-manno-heptopyranosyl-(1,3)-2-O-
benzoyl-4,6,7-tri-O-benzyl-L-glycero-1-thio-α-D-manno-heptopyra-
nosyl-(1,7)-4-O-benzyl-2,3-di(2-naphthylmethyl)-α-D-glucopyrano-
side 5. To a mixture of L,D-Hep thioglycoside 6 (0.14 g, 0.218 mmol),
dibutyl phosphate (46 μL, 0.234 mmol), and activated 4 Å molecular
sieves (0.4 g) in dried DCM (4.4 mL) were added NIS (49 mg, 0.218
mmol) and TMSOTf (8 μL, 0.044 mmol) at −20 °C. After the
mixture was stirred at −20 °C for 1.5 h, L,D-Hep thioglycoside
acceptor 7 (0.126 g, 0.182 mmol) and TMSOTf (49 μL, 0.273 mmol)
were added, and the resulting mixture was stirred at −20 °C for 3 h.
Then reducing-end L,D-Hep acceptor 8 (82.4 mg, 0.146 mmol) and
NIS (41 mg, 0.182 mmol) were added followed by stirring at −20 °C
for additional 3 h. The reaction was quenched by addition of Et3N
(45 μL) and MS was removed by filtration over Celite. The filtrate
was diluted with DCM (8 mL) then washed with satd Na2S2O3 (10
mL) and brine (10 mL). The organic phase was dried (over MgSO4),
filtered, and concentrated for chromatography purification (elution:
hexanes/EtOAc, 4:1) to give trisaccharide 5 as a light yellow glassy
solid (0.13 g, 45%). Analytical data for 5: Rf = 0.20 (hexanes/EtOAc,
4:1); [α]D25 = +12.0 (c 0.5, CHCl3); 1H NMR (600 MHz, CDCl3) δ
8.05−8.02 (m, 4H, ArH), 7.79−7.68 (m, 8H, ArH), 7.56−7.54 (m,
2H, ArH), 7.48−7.18 (m, 35H, ArH), 7.13−7.12 (m, 5H, ArH), 5.55
(s, 1H, H-2), 5.35 (s, 1H, H-2′), 5.26 (s, 1H, H-1), 5.15 (d, J = 11.4
Hz, 1H), 5.03 (s, 1H, H-1′), 4.97 (d, J = 10.8 Hz, 2H), 4.95−4.89 (m,
2H), 4.85 (d, J = 10.8 Hz, 2H), 4.75 (d, J = 11.4 Hz, 1H), 4.67−4.65
(m, 2H, including H-1″), 4.60 (d, J = 11.4 Hz, 1H), 4.56 (d, J = 11.4
Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.45−4.40 (m, 2H), 4.37−4.32
(m, 4H), 4.21 (s, 1H), 4.09−4.05 (m, 4H), 3.99 (s, 1H), 3.92−3.90
(m, 1H), 3.86−3.83 (m, 2H), 3.81−3.80 (m, 1H), 3.76−3.74 (m,
2H), 3.67−3.66 (m, 1H), 3.61−3.58 (m, 2H), 3.49−3.46 (m, 1H),
3.39 (s, 3H, OCH3), 1.41 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C{1H}
NMR (150 MHz, CDCl3) δ 165.7 (CO), 165.5 (CO), 138.98,
138.95, 138.4, 138.20, 138.17, 138.0, 136.6, 135.9, 133.5, 133.44,
133.41, 133.3, 133.2, 133.1, 130.2, 130.1, 129.9, 128.7, 128.59, 128.55,
128.50, 128.38, 128.36, 128.30, 128.14, 128.05, 127.9, 127.82, 127.78,
127.71, 127.6, 127.5, 126.9, 126.5, 126.23, 126.18, 126.12, 126.05,
125.8, 100.0 (C-1), 97.9 (C-1″), 97.8 (C-1′), 82.4, 80.6, 78.0, 77.80,
Preparation of Building Block 7. Preparation of Tolyl 4-O-
Benzyl-2,3-O-isopropylidene-L-glycero-1-thio-α-D-heptopyranoside
15. Thioheptopyranoside 15 is a known compound prepared as a
colorless glassy solid (1.67 g, 6.8% over nine steps) from D-mannose
(10 g, 55 mmol) following the literature procedures.16
Preparation of Tolyl 4,6,7-Tri-O-benzyl-L-glycero-1-thio-α-D-
manno-heptopyranoside 16. To a solution of L,D-Hep thioglycoside
15 (2.7 g, 5.9 mmol) and BnBr (1.9 mL, 16.5 mmol) in DMF (20
mL) was added NaH (0.4 g, 16.5 mmol) at 0 °C. After the mixture
was stirred at 0 °C for 30 min, the reaction temperature was raised to
rt and the stirring was continued for additional 2 h. Then the reaction
was quenched with satd NH4Cl (10 mL). The reaction mixture was
diluted with DCM (40 mL), which was washed with H2O (30 mL)
and brine (30 mL), dried (over MgSO4), and filtered. The DCM
filtrate was concentrated to give a crude product for subsequent
reaction.
The crude benzylation product above was absorbed in 90% AcOH
(30 mL) solution and the reaction mixture was stirred at 70 °C for 4
h. After the hydrolysis of the acetal group was complete, the solvent
was reduced by a rotary evaporator. The resulting residue was
absorbed in 40 mL of EtOAc, which was washed with satd NaHCO3
(30 mL), brine (30 mL), dried (over MgSO4), and filtered. The
EtOAc filtrate was concentrated for column chromatography
purification (elution: hexanes/EtOAc, 1:1) to give L,D-Hep diol 16
(2.3 g, 77% over two steps). Analytical data for 16: Rf = 0.20
25
1
(hexanes/EtOAc, 1:1); [α]D = +182.3 (c 0.34, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.34−7.24 (m, 17H, ArH), 7.03 (d, J = 7.6 Hz,
2H, ArH), 5.57 (s, 1H, H-1), 4.82−4.76 (m, 2H), 4.48 (d, J = 11.6
Hz, 1H), 4.44 (d, J = 11.2 Hz, 1H), 4.38 (d, J = 12.0 Hz, 1H), 4.33
(d, J = 12.0 Hz, 1H), 4.16 (d, J = 9.6 Hz, 1H, H-5), 4.10 (t, J = 5.2
Hz, 1H, H-6), 3.98 (br, 1H, H-2), 3.91 (td, J = 8.0, 3.2 Hz, 1H, H-3),
3.82 (t, J = 9.0 Hz, 1H, H-4), 3.63 (dd, J = 10.0, 6.4 Hz, 1H, H-7a),
3.41 (dd, J = 10.0, 4.8 Hz, 1H, H-7b), 3.16 (m, 1H, OH), 2.53 (dd, J
= 7.24, 0.8 Hz, 1H, OH), 2.31 (s, 3H, SCH3); 13C{1H} NMR (100
MHz, CDCl3) δ 138.6, 138.29, 138.27, 137.4, 131.4, 130.3, 130.0,
128.7, 128.64, 128.56, 128.50, 128.1, 128.0, 127.81, 127.76, 87.7 (C-
1), 75.9 (C-4), 75.7 (C-6), 74.5 (CH2Ar), 73.5 (CH2Ar), 73.3
H
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75.8, 75.4, 75.1, 75.0, 74.2, 73.61, 73.56, 72.8, 72.2, 71.9, 71.5, 71.0,
69.8, 69.4, 66.4, 65.3, 55.4 (OCH3), 26.4 (CH3), 26.1 (CH3); HRMS
(ESI-TOF) (m/z) [M + Na]+ calcd for C102H102O20Na 1669.6857,
found 1669.6888.
Preparation of Tolyl 4-O-Benzyl-2,3-O-isopropylidene-1-thio-α-
L-rhamnopyranoside 18. Thio-L-rhamnopyranoside 18 is a known
compound prepared as a white amorphous solid (1.9 g, 45% over five
steps) from L-rhamnose (2.0 g, 12 mmol) following the literature
procedures.46
3), 4.13 (d, J = 5.7 Hz, 1H), 3.99 (m, 1H, H-6), 3.80 (dd, J = 10.8, 6.6
Hz, 1H), 3.75−3.66 (m, 2H), 3.62 (d, J = 10.1 Hz, 1H), 3.37 (s, 3H,
OCH3), 2.29 (d, J = 8.9 Hz, 1H, H-7a), 2.19−2.08 (m, 1H, H-7b),
1.53 (s, 3H, CH3), 1.37 (s, 3H, CH3); 13C{1H} NMR (100 MHz,
CDCl3) δ 138.0, 128.4, 128.1, 127.8, 109.5, 98.5 (C-1), 78.6, 75.4,
75.2, 73.1, 69.4, 68.9, 64.8, 55.2, 28.0 (CH3), 26.3 (CH3).
Preparation of Methyl 4,6,7-Tri-O-benzyl-L-glycero-α-D-
manno-heptopyranoside 22a.
Preparation of Building Block 19 via Intermediates 21 and
22. Preparation of Methyl 4-O-Benzyl-6-deoxy-2,3-O-isopropyli-
dene-α-D-manno-hept-1,7-dialdopyranoside 21. To a solution of
methyl α-mannoside 2047 (6.9 g, 21.27 mmol) in DMSO (106 mL)
was added IBx (11.92 g, 42.54 mmol). The reaction mixture was
stirred at 50 °C for 3 h. Then the reaction mixture was cooled to rt
followed by addition of brine (60 mL). The resulting mixture was
filtered, and the filtrate was diluted with DCM (120 mL) and then
washed with brine (2 × 50 mL), dried (over MgSO4), and filtered.
The DCM filtrate was concentrated to give the crude 1,7-dialdo
substrate 21 for the Wittig olefination.16
To a mixture of L,D-Hep diol 22 (3.0 g, 8.6 mmol) and BnBr (2.9 mL,
24.1 mmol) in DMF (28 mL) was added NaH (0.58 g, 24.1 mmol) at
0 °C. After the mixture was stirred at 0 °C for 30 min, the reaction
temperature was raised to rt and the stirring was continued for 2 h.
The reaction was quenched with satd NH4Cl (10 mL) and then
diluted with DCM (40 mL). The DCM solution was washed with
H2O (30 mL) and brine (30 mL), dried (over MgSO4), and filtered.
The DCM solution was concentrated to give the crude benzylation
product; which was directly subjected to acetal deprotection by acetic
acid (AcOH).
The foregoing crude benzylation product was absorbed in 30 mL of
90% AcOH and the mixture was stirred at 50 °C for 4 h. After the
cleavage of the isopropylidene acetal group was complete, the solvent
was removed by a rotary evaporator to give a light-yellow syrup. The
syrup was absorbed in 40 mL of EtOAc, which was washed with satd
NaHCO3 (30 mL), brine (30 mL), dried (over MgSO4), and filtered.
The EtOAc filtrate was subsequently concentrated for column
chromatography purification (elution: hexanes/EtOAc, 1:1) to give
L,D-Hep 2,3-diol 22a as a colorless glassy substance (3.1 g, 75% over 2
steps). NMR spectroscopic data for 22a: Rf = 0.15 (hexanes/EtOAc,
1:1); 1H NMR (400 MHz, CDCl3) δ 7.41−7.22 (m, 15H, ArH), 4.80
(d, J = 12.0 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.72 (s, 1H, H-1),
4.54 (m, 2H), 4.51 (d, J = 11.6 Hz, 1H), 4.43 (d, J = 11.4 Hz, 1H),
4.10 (t, J = 6.0 Hz, 1H), 3.92 (m, 1H), 3.86−3.79 (m, 2H), 3.79−
3.72 (m, 3H), 3.28 (s, 3H, OCH3), 2.59 (m, 1H, OH), 2.42 (d, J =
7.3 Hz, 1H, OH); 13C{1H} NMR (100 MHz, CDCl3) δ 138.6, 138.2,
137.9, 128.5, 128.4, 128.2, 127.8, 127.7, 100.6 (C-1), 75.7, 75.1, 74.1,
73.5, 73.0, 72.3, 71.0, 70.3, 70.1, 55.0 (OCH3). Noted 22a was
employed for preparation of building block 19. Its optical rotation and
HRMS data were not acquired.
To a solution of CH3OCH2PPh3Cl salt (21.8 g, 63.6 mmol) in
THF (60 mL) was added NaHMDS (2 M in THF, 30 mL, 59.4
mmol) at 0 °C. After the mixture was stirred for 1 h, the 1,7-dialdo
substrate 21 in 46 mL of THF was transferred to the mixture. The
resulting mixture was stirred at 0 °C overnight, and the reaction
mixture was diluted with EtOAc (100 mL). The EtOAc solution was
washed with H2O (80 mL), brine (100 mL), dried (over MgSO4),
and filtered. The EtOAc filtrate was concentrated for column
chromatography purification (elution: hexanes/EtOAc, 6:1) to give
a cis/trans mixture of enol ether isomers (5.37 g, 72% over two steps)
(Rf = 0.43 and 0.49 for cis- and trans-isomers, hexanes/EtOAc, 4:1).
To a mixture of the foregoing enol ether isomers (5.37 g, 15.3
mmol) in acetone (150 mL) was added 2 N HCl(aq) (3.8 mL). The
mixture was stirred vigorously at rt for 30 min, and a solution of satd
Na2CO3 (15 mL) was added to quench the reaction. The mixture was
diluted with EtOAc (100 mL) and then washed with H2O (60 mL)
and brine (80 mL), dried (over MgSO4), and filtered. The EtOAc
filtrate was concentrated for column chromatography purification
(elution: hexanes/EtOAc, 4:1) to give the known L,D-Hep 1,7-dialdo
substrate 21 (4.8 g, 67% from 20 over three steps).16 Spectroscopic
1
data for 21: Rf = 0.39 (hexanes/EtOAc, 4:1); H NMR (400 MHz,
CDCl3) δ 9.76 (s, 1H, CHO), 7.35−7.30 (m, 5H, ArH), 4.90 (d, J =
11.6 Hz, 1H), 4.85 (s, 1H, H-1), 4.58 (d, J = 11.5 Hz, 1H), 4.30 (t, J
= 6.3 Hz, 1H), 4.15 (d, J = 5.4 Hz, 1H), 3.40 (s, 3H, OCH3), 3.35−
3.26 (m, 2H), 2.85 (dd, J = 16.6, 2.0 Hz, 1H, H-6a), 2.55 (ddd, J =
16.4, 8.6, 2.8 Hz, 1H, H-6b), 1.52 (s, 3H, CH3), 1.38 (s, 3H, CH3);
13C{1H} NMR (100 MHz, CDCl3) δ 200.1 (CHO), 137.8, 128.4,
Preparation of Methyl 2-O-Benzoyl-4,6,7-tri-O-benzyl-L-glycero-
α-D-manno-heptopyranoside 19. To a solution of the L,D-Hep 2,3-
diol 22a (3.1 g, 6.4 mmol) in CH3CN (31 mL) were added CSA (148
mg, 0.64 mmol) and PhC(OMe)3 (1.6 mL, 9.6 mmol). The reaction
mixture was stirred at rt for 1 h. After completion of the ortho-ester
formation, the reaction was quenched with Et3N then CH3CN was
removed by a rotary evaporator. The crude ortho-ester was absorbed
in EtOAc (20 mL), which was treated with 1 N HCl(aq) (5.0 mL).
The resulting mixture was stirred vigorously for 10 min. After
completion of the benzoyl ester formation, the mixture was diluted
with EtOAc (20 mL), which was washed with satd NaHCO3 (20 mL)
and brine (20 mL), dried (over MgSO4), and filtered. The EtOAc
filtrate was subsequently concentrated for column chromatography
purification (elution: hexanes/EtOAc, 6:1) to give reducing-end L,D-
Hep acceptor 19 (2.9 g, 76%). Analytical data for 19: Rf = 0.18
128.1, 127.8, 109.4, 98.2 (C-1), 78.5, 78.3, 75.8, 72.6, 63.5, 55.4, 45.9,
28.0 (CH3), 26.2 (CH3).
Preparation of Methyl 4-O-Benzyl-2,3-O-isopropylidene-L-glyc-
ero-α-D-heptopyranoside 22. To a solution of the foregoing L,D-Hep
1,7-dialdo substrate 21 (3.6 g, 10.7 mmol) in CH3CN (210 mL) were
added L-Pro (0.62 g, 5.35 mmol) and PhNO (3.44 g, 32.1 mmol) at
−20 °C. The reaction mixture was stirred at −20 °C for 2 d. Then
NaBH4 (1.21 g, 32.1 mmol) in ethanol (10 mL) was added, and the
resulting mixture was stirred at 0 °C for 1 h. The reaction was then
quenched with satd NH4Cl (5 mL). The mixture was diluted with
EtOAc (50 mL) and washed with H2O (40 mL) and brine (40 mL),
dried (over MgSO4), and filtered. The EtOAc filtrate was
concentrated with a rotary evaporator to give the crude 6-
(anilinyl)oxy-L,D-Hep intermediate.
To a solution of the crude 6-(anilinyl)oxy-L,D-Hep intermediate in
DCM (35 mL) was added PhNO (2.3 g, 21.4 mmol). The reaction
was stirred at rt for 1 d. Then the reaction mixture was concentrated
for column chromatography purification (elution: hexanes/EtOAc,
3:1) to give the known L,D-Hep diol 22 as a light-yellow oily substance
(1.52 g, 40% from 21 over three steps).16 NMR spectroscopic data for
22: Rf = 0.16 (hexanes/EtOAc, 1:1); 1H NMR (400 MHz, CDCl3) δ
7.38−7.28 (m, 5H, ArH), 4.93 (s, 1H, H-1), 4.92 (d, J = 11.5 Hz, 1H,
CH2Ar), 4.65 (d, J = 11.5 Hz, 1H, CH2Ar), 4.32 (t, J = 6.3 Hz, 1H, H-
25
1
(hexanes/EtOAc, 4:1); [α]D = −8.0 (c 0.013, CHCl3); H NMR
(400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 2H, ArH), 7.56 (t, J = 7.4
Hz, 1H, ArH), 7.42−7.24 (m, 17H, ArH), 5.33 (dd, J = 2.8, 1.6 Hz,
1H, H-2), 4.93 (d, J = 11.7 Hz, 1H), 4.85 (s, 1H, H-1), 4.80 (d, J =
11.3 Hz, 1H), 4.57 (m, 2H), 4.55 (d, J = 12.0 Hz), 4.48 (d, J = 11.6
Hz, 1H), 4.31−4.24 (m, 1H, H-3), 4.19 (t, J = 6.2 Hz, 1H), 4.08 (t, J
= 9.5 Hz, 1H), 3.91 (dd, J = 9.5, 6.3 Hz, 1H), 3.86 (d, J = 9.7 Hz,
1H), 3.81 (dd, J = 9.5, 6.3 Hz, 1H), 3.31 (s, 3H, OCH3), 2.16−2.18
(m, 1H, OH); 13C{1H} NMR (100 MHz, CDCl3) δ 166.2 (CO),
138.7, 138.4, 138.0, 133.2, 129.9, 129.6, 128.4, 127.7, 127.61, 127.58,
127.51, 98.4 (C-1), 75.6, 75.2, 74.5 (C-4), 73.5, 72.8, 71.0, 70.8, 70.1,
I
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54.9 (OCH3); HRMS (ESI-TOF) (m/z) [M + Na]+ calcd for
C36H38O8Na 621.2459, found 621.2453.
mL) was added 10% Pd/C (75 mg). The resulting suspension was
stirred at rt under H2 atmosphere for 18 h. Then the Pd catalyst was
removed by filtration (over a Celite pad), and the filtrate was
concentrated for purification, which was carried out byy FPLC
(elution: 1:1 MeOH/NH4HCO3(aq), flow rate 0.5 mL/min) to give
17 (57 mg, 90%). Analytical data for 17: Rf = 0.40 (NH3(aq)/IPA,
1:1); [α]D25 = +6.15 (c 0.005, H2O); 1H NMR (600 MHz, CDCl3) δ
5.13 (s, 1H, H′-1), 4.87 (s, 1H, H‴-1), 4.76 (s, 1H, H″-1), 4.62 (s,
1H, H-1), 4.13 (t, J = 1.8 Hz, 1H, H′-2), 3.94−3.91 (broad m, 5H,
including H3′ and H2), 3.85 (broad m, 2H, including H″-2), 3.84
(broad m, 1H), 3.82 (s, 1H, H‴-2), 3.75−3.67 (m, 4H) 3.64−3.57
(m, 4H), 3.53 (dd, J = 11.2, 5.8 Hz, 1H), 3.47 (d, J = 10.0 Hz, 1H),
3.35 (dt, J = 16.2, 9.7 Hz, 1H), 3.26 (s, 3H, OCH3), 1.19 (d, J = 6.3
Hz, 3H, Rha-H6), 1.16 (d, J = 6.2 Hz, 3H, Rha-H6); 13C{1H} NMR
(150 MHz, CDCl3) δ 100.8 (C-1), 99.2 (C′-1), 98.3 (C″-1), 96.8
(C‴-1), 78.9, 74.0, 72.1, 72.0, 71.9. 71.4, 71.1, 70.6, 70.3, 69.9, 69.7,
69.0, 68.8, 68.61, 68.59, 65.3, 64.4, 62.8, 62.6, 54.7, 17.0 (Rha-C6),
16.5 (Rha-C6); HRMS (ESI-TOF) (m/z) [M + H]+ calcd for
C27H49O21 709.2761, found 709.2763.
One-Pot Synthesis of Methyl 4-O-Acetyl-2,3-O-isopropylidene-α-
L-rhamnopyranosyl-(1,2)-[4-O-acetyl-2,3-O-isopropylidene-α-L-
rhamno-pyranosyl-(1,3)]-4,6,7-tri-O-benzyl-L-glycero-α-D-manno-
heptopyranosyl-(1,3)-2-O-benzoyl-4,6,7-tri-O-benzyl-L-glycero-α-D-
manno-heptopyranoside 23. To a solution of thiorhamnoside 18
(273 mg, 0.776 mmol) and dibutyl phosphate (161 μL, 0.812 mmol)
in dried DCM (7.0 mL) with activated 4 Å molecular sieves (0.7 g)
were added NIS (182 mg, 0.812 mmol) and TMSOTf (9.0 μL, 0.053
mmol) at −20 °C. After the mixture was stirred for 1.5 h, L,D-Hep
thioglycoside acceptor 16 (207 mg, 0.353 mmol) and TMSOTf (95
μL, 0.53 mmol) were added at −20 °C. The mixture was stirred at
−20 °C for 1.5 h, and then reducing-end L,D-Hep acceptor 9 (170 mg,
0.283 mmol), NIS (71 mg, 0.318 mmol) and TMSOTf (51 μL, 0.283
mmol) were added. After reaction at −20 °C for additional 2 h, the
reaction was quenched by Et3N (0.15 mL). The MS was removed by
filtration and the filtrate was diluted with DCM (12 mL) then washed
with satd Na2S2O3 (15 mL × 2) and brine (15 mL). The organic
phase was separated, dried (over MgSO4), filtered, and concentrated
for column chromatography purification (elution: hexanes/DCM/
EtOAc, 6:1:1) to give tetrasaccharide 23 (185 mg, 42%) as a white
amorphous substance. Analytical data for 23: Rf = 0.23 (hexanes/
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01828.
■
sı
25
1
DCM/EtOAc, 6:1:1); [α]D = −25.5 (c 0.022, CHCl3); H NMR
(600 MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H, ArH), 7.52 (t, J = 7.4
Hz, 1H, ArH), 7.41−7.36 (m, 26H, ArH), 7.19 (d, J = 7.1 Hz, 2H,
ArH), 5.37 (s, 1H, H-2), 5.23 (s, 1H, H′-1), 5.03 (s, 1H, H‴-1), 4.96
(d, J = 12.0 Hz, 1H), 4.90 (d, J = 11.6 Hz, 1H), 4.81 (dd, J = 9.8, 8.5
Hz, 1H, H″-4), 4.75 (s, 1H, H″-1), 4.73 (s, 1H, H-1), 4.69−4.63 (m,
4H), 4.56 (s, 3H), 4.51−4.43 (m, 2H), 4.44 (br, 1H), 4.39 (d, J =
11.5 Hz, 1H), 4.33 (dd, J = 9.5, 2.6 Hz, 1H, H-3), 4.25−4.20 (m,
1H), 4.20−4.16 (m, 1H, H″-3), 4.16−4.09 (m, 4H), 4.07 (d, J = 5.2
Hz, 1H), 4.04 (d, J = 9.5 Hz, 1H), 4.02−3.95 (m, 3H), 3.92 (d, J =
9.0 Hz, 1H), 3.91 (dd, J = 6.0, 3.6 Hz, 1H), 3.86 (s, 1H), 3.85 (s,
1H), 3.80 (dd, J = 9.7, 6.2 Hz, 2H), 3.60 (dt, J = 11.8, 5.9 Hz, 1H,
H‴-5), 3.25 (s, 3H, OCH3), 2.08 (s, 3H, COCH3), 1.93 (s, 3H, C
= OCH3), 1.53 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.27 (s, 3H, CH3),
1.24 (s, 3H, CH3), 1.07 (d, J = 6.2 Hz, 3H, H‴-6), 0.60 (d, J = 4.8 Hz,
3H, H″-6); 13C{1H} NMR (150 MHz, CDCl3) δ 170.2 (CO),
170.1 (CO), 139.2, 138.7, 138.6, 138.4, 138.1, 137.8, 133.3, 133.0,
129.8, 128.8, 128.59, 128.58, 128.56, 128.46, 128.3, 128.2, 128.0,
127.89, 127.87, 127.77, 127.70, 127.6, 127.5, 127.4, 127.24, 127.19,
1H, 13C, COSY-, and HSQC-NMR spectra and HRMS
data of the compounds synthesized in the present study
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Kwok-Kong Tony Mong − Applied Chemistry Department,
National Chiao Tung University, Hsinchu City, Taiwan
30010, ROC; orcid.org/0000-0002-5787-1072;
Email: tmong@mail.nctu.edu.tw
Authors
Kuang-Chun Cheng − Applied Chemistry Department,
National Chiao Tung University, Hsinchu City, Taiwan
30010, ROC
127.1, 109.88, 109.86, 99.0 (C′-1, 1JCH = 167.0 Hz), 98.5 (C-1, 1JCH
=
I-Chen Lu − Applied Chemistry Department, National Chiao
Tung University, Hsinchu City, Taiwan 30010, ROC
Chia-Wei Pan − Applied Chemistry Department, National
Chiao Tung University, Hsinchu City, Taiwan 30010, ROC
Yi-Fang Wang − Applied Chemistry Department, National
Chiao Tung University, Hsinchu City, Taiwan 30010, ROC
Li-Ching Shen − Applied Chemistry Department, National
Chiao Tung University, Hsinchu City, Taiwan 30010, ROC
1
1
168.3 Hz), 94.8 (C″-1, JCH = 171.1 Hz), 91.9 (C‴-1, JCH = 168.9
Hz), 76.04, 76.02, 75.8, 75.6, 75.1, 74.9, 74.7, 74.5, 74.2, 73.7, 73.5,
73.4, 72.8, 72.6, 71.8, 71.77, 71.74, 71.66, 70.0, 64.5 (C‴-5), 63.7
(C″-5), 55.0, 27.9, 27.8, 26.6, 21.2, 21.1, 17.4, 16.4. HRMS (ESI-
TOF) (m/z) [M + Na]+ calcd for C86H100O24Na 1539.6359, found
1539.6357.
Inner Core Structure from LPS of Ralstonia solanacearum
Toudk-2 (17). To a solution of 23 (185 mg, 0.12 mmol) in CH3CN
(1.2 mL) was added zinc nitrate hexahydrate [Zn(NO3)2·6H2O] (68
mg, 0.36 mmol). The reaction mixture was stirred at 40 °C for 16 h
and was then quenched with satd NH4Cl (3 mL). The mixture was
diluted with EtOAc (15 mL), which was washed with H2O (8 mL ×
2) and brine (12 mL). The organic layer was dried over MgSO4 and
concentrated for column chromatography purification (elution:
hexanes/EtOAc, 3:1) to give a deisopropylidene intermediate (149
mg, 87%) with Rf = 0.33 (hexanes/EtOAc, 3:1). To a solution of
deisopropylidene tetrasaccharide in THF (1.5 mL) and methanol (0.5
mL) was added K2CO3 (35 mg, 0.6 mmol). The reaction mixture was
stirred at 50 °C for 2 h. After the deprotection was complete, the
mixture was neutralized with 1 N HCl (3 mL), then diluted with
DCM (15 mL) and washed with H2O (8 mL) and brine (12 mL).
The DCM organic phasewas dried over MgSO4, filtered, and
concentrated for column chromatography purification (elution:
DCM/MeOH, 8:1) to give a debenzoyl tetrasaccharide intermediate
(110 mg, 85%) with Rf = 0.25 (DCM/MeOH, 8:1).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01828
Author Contributions
‡K.-C.C. and I-C.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are in debted to the Ministry of Science and Technology of
Taiwan (MOST) for financial support (Grant No. MOST 108-
2113 M-009-021). We thank the Center for Advanced
Instrumentation and Department of Applied Chemistry at
NCTU for mass spectrometry analysis and Dr. Helen
McPherson from Edanz Group (https://en-author-services.
edanzgroup.com/ac) for editing a draft of this manuscript.
To a solution of the debenzoyl tetrasaccharide (110 mg, 0.09
mmol) in MeOH (4.0 mL) and a trace amount of acetic acid (0.2
J
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