Organoboron-Promoted Regioselective Glycosylations in the Synthesis of a Saponin-Derived Pentasaccharide from Spergularia ramosa

Article abstract of DOI:10.1021/acs.joc.5b00950

Organoboron-mediated regioselective glycosylations were employed as key steps in the total synthesis of a branched pentasaccharide from a saponin natural product. The ability to use organoboron activation to differentiate OH groups in an unprotected glycosyl acceptor, followed by substrate-controlled reactions of the obtained disaccharide, enabled a streamlining of the synthesis relative to a protective group-based approach. This study revealed a matching/mismatching effect of the relative configuration of donor and acceptor on the efficiency of a regioselective glycosylation reaction, a problem that was solved through the development of a novel boronic acid-amine copromoter system for glycosyl acceptor activation.

Full text of DOI:10.1021/acs.joc.5b00950

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pubs.acs.org/joc
Organoboron-Promoted Regioselective Glycosylations in the
Synthesis of a Saponin-Derived Pentasaccharide from Spergularia
ramosa
Ross S. Mancini, Corey A. McClary, Stefi Anthonipillai, and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: Organoboron-mediated regioselective glycosy-
lations were employed as key steps in the total synthesis of a
branched pentasaccharide from a saponin natural product. The
ability to use organoboron activation to differentiate OH
groups in an unprotected glycosyl acceptor, followed by
substrate-controlled reactions of the obtained disaccharide,
enabled a streamlining of the synthesis relative to a protective
group-based approach. This study revealed a matching/
mismatching effect of the relative configuration of donor and
acceptor on the efficiency of a regioselective glycosylation
reaction, a problem that was solved through the development
of a novel boronic acid−amine copromoter system for glycosyl acceptor activation.
Herein, we describe the synthesis of a branched pentasac-
charide derived from a saponin-type natural product, employing
organoboron-mediated regioselective glycosylations as key steps.
This contribution details a new protocol for boronic acid/Lewis
base-promoted activation of glycosyl acceptors and demonstrates
how differentiation of hydroxyl (OH) groups by selective
glycosylation can minimize protection/deprotection steps in the
synthesis of branched oligosaccharides.
INTRODUCTION
■
Despite advances in methodology and technology for glycosidic
bond construction, including one-pot reactivity-based assembly,1
substrate-controlled, regioselective glycosylations,2 and auto-
mated synthesis,3 the laboratory synthesis of oligosaccharide
natural products remains a time-consuming, laborious, and
material-intensive task. A primary source of inefficiency in
oligosaccharide synthesis is the use of protective groups to enable
regiocontrolled glycosylations. The preparation of selectively
protected building blocks often occupies a significant fraction of
the total research time involved, and protection/deprotection
steps almost invariably outnumber glycosylations.4,5 Recently
disclosed chemoenzymatic syntheses of the blood group B
antigen,6 heparins,7 and asymmetrically branched N-glycans8
illustrate the dramatic increases in efficiency that are possible by
minimizing protective group manipulations in oligosaccharide
synthesis.9
RESULTS AND DISCUSSION
■
Retrosynthetic Analysis. Triterpenoid saponins 1a−d
(Figure 1) are amphiphilic glycosides isolated from the South
American herbaceous plant Spergularia ramosa.16 Saponin
natural products exert a wide range of biological effects, including
stimulation of the immune response and augmentation of
targeted immunotoxins. Although biological activities of 1a−d
have not been reported, the plant from which they are derived
has been employed in indigenous medicine as an antitubercular
agent. The pentasaccharide substituent R1 common to 1a−d is
composed of β-D-glucopyranosyl, β-D-xylopyranosyl, α-L-rham-
nopyranosyl-, β-D-fucopyranosyl, and α-L-arabinopyranosyl
moieties. We anticipated that the two 1,2-trans-configured
glycosidic linkages at the equatorial positions of pyranoside-
derived cis-vicinal diol groups (that is, the β-(1→3)-D-Fuc-L-Ara
and β-(1→3)-D-Glc-L-Rha linkages) could be constructed from
unprotected pyranosides as glycosyl acceptors using borinic acid-
catalyzed protocols developed in our laboratories.12a The
prospect of using such selective glycosylations as key steps in
Although reagent-10,11 and catalyst-controlled glycosylations12
arguably represent a complementary set of tools for streamlining
the synthesis of oligosaccharides,13 applications in the prepara-
tion of complex targets of this type have been slow to emerge. A
pioneering example was reported by O’Doherty and co-workers,
who employed Pd-catalyzed, regioselective glycosylation of a
stannylene acetal as a key step in the synthesis of the cleistrioside
and cleistetroside natural products.14 Recently, the O’Doherty
group has developed a dual catalytic method that merges Pd-
mediated glycosyl donor activation with the organoboron-
mediated glycosyl acceptor activation strategy developed in our
laboratory;12a when combined with borinic acid-catalyzed
regioselective acylations, this method enabled elegant syntheses
of all members of the mezzettiaside family of natural products.15
Received: April 28, 2015
© XXXX American Chemical Society
A
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require an orthogonal protective group: the n-pentenyl group
was chosen for this purpose, as it allows for either hydrolysis to
the free hemiacetal17 (which, in turn, is a useful precursor to
several classes of glycosyl donors) or direct application as a
glycosyl donor by activation with an electrophilic iodinating
reagent.18
Direct precedent for the approach shown in Scheme 1 (and the
only reported synthesis of the pentasaccharide moiety common
to 1a−d) is the work of Gu and Du, who prepared a peracylated
allyl β-glycoside analogue of pentasaccharide 2.19 This previous
synthesis made use of a similar convergent approach to that
described above, coupling a disaccharide-derived acceptor to a
trisaccharide-derived donor, but employed a more conventional,
protective-group-based approach to OH group differentiation.
The reported synthesis provides a benchmark for evaluating the
utility of regioselective glycosylations in the current approach.
Preparation of Trisaccharide 3a. Our initial efforts were
focused on the preparation of trisaccharide 3a (Scheme 2). The
a
Scheme 2. Synthesis of Trisaccharide 3a
Figure 1. Triterpenoid saponins 1a−d from Spergularia ramosa.
the preparation of 4-methoxyphenyl (PMP) α-glycoside 2 led to
the retrosynthetic analysis depicted in Scheme 1.
A regioselective fragment coupling was envisioned wherein a
trisaccharide-derived donor (3) would react selectively with the
2-OH group of partially protected β-(1→3)-D-Fuc-L-Ara
disaccharide acceptor 4a. The latter could be accessed directly
by regioselective glycosylation of 4-methoxyphenyl arabinopyr-
anoside. We anticipated that the requisite trisaccharide donor
could be generated from the product of a regioselective
glycosylation through protection and glycosylation of the
rhamnosyl 2-OH and 4-OH groups, respectively. The relative
reactivities of these two OH groups would determine the order in
which these two operations would be executed. The use of
regioselective glycosylations as initial OH group differentiation
steps suggested the possibility of a simple protective group
strategy, employing ester groups for all nonanomeric OH
moieties, and thus enabling the use of a final, global deprotection.
Only the anomeric position of the rhamnosyl group would
a
Reagents and conditions: (a) catalyst (5a or 5b, 10 mol %), Ag2O,
CH3CN, T °C (catalyst 5a, 23 °C: 59%; catalyst 5b, − 45 °C: 81%);
(b) BzCl, pyridine, 0 °C; (c) 8a or 8b, TMSOTf (10 mol %), CH2Cl2,
0 °C (9: 75%; 3a: 98%).
a
Scheme 1. Retrosynthetic Analysis of Pentasaccharide 2
a
X denotes a halogen (Br or Cl); LG denotes a leaving group; PMP = 4-methoxyphenyl.
B
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coupling of pentenyl α-rhamnopyranoside (prepared over two
steps in 50% yield from commercially available 1,2,3,4-tetra-O-
acetyl-α/β-L-rhamnopyranose)20 with peracetylated glucopyr-
anosyl bromide was accomplished in a modest 59% yield using
our previously reported protocol, with borinic ester 5a as
precatalyst.12a Control experiments revealed that an uncatalyzed
background reaction was responsible for the formation of
regioisomeric byproducts. This problem could be overcome by
carrying out the reaction at reduced temperature (−45 °C) in the
presence of oxaboraanthracene-derived borinic acid catalyst 5b.
Under these conditions, disaccharide 6 was obtained in 81%
yield. We have previously shown that incorporating the borinic
acid group into a 6π electron system, as in 5b, results in improved
catalytic activity for several substrate combinations.21 Reaction
kinetics and computational studies suggested that this effect
results from the higher nucleophilic reactivity of borinates
derived from 5b relative to those derived from diphenylborinic
acid. The present work demonstrates that the ability to conduct
glycosylations at lower temperature and thus to suppress poorly
selective background reactions is an additional advantage of 5b.
Based on transformations of 3-O-benzyl-α-rhamnopyrano-
sides described by Yang and co-workers,22 we attempted
selective benzoylation of the 2-OH group of disaccharide 6.
This was achieved in good yield using benzoyl chloride in
pyridine at 0 °C,23 conditions distinct from those developed for
the 3-O-Bn-protected substrate in the study mentioned above
(BzCl, Ag2O, KI, CH2Cl2, 23 °C). Presumably, acylation of the 4-
OH group is hindered by the presence of two relatively bulky,
equatorially oriented vicinal substituents.24 At this stage,
formation of a β-xylopyranosyl linkage to the free 4-OH group
of 7 was required. Coupling with acetylated xylosyl trichlor-
oacetimidate 8a in the presence of trimethylsilyl trifluorometha-
nesulfonate (TMSOTf) resulted in orthoester 9 as the major
product. Attempts to generate the corresponding trisaccharide
by varying the identity or the stoichiometry of the Lewis acid
promoter, or by effecting a Lewis acid-promoted rearrangement
of 9, were unsuccessful.25 However, the desired trisaccharide was
obtained in good yield using xylosyl donor 8b, bearing sterically
hindered pivaloyl protective groups (prepared in four steps from
D-xylose), in place of per-acetylated 8a.26
Preparation of Disaccharide Acceptor 4a. The other
fragment required for this convergent approach, β-(1→3)-Fuc-
Ara derivative 4a, was targeted by application of a second
catalyst-controlled glycosylation of a pyranoside-derived triol.
However, the reaction of PMP α-L-arabinopyranoside with per-
acetylated D-fucosyl bromide using catalyst 5a generated 4a in
only 17% yield (Scheme 3). A significant amount of the β-(1 →
4)-linked regioisomer was formed under these conditions: a ratio
of 1:1.3 in favor of the undesired 4-O-glycosylated regioisomer
was determined by HPLC analysis of the unpurified reaction
mixture. An experiment using the L-configured fucopyranosyl
bromide donor in place of the D-enantiomer under otherwise
identical conditions generated the diastereomeric disaccharide
(4b) in appreciably higher regioselectivity (4.4:1 3-O-glyco-
sylation to 4-O-glycosylation by HPLC analysis, 49% isolated
yield after purification). These observations suggest that a
mismatch between the configurations of the glycosyl donor and
the acceptor may contribute to the poor regioselectivity observed
in the synthesis of 4a. Acceptor/donor complementarity in
glycosylation reactions has been discussed in detail:27 whereas
effects of donor/acceptor relative configuration on stereo-
selectivity have been reported,28 the majority of investigations
related to regiocontrol have concerned variation of the type of
Scheme 3. Matching/Mismatching Effects on Regioselective
Glycosylation
a
a
Reagents and conditions: 5a (10 mol %), Ag2O, CH3CN, 23 °C.
glycosyl donor or activation method used.29 As definitive
illustrations of the effects of donor/acceptor relative config-
uration on regiocontrol are rare,30 further studies exploring the
generality of this observation may be warranted. In the present
case, we speculate that the lack of a bulky substituent at C-5 of the
glycosyl acceptor, along with the use of a 6-deoxypyranosyl
donor that is not fully disarmed,31 may also contribute to the low
selectivity. However, using the glycosyl chloride in the presence
of the bromide was not fruitful, and employing catalyst 5b in
place of 5a resulted in only a modest improvement in yield (31%
versus 17%).
In light of our inability to access 4a in a synthetically useful
yield by catalyst-controlled glycosylation, we considered an
organoboron-mediated protocol involving Lewis base activation
of a boronic ester. Processes of this type were developed in the
laboratory of Aoyama for regioselective transformations of
carbohydrate derivatives:11,32 in particular, tetracoordinate
boronates (e.g., 10, Scheme 4) were found to behave as activated
acceptors in couplings with glycosyl bromides. With the aim of
developing an operationally simple protocol employing
commercially available reagents, we elected to explore conditions
akin to those employed by Aoyama for carbohydrate alkylation,32
Scheme 4. Glycosylation of a Tetracoordinate Boronate by
a
Aoyama and Co-workers
a
Reagents and conditions: 4 Å MS, THF, reflux; then Et4N+I−, 23 °C;
then Ag2CO3, 0 → 23 → 50 °C.
C
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using a combination of boronic acid and Lewis base reagents. We
have shown that such combinations, with both components used
in catalytic amounts, also promote selective silylations of
pyranoside derivatives, suggesting that the general approach is
suitable for several classes of electrophiles.33 An advantage is the
ability to rapidly evaluate combinations of components, enabling
“tailoring” of the system for a particular set of coupling partners.
Indeed, we found that the yield of 4a was dependent, and not in a
straightforward way, on the identity of the boronic acid and
Lewis base employed (Table 1). The optimal conditions
Scheme 5. Attempts at Glycosidation and Hydrolysis of
Pentenyl Glycoside 3a
a
Table 1. Evaluation of Boronic Acid/Lewis Base
Combinations for the Regioselective Synthesis of 4a
a
a
Reagents and conditions: (a) 4a, NIS, TMSOTf (30 mol %), CH2Cl2,
23 °C; (b) NBS, 1% H2O in CH3CN, <30%; (c) NIS, TMSOTf (30
mol %), 0.1% H2O in CH2Cl2, 72%.
of hemiacetal 3b, along with the alkene-derived vicinal dibromide
and bromohydrin products 3c and 3d. This problem was
overcome by carrying out the hydrolysis in the presence of NIS
and TMSOTf, promoters that are typically used for glycosidation
reactions of this class of compounds.35 Under these conditions,
the anomeric hemiacetal was obtained in 72% yield, with the
iodohydrin 3e being the only detectable byproduct (22% yield).
Subjecting the simpler substrate pentenyl 2,3,4-tri-O-benzoyl-α-
L-rhamnopyranoside to these two sets of reaction conditions
gave rise to analogous observations: NBS in aqueous acetonitrile
generated the free hemiacetal in only 20% yield, along with
vicinal dibromide and bromohydrin byproducts (15% and 26%
yield, respectively), whereas NIS/TMSOTf in dichloromethane/
water resulted in a 70% yield of hemiacetal, along with 15% of the
iodohydrin byproduct.
b
boronic acid
Lewis base
yield (%)
3,5-(CF3)2-C6H3B(OH)2
PhB(OH)2
Et3N
Et3N
Et3N
Et3N
Et3N
22
43
49
63
68
<5
33
<5
9-anthraceneboronic acid
4-(OMe)-C6H4B(OH)2
C6F5B(OH)2
C6F5B(OH)2
Me3NO
C6F5B(OH)2
iPr2NH
C6F5B(OH)2
quinuclidine
N-methylmorpholine
c
C6F5B(OH)2
74
a
Reagents and conditions: arabinopyranoside, RB(OH)2 (1.0 equiv), 4
Å MS, CH2Cl2, 23 °C; then Ag2O (1.0 equiv), Lewis base (6 equiv)
and glycosyl bromide (1.1 equiv), 0 → 23 °C. Yields of 4a after
purification by silica gel chromatography. Portionwise addition of
b
c
The final glycosylation was achieved by conversion of 3b to the
corresponding α-configured trichloroacetimidate, followed by
coupling with 4a in the presence of TMSOTf (Scheme 6). The
selective 2-O-glycosylation of 4a is presumably the result of steric
effects. The primary side product−an octasaccharide generated
through bis-glycosylation of 4a, could be minimized by using 1.5
equiv of the acceptor. Under these conditions, protected
pentasaccharide 11 was generated in 85% yield. Global
deprotection was accomplished by saponification with potassium
hydroxide in methanol, generating PMP glycoside 2 in 74% yield
after purification by size exclusion chromatography. With the
exception of expected differences in the chemical shifts of
resonances corresponding to the arabinopyranoside moiety, the
proton nuclear magnetic resonance spectrum of 2 in CD3OD was
in excellent agreement with the data reported for the
pentasaccharide segment of 1a (Supporting Information, Table
S1).16
glycosyl donor over 8 h.
involved activation of the acceptor-derived pentafluorophenyl-
boronate with N-methylmorpholine (NMM), generating 4a in
74% yield. A one-pot protocol was employed in which the
boronic acid and arabinopyranoside were stirred at 23 °C in the
presence of molecular sieves (MS) prior to addition of the
glycosyl donor, Lewis base, and Ag2O.
Fragment Coupling and Synthesis of 2. Having achieved the
synthesis of the di- and trisaccharide building blocks, we turned
our attention to the fragment coupling reaction. Attempts to
employ the pentenyl glycoside 3a directly in a regioselective
coupling with 4a were not successful: activation of the pentenyl
group with N-iodosuccinimide (NIS) and TMSOTf led to a
complex mixture of products, whereas milder conditions (I2, 1,2-
dichloroethane, −25 °C34) led to recovery of the starting
materials (Scheme 5).
After failing to improve upon these results through additional
experimentation, we attempted the hydrolysis of the pentenyl
glycoside to the corresponding free hemiacetal, which could then
be converted into another glycosyl donor. However, subjecting
3a to the standard conditions for pentenyl glycoside hydrolysis
developed by Fraser-Reid and co-workers (N-bromosuccinimide
(NBS), aqueous CH3CN17) resulted in only a low (<30%) yield
CONCLUSIONS
■
The synthesis of pentasaccharide 2 was accomplished in a longest
linear sequence of nine steps and 13% overall yield from
commercially available 1,2,3,4-tetra-O-acetyl-α/β-L-rhamnopyr-
anose (seven steps from the previously reported pentenyl α-L-
rhamnopyranoside). Taking into account the preparation of 4a
(three steps from 1,2,3,4-tetra-O-acetyl-L-arabinopyranose and
D
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Finally, two transformations (the selective benzoylation of 6
and the glycosylation of 4a) illustrate the utility of
regioselectively manipulating disaccharide-derived diols pre-
pared by organoboron-mediated glycosylation. We anticipate
that this tactic of using catalyst- or reagent-controlled
glycosylations as initial OH differentiation steps, followed by
substrate-controlled transformations of the resulting disacchar-
ides, may be applicable to the synthesis of other oligosaccharide
targets.
Scheme 6. Fragment-Coupling Glycosylation and Global
Deprotection
a
EXPERIMENTAL SECTION
Experimental procedures and characterization data are provided below
for all new compounds reported here.
■
General Procedures. Stainless steel syringes were used to transfer
air- and moisture-sensitive liquids. Flash chromatography was
performed using silica gel (230−400 mesh). Thin-layer chromatography
(TLC) was performed using aluminum-backed silica gel plates.
Preparative TLC was performed using glass-backed silica gel plates
(mean particle size 25 μm).
Materials. Dichloromethane and acetonitrile were purified by
passing through two columns of activated alumina under nitrogen.
Deionized water was acquired from an in-house supply. N-
Iodosuccinamide (NIS) was recrystallized by a 1:1 (v/v) mixture of
1,4-dioxane and diethyl ether, and N-bromosuccinimide was recrystal-
lized from water. Pyridine was dried over calcium hydride with stirring at
80 °C. The remainder of the reagents and solvents were purchased from
commercial suppliers and used without further purification.
a
Reagents and conditions: (a) Cl3CCN, Cs2CO3, CH2Cl2, 0 °C, 80%
(α:β > 9:1); (b) 4a, TMSOTf (10 mol %), CH2Cl2, −78 °C, 85% (α:β
> 19:1); (c) KOH, CH3OH, 23 °C, 74%.
Instrumentation. Proton nuclear magnetic resonance (1H NMR)
spectra and carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on a 300, 400, 500, 600, or 700 MHz spectrometer (500
and 700 spectrometers are equipped with a cryogenic probe). Chemical
shifts for protons are reported in parts per million (ppm) downfield
from tetramethylsilane and are referenced to residual protium in the
NMR solvent (CDCl3: δ 7.26; CD3CN: δ 1.94; CD3OD: δ 3.31; D2O: δ
4.79). Chemical shifts for carbon are reported in parts per million
downfield from tetramethylsilane and are referenced to the carbon
resonances of the solvent (CD3CN: δ 1.32; CDCl3: δ 77.16; CD3OD: δ
49.00). Data are represented as follows: chemical shift (δ, ppm);
multiplicity (s, singlet; d, doublet; app t, apparent triplet; app q, apparent
quartet; m, multiplet); integration; coupling constant (J, Hz), proton
assignment. Proton resonances were assigned based on 2-D COSY,
HSQC, and HMBC experiments. Glycosidic linkages were confirmed by
2-D COSY and HMBC experiments. High-resolution mass spectra
(HRMS) were obtained on a VS 70−250S (double focusing) mass
spectrometer at 70 eV using either electrospray ionization (ESI) or
direct analysis in real time (DART) methods. Infrared (IR) spectra were
obtained on a Fourier-transform IR instrument equipped with a single-
bounce diamond/ZnSe ATR accessory. Spectral features are repre-
sented as follows: wavenumber (cm−1); intensity (s, strong; m, medium;
w, weak). Melting points were measured using a Fisher−Johns apparatus
and are uncorrected. Optical rotations were measured on an automatic
polarimeter.
Preparation of Monosaccharide Starting Materials. 2,3,4,6-
Tetra-O-acetyl-α-D-glucopyranosyl Bromide.37 Acetic anhydride
(28.4 mL, 300 mmol) was added to a solution of D-glucose (5.40 g,
30.0 mmol) in pyridine (50.0 mL) and stirred at 23 °C overnight. The
solution was diluted with ethyl acetate and washed three times with
aqueous hydrochloric acid (1 M). The organic phase was dried over
MgSO4 and filtered, and the solvent was removed under reduced
pressure to give a white solid. The crude material was dissolved in
anhydrous CH2Cl2 (60.0 mL) in an oven-dried round-bottom flask
equipped with a stir bar and 4 Å molecular sieves under an atmosphere
of argon and cooled to 0 °C. A solution of HBr (33% wt) in acetic acid
(30.0 mL) was added slowly to the solution, and the flask was covered
with aluminum foil. Once complete, as judged by disappearance of
starting material on TLC, the reaction was diluted with CH2Cl2, filtered
through Celite, and washed three times with water, saturated NaHCO3,
and water. The organic phase was collected, dried over MgSO4, and
filtered, and solvent was removed under reduced pressure to give a white
per-acetylated D-fucopyranosyl bromide) and 8b (four steps
from D-xylose) gives a total of 16 steps. The previously reported
synthesis of Gu and Du generated the allyl glycoside analogue of
2 in a longest linear sequence of 11 steps from L-arabinose
(assuming that a global deprotection similar to the conversion of
11 to 2 could be carried out on the peracylated product of the
latter study) and a total of 22 steps from commercially available
precursors. The use of organoboron-catalyzed and -mediated
glycosylations thus enabled an improvement in efficiency,
especially as reflected by the total number of steps required for
the two syntheses.36 This lower step count resulted from a
reduced number of protective group installation/removal
reactions. For instance, the synthesis of the β-(1→3)-D-Fuc-L-
Ara disaccharide fragment by Gu and Du involved the
preparation of a 3,4-O-isopropylidene-protected arabinopyrano-
side, followed by 2-O-acetylation, hydrolysis of the isopropyli-
dene group, sequential 3-O-silylation, and 4-O-benzoylation,
followed by desilylation and glycosylation of the free 3-OH
group. Selective saponification of the 2-O-acetyl group was then
followed by coupling with a trisaccharide-derived trichloroace-
timidate to construct the α-(1 → 2)-L-Ara-L-Rha linkage, thus
generating the pentasaccharide target (a nine-step sequence from
the arabinopyranoside starting material). In the present study,
boronic acid activation of the arabinopyranoside enabled the
selective preparation of the β-(1→3)-D-Fuc-L-Ara disaccharide
4a, which was subjected directly to a regioselective 2-O-
glycosylation with trisaccharide donor 3e to form pentasacchar-
ide 11 (a two-step glycosylation sequence).
Several observations from this work can be highlighted. The
relatively high catalytic activity of oxaboraanthracene-derived
borinic acid 5b at low temperature proved to be instrumental to
the efficient, regioselective construction of the β-(1→3)-D-Glc-L-
Rha linkage. A matching/mismatching effect of glycosyl donor
configuration on regioselectivity was inferred in the synthesis of
the β-(1→3)-D-Fuc-L-Ara disaccharide. This challenge was
ultimately overcome by the development of a boronic acid/
amine copromoter system for regioselective glycosylation.
E
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solid. The crude isolate was recrystallized from ethanol to give the title
compound as white needle-like prisms (9.05 g, 73%). NMR spectral data
were in agreement with those reported previously.37 1H NMR (300
MHz, CDCl3): δ (ppm) 6.61 (d, 1H, J = 4.0 Hz, H-1), 5.56 (app t, 1H, J
= 10.0 Hz, H-3), 5.16 (app t, 1H, J = 10.0 Hz, H-4), 4.84 (dd, 1H, J =
10.0, 4.0 Hz, H-2), 4.35−4.28 (m, 2H, H-5, H-6), 4.15−4.11 (m, 1H, H-
6), 2.10 (s, 3H, CH3CO), 2.10 (s, 3H, CH3CO), 2.05 (s, 3H, CH3CO),
2.04 (s, 3H, CH3CO).
(νmax, neat, cm−1): 3315 (w), 2971 (m), 2902 (w), 2873 (w), 1736 (s),
1672 (m), 1479 (m), 1459 (m), 1397 (w), 1366 (w), 1353 (w), 1276
(s), 1177 (s), 1144 (s), 1130 (s), 1108 (s), 1075 (s), 1026 (s), 973 (s),
911 (m), 886 (m), 835 (m), 794 (s), 762 (m), 740 (m), 705 (m). 1H
NMR (400 MHz, CDCl3): δ (ppm) 8.63 (s, 1H, C(NH)CCl3), 6.45 (d,
1H, J = 3.6 Hz, H-1), 5.62 (app t, 1H, J = 9.8 Hz, H-3), 5.09−5.02 (m,
2H, H-2, H-4), 3.90 (dd, 1H, J = 11.2, 6.0 Hz, H-5eq), 3.72 (dd, 1H, J =
11.2, 10.9 Hz, H-5ax), 1.17 (s, 9H, (CH3)3CCO), 1.16 (s, 9H,
(CH3)3CCO), 1.14 (s, 9H, (CH3)3CCO). 13C NMR (100 MHz,
CDCl3): δ (ppm) 177.5, 177.4, 177.1, 161.0, 96.1, 93.3, 70.0, 69.0, 68.5,
60.9, 38.97, 38.95, 38.92, 27.3, 27.23, 27.20. HRMS (ESI, m/z): calcd for
[C20H33O7] (M − Cl3CCONH2)+ 385.2221, found 385.2217. β-
Anomer. 1H NMR (400 MHz, CDCl3): δ (ppm) 8.71 (s, 1H,
C(NH)CCl3), 5.97 (d, 1H, J = 6.4 Hz, H-1), 5.33 (app t, 1H, J = 7.9
Hz, H-3), 5.23 (dd, 1H, J = 7.9, 6.4 Hz, H-2), 5.09−4.93 (m, 1H, H-4),
4.20 (dd, 1H, J = 12.0, 4.8 Hz, H-5eq), 3.56 (dd, 1H, J = 12.0, 7.9 Hz, H-
5ax), 1.15 (s, 9H, (CH3)3CCO), 1.14 (s, 9H, (CH3)3CCO), 1.12 (s, 9H,
(CH3)3CCO).
p-Methoxyphenyl α-L-Arabinopyranoside. Acetic anhydride (7.60
mL, 80.0 mmol) was added to a solution of L-arabinose (1.50 g, 10.0
mmol) in pyridine (10.0 mL) and stirred at 23 °C overnight. The
solution was diluted with dichloromethane and washed three times with
aqueous hydrochloric acid (1 M). The organic phase was dried over
MgSO4 and filtered and solvent removed under reduced pressure to give
1,2,3,4-tetra-O-acetyl-α/β-L-arabinopyranose as a viscous oil and was
used without further purification. The oil was dissolved in anhydrous
CH2Cl2 (15.0 mL) and added by syringe to an oven-dried round-
bottomed flask equipped with a stir bar, p-methoxyphenol (1.86 g, 15.0
mmol), and 4 Å molecular sieves under an atmosphere of argon and
stirred for 10 min at room temperature before cooling to 0 °C. Boron
trifluoride diethyl etherate (6.20 mL, 50.0 mmol) was added dropwise to
the reaction flask, and the reaction was allowed to warm to room
temperature. After 24 h, the reaction diluted with CH2Cl2 and quenched
with aqueous NaHCO3. The solution was filtered through a pad of
Celite and washed sequentially with saturated aqueous NaHCO3
solution, water, and brine. The organic phase was collected, dried
over MgSO4, and filtered, and the solvent was removed under reduced
pressure. The crude isolate was purified by flash chromatography to
afford 2,3,4-tri-O-acetyl-p-methoxyphenyl α-L-arabinopyranoside as a
colorless, viscous oil. The oil was dissolved in methanol (13.0 mL), and
sodium methoxide (22.0 mg, 0.400 mmol) was added. The reaction was
stirred at 23 °C until judged complete by disappearance of starting
material on TLC. Dowex 50WX2-100 H+ resin was rinsed with
methanol and added to the reaction to neutralize the solution. The
solution was filtered, and the solvent was removed under reduced
pressure to afford a white solid (859 mg, 34% over three steps). The
solid was recrystallized from boiling ethanol to give the title compound
as white needle-like prisms (632 mg). Mp: 165−168 °C. [α]20D = −3.60
(c = 10 mg/mL, CH3OH). FTIR (powder, cm−1): 3534 (w), 3367 (m),
1508 (m), 1209 (m), 1070 (s), 1031 (s), 1011 (s). 1H NMR (400 MHz,
D2O): δ (ppm) 7.14 (d, 2H, J = 9.1 Hz, o-ArH), 7.01 (d, 2H, J = 9.1 Hz
m-ArH), 4.93 (d, 1H, J = 6.9 Hz, H-1), 4.02−3.96 (m, 2H, H-4, H-5),
3.84−3.77 (m, 6H, H-2, H-3, H-5, OCH3). 13C NMR (100 MHz,
DMSO-d6): δ (ppm) 154.3, 151.2, 117.9, 114.5, 102.0, 72.5, 70.4, 67.7,
65.6, 55.4. HRMS (ESI, m/z): calcd for [C12H16NaO6] (M + Na)+
279.0839, found 279.0839.
n-Pentenyl α-L-Rhamnopyranoside.20 Acetic anhydride (15.0 mL,
160 mmol) was added to a solution of L-rhamnose (3.30 g, 20.0 mmol)
in pyridine (20.0 mL) and stirred at overnight. The solution was diluted
with dichloromethane and washed three times with aqueous hydro-
chloric acid (1 M). The organic phase was dried over MgSO4 and filtered
and solvent removed under reduced pressure to give 1,2,3,4-tetra-O-
acetyl-α/β-L-rhamnopyranose as a viscous oil. The oil was dissolved in
anhydrous CH2Cl2 (35 mL) and added by syringe to an oven-dried
round-bottom flask equipped with a stir bar and 4 Å molecular sieves
under an atmosphere of argon. 4-Penten-1-ol (3.00 mL, 30.0 mmol) was
added, and the solution was stirred for 10 min at room temperature
before cooling to 0 °C. Boron trifluoride diethyl etherate (10.0 mL, 80.0
mmol) was added dropwise to the reaction flask, and the reaction was
allowed to warm to room temperature. After 24 h, the reaction was
diluted with CH2Cl2 and quenched with aqueous NaHCO3. The
solution was filtered through a pad of Celite and washed with saturated
NaHCO3, water, and brine. The organic phase was collected, dried over
MgSO4, and filtered. The solvent was removed under reduced pressure.
The crude isolate was purified by flash chromatography to afford n-
pentenyl 2,3,4-tri-O-acetyl-α-L-rhamnopyranoside as a clear viscous oil.
The oil was dissolved in methanol (74.0 mL), and sodium methoxide
(120 mg, 2.20 mmol) was added to the reaction mixture and stirred at 23
°C until judged to be complete by disappearance of starting material on
TLC. Dowex 50WX2-100 H+ resin was rinsed with methanol and added
to the reaction to neutralize the solution. The solution was filtered, and
the solvent was removed under reduced pressure to afford the title
compound as a clear viscous oil (2.30 g, 50%). NMR spectral data were
in agreement with those reported previously.20,38 1H NMR (300 MHz,
CDCl3): δ 5.84−5.75 (m, 1H, OCH2CH2CH2CHCH2), 5.06−4.95 (m,
2H, OCH2CH2CH2CHCH2), 4.73 (d, 1H, J = 1.5 Hz, H-1), 4.22 (d, J =
6.6 Hz, 1H, OH), 3.93−3.88 (m, 2H, H-2, OH), 3.82−3.74 (m, 2H, H-3,
OH), 3.68−3.61 (m, 2H, H-5, one of OCH2), 3.50−3.39 (m, 2H, H-4,
one of OCH2), 2.14−2.07 (m, 2H, OCH2CH2CH2), 1.71−1.64 (m, 2H,
OCH2CH2), 1.30 (d, 3H, J = 6.0 Hz, CH3). 13C NMR (100 MHz,
CDCl3): δ 138.0, 115.2, 99.9, 73.0, 71.9, 71.2, 68.2, 67.2, 30.4, 28.7, 17.7.
Rf = 0.2 (EtOAc/pentanes 7:3).
2,3,4-Tris-O-(trimethylacetyl)-α/β-D-xylopyranosyl Trichloroaceti-
midate (8b). Prepared in two steps from 2,3,4-tris-O-(trimethylacetyl)-
α-D-xylopyranosyl bromide. Hydrolysis of 2,3,4-tris-O-(trimethylace-
tyl)-α-D-xylopyranosyl bromide39 to 2,3,4-tris-O-(trimethylacetyl)-α/β-
D-xylopyranose was carried out by adapting a published protocol.40
2,3,4-Tris-O-(trimethylacetyl)-α-D-xylopyranosyl bromide (4.14 g, 8.90
mmol) was dissolved in acetone (55.0 mL). Water (0.600 mL, 33.8
mmol) was added, and the solution was cooled to 0 °C. Silver(I)
carbonate (3.68 g, 13.4 mmol) was added, and the flask was covered with
aluminum foil and stirred until judged to be complete by disappearance
of starting material on TLC (approximately 2 h). Once complete, the
solution was filtered through Celite, and the solvent was removed under
reduced pressure to yield the corresponding hemiacetal as a white solid
(3.56 g, α:β = 1:1.7). Without further purification, this material was
dissolved in anhydrous CH2Cl2 (88.5 mL) in an oven-dried round-
bottomed flask equipped with a stir bar. Trichloroacetonitrile (6.20 mL,
62.0 mmol) and cesium carbonate (1.44 g, 4.40 mmol) were added, and
the reaction was stirred until judged to be complete by disappearance of
starting material on TLC (1 h). The solution was filtered through Celite,
and the solvent was removed under reduced pressure. The crude isolate
was purified by flash chromatography (9:1 pentanes/ethyl acetate) to
yield 8b as a white solid (3.80 g, 70% over four steps from D-xylose. α:β =
1.6:1). Pure α-anomer was obtained for melting point analysis by
recrystallization of the anomeric mixture from boiling ethanol to yield
white prisms. α-Anomer. Mp: 125−128 °C. TLC Rf: 0.84 (pentane/
2,3,4-Tri-O-acetyl-α-D-fucopyranosyl Bromide. Acetic anhydride
(7.60 mL, 80.0 mmol) was added to a solution of D-fucose (1.64 g, 10.0
mmol) in pyridine (10.0 mL) and stirred at 23 °C overnight. The
solution was diluted with ethyl acetate and washed three times with
aqueous hydrochloric acid (1 M). The organic phase was dried over
MgSO4 and filtered, and the solvent was removed under reduced
pressure. The crude material was passed through a short column of silica
gel (1:1 pentane/ether) to give 1,2,3,4-tetra-O-acetyl-α-D-fucopyranose
as a clear oil. The oil was dissolved in anhydrous CH2Cl2 (20.0 mL) in an
oven-dried round-bottom flask equipped with a stir bar and 4 Å
molecular sieves under an atmosphere of argon and cooled to 0 °C. A
solution of HBr (33% wt) in acetic acid (9.00 mL) was added dropwise
to the solution, and the flask was covered with aluminum foil. The
reaction was stirred for 30 min, diluted with CH2Cl2, and washed
ethyl acetate 9:1). [α]20 = +61.0 (c = 10.0 mg/mL, CHCl3). FTIR
D
F
DOI: 10.1021/acs.joc.5b00950
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The Journal of Organic Chemistry
Featured Article
successively with water, saturated aqueous NaHCO3 solution, and
water. The organic phase was dried over MgSO4 and filtered. Solvent
was removed under reduced pressure to give a viscous oil which was
purified by passing through a short plug of silica gel (1:1 pentane/ether).
The product was dried under high vacuum to give 2,3,4-tri-O-acetyl-α-D-
fucopyranosyl bromide as an amorphous white solid (2.30 g, 65%).
NMR spectral data were in agreement with those reported previously.41
1H NMR (400 MHz, CDCl3): δ ppm 6.68 (d, 1H, J = 3.9 Hz, H-1),
5.43−5.35 (m, 2H, H-3, H-4), 5.03 (dd, 1H, J = 10.5, 3.9 Hz, H-2), 4.41
(app q, 1H, J = 6.7 Hz, H-5), 2.17 (s, 3H, CH3CO), 2.11 (s, 3H,
CH3CO), 2.01 (s, 3H, CH3CO), 1.22 (d, 3H, J = 6.7 Hz, CH3). Rf = 0.8
(EtOAc/pentanes; 1:3). An analogous protocol was used to prepare the
α-L-enantiomer from L-fucose.
3.95 (m, 2H, H-3, H-6′), 3.79−3.66 (m, 4H, H-4, H-5, H-5′, one of
OCH2), 3.48−3.42 (m, 1H, one of OCH2), 2.54 (s, 1H, OH), 2.18−2.13
(m, 2H, OCH2CH2CH2), 2.06 (s, 3H, CH3CO),1.98 (s, 3H, CH3CO),
1.97 (s, 3H, CH3CO), 1.81 (s, 3H, CH3CO), 1.76−1.68 (m, 2H,
OCH2CH2), 1.35 (d, 3H, J = 6.0 Hz, CH3). 13C NMR (100 MHz,
CDCl3): δ (ppm) 170.8, 170.3, 170.2, 169.5, 166.1, 138.0, 133.2, 130.1,
130.0, 128.5, 115.2, 100.9, 97.6, 80.0, 72.6, 71.9, 71.8, 71.7, 71.3, 68.0,
67.8, 67.5, 61.7, 30.4, 28.8, 20.9, 20.72, 20.69, 20.5, 17.9. HRMS (ESI,
m/z): calcd for [C32H46NO15] (M + NH4)+ 684.2862, found 684.2861.
n-Pentenyl 2-O-Benzoyl-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-gluco-
pyranosyl)-4-O-(2″,3″,4″-tris-O-(trimethylacetyl)-β-D-xylopyrano-
syl)-α-L-rhamnopyranoside (3a). Glycosyl trichloroacetimidate 8b
(3.80 g, 6.98 mmol) and acceptor 7 (3.10 g, 4.65 mmol) were dissolved
in anhydrous CH2Cl2 (23.3 mL) in an oven-dried round-bottomed flask
equipped with a stir bar and 4 Å molecular sieves under an atmosphere
of argon and cooled to 0 °C. A freshly prepared 1.0 M solution of
TMSOTf in anhydrous CH2Cl2 (0.460 mL, 0.460 mmol) was added
dropwise, and the reaction was stirred for 1 h. The reaction was
quenched with excess triethylamine and filtered through a pad of Celite.
The solvent was removed under reduced pressure, and the crude isolate
was purified by flash chromatography (8:2 pentane/ethyl acetate) to
yield 3a as an amorphous white solid (4.77 g, 98%). The configuration of
the glycosidic linkage was assigned as β based on the J3H‑1″,H‑2″ value of
7.8 Hz. TLC Rf: 0.80 (pentane/ethyl acetate 6:4). [α]20D = −36.26 (c =
10.7 mg/mL, CHCl3). FTIR (powder, cm−1): 2977 (w), 2938 (w), 2875
(w), 1738(s), 1602 (w), 1480 (w), 1452 (w), 1365 (m), 1324 (w), 1272
(s), 1215 (s), 1139 (s), 1112 (s), 1035 (s), 990 (s), 906 (m) 825 (m),
762 (w), 713 (s). 1H NMR (600 MHz, CDCl3): δ (ppm) 7.98 (dd, 2H, J
= 8.4, 1.2 Hz, o-ArH), 7.56 (tt, 1H, J = 7.8, 1.2 Hz, p-ArH), 7.44 (dd, 2H,
Synthesis of 2. n-Pentenyl 3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-
glucopyranosyl)-α-L-rhamnopyranoside (6). n-Pentenyl α-L-rhamno-
pyranoside (1.16 g, 5.00 mmol) was dissolved in anhydrous acetonitrile
(25.0 mL) in a round-bottomed flask equipped with magnetic stir bar
and cooled to −45 °C. 10H-Dibenzo[b,e][1,4]oxaborinin-10-ol21 (98.0
mg, 0.5 mmol), 2,3,4,6-tetra-O-acetyl-α-D-bromoglucopyranoside (2.26
g, 5.50 mmol), and silver(I) oxide (1.16 g, 5.00 mmol) were added, and
the solution was stirred vigorously overnight, allowing the temperature
to rise gradually. After 20.5 h, the reaction was quenched with methanol
and filtered through a pad of Celite. The filtrate was concentrated under
reduced pressure and then purified by flash chromatography (gradient
elution from 10% to 15% acetone in dichloromethane) to afford 6 as an
amorphous white solid (2.29 g, 81%). The regiochemical outcome of the
glycosylation was supported by the downfield shift of the H-3 proton
resonance, and confirmed by COSY NMR (correlations between 2-
OH/H-2 and 4-OH/H-4 observed). The configuration of the glycosidic
linkage was assigned as β based on the J3H‑1′,H‑2′ value of 8.0 Hz. TLC Rf:
0.45 (CH2Cl2/acetone 8:2). FTIR (powder, cm−1): 3534 (w), 3484 (w),
2932 (w), 1748 (s), 1367 (m), 1260 (m), 1214 (s), 1168 (m), 1130 (m),
1085 (s), 1034 (s), 921 (m), 899 (m), 837 (w), 805 (m), 691 (m). 1H
NMR (400 MHz, CDCl3): δ (ppm) 5.84−5.77 (m, 1H,
OCH2CH2CH2CHCH2), 5.24 (app t, 1H, J = 9.5 Hz, H-3′), 5.08−
4.97 (m, 4H, H-2′, H-4′, OCH2CH2CH2CHCH2), 4.79 (d, 1H, J = 1.6
Hz, H-1), 4.71 (d, 1H, J = 8.0 Hz, H-1′), 4.20 (d, 2H, J = 4.0 Hz, H-6′, H-
6′), 3.97 (ddd, 1H, J = 4.5, 3.0, 1.5 Hz, H-2), 3.80−3.61 (m, 5H, H-3, H-
4, H-5, H-5′, one of OCH2), 3.43−3.41 (m, 1H, one of OCH2), 2.65 (d,
1H, J = 3.0 Hz, C-2 OH), 2.24 (d, 1H, J = 2.8 Hz, C-4 OH), 2.13−2.07
(m, 2H, OCH2CH2CH2), 2.08 (s, 3H, CH3CO), 2.06 (s, 3H, CH3CO),
2.03 (s, 3H, CH3CO), 2.01 (s, 3H, CH3CO), 1.73−1.66 (m, 2H,
OCH2CH2), 1.31 (d, 3H, J = 6.0 Hz, CH3). 13C NMR (100 MHz,
CDCl3): δ (ppm) 170.8, 170.3, 170.1, 169.5, 138.0, 115.1, 101.2, 99.4,
83.4, 72.5, 72.1, 71.8, 71.1, 69.8, 68.5, 67.6, 67.0, 61.9, 30.4, 28.7, 20.9,
20.8, 20.74, 20.71, 17.7. HRMS (DART, m/z): calcd for [C25H42NO14]
(M + NH4)+ 580.2600, found 580.2598.
J
= 7.8 Hz, 8.4 Hz, m-ArH), 5.82−5.75 (m, 1H,
OCH2CH2CH2CHCH2), 5.35 (dd, 1H, J = 3.6, 1.8 Hz, H-2), 5.23
(dd, 1H, J = 9.6, 9.6 Hz, H-3″), 5.13 (app t, 1H, J = 9.6, Hz, H-3′), 5.06−
4.90 (m, 6H, H-2′, H-4′, H-2″, H-4″, OCH2CH2CH2CHCH2), 4.82 (d,
1H, J = 1.8 Hz, H-1), 4.79 (d, 1H, J = 7.8 Hz, H-1″), 4.73 (d, 1H, J = 7.8
Hz, H-1′), 4.12 (dd, 1H, J = 11.4, 5.4 Hz, H-5″), 4.08−4.06 (m, 2H, H-3,
H-6′), 4.02−3.98 (m, 2H, H-4, H-6′), 3.68−3.60 (m, 3H, H-5, H-5′, one
of OCH2), 3.43−3.40 (m, 1H, one of OCH2), 4.34 (dd, 1H, J = 11.4,
10.2 Hz, H-5″), 2.29 (s, 3H, CH3CO), 2.13−2.07 (m, 2H,
OCH2CH2CH2), 1.96 (s, 3H, CH3CO), 1.96 (s, 3H, CH3CO), 1.77
(s, 3H, CH3CO), 1.72−1.67 (m, 2H, OCH2CH2), 1.27 (d, 3H, J = 6.6
Hz, CH3), 1.20 (s, 9H, (CH3)3CCO), 1.15 (s, 9H, (CH3)3CCO), 1.11
(s, 9H, (CH3)3CCO). 13C NMR (125 MHz, CDCl3): δ (ppm) 177.4,
177.3, 176.7, 170.8, 170.2, 170.1, 169.4, 166.0, 137.9, 133.1, 130.3, 130.0,
128.5, 115.3, 100.8, 99.1, 96.7, 80.5, 73.5, 73.3, 72.2, 72.1, 71.9, 71.6,
71.4, 69.4, 67.9, 67.2, 66.6, 62.7, 61.6, 38.91, 38.89, 38.82, 30.4, 28.7,
27.34, 27.26, 27.21, 21.7, 20.68, 20.65, 20.5, 18.2. HRMS (ESI, m/z):
calcd for [C52H75O22] (M + H)+ 1051.4745, found 1051.4744.
n-Pentenyl 2-O-Benzoyl-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-gluco-
pyranosyl)-α-L-rhamnopyranoside (7). A published protocol for
selective protection with trimethylacetyl chloride was adapted.24
Compound 6 (2.95 g, 5.25 mmol) was dissolved in anhydrous pyridine
(7.80 mL) in an oven-dried round-bottomed flask equipped with a stir
bar and cooled to 0 °C. Benzoyl chloride (0.73 mL, 6.30 mmol) was
added quickly to the solution with rapid stirring, and the reaction was
stirred for 1 h. The solution was diluted with ethyl acetate and washed
three times with aqueous hydrochloric acid (1 M). The organic phase
was dried over MgSO4 and filtered, and the solvent was removed under
reduced pressure. The crude isolate was purified by flash chromatog-
raphy (20 → 40% ethyl acetate in pentane) to give 7 as an amorphous
white solid (3.11 g, 89%). The assignment of the regiochemical outcome
p-Methoxyphenyl 3-O-(2′,3′,4′-Tri-O-acetyl-β-D-fucopyranosyl)-
α-L-arabinopyranoside (4a). p-Methoxyphenyl α-L-arabinopyranoside
(128 mg, 0.500 mmol), pentafluorophenylboronic acid (106 mg, 0.500
mmol), and 4 Å molecular sieves (500 mg) were placed in an oven-dried
round-bottomed flask equipped with a stir bar. Anhydrous CH2Cl2 (3.85
mL) was added, and the reaction was stirred at 23 °C overnight. The
reaction was then cooled to 0 °C before addition of silver(I) oxide (116
mg, 0.500 mmol) and 4-methylmorpholine (0.330 mL, 3.00 mmol).
2,3,4-Tri-O-acetyl-α-D-fucopyranosyl bromide (194 mg, 0.550 mmol)
was added portionwise (approximately 24.0 mg every hour for 8 h).
Once donor addition was complete, the reaction was stirred overnight
and allowed to warm gradually to room temperature. Once complete,
the reaction was quenched by addition of excess methanol, and the
solution was filtered through a thin pad of Celite. The solvent was
removed under reduced pressure, and the crude isolate was purified by
flash chromatography (5% → 10% acetone in dichloromethane) to give
4a as a white solid (196 mg, 74%). The regiochemical outcome was
assigned based on the large downfield shift of the C-3 carbon resonance.
The configuration of the glycosidic linkage was assigned as β based on
the J3H‑1′,H‑2′ value of 8.0 Hz. Mp: 90−94 °C. TLC Rf = 0.5 (acetone/
CH2Cl2 1:4). [α]20D = +8.46 (c = 8.75 mg/mL, CHCl3). HPLC (cyano-
functionalized silica column, 5 μm pore size, 25 cm × 4.6 mm column,
80:20 hexanes/2-propanol, 1 mL/min, UV detection at 245 nm): tR =
1
is based on the downfield shift of the H-2 resonance in the H NMR
spectrum. TLC Rf: 0.62 (pentane/ethyl acetate 6:4). [α]20D = −8.15 (c =
8.1 mg/mL, CHCl3). FTIR (powder, cm−1): 3512 (br), 2933 (w), 1745
(s), 1721 (s), 1451 (w), 1365 (m), 1214 (s), 1035 (s), 908 (m), 712 (s).
1H NMR (400 MHz, CDCl3): δ (ppm) 8.00 (d, 2H, J = 7.5 Hz, o-Ar),
7.56 (app t, 1H, J = 7.5 Hz, p-Ar), 7.44 (app t, 2H, J = 7.5 Hz, m-Ar),
5.88−5.78 (m, 1H, OCH2CH2CH2CHCH2), 5.31 (dd, 1H, J = 3.5, 1.5
Hz, H-2), 5.17 (app t, 1H, J = 9.5 Hz, H-3′), 5.08−4.93 (m, 4H,
OCH2CH2CH2CHCH2, H-2′, H-4′), 4.83 (d, 1H, J = 1.5 Hz, H-1), 4.72
(d, 1H, J = 8.0 Hz, H-1′), 4.07 (dd, 1H, J = 12.0, 4.0 Hz, H-6′), 3.99−
G
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19.9 min. FTIR (powder, cm−1): 3490 (br), 2960 (m), 2929 (m), 2873
(m), 1741 (s), 1507 (s), 1367 (m), 1216 (s), 1064 (s), 1035 (s), 906
(m), 872 (w), 829 (m), 787 (w), 742 (m), 664 (w). H NMR (400
914 (m), 830 (m), 745 (m). HRMS (DART, m/z): calcd for
[C24H36NO13] (M + NH4)+ 546.2186, found 546.2193.
1
2-O-Benzoyl-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)-
4-O-(2″,3″,4″-tris-O-(trimethylacetyl)-β-D-xylopyranosyl)-α-L-rham-
nopyranose (3b). Compound 3b was prepared using a modified
literature procedure.42 Compound 3a (210 mg, 0.200 mmol) was
dissolved in 0.1% aqueous CH2Cl2 (8.00 mL) in an oven-dried round-
bottomed flask equipped with a stir bar. N-Iodosuccinimide (90.0 mg,
0.400 mmol) was added to the reaction flask, followed by dropwise
addition of a freshly prepared 0.25 M solution of TMSOTf in anhydrous
CH2Cl2 (240 μL, 60.0 μmol) over a period of 2.5 min. The reaction was
stirred at 23 °C for an additional 30 s before quenching with a 10%
aqueous solution of sodium thiosulfate. The solution was diluted with
CH2Cl2 and washed with 10% aqueous Na2S2O3, saturated NaHCO3,
and brine. The organic phase was dried over MgSO4 and filtered. Solvent
was removed under reduced pressure, and the crude isolate was purified
by flash chromatography (20% → 50% ethyl acetate in pentanes) to
yield 3b as an amorphous white solid (141 mg, 72%). TLC Rf: 0.57
(pentane/ethyl acetate 6:4). FTIR (powder, cm−1): 2966 (w), 1740 (s),
1480 (w), 1452 (w), 1366 (m), 1274 (s), 1215 (s), 1141 (s), 1111 (s),
MHz, CDCl3): δ 7.02 (d, 2H, J = 9.0 Hz, ArH), 6.82 (d, 2H, J = 9.0 Hz,
ArH), 5.27−5.21 (m, 2H, H-2′, H-4′), 5.06 (dd, 1H, J = 10.6, 3.3 Hz, H-
3′), 4.76 (d, 1H, J = 8.0 Hz, H-1′), 4.70 (d, 1H, J = 7.2 Hz, H-1), 4.11
(dd, 1H, J = 12.9, 2.5 Hz, H-5a), 4.06−3.97 (m, 2H, H-2, H-4), 3.85 (m,
1H, H-5′), 3.77 (s, 3H, OCH3), 3.72 (dd, 1H, J = 8.9, 3.4 Hz, H-3), 3.57
(dd, 1H, J = 12.9, 2.0, H-5b), 2.80 (d, 1H, J = 2.3 Hz, C-4 OH), 2.44 (d,
1H, J = 2.8 Hz, 1H, C-2 OH), 2.20 (s, 3H, CH3CO), 2.07 (s, 3H,
CH3CO), 2.00 (s, 3H, CH3CO), 1.22 (d, 3H, J = 6.4 Hz, CH3). 13C
NMR (100 MHz, CDCl3): δ 170.7, 170.3, 170.2, 155.6, 151.0, 119.0,
114.7, 102.5, 101.9, 81.9, 71.0, 70.5, 70.1, 69.6, 69.1, 67.5, 65.3, 55.8,
21.0, 20.81, 20.77, 16.3. HRMS (ESI, m/z): calcd for [C24H36NO13] (M
+ NH4)+ 546.2187, found 546.2199.
p-Methoxyphenyl 3-O-(2′,3′,4′-Tri-O-acetyl-β-L-fucopyranosyl)-α-
L-arabinopyranoside (4b). An oven-dried round-bottomed flask
equipped with a stir bar was charged with p-methoxyphenyl α-L-
arabinopyranoside (51.0 mg, 0.200 mmol), 2-aminoethyl diphenylbori-
nate (4.50 mg, 20.0 μmol), and silver(I) oxide (46.0 mg, 0.200 mmol). A
solution of 2,3,4-tri-O-acetyl-α-L-fucopyranosyl bromide in acetonitrile
(1.0 mL) was added, and the suspension was stirred overnight at room
temperature. Once complete, the reaction was quenched by addition of
excess methanol, and the solution was filtered through a thin pad of
Celite. The solvent was removed under reduced pressure, and the crude
isolate was purified by flash chromatography (5% → 10% acetone in
dichloromethane) to give 4b as an amorphous white solid (52.0 mg,
49%). The regiochemical outcome was assigned on the basis of 2-D
HMBC analysis (correlation observed between H-1′/C-3). The
configuration of the glycosidic linkage was assigned as β based on the
1
1035 (s), 988 (s), 894 (m), 846 (w), 799 (w), 762 (w), 713 (m). H
NMR (600 MHz, CDCl3): δ (ppm) 8.00−7.98 (m, 2H, o-Ar), 7.57−
7.55 (m, 1H, p-Ar), 7.47−7.44 (m, 2H, m-Ar), 5.43 (dd, 1H, J = 3.5, 2.5
Hz, H-2), 5.24 (d, 1H, J = 2.5 Hz, H-1), 5.22 (app t, 1H, J = 10.0 Hz, H-
3″), 5.12 (app t, 1H, J = 9.5 Hz, H-3′), 5.05−4.91 (m, 4H, H-2′, H-2″, H-
4′, H-4″), 4.79 (d, 1H, J = 8.0 Hz, H-1″), 4.73 (d, 1H, J = 8.0 Hz, H-1′),
4.19−4.10 (m, 2H, H-3, H-5″eq), 4.05−3.99 (m, 3H, H-4, H-6′, H-6′),
3.65 (m, 1H, H-5′), 3.33 (dd, 1H, J = 12.0, 10.0 Hz, H-5″ax), 2.29 (s, 3H,
CH3CO), 1.97 (s, 3H, CH3CO), 1.96 (s, 3H, CH3CO), 1.85 (s, 3H,
CH3CO), 1.27 (d, 3H, J = 6.0 Hz, CH3), 1.22 (s, 9H, (CH3)3CCO), 1.15
(s, 9H, (CH3)3CCO), 1.12 (s, 9H, (CH3)3CCO). 13C NMR (150 MHz,
CDCl3): δ (ppm) 177.4, 177.3, 176.8, 171.0, 170.2, 169.8, 169.4, 166.0,
133.2, 130.2, 130.0, 128.5, 100.9, 99.3, 91.7, 79.8, 77.4, 72.7, 72.0, 71.9,
71.7, 71.5, 69.4, 68.0, 66.9, 62.7, 61.6, 38.91, 38.83, 38.82, 27.36, 27.25,
27.20, 21.6, 20.7, 20.6, 20.5, 18.3. HRMS (ESI, m/z): calcd for
C47H66O22 [M + NH4]+ 1000.4384, found 1000.4373.
2-O-Benzoyl-3-O-(2′,3′,4′,6′-tetra-O-acetyl-β-D-glucopyranosyl)-
4-O-(2″,3″,4″-tris-O-(trimethylacetyl)-β-D-xylopyranosyl)-α-L-rham-
nopyranosyl trichloroacetimidate (3e). Compound 3b (197 mg, 0.200
mmol) and Cl3CCN (140 μL, 1.40 mmol) were dissolved in anhydrous
CH2Cl2 (2.00 mL) in an oven-dried round-bottomed flask equipped
with a stir bar. The solution was cooled to 0 °C, and Cs2CO3 (33.0 mg,
0.100 mmol) was added to the reaction flask. The flask was removed
from the ice bath and allowed to warm to room temperature with
stirring. After 8 h, the solution was diluted with dichloromethane and
filtered through a thin pad of Celite. The solvent was removed under
reduced pressure, and the crude mixture was purified by flash
chromatography (8:2 → 7:3 pentanes/ethyl acetate) to yield 3e as an
amorphous white solid (181 mg, 80%). TLC Rf: 0.78 (pentane/ethyl
acetate 6:4). [α]20D = −35.40 (c = 9.20 mg/mL, CHCl3). FTIR (powder,
cm−1): 2972 (w), 2936 (w), 2872 (w), 1739 (s), 1679 (w), 1480 (w),
1453 (w), 1366 (m), 1319 (w), 1216 (s), 1141 (s), 1111 (s), 1066 (s),
1035 (s), 974 (s), 926 (m), 894 (m), 796 (s), 762 (w), 712 (s), 687 (w).
1H NMR (600 MHz, CD3CN): δ (ppm) 9.12 (s, 1H, NH), 8.01 (dd,
J3H‑1′,H‑2′ value of 7.8 Hz. TLC Rf = 0.5 (acetone/CH2Cl2 1:4). [α]20
=
D
+1.14 (c = 8.75 mg/mL, CHCl3). HPLC (Rx-C18 silica column, 5 μm
pore size, 25 cm × 4.6 mm column, 80:20 water/acetonitrile, 1 mL/min,
UV detection at 245 nm): tR = 18.9 min. The 4-O-fucosylated
regioisomer had tR = 28.9 min under these conditions. FTIR (powder,
cm−1): 3460 (br), 2980 (w), 2941 (w), 2901 (w), 2834 (w), 1742 (s),
1507 (s), 1441 (s), 1368 (m), 1214 (s), 1172 (m), 1061 (s), 1020 (s)
1
907 (w), 830 (m), 786 (w), 741 (m), 667 (m). H NMR (400 MHz,
CDCl3): δ (ppm) 7.05−7.01 (m, 2H, o-Ar), 6.82−6.78 (m, 2H, m-Ar),
5.26−5.21 (m, 2H, H-2′, H-4′), 5.05 (dd, 1H, J = 10.5, 3.4 Hz, H-3′),
4.72 (d, 1H, J = 7.5 Hz, H-1), 4.59 (d, 1H, J = 7.8 Hz, H-1′), 4.10 (dd,
1H, J = 13.0, 1.9 Hz, H-5), 4.00 (dd, 1H, J = 9.0, 7.8 Hz, H-2), 3.92−3.88
(m, 2H, H-4, H-5′), 3.75 (s, 3H, OCH3), 3.61 (dd, 1H, J = 9.0, 3.5 Hz,
H-3), 3.55 (dd, 1H, J = 13.0, 1.2 Hz, H-5), 2.19 (s, 3H, CH3CO), 2.08 (s,
3H, CH3CO), 2.00 (s, 3H, CH3CO), 1.24 (d, 3H, J = 6.3 Hz, CH3). 13
C
NMR (100 MHz, CDCl3): δ (ppm) 170.7, 170.2, 170.0, 155.6, 151.1,
119.2, 114.6, 102.6, 101.4, 84.4, 70.9, 70.0, 69.9, 69.6, 69.3, 67.7, 65.6,
55.7, 20.9, 20.8, 20.7, 16.1. HRMS (ESI, m/z) calcd for [C24H32NaO13]
(M + Na)+ 551.1735, found 551.1733.
p-Methoxyphenyl 4-O-(2′,3′,4′-Tri-O-acetyl-β-D-fucopyranosyl)-
α-L-arabinopyranoside (4c). Compound 4c was isolated as a byproduct
in the catalytic preparation of compound 4a. The regiochemical
outcome was assigned based on 2-D COSY NMR (correlations between
2-OH/H-2 and 3-OH/H-3). The configuration of the glycosidic linkage
was assigned as β on the basis of the J3
value of 7.9 Hz. HPLC
H‑1′,H‑2′
2H, J = 8.5, 1.5 Hz, o-Bz), 7.68 (m, 1H, p-Bz), 7.55 (m, 2H, J = 6 Hz, m-
Bz) 6.32 (d, 1H, J = 2.5 Hz, H-1) 5.59 (dd, 1H, J = 3.5, 2.5 Hz, H-2)
5.26−5.20 (m, 2H, H-3″, H-3′), 4.97−4.85 (m, 6H, H-1′, H-1″, H-2′,
H2″, H-4′, H-4″), 4.31 (dd, 1H, J = 9.0, 3.5 Hz, H-3), 4.12−4.09 (m, 2H,
H-4, H-5″) 3.97 (dd, 1H, J = 12.0, 4.0 Hz, H-6′), 3.93 (dd, 1H, J = 12.0,
2.5 Hz, H-6′), 3.90−3.87 (m, 1H, H-5), 3.85−3.82 (m, 1H, H-5′), 3.34
(dd, 1H, J = 12.0, 10.0 Hz, H-5″), 2.24 (s, 3H, CH3CO), 2.15 (s, 3H,
CH3CO), 1.95 (s, 3H, CH3CO), 1.77 (s, 3H, CH3CO), 1.30 (d, 3H, J =
6.0 Hz, CH3), 1.21 (s, 9H, (CH3)3CCO), 1.15 (s, 9H, (CH3)3CCO),
1.11 (s, 9H, (CH3)3CCO). 13C NMR (150 MHz, CD3CN): δ (ppm)
177.98, 177.96, 177.6, 171.2, 170.9, 170.8, 170.4, 166.3, 160.2, 134.5,
130.8, 130.6, 129.7, 100.1, 99.9, 94.7, 80.0, 73.5, 72.8, 72.6, 72.25, 72.21,
71.4, 70.2, 70.1, 68.8, 63.4, 62.6, 39.52, 39.42, 39.36, 27.6, 27.4, 27.3,
22.0, 20.85, 20.81, 20.7, 18.5. HRMS (ESI, m/z): calcd for
[C49H66Cl3NNaO22] (M + Na)+ 1148.3034, found 1148.2999.
(cyano-functionalized silica column, 5 μm pore size, 25 cm × 4.6 mm
column, 80:20 hexanes/2-propanol, 1 mL/min, UV detection at 245
nm): tR = 22.8 min. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.01−6.99
(m, 2H, o-ArH), 6.84−6.80 (m, 2H, m-ArH), 5.28−5.22 (m, 2H, H-2′,
H-4′), 5.03 (dd, 1H, J = 10.5, 3.6 Hz, H-3′), 4.71 (d, 1H, J = 7.0 Hz, H-
1), 4.66 (d, 1H, J = 7.9 Hz, H-1′), 4.23 (dd, 1H, J = 12.8, 2.9 Hz, H-5),
3.97−3.95 (m, 1H, H-4), 3.87−3.80 (m, 2H, H-2, H-5′), 3.77 (s, 3H,
OCH3), 3.74−3.69 (m, 1H, H-3), 3.61 (dd, 1H, J = 12.8, 1.7 Hz, H-5),
2.55 (d, 1H, J = 7.8 Hz, 3-OH), 2.51 (d, 1H, J = 2.7 Hz, 2-OH), 2.17 (s,
3H, CH3CO), 2.09 (s, 3H, CH3CO), 1.99 (s, 3H, CH3CO), 1.20 (d, 3H,
J = 6.4 Hz, CH3). 13C NMR (100 MHz, CDCl3): δ (ppm) 170.8, 170.3,
170.0, 155.6, 151.1, 118.7, 114.7, 102.7, 102.3, 77.4, 72.4, 72.1, 71.4,
70.2, 69.5, 69.3, 65.5, 55.8, 21.0, 20.9, 20.8, 16.3. FTIR (νmax, neat,
cm−1): 3400 (br, w), 2980 (w), 2921 (w), 2834 (w), 1741 (s), 1644 (w),
1507 (s), 1443 (w), 1369 (m), 1218 (s), 1173 (m) 1062 (s), 1035 (s),
H
DOI: 10.1021/acs.joc.5b00950
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
para-Methoxyphenyl 2-O-[2′-O-Benzoyl-3′-O-(2″,3″,4″,6″-tetra-
O-acetyl-β-D-glucopyranosyl)-4′-O-(2‴,3‴,4‴-tris-O-(trimethylace-
tyl)-β-D-xylopyranosyl)-α-L-rhamnopyranosyl]-3-O-(2″″,3″″,4″″-tri-
O-acetyl-β-D-fucopyranosyl)-α-L-arabinopyranoside (11). Donor 3e
and acceptor 4a were each dried by azeotropic removal of water with
toluene and placed under high vacuum for 6 h to remove residual solvent
prior to use. Compounds 3e (113 mg, 0.100 mmol) and 4a (79.0 mg,
0.150 mmol) were dissolved in anhydrous CH2Cl2 (0.750 mL) in an
oven-dried round-bottomed flask equipped with a stir bar and 4 Å
molecular sieves under an atmosphere of argon. The reaction was cooled
to −78 °C, and a freshly prepared 0.25 M solution of TMSOTf (40.0 μL,
10.0 μmol) in anhydrous CH2Cl2 was added dropwise to give a faint
yellow solution. The reaction was stirred at −78 °C for 40 min and then
quenched by addition of excess triethylamine. Solvent was removed
under reduced pressure, and the crude isolate was purified by flash
chromatography (5% → 10% acetone in dichloromethane) to yield 112
mg of pure product as an amorphous white solid. The fractions of
product that had coeluted with the excess acceptor were combined and
purified by preparative TLC (50% → 60% ethyl acetate in pentane) to
yield an additional 16.0 mg of product for a total yield of 128 mg (85%).
The regiochemical outcome was assigned based on 2-D HMBC analysis
(correlation observed between H-1′[Rha]/C-2[Ara] and H-2[Ara]/C-
1′ [Rha]). The configuration of the glycosidic linkage was assigned as α
24.7 mg of the title compound as an amorphous white solid (23%) as a
byproduct of the reaction. Regiochemistry of the glycosidic linkage was
1
confirmed by H/13C HMBC experiment. All glycosidic bonds were
confirmed as shown on the basis of 1D and 2D NMR analysis (1H/13C).
1H NMR (700 MHz, CDCl3): δ (ppm) 8.0 (m, 2H, o-Bz), 7.57−7.54
(m, 1H, p-Bz), 7.44−7.42 (m, 2H, m-Bz), 6.95−6.93 (m, 2H, o-Ar),
6.89−6.86 (m, 2H, m-Ar), 5.49 (dd, 1H, J = 3.8, 1.3 Hz, H-2″), 5.32−
5.30 (m, 2H, H-1″, H-4′), 5.20−5.17 (m, 2H, H-3″″, H-2′), 5.08 (app t,
1H, J = 9.5 Hz, H-3‴), 5.03 (app t, 1H, J = 9.5 Hz, H-4‴), 4.98−4.95 (m,
4H, H-2‴, H-2″″, H-4″″, H-3′), 4.90 (d, 1H, J = 7.5 Hz, H-1′), 4.78 (d,
1H, J = 7.3 Hz, H-1), 4.77 (d, 1H, J = 7.2 Hz, H-1″″), 4.68 (d, 1H, J = 7.8
Hz, H-1‴), 4.25−4.19 (m, 2H, H-5″, H-6‴), 4.16−4.11 (m, 2H, H-2, H-
5″″), 4.07−3.90 (m, 5H, H-4, H-3″, H-4″, H-6‴, H-5′), 3.87−3.84 (m,
2H, H-3, H-5), 3.79 (s, 3H, OCH3), 3.60 (dt, 1H, J = 9.8, 2.7 Hz, H-5‴),
3.55 (d, 1H, J = 11.8 Hz, H-5), 3.26 (dd, 1H, J = 11.6, 9.6 Hz, H-5″″),
2.24 (s, 3H, CH3CO), 2.13 (s, 3H, CH3CO), 1.98 (s, 3H, CH3CO), 1.98
(s, 3H, CH3CO), 1.95 (s, 3H, CH3CO), 1.91 (s, 3H, CH3CO), 1.50 (s,
3H, CH3CO), 1.32 (d, 3H, J = 6.0 Hz, CH3), 1.21 (d, 3H, J = 6.2 Hz,
CH3), 1.15 (s, 9H, (CH3)3CCO), 1.11 (s, 9H, (CH3)3CCO), 1.10 (s,
9H, (CH3)3CCO). 13C NMR (125 MHz, CDCl3): δ (ppm) 177.4,
177.4, 176.4, 171.0, 170.8, 170.3, 170.1, 169.8, 169.3, 169.3, 165.4, 155.1,
151.4, 133.2, 130.3, 130.0, 128.5, 117.6, 114.9, 101.2, 100.7, 100.3, 99.3,
96.3, 80.41, 79.7, 74.2, 73.3, 72.3, 71.8, 71.8, 71.8, 71.6, 71.5, 71.5, 70.9,
70.0, 69.3, 69.1, 69.1, 68.0, 67.3, 66.5, 62.5, 61.1, 55.7, 38.9, 38.8, 38.8,
27.3, 27.2, 27.2, 21.5, 20.8, 20.7, 20.7, 20.7, 20.6, 20.3, 18.0, 16.3. HRMS
(ESI, m/z): calcd for [C71H100NO34] (M + NH4)+ 1510.61, found
1510.61.
based on the J3
value of 2.0 Hz. All glycosidic bonds were
H‑1′,H‑2′
confirmed as shown based on 1D and 2D NMR analysis (1H/13C). TLC
Rf: 0.73 (ethyl acetate/pentane 7:3). [α]20D = −31.45 (c = 12.4 mg/mL,
CHCl3). FTIR (powder, cm−1): 2972 (w), 2940 (w), 2874 (w), 1740
(s), 1507 (m), 1480 (w), 1452 (w), 1367 (m), 1215 (s), 1172 (m), 1140
(s), 1111 (s), 1061 (s), 1033 (s), 905 (m), 842 (m), 803 (w), 761 (w),
713 (m). 1H NMR (700 MHz, CDCl3): δ (ppm) 8.01−7.99 (m, 2H, o-
Bz), 7.59−7.56 (m, 1H, p-Bz), 7.46−7.44 (m, 2H, m-Bz), 6.96−6.93 (m,
2H, o-PMP), 6.88−6.85 (m, 2H, m-PMP), 5.42 (dd, 1H, J = 3.6, 1.8 Hz,
H-2′), 5.31 (dd, 1H, J = 2.8, 1.3 Hz, H-4″″), 5.21−5.18 (m, 4H, H-1′, H-
2″″, H-3″″, H-3‴), 5.11 (app t, 1H, J = 9.5 Hz, H-3″), 5.03−4.94 (m,
5H, H-1, H-2″, H-2‴, H-4″, H-4‴), 4.81 (app t, 1H, J = 3.9 Hz, H-1″″),
4.78 (d, 1H, J = 7.3 Hz, H-1‴), 4.72 (d, 1H, J = 7.8 Hz, H-1″), 4.17 (dd,
1H, J = 12.2, 2.0 Hz, H-6″), 4.13 (dd, 1H, J = 11.6, 5.5 Hz, H-5‴eq),
4.09−3.95 (m, 9H, H-2, H-3′, H-3, H-4′, H-4, H-5′, H-5ax, H-5″″, H-
6″), 3.78 (s, 3H, OCH3), 3.55 (ddd, 1H, J = 10.0, 2.5, 3.5, Hz, H-5″),
3.53 (dd, 1H, J = 12.0, 2.6 Hz, H-5eq), 3.29 (dd, 1H, J = 11.7, 9.6 Hz, H-
5‴ax), 2.26 (s, 3H, CH3CO), 2.18 (s, 3H, CH3CO), 1.98 (s, 3H,
CH3CO), 1.96 (s, 3H, CH3CO), 1.94 (s, 3H, CH3CO), 1.91 (s, 3H,
CH3CO), 1.68 (s, 3H, CH3CO), 1.30 (d, 3H, J = 6.2 Hz, CH3
rhamnose), 1.23 (d, 3H, J = 6.4 Hz, CH3 fucose), 1.15 (s, 9H,
(CH3)3CCO), 1.13 (s, 9H, (CH3)3CCO), 1.11(s, 9H, (CH3)3CCO).
13C NMR (125 MHz, CDCl3): δ (ppm) 177.41, 177.35, 176.5, 170.9,
p-Methoxyphenyl 2-O-[3′-O-(β-D-Glucopyranosyl)-4′-O-(β-D-xylo-
pyranosyl)-α-L-rhamnopyranosyl]-3-O-(β-D-fucopyranosyl)-α-L-ara-
binopyranoside (2). Pentasaccharide 11 (65.0 mg, 40.0 μmol) was
dissolved in methanol (1.30 mL), and potassium hydroxide (73.0 mg,
1.30 mmol) was added. The solution was stirred overnight at room
temperature and then acidified to neutral pH with Amberlite IR-120 H+
resin that had been rinsed with methanol. The solution was filtered, and
solvent was removed under reduced pressure to give approximately 50
mg of crude material. The crude isolate was purified by size-exclusion
chromatography using Bio Rad Bio-Gel P4 Gel (elution with H O). The
̅
2
product fractions were collected, and solvent was removed under
reduced pressure. The resulting white solid was azeotroped twice with
toluene and dried in vacuo to remove residual solvent before lyophilizing
to remove residual water and acetic acid. Compound 2 was isolated as a
white, amorphous solid (25.0 mg, 74%). Glycosidic linkages were
confirmed through analysis of the 2-D HMBC NMR spectrum. NMR
data were consistent with those reported for the isolated natural
product, with the exception of expected differences in the signals
corresponding to the arabinopyranosyl moiety.43 [α]20D = −30.24 (c =
8.40 mg/mL, CH3OH). 1H NMR (700 MHz, CD3OD): δ (ppm) 6.96−
6.94 (m, 2H, o-Ar), 6.85−6.83 (m, 2H, m-Ar), 5.21 (d, 1H, J = 1.7 Hz, H-
1′), 4.89 (d, 1H, J = 7.4 Hz, H-1), 4.68 (d, 1H, J = 7.8 Hz, H-1‴), 4.53 (d,
1H, J = 7.6 Hz, H-1″), 4.44 (d, 1H, J = 7.5 Hz, H-1″″), 4.33 (dd, 1H, J =
3.0, 1.9 Hz, H-2′), 4.12 (m, 1H, H-4), 4.10−4.07 (m, 1H, H-5′), 4.00
(dd, 1H, J = 9.1, 7.4 Hz, H-2), 3.93−3.90 (m, 2H, H-3′, H-5), 3.85 (dd,
1H, J = 12.0, 2.0 Hz, H-6″), 3.83−3.81 (m, 2H, H-3, H-5‴) 3.75 (s, 3H,
OCH3), 3.71−3.67 (m, 4H, H-4′, H-5″″, H-5, H-6″), 3.63 (d, 1H, J = 3.2
Hz, H-4″″), 3.57 (dd, 1H, J = 9.8, 7.5 Hz, H-2″″), 3.53 (dd, 1H, J = 9.8,
3.2 Hz, H-3″″), 3.48−3.44 (m, 1H, H-4‴), 3.33−3.28 (m, 4H, H-2″, H-
3″, H-4″, H-5″), 3.26 (app t, 1H, J = 9.1 Hz, H-3‴), 3.15 (app t, 1H, J =
11.0 Hz, H-5‴), 3.05 (dd, 1H, J = 9.3, 8.0 Hz, H-2‴), 1.28 (d, 3H, J = 6.2
Hz, CH3 rhamnose), 1.26 (d, 3H, J = 6.5 Hz, CH3 fucose). 13C NMR
(125 MHz, CD3OD): δ (ppm) 156.4, 152.4, 118.4, 115.6, 106.1, 105.2,
104.9, 102.4, 101.3, 84.6, 83.1, 78.9, 78.4, 78.1, 77.7, 76.5, 75.6, 75.3,
75.0, 72.9, 72.4, 71.8, 71.5, 71.4, 71.3, 69.9, 68.4, 67.0, 66.5, 62.5, 56.1,
18.4, 16.9. FTIR (νmax, neat, cm−1): 3260 (broad, w), 2919 (w), 1561
(m), 1507 (m), 1383 (m), 1218 (m), 1163 (m), 1063 (s), 1029 (s), 898
(m), 825 (m), 744 (m), 721 (m). HRMS (EI, m/z): calcd for
[C35H54NaO23] (M + Na)+ 865.2948, found 865.2957.
170.8, 170.2, 170.1, 169.9, 169.7, 169.3, 165.7, 155.2, 150.9, 133.3, 130.1,
130.0, 128.6, 117.9, 114.9, 101.0, 100.8, 99.3, 99.0, 96.6, 79.8, 79.6,
73.32, 73.26 (2 signals), 72.3, 71.8 (2 signals), 71.6, 71.5, 71.2, 70.5, 69.7,
69.3, 68.9, 67.8, 67.0, 66.9, 63.2, 62.6, 61.2, 38.9, 38.8 (2 signals), 27.29,
27.23, 27.19, 21.5, 20.9, 20.69, 20.67, 20.63, 20.5, 18.1, 16.1. HRMS
(DART, m/z): Calculated for C71H96O34 [M + NH4]+: 1510.6121;
Found: 1510.6115.
para-Methoxyphenyl 3-O-(2′, 3′, 4′-Tri-O-acetyl-β-D-fucopyrano-
syl)-4-O-[2″-O-benzoyl-3″-O-(2‴,3‴,4‴,6‴-tetra-O-acetyl-β-D-gluco-
pyranosyl)-4″-O-(2″″,3″″,4″″-tris-O-(trimethylacetyl)-β-D-xylopyra-
nosyl)-α-L-rhamnopyranosyl]-α-L-arabinopyranoside (12, Side Prod-
uct Obtained from Coupling of 3e and 4a). Donor 3e and acceptor 4a
were each dried via azeotropic removal of water with toluene and placed
under high vacuum for 6 h to remove residual solvent prior to use.
Compounds 3e (79.0 mg, 70.0 μmol) and 4a (26.5 mg, 50.0 μmol) were
dissolved in anhydrous CH2Cl2 (0.250 mL) in an oven-dried round-
bottom flask equipped with a stir bar under an atmosphere of argon. The
reaction was cooled to −78 °C, and a freshly prepared 0.10 M solution of
TMSOTf in anhydrous CH2Cl2 was added with slow dropwise addition
(50.0 μL, 5.00 μmol) to the reaction flask to give a faint yellow solution.
The reaction was stirred at −78 °C for 45 min and then quenched by
addition of excess triethylamine. Solvent was removed under reduced
pressure, and the crude isolate was purified by flash chromatography
gradient elution from 20% to 50% ethyl acetate in pentanes) to yield
I
DOI: 10.1021/acs.joc.5b00950
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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(16) De Tommasi, N.; Piacente, S.; Gacs-Baitz, E.; De Simone, F.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b00950.
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110, 2662.
(18) Fraser-Reid, B.; Konradsson, P.; Mootoo, D. R.; Udodong, U. J.
Chem. Soc., Chem. Commun. 1988, 823.
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A.; Sucheck, S. J. J. Am. Chem. Soc. 2010, 132, 17236.
1H and 13C NMR spectra of new compounds, copies of
HPLC chromatograms, and a table comparing the H
NMR chemical shift data for compounds 2 and 1a (PDF)
1
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(21) Dimitrijevic, E.; Taylor, M. S. Chem. Sci. 2013, 4, 3298.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mtaylor@chem.utoronto.ca.
Notes
(22) Yang, Q.; Lei, M.; Yin, Q.-J.; Yang, J.-S. Carbohydr. Res. 2007, 342,
1175.
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(23) Williams, J. M.; Richardson, A. C. Tetrahedron 1967, 23, 1369.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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(27) Bohe, L.; Crich, D. Trends Glycosci. Glycotechnol. 2010, 22, 1.
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Financial support from NSERC (Discovery Grants and Canada
Research Chairs programs), Boehringer Ingelheim (Canada)
Ltd., the A. P. Sloan Foundation, the Province of Ontario (Early
Researcher Award), and the Canada Foundation for Innovation
(Project Nos. 17545 and 19119) is gratefully acknowledged.
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