A scalable approach to obtaining orthogonally protected β-d-idopyranosides

Article abstract of DOI:10.1021/jo300764k

A practical method to obtain orthogonally protected d-idopyranose from d-galactose has been developed, which is the first method to enable synthesis of the challenging β-d-idopyranoside linkage. The method relies on a key double inversion at O-2 and O-3 in an easily prepared d-galactose derivative, which proceeds regio- and stereoselectively through a 2,3-anhydrotalopyranoside; reaction using a selection of alkoxides affords exclusively the 3-O-alkylidopyranoside, which can be used to generate an orthogonally protected monosaccharide. The process is scalable and requires minimal purification, so it could be used to produce building blocks to aid in the synthesis of various β-idopyranose-containing oligosaccharide targets to further probe their biological functions.

Full text of DOI:10.1021/jo300764k

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pubs.acs.org/joc
A Scalable Approach to Obtaining Orthogonally Protected β-D-
Idopyranosides
Rachel Hevey, Alizee Morland, and Chang-Chun Ling*
́
Alberta Glycomics Centre, Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4,
Canada
S
* Supporting Information
ABSTRACT: A practical method to obtain orthogonally
protected D-idopyranose from D-galactose has been developed,
which is the first method to enable synthesis of the challenging
β-D-idopyranoside linkage. The method relies on a key double
inversion at O-2 and O-3 in an easily prepared D-galactose
derivative, which proceeds regio- and stereoselectively through
a 2,3-anhydrotalopyranoside; reaction using a selection of
alkoxides affords exclusively the 3-O-alkylidopyranoside, which
can be used to generate an orthogonally protected
monosaccharide. The process is scalable and requires minimal purification, so it could be used to produce building blocks to
aid in the synthesis of various β-idopyranose-containing oligosaccharide targets to further probe their biological functions.
groups on the sugar ring. Upon deprotection, these sites can be
further modified to yield the desired product. The generation of
orthogonally protected monosaccharide units also allows for
the same building blocks to be used in the syntheses of various
oligosaccharide targets with improved efficiency.3
INTRODUCTION
■
Ido-configured sugars have unique conformational properties
due to the high energy chair conformation which most other
sugars adopt because the 2-, 3-, and 4-O-substituents are forced
to adopt an axial orientation. As a result, the L-iduronic acids
(Figure 1a), naturally abundant in heparin, heparan, and
Although the ability to obtain orthogonally protected idose
units has been recognized as a significant synthetic challenge
because of its unique conformational and chemical properties,
efforts to obtain the L-series of orthogonally protected building
blocks has recently seen some progress.4−10 An early method
beginning from D-glucuronolactone was developed by Wong et
al. that produced orthogonally protected L-iduronic acid in
eight steps; the method relied on a key inversion at C-5 that
was achieved via radical bromination of methyl 1,2,3,4-tetra-O-
acetyl-α- or β-D-glucopyranuronate and a subsequent stereo-
selective reduction using tributyltin hydride to afford the
desired L-ido configuration over the D-gluco in a 2:1 ratio for the
α-anomer and a 3:1 ratio for the β-anomer;9 the isolated
tetraacetates of methyl α- or β-L-idopyranuronates were both
converted to the 1,2-acetal-protected derivative on the basis of
previous work done by the Seeberger group;11 the 3,4-di-O-
acetate was selectively deprotected at O-3 and then reprotected
with a benzoyl or pivaloyl group to give the orthogonally
protected methyl L-idopyranuronates.
Figure 1. Examples of L-iduronic acid and 6-deoxy-D-ido-heptopyrano-
side found in heparin (a) and C. jejuni capsular polysaccharides (b).
1
4
dermatan sulfates, often interconvert rapidly between C4, C1,
2
and SO because of the low energy barrier between conforma-
tional isomers.1 These glycosaminoglycans (GAGs) have
generated interest because of their bioactivity and mediation
of various physiological processes such as cell growth and
differentiation and blood coagulation.2 Because of the diversity
of GAG oligosaccharides obtained from natural sources, it is
often difficult to determine which fragments are responsible for
mediating activity; therefore, the synthesis of well-defined
derivatives has been pursued in order to better understand the
structure−activity relationship. As a result, a method to control
the sulfation through chemical synthesis is necessary; this can
be achieved with orthogonal protection of the five hydroxyl
An alternate route was published by Whitfield et al. involving
a seven-step synthesis beginning from 1,2-O-isopropylidene-
6,3-D-glucuronolactone,7,8 which is an expensive starting
material; the synthesis involved the activation of OH-5 via 5-
triflate followed by a C-5 inversion with pivalate, and the
obtained 1,2-O-isopropylidene-6,3-L-iduronolactone was then
Received: April 13, 2012
Published: July 3, 2012
© 2012 American Chemical Society
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converted to the methyl ester, which was accompanied by a
concomitant pivaloyl migration from O-5 to O-3; unfortu-
nately, multiple low-yielding reactions (a 13% yield four-step
sequence) were followed during the subsequent transformation
of furanose to the pyranose, and a 2,4-di-O-acetyl-3-O-pivaloyl-
protected imidate glycosyl donor was eventually obtained as an
α/β mixture (73%), which showed good glycosylation
properties to provide α-linked disaccharides in 64−85% yields;
the neighboring-group participation at O-2 (Ac) provided
excellent stereocontrol during glycosylations. A third method of
obtaining orthogonally protected L-idose from Hung et al.
utilizes diacetone α-D-glucose and involves seven steps but
involves a low-yielding inversion step at a late stage of the
synthesis.4,5,12 In addition, the protecting group at O-3 is
restricted to a benzyl ether, and the groups at O-2 and O-6 are
restricted to ester linkages.
Scheme 1. Efficient, Scalable Method To Obtain
Orthogonally Protected D-Idose from D-Galactose
While efforts to obtain the L-idose and derivatives through
chemical synthesis have progressed over the past decade, the
exploration of routes to obtain orthogonally protected D-idose
has been extremely limited. Although much less prevalent, D-
ido-configured sugars have garnered interest in library screening
studies for bioactivity,13−15 and their potential utility arguably
remains underexplored. The recently identified capsular
polysaccharide (CPS) structure of Campylobacter jejuni
(serotype HS:4, strain CG8486) contains a 6-deoxy-β-D-ido-
heptopyranose (Figure 1b, partially modified by O-methyl
phosphoramidate at O-2/O-7) as part of a repeating
disaccharide unit,16 which could potentially elicit an important
immunological response owing to its unique nature; it could
potentially redirect the immune response and subsequently
several other side products. To improve the yield, they followed
an alternate route by starting from the methyl 4,6-O-
benzylidene-2-O-tosylgalactopyranoside (prepared from the
methyl galactoside via a five step protection−deprotection
sequence21) and carried out a base-catalyzed detosylation. The
epoxide 4 was then converted to the desired methyl 3-O-
methyl-β-D-idopyranoside in a separate treatment with sodium
methoxide in hot methanol (49% yield over 2 steps); the
reaction also afforded a tiny amount of methyl 2-O-methyl-β-D-
galactopyranoside as a side product (<0.01%). Recently,
Frahn22 reported that when the 2,3-di-O-tosylate 3 was treated
with sodium methoxide in dioxane, the talo-epoxide 4 was
isolated in 66% yield after 4 h at room temperature, while the
methyl 3-O-methyl-β-D-idopyranoside was isolated in 12%
yield. By thin layer chromatography (TLC) the author also
observed that the amount of the idopyranoside increased
progressively over time, but no further information was
provided.
The synthesis of oligosaccharide analogues related to the
CPS of C. jejuni requires access to orthogonally protected β-D-
idopyranosides. It appears that the only route which would
easily allow for such protected products is the approach
established by Wiggins,20 although their limited study only
examined the formation of di-O-methyl protected idopyrano-
sides, and unfortunately the lack of selectivity and harsh
conditions required for cleavage of these methyl ethers severely
limits the use of these compounds for subsequent chemical
modifications. However, the general scope and applicability of
the approach to other nucleophiles and substrates was not
known, so we decided to examine the feasibility of developing
such an approach to become a general method for synthesizing
D-idopyranoside-containing oligosaccharides (Scheme 1). In-
deed, preliminary results indicated that under optimized
reaction conditions, the 4,6-O-benzylidene-3-O-methyl-β-D-
idopyranoside could be directly obtained in a much improved
yield (66%) from either 2,3-di-O-tosylate (3) or 2,3-di-O-
mesylate (2, Scheme 1).
́
decrease the risk of Guillain−Barre syndrome, which has been
associated with antibody production against C. jejuni lip-
opolysaccharide.17−19 The characteristic feature in the repeating
disaccharide unit of the CPS is the presence of a β-linked idose
glycosyl unit which presents a considerable synthetic challenge.
Unfortunately, all above-mentioned methods for L-idose are
designed to form α-glycosidic linkages thus no method has yet
been able to accommodate a β-glycosidic bond formation in
idose chemistry. It is also difficult to take advantage of the
anchimeric assistance strategy or the anomeric effect to prepare
such glycosidic linkage. The development of orthogonally
protected D-idose units is the key to facilitate subsequent O-3
glycosylation and C-6 chain extension for the 6-deoxy-β-D-ido-
heptopyranose synthesis, and the obtained results would enable
access to a variety of D-idose-containing oligosaccharides that
could be used in conjugate vaccines to better probe the
potential immune response generated by this unique C. jejuni
CPS structure. In addition, the developed orthogonal
protecting strategy could allow for a selective modification
with the phosphoramidate group at O-2 or O-7 position of the
generated 6-deoxy-β-D-ido-heptopyranose.
RESULTS AND DISCUSSION
■
Although a few efforts have been designed to obtain the
unusual D-ido-pyranose configuration, a general and widely
applicable method to synthesize β-D-idopyranosides is not
available. Wiggins et al. briefly investigated the synthesis of a
methyl 3-O-methyl-β-D-idopyranoside in 1944:20 methyl 4,6-O-
benzylidene-2,3-di-O-tosyl-β-D-galactopyranoside (3, Scheme
1) was treated with sodium methoxide in refluxing methanol
to obtain a complex mixture containing methyl 3-O-methyl-β-D-
idopyranoside (32% yield) and methyl 2,3-anhydro-4,6-O-
benzylidene-β-D-talopyranoside (4, 4.1% yield), together with
Reaction of the disulfonates with benzyloxide in benzyl
alcohol-dioxane at room temperature provided directly the
desired methyl 3-O-benzyl-4,6-O-benzylidene-β-D-idopyrano-
side 5 as the only product isolated in modest yields (47%);
no 2-O-benzyl substituted galactopyranoside byproduct was
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Scheme 2. Proposed Mechanism of Diinversion To Afford D-Idose from D-Galactose
4
1
Figure 2. C1, C4, and OS2 conformations of methyl β-D-idopyranoside.
detected. Although TLC indicated that only a single product
had formed during the reaction, difficulty in removing the
excess benzyl alcohol resulted in a lower purified yield than
what had been observed previously for the reaction with
methoxide. In switching to a more volatile alcohol, treatment of
the sulfonates with allyloxide in either allyl alcohol-dioxane or
allyl alcohol-benzene also afforded the desired 3-O-allylated β-
D-idopyranoside analogue 6 exclusively which was isolated in a
greatly improved yield (79%). Although isomerization of allyl
ethers has often been reported to occur in strong base, this was
not observed under the described reaction conditions, likely a
result of the above reaction proceeding at room temperature.
This method is highly desirable because it is easily scalable; we
were able to perform all steps toward the preparation of 5 and 6
in greater than 10 g quantities, and in addition, the reaction
sequence could be carried through from 1 to ido-configured 5
or 6 with only a single column chromatography purification
required after the final di-inversion step. The subsequent 2-O-
benzylation of 5 afforded the 2,3-di-O-benzylated compound 7
in 80% yield, and the 4,6-benzylidene was subsequently
removed in 80% acetic acid−water to provide the correspond-
ing diol 8 (86% yield).
77% yield. The primary 6-OH group could be further
regioselectively modified, which should provide an intermediate
that has the remaining three secondary positions orthogonally
protected; through protecting group manipulations, each
position can be accessed selectively.
The interesting regio- and stereoselectivity observed in the
key di-inversion reaction results from selective attack of the
alkoxide at the sulfur center of the 3-sulfonate to effectively
cleave the S−O bond and produce the O-3 anionic sugar A,
which can then undergo an intramolecular attack to afford the
2,3-anhydro-taloside 4 (Scheme 2); this type of S−O cleavage
has been previously observed and confirmed through 18O-
labeling base-catalyzed hydrolysis reactions.23−26 Upon oxirane
formation, selective attack at C-3 by the nucleophile results in
the diaxial products 5/6, which are preferred over the
diequatorial products because of their lower energy transition
states (a consequence of the Furst-Plattner rule). Our improved
̈
regioselectivity in epoxide opening as compared to the previous
attempt discussed earlier by Wiggins et al.20 likely results from
performing the reaction at room temperature instead of at
reflux, to afford a better yield of the kinetic product.
Although no galactoside byproduct was observed in any of
our reactions, in a few attempts a trace amount of the methyl
2,3-anhydro-4,6-O-benzylidene-β-D-guloside (11) was isolated
(2% yield); this could result from attack of the 2-sulfonate (→
B) to produce the diastereomeric epoxide (11). Theoretically,
the alkoxide could attack this regioisomer to afford the 2-O-
alkyl-idopyranoside; however, this byproduct was never
Furthermore, this method also provides an opportunity to
introduce orthogonal protecting groups onto the β-D-
idopyranoside. For example, starting from compound 6 which
has a 3-O-allyl protecting group, O-benzylation at the O-2
position was carried out; compound 9 which has the O-2 and
O-3 differentially protected was obtained in 77% yield, and we
subsequently removed the 4,6-benzylidene protecting group in
a similar manner as 7 to afford the corresponding 4,6-diol 10 in
1
observed in the crude H NMR. This was likely a result of
2,3-anhydro-D-gulo- and talopyranosides preferring to adopt an
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Scheme 3. Reaction of Sodium Methoxide with Methyl 4,6-O-Benzylidene-2,3-di-O-mesylgalactopyranoside 14
OH5 half-chair conformation; the OH5 conformation can be
confirmed via 1H NMR coupling constants between vicinal H-1
and H-4 protons: a very small coupling constant (<1.5 Hz)
when the relationship is trans, and a slightly larger coupling
constant (<5.6 Hz) when the relationship is cis.27,28 It was
was obtained in two steps from methyl α-D-galactopyrano-
side,31,32 and then reacted with sodium methoxide solution at
room temperature (Scheme 3). After several days a mixture of
talo- (15) and gulo-epoxides (16) were isolated; the lack of
further nucleophilic attack to open the epoxide could be
explained by the unfavorable 1,3-diaxial-type interactions that
prevent approach of the nucleophile at both the C-2 and C-3
positions. A previous attempt to form epoxides from similar
conditions also resulted in a mixture of gulo- and talo-
epoxides,24 suggesting that although nucleophilic attack on
these isomers has been observed to be stereospecific (at
elevated temperatures) to give the expected diaxial products,29
the poor stereoselectivity observed for epoxide formation from
the dimesylate suggests that using our approach in α-
galactoside will not be as successful as in the β-isomers.
O
previously demonstrated that in this preferred H5 conforma-
tion, the approach of a nucleophile to attack the epoxide ring is
significantly more sterically hindered in the gulo- as compared
to the talo-stereoisomer;27−30 this interference of approach of
the nucleophile could prevent the gulo-epoxide from reacting at
room temperature. This decreased reactivity was confirmed by
reacting the gulo-epoxide (11) with sodium methoxide: after
several days at room temperature and even heating at 70 °C for
18 h, it was found that the reaction did not go to completion.
Upon workup, the crude 1H NMR indicated only partial
conversion to the methyl 4,6-O-benzylidene-2-O-methylidopyr-
anoside 12 as the exclusive new product, present with the
remaining starting material (1:2 ratio of gulo-:ido-).
To further probe the requirements of the anomeric center,
several other O-glycosides and S-glycosides were synthesized
(Scheme 4). For example, 4,6-O-benzylidenated allyl β-D-
Success in obtaining the idose structure was confirmed using
NMR methods, since its unique 3JH,H coupling constants can be
used to infer its conformational preferences. Small coupling
Scheme 4. Formation of a D-Idose Derivative from Allyl 4,6-
O-Benzylidene-2,3-di-O-mesylgalactoside 18 and β-D-
Thiogalactosides 21 and 25
3
3
3
constants observed for JH‑1,H‑2, JH‑2,H‑3, and JH‑3,H‑4 indicate
small dihedral angles which suggests that the β-idopyranoside
prefers to adopt a 4C1 chair over a 1C4 chair, although in some
compounds coupling has been observed between H-2 and H-4
which suggests that these structures likely fluctuate from 4C1 to
other nonchair conformations, such as OS2 (Figure 2).1,28,29
Although methyl 4,6-O-benzylidene-α-D-idopyranose has been
observed to prefer the 4C1 conformation, which is stabilized by
intramolecular H-bonding between OH-2 and O-4 and likely
also between OH-3 and O-1, the β-epimer has a large 3JH‑2,OH‑2
coupling constant (11.5−12.1 Hz) which suggests an
antiperiplanar orientation (based on the Karplus curve)
between OH-2 and H-2.28 This also supports the preference
for adopting a skew conformation in which H-bonding to O-4
would be unfavorable, although the possibility of OH-2 and O-
1 H-bonding exists instead, as previously discussed by Perlin et
al.28
In an effort to better understand the scope of the reaction, a
study of which types of nucleophiles were appropriate for the
transformation was undertaken. Simple alkoxides appear most
successful (methoxide, allyloxide, benzyloxide), and the use of a
thiolate (thiomethoxide, thioethoxide) resulted in a quantitative
recovery of starting material after several days at room
temperature. This suggests that an anionic oxygen is more
effective at cleaving the S−O bond, although the cleavage of a
sulfonate linkage via attack on the sulfur center by
thiophenoxide has been reported in literature.23
galactopyranoside (17)33 was mesylated to obtain the desired
target 18, which upon reaction with potassium benzyloxide,
afforded exclusively the desired allyl 3-O-benzyl-4,6-O-benzyli-
dene-β-D-idopyranoside 19 in 71% yield. On the other hand,
reactions with β-D-thioglycoside analogues 2034 and 2435 were
much less successful (Scheme 4). When the dimesylate (21) of
ethyl thioglycoside 20 was treated with allyloxide in an allyl
alcohol−dioxane mixture, the desired 3-O-allyl β-D-thioidopyr-
anoside 22 was obtained in 33% yield together with 23 (20%
yield) which bears a 3-thioethyl group; alternatively, when the
Next, the effect of the anomeric linkage was probed by first
studying its stereochemical requirements. Synthesis of methyl
4,6-O-benzylidene-2,3-di-O-mesyl-α-D-galactopyranoside 14
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Scheme 5. Synthesis of Two D-Idose-Containing Disaccharides
Scheme 6. Deprotection Scheme for Disaccharide 39
dimesylate (25) from p-chlorophenyl thioanalogue 24 was
subjected to the same reaction conditions, no desired product
was obtained, but the reaction indeed afforded an analogous 3-
thio-p-chlorophenyl-substituted byproduct (26) and other
unidentified elimination products. Clearly the byproducts 23
and 26 must be obtained via an interesting intermolecular
attack by thioethyl or thio-p-chlorophenyl on the intermediate
2,3-anhydrotaloside in each case; the increased nucleophilicity
of the anomeric sulfur atom over negatively charged allyloxide
is likely to account for the observed byproduct formation.
To further appreciate the scope of the reaction and also
demonstrate that this indeed was a suitable method for
installing β-ido-glycosidic linkages, we prepared two β-D-ido-
(1→4)-β-D-GlcNAc disaccharide analogues related to C. jejuni
CPS (Scheme 5). Thus, starting from the previously known D-
glucosamine thioglycoside 27,35 we protected the O-3 position
with benzyl (→28, 90% yield). After regioselective opening of
the 4,6-O-benzylidene acetal group using triethylsilane, the
alcohol 29 was obtained (86% yield). Boron trifluoride
etherate-mediated activation of the imidate donor 3036 enabled
the glycosylation reaction with 29 to afford the desired
thiodisaccharide 31 in 80% yield (based on recovered glycosyl
acceptor). The thioglycoside was then deacetylated via
for this intermediate compound. Fortunately, heating the
product in acetic anhydride and pyridine restored the
phthalimido group to afford the desired acetylated product
34 in 76% yield, with a few minor byproducts indicated by thin
layer chromatography. Based on the previous observations
made for the monosaccharides, one of the byproducts observed
for this transformation may have been due to the nucleophilic
thioglycoside, although the effect of the thio-linkage in this
latter instance was much less detrimental to the di-inversion
reaction than what had been observed previously. A subsequent
deacetylation of the OH-2′ position provided alcohol 35 which
was fully characterized by 1D 1H, 13C, and 2D GCOSY,
GHSQC NMR experiments as well as high-resolution mass
spectrometry.
Alternatively, the thioglycoside 31 was converted to an O-
methyl glycoside 36 via a subsequent N-iodosuccinimide/triflic
acid-mediated glycosylation reaction with methanol. Deacety-
lation of the methyl glycoside afforded diol intermediate 37,
which gave the target compound 38 after a dimesylation;
treatment of 38 with benzyloxide afforded the desired β-D-
idopyranosyl substituted disaccharide, which had the phthali-
mido group partially opened as before; again, acetylation was
necessary to restore the integrity of the phthalimido-protecting
group to afford the desired product 39 in 75% yield over two
steps; in this instance with the O-glycoside, no other
byproducts were observed in these 2 reactions. Interestingly,
the half-width of the phthalimido peaks in the 13C NMR varied
greatly between the O-glycoside and the S-glycoside analogues.
The half-widths were observed to be significantly greater for the
O-glycosides, indicating that in these compounds the
phthalimido carbons were more sterically restrained resulting
in their faster relaxation times.37 This could be a result of the
Zemplen transesterification to afford intermediate diol 32
́
which was directly di-O-mesylated to afford compound 33. The
reaction of the dimesylate with allyloxide afforded a
disaccharide with the expected 3′-O-allyl-substituted β-D-
idopyranosyl unit. Interestingly, due to the sensitivity of the
phthalimido-protecting group to strong bases, partial cleavage
of this N-protecting group occurred upon alkoxide treatment to
produce the corresponding carboxylic acid derivative, which
became evident by the significant increase in polarity observed
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1H, H-4), 3.89 (dd, 1H, J = 2.9, 2.9 Hz, H-3), 3.77 (m, 1H, H-2), 3.75
shorter anomeric C−O bond which results in a more restricted
C−N bond rotation for the phthalimido group.
(m, 1H, H-5), 3.59 (s, 3H, CH3), 3.16 (d, 1H, J = 11.7 Hz, 2-OH). 13
C
NMR (CDCl3, 100 MHz): δ 137.6 (Ph), 137.5 (Ph), 129.4 (Ph),
128.8 (Ph), 128.5 (Ph), 128.4 (Ph), 127.8 (Ph), 126.3 (Ph), 101.7
(PhCH), 100.5 (C-1), 76.8 (C-3), 73.8 (C-4), 72.8 (PhCH2), 69.9 (C-
6), 67.3 (C-2), 67.0 (C-5), 57.2 (CH3). HRMS (ESI): calcd m/z for
C21H24O6 (M + Na)+ 395.1465, found 395.1464.
The O-linked disaccharide 39 was then deprotected (Scheme
6) via hydrogenation to concomitantly remove both the
benzylidene acetal and benzyl groups (→41). This intermediate
was then subjected to hydrazine hydrate which simultaneously
removed the phthalimido and acetyl groups;38 the product was
not isolated but instead fully acetylated to afford 42, which
upon a selective de-O-acetylation provided the final depro-
tected product 43 in 62% yield over the four-step deprotection
sequence. It was found that the β-D-idopyranosyl linkage is
somewhat sensitive to acidic conditions, thus full acetylation in
pyridine (basic) was performed instead of using more direct
Ac2O−MeOH condition (acidic) for selective N-acetylation.
Methyl 3-O-Allyl-4,6-O-benzylidene-β-D-idopyranoside (6). A
solution of potassium tert-butoxide in allyl alcohol (3.23 M, 52 mL,
0.17 mmol) was added to a solution of the ditosylate starting material
3 (11.06 g, 18.72 mmol) in benzene (150 mL). After 4 days, the
reaction mixture was evaporated to dryness, redissolved in ethyl
acetate (200 mL), washed with saturated sodium chloride solution (2
× 200 mL) and water (1 × 200 mL), dried with sodium sulfate,
filtered, and evaporated to dryness. The crude mixture was purified by
column chromatography on silica gel using 25% ethyl acetate−hexanes
to afford the pure product as a white solid (4.77 g, 14.8 mmol, 79%
yield). Rf 1= 0.49 (ethyl acetate/toluene 1:1). [α]20D: −55.5° (c 1.01,
CHCl3). H NMR (400 MHz, CDCl3) δ 7.46−7.41 (m, 2H, Ph),
7.32−7.27 (m, 3H, Ph), 5.84 (dddd, 1H, J = 17.1, 10.5, 5.6, 5.6 Hz,
CH2CHCH2), 5.46 (s, 1H, PhCH), 5.25 (dddd, 1H, J = 17.2, 1.5,
1.5, 1.5 Hz, CH2CHCH2), 5.18 (dddd, 1H, J = 10.4, 1.3, 1.3, 1.3 Hz,
CH2CHCH2), 4.62 (d, 1H, J = 0.6 Hz, H-1), 4.33 (dd, 1H, J = 12.5,
1.3 Hz, H-6a), 4.08 (dddd, 1H, J = 12.8, 5.6, 1.4, 1.4 Hz, CH2CH
CH2), 4.04 (dddd, 1H, J = 12.9, 5.4, 1.4, 1.4 Hz, CH2CHCH2), 4.04
(dd, 1H, J = 12.6, 1.6 Hz, H-6b), 3.95 (m, 1H, H-4), 3.77 (dd, 1H, J =
2.9, 2.9 Hz, H-3), 3.69 (m, 2H, H-2 and H-5), 3.55 (s, 3H, OCH3),
3.14 (d, 1H, J = 11.7 Hz, 2-OH). 13C NMR (CDCl3, 100 MHz): δ
137.4 (Ph), 133.9 (CH2CHCH2), 129.2 (Ph), 128.3 (Ph), 126.1
(Ph), 117.9 (CH2CHCH2), 101.5 (PhCH), 100.4 (C-1), 76.3 (C-
3), 73.7 (C-4), 71.5 (CH2CHCH2), 69.7 (C-6), 67.2 (C-2 or C-5),
66.8 (C-2 or C-5), 57.0 (OCH3). HRMS (ESI): calcd m/z for
C17H22O6 (M + Na)+ 345.1309, found 345.1306. Anal. Calcd for
C17H22O6: C, 63.34; H, 6.88. Found: C, 63.26; H, 6.87.
CONCLUSIONS
■
In conclusion, we have developed a practical method to obtain
D-idopyranose from D-galactose, which is the first approach that
enables access to orthogonally protected D-idose. In addition, it
is the first method to allow for the synthesis of oligosaccharides
containing the challenging β-1,2-cis-linked idopyranosides. The
key double inversions of galactose at O-2 and O-3 were
achieved through the regio- and stereoselective opening of 2,3-
anhydro talopyranosides using a selection of alkoxides, and the
process is scalable and requires minimal purification, so could
be used to produce building blocks to aid in the synthesis of
various β-idopyranose-containing oligosaccharide targets to
further probe their biological functions.
EXPERIMENTAL SECTION
■
Methyl 2,3-Di-O-benzyl-4,6-O-benzylidene-β-D-idopyranoside (7).
The starting material 5 (1.000 g, 2.68 mmol) was dissolved in dry
tetrahydrofuran (10.0 mL), and then the solution was cooled to 0 °C
using an ice−water bath. Sodium hydride (57−63% oil dispersion, 225
mg, 5.62 mmol) was added in a portionwise fashion, followed by
benzyl bromide (0.42 mL, 3.5 mmol) which was also added
portionwise over 10 min. The mixture was warmed to room
temperature and then allowed to mix under argon overnight. The
reaction was quenched via the addition of methanol (3 mL),
evaporated to dryness, and then redissolved in ethyl acetate (120
mL). The organic phase was washed with saturated aqueous sodium
chloride solution (2 × 120 mL) and water (1 × 120 mL), dried with
sodium sulfate, filtered, and evaporated to dryness. The crude mixture
was purified by column chromatography on silica gel using 20% ethyl
acetate−hexanes to afford the desired product as a yellow syrup (990
General Methods. All commercial reagents were used as supplied
unless otherwise stated. Thin-layer chromatography was performed on
silica gel 60-F254 with detection by fluorescence, charring with 5%
aqueous sulfuric acid, or a ceric ammonium molybdate solution.
Column chromatography was performed on silica gel 60, and solvent
gradients given refer to stepped gradients and concentrations are
reported as % v/v. Organic solutions were concentrated and/or
evaporated to dryness under vacuum in a water bath (<60 °C).
Molecular sieves were stored in an oven at 100 °C and flame-dried
under vacuum before use. Amberlite IR-120H ion-exchange resin was
washed multiple times with methanol prior to use. Optical rotations
were determined in a 5 cm cell at 20 2 °C; [α]20D values are given in
units of 10−1 deg·cm2/g. NMR spectra were recorded at either 400 or
600 MHz (as indicated), and the first-order proton chemical shifts δH
and δC are reported in δ (ppm) and referenced to residual CHCl3 (δH
7.24 and δC 77.23, CDCl3) or CD2HOD (δH 3.31, δC 49.15, CD3OD).
1H and 13C NMR spectra were assigned with the assistance of 2D
GCOSY, 2D GTOCSY, 2D GHSQC, 2D GHMBC, 1D TOCSY, and/
or 1D HMBC experiments. High-resolution mass spectra were
recorded using ESI-QTOF LC/MS mass spectrometry.
mg, 2.14 mmol, 80% yield). Rf = 0.66 (acetone/hexanes 4:6). [α]20
:
D
−24.1 (c 0.99, CHCl3). 1H NMR (CDCl3, 400 MHz) δ: 7.61 (dd, 2H,
J = 7.6, 1.8 Hz, PhCH), 7.45−7.29 (m, 13H, Ph), 5.55 (s, 1H, PhCH),
4.90 (d, 1H, J = 12.0 Hz, PhCH2), 4.80 (d, 1H, J = 1.4 Hz, H-1), 4.71
(d, 1H, J = 12.1 Hz, PhCH2), 4.65 (d, 1H, J = 12.3 Hz, PhCH2), 4.62
(d, 1H, J = 12.2 Hz, PhCH2), 4.41 (dd, 1H, J = 12.5, 0.9 Hz, H-6a),
4.10 (dd, 1H, J = 12.5, 2.0 Hz, H-6b), 4.02−3.99 (m, 2H, H-3 and H-
4), 3.73 (m, 1H, H-5), 3.70 (m, 1H, H-2), 3.64 (s, 3H, OMe). 13C
NMR (CDCl3, 100 MHz) δ: 138.7 (Ph), 138.2 (Ph), 137.6 (Ph),
128.8 (Ph), 128.5 (Ph), 128.03 (Ph), 127.96 (Ph), 127.93 (Ph),
127.65 (Ph), 127.59 (Ph), 127.2 (Ph), 126.8 (Ph), 101.2 (PhCH),
100.6 (C-1), 76.5 (C-3), 73.8 (C-2), 73.2 (C-4), 72.9 (PhCH2), 72.3
(PhCH2), 69.6 (C-6), 66.6 (C-5), 56.6 (OMe). HRMS (ESI): calcd
m/z for C28H30O6 (M + Na)+ 485.1935, found 485.1934.
Methyl 3-O-Benzyl-4,6-O-benzylidene-β-D-idopyranoside (5). A
solution of potassium tert-butoxide in benzyl alcohol (2.07 M, 5.0 mL,
10.3 mmol) was added to a solution of the ditosylate starting material
3 (1.099 g, 1.86 mmol) in 1,4-dioxane (15 mL). After 2 days, the
reaction mixture was evaporated to dryness via coevaporation with
water (2 × 20 mL), redissolved in ethyl acetate (100 mL), washed with
water (3 × 100 mL), dried with sodium sulfate, filtered, and
concentrated under reduced pressure to a viscous syrup. The crude
mixture was purified by column chromatography on silica gel using
10→15→18% ethyl acetate−hexanes to afford the pure product as a
yellow syrup (323 mg, 0.868 mmol, 47% yield). Rf = 0.82 (ethyl
acetate/toluene 1:1). [α]20D: −35.0 (c 1.04, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ 7.47 − 7.44 (m, 2H, Ph), 7.37−7.29 (m, 8H,
Ph), 5.48 (s, 1H, PhCH), 4.69 (d, 1H, J = <1 Hz, H-1), 4.66 (d, 1H, J
= 11.8 Hz, PhCH2), 4.62 (d, 1H, J = 11.8 Hz, PhCH2), 4.38 (dd, 1H, J
= 12.5, 1.4 Hz, H-6a), 4.07 (dd, 1H, J = 12.5, 1.9 Hz, H-6b), 4.01 (m,
Methyl 2,3-Di-O-benzyl-β-D-idopyranoside (8). The starting ma-
terial 7 (243 mg, 0.526 mmol) was dissolved in acetic acid (2.0 mL)
and water (0.5 mL) and heated at 60 °C. After 3 h, the mixture was
concentrated and coevaporated with toluene (3 × 2 mL). The crude
mixture was purified by column chromatography on silica gel using
15→20% acetone−hexanes to afford the desired product as a yellow
syrup (169 mg, 0.451 mmol, 86% yield). Rf = 0.37 (acetone/hexanes
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1
4:6). [α]20D: −71.0 (c 1.04, CHCl3). H NMR (CDCl3, 400 MHz): δ
(C-4), 63.0 (C-6), 57.3 (CH3). HRMS (ESI): calcd m/z for C17H24O6
(M + Na)+ 347.1465, found 347.1464.
Methyl 2,3-Anhydro-4,6-O-benzylidene-β-D-gulopyranoside (11).
The byproduct 11 was isolated as a white solid in trace amounts (2%)
in a few instances during the synthesis of 6; the data collected agrees
with published literature.30,39
7.34−7.26 (m, 8H, Ph), 7.22−7.18 (m, 2H, Ph), 4.83 (d, 1H, J = 12.1
Hz, PhCH2), 4.68 (d, 1H, J = 0.7 Hz, H-1), 4.61 (d, 1H, J = 12.1 Hz,
PhCH2), 4.49 (d, 1H, J = 11.9 Hz, PhCH2), 4.46 (d, 1H, J = 11.9 Hz,
PhCH2), 3.98 (ddd, 1H, J = 11.1, 7.2, 3.4 Hz, H-6a), 3.92 (ddd, 1H, J
= 7.2, 3.9, 1.0 Hz, H-5), 3.79 (ddd, 1H, J = 11.1, 8.8, 3.9 Hz, H-6b),
3.75 (dd, 1H, J = 3.3, 3.3 Hz, H-3), 3.63 (m, 1H, H-4), 3.61 (m, 1H,
H-2), 3.56 (d, 1H, J = 11.4 Hz, 4-OH), 3.56 (s, 3H, Me), 2.24 (dd, 1H,
J = 8.8, 3.5 Hz, 6-OH). 13C NMR (CDCl3, 100 MHz): δ 137.61 (Ph),
137.58 (Ph), 128.74 (Ph), 128.66 (Ph), 128.3 (Ph), 128.2 (Ph), 127.8
(Ph), 101.2 (C-1), 76.0 (C-3), 75.5 (C-5), 74.8 (C-2), 74.5 (PhCH2),
72.4 (PhCH2), 67.5 (C-4), 63.1 (C-6), 57.3 (Me). HRMS (ESI): calcd
m/z for C21H26O6 (M + Na)+ 397.1622, found 397.1631.
Methyl 4,6-O-Benzylidene-2-O-methyl-β-D-idopyranoside (12).
The starting material 11 and sodium methoxide solution (1.5 M
NaOMe in MeOH; 0.4 mmol) were dissolved in dioxane (0.3 mL) and
allowed to mix at room temperature. After 3 days no significant change
was evident on TLC, so the reaction mixture was heated at 70 °C for
18 h and then evaporated to dryness. The crude material was
redissolved in ethyl acetate (5 mL), washed with water (5 mL), and
then evaporated to dryness to obtain the crude product (as a mixture
with unreacted 11) which was directly analyzed by 1H NMR and
Methyl 3-O-Allyl-2-O-benzyl-4,6-O-benzylidene-β-D-idopyrano-
side (9). The starting material 6 (325 mg, 1.01 mmol) was dissolved
in dry tetrahydrofuran (3.5 mL) and then the solution was cooled to 0
°C using an ice−water bath. Sodium hydride (57−63% oil dispersion,
65 mg, 1.6 mmol) was added in a portionwise fashion, followed by
benzyl bromide (0.32 mL, 2.7 mmol) dropwise over several minutes.
The mixture was warmed to room temperature and then allowed to
mix under argon overnight. The reaction was quenched via the
addition of methanol (1 mL), evaporated to dryness, and then
redissolved in ethyl acetate (60 mL). The organic phase was washed
with saturated aqueous sodium chloride solution (2 × 60 mL) and
water (1 × 60 mL), dried with sodium sulfate, filtered, and evaporated
to dryness. The crude mixture was purified by column chromatog-
raphy on silica gel using 20% ethyl acetate−hexanes to afford the
desired product as a clear, colorless syrup (322 mg, 0.781 mmol, 77%
yield). Rf = 0.64 (ethyl acetate/toluene 6:4). [α]20D: −31.0 (c 0.93,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.55−7.51 (m, 2H, PhCH),
7.41−7.36 (m, 2H, PhCH2), 7.33−7.23 (m, 6H, Ph), 5.86 (dddd, 1H,
J = 17.2, 10.4, 5.6, 5.6 Hz, CH2CHCH2), 5.50 (s, 1H, PhCH), 5.25
(dddd, 1H, J = 17.2, 1.6, 1.6, 1.6 Hz, CH2CHCH2), 5.19 (dddd, 1H,
J = 10.4, 1.4, 1.4, 1.4 Hz, CH2CHCH2), 4.88 (d, 1H, J = 12.0 Hz,
PhCH2), 4.69 (d, 1H, J = 1.4 Hz, H-1), 4.68 (d, 1H, J = 12.0 Hz,
PhCH2), 4.36 (dd, 1H, J = 12.5, 1.1 Hz, H-6a), 4.07 (dd, 1H, J = 12.5,
2.0 Hz, H-6b), 4.05 (m, 2H, CH2CHCH2), 3.91 (ddd, 1H, J = 1.6,
1.6, <1 Hz, H-4), 3.85 (dd, 1H, J = 3.3, 2.2 Hz, H-3), 3.66 (m, 1H, H-
5), 3.59 (m, 1H, H-2), 3.58 (s, 3H, OMe). 13C NMR (CDCl3, 100
MHz): δ 138.9 (Ph), 138.2 (Ph), 134.2 (CH2CHCH2), 129.0 (Ph),
128.2 (Ph), 128.1 (Ph), 127.8 (Ph), 127.3 (Ph), 126.9 (Ph), 117.7
(CH2CHCH2), 101.4 (PhCH), 100.8 (C-1), 76.4 (C-3), 73.9 (C-
2), 73.4 (C-4), 73.2 (PhCH2), 71.4 (CH2CHCH2), 69.8 (C-6), 66.7
(C-5), 56.8 (OMe). HRMS (ESI): calcd m/z for C24H28O6 (M + Na)+
435.1778, found 435.1774.
1
GCOSY. H NMR (CDCl3, 400 MHz): δ 7.52−7.50 (m, 2H, Ph),
7.36−7.30 (m, 3H, Ph), 5.45 (s, 1H, PhCH), 4.77 (d, 1H, J = 1.5 Hz,
H-1), 4.33−4.28 (m, 1H, H-6a), 4.24 (m, 1H, H-3), 4.03 (dd, 1H, J =
12.6, 2.1 Hz, H-6b), 3.87 (dd, 1H, J = 1.5, 1.5 Hz, H-4), 3.69 (m, 1H,
H-5), 3.54 (s, 3H, OMe), 3.50 (s, 3H, OMe), 3.34 (dd, 1H, J = 4.3, 1.3
Hz, H-2), 2.15 (broad, 1H, 3-OH).
Methyl 4,6-O-Benzylidene-2,3-di-O-mesyl-α-D-galactopyranoside
(14). The starting material 13 (152 mg, 0.539 mmol) and
methanesulfonyl chloride (0.19 mL, 2.4 mmol) were dissolved in
dry dichloromethane (1.0 mL) and pyridine (0.5 mL) and allowed to
mix at room temperature under argon. After 24 h, the reaction was
quenched via the addition of methanol (0.5 mL), evaporated to
dryness, and then redissolved in ethyl acetate (20 mL). The organic
phase was washed with saturated sodium chloride solution (3 × 20
mL), dried with sodium sulfate, filtered, and evaporated to dryness.
The crude material was purified by column chromatography on silica
gel using 20% ethyl acetate−toluene to afford the pure product as a
white solid (206 mg, 0.523 mmol, 97% yield). Rf = 0.47 (ethyl acetate/
1
toluene 1:1). [α]20D: +152 (c 0.98, CHCl3). H NMR (CDCl3, 400
MHz): δ 7.51−7.46 (m, 2H, Ph), 7.39−7.33 (m, 3H, Ph), 5.55 (s, 1H,
PhCH), 5.09 (d, 1H, J = 3.4 Hz, H-1), 5.08 (dd, 1H, J = 10.4, 3.6 Hz,
H-3), 4.99 (dd, 1H, J = 10.2, 3.6 Hz, H-2), 4.53 (dd, 1H, J = 3.6, <1
Hz, H-4), 4.24 (dd, 1H, J = 12.7, 1.5 Hz, H-6a), 4.04 (dd, 1H, J = 12.7,
1.6 Hz, H-6b), 3.71 (m, 1H, H-5), 3.44 (s, 3H, OCH3), 3.06 (s, 3H,
SO2CH3), 3.04 (s, 3H, SO2CH3). 13C NMR (CDCl3, 100 MHz): δ
137.2 (Ph), 129.4 (Ph), 128.4 (Ph), 126.3 (Ph), 101.0 (PhCH), 98.5
(C-1), 75.2 (C-4), 74.5 (C-3), 73.7 (C-2), 68.8 (C-6), 62.2 (C-5), 56.1
(OCH3), 39.1 (CH3), 38.7 (CH3). HRMS (ESI): calcd m/z for
C16H22O10S2 (M + NH4)+ 456.0993, found 456.0980.
Methyl 2,3-Anhydro-4,6-O-benzylidene-α-D-talopyranoside (15)
and Methyl 2,3-Anhydro-4,6-O-benzylidene-α-D-gulopyranoside
(16). A solution of sodium methoxide (1.5 M sodium methoxide in
methanol, 1.4 mL, 2.1 mmol) was added to a solution of 14 (175 mg,
0.399 mmol) in dioxane (3.5 mL) and allowed to mix at room
temperature under argon. After 3 days, the reaction mixture was
evaporated to dryness, redissolved in ethyl acetate (20 mL), washed
with saturated sodium chloride solution (3 × 20 mL), dried with
sodium sulfate, filtered, and evaporated to dryness. The crude material
was purified by column chromatography on silica gel using 20→30→
50% ethyl acetate−hexanes to afford 15 (27 mg, 0.10 mmol, 25%
yield) and 16 (62 mg, 0.23 mmol, 59% yield) as white solids; their full
characterization agrees with those previously published in litera-
ture.22,30,40
Methyl 3-O-Allyl-2-O-benzyl-β-D-idopyranoside (10). A solution of
the starting material 9 (3.45 g, 8.36 mmol) in aqueous acetic acid (50
mL; acetic acid/water 4:1) was allowed to mix at 80 °C. After 16 h, the
reaction mixture was evaporated to dryness via coevaporation with
toluene (3 × 20 mL) and then redissolved in methanol (40 mL). A
sodium methoxide solution was added (1.5 M NaOMe in MeOH, to
pH 8), and the solution was allowed to mix at room temperature for 1
h. The mixture was then neutralized with ion-exchange resin
(Amberlite IR-120H, to pH 6), filtered, and evaporated to dryness.
The crude mixture was purified by column chromatography on silica
gel using 20% acetone−hexanes to afford the desired product as a
yellow syrup (2.09 g, 6.44 mmol, 77% yield). Rf = 0.18 (ethyl acetate/
toluene 6:4). [α]20D: −86.9° (c 0.93, CHCl3). H NMR (CDCl3, 400
1
MHz): δ 7.34−7.27 (m, 5H, Ph), 5.76 (dddd, 1H, J = 17.2, 10.4, 5.6,
5.6 Hz, CH2CHCH2), 5.16 (dddd, 1H, J = 17.2, 1.6, 1.6, 1.6 Hz,
CH2CHCH2), 5.12 (dddd, 1H, J = 10.4, 1.3, 1.3, 1.3 Hz, CH2CH
CH2), 4.87 (d, 1H, J = 12.1 Hz, PhCH2), 4.64 (d, 1H, J = 0.9 Hz, H-
1), 4.63 (d, 1H, J = 12.1 Hz, PhCH2), 3.97 (ddd, 1H, J = 11.4, 7.1, <1
Hz, H-6a), 3.93 (dddd, 2H, J = 5.7, 1.2, 1.2, 1.2 Hz, CH2CHCH2),
3.87 (ddd, 1H, J = 7.1, 4.3, <1 Hz, H-5), 3.78 (ddd, 1H, J = 11.4, 4.2,
<1 Hz, H-6b), 3.68 (m, 1H, H-3), 3.59−3.58 (m, 3H, H-2, H4, and 4-
OH), 3.56 (s, 3H, CH3), 2.29 (broad, 1H, 6-OH). 13C NMR (CDCl3,
100 MHz): δ 137.6 (Ph), 134.1 (CH2CHCH2), 128.6 (Ph), 128.3
(Ph), 128.2 (Ph), 117.9 (CH2CHCH2), 101.2 (C-1), 75.8 (C-3),
75.4 (C-5), 74.9 (C-2), 74.5 (PhCH2), 71.4 (CH2CHCH2), 67.6
Allyl 4,6-O-benzylidene-2,3-di-O-mesyl-α-D-galactopyranoside
(18). Methanesulfonyl chloride (2.8 mL, 36 mmol) was added to a
solution of the starting material 17 (153 mg, 49.6 mmol) in dry
dichloromethane (30 mL) and dry pyridine (15 mL). The reaction was
allowed to mix for 24 h at room temperature, quenched via the
addition of methanol (10 mL), concentrated and then redissolved in
ethyl acetate (60 mL). The organic phase was washed with saturated
aqueous sodium chloride solution (3 × 60 mL), dried with sodium
sulfate, filtered, and evaporated to dryness. The crude mixture was
purified by column chromatography on silica gel using 10% ethyl
acetate−toluene to afford the desired product as a white solid (192
mg, 41.3 mmol, 83% yield). Rf = 0.53 (acetone/toluene 2:8). [α]20
:
D
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+23.5 (c 1.06, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.48 (m, 2H,
Ph), 7.37−7.29 (m, 3H, Ph), 5.87 (dddd, 1H, J = 17.2, 10.4, 6.6, 5.3
Hz, CH2CHCH2), 5.51 (s, 1H, PhCH), 5.30 (dddd, 1H, J = 17.2,
1.5, 1.5, 1.5 Hz, CH2CHCH2), 5.21 (dddd, 1H, J = 10.4, 1.2, 1.2, 1.2
Hz, CH2CHCH2), 4.83 (dd, 1H, J = 10.0, 7.7 Hz, H-2), 4.75 (dd,
1H, J = 10.0, 3.6 Hz, H-3), 4.56 (d, 1H, J = 7.7 Hz, H-1), 4.45 (dd, 1H,
J = 3.6, 0.5 Hz, H-4), 4.41 (dddd, 1H, J = 12.5, 5.3, 1.4, 1.4 Hz,
CH2CHCH2), 4.24 (dd, 1H, J = 12.6, 1.4 Hz, H-6a), 4.09 (dddd,
1H, J = 12.5, 6.6, 1.1, 1.1 Hz, CH2CHCH2), 4.02 (dd, 1H, J = 12.6,
1.6 Hz, H-6b), 3.46 (m, 1H, H-5), 3.12 (s, 3H, CH3), 3.09 (s, 3H,
CH3). 13C NMR (CDCl3, 100 MHz): δ 137.3 (Ph), 133.0 (CH2CH
CH2), 129.2 (Ph), 128.3 (Ph), 126.4 (Ph), 118.9 (CH2CHCH2),
100.9 (PhCH), 98.9 (C-1), 77.1 (C-3), 76.8 (C-2), 75.0 (C-4), 70.3
(CH2CHCH2), 68.5 (C-6), 66.1 (C-5), 39.5 (CH3), 39.1 (CH3).
HRMS (ESI): calcd m/z for C18H24O10S2 (M + Na)+ 487.0703, found
487.0705. Anal. Calcd for C18H24O10S2: C, 46.54; H, 5.21. Found: C,
46.85; H, 4.75.
(C-2), 69.6 (C-5), 68.8 (C-6), 39.9 (SO2CH3), 39.2 (SO2CH3), 23.2
(CH2CH3), 14.9 (CH2CH3). HRMS (ESI): calcd m/z for C17H24O9S3
(M + NH4)+ 486.0921, found 486.0906.
Ethyl 3-O-Allyl-4,6-O-benzylidene-1-thio-β-D-idopyranoside (22)
and Ethyl 4,6-O-Benzylidene-3-deoxy-3-S-ethyl-1-thio-β-D-idopyra-
noside (23). A solution of potassium tert-butoxide in allyl alcohol (4.9
M, 1.36 mL, 20 mmol) was added to a solution of the dimesylate
starting material 21 (312 mg, 0.666 mmol) in dioxane (10 mL). After
24 h, the reaction mixture was evaporated to dryness, redissolved in
ethyl acetate (50 mL), washed with saturated sodium chloride solution
(2 × 50 mL), water (50 mL), dried with sodium sulfate, filtered, and
evaporated to dryness. The crude mixture was purified by column
chromatography on silica gel using 7→10→15% ethyl acetate−
hexanes to afford 22 as a white solid (76 mg, 0.22 mmol, 33% yield)
and the byproduct 23 as a white solid (47 mg, 0.13 mmol, 20% yield).
Data for 22. Rf 0.74 (ethyl acetate/toluene 1:1). [α]20D: −80.4 (c 1.08,
1
CHCl3). H NMR (CDCl3, 400 MHz): δ 7.48−7.43 (m, 2H, Ar),
7.36−7.31 (m, 3H, Ar), 5.88 (dddd, 1H, J = 17.2, 10.4, 5.6, 5.6 Hz,
CH2CHCH2), 5.48 (s, 1H, PhCH), 5.28 (dddd, 1H, J = 17.2, 1.5,
1.5, 1.5 Hz, CH2CHCH2), 5.21 (dddd, 1H, J = 10.4, 1.4, 1.2, 1.2 Hz,
CH2CHCH2), 4.94 (d, 1H, J = <1 Hz, H-1), 4.36 (dd, 1H, J = 12.5,
1.4 Hz, H-6a), 4.12 (dddd, 1H, J = 12.8, 5.6, 1.4, 1.3 Hz, CH2CH
CH2), 4.08 (dddd, 1H, J = 12.9, 5.7, 1.4, 1.4 Hz, CH2CHCH2), 4.03
(dd, 1H, J = 12.6, 1.8 Hz, H-6b), 4.00 (ddd, 1H, J = 2.6, 1.4, 1.2 Hz,
H-4), 3.75 (m, 1H, H-3), 3.72 (m, 1H, H-2), 3.69 (m, 1H, H-5), 3.34
(d, 1H, J = 11.8 Hz, 2-OH), 2.76 (q, 2H, J = 7.4 Hz, CH2CH3), 1.31
(t, 3H, J = 7.4 Hz, CH2CH3). 13C NMR (CDCl3, 100 MHz): δ 137.6
(Ar), 134.1 (CH2CHCH3), 129.4 (Ar), 128.5 (Ar), 126.3 (Ar), 118.1
(CH2CHCH2), 101.8 (PhCH), 83.2 (C-1), 75.4 (C-3), 73.8 (C-4),
71.6 (CH2CHCH2), 70.1 (C-6), 69.1 (C-2), 68.6 (C-5), 25.4
(CH2CH3), 15.3 (CH2CH3). HRMS (ESI): calcd m/z for C18H24O5S
(M + NH4)+ 370.1683, found 370.1679. Data for 23. Rf = 0.63 (ethyl
acetate/hexanes 1:4). [α]20D: −37.7 (c 0.88, CHCl3). 1H NMR
(CDCl3, 400 MHz): δ 7.49−7.44 (m, 2H, Ar), 7.36−7.32 (m, 3H, Ar),
5.46 (s, 1H, PhCH), 5.00 (d, 1H, J = <1 Hz, H-1), 4.36 (dd, 1H, J =
12.5, 1.5 Hz, H-6a), 4.05 (m, 1H, H-4), 4.02 (dd, 1H, J = 12.5, 1.8 Hz,
H-6b), 3.78 (dddd, 1H, J = 12.1, 2.4, 1.2, 1.2 Hz, H-2), 3.72 (m, 1H,
H-5), 3.64 (d, 1H, J = 12.1 Hz, 2-OH), 3.28 (dd, 1H, J = 2.4, 2.4 Hz,
H-3), 2.76 (q, 2H, J = 7.4 Hz, CH2CH3), 2.67 (q, 2H, J = 7.4 Hz,
CH2CH3), 1.31 (q, 3H, J = 7.4 Hz, CH2CH3), 1.30 (q, 3H, J = 7.4 Hz,
CH2CH3). 13C NMR (CDCl3, 100 MHz): δ 137.5 (Ar), 129.5 (Ar),
128.6 (Ar), 126.4 (Ar), 101.9 (PhCH), 83.3 (C-1), 75.8 (C-4), 71.2
(C-2), 70.3 (C-6), 68.4 (C-5), 47.6 (C-3), 27.2 (CH2CH3), 25.5
(CH2CH3), 15.3 (CH2CH3), 15.1 (CH2CH3). HRMS (ESI): calcd m/
z for C17H24O4S2 (M + NH4)+ 374.1454, found 374.1454.
Allyl 3-O-Benzyl-4,6-O-benzylidene-β-D-idopyranoside (19). A
solution of potassium tert-butoxide (286 mg, 2.55 mmol) in benzyl
alcohol (1.00 mL, 9.65 mmol) was left for 30 min and then added to a
solution of the dimesylate starting material 18 (139 mg, 0.300 mmol)
in benzene (2.0 mL), and the contents of the flask were allowed to mix
at room temperature. After 2 days, the reaction mixture was
evaporated to dryness, and the crude contents were redissolved in
ethyl acetate (60 mL). The organic phase was washed with saturated
aqueous sodium chloride solution (3 × 60 mL), dried with sodium
sulfate, filtered, and evaporated to dryness. The crude mixture was
purified by column chromatography on silica gel using 20% ethyl
acetate−hexanes to afford the desired product as a pale yellow syrup
(85 mg, 0.21 mmol, 71% yield). Rf = 0.75 (ethyl acetate/toluene 1:1).
[α]20D: −35.1 (c 1.01, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.47−
7.42 (m, 2H, Ph), 7.38−7.28 (m, 8H, Ph), 5.96 (dddd, 1H, J = 17.2,
10.4, 6.5, 5.1 Hz, CH2CHCH2), 5.48 (s, 1H, PhCH), 5.29 (dddd,
1H, J = 17.2, 1.6, 1.6, 1.6 Hz, CH2CHCH2), 5.19 (dddd, 1H, J =
10.4, 1.7, 1.2, 1.2 Hz, CH2CHCH2), 4.82 (d, 1H, J = 0.9 Hz, H-1),
4.66 (d, 1H, J = 11.8 Hz, PhCH2), 4.61 (d, 1H, J = 11.8 Hz, PhCH2),
4.45 (dddd, 1H, J = 12.8, 5.1, 1.5, 1.5 Hz, CH2CHCH2), 4.37 (dd,
1H, J = 12.5, 1.5 Hz, H-6a), 4.15 (dddd, 1H, J = 12.8, 6.5, 1.3, 1.3 Hz,
CH2CHCH2), 4.06 (dd, 1H, J = 12.5, 1.9 Hz, H-6b), 4.00 (ddd, 1H,
J = 2.8, 1.1, 1.1 Hz, H-4), 3.89 (dd, 1H, J = 2.9, 2.9 Hz, H-3), 3.77
(dddd, 1H, J = 11.6, 3.1, 1.0, 1.0 Hz, H-2), 3.74 (m, 1H, H-5), 3.16 (d,
1H, J = 11.7 Hz, 2-OH). 13C NMR (CDCl3, 100 MHz): δ 137.6 (Ph),
137.5 (Ph), 134.5 (CH2CHCH2), 129.4 (Ph), 128.8 (Ph), 128.5
(Ph), 128.4 (Ph), 127.9 (Ph), 126.3 (Ph), 117.8 (CH2CHCH2),
101.7 (PhCH), 98.3 (C-1), 76.8 (C-3), 73.9 (C-4), 72.8 (PhCH2),
70.2 (CH2CHCH2), 69.9 (C-6), 67.5 (C-2), 67.0 (C-5). HRMS
(ESI): calcd m/z for C23H26O6 (M + Na)+ 421.1622, found 421.1627.
Ethyl 4,6-O-Benzylidene-2,3-di-O-mesyl-1-thio-β-D-galactopyra-
noside (21). The starting material 20 (195 mg, 0.625 mmol) and
methanesulfonyl chloride (0.50 mL, 6.5 mmol) were dissolved in dry
dichloromethane (6.0 mL) and dry pyridine (3.0 mL) and allowed to
mix at room temperature. After 16 h, excess reagent was quenched by
the addition of methanol (5 mL), and then the reaction mixture was
concentrated to a viscous syrup via coevaporation with toluene (2 × 5
mL). The crude product was redissolved in ethyl acetate (50 mL),
washed with saturated sodium chloride solution (2 × 50 mL), dried
with sodium sulfate, filtered, and evaporated to dryness. The crude
mixture was purified by column chromatography on silica gel using
25% ethyl acetate−toluene to afford the desired product as a white
solid (270 mg, 0.577 mmol, 92% yield). Rf = 0.60 (ethyl acetate/
p-Chlorophenyl 4,6-O-Benzylidene-2,3-di-O-mesyl-1-thio-β-D-
galactopyranoside (25). The starting material 24 (0.79 g, 2.0
mmol) and methanesulfonyl chloride (1.00 mL, 12.9 mmol) were
dissolved in dry dichloromethane (10 mL) and dry pyridine (5 mL)
and allowed to mix at room temperature. After 16 h, excess reagent
was quenched by the addition of methanol (10 mL), and then the
reaction mixture was evaporated to dryness. The crude product was
redissolved in ethyl acetate (60 mL), washed with saturated sodium
chloride solution (2 × 60 mL), dried with sodium sulfate, filtered, and
evaporated to dryness. The crude mixture was purified by column
chromatography on silica gel using 25% ethyl acetate−toluene to
afford the desired product as a white solid (1.08 g, 1.96 mmol, 98%
yield). Rf = 0.55 (ethyl acetate/toluene 1:1). [α]20D: −28.3 (c 1.06,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.63−7.58 (m, 2H, SPhCl),
7.41−7.36 (m, 3H, PhCH), 7.33−7.29 (m, 2H, PhCH), 7.19−7.14 (m,
2H, SPhCl), 5.52 (s, 1H, PhCH), 4.93 (dd, 1H, J = 9.5, 9.5 Hz, H-2),
4.79 (dd, 1H, J = 9.5, 3.5 Hz, H-3), 4.65 (d, 1H, J = 9.5 Hz, H-1), 4.55
(dd, 1H, J = 3.5, 0.8 Hz, H-4), 4.35 (dd, 1H, J = 12.5, 1.7 Hz, H-6a),
4.02 (dd, 1H, J = 12.5, 1.6 Hz, H-6b), 3.59 (m, 1H, H-5), 3.21 (s, 3H,
CH3), 3.11 (s, 3H, CH3). 13C NMR (CDCl3, 100 MHz): δ 137.1 (Ar),
135.9 (SPhCl), 135.4 (Ar), 129.7 (PhCH), 129.4 (SPhCl), 128.6
(PhCH), 128.1 (Ar), 126.5 (PhCH), 101.4 (PhCH), 84.1 (C-1), 78.0
(C-3), 74.6 (C-4), 74.0 (C-2), 69.7 (C-5), 68.9 (C-6), 40.1 (CH3),
39.4 (CH3). HRMS (ESI): calcd m/z for C21H23ClO9S3 (M + NH4)+
568.0531, found 568.0524.
1
toluene 1:1). [α]20D: −2.1 (c 0.97, CHCl3). H NMR (CDCl3, 400
MHz): δ 7.55−7.51 (m, 2H, Ph), 7.45−7.39 (m, 3H, Ph), 5.58 (s, 1H,
PhCH), 5.08 (dd, 1H, J = 9.6, 9.6 Hz, H-2), 4.84 (dd, 1H, J = 9.6, 3.6
Hz, H-3), 4.59 (dd, 1H, J = 3.6, <1 Hz, H-4), 4.57 (d, 1H, J = 9.7 Hz,
H-1), 4.33 (dd, 1H, J = 12.6, 1.5 Hz, H-6a), 4.03 (dd, 1H, J = 12.6, 1.6
Hz, H-6b), 3.58 (m, 1H, H-5), 3.25 (s, 3H, SO2CH3), 3.18 (s, 3H,
SO2CH3), 2.92 (dq, 1H, J = 12.3, 7.5 Hz, CH2CH3), 2.81 (dq, 1H, J =
12.3, 7.5 Hz, CH2CH3), 1.36 (dd, 3H, J = 7.5, 7.5 Hz, CH2CH3). 13
C
NMR (CDCl3, 100 MHz): δ 137.4 (Ph), 129.4 (Ph), 128.4 (Ph),
126.4 (Ph), 101.2 (PhCH), 82.3 (C-1), 78.0 (C-3), 75.0 (C-4), 74.5
6767
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p-Chlorophenyl 4,6-O-Benzylidene-3-S-p-chlorophenyl-3-deoxy
1-thio-β-D-idopyranoside (26). A solution of potassium tert-butoxide
in allyl alcohol (4.89 M, 1.61 mL, 23.6 mmol) was added to a solution
of the starting material 25 (433 mg, 0.786 mmol) in dioxane (10 mL).
After 3 days, the reaction mixture was evaporated to dryness,
redissolved in ethyl acetate (100 mL), washed with saturated sodium
chloride solution (2 × 100 mL) and water (100 mL), dried with
sodium sulfate, filtered, and evaporated to dryness. The crude mixture
was purified by column chromatography on silica gel using 7→10→
16→40% ethyl acetate−hexanes to afford a number of products, none
of which was the desired 3-O-allyl-substituted idose compound;
instead, byproduct 26 was obtained as a white solid (57 mg, 0.11
mmol, 14% yield) along with a few unidentified elimination products.
Rf = 0.90 (ethyl acetate/toluene 1:1). [α]20D: +8.9 (c 1.01, CHCl3). 1H
NMR (CDCl3, 400 MHz): δ 7.50−7.44 (m, 4H, Ar), 7.38−7.26 (m,
9H, Ar), 5.46 (s, 1H, PhCH), 5.23 (d, 1H, J = <1 Hz, H-1), 4.40 (dd,
1H, J = 12.6, 1.3 Hz, H-6a), 4.06 (m, 1H, H-4), 4.04 (dd, 1H, J = 12.6,
1.7 Hz, H-6b), 3.93 (m, 1H, H-2), 3.85 (m, 1H, H-5), 3.77 (d, 1H, J =
12.2 Hz, 2-OH), 3.76 (dd, 1H, J = 2.3, 2.3 Hz, H-3). 13C NMR
(CDCl3, 100 MHz): δ 137.2 (Ar), 133.8 (Ar), 133.0 (Ar), 132.84 (Ar),
132.79 (Ar), 131.1 (Ar), 130.0 (Ar), 129.6 (Ar), 129.3 (Ar), 128.6
(Ar), 126.3 (Ar), 102.0 (PhCH), 86.6 (C-1), 74.3 (C-4), 70.2 (C-6),
70.0 (C-2), 68.3 (C-5), 50.6 (C-3). HRMS (ESI): calcd m/z for
C25H22Cl2O4S2 (M + NH4)+ 538.0675, found 538.0661.
= 10.1, 10.1 Hz, H-2), 3.82 (dd, 1H, J = 10.4, 5.1 Hz, H-6a), 3.79 (m,
1H, H-4), 3.78 (dd, 1H, J = 10.4, 4.5 Hz, H-6b), 3.67 (ddd, 1H, J =
9.5, 4.8, 4.6 Hz, H-5), 2.91 (d, 1H, J = 2.9 Hz, 4-OH). 13C NMR
(CDCl3, 100 MHz): δ 168.3 (Phth), 167.5 (Phth), 138.1 (Ar), 137.8
(Ar), 134.4 (Ar), 134.3 (Ar), 134.2 (Ar), 134.1 (Ar), 131.8 (Ar), 130.6
(Ar), 129.1 (Ar), 128.7 (Ar), 128.4 (Ar), 128.12 (Ar), 128.10 (Ar),
127.9 (Ar), 127.7 (Ar), 123.7 (Ar), 123.5 (Ar), 83.5 (C-1), 79.9 (C-3),
78.2 (C-5), 74.8 (PhCH2), 74.0 (C-4), 73.9 (PhCH2), 70.7 (C-6), 54.6
(C-2). HRMS (ESI): calcd m/z for C34H30ClNO6S (M + NH4)+
633.1821, found 633.1817.
p-Chlorophenyl 2,3-Di-O-acetyl-4,6-O-benzylidene-β-D-galacto-
pyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-
D-glucopyranoside (31). A solution of glycosyl donor 30 (1.457 g,
2.932 mmol), glycosyl acceptor 29 (1.166 g, 1.893 mmol), and
molecular sieves (4 Å, crushed, 1.858 g) was prepared in dry
dichloromethane (24 mL), and then the contents were divided in
roughly equal amounts into two flasks. After being mixed at room
temperature under argon for 2 h, the mixtures were cooled to −72 °C,
boron trifluoride diethyl etherate was added (to pH 3), and the
mixtures were warmed slowly to room temperature. After 16 h, the
reactions were quenched via addition of triethylamine (to pH 8),
filtered, and then evaporated to dryness. The crude material was
combined and redissolved in ethyl acetate (120 mL), washed with
saturated sodium bicarbonate solution (100 mL), saturated sodium
chloride solution (100 mL), and water (100 mL), dried with sodium
sulfate, filtered, and evaporated to dryness. The crude mixture was
purified by column chromatography on silica gel using 20→30% ethyl
acetate−hexanes to afford recovered starting material (310 mg, 0.503
mmol) and the desired product as a white solid (1.571 g, 1.653 mmol,
80% yield based on recovered starting material). Rf = 0.48 (ethyl
acetate/toluene 3:7). [α]20D: +44.5 (c 0.97, CHCl3). 1H NMR
(CDCl3, 600 MHz): δ 7.78 (d, 1H, J = 7.1 Hz, Phth), 7.70−7.64 (m,
2H, Phth), 7.59 (d, 1H, J = 7.2 Hz, Phth), 7.41−7.37 (m, 2H, Ar),
7.36−7.29 (m, 7H, Ar), 7.22−7.16 (m, 3H, Ar), 7.13−7.10 (m, 2H,
Ar), 6.96−6.93 (m, 2H, Ar), 6.75−6.71 (m, 3H, Ar), 5.42 (d, 1H, J =
10.6 Hz, GlcN_H1), 5.40 (s, 1H, PhCH), 5.34 (dd, 1H, J = 10.4, 7.9
Hz, Gal_H2), 4.94 (d, 1H, J = 12.6 Hz, PhCH2), 4.80 (dd, 1H, J =
10.4, 3.6 Hz, Gal_H3), 4.71 (d, 1H, J = 11.8 Hz, PhCH2), 4.63 (d, 1H,
J = 7.9 Hz, Gal_H1), 4.53 (d, 1H, J = 12.6 Hz, PhCH2), 4.50 (d, 1H, J
= 11.8 Hz, PhCH2), 4.26 (dd, 1H, J = 3.8, <1 Hz, Gal_H4), 4.26 (dd,
1H, J = 12.3, 1.4 Hz, Gal_H6a), 4.25 (dd, 1H, J = 10.0, 8.4 Hz,
GlcN_H3), 4.16 (dd, 1H, J = 10.5, 10.2 Hz, GlcN_H2), 4.05 (dd, 1H,
J = 10.0, 8.5 Hz, GlcN_H4), 3.90 (dd, 1H, J = 12.4, 1.7 Hz, Gal_H6b),
3.81 (dd, 2H, J = 2.6, <1 Hz, GlcN_H6a and GlcN_H6b), 3.57 (ddd,
1H, J = 10.0, 2.6, 2.4 Hz, GlcN_H5), 3.25 (m, 1H, Gal_H5), 2.03 (s,
3H, Ac), 2.03 (s, 3H, Ac). 13C NMR (CDCl3, 150 MHz): δ 170.9
(Ac), 169.2 (Ac), 168.0 (Phth), 167.5 (Phth), 138.6 (Ar), 138.2 (Ar),
137.8 (Ar), 134.7 (Ar), 134.5 (Ar), 134.1 (Ar), 133.9 (Ar), 131.9 (Ar),
131.8 (Ar), 130.3 (Ar), 129.2 (Ar), 129.1 (Ar), 128.7 (Ar), 128.6 (Ar),
128.3 (Ar), 128.1 (Ar), 128.01 (Ar), 127.98 (Ar), 127.1 (Ar), 126.6
(Ar), 123.62 (Ar), 123.56 (Ar), 101.3 (PhCH), 100.7 (Gal_C1), 83.2
(GlcN_C1), 79.4 (GlcN_C5), 78.2 (GlcN_C4), 78.0 (Gal_C4), 75.5
(PhCH2), 73.7 (PhCH2), 73.5 (GlcN_C3), 72.3 (Gal_C3), 69.5
(Gal_C2), 68.9 (Gal_C6), 68.1 (GlcN_C6), 66.4 (Gal_C5), 55.0
(GlcN_C2), 21.09 (Ac), 21.08 (Ac). HRMS (ESI): calcd m/z for
C51H48ClNO13S (M + Na)+ 972.2427, found 972.2426.
p-Chlorophenyl 3-O-Benzyl-4,6-O-benzylidene-2-deoxy-2-N-
phthalimido-1-thio-β-D-glucopyranoside (28). Starting material 27
(294 mg, 0.561 mmol) was dissolved in dry N,N-dimethylformamide
(3.0 mL), sodium hydride (57−63% oil dispersion, 36 mg, 0.91 mmol)
was added , and then benzyl bromide (0.08 mL, 0.7 mmol) was slowly
added. After 30 min, the reaction was quenched via the addition of
methanol (1 mL), and then the reaction solution was evaporated to
dryness, redissolved in ethyl acetate (60 mL), washed with saturated
aqueous sodium chloride solution (2 × 60 mL), dried with sodium
sulfate, filtered, and evaporated to dryness. The crude mixture was
purified by column chromatography on silica gel using 15% ethyl
acetate−hexanes to afford the desired product as a white solid (310
mg, 0.505 mmol, 90% yield). Rf = 0.90 (acetone: toluene 1:4). [α]20
:
D
+71.0 (c 1.01, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.86−7.61 (m,
4H, Ar), 7.52−7.49 (m, 2H, Ar), 7.41−7.36 (m, 3H, Ar), 7.32−7.27
(m, 2H, Ar), 7.23−7.19 (m, 2H, Ar), 6.98−6.83 (m, 5H, Ar), 5.61 (s,
1H, PhCH), 5.56 (d, 1H, J = 10.5 Hz, H-1), 4.76 (d, 1H, J = 12.3 Hz,
PhCH2), 4.48 (d, 1H, J = 12.3 Hz, PhCH2), 4.41 (dd, 1H, J = 9.8, 8.9
Hz, H-3), 4.41 (dd, 1H, J = 10.3, 4.5 Hz, H-6a), 4.25 (dd, 1H, J = 10.4,
10.1 Hz, H-2), 3.82 (dd, 1H, J = 9.9, 9.9 Hz, H-6b), 3.77 (dd, 1H, J =
9.6, 8.9 Hz, H-4), 3.70 (ddd, 1H, J = 9.6, 9.6, 4.6 Hz, H-5). 13C NMR
(CDCl3, 100 MHz): δ 168.0 (Phth), 167.4 (Phth), 137.8 (Ar), 137.4
(Ar), 134.8 (Ar), 134.7 (Ar), 134.2 (Ar), 134.1 (Ar), 131.7 (Ar), 129.9
(Ar), 129.2 (Ar), 128.5 (Ar), 128.3 (Ar), 128.2 (Ar), 127.6 (Ar), 126.2
(Ar), 123.7 (Ar), 123.6 (Ar), 101.5 (PhCH), 83.9 (C-1), 82.9 (C-4),
75.6 (C-3), 74.4 (PhCH2), 70.6 (C-5), 68.8 (C-6), 54.9 (C-2). HRMS
(ESI): calcd m/z for C34H28ClNO6S (M + Na)+ 636.1218, found
636.1218.
p-Chlorophenyl 3,6-Di-O-benzyl-2-deoxy-2-phthalimido-1-thio-
β-D-glucopyranoside (29). The starting material 28 (1.93 g, 3.14
mmol) was dissolved in dry dichloromethane (20 mL), cooled to 0 °C
in an ice−water bath, and triethylsilane (2.5 mL, 16 mmol) was added
followed by the slow addition of boron trifluoride diethyl etherate
(0.80 mL, 6.4 mmol). After 3.5 h, the reaction was quenched via
neutralization with triethylamine (to pH 8) and concentrated to a
syrup. The crude mixture was purified by column chromatography on
silica gel using 15→20% acetone−hexanes to afford the desired
product as a white solid (1.66 g, 2.69 mmol, 86% yield) as well as a
small amount of recovered starting material (87 mg, 0.14 mmol, 5%
recovered yield). Rf = 0.69 (acetone/toluene 1:4). [α]20D: +61.4 (c
1.05, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 7.81 (d, 1H, J = 6.2 Hz,
Ar), 7.70−7.67 (m, 3H, Ar), 7.39−7.27 (m, 7H, Ar), 7.15−7.11 (m,
2H, Ar), 7.04−6.99 (m, 2H, Ar), 6.96−6.90 (m, 3H, Ar), 5.49 (d, 1H,
J = 10.0 Hz, H-1), 4.71 (d, 1H, J = 12.2 Hz, PhCH2), 4.60 (d, 1H, J =
11.8 Hz, PhCH2), 4.55 (d, 1H, J = 11.8 Hz, PhCH2), 4.51 (d, 1H, J =
12.2 Hz, PhCH2), 4.24 (dd, 1H, J = 10.1, 8.3 Hz, H-3), 4.20 (dd, 1H, J
p-Chlorophenyl 4,6-O-Benzylidene-β-D-galactopyranosyl-(1→4)-
3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside
(32). A sodium methoxide solution was added dropwise (1.5 M
NaOMe/MeOH, to pH 10) to a solution of the starting material 31
(910 mg, 957 mmol) in dry methanol (0.5 mL) and dry
dichloromethane (0.5 mL) and allowed to mix at room temperature
for 1 h. The reaction was then neutralized using ion-exchange resin
(Amberlite IR-120H, to pH 6), filtered, and evaporated to dryness to
obtain the pure product as a white solid (796 mg, 919 mmol, 96%
yield). Rf 1= 0.40 (ethyl acetate/toluene 1:1). [α]20D: +17.8 (c 0.98,
CHCl3). H NMR (CDCl3, 400 MHz): δ 7.85−7.64 (m, 4H, Ar),
7.44−7.34 (m, 9H, Ar), 7.30−7.25 (m, 3H, Ar), 7.20−7.15 (m, 2H,
Ar), 7.05−7.03 (m, 2H, Ar), 6.90−6.82 (m, 3H, Ar), 5.49 (d, 1H, J =
10.5 Hz, GlcN_H1), 5.48 (s, 1H, PhCH), 4.99 (d, 1H, J = 12.3 Hz,
6768
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Featured Article
PhCH2), 4.72 (d, 1H, J = 12.0 Hz, PhCH2), 4.62 (d, 1H, J = 12.0 Hz,
PhCH2), 4.58 (d, 1H, J = 7.0 Hz, Gal_H1), 4.57 (d, 1H, J = 12.4 Hz,
PhCH2), 4.44 (dd, 1H, J = 10.1, 8.7 Hz, GlcN_H3), 4.25 (dd, 1H, J =
10.4, 10.3 Hz, GlcN_H2), 4.22 (dd, 1H, J = 12.3, 1.2 Hz, Gal_H6a),
4.14 (dd, 1H, J = 9.8, 9.0 Hz, GlcN_H4), 4.10 (dd, 1H, J = 11.3, 3.7
Hz, GlcN_H6a), 4.09 (dd, 1H, J = 3.8, <1 Hz, Gal_H4), 3.91 (m, 1H,
Gal_H6b), 3.90 (m, 1H, GlcN_H6b), 3.74 (m, 1H, Gal_H2), 3.73
(m, 1H, GlcN_H5), 3.53 (ddd, 1H, J = 9.4, 9.1, 3.7 Hz, Gal_H3), 3.30
(d, 1H, J = 2.3 Hz, Gal_2OH), 3.16 (m, 1H, Gal_H5), 2.61 (d, 1H, J
= 8.8 Hz, Gal_3OH). 13C NMR (CDCl3, 100 MHz): δ 168.2 (Phth),
167.4 (Phth), 138.6 (Ar), 138.1 (Ar), 137.9 (Ar), 134.8 (Ar), 134.6
(Ar), 134.1 (Ar), 134.0 (Ar), 131.8 (Ar), 130.1 (Ar), 129.3 (Ar), 129.1
(Ar), 128.6 (Ar), 128.3 (Ar), 128.07 (Ar), 128.06 (Ar), 128.0 (Ar),
127.2 (Ar), 126.6 (Ar), 123.6 (Ar), 123.5 (Ar), 103.2 (Gal_C1), 101.5
(PhCH), 83.2 (GlcN_C1), 79.3 (GlcN_C5), 79.2 (GlcN_C3), 78.6
(GlcN_C4), 75.3 (PhCH2), 75.2 (Gal_C4), 73.6 (PhCH2), 73.0
(Gal_C3), 72.6 (Gal_C2), 69.1 (Gal_C6), 68.5 (GlcN_C6), 66.7
(Gal_C5), 55.1 (GlcN_C2). HRMS (ESI): calcd m/z for
C47H44ClNO11S (M + Na)+ 888.2216, found 888.2213.
CH2), 5.19 (dddd, 1H, J = 10.4, 1.4, 1.2, 1.2 Hz, CH2CHCH2), 4.98
(d, 1H, J = 11.5 Hz, PhCH2), 4.98 (d, 1H, J = 8.2 Hz, GlcN_H1), 4.90
(d, 1H, J = <1 Hz, Ido_H1), 4.71 (d, 1H, J = 11.4 Hz, PhCH2), 4.56
(d, 1H, J = 11.8 Hz, PhCH2), 4.52 (d, 1H, J = 11.8 Hz, PhCH2), 4.17
(dd, 1H, J = 12.6, <1 Hz, Ido_H6a), 4.12 (m, 1H, GlcN_H2), 4.10
(m, 1H, GlcN_H3), 4.05 (m, 1H, GlcN_H4), 4.05 (dddd, 1H, J =
12.8, 5.6, 1.4, 1.4 Hz, CH2CHCH2), 4.01 (dddd, 1H, J = 12.9, 5.7,
1.4, 1.3 Hz, CH2CHCH2), 3.92 (m, 1H, Ido_H4), 3.90 (dd, 1H, J =
12.6, 1.6 Hz, Ido_H6b), 3.82 (dd, 1H, J = 11.8, 5.3 Hz, GlcN_H6a),
3.75 (m, 1H, GlcN_H6b), 3.75 (m, 1H, GlcN_H5), 3.75 (m, 1H,
Ido_H3), 3.67 (m, 1H, Ido_H2), 3.53 (m, 1H, Ido_H5). 13C NMR
(CDCl3, 100 MHz): δ 182.1 (Ac), 170.7 (Phth), 145.9 (Ar), 138.4
(Ar), 134.3 (CH2CHCH2), 134.0 (Ar), 132.2 (Ar), 131.1 (Ar),
129.2 (Ar), 128.6 (Ar), 128.5 (Ar), 128.4 (Ar), 127.9 (Ar), 127.6 (Ar),
126.2 (Ar), 118.3 (CH2CHCH2), 101.7 (PhCH), 99.4 (Ido_C1),
85.0 (GlcN_C1), 79.5 (GlcN_C4), 79.2 (GlcN_C5), 76.9
(GlcN_C3), 76.2 (Ido_C3), 74.3 (PhCH2), 73.6 (Ido_C4), 73.4
(PhCH2), 71.8 (CH2CHCH2), 69.7 and 69.5 (Ido_C6 and
GlcN_C6), 67.7 (Ido_C2), 67.3 (Ido_C5), 54.2 (GlcN_C2).
HRMS (ESI): calcd m/z for C50H50ClNO12S (M + Na)+ 946.2634,
found 946.2592. The crude material was then redissolved in dry
pyridine (1.0 mL) and acetic anhydride (1.0 mL) and allowed to mix
at 65 °C. After 16 h, the reaction mixture was evaporated to dryness
via coevaporation with toluene (2 × 1 mL), redissolved in ethyl acetate
(40 mL), washed with saturated sodium chloride solution (2 × 40 mL)
and water (40 mL), dried with sodium sulfate, filtered, and evaporated
to dryness. The crude material was then purified via column
chromatography on silica using 10→20% acetone−hexanes to afford
the pure product as a white solid (398 mg, 0.420 mmol, 76% yield). Rf
p-Chlorophenyl 4,6-O-Benzylidene-2,3-di-O-mesyl-β-D-galacto-
pyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-
D-glucopyranoside (33). The starting material 32 (724 mg, 0.835
mmol) and methanesulfonyl chloride (0.32 mL, 4.1 mmol) were
dissolved in dry dichloromethane (3.5 mL) and dry pyridine (3.5 mL)
and then allowed to mix at 45 °C. After 16 h, the reaction was
quenched via the addition of water (1 mL) and concentrated via
coevaporation with toluene (2 × 2 mL). The crude mixture was
redissolved in ethyl acetate (60 mL), washed with saturated sodium
chloride solution (2 × 60 mL) and water (60 mL), dried with sodium
sulfate, filtered, and evaporated to dryness. The crude mixture was
purified by column chromatography on silica gel using 0.5→0.7%
methanol−dichloromethane to afford the desired product as a white
solid (683 mg, 0.668 mmol, 80% yield). Rf = 0.75 (ethyl acetate/
1
= 0.33 (acetone/hexanes 3:7). [α]20D: +14.9° (c 1.03, CHCl3). H
NMR (CDCl3, 600 MHz): δ 7.80 (d, 1H, J = 7.0 Hz, Phth), 7.70−7.66
(m, 2H, Phth), 7.61 (d, 1H, J = 7.1 Hz, Phth), 7.42−7.40 (m, 2H, Ar),
7.36−7.30 (m, 7H, Ar), 7.24−7.20 (m, 3H, Ar), 7.13−7.10 (m, 2H,
Ar), 6.99−6.97 (m, 2H, Ar), 6.79−6.74 (m, 3H, Ar), 5.82 (dddd, 1H, J
= 17.1, 10.5, 5.6, 5.6 Hz, CH2CHCH2), 5.43 (d, 1H, J = 10.5 Hz,
GlcN_H1), 5.39 (s, 1H, PhCH), 5.25 (dddd, 1H, J = 17.2, 1.5, 1.5, 1.5
Hz, CH2CHCH2), 5.18 (dddd, 1H, J = 10.4, 1.3, 1.3, 1.3 Hz,
CH2CHCH2), 5.07 (d, 1H, J = 1.2 Hz, Ido_H1), 4.99 (d, 1H, J =
12.3 Hz, PhCH2), 4.89 (ddd, 1H, J = 3.4, 1.4, 1.4 Hz, Ido_H2), 4.61
(d, 1H, J = 12.3 Hz, PhCH2), 4.57 (m, 2H, PhCH2), 4.32 (dd, 1H, J =
10.2, 8.7 Hz, GlcN_H3), 4.24 (dd, 1H, J = 12.5, 1.2 Hz, Ido_H6a),
4.15 (dd, 1H, J = 10.4, 10.4 Hz, GlcN_H2), 4.13 (dd, 1H, J = 9.8, 8.8
Hz, GlcN_H4), 4.10 (dddd, 1H, J = 12.8, 5.4, 1.4, 1.4 Hz, CH2CH
CH2), 4.05 (dddd, 1H, J = 12.8, 5.8, 1.4, 1.4 Hz, CH2CHCH2), 3.89
(dd, 1H, J = 12.5, 1.9 Hz, Ido_H6b), 3.82 (dd, 1H, J = 11.0, 1.7 Hz,
GlcN_H6a), 3.78 (m, 1H, Ido_H4), 3.78 (m, 1H, Ido_H3), 3.75 (dd,
1H, J = 11.0, 3.4 Hz, GlcN_H6b), 3.65 (ddd, 1H, J = 9.9, 3.4, 1.7 Hz,
GlcN_H5), 3.48 (m, 1H, Ido_H5), 1.98 (s, 3H, Ac). 13C NMR
(CDCl3, 150 MHz): δ 171.0 (Ac), 168.2 (Phth), 167.4 (Phth), 138.8
(Ar), 138.6 (Ar), 138.4 (Ar), 134.9 (Ar), 134.6 (Ar), 134.1
(CH2CHCH2), 134.0 (Ar), 131.9 (Ar), 131.8 (Ar), 130.0 (Ar),
129.2 (Ar), 129.1 (Ar), 128.5 (Ar), 128.2 (Ar), 128.1 (Ar), 127.8 (Ar),
127.5 (Ar), 127.3 (Ar), 126.7 (Ar), 123.7 (Ar), 123.5 (Ar), 118.2
(CH2CHCH2), 101.3 (PhCH), 98.0 (Ido_C1), 82.8 (GlcN_C1),
79.1 (GlcN_C5), 78.2 (GlcN_C3), 78.2 (GlcN_C4), 75.1 (PhCH2),
74.8 (Ido_C3), 73.3 (PhCH2), 72.0 (Ido_C4), 71.7 (CH2CHCH2),
69.5 (Ido_C6), 68.9 (GlcN_C6), 67.4 (Ido_C2), 67.0 (Ido_C5), 54.9
(GlcN_C2), 21.3 (Ac). HRMS (ESI): calcd m/z for C52H50ClNO12S
(M + Na)+ 970.2634, found 970.2634.
1
toluene 1:1). [α]20D: +21.7 (c 0.96, CHCl3). H NMR (CDCl3, 600
MHz): δ 7.79 (d, 1H, J = 7.1 Hz, Phth), 7.71−7.65 (m, 2H, Phth),
7.60 (d, 1H, J = 7.8 Hz, Phth), 7.42−7.35 (m, 6H, Ar), 7.32−7.29 (m,
4H, Ar), 7.31−7.29 (m, 4H, Ar), 6.96−6.93 (m, 2H, Ar), 6.78−6.71
(m, 3H, Ar), 5.45 (s, 1H, PhCH), 5.45 (d, 1H, J = 10.0 Hz,
GlcN_H1), 4.91 (d, 1H, J = 12.4 Hz, PhCH2), 4.77 (d, 1H, J = 11.8
Hz, PhCH2), 4.77 (dd, 1H, J = 10.0, 7.8 Hz, Gal_H2), 4.55 (d, 1H, J =
7.8 Hz, Gal_H1), 4.49 (dd, 1H, J = 10.0, 3.8 Hz, Gal_H3), 4.47 (d,
1H, J = 12.4 Hz, PhCH2), 4.43 (d, 1H, J = 11.9 Hz, PhCH2), 4.38 (dd,
1H, J = 3.8, <1 Hz, Gal_H4), 4.29 (dd, 1H, J = 12.5, 1.4 Hz,
Gal_H6a), 4.26 (dd, 1H, J = 10.2, 8.6 Hz, GlcN_H3), 4.18 (dd, 1H, J
= 10.2, 10.2 Hz, GlcN_H2), 4.15 (dd, 1H, J = 9.9, 8.6 Hz, GlcN_H4),
4.01 (dd, 1H, J = 11.3, 2.9 Hz, GlcN_H6a), 3.91 (dd, 1H, J = 12.5, 1.7
Hz, Gal_H6b), 3.80 (dd, 1H, J = 11.3, 1.4 Hz, GlcN_H6b), 3.64 (ddd,
1H, J = 10.0, 2.7, 1.4 Hz, GlcN_H5), 3.12 (m, 1H, Gal_H5), 3.08 (s,
3H, CH3), 3.07 (s, 3H, CH3). 13C NMR (CDCl3, 150 MHz): δ 168.1
(Phth), 167.5 (Phth), 138.4 (Ar), 138.3 (Ar), 137.3 (Ar), 134.51 (Ar),
134.46 (Ar), 134.1 (Ar), 134.0 (Ar), 131.85 (Ar), 131.75 (Ar), 130.4
(Ar), 130.0 (Ar), 129.4 (Ar), 129.2 (Ar), 128.8 (Ar), 128.7 (Ar), 128.6
(Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar), 128.0 (Ar), 127.3 (Ar), 126.4
(Ar), 123.65 (Ar), 123.57 (Ar), 101.4 (PhCH), 99.4 (Gal_C1), 83.3
(GlcN_C1), 79.0 (GlcN_C5), 78.2 (GlcN_C4), 77.9 (GlcN_C3),
77.1 (Gal_C3), 76.6 (Gal_C2), 75.5 (PhCH2), 74.3 (Gal_C4), 73.7
(PhCH2), 68.5 (Gal_C6), 68.1 (GlcN_C6), 65.8 (Gal_C5), 55.0
(GlcN_C2), 39.8 (CH3), 39.7 (CH3). HRMS (ESI): calcd m/z for
C49H48ClNO15S3 (M + Na)+ 1044.1767, found 1044.1768.
p-Chlorophenyl 2-O-Acetyl-3-O-allyl-4,6-O-benzylidene-β-D-ido-
pyranosyl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-
D-glucopyranoside (34). A solution of potassium tert-butoxide in allyl
alcohol (4.35 M, 1.00 mL, 14.7 mmol) was added to a solution of the
starting material 33 (564 mg, 0.551 mmol) in dioxane (10.0 mL).
After 6 days, the reaction mixture was evaporated to dryness to afford
the partially hydrolyzed phthalimido intermediate 33B: Rf 0.06 (ethyl
acetate/toluene 1:1). 1H NMR (CDCl3, 400 MHz): δ 7.96 (d, 1H, J =
7.9 Hz, Ar), 7.46−7.10 (m, 22H, Ar), 6.81 (d, 1H, J = 8.6 Hz, NH),
5.81 (dddd, 1H, J = 17.1, 10.4, 5.6, 5.6 Hz, CH2CHCH2), 5.44 (s,
1H, PhCH), 5.24 (dddd, 1H, J = 17.2, 1.5, 1.5, 1.5 Hz, CH2CH
p-Chlorophenyl 3-O-Allyl-4,6-O-benzylidene-β-D-idopyranosyl-
(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyr-
anoside (35). A sodium methoxide solution was added dropwise (1.5
M NaOMe/MeOH, to pH 10) to a solution of the starting material 34
(170 mg, 0.179 mmol) in dry methanol (1.0 mL) and dry
dichloromethane (1.0 mL) and allowed to mix at room temperature.
After 20 min, the reaction was then neutralized using ion-exchange
resin (Amberlite IR-120H, to pH 6), filtered, and evaporated to
dryness. The crude material was then purified via column
chromatography using 20% acetone - hexanes to afford the pure
product as a white solid (152 mg, 0.168 mmol 94% yield). Rf = 0.44
6769
dx.doi.org/10.1021/jo300764k | J. Org. Chem. 2012, 77, 6760−6772

The Journal of Organic Chemistry
Featured Article
(acetone/hexanes 3:7). [α]20D: +2.4° (c 0.98, CHCl3). 1H NMR
(CDCl3, 600 MHz): δ 7.78 (d, 1H, J = 7.0 Hz, Phth), 7.69−7.65 (m,
2H, Phth), 7.61 (d, 1H, J = 7.1 Hz, Phth), 7.34−7.24 (m, 12H, Ar),
7.13−7.10 (m, 2H, Ar), 7.01−6.99 (m, 2H, Ar), 6.81−6.75 (m, 3H,
Ar), 5.80 (dddd, 1H, J = 17.2, 10.4, 5.6, 5.6 Hz, CH2CHCH2), 5.45
(d, 1H, J = 10.5 Hz, GlcN_H1), 5.42 (s, 1H, PhCH), 5.23 (dddd, 1H,
J = 17.2, 1.5, 1.5, 1.5 Hz, CH2CHCH2), 5.17 (dddd, 1H, J = 10.4,
1.3, 1.3, 1.3 Hz, CH2CHCH2), 4.98 (d, 1H, J = <1 Hz, Ido_H1),
4.98 (d, 1H, J = 12.3 Hz, PhCH2), 4.59 (d, 1H, J = 11.9 Hz, PhCH2),
4.57 (d, 1H, J = 12.0 Hz, PhCH2), 4.54 (d, 1H, J = 12.3 Hz, PhCH2),
4.43 (dd, 1H, J = 10.2, 8.7 Hz, GlcN_H3), 4.27 (dd, 1H, J = 12.4, 1.1
Hz, Ido_H6a), 4.16 (dd, 1H, J = 10.4, 10.3 Hz, GlcN_H2), 4.09 (dd,
1H, J = 9.8, 8.8 Hz, GlcN_H4), 4.04 (dddd, 1H, J = 12.8, 5.6, 1.4, 1.4
Hz, CH2CHCH2), 4.00 (dddd, 1H, J = 12.8, 5.7, 1.4, 1.4 Hz,
CH2CHCH2), 3.92 (m, 1H, Ido_H4), 3.92 (dd, 1H, J = 12.4, 1.8
Hz, Ido_H6b), 3.84 (dd, 1H, J = 11.0, 1.8 Hz, GlcN_H6a), 3.81 (dd,
1H, J = 11.0, 3.3 Hz, GlcN_H6b), 3.79 (dd, 1H, J = 3.0, 2.9 Hz,
Ido_H3), 3.73 (m, 1H, Ido_H2), 3.73 (m, 1H, GlcN_H5), 3.58 (m,
1H, Ido_H5), 3.27 (d, 1H, J = 11.9 Hz, Ido_2OH). 13C NMR
(CDCl3, 150 MHz): δ 168.1 (Phth), 167.5 (Phth), 138.8 (Ar), 138.5
(Ar), 137.6 (Ar), 135.0 (Ar), 134.6 (Ar), 134.1 (CH2CHCH2),
134.05 (Ar), 133.96 (Ar), 131.9 (Ar), 131.8 (Ar), 129.9 (Ar), 129.4
(Ar), 129.1 (Ar), 128.5 (Ar), 128.4 (Ar), 128.1 (Ar), 127.8 (Ar), 127.5
(Ar), 127.2 (Ar), 126.2 (Ar), 123.6 (Ar), 123.5 (Ar), 118.1
(CH2CHCH2), 101.7 (PhCH), 100.1 (Ido_C1), 82.8
(GlcN_C1), 79.2 (GlcN_C5), 79.0 (GlcN_C4), 78.5 (GlcN_C3),
76.4 (Ido_C3), 75.4 (PhCH2), 73.5 (Ido_C4), 73.3 (PhCH2), 71.6
(CH2CHCH2), 69.8 (Ido_C6), 68.8 (GlcN_C6), 67.7 (Ido_C2),
67.2 (Ido_C5), 55.0 (GlcN_C2). HRMS (ESI): calcd m/z for
C50H48ClNO11S (M + Na)+ 928.2529, found 928.2524.
(OCH3), 55.9 (GlcN_C2), 21.09 (Ac), 21.06 (Ac). HRMS (ESI):
calcd m/z for C46H47NO14 (M + NH4)+ 855.3335, found 855.3313.
Methyl 4,6-O-Benzylidene-β-D-galactopyranosyl-(1→4)-3,6-di-O-
benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (37). A sodium
methoxide solution was added dropwise (1.5 M NaOMe in MeOH, to
pH 10) to a solution of the starting material 36 (382 mg, 0.456 mmol)
in dry methanol (2.0 mL) and dry dichloromethane (2.0 mL) and the
solution allowed to mix at room temperature. After 15 min, the
reaction was then neutralized using ion-exchange resin (Amberlite IR-
120H, to pH 6), filtered, and evaporated to dryness to obtain the pure
product as a white solid (345 mg, 0.458 mmol, quantitative yield). Rf =
1
0.17 (ethyl acetate/toluene 3:7). [α]20D: +26.8 (c 1.05, CHCl3). H
NMR (CDCl3, 600 MHz): δ 7.74−7.65 (m, 4H, Phth), 7.39−7.33 (m,
6H, Ar), 7.30−7.22 (m, 4H, Ar), 7.04−7.00 (m, 2H, Ar), 6.86−6.79
(m, 3H, Ar), 5.44 (s, 1H, PhCH), 5.02 (d, 1H, J = 8.5 Hz, GlcN_H1),
4.96 (d, 1H, J = 12.4 Hz, PhCH2), 4.75 (d, 1H, J = 12.2 Hz, PhCH2),
4.58 (d, 1H, J = 12.2 Hz, PhCH2), 4.55 (d, 1H, J = 8.0 Hz, Gal_H1),
4.53 (d, 1H, J = 12.4 Hz, PhCH2), 4.40 (dd, 1H, J = 10.7, 8.6 Hz,
GlcN_H3), 4.18 (dd, 1H, J = 10.6, 8.5 Hz, GlcN_H2), 4.18 (dd, 1H, J
= 12.7, 1.1 Hz, Gal_H6a), 4.16 (m, 1H, GlcN_H4), 4.07 (dd, 1H, J =
11.3, 3.2 Hz, GlcN_H6a), 4.05 (dd, 1H, J = 3.7, <1 Hz, Gal_H4), 3.85
(dd, 1H, J = 12.7, 1.6 Hz, Gal_H6b), 3.83 (dd, 1H, J = 11.5, 1.9 Hz,
GlcN_H6b), 3.69 (ddd, 1H, J = 9.6, 7.9, 2.0 Hz, Gal_H2), 3.65 (ddd,
1H, J = 9.9, 3.0, 2.0 Hz, GlcN_H5), 3.47 (ddd, 1H, J = 9.2, 9.2, 3.8 Hz,
Gal_H3), 3.37 (s, 3H, OCH3), 3.32 (broad, 1H, Gal_2OH), 3.08 (m,
1H, Gal_H5), 2.50 (broad, 1H, Gal_3OH). 13C NMR (CDCl3, 150
MHz): δ 168.4 (Phth), 167.8 (Phth), 138.8 (Ar), 138.1 (Ar), 137.9
(Ar), 133.9 (Ar), 131.9 (Ar), 129.3 (Ar), 128.6 (Ar), 128.4 (Ar),
128.13 (Ar), 128.07 (Ar), 127.92 (Ar), 127.90 (Ar), 127.2 (Ar), 126.6
(Ar), 123.5 (Ar), 103.2 (Gal_C1), 101.5 (PhCH), 99.5 (GlcN_C1),
78.9 (GlcN_C4), 78.4 (GlcN_C3), 75.2 (Gal_C4), 75.0 (PhCH2),
74.9 (GlcN_C5), 73.6 (PhCH2), 73.0 (Gal_C3), 72.7 (Gal_C2), 69.2
(Gal_C6), 68.4 (GlcN_C6), 66.7 (Gal_C5), 56.8 (OCH3), 56.0
(GlcN_C2). HRMS (ESI): calcd m/z for C42H43NO12 (M + NH4)+
771.3123, found 771.3094.
Methyl 4,6-O-Benzylidene-2,3-di-O-mesyl-β-D-galactopyranosyl-
(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyrano-
side (38). The starting material 37 (237 mg, 0.314 mmol) and
methanesulfonyl chloride (0.08 mL, 1 mmol) were dissolved in dry
pyridine (1.4 mL) and dry dichloromethane (1.5 mL) and allowed to
mix at 45 °C. After 16 h, the reaction was quenched via the addition of
water (0.5 mL), the crude mixture evaporated to dryness via
coevaporation with toluene (2 × 1 mL) and then redissolved in
ethyl acetate (30 mL). The organic phase was washed with saturated
sodium chloride solution (2 × 30 mL), water (30 mL), dried with
sodium sulfate, filtered, and evaporated to dryness. The crude material
was then purified via column chromatography on silica using 0.4 →
0.7% methanol−dichloromethane to afford the pure product as a white
solid (261 mg, 0.287 mmol, 91% yield). Rf = 0.42 (methanol/
dichloromethane 1:49). [α]20D: +6.0 (c 0.95, CHCl3). 1H NMR
(CDCl3, 600 MHz): δ 7.79−7.57 (m, 4H, Phth), 7.42−7.35 (m, 5H,
Ar), 7.33−7.30 (m, 2H, Ar), 7.24−7.23 (m, 1H, Ar), 7.22−7.18 (m,
2H, Ar), 6.98−6.94 (m, 2H, Ar), 6.79−6.73 (m, 3H, Ar), 5.45 (s, 1H,
PhCH), 5.02 (d, 1H, J = 8.5 Hz, GlcN_H1), 4.92 (d, 1H, J = 12.4 Hz,
PhCH2), 4.85 (d, 1H, J = 12.0 Hz, PhCH2), 4.75 (dd, 1H, J = 9.9, 7.9
Hz, Gal_H2), 4.49 (d, 1H, J = 7.8 Hz, Gal_H1), 4.46 (d, 1H, J = 12.4
Hz, PhCH2), 4.44 (dd, 1H, J = 10.0, 3.9 Hz, Gal_H3), 4.40 (d, 1H, J =
12.0 Hz, PhCH2), 4.36 (dd, 1H, J = 3.8, <1 Hz, Gal_H4), 4.29 (dd,
1H, J = 12.5, 1.4 Hz, Gal_H6a), 4.25 (dd, 1H, J = 10.7, 8.5 Hz,
GlcN_H3), 4.18 (dd, 1H, J = 9.7, 8.5 Hz, GlcN_H4), 4.14 (dd, 1H, J
= 10.7, 8.5 Hz, GlcN_H2), 4.03 (dd, 1H, J = 11.1, 2.8 Hz,
GlcN_H6a), 3.91 (dd, 1H, J = 12.5, 1.7 Hz, Gal_H6b), 3.80 (dd, 1H, J
= 11.1, 1.5 Hz, GlcN_H6b), 3.61 (ddd, 1H, J = 9.9, 2.6, 1.6 Hz,
GlcN_H5), 3.37 (s, 3H, OCH3), 3.08 (s, 3H, SO2CH3), 4.08 (m, 1H,
Gal_H5), 3.07 (s, 3H, SO2CH3). 13C NMR (CDCl3, 150 MHz): δ
168.3 (Phth), 167.9 (Phth), 138.7 (Ar), 138.4 (Ar), 137.3 (Ar), 133.9
(Ar), 132.0 (Ar), 129.4 (Ar), 128.8 (Ar), 128.6 (Ar), 128.44 (Ar),
128.35 (Ar), 128.0 (Ar), 127.2 (Ar), 126.4 (Ar), 123.5 (Ar), 101.4
(PhCH), 99.5 (GlcN_C1), 99.3 (Gal_C1), 78.6 (GlcN_C4), 77.2
(Gal_C3), 77.1 (GlcN_C3), 76.6 (Gal_C2), 75.3 (PhCH2), 74.7
Methyl 2,3-Di-O-acetyl-4,6-O-benzylidene-β-D-galactopyranosyl-
(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyrano-
side (36). The disaccharide donor 31 (859 mg, 0.903 mmol), dry
methanol (0.30 mL, 7.4 mmol), and molecular sieves (4 Å crushed,
1.148 g) were added to dry dichloromethane (9.0 mL) and allowed to
mix under argon at room temperature. After 1.5 h, the flask was cooled
to −75 °C, and then N-iodosuccinimide (422 mg, 1.88 mmol) and
triflic acid (100 μL) were added. The flask was warmed up to room
temperature, allowed to mix for 16 h, and then neutralized with
triethylamine (to pH 8). The reaction contents were filtered through
Celite and the molecular sieves washed with dichloromethane (2 × 25
mL). The organic phase was washed with saturated sodium
bicarbonate solution (60 mL), saturated sodium chloride solution
(60 mL), water (60 mL), dried with sodium sulfate, filtered, and
evaporated to dryness. The crude material was then purified via
column chromatography using 20→25% acetone - hexanes to afford
the pure product as a white solid (522 mg, 0.623 mmol, 79% yield
based on recovered starting material) and recovered starting material
(102 mg, 0.118 mmol, 13% yield). Rf = 0.54 (ethyl acetate/toluene
1
3:7). [α]20D: +39.6 (c 0.97, CHCl3). H NMR (CDCl3, 600 MHz): δ
7.78−7.56 (m, 4H, Ar), 7.39−7.30 (m, 7H, Ar), 7.24−7.17 (m, 3H,
Ar), 6.97 (m, 2H, Ar), 6.78−6.71 (m, 3H, Ar), 5.40 (s, 1H, PhCH),
5.34 (dd, 1H, J = 10.4, 8.0 Hz, Gal_H2), 5.00 (d, 1H, J = 8.5 Hz,
GlcN_H1), 4.98 (d, 1H, J = 12.6 Hz, PhCH2), 4.80 (d, 1H, J = 12.0
Hz, PhCH2), 4.77 (dd, 1H, J = 10.4, 3.7 Hz, Gal_H3), 4.62 (d, 1H, J =
8.0 Hz, Gal_H1), 4.53 (d, 1H, J = 12.6 Hz, PhCH2), 4.50 (d, 1H, J =
12.0 Hz, PhCH2), 4.26 (m, 1H, Gal_H6a), 4.25 (m, 1H, GlcN_H3),
4.25 (m, 1H, Gal_H4), 4.13 (dd, 1H, J = 10.8, 8.6 Hz, GlcN_H2),
4.10 (dd, 1H, J = 9.8, 8.5 Hz, GlcN_H4), 3.90 (dd, 1H, J = 12.3, 1.7
Hz, Gal_H6b), 3.84 (dd, 1H, J = 10.9, 3.3 Hz, GlcN_H6a), 3.80 (dd,
1H, J = 10.9, 1.7 Hz, GlcN_H6b), 3.52 (ddd, 1H, J = 9.9, 3.2, 1.7 Hz,
GlcN_H5), 3.36 (s, 3H, OCH3), 3.22 (m, 1H, Gal_H5), 2.04 (s, 3H,
OAc), 2.03 (s, 3H, OAc). 13C NMR (CDCl3, 150 MHz): δ 170.9 (Ac),
169.2 (Ac), 168.3 (Phth), 167.9 (Phth), 138.9 (Ar), 138.3 (Ar), 137.9
(Ar), 133.8 (Phth), 132.1 (Phth), 131.9 (Phth), 129.2 (Ar), 128.7
(Ar), 128.4 (Ar), 128.3 (Ar), 128.2 (Ar), 128.1 (Ar), 127.9 (Ar), 127.1
(Ar), 126.6 (Ar), 123.4 (Phth), 101.3 (PhCH), 100.6 (Gal_C1), 99.4
(GlcN_C1), 78.5 (GlcN_C4), 77.2 (GlcN_C3), 75.3 (PhCH2), 75.2
(GlcN_C5), 73.8 (PhCH2), 73.5 (Gal_C4), 72.3 (Gal_C3), 69.5
(Gal_C2), 68.9 (Gal_C6), 67.9 (GlcN_C6), 66.3 (Gal_C5), 56.8
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(GlcN_C5), 74.3 (Gal_C4), 73.7 (PhCH2), 68.6 (Gal_C6), 67.9
(GlcN_C6), 65.8 (Gal_C5), 57.0 (OCH3), 55.9 (GlcN_C2), 39.8
(SO2CH3), 39.7 (SO2CH3). HRMS (ESI): calcd m/z for
C44H47NO16S2 (M + Na)+ 932.2229, found 932.2202.
128.43 (Ar), 128.37 (Ar), 128.3 (Ar), 128.0 (Ar), 127.9 (Ar), 127.6
(Ar), 127.5 (Ar), 127.1 (Ar), 126.2 (Ar), 101.7 (PhCH), 100.0
(Ido_C1), 99.5 (GlcN_C1), 79.4 (GlcN_C4), 77.7 (GlcN_C3), 76.7
(Ido_C3), 75.2 (PhCH2), 75.0 (GlcN_C5), 73.6 (Ido_C4), 73.3
(PhCH2), 72.8 (PhCH2), 69.8 (Ido_C6), 68.7 (GlcN_C6), 67.7
(Ido_C2), 67.2 (Ido_C5), 56.8 (OCH3), 56.0 (GlcN_C2). HRMS
(ESI): calcd m/z for C49H49NO12 (M + NH4)+ 861.3593, found
861.3656.
Methyl 2-O-Acetyl-3-O-benzyl-4,6-O-benzylidene-β-D-idopyrano-
syl-(1→4)-3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyra-
noside (39). A solution of potassium tert-butoxide in benzyl alcohol
(4.01 M, 0.54 mL, 2.2 mmol) in dioxane (0.5 mL) was added to a
solution of the starting material 38 (261 mg, 0.287 mmol) in dioxane
(5.0 mL). After 6 days, the reaction mixture was evaporated to dryness
via coevaporation with water (3 × 5 mL) and then redissolved in dry
pyridine (2 mL) and acetic anhydride (2 mL) and allowed to mix at 70
°C. After 16 h, the reaction mixture was evaporated to dryness via
coevaporation with toluene (3 × 2 mL), redissolved in ethyl acetate
(30 mL), washed with saturated sodium chloride solution (2 × 30 mL)
and water (30 mL), dried with sodium sulfate, filtered, and evaporated
to dryness. The crude material was then purified via column
chromatography on silica using 20% acetone−hexanes to afford the
pure product as a white solid (189 mg, 0.214 mmol, 75% yield). Rf =
0.45 (acetone/hexanes 3:7). [α]20D: +32.3° (c 0.99, CHCl3). 1H NMR
(CDCl3, 600 MHz): δ 7.81−7.69 (m, 4H, Phth), 7.46−7.45 (m, 2H,
Ar), 7.37−7.31 (m, 9H, Ar), 7.30−7.24 (m, 4H, Ar), 7.08−7.04 (m,
2H, Ar), 6.87−6.80 (m, 3H, Ar), 5.41 (s, 1H, PhCH), 5.18 (d, 1H, J =
0.8 Hz, Ido_H1), 5.09 (d, 1H, J = 12.2 Hz, PhCH2), 5.07 (d, 1H, J =
8.5 Hz, GlcN_H1), 5.02 (m, 1H, Ido_H2), 4.70 (d, 1H, J = 11.8 Hz,
PhCH2), 4.66 (d, 1H, J = 12.2 Hz, PhCH2), 4.61 (d, 1H, J = 11.7 Hz,
PhCH2), 4.59 (d, 1H, J = 11.9 Hz, PhCH2), 4.55 (d, 1H, J = 12.0 Hz,
PhCH2), 4.39 (dd, 1H, J = 10.7, 8.6 Hz, GlcN_H3), 4.29 (dd, 1H, J =
12.4, <1 Hz, Ido_H6a), 4.25 (dd, 1H, J = 9.8, 8.7 Hz, GlcN_H4), 4.21
(dd, 1H, J = 10.7, 8.5 Hz, GlcN_H2), 3.92 (dd, 1H, J = 12.3, 1.9 Hz,
Ido_H6b), 3.91 (m, 1H, Ido_H3), 3.84 (dd, 1H, J = 10.9, 1.6 Hz,
GlcN_H6a), 3.83 (m, 1H, Ido_H4), 3.77 (dd, 1H, J = 11.0, 3.4 Hz,
GlcN_H6b), 3.65 (ddd, 1H, J = 9.8, 3.2, 1.6 Hz, GlcN_H5), 3.53 (m,
1H, Ido_H5), 3.41 (s, 3H, OCH3), 2.03 (s, 3H, OAc). 13C NMR
(CDCl3, 150 MHz): δ 171.0 (OAc), 168.6 (Phth), 167.5 (Phth), 139.0
(Ar), 138.6 (Ar), 138.4 (Ar), 137.5 (Ar), 133.8 (Ar), 132.0 (Ar), 129.2
(Ar), 128.7 (Ar), 128.40 (Ar), 128.39 (Ar), 128.3 (Ar), 128.2 (Ar),
128.03 (Ar), 127.96 (Ar), 127.6 (Ar), 127.4 (Ar), 127.2 (Ar), 126.6
(Ar), 123.4 (Ar), 101.3 (PhCH), 99.5 (GlcN_C1), 97.7 (Ido_C1),
78.4 (GlcN_C4), 77.3 (GlcN_C3), 75.1 (Ido_C3), 74.85
(GlcN_C5), 74.84 (PhCH2), 73.2 (PhCH2), 72.8 (PhCH2), 72.1
(Ido_C4), 69.5 (Ido_C6), 68.7 (GlcN_C6), 67.2 (Ido_C2), 66.9
(Ido_C5), 56.7 (OCH3), 55.8 (GlcN_C2), 21.3 (OAc). HRMS (ESI):
calcd m/z for C51H51NO13 (M + Na)+ 908.3253, found 908.3225.
Methyl 3-O-Benzyl-4,6-O-benzylidene-β-D-idopyranosyl-(1→4)-
3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (40).
A sodium methoxide solution was added dropwise (1.5 M NaOMe/
MeOH, to pH 10) to a solution of the starting material 39 (34 mg,
0.039 mmol) in dry methanol (0.2 mL) and dry dichloromethane (0.2
mL) and the solution allowed to mix at room temperature. After 15
min, the reaction was neutralized using ion-exchange resin (Amberlite
IR-120H, to pH 6), filtered, and evaporated to dryness to afford the
pure product as a white solid (32 mg, 0.037 mmol, 97% yield). Rf =
Methyl 2-O-Acetyl-β-D-idopyranosyl-(1→4)-2-deoxy-2-phthalimi-
do-β-D-glucopyranoside (41). The protected disaccharide 39 (75 mg,
0.085 mmol), palladium(0) (10% Pd on charcoal; 33 mg), and acetic
acid (2 drops) were added to dry methanol (3.0 mL), and the solution
was allowed to mix under positive pressure hydrogen gas. After 2 days,
the mixture was filtered and evaporated to dryness. The crude material
was then purified via column chromatography on silica using 8%
methanol−dichloromethane to afford the pure product as a white solid
(46 mg, 0.087 mmol, quantitative yield). Rf = 0.45 (methanol/
dichloromethane 1:9). [α]20D: −24.8 (c 0.77, CHCl3). 1H NMR
(CDCl3, 600 MHz): δ 7.82−7.78 (m, 2H, Phth), 7.71−7.67 (m, 2H,
Phth), 5.08 (d, 1H, J = 8.5 Hz, GlcN_H1), 5.06 (dd, 1H, J = 2.8, <1
Hz, Ido_H2), 5.03 (d, 1H, J = <1 Hz, Ido_H1), 4.80 (broad, 1H,
GlcN_3OH), 4.52 (broad, 1H, Ido_3OH), 4.38 (ddd, 1H, J = 10.5,
8.9, <1 Hz, GlcN_H3), 4.09 (m, 1H, Ido_H5), 4.04 (dd, 1H, J = 10.7,
8.5 Hz, GlcN_H2), 4.01 (m, 1H, Ido_H3), 3.90 (m, 1H, GlcN_H6a),
3.83−3.76 (m, 4H, GlcN_H4, GlcN_H6b, Ido_H6a, and Ido_H6b),
3.64−3.59 (m, 3H, Ido_H4, GlcN_6OH, and Ido_6OH), 3.45 (m,
1H, GlcN_H5), 3.36 (s, 3H, OCH3), 3.10 (broad, 1H, J = 8.7 Hz,
Ido_4OH), 2.09 (s, 3H, Ac). 13C NMR (CDCl3, 150 MHz): δ 170.2
(Ac), 168.65 (Phth), 168.62 (Phth), 134.4 (Ar), 132.0 (Ar), 124.0
(Ar), 123.4 (Ar), 99.6 (GlcN_C1), 99.1 (Ido_C1), 81.5 (GlcN_C4),
76.0 (Ido_C5), 74.6 (GlcN_C5), 70.4 (Ido_C2), 70.2 (GlcN_C3),
69.5 (Ido_C3), 68.5 (Ido_C4), 62.1 (Ido_C6), 60.9 (GlcN_C6), 57.3
(OCH3), 56.2 (GlcN_C2), 21.2 (Ac). HRMS (ESI): calcd m/z for
C23H29NO13 (M + NH4)+ 545.1977, found 545.1965.
Methyl 2,3,4,6-Tetra-O-acetyl-β-D-idopyranosyl-(1→4)-2-acet-
amido-3,6-di-O-acetyl-2-deoxy-β-D-glucopyranoside (42). The start-
ing material 41 (46 mg, 0.087 mmol) and hydrazine monohydrate (15
μL, 0.30 mmol) were refluxed in 95% ethanol (1.0 mL) for 24 h to
afford the free amine (Rf 0.53 in water: methanol 1:3). The reaction
mixture was evaporated to dryness and then redissolved in dry
pyridine (0.5 mL) and acetic anhydride (0.5 mL). After the mixture
was heated at 70 °C for 14 h, it was evaporated to dryness via
coevaporation with toluene (2 × 1 mL) and then purified via column
chromatography on silica using 1→ 3% methanol−dichloromethane to
afford the pure product as a white solid (35 mg, 0.054 mmol, 62%
yield over two steps). Rf = 0.29 (methanol/dichloromethane 3:97).
1
[α]20D: −21.3 (c 1.05, CHCl3). H NMR (CDCl3, 400 MHz): δ 5.58
(d, 1H, J = 9.2 Hz, NHAc), 5.15 (dd, 1H, J = 4.8, 4.8 Hz, Ido_H3),
5.09 (dd, 1H, J = 10.3, 8.7 Hz, GlcN_H3), 4.88 (dd, 1H, J = 5.0, 2.2
Hz, Ido_H2), 4.83 (d, 1H, J = 2.2 Hz, Ido_H1), 4.79 (dd, 1H, J = 4.5,
2.6 Hz, Ido_H4), 4.39 (dd, 1H, J = 11.8, 2.7 Hz, GlcN_H6a), 4.39 (d,
1H, J = 8.1 Hz, Ido_H1), 4.27 (dd, 1H, J = 12.0, 4.8 Hz, GlcN_H6b),
4.21−4.14 (m, 3H, Ido_H5, Ido_H6a, and Ido_H6b), 3.92 (ddd, 1H,
J = 10.3, 9.2, 8.2 Hz, GlcN_H2), 3.73 (dd, 1H, J = 9.4, 8.8 Hz,
GlcN_H4), 3.60 (ddd, 1H, J = 9.5, 4.7, 2.6 Hz, GlcN_H5), 3.44 (s,
3H, OMe), 2.09 (s, 3H, Ac), 2.08 (s, 3H, Ac), 2.06 (s, 3H, Ac), 2.06 (s,
3H, Ac), 2.06 (s, 3H, Ac), 2.05 (s, 3H, Ac), 1.93 (s, 3H, Ac). 13C NMR
(CDCl3, 100 MHz): δ 171.3 (Ac), 170.74 (Ac), 170.69 (Ac), 170.5
(Ac), 169.82 (Ac), 169.75 (Ac), 168.8 (Ac), 102.0 (GlcN_C1), 97.6
(Ido_C1), 76.0 (GlcN_C4), 72.9 (GlcN_C3), 72.6 (GlcN_C5), 71.5
(Ido_C5), 67.5 (Ido_C3), 67.2 (Ido_C2), 66.7 (Ido_C4), 63.0
(GlcN_C6), 62.6 (Ido_C6), 56.9 (OMe), 54.0 (GlcN_C2), 23.5
(Ac), 21.01 (Ac), 20.96 (Ac), 20.9 (Ac), 20.8 (Ac). HRMS (ESI):
calcd m/z for C27H39NO17 (M + H)+ 650.2291, found 650.2285.
Methyl β-D-Idopyranosyl-(1→4)-2-acetamido-2-deoxy-β-D-gluco-
pyranoside (43). A sodium methoxide solution was added dropwise
(1.5 M NaOMe in MeOH, to pH 10) to a solution of the starting
material 42 (18 mg, 0.028 mmol) in dry methanol (0.20 mL), and the
solution was allowed to mix at room temperature. After 12 h, the
reaction was then neutralized using ion-exchange resin (Amberlite IR-
1
0.29 (acetone/hexanes 3:7). [α]20D: +3.1 (c 1.08, CHCl3). H NMR
(CDCl3, 600 MHz): δ 7.77−7.64 (m, 4H, Phth), 7.36−7.35 (m, 2H,
Ar), 7.31−7.23 (m, 13H, Ar), 7.04−7.02 (m, 2H, Ar), 6.82−6.78 (m,
3H, Ar), 5.40 (s, 1H, PhCH), 5.05 (d, 1H, J = <1 Hz, Ido_H1), 5.03
(d, 1H, J = 8.6 Hz, GlcN_H1), 5.02 (d, 1H, J = 12.3 Hz, PhCH2), 4.56
(d, 1H, J = 11.8 Hz, PhCH2), 4.56 (d, 1H, J = 12.0 Hz, PhCH2), 4.56
(d, 1H, J = 12.3 Hz, PhCH2), 4.53 (d, 1H, J = 12.1 Hz, PhCH2), 4.52
(d, 1H, J = 11.8 Hz, PhCH2), 4.44 (dd, 1H, J = 10.7, 8.6 Hz,
GlcN_H3), 4.27 (dd, 1H, J = 12.5, 1.1 Hz, Ido_H6a), 4.16 (m, 1H,
GlcN_H2), 4.16 (m, 1H, GlcN_H4), 3.92 (m, 1H, Ido_H4), 3.90
(dd, 1H, J = 12.5, 1.7 Hz, Ido_H6b), 3.86 (dd, 1H, J = 2.9, 2.9 Hz,
Ido_H3), 3.82 (dd, 1H, J = 11.0, 1.8 Hz, GlcN_H6a), 3.79 (dd, 1H, J
= 11.0, 3.3 Hz, GlcN_H6b), 3.77 (m, 1H, Ido_H2), 3.68 (ddd, 1H, J =
9.9, 3.1, 2.0 Hz, GlcN_H5), 3.60 (m, 1H, Ido_H5), 3.37 (s, 3H,
OCH3), 3.28 (d, 1H, J = 11.9 Hz, Ido_2OH). 13C NMR (CDCl3, 150
MHz): δ 168.1 (Phth), 139.0 (Ar), 138.5 (Ar), 137.64 (Ar), 137.56
(Ar), 133.8 (Ar), 132.0 (Ar), 129.4 (Ar), 128.8 (Ar), 128.5 (Ar),
6771
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Featured Article
120H, to pH 6), filtered, and evaporated to dryness to afford the pure
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product as a colorless syrup (11 mg, 0.028 mmol, quantitative yield).
1
[α]20D: −9.9 (c 0.95, MeOH). H NMR (CD3OD, 400 MHz): δ 4.89
(d, 1H, J = <1 Hz, Ido_H1), 4.33 (d, 1H, J = 8.1 Hz, GlcN_H1),
4.00−3.95 (m, 2H, Ido_H5 and Ido_H3), 3.84 (dd, 1H, J = 12.1, 2.2
Hz, GlcN_H6a), 3.81 (dd, 1H, J = 11.5, 7.6 Hz, Ido_H6a), 3.76−3.64
(m, 6H, GlcN_H6b, GlcN_H2, Ido_H6b, Ido_H2, GlcN_H4, and
GlcN_H3), 3.53 (m, 1H, Ido_H4), 3.46 (s, 3H, OMe), 3.40 (ddd, 1H,
J = 9.1, 4.3, 2.1 Hz, GlcN_H5), 1.97 (s, 3H, Ac). 13C NMR (CD3OD,
100 MHz): δ 173.8 (Ac), 103.8 (GlcN_C1), 101.1 (Ido_C1), 81.1
(GlcN_C4), 77.2 (Ido_C5), 76.7 (GlcN_C5), 74.3 (GlcN_C3), 72.0
(Ido_C2), 71.5 (Ido_C3), 70.4 (Ido_C4), 62.9 (Ido_C6), 62.1
(GlcN_C6), 57.2 (OMe), 56.8 (GlcN_C2), 23.1 (Ac). HRMS (ESI):
calcd m/z for C15H27NO11 (M + Na)+ 420.1476, found 420.1478.
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1974, 2024.
(30) Cunningham, D.; Gavin, N.; Lee, E.; McArdle, P.; Ocallaghan,
J.; Higgins, T. Carbohydr. Res. 1988, 177, 1.
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S
* Supporting Information
1H and 13C NMR spectra for all compounds and H_1H
1
GCOSY spectra for all synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (+1) 403 289-9488. E-mail: ccling@ucalgary.ca.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada, the Canadian Foundation for Innovation,
and the Government of Alberta for support of this project.
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