Glycosyl dithiocarbamates: β-selective couplings without auxiliary groups

Article abstract of DOI:10.1021/jo500032k

In this article, we evaluate glycosyl dithiocarbamates (DTCs) with unprotected C2 hydroxyls as donors in β-linked oligosaccharide synthesis. We report a mild, one-pot conversion of glycals into β-glycosyl DTCs via DMDO oxidation with subsequent ring opening by DTC salts, which can be generated in situ from secondary amines and CS₂. Glycosyl DTCs are readily activated with Cu(I) or Cu(II) triflate at low temperatures and are amenable to reiterative synthesis strategies, as demonstrated by the efficient construction of a tri-β-1,6-linked tetrasaccharide. Glycosyl DTC couplings are highly β-selective despite the absence of a preexisting C2 auxiliary group. We provide evidence that the directing effect is mediated by the C2 hydroxyl itself via the putative formation of a cis-fused bicyclic intermediate.

Full text of DOI:10.1021/jo500032k

Article
pubs.acs.org/joc
Glycosyl Dithiocarbamates: β‑Selective Couplings without Auxiliary
Groups
Panuwat Padungros,† Laura Alberch, and Alexander Wei*
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States
S
* Supporting Information
ABSTRACT: In this article, we evaluate glycosyl dithiocarba-
mates (DTCs) with unprotected C2 hydroxyls as donors in β-
linked oligosaccharide synthesis. We report a mild, one-pot
conversion of glycals into β-glycosyl DTCs via DMDO
oxidation with subsequent ring opening by DTC salts, which
can be generated in situ from secondary amines and CS2.
Glycosyl DTCs are readily activated with Cu(I) or Cu(II)
triflate at low temperatures and are amenable to reiterative
synthesis strategies, as demonstrated by the efficient
construction of a tri-β-1,6-linked tetrasaccharide. Glycosyl
DTC couplings are highly β-selective despite the absence of a
preexisting C2 auxiliary group. We provide evidence that the directing effect is mediated by the C2 hydroxyl itself via the putative
formation of a cis-fused bicyclic intermediate.
DTCs are excellent candidates for electrophilic activation
based on their strong affinity for metals11 and the relatively low
oxidative potentials of thioamide species.17,18 The latter is
significant, as the activation barriers of thioglycosides and
related species have been shown to correlate with their
oxidative potentials.19 Surprisingly, glycosyl DTCs have been
largely overlooked as donors despite the use of closely related
glycosyl thioimidates in carbohydrate synthesis.1 This may be
partly due to earlier challenges in the preparation of glycosyl
DTCs by the nucleophilic substitution of glycosyl halides with
DTC salts20,21 or by the dehydrative substitution of lactols
(hemiacetals) under phase-transfer conditions.22 Furthermore,
although glycosyl DTCs have been shown to produce
disaccharides in good yield, the coupling conditions involve
excess activating agent and offer limited stereocontrol. We find
that glycosyl DTCs are efficiently prepared from glycals, and we
demonstrate their use in the synthesis of oligosaccharides using
mild Lewis acids.
A remarkable aspect of this study is that glycosyl DTCs are
highly β-selective in the absence of predesignated auxiliary
groups. β-Linked glycosides are typically formed using glycosyl
donors with an acyl group at the C2 position (Figure 1, top).
However, acylated glycosyl donors can have variable reactivity:
in some cases, a 2-O-benzoate or pivaloate can enhance donor
reactivity,1,23 but in other cases, the electron-withdrawing
nature of acyl groups can be deactivating.24 Furthermore,
donors with C2 acyl groups can form stabilized 1,2-
dioxolenium intermediates whose ambident nature can give
rise to competing orthoester byproducts, particularly when
INTRODUCTION
■
Thioglycosides are widely used as glycosyl donors in the
synthesis of complex oligosaccharides because their stability,
ease of activation, and flexibility in the tuning of glycosyl
coupling conditions. Numerous thioglycosyl donors have been
developed, resulting in both technological advances and
mechanistic insights for glycosyl activation.1 For example,
thioglycosides are often orthogonal with respect to glycosyl
donors that are activated by Lewis acids,2 and their reactivities
can be tuned to enable programmable one-pot oligosaccharide
syntheses.3 Thioglycosyl donors can also be activated at low
temperatures to generate highly reactive glycosyl triflates
followed by coupling with an acceptor.4−7 However, thioglyco-
sides are susceptible to side reactions, such as aglycon transfer
or cross-reactivity between the thiophilic promoter and
acceptor,8 and the influence of protecting groups on donor
reactivity (i.e., armed vs disarmed) can sometimes be
counterproductive toward glycosyl coupling. Such limitations
motivate the search for new glycosyl donors and activation
conditions.
In this article, we evaluate glycosyl dithiocarbamates (DTCs)
as activatible donors for glycoconjugate and oligosaccharide
synthesis. We have recently described the in situ generation of
glycosyl DTCs as intermediates in a modified version of glycal
assembly;9 here, we deliberately isolate glycosyl DTCs to
understand their reactivities further. DTCs already have broad
applicability in organic synthesis,10 as ligands in coordination
chemistry,11 and for the functionalization of metal surfa-
ces.12−14 An especially appealing quality of DTCs is that many
of them can be prepared in situ simply by adding amines to CS2
in polar solvents.15,16
Received: January 12, 2014
Published: February 18, 2014
© 2014 American Chemical Society
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Figure 1. β-Selective glycosylation using (i) 2-O-acyl glycosyl donors (with potential formation of orthoester byproduct) or (ii) glycosyl
dithiocarbamates with free C2 hydroxyls.
challenged with sterically hindered acceptors.23,25 Such issues
Table 1. One-Pot Synthesis of Glycosyl Dithiocarbamates
from Glycals
a
are neatly circumvented when using glycosyl DTCs (Figure 1,
bottom). With regard to the basis for β-selectivity, we present a
series of experiments to show that the C2 hydroxyl itself plays
an essential directing role in β-glycoside formation.
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Glycosyl Dithio-
carbamates. At the outset, we presumed β-glycosyl DTCs
could be readily prepared via SN2 epoxide ring opening of α-
epoxyglycals, which are in turn prepared selectively by treating
glycals with dimethyldioxirane (DMDO).23,26,27 In our previous
studies with glycals and the closely related 4-deoxypenteno-
sides, their corresponding epoxides reacted readily in THF with
mildly basic nucleophiles such as thiolates.26,27 However, initial
attempts to treat tri-O-benzyl epoxyglucal 1 with Et2DTC
diethylammonium salt (prepared in situ from a 2:1 ratio of
Et2NH and CS2) resulted in little to no glycosyl DTC
formation. The addition of Lewis acids such as LiClO4, which
has been reported to catalyze epoxyglycal ring opening under
aprotic conditions,28 did not lead to significant improvements.
However, epoxide ring openings with DTC salts in protic
solvents proved to be highly effective. Thus, treatment of 1 with
stoichiometric amounts of DMDO produced α-epoxyglycal
with high stereoselectivity, with subsequent addition of various
dialkyl-DTCs in MeOH giving β-glycosyl DTCs 2−5 in good
to high overall yields (Table 1). The glycosyl DTCs were stable
toward chromatographic separation and could be stored at −20
°C for months without any decomposition. 13C NMR chemical-
shift analysis indicated the anomeric (C1) and CS carbonyl
signals to be at 90−92 and 192−198 ppm; 1H NMR analysis of
diethyl-DTC glycoside 2 revealed the C1 methine proton to be
a
Standard conditions: (i) DMDO (1.5 equiv), 0 °C, DCM; (ii) CS2 (4
equiv), R2NH (8 equiv), 4:1 THF/MeOH, 0 °C to rt; [rxn] = 0.1 M.
Facioselectivity of epoxidation was 10:1 α/β. Isolated yield of β-
glycosyl DTC.
a
Table 2. Synthesis of Glycosyl N,N-Diphenyl-DTC 6
3
b
notably downfield (δ 6.10 ppm; J = 10 Hz), consistent with
entry
solvent
yield
previous literature.20
1
2
3
4
5
THF/CH3OH (1:2)
THF/H2O (1:2)
82%
77%
65%
37%
18%
Glycosyl N,N-diphenyl-DTC 6 was synthesized in a similar
fashion except that a DTC lithium salt was generated from CS2
and Ph2NLi, with the latter prepared from diphenylamine with
Li-dimsyl. Again, epoxide ring openings proceeded most
efficiently when performed in a mixture of THF and MeOH
(82% yield); other aprotic polar solvents produced glycosyl
DTC 6 in lower yields (Table 2).29 It is worth noting that
epoxide ring openings with DTCs were also efficient in aqueous
THF, but reactions in pure MeOH or other alcohols gave
poorer results (entries 2 and 3). We did not observe significant
amounts of solvolysis despite the well-established sensitivity of
epoxyacetals to alcohols under mildly acidic conditions.27,30
The efficiency of epoxide ring opening under protic
conditions can be attributed to the combination of the high
nucleophilicity of DTC anion and the low activation barrier for
c
CH3OH
THF/CH3CN (1:1)
DMF
a
Standard conditions: (i) DMDO (1.5 equiv), 0 °C, DCM; (ii) CS2 (4
b
equiv), Ph2NLi (2 equiv), 0 °C to rt; [1] = 0.1 M. 10:1 α/β. Isolated
yield of β-glycosyl DTC. Other alcohols (EtOH, i-PrOH, tBuOH)
gave inferior results.
c
reprotonation. The importance of protic solvents in epoxyglycal
ring opening has been noted previously.31 It is also worth
mentioning that the α-mannosyl DTC (the expected ring-
opening product from the minor β-epoxyglucal) is never
observed; 1H NMR analysis of the crude reaction mixture after
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DTC treatment revealed only β-glucosyl DTC without any
trace of mannosyl DTC. This implies that the β-epoxide is
unreactive to the DTC anion and decomposes upon workup, a
form of chiral resolution favoring the α-epoxyglycal. The
practical result is a clean isolation of β-glycosyl DTC products
regardless of the facioselectivity of glycal epoxidation.27,32
Glycosyl DTC 2 was converted into tetra-O-benzylglucosyl
DTC (2a), which produced high-quality crystals via slow
evaporation of a toluene−hexanes solution at room temper-
Table 3. Glycosyl Coupling of DTC Donor 2 and Glycal
Acceptor 7
4
ature (Figure 2). X-ray crystallographic analysis revealed a C1
Figure 2. X-ray crystal structure of tetra-O-benzylglucosyl DTC (2a),
displayed as a capped-stick model (left) with 50% ellipsoids (right).
conformation with the dithiocarbamate adopting an exoano-
meric (least sterically encumbered) conformation. The O5−
C1−S bond angle (109.25°) is essentially that of a tetrahedral
sp3 carbon, with minimal torsional strain and no evidence of
secondary interactions between the carbodithioate and the
carbohydrate structure. We thus assume DTC activation to be
driven by its affinity for the thiophilic agent.
a
Standard conditions: [2] = 0.15 M; acceptor 7 (1.5 equiv), Lewis acid
(2 equiv), base (2 equiv), 4 Å molecular sieves, DCM, −50 to −30 °C.
b
c
d
e
1:1 DCE/DCM. Isolated yields. Warmed to 0 °C. Warmed to rt.
f
g
Disaccharide 9 was produced in 48% yield. Determined by 1H NMR
h
signal integration. Disaccharide 9 was isolated but not fully
characterized; 1H and 13C NMR spectra are available in the Supporting
Information.
Optimization of Glycosylation Conditions. The
straightforward conversion of glycals into glycosyl DTC donors
prompted us to investigate their coupling with glycal acceptors,
inspired by the seminal studies by Danishefsky and co-
workers.33 Glycosyl coupling conditions were systematically
screened using N,N-diethyl-DTC donor 2 and 4,6-benzylidene-
protected acceptor 7 (Table 3). Standard Lewis acids such as
TMSOTf did not produce disaccharide glycals at low
temperatures, and warming the reaction to 0 °C resulted in
decomposition of 2 (entry 1).34 Thiophilic agents such as
dimethylsulfonium triflate (DMTST)20 gave complex mixtures,
most likely because of the sensitivitiy of the enol ether moieties
in the acceptor and product (entry 2). We then examined metal
triflate salts, which have high affinity for the DTC group and
low reactivity toward the enol ether functionality. Zn(OTf)2
and AgOTf were previously used for glycosyl DTC activation,22
but neither gave satisfactory results (entries 3 and 4).
Fortunately, CuII(OTf)2 proved to be highly effective and
produced β-1,3-linked disaccharide 8 as the major product
(entry 5). The highest and most reproducible yields were
obtained by (i) sequential addition of acceptor 7 to preactivated
donor 2 and (ii) using a weak base such as tri-tert-
butylpyrimidine (TTBP). Couplings performed in the presence
of stronger bases like Et2NiPr (entry 6) required higher
temperatures (0 °C) to reach completion, presumably because
of coordination between the amine and Cu(OTf)2. We note
that Bronsted bases were not used in earlier reports involving
glycosyl DTC or thioimidate activation.1,20−22 However, in the
absence of base, the coupling reaction was compromised by
self-condensation of acceptor 7 into disaccharide 9 via Ferrier
rearrangement (entry 7). Lastly, β selectivity was maximized by
using 1:1 dichloroethane/dichloromethane (DCE/DCM) at
−30 °C (entry 8), but more polar solvents such as acetonitrile
or diethyl ether resulted in low yields. The basis for β selectivity
will be discussed in a later section.
To determine if the oxidation state of Cu had any influence
on glycosyl DTC activation, we also performed couplings with
CuIOTf·(C6H6)0.5, an air-sensitive metal salt.35 Controlled
addition of solid CuIOTf at low temperature to the reaction
mixture produced similar results, often with slightly better
isolated yields. CuIOTf was likewise compatible with acid-
sensitive functional groups such as benzylidene acetals and enol
ethers. We therefore used CuIOTf and CuII(OTf)2 interchange-
ably for all subsequent glycosyl couplings.
To determine whether Cu(OTf)x-mediated coupling could
be influenced by the redox potential of the glycosyl DTC
donor, we compared the efficiencies of coupling donors 2−6
with acceptor 7. Donors 2−6 were chosen on the basis of an
earlier electrochemical study that showed the redox potentials
of N,N-disubstituted DTCs to be influenced by their
substituents, with E0 values (versus SCE) ranging from ca.
−225 (for Ph2-DTC) to −302 mV (for Et2DTC).36 These
values suggested that glycosyl DTC 6 might be more reactive
than 2−4 if electron transfer was involved. Instead, N,N-
diphenyl DTC 6 was the least reactive donor, and unreacted
donor was recovered after workup. This series implies that
DTC activation is essentially driven by Lewis acid−base
interactions (Table 4) and confirms Et2-DTC derivative 2 to
be the most efficient and most practical donor for glycosyl
couplings.
One-Pot Cu(OTf)x-Mediated Coupling with Glycals via
Glycosyl Dithiocarbamates. Glycosyl DTC donor 2 was
tested with a variety of acceptors and was found to produce β-
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a
a
Table 4. Donor Activity of Glycosyl DTCs 2−6
Table 5. β-Selective Glycal Assembly via Glycosyl DTCs
b
c
glycosyl donor
yield
α/β
2 (R2 = Et2)
71%
58%
61%
1:9
1:8
1:9
1:8
3 (R2 = -(CH2)5-)
4 (R2 = Bn2)
6 (R2 = Ph2)
d
47%
a
Standard conditions: acceptor 7 (1.5 equiv), Cu(OTf)2 (2 equiv),
TTBP (2 equiv), 4 Å molecular sieves, 1:1 DCE/DCM, −50 to −30
b
c
1
°C; [rxn] = 0.1 M. Isolated yields. Determined by H NMR signal
d
integration. Twenty-three percent of glycosyl DTC 6 was recovered.
coupling products in good to high yields (Table 5, entries 1−
8). The glycosyl DTC couplings were efficient with 1.2−1.5
equiv of acceptor and compatible with acid-sensitive functional
groups. Importantly, the coupling procedure was simplified by
performing three operations (DMDO oxidation, DTC ring
opening, and glycosylation) in sequence without workup or
chromatographic purification of the glycosyl DTC.9 Thus,
DMDO oxidation of glycal 1 was followed immediately by
stoichiometric addition of diethyl-DTC salt in MeOH to afford
the corresponding β-glycosyl DTC 2, which was then dried by
azeotropic distillation with toluene and subjected to Cu(OTf)x-
mediated glycosyl couplings under the optimized conditions
above. This one-pot procedure produced β-glycosides such as
10−12, β-1,6-linked disaccharides 13−15, and β-1,4-linked
disaccharides 16 and 17, all with exclusive β selectivity.
We also evaluated Cu(OTf)x-mediated coupling with 4,6-
benzylidene-protected glucal 18 and galactal 20 (Table 5,
entries 9 and 10). The DTC donor derived from 18 was
combined with acceptor 7 but found to be significantly less
reactive relative to 2 (cf. Table 3); the reaction was warmed to
0 °C before affording disaccharide 19 in 42% yield. The lower
reactivity and yield can be attributed to the conformational
constraint imposed by the 4,6-benzylidene acetal (to be
discussed below). The DTC donor derived from galactal 20
was coupled with 3,4-di-O-benzyl glucal (22) to produce β-1,6-
linked disaccharide 21 in 78% yield, albeit with moderate
selectivity (β/α, 5:1). In these limiting cases, issues of reactivity
and stereoselectivity are readily addressed by installing a C2
auxiliary such as a benzoate onto the glycosyl DTC donor,
which guarantees β selectivity and improves the coupling yield
by as much as 30%.9
Having established an efficient and β-selective glycosylation
via in situ generation of glycosyl DTCs, we applied this
methodology toward the reiterative synthesis of a β-1,6-linked
tetrasaccharide (Scheme 1). First, glucal 1 was converted into 2
and coupled with acceptor 22 using CuOTf-mediated
glycosylation to afford β-1,6-linked disaccharide 13 in 69%
overall yield. The C2′ hydroxyl of 13 was then protected as
benzyl ether 23 and subjected to DMDO oxidation and
Et2NH/CS2 ring opening to yield glycosyl DTC 24 with >95%
β selectivity. CuOTf-mediated glycosylation with a second
round of 22 yielded β,β-linked trisaccharide 25 in 63% isolated
yield along with 7% of the β,α-linked product. 2′-O-Benzylation
of trisaccharide 25 afforded trisaccharide glycal 26 followed by
in situ conversion into β-glycosyl DTC 27 and coupling with
22 to obtain β,β,β-linked tetrasaccharide 28 in 49% isolated
yield as well as 10% of the β,β,α-linked product. Overall, the
synthesis of tetrasaccharide 28 was accomplished in just 11
a
Standard conditions: (i) DMDO (1.5 equiv), DCM, 0 °C; (ii) CS2
(1.05 equiv), Et2NH (2.1 equiv), 4:1 THF/MeOH, rt; (iii) Cu(OTf)2
(2 equiv), TTBP (2 equiv), 4 Å molecular sieves, 1:1 DCE/DCM,
b
−50 °C, then acceptor (1.5 equiv), −30 °C; [rxn] = 0.1 M. Isolated
c
yield of β isomer, unless stated otherwise. Also isolated 9% of α
d
e
f
isomer. See ref 9. CuIOTf was used at −50 °C. Ratio determined by
1H NMR signal integration.
steps and 19% overall yield from glucal donor 1 and 4.5 equiv
of glucal acceptor 22.
It should be noted that the C2′ protecting group in
disaccharides 23 and 26 was important for high facioselectivity
during epoxidation. DMDO oxidation of glycal 13 at −50 °C
resulted in a 3:1 ratio of α- and β-epoxides, whereas
epoxidation of 23 and 26 at −50 °C yielded the desired α-
epoxyglycals in >20:1 α/β selectivity. We have observed similar
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Scheme 1. Reiterative Synthesis of β-1,6-Linked Tetrasaccharide via Glycosyl DTC Intermediates
effects in the DMDO oxidation of a 4-deoxypentenosyl (4-DP)
disaccharide having a remote hydroxyl group.37
glycosylation with 29 produced 30 in equally high yield but
with poor stereoselectivity, suggesting an active role for the C2
hydroxyl in stereoselective coupling.
Mechanistic Insights into β-Selective Glycosyl Cou-
plings. The glycosyl DTC couplings proceed cleanly with high
yields and β selectivities despite the presence of a free C2
hydroxyl on the donor. Moreover, oligomerization of the
glycosyl donor is never observed. A survey of the literature
reveals just a handful of examples on β-selective coupling of
glycosyl donors with free C2 hydroxyls using either glycosyl
phosphates or thioglycosides.34,38 In the latter case, β selectivity
was attributed to in situ generation of an α-oxonium
intermediate (i.e., protonated epoxyglycal) followed by SN2
ring opening at C1 to produce β-glycosides. However, one
must also consider the conformational strain of placing the C2
hydroxyl of the glucopyranose in a pseudoaxial position prior to
epoxide ring closure.39,40 To test the putative α-oxonium
intermediate, we treated an α-epoxyglucal and acceptor at low
temperature with either TfOH or Cu(OTf)2 (Scheme 2A).
However, neither condition resulted in the selective formation
of β-glycosides, allowing us to eliminate this as a possible
intermediate.
We also considered whether β selectivity could be attributed
to SN2-like reactivity of an α-glycosyl triflate intermediate,
which is known to exist at low temperatures following glycosyl
activation.41−44 However, Cu(OTf)2-mediated glycosylation of
the 4,6-benzylidene-protected DTC donor derived from 18
produces β-coupling product exclusively and is also slow
relative to unconstrained donor 2, requiring temperatures up to
0 °C to reach completion (Table 5, entry 9). In addition, it has
been shown that conformationally constrained donors with 4,6-
benzylidene acetals favor α-glycoside formation, as the
increased stability of the α-glycosyl triflate forces the coupling
to proceed through the more reactive β-glycosyl triflate.45 We
thus rule out the intermediacy of an α-glycosyl triflate.
We propose that Cu(OTf)x activation of the glycosyl DTC
promotes intramolecular addition of the C2 hydroxyl to form a
bicyclic, trans-fused orthodithiocarbamate, which rapidly
equilibrates via an oxocarbenium intermediate to a cis-fused
bicyclic system with reduced torsional strain, accompanied by a
stabilizing anomeric effect on the C−S axial bond (Scheme
3).46 The activated orthodithiocarbamate is thus directed by the
Scheme 2. Control Experiments to Determine the Basis for
Selective β-Glycosylation
Scheme 3. Proposed Mechanism for the β Selectivity of
Activated Glycosyl Dithiocarbamates
To determine whether the C2 hydroxyl was important for β-
selective glycosylation, we compared donor 2 (with free C2
hydroxyl) with 2-O-triethylsilyl (TES) ether 29 using
isopropanol and Cu(OTf)2 for activation (Scheme 2B, C). As
expected, glycosylation with 2 was highly β-selective and
yielded β-isopropyl glucoside 10 as the major product, whereas
neighboring C2 hydroxyl, allowing the acceptor to attack the
exposed β-face for β-glycoside formation. We note that a similar
equilibration may be possible for glycosyl phosphates and
dithiophosphates.34,47
Additional evidence supporting the bicyclic orthodithiocar-
bamate intermediate was obtained by attempts to alkylate
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glycosyl DTC 6 under basic conditions. Exposure of 6 to NaH
or NaHDMS and BnBr in DMF produced the desired 2-O-
benzyl ether 31 in low yields along with major side product 32,
formed by the migration of the thiocarbamoyl unit to the C2
hydroxyl and S-benzylation at C1 (Scheme 4). This necessarily
implies the facile formation of the bicyclic orthodithiocarba-
mate, which decomposes under anionic conditions to the C2
thiocarbamate and C1 thiolate prior to alkylation. A similar
migration has been observed in attempts to alkylate glycosyl
phosphoryldithioates, which produced a S-alkyl, 2-O-thiophos-
phoryl glycoside.47
The β-selective coupling was further investigated by low-
temperature 13C NMR experiments using CuOTf activation
because of its diamagnetic character.48 Glycosyl DTC 2 was
treated at −50 °C with CuOTf·(C6H6)0.5 in CD2Cl2 and
minimal 2-butanone to produce a green heterogeneous mixture,
which caused the disappearance of the thiocarbonyl signal (C7)
at 190.7 ppm and a reduction or broadening of the remaining
signals (Figure 3). Warming the solution to −10 °C resulted in
additional changes: (i) the appearance of two new peaks at
111.0 and 111.7 ppm, (ii) the loss of signal at 89.1 ppm (C1)
and the appearance of two new peaks at 97.2 and 97.5 ppm,
and (iii) the loss of signals at 47.1 and 49.8 ppm (methylene
carbons of Et2DTC) and the appearance of four new peaks
between 23−33 ppm. These signals can be ascribed to the
formation of orthodithiocarbamates (C7 epimers). We also
observe a minor signal at 197 ppm, suggesting the coexistence
of a stabilized oxocarbenium species,7,49−51 possibly generated
by reversible ligand dissociation from the 2−Cu complex.
A similar low-temperature 13C NMR study was performed on
tetra-O-benzylglucosyl DTC (2a). At −10 °C, new signals
could again be observed, but these are not suggestive of the
putative orthodithiocarbamate. Changes include the replace-
ment of thiocarbonyl signal at 191.9 with two peaks at 197.2
and 193 ppm (the latter attributable to free CS2), and the
replacement of the C1 signal at 89.1 ppm with a new peak at δ
104.3 ppm (Figure 4). Although the latter value is close to the
C1 chemical shift for glucosyl triflates,44,45,49,52 such species are
Scheme 4. Thiocarbamoyl Migration in 6 via Bicyclic
Orthodithiocarbamate Intermediate
Figure 3. 13C NMR analysis of glycosyl DTC activation using CuOTf·(C6H6)0.5 with a small amount of 2-butanone (CD2Cl2, 125 MHz). Bottom,
glycosyl DTC 2 at −50 °C; middle, 2 + CuOTf at −50 °C; and top, 2 + CuOTf at −10 °C. Butanone and impurity are marked with B and *,
respectively.
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Figure 4. 13C NMR analysis of glycosyl DTC−CuOTf complex using 2a and CuOTf·(C6H6)0.5 with a small amount of 2-butanone (CD2Cl2, 125
MHz). Bottom, glucosyl DTC 2a at −50 °C; top, 2a after treatment with CuOTf at −50 °C and warming to −10 °C. Butanone and impurity are
marked with B and *, respectively.
plates (G60F254) and detected by UV absorption at 254 nm or by
staining with p-anisaldehyde−sulfuric acid at 150 °C.
known to decompose above −20 °C, whereas activated 2a
appeared to be stable at −10 °C. This indicates that glycosyl
DTC−CuOTf complexes are more stable than glycosyl triflates
but retain sufficient reactivity for efficient coupling (cf. Scheme
2).
General Procedure for Epoxidations Using DMDO and in
Situ Formation of Glycosyl DTCs. DMDO solutions were prepared
according to our previous report.27 In a typical procedure, a glycal
(0.25 mmol) is dried by azeotropic distillation with toluene and
dissolved in CH2Cl2 (ca. 0.3 M), treated at 0 °C with a precooled
solution of DMDO (0.22 M in CH2Cl2, 1.5 equiv), and stirred for 1 h
or until the starting material is completely consumed. The reaction
mixture is carefully concentrated to dryness under reduced pressure,
starting at −78 °C with gradual warming to rt over 1 h until a white
solid is obtained. The crude α-epoxyglycal is dissolved in degassed
THF (2 mL) and cooled to 0 °C. In parallel, a degassed solution of
diethylamine (560 μL, 5.2 mmol) in MeOH (4.9 mL) is cooled to 0
°C under an argon atmosphere followed by dropwise addition of CS2
(160 μL, 2.6 mmol) and stirring at rt for 30 min to obtain a pale
yellow solution of Et2DTC (0.53 M in MeOH). A portion of this stock
(0.49 mL, 1.05 equiv) is added dropwise at 0 °C to the stirred
epoxyglycal solution, which is then warmed to rt for 2.5 h. The
reaction mixture is concentrated to dryness under reduced pressure
and further dried by azeotropic distillation with toluene (3 × 2 mL).
The glycosyl DTC can be used without further workup or purification.
Cu(OTf)x-Mediated Glycosyl Couplings. In a typical procedure,
the crude glycosyl DTC (0.25 mmol) is dried by azeotropic distillation
with toluene, dissolved in degassed 1:1 DCE/DCM (1.7 mL), treated
with TTBP (124 mg, 0.5 mmol) and activated 4 Å molecular sieves
(200 mg), and stirred for 1 h at rt. The reaction mixture is cooled to
−50 °C for 15 min, treated with anhydrous CuIIOTf2 (184 mg, 2
equiv) or CuIOTf·(C6H6)0.5 (126 mg, 2 equiv) in one portion, and
stirred for 10 min, during which the color turns from pale yellow to
brown to dark green. A solution of glycosyl acceptor in degassed 1:1
DCE/DCM (0.8 mL, 1.5 equiv) is cooled to −50 °C, added dropwise
to the reaction mixture via cannula, stirred for 5 min, warmed to −30
°C over a period of 45 min, and stirred at −30 °C for an additional 12
h. The dark green reaction mixture is warmed to 10 °C over a period
of 3 h, then quenched with a saturated NaHCO3 solution with
vigorous stirring for 15 min at rt. The yellow reaction mixture is then
passed through a pad of Celite and washed with EtOAc (3 × 5 mL)
prior to standard aqueous workup and purification by silica gel
chromatography.
CONCLUSIONS
■
Glycosyl dithiocarbamates can be prepared efficiently from
glycals by in situ DMDO oxidation and DTC ring opening,
enabling a one-pot glycosyl coupling with various acceptors.
The Cu(OTf)x-mediated glycosylations are highly β-selective
despite the absence of a predesignated C2 acyl group for
anchimeric assistance. We note that yields can be further
improved by chromatography-free acylation of the glycosyl
DTC donor prior to glycosyl coupling.9 Glycosyl DTCs are
useful in the reiterative assembly of β-linked oligosaccharides,
as demonstrated by an 11-step synthesis of a 1,6-linked
tetrasaccharide from glucal 1 in 19% overall yield. Control
experiments and low-temperature NMR analysis suggest the
involvement of a cis-fused bicyclic orthodithiocarbamate in the
β-selective coupling.
EXPERIMENTAL SECTION
■
General Methods. All starting materials and reagents were
obtained from commercial sources and used as received unless
otherwise noted. All experiments were performed under an argon
atmosphere unless otherwise specified. All solvents used were freshly
distilled prior to use; 4 Å molecular sieves were flame-dried under
reduced pressure. CuOTf·(C6H6)0.5 was prepared according to
literature procedures35 and handled under anaerobic conditions. H
1
and 13C NMR spectra were recorded on spectrometers operating at
300, 400, or 500 MHz and referenced to the solvent used (7.16 and
128.06 ppm for C6D6, 7.26 and 77.00 ppm for CDCl3). FT-IR spectra
were acquired using an attenuated total reflectance (ATR) module.
Optical rotations were measured at room temperature with a
polarimeter. Mass spectra were acquired using electrospray ionization.
Silica gel chromatography was performed in hand-packed columns,
and preparative TLC separations were performed with 0.5 mm silica-
coated plates. TLC analysis was monitored with 0.25 mm silica-coated
3,4,6-Tri-O-benzyl-β-D-glucopyranosyl 1-Diethyldithiocarba-
mate (2). Tri-O-benzyl glucal 1 (91 mg, 0.22 mmol) was subjected to
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DMDO oxidation at 0 °C for 1 h to provide α-epoxyglucal in
quantitative yield (10:1, α/β). The crude epoxyglucal was subjected to
DTC ring opening in THF with a freshly prepared solution of Et2DTC
(0.88 mmol, 0.5 M in MeOH) as described above. After workup, the
pale yellow syrup was purified by silica gel chromatography
(neutralized with 1% Et3N) using a 5−40% EtOAc in hexanes
gradient with 1% Et3N, with mixed fractions separated by preparative
TLC (30% EtOAc in hexanes with 1% Et3N) to afford glycosyl DTC 2
The reaction mixture was concentrated and purified by silica gel
chromatography using a 5−50% EtOAc in hexanes gradient with 1%
Et3N to afford glycosyl DTC 3 as a colorless syrup (121 mg, 89%). 1H
NMR (500 MHz, C6D6): δ 7.38 (d, 2H, J = 7.5 Hz), 7.28−7.07 (m,
13H), 6.20 (d, 1H, J = 10.3 Hz), 5.02 (d, 1H, J = 11.5 Hz), 4.87 (t, 2H,
J = 10.6 Hz), 4.64 (d, 1H, J = 11.4 Hz), 4.43 (d, 1H, J = 12.0 Hz), 4.26
(d, 1H, J = 12.0 Hz), 4.05 (t, 2H, J = 9.5 Hz), 3.94 (t, 2H, J = 9.1 Hz),
3.78−3.67 (m, 4H), 3.43−3.18 (m, 2H), 2.71 (br s, 1H), 1.16 (br s,
2H), 0.98 (br s, 4H). 13C NMR (125 MHz, C6D6): δ 192.2, 139.5,
139.2, 139.0, 138.8, 138.4, 136.7, 135.0, 128.3, 128.2, 128.0, 127.9,
127.8, 127.6, 90.3, 87.3, 79.9, 77.6, 75.2, 74.5, 73.4, 73.3, 69.0, 52.6,
51.1, 25.6, 25.0, 23.8. IR (thin film): 2941, 2852, 1480, 1421, 1362,
1244, 1222, 1067, 738, 691 cm−1. [α]D25 = +30.6° (c 2.0, CH2Cl2).
HRESI−MS: m/z calcd for C33H39NO5S2Na [M + Na]+, 616.2167;
found, 616.2160. Compound 3 was also characterized as the 2-O-
acetate by treatment with Ac2O (1 mL) in pyridine (2 mL) as
described above. The 1H NMR and pfg-COSY spectrum of 2-O-acetyl-
3 confirmed the β configuration (J1,2 = 10.8 Hz).
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl 1-Piperidi-
nyldithiocarbamate (2-O-acetyl 3). 1H NMR (400 MHz, C6D6): δ
7.47−6.83 (m, 15H), 6.38 (d, 1H, J = 10.8 Hz), 5.78 (dd, 1H, J = 10.8,
8.9 Hz), 4.74 (dd, 2H, J = 8.8, 11.6 Hz), 4.63 (d, 1H, J = 11.7 Hz),
4.56 (d, 1H, J = 11.4 Hz), 4.42 (d, 1H, J = 12.0 Hz), 4.25 (d, 1H, J =
11.9 Hz), 4.07 (m, 1H), 3.93 (t, 1H, J = 9.3 Hz), 3.82−3.73 (m, 2H),
3.72 (d, 1H, J = 1.7 Hz), 3.68 (dd, 1H, J = 3.2, 11.2 Hz), 3.23 (t, 1H, J
= 11.4 Hz), 3.09 (d, 1H, J = 14.6 Hz), 1.66 (s, 3H), 1.22−0.99 (m,
3H), 0.99−0.59 (m, 4H).
1
as a colorless syrup (111 mg, 87%). H NMR (500 MHz, C6D6): δ
7.39−7.05 (m, 15H), 6.15 (d, 1H, J = 10.4 Hz), 5.00 (d, 1H, J = 11.5
Hz), 4.89 (d, 1H, J = 11.5 Hz), 4.85 (d, 1H, J = 11.5 Hz), 4.63 (d, 1H,
J = 11.5 Hz), 4.42 (d, 1H, J = 12.0 Hz), 4.25 (d, 1H, J = 12.0 Hz), 4.00
(dd, 1H, J = 9.0, 9.5 Hz), 3.92 (dd, 1H, J = 9.0, 9.5 Hz), 3.74−3.57 (m,
6H), 3.18−3.02 (m, 2H), 2.65 (br s, 1H), 0.96 (t, 3H, J = 7.0 Hz),
0.75 (t, 3H, J = 7.5 Hz). 13C NMR (125 MHz, C6D6): δ 192.6, 139.7,
139.4, 139.0, 128.6, 128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 127.6,
90.5, 87.6, 80.1, 77.8, 75.5, 74.8, 73.7, 73.5, 69.1, 49.7, 47.0, 12.6, 11.6.
IR (thin film): 2869, 1502, 1451, 1413, 1354, 1261, 1202, 1067, 919,
746, 695 cm−1. [α]D25 = +23.0° (c 2.0, CH2Cl2). HRESI−MS: m/z
calcd for C32H39NO5S2Na [M + Na]+, 604.2167; found, 604.2158.
Compound 2 was also characterized as the 2-O-acetate by treatment
with Ac2O (1 mL) in pyridine (2 mL) at rt for 12 h followed by
concentration and azeotropic distillation with toluene (3 × 1 mL). The
1H NMR and pfg-COSY spectrum of 2-O-acetyl-2 confirmed the β
configuration (J1,2 = 10.7 Hz).
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl 1-Diethyl-
1
dithiocarbamate (2-O-acetyl 2). H NMR (500 MHz, C6D6): δ
7.25 (dd, 6H, J = 7.6, 9.5 Hz), 7.22−7.02 (m, 9H), 6.30 (d, 1H, J =
10.7 Hz), 5.72 (t, 1H, J = 10.7 Hz), 4.72 (dd, 2H, J = 9.0, 11.5 Hz),
4.62 (d, 1H, J = 11.7 Hz), 4.55 (d, 1H, J = 11.4 Hz), 4.41 (d, 1H, J =
11.9 Hz), 4.24 (d, 1H, J = 11.9 Hz), 3.89 (m, 1H), 3.80−3.74 (m, 2H),
3.72 (m, 1H), 3.70−3.58 (m, 2H), 3.53 (dt, 1H, J = 13.9, 7.0 Hz), 3.00
(q, 2H, J = 7.0 Hz), 1.64 (s, 3H), 0.90 (t, 3H, J = 7.0 Hz), 0.66 (t, 3H,
J = 7.1 Hz). 13C NMR (120 MHz, C6D6): δ 192.1, 169.4, 139.3, 139.2,
139.0, 128.6, 128.5, 128.4, 128.3, 128.1, 128.1, 127.9, 127.8, 127.7,
127.7, 127.6, 88.5, 85.6, 80.2, 78.1, 75.4, 74.8, 73.5, 71.2, 69.0, 49.6,
46.7, 20.6, 12.8, 11.5. IR (thin film): 2876, 1745, 1492, 1458, 1413,
3,4,6-Tri-O-benzyl-β-D-glucopyranosyl 1-Dibenzyldithiocar-
bamate (4). Tri-O-benzyl glucal 1 (95 mg, 0.23 mmol) was subjected
to DMDO oxidation at 0 °C for 1 h to provide α-epoxyglucal in
quantitative yield followed by DTC ring opening in THF with
Bn2DTC (0.92 mmol, 0.5 M solution in MeOH) as described above.
The pale yellow syrup was concentrated and purified by silica gel
chromatography using a 5−50% EtOAc in hexanes gradient with 1%
Et3N to afford glycosyl DTC 4 as a colorless syrup (135 mg, 83%). 1H
NMR (500 MHz, C6D6): δ 7.34 (d, 2H, J = 7.3 Hz), 7.28−7.26 (m,
3H), 7.23 (d, 2H, J = 7.3 Hz), 7.20−6.98 (m, 16H), 6.93 (d, 2H, J =
6.5 Hz), 6.15 (d, 1H, J = 10.3 Hz), 5.29 (d, 1H, J = 14.8 Hz), 5.17 (d,
1H, J = 14.8 Hz), 4.91 (d, 1H, J = 11.5 Hz), 4.86 (d, 1H, J = 11.4 Hz),
4.81 (d, 1H, J = 11.5 Hz), 4.62 (d, 1H, J = 11.0 Hz), 4.61−4.52 (m,
2H), 4.42 (d, 1H, J = 11.9 Hz), 4.27 (d, 1H, J = 11.9 Hz), 3.90 (t, 1H,
J = 9.2 Hz), 3.82 (dd, 1H, J = 8.6, 10.3 Hz), 3.78−3.60 (m, 4H), 3.58
(br s, 1H). 13C NMR (125 MHz, C6D6): δ 196.7, 139.4, 139.2, 138.8,
135.7, 128.9, 128.7, 128.3, 128.3, 128.2, 128.1, 127.9, 127.4, 127.0,
91.2, 87.1, 80.0, 77.5, 75.1, 74.5, 73.2, 73.2, 68.8, 56.4, 54.1. IR (thin
film): 2928, 1506, 1451, 1404, 1341, 1219, 1079, 746, 700 cm−1. [α]D25
= +36° (c 1.0, CH2Cl2). HRESI−MS: m/z calcd for C42H43NO5S2Na
[M + Na]+, 728.2480; found, 728.2474. Compound 4 was also
characterized as the 2-O-acetate by treatment with Ac21O (1 mL) in
pyridine (2 mL) at rt for 12 h as described above. The H NMR and
pfg-COSY spectrum of 2-O-acetyl-4 confirmed the β configuration
(J1,2 = 10.5 Hz).
1359, 1268, 1231, 1206, 1149, 1061, 917, 823, 746, 701 cm−1. [α]D25
+30.9° (c 3.8, CH2Cl2).
=
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl 1-Diethyldithio-
carbamate (2a). Glycosyl DTC 2 (273 mg, 0.47 mmol) was
disolved in DMF (5.8 mL), cooled to −50 °C under argon, and then
treated with BnBr (280 μL, 2.35 mmol). A 0.6 M solution of
NaHMDS in toluene (1.6 mL, 0.94 mmol) was added dropwise to the
reaction mixture, and the mixture was stirred at −50 °C for 5 min. The
reaction mixture was allowed to warm to room temperature over a
period of 2 h, quenched at 0 °C with saturated NH4Cl (10 mL), and
extracted with Et2O (3 × 10 mL). The combined organic extracts were
washed with H2O (3 × 10 mL) and brine (10 mL), dried over
Na2SO4, and concentrated under reduced pressure. After workup, the
yellow syrup was purified by silica gel chromatography (neutralized
with 1% Et3N) using a 5−60% EtOAc in hexanes gradient with 1%
Et3N to afford glycosyl DTC 2a as a colorless syrup (259 mg, 82%).
1H NMR (500 MHz, C6D6): δ 7.47−6.91 (m, 20H), 6.46 (d, 1H, J =
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl 1-Diben-
1
zyldithiocarbamate (2-O-acetyl 4). H NMR (500 MHz, C6D6):
δ 7.45−6.71 (m, 25H), 6.30 (d, 1H, J = 10.5 Hz), 5.70 (dd, 1H, J =
9.0, 10.5 Hz), 5.30 (d, 1H, J = 14.9 Hz), 5.15 (d, 1H, J = 14.9 Hz),
4.73 (dd, 2H, J = 8.3, 11.6 Hz), 4.63 (d, 1H, J = 11.7 Hz), 4.58−4.50
(m, 2H), 4.51−4.42 (m, 2H), 4.32 (d, 1H, J = 12.0 Hz), 3.87 (t, 1H, J
= 9.3 Hz), 3.84−3.73 (m, 3H), 3.68 (dd, 1H, J = 3.8, 11.4 Hz), 1.61 (s,
3H).
10.1 Hz), 4.88 (d, 1H, J = 11.4 Hz), 4.86−4.80 (m, 2H), 4.79 (s, 2H),
4.68 (d, 1H, J = 11.4 Hz), 4.42 (d, 1H, J = 11.9 Hz), 4.24 (d, 1H, J =
11.9 Hz), 4.00 (ddd, 1H, J = 2.4, 6.5, 9.2), 3.84−3.79 (m, 2H), 3.78−
3.56 (m, 5H), 3.13 (dt, 1H, J = 7.2, 14.4 Hz), 3.01 (dt, 1H, J = 7.2,
14.7 Hz), 0.96 (t, 3H, J = 7.0 Hz), 0.72 (t, 3H, J = 7.1 Hz). 13C NMR
(125 MHz, C6D6): δ 192.3, 139.3, 139.2, 138.9, 138.8, 128.3, 128.2,
127.8, 127.6, 127.4, 89.5, 87.3, 80.3, 79.7, 78.0, 75.5, 75.0, 74.6, 73.3,
68.9, 49.4, 46.5, 12.4, 11.4. IR (thin film): 2931, 2866, 1489, 1454,
3,4,6-Tri-O-benzyl-β-D-glucopyranosyl 1-Diisopropyldithio-
carbamate (5). Tri-O-benzyl glucal 1 (29 mg, 0.07 mmol) was
subjected to DMDO oxidation at 0 °C for 1 h to provide α-
epoxyglucal in quantitative yield followed by DTC ring opening in
THF with (i-Pr)2DTC (0.28 mmol, 0.5 M in MeOH) as described
above. The pale yellow syrup was concentrated and purified by silica
gel chromatography using a 5−30% EtOAc in hexanes gradient with
1% Et3N; mixed fractions were separated by preparative TLC (15%
EtOAc in hexanes with 1% Et3N) to afford glycosyl DTC 5 as a pale
1417, 1356, 1269, 1207, 1090, 1070, 916, 829, 735, 698 cm−1. [α]D25
=
+21.3° (c 0.3, CH2Cl2). HRESI−MS: m/z calcd for C39H46NO5S2 [M
+ H]+, 672.2817; found, 672.2812.
3,4,6-Tri-O-benzyl-β-D-glucopyranosyl 1-Piperidinyldithio-
carbamate (3). Tri-O-benzyl glucal 1 (95 mg, 0.23 mmol) was
subjected to DMDO oxidation at 0 °C for 1 h to produce α-
epoxyglucal in quantitative yield followed by DTC ring opening with
piperidinyl-DTC (0.92 mmol, 0.5 M in MeOH) as described above.
1
yellow syrup (22 mg, 52%). H NMR (500 MHz, C6D6): δ 7.36 (d,
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2H, J = 7.5 Hz), 7.27−7.19 (m, 4H), 7.18−7.05 (s, 9H), 4.99 (d, 1H, J
= 11.5 Hz), 4.87 (d, 1H, J = 11.4 Hz), 4.83 (d, 1H, J = 11.5 Hz), 4.62
(d, 1H, J = 11.4 Hz), 4.39 (d, 1H, J = 11.9 Hz), 4.23 (d, 1H, J = 11.9
Hz), 4.03 (br s, 1H), 3.91 (t, 1H, J = 9.4 Hz), 3.74−3.61 (m, 5H), 2.67
(br s, 1H), 1.70−0.67 (m, 14H). 13C NMR (100 MHz, C6D6): δ
139.7, 139.5, 139.0, 128.6, 128.5, 128.3, 128.2, 128.1, 127.8, 127.7,
127.6, 87.6, 80.1, 77.8, 75.4, 74.8, 73.7, 73.6, 73.4, 69.1, 19.7. IR (thin
film): 2869, 1455, 1379, 1298, 1198, 1063, 700 cm−1. [α]D25 = +22.2° (c
1.5, CH2Cl2). HRESI−MS: m/z calcd for C34H44NO5S2 [M + H]+,
610.2661; found, 610.2673. Compound 5 was also characterized as the
2-O-acetate by treatment with Ac2O (1 mL) in pyridine (2 mL) at rt
for 12 h as described above. The 1H NMR and pfg-COSY spectrum of
2-O-acetyl 5 confirmed the β configuration (J1,2 = 9.7 Hz).
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl 1-Diiso-
propyldithiocarbamate (2-O-acetyl 5). 1H NMR (500 MHz,
C6D6): δ 7.26 (t, 5H, J = 7.8 Hz), 7.22−7.01 (m, 10H), 6.43 (d, 1H, J
= 10.5 Hz), 5.76 (t, 1H, J = 9.7 Hz), 4.73 (dd, 2H, J = 9.0, 11.5 Hz),
4.62 (d, 1H, J = 11.7 Hz), 4.55 (d, 1H, J = 11.4 Hz), 4.40 (d, 1H, J =
11.9 Hz), 4.25 (d, 1H, J = 11.9 Hz), 3.89 (t, 1H, J = 9.3 Hz), 3.81−
3.69 (m, 3H), 3.65 (dd, 1H, J = 3.4, 11.2 Hz), 1.65 (s, 3H), 1.68−0.39
(m, 12H). 13C NMR (100 MHz, C6D6): δ 169.4, 139.3, 139.2, 139.1,
128.6, 128.5, 128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 85.7, 80.2, 78.2,
75.4, 74.8, 73.4, 68.9, 20.7, 19.6.
diastereomeric mixture was recrystallized with 5% benzene in hexanes
at −20 °C to afford pure β-1,3-linked disaccharide glucal 8 as a white
solid. 1H NMR (500 MHz, C6D6): δ 7.56 (d, 1H, J = 7.2 Hz), 7.37 (d,
1H, J = 7.3 Hz), 7.29 (d, 1H, J = 7.3 Hz), 7.23 (d, 1H, J = 7.2 Hz),
7.19−7.07 (m, 16H), 6.10 (dd, 1H, J = 1.2, 6.1 Hz), 5.31 (s, 1H), 5.06
(d, 1H, J = 11.5 Hz), 4.89 (d, 1H, J = 11.3 Hz), 4.86 (dd, 1H, J = 1.9,
6.1 Hz), 4.80 (d, 1H, J = 11.5 Hz), 4.64 (d, 1H, J = 7.6 Hz), 4.57 (d,
1H, J = 11.4 Hz), 4.53 (d, 1H, J = 8.0 Hz), 4.42 (d, 2H, J = 4.2 Hz),
4.10 (dd, 1H, J = 5.2, 10.4), 3.99 (dd, 1H, J = 7.7, 10.2 Hz), 3.77 (t,
1H, J = 8.4 Hz), 3.73−3.57 (m, 5H), 3.48 (t, 1H, J = 10.4 Hz), 3.40
(dt, 1H, J = 10.0, 3.5 Hz), 2.76 (s, 1H). 13C NMR (125 MHz, C6D6):
δ 144.7, 139.8, 139.3, 139.1, 137.9, 129.2, 128.6, 128.5, 128.5, 128.4,
128.4, 128.3, 128.1, 128.0, 127.9, 127.7, 127.7, 127.6, 126.8, 102.8,
101.8, 101.4, 84.8, 78.5, 77.8, 76.0, 75.0, 75.0, 74.4, 73.6, 71.6, 69.4,
69.3, 68.4. IR (thin film): 3515, 2522, 2862, 1646, 1498, 1453, 1359,
1229, 1104, 1064, 755, 701 cm−1. [α]D25 −18.2° (c 0.9, CH2Cl2).
HRESI−MS: m/z calcd for C40H42O9Na [M + Na]+, 689.2727; found,
689.2737. Product 8 was also characterized as the 2-O-acetate; the 1H
NMR and pfg-COSY spectrum of 2-O-acetyl-8 confirmed the β
configuration (J1,2 = 8.5 Hz).
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl-(1→3)-4,6-
O-benzylidene-D-glucal (2′-O-acetyl 8). 1H NMR (500 MHz,
C6D6): δ 7.62 (d, 2H, J = 7.3 Hz), 7.29 (t, 4H, J = 8.1 Hz), 7.19−7.02
(m, 14H), 6.07 (dd, 1H, J = 1.5, 6.0 Hz), 5.45 (t, 1H, J = 8.5 Hz), 5.33
(s, 1H), 4.74−4.57 (m, 5H), 4.53 (dt, 1H, J = 7.0, 2.0 Hz), 4.44 (m,
1H), 4.42 (s, 2H), 4.11 (dd, 1H, J = 5.1, 10.4 Hz), 4.03 (dd, 1H, J =
7.3, 10.3 Hz), 3.69 (dt, 1H, J = 5.0, 10.2 Hz), 3.65 (dd, 1H, J = 1.9,
11.0 Hz), 3.62−3.53 (m, 3H), 3.48 (t, 1H, J = 10.4 Hz), 3.42 (m, 1H),
1.71 (s, 3H).
Isopropyl 3,4,6-Tri-O-benzyl-β-D-glucopyranoside (10). Tri-
O-benzyl glucal 1 (104 mg, 0.25 mmol) was subjected to DMDO
oxidation at 0 °C for 1 h followed by DTC ring opening as previously
described. The crude glycosyl DTC 2 was then subjected to
Cu(OTf)2-mediated glycosylation with i-PrOH (29 μL, 0.38 mmol)
as described in the general procedure. After workup, the crude mixture
was passed through a plug of silica gel (neutralized with 1% Et3N)
packed on a fritted funnel and eluted with 1% EtOAc in toluene with
1% Et3N to remove nonpolar byproducts followed by EtOAc with 1%
Et3N to collect the product mixture. The pale yellow syrup was
concentrated and repurified by silica gel chromatography using a 5−
20% EtOAc in hexanes gradient with 1% Et3N to afford β-i-Pr
glucoside 10 as a colorless syrup (87 mg, 71%) and α-i-Pr glucoside
10′ as a crystalline solid (11 mg, 9%). Major isomer 10: 1H NMR (500
MHz, C6D6): δ 7.42 (d, 2H, J = 7.4 Hz), 7.30 (d, 2H, J = 7.5 Hz), 7.24
(d, 2H, J = 7.4 Hz), 7.18−7.16 (m, 6H), 7.13−7.05 (m, 3H), 5.13 (t,
1H, J = 9.9 Hz), 4.92 (d, 1H, J = 11.3 Hz), 4.89 (d, 1H, J = 11.6 Hz),
4.55 (d, 1H, J = 11.3 Hz), 4.47 (d, 1H, J = 12.5 Hz), 4.42 (d, 1H, J =
12.5 Hz), 4.22 (d, 1H, J = 7.2 Hz), 3.86 (dt, 1H, J = 12.3, 6.2 Hz),
3.74−3.61 (m, 5H), 3.41 (m, 1H), 2.41 (br s, 1H), 1.21 (d, 3H, J = 6.2
Hz), 1.01 (d, 3H, J = 6.1 Hz). 13C NMR (125 MHz, C6D6): δ 140.1,
139.7, 139.4, 128.9, 128.9, 128.8, 128.7, 128.6, 128.4, 128.3, 128.2,
128.0, 128.0, 102.1, 85.3, 78.4, 76.0, 75.4, 73.8, 71.9, 69.9, 24.2, 22.4.
IR (thin film): 3468, 2898, 1464, 1362, 1109, 1054, 738, 700 cm−1.
[α]D25 = −8.0° (c 3.5, CH2Cl2). HRESI−MS: m/z calcd for
C30H36O6Na [M + Na]+, 515.2410; found, 515.2417. Major isomer
10 was also characterized as the 2-O-acetate; 1H NMR and pfg-COSY
confirmed the β configuration (J1,2 = 8.6 Hz).
3,4,6-Tri-O-benzyl-β-D-glucopyranosyl 1-Diphenyldithiocar-
bamate (6). Tri-O-benzyl glucal 1 (31 mg, 0.075 mmol) was
subjected to DMDO oxidation at 0 °C for 1 h to provide α-
epoxyglucal (10:1 α:β) in quantitative yield followed by DTC ring
opening in THF with Li-(Ph)2DTC (0.15 mmol) dissolved in MeOH.
The pale yellow syrup was purified by silica gel chromatography using
a 5−50% EtOAc in hexanes gradient with 1% Et3N; mixed fractions
were separated by preparative TLC (20% EtOAc in hexanes with 1%
Et3N) to afford glycosyl DTC 6 as a colorless solid (42 mg, 82%). 1H
NMR (500 MHz, C6D6): δ 7.30 (d, 2H, J = 7.5 Hz), 7.23 (d, 2H, J =
7.4 Hz), 7.21 (d, 2H, J = 7.5 Hz), 7.19−7.05 (m, 13H), 7.00 (dd, 4H, J
= 9.5, 10 Hz), 6.91 (dd, 2H, J = 7.5, 9.5 Hz), 5.99 (d, 1H, J = 10.1 Hz),
4.84 (dd, 2H, J = 11.0, 11.5 Hz), 4.77 (d, 1H, J = 11.5 Hz), 4.60 (d,
1H, J = 11.4 Hz), 4.40 (d, 1H, J = 11.9 Hz), 4.21 (d, 1H, J = 11.9 Hz),
3.85 (dd, 1H, J = 11.0, 11.5 Hz), 3.73−3.63 (m, 4H), 3.59 (dd, 1H, J =
10.5, 11.0 Hz), 1.96 (br s, 1H). 13C NMR (100 MHz, C6D6): δ 198.3,
139.6, 139.4, 138.9, 129.7, 128.6, 128.5, 128.5, 128.3, 128.2, 128.1,
127.8, 127.7, 127.6, 127.6, 90.7, 87.4, 79.9, 77.7, 75.3, 74.7, 73.5, 72.9,
69.1. IR (thin film): 2877, 1590, 1489, 1455, 1353, 1041, 755, 700
cm−1. [α]D25 = +11.3° (c 0.4, CH2Cl2). HRESI−MS: m/z calcd for
C40H39NO5S2Na [M + Na]+, 700.2167; found, 700.2159. Product 6
was also characterized as the 2-O-acetate by treatment with Ac2O (1
1
mL) in pyridine (2 mL) at rt for 12 h as described above. The H
NMR and pfg-COSY spectrum of 2-O-acetyl-6 confirmed the β
configuration (J1,2 = 10.5 Hz).
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl 1-Diphe-
nyldithiocarbamate (2-O-acetyl 6). 1H NMR (300 MHz,
CDCl3): δ 7.30−7.04 (m, 30H), 5.53 (d, 1H, J = 10.5 Hz), 5.03 (t,
1H, J = 10.5 Hz), 4.69 (d, 1H, J = 11.1 Hz), 4.65 (d, 1H, J = 10.2 Hz),
4.57 (d, 1H, J = 10.4 Hz), 4.55(d, 1H, J = 12.0 Hz), 4.43(d, 1H, J = 9.0
Hz), 4.39 (d, 1H, J = 10.2 Hz), 3.71−3.60 (m, 4H), 3.53 (m, 1H), 1.79
(s, 3H).
3,4,6-Tri-O-benzyl-β-D-glucopyranosyl-(1→3)-4,6-O-Benzyli-
dene-D-glucal (8).53 Glycosyl DTC 2 (58 mg, 0.1 mmol) was
subjected to Cu(OTf)2-mediated glycosylation with glucal acceptor 7
(35 mg, 0.15 mmol) as previously described with a slight modification:
glucal acceptor 7 was added into the reaction mixture in 1:1 DCE/
DCM without precooling because of its limited solubility. After
workup, the crude mixture was passed through a plug of silica gel
(neutralized with 1% Et3N) packed on a fritted funnel and eluted with
2% EtOAc in toluene with 1% Et3N to remove nonpolar byproducts
followed by EtOAc to collect the product, which was concentrated to
dryness. The pale yellow syrup was purified by preparative TLC (10%
EtOAc in toluene with 1% Et3N and then 15% EtOAc in toluene with
1% Et3N) to afford an inseparable mixture of 1,3-linked disaccharide
glucals as a colorless syrup (47 mg, 70% α/β 1:9). The α/β ratio was
determined by the peak integration of the 2′-O-acetyl derivative. The
Isopropyl 2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyrano-
1
side (2-O-acetyl 10). H NMR (300 MHz, CDCl3): δ 7.40−6.96
(m, 15H), 4.88 (t, 1H, J = 8.6 Hz), 4.72 (d, 2H, J = 11.4 Hz), 4.63−
4.42 (m, 4H), 4.32 (d, 1H, J1,2 = 8.0 Hz), 3.83 (q, 1H, J = 6.1 Hz),
3.72−3.50 (m, 4H), 3.41 (m, 1H), 1.89 (s, 3H), 1.16 (d, 3H, J = 6.2
Hz), 1.04 (d, 3H, J = 6.1 Hz).
Isopropyl 3,4,6-Tri-O-benzyl-α-D-glucopyranoside (10′).54
1H NMR (500 MHz, C6D6): δ 7.41 (d, 2H, J = 7.4 Hz), 7.30 (d,
2H, J = 7.5 Hz), 7.26 (d, 2H, J = 7.3 Hz), 7.18−7.07 (m, 9H), 5.02 (d,
1H, J = 11.4 Hz), 4.95 (d, 1H, J = 11.2 Hz), 4.85 (d, 1H, J = 4.0 Hz),
4.78 (d, 1H, J = 11.4 Hz), 4.60 (d, 1H, J = 11.2 Hz), 4.45 (d, 1H, J =
12.2 Hz), 4.38 (d, 1H, J = 12.2 Hz), 4.05 (ddd, 1H, J = 1.7, 4.5, 10.0
Hz), 3.87 (t, 1H, J = 9.0 Hz), 3.78 (dr, 1H, J = 4.0, 9.6 Hz), 3.75−3.68
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(m, 3H), 3.66 (dd, 1H, J = 1.8, 10.7 Hz), 1.88 (d, 1H, J = 9.9 Hz), 1.09
(d, 3H, J = 6.2 Hz), 0.90 (d, 3H, J = 6.1 Hz). 13C NMR (125 MHz,
C6D6): δ 139.8, 139.4, 139.1, 128.6, 128.5, 128.3, 128.2, 128.0, 128.0,
127.9, 127.7, 127.6, 127.6, 97.6, 84.4, 78.1, 75.4, 75.1, 73.7, 73.5, 71.5,
70.6, 69.6, 23.4, 21.7. IR (thin film): 3497, 2917, 2857, 1500, 1458,
1363, 1330, 1129, 1074, 1025, 741, 702 cm−1. [α]D25 = +77.1° (c 1.5,
CH2Cl2). HRESI−MS: m/z calcd for C30H36 O6Na [M + Na]+,
515.2410; found, 515.2418.
as a colorless syrup (86 mg, 48%). 1H NMR (500 MHz, C6D6): δ 7.49
(d, 2H, J = 7.6 Hz), 7.41 (d, 2H, J = 7.5 Hz), 7.36 (d, 2H, J = 7.5 Hz),
7.26−7.05 (m, 24H), 5.31 (d, 1H, J = 11.5 Hz), 5.10 (d, 1H, J = 12.0
Hz), 5.05 (d, 1H, J = 11.5 Hz), 4.89 (dd, 1H, J = 7.5, 11.5 Hz), 4.74
(d, 1H, J = 8.0 Hz), 4.63−4.21 (m, 8H), 4.04 (dd, 1H, J = 9.5 Hz),
4.04 (dd, 1H, J = 3.0, 11.0 Hz), 3.90 (br s, 1H), 3.82−3.75 (m, 2H),
3.70 (dd, 1H, J = 1.5, 11.0 Hz), 3.63 (t, 2H, J = 9.0 Hz), 3.59 (dd, 1H,
J = 4.0, 11.0 Hz), 3.55 (d, 1H, J = 9.5 Hz), 3.52 (dd, 1H, J = 3.5, 8.5
Hz), 3.39 (d, 1H, J = 9.5 Hz), 3.31 (d, 1H, J = 2.5 Hz), 3.13 (s, 3H),
3.03 (s, 1H). 13C NMR (125 MHz, C6D6): δ 140.2, 139.6, 139.2,
138.9, 138.4, 128.5, 128.3, 128.2, 128.1, 127.9, 127.4, 127.3, 127.0,
103.5, 98.3, 84.9, 80.7, 80.4, 77.6, 77.5, 75.9, 75.7, 74.9, 74.7, 73.5,
73.3, 73.0, 70.3, 69.1, 68.9, 54.8. IR (thin film): 3466, 2919, 1725,
1501, 1455, 1365, 1274, 1107, 1061, 741, 704 cm−1. [α]D25 = +34.0° (c
2.0, CH2Cl2). HRESI−MS: m/z calcd for C55H60O11Na [M + Na]+,
919.4033; found, 919.4038. Product 16 was also characterized as the
Benzyl 3,4,6-Tri-O-benzyl-β-D-glucopyranoside (11).55 Tri-O-
benzyl glucal 1 (104 mg, 0.25 mmol) was subjected to DMDO
oxidation at 0 °C for 1 h followed by DTC ring opening as previously
described. The crude glycosyl DTC 2 was subjected to Cu(OTf)2-
mediated glycosylation with benzyl alcohol (39 μL, 0.38 mmol) as
described in the general procedure. After workup, the crude mixture
was passed through a plug of silica gel (neutralized with 1% Et3N)
packed on a fritted funnel and eluted with 0.5% EtOAc in toluene with
1% Et3N to remove byproducts followed by EtOAc with 1% Et3N to
collect the product mixture. The pale yellow syrup was concentrated
and repurified by silica gel chromatography using a 5−30% EtOAc in
hexanes gradient with 1% Et3N to afford β-benzyl glucoside 11 as a
crystalliine solid (85 mg, 63%) and α-benzyl glucoside 11′ as a
1
2′-O-acetate; H NMR and pfg-COSY confirmed the β configuration
(J1′,2′ = 9.4 Hz).
Methyl 2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl-
(1→4)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (2′-O-acetyl
1
16). H NMR (500 MHz, C6D6): δ 7.48 (d, 2H, J = 7.4 Hz), 7.35
1
(d, 2H, J = 7.4 Hz), 7.32 (d, 2H, J = 7.2 Hz), 7.28 (d, 2H, J = 7.6 Hz),
7.24 (d, 2H, J = 7.1 Hz), 7.21−7.00 (m, 20H), 5.46 (t, 1H, J = 9.4 Hz),
5.27 (d, 1H, J = 11.9 Hz), 4.95 (d, 1H, J = 11.9 Hz), 4.88 (d, 1H, J =
8.0 Hz), 4.74 (d, 1H, J = 11.6 Hz), 4.70−4.53 (m, 5H), 4.51−4.39 (m,
5H), 4.32−4.20 (m, 2H), 3.98−3.94 (m, 2H), 3.71 (dd, 1H, J = 2.5,
9.5 Hz), 3.69 (d, 1H, J = 6.8 Hz), 3.66 (dd, 1H, J = 1.5, 11.0 Hz),
3.59−3.51 (m, 3H), 3.42 (dd, 1H, J = 3.4, 8.9 Hz), 3.12 (s, 3H), 1.69
(s, 3H).
crystalline solid (12 mg, 9%). Major isomer 11: H NMR (500 MHz,
C6D6): δ 7.39 (d, 2H, J = 7.8 Hz), 7.34−7.27 (m, 4H), 7.26−7.22 (m,
2H), 7.21−7.13 (m, 8H), 7.13−7.07 (m, 4H), 5.05 (d, 1H, J = 11.5
Hz), 4.90 (d, 1H, J = 11.3 Hz), 4.86 (d, 1H, J = 11.9 Hz), 4.82 (d, 1H,
J = 11.5 Hz), 4.55 (d, 1H, J = 11.3 Hz), 4.45 (dd, 2H, J = 5.6, 12.0
Hz), 4.40 (d, 1H, J = 12.2 Hz), 4.24 (d, 1H, J = 7.7 Hz), 3.76−3.67
(m, 4H), 3.59 (t, 1H, J = 8.9 Hz), 3.37 (ddd, 1H, J = 2.6, 4.0, 9.7 Hz),
2.09 (br s, 1H). 13C NMR (125 MHz, C6D6): δ 139.7, 139.4, 139.0,
138.1, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 127.9, 127.7,
127.7, 102.3, 84.9, 78.0, 75.7, 75.7, 75.1, 75.0, 73.6, 71.0, 69.5. IR (thin
Isopropyl 3,4,6-Tri-O-benzyl-β-D-glucopyranosyl-(1→4)-3-O-
acetyl-6-O-tert-butyl-diphenylsilyl-2-phthalimido-β-D-gluco-
pyranoside (17). Tri-O-benzyl glucal 1 (42 mg, 0.1 mmol) was
subjected to DMDO oxidation at 0 °C for 1 h and then subjected to
DTC ring opening as previously described. The crude glycosyl DTC 2
was subjected to Cu(OTf)2-mediated glycosylation with the acceptor
(76 mg, 0.12 mmol) as described in the general procedure. After
workup, the crude mixture was passed through a plug of silica gel
(neutralized with 1% Et3N) packed on a fritted funnel and eluted with
2% EtOAc in toluene with 1% Et3N to remove byproducts followed by
EtOAc with 1% Et3N to collect the product mixture. The pale yellow
syrup was concentrated and repurified by preparative TLC (30%
EtOAc in hexanes with 1% Et3N and then 40% EtOAc in hexanes with
1% Et3N) to afford 1,4-β-linked disaccharide 17 as a colorless syrup
film): 3481, 2873, 1502, 1455, 1358, 1117, 1058, 695 cm−1. [α]D25
=
−18.0° (c 1.0, CH2Cl2). HRESI−MS: m/z calcd for C34H36O6Na [M
+ Na]+, 563.2410; found, 563.2407. Product 11 was also characterized
as the 2-O-acetate; 1H NMR and pfg-COSY confirmed a β
configuration (J1,2 = 9.2 Hz).
Benzyl 2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranoside
1
(2-O-acetyl 11). H NMR (500 MHz, C6D6): δ 7.30 (t, 5H, J =
7.4 Hz), 7.25−7.00 (m, 15H), 5.54 (dd, 1H, J2,3 = 8.0, J1,2 = 9.2 Hz),
4.86 (d, 1H, J = 12.4 Hz), 4.71 (dd, 2H, J = 7.8, 11.3 Hz), 4.64 (d, 1H,
J = 11.6 Hz), 4.53 (d, 1H, J = 12.4 Hz), 4.45 (t, 3H, J = 11.5 Hz), 4.39
(m, 1H), 3.72−3.60 (m, 3H), 3.57 (t, 1H, J = 8.6 Hz), 3.41 (m, 1H),
1.69 (s, 3H).
1
Benzyl 3,4,6-Tri-O-benzyl-α-D-glucopyranoside (11′).56 1H
NMR (300 MHz, CDCl3): δ 7.40−7.23 (m, 18H), 7.13 (dd, 2H, J =
2.8, 6.6 Hz), 4.93 (d, 1H, J = 3.6 Hz), 4.82 (dd, 2H, J = 2.6, 10.9 Hz),
4.75 (d, 1H, J = 11.7 Hz), 4.64 (d, 1H, J = 12.0 Hz), 4.58−4.43 (m,
3H), 3.86−3.56 (m, 7H), 2.10 (d, 1H, J = 8.8 Hz). Product 11′ was
also characterized as the 2-O-acetate; 1H NMR and pfg-COSY
confirmed the α configuration (J1,2 = 3.7 Hz).
(60 mg, 56%). H NMR (500 MHz, C6D6): δ 7.99 (dd, 2H, J = 1.3,
8.0 Hz), 7.94 (d, 2H, J = 6.8 Hz), 7.53 (d, 1H, J = 6.3 Hz), 7.46 (d,
1H, J = 6.4 Hz), 7.43 (d, 2H, J = 7.5 Hz), 7.33−7.04 (m, 19H), 6.90−
6.74 (m, 2H), 6.34 (t, 1H, J = 10.8 Hz), 5.84 (d, 1H, J = 8.4 Hz), 5.11
(d, 1H, J = 11.6 Hz), 4.92 (d, 2H, J = 11.4 Hz), 4.83 (dd, 1H, J = 8.5,
10.8 Hz), 4.75 (d, 1H, J = 7.6 Hz), 4.57 (d, 1H, J = 11.3 Hz), 4.39 (t,
1H, J = 9.4 Hz), 4.27 (d, 2H, J = 11.9 Hz), 4.19 (d, 1H, J = 11.9 Hz),
4.12 − 3.95 (m, 2H), 3.77 (t, 1H, J = 9.2 Hz), 3.73 − 3.46 (m, 7H),
1.88 (s, 3H), 1.20 (d, 3H, J = 6.2 Hz), 1.17 (s, 9H), 0.97 (d, 3H, J =
6.1 Hz). 13C NMR (125 MHz, C6D6): δ 139.7, 139.4, 139.0, 138.1,
128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 127.9, 127.7, 127.7,
102.3, 84.9, 78.0, 75.7, 75.7, 75.1, 75.0, 73.6, 70.9, 69.5. IR (thin film):
Benzyl 2-O-Acetyl-3,4,6-tetra-O-benzyl-α-D-glucopyrano-
1
side (2-O-acetyl 11′). H NMR (300 MHz, CDCl3): δ 7.55−6.96
(m, 20H), 5.11 (d, 1H, J = 3.7 Hz), 4.89 (dd, 1H, J = 3.7, 10.1 Hz),
4.85−4.78 (m, 2H), 4.73−4.62 (m, 2H), 4.56−4.44 (m, 3H), 4.06 (t,
1H, J = 8.7 Hz), 3.86 (dq, 1H, J = 10.1, 1.8 Hz), 3.79−3.68 (m, 2H),
3.62 (dd, 2H, J = 1.9, 10.7 Hz), 2.00 (s, 3H).
3432, 2936, 1722, 1384, 1229, 1117, 1041, 763, 695 cm−1. [α]D25
=
Methyl 3,4,6-Tri-O-benzyl-β-D-glucopyranosyl-(1→4)-2,3,6-
tri-O-benzyl-α-D-glucopyranoside (16). Tri-O-benzyl glucal 1
(83 mg, 0.2 mmol) was subjected to DMDO oxidation at 0 °C for
1 h followed by DTC ring opening as previously described. The crude
glycosyl DTC 2 was subjected to Cu(OTf)2-mediated glycosylation
with methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (139 mg, 0.3
mmol) as described in the general procedure to yield the desired
1,4-linked disaccharide. After workup, the crude mixture was passed
through a plug of silica gel (neutralized with 1% Et3N) packed on a
fritted funnel and eluted with 2% EtOAc in toluene with 1% Et3N to
remove byproducts followed by EtOAc with 1% Et3N to collect the
product mixture. The pale yellow syrup was concentrated and
repurified by silica gel chromatography using a 5−30% EtOAc in
hexanes gradient with 1% Et3N to afford 1,4-β-linked disaccharide 16
+20.9° (c 1.0, CH2Cl2). HR-MALDI−MS: m/z calcd for C62H69
NO13SiNa [M + Na]+, 1086.4434; found, 1086.4458. Product 17 was
also characterized as the 2′-O-acetate; 1H NMR and pfg-COSY
confirmed the β configuration (J1′,2′ = 8.6 Hz).
Isopropyl 2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-glucopyranosyl-
(1→4)-3-O-acetyl-6-O-tert-butyldiphenylsilyl-2-phthalimido-β-
1
D-glucopyranoside (2′-O-acetyl 17). H NMR (500 MHz, C6D6):
δ 7.97 (d, 2H, J = 8.0 Hz), 7.87 (d, 2H, J = 8.0 Hz), 7.56 (d, 1H, J =
6.7 Hz), 7.47 (d, 1H, J = 6.8 Hz), 7.35 (d, 3H, J = 7.2 Hz), 7.31 (d,
3H, J = 7.5 Hz), 7.30−7.04 (m, 15H), 6.88−6.76 (m, 2H), 6.28 (t, 1H,
J = 10.7 Hz), 5.74 (d, 1H, J = 8.5 Hz), 5.39 (t, 1H, J = 8.6 Hz), 4.93
(d, 1H, J1,2 = 8.1 Hz), 4.79 (dd, 2H, J = 6.3, 15.3 Hz), 4.68 (d, 2H, J =
11.3 Hz), 4.45 (d, 1H, J = 11.3 Hz), 4.36 (t, 1H, J = 9.5 Hz), 4.26 (d,
1H, J = 11.8 Hz), 4.18 (d, 1H, J = 11.8 Hz), 4.03 (dd, 1H, J = 2.8, 11.3
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Hz), 3.97 (dt, 1H, J = 12.4, 6.2 Hz), 3.88 (d, 1H, J = 10.7 Hz), 3.70−
3.58 (m, 5H), 3.51 (m, 1H), 1.85 (s, 3H), 1.62 (s, 3H), 1.19 (d, 3H, J
= 6.2 Hz), 1.14 (s, 9H), 0.98 (d, 3H, J = 6.1 Hz).
4.0, 12.5 Hz), 4.31 (d, 1H, J = 12.0 Hz), 4.26−4.28 (m, 4H), 4.13 (m,
1H), 4.07 (br s, 1H), 3.99 (dd, 1H, J = 5.5, 11.0 Hz), 3.90 (t, 1H, J =
7.0 Hz), 3.86 (br s, 1H), 3.70 (t, 1H, J = 8.0 Hz), 3.56 (dd, 1H, J = 5.5,
9.0 Hz), 3.38 (t, 1H, J = 6.5 Hz), 3.33 (dd, 1H, J = 2.5, 10.0 Hz), 1.81
(s, 3H). 13C NMR (125 MHz, C6D6): δ 169.0, 144.8, 139.3, 138.8,
138.8, 128.7, 128.6, 128.6, 128.5, 128.3, 128.2, 128.1, 127.9, 127.8,
127.7, 127.5, 102.2, 100.0, 81.0, 76.8, 75.2, 74.8, 74.6, 74.0, 73.6, 73.4,
73.2, 71.9, 71.4, 70.2, 68.9, 67.5, 20.9. IR (thin film): 3371, 2877, 1763,
1645, 1510, 1455, 1358, 1253, 1071, 734, 691 cm−1. [α]D25 = +4.9° (c
0.9, CH2Cl2). HRESI−MS: m/z calcd for C49H52O10Na [M + Na]+,
823.3458; found, 823.3466.
2-O-Acetyl-3,4,6-tri-O-benzyl-α-D-galactopyranosyl-(1→6)-
3,4-di-O-benzyl-D-glucal (minor isomer, 2′-O-acetyl 21′). 1H
NMR (500 MHz, C6D6): δ 7.35−7.06 (m, 25H), 6.18 (dd, 1H, J = 0.7,
6.1 Hz), 5.84 (dd, 1H, J = 3.7, 10.5 Hz), 5.52 (d, 1H, J = 3.7 Hz), 5.00
(d, 1H, J = 11.5 Hz), 4.83 (d, 1H, J = 11.4 Hz), 4.67−4.64 (m, 2H),
4.57 (d, 1H, J = 11.5 Hz), 4.47−4.40 (m, 3H), 4.33−4.24 (m, 4H),
4.10−4.08 (m, 2H), 4.04 (dd, 1H, J = 4.3, 12.0 Hz), 3.96−3.93 (m,
2H), 3.79 (t, 1H, J = 7.7 Hz), 3.75 (dd, 1H, J = 1.5, 12.9 Hz), 3.69 (dd,
1H, J = 5.7, 13.5 Hz), 1.85 (s, 3H). 13C NMR (125 MHz, C6D6): δ
169.9, 144.6, 139.4, 139.2, 139.2, 138.9, 128.6, 128.5, 128.3, 128.1,
127.8, 127.5, 100.3, 97.8, 77.4, 77.1, 76.1, 75.2, 75.1, 73.8, 73.6, 72.4,
71.7, 70.5, 70.1, 69.4, 66.3, 20.9. IR (thin film): 2936, 2848, 1738,
1502, 1447, 1362, 1244, 1113, 1063, 750, 695 cm−1. [α]D25 = +39° (c
0.6, CH2Cl2). HRESI−MS: m/z calcd for C49H52O10Na [M + Na]+,
823.3458; found, 823.3462.
3-O-Benzyl-4,6-O-benzylidene-β-D-glucopyranosyl-(1→3)-
4,6-O-benzylidene-D-glucal (19). 4,6-Benzylidene glucal 18 (49
mg, 0.15 mmol) was subjected to DMDO oxidation at 0 °C for 1 h
followed by DTC ring opening as previously described. The crude
DTC glycosyl donor was subjected to Cu(OTf)2-mediated glyco-
sylation with 4,6-benzylidene glucal 7 (54 mg, 0.23 mmol) as
described in the general procedure except that acceptor 7 was added to
the reaction mixture without precooling because of its low solubility.
After workup, the crude mixture was passed through a plug of silica gel
(neutralized with 1% Et3N) packed on a fritted funnel and eluted with
2% EtOAc in toluene with 1% Et3N to remove byproducts followed by
EtOAc with 1% Et3N to collect the product mixture. The pale yellow
solid was concentrated and repurified by preparative TLC (5% EtOAc
in DCE with 1% Et3N and then 10% EtOAc in DCE with 1% Et3N) to
afford 1,3-β-linked disaccharide glucal 19 as a white solid (36 mg,
42%). 1H NMR (500 MHz, 1:1 C6D6/CDCl3): δ 7.56−7.39 (m, 5H),
7.31 (d, 3H, J = 6.9 Hz), 7.20−7.09 (m, 7H), 6.40 (dd, 1H, J = 2, 6.5
Hz), 5.62 (s, 1H), 5.54 (s, 1H), 4.94 (d, 1H, J = 12.0 Hz), 4.86 (dd,
1H, J = 1.9, 6.1 Hz), 4.79 (d, 1H, J = 12.0 Hz), 4.63 (d, 1H, J = 7.5
Hz), 4.60 (d, 1H, J = 7.0 Hz), 4.38 (dd, 1H, J = 5.0, 10.5 Hz), 4.24
(dd, 1H, J = 5.0, 10.5 Hz), 4.02 (dt, 1H, J = 5.2, 10.3 Hz), 4.02 (t, 1H,
J = 7.5 Hz), 3.94 (dt, 1H, J = 5.0, 10.0 Hz), 3.85 (t, 1H, J = 10 Hz),
3.77 (t, 1H, J = 10 Hz), 3.71−3.61 (m, 3H), 3.39 (m, 1H), 2.57 (s,
1H). 13C NMR (125 MHz, 1:1 C6D6/CDCl3): δ 145.1, 139.2, 138.1,
137.7, 129.4, 129.1, 128.6, 128.4, 128.3, 128.1, 127.9, 126.5, 102.0,
101.8, 101.5, 81.6, 80.5, 78.4, 74.6, 74.4, 73.1, 69.2, 69.0, 68.4, 67.0. IR
(thin film): 2923, 1645, 1451, 1362, 1235, 1100, 1016, 695 cm−1. [α]D25
= −18.0° (c 0.7, CH2Cl2). HRESI−MS: m/z calcd for C33H34O9Na
[M + Na]+, 597.2101; found, 597.2107. Product 19 was also
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-
benzyl-D-glucal (23). 1,6-β-Linked disaccharide 13 (1.65 g, 2.1
mmol) and TBAI (214 mg, 0.6 mmol) were dissolved in DMF (29
mL), cooled to 0 °C under argon, and treated with BnBr (500 μL, 4.2
mmol) and a 60% dispersion of NaH in mineral oil (336 mg, 8.4
mmol). The reaction was stirred at rt for 12 h, quenched at 0 °C with
saturated NH4Cl (25 mL), and extracted with Et2O (3 × 25 mL). The
combined organic extracts were washed with H2O (3 × 25 mL) and
brine (25 mL), dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography using a
5−20% EtOAc−hexanes gradient with 1% Et3N to afford the
1
characterized as the 2′-O-benzoate; H NMR and pfg-COSY of 2′-
O-benzoyl 19 confirmed the β configuration (J1′,2′ = 7.8 Hz).
2-O-Benzoyl-3-O-benzyl-4,6-O-benzylidene-β-D-glucopyra-
1
nosyl-(1→3)-4,6-O-benzylidene-D-glucal (2′-O-benzoyl 19). H
NMR (500 MHz, 5:2 C6D6/CDCl3): δ 8.00−7.97 (m, 2H), 7.46 (d,
2H, J = 7.6 Hz), 7.42 (d, 2H, J = 7.7 Hz), 7.29−7.03 (m, 11H), 7.02−
6.83 (m, 3H), 5.89 (d, 1H, J = 6.2 Hz), 5.45 (t, 1H, J = 7.8 Hz), 5.21
(d, 2H, J = 4.2 Hz), 4.75 (d, 1H, J = 12.3 Hz), 4.64 (d, 1H, J = 12.2
Hz), 4.57 (d, 1H, J = 7.7 Hz), 4.43 (dd, 1H, J = 1.2, 6.2 Hz), 4.32 (d,
1H, J = 7.3 Hz), 4.13 (dd, 1H, J = 4.9, 10.4 Hz), 4.07 (dd, 1H, J = 5.1,
10.5 Hz), 3.76 (dd, 1H, J = 7.4, 10.2 Hz), 3.70 (t, 1H, J = 8.7 Hz), 3.67
(t, 1H, J = 9.0 Hz), 3.61 (dt, 1H, J = 10.3, 5.2 Hz), 3.56 (t, 1H, J = 10.2
Hz), 3.44 (t, 1H, J = 10.3 Hz), 3.27 (dt, 1H, J = 5.0, 9.4 Hz).
3,4,6-Tri-O-benzyl-β-D-galactopyranosyl-(1→6)-3,4-di-O-
benzyl-D-glucal (21). Tri-O-benzyl galactal 20 (64 mg, 0.15 mmol)
was subjected to DMDO oxidation at −50 °C for 12 h to provide α-
epoxygalactal (20:1 α/β) in quantitative yield. We note that DMDO
oxidation of galactal 20 at 0 °C caused significant overoxidation, as
identified by an aldehyde proton signal at δ 9.6 ppm in 1H NMR and
by additional UV-active byproducts. The α-epoxygalactal was
subjected to DTC ring opening as previously described; the crude
DTC donor was then subjected to CuOTf-mediated glycosylation with
3,4-di-O-benzyl-D-glucal 22 (75 mg, 0.23 mmol) as described in the
general procedure. After workup, the pale yellow syrup was purified by
silica gel chromatography using a 2−7% EtOAc in toluene gradient
with 1% Et3N to afford an inseparable mixture of 1,6-linked
disaccharide glucals as a colorless syrup (92 mg, 78%; α/β 1:5); the
α/β ratio was determined by NMR peak integration of the 2′-O-acetyl
derivatives. These were separated by preparative TLC (10% EtOAc in
1
corresponding benzyl ether 23 as a white solid (1.83 g, 95%). H
NMR (400 MHz, C6D6): δ 7.45−7.06 (m, 30H), 6.30 (d, 1H, J = 6.0
Hz), 5.16 (d, 1H, J = 11.2 Hz), 5.01 (d, 1H, J = 11.2 Hz), 4.86 (d, 1H,
J = 11.4 Hz), 4.83 (d, 1H, J = 11.4 Hz), 4.79 (d, 1H, J = 11.3 Hz), 4.74
(dd, 1H, J = 2.8, 6.2 Hz), 4.72 (d, 1H, J = 12.2 Hz), 4.58 (t, 1H, J =
12.6 Hz), 4.48 (d, 1H, J = 12.2 Hz), 4.44−4.39 (m, 3H), 4.36 (dd, 1H,
J = 2.0, 11.2 Hz), 4.31 (m, 1H), 4.19 (t, 1H, J = 5.9 Hz), 4.12 (br s,
1H), 3.96 (dd, 1H, J = 5.8, 11.3 Hz), 3.93 (d, 1H, J = 5.9 Hz), 3.75−
3.61 (m, 5H), 3.32 (dt, 1H, J = 9.5, 2.5 Hz), 2.11 (br s, 1H). 13C NMR
(100 MHz, C6D6): δ 144.4, 139.2, 139.1, 139.0, 139.0, 138.8, 138.7,
128.2, 128.1, 127.9, 127.7, 127.6, 127.4, 127.3, 104.2, 99.8, 84.7, 82.2,
77.9, 76.6, 75.2, 75.1, 74.7, 74.6, 74.5, 73.2, 73.0, 70.0, 69.0, 68.2. IR
(thin film): 2884, 1651, 1502, 1349, 1109, 1066, 752, 697 cm−1. [α]D25
= +17.4° (c 0.5, CH2Cl2). HRESI−MS: m/z calcd for C54H56O9Na [M
+ Na]+, 871.3822; found, 871.3804.
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-
benzyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-benzyl-D-glucal
(25). Disaccharide glucal 23 (604 mg, 0.71 mmol) was subjected to
DMDO oxidation at −50 °C for 12 h to produce α-epoxyglucal (20:1,
α/β) in quantitative yield followed by DTC ring opening as previously
described. The crude glycosyl DTC donor was then subjected to
CuOTf-mediated glycosylation with 3,4-di-O-benzyl glucal 22 (278
mg, 0.85 mmol) as described in the general procedure. After workup,
the pale yellow syrup was purified by silica gel chromatography using a
5−20% EtOAc gradient in hexanes with 1% Et3N; the mixed fractions
were further separated by preparative TLC (15% EtOAc in hexanes
with 1% Et3N) to afford β,β-1,6-linked trisaccharide glucal 25 as a
white solid (537 mg, 63%) and β,α-1,6-linked trisaccharide glucal 25′
as a minor product (56 mg, 7%). Major β,β-isomer 25: 1H NMR (500
MHz, C6D6): δ 7.53−7.15 (m, 40H), 6.38 (d, 1H, J = 6.5 Hz), 5.18
(dd, 2H, J = 6.0, 11.5 Hz), 5.10 (d, 1H, J = 11.5 Hz), 4.97−4.86 (m,
6H), 4.82 (dd, 1H, J = 4.2, 6.0 Hz), 4.75 (d, 1H, J = 12.0 Hz), 4.67
(dd, 2H, J = 6.0, 11.5 Hz), 4.63 (d, 1H, J = 7.5 Hz), 4.59 (d, 1H, J =
toluene with 1% Et3N) to afford 2′-O-acetyl-β-disaccharide 21 (J1,2
=
9.3 Hz) as the major product and 2′-O-acetyl-α-disaccharide 21′ (J1′,2′
= 3.7 Hz) as the minor product.
2-O-Acetyl-3,4,6-tri-O-benzyl-β-D-galactopyranosyl-(1→6)-
3,4-di-O-benzyl-D-glucal (major isomer, 2′-O-acetyl 21). 1H
NMR (500 MHz, C6D6): δ 7.30−7.05 (m, 25H), 6.25 (d, 1H, J = 6.2
Hz), 5.93 (t, 1H, J = 9.3 Hz), 4.92 (d, 1H, J = 11.6 Hz), 4.73 (d, 1H, J
= 11.7 Hz), 4.70 (dd, 1H, J = 3.0, 6.0 Hz), 4.63 (d, 1H, J = 11.5 Hz),
4.52 (d, 1H, J = 11.5 Hz), 4.43 (d, 1H, J = 8.0 Hz), 4.39 (dd, 2H, J =
2621
dx.doi.org/10.1021/jo500032k | J. Org. Chem. 2014, 79, 2611−2624

The Journal of Organic Chemistry
Article
12.5 Hz), 4.54 (d, 1H, J = 5.5 Hz), 4.51 (d, 1H, J = 7.0 Hz), 4.42−4.40
(m, 3H), 4.35 (d, 1H, J = 8.0 Hz), 4.21 (m, 1H), 4.16 (dt, 1H, J = 2.0,
6.0 Hz), 3.98−3.93 (m, 2H), 3.91−3.68 (m, 8H), 3.57 (t, 1H, J = 7.0
Hz), 3.47 (m, 1H), 3.48 (dd, 1H, J = 7.0, 14.0 Hz), 2.71 (br s, 1H).
13C NMR (100 MHz, C6D6): δ 144.64, 139.7, 139.3, 139.2, 139.1,
139.0, 128.6, 128.5, 128.5, 128.3, 128.1, 127.9, 127.8, 127.6, 104.6,
103.8, 100.4, 85.2, 84.9, 82.6, 78.4, 76.8, 75.7, 75.6, 75.4, 75.1, 75.0,
74.9, 73.6, 73.6, 70.4. IR (thin film): 2920, 1645, 1506, 1459, 1345,
1063, 733, 700 cm−1. [α]D25 = +13.4° (c 0.5, CH2Cl2). HRESI−MS: m/
z calcd for C74H78O14Na [M + Na]+, 1213.5289; found, 1213.5292.
described in the general procedure. After workup, the crude mixture
was passed through a plug of silica gel (neutralized with 1% Et3N)
packed on a fritted funnel and eluted with 2% EtOAc in toluene with
1% Et3N to remove byproducts followed by EtOAc with 1% Et3N to
collect the product mixture. The residue was repurified by silica gel
chromatography using a 0−30% EtOAc−hexanes gradient with 1%
Et3N to afford the desired β,β,β-1,6-linked tetrasaccharide 28 as a
white solid (68 mg, 49%) and β,β,α-1,6-linked tetrasaccharide 28′ as a
1
minor product (14 mg, 10%). Major β,β,β-isomer 28: H NMR (500
MHz, C6D6): δ 7.60−6.91 (m, 55H), 6.28 (d, 1H, J = 5.9 Hz), 5.18−
5.03 (m, 4H), 5.00 (dd, 2H, J = 3.8, 11.3 Hz), 4.90−4.75 (m, 6H),
4.76−4.66 (m, 2H), 4.63−4.20 (m, 14H), 4.14 (d, 1H, J = 6.6 Hz),
4.05 (m, 1H), 3.93 (t, 1H, J = 7.5 Hz), 3.90−3.50 (m, 16H), 3.43−
3.37 (m, 2H), 1.04 (t, 1H, J = 7.1 Hz). 13C NMR (125 MHz, C6D6) δ
144.7, 139.7, 139.5, 139.4, 139.3, 139.3, 139.2, 139.0, 128.7, 128.6,
18.6, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.9, 127.7,
127.7, 127.6, 104.7, 103.7, 100.4, 85.2, 85.2, 84.9, 82.8, 82.7, 78.7, 78.4,
78.1, 76.9, 76.0, 75.6, 75.5, 75.4, 75.3, 75.1, 75.1, 75.0, 74.9, 74.8, 73.7,
73.6, 70.5, 69.5, 69.2, 68.9, 68.4. IR (thin film): 2924, 1717, 1464,
1274, 1058, 809, 738, 695 cm−1. [α]D25 = +5.8° (c 0.6, CH2Cl2). ESI−
MS: m/z for C101H106O19Na [M + Na]+, 1646.60. Minor β,β,α-isomer
28′: 1H NMR (500 MHz, C6D6): δ 7.67−6.81 (m, 55H), 6.21 (d, 1H,
J = 6.0 Hz), 5.12 (t, 2H, J = 10.7 Hz), 5.01 (d, 2H, J = 11.2 Hz), 4.96
(d, 2H, J = 10.3 Hz), 4.91 (d, 1H, J = 3.6 Hz), 4.90−4.71 (m, 7H),
4.71−4.61 (m, 3H), 4.60−4.45 (m, 4H), 4.43 (d, 2H, J = 11.8 Hz),
4.39−4.24 (m, 3H), 4.13 (m, 1H), 4.11−4.03 (m, 2H), 3.98−3.89 (m,
3H), 3.86−3.82 (m, 3H), 3.79−3.58 (m, 12H), 3.48 (ddd, 1H, J = 2.0,
5.6, 9.6 Hz), 3.38 (dt, 1H, J = 9.9, 3.1 Hz), 2.15 (d, 1H, J = 9.2 Hz).
13C NMR (125 MHz, C6D6): δ 144.7, 139.7, 139.6, 139.5, 139.5,
139.4, 139.3, 139.0, 128.7, 128.7, 128.6, 128.6, 128.5, 128.4, 128.3,
128.1, 128.0, 127.9, 127.7, 127.6, 104.8, 104.3, 100.4, 99.7, 85.2, 85.2,
83.7, 82.7, 82.7, 78.6, 78.3, 78.1, 76.6, 76.1, 75.6, 75.4, 75.3, 75.0, 74.9,
74.8, 74.7, 73.9, 73.6, 71.4, 70.4, 69.4, 69.0, 66.7. IR (thin film): 2898,
1
Minor β,α-isomer 25′: H NMR (500 MHz, C6D6): δ 7.50−7.04 (m,
40H), 6.21 (d, 1H, J = 8.5 Hz), 5.12 (d, 1H, J = 11.5 Hz), 4.98 (dd,
2H, J = 9.0, 10.0 Hz), 4.89−4.72 (m, 7H), 4.70 (dd, 1H, J = 2.5, 6.0
Hz), 4.64−4.61 (t, 2H, J = 9.5 Hz), 4.56 (d, 1H, J = 11.5 Hz), 4.48 (d,
1H, J = 12.0 Hz), 4.44−4.40 (m, 3H), 4.33 (d, 1H, J = 9.5 Hz), 4.28
(d, 1H, J = 11.5 Hz), 4.12 (dd, 2H, J = 3.0, 8.0 Hz), 4.06 (dd, 1H, J =
5.0, 11.0 Hz), 3.96 (m, 1H), 3.94−3.87 (m, 2H), 3.82 (dt, 1H, J = 4.0,
9.5 Hz), 3.73−3.65 (m, 7H), 3.60 (t, 1H, J = 8.5 Hz), 3.35 (dt, 1H, J =
2.5, 9.5 Hz), 2.05 (d, 1H, J = 9.5 Hz). 13C NMR (125 MHz, C6D6): δ
144.7, 139.6, 139.5, 139.3, 139.1, 139.0, 129.2, 128.7, 128.5, 128.3,
128.1, 127.8, 109.5, 104.5, 85.2, 82.6, 78.4, 78.2, 75.6, 74.9, 74.7, 74.1,
73.6, 71.3, 71.1, 70.4, 69.4, 69.0, 30.2. IR (thin film): 3966, 2911, 1648,
1498, 1458, 1362, 1081, 1027, 741, 704 cm−1. [α]D25 = +23.0° (c 0.8,
CH2Cl2). HRESI−MS: m/z calcd for C74H78O14Na [M + Na]+,
1213.5289; found, 1213.5321. Trisaccharide glycal 25 was also
1
characterized as the 2′-O-acetate; H NMR and pfg-COSY confirmed
the β configuration (J1′,2′ = 8.2 Hz).
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-2-O-ace-
tyl-3,4-di-O-benzyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-benzyl-
1
D-glucal (2′-O-acetyl 25). H NMR (400 MHz, CDCl3): δ 7.65−
6.78 (m, 40H), 6.28 (d, 1H, J = 6.2 Hz), 5.50 (t, 1H, J = 8.2 Hz), 5.04
(t, 1H, J = 11.6 Hz), 4.92−4.58 (m, 15H), 4.55 (d, 1H, J = 12.0 Hz),
4.46 (d, 1H, J = 12.2 Hz), 4.39 (d, 1H, J = 7.8 Hz), 4.31 (d, 1H, J =
12.2 Hz), 4.26 (d, 1H, J = 11.3 Hz), 4.01−4.07 (m, 2H), 3.91−3.87
(m, 2H), 3.81−3.74 (m, 5H), 3.64−3.54 (m, 3H), 3.53−3.45 (m, 2H),
1.72 (s, 3H).
1746, 1497, 1451, 1362, 1236, 1101, 1046, 742, 683 cm−1. [α]D25
=
+8.9° (c 1.3, CH2Cl2). ESI−MS: m/z for C101H106O19Na [M + Na]+,
1647. Tetrasaccharide glycals 28 and 28′ were also characterized as 2′-
1
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-benzyl-D-glucal
(26). Trisaccharide glucal 25 (186 mg, 0.16 mmol) and TBAI (12 mg,
0.03 mmol) were dissolved in DMF (1.6 mL), cooled to 0 °C under
argon, and then treated with BnBr (38 μL, 0.32 mmol) and a 60%
dispersion of NaH in mineral oil (13 mg, 0.31 mmol). The ice bath
was removed, and the reaction mixture was stirred at rt for 12 h,
quenched at 0 °C with saturated NH4Cl (3 mL), and extracted with
Et2O (3 × 5 mL). The combined organic extracts were washed with
H2O (3 × 10 mL) and brine (5 mL), dried over Na2SO4, and
concentrated under reduced pressure. The resulting foamy solid was
recrystallized with Et2O in hexanes to afford benzyl ether 26 as white
O-acetates; H NMR and pfg-COSY confirmed the β configuration of
28 (J1′,2′ = 9.5 Hz) and the α configuration of 28′ (J1′,2′ = 3.6 Hz).
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzyl-β-D-glucopyranosyl-(1→6)-2-O-acetyl-3,4-di-O-ben-
zyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-benzyl-D-glucal (2-O-
1
acetyl 28). H NMR (500 MHz, C6D6): δ 7.73−6.64 (m, 55H),
6.38 (dd, 1H, J = 1.4, 6.2 Hz), 5.56 (dd, 1H, J = 8.0, 9.5 Hz), 5.31−
5.01 (m, 3H), 5.01−4.83 (m, 8H), 4.83−4.30 (m, 18H), 4.21−4.16
(m, 2H), 4.05−3.62 (m, 14H), 3.63−3.40 (m, 3H), 1.80 (s, 3H).
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzyl-β-D-glucopyranosyl-(1→6)-2-O-acetyl-3,4-di-O-ben-
zyl-α-D-glucopyranosyl-(1→6)-3,4-di-O-benzyl-D-glucal (2-O-
1
1
acetyl 28′). H NMR (500 MHz, C6D6): δ 7.52−6.96 (m, 55H),
crystals (184 mg, 92% yield). H NMR (500 MHz, C6D6): δ 7.45−
6.14 (dd, 1H, J = 1.3, 6.1 Hz), 5.49 (d, 1H, J = 3.6 Hz), 5.23 (dd, 1H, J
= 3.5, 10.1 Hz), 5.13 (d, 2H, J = 11.4 Hz), 5.01 (d, 2H, J = 11.2 Hz),
4.92 (d, 1H, J = 11.6 Hz), 4.89−4.71 (m, 12H), 4.69−4.23 (m, 15H),
4.18 (ddd, 1H, J = 1.8, 5.1, 10.1 Hz), 4.10 (dt, 1H, J = 6.6, 1.8 Hz),
4.06−3.95 (m, 2H), 3.86 (dd, 1H, J = 5.9, 11.4 Hz), 3.83−3.58 (m,
16H), 3.54 (ddd, 1H, J = 1.9, 5.9, 9.7 Hz), 3.39 (dt, 1H, J = 9.8, 3.2
Hz), 1.80 (s, 3H).
7.06 (m, 45H), 6.31 (d, 1H, J = 6.0 Hz), 5.17 (d, 1H, J = 11.0 Hz),
5.12 (d, 1H, J = 11.0 Hz), 5.00 (d, 2H, J = 11.5 Hz), 4.87−4.77 (m,
6H), 4.74 (d, 1H, J = 5.0 Hz), 4.67 (d, 1H, J = 12.0 Hz), 4.61−4.54
(m, 4H), 4.50 (d, 1H, J = 12.0 Hz), 4.45−4.38 (m, 4H), 4.33 (d, 1H, J
= 11.5 Hz), 4.29 (d, 1H, J = 12.0 Hz), 4.13 (m, 1H), 4.09 (br s, 1H),
3.93 (dd, 1H, J = 5.5, 11.0 Hz), 3.89 (t, 1H, J = 7.0 Hz), 3.80 (dd, 1H,
J = 6.0, 11.0 Hz), 3.75−3.59 (m, 8H), 3.46 (m, 1H), 3.40 (m, 1H). 13C
NMR (125 MHz, C6D6): δ 144.8, 139.6, 139.5, 139.4, 139.3, 139.2,
139.0, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.7, 104.6,
104.3, 100.2, 85.2, 85.1, 82.7, 78.6, 78.4, 76.8, 75.6, 75.5, 75.3, 75.1,
74.9, 74.8, 73.6, 73.4, 70.3, 69.5, 68.9, 68.4. IR (thin film): 2915, 1510,
1451, 1366, 1075, 733, 695 cm−1. [α]D25 = +18.0° (c 2.0, CH2Cl2).
ESI−MS: m/z for C81H84O14Na [M + Na]+, 1304.07.
2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl-(1→6)-2,3,4-tri-
O-benzyl-β-D-glucopyranosyl-(1→6)-3,4-di-O-benzyl-β-D-glu-
copyranosyl-(1→6)-3,4-di-O-benzyl-D-glucal (28). Trisaccharide
glycal 26 (111 mg, 0.087 mmol) was subjected to DMDO oxidation at
−50 °C for 12 h to produce α-epoxyglucal (20:1, α/β) in quantitative
yield followed by DTC ring opening as previously described. The
crude glycosyl DTC donor was subjected to CuOTf-mediated
glycosylation with 3,4-di-O-benzyl glucal 22 (42 mg, 0.13 mmol) as
3,4,6-Tri-O-benzyl-2-O-triethylsilyl-β-D-glucopyranosyl 1-di-
ethyldithiocarbamate (29). Glycosyl DTC 2 (116 mg, 0.2 mmol)
and imidazole (48 mg, 0.7 mmol) were disolved in THF (2 mL),
cooled to 0 °C under argon, and treated with TESCl (170 μL, 1
mmol). The reaction mixture was stirred at room temperature for 12
h, quenched at 0 °C with saturated NaHCO3 (10 mL), and extracted
with EtOAc (3 × 20 mL). The combined organic extracts were washed
with brine (10 mL), dried over Na2SO4, and concentrated under
reduced pressure. After workup, the yellow syrup was purified by silica
gel chromatography (neutralized with 1% Et3N) using a 20−50%
EtOAc in hexanes gradient with 1% Et3N to afford 2-O-triethylsilyl
1
glycosyl DTC 29 as a colorless syrup (115 mg, 83%). H NMR (500
MHz, C6D6): δ 7.35 (d, 2H, J = 7.5 Hz), 7.23 (d, 2H, J = 7.5 Hz),
7.20−7.02 (m, 11H), 6.22 (d, 1H, J = 10.1 Hz), 5.01 (d, 1H, J = 11.8
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Article
Hz), 4.82 (d, 1H, J = 11.8 Hz), 4.73 (d, 1H, J = 11.2 Hz), 4.64 (d, 1H,
J = 11.2 Hz), 4.40 (d, 1H, J = 11.9 Hz), 4.21 (d, 1H, J = 11.9 Hz), 4.13
(dd, 1H, J = 8.4, 10.0 Hz), 4.00 (t, 1H, J = 9.5 Hz), 3.77−3.62 (m,
6H), 3.29 (m, 1H), 3.09 (m, 1H), 1.01 (t, 9H, J = 8.0 Hz), 0.99−0.96
(m, 3H), 0.81 (t, 3H, J = 7.0 Hz), 0.73 (q, 6H, J = 7.8 Hz). 13C NMR
(125 MHz, C6D6): δ 192.9, 140.0, 139.5, 139.3, 128.8, 128.8, 128.7,
128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.7, 127.3, 91.8, 88.4, 80.2,
79.1, 75.7, 75.0, 73.9, 73.7, 69.4, 49.9, 46.9, 13.0, 11.9, 7.7, 6.3. IR (thin
film): 2936, 2874, 1489, 1458, 1416, 1351, 1263, 1203, 1143, 1070,
1016, 922, 800, 732, 692 cm−1. [α]D25 = +7.2° (c 0.9, CH2Cl2).
HRESI−MS: m/z calcd for C38H53NO5S2SiNa [M + Na]+, 718.3032;
found, 718.3039.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Institutes of
Health (GM-06982), the National Science Foundation (CHE-
0957738), and a predoctoral scholarship from the Royal Thai
government for P.P. We also acknowledge the NMR and mass
spectrometry support from the Purdue University Center for
Cancer Research. We thank Dr. John Harwood for assistance
with low-temperature NMR experiments and Dr. Philip
Fanwick for X-ray crystallography.
Isopropyl 3,4,6-Tri-O-benzyl-2-O-triethylsilyl-β-D-glucopyra-
noside (30). 2-O-Triethylsilyl glycosyl DTC 29 (35 mg, 0.05 mmol)
was subjected to Cu(OTf)2-mediated glycosylation with i-PrOH (8
μL, 0.1 mmol) as described in the general procedure. After workup,
the crude mixture was passed through a plug of silica gel (neutralized
with 1% Et3N) packed on a fritted funnel and eluted with 2% EtOAc
in toluene with 1% Et3N to remove byproducts followed by EtOAc
with 1% Et3N to collect the product mixture. The pale yellow syrup
was concentrated and repurified by preparative TLC (5% EtOAc−
hexanes with 1% Et3N) to afford β-i-Pr glucoside 30 as a colorless
syrup (16 mg, 53%) and α-i-Pr glucoside 30′ as a colorless syrup (8
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ASSOCIATED CONTENT
■
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Corresponding Author
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