Toward the solid-phase synthesis of heparan sulfate oligosaccharides: Evaluation of iduronic acid and idose building blocks

Article abstract of DOI:10.1021/jo400467g

Glycan arrays have been established as the premier technical platform for assessing the specificity of carbohydrate binding proteins, an important step in functional glycomics research. Access to large libraries of well-characterized oligosaccharides rema

Full text of DOI:10.1021/jo400467g

Article
pubs.acs.org/joc
Toward the Solid-Phase Synthesis of Heparan Sulfate
Oligosaccharides: Evaluation of Iduronic Acid and Idose Building
Blocks
Nerea Guedes,† Pawel Czechura,† Begona Echeverria,† Ada Ruiz,† Olatz Michelena,†
̃
Manuel Martin-Lomas,†,‡ and Niels-Christian Reichardt*,†,‡
†Biofunctional Nanomaterials Unit, CICbiomaGUNE, Paseo Miramon 182, 20009 San Sebastian, Spain
‡CIBER-BBN, Paseo Miramon 182, 20009 San Sebastian, Spain
S
* Supporting Information
ABSTRACT: Glycan arrays have been established as the premier technical platform for assessing the specificity of carbohydrate
binding proteins, an important step in functional glycomics research. Access to large libraries of well-characterized
oligosaccharides remains a major bottleneck of glycan array research, and this is particularly true for glycosaminoglycans (GAGs),
a class of linear sulfated polysaccharides which are present on most animal cells. Solid-supported synthesis is a potentially
powerful tool for the accelerated synthesis of relevant GAG libraries with variations in glycan sequence and sulfation pattern. We
have evaluated a series of iduronic acid and idose donors, including a couple of novel n-pentenyl orthoester donors in the
sequential assembly of heparan sulfate precursors from monosaccharide building blocks in solution and on a polystyrene resin.
The systematic study of donor and acceptor performance up to the trisaccharide stage in solution and on the solid support have
resulted in a general strategy for the solid-phase assembly of this important class of glycans.
chain length, monosaccharide sequence, and sulfation pattern is
a result of the sequential action and specificity of these enzymes
involved in HS biosynthesis.1,2
The degree of specificity in HS−protein interactions is still a
matter of debate, but a growing body of scientific evidence has
demonstrated that GAG expression is strictly regulated,
resulting in a species- and tissue-specific polysaccharide
composition, and specific epitopes are recognized by some
receptors, while others show far more relaxed structural
requirements for binding to HS.2
HS−protein interactions are implicated in many biological
processes, such as angiogenesis, blood coagulation, viral entry,
etc.,3 but SAR studies have been hampered by the high
heterogeneity of the biological material and the associated
problems in isolating pure samples. Therefore, considerable
efforts have been invested in the development of synthetic
INTRODUCTION
■
Glycosaminoglycans (GAGs) are highly charged and linear
polysaccharides composed of (2-amino-2-deoxyhexo-
pyranosyl)pyranuronic acid disaccharide repeating units (with
the exception of keratan sulfate), which are further classified
according to their monosaccharide composition and glycosidic
linkage (Figure 1). Heparan sulfates (HSs) are composed of 1−
4-linked hexuronic acid (β-D-glucuronic or α-L-iduronic) and
glucosamine disaccharide repeating units with a variable degree
of O- and N-sulfation (Figure 1). Expressed on serine residues
of proteoglycans, they are present on most animal cell surfaces
and in the extracellular matrix, where they engage through ionic
interactions with a large number of proteins, including growth
factors and their receptors. HS biosynthesis is performed by the
orchestrated action of two polymerases, a glucuronyl C-5-
epimerase, various N-deacetylases/N-sulfotransferases, and O-
sulfotransferases in the ER/Golgi, and further modifications are
then produced by extracellular sulfatases.1 The very large
structural heterogeneity of HS with nonrandom differences in
Received: March 22, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
synthesizers.19 As a result, only very few studies related to the
solid-phase synthesis of GAGs have been reported to
date.15−17,20,18
The solid-phase synthesis of neutral oligosaccharides has
been more straightforward, and various biologically important
glycan structures have been prepared even in an automated
fashion.21−23
We have recently described a synthetic strategy for the solid-
phase synthesis of HS precursors based on the sequential
assembly of idose and glucosamine monosaccharide building
blocks.15 As an excess of reagents is usually employed for solid-
phase reactions to proceed with high conversion, the use of
monosaccharide building blocks is generally preferred over that
of more elaborate disaccharide building blocks. In spite of
employing a substantial donor excess in this preliminary
investigation, we did not obtain the high coupling yields
required for the preparation of larger HS oligomers. Therefore,
we decided to study in more detail the requirements for an
efficient solid-phase assembly of HS oligosaccharides from
monosaccharide building blocks.
In general terms, the main criteria to assess the efficiency of a
solid-phase synthesis of HS oligosaccharides can be summar-
ized as follows: (1) the assembly of glycosyl donors and
glycosyl acceptors must occur with high yield and complete
stereoselectivity; (2) only a low number of glycosylation cycles
must be needed to achieve the above yield and stereoselectivity;
(3) the reaction conditions and the experimental prcedure may
allow automation of the entire synthetic process at a later stage.
In this context we present here the results of a systematic
evaluation of iduronic acid (IdoA) and idose (Ido) glycosyl
donors, among them new highly reactive n-pentenyl orthoesters
(NPOEs), with variations in the protecting group pattern and
the leaving group, for the sequential solution- and solid-phase
synthesis of HS precursors. The direct use of IdoA donors for
the oligomer assembly directly reduces the steric hindrance
exerted by a voluminous protecting group at C-6 of Ido donors
and avoids additional deprotection and oxidation steps to
produce the natural structure. Uronic acid donors due to their
electron-withdrawing ester function, however, are known to be
less reactive than their nonoxidized analogues,24 and our study
was intended to clarify whether their direct use in the solid-
phase assembly is viable and justified.
Figure 1. Disaccharide repeating units of different classes of GAGs.
strategies for the preparation of HS oligosaccharides with
defined sequence and sulfation patterns.4−14 (Automated)
solid-phase synthesis is especially suited for the preparation
of linear biopolymers such as oligonucleotides and oligopep-
tides, and efforts toward its extension to oligosaccharides and
particularly GAGs15−18 are currently under way, although
accompanied by a number of additional challenges.
Unlike peptides or oligonucleotides, common sugar mono-
mers have up to five hydroxyl groups of similar reactivity which
require adequate differentiation and protection throughout the
synthesis. In addition, reliable strategies and experimental
setups for the stereoselective,5 high-yielding coupling reactions
between monomers have to be developed. The need for
moisture-free and low-temperature coupling conditions has
further implications for the design of specialized automated
Figure 2. Ido, IdoA, and azidoglucose donors employed in this study. TBDPS = tert-butyldiphenylsilyl, TDS = thexyldimethylsilyl, PMP = p-
methoxyphenyl, PMB = p-methoxybenzyl, and TOM = [(triisopropylsilyl)oxy]methyl.
B
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
thioglycosides 22 and 23, respectively, which, after selective
reductive ring-opening with triethylsilane and trifluoracetic
acid,29 furnished compounds 24 and 25. These compounds
were further levulinated to obtain donors 9 and 12,
respectively. Finally, exchange of the tert-butyldiphenylsilyl
ether in 7 for an acetate or [(triisopropylsilyl)oxy]methyl
(TOM) group afforded the thioglycosides 10 and 13.
Imidates 16 and 17 were obtained in a five-step sequence
from known 2-azidoglucose derivative 26.30 Thiol-mediated
transacetalization furnished diol 27; selective benzoylation31
with benzoyl cyanide at low temperature afforded alcohol 28,
which was levulinated under standard conditions to give
intermediate 29. Hydrolysis of the anomeric silyl group with
buffered TBAF afforded the corresponding hemiacetal, which
was activated either with trichloroacetonitrile to the trichloro-
16 or with N-phenyltrifluoroacetimidoyl chloride32 to the N-
phenyltrifluoroacetimidate 17 (Scheme 2).
NPOEs have been described by Fraser-Reid et al. as potent
glycosyl donors of mannose,33 glucose,33 and galactose.34
Depending on the monosaccharide configuration, n-pentenyl
glycosides (NPGs) and NPOEs can react via distinct
intermediates, and the mannose-NPOE, with a 1,2-cis-diol
configuration found also in the stable L-idose-NPOE 1C4
conformer, was found to be more reactive than the
corresponding 2-O-acyl NPG.35,32 NPOEs hold an activated
anomeric position as a glycosyl donor and differentiated
positions C-2 and C-4 at the same time, a feat that would
require multiple additional steps for other glycosyl donor types.
A further hallmark of NPOEs is their facile preparation from
peracylated anomeric bromides by treatment with a soft base in
the presence of 1-pentanol.29
RESULTS AND DISCUSSION
■
All Ido and IdoA donors studied were prepared under the
following constraints: Acyl groups were chosen for anchimeric
assistance in the 1,2-trans-selective glycosylation reactions and
as temporary protection of sulfated hydroxyl positions in the
final molecule, while hydroxyl functions unchanged during the
assembly and sulfation were protected as benzyl ethers.
With this in mind, IdoA donors 125−6, Ido thioglycosides
79−13, trichloroacetimidates 14 and 15 with protecting groups
of varying size at C-6, and azidoglucose donors 16 and 17 were
prepared and evaluated as building blocks in the solid-phase
assembly of HS precursors (Figure 2).
All Ido donors were prepared from 1,6-anhydro compound
18, which was synthesized from diacetone glucose in seven
steps with an overall yield of 20% (Scheme 1).26 Thioglycoside
Scheme 1. Synthesis of the Thiophenyl Idopyranoside
a
Donors 8−13
Surprisingly, in spite of these obvious advantages, NPOEs
have not been evaluated to date as potential glycosyl donors for
the synthesis of HS oligosaccharides, while NPGs have been
investigated previously.25,36
We synthesized orthoesters 3−6 via the bromosugars from
triol 3037 as shown in Scheme 3. Briefly, triol 30 was acylated
with acetic anhydride, levulinic acid, or benzoyl chloride to
afford the corresponding triacyl compounds 31,38 32, and 33
respectively. Tribenzoate 33 was most readily obtained and
easily crystallized, while acetate 31 and levulinate 32 required
very careful adjustment of the reaction conditions to suppress
the competing furanoside formation.38 Formation of 1-
bromosugars was achieved in high yield by treatment with
either HBr/AcOH or TiBr4, which were rapidly reacted with 1-
pentenol to the mixed orthoesters 3−5 (Scheme 3)25
Orthoester 6 was prepared from 5 through replacement of
the benzoate ester at C-4 by a temporary levulinic ester
protecting group. Unfortunately, the hydrolysis of the benzoate
group under harsh conditions using sodium methoxide was
accompanied by extensive elimination to the alkene 34. Mild
ester hydrolysis of compound 5 with trimethyltin hydroxide,39
however, allowed debenzoylation without any elimination.
Carbodiimide-mediated re-esterification of the acid function
cleanly produced the free alcohol 35, although care had to be
taken in the workup to avoid the cleavage of the acid-labile
orthoester function. Final levulination of the 4-hydroxy
function produced the fully differentiated orthoester glycosyl
donor 6.
a
Reagents and conditions: (a) Me3SiSPh, ZnI2, rt, o/n, 77%; (b) for
20, (TDS)Cl, cat. DMAP, pyridine, rt, o/n, 85%; for 21, (PMP)OH,
PPh3, DIAD, THF, 2 h, 80 °C, 70%; (c) LevOH, EDC·HCl, cat.
DMAP, CH2Cl2, 5 h, 65% (8), 94% (9), 90% (11), 90% (12); (d)
PhCH(OMe)2 (for 22), p-methoxybenzaldehyde (for 23), CSA, DMF,
80 °C, 5 h, 79% (22), 84% (23); (e) TES, TFA, 0 °C to rt, 2 h, 70%
(24), I2, NaCNBH3, −20 °C, CH2Cl2, 61% (25); (f, g) HF−pyridine,
THF, 0 °C to rt, 50%; for 10, Ac2O, pyridine, CH2Cl2, quant; for 13,
(TOM)Cl, DIPEA, CH2Cl2, 0 °C to rt, 64%.
19 was accessible via thiolysis of 18 with trimethyl(phenylthio)-
silane and zinc iodide (Scheme 1).27 Selective protection of
HO-6 with a thexyldimethylsilyl chloride or p-methoxyphenol
by Mitsunobu reaction28 afforded 20 and 21, respectively.
Levulination of the free HO-4 afforded intermediates 8 and 11,
which after hydrolysis of the thiophenyl group, were treated
with trichloroacetonitrile and DBU to afford imidates 14 and
15. Acid-catalyzed acetalization of diol 19 with dimethox-
ybenzylidene acetal or p-methoxybenzaldehyde afforded
The conformation of the pyranoid ring in all Ido and IdoA
glyosyl donors described so far, including NPOEs 3−6, was
unambigously established as 1C4, and the stereochemistry of the
C
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 2. Synthesis of Trichloroacetimidates 16 and 17
a
Reagents and conditions: (a) EtSH, pTSA, CH2Cl2, 3 h, rt, 89%; (b) BzCN, cat. Et3N, AcCN, 7 h, −40 °C, 90%; (c) EDC·HCl, LevOH, cat.
DMAP, CH2Cl2, rt, 91%; (d) TBAF, AcOH, THF, 0 °C, 3 h; (e) for 16, trichloroacetonitrile, DBU, CH2Cl2, 0 °C, 2 h, 85% over two steps; for 17,
N-phenyltrifluoroacetimidoyl chloride, K2CO3, acetone, rt, o/n, 91% over two steps.
a
Scheme 3. Synthesis of Orthoesters with Increasing Steric Bulk at the Exocyclic Carbon
a
Reagents and conditions: (a) AcCl, pyridine, DMAP, CH2Cl2, −40 °C to rt, 78%; (b) LevOH, EDC·HCl, DMAP, −25 °C to rt, 80%; (c) BzCl,
pyridine, CH2Cl2, −40 °C to rt, 91%; (d) HBr/AcOH, CH2Cl2; (e) 4-pentenol, 2,6-lutidine, CH2Cl2; (f) trimethyltin hydroxide, toluene, microwave,
100 °C; (g) NaOMe/MeOH, microwave, 60 °C; (h) MeOH, EDC·HCl, DMAP, 60% over three steps; (i) LevOH, EDC·HCl, DMAP, CH2Cl2,
90%.
a
Scheme 4. Glycosylation of Linker 36 with Different Ido and IdoA Donors
a
Reagents and conditions: (a) NIS, (TMS)OTf or TfOH; for yields and details see Table 1.
orthoesters was determined to be exo, in both cases using NMR
With all donors in hand, their performance in key
glycosylation reactions involved in the assembly of HS
oligosaccharides was investigated. First we looked at the
spectroscopy.
D
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
glycosylation of the carbamate spacer linker 36,15 which had
been specially designed for the release of oligosaccharides as 5-
aminopentyl glycosides for facile attachment to glycan array
surfaces (Scheme 4). Linker 36 also bears a benzoyl group to
mimic the ester linkage toward a polystyrene resin.
glycosylation of Ido/IdoA acceptors with donors 16 and 17.
Deprotection of the 4-O-levulinic ester in glycosides 3715−44
with hydrazine acetate provided the glycosyl acceptors (with a
broad variation of the protecting group at position C-6) that
were submitted to glycosylation with glycosyl donors 16 and 17
(Scheme 5). As a general trend, the glycosylation yields
increased with a reduced steric demand of the protecting group
at C-6 (Table 2). Substitution of the TBDPS group (entries 1
The glycosylation reactions involving donors 1 and 6−13
and acceptor 36 are shown in Table 1. All reactions were
Table 1. Test Glycosylations of Linker 36 in Solution Using
Glycosyl Donors 1 and 6−13
Table 2. Glycosylations of Different Ido and IdoA Acceptors
with Azidoglucose Donors 16 and 17 in Solution
a
entry
donor
temp
product
yield (%)
b
amt of (TMS)OTf
(equiv)
yield
(%)
1
2
7
7
−20 °C to rt
0 °C to rt
37
37
37
38
39
40
41
42
43
44
44
44
82
60
63
80
79
82
70
90
52
55
66
69
entry donor
temp
product
b
b
b
b
b
b
c
1
2
16
17
16
16
16
16
16
16
17
16
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
0 °C to rt
0.25
0.25
0.25
0.25
0.25
0.25
0.10
0.10
0.05
45
45
46
47
48
49
50
51
52
52
42
3
7
−45 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
−20 °C to rt
a
32
4
8
3
51
65
58
61
50
5
11
9
4
6
5
7
12
13
10
1
6
8
c
7
9
b
b
8
15
10
11
12
0 °C to rt
rt
d
9
32
48
1
d
10
0 °C to rt
0.05
6
0 °C to rt
a
b
a
b
Conversion determined by LC−MS analysis. Obtained as an α/β
Only the α-anomer formed. A 1.5 equiv sample of donor, 1.5 equiv
of NIS, and 0.25 equiv of (TMS)OTf were used. A 1.2 equiv sample
of donor, 1.5 equiv of NIS, and 0.1 equiv of TfOH were used. A 1.5
c
mixture.
d
equiv sample of donor, 3 equiv of NIS, and 0.25 equiv of (TMS)OTf
were used.
and 2) with a TOM group (entry 7), used extensively in nucleic
acid chemistry, did not improve the accessibility to the acceptor
site substantially, and the disaccharide 50 was formed in 50%
yield. A change from the bulky TBDPS group to the smaller
thexyldimethylsilyl (TDS) group (entry 3) led to a slight
increase in the formation of the corresponding disaccharide 46.
A more pronounced effect was observed for 6-O-p-methox-
yphenyl (PMP), -Bn, and -p-methoxybenzyl (PMB) protected
Ido acceptors (entries 4−6), which demonstrated higher
accessibility of the axial acceptor function to the azidoglucose
donor and gave rise to the disaccharides 47−49 in good yields.
This effect was reversed, however, when small but electron-
withdrawing groups were employed for protection of C-6. Both
the 6-O-acetate (entry 8) and the IdoA derivative (entries 9 and
10) were poorer acceptors in this comparison, with yields for
the corresponding disaccharides 51 and 52 below 50%,
probably as a result of decreased nucleophilicity of the axial
HO-4 acceptor. Furthermore, as a further consequence of this
carried out at −20 °C after temperature optimization in a series
of test glycosylations employing the 6-O-tert-butyldiphenylsilyl
(TBDPS) derivative 7 (entries 1−3, 3715). Thioglycoside
donors (1, 7−13) reacted in good to excellent yields with the
primary hydroxyl function of the benzoylated linker 36
independent of the size of the substituent at C-6. Donors 1,
6, and 10 with electron-withdrawing substituents at position C-
6 performed less well unless stronger activation conditions were
employed (entry 11). In general, the glycosylation of the
primary linker hydroxyl functional group proved to be
straightforward for all glycosyl donors evaluated, and orthoester
derivative 6 (entry 12) performed equally well as the
corresponding phenyl thioglycoside 1 (entry 11).
Stronger differences between the derivatives with different
protecting group regimes were expected in the following
Scheme 5. Glycosylation of Different Ido/IdoA Acceptors with Azidoglucose Trichloroacetimidate 16 and Trifluoroacetimidate
a
17
a
Reagents and conditions: (a) hydrazine acetate, CH2Cl2; (b) (TMS)OTf, CH2Cl2, 1.2−1.4 equiv of donor; for yields see Table 2.
E
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 3. Glycosylation of azidoglucose acceptors 53−55 with Ido n-pentenyl orthoesters.
decreased reactivity, an α/β mixture which could not be
separated was obtained in the case of the 6-O-acetate derivative
51.
anomer (Table 3). After this promising result, we compared
IdoA thioglycoside and n-pent-4-enyl orthobenzoate donors in
the glycosylation of the disaccharide acceptor 55.
In a direct comparison of the imidate donors 16 and 17
(entries 1, 2 and 9, 10), the trichloroacetimidate 16 performed
with both Ido and IdoA acceptors consistently better than the
corresponding N-phenyltrifluorocetimidate 17.
Both reactions involving thioglycoside 1 and orthoester 6
proceeded less well than expected from the previous results,
with a less than 50% yield of trisaccharide 59 being obtained
after workup (Table 3). In any case, the orthoester 6 performed
slightly better than the thioglycoside 1 derivative in this trial,
and we moved on to evaluate the orthoester and thioglycoside
donors in the solid-phase assembly of building blocks with the
possibility of increasing conversion by use of a donor excess
and various cycles of glycosylation.
A particular challenge in the chemical synthesis of HS
oligosaccharides is the efficient glycosylation of HO-4 of
glucosamine residues.40 While little difference between Ido and
IdoA donors was found for the glycosylation of the primary
hydroxy group of the anomeric aminopentyl linker, we were
intrigued to investigate the performance of the IdoA
orthoesters and thioglycosides in the notoriously difficult
glycosylation of the azidoglucose acceptors 5341−55. The n-
pent-4-enyl orthoacetate 3, ortholevulinoate 4, and orthoben-
zoate 5 were activated with NIS and a catalytic amount of
(TMS)OTf and reacted with the azidoglucose acceptors 53 and
55 (Figure 3). Glycosylations involving the orthoacetate 3 and
ortholevulinoate 5 produced the disaccharides 56 and 57 in
30% and 36% yield, respectively (Table 3). These compounds
Solid-phase trials were performed on a polystyrene resin
functionalized with the carbamate-type linker 60 at 0.2 or 0.4
mmol/g prepared as described recently15 (Scheme 6). After
methylation of the unreacted carboxylic acid functions using
diazomethane, the resin-bound linker SP-6115 was deprotected
with HF−pyridine, affording the acceptor SP-62.15 Glyco-
sylation with 3 equiv of the IdoA trichloroacetimidate 2 under
(TMS)OTf catalysis at −40 °C afforded resin-bound
monosaccharide SP-63. LC−MS analysis of a cleaved aliquot
of the resin afforded compound 64 in a conversion of 84%
(Table 4). Similar yields were achieved employing 5 equiv of
either thioglycoside donor 1 or orthoester 6 under conven-
tional NIS/(TMS)OTf activation, thus reproducing the high
yields of the solution-phase experiments for this reaction. The
following deprotection of the levulinic ester at C-4 in SP-63
with 3 equiv of hydrazine acetate to the resin-bound acceptor
SP-65 was monitored by a dibutyltin oxide-mediated39 cleavage
of an analytical sample from the resin. Subsequent glycosylation
of SP-65 with 3 equiv of azidoglucose donor 16 at −40 °C
afforded resin SP-66. Cleavage of a resin aliquot with sodium
methoxide suggested a low conversion to disaccharide 67, 21%
after one cycle (Table 4). However, after four cycles the
conversion of the analogue disaccharide 68 (cleaved with
dibutyltin oxide (DBTO)) was increased to 86%. Again
hydrazinolysis of the levulinic acid afforded resin-bound
acceptor SP-69, which was condensed with the n-pent-4-enyl
orthoester donor 6 with NIS and (TMS)OTf at 0 °C. The
glycosylation was repeated twice, affording resin SP-70, and
LC−MS analysis of a cleaved sample, 71, suggested conversion
of around 76% after three cycles (Table 4). Preparative cleavage
of the trisaccharide 71 from the resin using DBTO to avoid
elimination was less effective than expected from the analytical
run and had to be repeated several times until no further
compound was cleaved.44 Employing lithium peroxide to
hydrolyze the ester groups prior to the methoxide-mediated
Table 3. Comparison of Thioglycoside 1 and n-Pentenyl
Orthoesters 3−6 in the Key Glycosylation with Azidoglucose
a
Acceptors 53−55
entry
donor
acceptor
conditions
product
yield (%)
1
2
3
4
5
3
4
5
1
6
53
54
54
55
55
a, 0 °C to rt
a, 0 °C to rt
b, 0 °C to rt
b, rt
56
57
58
59
59
30
36
85
34
45
b, 0 °C to rt
a
Reagents and conditions: (a) 1.2 equiv of donor, 1.2 equiv of NIS, 0.2
equiv of (TMS)OTf; (b) 1.2−1.5 equiv of donor, 3.0 equiv of NIS, 0.2
equiv of (TMS)OTf.
were accompanied by up to 30% of a disaccharide with
undetermined stereochemistry lacking the HO-2 protecting
group, which had presumably formed via an orthoester
exchange mechanism after attack on the exocyclic carbon.42,43
We reasoned that the increase of the bulk of the orthoester
alkyl substituent from methyl to phenyl (compounds 3 and 5,
Scheme 3) should favor the attack of the nucleophile at the
anomeric rather than the exocyclic carbon, leading to a stronger
stereocontrol in the glycosylation, and indeed, after activation
of the orthobenzoate 5 with NIS/(TMS)OTf, the disaccharide
58 was produced in an excellent 85% yield as the pure α-
F
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 6. Solid-Phase Synthesis of a Trisaccharide Employing IdoA Donors
a
Reagents and conditions: (a) carboxypolystyrene resin, DIC, DMAP, CH2Cl2, then Me3SiCHN2, THF, MeOH; (b) HF−pyridine, THF; (c) 1, 2,
or 6, NIS, (TMS)OTf, CH2Cl2; (d) hydrazine acetate, CH2Cl2; (e) NaOMe, MeOH; (f) 16, (TMS)OTf, CH2Cl2; (g) Bu2SnO, MeOH, CH2Cl2;
(h) 6, NIS, (TMS)OTf, CH2Cl2; for conversions see Table 4.
Table 4. Evaluation of Iduronic Acid Derivatives 1, 2, and 6 in the Solid-Phase Synthesis of HS Trisaccharide Precursors
a
entry
donor
acceptor
conditions
product
conversion (%)
1
2
3
4
5
6
2
1
SP-62
SP-62
SP-62
SP-65
SP-65
SP-70
1 × 3 equiv, −40 °C to rt, 10% (TMS)OTf
1 × 5 equiv, rt, NIS (3.5 equiv), 15% (TMS)OTf
1 × 5 equiv, 0 °C to rt, NIS (3.5 equiv), 15% (TMS)OTf
1 × 3 equiv, −20 °C to rt, 15% (TMS)OTf
4 × 3 equiv, −20 °C to rt, 15% (TMS)OTf
3 × 3 equiv, 0 °C to rt, 15% (TMS)OTf
64
64
64
67
68
71
84
87
85
21
84
76
6
16
16
6
a
Conversion was determined by LC−MS analysis after cleavage from the resin.
cleavage from the resin was hampered by the low swelling of
the hydrophilic resin in the aqueous reagent solution. After
rebenzoylation and purification by preparative TLC, the
protected trisaccharide 59 was isolated in 8% overall yield
over eight steps.
glycosylation (Table 2, entry 8), albeit with complete α-
selectivity.
Next, employing the TDS-protected thioglycoside 8, we
prepared resin SP-77 in near-quantitative yield (78).
Hydrazinolysis to SP-79 was followed by treatment with 3 ×
3 equiv of the imidate 16, giving rise to the resin-bound
disaccharide SP-80 with excellent conversion (77%, 81) (Table
5). Delevulination to SP-82 and coupling with the imidate 14
in four cycles afforded trisaccharide SP-83 in 70% yield (84)
(Table 5), a result comparable to the one obtained with the
orthoester IdoA donor 6.
When we scaled up the reaction, these promising results were
however undermined by the (TMS)OTf-promoted partial loss
of the silyl group and subsequent overglycosylation at C-6, so
we decided to abandon the TDS-protected donors. We turned
our attention to the 6-O-PMP-protected derivative 11 offering
high stability under Lewis acid conditions and excellent
acceptor properties in the solution-based glycosylation trials
(Table 2, entry 4). Preparation of resin-bound glycoside SP-85
proceeded in excellent conversion (86) (Table 5). Depro-
Both low reactivity of IdoA donors and their incompatibility
with the effective methoxide-promoted linker cleavage led us to
study idose donors instead for the solid-phase assembly of HS
oligosaccharides. First, resin-bound glycoside SP-72 was
synthesized in near-quantitative yield as the analysis of the
methoxide cleavage product 73 suggested employing the 6-O-
acetate-protected thioglycoside donor 10 (Scheme 7).
Hydrazinolysis afforded the acceptor SP-74, which was reacted
with the azidoglucose derivative 16 to produce the disaccharide
SP-75, albeit in only 22% yield as seen by LC−MS analysis of
the cleaved compound 76 (Table 5). Apparently, the electronic
effect of the 6-O-acetate group on the nucleophilicity of the
OH-4 acceptor compensated any favorable reduction of the
steric bulk at C-6, leading to an overall poor yield in the
glycosylation, confirming the results of the solution-phase
G
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 7. Solid-Phase Synthesis of Trisaccharide Precursors Involving Idose Donors
a
Reagents and conditions: (a) 8, 11, or 10, NIS, (TMS)OTf; (b) hydrazine acetate, CH2Cl2; (c) NaOMe, MeOH; (d) 16 or 17, (TMS)OTf,
CH2Cl2; (e) 14 or 15, NIS, (TMS)OTf, CH2Cl2; for conversions see Table 5.
Table 5. Evaluation of Idose Derivatives 8, 10, and 11 in the Solid-Phase Synthesis of HS Trisaccharide Precursors
a
entry
donor
acceptor
conditions
product
conversion (%)
1
2
10
16
8
SP-62
SP-74
SP-62
SP-79
SP-82
SP-62
SP-87
SP-87
SP-87
SP-87
SP-87
SP-87
SP-90
1 × 5 equiv, −20 °C to rt, NIS (6.5 equiv), 10% (TMS)OTf
1 × 3 equiv, −20 to rt, 10% (TMS)OTf
1 × 5 equiv, −20 °C to rt, NIS (6.5 equiv), 10% (TMS)OTf
3 × 3 equiv, −20 °C to rt, 10% (TMS)OTf
4 × 3 equiv, −20 °C to rt, 10% (TMS)OTf
1 × 5 equiv, −20 °C to rt, NIS (6.5 equiv), 10% (TMS)OTf
2 × 6 equiv, −20 °C to rt, 10% (TMS)OTf
4 × 3 equiv, −20 °C to rt, 10% (TMS)OTf
2 × 6 equiv, −20 °C to rt, 10% (TMS)OTf
1 × 12 equiv, −20 °C to rt, 10% (TMS)OTf
1 × 12 equiv + 1 × 6 equiv, −20 °C to rt, 10% (TMS)OTf
3 × 6 equiv, −20 °C to rt, 10% (TMS)OTf
73
76
78
81
84
86
89
89
89
89
89
89
92
96
22
3
>95
77
4
16
14
11
17
16
16
16
16
16
15
5
70
6
>95
71
7
8
80
9
85
10
11
12
13
68
85
90
2 × 6 equiv, −20 °C to rt, 10% (TMS)OTf
94
a
Conversion was determined by LC−MS analysis after cleavage from the resin.
tection of the levulinuic ester (SP-87) and glycosylation with
trifluoroacetimidate 17 produced resin-bound disaccharide SP-
88 in 71% yield (89, entry 7).
was applied to linker resin SP-62 to obtain 39 mg of the crude
heparin sulfate precursor 92 (for the complete synthesis see the
Supporting Information). For purification purposes cleaved
crude trisaccharide 92 was acetylated, providing 93 in 72%
overall yield over eight steps with an average yield of 95% per
step (Scheme 7). Measurement of the three C,H heteronuclear
anomeric coupling constants confirmed a 1,2-cis configuration
for all glycosidic linkages (idose JC,H = 169 and 170 Hz and
azidoglucose JC,H = 172 Hz, Figure 4).45
Coupling with imidate 16 in four cycles of 3 equiv raised the
yield of SP-88 to 80% (89, entry 8). A larger donor excess of 6
equiv improved the yield slightly after only two cycles to 85%,
while a single cycle of 12 equiv resulted in a slightly lower yield
(Table 5, entries 9 and 10). A conversion of 90% was achieved
with three cycles of 6 equiv of donor 16 (entry 12). Finally,
after removal of the levulinic ester, acceptor SP-90 was coupled
in two cycles with imidate 15 to afford the resin-bound
trisaccharide SP-91 with 94% conversion (92, entry 13).
Then the previously established full solid-phase glycosylation
procedure consisting of mono-, di-, and trisaccharide formation
CONCLUSIONS
■
In conclusion, we have investigated the donor and acceptor
properties of a range of idose and iduronic acid donors with
particular focus on the steric bulk around the C-4 acceptor
H
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 4. HSQC NMR spectra of heparin trisaccharide precursor 93. JC,H coupling values (∼170 Hz) confirmed α-selectivity of the glycosylation
reactions.
transferred with oven-dried syringes or cannulae. Purification of
compounds was performed on a automated flash chromatography
system or by conventional flash chromatography using silica gel 60
(63−200 mesh). Size exclusion chromatography was performed on
Sephadex LG-20. All solution-phase reactions were monitored using
analytical thin-layer chromatography (TLC) with 0.2 mm precoated
silica gel 60 F254 aluminum plates. Components were visualized by
illumination with a short-wavelength (254 nm) ultraviolet light and/or
by charring with vanillin, ceric ammonium molybdate, potassium
permanganate, or phosphomolybdate staining solution. All solvents
used for anhydrous reactions were distilled. Tetrahydrofuran (THF)
was distilled from sodium/benzophenone under argon. Dichloro-
methane and acetonitrile were distilled from calcium hydride.
Methanol was distilled from calcium sulfate. N,N-dimethylformamide
(DMF) was stored over activated 4 Å molecular sieves under argon.
Solid-phase reactions were performed either in a Schlenk tube fitted
with a cooling jacket or in a normal Schlenk tube under an argon
atmosphere.
position, which had been found to compromise yields in
glycosylation on the sterically demanding TBDPS derivative 7.
For the first time a series of iduronic acid n-pentenyl orthoester
donors have been prepared and evaluated in the solution- and
solid-phase synthesis of trisaccharide heparin sulfate precursors
including all major structural features of larger HS chains. We
have found that the use of IdoA donors for the solid-phase
heparin sulfate synthesis was not compatible with the strong
basic conditions required to cleave our ester linker, and
considerable elimination of IdoA ester residues to the alkene
was observed. A change to base-labile linkers cleaved under less
harsh conditions or to orthogonal photolinkers18 in the future
could permit the direct use of IdoA donors.
Our results also demonstrate that idose donors with less
bulky electron-donating groups at C-6 outperform iduronic acid
as glycosyl donors and acceptors in the glycosylation with
azidoglucose derivatives 16, 17, 53, and 54 even though
additional off-bead oxidation is required to arrive at the natural
products. In particular, the solution- and solid-phase synthesis
involving the 6-O-PMP-protected idose derivatives 11 and 15
showed promisingly high yields for all conversions studied,
suggesting a viable and robust route which is currently being
employed in our laboratory for the synthesis of larger heparan
sulfate fragments, related glycosaminoglycan oligosaccharides,
and simpler heparin mimetics. In future studies we will
investigate the possibility of including idose deprotection and
oxidation into the solid-phase protocol.
1H, DQF-COSY, HSQC, and 13C NMR spectra were recorded at
ambient temperature on a 500 MHz NMR spectrometer to confirm
the NMR peak assigments. Deuterated chloroform (CDCl3), methanol
(CD3OD), or water (D2O) was used as the solvent for NMR
experiments, unless otherwise stated. Chemical shifts are reported in
parts per million downfield from TMS and corrected using the solvent
residual peak or TMS as an internal standard. Splitting patterns are
designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. Low-resolution mass spectrometry (LRMS) was
performed on an electrospray ionization time of flight mass
spectrometer equipped with an electrospray source with a pump rate
of 5 μL/min using electrospray ionization (ESI) or a matrix-assisted
desorption ionization time of flight (MALDI-TOF) mass spectrometer
operated in the reflectron/positive ion mode with DHB in MeOH as
the MALDI matrix. High-resolution mass spectrometry (HRMS) data
were acquired on a time of flight mass spectrometer. Samples in
CH2Cl2/MeOH (1:1) were mixed with ES tuning mix for internal
EXPERIMENTAL SECTION
General Methods. All anhydrous reactions were performed in
flame-dried or oven-dried glassware under a positive pressure of dry
argon. Air- or moisture-sensitive reagents and anhydrous solvents were
■
I
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
calibration and infused into the mass spectrometer at 5 μL/min. For
microwave heating of reactions a monomode oven was used.
transferred to an Eppendorf vial, and the solution was concentrated to
dryness by an air stream. The residue was redissolved in 100 μL of
methanol (HPLC grade). A 1:10 dilution of this solution was used for
LC−MS analysis.
Procedure A (Levulination). To a solution of 4-hydroxy acceptor
(1 equiv) in dry CH2Cl2 (∼10 mL/mmol) was added a catalytic
amount of DMAP at room temperature, followed by addition of
levulinic acid (1.5−5 equiv) and EDC·HCl (1.5−5 equiv). After 5 h,
the TLC control (hexane/ethyl acetate, 2:1 or 3:1) indicated full
conversion of the starting material. The reaction mixture was diluted
with CH2Cl2 (∼150 mL) and subsequently washed with saturated
NaHCO3 aq solution (2 × ∼200 mL), 1 M HCl (∼200 mL), water
(∼200 mL), and brine (∼200 mL). After being dried over MgSO4 and
concentrated, the crude reaction mixuture was purified by column
chromatography on silica using a hexane/ethyl acetate gradient (100%
→ 50% hexane).
Procedure B (Glycosylation with Thiophenyl Idose Deriva-
tives and n-Pentenyl Orthoester Derivatives). The linker
acceptor and thiophenyl donor (1.2−1.5 equiv) were dissolved in
dry CH2Cl2 (2 mL) under argon and then cooled to the desired
temperature. N-Iodosuccinimide and a catalytic amount of trimethyl-
silyl triflate ((TMS)OTf) or triflic acid (TfOH) were added, and the
reaction mixture was allowed to warm to room temperature. After
1.5−3 h, the crude reaction mixture was quenched with saturated
NaHCO3 aq solution and solid Na2S2O3. The mixture was filtered and
washed with saturated NaHCO3 aq solution, water, and brine. The
crude reaction mixture was purified by column chromatography.
Procedure C (Glycosylation with Azidoglucose Trichloroa-
cetimidate Donor, Disaccharide Synthesis). The idose acceptor
and azidoglucose donor were dissolved in dry CH2Cl2 (15 mL/mmol)
under argon and then cooled to −20 °C (0 °C for iduronic acid). After
addition of (TMS)OTf, the reaction mixture was allowed to warm
slowly to room temperature. After 2 h, the reaction mixture was
quenched with triethylamine. The crude reaction mixture was diluted
with CH2Cl2 and washed with saturated NaHCO3 aq solution, water,
and brine. The concentrated crude reaction was purified by column
chromatography.
Procedure E (Solid-Phase Capping and Delevulination).
Solid-phase synthesis was performed either in a Schlenk tube fitted
with a cooling jacket or in a normal Schlenk tube under an argon
atmosphere. The resin was swollen in dry CH2Cl2 (1 mL/100 mg of
resin) for 10 min, followed by addition of pyridine (300 μL/100 mg of
resin), acetic anhydride (300 μL/100 mg of resin), and a catalytic
amount of DMAP. After 5 h at room temperature the resin was
washed with CH2Cl2 (5 × 3 mL/100 mg of resin), MeOH (5 × 3 mL/
100 mg of resin), and dry diethyl ether (2 × 3 mL/100 mg of resin)
and dried in high vacuum. The resin was used without further
characterization for the delevulination: The resin was swollen in dry
CH2Cl2 (1 mL/100 mg resin) for 10 min, followed by addition of
hydrazine acetate (5 equiv in 200 μL of methanol). After 5 h at room
temperature the resin was washed with CH2Cl2 (5 × 3 mL/100 mg of
resin), methanol (5 × 3 mL/100 mg of resin), and dry diethyl ether (2
× 3 mL/100 mg of resin) and dried in high vacuum. The resin was
used without further characterization for the subsequent glycosylation.
Methyl 2-O-Benzoyl-3-O-benzyl-4-O-levulinoyl-α/β-L-idopyr-
anosyluronate Trichloroacetimidate (2). To a solution of
thioglycoside 1 (110 mg, 0.18 mmol) in CH2Cl2 (1.86 mL) were
added NIS (84 mg, 0.37 mmol) and trifluoroacetic acid (28 μL, 0.37
mmol) at 0 °C. After 15 min TLC analysis showed complete
consumption of the starting material. The reaction was quenched with
saturated Na2S2O3 aq solution and was washed with saturated
NaHCO3 aq solution. The organic layer was dried over MgSO4 and
concentrated in vacuum. The crude was dissolved in dry CH2Cl2 (2.4
mL), and trichloroacetonitrile (0.36 mL, 3.6 mmol) and a catalytic
amount of DBU (3.6 μL, 0.024 mmol) were added at 0 °C. After being
stirred for 1 h at room temperature, the reaction mixture was
concentrated. The residue was purified by column chromatography
(hexane/ethyl acetate, 7:3, with 1% of Et3N) to yield 2 as a viscous oil
1
Procedure D (Solid-Phase Glycosylation). Solid-phase glyco-
sylations were performed in either a Schlenk tube fitted with a cooling
jacket or a normal Schlenk tube under an argon atmosphere. Unless
otherwise noted, the resin was swollen with the glycosyl donor
(thioglycoside or trichloroacetimidate) in dry CH2Cl2 (750 μL/100
mg of resin). The reaction mixture was shaken for 10 min on a vortex
or an orbital shaker. Then the Schlenk tube with a cooling jacket was
connected to a cryostat and cooled to the specified temperature. The
normal Schlenk tube was cooled in a Dewar flask containing acetone at
the specified temperature. After additional shaking for 10 min the
activator (NIS, (TMS)OTf/TfOH for thioglycosides or (TMS)OTf
for trichloroacetimidates) was added. The mixture was shaken for 10
min at the specified temperature. Then the mixture was allowed to
warm to room temperature and was shaken for 1−1.5 h. The resin was
washed with THF (5 × 3 mL/100 mg of resin), CH2Cl2 (5 × 3 mL/
100 mg of resin), and dry diethyl ether (2 × 3 mL/100 mg of resin)
and dried in high vacuum. The THF washings were collected for
possible recovery of the donor. The conversion was analyzed by LC−
MS after NaOMe cleavage: A 5 mg sample of resin was placed into a
small microwave vial (0.2−0.5 mL) equipped with a magnetic stir bar.
After the resin was swollen with 250 μL of anhydrous CH2Cl2, 50 μL
of a 0.2 M sodium methoxide solution was added. The mixture was
irradiated in a microwave oven for 5 min at 55 °C with prestirring for
30 s. After the mixture was cooled to room temperature, the
supernatant was transferred to an Eppendorf vial, and the solution was
concentrated to dryness by an air stream. The residue was redissolved
in 100 μL of methanol (HPLC grade). A 1:10 dilution of this solution
was used for LC−MS analysis. For iduronic acid donors the
conversion was analyzed by LC−MS after dibutyltin oxide cleavage:
A 5 mg sample of resin and 4 mg of dibutyltin oxide were placed into a
small microwave vial (0.2−0.5 mL) equipped with a magnetic stir bar.
After the resin was swollen with 200 μL of anhydrous dichloro-
methane, 100 μL of MeOH was added. The mixture was irradiated in a
microwave oven for 10 min at 120 °C with prestirring for 30 s. After
the mixture was cooled to room temperature, the supernatant was
(90 mg, 75%): H NMR (500 MHz, CDCl3) δ = 8.74 (s, 0.8 H,
NHCCCl3), 8.69 (s, 0.2H, NHCCCl3), 8.11−8.08 (m, 2H, aromatic),
7.59−7.53 (m, 1H, aromatic), 7.45−7.26 (m, 7H, aromatic), 6.56 (s,
0.8H, H-1α), 6.34 (s, J = 1.8 Hz, H-1β), 5.51 (m, 0.2H, H-2β), 5.37
(m, 0.8H, H-2α), 5.34 (m, 0.8H, H-4α), 5.28 (m, 0.2H, H-4β), 5.12
(d, J = 1.9 Hz, 0.8H, H-5α), 4.86−4.75 (m, 2.2H, CH2Ph, H-5β), 4.14
(t, 0.2H, H-3β), 4.01 (m, 0.8H, H-3α), 3.79 (s, 3H, CH3COOMe), 2.60−
2.56 (m, 2H, CH2Lev), 2.45−2.40 (m, 2H, CH2Lev), 2.36−2.31 (m, 2H,
CH2Lev), 2.06 and 2.04 (2s, 3H, CH3Lev) ppm; 13C NMR (126 MHz,
CDCl3) δ = 205.7, 171.5, 168.0, 167.1, 165.4, 164.9, 160.2, 160.0,
137.1, 136.8, 133.8, 133.5, 129.9, 129.0, 128.6, 128.5, 128.3, 127.9,
127.6, 95.0 (C-1α), 94.5 (C-1β), 73.3 (C-5β), 73.1 (C-3β), 72.6, 71.5
(C-3α), 67.7 (C-5α), 67.4 (C-4α), 67.3 (C-4β), 66.0 (C-2β), 65.2 (C-
2α), 52.7 (CH3COOMe), 37.7, 29.5, 27.8 ppm.
Methyl (4-O-Acetyl-3-O-benzyl-1,2-O-[(1-pent-4-enyloxy)-
ethylidene]-β-L-idopyranuronate (3). The peracetylated com-
pound 31 (109 mg, 0.257 mmol) was dissolved in dry CH2Cl2 (2.6
mL), and 30% HBr in AcOH (0.26 mL) was added at 0 °C and the
resulting mixture stirred for 3 h. The reaction mixture was diluted with
cold CH2Cl2 and washed with ice-cold water and cold saturated
NaHCO3 aq solution. The organic layer was dried over MgSO4,
filtered, concentrated, and used in the next reaction without further
purification. A solution of bromide in dry CH2Cl2 (0.5 mL) containing
2,6-lutidine (0.59 mL, 5.1 mmol), and 1-pentenol (0.26 mL, 2.6
mmol) was stirred for 20 h at room temperature under a dry
atmosphere of argon. The mixture was diluted with CH2Cl2 and
washed with saturated NaHCO3 aq solution and water. The organic
layer was dried over MgSO4, filtered, and concentrated. The residue
was purified by column chromatography (hexane/ethyl acetate, 6:4,
containing 1% triethylamine) to obtain the orthoacetate 3 as a viscous
oil (71 mg, 0.15 mmol, 60% in two steps): [α]2D0 = −19.2 (c = 1,
CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.48−7.32 (m, 5H,
aromatic), 5.83−5.75 (m, 1H, CHpent), 5.53 (d, J = 2.7 Hz, H-1),
5.22−5.19 (m, 1H, H-4), 5.03−4.94 (m, 2H, CH2pent), 4.81 (d, J =
11.7 Hz, 1H, CH2Ph), 4.68 (d, J = 11.7 Hz, 1H, CH2Ph), 4.54 (d, 1H,
J
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 1.3 Hz, H-5), 4.12 (t, J = 2.3 Hz, 1H, H-3), 4.05−4.04 (m, 1H, H-
2), 3.78 (s, 3H, CH3COOMe), 3.53−3.41 (m, 2H, CH2pent), 2.12−2.07
(m, 2H, CH2pent), 2.03 (s, 3H, CH3Ac), 1.73 (s, 3H, CH3), 1.66−1.62
(m, 2H, CH2pent) ppm; 13C NMR (126 MHz, CDCl3) δ = 170.3,
168.3, 138.2 (CHpent), 137.0, 128.7−128.1 (Caromatic), 124.1 (Cq,
orthoester), 115.0 (CH2pent), 96.7 (C-1), 76.0 (C-2), 73.04 (CBn), 71.5
(C-3), 69.8 (C-5), 67.0 (C-4), 61.3 (CH2pent), 52.7 (CH3COOMe), 30.3
(CH2pent), 28.7 (CH2pent), 25.3 (CH3), 20.9 (CH3Ac) ppm; HRMS
(ESI) m/z calcd for C23H30O9 [M + Na]+ 473.1782, found 473.1763.
Methyl (3-O-Benzyl-4-O-levulinoyl-1,2-O-[(1-pent-4-
enyloxy)levulinylidene]-β-L-idopyranuronate (4). The per-levuli-
nated compound 32 (133 mg, 0.22 mmol) was dissolved in dry
CH2Cl2, and 30% HBr in AcOH (0.76 mL) was added at 0 °C and the
resulting mixture stirred for 3 h. The mixture was diluted with cold
CH2Cl2 and sequentially washed with ice-cold water and cold
saturated NaHCO3 aq solution. The organic layer was dried over
MgSO4, filtered, concentrated, and used in the next reaction without
further purification. A solution of the bromide in dry CH2Cl2 (0.5 mL)
containing 2,6-lutidine (0.52 mL, 4.47 mmol), and 1-pentenol (0.23
mL, 2.26 mmol) was stirred for 20 h at room temperature under
argon. The mixture was diluted with CH2Cl2 and washed with
saturated NaHCO3 aq solution, and water. The organic layer was dried
over MgSO4, filtered, and concentrated. The residue was purified by
column chromatography (hexane/ethyl acetate, 6:4, containing 1%
triethylamine) to obtain 4 as a viscous oil (91 mg, 73%): [α]2D0 = −7.4
(c = 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.38−7.31 (m, 5H,
aromatic), 5.82−5.74 (m, 1H, CHpent), 5.49 (d, J = 2.7 Hz, 1H, H-1),
5.20−5.19 (m, 1H, H-4), 5.03−4.95 (m, 2H, CH2pent), 4.81 (d, J =
11.7 Hz, 1H, CH2Ph), 4.66 (d, J = 11.7 Hz, 1H, CH2Ph), 4.51 (d, 1H,
J = 1.3 Hz, H-5), 4.08−4.05 (m, 2H, H-3, H-2), 3.79 (s, 3H,
CH3COOMe), 3.51−3.41 (m, 2H, CH2pent), 2.81−2.69 (m, 4H, CH2Lev),
2.54−2.51 (m, 2H, CH2Lev), 2.29−2.25 (m, 2H, CH2Lev), 2.18 (s, 3H,
CH3Lev), 2.16 (s, 3H, CH3Lev), 2.10−2.06 (m, 2H, CH2pent), 1.65−1.60
(m, 2H, CH2,pent) ppm; 13C NMR (126 MHz, CDCl3) δ = 208.4,
206.3, 172.0, 167.9, 138.1 (CHpent), 137.0, 128.8, 128.4, 128.1, 124.4
(Cq, orthoester), 115.1 (CH2pent), 96.5 (C-1), 75.6 (C-2), 73.1 (CBn),
71.8 (C-3), 69.7 (C-5), 67.0 (C-4), 61.5 (CH2pent), 52.7 (CH3COOMe),
38.7, 37.9 (CH2Lev), 32.0 (CH2Lev), 30.3 (CH2pent), 30.0, 29.9
(CH3Lev), 28.7 (CH2pent), 28.1 (CH2Lev) ppm; HRMS (ESI) m/z
calcd for C29H38O11 [M + Na]+ 585.2312, found 585.2309.
Methyl (3-O-Benzyl-4-O-levulinoyl-1,2-O-[(1-pent-4-
enyloxy)benzylidene)]-β-L-idopyranuronate (6). The reaction
was carried out according to general procedure A using compound
35 (205 mg, 0.44 mmol), levulinic acid (152 mg, 1.31 mmol),
EDC·HCl (250 mg, 1.31 mmol), and a catalytic amount of DMAP in
dry CH2Cl2 (4 mL). The crude product was purified by flash
chromatography (hexane/ethyl acetate, 8:2, with 1% triethylamine) to
obtain compound 6 as a viscous oil (225 mg, 90%): [α]2D0 = +19.7 (c =
1
1, CHCl3); H NMR (500 MHz, CDCl3) δ = 7.75−7.73 (m, 2H,
aromatic), 7.38−7.33 (m, 5H, aromatic), 5.80−5.74 (m, 1H, CHpent),
5.66 (d, J = 2.8 Hz, H-1), 5.17 (m, 1H, H-4), 5.02−4.94 (m, 2H,
CH2pent), 4.82 (d, J = 11.8 Hz, 1H, CH2Ph), 4.70 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.55 (d, J = 1.0 Hz, 1H, H-5), 4.31−4.30 (m, 1H, H-2),
4.14−4.13 (m, 1H, H-3), 3.75 (s, 3H, CH3COOMe), 3.48−3.41 (m, 2H,
CH2pent), 2.34−2.18 (m, 2H, CH2Lev), 2.13−2.08 (m, 2H, CH2Lev),
2.00 (s, 3H, CH3Lev), 1.70−1.64. (m, 2H, CH2pent) ppm; 13C NMR
(126 MHz, CDCl3) δ = 206.4, 171.7, 167.9, 138.1 (CHpent), 137.4,
137.0, 129.2, 128.8, 128.4, 128.1, 128.0, 127.0, 122.4 (Cq, orthoester),
115.0 (CH2pent), 96.8 (C-1), 75.4 (C-2), 73.1 (CBn), 71.6 (C-3), 69.7
(C-5), 66.8 (C-4), 63.3 (CH2pent), 52.6 (CH3COOMe), 37.6 (CH2Lev),
30.3 (CH2Lev), 29.7 (CH3Lev), 28.9 (CH2Lev), 28.1 (CH2Lev) ppm;
HRMS (ESI) m/z calcd for C31H36O10 [M + Na]+ 591.2206, found
591.2197.
Phenyl 2-O-Benzoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-4-
O-levulinoyl-1-thio-α-L-idopyranoside (8). The reaction was
carried out according to general procedure A using compound 20
(1.13 g, 1.86 mmol), levulinic acid (1.30 g, 11.2 mmol), EDC·HCl
(2.15 g, 11.2 mmol), and a catalytic amount of DMAP in dry CH2Cl2
(20 mL). Compound 8 was obtained as a colorless syrup (860 mg,
65%): Rf = 0.33 (hexane/ethyl acetate, 4:1); [α]2D0 = −13.5 (c = 1.0,
CHCl3); 1H NMR (500 MHz, CDCl3) δ = 8.10−8.05 (m, 2H,
aromatic), 7.59−7.55 (m, 3H, aromatic), 7.47−7.43 (m, 4H,
aromatic), 7.39−7.36 (m, 2H, aromatic), 7.33−7.23 (m, 4H,
aromatic), 5.64 (s, 1H, H-1), 5.46−5.44 (m, 1H, H-2), 5.10 (s, 1H,
H-4), 4.89 (d, J = 11.9 Hz, 1H, CH2Ph), 4.87−4.83 (td, J = 2.0, 6.5
Hz, 1H, H-5), 4.79 (d, J = 11.9 Hz, 1H, CH2Ph), 3.99−3.95 (m, 1H,
H-3), 3.82−3.77 (m, 2H, H-6ab), 2.67−2.52 (m, 3H, CH2Lev), 2.47−
2.38 (m, 1H, CH2Lev), 2.07 (s, 3H, CH3Lev), 1.66−1.58 (m, 1H,
CHthexyl), 0.90 (d, J = 6.9 Hz, 6H, CH3thexyl), 0.85 (2s, 6H, CH3thexyl),
0.13 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3) ppm; 13C NMR (126 MHz,
CDCl3) δ = 205.9, 172.1, 165.2, 137.5, 136.4, 133.6, 131.4, 129.9,
129.6, 129.0, 128.5, 127.9, 127.6, 127.3, 86.1 (C-1), 72.8 (CBn), 72.3
(C-3), 70.0 (C-2), 67.4 (C-5), 67.2 (C-4), 61.4 (C-6), 37.8 (CH2Lev),
34.2 (CHthexyl), 29.7 (CH3Lev), 28.0 (CH2Lev), 25.2 (Cqthexyl), 20.3,
20.2, 18.6 (CH3thexyl), −3.5, −3.7 (Si(CH3)2) ppm; HRMS (ESI) m/z
calcd for C39H50O8SSi [M + Na]+ 729.2893, found 729.2894.
Phenyl 2-O-Benzoyl-3,6-di-O-benzyl-4-O-levulinoyl-1-thio-
α-L-idopyranoside (9). The reaction was carried out according to
general procedure A using compound 24 (220 mg, 395 μmol),
levulinic acid (140 mg, 1.18 mmol), EDC·HCl (225 mg, 1.18 mmol),
and a catalytic amount of DMAP in dry CH2Cl2 (3 mL). Compound 9
was obtained as a colorless syrup (258 mg, 94%): Rf = 0.45 (hexane/
Methyl (4-O-Benzoyl-3-O-benzyl-1,2-O-[(1-pent-4-enyloxy)-
benzylidene]-β-L-idopyranuronate (5). The perbenzoylated com-
pound 33 (310 mg, 0.508 mmol) was dissolved in dry CH2Cl2 (9.3
mL), 30% HBr in AcOH (1.72 mL) was added at 0 °C, and the
solution was stirred for 3 h. The mixture was diluted with cold CH2Cl2
and washed with ice-cold water and cold saturated NaHCO3 aq
solution. The organic layer was dried over MgSO4, filtered,
concentrated, and used in the next reaction without further
purification. A solution of bromide in dry CH2Cl2 (1 mL) containing
2,6-lutidine (1.18 mL, 10.2 mmol) and 1-pentenol (0.52 mL, 5.1
mmol) was stirred for 20 h at room temperature under a dry
atmosphere of argon. The mixture was diluted with CH2Cl2 (200 mL)
and washed with saturated NaHCO3 solution and water. The organic
layer was dried over MgSO4, filtered, and concentrated. The residue
was purified by column chromatography (hexane/ethyl acetate, 7:3,
containing 1% triethylamine) to obtain the syrupy 5 (214 mg, 73%):
[α]2D0 = −1.7 (c = 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.73−
7.21 (m, 16H, aromatic), 5.80−5.73 (m, 1H, CHpent), 5.71 (d, J = 2.7
1
ethyl acetate, 3:1); [α]D20 = −10.7 (c = 1.0, CHCl3); H NMR (500
MHz, CDCl3, 25) δ = 8.08−8.06 (m, 2H, aromatic), 7.59−7.54 (m,
3H, aromatic), 7.42−7.19 (m, 15H, aromatic), 5.62 (s, 1H, H-1),
5.45−5.42 (m, 1H, H-2), 5.13−5.09 (m, 1H, H-5), 5.08−5.06 (m, 1H,
H-4), 4.90 (d, J = 11.8 Hz, 1H, CH2Ph), 4.77 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.58 (d, J = 11.4 Hz, 1H, CH2Ph), 4.53 (d, J = 11.8 Hz, 1H,
CH2Ph), 3.92−3.90 (m, 1H, H-3), 3.76−3.71 (m, 1H, H-6a), 3.71−
3.66 (m, 1H, H-6b), 2.65−2.43 (m, 3H, CH2Lev), 2.40−2.31 (m, 1H,
CH2Lev), 2.06 (s, 3H, CH3Lev) ppm; 13C NMR (126 MHz, CDCl3) δ =
205.8, 171.9, 165.2, 133.3−125.1 (Caromatic), 86.1 (C-1), 72.7 (CBn),
71.9 (CBn), 71.5 (C-3), 70.7 (C-2), 68.5 (C-6), 67.2 (C-4), 66.4 (C-5),
37.7 (CH2Lev), 29.6 (CH3Lev), 27.8 (CH2Lev) ppm; HRMS (ESI) m/z
calcd for C38H38O8S [M + Na]+ 677.2180, found 677.2155.
Hz, 1H, H-1), 5.47−5.46 (m, 1H, H-4), 5.01−4.97 (m, 3H, CH2pent
,
CH2Ph), 4.78 (d, J = 11.7 Hz, CH2Ph), 4.68 (d, J = 1.3 Hz, 1H, H-5),
4.38−4.37 (m, 1H, H-2), 4.28 (t, J = 2.17 Hz, 1H, H-3), 3.69 (s, 3H,
CH3COOMe), 3.44−3.34 (m, 2H, CH2pent), 2.11−2.05 (m, 2H, CH2pent),
1.68−1.62 (m, 2H, CH2pent) ppm; 13C NMR (126 MHz, CDCl3) δ =
168.1, 165.9, 138.1 (CHpent), 137.0, 136.9, 133.2, 130.0, 129.2, 128.8,
128.4, 128.4, 128.1, 127.1, 122.4 (Cq, orthoester), 115.0 (CHpent),
96.9 (C-1), 75.4 (C-2), 73.2 (CBn), 72.1 (C-3), 70.2 (C-5), 67.1 (C-4),
63.5 (CH2pent), 52.7 (CH3COOMe), 30.3 (CH2pent), 28.9 (CH2pent) ppm;
HRMS (ESI) m/z calcd for C33H34O9 [M + Na]+ 597.2101, found
597.2082.
Phenyl 6-O-Acetyl-2-O-benzoyl-3-O-benzyl-4-O-levulinoyl-
1-thio-α-L-idopyranoside (10). To a solution of 7 (400 mg, 0.498
mmol) in THF (2 mL) at 0 °C was added HF−pyridine (1 mL). The
reaction mixture was allowed to warm to room temperature and stirred
overnight. Next the reaction was quenched by addition of saturated
K
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NaHCO3 aq solution and solid NaHCO3 and washed with saturated
NaHCO3 aq solution and water. The organic layer was dried over
MgSO4 and concentrated in vacuo. Flash chromatography (0−20%
ethyl acetate/hexane) afforded phenyl 2-O-benzoyl-3-O-benzyl-4-O-
levulinoyl-1-thio-α-L-idopyranoside (141 mg, 50%): 1H NMR (500
MHz, CDCl3) δ = 8.16−8.08 (m, 2H, aromatic), 7.64−7.56 (m, 3H,
aromatic), 7.54−7.26 (m, 10H, aromatic), 5.64 (s, 1H, H-1), 5.52−
5.48 (m, 1H, H-2), 5.14−5.10 (m, 1H, H-5), 4.99−4.91 (m, 1H, H-4),
4.94 (d, J = 11.8 Hz, 1H, CH2Ph), 4.80 (d, J = 11.8 Hz, 1H, CH2Ph),
3.96−3.91 (m, 1H, H-3), 3.85 (dd, J = 11.6, 6.9 Hz, 1H, H-6a), 3.76
(dd, J = 11.6, 6.3 Hz, 1H, H-6b), 2.79−2.69 (m, 1H, CH2Lev), 2.69−
2.56 (m, 2H, CH2Lev), 2.44−2.34 (m, 1H, CH2Lev), 2.12 (s, 3H,
CH3Lev) ppm; 13C NMR (126 MHz, CDCl3) δ 206.4, 172.5, 165.1,
137.1, 135.6, 133.5, 131.8, 129.7, 129.4, 129.0, 128.4, 128.4, 127.8,
127.5, 86.1, 72.5, 72.1, 69.1, 67.2, 66.8, 61.1, 37.8, 29.5, 27.8 ppm;
MALDI-TOF m/z calcd for C31H32O8S [M + Na]+ 587.2, found 587.4.
To a solution of phenyl 2-O-benzoyl-3-O-benzyl-4-O-levulinoyl-1-thio-
α-L-idopyranoside (0.095 g, 0.168 mmol) in CH2Cl2 (1 mL) at 0 °C
were added pyridine (0.020 mL, 0.252 mmol) and acetic anhydride
(0.021 g, 0.202 mmol). The reaction was allowed to warm to room
temperature and stirred until completion. The mixture was diluted
with CH2Cl2 and washed with saturated CuSO4 aq solution and water.
The organic layer was dried over MgSO4, filtered, and concentrated in
vacuum. Flash column chromatography (0−30% ethyl acetate/hexane)
afforded 10 as a colorless syrup (102 mg, quantitative): 1H NMR (500
MHz, CDCl3) δ = 8.15−8.08 (m, 2H, aromatic), 7.65−7.56 (m, 3H,
aromatic), 7.54−7.25 (m, 10H, aromatic), 5.70−5.64 (m, 1H, H-1),
5.50−5.44 (m, 1H, H-2), 5.16−5.09 (m, 1H, H-5), 5.07−5.02 (m, 1H,
H-4), 4.94 (d, J = 11.8 Hz, 1H, CH2Ph), 4.79 (d, J = 11.7 Hz, 1H,
CH2Ph), 4.33 (dd, J = 7.9, 11.5 Hz, 1H, H-6a), 4.28 (dd, J = 5.0, 11.5
Hz, 1H, H-6b), 3.98−3.92 (m, 1H, H-3), 2.72−2.52 (m, 3H, CH2Lev),
aromatic), 6.87 (d, J = 8.6 Hz, 1H, aromaticPMB), 5.62 (br s, 1H, H-
1), 5.44 (m, 1H, H-2), 5.11−5.03 (m, 2H, H-4, H-5), 4.90 (d, J = 11.8
Hz, 1H, CH2Ph), 4.77 (d, J = 11.8 Hz, 1H, CH2Ph), 4.52 (d, J = 11.4
Hz, 1H, CH2PMB), 4.46 (d, J = 11.5 Hz, 1H, CH2PMB), 3.93−3.90 (m,
1H, H-3), 3.80 (s, 3H, CH3PMB), 3.72 (dd, J = 9.9, 6.8 Hz, 1H, H-6a),
3.66 (dd, J = 10.0, 5.4 Hz, 1H, H-6b), 2.66−2.57 (m, 1H, CH2Lev),
2.57−2.44 (m, 2H, CH2Lev), 2.39−2.31 (m, 1H, CH2Lev), 2.07 (s, 3H,
CH3Lev) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.0, 172.1, 165.3,
159.3, 137.4, 136.0, 133.6, 132.1, 132.1, 130.3, 130.0, 130.0, 129.7,
129.6, 129.5, 129.1, 129.1, 129.0, 128.6, 128.5, 127.9, 127.7, 127.7,
127.6, 113.8 (CaromaticPMB), 86.3 (C-1), 73.1 (CH2PMB), 72.8 (CBn),
72.3 (C-3), 69.5 (C-2), 68.7 (C-6), 67.6 (C-4), 65.8 (C-5), 55.4
(CH3PMB), 37.9 (CH2Lev), 29.8 (CH3Lev), 27.9 (CH2Lev) ppm; HRMS
(ESI) m/z calcd for C39H40O9S [M + NH4]+ 702.2731 found
702.2722.
Phenyl 2-O-Benzoyl-3-O-benzyl-4-O-levulinoyl-1-thio-6-O-
[(triisopropylsiloxy)methyl]-α-L-idopyranoside (13). To a sol-
ution of phenyl 2-O-benzoyl-3-O-benzyl-4-O-levulinoyl-1-thio-α-L-
idopyranoside (0.260 g, 0.460 mmol) in CH2Cl2 (2 mL) at 0 °C
were added freshly distilled DIPEA (0.402 mL, 2.302 mmol) and
(triisopropylsiloxy)methyl chloride (0.260 mL, 0.921 mmol). The
reaction was allowed to warm to room temperature and stirred until
completion. The mixture was diluted with CH2Cl2, washed with water,
dried over MgSO4, and concentrated in vacuum. Flash column
chromatography (0−20% ethyl acetate/hexane) afforded 13 as a
1
colorless syrup (220 mg, 64%): H NMR (500 MHz, CDCl3) δ =
8.15−7.10 (m, 15H, aromatic), 5.63 (s, 1H, H-1), 5.50−5.44 (m, 1H,
H-2), 5.11−5.05 (m, 2H, H-4, H-5), 4.99−4.93 (m, 2H, CH2TOM),
4.92 (d, J = 11.8 Hz, 1H, CH2Ph), 4.81 (d, J = 11.8 Hz, 1H, CH2Ph),
3.98−3.93 (m, 1H, H-3), 3.88−3.78 (m, 2H, H-6ab), 2.71−2.52 (m,
3H, CH2Lev), 2.49−2.39 (m, 1H, CH2Lev), 2.10 (s, 3H, CH3Lev), 1.11−
1.07 (m, 21H, 6CH3TOM, 3CHTOM) ppm; 13C NMR (126 MHz,
CDCl3) δ = 205.7, 172.0, 165.2, 137.3, 135.9, 133.4, 131.94, 129.8,
129.5, 128.8, 128.4, 127.8, 127.5, 127.4, 90.1 (CH2TOM), 86.2 (C-1),
72.6 (CBn), 72.0 (C-3), 69.4 (C-2), 67.4 (C-4), 66.3 (C-6), 65.6 (C-5),
37.8 (CH2Lev), 29.6 (CH3Lev), 27.8 (CH2Lev), 17.8 (CH3TOM), 12.0
(CHTOM) ppm; LRMS (MALDI-TOF) m/z calcd for C41H54O9SSi [M
+ Na]+ 774.00, found 773.95; HRMS (ESI) m/z calcd for
C41H54O9SSi [M + Na]+ 773.3156, found 773.3118.
2.47−2.37 (m, 1H, CH2Lev), 2.11 (s, 3H, CH3Lev), 2.07 (s, 3H, CH3Ac
)
ppm; 13C NMR (126 MHz, CDCl3) δ = 205.7, 171.9, 170.5, 165.0,
137.1, 135.7, 133.5, 131.7, 129.8, 129.4, 128.8, 128.4, 128.3, 127.9,
127.6, 127.5, 86.0 (C-1), 72.7 (CBn), 71.9 (C-3), 68.8 (C-2), 67.0 (C-
4), 64.6 (C-5), 62.7 (C-6), 37.7 (CH2Lev), 29.5 (CH3Lev), 27.8
(CH2Lev), 20.7 (CH3Ac) ppm; LRMS (MALDI-TOF) m/z calcd for
C33H34O9S [M + Na]+ 629.2, found 629.7; HRMS (ESI) m/z calcd for
C33H34O9S [M + Na]+ 629.1821, found 629.1844.
2-O-Benzoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-4-O-levu-
linoyl-α/β-L-idopyranosyl Trichloroacetimidate (14). The thio-
glycoside 8 (820 mg, 1.16 mmol) was hydrolyzed using NIS (662 mg,
2.94 mmol) and TfOH (11 μL, 0.12 mmol) in wet THF at room
temperature for 6 h. The reaction mixture was quenched with
saturated NaHCO3 aq solution and solid Na2S2O3. The mixture was
filtered and washed with saturated NaHCO3 aq solution, water, and
brine. The organic layer was dried over MgSO4, filtered, and
concentrated. The reaction crude was purified by column chromatog-
raphy on silica (hexane/ethyl acetate, 4:1). 2-O-Benzoyl-3-O-benzyl-6-
O-(dimethylthexylsilyl)-4-O-levulinoyl-α/β-L-idopyranose was ob-
tained as a colorless syrup (534 mg, 75%): Rf = 0.23 (hexane/ethyl
acetate, 4:1); MALDI-TOF m/z calcd for C33H46O9Si [M + Na]+
637.28, found 637.57. 2-O-Benzoyl-3-O-benzyl-6-O-(dimethylthexyl-
silyl)-4-O-levulinoyl-α/β-L-idopyranose (753 mg, 1.25 mmol) and
trichloroacetonitrile (2.51 mL, 25 mmol) were dissolved in anhydrous
CH2Cl2 (10 mL) with activated molecular sieves. After 30 min of
stirring, the solution was cooled to 0 °C and DBU (55 μL, 0.38 mmol)
was added. After 2 h, TLC (hexane/ethyl acetate, 4:1) indicated
complete conversion of the starting material. The mixture was
concentrated under reduced pressure and purified by column
chromatography on silica (hexane 100% → hexane/ethyl acetate,
4:1, with 1% triethylamine) to obtain compound 14 as a colorless
solid, α/β mixture (ratio 5.8:1) (683 mg, 72%), Rf = 0.23 (hexane/
ethyl acetate, 4:1). Data for the α-anomer: 1H NMR (500 MHz,
CDCl3) δ = 8.63 (s, 1H, OCNHCCl3), 8.10 (d, J = 7.7 Hz, 2H,
aromatic), 7.59 (t, J = 7.4 Hz, 1H, aromatic), 7.49−7.24 (m, 7H,
aromatic), 6.41 (s, 1H, H-1), 5.38 (s, 1H, H-2), 5.12 (br s, 1H, H-4),
4.84 (d, J = 11.6 Hz, 1H, CH2Ph), 4.75 (d, J = 11.6 Hz, 1H, CH2Ph),
4.55 (t, J = 6.5 Hz, 1H, H-5), 3.99 (s, 1H, H-3), 3.80−3.70 (m, 2H, H-
6), 2.64−2.36 (m, 4H, 2CH2Lev), 2.07 (s, 3H, CH3Lev), 1.28−1.24 (m,
Phenyl 2-O-Benzoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-me-
thoxyphenyl)-1-thio-α-L-idopyranoside (11). The reaction was
carried out according to general procedure A using compound 21 (246
mg, 420 μmol), levulinic acid (146 mg, 1.26 mmol), EDC·HCl (242
mg, 1.26 mmol), and a catalytic amount of DMAP in dry CH2Cl2 (3
mL). Compound 11 was obtained as a colorless syrup (259 mg, 90%):
Rf = 0.22 (hexane/ethyl acetate, 3:1); [α]2D0 = −15.1 (c = 1.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ = 7.89−7.80 (m, 2H, aromatic), 7.59−
7.54 (m, 2H, aromatic), 7.52−7.48 (m, 1H, aromatic), 7.42−7.19 (m,
10H, aromatic), 6.88 (d, J = 9.2 Hz, 2H, aromaticPMP), 6.83 (d, J = 9.2
Hz, 2H, aromaticPMP), 5.59 (s, 1H, H-1), 5.48−5.46 (m, 1H, H-2),
5.28−5.24 (m, 1H, H-5), 5.15 (br s, 1H, H-4), 4.93 (d, J = 11.8 Hz,
1H, CH2Ph), 4.79 (d, J = 11.7 Hz, 1H, CH2Ph), 4.18 (dd, J = 9.9, 7.2
Hz, 1H, H-6a), 4.10 (dd, J = 9.9, 5.2 Hz, 1H, H-6b), 3.96−3.94 (m,
1H, H-3), 3.77 (s, 3H, CH3PMP), 2.64−2.48 (m, 3H, CH2Lev), 2.40−
2.34 (m, 1H, CH2Lev), 2.06 (s, 3H, CH3Lev) ppm; 13C NMR (126
MHz, CDCl3) δ = 206.1, 172.6, 165.3, 154.2, 152.9, 137.4, 135.9,
133.6−127.6 (Caromatic), 115.8, 114.7 (CaromaticPMP), 86.3 (C-1), 72.8
(CBn), 72.2 (C-3), 69.3 (C-2), 67.7 (C-6), 67.5 (C-4), 65.5 (C-5), 55.8
(CH3PMP), 37.8 (CH2Lev), 29.7 (CH3Lev), 28.0 (CH2Lev) ppm; HRMS
(ESI) m/z calcd for C38H38O9S [M + Na]+ 693.2134, found 693.2120.
Phenyl 2-O-Benzoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-me-
thoxybenzyl)-1-thio-α-L-idopyranoside (12). The reaction was
carried out according to general procedure A using compound 25 (127
mg, 216 μmol), levulinic acid (50 mg, 433 μmol), EDC·HCl (83 mg,
0.433 μmol), and a catalytic amount of DMAP in dry CH2Cl2 (2 mL).
Compound 12 was obtained as a colorless syrup (120 mg, 81%): Rf =
1
0.25 (hexane/ethyl acetate, 3:1); [α]2D0 = −49.6 (c = 1.0, CHCl3); H
NMR (500 MHz, CDCl3) δ 8.11−8.05 (m, 2H, aromatic), 7.61−7.54
(m, 3H, aromatic), 7.49−7.40 (m, 4H, aromatic), 7.40−7.36 (m, 2H,
aromatic), 7.34−7.29 (m, 1H, aromatic), 7.28−7.21 (m, 5H,
L
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H, CHthexyl), 0.85 (d, J = 6.7 Hz, 2 × 3H, CH3thexyl), 0.81 (s, 6H,
CH3thexyl), 0.08 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3) ppm; 13C NMR
(126 MHz, CDCl3) δ = 205.4, 171.9, 165.0, 129.7−127.4 (Caromatic),
94.9 (C-1), 72.3 (CBn), 71.9 (C-3), 68.5 (C-5), 66.5 (C-2), 66.3 (C-4),
61.1 (C-6), 37.7 (CH2Lev), 33.9 (CHthexyl) 29.7 (CH3Lev) 27.9
(CH2Lev), 27.8 (CH2Lev), 20.2 (CH3thexyl), 18.5 (CH3thexyl), −4.1
(SiCH3) ppm; MALDI-TOF m/z calcd for C35H46Cl3NO9Si [M +
Na]+ 780.19, found 780.10.
171.5 (Cq), 166.0 (Cq), 160.4 (Cq), 137.2−128.0 (Caromatic), 94.2 (C-
1), 77.6 (C-3), 77.2 (CCl3), 75.1 (CBn), 70.8 (C-5), 70.0 (C-4), 62.6
(C-2), 62.2 (C-6), 37.7 (CH2Lev), 29.6 (CH3Lev), 27.8 (CH2Lev) ppm;
HRMS (ESI) m/z calcd for C27H27Cl3N4O8 [M + Na]+ 663.0787,
found 663.0784.
2-Azido-6-O-benzoyl-3-O-benzyl-2-deoxy-4-O-levulinoyl-α/
β-D-glucopyranosyl N-Phenyltrifluoroacetimidate (17). To a
cooled (0 °C) solution of compound 29 (0.773 g, 1.26 mmol) in dry
THF (6 mL) were added AcOH (0.079 mL) and TBAF (1.38 mL,
1.26 mmol). After 3 h, water was added and the mixture was diluted
with ethyl acetate and washed with water. The aqueous layer was
extracted with ethyl acetate, and the combined organic layers were
dried over MgSO4 and concentrated to dryness. The residue was
concentrated and used in the next reaction without further
purification. To a solution of hemiacetal (636 mg, 1.28 mmol) in
acetone (10 mL) were added potassium carbonate (350 mg, 2.56
mmol) and N-phenyltrifluoroacetimidoyl chloride (600 mg, 2.89
mmol). The reaction was stirred overnight, and the solvent was
removed in vacuo. Flash chromatography on silica gel (hexane →
hexane/ethyl acetate, 2:1, with 1% triethylamine) afforded a mixture
2-O-Benzoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-methoxy-
phenyl)-α/β-L-idopyranosyl Trichloroacetimidate (15). The
thioglycoside 11 (2.10 g, 3.13 mmol) was hydrolyzed using NIS
(1.76 g, 7.83 mmol) and TfOH (27 μL, 0.31 mmol) in wet THF at
room temperature for 6 h. The reaction mixture was quenched with
saturated NaHCO3 solution and solid Na2S2O3. The mixture was
filtered and washed with saturated NaHCO3 solution, water, and brine.
The reaction crude was purified by column chromatography on silica
(hexane/ethyl acetate, 4:1): Rf = 0.21 (hexane/ethyl acetate, 2:1);
MALDI-TOF m/z calcd for C33H46O9Si [M + Na]+ 637.28, found
637.57. 2-O-Benzoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-methoxyphen-
yl)-α/β-L-idopyranose (3.13 mmol) and trichloroacetonitrile (3.14
mL, 31.3 mmol) were dissolved in anhydrous CH2Cl2 (16 mL) with
activated molecular sieves. After 30 min of stirring, the solution was
cooled to 0 °C and DBU (417 μL, 0.32 mmol) was added. After 2 h,
TLC (hexane/ethyl acetate, 3:1) indicated complete conversion of the
starting material. The mixture was concentrated under reduced
pressure and purified by column chromatography on silica (hexane
100% → hexane/ethyl acetate, 2:1) to obtain compound 15 as a
colorless syrup, α/β mixture (ratio 2:1) (1.27 g, 56% over two steps),
Rf = 0.40 (hexane/ethyl acetate, 2:1). Data for the α-anomer: 1H NMR
(500 MHz, CDCl3) δ = 8.61 (s, 1H, OCNHCCl3), 8.09−7.93 (m, 2H,
aromatic), 7.56−7.45 (m, 1H, aromatic), 7.43−7.20 (m, 7H,
aromatic), 6.83−6.65 (m, 4H, aromaticPMP), 6.38 (s, 1H, H-1), 5.33
(s, 1H, H-2), 5.13 (s, 1H, H-4), 4.81 (d, J = 11.6 Hz, 1H, CH2Ph),
4.74 (s, 1H, H-5), 4.69 (d, J = 11.6 Hz, 1H, CH2Ph), 4.10−4.07 (m,
1H, H-6a), 4.01−3.95 (m, 1H, H-6b), 3.93 (s, 1H, H-3), 3.68 (s, 3H,
1
(1:1) of 17α and 17β (765 mg, 91%). Data for the α-anomer: H
NMR (500 MHz, CDCl3) δ = 8.05−8.03 (m, 2H, aromatic), 7.59−
7.56 (m, 1H, aromatic), 7.45−7.42 (m, 2H, aromatic), 7.37−7.31 (m,
5H, aromatic), 7.26−7.22 (m, 2H, aromatic), 7.11−7.08 (m, 1H,
aromatic), 6.72 (d, 2H, aromatic), 6.42 (br s, 1H, H-1), 5.27 (t, J = 9.8
Hz, 1H, H-4), 4.88 (d, J = 11.0 Hz, CH2Ph), 4.77 (d, J = 11.0 Hz,
CH2Ph), 4.51 (dd, J = 12.4 Hz, 2.3 Hz, 1H, H-6a), 4.36 (dd, J = 12.4,
5.4 Hz, 1H, H-6b), 4.19−4.17 (m, 1H, H-5), 4.05 (t, J = 9.7 Hz, 1H,
H-3), 3.76−3.74 (m, 1H, H-2), 2.67−2.64 (m, 2H, CH2Lev), 2.6−2.53
(m, 1H, CH2Lev), 2.46−2.40 (m, 1H, CH2Lev), 2.13 (s, 3H, CH3Lev
)
ppm; 13C NMR (126 MHz, CDCl3) δ = 206.2, 171.7, 166.2, 143.1,
137.4, 133.3, 129.9, 129.0, 128.7, 128.6, 128.2, 124.7, 119.4, 92.7 (C-
1), 78.0 (C-3), 75.5 (CBn), 70.9 (C-5), 70.2 (C-4), 62.7 (C-2), 62.4
(C-6), 37.9 (CH2Lev), 29.8 (CH3Lev), 28.0 (CH2Lev) ppm. Data for the
β-anomer: 1H NMR (500 MHz, CDCl3) δ = 8.02−8.00 (m, 2H,
aromatic), 7.56−7.53 (m, 1H, aromatic), 7.39−7.30 (m, 7H,
aromatic), 7.25−7.22 (m, 2H, aromatic), 7.12−7.09 (m, 1H,
aromatic), 6.75−6.74 (m, 2H, aromatic), 5.60 (br s, 1H, H-1), 5.17
(t, J = 9.7 Hz, 1H, H-4), 4.85 (d, J = 11.3 Hz, 1H, CH2Ph), 4.74 (d, J =
11.3 Hz, 1H, CH2Ph), 4.49 (dd, J = 12.4, 2.2 Hz, 1H, H-6a), 4.32 (dd,
J = 12.3, 6.2 Hz, 1H, H-6b), 3.79−3.75 (m, 2H, H-2, H-5), 3.60−3.56
(m, 1H, H-3), 2.74−2.62 (m, 2H, CH2Lev), 2.54−2.48 (m, 1H,
CH2Lev), 2.44−2.38 (m, 1H, CH2Lev), 2.12 (s, 3H, CH3Lev) ppm; 13C
NMR (126 MHz, CDCl3) δ = 206.2, 171.7, 166.2, 143.1, 137.5, 133.2,
129.9, 129.8, 128.9, 128.8, 128.6, 128.5, 128.26, 128.2, 124.6, 119.3,
95.5 (C-1), 80.3 (C-3), 75.4 (CBn), 73.3 (CF3), 70.0 (C-4), 65.1 (C-5,
C-2), 62.7 (C-6), 37.9 (CH2Lev), 29.8 (CH3Lev), 28.0 (CH2Lev) ppm.
Phenyl 2-O-Benzoyl-3-O-benzyl-1-thio-α-L-idopyranoside
(19). To a solution of 1,6-anhydro compound 18 (328 mg, 0.920
mmol) in dry CH2Cl2 (3.5 mL) were added trimethyl(phenylthio)-
silane (0.57 mL, 3.0 mmol) and ZnI2 (0.65 g, 1.8 mmol, protected
from light and dried under high vacuum). The mixture was stirred at
room temperature overnight and filtered through a pad of Celite. The
filtrate was diluted with CH2Cl2, after which a solution of HCl in
dioxane and water were added. The mixture was stirred at room
temperature for 15 min, and the organic layer was washed with aq 1 M
HCl solution, saturated NaHCO3 aq solution, and water, filtered, and
concentrated. The crude product was purified by flash chromatography
(hexane/ethyl acetate, 4:1 to 1:1) to obtain compound 19 as a white
solid (0.252 g, 77%): 1H NMR (500 MHz, CDCl3) δ = 8.03−8.02 (m,
2H, aromatic), 7.58−7.24 (m, 15H, aromatic), 5.64 (s, 1H, H-1), 5.54
(s, 1H, H-2), 4.93−4.90 (d, J = 11.8 Hz, 1H, CH2Ph), 4.78 (m, 1H, H-
5), 4.67 (d, J = 11.8 Hz, 1H, CH2Ph), 3.97 (dd, J = 11.8, 6.3 Hz, 1H,
H-6a), 3.93−3.82 (m, 3H, H-6b, H-3, H-4), 3.10−2.51 (br s, 1H,
OH), 2.04−1.65 (br s, 1H, OH) ppm; 13C NMR (126 MHz, CDCl3)
δ = 165.0, 137.2, 135.6, 133.7, 132.0, 129.7, 129.1, 128.7, 128.5, 128.0,
127.8, 127.7, 127.5, 86.7 (C-1), 74.0 (C-3), 72.3 (CBn), 69.9 (C-2),
68.4 (C-4), 68.2 (C-5), 63.3 (C-6) ppm; HRMS (ESI) m/z calcd for
C26H26O6S [M + Na]+ 489.1348, found 489.1320.
CH3PMP), 2.55−2.22 (m, 4H, CH2Lev), 1.97 (s, 3H, CH3Lev) ppm; 13
C
NMR (126 MHz, CDCl3) δ = 205.9, 172.0, 165.5, 165.1, 160.6, 160.3,
154.2, 152.4, 133.6−128.2 (Caromatic), 115.9−114.6 (CaromaticPMP), 94.8
(C-1), 91.1 (CCl3) 72.5 (CBn), 71.9 (C-3), 67.5 (C-2), 67.1 (C-6),
66.5 (C-5), 66.0 (C-4), 55.7 (CH3PMP), 37.7 (CH2Lev), 29.7 (CH3Lev),
27.8 (CH2Lev) ppm; MALDI-TOF m/z calcd for C35H46Cl3NO9Si [M
+ Na]+ 780.19, found 780.10; HRMS (ESI) m/z calcd for
C34H34Cl3NO10 [M + Na]+ 744.1146, found 744.1146.
2-Azido-6-O-benzoyl-3-O-benzyl-2-deoxy-4-O-levulinoyl-α-
D-glucopyranosyl Trichloroacetimidate (16). To a cooled (0 °C)
solution of compound 29 (2.0 g, 3.26 mmol) in dry THF (16 mL)
were added AcOH (0.20 mL) and TBAF (1.38 mL, 3.59 mmol). After
3 h, water was added and the mixture was diluted with ethyl acetate
and washed with water. The aqueous layer was extracted with ethyl
acetate, and the combined organic layers were dried over MgSO4 and
concentrated to dryness. The residue was concentrated and used in the
next reaction without further purification. The hemiacetal (1.62 g, 3.27
mmol) and trichloroacetonitrile (4.9 mL, 49 mmol) were dissolved in
anhydrous CH2Cl2 (32 mL) with activated molecular sieves. After 30
min of stirring, the solution was cooled to 0 °C and DBU (48 μL, 0.33
mmol) was added. After 2 h, TLC (hexane/ethyl acetate, 3:1)
indicated complete conversion of the starting material. Then the
mixture was concentrated under reduced pressure. The title
compound 16 was obtained after column chromatography on silica
(hexane 100% → hexane/ethyl acetate, 2:1) as a colorless solid (1.78
g, 85%): [α]2D0 = +64.9 (c = 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ = 8.75 (s, 1H, OCNHCl3), 8.01 (m, 2H, aromatic), 7.55 (m,
1H, aromatic), 7.42 (m, 2H, aromatic), 7.33 (m, 2H, aromatic), 6.45
(d, J = 3.5 Hz, 1H, H-1), 5.30 (dd, J = 9.6, 9.3 Hz, 1H, H-4), 4.86 (d, J
= 11.0 Hz, 1H, CH2Ph), 4.77 (d, J = 11.0 Hz, 1H, CH2Ph), 4.50 (dd, J
= 12.3, 2.1 Hz, 1H, H-6a), 4.32 (dd, J = 12.3, 5.1 Hz, 1H, H-6b), 4.26
(ddd, J = 9.3, 5.1, 2.1 Hz, 1H, H-5), 4.08 (dd, J = 10.1, 9.6 Hz, 1H, H-
3), 3.78 (dd, J = 10.1, 3.5 Hz, 1H, H-2), 2.77−2.62 (m, 2H, CH2Lev),
2.54−2.50 (m, 1H, CH2Lev), 2.45 (m, 1H, CH2Lev), 2.12 (s, 3H,
CH3Lev) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.1 (OCNH),
M
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Phenyl 2-O-Benzoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-1-
thio-α-L-idopyranoside (20). To a solution of thiophenyl glycoside
19 (1.02 g, 2.19 mmol) in dry pyridine (9 mL) was added a catalytic
amount of DMAP, followed by addition of (TDS)Cl (2.63 mmol).
The reaction mixture was stirred overnight at room temperature. The
TLC control (hexane/ethyl acetate, 2:1) indicated full conversion of
the starting material. The mixture was diluted with CH2Cl2 (∼100
mL) and washed with saturated CuSO4 aq solution (3 × ∼100 mL),
water (∼100 mL), and brine (∼100 mL). The organic layer was dried
over MgSO4, filtered, and concentrated. The crude product was
purified by column chromatography on silica using a hexane/ethyl
acetate gradient (100% → 50% hexane). The title compound was
obtained as a colorless oil (1.13 g, 85%): Rf = 0.56 (hexane/ethyl
(Caromatic), 101.0 (Cacetal), 85.9 (C-1), 73.2 (C-4), 73.1 (C-3), 72.4
(CBn), 69.9 (C-6), 67.8 (C-2), 60.6 (C-5) ppm; MALDI-TOF m/z
calcd for C33H30O6S 577.17 [M + Na]+, found 577.36; HRMS (ESI)
m/z calcd for C33H30O6S [M + Na]+ 577.1661, found 577.1683.
Phenyl 2-O-Benzoyl-3-O-benzyl-4,6-O-(p-methoxybenzyli-
dene)-1-thio-α-L-idopyranoside (23). To a solution of diol 19
(250 mg, 536 μmol) and p-anisaldehyde (650 μL, 5.36 mmol) in
toluene (5 mL) was added a catalytic amount of CSA, and the mixture
was heated under reflux (Dean−Stark) for 2 h. After being cooled to
room temperature, the mixture was neutralized with triethylamine, and
the crude product was concentrated under reduced pressure. The
crude material was purified by column chromatography on silica using
hexane/ethyl acetate (gradient 4:1 → 2:1). The title compound was
obtained as a colorless syrup (263 mg, 84%): Rf1= 0.65 (hexane/ethyl
acetate, 3:1); [α]2D0 = −77.3 (c = 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ = 8.01−7.97 (m, 2H, aromatic), 7.60−7.20 (m, 15H,
aromatic), 6.79 (m, 2H, aromaticPMP), 5.83 (br s, 1H, H-1), 5.57−5.51
(m, 2H, H-2, Hacetal), 4.99 (d, J = 11.8 Hz, 1H, CH2Ph), 4.72 (d, J =
11.8 Hz, 1H, CH2Ph), 4.52 (br s, 1H, H-5), 4.38 (dd, J = 12.7, 1.7 Hz,
1H, H-6a), 4.19 (dd, J = 12.8, 2.0 Hz, 1H, H-6b), 4.11 (br s, 1H, H-4),
3.92 (br s, 1H, H-3), 3.80 (s, 3H, CH3PMP) ppm; 13C NMR (126
MHz, CDCl3) δ = 165.8, 160.3, 137.4, 136.7, 133.2, 130.6, 130.6,
130.2, 129.7, 129.1, 128.7, 128.3, 128.2, 128.0, 127.8, 127.1, 113.5
(CaromaticPMP), 101.2 (Cacetal), 86.1 (C-1), 73.3 (C-3), 73.3 (C-4), 72.6
(CBn), 70.1 (C-6), 68.1 (C-2), 60.7 (C-5), 55.4 (CH3PMP) ppm;
MALDI-TOF m/z calcd for C34H32O7S 607.18 [M + Na]+, found
607.9; HRMS (ESI) m/z calcd for C34H32O7S [M + Na]+ 607.1766,
found 607.1776.
1
acetate, 4:1); H NMR (126 MHz, CDCl3) δ = 8.04−7.98 (m, 2H,
aromatic), 7.60−7.53 (m, 3H, aromatic), 7.46−7.22 (m, 10H,
aromatic), 5.61 (br s, 1H, H-1), 5.50−5.48 (m, 1H, H-2), 4.91 (d, J
= 12.0 Hz, 1H, CH2Ph), 4.83 (td, J = 5.3, 1.5 Hz, 1H, H-5), 4.78 (d, J
= 11.9 Hz, 1H, CH2Ph), 3.94−3.85 (m, 4H, H-3, H-6ab, H-4), 3.01
(br s, OH), 1.68−1.60 (m, 1H, CHthexyl), 0.89 (d, J = 6.9 Hz, 6H,
CH3thexyl), 0.87 (s, 6H, CH3thexyl), 0.11 (s, 6H, SiCH3) ppm; 13C NMR
(126 MHz, CDCl3) δ = 167.1, 129.8, 129.7, 133.4, 131.6, 128.8, 128.2,
127.5, 127.1, 85.9, 77.0, 72.7, 72.1, 69.8, 67.0, 67.2, 61.2, 37.7, 29.7,
27.8, 27.7, 27.6, 20.1, 18.6, −3.4, −3.7 ppm; MALDI-TOF m/z calcd
for C34H44O6SSi 631.25 [M + Na]+, found 631.33 [M + Na]+; HRMS
(ESI) m/z calcd for C34H44O6SSi [M + Na]+ 631.2526, found
631.2534.
Phenyl 2-O-Benzoyl-3-O-benzyl-6-O-(p-methoxyphenyl)-1-
thio-α-L-idopyranoside (21). A solution of compound 19 (2.20 g,
1.85 mmol) and p-methoxyphenol (2.92 g, 23.5 mmol) in dry THF (6
mL) was added to a solution of DIAD (1.85 mL, 9.40 mmol) and
triphenylphosphine (2.47 g, 9.40 mmol) in dry THF (5 mL). After
being stirred overnight at room temperature, the mixture was diluted
with ethyl acetate and washed with 1 M NaOH aq, water, and brine.
After being dried over MgSO4 and concentrated under reduced
pressure, the crude material was purified by column chromatography
on silica using hexane/ethyl acetate (gradient 3:1 → 1:1). The title
compound was obtained as a colorless syrup (1.75 g, 70%): Rf = 0.38
Phenyl 2-O-Benzoyl-3,6-di-O-benzyl-1-thio-α-L-idopyrano-
side (24). Under an argon atmosphere, trifluoroacetic acid (172 μL,
2.25 mmol) was added slowly to a solution of the acetal 22 (250 mg,
451 μmol) and triethylsilane (360 μL, 2.25 mmol) in dry THF (2 mL)
at 0 °C and the resulting mixture stirred for 2 h. The mixture was
diluted with CH2Cl2 (25 mL) and washed with saturated NaHCO3 aq
solution. After being dried over MgSO4 and concentrated under
reduced pressure, the crude material was purified by column
chromatography on silica using hexane/ethyl acetate (gradient 3:1
→ 1:1). The title compound was obtained as a colorless syrup (175
mg, 70%): Rf = 0.40 (hexane/ethyl acetate, 3:1); [α]2D0 = +25.9 (c =
(hexane/ethyl acetate, 3:1); [α]2D0 = +8.8 (c = 1.0, CHCl3); H NMR
1
(500 MHz, CDCl3) δ = 8.01−7.99 (m, 2H, aromatic), 7.66−7.65 (m,
2H, aromatic), 7.61−7.57 (m, 1H, aromatic), 7.49−7.29 (m, 10H,
aromatic), 6.90 (d, J = 9.2 Hz, 2H, aromaticPMP), 6.84 (d, J = 9.2 Hz,
2H, aromaticPMP), 5.61 (s, 1H, H-1), 5.56−5.54 (m, 1H, H-2), 5.21−
5.17 (m, 1H, H-5), 4.95 (d, J = 11.8 Hz, 1H, CH2Ph), 4.71 (d, J = 11.8
Hz, 2H, CH2Ph), 4.25 (d, J = 5.9 Hz, 2H, H-6ab), 3.95−3.88 (m, 2H,
H-3, H-4), 3.78 (s, 3H, CH3PMP) ppm; 13C NMR (126 MHz, CDCl3)
δ = 164.9, 154.1, 153.0, 137.3, 135.8, 133.7−127.8 (Caromatic), 115.6−
114.7 (CaromaticPMP), 86.8 (C-1), 74.0 (C-3), 72.4 (CBn), 70.1 (C-2),
68.3 (C-6), 67.6 (C-4), 67.2 (C-5), 55.7 (CH3PMP) ppm; MALDI-
TOF m/z calcd for C33H32O7S 595.18 [M + Na]+, found 595.44;
HRMS (ESI) m/z calcd for C33H32O7S [M + Na]+ 595.1766, found
595.1754.
Phenyl 2-O-Benzoyl-3-O-benzyl-4,6-O-benzylidene-1-thio-
α-L-idopyranoside (22). To a solution of diol 19 (500 mg, 1.07
mmol) and benzyladehyde dimethyl acetal (10.7 mmol, 1.1 mL) in
DMF (5 mL) was added a catalytic amount of CSA, and the mixture
was heated to 60 °C under reduced pressure for 5 h. After being
cooled to room temperature, the mixture was diluted with CH2Cl2
(100 mL), and the organic layer was washed with saturated NH4Cl aq
solution (3 × 100 mL), water (100 mL), and brine (100 mL). After
being dried over MgSO4 and concentrated under reduced pressure, the
crude material was purified by column chromatography on silica using
hexane/ethyl acetate (gradient 4:1 → 2:1). The title compound was
obtained as a colorless syrup (468 mg, 79%): Rf1= 0.56 (hexane/ethyl
acetate, 3:1); [α]2D0 = +42.5 (c = 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ = 7.88 (d, J = 8.3, 2H, aromatic), 7.51−7.07 (m, 18H,
aromatic), 5.75 (br s, 1H, H-1), 5.52 (s, 1H, Hacetal), 5.48−5.43 (br s,
1H, H-2), 4.91 (d, J = 11.8 Hz, 1H, CH2Ph), 4.64 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.45 (br s, 1H, H-5), 4.32 (d, J = 12.6 Hz, 1H, H-6a), 4.13
(d, J = 12.6 Hz, 1H, H-6b), 4.05 (br s, 1H, H-4), 3.85 (br s, 1H, H-3)
ppm; 13C NMR (126 MHz, CDCl3) δ = 165.7 (Cq), 137.8−126.3
1
1.0, CHCl3); H NMR (500 MHz, CDCl3) δ = 8.03−7.99 (m, 2H,
aromatic), 7.62−7.56 (m, 3H, aromatic), 7.48−7.42 (m, 4H,
aromatic), 7.40−7.28 (m, 8H, aromatic), 7.26−7.20 (m, 3H,
aromatic), 5.62 (s, 1H, H-1), 5.54−5.51 (m, 1H, H-2), 5.03−4.99
(m, 1H, H-5), 4.93 (d, J = 11.8 Hz, 1H, CH2Ph), 4.68 (d, J = 11.8 Hz,
1H, CH2Ph), 4.64 (d, J = 11.8 Hz, 1H, CH2Ph), 4.59 (d, J = 11.8 Hz,
1H, CH2Ph), 3.92−3.81 (m, 1H, H-3, H-4, H-6ab), 2.72 (br s, 1H,
OH) ppm; 13C NMR (126 MHz, CDCl3) δ = 165.2, 138.1, 137.5,
136.0, 133.7−127.7 (Caromatic), 86.9 (C-1), 74.3 (C-3), 73.6 (CBn), 72.5
(CBn), 70.5 (C-6), 70.1 (C-2), 68.1 (C-4), 67.4 (C-5) ppm; MALDI-
TOF m/z calcd C33H32O6S [M + Na]+ 579.18, found 579.25; HRMS
(ESI) m/z calcd for C33H32O6S [M + Na]+ 579.1817, found 579.1809.
Phenyl 2-O-Benzoyl-3-O-benzyl-6-O-(p-methoxybenzyl)-1-
thio-α-L-idopyranoside (25). Under an argon atmosphere, I2 (416
mg, 1.64 mmol) was added portionwise in 5 min to a solution of the
acetal 23 (240 mg, 410 μmol) and sodium cyanoborohydride (258 mg,
4.10 mmol) in dry CH2Cl2 (2 mL) at −20 °C and the resulting
mixutre stirred for 15 min. The mixture was diluted with CH2Cl2 (25
mL) and washed with saturated NaHCO3 aq solution. After being
dried over MgSO4 and concentrated under reduced pressure, the crude
material was purified by column chromatography on silica using
hexane/ethyl acetate (gradient 3:1 → 1:1). The title compound was
obtained as a colorless syrup (146 mg, 61%): Rf1= 0.34 (hexane/ethyl
acetate, 3:1); [α]2D0 = −97.7 (c = 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ = 8.02−7.97 (m, 2H, aromatic), 7.61−7.55 (m, 3H,
aromatic), 7.48−7.40 (m, 4H, aromatic), 7.40−7.35 (m, 2H,
aromatic), 7.34−7.21 (m, 6H, aromatic), 6.90−6.85 (m, 2H,
aromaticPMB), 5.61 (br s, 1H, H-1), 5.52−5.49 (m, 1H, H-2), 4.99−
4.95 (m, 1H, H-5), 4.91 (d, J = 11.8 Hz, 1H, CH2Ph), 4.67 (d, J = 11.8
Hz, 1H, CH2Ph), 4.57 (d, J = 11.5 Hz, 1H, CH2PMB), 4.51 (d, J = 11.4
Hz, 1H, CH2PMB), 3.88 (td, J = 2.9, 1.4 Hz, 1H, H-3), 3.86−3.76 (m,
N
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6H, H-4, H-6, CH3PMB), 2.87 (br s, 1H, OH) ppm; 13C NMR (126
MHz, CDCl3) δ = 165.2, 159.4, 137.5, 136.0, 133.7, 132.2, 130.2,
129.9, 129.5, 129.5, 129.4, 129.0, 128.8, 128.7, 128.6, 128.1, 128.0,
127.9, 127.7, 113.9 (CaromaticPMB), 86.9 (C-1), 74.3 (C-3), 73.3 (CBn),
72.5 (CBn), 70.2 (C-6), 70.0 (C-2), 68.2 (C-4), 67.4 (C-5), 55.4
(CH3PMB) ppm; MALDI-TOF m/z calcd for C34H34O7S [M + Na]+
609.19, found 608.96; HRMS (ESI) m/z calcd for C34H34O7S [2M +
NH4]+ 1190.4389, found 1190.4389.
(CH3TBS) ppm; HRMS (ESI) m/z calcd for C31H41N3O8Si [M + Na]+
634.2561, found 634.2565.
Methyl 1,2,4-tri-O-levulinoyl-3-O-benzyl-β-L-idopyranurate
(32). Compound 30 (1.0 g, 3.35 mmol) was dissolved in dry
CH2Cl2 at −25 °C, and EDC·HCl (3.2 g, 16.75 mmol), DMAP (1.64
g, 13.4 mmol), and levulinic acid (1.7 mL, 16.75 mmol) were added.
The mixture was stirred overnight at −25 °C, warmed to room
temperature, and stirred for 3 h. The reaction was diluted with CH2Cl2
and washed with 1 M HCl, water, saturated NaHCO3 aq solution, and
brine. The organic layer was dried over MgSO4, filtered, and
concentrated. The crude product was purified by column chromatog-
raphy (hexane/ethyl acetate, 7:3), and syrupy compound 32 was
2-Azido-3-O-benzyl-1-O-(tert-butyldimethylsilyl)-2-deoxy-β-
D-glucopyranose (27). EtSH (8 mL, 103.52 mmol) and catalytic
pTsOH were added to a solution of 2-azido-3-O-benzyl-4,6-O-
benzylidene-1-O-(tert-butyldimethylsilyl)-2-deoxy-β-D-glucopyranose
(26) (10.3 g, 20.70 mmol) in dry CH2Cl2. After being stirred for 3 h
under argon, the mixture was neutralized with solid NaHCO3, diluted
with CH2Cl2, and washed with H2O. The organic layer was dried over
MgSO4 and concentrated. The purification of the residue was carried
out by column chromatography (hexane/ethyl acetate, 7:3) to yield 27
obtained (1.58 g, 80%): [α]2D0 = +2.2 (c = 1, CHCl3); H NMR (500
1
MHz, CDCl3) δ = 7.38−7.29 (m, 5H, aromatic), 6.05 (d, J = 1.7 Hz,
H-1), 5.19−5.17 (m, 1H, H-4), 5.06−5.04 (m, 1H, H-2), 4.76 (d, J =
2.2 Hz, 1H, H-5), 4.72 (m, 2H, CH2Ph), 3.94 (t, J = 3.0 Hz, 1H, H-3),
3.78 (s, 3H, CH3), 2.86−2.49 (m, 12H, CH2Lev), 2.17 (s, 6H, CH3Lev),
2.16 (s, 3H, CH3Lev) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.38
(CO, Lev), 206.28 (2 × CO, Lev), 172.13, 171.91, 170.70,
167.34, 136.86, 128.65, 128.29, 127.90, 90.36 (C-1), 73.44 (C-3),
73.38 (C-5), 73.23 (CBn), 67.18 (C-4), 66.27 (C-2), 52.71
(CH3COOMe), 37.83 (CH2Lev), 37.77 (CH2Lev), 37.69 (CH2Lev), 29.93
(CH3Lev), 29.88 (CH3Lev), 29.84 (CH3Lev), 27.97 (CH2Lev), 27.93
(CH2Lev), 27.89 (CH2Lev) ppm; HRMS (ESI) m/z calcd for C29H36O13
[M + Na]+ 615.2054, found 615.2031.
1
(7.25 g, 89%): H NMR (500 MHz, CDCl3) δ = 7.38−7.29 (m, 5H,
aromatic), 4.95 (d, J = 11.5 Hz, 1H, CH2Ph), 4.71 (d, J = 11.4 Hz, 1H,
CH2Ph), 4.57 (d, J = 7.6 Hz, 1H, H-1), 3.83 (dd, J = 11.8, 3.7 Hz, 1H,
H-6a), 3.74 (dd, J = 11.8, 5.0 Hz, 1H, H-6b), 3.58 (dd, J = 9.7, 8.7 Hz,
1H, H-4), 3.32−3.27 (m, 2H, H-2, H-5), 3.21 (dd, J = 9.9, 8.7 Hz, 1H,
H-3), 0.95 (s, 9H, TBS), 0.17 and 0.16 (2s, 6H, TBS) ppm; 13C NMR
(126 MHz, CDCl3) δ = 138.2, 128.8, 128.3, 128.2, 97.4 (C-1), 82.5
(C-3), 75.3 (C-5), 75.1 (CBn), 70.6 (C-4), 68.4 (C-2), 62.7 (C-6), 25.7
(CH3TBS), 18.1 (CqTBS), −4.2 (CH3TBS), −5.0 (CH3TBS) ppm; HRMS
(ESI) m/z calcd for C19H31N3O5Si [M + Na]+ 432.1931, found
432.1913.
Methyl 1,2,4-Tri-O-benzoyl-3-O-benzyl-β-L-idopyranurate
(33). The triol 30 (2.08g, 6.97 mmol) was dissolved in dry CH2Cl2
at −40 °C, benzoyl chloride (6.1 mL, 53 mmol), pyridine (5.6 mL,
69.7 mmol), and DMAP (0.1 equiv) were added, and the reaction was
stirred overnight. The residue was dissolved in CH2Cl2, and water was
carefully added with cooling and vigorous stirring to decompose the
excess benzoyl chloride. The product was extracted with CH2Cl2, 1 M
aq HCl, a saturated aqueous solution of NaHCO3, water, and brine,
dried, and evaporated. The crude product was purified by column
chromatography (hexane/ethyl acetate, 8:2) to obtain the perbenzoy-
2-Azido-6-O-benzoyl-3-O-benzyl-1-O-(tert-butyldimethylsil-
yl)-2-deoxy-β-D-glucopyranose (28). BzCN (2.1 mL of a 0.9 M
solution in dry CH3CN) and catalytic Et3N (3.5 mL) were added to a
cooled (−40 °C) solution of 27 (7.25 g, 17.70 mmol) in dry CH3CN
(35 mL). After 4 h, additional BzCN was added (0.5 mL) until the
starting material had disappeared. After 7 h, MeOH was added and the
mixture was allowed to reach room temperature. The solvent was
evaporated, and the residue was dissolved in MeOH and concentrated
to dryness. Purification was carried out by column chromatography
(hexane/ethyl acetate, 4:1) to afford the product 28 (8.18 g, 90%): 1H
NMR (500 MHz, CDCl3) δ = 8.06−8.04 (m, 2H, aromatic), 7.59−
7.56 (m, 1H, aromatic), 7.45−7.32 (m, 7H, aromatic), 5.96 (d, J = 11.4
Hz, 1H, CH2Ph), 4.76 (d, J = 11.4 Hz, 1H, CH2Ph), 4.61−4.58 (m,
2H, H-6a, H-1), 4.55 (dd, J = 12.0 Hz, 5.1 Hz, 1H, H-6b), 3.58−3.51
(m, 2H, H-4, H-5), 3.35 (dd, J = 7.6 Hz, 9.9 Hz, 1H, H-2), 3.25 (dd, J
= 9.9, 8.0 Hz, 1H, H-3), 2.74 (br s, 1H, OH), 0.93 (s, 9H, CH3TBS),
0.16 and 0.15 (2s, 6H, CH3TBS) ppm; 13C NMR (126 MHz, CDCl3) δ
= 166.9, 138.1, 133.3, 130.0, 129.9, 129.9, 129.8, 128.8, 128.8, 128.5,
128.5, 128.4, 128.3, 128.2, 97.5 (C-1), 82.2 (C-3), 75.3 (CH2Ph), 74.0
(C-5), 70.4 (C-4), 68.3 (C-2), 64.0 (C-6), 25.7 (CH3TBS), 18.1
(CqTBS), −4.2 (CH3TBS), −5.1 (CH3TBS) ppm; HRMS (ESI) m/z
calcd for C26H35N3O6Si [M + Na]+ 536.2187, found 536.2214.
2-Azido-6-O-benzoyl-3-O-benzyl-1-O-(tert-butyldimethylsil-
yl)-2-deoxy-4-O-levulinoyl-β-D-glucopyranose (29). The reaction
was carried out according to general procedure A using compound 28
(9.81 g, 19.09 mmol), levulinic acid (3.32 g, 28.6 mmol), EDC·HCl
(5.5 g, 28.6 mmol), and a catalytic amount of DMAP (50 mg, 0.44
mmol) in dry CH2Cl2 (5 mL). The residue was purified by column
chromatography (hexane/ethyl acetate, 9:1) to obtain compound 29
lated compound 33 (3.86g, 91%): [α]2D0 = −18.3 (c = 1, CHCl3); H
1
NMR (500 MHz, CDCl3) δ = 8.05−7.13 (m, 20H, aromatic), 6.49 (d,
J = 1.3 Hz, H-1), 5.50−5.49 (m, 2H, H-2, H-4), 5.08 (d, J = 1.9 Hz,
1H, H-5), 4.93 (d, J = 11.6 Hz, 1H, CH2Ph), 4.90 (d, J = 11.6 Hz, 1H,
CH2Ph), 4.37 (t, J = 3.0 Hz, 1H, H-3), 3.73 (s, 3H, CH3) ppm; 13C
NMR (126 MHz, CDCl3) δ = 167.70, 165.74, 165.66, 164.45, 136.89,
133.73, 133.63, 133.38, 130.34, 130.12, 129.22, 128.99, 128.82, 128.58,
128.48, 128.29, 128.10, 91.01 (C-1), 73.83, 73.79 (C-5, C-3), 73.50
(CBn), 68.09, 66.97 (C-2, C-4), 52.79 (CH3COOMe) ppm; HRMS (ESI)
m/z calcd for C35H30O10 [M + Na]+ 633.1736, found 633.1757.
Methyl (3-O-Benzyl-1,2-O-[(1-pent-4-enyloxy)benzylidene]-
β-L-threo-hex-4-enopyranuronate (34). Compound 5 (0.020 g,
0.035 mmol) was dissolved in MeOH (0.5 mL) and treated with a
catalytic amount of sodium methoxide (0.5 equiv) overnight. The
crude reaction mixture was quenched with Amberlite IR120 (H+),
filtered, and concentrated to obtained compound 34 (14 mg, 90%):
1H NMR (500 MHz, CDCl3) δ = 7.54−7.31 (m, 10H, aromatic), 6.22
(dd, J = 1.1 Hz, 5.2 Hz, H-4), 5.96 (d, J = 4.0 Hz, H-1), 5.83−5.74 (m,
1H, CHpent), 5.03−4.95 (m, 2H, CH2pent), 4.80−4.76 (m, 1H, H-2),
4.67 (d, J = 11.7 Hz, 1H, CH2Ph), 4.60 (d, J = 11.7 Hz, 1H, CH2Ph),
4.27−4.25 (dd, J = 2.1, 5.2 Hz, 1H, H-3), 3.73 (s, 3H, CH3), 3.52−
3.43 (m, 2H, CH2pent), 2.14−2.10 (m, 2H, CH2pent), 1.71−1.66 (m,
2H, CH2pent) ppm; 13C NMR (126 MHz, CDCl3) δ = 162.1, 143.6,
138.1 (CHpent), 137.4, 137.1, 129.3, 128.7, 128.5, 128.3, 128.2, 128.1,
126.4, 122.3, 115.1 (CH2pent), 108.1 (C-4), 96.8 (C-1), 71.2 (CBn),
67.1 (C-3), 63.2 (CH2pent), 52.6 (CH3COOMe), 30.3 (CH2pent), 28.8
(CH2pent) ppm.
Methyl 3-O-Benzyl-1,2-O-[(1-pent-4-enyloxy)benzylidene]-
β-L-idopyranuronate (35). To a solution of compound 5 (105
mg, 0.182 mmol) in dry toluene (0.4 mL) was added trimethyltin
hydroxide (18 mg, 0.201 mmol). The reaction mixture was stirred in
the microwave at 100 °C until TLC indicated the disappearance of the
starting material (1 h). The mixture was concentrated and dried under
high vacuum. The residue was dissolved in dry MeOH, and a solution
of 1 M NaOMe (0.27 mL) was added. The mixture was placed in the
1
(9.96 g, 91%): H NMR (500 MHz, CDCl3) δ = 8.06−8.02 (m, 2H,
aromatic), 7.58−7.53 (m, 1H, aromatic), 7.46−7.40 (m, 2H,
aromatic), 7.38−7.26 (m, 5H, aromatic), 5.09−5.02 (m, 1H, H-4),
4.82 (d, J = 11.4 Hz, 1H, CH2Ph), 4.67 (d, J = 11.4 Hz, 1H, CH2Ph),
4.57 (m, 1H, H-1), 4.49 (dd, J = 12.1, 2.4 Hz, 1H, H-6), 4.28 (dd, J =
12.1, 6.8 Hz, 1H, H-6), 3.73−3.68 (m, 1H, H-5), 3.44−3.40 (m, 2H,
H-2, H-3), 2.77−2.58 (m, 2H, CH2Lev), 2.54−2.46 (m, 1H, CH2Lev),
2.42−2.34 (m, 1H, CH2Lev), 2.12 (s, 3H, CH3Lev), 0.89 (s, 9H, TBS),
0.11 (s, 6H, TBS) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.28,
171.80, 166.22, 137.96, 133.22, 129.94, 129.89, 128.56, 128.44, 128.12,
127.99, 97.34 (C-1), 80.01 (C-3), 75.01 (CBn), 72.43 (C-5), 70.72 (C-
4), 68.46 (C-2), 63.36 (C-6), 37.95 (CH2Lev), 29.83 (CH3Lev), 27.99
(CH2Lev), 25.66 (CH3TBS), 18.06 (CqTBS), −4.21 (CH3TBS), −5.14
O
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
microwave at 60 °C and after 1 h 30 min was quenched with Amberlite
IR-120 (H+) until pH 7. The reaction crude was dissolved in dry
CH2Cl2 (0.4 mL), and MeOH (1.1 mL), EDC·HCl (286 mg, 1.5
mmol), and DMAP (86 mg, 0.71 mmol) were added. After being
stirred overnight, the reaction mixture was concentrated and purified
by flash chromatography (hexane/ethyl acetate, 6:4, with 1%
triethylamine) to obtain compound 35 (52 mg, 60%): 1H NMR
(500 MHz, MeOD) δ = 7.72−7.32 (m, 10H, aromatic), 5.80 (m, 1H,
CHpent), 5.63 (d, J = 2.8 Hz, 1H, H-1), 5.05−4.92 (m, 2H, CH2pent),
4.74 (m, 2H, CH2Ph), 4.50 (d, J = 1.7 Hz, 1H, H-5), 4.36−4.32 (m,
1H, H-2), 4.07−4.02 (m, 2H, H-3, H-4), 3.73 (s, 3H, CH3), 3.44 (m,
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((2-O-ben-
zoyl-3,6-di-O-benzyl-4-O-levulinoyl-α-L-idopyranosyl)oxy)-
pentyl]carbamate (40). The reaction was carried out according to
general procedure B using linker acceptor 36 (100 mg, 0.217 mmol)
and thiophenyl donor 9 (213 mg, 0.326 mmol). NIS (1.5 equiv, 73
mg, 0.33 mmol) and (TMS)OTf (0.25 equiv, 9.8 μL, 0.054 mmol)
were added at −20 °C. The product was obtained as a colorless syrup
(179 mg, 82%): 1H NMR (500 MHz, CDCl3) δ = 8.09−8.05 (m, 4H,
aromatic), 7.59−7.52 (m, 2H, aromatic), 7.49−7.11 (m, 23H,
aromatic), 5.35 (s, 2H, CH2PhBz), 5.20−5.14 (m, 3H, H-2,
CH2Phcarba), 5.04−5.01 (m, 1H, H-4), 4.98−4.93 (m, 1H, H-1),
4.83−4.76 (m, 1H, CH2Ph), 4.68 (d, J = 11.8 Hz, 1H, CH2Ph), 4.58
(d, J = 11.9 Hz, 1H, CH2Ph), 4.54−4.49 (m, 2H, H-5, CH2Ph), 4.46
(d, J = 15.0 Hz, 2H, CH2PhN), 3.85−3.82 (m, 1H, H-3), 3.80−3.70
(m, 1H, OCH2Linker), 3.65 (dd, J = 10.0, 6.7 Hz, 1H, H-6a), 3.60 (dd, J
= 10.0, 5.6 Hz, H-6b), 3.47−3.36 (m, 1H, OCH2Linker), 3.21−3.10 (m,
2H, NCH2Linker), 2.63−2.49 (m, 3H, CH2Lev), 2.43−2.39 (m, 1H,
CH2Lev), 2.07 (s, 3H, CH3Lev), 1.67−1.42 (m, 4H, CH2Linker), 1.36−
1.28 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.1,
172.1, 166.5, 165.4, 156.8, 156.2, 138.2, 138.0, 137.2, 135.8, 133.5,
133.2, 130.2, 130.0, 129.9, 129.8, 129.8, 128.7, 128.6, 128.5, 128.5,
128.4, 128.4, 128.3, 128.2, 127.9, 127.9, 127.8, 127.7, 127.6, 127.4,
127.2, 98.2 (C-1), 73.5 (CBn), 73.3 (C-3), 72.2 (CBn), 69.2 (C-6), 68.0
(OCH2Linker), 67.9 (C-2, C-4), 66.9 (CH2PhCarba), 66.5 (CH2PhBz),
65.0 (C-5), 50.6, 50.3 (CH2PhN), 47.4, 46.3 (NCH2Linker), 37.9
(CH2Lev), 29.8 (CH3Lev), 29.3 (CH2Linker), 28.0 (CH2Lev), 27.6, 23.6
(CH2Linker) ppm; MALDI-TOF: m/z calcd for C60H63NO13 [M + Na]+
1028.42, found 1028.39; HRMS (ESI) m/z calcd for C60H63NO13 [M
+ Na]+ 1028.4192, found 1028.4195.
2H, CH2pent), 2.11 (m, 2H, CH2pent), 1.70−1.59 (m, 2H, CH2pent
)
ppm; 13C NMR (126 MHz, MeOD) δ = 170.8, 139.2, 139.0, 138.8,
130.2, 129.6, 129.2, 129.1, 129.0, 127.8, 123.5, 115.4, 98.6 (C-1), 77.4
(C-2), 76.0 (C-3), 73.8 (CBn), 73.0 (C-5), 68.0 (C-4), 64.1 (CH2pent),
52.6 (CH3COOMe), 31.3 (CH2pent), 29.9 (CH2pent) ppm; HRMS (ESI)
m/z calcd for C26H30O8 [M + Na]+ 493.1838, found 493.1832.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((2-O-ben-
zoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-4-O-levulinoyl-α-L-
idopyranosyl)oxy)pentyl]carbamate (38). The reaction was
carried out according to general procedure B using linker acceptor
36 (100 mg, 0.217 mmol), thiophenyl donor 8 (230 mg, 0.326 mmol),
and (TMS)OTf (0.25 equiv, 2.83 μL, 0.03 mmol). The product was
1
obtained as a colorless syrup (183 mg, 80%): H NMR (500 MHz,
CDCl3) δ = 8.10−8.04 (m, 4H, aromatic), 7.59−7.52 (m, 2H,
aromatic), 7.46−7.09 (m, 18H, aromatic), 5.35 (s, 2H, CH2PhBz),
5.20−5.13 (m, 3H, H-2, CH2PhCarba), 5.04−5.00 (m, 1H, H-4), 4.95
(br s, 1H, H-1), 4.81−4.75 (m, 1H, CH2Ph), 4.70 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.47 (d, J = 14.1 Hz, 2H, CH2PhN), 4.36−4.29 (m, 1H, H-
5), 3.89−3.86 (m, 1H, H-3), 3.80−3.67 (m, 3H, H-6, OCH2Linker),
3.46−3.34 (m, 1H, OCH2Linker), 3.25−3.11 (m, 2H, NCH2Linker),
2.68−2.53 (m, 3H, CH2Lev), 2.50−2.42 (m, 1H, CH2Lev), 2.08 (s, 3H,
CH3Lev), 1.66−1.46 (m, 5H, CH2Linker, CHthexyl), 1.37−1.25 (m, 2H,
CH2Linker), 0.86 (d, J = 7.0 Hz, 6H, CH3thexyl), 0.83 (s, 6H, CH3thexyl),
0.11 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si) ppm; 13C NMR (126 MHz,
CDCl3) δ = 206.0, 172.2, 166.5, 165.4, 156.2, 138.1, 137.1, 135.9,
135.8, 133.5, 133.2, 130.2, 129.9, 129.8, 128.7, 128.55, 128.5, 128.4,
128.3, 128.2, 127.9, 127.7, 127.6, 127.2, 98.1 (C-1), 73.5 (C-3), 72.3
(CBn), 68.5 (C-2), 67.9, 67.8 (C-4, OCH2Linker), 66.9 (CH2PhCarba),
66.6 (C-5), 66.5 (CH2PhBz), 61.8 (CHthexyl), 50.4 (CH2PhN), 46.4
(NCH2Linker), 37.9 (CH2Lev), 34.2 (CHthexyl), 29.8 (CH3Lev), 29.3
(CH2Linker), 28.0 (CH2Lev), 25.2 (Cqthexyl), 23.6 (CH2Linker), 20.4, 20.3,
18.7, 18.6 (CH3thexyl), −3.4, −3.5 (CH3Si) ppm; HRMS (ESI) m/z
calcd for C61H75NO13Si [M + Na]+ 1080.4900, found: 1080.4887.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((2-O-ben-
zoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-methoxyphenyl)-α-L-
idopyranosyl)oxy)pentyl)carbamate (39). The reaction was
carried out according to general procedure B using linker acceptor
36 (100 mg, 0.217 mmol), thiophenyl donor 11 (218 mg, 0.326
mmol), and (TMS)OTf (0.25 equiv, 2.83 μL, 0.03 mmol). The
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((2-O-ben-
zoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-methoxybenzyl)-α-L-
idopyranosyl)oxy)pentyl]carbamate (41). The reaction was
carried out according to general procedure B using linker acceptor
36 (100 mg, 0.217 mmol) and thiophenyl donor 12 (222 mg, 0.326
mmol). NIS (1.5 equiv, 73 mg, 0.33 mmol) and (TMS)OTf (0.25
equiv, 2.83 μL, 0.03 mmol) were added at −20 °C. The product was
1
obtained as a colorless syrup (157 mg, 70%): H NMR (500 MHz,
CDCl3) δ = 8.11−8.03 (m, 4H, aromatic), 7.58−7.53 (m, 2H,
aromatic), 7.46−7.21 (m, 20H, aromatic), 6.85 (d, J = 8.1 Hz, 2H,
aromaticPMB), 5.35 (s, 2H, CH2PhBz), 5.22−5.11 (m, 3H, H-2,
CH2PhCarba), 5.03−5.00 (m, 1H, H-4), 4.94 (d, J = 6.2 Hz, 1H, H-1),
4.79 (d, J = 11.6 Hz, 1H, CH2Ph), 4.67 (d, J = 11.8 Hz, 1H, CH2Ph),
4.53−4.39 (m, 5H,CH2PMB, CH2PhN, H-5), 3.82 (td, J = 2.8, 1.3 Hz,
1H, H-3), 3.77 (s, 3H, CH3PMB), 3.76−3.69 (m, 1H, OCH2Linker),
3.64−3.54 (m, 2H, H-6), 3.47−3.35 (m, 1H, OCH2Linker), 3.24−3.08
(m, 2H, NCH2Linker), 2.66−2.43 (m, 3H, CH2Lev), 2.42−2.32 (m, 1H,
CH2Lev), 2.08 (s, 3H, CH3Lev), 1.58−1.45 (m, 4H, CH2Linker), 1.36−
1.25 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.1,
172.1, 166.5, 165.4, 159.3, 156.8, 156.2, 138.0, 137.1, 135.9, 133.5,
133.2, 130.3, 130.2, 130.0, 129.9, 129.8, 129.5, 128.8, 128.7, 128.6,
128.5, 128.4, 128.4, 128.2, 128.2, 127.9, 127.7, 127.6, 127.4, 127.2,
113.8 (CaromaticPMB), 98.2 (C-1), 73.2, 72.1, 68.7, 68.0, 67.9, 66.9, 66.5,
64.9, 55.4 (CH3PMB), 50.7, 50.3 (CH2PhN), 47.4, 46.4 (NCH2Linker),
37.9 (CH2Lev), 29.8 (CH3Lev), 29.3 (CH2Linker), 28.0 (CH2Lev), 27.6
(CH2Linker), 23.6 (CH2Linker) ppm; HRMS (ESI) m/z calcd for
C61H65NO14 [M + NH4]+ 1053.4743 found 1053.4774.
1
product was obtained as a colorless syrup (175 mg, 79%): H NMR
(500 MHz, CDCl3) δ = 8.12−8.00 (m, 4H, aromatic), 7.60−7.52 (m,
2H, aromatic), 7.48−7.33 (m, 9H, aromatic), 7.30−7.10 (m, 9H,
aromatic), 6.85−6.76 (m, 4H, aromaticPMP), 5.34 (s, 2H, CH2PhBz),
5.21−5.12 (m, 3H, H-2, CH2PhCarba), 5.09 (s, 1H, H-4), 4.98 (d, J =
9.1 Hz, 1H, H-1), 4.85−4.79 (m, 1H, CH2Ph), 4.72−4.62 (m, 2H, H-
5, CH2Ph), 4.46 (d, J = 16.2 Hz, 2H, CH2PhN), 4.11 (dd, J = 11.9, 4.7
Hz, 1H, H-6a), 4.02 (d, J = 4.0 Hz, 1H, H-6b), 3.87 (s, 1H, H-3),
3.80−3.74 (m, 4H, CH3PMP, OCH2Linker), 3.49−3.36 (m, 1H,
OCH2Linker), 3.21−3.15 (m, 2H, NCH2Linker), 2.63−2.49 (m, 3H,
CH2Lev), 2.43−2.39 (m, 1H, CH2Lev), 2.07 (s, 3H, CH3Lev), 1.72−1.52
(m, 4H, CH2Linker), 1.38−1.27 (m, 2H, CH2Linker) ppm; 13C NMR
(126 MHz, CDCl3) δ = 205.9, 172.1, 166.5, 165.1, 156.1, 154.1, 152.7,
133.2−127.1 (Caromatic), 116.6−114.5 (CaromaticPMP), 98.1 (C-1), 73.0
(C-3), 72.1 (CBn), 68.7 (C-4), 67.9 (OCH2Linker), 67.7 (C-6), 67.5 (C-
2), 66.7 (CH2PhCarba), 66.4 (CH2PhBz), 64.5 (C-5), 54.7 (CH3PMP),
50.4 (CH2PhN), 46.2 (NCH2Linker), 37.8 (CH2Lev), 29.8 (CH3Lev),
29.1−23.5 (CH2Lev, CH2Linker) ppm; HRMS (ESI) m/z calcd for
C60H63NO14 [M + Na]+ 1044.4141, found 1044.4147.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((2-O-ben-
zoyl-3-O-benzyl-4-O-levulinoyl-6-O-[(triisopropylsiloxy)-
methyl]-α-L-idopyranosyl)oxy)pentyl]carbamate (42). The re-
action was carried out according to general procedure B using linker
acceptor 36 (75 mg, 0.16 mmol) and thiophenyl donor 13 (100 mg,
0.133 mmol). NIS (45 mg, 0.20 mmol) and TfOH (1.1 μL, 0.013
mmol) were added at −20 °C. The residue was purified by preparative
1
TLC (30% ethyl acetate/hexane) to afford 42 (131 mg, 91%): H
NMR (500 MHz, CDCl3) δ = 8.12−8.02 (m, 4H, aromatic), 7.61−
7.10 (m, 20H, aromatic), 5.39−5.32 (s, 2H, CH2PhBz), 5.23−5.12 (m,
3H, H-2, CH2PhCarba), 5.02−4.97 (m, 1H, H-4), 4.96−4.88 (m, 3H, H-
1, CH2TOM), 4.83−4.74 (m, 1H, CH2Ph), 4.68 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.53−4.40 (m, 3H, H-5, CH2PhN), 3.87−3.80 (m, 1H, H-3),
3.80−3.68 (m, 3H, H-6, OCH2Linker), 3.46−3.33 (m, 1H, OCH2Linker),
P
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3.28−3.10 (m, 2H, NCH2Linker), 2.69−2.52 (m, 3H, CH2Lev), 2.51−
2.40 (m, 1H, CH2Lev), 2.08 (s, 3H, CH3Lev), 1.70−1.40 (m, 4H,
CH2Linker), 1.40−1.20 (m, 2H, CH2Linker), 1.15−1.00 (m, 21H,
6CH3TOM, 3CHTOM) ppm; 13C NMR (126 MHz, CDCl3) δ = 205.8,
172.0, 166.4, 165.3, 156.6, 137.9, 137.8, 137.0, 136.9, 135.7, 133.4,
133.0, 130.1, 129.8, 129.7, 128.5, 128.4, 128.4, 128.3, 128.2, 128.0,
127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1, 97.9 (C-1), 90.1
(CH2TOM), 73.0 (C-3), 71.9 (CBn), 67.8 (C-4, CH2Linker), 67.7 (C-2),
66.7 (CH2PhCarba), 66.6 (C-6), 66.3 (CH2PhBz), 64.8 (C-5), 50.5, 50.2
(CH2PhN), 47.2, 46.2 (NCH2Linker), 37.8 (CH2Lev), 29.6 (CH3Lev),
29.3, 29.1 (CH2Linker), 27.9 (CH2Lev), 27.5 (CH2Linker), 23.4
(CH2Linker), 17.8 (CH3TOM), 11.9 (CHTOM) ppm; LRMS (MALDI-
TOF) m/z calcd for C63H79NO14Si [M + Na]+ 1125.37, found
1125.00; HRMS (ESI) m/z calcd for C63H79NO14Si [M + Na]+
1124.5167, found 1124.5140.
3.25−3.12 (m, 2H, NCH2Linker), 2.63−2.61 (m, 2H, CH2Lev), 2.50−
2.37 (m, 2H, CH2Lev), 2.08 (s, 3H, CH3Lev), 1.60−1.51 (m, 4H,
CH2Linker), 1.30−1.26 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz,
CDCl3) δ = 205.9, 171.6, 169.1, 166.5, 165.3, 156.7, 156.2, 138.0,
137.6, 137.1, 137.0, 135.9, 133.6, 133.1, 130.2, 129.9, 129.8, 129.6,
128.6, 128.5, 128.4, 128.1, 127.8, 127.6, 127.3, 127.2, 98.5 (C-1), 72.5
(C-3), 72.2 (CH2Ph), 68.7 (OCH2Linker), 68.2 (C-4), 67.0 (C-2), 66.9
(CH2PhCarba), 66.5 (CH2PhBz), 66.0 (C-5), 52.6 (CH3COOMe), 50.6,
50.3 (CH2PhN), 47.3, 46.3 (NCH2Linker), 37.8 (CH2Lev), 29.7
(CH3Lev), 29.2 (CH2Linker), 28.0 (CH2Lev), 27.62 (CH2Linker), 23.4
(CH2Linker) ppm; HRMS (ESI) m/z calcd for C54H57NO14 [M + Na]+
966.3677, found 966.3693.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-3-O-benzyl-2-O-benzoyl-6-O-(tert-butyldi-
phenylsilyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (45).
Compound 39 (125 mg, 108 mmol) was delevulinated with hydrazine
acetate (19 mg, 216 μmol) in CH2Cl2/MeOH (2.7 mL/0.27 mL).
When TLC (hexane/ethyl acetate, 2:1) showed complete conversion,
the reaction mixture was diluted with dichloromethane (50 mL) and
washed twice with 1 M HCl (100 mL), saturated NaHCO3 aq solution
(100 mL), and brine (100 mL). The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The crude product
was purified by column chromatography (hexane/ethyl acetate, 8:2) to
obtain 4-[(phenylcarboxy)methyl]benzyl N-benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-α-D-glucopyranosyl)-3-O-ben-
zyl-2-O-benzoyl-6-O-(tert-butyldiphenylsilyl)-α-L-idopyranosyl)oxy)-
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((6-O-ace-
tyl-2-O-benzoyl-3-O-benzyl-4-O-levulinoyl-α-L-idopyranosyl)-
oxy)pentyl]carbamate (43). The reaction was carried out according
to general procedure B using linker acceptor 36 (20 mg, 0.041 mmol)
and thiophenyl donor 10 (30 mg, 0.050 mmol). NIS (17 mg, 0.075
mmol) and TfOH (41 μL of a 0.1 M solution in CH2Cl2) were added
at −20 °C. The residue was purified by preparative TLC (40% ethyl
1
acetate/hexane) to afford 43 (21 mg, 52%): H NMR (500 MHz,
CDCl3) δ = 8.14−8.02 (m, 4H, aromatic), 7.62−7.08 (m, 20H,
aromatic), 5.35 (s, 2H, CH2PhBz), 5.24−5.08 (m, 3H, H-2,
CH2PhCarba), 4.99−4.90 (m, 2H, H-1, H-4), 4.87−4.74 (m, 1H,
CH2Ph), 4.67 (d, J = 11.6 Hz, 1H, CH2Ph), 4.56−4.40 (m, 3H, H-5,
CH2PhN), 4.30−4.08 (m, 2H, H-6), 3.86−3.80 (m, 1H, H-3), 3.79−
3.64 (m, 1H, OCH2Linker), 3.50−3.34 (m, 1H, OCH2Linker), 3.30−3.10
(m, 2H, NCH2Linker), 2.70−2.51 (m, 3H, CH2Lev), 2.50−2.39 (m, 1H,
CH2Lev), 2.09 (s, 3H, CH3Lev), 2.07−1.99 (m, 3H, CH3Ac), 1.70−1.45
(m, 4H, CH2Linker), 1.40−1.20 (m, 2H, CH2Linker) ppm; 13C NMR
(126 MHz, CDCl3) δ = 205.8, 172.0, 170.5, 166.4, 165.2, 156.6, 137.9,
137.7, 137.0, 136.9, 135.7, 133.5, 133.0, 130.1, 129.8, 129.7, 129.5,
128.5, 128.4, 128.2, 128.0, 127.7, 127.5, 127.3, 127.2, 127.1, 97.9 (C-
1), 72.8 (C-3), 72.1 (CBn), 67.9 (CH2Linker), 67.4 (C-4), 67.2 (C-2),
66.7 (CH2Phcarba), 66.3 (CH2PhBz), 63.7 (C-5), 62.8 (C-6), 50.5, 50.2
(CH2PhN), 47.2, 46.2 (NCH2Linker), 37.8 (CH2Lev), 29.6 (CH3Lev),
29.1 (CH2Linker), 27.9 (CH2Lev), 27.5 (CH2Linker), 23.5 (CH2Linker), 20.7
(CH3Ac) ppm; LRMS (MALDI-TOF) m/z calcd for C55H59NO14 [M
+ Na]+ 981.04, found 980.85. HRMS (ESI) m/z calcd for C55H59NO14
[M + Na]+ 980.3828, found 980.3755.
1
pentyl]carbamate (97 mg, 85%): H NMR (500 MHz, CDCl3) δ =
8.13−7.20 (m, 34H, aromatic), 5.40 (s, 2H, CH2PhBz), 5.31−5.22 (m,
3H, H-2, CH2PhCarba), 5.02 (s, 1H, H-1), 4.89 (d, J = 11.8 Hz, 1H,
CH2Ph), 4.69 (d, J = 11.8 Hz, 1H, CH2Ph), 4.54−4.51 (m, 2H,
CH2PhN), 4.39 (m, 1H, H-5), 3.99−3.98 (m, 2H, H-6), 3.90−3.83
(m, 3H, H-3, H-4, OCH2Linker), 3.46−3.44 (m, 1H, OCH2Linker), 3.28−
3.21 (m, 2H, NCH2Linker), 2.79 (br s, 1H, OH), 1.68−1.56 (m, 4H,
CH2Linker), 1.37−1.29 (m, 2H, CH2Linker), 1.13 (9H, s, (CH3)3C) ppm.
The glycosylation reaction was carried out according to general
procedure C using idose acceptor (20 mg, 0.019 mmol), azidoglucose
donor 16 (17 mg, 0.026 mmol), and (TMS)OTf (0.25 equiv, 47 μL of
a 0.1 M solution). The reaction mixture was purified by column
chromatography using hexane/ethyl acetate (8:2) to obtain compound
1
45 (12 mg, 42%): H NMR (500 MHz, CDCl3) δ = 8.14−8.06 (m,
5H, aromatic), 7.97−7.94 (m, 2H, aromatic), 7.75−7.68 (m, 4H,
aromatic), 7.51−7.13 (m, 34H, aromatic), 5.35 (s, 2H, CH2PhBz),
5.20−5.12 (m, 3H, H-2, CH2PhCarba), 5.09−5.03 (m, 2H, H-1, H-4′),
4.87 (d, J = 11.5 Hz, 1H, CH2Ph), 4.81 (d, J = 3.7 Hz, 1H, H-1′), 4.74
(d, J = 11.5 Hz, CH2Ph), 4.48−4.42 (m, 2H, CH2PhN), 4.35−4.28
(m, 3H, H-5, CH2Ph), 4.18−4.14 (m, 1H, H-3), 4.07 (d, J = 3.0 Hz,
2H, H-6′), 3.96−3.87 (m, 3H, H-6, H-5′), 3.84−3.80 (m, 1H, H-4),
3.75−3.69 (m, 1H, OCH2Linker), 3.66 (t, J = 9.7 Hz, 1H, H-3′), 3.35
(dd, J = 10.0, 3.8 Hz, 2H, H-2′, OCH2Linker), 3.21−3.10 (m, 2H,
NCH2Linker), 2.64−2.60 (m, 2H, CH2Lev), 2.47−2.40 (m, 1H, CH2Lev),
2.36−2.30 (m, 1H, CH2Lev), 2.09 (s, 3H, CH3Lev), 1.59−1.46 (m, 4H,
CH2Linker), 1.30−1.19 (m, 2H, CH2Linker), 1.06 (s, 9H, (CH3)3C) ppm.
13C NMR (126 MHz, CDCl3) δ = 206.0, 171.4, 166.5, 166.1, 165.8,
156.7, 156.2, 138.0, 137.5, 135.9, 135.8, 135.7, 133.3, 133.2, 133.1,
133.0, 130.2, 130.1, 130.0, 130.0, 129.9, 129.8, 128.7, 128.6, 128.5,
128.4, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.2, 98.5 (C-1), 97.6
(C-1′), 78.6 (C-3′), 75.1 (CBn), 74.3 (C-4), 73.5 (C-3), 72.6 (CBn),
70.4 (C-4′), 69.9 (C-2), 68.9 (C-5′), 68.5 (C-5), 67.9 (OCH2Linker),
66.9 (CH2PhCarba), 66.5 (CH2PhBz), 63.7 (C-6), 63.6 (C-2′), 62.3 (C-
6′), 50.6, 50.3 (CH2PhN), 47.4, 46.4 (NCH2Linker), 37.9 (CH2Lev), 37.8
(CH2Lev), 29.8 (CH3Lev), 29.5 (CH2Linker), 29.2 (CH2Linker), 28.2, 28.1,
27.9 (CH2Lev), 27.7 (CH2Linker), 27.0, 26.9 (CH3Lev), 23.6, 23.5
(CH2Linker), 19.3, 19.2 (CH3)3) ppm; HRMS (ESI) m/z calcd for
C89H94N4O18Si [M + Na]+ 1558.6261, found 1558.6282.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-(methyl ((2-
O-benzoyl-3-O-benzyl-4-O-levulinoyl-α-L-idopyranosyl)oxy)-
uronate)pentyl]carbamate (44). The glycosylation was carried out
according to general procedure B using the following conditions:
(1) Linker acceptor 36 (35 mg, 0.076 mmol) and thiophenyl donor
1 (55 mg, 0.093 mmol). NIS (21 mg, 0.093 mmol) and
(TMS)OTf (1.6 μL, 0.008 mmol) were added at 0 °C. The
crude product was purified by column chromatography using
hexane/ethyl acetate (7:3) to obtain compound 44 as a white
solid (0.040 g, 55%).
(2) Linker acceptor 36 (30 mg, 0.051 mmol) and thiophenyl donor
1 (19 mg, 0.042 mmol). NIS (28 mg, 0.123 mmol) and
(TMS)OTf (1.5 μL, 0.008 mmol) were added at room
temperature. The crude product was purified by column
chromatography using hexane/ethyl acetate (7:3) to obtain
compound 44 (0.026 g, 66%).
(3) Linker acceptor 36 (35 mg, 0.073 mmol) and n-pentenyl donor
6 (50 mg, 0.088 mmol). NIS (49 mg, 0.219 mmol) and
(TMS)OTf (2.3 μL, 0.015 mmol) were added at 0 °C. The
crude product was purified by column chromatography using
hexane: ethyl acetate (7:3) to obtain compound 44 (0.047 g,
69%).
Data for 44: 1H NMR (500 MHz, CDCl3) δ = 8.07−7.19 (m, 24H,
aromatic), 5.35 (s, 2H, CH2PhBz), 5.26 (m, 1H, H-4), 5.19−5.15 (m,
3H, H-2, CH2PhCarba), 5.12 (br s, 1H, H-1), 4.93 (br s, 1H, H-5), 4.82
(d, J =11.8 Hz, 1H, CH2Ph), 4.72 (d, J = 11.8 Hz, 1H, CH2Ph), 4.47
(d, J = 12.4 Hz, 2H, CH2PhN), 3.89 (m, 1H, H-3), 3.79 (s, 3H, CH3),
3.79−3.73 (m, 1H, OCH2Linker), 3.50−3.40 (m, 1H, OCH2Linker),
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-3-O-benzyl-2-O-benzoyl-6-O-(dimethylthex-
ylsilyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (46). Compound
38 (150 mg, 142 μmol) was delevulinated with hydrazine acetate (20
Q
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mg, 212 μmol) in CH2Cl2/methanol (4:1, 2.5 mL). When TLC
(hexane/ethyl acetate, 2:1) showed complete conversion, the mixture
was concentrated, and the residue was purified by column
chromatography (0−30% ethyl acetate/hexane) to afford the glycosyl
acceptor (125 mg, 91%): 1H NMR (500 MHz, CDCl3) δ = 8.11−7.98
(m, 4H, aromatic), 7.61−7.52 (m, 2H, aromatic), 7.48−7.11 (m, 18H,
aromatic), 5.36 (s, 2H, CH2PhBz), 5.25−5.12 (m, 3H, H-2,
CH2PhCarba), 4.95−4.90 (br s, 1H, H-1), 4.82 (d, J = 11.7 Hz, 1H,
CH2Ph), 4.63 (d, J = 11.7 Hz, 1H, CH2Ph), 4.48 (d, J = 11.3 Hz, 2H,
CH2PhN), 4.28−4.20 (m, 1H, H-5), 3.88−3.80 (m, 4H, H-6, H-3, H-
4), 3.80−3.72 (m, 1H, OCH2Linker), 3.48−3.35 (m, 1H, OCH2Linker),
3.28−3.13 (m, 2H, NCH2Linker), 2.86 (br s, 1H, OH), 1.68−1.47 (m,
5H, CHthexyl, CH2Linker), 1.42−1.24 (m, 2H, CH2Linker), 0.89 (d, J = 7.0
Hz, 6H, CH3thexyl), 0.87 (s, 6H, CH3thexyl), 0.14, 0.13 (2s, CH3Si) ppm;
13C (126 MHz, CDCl3) δ = 166.5, 165.3, 156.7, 156.2, 138.1, 137.0,
130.2, 129.9, 129.5, 129.4, 128.8, 128.7, 128.6, 128.5, 128.5, 128.4,
128.2, 127.9, 127.8, 127.4, 127.4, 127.2, 115.7, 114.8, 98.5, 75.1, 71.9,
68.6, 68.1, 68.0, 67.6, 66.9, 66.5, 66.0, 55.8, 50.3, 47.3, 46.3, 29.3, 23.6
ppm; HRMS (ESI) m/z calcd for C55H57NO12 [M + NH4]+ 941.4219,
found 941.4220. The glycosylation reaction was carried out according
to general procedure C using idose acceptor (60 mg, 65 μmol),
azidoglucose donor 16 (58 mg, 91 μmol), and (TMS)OTf (0.25 equiv,
2.89 μL, 16 μmol). The product 47 was obtained as a colorless syrup
1
(60 mg, 65%): H NMR (500 MHz, CDCl3) δ = 8.23−8.16 (m, 2H,
aromatic), 8.08−8.05 (m, 2H, aromatic), 8.03−7.97 (m, 2H,
aromatic), 7.63−7.10 (m, 28H, aromatic), 6.92−6.75 (m, 4H,
aromaticPMP), 5.35 (s, 2H, CH2PhBz), 5.25−5.11 (m, 3H, CH2PhCarba
,
H-2), 5.05−4.99 (m, 2H, H-1, H-4′), 4.88 (d, J = 11.8 Hz, CH2Ph),
4.82 (d, J = 3.2 Hz, 1H, H-1′), 4.69 (d, J = 12.6 Hz, CH2Ph), 4.65−
4.58 (m, 1H, H-5), 4.47 (d, J = 12.2 Hz, 2H, CH2PhN), 4.35−4.23 (m,
4H, H-6a′, H-6a, CH2Ph), 4.19−4.04 (m, 3H, H-6b′, H-6b, H-3),
4.08−4.03 (m, 1H, H-5′), 3.97−3.93 (m, 1H, H-4), 3.81−3.68 (m,
5H, H-3′, OCH2Linker, CH3PMP), 3.47−3.38 (m, 1H, OCH2Linker), 3.34
(dd, J = 10.1, 3.5 Hz, 1H, H-2′), 3.25−3.11 (m, 2H, NCH2Linker),
2.67−2.53 (m, 2H, CH2Lev), 2.40−2.23 (m, 2H, CH2Lev), 2.09 (s, 3H,
135.8, 133.5, 133.2, 130.2, 129.9, 129.8, 129.6, 128.6, 128.5, 128.5,
128.4, 128.4, 128.1, 128.1, 127.9, 127.8, 127.7, 127.4, 127.2, 98.5, 75.6,
71.9, 68.5, 67.9, 67.6, 66.9, 66.5, 63.2, 50.7, 50.4, 47.4, 46.3, 34.2, 29.3,
28.1, 27.7, 25.2, 23.6, 20.4, 18.7, 18.6 ppm; HRMS (ESI) m/z calcd for
C56H73N2O11Si [M + NH4]+ 977.4978, found 977.5001. The
glycosylation reaction was carried out according to general procedure
C using idose acceptor (46 mg, 48 μmol), azidoglucose donor 16 (43
mg, 67 μmol), and (TMS)OTf (0.25 equiv, 2.16 μL, 12 μmol). The
product 46 was obtained as a colorless syrup (35 mg, 51%): 1H NMR
(500 MHz, CDCl3) δ = 8.17−7.97 (m, 6H, aromatic), 7.62−7.05 (m,
28H, aromatic), 5.35 (s, 2H, CH2PhBz), 5.25−5.10 (m, 4H, H-2, H-4′,
CH2PhCarba), 5.04 (br s, 1H, H-1), 4.89 (d, J = 3.7 Hz, 1H, H-1′),
4.85−4.79 (m, 1H, CH2Ph), 4.72 (d, J = 11.6 Hz, 1H, CH2Ph), 4.51−
4.34 (m, 5H, CH2PhN, CH2Ph, H-6a′), 4.30 (dd, J = 12.3, 4.6 Hz, 1H,
H-6b′), 4.25−4.10 (m, 3H, H-3, H-5, H-5′), 3.94−3.84 (m, 3H, H-6,
H-4), 3.83−3.70 (m, H-3′, OCH2Linker), 3.47−3.33 (m, 2H, H-2′,
OCH2Linker), 3.26−3.06 (m, 2H, OCH2−Linker), 2.77−2.58 (m, 2H,
CH2Lev), 2.57−2.46 (m, 1H, CH2Lev), 2.43−2.31 (m, 1H, CH2Lev),
2.11 (s, 3H, CH3Lev), 1.68−1.46 (m, 5H, CHthexyl, CH2Linker), 1.34−
1.23 (m, 2H, CH2Linker), 0.97−0.81 (m, 12H, CH3thexyl), 0.16 (s, 3H,
CH3−Si), 0.14 (s, 3H, CH3−Si) ppm; 13C NMR (126 MHz, CDCl3) δ
= 207.1, 206.1, 171.6, 166.5, 166.2, 165.7, 156.8, 156.2, 138.0, 137.5,
137.1, 135.9, 133.3, 133.3, 133.2, 130.2, 130.1, 129.9, 129.8, 128.7,
128.5, 128.4, 128.4, 128.1, 128.0, 127.9, 127.8, 127.4, 127.2, 98.5 (C-
1), 97.5 (C-1′), 78.3 (C-3′), 75.1 (CBn), 73.7 (C-4), 73.6 (C-3), 72.7
(CBn), 70.7, 70.3 (C-2, C-4′), 69.0, 68.9 (C-5, C-5′), 68.1
(OCH2Linker), 66.9 (CH2PhBz), 66.5 (CH2PhBz), 63.6 (C-2′), 62.7
(C-6′), 62.5 (C-6), 50.7, 50.4 (CH2PhN), 47.4, 46.4 (NCH2Linker),
37.9 (CH2Lev), 34.2 (CHthexyl), 29.8 (CH3Lev), 29.3, 28.2 (CH2Linker),
28.0, 27.7 (CH2Lev, CH2Linker), 25.3 (Cqthexyl), 23.6 (CH2Linker), 20.5,
20.5, 18.7 (CH3thexyl), −3.1, −3.3 (CH3−Si) ppm; HRMS (ESI) m/z
calcd for C81H94N4O18Si [M + Na]+ 1461.6225, found 1461.6293.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-3-O-benzyl-2-O-benzoyl-6-O-(p-methoxy-
phenyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (47). Com-
pound 39 (110 mg, 107 μmol) was delevulinated with hydrazine
acetate (20 mg, 212 μmol) in CH2Cl2/methanol (4:1, 2.5 mL). When
TLC (hexane/ethyl acetate, 2:1) showed complete conversion, the
reaction mixture was diluted with dichloromethane (50 mL) and
washed twice with 1 M HCl (100 mL), saturated NaHCO3 solution
(100 mL), and brine (100 mL). The organic phase was dried over
MgSO4, concentrated under reduced pressure, and purified by column
chromatography (0−30% ethyl acetate/hexane) to afford the glycosyl
CH3Lev), 1.59−1.46 (m, 4H, CH2Linker), 1.37−1.24 (m, 2H, CH2Linker
)
ppm; 13C NMR (126 MHz, CDCl3) δ = 206.1, 171.6, 166.5, 166.2,
165.9, 154.3, 152.4, 137.8, 137.5, 135.9, 133.5, 133.2, 133.2, 130.2,
130.0, 129.9, 129.9, 129.8, 128.7, 128.5, 128.4, 128.2, 128.1, 128.0,
127.9, 127.2, 115.4, 114.9 (CaromaticPMP), 98.6 (C-1), 96.7 (C-1′), 78.3
(C-3′), 75.1 (CBn), 72.2 (CBn), 72.1 (C-4), 71.8 (C-3), 70.6 (C-4′),
69.0 (C-2, C-5′), 68.1 (OCH2Linker), 66.9 (CH2PhCarba), 66.7
(CH2PhBz), 66.5 (C-6), 65.4 (C-5), 63.5 (C-2′), 62.6 (C-6′), 55.8
(CH3PMP), 50.7, 50.4 (CH2PhN), 47.4, 46.4 (NCH2Linker), 37.9
(CH2Lev), 29.8 (CH3Lev), 28.1, 27.9 (CH2Linker), 27.7 (CH2Lev), 23.6
(CH2Linker) ppm; HRMS (ESI) m/z calcd for C80H82N4O19 [M +
NH4]+ 1420.5912, found 1420.5927.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-2-O-benzoyl-3,6-di-O-benzyl-α-L -
idopyranosyl)oxy)pentyl]carbamate (48). Compound 40 (145
mg, 0.144 mmol) was delevulinated with hydrazine acetate (20 mg,
212 μmol) in CH2Cl2/MeOH (4:1, 2.5 mL). When TLC (hexane/
ethyl acetate, 2:1) showed complete conversion, the mixture was
concentrated, and the residue was purified by column chromatography
(0−30% ethyl acetate/hexane) to afford the glycosyl acceptor (119
1
mg, 91%): H NMR (500 MHz, CDCl3) δ = 8.09−8.05 (m, 2H,
aromatic), 8.04−7.98 (m, 2H, aromatic), 7.61−7.52 (m, 2H,
aromatic), 7.48−7.11 (m, 23H, aromatic), 5.35 (s, 2H, CH2PhBz),
5.22 (br s, 1H, H-2), 5.20−5.13 (d, J = 16.2 Hz, 2H, CH2PhCarba), 4.95
(d, J = 6.7 Hz, 1H, H-1), 4.86−4.78 (m, 1H, CH2Ph), 4.61 (m, 3H,
CH2Ph), 4.51−4.35 (m, 3H, CH2PhN, H-5), 3.85−3.70 (m, 4H, H-3,
H-4, H-6), 3.46−3.36 (m, 1H, OCH2Linker), 3.27−3.09 (m, 2H,
NCH2Linker), 2.77 (br s, 1H, OH), 1.67−1.47 (m, 4H, CH2Linker),
1.38−1.28 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ =
166.5, 165.3, 138.2, 138.0, 135.9, 133.6, 133.2, 130.2, 129.9, 129.8,
129.6, 128.7, 128.7, 128.6, 128.5, 128.4, 128.2, 127.9, 127.8, 127.8,
127.8, 127.7, 127.4, 127.2, 98.6, 75.3, 73.7, 71.9, 70.5, 68.2, 68.1, 66.9,
66.5, 66.3, 53.6, 50.7, 50.3, 47.4, 46.4, 29.3, 28.1, 27.6, 23.6 ppm;
HRMS (ESI) m/z calcd for C55H57NO11 [M + NH4]+ 925.4270, found
925.4261. The glycosylation reaction was carried out according to
general procedure C using idose acceptor (57 mg, 63 μmol),
azidoglucose donor 16 (58 mg, 88 μmol), and (TMS)OTf (0.25
equiv, 2.84 μL, 16 μmol). The product was obtained as a colorless
syrup (45 mg, 51%): 1H NMR (500 MHz, CDCl3) δ = 8.17−8.13 (m,
2H, aromatic), 8.09−8.05 (m, 2H, aromatic), 8.02−7.98 (m, 2H,
aromatic), 7.59−7.09 (m, 33H, aromatic), 5.35 (s, 2H, CH2PhBz),
5.23−5.12 (m, 3H, CH2PhCarba, H-2), 5.08 (t, J = 9.7 Hz, 1H, H-4′),
5.00 (br s, 1H, H-1), 4.85 (d, J = 11.7 Hz, 1H, CH2Ph), 4.81 (d, J =
3.6 Hz, 1H, H-1′), 4.69 (d, J = 11.7 Hz, 1H, CH2Ph), 4.52 (s, 2H,
CH2Ph), 4.49−4.39 (m, 3H, CH2PhN, H-5), 4.34 (dd, J = 12.2, 2.4
Hz, 1H, H-6a′), 4.31 (d, J = 11.0 Hz, 1H, CH2Ph), 4.27 (d, J = 10.9
Hz, 1H, CH2Ph), 4.21 (dd, J = 12.3, 5.0 Hz, 1H, H-6b′), 4.17−4.08
(m, 2H, H-5, H-3), 3.82−3.79 (m, 1H, H-4), 3.79−3.70 (m, 4H, H-
6ab, H-3′, OCH2Linker), 3.46−3.38 (m, 1H, OCH2Linker), 3.36 (dd, J =
1
acceptor (88 mg, 90%): H NMR (500 MHz, CDCl3) δ = 8.20−7.97
(m, 4H, aromatic), 7.70−7.52 (m, 2H, aromatic), 7.49−7.11 (m, 18H,
aromatic), 6.91−6.76 (m, 4H, aromaticPMP), 5.34 (s, 2H, CH2PhBz),
5.25 (s, 1H, H-2), 5.16 (d, J = 18.7 Hz, 2H, CH2PhCarba), 4.96 (d, J =
7.6 Hz, 1H, H-1), 4.84 (dd, J = 11.3, 2.4 Hz, 1H, CH2Ph), 4.62 (d, J =
13.2 Hz, 2H, CH2Ph, H-5), 4.47 (d, J = 12.8 Hz, 2H, CH2PhN), 4.16
(s, 2H, H-6), 3.92−3.76 (m, 3H, H-4, H-3, OCH2Linker), 3.75 (s, 3H,
CH3PMP), 3.55−3.36 (m, 1H, OCH2Linker), 3.30−3.11 (m, 2H,
NCH2Linker), 2.61 (br s, 1H, OH), 1.59 (s, 4H, CH2Linker), 1.33 (s,
2H CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ = 166.6, 165.2,
154.2, 153.0, 138.1, 138.1, 138.0, 137.2, 137.1, 135.9, 133.8, 133.2,
R
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
10.1, 3.5 Hz, 1H, H-2′), 3.25−3.10 (m, 2H, NCH2Linker), 2.74−2.57
(m, 2H, CH2Lev), 2.53−2.45 (m, 1H, CH2Lev), 2.41−2.32 (m, 1H,
CH2Lev), 2.12 (s, 3H, CH3Lev), 1.58−1.43 (m, 4H, CH2Linker), 1.35−
1.24 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ = 206.1,
171.6, 166.5, 166.2, 165.8, 156.8, 156.2, 138.1, 138.0, 137.9, 137.5,
137.0, 135.9, 133.4, 133.2, 130.2, 130.1, 130.0, 129.9, 129.8, 128.7,
128.5, 128.4, 128.4, 128.2, 128.0, 128.0, 128.0, 127.8, 127.8, 127.6,
127.4, 127.2, 98.5 (C-1), 97.7 (C-1′), 78.4 (C-3′), 75.0 (CBn), 74.1 (C-
4), 73.4 (CBn), 72.8 (C-3), 72.4 (CBn), 70.7 (C-4′), 69.4 (C-6), 69.3
(C-2), 69.1 (C-5), 68.1 (OCH2Linker), 66.9 (CH2PhCarba), 66.5
(CH2PhBz), 66.3 (C-5), 63.6 (C-2′), 62.7 (C-6′), 50.7, 50.4
(CH2PhN), 47.4, 46.3 (NCH2Linker), 37.9 (CH2Lev), 29.8 (CH3Lev),
29.3 (CH2Linker), 28.0 (CH2Lev), 27.7, 23.6 (CH2Linker) ppm; HRMS
(ESI) m/z calcd for C80H82N4O18 [M + Na]+ 1409.5516, found
1409.5499.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-3-O-benzyl-2-O-benzoyl-6-O-(p-methoxyben-
zyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (49). Compound 41
(110 mg, 106 μmol) was delevulinated with hydrazine acetate (20 mg,
212 μmol) in CH2Cl2/methanol (4:1, 2.5 mL). When TLC (hexane/
ethyl acetate, 2:1) showed complete conversion, the reaction mixture
was diluted with dichloromethane (50 mL) and washed twice with 1
M HCl (100 mL), saturated NaHCO3 solution (100 mL), and brine
(100 mL). The organic phase was dried over MgSO4, concentrated
under reduced pressure, and purified by column chromatography (0−
30% ethyl acetate/hexane) to afford the glycosyl acceptor (85 mg,
86%): 1H NMR (500 MHz, CDCl3) δ = 8.10−8.04 (m, 2H, aromatic),
8.03−7.99 (m, 2H, aromatic), 7.65−7.50 (m, 2H, aromatic), 7.49−
7.36 (m, 7H, aromatic), 7.36−7.19 (m, 12H, aromatic), 7.14 (d, J = 7.1
Hz, 1H, aromatic), 6.86 (d, J = 8.0 Hz, 2H, aromaticPMB), 5.34 (s, 2H,
CH2PhBz), 5.21 (s, 1H, H-2), 5.17 (d, J = 17.2 Hz, 2H, CH2PhCarba),
4.94 (d, J = 6.3 Hz, 1H, H-1), 4.81 (d, J = 11.0 Hz, 1H, CH2Ph), 4.60
(d, J = 11.7 Hz, 1H, CH2Ph), 4.52 (s, 2H, CH2PMB), 4.50−4.43 (m,
2H, CH2PhN), 4.39 (br s, 1H, H-5), 3.82−3.75 (m, 5H, H-3, H-4,
CH3PMB), 3.71 (d, J = 5.4 Hz, 2H, H-6ab), 3.41 (d, J = 19.8 Hz, 1H,
OCH2Linker), 3.28−3.10 (m, 2H, NCH2Linker), 2.80 (br s, 1H, OH),
1.54 (m, 4H, CH2Linker), 1.32 (m, 2H, CH2Linker) ppm; 13C NMR (126
MHz, CDCl3) δ = 166.6, 165.3, 159.4, 138.1, 133.6, 133.2, 130.2,
130.2, 129.9, 129.8, 129.4, 128.7, 128.5, 128.4, 128.2, 127.9, 127.8,
127.8, 127.5, 127.3, 113.9, 98.6, 75.4, 73.4, 71.9, 70.2, 68.2, 68.0, 66.9,
66.5, 66.3, 55.4, 50.7, 50.4, 47.4, 46.3, 29.3, 23.6 ppm; HRMS (ESI)
m/z calcd for C56H59NO12 [M + NH4]+ 960.3929, found 960.3662.
The glycosylation reaction was carried out according to general
procedure C using idose acceptor (62 mg, 66 μmol), azidoglucose
donor 16 (59 mg, 92 μmol), and (TMS)OTf (0.25 equiv, 3.0 μL, 16.5
μmol). The product was obtained as a colorless syrup (57 mg, 61%):
1H NMR (500 MHz, CDCl3) δ = 8.21−8.13 (m, 2H, aromatic), 8.09−
8.05 (m, 2H, aromatic), 8.03−7.99 (m, 2H, aromatic), 6.84 (d, J = 8.3
Hz, 1H, aromaticPMB), 5.35 (s, 2H, CH2PhBz), 5.22−5.13 (m, 3H, H-2,
CH2PhCarba), 5.09 (t, J = 9.7 Hz, 1H, H-4′), 4.99 (br s, 1H, H-1), 4.85
(d, J = 12.0 Hz, 1H, CH2Ph), 4.82 (d, J = 3.6 Hz, 1H, H-1′), 4.69 (d, J
= 11.7 Hz, 1H, CH2Ph), 4.50−4.38 (m, 5H, CH2PhN, H-5, CH2PMB),
4.38−4.21 (m, 4H, H-6ab′, CH2Ph), 4.17−4.13 (m, 1H, H-5′), 4.11 (t,
J = 3.3 Hz, 1H, H-3), 3.82−3.79 (m, 1H, H-4), 3.78−3.68 (m, 7H, H-
6ab, H-3′, CH3PMB, OCH2Linker), 3.47−3.38 (m, 1H, OCH2Linker), 3.36
(dd, J = 10.1, 3.6 Hz, 1H, H-2′), 3.26−3.10 (m, 2H, NCH2Linker),
2.75−2.59 (m, 2H, CH2Lev), 2.56−2.47 (m, 1H, CH2Lev), 2.42−2.33
(m, 1H, CH2Lev), 2.12 (s, 3H, CH3Lev), 1.60−1.45 (m, 4H, CH2Linker),
1.37−1.28 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ =
206.2, 171.6, 166.5, 166.2, 165.8, 159.3, 156.7, 156.2, 137.9, 137.5,
135.9, 133.4, 133.2, 130.2, 130.0, 130.0, 129.9, 129.8, 129.8, 129.3,
128.7, 128.6, 128.6, 128.5, 128.4, 128.4, 128.2, 128.0, 128.0, 127.8,
127.4, 127.2, 113.9 (CaromaticPMB), 98.5 (C-1), 97.6 (C-1′), 78.4 (C-3′),
75.0 (CBn), 74.0 (C-4), 73.1 (CH2PMB), 72.8 (C-3), 72.3 (CBn), 70.7
(C-4′), 69.3 (C-6, C-2), 69.1 (C-5′), 68.0 (OCH2Linker), 66.9
(CH2PhCarba), 66.5 (CH2PhBz), 66.3 (C-5), 63.6 (C-2′), 62.7 (C-6′),
55.3 (CH3PMB), 50.6, 50.4 (CH2PhN), 47.4, 46.3 (NCH2Linker), 37.9
(CH2Lev), 29.8 (CH3Lev), 29.2 (CH2Linker), 28.0 (CH2Lev), 27.6, 23.5
(CH2Linker) ppm; HRMS (ESI) m/z calcd for C81H84N4O19 [M +
NH4]+ 1439.5622, found 1439.5650.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
g l u c o p y r a n o s y l ) - 2 - O - b e n z o y l - 3 - O - b e n z y l - 6 - O -
[(triisopropylsiloxy)methyl]-α-L-idopyranosyl)oxy)pentyl]-
carbamate (50). Compound 42 (31 mg, 0.028 mmol) was
delevulinated with hydrazine acetate (5 mg, 57 μmol) in CH2Cl2/
MeOH (9:1, 1 mL). When TLC (hexane/ethyl acetate, 2:1) showed
complete conversion (2 h), the mixture was concentrated, and the
residue was purified by column chromatography (0−30% ethyl
acetate/hexane) to afford the idose acceptor (20 mg, 71%): 1H
NMR (500 MHz, CDCl3) δ = 8.12−7.98 (m, 4H), 7.64−7.10 (m,
20H), 5.35 (s, 2H), 5.24−5.12 (m, 3H), 4.99−4.88 (m, 3H), 4.85−
4.77 (m, 1H), 4.62 (d, J = 11.8 Hz, 1H), 4.53−4.43 (m, 2H), 4.43−
4.36 (m, 1H), 3.91−3.68 (m, 5H), 3.47−3.32 (m, 1H), 3.28−3.10 (m,
2H), 2.75 (d, J = 8.6 Hz, 1H), 1.72−1.44 (m, 4H), 1.40−1.20 (m,
2H), 1.17−0.99 (m, 21H) ppm; 13C NMR (126 MHz, CDCl3) δ =
166.4, 165.2, 156.1, 137.9, 137.1, 136.9, 135.7, 133.4, 133.0, 130.1,
129.8, 129.7, 129.4, 128.5, 128.4, 128.3, 128.2, 128.0, 127.8, 127.6,
127.5, 127.3, 127.2, 127.1, 98.5, 90.1, 75.2, 71.7, 68.1, 67.8, 67.6, 66.7,
66.4, 66.1, 50.5, 50.2, 47.2, 46.2, 29.7, 29.1, 28.0, 27.5, 23.4, 17.8, 12.0
ppm; HRMS (ESI) m/z calcd for C58H73NO12Si [M + Na]+
1026.4800, found 1026.4738. The glycosylation reaction was carried
out according to general procedure C using idose acceptor (20 mg, 20
μmol), azidoglucose donor 16 (16 mg, 24 μmol), and (TMS)OTf
(0.10 equiv, 20 μL of a 0.1 M solution). The residue was purified by
preparative TLC (40% ethyl acetate/hexane) to afford 50 (15 mg,
50%): 1H NMR (500 MHz, CDCl3) δ = 8.20−7.96 (m, 6H, aromatic),
7.64−7.06 (m, 28H, aromatic), 5.35 (s, 2H, CH2PhBz), 5.24−5.08 (m,
4H, CH2PhCarba, H-2, H-4′), 5.00−4.89 (m, 3H, CH2TOM, H-1), 4.85−
4.80 (m, 2H, H-1′, CH2Ph), 4.69 (d, J = 11.6 Hz, 1H, CH2Ph), 4.52−
4.43 (m, 2H, CH2PhN), 4.42−4.21 (m, 2H, H-6′, H-5, CH2Ph),
4.19−4.13 (m, 1H, H-5′), 4.11−4.06 (m, 1H, H-3), 3.94−3.80 (m,
3H, H-6, H-4), 3.80−3.68 (m, 2H, H-3′, OCH2Linker), 3.45−3.32 (m,
2H, H-2′, OCH2Linker), 3.28−3.06 (m, 2H, NCH2Linker), 2.73−2.57 (m,
2H, CH2Lev), 2.55−2.43 (m, 1H, CH2Lev), 2.42−2.28 (m, 1H, CH2Lev),
2.10 (s, 3H, CH3Lev), 1.75−1.40 (m, 4H, CH2Linker), 1.40−1.20 (m,
2H, CH2Linker), 1.15−0.95 (m, 21H, 6CH3TOM, 3CHTOM) ppm; 13C
NMR (126 MHz, CDCl3) δ = 205.9, 171.4, 166.4, 166.1, 165.7, 156.6,
156.1, 137.8, 137.4, 136.9, 135.7, 133.2, 133.0, 130.1, 129.8, 129.8,
129.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.2,
127.1, 98.3 (C-1), 97.3 (C-1′), 89.9 (CH2TOM), 78.3 (C-3′), 74.9
(CBn), 73.5 (C-4), 72.8 (C-3), 72.2 (CBn), 70.5, 69.4 (C-2, C-4′), 68.9
(C-5′), 67.9 (OCH2Linker), 66.7 (CH2PhCarba), 66.4 (C-5, CH2PhBz),
66.3 (C-6), 63.4 (C-2′), 62.5 (C-6′), 50.5, 50.2 (CH2PhN), 47.2, 46.2
(NCH2Linker), 37.8 (CH2Lev), 29.7 (CH3Lev), 29.1−27.5 (CH2Lev
,
)
CH2Linker), 23.4 (CH2Linker), 18.0, 17.8 (CH3TOM), 11.9 (CHTOM
ppm; LRMS (MALDI-TOF) m/z calcd for C83H98N4O19Si [M + Na]+
1506.65, found 1505.33; HRMS (ESI) m/z calcd for C83H98N4O19Si
[M + Na]+ 1506.6487, found 1506.6523.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-6-O-acetyl-2-O-benzoyl-3-O-benzyl-α-L-
idopyranosyl)oxy)pentyl]carbamate (51). Compound 43 (31 mg,
0.028 mmol) was delevulinated with hydrazine acetate (5 mg, 57
μmol) in CH2Cl2/MeOH (9:1, 1 mL). When TLC (hexane/ethyl
acetate, 2:1) showed complete conversion (2 h), the mixture was
concentrated, and the residue was purified by column chromatography
(0−40% EtOAc/hexanes) to afford the idose acceptor (20 mg, 91%):
1H NMR (500 MHz, CDCl3) δ = 8.12−7.94 (m, 4H, aromatic), 7.66−
7.06 (m, 20H, aromatic), 5.35 (s, 2H, CH2PhBz), 5.26−5.10 (m, 3H,
H-2, CH2PhCarba), 4.96−4.88 (d, J = 7.2 Hz, 1H, H-1), 4.87−4.78 (m,
1H, CH2Ph), 4.62 (d, J = 11.8 Hz, 1H, CH2Ph), 4.54−4.39 (m, 3H, H-
5, CH2PhN), 4.35 (dd, J = 11.6, 7.5 Hz, 1H, H-6a), 4.27 (dd, J = 11.3,
4.5 Hz, 1H, H-6b), 3.85−3.79 (br s, 1H, H-3), 3.79−3.65 (m, 2H, H-4,
OCH2Linker), 3.51−3.34 (m, 1H, OCH2Linker), 3.31−3.10 (m, 2H,
NCH2Linker), 2.08−2.00 (m, 3H, CH3Ac), 1.72−1.44 (m, 4H,
CH2Linker), 1.44−1.16 (m, 2H, CH2Linker) ppm; 13C NMR (125
MHz, CDCl3) δ = 170.7, 166.4, 165.0, 156.1, 137.9, 137.7, 137.0,
S
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
136.9, 135.8, 133.6, 133.0, 130.1, 129.7, 129.1, 128.6, 128.5, 128.4,
128.3, 128.3, 128.0, 127.8, 127.6, 127.3, 127.3, 127.1, 98.2 (C-1), 74.8
(C-3), 71.8 (CBn), 67.9 (OCH2Linker), 67.7 (C-2), 67.1 (C-4), 66.8
(CH2PhCarba), 66.3 (CH2PhBz), 65.4 (C-5), 63.7 (C-6), 50.5, 50.2
(CH2PhN), 47.2, 46.2 (NCH2Linker), 29.1, 28.0, 27.5, 23.5 (CH2Linker),
20.8 (CH3Ac) ppm. The glycosylation reaction was carried out
according to general procedure C using idose acceptor (123 mg, 128
μmol), azidoglucose donor 16 (115 mg, 179 μmol), and (TMS)OTf
(7 μL, 32 μmol). The product 51 was obtained as an unseparable α/β
(C-5), 66.7 (CH2PhCarba), 66.3 (CH2PhBz), 63.2 (C-2′), 61.8 (C-6),
52.3 (CH3COOMe), 50.4, 50.1 (CH2PhN), 47.1, 46.0 (NCH2Linker), 37.7
(CH2Linker), 29.6 (CH3Lev), 29.0 (CH2Linker), 27.8 (CH2Lev, CH2Linker),
27.4 (CH2Linker), 23.3 (CH2Linker) ppm; LRMS (MALDI-TOF) m/z
calcd for C74H76N4O19 [M + Na]+ 1348.40, found 1347.78; HRMS
(ESI) m/z calcd for C74H76N4O19 [M + Na]+ 1347.5001, found
1347.4924.
tert-Butyldimethylsilyl 2-Azido-3,6-di-O-benzyl-2-deoxy-D-
glucopyranose (53). To a solution of tert-butyldimethylsilyl 2-
azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-β-D-glucopyranoside
(26) (180 mg, 0.36 mmol) in dry CH2Cl2 were added triethylsilane
(0.34 mL, 2.17 mmol) and trifluoroacetic acid (0.17 mL, 2.17 mmol)
at 0 °C. After 2 h, the reaction was quenched with triethylamine and
concentrated. The crude product was purified by column chromatog-
raphy (hexane/ethyl acetate, 9:1 to 7:3) to obtain 53 (140 mg, 78%):
1H NMR (500 MHz, CDCl3) δ = 7.44−7.28 (m, 10H, aromatic), 4.93
1
mixture (25 mg, 15%). Selected characteristic NMR signals: H NMR
(500 MHz, CDCl3) δ = 5.29−5.25 (m, 3H, H-1′α, CH2PhCarba), 4.98
(d, J = 3.5 Hz, 1H, H-1β), 4.91−4.83 (m, 2H, H-1α), 4.67−4.57 (m, 3
H, H-1′β, CH2−Bn) ppm; 13C NMR (126 MHz, CDCl3) δ = 97.9 (C-
1α, JC,H = 171 Hz), 97.8 (C-1α, JC,H = 172 Hz), 96.3 (C-1′β, JC,H
=
162 Hz), 91.9 (C-1′α, JC,H = 171 Hz) ppm; HRMS (ESI) m/z calcd
for C75H78N4O19 [M + Na]+ 1361.5152, found 1361.5129.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-(methyl ((4-
O-(2-azido-3-O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-
D-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-α-L-idopyranosyl)-
oxy)uronate)pentyl]carbamate (52). To a solution of 44 (169 mg,
0.179 mmol) in dry CH2Cl2/MeOH (4.5 mL/0.45 mL) was added
hydrazine acetate (24 mg, 0.27 mmol). The reaction was stirred for 3 h
at room temperature. The crude product was purified by columm
chromatography (hexane/ethyl acetate, 6:4) to afford the idose
acceptor (0.128 g, 85%): 1H NMR (500 MHz, CDCl3) δ = 8.12−7.95
(m, 4H, aromatic), 7.64−7.10 (m, 20H, aromatic), 5.35 (s, 2H,
CH2PhBz), 5.24−5.16 (m, 3H, H-2, CH2PhCarba), 5.12 (br s, 1H, H-1),
4.90 (m, 1H, H-5), 4.82 (m, 1H, CH2Ph), 4.64 (d, 1H, J = 11.6 Hz,
CH2Ph), 4.47 (d, J = 11.4 Hz, 2H, CH2PhN), 4.11 (br s, 1H, H-4),
3.87 (m, 1H, H-3), 3.82 (s, 3H, CH3COOMe), 3.78−3.73 (m, 1H,
CH2Linker), 3.51−3.45 (m, 1H, CH2Linker), 3.24−3.14 (m, 2H,
CH2Linker), 2.80 (br s, 1H, OH), 1.64−1.43 (m, 4H, CH2Linker),
1.40−1.24 (m, 2H, CH2Linker) ppm; 13C NMR (125 MHz, CDCl3) δ =
170.0, 166.3, 165.0, 156.0, 137.8, 137.5, 137.0, 135.7, 133.7, 133.0,
130.0, 129.7, 129.7, 129.0, 128.6, 128.5, 128.4, 128.3, 128.0, 127.8,
127.7, 127.6, 127.3, 127.2, 127.1, 98.7, 74.3, 71.8, 68.7, 68.2, 67.6, 67.3,
66.8, 66.3, 52.4, 50.5, 50.2, 47.2, 46.1, 29.7, 29.1, 27.9, 27.5, 23.3 ppm.
The glycosylation reaction was carried out according to general
procedure C using the following conditions:
(d, J = 11.4 Hz, 1H, CH2Ph), 4.78 (d, J = 11.4 Hz, 1H, CH2Ph), 4.64−
4.52 (m, 3H, CH2Ph, H-1), 3.73 (d, J = 4.7 Hz, 2H, H-6), 3.65 (dd, J =
8.8, 9.5 Hz, 1H, H-4), 3.46−3.39 (m, 1H, H-5), 3.33 (dd, J = 7.6, 10.0
Hz, 1H, H-2), 3.23 (dd, J = 8.7, 9.9 Hz, 1H, H-3), 2.90−2.50 (br s, 1H,
OH), 0.96 (s, 9H, CH3TBS), 0.19 (s, 6H, CH3TBS) ppm; 13C NMR
(125 MHz, CDCl3) δ = 138.2, 137.8, 128.6, 128.4, 128.0, 127.9, 127.7,
127.6, 97.2 (C-1), 82.3 (C-3), 74.9 (CBn), 74.0 (C-5), 73.7 (CBn), 71.9
(C-4), 70.3 (C-6), 68.1 (C-2), 25.6 (CH3TBS), −4.3 (SiCH3), −5.3
(SiCH3) ppm; HRMS (ESI) m/z calcd for C26H37N3O5Si [M + Na]+
522.2400, found 522.2388.
Dimethylthexylsilyl 2-Azido-6-O-benzoyl-3-O-benzyl-2-
deoxy-D-glucopyranose (54). EtSH (0.25 mL, 3.3 mmol) and
catalytic pTsOH (35 mg) were added to a solution of dimethylthex-
ylsilyl 2-azido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-α,β-D-glucopyra-
nose (350 mg, 0.66 mmol) in dry CH2Cl2 (8 mL). After being stirred
for 3 h under argon, the mixture was neutralized with solid NaHCO3,
diluted with CH2Cl2, washed with water, dried over MgSO4, and
concentrated. The purification of the residue was carried out by
column chromatography (hexane/ethyl acetate, 8:2) to yield
dimethylthexylsilyl 2-azido-3-O-benzyl-2-deoxy-α,β-D-glucopyranose
1
(271 mg, 94%): H NMR (500 MHz, CDCl3) δ = 7.41−7.28 (m,
5H, aromatic), 4.95 (d, J = 11.4 Hz, 1H, CH2Ph), 4.72 (d, J = 11.4 Hz,
1H, CH2Ph), 4.55 (d, J = 7.5 Hz, 1H, H-1), 3.81 (dd, J = 11.8, 3.6 Hz,
1H, H-6a), 3.73 (dd, J = 11.8, 4.8 Hz, 1H, H-6b), 3.56 (dd, J = 9.7, 8.7
Hz, 1H, H-4), 3.27 (m, 2H, H-2, H-5), 3.21 (m, 1H, H-3), 1.68 (m,
1H, CHthexyl), 0.92−0.90 (2s, 12H, CH3thexyl), 0.21 and 0.20 (2s, 6H,
Si(CH3)2) ppm; 13C NMR (126 MHz, CDCl3) δ = 138.2, 128.8,
128.2, 128.1, 97.2, 82.6, 75.2, 75.1, 70.6 68.6, 62.6, 34.0, 24.9, 20.1,
20.0, 18.60, 18.5, −1.9, −3.1. BzCN (76 mg, 0.58 mmol) and a
catalytic amount of Et3N were added to a cooled (−40 °C) solution of
dimethylthexylsilyl 2-azido-3-O-benzyl-2-deoxy-α,β-D-glucopyranose
(250 mg, 0.57 mmol) in dry CH3CN (11 mL). After 4 h, MeOH
was added and the mixture was allowed to reach room temperature.
The solvent was evaporated, and the residue was dissolved in MeOH
and concentrated to dryness. The purification was carried out by flash
column chromatography (hexane/ethyl acetate, 9:1) to afford 54 (250
(1) Idose acceptor (56 mg, 0.066 mmol) and azidoglucose donor
17 (62 mg, 0.093 mmol). (TMS)OTf (0.6 μL, 0.003 mmol)
was added at 0 °C. The reaction mixture was purified by flash
column chromatography using hexane/ethyl acetate (8:2) to
obtain compound 52 (26 mg, 32%).
(2) Acceptor (40 mg, 0.047 mmol) and azidoglucose donor 16 (42
mg, 0.065 mmol). (TMS)OTf (0.6 μL, 0.003 mmol) was added
at 0 °C. The reaction mixture was purified by flash column
chromatography using toluene/ethyl acetate (6:4) followed by
preparative TLC eluting with hexane/ethyl acetate (6:4) to
obtain compound 52 (30 mg, 48%).
1
Data for 52: H NMR (500 MHz, CDCl3) δ = 8.22−8.17 (m, 2H,
1
aromatic), 8.10−8.02 (m, 4H, aromatic), 7.11 (m, 28H, aromatic),
5.36 (s, 2H, CH2PhBz), 5.21−5.13 (m, 5H, H-1, H-2, H-4′,
CH2PhCarba), 4.92 (d, J = 11.5 Hz, CH2Ph), 4.87 (s, 1H, H-5), 4.77
(d, J = 3.10 Hz, H-1′), 4.74 (d, J = 11.5 Hz, CH2Ph), 4.61 (dd, J = 1.8,
12.4 Hz, 1H, H-6′a), 4.48 (d, J = 10.8 Hz, 2H, CH2PhN), 4.28 (dd, J =
1.8, 12.4 Hz, 1H, H-6′b), 4.20−4.17 (m, 1H, H-4), 4.16−4.11 (m, 1H,
H-5′), 4.09−4.06 (m, 2H, H-3, CH2Ph), 4.02 (d, J = 10.8 Hz, 1H,
CH2Ph), 3.82 (s, 3H, CH3COOMe), 3.77−3.74 (m, 1H, OCH2Linker),
3.62 (t, J = 9.4 Hz, H-3′), 3.55−3.42 (m, 1H, OCH2Linker), 3.30 (dd, J
= 3.1, 9.9 Hz, H-2′), 3.24−3.17 (m, 2H, NCH2Linker), 2.69−2.66 (m,
2H, CH2Lev), 2.57−2.42 (m, 2H, CH2Lev), 2.11 (s, 3H, CH3Lev), 1.63−
1.51 (m, 4H, CH2Linker), 1.31−1.27 (m, 2H, CH2Linker) ppm; 13C NMR
(126 MHz, CDCl3) δ = 205.9, 171.1, 169.6, 166.3, 166.0, 165.4, 156.5,
156.0, 137.8, 137.7, 137.4, 137.2, 136.9, 136.9, 136.8, 136.8, 135.6,
133.3, 132.9, 132.9, 130.0, 129.8, 129.6, 129.6, 128.5, 128.4, 128.3,
128.2, 127.9, 127.8, 127.7, 127.6, 127.2, 127.2, 127.0, 99.1 (C-1), 99.0
(C-1), 77.9 (C-3′), 76.0 (C-4), 74.5 (CH2Ph), 72.6 (C-3), 72.2
(CH2Ph), 70.1 (C-4′), 68.9 (C-5′), 68.5 (CH2Linker), 68.0 (C-2), 67.2
mg, 80%): H NMR (500 MHz, CDCl3) δ = 8.05−8.03 (m, 2H,
aromatic), 7.59−7.55 (m, 1H, aromatic), 7.47−7.42 (m, 2H,
aromatic), 7.40−7.30 (m, 5H, aromatic), 4.97 (d, J = 11.4 Hz, 1H,
CH2Ph), 4.74 (d, J = 11.4 Hz, 1H, CH2Ph), 4.57−4.56 (m, 3H, H-6ab,
H-1), 3.56−3.50 (m, 2H, H-4, H-5), 3.32 (dd, J = 9.9, 7.6 Hz, 1H, H-
2), 3.26−3.22 (m, 1H, H-3), 2.52 (br s, OH), 1.67−1.61 (m, 1H,
CHthexyl), 0.88−0.86 (3s, 12H, CH3thexyl), 0.18−0.16 (2s, 6H,
Si(CH3)2) ppm; 13C NMR (126 MHz, CDCl3) δ = 207.2, 166.9,
133.4, 129.9, 128.9, 128.5, 128.3, 97.3 (C-1), 82.3 (C-3), 75.3 (CBn),
74.0, 70.4 (C-4, C-5), 68.5 (C-2), 63.9 (C-6), 34.0 (CHthexyl), 20.1,
20.0, 18.6, 18.5 (CH3thexyl), −2.0, −3.1 (Si(CH3)2) ppm; HRMS (ESI)
m/z calcd for C28H39N3O6Si [M + Na]+ 564.2506, found 564.2471.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-(methyl ((4-
O-(2-azido-6-O-benzoyl-3-O-benzyl-2-deoxy-α-D-glucopyrano-
syl)-2-O-benzoyl-3-O-benzyl-α-L-idopyranosyl)oxy)uronate)-
pentyl]carbamate (55). To a solution of 52 (94 mg, 0.071 mmol) in
dry CH2Cl2/MeOH (25 mL/2.5 mL) was added hydrazine acetate (9
mg, 0.106 mmol). The reaction was stirred for 3 h, and the crude
T
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
product was concentrated and purified using hexane/ethyl acetate
(6:4) to obtain 55 as a white solid (70 mg, 80%): 1H NMR (500 MHz,
CDCl3) δ = 8.20−8.15 (m, 2H, aromatic), 8.10−8.00 (m, 4H,
aromatic), 7.58−7.15 (m, 28H, aromatic), 5.36 (s, 2H, CH2PhBz),
5.19−5.16 (m, 4H, H-1, H-2, CH2PhCarba), 4.88−4.82 (m, 4H, H-5, H-
1′, H-6a, CH2Ph), 4.74 (d, 1H, CH2Ph), 4.47−4.45 (m, 3H, CH2Ph,
H-6b), 4.36 (d, 1H, CH2Ph), 4.16−4.13 (m, 3H, CH2Ph, H-3, H-4),
4.04−4.02 (m, 1H, H-5′), 3.83 (s, 3H, CH3COOMe), 3.78−3.75 (m, 1H,
OCH2Linker), 3.54−3.46 (m, 3H, H-3′, H-4′, OCH2Linker), 3.23−3.13
(m, 3H, H-2′, NCH2Linker), 3.04 (br s, 1H, OH), 1.63−1.50 (m, 4H,
CH2Linker), 1.31−1.25 (m, 2H, CH2Linker) ppm; 13C NMR (126 MHz,
CDCl3) δ = 169.9, 167.5, 166.5, 165.6, 156.7, 156.2, 137.9, 137.7,
133.5, 133.1, 130.1, 129.9, 129.8, 129.5, 128.8, 128.6, 128.5, 128.4,
128.1, 128.0, 127.9, 127.4, 127.2, 99.4 (C-1′), 99.2 (C-1), 79.3 (C-3′),
75.7 (C-4), 75.0 (CH2Ph), 73.2 (C-3), 72.4 (CH2Ph), 71.4 (C-4′),
70.5 (C-5′), 68.7 (CH2Linker), 68.0 (C-2), 67.5 (C-5), 66.9
(CH2PhCarba), 66.5 (CH2PhBz), 63.2 (C-2′), 63.1 (C-6′), 52.4
(CH3COOMe), 50.6, 50.3 (CH2PhN), 47.3 (NCH2Linker), 46.3
CHCl3); 1H NMR (500 MHz, CDCl3) δ = 8.06−7.95 (m, 4H,
aromatic), 7.67−7.62 (m, 2H, aromatic), 7.57−7.48 (m, 2H,
aromatic), 7.44−7.17 (m, 15H, aromatic), 7.01−7.95 (m, 2H,
aromatic), 5.41−5.37 (m, 2H, H-1′, H-4′), 5.22−5.15 (m, 2H, H-5′,
H-2′), 4.89−4.82 (m, 3H, CH2Ph, H-6), 4.74 (d, J = 10.9 Hz, CH2Ph),
4.70 (d, J = 10.9 Hz, CH2Ph), 4.54 (d, J = 7.2 Hz, 1H, H-1), 4.42 (dd,
J = 11.9, 6.1 Hz, 1H, H-6), 4.14−4.11 (m, 1H, H-3′), 3.98 (dd, J = 9.8,
8.6 Hz, 1H, H-4), 3.69−3.63 (m, 1H, H-5), 3.40−3.30 (m, 5H,
CH3COOMe, H-2, H-3), 1.64−1.58 (m, 1H, CHthexyl), 0.85−0.83 (12H,
CH3thexyl), 0.14−0.11 (6H, Si(CH3)2) ppm; 13C NMR (126 MHz,
CDCl3) δ = 168.8, 166.1, 165.6, 165.4, 138.1, 137.4, 133.6, 133.3,
133.1, 130.1, 130.0, 129.9, 129.4, 128.9, 128.6, 128.4, 128.4, 128.3,
128.2, 127.7, 127.5, 97.8 (JC1′,H1′ = 171 Hz, C-1′), 97.2 (JC1,H1 = 160
Hz, C-1), 81.1 (C-3), 75.2 (C-4), 74.8 (CBn), 73.8 (C-5), 73.0 (CBn),
72.9 (C-3′), 69.1 (C-2), 68.5 (C-4′), 67.7 (C-2′), 67.1 (C-5′), 63.2
(C-6), 52.3 (CH3COOMe), 34.0 (CHthexyl), 20.1, 20.0, 18.6, 18.5
(CH3thexyl), −2.0, −3.2 (Si(CH3)2) ppm; HRMS (ESI) m/z calcd for
C56H63N3O14Si [M + Na]+ 1052.3977, found 1052.3912.
4-[(Phenylcarboxy)methyl]benzyl N-Benzyl-N-[5-(methyl ((4-
O-(2-azido-6-O-benzoyl-3-O-benzyl-2-deoxy-4-O-(methyl (2-
O-benzoyl-3-O-benzyl-4-O-levulinoyl -L-idopyranosyl)-
uronate)-α-D-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-α-L-
idopyranosyl)oxy)uronate)pentyl]carbamate (59). The glycosy-
lation was carried out according to general procedure B using the
following conditions:
(CH2Linker), 29.2 (CH2Linker), 27.63 (CH2Linker), 23.5 (CH2Linker
)
ppm; HRMS (ESI) m/z calcd for C69H70N4O17 [M + Na]+
1249.4634, found 1249.4623.
tert-Butyldimethylsilyl 2-Azido-3,6-di-O-benzyl-2-deoxy-4-
O-(methyl (2,4-di-O-acetyl-3-O-benzyl-α-L-idopyranosyl)-
uronate)-D-glucopyranose (56). The reaction was carried out
according to general procedure B using acceptor 53 (32 mg, 0.064
mmol) and n-pentenyl donor 3 (222 mg, 0.326 mmol). NIS (22 mg,
0.097 mmol) and (TMS)OTf (2.3 μL, 0.013 mmol) were added at 0
°C, and the mixture was stirred for 2 h. The crude product was
concentrated, and analysis by LC−MS showed 40% formation of the
desired disaccharide (calcd for C44H57N3O13SiNa 886.37 g/mol, found
886.29 g/mol) and 20% of a disaccharide lacking one acetyl group
(calcd for C42H55N3O12SiNa 844.36 g/mol, found 844.28 g/mol). The
crude product was dissolved in dry pyridine (1 mL), acetic anhydride
(0.5 mL) was added at 0 °C, and the reaction was stirred overnight.
EtOH was added, and the reaction crude was concentrated. The crude
product was purified by column chromatography (hexane/ethyl
(1) Acceptor 55 (35 mg, 0.028 mmol) and thiophenyl donor 1 (21
mg, 0.034 mmol) (55 mg, 0.093 mmol). NIS (19 mg, 0.084
mmol) and (TMS)OTf (1.5 μL, 0.006 mmol) were added at
room temperature. The crude was product was purified by
column chromatography using hexane/ethyl acetate (7:3) to
obtain compound 59 (16 mg, 34%).
(2) Acceptor 55 (64 mg, 0.052 mmol) and donor 6 (36 mg, 0.062
mmol). NIS (35 mg, 0.156 mmol) and (TMS)OTf (1.8 μL,
0.01 mmol) were added at 0 °C. The crude product was
purified by column chromatography using hexane/ethyl acetate
(7:3) to obtain compound 59 (40 mg, 45%).
1
acetate, 8:2) to obtain 56 (27 mg): H NMR (500 MHz, CDCl3) δ
1
Data for 59: H NMR (500 MHz, CDCl3) δ = 8.12−8.00 (m, 8H,
= 7.40−7.19 (m, 15H, aromatic), 5.21 (br s, 1H, H-1′), 5.08−5.04 (m,
1H), 5.02 (d, J = 2.3 Hz, 1H), 4.87−4.83 (m, 1H), 4.72−4.68 (m, 3H,
CH2Ph), 4.60 (d, J = 12.3 Hz, 1H, CH2Ph), 4.53−4.47 (m, 3H,
CH2Ph, H-1), 4.00 (t, J = 9.5 Hz, 1H), 3.82−3.79 (m, 1H), 3.72 (dd, J
= 11.2, 3.8 Hz, 1H, H-6a), 3.67 (dd, J = 11.4, 2.3 Hz, 1H, H-6b), 3.38
(m, 5H, CH3COOMe), 3.21 (t, J = 9.6 Hz, 1H), 2.01 and 2.00 (2s, 6H,
CH3Ac), 0.93 (s, 9H, CH3TBS), 0.15 (s, 3H, SiCH3), 0.14 (s, 3H,
SiCH3) ppm; 13C NMR (126 MHz, CDCl3) δ = 170.2, 169.9, 168.7,
138.3, 138.2, 137.5, 128.6, 128.4, 128.3, 128.2, 128.1, 127.6, 127.6,
127.4, 97.5 (C-1), 97.4 (C-1′), 81.0, 75.4, 74.5 (CBn), 74.1, 73.3 (CBn),
72.6 (CBn), 72.5, 68.9, 68.2 (C-6), 68.0, 67.2, 66.4, 52.2 (CH3COOMe),
25.7 (CH3TBS), 21.1, 20.9 (CH3Ac), 18.1 (CqTBS), −4.1, −5.1
(Si(CH3)2) ppm; HRMS (ESI) m/z calcd for C44H57N3NaO13Si [M
+ Na]+ 886.3553, found 886.3527.
aromatic), 7.57−7.13 (m, 36H, aromatic), 5.44 (d, J = 3.6 Hz, 1H, H-
1″), 5.35 (s, 2H, CH2PhBz), 5.20−5.16 (m, 5H, H-1, H-2″, H-4″,
CH2PhCarba), 5.09 (s, 1H, H-2), 4.88 (d, J = 11.4 Hz, 1H, CH2Ph),
4.83−4.70 (m, 7H, H-6a, H-5″, H-1′, H-5, CH2Ph), 4.48−4.45 (m, 3H,
H-6b, CH2PhN), 4.41 (d, J = 10.4 Hz, 4H, CH2Ph), 4.13−4.09 (m,
1H, H-3), 4.03−3.89 (m, 5H, H-4′, H-5′, H-3″, H-4, CH2Ph), 3.78−
3.70 (m, 1H, OCH2Linker), 3.68 (s, 3H, CH3COOMe), 3.55−3.46 (m, 2H,
H-3′, OCH2Linker), 3.42 (s, 3H, CH3COOMe), 3.27 (dd, J = 10.3, 3.4 Hz,
1H, H-2′), 3.24−3.11 (m, 2H, NCH2Linker), 2.59 (t, J = 6.6 Hz, 2H,
CH2Lev), 2.38 (t, J = 6.6 Hz, 2H, CH2Lev), 2.09 (s, 3H, CH3Lev), 1.58−
1.43 (m, 4H, CH2Linker), 1.35−1.24 (m, 2H, CH2Linker) ppm; 13C NMR
(126 MHz, CDCl3) δ = 205.8, 171.6, 169.8, 168.7, 166.5, 166.1, 165.7,
165.1, 156.7, 156.2, 138.0, 137.7, 137.3, 137.0, 135.8, 133.6, 133.5,
133.1, 133.0, 130.2, 130.0, 129.8, 129.3, 128.7, 128.6, 128.5, 128.4,
128.2, 128.1, 128.0, 127.9, 127.5, 127.3, 127.2, 99.1 (C-1, JC1,H1 = 171
Hz), 98.9 (C-1′, JC1′,H1′ = 169 Hz), 98.1 (C-1″, JC1″,H1″ = 171 Hz), 78.6
(H-3′), 75.7, 75.6 (C-4, C-4′), 74.6 (CH2Ph), 74.3 (C-3), 73.4
(CH2Ph), 72.8 (C-3″), 72.4, 70.2 (C-5′), 69.8 (C-2″), 68.6
(CH2Linker), 68.3 (C-2, C-4″), 67.6 (C-5), 66.9 (CH2Phcarba), 66.5
(CH2PhBz), 63.8 (C-2′), 62.2 (C-6), 52.4 (CH3COOMe), 52.0
(CH3COOMe), 50.6, 50.3 (CH2PhN), 47.3, 46.3 (NCH2Linker), 37.7
(CH2Lev), 29.7 (CH3Lev), 29.2 (CH2Linker), 28.1 (CH2Linker), 27.8
(CH2Linker, CH3Lev), 27.6 (CH2Linker), 23.5 (CH2Linker) ppm; HRMS
(ESI) m/z calcd for C95H96N4O26 [M + Na]+ 1731.6205, found
1731.6274.
Dimethylthexylsilyl 2-Azido-6-O-benzoyl-3-O-benzyl-2-
deoxy-4-O-(methyl (3-O-benzyl-2,4-di-O-levulinoyl-α-L-
idopyranosyl)uronate)-D-glucopyranose (57). The reaction was
carried out according to general procedure B using acceptor 54 (32
mg, 0.064 mmol) and n-pentenyl donor 4 (29 mg, 0.051 mmol). NIS
(12 mg, 0.055 mmol) and (TMS)OTf (1.33 μL, 0.010 mmol) were
added at 0 °C, and the mixture was stirred for 2 h. The crude product
was concentrated, and the conversion to disaccharide 57 was
+
determinated by LC−MS to be 30% (calcd for C52H67N3O16SiNH4
1040.43 g/mol, found 1040.42 g/mol).
Dimethylthexylsilyl 2-Azido-6-O-benzoyl-3-O-benzyl-2-
deoxy-4-O-(methyl (2,4-di-O-benzoyl-3-O-benzyl-α-L-
idopyranosyl)uronate)-D-glucopyranose (58). The reaction was
carried out according to general procedure B using acceptor 53 (45
mg, 0.083 mmol) and n-pentenyl donor 5 (76 mg, 0.083 mmol). NIS
(56 mg, 0.249 mmol) and (TMS)OTf (3 μL, 0.016 mmol) were added
at 0 °C, and the mixture was stirred for 2 h. The crude product was
concentrated and purified by column chromatography (hexane/ethyl
acetate, 7:3) to obtain 58 (73 mg, 85%): [α]2D0 = −33.6 (c = 1,
Resin-Bound DOXyl N-Benzyl-N-[5-(methyl ((2-O-benzoyl-3-
O-benzyl-4-O-levulinoyl-α-L-idopyranosyl)oxy)uronate)-
pentyl]carbamate (SP-63). The reaction was performed according
to general procedure D employing the following conditions:
(1) Resin SP-62 (200 mg, 0.22 mmol/g), donor 1 (120 mg, 0.20
mmol), NIS (58 mg, 0.26 mmol), and (TMS)OTf (1.4 μL,
0.008 mmol) in dry CH2Cl2 (2 mL) at room temperature.
U
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2) Resin SP-62 (250 mg, 0.2 mmol/g), donor 2 (200 mg, 0.15
mmol), and (TMS)OTf (1.1 μL, 0.006 mmol) in dry CH2Cl2
(2 mL) at −40 °C.
MeOH, filtered, taken up in CH2Cl2 (0.2 mL), and treated with
pyridine (0.9 mL, 0.52 mmol), benzoyl chloride (1.2 mL, 0.26 mmol),
and a catalytic amount of DMAP. After 12 h, the reaction mixture was
diluted with CH2Cl2 and successively washed with a saturated aq
solution of CuSO4 and H2O. The organic phase was then dried over
anhydrous MgSO4, filtered, and concentrated. Column chromatog-
raphy and preparative TLC (30% EtOAc/hexane) afforded compound
59 as a white solid (3.7 mg, 8% overall yield).
Resin-Bound DOXyl N-Benzyl-N-[5-((6-O-acetyl-2-O-benzo-
yl-3-O-benzyl-4-O-levulinoyl-α-L-idopyranosyl)oxy)pentyl]-
carbamate (SP-72). The reaction was performed according to
general procedure D using resin SP-62 (100 mg, 0.44 mmol/g) and
thioglycoside 10 (3 equiv, 73 mg, 0.12 mmol). NIS (36 mg, 0.16
mmol) and TfOH (44 μL of a 0.1 M solution in CH2Cl2) were added
at −20 °C. Conversion was determined after analytical NaOMe
cleavage: 4-(hydroxymethyl)benzyl N-benzyl-N-[5-((3-O-benzyl-α-L-
idopyranosyl)oxy)pentyl]carbamate (73). Conversion: 96%. LC−MS
(ESI) (m/z): calcd C34H43N43O9 [NH4]+ 627.29, found 627.30. The
resin SP-72 (100 mg, 0.44 mmol/g) was transformed to resin-bound
4-(hydroxymethyl)benzyl N-benzyl-N-[5-((6-O-acetyl-2-O-benzoyl-3-
O-benzyl-α-L-idopyranosyl)oxy)pentyl]carbamate (SP-74) using gen-
eral procedure E.
(3) Resin SP-62 (160 mg, 0.2 mmol/g), donor 6 (94 mg, 0.16
mmol), and (TMS)OTf (1.2 μL, 0.007 mmol) in dry CH2Cl2
(2 mL) at 0 °C.
The conversion of every glycosylation reaction was determined after
analytical NaOMe cleavage: 4-(hydroxymethyl)benzyl N-benzyl-N-[5-
(methyl ((2-O-benzoyl-3-O-benzyl-4-O-levulinoyl-α-L-idopyranosyl)-
oxy)uronate)pentyl]carbamate (64). Conversions: (1) 84%, (2)
87%, (3) 85%. LC−MS (ESI) (m/z): retention time (tR) at 5.10
min (64), calcd for C34H41NO10 [Na]+ 646.3, found 646.2; tR at 5.79
min (64 + Me), calcd for C35H43NO10 [Na]+ 660.3, found 660.2. The
resin SP-63 (94 mg, 0.22 mmol/g) was transformed to resin-bound 4-
(hydroxymethyl)benzyl N-benzyl-N-[5-(methyl ((2-O-benzoyl-3-O-
benzyl-α-L-idopyranosyl)oxy)uronate)pentyl]carbamate (SP-65)
using general procedure E.
Resin-Bound DOXyl N-Benzyl-N-[5-(methyl ((4-O-(2-azido-3-
O-benzyl-6-O-benzoyl-2-deoxy-4-O-levulinoyl-α-D-glucopyra-
nosyl)-2-O-benzoyl-3-O-benzyl-α-L-idopyranosyl)oxy)-
uronate)pentyl]carbamate (SP-66). The reaction was performed
according to general procedure D using the following conditions:
Resin-Bound DOXyl N-Benzyl-N-[5-((6-O-acetyl-4-O-(2-
azido-6-O-benzoyl-3-O-benzyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-2-O-benzoyl-3-O-benzyl-α-L-idopyranosyl)-
oxy)pentyl]carbamate (SP-75). The reaction was performed
according to general procedure D using one cycle on resin SP-74
(100 mg, 0.44 mmol/g) with trichloroacetimidate 16 (1 × 3 equiv, 80
mg) and (TMS)OTf (1.8 μL, 0.01 mmol) at −40 °C. Conversion was
determined after analytical sodium methoxide cleavage: 4-
(hydroxymethyl)benzyl N-benzyl-N-[5-((4-O-(2-azido-3-O-benzyl-2-
deoxy-α-D-glucopyranosyl)-3-O-benzyl-α-L-idopyranosyl)oxy)pentyl]-
carbamate (76). Conversion: 22%. LC−MS (ESI) (m/z): calcd for
C47H58N4O13 [NH4]+ 904.40, found 904.37.
Resin-Bound DOXyl N-Benzyl-N-[5-((2-O-benzoyl-3-O-ben-
zyl-6-O-(dimethylthexylsilyl)-4-O-levulinoyl-α-L-idopyranosyl)-
oxy)pentyl]carbamate (SP-77). The reaction was performed
according to general procedure D using resin SP-62 (150 mg, 0.44
mmol/g, 66 μmol), thioglycoside 8 (5 equiv, 116 mg, 0.165 mmol),
NIS (6.5 equiv, 48 mg, 0.215 mmol), and (TMS)OTf (33 μL, 0.1 M
solution in CH2Cl2). Conversion was determined after analytical
NaOMe cleavage as 4-(hydroxymethyl)benzyl N-benzyl-N-[5-((3-O-
benzyl-6-O-(dimethylthexylsilyl)-α-L-idopyranosyl)oxy)pentyl]-
carbamate (78). Conversion: >95%. LC−MS (ESI) (m/z): calcd for
C42H61N1O9Si [NH4]+ 769.44, found 769.25. The resin SP-77 (150
mg, 0.44 mmol/g, 66 μmol) was transformed to resin-bound 4-
(hydroxymethyl)benzyl N-benzyl-N-[5-((2-O-benzoyl-3-O-benzyl-6-
O-(dimethylthexylsilyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (SP-
79) using general procedure E.
(1) One cycle on resin SP-65 (250 mg, 0.44 mmol/g) with
trichloroacetimidate 16 (1 × 3 equiv, 192 mg) and (TMS)OTf
(1.8 μL, 0.01 mmol) in dry CH2Cl2 (1.4 mL) at −40 °C.
Conversion was determined after analytical sodium methoxide
cleavage: 4-(hydroxymethyl)benzyl N-benzyl-N-[5-(methyl
((4-O-(2-azido-3-O-benzyl-6-O-benzoyl-2-deoxy-α-D-glucopyr-
anosyl)-2-O-benzoyl-3-O-benzyl-α-idopyranosyl)oxy)uronate)-
pentyl]carbamate (67). Conversion: 21%. LC−MS (ESI) (m/
z) tR at 5.86 min, calcd for C47H56N4O14 [NH4]+ 918.38, found
918.36.
(2) Four cycles on resin SP-65 (155 mg, 0.22 mmol/g) with
trichloroacetimidate 16 (3 × 5 equiv, 65 mg, 0.16 mmol) and
(TMS)OTf (68 μL of a 0.1 M solution of (TMS)OTf) in dry
CH2Cl2 (1.2 mL) at −20 °C. Conversion was determined after
analytical dibutyltin oxide cleavage as 4-(hydroxymethyl)benzyl
N-benzyl-N-[5-(methyl ((4-O-(2-azido-3-O-benzyl-6-O-benzo-
yl-2-deoxy-α-D-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-α-
idopyranosyl)oxy)uronate)pentyl]carbamate (68). Conversion:
84%. LC−MS (ESI) (m/z): tR at 11.96 min, calcd for
C67H72N4O18 [NH4]+ 1238.4, found 1238.3. The resin SP-66
(135 mg, 0.22 mmol/g) was transformed to resin-bound 4-
(hydroxymethyl)benzyl N-benzyl-N-[5-(methyl ((4-O-(2-
azido-3-O-benzyl-6-O-benzoyl-2-deoxy-α-D-glucopyranosyl)-2-
O-benzoyl-3-O-benzyl-α-idopyranosyl)oxy)uronate)pentyl]-
carbamate (SP-69) using general procedure E.
Resin-Bound DOXyl N-Benzyl-N-[5-(methyl ((4-O-(2-azido-3-
O-benzyl-6-O-benzoyl-2-deoxy-4-O-(methyl (2-O-benzoyl-3-O-
benzyl-4-O-levulinoyl-α-L-idopyranosyl)uronate)-α-D-gluco-
pyranosyl)-2-O-benzoyl-3-O-benzyl-α-L-idopyranosyl)oxy)-
uronate)pentyl]carbamate (SP-70). The reaction was performed
according to general procedure D using three cycles on resin SP-69
(127 mg, 0.22 mmol/g) with donor 6 (79 mg, 0.14 mmol) and
(TMS)OTf (56 μL of a 0.1 M solution of (TMS)OTf) in dry CH2Cl2
(0.96 mL) at −20 °C. Conversion was determined after analytical
dibutyltin oxide-mediated cleavage: 4-(hydroxymethyl)benzyl N-
benzyl-N-[5-(methyl ((4-O-(2-azido-3-O-benzyl-6-O-benzoyl-2-
deoxy-4-O-(methyl (2-O-benzoyl-3-O-benzyl-4-O-levulinoyl-α-L-
idopyranosyl)uronate)-α-D-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-
α-L-idopyranosyl)oxy)uronate)pentyl]carbamate (71). Conversion:
76%. LC−MS (ESI) (m/z): tR at 13.35 min, calcd for C88H92N4O25
[NH4]+ 1622.6, found 1622.4. The resin SP-70 (125 mg, 0.2 mmol/g)
was swollen in dry CH2Cl2 (2 mL), dry MeOH (1 mL) and dibutyltin
oxide (123 mg) were added, and the reaction was treated in the
microwave for 10 min at 120 °C. The resin was washed three times
with a solution of CH2Cl2/MeOH (1:1) and three times with MeOH.
This cleavage was repeated until no further release of compound from
the resin was observed and employing a large excess of dibutyltin oxide
(820 mg) in the last cleavage cycle. The crude was dissolved in
Resin-Bound DOXyl N-Benzyl-N-[5-((4-O-(2-azido-6-O-ben-
zoyl-3-O-benzyl-2-deoxy-4-O-levulinoyl-α-D-glucopyranosyl)-
2-O-benzoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-α-L-
idopyranosyl)oxy)pentyl]carbamate (SP-80). The reaction was
performed according to general procedure D using three cycles on
resin SP-79 (150 mg, 0.44 mmol/g, 66 μmol) and trichloroacetimidate
16 (3 × 3 equiv, 64 mg, 0.198 mmol). (TMS)OTf (33 μL, 0.1 M
solution in CH2Cl2) was added at −20 °C. Conversion was
determined after analytical NaOMe cleavage: 4-(hydroxymethyl)-
benzyl N-benzyl-N-[5-((4-O-(2-azido-3-O-benzyl-2-deoxy-α-D-gluco-
pyranosyl)-3-O-benzyl-6-O-(dimethylthexylsilyl)-α-L-idopyranosyl)-
oxy)pentyl]carbamate (81). Conversion: 77%. LC−MS (ESI) (m/z):
calcd for C55H76N4O13Si [NH4]+ 1046.55, found 1046.69. The resin
SP-80 (150 mg, 0.44 mmol/g, 66 μmol) was transformed to resin-
bound 4-(hydroxymethyl)benzyl N-benzyl-N-[5-((4-O-(2-azido-6-O-
benzoyl-3-O-benzyl-2-deoxy-α-D-glucopyranosyl)-2-O-benzoyl-3-O-
benzyl-6-O-(dimethylthexylsilyl)-α-L-idopyranosyl)oxy)pentyl]-
carbamate (SP-82) using general procedure E.
Resin-Bound DOXyl N-Benzyl-N-[5-((4-O-(2-azido-6-O-ben-
zoyl-4-O-(2-O-benzoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-α-
L-idopyranosyl)-3-O-benzyl-2-deoxy-α-D-glucopyranosyl)-2-O-
benzoyl-3-O-benzyl-6-O-(dimethylthexylsilyl)-α-L -
V
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
idopyranosyl)oxy)pentyl]carbamate (SP-83). The reaction was
performed according to general procedure D using three cycles on
resin SP-82 (70 mg, 0.44 mmol/g, 31 μmol), trichloroacetimidate 14
(4 × 3 equiv, 70 mg, 92 μmol), and (TMS)OTf (31 μL, 0.1 M
solution in CH2Cl2). Conversion was determined after analytical
NaOMe cleavage: 4-(hydroxymethyl)benzyl N-benzyl-N-[5-((4-O-(2-
azido-4-O-(3-O-benzyl-6-O-(dimethylthexylsilyl)-α-L-idopyranosyl)-3-
O-benzyl-2-deoxy-α-D-glucopyranosyl)-3-O-benzyl-6-O-(dimethylthex-
ylsilyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (84). Conversion:
77%. LC−MS (ESI) (m/z): calcd for C55H76N4O13Si [NH4]+
1046.55, found 1046.69.
Resin-Bound DOXyl N-Benzyl-N-[5-((2-O-benzoyl-3-O-ben-
zyl-4-O-levulinoyl-6-O-(p-methoxyphenyl)-α-L-idopyranosyl)-
oxy)pentyl]carbamate (SP-85). The reaction was performed
according to general procedure D using resin SP-62 (200 mg, 0.44
mmol/g, 88 μmol), thioglycoside 11 (5 equiv, 295 mg, 0.44 mmol),
NIS (6.5 equiv, 128 mg, 0.572 mmol), and (TMS)OTf (88 μL, 0.1 M
solution in CH2Cl2). Conversion was determined after analytical
NaOMe cleavage as 4-(hydroxymethyl)benzyl N-benzyl-N-[5-((3-O-
benzyl-6-O-(p-methoxyphenyl)-α-L-idopyranosyl)oxy)pentyl]-
carbamate (86). Conversion: >95%. LC−MS (ESI) (m/z): calcd for
C41H49NO10 [NH4]+ 733.37, found 733.26. The resin SP-85 (200 mg,
0.44 mmol/g, 88 μmol) was transformed to resin-bound 4-
(hydroxymethyl)benzyl N-benzyl-N-[5-((2-O-benzoyl-3-O-benzyl-6-
O-(p-methoxyphenyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (SP-
87) using general procedure E.
M solution in CH2Cl2). Conversion was determined after analytical
NaOMe cleavage: DOXyl N-benzyl-N-[5-((4-O-(2-azido-4-O-(3-O-
benzyl-6-O-(p-methoxyphenyl)-α-L-idopyranosyl)-3-O-benzyl-2-
deoxy-α-D-glucopyranosyl)-3-O-benzyl-6-O-(p-methoxyphenyl)-α-L-
idopyranosyl)oxy)pentyl]carbamate (92). Conversion: 94%. LC−MS
(ESI) (m/z): calcd for C74H86N4O20 [NH4]+ 1368.62, found 1368.20.
4-(Acetoxymethyl)benzyl N-Benzyl-N-[5-((2-O-acetyl-4-O-(6-
O-acetyl-2-azido-4-O-(2,4-di-O-acetyl-3-O-benzyl-6-O-(p-me-
thoxyphenyl)-α-L-idopyranosyl)-3-O-benzyl-2-deoxy-α-D-glu-
copyranosyl)-3-O-benzyl-6-O-(p-methoxyphenyl)-α-L-
idopyranosyloxy)pentyl]carbamate (93). Monosaccharide forma-
tion was performed according to general procedure D using resin SP-
62 (1.18 g, 0.22 mmol/g, 260 μmol), thioglycoside 11 (5 equiv, 870
mg, 1.29 mmol), NIS (6 equiv, 350 mg, 1.56 mmol), and (TMS)OTf
(5 μL, 30 μmol). After capping and delevulination, disacccharide
formation was performed according to general procedure D using
three cycles on resin SP-87 (180 mg (198 mg), 0.44 mmol/g, 40
μmol) with trichloroacetimidate 16 (3 × 6 equiv, 152 mg, 238 μmol)
and (TMS)OTf (79 μL, 0.1 M solution in CH2Cl2). After capping and
delevulination, disacccharide formation was performed according to
general procedure D using two cycles on resin SP-91 (180 mg (198
mg), 0.44 mmol/g, 40 μmol) with trichloroacetimidate 15 (2 × 6
equiv, 171 mg, 237 μmol) and (TMS)OTf (79 μL, 0.1 M solution in
CH2Cl2). The resin SP-91 (175 mg, resin after cleavage 136 mg, 299
μmmol) was swollen in 4 mL of dry CH2Cl2 and then treated with
0.25 M NaOMe solution (1 mL) for 5 min at 55 °C under microwave
irradiation. Then the resin was washed with 2 × 5 mL of CH2Cl2/
MeOH (1:1) and 2 × 5 mL of MeOH. This procedure was repeated
until the TLC control (CH2Cl2/MeOH, 98:2) showed no further
compound cleavage (eight cycles). The washing solutions were pooled
and neutralized with Amberlite IR-120 (H+). After concentration,
crude 92 (39 mg) was acetylated overnight at room temperature with
Ac2O and a catalytic amount of DMAP in pyridine. The reaction
mixture was diluted with CH2Cl2 (50 mL), and the organic layer was
washed with 2 × 1 M HCl (50 mL), saturated CuSO4 (50 mL), water,
and brine. After concentration the crude product was purified by
column chromatography on silica gel using a hexane/acetone gradient.
Resin-Bound 4-(Hydroxymethyl)benzyl N-Benzyl-N-[5-((4-O-
(2-azido-6-O-benzoyl-3-O-benzyl-2-deoxy-4-O-levulinoyl-α-D-
glucopyranosyl)-2-O-benzoyl-3-O-benzyl-6-O-(p-methoxy-
phenyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (SP-88). The
reactions were performed according to general procedure D using
the following conditions:
(1) Four cycles on resin SP-87 (200 mg, 0.44 mmol/g, 88 μmol)
with trichloroacetimidate 16 (3 equiv, 169 mg, 0.264 mmol))
and (TMS)OTf (44 μL, 0.1 M solution in CH2Cl2).
(2) Two cycles on resin SP-87 (120 mg, 0.44 mmol/g, 52.8 μmol)
with trichloroacetimidate 16 (6 equiv, 203 mg, 0.157 mmol))
and (TMS)OTf (44 μL, 0.1 M solution in CH2Cl2).
1
The product was obtained as a colorless syrup (34 mg, 72%): H
NMR (500 MHz, CDCl3) δ = 7.37−7.28 (m, 14H, aromatic), 7.26−
7.20 (m, 10H, aromatic), 7.14−6.95 (m, 6H, aromaticPMP), 6.85−6.73
(m, 2H, aromatic−PMP), 5.19−5.09 (m, 2H, CH2PhCarba), 5.08 (s, 2H,
CH2PhAc), 4.99−4.96 (m, 1H, H-2), 4.98−4.90 (m, 3H, H-4″, H-1′,
H-1″), 4.86−4.78 (m, 4H, H-2″, H-1, CH2Ph), 4.74−4.58 (m, 4H,
CH2Ph), 4.57−4.51 (m, 2H, H-5, H-5″), 4.50−4.43 (m, 2H,
CH2PhN), 4.31 (dd, J = 12.3, 2.1 Hz, 1H, H-6′), 4.20−4.15 (m,
1H, H-6″), 4.11−4.04 (m, 2H, H-6″, H-6′), 3.96−3.85 (m, 3H, H-3,
H-4, H-5′), 3.85−3.77 (m, 2H, H-3′, H-4′), 3.76−3.65 (m, 10H, H-3″,
H-6, OCH2Linker, 2 × CH3PMP), 3.45−3.34 (m, 1H, OCH2Linker), 3.32
(dd, J = 9.6, 3.6 Hz, 1H, H-2′), 3.25−3.13 (m, 2H, CH2NLinker), 2.11
(s, 3H, CH3Ac), 2.09 (s, 3H, CH3Ac), 2.01 (s, 3H, CH3Ac), 1.99 (s, 3H,
CH3Ac), 1.97 (s, 3H, CH3Ac), 1.67−1.47 (m, 4H, CH2Linker), 1.38−1.24
(m, 2H, CH2Linker) ppm; 13C NMR (126 MHz, CDCl3) δ = 171.0,
170.6, 170.3, 170.3, 169.6, 154.2, 154.1, 152.6, 152.3, 138.0, 137.8,
137.8, 137.5, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.2, 128.2,
128.1, 127.9, 127.8, 127.8, 127.7, 127.4, 127.2, 115.4, 115.4, 115.0,
114.6 (CaromaticPMP), 98.2 (JC,H = 170 Hz, C-1), 98.0 (JC,H = 169 Hz, C-
1″), 95.9 (JC,H = 171 Hz, C-1′), 78.9 (C-3′), 75.2 (CBn), 74.7 (C-4′),
73.1 (C-3″), 72.6 (CBn), 72.2 (CBn), 71.5 (C-3), 70.4 (C-4), 69.9 (C-
5′), 68.2 (C-2), 68.1 (C-2″, OCH2Linker), 67.6 (C-4″), 66.9
(CH2Phcarba), 66.7 (C-6, C-6″), 66.1 (CH2PhAc), 65.4, 65.3 (C-5, C-
5″), 64.0 (C-2′), 62.3 (C-6′), 55.8 (CH3PMP), 55.7 (CH3PMP), 50.6,
50.3 (CH2PhN), 47.4, 46.3 (NCH2Linker), 29.3, 28.1, 27.6, 23.5
(CH2Linker), 21.1, 21.0, 21.0, 20.9 (CH3Ac) ppm; HRMS (ESI) m/z
calcd for C84H96N4O25 [M + Na]+ 1583.6256, found 1583.6265.
(3) One cycle on resin SP-87 (120 mg, 0.44 mmol/g, 52.8 μmol)
with trichloroacetimidate 16 (12 equiv, 406 mg, 0.364 mmol)
and (TMS)OTf (52 μL, 0.1 M solution in CH2Cl2).
(4) Two cycles on resin SP-87 (200 mg, 0.44 mmol/g, 88 μmol)
with trifluoroacetimidate 17 (6 equiv, 353 mg, 0.528 mmol)
and (TMS)OTf (88 μL, 0.1 M solution in CH2Cl2).
(5) Two cycles on resin SP-87 (120 mg, 0.44 mmol/g, 52.8 μmol)
with trichloroacetimidate 16 (cycle 1, 12 equiv, 406 mg, 0.364
mmol; cycle 2, 6 equiv, 203 mg, 0.157 mmol) and (TMS)OTf
(44 μL, 0.1 M solution in CH2Cl2).
(6) One cycle on resin SP-87 (200 mg, 0.22 mmol/g, 44 μmol)
with trichloroacetimidate 16 (1 × 6 equiv, 203 mg, 0.157
mmol) and (TMS)OTf (44 μL, 0.1 M solution in CH2Cl2).
The conversions were determined after analytical NaOMe cleavage:
DOXyl N-benzyl-N-[5-((4-O-(2-azido-3-O-benzyl-2-deoxy-α-D-gluco-
pyranosyl)-3-O-benzyl-6-O-(p-methoxyphenyl)-α-L-idopyranosyl)-
oxy)pentyl]carbamate (89). Conversions: (1) 80%, (2) 85%, (3) 68%,
(4) 70%, (5) 85%, (6) 90%. LC−MS (ESI) (m/z): calcd for
C54H64N4O14 [Na]+ 1015.43, found 1015.29. The resin SP-88 (340
mg, 0.22 mmol/g, 74.8 μmol) was transformed to resin-bound 4-
(hydroxymethyl)benzyl N-benzyl-N-[5-((4-O-(2-azido-6-O-benzoyl-3-
O-benzyl-2-deoxy-α-D-glucopyranosyl)-2-O-benzoyl-3-O-benzyl-6-O-
(p-methoxyphenyl)-α-L-idopyranosyl)oxy)pentyl]carbamate (SP-90)
using general procedure E.
Resin-Bound DOXyl N-Benzyl-N-[5-((4-O-(2-azido-4-O-(2-O-
benzoyl-3-O-benzyl-4-O-levulinoyl-6-O-(p-methoxyphenyl)-α-
L-idopyranosyl)-6-O-benzoyl-3-O-benzyl-2-deoxy-α-D-gluco-
pyranosyl)-2-O-benzoyl-3-O-benzyl-6-O-(p-methoxyphenyl)-
α-L-idopyranosyl)oxy)pentyl]carbamate (SP-91). The reaction
was performed according to general procedure D using two cycles on
resin SP-90 (200 mg, 0.44 mmol/g, 88 μmol) with trichloroacetimi-
date 15 (2 × 6 equiv, 388 mg, 528 μmol) and (TMS)OTf (88 μL, 0.1
ASSOCIATED CONTENT
■
S
* Supporting Information
Annotated HPLC traces of solid-phase reactions after cleavage
1
of a resin aliquot and H and 13C NMR and HSQC (only for
W
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(21) Krock, L.; Esposito, D.; Castagner, B.; Wang, C.-C.;
Bindschadler, P.; Seeberger, P. H. Chem. Sci. 2012, 3, 1617.
final compound 93) spectra for all new compounds. This
material is available free of charge via Internet at http://pubs.
acs.org.
(22) Walvoort, M. T. C.; van den Elst, H.; Plante, O. J.; Krock, L.;
̈
Seeberger, P. H.; Overkleeft, H. S.; van der Marel, G. A.; Codee
́
, J. D.
C. Angew. Chem. 2012, 124, 4469.
AUTHOR INFORMATION
Corresponding Author
*Fax: +34-9-430-053-14. E-mail: nreichardt@cicbiomagune.es.
■
(23) Hsu, C.-H.; Hung, S.-C.; Wu, C.-Y.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2011, 50, 11872.
(24) van den Bos, L. J.; Codee, J. D. C.; Litjens, R. E. J. N.; Dinkelaar,
́
J.; Overkleeft, H. S.; van der Marel, G. A. Eur. J. Org. Chem. 2007,
2007, 3963.
Notes
The authors declare no competing financial interest.
(25) Tabeur, C.; Machetto, F.; Mallet, J. M.; Duchaussoy, P.; Petitou,
M. Carbohydr. Res. 1996, 281, 253.
(26) Lu, L.-D.; Shie, C.-R.; Kulkarni, S. S.; Pan, G.-R.; Lu, X.-A.;
Hung, S.-C. Org. Lett. 2006, 8, 5995.
(27) Tatai, J.; Osztrovszky, G.; Kajtar
Carbohydr. Res. 2008, 343, 596.
ACKNOWLEDGMENTS
■
́
Funding from the Ministerio de Economia y Competitividad,
́
-Peredy, M.; Fugedi, P.
̈
Projects CTQ2008-04444/BQA and CTQ2011-27874 and a
grant to N.G. (BES-2009-027360), the Government of the
Basque Country, Etortek grant, and the European Union, ITN-
Euroglycoarrays grant, is gratefully acknowledged. We thank
Sebastian Kopitzki for his contributions in the synthetic
development during this project and Dr. Javier Calvo for the
acquisition of high-resolution mass spectra and help in HPLC
method development.
(28) Goto, F.; Ogawa, T. Biorg. Med. Chem. Lett. 1994, 4, 619.
(29) Arasappan, A.; Fraser-Reid, B. J. Org. Chem. 1996, 61, 2401.
(30) Murakata, C.; Ogawa, T. Carbohydr. Res. 1992, 234, 75.
(31) Gege, C.; Vogel, J.; Bendas, G.; Rothe, U.; Schmidt, R. R.
Chem.Eur. J. 2000, 6, 111.
(32) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. J. Org. Chem. 1993, 58, 32.
(33) Mach, M.; Schlueter, U.; Mathew, F.; Fraser-Reid, B.; Hazen, K.
C. Tetrahedron 2002, 58, 7345.
REFERENCES
■
(34) Allen, J. G.; Fraser-Reid, B. J. Am. Chem. Soc. 1999, 121, 468.
(35) Fraser-Reid, B.; Grimme, S.; Piacenza, M.; Mach, M.; Schlueter,
U. Chem.Eur. J. 2003, 9, 4687.
(1) Biosynthesis of Heparin and Heparan Sulfate; Mizumoto, S.,
Kitagawa, H., Sugahara, K., Eds.; Elsevier: Oxford, 2005.
(2) Lindahl, U.; Li, J. Int. Rev. Cell. Mol. Biol. 2009, 276, 105.
(3) Linhardt, R. J.; Toida, T. Acc. Chem. Res. 2004, 37, 431.
(4) Hu, Y. P.; Lin, S. Y.; Huang, C. Y.; Zulueta, M. M. L.; Liu, J. Y.;
Chang, W.; Hung, S. C. Nat. Chem. 2011, 3, 557.
(5) Zulueta, M. M. L.; Lin, S.-Y.; Lin, Y.-T.; Huang, C.-J.; Wang, C.-
C.; Ku, C.-C.; Shi, Z.; Chyan, C.-L.; Irene, D.; Lim, L.-H.; Tsai, T.-I.;
Hu, Y.-P.; Arco, S. D.; Wong, C.-H.; Hung, S.-C. J. Am. Chem. Soc.
2012, 134, 8988.
(6) Arungundram, S.; Al-Mafraji, K.; Asong, J.; Leach, F. E., III;
Amster, I. J.; Venot, A.; Turnbull, J. E.; Boons, G. J. J. Am. Chem. Soc.
2009, 131, 17394.
(7) Wang, Z.; Xu, Y.; Yang, B.; Tiruchinapally, G.; Sun, B.; Liu, R.;
Dulaney, S.; Liu, J.; Huang, X. Chem.Eur. J. 2010, 16, 8365.
(8) Baleux, F.; Loureiro-Morais, L.; Hersant, Y.; Clayette, P.;
(36) Reichardt, N. C.; Martin-Lomas, M. ARKIVOC (Gainesville, FL,
U. S.) 2005, 133.
(37) Jacquinet, J.-C.; Petitou, M.; Duchaussoy, P.; Lederman, I.;
Choay, J.; Torri, G.; Sinay, P. Carbohydr. Res. 1984, 130, 221.
̈
(38) Dilhas, A.; Bonnaffe,
́
D. Carbohydr. Res. 2003, 338, 681.
(39) Furlan, R. L. E.; Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett.
́
1996, 37, 5229.
(40) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 123, 6819.
(41) Orgueira, H. A.; Bartolozzi, A.; Schell, P.; Litjens, R. E. J. N.;
Palmacci, E. R.; Seeberger, P. H. Chem.Eur. J. 2002, 9, 140.
(42) Kong, F. Carbohydr. Res. 2007, 342, 345.
(43) Ber
́
ces, A.; Whitfield, D. M.; Nukada, T.; do Santos, Z, I.;
Obuchowska, A.; Krepinsky, J. J. Can. J. Chem. 2004, 82, 1157.
(44) Petitou, M.; Duchaussoy, P.; Lederman, I.; Choay, J.; Sinay, P.;
̈
Arenzana-Seisdedos, F.; Bonnaffe,
2009, 5, 743.
(9) Polat, T.; Wong, C. H. J. Am. Chem. Soc. 2007, 129, 12795.
(10) Canales, A.; Angulo, J.; Ojeda, R.; Bruix, M.; Fayos, R.; Lozano,
́
D.; Lortat-Jacob, H. Nat. Chem. Biol.
Jacquinet, J.-C.; Torri, G. Carbohydr. Res. 1986, 147, 221.
(45) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 0,
293.
R.; Gimen
Barbero, J. J. Am. Chem. Soc. 2005, 127, 5778.
(11) de Paz, J. L.; Angulo, J.; Lassaletta, J. M.; Nieto, P. M.; Redondo-
Horcajo, M.; Lozano, R. M.; Gimenez-Gallego, G.; Martín-Lomas, M.
ChemBioChem 2001, 2, 673.
́ ́
ez-Gallego, G.; Martín-Lomas, M.; Nieto, P. M.; Jimenez-
́
(12) Orgueira, H. A.; Bartolozzi, A.; Schell, P.; Litjens, R. E. J. N.;
Palmacci, E. R.; Seeberger, P. H. Chem.Eur. J. 2003, 9, 140.
(13) Petitou, M.; Duchaussoy, P.; Driguez, P. A.; Jaurand, G.;
Her
́
ault, J. P.; Lormeau, J. C.; van Boeckel, C. A. A.; Herbert, J. M.
Angew. Chem., Int. Ed. 1998, 37, 3009.
(14) Daragics, K.; Fugedi, P. Tetrahedron 2010, 66, 8036.
̈
(15) Czechura, P.; Guedes, N.; Kopitzki, S.; Vazquez, N.; Martin-
Lomas, M.; Reichardt, N.-C. Chem. Commun. 2011, 47, 2390.
(16) Ojeda, R.; de Paz, J. L.; Martín-Lomas, M. Chem. Commun.
2003, 2486.
(17) Ojeda, R.; Terenti, O.; de Paz, J. L.; Martin-Lomas, M.
Glycoconjugate J. 2004, 21, 179.
(18) Eller, S.; Collot, M.; Yin, J.; Hahm, H. S.; Seeberger, P. H.
Angew. Chem., Int. Ed. 2013, 52, 5858.
(19) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291,
1523.
(20) Walvoort, M. T. C.; Volbeda, A. G.; Reintjens, N. R. M.; van den
Elst, H.; Plante, O. J.; Overkleeft, H. S.; van der Marel, G. A.; Codee
́
, J.
D. C. Org. Lett. 2012, 14, 3776.
X
dx.doi.org/10.1021/jo400467g | J. Org. Chem. XXXX, XXX, XXX−XXX