Access to 3-O-Functionalized N-Acetylneuraminic Acid Scaffolds

Article abstract of DOI:10.1021/acs.joc.5b00992

Direct access to 3-O-functionalized 2-α-N-acetylneuraminides and their corresponding 2,3-dehydro-2-deoxy-N-acetylneuraminic acid derivatives is described. Initially, a stereoselective ring-opening of the key intermediate N-acetylneuraminic acid (Neu5Ac) 2,3-β-epoxide with an alcohol provided the 3-hydroxy α-glycoside. O-Alkylation of the C3 hydroxyl group generated novel 3-O-functionalized Neu5Ac derivatives that provided the corresponding unsaturated derivatives upon elimination.

Full text of DOI:10.1021/acs.joc.5b00992

Note
pubs.acs.org/joc
Access to 3‑O‑Functionalized N‑Acetylneuraminic Acid Scaffolds
Mauro Pascolutti, Paul D. Madge, Robin J. Thomson, and Mark von Itzstein*
Institute for Glycomics, Griffith University − Gold Coast Campus, Queensland 4222, Australia
S
* Supporting Information
ABSTRACT: Direct access to 3-O-functionalized 2-α-N-
acetylneuraminides and their corresponding 2,3-dehydro-2-
deoxy-N-acetylneuraminic acid derivatives is described.
Initially, a stereoselective ring-opening of the key intermediate
N-acetylneuraminic acid (Neu5Ac) 2,3-β-epoxide with an
alcohol provided the 3-hydroxy α-glycoside. O-Alkylation of
the C3 hydroxyl group generated novel 3-O-functionalized
Neu5Ac derivatives that provided the corresponding unsaturated derivatives upon elimination.
Scheme 1. Synthesis of C3-Hydroxy Neu5Ac α-Glycosides
ialic acids, including N-acetylneuraminic acid (Neu5Ac),
Sare essential to a range of biological, pathological, and
immunological processes.1 In nature, α-glycosidically linked
sialic acids are found as a part of glycoconjugates, often as the
terminating carbohydrate residue.1 Sialyl-O-glycosides are often
utilized to investigate and understand the recognition and
functional characteristics of sialic acid-recognizing proteins.2
Sialic acids are naturally unsubstituted at C3, and little
exploration has been undertaken to date to incorporate, and
biologically assess, extensive functionalization at this position.
Some glycosides of 3-hydroxy-Neu5Ac are known to be
refractory to sialidase activity,3,4 and some inhibit Siglecs,5
while 3-fluoro-neuraminyl fluorides6,7 are known to inhibit
sialidase action. In addition, C3 C-linked alkyl derivatives of the
general sialidase inhibitor 2,3-dehydro-2-deoxy-N-acetylneur-
aminic acid (Neu5Ac2en) have provided novel probes of
influenza virus sialidase.8
The synthesis of C3-modified Neu5Ac and Neu5Ac2en
derivatives as biological probes remains a relatively unexplored
area. To expand the repertoire of C3 functionality on Neu5Ac
and Neu5Ac2en derivatives we sought to introduce C3-oxygen
linked functionalities on the Neu5Ac template. Our synthetic
strategy toward C3 oxygen-functionalized derivatives requires
initial introduction of a hydroxyl group in an equatorial
configuration at C3 of the Neu5Ac template. Alkylation of the
C3 hydroxyl group, followed by elimination of the C3 proton
and an “activating” substituent at the anomeric (C2) position
would provide a C3 O-functionalized Neu5Ac2en derivative.
Introduction of the desired equatorially substituted hydroxyl
group at C3 of the Neu5Ac template can be achieved via
opening of the 2,3-β-epoxide 5 (Scheme 1). The epoxide itself
is ultimately derived from protected Neu5Ac2en derivative 1.
Direct epoxidation of the 2,3-double bond of 1 was reportedly
unsuccessful;9,10 therefore, we (data not shown) and others9
have generated epoxide 5 via reaction of trans-diaxial
bromohydrin 3 with DBU.9 Bromohydroxylation of 1 (NBS,
CH3CN/H2O, 80 °C, 20 min) provides a mixture of trans-2,3-
diequatorial (2) and trans-2,3-diaxial (3) bromohydrins in a
reported9 maximum ratio of 1:3 (Scheme 1). In our hands,
despite the use of different solvent combinations, 2 and 3 were
found to be difficult to separate on silica gel and required
several chromatographic purifications for reasonable separation.
The need for a high-yielding synthesis of epoxide 5 led us to
investigate the stereoselective formation of the precursor trans-
2,3-diaxial bromohydrin 3. Bromohydroxylation of Neu5Ac2en
derivative 1 using KBr and H2O2 catalyzed by chloroperoxidase
provided exclusively trans-2,3-diaxial bromohydrin 3; however,
Received: May 3, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2. Synthetic Approach to C3-O-Functionalized Neu5Ac2en Derivatives
the reaction yield was only moderate (65%).11 We examined
preparation of 3 through a quick, two-step reaction sequence
(Scheme 1), involving initial 2,3-dibromination of Neu5Ac2en
derivative 1 followed by hydrolysis of the anomeric bromide to
give the trans-2,3-diaxial bromohydrin 3 as a single isomer. This
pathway takes advantage of the high-yielding formation of 2,3-
diaxial dibromide 49 achieved in reaction of Neu5Ac2en 1 with
Br2 in DCM.
Investigations were undertaken to find an efficient method to
hydrolyze the anomeric bromide of 4 to produce 3 (a full list of
methods examined is given in the Supporting Information,
Table S1). Gratifyingly, reaction of 4 under commonly used
glycosylation conditions employing AgOTf and Na2HPO4,12
with water as the glycosyl acceptor, proved successful in
generating the trans-2,3-diaxial bromohydrin 3 in high yield
(87% yield; Table S1, entry 7). Under optimized conditions,
hydrolysis of the glycosyl bromide was reproducible and scale-
independent (Table S1, entry 8). Alternative glycosylation
conditions using a combination of AgClO4 and Ag2CO3,13,14 in
an optimal 1:1 ratio, resulted in an even higher yield (94%
yield; Table S1, entry 11). To the best of our knowledge, this is
the first report that describes the synthesis of a single
bromohydrin isomer in such high yield. The yield of the target
trans-2,3-diaxial bromohydrin 3 over two steps from 1 was 91%.
Epoxide 5 was subsequently obtained by reaction of 3 with
DBU in acetonitrile according to the reported procedure,9 in
good isolated yield (Scheme 1).
Previous publications have reported ring opening of epoxide
5 leading to 2β-halo 3-eq-hydroxy-Neu5Ac derivatives,9 or to
the 3-eq-hydroxy Neu5Ac α-methyl glycoside derivative.15
While a halide at the anomeric position would make for an
easier introduction of the 2,3-double bond in the subsequent
synthetic pathway to C3-substituted Neu5Ac2en derivatives, it
would undoubtedly prove to be a liability during alkylation
reactions on the 3-hydroxy-Neu5Ac template. Therefore, we
chose to introduce the p-methoxybenzyl group (PMB) for the
protection of the anomeric center because it would be stable to
O-alkylation reaction conditions and could be readily and
selectively removed for the introduction of an activating species
at C2.
alcohol was used, this reaction was found not only to be rapid
and high-yielding (89% yield), but also showed an excellent
stereoselectivity (>95:5 α:β). The α-anomeric configuration of
1
the glycoside was confirmed by H NMR spectroscopy, which
showed a vicinal coupling constant between H-7 and H-8 of 8.4
Hz and a Δδ |H-9a;H-9b| of 0.2 ppm, which is in accordance
with the reported data for α-glycosides of Neu5Ac deriva-
tives.3,10,15 To confirm this, NOE spectroscopy was employed
and showed a long-range coupling between H-3 and the
benzylic methylene protons indicating the α-configuration of
the p-methoxybenzyl group at C2.
Given the successful stereoselective formation of the p-
methoxybenzyl α-glycoside 6a, we were interested to see if
other alcohols would give a similar result. It has been reported
that reactions of epoxide 5 with a carbohydrate primary
hydroxyl group was unsuccessful under CSA catalysis,15
whereas primary or secondary carbohydrate hydroxyl groups
under Lewis acid catalysis produced only the β-glycosides.15
Benzyl alcohol, allyl alcohol, and propargyl alcohol were reacted
with 5 in the presence of CSA, and in each case the
corresponding α-glycoside (6b−6d) was provided in good
yield with excellent stereoselectivity (Scheme 1). While the
PMB and benzyl glycosides offer temporary, readily removed
protection of the anomeric position, the allyl and propargyl
glycosides provide opportunities for further functionalization.16
The efficient formation of the allyl and propargyl 3-hydroxy-
Neu5Ac α-glycosides described herein offers entry into
potentially sialidase-resistant compounds with a range of
functionality at the anomeric position to explore interactions
with biologically important sialic acid-recognizing proteins.3,5
Moreover, the presence of the C3 hydroxyl group on Neu5Ac
α-glycosides 6a−d provides opportunity for further manipu-
lation to investigate the C3 binding domain of N-acetylneur-
aminic acid-recognizing proteins.
To advance the design of 3-O-substituted Neu5Ac2en
derivatives, we considered the introduction of a functionalized
C3 side-chain with the potential for further manipulation. We
decided to introduce a nitrogen-terminated alkyl side-chain
because of its versatility in chemical derivatization. Many
attempts to obtain C3-O-alkylated species using electrophiles
such as TsOCH2CH2N3, BrCH2CH2OTHP, or BrCH2CH2Br-
(N3) either under neutral conditions (Ag2O in DCM or DMF)
or in the presence of a strong base such as sodium hydride, at
room temperature, failed. This may have been due to either
insufficient reactivity of these electrophiles or the tendency for
Accordingly, reaction of epoxide 5 was carried-out with p-
methoxybenzyl alcohol in 1,2-dichloroethane (DCE) in the
presence of a catalytic amount of camphorsulfonic acid
(CSA),15 successfully producing the p-methoxybenzyl α-
glycoside 6a. When a large excess (20 mol equiv) of the
B
DOI: 10.1021/acs.joc.5b00992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
these halides to undergo elimination rather than substitution.
We therefore thought to introduce at C3 a nitrogen-terminated
alkyl side-chain masked as a cyanomethyl ether. Thus,
alkylation of the C3 hydroxyl group in 6a using bromoacetoni-
trile and freshly prepared silver(I) oxide in DCM successfully
produced the C3 cyanomethyl ether derivative 7 in 81% yield
(Scheme 2).
EXPERIMENTAL SECTION
■
1
For H and 13C spectra, chemical shifts are expressed as parts per
million (ppm, δ) and are relative to the solvent used [CDCl3: 7.26 (s)
1
1
for H; 77.0 (t) for 13C]. H−1H correlation spectroscopy (COSY)
1
and H−13C heteronuclear single quantum coherence (HSQC) was
used to confirm 1H and 13C assignments. High-resolution mass spectra
(HRMS) were recorded using a Fourier transform MS (FTMS)
instrument fitted with an ESI source.
Transformation at the anomeric center to introduce an
appropriate leaving group for subsequent β-elimination
commenced with cleavage of the PMB ether. Reaction of 7
with DDQ in a solution of DCM/H2O (9:1) for 54 h generated
C2 β-hydroxy derivative 8 as a single isomer in 82% yield.
Acetylation of 8 using standard conditions (Ac2O, DMAP,
pyridine) provided the corresponding C2 acetoxy derivative 9
in almost quantitative yield. Conversion of the cyano moiety
into its corresponding protected amine was accomplished by
reducing derivative 9 under a hydrogen atmosphere (40 psi) in
the presence of a stoichiometric amount of aq HCl giving the
amino salt derivative 10, which was subsequently Troc-
protected to give derivative 11 in 89% yield over two steps.
The insertion of the 2,3-double bond in derivative 11 was
initially explored by following our previous reports for the
synthesis of C3-C-substituted Neu5Ac2en derivatives,8 through
the formation of a glycosyl chloride and subsequent DBU
promoted elimination (i. AcCl, MeOH/DCM, 5 °C-rt, 48h; ii.
DBU, DCM, rt, 16 h). Unfortunately, this method did not
produce the desired eliminated species. Further investigation
using different bases (NaH, LiHMDS, tBuOK) or silver salts to
activate the anomeric chloride proved also to be unsuccessful.
Lewis acids were also employed as a promoter of the anomeric
acetoxy group of 11 (TMSOTf,17 BF3Et2O18) without any
encouraging results. In our opinion, the presence of an ether
substituent at C3 in the first instance reduces the acidity of H3
and also potentially deactivates the anomeric center for the
subsequent elimination. To our delight, introduction of the
glycosyl bromide (found to be highly unstable) led to the
successful generation of the 2,3-unsaturated species 12. This
was accomplished through a two step sequence: conversion of
2-O-acetyl derivative 11 to the 2β-bromo derivative by reaction
with in situ generated HBr (AcBr/MeOH at 0 °C in DCE)19
followed by treatment with DBU in DCM which afforded the
desired 3-O-[2′-(N-Troc)aminoethyl]-Neu5Ac2en derivative
12 in 79% yield.
In summary, we have developed a synthetic approach to
provide the first examples of C3-alkoxy-substituted N-
acetylneuraminic acid derivatives. The high-yielding synthesis
of Neu5Ac trans-2,3-diaxial bromohydrin 3 improves access to
the 2,3-β-epoxide 5, which can be used to introduce
functionality at C2 and C3. The highly stereoselective ring-
opening of epoxide 5, to give the 2-α-O-p-methoxybenzyl
glycoside and other glycosides, provides not only useful
transient protection of the anomeric center but also the
possibility of creating a range of 3-O-functionalized Neu5Ac α-
glycosides as a starting point for further investigation of the C3
binding domain. Finally, we have also developed the synthesis
to allow introduction of the 2,3-double bond in the presence of
C3-O-substituents. This provides a novel scaffold to explore the
C3 binding of unsaturated N-acetylneuraminic acid derivatives,
as shown, for example, with C3-C-substituted Neu5Ac2en in
influenza virus sialidase.8
General Procedure A for the Synthesis of Neu5Ac α-
Glycosides 6a−6d. To a solution of epoxide 5 (0.204 mmol) in
anhydrous 1,2-dichloroethane (2 mL) at 0 °C under argon was added
alcohol (4.08 mmol) followed by a catalytic amount of CSA. After the
reaction mixture was stirred for 15 min at 0 °C, the reaction was
allowed to warm to room temperature for 1 h. The chlorinated solvent
was removed under vacuum, and the residual oily solution was diluted
with EtOAc and washed successively with water and brine. The
organic phase was dried over Na2SO4 and then concentrated. The
residue was purified by chromatography on silica gel.
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-
dideoxy-D-glycero-D-galacto-non-2-enonate (1). Preparation was
completed according to the reported procedure.20
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-2,3-dibromo-
2,3,5-trideoxy-β-D-erythro-L-manno-non-2-ulopyranosonate
(4). According to the procedure of Okamoto et al.,9 bromine (5.17
mL, 100.42 mmol) was added slowly to a solution of glycal 1 (36.0 g,
76.08 mmol) in anhydrous DCM (300 mL) at 0 °C under argon. The
solution was stirred for 10 min at 0 °C and for a further 10 min at
room temperature. At the completion of the reaction, the mixture was
concentrated to dryness under reduced pressure to afford dibromo
derivative 4 (46.7 g, yield 97%). The crude product was purified by
1
crystallization from EtOAc/hexane. Rf 0.59 (EtOAc). H NMR (300
MHz, CDCl3): δ 1.94, 2.04, 2.07, 2.10, 2.14 (15H, 5 × s, NHCOCH3,
OCOCH3 × 4), 2.31 (OH), 3.89 (3H, s, COOCH3), 4.11 (1H, dd,
J9a,8 5.4 Hz, J9a,9b 12.6 Hz, H-9a), 4.39−4.54 (3H, m, H-5, H-6, H-9b),
5.02 (1H, d, J3,4 3.3 Hz, H-3), 5.23 (1H, m, H-8), 5.39−5.42 (2H, m,
H-7, NHCOCH3), 5.74 (1H, dd, J4,3 3.3 Hz, J4,5 10.2 Hz, H-4). LRMS
(ESI): m/z 654.0 [(C20H2779Br2NO12+Na)+, 50%], 656.0
[(C20H2779,81Br2NO12+Na)+, 100%], 657.9 [(C20H2781Br2NO12+Na)+,
50%]. The 1H NMR data was in accordance with that previously
reported.9
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3-bromo-3,5-di-
deoxy-β-D-erythro-L-manno-non-2-ulopyranosonate (3; Table
S1, Entry 11). To a solution of dibromide 4 (1.10 g, 1.74 mmol) and
H2O (38 μL, 2.09 mmol) in DCM (40 mL) at 0 °C was added
AgClO4 (542 mg, 2.61 mmol), and the reaction was stirred in the dark
for 2−3 min. Ag2CO3 (720 mg, 2.61 mmol) was then added, and the
solution was stirred vigorously for 10 min at 0 °C and for a further 15
min at room temperature. At the completion of the reaction, the
reaction mixture was filtered through Celite; the solid precipitate was
washed thoroughly with EtOAc to remove product from the
agglomeration of silver salts, and the combined filtrate was
concentrated under reduced pressure. The residue was dissolved in
EtOAc, and the solution was washed successively with satd aq
NaHCO3, water, and brine; dried (Na2SO4); filtered; and evaporated
under reduced pressure. The crude product was purified by
chromatography on silica (hexane/acetone 6:4) to afford the title
compound 3 (934 mg, 94%) as a white foam. Note: this reaction was
not reproducible on a larger scale (>5 g of 4) potentially because of
the large amount of agglomerated silver salts produced. Rf 0.5
1
(EtOAc). H NMR (300 MHz, CDCl3): δ 1.90, 2.02, 2.05, 2.07, 2.16
(15H, 5 × s, NHCOCH3, OCOCH3 × 4), 3.78 (3H, s, COOCH3),
4.12 (1H, dd, J9a,8 8.7 Hz, J9a,9b 12.3 Hz, H-9a), 4.36 (2H, m, H-5, H-
6), 4.59 (1H, d, J3,4 3.9 Hz, H-3), 4.92 (dd, J9b,8 2.4 Hz, J9a,9b 12.3 Hz,
H-9b). 5.25 (1H, m, H-8), 5.34−5.40 (2H, m, H4, H-7), 6.26 (1H, br
d, JNH,5 9.3 Hz, NHCOCH3), 6.35 (1H, br s, OH). 13C NMR (75.5
MHz, CDCl3): δ 20.8, 20.9, 21.0, 21.2 (OCOCH3 × 4), 23.2
(NHCOCH3), 45.8 (C-3), 51.4 (C-5), 53.2 (COOCH3), 63.0 (C-9),
68.7 (C-7), 68.9 (C-4), 71.8 (C-8), 73.2 (C-6), 96.3 (C-2), 167.5 (C-
1), 170.6, 170.7, 171.5, 172.4 (NHCOCH3, OCOCH3 × 4). LRMS
(ESI): m/z 592.0 [(C20H2879BrNO13+Na)+, 95%], 594.0
C
DOI: 10.1021/acs.joc.5b00992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
[(C20H2881BrNO12+Na)+, 100%]. The 1H NMR data was in
accordance with that previously reported.9
β, 103 mg, 84%) as a white solid. α anomer (6b): purification by
chromatography on silica (EtOAc/hexane 9:1; Rf 0.33 EtOAc/hexane
9:1). 1H NMR (CDCl3, 400 MHz): δ 1.86, 2.00, 2.04, 2.06, 2.09 (15H,
5 × s, NHCOCH3, OCOCH3 × 4), 3.76 (3H, s, COOCH3), 3.87 (1H,
d, J3,4 9.2 Hz, H-3), 4.03 (1H, dd, J9a,8 6.0, J9a,9b 12.4 H-9a), 4.21−4.29
(2H, m, H-5, H-9b), 4.56 (1H, dd, J6,7 2.0, J6,5 10.8 Hz, H-6), 4.72
(2H, AB q, J 12.0 Hz, CH2Ar), 5.18 (1H, app t J4,3 ≈ J4,5 10.0 Hz, H-
4), 5.26 (1H, dd, J7,6 2.0 Hz, J7,8 8.0 Hz, H-7), 5.31−5.36 (1H, m, H-
8), 5.84 (1H, d, JNH,5 10.0 Hz, NHCOCH3), 7.23−7.40 (5H, m, ArH).
13C NMR (CDCl3, 100.6 MHz): δ 20.72, 20.75, 20.8, 20.9 (COCH3 ×
4), 23.0 (NHCOCH3), 48.3 (C-5), 52.7 (COOCH3), 62.4 (C-9), 67.1
(CH2Ar), 67.3 (C-7), 68.9 (C-8), 72.5 (C-6), 73.6 (C-4), 74.4 (C-3),
100.3 (C-2), 127.7, 127.8, 128.3, 137.7 (ArC × 5), 169.3, 169.8, 170.1,
170.3, 170.6, 171.7 (C-1, NHCOCH3, OCOCH3 × 4). LRMS (ESI):
m/z 620.3 [(M+Na)+, 100%]. HRMS m/z calcd for
[C27H35NO14+H]+: 598.2136: Found: 598.2152.
Reaction of 4 with AgOTf and Na2HPO4 in Toluene (Table S1,
Entry 6). To a solution of dibromide 4 (100 mg, 0.16 mmol),
Na2HPO4 (80 mg, 0.62 mmol), and H2O (3.4 μL, 0.19 mmol) in
toluene at 0 °C was added slowly a solution of AgOTf (56 mg, 0.22
mmol) in anhydrous toluene (2 mL). The reaction was stirred
vigorously for 15 min at 0 °C and for a further 45 min at room
temperature. The progress of the reaction was monitored by TLC. The
reaction mixture was filtered through Celite; the solid precipitate was
washed thoroughly with EtOAc (2 × 5 mL), and the combined filtrate
was concentrated under reduced pressure. The residue was dissolved
in EtOAc, and the solution was washed successively with satd aq
NaHCO3, water, and brine; dried (Na2SO4); filtered; and evaporated
under reduced pressure. The crude product was purified by
chromatography on silica (hexane/acetone 6:4) to afford the title
compound 3 (72.9 mg, yield 81%) as a white foam.
Reaction of 4 with AgOTf and Na2HPO4 in Toluene-DCM (Table
S1, Entry 8). To a solution of dibromide 4 (5.00 g, 8.07 mmol),
Na2HPO4 (4.47 g, 31.5 mmol), and H2O (173 μL, 9.68 mmol) in
DCM (50 mL) at 0 °C was added slowly a solution of AgOTf (2.90 g,
11.3 mmol) in anhydrous toluene (30 mL). The reaction was stirred
vigorously for 30 min at 0 °C and for a further 1.5 h at room
temperature. Workup of the reaction as described above for reaction in
toluene (Table S1 in the Supporting Information, entry 6) afforded the
title compound 3 (3.99 g, yield 87%) as a white foam.
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-2,3-anhydro-5-
deoxy-β-D-erythro-L-gluco-non-2-ulopyranosonate (5). Accord-
ing to the method of Okamoto et al.,9 a solution of 3 (2.45 g, 4.30
mmol) in anhydrous acetonitrile (15 mL) under argon at room
temperature was treated with DBU (0.81 mL, 5.27 mmol). The
mixture was stirred for 15 min at room temperature; then, the reaction
mixture was evaporated to a one-third of the initial volume. The
solution was loaded onto a silica gel column and chromatographed
(toluene/acetone 3:2) to give the title compound 5 (1.85 g, 88%
yield) as a white foam. Rf 0.53 (EtOAc). 1H NMR (300 MHz,
CDCl3): δ 1.89, 2.03, 2.05, 2.09, 2.10 (15H, 5 × s, NHCOCH3,
OCOCH3 × 4), 3.59 (1H, s, H-3), 3.83 (3H, s, COOCH3), 4.05 (1H,
dd, J6,7 4.5 Hz, J6,5 8.4 Hz, H-6), 4.15 (1H, dd, J9a,8 6.9 Hz, J9a,9b 12.6
Hz, H-9a), 4.24 (1H, m, H-5), 4.51 (1H, dd, J9b,8 3.0 Hz, J9b,9a 12.6 Hz,
H-9b), 5.18 (1H, d, J4,5 7.5 Hz, H-4), 5.25 (1H, m, H-8), 5.40 (1H, dd,
J7,6 4.5 Hz, J7,8 5.1 Hz, H-7), 5.51 (1H, d, JNH,5 10.2 Hz, NHCOCH3).
LRMS (ESI): m/z 512.1 [(M+Na)+, 100%]. The 1H NMR data was in
accordance with that previously reported.9
Methyl (Allyl 5-acetamido-4,7,8,9-tetra-O-acetyl-5-deoxy-α-
D-erythro-L-gluco-non-2-ulopyranosid)onate (6c). According to
the general procedure A, epoxide 5 (100 mg, 0.204 mmol) was treated
with allyl alcohol (250 μL, 4.08 mmol) to yield 6c (>95:5 α/β, 94 mg,
85%) as a white solid. α anomer (6c): purification by chromatography
1
on silica (EtOAc/hexane 9:1; Rf 0.30 EtOAc/hexane 9:1). H NMR
(400 MHz, CDCl3): δ 1.88, 22.03, 2.07, 2.08, 2.13 (15H, 5 × s,
NHCOCH3, OCOCH3 × 4), 3.81 (3H, s, COOCH3), 3.85 (1H, d, J3,4
9.6 Hz), 4.04−4.11 (2H, m, H-9a, OCH2), 4.22 (1H, app q, J5,4 ≈ J5,NH
≈ J5,6 10.4 Hz, H-5), 4.26−4.34 (2H, m, H-9b, OCH2), 4.54 (1H, dd,
J6,7 2.0, J6,5 10.8 Hz, H-6), 5.14 (1H, app t J4,3 ≈ J4,5 10.4 Hz, H-4),
5.19 (1H, m, CHCH2), 5.26 (1H, dd, J7,6 2.0 Hz, J7,8 8.0 Hz, H-7),
5.28−5.37 (2H, m, CHCH2, H-8), 5.52 (1H, d, JNH,5 10.4 Hz,
NHCOCH3), 5.88−5.98 (1H, m, CHCH2). 13C NMR (CDCl3,
100.6 MHz) δ 20.82, 20.84, 21.0, 21.1 (COCH3 × 4), 23.1
(NHCOCH3), 48.4 (C-5), 52.7 (COOCH3), 62.5 (C-9), 66.3
(OCH2), 67.3 (C-7), 68.8 (C-8), 72.6 (C-6), 73.4 (C-4), 74.3 (C-
3), 100.1 (C-2), 117.3 (CHCH2), 133.9 (CHCH2), 169.1, 169.8,
170.2, 170.6, 170.6, 171.7 (C-1, NHCOCH3, OCOCH3 × 4). LRMS
(ESI): m/z 570.3 [(M+Na)+, 100%]. HRMS m/z calcd for
[C23H33NO14+H]+: 548.1974. Found: 548.1986.
Methyl (Prop-2′-ynyl 5-acetamido-4,7,8,9-tetra-O-acetyl-5-
deoxy-α-D-erythro-L-gluco-non-2-ulopyranosid)onate (6d). Ac-
cording to the general procedure A, epoxide 5 (100 mg, 0.204 mmol)
was treated with propargyl alcohol (240 μL, 4.08 mmol) to yield 6d
(>95:5 α/β, 92 mg, 83%) as a white solid. α anomer (6d): purification
by chromatography on silica (EtOAc/hexane 9:1; Rf 0.28 EtOAc/
1
hexane 9:1). H NMR (CDCl3, 400 MHz): δ 1.89, 2.03, 2.07, 2.08,
Methyl (p-Methoxybenzyl 5-acetamido-4,7,8,9-tetra-O-ace-
tyl-5-deoxy-α-D-erythro-L-gluco-non-2-ulopyranosid)onate
(6a). According to the general procedure A, epoxide 5 (1.11 g, 2.28
mmol) was treated with p-methoxybenzyl alcohol (6.3 mL, 45.6
mmol) to yield 6a (>95:5 α/β, 1.27 g, 89%) as a white solid. α anomer
(6a): purification by chromatography on silica (EtOAc/DCM gradient
1:1 to 8:2; Rf 0.39 EtOAc). 1H NMR (400 MHz, CDCl3): δ 1.88, 2.01,
2.04, 2.08, 2.12 (15H, 5 × s, NHCOCH3, OCOCH3 × 4), 2.80 (1H, d,
JOH,3 5.2 Hz, OH), 3.79 (3H, s, ArOCH3), 3.80 (3H, s, COOCH3),
3.85 (1H, dd, J3,4 9.6 Hz, J3,OH 5.2 Hz, H-3), 4.04 (1H, dd, J9a,8 6.0 Hz,
J9a,9b 12.4 Hz, H-9a), 4.20−4.28 (2H, m, H-5, H-9b), 4.58 (1H, dd, J6,7
2.0 Hz, J6,5 10.8 Hz, H-6), 4.64 (2H, AB q, J 11.6 Hz, CH2Ar), 5.13
(1H, app t, J4,3 ≈ J4,5 10.0 Hz, H-4), 5.26 (1H, dd, J7,6 2.0 Hz, J7,8 8.4
Hz, H-7), 5.37 (1H, m, H-8), 5.43 (1H, d, JNH,5 10.0 Hz, NHCOCH3),
6.86 (2H, d, J 8.7 Hz, ArH-m-OCH3), 7.31 (2H, d, J 8.7 Hz, ArH-o-
OCH3); 13C NMR (100.6 MHz, CDCl3): δ 20.7, 20.8, 20.9, 21.0
(OCOCH3 × 4), 23.1 (NHCOCH3), 48.4 (C-5), 52.7, 55.3 (ArOCH3,
COOCH3), 62.4 (C-9), 67.0 (CH2Ar), 67.3 (C-7), 68.7 (C-8), 72.6
(C-6), 73.2 (C-4), 74.45 (C-3), 100.2 (C-2), 113.7, 129.5, 129.6, 159.3
(ArC × 6), 169.2, 169.8. 170.1, 170.2 170.6, 171.6 (C-1, NHCOCH3,
OCOCH3 × 4). LRMS (ESI): m/z 649.9 [(M+Na)+, 100%]. HRMS
m/z calcd for [C28H37NNaO15]+: 650.2055. Found: 650.2073.
Methyl (Benzyl 5-acetamido-4,7,8,9-tetra-O-acetyl-5-deoxy-
α-D-erythro-L-gluco-non-2-ulopyranosid)onate (6b). According
to the general procedure A, epoxide 5 (100 mg, 0.204 mmol) was
treated with benzyl alcohol (420 μL, 4.08 mmol) to yield 6b (>95:5 α/
2.13 (15H, 5 × s, NHCOCH3, OCOCH3 × 4), 2.49 (1H, t, J 2.4 Hz,
CCH), 3.83 (3H, s, COOCH3), 3.88 (1H, d, J3,4 9.6 Hz, H-3), 4.06
(1H, dd, J9a,8 6.4, J9a,9b 12.4 Hz, H-9a), 4.18−4.29 (2H, m, H-5, H-9b),
4.32 (1H, dd, J 2.4, J 15.6 Hz, OCH2), 4.48 (1H, dd, J 2.4, J 15.6 Hz,
CH2), 4.53 (1H, dd, J6,7 2.0, J6,5 10.8 Hz, H-6), 5.17 (1H, app. t, J4,3
≈
J4,5 10.0 Hz, H-4), 5.24 (1H, dd, J7,6 2.0 Hz, J7,8 8.4 Hz, H-7), 5.36
(1H, m, H-8), 5.52 (1H, d, JNH,5 10.0 Hz, NHCOCH3). 13C NMR
(CDCl3, 100.6 MHz): δ 20.81, 20.82, 20.9, 21.1 (COCH3 × 4), 23.1
(NHCOCH3), 48.3 (C-5), 52.8 (COOCH3), 53.3 (OCH2), 62.5 (C-
9), 67.2 (C-7), 68.6 (C-8), 72.7 (C-6), 73.1 (C-4), 74.1 (C-3), 74.6
(CCH), 77.2 (CCH), 99.9 (C-2) 168.6, 169.8, 170.17, 170.20,
170.6, 171.7 (C-1, NHCOCH3, OCOCH3 × 4). LRMS (ESI): m/z
568.2 [(M+Na)+, 100%]. HRMS m/z calcd for [C23H31NO14+H]+:
546.1817. Found: 546.1835.
Methyl (p-Methoxybenzyl 5-acetamido-4,7,8,9-tetra-O-ace-
tyl-3-O-cyanomethyl-5-deoxy-α-D-erythro-L-gluco-non-2-
ulopyranosid)onate (7). Compound 6a (2.89 g, 4.61 mmol) was
dissolved in anhydrous DCM (85 mL) under argon at room
temperature and activated MS 4 Å (4.6 g) were added followed by
bromoacetonitrile (1.23 mL, 18.41 mmol). After the mixture was
stirred for 1 h, freshly prepared Ag2O (4.27 g, 18.41 mmol) and TBAI
(1.70 g, 4.61 mmol) were added. After completion of addition, the
reaction mixture was stirred, protected from light, for 16 h at room
temperature. The solution was filtered through Celite, and the filtrate
was concentrated under reduced pressure. The residue was purified by
chromatography on silica (Hexane/acetone 6:4) to yield 7 (2.47 g,
D
DOI: 10.1021/acs.joc.5b00992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
81%) as a white solid foam. Rf 0.68 (EtOAc). H NMR (300 MHz,
CDCl3): δ 1.88, 2.01, 2.07, 2.13 (15H, 4 × s, NHCOCH3, OCOCH3 ×
4), 3.71 (1H, d, J3,4 10.6 Hz, H-3), 3.80 (3H, s, ArOCH3), 3.82 (3H, s,
COOCH3), 4.03 (1H, dd, J9a,8 6.0 Hz, J9a,9b 12.3 Hz, H-9a), 4.21 (1H,
dd, J9b,8 2.4 Hz, J9b,9a 12.3 Hz, H-9b), 4.29 (1H, app q, H-5), 4.43 (2H,
app d, J 2.7 Hz, CH2CN), 4.61 (2H, AB q, J 11.4 Hz, CH2Ar), 4.71
(1H, m, H-6), 5.13 (1H, dd, J4,5 9.6 Hz, J4,3 10.6 Hz, H-4), 5.26 (1H,
dd, J7,6 2.1 Hz, J7,8 9.0 Hz, H-7), 5.29 (1H, m, NHCOCH3), 5.35 (1H,
m, H-8,), 6.86 (2H, d, J 11.4 Hz, ArH-m-OCH3), 7.29 (2H, d, J 11.4
Hz, ArH-o-OCH3). 13C NMR (75.5 MHz, CDCl3): δ 20.7−20.9
(OCOCH3 × 4), 23.1 (NHCOCH3), 48.3 (C-5), 52.8 (ArOCH3),
55.3 (COOCH3), 56.9 (CH2CN), 62.5 (C-9), 66.9 (C-7), 67.6
(CH2Ar), 68.2 (C-8), 71.7 (C-4), 72.6 (C-6), 82.1 (C-3), 100.3 (C-2),
115.5 (CH2CN), 113.8, 128.9 129.4, 159.4 (ArC × 6), 168.9, 169.6,
170.1, 170.2, 170.6, 171.3 (C-1, NHCOCH3, OCOCH3 × 4). LRMS
(ESI): m/z 688.9 [(M+Na)+, 100%]. HRMS m/z calcd for
[C30H38N2NaO15]+: 689.2164. Found: 689.2164.
apparatus at a hydrogen pressure of 40 psi. The reaction mixture was
then filtered through Celite, and the filtrate was concentrated to
dryness under vacuum. The crude product 10 was ninhydrin positive
on TLC and was employed without purification for the following
amine protection reaction. Rf 0.42 (EtOAc/MeOH/H2O 7:2:1).
To an ice-cold solution of 10 (603 mg, 0.95 mmol) in anhydrous
DCM (10 mL) and anhydrous pyridine (7.5 mL) under argon was
added dropwise trichloroethyl chloroformate (260 μL, 1.90 mmol).
The reaction was stirred at room temperature until the disappearance
of the starting material by TLC. After 4 h, the reaction mixture was
concentrated to dryness and the crude residue was purified by
chromatography on silica (hexane/acetone 6:4) to give derivative 11
1
(626 mg, 86% over two steps from 9). Rf 0.48 (EtOAc). H NMR
(300 MHz, CDCl3): δ 1.85, 2.01, 2.03, 2.06, 2.10, 2.17, (18H, 6 × s,
NHCOCH3, OCOCH3 × 5), 3.28 (2H, m, CH2b), 3.69 (2H, m,
CH2a), 3.80 (3H, s, COOCH3), 3.85 (1H, d, J3,4 10.2 Hz, H-3), 4.01−
4.10 (2H, m, H-6, H-9a), 4.22 (1H, app q, H-5), 4.45 (1H, dd, J9b,8 2.4
Hz, J9b,9a 12.3 Hz, H-9b), 4.69 (2H, app s, CH2c), 5.01 (1H, m, H-8),
5.18 (1H, app t, J4,3 ≈ J4,5 10.2 Hz, H-4), 5.32 (1H, dd, J7,6 2.4 Hz, J7,8
5.1 Hz, H-7), 5.42 (1H, br d, JNH,5 9.9 Hz, NHCOCH3), 5.56 (1H, br
t, JNH,CH2 5.4 Hz, NHTroc). 13C NMR (75.5 MHz, CDCl3): δ 20.7,
20.8, 20.9, 21.0 (OCOCH3 × 5), 23.0 (NHCOCH3), 41.2 (Cb), 48.0
(C-5), 53.4 (COOCH3), 62.0 (C-9), 67.4 (C-7), 71.3 (C-8), 72.2 (C-
6), 72.3 (Ca), 73.0 (C-4), 74.5 (Cc), 78.8 (C-3), 95.6 (CCl3), 97.3 (C-
2), 154.7 (COOCH2CCl3), 165.6 (C-1), 168.1, 170.1, 170.2, 170.4,
170.6, 171.2 (NHCOCH3, OCOCH3 × 5). LRMS (ESI): m/z 789.1
(95%), 790.0 (30%), 791.1 (100%), 792.1 (30%), 793.1 (35%)
[ C 2 7 H 3 7 C l 3 N 2 O 1 7 + N a + ] . H R M S m / z c a l c d f o r
[C2 7 H3 7 3 5 Cl3 N2 NaO1 7 ]+ : 789.1050. Found: 789.1043.
[C27H3735Cl237ClN2NaO17]+: 791.1021. Found: 791.1020.
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-3-O-cyano-
methyl-5-deoxy-β-D-erythro-L-gluco-non-2-ulopyranosonate
(8). To a solution of 7 (2.43 g, 3.65 mmol) in a mixture of DCM (150
mL) and H2O (15 mL) was added DDQ (2.48 g, 10.95 mmol). The
reaction was stirred for 54 h at room temperature. The reaction
mixture was then washed with satd aq NaHCO3 and brine, dried
(Na2SO4), and filtered. The organic phase was concentrated under
reduced pressure, and the crude residue was purified by chromatog-
raphy on silica (hexane/acetone 6:4) to yield 8 (1.63 mg, 82%). Rf
1
0.52 (EtOAc). H NMR (300 MHz, CDCl3): δ 1.86, 2.00, 2.08, 2.09,
2.12, (15H, 5 × s, NHCOCH3, OCOCH3 × 4), 3.89 (1H, m, H-9a),
3.93 (3H, s, COOCH3), 4.11 (1H, d, J3,4 9.6 Hz, H-3), 4.21−4.33 (2H,
m, H-5, H-6), 4.36 (2H, app d, J 2.1 Hz, CH2CN), 4.46 (1H, dd, J9b,8
2.4 Hz, J9b,9a 12.3 Hz, H-9b), 5.17 (2H, m, H-4, H-8), 5.31 (1H, dd, J7,6
1.5 Hz, J7,8 5.1 Hz, H-7), 6.01 (1H, br d, JNH,5 12.6 Hz NHCOCH3).
13C NMR (75.5 MHz, CDCl3): δ 20.7, 20.9, 21.0 (OCOCH3 × 4),
23.0 (NHCOCH3), 49.0 (C-5), 54.0 (COOCH3), 57.5 (CH2CN),
62.4 (C-9), 67.8 (C-7), 70.7 (C-6), 71.6 (C-8), 72.6 (C-4), 79.5 (C-3),
94.9 (C-2), 115.6 (CH2CN), 167.9 (C-1), 170.1, 170.3, 171.0, 171.1,
171.3 (NHCOCH3, OCOCH3 × 4). LRMS (ESI): m/z 569.1 [(M
+Na)+, 100%]. HRMS m/z calcd for [C22H30N2NaO14]+: 569.1589.
Found: 569.1611.
Methyl 5-Acetamido-2,4,7,8,9-penta-O-acetyl-3-O-cyano-
methyl-5-deoxy-β-D-erythro-L-gluco-non-2-ulopyranosonate
(9). Compound 8 (1.45 g, 2.66 mmol) was dissolved in anhydrous
pyridine (15 mL), and acetic anhydride (10 mL) and DMAP (catalytic
amount) were added to the reaction mixture. After the reaction
mixture was stirred for 16 h, the reaction mixture was concentrated
and the residue was diluted with EtOAc (100 mL) and washed with 1
M aq sol HCl. The aqueous phase was extracted with EtOAc (3 × 100
mL). The organic phases were combined and washed with satd aq
NaHCO3 and brine, dried (Na2SO4), filtered, and evaporated under
reduced pressure, and the residue was purified by chromatography on
silica (hexane/acetone 6:4) yielding 9 (1.52 g, 97%). Rf 0.48 (EtOAc).
1H NMR (300 MHz, CDCl3): δ 1.86, 2.02, 2.04, 2.11, 2.13, 2.14 (18H,
Methyl 5-Acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3-
O-[2′-(2″,2″,2″-trichlorethoxycarbamido)-ethyl]-5-deoxy-D-
glycero-D-galacto-non-2-enonate (12). Compound 11 (796 mg
1.03 mmol) was dissolved in anhydrous 1,2-dichloroethane (15 mL)
and acetyl bromide (2.3 mL, 30.9 mmol) under argon, and the
solution was cooled to 0 °C, when anhydrous methanol (0.63 mL,15.5
mmol) was added dropwise. The reaction mixture was stirred at room
temperature in a sealed vessel for 56 h. The reaction mixture was
concentrated under reduced pressure and azeotroped with toluene (2
× 10 mL), giving the corresponding β-glycosyl bromide derivative as a
yellow solid, which was used without purification for the subsequent
elimination reaction. The crude β-glycosyl bromide was taken up in
anhydrous DCM (4 mL) under argon; the solution was cooled to 0
°C; DBU (632 mL, 4.16 mmol) was added, and the reaction was left
to stir at room temperature for 16 h. The reaction mixture was diluted
with DCM and washed with satd aq NH4Cl, water, and brine; dried
(Na2SO4); filtered; and concentrated under reduced pressure. The
residue was purified by chromatography on silica (hexane/acetone
6:4) to give compound 12 (580 mg, 79% over two steps from 11) as a
1
white foam. Rf 0.50 (EtOAc). H NMR (300 MHz, CDCl3): δ 1.92,
6 × s, NHCOCH3, OCOCH3 × 5), 3.81 (3H, s, COOCH3), 4.02 (1H,
dd, J9a,8 6.6 Hz, J9a,9b 12.3 Hz, H-9a), 4.12 (1H, d, J3,4 9.6 Hz, H-3),
4.12−4.23 (2H, m, H-5, H-6), 4.39 (2H, AB q, J 16.8 Hz, CH2CN),
4.42 (1H, dd, J9b,8 2.7 Hz, J9b,9a 12.3 Hz, H-9b), 5.06 (1H, m, H-8),
5.14 (1H, dd, J4,3 9.6 Hz, J4,5 10.2 Hz, H-4), 5.32 (1H, dd, J7,6 1.8 Hz,
J7,8 6.0 Hz, H-7), 5.35 (1H, m, NHCOCH3). 13C NMR (75.5 MHz,
CDCl3): δ 20.7−20.8 (OCOCH3 × 5), 23.1 (NHCOCH3), 48.7 (C-
5), 53.5 (COOCH3), 57.5 (CH2CN), 62.0 (C-9), 67.1 (C-7), 70.8 (C-
8), 71.7 (C-4), 72.2 (C-6), 78.7 (C-3), 97.2 (C-2), 115.8 (CH2CN),
165.8 (C-1), 167.8, 169.9, 170.1, 170.2, 170.6, 171.4 (NHCOCH3,
OCOCH3 × 5). LRMS (ESI): m/z 611.2 [(M+Na)+, 100%]. HRMS
m/z calcd for [C24H32N2NaO15]+: 611.1695. Found: 611.1712.
Methyl 5-Acetamido-2,4,7,8,9-penta-O-acetyl-5-deoxy-3-O-
[2′-(2″,2″,2″-trichlorethoxycarbamido)-ethyl]-β-D-erythro-L-
gluco-non-2-ulopyranosonate (11). To a mixture of 9 (950 mg,
1.62 mmol) and Pd/C (10%, 920 mg) in methanol (20 mL) was
added 1 M aq sol of HCl (1.8 mL, 1.8 mmol). The mixture was stirred
and shaken for 16 h at room temperature in a Parr hydrogenation
2.03, 2.05, 2.11 (15H, 4 × s, NHCOCH3, OCOCH3 × 4), 3.46 (2H,
m, CH2b), 3.76−3.83 (1H, m, CHa), 3.80 (3H, s, COOCH3), 4.00−
4.05 (1H, m, CHa), 4.15 (1H, dd, J9a,8 6.6 Hz, J9a,9b 12.3 Hz, H-9a),
4.26 (1H, dd, J6,7 3.9 Hz, J6,5 8.7 Hz, H-6), 4.33 (1H, m, H-5), 4.55
(1H, dd, J9b,8 3.0 Hz, J9b,9a 12.3 Hz, H-9b), 4.72 (2H, AB q, J 12.0 Hz,
CH2c), 5.28 (1H, m, H-8), 5.46 (1H, dd, J7,6 3.9 Hz, J7,8 5.1 Hz, H-7),
5.55 (1H, br d, JNH,5 8.7 Hz, NHCOCH3), 5.78 (1H, dd, J4,5 6.6 Hz, H-
4), 6.17 (1H, br t, JNH,CH2 5.4 Hz, NHTroc). 13C NMR (75.5 MHz,
CDCl3): δ 20.7−20.9 (OCOCH3 × 4), 23.2 (NHCOCH3), 41.0 (Cb),
48.3 (C-5), 52.5 (COOCH3), 61.9 (C-9), 67.2 (C-7), 67.7 (C-4), 70.4
(C-8), 72.2 (Ca), 74.5 (Cc), 76.2 (C-6), 95.7 (CCl3), 136.7 (C-3),
142.3 (C-2), 154.8 (COOCH2CCl3), 161.2 (C-1), 170.0, 170.1, 170.6,
170.8 (NHCOCH3, OCOCH3 × 4). LRMS (ESI): m/z 729.6 (85%),
730.4 (30%), 731.1 (100%), 732.1 (30%), 733.1 (35%)
[ C 2 5 H 3 3 C l 3 N 2 O 1 5 + N a ] + . H R M S m / z c a l c d f o r
[C2 5 H3 3 3 5 Cl3 N2 NaO1 5 ]+ : 729.0839. Found 729.0842.
[C25H3335Cl237ClN2NaO15]+: 731.0809. Found: 739.0814.
E
DOI: 10.1021/acs.joc.5b00992
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(16) (a) Roy, R.; Laferriere, C. A. Carbohydr. Res. 1988, 177, c1.
(b) Chefalo, P.; Pan, Y.; Nagy, C.; Guo, Z. Glycoconjugate J. 2004, 20,
407. (c) Gan, Z.; Roy, R. Can. J. Chem. 2002, 80, 908. (d) Campo, V.
L.; Sesti-Costa, R.; Carneiro, Z. A.; Silva, J. S.; Schenkman, S.;
Carvalho, I. Bioorg. Med. Chem. 2012, 20, 145. (e) Xiong, D.-C.; Zhou,
Y.; Cui, Y.; Ye, X.-S. Tetrahedron 2014, 70, 9405.
(17) (a) Burkart, M. D.; Vincent, S. P.; Wong, C.-H. Chem. Commun.
1999, 1525. (b) Zbiral, E.; Brandstetter, H. H.; Christian, R.; Schauere,
R. Liebigs Ann. Chem. 1987, 1987, 781. (c) Chang, C.-W.; Norsikian,
S.; Guillot, R.; Beau, J.-M. Eur. J. Org. Chem. 2010, 2010, 2280.
(18) Morais, G. R.; Oliveira, R. S.; Falconer, R. A. Tetrahedron Lett.
2009, 50, 1642.
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra for all novel compounds and table of
optimization reactions for hydrolysis of 4 to give 3. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b00992.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: m.vonitzstein@griffith.edu.au. Tel: +61755527025.
Fax: +61755529040.
■
(19) Byramova, N. E.; Tuzikov, A. B.; Bovin, N. V. Carbohydr. Res.
1992, 237, 161.
(20) Kulikova, N. Y.; Shpirt, A. M.; Kononov, L. O. Synthesis 2006,
2006, 4113.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
M.v.I. gratefully acknowledges the Australian Research Council
(DP130102945) and the National Health and Medical
Research Council (1006618) for financial support. M.P. and
P.D.M. gratefully acknowledge Griffith University for the award
of Postgraduate Scholarships.
REFERENCES
■
(1) Varki, A.; Schauer, R. In Essentials of Glycobiology, 2nd ed. Varki,
A., Cummings, R. D., Esko, J. D., Eds.; Cold Spring Harbor Laboratory
Press: Cold Spring Harbor, NY, 2009; Chapter 14.
(2) (a) Chokhawala, H. A.; Huang, S.; Lau, K.; Yu, H.; Cheng, J.;
Thon, V.; Ziola, N. H.; Guerrero, J. A.; Varki, A.; Chen, X. ACS Chem.
Biol. 2008, 3, 567. (b) Stencel-Baerenwald, J. E.; Reiss, K.; Reiter, D.
M.; Stehle, T.; Dermody, T. S. Nat. Rev. Microbiol. 2014, 12, 739.
(c) Lai, J. C. C.; Garcia, J.-M.; Dyason, J. C.; Bohm, R.; Madge, P. D.;
̈
Rose, F. J.; Nicholls, J. M.; Peiris, J. S. M.; Haselhorst, T.; von Itzstein,
M. Angew. Chem., Int. Ed. 2012, 51, 2221. (d) Blaum, B. S.; Hannan, J.
P.; Herbert, A. P.; Kavanagh, D.; Uhrín, D.; Stehle, T. Nat. Chem. Biol.
2015, 11, 77. (e) Amonsen, M.; Smith, D. F.; Cummings, R. D.; Air,
G. M. J. Virol. 2007, 81, 8341.
(3) Sun, X.-L.; Kanie, Y.; Guo, C.-T.; Kanie, O.; Suzuki, Y.; Wong,
C.-H. Eur. J. Org. Chem. 2000, 2000, 2643.
(4) Okamoto, K.; Hasegawa, T.; Toyomaki, Y.; Yamakawa, M.;
Okukado, N. Chem. Pharm. Bull. 1992, 40, 2728.
(5) Prescher, H.; Schweizer, A.; Kuhfeldt, E.; Nitschke, L.; Brossmer,
R. ACS Chem. Biol. 2014, 9, 1444.
(6) Kim, J.-H.; Resende, R.; Wennekes, T.; Chen, H.-M.; Bance, N.;
Buchini, S.; Watts, A. G.; Pilling, P.; Streltsov, V. A.; Petric, M.;
Liggins, R.; Barrett, S.; McKimm-Breschkin, J. L.; Niikura, M.; Withers,
S. G. Science 2013, 340, 71.
(7) Dirr, L.; El-Deeb, I. M.; Guillon, P.; Carroux, C. J.; Chavas, L. M.;
von Itzstein, M. Angew. Chem., Int. Ed. 2015, 54, 2936.
(8) (a) Rudrawar, S.; Dyason, J. C.; Rameix-Welti, M.-A.; Rose, F. J.;
Kerry, P. S.; Russell, R. J. M.; van der Werf, S.; Thomson, R. J.;
Naffakh, N.; von Itzstein, M. Nat. Commun. 2010, 1, 113.
(b) Rudrawar, S.; Kerry, P. S.; Rameix-Welti, M.-A.; Maggioni, A.;
Dyason, J. C.; Rose, F. J.; van der Werf, S.; Thomson, R. J.; Naffakh,
N.; Russell, R. J. M.; von Itzstein, M. Org. Biomol. Chem. 2012, 10,
8628.
(9) Okamoto, K.; Kondo, T.; Goto, T. Bull. Chem. Soc. Jpn. 1987, 60,
631.
(10) Okamoto, K.; Goto, T. Tetrahedron 1990, 46, 5835.
(11) Fu, H.; Kondo, H.; Ichikawa, Y.; Look, G. C.; Wong, C.-H. J.
Org. Chem. 1992, 57, 7265.
(12) (a) Okamoto, K.; Kondo, T.; Goto, T. Chem. Lett. 1986, 15,
1449. (b) Okamoto, K.; Kondo, T.; Goto, T. Tetrahedron 1987, 43,
5909.
(13) Paulsen, H. Angew. Chem., Int. Ed. Engl. 1982, 21, 155.
(14) Banoub, J.; Boullanger, P.; Lafont, D. Chem. Rev. 1992, 92, 1167.
(15) Okamoto, K.; Kondo, T.; Goto, T. Bull. Chem. Soc. Jpn. 1987,
60, 637.
F
DOI: 10.1021/acs.joc.5b00992
J. Org. Chem. XXXX, XXX, XXX−XXX