Selective Catalytic Oxidation of Unprotected Carbohydrates

Article abstract of DOI:10.1021/acscatal.6b01501

The development of new strategies for the direct catalytic functionalization of unprotected carbohydrates would be an enabling advance for glycoscience. Herein we report that the catalytic oxidation of unprotected carbohydrates can be carried out selectively with [(neocuproine)Pd(OAc)]₂(OTf)₂ (1) to generate the 3-ketoses. Catalytic aerobic oxidation can be carried out with Pd loadings as low as 1% in the presence of phenolic additives. Catalytic oxidation of a variety of unprotected pyranosides in acetonitrile or acetonitrile/water with Pd catalyst 1 with either oxygen or benzoquinone selectively generates the 3-ketoses. Minor amounts of the 4-ketoses are formed competitively, particularly in the case of pyranosides bearing axial substituents at C4 of the pyranoside. Catalytic oxidations can also be carried out in trifluorethanol, but for pyranosides bearing axial substituents at C2 or C4, selective oxidation to the 3-ketose is accompanied by epimerization to afford the equatorial 3-ketoses. Catalytic oxidation of unprotected hexafuranosides or sialic acid derivatives occurs selectively at the exocyclic diol or triol in trifluoroethanol to generate exocyclic hydroxyketones.

Full text of DOI:10.1021/acscatal.6b01501

Research Article
pubs.acs.org/acscatalysis
Selective Catalytic Oxidation of Unprotected Carbohydrates
Kevin Chung and Robert M. Waymouth*
Department of Chemistry, Stanford University, Stanford, 94305 California, United States
*
S Supporting Information
ABSTRACT: The development of new strategies for the
direct catalytic functionalization of unprotected carbohydrates
would be an enabling advance for glycoscience. Herein we
report that the catalytic oxidation of unprotected carbohy-
drates can be carried out selectively with [(neocuproine)Pd-
(
OAc)] (OTf)2 (1) to generate the 3-ketoses. Catalytic
2
aerobic oxidation can be carried out with Pd loadings as low
as 1% in the presence of phenolic additives. Catalytic oxidation
of a variety of unprotected pyranosides in acetonitrile or
acetonitrile/water with Pd catalyst 1 with either oxygen or
benzoquinone selectively generates the 3-ketoses. Minor amounts of the 4-ketoses are formed competitively, particularly in the
case of pyranosides bearing axial substituents at C4 of the pyranoside. Catalytic oxidations can also be carried out in
trifluorethanol, but for pyranosides bearing axial substituents at C2 or C4, selective oxidation to the 3-ketose is accompanied by
epimerization to afford the equatorial 3-ketoses. Catalytic oxidation of unprotected hexafuranosides or sialic acid derivatives
occurs selectively at the exocyclic diol or triol in trifluoroethanol to generate exocyclic hydroxyketones.
KEYWORDS: selective oxidation, homogeneous catalysis, carbohydrates, palladium, solvent effects, aerobic, alcohol oxidation
25,26
INTRODUCTION
substrates to yield the hyroxyketones.
Early attempts in our
■
laboratories to oxidize glucose were unselective, but de Vries
and Minaard reported that oxidation of equatorial alkyl
glycosides with Pd catalyst 1 was highly chemoselective to
afford the 3-ketoses.
Herein we describe improved catalytic methods for the
selective catalytic oxidation of unprotected pyranosides with
Carbohydrates are the most abundant renewal carbon-based
1
resources on the planet, are key components of renewable
2
3,4
materials, and exhibit a diverse, critical role in life processes.
22
The utilization of carbohydrates for bulk and fine chemical
synthesis is well-known, but is limited by the formidable
challenges for the selective synthesis of regiochemically and
stereochemically defined sugars. Carbohydrate synthesis has
historically relied on sophisticated protecting group gymnastics
to isolate particular hydroxyl groups for synthetic elaboration.
O , studies to assess the influence of pyranose structure and
2
solvents on the stereo- and chemoselectivity, and selective
oxidations of exocyclic alcohols in hexofuranosides and sialic
acid derivatives.
5
−8
9,10
Exquisite stoichiometric
and catalytic strategies
have
been developed for the selective introduction and removal of
protecting groups; these methods have proven critical for the
development of sophisticated automated syntheses of oligo-
RESULTS AND DISCUSSION
■
1
1
Improved Methods for the Oxidation of Glycosides
saccharides.
The development of new strategies for the direct catalytic
with O . The cationic complex [(neocuproine)Pd-
2
12
(OAc)]
(OTf) (1) is an effective catalyst for the selective
2 2
functionalization of unprotected carbohydrates would be an
3
,13−15
oxidation of primary and secondary alcohols, vicinal diols,
enabling advance for glycoscience.
Notable advances
23−30
22
polyols,
and carbohydrates. Both air or quinones can be
include the chemoselective catalytic acylation, alkylation,
silylation, phosphorylation, or sulfation of hydroxyl
used as terminal oxidants, but aerobic oxidations require Pd
loadings of 10 mol %, due to the oxidative degradation of the
9
,13,15,16
groups.
Selective catalytic oxidations of unprotected
23,26,28,29
23,30,31
ligand.
Mechanistic studies
had implied that the
carbohydrates have historically been restricted to the
1
7
competitive oxidative degradation of the neocuproine ligand
was mediated by peroxides generated in the course of oxygen
enzymes, but recent advances in the selective catalytic
1
4,18
oxidations of primary C6 hydroxyls utilizing TEMPO,
secondary hydroxyls by Sn
or
3
1
19−21
22
reduction/hydrogen peroxide disproportionation. These
studies inspired us to investigate the addition of sacrificial
reductants to improve the catalyst lifetimes; these studies, to be
or Pd complexes, provide
exciting opportunities for the direct synthesis of natural and
non-natural aldoses and ketoses.
We have developed a cationic palladium catalyst
32
reported in detail elsewhere, revealed that the addition of
[
(neocuproine)Pd(OAc)] (OTf) (1) (neocuproine = 2,9-
2 2
23,24
dimethyl-1,10-phenanthroline)
that exhibits high chemo-
Received: May 28, 2016
selectivity for the oxidation of vicinal diols in polyhydroxylated
©
XXXX American Chemical Society
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a
Table 1. Preparative Scale Oxidation of Glycosides in Acetonitrile
a
b
c
d
Acetonitrile solvent, unless otherwise noted. 1 atm O . 1.5 equiv benzoquinone. Solvent = 10:1 CH CN:H O.
2
3
2
phenols enables catalytic oxidations with 1 to be carried out
terminal oxidant does not influence the chemoselectivity
utilizing 1.
with O at room temperature with much lower Pd loadings.
2
To test the effectiveness of this new protocol, we investigated
the influence of phenolic additives on the oxidations of a variety
The preparative scale oxidation of a variety of pyranosides
was carried out both with O /2,6-di-isopropylphenol (diPP)
2
2
2,33
of glycosides
.107 g (0.36 mmol) of octyl-β-D-glucopyranoside 3 with 1 mol
Pd catalyst 1 and 0.172 mmol of 2,5-diisopropylphenol in
with O (Table 1). The catalytic oxidation of
2
(Table 1, entries 1−4) and with benzoquinone (Table 1, entries
0
22,26
5
−8).
The mild conditions of this procedure are evident
%
from the selective aerobic oxidation of the 1-azido-β-D-
glucopyranoside 4 to afford the corresponding 3-ketose 4a in
acetonitrile at 60 °C occurred selectively at the 3-hydroxyl
position to afford the 3-ketose octyl-β-D-ribo-hexapyranoside-3-
ulose 3a, which could be isolated in 74% yield (eq 1). Further
6
0% isolated yield (Table 1, entry 3). This compound is rich in
chemical handles: alkyne addition to azides generates triazoles,
34−36
and azides serve as useful amine precursors.
The oxidation of 4-methoxyphenyl-β-D-glucopyranoside 5
(
Table 1, entry 4) afforded the corresponding 3-ketose 5a in
6
3
4% isolated yield. The high chemoselectivity for oxidation of
-hydroxyl is also observed for the 6-deoxy glucopyranoside 6
(
Table 1, entry 5) as well as methyl-α-D-xylopyranoside 7 to
generate the 3-ketoses in 71−73% isolated yields. As described
in detail below, these results imply that the selectivity for
oxidation at the 3-position is not due to the presence or
absence of a hydroxyl at the 6-position of the glycoside.
Additional preparative scale oxidations were carried out with
benzoquinone as the terminal oxidant. Oxidation of methyl-α-L-
fucopyranoside 8, possessing an axial hydroxyl at C4, afforded a
much lower isolated yield (31%, Table 1, entry 7) of the 3-
ketose 8a than that observed for the related all-equatorial
isomer 6-deoxy glucopyranoside 6 (71%, Table 1, entry 3).
Oxidation of methyl-α-L-rhamnopyranoside 9, containing an
axial hydroxyl at C2, yielded the 3-ketose 9a in 63% isolated
yield. In contrast, the related C2-axial methyl-α-D-mannopyr-
studies revealed that aerobic glycoside oxidation conducted
with diisopropylphenol loadings as low as 0.1 equiv relative to
substrate led to high conversion. This new oxidation protocol
with Pd catalyst 1 provides an expedient method for the
selective oxidation of a variety of pyranosides. Selective catalytic
oxidations can be carried out with low Pd loadings; the use of
O /phenol rather than quinones as terminal oxidants
2
considerably simplifies the isolation of the products. The high
regioselectivity for oxidation at the 3-position is similar to that
22
26
22
observed by Jag
̈
er et.al., indicating that the nature of the
anoside was reported to give a mixture of products.
4
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a
Table 2. Chemoselectivities for Oxidation of Glycosides in Acetonitrile
a
Reactions carried out at 50 °C in CD CN:D O 10:1, with 1.5 equiv of benzoquinone (vs substrate), with dimethylsulfone as internal standard.
3
2
b
c
d
e
0
.15 mmol scale. 0.10 mmol scale. Neat CD CN solvent. 1 mol % Pd with 1 atm O and 0.05 mmol of 2,5-di-isopropylphenol.
3
2
Oxidation of the conformationally constrained 1,6-anhydro-
to spectra of products isolated from the preparative experi-
ments, as well as those reported in the literature (unless
otherwise noted, see Supporting Information).
pyranoses 10 and 11, bearing an axial C3 hydroxyl, occurred
selectivity at the 3-position to afford the corresponding 3-
ketoses 10a and 11a in 66% and 91% isolated yields,
respectively. 1,6-Anhydropyranoses serve as useful synthetic
The oxidation of the equatorial glycosides methyl α-D-
glucopyranoside 12, 6-deoxy glucopyranoside 6, and methyl-α-
D-xylopyranoside 7 in 10/1 CD CN/D O at 50 °C with
3
7−41
intermediates.
Oxidation of 1,6-anhydropyranoses thus
3
2
provides a way to selectively oxidize mannose and galactose
derivatives at C3, as the unconstrained glycosides methyl-α-D-
mannopyranoside and methyl-α-D-galactopyranoside are not
benzoquinone as the terminal oxidant afforded the correspond-
ing 3-ketoses with selectivities of 76−88%, but also generated
the 4-ketoses as the predominant minor products (Table 2,
entries 1−3).
The oxidation of pyranosides containing an axial hydroxyl are
less selective, unless constrained as the bicyclic 1,6-
anhydropyranoses. Oxidation of methyl-α-L-fucopyranoside 8,
possessing an axial hydroxyl at C4, was unselective, affording a
mixture of the 3-ketose 8a and 4-ketose 8b in almost equal
yields (38% and 42%, respectively, Table 2, entry 7). In
addition, a minor amount of the epimerized 3-ketose 8c (2%)
could also be identified. Oxidation of methyl-β-D-arabinopyr-
anoside 13, bearing an axial hydroxyl at C4 but lacking a
substituent at C5, exhibited a modest but slightly higher
22
selectively oxidized with Pd catalyst 1.
Chemoselectivity of Pyranoside Oxidation: Identifica-
tion of Minor Products. To assess the influence of the
structure of the pyranoside on the oxidation chemoselectivity,
we carried out a series of experiments to identify the nature of
the major as well as minor products formed in the catalytic
oxidations of a variety of pyranosides with Pd catalyst 1. These
experiments were carried out at 50 °C in CD CN:D O 10:1, at
3
2
3
mol % Pd with 1.5 equiv of benzoquinone. The identities of
the major and minor products were determined by 2D NMR
directly from the crude reaction mixtures, and were compared
4
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selectivity for the 3-ketose 13a (51%) than 8, but also
generated a significant amount of the 4-ketose 13b (21%).
also oxidized selectively at C3 implies that the substituents at
C5 do not provide a steric bias against oxidation at C4. These
results are complementary to the selectivities observed with
catalytic Sn complexes, which typically generate the 4-ketose
from oxidation of the 4-axial hydroxyl of the galactopyrano-
26
We have previously reported that conformationally locked
cyclohexane-1,2-diols bearing both an axial and an equatorial
alcohol were preferentially oxidized at the axial alcohol. Thus,
the lower selectivity observed for the oxidation of C4 axial
pyranosides (8, 13) may be a consequence of a competitive
selectivity for oxidation of axial hydroxyls and what appears to
be an intrinsic preference for oxidation at the 3-position. The
low selectivity observed for the C4-axial pyranosides 8 and 13
20
sides. The conformationally constrained 1,6-anhydropyra-
noses 10 and 11 also oxidize selectively at the 3-position, even
though the C3 hydroxyl is constrained in an axial orientation.
The relatively modest range of pyranosides investigated
(Tables 1 and 2) does not provide a clear picture of the factors
which govern this remarkable selectivity for the regioselective
oxidation of unprotected glycosides at the C3 position.
22
correlates to observations by de Vries and Minnaard who had
reported that oxidation of methyl-α-D-galactopyranoside,
bearing an axial C4 hydroxyl group, was oxidized unselectively
with Pd catalyst 1.
2
6
Previous kinetic studies had implicated that the facile
oxidation of vicinal diols was due to the formation of chelating
Pd hydroxyalkoxides. The formation of chelating structures of
the Pd with the vicinal diols at C3 and C4 (Figure 1) could
In contrast, pyranosides such as 9, bearing an axial hydroxyl
at C2, do not undergo oxidation at the 2-position, but generate
a mixture of the 3-ketose 9a (61%) and the 4-ketose 9b (19%,
Table 2, entry 6). de Vries and Minnaard reported that methyl-
α-D-mannopyranoside, bearing an axial C2 hydroxyl group,
22
oxidizes unselectively to unidentified products. We propose
that the oxidation at the 2-position is disfavored electronically.
Previous studies had shown that the Pd catalyst 1 oxidizes
24−26
polyols selectively to hydroxy ketones,
but the resulting
hydroxyketones are resistant to further oxidation. This we
attribute to the reticence of Pd alkoxides α to a ketone or acetal
to undergo β-H elimination with Pd catalyst 1.
While oxidation of the conformationally constrained 1,6-
anhydropyranoses 10 and 11, bearing an axial C3 hydroxyl,
occurred selectivity at the 3-position with high selectivity (80%
and 90%, respectively, see Table S2 of Supporting Informa-
tion), the oxidation of 1,6-anhydro-β-D-glucopyranoside 14,
bearing axial hydroxyls at C2, C3, and C4, yielded the 3-ketose
in lower selectivity (58% NMR yield), and approximately 15%
of another product that could not be identified. The lower
selectivities observed for the all-axial substrate 14 may be a
consequence of all-trans arrangements of the vicinal diols,
which would preclude chelation of the vicinal diols to the Pd
center. We had previously proposed that chelation of vicinal
diols was responsible for the faster rate of vicinal diol oxidation
Figure 1. Proposed chelation and β-H elimination to generate 3-
ketose (a) or 4-ketose (b).
rationalize the competitive oxidation at the C3 and C4
hydroxyls. Nevertheless, the stereoelectronic factors which
favor β-H elimination at the C3 C−H bond (Figure 1a) remain
unclear and are the subject of ongoing studies.
Oxidation in Fluorinated Alcohol Solvents. The high
solubility of glycosides in fluorinated alcohols, the resistance of
these solvents to oxidation, and their H-bonding ability
prompted us to investigate these solvents for the oxidation of
unprotected carbohydrates. Catalytic oxidation of the glucopyr-
anoside 12, 6-deoxy-α-D-glucopyranoside 6, and methyl-α-
xylopyranoside 7 in 2,2,2-trifluoroethanol (TFE) afforded a
slightly higher selectivity (3−6% improvement) for C3
26
relative to that of alcohols lacking a vicinal OH group;
nevertheless, the Pd catalyst 1 is capable of oxidizing trans
diaxial vicinal diols, albeit with lower selectivity than axial−
22
oxidation relative to the analogous oxidation in acetonitrile/
water (Tables 2 and 3). In contrast, oxidation of methyl-α-L-
fucopyranoside 8 in TFE afforded, as the major product, the
epimerized 3-ketose 8c (73% NMR yield) along with the 4-
ketose 8b (11%), and only a minor amount of the
nonepimerized 3-ketose 8a (3%). Preparative oxidation of 8
on a 1.7 mmol scale with 3 mol % Pd in trifluoroethanol
afforded the epimerized ketose 8c as a crystalline solid in 64%
isolated yield after 14 h at 50 °C (Table 3, entry 4).
26
equatorial vicinal diols.
The results of Tables 1 and 2 reveal that oxidation of
pyranosides bearing equatorial hydroxyls occurs selectively to
generate the 3-ketoses in isolated yields of 60−74%. The high
selectivity for oxidation of equatorial pyranosides at the 3-
position is accompanied by a minor amount of oxidation at the
4-position, which depends on the substituent pattern of the
pyranoside, but does not appear to be influenced by the nature
of the terminal oxidant (O vs benzoquinone) or by the
A similar selectivity for 8c was observed when the oxidation
was carried out in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP).
Preliminary studies reveal that when the catalytic oxidation of
the 4-axial fucopyranoside 8 is carried out in deuteriated
DOCH CF (TFE-d ), no deuterium is incorporated into the
2
presence or absence of water in CH CN (see Supporting
3
Information). For unprotected alkyl or azido pyranosides
containing equatorial hydroxyl substituents, the selectivities for
the 3-ketose are high (70−88%); for pyranosides containing
axial hydroxyl substituents at C2 or C4, the selectivity for the 3-
ketoses are lower, and in the case of methyl-α-L-fucopyranoside
2
3
1
epimerized ketose 8c. This latter observation would imply that
epimerization is not a consequence of keto−enol equilibration
of the 3-ketose, but further studies are underway to address the
mechanism of this oxidation−epimerization pathway.
8, bearing an axial hydroxyl at C4, there is a slight preference
for the 4-ketose. The high selectivity for oxidation to the 3-
ketose is not restricted to equatorial glucopyranosides or 2-
The one-step epimerization and oxidation of 8 provides an
attractive method of generating 8c, the equatorial keto-
22
desoxyglucopyranosides, but extends to the 6-deoxypyrano-
sides 2 and xylopyranosides 7 as well. The observation that 6-
deoxy glucopyranoside 6 and methyl-α-D-xylopyranoside 7 are
42
glycoside of the rare sugar 6-deoxy-L-glucose (L-quinovose).
Treatment of 8c with hydroxylamine produced the oxime 8d as
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a
Table 3. Chemoselectivities for Oxidation of Glycosides in Fluorinated Alcohol Solvents
a
Reactions carried out at 50 °C in TFE with 0.1 mmol of substrate, at 3 mol % Pd with 1.5 equiv of benzoquinone (vs substrate), with
dimethylsulfone as internal standard.
a mixture of E/Z isomers in 79.6% yield. Similar oximes have
been used to form N−O glycosidic linkages, motifs present in
substituted glycoside 18 preferentially generated the 3-ketose
18a, but upon silica gel chromatography, partial elimination of
the azide occurred to afford a mixture of 18a and α,β-
unsaturated pyrone 18b.
43−45
the antitumor agents calicheamicin and esperamicin.
Addition of methoxylamine to 8c generated the methyl oxime
e as a mixture of E/Z isomers, which was cleanly
hydrogenated to the amine 8f. The peracetylated aminosugar
8
In trifluoroethanol, oxidation of a variety of pyranosides
bearing axial hydroxyls occurs selectively to give the epimerized
3-ketoses (Table 4, entries 5−7). Oxidation of methyl-α-
galactopyranoside 20 in TFE at 50 °C affords methyl-α-D-ribo-
hexanpyranoside-3-ulose 12a in 70% isolated yield. In
acetonitrile/water, oxidation of methyl-α-galactopyranoside 19
8
g was also efficiently formed (eq 2).
22
was reported to be unselective yielding a uncharacterized
mixture of products, whereas oxidation in TFE affords 12a in
excellent yield, albeit as the epimerized ketose. The ketose 12a
can also be generated selectively by oxidation of methyl α-D-
22
glucopyranoside 12 with catalyst 1 in acetonitrile/water (see
also Table 2, entry 1).
Similarly, oxidation of other pyranosides bearing axial C4
hydroxyls in TFE, such as methyl-α-L-fucopyranoside 8 (eq 2)
or methyl-β-D-arabinopyranoside 13, selectively yields the
epimerized ketoses 8c and 13a in isolated yields of 64% and
5
6%, respectively. Under similar conditions, methyl-α-L-
Preparative Oxidations in Trifluoroethanol. The different
rhamnopyranoside 9, a glycoside bearing a C2 axial hydroxyl,
was also preferentially converted to the epimerized ketose 8c in
selectivities observed in TFE, coupled with the high solubility
of a series of sugars in this solvent, encouraged us to investigate
a series of preparative-scale oxidations in TFE (Table 4).
Initially, aerobic conditions were investigated; while the use of
4
5% isolated yield (Table 3, entry 7). The formation of the
ketose 8c from oxidation of either 8 or 9 with Pd catalyst 1 in
TFE indicates that the oxidation of pyranosides bearing axial
substitutuents at the C2 and C4 positions is selective for the 3-
ketose, but is accompanied by epimerization to generate the
equatorial ketoses.
The selective oxidation/epimerization of either L-fucopyrano-
side 8 or L-rhamnopyranoside 9 provides a selective synthesis
of 8c, the 3-ketose of 6-deoxy-L-glucose (L-quinovose).
2
,6-diisopropylphenol as an additive was similarly able to
increase the yields of the C3 oxidized ketose, the overall yields
using aerobic conditions in TFE were moderate at best (see
Table S3 in the Supporting Information). The benzoquinone-
assisted oxidation of methyl 2-acetamido-2-deoxy-α-D-glucopyr-
anoside 16 or methyl 2-acetamido-2-deoxy-β-D-glucopyrano-
side 17 in TFE afforded the corresponding 3-ketoses 16a and
42
1
7a in 63% or 69% isolated yields, respectively. The oxidation
Moreover, selective oxidation of methyl-β-D-arabinopyranoside
13 in TFE affords 13a, the 3-ketose of L-xylopyranoside. Thus,
this oxidation, epimerization sequence provides a strategy for
22
of 16 in acetonitrile/water has previously been reported, but
we were unable to effect this oxidation efficiently in this solvent
42
mixture. However, oxidation of 16 in TFE at 60 °C gave 16a in
generating the rare 3-ketoses of the L-sugars.
1
77% by H NMR after just 1 h, and a 63% isolated yield when
The high selectivity of Pd catalyst 1 is also manifested in the
selective oxidation of exocyclic polyols in hexafuranosides and
sialic acid derivatives (Table 4, entries 8−10). Oxidation of the
unprotected octyl-β-D-galactofuranoside 21 at 50 °C with Pd
catalyst 1 in TFE occurred selectively at the exocyclic secondary
alcohol to provide 21a in 73% isolated yield. While C5 hydroxyl
oxidations of hexofuranosides have been demonstrated on
carried out for 3.5 h (Table 4, entry 1). The β-anomer 17
behaved similarly and could be oxidized to the 3-ketose in 69%
isolated yield, which slowly dimerized.
ately after oxidation with acetic anhydride affords the stable
peracylated derivative of ketose 17a in solid form, with 37%
overall yield over two steps. Oxidation of the acetamido-azido-
20,26
Acylation immedi-
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a
Table 4. Preparative Scale Oxidation of Glycosides in Trifluoroethanol
a
b
1
.5 equiv of benzoquinone unless otherwise stated. Combined yield of mixture.
4
7,48
acetonide protected systems (Table 3, entry 8),
the
at C4 of the pyranoside. In trifluoroethanol solvent, catalytic
oxidation of pyranosides bearing axial substituents at the C2
and C4 positions is selective for the 3-ketose, but is
accompanied by epimerization to generate the equatorial
ketoses. Catalytic oxidation of unprotected hexafuranosides or
sialic acid derivatives occurs selectively at the exocyclic diol or
triol to generate exocyclic hydroxyketones. These results reveal
that catalytic oxidations of unprotected carbohydrates, long
restricted to the enzymes, can now be carried out efficiently
with appropriate homogeneous catalysts.
selective oxidation of the exocyclic alcohol in the presence of
the unprotected vicinal diol of 21 is noteworthy.
Oxidation of N-acetylneuraminic acid methyl ester 22 occurs
selectively at C8 to afford the exocyclic hydroxyketone 22a in
9% isolated yield. The selective oxidation of 22 is remarkable,
given that it contains multiple exocyclic secondary alcohols as
well as a C3 hydroxyl, all of which are known to be rapidly
The neuraminic (sialic) acids
exhibit diverse biological roles and are important components
of the oligosaccharide chains of mucins, glycoproteins and
glycolipids. In addition, natural and artificial sialic acid
derivatives have shown antiviral activity through neuraminidase
4
25,26
oxidized in other contexts.
4
6
ASSOCIATED CONTENT
■
*
S
Supporting Information
4
6−48
inhibition.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b01501.
CONCLUSION
Materials and methods, synthetic procedures, character-
ization of products, NMR spectra, and chromatograms
■
In summary, we describe a method for the selective catalytic
oxidation of unprotected carbohydrates with Pd loadings as low
as 1−2% for Pd catalyst 1. Catalytic oxidation of a variety of
unprotected pyranosides in acetonitrile or acetonitrile/water
with Pd catalyst 1 with either oxygen or benzoquinone
selectively generates the 3-ketoses. The selectivity for the 3-
ketoses is highest for equatorial glycosides; the 4-ketoses are
formed competitively, particularly in the case of axial hydroxyls
(PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: waymouth@stanford.edu.
■
*
Notes
The authors declare no competing financial interest.
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(
35) Malkinson, J. P.; Falconer, R. A.; Toth, I. J. Org. Chem. 2000, 65,
ACKNOWLEDGMENTS
■
5
(
1
249−5252.
36) Gyorgydeak
993, 12, 139−163.
This work was supported by the Department of Energy (DE
SC0005430). K.C. acknowledges a Stanford Graduate Fellow-
ship.
̈
́ ́
, Z.; Szilagyi, L.; Paulsen, H. J. Carbohydr. Chem.
(37) Chang, K.-L.; Zulueta, M. M. L.; Lu, X.-A.; Zhong, Y.-Q.; Hung,
S.-C. J. Org. Chem. 2010, 75, 7424−7427.
(
38) Ko, Y.-C.; Tsai, C.-F.; Wang, C.-C.; Dhurandhare, V. M.; Hu, P.-
REFERENCES
■
L.; Su, T.-Y.; Lico, L. S.; Zulueta, M. M. L.; Hung, S.-C. J. Am. Chem.
(
1) Klemm, D.; Heublein, B.; Fink, H. P.; Bohn, A. Angew. Chem., Int.
Ed. 2005, 44, 3358−3393.
2) Huber, T.; Muessig, J.; Curnow, O.; Pang, S.; Bickerton, S.;
Staiger, M. P. J. Mater. Sci. 2012, 47, 1171−1186.
3) Hudak, J. E.; Bertozzi, C. R. Chem. Biol. 2014, 21, 16−37.
4) Kiessling, L. L.; Splain, R. A. Annu. Rev. Biochem. 2010, 79, 619−
Soc. 2014, 136, 14425−14431.
(39) Lepage, M. L.; Bodlenner, A.; Compain, P. Eur. J. Org. Chem.
(
2
013, 2013, 1963−1972.
40) Lee, J.-C.; Tai, C.-A.; Hung, S.-C. Tetrahedron Lett. 2002, 43,
51−855.
41) Zottola, M.; Rao, B. V.; Fraser-Reid, B. J. Chem. Soc., Chem.
Commun. 1991, 969−970.
42) Frihed, T. G.; Bols, M.; Pedersen, C. M. Chem. Rev. 2015, 115,
(
8
(
(
(
6
53.
(
3
(
8
5) Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry 2000, 11,
85−387.
6) Franca
816−8819.
7) Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang, B.-J.; Hsu, C.-Y.;
Hung, S.-C. Angew. Chem., Int. Ed. 2005, 44, 1665−1668.
8) Dong, H.; Zhou, Y.; Pan, X.; Cui, F.; Liu, W.; Liu, J.; Ramstro
O. J. Org. Chem. 2012, 77, 1457−1467.
9) Taylor, M. In Topics in Current Chemistry; Springer: Berlin, 2015;
(
3
(
615−3676.
̧ is, A.; Urban, D.; Beau, J.-M. Angew. Chem. 2007, 119,
43) Yu, J.; Sun, J.; Yu, B. Org. Lett. 2012, 14, 4022−4025.
44) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton,
(
(
G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464−3466.
(
M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem.
Soc. 1987, 109, 3462−3464.
(
45) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi,
(
̈
m,
(
46) Luchansky, S. J.; Goon, S.; Bertozzi, C. R. ChemBioChem 2004,
pp 1−31.
5
(
, 371−374.
(
(
7
(
(
(
2
(
(
10) Taylor, M. S. Acc. Chem. Res. 2015, 48, 295−305.
47) Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.;
11) Seeberger, P. H.; Werz, D. B. Nat. Rev. Drug Discovery 2005, 4,
Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai,
51−763.
C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681−
12) Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193−205.
13) Saloranta, T.; Leino, R. Synlett 2015, 26, 421−425.
6
90.
(48) Herrler, G.; Gross, H.; Imhof, A.; Brossmer, R.; Milks, G.;
14) Bragd, P. L.; van Bekkum, H.; Besemer, A. C. Top. Catal. 2004,
Paulson, J. J. Biol. Chem. 1992, 267, 12501−12505.
7, 49−66.
15) Jager, M.; Minnaard, A. J. Chem. Commun. 2016, 52, 656−664.
16) Chung, M. K.; Schlaf, M. J. Am. Chem. Soc. 2005, 127, 18085−
1
8092.
(
1
(
17) Freimund, S.; Huwig, A.; Giffhorn, F.; Ko
998, 4, 2442−2455.
18) Breton, T.; Bashiardes, G.; Leger, J.-M.; Kokoh, K. B. Eur. J. Org.
̈
pper, S. Chem. - Eur. J.
Chem. 2007, 2007, 1567−1570.
(
(
(
(
19) Tsuda, Y. Yuki Gosei Kagaku Kyokaishi 1997, 55, 907−919.
20) Muramatsu, W. Org. Lett. 2014, 16, 4846−4849.
21) David, S. Prep. Carbohydr. Chem. 1997, 69−83.
̈
22) Jager, M.; Hartmann, M.; de Vries, J. G.; Minnaard, A. J. Angew.
Chem., Int. Ed. 2013, 52, 7809−7812.
23) Conley, N. R.; Labios, L. A.; Pearson, D. M.; McCrory, C. C. L.;
Waymouth, R. M. Organometallics 2007, 26, 5447−5453.
24) De Crisci, A. G.; Chung, K.; Oliver, A. G.; Solis-Ibarra, D.;
Waymouth, R. M. Organometallics 2013, 32, 2257−2266.
25) Painter, R. M.; Pearson, D. M.; Waymouth, R. M. Angew. Chem.,
Int. Ed. 2010, 49, 9456−9459.
26) Chung, K.; Banik, S. M.; De Crisci, A. G.; Pearson, D. M.; Blake,
(
(
(
(
T. R.; Olsson, J. V.; Ingram, A. J.; Zare, R. N.; Waymouth, R. M. J. Am.
Chem. Soc. 2013, 135, 7593−7602.
(
27) Pearson, D. M.; Waymouth, R. M. Organometallics 2009, 28,
3
(
896−3900.
28) Pearson, D. M.; Conley, N. R.; Waymouth, R. M. Organo-
metallics 2011, 30, 1445−1453.
29) Blake, T. R.; Waymouth, R. M. J. Am. Chem. Soc. 2014, 136,
252−9255.
30) Ingram, A. J.; Solis-Ibarra, D.; Zare, R. N.; Waymouth, R. M.
Angew. Chem., Int. Ed. 2014, 53, 5648−5652.
31) Ingram, A. J.; Walker, K. L.; Zare, R. N.; Waymouth, R. M. J.
Am. Chem. Soc. 2015, 137, 13632−13646.
32) Ho, W. C.; Chung, K.; Ingram, A. J.; Waymouth, R. M.
Organometallics 2016, manuscript in preparation.
33) Armenise, N.; Tahiri, N.; Eisink, N. N. H. M.; Denis, M.; Jager,
M.; De Vries, J. G.; Witte, M. D.; Minnaard, A. J. Chem. Commun.
016, 52, 2189−2191.
34) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002,
7, 3057−3064.
(
9
(
(
(
(
2
(
6
4
659
DOI: 10.1021/acscatal.6b01501
ACS Catal. 2016, 6, 4653−4659