1,2-cis Alkyl glycosides: Straightforward glycosylation from unprotected 1-thioglycosyl donors

Article abstract of DOI:10.1039/c4ob00626g

A 1,2-cis-alkyl glycosidation protocol that makes use of unprotected phenyl 1-thioglycosyl donors is reported. Glycosylation of various functionalized alcohols was accomplished in moderate to high yield and selectivity to give the 1,2-cis-glycosides. In order to quickly develop optimum glycosylation conditions, an FIA (flow injection analysis)-ESI-TOF-MS method was developed that enabled rapid and quantitative evaluation of yield on small scale. This methodology, coupled with NMR spectroscopy, allowed for rapid evaluation of the overall reactions.

Full text of DOI:10.1039/c4ob00626g

Organic &
Biomolecular Chemistry
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1,2-cis Alkyl glycosides: straightforward
glycosylation from unprotected 1-thioglycosyl
donors†
Cite this: Org. Biomol. Chem., 2014,
12, 5182
Bo Meng, Zhenqian Zhu and David C. Baker*
A 1,2-cis-alkyl glycosidation protocol that makes use of unprotected phenyl 1-thioglycosyl donors is
reported. Glycosylation of various functionalized alcohols was accomplished in moderate to high yield
and selectivity to give the 1,2-cis-glycosides. In order to quickly develop optimum glycosylation con-
ditions, an FIA (flow injection analysis)–ESI-TOF-MS method was developed that enabled rapid and quan-
titative evaluation of yield on small scale. This methodology, coupled with NMR spectroscopy, allowed for
rapid evaluation of the overall reactions.
Received 24th March 2014,
Accepted 3rd June 2014
DOI: 10.1039/c4ob00626g
www.rsc.org/obc
separation processes, and low yields and poor stereoselec-
tivities. Ether protecting groups, most often the benzyl group,
I. Introduction
As essential components in the cell membrane, carbohydrates are routinely used for protecting free hydroxyl groups in the
and glycoconjugates serve many protective, stabilizing, organ- synthesis of 1,2-cis-glycosides,14 but benzyl deprotection by H2/
izational, barrier, and recognition functions.1 The chemical Pd will destroy a number of groups (alkene, alkyne, nitro,
synthesis of these glycoconjugates, including proteoglycans, halogen) on functionalized alkyl glycosides.15 The elegant
glycolipids, and glycoproteins, is in great demand for biologi- intramolecular aglycon delivery (IAD) approach offers a stereo-
cal studies of their functions as cell-wall components that are specific 1,2-cis-glycosidic synthesis, albeit from selectively pro-
collectively termed the glycocalyx. Anomerically pure alkyl gly- tected intermediates.16–19
cosides serving as fundamental building blocks are in demand
In principle, many of these issues can be circumvented
to achieve the stereoselective synthesis of these cell-wall struc- through conversion of an unprotected glycosyl donor directly
tures. Some alkyl glycosides, such as propargyl2 and allyl3 gly- into the desired 1,2-cis-alkyl glycosides. Glycosylation by an
cosides are essential components in simple approaches for the unprotected sugar donor has several practical values:20 the
construction of microarrays4,5 and glycodendrimers.6
often tedious protection and deprotection process can be
Generally, 1,2-trans-alkyl glycosidation can be reliably avoided;21 unprotected donors possess higher reactivity com-
achieved via neighboring-group participation of a C-2 acyl pared to O-acyl-protected donors, and the better solubility of
group on a glycosyl donor, while stereochemical control for unprotected donors in short-chain alcohols (the acceptors)
1,2-cis-alkyl glycosidation can be challenging.7 The convention- enables glycosylation at lower temperatures, which reduces the
al Fischer glycosidation reaction, a straightforward way to formation of by-products.
afford short-chain, uncomplicated, thermodynamically favored
Mamidyala and Finn have reported glycosylation using
1,2-cis-alkyl glycosides, has been improved by using various unprotected alkynyl donors and AuCl3 as an effective activa-
acid catalysts,8–10 microwave irradiation,11 ultrasonication,12 tor.22,23 Very recently, Nitz and co-workers reported glycosida-
and ionic liquids.13 Since free sugars have limited solubility in tion in relatively good yields using a protecting-group-free
longer chain alcohols (acceptors), harsh conditions (e.g., high protocol with 1-p-toluenesulfonyl hydrazide and glycosyl chlor-
temperature, microwave, ultrasonication) are often required to ide donors; however, anomeric selectivities were generally
push the reaction, which results in decomposition of the pro- lacking.24 Among the various classes of glycosyl donors,
ducts,8 formation of various side products, time-consuming phenyl 1-thioglycosyl compounds have been regarded as ideal
choices for donor precursors (including precursors for light-
induced glycosidation21) because they are stable, easily syn-
Department of Chemistry, The University of Tennessee, Knoxville, Tennessee 37996-
thesized, and for the most part, crystalline.25 Herein, we report
1600, USA. E-mail: dcbaker@utk.edu
†Electronic supplementary information (ESI) available. See DOI:
a 1,2-cis-alkyl glycosidation protocol that makes use of un-
protected phenyl 1-thioglycosyl donors.21
10.1039/c4ob00626g
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neither TMSOTf nor NIS alone was able to trigger the glycosyla-
tion reaction (entries 11 and 12).
II. Results and discussion
A. Glycosidations
It is presumed that TMSOTf in excess alcoholic acceptor–
Phenyl 1-thio-β-D-galactopyranoside (1a)26 and propargyl solvent is hydrolyzing to trifluoromethanesulfonic acid (TfOH)
alcohol (2a) were selected as the unprotected glycosyl donor and that the reagent provides a metered amount of acid.
and acceptor-solvent, respectively, for the model glycosylation Varying amounts of TMSOTf were added to the reaction
reaction (Table 1). Initially, the reaction was carried out mixture of 1a and 2a as described in Table 1. When the
between 1a and dry 2a (40 equiv.) under the activation of amount of TMSOTf was increased from 0.2 to 0.4 equiv., no
N-iodosuccinimide (NIS)–trimethylsilyl triflate (TMSOTf). The improvement in yield or selectivity was observed; at 1.0 equiv.,
desired product was obtained in respectable yield and with by-product formation became evident, and both yield and
high α stereoselectivity (Table 1, entry 1). TLC analysis of the stereoselectivity were decreased to 52% and 5 : 1, respectively.
crude product showed only the desired α,β anomers. Further Addition of 2.0 equiv. of TMSOTf resulted in a series of by-pro-
experiments revealed other 1,2-cis-glycosidations that used the ducts as observed on TLC.
Lewis acids BF3·OEt2 and TfOH27 provided similar yields and
7
9
B. Rapid high-throughput screening of reactions
stereoselectivities, while H2SO4·SiO2 gave a lower yield (a
result also reported from another laboratory28) but higher
stereoselectivity (compare entries 2–4). We surmise that the
results may be due to the heterogeneity of the H2SO4·SiO2 cata-
lyst. The bisulfate counterion would be trapped in the silica
gel matrix, leading to the formation of a loosely solvent-separ-
ated ion pair (SSIP) between the bisulfate counterion and the
oxocarbenium ion, suggesting a unimolecular (SN1) favored
transition state and better α selectivity due to the anomeric
effect.29–31 We also examined the activation by Lewis acids and
N-bromosuccinimide (NBS). As anticipated, relatively lower
yields and stereoselectivities were observed (entries 5 and 6),
which could be attributed to the diminished electrophilic pro-
perties of the bromonium ion. Moreover, experimentation
showed that glycosylation was most favored when the amount
of alcohol was in the range of 40–60 equiv. (entries 1–3 and 9
vs. entries 7–8 and 10). Experiments further demonstrated
In order to rapidly evaluate and identify optimum glycosylation
conditions for a number of reactions, we adapted the concept
of a high-throughput screening using mass spectrometry (MS)
similar to that reported by Ito and co-workers, who employed
MALDI-TOF-MS.32,33 In our reactions with small molecules, we
used a coupled flow-injection system with ESI-TOF-MS (FIA–
ESI-TOF-MS) that enabled quantitative evaluation of glycosyla-
tion yield with products of MW < 500 amu. (For details, see
ESI,† section 1.) Furthermore, the method provided a more
accurate estimation of yield in two ways: (1) an average value
from a certain volume of sample (e.g., 2.5 μL with our flow-
injection equipment) was evaluated rather than a tiny spot
excited by the laser on MALDI. (2) Integration of the ion inten-
sity peaks was used to calculate yield instead of the m/z peak
height as in the MALDI method.32,33
In order to provide an internal standard for the FIA–ESI-
TOF-MS studies, propargyl α,β-D-galactopyranoside (3a,
Scheme 1) was acetylated with Ac2O-d6 to afford the per-deuter-
ated glycosides; the α anomer (4) was separated out by column
chromatography. While it is known that the ionizing pro-
perties of deuterated and nondeuterated glycosides are nearly
identical.,32 the fact was confirmed in this study specifically
for these compounds. Details of the calibration work are pro-
vided in the ESI,† section 2. The FIA–ESI-TOF-MS responses
were found essentially the same for either the 1H- or 2H-
labeled compounds, thus facilitating a relatively uncompli-
cated rapid analysis of the reactions.
Table 1 Optimization of reaction conditionsa
Halogen
source
Propargyl alcohol
(mol equiv.)
Yieldb
(%)
Entry
Lewis acid
α : βc
1
2
3
4
5
6
7
8
TMSOTf
BF3·OEt2
TfOH
NIS
NIS
NIS
NIS
NBS
NBS
NIS
NIS
NIS
NIS
None
NIS
40
40
40
40
40
40
20
30
60
100
40
40
75
74
76
52
59
38
50
53
76
58
0
10 : 1
10 : 1
9 : 1
15 : 1
5 : 1
5 : 1
7 : 1
10 : 1
10 : 1
11 : 1
—
C. Optimization studies and scope of the reaction
H2SO4·SiO2
TMSOTf
BF3·OEt2
TMOSTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
None
Optimization studies were conducted as in the following para-
graphs in which several solvents were examined. The con-
9
10
11
12
0
—
a The reaction was conducted using 0.37 mmol of 1a, 1.03 mmol (2.8
equiv.) of NIS–NBS, and 0.07 mmol (0.20 equiv.) of Lewis acid for 2 h.
b The yield was determined after acetylation of 3a by FIA–ESI-TOF-MS.
c The anomeric ratio was determined by integration of H-1 in the 1H
NMR spectrum of the crude product 3a.
Scheme 1 Synthesis of deuterated glycoside substrate as the internal
standard.
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ditions were those of Table 1, with variations. The effect of alcohol and account for the generally higher cis-selectivities in
N,N-dimethylformamide (DMF) in the solvent on stereo- the other examples. The role of such H-bonding in stereoselec-
selective α-glycosylation has been well documented,34 and we tion in glycosylation has been addressed in numerous
anticipated that adding a catalytic amount of DMF might articles.37–41 We, however, hasten to add that other factors,
promote the formation of the 1,2-cis-glycosidic bond. After including a change in the anomeric effect, may also contribute
screening with added DMF, other solvents, including CH2Cl2, to the observed change of the α : β ratio in the products.
THF and Et2O (0.2 equiv.), were examined; however, no
obvious improvement in yield or α selectivity was observed
with any of these additives, and a further increase of the
amount of solvent added (6 equiv.) led to a general decrease in
stereoselectivity and yield, which indicates that a neat alcohol
environment is essential for optimum glycosylation under
these conditions. Details of the above studies are provided in
the ESI, Table S2.†
D. Conclusions
In summary, a facile and general strategy for the direct con-
struction of 1,2-cis-alkyl glycosides has been developed. Glyco-
sylations between several unprotected phenyl 1-thioglycosyl
donors and alcohols bearing various functional groups pro-
ceeds smoothly to give satisfying yields and 1,2-cis selectivity.
Use of an FIA–ESI-TOF-MS/NMR protocol facilitated rapid and
efficient optimization of conditions. We anticipate that the
synthetic procedures described herein will find application in
a number of areas where enhanced 1,2-cis selectivity in glyco-
sylated products is required.
The reaction was performed on 1a as in Table 1, entry 1,
and the results were evaluated with different reaction times.
Over a time course of 5 min to 2 h, essentially no changes in
anomeric ratios of 3a were observed. Yields, however, showed a
trend of increasing with time up to 2 h as follows: 5 min, 67%,
α/β 9.8 : 1; 30 min, 71%, α/β 9.8 : 1; 2 h, 75%, α/β 10 : 1. Reac-
tion temperatures were also scrutinized. When NIS and
TMSOTf were added at −30 °C, the solution turned maroon
(black with propargyl alcohol, entry 1). When NIS and TMSOTf
were added at −10 to 0 °C, the yield decreased slightly with a
little faded maroon or black color obtained. But when NIS and
TMSOTf were added at room temperature, the solution turned
yellow, and a low yield (<30%) was obtained with most of the
donor unreacted. The α/β selectivity remained essentially the
same over these temperature ranges. For some alcohols so
designated in Table 2 (i.e., those with higher mp’s), a tempera-
ture range of −10 to 0 °C was selected (see Table 2, entries 2
and 5–8).
With the appropriate conditions for 1,2-cis-alkyl glycosida-
tion in hand, we investigated the scope of the reaction with
several unprotected glycosyl donors and alcohols bearing
various functional groups (see Table 2). The stereoselectivity of
glycosylation with unprotected D-glucose, D-mannose and di-
saccharide donors and propargyl alcohol spanned from
modest to high (Table 2, entries 1, 9–13). It is noteworthy that
the major product from phenyl 1-thio-α-D-mannoside is the
β (cis) anomer (Table 2, entry 10) that is formed. Glycosylation
with various functionalized alcohols was accomplished
without difficulty (Table 2, entries 2–8). A variety of groups on
alcohols were tolerated to provide the corresponding 1,2-cis-
substituted-alkyl glycosides. These results indicate the general-
ity and applicability of the present glycosylation method.
A mechanistic explanation of the observed results from
these glycosylations is no doubt complex, as numerous
alcohol-substrate-Lewis acid reagent associations (including
H-bonding interactions) are possible and difficult to sort out.
We presume the role of NIS–TMSOTf follows that established
for the activation of related systems.35,36 Perhaps noteworthy is
the fact that we observed (Table 2, entry 13) that a 2-deoxy-1-
III. Experimental section
A. General methods
All chemicals were purchased as reagent grade and used
without further purification, unless otherwise noted. Alcohols
that were opened and stored for a period of time were pre-
dried by Drierite® (anhyd calcium sulfate). Reagent grade
dichloromethane (CH2Cl2), tetrahydrofuran (THF), ether (Et2O),
methanol (MeOH), N,N-dimethylformamide (DMF) and toluene
were obtained from the Pure-Solv (Innovation Technologies)
solvent system that uses alumina columns except for DMF,
which was dried over a column of 5 Å molecular sieves. Pyridine
was distilled over CaH2 prior to use. All reactions were performed
under anhydrous conditions unless otherwise noted. Reactions
were monitored by thin-layer chromatography (TLC) on silica
gel precoated aluminum plates. Zones were detected by UV
irradiation using a 254 nm lamp and/or by heat/charring with
p-anisaldehyde–sulfuric acid development reagent.42 Column
chromatography was performed on silica gel (40–63 μm). Optical
rotation values were obtained at the sodium D line using a
Perkin-Elmer 241 polarimeter. 1H (500 MHz) and 13C NMR
(125 MHz) spectra were recorded at room temperature with a
Varian Inova 500 MHz instrument. Chemical shifts are reported
1
in δ-units (ppm) relative to the residual H CDCl3 at δ 7.26 ppm
and 13C at δ 77.16 ppm. All two-dimensional experiments
(gCOSY, gHSQC and gHMBC) were recorded on the same instru-
ment using Varian protocols. Mass spectrometric analysis was
performed on a QSTAR Elite quadrupole time-of-flight (QTOF)
mass spectrometer with an ESI source.
B. General synthetic and analytical procedures
1. Synthesis of the phenyl thioglycoside donors 1a–1f.26 The
thioglycoside (1f), an analog of 1a, gives a significantly dimin- selected free sugar (5.00 g, 27.8 mmol for D-galactose, 1.0 g,
ished α selectivity of only 1.7 : 1, possibly indicating a special 5.6 mmol for D-glucose and D-mannose, 1.0 g, 6.1 mmol for
role for the 2-OH group that might coordinate with the reagent 2-deoxy-D-galactose, and 1.0 g, 2.9 mmol for a disaccharide)
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Table 2 Scope of the reactiona
Entry
1
Donor
Acceptor
cis-Product
% Yieldb
75
α : βc
10 : 1
2d
1a
1a
1a
1a
62
71
93e
85
10 : 1
7 : 1
3
4
5 : 1f
5 : 1
5g
6d
1a
1a
56
42
3 : 1
7d
>20 : 1
8d
1a
72
79
81
3 : 1
7 : 1
1 : 2
9
2a
2a
2a
10
11
69
8 : 1
12
13
2a
2a
57
67
12 : 1
1.7 : 1
a For details of the synthetic procedures, see the Experimental section. Reaction time = 2 h, and temperature = −30 °C, unless otherwise noted.
b Isolated yields of the anomeric mixtures 4a–4m after acetylation and chromatographic separation. c The anomeric ratio was determined by
integrating the 1H NMR spectrum of the crude product. d The reaction was performed at −10 °C. e Isolated yield without acetylation. f The
anomeric ratio was determined from isolated products. g The reaction was performed at 0 °C. h Anomeric mixture; anomers not separated.
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was suspended in a mixture of NaOAc (2.50 g, 30.5 mmol for 89.04, 80.29, 79.65, 73.92, 72.11, 71.53, 71.49, 71.12, 70.38,
D-galactose, 0.50 g, 6.1 mmol for the other sugars) and Ac2O 67.94, 62.84. HRESIMS: (m/z) (M + Na)+ calcd for C29H38O18Na+
(25 mL, 262.3 mmol for D-galactose, or 5.0 mL, 52.5 mmol for 457.1144; found 457.1146.
the other sugars), and the mixture was heated under an N2
2. Glycosylation to give glycosides 3a–3m. Phenyl 1-thio-
atmosphere at 70 °C. After 24 h, the yellow solution was cooled galactoside donor 1a (100 mg, 0.37 mmol) was dissolved in
to room temperature, poured onto ice and quenched with satd propargyl alcohol (2a, 0.87 mL, 0.82 g, 14.7 mmol), followed by
aq. NaHCO3. The aqueous phase was extracted with CH2Cl2 the addition of pre-activated powdered 4 Å molecular sieves
(3 × 50 mL). The organic extract was washed successively with (150 mg), and stirring was continued for 1 h under nitrogen at
water and brine, dried over anhyd Na2SO4, and concentrated to room temperature. Then the mixture was cooled to −30 °C,
afford the per-acetylated sugar as a solid that was used directly and NIS (232 mg, 1.03 mmol) and TMSOTf (13.3 μL,
without further purification.
0.074 mmol) were added, which made a black (maroon with
Thiophenol (3.60 mL, 35.2 mmol for the peracetylated most other alcohols) solution. After 2 h, satd aq. Na2S2O3 was
D-galactose; amounts for the other sugars were adjusted corres- added to quench the reaction, and the dark color faded. The
pondingly) was then added to a solution of per-acetylated mixture was then filtered through Celite®, and the solution
sugar (10.6 g, 27.1 mmol) in dry CH2Cl2 (20 mL) at 0 °C, and was concentrated in vacuo to give crude 3a. Other alcohols
the mixture was stirred for 30 min. Then BF3·Et2O (10.3 mL, were reacted in a similar manner to give glycosides 3b–3m.
81.3 mmol) was slowly injected into the mixture, which was
3. Acetylation of alkyl glycosides to give per-acetylated
allowed to warm to room temperature. After 5 h, the mixture glycosides 4a–4c and 4e–4m. The residue from the foregoing
was diluted by CH2Cl2, washed with satd aq. NaHCO3 and step (3a) was dissolved in dry pyridine (10 mL), and 4-(di-
brine, dried over anhyd Na2SO4, concentrated in vacuo, and methylamino)pyridine (DMAP, catalytic amt.) and Ac2O (1 mL,
purified by column chromatography (hexanes–EtOAc 5 : 1, 10.6 mmol) were added with stirring overnight at room temp-
hexanes–EtOAc 2.5 : 1 for the disaccharides) to afford the per- erature. After concentrating the mixture, the residue was parti-
acetylated phenyl thioglycoside as a colorless syrup.
tioned between EtOAc and water, and the organic layer was
The per-acetylated phenyl thioglycoside (22.5 mmol for the washed with satd aq. NaHCO3 and brine, dried over anhyd
peracetylated phenyl 1-thio-D-galactoside; comparable yields Na2SO4, and concentrated in vacuo to afford the crude product
for the other sugars were obtained) was then dissolved in dry 4a. In a similar manner compounds 4b–4c and 4e–4m were
MeOH (20 mL), followed by the addition of a small amount of prepared. For the compounds in Table 2, the α anomers were
NaOMe to afford pH 9. After 2 h the solution was quenched by typically separated and purified by column chromatography
the addition of Amberlite® IR-120 (H+) resin. The resin was fil- for characterization; yields were typically based on total acetyl-
tered off, and the solvent was removed in vacuo to afford the ated products.
Experimental data for compounds 3d, 4, 4a–4c and 4e–4m.
unprotected phenyl thioglycoside donor as a white powdery
solid.
Literature reports for the phenyl thioglycosides 1a–c and 1e
are as follows: phenyl 1-thio-β-D-galactopyranoside (1a),26
phenyl 1-thio-β-D-glucopyranoside (1b),43 phenyl 1-thio-
α-D-mannopyranoside (1c),44 and phenyl β-D-galactopyranosyl-
(1→4)-1-thio-β-D-glucopyranoside (1e).45 Phenyl α-D-galacto- Propargyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (4aα). The
pyranosyl-(1→6)-1-thio-β-D-glucopyranoside (1d), a new com- compound was synthesized according to the general glycosyla-
pound, was prepared as in the foregoing paragraphs and is tion and acetylation procedures B.2 and B.3, above. The crude
characterized NMR spectroscopy and high-resolution MS in product was purified by silica gel chromatography (5 : 1 to 4 : 1,
the following paragraph.
hexanes–EtOAc) to give 4a (106.7 mg, 75.1%, α/β = 10 : 1) as a
mixture of anomers. Data for 4aα: Rf 0.23 (2.5 : 1, hexanes–
EtOAc). [α]2D0 +148.5 (c 1.00, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 5.46 (1H, dd, J = 3.4, 1.4 Hz, H-4), 5.36 (1H, dd, J =
10.9, 3.4 Hz, H-3), 5.32 (1H, d, J = 3.6 Hz, H-1), 5.17 (1H, dd,
J = 10.9, 3.7 Hz, H-2), 4.27 (2H, dd, J = 2.4, 1.0 Hz,
CH2–CuCH), 4.25 (1H, m, H-5), 4.11–4.09 (2H, m, H-6a, H-6b),
2.45 (1H, t, J = 2.4 Hz, CH2–CuCH), 2.14, 2.08, 2.04, 1.98 (12H,
4 s, 4 × COCH3). 13C NMR (125 MHz, CDCl3): δ 170.50, 170.48,
Phenyl α-D-galactopyranosyl-(1→6)-1-thio-β-D-glucopyranoside
(1d). 1H NMR (500 MHz, CD3OD): δ 7.56–7.54 (m, 2H), 170.29, 170.05 (4 × COCH3) 95.08 (C-1), 78.39 (CH2–CuCH),
7.36–7.33 (m, 2H), 7.29–7.26 (m, 1H), 4.89 (d, J = 3.5 Hz, 1H, 75.32 (CH2–CuCH), 68.11 (C-4), 67.88 (C-2), 67.53 (C-3), 66.94
H-1′), 4.70 (d, J = 9.8 Hz, 1H, H-1), 3.92 (dd, J = 10.8, 6.1 Hz, (C-5), 61.63 (C-6), 55.43 (CH2–CuCH), 20.91, 20.83, 20.78,
1H), 3.88 (ddd, J = 6.6, 5.6, 1.4 Hz, 1H), 3.83 (m, 1H), 3.80–3.73 20.77 (4 × COCH3). HRESIMS: (m/z) calcd for C17H22O10Na+
(m, 3H), 3.70 (m, 2H), 3.59–3.56 (m, 1H), 3.43 (t, J = 8.8 Hz, (M + Na)+ 409.1111; found 409.1114. Compound 4a has been
1H), 3.37 (m, 1H), 3.27 (dd, J = 9.8, 8.6 Hz, 1H). 13C NMR reported (NMR spectral data match those above) from the
(125 MHz, CD3OD): δ 135.29, 132.15, 130.01, 128.26, 100.10, silica gel/H2SO4 glycosidation of the free sugar, a process we
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were unable to duplicate in yield and purity.9 A similar Allyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (4c). The com-
problem has been reported by at least one other laboratory.28
pound was synthesized according to the general glycosylation
and acetylation procedures B.2 and B.3, above. The crude
product was purified by silica gel chromatography (5 : 1 to 4 : 1,
hexanes–EtOAc) to give 4c (101. 2 mg, 70.9%, α/β = 7 : 1) as a
mixture of anomers. Data for 4cα: Rf 0.29 (2.5 : 1, hexanes–
EtOAc). [α]2D0 +163.0 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 5.87 (1H, dddd, J = 17.2, 10.4, 6.1, 5.2 Hz, CH2CHvCH2) 5.45
(1H, dd, J = 3.4, 1.3 Hz, H-4), 5.38 (1H, dd, J = 12.0, 3.4 Hz, H-3),
5.31 (1H, dq, J = 17.2, 1.6 Hz, CH2CHvCH2), 5.22 (1H, dq, J =
10.4, 1.3 Hz, CH2CHvCH2), 5.15 (1H, d, J = 3.8 Hz, H-1), 5.12
(1H, m, H-2), 4.24 (1H, m, H-5), 4.18 (1H, ddt, 13.1, 5.2, 1.4 Hz,
H-6a/H-6b), 4.09 (2H, m, CH2CHvCH2), 4.02 (1H, ddt, 13.1, 6.1,
1.4 Hz, H-6a/H-6b), 2.13, 2.07, 2.04, 1.97 (12H, 4 s, 4 × COCH3).
13C NMR (125 MHz, CDCl3): δ 170.50, 170.48, 170.33, 170.09
(4 × COCH3), 133.34 (CH2CHvCH2), 118.12 (CH2CHvCH2),
95.47 (C-1), 68.90 (C-6), 68.25 (C-4), 68.21 (C-2), 67.73 (C-3),
66.49 (C-5), 61.86 (CH2CHvCH2), 20.91, 20.81, 20.78, 20.77 (4 ×
Propargyl 2,3,4,6-tetra-O-(acetyl-d3)-α-D-galactopyranoside (4).
Compound 3a (64.3 mg, 0.295 mmol) was dissolved in dry pyri-
dine (10 mL), and DMAP (catalytic amt.) and Ac2O-d6 (0.56 mL,
5.92 mmol) were added with stirring overnight at room temp-
erature. After concentration, the residue was partitioned
between CH2Cl2–water, and the organic layer was washed with
satd aq. NaHCO3 and brine, dried over anhyd Na2SO4 and con-
centrated in vacuo. The crude product was purified by silica gel
chromatography (4 : 1 hexanes–EtOAc) to give 4 (106.1 mg,
90.4%) as a colorless syrup. Rf 0.23 (2.5 : 1, hexanes–EtOAc).
COCH3).
HRESIMS:
(m/z)
calcd
for
C17H24O10Na+
1
[α]2D1 +148.2 (c 1.00, CHCl3). H NMR (500 MHz, CDCl3): δ 5.46
(M + Na)+411.1267; found 411.1267. The β anomer of compound
4c has been characterized.46
(1H, dd, J = 3.4, 1.4 Hz, H-4), 5.36 (1H, dd, J = 10.9, 3.3 Hz,
H-3), 5.31 (1H, d, J = 3.8 Hz, H-1), 5.16 (1H, dd, J = 10.9,
3.7 Hz, H-2), 4.26 (2H, dd, J = 2.4, 1.1 Hz, CH2–CuCH),
4.25 (1H, m, H-5), 4.10 (2H, m, H-6a, H-6b), 2.45 (1H, t, J =
2.4 Hz, CH2–CuCH). 13C NMR (125 MHz, CDCl3): δ 170.49
(×2), 170.30, 170.05 (4
× COCH3) 95.06 (C-1), 78.38
(CH2–CuCH), 75.31 (CH2–CuCH), 68.06 (C-4), 67.83 (C-2),
67.48 (C-3), 66.93 (C-5), 61.58 (C-6), 55.42 (CH2–CuCH).
2-Nitroethyl α-D-galactopyranoside (3d). The compound was
synthesized according to the general glycosylation procedure
B.2, above. (The compound partially decomposed when sub-
jected to the acetylation conditions.) The crude product was
purified by silica gel chromatography (15 : 1 to 7 : 1, EtOAc–
MeOH) to give 3d (86.6 mg, 93.0%, α/β = 5 : 1) as a mixture of
anomers. Data for 3dα: Rf 0.43 (3 : 1, EtOAc–MeOH). [α]2D0 +24.7
HRESIMS: (m/z) calcd for C17H10D12O10Na+ (M
+
Na)+
421.2050; found 421.2048.
1
(c 1.00, CH3OH). H NMR (500 MHz, CD3OD): δ 4.94 (1H, d, J =
3.9 Hz, H-1), 4.78 (2H, m, OCH2CH2NO2), 4.33 (1H, ddd, J =
11.9, 5.8, 4.6 Hz, OCH2CH2NO2), 4.04 (1H, ddd, J = 11.9, 5.8,
4.6 Hz, OCH2CH2NO2), 3.96 (1H, dd, J = 3.3, 1.2 Hz, H-4), 3.85
(1H, m, H-5), 3.82 (1H, m, H-2), 3.79–3.72 (3H, m, H-3, H-6a,
H-6b). 13C NMR (125 MHz, CD3OD): δ 100.91 (C-1), 75.87
(OCH2CH2NO2), 72.60 (C-5), 71.24 (C-3), 71.05 (C-4), 69.90 (C-2),
65.06 (OCH2CH2NO2), 62.69 (C-6). HRESIMS: (m/z) calcd for
C8H15O8NNa+ (M + Na)+ 276.0695; found 276.0694. Compound
3d has been reported.47 Partial characterization was by 13C NMR
spectroscopy (reported only seven peaks) in DMSO-d6.
3-(Trimethylsilyl)propargyl
2,3,4,6-tetra-O-acetyl-α-D-galacto-
pyranoside (4b). The compound was synthesized according to
the general glycosylation and acetylation procedures B.2 and
B.3, above. The crude product was purified by silica gel
chromatography (5 : 1 to 4.5 : 1, hexanes–EtOAc) to give 4b
(104.9 mg, 62.2%, α/β = 10 : 1) as a mixture of anomers. Data for
4bα: Rf 0.37 (2.5 : 1, hexanes–EtOAc). [α]2D0 144.4 (c 1.00, CHCl3).
1H NMR (500, CDCl3 MHz): δ 5.46 (1H, dd, J = 3.4, 1.3 Hz, H-4),
5.38 (1H, dd, J = 10.9, 3.4 Hz, H-3), 5.34 (1H, d, J = 3.7 Hz, H-1),
5.16 (1H, dd, J = 10.9, 3.7 Hz, H-2), 4.26 (3H, m, CH2–CuCH,
H-5), 4.14–4.05 (2H, m, H-6a, H-6b), 2.14, 2.09, 2.04, 1.99 (12H,
4 s, 4 × COCH3), 0.17 (9H, s, –Si(CH3)3). 13C NMR (125 MHz,
CDCl3): δ 170.51, 170.36, 170.34, 170.11 (4 × COCH3), 99.92
(CH2–CuC–TMS), 94.71 (C-1), 92.52 (CH2–CuC–TMS), 68.11
(C-4), 67.93 (C-2), 67.56 (C-3), 66.84 (C-5), 61.58 (C-6), 56.05
(CH2–CuC–TMS), 20.93, 20.83, 20.81, 20.79 (4 × COCH3), −0.16
(–Si(CH3)3). HRESIMS: (m/z) calcd for C20H30O10SiNa+ (M + Na)+
481.1506; found 481.1507.
1,3-Dichloropropan-2-yl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranos-
ide (4e). The compound was synthesized according to the
general glycosylation and acetylation procedures B.2 and B.3,
above. The crude product was purified by silica gel chromato-
graphy (5 : 1 to 4 : 1, hexanes–EtOAc) to give 4e (143.1 mg,
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84.9%, α/β = 5 : 1) as a mixture of anomers. Data for 4eα: Rf one of OCH2CH2CH2CH2–CuCH 3.45 (1H, dt, J = 9.9, 6.3 Hz,
0.38 (2 : 1, hexanes–EtOAc). [α]2D2 +154.3 (c 1.00, CHCl3). 1H the other one of OCH2CH2CH2CH2–CuCH), 2.23 (2H, tdd,
NMR (500 MHz, CDCl3): δ 5.48 (1H, dd, J = 3.4, 1.3 Hz, H-4), J = 6.9, 2.7, 0.7 Hz, OCH2CH2CH2CH2–CuCH), 2.14, 2.07, 2.04,
5.36 (1H, d, J = 3.9 Hz, H-1), 5.34 (1H, dd, J = 11.0, 3.4 Hz, 1.98 (12H, 4 s, 4 × COCH3), 1.95 (1H, t, J = 2.6 Hz,
H-3), 5.08 (1H, dd, J = 11.0, 3.9 Hz, H-2), 4.45 (1H, ddd, J = 6.9, OCH2CH2CH2CH2–CuCH),
5.6, 1.1 Hz, H-5), 4.10 (2H, m, H-6a, H-6b), 4.00 (1H, m, OCH2CH2CH2CH2–CuCH),
1.75–1.69
1.64–1.59
(2H,
(2H,
m,
m,
CH(CH2Cl)2), 3.74 (2H, d, J = 5.1 Hz, CH(CH2Cl)2), 3.66 (2H, m, OCH2CH2CH2CH2–CuCH). 13C NMR (125 MHz, CDCl3): δ
CH(CH2Cl)2), 2.14, 2.08, 2.05, 2.00 (12H, 4 s, 4 × COCH3). 13C 170.56, 170.54, 170.37, 170.17 (4 × COCH3), 96.29 (C-1), 84.10
NMR (125 MHz, CDCl3): δ 170.77, 170.49, 170.26, 170.07 (4 × (OCH2CH2CH2CH2–CuCH),
68.85
(OCH2CH2CH2CH2–
COCH3), 96.87 (C-1), 78.97 (CH(CH2Cl)2), 68.14 (C-2, C-4), CuCH), 68.36 (C-2), 68.26 (C-4), 68.16 (OCH2CH2CH2CH2–
67.44 (C-3), 67.34 (C-5), 62.14 (C-6), 44.16, 43.59 (CH(CH2Cl)2), CuCH), 67.80 (C-3), 66.39 (C-5), 61.96 (C-6), 28.45
20.93, 20.80, 20.79, 20.75 (4 × COCH3). HRESIMS: (m/z) calcd (OCH2CH2CH2CH2–CuCH),
25.21
(OCH2CH2CH2CH2–
COCH3), 18.23
for C17H24O10Cl2Na+ (M + Na)+ 481.0644; found 481.0645, CuCH), 20.93, 20.84, 20.81, 20.79 (4
×
483.0619, 485.0626 (ratio of molecular ion isotopic peak (OCH2CH2CH2CH2–CuCH). HRESIMS: (m/z) calcd for
heights ≈9 : 6 : 1).
C20H28O10Na+ (M + Na)+ 451.1580; found 451.1580.
3-Bromopropyl
2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside
(4f). The compound was synthesized according to the general
glycosylation and acetylation procedures B.2 and B.3, above.
The crude product was purified by silica gel chromatography
(5 : 1 to 4.5 : 1, hexanes–EtOAc) to give 4f (96.5 mg, 56.0%, α/β
= 3 : 1) as a mixture of anomers. 4fα: Rf 0.37 (2 : 1, hexanes–
EtOAc). [α]2D0 +98.6 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 5.45 (1H, dd, J = 3.4, 1.4 Hz, H-4), 5.34–5.31 (1H, m, H-3),
5.13 (1H, m, H-2), 5.12 (1H, d, J = 3.7 Hz, H-1), 4.23 (1H, m,
H-5), 4.10 (2H, m, H-6a, H-6b), 3.87 (1H, ddd, J = 9.9, 6.0,
5.0 Hz, one of OCH2CH2CH2Br), 3.58–3.49 (3H, m, the other
OCH2CH2CH2Br and two OCH2CH2CH2Br), 2.17–2.10 (5H, m,
OCH2CH2CH2Br, COCH3), 2.08, 2.04, 1.98 (9H, 3 s, 3 ×
COCH3). 13C NMR (125 MHz, CDCl3): δ 170.56, 170.49, 170.35,
170.20 (4 × COCH3), 96.63 (C-1), 68.26 (C-2), 68.19 (C-4), 67.69
(C-3), 66.56 (C-5), 65.96 (OCH2CH2CH2Br), 61.91 (C-6), 32.15
(OCH2CH2CH2Br), 30.17 (OCH2CH2CH2Br), 20.93, 20.86,
Benzyl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (4h). The
compound was synthesized according to the general glycosyla-
tion and acetylation procedures B.2 and B.3, above. The crude
product was purified by silica gel chromatography (5 : 1 to
4.5 : 1, hexanes–EtOAc) to give 4h (116.5 mg, 72.3%, α/β = 3 : 1)
as a mixture of anomers. Data for 4hα: Rf 0.40 (2 : 1, hexanes–
EtOAc). [α]2D1 +126.8 (c 1.00, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 7.37–7.31 (5H, m, Harom), 5.46 (1H, dd, J = 3.5,
1.3 Hz, H-4), 5.40 (1H, dd, J = 10.7, 3.4 Hz, H-3), 5.18 (1H, d,
J = 3.7 Hz, H-1), 5.14 (1H, dd, J = 10.7, 3.7 Hz, H-2), 4.74–4.53
(2H, dd, J = 96.5, 12.1 Hz, CH2Ph), 4.27 (1H, td, J = 6.7, 1.4 Hz,
H-5), 4.08 (2H, qd, J = 11.2, 6.6 Hz, H-6a, H-6b), 2.13, 2.05, 2.03,
1.98 (12H, 4 s, 4 × COCH3). 13C NMR (125 MHz, CDCl3): δ
170.50, 170.40, 170.33, 170.11 (4 × COCH3), 136.90, 128.65,
128.24, 128.01 (Carom), 95.52 (C-1), 70.09 (CH2Ph), 68.23 (C-4),
68.20 (C-2), 67.78 (C-3), 66.63 (C-5), 61.81 (C-6), 20.86, 20.84,
20.81, 20.78 (4
×
COCH3). HRESIMS: (m/z) calcd for
Na)+ 491.0529, 493.0511; found
20.79, 20.77 (4
× COCH3). HRESIMS: (m/z) calcd for
C17H25O10BrNa+ (M
+
C21H26O10Na+ (M + Na)+ 461.1424; found 461.1426. Compound
4h has been used in experiments apparently without character-
ization.49 The β anomer is characterized in another paper.50
491.0526, 493.0502 (ratio of molecular ion isotopic peak
heights ≈1 : 1). Compound 4f has been reported.48 NMR spec-
tral data match those above.
Propargyl 2,3,4,6-tetra-O-acetyl-α-D-glucopyranoside (4i). The
Hex-5-yn-1-yl 2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside (4g) compound was synthesized according to the general glycosyla-
The compound was synthesized according to the general glyco- tion and acetylation procedures B.2 and B.3, above. The crude
sylation and acetylation procedures B.2 and B.3, above. The product was purified by silica gel chromatography (5 : 1 to 4 : 1,
crude product was purified by silica gel chromatography (5 : 1 hexanes–EtOAc) to give 4i (112.8 mg, 79.4%, α/β = 7 : 1) as a
to 4.5 : 1, hexanes–EtOAc) to give 4g (66.3 mg, 42.1%, α/β > mixture of anomers. Data for 4iα: Rf 0.35 (2 : 1, hexanes–
20 : 1) as a colorless syrup. Data for 4gα: Rf 0.38 (2 : 1, hexanes– EtOAc). [α]2D1 +163.6 (c 1.00, CHCl3). 1H NMR (500 MHz,
EtOAc). [α]2D0 +139.1 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3): δ 5.48 (1H, m, H-3), 5.28 (1H, d, J = 3.8 Hz, H-1), 5.08
CDCl3): δ 5.45 (1H, dd, J = 3.4, 1.3 Hz, H-4), 5.36–5.32 (1H, m, (1H, dd, J = 10.1, 9.4 Hz, H-4), 4.91 (1H, dd, J = 10.3, 3.8 Hz,
H-3), 5.12 (1H, m, H-2), 5.10 (1H, d, J = 3.4 Hz, H-1), 4.21 (1H, H-2), 4.27 (2H, d, J = 2.4 Hz, CH2–CuCH), 4.25–4.10 (2H, m,
m, H-5), 4.10 (2H, m, H-6a, H-6b), 3.73 (1H, dt, J = 9.9, 6.1 Hz, H-6a, H-6b), 4.04 (1H, m, H-5), 2.44 (1H, t, J = 2.4 Hz, CH2–
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CuCH), 2.08, 2.07, 2.02, 2.00 (12H, 4 s, 4 × COCH3). 13C NMR 2.49 (1H, t, J = 2.4 Hz, CH2–CuCH), 2.13, 2.11, 2.07, 2.04, 2.03,
(125 MHz, CDCl3): δ 170.75, 170.22, 170.14, 169.66 (4 × 2.00, 1.97 (21H, 7 s, 7 × COCH3). 13C NMR (125 MHz, CDCl3): δ
COCH3) 94.69 (C-1), 78.28 (CH2–CuCH), 75.41 (CH2–CuCH), 170.66, 170.52, 170.32, 170.27, 170.19, 170.00, 169.64 (7 ×
70.56 (C-2), 70.04 (C-3), 68.52 (C-4), 67.94 (C-5), 61.82 (C-6), COCH3), 96.39 (C-1′), 94.49 (C-1), 78.31 (CH2–CuCH), 75.57
55.52 (CH2–CuCH), 20.84, 20.79, 20.78, 20.72 (4 × COCH3). (CH2–CuCH), 70.63 (C-2), 70.09 (C-3), 69.16 (C-4), 68.93 (C-5),
HRESIMS: (m/z) calcd for C17H22O12Na+ (M + Na)+ 409.1111; 68.27 (C-4′), 68.25 (C-2′), 67.60 (C-3′), 66.58 (C-5′), 66.31 (C-6),
found 409.1112. Compound 4i has been reported.9 The NMR 61.90 (C-6′), 55.51 (CH2–CuCH), 20.94, 20.86, 20.82, 20.81
data match those reported above.
(×2), 20.79, 20.78 (7 × COCH3). HRESIMS: (m/z) calcd for
C29H38O18Na+ (M + Na)+ 697.1956; found 697.1956.
Propargyl 2,3,4,6-tetra-O-acetyl-β-D-mannopyranoside (4j). The
compound was synthesized according to the general glycosyla-
tion and acetylation procedures B.2 and B.3, above. The crude
product was purified by silica gel chromatography (4 : 1 to
2.5 : 1, hexanes–EtOAc) to give 4j (115.6 mg, 81.4%, α/β = 1 : 2)
as a mixture of anomers. Data for 4jβ: Rf 0.18 (2 : 1, hexanes–
EtOAc). [α]2D0 −82.8 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3):
δ 5.48 (1H, dd, J = 3.3, 1.1 Hz, H-2), 5.26 (1H, t, J = 9.9 Hz,
H-4), 5.09 (1H, dd, J = 10.0, 3.3 Hz, H-3), 4.94 (1H, d, J = 1.1
Hz, H-1), 4.38 (2H, m, CH2–CuCH), 4.31 (1H, dd, J = 12.3, 5.3
Hz, H-6a), 4.16 (1H, dd, J = 12.3, 2.5 Hz, H-6b), 3.69 (1H, ddd,
J = 9.9, 5.3, 2.6 Hz, H-5), 2.48 (1H, t, J = 2.4 Hz, CH2–CuCH),
2.17, 2.08, 2.03, 1.98 (12H, 4 s, 4 × COCH3). 13C NMR
(125 MHz, CDCl3): δ 170.79, 170.36, 170.10, 169.68 (4 ×
COCH3), 95.76 (C-1, JC1–H1 = 158.76 Hz), 77.94 (CH2–CuCH),
76.09 (CH2–CuCH), 72.66 (C-5), 71.21 (C-3), 68.85 (C-2), 66.08
(C-4), 62.45 (C-6), 55.91 (CH2–CuCH), 20.95, 20.88, 20.81,
20.69 (4 × COCH3). HRESIMS: (m/z) calcd for C17H22O12Na+
(M + Na)+ 409.1111; found 409.1111. The JC1–H1 cited above is
in line with that generally expected for a β-D-mannoside.51
A recent example is that of Demchenko and co-workers.52
Propargyl
4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-
2,3,6-tri-O-acetyl-α-D-glucopyranoside (4l). The compound was
synthesized according to the general glycosylation and acetyl-
ation procedures B.2 and B.3, above. The crude product was
purified by silica gel chromatography (2 : 1 to 1.5 : 1, hexanes–
EtOAc) to give 4l (140.6 mg, 56.7%, α/β = 12 : 1) as a mixture of
anomers. Data for 4lα: Rf 0.22 (1 : 1, hexanes–EtOAc).
[α]2D2 +59.7 (c 1.00, CHCl3). H NMR (500 MHz, CDCl3): δ 5.47
1
(1H, dd, J = 10.3, 9.2 Hz, H-3), 5.34 (1H, dd, J = 3.6, 1.2 Hz,
H-4′), 5.20 (1H, d, J = 3.8 Hz, H-1), 5.10 (1H, dd, J = 10.4,
7.9 Hz, H-2′), 4.95 (1H, dd, J = 10.4, 3.5 Hz, H-3′), 4.83 (1H, dd,
J = 10.3, 3.8 Hz, H-2), 4.48 (1H, d, J = 7.9 Hz, H-1′), 4.45 (1H,
dd, J = 12.0, 2.1 Hz, H-6a), 4.25 (2H, dd, J = 3.3, 2.4 Hz, CH2–
CuCH), 4.14 (2H, m, H-6b, H-6′a), 4.07 (1H, dd, J = 11.1,
7.5 Hz, H-6′b), 3.96 (1H, m, H-5), 3.86 (1H, ddd, J = 7.5, 6.3,
1.2 Hz, H-5′), 3.76 (1H, dd, J = 10.1, 9.2 Hz, H-4), 2.43 (1H, t,
J = 2.4 Hz, CH2–CuCH), 2.14, 2.12, 2.06, 2.05, 2.04, 2.04, 1.95
(21H, 7s, 7 × COCH3). 13C NMR (125 MHz, CDCl3): δ 170.50,
170.48, 170.47, 170.30, 170.21, 169.59, 169.13 (7 × COCH3),
101.16 (C-1′), 94.41 (C-1), 78.30 (CH2–CuCH), 76.42 (C-4),
75.37 (CH2–CuCH), 71.19 (C-3′), 70.79 (C-2), 70.77 (C-5′), 69.76
(C-3), 69.27 (C-2′), 68.85 (C-5), 66.74 (C-4′), 61.86 (C-6), 60.94
(C-6′), 55.30 (CH2–CuCH), 21.00 (×2), 20.84, 20.78 (×2), 20.77,
20.64 (7 × COCH3). HRESIMS: (m/z) calcd for C29H38O18Na+
(M + Na)+ 697.1956; found 697.1956. Compound 4l has been
reported.12 However, the NMR data differ from those we report
and assign above. Our assignments are based on 2D NMR
data. See the NMR spectra in the ESI.†
Propargyl
6-O-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-
2,3,4-tri-O-acetyl-α-D-glucopyranoside (4k). The compound was
synthesized according to the general glycosylation and acetyl-
ation procedures B.2 and B.3, above. The crude product was
purified by silica gel chromatography (2 : 1, hexanes–EtOAc) to
give 4k (172.1 mg, 69.4%, α/β = 8 : 1) as a mixture of anomers.
Data for 4kα: Rf 0.29 (1 : 1, hexanes–EtOAc). [α]2D0 +166.2
1
(c 1.00, CHCl3). H NMR (500 MHz, CDCl3): δ 5.48 (1H, dd, J =
10.3, 9.3 Hz, H-3), 5.45 (1H, dd, J = 3.4, 1.3 Hz, H-4′), 5.34 (1H,
dd, J = 10.8, 3.3 Hz, H-3′), 5.24 (1H, d, J = 3.7 Hz, H-1), 5.16
(1H, d, J = 3.7 Hz, H-1′), 5.11 (1H, dd, J = 10.8, 3.6 Hz, H-2′), Propargyl 3,4,6-tri-O-acetyl-2-deoxy-α,β-D-lyxo-hexopyranoside
5.05 (1H, dd, J = 10.2, 9.3 Hz, H-4), 4.85 (1H, dd, J = 10.3, (4m). In addition, the thiophenyl glycoside (donor) of 2-deoxy-
3.8 Hz, H-2), 4.28 (2H, dd, J = 2.5, 0.7 Hz, CH2–CuCH), 4.25 D-lyxo-hexopyranose (phenyl 2-deoxy-1-thio-β-D-lyxo-hexopyrano-
(1H, m, H-5′), 4.07 (2H, m, H-6′a,b), 4.02 (1H, m, H-5), 3.72 (1H, side, 1f) was also synthesized and applied in this glycosylation
dd, J = 11.3, 5.4 Hz, H-6a), 3.55 (1H, dd, J = 11.3, 2.4 Hz, H-6b), reaction to afford propargyl 3,4,6-tri-O-acetyl-2-deoxy-α,β-D-lyxo-
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hexopyranoside (alias: “propargyl 3,4,6-tri-O-acetyl-2-deoxy- 20 S. Hanessian and B. L. Lou, Chem. Rev., 2000, 100,
α,β-D-galactopyranoside,” 4m).53 However, a moderate yield
4443–4463.
(67%) and low stereoselectivity (α : β = 1.7 : 1) were achieved. 21 M. Nakanishi, D. Takahashi and K. Toshima, Org. Biomol.
The acetylated mixture 4m was not further separated into its
Chem., 2013, 11, 5079–5082.
anomers.
22 S. K. Mamidyala and M. G. Finn, J. Org. Chem., 2009, 74,
8417–8420.
23 S. K. Mamidyala and M. G. Finn, J. Org. Chem., 2010, 75,
1329.
Acknowledgements
24 R. J. Williams, C. E. Paul and M. Nitz, Carbohydr. Res.,
2014, 386, 73–77.
Dr Liguo Song is thanked for his assistance with the FIA–ESI-
TOF-MS analyses. Financial support was from the National 25 J. Tatai and P. Fugedi, Org. Lett., 2007, 9, 4647–4650.
Science Foundation, grant no. 0906752.
26 A. J. Janczuk, W. Zhang, P. R. Andreana, J. Warrick and
P. G. Wang, Carbohydr. Res., 2002, 337, 1247–1259.
27 T. Shirahata, A. Kojima, S. Teruya, J. I. Matsuo,
M. Yokoyama, S. Unagiike, T. Sunazuka, K. Makino, E. Kaji,
S. Omura and Y. Kobayashi, Tetrahedron, 2011, 67,
6482–6496.
References
1 Essentials of Glycobiology, ed. A. Varki, R. D. Cummings,
J. D. Esko, H. H. Freeze, P. Stanley, C. R. Bertozzi, 28 K. K. Yeoh, T. D. Butters, B. L. Wilkinson and
G. W. Hart and M. E. Etzler, Cold Spring Harbor Laboratory
Press, Cold Spring Harbor, NY, 2nd edn, 2009.
A. J. Fairbanks, Carbohydr. Res., 2009, 344, 586–591.
29 D. Crich, Acc. Chem. Res., 2010, 43, 1144–1153.
2 J. S. Zhao, Y. F. Liu, H. J. Park, J. M. Boggs and A. Basu, Bio- 30 M. Huang, G. E. Garrett, N. Birlirakis, L. Bohe, D. A. Pratt
conjugate Chem., 2012, 23, 1166–1173. and D. Crich, Nat. Chem., 2012, 4, 663–667.
3 M. Pérez, F. J. Muñoz, E. Muñoz, M. Fernández, 31 M. T. C. Walvoort, J. Dinkelaar, L. J. van den Bos,
J. V. Sinisterra and M. J. Hernáiz, J. Mol. Catal. B: Enzym.,
2008, 52–3, 153–157.
G. Lodder, H. S. Overkleeft, J. D. C. Codee and G. A. van
der Marel, Carbohydr. Res., 2010, 345, 1252–1263.
4 T. Horlacher and P. H. Seeberger, Chem. Soc. Rev., 2008, 37, 32 A. Ishiwata and Y. Ito, Tetrahedron Lett., 2005, 46,
1414–1422. 3521–3524.
5 S. Park, M. R. Lee and I. Shin, Chem. Commun., 2008, 4389– 33 A. Ishiwata, Y. Munemura and Y. Ito, Tetrahedron, 2008, 64,
4399. 92–102.
6 C. Wang, B. Sanders and D. C. Baker, Can. J. Chem., 2011, 34 S. R. Lu, Y. H. Lai, J. H. Chen, C. Y. Liu and K. K. T. Mong,
89, 959–963. Angew. Chem., Int. Ed., 2011, 50, 7315–7320.
7 Y. Q. Geng, Q. Qin and X. S. Ye, J. Org. Chem., 2012, 77, 35 S. S. Chang, C. C. Lin, Y. K. Li and K. K. T. Mong, Carbo-
5255–5270. hydr. Res., 2009, 344, 432–438.
8 G. Guchhait and A. K. Misra, Catal. Commun., 2011, 14, 52– 36 G. H. Veeneman, S. H. Vanleeuwen and J. H. Vanboom,
57. Tetrahedron Lett., 1990, 31, 1331–1334.
9 B. Roy and B. Mukhopadhyay, Tetrahedron Lett., 2007, 48, 37 V. Di Bussolo, A. Fiasella, M. R. Romano, L. Favero,
3783–3787. M. Pineschi and P. Crotti, Org. Lett., 2007, 9, 4479–4482.
10 E. A. Smith, W. D. Thomas, L. L. Kiessling and R. M. Corn, 38 F. Q. Ding, R. William, S. M. Wang, B. K. Gorityala and
J. Am. Chem. Soc., 2003, 125, 6140–6148. X. W. Liu, Org. Biomol. Chem., 2011, 9, 3929–3939.
11 L. F. Bornaghi and S. A. Poulsen, Tetrahedron Lett., 2005, 39 J. Lawandi, S. Rocheleau and N. Moitessier, Tetrahedron,
46, 3485–3488. 2011, 67, 8411–8420.
12 N. Shaikh, L. Russo, L. Cipolla and F. Nicotra, Mol. Diver- 40 M. T. C. Walvoort, G. A. van der Marel, H. S. Overkleeft and
sity, 2011, 15, 341–345.
J. D. C. Codee, Chem. Sci., 2013, 4, 897–906.
41 J. P. Yasomanee and A. V. Demchenko, J. Am. Chem. Soc.,
2012, 134, 20097–20102.
42 J. P. Schaumberg, G. C. Hokanson, J. C. French, E. Smal
and D. C. Baker, J. Org. Chem., 1985, 50, 1651–1656.
43 M. S. Cheng, Q. L. Wang, Q. Tian, H. Y. Song, Y. X. Liu,
Q. Li, X. Xu, H. D. Miao, X. S. Yao and Z. Yang, J. Org.
Chem., 2003, 68, 3658–3662.
44 F. S. Ekholm, M. Polakova, A. J. Pawlowicz and R. Leino,
Synthesis, 2009, 567–576.
45 Y. Nagao, T. Nekado, K. Ikeda and K. Achiwa, Chem. Pharm.
Bull., 1995, 43, 1536–1542.
13 J. Auge and G. Sizun, Green Chem., 2009, 11, 1179–1183.
14 H. D. Premathilake and A. V. Demchenko, Top. Curr.
Chem., 2011, 301, 189–221.
15 R. Rodebaugh, J. S. Debenham and B. FraserReid, Tetra-
hedron Lett., 1996, 37, 5477–5478.
16 E. Attolino, T. W. D. F. Rising, C. D. Heidecke and
A. J. Fairbanks, Tetrahedron: Asymmetry, 2007, 18,
1721–1734.
17 A. T. Carmona, A. J. Moreno-Vargas and I. Robina, Curr.
Org. Synth., 2008, 5, 33–60.
18 I. Cumpstey, Carbohydr. Res., 2008, 343, 1553–1573.
19 A. Ishiwata, Y. J. Lee and Y. Ito, Org. Biomol. Chem., 2010, 8, 46 S. Kopitzki, K. J. Jensen and J. Thiem, Chem. – Eur. J., 2010,
3596–3608.
16, 7017–7029.
5190 | Org. Biomol. Chem., 2014, 12, 5182–5191
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
47 M. Casali, L. Tarantini, S. Riva, Z. Hunkova, L. 50 Z. Pakulski, Synthesis, 2003, 2074–2078.
Weignerova and V. Kren, Biotechnol. Bioeng., 2002, 77, 51 K. Bock and C. Pedersen, J. Chem. Soc., Perkin Trans 2,
105–110. 1974, 293–297.
48 H. Abe, D. Murayama, F. Kayamori and M. Inouye, Macro- 52 S. G. Pistorio, J. P. Yasomanee and A. V. Demchenko, Org.
molecules, 2008, 41, 6903–6909. Lett., 2014, 16, 716–719.
49 A. R. Moen and T. Anthonsen, Biocatal. Biotransform., 2009, 53 B. S. Babu and K. K. Balasubramanian, Carbohydr. Lett.,
27, 226–236.
1999, 3, 339–342.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 5182–5191 | 5191