Mechanistic study of glycosylation using a prop-1-enyl donor

Article abstract of DOI:10.1021/jo301664c

Studies have been conducted to elucidate the mechanism of glycosylation reactions using a prop-1-enyl donor isomerized directly from an allyl glycoside. The reactions promoted by NIS/TfOH can take place in high yields in acetonitrile at room temperature. Activation of the anomeric prop-1-enyl group often leads to both the desired glycoside (e.g., 9) and the addition-reaction product (e.g., the anomeric mixed acetal 10). TfOH perhaps has a dual role in the reaction: i.e., (a) producing IOTf in situ to activate the prop-1-enyl group and (b) catalyzing the transformation from the addition-reaction product to the desired glycoside (e.g., from 10 to 9). The latter process involves multiple competing pathways.

Full text of DOI:10.1021/jo301664c

Article
pubs.acs.org/joc
Mechanistic Study of Glycosylation Using a Prop-1-enyl Donor
Haishen Yang and Pengfei Wang*
Department of Chemistry, University of Alabama at Birmingham, 901 14th Street South, Birmingham, Alabama 35294, United States
S
* Supporting Information
ABSTRACT: Studies have been conducted to elucidate the
mechanism of glycosylation reactions using a prop-1-enyl
donor isomerized directly from an allyl glycoside. The
reactions promoted by NIS/TfOH can take place in high
yields in acetonitrile at room temperature. Activation of the
anomeric prop-1-enyl group often leads to both the desired
glycoside (e.g., 9) and the addition-reaction product (e.g., the
anomeric mixed acetal 10). TfOH perhaps has a dual role in
the reaction: i.e., (a) producing IOTf in situ to activate the
prop-1-enyl group and (b) catalyzing the transformation from
the addition-reaction product to the desired glycoside (e.g., from 10 to 9). The latter process involves multiple competing
pathways.
This approach has some salient advantages. For example,
prop-1-enyl glycosides can be directly isomerized from widely
used allyl glycosides without time-consuming anomeric group
replacement and intermediate purification by column chroma-
tography, a variety of facile and highly effective methods are
available for allyl to prop-1-enyl isomerization,3 and allyl
glycosides can be conveniently prepared. This approach should
significantly advance the latent-active strategy of iterative
oligosaccharide synthesis.4,2e,f,5 The latent-active strategy does
not require building block reactivity tuning through extensive
protecting group manipulation, as is mandatory for the armed/
disarmed approach employing thio or n-pentenyl building
blocks.5−8
INTRODUCTION
■
Organic synthesis is a key force in providing structurally well-
defined carbohydrates for both basic and applied research in the
fields of glycobiology, biochemistry, immunology, and related
biomedical sciences. Despite significant progress, efficient
synthesis of complex carbohydrates remains a challenging
task. Improving the overall synthetic efficiency requires step-
economical synthetic approaches that comprise simple, facile,
and cost-effective glycosylation methods. An ideal glycosylation
method should minimize the number of steps in anomeric
manipulation and intermediate purification.
We have recently demonstrated that, in a one-pot fashion
(Scheme 1), the allyl glycoside 1 can be first isomerized to its
We first demonstrated that prop-1-enyl xylosides underwent
glycosidic bond formation in high yields upon activation with a
stoichiometric amount of N-iodosuccinimide (NIS) in
acetonitrile at room temperature.1a While these preliminary
results were encouraging, the initial protocol utilizing only NIS
as the activator had limitations. For instance, under the same
conditions, perbenzylated prop-1-enyl glucosyl donors pro-
duced the desired disaccharides in only moderate yields (62−
68%). Moreover, activation of prop-1-enyl mannosides and
rhamnosides or disarmed prop-1-enyl glycosides with sole NIS
resulted in a significant amount of byproducts originating from
NIS-promoted addition of the acceptor to the CC bond of
the anomeric enol ether moiety. To overcome these limitations,
it was imperative to use a catalytic amount of triflic acid
(TfOH) with NIS.1b The NIS/TfOH combination (or NIS
with other Lewis acids) has been frequently used in activating
the anomeric pentenyl or sulfide group of disarmed donors.9 It
Scheme 1. Glycosylation with Allyl Glycosyl Building Blocks
corresponding prop-1-enyl glycoside 2 followed by chemo-
selective activation of the anomeric enol ether moiety of 2 in
the presence of the allyl glycosyl acceptor 3 with a proper
electrophile (E+).1,2 The new allyl glycoside 4 is generated
along with the α-substituted propanal 5. We postulated that the
reaction passes through the reactive intermediates 6 and 7
sequentially.
Special Issue: Howard Zimmerman Memorial Issue
Received: August 4, 2012
Published: October 30, 2012
© 2012 American Chemical Society
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was rationalized that the highly reactive IOTf was generated in
situ from NIS/TfOH, which activated, for example, the
otherwise unreactive CC bond of the anomeric pent-1-enyl
group. Although activation of the anomeric prop-1-enyl group
also starts from electrophilic activation of the CC bond (e.g.,
from 2 to 6 in Scheme 1), our results reveal that TfOH may not
only play its role by forming IOTf.
10 observed only in the case of activation with sole NIS is
probably from the reaction of the intermediate 12 and the
acceptor alcohol. One rationale for the absence of the mixed
acetal 10 in the products of the NIS/TfOH-promoted reaction
could be that the byproduct 10 is probably also produced from
the same intermediate 12 but it is converted to the desired
glycosylation product 9 by TfOH. The different 9α/9β ratios
with different activators can be attributed to acid-promoted
anomeric epimerization favoring the more stable 9α.1b
Although mixed acetals (at 2-O) have been utilized in
intramolecular aglycon delivery (IAD) for 1,2-cis stereo-
control,11 there are few reports on the chemistry of anomeric
mixed acetals in the literature. Chenault and co-workers
demonstrated that both α and β anomers of isopropenyl D-
glucopyranoside generated the corresponding glucosyl methyl
acetonides upon treatment with DCl (1 mM) in methanol-d4.
These compounds were stable under acidic conditions, and
methyl glucopyranosides were not observed in these
reactions.12 In other reports, anomeric mixed acetals were
converted to the corresponding hemiacetals upon acidic
treatment.13 This chemistry was utilized in tumor-selective
activation of cytocidal drugs to release various cytotoxic
aldehydes in a proton-mediated hydrolysis process.14 However,
conversion of a C-1 mixed acetal such as 10 to a new glycoside
such as 9 upon acid treatment has not yet been reported.
Acid-Promoted Glycosylation Reaction of Anomeric
Mixed Acetals. Our experiment proved that the anomeric
mixed acetal 10 could indeed be converted to the mannoside 9
(Scheme 4). Thus, the reaction of the anomeric mixed acetal 10
RESULTS AND DISCUSSION
■
Alternative Pathways. In this paper, we focused on
elucidating the mechanism by using the perbenzylated propenyl
mannoside donor 8 (Scheme 2). We observed that treating the
Scheme 2. Glycosylation with Allyl Glycosyl Building Blocks
mannoside 8 (0.046 M in acetonitrile) with NIS in the presence
of the acceptor 3-phenyl-1-propanol at room temperature for
20 min led to a mixture of the 3-phenylpropyl mannoside 9 (α/
β = 65/35) and the anomeric mixed acetal 10 in a ∼1/1 ratio of
9/10 on the basis of 1H NMR analysis.10 This result, along with
our earlier results on xylosides and glucosides,1a indicates that
the originally proposed mechanism in Scheme 1 should operate
in producing the desired glycosylation product when an acid
catalyst such as TfOH is absent. However, under the same
conditions, activation of 8 with premixed NIS/TfOH led to a
clean reaction to produce the mannoside 9 (α/β = 98/2) and
the dimeric mannoside 11 in a 9/1 yield ratio. This improved
production of the mannoside 9 and the absence of 10 in the
reaction products suggest alternative pathways to 9 under the
acidic reaction conditions.
Scheme 4. Glycosylation of Anomeric Mixed Acetals
with 10 mol % of TfOH in MeCN was complete in 20 min.
Inspection of the crude reaction mixture by 1H NMR
spectroscopy revealed that the product yield ratio of 9/11
was about 4/1. A control experiment showed that the dimer 11
did not produce a detectable amount of 9 upon treatment with
10 mol % of TfOH in the presence of 4 equiv of 3-phenyl-1-
propanol in acetonitrile. Interestingly, the same reaction of 10
was complete in 27 min in toluene with a 9/11 yield ratio of
55/46, consistent with the isolated yields of 9 (50%) and 11
(44%).
We postulate that, with either NIS or NIS/TfOH as the
activator, the cationic intermediate 12 is generated (Scheme 3).
It proceeds to the oxocarbenium 13 and leads to the
glycosylation product 9. The anomeric mixed acetal product
Scheme 3. Mechanism of Glycosylation with Donor 8
To rationalize the reaction observations in acetonitrile, we
hypothesize that the mixed acetal 10 is probably in equilibrium
with the oxocarbenium intermediate 12 and the alcohol ROH
under the reaction conditions (Scheme 5). The intermediate 12
can break down to the aldehyde 5 and the oxocarbenium 13
(Scheme 5, pathway I). In the presence of the alcohol ROH,
the desired mannoside 9 thus forms. Alternatively, in pathway
II, the indicated glycosidic bond would break in a Fischer
glycosylation fashion, leading to the oxocarbenium 13 and the
hemiacetal 14. The latter would undergo fragmentation to
produce the aldehyde 5 and the alcohol ROH. Combination of
13 and ROH would also lead to the desired mannoside 9. This
pathway perhaps involves mixed SN1 and SNi mechanisms
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Scheme 5. Proposed Mechanism of Glycosylation with Anomeric Mixed Acetals
Scheme 6. Aglycon Transfer Mechanism
differing only in the source of ROH. Pathways I and II are
indistinguishable on the basis of product analysis. However, in
pathway III, cleavage of the indicated C−O should result in a
different set of intermediates, the hemiacetal 15 and the
oxocarbenium 16. In the presence of the alcohol ROH (from
other pathways) the acetal 17 would form while the
intermediate oxocarbenium 13 and the hemiacetal 15 would
combine to produce the dimeric mannoside 11. These
pathways probably coexist. Between pathways II and III, the
product population in the mannoside case (i.e., a 4/1 yield ratio
of 9/11 shown in Scheme 4) suggests that the pathway II
predominated. One rationale could be that the activated
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Scheme 7. Activation of 8 with Different Intervals between Adding NIS and TfOH
anomeric oxygen in [10·H+]′ was already properly aligned in
the antiperiplanar position with respect to the nonbonding
electron pair of the pyranose oxygen, facilitating the anomeric
bond cleavage for the formation of the oxocarbenium
intermediate 13.15 On the other hand, for pathway III, the
breaking C1′−O bond and the nonbonding electron pair on
the geminal oxygen were not always properly aligned for
elimination. As a result, cleaving the C1′−O bond would either
take place in an SN1 fashion without much assistance from the
geminal oxygen or have to rotate the C1′−OR bond to the
properly aligned antiperiplanar position first. Either way would
slow down the reaction. Production of the dimer 11 at a
constant ratio in repeated runs using different batches of
properly dried reagent and solvent ruled out the possibility that
its formation was due to traces of adventitious water.
In addition to what is illustrated in Scheme 5, the
oxocarbenium 13 might initiate aglycon transfer by attaching
to the oxygen of the mixed acetal moiety, where the proton
attaches in [10·H+] and [10·H+]′, leading to direct formation
of 9 and 11, respectively (Scheme 6).16 In fact, repeating the
reaction in Scheme 4 in the presence of 1 equiv of the acceptor
ROH led to improved production of 9, with a 96/4 yield ratio
of 9/11, suggesting that increasing the concentration of the
acceptor improved its trapping of the oxocarbenium
intermediate 13 and diminished production of 11 from the
possible aglycon transfer pathway. Otherwise, we would expect
more hemiacetal 15 left unreacted if 9 and 11 were only formed
through competition between the acceptor and the hemiacetal
15 for the oxocarbenium 13 (Scheme 5).
More Mechanistic Studies. The current experimental data
support that transformation from 10 to 9 is viable in the
presence of TfOH (Schemes 5 and 6),17 which could explain
the difference in reaction outcomes between using NIS or NIS/
TfOH as the activator.
For more mechanistic insights, we conducted another set of
experiments (Scheme 7). Thus, we first treated the prop-1-enyl
mannoside donor 8 and the acceptor 3-phenylpropanol with a
premixed MeCN solution of NIS and 10 mol % of TfOH for 20
min at room temperature. The glycoside 9 and the dimeric
mannoside 11 were obtained in a 9/1 yield ratio on the basis of
1H NMR analysis. In the second run, the donor and the
acceptor were first treated with NIS only. In 10 min, conversion
of the prop-1-enyl mannoside 8 reached 77%, and the
mannoside 9 (α/β = 66/34) and the mixed acetal 10 were
obtained with a ∼1/1 ratio. Treatment of this mixture with
TfOH (10 mol %) for 20 min resulted in a reaction mixture
with a product distribution identical with that in the first run
activated by premixed NIS/TfOH. In the third run, the donor
and the acceptor were treated with NIS alone for 23 min. The
donor was completely consumed, and a mixture of the
mannoside 9 (α/β = 65/35) and the mixed acetal 10 was
obtained with the same 9/10 ratio as in the second run prior to
the acid treatment. This reaction mixture was then treated with
TfOH (10 mol %) for 20 min, and again, an product
distribution identical with that in the previous two runs was
obtained.
The appearance of the dimeric mannoside 11 in the product
mixtures in all three runs indicates involvement of the mixed
acetal intermediate 10 as an intermediate even in the first run,
for it is a characteristic byproduct from 10 upon its treatment
with TfOH, as shown in Scheme 4. It is noteworthy that the
yield ratio of 9/11 from these three runs was different from that
of the glycosylation of the mixed acetal 10 (Scheme 4), i.e., 9/1
versus 4/1. This discrepancy in the product yield ratio rules out
a mechanistic scenario where the mannoside product 9 forms
exclusively through the intermediacy of the mixed acetal 10,
confirming that multiple pathways must operate simulta-
neously.
The constant 9/1 yield ratio of 9/11 in the three runs also
suggests that the same ratio of 10/9 was probably produced
upon activation regardless of the activator (i.e., NIS or NIS/
TfOH). As a result, subsequent reactions of the mixed acetal 10
in different runs would lead to the same ratio of 9/11. In fact,
the 9/11 yield ratios observed in the reaction of 10 (i.e., 4/1)
(Scheme 4) and that of the prop-1-enyl mannoside (i.e., 9/1)
are in agreement with the observation that a mixture of 9 and
10 (∼1/1) was produced upon activation of 8 prior to
treatment of TfOH in the second and third runs.
In the first run, IOTf was probably produced and was mainly
responsible for the activation of the prop-1-enyl mannoside
donor. It has been previously demonstrated that glycosylation
reactions of prop-1-enyl donors promoted by NIS/TfOH
typically finish within 1 min.1 Since it took about 20 min for
NIS alone to completely consume all the donors, NIS/TfOH
probably produced the more reactive iodonium species (i.e.,
IOTf) to convert the prop-1-enyl donors to various
intermediates much more efficiently in the first run and also
in the second run after TfOH was introduced.18 Thus, in those
runs, TfOH in the NIS/TfOH combination has a dual role: i.e.,
to produce the more reactive activator IOTf in situ to activate
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1H), 4.90 (d, J = 10.8 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 4.72−4.56
(m, 4H), 4.55−4.36 (m, 3H), 4.06−3.83 (m, 5H), 3.74−3.59 (m, 3H),
3.40 (dt, J = 9.4, 6.4 Hz, 1H), 2.71−2.49 (m, 2H), 1.86−1.66 (m, 5H);
13C NMR (75 MHz, CDCl3) δ141.8, 138.5, 138.4, 138.3, 138.2,
128.41, 128.36, 128.31, 128.26, 128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 125.8, 106.1, 98.1, 79.4, 75.0, 74.7, 74.5, 73.3, 72.7, 72.6,
72.3, 69.3, 68.2, 32.1, 31.1, 27.8, 21.2; IR (neat) 3028, 2925, 2866,
1493, 1454, 1097, 1028, 739, 700; HRMS (ESI) m/e calcd for
C46H51IO7Na 865.2577, found 865.2568. For the diastereomer of 10
the CC bond of the anomeric enol ether moiety and to
promote the conversion of the mixed acetal intermediate 10 to
the mannoside product 9. The experimental results suggest the
former process is probably much faster than the latter.
Otherwise, the reaction of the mixed acetal 10 would take
place in the presence of the acceptor, which would lead to a
smaller amount of the dimer 11 (vide supra) and, as a result,
would change the overall ratio of 9/11.
1
In summary, on the basis of the results of this work and our
earlier results,1 we propose a plausible general mechanism for
the glycosylation reaction with prop-1-enyl donors activated by
NIS or NIS/TfOH. Thus, upon activation with NIS or NIS/
TfOH, the oxocarbenium intermediate 6 forms (Scheme 2). It
would produce the glycoside 4 and also the addition-reaction
products. Formation of the latter is affected by the nature of the
donor. On one hand, formation of the addition-reaction
products is negligible for reactive donors such as a
perbenzylated prop-1-enyl xyloside, and high yields of desired
product were obtained even with NIS alone as the activator. On
the other hand, for prop-1-enyl mannosides and rhamnosides
or disarmed prop-1-enyl glycosides, fragmentation of 6 to the
oxocarbenium 7 becomes slower, and more of the addition-
reaction products thus form. In the presence of TfOH, the
addition-reaction products can be converted to the desired new
glycoside 4, accompanied by a characteristic minor dimer of the
donor. TfOH in the NIS/TfOH combination has a dual role: it
can generate IOTf with NIS to accelerate activation of the
anomeric enol ether group and it is also imperative in
promoting subsequent conversion of the addition-reaction
products to the final glycosylation product 4.
with higher polarity: H NMR (300 MHz, CDCl3) δ 7.42−7.13 (m,
25H), 5.11 (d, J = 1.9 Hz, 1H), 4.87 (d, J = 10.9 Hz, 1H), 4.78 (d, J =
12.4 Hz, 1H), 4.72−4.61 (m, 4H), 4.51 (dd, J = 11.5, 3.7 Hz, 2H),
4.33 (d, J = 3.9 Hz, 1H), 4.09 (qd, J = 6.9, 3.9 Hz, 1H), 4.04−3.86 (m,
3H), 3.81−3.66 (m, 3H), 3.54 (dt, J = 9.2, 6.2 Hz, 1H), 3.36 (dt, J =
9.2, 6.4 Hz, 1H), 2.66 (dd, J = 8.6, 6.8 Hz, 2H), 1.95−1.73 (m, 5H);
13C NMR (75 MHz, CDCl3) δ 141.6, 138.5, 138.4, 138.3, 128.5, 128.4,
128.3, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 125.9, 102.2,
95.7, 79.9, 75.1, 75.0, 74.8, 73.3, 73.0, 72.6, 69.3, 68.1, 32.2, 31.3, 27.1,
22.4; IR (neat) 3028, 2917, 2865, 1496, 1454, 1097, 1027, 737, 698;
HRMS (ESI) m/e calcd for C46H51IO7Na 865.2577, found 865.2577.
Glycosylation of 10 in MeCN. To a stirred solution of the acetal
10 (75 mg, 0.089 mmol) in CH3CN (1.7 mL) was added TfOH (0.8
μL, 8.9 μmol) at room temperature. After 20 min, the reaction mxture
was quenched with triethylamine and concentrated for 1H NMR. The
1H NMR analysis indicated that the yields of 9, 11, and 17 were 79%
(α/β = 96:4), 20%, and 12%, respectively. The yields were determined
by comparing the intergration of characteristic peaks from 9 and 11
with internal standards. For 17, Rf = 0.39 (petroleum ether/ethyl
acetate = 10/1): 1H NMR (300 MHz, CDCl3) δ 7.38−7.12 (m, 10H),
4.38 (d, J = 5.5 Hz, 1H), 4.17 (qd, J = 7.0, 5.4 Hz, 1H), 3.73−3.42 (m,
4H), 2.78−2.66 (m, 4H), 2.00−1.84 (m, 7H); 13C NMR (75 MHz,
CDCl3) δ 141.8, 128.5, 128.4, 125.8, 105.6, 67.0, 66.8, 32.3, 31.3, 26.8,
22.5; IR (neat) 3026, 2926, 1603, 1496, 1454, 1106, 1042, 747, 699;
HRMS (ESI) m/e calcd for C21H27IO2Na 461.0953, found 461.0946.
Control Experiment. A mixture of dimeric mannoside 11 (33 mg,
0.031 mmol), 3-phenylpropan-1-ol (16.7 μL, 0.124 mmol), and TfOH
(0.27 μL, 0.0031 mmol) in toluene (0.31 mL) was stirred at room
EXPERIMENTAL SECTION
■
General Considerations. Organic solutions were concentrated by
rotary evaporation at ca. 12 Torr. Flash column chromatography was
performed employing 230−400 mesh silica gel. Thin-layer chromatog-
raphy was performed using glass plates precoated to a depth of 0.25
mm with 230−400 mesh silica gel impregnated with a fluorescent
indicator (254 nm). Infrared (IR) data are presented as frequency of
absorption (cm−1). Proton and carbon-13 nuclear magnetic resonance
(1H NMR or 13C NMR) spectra were recorded on 300, 400, and 700
MHz NMR spectrometers. Chemical shifts are expressed in parts per
million (δ scale) downfield from tetramethylsilane and are referenced
to residual protium in the NMR solvent (CHCl3: δ 7.26). Data are
presented as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet and/or multiple
resonances), coupling constant in hertz (Hz), integration.
1
temperature for 20 h. TLC and H NMR analyses showed no sign of
decomposition of 11.
Glycosylation of 10 in Toluene. To a stirred solution of acetal
10 (68.8 mg, 0.08 mmol) in toluene (1.0 mL) was added TfOH (0.7
μL, 8 μmol) at room temperature. After 27 min, the reaction mixture
was quenched with triethylamine and concentrated for 1H NMR. The
1H NMR analysis indicated that the yields of 9, 11, and 17 were 55%
(α/β = 88/12), 45%, and 26%, respectively. Flash column
chromatograhpy (petroleum ether/ethyl acetate = 8/1) afforded the
9 (27 mg, 50% (α/β = 88:12)), 11 (19.3 mg, 44%), and 17 (7.7 mg,
22%) as clear oils.
Role of TfOH in Glycosylation of Prop-1-enyl Donors
Activated by NIS/TfOH. Run 1 (with Premixed NIS/TfOH). To a
stirred solution of 8 (52 mg, 0.09 mmol) and 3-phenylpropan-1-ol
(12.2 μL, 0.09 mmol) in CH3CN (1.0 mL) was added a solution of
NIS (21.5 mg, 0.096 mmol) and TfOH (0.8 μL, 0.009 mmol)
premixed in CH3CN (0.7 mL) at room temperature. After 20 min, the
Materials. Tetrahydrofuran was distilled from appropriate drying
reagents under a nitrogen atmosphere at 760 Torr. Other chemicals
were obtained from commercial vendors and used without further
purification.
Preparation of the Mannoside Mixed Acetal 10. Potassium
tert-butoxide (0.425 g, 3.78 mmol) was added to allyl 2,3,4,6-tetra-O-
benzyl-D-mannoside (1.0 g, 1.72 mmol) in 6.4 mL of DMSO, and the
reaction mixture was stirred at room temperature until the reaction
was complete. The reaction was worked up with ethyl acetate and
water. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated to provide prop-1-enyl 2,3,4,6-tetra-O-
benzyl-D-mannoside (0.92 g, 92%) as a waxy solid. To a stirred
solution of the prop-1-enyl mannoside (200 mg, 0.34 mmol) and 3-
phenylpropan-1-ol (135 μL, 1.03 mmol) in toluene (1.0 mL) was
added N-iodosuccinimide (93 mg, 0.41 mmol) at room temperature.
After 45 min, the mixture was concentrated for flash column
chromatography (petroleum ether/ethyl acetate = 10/1, Rf = 0.39)
to afford the mannoside acetal 10 (269 mg, 93%) as a mixture of
1
reaction mixture was quenched with Et3N and concentrated. The H
NMR analysis of the crude reaction mixture indicated that the yields of
9 and 11 were 90% (α/β = 98/2) and 10%, respectively.
Run 2. To a stirred solution of 8 (52 mg, 0.09 mmol) and 3-
phenylpropan-1-ol (12.2 μL, 0.09 mmol) in CH3CN (1.7 mL) was
added NIS (21.8 mg, 0.097 mmol) at room temperature. After 10 min,
TfOH (0.8 μL, 0.009 mmol) was added and the mixture was stirred for
20 min. The reaction mixture was then quenched with Et3N and
1
concentrated. The H NMR analysis of the crude reaction mixture
indicated that the yields of 9 and 11 were 90% (α/β = 98/2) and 10%,
respectively. In a parallel run, to a stirred solution of 8 (45.2 mg, 0.078
mmol) and 3-phenylpropan-1-ol (10.5 μL, 0.078 mmol) in CH3CN
(1.7 mL) was added NIS (19.0 mg, 0.084 mmol, 1.08 equiv) at room
temperature. After 10 min, the reaction mixture was quenched with a
1
diastereomers. For the diastereomer of 10 with lower polarity: H
1
NMR (300 MHz, CDCl3) δ 7.43−7.08 (m, 25H), 4.98 (d, J = 1.8 Hz,
saturated aqueous solution of Na2SO3. The crude H NMR indicated
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that 23% of 8 was left and the yield ratio of 9 (α/β = 66/34) to 10 was
47/53.
2292. (g) Baeschlin, D. K.; Chaperon, A. R.; Charbonneau, V.; Green,
L. G.; Ley, S. V.; Lucking, U.; Walther, E. Angew. Chem., Int. Ed. 1998,
̈
Run 3. To a stirred solution of 8 (46.7 mg, 0.08 mmol) and 3-
phenylpropan-1-ol (10.9 μL, 0.08 mmol) in CH3CN (1.7 mL) was
added NIS (18.4 mg, 0.082 mmol) at room temperature. After 23 min,
TfOH (0.71 μL, 0.008 mmol) was added and the resulting mixture
stirred for 20 min. The reaction mixture was then quenched with Et3N
and concentrated. The 1H NMR analysis of the crude reaction mixture
indicated that the yields of 9 and 11 were 90% (α/β = 98/2) and 10%,
respectively. In a parallel run, to a stirred solution of 8 (45.2 mg, 0.078
mmol) and 3-phenylpropan-1-ol (10.5 μL, 0.078 mmol) in CH3CN
(1.7 mL) was added NIS (19.0 mg, 0.084 mmol, 1. 08 equiv) at room
temperature. After 20 min, the reaction mixture was quenched and the
1H NMR indicated that the yield ratio of 9 (α/β = 65/35) to 10 was
44/55.
37, 3423. (h) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.;
Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734. (i) Ye, X.-
S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410. (j) Huang, L.; Wang, Z.;
Huang, X. Chem. Commun. 2004, 1960.
(8) To simplify building block preparation and thus to improve
synthetic efficiency, preactivation of thioglycosides has recently
emerged as an appealing approach. See: (a) Yamago, S.; Yamada,
T.; Maruyama, T.; Yoshida, J. Angew. Chem., Int. Ed. 2004, 43, 2145.
(b) Huang, X.; Huang, L.; Wang, H.; Ye, X.-S. Angew. Chem., Int. Ed.
2004, 43, 5221. (c) Codee, J.; van den Bos, L.; Litjens, R.; Overkleeft,
H.; van Boeckel, C.; van Boom, J.; van der Marel, G. Tetrahedron 2004,
60, 1057.
(9) (a) Zhong, W.; Boons, G.-J. In Handbook of Chemical
Glycosylation; Demchenko, A., Ed.; Wiley-VCH: Weinheim, Germany,
2008; pp 261−302. (b) Fraser-Reid, B.; Lopez, J. C. In Handbook of
Chemical Glycosylation; Demchenko, A., Ed.; Wiley-VCH: Weinheim,
Germany, 2008; pp 381−415.
(10) The anomeric mixed acetal 10 formed exclusively when the
alcohol was used as the solvent or in dichloromethane, benzene, or
toluene with a stoichiometric amount of the alcohol when only NIS
was used as the activator.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figures giving NMR spectra of 8, 9α, 9β, 10, 11, 15, and 17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wangp@uab.edu.
(11) Fairbanks, A. Synlett 2003, 1945 and references cited therein.
(12) Chenault, H. K.; Chafin, L. F. J. Org. Chem. 1994, 59, 6167.
(13) (a) Koto, S.; Inada, S.; Narita, T.; Morishima, N.; Zen, S. Bull.
Chem. Soc. Jpn. 1982, 55, 3665. (b) Chenault, H. K.; Castro, A.;
Chafin, L. F.; Yang, J. J. Org. Chem. 1996, 61, 5024.
■
Notes
The authors declare no competing financial interest.
(14) Tietze, L. F.; Feuerstein, T. Curr. Pharm. Design 2003, 9, 2155
and references cited therein.
(15) In a control experiment, the reaction of the β glucoside
counterpart of 10 under the same reaction conditions was less clean
with a lower yield of the corresponding 3-phenylpropyl glucoside
product.
ACKNOWLEDGMENTS
We thank the University of Alabama at Birmingham for
support.
■
(16) Li, Z.; Gildersleeve, J. J. Am. Chem. Soc. 2006, 128, 11612.
(17) A transformation similar to that from 10 to 9 was also confirmed
with perbenzylated rhamnosides, glucosides, and xylosides. The
transformation of the corresponding anomeric mixed acetal can be
carried out not only in acetonitrile but also in DCM, THF, and even
hexane or toluene. A variety of acids proved to be effective in
promoting the reaction. For instance, with the anomeric mixed acetal
of rhamnoside in DCM, a catalytic amount of Yb(OTf)3, BF3·OEt2,
Cu(OTf)2, SbCl5, SnCl4, or TMSOTf can promote the reaction. The
reaction could be carried out over a broad temperature range (i.e., 0−
60 °C) without affecting the product yields significantly.
(18) Glycosylation of 8 promoted only by a catalytic amount of
TfOH (10 mol %) proved to be feasible, but it was less clean and
slower than the same reaction promoted by NIS/TfOH. This
observation suggested that promoting the formation of an
oxocarbenium intermediate such as 12 from 8 by TfOH only might
not play a significant role in the reactions using NIS/TfOH, although
it is known in the literature that various vinyl glycosylide donors can
be activated by Lewis acids such as TMSOTf for glycosidic bond
construction.2
DEDICATION
■
Dedicated to the memory of Professor Howard E. Zimmerman.
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