Fluorous-assisted one-pot oligosaccharide synthesis

Article abstract of DOI:10.1002/ejoc.200901155

A new method for oligosaccharide assembly that combines the advantages of one-pot synthesis and fluorous separation is described. After one-pot glycosylations are completed, a fluorous tag is introduced into the reaction mixture to selectively catch the desired oligosaccharide, which is rapidly separated from non-fluorous impurities by fluorous solidphase extraction (F-SPE). Subsequent release of the fluo-rous tag and F-SPE achieved the purification of the desired oligosaccharide without the use of time- and solvent-consuming silica gel chromatography. Linear and branched oligosaccharides have been synthesized with this approach in just a few hours (for the overall oligosaccharide assembly and purification process).

Full text of DOI:10.1002/ejoc.200901155

FULL PAPER
DOI: 10.1002/ejoc.200901155
Fluorous-Assisted One-Pot Oligosaccharide Synthesis
Bo Yang,[a] Yuqing Jing,[a] and Xuefei Huang*[a]
Keywords: Carbohydrates / Fluorous separation / Hydrazones / Immobilization / One-pot synthesis
A new method for oligosaccharide assembly that combines
the advantages of one-pot synthesis and fluorous separation
is described. After one-pot glycosylations are completed, a
fluorous tag is introduced into the reaction mixture to selec-
tively “catch” the desired oligosaccharide, which is rapidly
separated from non-fluorous impurities by fluorous solid-
phase extraction (F-SPE). Subsequent “release” of the fluo-
rous tag and F-SPE achieved the purification of the desired
oligosaccharide without the use of time- and solvent-con-
suming silica gel chromatography. Linear and branched oli-
gosaccharides have been synthesized with this approach in
just a few hours (for the overall oligosaccharide assembly and
purification process).
fication of the final product from one-pot reactions could
also be expedited to improve the overall efficiencies.
Recently, fluorous chemistry has become popular to fa-
cilitate organic synthesis and catalysis.[31–34] Highly fluori-
nated (fluorous) compounds have strong affinities with flu-
orinated silica gel. This property is utilized in F-SPE, which
is an attractive technique to expedite purification.[32,35] F-
SPE separates compounds containing fluorous tags from
non-fluorous counterparts regardless of polarities through
solid-phase extraction. As it does not require large amounts
of solvents to elute the samples, F-SPE is faster than tradi-
tional silica gel chromatography and uses less organic sol-
vents.[32,35] In order to take advantage of this unique prop-
erty in carbohydrate synthesis, a fluorous tag can be intro-
duced into a building block, typically a glycosyl acceptor,
prior to glycosylation.[35–42] The fluorous acceptor is then
coupled to a glycosyl donor to yield a fluorous disaccha-
ride, which can be purified by F-SPE. This process can be
repeated, which leads to fluorous oligosaccharides. As an
alternative to tagging glycosyl acceptors, fluorous tags can
also be introduced into glycosyl donors as protective
groups[43–45] or the aglycon leaving group.[46] Recently, an-
other method has been developed where a fluorinated silyl
protective group has been used to selectively tag the desired
product after oligosaccharide assembly on the solid
phase.[47] This facilitated purification of a model trisaccha-
ride product from the deletion sequences in an automated
solid-phase synthesis.
Introduction
Carbohydrates are widely present in nature with impor-
tant roles in numerous biological processes.[1,2] In order to
illustrate the functions of carbohydrates, carbohydrate syn-
thesis has been extensively studied over the past three dec-
ades. Traditional oligosaccharide assembly is a time-con-
suming process because of the need for multiple protective
group adjustments and aglycon manipulations on oligosac-
charide intermediates. Many novel methods to expedite oli-
gosaccharide assembly have been introduced,[3–8] which in-
clude orthogonal glycosylation,[9,10] active-latent acti-
vation,[11–13] reactivity-based armed-disarmed glycosyl-
ation,[14–16] reactivity-independent chemoselective glycosyl-
ation,[17–20] and automated solid-phase synthesis.[21] Several
of these strategies have been adopted into one-pot proto-
cols, by which multiple glycosylation reactions can be car-
ried out in a single flask without the need to purify the
intermediates, thus greatly enhancing the efficiencies for oli-
gosaccharide assembly.[22,23] Many large complex oligosac-
charides have been assembled through one-pot methods,
such as the phytoalexin elicitor heptasaccharide,[24] dimeric
LewisX antigens,[25,26] Globo-H hexasaccharide,[27,28] the
Lewis Y carbohydrate hapten,[29] and the core-fucosylated
bi-antennary N-glycan dodecasaccharide.[30] Common to
all one-pot methodologies, upon completion of the synthe-
sis, silica gel chromatography is required to purify the de-
sired product from side products such as disulfide and de-
composed donors generated in the reaction, which can be
time- and solvent-consuming. It would be desirable if puri-
One of the goals of our research program is to develop
new methodologies expediting oligosaccharide assembly.
Our initial foray into fluorous chemistry involved the devel-
opment of a fluorous thiol as the aglycon leaving group for
thioglycoside building blocks.[46] In this paper, we report
our results on the use of fluorous reagents to aid one-pot
oligosaccharide assembly.
[a] Department of Chemistry, Michigan State University,
East Lansing, Michigan 48824, USA
E-mail: xuefei@chemistry.msu.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901155.
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Fluorous-Assisted One-Pot Oligosaccharide Synthesis
of a thioglycosyl donor by the promoter pTolSCl/AgOTf,
thereby generating a reactive intermediate[55] in the absence
of an acceptor.[20] Upon addition of a thioglycosyl acceptor
to the preactivated donor, a disaccharide will be formed,
which can be activated for the next round of glycosylation.
This process can be repeated in the same flask until the
desired oligosaccharide length is achieved. The last ac-
ceptor at the reducing end of the oligosaccharide will bear
a functionalized linker, which can react with a fluorous tag.
After one-pot glycosylation reactions are completed, the
fluorous tag is added into the reaction mixture to selectively
“catch” the desired oligosaccharide, which is easily sepa-
rated from non-fluorous impurities by F-SPE. Subsequent
release of the tag and F-SPE will lead to the pure desired
oligosaccharide product without the need for any silica gel
column purification.
Results and Discussion
Our journey started by attaching a fluorous group to the
glycosyl acceptor prior to glycosylation. Serious difficulties
were encountered with this approach,[48] as the fluorous di-
saccharide acceptor 2a reacted poorly with trisaccharide
donor 1 (Figure 1a); main side products resulted from do-
nor decomposition or hydrolysis. In contrast, under iden-
tical reaction conditions, the reaction of the corresponding
non-fluorous lactoside 2b with 1 produced pentasaccharide
3b in 70% yield (Figure 1b). The exact reason for the poor
reactivity of 2a is not clear as other fluorous acceptors have
successfully been glycosylated.[35–39] Addition of a fluorous
solvent 1-(ethoxy)nonafluorobutane to the reaction to en-
hance solubility or elevation of the reaction temperature did
not improve the outcome.[48] Another potential complica-
tion of the introduction strategy of this pre-glycosylation
fluorous tag is that, in the synthesis of large oligosaccha-
rides, the original fluorous chain installed may not be suf-
ficient to retain the growing oligosaccharides during F-SPE
with the increasing size of the organic components. These
considerations led us to explore an alternative strategy for
fluorous-assisted carbohydrate synthesis.
Figure 2. Fluorous-assisted one-pot oligosaccharide synthesis.
We envisioned that this fluorous “catch and release” pro-
tocol could potentially address the aforementioned limita-
tions of the introduction of the pre-glycosylation tag. As
no fluorous groups are present during glycosylation, typical
glycosylation conditions can directly be adopted without
extensive optimization of the reaction conditions. Further-
more, the post-glycosylation introduction of the fluorous
tag allows the flexibility of choosing the appropriate fluo-
rous groups to “catch” the oligosaccharides. In order for
the fluorous “catch and release” protocol to be successful,
the functionalized linker should be inert under glycosyl-
ation conditions and must not interfere with the glycosyl-
ation. Furthermore, the “catch” and “release” reactions
must be highly chemoselective in the presence of the heavily
functionalized oligosaccharides, and the reactions should
be rapid, ideally completed within minutes.
Figure 1. While glycosylation of trisaccharide donor 1 failed with
(a) the fluorous acceptor 2a, its glycosylation with (b) acceptor 2b
was successfully performed under identical reaction conditions.
The first reaction we examined is the Staudinger reaction
As outlined in Figure 2, this new approach combines a between mannosyl azide 4[56] and the commercially avail-
fluorous “catch and release” protocol[46–54] with a preacti- able fluorous phosphane 5. However, the resulting aza-ylide
vation-based one-pot synthesis, which begins by activation 6 was hydrolyzed during F-SPE after the “catch” reaction.
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B. Yang, Y. Jing, X. Huang
FULL PAPER
drance around the carbonyl group in ketone 15, its “catch”
reaction with fluorous hydrazine 13 turned out to be very
slow and required more than 24 h to complete, which ren-
dered it unattractive.
The slow reaction rate of 15 with hydrazine 13 prompted
the design of fluorous hydrazide 16. The preparation of hy-
drazide 16 started from fluorous carboxylic acid 18, which
was first coupled to tert-butyl carbazate 19 to provide com-
pound 20 in 74% yield. Removal of the Boc group from
20 by TFA gave fluorous tag 16 in 100% yield (Scheme 2).
Hydrazide 16 was much more reactive, reacting with ketone
15 in 5 min to lead to 17. Compound 17 was stable under
neutral conditions; the hydrazone bond can be cleaved with
0.5% TFA in acetone to release ketone 15 within 10 min in
quantitative yield.
Hydrazone formation was explored next with aldehyde 9
and fluorous hydrazine 13. Aldehyde 9 was synthesized
from compound 7,[14] which was first glycosylated with 4-
penten-1-ol to give compound 8 followed by ozonolysis to
introduce the aldehyde moiety (Scheme 1a). Triphenylphos-
phane was used initially to reduce the trioxolane intermedi-
ate from ozonolysis. Although the reaction was successful,
it turned out to be difficult to separate cleanly the desired
product from triphenylphosphane oxide generated in the re-
action. This problem was solved by employing the solid-
phase-supported triphenylphosphane (PS-PPh3), which was
easily removed after the reaction by simple filtration. Re-
moval of the TBDPS group in 8 by HF in pyridine led to
aldehyde 9. Hydrazine 13 was obtained by 1-ethyl-3-(3-di-
methyl-aminopropyl)carbodiimide hydrochloride (EDC)
mediated coupling of compound 10[63] and compound 11
and subsequent deprotection with trifluoroacetic acid
(TFA) (Scheme 1b). The “catch and release” reactions be-
tween 9 and 13 were then performed. Unfortunately, alde-
hyde 9 was found to be unstable as it oxidized in air. To
overcome this obstacle, ketone 15 was prepared. Glycosyl-
ation of compound 7 with 4-hydroxy-2-butanone gave com-
pound 14, which was treated with HF in pyridine to yield
ketone 15 (Scheme 1c). However, with increased steric hin-
Scheme 2. Synthesis of fluorous hydrazide 16.
With compound 16 in hand, its utility in oligosaccharide
synthesis was examined first in a single-step glycosylation
reaction. Glycosylation of acceptor 15 by donor 21[14] pro-
moted by pTolSCl/AgOTf led to disaccharide 22. Upon
completion of the reaction, the reaction mixture (Scheme 3,
TLC Lane 1, and Figure 3a) was redispersed in DCM and
methanol (1:1), followed by addition of fluorous hydrazide
16. The “catch” reaction was completed in 5 min, followed
by F-SPE, which removed all non-fluorous compounds.
The fluorous fraction was then dissolved in acetone with
0.5% TFA to cleave the hydrazone bond in 10 min (Lane
2). After subsequent F-SPE, pure disaccharide 22 was ob-
tained in 80% yield after the overall purification process
(Lane 3, and Figure 3b). The purity and structure of the
product were confirmed by NMR spectroscopy, MS, and
HPLC analysis. The success of this reaction proved that the
ketone moiety is stable and it does not interfere with the
glycosylation reaction. The whole “catch and release” puri-
fication process took less than 1 h to complete with less
than 30 mL organic solvent. In contrast, a typical silica gel
chromatography separation requires a few hours and con-
sumes several hundred milliliters of solvent. The speed in
obtaining 22 highlights the advantage of our approach. The
linker in 22 was removed through a reverse Michael reac-
tion under basic conditions, together with the benzoyl pro-
tective groups, to produce 23 in 80% yield.
Scheme 1. Synthesis of aldehyde 9, fluorous hydrazine 13, and
ketone 15.
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Fluorous-Assisted One-Pot Oligosaccharide Synthesis
tionalized linker. To solve this problem, we found that by
raising the reaction temperature to room temperature after
each glycosylation, the acceptor was completely consumed
and no deletion sequences were observed. The fluorous hy-
drazide 16 then successfully caught and released pure trisac-
charide 27 from the reaction mixture. The overall process
of acquiring trisaccharide 27 through a one-pot synthesis
and “catch and release” purification took 4 h with an over-
all yield of 62% starting from donor 24.
Scheme 3. Synthesis of disaccharide 23. TLC: Lane 1, reaction mix-
ture after glycosylation; Lane 2, reaction mixture after “catch”,
first F-SPE, and “release”; Lane 3, organic fraction after the sec-
ond F-SPE.
Scheme 4. Synthesis of LewisX trisaccharide 27.
To further examine the scope of our method, a linear
tetrasaccharide was synthesized through a four–component,
one-pot synthesis. Sequential preactivation-based one-pot
glycosylations of 21,[14] 28,[61] 28, and 15 gave tetrasaccha-
ride 29 (Scheme 5). The temperature-cycling protocol was
adopted to minimize deletion sequences. F-SPE purification
with hydrazide 16 generated pure tetrasaccharide 29 in 61%
yield from galactoside donor 21 within just a few hours.
Figure 3. (a) HPLC chromatogram of the crude reaction mixture
of compound 22 after the glycosylation reaction. The peak marked
with an * was ditolyl disulfide, which was a side product from do-
nor activation and has a strong UV absorbance band. This chroma-
togram corresponds to lane 1 of the TLC shown in Scheme 3; (b)
HPLC chromatogram of the organic fraction after the second F-
SPE, which corresponds to lane 3 of the TLC shown in Scheme 3.
(HPLC mobile phase: hexanes/ethyl acetate = 2:1, flow rate 1 mL/
min, UV monitoring at 256 nm, HPLC column: SupelCOSIL LC-
Si, 25 cmϫ4.6 mm, 5-µm particle size).
Scheme 5. Synthesis of tetrasaccharide 29.
On the basis of the success of disaccharide synthesis, we
moved on to test the feasibility of the fluorous-assisted as-
A potential concern with the acidic conditions employed
sembly of a branched oligosaccharide, LewisX trisaccha- for detagging is acid-mediated glycosidic linkage cleavage.
ride. LewisX is biologically important[57,58] and has been Although, in general, glycosidic linkages can be sensitive to
shown to be a good testing candidate for new synthetic acids, the cleavage rate is dependent on the amount of acid
methodologies.[25,26,59,60] For our synthesis, donor 24[27] was used. The LewisX trisaccharide 27 with the acid-labile fuco-
first preactivated by pTolSCl/AgOTf, which regiospecif- syl linkage was stable under the mild acidic conditions em-
ically glycosylated glucosamine diol 25 at its 4-hydroxy ployed for tag removal (0.5% TFA in acetone, 10 min).
group. Upon complete consumption of the acceptor 25, the Control experiments have shown that 27 was un-affected in
resulting disaccharide was immediately subject to fucosyl- 5% TFA over 30 min. Thus, the fluorous catch-and-release
ation by fucosyl donor 26[14] in the same reaction flask, protocol can be of general utility.
which led to the formation of LewisX trisaccharide 27 in
During our work, Seeberger and co-workers have re-
3 h (Scheme 4). One potential obstacle of the fluorous-as- ported a fluorinated silyl triflate to cap the non-fluorous
sisted one-pot synthesis was the incomplete consumption of oligosaccharide bearing a free hydroxy group assembled on
acceptors that leads to multiple products bearing the func- a solid phase,[47] which was the first time a fluorous-capping
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B. Yang, Y. Jing, X. Huang
FULL PAPER
4-Oxobutyl 2,3,4-Tri-O-benzoyl-β-
D
-galactopyranoside (9): p-
protocol on a desired product was adopted for carbo-
hydrate synthesis. Our fluorous hydrazide offers an alterna-
tive to the silyl triflate chemistry, as it does not require a
free hydroxy group in the oligosaccharide product with very
fast rates of tagging and release.
Methyl 2,3,4-tri-O-benzoyl-6-O-tert-butyl-diphenylsilyl-1-thio-β--
galactopyranoside 7[14] (540 mg, 0.65 mmol) was dissolved in DCM
(5 mL) and stirred at –78 °C with freshly activated molecular sieves
(MS 4 Å, 1 g) for 30 min. Silver triflate (498 mg, 1.94 mmol) dis-
solved in acetonitrile (0.3 mL) was added to the reaction mixture.
Five minutes later, orange pTolSCl (102 µL, 0.65 mmol) was added
directly into the reaction mixture. This addition needs to be per-
formed quickly in order to prevent pTolSCl from freezing inside
the syringe tip or on the flask wall. The yellow color of the solution
quickly dissipated within a few seconds, which indicates the com-
plete consumption of pTolSCl. 4-Penten-1-ol (80 µL, 0.7746 mmol,
dried by dissolving in DCM and by stirring with MS 4 Å molecular
sieves overnight before use) was then added slowly along the wall
of the flask. The reaction mixture was warmed to room tempera-
ture whilst stirring for 2 h. The reaction mixture was then diluted
with DCM and filtered through Celite. The Celite was washed with
Conclusions
We have developed a new fluorous “catch and release”
protocol, which facilitates the purification of the desired oli-
gosaccharide after a one-pot synthesis without the need for
any silica gel chromatography. Among several reactions ex-
amined, the easily accessible hydrazide 16 was found to be
the most suitable; it rapidly reacted with ketone-function-
alized oligosaccharides. Both linear and branched oligosac-
charides can be constructed with this strategy as exem- DCM until no organic compounds were present in the filtrate. The
filtrate was extracted with a saturated solution of NaHCO3. The
organic layer was then dried with Na2SO4 and concentrated to dry-
ness. The residue was purified by silica gel column chromatography
(hexanes/EtOAc, 4:1) to give compound 4-oxobutyl 2,3,4-tri-O-
plified by the one-pot assemblies of LewisX trisaccharide
27 and the galactose containing tetrasaccharide 29. Because
of the rapid reaction rates and substantially reduced volume
of organic solvents employed for purification, this post-gly-
cosylation tagging strategy provides an attractive alternative
to the current practice of pre-glycosylation introduction of
fluorous tags.
benzoyl-6-tert-butyl-diphenylsilyl-β--galactopyranoside
8
(464
mg, 90%). [α]2D0 = +83, (c = 1.0, CH2Cl2). 1H NMR (500 MHz,
CDCl3): δ = 8.02–7.08 (m, 25 H, COPh, Ph), 6.01 (dd, J3,4 = 3.5,
J4,5 = 1 Hz, 1 H, 4-H), 5.68 (dd, J1,2 = 7.5, J2,3 = 10.5 Hz, 1 H, 2-
H), 5.64–5.60 (m, 1 H, OCH2CH2CH2CHCH2), 5.59 (dd, J2,3
10.5, J3,4 3.5 Hz, H, 3-H), 4.81–4.76 (m,
=
H,
=
1
2
Experimental Section
OCH2CH2CH2CHCHH), 4.71 (d, J1,2 = 7.5 Hz, 1 H, 1-H), 4.03
(dt, J4,5 = 1, J5,6 = 7 Hz, 1 H, 5-H), 3.91–3.87 (m, 1 H,
OCHHCH2CH2CHCH2), 3.81 (d, J5,6 = 7 Hz, 2 H, 6-H), 3.52–3.47
(m, 1 H, OCHHCH2CH2CHCH2), 1.97–1.91 (m, 2 H, OCH2CH2-
CHHCHCH2), 1.65–1.55 (m, 2 H, OCH2CHHCHCHCH2), 0.98
[s, 9 H, C(CHH2)3] ppm. 13C NMR (125 MHz, CDCl3): δ = 165.6,
165.4, 165.2 (3 C, COPh), 137.7, 136.4, 135.5, 135.4, 133.2, 133.0,
132.9, 132.6, 130.1, 129.9, 129.8, 129.7, 129.6, 129.6, 129.5, 129.5,
129.3, 129.0, 128.4, 128.3, 128.2, 127.7, 127.6, 127.5, 114.7, 101.5,
73.8, 71.9, 70.1, 69.3, 67.9, 61.4, 29.7, 28.5, 26.6 [C(CH3)3], 18.9
[C(CH3)3] ppm. HRMS: calcd. for C48H50O9SiNa [M + Na]+
821.3122; found 821.3162. This compound was dissolved in pyr-
idine (4 mL) in a plastic flask, followed by addition of 65–70%
an HF·pyridine solution (4 mL) at 0 °C. The solution was stirred
overnight until complete disappearance of the starting material as
judged from TLC analysis. The reaction mixture was diluted with
EtOAc and washed with 10% aqueous CuSO4 solution. The aque-
ous phase was extracted with EtOAc twice, and the combined or-
ganic layers were washed with saturated aqueous NaHCO3 solu-
tion. After drying over Na2SO4 and after concentration, the residue
was purified by silica gel column chromatography (hexanes/EtOAc,
5:2 then 2:1). The product was dissolved in DCM (3 mL) in a three-
neck flask and stirred at –78 °C, and O3 was bubbled into the solu-
tion. The solution turned blue after a few seconds, and polymer-
supported triphenylphosphane (3.0 mmol/g, 600 mg) was added
into the flask. The reaction mixture was further stirred overnight
at room temperature. The polymer was removed by filtration, and
the solution was concentrated and purified by silica gel chromatog-
raphy (hexanes/EtOAc, 1:1) to give compound 9 (228 mg, 80%).
However, this compound was not very stable and was partially oxi-
General Experimental Procedures: All reactions were carried out
under nitrogen with anhydrous solvents in flame-dried glassware,
unless otherwise noted. Glycosylation reactions were performed in
the presence of molecular sieves, which were flame-dried right be-
fore the reaction under high vacuum. Glycosylation solvents were
dried by using a solvent purification system and used directly with-
out further drying. HPLC grade hexanes and ethyl acetate were
used as the HPLC solvents. The HPLC column used was SupelCO-
SIL LC-Si, with the dimensions of 25 cmϫ4.6 mm and a 5-µm
particle size. The chemicals used were of reagent grade as supplied,
except where noted. Compound 5 and the fluorous silica gel were
purchased from Fluorous Technologies Incorporated. Analytical
thin-layer chromatography was performed by using silica gel 60
F254 glass plates. The compounds were visualized by a UV light
(254 nm) and by staining with a yellow solution containing
Ce(NH4)2(NO3)6 (0.5 g) and (NH4)6Mo7O24·4H2O (24.0 g) in 6%
H2SO4 (500 mL). Flash column chromatography was performed on
silica gel 60 (230–400 Mesh). Fluorous column chromatography
was performed on a 40-µm fluorous silica gel purchased from Fluo-
rous Technologies. NMR spectra were referenced by using residual
CHCl3 (δ = 1H NMR 7.26 ppm, 13C NMR 77.0 ppm). Peak and
coupling constant assignments are based on 1H NMR, 1H-1H
gCOSY and/or 1H-13C gHMQC and 1H-13C gHMBC experiments.
All optical rotations were measured at 25 °C by using the sodium
D line.
Characterization of Anomeric Stereochemistry: The stereochem-
istries of the newly formed glycosidic linkages in disaccharide 22,
LewisX trisaccharide 27, and tetrasaccharide 29 were determined
3
1
by JH1,H1 through 1H NMR and/or JC1,H1 through gHMQC 2-
1
dized to carboxylic acid over time, as evidenced by H NMR and
D NMR (without 1H decoupling) spectroscopy. Smaller coupling
1
13C NMR spectroscopy. H NMR (500 MHz, CDCl3): δ = 9.53 (t,
3
constants of JH1,H2 (about 3 Hz) indicate α linkages and larger
J = 1 Hz, 1 H, CHO, this peak became smaller over time), 8.11–
7.22 (m, 15 H, COPh), 5.83–5.79 (m, 2 H, 2-H, 4-H), 5.58 (dd, J2,3
= 10, J3,4 = 3 Hz, 1 H, 3-H), 4.77 (dd, J1,2 = 8 Hz, 1 H, 1-H), 4.01–
coupling constants of 3JH1,H1 (7.2 Hz or larger) indicate β linkages.
1JC1,H1 of about 170 Hz suggests α linkages and 160 Hz suggests β
linkages.[62]
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Fluorous-Assisted One-Pot Oligosaccharide Synthesis
3.95 (m, 2 H, 5-H, OCHHCH2CH2CHO), 3.83–3.80 (m, 1 H, 6- 7.5 Hz, 1 H, 1-H), 4.18–4.15 (m, 1 H, OCHHCH2CO), 4.05 (dt,
H), 3.66–3.59 (m, 2 H, 6Ј-H, OCHHCH2CH2CHO), 2.47–2.35 (m, J4,5 = 1, J5,6 = 9 Hz, 1 H, 5-H), 3.97–3.92 (m, 1 H, OCHHCH2CO),
2 H, OCH2CH2CHHCHO), 1.89–1.80 (m, 2 H, OCH2CHHCH2-
3.84–3.82 (m, 1 H, 6-H), 3.69–3.65 (m, 1 H, 6-H), 2.82 (m, 1 H,
CHO) ppm. 13C NMR (125 MHz, CDCl3): δ = 202.5 (CHO), 173.9 OH), 2.76–2.69 (m, 1 H, OCH2CHHCO), 2.66–2.61 (m,1 H,
(COOH, formed from oxidation of aldehyde), 165.0, 164.9, 164.6
(3 C, COPh), 133.7, 133.6, 133.6, 129.1, 129.1, 129.0, 128.9, 128.8,
128.8, 128.8, 128.7, 128.6, 99.7, 72.9, 71.9, 70.1, 68.3, 68.2, 68.1,
58.9, 29.7, 24.5, 21.7 ppm.
OCH2CHHCO), 1.99 (s, 1
H, COCHH2) ppm. 13C NMR
(125 MHz, CDCl3): δ = 206.6 (COCH3), 166.5, 165.4, 165.3 (3 C,
COPh), 133.6, 133.2, 133.1, 129.9, 129.6, 129.2, 128.7, 128.7, 128.5,
128.2, 128.2, 101.8, 74.0, 71.7, 69.8, 68.8, 65.3, 60.5, 43.3, 30.3,
20.9, 14.0 ppm. HRMS : calcd. for C13H13F17N3O [M + H]+
585.1737; found 585.1726.
Fluorous Alkyl Hydrazine (13): Tri-Boc-protected α-hydrazinoacetic
acid 10[63] (378 mg, 0.97 mmol) and 3-(perfluorooctyl)propylamine
11 (463 mg, 0.97 mmol) were dissolved in DMF (6 mL), and EDC
(278 mg, 1.46 mmol) and 4-dimethylaminopyridine (177 mg,
1.46 mmol) were added to the solution. The reaction mixture was
stirred at room temperature overnight. DMF was removed, and the
residue was purified by silica gel column chromatography (hexanes/
EtOAc, 3:1) to yield tri-Boc-protected ester, which was dissolved in
DCM (3 mL), followed by treatment with trifluoroacetic acid
(3 mL) overnight at room temperature. The solvent was removed
and dried under high vacuum to provide compound 13 (450 mg,
70% over two steps) in the form of a salt. 1H NMR (500 MHz,
CD3OD): δ = 3.64, 3.51 (s, 2 H, NH2NHCHHCO), 3.33 (t, 2 H,
CHHC8F17), 2.27–2.16 (m, 2 H, CONHCHH), 1.99–1.85 (m, 2 H,
NHCH2CHHCH2C8F17) ppm. 13C NMR (125 MHz, CD3OD): δ
= 170.5 (CO of TFA), 169.3 (CONH), 50.5, 38.1, 28.2, 20.3 ppm.
19F NMR (282 MHz, CD3OD): δ = –77.18 (s, 3 F), –82.43 (t, 3 F),
–115.31 (m, 2 F), –122.91 (m, 6 F), –123.76 (m, 2 F), –124.40 (m,
2 F), –127.31 (m, 2 F) ppm. HRMS : calcd. for C13H13F17N3O [M
+ H]+ 550.0800; found 550.0787.
Fluorous Acyl Hydrazide (16): 2H,2H,3H,3H-Perfluoroundecanoic
acid 18 (241 mg, 0.49 mmol) and tert-butyl carbazate 19 (77.6 mg,
0.59 mmol) were dissolved in DMF (5 mL), followed by the ad-
dition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride (141 mg, 0.74 mmol). The resulting solution was stirred
overnight at room temperature. DMF was removed, and the residue
was purified by silica gel column chromatography (hexanes/EtOAc,
3:1) to give Boc-protected 20, which was further treated with tri-
fluoroacetic acid (3 mL) in DCM (3 mL). After stirring the mixture
at room temperature overnight, the solvent was removed, and the
residue was dried under high vacuum to give compound 16
(225 mg, 74% over two steps) in the form of salt. 1H NMR
(500 MHz, CD3OD): δ = 2.61 (m, 4 H) ppm. 13C NMR (125 MHz,
CD3OD): δ = 171.4 (CO of TFA), 162.6 (CONHNH2), 27.1, 25.3
ppm. 19F NMR (282 MHz, CD3OD): δ = –77.01 (m, 2 F), –82.59
(t, 3 F), –115.84 (m, 1 F), –123.01 (m, 3 F), –123.87 (m, 1 F),
–124.64 (m, 1 F), –127.44 (m, 1 F) ppm. HRMS : calcd. for
C11H8F17N2O [M + H]+ 507.0365; found 507.0369.
3-Oxobutyl 2,3,4-Tri-O-benzoyl-β-D-galactopyranoside (15): p-Tolyl
General Procedure for “Catch” and “Release”: The reaction mixture
was dispersed in DCM/MeOH (1:1, 2 mL). Fluorous hydrazide
(2 equiv., by assuming that the glycosylation yield was quantitative)
was added to the solution. After stirring at room temperature for
5 min, the solution was neutralized by NaHCO3 to pH 6–7. Follow-
ing the removal of the solvent, the residue was loaded into a short
fluorous silica gel column (5 g fluorous silica) with MeOH
(0.3 mL). The column was first flushed with MeOH/H2O (4:1,
5 mL), and all the non-fluorous compounds came out immediately.
This was followed by flushing with MeOH (5 mL) to elute the fluo-
rous compounds. The fluorous fraction was collected and concen-
trated to dryness. The residue was then dissolved in a solution of
0.5% TFA in acetone (2 mL). After stirring the solution at room
temperature for 10 min, the solvent was removed, and the residue
was loaded onto a fluorous column. After flushing with MeOH/
H2O (4:1, 5 mL), the desired product came out immediately, which
was concentrated and dried under high vacuum to provide the pure
product.
2,3,4-tri-O-benzoyl-6-O-tert-butyl-diphenylsilyl-1-thio-β--galacto-
pyranoside 7[64] (299 mg, 0.36 mmol) and 4-hydroxy-2-butanone
(37 µL, 0.43 mmol, dried by dissolving in DCM and by stirring
with MS 4 Å molecular sieves overnight before use) were dissolved
in DCM (5 mL) and stirred at –78 °C with freshly activated molec-
ular sieves (MS 4 Å, 600 mg) for 30 min. Silver triflate (276 mg,
1.07 mmol) dissolved in acetonitrile (0.3 mL) was added to the re-
action mixture. Five minutes later, orange pTolSCl (56.6 µL,
0.36 mmol) was added directly into the reaction mixture. This ad-
dition needs to be performed quickly in order to prevent pTolSCl
from freezing inside the syringe tip or on the flask wall. The yellow
color of the solution quickly dissipated within one minute, which
indicates the complete consumption of pTolSCl. The reaction mix-
ture was warmed to room temperature whilst stirring for 2 h. The
reaction mixture was then diluted with DCM and filtered through
Celite. The Celite was washed with DCM until no organic com-
pounds were present in the filtrate. The filtrate was extracted with
a saturated solution of NaHCO3. The organic layer was then dried
with Na2SO4 and concentrated to dryness. The residue was purified
by silica gel column chromatography (hexanes/EtOAc, 4:1). The
product was dissolved in pyridine (4 mL) in a plastic flask followed
by addition of a 65–70% HF·pyridine solution (2.5 mL) at 0 °C.
The solution was stirred overnight until complete disappearance of
the starting material as judged from TLC analysis. The reaction
mixture was diluted with EtOAc and washed with 10% aqueous
CuSO4 solution. The aqueous phase was extracted with EtOAc
twice, and the combined organic layers were washed with a satu-
rated aqueous NaHCO3 solution. After drying over Na2SO4 and
after concentration, the residue was purified by silica gel column
chromatography (hexanes/EtOAc, 1:1 then 1:2) to give compound
15 (148 mg, 74% over two steps). [α]2D0 = +162 (c = 0.2, CH2Cl2).
3-Oxobutyl 2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl-(1Ǟ6)-
2,3,4-tri-O-benzoyl-β- -galactopyranoside (22): p-Tolyl 2,3,4,6-
D
tetra-O-benzoyl-1-thio-β--galactopyranoside[14] (29 mg, 0.041
mmol) and compound 15 (19 mg, 0.034 mmol) were dissolved in
DCM (3 mL) and stirred at –78 °C with freshly activated molecular
sieves (MS 4 Å, 150 mg) for 30 min. Silver triflate (32 mg,
0.12 mmol) dissolved in acetonitrile (30 µL) was added to the reac-
tion mixture. Five minutes later, orange pTolSCl (6.53 µL,
0.041 mmol) was added directly into the reaction mixture. This ad-
dition needs to be performed quickly in order to prevent pTolSCl
from freezing inside the syringe tip or on the flask wall. The yellow
color of the solution quickly dissipated within a few seconds, which
indicates the complete consumption of pTolSCl. The reaction mix-
1H NMR (500 MHz, CDCl3): δ = 8.07–7.18 (m, 15 H, COPh), ture was warmed to room temperature whilst stirring for 2 h. The
5.83–5.81 (m, 1 H, 4-H), 5.75 (dd, J1,2 = 7.5, J2,3 = 10.5 Hz, 1 H,
2-H), 5.59 (dd, J2,3 = 10.5, J3,4 = 3 Hz, 1 H, 3-H), 4.86 (d, J1,2
reaction mixture was then concentrated to dryness and redispersed
in DCM/MeOH (1:1). Compound 16 (51 mg, 0.082 mmol) was
=
Eur. J. Org. Chem. 2010, 1290–1298
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1295

B. Yang, Y. Jing, X. Huang
FULL PAPER
added to the solution. Following the general procedure for “catch
3-Oxobutyl 2-O-Benzoyl-3,4,6-tri-O-benzyl-β-
(1Ǟ4)-[2,3,4-tri-O-benzyl-α- -fucopyranosyl-(1Ǟ3)]-6-O-benzyl-2-
-glucopyranoside (27): p-Tolyl 2-O-ben-
D-galactopyranosyl-
and release”, compound 22 (31 mg, 80%) was obtained. [α]2D0
=
L
+100 (c = 0.1, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 8.09– deoxy-2-N-phthalimido-β-
D
7.19 (m, 35 H, COPh), 5.96–5.91 (m, 1 H, 4Ј-H), 5.87–5.81 (m, 1 zoyl-3,4,6-tri-O-benzyl-1-thio-β--galactopyranoside 24[27] (40.3
H, 4-H), 5.76 (dd, J1Ј,2Ј = 8, J2Ј,3Ј = 10.5 Hz, 1 H, 2Ј-H), 5.65–5.57 mg, 0.061 mmol) was dissolved in DCM (5 mL) and stirred at
(m, 2 H, 2-H, 3Ј-H), 5.47 (dd, J2,3 = 10, J3,4 = 3.5 Hz, 1 H, 3-H), –78 °C with freshly activated molecular sieves (MS 4 Å, 300 mg) for
4.93 (d, J1Ј,2Ј = 8 Hz, 1 H, 1Ј-H), 4.68 (d, J1,2 = 8 Hz, 1 H, 1-H),
30 min. Silver triflate (47 mg, 0.19 mmol) dissolved in acetonitrile
4.44 (m, 1 H, 6Ј-H), 4.29–4.24 (m, 2 H, 5Ј-H, 6Ј-H), 4.16–4.12 (m, (50 µL) was added to the reaction mixture. Five minutes later,
2 H, 5-H, 6-H), 3.88–3.78 (m, 2 H, 6-H, OCHHCH2CO), 3.66– orange pTolSCl (9.65 µL, 0.061 mmol) was added directly into the
3.61 (m, 1 H, OCHHCH2CO), 2.55–2.50 (m, 1 H, OCH2CHHCO),
2.31–2.27 (m, 1 H, OCH2CHHCO), 1.87 (s, 3 H, COCHH2) ppm.
13C NMR (125 MHz, CDCl3): δ = 206.6 (COCH3), 165.9, 165.5,
165.5, 165.3, 165.3, 165.2, 165.0 (7 C, COPh), 133.5, 133.4, 133.2,
133.2, 133.1, 133.1, 130.0, 129.9, 129.7, 129.7, 129.7, 129.3, 129.3,
129.3, 129.1, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 128.4, 128.3,
reaction mixture. This addition needs to be performed quickly in
order to prevent pTolSCl from freezing inside the syringe tip or on
the flask wall. The yellow color of the solution quickly dissipated
within a few seconds, which indicates the complete consumption of
pTolSCl. Glucosamine acceptor 25 (23 mg, 0.049 mmol) dissolved
in DCM (0.2 mL) was then added dropwise to the reaction mixture.
The mixture was stirred for a further 1 h, at which point the tem-
perature reached room temperature and glucosamine acceptor 25
was completely consumed. The fucose donor 26 (53.5 mg,
0.099 mmol) dissolved in DCM (1 mL) was added to the mixture.
The solution was cooled back to –78 °C, and silver triflate
(50.3 mg, 0.196 mmol) dissolved in acetonitrile (50 µL) was added.
Five minutes later, orange pTolSCl (15.6 µL, 0.099 mmol) was
added directly into the reaction mixture. The reaction mixture was
warmed to room temperature whilst stirring for 1 h. The reaction
mixture was then concentrated to dryness and redispersed in DCM/
MeOH (1:1). Compound 16 (61 mg, 0.098 mmol) was added to the
solution. Following the general procedure for fluorous “catch and
release”, pure 27 (44 mg, 62%) was obtained. [α]2D0 = –49 (c = 0.3,
CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.93–6.87 (m, 44 H,
CH2Ph, COPh, H of NPhth), 5.11 (dd, J1Ј,2Ј = 10, J2Ј,3Ј = 8 Hz, 1
H, 2Ј-H), 4.90–4.80 (m, 3 H, 1-H), 4.67–4.26 (m, 15 H, 1Ј-H, 1ЈЈ-
H), 4.17–4.04 (m, 3 H), 3.86–3.72 (m, 6 H, OCHHCH2CO), 3.64–
3.17 (m, 7 H, OCHHCH2CO), 2.51–2.45 (m, 1 H, OCH2CHHCO),
1.78 (s, 3 H, COCHH2), 1.21 (d, J = 6.5 Hz, 3 H, CH3 of fucose)
ppm. 13C NMR (125 MHz, CDCl3): δ = 206.3 (COCH3), 164.6 (1
C, COPh), 139.3, 139.1, 138.6, 138.2, 138.1, 137.8, 137.7, 133.9,
133.0, 129.8, 129.7, 128.7, 128.5, 128.4, 128.4, 128.3, 128.1, 128.0,
127.8, 127.8, 127.8, 127.8, 127.7, 127.7, 127.6, 127.4, 127.1, 127.0,
128.2, 128.1, 101.6 (JC1,H1 = 160.9 Hz, 1 C), 101.1 (JC1Ј,H1Ј
=
161.5 Hz, 1 C), 73.2, 71.5, 71.5, 71.2, 69.8, 69.7, 68.6, 68.0, 67.9,
64.9, 61.7, 43.0, 30.4, 29.6 ppm. HRMS : calcd. for C65H56O19Na
[M + Na]+ 1163.3314; found 1163.3339.
6-O-β-D-Galactopyranosyl-D-galactose (23): To compound 22
(38 mg, 0.033 mmol) dissolved in MeOH (4 mL) was added drop-
wise 0.1  NaOMe/MeOH, until the pH was 11. The reaction mix-
ture was stirred at room temperature for 4 h. After the reaction
was complete, the solution was neutralized by acidic resin. After
filtration and size-exclusion chromatography by using Sephadex G-
15, compound 23 was isolated in 80% yield. The identity of com-
pound 23 was confirmed by comparison with literature NMR spec-
troscopic data and MS analysis.[64]
3-Oxobutyl 6-O-Benzyl-2-deoxy-2-N-phthalimido-β-D-glucopyran-
oside (25): p-Tolyl 6-O-benzyl-2-deoxy-2-N-phthalimido-1-thio-β-
-glucopyranoside[65] (292 mg, 0.58 mmol) and 4-hydroxy-2-but-
anone (498 µL, 5.78 mmol, dried by dissolving in DCM and by
stirring with MS 4 Å molecular sieves overnight before use) were
dissolved in DCM (5 mL) and stirred at –78 °C with freshly acti-
vated molecular sieves (MS 4 Å, 800 mg) for 30 min. Silver triflate
(445 mg, 1.73 mmol) dissolved in acetonitrile (0.3 mL) was added
to the reaction mixture. Five minutes later, orange pTolSCl
(91.3 µL, 0.58 mmol) was added directly into the reaction mixture.
This addition needs to be performed quickly in order to prevent
pTolSCl from freezing inside the syringe tip or on the flask wall.
The yellow color of the solution quickly dissipated within a few
seconds, which indicates the complete consumption of pTolSCl.
The reaction mixture was warmed to room temperature whilst stir-
ring for 2 h. The reaction mixture was then diluted with DCM and
filtered through Celite. The Celite was washed with DCM until no
organic compounds were present in the filtrate. The filtrate was
extracted with a saturated solution of NaHCO3. The organic layer
was then dried with Na2SO4 and concentrated to dryness. The resi-
due was purified by silica gel column chromatography (hexanes/
EtOAc, 1:2) to give compound 25 (243 mg, 90%). [α]2D0 = –45 (c =
126.9, 126.9, 123.4, 99.8 (JC1Ј,H1Ј = 162.2 Hz, 1 C), 98.5 (JC1,H1
=
163.8 Hz, 1 C), 96.9 (JC1ЈЈ,H1ЈЈ = 170.2 Hz, 1 C), 80.2, 79.4, 78.5,
75.4, 74.9, 74.8, 74.2, 73.8, 73.5, 73.4, 72.9, 72.7, 72.4, 72.0, 71.9,
71.6, 71.1, 67.7, 66.5, 64.6, 56.3, 43.0, 30.2, 29.6, 16.3 ppm. HRMS
: calcd. for C86H87NO18Na [M + Na]+ 1444.5821; found 1444.5787.
3-Oxobutyl (2,3,4,6-Tetra-O-benzoyl-β-
[(2,3,4,6-tetra-O-benzoyl-β- -galactopyranosyl)-(1Ǟ6)]-[(2,3,4,6-
tetra-O-benzoyl-β- -galactopyranosyl)-(1Ǟ6)]-2,3,4,6-tetra-O-benz-
oyl-β-
D-galactopyranosyl)-(1Ǟ6)-
D
D
D
-galactopyranoside (29): p-Tolyl 2,3,4,6-tetra-O-benzoyl-1-
thio-β--galactopyranoside 21[14] (50 mg, 0.071 mmol) was dis-
solved in DCM (5 mL) and stirred at –78 °C with freshly activated
molecular sieves (MS 4 Å, 400 mg) for 30 min. Silver triflate
(55 mg, 0.21 mmol) dissolved in acetonitrile (50 µL) was added to
0.1, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 7.82–7.24 (m, 9 H, the reaction mixture. Five minutes later, orange pTolSCl (11.25 µL,
CH2Ph, H of NPhth), 5.16 (d, J1,2 = 8.5 Hz, 1 H, 1-H), 4.54–4.63 0.071 mmol) was added directly into the reaction mixture. This ad-
(m, 2 H, CH2Ph), 4.33–4.29 (m, 1 H, 3-H), 4.06 (d, J1,2 = 8.5, J2,3
= 11 Hz, 1 H, 2-H), 3.99–3.94 (m, 1 H, OCHHCH2CO), 3.80–3.68
(m, 3 H, 5-H, 6-H, OCHHCH2CO), 3.62–3.55 (m, 2 H, 4-H, 6-H),
dition needs to be performed quickly in order to prevent pTolSCl
from freezing inside the syringe tip or on the flask wall. The yellow
color of the solution quickly dissipated within a few seconds, which
3.24 (d, JH-4,OH-4 = 2.5 Hz, 1 H, OH-4), 2.82 (d, JH-3,OH-3 = 4.5 Hz, indicates the complete consumption of pTolSCl. Acceptor 28
1 H, OH-3), 2.60–2.54 (m, 1 H, OCH2CHHCO), 2.48–2.43 (m, 1 (34 mg, 0.057 mmol) dissolved in DCM (1 mL) was then added
H, OCH2CHHCO), 1.87 (s, 3 H, COCHH2) ppm. 13C NMR dropwise to the reaction mixture. This mixture was warmed up to
(125 MHz, CDCl3): δ = 206.5 (COCH3), 168.3 (1 C, COPh), 137.6,
134.0, 131.7, 128.5, 127.9, 127.7, 123.3, 98.5, 73.8, 71.5, 70.3, 64.8,
56.1, 43.1, 30.2 ppm. HRMS : calcd. for C25H27NO8Na [M +
Na]+ 492.1634; found 492.1612.
room temperature whilst stirring for 1 h. The reaction mixture was
kept at room temperature for 0.5 h to completely decompose the
excess activated donor. The solution was then cooled back to
–78 °C. Silver triflate (29 mg, 0.11 mmol) dissolved in acetonitrile
1296
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1290–1298

Fluorous-Assisted One-Pot Oligosaccharide Synthesis
[9] A. V. Demchenko, P. Pornsuriyasak, C. De Meo, N. N. Malysh-
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Soc. 2001, 123, 8477–8481.
(50 µL) was added to the reaction mixture. Five minutes later,
orange pTolSCl (9 µL, 0.057 mmol) was added directly into the re-
action mixture. After 5 min, acceptor 28 (26.8 mg, 0.045 mmol) dis-
solved in DCM (1 mL) was added dropwise to the reaction mixture.
The reaction mixture was warmed up to room temperature whilst
stirring for 1 h and kept at room temperature for 0.5 h to com-
pletely decompose the excess activated donor. Acceptor 15
(14.7 mg, 0.026 mmol) dissolved in DCM (1 mL) was then added
to the reaction mixture. The solution was cooled back to –78 °C.
Silver triflate (23 mg, 0.090 mmol) dissolved in acetonitrile (50 µL)
was added to the reaction mixture. Five minutes later, pTolSCl
(7 µL, 0.045 mmol) was added directly into the reaction mixture.
This was warmed up to room temperature whilst stirring for 1 h.
The reaction mixture was then concentrated to dryness and redis-
persed in DCM/MeOH (1:1). Compound 16 (34 mg, 0.052 mmol)
was added to the solution. Following the general procedure for
fluorous “catch and release”, pure 29 (34 mg, 61%) was obtained.
[12] M. Johnson, C. Aries, G.-J. Boons, Tetrahedron Lett. 1998, 39,
9801–9804.
[13] R. Roy, F. O. Andersson, M. Letellier, Tetrahedron Lett. 1992,
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H. Wong, J. Am. Chem. Soc. 1999, 121, 734–753.
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Am. Chem. Soc. 1988, 110, 5583–5584.
[17] J. D. C. Codee, L. J. van den Bos, R. E. J. N. Litjens, H. S. Ov-
erkleeft, C. A. A. van Boeckel, J. H. van Boom, G. A.
van der Marel, Tetrahedron 2004, 60, 1057–1064 and references
cited therein.
1
[α]2D0 = +68 (c = 0.1, CH2Cl2). H NMR (500 MHz, CDCl3): δ =
8.06–7.17 (m, 65 H, COPh), 5.89–5.79 (m, 4 H, 4-H, 4Ј-H, 4ЈЈ-H,
4ЈЈЈ-H), 5.66–5.38 (m, 8 H, 2-H, 2Ј-H, 2ЈЈ-H, 2ЈЈЈ-H, 3-H, 3Ј-H,
3ЈЈ-H, 3ЈЈЈ-H), 4.79 (d, J = 8 Hz, 1 H, 1ЈЈЈ-H), 4.66 (d, J = 8 Hz,
1 H, 1-H), 4.53–4.49 (m, 2 H, HЈ, HЈЈ), 4.22-. 3.72 (m, 11 H, 5-H,
5Ј-H, 5ЈЈ-H, 5ЈЈЈ-H, 6-H, 6Ј-H, 6ЈЈ-H, 6ЈЈ-H, 6ЈЈЈ-H, 6ЈЈЈ-H,
OCHHCH2CO), 3.65–3.60 (m, 1 H, OCHHCH2CO), 3.56–3.52 (m,
1 H, 6Ј-H), 3.34–3.31 (m, 1 H, 6-H), 2.52–2.47 (m, 1 H,
OCH2CHHCO), 2.30–2.25 (m, 1 H, OCH2CHHCO), 1.84 (s, 3 H,
COCH3) ppm. 13C NMR (125 MHz, CDCl3): δ = 206.3 (COCH3),
165.7, 165.5, 165.4, 165.3, 165.3, 165.2, 165.2, 165.1, 165.0, 164.9
(13 C, COPh), 133.4, 133.2, 133.1, 133.1, 133.0, 133.0, 132.9, 130.1,
130.0, 130.0, 129.9, 129.8, 129.7, 129.7, 129.7, 129.7, 129.6, 129.4,
129.4, 129.3, 129.3, 129.2, 129.0, 128.9, 128.9, 128.7, 128.5, 128.4,
[18] S. Yamago, T. Yamada, T. Maruyama, J.-I. Yoshida, Angew.
Chem. Int. Ed. 2004, 43, 2145–2148.
[19] D. Crich, W. Li, H. Li, J. Am. Chem. Soc. 2004, 126, 15081–
15086 and references cited therein.
[20] X. Huang, L. Huang, H. Wang, X.-S. Ye, Angew. Chem. Int.
Ed. 2004, 43, 5221–5224.
[21] O. J. Plante, E. R. Palmacci, P. H. Seeberger, Science 2001, 291,
1523–1527.
[22] Y. Wang, X.-S. Ye, L.-H. Zhang, Org. Biomol. Chem. 2007, 5,
2189–2200.
[23] B. Yu, Z. Y. Yang, H. Z. Cao, Curr. Org. Chem. 2005, 9, 179–
194.
[24] H. Tanaka, M. Adachi, H. Tsukamoto, T. Ikeda, H. Yamada,
T. Takahashi, Org. Lett. 2002, 4, 4213–4216.
[25] A. Miermont, Y. Zeng, Y. Jing, X.-S. Ye, X. Huang, J. Org.
Chem. 2007, 72, 8958–8961.
[26] H. Tanaka, N. Matoba, H. Tsukamoto, H. Takimoto, H. Yam-
ada, T. Takahashi, Synlett 2005, 824–828 and references cited
therein.
128.4, 128.4, 128.3, 128.3, 128.2, 128.1, 128.1, 101.6 (JC1ЈЈЈ,H1ЈЈЈ
=
162.5 Hz, 1 C), 101.0 (JC1,H1 = 162.5 Hz, 1 C), 100.8, 100.7 (JC1Ј,H1Ј
= 160.1, JC1ЈЈ,H1ЈЈ = 160.1 Hz, 2 C), 72.9, 72.5, 72.2, 71.6, 71.5,
71.1, 69.9, 69.8, 69.8, 69.7, 68.5, 67.8, 67.8, 67.7, 67.5, 66.3, 66.2,
64.9, 61.3, 43.0, 36.6, 30.3, 29.6, 24.6 ppm. HRMS : calcd. for
[27] Z. Wang, L. Zhou, K. El-boubbou, X.-S. Ye, X. Huang, J. Org.
Chem. 2007, 72, 6409–6420.
C
119H100O35Na [M + Na]+ 2111.5943; found 2111.5969.
[28] C.-Y. Huang, D. A. Thayer, A. Y. Chang, M. D. Best, J. Hoff-
man, S. Head, C.-H. Wong, Proc. Natl. Acad. Sci. USA 2006,
103, 15–20.
Supporting Information (see footnote on the first page of this arti-
cle): TLC for “catch and release” of compounds 27 and 29, HPLC
chromatogram for reaction mixtures and pure compounds 27 and
29 after “catch and release”, and NMR spectroscopic data of all
new compounds.
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We are grateful to the National Institutes of Health (R01-GM-
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Received: October 13, 2009
Published Online: January 27, 2010
1298
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1290–1298