One-pot catalytic glycosidation/Fmoc removal - An iterable sequence for straightforward assembly of oligosaccharides related to HIV gp120

Article abstract of DOI:10.1002/ejoc.200901122

The removal of a transient Fmoc protecting group can be simply performed by the addition of excess Et₃N just after the accomplishment of a Bi(OTf)₃-promoted glycosidation reaction. The obtained oligosaccharide can be directly employed as a glycosyl acceptor for further elongation of the saccharide. The preparation of biologically important, linear and branched mannans incorporated into HIV gp 120 demonstrates that the iteration of this one-pot sequence leads to a very straightforward oligosaccharide assembly.

Full text of DOI:10.1002/ejoc.200901122

FULL PAPER
DOI: 10.1002/ejoc.200901122
One-Pot Catalytic Glycosidation/Fmoc Removal – An Iterable Sequence for
Straightforward Assembly of Oligosaccharides Related to HIV gp120[‡]
Antonello Pastore,*[a] Matteo Adinolfi,[a] Alfonso Iadonisi,*[a] and Silvia Valerio[a][‡‡]
Keywords: Oligosaccharides / Glycosylation / Protecting groups / One-pot synthesis / Fmoc / Synthetic methods
The removal of a transient Fmoc protecting group can be
simply performed by the addition of excess Et3N just after
the accomplishment of a Bi(OTf)3-promoted glycosidation re-
action. The obtained oligosaccharide can be directly em-
ployed as a glycosyl acceptor for further elongation of the
saccharide. The preparation of biologically important, linear
and branched mannans incorporated into HIV gp120 demon-
strates that the iteration of this one-pot sequence leads to a
very straightforward oligosaccharide assembly.
cosidations.[5] Further progress in all these strategies has
been attained through the implementation of sequential gly-
cosidations in a one-pot fashion.[6] In this regard, we have
very recently reported the first examples of one-pot, mul-
tiple glycosidations exclusively relying on catalytic condi-
tions for donor activation as well as on the use of experi-
mentally convenient, moisture-stable promoters.[7,8] With
few exceptions, the sequential glycosidations so far de-
scribed involve the elongation of the oligomer starting from
the nonreducing terminus of the target. However, with the
exception of the above-mentioned preactivation strategy,
the success of the elongation is critically dependent on the
availability of a set of glycosyl donors displaying well-differ-
entiated reactivities.
Introduction
In recent years, the ever-expanding interest in the appli-
cative potential of oligosaccharides in biochemical and
pharmacological studies has elicited a massive effort
towards the development of efficient approaches to gain
complex sequences in relatively short times.[1] Typical pro-
cedures in oligosaccharide synthesis often suffer from
lengthy experimental operations; numerous steps are re-
quired for both preparing the requisite saccharide precur-
sors from commercially available compounds and assemb-
ling the oligomeric target through a sequence of coupling
reactions alternated with protection/deprotection steps.
Most of these synthetic steps also entail lengthy chromato-
graphic procedures.
In this paper, we follow the less common approach of
sequential glycosidations featuring the opposite elongation
direction.[9] In general terms, this can be pursued by first
coupling a glycosyl donor with a glycosyl acceptor and then
removing in the same reaction vessel a transient protecting
group from the in-situ-generated di- or oligosaccharide. In
this way, after a single purification process, a potential gly-
cosyl acceptor, ready for a further glycosidation step, is di-
rectly obtained. Apart from the reduced overall number of
synthetic operations, this strategy is advantageous because
it is independent of the anomeric reactivity of the involved
components since, in each glycosidation step, there is no
competition between two potential glycosyl donors. So far,
only a few sparse examples of this tactic have been re-
ported.[10] Almost all of them exploit the acidic conditions
required in the glycosidation step for performing, upon ad-
justment of the experimental conditions, the subsequent re-
moval of the transient protecting group. A much less ex-
ploited synthetic route is, instead, the removal of a base-
labile protecting group immediately after an acid-promoted
glycosidation. In this regard, the fluorenylmethoxycarbonyl
(Fmoc) group was recently applied as a transient protecting
Despite the recent exceptional advancements in oligosac-
charide solid-phase synthesis,[2] a wide effort is currently
underway to streamline solution-phase procedures, which
are more cost-effective to scale up.[3] To this end, several
strategies have been developed for assembling oligosaccha-
rides exclusively through sequential glycosidations.[4] An
advantage of these approaches lies in suppressing the pro-
tection/deprotection steps interposed between glycosida-
tions. These schemes rely on either orthogonally activatable
glycosyl donors or the reactivity tuning of glycosyl donors
of the same class by the proper choice of their protecting
groups.[4] More recently, a preactivation strategy emerged
as an alternative, useful tool for performing sequential gly-
[‡] Part of this work has been presented at the 15th European
Carbohydrate Symposium, Vienna, July 2009, abstract OC 67.
[‡‡]Current address: International Chemical Industry,
81030 Cellole (CE), Italy
[a] Dipartimento di Chimica Organica e Biochimica, Università
degli Sudi di Napoli “Federico II”,
Via Cinthia 4, 80126 Napoli, Italy
Fax: +39-081-674393
E-mail: antonello.pastore@unina.it
Iadonisi@unina.it
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group[11] in the synthesis of β-(1Ǟ6) gluco oligosaccharides
conducted in microreactors.[12] The group survived the
acidic activation (with 2–3 equiv. of TMSOTf) of glycosyl
phosphate donors and was removed by the simple addition
of on excess of a mild base (piperidine/DMF, 1:4) to the
glycosidation medium. The excess promoter caused partial
trimethylsilylation of the liberated alcohol, a process which
required the addition of desilylation agents in the deprotec-
tion mixture. By a similar approach, Fmoc was removed in
situ from oligosaccharide intermediates generated by elec-
trochemical glycosidations.[13]
Results and Discussion
A retrosynthetic analysis of the target 1[17] (Figure 2) en-
tailed the availability of only two mannose building blocks,
3 and 4, the latter being the precursor of the reducing ter-
minal residue.
In this paper, we wish to describe the effective application
of Fmoc as a transient group in an iterable sequence for
solution oligosaccharide synthesis based on the Bi(OTf)3-
catalyzed activation[8,14] of glycosyl trihaloacetimidates. The
devised strategy has been targeted to the rapid assembly
of two biologically relevant targets, the protected mannose
tetrasaccharide 1 and the branched pentasaccharide 2, both
corresponding to moieties incorporated into HIV glycopro-
tein gp120 (Figure 1).
Figure 2. Retrosynthesis of 1.
We synthesized acceptor 4 (Scheme 1) starting from com-
mercially available methyl α--mannopyranoside. This we
initially allylated at O-3 and per-O-benzylated to give 5 as
previously reported.[8] Deallylation of 5 smoothly afforded
acceptor 4 (Scheme 1).
Scheme 1. Synthesis of acceptor 4.
We prepared 3 from intermediate 6 (Scheme 2), obtained
by a previously described one-pot sequence.[8,18] We submit-
ted ortho ester 6 to an acid-promoted rearrangement in the
presence of allyl alcohol to give 7, which we directly submit-
ted to 2-O deacetylation and Fmoc protection to give 8 in
62% yield over three steps. Sequential anomeric deallylation
and installation of the trifluoroacetimidate[19] leaving group
completed the preparation of 3 (90% yield over two steps).
With the appropriate building blocks in hand, we exam-
ined the sequence of Bi(OTf)3-promoted coupling of 3 with
4
and the addition of Et3N (for Fmoc removal;
Scheme 3).[20] We investigated the solvent mixtures (DCE/
dioxane or toluene/Et2O/dioxane) previously found com-
patible with the mild Bi(OTf)3 activation of trifluoroacet-
Figure 1. Structures of the gp120 glycan and the synthetic targets
of the present work.
In particular, tetrasaccharide 1 represents the so-called imidate donors.[8,14] In a preliminary screening, the use of the
D1 arm of the highly mannosylated ensemble, whereas 2 former binary mixture for the coupling of 3 with a variety
embodies both the D2 and D3 arms. Both sequences were of secondary acceptors provided significant amounts of β-
found to exhibit high affinity to human antibody 2G12[15] linked glycosides, in spite of the expected participation ef-
and are currently under investigation for immunogenic ap- fect of the 2-O-Fmoc group. Instead, we observed the best
plications.[16]
result with the ternary solvent mixture (toluene/Et2O/diox-
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One-Pot Catalytic Glycosidation/Fmoc Removal
Scheme 2. Synthesis of donor 3.
Scheme 4. Assembly of tetrasaccharide 1.
ane), and the one-pot sequence in Scheme 3 afforded essen-
tially pure 9 in almost 90% yield after chromatographic pu-
rification. Notably, at this stage, the whole glycosidation/
Fmoc removal sequence took less than 2 h.
We then applied the strategy illustrated above to the
more demanding target mannan pentasaccharide 2 (Fig-
ure 1). This sequence required diol 11 (Scheme 5) as the
precursor of the reducing terminus. During the screening of
several known preparations of this target based on three
synthetic steps,[21,22] we found a practical two-step pro-
cedure. In the first step, we submitted methyl mannopyr-
anoside to a double benzylidenation by slightly modifying
a previously reported procedure described by Liptak and
co-workers.[23] We obtained product 12 after chromato-
graphic purification as an almost equimolar diasteroisom-
eric mixture (endo/exo = 1.2:1). It is well established by sev-
eral precedents[24,25] that the reductive opening of five-
membered benzylidenes displays complementary regioselec-
tivity according to the configuration of the starting mate-
rial. However, we have observed that when the exo/endo
mixture of 12 was directly submitted to the reductive open-
ing conditions reported by Hung and co-workers [excess
BH3·THF and 0.3 equiv. of copper(II) triflate][26] the de-
Scheme 3. Synthesis of disaccharide 9.
Once we established the optimized reaction conditions, sired 3,6-diol 11 largely prevailed. Curiously, we also iso-
we attempted the elongation of the disaccharide with the lated minor amounts (ca. 10%) of the unexpected 3,4-diol
glycosidation of the sterically encumbered, axial 2-OH and characterized it in its acetylated form.
(Scheme 4). The application of the optimized protocol with
slight modifications gave acceptor trisaccharide 10 in an ex-
cellent overall yield (90%), comparable with that of the pre-
vious one-pot sequence. Further coupling with 3 under
analogous conditions gave tetrasaccharide 1 in a rewarding,
albeit lower overall yield (64%). The whole sequence of the
three synthetic operations gave the D1 tetrasaccharide 1 in
about 50% overall yield over six steps, corresponding to an
almost 90% average yield for each step. Additionally, this
scheme required only three chromatographic purifications.
Scheme 5. Synthesis of diol acceptor 11.
A comparison of NMR spectroscopic data with those re-
ported for a differently synthesized tetrasaccharide 1[17a]
Having established straightforward access to the reducing
confirmed the identity of the obtained product, with the terminus precursor 2, we attempted its direct double glycos-
anomeric linkages all being α-configured. idation. The simultaneous attachment of two mannose resi-
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dues to acceptor diol 11 is not a trivial task (Scheme 6). linkages.[22] We note that we obtained oligosaccharides 1
As a matter of fact, in some cases, the assembly of this and 2 in partially protected forms, which can be exploited
trisaccharide structure entails long sequences, in which the for further elaborations.
mannose residues are added to the branching unit at dif-
ferent stages.[27] Additionally, a literature survey[28] revealed
that the removal of poorly accessible 2-O-substituted pro-
tecting groups from the inserted mannoses did not fre-
quently proceed in yields higher than 90%. After a prelimi-
nary screening, for this application (Scheme 6) trichloroace-
timidate 13[29] proved more efficient than the trifluoro
counterpart 3 at providing trisaccharide 14. Indeed, with
the latter donor, we detected higher amounts of intermedi-
ate dimannosides; with donor 13, we instead satisfyingly
carried out the sequence of bis(glycosylation) and bis(dep-
rotection) under very mild conditions, in short times, and
in a very high overall yield (72% over four synthetic steps,
Scheme 6). We then exposed trisaccharide diol 14 to tri-
chloroacetimidate 13 under Bi(OTf)3 activation to afford
pentasaccharide 2 in 63% overall yield. We performed the
whole synthesis in only two synthetic operations, and the
overall yield (ca. 45%) of its eight synthetic steps corre-
sponded once again to an approximate average yield of 90%
for each step.
Conclusions
In this paper, we have shown that the Fmoc protecting
group can be simply removed in the same vessel where a
Bi(OTf)3-promoted glycosidation is conducted. The itera-
tion of this one-pot sequence leads to biologically useful
mannose oligosaccharides related to HIV gp120 by per-
forming a smaller number of synthetic operations than re-
quired in other reported procedures towards similar se-
quences. As to yields, the effectiveness of the present ap-
proach often compares favourably with most of the syn-
thetic schemes so far described,[15,16a,17,21,22,27,28] with ex-
ceptions being found in a few examples of especially high-
yielding synthetic routes.[24,28h,28p–28r] Nevertheless, the ac-
tual merit of the strategy resides in the combination, rather
unusual in other schemes, of simultaneous advantages such
as the reduced experimental work (also because of the mini-
mal number of required precursors), the attainment of high
yields and the exclusive use of a catalytic and moisture-
stable glycosidation promoter. Furthermore, the present, it-
erable, one-pot scheme is anticipated to be of broad appli-
cability, thus adding a further useful complement to the re-
cent strategic advances in oligosaccharide synthesis.
Experimental Section
General Methods: 1H and 13C NMR spectra were recorded in
CDCl3 (internal standard, for 1H: CHCl3 at δ = 7.26 ppm; for 13C:
CDCl3 at δ = 77.0 ppm). 1H NMR assignments were based on
homo-decoupling experiments. MALDI mass spectra were re-
corded in the positive mode; compounds were dissolved in CH3CN
at a concentration of 0.1 mg/mL, and 1 µL of these solutions was
mixed with 1 µL of a 20 mg/mL solution of 2,5-dihydroxybenzoic
acid in CH3CN/H2O (7:3) or, in the case of trifluoroacetimidate
derivatives, with a 10 mg/mL solution of trihyroxyacetophenone in
MeOH/H2O (1:1). Analytical thin layer chromatography (TLC) was
performed on aluminium plates precoated with Silica Gel 60 F254
as the adsorbent. The plates were developed with the application
of 5% H2SO4 ethanolic solution followed by heating to 130 °C.
Column chromatography was performed on silica gel (63–
200 mesh). [α]2D9 values are given in 10–1 degcm2 g–1. Glycosidations
were performed with commercially available, anhydrous solvents.
Bi(OTf)3 was coevaporated three times in toluene and dried under
vacuum for 30–45 min and then dissolved in dioxane in the pres-
ence of freshly activated molecular sieves (4 Å).
Methyl 2,4,6-Tri-O-benzyl-α-D-mannopyranoside (4): To a solution
of 5[8] (260 mg, 0.515 mmol) in MeOH/DCM (2.5:1, 3.5 mL) was
added at room temp. palladium chloride (10 mg, 0.056 mmol). The
mixture was stirred overnight and then concentrated under vac-
uum. The residue was then filtered through a short plug of silica gel
(eluent: DCM/MeOH, 95:5), concentrated and purified by silica-gel
flash chromatography (eluent: petroleum ether/EtOAc from 8:2 to
7:3) to provide 4 as an oil (215 mg, 90%). [α]2D9 = +15.6 (c = 1.0,
in CHCl3), (ref.[30] [α]2D9 = +14.5 (c = 1.0, CHCl3). 1H NMR
Scheme 6. Assembly of pentasaccharide 2.
A comparison of NMR spectroscopic data of the ob-
tained pentasaccharide with those of close analogues of 2
(differentiated exclusively for the aglycon)[22,24] confirmed
the identity of the structure and the lack of β-mannosidic (400 MHz, CDCl3): δ = 7.40–7.15 (Ar), 4.87 (br. s, 1 H, 1-H), 4.90–
714
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One-Pot Catalytic Glycosidation/Fmoc Removal
4.50 (3 AB, 6 H, 3 CH2Ph), 4.05–3.95 (m, 1 H, 5-H), 3.85–3.70 3,4,6-Tri-O-benzyl-2-O-fluorenylmethoxycarbonyl-α,β-D-mannopyr-
(overlapped signals, 4 H, 2-H, 4-H and 6-H2), 3.37 (s, 3 H, 1- anosyl N-Phenyltrifluoroacetimidate (3): To a solution of 8 (474 mg,
OCH3), 2.50 (br. s, 1 H, 3-OH) ppm. 13C NMR (50 MHz, CDCl3): 0.67 mmol) in MeOH/DCM (1.6:1, 6.7 mL) was added at room
δ = 138.3, 138.1, 137.6 (aromatic C), 128.4–127.4 (aromatic CH), temp. palladium chloride (12 mg, 0.068 mmol). The mixture was
97.7 (C-1), 78.1, 76.4, 74.6, 73.2, 72.6, 71.6, 70.6, 69.0, 54.7 ppm.
MALDI-TOF MS: calcd. for [M + Na]+ 487.21; found 487.45.
C28H32O6 (487.21): calcd. C 72.39, H 6.94; found C 72.20, H 6.85.
stirred overnight and then concentrated under vacuum. The residue
was then filtered through a short plug of silica gel (eluent DCM/
MeOH, 95:5) and concentrated to yield the hemiacetal intermediate
in a satisfying purity to be directly submitted to the following step.
Spectroscopic data: 1H NMR (200 MHz, CDCl3): significant sig-
nals at δ = 7.90–7.20 (Ar), 5.41 (br. s, 1 H, 1-H), 5.30 (br. d, 1 H,
2-H), 4.14 (dd, J2,3 = 2.4 Hz, J3,4 = 9.0 Hz, 1 H, 3-H), 3.90–3.70
(m, 2 H, 6-H2) ppm. 13C NMR (50 MHz, CDCl3): δ = 154.6 (Fmoc
CO2), 143.3, 143.1, 141.0, 138.1, 137.8, 137.6 (aromatic C), 128.2–
127.0, 125.2, 125.0, 119.8 (aromatic CH), 91.9 (C-1), 77.6, 74.9,
74.5, 73.2, 73.0, 71.6, 70.7, 70.0, 69.4 ppm. To a solution of the
hemiacetal in acetone (6 mL) were sequentially added at 0 °C
Cs2CO3 (239 mg, 0.733 mmol) and (N-phenyl)trifluoroacetimidoyl
chloride (230 µL, 1.82 mmol). The mixture was warmed to room
temp. and, after 3 h, was diluted with DCM, filtered through Celite
(eluent: EtOAc) and concentrated under vacuum. The residue was
purified by silica-gel flash chromatography (eluent: petroleum
ether/EtOAc from 9:1 to 8.5:1.5) to yield 3 as a yellow oil (anomeric
mixture, α/β ≈ 7.6:1, 506 mg, 90 % over two steps). 1H NMR
(400 MHz, CDCl3): signals of α-anomer at δ = 7.90–7.00 (Ar), 6.61
(br. s, 1 H, 1-H), 5.55 (br. s, 1 H, 2-H), 5.12–4.70 (6 H, 3 CH2Ph),
4.63–4.48 (3 H, Fmoc OCH2CH), 4.42–4.10 (3 H, 3-H, 4-H and 5-
H), 4.05–3.90 (2 H, 6-H) ppm. 13C NMR (50 MHz, CDCl3): δ =
154.3 (Fmoc CO2), 143.1, 142.9, 142.8, 141.3, 141.0, 137.8 (2 C),
137.3 (aromatic C), 128.8–125.7, 120.4, 119.8, 119.1 (aromatic CH),
93.9 (C-1), 77.3, 75.2, 74.0, 73.4, 73.2, 72.1, 71.1, 70.2, 68.3 ppm.
MALDI-TOF MS: calcd. for [M + Na]+ 866.30; found 866.15.
C50H44F3NO8 (866.30): calcd. C 71.16, H 5.26; found C 71.00, H
5.35.
Allyl 3,4,6-Tri-O-benzyl-2-O-fluorenylmethoxycarbonyl-α-D-manno-
pyranoside (8): Ortho ester 6[8] (181 mg, 0.357 mmol) was coevapo-
rated three times with toluene (3ϫ2 mL) and dried under vacuum.
After adding freshly activated molecular sieves (4 Å), 6 was dis-
solved at room temp. in dry DCM (1.6 mL), and allyl alcohol
(120 µL, 1.79 mmol) was subsequently added. The mixture was
then cooled to 0 °C and stirred for ca. 10 min. A solution of
BF3·OEt2 (0.4  in DCM, 180 µL, 0.073 mmol) was then added at
0 °C under argon. After 15 min, the reaction was quenched at the
same temperature with 5 drops of pyridine, and the mixture was
filtered through a short plug of silica gel (eluent: DCM/MeOH/
CH3CN, 85:10:5) and concentrated in vacuo to obtain crude 7 as
an oil, which was directly submitted to the following step. 1H NMR
(200 MHz, CDCl3): δ = 7.60–7.15 (Ar), 6.05–5.90 (m, 1 H,
CH=CH2), 5.50 (br. s, 1 H, 2-H), 5.36 (br. d, JE = 17.4 Hz, 1 H,
CH2CH=CHZHE), 5.28 (br. d, JZ
=
10.2 Hz,
1
H,
CH2CH=CHZHE), 5.00 (br. s, 1 H, 1-H), 4.98–4.55 (6 H, 3
CH2Ph), 4.26 (m, 1 H, CHaHbCH=CH2), 4.15–3.98 (3 H), 3.95–
3.79 (3 H), 2.23 (s, 3 H, COCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 170.1 (COCH3), 138.2, 138.0, 137.8 (aromatic C),
133.2 (CH=CH2), 128.2–127.4 (aromatic CH), 117.5 (CH=CH2),
96.7 (C-1), 78.0, 74.9, 74.2, 73.2, 71.6, 71.3, 68.7, 68.6, 67.9 ppm.
Crude 7 was dissolved in MeOH/DCM (1.3:1, 6.4 mL), and the
mixture was then cooled to 0 °C. At this temperature, 8 drops of a
solution of MeONa (2  in MeOH) were added, and the mixture
was warmed to room temp. and stirred overnight. After the ad-
dition of Amberlist 15, the supernatant was removed and concen-
trated in vacuo to obtain an oil in a satisfying purity to be directly
submitted to the last step of this one-pot sequence. Spectroscopic
data of the 2-O-deacetylated intermediate:[28m] 1H NMR
(400 MHz, CDCl3): δ = 7.40–7.10 (Ar), 6.00–5.80 (m, 1 H,
CH=CH2), 5.30–5.15 (2 H, CH=CH2), 5.02 (d, J1,2 = 1.6 Hz, 1 H,
3,4,6-Tri-O-benzyl-2-O-fluorenylmethoxycarbonyl-α,β-D-mannopyr-
anosyl Trichloracetimidate (13): To a solution of 8 (318 mg,
0.447 mmol) in MeOH/DCM (1.6:1, 4.5 mL) was added at room
temp. palladium chloride (8 mg, 0.045 mmol). The mixture was
stirred overnight and then concentrated under vacuum. The residue
was then filtered through a short plug of silica gel (eluent: DCM/
MeOH, 95:5) and concentrated to yield the hemiacetal as a foam.
The obtained hemiacetal was dissolved in trichloroacetonitrile
(6.7 mL), and the solution was added dropwise to a reaction vessel
containing sodium hydride (60% in oil, 1.9 mg) at 0 °C under mag-
netic stirring. After 15 min at the same temperature, the mixture
was neutralized by the portion-wise addition of silica gel, and the
residue was purified by silica-gel flash chromatography (eluent: tol-
uene/acetone, 20:1) to yield 13 as a foam (anomeric mixture, α/β ≈
1-H), 4.90–4.45 (6 H,
3
CH2Ph), 4.25–4.10 (m,
1 H,
CHaHbCH=CH2), 4.08–3.95 (2 H, CHaHbCH=CH2 and 2-H),
3.90–3.65 (4 H, 3-H, 4-H, 5-H and 6-H2), 2.44 (d, J2,OH = 2.2 Hz,
1 H, 2-OH) ppm. The product from the previous step was dissolved
in dry DCM (3.5 mL) at room temp., and pyridine (300 µL,
3.73 mmol) and FmocCl (120 mg, 0.464 mmol) were sequentially
added under argon to the solution. The mixture was stirred for
25 min and was then diluted with EtOAc, washed three times with
aqueous saturated CuSO4, and the organic phase was dried with
anhydrous Na2SO4 and concentrated in vacuo to give a residue,
which was purified by silica-gel flash chromatography (eluent: pe-
troleum ether/EtOAc from 9:1 to 8:2) to yield 8 as a yellow oil
(157 mg, 62% over three steps). [α]2D9 = +19.9 (c = 0.6, in CHCl3).
1H NMR (200 MHz, CDCl3): δ = 7.80–7.10 (Ar), 6.00–5.80 (m, 1
1
8.3:1, 348 mg, 95% over two steps). H NMR (400 MHz, CDCl3):
signals of α-anomer at δ = 8.83 (s, 1 H, NH), 8.00–7.15 (Ar), 6.57
(d, J1,2 = 1.6 Hz, 1 H, 1-H), 5.47 (t, J2,3 = 1.6 Hz, 1 H, 2-H), 4.55–
4.35 (3 H, Fmoc CHCH2O), 4.26 (t, J3,4 = J4,5 = 9.6 Hz,1 H, 4-
H), 4.20 (dd, 1 H, 3-H), 4.20–4.13 (m, 1 H, 5-H), 3.98 (dd, J5,6a
=
4.4, J6a,6b = 11.2 Hz, 1 H, 6a-H), 3.87 (dd, J5,6b = 1.6 Hz, 1 H, 6b-
H) ppm. Significant signals of the β-anomer at δ = 8.78 (s, 1 H,
NH), 6.05 (s, 1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): signals
of α-anomer at δ = 160.0 (C=NH), 154.6 (OCO2), 143.4, 143.2,
141.3 (2 C, Fmoc aromatic C), 138.1, 137.9, 137.4 (benzyl aromatic
C), 128.4–127.3, 125.4, 125.3, 120.1 (aromatic CH), 95.3 (C-1),
77.5, 75.6, 74.6, 73.8, 73.5, 72.2, 71.4, 70.6, 68.6, 46.6 ppm.
H, CH=CH2), 5.35–5.18 (3 H, CH=CH2 and 2-H), 5.02 (d, J1,2
1.6 Hz, 1 H, 1-H), 4.95–4.25 (9 H, 3 CH2Ph and Fmoc OCH2CH),
4.25–4.15 (m, H, CHaHbCH=CH2), 4.10–3.70 (6 H,
=
1
CHaHbCH=CH2, 3-H, 4-H, 5-H, 6-H2) ppm. 13C NMR (50 MHz,
CDCl3): δ = 154.5 (Fmoc CO2), 143.2, 142.9, 141.0, 140.9, 138.0,
137.9, 137.7 (aromatic C), 133.1 (CH=CH2), 128.0–126.9, 122.1,
124.9, 119.7 (aromatic CH), 117.5 (CH=CH2), 96.3 (C-1), 78.0,
75.0, 74.1, 73.1, 72.4, 71.5, 71.3, 69.9, 68.6, 67.8, 46.3 ppm.
MALDI-TOF MS: calcd. for [M + Na]+ 735.30; found 735.25.
C45H44O8 (712.84): calcd. C 75.82, H 6.22; found C 75.53, H 6.15.
Methyl 2,4-Di-O-benzyl-α-D-mannopyranoside (11): BH3 (1  in
THF, 1.5 mL, 1.5 mmol) was added to 12[23,25a] (endo/exo, 1.2:1,
55 mg, 0.15 mmol) at 0 °C under argon. To the resulting solution
was added at 0 °C copper(II) triflate (0.069  in THF, 0.65 mL,
Eur. J. Org. Chem. 2010, 711–718
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715

A. Pastore, M. Adinolfi, A. Iadonisi, S. Valerio
FULL PAPER
0.045 mmol). After 30 min, the ice bath was removed, and the reac-
tion vessel was warmed to room temp. After a few minutes, a black
precipitate appeared. After 1 h and 40 min from the start, the reac-
tion was quenched with Et3N (25 µL) and MeOH (0.2 mL). The
mixture was concentrated in vacuo, and the residue was purified
by silica-gel flash chromatography (eluent: n-hexane/EtOAc from
32:18 to 55:45) to yield diol 11 as a colourless oil (34 mg, 61%
yield). The acetylation of a sample confirmed the presence of free
hydroxy groups at O-3 and O-6, as indicated by 1H NMR. 1H
NMR (200 MHz, CDCl3): δ = 5.16 (dd, J2,3 = 3.3, J3,4 = 9.0 Hz, 1
through a short plug of silica gel and repeatedly washed with
DCM/MeOH/CH3CN (85:10:5). The filtrate was concentrated, and
the residue was purified by silica-gel flash chromatography (eluent:
n-hexane/EtOAc from 3:1 to 2:1) to yield trisaccharide 10 as an oil
(59 mg, 90% overall yield). [α]2D8 = +34.2 (c = 1.3, in CHCl3). H
1
NMR (400 MHz, CDCl3): δ = 7.45–7.10 (Ar), 5.31 (d, J1,2
=
1.6 Hz, 1 H, 1ЈЈ-H), 5.13 (d, J1,2 = 1.6 Hz, 1 H, 1Ј-H), 4.85 (d, J1,2
= 1.6 Hz, 1 H, 1-H), 4.92–4.41 (18 H, 9 CH2Ph), 4.18–4.12 (2 H),
4.10–3.80 (9 H), 3.80–3.65 (6 H), 3.55 (br. d, J = 10.0 Hz, 1 H),
3.33 (s, 3 H, OCH3), 2.48 (br. s, 1 H, 2-OH) ppm. 13C NMR
H, 3-H), 4.30 (dd, J5,6a = 3.0, J6a,6b = 12.4 Hz, 1 H, 6a-H), 4.22 (100 MHz, CDCl3): δ = 138.8, 138.6, 138.55, 138.48 (2 C), 138.41
(dd, J5,6b = 4.2 Hz, 1 H, 6b-H) ppm. Compound 11: [α]2D8 = +21.5
(c = 1.1, in CHCl3), [ref.[25a] [α]2D9 = +23.5 (c = 0.77, in CHCl3)].
(2 C), 138.2, 138.1 (aromatic C), 128.5–127.3 (aromatic CH), 101.0
(2 C), 98.2 (anomeric CH), 79.9, 79.5, 77.7, 75.4, 75.0, 74.9, 74.7,
74.3, 73.4, 73.3, 73.2, 72.7, 72.2, 72.1, 72.0, 71.8, 69.7, 69.3, 68.6,
68.5 54.8 ppm. MALDI-TOF MS: calcd. for [M + Na]+ 1351.60;
found 1351.48. C82H88O16 (1351.60): calcd. C 74.18, H 6.67; found
C 73.95, H 6.71.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.25 (Ar), 4.75 (d, J1,2
=
1.6 Hz, 1 H, anomeric proton), 4.92–4.59 (4 H, 2 CH2Ph), 3.99 (dd,
J2,3 = 3.2, J3,4 = 9.6 Hz, 1 H, 3-H), 3.86 (dd, J5,6a = 3.2, J6a,6b
=
11.6 Hz, 1 H, 6a-H), 3.77 (dd, J5,6b = 4.4 Hz, 1 H, 6b-H), 3.73 (dd,
1 H, 2-H), 3.68 (t, J4,5 = 9.6 Hz, 1 H, 4-H), 3.60–3.55 (m, 1 H, 5-
H), 3.32 (s, 3 H, OCH3) ppm. 13C NMR (50 MHz, CDCl3): δ =
138.3, 137.6 (aromatic C), 128.6–127.8 (aromatic CH), 98.1 (C-1),
78.3, 74.8, 73.1, 71.7, 71.1, 62.3, 54.8 (OCH3) ppm. MALDI-TOF
MS: calcd. for [M + Na]+ 397.17; found 397.25. C21H26O6 (374.43):
calcd. C 67.36, H 7.00; found C 67.05, H 7.10.
Methyl 3,4,6-Tri-O-benzyl-α-
benzyl-α- -mannopyranosyl-(1Ǟ2)-3,4,6-tri-O-benzyl-α-
pyranosyl-(1Ǟ3)-2,4,6-tri-O-benzyl-α- -mannopyranoside (1): A
D
-mannopyranosyl-(1Ǟ2)-3,4,6-tri-O-
D
D
-manno-
D
mixture of donor 3 (11 mg, 13 µmol) and acceptor 10 (10 mg,
7.5 µmol) was coevaporated three times with anhydrous toluene
(3ϫ1 mL) and then dried in vacuo for 30 min. After the addition
of molecular sieves (4 Å, AW 300), the mixture was dissolved under
argon in toluene/Et2O (4:1, 0.51 mL), cooled to –30 °C and stirred
for 15 min. Bi(OTf)3 (14.3 mg/mL in dioxane, 34 µL, 0. 75 µmol)
was then added, and the temperature was allowed to rise to room
temp. over 2.5 h. Upon the completion of the glycosidation step
(TLC analysis, eluent: n-hexane/EtOAc, 7:3), Et3N (0.13 mL) was
added. After 1 h from the addition, the reaction mixture was fil-
tered through a short plug of silica gel and repeatedly washed with
DCM/MeOH/CH3CN (85:10:5). The filtrate was concentrated, and
the residue was purified by silica-gel flash chromatography (eluent:
toluene/EtOAc from 10:0 to 85:15) to yield tetrasaccharide 1 as an
oil (8 mg, 64% overall yield). [α]2D8 = +28.5 (c = 0.8, in CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.40–7.05 (Ar), 5.25 (br. s, 1 H, 1ЈЈЈ-
Methyl 3,4,6-Tri-O-benzyl-α-
D-mannopyranosyl-(1Ǟ3)-2,4,6-tri-O-
benzyl-α- -mannopyranoside (9): A mixture of donor 3 (147 mg,
D
0.174 mmol) and acceptor 4 (49 mg, 0.105 mmol) was coevaporated
three times with anhydrous toluene (3ϫ2 mL) and then dried in
vacuo for 30 min. After the addition of molecular sieves (4 Å, AW
300), the mixture was dissolved under argon in toluene/Et2O (4:1,
3.3 mL), cooled to –30 °C and stirred for 15 min. Bi(OTf)3
(14.5 mg/mL in dioxane, 0.38 mL, 8.4 µmol) was then added, and
the temperature was allowed to slowly rise. After 50 min (tempera-
ture at –20 °C), the glycosidation step was complete (TLC analysis,
eluent: n-hexane/EtOAc, 7:3). Et3N (0.8 mL) was added, and the
reaction vessel was immediately warmed to room temp. After 1 h,
the reaction mixture was filtered through a short plug of silica gel
and repeatedly washed with DCM/MeOH/CH3CN (85:10:5). The
filtrate was concentrated, and the residue was purified by silica-gel
flash chromatography (eluent: n-hexane/EtOAc from 3:1 to 2:1) to
H), 5.18 (br. s, 1 H, 1ЈЈ-H), 5.14 (br. s, 1 H, 1Ј-H), 4.70 (d, J1,2
=
1.5 Hz, 1 H, 1-H), 4.85–4.22 (24 H, 12 CH2Ph), 4.12–4.08 (2 H),
4.00 (J = 1.5 Hz, 1 H), 3.98–3.60 (18 H), 3.55 (dd, J = 11.5, 3.0 Hz,
1 H), 3.47 (br. d, J = 11.5 Hz, 1 H), 3.43 (br. d, J = 10.0 Hz, 1 H),
yield disaccharide 9 as an oil (84 mg, 87% overall yield). [α]2D8
=
+29.1 (c = 1.0, in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40– 3.26 (s, 3 H, OCH3), 2.39 (br. s, 1 H, 2-OH) ppm. 13C NMR
7.10 (Ar), 5.22 (d, J1,2 = 1.2 Hz, 1 H, 1Ј-H), 4.72 (d, J1,2 = 1.6 Hz,
1 H, 1-H), 4.85–4.46 (12 H, 6 CH2Ph), 4.13 (dd, J = 3.2, 10.6 Hz,
(100 MHz, CDCl3): δ = 138.8–138.1 (aromatic C), 128.5–127.2
(aromatic CH), 101.0, 100.9, 100.8 and 98.2 (anomeric CH), 80.0,
1 H), 4.02–3.60 (11 H), 3.29 (s, 3 H, OCH3), 2.31 (d, J = 2.4 Hz, 79.6, 79.4, 79.2, 79.0, 77.6, 77.2, 75.6, 75.1, 74.9, 74.7, 74.2, 73.4,
1 H, 2-OH) ppm. 13C NMR (50 MHz, CDCl3): δ = 138.6, 138.3 (3
C), 138.1, 137.9 (aromatic C), 128.5–127.5 (aromatic CH), 101.2
and 98.2 (anomeric CH), 80.0, 78.4, 75.2, 75.0, 74.9, 74.4, 72.1,
73.3, 73.0, 72.6, 72.5, 72.4, 72.1, 72.0, 71.9, 71.7, 71.6, 69.7, 69.3,
69.0, 68.7, 68.5, 54.7 ppm. MALDI-TOF MS: calcd. for [M +
Na]+ 1784.79; found 1784.45. C109H116O21 (1784.79): calcd. C
72.0, 71.9, 71.7, 69.2, 69.0, 68.6, 54.8 ppm. MALDI-TOF MS: 74.30, H 6.64; found C 73.95, H 6.50.
calcd. for [M + Na]+ 919.40; found 919.27. C55H60O11 (919.40):
Methyl [3,4,6-Tri-O-benzyl-α-
O-benzyl-α-D-mannopyranosyl-(1Ǟ6)-2,4-di-O-benzyl-α-D-manno-
D
-mannopyranosyl-(1Ǟ3)]-3,4,6-tri-
calcd. C 73.64, H 6.74; found C 73.50, H 6.65.
Methyl 3,4,6-Tri-O-benzyl-α- -mannopyranosyl-(1Ǟ2)-3,4,6-tri-O-
benzyl-α- -mannopyranosyl-(1Ǟ3)-2,4,6-tri-O-benzyl-α- -manno-
D
pyranoside (14): A mixture of donor 13 (78 mg, 95 µmol) and diol
11 (12 mg, 29 µmol) was coevaporated three times with anhydrous
toluene (3ϫ2 mL) and then dried in vacuo for 30 min. After the
addition of molecular sieves (4 Å, AW 300), the mixture was dis-
solved under argon in toluene/Et2O (4:1, 2.8 mL), cooled to –30 °C
and stirred for 15 min. Bi(OTf)3 (14.5 mg/mL in dioxane, 135 µL,
0.29 µmol) was then added, and the temperature was allowed to
rise to –10 °C over 45 min. Upon the completion of the glycosid-
ation step (TLC analysis, eluent: petroleum ether/EtOAc, 7:3),
Et3N (0.70 mL) was added, and the reaction vessel was immediately
warmed to room temp. After 1 h, the reaction mixture was filtered
through a short plug of silica gel and repeatedly washed with
DCM/MeOH/CH3CN (85:10:5). The filtrate was concentrated, and
D
D
pyranoside (10): A mixture of donor 3 (74 mg, 88 µmol) and ac-
ceptor 9 (45 mg, 49 µmol) was coevaporated three times with anhy-
drous toluene (3ϫ1 mL) and then dried in vacuo for 30 min. After
the addition of molecular sieves (4 Å, AW 300), the mixture was
dissolved under argon in toluene/Et2O (4:1, 3.3 mL), cooled to
–30 °C and stirred for 1 5 min. Bi(OTf)3 (14.5 mg/mL in dioxane,
0.22 mL, 4.9 µmol) was then added, and the temperature was al-
lowed to rise to –5 °C over 75 min. Upon the completion of the
glycosidation step (TLC analysis, eluent n-hexane/EtOAc, 7:3),
Et3N (0.83 mL) was added, and the reaction vessel was immediately
warmed to room temp. After 1 h, the reaction mixture was filtered
716
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 711–718

One-Pot Catalytic Glycosidation/Fmoc Removal
[4]
[5]
[6]
For a review, see: J. D. C. Codee, R. E. J. N. Litjens, L. J.
Van den Bos, H. S. Overkleeft, G. A. Van der Marel, Chem.
Soc. Rev. 2005, 34, 769–782.
a) S. Yamago, T. Yamada, T. Maruyama, J. Yoshida, Angew.
Chem. Int. Ed. 2004, 43, 2145–2148; b) X. Huang, L. Huang,
H. Wang, X.-S. Ye, Angew. Chem. Int. Ed. 2004, 43, 5221–5224.
For a review, see: Y. Wang, X.-S. Ye, L.-H. Zhang, Org. Biomol.
Chem. 2007, 5, 2189–2200.
the residue was purified by silica-gel flash chromatography (eluent:
n-hexane/acetone/DCM from 3:1:0.5 to 2:1:0.5) to yield trisaccha-
ride 14 as an oil (26 mg, 72% overall yield). [α]2D6 = +25.9 (c = 0.77,
1
in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.40–7.10 (Ar), 5.23
(d, J1,2 = 1.2 Hz, 1 H, 1Ј3-H), 5.09 (d, J1,2 = 1.2 Hz, 1 H, 1Ј6-H),
4.66 (d, J1,2 = 1.6 Hz, 1 H, 1-H), 4.87–4.46 (16 H, 8 CH2Ph), 4.15–
4.10 (2 H), 4.05–3.95 (2 H), 3.95–3.80 (8 H), 3.80–3.60 (6 H), 3.25
(s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.5,
138.4, 138.3 (2 C), 138.2, 138.1, 137.9 (2 C, aromatic C), 128.6–
127.5 (aromatic CH), 101.4, 98.7, and 98.2 (anomeric CH), 80.1,
79.5, 78.9, 77.7, 75.0, 74.9, 74.8, 74.4, 74.2, 73.6, 73.3, 72.3, 72.0,
71.9, 71.4, 71.1, 69.4, 68.8, 68.7, 68.0, 66.1, 54.7 ppm. MALDI-
TOF MS: calcd. for [M + Na]+ 1261.55; found 1261.15. C75H82O16
(1261.55): calcd. C 72.68, H 6.67; found C 72.35, H 6.50.
[7]
[8]
M. Adinolfi, A. Iadonisi, A. Ravidà, Synlett 2006, 583–586.
S. Valerio, M. Adinolfi, A. Iadonisi, A. Pastore, J. Org. Chem.
2008, 73, 4496–4503.
[9]
For some examples of this unusual elongation strategy, see: a)
T. Zhu, G.-J. Boons, Synlett 1997, 809–811; b) T. Zhu, G.-J.
Boons, Tetrahedron Lett. 1998, 39, 2187–2190; c) T. Zhu, G.-J.
Boons, Angew. Chem. Int. Ed. 1998, 37, 1898–1900; d) T. Zhu,
G.-J. Boons, J. Chem. Soc. Perkin Trans. 1 1998, 857–861; e) T.
Zhu, G.-J. Boons, Angew. Chem. Int. Ed. 1999, 38, 3495–3497.
a) Y. Du, M. Zhang, F. Kong, Org. Lett. 2000, 2, 3797–3800;
b) S. Bhattacharyya, B. G. Magnusson, U. Wellmar, U. J. Nils-
son, J. Chem. Soc. Perkin Trans. 1 2001, 886–890; c) Y. Vohra,
M. Vasan, A. Venot, G.-J. Boons, Org. Lett. 2008, 10, 3247–
3250.
For examples of the use of Fmoc in oligosaccharide solid-phase
synthesis, see: a) F. Roussel, L. Knerr, M. Grathwohl, R. R.
Schmidt, Org. Lett. 2000, 2, 3043–3046; b) D. B. Werz, B. Cas-
tagner, P. H. Seeberger, J. Am. Chem. Soc. 2007, 129, 2770–
2771; for examples in solution synthesis, see: c) A. Prabhu, A.
Venot, G.-J. Boons, Org. Lett. 2003, 5, 4975–4978; d) D. B.
Werz, P. H. Seeberger, Angew. Chem. Int. Ed. 2005, 44, 6315–
6318; e) M. A. Oberli, P. Bindschafler, D. B. Werz, P. H. See-
berger, Org. Lett. 2008, 10, 905–908.
F. R. Carrel, K. Geyer, J. D. C. Codèe, P. H. Seeberger, Org.
Lett. 2007, 9, 2285–2288.
T. Nokami, H. Tsuyama, A. Shibuya, T. Nakatsutsumi, J.
Yoshida, Chem. Lett. 2008, 37, 942–943.
a) M. Adinolfi, A. Iadonisi, A. Ravidà, S. Valerio, Tetrahedron
Lett. 2006, 47, 2595–2599; b) M. Adinolfi, D. Giacomini, A.
Iadonisi, A. Quintavalla, S. Valerio, Eur. J. Org. Chem. 2008,
2895–2899.
H.-K. Lee, C. N. Scanlan, C.-Y. Huang, A. Y. Chang, D. A.
Calarese, R. A. Dwek, P. M. Rudd, D. R. Burton, I. A. Wilson,
C.-H. Wong, Angew. Chem. Int. Ed. 2004, 43, 1000–1003.
a) J. Wang, H. Li, Z. Guozhang, L.-X. Wang, Org. Biomol.
Chem. 2007, 5, 1529–1540; b) D. A. Calarese, H.-K. Lee, C.-
Y. Huang, M. D. Best, R. D. Astronomo, R. L. Stanfield, H.
Katinger, D. R. Burton, C.-H. Wong, I. A. Wilson, Proc. Natl.
Acad. Sci. USA 2005, 102, 13372–13377; c) S.-K. Wang, P.-H.
Liang, R. D. Astronomo, T.-L. Hsu, S.-L. Hsieh, D. R. Burton,
C.-H. Wong, Proc. Natl. Acad. Sci. USA 2008, 105, 3690–3695.
For other synthetic approaches to the D1 sequence, see
ref.[13,14a] For further references, see: a) R. K. Jain, X.-G. Liu,
S. R. Oruganti, E. V. Chandrasekaran, K. L. Matta, Carbohydr.
Res. 1995, 271, 185–196; b) P. Grice, S. V. Ley, J. Pietruzska,
H. W. M. Priepke, Angew. Chem. Int. Ed. Engl. 1996, 35, 197–
200; c) A. Düffels, S. V. Ley, J. Chem. Soc. Perkin Trans. 1 1999,
375–378; d) M. Takatani, Y. Ito, Chem. Asian J. 2006, 1–2, 64–
75.
Methyl [3,4,6-Tri-O-benzyl-α-
benzyl-α- -mannopyranosyl-(1Ǟ3)]-[3,4,6-tri-O-benzyl-α-
pyranosyl-(1Ǟ2)-3,4,6-tri-O-benzyl-α- -mannopyranosyl-(1Ǟ6)]-
2,4-di-O-benzyl-α- -mannopyranoside (2): A mixture of donor 13
D-mannopyranosyl-(1Ǟ2)-3,4,6-tri-O-
[10]
[11]
D
D-manno-
D
D
(40 mg, 49 µmol) and diol 14 (14 mg, 11 µmol) was coevaporated
three times with anhydrous toluene (3ϫ1 mL) and then dried in
vacuo for 30 min. After the addition of molecular sieves (4 Å, AW
300), the mixture was dissolved under argon in toluene/Et2O (4:1,
2.1 mL), cooled to –30 °C and stirred for 15 min. Bi(OTf)3
(14.5 mg/mL in dioxane, 100 µL, 2.2 µmol) was then added, and
the temperature was allowed to rise to 5 °C over 1 h. Upon the
completion of the glycosidation step (TLC analysis, eluent petro-
leum ether/EtOAc, 7:3), Et3N (0.35 mL) was added, and the reac-
tion mixture immediately warmed to room temp. The reaction mix-
ture was then filtered through a short plug of silica gel and repeat-
edly washed with DCM/MeOH/CH3CN (85:10:5). The filtrate was
concentrated, and the residue was purified by silica-gel flash
chromatography (eluent: n-hexane/acetone/DCM 3:1:0.5) to yield
[12]
[13]
[14]
pentasaccharide 2 as an oil (15 mg, 63% overall yield). [α]2D8
=
+34.7 (c = 0.7, in CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40–
7.10 (Ar), 5.25, 5.11 and 5.05 (3 d, J1,2 = 1.6 Hz, 3 H, 2 1ЈЈ-H and
1Ј3-H), 4.97 (d, J1,2 = 1.6 Hz, 1 H, 1Ј6-H), 4.64 (d, J1,2 = 1.6 Hz, 1
H, 1-H), 4.98–4.30 (28 H, 14 CH2Ph), 4.15–4.05 (4 H), 4.05–3.95
(3 H), 3.95–3.75 (13 H), 3.75–3.63 (6 H), 3.60–3.40 (4 H), 3.16 (s,
3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.7–138.0
(aromatic C), 128.6–127.0 (aromatic CH), 101.1 (3 C), 99.1, and
97.9 (anomeric CH), 80.3, 80.0, 79.9, 79.6, 78.9, 77.8, 75.3, 75.0,
74.9, 74.8, 74.7, 74.6, 74.5, 74.3, 74.2, 73.4, 73.3, 72.7, 72.1, 72.0,
71.8, 71.6, 71.5, 71.0, 69.7, 69.1, 68.9, 68.6, 68.5, 66.5, 54.6 ppm.
MALDI-TOF MS: calcd. for [M + Na]+ 2126.94; found 2126.11.
C129H138O26 (2126.94): calcd. C 73.62, H 6.61; found C 73.35, H
6.70.
[15]
[16]
[17]
Acknowledgments
NMR and MS facilities of the Centro Interdipartimentale di Meto-
dologie Chimico-Fisiche dell’Università di Napoli (CIMCF) are ac-
knowledged. We thank Dr. Alessandra Ravidà for useful sugges-
tions.
[18]
M. Adinolfi, A. Iadonisi, M. Schiattarella, A. Ravidà, Tetrahe-
dron Lett. 2003, 44, 7863–7866.
[19]
[20]
B. Yu, H. Tao, Tetrahedron Lett. 2001, 42, 2405–2407.
a) K. C. Nicolaou, N. Watanabe, J. Li, J. Pastor, N. Winssinger,
Angew. Chem. Int. Ed. 1998, 37, 1559–1561; b) T. Zhu, G.-J.
Boons, Tetrahedron: Asymmetry 2000, 11, 199–205.
T. Ogawa, K. Sasajima, Tetrahedron 1981, 37, 2779–2786.
N. Teumelsan, X. Huang, J. Org. Chem. 2007, 72, 8976–8979.
Z. Szurmai, L. Balatoni, A. Liptak, Carbohydr. Res. 1994, 254,
301–309.
[1] P. H. Seeberger, D. B. Werz, Nature 2007, 446, 1046–1051.
[2] a) O. J. Plante, P. H. Seeberger, E. R. Palmacci, Science 2001,
291, 1523–1527; b) P. H. Seeberger, Chem. Soc. Rev. 2008, 37,
19–28.
[3] For a review of recent advances in oligosaccharide synthesis,
see: X. Zhu, R. R. Schmidt, Angew. Chem. Int. Ed. 2009, 48,
1900–1934.
[21]
[22]
[23]
[24]
S. N. Lam, J. Gervay-Hague, J. Org. Chem. 2005, 70, 8772–
8779.
Eur. J. Org. Chem. 2010, 711–718
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717

A. Pastore, M. Adinolfi, A. Iadonisi, S. Valerio
FULL PAPER
[25] a) S. C. Ennis, I. Cumpstey, A. J. Fairbanks, T. D. Butters, M.
Mackeenb, M. R. Wormaldb, Tetrahedron 2002, 58, 9403–9411;
b) L. Jiang, T. H. Chan, Tetrahedron Lett. 1998, 39, 355–358;
c) K. Daragics, P. Fugedi, Tetrahedron Lett. 2009, 50, 2914–
2916.
[26] C.-R. Shie, Z.-H. Tzeng, S. S. Kulkarni, B.-J. Uang, C.-Y. Hsu,
S.-C. Hung, Angew. Chem. Int. Ed. 2005, 44, 1665–1668.
[27] J. R. Merritt, E. Naisang, B. Fraser-Reid, J. Org. Chem. 1994,
59, 4443–4449.
[28] For other approaches towards branched mannose tri- and
pentasaccharides related to 14 and 2, see ref.[15,17b,20,21,23] For
further references, see: a) O. P. Srivastava, O. Hindsgaul, J. Org.
Chem. 1987, 52, 2869–2875; b) S. J. Danishefsky, S. Hu, P. F.
Cirillo, M. Eckardt, P. H. Seeberger, Chem. Eur. J. 1997, 3,
1617–1628; c) J. Rademann, A. Geyer, R. R. Schmidt, Angew.
Chem. Int. Ed. 1998, 37, 1241–1245; d) Y. Du, M. Zhang, F.
Kong, Tetrahedron 2001, 57, 1757–1763; e) Y. Zhu, F. Kong,
Synlett 2001, 1217–1220; f) J. Zhang, F. Kong, Tetrahedron:
Asymmetry 2002, 13, 243–252; g) B. Fraser-Reid, J. C. Lopez,
K. V. Radhakrishnan, M. V. Nandakumar, A. M. Gomez, C.
Uriel, Chem. Commun. 2002, 2104–2105; h) D. M. Ratner, O. J.
Plante, P. H. Seeberger, Eur. J. Org. Chem. 2002, 826–833; i)
L. V. Backinowsky, P. I. Abronina, A. S. Shaskov, A. A. Gra-
chev, N. K. Kochetkov, S. A. Nepogodiev, J. F. Stoddart, Chem.
Eur. J. 2002, 8, 4412–4423; j) I. Matsuo, M. Wada, S. Manabe,
Y. Yamaguguchi, K. Otake, K. Kato, Y. Ito, J. Am. Chem. Soc.
2003, 125, 3402–3403; k) M. Mandal, V. Y. Dudkin, X. Geng,
S. J. Danishefsky, Angew. Chem. Int. Ed. 2004, 43, 2557–2561;
l) M. Dowlut, D. G. Hall, O. Hindsgaul, J. Org. Chem. 2005,
70, 9809–9813; m) R. Blattner, R. H. Furneaux, M. Ludewig,
Carbohydr. Res. 2006, 341, 299–321; n) Z.-G. Wang, J. D. War-
ren, V. Y. Dudkin, X. Zhang, U. Iserloh, M. Visser, M. Eckh-
ardt, P. H. Seeberger, S. J. Danishefsky, Tetrahedron 2006, 62,
4954–4978; o) K. N. Jayaprakash, S. R. Chaudhuri, C. V. S. R.
Murty, B. Fraser-Reid, J. Org. Chem. 2007, 72, 5534–5545; p)
F. A. Jaipuri, N. L. Pohl, Org. Biomol. Chem. 2008, 6, 2686–
2691; q) I. Imagawa, A. Kinoshita, Y. Yamamoto, K. Namba,
M. Nishizawa, Synlett 2008, 1981–1984; r) C. T. Tanifum, C.-
W. T. Chang, J. Org. Chem. 2009, 74, 634–644.
[29]
S. Jonke, K. Liu, R. R. Schmidt, Chem. Eur. J. 2006, 12, 1274–
1290.
[30] T. G. George, P. Szolcsanyi, S. G. Koenig, D. E. Paterson, Y.
Isshiki, A. Vasella, Helv. Chim. Acta 2004, 87, 1287–1298.
Received: October 5, 2009
Published Online: December 14, 2009
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