Gold(I)-Catalyzed glycosylation with glycosyl ortho-alkynylbenzoates as donors: General scope and application in the synthesis of a cyclic triterpene saponin

Article abstract of DOI:10.1002/chem.200902548

Glycosyl ortho-alkynylbenzoates have emerged as a new generation of donors for glycosidation under the catalysis of gold(I) complexes such as Ph ₃PAuOTf and Ph₃PAuNTf₂ (Tf= trifluoromethanesulfonate). A wide variety of these donors, including 2-deoxy sugar and sialyl donors, are easily prepared and shelf stable. The glycosidic coupling yields with alcohols are gener-ally excellent; even direct coupling with the poorly nucleophilic amides gives satisfactory yields. Moreover, excellent α-selective glycosylation with a 2-deoxy sugar donor and β-selective sialylation have been realized. Application of the present glycosylation protocol in the efficient synthesis of a cyclic triterpene tetrasaccharide have further demonstrated the versatility and efficacy of this new method, in that a novel chemoselective glycosylation of the carboxylic acid and a new one-pot sequential glycosylation sequence have been implemented.

Full text of DOI:10.1002/chem.200902548

FULL PAPER
DOI: 10.1002/chem.200902548
Gold(I)-Catalyzed Glycosylation with Glycosyl ortho-Alkynylbenzoates as
Donors: General Scope and Application in the Synthesis of a Cyclic
Triterpene Saponin
Yao Li,[a] Xiaoyu Yang,[a] Yunpeng Liu,[b] Cunsheng Zhu,[a] You Yang,[c] and Biao Yu*[a]
Dedicated to Professor Yongzheng Hui on the occasion of his 70th birthday
Abstract: Glycosyl ortho-alkynylben-
zoates have emerged as a new genera-
tion of donors for glycosidation under
the catalysis of gold(I) complexes such
as Ph3PAuOTf and Ph3PAuNTf2 (Tf=
trifluoromethanesulfonate). A wide va-
riety of these donors, including 2-deoxy
sugar and sialyl donors, are easily pre-
pared and shelf stable. The glycosidic
coupling yields with alcohols are gener-
ally excellent; even direct coupling
with the poorly nucleophilic amides
gives satisfactory yields. Moreover, ex-
cellent a-selective glycosylation with a
2-deoxy sugar donor and b-selective
sialylation have been realized. Applica-
tion of the present glycosylation proto-
col in the efficient synthesis of a cyclic
triterpene tetrasaccharide have further
demonstrated the versatility and effica-
cy of this new method, in that a novel
chemoselective glycosylation of the car-
boxylic acid and a new one-pot sequen-
tial glycosylation sequence have been
implemented.
Keywords: glycosylation
· gold ·
homogeneous catalysis · sialylation ·
triterpene saponin
Introduction
protocols associated with hundreds of their variants have
been developed.[1,2] However, it is still not an easy task in
building many of the glycosidic linkages, especially com-
pared to the synthesis of the phosphodiester and amide link-
ages occurring respectively in the other two fundamental
biopolymers (i.e., nucleic acids and peptides). The limited
accessibility to homogeneous oligosaccharides and glycocon-
jugates still remains as a major impediment to the study of
the function of carbohydrates.[2]
Glycosylation to construct glycosidic linkages is the central
theme in the synthesis of oligosaccharides and glycoconju-
gates, which play important roles in numerous biological
processes.[1,2] In fact, chemists have studied glycosylation
chemistry for over a century, and dozens of glycosylation
[a] Y. Li, X. Yang, Dr. C. Zhu, Prof. Dr. B. Yu
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
The overwhelmingly applied glycosylation approach em-
ploys substitution of a leaving group on the anomeric
carbon of a glycosyl donor with an acceptor (a nucleophile).
Categorized by the leaving groups, which determine largely
the glycosylation conditions, the major glycosylation proto-
cols employ the following types of glycosyl donors: glycosyl
halides;[3–5] thioglycosides;[6] trichloroacetimidates;[7] phos-
phate/phosphite derivatives;[8,9] sulfoxides;[10] glycals;[11] 1-
acyl-,[12] 1-carbonates,[13] and variants; n-pentenyl glyco-
sides;[14] orthoesters;[15] 1,2-anhydro sugars;[16] and glycosyl
diazirines.[17] More recently, 1-hydroxyl sugars,[18] 1-(2’-car-
boxy)benzyl sugars,[19] glycosyl iodides,[20] and glycosyl thio-
imidates[21] have also attracted additional attention.
354 Fenglin Road, Shanghai 200032 (China)
Fax : (+86)21-64166128
E-mail: byu@mail.sioc.ac.cn
[b] Dr. Y. Liu
Key Laboratory of Marine Drugs
Marine Drug and Food Institute
Ocean University of China, Qingdao 266003 (China)
[c] Y. Yang
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902548. It includes experi-
Most of these glycosyl donors demand, mechanistically, a
stoichiometric amount of the promoter to assist the depar-
ture of the leaving group. Most of these promoters are ex-
pensive and toxic, such as the heavy metal salts for glycosyl
1
mental procedures, analytical data, and reproductions of H and
13C NMR spectra for all new compounds as well as X-ray data for
compounds 3ab, 3ga, and 3hb.
Chem. Eur. J. 2010, 16, 1871 – 1882
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1871

halides, thiophilic reagents for thioglycosides, and dehydrat-
ing reagents for 1-hydroxyl sugars. In addition, the stoichio-
metric promoter could be detrimental to a glycosylation re-
action with multifunctional acceptors. In this regard, glyco-
syl trichloroacetimidates and phosphites are exceptional; in
a wide scope, they are capable of being activated for glycosi-
dation by a catalytic amount of a Lewis acid as promoter.
A speculation about the catalytic cycle of a glycosylation
reaction is simplified as shown in Scheme 1, in which the re-
complexes, possess little oxophilic character, thus displaying
good functional-group compatibility and low air and mois-
ture sensitivity.[26] We envisioned that sugar derivatives anal-
ogous to n-pentenyl glycosides,[14,24] one of the major types
of glycosyl donors or its variants (such as glycosyl pente-
noates, 6-phenyl-5-hexynoates, and gem-dimethyl-4-pentenyl
glycosides)[27–29] by positioning a C C triple bond in the
ꢁ
leaving group (e.g., E1, E2, and E3) might be able to be ac-
tivated by
a gold complex to undergo glycosidation
(Scheme 2). One obvious advantage of using a gold complex
Scheme 1. A catalytic version of the glycosylation reaction (P=protect-
ing group).
generation of the promoter E+Xꢀ requires the protonated
leaving group (LH; the H+ is from the acceptor HOR) to
be an inert species that neither interferes with the promoter
E+Xꢀ nor competes with the acceptor for glycosidation of
the oxocarbenium B. Evidently, the LH generated from gly-
Scheme 2. Analogy of the proposed new glycosylation protocol to the
conventional glycosylation reaction with n-pentenyl glycosides as donors.
cosyl trichloroacetimidates is NH
cosyl phosphites HOP(OR)2, which fulfill largely these re-
quirements. Occasionally, NH2A(C=O)CCl3 could still be
2ACHTNUGTREN(UNGN C=O)CCl3, and from gly-
G
as promoter would be its inertness toward the oxo groups
enriched in the carbohydrate substrates. In addition, proto-
nation of the resulting Au species D2 (by the acceptor
HOR) would regenerate the active gold(I) to ensure a cata-
lytic cycle of the glycosidation.
competitive with poorly nucleophilic or highly stereo-de-
manding acceptors.[22,23d,l] In this circumstance, glycosyl N-
phenyltrifluoroacetimidates demonstrate an advantage as
(C=O)CF3 instead.[23]
glycosyl donors that generate PhNHACHTNUGTERNUNNG A
problem related to these donors that bear such leaving
groups is their shelf stability. In fact, a few of the ꢁarmedꢂ[24]
glycosyl trichloroacetimidates and phosphites could barely
be purified and stored, and therefore could only be used di-
rectly after preparation.
We recently disclosed a novel catalytic glycosylation pro-
tocol with glycosyl ortho-hexynylbenzoates, which are
stable, as donors, and Ph3PAuOTf (Tf=trifluoromethanesul-
fonate) as a catalyst,[25a] and which was highlighted in the
total synthesis of N,N,N-trimethyl-d-glucosamine (TMG)
chitotriomycin.[25b] In this full account, we demonstrate the
great generality and versatility of this new glycosylation
method.
We then prepared several variants of the n-pentenyl gly-
ꢁ
cosides, such as E1, E2, and E3, which possess a C C triple
bond g or d to the exo-anomeric oxygen (data not shown).
However, these glycosides stayed intact in the presence of
an alcohol and a variety of the gold complexes (e.g., AuCl3,
PPh3AuOTf, and PPh3AuNTf2) even at elevated tempera-
tures (heated to reflux in CH2Cl2). Upon exposure to mois-
ture, trace amounts of the methyl ketone products (from E1
and E2) were detected, thus indicating that activation of the
Results and Discussion
The evolution of glycosyl alkynylbenzoates as glycosylation
donors: Recent studies have shown that cationic gold com-
plexes are highly carbophilic Lewis acids that activate C C
ꢀ
multiple bonds (especially triple bonds) toward nucleophilic
attack.[26] Meanwhile, these complexes, particularly gold(I)
C C triple bond did take place but was not strong enough
ꢁ
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Chem. Eur. J. 2010, 16, 1871 – 1882

Glycosylation with Glycosyl ortho-Alkynylbenzoates
FULL PAPER
Table 1. Preparation of glycosyl ortho-hexynylbenzoates 3a–i.
for receiving a nucleophilic attack by the exo-anomeric
oxygen.
From another viewpoint, we speculated that glycosidation
of E1, E2, or E3 would require the generation of an exo-
methylene penta- or hexacyclic derivative (D2); this was un-
favorable compared to the formation of a tetrahydrofuran
D1 from the n-pentenyl glycosides (Scheme 2). To force the
glycosidation to proceed, the leaving group should be able
to be converted into a more stable methylene derivative D2.
We thus attempted to introduce aromaticity into the leaving
group. Alkynylbenzoates turned out to be a good choice
that would be converted into an isocoumarin derivative
upon leaving behind a glycosyl oxocarbenium B for glycosi-
dation (Scheme 3). Coincidentally, alkanol ortho-alkynyl-
benzoates have just been introduced as alkylating agents in
Entry Lactol
Conditions[a] Glycosyl benzoate
(yield, b/a)
1
2
3
4
5
1a (R=R1 =Ac)
A
A
B
B
B
3a (97%, 1:1.2)
3b (98%, 1.4:1)
3b (97%, 1:1.2)
3c (97%, 1:1.5)
3d (95%, 1:0)
1b (R=R1 =Bz)
1b
1c (R=R1 =Bn)
1d (R=Bn, R1 =Bz)
the presence of HgACHTUNGTRENNUNG
(OTf)2 or Ph3PAuCl/AgOTf.[30]
6
B
7
A
B
B
C
8
Scheme 3. The proposed new glycosylation reaction with glycosyl ortho-
alkynylbenzoates as donors and gold(I) as catalyst.
9
It should be noted that Imagawa and co-workers have re-
ported that perbenzylglucopyranosyl alkynoates could un-
10
dergo glycosidation under the catalysis of HgACTHNUTRGNEUNG
(OTf)2.[31a]
Hotha and co-workers have described that ꢁarmedꢂ proparg-
yl glycosides such as E4 (when R=Bn) could also undergo
glycosidation in the presence of AuCl3 (0.03 equiv AuCl3,
acetonitrile, 608C), whereas the ꢁdisarmedꢂ ones could
not.[31b] More recently, they found that under stronger condi-
tions (0.1 equiv AuBr3, acetonitrile, 708C) ꢁarmedꢂ methyl
glycosides could also undergo glycosidation,[31d] thereby im-
[a] Conditions A: DCC, DMAP, CH2Cl2, at RT. Conditions B: EDCI,
DMAP, DIPEA, CH2Cl2, at RT. Conditions C: 2,4,6-trichlorobenzoyl
chloride, DMAP, iPr2NH, toluene, at RT.
The aldose derivatives 1a–h were converted conveniently
into the corresponding glycosyl ortho-hexynylbenzoates
(3a–h) in excellent yields (>94%) under the action of dicy-
plying the goldACHTUNGTRENNUNG(III) catalyst activates the exo-anomeric
ꢁ
oxygen instead of the C C triple bond.
clohexylcarbodiimide
(DCC)
(dimethylaminopyridine
Preparation of glycosyl ortho-alkynylbenzoates: 1-OH
sugars (1) are common saccharide building blocks in prepa-
rative carbohydrate chemistry that are precursors to the
widely applied glycosyl trichloroacetimidates and phos-
phites. ortho-Hexynylbenzoic acid (2) was easily prepared
from the cheap methyl 2-iodobenzoate in two steps and in
nearly quantitative yield (Table 1).[32] Condensation of lactol
derivative 1 with benzoic acid 2 could be effected under
many ester-forming conditions. Thus, a number of the glyco-
syl ortho-alkynylbenzoates (3a–i), including those of the 2-
deoxyglucose and sialic acid derivatives (3h and 3i), were
readily prepared. Some selected preparative conditions and
outcomes are given in Table 1.
(DMAP), CH2Cl2, at RT) or 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride (EDCI) (DMAP, N,N-diiso-
propylethylamine (DIPEA), CH2Cl2, at RT). Other condi-
tions could also effect the condensation, but led to lower
yields (ꢂ80%, data not shown), such as benzoyl chloride
formation followed by acylation (2, SOCl2, heated to reflux;
then Et3N, DMAP, CH2Cl2, at RT) or treatment of the gly-
cosyl bromides with benzoic acid 2 under phase-transfer
conditions (BnEt3N+Clꢀ, K2CO3, H2O, CH2Cl2, at RT).
However, preparation of the sialyl ortho-hexynylbenzoate 3i
did not succeed under all these conditions. Finally, com-
pound 3i was obtained in a high yield of 88% under the Ya-
maguchi conditions (2,4,6-trichlorobenzoyl chloride, DMAP,
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1873

B. Yu et al.
iPr2NH, toluene, at RT).[33] The a/b ratio in the glycosyl
ortho-hexynylbenzoate products is mainly dependent on the
nature of the starting sugars. Thus, for 2-O-benzoyl-3,4,6-tri-
O-benzyl-d-glucose (1d), the 2-N-Phth- and 2-azido-glucose
derivatives (1 f and 1g), and the N-acetylneuraminic acid
(Neu5Ac) tetraacetate (1i), the b products were obtained
exclusively or predominantly (Table 1, entries 5, 7, 8, and
10). Varying the condensation conditions could also affect
slightly the a/b ratio in the products (entries 2 and 3). These
a/b anomers are difficult to separate on a large scale; never-
theless, they behaved similarly well in the following glycosi-
dation reactions. Also worth noting is the stability of these
glycosyl ortho-hexynylbenzoates, including the 2-deoxyglu-
cose derivative 3h, which remained intact on the shelf for at
least ten months.
Table 2. Glycosylation with glycosyl ortho-hexynylbenzoates 3b and 3 f.
With these glycosyl ortho-hexynylbenzoates (3a–i) readily
available and well characterized,[32,34] we then examined
their glycosidation reaction with a wide range of acceptors
under a variety of conditions.
Glycosylation with donors bearing a neighboring participat-
ing group (3a, 3b, 3d–f): We first tried the glycosylation re-
action of 2,3,4,6-tetra-O-acetyl-d-glucopyranosyl ortho-hex-
ynylbenzoate (3a) and cholesterol (4a) (Scheme 4). In the
Entry
Donor
Acceptor
cholesterol (4a)[a]
4-penten-1-ol (4b)
2,6-dimethylphenol (4c)
4d
4e
4a
4b
4c
4d
4e
Product
Yield [%][b]
1
2
3
4
5
6
7
8
3b
3b
3b
3b
3b
3 f
3 f
3 f
3 f
3 f
8
9
98
98
97
99
10
11
12
13
14
15
16
17
81 (98)[c]
99
99
91
99
9
10
63 (93)[c]
[a] A similar result was obtained with PPh3AuNTf2 as the catalyst.
[b] Isolated yield. [c] Recovery yield.
Scheme 4. Glycosylation with peracetyl glycosyl ortho-hexynylbenzoates
3a and 3e.
n-pentenol (4b), 2,6-dimethylphenol (4c), glucose-6-OH de-
rivative (4d), and glucose-4-OH derivative (4e), were tested
as the representative acceptors for glycosylation with 3b
under similar conditions. All these coupling reactions pro-
ceeded cleanly within three hours. With 4b–4d as acceptors
the desired b-glycosides 9–11 were obtained in >97% yield
(entries 2–4). With the sterically hindered 4e as acceptor,
the coupling product 12 was isolated in 81% yield and the
remaining 4e was recovered completely (entry 5). In com-
parison, in a recent report glycosylation of 4e with methyl
presence of AuCl3 (0.1 equiv; CH2Cl2, 4 ꢃ molecular sieves
(MS), at RT), the major product turned out to be the or-
thoester 5 (85%). With PPh3AuOTf as a catalyst instead, or-
thoester 5 was still the major product, but it decomposed
readily afterwards. However, 2,3,4-tri-O-acetyl-l-rhamnopy-
ACHTUNGTRENNUNGranosyl ortho-hexynylbenzoate (3e) behaved as an excellent
donor, which coupled with the b-glucopyranoside-2,4-diol
6[35a,b] under the catalysis of PPh3AuOTf (0.1 equiv; CH2Cl2,
4 ꢃ MS, at RT) to provide trisaccharide 7 in nearly quantita-
tive yield, which after deprotection is the natural saponin di-
oscin that possesses a variety of bioactivities.[35]
2,3,4,6-tetra-O-benzoyl-1-thio-d-glucopyranoside under
a
powerful promotion system (Me2S2/Tf2O) provided the cou-
pled disaccharide 12 in 67% yield.[37] By employing 3,4,6-tri-
A ready alternative to avoid the orthoester formation in
glycosylation is to replace the 2-O-acetyl group on the
donor with a more sterically demanding acyl group,[36a] such
as the benzoyl group.[36b] Indeed, glycosylation of cholesterol
(4a) with 2,3,4,6-tetra-O-benzoyl-d-glucopyranosyl ortho-
hexynylbenzoate (3b, 1.2 equiv) under the previous condi-
tions (0.1 equiv PPh3AuOTf, CH2Cl2, 4 ꢃ MS, at RT) pro-
O-acetyl-2-deoxy-2-phthalimido-d-glucopyranosyl
ortho-
hexynylbenzoate (3 f) as the donor, similar results were ob-
tained for the glycosylation of the alcohols 4a–4e (en-
tries 6–10).[25a]
It should be noted that the coupling of 3b and cholesterol
(4a) as a model reaction could not proceed under the action
of AgOTf, CuACHTUNGRTENNUG(OTf)2, PdACHTUNGTERN(NUGN OAc)2, PtCl2, TMSOTf (TMS=tri-
vided the desired b-glycoside
(Table 2, entry 1). Then a small panel of alcohols, including
8
nearly quantitatively
methylsilyl), BF3·OEt2, TfOH, or Bi
ACHTUNGRTEN(NUNG OTf)3, with the starting
3b being fully recovered.[38]
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Chem. Eur. J. 2010, 16, 1871 – 1882

Glycosylation with Glycosyl ortho-Alkynylbenzoates
FULL PAPER
Table 3. Glycosylation with glycosyl ortho-hexynylbenzoates 3c, 3g, and
3h.
Construction of the N-glycosidic linkage of amides is im-
portant in the synthesis of N-glycopeptides; however, direct
N-glycosylation is difficult due to the poor nucleophilicity of
the amide nitrogen.[10,18b] Only recently, direct N-glycosyla-
tion of an amide was carried out by employing glycosyl tri-
fluoroacetimidates as donors.[23d,m] To explore the efficiency
of the present glycosylation protocol, we examined the
direct N-glycosylation of the asparagine derivatives 18 and
19 with 3,4,6-tri-O-benzyl-2-O-benzoyl-d-glucopyranosyl
ortho-hexynylbenzoate (3d). Under the catalysis of
0.2 equiv of Ph3PAuOTf (or Ph3PAuNTf2) in CH3NO2/
CH2Cl2 (3:1) at RT, the glycosylation of amides 18 and 19
with 3d (1.0 equiv) provided the corresponding b-N-glyco-
sides 20 and 21 in a good yields of 54 and 72%, respective-
ly.[23d] The major byproduct was the 1,6-anhydride 22 derived
from the donor (Scheme 5).
Entry Donor Acceptor Product Solvent Yield [%][a] (a/b ratio)[b]
1
2
3
4
5
6
7
8
3c
3c
3g
3g
3h
3h
4a
4d
4a
4d
4a
4d
23
24
25
26
27
28
CH2Cl2 98 (1:1)
Et2O 70 (4.4:1)
CH2Cl2 99 (1.2:1)
Et2O 74 (5.3:1)
CH2Cl2 98 (2.5:1)
Et2O 72 (8.8:1)
CH2Cl2 98 (2.7:1)
Et2O 95 (10.2:1)
CH2Cl2 98 (2.5:1)
Et2O 98 (1.7:1)
CH2Cl2 98 (2.7:1)
Et2O 98 (2.0:1)
9
10
11
12
[a] Isolated yield. [b] The a/b ratio was determined by 1H NMR spectro-
scopic measurements.
maining acceptors (entries 2 and 4). This might be attributed
to the transient coordination of Et2O with the active gold(I)
species. Similar results were obtained with 3,4,6-tri-O-acetyl-
2-azido-2-deoxy-d-glucopyranosyl ortho-hexynylbenzoate 3g
as donors (entries 5–8). When 3,4,6-tri-O-acetyl-2-deoxy-d-
glucopyranosyl ortho-hexynylbenzoate 3h was used as
donor to couple with alcohols 4a and 4d under similar con-
ditions, all the reactions went smoothly (either in CH2Cl2 or
Et2O) and provided the corresponding glycosides 27 and 28
in excellent yields (98%) and similar a/b ratios (1.7:1 to
2.7:1, entries 9–12). These results demonstrate that the 2-
deoxy sugar donors are more active than the corresponding
2-azido and 2-benzyloxy sugar donors for glycosidation.
Moreover, we found that with Ph3PAuNTf2 (0.2 equiv) as
the catalyst, the glycosidation of 3h proceeded in CH2Cl2
(ꢀ728C to RT) with extremely high yields and a selectivity
(Table 4). The coupling with both primary alcohols (choles-
terol (4a), 4-penten-1-ol (4b), and sugar-6-ols 4d and 4 f)
and the sterically demanding secondary alcohols (sugar-4-ol
4e and -3-ol 4g) all afforded the corresponding coupled
products (27–32) in nearly quantitative yields (>97%) and
with nearly complete a selectivity (a/b>30:1). The present
superior results for a-selective glycosidation of 2-deoxy
sugars are unprecedented.[40,41] In comparison, in a recent
report the coupling of alcohol 4 f with 3,4,6-tri-O-acetyl-2-
deoxy-d-glucopyranosyl trichloroacetimidate (TMSOTf,
CH2Cl2, ꢀ788C) provided the disaccharide 31 in 90% yield
and with an a/b ratio of 4:1.[41a] The a selectivity is known
to be a result of the anomeric effect.[42] The present superior
a selectivity suggests that the anomeric effect acts as the
Scheme 5. N-Glycosylation of amides with glycosyl ortho-hexynylben-
zoate 3d.
Glycosylation with donors without neighboring participating
group (3c, 3g, and 3h): Donors without a neighboring par-
ticipating group (ꢁarmedꢂ) are more active than those with a
participating acyl group at 2-OH (ꢁdisarmedꢂ), although they
lead to a/b anomers by means of glycosidation of the corre-
sponding sugar oxocarbenium B intermediate (Scheme 1).
Thus, not surprisingly, coupling of cholesterol (4a) and
sugar alcohol 4d with 2,3,4,6-tetra-O-benzyl-d-glucopyrano-
syl ortho-hexynylbenzoate 3c under the catalysis of
Ph3PAuOTf (0.1 equiv) in CH2Cl2 at RT provided the corre-
sponding glycosides 23 and 24 in nearly quantitative yields
and 1:1 ratios of the a,b-anomers (Table 3, entries 1 and 3).
It is well known that ether as a solvent, which might coordi-
nate to the sugar oxocarbenium B to favorably form an
equatorial oxonium ion (due to the reverse anomeric
effect), leads to a-selective glycosylation.[1a,39] Evidently,
coupling of alcohols 4a and 4d with ortho-hexynylbenzoate
3c in Et2O provided the corresponding glycosides 23 and 24
with good a selectivity (a/b=4.4:1 and 5.3:1, respectively).
Nevertheless, the present glycosylation reaction in Et2O pro-
ceeded much less efficiently relative to the reaction in
CH2Cl2, as it provided the coupled glycosides 23 and 24 in
only around 70% yields, with complete recovery of the re-
Chem. Eur. J. 2010, 16, 1871 – 1882
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1875

B. Yu et al.
Table 4. Highly efficient a-selective glycosidation of 3h.
Table 5. Sialylation of alcohol 4d with 3i.
Entry AuI (equiv)
Solvent
T
[8C]
t
Yield
[%][a]
(a/b
ratio)[b]
1
2
3
4
5
6
7
PPh3AuOTf
(0.1)
PPh3AuOTf
(0.1)
PPh3AuOTf
(0.2)
PPh3AuNTf2
(0.1)
PPh3AuOTf
(0.2)
PPh3AuOTf
(0.4)
PPh3AuNTf2
(0.4)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
RT
5 min 83 (1:8.3)
ꢀ40
ꢀ78
RT
3 h
6 h
82 (1:6.3)
79 (1:5.6)
Entry
Acceptor
Product
Yield [%][a] (a/b ratio)[b]
5 min 80 (1:12.5)
1
2
3
4
5
6
4a
4b
4d
4e
4 f
4g
27a
29
28a
30
31
32
99 (a only)
99 (a only)
99 (ꢂ30:1)
97 (a only)
99 (ꢂ30:1)
99 (a only)
CH2Cl2/CH3CN
(1:1)
CH2Cl2/CH3CN
(1:1)
CH2Cl2/CH3CN
(1:1)
RT
2 h
7 h
7 h
62 (5:4)
72 (5:3)
77 (1:2)
ꢀ78
ꢀ78
[a] Isolated yield. [b] The a/b ratio was determined by 1H NMR spectro-
scopic measurements of the crude products.
[a] Isolated yield. [b] The a/b ratio was determined by 1H NMR spectro-
scopic measurements.
sole or dominant element governing the stereoselectivity in
the present reaction in that the oxocarbenium B is barely
coordinated with other species, which include the solvent
CH2Cl2, the isocoumarin D3 derived from the leaving group,
and the catalyst Ph3PAuNTf2 (ꢀNTf2 is a more weakly coor-
CH3CN was introduced as a solvent. This might also be at-
tributed to the coordination of CH3CN with the gold(I) cat-
alyst, although the a/b ratios was indeed remarkably in-
creased (entries 5–7).
ꢀ
dinating anion than OTf).[43]
Since the excellent b-selective sialylation was observed in
the coupling of the primary sugar alcohol 4d with sialyl 2-
ortho-hexynylbenzoate 3i in the presence of Ph3PAuNTf2 in
CH2Cl2, we then examined with more alcohols as acceptors,
including n-pentenol (4b), the steroidal 34, the galactose
diol 36, and the triols 35 and 37 (Scheme 6). All the reac-
tions proceeded smoothly and provided the desired coupled
products 38–42 in good yields (65–80%) and excellent b se-
lectivity (a/b>10:1). For the sialylation of galactose diol
and triols (35–37), the reported regioselectivity as same as
those with other types of the sialyl donors was ob-
Sialylation: Sialylation to make the ketosidic linkages is one
of the most challenging tasks in glycosylation chemistry.[44]
The electron-withdrawing C1 carboxylic function, which dis-
favors the oxocarbenium formation, restricts glycosidation
both electronically and sterically; moreover, an elimination
to produce the 2,3-dehydroglycals can be a significant com-
peting pathway. In fact, only limited glycosylation protocols
are applicable for direct sialylation.[45] Those mainly include
glycosylation with sialyl 2-sulfide,[46] xanthate,[47] phos-
phite,[48] and trifluoroacetimidate as donors.[49,50]
AHCTUNGTRENNUNG
tained.[46a,e,47,49a,50a]
We found that sialyl 2-ortho-hexynylbenzoate 3i behaved
as an excellent donor in coupling with sugar alcohol 4d in
the presence of Ph3PAuOTf (0.1 equiv) in CH2Cl2 (Table 5).
At room temperature, the reaction was completed in 5 min
and provided the coupled disaccharide 33 in 83% yield in
favor of the thermodynamically more stable b-anomer (a/
b=1:8.3, entry 1). With the commercially available and air-
stable Ph3PAuNTf2 as catalyst, even better b selectivity was
obtained (80%, a/b=1:12.5, entry 4). At ꢀ788C, the reac-
tion became sluggish; the formation of a comparable yield
of the disaccharide 33 (79%) required 0.2 equiv of the cata-
lyst for 6 h. The a/b selectivity was not much changed (a/
b=1:5.6, entry 3).
Application to the synthesis of a cyclic triterpene saponin:
To further prove the usefulness of the present glycosylation
protocol, we applied it to the total synthesis of a complex
cyclic triterpene saponin 43.[52] Cyclic triterpene saponins,
such as Lobatoside E, constitute a very small family of the
The a-selective sialylation with silalyl donors in the ab-
sence of a temporary directing group at the C3 position is
usually affected by the nitrile solvent effect.[44,51] However,
the present glycosylation protocol became inefficient when
1876
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Chem. Eur. J. 2010, 16, 1871 – 1882

Glycosylation with Glycosyl ortho-Alkynylbenzoates
FULL PAPER
the acetyl, benzoyl, tert-butyldi-
phenylsilyl, and 4-methoxyben-
zyl groups were temporary pro-
tecting groups to facilitate the
sequential assembly of the
units.
Thus, the assembly of the
cyclic triterpene saponin 43
commenced with a successful
chemoselective glycosylation of
the 28-carboxylic acid of the
abundant oleanolic acid (44)
with the arabinosyl ortho-hexy-
nylbenzoate 46 (Ph3PAuOTf
(0.1 equiv),
BF3·OEt2
1,8-diazabicyclo-
ACTHNUGNRTE[NUG 5.4.0]undec-7-ene (DBU;
(3.0 equiv),
2.0 equiv), CH2Cl2, 4 ꢃ MS, at
RT), thereby providing ester a-
l-arabinoside 50 predominantly
Scheme 6. b-Selective sialylation with sialyl 2-ortho-hexynylbenzoate 3i as donor.
in
a satisfactory 72% yield
(Scheme 8). Such a chemoselec-
triterpene glycosides, which have two oligosaccharides flank-
ing a pentacyclic triterpene bridged with 3-hydroxy-3-methyl
glutarate. They show significant antitumor activities. We
have recently achieved the first total synthesis of Lobatosi-
de E,[53] in which a total of 73 steps were required and the
five glycosidic linkages were constructed by the convention-
al methods with glycosyl trichloroacetimidates, glycosyl bro-
mide, and thioglycoside as donors. Efficient synthesis
toward simplified structures to decipher the structure–activi-
ty relationship and mechanism of action was an ongoing
project in our lab. Compound 43 turned out naturally to be
the first simplified structure to testify to the importance of
the 2,23-dihydroxy group in the triterpene aglycone, the 3’-
hydroxy and -methyl groups in the acyl moiety, and the ter-
minal glucose (cf. Lobatoside E) to the antitumor activity.
Removal of these structural elements would greatly shorten
the synthetic steps relative to the total synthesis of the natu-
ral Lobatoside E.
Scheme 7. The simplified cyclic triterpene saponin 43 and its retrosynthe-
To realize a whole gold-catalyzed approach to the assem-
bly of the sugar units in 43, four sugar donors 45–48 were
designed (Scheme 7). The arabinosyl, galactosyl, and rham-
nosyl ortho-hexynylbenzoates 46–48 were readily prepared
by condensation of the corresponding lactols with ortho-hex-
ynylbenzoic acid 2 in excellent yields (>87%) in a manner
similar to the preparation of donors 3a–h.[32] 1,2-Anhydro-
3,4,6-tri-O-benzyl-d-glucose (45)[54] was used as a donor be-
cause we have recently found that 1,2-anhydro sugar could
undergo glycosidation smoothly under the catalysis of
Ph3PAuOTf,[55] and the resulting 2-OH would be subsequent-
ly glycosylated in a one-pot fashion with a glycosyl ortho-
hexynylbenzoate under the action of the same gold catalyst.
The global protecting-group strategy was adopted from the
previous total synthesis of Lobatoside E,[53] thus the benzyl
group was chosen as the permanent protecting group, and
sis.
tive glycosylation of carboxylic acid in the presence of an al-
cohol has only been achieved with glycosyl bromides under
phase-transfer conditions;[56] the corresponding 2-O-acetyl-
3,4-di-O-benzyl-l-arabinopyranosyl bromide was unstable,
thus was used uncharacterized after preparation.[53]
Then we examined the gold-catalyzed one-pot sequential
glycosylation with the 1,2-anhydroglucose 45 and galactosyl
ortho-hexynylbenzoate 47 to assemble the left-handed disac-
charide. As expected, treatment of 50 with 1,2-anhydroglu-
cose 45 in the presence of PPh3AuOTf (0.2 equiv) (CH2Cl2,
ꢀ788C to RT) gave the desired 3-O-b-glucoside 51. Subse-
quent addition of the ortho-hexynylbenzoate 47 and an addi-
Chem. Eur. J. 2010, 16, 1871 – 1882
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1877

B. Yu et al.
tional portion of PPh3AuOTf
(0.37 equiv) led to the desired
trisaccharide 52 in a good 60%
yield.
Removal of the 2-O-acetyl
group on the arabinose unit in
52 with DBU (MeOH, CH2Cl2,
at RT) gave 53.[57] Glycosylation
of the resulting 2-OH with the
rhamnosyl
zoate 48 under the standard
gold-catalyzed conditions
ortho-hexynylben-
(0.2 equiv PPh3AuOTf, 4 ꢃ MS,
CH2Cl2, at RT) proceeded
smoothly and provided the tet-
rasaccharide 54 in nearly quan-
titative yield. Exchange of the
2-O-benzoyl group on the gal-
actose unit in 54 with a benzyl
group led to 55 (83% for two
steps).
Tetrasaccharide 55 possesses
Scheme 8. Assembly of tetrasaccharide 55.
two
orthogonal
protecting
groups (tert-butyldiphenylsilyl
(TBDPS) and p-methoxybenzyl
(PMB)) at the two ends. Alternatively, deprotection of the
4-O-PMB group of the rhamnose unit with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) gave 56 (82%, Scheme 9).
Treatment of alcohol 56 with glutaric anhydride 49 in the
presence of DMAP in pyridine at 708C provided ester 57
(84%). The 6-O-TBDPS group of the galactose unit in 57
was then cleaved with tertabutylammonium fluoride
(TBAF) in THF to afford alcohol acid 58 (100%), which
was subjected to macrocyclization under Yamaguchi condi-
tions[33] to provide the cyclic glycoconjugate 59 in a satisfac-
tory 78% yield. Finally, removal of the Bn groups by hydro-
genolysis over Pd(OH)2/C furnished the target cyclic triter-
pene saponins 43 cleanly in 60% yield.
Thus, the cyclic triterpene saponin 43 was assembled with
only 11 steps and in around 11% overall yield from six read-
ily available building blocks by employing the present gold-
catalyzed glycosylation as key steps.
Conclusion
Glycosyl ortho-alkynylbenzoates have been introduced as a
new generation of donors for glycosidation under the cataly-
sis of gold(I) complexes, such as Ph3PAuOTf and
Ph3PAuNTf2. This new glycosylation protocol has shown sig-
nificant merits: 1) the donors are easily prepared and shelf
stable; 2) the glycosidic coupling yields are generally excel-
lent; 3) the promotion is catalytic; 4) the promotion condi-
tions are orthogonal to the conventional ones; 5) the reac-
tion conditions are mild and neutral; and therefore 6) side
reactions are minimal. The versatility of the present method
has been demonstrated by the successful glycosylation of
Scheme 9. Elaboration of the cyclic saponin 43.
1878
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Chem. Eur. J. 2010, 16, 1871 – 1882

Glycosylation with Glycosyl ortho-Alkynylbenzoates
FULL PAPER
72.8, 70.8, 68.9, 62.6, 30.5, 22.0, 19.4, 13.6 ppm; HRMS (MALDI): m/z:
calcd for C47H40O11 [M+Na]+: 803.2463; found: 803.2479.
amides, superior a-selective glycosidation of 2-deoxy sugars,
and b-selective sialylation. Further evidence of the efficacy
of the present method is provided by its application to the
efficient synthesis of the complex cyclic triterpene glycoside
43, in that a novel chemoselective glycosylation of carboxyl-
ic acid and a new one-pot sequential glycosylation sequence
have been realized. However, the working mechanism of
this new glycosylation protocol has not yet been validated,
nor has a new solution for the general issue of the a/b selec-
tivity been provided.
Compound 3b (Conditions B): A solution of lactol 1b (2.16 g, 4.0 mmol),
2
(970 mg, 4.8 mmol), DMAP (488 mg, 4.0 mmol), EDCI (955 mg,
5.0 mmol), and DIPEA (1.3 mL, 7.2 mmol) in dry CH2Cl2 (4 mL) was
stirred for 3 h at RT, and was then diluted with CH2Cl2. The resulting
mixture was washed with saturated NaHCO3 and brine, respectively. The
filtrates were concentrated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate 10:1) to provide 3b as a white
solid (2.82 g, 97%; b/a=1:1.2).
Compound 3i (Conditions C): Triethylamine (0.58 mL, 4.18 mmol) and
2,4,6-trichlorobenzoylchloride (0.52 mL, 3.34 mmol) were added to a so-
lution of 2 (338 mg, 1.67 mmol) in toluene at RT. After stirring at RT for
2 h, compound 1i (820 mg, 1.67 mmol) in toluene was added, followed by
the addition of DMAP (510 mg, 4.18 mmol) in toluene. After stirring for
an additional 1 h, the mixture was concentrated. The residue was subject-
ed to flash chromatography on silica gel (CH2Cl2/methanol 120:1) to pro-
vide 3i as a white solid (992 mg, 88%; b/a =10:1). A small portion of
the a,b-anomers were separated and characterized. Compound 3ib:
[a]2D0 =ꢀ12.5 (c=0.6 in CH2Cl2); 1H NMR (300 MHz, CDCl3): d=7.92–
7.91 (m, 1H), 7.55–7.53 (m, 1H), 7.50–7.47 (m, 1H), 7.38–7.37 (m, 1H),
5.41–5.36 (m, 3H), 5.13–5.10 (m, 1H), 4.52 (dd, J=13.0, 2.67 Hz, 1H),
4.22–4.15 (m, 3H), 3.82 (s, 3H), 2.73 (dd, J=13.6, 5.1 Hz, 1H), 2.45 (t,
J=7.1 Hz, 2H), 2.20 (dd, J=13.5, 11.6 Hz, 1H), 2.16 (s, 3H), 2.03 (s,
3H), 1.88 (s, 3H), 1.87 (s, 3H), 1.62–1.58 (m, 2H), 1.51–1.46 (m, 2H),
Experimental Section
General procedures: Please see the Supporting Information.
Preparation of compound 2: [PdCl2ACHTUNTGRNEUNG(PPh3)2] (4.20 g, 6.0 mmol), CuI
(1144 mg, 6.0 mmol), and PPh3 (3.14 g, 12.0 mmol) were added to methyl
2-iodobenzoate (18.0 mL, 120.0 mmol) in dry iPr2NH (180 mL). After
stirring at RT for 1 h under an Ar atmosphere, 1-hexyne (20.8 mL,
180.0 mmol) was slowly added at 08C. The mixture was allowed to stir at
RT for 18 h (or at 608C for 6 h) and saturated NH4Cl (400 mL) was
added. After vigorously stirring for 30 min, petroleum ether (400 mL)
was added and the phases separated. The aqueous layer was extracted
with hexane/EtOAc (100:1), the combined organic layers were washed
with H2O and brine, dried over Na2SO4, then concentrated. The crude
product was purified by column chromatography on silica gel (hexane/
EtOAc 50:1) to provide methyl 2-hex-1-ynyl benzoate as a yellow oil
(25.9 g, 99%). This oil was dissolved in THF (500 mL) and aqueous
NaOH (1n, 500 mL) was added. After stirring at 508C for 12 h, the solu-
tion was cooled to 08C and then acidified with concentrated HCl. After
removal of THF by rotary evaporation, the residue was contracted with
CH2Cl2 five times. The combined organic layers were dried over Na2SO4
and then concentrated to give 2[58] as a yellow oil (24.2 g, 100%), which
became a light yellow solid when stored at ꢀ188C. 1H NMR (300 MHz,
CDCl3): d=8.07 (d, J=7.8 Hz, 1H), 7.57–7.44 (m, 2H), 7.36 (t, J=
7.2 Hz, 1H), 2.50 (t, J=6.6 Hz, 2H), 1.70–1.45 (m, 4H), 0.96 ppm (t, J=
6.9 Hz, 3H).
0.95 ppm (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d
= 170.9,
170.6, 170.2, 170.0, 166.3, 163.4, 134.7, 132.4, 130.4, 130.0, 127.3, 125.2,
98.2, 97.0, 79.0, 72.9, 71.1, 68.6, 67.6, 62.1, 53.2, 49.5, 36.1, 30.6, 23.1, 22.0,
20.8, 20.7, 19.5, 13.6 ppm; HRMS (ESI): m/z: calcd for C33H41NO14Na
[M+Na]+: 698.2419; found 698.2426. Compound 3ia: [a]2D0 =+3.1 (c=1.2
1
in CHCl3); H NMR (300 MHz, CDCl3): d=7.92–7.91 (m, 1H), 7.52–7.51
(m, 1H), 7.48–7.44 (m, 1H), 7.36–7.32 (m, 1H), 5.82 (d, J=9.8 Hz, 1H),
5.41 (dd, J=6.3, 2.2 Hz, 1H), 5.27–5.24 (m, 1H), 5.17 (td, J=11.8, 5.0 Hz,
1H), 4.69 (dd, J=10.8, 2.3 Hz, 1H), 4.42 (dd, J=12.4, 2.8 Hz, 1H), 4.25
(q, J=10.2 Hz, 1H), 4.13 (dd, J=12.4, 6.0 Hz, 1H), 3.80 (s, 3H), 2.78
(dd, J=13.3, 5.0 Hz, 1H), 2.47 (t, J=7.1 Hz, 2H), 2.27 (dd, J=13.2,
11.2 Hz, 1H), 2.11 (s, 3H), 2.10 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.91 (s,
3H), 1.64–1.58 (m, 2H), 1.53–1.47 (m, 2H), 0.95 ppm (t, J=7.3 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=170.8, 170.5, 170.3, 170.0, 168.3, 163.5,
134.3, 132.1, 130.8, 130.1, 127.1, 125.0, 96.6, 96.4, 78.7, 73.8, 70.4, 68.8,
67.6, 62.1, 52.8, 49.0, 36.7, 30.6, 23.1, 22.0, 20.8, 20.7, 20.6, 19.4, 13.5 ppm;
HRMS (ESI): m/z: calcd for C33H41NO14Na [M+Na]+: 698.2419; found:
698.2416.
Typical procedures for the preparation of glycosyl ortho-hexynylben-
zoates
Typical procedure for the glycosylation with glycosyl ortho-hexynylben-
Compound 3b (Conditions A): A solution of lactol 1b (1.08 g, 2.0 mmol),
2 (485 mg, 2.4 mmol), DMAP (366 mg, 3.0 mmol), and DCC (618 mg,
3.0 mmol) in dry CH2Cl2 (3 mL) was stirred for 3 h at RT, and was then
diluted with CH2Cl2. The resulting mixture was filtered through Celite.
The filtrates were washed with saturated NaHCO3 solution and then con-
centrated in vacuum. The residue was purified by silica gel column chro-
matography (hexane/ethyl acetate 10:1) to provide 3b as a white solid
(1.42 g, 98%; b/a=1.4:1). A small portion of the a,b-anomers were sepa-
rated and characterized. Compound 3ba: [a]2D7 =98.3 (c=4.1 in CHCl3);
1H NMR (300 MHz, CDCl3): d=8.09–7.22 (m, 24H), 6.93 (d, J=3.3 Hz,
1H), 6.32 (t, J=10.2 Hz, 1H), 5.90 (t, J=9.9 Hz, 1H), 5.73 (dd, J=10.2,
2.7 Hz, 1H), 4.75–4.64 (m, 2H), 4.52 (dd, J=12.3, 3.9 Hz, 1H), 2.49 (m,
2H), 1.58 (m, 2H), 1.45 (m, 2H), 0.91 ppm (t, J=7.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=166.0, 165.7, 165.3, 165.1, 163.9, 135.0, 133.5, 133.4,
133.3, 133.1, 132.4, 130.7, 129.9, 129.8, 129.7 (3C), 129.4, 128.8, 128.6,
128.5, 128.4, 128.3 (2C), 127.3, 125.3, 97.2, 90.0, 79.5, 70.6, 70.4, 70.4, 68.8,
62.3, 30.6, 22.0, 19.5, 13.6 ppm; HRMS (MALDI): m/z: calcd for
zoates as donors (3b+4a!8):
A freshly prepared solution of
PPh3AuOTf in CH2Cl2 (0.05n, 0.2 mL) was added to a mixture of o-hexy-
nylbenzoate 3b (94 mg, 0.12 mmol), cholesterol 4a (39 mg, 0.10 mmol),
and 4 ꢃ MS in dry CH2Cl2 (2 mL).[32,59] After stirring at RT for 3 h, the
mixture was filtered through Celite. The filtrates were concentrated. The
residue was purified by silica gel column chromatography (hexane/ethyl
acetate 10:1) to provide 8[60] as a white solid (95 mg, 98%).
Glycosylations in the total synthesis of the cyclic triterpene saponin 43
Chemoselective glycosylation (44+46!50): DBU (0.85 mL, 5.82 mmol)
was added to
a stirred mixture of glycosyl benzoate 46 (1.62 g,
2.91 mmol), oleanolic acid 44 (1.57 g, 3.44 mmol), and 4 ꢃ MS in CH2Cl2
(25 mL) at RT. After stirring for 20 min, BF3·Et2O (1.01 mL, 8.73 mmol)
and a freshly prepared solution of Ph3PAuOTf in CH2Cl2 (0.06m, 5 mL)
was added sequentially. After stirring overnight, the mixture was filtered
through Celite, and the filtrates were concentrated. The resulting residue
was purified by silica gel column chromatography (toluene/EtOAc 30:1)
to afford 50 (1.70 g, 72%) as a white foam. [a]2D0 =30.3 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.34–7.16 (m, 10H), 5.63 (d, J=4.5 Hz,
1H), 5.30 (d, J=3.3 Hz, 1H), 5.25 (t, J=5.1 Hz, 1H), 4.66 (s, 2H), 4.59
(s, 2H), 4.13–4.07 (m, 1H), 3.76–3.68 (m, 2H), 3.52 (dd, J=2.4, 11.4,
1H), 3.20 (brs, 1H), 2.85 (dd, J=5.1, 14.4 Hz, 1H), 2.04, 1.12, 0.99, 0.90,
0.87, 0.78, 0.76 ppm (s, each 3H); 13C NMR (75 MHz, CDCl3): d=175.8,
169.1, 143.3, 138.0, 137.9, 128.3, 128.2, 127.8, 127.7, 127.6, 127.4, 122.7,
91.2, 78.9, 75.1, 72.1, 71.7, 71.3, 69.3, 61.2, 55.3, 47.6, 46.9, 45.8, 41.8, 41.1,
C47H40O11 [M+Na]+: 803.2463; found: 803.2462. Compound 3bb: [a]2D7
=
1
54.2 (c=4.5 in CHCl3); H NMR (300 MHz, CDCl3): d=8.06–7.22 (m,
24H), 6.35 (d, J=7.8 Hz, 1H), 6.03 (t, J=9.3 Hz, 1H), 5.84 (m, 2H), 4.69
(dd, J=12.3, 2.1 Hz, 1H), 4.53 (dd, J=12.0, 4.2 Hz, 1H), 4.44 (m, 1H),
2.46 (t, J=6.6 Hz, 2H), 1.61 (m, 2H), 1.49 (m, 2H), 0.94 ppm (t, J=
7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=166.0, 165.6, 165.0 (2C),
163.3, 134.5, 133.4 (2C), 133.2, 133.0, 132.4, 130.8, 129.7 (2C), 129.4,
129.0, 128.6, 128.5, 128.3 (2C), 128.2, 127.1, 125.8, 97.3, 92.4, 78.9, 73.0,
Chem. Eur. J. 2010, 16, 1871 – 1882
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B. Yu et al.
39.3, 38.7, 38.5, 37.0, 33.8, 33.0, 32.0, 30.6, 28.1, 27.8, 27.2, 25.7, 23.5, 22.7,
20.8, 18.3, 17.0, 15.5, 15.3 ppm; HRMS (MALDI): m/z: calcd for
C51H70O8Na [M+Na]+: 833.4963; found: 833.4959.
Schmidt, Angew. Chem. 1986, 98, 213–236; Angew. Chem. Int. Ed.
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Tetrahedron 1996, 52, 1095–1121; h) S. J. Danishefsky, M. T. Bilo-
deau, Angew. Chem. 1996, 108, 1482–1522; Angew. Chem. Int. Ed.
Engl. 1996, 35, 1380–1419; i) B. G. Davis, J. Chem. Soc. Perkin
Trans. 1 2000, 2137–2160; j) P. H. Seeberger, W.-C. Haase, Chem.
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1624.
One-pot glycosylation (50+45+47!52): A freshly prepared solution of
Ph3PAuOTf in CH2Cl2 (0.06m, 0.45 mL) was added to a stirred mixture
of 50 (105 mg, 0.129 mmol) and 4 ꢃ MS in dry CH2Cl2 (5 mL). The mix-
ture was stirred at RT for 30 min and was then cooled to ꢀ788C. A
cooled solution (08C) of 1,2-anhydroglucose 45 in CH2Cl2 (5 mL), freshly
prepared from 3,4,6-tri-O-benzyl-d-glucal (65 mg, 0.156 mmol),[54] was
then added slowly by syringe. The resulting mixture was allowed to warm
up naturally. After stirring overnight, a freshly prepared solution of
Ph3PAuOTf in CH2Cl2 (0.06m, 1.6 mL) and a solution of 47 in CH2Cl2
(230 mg, 5 mL, 0.26 mmol) were added sequentially. After stirring over-
night, the mixture was filtered through Celite and concentrated. The resi-
due was purified by silica gel column chromatography (petroleum ether/
EtOAc 7:1) to afford 52 (148 mg, 60%) as a white foam. [a]2D4 =156.8
(c=1.1 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.87 (d, J=7.2 Hz,
2H), 7.60 (t, J=6.9 Hz, 4H), 7.47–7.20 (m, 42H), 7.04 (brs, 2H), 5.68 (d,
J=4.5 Hz, 1H), 5.65 (m, 1H), 5.08 (d, J=10.8 Hz, 1H), 4.97 (d, J=
8.1 Hz, 1H), 4.69–4.38 (m, 13H), 4.24 (d, J=8.1 Hz, 1H), 4.14 (m, 2H),
3.96 (t, J=9.6 Hz, 1H), 3.75–3.48 (m, 12H), 2.97 (dd, J=3.6, 10.8 Hz,
1H), 2.86 (d, J=10.8 Hz, 1H), 2.09, 1.25, 1.09, 1.02, 0.92, 0.88, 0.87, 0.83,
0.77, 0.54 (s, each 3H), 1.08 ppm (s, 9H); 13C NMR (100 MHz, CDCl3):
d=175.8, 169.2, 165.0, 143.3, 137.9, 135.5, 135.4, 129.7, 128.3, 128.2 (2C),
127.9, 127.7 (2C), 127.6 (2C), 127.4 (2C), 127.3, 100.5, 85.7, 77.3, 77.1,
74.6, 74.5, 73.2, 72.7, 72.0, 71.6, 71.5, 71.3, 69.2, 46.8, 41.6, 39.3, 39.0, 36.6,
33.0, 30.5, 27.5, 26.9, 25.6, 23.5, 20.8, 19.1, 17.0, 16.0, 15.2 ppm; HRMS
(MALDI): m/z: calcd for C121H142O19SiNa [M+Na]+: 1949.9807; found:
1949.9827.
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Standard glycosylation (53+48!54): A freshly prepared solution of
Ph3PAuOTf in CH2Cl2 (0.06m, 0.23 mL) was added to a stirred mixture
of the glycosyl benzoate 48 (43 mg, 0.066 mmol), trisaccharide saponin 53
(85 mg, 0.045 mmol), and 4 ꢃ MS in CH2Cl2 (5 mL) at RT. After stirring
overnight, the mixture was filtered through Celite and concentrated. The
residue was purified by silica gel column chromatography (petroleum
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ether/EtOAc 5:1) to afford 54 (102 mg, 97%) as a white foam. [a]D25
=
130.9 (c=1.1 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.88 (d, J=
7.5 Hz, 2H), 7.60 (t, J=8.1 Hz, 4H), 7.48–7.15 (m, 54H), 7.07–7.03 (m,
2H), 6.83 (d, J=8.4 Hz, 2H), 5.81 (d, J=1.8 Hz, 1H), 5.66 (dd, J=9.9,
8.1 Hz, 1H), 5.30 (brs, 1H), 5.10 (d, J=11.1 Hz, 1H), 4.99 (d, J=7.8 Hz,
1H), 4.82 (d, J=10.8 Hz, 2H), 4.71–4.39 (m, 18H), 4.26 (d, J=7.8 Hz,
1H), 4.16 (brs, 1H), 4.09 (t, J=9.9 Hz, 1H), 3.98 (t, J=9.3 Hz, 1H), 3.93
(br, 1H), 3.85–3.33 (m, 19H), 3.75 (s, 3H), 2.98 (dd, J=4.2, 10.8 Hz, 1H),
2.87 (dd, J=12.9, 3.0 Hz, 1H), 1.38 (d, J=6.6 Hz, 3H), 1.08 (s, 9H), 1.07,
0.94 (s, each 3H), 0.87 (s, 6H), 0.84, 0.77, 0.56 ppm (s, each 3H);
13C NMR (100 MHz, CDCl3): d=175.7, 165.0, 159.1, 143.4, 138.9, 138.6,
138.5, 138.3, 138.2, 138.0, 137.9, 137.8, 135.5, 135.4, 133.3, 133.0, 132.6,
130.7, 130.2, 129.7, 129.4, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6,
127.5, 127.4, 127.3, 126.9, 122.5, 104.2, 100.5, 97.9, 91.7, 90.8, 85.7, 80.1,
80.0, 79.8, 75.3, 75.1, 74.8, 74.6, 74.5, 74.4, 74.3, 73.3, 72.8, 72.6, 72.2, 72.1,
71.6, 71.2, 69.2, 68.8, 61.4, 59.5, 55.6, 55.2, 47.5, 46.8, 45.8, 41.6, 41.2, 39.3,
39.0, 38.5, 36.6, 33.8, 33.0, 32.8, 32.1, 30.6, 27.8, 27.5, 26.9, 25.9, 25.6, 23.5,
22.5, 19.1, 18.1, 17.9, 17.1, 16.0, 15.2 ppm; HRMS (MALDI): m/z: calcd
for C147H170O23SiNa [M+Na]+: 2354.1794; found: 2354.1760.
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This work is supported by the National Natural Science Foundation of
China (20932009 and 20621062) and the Ministry of Sciences and Tech-
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Received: September 16, 2009
Published online: December 28, 2009
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