NIS/TMSOTf-Promoted Glycosidation of Glycosyl ortho-Hexynylbenzoates for Versatile Synthesis of O-Glycosides and Nucleosides

Article abstract of DOI:10.1021/acs.joc.1c00151

Glycosidation plays a pivotal role in the synthesis of O-glycosides and nucleosides that mediate a diverse range of biological processes. However, efficient glycosidation approach for the synthesis of both O-glycosides and nucleosides remains challenging in terms of glycosidation yields, mild reaction conditions, readily available glycosyl donors, and cheap promoters. Here, we report a versatile N-iodosuccinimide/trimethylsilyl triflate (NIS/TMSOTf)-promoted glycosidation approach with glycosyl ortho-hexynylbenzoates as donors for the highly efficient synthesis of O-glycosides and nucleosides. The glycosidation approach highlights the merits of mild reaction conditions, cheap promoters, extremely wide substrate scope, and good to excellent yields. Notably, the glycosidation approach performs very well in the construction of a series of challenging O- and N-glycosidic linkages. The glycosidation approach is then applied to the efficient synthesis of oligosaccharides via the one-pot strategy and the stepwise strategy. On the basis of the isolation and characterization of the departure species derived from the leaving group, a plausible mechanism of NIS/TMSOTf-promoted glycosidation of glycosyl ortho-hexynylbenzoates is proposed.

Full text of DOI:10.1021/acs.joc.1c00151

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Article
NIS/TMSOTf-Promoted Glycosidation of Glycosyl ortho-
Hexynylbenzoates for Versatile Synthesis of O‑Glycosides and
Nucleosides
Rongkun Liu, Qingting Hua, Qixin Lou, Jiazhe Wang, Xiaona Li, Zhi Ma, and You Yang*
Cite This: J. Org. Chem. 2021, 86, 4763−4778
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ABSTRACT: Glycosidation plays a pivotal role in the synthesis of O-
glycosides and nucleosides that mediate a diverse range of biological
processes. However, efficient glycosidation approach for the synthesis of both
O-glycosides and nucleosides remains challenging in terms of glycosidation
yields, mild reaction conditions, readily available glycosyl donors, and cheap
promoters. Here, we report a versatile N-iodosuccinimide/trimethylsilyl
triflate (NIS/TMSOTf)-promoted glycosidation approach with glycosyl
ortho-hexynylbenzoates as donors for the highly efficient synthesis of O-
glycosides and nucleosides. The glycosidation approach highlights the merits
of mild reaction conditions, cheap promoters, extremely wide substrate scope,
and good to excellent yields. Notably, the glycosidation approach performs
very well in the construction of a series of challenging O- and N-glycosidic
linkages. The glycosidation approach is then applied to the efficient synthesis
of oligosaccharides via the one-pot strategy and the stepwise strategy. On the basis of the isolation and characterization of the
departure species derived from the leaving group, a plausible mechanism of NIS/TMSOTf-promoted glycosidation of glycosyl ortho-
hexynylbenzoates is proposed.
such as Hg(II) salt,4a,5h silver(I) salt,4g iodine,4d trimethylsilyl
INTRODUCTION
■
triflate (TMSOTf),5d and N-iodosuccinimide/trimethylsilyl
Glycosidation is the key reaction for the chemical synthesis of
triflate (NIS/TMSOTf)5e−g remains underexplored. Further-
numerous oligosaccharides and glycoconjugates with signifi-
more, efficient synthesis of both O-glycosides and nucleosides
cant bioactivities.1,2 To tackle the construction of various types
from one single type of glycosyl donors is still a challenging
of challenging glycosidic linkages that exist in naturally
task considering glycosidation yields, mild reaction conditions,
occurring oligosaccharides and glycoconjugates, alkyne-based
readily available glycosyl donors, and cheap promoters.5f,9−11
glycosyl donors have attracted great attention in the past 15
To overcome the above issues, we envisioned that
years.3−6 Among the glycosidation that employs alkyne-based
introduction of the cheap and readily available NIS and
glycosyl donors, the triple bonds are usually activated by a
TMSOTf as promoters to activate the glycosyl ortho-
catalytic amount of gold complex.3 Especially, the Yu
alkynylbenzoate donors might expand the substrate scope
glycosidation that utilizes glycosyl ortho-alkynylbenzoates as
and improve the glycosidation yields of the O- and N-
donors and gold(I) complexes as catalysts has been extensively
glycosidation reactions. Here, we describe a versatile approach
investigated and broadly applied to the synthesis of a wide
for the highly efficient synthesis of O-glycosides and nucleo-
variety of glycans and glycoconjugates.3,4b,c
sides with glycosyl ortho-hexynylbenzoates as donors and NIS/
Since the first introduction of chemical glycosidation into
TMSOTf as promoters. The glycosidation approach features
carbohydrate chemistry over 140 years ago,7 a notable feature
mild reaction conditions, cheap promotors, extremely wide
of the most widely used glycosidation approaches is the
substrate scope, and good to excellent yields. In particular, the
development of various promoters for the activation of glycosyl
glycosidation approach performs very well in the construction
donors such as thioglycosides, glycosyl halides, and glycosyl
imidates.2f,k,8 Thus, the promising glycosidation that utilizes
alkyne-based glycosyl donors is also highly required to be
Received: January 20, 2021
Published: March 9, 2021
activated by various types of promoters for expansion of the
substrate scope and enhancement of the synthetic efficiencies.
However, except for the gold-catalyzed glycosidation with
alkyne-based glycosyl donors,3 effective activation of the triple
bonds of alkyne-based glycosyl donors by other promoters
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of a series of challenging O- and N-glycosidic linkages.
Furthermore, the glycosidation approach is successfully applied
to the efficient assembly of oligosaccharides via the one-pot
strategy and the stepwise strategy.
and 2c, serine derivative 2d, 4-hydroxy-2-pyrone 2e, and
benzyl oleanolate 2f, proceeded smoothly to provide the
corresponding β-glucosides 3b−f in 82−96% yields. Reaction
of 1a with pyranosyl and furanosyl alcohols 2g−m including
the sterically hindered 4-hydroxyl acceptor 2k afforded the β-
(1 → 6)-, β-(1 → 2)-, β-(1 → 3)-, and β-(1 → 4)-
disaccharides 3g−m in satisfactory yields (67−99%). Besides
the disarmed perbenzoylated glucosyl donor 1a, the armed
perbenzylated glucosyl ortho-hexynylbenzoate 1d was also
glycosidated with 2a and 2g to afford the coupled glycosides
3n and 3o in excellent yields as an anomeric mixture (3n: 97%,
α/β = 1.2:1; 3o: 91%, α/β = 1.8:1). With perbenzoylated L-
rhamnosyl-, 3,4,6-tri-acetyl-2-N-Troc-protected D-galactosa-
minyl-, and perbenzoylated D-ribofuranosyl ortho-hexynylben-
zoates 1e−g as donors, glycosylation of various acceptors with
different nucleophilicities (2a, 2g, 2k) underwent very clean
reactions, providing the corresponding glycosides 3p−v in
excellent yields (87−100%).
RESULTS AND DISCUSSION
■
To test the reactivities of alkyne-based ester-type glycosyl
donors under the promotion of NIS and TMSOTf,
glycosidation of three types of perbenzoylated glycosyl donors,
i.e., glucosyl ortho-hexynylbenzoate4b 1a, glucosyl alkynoate4a
1b, and glucosyl butynoate4h 1c with 1-adamantanol 2a in
dichloromethane at 0 °C to room temperature was examined
(Table 1). Glycosidation of glucosyl ortho-hexynylbenzoate 1a
Table 1. Optimization of Conditions for Glycosidation with
Alkyne-Based Glucosyl Donors 1a−c
During our synthetic studies toward the synthesis of the β-(1
→ 3)-linked Gal-GalNAc disaccharide moiety that is overex-
pressed in colorectal cancer,13 construction of the challenging
O-glycosidic linkage met with difficulty using the Yu
glycosidation (Table 2). It was found that peracetylated
galactosyl ortho-hexynylbenzoate 1h reacted with 2-N-Troc-
protected D-galactosaminyl acceptor14 2n under the Yu
glycosidation conditions (0.2 equiv PPh3AuOTf, 0.2 equiv
TfOH) to give the desired β-linked disaccharide 3w in a very
low yield (7%), in which a large amount of the hydrolyzed
product of donor 1h was detected (Table 2, entry 1). This
result could be explained by the mismatch among the donor
1h, acceptor 2n, and promoters. By replacement of the
gold(I)-catalyzed conditions with NIS (1.5 equiv) and
TMSOTf (0.2 equiv), the above glycosidation proceeded
smoothly to afford disaccharide 3w in 71% yield (Table 2,
entry 2), demonstrating the advantage of the NIS/TMSOTf-
promoted glycosidation with the peracetylated glycopyranosyl
ortho-hexynylbenzoate as donor for the construction of the
challenging O-glycosidic linkages compared with the Yu
glycosidation.3a,15
Because of the poor nucleophilicity and solubility of
nucleobases, the N-glycosylation of pyrimidines and purines
remains challenging despite the fact that a few efficient
approaches for the synthesis of nucleosides have been
reported.5f,9−11 The remarkable properties of the NIS/
TMSOTf-promoted glycosidation of glycosyl ortho-hexynyl-
benzoates for the construction of O-glycosidic linkages
prompted us to explore its substrate scope for the synthesis
of nucleosides (Scheme 2). Thus, silylation of thymine 4a (2.0
equiv) with N,O-bis(trimethylsilyl)trifluoroacetamide
(BSTFA) in acetonitrile resulted in the soluble silylated
thymine derivative, which was glycosylated smoothly with
perbenzoylated D-ribofuranosyl ortho-hexynylbenzoate 1g
under the promotion of NIS (1.5 equiv) and TMSOTf (0.2
equiv) at 0 °C to room temperature to provide the pyrimidine
nucleoside 5a in an excellent (88%) yield. Under the similar
conditions, glycosidation of 1g with uridine 4b and N4-
benzoylcytosine 4c afforded the pyrimidine nucleosides 5b and
5c in 93 and 88% yields, respectively. When the pyranosyl
ortho-hexynylbenzoates 1a, 1h, and 1i including peracylated
gluco- and peracetylated galatopyranosyl donors were coupled
with nucleobases 4a−c, the reactions still proceeded cleanly to
produce the corresponding nucleosides 5d−k in good to
excellent yields (71−94%). Compared with the yields of the
a
entry
donor
promoters (equiv)
yield (%)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1b
NIS (1.7), TMSOTf (0.5)
NIS (1.5), TMSOTf (0.2)
NIS (1.5), TMSOTf (0.1)
NIS (1.5)
TMSOTf (0.2)
NIS (1.5), TMSOTf (0.2)
NIS (1.5), TMSOTf (0.2)
90
88
55
0
NR
NR
b
b
b
1c
b
NR
a
Isolated yield. No reaction.
with tertiary alcohol 2a under the activation of NIS (1.7 equiv)
and TMSOTf (0.5 equiv) proceeded smoothly to give the
desired β-glucoside 3a in an excellent (90%) yield (entry 1).
When the amount of NIS and TMSOTf was decreased to 1.5
and 0.2 equiv, respectively, the glycosidation still afforded β-
glucoside 3a in 88% yield (entry 2). However, further
decreasing the amount of TMSOTf to 0.1 equiv for the
above glycosidation led to 3a in only 55% yield (entry 3). By
employing only NIS (1.5 equiv) as a promoter, most of the
ortho-hexynylbenzoate donor 1a was activated to give the
glycosyl succinimide derivative12 and product 3a was not
formed (entry 4), while no reaction occurred when only
TMSOTf (0.2 equiv) was used as a promoter (entry 5). In
comparison to glucosyl ortho-hexynylbenzoate 1a, the similar
glycosidation of glucosyl alkynoate 1b or glucosyl butynoate 1c
with 1-adamantanol 2a under the optimal conditions (1.5
equiv NIS, 0.2 equiv TMSOTf) did not take place due to the
low reactivities of disarmed donors 1b and 1c (entries 6 and
7).4a,h
With the optimal glycosidation conditions in hand, we set
out to expand the substrate scope of the NIS/TMSOTf-
promoted glycosidation of glycosyl ortho-hexynylbenzoates for
the synthesis of O-glycosides (Scheme 1). Under the activation
of NIS (1.5 equiv) and TMSOTf (0.2−0.3 equiv) in
dichloromethane at 0 °C to room temperature, the scope of
the glycosidation protocol was investigated with a wide range
of both ortho-hexynylbenzoates donors (1a, 1d−g) and
alcohols (2b−m). As expected, glycosidation of 1a with a
series of primary and secondary alcohols, i.e., alkyl alcohols 2b
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Scheme 1. Scope of O-Glycoside Synthesis with Glycosyl ortho-Hexynylbenzoates as Donors under the Promotion of NIS/
TMSOTf
Table 2. Comparison of the Construction of the
Challenging O-Glycosidic Linkage
nucleosides 5a−k using the Yu glycosidation,10 the present
glycosidation protocol gave access to the nucleosides 5a−k in
comparable yields. It is noteworthy that the yields for 5f and
5k using the present glycosidation protocol were nearly 20%
higher than those obtained by the Yu glycosidation.10
The N-glycosylation with purine nucleobases showed
limited success due to the low coupled yields and moderate
N9/N7 regioselectivity.16 With the soluble tert-butoxycarbonyl
(Boc)-protected purine derivatives17 4d and 4e as coupling
partners, we were pleased to find that glycosidation of D-
ribofuranosyl ortho-hexynylbenzoate 1g with 4d and 4e under
the activation of NIS (1.5 equiv) and TMSOTf (0.1 equiv) in
dichloromethane at 0 °C to room temperature proceeded
smoothly to give the N9 nucleosides 5l and 5m in 74 and 81%
yields, respectively (Scheme 2). It is worth mentioning that
reactions of perbenzoylated glucosyl ortho-hexynylbenzoate 1a
with purine derivatives 4d and 4e under the same conditions
furnished the corresponding N9 nucleosides 5n and 5o in
a
entry
promoters (equiv)
T (°C)
yield (%)
1
2
PPh3AuOTf (0.2), TfOH (0.2)
NIS (1.5), TMSOTf (0.2)
rt
7
71
0 to rt
a
Isolated yield.
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Scheme 2. Scope of Nucleoside Synthesis with Glycosyl ortho-Hexynylbenzoates as Donors under the Promotion of NIS/
TMSOTf
higher yields (87% for 5n, 74% for 5o) than those obtained by
the Yu glycosidation (48% for 5n, 56% for 5o).10 Furthermore,
coupling of peracetylated L-rhamnosyl ortho-hexynylbenzoate
1j with purine derivatives 4d and 4e was also carried out to
afford the desired N9 nucleosides 5p and 5q in 70 and 81%
yields, respectively.
produced 3a in good yield (79%) and peracetylated β-
glucoside 7 in low yield (12%), and the ethylthioglucoside 6c
was recovered in 83% yield. Based on the sharp difference
between the donor reactivities of glycosyl ortho-hexynylben-
zoate and phenylthioglycoside, one-pot synthesis of trisacchar-
ide 9 was envisaged.2i,19 As planned, glycosidation of glucosyl
ortho-hexynylbenzoate 1a (1.2 equiv) with disarmed thiogluco-
side 8 (1.0 equiv) under the promotion of NIS (1.5 equiv) and
TMSOTf (0.2 equiv) gave the corresponding disaccharide,
which was further coupled with the acceptor 2g (0.8 equiv) in
the presence of NIS (1.5 equiv) and TMSOTf (0.3 equiv) to
provide the desired trisaccharide 9 in 71% yield in a one-pot
manner. It is worth noting that no desired trisaccharide 9 was
formed without the addition of a second portion of TMSOTf
(0.3 equiv) as a promoter.
To evaluate the synthetic efficiency of the present
glycosidation protocol in the synthesis of oligosaccharides,
stepwise assembly of the tetrasaccharide skeleton 19 of type I
fucoidan that has long been known as modulators of
coagulation was performed (Scheme 4).20 Thus, treatment of
the alcohol 1021 with chloroacetylchloride (ClAcCl) gave
compound 11 in 97% yield. Removal of the anomeric p-
methoxyphenyl (MP) group with ceric ammonium nitrate
(CAN) in toluene, acetonitrile, and water followed by
As the NIS/TMSOTf promoter system has been widely
utilized for the activation of thioglycosides,8,18 the donor
reactivities of three types of thioglycosides were compared with
glycosyl ortho-hexynylbenzoate (Scheme 3). A competitive
glycosylation of 1-adamantanol 2a with perbenzoylated
glucosyl ortho-hexynylbenzoate 1a (α/β = 1/2.3) and
peracetylated 5-tert-butyl-2-methyl β-phenylthioglucoside 6a
in dichloromethane at 0 °C to room temperature was carried
out under the action of NIS (1.5 equiv) and TMSOTf (0.2
equiv). After 30 min, ortho-hexynylbenzoate 1a was coupled
with 2a to afford β-glucoside 3a in 90% yield, while the 5-tert-
butyl-2-methyl phenylthioglucoside 6a was completely recov-
ered (100%). Moreover, the NIS/TMSOTf-promoted reaction
of 2a with 1a and peracetylated β-phenylthioglucoside 6b led
to similar results, providing 3a in excellent yield (90%) along
with the almost intact phenylthioglucoside 6b (96%). Never-
theless, when the more reactive peracetylated β-ethylthiogluco-
side 6c was employed, the similar competitive glycosidation
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Scheme 3. Comparison of the Donor Reactivities of Glycosyl ortho-Hexynylbenzoate and Thioglycosides under the Activation
of NIS/TMSOTf and One-Pot Synthesis of Trisaccharide 9
condensation with ortho-hexynylbenzoic acid with the aid of
N,N’-dicyclohexylcarbodiimide (DCC) and 4-dimethylamino-
pyridine (DMAP) afforded L-fucosyl ortho-hexynylbenzoate 12
in 79% yield over two steps. Coupling of ortho-hexynylben-
zoate 12 with acceptor 10 under the activation of NIS (1.5
equiv) and TMSOTf (0.2 equiv) proceeded rapidly, providing
the α-(1 → 3)-difucoside 13 as the only product in 95% yield
within 30 min. Treatment of 13 with 2,4,6-collidine and
thiourea in methanol and chloroform under reflux generated
the disaccharide acceptor 14 in 97% yield. Following the
similar reaction sequence from compounds 11 and 12, glycosyl
ortho-hexynylbenzoate 15 was obtained from 13 in 74% yield
over two steps. The [2 + 2] coupling of ortho-hexynylbenzoate
15 with acceptor 14 in the presence of NIS (1.5 equiv) and
TMSOTf (0.2 equiv) resulted in a very clean reaction,
affording the desired α-(1 → 3)-linked tetrafucoside 16
exclusively in an excellent (90%) yield within 30 min.
Analogous to the transformations from 13 to 15, compound
16 was then converted to glycosyl ortho-hexynylbenzoate 17 in
76% yield over two steps. To install an azide-containing linker
at the reducing end of tetrasaccharide 17 for further click
reaction in biological studies,22 compound 17 was glycosidated
with 6-azido hexyl linker 18 under the action of NIS (1.5
equiv) and TMSOTf (0.2 equiv) to provide the desired
tetrasaccharide 19 in excellent yield with the α-anomer as the
major product (94%, α/β = 4.1:1), which is related to the
homofucose backbone chain of type I fucoidan.20
of the β-linked disaccharide 3h in 98% yield. Based on these
experimental results, a plausible mechanism for NIS/TMSOTf-
promoted glycosidation of glycosyl ortho-hexynylbenzoates was
proposed as shown in Scheme 5. Activation of the CC triple
bond of glycosyl ortho-hexynylbenzoate A with the iodonium
species generated from the cooperation of NIS and TMSOTf
led to the iodovinyl cation species B. Subsequently,
nucleophilic attack of the ester carbonyl group on the remote
carbon of the double bond of B induced the formation of the
sugar oxocarbenium ion C and the 4-iodoisocoumarin
derivative 20. The sugar oxocarbenium ion C was then
captured by alcoholic nucleophiles or nucleobases to provide
O-glycosides D and nucleosides E, respectively. Meanwhile, the
H+ that was released from the alcoholic nucleophiles and
nucleobases could be trapped by silylated succinimide to
regenerate TMSOTf for another catalytic cycle.
CONCLUSIONS
■
We have developed a versatile glycosidation approach for the
highly efficient synthesis of O-glycosides and nucleosides with
glycosyl ortho-hexynylbenzoates as donors and NIS/TMSOTf
as promoters. Under the mild conditions using the cheap and
readily available NIS/TMSOTf as promoters, the present
glycosidation approach has been demonstrated to possess a
very broad substrate scope, providing both O-glycosides and
nucleosides in good to excellent yields. Remarkably, a series of
challenging O- and N-glycosidic linkages found in O-glycosides
and nucleosides were efficiently constructed by the present
glycosidation approach in high yields. In view of the higher
reactivities of glycosyl ortho-hexynylbenzoates than thioglyco-
sides under the activation of NIS/TMSOTf, one-pot synthesis
of a trisaccharide was successfully established. Furthermore,
NIS/TMSOTf-mediated synthesis of a tetrafucoside related to
type I fucoidan fragment with glycosyl ortho-hexynylbenzoates
To probe the mechanism of the NIS/TMSOTf-mediated
glycosidation with glycosyl ortho-hexynylbenzoates as donors,
glycosidation of glucosyl ortho-hexynylbenzoate 1a with sugar
alcohol 2h under the activation of NIS (1.5 equiv) and
TMSOTf (0.2 equiv) was carefully carried out to capture the
species derived from the leaving group (Scheme 5). Indeed,
after the reaction was stirred for 30 min, the 4-iodoisocoumar-
in derivative 20 was isolated in 97% yield besides the formation
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Scheme 4. Stepwise Synthesis of the Tetrasaccharide Backbone 19 of Type I Fucoidan by the NIS/TMSOTf-Promoted
Glycosidation of Glycosyl ortho-Hexynylbenzoate
of doublet of doublets (ddd), doublet of triplets (dt), triplet of
doublets (td), or multiplet (m). All NMR chemical shifts (δ) were
given in ppm, and coupling constants (J) were given in hertz. High-
resolution mass spectra (HRMS) were measured on electrospray
ionization time-of-flight (ESI-TOF) spectrometers.
as donors was achieved in an efficient manner. Finally, a
plausible mechanism of NIS/TMSOTf-promoted glycosida-
tion of glycosyl ortho-hexynylbenzoates was proposed based on
the isolation of the departure species derived from the leaving
group. With the versatility and efficiency as striking features,
we believe that the present glycosidation approach can serve as
a very practical tool for the synthesis of various types of O-
glycosides and nucleosides.
Preparation of Glycosyl ortho-Hexynylbenzoates (1a, 1d−j).
To a solution of the corresponding glycosyl lactols (1.00 mmol) and
ortho-hexynylbenzoic acid (303 mg, 1.50 mmol) in anhydrous CH2Cl2
(20 mL) at room temperature were added EDCI (383 mg, 2.00
mmol) and DMAP (305 mg, 2.50 mmol). After stirring at room
temperature for 8 h, the mixture was quenched with saturated
aqueous NaHCO3 and extracted with CH2Cl2. The combined organic
layers were washed with brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified by silica gel column
chromatography to afford glycosyl ortho-hexynylbenzoates 1a, 1d−j.
The known compound 1a was prepared according to the previous
report.15b 748 mg, 96%, α/β = 1/2.3, white foam, petroleum ether/
EtOAc: 100/0 → 8/1. Rf: 0.63 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data of 1aβ were in accordance with those
EXPERIMENTAL SECTION
■
General Information. All chemical reactions were carried out
with anhydrous solvents in dry glassware with magnetic stirring under
argon unless otherwise stated. The chemical reagents were utilized as
supplied except where noted. Analytical thin-layer chromatography
(TLC) was performed on precoated plates of silica gel (0.25−0.3 mm,
Shanghai, China). The TLC plates were visualized by exposure to
ultraviolet light or staining with a sulfuric acid−ethanol solution. Silica
gel column chromatography was conducted on silica gel AR (100−
200 mesh, Shanghai, China). Optical rotations (OR) were measured
on a Rudolph Research Analytical Autopol I automatic polarimeter.
NMR spectra were measured on a Bruker Avance III 400 or Bruker
previously reported.15b 1aβ H NMR (400 MHz, CDCl3) δ 8.05−
1
7.84 (m, 9 H), 7.55−7.25 (m, 15 H), 6.34 (d, J = 8.0 Hz, 1 H, H-1),
6.02 (t, J = 9.6 Hz, 1 H), 5.86−5.81 (m, 2 H), 4.66 (dd, J = 2.8, 12.4
Hz, 1 H), 4.52 (dd, J = 4.8, 12.4 Hz, 1 H), 4.42−4.37 (m, 1 H), 2.46
(t, J = 7.2 Hz, 2 H), 1.64−1.57 (m, 2 H), 1.53−1.43 (m, 2 H), 0.94 (t,
J = 7.2 Hz, 3 H).
1
Avance III 600 spectrometer. The H and 13C{1H} NMR spectra
were calibrated using the residual proton and carbon signals of the
solvent as internal reference (CDCl3: δH = 7.26 ppm and δC = 77.2
ppm). Multiplicities are abbreviated as singlet (s), broad singlet (br s),
doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet
The known compound 1d was prepared according to the previous
report.4b 725 mg, 100%, α/β = 1/2.2, colorless syrup, petroleum
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H), 4.53 (d-like, J = 12.0 Hz, 1 H), 4.39 (t, J = 6.8 Hz, 1 H), 4.15 (dd,
J = 7.2, 11.2 Hz, 1 H), 4.06 (dd, J = 6.4, 11.2 Hz, 1H), 2.56−2.39 (m,
2 H), 2.19 (s, 3 H), 1.99 (s, 6 H), 1.66−1.59 (m, 2 H), 1.53−1.44 (m,
2 H), 0.95 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (100 MHz, CDCl3) δ
170.6, 170.4, 165.0, 154.4, 135.8, 132.8, 131.5, 129.7, 127.9, 124.6,
97.2, 95.5, 92.5, 81.3, 74.8, 69.0, 68.9, 66.7, 61.3, 49.0, 30.9, 22.3,
20.9, 20.8, 19.6, 13.8; HRMS (ESI) m/z: [M + Na]+ calcd for
C28H32O11NCl3Na 686.0939; Found 686.0935.
Scheme 5. Isolation of 4-Iodoisocoumarin Derivative
Derived from the Leaving Group and a Plausible
Mechanism of NIS/TMSOTf-Promoted Glycosidation of
Glycosyl ortho-Hexynylbenzoates
The known compound 1g was prepared according to the previous
report.23 592 mg, 92%, α/β = 4.5/1, colorless syrup, petroleum ether/
EtOAc: 100/0 → 6/1. Rf: 0.31 (petroleum ether/EtOAc = 6/1 (v/
v)). Spectroscopic data of 1gα were in accordance with those
previously reported.23 1gα:1H NMR (600 MHz, CDCl3) δ 8.05−8.03
(m, 2 H), 7.94 (dd, J = 1.2, 8.4 Hz, 2 H), 7.89−7.87 (m, 3 H), 7.62−
7.59 (m, 1 H), 7.54−7.51 (m, 2 H), 7.46−7.42 (m, 4 H), 7.34−7.31
(m, 2 H), 7.27−7.24 (m, 1 H), 7.21−7.19 (m, 2 H), 6.68 (s, 1 H),
6.03−5.97 (m, 2 H), 4.86−4.84 (m, 1 H), 4.73 (dd, J = 3.6, 12.0 Hz,
1 H), 4.57 (dd, J = 4.8, 12.0 Hz, 1 H), 2.54 (t, J = 7.2 Hz, 2 H), 1.65−
1.60 (m, 2 H), 1.50−1.44 (m, 2 H), 0.92 (t, J = 7.2 Hz, 3 H).
The known compound 1h was prepared according to the previous
report.10 500 mg, 94%, α/β = 1/10, colorless syrup, petroleum ether/
EtOAc: 100/0 → 5/1. Rf: 0.48 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data of 1hβ were in accordance with those
previously reported.10 1hβ:1H NMR (600 MHz, CDCl3) δ 7.97 (dd, J
= 1.2, 7.8 Hz, 1 H), 7.54 (m, 1 H), 7.47 (dt, J = 1.2, 7.2 Hz, 1 H),
7.34−7.31 (m, 1 H), 5.94 (d, J = 8.4 Hz, 1 H, H-1), 5.52−5.47 (m, 2
H), 5.15 (dd, J = 3.6, 10.8 Hz, 1 H), 4.21−4.12 (m, 3 H), 2.51 (t, J =
7.2 Hz, 2 H), 2.19 (s, 3 H), 2.05 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H),
1.67−1.62 (m, 2 H), 1.54−1.48 (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H).
The known compound 1i was prepared according to the previous
report.15b 508 mg, 95%, α/β = 1/4.3, colorless syrup, petroleum
ether/EtOAc: 100/0 → 6/1. Rf: 0.43 (petroleum ether/EtOAc = 3/1
(v/v)). Spectroscopic data of 1iβ were in accordance with those
previously reported.15b 1iβ:1H NMR (600 MHz, CDCl3) δ 7.94 (dd, J
= 1.2, 8.4 Hz, 1 H), 7.53 (dd, J = 0.6, 7.8 Hz, 1 H), 7.47 (dt, J = 1.2,
7.8 Hz, 1 H), 7.32 (dt, J = 1.2, 7.8 Hz, 1H), 5.97 (d, J = 8.4 Hz, 1 H),
5.35−5.30 (m, 2 H), 5.22−5.16 (m, 1 H), 4.33 (dd, J = 4.2, 12.6 Hz,
1 H), 4.13 (dd, J = 1.8, 12.6 Hz, 1 H), 3.93 (ddd, J = 1.8, 4.2, 10.2 Hz,
1 H), 2.50 (t, J = 7.2 Hz, 2 H), 2.08 (s, 3 H), 2.05 (s, 3 H), 2.04 (s, 3
H), 1.99 (s, 3 H), 1.68−1.61 (m, 2 H), 1.54−1.48 (m, 2 H), 0.96 (t, J
= 7.2 Hz, 3 H).
ether/EtOAc: 100/0 → 9/1. Rf: 0.61 (petroleum ether/EtOAc = 3/1
(v/v)). Spectroscopic data of 1dβ were in accordance with those
previously reported.4b 1dβ 1H NMR (600 MHz, CDCl3) δ 7.93 (dd, J
= 1.2, 7.8 Hz, 1 H), 7.54 (dd, J = 1.2, 7.8 Hz, 1 H), 7.47−7.43 (m, 1
H), 7.33−7.27 (m, 13 H), 7.25−7.15 (m, 8 H), 5.89 (d, J = 8.4 Hz, 1
H, H-1), 4.92 (d-like, J = 10.8 Hz, 1 H), 4.85−4.83 (m, 2 H), 4.80 (d-
like, J = 11.4 Hz, 1 H), 4.75 (d-like, J = 11.4 Hz, 1 H), 4.62 (d, J =
12.0 Hz, 1 H), 4.57 (d, J = 10.8 Hz, 1 H), 4.49 (d, J = 12.0 Hz, 1 H),
3.83−3.73 (m, 5 H), 3.67−3.64 (m, 1 H), 2.47 (t, J = 7.2 Hz, 2 H),
1.64−1.59 (m, 2 H), 1.51−1.45 (m, 2 H), 0.94 (t, J = 7.2 Hz, 3 H).
2,3,4-Tri-benzoyl-L-rhamnopyranosyl ortho-hexynyl-benzoate 1e.
628 mg, 95%, α/β = 1.4/1, white foam, petroleum ether/EtOAc:
100/0 → 10/1. Rf: 0.70 (petroleum ether/EtOAc = 3/1 (v/v)). 1eα:
[α]D = +82.2 (c 0.50, CHCl3); H NMR (600 MHz, CDCl3) δ
8.14−8.12 (m, 2 H), 8.05 (dd, J = 1.2, 7.8 Hz, 1 H), 7.97−7.95 (m, 2
H), 7.83−7.81 (m, 2 H), 7.65−7.60 (m, 2 H), 7.53−7.51 (m, 4 H),
7.45−7.37 (m, 4 H), 7.28−7.25 (m, 2 H), 6.56 (d, J = 1.8 Hz, 1 H),
6.00 (dd, J = 3.6, 10.2 Hz, 1 H), 5.86 (dd, J = 1.8, 3.6 Hz, 1 H), 5.78
(t, J = 10.2 Hz, 1 H), 4.45−4.41 (m, 1 H), 2.62−2.53 (m, 2 H),
1.68−1.63 (m, 2 H), 1.52−1.45 (m, 2 H), 1.41 (d, J = 6.6 Hz, 3 H),
0.93 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (150 MHz, CDCl3): δ 165.9,
165.7, 165.5, 164.2, 135.1, 133.8, 133.6, 133.4, 132.5, 131.0, 130.4,
130.2, 129.9, 129.3, 129.2, 128.8, 128.6, 128.5, 127.6, 125.4, 97.3,
91.8, 79.7, 71.6, 70.0, 69.9, 69.6, 30.9, 22.3, 19.8, 17.9, 13.8. HRMS
(ESI) m/z: [M + Na]+ calcd for C40H36O9Na 683.2257; Found
683.2256.
The known compound 1j was prepared according to the previous
report.15b 440 mg, 93%, α/β = 1.4/1, colorless syrup, petroleum
ether/EtOAc: 100/0 → 3/1. Rf: 0.30 (petroleum ether/EtOAc = 5/1
(v/v)). Spectroscopic data of 1jα were in accordance with those
previously reported.15b 1jα:1H NMR (600 MHz, CDCl3) δ 7.94 (dd, J
= 1.2, 7.8 Hz, 1 H), 7.55 (dd, J = 1.2, 7.8 Hz, 1 H), 7.48 (dt, J = 1.2,
7.2 Hz, 1 H), 7.35 (dt, J = 1.2, 7.8 Hz, 1H), 6.28 (d, J = 1.8 Hz, 1 H),
5.47 (dd, J = 3.6, 10.2 Hz, 1 H), 5.41 (dd, J = 2.4, 3.6 Hz, 1 H), 5.18
(t, J = 10.2 Hz, 1 H), 4.15−4.10 (m, 1 H), 2.55−2.46 (m, 2 H), 2.20
(s, 3 H), 2.06 (s, 3 H), 2.01 (s, 3 H), 1.65−1.60 (m, 2 H), 1.52−1.46
(m, 2 H), 1.26 (d, J = 6.6 Hz, 3 H), 0.95 (t, J = 7.2 Hz, 3 H).
Preparation of Glucosyl Alkynoate (1b) and Glucosyl
Butynoate (1c). To a solution of 2,3,4,6-tetra-O-benzoyl D-
glucopyranosyl lactol (179 mg, 0.30 mmol) and 5-hexynoic acid
(50 μL, 0.45 mmol) in anhydrous CH2Cl2 (6 mL) at room
temperature were added EDCI (115 mg, 0.60 mmol) and DMAP
(92 mg, 0.75 mmol). After stirring at room temperature for 2 h, the
reaction was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4 and concentrated in vacuo. The residue was purified by
silica gel column chromatography (petroleum ether/EtOAc: 100/0 →
8/1) to provide 1b (191 mg, 92%, α/β = 1/1.2) as a white foam. Rf:
25
1
3,4,6-Tri-acetyl-2-N-Troc-protected D-galactosaminyl ortho-hexy-
nylbenzoate 1f. 620 mg, 93%, α/β = 8.5/1, colorless syrup, petroleum
ether/EtOAc: 100/0 → 4/1. Rf: 0.37 (petroleum ether/EtOAc = 3/1
25
0.48 (petroleum ether/EtOAc = 3/1 (v/v)). 1bβ: [α]D = +15.1 (c
1
0.37, CHCl3); H NMR (600 MHz, CDCl3) δ 8.05−8.03 (m, 2 H),
25
1
7.94 (dd, J = 1.2, 8.4 Hz, 2 H), 7.90 (dd, J = 1.2, 8.4 Hz, 2 H), 7.83
(dd, J = 1.2, 8.4 Hz, 2 H), 7.57−7.49 (m, 3 H), 7.45−7.34 (m, 7 H),
7.29 (t, J = 7.8 Hz, 2 H), 6.10 (d, J = 8.4 Hz, 1 H), 5.95 (t, J = 9.6 Hz,
1H), 5.74 (t, J = 9.6 Hz, 1 H), 5.67 (dd, J = 8.4, 10.2 Hz, 1 H), 4.63
(dd, J = 3.0, 12.6 Hz, 1 H), 4.48 (dd, J = 4.8, 12.0 Hz, 1 H), 4.32−
(v/v)). 1fα [α]D = +50.0 (c 1.00, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 7.6 Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H), 7.51
(dt, J = 1.2, 7.6 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 6.52 (d, J = 4.0 Hz,
1H), 5.49 (d, J = 2.4 Hz, 1 H), 5.44 (d, J = 10.0 Hz, 1 H), 5.33 (dd, J
= 2.8, 11.2 Hz, 1 H), 4.94 (d-like, J = 12.0 Hz, 1 H), 4.61−4.56 (m, 1
4769
https://dx.doi.org/10.1021/acs.joc.1c00151
J. Org. Chem. 2021, 86, 4763−4778

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4.29 (m, 1 H), 2.53−2.42 (m, 2 H), 2.14−2.11 (m, 2 H), 1.85 (t, J =
3.0 Hz, 1 H), 1.79−1.71 (m, 2 H). 13C{1H} NMR (150 MHz,
CDCl3) δ 171.4, 166.3, 165.8, 165.3, 165.2, 133.7, 133.5, 133.3, 130.0,
129.9, 129.7, 128.9, 128.8, 128.7, 128.6, 128.5, 92.3, 82.9, 73.4, 73.0,
71.0, 69.5, 69.2, 62.8, 32.8, 23.2, 17.7; HRMS (ESI) m/z: [M + Na]+
calcd for C40H34O11Na 713.1999; Found 713.1998.
To a solution of 2,3,4,6-tetra-O-benzoyl D-glucopyranosyl lactol
(179 mg, 0.30 mmol) and 2-butynoic acid (38 mg, 0.45 mmol) in
anhydrous CH2Cl2 (3 mL) at room temperature were added DCC
(93 mg, 0.45 mmol) and DMAP (7.3 mg, 0.06 mmol). The mixture
was stirred at room temperature for 2 h and filtered. The filtrate was
concentrated in vacuo, and the resulting residue was purified by silica
gel column chromatography (petroleum ether/EtOAc: 100:0 → 12/
1) to give 1c (190 mg, 95%, α/β = 3.8/1, inseparable mixture) as a
white foam. Rf: 0.37 (petroleum ether/EtOAc = 3/1 (v/v)). 1H NMR
(400 MHz, CDCl3) δ 8.07−7.83 (m, 10 H), 7.58−7.28 (m, 16 H),
6.67 (d, J = 3.6 Hz, 1 H), 6.23 (t, J = 10.0 Hz, 1 H), 6.15 (d, J = 8.0
Hz, 0.26 H), 5.94 (t, J = 9.6 Hz, 0.26 H), 5.83−5.67 (m, 1.52 H), 5.57
(dd, J = 3.6, 10.4 Hz, 1 H), 4.65−4.56 (m, 2.26 H), 4.51−4.45 (m,
1.26 H), 4.34−4.30 (m, 0.26 H), 2.07 (s, 3 H), 1.94 (s, 0.78 H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.3, 166.0, 165.8, 165.6,
J = 9.6 Hz, 1 H), 5.52 (dd, J = 8.0, 9.6 Hz, 1 H), 4.86 (d, J = 8.0 Hz, 1
H), 4.64 (dd, J = 3.2, 12.4 Hz, 1 H), 4.50 (dd, J = 5.2, 12.0 Hz, 1 H),
4.19−4.14 (m, 1 H), 4.04−3.99 (m, 1 H), 3.72−3.67 (m, 1 H), 2.14
(td, J = 2.4, 6.8 Hz, 2 H), 1.82−1.66 (m, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 166.3, 166.0, 165.4, 165.3, 133.6, 133.4, 133.3, 130.0,
129.9, 129.8, 129.4, 129.0, 128.9, 128.6, 128.5, 128.4, 101.6, 83.5,
73.1, 72.4, 72.1, 70.0, 68.8, 68.7, 63.4, 28.4, 14.9; HRMS (ESI) m/z:
[M + Na]+ calcd for C39H34O10Na 685.2050; Found 685.2051.
3d. 38 mg, 84%, white solid, petroleum ether/EtOAc: 100/0 → 8/
1, known compound.24 Rf: 0.35 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.24 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.2 Hz, 2 H),
7.95−7.89 (m, 4 H), 7.83 (d, J = 7.2 Hz, 2 H), 7.56−7.27 (m, 22 H),
5.86 (t, J = 9.6 Hz, 1 H), 5.64 (t, J = 9.6 Hz, 1 H), 5.57 (d, J = 8.0 Hz,
1 H), 5.46 (dd, J = 8.0, 9.6 Hz, 1 H), 5.18−5.10 (m, 2 H), 5.03 (d-
like, J = 12.4 Hz, 1 H), 4.95 (d-like, J = 12.4 Hz, 1 H), 4.78 (d, J = 7.6
Hz, 1 H), 4.61 (dd, J = 3.2, 12.4 Hz, 1 H), 4.52 (m, 1 H), 4.43 (dd, J
= 5.2, 12.0 Hz, 1 H), 4.38 (dd, J = 2.4, 10.0 Hz, 1 H), 4.05−4.00 (m,
1 H), 3.92 (dd, J = 3.2, 10.0 Hz, 1 H).
3e. 34 mg, 96%, white solid, petroleum ether/EtOAc: 100/0 → 3/
1, known compound.4i Rf: 0.15 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.4i 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2 H),
7.96−7.92 (m, 4 H), 7.84 (d, J = 7.2 Hz, 2 H), 7.59−7.29 (m, 12 H),
5.98 (t, J = 9.6 Hz, 1 H), 5.80−5.68 (m, 4 H), 5.50 (d, J = 7.2 Hz, 1
H), 4.67 (dd, J = 2.4, 12.0 Hz, 1 H), 4.45 (dd, J = 6.8, 12.0 Hz, 1 H),
4.35 (ddd, J = 2.4, 6.8, 9.6 Hz, 1 H), 2.13 (s, 3 H).
3f. 46 mg, 82%, white solid, petroleum ether/EtOAc: 100/0 → 10/
1, known compound.5f Rf: 0.78 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.5f 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2 H),
7.95−7.91 (m, 4 H), 7.83 (d, J = 7.2 Hz, 2 H), 7.56−7.48 (m, 3 H),
7.44−7.28 (m, 14 H), 5.91 (t, J = 9.6 Hz, 1 H), 5.61−5.55 (m, 2 H),
5.29 (br s, 1 H), 5.10−5.01 (m, 2 H), 4.86 (d, J = 8.0 Hz, 1 H), 4.61−
4.52 (m, 2 H), 4.17−4.12 (m, 1 H), 3.10 (dd, J = 4.4, 11.6 Hz, 1 H),
2.91 (dd, J = 3.6, 13.6 Hz, 1 H), 1.08 (s, 3 H), 0.93 (s, 3 H), 0.91 (s, 3
H), 0.80 (s, 3 H), 0.68 (s, 3 H), 0.62 (s, 3 H), 0.55 (s, 3 H).
3g. 50 mg, 96%, colorless syrup, petroleum ether/EtOAc: 100/0 →
6/1, known compound.5e Rf: 0.33 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.5e 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.2 Hz, 2 H),
7.90 (d, J = 7.6 Hz, 4 H), 7.83 (d, J = 7.6 Hz, 2 H), 7.54−7.48 (m, 2
H), 7.44−7.20 (m, 23 H), 7.06 (m, 2 H), 5.90 (t, J = 9.6 Hz, 1 H),
5.68 (t, J = 9.6 Hz, 1 H), 5.60 (dd, J = 8.0, 9.6 Hz, 1 H), 4.90 (d, J =
10.8 Hz, 1 H), 4.83 (d, J = 7.6 Hz, 1 H), 4.74 (d-like, J = 12.4 Hz, 1
H), 4.69 (d-like, J = 10.8 Hz, 1 H), 4.63−4.58 (m, 2 H), 4.54−4.49
(m, 3 H), 4.29 (d, J = 11.2 Hz, 1 H), 4.17−4.08 (m, 2 H), 3.89 (t, J =
9.2 Hz, 1 H), 3.77−3.71 (m, 2 H), 3.44 (dd, J = 3.6, 9.6 Hz, 1 H),
3.38 (t, J = 9.2 Hz, 1 H), 3.21 (s, 3 H).
3h. 41 mg, 98%, white solid, petroleum ether/EtOAc: 100/0 → 6/
1, known compound.5e Rf: 0.44 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.5e 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 2 H),
7.97 (d, J = 7.6 Hz, 2 H), 7.90 (d, J = 7.2 Hz, 2 H), 7.83 (d, J = 7.2
Hz, 2 H), 7.56−7.47 (m, 3 H), 7.44−7.28 (m, 9 H), 5.90 (t, J = 9.6
Hz, 1 H), 5.68 (t, J = 9.6 Hz, 1 H), 5.53 (dd, J = 8.0, 9.6 Hz, 1 H),
5.42 (d, J = 5.2 Hz, 1 H), 5.04 (d, J = 8.0 Hz, 1 H), 4.64 (dd, J = 2.8,
12.0 Hz, 1 H), 4.49 (dd, J = 5.2, 12.0 Hz, 1 H), 4.43 (dd, J = 2.0, 8.0
Hz, 1 H), 4.22−4.15 (m, 2 H), 4.09 (m, 1 H), 4.01 (dd, J = 3.2, 10.4
Hz, 1 H), 3.90−3.83 (m, 2 H), 1.37 (s, 3 H), 1.24 (s, 3 H), 1.20 (s, 3
H), 1.19 (s, 3 H).
165.4, 165.2, 165.1, 164.8, 151.6, 151.4, 133.8, 133.7, 133.6, 133.5,
133.4, 133.3, 130.1, 130.0, 129.9, 129.7, 129.6, 129.0, 128.8, 128.6,
128.5, 92.7, 90.5, 89.4, 89.0, 73.5, 73.0, 71.7, 70.7, 70.3, 69.0, 68.8,
62.8, 62.5, 4.2, 4.1; HRMS (ESI) m/z: [M + Na]+ calcd for
C38H30O11Na 685.1686; Found 685.1688.
General Procedure for NIS/TMSOTf-Promoted O-Glycosida-
tion with Glucosyl ortho-Hexynylbenzoate (1a). A mixture of 1a
(47 mg, 0.06 mmol), alcohols 2a−m (8 mg for 2a, 6.2 μL for 2b, 4.7
μL for 2c, 16 mg for 2d, 27 mg for 2e, 6.3 mg for 2f, 23 mg for 2g, 13
mg for 2h, 19 mg for 2i, 19 mg for 2j, 13 mg for 2k, 13 mg for 2l, 23
mg for 2m; 0.05 mmol), and freshly activated 4 Å MS (150 mg) in
anhydrous CH2Cl2 (1.5 mL) was stirred at room temperature for 0.5
h under argon. NIS (17 mg, 0.075 mmol) and a freshly prepared
solution of TMSOTf in CH2Cl2 (0.1 mL for 2a, 2d−k and 2m; 0.15
mL for 2b, 2c and 2l; 0.1 M) were added at 0 °C under argon, and the
mixture was stirred for an additional 2 h at room temperature. The
mixture was quenched with Et3N and filtered through Celite. The
filtrate was concentrated in vacuo. The residue was purified by silica
gel column chromatography to give 3a−m.
3a. 32 mg, 88%, white solid, petroleum ether/EtOAc: 100/0 →
10/1, known compound.5e Rf: 0.67 (petroleum ether/EtOAc = 3/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.5e 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2 H),
7.95 (d, J = 7.2 Hz, 2 H), 7.91 (d, J = 7.2 Hz, 2 H), 7.83 (d, J = 7.2
Hz, 2 H), 7.55−7.48 (m, 3 H), 7.45−7.29 (m, 9 H), 5.92 (t, J = 9.6
Hz, 1 H), 5.55 (t, J = 9.6 Hz, 1 H), 5.49 (dd, J = 8.4, 10.0 Hz, 1 H),
5.12 (d, J = 8.0 Hz, 1 H), 4.58 (dd, J = 3.2, 12.0 Hz, 1 H), 4.48 (dd, J
= 7.2, 12.0 Hz, 1 H), 4.18 (ddd, J = 2.8, 7.2, 10.0 Hz, 1 H), 2.02 (s, 3
H), 1.82 (d-like, J = 11.6 Hz, 3 H), 1.65 (d-like, J = 11.6 Hz, 3 H),
1.54−1.47 (m, 6 H).
3b. 31 mg, 91%, white solid, petroleum ether/EtOAc: 100/0 →
10/1. Rf: 0.41 (petroleum ether/EtOAc = 3/1 (v/v)). [α]D25 = +14.7
(c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz,
2 H), 7.96 (d, J = 7.2 Hz, 2 H), 7.90 (d, J = 7.2 Hz, 2 H), 7.83 (d, J =
7.2 Hz, 2 H), 7.56−7.28 (m, 12 H), 5.90 (t, J = 9.6 Hz, 1 H), 5.67 (t,
J = 9.6 Hz, 1 H), 5.52 (dd, J = 8.0, 10.0 Hz, 1 H), 4.83 (d, J = 8.0 Hz,
1 H), 4.64 (dd, J = 3.2, 12.4 Hz, 1 H), 4.51 (dd, J = 5.2, 12.0 Hz, 1
H), 4.18−4.13 (m, 1 H), 3.94−3.89 (m, 1 H), 3.57−3.51 (m, 1 H),
1.58−1.42 (m, 2 H), 1.28−1.00 (m, 6 H), 0.73 (t, J = 6.8 Hz, 3 H);
13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 166.0, 165.4, 165.3,
133.6, 133.4, 133.3, 133.2, 130.0, 129.9, 129.8, 129.5, 129.0, 128.9,
128.6, 128.5, 128.4, 101.5, 73.1, 72.3, 72.1, 70.6, 70.0, 63.4, 31.6, 29.5,
25.6, 22.6, 14.1; HRMS (ESI) m/z: [M + Na]+ calcd for
C40H40O10Na 703.2519; Found 703.2520.
3i. 47 mg, 99%, white solid, petroleum ether/EtOAc: 100/0 → 6/1,
known compound.25 Rf: 0.35 (petroleum ether/EtOAc = 3/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.25 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.2 Hz, 2
H), 7.93 (d, J = 7.2 Hz, 2 H), 7.89 (d, J = 7.2 Hz, 2 H), 7.82 (d, J =
7.2 Hz, 2 H), 7.60−7.12 (m, 20 H), 6.99 (m, 2 H), 5.93 (t, J = 9.6 Hz,
1 H), 5.74−5.68 (m, 2 H), 5.50 (s, 1 H), 5.20 (d, J = 8.0 Hz, 1 H),
4.98 (d, J = 3.6 Hz, 1 H), 4.75 (dd, J = 2.8, 12.0 Hz, 1 H), 4.55 (d-
like, J = 11.6 Hz, 1 H), 4.47 (dd, J = 5.2, 12.0 Hz, 1 H), 4.41 (d-like, J
3c. 27 mg, 82%, white solid, petroleum ether/EtOAc: 100/0 → 6/
25
1. Rf: 0.46 (petroleum ether/EtOAc = 3/1 (v/v)). [α]D = +24.7 (c
1
0.60, CHCl3); H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2
H), 7.97 (d, J = 7.2 Hz, 2 H), 7.90 (d, J = 7.2 Hz, 2 H), 7.83 (d, J =
7.2 Hz, 2 H), 7.56−7.28 (m, 12 H), 5.91 (t, J = 9.6 Hz, 1 H), 5.68 (t,
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= 11.6 Hz, 1 H), 4.27 (dd, J = 4.8, 10.4 Hz, 1 H), 4.18−4.13 (m, 1
H), 3.94 (t, J = 9.2 Hz, 1 H), 3.85−3.77 (m, 2 H), 3.69 (t, J = 10.4
Hz, 1 H), 3.54 (t, J = 9.2 Hz, 1 H), 3.39 (s, 3 H).
CDCl3) δ 7.34−7.10 (m, 98 H), 4.97− 4.89 (m, 10 H), 4.83−4.49
(m, 31 H), 4.45−4.39 (m, 3 H), 4.34 (d, J = 7.8 Hz, 1 H, H-1β), 4.17
(dd, J = 1.8, 10.8 Hz,1 H), 4.00−3.93 (m, 4.8 H), 3.83−3.41 (m, 30
H), 3.34 (s, 5.4 H), 3.32 (s, 3 H).
3j. 46 mg, 97%, white solid, petroleum ether/EtOAc: 100/0 → 6/1,
known compound.5f Rf: 0.43 (petroleum ether/EtOAc = 3/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.5f 1H NMR (400 MHz, CDCl3) δ 7.99−7.94 (m, 4 H),
7.86 (d, J = 7.2 Hz, 2 H), 7.80 (d, J = 7.2 Hz, 2 H), 7.52−7.23 (m, 20
H), 7.11 (m, 2 H), 5.89 (t, J = 9.6 Hz, 1 H), 5.72−5.64 (m, 2 H), 5.56
(s, 1 H), 5.26 (d, J = 8.0 Hz, 1 H), 4.59 (d-like, J = 12.4 Hz, 1 H),
4.50 (dd, J = 3.2, 12.0 Hz, 1 H), 4.33−4.26 (m, 3 H), 4.23−4.18 (m,
2 H), 3.98−3.94 (m, 1 H), 3.77 (td, J = 4.4, 9.6 Hz, 1 H), 3.69 (t, J =
10.0 Hz, 1 H), 3.62 (t, J = 9.2 Hz, 1 H), 3.43 (dd, J = 3.6, 9.2 Hz, 1
H), 3.27 (s, 3 H).
3k. 49 mg, 94%, white solid, petroleum ether/EtOAc: 100/0 → 6/
1, known compound.5f Rf: 0.48 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.5f 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 2 H),
7.88 (d, J = 7.6 Hz, 4 H), 7.79 (d, J = 7.6 Hz, 2 H), 7.55−7.28 (m, 23
H), 7.22−7.15 (m, 4 H), 5.61 (t, J = 9.6 Hz, 1 H), 5.54 (t, J = 9.6 Hz,
1 H), 5.46 (t, J = 9.2 Hz, 1 H), 5.07 (d-like, J = 11.2 Hz, 1 H), 4.81−
4.73 (m, 4 H), 4.60−4.54 (m, 2 H), 4.39 (dd, J = 3.2, 12.0 Hz, 1 H),
4.34 (d-like, J = 12.0 Hz, 1 H), 4.25 (dd, J = 4.8, 12.0 Hz, 1 H), 3.96
(t, J = 9.2 Hz, 1 H), 3.87 (t, J = 9.2 Hz, 1 H), 3.74−3.68 (m, 2 H),
3.51−3.41 (m, 3 H), 3.28 (s, 3 H).
General Procedure for NIS/TMSOTf-Promoted O-Glycosida-
tion with L-Rhamnosyl ortho-Hexynylbenzoate (1e). A mixture
of 1e (40 mg, 0.06 mmol), alcohols 2a and 2k (8 mg for 2a, 23 mg for
2k; 0.05 mmol), and freshly activated 4 Å MS (150 mg) in anhydrous
CH2Cl2 (1.5 mL) was stirred at room temperature for 0.5 h. NIS (17
mg, 0.075 mmol) and a freshly prepared solution of TMSOTf in
CH2Cl2 (0.1 mL, 0.1 M) were added at 0 °C under argon, and the
mixture was stirred for an additional 2 h at room temperature. The
mixture was quenched with Et3N and filtered through Celite. The
filtrate was concentrated in vacuo. The residue was purified by silica
gel column chromatography to give 3p and 3q.
3p. 31 mg, 100%, white foam, petroleum ether/EtOAc: 100/0 →
15/1, known compound.5e Rf: 0.78 (petroleum ether/EtOAc = 6/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.5e 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.2 Hz, 2 H),
8.00 (d, J = 7.2 Hz, 2 H), 7.84 (d, J = 7.2 Hz, 2 H), 7.61 (t, J = 7.2 Hz,
1 H), 7.54−7.47 (m, 3 H), 7.44−7.37 (m, 3 H), 7.28−7.24 (m, 2 H),
5.90 (dd, J = 3.2, 10.0 Hz, 1 H), 5.66 (t, J = 10.0 Hz, 1 H), 5.47 (dd, J
= 2.0, 4.0 Hz, 1 H), 5.44 (s, 1 H), 4.42−4.35 (m, 1 H), 2.19 (br s, 3
H), 1.95−1.88 (m, 6 H), 1.69−1.63 (m, 6 H), 1.32 (d, J = 6.0 Hz, 3
H).
3q. 45 mg, 98%, white foam, petroleum ether/EtOAc: 100/0 → 6/
1, known compound.5f Rf: 0.33 (toluene/EtOAc = 10/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.5f 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.2 Hz, 2
H), 7.90 (d, J = 7.2 Hz, 2 H), 7.86 (d, J = 7.2 Hz, 2 H), 7.62−7.28
(m, 18 H), 7.21−7.11 (m, 6 H), 5.79 (dd, J = 3.2, 10.0 Hz, 1 H),
5.63−5.56 (m, 2 H), 5.23−5.20 (m, 2 H), 4.85 (d, J = 11.2 Hz, 1 H),
4.77 (d-like, J = 12.0 Hz, 1 H), 4.66−4.53 (m, 4 H), 4.40−4.33 (m, 1
H), 4.05−3.84 (m, 4 H), 3.74 (d, J = 10.4 Hz, 1 H), 3.65 (dd, J = 3.6,
9.2 Hz, 1 H), 3.41 (s, 3 H), 0.89 (d, J = 6.0 Hz, 3 H).
3l. 28 mg, 67%, white solid, petroleum ether/EtOAc: 100/0 → 6/1,
known compound.5e Rf: 0.41 (petroleum ether/EtOAc = 3/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.5e 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2
H), 7.94 (d, J = 7.2 Hz, 2 H), 7.89 (d, J = 7.2 Hz, 2 H), 7.82 (d, J =
7.2 Hz, 2 H), 7.56−7.47 (m, 3 H), 7.44−7.28 (m, 9 H), 5.92−5.85
(m, 2 H), 5.67 (t, J = 9.6 Hz, 1 H), 5.54 (dd, J = 7.6, 9.6 Hz, 1 H),
4.95 (d, J = 7.6 Hz, 1 H), 4.64 (dd, J = 3.2, 12.0 Hz, 1 H), 4.52−4.47
(m, 2 H), 4.18−4.06 (m, 4 H), 3.74−3.68 (m, 2 H), 1.37 (s, 3 H),
1.28 (s, 3 H), 1.16 (s, 3 H), 1.09 (s, 3 H).
3m. 38 mg, 91%, white solid, petroleum ether/EtOAc: 100/0 → 0/
1, known compound.26 Rf: 0.31 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.26 1H NMR (400 MHz, CDCl3) δ 8.03−7.91 (m, 6 H), 7.80
(d, J = 7.2 Hz, 2 H), 7.58−7.28 (m, 12 H), 5.90 (t, J = 9.6 Hz, 1 H),
5.74−5.68 (m, 2 H), 5.58 (d, J = 3.6 Hz, 1 H), 5.12 (d, J = 8.0 Hz, 1
H), 4.69 (dd, J = 3.2, 12.4 Hz, 1 H), 4.63 (t, J = 3.6 Hz, 1 H), 4.57
(dd, J = 6.0, 12.0 Hz, 1 H), 4.29−4.19 (m, 2 H), 4.07−4.01 (m, 2 H),
3.76−3.67 (m, 2 H), 1.50 (s, 3 H), 1.42 (s, 3 H), 1.24 (s, 6 H).
General Procedure for NIS/TMSOTf-Promoted O-Glycosida-
tion with Glucosyl ortho-Hexynylbenzoate (1d). A mixture of
1d (43 mg, 0.06 mmol), alcohols 2a and 2g (8 mg for 2a, 23 mg for
2g; 0.05 mmol), and freshly activated 4 Å MS (150 mg) in anhydrous
CH2Cl2 (1.5 mL) was stirred at room temperature for 0.5 h. NIS (17
mg, 0.075 mmol) and a freshly prepared solution of TMSOTf in
CH2Cl2 (0.1 mL, 0.1 M) were added at 0 °C under argon, and the
mixture was stirred for an additional 2 h at room temperature. The
mixture was quenched with Et3N and filtered through Celite. The
filtrate was concentrated in vacuo. The residue was purified by silica
gel column chromatography to give 3n and 3o.
General Procedure for NIS/TMSOTf-Promoted O-Glycosida-
tion with N-Troc-Protected D-Galactosaminyl ortho-Hexynyl-
benzoate (1f). A mixture of 1f (40 mg, 0.06 mmol), alcohols 2a, 2g,
and 2k (8 mg for 2a, 23 mg for 2g, 23 mg for 2k; 0.05 mmol), and
freshly activated 4 Å MS (150 mg) in anhydrous CH2Cl2 (1.5 mL)
was stirred at room temperature for 0.5 h. NIS (17 mg, 0.075 mmol)
and a freshly prepared solution of TMSOTf in CH2Cl2 (0.1 mL, 0.1
M) were added at 0 °C under argon, and the mixture was stirred for
an additional 2 h at room temperature. The mixture was quenched
with Et3N and filtered through Celite. The filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatography
to give 3r−t.
3r. 27 mg, 87%, white foam, petroleum ether/EtOAc: 100/0 → 3/
25
1. Rf: 0.28 (petroleum ether/EtOAc = 3/1 (v/v)). [α]D = −1.9 (c
1
0.70, CHCl3); H NMR (400 MHz, CDCl3) δ 5.39−5.37 (m, 2 H),
5.09 (d, J = 7.6 Hz, 1 H), 4.95 (d, J = 7.6 Hz, 1 H), 4.74−4.67 (m, 2
H), 4.17 (dd, J = 6.8, 11.2 Hz, 1 H), 4.09 (dd, J = 6.8, 11.2 Hz, 1 H),
3.91 (t, J = 6.4 Hz, 1 H), 3.71−3.61 (m, 1 H), 2.13 (s, 6 H), 2.03 (s, 3
H), 1.99 (s, 3 H), 1.84−1.81 (m, 3 H), 1.74−1.71 (m, 3 H), 1.62−
1.55 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 170.5,
170.4, 154.0, 95.6, 94.0, 76.0, 74.6, 70.5, 69.6, 67.0, 61.8, 53.5, 42.5,
36.3, 30.8, 20.9, 20.8; HRMS (ESI) m/z: [M + Na]+ calcd for
C25H34O10NCl3Na 636.1146; Found 636.1143.
3n. 33 mg, 97%, α/β = 1.2/1, inseparable mixture, colorless syrup,
petroleum ether/EtOAc: 100/0 → 10/1, known compound.5f Rf: 0.80
(petroleum ether/EtOAc = 3/1 (v/v)). Spectroscopic data were in
accordance with those previously reported.5f 1H NMR (600 MHz,
CDCl3) δ 7.38−7.25 (m, 39.6 H), 7.21 (m, 2 H), 7.15 (m, 2.4 H),
5.30 (d, J = 3.6 Hz, 1.2 H, H-1α), 5.03−5.00 (m, 2.2 H), 4.93 (d, J =
10.8 Hz, 1 H), 4.86−4.78 (m, 4.4 H), 4.74−4.70 (m, 4.2 H, H-1β),
4.65 (d-like, J = 12.0 Hz, 1 H), 4.62−4.55 (m, 3 H), 4.49−4.46 (m,
2.4 H), 4.05−4.02 (m, 2.4 H), 3.79−3.74 (m, 2.2 H), 3.68−3.62 (m,
4.4 H), 3.57−3.44 (m, 4.2 H), 2.17−2.15 (m, 6 H), 1.95 (m, 3 H),
1.89−1.82 (m, 10 H), 1.67−1.61 (m, 14 H).
3s. 43 mg, 93%, colorless syrup, petroleum ether/EtOAc: 100/0 →
2/1. Rf: 0.19 (petroleum ether/EtOAc = 2/1 (v/v)). [α]D25 = +8.4 (c
1.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37−7.29 (m, 15 H),
5.33 (d, J = 3.2 Hz, 1 H), 5.10 (d-like, J = 9.6 Hz, 1 H), 4.99 (d-like, J
= 10.8 Hz, 1 H), 4.88−4.81 (m, 3 H), 4.77 (d, J = 3.2 Hz, 1 H), 4.65
(d-like, J = 12.4 Hz, 1 H), 4.61−4.47 (m, 4 H), 4.39 (d, J = 8.4 Hz, 1
H), 4.13−4.08 (m, 3 H), 3.99 (t, J = 9.2 Hz, 1 H), 3.86−3.74 (m, 3
H), 3.68 (dd, J = 3.6, 10.4 Hz, 1 H), 3.51−3.46 (m, 2 H), 3.37 (s, 3
H), 2.10 (s, 3 H), 2.02 (s, 3 H), 1.96 (s, 3 H); 13C{1H} NMR (100
MHz, CDCl3) δ 170.6, 170.5, 170.3, 154.0, 138.8, 138.7, 138.2, 128.7,
128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.8, 101.4, 98.2, 95.5, 82.2,
79.9, 76.0, 74.7, 74.4, 73.5, 70.8, 69.8, 69.6, 68.2, 66.8, 61.4, 55.4,
3o. 45 mg, 91%, α/β = 1.8/1, inseparable mixture, white solid,
petroleum ether/EtOAc: 100/0 → 8/1, known compound.5f Rf: 0.67
(petroleum ether/EtOAc = 3/1 (v/v)). Spectroscopic data were in
accordance with those previously reported.5f 1H NMR (600 MHz,
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52.7, 20.8, 20.7; HRMS (ESI) m/z: [M + Na]+ calcd for
C43H50O15NCl3Na 948.2144; Found 948.2125.
28.9, 28.3, 26.6, 25.6; HRMS (ESI) m/z: [M + Na]+ calcd for
C27H35O9N4Cl3Na 687.1367; Found 687.1364.
To a solution of the above glycoside S1 (58.7 mg, 0.088 mmol) in
CH2Cl2 (3.6 mL) and pyridine (0.6 mL) at 0 °C was added hydrazine
acetate (90.9 mg, 0.77 mmol). After stirring at room temperature for
1 h, the reaction mixture was quenched with acetone, diluted with
EtOAc, washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel chromatography
(petroleum ether/EA: 1/1.5) to give 2n (41 mg, 82%) as a white
3t. 42 mg, 91%, colorless syrup, petroleum ether/EtOAc: 100/0 →
3/1. Rf: 0.20 (petroleum ether/EtOAc = 3/1(v/v)). [α]D25 = −36.3 (c
1
1.03, CHCl3); H NMR (600 MHz, CDCl3) δ 7.50 (t, J = 7.8 Hz, 1
H), 7.43−7.38 (m, 5 H), 7.33−7.24 (m, 8 H), 5.19 (d, J = 3.0 Hz, 1
H), 4.95 (d, J = 10.8 Hz, 1 H), 4.85 (d, J = 12.0 Hz, 1 H), 4.79−4.75
(m, 3 H), 4.63−4.54 (m, 4 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.14 (d, J =
7.2 Hz, 1 H, H-1β), 3.88−3.78 (m, 4 H), 3.71−3.67 (m, 3 H), 3.60
(m, 1 H), 3.56−3.54 (m, 1 H), 3.48−3.45 (m, 2 H), 3.35 (s, 3 H),
2.06 (s, 3 H), 2.01 (s, 3 H), 1.96 (s, 3 H); 13C{1H} NMR (150 MHz,
CDCl3) δ 170.4, 170.3, 154.2, 139.6, 138.4, 137.5, 129.9, 129.3, 129.1,
128.5, 128.3, 128.2, 128.0, 127.5, 127.4, 100.9, 98.7, 95.8, 80.0, 78.7,
75.4, 74.6, 73.9, 73.8, 70.4, 70.2, 69.3, 67.3, 66.1, 60.8, 55.4, 52.7,
20.9, 20.8; HRMS (ESI) m/z: [M + Na]+ calcd for C43H50O15NCl3Na
948.2144; Found 948.2144.
General Procedure for NIS/TMSOTf-Promoted O-Glycosida-
tion with D-Ribofuranosyl ortho-Hexynylbenzoate (1g). A
mixture of 1g (39 mg, 0.06 mmol), alcohols 2g and 2k (23 mg for
2g, 23 mg for 2k; 0.05 mmol), and freshly activated 4 Å MS (150 mg)
in anhydrous CH2Cl2 (1.5 mL) was stirred at room temperature for
0.5 h. NIS (17 mg, 0.075 mmol) and a freshly prepared solution of
TMSOTf in CH2Cl2 (0.1 mL, 0.1 M) were added at 0 °C under
argon, and the mixture was stirred for an additional 2 h at room
temperature. The mixture was quenched with Et3N and filtered
through Celite. The filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography to give 3u and 3v.
3u. 44 mg, 97%, colorless syrup, petroleum ether/EtOAc: 100/0 →
5/1, known compound.27 Rf: 0.41 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.27 1H NMR (400 MHz, CDCl3) δ 8.04−7.99 (m, 4 H), 7.87
(d, J = 7.6 Hz, 2 H), 7.59−7.18 (m, 24 H), 5.82 (dd, J = 5.2, 6.4 Hz, 1
H), 5.64 (d, J = 5.2 Hz, 1 H), 5.15 (s, 1 H), 4.99 (d, J = 10.8 Hz, 1
H), 4.87 (d, J = 11.2 Hz, 1 H), 4.83−4.77 (m, 2 H), 4.72−4.52 (m, 6
H), 4.00−3.95 (m, 2 H), 3.73 (dd, J = 3.2, 9.6 Hz, 1 H), 3.62 (dd, J =
4.8, 10.8 Hz, 1 H), 3.57−3.49 (m, 2 H), 3.33 (s, 3 H).
3v. 41 mg, 90%, colorless syrup, petroleum ether/EtOAc: 100/0 →
6/1, known compound.27 Rf: 0.37 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.27 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2 H),
7.93 (d, J = 7.2 Hz, 2 H), 7.87 (d, J = 7.6 Hz, 2 H), 7.57−7.49 (m, 3
H), 7.41−7.13 (m, 21 H), 5.75 (t, J = 5.2 Hz, 1 H), 5.64 (d, J = 1.6
Hz, 1 H), 5.59 (dd, J = 2.0, 4.8 Hz, 1 H), 4.99 (d, J = 10.4 Hz, 1 H),
4.88 (d, J = 10.4 Hz, 1 H), 4.74 (d, J = 12.4 Hz, 1 H), 4.63−4.45 (m,
7 H), 3.95−3.88 (m, 2 H), 3.79 (dd, J = 3.6, 10.8 Hz, 1 H), 3.68−
3.66 (m, 2 H), 3.52 (dd, J = 3.2, 9.2 Hz, 1 H), 3.36 (s, 3 H).
NIS/TMSOTf-Promoted Glycosidation of (1h) with Alcohol
(2n). A solution of 5-tert-butyl-2-methylphenyl 3-O-levulinoyl-4,6-O-
benzylidene-2-deoxy-1-thio-2-(2,2,2-trichloroethoxycarbonylamino)-
D-galactopyranoside28 (4.7 g, 6.70 mmol), 6-azido hexyl linker 18 (1.4
g, 10.05 mmol), and freshly activated 4 Å MS (6.1 g) in anhydrous
CH2Cl2 (113 mL) was stirred at room temperature for 1 h. The
mixture was then cooled to 0 °C, to which NIS (2.3 g, 10.05 mmol)
and TfOH (71 μL, 0.80 mmol) were added. After stirring at room
temperature for an additional 1 h, the mixture was filtered through
Celite. The filtrate was diluted with CH2Cl2 and washed successively
with saturated aqueous Na2S2O3, brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (petroleum ether/EtOAc: 2/1) to give the desired
glycoside S1 (3.4 g, 76%) as a white solid. Rf: 0.38 (petroleum ether/
EtOAc = 2/1 (v/v)). [α]D25 = +28.2 (c 0.93, CHCl3); 1H NMR (600
MHz, CDCl3) δ 7.52 (dd, J = 1.8, 7.8 Hz, 2 H), 7.38−7.33 (m, 3 H),
5.52 (s, 1 H), 5.27 (d, J = 10.2 Hz, 1 H), 5.19 (d, J = 7.2 Hz, 1 H),
4.75−4.69 (m, 3 H), 4.32−4.30 (m, 2 H), 4.06 (dd, J = 1.8, 12.6 Hz,
1 H), 3.95−3.89 (m, 2 H), 3.50−3.46 (m, 2 H), 3.25 (t, J = 7.2 Hz, 2
H), 2.75−2.66 (m, 2 H), 2.59−2.57 (m, 2 H), 2.07 (s, 3 H), 1.62−
1.56 (m, 4 H), 1.39−1.34 (m, 4 H); 13C{1H} NMR (150 MHz,
CDCl3) δ 206.6, 172.6, 154.1, 137.8, 129.2, 128.3, 126.5, 101.0, 100.6,
95.8, 74.5, 73.3, 70.6, 69.5, 69.3, 66.4, 52.6, 51.5, 38.0, 29.8, 29.4,
25
solid. Rf: 0.25 (petroleum ether/EtOAc = 1/1 (v/v)). [α]D = −4.2
(c 0.40, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.52−7.50 (m, 2 H),
7.39−7.35 (m, 3 H), 5.58 (s, 1 H), 5.21 (br s, 1 H), 4.76−4.69 (m, 2
H), 4.59 (d, J = 6.0 Hz, 1 H, H-1), 4.33 (dd, J = 1.2, 12.6 Hz, 1 H),
4.21 (d, J = 3.6 Hz, 1 H), 4.08 (dd, J = 1.8, 12.6 Hz, 1 H), 4.01 (br s,
1 H), 3.95−3.92 (m, 1 H), 3.64 (br s, 1 H), 3.49−3.45 (m, 2 H), 3.26
(t, J = 7.2 Hz, 2 H), 2.79 (br s, 1 H), 1.61−1.57 (m, 4 H), 1.41−1.33
(m, 4 H); 13C{1H} NMR (150 MHz, CDCl3) δ 154.8, 137.6, 129.5,
128.5, 126.6, 101.5, 100.6, 95.6, 75.2, 74.7, 70.4, 69.5, 69.3, 66.8, 56.0,
51.5, 29.5, 28.9, 26.6, 25.7; HRMS (ESI) m/z: [M + Na]+ calcd for
C22H29O7N4Cl3Na 589.1000; Found 589.1001.
A mixture of 1h (32 mg, 0.06 mmol), alcohol 2n (28 mg, 0.05
mmol) and freshly activated 4 Å MS (150 mg) in anhydrous CH2Cl2
(1.5 mL) was stirred at room temperature for 0.5 h. NIS (17 mg,
0.075 mmol) and a freshly prepared solution of TMSOTf in CH2Cl2
(0.1 mL, 0.1 M) were added at 0 °C under argon, and the mixture was
stirred for an additional 2 h at room temperature. The mixture was
quenched with Et3N and filtered through Celite. The filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc: 100/0 → 1/1) to give 3w
(32 mg, 71%) as a white solid. Rf: 0.63 (toluene/acetone = 3/1 (v/
v)). [α]D25 = +16.1 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.56−7.50 (m, 2 H), 7.40−7.34 (m, 3 H), 5.57 (s, 1 H), 5.43 (d-like, J
= 5.2 Hz, 1 H), 5.36 (d, J = 3.2 Hz, 1 H), 5.21 (dd, J = 8.0, 10.4 Hz, 1
H), 4.97 (dd, J = 3.2, 10.4 Hz, 1 H), 4.90 (d, J = 7.6 Hz, 1 H), 4.85
(d-like, J = 12.0 Hz, 1 H), 4.78 (d, J = 7.6 Hz, 1 H), 4.61 (d-like, J =
12.0 Hz, 1 H), 4.48 (d-like, J = 9.6 Hz, 1 H), 4.33−4.31 (m, 2 H),
4.16−4.05 (m, 3 H), 3.93−3.86 (m, 2 H), 3.55−3.40 (m, 3 H), 3.25
(t, J = 6.8 Hz, 2 H), 2.16 (s, 3 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 1.97 (s,
3 H), 1.61−1.56 (m, 4 H), 1.38−1.34 (m, 4 H); 13C{1H} NMR (150
MHz, CDCl3) δ 170.5, 170.4, 170.3, 169.5, 154.8, 154.1, 137.9, 137.6,
129.5, 129.1, 128.4, 128.3, 126.6, 126.4, 101.9, 100.9, 99.5, 95.7, 76.2,
76.0, 75.2, 74.5, 71.0, 69.8, 69.4, 69.3, 69.1, 67.2, 66.8, 66.6, 61.7,
56.0, 54.1, 51.5, 29.5, 28.9, 26.7, 25.7, 20.9, 20.8, 20.7; HRMS (ESI)
m/z: [M + Na]+ calcd for C36H47O16N4Cl3Na 919.1950; Found
919.1947.
General Procedure for NIS/TMSOTf-Promoted N-Glycosyla-
tion with Pyrimidines. BSTFA (80−120 μL, 0.30−0.45 mmol) was
added to the mixture of 1a and 1g−i (59 mg for 1a, 49 mg for 1g, 40
mg for 1h, 40 mg for 1i; 0.075 mmol) and pyrimidines 4a−c (19 mg
for 4a, 17 mg for 4b, 32 mg for 4c; 0.15 mmol) in anhydrous CH3CN
(3.0 mL). The suspension was stirred at room temperature for 0.5 h
until it became clear. NIS (25 mg, 0.1125 mmol) and a freshly
prepared solution of TMSOTf in CH2Cl2 (2.71 μL, 0.015 mmol)
were added at 0 °C under argon, and the solution was stirred for an
additional 2 h at room temperature. The mixture was quenched with
Et3N and concentrated in vacuo. The residue was purified by silica gel
column chromatography to give 5a−k.
5a. 38 mg, 88%, white solid, petroleum ether/EtOAc: 100/0 →
2.5/1, known compound.10 Rf: 0.26 (petroleum ether/EtOAc = 2/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.10,11,29 1H NMR (400 MHz, CDCl3) δ 8.16−8.14 (m, 2 H),
8.03−7.94 (m, 4 H), 7.66−7.50 (m, 5 H), 7.43−7.35 (m, 4 H), 7.16
(d, J = 1.2 Hz, 1 H), 6.43 (d, J = 6.4 Hz, 1 H), 5.91 (dd, J = 3.6, 6.0
Hz, 1 H), 5.75 (t, J = 6.4 Hz, 1 H), 4.89 (dd, J = 2.8, 12.4 Hz, 1 H),
4.70 (dd, J = 2.8, 6.0 Hz, 1 H), 4.65 (dd, J = 3.6, 12.4 Hz, 1 H), 1.59
(d, J = 0.8 Hz, 3 H).
5b. 39 mg, 93%, white solid, petroleum ether/EtOAc: 100/0 →
2.5/1, known compound.10 Rf: 0.19 (petroleum ether/EtOAc = 2/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.10,11,29 1H NMR (400 MHz, CDCl3) δ 8.81 (br s, 1 H),
4772
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8.11−8.09 (m, 2 H), 7.99−7.93 (m, 4 H), 7.63−7.53 (m, 3 H), 7.49
(t, J = 7.6 Hz, 2 H), 7.42−7.35 (m, 5 H), 6.32 (d, J = 5.6 Hz, 1 H),
5.89 (t, J = 5.6 Hz, 1 H), 5.75 (t, J = 5.6 Hz, 1 H), 5.61 (d, J = 8.0 Hz,
1 H), 4.84 (dd, J = 2.4, 12.0 Hz, 1 H), 4.72 (dd, J = 4.0, 6.8 Hz, 1 H),
4.67 (dd, J = 4.0, 12.0 Hz, 1 H).
5c. 44 mg, 88%, white solid, petroleum ether/EtOAc: 100/0 → 2/
1, known compound.10 Rf: 0.15 (petroleum ether/EtOAc = 2.5/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,11,29 1H NMR (400 MHz, CDCl3) δ 8.85 (br s, 1 H), 8.11
(d, J = 7.2 Hz, 2 H), 7.98−7.89 (m, 7 H), 7.64−7.49 (m, 9 H), 7.37
(t-like, J = 7.6 Hz, 4 H), 6.46 (d, J = 4.4 Hz, 1 H), 5.92 (t, J = 5.6 Hz,
1 H), 5.85 (t, J = 5.6 Hz, 1 H), 4.87 (dd, J = 2.8, 12.4 Hz, 1 H), 4.81−
4.78 (m, 1 H), 4.73 (dd, J = 3.6, 12.4 Hz, 1 H).
5d. 27 mg, 79%, white solid, petroleum ether/EtOAc: 100/0 → 1/
1, known compound.10 Rf: 0.22 (petroleum ether/EtOAc = 1/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1 H), 7.14 (d, J
= 0.8 Hz, 1 H), 5.86 (d, J = 9.2 Hz, 1 H), 5.38 (t, J = 9.6 Hz, 1 H),
5.21−5.12 (m, 2 H), 4.27 (dd, J = 5.2, 12.4 Hz, 1 H), 4.11 (dd, J =
1.6, 12.4 Hz, 1 H), 3.93 (ddd, J = 2.0, 4.8, 10.0 Hz, 1 H), 2.09 (s, 3
H), 2.05 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H), 1.95 (s, 3 H).
5e. 41 mg, 77%, white solid, petroleum ether/EtOAc: 100/0 → 2/
1, known compound.10 Rf: 0.21 (petroleum ether/EtOAc = 2/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.50 (br s, 1 H), 8.04
(d, J = 7.2 Hz, 2 H), 7.93−7.80 (m, 6 H), 7.59−7.28 (m, 13 H), 6.26
(d, J = 9.6 Hz, 1 H), 6.08 (t, J = 9.6 Hz, 1H), 5.78 (t, J = 9.6 Hz, 1 H),
5.67 (t, J = 9.6 Hz, 1 H), 4.67 (dd, J = 2.4, 12.4 Hz, 1 H), 4.48 (dd, J
= 4.8, 12.0, Hz, 1 H), 4.39 (ddd, J = 2.8, 4.8, 9.6 Hz, 1 H), 1.93 (s, 3
H).
5.31−5.26 (m, 1 H), 5.22 (dd, J = 2.8, 10.0 Hz, 1 H), 4.19−4.06 (m,
3 H), 2.18 (s, 3 H), 2.04 (s, 3 H), 2.01 (s, 3 H), 1.99 (s, 3 H).
5k. 38 mg, 93%, white solid, petroleum ether/EtOAc: 100/0 → 1/
1.25, known compound.10 Rf: 0.13 (petroleum ether/EtOAc = 1/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.87 (br s, 1 H), 7.89
(d, J = 7.2 Hz, 2 H), 7.82 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 2
H), 7.50 (t, J = 7.6 Hz, 2 H), 6.09 (d, J = 8.8 Hz, 1 H), 5.52 (d, J = 2.8
Hz, 1 H), 5.32−5.28 (m, 1 H), 5.24 (dd, J = 3.2, 10.4 Hz, 1 H), 4.19−
4.08 (m, 3 H), 2.20 (s, 3 H), 2.03 (s, 3 H), 1.98 (s, 6 H).
General Procedure for NIS/TMSOTf-Promoted N-Glycosyla-
tion with Purines. A mixture of 1a, 1g, and 1j (47 mg for 1a, 39 mg
for 1g, 28 mg for 1j; 0.06 mmol), purines 4d and 4e (17 mg for 4d, 13
mg for 4e; 0.05 mmol), and freshly activated 4 Å MS (150 mg) in
anhydrous CH2Cl2 (1.5 mL) was stirred at room temperature for 0.5
h. NIS (17 mg, 0.075 mmol) and a freshly prepared solution of
TMSOTf in CH2Cl2 (0.05 mL, 0.1 M) were added at 0 °C under
argon, and the mixture was stirred for an additional 2 h at room
temperature. The mixture was quenched with Et3N and filtered
through Celite. The filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography to give 5l−q.
5l. 29 mg, 74%, white solid, petroleum ether/EtOAc: 100/0 → 3/1,
known compound.10 Rf: 0.33 (petroleum ether/EtOAc = 3/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1 H), 8.22
(s, 1 H), 8.11 (d, J = 7.2 Hz, 2 H), 8.01 (d, J = 7.2 Hz, 2 H), 7.91 (d, J
= 7.2 Hz, 2 H), 7.61−7.52 (m, 3 H), 7.48−7.34 (m, 6 H), 6.49 (d, J =
5.6 Hz, 1 H), 6.38 (t, J = 5.6 Hz, 1 H), 6.25 (t, J = 4.8 Hz, 1 H), 4.91
(dd, J = 3.2, 12.0 Hz, 1 H), 4.84 (dd, J = 4.0, 8.0 Hz, 1 H), 4.72 (dd, J
= 4.0, 12.0 Hz, 1 H), 1.43 (s, 18 H).
5f. 28 mg, 85%, white solid, petroleum ether/EtOAc: 100/0 → 1/
1, known compound.10 Rf: 0.13 (petroleum ether/EtOAc = 1/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.51 (br s, 1 H), 7.33
(d, J = 8.4 Hz, 1 H), 5.85 (d, J = 9.6 Hz, 1 H), 5.82 (d, J = 8.4 Hz, 1
H), 5.39 (t, J = 9.6 Hz, 1 H), 5.19−5.11 (m, 2 H), 4.27 (dd, J = 4.8,
12.4 Hz, 1 H), 4.12 (dd, J = 1.6, 12.4 Hz, 1 H), 3.93 (ddd, J = 2.0, 4.8,
10.0 Hz, 1 H), 2.09 (s, 3 H), 2.06 (s, 3 H), 2.02 (s, 3 H), 2.01 (s, 3
H).
5g. 44 mg, 85%, white solid, petroleum ether/EtOAc: 100/0 → 2/
1, known compound.10 Rf: 0.30 (toluene/EtOAc = 2.5/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.25 (br s, 1 H),
8.03 (d, J = 7.2 Hz, 2 H), 7.93−7.87 (m, 4 H), 7.80 (d, J = 7.2 Hz, 2
H), 7.60−7.28 (m, 13 H), 6.23 (d, J = 9.6 Hz, 1 H), 6.08 (t, J = 9.6
Hz, 1 H), 5.82 (d, J = 8.4 Hz, 1 H), 5.76 (t, J = 9.6 Hz, 1 H), 5.65 (t, J
= 9.6 Hz, 1 H), 4.65 (dd, J = 2.4, 12.4 Hz, 1 H), 4.49 (dd, J = 5.2, 12.4
Hz, 1 H), 4.41−4.37 (m, 1 H).
5h. 29 mg, 71%, white solid, petroleum ether/EtOAc: 100/0 → 1/
1, known compound.10 Rf: 0.31 (petroleum ether/EtOAc = 1/3 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.70 (br s, 1 H), 7.89
(d, J = 7.2 Hz, 2 H), 7.78 (d, J = 7.2 Hz, 1 H), 7.62 (t-like, J = 7.6 Hz,
2 H), 7.52 (t-like, J = 7.6 Hz, 2 H), 6.13 (d, J = 9.6 Hz, 1 H), 5.43 (t, J
= 9.6 Hz, 1 H), 5.21−5.15 (m, 2 H), 4.29 (dd, J = 4.8, 12.4 Hz, 1 H),
4.13 (dd, J = 1.6, 12.4 Hz, 1 H), 3.96 (ddd, J = 2.0, 5.2, 10.4 Hz, 1 H),
2.10 (s, 3 H), 2.06 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H).
5i. 31 mg, 91%, white solid, petroleum ether/EtOAc: 100/0 → 1/1,
known compound.10 Rf: 0.21 (petroleum ether/EtOAc = 1/1.5 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1 H), 7.15 (d, J
= 0.8 Hz 1 H), 5.84 (d, J = 9.2 Hz, 1 H), 5.50 (d, J = 3.2 Hz, 1 H),
5.30 (t, J = 10.0 Hz, 1 H), 5.21 (dd, J = 3.2, 10.0 Hz, 1 H), 4.19−4.07
(m, 3 H), 2.21 (s, 3 H), 2.05 (s, 3 H), 2.00 (s, 3 H), 1.99 (s, 3 H),
1.97 (s, 3 H).
5m. 29 mg, 81%, white solid, petroleum ether/EtOAc: 100/0 → 3/
1, known compound.10 Rf: 0.31 (petroleum ether/EtOAc = 3/1 (v/
v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1 H), 8.03−
7.99 (m, 4 H), 7.93 (d, J = 7.2 Hz, 2 H), 7.60−7.52 (m, 4 H), 7.43−
7.34 (m, 6 H), 6.60 (t, J = 6.0 Hz, 1 H), 6.31−6.27 (m, 2 H), 4.96
(dd, J = 4.0, 12.0 Hz, 1 H), 4.91−4.87 (m, 1 H), 4.78 (dd, J = 5.6,
12.0 Hz, 1 H), 1.48 (s, 9 H).
5n. 40 mg, 87%, white solid, petroleum ether/EtOAc: 100/0 →
2.5/1, known compound.10 Rf: 0.41 (petroleum ether/EtOAc = 2/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1 H), 8.42 (s, 1
H), 8.01 (d, J = 7.2 Hz, 2 H), 7.94 (d, J = 7.2 Hz, 2 H), 7.82 (d, J =
7.2 Hz, 2 H), 7.69 (d, J = 7.2 Hz, 2 H), 7.57−7.50 (m, 2 H), 7.45−
7.35 (m, 6 H), 7.29−7.22 (m, 4 H), 6.34 (d, J = 9.6 Hz, 1 H), 6.20−
6.12 (m, 2 H), 5.93 (t, J = 9.6 Hz, 1 H), 4.73−4.68 (m, 1 H), 4.55−
4.49 (m, 2 H), 1.32 (s, 18 H).
5o. 31 mg, 74%, white solid, petroleum ether/EtOAc: 100/0 →
3.5/1, known compound.10 Rf: 0.19 (petroleum ether/EtOAc = 3/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.10 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1 H), 8.01 (d, J =
7.2 Hz, 2 H), 7.94 (d, J = 7.6 Hz, 2 H), 7.81 (d, J = 7.2 Hz, 2 H), 7.75
(d, J = 7.2 Hz, 2 H), 7.57−7.50 (m, 2 H), 7.45−7.36 (m, 7 H), 7.29−
7.23 (m, 4 H), 6.29 (d, J = 9.6 Hz, 1 H), 6.18 (t, J = 9.6 Hz, 1 H),
6.02 (t, J = 9.6 Hz, 1 H), 5.89 (t, J = 9.6 Hz, 1 H), 4.71−4.65 (m, 1
H), 4.56−4.49 (m, 2 H), 1.58 (s, 9 H).
5p. 21 mg, 70%, white solid, petroleum ether/EtOAc: 100/0 → 2/
1, known compound.10 Rf: 0.19 (toluene/EtOAc = 2/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.10 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1 H), 8.27 (s,
1 H), 6.18 (d, J = 6.8 Hz, 1 H), 6.09 (dd, J = 3.6, 6.8 Hz, 1 H), 5.57
(dd, J = 3.6, 5.6 Hz, 1 H), 5.03 (t, J = 5.6 Hz, 1 H), 4.20−4.14 (m, 1
H), 2.17 (s, 3 H), 2.15 (s, 3 H), 1.93 (s, 3 H), 1.46−1.45 (m, 21 H).
5q. 22 mg, 81%, white solid, petroleum ether/EtOAc: 100/0 →
1.5/1, known compound.10 Rf: 0.44 (petroleum ether/EtOAc = 1/1
(v/v)). Spectroscopic data were in accordance with those previously
reported.10 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1 H), 7.82 (s, 1
H), 6.25 (t, J = 4.4 Hz, 1 H), 5.98 (d, J = 4.4 Hz, 1 H), 5.73 (dd, J =
3.6, 7.2 Hz, 1 H), 5.08 (t, J = 7.2 Hz, 1 H), 4.00−3.94 (m, 1 H), 2.13
5j. 31 mg, 94%, white solid, petroleum ether/EtOAc: 100/0 → 1/1,
known compound.10 Rf: 0.23 (petroleum ether/EtOAc = 1/1 (v/v)).
Spectroscopic data were in accordance with those previously
reported.10,29 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1 H), 7.38
(d, J = 8.0 Hz, 1 H), 5.87−5.83 (m, 2 H), 5.49 (d, J = 2.8 Hz, 1 H),
4773
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(s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 1.54 (s, 9 H), 1.36 (d, J = 6.4
Hz, 3 H).
→ 3/1) gave the corresponding lactol (609 mg, 81%) as a yellow
syrup. Rf: 0.31 (petroleum ether/EtOAc = 2/1 (v/v)). To a solution
of the above lactol (365 mg, 0.84 mmol) in anhydrous CH2Cl2 (17
mL) at room temperature were added ortho-hexynylbenzoic acid (255
mg, 1.26 mmol), DCC (433 mg, 2.10 mmol), and DMAP (31 mg,
0.252 mmol). The mixture was stirred at room temperature for 2 h
and filtered. The filtrate was concentrated in vacuo and purified by
silica gel column chromatography (petroleum ether/EtOAc: 100:0 →
10/1) to give 12 (505 mg, 97%, α/β = 1:1.5) as a yellow syrup. Rf:
Typical Procedure for Comparison of the Donor Reactiv-
ities of Glycosyl ortho-Hexynylbenzoate and Thioglycosides
under the Activation of NIS/TMSOTf. To a mixture of 1a (47 mg,
0.06 mmol), 6a30 (31 mg, 0.06 mmol), 2a (8 mg, 0.05 mmol), and
freshly activated 4 Å MS (150 mg) in anhydrous CH2Cl2 (1.5 mL) at
0 °C were added NIS (17 mg, 0.075 mmol) and a freshly prepared
solution of TMSOTf in anhydrous CH2Cl2 (0.1 M, 0.1 mL) under
argon. After stirring at room temperature for 2 h, the mixture was
quenched with Et3N and filtered through Celite. The filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc: 100/0 → 3/1) to give 3a
(33 mg, 90%) as a white solid and recover 6a (31 mg, 100%) as a
white solid. 6a Rf: 0.37 (petroleum ether/EtOAc = 3/1 (v/v)).
One-Pot Synthesis of Trisaccharide (9). To a mixture of
glucosyl ortho-hexynylbenzoate donor 1a (47 mg, 0.06 mmol),
glucosyl acceptor 8 (29 mg, 0.05 mmol), and freshly activated 4 Å MS
(150 mg) in anhydrous CH2Cl2 (1.5 mL) at 0 °C were added NIS
(17 mg, 0.075 mmol) and a freshly prepared solution of TMSOTf
(0.1 mL, 0.1 M) dropwise. After stirring at room temperature for 2 h,
the reaction mixture was cooled to 0 °C, to which glucosyl acceptor
2g (19 mg, 0.04 mmol), NIS (17 mg, 0.075 mmol), and a freshly
prepared solution of TMSOTf (0.15 mL, 0.1 M) were added
successively. The resulting mixture was stirred at room temperature
for another 2 h. Then, Et3N was added to quench the reaction. The
mixture was filtered through Celite, and the filtrate was concentrated
in vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc: 100:0 → 3/1) to afford
9 (43 mg, 71% overall yield, known compound31) as a white solid. Rf:
0.22 (petroleum ether/EtOAc = 3/1(v/v)). Spectroscopic data were
in accordance with those previously reported.31 1H NMR (400 MHz,
CDCl3) δ 8.03−7.92 (m, 4 H), 7.87−7.76 (m, 9 H), 7.55−7.13 (m,
35 H), 6.97−6.95 (m, 2 H), 5.85 (t, J = 9.6 Hz, 1 H), 5.76 (t, J = 9.6
Hz, 1 H), 5.61 (t, J = 9.6 Hz, 1 H), 5.51−5.44 (m, 2 H), 5.30 (t, J =
9.6 Hz, 1 H), 5.00 (d, J = 8.0 Hz, 1 H), 4.89 (d-like, J = 11.2 Hz, 1
H), 4.75 (d-like, J = 12.4 Hz, 1 H), 4.68 (d-like, J = 10.8 Hz, 1 H),
4.61−4.57 (m, 3 H), 4.50 (d, J = 8.0 Hz, 1 H), 4.41 (dd, J = 5.6, 12.4
Hz, 1 H), 4.36 (d, J = 11.2 Hz, 1 H), 4.15 (d, J = 11.2 Hz, 1 H),
4.09−3.99 (m, 2 H), 3.93−3.83 (m, 4 H), 3.53−3.36 (m, 4 H), 3.34
(s, 3 H).
25
0.82 (petroleum ether/EtOAc = 3/1 (v/v)). 12β: [α]D = −53.1 (c
0.67, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.2 Hz, 2
H), 7.99 (d, J = 7.6 Hz, 1 H), 7.66−7.47 (m, 5 H), 7.36−7.32 (m, 1
H), 7.24−7.18 (m, 5 H), 6.00 (d, J = 8.0 Hz, 1 H), 5.53 (d, J = 3.2
Hz, 1 H), 5.27 (dd, J = 3.6, 10.0 Hz, 1 H), 4.78 (d-like, J = 11.6 Hz, 1
H), 4.66 (d-like, J = 11.6 Hz, 1 H), 4.14 (dd, J = 6.0, 12.4 Hz, 1 H),
4.03 (dd, J = 8.4, 10.0 Hz, 1 H), 3.91 (d-like, J = 15.2 Hz, 1 H), 3.83
(d-like, J = 15.2 Hz, 1 H), 2.50 (t, J = 7.2 Hz, 2 H), 1.67−1.59 (m, 2
H), 1.52−1.43 (m, 2 H), 1.30 (d, J = 6.4 Hz, 3 H), 0.93 (t, J = 7.2 Hz,
3 H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.7, 166.4, 164.0,
137.7, 134.8, 133.8, 132.5, 130.7, 130.3, 130.1, 129.4, 128.8, 128.5,
128.0, 127.3, 125.9, 97.4, 94.6, 79.3, 75.6, 75.3, 75.2, 71.0, 70.4, 40.7,
30.8, 22.3, 19.8, 16.3, 13.8; HRMS (ESI) m/z: [M + Na]+ calcd for
C35H35O8ClNa 641.1918; Found 641.1920.
A mixture of donor 12 (371 mg, 0.60 mmol), alcohol 10 (232 mg,
0.50 mmol) and freshly activated 4 Å MS (1.5 g) in anhydrous
CH2Cl2 (15 mL) was stirred at room temperature for 0.5 h. NIS (169
mg, 0.75 mmol) and TMSOTf (18 μL, 0.10 mmol) were added at 0
°C under argon, and the solution was stirred for an additional 2 h at
room temperature. The mixture was quenched with Et3N and filtered
through Celite. The filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography (petroleum ether/
EtOAc: 100/0 → 7/1) to give 13 (419 mg, 95%) as a white foam. Rf:
0.54 (petroleum ether/EtOAc = 3/1 (v/v)). [α]D25 = −190.0 (c 1.17,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.03−7.94 (m, 4 H), 7.62−
7.29 (m, 11 H), 7.18−7.05 (m, 7 H), 6.89−6.85 (m, 2 H), 5.73 (d, J
= 2.8 Hz, 1 H), 5.57 (d, J = 3.6 Hz, 1 H, H-1), 5.51 (dd, J = 3.2, 10.4
Hz, 1 H), 5.40 (d, J = 3.2 Hz, 1 H, H-1′), 5.29 (d, J = 2.8 Hz, 1 H),
4.81−4.74 (m, 2 H), 4.60−4.51 (m, 3 H), 4.36−4.31 (m, 2 H), 4.18
(dd, J = 3.6, 10.0 Hz, 1 H), 3.94 (dd, J = 3.6, 10.4 Hz, 1 H), 3.80 (s, 3
H), 3.78 (d-like, J = 15.2 Hz, 1 H), 3.68 (d, J = 15.2 Hz, 1 H), 1.18
(d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.4 Hz, 3 H); 13C{1H} NMR (150
MHz, CDCl3) δ 166.6, 166.4, 155.3, 151.4, 138.1, 138.0, 133.5, 133.3,
130.1, 129.9, 129.7, 129.6, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2,
127.9, 127.6, 118.4, 114.8, 97.2, 93.2, 74.6, 73.2, 72.6, 72.3, 72.1, 70.5,
69.7, 65.9, 64.8, 55.8, 40.8, 16.5, 16.0; HRMS (ESI) m/z: [M + Na]+
calcd for C49H49O13ClNa 903.2759; Found 903.2763.
To a solution of 13 (125 mg, 0.14 mmol) in MeOH/CHCl3 (4.2
mL/0.7 mL) were added 2,4,6-collidine (18.5 μL, 0.14 mmol) and
thiourea (51 mg, 0.672 mmol) at room temperature. The reaction
mixture was then stirred under reflux in an oil bath for 24 h. After
cooling to room temperature, the reaction was poured into water and
extracted with EtOAc. The organic layer was washed with 1 M
aqueous HCl and brine and dried over Na2SO4. Filtration,
concentration in vacuo, and purification by silica gel column
chromatography (petroleum ether/EtOAc: 100:0 → 5/1) gave 14
(110 mg, 97%) as a colorless syrup. Rf: 0.30 (petroleum ether/EtOAc
= 3/1 (v/v)). [α]D25 = −180.2 (c 1.40, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 7.2 Hz, 2 H), 7.97 (d, J = 7.2 Hz, 2 H), 7.59−
7.55 (m, 2 H), 7.45−7.40 (m, 4 H), 7.35−7.29 (m, 5 H), 7.20−7.14
(m, 5 H), 7.08−7.04 (m, 2 H), 6.89−6.85 (m, 2 H), 5.76 (d, J = 2.8
Hz, 1 H), 5.54 (d, J = 3.6 Hz, 1 H), 5.49 (d, J = 3.2 Hz, 1 H), 5.25 (d,
J = 2.8 Hz, 1 H), 4.75 (s, 2 H), 4.63−4.60 (m, 2 H), 4.47 (q, J = 6.4
Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.34 (q, J = 6.4 Hz, 1 H), 4.23−
4.20 (m, 1 H), 4.17 (dd, J = 3.6, 10.4 Hz, 1 H), 3.83−3.80 (m, 4 H),
2.12 (s, 1 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.10 (d, J = 6.8 Hz, 3 H);
13C{1H} NMR (150 MHz, CDCl3) δ 166.6, 166.5, 155.2, 151.3,
138.1, 137.8, 133.4, 133.2, 130.1, 130.0, 129.9, 129.7, 128.7, 128.6,
128.5, 128.1, 128.0, 127.8, 118.3, 114.8, 97.3, 92.3, 75.7, 74.5, 73.7,
73.1, 72.0, 70.3, 69.9, 68.1, 66.0, 65.3, 55.8, 16.5, 16.3; HRMS (ESI)
m/z: [M + Na]+ calcd for C47H48O12Na 827.3043; Found 827.3045.
Synthesis of the Tetrasaccharide Backbone 19 of Type I
Fucoidan. To a solution of monosaccharide 1021 (697 mg, 1.50
mmol) in anhydrous CH2Cl2 (7.5 mL) and pyridine (0.49 mL, 6.00
mmol) was added chloroacetylchloride (0.24 mL, 3.00 mmol). After
stirring at room temperature for 1 h, the mixture was diluted with
CH2Cl2 and washed with 1 M aqueous HCl, water, and saturated
aqueous NaCl successively. The combined organic layers were dried
over Na2SO4, and the filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography (petroleum ether/
EtOAc: 100:0 → 8/1) to afford 11 (787 mg, 97%) as a colorless
25
syrup. Rf: 0.67 (petroleum ether/EtOAc = 3/1 (v/v)). [α]D
=
−103.5 (c 1.73, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J =
7.2 Hz, 2 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.50 (t, J = 7.6 Hz, 2 H),
7.31−7.27 (m, 5 H), 7.05 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 9.2 Hz, 2
H), 5.70 (dd, J = 3.2, 10.4 Hz, 1 H), 5.60 (d, J = 2.8 Hz, 1 H), 5.49
(d, J = 3.2 Hz, 1 H), 4.72 (d, J = 12.0 Hz, 1 H), 4.66 (d, J = 12.4 Hz, 1
H), 4.40 (dd, J = 6.4, 13.2 Hz, 1 H), 4.12 (dd, J = 3.6, 10.4 Hz, 1 H),
3.99−3.91 (m, 2 H), 3.80 (s, 3 H), 1.17 (d, J = 6.8 Hz, 3 H); 13C{1H}
NMR (150 MHz, CDCl3) δ 166.8, 166.4, 155.3, 151.0, 137.8, 133.6,
130.0, 129.6, 128.7, 128.6, 128.1, 128.0, 118.0, 114.8, 97.0, 73.3, 73.1,
72.3, 71.8, 65.5, 55.8, 40.8, 16.2; HRMS (ESI) m/z: [M + Na]+ calcd
for C29H29O8ClNa 563.1449; Found 563.1448.
To a solution of compound 11 (933 mg, 1.72 mmol) in toluene/
CH3CN/H2O (8.6/12.9/8.6 mL) was added CAN (2.83 g, 5.16
mmol). After stirring at room temperature for 30 min, the solution
was poured into ice water and extracted with CH2Cl2. The organic
layer was washed with saturated aqueous NaHCO3 and brine and
dried over Na2SO4. Filtration, concentration in vacuo, and purification
by silica gel column chromatography (petroleum ether/EtOAc: 100:0
4774
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To a solution of compound 13 (705 mg, 0.80 mmol) in toluene/
CH3CN/H2O (4.0 mL/6.0 mL/4.0 mL) was added CAN (1.10 g,
2.00 mmol). After stirring at room temperature for 30 min, the
solution was poured into ice water and extracted with CH2Cl2. The
organic layer was washed with saturated aqueous NaHCO3 and brine
and dried over Na2SO4. Filtration, concentration in vacuo, and
purification by silica gel column chromatography (petroleum ether/
EtOAc: 100:0 → 2.5/1) gave the corresponding lactol (472 mg, 76%)
as a yellow syrup. Rf: 0.18 (petroleum ether/EtOAc = 3/1 (v/v)). To
a solution of the above lactol (419 mg, 0.54 mmol) in anhydrous
CH2Cl2 (15 mL) at room temperature were added ortho-
hexynylbenzoic acid (164 mg, 0.81 mmol), DCC (279 mg, 1.35
mmol), and DMAP (20 mg, 0.162 mmol). The mixture was stirred at
room temperature for 2 h and filtered. The filtrate was concentrated
in vacuo and purified by silica gel column chromatography
(petroleum ether/EtOAc: 100:0 → 9/1) to give 15 (508 mg, 98%,
α/β = 1/2.8) as a yellow syrup. Rf: 0.70 (petroleum ether/EtOAc =
3/1 (v/v)). 15β: [α]D = −202.6 (c 0.43, CHCl3); H NMR (600
MHz, CDCl3) δ 8.09−8.07 (m, 3 H), 7.92−7.90 (m, 2 H), 7.60−7.54
(m, 3 H), 7.49 (dt, J = 1.2, 7.8 Hz, 1 H), 7.45−7.30 (m, 9 H), 7.27−
7.25 (m, 1 H), 7.20−7.15 (m, 3 H), 7.10−7.08 (m, 2 H), 6.02 (d, J =
7.2 Hz, 1 H, H-1β), 5.69 (d, J = 3.0 Hz, 1 H), 5.44 (dd, J = 3.0, 10.2
Hz, 1 H), 5.36 (d, J = 3.6 Hz, 1 H, H-1′α), 5.09 (d, J = 2.4 Hz, 1 H),
4.93 (d, J = 10.2 Hz, 1 H), 4.73 (d, J = 10.2 Hz, 1 H), 4.51 (d, J =
12.6 Hz, 1 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.27 (dd, J = 6.0, 13.2 Hz, 1
H), 4.15−4.09 (m, 2 H), 4.05 (q, J = 6.6 Hz, 1 H), 3.90 (dd, J = 3.6,
10.2 Hz, 1 H), 3.77 (d-like, J = 15.0 Hz, 1 H), 3.67 (d-like, J = 15.0
Hz, 1 H), 2.54 (t, J = 7.2 Hz, 2 H), 1.68−1.64 (m, 2 H), 1.54−1.48
(m, 2 H), 1.30 (d, J = 6.0 Hz, 3 H), 0.95 (t, J = 7.2 Hz, 3 H), 0.79 (d,
J = 6.6 Hz, 3 H); 13C{1H} NMR (150 MHz, CDCl3): δ 166.7, 166.6,
166.4, 164.2, 137.9, 137.6, 134.9, 133.5, 133.4, 132.5, 130.8, 130.4,
130.2, 129.9, 129.6, 128.8, 128.7, 128.6, 128.3, 128.2, 128.0, 127.7,
127.4, 125.9, 97.3, 95.2, 93.3, 79.4, 76.2, 74.1, 72.7, 72.3, 72.2, 71.9,
70.8, 68.5, 64.7, 40.7, 30.9, 22.3, 19.8, 16.6, 15.7, 13.9; HRMS (ESI)
m/z: [M + Na]+ calcd for C55H55O13ClNa 981.3229; Found
981.3237.
purification by silica gel column chromatography (petroleum ether/
EtOAc: 100:0 → 3/1) gave the corresponding lactol (109 mg, 79%)
as a yellow syrup. Rf: 0.25 (petroleum ether/EtOAc = 2/1 (v/v)). To
a solution of the above lactol (160 mg, 0.11 mmol) in anhydrous
CH2Cl2 (2.5 mL) at room temperature were added ortho-
hexynylbenzoic acid (33 mg, 0.165 mmol), DCC (57 mg, 0.275
mmol), and DMAP (4.0 mg, 0.033 mmol). The mixture was stirred at
room temperature for 2 h and filtered. The filtrate was concentrated
in vacuo and purified by silica gel column chromatography
(petroleum ether/EtOAc: 100:0 → 6/1) to give 17 (173 mg, 96%,
α/β = 1/1.2) as a colorless syrup. Rf: 0.50 (petroleum ether/EtOAc =
2/1 (v/v)). 17β: [α]D = −184.2 (c 0.33, CHCl3); H NMR (600
MHz, CDCl3) δ 8.14 (d, J = 7.2 Hz, 2 H), 8.03−8.01 (m, 1 H), 7.93
(d, J = 7.2 Hz, 2 H), 7.89−7.87 (m, 4 H), 7.62 (t, J = 7.2 Hz, 1 H),
7.58−7.53 (m, 3 H), 7.50−7.28 (m, 16 H), 7.24−7.11 (m, 11 H),
7.05 (m, 2 H), 7.00 (m, 2 H), 6.02 (d, J = 7.8 Hz, 1 H, H-1β), 5.69
(d, J = 2.4 Hz, 1 H), 5.30−5.27 (m, 4 H), 5.15 (d, J = 2.4 Hz, 1 H),
5.06 (d, J = 3.0 Hz, 1 H), 4.95−4.93 (m, 2 H), 4.70 (d, J = 10.2 Hz, 1
H), 4.62 (d, J = 11.4 Hz, 1 H), 4.57 (d, J = 10.8 Hz, 1 H), 4.41 (d, J =
12.6 Hz, 1 H), 4.37−4.32 (m, 3 H), 4.19−4.08 (m, 7 H), 4.05 (q, J =
6.6 Hz, 1 H), 3.98 (dd, J = 3.6, 10.2 Hz, 1 H), 3.95 (dd, J = 3.6, 10.2
Hz, 1 H), 3.76 (dd, J = 3.6, 10.2 Hz, 1 H), 3.68 (d, J = 15.6 Hz, 1 H),
3.57 (d, J = 15.6 Hz, 1 H), 2.52 (t, J = 7.2 Hz, 2 H), 1.67−1.62 (m, 2
H), 1.52−1.46 (m, 2 H), 1.30 (d, J = 6.6 Hz, 3 H), 0.94 (t, J = 7.2 Hz,
3 H), 0.87−0.85 (m, 6 H), 0.55 (d, J = 6.0 Hz, 3 H); 13C{1H} NMR
(150 MHz, CDCl3) δ 166.7, 166.6, 166.4, 166.3, 164.2, 138.2, 137.9,
137.8, 137.7, 134.9, 133.5, 133.4, 133.3, 133.1, 132.4, 130.8, 130.5,
130.2, 130.1, 130.0, 129.9, 129.8, 129.7, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2, 127.8, 127.7, 127.6, 127.5, 127.3, 125.8, 97.3, 95.0, 93.8,
92.8, 92.5, 79.4, 76.0, 74.4, 74.2, 73.0, 72.9, 72.6, 72.4, 72.2, 72.0,
70.9, 70.5, 70.4, 69.9, 69.7, 69.0, 65.5, 64.8, 64.3, 40.7, 30.9, 22.3,
19.8, 16.6, 16.3, 16.1, 15.6, 13.9; HRMS (ESI) m/z: [M + Na]+ calcd
for C95H95O23ClNa 1661.5850; Found 1661.5857.
25
1
25
1
A mixture of 17 (106 mg, 0.065 mmol), 6-azido hexyl linker 18 (14
mg, 0.098 mmol), and freshly activated 4 Å MS (195 mg) in
anhydrous CH2Cl2 (2.0 mL) was stirred at room temperature for 0.5
h. NIS (22 mg, 0.098 mmol) and a freshly prepared solution of
TMSOTf in anhydrous CH2Cl2 (0.13 mL, 0.1 M) were added at 0 °C
under argon, and the mixture was stirred for an additional 2 h at room
temperature. The mixture was quenched with Et3N and filtered
through Celite. The filtrate was concentrated in vacuo. The residue
was purified by silica gel column chromatography (petroleum ether/
A mixture of 15 (48 mg, 0.05 mmol), 14 (32 mg, 0.04 mmol) and
freshly activated 4 Å MS (120 mg) in anhydrous CH2Cl2 (1.2 mL)
was stirred at room temperature for 0.5 h. NIS (135 mg, 0.06 mmol)
and a freshly prepared solution of TMSOTf in anhydrous CH2Cl2 (80
μL, 0.1 M) were added at 0 °C under argon, and the mixture was
stirred for an additional 2 h at room temperature. The mixture was
quenched with Et3N and filtered through Celite. The filtrate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc: 100/0 → 5/1) to give 16
(56 mg, 90%) as a white foam. Rf: 0.48 (petroleum ether/EtOAc = 3/
EtOAc: 100/0 → 7/1) to give 19 (97 mg, 94%, α/β = 4.1:1) as a
25
yellow syrup. Rf: 0.44 (toluene/EtOAc = 30/1 (v/v)). 19α: [α]D
=
−118.1 (c 0.33, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J =
7.2 Hz, 2 H), 7.96 (d, J = 7.2 Hz, 2 H), 7.87 (t, J = 7.2 Hz, 4 H),
7.61−7.11 (m, 28 H), 7.06−6.99 (m, 4 H), 5.67 (d, J = 2.8 Hz, 1 H),
5.47 (d, J = 2.0 Hz, 1 H), 5.31−5.26 (m, 3 H), 5.15 (d, J = 2.4 Hz, 1
H), 5.08 (d, J = 3.2 Hz, 1 H), 4.95 (d, J = 2.8 Hz, 1 H), 4.89 (d, J =
3.6 Hz, 1 H), 4.79 (d-like, J = 12.0 Hz, 1 H), 4.74 (d-like, J = 11.6 Hz,
1 H), 4.61 (d, J = 11.2 Hz, 1 H), 4.56 (d, J = 10.8 Hz, 1 H), 4.43−
4.33 (m, 6 H), 4.19−4.09 (m, 5 H), 4.02 (td, J = 3.2, 11.2 Hz, 2 H),
3.93 (dd, J = 3.2, 10.0 Hz, 1 H), 3.76 (dd, J = 3.2, 10.4 Hz, 1 H),
3.73−3.67 (m, 2 H), 3.58 (d-like, J = 15.2 Hz, 1 H), 3.53−3.47 (m, 1
H), 3.26 (t, J = 6.8 Hz, 2 H), 1.68 (m, 3 H), 1.43 (m, 5 H), 1.16 (d, J
= 6.4 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H), 0.75 (d, J = 6.4 Hz, 3 H),
0.57 (d, J = 6.4 Hz, 3 H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.7,
166.5, 166.4, 166.3, 138.3, 138.2, 138.1, 137.9, 133.4, 133.3, 133.1,
130.2, 130.1, 130.0, 129.9, 129.8, 129.7, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 97.8, 93.5, 92.8, 92.7,
74.4, 74.2, 73.4, 73.3, 72.8, 72.7, 72.6, 72.4, 72.2, 72.0, 71.0, 70.7,
70.4, 70.3, 70.2, 69.7, 68.4, 65.5, 65.3, 64.9, 64.3, 51.5, 40.7, 29.6,
29.0, 26.7, 26.0, 16.5, 16.4, 16.1, 15.6; HRMS (ESI) m/z: [M + Na]+
calcd for C88H94O22N3ClNa 1602.5915; Found 1602.5924.
25
1
1(v/v)). [α]D = −131.9 (c 0.50, CHCl3); H NMR (400 MHz,
CDCl3) δ 8.07 (d, J = 8.0 Hz, 2 H), 7.97 (d, J = 8.0 Hz, 2 H), 7.88 (t-
like, J = 6.4 Hz, 4 H), 7.63−7.31 (m, 18 H), 7.24−7.01 (m, 16 H),
6.86 (d, J = 8.8 Hz, 2 H), 5.74 (d, J = 2.4 Hz, 1 H), 5.50 (m, 2 H),
5.35−5.28 (m, 3 H), 5.17 (d, J = 2.4 Hz, 1 H), 5.10 (d, J = 3.2 Hz, 1
H), 4.97 (d, J = 2.8 Hz, 1 H), 4.79 (s, 2 H), 4.66−4.57 (m, 3 H),
4.44−4.30 (m, 6 H), 4.21−4.15 (m, 5 H), 4.04 (dd, J = 3.2, 10.4 Hz,
1 H), 3.95 (dd, J = 3.2, 10.0 Hz, 1 H), 3.80−3.76 (m, 4 H), 3.70 (d, J
= 14.8 Hz, 1 H), 3.58 (d, J = 15.2 Hz, 1 H), 1.17 (d, J = 6.4 Hz, 3 H),
1.06 (d, J = 6.4 Hz, 3 H), 0.79 (d, J = 6.4 Hz, 3 H), 0.59 (d, J = 6.4
Hz, 3 H); 13C{1H} NMR (150 MHz, CDCl3) δ 166.7, 166.5, 166.4,
166.3, 155.3, 151.3, 138.2, 138.1, 138.0, 137.9, 133.4, 133.3, 133.2,
133.1, 130.1, 130.0, 129.9, 129.8, 129.7, 128.7, 128.6, 128.5, 128.4,
128.3, 128.2, 127.8, 127.7, 127.6, 127.4, 118.3, 114.8, 97.4, 93.8, 92.8,
74.3, 74.2, 73.4, 73.3, 72.9, 72.6, 72.4, 72.2, 72.1, 71.0, 70.7, 70.4,
70.3, 70.2, 69.7, 66.1, 65.6, 64.9, 64.3, 55.8, 40.7, 16.5, 16.4, 16.1,
15.6; HRMS (ESI) m/z: [M + Na]+ calcd for C89H89O23ClNa
1583.5381; Found 1583.5406.
To a solution of tetrasaccharide 16 (148 mg, 0.095 mmol) in
toluene/CH3CN/H2O (0.48 mL/0.72 mL/0.48 mL) was added CAN
(156 mg, 0.285 mmol). After stirring at room temperature for 30 min,
the solution was poured into ice water and extracted with CH2Cl2.
The organic layer was washed with saturated aqueous NaHCO3 and
brine and dried over Na2SO4. Filtration, concentration in vacuo, and
Isolation of 4-Iodoisocoumarin Derivative (20). A mixture of
1a (94 mg, 0.12 mmol), alcohol 2h (26 mg, 0.10 mmol), and freshly
activated 4 Å MS (300 mg) in anhydrous CH2Cl2 (3.0 mL) was
stirred at room temperature for 0.5 h. NIS (34 mg, 0.15 mmol) and a
freshly prepared solution of TMSOTf in CH2Cl2 (0.2 mL, 0.1 M)
were added at 0 °C under argon, and the mixture was stirred for an
4775
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J. Org. Chem. 2021, 86, 4763−4778

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additional 2 h at room temperature. The mixture was quenched with
Et3N and filtered through Celite. The filtrate was concentrated in
vacuo. The residue was purified by silica gel column chromatography
(petroleum ether/EtOAc: 100/0 → 6/1) to give 3h (82 mg, 98%) as
a white solid and 20 (38 mg, 97%, known compound32) as a pale
yellow oil.
20. Rf: 0.86 (petroleum ether/EtOAc = 3/1 (v/v)). Spectroscopic
data were in accordance with those previously reported.32 1H NMR
(400 MHz, CDCl3) δ 8.24−8.22 (m, 1 H), 7.78−7.72 (m, 2 H),
7.52−7.48 (m, 1 H), 2.93 (t, J = 8.0 Hz, 2 H), 1.77−1.69 (m, 2 H),
1.49−1.39 (m, 2 H), 0.97 (t, J = 7.2 Hz, 3 H); 13C{1H} NMR (150
MHz, CDCl3) δ 162.1, 158.3, 138.2, 135.8, 130.6, 129.8, 128.7, 120.1,
76.3, 37.3, 29.5, 22.4, 14.0; HRMS (ESI) m/z: [M + H]+ calcd for
C13H14O2INa 329.0038; Found 329.0041.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00151.
■
sı
Copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
You Yang − Shanghai Key Laboratory of New Drug Design,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China; orcid.org/0000-
0003-4438-2162; Email: yangyou@ecust.edu.cn
■
Authors
Rongkun Liu − Shanghai Key Laboratory of New Drug
Design, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, China
Qingting Hua − Shanghai Key Laboratory of New Drug
Design, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, China
Qixin Lou − Shanghai Key Laboratory of New Drug Design,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Jiazhe Wang − Shanghai Key Laboratory of New Drug Design,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Xiaona Li − Shanghai Key Laboratory of New Drug Design,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Zhi Ma − Shanghai Key Laboratory of New Drug Design,
School of Pharmacy, East China University of Science and
Technology, Shanghai 200237, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00151
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (21871081 and 22071054) and the
Fundamental Research Funds for the Central Universities
(50321031916002 and 22221818014) is gratefully acknowl-
edged.
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