Tris(pentafluorophenyl)borane-Catalyzed Stereoselective C-Glycosylation of Indoles with Glycosyl Trichloroacetimidates: Access to 3-Indolyl-C-glycosides

Article abstract of DOI:10.1021/acs.joc.1c00698

An efficient and highly regioselective method for the synthesis of 3-indolyl-C-glycosides has been developed through coupling of glycosyl trichloroacetimidates with a wide range of substituted indoles in the presence of catalytic amounts of B(C6F5)3 within a few minutes. This methodology has a wide scope of substrates under mild reaction conditions and provides exclusively β-stereoselective 3-indolyl-C-glycosides in 64-87% yields.

Full text of DOI:10.1021/acs.joc.1c00698

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Note
Tris(pentafluorophenyl)borane-Catalyzed Stereoselective
C‑Glycosylation of Indoles with Glycosyl Trichloroacetimidates:
Access to 3‑Indolyl‑C‑glycosides
Atul Dubey, Ashwani Tiwari, and Pintu Kumar Mandal*
Cite This: J. Org. Chem. 2021, 86, 8516−8526
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ABSTRACT: An efficient and highly regioselective method for
the synthesis of 3-indolyl-C-glycosides has been developed through
coupling of glycosyl trichloroacetimidates with a wide range of
substituted indoles in the presence of catalytic amounts of
B(C6F5)3 within a few minutes. This methodology has a wide
scope of substrates under mild reaction conditions and provides
exclusively β-stereoselective 3-indolyl-C-glycosides in 64−87%
yields.
ryl-C-glycosides are unique structural motifs, signify a
1
Ametabolically stable class of saccharides or glycoconju-
gates that extensively arise in biologically relevant natural
products and pharmaceutical agents.2 Conjugation of five-
membered nitrogen heterocycles such as indoles to the
anomeric carbon of sugars, directly connected through a C−
C bond, produces indole-C-glycosides, an important heteroaryl
subclass of C-glycoside. Indeed, indole-C-glycosides with
framework analogues of the natural N-nucleosides3 have
been the focus of much synthetic as well as biological research
owing to the frequent incidence of these structural skeletons in
biologically significant proteins4 and antiviral activities.5 These
particular indole-C-glycosides have distinct motifs, either of
natural or synthetic origin, embedded in various biological
activities (Figure 1).6
Notably, α-C-mannosyltryptophan, as the first naturally
occurring C-glycosyl amino acid, was discovered from the
Trp7 of ribonuclease II.4a In addition, it has been gradually
recognized as a well-known post-translational modification
(PTM) of proteins, observed in the thrombospondin type-1
repeat (TSR) superfamily, type I cytokine receptor family, and
many others.7 It is worth mentioning that recently synthetic 3-
indolyl-C-glycosides have also been approved as sodium-
dependent glucose cotransporter 2 (SGLT2) inhibitors8 for
the treatment of type-2 diabetes.
In this context, different synthetic methods have been
established to construct these valuable scaffolds. The first most
common approach involves the formation of a C-glycosides
through sequential addition of a carbanion to gluconolac-
tone5d,9 or 1,2-anhydro sugars10 followed by reductive
deoxygenation and C-glycosylation of indole derivatives with
Figure 1. Some examples of bioactive molecules containing indole-C-
glycosides.
Received: March 24, 2021
Published: May 31, 2021
https://doi.org/10.1021/acs.joc.1c00698
© 2021 American Chemical Society
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various glycosyl donors11 using either the heteroaryl
compounds in the presence of Lewis acids or the metalated
heteroaryl compounds (Scheme 1a).
However, these traditional methods suffer from unsatis-
factory yields, harsh reaction conditions, or low regio- as well
as stereoselectivities. The other approach includes the
generation of a nitrogen-containing heterocyclic ring,12 which
allows the reaction of the sugar one carbon unit with the
corresponding benzene derivatives. In this regard, a sequential
heterocyclization and C-glycosylation sequence of o-alkynylani-
lines with 1-iodoglycals was developed to construct 3-indolyl-
C-glycosides (Scheme 1b).12a Moreover, recently, the for-
mation of indoles glycosides via ortho-directed C−H
glycosylation promoted by palladium catalyst using glycosyl
chloride as a donor was developed by Chen and co-workers
(Scheme 1c).13
Scheme 1. Representative Methods for the Synthesis of
Aryl-C-glycosides and Indole-C-glycosides
Despite these advances, some of these syntheses are
equivocal, as they are performed under a strident environment
and often require a multistep reaction sequence with auxiliary
and delicate operation conditions. Although significant
progress has been made over the past few decades, only one
report on the effective synthesis of stereoselective 3-indolyl-C-
glycosides has been reported until date.13a Thus, the study of
direct and adequate stereoselective protocols for 3-indolyl-C-
glycosides is still highly desirable. Keeping these impediments
in mind, we have investigated the efficient strategy for directly
forming a C-glycosidic linkage (direct C-glycosylation) via
Friedel−Crafts-type glycosylation, like a standard O-glycosyla-
tion.
Tris(pentafluorophenyl)borane (B(C6F5)3 or BCF) catalyst
possess relatively less Lewis acidity which may be the reason
for optimal temperature for the activation of Schmidt’s
trichloroacetimidates donors.14 In spite of a few reported
applications of B(C6F5)3 in carbohydrate synthesis,15 its
function in C-glycosylation reactions for the generation of
biologically appealing 3-glycosyl indoles has not yet been
reported. In addition, the electron-withdrawing nature as well
as the steric bulkiness of the three C6F5 groups present around
the boron also encouraged us to examine the activation of most
used Schmidt’s glycosyl donors for stereoselective C-glyco-
sylation with BCF. Based on this concept, we report our results
for the synthesis of 3-indolyl-C-glycosides by B(C6F5)3-
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
D/A
catalyst (mol %)
solvent
temp (°C)
time
yield (%)
α/β
d
1
1.2/1
2.0/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
1.2/1
BCF(10)
BCF (10)
BCF (10)
BCF (20)
BCF (10)
BCF (10)
BCF (10)
BCF (10)
BCF(10)
BCF (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
25
25
25
0
−10
−20
−30
−10
−10
15 min
45 min
15 min
45 min
15 min
15 min
3 h
6 h
3h
3h
42
44
62
64
75
82
66
42
20
β only
β only
β only
β only
β only
β only
β only
β only
ND
e
2
3
4
5
6
7
8
9
10
CH3CN
<10
ND
a
b
c
The reaction was conducted with 1a (1.2 equiv), 2a (1.0 equiv), B(C6F5)3 (10 mol %), solvent (4 mL). Isolated yield. α/β ratio was measured
d
e
1
using H NMR. Molecular sieves were added. Decomposition of the donor was observed.
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a
Scheme 2. B(C6F5)3-Catalyzed Direct 3-C-Indole Glycosylation with Donor 1a
a
b
c
1
Reaction conditions: 1a (1.2 equiv), 2 (1.0 equiv), B(C6F5)3 (10 mol %), solvent (4 mL). Isolated yield. α/β ratio measured using H NMR.
catalyzed with readily accessible glycosyl imidate donors
(Scheme 1d).
suggesting the dichloromethane was the most suitable solvent
for this C-glycosylation.
Our investigation began with the optimization of the
reaction conditions with perbenzylated glucose α-imidate
(1a)16 and 2-methylindole (2a) as the model substrates in
dichloromethane (Table 1).
Before evaluating the generality of this new methodology,
the standard conditions were applied to the glycosylation of 1a
with 2 unsubstituted 5-(benzyloxy)-1H-indole and resulted in
the desired product 3c in 77% yield with good selectivity
(Scheme 2).
Upon glycosylation of glycosyl donor 1a with glycosyl
acceptor 2a in 1.2:1 molar ratio in the presence of 10 mol % of
B(C6F5)3 and a pinch of molecular sieves (4 Å) at room
temperature (∼25 °C), the desired C-glycoside 3a was isolated
in 42% yield within 10 min with exclusively β-selectivity (Table
1, entry 1). However, we have not observed any α-product.
The exact structure of 3a and stereochemistry at the new
stereogenic center was unequivocally established by spectro-
scopic analysis (for details, see the Supporting Information). In
This suggests that the optimum conditions would be applied
to the C-glycosylation of the unsubstituted indole substrates
also. We then evaluated the synthesis of 3-indolyl-C-glycosides
with various substituted indoles at different positions using
perbenzylated glucose α-imidate (1a). However, examination
of the obtained results in Scheme 2 showed a favorable trend
of C2-substituted indoles producing a slightly higher yield.
Unlike C2-unsubstituted indole, this gave a poor yield possible
due to the formation of minor C-2 glycosylated product.
Notably, the tested substrates bearing either electron-donating
groups (Me, OMe, 3d, 3e) or an electron-withdrawing group
(CO2Me, 3f) at the 5-position of the indole ring were well
tolerated. However, electron-donating groups (Me, OMe) at
the 5-position of indole enhanced the yield to some extent. It
appears that the electronic effect of the substituents exerted
influences on the yield. In comparison with indoles containing
an electron-withdrawing group such as CO2Me, indoles with
an electron-donating group such as Me and OMe exhibited
higher reactivity. Besides, there was no evidence for N-
glycosylated isomer formation in any case. Further, N-
methylindole systems were also evaluated, and these also
provided good yields of the corresponding 3-indolyl-C-
glycosides (3g−3i). Obviously, C-glycosylated indoles are
particularly prone to this reaction with β-selectivity. In
addition, all of the obtained results indicated that BCF may
undergo an intramolecular acid−base-type reaction. However,
after fast adduct formation with indole this adduct reacted in
stereoselective manner with the donor to afford preferentially
β-stereoselective glycoside.
1
the H NMR spectra, the indole 3-H signals were absent and
the signal of the anomeric proton (at δ 4.54) with the J1,2
values (9.3 Hz) established the β-anomeric configuration.
When the reaction was carried out changing the ratio with
donor 1a and acceptor 2a from a 1.2:1 to 2:1 molar ratio, no
improvement of yield was observed even after a long time
(entry 2). However, when the glycosylation was carried out in
the absence of molecular sieves, surprisingly the reaction also
proceeded efficiently to give the desired C-glycosides 3a in
62% yield within 15 min with exclusively β-selectivity (Table 1,
entry 3). In fact, similar observations were previously reported
in the case of B(C6F5)3-catalyzed glycosylation.14,17 To further
increase the yield, we have screened the higher concentration
of 20 mol % of B(C6F5)3. However, there was no significant
change observed in the product yield even after a longer time
(entry 4). Thereafter, we performed the glycosylation reaction
at different temperatures without using molecular sieves. As a
result, the desired glycoside 3a was obtained in 75% yield with
β-selectivity at 0 °C (Table 1, entry 5). However, the
glycosylation reaction at −10, −20, and −30 °C showed that
the reaction progressed easily at −10 °C to furnish the highest
yield 3a in 82% with exclusively β-selectivity (Table 1, entries
6−8). Moving forward, we performed the reaction in other
solvents also, such as acetonitrile and THF at −10 °C (Table
1, entries 9 and 10), but obtained lower yield in both cases,
To further explore the effect of different commonly used
glycosyl imidate donors (1b−k), such reactions were
investigated (Scheme 3).
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Scheme 3. Substrate Scope for Various Glycosyl Imidates and Substituted Indolesa
a
b
c
1
Reaction conditions: 1 (1.2 equiv), 2 (1.0 equiv), B(C6F5)3 (10 mol %), solvent (4 mL). Isolated yield. α:β ratio measured using H NMR.
Initially, the glycosylation was tested with perbenzylated
were produced in good yield. Furthermore, when peracetylated
glycosyl imidates 1c and 1d were applied for C-glycosylation
with various indoles derivatives, the corresponding products
3p, 3q, 3r, and 3s were furnished in moderate to good yields.
In addition, C-glycosylation was also investigated with the
acetyl and benzyl group containing-6-deoxy donors, such as L-
arabonopyranose α-imidate (1f, 1g) donors. In general, all of
galactose α-imidate (1b) with various substituted indoles.
Delightfully, the reaction proceeded smoothly and gave the 3-
indole C-glycosides 3j−3m in 81−87% yield with exclusive β
selectivity. Similarly, the glycosylation was again tested with
more complex perbenzylated disaccharide α-imidate (1e); as a
result, the corresponding desired indole C-glycosides 3n−3o
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the reactions proceeded smoothly to provide the desired
products 3t−3v in 64−68% yield, but with lower stereo-
selectivity (α:β = 1:4−1:7) probably due to their high
reactivity by the lack of substitution of carbohydrate ring and
conformation.18 On the other hand, the peracetylated
rhamnosyl imidate 1h gave α-selective glycoside 3w in 74%
yield. Moreover, the reaction between picoloyl-protected
rhamnosyl trichloroacetimidate 1i with substituted indoles
proceeded in good yield with α-selective product (Scheme 3).
Encouraged by these results, we decided to further expand the
scope of this methodology by performing the reaction using
glycofuranosyl imidates (1j, 1k) as a donor. Glycosylation of
perbenzylated ribofuranosyl imidate 1j with 2-methylindole
(2a) proceeded smoothly to give indole C-glycosides 3y in
good yields (85%) with good selectivity. Similarly, when the
isopropylidene protected mannofuranosyl imidate 1k was
subjected to establish reaction conditions with different
substituted indoles to give their corresponding C-glycosides
3z and 3aa in 68% and 71% yields, respectively, with moderate
selectivity (Scheme 3).
Scheme 4. Plausible Mechanism
However, the exact mechanism is still uncertain. On the
basis of the above discussion and previous literature
reports,14,19 we speculate that instead of an SN1 mechanism
the reaction might progress via an SN2 or acid−base
mechanism. In this regard, we performed the 1H NMR
experiment with 2-methylindole (acceptor) both in the
presence as well as the absence of the promoter BCF (1.0
equiv) at room temperature in CDCl3. We noticed that there
are some interaction of the peaks 3-H to the indole in the
presence of BCF, thus demonstrating the formation of the
acceptor-activator adduct (Figure S1). In addition, the glycosyl
imidate donor 1a did not go through disintegration at −10 °C
in the presence of 10 mol % of BCF. Only by raising the
temperature did slow decomposition of 1a take place. In
previous reports, similar observations of glycosyl acceptor
activation with boron-based catalysts such as BCF,14 PhBF2,19a
and other acid−base catalyst gold chlorides were described.19b
Derived from the experimental data and the literature reports,
mm E. Merck silica gel plates (60F-254) using UV light as the
visualizing agent also by warming ceric sulfate [2% Ce(SO4)2 in 5%
H2SO4 in EtOH]-sprayed plates on a hot plate. Silica gel 230−400
1
mesh was used for column chromatography. H NMR spectra were
recorded in CDCl3 on a Bruker AV 400 (400 MHz) spectrometer.
13C{1H} NMR spectra were recorded in CDCl3 on a Bruker 400 (100
MHz) and Bruker 300 (75 MHz) spectrometer. Chemical shifts are
reported relative to CDCl3 (δ 7.26 ppm) for 1H NMR and CDCl3 (δ
77.0 ppm) for 13C{1H} NMR. Coupling constants are given in hertz.
Structural assignments were made with additional information from
gCOSY, gHSQC, and DEPT-135 experiments. High-resolution mass
spectra (HRMS) were recorded as ESI-HRMS on Q-TOF mass
spectrometer. Either protonated molecular ions [M + H]+, sodium
adducts [M + Na]+, or ammonium adducts [M + NH4]+ were used
for empirical formula confirmation. Commercially available grades of
organic solvents are used for column chromatography for
purifications. The known compounds 1a,16 1b,20a 1c,20b 1d,20b
1e,20c 1f,20d 1g,20e 1h,20f 1j,20g and 1k20h showed characterization
data in full agreement with previously reported data.
Experimental Procedures. 3-O-Benzyl-4-O-benzoyl-2-O-(2-pyri-
dinecarbonyl)-α-L-rhamnopyranoside Trichloroacetimidate (1i). N-
Bromosuccinimide (737 mg, 4.1 mmol) was added at 0 °C to a
solution of ethyl 3-O-benzyl-4-O-benzoyl-2-O-(2-pyridinecarbonyl)-1-
thio-α-L-rhamnopyranoside (1.0 g, 1.9 mmol) in acetone (9 mL) and
water (1 mL), and the mixture was stirred for 30 min. The reaction
was quenched by addition of saturated aqueous sodium bicarbonate.
The organic solvent was removed in vacuo, and the remaining
aqueous solution was extracted with ethyl acetate. After being dried
over anhydrous sodium sulfate, the extract was concentrated, and then
the residue was dissolved in dry dichloromethane (10 mL) and cooled
to 0 °C. Trichloroacetonitrile (0.24 mL, 2.4 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 0.9 mmol) were added.
The reaction mixture was stirred for 2 h. The solvent was evaporated,
and the residue was purified over SiO2 using hexane−EtOAc (9:1) as
eluent to give pure compound 1i as colorless oil (0.52 g, 85% yield).
IR (neat): 3794, 3344, 3017, 2920, 1727, 1672, 1456, 1216, 1164,
765, 669 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.84−8.83 (m, 1 H),
8.76 (s, 1 H), 8.21 (d, J = 7.9 Hz, 1 H), 7.99−7.98 (m, 2 H), 7.92−
7.88 (m, 1 H), 7.63−7.59 (m, 1 H), 7.53−7.50 (m, 1 H), 7.49−7.45
(m, 2 H), 7.18−7.08 (m, 5 H), 6.43 (d, J = 1.6 Hz, 1 H), 5.88−5.87
(m, 1 H), 5.53(t, J = 9.9 Hz, 1 H), 4.67 (d, J = 12.5 Hz, 1 H), 4.52 (d,
J = 12.5 Hz, 1 H), 4.18−4.12 (m, 2 H), 1.33 (d, J = 6.3 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 165.8, 163.8, 159.9, 150.5,
2
we anticipated that in place of performing a simple SN -type
mechanism the BCF may undergo an acid−base-type reaction.
Incipiently, the nucleophilic acceptor undergoes complex
formation with the catalyst, which promotes the perbenzylated
α-glucosyl imidate donor to furnish β-selective glycosides, as
shown in Scheme 4.
In summary, we have successfully developed the application
of tris(pentafluorophenyl)borane as a productive catalyst for
stereoselective C-glycosylation reactions involving trichloroa-
cetimidate glycosyl donors with indoles. The reaction
progresses cleanly in good to excellent yields without the
need of molecular sieves and also does not require extremely
low temperatures. Furthermore, the conditions are practical
and mild, have broad substrate scope, and can be scaled up.
Based on these outcomes, we hope that this method will
acquire widespread applications in the formation of other
heterocycle substrates for biological activities.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out under an argon
atmosphere with dry solvents under anhydrous conditions in oven-
dried round-bottom flasks unless otherwise noted. Reagents were
purchased at the highest commercial quality available and used
without further purification unless otherwise stated. Reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25
147.4, 137.4, 137.1, 133.5, 130.1, 129.7, 128.6, 128.5, 128.1, 127.4,
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125.9, 95.1, 73.5, 72.4, 71.6, 69.9, 68.4, 7.9. HRMS (ESI) m/z: [M +
Na]+ Calcd for C28H25Cl3N2NaO7 629.0620; Found 629.0615.
General Glycosylation Procedures for the Prepration of 3-
Indolyl-C-glycosides (3a−3z, 3aa). To a stirred solution of
trichloroacetimidate glycosyl donor 1 (1.2 mmol) in freshly dried
DCM (4 mL) was added substituted indole (1.0 mmol) acceptor. The
reaction mixture was cooled to −10 °C and allowed to stir for 5 min,
to which the activator B(C6F5)3 or BCF (0.12 mmol with respect to
donor) was added. The reaction was stirred further for 15−20 min at
the same temperature, quenched by the addition of triethylamine (0.1
mL), and diluted with 20 mL of DCM. The organic layer was washed
with NaHCO3 (aq) and dried over Na2SO4. Further, the organic layer
was filtered, concentrated, and subjected to column chromatography
purification (hexane/ethyl acetate) using silica gel (SiO2: 100−200)
to afford the corresponding C-glycosides (3a−3z, 3aa).
75.2, 74.6, 73.5, 70.7, 6934. HRMS (ESI) m/z: [M + NH4]+ Calcd for
C49H51N2O6 763.3742; Found 763.3742.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-5-methyl-1H-in-
dole (3d). Synthesized according to the general procedure on a 1
mmol scale to afford 3d (490 mg, yield 75%, β only); eluent, hexane−
EtOAc (6:1). Colorless jelly. IR (neat): 3455, 3017, 2945, 1765, 1601,
1456,, 1064, 765, 655 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.05 (s,
1 H), 7.60 (s, 1 H), 7.36−7.26 (m, 16 H), 7.16−7.12 (m, 4 H), 7.01
(d, J = 8.1 Hz, 1 H), 6.84−6.82 (m, 2 H), 4.98−4.88 (m, 3 H), 4.69
(t, J = 10.8 Hz, 2 H), 4.54−4.51 (m,, 2 H), 4.32 (d, J = 10.4 Hz, 1 H),
3.96−3.86 (m, 3 H), 3.84−3.79 (m, 2 H), 3.78−3.75 (m, 1 H), 3.65−
3.62 (m, 1 H), 2.37 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ
138.7, 138.5, 138.4, 137.9, 134.9, 129.1, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 127.6, 127.5, 127.4, 126.3, 124.1, 123.4, 120.3,
120.2, 113.7, 110.9, 86.7, 82.8, 79.3, 78.5, 76.6, 75.7, 75.2, 74.6, 73.4,
69.2, 21.4. HRMS (ESI) m/z: [M + NH4]+ Calcd for C43H47N2O5
671.3479; Found 671.3478.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-5-methoxy-1H-in-
dole (3e). Synthesized according to the general procedure on a 1
mmol scale to afford 3e (495 mg, yield 74%, β only); eluent, hexane−
EtOAc (6:1). Colorless jelly. IR (neat): 3455, 3017, 2945, 1765, 1601,
1490, 1064, 765, 665 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1
H), 7.32−7.23 (m, 19 H), 7.20−7.14 (m, 3 H), 6.86- 6.83 (m, 2 H),
4.98−4.89 (m, 3 H), 4.73−4.62 (m, 2 H), 4.54−4.49 (m, 2 H), 4.35
(d, J = 10.4 Hz, 1 H), 3.95 (t, J = 8.7 Hz, 1 H), 3.88−3.37 (m, 5 H),
3.64 (s, 3 H), 3.62−3.59 (m, 1 H). 13C{1H} NMR (100 MHz,
CDCl3): δ154.1, 138.7, 138.4, 138.0, 131.7, 128.5, 128.3, 128.1, 128.0,
127.9, 127.8, 127.7, 127.6, 127.5, 126.6, 123.9, 113.9, 112.9, 112.1,
102.1, 91.3, 86.8, 82.6, 79.2, 78.4, 77.3, 76.6, 75.8, 75.2, 74.7, 73.4,
69.2, 55.7. HRMS (ESI) m/z: [M + NH4]+ Calcd for C43H47N2O6
687.3429; Found 687.3426.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-2-methyl-1H-in-
dole (3a). Glycosyl trichloroacetimidate donor 1a (820 mg, 1.2
mmol) and 2-methylindole (2a, 131.07 mg, 1.0 mmol) were dissolved
in freshly dried DCM (4 mL). The reaction mixture was cooled to
−10 °C and allowed to stir for 5 min, to which the activator B(C6F5)3
or BCF (61.4 mg, 0.12 mmol with respect to donor) was added. The
reaction was stirred further for 15 min at the same temperature,
quenched by the addition of triethylamine (0.1 mL), and diluted with
20 mL of DCM. The organic layer was washed with with NaHCO3
(aq), dried (Na2SO4), and concentrated. The crude product was
purified over SiO2 using hexane−EtOAc (7:1) as eluent to give pure
compound 3a (535 mg, yield 82%, β only). Colorless jelly. IR (neat):
1
3466, 3017, 2920, 1727, 1601, 1456, 1216, 1064, 765, 669 cm−1. H
NMR (400 MHz, CDCl3): δ 7.83 (s, 1 H), 7.77 (d, J = 7.9 Hz, 1 H),
7.35−7.23 (m, 16 H), 7.14−7.09 (m, 4 H), 7.05−7.01 (m, 1 H),
6.84−6.82 (m, 2 H), 4.96 (d, J = 11.0 Hz, 1 H), 4.91(dd, J = 10.8 Hz,
2 H), 4.71 (d, J = 10.8 Hz, 1 H), 4.66 (d, J = 12.3 Hz, 1 H), 4.55−
4.52 (m, 2 H), 4.30 (d, J = 10.6 Hz, 1 H), 3.97−3.91 (m, 2 H), 3.87
(dd, J = 3.6, 10.8 Hz, 1 H), 3.84−3.77 (m, 2 H), 3.74 (d, J = 10.5 Hz,
1 H), 3.65−3.61 (m, 1 H), 2.36 (s, 3 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 138.9, 138.6, 138.5, 138.2, 135.5, 133.1, 128.5, 128.4,
128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 121.3,
120.1, 119.7, 110.3, 109.7, 86.8, 82.5, 79.3, 78.5, 75.7, 75.2, 74.6, 73.4,
69.3, 12.3. HRMS (ESI) m/z: [M + H]+ Calcd for C43H44NO5
654.3214; Found 654.3217.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-5-methylcarboxy-
late-1H-indole (3f). Synthesized according to the general procedure
on a 1 mmol scale to afford 3f (495 mg, yield 71%, β only); eluent,
hexane−EtOAc (8:1). Colorless jelly. IR (neat): 3466, 3017, 2986,
1750, 1601, 1456, 1255, 1064, 765, 635 cm−1; 1H NMR (400 MHz,
CDCl3): δ 8.58 (s, 1 H), 8.52 (s, 1 H), 7.88 (dd, J = 1.6, 8.7 Hz, 1 H),
7.32−7.31 (m, 10 H), 7.25−7.20 (m, 6 H), 7.11−7.04 (m, 4 H), 6.78
(dd, J = 1.3, 7.6 Hz, 2 H), 4.93 (m, 3 H), 4.66 (dd, J = 10.7 Hz, 2 H),
4.54 (dd, J = 12.6 Hz, 2 H), 4.35 (d, J = 10.6 Hz, 1 H), 3.91−3.85 (m,
2 H), 3.84 (s, 3 H), 3.83−3.76 (m, 3 H), 3.69−3.65 (m, 1 H).
13C{1H} NMR (100 MHz, CDCl3): δ 168.1, 139.1, 138.6, 138.3,
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-2-phenyl-1H-in-
dole (3b). Synthesized according to the general procedure on a 1
mmol scale to afford 3b (586 mg, yield 82%, β only); eluent, hexane−
EtOAc (8:1). Colorless jelly. IR (neat): 3455, 3017, 2945, 1750, 1612,
138.2, 137.8, 128.5, 128.4, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6,
127.5, 127.4, 125.7, 124.8, 123.7, 123.2, 121.9, 115.4, 111.2, 86.9,
82.9, 79.4, 78.6, 76.1, 75.8, 75.2, 74.7, 73.5, 69.4, 51.8. HRMS (ESI)
m/z: [M + NH4]+ Calcd for C44H47N2O7 715.3378; Found 715.3378.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-1,2-dimethylin-
dole (3g). Synthesized according to the general procedure on a 1
mmol scale to afford 3g (554 mg, yield 83%, β only); eluent, hexane−
EtOAc (9:1). Brown oil. IR (neat): 3466, 3017, 2920, 1727, 1601,
1456, 1216, 1064, 765, 732, 669 cm−1; 1H NMR (400 MHz, CDCl3):
δ 7.79 (d, J = 7.9 Hz, 1 H), 7.35−7.22 (m, 16 H), 7.18−7.08 (m, 4
H), 7.05−7.01 (m, 1 H), 6.76−6.75 (m, 2 H), 4.96 (d, J = 10.9 Hz, 1
H), 4.91(dd, J = 8.3, 10.8 Hz, 2 H), 4.72 (d, J = 10.6 Hz, 1 H), 4.66
(d, J = 12.2 Hz, 1 H), 4.56−4.51 (m, 2 H), 4.32 (d, J = 10.6 Hz, 1 H),
3.98−3.92 (m, 2 H), 3.89 (dd, J = 3.6, 10.9 Hz, 1 H), 3.84−3.76 (m,
2 H), 3.70 (d, J = 10.5 Hz, 1 H), 3.63−3.62 (m, 1 H), 3.61 (s, 3 H),
2.30 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 138.9, 138.7,
138.5, 138.2, 137, 134.9, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8,
127.7, 127.6, 127.4, 127.3, 120.9, 120.1, 119.3, 108.9, 108.7, 869, 82.7,
79.4, 78.5, 76.1, 75.7, 75.2, 74.7, 73.4, 69.3, 29.4, 10.9. HRMS (ESI)
m/z: [M + H]+ Calcd for C44H46NO5 668.3371; Found 668.3369.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-1-methyl-2-phe-
nylindole (3h). Synthesized according to the general procedure on a 1
mmol scale to afford 3h (605 mg, yield 83%, β only); eluent, hexane−
EtOAc (9:1). Brown oil. IR (neat): 3455, 3017, 2945, 1750, 1612,
1
1456, 1256, 1086, 765, 668 cm−1. H NMR (400 MHz, CDCl3): δ
8.13 (s, 1 H), 7.91 (d, J = 7.9 Hz, 1 H,), 7.69 (d, J = 6.6 Hz, 2 H),
7.41−7.33 (m, 5 H), 7.31−7.24 (m, 14 H), 7.22−7.18 (m, 1H),
7.11−7.02 (m, 4 H), 6.82(d, J = 6.9 Hz, 2 H), 4.96−4.86 (m, 3 H),
4.76−4.69 (m, 2 H), 4.62 (d, J = 12.1 Hz, 1 H), 4.46 (d, J = 12.1 Hz,
1 H), 4.31 (d, J = 10.8 Hz, 1 H), 4.19 (t, J = 7.4 Hz, 1 H), 3.99−3.93
(m, 2 H), 3.86−3.72 (m, 3 H), 3.55−3.52 (m, 1 H). 13C{1H} NMR
(100 MHz, CDCl3): δ 138.9, 138.7, 138.5, 138.1, 137.1, 136.1, 132.5,
129.1, 128.8, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.5, 127.4,
127.3, 122.6, 120.1, 110.9, 110.6, 86.9, 82.2, 79.2, 78.4, 75.7, 75.2,
75.1, 74.6, 73.4, 69.2. HRMS (ESI) m/z: [M + H]+ Calcd for
C48H46NO5 716.3371; Found 716.3377.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-5-O-benzyl-1H-
indole (3c). Synthesized according to the general procedure on a 1
mmol scale to afford 3c (573 mg, yield 77%, β only); eluent, hexane−
EtOAc (8:1). Colorless jelly. IR (neat): 3466, 3017, 2945, 1750, 1601,
1
1456, 1240, 1064, 765, 668 cm−1; H NMR (400 MHz, CDCl3): δ
8.01 (s, 1 H), 7.39−7.37 (m, 22 H), 7.25−7.20 (m, 6 H), 7.23−7.10
(m, 4 H), 6.92 (dd, J = 2.4, 8.8 Hz, 1 H), 6.82 (dd, J = 6.8 Hz, 2 H),
4.98−4.91 (m, 5 H), 4.71−4.64 (m, 2 H), 4.54−4.48 (m, 2 H), 4.28
(d, J = 10.7 Hz, 1 H), 3.94−3.86 (m, 1 H), 3.85−3.78 (m, 4 H), 3.74
(d, J = 10.3 Hz, 1 H), 3.65−3.61 (m, 1 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 153.7, 138.8, 138.4, 138.1, 137.7, 131.9, 128.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 126.5,
124.1, 113.9, 113.4, 111.9, 103.9, 86.8, 82.6, 79.3, 78.4, 76.6, 75.7,
1
1456, 1256, 1086, 906, 832, 765, 668 cm−1. H NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 7.9 Hz, 1 H,), 7.41−7.39 (m, 5 H), 7.35−7.23
(m, 17 H), 7.14−7.05 (m, 4 H), 6.79 (d, J = 7.2 Hz, 2 H), 4.93−4.83
(m, 3 H), 4.70−4.63 (m, 2 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.42 (d, J =
8521
https://doi.org/10.1021/acs.joc.1c00698
J. Org. Chem. 2021, 86, 8516−8526

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
9.6 Hz, 1 H), 4.36 (d, J = 11.8 Hz, 1 H), 4.13 (t, J = 8.4 Hz, 1 H),
3.95−3.90 (m, 2 H), 3.86−3.69 (m, 3 H), 3.58 (s, 1 H), 3.49−3.46
(m, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ140.1, 138.9, 138.8,
138.6, 138.3, 137.7, 131.2, 131.1, 128.4, 128.3, 128.2, 127.9, 127.8,
127.6, 127.5, 127.4, 127.3, 126.3, 122.1, 120.9, 119.9, 110.6, 109.6,
86.9, 82.3, 79.2, 78.5, 75.8, 75.7, 75.6, 75.1, 74.6, 73.4, 69.3, 30.9.
HRMS (ESI) m/z: [M + H]+ Calcd for C49H48NO5 730.3527; Found
730.3530.
3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-1-methylindole
(3i). Synthesized according to the general procedure on a 1 mmol
scale to afford 3i (483 mg, yield 74%, β only); eluent, hexane−EtOAc
(9:1). Brown oil. IR (neat): 3466, 3017, 2920, 1727, 1601, 1456,
1216, 1064, 765, 669 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J
= 7.8 Hz, 1 H), 7.35−7.21 (m, 17 H), 7.14−7.08 (m, 4 H), 7.06−7.05
(m, 1 H), 6.79−6.77 (m, 2 H), 4.96 (d, J = 10.9 Hz, 1 H), 4.90 (dd, J
= 8.3, 10.9 Hz, 2 H), 4.69 (d, J = 10.6 Hz, 1 H), 4.64 (d, J = 12.1 Hz,
1 H), 4.54−4.51 (m, 2 H), 4.34 (d, J = 10.4 Hz, 1 H), 3.92−3.76 (m,
6 H), 3.73 (s, 3 H), 3.64−3.61 (m, 1 H). 13C{1H} NMR (100 MHz,
CDCl3): δ138.8, 138.5, 138.4, 138.1, 137.4, 128.5, 128.4, 128.3, 128.2,
128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 126.7, 121.9, 120.7,
119.4, 112.7, 109.4, 86.9, 83.1, 79.4, 78.5, 76.4, 75.7, 75.2, 74.7, 73.4,
69.3, 32.8. HRMS (ESI) m/z: [M + H]+ Calcd for C43H44NO5
654.3214; Found 654.3215.
74.5, 73.5, 72.5, 68.7, 60.9, 14.4. HRMS (ESI) m/z: [M + H]+ Calcd
for C45H46NO7 712.3269; Found 712.3270.
3-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-2-methyl-5-me-
thoxy-1H-indole (3m). Synthesized according to the general
procedure on a 1 mmol scale to afford 3m (566 mg, yield 83%, β
only); eluent, hexane−EtOAc (6:1). Colorless jelly. IR (neat): 3465,
1
3017, 2945, 1785, 1601, 1490, 1085, 765, 675 cm−1. H NMR (400
MHz, CDCl3): δ 7.63 (s, 1 H), 7.40−7.37 (m, 3 H), 7.32−7.24 (m,
14 H), 7.14−7.06 (m, 3 H), 6.89−6.88 (m, 1 H), 6.69−6.67 (m, 1
H), 5.08 (d, J = 10.8 Hz, 1 H), 4.82 (brs, 2 H), 4.63 (d, J = 10.7 Hz, 1
H), 4.49−4.46 (m, 3 H), 4.39−4.34 (m, 2 H), 4.17 (brs, 1 H), 3.83−
3.72 (m, 4 H), 3.65−3.64 (m, 1 H), 3.35 (brs, 3 H), 2.31 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 153.9, 139.3, 138.9, 138.5,
137.9, 133.5, 130.4, 128.5, 128.4, 128.2, 128.1, 128.0, 127.8, 127.5,
127.3, 111.5, 110.8, 110.2, 101.8, 84.3, 78.8, 76.4, 75.7, 75.2, 74.9,
74.8, 74.7, 73.6, 72.6, 68.7, 55.2, 12.2. HRMS (ESI) m/z: [M + H]+
Calcd for C44H46NO6 684.3320; Found 684.3318.
3-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-
O-benzyl-β-D-glucopyranoside-2-methyl-1H-indole (3n). Synthe-
sized according to the general procedure on a 1 mmol scale to afford
3n (868 mg, yield 80%, β only); eluent, hexane−EtOAc (4:1).
Colorless jelly. IR (neat): 3465, 3017, 2945, 1795, 1601, 1490, 1157,
1
1250, 1286, 1085, 765, 665 cm−1. H NMR (400 MHz, CDCl3): δ
3-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-2-methyl-1H-
indole (3j). Synthesized according to the general procedure on a 1
mmol scale to afford 3j (561 mg, yield 86%, β only); eluent, hexane−
EtOAc (6:1). Colorless jelly. IR (neat): 3455, 3115, 2940, 1765, 1636,
1456,, 1064, 765, 665 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.88 (d,
J = 7.9 Hz, 1 H), 7.74 (brs, 1 H), 7.46−7.44 (m, 2 H), 7.39−7.35 (m,
4 H), 7.33−7.21 (m, 10 H), 7.13−7.06 (m, 4 H), 6.97−6.94 (m, 1
H), 6.86−6.84 (m, 2 H), 5.13 (d, J = 11.5 Hz, 1 H), 4.79 (ABq, J =
12.0 Hz, 2 H), 4.67 (d,, J = 11.4 Hz, 1 H), 4.52 (d, J = 9.4 Hz, 1 H),
4.44 (ABq, J = 12.0 Hz, 2 H), 4.41−4.36 (m, 2 H), 4.15 (d, J = 2.3
Hz, 1 H), 3.79−3.70 (m, 4 H), 3.65−3.61 (m, 1 H), 2.34 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 139.4, 138.9, 138.5, 138.1,
137.4, 135.5, 132.9, 128.4, 128.3, 128.2, 128.1, 127.9, 127.7, 127.5,
127.4, 127.3, 127.2, 121.3, 121.2, 120.5, 119.6, 110.5, 110.1, 84.4,
79.4, 76.6, 75.6, 75.1, 74.5, 74.4, 73.5, 72.5, 68.8, 12.2. HRMS (ESI)
m/z: [M + H]+ Calcd for C43H44NO5 654.3214; Found 654.3212.
3-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-2-phenyl-1H-
indole (3k). Synthesized according to the general procedure on a 1
mmol scale to afford 3k (622 mg, yield 87%, β only); eluent, hexane−
EtOAc (7:1). Colorless jelly. IR (neat): 3455, 3017, 2955, 1765, 1640,
1456, 1256, 1086, 740, 665 cm. 1H NMR (400 MHz, CDCl3): δ 8.05
(d, J = 7.9 Hz, 1 H,), 8.03 (brs, 1 H), 7.65−7.63 (m, 2 H), 7.47−7.45
(m, 2 H), 7.38−7.23 (m, 17 H), 7.15−7.12 (m, 1 H), 7.07−6.95 (m,
4 H), 6.85−6.83 (m, 2 H), 5.13 (d, J = 11.2 Hz, 1 H), 4.82−4.73 (m,
2 H), 4.74−4.65 (m, 3 H), 4.44−4.36 (m, 3 H), 4.16 (brs, 1 H), 3.98
(d, J = 10.8 Hz, 1 H), 3.73−3.66 (m, 3 H), 3.57−3.55 (m, 1 H).
13C{1H} NMR (100 MHz, CDCl3): δ 139.5, 138.9, 138.4, 138.1,
7.79 (s, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.35−7.27 (m, 28 H), 7.24−
7.07 (m, 7 H), 6.98 (t, J = 7.5 Hz, 1 H), 6.82 (d, J = 6.1 Hz, 2 H),
5.14 (d, J = 10.8 Hz, 1 H), 4.99 (d, J = 11.6 Hz, 1 H), 4.84 (quart, 3
H), 4.73 (brs, 3 H), 4.63−4.61 (m, 2 H), 4.57 (d, J = 11.2 Hz, 1 H),
4.50 (d, J = 9.7 Hz, 1 H), 4.41−4.37 (m, 3 H), 4.27- 4.25 (m, 2 H),
3.99 (dd, J = 3.5, 11.3 Hz, 1 H), 3.95 (d, J = 2.8 Hz, 1 H), 3.88−3.83
(m, 2 H), 3.75−3.69 (m, 3 H), 3.59−3.41 (m, 5 H), 2.33 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3): δ 138.8, 138.7, 138.5, 138.2,
135.5, 133.1, 128.4, 128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 127.5,
127.4, 127.3, 127.2, 127.1, 121.2, 120.2, 119.6, 110.2, 109.8, 102.8,
85.1, 82.7, 81.9, 80.2, 79.8, 75.8, 75.5, 75.4, 74.9, 74.8, 73.9, 73.5,
73.1, 72.7, 68.5, 68.2, 12.3. HRMS (ESI) m/z: [M + NH4]+ Calcd for
C70H75N2O10 1103.5416; Found 1103.5359.
3-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-(1→4)-2,3,6-tri-
O-benzyl-β-D-glucopyranoside-2-phenyl-1H-indole (3o). Synthe-
sized according to the general procedure on a 1 mmol scale to afford
3o (940 mg, yield 82%, β only); eluent, hexane−EtOAc (4:1).
Colorless jelly. IR (neat): 3465, 3017, 2945, 1795, 1601, 1490, 1157,
1
1250, 1286, 1085, 800, 770, 740, 665 cm−1. H NMR (400 MHz,
CDCl3): δ 8.09 (s, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.68 (d, J = 7.3 Hz,
2 H), 7.35−7.21 (m, 34 H), 7.12−7.09 (m, 2 H), 7.05- 7.01 (m, 3 H),
6.83 (d, J = 7.1 Hz, 2 H), 5.14 (d, J = 10.4 Hz, 1 H), 4.99 (d, J = 11.4
Hz, 1 H), 4.83−4.78 (m, 2 H), 4.72 (t, J = 10.8 Hz, 4 H), 4.62−4.56
(m, 3 H), 4.44−4.26 (m, 5 H), 4.14 (t, J = 9.7 Hz, 1 H), 3.99−3.94
(m, 3 H), 3.82−3.79 (m, 1H), 3.72 (t, J = 8.9 Hz, 1 H), 3.65−3.58
(m, 2 H), 3.48−3.42 (m, 4 H). 13C{1H} NMR (100 MHz, CDCl3): δ
139.2, 138.9, 138.7, 138.4, 138.3, 137.1, 129.1, 128.8, 128.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.7, 127.5, 127.4,
127.4, 127.3, 127.2, 127.0, 122.5, 120.1, 110.8, 102.8, 85.2, 82.6, 80.3,
79.7, 76.7, 75.6, 75.4, 74.9, 74.8, 73.9, 73.5, 73.1, 73.1, 72.8, 68.2.
HRMS (ESI) m/z: [M + NH4]+ Calcd for C75H77N2O10 1165.5573;
Found 1165.5510.
136.7, 136.2, 132.6, 129.1, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1,
127.9, 127.8, 127.6, 127.5, 127.4, 127.3, 127.2, 122.5, 120.1, 111.3,
110.8, 84.6, 79.1, 76.4, 75.3, 75.1, 74.7, 74.4, 73.5, 72.5, 68.8. HRMS
(ESI) m/z: [M + H]+ Calcd for C48H46NO5 716.3371; Found
716.3366.
3-(2,3,4,6-Tetra-O-benzyl-β-D-galactopyranosyl)-2-ethylcarboxy-
late-1H-indole (3l). Synthesized according to the general procedure
on a 1 mmol scale to afford 3l (575 mg, yield 81%, β only); eluent,
hexane−EtOAc (7:1). Colorless jelly. IR (neat): 3465, 3017, 2945,
3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-2-methyl-1H-in-
dole (3p). Synthesized according to the general procedure on a 1
mmol scale to afford 3p (350 mg, yield 76%, β only); eluent, hexane−
EtOAc (5:1). Colorless jelly. IR (neat): 33375, 3017, 1795, 1490,
1372, 1250, 1085, 924, 770, 665 cm−1; 1H NMR (400 MHz, CDCl3):
δ 7.94 (s, 1 H), 7.66 (dd, J = 2.4, 6.3 Hz, 1 H), 7.23−7.21 (m,1 H),
7.11−7.05 (m, 2 H), 5.63 (t, J = 9.9 Hz, 1 H), 5.57 (dd, J = 0.8, 3.3
Hz, 1 H), 5.23 (dd, J = 3.3, 10.2 Hz, 1 H), 4.73 (d, J = 9.8 Hz, 1 H),
4.23 (dd, J = 6.9, 11.1 Hz, 1 H), 4.15 (dd, J = 6.4, 11.3 Hz, 1 H),
4.09−4.06 (m, 1 H), 2.47 (s, 3 H), 2.26 (s, 3 H), 2.03 (s, 3 H), 1.99
(s, 3 H), 1.65 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.5,
170.4, 170.3, 169.1, 135.1, 133.5, 127.3, 121.4, 119.8, 118.5, 110.4,
107.3, 74.6, 74.4, 72.5, 69.5, 68.1, 61.8, 20.8, 20.7, 20.6, 20.4, 12.2.
HRMS (ESI) m/z: [M + H]+ Calcd for C23H28NO9 462.1759; Found
462.1759.
1
1795, 1601, 1490, 1286, 1085, 765, 665 cm−1. H NMR (400 MHz,
CDCl3): δ 8.74 (s, 1 H), 8.14 (d, J = 8.2 Hz, 1 H), 7.46−7.44 (m, 2
H), 7.39−7.36 (m, 4 H), 7.33−7.25 (m, 11 H), 7.09−7.07 (m, 3 H),
6.96 (t, J = 7.5 Hz, 1 H), 6.85−6.84 (m, 2 H), 5.46 (d, J = 9.3 Hz, 1
H), 5.14 (d, J = 11.4 Hz, 1 H), 4.80 (d, J = 11.9 Hz, 2 H), 4.68 (d, J =
11.3 Hz, 1 H), 4.47 (dd, J = 11.9 Hz, 2 H), 4.41 (d, J = 10.8 Hz, 1 H),
4.38−4.29 (m, 3 H), 4.18 (d, J = 2.2 Hz, 1 H), 3.83−3.72 (m, 4 H),
3.63 (dd, J = 5.1, 8.6 Hz, 1 H), 1.33 (t, J = 7.1 Hz, 1 H). 13C{1H}
NMR (100 MHz, CDCl3): δ 161.8, 139.4, 138.8, 138.5, 137.9, 135.9,
128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3,
127.1, 125.6, 124.2, 123.9, 121.1, 120.5, 111.5, 84.3, 79.5, 74.7, 74.6,
8522
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J. Org. Chem. 2021, 86, 8516−8526

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
3-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)- 2-phenyl-1H-
indole (3q). Synthesized according to the general procedure on a 1
mmol scale to afford 3q (407 mg, yield 78%, β only); eluent, hexane−
EtOAc (5:1). Colorless jelly. IR (neat): 33375, 3022, 1746, 1452,
1372, 1220, 1051, 924, 766, 669 cm−1. 1H NMR (400 MHz, CDCl3):
δ 8.23 (s, 1 H), 7.93 (d, J = 7.5 Hz, 1 H), 7.63−7.61 (m, 2 H), 7.52−
7.42 (m, 3 H), 7.32 (dd, J = 1.6, 7.2 Hz, 1 H), 7.22−7.14 (m, 2 H),
5.89 (t, J = 9.7 Hz, 1 H), 5.54 (d, J = 3.5 Hz, 1 H), 5.20 (dd, J = 3.3,
10.1 Hz, 1 H), 4.87 (d, J = 9.9 Hz, 1 H), 4.19 (dd, J = 7.2, 11.3 Hz, 1
H), 4.11 (dd, J = 6.2, 11.3 Hz, 1 H), 4.03−3.99 (m, 1 H), 2.28 (s, 3
H), 1.99 (s, 3 H), 1.98 (s, 3 H), 1.69 (s, 3 H). 13C{1H} NMR (100
MHz, CDCl3): δ 170.5, 170.4, 170.3, 168.6, 137.3, 135.9, 132.3,
128.9, 128.7, 128.5, 127.2, 122.8, 120.4, 111.1, 108.1, 74.7, 74.2, 72.7,
68.9, 68.1, 61.8, 20.8, 20.7, 20.6, 20.5. HRMS (ESI) m/z: [M + H]+
Calcd for C28H30NO9 524.1915; Found 524.1910.
20.8, 20.5. HRMS (ESI) m/z: [M + H]+ Calcd for C25H26NO7
452.1704; Found 452.1704.
3-(2,3,4-Tri-O-benzyl-α/β-L-arabinopyranosyl)-2-phenyl-1H-in-
dole (3v). Synthesized according to the general procedure on a 1
mmol scale to afford 3v (404 mg, yield 68%,α:β = 1:4); eluent,
hexane−EtOAc (7:1). Colorless jelly. IR (neat): 3465, 2945, 1795,
1601, 1490, 1286, 1085, 765, 665 cm−1. 1H NMR (400 MHz,
CDCl3): δ 8.13 (s, 1 H), 7.96 (d, J = 7.9 Hz, 1 H), 7.60−7.57 (m,
1H), 7.44−7.41 (m, 1 H), 7.35- 7.29 (m, 9 H), 7.28−7.23 (m, 5 H),
7.14−7.10 (m, 2 H), 7.04−7.02 (m, 2 H), 5.30 (d, J = 8.1 Hz, 1 H),
4.75 (dd, J = 4.8, 8.1 Hz, 1 H), 4.64- 4.59 (m, 2 H), 4.53−4.52 (m, 2
H), 4.45 (dd, J = 5.1, 9.8 Hz, 1 H), 4.34 (brs, 1 H), 4.31 (t, J = 4.7
Hz, 1H), 4.18−4.08 (m, 1 H), 3.63 (d, J = 5.2 Hz, 2 H). 13C{1H}
NMR (100 MHz, CDCl3): δ 138.5, 138.3, 138.2, 137.9, 137.5, 136.4,
132.2, 128.9, 128.8, 128.7, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 127.4, 127.1, 123.5, 122.6, 122.4, 120.9,
120.2, 119.8, 110.9, 110.7, 88.2, 86.4, 86.2, 85.3, 81.5, 80.8, 78.2, 73.4,
73.3, 72.5, 72.2, 72.1, 71.9, 70.5. HRMS (ESI) m/z: [M + H]+ Calcd
for C40H38NO4 596.2795; Found 596.2797.
3-(2,3,4-Tri-O-acetyl-α-L-rhamnopyranosyl)-2-phenyl-1H-indole
(3w). Synthesized according to the general procedure on a 1 mmol
scale to afford 3w (344 mg, yield 74%, α only); eluent, hexane−
EtOAc (4:1). Colorless jelly. IR (neat): 3340, 1746, 1452, 1372, 1220,
1051, 924, 766, 669 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.20 (s, 1
H), 8.05 (dd, J = 1.2, 7.3 Hz, 1 H), 7.49−7.39 (m, 5 H), 7.27−7.26
(m, 1 H), 7.17−7.09 (m, 2 H), 5.57 (dd, J = 1.3, 3.3 Hz, 1 H), 5.29−
5.19 (m, 2 H), 4.99 (brs, 1 H), 3.62−3.55 (m, 1 H), 2.06 (s, 3 H),
1.98 (s, 3 H), 1.90 (s, 3 H), 1.30 (d, J = 6.2 Hz, 3 H). 13C{1H} NMR
(100 MHz, CDCl3): δ 170.4, 170.2, 135.9, 135.3, 132.3, 128.9, 128.8,
128.5, 127.5, 122.9, 122.5, 119.8, 110.7, 109.1, 74.7, 74.5, 72.9, 72.2,
71.2, 20.9, 20.8, 20.7, 17.9. HRMS (ESI) m/z: [M + H]+ Calcd for
C26H28NO7 466.1860; Found 466.1861.
3-(3-O-Benzyl-4-O-benzoyl-2-O-(2-pyridinecarbonyl)-α-L-rham-
nopyranoside)-2-methyl-1H-indole (3x). Synthesized according to
the general procedure on a 1 mmol scale to afford 3x (443 mg, yield
77%, α only); eluent, hexane−EtOAc (7:1). Colorless jelly. IR (neat):
3390, 3018, 2924, 2403, 1724, 1590, 1456, 1357, 1268, 1217, 1178,
1084, 1026, 764, 668, 623 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.48
(dd, J = 0.8, 4.7 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.05 (s, 1 H),
8.01 (dd, J = 1.4, 8.6 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.72 (td, 1
H, J = 1.7, 7.6 Hz), 7.61−7.57 (m, 1 H), 7.48−7.44 (m, 2 H), 7.18−
7.09 (m, 7 H), 7.09−6.97 (m, 2 H), 5.50−5.45 (m, 2 H), 4.73 (d, J =
12.4 Hz, 1 H), 4.56 (dd, J = 2.3, 4.0 Hz,1 H), 4.51 (d, J = 12.4 Hz, 1
H), 3.91 (dd, J = 4.1, 9.6 Hz, 1 H), 3.62−3.55 (m, 1 H), 2.51 (s, 3
H), 1.18 (d, J = 6.3 Hz, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ
165.7, 160.3, 148.6, 137.5, 136.5, 134.9, 133.9, 133.2, 129.9, 129.8,
128.4, 128.2, 127.8, 127.7, 127.1, 122.9, 120.9, 120.7, 120.5, 119.8,
111.8, 110.1, 97.2, 76.6, 75.7, 72.9, 71.1, 69.8, 17.6, 13.5. HRMS
(ESI) m/z: [M + H]+ Calcd for C35H33N2O6 577.2333; Found
577.2332.
3-(2,3, 5-Tri-O-benzyl-β-D-ribofuranose)-2-methyl-1H-indole
(3y). Synthesized according to the general procedure on a 1 mmol
scale to afford 3y (453 mg, yield 85%, β only); eluent, hexane−EtOAc
(7:1). Colorless jelly. IR (neat): 3466, 3017, 2923, 1617, 1457, 1216,
1079, 762, 700, 669 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1
H), 7.63 (d, J = 7.8 Hz, 1 H), 7.48 (dd, J = 1.5, 8.2 Hz, 2 H), 7.36−
7.21 (m, 9 H), 7.15−6.99 (m, 5 H), 6.86−6.82 (m, 2 H), 5.00 (d, J =
9.7 Hz, 1 H), 4.94 (dd, J = 12.1 Hz, 2 H), 4.60 (q, J = 12.1 Hz, 2 H),
4.29−4.27 (m, 1 H), 4.06 (d, J = 11.8 Hz, 1 H), 3.99−3.77 (m, 2 H),
3.93 (d, J = 11.9 Hz, 1 H), 3.76 (d, J = 2.4, 9.8 Hz, 1 H), 3.73−3.69
(m, 1 H), 2.34 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 139.6,
138.5, 138.4, 135.5, 133.6, 128.5, 128.3, 128.1, 127.9, 127.8, 127.7,
127.4, 127.3, 127.2, 121.1, 119.8, 119.4, 110.3, 109.6, 78.8, 76.3, 75.2,
74.1, 71.8, 71.4, 71.1, 64.6, 12.2. HRMS (ESI) m/z: [M + H]+ Calcd
for C35H36NO4 534.2639; Found 534.2636.
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-2-methyl-1H-in-
dole (3r). Synthesized according to the general procedure on a 1
mmol scale to afford 3r (341 mg, yield 74%, β only); eluent, hexane−
EtOAc (4:1). Colorless jelly. IR (neat): 33375, 3022, 1750, 1746,
1
1452, 1372, 1220, 1051, 924, 766, 669 cm−1. H NMR (400 MHz,
CDCl3): δ 7.91 (s, 1 H), 7.62−7.61 (m, 1 H), 7.22−7.21 (m, 1 H),
7.09−7.07 (m, 2 H), 5.39−5.32 (m, 3 H), 4.78−4.77 (m, 1 H), 4.29−
4.20 (m, 2 H), 3.87−3.85 (m, 1 H), 2.46 (s, 3 H), 2.09 (s, 3 H), 2.08
(s, 3 H), 2.00 (s, 3 H), 1.64 (s, 3 H). 13C{1H} NMR (100 MHz,
CDCl3): δ 170.8, 170.5, 169.6, 168.9, 135.1, 133.4, 127.2, 121.5,
119.9, 118.6, 110.3, 106.8, 76.1, 74.5, 74.4, 72.1, 68.7, 62.4, 20.8, 20.7,
20.3, 12.4. HRMS (ESI) m/z: [M + H]+ Calcd for C23H28NO9
462.1759; Found 462.1755.
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-2-phenyl-1H-in-
dole (3s). Synthesized according to the general procedure on a 1
mmol scale to afford 3s (402 mg, yield 77%, β only); eluent, hexane−
EtOAc (4:1). Colorless jelly. IR (neat): 33375, 3022, 1746, 1452,
1372, 1220, 1051, 924, 766, 669 cm−1;. 1H NMR (400 MHz, CDCl3):
δ 8.25 (s, 1 H), 7.85 (d, J = 7.4 Hz, 1 H), 7.62−7.49 (m, 2 H), 7.52−
7.43 (m, 3 H), 7.32−7.29 (m, 1 H), 7.22−7.14 (m, 2 H), 5.73−5.68
(m, 1 H), 5.37−5.31 (m, 2 H), 4.88 (d, J = 9.9 Hz, 1 H), 4.23 (dd, J =
4.3, 12.2 Hz, 1 H), 4.16 (dd, J = 2.4, 12.3 Hz, 1 H), 3.81−3.77 (m, 1
H), 2.07 (s, 3 H0, 2.05 (S, 3 H), 1.99 (S, 3 H), 1.69 (S, 3 H);
13C{1H} NMR (100 MHz, CDCl3): δ 170.8, 170.6, 169.6, 168.6,
137.6, 135.9, 132.2, 129.1, 128.7, 128.6, 126.8, 122.9, 120.5, 111.1,
107.5, 75.7, 74.9, 74.4, 71.3, 68.7, 62.4, 20.8, 20.7, 20.6, 20.4. HRMS
(ESI) m/z: [M + H]+ Calcd for C28H30NO9 524.1915; Found
524.1902.
3-(2,3,4-Tri-O-acetyl-α/β-L-arabinopyranosyl)-2-methyl-1H-in-
dole (3t). Synthesized according to the general procedure on a 1
mmol scale to afford 3t (248 mg, yield 64%, α:β = 1:7); eluent,
hexane−EtOAc (6:1). Colorless jelly. IR (neat): 3340, 1746, 1452,
1372, 1220, 1051, 924, 766, 665 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.93 (s, 1 H), 7.72- 7.67 (m, 1 H), 7.22−7.19 (m, 1H), 7.10−7.05
(m, 2 H), 5.68 (t, J = 9.8 Hz, 1 H), 5.43- 5.40 (m, 1 H), 5.23 (dd, J =
3.4, 10.1 Hz, 1H), 4.62 (d, J = 9.7 Hz, 1 H), 4.17 (dd, J = 2.2, 13.2
Hz, 1 H), 3.8 (d, J = 13.2 Hz, 1 H), 2.46 (s, 3 H), 2.27 (s, 3 H), 2.01
(s, 3 H), 1.65 (s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.5,
170.4, 169.1, 135.1, 133.5, 127.3, 121.5, 121.4, 119.8, 118.9, 118.6,
110.5, 110.3, 107.5, 75.1, 72.2, 69.7, 69.4, 68.2, 21.2, 20.8, 20.4, 12.1.
HRMS (ESI) m/z: [M + H]+ Calcd for C20H24NO7 390.1547; Found
390.1550.
3-(2,3,4-Tri-O-acetyl-α/β-L-arabinopyranosyl)-2-phenyl-1H-in-
dole (3u). Synthesized according to the general procedure on a 1
mmol scale to afford 3u (297 mg, yield 66%, α:β = 1:6); eluent,
hexane−EtOAc (6:1). Colorless jelly. IR (neat): 3340, 1746, 1452,
1372, 1220, 1051, 924, 766, 669 cm−1. 1H NMR (400 MHz, CDCl3):
δ 8.20 (s, 1 H), 7.96 (d, J = 7.3 Hz, 1 H), 7.60−7.41 (m, 5 H), 7.33−
7.28 (m, 1 H), 7.22- 7.14 (m, 2 H), 5.97 (t, J = 9.7 Hz, 1 H), 5.41-
5.37 (m, 1 H), 5.20 (dd, J = 3.4, 10.1 Hz, 1H), 4.08 (dd, J = 2.4, 13.2
Hz, 1 H), 3.7 (d, J = 13.2 Hz, 1 H), 2.30 (s, 3 H), 2.01 (s, 3 H), 1.71
(s, 3 H). 13C{1H} NMR (100 MHz, CDCl3): δ 170.5, 170.4, 168.7,
137.3, 136.2, 135.9, 132.3, 131.9, 128.9, 128.8, 128.6, 128.4,, 122.7,
120.4, 120.1, 111.1, 108.3, 75.1, 72.4, 69.4, 69.2, 67.9, 63.7, 21.2, 20.9,
3-(2,3,5,6-Di-O-isopropylidene-α/β-D-manofuranose)-2-methyl-
1H-indole (3z). Synthesized according to the general procedure on a 1
mmol scale to afford 3z (253 mg, yield 68%, α:β = 1:4); eluent,
hexane−EtOAc (5:1). Colorless jelly. IR (neat): 3421, 3320, 2930,
1
1612, 1511, 1456, 1379, 1251, 1084, 762, 700, 669 cm−1; H NMR
8523
https://doi.org/10.1021/acs.joc.1c00698
J. Org. Chem. 2021, 86, 8516−8526

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(400 MHz, CDCl3): δ 7.49 (d, J = 7.8 Hz, 1 H), 713- 7.07 (m, 3 H),
6.27 (brs, 1 H), 6.01 (d, J = 1.8 Hz, 1 H), 5.47 (dd, J = 1.9, 5.8 Hz, 1
H), 5.22−5.20 (m, 1 H), 4.48- 4.43 (m, 1 H), 4.35 (dd, J = 3.8, 7.5
Hz, 1 H), 4.08- 4.04 (m, 1 H), 3.97 (dd, J = 4.5, 8.7 Hz, 1 H), 2.46 (s,
3 H), 1.62 (s, 3 H), 1.41 (s, 6 H), 1.37 (s, 3 H). 13C{1H} NMR (100
MHz, CDCl3): δ 137.2, 135.7, 135.2, 133.4, 130.3, 129.3, 121.3,
120.3, 120.2, 119.7, 119.2, 119.1, 117.5, 113.7, 112.9, 109.7, 109.4,
108.2, 102.8, 99.8, 91.5, 86.7, 84.8, 84.3, 83.1, 81.4, 80.4, 80.3, 74.2,
73.5, 66.7, 65.6, 26.9, 26.7, 26.6, 26.5, 26.0, 25.3, 25.2, 24.8, 24.6,
13.7, 13.6. HRMS (ESI) m/z: [M + H]+ Calcd for C21H28NO5
374.1962; Found 374.1974.
EMR/2017/001791), New Delhi, India, and SAIF Division of
CSIR-CDRI for providing the spectroscopic and analytical
data. CDRI communication no. 10252.
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1
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m/z: [M + H]+ Calcd for C26H30NO5 436.2118; Found 436.2112.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00698.
1
Copies of H NMR spectra of 2-methylindole in the
presence of and absence of B(C6F5)3 and 1H, 13C{1H},
and HRMS spectra of 1i, glycoside 3a−3z and 3aa
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 1i, 3a−3z, and 3aa (ZIP)
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R.; Lee, J.-C. Synthesis and biological evaluation of novel C-
AUTHOR INFORMATION
Corresponding Author
■
Pintu Kumar Mandal − Medicinal and Process Chemistry
Division, CSIR-Central Drug Research Institute, Lucknow
226 031, India; Academy of Scientific and Innovative
Research (AcSIR), Ghaziabad 201002, India; orcid.org/
0000-0002-5813-9756; Email: pintuchem06@gmail.com,
pk.mandal@cdri.res.in
Authors
Atul Dubey − Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute, Lucknow 226 031,
India
Ashwani Tiwari − Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute, Lucknow 226 031,
India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00698
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.D. thanks UGC, New Delhi and A.T. thanks DST-SERB, for
providing a Research Fellowship. The author gratefully
acknowledges financial support by DST-SERB (Scheme No.
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