InCl3-catalyzed asymmetric aza-Friedel-Crafts reaction of indoles with imines generated from O-pivaloylated β-d-galactosylamine

Article abstract of DOI:10.1016/j.carres.2010.05.025

The highly diastereoselective InCl₃-catalyzed aza-Friedel-Crafts reaction of substituted indoles with aldimines generated from Kunz's amine was studied. The reaction afforded the desired product in good to high yields with up to >19:1 diastereo

Full text of DOI:10.1016/j.carres.2010.05.025

Carbohydrate Research 345 (2010) 1708–1712
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
InCl3-catalyzed asymmetric aza-Friedel–Crafts reaction of indoles
with imines generated from O-pivaloylated b-D-galactosylamine
*
*
Bo-Yu Li, Zhong-Jun Li , Xiang-Bao Meng
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The highly diastereoselective InCl3-catalyzed aza-Friedel–Crafts reaction of substituted indoles with aldi-
mines generated from Kunz’s amine was studied. The reaction afforded the desired product in good to
high yields with up to >19:1 diastereoselective ratios. The O-pivaloylated b-D-galactosyl moiety could
not be cleaved under the traditional acidic conditions. It was removed successfully after unmasking of
the O-pivaloyl groups using MeOH/NaOMe and treatment with HOAc/H2O subsequently, to yield the
3-indolyl aryl methanamine derivatives in high optical purity.
Received 27 April 2010
Received in revised form 14 May 2010
Accepted 24 May 2010
Available online 2 June 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Asymmetric synthesis
Aza-Friedel–Crafts reaction
Carbohydrate auxiliary
InCl3
3-Indolyl methanamine derivatives
1. Introduction
azoline complexes,36 9-thiourea cinchona alkaloids,37 chiral phos-
phoric acid,38–40 and axially chiral cyclometalated bidentate
Carbohydrate derivatives are effective chiral auxiliaries in many
asymmetric syntheses.1–3 In particular, O-pivaloylated b-
-galacto-
N-heterocyclic carbene palladium(II) complexes41 have been used
as the catalysts. In the reactions reported with a variety of aldimines
and indoles with different electronic properties, the steric hindrance
of the indole derivatives has been a problem.40 In addition, the
removals of the N-protecting groups remain unsolved.33–41 In this
note, we present an InCl3-catalyzed aza-Friedel–Crafts reaction of
indoles, including the 2-substituted indoles, with aldimines
D
sylamine, which was developed by Kunz et al., has been used in a
series of reactions, such as Strecker reaction,4–6 Ugi reaction,7–12
Mannich reaction,13–15 and hetero-Diels–Alder reaction.16 Chiral
homoallyl amines,17–19
and
a
-aminophosphonic acid derivatives,15,20
a
-amino (phenyl)methyl(phenyl)phosphinic acids21 were also
synthesized with this chiral amine. In recent years, some examples
prepared from O-pivaloylated b-D-galactosylamine. The reaction
proceeds in good to high yields with high diastereoselectivity.
of alkaloid synthesis22–25 were reported using Domino Mannich–
Michael reactions,26–30 in which O-pivaloylated b-
D-galactosyl-
amine was utilized to generate the crucial chiral center. The use
of O-pivaloylated b-galactosylamine as a chiral auxiliary to induce
high enantioselectivity has been well defined.
2. Results and discussion
It is well known that the acid-triggered aza-Friedel–Crafts reac-
tion of indoles is often associated with the side reaction to form
bisindole compounds. The extent of the side reaction is largely
dependent on the catalyst and the N-protection group of the
aldimine. Since a specific N-protection group as the chiral auxiliary
was used in our method, we then investigated different Lewis acid
catalysts to find one that can catalyze the reaction efficiently and
has limited side reaction. The reaction of 4-nitro-N-(2,3,4,6-tetra-
Indole-containing compounds have attracted much attention
due to their widely recognized unique properties in drug design.
These structures exist in numerous alkaloids as well as other syn-
thesized bioactive agents that show significant biological activi-
ties.31,32 Among those, the 3-indolyl methanamine derivatives are
of particular interest to us. Direct asymmetric aza-Friedel–Crafts
reaction of indoles with aldimines is a convenient approach to
the synthesis of these 3-indolyl methanamine derivatives. Initially,
O-pivaloyl-b-D-galactosyl) benzylideneamine (1a) and indole (2a)
the imines were limited to the highly active N-protected
a-imino
was used to screen the Lewis acid catalysts (Scheme 1). At
ꢀ30 °C with 4 equiv of indole and 0.2 equiv of catalyst in dichloro-
methane, the reaction proceeded smoothly with all Lewis acids
tested. Good yields were obtained when MgBr2ꢁEt2O and ZnCl2
were used, but the diastereoselectivity was moderate (Table 1,
esters.33–35 Later, it was extended to aryl aldimines. Several new
methods have been developed recently, in which Cu(OTf)2/bisox-
* Corresponding authors. Tel.: +86 10 82801714 (X.-B.M.).
E-mail address: xbmeng@bjmu.edu.cn (X.-B. Meng).
42
entries 1–2). When SnCl4 and FeCl3 were used, on the contrary,
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.05.025

B.-Y. Li et al. / Carbohydrate Research 345 (2010) 1708–1712
1709
OPiv
O
NO2
OPiv
PivO
OPiv
O
OPiv
PivO
NO2
cat. (n equiv.)
H
N
N
+
PivO
N
H
PivO
1a
N
H
2a
3a
Scheme 1. Aza-Friedel–Crafts reaction of indole with imine.
Table 1
Catalysts screened for aza-Friedel–Crafts reaction
Entrya
T (°C)
Time (h)
Indole (equiv)
Catalyst
n (equiv)
Yieldb (%)
Ratioc
1
2
3
4
5
6
7
8
9
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ40
ꢀ50
ꢀ40
ꢀ40
1
15
3
4
4
4
4
4
4
4
4
MgBr2ꢁEt2O
ZnCl2
SnCl4
FeCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
0.2
0.2
0.2
0.2
0.2
0.5
0.2
0.2
0.2
0.2
85
70
18
47
80
73
82
25
64
42
6:1
5:1
10:1
13:1
>19:1
15:1
>19:1
>19:1
>19:1
12:1
3
15
15
15
42
15
15
2
1.1
10
a
b
c
All reactions were carried out with 0.5 g 4 Å molecular sieves in dry CH2Cl2.
Isolated yield after column chromatography.
Ratio of diastereomers was determined by 400 MHz 1H NMR.
the reaction product was obtained with high diastereoselectivity
but in low yield, due to the formation of the bisindole side product
(entries 3–4). InCl343–47 turned out to be the most efficient catalyst.
The aza-Friedel–Crafts reaction catalyzed by InCl3 afforded the
product in 80% yield and the ratio of diastereomers was >19:1 (en-
try 5).
as the nitro- and cyano- groups were present, the reaction pro-
ceeded smoothly and gave the product in moderate to good yields
(65–80%), and the diastereoselectivity ratio was up to >19:1 (en-
tries 1–3). The 2-nitro-substituted benzaldimine did not affect
the diastereoselectivity (entry 2, ratio >19:1), which indicated that
the reaction was tolerant for the steric hindrance of aldimine,
although the yield was moderate. Moreover, the basic 3-pyridinyl
aldimine yielded the product in 70% yield with good diastereose-
lectivity, although more catalyst and indole were needed (entry
6). Aldimines formed from the 4-trifluoromethyl, or 4-fluoro benz-
aldehyde afforded no desired product but the bisindole by-product
(entries 4–5).
For substituted indoles, most of the reactions proceeded
smoothly to afford the final product 3 except that in entries 8
and 9 of Table 2. It was expected that the 3-Me indole would fail
to react to form product 3i (entry 9) due to the weaker nucleo-
philicity of the 2-position of indole comparing with the 3-posi-
tion. And the N-Boc-protected indole also afforded no product
as a result of the electron-withdrawing property of the Boc
group (entry 8). Indoles bearing electron-donating groups gener-
ally provided better yields (entries 7 and 10, yields were >90%,
respectively, compared to entry 11, with yield of 60%). The elec-
tronic property of substituted indole did not affect the diastere-
oselectivity significantly, since 5-methoxyindole provided
product in 8:1 dr (entry 10), and the reaction of 6-cloroindole
proceeded with slightly higher diastereoselectivity (entry 11).
We found that the reaction with 2-methylindole proceeded with
We then optimized the ratio of the catalyst and indole as well as
the reaction temperature. We found that when the catalyst ratio
was increased to 0.5 equiv, both the yield and the diastereoselec-
tivity decreased slightly (entry 6). Lowering the temperature to
ꢀ40 °C resulted in a slight increase in yield with the same diaste-
reoselectivity (entry 7). However, at ꢀ50 °C, the reaction pro-
ceeded so slowly that even after 42 h, only a small portion of the
reactant 1a was consumed and the product was obtained in 25%
yield (entry 8). Decreasing the amount of indole proved to be
unsuccessful (entries 9–10), with a dramatic drop in yield due to
the formation of the bisindole by-product. It was probably because
the amount of indole greatly affected the aza-Friedel–Crafts reac-
tion rate, but had little effect on the formation of the side product.
Under the optimized reaction conditions, which were at ꢀ40 °C
with 0.2 equiv of InCl3 as the catalyst and 4 equiv of indole in dry
dichloromethane, the scope of this method was tested with a vari-
ety of aldimines and indoles. The reactions of various aldimines
formed from different aldehydes with the unsubstituted indole
and the reactions of the aldimine 1a with various substituted in-
doles were investigated (Scheme 2). The results are summarized
in Table 2. For aldimines, when electron-withdrawing groups such
R
X
OPiv
O
OPiv
OPiv
OPiv
PivO
R
X
R'
InCl3
O
H
N
PivO
N
+
R'
MS/ dry CH2Cl2
N
H
PivO
PivO
N
H
1
2
3
Scheme 2. Aza-Friedel–Crafts reaction of indole derivatives with aldimines.

1710
B.-Y. Li et al. / Carbohydrate Research 345 (2010) 1708–1712
Table 2
3. Experimental
Aza-Friedel–Crafts reaction of indole derivatives with various aldimines
Entrya
X
R
R0
T (°C) Time (h) Yieldb (%) Ratioc
3.1. General methods
1
2
3
4
5
6
7
8
9
1a: C p-NO2 2a: H
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ30
ꢀ40
ꢀ20
ꢀ40
15
15
15
15
15
15
15
15
15
15
15
80
65
73
—
>19:1
>19:1
10:1
—
All reagents were obtained from commercial suppliers and were
used without further purification. CH2Cl2 was distilled over CaH2.
Reactions were monitored by thin-layer chromatography (TLC)
using commercial silica gel HSGF254 plates. Column chromatogra-
phy was performed on Silica Gel 60 (E. Merck, 0.063–0.200 mm).
The 1H (400 MHz) and 13C NMR (100.6 MHz) spectra were recorded
with Bruker AM-400 spectrometer in DMSO-d6 solution. Chemical
shifts were referenced to the residual solvent signals (2.50 ppm for
1H and 39.43 ppm for 13C). The HR-ESI-MS data were measured on
a Bruker Apex IV FTMS. Enantiomeric ratio (er) was determined
using a Hitachi HPLC system with a Hitachi L6200 pump and an ABI
783A UV detector with Daicel Chiralcel OD-H column (25 cm ꢂ
0.46 cm ID, n-hexane/i-PrOH = 30:70, 0.5 mL/min, 254 nm).
1b: C o-NO2
1c: C p-CN
1d: C p-CF3
1e: C p-F
H
H
H
H
H
—
—
1f: N
H
70
92
—
—
90
60
10:1d
>19:1
—
1a: C p-NO2 2g: 2-Me
C
C
C
C
p-NO2 2h: 1-Boc
p-NO2 2i: 3-Me
p-NO2 2j: 5-MeO ꢀ40
p-NO2 2k: 6-Cl
ꢀ40
—
8:1
19:1
10
11
a
Without specific indication, all reactions were carried out with 0.2 equiv InCl3,
4 equiv indole, and 0.5 g 4 Å MS at the shown temperature in dry CH2Cl2.
b
Isolated yield by column chromatography.
Ratio of diastereomers was determined by 400 MHz 1H NMR.
c
d
The reaction was carried out with 1.2 equiv InCl3 and 10 equiv indole.
3.2. General procedure for the aza-Friedel–Crafts reaction to
form the compounds 3a–k
good yield (90%) and excellent diastereoselectivity (>19:1), indi-
cating that 2-substituted indole did not affect the diastereoselec-
tivity as previously reported.40
An oven-dried 10 mL vial was charged with O-pivaloylated b-
galactosylaldimine (0.30 mmol), InCl3 (0.06 mmol, 0.2 equiv) and
0.5 g4 Åmolecularsieves. Afterthevesselwasflushedwithalternat-
ing vacuum and nitrogen purge cycles, 4 mL of dry CH2Cl2 was added
to the vessel via a syringe, and the mixture was stirred under N2 at
ꢀ40 °C for 15 min before indole or substituted indole (1.2 mmol,
4 equiv) was added. The resulting mixture was stirred for the indi-
cated time until the reaction was completed as shown by TLC (usu-
ally 15 h). Then three drops of triethylamine were added and the
mixture was gradually warmed to room temperature. After removal
of the molecular sieves by filtration, the mixture was extracted with
CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4,
and filtered, and the volatiles were removed under vacuum. The res-
idue was purified by column chromatography on silica gel (petro-
leum ether/ethyl acetate = 8/1), yielding the corresponding
compounds 3a–k as mixed diastereomers. The diastereomers could
not be separated by flash chromatography.
To prepare the final product 3-indolyl methanamine deriva-
tives, we tested different methods to remove the auxiliary. The
typical method with HCl4–19,21–30 in methanol was not successful
since the 3-indolyl methane was the only product. We later found
that a new method using HOAc–H2O after treatment with NaOMe
in methanol20 (Scheme 3) generated the desired 3-indolyl methan-
amine derivatives 4g and 4k with high yields and without racemi-
zation, as representative examples.
In summary, we have developed a method to synthesize 3-indo-
lyl methanamine derivatives with InCl3 as the catalyst and using
O-pivaloylated b-D-galactosylamine as a chiral auxiliary. Excellent
yield and diastereoselectivity were obtained (yield up to 92% and
dr up to >19:1). Even the 2-substituted indole reacted to generate
the desired product in high yield and diastereoselectivity, which
was difficult to obtain under previously reported conditions. More-
over, a new method to remove the sugar moiety using aqueous
HOAc after treatment with NaOMe in methanol was developed.
This deprotection method may be useful for the removal of the
protecting group of other N-glycoside substrates with high acid
sensitivity.
3.2.1. N-[Indol-3-yl-(4-nitrophenyl)methyl]-(2,3,4,6-tetra-O-
pivaloyl-b-D-galactosyl)amine (3a)
lH NMR: d 11.00 (s, 1H, indole NH), 8.16 (d, J 8.8 Hz, 2H, ph), 7.74
(d, J 8.8 Hz, 2H, ph), 7.57 (d, J 8.0 Hz, 1H, indole), 7.34 (d, J 8.0 Hz,
NO2
NO2
OPiv
O
OPiv
PivO
H
N
H2N
1). MeOH/Na
2). HOAc, H2O
PivO
N
H
N
H
3g >19:1 dr
4g
90%, 98:2 er
NO2
NO2
OPiv
OPiv
PivO
O
H
N
H2N
1). MeOH/Na
2). HOAc, H2O
PivO
N
Cl
N
H
Cl
H
3k 19:1 dr
4k
86%, 95:5 er
Scheme 3. Cleavage of chiral auxiliary under basic conditions.

B.-Y. Li et al. / Carbohydrate Research 345 (2010) 1708–1712
1711
1H, indole), 7.15 (s, 1H, indole), 7.05 (t, J 7.6 Hz, 1H, indole), 6.91 (t, J
7.6 Hz, 1H, indole), 5.68 (s, 1H, CH), 5.26–5.23 (m, 2H, 3-H,4-H),
5.10 (t, J2,3 9.6 Hz, J1,2 8.8 Hz, 1H, 2-H), 4.16–4.06 (m, 3H, 1-H, 5-
H, 6a-H), 3.92 (dd, J6a,6b 9.2 Hz, J6b,5 4.8 Hz, 1H, 6b-H), 1.21 (s, 9H,
C(CH3)3), 1.19 (s, 9H, C(CH3)3), 1.16 (s, 9H, C(CH3)3), 1.03 (s, 9H,
C(CH3)3). 13C NMR: d176.83, 176.30, 176.18, 176.11, 151.42,
146.34, 136.33, 128.65, 124.98, 123.26, 122.41, 121.30, 118.61,
118.50, 116.78, 111.61, 85.31, 71.20, 70.35, 68.92, 67.40, 61.15,
53.47, 26.95, 26.72, 26.68, 26.65, 26.60. HR-ESI-MS: Calcd for
(d, J1,2 8.8 Hz, 1H, 1-H), 4.13 (t, J5,6a 6.4 Hz, J5,6b 6.8 Hz, 1H, 5-H),
4.06 (dd, J6a,6b 10.4 Hz, J5,6b 6.8 Hz, 1H, 6b-H), 3.92 (dd, J6a,6b
10.4 Hz, J5,6a 6.4 Hz, 1H, 6a-H), 2.40 (s, 3H, CH3), 1.26 (s, 9H,
C(CH3)3), 1.17 (s, 9H, C(CH3)3), 1.16 (s, 9H, C(CH3)3), 1.04 (s, 9H,
C(CH3)3). 13C NMR: d 176.86, 176.26, 176.23, 176.17, 151.94,
146.06, 134.91, 131.94, 127.93, 126.08, 123.29, 120.19, 118.57,
118.26, 111.55, 110.52, 85.54, 71.36, 70.49, 69.02, 67.49, 61.37,
52.90, 27.04, 26.74, 26.70, 26.64, 11.96. HR-ESI-MS: Calcd for
C
42H57N3O11 [M+Na]+: 802.3885, found: 802.3867.
C
41H55N3O11 [M+Na]+: 788.3729, found: 788.3713.
3.2.6. N-[5-Methoxy-Indol-3-yl-(4-nitrophenyl)methyl]-(2,3,4,6-
tetra-O-pivaloyl-b- -galactosyl)amine (3j)
3.2.2. N-[Indol-3-yl-(2-nitrophenyl)methyl]-(2,3,4,6-tetra-O-
pivaloyl-b- -galactosyl)amine (3b)
D
lH NMR: d 10.86 (s, 1H, indole NH), 8.18 (d, J 8.4 Hz, 2H, ph), 7.74
(d, J 8.4 Hz, 2H, ph), 7.24 (d, J 8.8 Hz, 1H, indole), 7.04 (d, J 2.0 Hz,
1H, indole), 6.96 (s, 1H, indole), 6.72 (dd, J1 2.0 Hz, J2 8.8 Hz, 1H, in-
dole), 5.64 (s, 1H, CH), 5.25–5.23 (m, 2H, 3-H,4-H), 5.09 (t, J2,3
10.0 Hz, J1,2 9.6 Hz, 1H, 2-H), 4.16–4.08 (m, 3H, 1-H, 5-H, 6a-H),
3.94 (dd, J6a,6b 10.0 Hz, J6b,5 6.0 Hz, 1H, 6b-H), 3.72 (s, 3H, OCH3),
1.19–1.16 (m, 27H, three C(CH3)3), 1.03 (s, 9H, C(CH3)3). 13C
NMR: d 176.86, 176.32, 176.22, 176.13, 153.08, 151.91, 151.40,
146.40, 131.27, 128.70, 125.36, 123.26, 116.45, 112.29, 111.46,
100.31, 99.50, 85.55, 71.24, 70.37, 68.89, 67.41, 61.22, 55.20,
53.30, 26.96, 26.75, 26.68, 26.62. HR-ESI-MS: Calcd for
D
lH NMR: d 11.01 (s, 1H, indole NH), 8.18 (d, J 8.0 Hz, 1H, ph), 7.84
(d, J 8.0 Hz, 1H, ph), 7.65 (t, J 8.0, 7.2 Hz, 1H, ph), 7.60 (d, J 8.0 Hz,
1H, indole), 7.49 (t, J 7.6 Hz, 1H, ph), 7.34 (d, J 8.0 Hz, 1H, indole),
7.06 (t, J 7.6 Hz, 1H, indole), 6.93–6.89 (m, 2H, indole), 6.10 (s, 1H,
CH), 5.26–5.24 (m, 2H, 3-H, 4-H), 5.06 (t, J2,3 9.6 Hz, J1,2 9.6 Hz,
1H, 2-H), 4.22–4.18 (m, 2H, 1-H, 5-H), 4.04 (dd, J6a,6b 10.8 Hz, J6a,5
7.6 Hz, 1H, 6a-H), 3.92 (dd, J6a,6b 10.8 Hz, J6b,5 7.2 Hz, 1H, 6b-H),
1.18 (s, 9H, C(CH3)3), 1.17 (s, 9H, C(CH3)3), 1.13 (s, 9H, C(CH3)3),
1.03 (s, 9H, C(CH3)3). 13C NMR: d 177.00, 176.25, 176.19, 176.10,
149.61, 146.34, 137.14, 136.26, 132.30, 129.70, 128.08, 125.19,
123.68, 122.97, 121.33, 118.67, 118.53, 116.22, 111.58, 85.81,
71.24, 70.40, 68.87, 67.42, 61.20, 54.82, 26.93, 26.70, 26.68,
26.61. HR-ESI-MS: Calcd for C41H55N3O11 [M+Na]+: 788.3729,
found: 788.3723.
C
42H58N3O12 [M+Na]+: 818.3834, found: 818.3822.
3.2.7. N-[6-Chloro-Indol-3-yl-(4-nitrophenyl)methyl]-(2,3,4,6-
tetra-O-pivaloyl-b- -galactosyl)amine (3k)
D
lH NMR: d 11.15 (s, 1H, indole NH), 8.16 (d, J 8.8 Hz, 2H, ph), 7.71
(d, J 8.8 Hz, 2H, ph), 7.54 (d, J 8.4 Hz, 1H, indole), 7.38 (d, J 1.6 Hz,
1H, indole), 7.22 (s, 1H, indole), 6.91 (dd, J1 8.4 Hz, J2 1.6 Hz, 1H, in-
dole), 5.64 (s, 1H, CH), 5.24–5.21 (m, 2H, 3-H,4-H), 5.10 (t, J2,3
9.6 Hz, J1,2 9.2 Hz, 1H, 2-H), 4.14–4.06 (m, 3H, 1-H, 5-H, 6a-H),
3.90 (dd, J6a,6b 9.6 Hz, J6b,5 6.4 Hz, 1H, 6b-H), 1.20 (s, 9H, C(CH3)3),
1.19 (s, 9H, C(CH3)3), 1.14 (s, 9H, C(CH3)3), 1.03 (s, 9H, C(CH3)3).
3.2.3. N-[Indol-3-yl-(4-cyanophenyl)methyl]-(2,3,4,6-tetra-O-
pivaloyl-b-D-galactosyl)amine (3c)
lH NMR: d 10.99 (s, 1H, indole NH), 7.77 (d, J 8.0 Hz, 2H, ph), 7.66
(d, J 8.0 Hz, 2H, ph), 7.55 (d, J 8.0 Hz, 1H, indole), 7.33 (d, J 8.0 Hz,
1H, indole), 7.12 (s, 1H, indole), 7.05 (t, J 8.0 Hz, 1H, indole), 6.90
(t, J 7.6 Hz, 1H, indole), 5.61 (s, 1H, CH), 5.26–5.23 (m, 2H, 3-H,4-
H), 5.09 (t, J2,3 9.2 Hz, J1,2 9.2 Hz, 1H, 2-H), 4.13–4.06 (m, 3H, 1-H,
5-H, 6a-H), 3.92 (dd, J6a,6b 9.6 Hz, J6b,5 6.0 Hz, 1H, 6b-H), 1.20 (s,
9H, C(CH3)3), 1.19 (s, 9H, C(CH3)3), 1.16 (s, 9H, C(CH3)3), 1.03 (s,
9H, C(CH3)3). 13C NMR: d 176.83, 176.30, 176.18, 176.09, 149.24,
136.30, 132.04, 128.49, 124.98, 122.28, 121.26, 118.76, 118.45,
116.98, 111.60, 109.49, 85.28, 71.17, 70.31, 68.94, 67.41, 61.17,
53.69, 26.95, 26.72, 26.68, 26.60. HR ESI MS: Calcd for
13C NMR:
d 176.84, 176.26, 176.20, 176.12, 151.20, 146.39,
136.52, 128.65, 128.03, 123.79, 123.32, 120.01, 118.78, 117.08,
111.18, 99.49, 85.34, 71.24, 70.29, 68.86, 67.34, 61.07, 54.82,
53.41, 26.96, 26.90, 26.72, 26.69. HR-ESI-MS: Calcd for
C
41H54ClN3O11 [M+Na]+: 822.3339, found: 822.3320.
C
42H55N3O9 [M+Na]+: 768.3830, found: 768.3813.
3.3. General procedure for the removal of the auxiliary to form
compounds 4g and 4k
3.2.4. N-[Indol-3-yl-(pyridine-3-yl)methyl]-(2,3,4,6-tetra-O-
pivaloyl-b- -galactosyl)amine (3f)
A solution of compound 3g or 3k (0.4 mmol) in dry methanol
(2 mL) was treated with a freshly prepared (0.5 M) solution of so-
dium methoxide (2 mL), which was prepared from sodium and dry
methanol. The solution was stirred until the reactant was con-
sumed (TLC control). To the mixture were added a few drops of
water, and the mixture was neutralized with acetic acid, after
which the mixture was stirred for another 4 h. Then the mixture
was extracted with EtOAc, washed with saturated aqueous NaH-
CO3, dried over MgSO4, and filtered, and the volatiles were re-
moved under vacuum. The residue was purified by column
chromatography on silica gel (CH2Cl2/MeOH = 30/1, with 0.1%
Et3N), yielding the corresponding compounds 4g or 4k.
D
lH NMR: d 10.98 (s, 1H, indole NH), 8.68 (s, 1H, py), 8.42 (br,
1H, py), 7.79 (d, J 8.0 Hz, 1H, indole), 7.55 (d, J 8.0 Hz, 1H, indole),
7.35–7.31 (m, 2H, py), 7.13 (s, 1H, indole), 7.05 (t, J 7.6 Hz, 1H, in-
dole), 6.91 (t, J 7.6 Hz, 1H, indole), 5.58 (s, 1H, CH), 5.27–5.24 (m,
2H, 3-H, 4-H), 5.09 (t, J2,3 9.6 Hz, J1,2 9.2 Hz, 1H, 2-H), 4.16–4.07
(m, 3H, 1-H, 5-H, 6a-H), 3.94 (dd, J6a,6b 10.4 Hz, J6b,5 6.0 Hz, 1H,
6b-H), 1.19 (s, 9H, C(CH3)3), 1.19 (s, 9H, C(CH3)3), 1.17 (s, 9H,
C(CH3)3), 1.03 (s, 9H, C(CH3)3). 13C NMR:
d 176.87, 176.31,
176.21, 176.07, 149.10, 148.07, 138.49, 136.20, 135.15, 134.42,
124.98, 123.28, 121.95, 121.28, 118.44, 117.30, 111.55, 85.17,
71.14, 70.39, 68.96, 67.50, 61.33, 51.71, 26.91, 26.74, 26.69,
26.64, 26.61. HR-ESI-MS: Calcd for
744.3830, found: 744.3819.
C
40H55N3O9 [M+Na]+:
3.3.1. N-[2-Metyl-Indol-3-yl-(4-nitrophenyl)methyl]amine (4g)
98:2 er, tmajor = 16.39 min and tminor = 19.74 min. lH NMR: d
10.84 (s, 1H, indole NH), 8.14 (d, J 8.8 Hz, 2H, ph), 7.74 (d, J
8.8 Hz, 2H, ph), 7.42 (d, J 8.0 Hz, 1H, indole), 7.21 (d, J 8.0 Hz, 1H,
indole), 6.93 (t, J 7.2 Hz, 1H, indole), 6.81 (t, J 7.2 Hz, 1H, indole),
5.52 (s, 1H, CH), 2.43 (s, 3H, CH3). 13C NMR: d 154.92, 145.62,
135.04, 131.73, 127.54, 126.22, 123.00, 119.96, 118.66, 118.16,
113.81, 110.36, 50.75, 11.75. HR-ESI-MS: Calcd for C16H15N3O2
[MꢀH]+: 280.1080, found: 280.1078.
3.2.5. N-[2-Metyl-Indol-3-yl-(4-nitrophenyl)methyl]-(2,3,4,6-
tetra-O-pivaloyl-b- -galactosyl)amine (3g)
D
lH NMR: d 10.92 (s, 1H, indole NH), 8.14 (d, J 8.8 Hz, 2H, ph), 7.74
(d, J 8.8 Hz, 2H, ph), 7.54 (d, J 8.0 Hz, 1H, indole), 7.21 (d, J 8.0 Hz,
1H, indole), 6.95 (t, J 7.6 Hz, 1H, indole), 6.84 (t, J 7.6 Hz, 1H, indole),
5.69 (s, 1H, CH), 5.27 (dd, J3,4 3.2 Hz, J2,3 10.0 Hz, 1H, 3-H), 5.23 (d,
J3,4 3.2 Hz, 1H, 4-H), 5.12 (t, J2,3 10.0 Hz, J1,2 8.8 Hz, 1H, 2-H), 4.24

1712
B.-Y. Li et al. / Carbohydrate Research 345 (2010) 1708–1712
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3.3.2. N-[6-Chloro-indol-3-yl-(4-nitrophenyl)methyl]amine (4k)
90:5 er, tmajor = 11.66 min and tminor = 14.66 min. lH NMR: d 8.15
(d, J 8.4 Hz, 2H, ph), 7.73 (d, J 8.4 Hz, 2H, ph), 7.47 (d, J 8.4 Hz, 1H,
indole), 7.37 (s, 1H, indole), 7.31 (s, 1H, indole), 6.92 (d, J 8.4 Hz, 1 H,
indole), 5.47 (s, 1H, CH). 13C NMR: d154.84, 145.93, 136.67, 127.95,
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