Organocatalytic asymmetric Michael addition of aliphatic aldehydes to indolylnitroalkenes: Access to contiguous stereogenic tryptamine precursors

Article abstract of DOI:10.1021/jo3024945

Because of the importance of the indole framework and the versatile transformation of nitro and formyl groups, the efficient synthesis of optically pure 2-alkyl-3-(1H-indol-3-yl)-4-nitrobutanals, one type of tryptamine precursors are of great interest for pharmaceutical and biological research. Herein, the Michael addition of aliphatic aldehydes to indolylnitroalkenes has been developed using (S)-diphenylprolinol trimethylsilyl ether as an organocatalyst, which provides the desired optically pure syn 2-alkyl-3-(1H-indol-3-yl)-4-nitrobutanal derivatives in up to 98% yield with up to >99:1 dr and >99% ee. To show the synthetic usefulness of this methodology, optically active 2-alkyl-4-nitro-3-(1-tosyl-1H-indol-3-yl)butan-1- ol and tryptamine derivatives are readily obtained by stepwise systematic transformations.

Full text of DOI:10.1021/jo3024945

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Article
Organocatalytic Asymmetric Michael Addition of
Aliphatic Aldehydes to Indolylnitroalkenes: Access
to Contiguous Stereogenic Tryptamine Precursors
Jian Chen, Zhi-Cong Geng, Ning Li, Xiao-Fei Huang, Feng-Feng Pan, and Xing-Wang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo3024945 • Publication Date (Web): 14 Feb 2013
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Organocatalytic Asymmetric Michael Addition of Aliphatic
Aldehydes to Indolylnitroalkenes: Access to Contiguous Stereogenic
Tryptamine Precursors
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Jian Chen, ZhiꢀCong Geng, Ning Li, XiaoꢀFei Huang, FengꢀFeng Pan, and
XingꢀWang Wang*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
People’s Republic of China
Fax: +(86)512ꢀ6588ꢀ0378 Eꢀmail: wangxw@suda.edu.cn
NHBoc
O
+
Ph
O2N
R1
R1
HO
Ph
OTMS
N
H
R2
N
H
H
R2
(10 mol%)
CH2Cl2
NO2
H
R4
O
N
N
Ts
up to 98% yield
>99:1 dr, >99% ee
N
R1
Ts
N
R3
ABSTRACT: Due to the importance of indole framework and the versatile
transformation of nitroꢀ and formylꢀgroups, the efficient synthesis of optically pure
2ꢀalkylꢀ3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ4ꢀnitrobutanals, one type of tryptamine precursors, are of
great interest for pharmaceutical and biological research. Herein, the Michael addition
of aliphatic aldehydes to indolylnitroalkenes has been developed using
(S)ꢀdiphenylprolinol trimethylsilyl ether as an organocatalyst, which provides the
desired optically pure syn 2ꢀalkylꢀ3ꢀ(1Hꢀindolꢀ3ꢀyl)ꢀ4ꢀnitrobutanal derivatives in up
to 98% yield with up to >99:1 dr and >99% ee. As synthetic usefulness of this
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methodology, optically active 2ꢀalkylꢀ4ꢀnitroꢀ3ꢀ(1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)butanꢀ1ꢀol and
tryptamine derivatives are readily obtained by stepwise systematic transformations.
INTRODUCTION
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Indole derivatives bearing chiral functional groups at the 3ꢀposition have been
found in a fascinating array of bioactive natural products, pharmaceutical compounds,
and intermediates of complex compounds (Figure 1).1 Tryptamine scaffolds are
especially important and extensively present in many natural products and therapeutic
agents.2 For example, Hapalindol D I3 is a member of the hapalindoles, which belong
to a group of 20 structurally related alkaloid natural products isolated from the
terrestrial blue green algae Hapalosiphon fontinalis, an organism found to exhibit
antibacterial and antimycotic activity. Compound II4 is a late stage intermediate in the
synthesis of the dual action migraine drug prototype. Isatisine A III5 is isolated from
the leaves of Isatis indigotica Fort. (Cruciferae). Meridianin F IV6 is a member of
alkaloids isolated from the south Atlantic tunicate Aplidium meridianum.
BMSꢀ594726 V7 is a highly potent and selective serotonin reuptake inhibitor.
Hamacanthin B VI8 reveals cytotoxic activities against a wide range of human tumor
cell lines with GI50 values at micromolar concentration.
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Me
N
O
N
5
6
7
8
O
H
HO
HO
NCS
N
S
O
NH
N
N
N
H
H
H
HO
I
II
III
9
Hapalindol D
drug prototype
isatisine A
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H2N
N
N
H
N
O
N
NC
Br
Br
Br
Br
N
H
N
N
HN
NH
H
IV
meridianin F
V
VI
Hamacanthin B
BMS-594726
Figure 1. Tryptamine derivatives and important indolꢀ3ꢀyl substituted compounds.
As highly practical and atomꢀeconomic carbonꢀcarbon bond formation reaction, the
Michael additions of active methyleneꢀcontaining carbonyl compounds to
nitroalkenes9 or nitroalkanes to
α
,βꢀunsaturated carbonyl compounds10 are efficient
methods for preparation of nitroalkane derivatives, which has been extensively
investigated in the last decade. Among them, Michael additions of aldehydes to
nitroalkenes
are
of
great
importance
to
furnish
very
useful
α
,βꢀdisubstitutedꢀ
γ
ꢀnitrobutanals11b, which can be readily converted to corresponding
amino acids or amino alcohols. Since List12 and Barbas III13 respectively reported the
organocatalytic14 asymmetric Michael addition of ketones or aldehydes to
nitroalkenes in 2001, considerable efforts have subsequently been devoted to finding
more effecient catalytic systems for such a transformation.15
Besides nitrostyrenes as being the most widely used Michael acceptors,9,15 some
functionalized nitroolefins16 such as βꢀnitroacrolein dimethyl acetal16b,c or
3ꢀnitroacrylate16e have also been recently reported as Michael acceptors. After
investigating the literatures reported, we disclosed that indolylnitroalkenes were less
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addressed in asymmetric transformation.17 In addition, although construction of
stereocenter on 3ꢀposition of indole scaffold mainly through FriedelꢀCrafts reactions
has been elaborately studied in the past decade,18 the Michael reactions of
construction of two continuous stereocenters with indole motifs was seldom
explored.19 Besides FriedelꢀCrafts reactions, an alternative approach to tryptamine
precursors involves the addtion of nitroalkanes to alkylideneindolenines.20
Considering the importance of the tryptamine derivatives and the versatile
transformation of nitroꢀ and formylꢀ groups, investigating the asymmetric Michael
addition between the indolylnitroalkenes and aliphatic aldehydes providing
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α,βꢀdisubstitutedꢀγꢀnitrobutanals with two adjacent stereocenters is highly desirable
(Scheme 1). Although Hayashi and coꢀworkers had already reported the Michael
addtion of aldehyde to nitroalkene by means of the HayashiꢀJørgensen catalyst,21 we
hoped to develop an efficient procedure for access to chiral functionalized tryptamine
derivatives. Herein, optically pure synꢀ2ꢀalkylꢀ4ꢀnitroꢀ3ꢀ(1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)
butanal derivatives, one type of tryptamine precursors, were found to be efficiently
synthesized in high yields with excellent diastereoꢀ and enantioselectivities through
the Michael additions of aliphatic aldehydes to indolylnitroalkenes with
(S)ꢀdiphenylprolinol trimethylsilyl ether as the organic catalyst.
Scheme 1. Synthetic Strategies for Tryptamine Precursors
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Reported work
NO2
R1
5
6
7
8
Friedel-Crafts
reaction
∗
NO2
+
R1
N
R
N
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R
Ts
R5
NO2
R3
R2
R4
R5
∗
Alkylation
NO2
R3
+
reaction
R4
R2
N
H
N
H
Our work: two continuous stereocenters
CHO
∗
NO2
NO2
R6
∗
R6
CHO
Michael Addition
reaction
+
N
R
N
R
RESULTS AND DISCUSSION
In order to verify our synthetic hypothesis, the Michael addition of butyraldehyde
2a with transꢀ3ꢀ(2ꢀnitroethenyl)ꢀNꢀtosylindole 3a was chosen as a model reaction for
the synthesis of desired chiral 2ꢀethylꢀ4ꢀnitroꢀ3ꢀ(1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)butanal 4a.
Proline 1a and proline derivatives 1b−1j were chosen as potential catalysts, and the
catalytic results are summarized in Table 1. Initially, we probed the Michael addition
of butyraldehyde 2a to transꢀ3ꢀ(2ꢀnitroethenyl)ꢀNꢀtosylindole 3a using (S)ꢀproline 1a
as catalyst, affording the Michael adduct 4a in 53% yield with 80:20 dr and 11% ee
within 0.5 hour (Table 1, entry 1). Organocatalysts 1c, 1e and 1h were proven to be
ineffective for the reaction, even prolonging the reaction time to 10 hours (Table 1,
entries 3, 5 and 8). To our delight, when (S)ꢀproline derived catalysts 1b, 1d, 1f and
1g were employed for this reaction, moderate yields and stereoselectivities were
observed (Table 1, entries 2, 4, 6 and 7). Subsequently, two diarylprolinol silyl ether
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catalysts 1i and 1j were used to catalyze this reaction. Fortunately, the reaction with 1j
proceeded very well to furnish the desired product 4a in 95% yield with 92:8 dr and
up to 99% ee (Table 1, entry 10). (S)ꢀdiphenylprolinol trimethylsilyl ether 1j was
finally confirmed to be the most effective catalyst in terms of both reactivity and
stereochemistry control.
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Table 1. Catalyst Screening for the Michael Addition of Butyraldehyde 2a with
transꢀ3ꢀ(2ꢀNitroethenyl)ꢀNꢀtosylindole 3aa
O2N
O
NO2
cat. 1 (10 mol%)
H
CHCl3, rt
H
N
O
N
Ts
Ts
2a
3a
4a
Ph
N
COOH
N
N
N
H
N
N
N
S
SO2Ph
Ar
H
H
H
H.HCl
Ph
HN N
HN
HN
Ph
1a
1b
1c
1d
1e
O
HO
O
Ar
OR
1h Ar = Ph, R = H
N
N
HN
N
H
H
H
HN
OMe
1i Ar = 3,5-(CH3)2Ph, R = TMS
1j Ar = Ph, R = TMS
1f
1g
entry
cat.
time (h)
yield (%)b
dr (syn/anti)c
ee (%)d
1
2
3
4
5
1a
1b
1c
1d
1e
0.5
0.5
10
53
48
80:20
86:14
−
11
60
−
NR
73
0.5
10
66:34
−
ꢀ12
−
NR
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1f
1g
1h
1i
0.5
0.5
10
15
80
85:15
85:15
−
63
71
−
8
NR
92
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9
0.5
0.5
87:13
92:8
96
99
10
1j
95
a Reactions were performed with 2a (1.0 mmol), 3a (0.2 mmol), and catalyst 1 (10 mol% with respect to 3a) in
b
c
d
CHCl3 (1.0 mL) at room temperature. Yield of isolated product. Determined by chiral HPLC analysis.
Determined by chiral HPLC analysis.
To further optimize the reaction conditions, some of reaction parameters including
solvents, additives and temperatures, were examined in the presence of 10 mol% of
catalyst 1j, and the results are shown in Table 2. Firstly, some polar and protic
solvents, such as DMF, MeOH and H2O, were tested for the model Michael addition.
All the reactions proceeded smoothly to produce the desired product 4a in 43–81%
yields with 72:28–89:11 drs and 84–98% ees, respectively (Table 2, entries 2−4).
Subsequently, some nonꢀpolar and aprotic solvents, such as hexane, THF, toluene and
CH2Cl2, were investigated for this reaction, CH2Cl2 turned out to be the best medium
in terms of both yield and stereoselectivity, which furnished the expected product 4a
in 95% yield with 93:7 dr and 99% ee (Table 2, entry 8 vs. entries 5−7). Furthermore,
a series of brønsted acids combined with 1j as the catalysts were tested but gave
inferior diastereoselectivities (87:13−92:8 drs) for all cases, albeit with retained
enantioselectivities (Table 2, entries 8−15). In addition, we also examined the
feasibility to reduce the catalyst loading to a practical level. When the catalyst loading
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of 1j was reduced to 5 mol%, prolonged reaction time was required and decreased
diastereoselectivity was exhibited (Table 2, entry 16). In order to improve the
diastereoselectivity, the reaction temperature was examined for this transformation.
Gratefully, by decreasing the reaction temperature from room temperature to −45 °C,
the diastereoselectivity was found to be dramatically increased from 93:7 to 99:1
without sacrifice of yields and enantioselectivities (Table 2, entries 17−20). With a
balance of reactivity and stereoselectivity, −30 °C turned out to be the optimal
reaction temperature.
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Table 2. Optimization of Catalytic Asymmetric Michael Addition of Butyraldehyde
2a with transꢀ3ꢀ(2ꢀNitroethenyl)ꢀNꢀtosylindole 3aa
O2N
O
NO2
1j (10 mol%)
H
add., solv.
H
N
O
N
Ts
3a
Ts
2a
solv.
4a
yield (%)b dr (syn/anti)c
entry
add.
time
(h)
ee
temp.(°C)
(%)d
1
2
3
4
5
6
7
CHCl3
DMF
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
rt
rt
rt
rt
rt
rt
rt
0.5
12
12
12
12
12
12
95
43
81
80
9
92:8
78:22
72:28
89:11
93:7
99
84
MeOH
H2O
88
98
hexane
THF
>99
93
41
89
74:26
92:8
toluene
99
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CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀꢀ
rt
rt
0.5
0.5
95
98
93:7
99
99
PhCOOH
89:11
9
4ꢀNO2ꢀC6H4COOH
CH3COOH
3
0.5
3
94
96
92
93
97
99
88:12
88:12
90:10
92:8
99
99
99
99
99
99
10
11
12
13
14
15
rt
10
11
12
13
14
15
16
17
18
19
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rt
CF3COOH
rt
DꢀCSA
4
rt
DꢀMandelic acid
LꢀMandelic acid
4
87:13
87:13
rt
4
rt
16e CH2Cl2
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
rt
18
4
94
98
97
95
96
92:8
96:4
97:3
98:2
99:1
99
99
17
18
19
20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
12
20
84
>99
>99
>99
−15
−30
−45
a Unless noted, reactions were performed with 2a (1.0 mmol), 3a (0.2 mmol), additive and 1j (10 mol% with
respect to 3a) in solvent (1.0 mL). b Yield of isolated product. c Determined by chiral HPLC analysis. d Determined
by chiral HPLC analysis. e 5 mol% of 1j was used.
Besides optimization of the reaction conditions, we also tried to elucidate whether
Nꢀprotected substituents on indole scaffold affected the catalytic results at room
temperature. For nonꢀprotected 3ꢀ(2ꢀnitrovinyl) indole 3b, the Michael addition could
produce the desired product 4b in 96% yield with 81:19 dr and 98% ee in the
presence of 10 mol% of catalyst 1j in CH2Cl2 (Table 3, entry 2). For substrate 3c
bearing Nꢀmethyl protected group, the yield and enantioselectivity value were
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somewhat dropped, albeit with diastereoselectivity retained (Table 3, entry 3 vs. entry
1). When substrate 3d with benzyl protected substituent was used, even if the reaction
time was prolonged to 72 hours, only trace amount of the expected product was
observed (Table 3, entry 4). When indolylnitroalkene 3e contained Nꢀphenylsulfonyl
group, excellent enantioselectivity of the desired product 4e was achieved for the
corresponding Michael addition, but slightly lowered yield and diastereoselectivity
were observed in comparison with the outcome (95% yield, 93:7 dr and 99% ee) of
Nꢀtosyl protected indolylnitroalkene 3a (Table 3, entry 5 vs. entry 1). Thus, it was
evident that Nꢀtosyl protected indolylnitroalkene 3a was the best choice for this
transformation.
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Table 3. Effect of NꢀProtecting Groups of Indolylnitroalkenes 3a−3e on the Michael
Reactiona
O2N
O
NO2
1j (10 mol%)
H
CH2Cl2, rt
H
N
O
N
R
R
2a
3a−3e
4a−4e
entry
R
product
time (h)
yield (%)b
dr (syn/anti)c
93:7
ee (%)d
99
1
2
3
4
5
Ts (3a)
H (3b)
Me (3c)
Bn (3d)
4a
4b
4c
4d
4e
0.5
40
95
96
80
<5
92
81:19
98
72
93:7
96
72
−
−
Phenylsulfonyl (3e)
0.5
91:9
99
a Reactions were performed with 2a (1.0 mmol), 3a−3e (0.2 mmol), and 1j (10 mol% with respect to 3a−3e) in
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b
c
d
CH2Cl2 (1.0 mL) at room temperature. Yield of isolated product. Determined by chiral HPLC analysis.
5
6
Determined by chiral HPLC analysis.
7
8
9
With the optimized conditions in hand (dichloromethane as reaction medium, 0 °C
~ −30 °C, 10 mol% of 1j as the catalyst), the substrate scope of the asymmetric
Michael addition was then investigated by applying a range of aliphatic aldehydes and
indolylnitroalkenes as donors and acceptors, and the results are summarized in Table 4.
When a variety of aldehydes, including nꢀbutanal 2a, pentanal 2b, isovaleral 2c,
heptanal 2d, octanal 2e and phenylpropylaldehyde 2f, were used as Michael donor
reagents to react with (E)ꢀ3ꢀ(2ꢀnitrovinyl)ꢀ1ꢀtosylꢀ1Hꢀindole 3a, all the reactions
proceeded very well and furnished the corresponding expected products 4a and 4f−4j
in 94−98% yields with 98:2−>99:1 drs and >99% ees (Table 4, entries 1−6). However,
for this transformation, it is obvious that different Michael donors show different
reactivities. For example, the Michael reactions with isovaleral 2c and octanal 2e as
nucleophilic substrates could not complete even after 120 hours at −30 °C. When the
reaction temperature were increased to 0 °C and −15 °C, the reactions were complete
within 30 hours to give the desired products 4g and 4i in excellent yields with perfect
stereoselectivities, respectively (Table 4, entries 3 and 5). Subsequently,
indolylnitroalkenes 3f and 3g bearing ꢀBr and ꢀOMe substituents on 5ꢀposition of
indole backbones were also respectively investigated for this transformation. All the
Michael addition reactions between 2b−2e and 3f−3g proceeded smoothly to
afford the corresponding products 4k−4q in 92−97% yields with 97:3−>99:1 drs
and >99 ees (Table 4, entries 7−13). When 6ꢀBr substituted indolylnitroalkenes 3h
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reacted with aliphatic aldehydes 2b−2e, excellent catalytic results (92−98% yields,
98:2−>99:1 drs and >99% ees) were achieved (Table 4, entries 14−17). More
indolylnitroalkenes 3i−3l bearing 2ꢀMe, 4ꢀMe, 6ꢀCl or 7ꢀNO2 substituents were also
proven to be suitable substrates for this transformation, and the Michael addition
reactions between 3i−3l and 2b proceeded smoothly to give Michael adducts
4v−4y in 90−98% yields with 97:3−99:1 drs and >99 ees (Table 4, entries 18−21).
In addition, 2ꢀmethylpropanal 2g was also used as a substrate for access to a
quaternary carbonꢀcontaining adduct 4z, but only 26% yield and 87% ee of the
desired product were obtained for this transformation (Scheme 2). Fortunately, single
crystals of 4u were obtained by recrystallization from hexane/ether, and its relative
syn configuration of the nitromethyl and formyl groups was unambiguously assigned
by Xꢀray crystallographic analysis.22
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Table 4. Organocatalytic Asymmetric Michael Addition of Aliphatic Aldehydes 2 to
Indolylnitroalkenes 3a
O2N
NO2
R2
R2
R1
1j (10 mol%)
O
R1
CH2Cl2, −30−0 °C
H
H
N
O
N
Ts
Ts
2
3
4
R1
R2
entry
product temp. time
yield
(%)b
dr (syn/
anti)c
ee
(h)
(%)d
(°C)
1
2
Et (2a)
H (3a)
H (3a)
4a
4f
18
40
95
96
98:2
>99
>99
−
−
30
30
nꢀPr (2b)
>99:1
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3
4
iꢀPr (2c)
nꢀPentyl (2d)
nꢀHexyl (2e)
Bn (2f)
H (3a)
H (3a)
4g
4h
4i
0
30
72
30
67
40
44
40
40
44
60
60
38
35
58
72
48
48
48
48
94
95
98
98
97
95
95
92
98
98
97
96
98
93
92
98
90
98
91
>99:1
99:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
−
30
15
30
30
5
H (3a)
>99:1
>99:1
97:3
−
−
−
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6
H (3a)
4j
7
nꢀPr (2b)
5ꢀBr (3f)
5ꢀBr (3f)
5ꢀBr (3f)
5ꢀBr (3f)
5ꢀMeO (3g)
4k
4l
8
iꢀPr (2c)
0
>99:1
97:3
9
nꢀPentyl (2d)
nꢀHexyl (2e)
nꢀPr (2b)
4m
4n
4o
4p
4q
4r
4s
−
15
15
30
15
15
30
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14
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21
97:3
−
−
−
−
−
>99:1
98:2
nꢀPentyl (2d) 5ꢀMeO (3g)
nꢀHexyl (2e) 5ꢀMeO (3g)
98:2
nꢀPr (2b)
iꢀPr (2c)
6ꢀBr (3h)
6ꢀBr (3h)
6ꢀBr (3h)
6ꢀBr (3h)
2ꢀCH3 (3i)
4ꢀCH3 (3j)
6ꢀCl (3k)
7ꢀNO2 (3l)
99:1
0
>99:1
98:2
nꢀPentyl (2d)
nꢀHexyl (2e)
nꢀPr (2b)
4t
−
15
15
4u
4v
4w
4x
4y
>99:1
97:3
−
−30
−30
−30
−30
nꢀPr (2b)
99:1
nꢀPr (2b)
99:1
nꢀPr (2b)
98:2
a Reactions were performed with 2 (1.0 mmol), 3 (0.2 mmol), and 1j (10 mol% with respect to 3) in CH2Cl2 (1.0
mL). b Yield of isolated product. c Determined by chiral HPLC analysis. d Determined by chiral HPLC analysis.
Scheme 2. Asymmetric Michael Addition of 2ꢀMethylpropanal 2g to 3a
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Citronellal 2h, as a natural perfume, used to synthesize menthol with an
antibacterial and antiphlogistic activity, was exploited to react with 3a in presence of
10 mol% of 1j, which afforded a couple of diastereomers of the desired adducts 5a
and 5b in 52% and 31% yields with >99% ees, respectively (Scheme 3). For the
further application of this transformation, the direct asymmetric cascade
Michael/reduction sequence was also attempted, which avoided the isolation and
purification of the Michael adducts. The Michael additions between nꢀbutanal 2a with
3h and propanal 2i with 3a were carried out in CH2Cl2 at −15 °C and −30 °C
respectively until judged complete by TLC. After replacing the dichloromethane with
methanol, NaBH4 (3.0 eq) was added portionwise, then the reaction proceeded for
another 6 hours. Pleasingly, the desired products were isolated in 94% yield with 99:1
dr and over 99% ee for 6a and 95% yield with 96:4 dr and over 99% ee for 6b,
respectively (Scheme 4).
Scheme 3. Asymmetric Michael Addition of Racemic Citronellal 2h to 3a
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CHO
NO2
1j (10 mol%)
NO2
+
CH2Cl2, rt
N
Ts
OHC
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N
Ts
2h
(±)-citronellal
3a
5a: 52% yield, >99% ee
5b: 31% yield, >99% ee
Scheme 4. Asymmetric Sequential Michael/Reduction Reaction for the Synthesis of
6a and 6b
O2N
R2
1) 1j (10 mol%),
CH2Cl2, −15 or −30 °C
NO2
R1
R2
O
R1
2) NaBH4, MeOH
H
N
OH
N
Ts
Ts
2a: n-butanal
2i: propanal
3h: R2 = 6-Br
3a: R2 = H
6a: 94% yield, 99:1 dr, >99% ee
6b: 95% yield, 96:4 dr, >99% ee
In order to show the synthetic utility of the transformation, we conducted the
hydrogenation of γꢀformyl nitro compound 4g with 10 mol% of Pd/C (10% w/w). The
cascade reductive amination/cyclization reaction proceeded successfully to furnish the
desired pyrrolidine with trans contiguous stereocenters. After removal of the catalyst
and the solvent, the crude product was directly transferred into its Nꢀtosyl protected
derivative 7 in 58% yield with 94:6 dr and over 99% ee (Scheme 5). In addition,
γꢀformyl nitro compound 4a was sequentially reduced by NaBH4 and Pd/C (10 mol%)
in anhydrous methanol to furnish 1,4ꢀamino alcohol compound. Subsequently, the
Tosyl group was removed by treatment with Mg and NH4Cl in methanol. Finally, the
resulting tryptamine product was directly transferred into its NHꢀBoc protected
derivative 8 in 74% yield with 98:2 dr and 99% ee (Scheme 6). Intriguingly, it was
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further disclosed that desulfonylation and nitro reduction of 4a could be
simultaneously carried out in the presence of magnesium and ammonium chloride in
methanol. After reductive amination by NaBH4 followed by in situ NꢀBoc protection,
cyclic tryptamine derivative 9 was obtained in 13% yield with 94:6 dr and 82% ee,
through a threeꢀstep, one pot operation (Scheme 6).
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Scheme 5. Synthesis of Cyclic Tryptamine Derivative 7
Ts
N
NO2
1) Pd(C), H2, CH3OH
2) TsCl, Et3N, CH2Cl2
H
O
N
N
Ts
Ts
4g
>99:1 dr, >99% ee
7
58% yield, 94:6 dr, >99% ee
Scheme 6. Synthesis of Tryptamine Derivative 8 and 9
NO2
1) NaBH4, CH3OH
2) Pd(C), H2
NHBoc
3) Mg, NH4Cl
H
4) (Boc)2O
HO
O
N
N
H
Ts
8
4a
74% yield, 98:2 dr, 99% ee
98:2 dr, >99% ee
NH
NO2
1) Mg, NH4Cl, CH3OH
2) NaBH4
3) (Boc)2O
H
O
N
N
Boc
Ts
9
4a
98:2 dr, >99% ee
13% yield, 94:6 dr, 82% ee
CONCLUSION
In summary, we have developed a direct asymmetric Michael addition of aliphatic
aldehydes to indoleꢀ3ꢀcarboxaldehyde derived nitroalkenes with (S)ꢀdiphenylprolinol
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trimethylsilyl ether as an efficient organic catalyst. The expected chiral tryptamine
precursors were obtained in excellent yields with nearly optically pure form for most
of cases. As instances of applications of this organocatalytic asymmetric Michael
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addition,
derivatives were readily achieved with both good diastereoselectivities and excellent
enantioselectivities. In addition, the optically pure
2ꢀalkylꢀ4ꢀnitroꢀ3ꢀ(1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl) butanal products could be facilely converted
into a wide array of useful frameworks such as 1,4ꢀamino alcohols or ꢀamino acids in
2ꢀalkylꢀ4ꢀnitroꢀ3ꢀ(1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)butanꢀ1ꢀol
and
tryptamine
γ
a straightforword manner. The useful methodology will be expected to be further
applied into the synthesis of some natural products and compounds of pharmaceutical
interest.
EXPERIMENTAL SECTION
General Information. Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. All reactions were carried
out in air and using undistilled solvent, without any precautions to exclude air and
moisture unless otherwise noted. Reactions were monitored by thinꢀlayer
chromatography (TLC) on silica gel GFꢀ254 precoated glass plates. Chromatograms
were visualized by fluorescence quenching with UV light at 254 nm. Flash column
chromatography was performed using silica gel. Melting points were measured on a
1
melting point apparatus and uncorrected. H and 13C NMR spectra were recorded in
CDCl3 or D6ꢀDMSO on 300 MHz or 400 MHz spectometers. Tetramethylsilane (TMS)
served as internal standard for 1H NMR and CDCl3 or D6ꢀDMSO was used as internal
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standard for 13C NMR. IR spectra were recorded on a FTꢀIR spectrometer. Mass
spectra were carried out using Quadrupole LC/MS system with ESI resource. HRMS
was recorded on a commercial apparatus (ESI Source). HPLC analysis was conducted
on a HPLC system equipped with chiralꢀstationaryꢀphase columns (Φ 0.46 cm × 25
cm). Optical rotations were measured on a polarimeter and reported as follows: [α]D
(c in g per 100 mL, solvent).
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General Procedure for the Preparation of Indolylnitroalkenes 3a−3l. Phosphorus
oxychloride was added dropwise to dimethyl formamide with iceꢀbath cooling. The
chosen indoles were added as a dimethyl formamide solution for preparation of
corresponding indole carbaldehydes. Subsequently, the ꢀNH group of indole
carbaldehydes were protected with methyl, tosyl, benzyl or phenylsulfonyl by using
corresponding halogenides under different basic conditions, such as sodium hydride
or potassium carbonate. Then, the resulting Nꢀprotected or unprotected indole
carbaldehydes reacted with nitromethane to furnish the desired indolylnitroalkenes in
presence of ammonium acetate as the catalyst. 23
(E)-3-(2-Nitrovinyl)-1-tosyl-1H-indole (3a): 1H NMR (300 MHz, D6ꢀDMSO) δ 8.73
(s, 1H), 8.35 (d, J = 13.5 Hz, 1H), 8.21 (d, J = 13.8 Hz, 1H), 8.10–7.85 (m, 4H),
7.53–7.29 (m, 4H), 2.26 (s, 3H); 13C NMR (75 MHz, D6ꢀDMSO) δ 146.3, 136.8,
134.7, 133.4, 133.3, 131.0, 130.5, 127.0, 126.9, 126.01, 124.7, 121.4, 113.7, 113.4,
21.0.
1
(E)-1-Benzyl-3-(2-nitrovinyl)-1H-indole (3d): H NMR (300 MHz, D6ꢀDMSO) δ
8.46–8.35 (m, 2H), 8.10–7.95 (m, 2H), 7.66–7.57 (m, 1H), 7.42–7.19 (m, 7H), 5.51 (s,
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2H); 13C NMR (75 MHz, D6ꢀDMSO) δ 138.7, 137.5, 136.7, 134.0, 131.6, 128.7,
127.8, 127.3, 125.3, 123.6, 122.3, 120.9, 111.7, 107.8, 49.8.
7
8
9
(E)-6-Bromo-3-(2-nitrovinyl)-1-tosyl-1H-indole (3h): 1H NMR (300 MHz,
D6ꢀDMSO) δ 8.74 (s, 1H), 8.35–8.11 (m, 2H), 8.11–7.80 (m, 4H), 7.56–7.28 (m, 3H),
2.30 (s, 3H); 13C NMR (75 MHz, D6ꢀDMSO) δ 146.6, 137.3, 135.3, 133.4, 133.2,
130.7, 130.3, 127.6, 127.0, 126.1, 123.1, 118.7, 115.8, 113.5, 21.1.
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General Procedure for the Michael Addition Reaction. (S)ꢀdiphenylprolinol
trimethylsilyl ether 1j (6.51 mg, 0.02 mmol) and indolylnitroalkene 3 (0.20 mmol)
were dissolved in DCM (1.0 mL) at rt or –30 °C. The solution was stirred for 10 min,
and then aliphatic aldehyde 2 (1.00 mmol) was added. The reaction mixture was then
stirred at suitable reaction temperature until complete consumption of nitroalkene
(monitored by TLC). The solvent was evaporated and the residue was purified by
flash column silicaꢀgel chromatography (PE/EA = 5/1 ~ 8/1) to provide the
corresponding Michael adducts.
(2S,3R)-2-Ethyl-4-nitro-3-(1-tosyl-1H-indol-3-yl)butanal (4a): Reaction at −30 °C,
pale yellow oil, 95% yield (78.7 mg), >99% ee, dr = 98/2. HPLC: Chiralcel ODꢀH,
hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor = 41.061 min,
tminor = 35.479 min; [α]D25 = +7.72 (c 0.26, CH3COCH3); 1H NMR (400 MHz, CDCl3):
δ 9.72 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H), 7.48 (d,
J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.0 Hz,
2H), 4.79–4.70 (m, 2H), 4.14–4.06 (m, 1H), 2.90 (q, J = 6.8 Hz, J = 13.6 Hz, 1H),
2.31 (s, 3H), 1.61–1.54 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
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δ 203.0, 145.4, 135.3, 134.6, 130.1, 129.4, 126.8, 125.5, 125.2, 123.9, 119.2, 118.4,
114.3, 77.4, 53.9, 34.3, 21.7, 20.6, 11.0; IR (KBr) νmax: 3114.0, 2959.9, 2937.7,
2873.7, 2729.5, 1720.9, 1553.1, 1448.7, 1370.5, 1172.5, 1127.6, 754.6, 668.8, 575.0
cm−1; MS (ESI): calcd for C21H22N2NaO5S [M+Na]+ 437.1, Found: 437.1; HRMS
(ESI): calcd for C21H26N3O5S [M+NH4]+ 432.1588, Found: 432.1575.
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2-Ethyl-3-(1H-indol-3-yl)-4-nitrobutanal (4b): Reaction at room temperature, pale
yellow oil, 96% yield (50.0 mg), 98% ee, dr = 81/19. HPLC: Chiralcel ODꢀH,
hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor = 25.731 min,
t
minor = 20.987 min; [α]D25 = −2.08 (c 2.16, CH3COCH3); 1H NMR (400 MHz, CDCl3):
δ 9.70 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.36–7.29 (m, 1H),
7.23−7.17 (m, 1H), 7.17−7.11 (m, 1H), 6.99 (s, 1H), 4.84−4.67 (m, 2H), 4.19−4.09 (m,
13
1H), 2.93–2.85 (m, 1H), 1.64–1.53 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H); C NMR (100
MHz, CDCl3) δ 204.3, 136.5, 126.0, 123.3, 122.7, 120.2, 118.6, 111.9, 111.1, 78.1,
54.8, 35.2, 20.7, 11.2; IR (KBr) νmax: 3134.5, 3057.7, 2957.0, 2877.0, 2724.3, 1717.2,
1550.8, 1448.1, 1376.2, 1094.8, 1015.6, 976.0, 747.5 cm−1; MS (ESI) calcd for
C14H16N2NaO3 [M+Na]+ 283.1, Found: 283.1; HRMS (ESI) calcd for C14H20N3O3
[M+NH4]+ 278.1499, Found: 278.1490.
2-Ethyl-3-(1-methyl-1H-indol-3-yl)-4-nitrobutanal (4c): Reaction at room
temperature, pale yellow oil, 80% yield (43.9 mg), 96% ee, dr = 93/7. HPLC:
Chiralcel ODꢀH, hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor
=
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27.079 min, tminor = 20.001 min; [α]D = −6.30 (c 1.84, CH3COCH3); H NMR (400
MHz, CDCl3): δ 9.72 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.31–7.22 (m, 2H),
7.17–7.11 (m, 1H), 6.92 (s, 1H), 4.79–4.68 (m, 2H), 4.17–4.08 (m, 1H), 3.73 (s, 3H),
2.92–2.85 (m, 1H), 1.65–1.57 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 204.2, 137.3, 127.8, 122.4, 122.3, 119.8, 118.7, 109.9, 109.6, 78.2, 54.9,
35.2, 33.0, 20.7, 11.3; IR (KBr) ν max: 3121.3, 3057.0, 2949.4, 2724.5, 1719.9,
1549.9, 1467.3, 1379.9, 1134.4, 969.0, 743.9 cm−1; MS (ESI) calcd for C15H18N2NaO3
[M+Na]+ 297.1, Found: 297.1; HRMS (ESI) calcd for C15H19N2O3 [M+H]+ 275.1390,
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2-Ethyl-4-Nitro-3-(1-(phenylsulfonyl)-1H-indol-3-yl)butanal (4e): Reaction at
room temperature, pale yellow oil, 92% yield (73.7 mg), 99% ee, dr = 91/9. HPLC:
Chiralcel ODꢀH, hexane/iꢀPrOH (80:20) , flow rate: 1.0 mLꢁmin−1, λ = 254 nm, tmajor
= 41.177 min, tminor = 34.343 min; [α]D25 = −3.52 (c 1.90, CH3COCH3); 1H NMR (400
MHz, CDCl3): δ 9.72 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.6 Hz,
2H), 7.56−7.47 (m, 3H), 7.47−7.39 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 4.81−4.68 (m,
2H), 4.12−4.03 (m, 1H), 2.95−2.85 (m, 1H), 1.64−1.54 (m, 2H), 0.86 (t, J = 7.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 203.0, 134.2, 129.5, 129.4, 126.8, 125.7, 125.2,
124.0, 119.3, 118.6, 114.4, 77.4, 53.8, 34.3, 20.7, 11.0; IR (KBr) νmax: 3109.2, 2958.5,
2937.6, 2875.4, 2726.1, 1720.1, 1553.4, 1447.7, 1370.9, 1174.2, 1126.5, 990.6, 960.4,
750.6, 580.5 cm−1; MS (ESI) calcd for C20H20N2NaO5S [M+Na]+ 423.1, Found: 423.1;
HRMS (ESI) calcd for C20H24N3O5S [M+NH4]+ 418.1431, Found: 418.1423.
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(S)-2-((R)-2-Nitro-1-(1-tosyl-1H-indol-3-yl)ethyl)pentanal (4f): Reaction at −30 °C,
pale yellow oil, 96% yield (82.3 mg), >99% ee, dr > 99/1. HPLC: Chiralcel ODꢀH,
hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor = 37.146 min,
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tminor = 27.158 min; [α]D = +14.29 (c 1.56, CH3COCH3); H NMR (400 MHz,
CDCl3): δ 9.70 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H),
7.47 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.28–7.22 (m, 1H), 7.20 (d, J = 8.0
Hz, 2H), 4.80–4.70 (m, 2H), 4.11–4.03 (m, 1H), 2.96–2.88 (m, 1H), 2.30 (s, 3H),
1.60–1.18 (m, 4H), 0.77 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.1,
145.4, 135.4, 134.7, 130.1, 129.4, 126.8, 125.5, 125.1, 123.9, 119.2, 118.5, 114.3,
77.3, 52.6, 34.8, 29.7, 21.7, 20.0, 14.1; IR (KBr) νmax: 3117.1, 2944.5, 2871.2, 2726.9,
1721.5, 1553.3, 1447.3, 1372.6, 1172.6, 1127.0, 751.5, 669.8, 575.9 cm−1; MS (ESI):
calcd for C22H24N2NaO5S [M+Na]+ 451.1, Found: 451.1; HRMS (ESI): calcd for
C22H28N3O5S [M+NH4]+ 446.1744, Found: 446.1741.
(2S,3R)-2-Isopropyl-4-nitro-3-(1-tosyl-1H-indol-3-yl)butanal (4g): Reaction at 0
°C, pale yellow solid (m.p. 51.0 °C), 94% yield (80.6 mg), >99% ee, dr > 99/1. HPLC:
Chiralcel ODꢀH, hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor
=
22.667 min, tminor = 18.604 min]; [α]D25 = +17.14 (c 0.77, CH3COCH3); 1H NMR (400
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MHz, CDCl3): δ 9.91 (d, J = 1.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz,
2H), 7.51 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.28–7.22 (m,
1H), 7.20 (d, J = 8.4 Hz, 2H), 4.76–4.66 (m, 2H), 4.21–4.10 (m, 1H), 3.03–2.98 (m,
1H), 2.30 (s, 3H), 1.85–1.76 (m, 1H), 1.12 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 204.2, 145.3, 135.5, 134.7, 130.1, 129.3, 126.8,
125.5, 125.4, 123.9, 119.1, 118.6, 114.4, 77.6, 57.7, 33.9, 28.4, 21.8, 21.7, 17.8; IR
(KBr) νmax: 3113.7, 2960.4, 2879.6, 2737.4, 1717.3, 1553.0, 1449.5, 1371.4, 1172.5,
1127.1, 754.3, 668.6, 575.2 cm−1; MS (ESI): calcd for C22H24N2NaO5S [M+Na]+
451.1, Found: 451.1; HRMS (ESI): calcd for C22H28N3O5S [M+NH4]+ 446.1744,
Found: 446.1734.
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(S)-2-((R)-2-Nitro-1-(1-tosyl-1H-indol-3-yl)ethyl)heptanal (4h): Reaction at −30 °C,
pale yellow oil, 95% yield (86.7 mg), >99% ee, dr = 99/1. HPLC: Chiralcel ODꢀH,
hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 254 nm, tmajor = 31.762 min,
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tminor = 23.591 min; [α]D = +19.29 (c 1.54, CH3COCH3); H NMR (400 MHz,
CDCl3): δ 9.70 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz,
2H), 7.51 (s, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.29ꢀ7.23 (m, 1H),
7.21 (d, J = 8.0 Hz, 2H), 4.81–4.68 (m, 2H), 4.11–4.04 (m, 1H), 2.95–2.87 (m, 1H),
2.31 (s, 3H), 1.59–1.41 (m, 2H), 1.32–1.11 (m, 6H), 0.79 (t, J = 6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 203.1, 145.4, 135.4, 134.7, 130.1, 129.4, 126.9, 125.5,
125.2, 123.9, 119.2, 118.4, 114.3, 77.3, 52.8, 34.8, 31.7, 27.6, 26.4, 22.4, 21.7, 14.0;
IR (KBr) νmax: 3120.3, 2932.5, 2860.2, 2726.4, 1721.0, 1630.2, 1554.3, 1449.2,
1371.1, 1173.1, 1125.9, 751.6, 673.1, 577.2 cm−1; MS (ESI): calcd for
C24H28N2NaO5S [M+Na]+ 479.2, Found: 479.2; HRMS (ESI): calcd for C24H32N3O5S
[M+NH4]+ 474.2057, Found: 474.2049.
(S)-2-((R)-2-Nitro-1-(1-tosyl-1H-indol-3-yl)ethyl)octanal (4i): Reaction at −15 °C,
pale yellow oil, 98% yield (92.2 mg), >99% ee, dr > 99/1. HPLC: Chiralcel ODꢀH,
hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor = 29.416 min,
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tminor = 21.959 min; [α]D = +13.85 (c 1.69, CH3COCH3); H NMR (400 MHz,
CDCl3): δ 9.70 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.52 (s, 1H),
7.47 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.28ꢀ7.23 (m, 1H), 7.20 (d, J = 7.6
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Hz, 2H), 4.82–4.68 (m, 2H), 4.12–4.03 (m, 1H), 2.96–2.87 (m, 1H), 2.31 (s, 3H),
1.59–1.41 (m, 2H), 1.30–1.10 (m, 8H), 0.80 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.1, 145.4, 135.4, 134.7, 130.1, 129.4, 126.8, 125.5, 125.2, 123.8, 119.2,
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118.4, 114.3, 77.3, 52.8, 34.8, 31.5, 29.2, 27.6, 26.6, 22.6, 21.7, 14.1；IR (KBr) νmax
:
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3120.3, 2930.8, 2860.5, 2728.3, 1721.6, 1552.9, 1448.3, 1371.5, 1172.9, 1127.7,
972.2, 751.0, 668.7, 575.3 cm−1; MS (ESI): calcd for C25H30N2NaO5S [M+Na]+ 493.2,
Found: 493.2; HRMS (ESI): calcd for C25H34N3O5S [M+NH4]+ 488.2214, Found:
488.2196.
(2S,3R)-2-Benzyl-4-nitro-3-(1-tosyl-1H-indol-3-yl)butanal (4j): Reaction at −30 °C,
pale yellow solid (m.p. 48.0−49.0 °C), 98% yield (93.4 mg), >99% ee, dr > 99/1.
HPLC: Chiralcel ODꢀH, hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 254 nm,
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tmajor = 44.852 min, tminor = 40.961 min]; [α]D = +1.57 (c 2.17, CH3COCH3); H
NMR (400 MHz, CDCl3): δ 9.67 (d, J = 1.2 Hz,1H), 7.97 (d, J = 8.4 Hz, 1H), 7.68 (d,
J = 8.4 Hz, 2H), 7.57 (s, 1H), 7.25–7.17 (m, 8H), 7.00 (d, J = 6.8 Hz, 2H), 4.88–4.81
(m, 1H), 4.76–4.70 (m, 1H), 4.09–4.00 (m, 1H), 3.25 (q, J = 7.5 Hz, 1H), 2.90–2.83
(m, 1H), 2.78–2.72 (m, 1H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.8,
145.4, 137.0, 135.4, 134.6, 130.1, 129.3, 129.0, 128.97, 128.6, 127.2, 126.8, 125.6,
125.1, 123.9, 119.2, 118.6, 114.3, 76.7, 54.4, 34.7, 34.2, 21.6; IR (KBr) νmax: 3030.2,
2925.4, 2863.0, 2733.0, 1717.8, 1551.7, 1444.0, 1370.6, 1171.3, 1126.3, 748.3, 681.2,
573.3 cm−1; MS (ESI): calcd for C26H24N2NaO5S [M+Na]+ 499.1, Found: 499.1;
HRMS (ESI): calcd for C26H28N3O5S [M+NH4]+ 494.1744, Found: 494.1733.
(S)-2-((R)-1-(5-Bromo-1-tosyl-1H-indol-3-yl)-2-nitroethyl)pentanal (4k): Reaction
at −30 °C, pale yellow oil, 97% yield (98.4 mg), >99% ee, dr = 97/3. HPLC: Chiralcel
ASꢀH, hexane/iꢀPrOH = 85:15, flow rate: 0.8 mLꢁmin−1, λ = 210 nm, tmajor = 35.317
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min, tminor = 28.237 min; [α]D = +11.22 (c 2.08, CH3COCH3); H NMR (300 MHz,
CDCl3): δ 9.70 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H),
7.62 (d, J = 1.5 Hz, 1H), 7.54 (s, 1H), 7.42 (dd, J = 8.9 Hz, 1H), 7.22 (d, J = 8.1 Hz,
2H), 4.82–4.68 (m, 2H), 4.07–3.97 (m, 1H), 2.96–2.86 (m, 1H), 2.32 (s, 3H),
1.39–1.21 (m, 4H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 202.8,
145.7, 134.3, 134.0, 131.2, 130.2, 128.5, 126.8, 126.4, 121.9, 117.9, 117.5, 115.7,
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77.1, 52.5, 34.5, 29.7, 21.7, 20.0, 14.1; IR (KBr) νmax: 3109.1, 2944.3, 2870.5, 2726.6,
1722.0, 1554.7, 1443.7, 1372.9, 1169.6, 804.1, 665.9, 580.9, 546.5 cm−1; MS (ESI)
calcd for C22H23BrN2NaO5S [M+Na]+ 529.0, Found: 529.0; HRMS (ESI) calcd for
C22H27BrN3O5S [M+NH4]+ 524.0849, Found: 524.0847.
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(2S,3R)-3-(5-Bromo-1-tosyl-1H-indol-3-yl)-2-isopropyl-4-nitrobutanal
(4l):
Reaction at 0 °C, white solid (m.p. 58.0−59.0 °C), 95% yield (96.4 mg), >99% ee,
dr > 99/1. HPLC: Chiralcel ASꢀH, hexane/iꢀPrOH (85:15) , flow rate: 0.8 mLꢁmin−1, λ
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= 254 nm, tmajor = 26.867 min, tminor = 23.952 min; [α]D = +13.42 (c 0.78,
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CH3COCH3); H NMR (400 MHz, CDCl3): δ 9.90 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H),
7.67–7.60 (m, 3H), 7.52 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H),
4.76–4.66 (m, 2H), 4.16–4.06 (m, 1H), 3.00–2.95 (m, 1H), 2.32 (s, 3H), 1.83–1.75 (m,
1H), 1.15 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 204.0, 145.7, 134.3, 134.1, 131.1, 130.2, 128.5, 126.8, 126.6, 121.9, 118.0, 117.5,
115.8, 77.5, 57.5, 33.7, 28.5, 21.8, 21.7, 17.9; IR (KBr) νmax: 3110.0, 2959.4, 2876.8,
2736.8, 1716.0, 1553.7, 1443.4, 1373.4, 1169.5, 804.1, 665.7, 581.3, 539.9 cm−1; MS
(ESI) calcd for C22H23BrN2NaO5S [M+Na]+ 529.0, Found: 529.0; HRMS (ESI) calcd
for C22H27BrN3O5S [M+NH4]+ 524.0849, Found: 524.0830.
(S)-2-((R)-1-(5-Bromo-1-tosyl-1H-indol-3-yl)-2-nitroethyl)heptanal
(4m):
Reaction at −15 °C, pale yellow oil, 95% yield (101.7 mg), >99% ee, dr = 97/3.
HPLC: Chiralcel ADꢀH, hexane/iꢀPrOH = 95:5, flow rate: 0.8 mLꢁmin−1, λ = 254 nm,
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tmajor = 26.867 min, tminor = 23.952 min; [α]D = +15.91 (c 3.37, CH3COCH3); H
NMR (400 MHz, CDCl3): δ 9.71 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.65 (d,
J = 8.4 Hz, 2H), 7.59 (d, J = 1.2 Hz, 1H), 7.50 (s, 1H), 7.43 (dd, J = 8.8 Hz, 1H), 7.23
(d, J = 8.0 Hz, 2H), 4.79–4.67 (m, 2H), 4.05–3.96 (m, 1H), 2.93–2.86 (m, 1H), 2.34 (s,
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3H), 1.57–1.42 (m, 2H), 1.32–1.12 (m, 6H), 0.81 (t, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl3) δ 202.8, 145.7, 134.4, 134.0, 131.2, 130.2, 128.5, 126.8, 126.4, 122.0,
117.9, 117.5, 115.7, 77.2, 52.6, 34.5, 31.7, 27.6, 26.3, 22.4, 21.7, 14.0; IR (KBr) νmax
:
3105.5, 2931.3, 2862.1, 2726.9, 1719.5, 1555.1, 1444.8, 1373.7, 1169.0, 1118.4,
805.5, 666.7, 581.1, 542.9 cm−1; MS (ESI) calcd for C24H27BrN2NaO5S [M+Na]+
557.1, Found: 557.0; HRMS (ESI) calcd for C24H31BrN3O5S [M+NH4]+ 552.1162,
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(S)-2-((R)-1-(5-Bromo-1-tosyl-1H-indol-3-yl)-2-nitroethyl)octanal (4n): Reaction
at −15 °C, pale yellow oil, 92% yield (101.1 mg), >99% ee, dr = 97/3. HPLC:
Chiralcel ADꢀH, hexane/iꢀPrOH = 95:5, flow rate: 0.8 mLꢁmin−1, λ = 254 nm, tmajor
=
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30.827 min, tminor = 28.821 min; [α]D = +15.01 (c 4.11, CH3COCH3); 1H NMR (400
MHz, CDCl3): δ 9.70 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz,
2H), 7.59 (s, 1H), 7.50 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H),
4.79–4.67 (m, 2H), 4.03–3.96 (m, 1H), 2.93–2.85 (m, 1H), 2.34 (s, 3H), 1.59–1.41 (m,
2H), 1.31–1.12 (m, 8H), 0.82 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
202.8, 145.7, 134.4, 134.0, 131.2, 130.2, 128.5, 126.8, 126.4, 122.0, 117.9, 117.5,
115.7, 77.2, 52.6, 34.6, 31.5, 29.2, 27.7, 26.5, 22.6, 21.7, 14.1; IR (KBr) νmax: 3115.0,
2930.0, 2860.6, 2726.2, 1720.9, 1556.0, 1447.3, 1372.2, 1168.7, 1118.1, 804.0, 667.0,
581.1, 542.6 cm−1; MS (ESI) calcd for C25H29BrN2NaO5S [M+Na]+ 571.1, Found:
571.1; HRMS (ESI) calcd for C25H33BrN3O5S [M+NH4]+ 566.1319, Found: 566.1302.
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(S)-2-((R)-1-(5-Methoxy-1-tosyl-1H-indol-3-yl)-2-nitroethyl)pentanal
Reaction at −30 °C, white oil, 98% yield (89.9 mg), >99% ee, dr > 99/1. HPLC:
Chiralcel ASꢀH, hexane/iꢀPrOH = 80:20, flow rate: 0.8 mLꢁmin−1, λ = 254 nm, tmajor
(4o):
=
44.523 min, tminor = 33.691 min; [α]D25 = +15.02 (c 4.36, CH3COCH3); 1H NMR (400
MHz, CDCl3): δ 9.69 (s, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.47
(s, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.88 (s, 1H), 4.80–4.68 (m,
2H), 4.06–3.99 (m, 1H), 3.80 (s, 3H), 2.93–2.85 (m, 1H), 2.30 (s, 3H), 1.57–1.22 (m,
4H), 0.78 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.1, 156.8, 145.3,
134.6, 130.5, 130.0, 126.7, 125.8, 118.6, 115.2, 114.2, 102.0, 77.2, 55.8, 52.5, 34.7,
29.6, 21.7, 20.0, 14.1; IR (KBr) νmax: 3112.3, 2947.8, 2873.3, 2727.6, 1721.4, 1600.9,
1557.5, 1460.5, 1369.8, 1217.3, 1166.5, 1133.0, 844.2, 815.4, 671.5, 586.1, 545.0
cm−1; MS (ESI) calcd for C23H26N2NaO6S [M+Na]+ 481.1, Found: 481.1; HRMS (ESI)
calcd for C23H30N3O6S [M+NH4]+ 476.1850, Found: 476.1844.
(S)-2-((R)-1-(5-Methoxy-1-tosyl-1H-indol-3-yl)-2-nitroethyl)heptanal
(4p):
Reaction at −15 °C, white oil, 98% yield (95.4 mg), >99% ee, dr = 98/2. HPLC:
Chiralcel ADꢀH, hexane/iꢀPrOH = 90:10, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor
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19.750 min, tminor = 20.991 min; [α]D25 = +20.16 (c 2.46, CH3COCH3); 1H NMR (300
MHz, CDCl3): δ 9.70 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.44
(s, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 9.0 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H),
4.79–4.65 (m, 2H), 4.06–3.96 (m, 1H), 3.82 (s, 3H), 2.93–2.83 (m, 1H), 2.32 (s, 3H),
1.59–1.41 (m, 2H), 1.31–1.08 (m, 6H), 0.80 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 203.2, 156.8, 145.3, 134.6, 130.5, 130.0, 126.8, 125.8, 118.6, 115.2, 114.2,
102.0, 77.3, 55.8, 52.7, 34.7, 31.7, 27.5, 26.4, 22.4, 21.7, 14.0; IR (KBr) νmax: 3114.3,
2936.0, 2861.7, 2724.2, 1722.1, 1603.7, 1554.9, 1461.9, 1372.0, 1219.2, 1170.3,
1133.0, 812.1, 672.8, 587.6, 544.1 cm−1; MS (ESI) calcd for C25H30N2NaO6S
[M+Na]+ 509.2, Found: 509.1; HRMS (ESI) calcd for C25H34N3O6S [M+NH4]+
504.2163, Found: 504.2160.
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(S)-2-((R)-1-(5-Methoxy-1-tosyl-1H-indol-3-yl)-2-nitroethyl)octanal
Reaction at −15 °C, white oil, 97% yield (97.1 mg), >99% ee, dr = 98/2. HPLC:
Chiralcel ADꢀH, hexane/iꢀPrOH = 90:10, flow rate: 1.0 mLꢁmin−1, λ = 210 nm, tmajor
(4q):
=
18.403 min, tminor = 19.530 min; [α]D25 = +18.37 (c 4.10, CH3COCH3); 1H NMR (400
MHz, CDCl3): δ 9.69 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.4 Hz,
2H), 7.48 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.94 (dd, J = 9.0 Hz, 1H), 6.88 (d, J = 2.4
Hz, 1H), 4.80–4.68 (m, 2H), 4.07–4.00 (m, 1H), 3.80 (s, 3H), 2.93–2.86 (m, 1H), 2.30
(s, 3H), 1.58–1.40 (m, 2H), 1.31–1.10 (m, 8H), 0.80 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 203.2, 156.8, 145.2, 134.6, 130.5, 130.0, 126.7, 125.8, 118.6,
115.1, 114.2, 102.0, 77.3, 55.8, 52.7, 34.6, 31.5, 29.2, 27.5, 26.6, 22.5, 21.6, 14.1; IR
(KBr) νmax: 3120.0, 2932.1, 2859.5, 2728.1, 1721.8, 1600.9, 1555.1, 1461.8, 1371.3,
1218.8, 1169.9, 848.0, 809.7, 673.9, 587.9, 543.8 cm−1; MS (ESI) calcd for
C26H32N2NaO6S [M+Na]+ 523.2, Found: 523.2; HRMS (ESI) calcd for C26H36N3O6S
[M+NH4]+ 518.2319, Found: 518.2318.
(S)-2-((R)-1-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-nitroethyl)pentanal (4r): Reaction
at −30 °C, pale yellow solid (m.p. 94.0−95.0 °C), 96% yield (97.4 mg), >99% ee, dr =
99/1. HPLC: Chiralcel ASꢀH, hexane/iꢀPrOH = 85:15, flow rate: 0.8 mLꢁmin−1, λ =
210 nm, tmajor = 33.930 min, tminor = 31.559 min; [α]D25 = +9.94 (c 1.47, CH3COCH3);
1H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 8.15 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H),
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7.49 (s, 1H), 7.39–7.33 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.79–4.68 (m, 2H),
4.08–4.01 (m, 1H), 2.92–2.84 (m, 1H), 2.33 (s, 3H), 1.55–1.19 (m, 4H), 0.77 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.8, 145.8, 135.9, 134.4, 130.3, 128.3,
127.3, 126.8, 125.5, 120.4, 119.3, 118.4, 117.3, 77.3, 52.6, 34.5, 29.7, 21.7, 20.0, 14.1;
IR (KBr) νmax: 3106.8, 2949.8, 2866.8, 2719.0, 1721.6, 1550.6, 1420.2, 1372.0,
1173.1, 1119.8, 809.3, 667.6, 582.7 cm−1; MS (ESI): calcd for C22H23BrN2NaO5S
[M+Na]+ 529.0, Found: 529.0; HRMS (ESI): calcd for C22H27BrN3O5S [M+NH4]+
524.0849, Found: 524.0845.
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(2S,3R)-3-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-isopropyl-4-nitrobutanal
(4s):
Reaction at 0 °C, white solid (m.p. 118.0 °C), 98% yield (99.5 mg), >99% ee, dr >
99/1. HPLC: Chiralcel ASꢀH, hexane/iꢀPrOH = 85:15, flow rate: 0.8 mLꢁmin−1, λ =
210 nm, tmajor = 29.995 min, tminor = 31.167 min; [α]D25 = +7.97 (c 0.59, CH3COCH3);
1H NMR (400 MHz, CDCl3): δ 9.90 (d, J = 1.2 Hz, 1H), 8.14 (s, 1H), 7.67 (d, J = 8.0
Hz, 2H), 7.49 (s, 1H), 7.39–7.33 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 4.69 (d, J = 6.8 Hz,
2H), 4.17–4.10 (m, 1H), 2.99–2.93 (m, 1H), 2.33 (s, 3H), 1.82–1.73 (m, 1H), 1.13 (d,
J = 7.2 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.0, 145.8,
136.0, 134.4, 130.3, 128.2, 127.3, 126.8, 125.7, 120.3, 119.2, 118.5, 117.4, 77.7, 57.7,
33.7, 28.5, 21.8, 21.76, 17.8; IR (KBr) νmax: 3116.4, 2959.2, 2727.6, 1720.2, 1551.0,
1427.9, 1370.7, 1168.0, 1148.6, 810.2, 666.1, 585.0 cm−1; MS (ESI): calcd for
C22H23BrN2NaO5S [M+Na]+ 529.0, Found: 529.0; HRMS (ESI): calcd for
C22H27BrN3O5S [M+NH4]+ 524.0849, Found: 524.0831.
(S)-2-((R)-1-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-nitroethyl)heptanal (4t): Reaction
at −15 °C, pale yellow solid (m.p. 139.0−140.0 °C), 93% yield (99.6 mg), >99% ee,
dr = 98/2. HPLC: Chiralcel ADꢀH, hexane/iꢀPrOH = 90:10, flow rate: 1.0 mLꢁmin−1, λ
25
= 210 nm, tmajor= 13.970 min, tminor = 15.796 min; [α]D = +19.34 (c 2.05,
1
CH3COCH3); H NMR (400 MHz, CDCl3): δ 9.69 (d, J = 1.2 Hz, 1H), 8.15 (s, 1H),
7.68 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.39–7.33 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H),
4.78–4.68 (m, 2H), 4.08–4.01 (m, 1H), 2.91–2.83 (m, 1H), 2.34 (s, 3H), 1.56–1.39 (m,
2H), 1.31–1.05 (m, 6H), 0.79 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
202.9, 145.8, 135.9, 134.4, 130.3, 128.3, 127.2, 126.8, 125.5, 120.4, 119.3, 118.4,
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117.3, 77.3, 52.8, 34.5, 31.7, 27.6, 26.3, 22.4, 21.7, 14.0; IR (KBr) νmax: 3106.4,
2932.8, 2859.4, 2728.4, 1721.2, 1550.0, 1423.9, 1372.0, 1172.0, 1132.1, 808.2, 667.9,
584.1 cm−1; MS (ESI): calcd for C24H27BrN2NaO5S [M+Na]+ 557.1; Found: 557.1;
HRMS (ESI): calcd for C24H31BrN3O5S [M+NH4]+ 552.1162, Found: 552.1161.
(S)-2-((R)-1-(6-Bromo-1-tosyl-1H-indol-3-yl)-2-nitroethyl)octanal (4u): Reaction
at −15 °C, pale yellow solid (m.p. 118.0−119.0 °C), 92% yield (101.1 mg), >99% ee,
dr > 99/1. HPLC: Chiralcel ASꢀH, hexane/iꢀPrOH = 85:15, flow rate: 0.8 mLꢁmin−1, λ
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= 210 nm, tmajor = 24.128 min, tminor = 27.467 min; [α]D = +19.35 (c 1.24,
1
CH3COCH3); H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 8.14 (s, 1H), 7.68 (d, J =
8.0 Hz, 2H), 7.50 (s, 1H), 7.39–7.33 (m, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.78–4.68 (m,
2H), 4.08–4.01 (m, 1H), 2.91–2.84 (m, 1H), 2.33 (s, 3H), 1.66–1.40 (m, 2H),
1.31–1.11 (m, 8H), 0.81 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 202.9,
145.7, 135.9, 134.4, 130.3, 128.3, 127.2, 126.8, 125.5, 120.4, 119.3, 118.4, 117.3,
76.9, 52.8, 34.5, 31.5, 29.2, 27.6, 26.6, 22.5, 21.7, 14.1; IR (KBr) νmax: 3104.4,
2928.6, 2857.9, 2729.4, 1717.6, 1551.8, 1425.9, 1371.6, 1171.4, 1133.0, 806.7, 668.3,
582.5 cm−1; MS (ESI): calcd for C25H29BrN2NaO5S [M+Na]+ 571.1, Found: 571.1;
HRMS (ESI): calcd for C25H33BrN3O5S [M+NH4]+ 566.1319, Found: 566.1315.
(S)-2-((R)-1-(2-Methyl-1-tosyl-1H-indol-3-yl)-2-nitroethyl)pentanal (4v): Reaction
at –30 °C, pale yellow oil, 98% yield (86.7 mg), >99% ee, dr = 97/3. HPLC: Chiralcel
ASꢀH, hexane/iꢀPrOH = 85:15, flow rate: 0.8 mLꢁmin−1, λ = 254 nm, tmajor = 36.956
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min, tminor = 28.893 min; [α]D = –17.19 (c 4.05, CH3COCH3); 1H NMR (300 MHz,
CDCl3): δ 9.65 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H),
7.31 (d, J = 7.5 Hz, 1H), 7.25–7.13 (m, 2H), 7.10 (d, J = 8.1 Hz, 2H), 4.66–4.59 (m,
2H), 4.05–3.93 (m, 1H), 3.02–2.90 (m, 1H), 2.50 (s, 3H), 2.23 (s, 3H), 1.28–1.18 (m,
4H), 0.53 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 203.3, 145.1, 137.0,
136.5, 135.8, 130.1, 130.0, 126.1, 124.6, 124.0, 118.3, 115.6, 115.1, 76.6, 51.5, 34.5,
29.8, 22.7, 21.7, 19.4, 13.0; IR (KBr) νmax: 2959.6, 2934.3, 2872.4, 2734.0, 1721.6,
1554.5, 1378.0, 1177.0, 749.4, 661.0, 576.6 cm−1; MS (ESI): calcd for
C23H26N2NaO5S [M+Na]+ 465.1, Found: 465.1; HRMS (ESI): calcd for
C23H26N2NaO5S [M+Na]+ 465.1455, Found: 465.1446.
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(S)-2-((R)-1-(4-Methyl-1-tosyl-1H-indol-3-yl)-2-nitroethyl)pentanal
(4w):
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Reaction at –30 °C, yellow oil, 90% yield (79.7 mg), >99% ee, dr = 99/1. HPLC:
Chiralcel ADꢀH, hexane/iꢀPrOH = 90:10, flow rate: 1.0 mLꢁmin−1, λ = 254 nm, tmajor
=
18.439 min, tminor = 19.581 min; [α]D25 = +43.97 (c 2.90, CH3COCH3); 1H NMR (300
MHz, CDCl3): δ 9.64 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.1 Hz,
2H), 7.45 (s, 1H), 7.18–7.06 (m, 3H), 6.89 (d, J = 7.5 Hz, 1H), 4.80–4.71 (m, 1H),
4.64–4.57 (m, 1H), 4.41–4.32 (m, 1H), 2.86–2.77 (m, 1H), 2.56 (s, 3H), 2.22 (s, 3H),
1.31–1.13 (m, 4H), 0.74 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 203.3,
145.4, 135.4, 134.6, 130.9, 130.06, 128.4, 126.9, 126.3, 125.2, 124.3, 120.2, 111.9,
78.1, 54.6, 35.1, 30.2, 21.7, 20.9, 20.5, 14.2; IR (KBr) νmax: 3137.1, 2962.2, 2870.3,
2736.1, 1722.1, 1553.0, 1401.3, 1384.2, 1098.6, 812.3, 666.2, 576.0 cm−1; MS (ESI):
calcd for C23H26N2NaO5S [M+Na]+ 465.1, Found: 465.1; HRMS (ESI): calcd for
C23H26N2NaO5S [M+Na]+ 465.1455, Found: 465.1444.
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(S)-2-((R)-1-(6-Chloro-1-tosyl-1H-indol-3-yl)-2-nitroethyl)pentanal (4x): Reaction
at –30 °C, yellow oil, 98% yield (90.7 mg), >99% ee, dr = 99/1. HPLC: Chiralcel
ASꢀH, hexane/iꢀPrOH = 80:20, flow rate: 1.0 mLꢁmin−1, λ = 254 nm, tmajor = 21.870
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min, tminor = 20.519 min; [α]D = +10.48 (c 4.20, CH3COCH3); H NMR (300 MHz,
CDCl3): δ 9.60 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H),
7.43 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.18–7.10 (m, 3H), 4.73–4.60 (m, 2H),
4.01–3.92 (m, 1H), 2.85–2.75 (m, 1H), 2.24 (s, 3H), 1.31–1.11 (m, 4H), 0.68 (t, J =
7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 202.8, 145.7, 135.6, 134.4, 131.5, 130.2,
127.9, 126.8, 125.6, 124.5, 120.1, 118.4, 114.3, 77.3, 52.6, 34.5, 29.6, 21.7, 20.0, 14.1.
IR (KBr) νmax: 2960.2, 2932.7, 2872.5, 2733.1, 1722.1, 1554.2, 1426.5, 1376.9,
1174.2, 1142.3, 811.8, 671.1, 579.9 cm−1; MS (ESI): calcd for C22H23ClN2NaO5S
[M+Na]+ 485.1, Found: 485.1; HRMS (ESI): calcd for C22H23ClN2NaO5S [M+Na]+
485.0908, Found: 485.0891.
(S)-2-((R)-2-Nitro-1-(7-nitro-1-tosyl-1H-indol-3-yl)ethyl)pentanal (4y): Reaction
at –30 °C, pale yellow oil, 91% yield (86.2 mg), >99% ee, dr = 98/2. HPLC: Chiralcel
ASꢀH, hexane/iꢀPrOH = 70:30, flow rate: 1.0 mLꢁmin−1, λ = 254 nm, tmajor = 49.337
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