Synergistic catalysis for asymmetric [3 + 2] cycloadditions of 2-indolylmethanols with α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/acs.joc.9b01234

A catalytic asymmetric [3 + 2] cycloaddition of 2-indolylmethanols with α,β-unsaturated aldehydes was developed for the first time. This transformation was achieved by a synergistic catalytic system consisting of a palladium complex, a Br?nsted acid, and a chiral secondary amine to synthesize biologically active cyclopenta[b]indole derivatives with excellent diastereo- A nd enantioselectivities (up to >20:1 dr, up to 99% ee).

Full text of DOI:10.1021/acs.joc.9b01234

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Note
Synergistic Catalysis for Asymmetric [3+2] Cycloadditions
of 2-Indolylmethanols with #,#-Unsaturated Aldehydes
Jia Mao, Hao Zhang, Xiang-Feng Ding, Xiaoyan Luo, and Wei-Ping Deng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01234 • Publication Date (Web): 31 Jul 2019
Downloaded from pubs.acs.org on July 31, 2019
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Synergistic Catalysis for Asymmetric [3+2] Cycloadditions of
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2-Indolylmethanols with α,β-Unsaturated Aldehydes
Jia Mao, Hao Zhang, Xiang-Feng Ding, Xiaoyan Luo* and Wei-Ping Deng*
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School of Pharmacy and Shanghai Key Laboratory of New Drug Design, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
OH
R2
Cat.
BH
Ar
Ar
Ar
OH
Ar
Pd(0)
R1
O
N
H
OSiPh3
Ar
R2
R1
N
H
Ar
N
H
Ar = 3,5-(CF3)2C6H3
Synergistic catalysis
Cat.
Abstract: A catalytic asymmetric [3+2] cycloaddition of 2-indolylmethanols with α,β-
unsaturated aldehydes was developed for the first time. This transformation was
achieved by a synergistic catalytic system consisting of a palladium complex, a
Brønsted acid, and a chiral secondary amine to synthesize biologically active
cyclopenta[b]indole derivatives with excellent diastereo- and enantioselectivities (up to
>20:1 dr, up to 99% ee).
Chiral cyclopenta[b]indole has been recognized as an important heterocyclic
skeleton which can be widely found in various natural products and pharmaceutically
active molecules (Figure 1).1 Therefore, the method of asymmetrically synthesizing this
skeleton has attracted considerable attention of the synthetic scientific community. 2
HN
N
H
H
HN
N
N
NH
O
NH2
H
NC
O
(I)
(II)
Yuehchukene
H
F
NH
CO2H
Cl
N
H
O
N
O
S O
H
O
H
HO
Bruceoline I
JBIR-03
Laropiprant
Figure 1. Representative biologically active molecules containing cyclopenta[b]indole
scaffold.
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Among numerous approaches, catalytic asymmetric reactions involving
indolylmethanols have been employed as an important strategy for the construction of
cyclopenta[b]indole scaffolds.3 In particular, 2-indolylmethanols have exhibited their
great potential in catalytic enantioselective cycloadditions. For instance, the
asymmetric interrupted Nazarov-type cyclization of C3-alkenyl-substituted 2-
indolylmethanols has been achieved by the Shi group, affording chiral
cyclopenta[b]indole derivatives (Scheme 1a).4 In addition, the Shi group reported an
asymmetric [3+2] cycloaddition of 2-indolymethanols with alkenes in the presence of
a chiral phosphoric acid (CPA) or a chiral phosphoramide (CPN) to synthesize
cyclopenta[b]indole derivatives (Scheme 1b).5 On the other hand, the Shi group has
described a cooperative catalysis-enabled asymmetric α-arylation of aldehydes
employing 2-indolylmethanols as arylation reagents.6 Based on the superiority of
cooperative catalysis7 and our continuing efforts in using chiral diarylprolinol silyl
ethers as an effective promoter for activation of 2-enals,8 we design the asymmetric
[3+2] cycloaddition of 2-indolylmethanols and α,β-unsaturated aldehydes, which was
catalyzed by a synergistic catalytic system consisting of Brønsted acids (BH) and
secondary amines, providing rapid access to various cyclopenta[b]indole derivatives
(Scheme 1c).
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Previous work: cycloadditions of 2-indolylmthanols
Ar1
Nu
Ar1


Ar
OH
Ar
BH*
Ar
Ar
(a)
(b)
Nu
R
R
Nazarov-type
cyclization
N
N
H
H
R2
R3

CPA or CPN
R2

Ar
Ar
Ar
OH
Ar
R1
R1
N
R3
[3+2] cycloaddition
N
H
H
R2 = Me, Ar, H
R3 = indolyl, phenyl
This work: 3+2] cycloadditions of 2-indolylmthanols with  , -unsaturated aldehydes
[
R2
O
secondary amine
BH


Ar
OH
Ar
Ar
Ar
R1
(c)
R1
O
R2
N
N
synergistic catalysis
H
H
Scheme 1. Catalytic asymmetric cycloadditions of 2-indolylmethanols.
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To testify our hypothesis, we started our investigations with the model reaction
shown in Table 1. 2-Indolylmethanol 1a was treated with Brønsted acid in chloroform
at room temperature, and then α,β-unsaturated aldehyde 2a and 20 mol% chiral
secondary amine (Cat-1) was slowly added. To our delight, the reaction proceeded
smoothly to generate the corresponding cyclopenta[b]indole derivative 3aa in good
yield (85%) and with high enantioselectivity (75%). Encouraged by this promising
result, several chiral amine catalysts (Cat-2-6) were screened (entries 2-6), Cat-6 was
found to deliver the reaction in the highest enantioselectivity (90% ee) and
diastereoselectivity (>20:1 dr). Then, screening of solvents (entries 7-12) revealed that
(i-Pr)2O was the optimal reaction medium on the part of enantioselectivities, affording
corresponding product 3aa in 94% ee. Subsequently, a series of Brønsted acids (BH)
were screened, which demonstrated that TsOH·H2O was the best additive in terms of
both yields and enantioselectivities (entries 13-15).
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Table 1. Optimization of the reaction conditions.a
Cat.
1)
(20 mol %)
Ph
OH
BH
(20 mol %)
Ph
OH
Ph
metal
, solvent, RT
Ph
Ph
O
Ph
N
2) NaBH4
THF, RT
N
H
H
1a
3aa
2a
Cat-1
Cat-2
Cat-3
Cat-4
Cat-5
Cat-6
: X = TMS, Ar = Ph
: X = TBS, Ar = Ph
: X = TMS, Ar = 3,5-(CF3)2C6H3
: X = TMS, Ar = 3,5-(t-Bu)2C6H3
: X = TBS, Ar = 3,5-(CF3)2C6H3
: X = SiPh3, Ar = 3,5-(CF3)2C6H3
Ar
OX
Ar
N
H
entry
cat.
solvent
BH
metal [mol%]
none
yield [%]b ee [%]c
drd
1
2
3
4
5
6
Cat-1
Cat-2
Cat-3
Cat-4
Cat-5
Cat-6
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
85
30
90
50
81
55
75
68
81
50
52
90
10:1
none
>20:1
>20:1
>20:1
>20:1
>20:1
none
none
none
none
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Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
Cat-6
THF
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
TsOH·H2O
CF3COOH
p-NO2BAg
CH3COOH
none
none
none
none
none
none
none
none
none
71
37
90
90
75
89
70
94
84
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
acetone
CH2Cl2
toluene
MeCN
9
61
10
11
12
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18
19e
20f
40
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70
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
(i-Pr)2O
70
51
N.P.h
N.P.
90
TsOH·H2O Pd2(dba)3 (2.5)
TsOH·H2O PPh3AuCl (5)
TsOH·H2O PPh3RhCl (5)
TsOH·H2O Pd2(dba)3 (2.5)
TsOH·H2O Pd2(dba)3 (2.5)
93
92
93
96
97
37
65
80
47
a General conditions: 1a (0.1 mmol), 2a (0.15 mmol), BH (20 mol%), metal (5 mol%) and Cat. (20
mol%) in solvent (1.0 mL) at room temperature. Isolated yield. Determined by chiral HPLC. d
b
c
1
e
f
Determined by crude H NMR spectroscopy. Reaction was conducted at 0 °C. Reaction was
conducted at -20 °C. g BA is benzoic acid. h N.P. is no product.
It was reported that the addition of some transition metals could stabilize the
delocalized cation generated from 2-indolylmethanols,9 which was beneficial for the
yield of the reaction. Therefore, various transition metals were screened in this reaction
to further improve the yield of the reaction (entries 16-18) and a palladium complex
was found to greatly improve the yield to 90% with a retained enantioselectivity. The
effect of temperature on the reaction activity was also investigated. Lowering the
temperature could improve the enantioselectivity, but the yield dropped significantly
(entries 19-20). Thus, the optimal reaction conditions were finally set as what entry 19
illustrated.
Table 2. Screening of substrate scope.a
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Cat-6
1)
(20 mol %)
R2
TsOH•H2O (20 mol %)
Pd2(dba)3 (2.5 mol%)
(i-Pr)2O, 0 °C
OH
Ar
OH
Ar
Ar
Ar
R1
R1
O
R2
2) NaBH4
THF, RT
N
H
N
H
9
1
2
3
10
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entry
1
3
R1/Ar
R2
yield [%]b
80
ee [%]c
96
drd
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
H/Ph (1a)
5-Br/Ph (1b)
5-Cl/Ph (1c)
5-Me/Ph (1d)
5-OMe/Ph (1e)
6-Br/Ph (1f)
6-OMe/Ph (1g)
Ph (2a)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
1.1:1
2
Ph (2a)
60
91
3
Ph (2a)
50
90
4
Ph (2a)
83
97
5
Ph (2a)
56
83
6
Ph (2a)
71
95
7
Ph (2a)
86
85
8
H/m-MeOC6H4 (1h)
H/p-MeOC6H4 (1i)
H/Ph (1a)
Ph (2a)
55
96
9
Ph (2a)
65
97
10
11
12
13
14
15
16
17
18
19
20
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
4-MeOC6H4 (2b)
3-MeOC6H4 (2c)
2-MeOC6H4 (2d)
4-MeC6H4 (2e)
3-MeC6H4 (2f)
4-ClC6H4 (2g)
3-ClC6H4 (2h)
5-piperonyl (2i)
1-naphthyl (2j)
2-thienyl (2k)
Et (2l)
89
96
H/Ph (1a)
88
96
H/Ph (1a)
99
94
H/Ph (1a)
80
95
H/Ph (1a)
60
96
H/Ph (1a)
81
91
H/Ph (1a)
45
89
H/Ph (1a)
84
95
3aj
3ak
3al
H/Ph (1a)
50
89
H/Ph (1a)
70
90
H/Ph (1a)
32/30
99/94
a General conditions: 1a (0.1 mmol), 2a (0.15 mmol), TsOH·H2O (20 mol%), Pd2(dba)3 (2.5 mol%)
and Cat-6 (20 mol%) in (i-Pr)2O (1.0 mL) at 0 °C. b Isolated yield. c Determined by chiral HPLC. d
Determined by crude 1H NMR spectroscopy.
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With the optimized reaction conditions in hand, the generality and substrate scope of
this process was investigated (Table 2). Firstly, various 2-indolylmethanols 1a-1i were
employed with α,β-unsaturated aldehyde 2a (entries 1-7), providing products 3 in
moderate to high yields (50-86%), with excellent diastereoselectivities (>20:1 dr) and
high to excellent enantioselectivities (83-97% ee). In addition, the two Ar groups in 1
could be changed from phenyl groups to methoxy substituted phenyl groups, which
generated the corresponding products 3ha and 3ia in moderate yields, with excellent
enantioselectivities (entries 8-9). In addition, a wide range of α,β-unsaturated aldehydes
(2b-2j) containing electron-rich (entries 10-14), electron-deficient (entries 15-16), and
electron-neutral (entries 17-18) substituents on any position of the phenyl ring were
employed, and the transformation worked efficiently, affording the corresponding
cycloadducts in moderate to excellent yields (45−99%), with high to excellent
enantioselectivities (89-96% ee). Furthermore, the outstanding outcome was still
obtained for heteroaromatic 2- thienyl derived α,β-unsaturated aldehyde 2k (entry 19).
Noteworthily, aliphatic substituted α,β-unsaturated aldehyde was also suitable to this
system, affording the corresponding product 3al in excellent enantioselectivity,
however with poor diastereoselectivity (entry 20).
10
11
12
13
14
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59
60
Cat-6
(20 mol %)
TsOH•H2O (20 mol %)
Pd2(dba)3 (2.5 mol %)
O
No desired product
OH
Ph
N
H
(i-Pr)2O, 0 °C
1j
2a
Cat-6
(20 mol %)
TsOH•H2O (20 mol %)
Pd2(dba)3 (2.5 mol %)
OH
Ph
O
No desired product
Ph
N
H
(i-Pr)2O, 0 °C
1k
2a
Scheme 2. Further Substrate Expansion.
In order to further explore the scope of the reaction, dimethyl (1j) and monophenyl
(1k) instead of diphenyl on the indole alcohol were employed as substrate to react with
α,β-unsaturated aldehyde 2a under the optimal condition. Unfortunately, no desired
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product were observed and only dimerization of 2-indolylmethanol occurred (Scheme
2). We also did a further screen of various Brønsted acids (TsOH•H2O, phosphoric acid,
PhCOOH), reaction temperature (30 °C, 0 °C), and aldehyde (methoxy substituted
phenyl group), however still no target product was observed. According to the
previously reports,10 the in-situ derived carbocation species from 1j or 1k is supposed
to be more easily attacked by nucleophiles at this benzylic position, which may account
10
11
12
13
14
15
16
17
18
19
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60
for the above dimerization.
a) Gram-scale experiment
Cat-6
1)
(20 mol %)
TsOH•H2O (20 mol %)
Pd2(dba)3 (2.5 mol %)
(i-Pr)2O, 0 °C
Ph
OH
Ph
OH
Ph
Ph
Ph
O
Ph
N
N
H
2) NaBH4
THF, RT
H
1a
2a
3aa
1.01 g, 79% yield
95% ee, >20:1 dr
897 mg
(3 mmol)
526 mg
(3.6 mmol)
b) Derivatization of Product
Cat-6
1)
(20 mol %)
Ph
TsOH•H2O (20 mol %)
Pd2(dba)3 (2.5 mol %)
(i-Pr)2O, 0 °C
CO2Et
Ph
OH
Ph
Ph
O
Ph
Ph
CO2Et
N
H
N
H
2)
Ph3P
toluene, reflux
1a
2a
4
65% yield
96% ee, >20:1 dr
Scheme 3. Demonstration of synthetic utility.
As a further demonstration of the utility of this process, the asymmetric
cycloaddition between 2-indolylmethanol 1a and α,β-unsaturated aldehyde 2a was
carried out on a gram scale with a lower aldehyde equivalent (1.2 equiv), and 3aa was
obtained in 79% yield with 95% ee and >20:1 dr (Scheme 3a). On the other hand, the
cycloadduct of 2-indolylmethanol 1a and α,β-unsaturated aldehyde 2a could undergo a
Wittig reaction to generate product 4 in 65% yield with 96% ee (Scheme 3b). And the
absolute stereochemistry of compound 4 was determined by single-crystal X-ray
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6
diffraction analysis as (1R,2S) (see the Supporting Information). The absolute
configurations of other products were assigned by analogy to 4.
7
8
O
N
9
Cat-6
10
11
12
13
14
15
16
17
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II
2

R2
R2
N
R2
R1
BH
Pd(0)
PdLn
Ar
Ar
OH
Ar
-Pd(0)
R1
R1
Ar
N
N
N
H
Ar
-H2O
H
H
Ar
III
1
I
R2
R2
Ar
R2
R2
R1
H
R1
isomerize
NaBH4
THF
R1
R1
O
N
OH
N
H2O
N
N
Ar
Ar
Ar
Ar
N
H
Ar
N
H
H
H
Ar
IV
Ar
3
VI
V
Scheme 4 Proposed mechanism.
Based on the observed absolute configuration and previously reports,6 a hypothetical
activation model is depicted in Scheme 4. Firstly, the dehydration of 2-
indolylmethanols 1 were promoted by the Pd(0)/BH to form the delocalized carbocation
I.11 Meanwhile, enamine intermediate II were formed through the reaction between 2
and Cat-6. Then, the γ- position of the enamine intermediate II attacked the carbon
cation of the intermediate I to give rise to a transient intermediate III, which underwent
intramolecular cyclization to form intermediate IV. Subsequently, the intermediate IV
rapidly isomerized into intermediate V, and hydrolysis of intermediate V generated VI
by releasing Cat-6. Finally, the product 3 were obtained after NaBH4 reduction
(Scheme 4).
In conclusion, we have developed an efficient catalytic asymmetric [3+2]
cycloaddition of 2-indolylmethanols with α,β-unsaturated aldehydes via synergistic
catalysis in the presence of palladium complex, Brønsted acid, and chiral secondary
amine, affording potential biologically active and synthetically challenging
polysubstituted fused cyclopenta[b]indole derivatives containing two stereocenters in
high yields (up to 99%) with excellent stereoselectivities (up to >20:1 dr, up to 99%
ee). The present strategy is obviously complementary to previous methods for the
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synthesis of biologically important enantioenriched cyclopenta[b]indole with high
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efficiency.
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EXPERIMENTAL SECTION
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General Information
1H NMR spectra were recorded on a Bruker DPX 400 MHz spectrometer in CDCl3.
Chemical shifts were reported in ppm with the internal TMS signal at 0.0 ppm as a
standard. The spectra are interpreted as: s = singlet, d = doublet, t= triplet, m = multiplet,
dd = doublet of doublets, brs = broad singlet, coupling constant(s) J are reported in Hz
and relative integrations are reported. 13C NMR (100 MHz) spectra were recorded on a
Bruker DPX 400 MHz spectrometer in CDCl3. Chemical shifts were reported in ppm
with the internal chloroform signal at 77.06 ppm as a standard. Optical rotations were
measured on an AUTOPOL V instrument. Diastereomeric ratios were determined from
crude 1H NMR spectroscopy interpretation or by analysis of HPLC traces. Enantiomer
ratios were determined by analysis of HPLC traces, obtained by using Chiralpak AD-
H column with n-hexane and i-propanol as solvents. (Chiralpak AD-H column was
purchased from Daicel Chemical Industries, LTD.) Melting points were obtained in
open capillary tubes using SGW X-4 micro melting point apparatus which were
uncorrected. Mass spectra were recorded on TOF mass spectrometer. Solvents were
dried and distilled following usual protocols. 2-Indolylmethanols 1 were prepared
according to the literature procedures,10a, 12, α,β-unsaturated aldehydes 2 were prepared
by reference to the literature procedures.13
General procedure for the synthesis of 2-indolylmethanols 1.
Substrates 1 were synthesized by modification of the literature method.10a In a flame-
dried Schlenk bottle under argon, phenylmagnesium bromide (40 mL, 1.0 mmol/mL)
was added to the Schlenk bottle. Then, in a ice-water bath, the solution of ethyl 1H-
indole-2-carboxylate (1.89 g, 10 mmol) in anhydrous THF (10 mL) was added to the
Schlenk bottle. Subsequently, the reaction mixture was moved to a oil bath, which was
refluxed at 80 °C overnight. After the completion of the reaction indicated by TLC, the
reaction mixture was quenched by saturated ammonium chloride solution and was
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extracted by ethyl acetate for three times. The combined organic layer was dried by
anhydrous sodium sulfate, which was concentrated under the reduced pressure. The
resulted residue was purified through flash chromatography on silica gel (petroleum
ether/ethyl acetate = 20/1) to afford the pure 2-indolylmethanol 1a in 80% yield.
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1
(1H-indol-2-yl)diphenylmethanol (1a): 2.4g; 80% yield; H NMR (400 MHz,
Chloroform-d) δ 8.31 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 – 7.26 (m, 11H), 7.20 –
7.13 (m, 1H), 7.11 – 7.05 (m, 1H), 6.18 – 6.00 (m, 1H), 2.94 (s, 1H). (The 1H NMR
data was consistent with the literature10a data)
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(5-bromo-1H-indol-2-yl)diphenylmethanol (1b): 2.3g; 62% yield; H NMR (400
MHz, Chloroform-d) δ 8.40 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.36 – 7.30 (m, 10H),
7.26 – 7.22 (m, 1H), 7.19 – 7.12 (m, 1H), 6.14 – 6.03 (m, 1H), 2.95 (s, 1H).
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(5-chloro-1H-indol-2-yl)diphenylmethanol (1c): 2.0g; 60% yield; H NMR (400
MHz, Chloroform-d) δ 8.39 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.42 – 7.24 (m, 10H),
7.19 (d, J = 8.6 Hz, 1H), 7.11 (dd, J = 8.6, 2.0 Hz, 1H), 6.11 – 6.04 (m, 1H), 2.96 (s,
1H).
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(5-methyl-1H-indol-2-yl)diphenylmethanol (1d): 2.4g; 78% yield; H NMR (400
MHz, Chloroform-d) δ 8.21 (s, 1H), 7.39 – 7.25 (m, 11H), 7.17 (d, J = 8.2 Hz, 1H),
6.99 (dd, J = 8.3, 1.7 Hz, 1H), 6.07 – 6.02 (m, 1H), 3.01 – 2.91 (m, 1H), 2.41 (s, 3H).
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(5-methoxy-1H-indol-2-yl)diphenylmethanol (1e): 2.5g; 75% yield; H NMR (400
MHz, Chloroform-d) δ 8.20 (s, 1H), 7.41 – 7.26 (m, 10H), 7.18 (d, J = 8.8 Hz, 1H),
6.99 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.5 Hz, 1H), 6.10 – 6.04 (m, 1H), 3.81 (s,
3H), 2.95 (s, 1H).
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(6-bromo-1H-indol-2-yl)diphenylmethanol (1f): 2.3g; 61% yield; H NMR (400
MHz, Chloroform-d) δ 8.36 (s, 1H), 7.48 – 7.43 (m, 1H), 7.41 – 7.29 (m, 11H), 7.18
(dd, J = 8.4, 1.7 Hz, 1H), 6.24 – 5.99 (m, 1H), 2.94 (s, 1H).
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(6-methoxy-1H-indol-2-yl)diphenylmethanol (1g): 1.8g; 55% yield; H NMR (400
MHz, Chloroform-d) δ 8.19 (s, 1H), 7.45 – 7.24 (m, 11H), 6.80 – 6.67 (m, 2H), 6.13 –
5.92 (m, 1H), 3.79 (s, 3H), 3.03 (s, 1H).
(1H-indol-2-yl)bis(3-methoxyphenyl)methanol (1h): 2.1g; 58% yield; 1H NMR (400
MHz, Chloroform-d) δ 8.29 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.33 – 7.26 (m, 1H), 7.28
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– 7.22 (m, 2H), 7.21 – 7.12 (m, 1H), 7.12 – 7.04 (m, 1H), 7.00 – 6.95 (m, 2H), 6.96 –
6.88 (m, 2H), 6.88 – 6.80 (m, 2H), 6.28 – 6.15 (m, 1H), 3.75 (s, 6H), 2.91 (s, 1H).
(1H-indol-2-yl)bis(4-methoxyphenyl)methanol (1i): 2.2g; 60% yield; 1H NMR (400
MHz, Chloroform-d) δ 8.31 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.32 – 7.20 (m, 5H), 7.20
– 7.11 (m, 1H), 7.12 – 7.03 (m, 1H), 6.88 – 6.80 (m, 4H), 6.16 – 6.06 (m, 1H), 3.79 (s,
6H), 2.86 (s, 1H).
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General procedure for the preparation of cyclopenta[b]indole (3aa-3an).
Under a nitrogen atmosphere, 2-indolylmethanol 1 (0.1 mmol), Pd2(dba)3 (0.0025
mmol) and TsOH·H2O (0.02 mmol) were dissolved in 1.0 mL dry (i-Pr)2O, and stirred
at room temperature for about 10 minutes. Then, chiral amine catalyst Cat-6 (0.02
mmol) was added, subsequently α,β-unsaturated aldehydes 2 (0.15 mmol) were added,
and the mixture was stirred at 0 °C until the reaction was completed monitored by TLC.
Then the crude product was purified by column chromatography using petroleum ether
and EtOAc (10:1) to get crude aldehyde compound. The aldehyde compound was
dissolved in THF, and NaBH4 (0.2 mmol) was added. The mixture was then stirred at
room temperature. After the reaction was completed (indicated by TLC), the solvent
was evaporated and the residue was purified by column chromatography on silica gel
(petroleum ether/EtOAc=4:1) to afford product 3.
2-((1R,2S)-1,3,3-Triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)ethan-1-ol
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(3aa): white solid, 34.1 mg, 80% yield, m.p: 252–253 °C; H NMR (400 MHz,
Chloroform-d) δ 7.85 (s, 1H), 7.63 – 7.53 (m, 2H), 7.47 – 7.36 (m, 4H), 7.36 – 7.30 (m,
3H), 7.30 – 7.23 (m, 2H), 7.22 – 7.16 (m, 3H), 7.11 – 7.04 (m, 1H), 6.97 – 6.86 (m,
2H), 6.80 – 6.70 (m, 2H), 4.06 (d, J = 8.4 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.45 – 3.30 (m,
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2H), 1.87 – 1.74 (m, 1H), 1.42 – 1.30 (m, 1H), 0.89 (brs, 1H). C {1H} NMR (100
MHz, Chloroform-d) δ 146.5, 144.8, 143.9, 143.3, 140.7, 129.0 (2C), 128.9 (2C), 128.7
(2C), 128.4 (2C), 128.0 (2C), 127.6 (2C), 126.9, 126.8, 126.7, 123.8, 121.8, 121.5,
119.9, 118.9, 111.9, 60.9, 59.9, 58.4, 50.2, 34.5. HRMS (EI-TOF) m/z: [M]+ calcd for
[C31H27NO]+: 429.2087; found: 429.2090; [α]D20= +31.6 (CH2Cl2, c=1.00); HPLC
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(Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=7.83 min,
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2-((1R,2S)-7-Bromo-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3ba): white solid, 30.3 mg, 60% yield, m.p: 229–230 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.88 (s, 1H), 7.62 – 7.52 (m, 2H), 7.49 – 7.41 (m, 2H), 7.40 –
7.34 (m, 4H), 7.34 – 7.26 (m, 2H), 7.25 – 7.17 (m, 3H), 7.21 – 7.09 (m, 2H), 7.04 –
6.98 (m, 1H), 6.78 – 6.65 (m, 2H), 4.01 (d, J = 8.4 Hz, 1H), 3.96 – 3.84 (m, 1H), 3.49
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– 3.25 (m, 2H), 1.86 – 1.72 (m, 1H), 1.41 – 1.30 (m, 1H), 0.86 (brs, 1H). C {1H}
NMR (100 MHz, Chloroform-d) δ 147.9, 144.5, 143.4, 143.0, 139.3, 129.1 (2C), 128.9
(2C), 128.8 (2C), 128.2 (2C), 128.1 (2C), 127.6 (2C), 127.1, 127.1, 126.9, 125.4, 124.4,
121.4 (2C), 113.3, 113.2, 60.9, 59.9, 58.3, 50.0, 34.4. HRMS (EI-TOF) m/z: [M]+ calcd
for [C31H2679BrNO]+: 507.1192; found: 507.1197; calcd for [C31H2681BrNO]+:
509.1172; found: 509.1187 [α]D20= +53.2 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H,
n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=9.49 min, 16.34 min.
2-((1R,2S)-7-Chloro-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3ca): white solid, 23 mg, 50% yield, m.p: 235–236 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.87 (s, 1H), 7.61 – 7.52 (m, 2H), 7.49 – 7.41 (m, 2H), 7.39 –
7.34 (m, 4H), 7.34 – 7.26 (m, 2H), 7.25 – 7.16 (m, 4H), 7.07 – 7.01 (m, 1H), 6.90 –
6.83 (m, 1H), 6.76 – 6.66 (m, 2H), 4.02 (d, J = 8.4 Hz, 1H), 3.97 – 3.87 (m, 1H), 3.45
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– 3.27 (m, 2H), 1.86 – 1.73 (m, 1H), 1.41 – 1.29 (m, 1H), 0.88 (brs, 1H). C {1H}
NMR (100 MHz, Chloroform-d) δ 148.1, 144.5, 143.4, 143.0, 139.0, 129.1 (2C), 128.9
(2C), 128.8 (2C), 128.3 (2C), 128.1 (2C), 127.6 (2C), 127.1, 127.1, 126.9, 125.5, 124.8,
121.8, 121.5, 118.4, 112.8, 60.9, 59.9, 58.3, 50.0, 34.4. HRMS (EI-TOF) m/z: [M]+
calcd for [C31H26ClNO]+: 463.1697; found: 463.1702; [α]D20= +48.1 (CH2Cl2, c=1.00);
HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm)
tR=9.62min, 17.78 min.
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2-((1R,2S)-7-Methyl-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3da): white solid, 36.8 mg, 83% yield, m.p: 230–232 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.73 (s, 1H), 7.60 – 7.51 (m, 2H), 7.47 – 7.36 (m, 4H), 7.36 –
7.22 (m, 4H), 7.22 – 7.14 (m, 4H), 6.93 – 6.87 (m, 1H), 6.78 – 6.66 (m, 3H), 4.02 (d, J
= 8.4 Hz, 1H), 3.94 – 3.83 (m, 1H), 3.45 – 3.27 (m, 2H), 2.27 (s, 3H), 1.85 – 1.74 (m,
1H), 1.39 – 1.30 (m, 1H), 0.86 (brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ
146.7, 144.9, 144.1, 143.4, 139.0, 129.2, 129.0 (2C), 128.9 (2C), 128.7 (2C), 128.4 (2C),
128.0 (2C), 127.7 (2C), 126.9, 126.8, 126.7, 124.0, 123.0, 121.3, 118.6, 111.6, 61.0,
59.9, 58.4, 50.2, 34.5, 21.4. HRMS (EI-TOF) m/z: [M]+ calcd for [C32H29NO]+:
443.2244; found: 443.2252; [α]D20= +37.0 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H,
n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=7.54 min, 13.95 min.
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2-((1R,2S)-7-Methoxy-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3ea): white solid, 25.7 mg, 56% yield, m.p: 110–111 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.71 (s, 1H), 7.60 – 7.50 (m, 2H), 7.47 – 7.34 (m, 4H), 7.37 –
7.22 (m, 4H), 7.25 – 7.11 (m, 4H), 6.80 – 6.69 (m, 3H), 6.40 – 6.30 (m, 1H), 4.03 (d, J
= 8.4 Hz, 1H), 3.95 – 3.86 (m, 1H), 3.63 (s, 3H), 3.45 – 3.31 (m, 2H), 1.87 – 1.74 (m,
1H), 1.42 – 1.30 (m, 1H), 0.88 (brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ
154.1, 147.5, 144.8, 143.8, 143.4, 135.8, 128.9 (4C), 128.7 (2C), 128.3 (2C), 128.0 (2C),
127.6 (2C), 126.9, 126.9, 126.7, 124.3, 121.6, 112.4, 110.8, 101.6, 61.0, 59.9, 58.3,
55.8, 50.1, 34.5. HRMS (EI-TOF) m/z: [M]+ calcd for [C32H29NO2]+: 459.2193; found:
459.2200; [α]D20= +53.4 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-
propanol=90/10, 1.0 mL/min, 220 nm) tR=9.21 min, 14.30 min.
2-((1R,2S)-6-Bromo-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3fa): white solid, 35.9 mg, 71% yield, m.p: 118–119 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.85 (s, 1H), 7.61 – 7.50 (m, 2H), 7.49 – 7.40 (m, 3H), 7.38 –
7.34 (m, 3H), 7.34 – 7.25 (m, 3H), 7.25 – 7.17 (m, 3H), 7.06 – 7.00 (m, 1H), 6.80 –
6.67 (m, 3H), 4.03 (d, J = 8.4 Hz, 1H), 3.96 – 3.88 (m, 1H), 3.45 – 3.29 (m, 2H), 1.87
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– 1.72 (m, 1H), 1.41 – 1.30 (m, 1H), 0.86 (brs, 1H). C {1H} NMR (100 MHz,
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Chloroform-d) δ 147.2, 144.5, 143.6, 143.0, 141.3, 129.0 (2C), 128.9 (2C), 128.8 (2C),
128.3 (2C), 128.1 (2C), 127.6 (2C), 127.1, 127.0, 126.9, 123.2, 122.6, 121.9, 120.0,
114.9, 114.8, 60.9, 60.0, 58.4, 50.1, 34.4. HRMS (EI-TOF) m/z: [M]+ calcd for
[C31H2679BrNO]+: 507.1192; found: 507.1196; calcd for [C31H2681BrNO]+: 507.1172;
found: 507.1186; [α]D20= +25.8 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-
hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=9.13 min, 20.34 min.
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2-((1R,2S)-6-Methoxy-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3ga): white solid, 39.5 mg, 86% yield, m.p: 122–123 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.72 (s, 1H), 7.59 – 7.52 (m, 2H), 7.47 – 7.34 (m, 4H), 7.37 –
7.22 (m, 4H), 7.24 – 7.16 (m, 3H), 6.84 – 6.70 (m, 4H), 6.63 – 6.56 (m, 1H), 4.02 (d, J
= 8.3 Hz, 1H), 3.95 – 3.85 (m, 1H), 3.76 (s, 3H), 3.45 – 3.30 (m, 2H), 1.86 – 1.73 (m,
1H), 1.40 – 1.29 (m, 1H), 0.88 (brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ
156.0, 145.1, 145.0, 144.1, 143.5, 141.5, 129.0 (2C), 128.9 (2C), 128.7 (2C), 128.3 (2C),
128.0 (2C), 127.6 (2C), 126.9, 126.8, 126.7, 121.7, 119.4, 118.2, 109.2, 96.1, 61.0,
60.0, 58.3, 55.7, 50.3, 34.5. HRMS (EI-TOF) m/z: [M]+ calcd for [C32H29NO2]+:
459.2193; found: 459.2199; [α]D20= +13.2 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H,
n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=13.33 min, 37.82 min.
2-((1R,2S)-3,3-Bis(3-methoxyphenyl)-1-phenyl-1,2,3,4-tetrahydrocyclopenta-
[b]indol-2-yl)ethan-1-ol (3ha): white solid, 26.9 mg, 55% yield, m.p: 105–106 °C; 1H
NMR (400 MHz, Chloroform-d) δ 7.87 (s, 1H), 7.40 – 7.36 (m, 2H), 7.35 – 7.29 (m,
3H), 7.28 – 7.22 (m, 2H), 7.20 – 7.14 (m, 1H), 7.16 – 7.02 (m, 3H), 6.95 – 6.82 (m,
3H), 6.77 – 6.70 (m, 1H), 6.40 – 6.32 (m, 2H), 4.07 (d, J = 8.3 Hz, 1H), 3.89 – 3.83 (m,
1H), 3.81 (s, 3H), 3.66 (s, 3H), 3.45 – 3.30 (m, 2H), 1.88 – 1.75 (m, 1H), 1.48 – 1.37
(m, 1H), 0.88 (brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ 160.0, 159.3, 146.4,
146.3, 144.9, 143.9, 140.7, 129.9, 128.8, 128.7 (2C), 128.4 (2C), 126.8, 123.8, 121.8,
121.5, 121.5, 120.2, 119.8, 118.9, 115.8, 114.5, 111.9, 111.2, 111.0, 61.0, 60.0, 58.6,
55.4, 55.1, 50.3, 34.4. HRMS (EI-TOF) m/z: [M]+ calcd for [C33H31NO3]+: 489.2298;
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found: 489.2300; [α]D20= +22.7 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-
hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=15.31 min, 46.47 min.
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2-((1R,2S)-3,3-Bis(4-methoxyphenyl)-1-phenyl-1,2,3,4-tetrahydrocyclopenta-
[b]indol-2-yl)ethan-1-ol (3ia): white solid, 31.8 mg, 65% yield, m.p: 141– 142°C; 1H
NMR (400 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.55 – 7.44 (m, 2H), 7.42 – 7.34 (m,
2H), 7.37 – 7.22 (m, 4H), 7.12 – 7.03 (m, 1H), 7.00 – 6.84 (m, 4H), 6.78 – 6.69 (m,
2H), 6.71 – 6.62 (m, 2H), 4.02 (d, J = 8.4 Hz, 1H), 3.90 – 3.77 (m, 4H), 3.76 (s, 3H),
3.46 – 3.31 (m, 2H), 1.86 – 1.71 (m, 1H), 1.45 – 1.31 (m, 1H), 0.86 (brs, 1H). 13C {1H}
NMR (100 MHz, Chloroform-d) δ 158.3, 158.3, 147.2, 144.0, 140.7, 137.0, 135.4,
130.0 (2C), 128.7 (2C), 128.6 (2C), 128.4 (2C), 126.8, 123.9, 121.4, 121.4, 119.8, 118.9,
114.2 (2C), 113.3 (2C), 111.9, 61.0, 58.8, 58.6, 55.4, 55.2, 50.3, 34.4. HRMS (EI-TOF)
m/z: [M]+ calcd for [C33H31NO3]+: 489.2298; found: 489.2299; [α]D20= +37.8 (CH2Cl2,
c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm)
tR=18.40 min, 69.86 min.
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2-((1R,2S)-1-(4-Methoxyphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]-
indol-2-yl)ethan-1-ol (3ab): white solid, 40.7 mg, 89% yield, m.p: 139–140 °C; 1H
NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.63 – 7.53 (m, 2H), 7.47 – 7.38 (m,
2H), 7.38 – 7.23 (m, 4H), 7.24 – 7.14 (m, 3H), 7.13 – 7.02 (m, 1H), 6.97 – 6.89 (m,
2H), 6.91 – 6.82 (m, 2H), 6.79 – 6.69 (m, 2H), 4.01 (d, J = 8.4 Hz, 1H), 3.90 – 3.82 (m,
1H), 3.80 (s, 3H), 3.47 – 3.32 (m, 2H), 1.87 – 1.72 (m, 1H), 1.40 – 1.29 (m, 1H), 0.91
(brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ 158.4, 146.4, 144.9, 143.3,
140.7, 135.8, 129.2 (2C), 129.0 (2C), 128.9 (2C), 128.0 (2C), 127.7 (2C), 126.9, 126.7,
123.8, 122.0, 121.5, 119.8, 118.9, 114.1 (2C), 111.9, 61.0, 59.9, 58.4, 55.3, 49.3, 34.5.
HRMS (EI-TOF) m/z: [M]+ calcd for [C32H29NO2]+: 459.2193; found: 459.2196;
[α]D20= +43.7 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10,
1.0 mL/min, 220 nm) tR=11.09 min, 42.01 min.
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indol-2-yl)ethan-1-ol (3ac) : white solid, 40.5 mg, 88% yield, m.p: 245–246 °C; H
NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.61 – 7.54 (m, 2H), 7.48 – 7.40 (m,
2H), 7.37 – 7.26 (m, 2H), 7.26 – 7.18 (m, 4H), 7.11 – 7.06 (m, 1H), 7.02 – 6.91 (m,
4H), 6.83 – 6.80 (m, 1H), 6.77 – 6.70 (m, 2H), 4.03 (d, J = 8.4 Hz, 1H), 3.97 – 3.88 (m,
1H), 3.75 (s, 3H), 3.46 – 3.35 (m, 2H), 1.88 – 1.75 (m, 1H), 1.42 – 1.30 (m, 1H), 0.94
(brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ 159.9, 146.5, 145.7, 144.9, 143.3,
140.7, 129.7, 129.0 (4C), 128.0 (2C), 127.7 (2C), 126.9, 126.7, 123.8, 121.7, 121.5,
120.7, 119.9, 119.0, 114.2, 112.0, 111.9, 61.0, 59.9, 58.2, 55.2, 50.3, 34.6. HRMS (EI-
TOF) m/z: [M]+ calcd for [C32H29NO2]+: 459.2193; found: 459.2196; [α]D20= +19.9
(CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min,
220 nm) tR=10.75 min, 25.94 min.
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2-((1S,2S)-1-(2-Methoxyphenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]-
indol-2-yl)ethan-1-ol (3ad) : white solid, 45.5 mg, 99% yield, m.p: 120–121 °C; 1H
NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.61 – 7.50 (m, 2H), 7.46 – 7.38 (m,
2H), 7.35 – 7.27 (m, 2H), 7.25 – 7.15 (m, 5H), 7.12 – 7.04 (m, 1H), 7.00 – 6.90 (m,
3H), 6.89 – 6.83 (m, 1H), 6.82 – 6.72 (m, 2H), 4.70 (d, J = 8.1 Hz, 1H), 3.95 – 3.88 (m,
1H), 3.86 (s, 3H), 3.46 – 3.34 (m, 2H), 1.87 – 1.72 (m, 1H), 1.44 – 1.32 (m, 1H), 0.98
(brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ 157.1, 146.5, 145.2, 143.6,
140.7, 132.1, 129.1 (3C), 128.8 (2C), 127.9 (2C), 127.7 (2C), 127.6, 126.8, 126.6, 123.8,
122.0, 121.3, 121.2, 119.7, 119.0, 111.8, 110.8, 61.0, 60.0, 58.5, 55.6, 35.0, 18.5.
HRMS (EI-TOF) m/z: [M]+ calcd for [C32H29NO2]+: 459.2193; found: 459.2202;
[α]D20= +29.9 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10,
1.0 mL/min, 220 nm) tR=10.63 min, 23.13 min.
2-((1R,2S)-3,3-Diphenyl-1-(p-tolyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3ae): white solid, 35.4 mg, 80% yield, m.p: 124–125 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.82 (s, 1H), 7.62 – 7.50 (m, 2H), 7.48 – 7.39 (m, 2H), 7.37 –
7.22 (m, 4H), 7.24 – 7.15 (m, 3H), 7.16 – 7.02 (m, 3H), 6.97 – 6.88 (m, 2H), 6.79 –
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6.69 (m, 2H), 4.02 (d, J = 8.4 Hz, 1H), 3.95 – 3.84 (m, 1H), 3.46 – 3.32 (m, 2H), 2.35
(s, 3H), 1.87 – 1.74 (m, 1H), 1.40 – 1.30 (m, 1H), 0.88 (brs, 1H). 13C {1H} NMR (100
MHz, Chloroform-d) δ 146.4, 144.9, 143.4, 140.8, 140.7, 136.3, 129.5 (2C), 129.0 (2C),
128.9 (2C), 128.2 (2C), 128.0 (2C), 127.7 (2C), 126.9, 126.7, 123.9, 122.0, 121.4, 119.8,
119.0, 111.9, 61.0, 59.9, 58.4, 49.7, 34.5, 21.2. HRMS (EI-TOF) m/z: [M]+ calcd for
[C32H29NO]+: 443.2244; found: 443.2247; [α]D20= +46.9 (CH2Cl2, c=1.00); HPLC
(Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=7.93 min,
29.64 min.
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2-((1R,2S)-3,3-Diphenyl-1-(m-tolyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)ethan-1-ol (3af): white solid, 25.0 mg, 60% yield, m.p: 181–182 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.83 (s, 1H), 7.62 – 7.54 (m, 2H), 7.47 – 7.41 (m, 2H), 7.38 –
7.26 (m, 2H), 7.24 – 7.15 (m, 6H), 7.14 – 7.03 (m, 2H), 6.98 – 6.90 (m, 2H), 6.78 –
6.69 (m, 2H), 4.02 (d, J = 8.4 Hz, 1H), 3.96 – 3.87 (m, 1H), 3.45 – 3.33 (m, 2H), 2.32
(s, 3H), 1.87 – 1.74 (m, 1H), 1.42 – 1.28 (m, 1H), 0.88 (brs, 1H). 13C {1H} NMR (100
MHz, Chloroform-d) δ 146.4, 144.9, 143.8, 143.3, 140.7, 138.2, 129.0, 129.0 (2C),
128.9 (2C), 128.6, 128.0 (2C), 127.7 (2C), 127.6, 126.9, 126.7, 125.4, 123.9, 121.9,
121.5, 119.8, 119.0, 111.9, 61.0, 59.9, 58.2, 50.1, 34.5, 21.6. HRMS (EI-TOF) m/z:
[M]+ calcd for [C32H29NO]+: 443.2244; found: 443.2247; [α]D20= +18.7 (CH2Cl2,
c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm)
tR=7.05 min, 16.58 min.
2-((1R,2S)-1-(4-Chlorophenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]-
indol-2-yl)ethan-1-ol (3ag): white solid, 37.4 mg, 81% yield, m.p: 133–134 °C; 1H
NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.60 – 7.52 (m, 2H), 7.48 – 7.39 (m,
2H), 7.37 – 7.32 (m, 1H), 7.32 – 7.26 (m, 5H), 7.24 – 7.16 (m, 3H), 7.14 – 7.05 (m,
1H), 7.00 – 6.88 (m, 2H), 6.79 – 6.69 (m, 2H), 4.03 (d, J = 8.3 Hz, 1H), 3.89 – 3.81 (m,
1H), 3.46 – 3.30 (m, 2H), 1.85 – 1.71 (m, 1H), 1.44 – 1.31 (m, 1H), 0.98 (brs, 1H). 13C
{1H} NMR (100 MHz, Chloroform-d) δ 146.7, 144.7, 143.1, 142.6, 140.7, 132.4, 129.7
(2C), 129.0 (2C), 128.9 (2C), 128.8 (2C), 128.0 (2C), 127.6 (2C), 127.0, 126.8, 123.6,
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121.6, 121.2, 120.0, 118.8, 112.0, 60.9, 60.0, 58.5, 49.7, 34.4. HRMS (EI-TOF) m/z:
[M]+ calcd for [C31H26ClNO]+: 463.1697; found: 463.1704; [α]D20= +42.1(CH2Cl2,
c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm)
tR=8.29 min, 22.14 min.
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2-((1R,2S)-1-(3-Chlorophenyl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]-
indol-2-yl)ethan-1-ol (3ah): white solid, 20.6 mg, 45% yield, m.p: 139–140 °C; 1H
NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.65 – 7.52 (m, 2H), 7.49 – 7.40 (m,
2H), 7.40 – 7.29 (m, 3H), 7.28 – 7.23 (m, 3H), 7.24 – 7.15 (m, 3H), 7.15 – 7.05 (m,
1H), 7.00 – 6.89 (m, 2H), 6.81 – 6.67 (m, 2H), 4.03 (d, J = 8.3 Hz, 1H), 3.92 – 3.81 (m,
1H), 3.48 – 3.29 (m, 2H), 1.85 – 1.72 (m, 1H), 1.49 – 1.34 (m, 1H), 0.95 (brs, 1H). 13C
{1H} NMR (100 MHz, Chloroform-d) δ 146.7, 146.3, 144.6, 143.1, 140.7, 134.5, 130.0,
129.0 (2C), 128.9 (2C), 128.5, 128.1 (2C), 127.6 (2C), 127.1, 127.0, 126.8, 126.6, 123.6,
121.7, 121.1, 120.0, 118.9, 112.0, 61.0, 60.0, 58.4, 50.1, 34.4. HRMS (EI-TOF) m/z:
[M]+ calcd for [C31H26ClNO]+: 463.1697; found: 463.1700; [α]D20= +24.5 (CH2Cl2,
c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm)
tR=9.12 min, 17.98 min.
2-((1R,2S)-1-(Benzo[d][1,3]dioxol-5-yl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclo-
penta[b]indol-2-yl)ethan-1-ol (3ai): white solid, 39.5 mg, 84% yield, m.p: 125–126 °C;
1H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.60 – 7.50 (m, 2H), 7.48 – 7.38
(m, 2H), 7.37 – 7.24 (m, 2H), 7.23 – 7.15 (m, 3H), 7.13 – 7.03 (m, 1H), 7.04 – 6.91 (m,
2H), 6.91 – 6.81 (m, 2H), 6.80 – 6.67 (m, 3H), 6.01 – 5.84 (m, 2H), 3.99 (d, J = 8.4 Hz,
1H), 3.88 – 3.75 (m, 1H), 3.50 – 3.34 (m, 2H), 1.86 – 1.71 (m, 1H), 1.45 – 1.31 (m,
1H), 0.99 (brs, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ 148.0, 146.4, 146.4,
144.8, 143.3, 140.7, 137.9, 128.9 (2C), 128.9 (2C), 128.0 (2C), 127.6 (2C), 126.9, 126.7,
123.8, 121.8, 121.5, 121.4, 119.9, 119.0, 111.9, 108.4, 108.3, 101.0, 61.1, 59.9, 58.5,
50.1, 34.5. HRMS (EI-TOF) m/z: [M]+ calcd for [C32H27NO3]+: 473.1985; found:
473.1993; [α]D20= +35.9 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-
propanol=90/10, 1.0 mL/min, 220 nm) tR=14.05 min, 53.58 min.
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2-((1R,2S)-1-(Naphthalen-1-yl)-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]-
indol-2-yl)ethan-1-ol (3aj): white solid, 24.1 mg, 50% yield, m.p: 141–142 °C; 1H
NMR (400 MHz, Chloroform-d) δ 7.91 – 7.75 (m, 5H), 7.64 – 7.57 (m, 2H), 7.52 –
7.41 (m, 5H), 7.39 – 7.26 (m, 2H), 7.27 – 7.18 (m, 3H), 7.13 – 7.01 (m, 1H), 6.90 –
6.73 (m, 4H), 4.24 (d, J = 8.3 Hz, 1H), 4.09 – 3.99 (m, 1H), 3.43 – 3.28 (m, 2H), 1.90
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– 1.76 (m, 1H), 1.48 – 1.36 (m, 1H), 0.88 (brs, 1H). C {1H} NMR (100 MHz,
Chloroform-d) δ 146.7, 144.8, 143.3, 141.5, 140.7, 133.6, 132.7, 129.0 (4C), 128.6,
128.0 (2C), 127.8, 127.8, 127.7 (2C), 127.0, 127.0, 126.8, 126.4, 126.1, 125.6, 123.8,
121.7, 121.5, 119.9, 119.0, 111.9, 61.0, 60.0, 58.1, 50.5, 34.5. HRMS (EI-TOF) m/z:
[M]+ calcd for [C35H29NO]+: 479.2244; found: 479.2248; [α]D20= -4.7 (CH2Cl2, c=1.00);
HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=11.13
min, 36.59 min.
2-((1S,2S)-3,3-Diphenyl-1-(thiophen-2-yl)-1,2,3,4-tetrahydrocyclopenta[b]indol-
2-yl)ethan-1-ol (3ak): white solid, 30.6 mg, 70% yield, m.p: 221–222 °C; 1H NMR
(400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.61 – 7.53 (m, 2H), 7.48 – 7.40 (m, 2H),
7.38 – 7.27 (m, 2H), 7.24 – 7.16 (m, 4H), 7.14 – 7.05 (m, 3H), 7.03 – 6.95 (m, 2H),
6.76 – 6.69 (m, 2H), 4.42 (d, J = 8.3 Hz, 1H), 4.03 – 3.93 (m, 1H), 3.59 – 3.43 (m, 2H),
1.88 – 1.75 (m, 1H), 1.47 – 1.37 (m, 1H). 13C {1H} NMR (100 MHz, Chloroform-d) δ
148.6, 146.0, 144.5, 143.1, 140.6, 129.0 (2C), 128.9 (2C), 128.0 (2C), 127.6 (2C), 127.0,
126.8, 126.8, 124.8, 124.1, 123.7, 121.7, 121.4, 120.0, 118.9, 112.0, 61.0, 59.8, 59.2,
45.2, 34.6. HRMS (EI-TOF) m/z: [M]+ calcd for [C29H25NOS]+: 435.1651; found:
435.1656; [α]D20= +39.3 (CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-
propanol=90/10, 1.0 mL/min, 220 nm) tR=11.47 min, 26.01 min.
2-((1S,2S)-1-ethyl-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)ethan-
1-ol (trans-3al): white solid, 13 mg, 32% yield, m.p: 89–90 °C; 1H NMR (400 MHz,
Chloroform-d) δ 7.78 (s, 1H), 7.65 – 7.55 (m, 1H), 7.48 – 7.39 (m, 2H), 7.39 – 7.21
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(m, 4H), 7.21 – 7.06 (m, 5H), 6.89 – 6.76 (m, 2H), 4.08 – 3.96 (m, 1H), 3.95 – 3.74
(m, 2H), 3.35 – 3.15 (m, 1H), 2.11 – 1.94 (m, 1H), 1.53 – 1.34 (m, 3H), 1.17 – 1.09
(m, 4H).13C {1H} NMR (100 MHz, Chloroform-d) (for trans-3al) δ 146.0, 145.9,
145.7, 140.1, 130.0 (2C), 128.8 (2C), 127.7 (2C), 127.3 (2C), 126.6, 126.5, 125.6,
122.5, 121.1, 120.2, 119.9, 111.8, 61.6, 58.5, 51.0, 42.3, 31.4, 23.6, 14.1. HRMS (EI-
TOF) m/z: [M]+ calcd for [C27H27NO]+: 381.2087; found: 381.2097; [α]D20= +133.4
(CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min,
220 nm) tR=12.15 min, 43.61 min.
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2-((1S,2R)-1-ethyl-3,3-diphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-yl)ethan-
1-ol (cis-3al): white solid, 11 mg, 30% yield, m.p: 95–96 °C; 1H NMR (400 MHz,
Chloroform-d) δ 7.72 (s, 1H), 7.63 – 7.50 (m, 3H), 7.44 – 7.33 (m, 2H), 7.34 – 7.26
(m, 2H), 7.21 – 7.07 (m, 5H), 6.80 – 6.70 (m, 2H), 3.75 – 3.62 (m, 2H), 3.61 – 3.52
(m, 1H), 3.12 – 3.02 (m, 1H), 2.16 – 2.01 (m, 1H), 1.85 – 1.68 (m, 1H), 1.61 – 1.53
(m, 1H), 1.52 – 1.40 (m, 1H), 1.18 (brs, 1H), 1.09 – 0.97 (m, 3H). 13C {1H} NMR
(100 MHz, Chloroform-d) (for cis-3al) δ 146.3, 145.7, 143.8, 140.9, 129.1 (2C),
128.7 (2C), 127.9 (2C), 127.8 (2C), 126.7, 126.5, 124.4, 121.6, 121.3, 119.8, 119.3,
111.9, 61.6, 60.2, 53.5, 45.5, 35.6, 26.1, 11.2. HRMS (EI-TOF) m/z: [M]+ calcd for
[C27H27NO]+: 381.2087; found: 381.2097; [α]D20= +17.7 (CH2Cl2, c=1.00); HPLC
(Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min, 220 nm) tR=16.27 min,
17.30 min.
Gram-Scale Procedure for the synthesis 3aa
Under a nitrogen atmosphere, 2-indolylmethanol 1a (897 mg, 3.0 mmol), Pd2(dba)3
(68.7 mg, 0.075 mmol) and TsOH·H2O (114 mg, 0.6 mmol) were dissolved in 30 mL
dry (i-Pr)2O, and stirred at room temperature for about 10 minutes. Then, chiral amine
catalyst Cat-6 (470 mg, 0.6 mmol) was added, subsequently α,β-unsaturated aldehydes
2a (526 mg, 3.6 mmol) were added, and the mixture was stirred at 0 °C until the reaction
was completed monitored by TLC. Then the crude product was purified by column
chromatography using petroleum ether and EtOAc (10:1) to get crude aldehyde
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compound. The aldehyde compound was dissolved in THF, and NaBH4 (227 mg, 6.0
mmol) was added. The mixture was then stirred at room temperature. After the reaction
was completed (indicated by TLC), the solvent was evaporated and the residue was
purified by column chromatography on silica gel (petroleum ether/EtOAc=4:1) to
afford product 3aa.
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General procedure for the synthesis of 4
Under a nitrogen atmosphere, 2-indolylmethanol 1a (59.8 mg, 0.20 mmol), Pd2(dba)3
(4.6 mg, 0.005 mmol) and TsOH·H2O (7.6 mg, 0.04 mmol) were dissolved in 2.0 mL
dry (i-Pr)2O, and stirred at room temperature for about 10 min. Then, chiral amine
catalyst Cat-6 (31.4 mg, 0.04 mmol) were added, subsequently add α,β-unsaturated
aldehydes 2a (44.0 mg, 0.30 mmol), and the mixture was stirred at 0 °C until the
reaction was completed monitored by TLC. Then the crude product was purified by
column chromatography using petroleum ether and EtOAc (10:1) to get crude aldehyde
compound. The aldehyde compound was dissolved in toluene, and ethyl
(triphenylphosphoranylidene) acetate (104.5 mg, 0.30 mmol) was added. The reaction
mixture was refluxed at 120 °C overnight. After the reaction was completed (indicated
by TLC), the solvent was evaporated and the residue was purified by column
chromatography on silica gel (petroleum ether/DCM=1:1) to afford product 4.
Ethyl
(E)-4-((1R,2S)-1,3,3-triphenyl-1,2,3,4-tetrahydrocyclopenta[b]indol-2-
yl)but-2-enoate (4): white solid, 64.7 mg, 65% yield, m.p: 197–198 °C; 1H NMR (400
MHz, Chloroform-d) δ 7.84 (s, 1H), 7.53 – 7.46 (m, 2H), 7.47 – 7.39 (m, 2H), 7.38 –
7.18 (m, 10H), 7.15 – 7.07 (m, 1H), 7.02 – 6.90 (m, 2H), 6.83 – 6.70 (m, 2H), 6.54 –
6.44 (m, 1H), 5.54 (d, J = 15.5 Hz, 1H), 4.18 – 3.98 (m, 3H), 3.85 – 3.72 (m, 1H), 2.43
– 2.29 (m, 1H), 2.21 – 2.05 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (100
MHz, Chloroform-d) δ 166.1, 147.4, 146.3, 144.4, 142.8, 142.8, 140.7, 129.0 (2C),
129.0 (2C), 128.8 (2C), 128.5 (2C), 128.1 (2C), 127.6 (2C), 127.0, 127.0, 126.8, 123.8,
122.3, 121.6, 121.2, 120.0, 119.2, 111.9, 61.7, 60.1, 60.0, 49.8, 33.7, 14.3. HRMS (EI-
TOF) m/z: [M]+ calcd for [C35H31NO2]+: 497.2349; found: 497.2356; [α]D20= +15.5
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(CH2Cl2, c=1.00); HPLC (Chiralpak AD-H, n-hexane/i-propanol=90/10, 1.0 mL/min,
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220 nm) tR=5.83 min, 6.75 min.
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ASSOCIATED CONTENT
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Supporting Information
The Supporting Information is available free of charge on the ACS Publications website
http://pubs.acs.org.
Crystallographic data (CIF)
Crystallographic data and NMR and HPLC spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-Mail: xyluo@ecust.edu.cn.
*E-Mail: weiping_deng@ecust.edu.cn.
ORCID
Wei-Ping Deng: 0000-0002-4232-1318
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is supported by the National Natural Science Foundation of China (No.
21572053) and the Fundamental Research Funds for the Central Universities.
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