Catalytic Asymmetric Synthesis of 3,3′-Bisindoles Bearing Single Axial Chirality

Article abstract of DOI:10.1021/acs.joc.0c01528

A catalytic asymmetric synthesis of 3,3′-bisindoles bearing single axial chirality has been established via chiral phosphoric acid (CPA)-catalyzed enantioselective addition reaction of 3,3′-bisindoles with ninhydrin-derived 3-indolylmethanols. The selection of ninhydrin-derived 3-indolylmethanols as suitable electrophiles is based on the consideration that the symmetric and bulky moiety of ninhydrin would increase the steric congestion around the axis to generate stable axial chirality and avoid the generation of central chirality. By this approach, a series of 3,3′-bisindoles bearing single axial chirality were synthesized via the dynamic kinetic resolution (DKR) process in generally acceptable yields and considerable enantioselectivities. In addition, an in-depth investigation on the property (stability and rotation barrier) of the synthesized axially chiral 3,3′-bisindoles was carried out, thus providing useful information on this class of axially chiral frameworks. This approach makes use of the strategy of dynamic kinetic resolution of 3,3′-bisindoles, therefore expanding the generality and applicability of this strategy for catalytic asymmetric synthesis of 3,3′-bisindoles bearing single axial chirality.

Full text of DOI:10.1021/acs.joc.0c01528

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Article
Catalytic Asymmetric Synthesis of 3,3’-
Bisindoles Bearing Single Axial Chirality
Ke-Wei Chen, Zhao-Shan Wang, Ping Wu, Xin-Yu Yan, Shu Zhang, Yu-Chen Zhang, and Feng Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01528 • Publication Date (Web): 15 Jul 2020
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Catalytic Asymmetric Synthesis of 3,3’-Bisindoles Bearing Single
Axial Chirality
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Ke-Wei Chen,a Zhao-Shan Wang,a Ping Wu,a Xin-Yu Yan,a Shu Zhang,*,b Yu-Chen
Zhang*,a and Feng Shi*,a
aSchool of Chemistry and Materials Science, Jiangsu Normal University, Xuzhou, 221116, China
bDepartment of Radiotherapy, The First Affiliated Hospital of Nanjing Medical University,
Nanjing, 210029, China
E-mail: fshi@jsnu.edu.cn; zhangyc@jsnu.edu.cn; zhangshu@njmu.edu.cn
Symmetric & bulky groups
H
N
Ar
R1
H
N
Ar
Ar
Ar
R1
+
steric congestion
stable axial chirality
without central chirality
O
O
CPA
DKR
R
O
OH
N
R
O
H
R2
N
H
18 examples
HN
N
up to 79% yield, 94:6 er
R2
H
ninhydrin-derived
3-indolylmethanols
3,3'-bisindoles bearing
single axial chirality
3,3'-bisindoles
Abstract: A catalytic asymmetric synthesis of 3,3’-bisindoles bearing single axial chirality has
been established via chiral phosphoric acid (CPA) catalyzed enantioselective addition reaction of
3,3’-bisindoles with ninhydrin-derived 3-indolylmethanols. The selection of ninhydrin-derived
3-indolylmethanols as suitable electrophiles is based on the consideration that the symmetric and
bulky moiety of ninhydrin would increase the steric congestion around the axis to generate stable
axial chirality and avoid the generation of central chirality. By this approach, a series of
3,3’-bisindoles bearing single axial chirality were synthesized via dynamic kinetic resolution
(DKR) process in generally acceptable yields and considerable enantioselectivities. In addition, an
in-depth investigation on the property (stability and rotation barrier) of the synthesized axially
chiral 3,3’-bisindoles were carried out, thus providing useful information for this class of axially
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chiral frameworks. This approach makes use of the strategy of dynamic kinetic resolution of
3,3’-bisindoles, therefore expanding the generality and applicability of this strategy for catalytic
asymmetric synthesis of 3,3’-bisindoles bearing single axial chirality.
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Introduction
Axially chiral indole-containing frameworks have emerged as a new class of family members
of atropisomeric hetero-biaryls.1-2 Consequently, a substantial attention from organic chemists has
recently been focused on the catalytic asymmetric construction of axially chiral indole-containing
frameworks3-8 due to the wide occurrence of such frameworks in natural products,9 bioactive
molecules10 and chiral ligands or catalysts.11,4a,4d Among them, axially chiral bisindole scaffolds
have gained particular attention from the synthetic community because such scaffolds exist in
many natural alkaloids9 and chiral ligands11c-d (Scheme 1a). However, the catalytic asymmetric
construction of axially chiral bisindole scaffolds is a challenging task because of the
characteristics of five-membered axially chiral skeletons such as low rotation barriers and weak
conformational stability.2
In our previous work (Scheme 1b),7a we devised a strategy to fulfil this task via catalytic
asymmetric addition reactions of 3,3’-bisindoles with isatin-derived indolylmethanols in the
presence of chiral Brønsted acid (B*-H). By this approach, we accomplished the catalytic
asymmetric synthesis of 3,3’-bisindoles bearing both axial and central chirality. However, there
are still some remaining issues to be solved regard to this strategy. For example, how to realize the
catalytic asymmetric synthesis of 3,3’-bisindoles bearing single axial chirality? Because
3,3’-bisindoles bearing single axial chirality can embody the actual property (stability and rotation
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barrier) of axially chiral 3,3’-bisindole frameworks without the effect of central chirality, thus
providing useful information for this new class of axially chiral frameworks. In addition, how to
expand the generality and applicability of this strategy in synthesizing axially chiral
3,3’-bisindoles? Therefore, it is still valuable to expand the generality and applicability of this
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strategy for catalytic asymmetric synthesis of 3,3’-bisindoles bearing single axial chirality.
a) Axially chiral bisindoles in natural products and chiral ligands
H
PPh
Br
2 PPh2
N
Br
Br
N
N
PPh2
PPh2
Me
Me
Br
Br
Br
Br
N
N
N
Br
Br
Br
N
tBuPh2SiO
OSiPh2tBu
chiral ligands
N
H
H
natural alkaloids
Characteristics:
weak conformational stability
low rotation barriers
b) Our previous work: synthesizing 3,3'-bisindoles with axial and central chirality
H
Ar
Ar
N
R3
H
N
R1
R2
R2
Ar
Ar
N
R1
O
N
O
B-H*
OH
R
+
R4
R3
R
N
H
N
H
N
H
HN
R4
3,3'-bisindoles bearing
both axial and central chirality
isatin-derived
3-indolylmethanols
3,3'-bisindoles
Remaining
issues:
Synthesizing 3,3'-bisindoles bearing single axial chirality
Expanding the generality and applicability of this strategy
Scheme 1. Axially chiral bisindoles and our previous work for accessing such molecules
To achieve this goal, based on our understanding of 3-indolylmethanols,12-14 we envisioned if
3-indolylmethanols bearing symmetric and bulky groups were employed as electrophiles to react
with 3,3’-bisindoles in the presence of B*-H, 3,3’-bisindoles bearing single axial chirality would
be synthesized (Scheme 2a). This is because the existence of symmetric and bulky groups in
3-indolylmethanols would increase the steric congestion around the axis to generate stable axial
chirality and avoid the generation of central chirality. Based on this strategy, we considered
ninhydrin-derived 3-indolylmethanols could serve as suitable reactants because of the symmetric
and bulky moiety of ninhydrin (Scheme 2b). According to this consideration, we designed a chiral
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phosphoric acid15 (CPA) catalyzed asymmetric addition reaction of 3,3’-bisindoles with
ninhydrin-derived 3-indolylmethanols. Namely, in the presence of CPA, ninhydrin-derived
3-indolylmethanols would transform into the corresponding carbocations via dehydration. Then,
CPA would simultaneously activate 3,3’-bisindoles and the carbocations via hydrogen-bonding
and ion-pairing interactions, thus facilitating a nucleophilic addition between them to give
3,3'-bisindoles bearing single axial chirality. On the basis of this design, we carried out an
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in-depth investigation on this reaction. Herein, we report the details of our investigation.
a) Our strategy: Using 3-indolylmethanols with symmetric & bulky groups as reactants
Symmetric & bulky groups
H
N
Ar
Ar
H
N
R1
Ar
Ar
R1
increase steric congestion
R2
R2
R2
R2
generate stable axial chirality
avoid generating central chirality
R
B-H*
OH
+
N
R
R3
H
N
H
N
HN
H
b) This work: synthesizing 3,3'-bisindoles bearing single axial chirality
H
N
Ar
Ar
H
N
R1
Ar
Ar
R1
+
O
O
CPA
O
OH
R
R2
R
N
O
H
N
H
N
H
HN
R2
ninhydrin-derived
3-indolylmethanols
3,3'-bisindoles bearing
single axial chirality
H
Ar
Ar
N
R1
O
O
CPA
R
N
-H2O
H
N
CPA
R2
H
O
O
P
*
Scheme 2. Design of the reaction for synthesizing 3,3'-bisindoles bearing single axial chirality
Results and Discussion
At the outset, the reaction of 3,3’-bisindole 1a with ninhydrin-derived 3-indolylmethanol 2a
in 1,2-dichloroethane (DCE) at 50 oC was employed as a model reaction for the screening of chiral
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catalysts (Table 1). However, in the presence of BINOL-derived CPA 4a-4g (entries 1-7), the
reactivity of ninhydrin-derived 3-indolylmethanol 2a was very low, and only CPA 4a, 4b and 4d
could catalyze the reaction to afford axially chiral product 3aa (entries 1-2 and 4). Among them,
CPA 4d bearing 3,3’-di(9-phenanthrenyl) groups displayed the highest catalytic activity in
delivering product 3aa in a moderate enantioselectivity of 80:20 er and an acceptable yield of 42%
(entry 4). To improve the enantioselectivity and the yield, we tentatively changed the backbone of
CPA 4d from BINOL to H8-BINOL and SPINOL (entries 8-9). However, H8-BINOL-derived
CPA 5a was inferior to CPA 4d in catalyzing the reaction with regard to the yield and the
enantioselectivity of product 3aa (entry 8 vs entry 4), and SPINOL-derived CPA 6a failed to
catalyze the reaction (entry 9). So, CPA 4d was selected as the optimal catalyst for this reaction.
Then, in the presence of catalyst 4d, several representative solvents were evaluated (entries
10-14). It was found that only ethyl acetate (entry 10) and acetonitrile (entry 12) could promote
the reaction, and no reaction occurred in other solvents including toluene, acetone and
tetrahydrofuran (entries 11 and 13-14). However, ethyl acetate and acetonitrile were still inferior
to 1,2-dichloroethane in terms of controlling the enantioselectivity (entries 10 and 12 vs entry 4).
In order to find more suitable solvents, a series of chloro-containing solvents were further
evaluated (entries 15-19). Nevertheless, none of them was better than 1,2-dichloroethane in
controlling the enantioselectivity of product 3aa (entries 15-19 vs entry 4). Thus,
1,2-dichloroethane was chosen as the most suitable solvent for this reaction.
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Table 1. Screening of catalysts and solventsa
5
6
7
8
9
G
G
G
4a
4b
4c
4d
4e
, G = 4-ClC6H4
, G = 2-Naphthyl
, G = 1-Naphthyl
, G = 9-Phenanthrenyl
, G = 9-Anthracenyl
, G = 2,4,6-(i-Pr)3C6H2
O
O
O
O
O
O
P
P
O
O
O
OH
OH
P
OH
G
G
10
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12
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4f
4g
G
5a
6a
(S)-
(S)-
, G = SiPh3
4
(S)-
G = 9-Phenanthrenyl
G = 9-Phenanthrenyl
H
N
H
Ph
Ph
Ph
Ph
N
O
O
Cat.
10 mol%
O
+
OH
solvent, 50 o
C
N
O
N
H
H
N
H
HN
3aa
1a
2a
entry
1
Cat.
solvent
DCE
yield (%)b
50
erc
50:50
63:27
-
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(S)-4f
(S)-4g
(S)-5a
(S)-6a
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
(S)-4d
2
DCE
47
3
DCE
N.R.
42
4
DCE
80:20
-
5
DCE
N.R.
N.R.
N.R.
38
6
DCE
-
7
DCE
-
8
DCE
74:26
-
9
DCE
N.R.
41
10
11
12
13
14
15
16
17
18
19
EtOAc
toluene
MeCN
acetone
THF
72:28
-
N.R.
30
72:28
-
N.R.
N.R.
20
-
CH2Cl2
CHCl3
77:23
76:24
82:14
53:47
77:23
39
Cl2CHCH2Cl
Cl3CCH3
28
43
Cl2CHCHCl2
22
aUnless indicated otherwise, the reaction was carried out in 0.05 mmol scale in a solvent (0.5 mL) at 50 oC for 12
h, and the molar ratio of 1a:2a was 1:1.2. bIsolated yields. cThe enantiomeric ratio (er) was determined by HPLC.
DCE = ClCH2CH2Cl. N.R. = No Reaction.
Subsequently, other reaction conditions were further optimized to increase the yield and the
enantioselectivity (Table 2). At first, some additives such as molecular sieves (MS) and anhydrous
sulfates were added to the reaction system (entries 2-6), and it was revealed that the addition of
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sodium sulfate could increase the yield and the enantioselectivity of 3aa to some extent (entry 6 vs
entry 1). Then, the concentration of the reaction was modulated by altering the volume of solvent
(entries 7-10). However, increasing the concentration had no evident effect on the reaction (entry
7 vs entry 6), while lowering the concentration led to a sharply decreased yield of 3aa (entries
8-10 vs entry 6). Next, the reaction temperature was either elevated or lowered (entries 11-13),
and it was discovered that the enantioselectivity could be improved from 84:16 er to 87:13 er
when lowering the reaction temperature from 50 oC to 30 oC (entry 6 vs entry 12). Because it was
reported that the addition of hexafluoroisopropanol (HFIP) could benefit the reaction in some
cases,16 we tentatively added some quantity of HFIP to the reaction (entries 14-16). Gratifyingly,
the addition of proper amount of HFIP could indeed improve the enantioselectivity of 3aa to 91:9
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o
er (entry 15 vs entry 12). The subsequent decreasing of the reaction temperature to 10 C led a
further enhanced enantioselectivity of 93:7 er but with a decreased yield of 42% (entry 17).
Finally, performing the reaction in a prolonged time resulted in a greatly increased yield of 75%
with a nearly retained enantioselectivity of 91:9 er (entry 18). Therefore, the optimal conditions
for this reaction were set as what entry 18 illustrated.
Table 2. Optimization of other reaction conditionsa
H
H
N
Ph
Ph
Ph
Ph
N
O
O
4d
10 mol% (S)-
O
+
OH
DCE (x mL), T o
additive
C
N
N
O
H
H
N
H
HN
1a
3aa
2a
entry
x (mL)
0.5
T (oC)
50
additive
-
yield (%)b
erc
1
2
3
4
5
6
42
20
80:20
81:19
-
0.5
50
3 Å MS
4 Å MS
5 Å MS
MgSO4
Na2SO4
0.5
50
N.R.
22
0.5
50
79:21
83:17
84:16
0.5
50
48
0.5
50
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0.25
1
50
50
50
50
70
30
20
30
30
30
10
10
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
53
36
33
29
51
52
42
48
49
46
42
75
84:16
84:16
84:16
84:16
80:20
87:13
87:13
90:10
91:9
9
2
10
11
12
13
14d
15e
16f
17e
18e,g
4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
10
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90:10
93:7
91:9
aUnless indicated otherwise, the reaction was carried out at 0.05 mmol scale with additives (50 mg) for 12 h, and
the molar ratio of 1a:2a was 1:1.2. bIsolated yield. cThe enantiomeric ratio (er) was determined by HPLC. dAdding
5 mol% hexafluoroisopropanol (HFIP). Adding 10 mol% HFIP. Adding 20 mol% HFIP. gThe reaction was
e
f
performed at 0.1 mmol scale for 48 h.
After establishing the optimal reaction conditions, we carried out the investigation on the
substrate scope of 3,3’-bisindoles 1 by the reaction with ninhydrin-derived 3-indolylmethanol 2a.
As shown in Table 3, this protocol could be applicable to a range of 3,3’-bisindoles 1 bearing
different R, R1 and R2 groups, and these substrates 1 smoothly participated in the catalytic
asymmetric addition reaction to afford 3,3’-bisindole products 3 bearing single axial chirality in
overall moderate yields (40%-79%) and good enantioselectivities (88:12 er to 94:6 er).
Specifically, both R2 (entries 2-6) and R (entries 7-9) groups could be different halogen and
electron-donating groups such as methyl and methoxyl. In addition, R1 groups could be phenyl
groups bearing electronically distinct substituents at different positions (entries 10-12).
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Table 3. Substrate scope of 3,3’-bisindoles 1a
H
R1
5
6
7
8
N
H
R1
R1
R
N
R1
R
4d
10 mol% (S)-
O
O
10 mol% HFIP
O
R2
+
OH
R2
DCE, Na2SO4,10 o
C
N
9
O
N
H
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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HN
H
1
2a
3
entry
3
R\R1\R2 (1)
yield (%)b
erc
1
2
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
H\Ph\H (1a)
H\Ph\5-F (1b)
75
62
43
40
75
63
79
45
41
43
54
65
91:9
93:7
92:8
91:9
91:9
3
H\Ph\5-Cl (1c)
4
H\Ph\5-Br (1d)
5
H\Ph\5-Me (1e)
H\Ph\5-OMe (1f)
5’-Br\Ph\H (1g)
5’-Me\Ph\H (1h)
5’-OMe\Ph\H (1i)
H\m-MeOC6H4\H (1j)
H\m-FC6H4\H (1k)
H\p-FC6H4\H (1l)
6
89:11
94:6
7
8
93:7
9
93:7
10
11
12
3ja
3ka
3la
88:12
90:10
88:12
aUnless indicated otherwise, the reaction was carried out at 0.1 mmol scale and catalyzed by 10 mol% (S)-4d in
DCE (0.5 mL) at 10 °C with 10 mol% HFIP and Na2SO4 (100 mg) as additives for 48 h, and the molar ratio of 1:2a
was 1:1.2. bIsolated yield. cThe er value was determined by HPLC.
Next, we investigated the substrate scope of ninhydrin-derived 3-indolylmethanols 2 by the
reactions with 1a under standard conditions (Table 4). As shown in entries 1-6, this approach
could be amenable to a series of ninhydrin-derived 3-indolylmethanols 2 bearing different
substituents at C5, C6 and C7-positions of the indole ring, and these substrates 2 took part in the
reaction to give axially chiral 3,3’-bisindoles 3 in acceptable yields (40%-76%) and considerable
enantioselectivities (85:15 er to 94:6 er). In addition, N-methyl-protected substrate 2g could also
smoothly take part in the reaction to generate axially chiral product 3ag albeit with a much lower
yield of 43% and a slightly decreased enantioselectivity of 88:12 er compared with product 3aa
(entry 7 vs entry 1), which was generated from N-H unprotected substrate 2a. In general, the
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unsatisfying yields of products 3 should be largely ascribed to the low reactivity of
ninhydrin-derived 3-indolylmethanols 2 because there were many remaining substrates in the
reaction system after a substantial reaction time of 48 hours.
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Table 4. Substrate scope of ninhydrin-derived 3-indolylmethanols 2a
H
N
Ph
Ph
H
Ph
Ph
N
O
N
4d
10 mol% (S)-
O
10 mol% HFIP
O
OH
+
5
6
N
DCE, Na2SO4, 10 o
C
O
H
R
N
H
N
R1
7
R1
R
3
1a
2
entry
3
R\R1 (2)
H\H (2a)
yield (%)b
erc
1
2
3
4
5
6
7
3aa
3ab
3ac
3ad
3ae
3af
3ag
75
47
46
43
40
76
43
91:9
88:12
94:6
5-Cl\H (2b)
5-Me\H (2c)
5-OMe\H (2d)
6-Br\H (2e)
7-Me\H (2f)
H\Me (2g)
92:8
85:15
87:13
88:12
aUnless indicated otherwise, the reaction was carried out at 0.1 mmol scale and catalyzed by 10 mol% (S)-4d in
DCE (0.5 mL) at 10 °C with 10 mol % HFIP and Na2SO4 (100 mg) as additives for 48 h, and the molar ratio of
1a:2 was 1:1.2. bIsolated yield. cThe er value was determined by HPLC.
The absolute configuration of axially chiral product 3ba (99:1 er after recrystallization) was
determined to be (Ra) by the analysis on its single-crystal structure.17 Because all products 3 were
synthesized in the presence of the same CPA (S)-4d, the absolute configurations of other axially
chiral products 3 were assigned to be (Ra) by analogy.
To investigate the possible activation mode of CPA (S)-4d to substrates 1 and 2, we
performed control experiments (Scheme 3). Firstly, N-methyl-protected substrate 1m was utilized
in the reaction with 2a under standard conditions (Scheme 3a). In this case, no reaction occurred,
and the outcome demonstrated the N-H group of substrates 1 played a crucial role in carrying out
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the addition reaction with substrates 2 possibly by forming a hydrogen bond with CPA (S)-4d.
5
6
a)
H
Ph
Ph
N
7
8
4d
10 mol% (S)-
O
10 mol% HFIP
O
No reaction
+
9
DCE, Na2SO4,10 o
C
OH
10
11
12
13
14
15
16
17
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N
N
H
Me
1m
2a
H
N
b)
Ph
Ph
H
Ph
Ph
N
4d
10 mol% (S)-
O
O
10 mol% HFIP
O
OH
+
DCE, Na2SO4,10 o
C
N
H
O
N
N
H
N
Me
Me
1a
2g
3ag
43% yield, 88:12 er
c)
O
O
O
O
4d
(S)-
O
O
O
O
OH
-H2O
R
R
R
R
N
R1
N
R1
N
N
R1
R1
2
delocalized cation
carbocation
vinyliminium
2g
2a
4d
(S)-
-H2O
-H2O
4d
(S)-
H
H
N
Ph
Ph
N
Ph
Ph
O
O
O
O
vs
N
N
1a
1a
H
N
H
N
Me
H
O
O
O
O
ion pair
P
P
ion pair &
hydrogen bond
*
*
Scheme 3. Control experiments and suggested activation mode
Secondly, instead of N-unprotected substrate 2a, N-methyl-protected substrate 2g was
employed to the reaction (Scheme 3b). Compared to the reaction of 2a (Table 4, entry 1), the
reaction of 2g could still occur to give product 3ag but with a much lower yield and a decreased
enantioselectivity. This result showed that the N-H group of ninhydrin-derived 3-indolylmethanols
2 was helpful for increasing the reactivity and the enantioselectivity, but it was not crucial for
substrates 2 to undergo the addition reaction, which indicated that substrates 2 might generate
ion-pairing interaction with CPA (S)-4d apart from hydrogen-bonding interaction. Based on the
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control experiments, we suggested a possible activation mode of CPA (S)-4d to the substrates. As
illustrated in Scheme 3c, in the presence of (S)-4d, ninhydrin-derived 3-indolylmethanols 2
underwent dehydration to transform into carbocation and vinyliminium intermediates, which
could be described as delocalized cation. In the reaction of 1a with 2a, the anion of CPA (S)-4d
could form hydrogen-bonding and ion-pairing interactions with the two reaction partners. While in
the reaction of 1a with 2g, CPA anion could not form hydrogen-bonding interaction with 2g.
Instead, an ion-pairing interaction between them was generated, which could also promote the
addition reaction.
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Table 5. Investigation on the stability of axially chiral product 3aaa
H
N
Ph
Ph
O
T oC, x hours
toluene
3aa
recovered
N
O
H
HN
3aa
91:9 er
entry
1
T (oC)
60
x (hour)
recovery yield of 3aa (%)b
er of recovered 3aac
2
4
98
96
97
98
97
97
98
96
98
96
98
96
96
97
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
91:9
2
60
3
60
6
4
60
8
5
60
10
24
2
6
60
7
80
8
80
4
9
80
6
10
11
12
13
14
80
8
80
10
24
24
24
80
120
130
aUnless indicated otherwise, the reaction was carried out at 0.1 mmol scale in toluene (1 mL) under argon
atmosphere. bIsolated yield. cThe enantiomeric ratio (er) was determined by HPLC.
In order to get some information on this class of 3,3’-bisindole frameworks bearing single
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axial chirality, we performed the investigation on the stability of axially chiral product 3aa (91:9
er) at different temperatures. As listed in Table 5, after being stirred at 60 oC (entries 1-6) or 80 oC
(entries 7-12) from 2 hours to 24 hours, no racemization was observed in the recovered 3aa.
Notably, the enantioselectivity of the recovered 3aa could still be retained even after being stirred
at a much higher temperature of 120 oC or 130 oC for 24 hours (entries 13-14). These experiments
demonstrated that this class of 3,3’-bisindole frameworks bearing single axial chirality has a high
stability even at a high temperature.
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Furthermore, we theoretically calculated the rotation barrier of compound 3aa (Scheme 4a),
and it was found that the rotation barrier of compound 3aa was very high (43.78 kcal mol-1),
which was in accordance with its high stability at high temperature (Table 5). The high rotation
barrier and stability of compound 3aa might be ascribed to the bulky moiety of ninhydrin. In
contrast, the rotation barrier of substrate 1a was very low (13.09 kcal mol-1),7 which was much
lower than the energy required for isolating the individual atropisomers (24 kcal mol-1).1a So,
substrate 1a could undergo rapid racemization during the reaction process, thus providing an
opportunity for the synthesis of axially chiral product 3aa in an enantioselective manner via the
process of dynamic kinetic resolution (DKR).
Based on the experimental results, we suggested a possible reaction pathway for the
generation of axially chiral product 3aa. As illustrated in Scheme 4b, (Ra)-1a was matched with
chiral catalyst (S)-4d. So, under the activation of (S)-4d via hydrogen-bonding and ion-pairing
interaction, a fast nucleophilic addition between (Ra)-1a and vinyliminium intermediate A
(generated from substrate 2a) occurred to give product (Ra)-3aa. In contrast, due to the
mismatched interaction between (Sa)-1a and catalyst (S)-4d, the reaction between (Sa)-1a and 2a
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was very slow. So, owing to the low rotation barrier of substrate 1a, (Sa)-1a continuously
transformed into (Ra)-1a to react with vinyliminium A, thus realizing the process of DKR and the
synthesis of axially chiral 3,3’-bisindole 3aa with (Ra)-configuration.
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a) Rotation barrier
H
N
Ph
Ph
H
Ph
Ph
N
O
N
O
H
H
N
HN
3aa
H
1a
rotation barrier
(kcal/mol):
13.09
43.78
rapid racemization
stable
b) Suggested reaction pathway
2a
(S)-
4d
3aa
(Sa)-
HN
NH
Ph
slow
Ph
1a
(Sa)-
H
N
henanthrenyl
9-P
Ph
Ph
Ph
Ph
NH
N
H
O
O
O
O
O
1a
(Ra)-
P
fast
O
H
N
O
N
H
9-P
HN
O
A
henanthrenyl
4d
(S)-
3aa
(Ra)-
Scheme 4. Calculated rotation barrier and suggested reaction pathway
To further investigate the scope of substrates 1, we tried using other groups to replace the
bisphenylmethyl group at the C2-position of substrates 1 (Scheme 5). When substrate 1n bearing a
small methyl group was employed to the reaction with 2a (Scheme 5a), the reaction could
smoothly occur to generate axially chiral product 3na in a good yield of 79% with some extent of
enantioselectivity (30% ee). When using substrate 1o bearing a cyclopropyl group at the
C2-position (Scheme 5b), the reaction still occurred to give product 3oa with axially chirality in a
considerable yield (74%) albeit with no improvement on the enantioselectivity (28% ee). To
further increase the size of the C2-substituent, substrate 1p bearing a bulky tertiary-butyl (t-Bu)
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group was employed to the reaction (Scheme 5c). However, in this case, no reaction occurred,
which indicated that the introduction of t-Bu group to the structure of substrates 1 greatly affected
the reactivity of substrates 1. From these results, it seemed that the bisphenylmethyl group at the
C2-position of substrates 1 was necessary for controlling the enantioselectivity with a suitable
reactivity.
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a)
H
N
H
Me
N
Me
4d
10 mol% (S)-
O
O
10 mol% HFIP
O
+
OH
DCE, Na2SO4, r.t.
N
O
N
H
H
N
HN
3na
H
1n
2a
79% yield, 30% ee
H
N
b)
H
N
4d
10 mol% (S)-
O
O
10 mol% HFIP
O
+
OH
DCE, Na2SO4, r.t.
N
O
N
H
H
N
HN
3oa
H
1o
2a
74% yield, 28% ee
c)
H
N
t-Bu
4d
10 mol% (S)-
O
10 mol% HFIP
O
+
No reaction
OH
DCE, Na2SO4, r.t.
N
H
N
H
1p
2a
Scheme 5. Further investigation on the scope of substrates 1
Finally, to demonstrate the practical utility of this synthetic method, a one-mmol-scale
reaction of substrates 1g and 2a was carried out (Scheme 6a). This larger-scale reaction smoothly
occurred to afford product 3ga in a good yield of 78% and a high enantioselectivity of 92:8 er,
which indicated that this reaction could be utilized for larger-scale synthesis of axially chiral
3,3’-bisindoles. In addition, some synthetic transformations of product 3ga were performed. As
illustrated in Scheme 6b, product 3ga underwent a Suzuki coupling with 4-chlorophenylboronic
acid to give compound 7 in a high yield of 81% with a retained enantioselectivity of 92:8 er. More
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importantly, product 3ga could transform into axially chiral phosphine 8 in a high yield (81%)
5
6
7
with a nearly maintained good enantioselectivity (90:10 er).
8
9
a) One-mmol-scale reaction
H
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Ph
Ph
N
H
Ph
Ph
N
Br
4d
10 mol% (S)-
O
O
10 mol% HFIP
Br
+
O
DCE, Na2SO4,10 o
C
OH
N
N
O
H
H
N
H
HN
3ga
1g
1 mmol
2a
1.2 mmol
78% (573 mg), 92:8 er
H
N
b) Synthetic transformations of 3ga
Ph
Ph
4-ClC6H4
O
4-ClC6H4B(OH)2
CsCO3, Pd(OAc)2
butyl di-1-adamantylphosphine
H
N
DCE, 80 o
C
Ph
Ph
N
O
H
HN
Br
7
O
81% yield, 92:8 er
N
H
O
H
Ph
Ph
N
HN
3ga
PPh2
O
92:8 er
1) n-BuLi, THF, -78 o
2) ClPPh2, -78 oC - 0 o
C
C
N
O
H
HN
8
87% yield, 90:10 er
Scheme 6. One-mmol-scale reaction and synthetic transformations
Conclusion
In summary, we have established the atroposelective synthesis of 3,3’-bisindoles bearing single
axial chirality via chiral phosphoric acid-catalyzed asymmetric addition reaction of3,3’-bisindoles
with
ninhydrin-derived
3-indolylmethanols.
The
selection
of
ninhydrin-derived
3-indolylmethanols as suitable electrophiles is based on the consideration that the symmetric and
bulky moiety of ninhydrin would increase the steric congestion around the axis to generate stable
axial chirality and avoid the generation of central chirality. By this approach, a series of
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3,3’-bisindoles bearing single axial chirality were synthesized via dynamic kinetic resolution
process in generally acceptable yields and considerable enantioselectivities. In addition, we
carried out an in-depth investigation on the property (stability and rotation barrier) of the
synthesized axially chiral 3,3’-bisindoles, thus providing useful information for this class of
axially chiral frameworks. This approach makes use of the strategy of dynamic kinetic resolution
of 3,3’-bisindoles, therefore expanding the generality and applicability of this strategy for catalytic
asymmetric synthesis of 3,3’-bisindoles bearing single axial chirality.
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Experimental Section
1H and 13C NMR spectra were measured at 400 and 100 MHz, respectively. The solvents
used for NMR spectroscopy were DMSO-d6 and CDCl3, using tetramethylsilane as the internal
reference. HR MS (ESI) was determined by a HR MS/MS instrument. The X-ray source used for
the single crystal X-ray diffraction analysis of compound 3ba was GaKα (λ = 1.34139), and the
thermal ellipsoid was drawn at the 30% probability level. Analytical grade solvents for the column
chromatography were used after distillation, and commercially available reagents were used as
received.
Methods for the synthesis of substrates 1:
Substrates 1a-1m could be conveniently synthesized according to the known literature
procedures.18 Among them, 1a-1b, 1d-1g, 1k, 1l-1m are known compounds, and the identities of
these compounds were confirmed by comparing the measured spectroscopic and physical data
with the literature data.18 Substrates 1n-1p could be conveniently synthesized according to the
known literature procedures.19 Among them, 1n is a known compound, and the identity of this
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compound was confirmed by comparing the measured spectroscopic and physical data with the
literature data.19
8
9
2-benzhydryl-5'-chloro-1H,1'H-3,3'-biindole (1c): Flash column chromatography (petroleum
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1
ether/ethyl acetate = 5/1); 44% yield (1.9 g); white solid; m.p. 213-214 °C; H NMR (400 MHz,
DMSO-d6) δ 11.46 (s, 1H), 10.99 (s, 1H), 7.49 – 7.39 (m, 2H), 7.34 (s, 1H), 7.32 (s, 2H), 7.30 (s,
3H), 7.27 – 7.21 (m, 4H), 7.20 – 7.13 (m, 4H), 7.11 – 7.05 (m, 1H), 7.01 – 6.93 (m, 1H), 5.68 (s,
1H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 143.2, 137.3, 136.8, 135.3, 129.2, 128.9, 128.2,
126.9, 126.1, 123.7, 121.6, 121.5, 119.4, 119.3, 119.0, 113.7, 111.9, 108.7, 108.6, 107.1, 107.0,
48.4; IR (KBr): 3448, 3055, 3021, 1450, 785, 746, 699 cm-1; HRMS (ESI-TOF) m/z: [M - H]-
Calcd for C29H20ClN2 431.1320, found 431.1322.
2-benzhydryl-5-methyl-1H,1'H-3,3'-biindole (1h): Flash column chromatography (petroleum
1
ether/ethyl acetate = 5/1); 70% yield (2.9 g); white solid; m.p. 218-219 °C; H NMR (400 MHz,
DMSO-d6) δ 11.19 (s, 1H), 10.77 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.35 – 7.26 (m, 6H), 7.23 (d, J
= 7.2 Hz, 2H), 7.21 – 7.14 (m, 4H), 7.13 – 7.09 (m, 2H), 7.08 (s, 1H), 6.97 – 6.86 (m, 2H), 5.69 (s,
1H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 143.4, 137.1, 136.8, 135.2, 129.2, 128.9,
128.7, 128.1, 127.5, 126.8, 124.2, 122.9, 121.6, 120.0, 119.3, 119.1, 112.1, 111.6, 109.0, 107.4,
48.4, 21.8; IR (KBr): 3456, 3430, 3048, 3025, 1482, 1454, 748, 706, 602 cm-1; HRMS (ESI-TOF)
m/z: [M - H]- Calcd for C30H23N2 411.1866, found 411.1863.
2-benzhydryl-5-methoxy-1H,1'H-3,3'-biindole (1i): Flash column chromatography
1
(petroleum ether/ethyl acetate = 5/1); 75% yield (3.2 g); white solid; m.p. 130-131 °C; H NMR
(400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.74 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.36 – 7.27 (m, 6H),
7.26 – 7.20 (m, 2H), 7.19 – 7.03 (m, 6H), 6.98 – 6.91 (m, 1H), 6.80 – 6.71 (m, 2H), 5.70 (s, 1H),
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3.62 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 153.6, 143.3, 137.6, 136.8, 131.9, 129.1,
128.8, 128.6, 127.8, 126.8, 124.0, 121.5, 119.9, 118.9, 112.4, 112.1, 111.3, 108.8, 107.7, 101.5,
55.7, 48.4; IR (KBr): 3409, 3055, 3023, 1618, 1482, 1088, 798, 743, 701 cm-1; HRMS (ESI-TOF)
m/z: [M - H]- Calcd for C30H23N2O 427.1816, found 427.1810.
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2-(bis(3-methoxyphenyl)methyl)-1H,1'H-3,3'-biindole (1j): Flash column chromatography
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(petroleum ether/ethyl acetate = 5/1); 44% yield (2.0 g); white solid; m.p.138-140 C; H NMR
(400 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.91 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.40 (d, J = 8.1 Hz,
1H), 7.29 (d, J = 7.9 Hz, 2H), 7.26 – 7.21 (m, 2H), 7.15 – 7.13 (m, 1H), 7.11 – 7.08 (m, 1H), 7.06
(d, J = 7.8 Hz, 1H), 6.96 – 6.92 (m, 2H), 6.84 – 6.80 (m, 2H), 6.75 (d, J = 7.5 Hz, 2H), 6.70 (s,
2H), 5.65 (s, 1H), 3.67 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 159.7, 144.6, 136.7, 129.8,
128.3, 128.0, 124.1, 121.5, 121.3, 119.9, 119.6, 119.0, 115.4, 112.1, 111.7, 108.7, 107.8, 55.4,
48.2; IR (KBr): 3411, 3052, 2833, 1579, 1455, 1486, 1047, 742, 697 cm-1; HRMS (ESI-TOF) m/z:
[M - H]- Calcd for C31H25N2O2 457.1921, found 457.1929.
2-cyclopropyl-1H,1'H-3,3'-biindole (1o): Flash column chromatography (petroleum
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ether/ethyl acetate = 10/1); 81% yield (2.2 g); white solid; m.p. 80-81 C; H NMR (400 MHz,
CDCl3) δ 8.26 (s, 1H), 7.72 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.47 (d, J =
8.1 Hz, 1H), 7.37 – 7.35 (m, 1H), 7.35 – 7.31 (m, 1H), 7.27 – 7.25 (m, 1H), 7.19 – 7.11 (m, 2H),
7.10 – 7.05 (m, 1H), 2.28 – 2.16 (m, 1H), 1.00 – 0.92 (m, 2H), 0.81 – 0.75 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 136.9, 136.2, 134.9, 129.3, 127.8, 123.0, 122.0, 121.3, 120.9, 119.6,
119.4, 119.3, 111.1, 110.4, 110.3, 107.6, 8.6, 7.7; IR (KBr): 3568, 3013, 1786, 1577, 1458, 1070,
897, 742, 669 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C19H15N2 271.1240, found
271.1255.
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ether/ethyl acetate = 10/1); 63% yield (1.8 g); white solid; m.p. 88-89 C; H NMR (400 MHz,
CDCl3) δ 8.20 (s, 1H), 8.14 (s, 1H), 7.47 – 7.43 (m, 1H), 7.41 – 7.34 (m, 2H), 7.26 – 7.21 (m, 1H),
7.20 – 7.12 (m, 3H), 7.10 – 7.05 (m, 1H), 7.02 – 6.96 (m, 1H), 1.35 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 144.6, 135.9, 133.8, 131.6, 129.4, 124.3, 121.9, 121.2, 120.5, 119.5, 119.4, 111.4,
110.9, 110.1, 104.4, 33.2, 30.7; IR (KBr): 3568, 3052, 2962, 1735, 1458, 1265, 741, 705 cm-1;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C20H20N2Na 311.1519, found 311.1528.
Methods for the synthesis of substrates 2:
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To the mixture of indole (10 mmol), ninhydrin (10 mmol) was added AcOH (10 mL). Then,
the reaction mixture was stirred at room temperature for 2 h. After the completion of the reaction
which was indicated by TLC, the reaction mixture was filtered to obtain a crude product, and the
residue was recrystallized from hot ethanol (water bath) to afford substrates 2.
2-hydroxy-2-(1H-indol-3-yl)-1H-indene-1,3(2H)-dione (2a): The product was recrystallized
1
from hot ethanol (water bath); 94% yield (2.6 g); yellow solid; m.p. 209-210 °C; H NMR (400
MHz, DMSO-d6) δ 11.20 (s, 1H), 8.04 – 7.97 (m, 4H), 7.79 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.1
Hz, 1H), 7.11 – 7.05 (m, 1H), 7.03 – 6.95 (m, 2H), 6.62 – 6.56 (m, 1H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 199.7, 139.6, 137.2, 137.0, 125.6, 125.4, 124.0, 122.1, 121.5, 119.6, 112.1, 110.8,
77.8; IR (KBr): 3353, 3129, 1743, 1703, 1585, 1119, 983, 853, 778, 665 cm-1; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C17H12NO3 278.0812, found 278.0810.
2-(5-chloro-1H-indol-3-yl)-2-hydroxy-1H-indene-1,3(2H)-dione (2b): The product was
recrystallized from hot ethanol (water bath); 93% yield (2.9 g); yellow solid; m.p. 187-188 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.07 – 7.96 (m, 4H), 7.81 (d, J = 8.4 Hz, 1H), 7.52 (s,
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1H), 7.16 (dd, J = 8.4, 1.6 Hz, 1H), 7.03 (d, J = 2.8 Hz, 1H), 6.66 (s, 1H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 199.5, 139.4, 137.4,135.5, 127.0, 126.9, 124.2, 124.1, 122.2, 120.9, 113.7,
110.6, 77.5; IR (KBr): 3506, 3279, 1747, 1707, 1464, 1354, 1140 , 976, 804, 652 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H11ClNO3 312.0422, found 312.0418.
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2-hydroxy-2-(5-methyl-1H-indol-3-yl)-1H-indene-1,3(2H)-dione (2c): The product was
recrystallized from hot ethanol (water bath); 89% yield (2.6 g); yellow solid; m.p. 208−209 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.03 – 7.94 (m, 4H), 7.62 (s, 1H), 7.21 (d, J = 8.3 Hz,
1H), 6.95 – 6.87 (m, 2H), 6.53 (s, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 199.6,
153.7, 139.6, 137.2, 132.2, 126.0, 125.9, 123.9, 112.7, 112.2, 110.3, 103.3, 77.9, 55.6; IR (KBr):
3472, 3265, 1743, 1705, 1590, 1147, 1078, 974, 865, 662, 589 cm-1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C18H14NO3 292.0968, found 292.0972.
2-hydroxy-2-(5-methoxy-1H-indol-3-yl)-1H-indene-1,3(2H)-dione (2d): The product was
recrystallized from hot ethanol (water bath); 92% yield (2.8 g); yellow solid; m.p. 207−208 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.00 (s, 4H), 7.63 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H),
6.96 – 6.88 (m, 2H), 6.54 (d, J = 6.0 Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6)
δ 199.7, 139.5, 137.2, 135.4, 128.0, 125.9, 125.4, 123.9, 123.7, 121.2, 111.7, 110.2, 78.0, 21.8; IR
(KBr): 3342, 3055, 1748, 1710, 1487, 1166, 1075, 1018, 864, 710, 660 cm-1; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C18H14NO4 308.0918, found 308.0915.
2-(6-bromo-1H-indol-3-yl)-2-hydroxy-1H-indene-1,3(2H)-dione (2e): The product was
recrystallized from hot ethanol (water bath); 90% yield (3.2 g); yellow solid; m.p. 192−193 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.04 – 7.99 (m, 4H), 7.81 (d, J = 8.6 Hz, 1H), 7.53
(s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.65 (s, 1H); 13C{1H} NMR (100 MHz,
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DMSO-d6) δ 199.5, 139.5, 137.9, 137.4, 126.3, 124.8, 124.1, 123.4, 122.5, 114.9, 114.6, 111.1,
77.5; IR (KBr): 3503, 3280, 1750, 1713, 1474, 1360, 1139 , 983, 795, 649 cm-1; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H11BrNO3 355.9917, found 355.9920.
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2-hydroxy-2-(7-methyl-1H-indol-3-yl)-1H-indene-1,3(2H)-dione (2f): The product was
recrystallized from hot ethanol (water bath); 93% yield (2.7 g); yellow solid; m.p. 185−186 °C; 1H
NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.06 – 7.97 (m, 4H), 7.60 – 7.53 (m, 1H), 6.99 (d, J
= 2.8 Hz, 1H), 6.91 – 6.85 (m, 2H), 6.63 – 6.37 (m, 1H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz,
DMSO-d6) δ 199.7, 139.6, 137.2, 136.5, 125.2, 125.0, 124.0, 122.5, 121.2, 119.8, 119.0, 111.3,
77.9, 17.1; IR (KBr): 3440, 2630, 2602, 2192, 1749, 1709, 1026, 665, 583 cm-1; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C18H14NO3 292.0968, found 292.0971.
2-hydroxy-2-(1-methyl-1H-indol-3-yl)-1H-indene-1,3(2H)-dione (2g): The product was
recrystallized from hot ethanol (water bath); 48% yield (1.4 g); yellow solid; m.p. 209-210 °C; 1H
NMR (400 MHz, DMSO-d6) δ 8.04 – 7.98 (m, 4H), 7.81 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.2 Hz,
1H), 7.18 – 7.12 (m, 1H), 7.06 – 7.01 (m, 2H), 6.58 (s, 1H), 3.67 (s, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 199.6, 139.5, 137.5, 137.3, 129.5, 126.0, 124.0, 122.2, 121.7, 119.7, 110.3,
109.8, 77.7, 32.8; IR (KBr): 3481, 3112, 1766, 1706, 1525, 1329, 1146, 957, 766, 651, 604 cm-1;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H14NO3 292.0968, found 292.0972.
General procedure for the synthesis of products 3
To the mixture of 3,3’-bisindoles 1 (0.1 mmol), ninhydrin-derived 3-indolylmethanols 2
(0.12 mmol), catalyst (S)-4d (7.0 mg, 0.01 mmol), hexafluoroisopropanol (1 μL, 0.01 mmol) and
Na2SO4 (100 mg) was added DCE (0.5 mL). Then, the reaction mixture was stirred at 10 oC for 48
h. Then, the reaction mixture was directly purified through preparative thin layer chromatography
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or flash column chromatography to afford products 3.
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(Ra)-2-(2'-benzhydryl-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,3(2H)-dio
ne (3aa): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1); 75% yield
(49.3 mg); yellow solid; m.p. 175-176 oC; [α]D20 = -335.0 (c 0.38, Acetone); 1H NMR (400 MHz,
CDCl3) δ 8.32 (s, 1H), 8.31 – 8.26 (m, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.4 Hz, 2H), 7.59
(s, 1H), 7.47 – 7.40 (m, 2H), 7.40 – 7.30 (m, 3H), 7.30 – 7.26 (m, 1H), 7.26 – 7.22 (m, 3H), 7.21 –
7.16 (m, 1H), 7.15 – 7.06 (m, 5H), 7.04 – 6.99 (m, 2H), 6.97 – 6.92 (m, 1H), 6.90 – 6.82 (m, 2H),
6.79 – 6.72 (m, 2H), 6.59 – 6.48 (m, 1H), 6.36 (d, J = 8.0 Hz, 1H), 5.57 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 197.3, 143.3, 141.8, 140.4, 140.2, 139.4, 137.0, 134.9, 134.8, 134.1, 133.9,
133.2, 130.6, 130.0, 129.7, 129.0, 128.8, 128.2, 127.0, 126.3, 126.1, 124.9, 123.1, 123.0, 122.6,
121.8, 121.4, 120.8, 120.7, 120.3, 120.2, 119.5, 119.0, 111.4, 110.4, 109.8, 109.2, 106.1, 105.6,
59.0, 48.8; IR (KBr): 3567, 1717, 1662, 1398, 791, 743, 697 cm-1; HRMS (ESI-TOF) m/z: [M -
H]- Calcd for C46H30N3O2 656.2343, found 656.2315; Enantiomeric ratio = 91:9, determined by
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HPLC (Daicel Chiralpak IA, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 C, 254
nm): tR = 6.257 min (major), tR = 41.357 min (minor).
(Ra)-2-(2'-benzhydryl-5-fluoro-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,3
(2H)-dione (3ba): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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62% yield (41.6 mg); yellow solid; m.p. 191-192 C; [α]D = -404.8 (c 0.46, Acetone); 1H NMR
(400 MHz, CDCl3) δ 8.34 – 8.31 (m, 1H), 8.28 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.3
Hz, 2H), 7.59 (s, 1H), 7.49 – 7.41 (m, 2H), 7.40 – 7.31 (m, 3H), 7.31 – 7.26 (m, 3H), 7.26 – 7.18
(m, 2H), 7.17 – 7.08 (m, 4H), 7.04 – 6.99 (m, 2H), 6.99 – 6.94 (m, 1H), 6.92 – 6.74 (m, 4H), 6.71
– 6.63 (m, 1H), 5.93 – 5.85 (m, 1H), 5.53 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3,
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197.2, 157.3 (J = 233 Hz), 143.1, 141.5, 141.0, 140.1, 139.3, 137.0, 135.0, 134.2, 133.8, 131.2,
130.6, 130.5, 130.4, 129.6, 128.9 (J = 10.6 Hz), 128.3, 127.1, 126.6, 126.1, 124.9, 123.1, 123.0,
122.5, 121.8, 120.9, 120.8, 120.0, 119.6, 111.5, 111.0 (J = 9.4 Hz), 110.0, 109.9, 109.7, 108.9,
106.1 (J = 4.7 Hz), 104.9, 104.7, 58.9, 48.9; IR (KBr): 3445, 3058, 1741, 1705, 1485, 1456, 744,
701 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C46H29FN3O2 674.2249, found 674.2248;
Enantiomeric ratio = 93:7, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol =
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70/30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 6.737 min (major), tR = 47.387 min
(minor).
(Ra)-2-(2'-benzhydryl-5-chloro-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,3
(2H)-dione (3ca): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
43% yield (29.5 mg); yellow solid; m.p. 188-190 oC; [α]D20 = -281.8 (c 0.440, Acetone); 1H NMR
(400 MHz, CDCl3) δ 8.34 – 8.33 (m, 1H), 8.30 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.4
Hz, 2H), 7.58 (s, 1H), 7.46 – 7.32 (m, 5H), 7.31 – 7.26 (m, 3H), 7.26 – 7.19 (m, 2H), 7.18 – 7.10
(m, 4H), 7.05 – 6.94 (m, 3H), 6.91 – 6.82 (m, 3H), 6.82 – 6.76 (m, 1H), 6.74 (d, J = 7.8 Hz, 1H),
6.20 (d, J = 2.0 Hz, 1H), 5.52 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3, 197.2, 142.8,
141.4, 141.2, 140.2, 139.4, 137.1, 135.1, 134.8, 134.2, 133.8, 133.0, 131.0, 130.5, 129.7, 129.0,
128.9, 128.3, 127.1, 126.9, 126.1, 124.9, 123.2, 123.1, 122.5, 121.9, 121.8, 121.0, 120.9, 120.0,
119.7, 119.6, 111.6, 111.5, 109.9, 108.9, 105.8, 104.7, 58.9, 49.0; IR (KBr): 3026, 2917, 2351,
1704, 1557, 1455, 743, 701 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C46H29ClN3O2
690.1954, found 690.1951; Enantiomeric ratio = 92:8, determined by HPLC (Daicel Chiralpak IA,
hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 6.783 min (major), tR
= 46.193 min (minor).
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(Ra)-2-(2'-benzhydryl-5-bromo-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,
3(2H)-dione (3da): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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40% yield (29.5 mg); yellow solid; m.p. 190-192 C; [α]D = -148.1 (c 0.87, Acetone); 1H NMR
(400 MHz, CDCl3) δ 8.40 – 8.25 (m, 2H), 8.04 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.4 Hz, 2H), 7.60
(s, 1H), 7.49 – 7.41 (m, 2H), 7.40 – 7.32 (m, 3H), 7.31 – 7.26 (m, 3H), 7.26 – 7.13 (m, 5H), 7.12
(d, J = 2.7 Hz, 1H), 7.03 – 6.98 (m, 3H), 6.94 – 6.83 (m, 3H), 6.82 – 6.72 (m, 2H), 6.42 – 6.35 (m,
1H), 5.54 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.3, 197.2, 142.7, 141.5, 141.2, 140.2,
139.4, 137.1, 135.1, 134.7, 134.3, 133.8, 133.3, 131.6, 130.5, 129.7, 128.9, 128.4, 127.2, 127.0,
126.1, 124.9, 124.4, 123.2, 123.1, 122.6, 122.5, 121.8, 121.0, 120.9, 120.0, 119.7, 112.7, 112.0,
111.6, 110.0, 108.9, 105.8, 104.7, 58.9, 49.0; IR (KBr): 3026, 2917, 1557, 1455, 1417, 795, 701
cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C46H29BrN3O2 734.1448, found 734.1440;
Enantiomeric ratio = 91:9, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol =
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(minor).
(Ra)-2-(2'-benzhydryl-5-methyl-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,
3(2H)-dione (3ea): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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75% yield (50.4 mg); yellow solid; m.p. 195-196 C; [α]D = -542.4 (c 0.58, Acetone); H NMR
(400 MHz, CDCl3) δ 8.31 – 8.25 (m, 1H), 8.23 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.4
Hz, 2H), 7.61 (s, 1H), 7.50 – 7.41 (m, 2H), 7.40 – 7.31 (m, 3H), 7.30 – 7.26 (m, 2H), 7.26 – 7.22
(m, 2H), 7.22 – 7.17 (m, 1H), 7.16 – 7.12 (m, 3H), 7.10 (d, J = 2.7 Hz, 1H), 7.06 – 7.00 (m, 2H),
6.98 (d, J = 8.3 Hz, 1H), 6.92 – 6.83 (m, 2H), 6.82 – 6.75 (m, 3H), 6.08 (s, 1H), 5.57 (s, 1H), 1.98
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.7, 197.6, 143.3, 141.9, 140.6, 140.3, 139.4,
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137.0, 134.9, 134.2, 133.9, 133.3, 133.1, 130.6, 130.3, 129.7, 129.2, 128.8, 128.2, 128.1, 127.0,
126.3, 126.2, 124.9, 123.2, 123.1, 123.0, 122.7, 121.9, 120.9, 120.1, 120.4, 120.0, 119.5, 111.5,
110.1, 109.8, 109.3, 105.8, 105.5, 59.0, 48.8, 21.0; IR (KBr): 3402, 3056, 2996, 1705, 1593, 1451,
777, 743, 598 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C47H32N3O2 670.2500, found
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670.2496; Enantiomeric ratio
= 91:9, determined by HPLC (Daicel Chiralpak IC,
hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR = 4.017 min(major), tR
= 4.660 min (minor).
(Ra)-2-(2'-benzhydryl-5-methoxy-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-
1,3(2H)-dione (3fa): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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63% yield (43.6 mg); yellow solid; m.p. 178-180 C; [α]D = -227.9 (c 1.08, Acetone); H NMR
(400 MHz, CDCl3) δ 8.37 – 8.33 (m, 1H), 8.27 (s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.71 – 7.60 (m,
3H), 7.48 – 7.39 (m, 2H), 7.38 – 7.31 (m, 3H), 7.30 – 7.27 (m, 1H), 7.26 – 7.23 (m, 3H), 7.23 –
7.18 (m, 1H), 7.17 – 7.10 (m, 3H), 7.10 – 7.08 (m, 1H), 7.07 – 7.02 (m, 2H), 6.99 (d, J = 8.8 Hz,
1H), 6.94 – 6.77 (m, 4H), 6.67 – 6.58 (m, 1H), 5.95 – 5.82 (m, 1H), 5.60 (s, 1H), 3.29 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 197.6, 197.5, 153.6, 143.7, 142.0, 140.2, 139.3, 137.1, 134.9,
134.2, 134.0, 130.7, 130.6, 129.9, 129.7, 129.0, 128.8, 128.3, 127.0, 126.4, 126.2, 125.0, 123.1,
122.9, 122.7, 122.0, 121.0, 120.8, 120.6, 119.5, 112.8, 111.6, 111.5, 109.9, 109.2, 105.8, 105.7,
100.9, 59.0, 55.4, 48.7; IR (KBr): 3397, 3056, 2965, 2360, 1705, 1456, 842, 797, 744 cm-1;
HRMS (ESI-TOF) m/z: [M - H]- Calcd for C47H32N3O3 686.2449, found 686.2450; Enantiomeric
ratio = 89:11, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 oC, 254 nm): tR = 7.397 min (major), tR = 38.140 min (minor).
(Ra)-2-(2'-benzhydryl-5'-bromo-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,
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3(2H)-dione (3ga): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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79% yield (58.4 mg); yellow solid; m.p. 198-200 C; [α]D = -804.0 (c 0.40, Acetone); H NMR
(400 MHz, CDCl3) δ 8.35 (s, 1H), 8.34 – 8.28 (m, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 – 7.60 (m,
4H), 7.47 – 7.30 (m, 5H), 7.27 (s, 2H), 7.21 – 7.15 (m, 2H), 7.15 – 7.06 (m, 5H), 7.04 – 6.99 (m,
2H), 6.98 – 6.91 (m, 2H), 6.81 – 6.70 (m, 2H), 6.59 – 6.48 (m, 1H), 6.32 (d, J = 8.0 Hz, 1H), 5.61
(s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 197.1, 142.7, 142.1, 141.4, 140.3, 139.6,
136.9, 135.2, 134.9, 134.6, 132.9, 132.4, 132.2, 129.8, 129.6, 129.0, 128.9, 128.3, 127.1, 126.5,
126.1, 124.9, 123.6, 123.3, 123.0, 122.4, 122.2, 121.9, 121.7, 120.7, 120.0, 119.2, 113.0, 111.5,
111.4, 110.5, 109.4, 105.4, 59.1, 48.8; IR (KBr): 3057, 2953, 1741, 1701, 1451, 1412, 837, 744,
699 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd for C46H29BrN3O2 734.1448, found 734.1428;
Enantiomeric ratio = 94:6, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol =
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70/30, flow rate 1.0 mL/min, T = 30 C, 254 nm): tR = 6.083 min (major), tR = 84.883 min
(minor).
(Ra)-2-(2'-benzhydryl-5'-methyl-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-1,
3(2H)-dione (3ha): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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45% yield (30.3 mg); yellow solid; m.p. 197-199 C; [α]D = -205.1 (c 0.81, Acetone); H NMR
(400 MHz, DMSO-d6) δ 11.27 (d, J = 2.4 Hz, 1H), 10.59 (s, 1H), 10.34 (s, 1H), 7.69 (d, J = 7.6
Hz, 1H), 7.63 – 7.59 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.42 – 7.30 (m, 5H),
7.27 – 7.22 (m, 2H), 7.22 – 7.15 (m, 3H), 7.14 – 7.06 (m, 3H), 7.03 – 6.94 (m, 3H), 6.93 – 6.82
(m, 2H), 6.58 – 6.52 (m, 1H), 6.44 – 6.36 (m, 1H), 6.14 (d, J = 4.7 Hz, 2H), 5.43 (s, 1H), 2.04 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 197.2, 142.7, 142.2, 141.5, 140.4, 139.7, 137.0,
135.3, 135.0, 134.7, 133.0, 132.5, 132.2, 129.8, 129.7, 129.0, 128.9, 128.4, 127.2, 126.5, 126.2,
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125.0, 123.6, 123.4, 123.1, 122.4, 122.3, 121.9, 121.7, 120.8, 120.0, 119.2, 113.1, 111.5, 111.5,
110.6, 109.4, 105.4, 59.1, 48.9; IR (KBr): 3056, 2964, 1558, 1449, 1417, 793, 743, 698, 599 cm-1;
HRMS (ESI-TOF) m/z: [M - H]- Calcd for C47H32N3O2 670.2500, found 670.2473; Enantiomeric
ratio = 93:7, determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 70/30, flow rate
1.0 mL/min, T = 30 oC, 254 nm): tR = 5.980 min (major), tR = 64.023 min (minor).
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(Ra)-2-(2'-benzhydryl-5'-methoxy-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-indene-
1,3(2H)-dione (3ia): Preparative thin layer chromatography (petroleum ether/ethyl acetate = 2:1);
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41% yield (28.1 mg); yellow solid; m.p. 197-199 C; [α]D = -314.8 (c 0.50, Acetone); H NMR
(400 MHz, CDCl3) δ 8.40 – 8.27 (m, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.51
– 7.36 (m, 5H), 7.36 – 7.26 (m, 4H), 7.26 – 7.18 (m, 2H), 7.17 – 7.05 (m, 5H), 7.03 – 6.98 (m,
2H), 6.98 – 6.90 (m, 1H), 6.69 (d, J = 8.7 Hz, 1H), 6.57 – 6.47 (m, 2H), 6.32 (d, J = 8.0 Hz, 1H),
6.24 – 6.19 (m, 1H), 5.52 (s, 1H), 3.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.7, 197.5,
154.0, 143.4, 141.8, 141.3, 140.3, 139.2, 137.1, 134.9, 134.8, 134.2, 133.6, 131.2, 130.0, 129.7,
129.1, 128.8, 128.7, 128.3, 127.0, 126.4, 126.2, 124.9, 123.2, 122.7, 121.8, 121.4, 120.9, 120.3,
119.1, 111.7, 111.5, 110.7, 110.5, 109.1, 106.0, 105.5, 101.0, 58.9, 55.5, 48.9; IR (KBr): 3056,
2360, 2342, 1702, 1589, 1485, 1449, 837, 797, 743 cm-1; HRMS (ESI-TOF) m/z: [M - H]- Calcd
for C47H32N3O3 686.2449, found 686.2424; Enantiomeric ratio = 93:7, determined by HPLC
(Daicel Chiralpak IA, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T = 30 oC, 254 nm): tR =
6.483 min (major), tR = 38.367 min (minor).
(Ra)-2-(2'-(bis(3-methoxyphenyl)methyl)-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-i
ndene-1,3(2H)-dione (3ja): Preparative thin layer chromatography (petroleum ether/ethyl acetate
= 2:1); 43% yield (30.9 mg); yellow solid; m.p. 170-172 oC; [α]D20 = -146.1 (c 0.74, Acetone); 1H
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NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.30 – 8.24 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.66 (s,
1H), 7.43 – 7.30 (m, 4H), 7.29 – 7.27 (m, 1H), 7.26 – 7.20 (m, 3H), 7.20 – 7.13 (m, 2H), 7.12 –
7.08 (m, 2H), 7.06 – 7.00 (m, 1H), 6.99 – 6.91 (m, 1H), 6.90 – 6.84 (m, 3H), 6.79 – 6.70 (m, 2H),
6.66 – 6.59 (m, 2H), 6.59 – 6.53 (m, 1H), 6.53 – 6.49 (m, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.47 (s,
1H), 3.81 (s, 3H), 3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.4, 197.3, 160.0, 159.5,
144.6, 143.2, 140.2, 140.1, 139.7, 137.0, 135.0, 134.9, 134.2, 134.0, 133.1, 130.5, 130.1, 129.7,
129.1, 126.2, 124.9, 123.0, 122.6, 121.9, 121.8, 121.6, 121.5, 120.8, 120.7, 120.3, 120.2, 119.4,
119.0, 115.8, 115.3, 112.3, 111.6, 111.4, 110.4, 109.9, 109.4, 106.2, 105.7, 59.0, 55.4, 55.2, 49.0
cm-1; IR (KBr): 3567, 3055, 1701, 1488, 1456, 1418, 836, 743, 695 cm-1; HRMS (ESI-TOF) m/z:
[M - H]- Calcd for C48H34N3O4 716.2555, found 716.2532; Enantiomeric ratio = 88:12,
determined by HPLC (Daicel Chiralpak IA, hexane/isopropanol = 70/30, flow rate 1.0 mL/min, T
= 30 oC, 254 nm): tR = 6.207 min (major), tR = 64.257 min (minor).
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(Ra)-2-(2'-(bis(3-fluorophenyl)methyl)-1H,1'H-[3,3'-biindol]-2-yl)-2-(1H-indol-3-yl)-1H-in
dene-1,3(2H)-dione (3ka): Preparative thin layer chromatography (petroleum ether/ethyl acetate
= 2:1); 54% yield (37.2 mg); yellow solid; m.p. 183-185 oC; [α]D20 = -238.1 (c 0.88, Acetone); 1H
NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.33 – 8.28 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.53 (s,
1H), 7.47 – 7.41 (m, 1H), 7.41 – 7.31 (m, 4H), 7.31 – 7.28 (m, 3H), 7.27 – 7.24 (m, 1H), 7.23 –
7.16 (m, 1H), 7.14 – 7.02 (m, 4H), 7.01 – 6.94 (m, 1H), 6.93 – 6.87 (m, 2H), 6.85 – 6.75 (m, 4H),
6.74 – 6.68 (m, 1H), 6.64 – 6.57 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.55 (s, 1H); 13C{1H} NMR
(100 MHz, CDCl3) δ 197.6, 197.2, 163.2 (J = 245 Hz), 162.9 (J = 245 Hz), 145.1(J = 6.8 Hz),
143.8 (J = 7.1 Hz), 140.3, 139.4, 138.9, 137.0, 135.1, 134.9, 133.3, 130.4, 130.3, 129.9, 129.8,
126.1, 125.2, 124.9, 123.2, 122.5, 121.9, 121.3, 120.8, 120.4, 119.9, 119.8, 119.5, 116.8 (J = 21.9
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