Multistep one-pot synthesis of enantioenriched polysubstituted cyclopenta[b] indoles

Article abstract of DOI:10.1002/anie.201107308

Simple steps, complex result: Consecutive organo-catalyzed reactions of 3-indolylmethanol compounds with aldehydes and N-protected indoles lead to the formation of structurally complex cyclopenta[b]indoles (see scheme, Bn=benzyl). These one-pot multistep reactions have a broad substrate scope and give the products in high yields, and with excellent diastereoselectivities and enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201107308

Angewandte
Chemie
DOI: 10.1002/anie.201107308
One-Pot Syntheses
Multistep One-Pot Synthesis of Enantioenriched Polysubstituted
Cyclopenta[b]indoles**
Biao Xu, Zhi-Lei Guo, Wan-Yan Jin, Zhi-Ping Wang, Yun-Gui Peng, and Qi-Xiang Guo*
The development of asymmetric methodologies for the
synthesis of chiral indoles has been a long-standing project
in organic synthesis. Indole skeletons are heterocyclic systems
and are present in numerous alkaloid products, pharmaceut-
icals, and agrochemicals.[1] Cyclopenta[b]indole skeletons can
be found in a number of indole alkaloids,[2] but have not been
extensively reported. Compounds that contain such a unit
exhibit a wide range of biological activities.[3] For example,
2-aminocyclopenta[b]indoles,[4a] cyclopenta[b]indole-substi-
Scheme 1. General strategy for the multistep one-pot synthesis of
chiral cyclopenta[b]indoles.
tuted acetic acids,[4b] and a series of yuehchukene analogues[5]
have been successfully synthesized and used in medicinal
chemistry. Although a number of methods have been
developed for the synthesis of cyclopenta[b]indoles,[6] only
few of them are asymmetric and especially catalytic asym-
metric methods.[7] To the best of our knowledge, there is only
one example of the synthesis of chiral cyclopenta[b]indoles by
asymmetric catalysis with acceptable enantioselectivities.[8]
The development of efficient methods for the construction
of cyclopenta[b]indole units is therefore highly desirable. As a
continuation of the work of our research group toward the
catalytic asymmetric a-alkylation of carbonyl compounds,[9]
we rationally designed a one-pot[10] three-step reaction, which
consisted of the a-alkylation of an aldehyde, catalyzed by a
primary-amine-substituted thiourea,[11] and two consecutive
Brønsted acid catalyzed Friedel–Crafts reactions of an
indole,[12] to construct chiral polysubstituted cyclopenta[b]in-
doles (Scheme 1). Herein, we report these consecutive
organocatalyzed reactions, which gave structurally diverse
cyclopenta[b]indoles in high yields (up to 85%), and with
excellent diastereoselectivities (up to > 99:1) and enantiose-
lectivities (up to 99% ee).
aldehydes have not been used as donors. For the method
reported herein, a,a-disubstituted aldehydes were very
important precursors because they could produce aldehydes
5 (Scheme 1), which could not be enolated during the
following Friedel–Crafts alkylations; thus, there were fewer
side reactions in this method. Several amine-based catalysts
were investigated in the a-alkylation reaction of aldehyde 4a.
As shown in Table 1, primary-amine-substituted thioureas
were good catalysts for promoting this a-alkylation reaction
(Table 1, entries 1–7). Catalyst 1h, which was used by Chen
and co-workers,[7c] was not a suitable choice for the reaction
(Table 1, entry 8). Thiourea 1a was chosen as the catalyst for
the a-alkylation because good yields and high enantioselec-
tivities could be obtained (Table 1, entry 1). After examining
various solvents, we found that CHCl3 was the best solvent
with regard to yield and enantioselectivity (Table 1, entry 1).
The number of equivalents of isobutylaldehyde 4a also
greatly influenced the yield. For example, the yield increased
significantly when the number of equivalents of 4a was
reduced to 1.2 (Table 1, entry 12 versus entry 1). The impact
of different acids was also examined. The compatibility
between the primary amine and the chiral acid was inves-
tigated first. Both (S,S)-1b and (R,R)-1i could cooperate with
(R)-2d to promote the alkylation efficiently, but the enantio-
selectivities were worse than that obtained with p-nitro-
benzoic acid 2a (Table 1, entries 13, 14, and 15). After
screening the compatibilities of acid additives with both 1a
and 1b (see the Supporting Information), the combination of
thiourea 1a and N-Boc-protected amino acid 2e turned out to
be the best choice of catalyst for this a-alkylation with regard
to yield (71%) and enantioselectivity (90% ee; Table 1,
entry 16).
The reactions shown in Scheme 1 were realized in three
stages. In the first stage, we examined the a-alkylation of
isobutylaldehyde 4a with 3-indolylmethanol 3a (step 1)
under catalysis by chiral amines 1 and acids 2. Although
several methods for the asymmetric amine-based catalysis
have been used in similar a-alkylation reactions of aldehydes
with diarylmethanol compounds,[11] to date a,a-disubstituted
[*] B. Xu, Z.-L. Guo, W.-Y. Jin, Z.-P. Wang, Prof. Y.-G. Peng,
Prof. Q.-X. Guo
Education Ministry Key Laboratory on Luminescence and
Real-Time Analysis, School of Chemistry and Chemical Engineering
Southwest University
Chongqing 400715 (China)
After establishing the optimal reaction conditions for the
a-alkylation of the aldehyde (Scheme 1, step 1), we examined
the feasibility of Brønsted acid catalyzed consecutive Friedel–
Crafts alkylations in steps 2 and 3. For these transformations,
we first chose N-Bn-protected indole 6a as the nucleophile,
4-methylbenzenesulfonic acid (p-TsOH) as the catalyst, and
E-mail: qxguo@swu.edu.cn
[**] We are grateful for financial support from the NSFC (20902074) and
the Fundamental Research Funds for the Central Universities
(XDJK2011C054).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107308.
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Table 1: Screening of catalysts and optimization of reaction conditions
for step 1 (Scheme 1).[a]
Scheme 2. Synthesis of cyclopenta[b]indole 7a. BA=Brønsted acid.
Bn=benzyl.
CHCl3 and proceeded smoothly to give the desired product
7a in high yield (95%) and excellent diastereoselectivity
(> 99:1), however, the enantioselectivity of 7a decreased
greatly (83% ee versus 67% ee). We then optimized the
reaction conditions by screening different Brønsted acid
catalysts (see the Supporting Information). Finally, compound
7a was obtained in good yield (82%), with excellent
diastereoselectivity (> 99:1) and almost unchanged enantio-
selectivity (82% ee), by using 2c as the catalyst (Scheme 2).
The optimal reaction conditions for step 1 and the
consecutive steps 2 and 3 were thus established. The compa-
tibilities of the catalysts and use of the same solvents enabled
these two procedures to be performed in a one-pot manner.
We thus tried to merge the procedures with the third stage
shown in Scheme 1, without isolating intermediate 5a. The
reaction of 3a and 4a was performed in CHCl3 with 1a and 2e
as catalysts. After the starting material 3a had been consumed
completely, the N-Bn-protected indole 6a was added to the
reaction system. We found that the Friedel–Crafts reaction in
step 2 could not proceed if no additional acid was added after
completion of step 1; the addition of Brønsted acid to steps 2
and 3 of this one-pot procedure was thus investigated again
(see the Supporting Information). The multistep one-pot
procedure proceeded smoothly and gave the desired product
7a in good yield, with excellent diastereoselectivity and good
enantioselectivity, by using a combination of 1a, 2e, and 2c as
the catalyst (Scheme 3). Notably, the total yield of 7a was
enhanced greatly when these three reactions were carried out
in a one-pot manner (70%) instead of in two separate
procedures (58%).
Entry
1
2
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1a
1a
1a
1a
1b
1i
2a
2a
2a
2a
2a
2a
2a
HOAc
2a
2a
2a
2a
2d
2d
2a
2e
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
m-xylene
benzene
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
48
24
48
48
48
48
46
64
48
96
96
48
24
24
24
40
65
75
83
60
51
67
86
50
29
63
44
81
63
86
73
71
89
83
75
85
84
85
78
À64[d,e]
9
90
10
11
12
13
14
15
16
89
87
89[f]
50[f]
À51[e,f,g]
À80[e,g]
90[f]
1i
1a
[a] Reaction conditions: 3a (0.1 mmol), 4a (1 mmol), 1 (0.01 mmol), 2
(0.01 mmol) in solvent (1 mL). [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis on a chiral stationary phase. [d] Reaction
conditions: 3a (0.2 mmol), 4a (0.24 mmol), 1h (0.01 mmol), and HOAc
(0.02 mmol) in CHCl3 (0.4 mL). [e] Negative ee value indicates the
formation of the enantiomer of 5a. [f] 1.2 equiv of 4a were used. [g] 2 mL
of solvent were used. Boc=tert-butyloxycarbonyl, Cbz=benzyloxycar-
bonyl, PG=protecting group, TMS=trimethylsilyl.
With the optimized general procedure in hand, we
investigated the substrate scope of these consecutive trans-
formations. We first examined the substrate scope of 3-
indolylmethanol compounds (Tables 2 and 3). Both electron-
rich and electron-deficient aryl groups were tolerated and
gave the desired products 7b–7r in good yields and with good
enantioselectivities (Table 2). Notably, only one diastereoiso-
mer was obtained in these examples. An ortho-substituted
phenyl group greatly improved the enantioselectivity. Excel-
lent enantioselectivities were obtained when 2-F-, 2-Cl-, and
2-Br-phenyl-, and 1-naphthyl-substituted (1H-indol-3-yl)aryl-
CHCl3 as the solvent. Our choice was based on the following:
1) a 3-indolylmethanol species would be formed and then
produce an active vinylogous imino intermediate through
dehydration when the indole reacted with the aldehyde under
acidic conditions;[11a–d] and 2) the Brønsted acid catalyst was
compatible with that used in step 1 and the solvent was the
same as that used in step 1; thus, the multistep reactions could
proceed in a one-pot manner. In addition, product 7a
represented a potentially useful bisindole subunit, which
exists in many natural and pharmaceutical compounds, such
as the natural product yuehchukene.[5] The reaction between
5a (see Table 1, entry 2) and 6a was promoted by p-TsOH in
Scheme 3. Synthesis of cyclopenta[b]indole 7a in one pot.
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Table 2: Substrate scope of 3-indolylmethanol compounds.[a]
Table 3: Substrate scope of 3-indolylmethanol compounds.[a]
Entry
7
Ar
t1/t2 [h][b] Yield [%][c] d.r.[d]
ee [%][e]
Entry
8
Ar
R1
t1/t2
Yield d.r.[d]
[%][c]
ee
[h][b]
[%][e]
1
2
3
4
5
6
7
8
7b
7c
7d
7e
7 f
7g
7h
7i
2-FC6H4
3-FC6H4
4-FC6H4
2-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
4-CNC6H4
4-CF3C6H4
4-tBuC6H4
87/56
66
68
61
70
68
80
63
>99:1 91[f]
87/102
88/99
>99:1 85[f]
>99:1 88
>99:1 95[f]
>99:1 88
>99:1 95[f]
>99:1 89[f]
>99:1 94[f]
>99:1 88[f]
>99:1 84
>99:1 87
>99:1 86
>99:1 88
>99:1 90
>99:1 88
>99:1 94
>99:1 88
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8 f
8g
8h
8i
1-naphthyl 6-F
1-naphthyl 5-Cl
1-naphthyl 5-Br
1-naphthyl 5-MeO 87/50
1-naphthyl 5-CH3
1-naphthyl 6-CH3
2-BrC6H4
2-BrC6H4
2-BrC6H4
2-BrC6H4
2-ClC6H4
2-ClC6H4
112/48 67
96/131 47
96/131 43
>99:1 93
>99:1 94
>99:1 94
>99:1 94[f]
>99:1 92[f]
>99:1 93
>99:1 92
>99:1 94
>99:1 93
>99:1 98
>99:1 94
>99:1 92
>99:1 92
>99:1 99
135/78
135/70
135/54
81/108
60
105/60 46
39/48
62
62
68
66
62
58
207/126 53
5-MeO 96/65
9
7j
7k
7l
159/96
48/48
65
67
45
85
81
82
81
73
70
5-CH3
6-CH3
7-CH3
96/65
84/48
94/48
10
11
12
13
14
15
16
17
9
2-MeOC6H4 68/72
10
11
12
13
14
8j
8k
8l
7m 3-MeOC6H4 120/62
5-MeO 84/60
7n
7o
7p
7q
7r
4-MeOC6H4 24/72
5-CH3
6-CH3
7-CH3
112/48 73
112/48 71
96/46
3-MeC6H4
4-MeC6H4
1-naphthyl
2-naphthyl
88/70
39/72
144/72
120/62
8m 2-ClC6H4
8n 2-ClC6H4
82
[a] Reaction conditions: 3 (0.2 mmol), 4a (0.24 mmol), 1a (0.02 mmol),
2e (0.04 mmol), 2c (0.04 mmol), 6a (0.3 mmol) in CHCl3 (2 mL).
[b] Reaction time: t1 for step 1, t2 for step 2. [c] Yields of isolated
products. [d] Determined by HNMR spectroscopy. [e] Determined by
HPLC analysis on a chiral stationary phase. [f] 20 mol% of 2e were used.
[a] Reaction conditions: 3 (0.2 mmol), 4a (0.24 mmol), 1a (0.02 mmol),
2e (0.02 mmol), 2c (0.04 mmol), 6a (0.3 mmol) in CHCl3 (2 mL).
[b] Reaction time: t1 for step 1, t2 for step 2. [c] Yield of isolated product.
[d] Determined by 1HNMR spectroscopy. [e] Determined by HPLC
analysis on a chiral stationary phase. [f] 20 mol% of 2e were used.
1
Table 4: Substrate scope of N-Bn-protected indoles and aldehydes.[a]
methanol compounds were used as electrophiles (Table 2,
entries 1, 4, 6, and 16). The reaction with a (1H-indol-3-
yl)arylmethanol componds that bears a 4-CN-substituted
phenyl group produced product 7i with an excellent enantio-
selectivity of 94% ee (Table 2, entry 8). The substrate scope
with respect to the substituent on the indole ring was also
explored (Table 3). (1H-Indol-3-yl)arylmethanol compounds
that bear both electron-withdrawing and electron-donating
substituents on the indole ring were good reaction partners
and able to participate in these reactions with excellent
stereochemical outcomes. In particular, greatly improved
enantioselectivities could be obtained with a 7-Me-substi-
tuted indole moiety. For example, reactions of 3-indolylme-
thanol compounds derived from 7-Me-substituted indole, and
ortho-substituted phenyl aldehydes produced compounds 8j
and 8n in 98% ee and 99% ee, respectively (Table 3,
entries 10 and 14).
The substrate scope of N-Bn-protected indoles and
aldehydes were investigated next (Table 4). N-Bn-protected
indoles bearing electron-withdrawing or electron-donating
groups were all suitable reaction partners and gave the
corresponding cyclopenta[b]indoles 9 in good yields, and with
excellent enantioselectivities and diastereoselectivities
(Table 4, entries 1–5). Cyclopenta[b]indoles with much
greater structural complexities could be obtained by changing
the aldehyde component. For example, spiro[cyclohexane-
cyclopenta[b]indole] 9 f could be synthesized with excellent
enantioselectivity by using a cyclohexanecarbaldehyde in the
asymmetric multistep one-pot procedure (Table 4, entry 6).
The use of an unsymmetric a,a-disubstituted aldehyde, such
as 2-methylbutanal 4c, in this procedure resulted in the
Entry
9
4
R4
t1/t2 [h][b] Yield [%][c] d.r.[d]
ee [%][e]
1
2
3
4
5
6
7
8
9
9a 4a 6-F
9b 4a 5-Cl
9c 4a 5-CH3 141/60
9d 4a 6-CH3 141/60
9e 4a 7-CH3 141/60
9 f 4b
9g 4c
9h 4d
141/60
141/60
73
82
69
82
77
68
78
35
38
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
ꢀ67:33 99
ꢀ85:15 90
ꢀ87:13 92
99
94
97
98
94
93
H
H
H
H
168/60
136/70
136/70
211/72
9i
4e
[a] Reaction conditions: diarylalcohol (0.2 mmol), 4a (0.24 mmol), 1a
(0.02 mmol), 2e (0.04 mmol), 2c (0.04 mmol), 6 (0.3 mmol) in CHCl3
(2 mL). [b] Reaction time: t1 for step 1, t2 for step 2. [c] Yields of isolated
products. [d] Determined by HNMR spectroscopy. [e] Determined by
HPLC analysis on a chiral stationary phase.
1
formation of a cyclopenta[b]indole that contains three
adjacent chiral carbon centers, one of which was a chiral
quaternary carbon center (Table 4, entry 7). a-Unsubstituted
aliphatic aldehydes, such as pentanal and hexanal, were also
able to participate in this reaction and gave the desired
products with excellent enantioselectivities, good diastereo-
selectivities, and in acceptable yields (Table 4, entries 8 and
9).
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Scheme 4. Synthesis of cyclopenta[b]indolines.
The absolute configuration of 8j (1S,3R) was established
by X-ray single-crystal analysis.[13] The configuration at C1
and C3 of compounds 7, 8, and 9 were assigned by analogy
with those of 8j (see the Supporting Information).
The cyclopenta[b]indole 8n was readily and stereoselec-
tively converted to fused indoline 10a by reduction
(Scheme 4). Thus, both indoles and indolines could be
accessed efficiently. The mechanism for the disconnection of
the N-Bn-protected indole unit is unclear.
In conclusion, we have described a highly efficient
diastereoselective and enantioselective one-pot multistep
reaction for the construction of cyclopenta[b]indoles. This
process was achieved through consecutive a-alkylation, which
was catalyzed by a primary-amine-substituted thiourea, and
two Brønsted acid catalyzed Friedel–Crafts alkylation reac-
tions. Structurally diverse cyclopenta[b]indoles were obtained
in high yields, with excellent diastereoselectivities and
enantioselectivities, under mild reaction conditions. The
cyclopenta[b]indoles could be converted into cyclopenta-
[b]indolines without loss of stereoselectivity.
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[13] CCDC 848551 (8j) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Received: October 17, 2011
Published online: December 13, 2011
Keywords: alkylations · indoles · multistep reactions ·
.
one-pot syntheses · organocatalysis
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