Enantioselective Michael/Mannich polycyclization cascade of indolyl enones catalyzed by quinine-derived primary amines

Article abstract of DOI:10.1002/anie.201103937

Three's a crowd: The title reaction provides a tetracylic core bearing three chiral centers (see scheme; Ts=4-toluenesulfonyl) with excellent enantioselectivity and good diastereoselectivity. The reaction was used to efficiently construct the (+)-kreysigi

Full text of DOI:10.1002/anie.201103937

DOI: 10.1002/anie.201103937
Asymmetric Catalysis
Enantioselective Michael/Mannich Polycyclization Cascade of Indolyl
Enones Catalyzed by Quinine-Derived Primary Amines**
Quan Cai, Chao Zheng, Jun-Wei Zhang, and Shu-Li You*
Cascade reactions have become a subject of intense research
in recent years,[1] as they often reduce labor and waste, and
enables the use of more readily available starting materials to
construct complex targets. Particularly with indole substrates,
a cascade involving nucleophilic addition of C3 of an indole
and subsequent intramolecular nucleophilic addition to the in
situ formed indolenine[2] proved to be a very useful strategy in
complex natural product synthesis.[3] In this regard, develop-
ing an enantioselective catalytic version of this synthetic
strategy is in great demand. To our knowledge, however, there
are only limited successful examples documented in the
literature.[4] Both the tricyclic and tetracyclic core of 1 has
drawn considerable attention because of its complexity and
frequent appearance in natural products and pharmaceuticals
(Figure 1).[5] An enantioselective cascade synthesis towards
these scaffolds is highly desirable but poses a challenge given
could be assembled through the nucleophilic polycyclization[7]
of the indolyl methyl enone 2 in a cascade process with the
proper choice of a chiral primary amine catalyst[8] (Scheme 1).
Scheme 1. Proposed catalytic cycle by a chiral primary amine.
The intramolecular Michael addition of the indolyl enone 2
generates the spirocyclic indolenine intermediate 5 through
iminium catalysis[9] and the tetracylic product 3 is obtained
through the intramolecular Mannich reaction by enamine
catalysis.[10] Herein we report such a novel asymmetric
intramolecular Michael/Mannich cascade reaction catalyzed
by a quinine-derived primary amine, thereby providing an
efficient synthesis of enantiopure tetracycles bearing multiple
chiral centers.
Figure 1. Representative natural products with tricyclic or tetracyclic
core 1.
the fact that three chiral centers including a quaternary all-
carbon center need to be formed in a single process.
As part of our ongoing program targeting new asymmetric
catalytic methods for the efficient construction of polycyclic
indole frameworks,[6] we envisaged that the tetracyclic core 3
We began the investigation by screening several readily
available chiral primary amines (Figure 2) with 2a as the
model substrate. By using 9-amino-9-deoxyepiquinine[11] (7a;
20 mol%) and TFA (40 mol%) in 1,4-dioxane, we were
delighted to find that the cascade reaction proceeded
smoothly to afford the desired tetracyclic product in 60%
yield with moderate selectivities (Table 1, entry 1). Fortu-
nately, the use of nitrobenzoic acids served to increase the
enantioselectivity significantly (Table 1, entries 8–11). After
further examination of different solvents and acid additives,
the optimal ee and d.r. values and yield were obtained with 7a
(20 mol%) and 2-nitrobenzoic acid (40 mol%) in EtOAc
(Table 1, entry 16).
[*] Q. Cai, C. Zheng, J.-W. Zhang, Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@mail.sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
[**] We thank the National Natural Science Foundation of China
(20732006, 20821002, 21025209), the National Basic Research
Program of China (973 Program 2010CB833300), and the Chinese
Academy of Sciences for generous financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103937.
Angew. Chem. Int. Ed. 2011, 50, 8665 –8669
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8665

Communications
Figure 2. Readily available chiral primary amines.
Table 1: Optimization of the reaction conditions for the cascade
reaction.
Entry Cat./HX
Solvent
t
[h]
Yield
[%][a]
ee
d.r.[c]
[%][b]
1
2
7a/TFA
7b/TFA
7c/TFA
7d/TFA
7e/TFA
7a/ (d)-CSA
7a/TfOH
7a/3,5-DNBA 1,4-dioxane
7a/3-NBA 1,4-dioxane
7a/3,4-DNBA 1,4-dioxane
7a/2-NBA 1,4-dioxane
7a/3,5-DNBA CH2Cl2
7a/3,5-DNBA CH3CN
7a/3,5-DNBA MeOH
7a/3,5-DNBA EtOAc
1,4-dioxane
1,4-dioxane
1,4-dioxane 216 trace
1,4-dioxane 144 37
1,4-dioxane 192 complex
1,4-dioxane 168 54
13 60
38 33
44
28
82:18
64:36
3[d]
4
n.d. n.d.
Scheme 2. Substrate scope of the cascade reaction. The yields are
those of the isolated major isomers and the ee values were determined
by HPLC analysis. The d.r. values were determined by 1H NMR analysis
of the crude reaction mixture. The absolute configuration was deter-
mined by the X-ray analysis of 3b.[12]
À23
50:50
5[d]
6
n.d. n.d.
À52
70:30
7
8
9
1,4-dioxane
48 trace
84
n.d. n.d.
5
95
94
98
89
91
48
5
94
98
98
78:22
85:15
77:23
89:11
74:26
49:51
44:56
78:22
89:11
86:14
24 53
24 52
48 40
18 51
24 27
96 22
15 62
10
11
12
13
14
15
16
17[d]
products with improved diastereoselectivities (3c and 3h).
Notably, the two product diastereoisomers (in all cases) were
easily separated by silica gel column chromatography.[13] In
addition, the reaction proceeded very slowly when the indole
nitrogen atom was protected with a methyl group.
7a/2-NBA
7a/2-NBA
EtOAc
EtOAc
2
78
Further exploration of the substrate scope revealed that
the ethyl ketone 2k was also suitable for the casacade reaction
(Scheme 3). The reaction went smoothly under the optimized
reaction conditions to afford a pair of diasteroisomers, 3k and
3k’, each bearing four chiral centers in good yield (89% yield)
and with good ee values, abeit with unsatisfactory diastereo-
selectivity.[14]
12 73
[a] Yield of the isolated major isomer. [b] Determined by HPLC analysis
(Chiralpak AD-H). [c] Determined by H NMR analysis of the crude
reaction mixture. [d] 20 mol% of the acid (HX) was added. n.d.=not
determined. d-CSA=d-camphorsulfonic acid, DNBA=dinitrobenzoic
acid, NBA=nitrobenzoic acid, TFA=trifluoroacetic acid, Tf=trifluoro-
methanesulfonyl, Ts=4-toluenesulfonyl.
1
We then extended our efforts to obtain the enantiomers of
the polycyclic products. Fortunately, using 20 mol% of 9-
amino 9-deoxy epiquinidine (7 f), the pseudoenantiomer of
7a, under the optimal reaction conditions, the enantiomers of
3c, 3 f, 3g, and 3h were accessed with excellent enantiose-
Under the optimal reaction conditions, various indolyl
enones were tested to examine the generality of this reaction.
Substrates bearing either an electron-withdrawing group (Br
or F) or an electron-donating group (Me) on the indole ring
all led the formation of tetracyclic products with excellent
ee values (3b–3e, Scheme 2). A slight decrease of yield and
diastereoselectivity was observed for the F-substituted indole
substrate 3e. The carbon-tethered indolyl enone substrates
were also well tolerated, thus affording the tetracyclic
products 3 f–3j with excellent yields and d.r. and ee values.
It should be pointed out that the substrates having a methyl
group on C4 of the indole led to the corresponding cyclization
Scheme 3. The cascade reaction of 2k.[14]
8666 www.angewandte.org
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Angew. Chem. Int. Ed. 2011, 50, 8665 –8669

lectivities and moderate to high diastereoselectivities
(Scheme 4).
To shed light on the reaction mechanism, we tried to
isolate the indolenine intermediate 5. The intermediate is
logue (10) was obtained in 99% ee and the absolute
configuration was in accordance with that of the natural
product.
In conclusion, we have developed an intramolecular
Michael/Mannich cascade reaction of indolyl methyl enones
catalyzed by a quinine-derived primary amine, thus affording
a series of highly enantioenriched tetracyclic compounds in
high yields with good diastereoselectivities and excellent
enantioselectivities. With this methodology, an analogue of
(+)-kreysiginine could be synthesized in a short and efficient
manner. Further application of this methodology to the total
synthesis of complex natural products is currently underway
in our lab.
Scheme 4. Synthesis of the enantiomers of 3c, 3 f, 3g, and 3h.
Experimental Section
General procedure for polycyclization cascade of indolyl enones: A
round bottom flask was charged with 9-epi-quinine amine 7a (6.4 mg,
0.02 mmol) and ethyl acetate (2 mL). Then 2-nitrobenzoic acid
(6.7 mg, 0.04 mmol) was added. After the salt was dissolved, substrate
2 (0.1 mmol) was added. After the reaction was complete (monitored
very reactive and inseparable under the optimal reaction
conditions. To our delight, 5c could be obtained in 35% yield
from 2c when catalyzed by a binol-derived phosphoric acid.
In the presence of catalytic amount of 7a and 2-NBA, 5c was
smoothly converted into product 3c in 95% yield (Scheme 5).
This result suggests that the cascade reaction likely proceeds
by a tandem Michael addition and Mannich reaction.
1
by TLC or H NMR spectroscopy), the solvent was removed under
reduced pressure. The diastereoselective ratio was determined by
1H NMR analysis of the crude reaction mixture. The residue was then
purified by silica gel column chromatography (hexanes/EtOAc 1:1) to
afford the product.
Received: June 9, 2011
Published online: July 26, 2011
Keywords: amines · asymmetric catalysis · cascade reactions ·
.
indoles · organocatalysis
Scheme 5. Preparation of 5c and investigations into the mechanism.
binol=2,2’-dihydroxy-1,1’-binaphthyl, PA=phosphoric acid.
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Scheme 6. Synthesis of the ACNO analogue of (+)-kreysiginine.
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Communications
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Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu, J.-G. Deng, Angew. Chem.
2007, 119, 393; Angew. Chem. Int. Ed. 2007, 46, 389; b) J.-W. Xie,
8668 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8665 –8669

[12] The absolute configuration was determined by the X-ray
diffraction analysis of enantiopure 3b. CCDC 808361 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.
[13] Since only two diastereoisomers were isolated, the origin of the
diastereoselectivity was studied by computational method. The
DFT calculations suggested that the Mannich reaction is
stereospecific because of the rigid polycylic skeleton. The cis-
fused [4.3.0] bicyclic structure is the only accessible product of
the cyclization process. See the Supporting Information for
details.
[14] The relative configurations of 3k and 3k’ were determined by
the X-ray diffraction. CCDC 828201 and 828107 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] a) J. Fridrichsons, A. Mcl. Mathieson, M. F. Mackay, Tetrahe-
dron 1970, 26, 1869; b) T. Kametani, T. Kohno, R. Charubala, K.
Fukumoto, Tetrahedron 1972, 28, 3227.
[16] J. Sapi, S. Dridi, J. Laronze, F. Sigaut, D. Patigny, J.-Y. Laronze, J.
Lꢂvy, Tetrahedron 1996, 52, 8209.
Angew. Chem. Int. Ed. 2011, 50, 8665 –8669
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8669