Enantioselective Construction of Spiroindolines with Three Contiguous Stereogenic Centers and Chiral Tryptamine Derivatives via Reactive Spiroindolenine Intermediates

Article abstract of DOI:10.1002/anie.201507193

The highly efficient synthesis of the enantioenriched spiroindolines by iridium-catalyzed asymmetric allylic dearomatization and reduction is presented. Spiroindolines containing three contiguous stereogenic centers were obtained with excellent diastereo- and enantioselectivity. In addition, a chiral tryptamine derivative could be easily accessed in good yield with excellent ee value through an unprecedented dearomatization/retro-Mannich/hydrolysis cascade reaction of an indole derivative.

Full text of DOI:10.1002/anie.201507193

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201507193
German Edition: DOI: 10.1002/ange.201507193
Asymmetric Catalysis
Enantioselective Construction of Spiroindolines with Three Contiguous
Stereogenic Centers and Chiral Tryptamine Derivatives via Reactive
Spiroindolenine Intermediates
Chun-Xiang Zhuo, Yong Zhou, Qiang Cheng, Lin Huang, and Shu-Li You*
Abstract: The highly efficient synthesis of the enantioenriched
spiroindolines by iridium-catalyzed asymmetric allylic dear-
omatization and reduction is presented. Spiroindolines con-
taining three contiguous stereogenic centers were obtained with
excellent diastereo- and enantioselectivity. In addition, a chiral
tryptamine derivative could be easily accessed in good yield
with excellent ee value through an unprecedented dearomati-
zation/retro-Mannich/hydrolysis cascade reaction of an indole
derivative.
C
hiral spiroindolenine and spiroindoline moieties are often
found as structural cores for biologically active natural
products and pharmaceutical agents.[1,2] In this regard, great
effort has been devoted to the development of enantioselec-
tive construction of these skeletons.[3] Among the methods,
the syntheses of spiroindolenine and spiroindoline derivatives
by catalytic asymmetric dearomatization (CADA) reactions
of indoles feature high efficiency, step economy, and ready
availability of starting materials.[4,5] However, the diastereo-
and enantioselective control usually suffers when the vicinal
tertiary and all-carbon quaternary stereocenters are gener-
ated in the dearomatization process.[6] Therefore, developing
an efficient strategy for the highly diastereo- and enantiose-
lective formation of spiroindolenine and spiroindoline motifs,
having multiple contiguous stereogenic centers, is highly
desirable.
In our ongoing efforts to investigate the transition-metal-
catalyzed asymmetric allylic dearomatization reactions, we
found that substituted indoles could undergo the asymmetric
allylic dearomatization reaction in an intramolecular fashion,
thus affording various spiroindolenines bearing vicinal ter-
tiary and quaternary carbon stereocenters.[4,7] Interestingly,
when the NBn-tethered indole substrate S1 was used, the
novel tetrahydro-b-carboline derivative S3, featuring the
migration of the original substituent from the C3 to C2
position of indole was obtained in excellent yield and ee
[Eq. (1), Scheme 1].[8] Preliminary mechanistic studies dem-
Scheme 1. Derivation of the reactive spiroindolenine intermediates:
syntheses of the spiroindolines with three contiguous stereogenic
centers, and chiral tryptamine derivatives.
onstrated the spiroindolenine S2 was formed first and then
underwent a rapid methanamine group migration. However,
the spiroindolenine intermediate was highly reactive and
could not be isolated. Therefore, we envisaged that installing
a substituent group on the 2-position of the indole ring may
prevent the migration, and thus enable the isolation of the
spiroindolenines 3 [Eq. (2), Scheme 1]. Herein, we report the
highly diastereo- and enantioselective syntheses of spiroindo-
lines (4) by iridium-catalyzed asymmetric allylic dearomati-
zation and reduction reactions. Furthermore, the chiral
tryptamine derivative 5 was easily accessed in good yield
and with excellent ee value by retro-Mannich/hydrolysis
cascade reaction of the spiroindolenine intermediate 3ꢀ
when an aromatic substituent was introduced in the benzylic
position of the indole substrate 2 [Eq. (3), Scheme 1].
[*] Dr. C.-X. Zhuo, Y. Zhou, Q. Cheng, L. Huang, 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@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
Our study was initiated by an exploration of the reaction
of the indole 2a with an iridium catalytic system comprising
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507193.
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Table 1: Ligand effect.[a]
By employing the newly developed asymmetric allylic
dearomatization/reduction reactions, various 3-indolyl allylic
carbonates (2) were explored to examine the generality of the
process (Table 2). Reactions of allylic carbonates having
various protecting groups (Bn, PMB, allyl), on the N in the
tether, all afforded the corresponding spiroindoline products
Table 2: The reaction substrate scope.[a]
Entry
1
t [h]
Conv. [%][b]
d.r.[b]
ee [%][c]
1
2
3
4
1a
1b
1c
1d
41
35
35
35
>95
>95
79
>95:5
>95:5
91:9
96
96
91
96
Entry
2: R1, R2, R3
t1, t2
[h]
d.r.[b]
Yield
[%][c]
ee
[%][d]
>95
>95:5
1
2
3
4
5
6
7
8
2a: Bn, Ph, H
2b: PMB, Ph, H
2c: allyl, Ph, H
2d: Bn, 4-FC6H4, H
2e: Bn, 4-Cl-C6H4, H
2 f: Bn, 4-MeC6H4, H
2g: Bn, 4-MeOC6H4, H
2h: Bn, Ph, 5-F
2i: Bn, Ph, 5-Cl
2j, Bn, Ph, 6-F
2k, Bn, Ph, 6-Cl
2l, Bn, Ph, 5-Me
44, 24
41, 19
41, 19
42, 23
40, 19
37, 18
42, 14
42, 14
37, 18
27, 18
27, 18
36, 21
>95:5
>95:5
>95:5
94:6
91:9
94:6
94:6
93:7
>95:5
95:5
93:7
4a, 81
4b, 81
4c, 73
4d, 62
4e, 62
4 f, 83
4g, 71
4h, 79
4i, 83
4j, 66
4k, 75
4l, 80
96
94
94
95
94
95
93
89
90
96
95
94
[a] Reaction conditions: 2 mol% of [{Ir(cod)Cl}2], 4 mol% of 1,
0.2 mmol of 2a and K3PO4 in THF (2.0 mL). [b] Determined by 1H NMR
analysis of the crude reaction mixture. [c] Determined by HPLC analysis.
cod=1,5-cyclooctadiene, THF=tetrahydrofuran.
[{Ir(cod)Cl}2] and the Feringa ligand 1a (Table 1).[9,10] In the
presence of 2 mol% of [{Ir(cod)Cl}2], 4 mol% of 1a, and
1.0 equivalents of K3PO4, the reaction of 2a in THF for
41 hours gave the spiroindolenine 3a in greater than 95%
conversion, greater than 95:5 d.r., and 96% ee (entry 1). The
effect of different chiral ligands was examined. The Alexakis
ligand 1b, combined with [{Ir(cod)Cl}2], was also quite
efficient for the reaction (entry 2). The catalyst derived
from the BHPphos 1c[11] catalyzed the reaction of 2a with
moderate conversion, and d.r. and ee values (entry 3). In
addition, the iridium catalyst derived from the THQphos
1d[11] was quite effective in promoting the allylic dearomati-
zation process (entry 4). However, during the purification of
the spiroindolenine product 3a from the crude reaction
mixture by silica gel column chromatography, decomposition
was observed (Scheme 2a). To our delight, 3a could be
reduced in situ to form the stable spiroindoline 4a. By using
LiAlH4 as the reductant, 4a, containing three contiguous
stereogenic centers, was easily accessed in 81% yield, 96% ee,
and with excellent diastereoselectivity (Scheme 2b).
9
10
11
12
>95:5
[a] Reaction conditions: (for step 1) 2 mol% of [{Ir(cod)Cl}2], 4 mol% of
(S,S,Sa)-1a, 0.2 mmol of 2 and K3PO4 in THF (2.0 mL) at 508C; (for step
2) 300 mol% of LiAlH4 in refluxed THF (2.0 mL). [b] Determined by
1H NMR analysis of the crude reaction mixture. [c] Yield of the isolated
product. [d] Determined by HPLC analysis.
in good yields with excellent d.r. and ee values (4a–c;
entries 1–3). Next, the electronic effect of the aromatic
substituents on the 2-position of the indole ring was explored.
Substrates bearing either an electron-withdrawing (4-F, 4-Cl)
(entries 4 and 5) or electron-donating (4-Me, 4-MeO)
(entries 6 and 7) group on the 2-aryl moiety of the indole
core all reacted to form the corresponding products in good
yields with excellent d.r. and ee values (4d–g; entries 4–7).
Meanwhile, when substrates bearing either an electron-with-
drawing (5-F, 5-Cl, 6-F, 6-Cl; entries 8–11) or electron-
donating (5-Me; entry 12) group on the indole core were
tested, the corresponding spiroindoline products 4 were
obtained in good to excellent yields, and d.r. and ee values
(4h–l; entries 8–12). The structure and stereochemistry of the
products were determined by an X-ray crystallographic
analysis of a crystal of the enantiopure 4a. The absolute
configuration of 4a was determined as (2S, 3S, 4’R).[12]
To test the practicality of the newly developed method-
ology, a gram-scale synthesis of chiral spiroindoline was
carried out. The intramolecular allylic dearomatization reac-
tion of 2 f on a 4.2 mmol scale and subsequent reduction gave
the desired product 4 f in 88% yield, 93:7 d.r., and 95% ee
(Scheme 3).
During the separation of the spiroindolenine product 3a,
the chiral tryptamine derivative 5a was obtained in 93% ee,
albeit with low yield (8% yield; Scheme 4). Next, we sought
Scheme 2. Derivation of the spiroindolenine product.
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In summary, we have developed an efficient strategy for
the synthesis of spiroindolines by the iridium-catalyzed
asymmetric allylic dearomatization and reduction reactions.
The spiroindoline products containing three contiguous
stereogenic centers were obtained in good yields, as well as
excellent diastereo- and enantioselectivity. In addition, the
chiral tryptamine derivative could be easily obtained by an
Scheme 3. A gram-scale synthesis of the spiroindoline 4 f.
unprecedented
dearomatization/retro-Mannich/hydrolysis
cascade reaction of an indole derivative. This new reaction
mode provides an efficient method for the synthesis of chiral
tryptamine derivatives. Furthermore, the observation and
derivation of the spiroindolenines also provide experimental
evidence for the existence of the spirointermediate during the
dearomatization/in situ migration of indoles[8] [Eq. (1),
Scheme 1]. Further investigation of the reaction mechanism
and application of the spiroindoline products are currently
underway in our laboratory.
Acknowledgements
Scheme 4. Rationale for the formation of the chiral tryptamine deriva-
tive.
We thank the National Basic Research Program of China (973
Program 2015CB856600) and National Natural Science
Foundation of China (21332009, 21421091) for generous
financial support.
to understand why the tryptamine derivative was generated in
this process. A possible reaction pathway is proposed for the
formation of 5a. Firstly, 3a was formed by the iridium-
catalyzed asymmetric allylic dearomatization. Then the
intermediate A was generated by a retro-Mannich reaction,
and was further hydrolyzed to form 5a. However, 5a was
obtained in low yield, and might be due to the rapid
decomposition of the unstable iminium cation of A. To
solve this problem, we installed an aromatic group at the
benzylic position of the indole core, as it was proposed to
Keywords: asymmetric catalysis · dearomatization ·
heterocycles · iridium · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14146–14149
Angew. Chem. 2015, 127, 14352–14355
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Received: August 2, 2015
Published online: September 25, 2015
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