Construction of Chiral Tetrahydro-β-Carbolines: Asymmetric Pictet–Spengler Reaction of Indolyl Dihydropyridines

Article abstract of DOI:10.1002/anie.201703178

A highly efficient synthesis of the enantioenriched tetrahydro-β-carbolines was developed by using a chiral phosphoric acid catalyzed Pictet–Spengler reaction of indolyl dihydropyridines. The reaction proceeds under mild reaction conditions to afford the desired chiral tetrahydro-β-carbolines in good to excellent yields (up to 96 %) and high enantioselectivities (up to 99 % ee). With this method, a formal synthesis of tangutorine and a total synthesis of deplancheine were achieved in a highly efficient manner.

Full text of DOI:10.1002/anie.201703178

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Accepted Article
Title: Construction of Chiral Tetrahydro-β-Carbolines through
Asymmetric Pictet-Spengler Reaction of Indolyl Dihydropyridines
Authors: Shuli You, Shou-Guo Wang, Zi-Lei Xia, Ren-Qi Xu, Xi-Jia Liu,
and Chao Zheng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201703178
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10.1002/anie.201703178
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Construction of Chiral Tetrahydro-β-Carbolines through
Asymmetric Pictet-Spengler Reaction of Indolyl Dihydropyridines
Shou-Guo Wang†§, Zi-Lei Xia†§, Ren-Qi Xu†, Xi-Jia Liu†, Chao Zheng†, and Shu-Li You†‡*
Abstract: A highly efficient synthesis of enantioenriched tetrahydro-
β-carbolines is developed via chiral phosphoric acid-catalyzed
Pictet-Spengler reaction of indolyl dihydropyridines. The reaction
proceeds under mild conditions to afford the desired chiral
tetrahydro-β-carbolines in good to excellent yields (up to 96%) and
high enantioselectivity (up to 99% ee). With this method, a formal
synthesis of Tangutorine and a total synthesis of Deplancheine were
achieved in a highly efficient manner.
piperidines.[6] As part of our ongoing research on
dearomatization reactions, we envisioned that a reductive
dearomatization/Pictet-Spengler reaction sequence from simple
indole and pyridine substrates could afford the enantioenriched
tetrahydro-β-carbolines (Scheme 1). Herein, we report such a
facile and efficient synthesis of chiral piperidine fused
tetrahydro-β-carbolines via chiral phosphoric acid (CPA)
catalyzed Pictet-Spengler reaction of indolyl dihydropyridines.
The chiral tetrahydro-β-carboline ring systems are attractive
synthetic targets as they are structural cores of many indole
alkaloids and pharmaceuticals, such as Deplancheine,
Tangutorine, Geissoschizine, and Vallesiachotamine (Figure
1).[1] The appealing architecture and significant biological
activities of these tetrahydro-β-carboline alkaloids have received
considerable attention among the synthetic and medicinal
chemists.[2] The catalytic asymmetric Pictet-Spengler reactions
has been emerged as one of the most efficient and
straightforward methods, providing direct access to the
enantioenriched tetrahydro-β-carbolines.[3] Pioneering studies by
Jacobsen, List, Hiemstra and many others have been carried out
on highly enantioselective Pictet-Spengler type reactions.[4]
However, to date, most of the reported Pictet-Spengler reactions
focused on the combination of tryptamine derivatives and
carbonyl functionality under acidic conditions. The development
of novel efficient catalytic reactions from alternative readily
available substrates for the construction of enantioenriched
tetrahydro-β-carbolines is highly desirable.
Scheme 1. Dearomatization/Pictet-Spengler reaction sequence. R = electron
withdrawing group, CPA = chiral phosphoric acid.
We began our studies by investigating different chiral phosphoric
acids in the Pictet-Spengler reaction of 1,4-dihydropyridine 2a,
readily prepared from 3-(2-bromoethyl)-1H-indole and 3-
acetylpyridine.[7] In the presence of a range of chiral phosphoric
acids, all the reactions proceeded smoothly in toluene at room
temperature to afford the desired tetrahydro-β-carboline 3a in
variable yields and moderate enantioselectivity (Table 1). The
evaluation of chiral phosphoric acids with regard to different
substituents and backbones indicated that (R)-SPINOL-derived
catalyst 1h[8] was an efficient catalyst, converting 2a to the
desired product 3a with the best enantioselectivity (80% yield,
62% ee, entry 8, Table 1).
Encouraged by these promising results, we set out to further
optimize the reaction conditions. Evaluation of solvents
disclosed that carbon tetrachloride is the best option in terms of
yield and enantioselectivity (85% yield, 72% ee, entry 14, Table
1). To our delight, 3 Å molecular sieves could improve the
enantioselectivity significantly, furnishing the target tetrahydro-β-
carboline 3a in 90% yield and 91% ee with a prolonged reaction
time (entry 15, Table 1). Lowering the reaction temperature to
0 °C led to decreased yield without notable increase of the
enantioselectivity (45% yield, 92% ee, entry 18, Table 1).
Therefore, the optimal reaction conditions for this reaction were
determined as follows: 10 mol% chiral phosphoric acid 1h, 3 Å
molecular sieves as the additive in CCl4 at room temperature.
The absolute configuration of the product was determined by
comparison of the specific rotation of product 3a to literature
data.[9]
Figure 1. Selected natural products containing a tetrahydro-β-carboline motif.
Meanwhile, asymmetric dearomatization reaction of pyridines
represents an intriguing protocol to afford chiral piperidines and
related alkaloids.[5] Recently, we reported a chiral phosphoric
acid catalyzed hydrogenative dearomatization/aza-Friedel-Crafts
sequence of substituted pyridines, affording the enantioenriched
[†]
Dr. S.-G. Wang, Z.-L. Xia, R.-Q. Xu, X.-J. Liu, Dr. C. Zheng, Prof. Dr.
S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Having established the optimal reaction conditions, the
substrate scope was then investigated to examine the generality
of the reaction. The results are summarized in Scheme 2. The
reaction conditions tolerated
a wide range of electron-
Homepage: http://shuliyou.sioc.ac.cn/
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science
and Engineering, Tianjin 300072 (China)
These authors contributed equally.
[‡]
[§]
withdrawing substituents, such as alkyl ketone, ester and cyano
group on the C3’ position of the 1,4-dihydropyridine core,
providing their corresponding products in good to excellent
yields and excellent enantioselectivity (3a to 3g, 67-95% yields,
88-96% ee, Scheme 2). To be noted, substrate 2c containing a
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10.1002/anie.201703178
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cyclohex-2-enone motif was also compatible for this reaction,
yield, 87% ee). Substrate 2l bearing 6-F substituent was well
tolerated, affording product 3l in 61% yield and 89% ee.
affording the desired product 3c in 75% yield and 90% ee.
Table 1: Optimization of the reaction conditions[a]
Yield
(%)[b]
ee
Entry
Catalyst
Solvent
Additive
t/h
(%)[c]
1
2
1a
1b
1c
1d
1e
1f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
DCM
--
3.5
10
66
42
56
10
81
80
70
80
69
81
77
83
95
85
90
90
82
45
38
10
31
14
25
11
35
62
20
40
62
55
47
72
91
89
74
92
--
3
--
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
12
4
--
5
--
6
--
7
1g
1h
1i
--
8
--
Scheme 2. Substrate scope. [a] For 3d, 3f and 3m-3ac, (S)-1h was used.
9
--
[b] At 0 oC.
10
11
12
13
14
15
16
17
18[d]
1j
--
--
1h
1h
1h
1h
1h
1h
1h
1h
To further explore the substrate scope, substrates bearing an
aryl ketone at the 3’ position of the 1,4-dihydropyridine core were
further explored. As shown in Scheme 2, the reaction of
substrate 2m afforded the corresponding product 3m in 92%
yield and 94% ee. Various substrates containing electron-
donating group substituted aryl ketone [p-OMe, p-Me, m-Me, o-
Me, p-nBu, p-tBu, m,m-(tBu)2] underwent the Pictet-Spengler
reaction smoothly affording products 3n-3t in excellent yields
and good to excellent enantioselectivity (85-95% yield, 66-92%
ee). Notably, the introduction of para-phenyl group (2u) was also
tolerated to give 3u in 90% yield and 83% ee. Interestingly,
electron-withdrawing group and halogen substituent (p-CF3, p-F,
p-Cl, p-Br, m-Br, o-Br, p-I) were well compatible for the
asymmetric Pictet-Spengler reaction (90-95% yields, 81-99%
ee). Particularly, the installation of F, Cl, Br at the para position
could significantly increase the enantioselective control, although
the mechanism is still unclear. Finally, furyl ketone (2ac) was
also tolerated, and 3ac was obtained in 93% yield and 76% ee.
To highlight the utility of this enantioselective Pictet-Spengler
reaction, transformations of products were conducted. As shown
in Scheme 3, treatment of product 3c with Boc2O in the presence
of DMAP gave the Boc protected indole 4 in 95% yield and 91%
ee (eq a), which was known as the key intermediate for the total
synthesis of Tangutorine.[10] The oxidative rearrangement of
tetrahydro-β-carboline 3a utilizing N-bromosuccinimide as the
--
CHCl3
CCl4
--
--
CCl4
3 Å MS
4 Å MS
5 Å MS
3 Å MS
CCl4
12
CCl4
8
CCl4
36
[a] Reactions were performed with 2a (0.1 mmol), 1 (10 mol%) and additive in
2.0 mL solvent at room temperature. [b] Isolated yield. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] At 0 oC.
The effect of substituent on the indole core was then examined.
Either an electron-donating group (6-Me, 7-Me, 5-OMe, 6-OMe)
or an electron-withdrawing group (6-F) on the indole ring was
well tolerated. The corresponding products were obtained in
moderate to excellent yields and high enantioselectivity (3h to 3l,
61-94% yields, 87-92% ee, Scheme 2). For the more reactive
substrates 2j and 2k, the reactions were carried out at 0 oC. The
desired products could be obtained in reasonable yields and
excellent enantioselectivity (3j, 66% yield, 92% ee; 3k, 67%
oxidant led to tetracyclic 3-spirooxindole
5
in good
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Scheme 3. Transformations of the products.
In summary, we have developed a highly efficient synthesis of
enantioenriched tetrahydro-β-carbolines via chiral phosphoric
acid-catalyzed
Pictet-Spengler
reaction
of
indolyl
dihydropyridines. Different from previous enantioselective Pictet-
Spengler reactions utilizing tryptamines and carbonyl
compounds as substrates, the current protocol employs
substrates readily prepared from simple indoles and pyridines.
Under mild conditions, these reactions proceeded smoothly
affording chiral tetrahydro-β-carbolines in good to excellent
yields (up to 96%) and high enantioselectivity (up to 99% ee). A
concise formal synthesis of Tangutorine and total synthesis of
Deplancheine further demonstrated the synthetic utility of this
newly developed methodology.
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Acknowledgements
We thank the National Key R&D Program of China
(2016YFA0202900), National Basic Research Program of China
(2015CB856600), the NSFC (21332009, 21361140373,
21421091), Program of Shanghai Subject Chief Scientist
(16XD1404300), and the CAS (XDB20000000, QYZDY-SSW-
SLH012) for generous financial support.
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Keywords: asymmetric catalysis • chiral phosphoric acid •
dearomatization • organocatalysis • Pictet-Spengler • tetrahydro-
β-carboline
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COMMUNICATION
Shou-Guo Wang†§, Zi-Lei Xia†§, Ren-Qi
Xu†, Xi-Jia Liu†, Chao Zheng†, and Shu-
Li You†‡*
Page No. – Page No.
Construction of Chiral Tetrahydro-β-
Carbolines
Pictet-Spengler Reaction of Indolyl
Dihydropyridines
through
Asymmetric
A highly efficient synthesis of enantioenriched tetrahydro-β-carbolines is developed
via chiral phosphoric acid-catalyzed Pictet-Spengler reaction of indolyl
dihydropyridines. The reaction proceeds under mild conditions to afford the desired
chiral tetrahydro-β-carbolines in good to excellent yields (up to 96%) and high
enantioselectivity (up to 99% ee). With this method, a formal synthesis of
Tangutorine and a total synthesis of Deplancheine were achieved in a highly
efficient manner.
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