Rapid Construction of Structurally Diverse Quinolizidines, Indolizidines, and Their Analogues via Ruthenium-Catalyzed Asymmetric Cascade Hydrogenation/Reductive Amination

Article abstract of DOI:10.1002/anie.201812647

A rapid construction of enantioenriched benzo-fused quinolizidines, indolizidines, and their analogues by ruthenium-catalyzed asymmetric cascade hydrogenation/reductive amination of quinolinyl- and quinoxalinyl-containing ketones has been developed. This

Full text of DOI:10.1002/anie.201812647

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Accepted Article
Title: Rapid Construction of Structurally Diverse Quinolizidines,
Indolizidines and Their Analogues via Ruthenium-Catalyzed
Asymmetric Cascade Hydrogenation/Reductive Amination
Authors: Ya Chen, Yan-Mei He, Shanshan Zhang, Tingting Miao, and
Qing-Hua Fan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812647
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10.1002/anie.201812647
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COMMUNICATION
Rapid Construction of Structurally Diverse Quinolizidines,
Indolizidines and Their Analogues via Ruthenium-Catalyzed
Asymmetric Cascade Hydrogenation/Reductive Amination
Ya Chen,[a] Yan-Mei He,[a] Shanshan Zhang, [a] Tingting Miao,[a] and Qing-Hua Fan*[a,b]
Abstract: A rapid construction of enantioenriched benzo-fused
quinolizidines, indolizidines and their analogues by ruthenium-
catalyzed asymmetric cascade hydrogenation/reductive amination of
quinolinyl- and quinoxalinyl-containing ketones has been developed.
This reaction proceeds under mild reaction conditions, affording
chiral benzo-fused aliphatic N-heterocyclic compounds with
structural diversity in good yields (up to 95%) with excellent
diastereoselectivity (up to > 20:1 dr) and enantioselectivity (up to >
99% ee). In addition, this catalytic protocol is applicable to the formal
synthesis of (+)-gephyrotoxin.
several benzo-fused quinolizidines, but the scope has proven to
be very limited. Therefore, it is highly desirable to develop new
efficient atom- and step-economic approaches to allow the
synthesis of structurally diverse quinolizidines, indolizidines and
their analogues in enantioenriched form.
Recently, we have demonstrated that the cationic ruthenium
complexes of chiral monosufonylated diamines are very efficient
catalysts for the asymmetric hydrogenation of various quinoline
and quinoxaline derivatives and cyclic ketimines.[8] In some
cases, the hydrogenation of quinoline derivatives bearing a
carbonyl group was selective for C=N (quinoline) over C=O
(ketone) bonds.[8e] Encouraged by these results, we envisioned
that this catalytic system could be applied to the direct synthesis
of benzo-fused quinolizidines and indolizidines via a cascade
reaction combining asymmetric hydrogenation of quinolines with
intramolecular reductive amination (Scheme 1). The difficulties
Fused aliphatic N-heterocyclic structures have been widely
embedded in many biologically active molecules, including
natural alkaloids and pharmaceutical agents.[1] Among these
fused
N-heterocycles,
substituted
quinolizidines
and
indolizidines are exceptionally prominent.[1d-f,2] Consequently,
numerous methods and strategies have been developed for the
stereoselective construction of such fused N-heterocyclic
compounds.[1c-e,3-5] However, catalytic enantioselective synthesis
of chiral quinolizidines, indolizidines and their analogues is still
less well explored,[5,6] and the direct catalytic asymmetric
synthesis of such fused N-heterocycles with structural diversity
is still a big challenge.
Recently, great progress has been made in the asymmetric
hydrogenation of the often challenging substrates of N-
heteroaromatic compounds.[7] This method proved to be a
straightforward and practical route to chiral fused N-heterocycles.
However, less success has been achieved so far. Zhou and co-
workers developed a highly effective iridium catalytic system for
the asymmetric hydrogenation of quinoline derivatives, affording
chiral 1,2,3,4-tetrahydroquinoline heterocycles which could be
converted to benzo-fused quinolizidine and indolizidine.[6a] Later,
Glorius and co-workers reported the ruthenium-catalyzed
asymmetric hydrogenation of indolizines followed by
diastereoselective heterogeneous reduction, providing a direct
access to indolizidine alkaloids.[6b] Alternatively, a sequential
chiral Brønsted acid and supported metal nanoparticle catalyzed
transfer hydrogenation/ hydrogenation protocol of 2-substituted
quinolines has been described by Rueping and co-workers.[6c]
This method realized two-step enantioselective synthesis of
Scheme 1. Synthesis of quinolizidines, indolizidines, and their analogues via
chemoselective
asymmetric
hydrogenation/intramolecular
asymmetric
reductive amination cascade process.
is two-fold: 1) the Ru-catalysts have proven to be excellent
catalysts for reduction of both ketones and ketimines,[9] and the
precisely control of chemoselectivity is difficult; 2) unlike the
hydrogenation of ketones and olefins, asymmetric reductive
amination is more difficult,[10] and particularly, asymmetric
hydrogenation of the in situ generated tetrasubstituted iminium
salt is a formidable challenge.[10e,10f] Herein, we report our study
on this tandem asymmetric hydrogenation/reductive amination of
quinolines and quinoxalines bearing a carbonyl group, providing
[a]
Y. Chen, Y.-M. He, S. Zhang, T. Miao, Prof. Dr. Q.-H. Fan
Beijing National Laboratory for Molecular Sciences
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences (ICCAS)
University of Chinese Academy of Sciences
Beijing 100190 (P. R. China)
a
direct access to structurally diverse quinolizidines,
indolizidines and their analogues under mild conditions. In
addition, the utility of this method was showcased by the formal
synthesis of (+)-gephyrotoxin.
E-mail:fanqh@iccas.ac.cn
[b]
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin 300072 (P. R. China)
For our initial investigations, the tandem reaction of 1a
catalyzed by (R,R)-C1 was chosen as the model reaction for the
optimization of reaction conditions (Table 1, Table S1 and Table
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201812647
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Table 1: Optimization of reaction conditions.[a]
Table 2: Synthesis of Chiral 1-Alkyl Quinolizidines and Indolizidines: Substrate
Scope.[a]
2a : 3a:
Ee of 2a
Entry
Solvent
Catalyst
Dr[b]
4a[b]
(%)[c]
1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
(R,R)-C1
(R,R)-C1
(R,R)-C1
(R,R)-C11
95 : 5: nd
95 : 5: nd
77 : 8: 15
95 : 5: nd
> 20 : 1
> 20 : 1
> 20 : 1
> 20 : 1
91
92
91
94
2[d]
3[e]
4
1,4-
dioxane/DCM
5
(R,R)-C11
95 : 5: nd
> 20 : 1
96
[a] Reactions were carried out on a 0.1 mmol scale using Ru-cat. (1.0 mol %)
and TfOH (5 mol %) in solvent (0.5 mL) under H2 atmosphere (50 atm) at rt for
24 h. [b] Determined by 1H NMR analysis of crude product, and full conversion
was observed in all cases. [c] Determined by HPLC analysis. [d] TfOH (10
mol %). [e] In the absence of TfOH.
S2 in Supporting Information). It was found that excellent
chemoselectivity and stereoselectivity were observed in 1,4-
dioxane (entry 1). We also studied the effect of acid amount on
the reaction. Excellent yield and similar stereoselectivity were
achieved when increasing the amount of TfOH to 10 mol %
(entry 2). While remarkable decrease in reactivity and
chemoselectivity in the absence of TfOH was observed and a
partially reduced product 4a was detected in the reaction mixture
(entry 3). These results indicate that acid additive played an
important role in the reductive amination process. Upon the
screening of a variety of catalysts, (R,R)-C11 was found to be
optimal (entry 4). To our delight, the enantioselectivity was
further improved to 96% when the reaction was performed in a
mixture of 1,4-dioxane and CH2Cl2 (entry 5).
Under the optimized reaction conditions, various (2-
quinolinyl)propyl alkyl ketones were examined. All reactions
proceeded smoothly affording the quinolizidines products with
excellent diastereoselectivity and enantioselectivity (Table 2). It
was found that the substitution at the 6-position of quinoline ring
had no obvious effect on either reactivity or selectivity (2a-2d).
However, the reaction was less reactive when the alkyl chain (R1)
was longer (2e-2g). While high yield and excellent
enantioselectivity of 2g were obtained with 2.0 mol % (R,R)-C11
at 50 oC. Encouraged by the excellent results, we then examined
the cascade reactions of (2-quinolinyl)ethyl alkyl ketones. A
quick survey with 1h as the model substrate revealed that (R,R)-
C10 was the superior catalyst (Table S3). As shown in Table 2,
similarly excellent results were obtained when different
substituents were introduced at the 6-position of quinoline ring
(2h-2k). Gratifyingly, in the case of substrate 1m bearing a
bulky tertiary butyl group, high yield and excellent
stereoselectivity were also achieved by elevating the reaction
temperature. Notably, a more challenging substrate 1n was
successfully transformed, constructing a seven-membered ring
with catalyst (R,R)-C1 at 80 oC.
[a] Reactions were carried out on a 0.2 mmol scale using TfOH (5.0 mol %) in
1,4-dioxane/DCM (v/v = 1:1, 1.0 mL) under H2 atmosphere (50 atm) at rt for 24
h. For 1a–1g: (R,R)-C11 (1.0 mol %). For 1h–1m: (R,R)-C10 (5.0 mol %).
Yields correspond to isolated products. [b] (R,R)-C11 (2.0 mol %) and stirred
at 50 oC. [c] 50 oC. [d] With the use of (R,R)-C1 (2.0 mol %) and TfOH (10
mol %) in ethanol (1.0 mL) at 80 oC.
containing aryl ketones (Table 3). In contrast to (2-
quinolinyl)propyl alkyl ketones. The cascade reaction of (2-
quinolinyl)propyl phenyl ketones (5a-5f) proceeded smoothly by
using 2.0 mol % (R,R)-C1 in the presence of 10 mol % TfOH in
ethanol (Table S4). The desired 1-aryl quinolizidines products
were obtained in good yield and excellent stereoselectivity. For
the cascade reaction of (2-quinolinyl)ethyl phenyl ketones (5g-
5m), [Bmim]SbF6 was found to be optimal (Table S5). A series
of 1-aryl indolizidines were achieved under the optimized
reaction conditions. Interestingly, the easily available (2-
quinolinyl)ethenyl phenyl ketone 5g’-5o’ could be directedly
reduced to 6g-6o in tri(ethylene glycol) (3-OEG) without the
addition of TfOH (Table S6) with similarly excellent
stereoselectivities and slightly lower chemoselectivities.
Furthermore, the asymmetric cascade reactions of 2-
quinoxalinyl-containing ketones were subsequently investigated
(Table 4), leading to a new type of valuable fused aliphatic N-
heterocycles with potential biological activity.[2d] Under the
optimized reaction conditions (Table S7), the reactions of
several (2-quinoxalinyl)ethenyl aryl ketones bearing different
substituents on the phenyl group catalyzed by (R,R)-C13
proceeded smoothly, providing the desired products (8a-8f) in
good yields with excellent stereocontrol. However, substitution
on the quinoxaline ring caused a remarkable decrease in both
reactivity and chemoselectivity, but high diastereoselectivity and
enantioselectivity were still obtained (8g and 8h). For the
To broaden the substrate scope of this cascade reaction,
we further examined the asymmetric hydrogenation of quinolinyl-
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Table 3: Synthesis of Chiral 1-Aryl Quinolizidines and Indolizidines: Substrate
Table 4: Substrate Scope of 2-quinoxalinyl-containing ketones.[a]
Scope.[a]
[a] Reactions were carried out on a 0.2 mmol scale using (R,R)-C13 (1.0
mol %) in 1,2-dichloroethane (DCE, 1.0 mL) under H2 atmosphere (50 atm) at
rt for 24 h. For 7k–7p: (R,R)-C13 (2.0 mol %), stirred at 70 oC. Yields
correspond to isolated products. [b] (R,R)-C13 (2.0 mol %). [c] 1,4-dioxane
(1.0 mL), (R,R)-C9 (1.0 mol %). [d] 1,4-dioxane (1.0 mL), (R,R)-C9 (5.0 mol %),
70 oC.
[a] Reactions were carried out on a 0.2 mmol scale using (R,R)-C1 (1.0
mol %) and TfOH (10 mol %) in [Bmim]SbF6 (1.0 mL) under H2 atmosphere
(50 atm) at rt for 24 h. For 5a–5f: (R,R)-C1 (2.0 mol %) in EtOH, stirred at 50
oC. Yields correspond to isolated products. [b] (R,R)-C1 (5.0 mol %). [c] Data
in parentheses were obtained with substrates of (2-quinolinyl)ethenyl phenyl
ketone 5g’-5o’ in 3-OEG (1.0 mL) without TfOH.
(2-quinoxalinyl)ethenyl alkyl ketones, good yields and moderate
stereoselectivities were obtained (8i and 8j) by using (R,R)-C9 in
1,4-dioxane. Gratifyingly, (R,R)-C13 was also successfully
applied to the cascade reaction of (2-quinoxalinyl)propyl ketones,
and excellent results were achieved with a range of substrates
when the reaction was carried out at 70 oC with 2.0 mol %
catalyst loading (8k-8p).
The absolute configurations of different products were
assigned in analogy to our previous studies on the asymmetric
hydrogenation of 2-substituted quinolines[8b] in combination with
NOE measurement or single-crystal X-ray analysis[11] (see
Supporting Information).
During the investigation, partially reduced ketone and
enamine intermediates as well as a linear reduced by-product
were observed before the reaction was completed (Table S8).
To understand more details about the catalytic reaction pathway,
several control experiments were carried out (Scheme 2).
Scheme 2. Control experiments.
configuration of the first chiral center formed in the
hydrogenation of quinoline ring.
To further demonstrate the synthetic utility of this
methodology, this catalytic protocol was successfully applied to
the scale-up syntheses of quinolizidine, indolizidine and their
analogues (Scheme S7) and the formal synthesis of (+)-
gephyrotoxin, an alkaloid possessing mild muscarinic activity
and interesting neurological activities.[12-14] By using our strategy,
a two-step synthesis of Ito’s intermediate 14 was designed from
the easily available quinoline derivative 12 (Scheme 3).13 The
cascade reaction of 12 proceeded smoothly in the presence of
Notably, when
a
partially reduced carbonyl-containing
tetrahydroquinoline intermediate 10b was subjected to the
reaction by using both enantiomers of Ru-catalyst C1, the same
diastereomer (1R,4aS)-6b was obtained in similar yields with
identical ee values. These results suggest that the generation of
the second chiral center is completely controlled by the absolute
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Scheme 3. Formal synthesis of (+)-gephyrotoxin.
2.0 mol % (S,S)-C10 on a gram-scale, affording 13 as the only
diastereoisomer observed in 78% yield with 95% ee. After
reduction of the ester group with LiAlH4, Ito’s intermediate 14
was obtained in 95% yield with both the diastereoselectivity and
enantioselectivity retained.
In summary, we have developed a highly efficient Ru-
catalyzed
cascade
asymmetric
hydrogenation/reductive
amination of quinolinyl- and quinoxalinyl-containing ketones. A
wide range of enantioenriched benzo-fused quinolizidines,
indolizidines and their analogues were obtained in good yields
with excellent diastereoselectivity and enantioselectivity under
mild reaction conditions. It was found that the generation of the
second chiral center in the reduction of the challenging
tetrasubstituted iminium salt is completely controlled by the
absolute configuration of the first chiral center formed in the
hydrogenation of quinoline ring. The practicality and the utility of
this protocol were further demonstrated by the formal synthesis
of (+)-gephyrotoxin, which presents the shortest route to date for
the enantioselective synthesis of Ito’s intermediate.
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Acknowledgements
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We thank the National Natural Science Foundation of China
(21790332, 21521002 and 21473216) and CAS (QYZDJSSW-
SLH023) for financial support.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: cascade reactions • hydrogenation • reductive
amination • indolizidines • quinolizidines
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10.1002/anie.201812647
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Ya Chen, Yan-Mei He, Shanshan
Zhang, Tingting Miao, Qing-Hua Fan*
Page No. – Page No.
Title:
Rapid
Construction
of
Structurally Diverse Quinolizidines,
Chemoselective and asymmetric hydrogenation
Intramolecular asymmetric reductive amination
Indolizidines and Their Analogues via
Ruthenium-Catalyzed
Asymmetric
Cascade
Hydrogenation/Reductive
Amination
Cascade reaction: A rapid construction of enantioenriched benzo-fused quinolizidines, indolizidines and their analogues by
ruthenium-catalyzed asymmetric cascade hydrogenation/reductive amination of quinolinyl- and quinoxalinyl-containing ketones has
been developed. A range of chiral benzo-fused aliphatic N-heterocyclic compounds were obtained in good yields (up to 95%) with
excellent enantio- and diastereoselectivities (up to > 99% ee, > 20:1 dr).
This article is protected by copyright. All rights reserved.