Counteranion-Controlled Unprecedented Diastereo- and Enantioselective Tandem Formal Povarov Reaction for Construction of Bioactive Octahydro-Dipyrroloquinolines

Article abstract of DOI:10.1021/acscatal.6b01492

The asymmetric inverse-electron-demand hetero-Diels-Alder (IEHDA) reactions of imines and dienophiles have emerged as an attractive tool for derivatizing optically active complex azaheterocycles. In comparison, such reactions involving iminium ions remain great challenges because of low association of iminium ions with neutral catalytic centers. To overcome this, we report a metal-phosphate-catalyzed asymmetric tandem hydroamination/formal Povarov reaction of secondary aminoalkynes via a chiral counteranion-controlled iminium ion intermediate strategy. Critical to the success of this challenging strategy was chiral phosphate as an ion pair to achieve counteranion-controlled asymmetric reaction of in situ-generated iminium ions. This method enables a convenient, powerful, and atom-economical access to tetracyclic octahydro-dipyrroloquinoline frameworks bearing multiple contiguous stereogenic centers in good yields with diastereo- and enantioselectivities, from acyclic starting materials, and the catalyst loadings could be as low as 1 mol %. The asymmetric cross-coupling reaction of different aminoalkynes has further been demonstrated with good results. Furthermore, this methodology was applied to enantioselective synthesis of incargranine B aglycone epimer in only two steps. The reaction is demonstrated to proceed through a stepwise process for formal Povarov reaction.

Full text of DOI:10.1021/acscatal.6b01492

Research Article
pubs.acs.org/acscatalysis
Counteranion-Controlled Unprecedented Diastereo- and
Enantioselective Tandem Formal Povarov Reaction for Construction
of Bioactive Octahydro-Dipyrroloquinolines
Xiao-Long Yu,§,† Liping Kuang,§,†,‡ Su Chen,§,† Xiao-Long Zhu,† Zhong-Liang Li,† Bin Tan,†
and Xin-Yuan Liu*,†
†Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, P. R. China
‡College of Chemistry and Molecular Science, Wuhan University, Wuhan, 430072, P. R. China
S
* Supporting Information
ABSTRACT: The asymmetric inverse-electron-demand het-
ero-Diels−Alder (IEHDA) reactions of imines and dienophiles
have emerged as an attractive tool for derivatizing optically
active complex azaheterocycles. In comparison, such reactions
involving iminium ions remain great challenges because of low
association of iminium ions with neutral catalytic centers. To
overcome this, we report a metal-phosphate-catalyzed asymmetric tandem hydroamination/formal Povarov reaction of secondary
aminoalkynes via a chiral counteranion-controlled iminium ion intermediate strategy. Critical to the success of this challenging
strategy was chiral phosphate as an ion pair to achieve counteranion-controlled asymmetric reaction of in situ-generated iminium
ions. This method enables a convenient, powerful, and atom-economical access to tetracyclic octahydro-dipyrroloquinoline
frameworks bearing multiple contiguous stereogenic centers in good yields with diastereo- and enantioselectivities, from acyclic
starting materials, and the catalyst loadings could be as low as 1 mol %. The asymmetric cross-coupling reaction of different
aminoalkynes has further been demonstrated with good results. Furthermore, this methodology was applied to enantioselective
synthesis of incargranine B aglycone epimer in only two steps. The reaction is demonstrated to proceed through a stepwise
process for formal Povarov reaction.
KEYWORDS: asymmetric, counteranion, hydroamination, octahydro-dipyrroloquinoline, Povarov reaction, phosphate
scope with low catalyst loadings remains a formidable challenge
for synthetic chemists.
INTRODUCTION
■
Asymmetric Povarov and inverse-electron-demand hetero-
Diels−Alder (IEHDA) reactions1 of preformed or in situ-
generated imines (2-azadienes) and dienophiles catalyzed by
chiral Lewis acids2 or chiral Brønsted acids3 are among the
most powerful in organic chemistry, providing an atom-
economical method for the synthesis of enantioenriched
complex azaheterocycles (Scheme 1a). Despite their wide-
spread utility and applications, catalytic enantioselective
Povarov reactions involving iminium ions are much scarcer
(Scheme 1a). This could be attributed in part to the low
association of the intermediate iminium ions with neutral
catalytic centers, therefore rendering it difficult to induce high
enantioselectivity in subsequent transformations. Thus, the
development of novel catalytic system to realize asymmetric
iminium ion cyclization reactions has long been recognized as a
preeminent goal for organic synthesis. Only recently, Seidel and
co-workers achieved a significant breakthrough by using
conjugate-base-stabilized Brønsted acids to enable enantiose-
lective Povarov reaction involving iminium ions, which were in
situ-generated from the reaction of secondary anilines and
aldehydes with 20 mol % of catalytic loadings.4 Therefore, the
exploration of more atom-economical and convenient asym-
metric complementary strategies tolerating a wide substrate
It is well-known that the octahydro-dipyrroloquinoline
framework with multiple stereogenic centers is a unique motif
found in a wide range of biologically active alkaloid natural
products, such as incargranine B5a,6g and seneciobipyrrolidine
(Figure 1).5b Moreover, the octahydro-dipyrroloquinoline
derivatives have been successfully applied as a key intermediate
in the synthesis of martinellic acid and martinelline as BK
receptor antagonists (Figure 1).5c Therefore, great endeavors
have been devoted to various nonasymmetric approaches to
access the tetracyclic amine core of these alkaloids for many
years.6 In this regard, more recently, our research group have
also successfully developed a gold(I)-catalyzed tandem process
of 1,4-aminoalkynes via hydroamination/formal Povarov path-
ways through an iminium ion intermediate, providing access to
octahydro-dipyrroloquinoline frameworks in good yields.7
However, the poor diastereoselectivity was observed in the
presence of both gold catalyst and dual gold/diphenyl
phosphate catalyst in all cases for 1,4-aminoalkyne substrates
(Scheme 1b). In spite of these attractive racemic attributes, the
Received: May 26, 2016
Revised: August 3, 2016
© XXXX American Chemical Society
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Scheme 1. Strategy for Asymmetric Formal Povarov Reaction of Iminium Ions
Figure 1. Natural octahydro-dipyrroloquinoline alkaloids and derivatives.
development of a catalytic enantioselective approach for the
construction of octahydro-dipyrroloquinoline frameworks
remains an unaddressed formidable challenge. Therefore, the
invention of novel asymmetric systems capable of constructing
structurally diverse octahydro-dipyrroloquinoline skeletons in a
highly enantioselective and straightforward way from readily
available starting materials is highly desirable and will be of
great synthetic importance.
Stimulated by the challenge of asymmetric version for the
construction of octahydro-dipyrroloquinoline skeletons, we
became interested in developing an asymmetric tandem
hydroamination/formal Povarov reaction of secondary 1,4-
aminoalkynes (Scheme 1c). To fulfill this, several considerable
challenges need to be addressed: (1) the control of
diastereoselectivity of three stereogenic centers is particularly
challenging because the poor diastereoselectivity has already
been observed in our previous racemic version catalyzed by
metal catalyst.7 (2) The rational design of appropriate catalytic
system to efficiently control enantioselectivity would also be a
great challenge due to the nature of the in situ-generated
iminium ion intermediate involving the low association with
neutral catalytic centers. Recently, chiral metal phosphate
catalysis has been demonstrated as a powerful strategy for the
development of asymmetric transformations involving cationic
intermediates to form a tight ion pair with the chiral
counteranion, since the pioneering studies carried out by
Toste, List, Rueping, and others.8−10 On the basis of this
strategy and in our continuous efforts in hydroamination and
asymmetric hydrogen-bond and counteranion catalysis,11 we
envisioned that a chiral metal phosphate might be able to
catalyze asymmetric tandem hydroamination/formal Povarov
reaction of secondary aminoalkynes, in which in situ-generated
metal-containing iminium ions would interact with chiral
phosphate as an ion pair to achieve counteranion-controlled
asymmetric formal Povarov reaction, thus providing a
convenient and powerful access to enantioenriched octahy-
dro-dipyrroloquinolines with excellent diastereo-/enantioselec-
tivity control (Scheme 1c). Herein, we disclose the details of
this new reaction system with unprecedented excellent
diastereo- and enantioselectivity and its application in the first
enantioselective synthesis of the incargranine B aglycone
epimer. To our knowledge, the asymmetric tandem process
reported herein not only represents the first highly
enantioselective construction of synthetic challenging enantio-
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Table 1. Evaluation of Chiral Metal Phosphates and Optimization of Reaction Conditions
a
b
c
entry
catalyst
solvent
temp (°C)
conversion (%)
dr
ee (%)
1
(R)-3a
(R)-3b
(S)-3c
(S)-3d
(S)-3e
(R)-3f
(R)-3f
(R)-3f
(R)-3f
(R)-3f
(R)-3f
(R)-3f
(R)-3g
(R)-3h
(R)-3i
(R)-3f
(R)-3f
(R)-3f
(R)-3j
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
n-heptane
60
60
60
60
60
60
60
60
60
20
40
80
60
60
60
60
60
60
60
100
100
100
80
5:1
2:1
−32
0
2
3
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
80
−26
−36
96
92
90
54
89
94
95
89
92
92
93
95
95
4
5
100
g
6
100(95)
7
100
100
100
30
8
toulene
9
DCM
10
11
12
13
14
15
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
63
100
60
57
7
d
16
100
100
100
trace
e
17
f
18
19
cyclohexane
a
b
c
d
Estimated from 1H NMR of the crude product. Determined by 1H NMR of the crude reaction mixture. Determined by chiral HPLC. (R)-3f (5
e
f
g
mol %). (R)-3f (1 mol %). (R)-3f (0.5 mol %), solvent (2.0 mL). Value in parentheses reflects isolated yield.
pure octahydro-dipyrroloquinoline skeletons but also provides
a particularly advantageous alternative to the asymmetric
Povarov reactions of iminium ions.4
(entry 1). This is in sharp contrast to the gold-catalyzed
racemic tandem process with poor diastereoselectivity.7 The
comparison of the present result with that observed for our
previous racemic work with gold catalysis clearly indicated that
the chiral bulky phosphate counteranion plays a crucial role in
the control of diastereo- and enantioselectivity. To further
improve the stereoselectivity, we screened other BINOL-
derived chiral silver phosphates 3b and 3c and found that 2,4,6-
triisopropylphenyl-BINOL-derived (S)-3c gave both an ex-
cellent yield and an excellent diastereoselectivity (>20:1 dr),
albeit with 80% ee (entries 2 and 3). Then, the evaluation of
SPINOL-derived catalysts 3d−3f was conducted, and (R)-3f
was the most effective one, giving 2a in 95% yield and 96% ee
along with >20:1 dr (entries 4−6). Furthermore, a solvent
effect was observed, and the best results were obtained with
cyclohexane as the solvent (entries 6−9). Among the reaction
temperatures examined, the reaction at 60−80 °C gave the best
results (entries 10−12). However, the corresponding copper-
(I),10a copper(II),10a and gold phosphates10b gave lower
reactivity albeit with excellent stereoselectivity, presumably
RESULTS AND DISCUSSION
■
Optimization of Reaction Conditions with Chiral
Metal Phosphate Catalysts. The initial investigation to
validate our hypothesis started with the designed tandem
reaction with linear aminoalkyne 1a as the model substrate for
the optimization of reaction conditions (Table 1). Since silver
phosphate catalysts have been proved not only as excellent π-
Lewis acid catalysts to activate unactivated alkynes12 but also as
chiral counteranion catalyst for a diverse range of asymmetric
reactions,9 a BINOL-based chiral silver phosphate (R)-3a was
first examined in this reaction. To our surprise, in the presence
of only 2 mol % of (R)-3a, the reaction of 1a proceeded
smoothly to give the corresponding endo octahydro-dipyrrolo-
quinoline 2a in almost quantitative yield, albeit with moderate
diastereoselectivity (5:1) and poor enantioselectivity (32% ee)
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a,b,c,d
Table 2. Reaction Scope with Respect to the Linear Aminoalkyne
a
b
c
d
All the reactions were conducted on a 0.1 mmol scale. Isolated yield. The ee were determined by HPLC analysis. The dr was determined by 1H
e
NMR of the crude reaction mixture. The reaction time was 48 h.
due to the low catalytic reactivity for these chiral metal catalysts
(entries 13−15). It should be noted that the catalyst loading
could be reduced from 5 to even 0.5 mol % without affecting
the reaction efficiency and stereoselectivity (entries 16−18),
which is unusual with such catalytic loadings in the asymmetric
Povarov reactions.1−4 A control experiment indicated that none
of the desired product was observed in the presence of chiral
phosphoric acid 3j, which unambiguously revealed that the
metal phosphate is essential for this reaction.
Substrate Scope. With the optimized conditions estab-
lished, the substrate scope and the generality of the current
method with respect to linear aminoalkyne were next
investigated. A wide range of substrates with different
substituents at different positions all reacted smoothly to afford
the corresponding products as a single diastereoisomer with
excellent efficiency and good to excellent enantioselectivities
(Table 2). For example, substrates 1 bearing disubstituted
groups of the aryl ring reacted efficiently to give 2a−2d in
excellent yields (92−98%) and excellent stereoselectivities
(>20:1 dr, 96−99% ee) along with exclusive regioselectivities. It
was revealed that with monosubstituted groups on the phenyl
ring the octahydro-dipyrroloquinolines (2f−2h) were obtained
as a single diastereoisomer in excellent yields and good
enantioselectivities (83−87% ee). The structure of 2h was
confirmed by X-ray diffraction analysis of its single crystals, and
the absolute configuration was assigned to be (3aR,3bS,11bR)
(Figure 2).
Having succeeded in the asymmetric reaction of linear
aminoalkynes, we then focused our attention on C-tethered
aminoalkynes to allow structurally diverse modifications. As
shown in Table 3, a variety of propargylic amino ester, bearing
electron-neutral (H), electron-donating (Me, Et, OMe,
CH2CO2Me) or electron-withdrawing (F, Cl) groups at the
para or meta positions of the phenyl ring, and disubstituted
groups on the phenyl ring, proved to be viable substrates for
this process, affording the desired products 5a−5j in 80−99%
Figure 2. X-ray structure of 2h.
yields with excellent diastereoselectivities (>17:1−20:1 dr) and
enantioselectivities (86−98% ee). Gratifyingly, when the meta-
substituted substrates 4k and 4l were used in this reaction, the
6-position C−H bond with less steric hindrance was selectively
activated to afford the corresponding products 5k and 5l as a
single diastereoisomer in 91% yield and 92% and 90% ee along
with 3.8:1 and >20:1 rr (regioisomeric ratio), respectively, thus
exhibiting not only excellent stereoselectivity but also good to
excellent regioselectivity for such a reaction. Meanwhile,
changing methyl ester to other esters, such as ethyl (4m−
4o), iso-propyl (4p), and benzyl (4q) group had no significant
influence on the reaction to give 5m−5q as a single
diastereoisomer in 93−99% yields and 92−99% ee.
To further evaluate the practicality of this methodology, we
performed this reaction on a gram scale with even only 1 mol %
of catalyst loading. The reaction afforded 5o in 96% yield and
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a,b,c,d
Table 3. Reaction Scope with Respect to Propargylic Amino Ester
a
b
c
d
All the reactions were conducted on a 0.1 mmol scale. Isolated yield. The ee was determined by HPLC analysis. The dr and rr were determined
e
1
by H -NMR of the crude reaction mixture. 4 mol % of catalyst.
Scheme 2. Gram Scale and Synthesis of Incargranine B Aglycone Epimer 6
91% ee (Scheme 2, eq 1). For the purpose of accessing
enantioenriched incargranine B aglycone epimer, whose
structure has been revised by Lawrence and co-workers,6g we
conducted the reaction of 1h under the standard conditions on
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Scheme 3. Control Experiments
Scheme 4. Proposed Mechanism and Proposed Transition State
a gram scale to give 2h in 98% yield and 87% ee (95% ee after a
single recrystallization process). Next, treatment of 95% ee of
2h with isopropylmagnesium bromide solution, followed by the
addition of ethylene oxide, afforded incargranine B aglycone
epimer 6 in 77% yield with >99% ee (Scheme 2, eq 2). The
structure resemblance with a variety of biologically active
compounds also encouraged us to evaluate the biological activity
of our products. Our preliminary biological studies revealed that
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Scheme 5. Cross-Coupling Reaction
randomly selected enantioenriched compounds 2a and 5o exhibited
good cytotoxicities against PC3 cancer cell lines with IC50 values of
38.6 and 12.4 μM, respectively, suggesting a potential application of
this class of chiral octahydro-dipyrroloquinolines in anticancer
studies.
enantioselectivity. The aromatization and protonation of
intermediate V would give the final endo product 2. To further
rationalize the observed stereochemistry for this reaction, an
interaction transition state based on Simon and Goodman’s
model18 and Terada’s DFT calculation19a was proposed
(Scheme 4), in which chiral phosphate anion interacts with
the iminium ion through not only electrostatic interactions but
also a C−H···O hydrogen bond interaction19 to form a tight
ion pair A. Due to the steric effect of the bulky substituent and
the SPINOL framework, the enamine, which acts as the
nucleophile, is forced to selectively attack the iminium ion from
only one side of the iminium ion, thus inducing endo
diastereoselectivity, which is in accordance with the exper-
imental findings.
Considering the possibility that the Mannich reaction is a
reversible step for this tandem process (Scheme 4), we
hypothesized that a cross-coupling reaction with two different
aminoalkynes could be realized under an appropriate catalytic
reaction system. As expected, our preliminary result showed
that racemic product 11 was obtained in 74% yield with 7.1:1.0
product ratio (11/5d), albeit with 1.9:1.0 dr for the reaction of
10 and 4d with AuCl3 (6 mol %) and diphenyl phosphate (8
mol %). Furthermore, enantioenriched product 11 was
obtained in 42% yield and 62% ee along with 9.0:1.0 dr with
1.3:1.0 product ratio (11/5d) with Pd(OAc)2 (5 mol %) and
(R)-3j (7.5 mol %) as the catalyst after the systematic
optimization of different reaction parameters (Scheme 5 and
Table S1 in SI). Clearly, there is still room for improvement of
the result of such reaction.
Mechanistic Investigations and Cross-Coupling Re-
action. Because the Povarov reaction could proceed in a
stepwise manner or via a concerted IEHDA mechanism,13
a
series of control experiments were conducted to rationalize the
current reaction process and its stereochemistry. Fortunately,
the Mannich adduct 714 was obtained in 38% yield, along with
the final product 5f (40% yield), when substrate 4f bearing Cl
substituent was used under otherwise identical conditions with
only 12 h (Scheme 3, eq 3). This result indicated a stepwise
mechanism of our subsequent enantioselective formal Povarov
reaction is feasible. Subsequent treatment of the Mannich
adduct 7 at 80 °C for 15 h in the presence of (R)-3f, (R)-3j, or
achiral 8 gave 5f in excellent yield via an intramolecular aza-
Friedel−Crafts (FC) reaction, further demonstrating a stepwise
Mannich/aza-FC process for this reaction. However, with chiral
(R)-3f or (R)-3j as catalyst, the corresponding product 5f was
obtained as a single diastereomer with 98% or 93% ee, while
with achiral 8, a 7:1 mixture of diastereomers was obtained
(Scheme 3, eq 4). These observations indicated that the
Mannich reaction is a reversible step. On the other hand, the
desired product 2a was obtained in 99% yield with 91% ee as a
single diastereomer when N-(4,4-diethoxybutyl)-3,5-dimethyla-
niline 9 was treated with a catalytic amount of chiral phosphoric
acid (R)-3j (2 mol %) in the presence of 4 Å MS in
cyclohexane at 60 °C for 24 h (Scheme 3, eq 5). This result,
along with the high diastereo- and enantioselectivity of 5f by
treatment of the intermediate 7 with phosphoric acid (R)-3j
(Scheme 3, eq 4), indicated that the silver catalyst is not
necessary for enantiocontrol.
On the basis of the above observations and by considering
previous works on silver-catalyzed hydroamination reactions,12
a reaction mechanism is proposed as depicted in Scheme 4.
Intramolecular hydroamination of 1 catalyzed by chiral silver
phosphate could generate the silver-enamine intermediate I
that is protonated to give enamine intermediate II. On the
other hand, intermediate II could undergo tautomerization with
chiral phosphoric acid15 to form iminium cation intermediate
III,7,9f wherein chiral phosphate anion could be coordinated as
a counteranion to the iminium part.16,17 The subsequent
reversible Mannich reaction of intermediate III and II followed
by the aza-FC cyclization yields an intermediate V, in which the
chiral counteranion could induce the high diastereo- and
CONCLUSIONS
■
We have successfully developed a first chiral metal-phosphate-
catalyzed asymmetric tandem hydroamination/formal Povarov
reaction of aminoalkynes via a chiral counteranion-controlled
iminium ion intermediate strategy to enable a straightforward
and efficient synthesis of biologically important tetracyclic
octahydro-dipyrroloquinolines bearing multiple contiguous
stereogenic centers in excellent yield with unprecedented
high levels of regio-, diastereo-, and enantioselectivity from
readily available starting materials at catalytic loadings even as
low as 1 mol %. Furthermore, this methodology allows for the
first synthesis of incargranine B aglycone epimer. Mechanistic
studies suggest that the key step of cyclization reaction
proceeds via a stepwise process, in which both diastereose-
lectivity and enantioselectivity are controlled by a chiral
phosphate counteranion. Further investigation of the corre-
sponding cross-coupling reaction with expected excellent
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ent types of iminium ions and dienophiles for other classes of
useful enantiopure complex azaheterocycles through metal
phosphate catalysts.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b01492.
■
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compounds (PDF)
X-ray data of 2h (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: liuxy3@sustc.edu.cn.
■
Author Contributions
§These authors contributed equally (X.-L.Y., L.K., and S.C.).
Notes
The authors declare no competing financial interest.
13273−13275. (h) Fustero, S.; Bello, P.; Miro,
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ACKNOWLEDGMENTS
́
■
́
́
Financial support from the National Natural Science
Foundation of China (Nos. 215722096, 21302088); the
National Key Basic Research Program of China (973 Program
2013CB834802); Shenzhen overseas high level talents
innovation plan of technical innovation project
(KQCX20150331101823702); Shenzhen special funds for the
development of biomedicine, Internet, new energy, and new
material industries (JCYJ20150430160022517); and South
University of Science and Technology of China (FRG-
SUSTC1501A-16) is greatly appreciated.
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