Organocatalytic Enantioselective Construction of Chiral Azepine Skeleton Bearing Multiple-Stereogenic Elements

Article abstract of DOI:10.1002/anie.202108040

Enantioselective construction of molecules bearing multiple stereogenic elements is increasingly related to the synthesis of enantiopure natural products, pharmaceuticals, and functional materials. However, atom-economical and enantioselective approaches

Full text of DOI:10.1002/anie.202108040

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Accepted Article
Title: Organocatalytic enantioselective construction of chiral azepine
skeleton bearing multiple-stereogenic elements
Authors: Shengli Huang, Haojun Wen, Yuhong Tian, Pengfei Wang,
Wenling Qin, and Hailong Yan
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10.1002/anie.202108040
Angewandte Chemie International Edition
RESEARCH ARTICLE
Organocatalytic Enantioselective Construction of Chiral Azepine
Skeleton Bearing Multiple-Stereogenic Elements
Shengli Huang, Haojun Wen, Yuhong Tian, Pengfei Wang, Wenling Qin, Hailong Yan*
[*]
S. Huang, H. Wen, Y. Tian, P. Wang, W. Qin, Prof. Dr. H. Yan
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chemical Biology Research Center, School of Pharmaceutical Sciences,
Chongqing University
Chongqing 401331 (P. R. China)
E-mail: yhl198151@cqu.edu.cn
Abstract: Enantioselective construction of molecules bearing multiple
stereogenic elements is increasingly related to the synthesis of
enantiopure natural products, pharmaceuticals, and functional
materials. However, atom-economical and enantioselective
approaches to install multiple stereogenic elements in a small
molecular template by limited chemical transformation remain
challenging. We describe an organocatalytic enantioselective method
for the preparation of polychiral molecules bearing four types of
stereogenic elements in fused azepines via vinylidene ortho-quinone
methide (VQM)-mediated intramolecular electrophilic aromatic
substitution. This method was proved robust with a wide range of
substrate scope (46-92% yield), with excellent diastereoselectivity
(>20:1 dr) and enantioselectivity achieved (up to 97% ee). Optical
properties and Ru3+-induced fluorescence responses of these
compounds suggest their potential applications in optoelectronic
materials and heavy metal ion detection.
Given the fact that current synthetic methods to afford
chirality-enriched entities largely remain unfulfilling, we set out to
explore this area by designing novel synthetic strategies.
Theoretically, if one single cyclic skeleton can be compatible with
more stereogenic elements, it may be used as the core template
to overcome match/mismatch effects in the installation of multiple
stereogenic elements. As a type of well-known and biologically
interesting seven-membered heterocycle, heteropin[9] is
considered as a hetero-analogue of cyclooctatetraene. When two
aromatic moieties are fused to its core ring, it becomes a rigid
molecule possessing a saddle-shaped structure and scarcely
undergoing flipping[10]. As a result, the introduction of proper
substituents into a fused heteropin scaffold can create unique
saddle-shaped chiral molecules. To our surprise, only Shibata
and co-workers reported two catalytic synthesis of chiral
heteropin, in which multisubstituted sulfur-containing seven-
membered ring (tribenzothiepins) was enantioselectively
prepared through a transition-metal-catalyzed cycloaddition[11]
.
Recently, Scott J. Miller and co-workers reported an example of
asymmetric catalytic construction of conformational chirality
caused by the diaryl [a,d] cycloheptane ring system[12]. However,
in general, achieving conformational chirality through asymmetric
catalysis is still remain challenging. We speculated that the
introduction of a nitrogen atom into the heteropin system to form
azepine heterocycles might generate conformational behavior of
the seven-membered ring and lead to stereogenic nitrogen center
and C-N axial chirality. Moreover, with the proper aryl substitution
attached to the azepine ring, an extra axial chiral biaryl chiral
element can be installed as well, thus dramatically increasing the
stereodiversity of target molecules.
Herein, we report a strategy based on organocatalytic
annulation of VQM intermediates[13,14] to carbazole ring to form
configurationally defined azepine heterocycles and realize the
enantioselective construction of four types of fully controlled
stereogenic elements in one single step (Figure 1c).
Introduction
The defined structure of chiral molecules bearing multiple
stereogenic elements holds a special place in the development of
bioactive compounds, advanced materials and asymmetric
catalytic systems, whose absolute and relative configurations are
both critically important for their inherent properties[1]. To date, a
number of asymmetric catalytic strategies have been developed
for the construction of multi-stereogenic chiral centers[2], and a
few atroposelective protocols of multiaxis[3,4], multihelical[5] and
multiplanar[6] systems have been recently explored (Figure 1a).
However, to the best of our knowledge, catalytic enantioselective
approaches installing more than three types of stereochemical
elements into different sites of a substrate within a single step are
intrinsically challenging and have not been reported[7]. Although
such frameworks can be theoretically constructed through
multiple synthetic steps, the construction process is time-
consuming and normally involves the extensive assessment of
reaction conditions. The direct, atom-economic and highly
enantioselective transformations toward the construction of
multiple stereogenic elements is arguably one of the least
employed fields in asymmetric synthesis, probably due to the
match/mismatch effects in formed additional stereogenic
elements and the influences of the intrinsic selectivity of a chiral
substrate on the facile formation of all possible stereoisomers
(Figure 1b)[8].
Results and Discussion
Reaction optimization. At the onset of our studies, we
subjected1-(2-(9H-carbazol-9-yl)phenyl)ethynyl)naphthalen-2-ol
(1a) to 10 mol% of various chiral bifunctional organocatalysts[15]
under the standard conditions (0.05 M DCM, -60 oC and 1,3-
dibromo-5,5-dimethylhydantoin (DBDMH) as the brominating
reagent) in the azepine cyclization reaction. Primarily, the survey
1
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10.1002/anie.202108040
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 1. Multiple stereogenic chiral structures using azepine as the template. (a) Compounds with multiple stereogenic centers/ axes/ helices/ planes. (b) Strategies
for introducing multiple chiral elements into one molecule. (c) This work: enantioselective synthesis of compounds with multiple stereogenic elements.
on cinchona alkaloid catalysts indicated significant impacts of the
catalyst backbones on the outcome of the reaction. When catalyst
A, B, C, D and E were used, the desired product 2a was obtained
in moderate yields, with poor to moderate enantioselectivities
(Table 1, entries 1-5). To our delight, the reaction with catalyst F
realized the enantiomeric excess up to 87% as well as moderate
yield (entry 6). In further exploration, Takemoto’s squaramide
catalyst G only gave -62% ee and 69% yield and no product was
detected in the reaction with dimeric cinchona alkaloid derivative
(DHQD)2PHAL (entries 7, 8). In short, the catalyst investigation
revealed that a crucial role of squaramide moiety in the
transformation. It was ascribed to the low pKa values of the
squaramide moiety and extended distances between the
reagents
such
as
N-bromosuccinimide
(NBS),
N-
bromoacetamide (NBA) and N-bromophthalimide (NBP) were
also examined (entries 20-22). NBS and NBP achieved elevated
yields (80%) and NBS showed the better enantioselectivity than
NBP (95% versus 89%). The better profile indicated that NBS was
the optimal brominating reagent, so it was employed in the
subsequent experiments. Finally, the increase in the
concentration of reaction system led to a slightly decreased yield
(78%), whereas the decreasing of reaction concentration (0.035
M and 0.025 M) led to the higher yields (82% and 85%,
respectively) (entries 23-25). The concentration change of the
reaction system within
a certain range only made minor
differences to the yields and almost showed no effect on the
enantioselectivity. Finally, the reaction conditions of entry 25 were
identified as the optimal one.
squaramide N−H bonds[16]
. Solvent screening hinted that
dichloromethane outperformed other counterparts, as no product
was detected in most other solvents (acetone, ethyl acetate,
tetrahydrofuran, N,N-dimethylformamide, diethyl ether and
methanol) (entries 11-16). Although the reaction also took place
in chloroform (45% yield) and toluene (78% yield), obvious
enantioselectivity loss was noticed (entries 9, 10). Studies on the
reaction temperature suggested low temperatures were vital to
the product formation and high temperatures ruined the
cyclization process (entries 17-19). The optimal outcome was
realized at -78 oC (75% yield, 89% ee) and obvious decreases in
both yield (57%) and ee (31%) were observed at 0 oC. When the
reaction was performed at room temperature, only 35%
conversion was achieved and the enantioselectivity dramatically
declined (11% ee). The efficiencies of different brominating
Substrate scope. Subsequently, the universality of the
reaction was evaluated by exploring the substrate scope. As
summarized in Scheme 1a, the methodology was proved quite
robust with substrates bearing substituted 2-naphthols and
achieved excellent enantioselectivities (92-97%) and moderate to
good yields. With regard to the substituents on the 7-position of
2-naphthol (2b-2d), the reaction proceeded well with aryl-(Ph),
electron-donating (OMe) or electron-withdrawing (Br) groups
(yields > 89%) and no obvious electronic effect on electronic
effect on stereoselectivity (ee > 94% and dr > 20:1) was found.
An exception was detected that the linear 7-phenylethynyl
modification decreased the yield (75%), yet it achieved excellent
enantioselectivity (92%) (2f). As for 2-naphthols modified at its 6-
2
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10.1002/anie.202108040
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RESEARCH ARTICLE
position, the electron-withdrawing (Br) group (2e) slightly raised
the yield (89%), with excellent enantioselectivity (96%). Whereas
the electron-donating (Et, nPr, iPr, and Cy) alkyls (2g-2j) led to
moderate to good yields (54-83%), still all products were acquired
with excellent enantioselectivities (93-97%). A bulky group (3-
methoxybenzyl) at the 5-position of 2-naphthol (2k) was also
found to be well tolerated as the enantioselectivity and the yield
Table 1. Optimization of the Reaction Conditions[a]
Entry
1
Catalyst
Solvent
DCM
T(oC)
-60
Br+
Yield[b] (%)
79
dr[c]
ee[d] (%)
7
A
DBDMH
>20:1
2
3
B
C
D
E
F
G
H
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
Toluene
Acetone
EA
-60
-60
-60
-60
-60
-60
-60
-60
-60
-60
-60
-60
-60
-60
-60
25
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
NBS
66
62
47
58
71
69
ND
45
78
ND
ND
ND
ND
ND
ND
35
57
75
80
45
80
78
82
85
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
-
-62
0
4
-46
-40
87
-62
-
5
6
7
8
9
>20:1
>20:1
-
49
50
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23[e]
24[f]
25[g]
-
-
THF
-
-
DMF
-
-
Et2O
-
-
CH3OH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
-
-
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
11
31
89
95
45
89
96
95
95
0
-78
-78
-78
-78
-78
-78
-78
NBA
NBP
NBS
NBS
NBS
[a] Reaction conditions: 1a (0.025 mmol, 1.0 equiv.), catalyst (0.0025 mmol, 10 mol%) in solvent (0.5 mL) at corresponding temperature for 30 min, then brominating
reagents (0.025 mmol, 1.0 equiv.) at corresponding temperature for 2 h. [b] Isolated yield. [c] Only one dominant diastereomer formed. [d] Enantiomeric excess (ee)
determined by HPLC. [e] Reaction in DCM (0.25 mL). [f] Reaction in DCM (0.75 mL). [g] Reaction in DCM (1.0 mL).
3
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RESEARCH ARTICLE
respectively reached 96% and 87%. Next, the scope of symmetric
3,6-disubstituted carbazoles was examined. Symmetric 3,6-
disubstituted carbazoles bearing aryl-(Ph) and alkyl-(t-Bu) groups
did not affect the cyclization reaction efficiency or stereoselectivity
notably irrespective of substitutions (Br or OMe) on the 6- or 7-
position of the 2-naphthols (2l-2p, 76-87% yields, 91-97% ee). In
detail, 3,6-diphenyl carbazole product (2l) has a higher yield
(82%) than that of 3,6-di-tert-butyl carbazole (2m, 76% yield).
However, an electron-withdrawing (Br) group at the 6-position of
the 2-naphthol (2n, 87% yield) compensated the conversion loss
and a similar effect was also observed in the 7-substituted 2-
naphthols (2o and 2p, 85-87% yields) regardless of the electronic
properties. This observation was also in accordance with non-
substituted carbazole products (2b-2e). We further made more
Scheme 1. Substrate scope. [a] Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), catalyst-F (0.02 mmol, 10 mol%) in DCM (8.0 mL) at -78 oC for 30 min, then NBS
(0.2 mmol, 1.0 equiv.) at -78 oC for 2 h.
4
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variations at the carbazole ring of the substrates. The
replacement of the carbazole with a phenoxazine ring (2q)
retained excellent enantioselectivity (97% ee) and led to a higher
yield (89%). Furthermore, the replacement of the carbazole with
a phenothiazine group was found to be also employable for the
reaction and gave 2r with excellent enantioselectivity in moderate
yield. Finally, when the bromine atom on the benzene ring is
replaced by a methyl group, the ee value of the target product 2s
decreases slightly (84% ee), although a good reaction yield was
obtained. In summary, this part of the investigation suggested a
broad substrate spectrum of the given methodology.
Scheme 2. Gram-scale synthesis.
In addition, the absolute configurations of 2b and 2g were de-
tected to be (aRC-N axis, aSC-C axis, RN) by single-crystal X-ray crys-
tallographic analysis and others were assigned to analogue. As
expected, the seven-membered azepine ring had a saddle-
shaped conformation. The nitrogen atom and the axial chiral biaryl
(aS-form) across from it are situated above the plane, whereas
the bromine substituted benzene ring and the phenyl part of
carbazole was below the plane. It was also ascertained that the
absolute configuration of the nitrogen atom was in its RN-form,
whereas the chiral C-N axis was in its aR-form. In this way, four
types of stereogenic elements were stereoselectively constructed
in this molecule (Scheme 1b).
To demonstrate the synthetic practicability of this catalytic
asymmetric transformation, the reaction was scaled up to 2.0
mmol and the desired product 2d was obtained in 84% yield with
95% ee and >20:1 dr (Scheme 2). The encouraging results imply
that the catalytic asymmetric reactions have the potential for a
large-scale production.
carbazole endowed it with a C-N chiral axis and led to racemic
substrates 3a-3c. When the reaction proceeded with 0.6 equiv.
NBS, kinetic resolution (KR) of racemic-3a could also be achieved
to afford the unreacted (R)-3a and cyclization products 4a with a
diastereoselectivity ratio of 1.45:1 (Scheme 3a.). Interestingly,
when the amount of NBS was increased to 1.0 equiv., all the raw
materials can be consumed, a pair of diastereomers of 4a can be
easily obtained with excellent enantioselectivities (95% and 96%
ee, respectively). This finding suggested a practical strategy for
accessing enantio-pure chemicals with the mentioned C-N chiral
axis. Moreover, an electron-withdrawing (Br) group on the 7-
position of the 2-naphthol raised the yields of both isomers (major
and minor product of 4b, 50% and 32% yields) with excellent
enantioselectivities (90% and 94%). In contrast, when there is no
substituent at the 7-position of 2-naphthol, the stereoselectivity of
the two isomers of 4c is slightly reduced (85% and 80%,
respectively), indicating an important role of substituent at the 7-
position in this process. In order to figure out which stereogenic
element has an inverted configuration during this transformation,
we determined the absolute configurations of 4a-major and 4b-
minor by X-ray crystallographic analysis[19]. As show in Scheme
Further applications. We then explored the possible
application scope of the reaction system. The replacement of
symmetric 3,6-disubstituted carbazoles with 4-substituted
Scheme 3. Catalytic kinetic resolution of racemic-3a and synthesis of diastereomers of 4. Reaction conditions: 3 (0.2 mmol, 1.0 equiv.), catalyst-F (0.02 mmol, 10
mol%) in DCM (8.0 mL) at -78 oC for 30 min, then NBS (0.6 equiv. or 1.0 equiv.) at -78 oC for 2 h.
5
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3b, the absolute configuration of the C-N axis and N atom of 4a-
the rate-determining step[18]. On the basis of both previous studies
and our observations, we speculated that two stereospecific steps
should be involved in this process: the C−C bond-forming addition
reaction and the proton migration to produce enantioenriched
azepine ring with the stereo control of four types of stereogenic
elements. In detail, a plausible reaction mechanism was proposed
based on the reaction of 1a with NBS in the presence of catalyst
F (Scheme 4c). First, complex I was generated through the
coordination of NBS and catalyst F with 1a and then chiral
brominated VQM intermediate was enantioselectively formed via
proton shift. In this case, the C1 position on the carbazole
aromatic ring is sp2 hybridized. Next, the sp3 hybridized
carbocation transition state TS-1 was generated by the
intramolecular electrophilic aromatic substitution at the C1
position of the carbazole moiety. In addition, a complementary
naphthyl-azepine biaryl was formed to construct the second
stereogenic axis.
Photophysical properties investigations. We further
investigated the photophysical properties of several selected
compounds. The UV/Vis absorption spectra of the tested
compounds in DCM are presented in Figure 2a. Although these
compounds had different absorption curves, their maximum
absorption peaks were observed at similar wavelengths (229-239
nm). The emission spectra (Figure 2b) and the CIE diagram
(Figure 2c) of the tested compounds exhibited similar
fluorescence patterns under the irradiation of UV light (543-584
nm). Among all the chemicals, 2l had the longest wavelength of
emission band, whereas non-substituted 2a had the shortest
wavelength of emission band, indicating a causal role of the 3,6-
diphenyl substitution on carbazole in the red-shift (ca. 40 nm).
major (aSC-N axis, SN-form) was opposite with 4b-minor (aRC-N axis
,
RN-form). Meanwhile, the saddle-shaped conformation of the
seven-membered ring has reversed, resulting in the nitrogen
atom and the axial chiral biaryl across from it turned below the
plane, whereas the bromine substituted benzene ring and the
phenyl part of carbazole were above the plane. Nevertheless, the
configuration of the C-C axis remained the same (aS-form), and
this led to the formation of diastereomers of product 4.
Control experiments and preliminary mechanistic
studies. To shed light on the mechanism of this cyclization
reaction with the formation of multistereogenic elements, some
control experiments were carried out. When the naphthyl hydroxyl
was protected by acetyl group or replaced with a formaldehyde or
methanol group to block the formation of VQM intermediate, the
reaction did not take place and only the starting material was
recovered from the reaction system (Scheme 4a). Hence, the
VQM system might be involved in this highly stereo-controlled
transformation. In addition, the kinetic isotope effect (KIE) was
measured based on parallel reactions of D-1a and 1a to give 2a’
and 2a (Scheme 4b). As shown in Scheme 4b, 1-deuterated
carbazole was converted into a mixture of deuterated product 2a’
and non-deuterated product 2a. As a result, a kH/kD value of 0.87
was obtained, indicating that the C−H bond cleavage might not be
the rate-determining step of this transformation. We speculate
that the reaction involves an inverse secondary isotope effect
(KIE<1)[17]. In this case, there will be a process in which the
aromatic ring forms a carbocation transition state. In the process
of forming a transition state, the substituted C-H bond may be
hybridized from near sp2 to near sp3, and this process might be
Scheme 4. Control experiments and preliminary mechanistic studies. (a) Control experiments. (b) Isotopic labeling experiment. (c) Plausible catalytic cycle.
6
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Figure 2. Photophysical properties of several selected compounds. (a) UV/Vis absorption spectra. (b) Fluorescence spectra. (c) Fluorescence lifetime decay curves.
(d) CIE diagram. (e) Photos under irradiation of UV (λ = 365 nm) light. (f) Longest wavelengths of UV/Vis absorption (2×10-5 M in DCM) and emission (excitation
wavelength: 300 nm, solid powder).
The fluorescent emission half-life (τ) time of all compounds
showed sharp distinctions. 2a had the longest half-life time, 3.88
ns, which was almost 3-folds of that of 2q, 1.38 ns (Figure 2d).
Hence, substitutions on the scaffold reduced the fluorescent
lifetime and caused red-shift. In addition, the replacement of
carbazole with phenoxazine led to major variations in optical
properties. We also explored the potential of 2b as fluorescence
sensors for the purpose of detecting transition metal ions.
Compared with some cations, such as Na+, K+, Mg2+, Bi3+, Ce3+,
In3+ and Zr4+, Ru3+ exhibited the most significant effect upon the
fluorescence property of 2b. The outcome indicated that 2b could
be used as a selective Ru3+ detection fluorescence sensor (see
Supporting Information).
access more complicated molecules. In addition, optical
properties of certain compounds were investigated, including UV
absorption, fluorescence irradiation and emission and they
showed potential application prospects in chiral organic
optoelectronic materials. Further study on the fluorescence
response behaviors induced by heavy metal ions suggested the
potential application of these compounds in Ru3+ detection.
Acknowledgements
This study was supported by National Natural Science
Foundation of China (Grant No: 21922101, 21772018, 21901026,
22001025) and the Fundamental Research Funds for the Central
Universities (Project No. 2020CQJQY-Z002).
Conclusion
In conclusion, we developed a perfectly atom-economic and
highly enantioselective organocatalytic process for the
construction of chiral molecules bearing four distinct stereogenic
elements. Our reaction was enabled via intramolecular
electrophilic aromatic substitution of carbazole moiety with in situ
generated chiral VQM intermediate in the presence of confined
chiral hydrogen bonding bifunctional catalysts so as to provide
access to the valuable enantiopure azepine ring system. With this
methodology, four types of stereogenic elements including chiral
nitrogen center, C-N axial chirality, C-C axial chirality and
conformational behavior of the seven-membered ring were
stereoselectively constructed. Further utility of this process was
illustrated by catalytic resolution of non-symmetrical substrates to
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis • multiple stereogenic
elements • seven-membered ring • azepine • organocatalytic
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8
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10.1002/anie.202108040
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
An organocatalytic enantioselective method for the preparation of polychiral molecules via vinylidene ortho-quinone methide (VQM)-
mediated intramolecular electrophilic aromatic substitution was developed. With this methodology, four types of stereogenic elements
including chiral nitrogen center, C-N axial chirality, C-C axial chirality and conformational behavior of the seven-membered ring were
stereoselectively constructed.
9
This article is protected by copyright. All rights reserved.