Homochiral Covalent Organic Framework for Catalytic Asymmetric Synthesis of a Drug Intermediate

Article abstract of DOI:10.1021/jacs.0c04722

(S)-2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetonitrile ((S)-CIK) is a key intermediate in the synthesis of (S)-clopidogrel, which is one of the most saleable worldwide antiplatelet and antithrombotic drugs. We show herein a facile method for the direct synthesis of (S)-CIK via Strecker reaction using a homochiral covalent framework catalyst in a heterogeneous way. The asymmetric synthesis involves a photothermal-conversion-triggered, thermally driven reaction which affords (S)-CIK in 98% yield with 94% enantiomeric excess under visible-light irradiation. Furthermore, the above approach is readily extended to a gram-scale level on a fixed-bed continuous-flow model reactor. The potential utility of this strategy is highlighted by the preparation of many more other types of chiral drugs and drug intermediates in a green and facile way.

Full text of DOI:10.1021/jacs.0c04722

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Communication
Homochiral Covalent Organic Framework for
Catalytic Asymmetric Synthesis of Drug Intermediate
Hui-Chao Ma, Gong-Jun Chen, Fang Huang, and Yu-Bin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c04722 • Publication Date (Web): 23 Jun 2020
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Homochiral Covalent Organic Framework for Catalytic
Asymmetric Synthesis of Drug Intermediate
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Hui-Chao Ma, Gong-Jun Chen,* Fang Huang, and Yu-Bin Dong*
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized
Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of
Education, Shandong Normal University, Jinan 250014, P. R. China.
ABSTRACT: (S)-2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetonitrile ((S)-CIK) is a key intermediate to
(S)-clopidogrel which is one of the most saleable worldwide antiplatelet and antithrombotic drugs. We show herein a facile method
for direct synthesis of (S)-CIK via Strecker reaction using homochiral covalent framework catalyst in a heterogeneous way. The
asymmetric synthesis involves a photothermal conversion triggered thermally-driven reaction which affords (S)-CIK in 98% yield
with 94% enantiomeric excess under visible-light irradiation. Furthermore, the above approach is readily extended to a gram-scale
level on a fixed-bed continuous-flow model reactor. The potential utility of this strategy is highlighted by the preparation of many
more other types of chiral drugs and drug intermediates in a green and facile way.
Chiral drugs are closely related to our health. For example, the
famous thalidomide tragedy1 allows us to fully realize that the
enantiomeric composition of chiral drugs is life-critical
because the biological targets are usually chiral.2,3 In
comparison to racemate resolution and chiral induction,
asymmetric catalysis has been recognized as the most efficient
approach to access chiral drugs and drug intermediates.4
Clopidogrel,5 as an important antiplatelet and antithrombotic
drug, its (S)-isomer is widely used to reduce the stroke risk,
blood clot, and serious heart problem. (S)-clopidogrel bisulfate
is now sold in 110 countries and has been become one of the
worldwide top-selling drugs.5-7 Instead of antithrombotic
function, its (R)-isomer can cause social turmoil as revealed by
the animal experiments.8
As reported, one of the most efficient approaches for
synthesis of (S)-clopidogrel is to proceed through a (S)-CIK
intermediate which can be readily transformed to (S)-
clopidogrel via subsequent alkaline hydrolysis and salt
formation steps.5,9 The existing methods for (S)-CIK
synthesis, however, usually suffer from high time, energy and
resource consumption, and tedious workup.5 For example, it
can be obtained in 92% yield with an enantiomeric ratio of
78:22, but the reaction was conducted at -20°C with chiral
molecular hydroquinone catalyst and NaF auxiliary in 16h in a
homogeneous way.9 Therefore, the development of step-
economical and environmentally benign (S)-CIK synthetic
methodology, especially for pharmaceutical industry,10 is
highly imperative.
Since the pioneering work of Yaghi in 2005,11 covalent
organic frameworks (COFs) have drawn more and more
attention due to their versatile potential applications. For
instance, several recent reports revealed that the homochiral
covalent organic frameworks (HCCOFs)-based catalysts can
elegantly promote asymmetric organic transformations in
heterogeneous way.12
Figure 1. Synthesis and crystal structure of (R)-CuTAPBN-COF,
and diagram representation of catalytic synthesis of (S)-CIK.
For meeting the multifaceted requirements of (S)-CIK
synthesis with a facile single-step operation, a 5,10,15,20-
tetrakis-(4-aminophenyl)-porphyrin-Cu-(II) (Cu-TAPP) and
6,6’-dichloro-2,2’-diethoxy-1,1’-binaphthyl-4,4’-dialdehyde
((R)-BINOL-DA) derived HCCOF, which possesses Lewis
acid (LA), chiral templating (CT) and photothermal
conversion (PTC) species, was designed and prepared (Figure
1, Supporting Information). Upon visible-light irradiation, the
obtained (R)-CuTAPBN-COF displays excellent catalytic
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activity and enantioselectivity for the (S)-CIK synthesis via
the crystallographic c axis. A long interlayer Cu···Cu distance
of ~1.4 nm was found due to the twisted configuration of (R)-
BINOL in (R)-CuTAPBN-COF (Figure 2a). HR-TEM
revealed that each bulky particle consists of a series of
crystalline flakes and a close analysis of the TEM-image
shows that (R)-CuTAPBN-COF features grid structure
(Figure 2b), which is well consistent with its structural
modeling analysis. Notably, (R)-CuTAPBN-COF herein with
other types of possible simulated space group gave the PXRD
pattern that significantly deviated from the measured profile
(Figure S1f).
asymmetric Strecker reaction (Figure 1).13, 14
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Figure 3. CD spectra showing that the pairs of (R)- and (S)-
CuTAPBN-COF, and (R)- and (S)-CIK are mirror images of
each other.
Figure 2. (a) Simulated and measured PXRD patterns of (R)-
CuTAPBN-COF. Its crystal structure (top and side views) is
shown as insets. (b) HR-TEM images of (R)-CuTAPBN-COF
with the region marked by the red square at a higher resolution.
The N2 absorption amount of (R)-CuTAPBN-COF at 77 K
is 196.6 cm3 g-1, and the corresponding surface area on basis
of BET model is 412.7 m2 g-1 (Figure S1g). The pore-size
distribution by nonlocal density functional theory (NLDFT)
analysis indicates that it possesses the narrow pore diameter
distribution centered at ~2.3 nm (Figure S1g inset). Owing to
the existence of (R)-BINOL, (R)-CuTAPBN-COF is optically
active and displays positive Cotton effect at 220 and 435 nm,
and negative dichroic signal at 265 nm in its CD spectrum
(Figure 3). In addition, the intense band at 419 nm, together
with the weak bands between 539-572 nm, in its UV-vis
spectrum demonstrates that the visible-light adsorption of Cu-
TAPP is well retained in (R)-CuTAPBN-COF (Figure S1h).
In addition, (R)-CuTAPBN-COF is stable against water, acid
and base, which was verified by the measured PXRD patterns
(Figure S1i).
Scanning electron microscopy (SEM) was used to visualize
the as-synthesized (R)-CuTAPBN-COF, and its particle
morphology was observed (Figure S1a). Thermogravimetric
analysis (TGA) indicated that (R)-CuTAPBN-COF remained
intact till temperature over 250°C (Figure S1b). In addition,
the existence of imine-connected Cu-TAPP and (R)-BINOL in
(R)-CuTAPBN-COF were directly evidenced by the IR
(Figure S1c) and 13C CP-MAS (Figure S1d) spectra.
The crystal structure of (R)-CuTAPBN-COF was elucidated
using PXRD (Figure 2a) by Materials Studio software (ver.
2018). The most probable structure was established, analogous
to that of HCCOF as a 2D staggered layered-sheets using the
chiral space group of C2 with the optimized parameters of a =
49.52, b = 33.72 and c = 15.30 Å; α = γ = 90°, β = 104.5°
(residuals Rwp = 2.15% and Rp = 3.03%, Table S1). The first
intense peak in the PXRD pattern at 3.2° (2θ), which
corresponds to the (110) reflection plane, along with a series
of weak peaks at 5.3°, 6.4°, 8.1°, 9.4° and 11.9°, attributed to
the (020), (220), (130), (221) and (002) reflection planes,
respectively. The difference plot indicates that PXRD obtained
through Pawley refinement well reproduces the experimental
pattern (Figure 2a). The structural modeling shows that the
Cu-TAPP is linked together via (R)-BINOL into a 2D net
extended in the crystallographic ab plane with rhombus-like
pore, in which the shortest opposite C···C distances are ~2.5
and 4.0 nm, respectively (Figure 1). These nets are further
linked together via interlayer Cl···H-C (dC-H = 1.914 Å,
Cl···H-C = 131.99) bonds (Figure S1e) into an AB-stacking
model to form the slightly reduced channels (~2.2 nm) along
The major advantage of (R)-CuTAPBN-COF is that the
Lewis acid (Cu(II)),15 chiral templating ((R)-BINOL) and
photothermal conversion (Cu-TAPP) species are logically
integrated on the HCCOF-platform, so its catalytic asymmetric
synthesis of (S)-CIK via Strecker reaction under visible-light
irradiation is highly expected.
The yield and enantiomeric excess (ee) for (R)-CuTAPBN-
COF-catalyzed (S)-CIK synthesis, together with a series of
control experiments, are displayed in Table 1 (entries 1-12).
The catalytic reactions were performed under various
conditions, including different solvents (entries 1-3), and
catalysts with or without visible-light irradiation and heating
(entries 4-12). The best result was obtained when the reaction
was conducted in CH3CN with (R)-CuTAPBN-COF (10 mg,
2.1 mol% Cu equiv) upon visible-light (λ = 420 nm)
irradiation for 3h (entry 1). The desired (S)-CIK was
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generated in 98% yield (TON = 46.7, TOF = 15.6 h-1) with
1
94% ee. The measured reaction solution temperature was
~50C under the given conditions, implying that the Cu-TAPP
involved (R)-CuTAPBN-COF is an effective photothermal
conversion material even at catalytic amount. Also, when the
reaction was performed in CH3CN with a lower catalyst
loading (1.0 mol% Cu), the product was generated in lower
90% yield (92% ee) (entry 4). However, more catalyst loading
(3.0 mol% Cu) did not afford higher yield (98%) and ee (95%)
(entry 5). Notably, when the reaction was performed at 50C
in dark, (S)-CIK was obtained in 98% yield with 92% ee
(entry 6). Furthermore, no product was detected once the
reaction was conducted in the dark at room temperature within
3 h (entry 7). All these results unambiguously demonstrated
that this HCCOF-promoted reaction herein is a thermally-
driven reaction.15 In the cases of copper-free (R)-TAPBN-
COF (entries 8 and 9), only modest yields (17 and 18%) but
with high enantioselectivity (93 and 95% ee) were observed
under irradiation or heating condition, implying that the
HCCOF-framework and the embedded Cu(II) are separately
responsible for the chiral confinement effect and catalytic
function, which was further supported by the cases of Cu-
TAPP monomer (entry 10), Cu(OAc)2 (entry 11) and the
mixture of Cu-TAPP and (R)-BNOL (molar ratio of 1:2)
(entry 12). Therefore, the confined environment, together with
the active metal catalytic center, might afford the suitable
compromise in enantioselectivity and yield for the chiral α-
aminonitrile formation under elevated temperature.16
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yield
EN
1
catalyst
solvent
CH3CN
PhMe
T (C)/hv
r.t./hv
(ee) %b
(R)-CuTAPBN-COF
(2.1 mol Cu %)
98 (94)
63 (90)
45 (87)
90 (92)
98 (95)
98 (92)
- (-)
(R)-CuTAPBN-COF
(2.1 mol Cu %)
2
r.t./hv
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(R)-CuTAPBN-COF
(2.1 mol Cu %)
3
EtOH
r.t./hv
(R)-CuTAPBN-COF
(1.0 mol Cu %)
4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
r.t./hv
(R)-CuTAPBN-COF
(3.0 mol Cu %)
5
r.t./hv
(R)-CuTAPBN-COF
(2.1 mol Cu %)
6
50C/dark
r.t./dark
r.t./hv
(R)-CuTAPBN-COF
(2.1 mol Cu %)
7
(R)-TAPBN-COF (2.1
8
17 (95)
18 (93)
mol %)
(R)-TAPBN-COF (2.1
9
50C/dark
mol %)
Cu-TAPP monomer (2.1
mol %)
10
11
CH3CN
CH3CN
CH3CN
r.t./hv
r.t./hv
r.t./hv
81 (-)
85 (-)
94(32)
Cu(OAc)2 (2.1 mol Cu %)
What's particularly intriguing is that the reaction could
effectively proceed even under the natural sunlight irradiation
(reaction solution temperature, ~47C), and (S)-CIK was
obtained in 70% yield with 92% ee within 3h (Table 1, entry
13). This provides a strong fundament for the future
Cu-TAPP (2.1 mol Cu %)
12c
and (R)-BNOL
(R)-CuTAPBN-COF
(2.1 mol Cu %)
13
CH3CN
r.t./sunlight
70 (92)
a Reaction conditions: catalyst, 2-chlorobenzaldehyde (56 μL, 0.5
mmol), 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (59 μL, 0.5 mmol),
trimethylsilyl cyanide (70 μL, 0.55 mmol), CH3CN (1.5 mL), 300
W xenon with a power density of 2.5 W cm-2 (λ = 420 nm), 3h, in
development
of
HCCOF-based
and
solar-powered
endothermic asymmetric catalysis.
The subtle chiral confinement of (R)-CuTAPBN-COF was
explored by preliminary molecular modeling studies. The
calculations show that the initially formed iminium
intermediate is restrained in the HCCOF pore by multiple C-
H···X (X = F and O) H-bonds, and only the iminium with
conformation tending to (S)-CIK can form the energy-
favorable host-guest system (Figure S3), which allows the
subsequent nucleophilic addition of CN- to the carbonium ion
of iminium along the pathway being lowered in energy and
steric hindrance, consequently, generating the (S)-CIK with
high optical purity.
air. Product structure was determined by 1H NMR and MS
b
spectra (Figures S2a-b), yield was determined by the GC on HP-5
column, and ee was determined by HPLC with a Chiralcel OD-H
column (90 : 10 = n-hexane : isopropanol, 0.8 mL min-1, 247 nm)
c
(Figure S2c). Mixture of Cu-TAPP (2.1 mol Cu %) and (R)-
BNOL with a molar ratio of 1:2.
To further evaluate the photothermal conversion of (R)-
CuTAPBN-COF, the visible-light induced temperature
increase (ΔT) was examined. When the reaction system of
CH3CN (1.5 mL)-HCCOF (10 mg) was irradiated with visible-
light (λ = 420 nm, 2.5 W cm-2) for 18 min., a significant
temperature increase of 25C was observed (Figure 4). As it is
known, the paramagnetic metal ions inserted porphyrins can
drastically decrease their excited-state lifetimes, thus
funneling excited states into nonradiative decay pathways and
quenching the porphyrin photochemistry intramolecularly,
thereby causing the nonfluorescent (R)-CuTAPBN-COF to
completely act in the photothermal mode, regardless of the
state of the supramolecular system.17-19 As a result, we
concluded that the metalloporphyrin and chiral BIONL
involved HCCOF herein is a multifunctional asymmetric
catalytic material that is endowed with catalysis, chiral
templating, and photothermal conversion functionalities.
In contrast, when the reaction was performed with (S)-
CuTAPBN-COF (Figure S4 and Table S2), (R)-CIK was
correspondingly obtained in 97% yield with 93% ee under the
same conditions (Figure 3 and Figure S5). This suggests that
we can consciously control the product enantioselectivity by
finely tuning the HCCOF chirality, consequently achieving
enantiopure product purposefully. Of note, the catalytic center
and the chirality control herein are not on the same molecular
entity, resembling what is happening in an enzyme pocket.
Table 1. Optimization of (R)-CuTAPBN-COF-Catalyzed
Synthesis of (S)-CIK via Strecker Reactiona
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Gong-Jun Chen − College of Chemistry, Chemical Engineering
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and Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, P. R. China; Email: gongjchen@126.com
Yu-Bin Dong − College of Chemistry, Chemical Engineering and
Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, P. R. China; orcid.org/0000-0002-9698-8863; Email:
yubindong@sdnu.edu.cn
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Authors
Hui-Chao Ma − College of Chemistry, Chemical Engineering
and Materials Science, -Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, P. R. China
Fang Huang − College of Chemistry, Chemical Engineering
and Materials Science, Collaborative Innovation Center of
Functionalized Probes for Chemical Imaging in Universities of
Shandong, Key Laboratory of Molecular and Nano Probes,
Ministry of Education, Shandong Normal University, Jinan
250014, P. R. China
Figure 4. Photothermal behavior of (R)-CuTAPBN-COF (10
mg) in CH3CN (1.5 mL).
The hot leaching test verified that (R)-CuTAPBN-COF is a
typical heterogeneous catalyst (Figure S6), as such, it could be
reused, and its catalytic yield was even up to 95% with 91% ee
after five catalytic runs without loss of its structural integrity
and crystallinity (Figure S6). Encouraged by the viability of
the (R)-CuTAPBN-COF-catalyzed (S)-CIK synthesis, we
then designed a model continuous flow-through setup for its
gram-scale preparation.20-23 This would allow overcoming the
issues associated with batch operation in practical drug and
drug intermediate production. Much to our delight, the
asymmetric Strecker reaction by continuous flow-through
operation proceeded smoothly under visible-light irradiation
and gave a 90% yield (1.29 g) with 93% ee for (S)-CIK in 8h
(Figure S7).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support from NSFC (Grant Nos.
21971153 and 21671122), Chang-Jiang Scholars Program of
China, Taishan Scholars Construction Project of Shandong
Province, and Shandong Provincial Natural Science Foundation
(No. ZR2018MB005).
REFERENCES
The generality of (R)-CuTAPBN-COF-catalyzed Strecker
reaction was supported by utilizing various substrates (Figures
S8-S9). The different aldehydes and secondary amines
provided good-to-excellent yields with excellent ee values
except those large-sized substrates, implying that the Strecker
reaction herein is an internal surface catalytic process.
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ASSOCIATED CONTENT
Supporting Information. Instruments and methods; synthesis
and additional characterization of (R)- and (S)-CuTAPBN-COF;
catalytic products characterization; Continuous flow-through
operation; molecular modeling studies; crystallographic
information for COFs (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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Abdi, S. H. R.; Bajaj, H. C. Modified Asymmetric Strecker Reaction
of Aldehyde with Secondary Amine: A Protocol for the Synthesis of
AUTHOR INFORMATION
Corresponding Author
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