Visible-Light-Promoted Biomimetic Reductive Functionalization of Quaternary Benzophenanthridine Alkaloids

Article abstract of DOI:10.1021/acs.jnatprod.1c00512

Reduction of an iminium C=N double bond is the most important phase I metabolism process associated with the cytotoxic property of quaternary benzophenanthridine alkaloids (QBAs). Inspired by the light-mediated reduction of QBAs with nicotinamide adenine dinucleotide, a visible-light-promoted reductive functionalization reaction of QBAs is reported in this study. C4-Alkyl-1,4-dihydropyridines (DHPs) enable the direct reductive alkylation of QBA independently, serving as both single-electron-transfer reductant reagents under irradiation with 455 nm blue light in the absence of photocatalysts and additional additives. Our protocol can be further applied to the semisynthesis of natural 6-substituted dihydrobenzophenanthridine derivatives such as O-acetyl maclekarpine E.

Full text of DOI:10.1021/acs.jnatprod.1c00512

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Note
Visible-Light-Promoted Biomimetic Reductive Functionalization of
Quaternary Benzophenanthridine Alkaloids
#
#
Lin Wang, Xinhao Wang, Wei Wang, Wei Liu, Yisong Liu, Hongqi Xie, Oliver Reiser, Jianguo Zeng,*
and Pi Cheng*
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sı Supporting Information
ABSTRACT: Reduction of an iminium CN double bond is the
most important phase I metabolism process associated with the
cytotoxic property of quaternary benzophenanthridine alkaloids
(
QBAs). Inspired by the light-mediated reduction of QBAs with
nicotinamide adenine dinucleotide, a visible-light-promoted
reductive functionalization reaction of QBAs is reported in this
study. C4-Alkyl-1,4-dihydropyridines (DHPs) enable the direct
reductive alkylation of QBA independently, serving as both single-
electron-transfer reductant reagents under irradiation with 455 nm
blue light in the absence of photocatalysts and additional additives.
Our protocol can be further applied to the semisynthesis of natural
6
-substituted dihydrobenzophenanthridine derivatives such as O-
acetyl maclekarpine E.
minium ions are common structural elements in natural
NADH, a naturally existing 1,4-dihydropyridine derivative,
primarily serves as a hydride ion or electron provider
(E(NADH /NADH) = 0.76 V vs SCE). When excited by
I
products including quaternary benzophenanthridine-type
1
•+
alkaloids, such as sanguinarine (1, Scheme 1), which exhibit
interesting cytotoxic properties such as inducing oxidative
light irradiation, NADH can also be employed as a potent
2
−4
11
DNA damage and rapid apoptosis.
The reduction of the
single-electron reductant. We speculated that light irradiation
CN double bond represents the most important phase-I
on the mixture of sanguinarine (1) and NADH probably
triggers the single-electron (SET) reduction of sanguinarine
5
−8
metabolic process of this kind of alkaloids in cells
and the
9
(
1), which leads to the generation of a persistent α-amino C-
detoxification process in sanguinarine-containing plants.
Sanguinarine reductase (SR), a nicotinamide adenine
dinucleotide (NADH)-dependent reductase, is a plant enzyme
that prevents the cytotoxic effects of quaternary benzophenan-
radical (5). A self-coupling reaction of radical 5 leads to the
formation of dimer 4. Meanwhile, radical 5 abstracts a
hydrogen atom from the oxidized NADH• via a hydrogen
atom transfer (HAT) procedure, thus giving dihydronsangui-
narine (2).
+
9
thridine alkaloids, the main phytoalexins of Papaveraceae.
This enzyme catalyzes the reduction of sanguinarine (1)
Scheme 1 A) to dihydrosanguinarine (2), a toxic
The discovery of visible-light-mediated reduction of
sanguinarine by NADH in the absence of photocatalysts
stimulated our research interest in the exploration of Hantzsch
esters, a kind of synthetic 1,4-dihydropyridine derivatives
(
benzophenanthridine, which re-enters the cytoplasm after its
primary accumulation in the cell wall region has reached a
threshold concentration. Interestingly, it was also documented
that sanguinarine could be directly reduced by NADH in the
•
+
(
DHPs, 6, Scheme 2), as SET reductants (E(DHP /DHP) =
11
10
1.03 V vs SCE). Compared with NADH, DHPs are easily
accessible from aldehydes. Especially when an alkyl group is
absence of protein enzymes (Scheme 1B). A covalent adduct
3) between sanguinarine (1) and NADH is formed via an ene
(
+
installed on the 4-position of DHPs, the HAT process between
reaction and then converted slowly to NAD and dihydro-
sanguinarine (2) in high yield. During our ongoing research on
the reductive metabolism of sanguinarine, we were curious to
find that a dihydrosanguinarine dimer (4) was detected as a
byproduct when a mixture of sanguinarine (1) and NADH was
stirred under the irradiation of 455 nm blue light (Scheme
+
5
and DHPs• will be prevented to a certain extent. Actually,
Received: May 28, 2021
1
C). The generation of a dihydrosanguinarine dimer obviously
points to a switch of the mechanism that differs from the ene
reaction pathway.
©
XXXX American Chemical Society and
American Society of Pharmacognosy
https://doi.org/10.1021/acs.jnatprod.1c00512
A
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Note
Scheme 1. Reduction of Sanguinarine to
Dihydrosanguinarine without and with Blue Light
Irradiation and Possible Mechanism
MeOH as solvent under the irradiation of a 455 nm blue LED
(entries 1, 2, Table 1), DMSO furnished the desired 6-
benzyldihydrosanguinarine 7a in 57−63% yield (entries 3, 4).
Interestingly, in the presence of catalytic amounts of common
iridium photocatalysts Ir(ppy) or Ir(ppy) dtbpy·PF , 7a was
3
2
6
obtained in 28% and 30% yields, respectively (entries 5, 6),
suggesting that DHPs directly engage in the single-electron
reductive process of sanguinarine. In line with this reasoning,
compound 7a could not be detected after 24 h of reaction at
room temperature or 60 °C in the absence of visible light
irradiation (entries 7, 8). The reaction was also carried out
open to air, but a lower yield of 7a was observed (entry 9).
With the optimized conditions in hand, we tested DHPs
(
6a−6j) with different alkyl units at the C4-position. Indeed,
both sanguinarine (1) and chelerythrine (8) could be
reductively benzylated using 6a−6e as reductants, giving 7a−
7
e in good yields (Table 2). The reaction was sensitive to
steric effects, resulting in poor yields of compounds 7f and 7ff
when the more bulky 1,1-diphenylmethyl radical was used as
coupling partner. Next, a series of secondary alkyl radicals (6g
and 6h) were used in this reductive coupling reaction,
affording the alkylated products in moderate to good yields.
We also evaluated the reaction efficacy with primary C-radicals
as coupling partners, while the desired compounds were not
detected (6i and 6j).
To further expand the scope of iminium substrates, N-
methyl phenanthridine salt 9, N-methyl isoquinoline salt 10,
and berberine 11 were selected as the coupling partners
(
Scheme 3). Under the “standard” conditions, the reductive
alkylation reaction was observed only with N-methyl
phenanthridine salt 9 as starting material, suggesting that the
+
reduction of the iminium CN bond requires the
phenanthridine core structure. The enamine motif of 13 and
1
4, a highly reductive substructure unit, probably disrupted the
desired radical reaction.
Considering that the fragmentation of 4-phenyl DHP’s
radical cation is obstructed, we attempted to use 4-phenyl
DHP as a single reductant in combination with suitable alkenes
as radical acceptors (Table 3). We were pleased to see that
when a mixture of quaternary benzophenanthridine, 4-phenyl
DHP (6k), and electron-deficient alkenes such as methyl
acrylate (15a), 2-vinylpryridine (15b), or methyl 2-
((phenylsulfonyl)methyl)acrylate (15c) was stirred at room
temperature under irradiation of 455 nm blue light for 24 h,
the desired addition products 16 were indeed obtained. Here,
4-phenyl DHP only serves as a SET reductant, while the
electron-deficient alkenes capture the generated α-amino C-
radical 5 to afford the radical type of Michael addition
products.
•
+
the radical cation DHPs will fragment to pyridine and an
•
12−18
alkyl radical R ,
which can subsequently couple with
19
radical 5, in line with the persistent radical effect of 5. This
strategy would provide the means to achieve photoinitiated
reductive alkylation of iminium cations and give 6-substituted
dihydrobenzophenanthridine alkaloids (7, Scheme 2). Notably,
-substituted dihydrobenzophenanthridine alkaloids are found
to naturally exist in many medicinal plants such as Macleaya
6
2
0
21
22
cordata, Macleaya macrocarpa, and Zanthoxylum nitidum.
Based on the 4-phenyl DHP-mediated reductive addition
reaction, further application of the current protocol in the
semisynthesis of natural 6-substituted dihydrobenzo-
For the optimization of the reaction conditions, we chose
sanguinarine (1) as a model substrate in combination with 4-
Bn-DHP (6a). While poor yields were obtained using DMF or
21
phenanthridine alkaloid maclekarpine E was evaluated. As
Scheme 2. Visible-Light-Triggered Reductive Functionalization of Quaternary Benzophenanthridine Alkaloids
B
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Note
a
Table 1. Optimization of Reaction Parameters
R5 on DHP 6a
yield of 7a (%)
b
entry
solvents
photocatalyst
1
2
3
4
5
6
DMF
Et
Et
Et
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
trace
5
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
57
63
28
30
0
Ir(ppy)3
Ir(ppy) dtbpy·PF6
2
c
7
8
d
0
43
9
a
b
Experiments were performed with 1 (0.2 mmol), 6a (2 equiv), photocatalyst (2 mol %), and solvent (2 mL) under an atmosphere of N ; Isolated
2
c
d
yields. In the dark. In the dark at 60 °C.
shown in Scheme 4, with 3-methoxy-4-hydroxybenzaldehyde
cannot be activated by 455 nm blue light. On the basis of our
experimental results, we envision the mechanistic scenario as
shown in Scheme 6. EDA complex 22 is first formed between
6a and quaternary salt 1. Upon excitation by 455 nm blue light,
complex 22 undergoes a SET process leading to the reduction
of sanguinarine (1) to α-amino C-radical 5 and the oxidation
(17) as starting material, β-3-methoxyl-4-acetoxyphenyl vinyl
sulfone (20) was first synthesized as radical acceptor. Using 4-
phenyl DHP (6k) as SET reductive reagent, a visible-light-
triggered radical addition/elimination reaction occurred
smoothly to give O-acetylmaclekarpine E (21) in 36% yield.
To gain the insight into the light-mediated reductive-
alkylation of quaternary benzophenanthridines, we performed
UV−vis spectroscopic measurements on 1, 6a, and the
combination of 1 and 6a in DMSO (Scheme 5A), since we
suspected the formation of an electron-donor−acceptor
•
+
•+
of DHP to DHP . Subsequently, the radical cation DHP
•
4
fragments to tetrasubstituted pyridine and alkyl radical R .
•
4
When R is secondary or benzylic, it will couple with α-amino
C-radical 5, giving rise to 7. Considering the unique
electrochemical properties of sanguinarine (1) already shown
in Scheme 5D, blue light irradiation of sanguinarine also
accelerates its SET reduction. It is also worth noting that
dihydrosanguinarine is detected as a byproduct during the
synthesis of 6-substituted dihydrobenzophenanthridines due to
(
EDA) complex, 22 (Scheme 5B), between 6a and quaternary
23−25
salts 1. According to the literature,
the EDA complex can
enable the direct SET oxidation of donor and reduction of
acceptor, respectively. Visible light irradiation could trigger the
SET reduction of a quaternary benzophenanthridine salt to α-
amino C-radical 5 under catalyst-free conditions. Under UV−
vis light, we observed an absorption peak at 455 nm and tail
absorption at 425 nm for sanguinarine (1) and DHP (6a),
respectively. UV−vis analysis of combined 1 and 6a showed
red-shifts and increased absorbance at 455 nm compared with
two substrates, indicating the suggested formation of an EDA
complex (Scheme 5A). Since sanguinarine (1) can absorb at
λmax 455 nm, we also recorded the emission spectra of 1 upon
excitation at 455 nm. As illustrated in Scheme 5C, there was a
dominant peak with a maximum at 570 nm in the emission
spectra of 1.
•
+
the HAT process between radical 5 and DHP . This HAT
•
4
process is more obvious when R on DHP is nonbenzylic or
•
+
secondary, as the fragmentation of DHP is more difficult.
The HAT process between DHP• and radical 5 finally gives
rise to aromatic 4-substituted pyridine and dihydrosanguinar-
ine (see Supporting Information).
+
In summary, we have described a biomimetic reductive
alkylation reaction of quaternary benzophenanthridine alka-
loids to prepare 6-substituted dihydrobenzophenanthridines.
DHPs were demonstrated to have the ability of serving as both
SET reductants and alkylation reagents in the absence of
photocatalyst and additional oxidants. Importantly, DHPs,
which are normally water-insensitive and easily accessible from
aldehydes, eliminate the drawbacks associated with organic
metal compounds as nucleophilic alkylation reagents in
Fluorescence characteristics of sanguinarine (1) suggested
that the redox potential of sanguinatine might change when
excited by 455 nm blue light. To verify this hypothesis, the
cyclic voltammetry analysis of sanguinarine (1) was performed
under the irradiation of 455 nm blue light. As illustrated in
Scheme 5D, the reduction potential of 1 slightly shifted to
higher potential compared with its cyclic voltammogram in the
dark, which indicated that the 455 nm blue light irradiation
could also facilitate the SET reduction procedure of
sanguinarine (1).
29
preparation of complex amines. The mild reaction conditions
developed in this study will enable the semisynthesis of
complex and biologically active natural 6-substituted
dihydrobenzophenanthridine alkaloids from medicinal plants.
EXPERIMENTAL SECTION
General Experimental Procedures. Column chromatography
silica gel (200−300 mesh) and TLC plates were purchased from
Qingdao Meijin Chemical Inc. (Qingdao; China); HRMS data were
■
26−28
On the basis of previous literature,
photoexcited DHP*
could also act as a SET reductant independently (E *
1
red
-
obtained in the ESI mode on an Agilent 6530 Q-TOF/MS system. H
•
+
1
3
(
DHP*/DHP ) = −2.2 V vs SCE). However, 4-Bn-DHP
6a) only has a tail absorption at 425 nm, indicating that 6a
NMR and C NMR spectra were recorded on a Bruker 400 MHz
(
spectrometer, and chemical shifts were given in δ with TMS as an
C
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Note
a
Table 2. Scope of 1,4-Dihydropyridines
D
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Note
Table 2. continued
a
Experiments were performed with 1 or 8 (0.2 mmol), 6 (2.0 equiv), and DMSO (2 mL) under an atmosphere of N under the irradiation of 455
2
b
nm blue light. Isolated yields.
Scheme 3. Further Screening of Iminium Salts
internal reference. Sanguinarine (1) and chelerythrine (8) were
isolated from Macleaya cordata in our lab. Cyclic voltammetry
measurements were done on a CHI 660E electrochemical workstation
μM) in a 1 cm quartz cuvette. Fluorescence spectra were obtained
with a Shimadzu RF-6000 spectrofluorophotometer in DMSO (5
μM) in 1 cm quartz cuvettes.
30
(
Chenhua, Shanghai, China) using a glassy carbon electrode as
Procedure for Synthesis of 4-Alkyl DHPs 6. t-Butyl
acetoacetate (3.16 g, 20 mmol) (or methyl acetoacetate and ethyl
acetoacetate), aldehyde (10 mmol), ethanol (20 mL), and an
ammonia aqueous solution (4.0 mL, 28%, 60 mmol) were added to
a 50 mL flask equipped with a condenser. The mixture was heated at
70 °C for 8 h and then allowed to cool to room temperature. The
reaction solution was concentrated under reduced pressure. A 50 mL
working electrode and a graphite rod as counter electrode. A saturated
calomel electrode (SCE) was used as reference electrode, and a 0.1 M
solution of tetrabutylammonium tetrafluoroborate was applied as
supporting electrolyte. The scan rate was set to 100 mV/s. The
applied solvents are specified in the descriptions of the corresponding
experiments. Absorption spectra were obtained on a Shimadzu UV-
1
280 UV/vis spectrometer. All spectra were recorded in DMSO (5
amount of H O was added to the concentrated residue, and the
2
E
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Note
a
Table 3. 4-Phenyl DHP-Mediated Reductive Addition Reactions
a
Experiments were performed with 1 or 8 (0.2 mmol), 6k (2 equiv), 15 (3.0 equiv), and DMSO (2 mL) under an atmosphere of N under the
2
b
irradiation of 455 nm blue light. Isolated yields.
a
Scheme 4
a
Reaction conditions: (a) 6.0 equiv of Ac O, pyridine, rt, 12 h; (b) 1.5 equiv of CH PPh Br, 2.0 equiv of K CO , THF, reflux 4 h; (c) 3.0 equiv of
2
3
3
2
3
PhSO Na, 1.5 equiv of NaOAc, 1.5 equiv of I , MeCN reflux 1 h.
2
2
aqueous layer was subsequently extracted with CH Cl (50 mL) three
chromatography eluted with PE/EA (10:1 v/v) to give 4-alkyl DHPs
2
2
times. The combined organic layers were washed with brine, dried
6.
with anhydrous MgSO , and filtered. The filtrate was concentrated
Procedure for Synthesis of 6-Substituted Dihydrobenzo-
4
under reduced pressure. The residue was purified by silica gel
phenanthridines 7. A Schlenk tube equipped with a magnetic stir
F
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Note
Scheme 5. (A) Optical Absorption Spectra of Sanguinarine (1), 6a, and the Combination Solution of 1 and 6a in DMSO (5
μM); (B) EDA Complex 17; (C) Emission Spectra of Sanguinarine upon Excitation at 455 nm in DMSO (5 μM); (D) Cyclic
Voltammogram of Sanguinarine (1) and the Related SET Redox Procedure
times. The combined organic layer was then washed with 20 mL of
Scheme 6. Putative Mechanism for Reductive Alkylation of
Quaternary Benzophenanthridines
H O three times and evaporated, to give a crude product, which was
2
purified by silica gel chromatography and eluted with PE/EA to give
target compounds 7.
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.jnatprod.1c00512.
■
*
HPLC-HR-MS spectra of blue-light-promoted reduction
of sanguinarine by NADH, HPLC-HR-MS spectra of
blue-light-promoted reduction of sanguinarine 6j, photo-
1
reactor and general procedure for photoreaction, and H
1
3
and C NMR data and spectra of compounds 7, 12, and
6−21 (PDF)
1
AUTHOR INFORMATION
Corresponding Authors
■
Jianguo Zeng − Hunan Key Laboratory of Traditional
Chinese Veterinary Medicine and College of Veterinary
Medicine, Hunan Agricultural University, Changsha, Hunan
bar (Figure S3) was charged with 0.2 mmol of quaternary
benzophenanthridine 1 or 8, 2.0 equiv of a 6-substituted DHP 6,
4
10128, China; Phone: +86-731-84673824;
and 2 mL of DMSO under a N atmosphere. The flask was sealed by a
2
Email: zengjianguo@hunau.edu.cn
plastic screw-cap with a Teflon-sealed inlet for a glass rod. A high-
power LED (λ = 455 nm) was attached to the top of the glass rod,
which then could act as an optical fiber. After irradiation at room
temperature for 24 h, the LED was removed, and the solvent was
Pi Cheng − Hunan Key Laboratory of Traditional Chinese
Veterinary Medicine and College of Veterinary Medicine,
Hunan Agricultural University, Changsha, Hunan 410128,
China; orcid.org/0000-0003-2385-9945; Phone: +86-
poured in 20 mL of H O and extracted with 20 mL of EtOAc three
2
G
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31-84673824; Email: picheng@hunau.edu.cn,
pubs.acs.org/jnp
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Veterinary Medicine, Hunan Agricultural University,
Changsha, Hunan 410128, China
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Changsha, Hunan 410128, China
Wei Wang − Hunan Key Laboratory of Traditional Chinese
Veterinary Medicine, Hunan Agricultural University,
Changsha, Hunan 410128, China
Wei Liu − Hunan Key Laboratory of Traditional Chinese
Veterinary Medicine and College of Veterinary Medicine,
Hunan Agricultural University, Changsha, Hunan 410128,
China
Yisong Liu − Hunan Key Laboratory of Traditional Chinese
Veterinary Medicine and College of Veterinary Medicine,
Hunan Agricultural University, Changsha, Hunan 410128,
China
Hongqi Xie − College of Veterinary Medicine and Hunan Key
Laboratory of Traditional Chinese Veterinary Medicine,
Hunan Agricultural University, Changsha, Hunan 410128,
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Oliver Reiser − Institut fu
Regensburg, 93053 Regensburg, Germany; orcid.org/
000-0003-1430-573X
̈
r Organische Chemie, Universität
(
0
(
2
(
Complete contact information is available at:
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Author Contributions
(
#
L.W. and X.W. contributed equally to this work.
(
Notes
The authors declare no competing financial interest.
(
2
(
ACKNOWLEDGMENTS
■
Cheng, P.; Zheng, Y.; Yuan, Z.; Zhou, Y.; Liu, J.; Tang, Z.; Zhuo, Y.;
Zhang, Y.; Yu, L.; Huang, J.; Yang, P.; Peng, Q.; Zhang, J.; Jiang, W.;
Zhang, Z.; Lin, K.; Ro, D.-K.; Chen, X.; Xiong, X.; Shang, Y.; Huang,
S.; Zeng, J. Mol. Plant 2017, 10, 975−989.
This research was financially supported by Changsha
Municipal Natural Science Foundation (No. kq2014064), the
Scientific Research Fund of Hunan Provincial Education
Department (No.18B106), and the China Agriculture
Research System (No. CARS-21).
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