Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization

Article abstract of DOI:10.1002/ange.202009399

We report herein a nonbiomimetic strategy for the total synthesis of the plicamine-type alkaloids zephycarinatines C and D. The key feature of the synthesis is a stereoselective reductive radical ipso-cyclization using visible-light-mediated photoredox ca

Full text of DOI:10.1002/ange.202009399

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Titel: Total Synthesis of Zephycarinatines via Photocatalytic Reductive
Radical ipso-Cyclization
Autoren: Haruka Takeuchi, Shinsuke Inuki, Kohei Nakagawa, Takaaki
Kawabe, Atsuhiko Ichimura, Shinya Oishi, and Hiroaki Ohno
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Zitierweise: Angew. Chem. Int. Ed. 10.1002/anie.202009399
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
Total Synthesis of Zephycarinatines via Photocatalytic Reductive
Radical ipso-Cyclization
Haruka Takeuchi, Shinsuke Inuki,* Kohei Nakagawa, Takaaki Kawabe, Atsuhiko Ichimura, Shinya
Oishi, and Hiroaki Ohno*
Abstract: We report herein a nonbiomimetic strategy for the total
synthesis of the plicamine-type alkaloids, zephycarinatines C and D.
The key feature of the synthesis was the stereoselective reductive
radical ipso-cyclization using visible-light-mediated photoredox
catalysis. This cyclization enabled the construction of a 6,6-spirocyclic
core structure by the addition of the carbon-centered radical onto the
aromatic ring. The biological evaluation of zephycarinatines and their
derivatives revealed that the synthetic derivative having a keto group
displayed moderate inhibitory activity against LPS-induced NO
production. This approach would offer future opportunities to expand
the chemical diversity derived from plicamine-type alkaloids as well
as provide useful intermediates for their syntheses.
(Scheme 1, route a),[4] which is similar to how it is formed from
knowledge of its biosynthetic pathway.[1] As part of an ongoing
program toward the synthesis of biologically active alkaloids,[5] we
designed a nonbiomimetic synthetic strategy for zephycarinatines
C (1a) and D (1b) through the creation of a quaternary carbon via
a different manner from the biosynthesis (nonbiomimetic route;
route b),[6] which would possibly expand their analog diversity. To
achieve this purpose, we planned a photocatalytic reductive
radical ipso-cyclization onto the aromatic rings as the key reaction,
enabling direct access to the 6,6-spirocyclic core structure of the
zephycarinatines (1).
Introduction
Amaryllidaceae alkaloids are structurally diverse natural
products
possessing
various
biological
activities.[1]
Zephycarinatines (1) were isolated from Zephyranthes carinata
Herbert (Amaryllidaceae) by Yao et al. in 2017 (Scheme 1).[2]
Their structure is classified as a plicamine-type alkaloid that has
a 6,6-spirocyclic core structure with multiple stereogenic centers.
As
a
structural
analog,
zephygranditines
including
zephygranditine A (2) have been reported (Scheme 1). Some of
the plicamine-type alkaloids and their derivatives show important
biological activities. For example, zephygranditines exhibit
cytotoxic properties against a variety of cancer cell lines, and anti-
inflammatory activities according to the inhibitory effects on LPS-
induced NO production.[3] In contrast, the detailed biological
activities of zephycarinatines (1) have not been reported.
Scheme 1. Structures of Zephycarinatine, Zephygranditine and Plicamine, and
Strategy for the Synthesis of Zephycarinatines
Owing to their biological importance and structural appeal,
these alkaloids have been the target of many synthetic studies.[1a,
1c] Whereas the total syntheses of zephycarinatines (1) have not
been accomplished, some groups have reported the total
synthesis of plicamine (3),[4] which has a p-hydroxyphenethyl
group on the nitrogen atom in the B-ring and a methoxy group on
the C-ring with the opposite configuration to the zephycarinatines.
One of the keys to the synthesis of zephycarinatines is the
construction of a quaternary carbon in the center of the core
scaffold. In the reported total synthesis of plicamine (3), its
quaternary carbon center was formed by an intramolecular
oxidative coupling reaction between electron-rich aromatic rings
Scheme 2. Oxidative and Reductive Radical ipso-Cyclization
The radical ipso-cyclization, classfied as either an oxidative
or a reductive type, has emerged as an attractive tool for the
synthesis of spirocycles (Scheme 2).[7] Various useful methods
have been reported for the oxidative cyclization,[7] which is
represented by Curran’s work involving the cyclization of an aryl
radical at the ipso-position of a p-O-aryl-substituted benzamide.[8]
By comparison, research into reductive radical ipso-cyclization is
relatively limited.[9] Our group developed a samarium(II)-mediated
reductive ipso-cyclization via an intramolecular ketyl radical
addition onto aromatic rings.[9d, 9e] During the course of this study,
Yoshimi et al. reported an intramolecular ipso-cyclization through
photoinduced electron transfer-promoted decarboxylation of
amino acid derivatives bearing an N-(2-phenyl)benzoyl group.[9h]
More recently, Jui developed a photocatalytic dearomative
[*]
H. Takeuchi, Prof. Dr. S. Inuki, K. Nakagawa, T, Kawabe, Dr. A.
Ichimura, Prof. Dr. S. Oishi, Prof. Dr. H. Ohno
Graduate School of Pharmaceutical Sciences
Kyoto University
Sakyo-ku, Kyoto 606-8501 (Japan)
E-mail: sinuki@pharm.kyoto-u.ac.jp, hohno@pharm.kyoto-u.ac.jp
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
Scheme 3. Retrosynthetic Analysis of Zephycarinatines
hydroarylation triggered by an aryl halide reduction.[9j] However,
despite their utility, their application to total synthesis still remains
a challenge, presumably because of the difficulty in carrying out
stereoselective ipso-cyclization using substrates congested with
functional groups.
prepared from L-serine and biphenyl carboxylic acid 8 as starting
materials.
We focused on visible-light-mediated decarboxylation of
amino acid derivatives for stereoselective ipso-cyclization. The
initial carbon radical generation required for cyclization can be
conducted under mild conditions, only irradiation with an LED
lamp.[10] This approach should facilitate the synthesis of
plicamine-type alkaloids and their analogs featuring substantial
structural and/or electronic variation, because the key radical
cyclization would likely not be limited only to those requiring highly
electron-rich and p-nucleophilic species. In this paper, the total
synthesis of zephycarinatines C and D via nonbiomimetic visible-
light-mediated ipso-cyclization is described. Evaluation of their
inhibitory activity against NO production is also presented.
Scheme 4. Synthesis of the Key Precursor 7.
Results and Discussion
Table 1. Investigation of the Coupling Reaction between 8 and 9
The retrosynthetic strategy for achieving zephycarinatines (1)
is illustrated in Scheme 3. We planned to introduce the R1 group
(nitrogen substituent) at the last stage of the synthetic route to
allow synthesis of a variety of analogs having substituents on the
amide nitrogen. We posited that the methoxy group would be
derived from the carbonyl group of 4. The precursor 4 was
envisaged to result from the oxidation of the 1,4-diene and
subsequent 1,4-addition reaction of the amide 5. The amide 5
could be obtained by functionalization of the hemiaminal 6,
including aminal deprotection, oxidation, and amide formation
with methylamine. We expected that the hemiaminal 6 could be
constructed through the visible-light-mediated radical ipso-
cyclization of carboxylic acid 7. This disconnection represented
the major synthetic challenge in this synthetic route, requiring a
stereoselective ipso-cyclization of the -amino carbon radical
intermediate A generated by the CO2-extrusion of the carboxyl
radical. For this purpose, we designed the oxazolidine substrate
7 having the potential to control the chiral center at the -position,
referring to the self-regeneration of stereocenters (SRS) principle
developed by Seebach et al.[11] The substrate 7 would be
Entry
Condition
Yield of 10 dr[c]
(%)[a][b]
1
2
8, 9, EDC, HOBt, CH2Cl2, rt
ND
ND
8, SOCl2, DMF, CH2Cl2 then 9, NaHCO3,
THF/H2O, 60 °C
3
4
5
6
8, Et3N, MsCl, CH2Cl2 then 9, 0 °C to rt
8, 9, Et3N, CH2Cl2 then MsCl, 0 °C to rt
8, 9, Et3N, CH2Cl2 then Ms2O, 0 °C to rt
8, 9, Et3N, CH2Cl2 then iBuOCOCl, 0 °C to rt
22
66
46
>99:1
>99:1
ND
[a] Isolated yields. [b] ND = not detected. [c] Determined by 1H NMR analysis.
Our preparation of the key precursor 7 for the radical ipso-
cyclization reaction is shown in Scheme 4 and Table 1. Initially,
we investigated the coupling reaction between the known
oxazolidine 9[12] derived from L-serine and the biphenyl-2-
carboxylic acid derivative 8.[13] The reaction using conventional
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
coupling reagents for the amide bond formation, such as EDC, did
not produce the amide 10 (Table 1, entry 1). When the
corresponding acid chloride prepared from 8 was used, the
desired product was not observed (entry 2). Macherla et al.
reported the MsCl-mediated coupling reaction of the oxazolidine
9 with an aliphatic carboxylic acid derivative.[14] Following the
literature procedure, the oxazolidine 9 was added to the reaction
mixture of the carboxylic acid 8 and MsCl to provide the desired
product 10 in low yield (22%, entry 3). After further examination,
we found that the addition of MsCl to the mixture of substrates 8,
9, and Et3N afforded the oxazolidine 10 in 66% yield as a single
diastereomer (entry 4). The preferential production of cis-10 could
be rationalized by the selective acylation of the cis-oxazolidine 9,
resulting from the steric difference between the equiblated cis-
and trans-isomers of 9 via a ring-opened intermediate.[15] The
reaction under these conditions proceeded with sufficient
reproducibility at a multi-gram scale. Changing MsCl to Ms2O or
iBuOCOCl was not effective (entries 5 and 6). Subsequently,
treatment of the ester 10 with LiOH·H2O furnished the key
carboxylic acid 7 (Scheme 4). The relative configuration of 7[16]
was confirmed by X-ray crystallography.
W LED bulb using an EvoluChemTM PhotoRedOx Box (Figure S1).
Treatment of 7 with K2CO3 and [Ir{dF(CF3)ppy}2(dtbpy)]PF6 as a
photoredox catalyst in DMF under irradiation with visible-light (the
known condition for generating a radical intermediate from a
carboxylic acid)[10c] gave a trace amount of the desired product 6
(entry 1). Changing the solvent from DMF to THF or CH2Cl2 did
not enhance the yield of 6 (entries 2 and 3). When MeCN was
used as the reaction solvent, the desired spiro-compound 6 was
obtained in 32% yield as a single diastereomer (entry 4). The
relative configuration of 6[16] was determined by X-ray
crystallography, indicating that the ipso-cyclization occurred from
the sterically less hindered face opposite to the tBu group as
expected. The use of Cs2CO3 or Na2CO3 decreased the yield of 6
(entries 5 and 6). Further optimization revealed that when the
reaction was carried out using two 40 W LED bulbs directly
irradiating the reaction vessel (Figure S2), the desired product 6
was afforded in 58% yield (entry 7). The reaction was amenable
to operation on 300 mg scale to furnish the spiro-compound 6 in
40% isolated yield. We next focused on optimizing the reaction
using a continuous flow reactor that allowed for efficient
conversion, mainly by improving the irradiation efficiency of the
reaction mixture compared with batch processing (Figure S3).[17]
The optimized condition (entry 7) was not suitable for use in flow
reactors because the inorganic base was not completely soluble
Table 2. Investigation of the Reductive Radical ipso-Cyclization of 7
in MeCN. Thus, we examined conditions that provide
a
homogeneous reaction mixture. When a mixed solvent of
MeCN/H2O (10:1) was used, a clear reaction mixture was formed
but the yields of 6 decreased to 31% (entry 8). Using a soluble
base such as TMG instead of K2CO3 provided the desired product
6 in 31% yield. These homogeneous conditions were applied to
continuous flow chemistry (Figure S3). The flow reactions with a
2 h residence time provided 6 in low to moderate yields (entries
10 and 11), while increasing the residence time to 4 h enhanced
the yield to 48% (entry 12). These results would contribute to the
development of further scale-up synthesis.
Entry
Process
Base
Solvent
Time (h)[b] Yield (%)[c][d]
1
2
Batch
Batch
Batch
Batch
Batch
Batch
Batch
Batch
Batch
Flow
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K2CO3
DMF
THF
24
24
24
24
24
24
24
24
24
2
trace
ND
ND
32
With the core spiro-scaffold in hand, we turned our attention
to the construction of the D-ring of zephycarinatine (Scheme 5).
The hemiaminal 6 was converted to the corresponding alcohol in
the presence of TsOH. The oxidation of the alcohol with
AZADOL[18] gave the carboxylic acid, which was treated with
methylamine and EDC to afford the N-methyl amide 5 in 64% yield
in two steps. Our investigation into the oxidation of the 1,4-diene
is summarized in Table 3. Referring to previous reports, we
attempted the oxidation using several oxidants such as
3
CH2Cl2
MeCN
MeCN
MeCN
MeCN
4
5
26
6
trace
58
7[e]
8[e]
9[e]
10
11
12
[20]
tBuOOH/PDC,[19] MnO2 and DDQ,[21] which did not afford the
K2CO3 MeCN/H2O (10/1)
TMG MeCN
K2CO3 MeCN/H2O (10/1)
31
desired product (entries 1–3). On the other hand, the oxidation
with catalytic tetrapropylammonium perruthenate (TPAP)[22]
provided the desired cyclic product 4 as a sole diastereomer
through the oxidation of 1,4-diene followed by intramolecular 1,4-
addition of the N-methyl amide (entry 4). When the reaction was
carried out at room temperature, the imine was observed as the
overoxidation side product. Several investigations revealed that
the desired product 4 was produced in 70% yield by careful
control of the reaction temperature (entry 5). After confirming the
completion of the oxidation of the 1,4-diene at –20 °C, the reaction
temperature was increased to 0 °C to furnish the 1,4-addition to
the ,-unsaturated ketone under a near-neutral condition. The
relative configuration of 4[16] was determined by X-ray
crystallography. In Ley’s synthesis of plicamine,[4a, 4b] the D-ring
formation was accomplished via a stereoselective 1,4-addition
under an acidic condition. In contrast, Miranda et al. reported that
31
22
Flow
TMG
TMG
MeCN
MeCN
2
40
Flow
4
48
[a] The reaction was carried out with irradiation from a 40 W blue LED light using
an EvoluChemTM PhotoRedOx Box. [b] In the cases of a flow reaction, the
residence time is shown. [c] Isolated yields. [d] ND = not detected. [e] 40 W blue
LED (× 2) were used instead of an EvoluChemTM. dF(CF3)ppy = 2-(2,4-
difluorophenyl)-5-(trifluoromethyl)pyridine; dtbpy
bipyridine. TMG = 1,1,3,3-tetramethylguanidine
=
4,4’-di-tert-butyl-2,2’-
Next, we examined the key radical ipso-cyclization reaction
(Table 2). Reactions were carried out under irradiation with a 40
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
a base-mediated 1,4-addition of various related substrates
proceeded with relatively low diastereoselectivity.[4c] These
findings implied that the selectivity for D-ring formation through
1,4-addition could depend mainly on the reaction condition, rather
than the substrate structure.
to the mesylate prepared from the corresponding alcohol and
MsCl.[24] Thus, we conducted the reaction of the alcohol 11 with
MsCl and Et3N. Unfortunately, the undesired chloride was
obtained without producing the corresponding mesylate, probably
because of the substitution of chloride derived from MsCl. Instead,
mesylation of 11 with Ms2O followed by treatment with MeOH was
investigated, resulting in successful incorporation of the methoxy
group with stereoinversion. Without purification, the subsequent
N-alkylation with isopentyl bromide and NaH completed the total
synthesis of zephycarinatine C (1a) in 23% in three steps from 11
with recovery of the precursor 13 in 21% (29% brsm). By changing
the electrophile to MeI, the total synthesis of zephycarinatine D
(1b) was accomplished in 52% in three steps with a small amount
of removable diene 14. All the spectroscopic data were in
agreement with those of the natural zephycarinatines C and D
reported in the literature[2] {zephycarinatine C: []26 +141 (c
D
0.060, MeOH); lit. []D +108 (c 0.14, MeOH), zephycarinatine D:
[]26D +172 (c 0.15, MeOH); lit. []D +176 (c 0.1, MeOH)}.
Scheme 5. Synthesis of the Ketone 4
Table 3. Optimization of the Oxidation of 1,4-Diene 5
Entry
Reagent
tBuOOH, PDC
MnO2
Solvent
DMF
Temp. (°C)
Yield (%)[a][b]
1
2
3
4
5
rt
rt
ND
ND
ND
50
CH2Cl2
THF
DDQ
0 to rt
rt
NMO, TPAP
NMO, TPAP
MeCN
MeCN
–20 to 0
70
[a] Isolated yield. [b] ND = not detected.
We next focused on the total syntheses of zephycarinatines
C and D (Scheme 6). The synthesis commenced with the
conversion of the carbonyl group to the methoxy group. Although
initial attempts to reduce the carbonyl group by employing
NaBH4/CeCl3 or DIBAL-H failed, treatment of 4 with LiAlH4
allowed the 1,2-reduction of the carbonyl group to provide the
alcohol 11 in 78% yield as a single diastereomer. Without
determining the relative configuration, the alcohol 11 was
converted into the corresponding N,O-dimethylated product 12 by
treatment of NaH and MeI in DMF. Unfortunately, the NMR
spectral data of 12 did not agree with those of natural
zephycarinatine D. NOESY correlation revealed that 12
possessed the H3/H4a-syn relative stereochemistry.[23] Additionally,
the observed H3-H4 (J = 10.3 Hz) and H4a-H4 (J = 12.6 Hz)
coupling constants established the pseudo-axial orientation of H3
and H4a. These observations indicated that the LiAlH4-reduction
proceeded from the side of the benzene ring of 4 to give the
precursor 11 of epi-zephycarinatine D (12). We next attempted to
introduce the methoxy group to the C3 position via
stereoinversion. Ley et al. reported that in the total synthesis of
obliquine (a plicamine analog), the introduction of the methoxy
group was accomplished through the nucleophilic attack of MeOH
Scheme 6. Total Synthesis of Zephycarinatines (1)
Scheme 7. Synthesis of Zephycarinatine Derivative 17
With
a
facile method to synthesize the natural
zephycarinatines in hand, we synthesized a derivative with a non-
substituted A ring (Scheme 7 and S2). The zephycarinatine D
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
analog 17 lacking a methylenedioxy group was obtained in a
similar manner. As expected, the key radical ipso-cyclization of
the substrate without an electron donating group proceeded
smoothly to provide the desired cyclization product 16 in 54%
yield in two steps.
Keywords: alkaloid • natural products • photocatalyst • radical
ipso-cyclization • total synthesis
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Finally, we evaluated the inhibitory activities of
zephycarinatines C, D, and their synthetic derivatives on NO
production by LPS-stimulated RAW264.7 cells (Figure 1).[3]
Although the natural zephycarinatines C (1a) and D (1b) as well
as their derivative 17 did not show significant inhibitory activities
at 30 M, the keto derivative 4 at 30 M displayed a comparable
level of activity to indomethacin at 100M (positive control). The
derivative 4 exhibited dose-dependent inhibition of NO production
(IC50 = 65.3 M, Figure 1b). No cytotoxicity was observed in the
concentration range of 0.3–300 M of 4 (data not shown).
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Figure 1. Inhibitory activity of eight compounds on NO production by LPS-
stimulated RAW264.7 cells. A) Inhibitory activities of each compound. B) Dose-
dependent inhibition of compound 4 on NO production by LPS-stimulated
RAW264.7 cells. The data represent the mean ± SEM (n = 3 in each treatment,
**p<0.01, *p<0.05 vs vehicle, one-way ANOVA and Dunnett’s test). IM =
indomethacin.
Conclusion
In conclusion, we accomplished the first total synthesis of
zephycarinatines C and D starting from the known carboxylic acid
8 (2.1% and 4.7% overall yields, respectively, 11 steps). The
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synthesis highlights
a
nonbiomimetic strategy for the
stereoselective construction of the B-ring based on photocatalytic
reductive radical ipso-cyclization. The TPAP oxidation of 1,4-
diene followed by intramolecular 1,4-addition allowed the
construction of D-ring. We found that the keto derivative
demonstrated moderate inhibitory activity against LPS-induced
NO production. This strategy would contribute to expanding the
chemical space of plicamine-type alkaloids that is normally
inaccessible using biomimetic approaches.
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This work was supported by the JSPS KAKENHI (Grant Numbers
JP20K06938, 20H04773 and 17H03971), and AMED under Grant
Number JP19gm1010007.
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contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
Conflict of interest
The authors declare no conflict of interest.
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
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10.1002/ange.202009399
Angewandte Chemie
RESEARCH ARTICLE
Entry for the Table of Contents
Total synthesis of the plicamine-type alkaloids, zephycarinatine C and D, has been achieved. The key feature of the synthesis was the
stereoselective radical ipso-cyclization using visible-light-mediated photoredox catalysis. The evaluation of zephycarinatines and their
derivatives revealed that a synthetic derivative displayed moderate inhibitory activity against LPS-induced NO production.
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