Palladium-catalyzed enol/enolate directed oxidative annulation: Functionalized naphthofuroquinone synthesis and bioactivity evaluation

Article abstract of DOI:10.1039/c9cc05233j

A palladium-promoted oxidative annulation reaction for the synthesis of structurally diverse naphthoquinone-containing heterocycles has been developed, providing switchable access to 1,2-naphthofuroquinones and densely functionalized cyclobutene-fused 1,4-naphthofuroquinones by selective enol/enolate-directed processes. The synthetic application was extended by late-stage functionalization of an anti-HIV drug. The practical value of 1,2-naphthofuroquinone synthesis was highlighted in endothelial protective lead compound development.

Full text of DOI:10.1039/c9cc05233j

Showcasing research from Professor Xiaobo Sun and Professor
Lei Wang’s laboratories at the Institute of Medicinal Plant
Development, the Chinese Academy of Medical Sciences
and Peking Union Medical College in Beijing, P. R. China.
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Volume 55 Number 98 21 December 2019 Pages 14703–14858
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Chemical Communications
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Palladium-catalyzed enol/enolate directed oxidative annulation:
functionalized naphthofuroquinone synthesis and bioactivity
evaluation
The synthesis of structurally diverse 1,2-naphthofuroquinones
and densely functionalized cyclobutene-fused
1,4-naphthofuroquinones has been developed via selective
enol/enolate-directed palladium catalysis. The synthetic
application was extended by late-stage functionalization
of an anti-HIV drug and highlighted in endothelial protective
lead compound development.
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Palladium-catalyzed enol/enolate directed
oxidative annulation: functionalized
naphthofuroquinone synthesis and
bioactivity evaluation†
Cite this: Chem. Commun., 2019,
55, 14729
Received 8th July 2019,
Accepted 16th September 2019
Shuaipeng Lv,‡a Haitao Liu,‡a Jie Kang,b Yun Luo,a Ting Gong,b Zhengqi Dong,a
DOI: 10.1039/c9cc05233j
a
Guibo Sun,a Chunnian He,a Xiaobo Sun*a and Lei Wang
*
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A palladium-promoted oxidative annulation reaction for the synthesis of
Within the rapidly growing realm of transition-metal catalysis,
structurally diverse naphthoquinone-containing heterocycles has been oxidative annulation of alkynes with substrates bearing versatile
developed, providing switchable access to 1,2-naphthofuroquinones functional groups has emerged as a powerful tactic in heterocycle
and densely functionalized cyclobutene-fused 1,4-naphthofuro- synthesis and structural diversification.4 Among the various
quinones by selective enol/enolate-directed processes. The synthetic catalytical strategies, the oxidative annulation of alkynes with
application was extended by late-stage functionalization of an anti-HIV carbonyl substrates, especially 1,3-dicarbonyl compounds (or
drug. The practical value of 1,2-naphthofuroquinone synthesis was their enol tautomers), to deliver a broad range of heterocycles
highlighted in endothelial protective lead compound development.
have been pioneeringly explored by Lam, You and Gogoi’s groups.5
However, these enol/enolate-directed oxidative annulations always
The development of efficient approaches to synthesize structurally achieved product selectivity through transition-metal catalyst con-
diverse heterocycles with broad biological activities under readily trol strategies. We hypothesized that it might be possible to realize
tuneable catalytic conditions is one of the central goals in modern product versatility by tuning the enol/enolate-directed annulation
organic synthesis.1 Among these heterocycles, naphthofuroqui- pathway without catalyst control processes.
nones are exceptionally prominent due to their existence in
Cyclobutenes have attracted considerable attention due to
numerous biologically active molecules (Fig. 1).2 However, the their wide existence as critical scaffolds in biologically relevant
reported protocols for naphthofuroquinone construction suffer molecules and high reactivities for versatile roles originating from
from disadvantages.3 Given the broad-spectrum bioactivities of ring strain.6 However, notwithstanding the progress,7 reported
naphthofuroquinones, the development of novel efficient methods synthetic protocols are incompatible with the extreme value of
for the synthesis of such heterocycles from simple starting materials such four-membered rings. Therefore, the synthesis of cyclobutenes
with high efficiency, including synthetic applications in drug dis- is needed for more flexible routes, especially embedding such
covery, is highly desirable.
densely substituted rings in polycyclic structures.
We envisioned that 2-hydroxy-1,4-naphthoquinone, featuring
a keto–enol moiety,5g,8 could be utilized as a coupling partner
with transition-metal catalysis via an enol/enolate-directed process
to assemble structurally diverse naphthoquinone-containing hetero-
cycles. However, challenges, such as chemoselectivity and trans-
formation efficiency, should be overcome. Herein, we report a
successful introduction of enol/enolate-directed palladium-
catalyzed oxidative annulation reactions, yielding biologically
relevant 1,2-naphthofuroquinones and highly substituted cyclo-
butene-fused 1,4-naphthofuroquinones together with synthetic
applications in late-stage functionalization (LSF) and lead com-
pound development (Scheme 1).
The designed palladium-catalyzed oxidative annulation
reaction was evaluated by using 2-hydroxy-1,4-naphthoquinone
1a (1.0 equiv.) and diphenylacetylene 2a (5.0 equiv.) in aceto-
nitrile (MeCN) at 100 1C. Interestingly, the reaction proceeded
smoothly and afforded the desired product 3a in moderate yield
Fig. 1 Representative bioactive natural products and pharmaceuticals.
a Institute of Medicinal Plant Development, Chinese Academy of Medical Science &
Peking Union Medical College, Beijing 100193, P. R. China.
E-mail: lwang@implad.ac.cn
b Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union
Medical College, Beijing 100050, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1909884 (3a),
1909885 (3r) 1909886 (3y), 876846 (4a) and 1909889 (5a). For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c9cc05233j
‡ These authors contributed equally.
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Table 2 1,2-Naphthofuroquinones synthesisa
Scheme 1 Enol/enolate-directed oxidative annulation reactions.
Table 1 Optimization of the reaction conditionsa
Yieldb (%)
Entry
Solvent
Oxidant/additive
T/1C
3a
4a
1
2
MeCN
MeCN
MeCN/AcOH
MeCN/AcOH
MeCN/AcOH
MeCN/AcOH
MeCN
Oxone
CuCl2
Oxone
Oxone/BQ/O2
Oxone/BQ/O2
Oxone/BQ/O2
CuCl2/N2
CuCl2/O2
CuCl2/N2
100
100
100
100
100
100
100
100
100
42
—
61
71
77
50
—
—
—
—
49
—
—
—
—
22
57
68
a
The reaction used 1 (0. 2 mmol, 1 eq.), 2 (1.0 mmol, 5 eq.), Pd(OAc)2
10 mol%, oxone 2.0 eq., BQ 1.0 eq., O2 1 atm, solvent 2 mL, 6–36 hours;
yields of the isolated product 3 after chromatography.
3c
4c
6c,e
7d
8
desired 1,2-naphthofuroquinones with high efficiency (3p–u).
However, erosive yields were achieved with unsymmetrical alkynes
as substrates (3w–y). Furthermore, this annulation reaction was
also extended by using E-stilbene as the starting material and
resulting in 3a and 3z with moderate yields, respectively. The
configurations of compounds 3a, 3r, and 3y were structurally
confirmed by X-ray diffraction analysis.9
9
10
DMA
DMA
a
This reaction was run with 1a (0. 2 mmol, 1 eq.), 2a (1.0 mmol, 5.0 eq.),
Pd(OAc)2 10 mol%, oxidant (0. 4 mmol, 2 eq.), additive (0. 4 mmol,
2.0 eq.), solvent 2 mL, 100 1C, 24 h. Yield of the isolated product 3a
b
c
d
after chromatography. MeCN/AcOH (v/v 3 : 1). MeCN/AcOH (v/v 1 : 1).
e
BQ (0.2 mmol, 1 eq.). O2 1 atm. N2 1 atm. BQ = 1,4-benzoquinone.
Then, the utility of enol/enolate-directed oxidative annulation
procedures was broadened by cyclobutene-embedded 1,4-naphtho-
furoquinone synthesis. As indicated in Table 3, different naphtho-
quinone and anthracenedione substrates bearing electron-neutral,
-releasing and -withdrawing substituents on the aromatic ring
were evaluated, giving the corresponding linear naphthofuro-
quinone products (4a–m) with moderate to very good yields. Also,
this annulation protocol in terms of various symmetrical and
unsymmetrical diaryl alkynes 2 was explored and achieved the
(Table 1, entry 1). Various solvents were then evaluated, revealing
that MeCN was still essential for the high efficiency of this
transformation (see ESI†). Further optimizations of reaction
conditions indicated that the mixture solvent MeCN/AcOH
(v/v 3 : 1), BQ and O2 could significantly affect the reaction with
an increased yield of 3a (77%) (entry 6). Upon switching from
oxone to CuCl2, the selective assembly of 4a was observed (entry 8).
Then, a significant solvent effect on the reactive efficiency was
achieved, and DMA was the solvent of choice with the generation of
4a instead of 3a with a good yield (68%) under a N2 atmosphere at
100 1C (entry 10).
Table 3 Cyclobutene-fused 1,4-naphthofuroquinones synthesisa
With the established optimal reaction conditions in hand,
an assessment of the reaction scope to assemble a range of
substituted 1,2-naphthofuroquinones was evaluated. As indicated
in Table 2, various 2-hydroxy-1,4-naphthoquinones 1 bearing
electron-neutral, electron-donating, and electron-withdrawing
substituents on the aromatic ring were found to be suitable for
this reaction to form the corresponding angular naphthofuro-
quinones (3a–m) with good to excellent yields. However, 1 bearing a
strong electron-withdrawing group such as 6-NO2 exhibited
poor reactivity in this kind of reaction (o10% yield). Notably,
2-hydroxy-1,4-anthracenedione and 3-hydroxy-1,4-anthracenedione
were also suitable substrates and afforded the desired products
with high efficiency (3n, 3o). Also, symmetrical and unsymmetrical
diaryl alkynes substituted with electron-rich and electron-deficient
a
The reaction used 1 (0. 2 mmol, 1 eq.), 2 (1.0 mmol, 5.0 eq.), Pd(OAc)2
10 mol%, CuCl2 2.0 eq., solvent 2 mL, reaction time 24–36 hours; yields
groups were all compatible, resulting in the assembly of various of the isolated product 4 after chromatography.
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desired polycyclic heterocycles with high efficiency in most cases
(4n–s), whereas 4r and 4s formed mixtures of regioisomers that
were inseparable by column chromatography. The configuration of
the products was assigned based on an X-ray crystallographic
analysis of compounds 4a.10
The application of the annulation approach in the context of
late-stage functionalization (LSF) was also intensively explored.11
Pharmaceutically relevant molecules such as efavirenz, a
commercially available anti-HIV drug, were then investigated
(Table 4). However, the targeted functionalized angular
naphthofuroquinone derivative was not formed, but yielded
exciting 1,4-naphthopyranoquinone products with moderate
yields (5a–c).12 Additionally, the extension of the LSF to 4-hydroxy-
coumarin, a keto–enol moiety embedded heterocycle, was also
achieved and formed the corresponding naphthopyranoquinone
product 6 with high efficiency. Using the cyclobutene-embedded
1,4-naphthofuroquinone catalytic system, LSF was also performed.
However, the functionalized linear naphthofuroquinone derivative
was not assembled under the standard conditions.
To further evaluate the pharmaceutical implication of this
oxidative annulation strategy, 1,2-naphthofuroquinone synthesis
in drug discovery was also explored. The endothelial protective
assays of 1,2-naphthofuroquinones in vitro were assessed in
parallel with sodium tanshinone IIA silate (see ESI†).13,14 As
shown in Fig. 2A and B, we found that 3x exhibited a strong
endothelial protective effect against oxidized low-density lipo-
protein (ox-LDL)-induced human umbilical vein endothelial cell
(HUVEC) injury. Additionally, 3x (0.25, 0.5 and 1 mM) has no
effects on the normal cells (Fig. 2C). Based on these findings,
the endothelial protective mechanism of 3x was then evaluated.
The HUVEC apoptosis was significantly reduced by treating with
3x (0.25 and 0.5 mM) via Annexin V/PI assay compared with the
model group, as indicated in Fig. 2D. The expression level of
reactive oxygen species, an important factor for cell apoptosis,
was remarkably decreased and detected by Carboxy-H2DCFDA
staining after 3x treatment, which implied the anti-oxidative
effects of 3x (Fig. 2E). This result was in accordance with the
assay in Fig. 2D. We then examined the expressions of Bcl-2,
Bax and cleaved-caspase-3 protein expression levels to further
Fig. 2 Protective effects of 3x on HUVECs injury. All values are expressed
as the mean Æ SD, n = 3. #p o 0.05, ##p o 0.01 ox-LDL group vs. control
group; *p o 0.05, **p o 0.01 vs. ox-LDL group. STS = sodium tanshinone
IIA silate. See the ESI† for details.
understand the mechanism (Fig. 2F and G). The expressions
of Bcl-2/Bax increased in a dose-dependent manner after 3x
treatment, whereas the cleaved-caspase-3 expression was obviously
decreased. All the results indicated the promise of 3x for future
applications in the treatment of coronary artery disease based on
dramatically strong endothelial protective effects.
Table 4 Late-stage functionalization of N-protected efavirenz
In summary, we have developed the first palladium-catalyzed
oxidative switchable annulation of naphthalquinones with alkynes
to assemble a series of biologically relevant functionalized 1,2-
naphthofuroquinones and densely functionalized cyclobutene
embedded 1,4-naphthofuroquinones in good yields. Notably, the
palladium catalyzed oxidative annulation strategy described here
allows the synthesis of the 1,2-naphthofuroquinones with dramati-
cally strong endothelial protective effects and represents an efficient
approach to diversify marketed drugs by late-stage functionalization.
Further applications of palladium-catalysis for the construction of
related heterocycles will be reported in due course.
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(c) L. Ackermann, Acc. Chem. Res., 2014, 47, 281; (d) L. Souillart and
We are grateful for financial support from the National Natural
Science Foundation of China (81602977), the CAMS Basic and
Innovation Fund for Medical Sciences (2019-RC-HL-010; 2017-
I2M-1-013 and 2016-I2M-1-012), the National Major Scientific and
Technological Special Project (2015ZX 09501005), the Science and
Technology Development Project of Jilin Province of China
(20190304050YY) and YESS (2017QNRC001).
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There are no conflicts to declare.
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