Construction of tetracyclic 3-spirooxindole through cross-dehydrogenation of pyridinium: Applications in facile synthesis of (±)-corynoxine and (±)-corynoxine B

Article abstract of DOI:10.1021/ja5121343

A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2-bromoethyl)indolin-2-one derivatives with 3-substituted pyridines. As examples of the application of this new methodology, two potentially medicinal natural products, (±)-corynoxine and (±)-corynoxine B, were efficiently synthesized in five scalable steps.

Full text of DOI:10.1021/ja5121343

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Communication
Construction of Tetracyclic 3-Spirooxindole through
Cross Dehydrogenation of Pyridinium: Applications in
Facile Synthesis of (±)-Corynoxine and (±)-Corynoxine B
Jun Xu, Li-Dong Shao, Dashan Li, Xu Deng, Yu-Chen Liu, Qin-Shi Zhao, and Chengfeng Xia
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Dec 2014
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Construction of Tetracyclic 3-Spirooxindole through Cross
Dehydrogenation of Pyridinium: Applications in Facile Syn-
thesis of (±)-Corynoxine and (±)-Corynoxine B
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Jun Xu,†,§,‡ LiꢀDong Shao,†, ‡ Dashan Li,†,§ Xu Deng,† YuꢀChen Liu,†,§ QinꢀShi Zhao,*, † and Chengfeng
Xia*,†
†State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Acadeꢀ
my of Sciences, Kunming 650201, Yunnan, China
§University of Chinese Academy of Sciences, Beijing 100049, China
Supporting Information Placeholder
method for the total synthesis of tetracyclic 3ꢀspirooxindole
alkaloids, including the first total synthesis of rhynchophylline,[10]
ABSTRACT: A facile and straightforward method was develꢀ
oped to construct the fused tetracyclic 3ꢀspirooxindole skeleton,
which exists widely in natural products. The formation of the
tetracyclic 3ꢀspirooxindole structure was achieved through a tranꢀ
sitionꢀmetalꢀfree intramolecular cross dehydrogenative coupling
of pyridinium, which were formed in situ by the condensation of
3ꢀ(2ꢀbromoethyl)indolinꢀ2ꢀone derivatives with 3ꢀsubstituted
pyridines. As examples of the application of this new methodoloꢀ
gy, two potentially medicinal natural products, (±)ꢀcorynoxine
and (±)ꢀcorynoxine B, were efficiently synthesized in 5 scalable
steps.
the
enantioselective
organocatalyzed
synthesis
of
secoyohimbanes,[11] the diastereoselective intramolecular iminium
ion spirocyclization/lactamization cascade sequence of 2ꢀ
halotryptamine,[12] and the unified approach to corynoxine,
corynoxine B, corynoxeine, and rhynchophylline.[13] Carreira et
al. have completed a collective total synthesis of 3ꢀspirooxindole
alkaloids using a MgI2ꢀmediated ringꢀexpansion reaction of
spiro[cyclopropaneꢀ1,3’ꢀoxindole] with a cyclic disubstituted
aldimine, in addition, a Mannichꢀlike reaction has also been
14]
utilized.[12b,
Others methods for the construction of the
tetracyclic 3ꢀspirooxindole ring system have been reported,
including Amat’s protocol for the dissymmetric condensation of
[15]
prochiral aldehydeꢀdiesters
and Grieco’s aza DielsꢀAlder
The tetracyclic 3ꢀspirooxindole system is a recurring structural
motif in a number of natural products, such as corynoxine,[1]
reaction.[16] However, these strategies resulted in triꢀ or tetracyclic
3ꢀspirooxindole intermediates that requried multistep conversions
to form the final natural tetracyclic 3ꢀspirooxindole alkaloids
skeleton. Therefore, a more efficient and straightforward method
is still required in the development of a synthetic methodology for
tetracyclic 3ꢀspirooxindole alkaloids.
3]
corynoxine B,[1] voachalotine oxindole,[2] rhynchophylline,[1b,
strychnophylline,[4] strychnofoline,[4a] and formosanine[5] (Figure
1). Most of these spirooxindole alkaloids were isolated from the
Apocynaceae and Rubiacae species, which play important roles in
traditional Chinese medicine. Among these natural products,
corynoxine and corynoxine B exhibit prominent potency in
preventing or treating Parkinson’s disease. The accumulation of
αꢀsynuclein (αꢀsyn) in the brain is a pathogenic feature and also a
causative factor in Parkinson’s disease.[6] Corynoxine and
corynoxine B promote the clearance of αꢀsyn, which is the major
component of Lewy bodies in Parkinson’s disease patients.[6ꢀ7]
Strychnofoline, isolated from the leaves of Strychnos
usambarensis,[4a] displays highly antimitotic activity in cultures of
mouse melanoma and Ehrlich tumor cells.[4b]
The appealing architecture and significant biological activities
of tetracyclic 3ꢀspirooxindole alkaloids have received
considerable attention from the community of synthetic organic
chemists. However, limited methods have been developed to
assemble the tetracyclic 3ꢀspirooxindole moiety of these
alkaloids. Biosynthetically, the tetracyclic 3ꢀspirooxindole moiety
is postulated to be formed by an oxidative rearrangement of the
tetrahydroꢀβꢀcarbolines ajmalicine and its derivatives (Scheme
1).[8] The oxidative rearrangement sequences of tetrahydroꢀβꢀ
carboline were also employed for the synthesis of the corynanthe
alkaloid dihydrocorynantheol by Martin et al.[9]. The
intramolecular Mannich reaction is the most widely adopted
Figure 1. Naturally occurring tetracyclic 3ꢀspirooxindole alkaꢀ
loids.
Direct CꢀH bond transformation is an efficient method and
enables wide applications in organic synthesis. Transitionꢀmetalꢀ
catalyzed coupling reactions have made significant progress since
1960s, although along with some drawbacks (such as expensive
transition metals and ligands,
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could effeciently catalyzed the coupling reaction, the reaction
1
2
proceeded slower and a competitive oxidation of the C3 of
oxindole occured.
3
Table 1. Optimization of synthesis of tetracyclic 3ꢀspirooxindole.
4
5
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9
Entry
Solvent
Base
Yield
(%)[a]
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1
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
THF
TEA
34
2
Na2CO3
K2CO3
85
3
76
4
NaHCO3
NaH2PO4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
70
Scheme 1. Approaches to tetracyclic 3ꢀspirooxindole synthesis.
5
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sensitive to oxygen and moisture, and unpredictable additives and
cocatalysts). Thus, the development of transitionꢀmetalꢀfree
coupling reactions to realize CꢀH functionalization is appealing,
and is considered as a significant step towards advanced greener
synthetic protocols in organic synthesis.[17] Due to the importance
of pyridine motifs in biologically active compounds,
pharmaceuticals, and functional materials, direct crossꢀ
dehydrogenative alkylations of pyridines have received great
attentions from chemistry community. Besides the well developed
transitionꢀmetalꢀcatalyzed pyridyl C–H bond functionalization,[18]
the transitionꢀmetalꢀfree direct alkylation of pyridines has also
been acheived, albeit with limited reports.[19] Herein, we report a
novel, scalable approach to the construction of the 3ꢀ
spirooxindole ring system through a transitionꢀmetalꢀfree intramoꢀ
lecular cross dehydrogenation of pyridinium. The efficiency of
this direct alkylation of pyridines made the concise total synthesis
of (±)ꢀcorynoxine and (±)ꢀcorynoxine B.
6
NR
NR
trace
NR
trace
60
7
8
DCM
9
DCE
10
11
12
13
14
Acetone
CHCl3
MeOH
DMF
74
69
DMSO
67
aIsolated yields by silica gel column.
A series of bases were subjected to the reaction, the results of
which suggested that Na2CO3 was the most efficient base to
promote the reaction (Table 1, entries 1 ꢀ 5). Different solvents
were also screened under the reaction conditions. Most of the
polar solvents (MeOH, DMF, and DMSO, Table 1, entries 10 ꢀ
12) were superior to the nonꢀpolar solvents (toluene, THF, DCM,
and DCE, Table 1, entries 6 ꢀ 9). These results could be ascribed
to the excellent solubilities of both of the starting material 2b and
product 3 in the polar solvents.
Scheme 2. Preparation of the pyridinium salts.
Moreover, different oxidants were also chosen to test their
efficiency. Although CAN, TBP, and TBHP (Table 2, entries 2,
6, 7) also promoted the cross dehydrogenative coupling reaction,
the efficiency of these oxidants was lower in both yield and
reaction time. However, none of the coupling product was
detected when DDQ or Na2S2O8 was used as the oxidant, while
less than 5% yield for K2S2O8. Because molecular oxygen was the
most effective and greenest oxidant for the cross dehydrogenative
reaction, it was used in the subsequent coupling.
The pyridinium salt 2a was obtained by the treatment of 3ꢀ
(2ꢀbromoethyl)indolinꢀ2ꢀone
1 with pyridine (Scheme 2).
Subsequently, the transitionꢀmetalꢀfree cross dehydrogenative
coupling was performed under various condition under aerobic
atmosphere. However, no product was detected while screening
numerous solvents (THF, MeCN, DCM, MeOH and DMF) or
varying the base (TEA, DIPEA, Na2CO3, DBU, and NaH). We
postulated that it was due to the low reactivity of the unsubstituted
pyridinium salt. To enhance the reactivity of pyridinium, an
electronꢀwithdrawing group at the 3ꢀposition of the pyridine ring
is necessary.[20] Methyl nicotinate was used to condense with 3ꢀ
Table 2. Cross dehydrogenative coupling with different oxidants.
(2ꢀbromoethyl)indolinꢀ2ꢀone
1
to give the corresponding
pyridinium salt 2b. As expected, the coupling reaction proceeded
smoothly and the dehydrogenative coupling product 3 was
obtained in the presence of TEA in 34% yield (Table 1, entry 1).
A dramatical improvement was acheived when the base was
switched from TEA to Na2CO3 (0.5 equiv.) and gave the coupling
product 3 in 85% yield (Table 1, entry 2). The ideal reaction
temperature was 50 °C. We found that the reaction proceeded
slowly at room temperature. When the reaction temperature was
Entry
Oxidant (2.0 equiv.)
O2 (balloon)
CAN
Yield (%)[a]
85
1
2
3
4
54
raised to 70 °C,
a
large amount of the byproduct
DDQ
complex
complex
spiro[cyclopropanꢀ3,3'ꢀoxindole] was formed. The amounts of
Na2CO3 were also examined. Although 0.1 equivalent of Na2CO3
Na2S2O8
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Dissolution of (±)ꢀcorynoxine in 2,2,2ꢀtrifluoroenthanol led to
5
6
7
K2S2O8
TBP
< 5
46
1
2
3
4
5
6
7
8
9
formation of the epimeric (±)ꢀcorynoxine B (Scheme 3). We
monitored this transformation in situ by TLC, which revealed an
equilibrium was established between (±)ꢀcorynoxine and (±)ꢀ
corynoxine B within 6 h in favor of (±)ꢀcorynoxine B.
Chromatographic separation of the mixture afforded a 90% yield
of (±)ꢀcorynoxine B along with recovered (±)ꢀcorynoxine (31%).
We obtained clear evidence for this equilibrium ratio when (±)ꢀ
corynoxine B was subject to identical conditions and the same
ratio was reached between (±)ꢀcorynoxine and (±)ꢀcorynoxine B
within 6 h. The spectroscopic data of the synthetic (±)ꢀcorynoxine
and (±)ꢀcorynoxine B were in agreement with the values
published for the natural products.
TBHP
58
aIsolated yields by silica gel column.
Using these optimized conditions, different substrates were
used to test the scope of this methodology (Table 3). The
pyridinium with a ketone on the C3 position also gave high yields
in the coupling reaction (compounds 5, 7, 9, and 12). When the
N1 of the oxindole was substituted with a methyl, allyl, or benzyl
group, the cross dehydrogenative coupling reaction proceeded
more efficiently with somewhat higher product yields. It was
observed that when the N1 position was substituted with an acetyl
group, the corresponding pyridinium 2 could not be prepared and
only afforded the spiro[cyclopropanꢀ3,3'ꢀoxindole] byproduct. We
reasoned that the acetyl group at N1 activated the C3 position,
which was easily deprotonated and subsequently underwent an
intramolecular SN2 reaction to form the 3ꢀcyclopropane
byproduct.
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Table 3. Synthesis of tetracyclic 3ꢀspirooxindole pyridinium salts.
Br-
Br-
R2
R2
N
N
Na2CO3, O2 (balloon)
MeCN, 50 oC, 12 h
O
O
N
R1
N
R1
O
Br-
Br-
Br-
CO2Me
CO2Et
N
N
N
O
O
O
N
Scheme 3. Total synthesis of (±)ꢀcorynoxine and (±)ꢀcorynoxine
B. a) NaBH4, dioxane/water, 78%; b) trimethyl orthoacetate, proꢀ
panoic acid, dioxane, sealed, 120 °C, 68%; c) LDA, HCO2Me,
THF, ꢀ78 °C to 0 °C; d) TMSCH2N2, Et2O/MeOH (1:1), 82%
brsm; e) PtO2, H2, CH2Cl2, 86%; f) 2,2,2ꢀtrifluoroethanol, RT,
90% brsm.
N
H
N
H
4, 79%
5, 81%
6, 89%
Br-
O
Br-
O
Br-
O
CO2Me
N
N
N
O
O
N
N
N
In summary, we have described a cross dehydrogenative
coupling reaction which provides direct access to tetracyclic 3ꢀ
spirooxindole system that found in many natural products with
intriguing biological activities. This novel method will be
applicable to the synthesis of a number of bioactive tetracyclic 3ꢀ
spirooxindole contained alkaloids. Efficiently total synthesis of
(±)corynoxine and (±)corynoxine B have been achieved within 5
steps.
7, 89%
8, 76%
9, 86%
Br-
Br-
O
Br-
O
O
CO2Et
CO2Me
N
N
N
O
N
N
N
Bn
Bn
12, 87%
10, 86%
11, 91%
To highlight the utility of the direct cross dehydrogenative
coupling,
two natural products, (±)ꢀcorynoxine and (±)ꢀ
corynoxine B, were facilely synthesized from the coupling
product 5. Gramꢀscale coupling product 5 was treated with
NaBH4 in a mixture of dioxane and water (20:1) (Scheme 3). Both
the pyridinium and the ketone were reduced to afford the alcohol
13. The configuration of the D ring was confirmed by 2D NMR of
the ketone compound 14, which was afforded by oxidation of the
alcohol 13 with DMP. Although no selectivity was observed at the
newly formed hydroxyl group, it did not affect the efficiency of
the total synthesis because both of the isomers afforded the same
final product. The alcohol 13 was then subjected to
Johnson−Claisen rearrangement[21] by heating in trimethyl
orthoacetate with a catalytic amount of propanoic acid to provide
the ester 15. Treatment of the ester 15 with LDA, followed by the
addition of excess methyl formate, resulted in the desired enol
ester intermediate in 36% yield (82% brsm.).[10, 22] The crude enol
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
xiachengfeng@mail.kib.ac.cn, qinshizhao@mail.kib.ac.cn.
Author Contributions
ester intermediate was then directly methylated with trimethylsilyl
‡These authors contributed equally.
23]
diazomethane to afford 16 in 62% yield.[10,
Finally, the
catalytic hydrogenation of 16 by PtO2 under a hydrogen
atmosphere gave the target compound, (±)ꢀcorynoxine, in an
excellent yield of 86%.[21a, 24]
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
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A. Patel, K. N. Houk, O. Kwon, Org. Lett. 2012, 14, 5388ꢀ5391; c) L. H.
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This work was financially supported by the National Basic
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Science Foundation of China (21272242 and 21302193), and
Yunnan HighꢀEnd Technology Professionals Introduction
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