Highly Enantioselective Tandem Michael Addition of Tryptamine-Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos Alkaloids

Article abstract of DOI:10.1002/anie.201800567

A highly enantioselective tandem Michael addition of tryptamine-derived oxindoles to alkynones was developed by taking advantage of a chiral N,N′-dioxide Sc(OTf)₃ catalyst. The reaction enables the facile preparation of enantioenriched spiro[pyrrolidine-3,3′-oxindole] compounds, which provides a novel strategy for the synthesis of monoterpenoid indole alkaloids. As a demonstration, the asymmetric synthesis of strychnos alkaloids [(?)-tubifoline, (?)-tubifolidine, (?)-dehydrotubifoline] was achieved in 10–11 steps.

Full text of DOI:10.1002/anie.201800567

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Accepted Article
Title: Highly Enantioselective Tandem Michael Addition of Tryptamine-
Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos
Alkaloids
Authors: Weigang He, Jiadong Hu, Pengyan Wang, Le Chen, Kai Ji,
Siyu Yang, Yin Li, Zhilong Xie, and Weiqing Xie
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Highly Enantioselective Tandem Michael Addition of Tryptamine-
Derived Oxindoles to Alkynones: Concise Synthesis of Strychnos
Alkaloids
Weigang He,† Jiadong Hu,† Pengyan Wang,† Le Chen, Kai Ji, Siyu Yang, Yin Li, Zhilong Xie and
Weiqing Xie*
Abstract: A highly enantioselective tandem Michael addition of
oxindole derived from tryptamine to alkynone is developed by taking
advantage of Sc(OTf)3-chiral N,N’-dioxide catalyst. The reaction
enables facile preparation of enantioenriched spiro[pyrrolidine-3,3’-
oxindole], which provides a novel strategy for the synthesis of
monoterpenoid indole alkaloids. As a demonstration, the asymmetric
synthesis of strychnos alkaloids [(-)-tubifoline, (-)-tubifolidine, (-)-
dehydrotubifoline] is achieved in 10-11 steps.
(strictosidine).[6]
Although
spiro[pyrrolidine-3,3’-oxindole]
contains the core structure (A, B and C rings) presented in those
two type of indole alkaloids (Figure 1), its application in
synthesis of strychnos alkaloids has never been explored.[3,5,7]
Monoterpenoid indole alkaloids constitute a large family of
indole alkaloids that widely distributed in nature.[1] Those
alkaloids feature complex structure, including polycyclic ring
system, consecutive stereocenters, and quaternary carbon
centers. Additionally, this subclass of indole alkaloids exhibited
important biological profiles, which has been a rich source for
medicine development. For example, reserpine and vinblastine
have been used for treatment of cardiovascular disease and
cancer respectively.[1] In this respect, spiro[pyrrolidine-3,3’-
oxindole] has been recognized as a privileged skeleton widely
present in indole alkaloids[2,3] (Figure 1, strychnofoline,[2a]
.
formosanine[2b]) and pharmaceutical molecules with diverse
biological activities.[3] Therefore, numerous strategies including
various enantioselective catalyzed methodologies have been
reported for the construction of this scaffold.[3]
Strychnos alkaloids belong to the monoterpenoid indole
alkaloid incorporated with a cyclohexane fused spiro[pyrrolidine-
3,3’-oxindoline] framework and a bridged D ring. Since the
milestone synthesis of strychnine by Woodward,[4] the
challenging complicate structure of strychnos alkaloids has long
served as inspiration and testament for new synthetic
methodologies and strategies.[5] Biologically, spirooxindole and
strychnos alkaloids share the same biosynthetic precursor
Figure 1. Monoterpenoids Incorporated with Spiro[pyrrolidine-3,3’-oxindole
scaffold and Enantioselective Tandem Michael Addition that Enables
Asymmetric Synthesis of Strychnos Alkaloids.
As a continuation of our work on synthesis of indole
alkaloids,[8] we hypothesized that the enone 1 could serve as a
versatile building block for the synthesis of strychnos alkaloids
by forging the bridged D ring via allylic substitution after
reduction of the enone moiety. Retrosynthetically, this
intermediate could be accessed by the intramolecular
condensation of spiro[pyrrolidine-3,3’-oxindole] 4 (Figure 1).
Drawn inspirations from previous work on tandem mixed Michael
addition[9] and enantioselective addition of oxindole to
alkynone[10], we surmised that tandem Michael addition of
[*]
Mr. W. He, Mr. J. Hu, Mr. P. Wang, Ms. L. Chen, Mr. K. Ji, Mr. S.
Yang, Mr. Y. Li, Mr. Z. Xie, Prof. Dr. W. Xie
Shaanxi Key Laboratory of Natural Products & Chemical Biology,
College of Chemistry & Pharmacy
Northwest A&F University
22 Xinong Road, Yangling 712100, Shaanxi, China
E-mail: xiewq@nwafu.edu.cn
Prof. Dr. W. Xie
State Key Laboratory of Bioorganic & Natural Products Chemistry,
Shanghai Institute of Organic Chemistry Chinese Academy of
Sciences
Key Laboratory of Botanical Pesticide R&D in Shaanxi Province,
Yangling, Shaanxi 712100, China
tryptamine-derived oxindole
2
to alkynone
3
through
†
intermolecular carbon-Michael
addition
followed by
Those authors contributed equally.
intramolecular aza-Michael addition via oxindole I would give
rise to the desired spirooxindole 4. Herein, we report the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201800567
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enantioselective construction of spiro[pyrrolidine-3,3’-oxindoline]
via this tandem process promoted by Sc(OTf)3-chiral N,N’-
dioxide.[11] Furthermore, the implementation of this new strategy
in the synthesis of strychnos alkaloids is also demonstrated.
diastereoselectivity (Table 1, entries 9 to 11 and supporting
information).
Table 1. Optimization of Reaction Conditions.[a]
entry
ligand
base
solvent
time
(h)
yield[b]
(%)
ee[c]
(%)
dr[c]
1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
60
84
60
72
60
48
60
48
72
83
78
93
73
94
84
85
27
96
96
96
87
93
96
96
86
9:1
8:1
5:1
3:1
5:1
5:1
8:1
4:1
2
3
4
5
6
7
CHCl3
8
THF
9
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
93
76
95
95
13
87
5:1
1:1
2:1
10
11
Cs2CO3
K3PO4
48
48
Scheme 1. Substrate Scope with Respect to Oxindole.
Upon identifying the optimal reaction conditions, an array of
tryptamine-derived oxindole was examined to expand the
substrate scope. The protecting group attached to the primary
amine was crucial for the tandem process. Sulfonyl-protected
oxindoles could smoothly be converted to the desired products
in excellent enantioselectivities (Scheme 1, 4a to 4c).
Carbamate-protected oxindoles only delivered carbon-Michael
addition product. This could be ascribed to the reduced
nucleophilicity of the nitrogen which impeded the aza-Michael
addition (Scheme 1, 4d and 4e). Those products together with
the isolation of the carbon-Michael addition intermediate for 4a
(see Supporting Information) strongly suggested the reaction
started with intermolecular carbon-Michael addition followed by
intramolecular aza-Michael addition. Electron-withdrawing
groups (F, Cl and Br) on indole were compatible with the
reaction conditions, affording corresponding spirooxindole in
excellent enantioselectivities (Scheme 1, 4f to 4i). To our
satisfactory, electron-donating substituents such as Me, OMe
was also tolerated, providing spirooxindole 4l and 4n in 91% ee
and 96% ee respectively. However, bromine or other electron
donating groups (Me, OMe) on the C-7 of oxindole were
[a] Reaction conditions: Reactions were performed with 2a (0.1 mmol), 3a
(0.11 mmol), base (0.1 mmol), Sc(OTf)3 (5 mol %) and ligand (6 mol %) in
solvent (1.0 mL) under dry air condition at RT. [b] Isolated yields. [c]
Determined by HPLC on ChiralPak IC column. Ts = p-toluenesulfonyl.
We initially focused on optimizing the reaction conditions of
the tandem Michael addition of tryptamine derived oxindole 2a to
alkynone 3a using Sc(OTf)3-chiral N,N’-dioxide catalyst.[10e]
Delightfully, the desired product 4a could be isolated in 83%
yield with 96% ee and 9:1 dr using L1 as ligand (Table 1, entry
1). Various chiral N,N’-dioxide ligands were subsequently
surveyed, while none of them gave better results than L1 (Table
1, entries 2 to 5). Solvent screening revealed that 1,2-
dichloroethane was the solvent of choice (Table 1, entries 6 to 8
and Supporting Information). Next, different inorganic and
organic bases were evaluated, which showed that Na2CO3 gave
superior outcome in terms of enantioselectivity and
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detrimental for the reaction, resulting in moderate
enantioselectivities. The structure of the product was firmly
established by X-ray crystallographic analysis of 4a.[12]
Scheme 3. Asymmetric Synthesis of Strychnos Alkaloids.
With the key tetracyclic intermediate
5 in hand, we
Scheme 2. Substrate Scope of Alkynone.
subsequently focused on building up the bridged D ring via
allylic substitution (Scheme 3). First, installation of propargyl
silane onto enone 7 could be achieved in 60% yield via a
sequence of Tosyl-protection, removal of 2-Nosyl, and alkylation
of the resulted secondary amine with propargyl iodide 6.
Subsequent reduction of enone 7 mediated by NaBH4/CeCl3 led
to allyl alcohol 8, setting the stage for the critical ring closure.
The cyclization of 8 was unexpectedly problematic as the allyl
cation intermediate 9 might involve in ring opening/cyclization
process via iminium 10, which resulted in dramatic erosion of
enantiopurity. After carefully optimizing the reaction conditions
(see Supporting Information, Table S4), it was revealed that the
racemization could be totally supressed by performing the
reaction in the presence of excessive SnCl4 (5.0 equiv) at low
temperature. Subsequent hydrogenation of allene 11 over Pd/C
in MeOH followed by the deprotection of Tosyl promoted by Mg
in MeOH furnished (-)-tubifoline in 81% yield. Reduction of (-)-
tubifoline with NaBH3CN/TiCl4 gave (-)-tubifolidine in 90%
yield.[16] On the other hand, semi-hydrogenation of allene 11
followed by removal of Tosyl provided (-)-dehydrotubifoline in 57%
yield.
In conclusion, an enantioselective construction of
spiro[pyrrolidine-3,3’-oxindole] was described by employing
tandem Michael addition of oxindole derived from tryptamine to
alkynone promoted by Sc(OTf)3-chiral N,N’-dioxide. This
protocol enabled asymmetric total synthesis of strychnos
alkaloids [(-)-tubifoline, (-)-tubifolidine, (-)-dehydrotubifoline] in
10 to 11 steps, which featured an intramolecular condensation to
form the E ring and a SnCl4-promoted allylic substitution to forge
the bridged D ring. Further application of this strategy in
asymmetric synthesis of other type of monoterpenoid alkaloids is
Furthermore, different alkynone was extensively explored as
the reaction partner to afford synthetically useful spirooxindoles.
As depicted in Scheme 2, both linear and branched aliphatic
alkynone could be transfer to corresponding spirooxindole in
good to excellent enantioselectivities (Scheme 2, 90% to 96%
ee for 4o-4x). To our delight, different functional groups such as
olefin, halide, TBS-protected hydroxyl, ester and acetal were
tolerated (Scheme 2, 4p-4v), which allowed further
manipulations for constructing advanced intermediates.
Aromatic alkynone also compatible with the reaction conditions,
albeit with decreased enantioselectivities (Scheme 2, 4y and 4z).
Having established a reliable protocol for constructing
enantioenriched spiro[pyrrolidine-3,3’-oxindole], we turned our
attention to the synthesis of strychnos alkaloids [(-)-tubifoline, (-
)-tubifolidine, (-)-dehydrotubifoline][13-15] by following the strategy
depicted in Figure 1. The synthesis commenced with the
preparation of spirooxindole ent-4c on decal gram scale using
this newly developed protocol (Scheme 3). Subsequently,
intramolecular condensation of the methyl ketone with oxindole
of ent-4c to forge the E ring proved to be quite challenging due
to the rapid racemization of ent-4c under acidic or basic
conditions.[7] After extensive screening of the reaction conditions,
we found that activation of the amide with Meerwein salt,
followed by formation of silyl enol ether and treatment with
TMSOTf in one pot smoothly delivered the tetracyclic product 5
in 82% yield over two steps without loss of enantiopurity.
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[10] For selected reviews on constructing quaternary carbon center using
oxindole as nucleophile, see: a) R. Dalpozzo, G. Bartoli, G. Bencivenni,
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currently pursued in our laboratory and the results will be
reported in due course.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (grand No. 21722206, 21672171),
the Scientific Research Foundation of Northwest A&F University.
Financial support from the Open Fund of State Key Laboratory
of Bioorganic & Natural Products is also acknowledged.
[11] During the preparation of this manuscript, Sasai and co-workers
developed a chiral amino-phosphine catalyzed sequential reaction of
tryptamine-derived oxindoles to alkynone. However, only one example
was reported with a best 84% ee being obtained. See: a) S. Takizawa,
K. Kishi, M. Kusaba, J. F. Bai, T. Suzuki, H. Sasai, Heterocycles 2017,
95, 761. During the submission of this manuscript, Liu and co-workers
reported the asymmetric cascade double Michael additions to construct
Keywords: tandem Michael addition, spiro[pyrrolidine-3,3’-
oxindole], Sc(OTf)3-chiral N,N’-dioxide, strychnos alkaloids,
tubifoline
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Weigang He, Jiadong Hu, Pengyan
Wang, Le Chen, Kai Ji, Siyu Yang, Ying
Li, Zhilong Xie and Weiqing Xie*
Page No. – Page No.
Highly Enantioselective Tandem
Michael Addition of Tryptamine-
Derived Oxindoles to Alkynones:
Concise Synthesis of Strychnos
Alkaloids
A novel strategy for synthesizing strychnos alkaloids is enabled by Sc(OTf)3-chiral
N,N’-dioxide catalyzed enantioselective tandem Michael addition of oxindole
derived from tryptamine to alkynone.
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