Dielectrophilic Allenic Ketone-Enabled [4 + 2] Annulation with 3,3'-Bisoxindoles: Enantioselective Creation of Two Contiguous Quaternary Stereogenic Centers

Article abstract of DOI:10.1021/acscatal.0c05225

We introduced a type of allenic ketone as a dielectrophilic C4 synthon in phosphine-mediated reactions. The high electrophilicity of the advanced intermediates created upon phosphine activation empowered the utilization of 3,3′-bis-oxindoles as a two-carbon reaction partner in a highly enantioselective [4 + 2] annulation, allowing for facile creation of spirocyclic bisindoline structures containing two contiguous quaternary stereogenic centers. Synthetic manipulations of the [4 + 2] annulation product led to concise total synthesis of (-)-folicanthine.

Full text of DOI:10.1021/acscatal.0c05225

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Research Article
Dielectrophilic Allenic Ketone-Enabled [4 + 2] Annulation with 3,3’-
Bisoxindoles: Enantioselective Creation of Two Contiguous
Quaternary Stereogenic Centers
Xiaodong Tang, Chuan Xiang Alvin Tan, Wai-Lun Chan, Fuhao Zhang, Wenrui Zheng, and Yixin Lu*
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ABSTRACT: We introduced a type of allenic ketone as a
dielectrophilic C4 synthon in phosphine-mediated reactions. The
high electrophilicity of the advanced intermediates created upon
phosphine activation empowered the utilization of 3,3′-bis-
oxindoles as a two-carbon reaction partner in a highly
enantioselective [4 + 2] annulation, allowing for facile creation
of spirocyclic bisindoline structures containing two contiguous
quaternary stereogenic centers. Synthetic manipulations of the [4 +
2] annulation product led to concise total synthesis of
(−)-folicanthine.
KEYWORDS: allenic ketone, bifunctional phosphine, [4 + 2] annulation, quaternary stereogenic centers, dielectrophilic, dinucleophilic
Thereafter, such cyclization mode quickly gained popularity
and received much attention from synthetic community, and a
good number of excellent enantioselective [3 + 2] annulations
employing simple allenes had been developed over the years.2
Subsequently, the Kwon group made another seminal finding;
they utilized γ-substituted allenoates and activated alkenes and
discovered a new mode of [4 + 2] annulation. Notably, allenes
served as C4 synthons in the Kwon [4 + 2] annulations (eq.
b).3 Recently, we discovered that when substituted allenic
ketones reacted with unsaturated ketones or imines under the
phosphine catalysis, a novel mode of [4 + 2] annulation took
place in which allenic ketones acted as a C2 synthon (eq. c).4
It is noteworthy that all the above [3 + 2] and [4 + 2]
annulation reactions rely on the phosphine attack on allene
substrates to generate active nucleophilic species, which then
proceed to capture suitable electrophilic reaction partners to
complete the cyclization events. In this context, Tong’s [4 + n]
annulation represents a remarkable breakthrough in phosphine
catalysis.5 Tong and co-workers designed a special type of
allenoate containing a β’-acetate group, which upon reaction
with a phosphine catalyst creates an electrophilic intermediate,
suitable for reactions with nucleophilic reaction partners (eq.
d). The reversal of electronic requirements for reaction
INTRODUCTION
■
The past decade has witnessed remarkable progress of
asymmetric phosphine catalysis.1 Various phosphine-mediated
cyclizations are certainly among the most investigated reaction
types, which have been proven to be powerful for the
construction of ring systems, especially for five- or six-
membered cyclic structures. In 1995, Lu disclosed his seminal
finding on phosphine-catalyzed [3 + 2] cyclization between
nonsubstituted allenoate and activated alkenes in which the
allene served as a C3 reaction partner (Figure 1, eq. a, R1 = H).
Received: November 30, 2020
Revised: December 30, 2020
Published: January 13, 2021
Figure 1. Utilization of allenes in phosphine-mediated annulations
(some regioisomers and imine substrates are not shown).
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components in Tong’s [4 + n] annulation, as opposed to the
[3 + 2]/[4 + 2] cyclizations discovered earlier by others, is
especially noteworthy. Such reverse-electron-demand on
substrates in phosphine-mediated reactions opens up new
avenues for synthetic chemists to discover new reactions.
Over the past few years, we introduced a family of amino
acid-based bifunctional phosphine catalysts and showed their
values for a range of asymmetric transformations.6 In an effort
to continuously push the frontiers of phosphine catalysis, we
reckon the importance of designing new reaction partners,
which ideally would offer unprecedented reactivity, thus
allowing novel reaction pathways to take place. To date,
there are only three examples of utilizing allenoates as
dielectrophilic reaction partners in asymmetric [4 + 1]
annulations with a 1,1-dinucleophile, reported by us5b and
the Fu group.5c,d On the other hand, phosphine-mediated
asymmetric [4 + 2] annulation reaction between dielectro-
philic allenes and 1,2-dinucleophiles is unknown.7 It is rather
striking to notice the substantially different modes of reaction
for α-substituted allenoates and simple allenoates. Further-
more, reverse-electron-demand substrates in phosphine
catalysis are currently very limited. Thus, we devised a new
allenic ketone with a β’-acetate group, which was anticipated to
be a valuable synthon in phosphine catalysis (Figure 2). We
Figure 3. Evaluation of allenic ketone 1a and allenic ester 1b in PPh3-
catalyzed [4 + 1] annulation. Reactions were performed with 1 (0.12
mmol), 2 (0.1 mmol), Cs2CO3 (0.12 mmol), and PPh3 (0.02 mmol)
in toluene (2 mL) at room temperature for 5 h. Both allenic ketone
and allenoate were fully consumed; yields refer to isolated products.
with different nucleophilic reaction partners. Our next goal is
to explore practical values of this newly designed β’-acetate
allenic ketone in the context of asymmetric phosphine
catalysis, aiming to develop new reactions and address
challenging synthetic problems.
Figure 2. Design of a novel dielectrophilic C4 synthon: our
Novel [4 + 2] Annulation of Allenic Ketones with 3,3’-
Bisoxindoles. We recently became interested in effective
enantioselective construction of dimeric hexahydropyrroloin-
dole (HPI) alkaloids,9 a class of natural products containing
two adjacent quaternary stereogenic centers.10 With our
ongoing medicinal chemistry program toward efficient
asymmetric synthesis of HPI alkaloids, we questioned whether
a phosphine-based catalytic methodology may be applied to
the total synthesis of (−)-folicanthine, a member of HPI
alkaloids possessing potential anticancer and antifungal
activities. We envisioned that the core structure of
(−)-folicanthine can be conveniently constructed from a
bisoxindole and allenic ketone 1a; dielectrophilic allenic
ketone and dinucleophilic bisoxindoles are anticipated to
undergo [4 + 2] annulation readily to deliver a spirocyclic
product bearing two adjacent quaternary stereogenic centers
(Figure 4). It should be noted that the proposed reaction
represents the first example of utilizing allenes as a
dielectrophilic reaction partner in enantioselective [4 + 2]
cycloaddition with a 1,2-dinucleophile.
The viability of our proposal was first evaluated. When
bisoxindole 4a was exposed to allenic ketone 1a under the
catalysis of triphenylphosphine, a [4 + 2] annulation took place
smoothly, quantitatively furnishing the desired annulation
product containing two sterically highly congested quaternary
carbon centers. In stark contrast, when allenoate 1b was
employed, the annulation product was only obtained in 35%
yield.11 Such comparison studies firmly established that the
high electrophilicity of the advanced intermediate rendered by
incorporating a ketone moiety in the allene structure indeed is
crucial, especially for promoting reactions with weaker
nucleophiles, which are otherwise synthetically less viable.
hypothesis.
envisioned that exposure of such an allenic ketone (A) to a
phosphine catalyst will lead to the elimination of the acetate
group, resulting in an advanced dielectrophilic intermediate
(B). The presence of the ketone functionality is expected to
endow B with high electrophilicity, permitting subsequent
reactions with relatively weak nucleophiles. If a dinucleophile
containing two methine hydrogens is employed, a potential [4
+ 2] annulation may readily deliver a six-membered ring
system containing two adjacent quaternary carbon centers.
Herein, we report the first enantioselective [4 + 2] annulation
between C4-dielectrophiles and dicarbon nucleophiles.
RESULTS AND DISCUSSION
■
Establishing Reactivity of Allenic Ketones. To start our
investigation, we first wanted to find out whether allenic
ketone8 1a would possess desirable reactivity toward a variety
of different nucleophiles, especially in comparison with Tong’s
β’-acetate allenoate 1b. Therefore, [4 + 1] annulation of 1a
with C1 reaction partners possessing two electron-withdrawing
groups was chosen to establish the reactivity profile, and the
results are summarized in Figure 3. When allenic ketone 1a
was employed, the [4 + 1] annulation with various
dinucleophilic C1 synthons proceeded very smoothly,
affording annulation products in high to nearly quantitative
yields (3a to 3f). In contrast, the [4 + 1] annulation with
allenoate 1b, under otherwise identical reaction conditions,
afforded the desired products only in moderate to good yields
(3a’ to 3f’). It is noteworthy that allenic ketone 1a displayed
improved reactivity compared to allenoate 1b in its reactions
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a
Table 1. Reaction Screening
Figure 4. Feasibility study of the projected [4 + 2] annulation.
Reactions were performed with 1 (0.1 mmol), 4 (0.12 mmol),
Na2CO3 (0.12 mmol), and PPh3 (0.02 mmol) in toluene (2 mL) at
room temperature for 7 h. Both allenic ketone and allenoate were fully
consumed; yields refer to isolated products.
b
c
entry
cat.
solvent
toluene
base
t [h] yield (%)
ee (%)
1
2
3
4
5
6
7
8
P1
P2
P3
P4
P5
P6
P5
P5
P5
P5
P5
P5
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Li2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
4
4
6
8
8
8
3
20
8
8
8
8
99
99
99
98
98
98
77
85
30
90
trace
15
40
50
77
96
10
96
96
96
96
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
To develop an asymmetric version of [4 + 2] annulation
between allenic ketone 1a and bisoxindole 4a, we screened the
catalytic effects of different amino acid-based bifunctional
phosphines, and the results are summarized in Table 1. L-
Threonine-derived phosphine−amide catalysts P1 and P2 led
to the formation of the desired annulation product in
quantitative yields; however, the enantioselectivities were
poor (entries 1 and 2). While dipeptide phosphines P3 and
P4 offered enhanced enantioselectivities (entries 3 and 4), L-
Thr-L-tert-Leu-derived P5 was found to be an excellent catalyst
(entry 5). Surprisingly, structurally similar L-Thr-L-tert-Leu-
derived P6 gave the product with extremely low ee values
(entry 6). We subsequently examined effects of different bases
and also screened a number of solvents, and the results could
not be further improved (entries 7−12). Under the optimized
reaction conditions, the [4 + 2] annulation between allenic
ketone 1a and bisoxindole 4a occurred smoothly under the
catalysis of P5 and Na2CO3, and annulation product 5a was
obtained in 98% yield and with 96% ee (entry 5).
With the optimal conditions in hand, we next explored the
substrate scope (Figure 5). The reaction was applicable to
symmetric bisoxindoles containing different aryl substituents,
and the spirocyclic products were formed in very high yields
and with excellent ee values (5b to 5f). When the unsymmetric
bisoxindoles bearing different aryl moieties were employed, the
reaction proceeded in a regioselective and enantioselective
manner, forming the desired products in high yields (5g to
5m). Such regioselectivity can be rationalized mechanistically:
the more efficiently stabilized oxindole anion is formed
preferentially, which then attacks the dielectrophilic phospho-
nium intermediate at the β’-position,5e finally producing a
specific regioisomer favorably. It is apparent that the electronic
property difference of the two aryl moieties in bisoxindoles
determines the level of regioselectivity, e.g., unsymmetric
substrate containing a simple oxindole and an oxindole with a
para-fluoro-substitution led to the formation of annulation
products in a highly regioselective manner (5 L, rr > 20:1).12
We also tested aryl allenic ketones with a methyl group at
9
10
11
12
CH2Cl2
CH3CN
1,4-dioxane
d
d
-
-
a
Reactions were performed with 1a (0.12 mmol), 4a (0.1 mmol),
Na2CO3 (0.12 mmol), and the catalyst (0.02 mmol) in the solvent
specified (2 mL) at room temperature. Yields of isolated products.
Determined by HPLC analysis on a chiral stationary phase. No
b
c
d
reaction.
different positions of the phenyl ring, and the corresponding
products were obtained in excellent chemical yields and ee
values (5n to 5p). Furthermore, aliphatic allenic ketone could
also be employed, and the [4 + 2] annulation product was
formed in a highly enantioselective manner (5q). The absolute
configuration of 5g was determined based on X-ray crystal
structure analysis,13 and the regioisomerism and the config-
urations of other [4 + 2] annulation products were assigned by
analogy.
Mechanism Insight. The proposed reaction mechanism is
illustrated in Figure 6. Phosphine first attacks the allenic
ketone, eliminating acetate and generating the diene
intermediate I. The anionic bisoxindole attacks dielectrophilic
I at the β’-position, creating advanced intermediate II. The
subsequent intramolecular proton transfer gives anionic III,
which undergoes cyclization with the alkene moiety to afford
cyclized intermediate IV. Finally, another intramolecular
proton transfer followed by regeneration of the phosphine
catalyst furnishes the desired [4 + 2] annulation product. To
rationalize asymmetric induction, we believe that amide and
carbamate moieties of the catalyst interact with the bisoxindole
substrate through hydrogen bonding interactions and thus
direct the addition of anionic bisoxindole to phosphonium
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intermediate I, leading to the formation of the observed
stereoisomer.14
To gain better mechanistic understanding of this [4 + 2]
annulation process, preliminary mechanistic investigations
were carried out. The phosphorus species involved in the
reaction process were monitored by 31P NMR. Two new
resonances at 31.7 and 28.5 ppm were observed during the
course of the reaction, which are different from the resonances
of phosphine catalyst P5 (−23.9 ppm), phosphine oxide (33.8
ppm), and phosphonium diene intermediate I (22.7 ppm).
These results suggested that the steps of phosphonium I
formation and the addition of anionic bisoxindole to
phosphonium diene I are fast reaction steps and thus not
rate-determining for the overall reaction. Our kinetic studies
showed that the annulation reaction is first-order in the
phosphine catalyst and in the allenic ketone and also is first-
order in the bisoxindole nucleophile (see the Supporting
Information for details). Furthermore, we preformed deute-
rium-labeling experiments, the result which is shown in eq 1.
Under the otherwise identical reaction conditions, the rate of
reaction employing 4a-D was much slower than that of 4a; the
kinetic isotope effect was observed (KIE = 4). Taken together,
all the experimental evidence we have collected so far is
consistent with our proposed mechanism, whereby the proton
transfer processes are likely to be rate-determining steps. Given
the fact that allenic ketones are more reactive in the annulation
reaction than the allenic ester counterparts, the second
intramolecular proton transfer (from IV to V) in the proposed
catalytic cycle is likely to be crucial for rate determination.
Total Synthesis of (−)-Folicanthine. (−)-Folicanthine
was isolated from Calycanthus floridus15 and also the seeds of
Chimonanthus praecox.16 It belongs to a big family of HPI
alkaloids and possesses prominent biological activities.9b In the
reported total synthesis of (+)-folicanthine, the challenging
two vicinal quaternary stereogenic centers were constructed in
a stepwise fashion.17 We envisioned that our [4 + 2]
annulation product, which contains two contiguous quaternary
stereogenic centers, could be readily elaborated to the core
structure of (−)-folicanthine (Scheme 1). We started our
synthesis by subjecting 5a to ozonolysis, which yielded
aldehyde 6 in 85% yield, and the two quaternary stereogenic
Figure 5. Scope of the reaction. Reactions were performed with 1 (0.1
mmol), 4 (0.12 mmol), Na2CO3 (0.12 mmol), and P5 (0.02 mmol)
in toluene (2 mL) at room temperature. Yields are for isolated
products. The ee values were determined by HPLC analysis on a chiral
stationary phase. The regioisomer ratios (rr) were determined by H
NMR analysis. The reaction time was 12 h for 5j and 5 k.
1
Scheme 1. Concise Total Synthesis of (−)-Folicanthine
Figure 6. Proposed mechanism.
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centers in 6 were intact. In the presence of the aldehyde
functionality, selective oxidation of the di-ketone moiety with
lead tetraacetate furnished ester 7 in excellent yield.
Subsequently, Jones oxidation, removal of the Boc protective
group, and simultaneous methylation on oxindole nitrogens
and the carboxylic acid were carried out, which delivered
diester 8 in good chemical yield. Treatment of 8 with
methylamine yielded diamide 9 in a virtually quantitative
manner. The following cyclization via reductive amination was
carried out by treating 9 with LDA/DIBAL.18 While mono-
and bis-cyclized products were both formed, the former was
converted to the latter by reacting with LiAlH4. The final
reduction of the lactam moiety by Red-Al then completed the
total synthesis of (−)-folicanthine.
Chuan Xiang Alvin Tan − Department of Chemistry,
National University of Singapore, 117543, Singapore;
Graduate School for Integrative Sciences & Engineering
(NGS), National University of Singapore, 117456, Singapore
Wai-Lun Chan − Department of Chemistry, National
University of Singapore, 117543, Singapore; orcid.org/
0000-0002-3995-5985
Fuhao Zhang − Department of Chemistry, National University
of Singapore, 117543, Singapore; Department of Chemistry,
Southern University of Science and Technology, Shenzhen
518000, China
Wenrui Zheng − National University of Singapore (Suzhou)
Research Institute, Suzhou, Jiangsu 215123, China;
Department of Chemistry, National University of Singapore,
117543, Singapore
CONCLUSIONS
■
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05225
In summary, we introduced a new type of allenic ketone as a
dielectrophilic C4 synthon in phosphine catalysis. The
presence of the ketone functionality endowed the advanced
dielectrophilic C4 species with high reactivity, allowing for
efficient reaction with weak nucleophiles. The value of our
newly developed C4 synthon was demonstrated in an
asymmetric [4 + 2] annulation with dinucleophilic bisox-
indoles. Remarkably, spirocyclic bisoxindole scaffolds contain-
ing two contiguous quaternary stereogenic centers were
constructed in a simple one-step operation, in very high
chemical yields and with excellent enantioselectivities.
Furthermore, the power of the synthetic strategy reported
herein was demonstrated in a concise total synthesis of
(−)-folicanthine. The high electrophilicity observed for the
allenic ketone-derived C4 synthon will empower many new
transformations to take place, which were previously not
possible under phosphine-catalyzed conditions. We are
currently working in this direction, and our findings will be
reported in due course.
Author Contributions
X.T. performed and analyzed the experiments. W.C., F.Z.,
W.Z., and A.T. participated in the early development of the
project. X.T. and Y.L. conceived and designed the project. Y.L.
overall supervised the project. X.T. and Y.L. prepared this
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Y.L. thanks the National Natural Science Foundation of China
(21672158), the Singapore National Research Foundation
(NRF) for the NRF Investigatorship Award (R-143-000-A15-
281), and the National University of Singapore (R-143-000-
695-114 and C-141-000-092-001) for generous financial
support.
REFERENCES
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05225.
■
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Experimental procedure, optimization tables, and
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AUTHOR INFORMATION
Corresponding Author
■
Yixin Lu − National University of Singapore (Suzhou)
Research Institute, Suzhou, Jiangsu 215123, China;
Department of Chemistry, National University of Singapore,
117543, Singapore; Graduate School for Integrative Sciences
& Engineering (NGS), National University of Singapore,
117456, Singapore; Joint School of National University of
Singapore and Tianjin University, International Campus of
Tianjin University, Binhai New City, Fuzhou 350207,
China; orcid.org/0000-0002-5730-166X;
Email: chmlyx@nus.edu.sg
Authors
Xiaodong Tang − National University of Singapore (Suzhou)
Research Institute, Suzhou, Jiangsu 215123, China;
Department of Chemistry, National University of Singapore,
117543, Singapore
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