Phosphine-Catalyzed (3+2) Annulation of Isoindigos with Allenes: Enantioselective Formation of Two Vicinal Quaternary Stereogenic Centers

Article abstract of DOI:10.1002/anie.201900758

Construction of contiguous all-carbon quaternary stereogenic centers is a long-standing challenge in synthetic organic chemistry. In this report, a phosphine-catalyzed enantioselective (3+2) annulation reaction between allenes and isoindigos, containing either two identical or different oxindole moieties, is introduced as a powerful strategy for the construction of spirocyclic bisindoline alkaloid core structures. The reported reactions feature high chemical yields, excellent enantioselectivities, and very good regioselectivities, and are highly useful for creating structurally challenging bisindoline natural products.

Full text of DOI:10.1002/anie.201900758

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Accepted Article
Title: Phosphine-catalyzed (3+2) Annulation of Isoindigos with Allenes:
Highly Enantioselective Creation of Two Vicinal Quaternary
Stereogenic Centers
Authors: Yixin Lu, Wai-Lun Chan, Xiaodong Tang, Fuhao Zhang,
Glenn Quek, and Guang-Jian Mei
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900758
Angew. Chem. 10.1002/ange.201900758
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10.1002/anie.201900758
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Phosphine-catalyzed (3+2) Annulation of Isoindigos with Allenes:
Highly Enantioselective Creation of Two Vicinal Quaternary
Stereogenic Centers
Wai-Lun Chan,a Xiaodong Tang,a,b Fuhao Zhang,a,c Glenn Quek,a Guang-Jian Meia* and Yixin Lua,b*
Abstract: Construction of contiguous all-carbon quaternary
stereogenic centers is a long-standing daunting challenge in synthetic
organic chemistry. In this report, we introduce a phosphine-catalyzed
enantioselective (3+2) annulation reaction between allenes and
isoindigos containing two identical/different oxindole moieties as a
powerful strategy for the construction of spirocyclic bisindoline
alkaloid core structures. The reported reactions are featured with high
chemical yields, excellent enantioselectivities, and very good
regioselectivities, and are highly useful for creating structurally
challenging bisindoline natural products.
and rewarding from the synthetic point of view, since two vicinal
all-carbon quaternary stereogenic centers can be created in a
single-step operation.[6] We thus set our goal to develop
enantioselective annulation reactions making use of tetra-
substituted alkenes as a reaction partner, for the efficient
construction of molecular architectures containing two contiguous
all-carbon quaternary stereogenic centers.
R3
R2
R1
R3P*
R2
EWG1
•
+
EWG2
R3
EWG1
(3+2) Annulation
R1
EWG2
Unknown
Tetra-substituted
Alkenes
Two Vicinal All-carbon
Quaternary Centers
E
ven though seminal reports on phosphine-catalyzed reactions
can be traced back to 1960s, the field of phosphine catalysis was
dormant thereafter for a few decades. Two landmark discoveries
in 1990s, Lu’s (3+2) annulation[1a] and Trost’s “umpolung”
addition[1b] refueled the field and led to the renaissance of
phosphine catalysis. It was the past decade that has witnessed
Scheme 1. Tetra-substituted activated alkenes are challenging substrates in
phosphine-catalyzed (3+2) annulation reactions with allenes.
R
O
O
Bn
H
Bn
HN
H
H
H
N
H
N
Me
N
tremendous advancement of asymmetric phosphine catalysis;[2]
a
N
N
N
N
Me
O
kaleidoscope
transformations,
MoritaBaylisHillman
of
phosphine-catalyzed
such as annulations,
(MBH)
enantioselective
additions,
RauhutCurrier
O
O
O
N
Me
N
NH
Bn
Me
N
N
N
H
N
N
reactions,
H
H
H
R
Bn
H
O
O
(-)-Chimonanthine (R = H)
(-)-Folicanthine (R= Me)
reactions, and so forth, have been intensively investigated.
Among all the reactions that have been developed to date,
phosphine-triggered annulation reactions are the most common
reaction types. As the “signature” reaction, phosphine-promoted
(3+2) annulations of allenes received enormous attention and
have been most extensively studied.[3] With the invention of
families of powerful chiral phosphine catalysts, numerous
enantioselective (3+2) cyclization processes of allenes with
activated alkenes or imines have emerged.[4] While mono-, di-, or
tri-substituted activated alkenes are routinely used as a reaction
partner for the creation of five-membered chiral carbocyclic
systems, the utilization of tetra-substituted alkenes in phosphine-
catalyzed (3+2) asymmetric annulation remains elusive (Scheme
1).[5] The synthetic challenges faced are intrinsic: the highly
crowded nature of the tetra-substituted alkenes makes the
addition of the phosphonium zwitterionic species extremely
difficult. On the other hand, such reactions are highly interesting
(-)-Ditryptophenaline
(+)-WIN 64821
R1
R1
Readily accessible
Structurally diverse
Versatile reactivity
N
N
R5
Enantioselective
(3+2) annulation
O
H
R3
R4
R7
R3P*
+
•
O
CO2R
N
R2
H
Bisindoline
N
alkaloid core
R2
Isoindigo
Scheme 2. Selected HPI alkaloids with vicinal quaternary stereocenters and our
proposed (3+2) annulation between isoindigos and allenes.
Natural products encompassing two or more contiguous all-
carbon quaternary stereogenic centers are prevalent scaffolds
with a plethora of promising biological activities, and such
molecular architectures pose a long-standing daunting synthetic
challenge to organic chemists and stimulated intensive research
activities.[7] In this context, we were attracted to dimeric and
polymeric hexahydropyrroloindole (HPI) alkaloids,[8] a structurally
and biologically fascinating class of cyclotryptamine alkaloids with
a centerpiece bispyrrolidino[2,3-b]indoline bearing two sterically
congested adjacent all-carbon quaternary stereogenic centers at
the C3a and C3a’ positions. A few selected HPI alkaloids are
illustrated in Scheme 2. Limited catalytic methods for efficient
asymmetric construction of these motifs have been reported to
date, including: radical dimerization,[9a9i] and double
functionalizations, i.e. double decarboxylative allylation,[9j,9k]
double Michael addition,[9l] and double alkylation,[9m] among
others.[9n9s] Given the importance of HPI alkaloids family, there
clearly exists a need to develop efficient catalytic asymmetric
synthetic approaches for facile and versatile synthesis of these
molecules and their structural analogues. In connection to our
disclosure of amino acid-derived bifunctional phosphines and
[a]
W.-L. Chan, X. Tang, F. Zhang, G. Quek, Dr. G.-J. Mei and
Prof. Dr. Y. Lu
Department of Chemistry, National University of Singapore
3 Science Drive 3, 117543, Singapore.
E-mail: chmmeig@nus.edu.sg & chmlyx@nus.edu.sg
X. Tang and Prof. Dr. Y. Lu
National University of Singapore (Suzhou) Research Institute, 377
Lin Quan Street, Suzhou Industrial Park, Suzhou, Jiangsu
215123, China.
[b]
[c]
F. Zhang
Department of Chemistry, Southern University of Science and
Technology, Shenzhen 518000, China.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.2019XXXXX.
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10.1002/anie.201900758
Angewandte Chemie International Edition
COMMUNICATION
their applications in asymmetric synthesis,[10] we envisioned that
the core bispyrrolidino[2,3-b]indoline structure in HPI alkaloids[11]
may be conveniently constructed by employing an isoindigo as a
starting substance, via a phosphine-catalyzed (3+2) annulation
with an allene. Whereas the idea of installing two vicinal all-carbon
quaternary stereocenters at the C3a and C3a’ through a single-step
operation was very appealing to us, we were mindful that tetra-
substituted alkenes are inherently sterically encumbered and
have never been utilized in phosphine-catalyzed asymmetric
(3+2) annulation processes. We reasoned that the two oxindole
moieties may provide sufficient activations to the internally buried
double bond, and the planar oxindole structures may be less
sterically demanding that thus makes this otherwise extremely
difficult reaction feasible. Herein, we document an unprecedented
(3+2) annulation between isoindigos and allenes for highly
enantioselective creation of structures containing two vicinal
quaternary stereogenic centers.
[a] Reaction conditions: 1a (0.05 mmol), 2a (0.75 mmol), and the catalyst
(20 mol%) in the solvent specified (1 mL) at room temperature. [b] Yields
refer to isolated yields. [c] The ee values were determined by HPLC analysis
on a chiral stationary phase. Bn: benzyl; rt: room temperature; N.D.: not
determined.
We started our investigation by examining the potential
reaction between isoindigo 1a and benzyl 2,3-butadienoate 2a in
the presence of various chiral phosphine catalysts. We initially
employed isoindigo with an N-Boc protection; while the reactions
went to completion within a minute and the desired (3+2)
annulation products were formed in high yields, the
stereoselectivities of the reaction was less satisfactory. We
subsequently chose a less reactive isoindigo 1a for further studies
(Table 1). To our delight,
L-Thr-derived phosphineamide
catalysts displayed remarkable catalytic effects, affording
spirobisoxindole 3a in high chemical yield and with good
enantioselectivity. The best catalyst was O-TBDPS-L-Thr-derived
P4,[12] furnishing the desired 3a in 94% yield and 92% ee within
15 minutes (entry 4). All the other bifunctional phosphines bearing
different hydrogen bond donating groups, i.e. sulfonamide (P1),
carbamate (P7), thiourea (P8), urea (P9), and dipeptide
phosphine P10 were found to be ineffective, and so was mono-
Table 1: Optimization of the reaction conditions for phosphine-catalyzed (3+2)
annulation between isoindigo 1a and allene 2a.[a]
Bn
BnO
O
N
Bn
O
Catalyst (20 mol%)
O
•
N
+
functional bisphosphine P11 (entries 1,
& 711). Solvent
CO2Bn
Solvent, rt
screening was then followed. In general, less polar aprotic
solvents were better choices when ee values were concerned,
suggesting the importance of hydrogen bonding interactions for
the asymmetric induction (entries 1216). Very poor reactivity was
observed when the reaction was run in THF or methanol, as
isoindigo 1a was barely soluble in these solvents (entries 17, 18).
Under the optimized reaction conditions, when the reaction was
performed in diethyl ether in the presence of phosphine P4,
spirobisoxindole 3a was obtained in 93% yield and with 99% ee
in 1 hour (entry 12). Moreover, -benzyl-substituted benzyl
allenoate was also tested, and was found unreactive.[13]
2a
O
1a
O
3a
N
N
Bn
Bn
Yield[b]
(%)
Entry
Catalyst
Solvent
Time
ee (%)[c]
With the optimal reaction conditions in hand, we subsequently
proceeded to establish the scope of the reaction (Scheme 3). To
allow for flexibility in the subsequent structural manipulations of
the bisoxindole annulation products, we examined isoindigos with
either an N-methyl or N-allyl group, and the corresponding
annulation products were obtained in excellent yields and ee
values (3b & 3c). However, the isoindigo with an N-Ts protection
was not suitable; messy reaction was observed without formation
of any major products, and we suspect this may due to the
substrate over-activation induced by the electron-withdrawing
tosyl group. The ester moiety in the allenoate could also be varied;
spirocyclic annulation products with different ester groups were
obtained in very high yields and enantioselectivities, which is
desirable if such esters are to be selectively manipulated in
subsequent synthesis (3d, 3e, 3f & 3g). Isoindigos containing
oxindoles with different substituents were next investigated.
However, it turned out that most substituted isoindigos were
virtually insoluble in ether; after much experimentation, we
adopted toluene as the solvent of choice and performed the
reactions at 20 oC for the substituted isoindigos. The annulation
reaction was applicable to the substrates with different halogen
atoms on the oxindoles, and different substitution patterns were
also well tolerated. In all the examples examined, high yields and
excellent enantioselectivities were attainable (3h3n). Moreover,
the substrate containing oxindole moieties with an electron-
1
2
P1
P2
P3
P4
P5
P6
P7
P8
P9
P10
P11
P4
P4
P4
P4
P4
P4
P4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Et2O
1 h
10 min
10 min
15 min
15 min
30 min
15 min
12 h
83
95
0
77
86
92
78
73
6
3
91
4
94
5
73
6
76
7
89
8
61
17
31
N.D.
0
9
12 h
68
10
11
12
13
14
15
16
17
18
12 h
<30
75
30 min
1 h
93
99
91
86
90
77
N.D.
N.D.
Dioxane
CH2Cl2
EtOAc
1 h
98
1 h
87
2 h
80
CH3CN
THF
6 h
64
12 h
trace
trace
CH3OH
12 h
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10.1002/anie.201900758
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donating methyl group was found to be suitable as well (3o).
However, when isoindigo bearing a 5,7-dichloro-oxindoles was
employed in the reaction, even though the chemical yield was
excellent, the enantioselectivity of the reaction was only modest
(3p). The structures of the (3+2) annulation products were
assigned on the basis of X-ray crystallographic analysis of product
3a.
products bearing two structurally similar oxindole motifs. We
hypothesized that such delicate structural variation could be
conveniently realized by selecting oxindoles with different
electronic and steric properties. To embark on our investigation,
we chose isoindigo 4a and explored its annulation with allene 2a.
Indeed, the annulation proceeded smoothly in a regioselective
manner, and product 5a was obtained in excellent yield, with a 4:1
regioisomeric ratio (rr) and 92% ee (for the major regioisomer).
The observed regioselectivity could be rationalized following
mechanistic pathway illustrated in Scheme 4. Phosphine attack
on allene 2a creates zwitterionic intermediate Int-1. Between the
two possible regioisomeric attacks, the less hindered -attack is
apparently more favored for the subsequent addition to
structurally encumbered activated CC double bond in 4a. The
presence of 5-chlorine atom in one of the oxindoles in 4a makes
C3 more electron-deficient than C3’, thus leading to regioselective
formation of Int-2. The subsequent cyclization, followed by proton
transfer and regeneration of phosphine catalyst, yields the final
annulation product 5a.
Scheme 4. Formation of specific regioisomers from unsymmetric isoindigos:
mechanistic rationale.
We next prepared a range of unsymmetric isoindigos and
subjected them to P4-promoted (3+2) annulation reactions with
allene 2a, and the results are shown in Scheme 5. While the
presence of 5-Cl or 6-Cl in one of the oxindole rings led to the
formation of the annulation product with good regioselectivity (5a
or 5b), isoindigos containing an oxindole with two chlorine atoms
exerted stronger electronic effects, and only one regioisomer was
observed (5c & 5d). In comparison with 5-Cl oxindole-containing
substrate, isoindigo with 6-Cl oxindole had enhanced
regioselectivity in the cyclization, and such observation is
correlated well with the electronic effects induced by the chlorine
atom at these two positions (5a vs. 5b). Isoindigo with 5-Br
displayed similar selectivity to the 5-Cl analogue, likely due to the
interplay of both electronic and steric factors (5e vs. 5a).
Introducing an electron-donating group in one oxindole moiety led
to anticipated electronic differentiation of isoindigo, resulting in the
Scheme 3. Substrate scope of phosphine-catalyzed (3+2) annulation of
symmetric isoindigos 1 with allenes 2. Reaction conditions: 1 (0.05 mmol), 2
(0.75 mmol), and P4 (20 mol%) in diethyl ether (1 mL) at 0 oC or in toluene (1
mL) at –20 oC. Isolated yields are reported. The ee values of 3 were determined
by HPLC analysis on a chiral stationary phase. The absolute configurations of
the annulation products were assigned based on X-ray crystallographic analysis
of 3a (CCDC 1874573).
Apart from isoindigos containing two identical oxindole
moieties, isoindigo building blocks may also be constructed from
different oxindole subunits, i.e. unsymmetric isoindigos could
potentially be employed in the annulation. This perspective is truly
exciting: we envisaged that the employment of unsymmetric
isoindigos may create intriguing regioisomers of the annulation
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formation of the corresponding regioisomer (5f). When
isoindigoes containing one electron-rich oxindole moiety and
another electron-poor oxindole subunit were employed,
regioselective products were formed as expected (5g & 5h).
Interestingly, electronic differentiation could also be achieved by
utilizing different protective groups on the oxindole nitrogen (5i).
We also strived to test the limit of electronic-differentiating
strategy; isoindigo containing 5-F and 7-F oxindole moieties, as
well as isoindigo bearing 5-Cl and 6-Cl oxindole units were
examined in the annulation. In both cases, electronic difference
was too subtle to be differentiated, and products were obtained
with virtually no regioselectivity (5j & 5k).
containing two contiguous all-carbon quaternary stereogenic
centers. By employing isoindigos bearing two identical oxindole
moieties and utilizing amino acid-derived bifunctional phosphines,
various challenging dimeric spirocyclic bisindoline alkaloid motifs
were efficiently constructed in high chemical yields and with
excellent enantiomeric excesses. Moreover, structurally distinct
spirocyclic molecules bearing two different oxindole moieties
were conveniently derived from the corresponding unsymmetrical
isoindigo precursors. To the best of our knowledge, regioselective
annulation reaction making use of substrates bearing two similar
moieties with subtle structural difference is unprecedented. The
synthetic values of our methodology and annulation products
were demonstrated by concise formal total syntheses of ()-
Ditryptophenaline, ()-WIN 64821, ()-Chimonanthine, ()-
Folicanthine, and ()-Calycanthine, using phosphine-catalyzed
enantioselective (3+2) annulation between isoindigos and allenes
as the key step. Currently, we are intensively developing other
phosphine-catalyzed enantioselective processes, which will be
broadly applied to the total syntheses of families of bisindoline
alkaloids.
a
Bn
O
O
OBn
Bn
N
Bn
N
i) O3, CH2Cl2
,
78 oC,
iii) CH(OMe)3, TsOH H2O,
MeOH, reflux
N
O
then Zn, AcOH, reflux
ii) Et3N, MeOH, reflux
68% yield (2 steps)
H
O
O
O
iv) NaH, allyl bromide, DMF
86% yield (2 steps)
CH(OMe)2
O
N
O
N
Bn
N
8
Bn
7
Bn
3a (S,S; 99% ee)
O
O
Bn
HN
Bn
H
H
H
H
Bn
N
N
N
N
N
,
78 oC,
N
v) O3, CH2Cl2
then PPh3
Me
O
ref [9p]
O
O
O
O
O
vi) HCl/HOAc, reflux
88% yield (2 steps)
O
Me
NH
Bn
N
N
N
N
O
N
H
H
H
H
N
Bn
O
O
9
Bn
(
)-Ditryptophenaline
(
)-WIN 64821
b
Bn
Bn
Bn
N
N
O
N
Scheme 5. Substrate scope of phosphine-catalyzed (3+2) annulation of
unsymmetric isoindigos 4 with allene 2a. Reaction conditions: isoindigo 4 (0.05
mmol), 2 (0.75 mmol), and P4 (20 mol%) in toluene (1 mL) at – 20 oC. Isolated
yields are reported. The ee values of 5 were determined by HPLC analysis on
a chiral stationary phase. The regioisomer ratios (rr) were determined by 1H
NMR analysis.
vii) CH(OMe)3, MeOH,
TsOH H2Oreflux
O
C
ix) HCl/HOAc, reflux
x) LiBH4, MeOH, Et2
MeO2
H
O
O
HO
O
viii) NaH, DMF,2
OH
CH(OMe)2
O
80% yield (2 steps)
MeO2
C
Br
O
O
N
N
N
Bn
73% yield (2 steps)
11
10
Bn
7
Bn
H
H
N
Me
Me
N
H
N
Me
N
Me
refs. [9]
N
Known
conditions
H
N
N
Me
The aforementioned highly enantioselective phosphine-
catalyzed (3+2) cyclization between isoindogos and allenes
allows for quick creation of challenging bisindoline alkaloid core
structures, which are amenable for further synthetic
transformations (Scheme 6). Spirocyclic annulation product 3a
(99% ee) was subjected to ozonolysis;[14] decarboxylation took
place to afford bisoxindole 7. The subsequent acetal formation
and allylation afforded 8 in high yield. Another ozonolysis and
cleavage of the acetal deprotection furnished bisoxindole
aldehyde 9, which can be converted to ()-Ditryptophenaline and
()-WIN 64821 following literature procedures.[9j] Alternatively,
intermediate 7 was transformed to compound 10, via a convenient
acetalation and alkylation reaction sequence. Cleavage of the
acetal, followed by reduction then yielded bisoxindole diol 11,
which can be transformed to ()-Chimonanthine using the
procedures that were described in the literature.[9n] Furthermore,
by utilizing known reaction conditions, ()-Chimonanthine can be
N
N
NH
Me
Me
N
N
H
H
(
)-Calycanthine
H
Me
)-Folicanthine
(
)-Chimonanthine
(
Known conditions
Scheme 6. Formal total syntheses of ()-Ditryptophenaline, ()-WIN 64821, ()-
Chimonanthine, ()-Folicanthine, and ()-Calycanthine.[9]
Acknowledgements
Y.L. thanks the Singapore National Research Foundation, Prime
Minister’s Office for the NRF Investigatorship Award (R-143-000-
A15-281). Financial supports from the National University of
Singapore (R-143-000-695-114) and the National Natural
Science Foundation of China (21672158) are also gratefully
acknowledged.
elaborated to ()-Folicanthine[9a,9l] and ()-Calycanthine[9a,9l]
.
In summary, we have developed the first phosphine-catalyzed
highly enantioselective (3+2) annulation between allenes and
tetra-substituted alkenes, for the creation of structural motifs
Keywords: chiral phosphines • annulations • quaternary
stereocenters • indole alkaloids • enantioselective syntheses
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10.1002/anie.201900758
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This article is protected by copyright. All rights reserved.

10.1002/anie.201900758
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
OTBDPS
Wai-Lun Chan,a Xiaodong Tang,a,b
PPh2
O
N
H
R1
O
O
OR3
Fuhao Zhang,a,c Glenn Quek,a Guang-
R1
N
(20 mol%)
R2
O
N
F3C
CF3
•
Jian Meia* and Yixin Lua,b
*
HPI
Alkaloids
+
CO2R3
toluene, -20 oC, 1 h or
ether, 0 oC, 4 12 h
O
R2
O
R2'
N
N
R2'
R1
R1
Page No. – Page No.
One-Step Creation of Vicinal All-Carbon Quaternary Stereogenic Centers
High Efficiency (80 98% yields), & High Enantioselectivities (up to 99% ee)
Phosphine-catalyzed (3+2)
Annulation of Isoindigos with
Allenes: Highly Enantioselective
Creation of Two Vicinal Quaternary
Stereogenic Centers
Facile Formal Syntheses of Hexahydropyrroloindole (HPI) Alkaloids
Phosphine-catalyzed enantioselective (3+2) annulation reaction between allenes
and isoindigos was introduced for the first time as a powerful strategy for the
construction of structural motifs containing two vicinal quaternary stereogenic
centers. The reactions documented are featured with high chemical yields,
excellent enantioselectivities, and very good regioselectivities, and are highly useful
for creating structurally challenging bisindoline natural products.
[a]
[b]
W.-L. Chan, X. Tang, F. Zhang, G. Quek, Dr. G.-J. Mei and
Prof. Dr. Y. Lu
Department of Chemistry, National University of Singapore
3 Science Drive 3, 117543, Singapore.
E-mail: chmmeig@nus.edu.sg & chmlyx@nus.edu.sg
X. Tang and Prof. Dr. Y. Lu
National University of Singapore (Suzhou) Research Institute, 377
Lin Quan Street, Suzhou Industrial Park, Suzhou, Jiangsu
This article is protected by copyright. All rights reserved.
215123, China.
F. Zhang
[c]