Catalytic Enantioselective Diels-Alder Reactions of Benzoquinones and Vinylindoles with Chiral Magnesium Phosphate Complexes

Article abstract of DOI:10.1021/acs.orglett.9b01437

Tetrahydrocarbazole and its derivatives have received much attention due to the prevalence of this scaffold in natural products and their use in organic synthesis. We have developed a Diels-Alder reaction of benzoquinones and 3-vinylindoles catalyzed by c

Full text of DOI:10.1021/acs.orglett.9b01437

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Enantioselective Diels−Alder Reactions of Benzoquinones
and Vinylindoles with Chiral Magnesium Phosphate Complexes
Yujia Bai, Jinping Yuan, Xiaoyue Hu, and Jon C. Antilla*
Institute for Molecular Design and Synthesis, School of Pharmaceutical Science and Technology, Health Science Platform, Tianjin
University, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: Tetrahydrocarbazole and its derivatives have received
much attention due to the prevalence of this scaffold in natural products
and their use in organic synthesis. We have developed a Diels−Alder
reaction of benzoquinones and 3-vinylindoles catalyzed by chiral
magnesium phosphate complexes to provide tetrahydrocarbazole
derivatives in excellent yields and enantioselectivities (up to >99%
yield, 99% ee). This transformation features a wide substrate scope,
excellent enantioselectivities, and mild conditions.
etrahydrocarbazole has received considerable interest as a
building block for the construction of bioactive natural
and report an efficient asymmetric Diels−Alder reaction for the
formation of tetrahydrocarbazole derivatives.
T
products that often exhibit significant biological activity
Chiral phosphoric acid based catalysts derived from
substituted BINOL have been previously successfully em-
ployed in enantioselective Diels−Alder reactions. In 2006,
Akiyama developed an aza-Diels−Alder reaction catalyzed by a
chiral phosphoric acid derived from BINOL, using 2-
hydroxyphenyl imines with Brassard’s diene.3 In the same
year, he also extended his results utilizing imine substrates.4
Terada also showed a hetero-Diels−Alder reaction of ethyl
glyoxylate and dienes to synthesize dihydropyrans in 2009.5
However, when one considers the use of chiral phosphate
metal catalysts with multiple coordination sites being possible,
often as alkali and alkaline-metal salts, one can realize why
chiral phosphates as ligands for asymmetric catalysis could be
attractive.6 Inanaga’s group pioneered the utilization of chiral
lanthanide phosphates and a series of other chiral phosphates
in asymmetric Diels−Alder reactions.7 Later, Feng8 and Zhu9
reported the hetero-Diels−Alder reactions with other chiral
BINOL derived catalysts. In addition, our group used metal
phosphates as catalysts to develop new enantioselective Diels−
Alder reactions.10 The Ricci group has reported that chiral
thioureas, a bifunctional acid−base organocatalyst system,
catalyze the D−A reaction of 3-vinylindoles with different
representative dienophiles for obtaining optically active
tetrahydrocarbazole derivatives.11 However, effective catalysts
have rarely been reported for the generation of optically active
tetrahydrocarbazole derivatives in D−A reactions.12 This
inspired our exploration of a catalytic system for preparing
(Figure 1).1a,b Carbazoles and derivatives are also frequently
Figure 1. Examples of the tetrahydrocarbazole core in natural
products and organic materials.
found in organic functional materials as the primary
scaffold.1c−e It is therefore of particular interest to develop or
improve synthetic methods for the controlled synthesis of
tetrahydrocarbazole derivatives. Diels−Alder type reactions are
one of the most powerful transformations for the construction
of six-membered ring structures in organic chemistry, rapidly
giving access to cyclic and polycyclic compounds that contain
multiple stereocenters.2 We based our work on the [4 + 2]
cycloaddition reactions of benzoquinones and 3-vinylindoles,
Received: April 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
enantioselective tetrahydrocarbazole skeletons utilizing the
Diels−Alder reaction.
enantioselectivity was obtained when using methylcyclohexane
as the solvent at −25 °C (entry 17).
We initiated our study for the asymmetric Diels−Alder
reaction by utilizing benzoquinone and 3-vinylindoles as
starting materials (ratio of 1a/2a = 1:1.5). We screened
various chiral metal BINOL phosphate catalysts (5 mol %) in
ether. Metal phosphates of calcium and magnesium were found
to be superior after an extensive initial discovery. The reaction
successfully gave the desired product 3a in full conversion and
in good isolated yields (Table 1, entries 1−11). Catalyst
We next we turned our attention to the substrate scope of
benzoquinones for the Diels−Alder reaction under the
optimized reaction conditions (Scheme 1, 3a−3h). A series
a−c
Scheme 1. Substrate Scope of Benzoquinones 1a−i
a c
−
Table 1. Optimization of Reaction Conditions
b
c
entry
catalyst
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ca[P1]2
Ca[P2]2
Mg[P2]2
Ca[P3]2
Mg[P3]2
Mg[P3]2
Mg[P4]2
Mg[P5]2
Mg[P6]2
Mg[P7]2
Mg[P8]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
Mg[P4]2
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
ether
90
85
87
92
94
91
94
90
92
85
93
87
92
93
76
94
91
94
90
84
17
7
4
24
47
20
78
53
25
10
38
74
79
83
7
61
96
85
75
62
d
hexane
cyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
methylcyclohexane
e
a
Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), 5 mol %
f
catalyst and 1.0 mL methylcyclohexane with 4 Å MS as an additive
g
b
under argon at room temperature. dr >95:5. Isolated yield.
c
d
h
Determined by chiral HPLC analysis. The absolute configurations
i
were determined by comparison of the data with literature values
19
20
e
from the Ricci group.11a The ratios of two products were determined
j
by HPLC.
a
Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), 5 mol %
catalyst, and 1.0 mL of ether with 4 Å MS as an additive under argon
b
c
at room temperature. Isolated yield. Determined by chiral HPLC
of benzoquinones bearing differing substituents were evaluated
as substrates. The desired products 3a−3f were obtained in
92−99% yields and 82−98% ee. Among these substrates, we
found that 1d and 1e were expectedly converted each into two
regioisomers (3d/3d′ and 3e/3e′) with high yields and
excellent enantioselectivities. Benzoquinones with a methyl
group (1d) or a hydroxyl group (1e) are suitable reaction
partners for this transformation. Under the control of the
catalyst, we found the ratio of these two regioisomers was
changed dramatically (from 86:14 to 7:93). Although we
cannot separate the two regioisomers, the chiral metal
phosphate catalyst appears to have a clear effect on the
reaction mechanism. With halogen groups on the benzoqui-
nones lower efficiency and/or enantioselectivity was found (3g
and 3h). There is possible speculation that the halogen atoms
d
e
f
analysis. Without 4 Å MS as an additive. Run at −78 °C. Reaction
g
h
temp: −50 °C. Reaction temp: −25 °C. Reaction temp: 0 °C.
i
j
Reaction temp: 50 °C. Reaction temp: 75 °C.
screening revealed that Mg[P4]2 could provide the product 3a
with the highest enantiomeric excess (94% yield, 78% ee). In
addition, a variety of common organic solvents were explored
for the optimum conditions (entries 12−14). To our delight,
methylcyclohexane was found to be the most suitable solvent
for this transformation, allowing for a 93% yield and 83% ee of
3a (entry 14). We also discovered that activated 4 Å molecular
sieves (MS) (entries 6−7), and lowering the temperature
(entries 15−20), were additional advantageous conditions,
significantly improving the ee value. Eventually, the best
B
DOI: 10.1021/acs.orglett.9b01437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
interfered with the interaction between substrates and the
catalyst.
Scheme 3. Substrate Scope of N-Protected Group of 3-
Vinylindoles
a b c
, ,
Subsequently, we varied the structure of the 3-vinylindoles
to investigate the generality of this transformation (Scheme 2,
a b c
, ,
Scheme 2. Substrate Scope of 3-Vinylindoles 2b−m
a
Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), 5 mol %
catalyst, and 1.0 mL of methylcyclohexane with 4 Å MS as an additive.
b
c
Isolated yield. Determined by chiral HPLC analysis.
good ee and yield. However, the use of a 4-chlorobenzyl group
led to a slightly lower ee (4r). We assumed that a possible
interference via H-bond interaction with the catalyst Mg[P4]2
and 3-vinylindole could explain the lower ee in the N−H
indole (2n) case (product 4n). The ee value of 4o was
presumably lower due to the steric hindrance formed by the
proximity of the PMP group to the reaction site. In addition,
an electron-donating group could render the diene more
reactive, leading to changes in the reaction.
a
Reaction conditions: 1a (0.05 mmol), 2a (0.075 mmol), 5 mol %
catalyst, and 1.0 mL of methylcyclohexane with 4 Å molecular sieve as
an additive; dr >95:5. Isolated yield. Determined by chiral HPLC
analysis. The relative configuration determined by NOESY spec-
troscopy (detail in Supporting Information). Reaction carried out at
b
c
d
e
−25 °C for 48 h.
On the basis of the above study, and the presumed catalyst
structure, we speculate a possible transition state for the
asymmetric Diels−Alder reaction catalyzed by the chiral
magnesium phosphate salt (Scheme 4). The carbonyl group
of benzoquinone would be presumed to coordinate with Mg2+
to obtain the tetrahydrocarbazole intermediate in which the
4b−4m). A halogen group (F, Br, Cl) at the 4-, 5-, 6-, and 7-
position of the indole nucleus was well tolerated (4b−4g),
furnishing the desired products with 85−96% ee. The use of
electron-donating groups (Me, OMe) on the indole induced
remarkably high selectivity for the respective products (4h−4l,
up to >99% ee). To investigate the effect of different alkenyl
isomers on the stereoselectivity of the reaction, we utilized
propenyl groups on the indole in the 3-position. The E/Z
mixture of diene 2m underwent the cycloaddition reaction,
giving the product 4m as a single diastereoisomer with
relatively good enantioselectivity. The decreased ee value
(83%) of the product 4m provided experimental evidence for
the possible speculation that the methyl group in the isomer
might cause unfavorable interactions in the transition state en
route to 4m.
Scheme 4. Proposed Transition State for the Magnesium
Phosphate Salt Catalyzed Asymmetric D−A Reaction
Further substrate modification of the N-protected groups on
the 3-vinylindoles was investigated in Scheme 3. The
protecting groups on nitrogen atoms have a significant effect
on this reaction: the products with N-benzyl groups resulted in
higher ee values. Use of the PMB group or a tert-butyl
substituted benzyl group gave the desired products (4p−4r) in
C
DOI: 10.1021/acs.orglett.9b01437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Angew. Chem., Int. Ed. 2002, 41, 1668−1698. (d) Fringuelli, F.;
Taticchi, A. The Diels−Alder Reaction: Selected Practical Methods;
Wiley: New York, 2002. (e) Andrus, M. B.; Saavedra, D. I. The
vinylarene Diels−Alder reaction, development and potential. Tetrahe-
dron DOI: 10.1016/j.tet.2019.02.039.
(3) Itoh, J.; Fuchibe, K.; Akiyama, T. Chiral Brønsted Acid
Catalyzed Enantioselective Aza-Diels−Alder Reaction of Brassard’s
Diene with Imines. Angew. Chem., Int. Ed. 2006, 45, 4796−4798.
(4) (a) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K.
Enantioselective Aza-Diels-Alder Reaction Catalyzed by a Chiral
Brønsted Acid: Effect of the Additive on the Enantioselectivity. Synlett
2006, 1, 141−143. (b) Akiyama, T.; Morita, H.; Fuchibe, K. Chiral
Brønsted Acid-Catalyzed Inverse Electron-Demand Aza Diels-Alder
Reaction. J. Am. Chem. Soc. 2006, 128, 13070−13071. (c) Masson, G.;
Lalli, C.; Benohoud, M.; Dagousset, G. Catalytic enantioselective [4 +
2]-cycloaddition: a strategy to access aza-hexacycles. Chem. Soc. Rev.
2013, 42, 902−923.
benzene ring of the dienophile is shielded by the TRIP group,
while leaving the CC double bond open for the 3-
vinylindole approach to form endo product 4d. Additionally,
the benzyl group was in proximity to the other TRIP group.
These analyses can explain the stereoselective outcomes of the
asymmetric D−A reaction catalyzed by Mg[P4]2. Since the
product 4d was found to be fairly easily aromatized in air over
time, its derivative 4d-1 was obtained directly by a reduction
reaction to make the tetrahydrocarbazole skeleton more stable
(Shown below in Scheme 4).
In conclusion, we have developed a mild Diels−Alder
reaction catalyzed by a chiral metal magnesium phosphate
complex with high enantioselectivity and efficiency. It provides
a suitable method for the formation of tetrahydrocarbazole
derivatives as exemplified in a number of investigations into
the substrate scope. Simultaneously, a proposed monoactiva-
tion is invoked as a possible explanation of the origin of
stereoselectivity in this interesting reaction.
(5) Momiyama, N.; Tabuse, H.; Terada, M. Chiral Phosphoric Acid-
Governed Anti-Diastereoselective and Enantioselective Hetero-Diels-
Alder Reaction of Glyoxylate. J. Am. Chem. Soc. 2009, 131, 12882−
12883.
ASSOCIATED CONTENT
* Supporting Information
(6) (a) Hatano, M.; Ikeno, T.; Matsumura, T.; Torii, S.; Ishihara, K.
Chiral Lithium Salts of Phosphoric Acids as Lewis Acid-Base
Conjugate Catalysts for the Enantioselective Cyanosilylation of
Ketones. Adv. Synth. Catal. 2008, 350, 1776−1780. (b) Klussmann,
M.; Ratjen, L.; Wakchaure, V.; Goddard, R.; List, B. Synthesis of
TRIP and Analysis of Phosphate Salt Impurities. Synlett 2010, 2010,
2189−2192. (c) Rueping, M.; Nachtsheim, B. J.; Koenigs, R. M.;
Ieawsuwan, W. Synthesis and Structural Aspects of N-Triflylphos-
phoramides and Their Calcium Salts-Highly Acidic and Effective
Brønsted Acids. Chem. - Eur. J. 2010, 16, 13116−13126. (d) Parra, A.;
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01437.
Experimental details, experimental preparations, charac-
terization, NMR spectra, chiral HPLC conditions, and
other data (PDF)
́
Reboredo, S.; Castro, A. M. M.; Aleman, J. Metallic organophosphates
AUTHOR INFORMATION
as catalysts in asymmetric synthesis: a return journey. Org. Biomol.
Chem. 2012, 10, 5001−5020.
■
Corresponding Author
*E-mail: jantilla@tju.edu.cn.
ORCID
(7) (a) Inanaga, J.; Furuno, H.; Hayano, T. Asymmetric Catalysis
and Amplification with Chiral Lanthanide Complexes. Chem. Rev.
2002, 102, 2211−2225. (b) Hayano, T.; Sakaguchi, T.; Furuno, H.;
Ohba, M.; Okawa, H.; Inanaga, J. Novel Cerium(III)-(R)-BNP
Complex as a Storable Chiral Lewis Acid Catalyst for the
Enantioselective Hetero-Diels-Alder Reaction. Chem. Lett. 2003, 32,
608−609. (c) Furuno, H.; Hayano, T.; Kambara, T.; Sugimoto, Y.;
Hanamoto, T.; Tanaka, Y.; Jin, Y. Z.; Kagawa, T.; Inanaga, J. Chiral
rare earth organophosphates as homogeneous Lewis acid catalysts for
the highly enantioselective hetero-Diels-Alder reactions. Tetrahedron
2003, 59, 10509−10523. (d) Furuno, H.; Kambara, T.; Tanaka, Y.;
Hanamoto, T.; Kagawa, T.; Inanaga, J. Highly enantioselective
homogeneous catalysis of chiral rare earth phosphates in the hetero-
Diels-Alder reaction. Tetrahedron Lett. 2003, 44, 6129−6132.
(8) Lin, L. L.; Liu, X. H.; Feng, X. M. Asymmetric Hetero-Diels-
Alder Reactions of Danishefsky’s and Brassard’s Dienes with
Aldehydes. Synlett 2007, 2007, 2147−2157.
Jon C. Antilla: 0000-0002-8471-3387
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Our work was supported by financial support from the
National 1000 Talent Plan of China and from Tianjin
University for start-up funds.
REFERENCES
■
̈
(1) (a) Knolker, H. J.; Reddy, K. R. Isolation and Synthesis of
Biologically Active Carbazole Alkaloids. Chem. Rev. 2002, 102, 4303−
(9) Mao, Z. J.; Li, W. P.; Shi, Y.; Mao, H. B.; Lin, A. J.; Zhu, C. J.;
Cheng, Y. X. Enantioselective Construction of Dihydropyran N-Fused
Indoles through Chiral Calcium Phosphate Catalyzed Oxo-Hetero-
Diels-Alder Reactions by Using 2-Oxoindolin-3-ylidenes as Hetero-
dienes. Chem. - Eur. J. 2013, 19, 9754−9759.
̈
4427. (b) Schmidt, A. W.; Reddy, K. R.; Knolker, H. J. Occurrence,
Biogenesis, and Synthesis of Biologically Active Carbazole Alkaloids.
Chem. Rev. 2012, 112, 3193−3328. (c) Wakim, S.; Bouchard, J.;
Simard, M.; Drolet, N.; Tao, Y.; Leclerc, M. Organic Micro-
electronics: Design, Synthesis, and Characterization of 6,12-
Dimethylindolo[3,2-b]Carbazoles. Chem. Mater. 2004, 16, 4386−
4388. (d) Boudreault, P. L.; Wakim, S.; Blouin, N.; Simard, M.;
Tessier, C.; Tao, Y.; Leclerc, M. Synthesis, Characterization, and
Application of Indolo[3,2-b]carbazole Semiconductors. J. Am. Chem.
Soc. 2007, 129, 9125−9136. (e) Blouin, N.; Leclerc, M. Poly(2,7-
carbazole)s: Structure-Property Relationships. Acc. Chem. Res. 2008,
41, 1110−1119.
(2) (a) Kagan, H. B.; Riant, O. Catalytic Asymmetric Diels-Alder
Reactions. Chem. Rev. 1992, 92, 1007−1019. (b) Jørgensen, K. A.
Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl
Compounds and Imines. Angew. Chem., Int. Ed. 2000, 39, 3558−
3588. (c) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. The Diels-Alder Reaction in Total Synthesis.
(10) (a) Zhang, Z. H.; Zheng, W. H.; Antilla, J. C. Highly
Enantioselective Catalytic Benzoyloxylation of 3-Aryloxindoles Using
Chiral VAPOL Calcium Phosphate. Angew. Chem. 2011, 123, 1167−
1170. (b) Zhang, Z. H.; Antilla, J. C. Enantioselective Construction of
Pyrroloindolines Catalyzed by Chiral Phosphoric Acids: Total
Synthesis of (−)-Debromoflustramine B. Angew. Chem., Int. Ed.
2012, 51, 11778−11782. (c) Li, G. L.; Liang, T.; Wojtas, L.; Antilla, J.
C. An Asymmetric Diels-Alder Reaction Catalyzed by Chiral
Phosphate Magnesium Complexes: Highly Enantioselective Synthesis
of Chiral Spirooxindoles. Angew. Chem., Int. Ed. 2013, 52, 4628−4632.
(d) Liang, T.; Li, G. L.; Wojtas, L.; Antilla, J. C. Chiral metal
phosphate catalysis: highly asymmetric hetero-Diels-Alder reactions.
Chem. Commun. 2014, 50, 14187−14190.
D
DOI: 10.1021/acs.orglett.9b01437
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) (a) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A.
Organocatalytic Asymmetric Diels-Alder Reactions of 3-Vinylindoles.
Angew. Chem., Int. Ed. 2008, 47, 9236−9239. (b) Gioia, C.; Bernardi,
L.; Ricci, A. Asymmetric Diels-Alder Reactions of Vinylindoles Using
Organocatalysis. Synthesis 2010, 2010, 161−170.
(12) (a) Pirovano, V.; Abbiati, G.; Dell’Acqua, M.; Facoetti, D.;
Giordano, M.; Rossi, E. Diels-Alder Reactions of 2-Vinylindoles with
Cyclic Dienophiles: Synthesis of [c]-Annulated Tetrahydrocarbazoles.
Synlett 2012, 23, 2913−2918. (b) Zhou, L. J.; Xu, B.; Zhang, J. L.
Metal-Free Dehydrogenative Diels-Alder Reactions of 2-Methyl-3-
Alkylindoles with Dienophiles: Rapid Access to Tetrahydrocarbazoles,
Carbazoles, and Heteroacenes. Angew. Chem., Int. Ed. 2015, 54,
9092−9096. (c) Wang, Y.; Tu, M. S.; Yin, L.; Sun, M.; Shi, F.
Brønsted Acid Catalyzed Asymmetric Diels-Alder Reactions: Stereo-
selective Construction of Spiro[tetrahydrocarbazole-3,3′-oxindole]
Framework. J. Org. Chem. 2015, 80, 3223−3232. (d) Wu, X.; Zhu,
H. J.; Zhao, S. B.; Chen, S. S.; Luo, Y. F.; Li, Y. G. An Asymmetric
Dehydrogenative Diels-Alder Reaction for the Synthesis of Chiral
Tetrahydrocarbazole Derivatives. Org. Lett. 2018, 20, 32−35. (e) Gu,
B. Q.; Yang, W. L.; Wu, S. X.; Wang, Y. B.; Deng, W. P.
Organocatalytic asymmetric synthesis of tetrahydrocarbazoles via an
inverse-electron-demand Diels-Alder reaction of 2,3-indole-dienes
with enals. Org. Chem. Front. 2018, 5, 3430−3434.
E
DOI: 10.1021/acs.orglett.9b01437
Org. Lett. XXXX, XXX, XXX−XXX