Highly Diastereo- and Enantioselective Synthesis of Cyclohepta[b]indoles by Chiral-Phosphoric-Acid-Catalyzed (4+3) Cycloaddition

Article abstract of DOI:10.1002/anie.201807069

A highly enantio- and diastereoselective formal (4+3) cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols in the presence of a chiral phosphoric acid catalyst is reported. The approach described herein provides efficient access to 6-aminotetrahydrocyclohepta[b]indoles in good yields with mostly complete diastereoselectivity and excellent levels of enantioselectivity (>98:2 dr and up to 98 % ee). Mild reaction conditions, facile scale-up, and versatile derivatization highlight the practicality of this methodology. A mechanistic study suggests that cycloaddition occurs in a stepwise fashion, after the formation of an ion pair between the chiral catalytic phosphate and the intermediate carbocation.

Full text of DOI:10.1002/anie.201807069

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Accepted Article
Title: Highly Diastereo- and Enantioselective Synthesis of Cyclo-
hepta[b]indoles via Chiral Phosphoric Acid-Catalyzed (4+3)-
Cycloaddition
Authors: Coralie Gelis, Guillaume Levitre, Jérémy Merad, Pascal
Retailleau, Luc Neuville, and Géraldine Masson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807069
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10.1002/anie.201807069
Angewandte Chemie International Edition
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Highly Diastereo- and Enantioselective Synthesis of Cyclo-
hepta[b]indoles via Chiral Phosphoric Acid-Catalyzed (4+3)-
Cycloaddition
Coralie Gelis,+ Guillaume Levitre,+ Jérémy Merad,+ Pascal Retailleau, Luc Neuville and Géraldine
Masson*
Abstract: A highly enantio- and diastereoselective formal (4+3)-
cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols
using a chiral phosphoric acid catalyst is reported. The approach
described herein provides efficient access to 6-amino-
tetrahydrocyclohepta[b]indoles in good yields with excellent levels of
enantioselectivity (>98:2 dr and up to 98% ee) and mostly complete
diastereoselectivity. Mild reaction conditions, easy scale-up, and
versatile derivatization highlight the practicality of this methodology.
The mechanism study suggests that cycloaddition occurs in a
stepwise fashion, after formation of an ion pair between the chiral
catalytic phosphate and the intermediate carbocation.
cycloadditions[8] appear as the most efficient, direct, and
approach. Surprisingly, only one asymmetric version
has been disclosed by Sun et al. in which Rh-catalyzed
dearomative (4+3)-cycloaddition of vinylindoles led to
cyclohepta[b]indolines with high ee. [9] However, the formation of
more complex and easily post-functionalizable scaffolds would be
particularly useful considering the structural diversity of
biologically active cyclohepta[b]indoles. In this way, we wish to
report the first highly diastereo- and enantioselective preparation
of polysubstituted cyclohepta[b]indoles based on an
organocatalyzed (4+3)-cycloaddition process.
Cyclohepta[b]indole unit is present in a large number of natural
[1,2]
products, and pharmaceutical drugs.
Examples include
exotines A and B isolated from Murraya exotica,[2a] actinophyllic
acid from the leaves of Alstonia actinophylla,[2b] ervitsine from
Pandacea boiteau,[2c] and a synthetic sirtuin 1 inhibitor (Figure
1).[2d,e] Although their prominence in natural and non-natural
bioactive molecules has stimulated considerable synthetic efforts
in this area,[1,2] the construction of cyclohepta[b]indoles in a
stereodefined way remains challenging[3] and very few methods
account for the asymmetric formation of such molecules.[4]. Multi-
step syntheses have been reported by the groups of Gaich[4a] and
Zheng and You[4b] in which the cyclohepta[b]indole moiety was
delivered by a diastereoselective cyclization of enantioenriched
preformed precursor. In 2011, Enders et al. reported the first
enantioselective synthesis of the corresponding seven-
membered ring based on two consecutive Friedel–Crafts
reactions catalyzed by a chiral thioamide and AuI sequentially.[4c]
Even though the enantioselectivity was excellent (up to 99% ee),
this elegant approach is mainly limited to the formation of mono-
substituted benzocyclohepta[b]indoles. Two years later, Hong et
al. described an enantioselective organocatalytic one pot, two-
Figure 1. Representative cyclohepta[b]indole compounds.
As part of a program directed toward the stereoselective synthesis
of heterocycles,[10] we recently described an efficient
enantioselective
synthesis
of
trisubstituted
cyclopenta[b]indoles[10c] via a chiral phosphoric acid-catalyzed
(3+2)-cycloaddition
generated in
between
from
alkylideneindoleninium
indolylarylmethanols[11]
ions
and
situ
enecarbamates as dienophiles.[12,13] We also reported that chiral
phosphoric catalysts were able to efficiently catalyze asymmetric
nitroso-Diels–Alder reactions with 1,3-diene-1-carbamates.[10b,14]
Since (4+3)-cycloadditions have already been established
starting from indolylarylmethanols,[1,6h-m] we reasoned that
dienecarbamates could suit well as partners to develop the first
catalytic enantioselective (4+3) cycloadditions in the presence of
a chiral phosphoric acid. To validate this assumption, we initially
attempted to conduct the reaction of indolyl(phenyl)methanol
derivative 1a with benzyl (penta-1,3-dien-1-yl)carbamate 2a with
step sequential
process to synthesize trisubstituted
cyclohepta[b]indoles with excellent enantioselectivity, albeit
moderate diastereoselectivity. [4d]
In this context, the development of a straightforward procedure for
the synthesis of enantiopure cyclohepta[b]indoles is highly
desirable. Among the practicable strategies,[1,3-7] (4+3)-
and
5 mol% of (R)-3,3'-bis(2,4,6-triisopropylphenyl)-BINOL
(TRIP) phosphoric acid 4 in CH2Cl2 in the presence of 4 Å
molecular sieves. Gratefully, the reaction proceeded smoothly to
afford the corresponding 6-aminotetrahydrocyclohepta[b]indole
3a in 78% yield with 91% ee as a single all-cis diastereomer (entry
1). Toluene was found to be a better solvent furnishing 3a in
slightly better yield with 97% ee (entry 2). Lowering the reaction
temperature markedly decreased the yield of 3a and did not have
a significant effect on the enantioselectivity (entry 3). Performing
the same reaction in the absence of 4 Å MS led to a lower yield,
indicating the deleterious effect of water on the overall process
(entry 4). Other drying agents were evaluated, but 4 Å MS
[]
C. Gelis,+ G. Levitre,+ Dr. J. Merad,+ P. Retailleau, Dr. L. Neuville, Dr.
G. Masson
Institut de Chimie des Substances Naturelles CNRS, Univ. Paris-Sud, 1
Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Fax: +33 1 69077247
E-mail: geraldine.masson@cnrs.fr
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the
document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201807069
Angewandte Chemie International Edition
COMMUNICATION
provided the best results in terms of both yield and
position of dienes does not affect the selectivity (3k). Next, the
scope of the reaction was successfully extended to other 3-
indolylmethanols 1 under similar conditions. Dipole precursors 1
bearing either electron-rich or electron-deficient aryl groups at 1’
enantioselectivity (entries
3 vs 5-8). Diversely substituted
carbamates can react with 1a but the best results were obtained
with Cbz-protected dienamines (entries 3 vs 9 – 12).
position
worked
well
providing
the
corresponding
Table 1. Survey of Reaction Conditions for Enantioselective (4+3)-
Cycloaddition[a]
cyclohepta[b]indoles 3l-3o in generally high enantioselectivities
(87−98%). Chalenging ortho-substituted aryl groups were also
tolerated in the cycloaddition, forming 3p in respectable yield and
high enantioselectivity. The displacement of the methoxy group
onto the indole C5-position also provides good results in term of
yields and selectivity (3q). Finally, we observed that the electronic
property of the substituents on the indole did not influence
Entry
1
Solvent
CH2Cl2
Additive
4Å MS
4Å MS
4Å MS
–
Product
3a
Yield [%][b]
ee [%][c,d]
91
78
81
67
63
64
74
59
69
83
63
57
79
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
3a
97
3[e]
4
3a
97
3a
86
5
3Å MS
5Å MS
MgSO4
Na2SO4
4Å MS
4Å MS
4Å MS
4Å MS
3a
96
6
3a
96
7
3a
89
8
3a
86
9[f]
10
11
12
3a
97
ent-3b[g
3c
94
87
ent-3d[g
95
[a] Reaction conditions: 1a (0.10 mmol), 2 (0.11 mmol) and 4 (0.005 mmol) in
2.0 mL of solvent for 18 h at RT. [b] Yields refer to chromatographically pure all
cis-isomer 3 determined to be higher than 98/2 by 1H NMR. [c] ee values were
determined by HPLC with a chiral stationary phase. [d] All cis-configuration was
determined by X-ray single crystal structure analysis of racemate (+/-)-3w and
the absolute configuration (6R,9S,10R) was assigned by X-ray single crystal
structure analysis of enantioenriched 9 (see Supporting Information). [e]
Performed at 0°C. [f] With 1.0 mmol scale of 1a. [e] Performed with ent-4.
Having optimized the reaction conditions for the synthesis of the
tetrahydrocyclohepta[b]indol-6-yl)carbamate 3a, we investigated
the scope of 4-catalyzed diastereo- and enantioselective (4+3)-
cycloaddition reactions of 1a with a variety of dienes 2. In general,
the reaction proceeded smoothly with excellent diastereo- and
enantioselectivity. For instance, the diene carbamates bearing
branched or linear alkyl chains at the C4 position led to
corresponding cycloadducts (3e-3f) in good yields. Chiral
dienecarbamate derived from (R)-citronellol gave 3g with an
excellent enantiomeric excess. Additionally, silyl ethers (3h) are
compatible functional groups in this process. The
diastereoselectivity was substantially affected when non terminal
substituted dienes were used. Nevertheless, appreciable level of
selectivity remained as observed for compounds 3i and 3j (3:1 dr)
with excellent enantioselectivity for the major isomer (96% and
97% ee respectively). On the other hand, substituents at the C3
Scheme 1. Scope of the enantioselective (4+3)-cycloaddition.[a,b,c,d] [a] General
reaction conditions: 1 (0.10 mmol), 2 (0.10 mmol), and 4 (0.005 mmol) in 2.0 mL
of toluene at 0°C to RT for 18 h with 4 Å MS. [b] Yield of isolated pure product
after column chromatography. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] If unspecified, dr >98/2, determined by 1H NMR. [e]
Synthesized using ent-4 catalyst (10 mol%).
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10.1002/anie.201807069
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isolated in 6% yield when the reaction between 1g and 2a was
much on the enantioselectivity, but strongly affected the reaction
yield. For instance, unsubstituted indoles (3r-3u) led to the
desired products in good yields whereas the presence of electron
poor substituents decreased the yield considerably (3v). To our
delight, indole bearing both an electron-poor and an electron-rich
aromatic moiety was successfully used to form 3w in a
respectable yield. More remarkably, the pinacol boronic ester was
tolerated allowing further functionalizations of 3x using cross-
coupling reactions. To finish, new opportunities in terms of
scaffold diversity and potential post-transformations were offered
by the synthesis of 3y in lower yields but high enantioselectivity.
performed in the presence of EtOH (15 eq).
To demonstrate the practicality and scalability of this
procedure, we conducted the reaction on a larger scale (1.0
mmol) under standard conditions, which furnished the pure
cyclohepta[b]indole product 3a (83% yield and 97% ee) without
any loss of efficiency and selectivity (Table 1, entry 9). Pleasingly,
3a can be readily transformed into other interesting derivatives
owing to the presence of functional groups. For instance, indole
addition to 3a using 5 mol% of Bi(OTf)3 as Lewis acid[17] to trigger
the formation of benzyl cation intermediate resulted in 72% yield
of 6 as a single diastereomer providing efficient acces to natural
related biologically active products.[18] Moreover, using PtO2, the
endocyclic olefin was chemoselectively hydrogenated in good
yield without affecting the N-benzyl group. The carbamate
functional group is ideally placed and can also serve as an
anchorage point for selective transformations. As illustration, the
treatment of 3a with TsOH.H2O afforded diene 8 in respectable
yield with no change of enantioselectivity. Finally, subjection of 1a
to aqueous basic conditions did not lead to the anticipated Cbz
deprotection. Instead, unexpected ketone 9 was isolated as the
sole product in 78% yield without racemization. Its structure was
unambiguously identified through an X-ray crystal structure
determination (see supporting information). Transition metal-free
allylic isomerization of alcohols leading to ketone have already
been reported. Depending on the base used, they involve a
deprotonation/reprotonation or a radical pathway. Accordingly, a
The mechanism of the cycloaddition is assumed to initially involve
of H2O from 1 to generate an ion pair between the new-formed
indolium and chiral phosphate. In the meantime, hydrogen
bonding between the dienecarbamate NH and the Lewis basic
phosphoryl oxygen ensures a highly organized transition state in
the enantio-determining step (Scheme 3). Based on the model
proposed by Goodman,[15] the facial selectivity (Re face of the
indole and Si face of the diene) can be rationalized by the chiral
environment provided by the tethering phosphoric acid as
proposed on scheme 3. Taking into account the reported
conformations of cylohepta-1,4-dienes[16] and the one of natural
products exotines (solution and solid state conformation),[2a] we
can hypothesize that a bent boat-like conformation would be
operative in the ring-closing step to afford the all-cis product as
the major isomer. In the absence of R1 group (3f and 3g), an easy
rotation around the C1-C2 bond would bring the aromatic
substituent in a more favorable equatorial position leading to a
lower diastereoselectivity (see supporting information). The
stepwise representation of this reaction is consistent with our
previous work on the (3+2)-cycloaddition,[10a] as well as other
reports,[12, 13a-f] Moreover, the trapped iminium intermediate 5 was
plausible mechanism could follow
a base-mediated allylic
isomerization leading to an enamide that would next be hydrolized
under the conditions.[19] Then, addition of allylmagnesium chloride
to 9 resulted in the formation of 10 in 78% yield with high
diastereoselectivity (95:5).
Scheme 3. Scale-Up and synthetic transformation of 3a. Reaction conditions
[a] Indole (1 eq), Bi(OTf)3 (5.0 mol%), toluene/EtOAc (2/1), RT; [b] PtO2 (5
mol%), H2 (1 atm), EtOAc, RT. [c] TsOH.H2O (5.0 eq), THF, RT. [d] LiOH (20
eq), dioxane/H2O (1.25:1), reflux, 12 h. [e] AllylMgCl (3.0 eq), THF, 0 °C to RT,
3 h.
We reported the first catalytic enantioselective formal (4+3)-
cycloaddition of 1,3-diene-1-carbamates with 3-indolylmethanols
to furnish 6-amino-tetrahydrocyclohepta[b]indoles containing 2 to
3 stereogenic centers in good yields with excellent diastereo- and
enantioselectivities (up to 99% ee). The trapping experiments
provided sound evidence that the present reaction proceeded via
a stepwise mechanism. The excellent yields, enantioselectivities,
and operational simplicity make this methodology attractive for
the synthesis of natural cyclohepta[b]indole products.
Scheme 3. Activation model via a putative transition state.
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10.1002/anie.201807069
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Acknowledgements
We thank ICSN and CNRS for financial support; C.G. and G.L.
thank Saclay University for the doctoral fellowships; J.M.
gratefully acknowledges CNRS for a postdoctoral fellowship.
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Keywords: (4+3)-cycloaddition• chiral phosphoric acid • cyclo-
hepta[b]indoles • heterocycle • hydrogen bonding
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DiPoto, H. Li, X. Han, Q. Meng, R. N. Cooney, J. Wu, G. G. Holz, Sci.
Rep. 2016, 6, 28934; i) H.-H. Zhang, Z.-Q. Zhu, T. Fan, J. Liang, F. Shi,
Adv. Synth. Catal. 2016, 358, 1259; j) J. Liu, L. Wang, X. Wang, L. Xu,
Z. Hao, J. Xiao, Org. Biomol. Chem. 2016, 14, 11510; k) K.-S. Cao, H.-
X. Bian, W.-H. Zheng, Org. Biomol. Chem. 2015, 13, 6449; l) W. Gong,
Y. Liu, J. Zhang, Y. Jiao, J. Xue, Y. Li, Chem. Asian J. 2013, 8, 546; m)
X.-P. Han, H. Li, R. P. Hughes, J. Wu, Angew. Chem. Int. Ed. 2012, 51,
10390; Angew. Chem. 2012, 124, 10536.
[14] Selected examples using dienecarbamates in enantioselective (4+2)-
cycloaddition: a) N. Momiyama, H. Tabuse, H. Noda, M. Yamanaka, T.
Fujinami, K. Yamanishi, A. Izumiseki, K. Funayama, F. Egawa, S. Okada,
H. Adachi, M Terada, J. Am. Chem. Soc. 2016, 138,11353; b) N.
Momiyama, K. Funayama, H. Noda, M. Yamanaka, N. Akasaka, S. Ishida,
T. Iwamoto, M. Terada ACS Catal. 2016, 6, 949; c) Y. Nishikawa, S.
Nakano, Y. Tahira, K. Terazawa, K. Yamazaki, C. Kitamura, O. Hara,
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Iwamoto, M. Terada, J. Am. Chem. Soc. 2011, 133, 19294.
[7] Examples using other cycloadditions, see: a) G. Mei, H. Yuan, Y. Gu, W.
Chen, L. W.; Chung, C.-C. Li, Angew. Chem. Int. Ed. 2014, 53, 11051;
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[8] Selected reviews a) J. L. Mascarenas, M. Gulias, F. Lopez, In
Comprehensive Organic Synthesis, 2nd ed.; P. Knochel, G. Molander,
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In Methods and Applications of Cycloaddition Reactions in Organic
Syntheses; N. Nishiwaki, Ed.; John Wiley & Sons: Hoboken, NJ, 2014, p
565; c) D. E. Jones, M. Harmata, In Methods and Applications of
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[18] Selected examples: a) B. N. Reddy, C. V. Ramana, Tetrahedron, 2017, 73,
888; b) J.-Z. Huang, C.-L. Zhang, Y.-F. Zhu, L.-L. Li, D.-F. Chen, Z.-Y.
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Han, L.-Z. Gong, Chem. Eur. J. 2015, 21, 8389; c) S.-S. Ma, W.-L. Mei,
Z.-K. Guo, S.-B. Liu, Y.-X. Zhao, D.-L. Yang, Y.- B. Zeng, B. Jiang, H.-F.
Dai, Org. Lett. 2013, 15, 1492.
[19] Selected examples: (a) H.-X. Zheng, Z.-F. Xiao, C.-Z. Yao, Q.-Q. Li, X.-S.
Ning, Y.-B. Kang and Y. Tang, Org. Lett. 2015, 17, 6102; (b) (c) K.
Mondal, B. Mondal and S. C. Pan, J. Org. Chem. 2016, 81, 4835; (c) S.
Martinez-Erro, A. Sanz-Marco, A. B. Gómez, A. Vázquez-Romero, M. S.
G. Ahlquist and B. Martín-Matute, J. Am. Chem. Soc. 2016, 138, 13408.
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Jérémy Merad, Coralie Gelis,+
Guillaume Levitre, + Pascal Retailleau,
Luc Neuville and Géraldine Masson*
Page No. – Page No.
Highly Diastereo- and
Enantioselective Synthesis of Cyclo-
hepta[b]indoles via Chiral Phosphoric
Acid-Catalyzed (4+3)-Cycloaddition
How chiral protons make large rings: The first chiral phosphoric acid-catalyzed
formal (4+3)-cycloaddition between dienecarbamates and 3-indolylmethanols is
reported. Various functionalities at different ends of both substrates offer rapid
access to optically active 6-amino-tetrahydrocyclohepta[b]indoles bearing three
stereogenic centers in one pot. The salient features of this reaction include mild
conditions, good yields, good to excellent diastero- and enantioselectivity, ease of
scale-up, and post- transformations.
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