Br?nsted Acid Catalyzed [3 + 2]-Cycloaddition of Cyclic Enamides with in Situ Generated 2-Methide-2H-indoles: Enantioselective Synthesis of Indolo[1,2-a]indoles

Article abstract of DOI:10.1021/acs.orglett.6b02898

An efficient formal [3 + 2]-cycloaddition toward the highly diastereo- and enantioselective synthesis of indolo[1,2-a]indoles is disclosed. A chiral BINOL-derived phosphoric acid catalyzed the highly enantioselective conjugate addition of cyclic enamides to in situ generated 2-methide-2H-indoles and subsequent aminalization to give rise to acetamide-substituted indolo[1,2-a]indoles carrying three contiguous stereogenic centers. Importantly, these products were formed as single diastereomers and with excellent yields and enantioselectivities. Mild reaction conditions at ambient temperatures, the facile removal of the acetamido group, and the possibility of a scale-up highlight the practicality of this methodology.

Full text of DOI:10.1021/acs.orglett.6b02898

Letter
pubs.acs.org/OrgLett
Brønsted Acid Catalyzed [3 + 2]-Cycloaddition of Cyclic Enamides
with in Situ Generated 2‑Methide‑2H‑indoles: Enantioselective
Synthesis of Indolo[1,2‑a]indoles
Kalisankar Bera and Christoph Schneider*
Institut fur Organische Chemie, Universitat Leipzig, Johannisallee 29, 04103 Leipzig, Germany
̈
̈
S
* Supporting Information
ABSTRACT: An efficient formal [3 + 2]-cycloaddition toward the highly diastereo- and enantioselective synthesis of indolo[1,2-
a]indoles is disclosed. A chiral BINOL-derived phosphoric acid catalyzed the highly enantioselective conjugate addition of cyclic
enamides to in situ generated 2-methide-2H-indoles and subsequent aminalization to give rise to acetamide-substituted
indolo[1,2-a]indoles carrying three contiguous stereogenic centers. Importantly, these products were formed as single
diastereomers and with excellent yields and enantioselectivities. Mild reaction conditions at ambient temperatures, the facile
removal of the acetamido group, and the possibility of a scale-up highlight the practicality of this methodology.
ndole-based nitrogen heterocycles have received consid-
erable attention in synthetic and medicinal chemistry owing
polycyclic indoles has become an important research area for
synthetic organic chemistry.
I
to their profound abundance as structural motifs in numerous
alkaloids and biologically active synthetic molecules.1 Indole
fused-polycyclic frameworks, particularly pyrrolo- and indolo-
[1,2-a]indoles have been found in various natural products and
are also attractive skeleta for drug discovery due to their
potentially diverse pharmacological properties.2,3 For example,
the flinderoles A−C which are part of an interesting dimeric
alkaloid family display selective antimalarial activity (Figure 1).4
In recent years, a few catalytic enantioselective syntheses of
the pyrrolo[1,2-a]indole skeleta have been reported, most of
which require multistep processes, however.5 On the other
hand, to the best of our knowledge, there is only one report
available for the enantioselective synthesis of the indolo[1,2-
a]indole skeleton, and this involved a chiral pool-based
intramolecular nitrone cycloaddition toward the cyclohexene
ring.6 However, this method has a rather limited substrate
scope. Thus, the development of a direct and broadly applicable
synthetic method toward this important structural motif is
highly desirable.
We recently reported a highly diastereo- and enantioselective
synthesis of pyrrolo[1,2-a]indoles through a phosphoric acid
catalyzed [3 + 2]-cycloaddition of 2-vinylindoles with 2-
methide-2H-indoles, which were obtained in situ from the
corresponding 1H-indol-2-yl carbinols by dehydration.7 We
anticipated that enamides8 3 could be employed, as well as
dienophiles, in a [3 + 2]-cycloaddition with 1H-indol-2-yl
carbinols 1 in the presence of a chiral phosphoric acid9 which
would give rise to an indolo[1,2-a]indole 4 as the primary
reaction product (Scheme 1). We envisioned that a chiral
phosphoric acid could activate both the in situ generated 2-
methide-2H-indole 2 and the enamide 3 through double
hydrogen bonding and thus promote the ensuing [3 + 2]-
cycloaddition. Han et al. have recently shown that enamides can
Figure 1. Representative natural products with a pyrrolo[1,2-a]indole
and indolo[1,2-a]indole skeleton.
Indolo-sesquiterpene alkaloids such as polyavolensin, poly-
avolensinol, polyavolensinone, and polysin were isolated from
the stem and stem bark of the medicinal plant Polyathia
suaveolens, available in West Africa, and are of value for treating
blackwater fever and stomach disorders (Figure 1).3 Thus, an
efficient and divergent enantioselective synthesis of such
Received: September 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02898
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with great success before, gave rise to only low selectivity
(entries 1−4). Eventually, we found the catalyst PA5, with 2,6-
dimethyl-4-tert-butyl phenyl groups, to be optimal for our
process. It provided indolo[1,2-a]indole 4a as a single
diastereomer in 83% isolated yield and with 88.5:11.5 er
(entry 5). Other bulky para-substituents within the 3,3′-aryl
groups did not further improve this selectivity (entries 6−7).
However, additional improvement of enantioselectivity was
achieved through solvent modification (entries 8−13). Though
the reaction time proved to be longer in the case of ethereal
solvents, this change provided better enantioselectivity
compared to hydrocarbon and chlorinated solvents (entries
8−13). Finally, we found 1,4-dioxane optimal for this reaction,
which gave rise to indolo[1,2-a]indole 4a in 86% yield and 95:5
er within 48 h at rt, in the presence of 10 mol % of PA5 (entry
13).
Scheme 1. Conceptualization of the Synthesis of Indolo[1,2-
a]indoles 4
add to N-protected indol-2-yl carbinols under Brønsted acid
catalysis, resulting in the formation of a single new C−C bond
with good-to-excellent enantioselectivity.10
Herein we report the successful execution of this strategy,
which has furnished indolo[1,2-a]indoles 4 in a one-step
process with excellent yields. Single diastereomers were
obtained with very high enantioselectivity in almost all cases
studied.
To identify suitable reaction conditions, various BINOL-
derived phosphoric acids PA1−7 (10 mol %) were examined in
the reaction between indol-2-yl carbinol 1a and the cyclic
enamide 3a in CH2Cl2 at rt (Table 1). In all cases, the desired
product indolo[1,2-a]indole 4a was obtained as a single
diastereomer and in good-to-excellent yield, although the
enantioselectivity was found to be highly dependent on the
steric bulk of the aryl groups at the 3,3′-position of the BINOL-
backbone. For example, phosphoric acids PA1−PA4, which
have routinely been employed by ourselves and other groups
These optimized reaction conditions were broadly applicable
to a range of enamides 3a−h (Scheme 2). Various substituents
a
Scheme 2. Substrate Scope of Enamides 3
a
Table 1. Catalyst Screening and Reaction Optimization
b
c
entry
PA
solvent
CH2Cl2
t (h)
yield (%)
er
a
Conditions: Catalyst PA5 (0.03 mmol, 0.1 equiv), 3 (0.45 mmol, 1.5
d
1
1
2
3
4
5
6
7
5
5
5
5
5
5
3
72
47:53
55:45
34:66
37:63
equiv), and 1a (0.3 mmol, 1 equiv) in 1.5 mL of dioxane at rt; isolated
2
CH2Cl2
3
88
b
yields after silica gel column chromatography. 0.9 mmol of enamides
d
d
3
CH2Cl2
3
62
3h was employed.
4
CH2Cl2
3
92
5
CH2Cl2
3
90 (83)
83
88.5:11.5
such as methoxy, methyl, and bromo on the aryl ring of the
benzannulated enamides were well tolerated and provided the
desired products 4b−f as single diastereomers with excellent
yields and enantioselectivities. The 7-membered cycloalkyl
enamide 3g also reacted smoothly with indol-2-yl carbinol 1a to
give rise to product 4g in moderate yield and enantioselectivity.
To our delight, this process was also efficient for a partial
kinetic resolution of racemic chiral enamide. Thus, reaction of
indolyl-2-carbinol 1a with enamide 3h (3 equiv) furnished
cycloadduct 4h as a 4:1 mixture of diastereomers in 85% yield
and excellent enantioselectivity.
d
6
CH2Cl2
3
47:53
7
CH2Cl2
3
66
78:22
82.5:17.5
89:11
93:7
8
chloroform
toluene
3
82
9
3
83
10
11
12
THF
48
48
48
48
75
diethyl ether
tetrahydropyran
dioxane
85
90:10
94:6
81
e
13
92 (86)
95:5
a
Conditions: Catalyst PA (0.01 mmol, 0.1 equiv), 3a (0.15 mmol, 1.5
b
equiv), and 1a (0.1 mmol, 1 equiv) in 0.5 mL solvent at rt. NMR
yield with anisole as an internal standard; in parentheses, isolated yield
To further expand the scope of this cycloaddition we
subjected various indol-2-yl carbinols 1b−m carrying different
aryl and alkyl groups at the carbinol center to the reaction with
enamides 3b−c (Scheme 3). Irrespective of the electronic and
c
after silica gel column chromatography. Determined by chiral HPLC.
d
e
Opposite enantiomer. Reaction was performed on 0.3 mmol scale
with 1.5 mL of solvent.
B
DOI: 10.1021/acs.orglett.6b02898
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Organic Letters
Letter
ab c
, ,
the reaction conditions and afforded the cycloadducts 5o−q as
single diastereomers in excellent yields and enantioselectivities
of >99:1 er.
Scheme 3. Substrate Scope
The relative as well as absolute configuration of the products
4 and 5 was unambigously determined by single crystal X-ray
analysis of indolo[1,2-a]indole 5f which was assigned to all
other products by analogy (Scheme 3).11
To shed some light on the mechanism of this formal [3 + 2]-
cycloaddition we carried out few control experiments (Scheme
4). The 1-indanone-derived enamide 3i reacted smoothly with
Scheme 4. Control Experiments
indolyl carbinol 1a and afforded the uncyclized product 6
exclusively in an interrupted cycloaddition. This result suggests
that the title reaction proceeded through a stepwise process
initiated by a conjugate addition and subsequent cyclization to
the aminal. When we submitted 6 to a reaction with tetralone-
derived enamide 3b, under otherwise identical reaction
conditions, only unreacted indole 6 could be quantitatively
recovered. This finding rules out the possibility of a reversible
first step in the sequence and suggests that step to be the
enantioselectivity-determining part of the process. Further, the
reaction using the N-methylated enamide 3j and carbinol 4a as
substrates failed to provide the desired cycloadduct at all. This
observation indicates that the free N−H moiety within the
enamide 3 plays a pivotal role in the successful activation and
preorganization of the substrates as outlined above.
In order to demonstrate the synthetic utility of our method, a
representative cycloaddition was carried out on gram-scale.
Only 5 mol % of Brønsted acid catalyst PA5 was sufficient to
catalyze the reaction of carbinol 1d (3.00 mmol, 0.80 g) with
enamide 3b (4.50 mmol, 0.98 g) which furnished acetamide-
substituted indolo[1,2-a]indole 5c in 87% yield (1.21 g), with
complete diastereoselectivity and 98.5:1.5 er over a period of
1.5 day at rt (Scheme 5). The reaction products could be
further functionalized via iminium ion generation followed by
the addition of nucleophiles. Thus, in a representative process
the above prepared cycloadduct 5c was subjected to Lewis acid
assisted hydrogenation conditions using TMSOTf and
a
Conditions: Catalyst PA5 (0.03 mmol, 0.1 equiv), 3 (0.45 mmol, 1.5
equiv) and 1 (0.3 mmol, 1 equiv) in 1.5 mL dioxane at rt; isolated
b
c
yields after silica gel column chromatography. dr 98:2. dr >95:5.
steric properties and the position of additional substituents on
the aryl ring of 1b−l, the indolo[1,2-a]indoles 5a−k were
obtained as single diastereomers (except for 5g and 5i where dr
was 98:2 and >95:5 respectively) with good-to-excellent yields
and enantioselectivities of up to er >99:1. However, the
reaction rate was highly dependent on the electronic nature of
the substituents. With electron-donating substituents such as
alkoxy and alkyl groups (5a−c and 5h−k), the reaction
proceeded faster compared to substrates carrying electron-
withdrawing groups such as halogens and the trifluoromethyl
group (5d−g). The lower yield for the alkyl-substituted
cycloadduct 5l was presumably a result of a faster
decomposition of the starting 2-methide-2H-indole intermedi-
ate 2m in an undesired pathway caused by the lack of extra π-
conjugation.
Scheme 5. Scale-up Reaction and Synthetic Application
Finally, structurally more diverse cycloadducts were obtained
by subjecting more highly substituted and functionalized 1H-
indol-2-yl carbinols to the [3 + 2]-cycloaddition (Scheme 3).
For example, cycloadducts 5m and 5n bearing methyl and
methoxy groups at the 5-position of the indole, respectively,
were obtained from enamide 3b, as single diastereomers in
excellent yields and enantioselectivities. Also, various sub-
stituted aryl groups, such as phenyl, 4-chlorophenyl, and 2-
naphthyl at the 3- position of indole, were well tolerated under
C
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triethylsilane to furnish the indolo[1,2-a]indole 7 in 84% yield
and with full retention of diastereoselectivity (Scheme 5). The
relative configuration of 7 was unambiguously determined
through an X-ray crystal structure analysis (for details see the
Supporting Information).11
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In conclusion, we have developed a chiral phosphoric acid
catalyzed, asymmetric, formal [3 + 2]-cycloaddition of cyclic
enamides 3 with 2-methide-2H-indoles 2 obtained via
dehydration in situ from 1H-indol-2-yl carbinols 1. The
products were typically obtained as single diastereomers in
excellent yields and enantioselectivities. This cycloaddition was
shown to proceed via a stepwise process initiated by a
conjugate addition and subsequent cyclization of the indole to
the aminal. A large-scale reaction demonstrated the practicality
of this process which furnished the product in identical yield
and enantioselectivity. In addition, further synthetic trans-
formation of final adduct was possible. Further extension of this
process with respect to other nucleophiles and the application
of this method to the synthesis of natural products and
biologically active molecules is currently in progress in our
laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02898.
Detailed experimental procedures, spectral data for all
new compounds, and crystallographic data for 5f and 7
(PDF)
(6) Beccalli, E. M.; Broggini, G.; Farina, A.; Malpezzi, L.; Terraneo,
A.; Zecchi, G. Eur. J. Org. Chem. 2002, 2002, 2080.
(7) Bera, K.; Schneider, C. Chem. - Eur. J. 2016, 22, 7074.
AUTHOR INFORMATION
Corresponding Author
■
(8) Representative reviews: (a) Matsubara, R.; Kobayashi, S. Acc.
Chem. Res. 2008, 41, 292. (b) Gopalaiah, K.; Kagan, H. B. Chem. Rev.
2011, 111, 4599.
*E-mail: schneider@chemie.uni-leipzig.de.
Notes
The authors declare no competing financial interest.
(9) Representative reviews: (a) Akiyama, T. Chem. Rev. 2007, 107,
5744. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(c) Terada, M. Chem. Commun. 2008, 4097. (d) Yamamoto, H.;
Payette, N. Hydrogen Bonding in Organic Synthesis; Pihko, P. M., Ed.;
Wiley-VCH: Weinheim, 2009; p 73. (e) Terada, M. Synthesis 2010,
2010, 1929. (f) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83, 101.
(g) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2010, 8, 5262. (h) Kampen, D.; Reisinger, C. M.; List, B. Top.
Curr. Chem. 2009, 291, 395. (i) Rueping, M.; Kuenkel, A.; Atodiresei,
I. Chem. Soc. Rev. 2011, 40, 4539. (j) Rueping, M.; Nachtsheim, B. J.;
Ieawsuwan, W.; Atodiresei, I. Angew. Chem., Int. Ed. 2011, 50, 6706.
(k) Akiyama, T. In Science of Synthesis: Asymmetric Organocatalysis, Vol.
2; Maruoka, K., Ed.; Thieme: Stuttgart, 2012; p 169. (l) Terada, M.;
Momiyama, N. Science of Synthesis: Asymmetric Organocatalysis, Vol. 2;
Maruoka, K., Ed.; Thieme: Stuttgart, 2012; p 219. (m) Parmar, D.;
Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev. 2014, 114, 9047.
(10) Liu, C.-Y.; Han, F.-S. Chem. Commun. 2015, 51, 11844.
(11) CCDC 1500399 and CCDC 1500401 contain the supple-
mentary crystallographic data for this paper. For details concerning the
crystal structure of 5f and 7, see the Supporting Information as well.
ACKNOWLEDGMENTS
We dedicate this manuscript with great respect and affection to
our friend and colleague Professor Gerhard Bringmann
■
(University of Wurzburg) on the occasion of his 65th
̈
anniversary. We thank the DFG for generous financial support
and Prof. J. Sieler and Dr. P. Lonnecke (University of Leipzig)
̈
for the crystal structure analysis. We are grateful to BASF and
Evonik for the donation of chemicals.
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DOI: 10.1021/acs.orglett.6b02898
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