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

Article abstract of DOI:10.1002/chem.201601020

Pyrrolo[1,2-a]indoles are privileged structural elements of many natural products and pharmaceuticals. An efficient one-step process for their highly diastereo- and enantioselective synthesis, comprising a direct [3+2]-cycloaddition, has been developed. A chiral BINOL-derived phosphoric acid catalyzes the reaction of in situ-generated 2-methide-2H-indoles with 2-vinylindoles, furnishing the target products incorporating three contiguous stereogenic centers as single diastereoisomers and with excellent yields and enantioselectivities. In one step: A chiral Br?nsted acid catalyzed the highly enantioselective [3+2]-cycloaddition of in situ generated 2-methide-2H-indoles with 2-vinylindoles to directly furnish complex pyrrolo[1,2-a]indoles with three contiguous chiral centers. The products were obtained as single diastereoisomers and with yields up to 97 % and enantiomeric ratios up to 99.5:0.5.

Full text of DOI:10.1002/chem.201601020

DOI: 10.1002/chem.201601020
Communication
&
Asymmetric Synthesis
Brønsted Acid Catalyzed [3+2]-Cycloaddition of 2-Vinylindoles
with In Situ Generated 2-Methide-2H-indoles: Highly
Enantioselective Synthesis of Pyrrolo[1,2-a]indoles
Kalisankar Bera and Christoph Schneider*[a]
drug for the treatment of certain cancers and also exhibits sig-
nificant antibacterial activity.[4]
Abstract: Pyrrolo[1,2-a]indoles are privileged structural el-
ements of many natural products and pharmaceuticals.
An efficient one-step process for their highly diastereo-
and enantioselective synthesis, comprising a direct [3+2]-
cycloaddition, has been developed. A chiral BINOL-derived
phosphoric acid catalyzes the reaction of in situ-generated
2-methide-2H-indoles with 2-vinylindoles, furnishing the
target products incorporating three contiguous stereogen-
ic centers as single diastereoisomers and with excellent
yields and enantioselectivities.
The pharmacological properties and structural complexity
associated with [1,2-a]-annulated polycyclic indoles has
prompted the development of many new synthetic methods
for their rapid generation. However, most of these methods in-
clude non-asymmetric processes.[5] Only a few enantioselective
syntheses have been reported in recent years and many re-
quire multistep processes.[6–9]
In 2006, Ellman and co-workers reported the synthesis of the
enantioenriched dihydropyrroloindole core of a PKC inhibitor
by a rhodium-catalyzed, enantioselective CÀH bond functional-
ization of N-allyl indole as the stereodefining step.[6] Schrader
and co-workers employed a CuH-catalyzed asymmetric 1,4-hy-
drosilylation as the key step to generate the pyrrolo[1,2-
a]indole skeleton of a S1P1 receptor agonist.[7] Furthermore, al-
lylic N-alkylation with indoles has been demonstrated to pro-
ceed with excellent enantioselectivity and the products have
been successfully converted into pyrrolo[1,2-a]indoles in a few
further steps,[8] and sequential reactions comprising hydroacy-
lations as a key step have also been developed.[9] Probably the
most attractive strategies studied, however, have been catalyt-
ic, asymmetric domino-type reactions of suitably substituted
indoles. Such processes were successfully established in partic-
ular by Enders and co-workers, who employed organocatalytic
aza-Michael/aldol condensations[10a–b] and quadruple domino
reactions comprising an aza-Michael/Michael/Michael/aldol re-
action, which gave rise to highly substituted products with up
to six stereogenic centers.[10c] In addition, the Enders group de-
veloped a highly stereocontrolled, NHC-catalyzed [3+2]-annu-
lation process with a-chloroaldehydes and vinyl nitroindoles as
substrates.[10d] Finally, both metal- and organocatalyzed Frie-
del–Crafts reactions with highly activated enones coupled to
a hemiaminalization have been reported to furnish products
with high stereocontrol.[10e,f] These processes, however, all re-
quired the presence of extra functional groups within the sub-
strates, which naturally ended up in the products as well,
whether needed or not.
Indole-based nitrogen heterocycles are ubiquitous structural
motifs in numerous biologically active natural products and
pharmaceuticals, and are also valuable building blocks for the
synthesis of more complex and fused indoles.[1] Moreover, the
pyrrolo[1,2-a]indole skeleton is found in various natural prod-
ucts (Figure 1) and has been shown to exhibit a broad range
of pharmacological properties.[2] For example, the flinderoles
A–C (1a–c), isoborreverine (2a), and dimethylisoborreverine
(2b) display selective antimalarial activity, among which the
latter compound 2b, with three contiguous chiral centers, is
most active and selective.[3] In addition, the natural product mi-
tomycin C (3) has been shown to be a powerful anticancer
Figure 1. Representative natural products with a pyrrolo[1,2-a]indole struc-
ture.
Although synthetic transformations based on 3-indolyl carbi-
nols are well documented,[11] the chemistry of 2-indolyl carbi-
nols is much less developed.[12,13] We envisioned that a 1H-
indol-2-yl carbinol 4 could be readily converted into a reactive
2-methide-2H-indole 5 upon dehydration with a chiral phos-
phoric acid. The hydrogen-bonded 2-methide-2H-indole 5 may
then engage 2-vinylindole 6 in a well-organized transition
state through additional hydrogen bonding and forge the en-
[a] Dr. K. Bera, Prof. Dr. C. Schneider
Institut für Organische Chemie, Universität Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
E-mail: schneider@chemie.uni-leipzig.de
Supporting information for this article can be found under
http://dx.doi.org/10.1002/chem.201601020.
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as a single diastereoisomer in excellent yield, albeit with poor
enantioselectivity (Table 1, entry 1). Gradually reducing the size
of the 3,3’-aryl groups steadily increased the enantioselectivity.
Thus, with phosphoric acid PA 2 carrying less bulky 2,4,6-trie-
thylphenyl groups, the enantiomeric ratio of 7a was improved
to 88.5:11.5 (Table 1, entry 2). Eventually, we found catalyst
PA 3, with 3,3’-mesityl groups, to be optimal for our process.
Pyrrolo[1,2-a]indole 7a was obtained as a single diastereoiso-
mer with 85% yield and 90:10 e. r. (Table 1, entry 3). Further-
more, additional improvement of enantioselectivity was realiz-
ed through solvent modification (Table 1, entries 9–13). Hydro-
carbon and in particular ethereal solvents turned out to pro-
vide better enantioselectivities, albeit, in the case of ethereal
solvents, at the expense of yield and reaction rate (Table 1,
entry 11). Thus, mixtures of toluene and ethereal solvents were
a good compromise between rate and selectivity (Table 1, en-
tries 12 and 13). Finally, we found a 1:1 mixture of toluene and
1,4-dioxane to be optimal for this reaction, which gave rise to
pyrrolo[1,2-a]indole 7a in 83% yield and with 98:2 e. r. after
36 h at RT (Table 1, entry 13).
Scheme 1. Conceptualization of the synthesis of pyrrolo[1,2-a]indoles 7.
suing [3+2]-cycloaddition (Scheme 1).[14] Dethe et al. devel-
oped a similar conceptual scheme, albeit with Cu(OTf)2 as
Lewis acid in a non-enantioselective fashion.[5k] Herein we
report the successful execution of this strategy furnishing the
products with excellent yields, as single diastereoisomers and
with very high enantioselectivity.
To identify suitable reaction conditions, we investigated the
reaction of indol-2-yl carbinol 4a with (E)-3-methyl-2-styryl-1H-
indole (6a) in the presence of various BINOL-derived phospho-
ric acids PA 1–8 (10 mol %) in CH2Cl2 at room temperature
(Table 1). Pyrrolo[1,2-a]indole 7a was obtained as a single dia-
stereoisomer and in good to excellent yields in all cases stud-
ied. However, the enantioselectivity turned out to be highly
dependent on the size of the substituents at the 3- and 3’-po-
sitions within the BINOL backbone. For example, phosphoric
acid PA 1, having 2,4,6-triisopropyl phenyl groups, provided 7a
We next studied the scope of this cycloaddition. First we
subjected various indol-2-yl carbinols 4a–m, with different aryl
and alkyl groups at the carbinol center, to the reaction with
(E)-3-methyl-2-styryl-1H-indole 6a under the optimized reac-
tion conditions (Table 2). Irrespective of the electronic and
Table 2. Substrate scope of 1H-indol-2-yl carbinols 4.[a]
Table 1. Catalyst screening and reaction condition optimization.[a]
Entry
R, R1, R2 (4)
7
Yield [%][b]
e.r.[c]
98:2
1
C6H5, Me, H (4a)
7a
83
88
91
81
94
87
90
86
85
80
81
95
51
80
92
97
97
96
91
2
3
4
5
6
7
8
9
10
11
12
13[d]
14[e]
15
16[f]
17[f]
18[f]
19
4-MeC6H4, Me, H (4b)
4-MeOC6H4, Me, H (4c)
4-tBuC6H4, Me, H (4d)
4-FC6H4, Me, H (4e)
4-ClC6H4, Me, H (4 f)
2-ClC6H4, Me, H (4g)
2-EtC6H4, Me, H (4h)
3-MeOC6H4, Me, H (4i)
3,5-Me2C6H3, Me, H (4j)
2,4-(MeO)2C6H3, Me, H (4k)
2-naphthyl, Me, H (4l)
Me, Me, H (4m)
C6H5, Me, Me (4n)
C6H5, Me, OMe (4o)
C6H5, C6H5, H (4p)
C6H5, 4-ClC6H4, H (4q)
C6H5, 2-naphthyl, H (4r)
4-CF3-C6H4, Me, H (4s
7b
7c
7d
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
97:3
98.5:1.5
95:5
98:2
97.5:2.5
94:6
Entry
PA
Solvent
t [h]
Yield [%][b]
e.r.[c]
76:24
88.5:11.5
90:10
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
4
12
6
86
89
85
85
73
77
85
81
85
85
73
83
83
97:3
98.5:1.5
99.5:0.5
96.5:3.5
98.5:1.5
80:20
97:3
97:3
99.5:0.5
99.5:0.5
99.5:0.5
94:6
88:12
3
86.5:13.5
86.5:13.5
88:12
12
12
6
9
5
96
36
36
37:63
9
toluene
92.5:7.5
86.5:13.5
97:3
96.5:3.5
98:2
10
11
12[d]
13[d]
chloroform
diethyl ether
toluene/diethyl ether
toluene/dioxane
7s
[a] Conditions: Catalyst PA 3 (0.02 mmol, 0.1 equiv),
4
(0.30 mmol,
[a] Conditions: Catalyst PA (0.01 mmol, 0.1 equiv), 4a (0.15 mmol,
1.5 equiv), and 6a (0.1 mmol, 1 equiv) in solvent (1 mL) at RT. [b] Yield of
product isolated by column chromatography on silica gel. [c] Determined
by chiral HPLC. [d] Ratio=1:1, 0.5 mL.
1.5 equiv), and 6a (0.2 mmol, 1 equiv) in a 1:1 dioxane/toluene solvent
mixture (1ml) at RT. [b] Yield of product isolated by column chromatogra-
phy on silica gel. [c] Determined by chiral HPLC. [d] Reaction was incom-
plete after 6 days with 20 mol% PA 3. [e] t=2.5 d. [f] t=3 d.
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steric properties and the position of additional substituents on
the aryl ring of 4a–l, the reaction proceeded smoothly within
2 days at room temperature in all cases and furnished pyrro-
lo[1,2-a]indoles 7a–l as single diastereoisomers with excellent
yields and enantiomeric ratios up to >99:1 (Table 2, entries 1–
12). Although alkyl-substituted 3-methyl-1H-indol-2-yl carbinol
4m reacted more slowly with 2-vinylindole 6a and required
a higher catalyst loading, we were able to isolate the desired
product 7m again as a single diastereoisomer with 51% yield
and 80:20 e. r. (Table 2, entry 13). The lower reactivity of alkyl-
substituted 1H-indol-2-yl carbinol 4m compared to its aryl con-
geners 4a–l is presumably caused by the lack of extra p-conju-
gation during the formation of the 2-methide-2H-indole inter-
mediate 5m.
More structural diversity can be introduced into the final
products by subjecting more highly substituted and function-
alized 1H-indol-2-yl carbinols 4n–r to the [3+2]-cycloaddition.
For example, 4n and 4o, bearing methyl and methoxy groups
at the 5-position of the indole, respectively, reacted smoothly
with 2-vinyl indole 6a and furnished the cycloadducts 7n and
7o, respectively, in excellent yields and enantioselectivities
(Table 2, entries 14 and 15). Various aryl groups, such as
phenyl, 4-chlorophenyl and 2-naphthyl, at the 3-position of
indole were also well tolerated under the reaction conditions
and provided the desired products 7p–r as single diastereoiso-
mers with excellent yields and enantiomeric ratios 99.5:0.5
(Table 2, entries 16–18). In addition, the strongly electron-with-
drawing substituent CF3 was readily tolerated within the carbi-
nol aryl moiety, which delivered pyrroloindole 7s with good
yield and selectivity (Table 2, entry 19).
Table 3. Substrate scope of 2-vinyl indoles 6.[a]
Entry
R (6)
t [d]
8
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
4-MeC6H4 (6b)
4-MeOC6H4 (6c)
4-ClC6H4 (6d)
4-FC6H4 (6e)
2-FC6H4 (6 f)
3-BrC6H4 (6g)
3-CF3C6H4 (6h)
3,5-Me2C6H3 (6i)
Me (6j)
2
2
2
2
8a
8b
8c
8d
8e
8 f
8g
8h
8i
90
95
92
89
86
83
84
78
47
53
96.5:3.5
97:3
97:3
97:3
95:5
96:4
97:3
90:10
95.5:4.5
90:10
2
2.5
2.5
2.5
1.5
1.5
9[d,e]
10[d,f]
Et (6k)
8j
[a] Conditions: Catalyst PA 3 (0.02 mmol, 0.1 equiv), 4 f (0.30 mmol,
1.5 equiv), and 6 (0.2 mmol, 1 equiv) in a 1:1 dioxane/toluene solvent
mixture (1ml) at RT. [b] Yield of product isolated by column chromatogra-
phy on silica gel. [c] Determined by chiral HPLC. [d] Yield of isolated
major diastereoisomer. [e] 4:1 d.r., obtained from crude 1H NMR.
1
[f] 5:1 d.r., obtained from crude H NMR.
To further expand the scope of this reaction, other 3-methyl-
2-vinyl-1H-indoles 6b–k, bearing various aryl and alkyl sub-
stituents at the terminal position of the vinyl moiety, were sub-
jected to reaction with 1H-indol-2-yl carbinol 4 f under the op-
timized conditions (Table 3). In general, both electron-with-
drawing and electron-donating substituents on the terminal
aryl group gave the cycloadducts 8a–h as single diastereoiso-
mers with excellent yields and enantioselectivities (Table 3, en-
tries 1–8). However, 2-vinyl-1H-indoles 6j and 6k, bearing alkyl
substituents at the terminal position, gave rise to the desired
products 8i and 8j as mixtures of stereoisomers, from which
the major diastereoisomers were isolated in moderate yields
and with 95.5:4.5 and 90:10 e.r., respectively (Table 3, entries 9
and 10).
Figure 2. X-ray crystal structure of 8 f. Thermal ellipsoids are set at 50%
probability.
The relative and absolute configurations of the products
were determined by single-crystal X-ray analysis of pyrroloin-
dole 8 f, which was assigned to all other products by analogy
(Figure 2).[15]
To demonstrate the synthetic utility of our method, a repre-
sentative cycloaddition was carried out on gram scale. With as
little as 5 mol% of Brønsted acid catalyst PA 3, the reaction of
carbinol 4e (4.50 mmol, 1.15 g) and 2-vinyl-1H-indole 6a
(3.00 mmol, 0.70 g) was completed within 6 days at room tem-
perature to furnish cycloadduct 7e with 96% yield (1.35 g),
complete diastereoselectivity, and 97:3 e. r. (Scheme 2).
To test the double hydrogen-bonding assumption outlined
above and gain some insight into the reaction mechanism, we
Scheme 2. Synthesis of pyrrolo[1,2-a]indole 7e on gram scale.
carried out a control experiment with the N-methylated 2-
vinyl-1H-indole 9 and carbinol 4a as substrates under other-
wise identical reaction conditions. However, this reaction failed
to provide the desired cycloadduct at all (Scheme 3). This ob-
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Scheme 3. Control experiment.
servation indicates that the free NÀH moiety within the 2-
styrylindole plays a pivotal role in the successful activation and
preorganization of the substrates.
In conclusion, we have developed the first asymmetric
[3+2]-cycloaddition of in situ-generated 2-methide-2H-indoles
5 and 2-vinyl indoles 6. The reaction is catalyzed by a chiral
phosphoric acid, which converts the starting 1H-indol-2-yl car-
binols 4 into 5 and, upon cycloaddition with 6, affords a broad
range of pyrrolo[1,2-a] indoles 7 bearing three contiguous
chiral centers. The products were typically obtained as single
diastereoisomers with excellent yields and enantioselectivities.
The feasibility of a large-scale reaction was demonstrated on
a gram-scale reaction for which only 5 mol% catalyst was re-
quired to obtain almost identical results. Further extension of
this process with respect to other nucleophiles and the appli-
cation of this method to the synthesis of natural products and
biologically active molecules are currently in progress in our
laboratory.
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Acknowledgements
We thank the DFG for generous financial support and Dr. P.
Lçnnecke (University of Leipzig) for the crystal structure analy-
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Keywords: asymmetric synthesis
·
phosphoric acids
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cycloaddition · heterocycles · organocatalysis
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Received: March 15, 2016
Published online on March 30, 2016
Chem. Eur. J. 2016, 22, 7074 – 7078
www.chemeurj.org
7078
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim