Building polycyclic indole scaffolds via gold(I)-catalyzed intra- and inter-molecular cyclization reactions of 1,6-enynes

Article abstract of DOI:10.1016/j.tet.2016.03.020

A gold(I) catalyzed cycloisomerization of indolyl-1,6-enynes via 5-exo-dig cyclization is reported. The reaction passes through an intermediate whose fate can be steered to yield different indole polycyclic scaffolds through various intra- and inter-molecular cyclization reactions. One of the key transformations of indolyl-1,6-enynes was a formal [2+2+2] cycloaddition reaction with various aldehydes to afford natural product-like tetracyclic indoles.

Full text of DOI:10.1016/j.tet.2016.03.020

Accepted Manuscript
Building Polycyclic Indole Scaffolds via Gold(I)-Catalyzed Intra- and Intermolecular
Cyclization Reactions of 1,6-Enynes
Patricia Pérez-Galán, Herbert Waldmann, Kamal Kumar
PII:
S0040-4020(16)30153-3
10.1016/j.tet.2016.03.020
TET 27560
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 January 2016
Revised Date: 3 March 2016
Accepted Date: 4 March 2016
Please cite this article as: Pérez-Galán P, Waldmann H, Kumar K, Building Polycyclic Indole Scaffolds
via Gold(I)-Catalyzed Intra- and Intermolecular Cyclization Reactions of 1,6-Enynes, Tetrahedron (2016),
doi: 10.1016/j.tet.2016.03.020.
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Building Polycyclic Indole Scaffolds via
Gold(I)-Catalyzed Intra- and Intermolecular
Cyclization Reactions of 1,6-Enynes
Leave this area blank for abstract info.
Patricia Pérez-Galán,a Herbert Waldmanna,b and Kamal Kumara,b
aMax-Planck -Institut für molekulare Physiologie Otto-Hahn Str. 11, 44227-Dortmund, Germany.
bFakultät Chemie und Chemische Biologie, Technische Universität Dortmund, Otto-Hahn Str. 6, 44227-Dortmund, Germany.
R2
LAu
N
AuL+
H
R2
R1
O
N
H
R1
N
R1
R2
R1
Indolyl-1,6-enynes
N
N
OMe

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Building Polycyclic Indole Scaffolds via Gold(I)-Catalyzed Intra- and Intermolecular
Cyclization Reactions of 1,6-Enynes
Patricia Pérez-Galán,a Herbert Waldmanna,b and Kamal Kumara,b,
aMax-Planck- Institut für molekulare Physiologie, Otto-Hahn Str. 11, 44227-Dortmund, Germany.
bFakultät Chemie und Chemische Biologie, Technische Universität Dortmund, Otto-Hahn Str. 6, 44227-Dortmund, Germany.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A gold (I) catalyzed cycloisomerization of indolyl-1,6-enynes via 5-exo-dig cyclization is
reported. The reaction passes through an intermediate whose fate can be steered to yield
different indole polycyclic scaffolds through various intra- and intermolecular cyclization
reactions. One of the key transformations of indolyl-1,6-enynes was a formal [2+2+2]
cycloaddition reaction with various aldehydes to afford natural product-like tetracyclic indoles.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Indole polycycles
Gold catalysis
Cycloisomerization
Enynes
Cycloadditions
———
Corresponding author. Tel.: +49-231-133-2480; fax: +49-231-133-2499; e-mail: kamal.kumar@mpi-dortmund.mpg.de
Corresponding author. Tel.: +49-231-133-2400; fax: +49-231-133-2499; e-mail: herbert.waldmann@mpi-dortmund.mpg.de

2
Tetrahedron
gold carbene intermediates (2).34-36 In the absence of external
1. Introduction
ACCEPTED MANUSCRIPT
nucleophiles, 1,6- and 1,7-enynes frequently deliver dienes (3,
Scheme 1b).37 Only in
a
few cases did enyne
Organic synthesis plays a vital role in medicinal and
chemical biology discoveries by providing novel small
molecule modulators of different biological functions.1-7
Therefore, there is a constant need to unravel new chemical
transformations for the synthesis of complex and novel
molecular scaffolds.8-11 In particular, chemical transformations
that could yield scaffolds resembling structural features of
natural products are highly desired.12-15 In this context, we
have been exploring different chemical reactivity to access
privileged indole scaffold based polycyclic frameworks and
derived compound collections.16-23 For instance, an
enantioselective routes to indolo-quinolizines catalyzed by
chiral Lewis acids was developed affording novel mitotic
modulators.24 Recently, we also employed gold(I) mediated
polycyclization reaction to build analogues of Harmicine
natural product (Scheme 1a).25
cycloisomerizations yield structurally complex compound
classes if additional modulating external nucleophiles were
absent.5-7 For instance, Echavarren et al used highly
electrophilic gold (I) catalysts to perform
a
[4+2]
cycloaddition of 1,6-enynes leading to molecules of type 4
(Scheme 1b).38 We could successfully transform 1,7-enynes
under different reaction conditions into either a scaffold
similar to 4 or into an exocyclic allenic framework (5, Scheme
1b).39 In order to explore and harness the potential of gold(I)-
catalyzed cycloisomerization of enynes for the synthesis of
complex molecular frameworks with privileged indole ring-
system,40-44 we designed the 1,6-enynes 7. Indolyl-enynes 7
upon gold activation can lead to either a 5-exo-dig cyclization
affording cyclopropyl gold(I) carbene intermediates (8) or a 6-
endo-dig cyclization yielding intermediate 9. Identifying the
reaction conditions that selectively yield one of these
intermediates could provide an opportunity for the synthesis
of polycyclic indoles by various intra- and intermolecular
cyclization reactions. For instance, on the one hand, the
intermediates 8 or 9 themselves can rearrange to provide
novel cyclic molecules and on the other hand molecular
rearrangements can also be triggered by the addition of
nucleophilic carbonyl compounds affording complex indole
polycycles.26 Here we present the gold(I)-catalyzed intra- and
intermolecular cyclization reactions of enynes 7 and their
potential in the synthesis of diverse and privileged complex
molecular structures (Scheme 1c).
a)
Cl
N
N
N
N
H
OHC
H
O
Homofascaplysin C
Fascaplysin
N
N
OH
O
N
H
N
R
H
H
Harmicine analogues
R1
Centrocountins
b)
X
R2
X
3
LAu
[Au]
R1
R2
R1
R2
X
R
R1 = Ar
2. Results and Discussion
X
H
H
R2
2
1
4
The synthesis of indolyl enynes 7 was carried out by means
of conventional methods (see the Supporting Information)
from commercially available indole 2-carboxylic acid. A
successful gold catalysis process requires a good balance of
both the electrophilic nature of ligands to enhance the
alkynophilicity as well as back-donating ability to release the
catalyst in the catalytic cycle in a facile manner. Based on the
extensive literature about 1,6-enyne cycloisomerization
reactions and our experience in this chemistry,39,45,46 we
focused on four different gold catalysts representing two
classes of ligands, i.e. N-heterocyclic carbenes and phosphines
and with different electronic and steric properties (A-D). The
gold(I) complexes with A-D were also prepared by means of
known procedures.47-53 While the cycloisomerization of enyne
7 via the cyclopropyl gold carbene intermediate 8 or 9 would
remain competitive reaction in intermolecular nucleophilic
addition of carbonyl function, the cycloisomerization was first
analyzed separately in the absence of any nucleophile with the
four catalysts A-D (Table 1).
R1 = Me
R2 = Ar
Ar
-
Nu
E
n = 1,2
R1 = H
C
X
+
5
E
X
Nu
R2
6
c)
LAu
R3
R2
N
R1
O
R3
[Au]
R4
R5
N
8
Indole polycycles
OR
R2
AuL
R3
R1
7
N
R2
R1
9
O
R4
R5
Scheme 1. a) Indole natural product analogues and derived
polycycles; b) gold mediated cycloisomerizations leading
to complex scaffolds; c) indolyl-1,6-enynes as substrates to
build diverse indole polycycles via gold mediated
transformations.
Among the set of chosen catalysts A-D, gold complex B is
the most electrophilic, and hence also the most reactive. These
characteristics often lead to lower selectivity. Catalyst A is
less electrophilic than B, but more than carbene gold(I)
complexes C or D. Catalysts C and D being less electrophilic
might take longer to complete the reactions, however, may
offer better chemo- and stereoselectivities. Different
electronic and steric properties of these catalysts would
nevertheless provide a better understanding of the reaction
mechanism.
Gold(I) catalyzed cycloisomerization reactions are efficient
transformations that have been extensively explored on 1,n-
enyne (n = 5-7) substrates affording a range of diverse
molecules (Scheme 1b).26-33 While these rearrangements have
often yielded carbo- and oxa- heterocycles, formation of aza-
heterocycles
has
been
less
explored.
Enyne
cycloisomerization reactions often pass through cyclopropyl

3
reaction did occur, the tricyclic indoles (10) which are
Table 1. Gold catalyzed cycloisomerization reaction of
enynes 7.
ACCEPTED MANUSCRIPT
products from the exo-dig pathway were formed (Scheme 1c).
The yields for the cycloisomerization of enyne 7a to afford
the tricyclic indole 10a were high using catalyst A or C,
whereas in other cases 10a was formed along with inseparable
impurities (entries 1-4, Table 1). In case of mono-substituted
olefins, methyl substitution in 7b led to a mixture of different
products including the cyclization product 10b. Phenyl
substitution in 7c was well tolerated and product 10c was
isolated in excellent yield (entry 6). Enyne 7e with a cyclic
olefin did react to provide the cyclization product 10e in high
yield; however, the product isolation was extremely difficult
(entry 7). In agreement with literature,54 no reaction occurred
with enynes supporting substituted alkynes (Table 1, entries
8-9) even after 24 h at room temperature, clearly suggesting to
use terminal acetylenes for further complexity generating
transformations using gold(I) catalysis with indolyl-enynes.
No. Enyne
1
Cat. Reaction
Time (h)
Yield
(%)a
Product
10
N
82
--b
N
1
A
1.
10a
7a
3
10a
10a
10a
B
2.
3.
4.
7a
7a
7a
The reaction mechanism for cycloisomerization of 1,6-
enynes 7 catalyzed by gold(I) is summarized in Scheme 2.
The reaction begins with an exo-dig cyclization of the olefin
to the acetylene to form the anti-cyclopropyl gold carbenes 8a
and 8b which evolve to provide single cleavage dienes as only
the alkene is cleaved in the process (Scheme 2a). We assume
that a substitution on alkyne (R3) might sterically disfavor the
formation of cyclopropane gold carbene 8a as observed in the
case of 7e-f (Table 1).
79
--b
C
D
3
3
N
5.
6.
N
N
--c
80
A
A
1
10b
7b
7c
Ph
N
10
10c
Ph
7.
8.
9.
N
N
N
N
10d
--
10
24
24
A
>60c
7d
7e
NR
A
A
--
NR
7f
a: isolated yields; b: mixture of inseparable products
formed; c:isolated as a mixture with another product that
could not be separated. NR = no reaction observed.
Scheme 2. a) Proposed reaction mechanism for cyclo-
isomerization of enyne 1 to scaffold 10. b) Predicted
formation of tetracyclic indoles 15 in a formal [2+2+2]
cycloaddition reaction.
With the information that enynes 7 under gold(I) catalytic
reaction conditions follow an exo-dig cyclization, we assumed
that aldehydes as O-nucleophiles would likewise add to the
intermediate 8 and further rearrangement would deliver
complex indole scaffolds. Plausibly, attack of an aldehyde on
the cyclopropane ring would form an oxonium cationic
intermediate 13 that cyclizes to form a tetracyclic intermediate
14 in a stereoselective manner (Scheme 2b).26 The gold(I)
catalyst leaves the catalytic cycle of this formal [2+2+2]
cycloaddition reaction to finally yield the complex tetracyclic
indole 15 (Scheme 2b).
Gold complex A was identified as suitable catalyst
delivering the intermediate cyclopropyl gold intermediate to
which an aldehyde could attack and lead to a formal [2+2+2]
Differently substituted indole enynes 7a-f were treated
with gold complexes A-D (Table 1). In all cases, when the

4
Tetrahedron
ACCEPTED MANUSCRIPT
cycloaddition reaction adduct 15. However, the less
applied. Electron-rich aromatic aldehydes performed better
electrophilic catalyst C also had been reported to effectively
catalyze such intermolecular reactions.55,43 Therefore, reaction
conditions to afford cycloadducts 15 were optimized with
both gold complex C as well as A (Table 2). At room
temperature, catalyst C led to only 21% of the desired product
15a and the tricyclic indole 10a was the major product (entry
1, Table 2). We envisaged that decreasing the reaction
temperature might slow down the intramolecular cyclization
and thereby favor the intermolecular reaction in the presence
of excess of aldehyde as nucleophile. Indeed, when the
reaction was conducted with catalyst C at 0 °C using 5
equivalents of aldehyde, the desired product 15a was obtained
in 70% yield along with 10a as minor product (entry 2). Using
3 equivalents of aldehyde reduced the yield for 15a (entry 3).
Also, further reducing the temperature was detrimental to the
yield of 15a (entries 4-5, Table 2) as the reaction was not
complete even after 48 h. The same reaction optimization was
performed with the catalyst A (entries 6-11, Table 2).
Interestingly, with catalyst A the reaction was still very
efficient even at low temperatures like -30 or -70°C (entries 7-
11) affording the cycloaddition product 15a as the major
product and in very good yields. The best result was obtained
when catalyst A was used at -70 °C, and with 3 equivalents of
the aldehyde 12a leading to 15a in 65% yield (Table 2, entry
10).
than electron-poor ones affording the desired adducts 15a-c in
moderate to very good yields (Scheme 3). With electron-
deficient p-nitrobenaldehyde only a lower yield of adduct 15d
could be recorded, primarily because of its tedious
purification from excess of aldehyde used in the reaction.
Indole 2-carbaldehyde was also successfully employed as
representative heterocycle in the cycloaddition reaction to
give cycloadduct 15e in high yield. Interestingly,
cyclohexanal as a representative alkyl aldehyde also provided
the desired tetracyclic indole 15f, albeit in lower yield
(Scheme 3). The main product in this case was the single
cleavage product 10a. Although, some other heterocyclic
aldehydes like 2-furaldehyde did provide corresponding
cycloaddition products (LC-MS), they could not be isolated
from impurities formed as well as excess of aldehyde used in
the reactions. For the same purification problem, isolated
yields of several adducts are lower than for instance, in case
of mesityl aldehyde in which case the product could be easily
isolated.
The origin of the complete diastereoselectivity for 15a-f
stems from the stereospecific formation of anti-cylopropane
gold carbene complex 8a to which oxo-nucleophile (12) adds
in
a Markovnikov manner leading to a carbocationic
intermediate 13 which undergoes Prins type stereospecific
cylization to afford the adduct 15 as single diastereoisomer
(Scheme 2b).26
Table 2. A formal [2+2+2] cycloaddition reaction between
enyne 1a and aldehyde 12a.
Entry
Cat.
(mol%)
C (5)
Temp.
(°C)
rt
12a
(equiv.)
5
Yield 15a
(%)a
1.
21
2.
C (5)
C (5)
C (5)
C (5)
A (5)
A (5)
A (3)
A (10)
A (5)
A (5)
0
5
3
5
5
3
3
3
3
3
5
70
62
55b
50b
20
63
43
40
65
62
3.
0
4.
-30
-70
0
5.
6.
7.
-30
-70
-70
-70
-70
8.
9.
10.
11.
Scheme 3. Scope of the gold(I) catalyzed [2+2+2] cyclo-
addition reaction between enyne 7 and various aldehydes
12.
a) Yield of isolated product. b) The reaction was not
complete even after 48 h.
The successful application of enyne cycloisomerization in
trapping aldehydes as nucleophiles raised our curiosity to test
other nucleophiles in both inter- and intramolecular fashion.
To this end, the indole enyne 7a was treated under the
optimized reaction conditions with methanol as solvent and
external nucleophile and led to formation of tricyclic indole
The gold catalyzed intermolecular formal [2+2+2]
cycloaddition reaction was further extended to more
aldehydes to explore the scope of the reaction (Scheme 3).
Reaction conditions optimized with both the catalysts were

5
16. Catalyst C provided better yield for 16 than catalyst A
(Scheme 4a). It seems that addition of methanol to
cyclopropane gold carbene intermediate opens up the ring
followed by proto-deauration to yield the compound 16
(Scheme 4a).
Unless otherwise noted, chemicals were obtained from
ACCEPTED MANUSCRIPT
Aldrich, Acros, or Alfa Aesar and were used without further
purification. Reactions were carried out in standard glassware
using anhydrous solvents. 1H and 13C NMR spectroscopic data
were recorded on a Varian Mercury VX 400 or Varian 500-
inova 500 spectrometer at RT unless stated otherwise. NMR
spectra were calibrated to the solvent signals of CDCl3,
(CD3)2CO, or CD3CN. Enantiomeric resolution was per-
formed using a Dionex UltiMate 2000 HPLC with a 10mm
Daicel IC column. HRMS-(FAB) MS were taken on Finnigan
MAT MS 70. HRMS-ESI were measured on an Accela
HPLC-System (HPLC column 50/1 Hypersil GOLD1.9 ꢀm)
with an LTQ Orbitrap mass spectrometer from Thermo
Scientific. (ESI)-MS were measured by using an Agilent 1100
series binary pump to ether with a reversed-phase HPLC
column (Macherey-Nagel). TLC was performed on Merck
silica gel 60 F254 aluminum sheet. For flash chromatography
silica gel from Baker (40-70 ꢀm) was used. MPLC was
performed using an Isco sq16 with prepacked cartridges (30
ꢀm, spherical silica gel) from Interchim were used. Melting
points were recorded on Büchi Melting points B-540
apparatus and are uncorrected.
Scheme 4. Inter- and intramolecular nucleophilic additions
to cyclopropyl gold carbene intermediate of indole-enynes.
Methanol is a simple and relatively hard nucleophile as
compared to aldehydes and therefore had only limited scope
to modulate the intermediate 8a into further novel
frameworks. To access further molecular complexity via gold
mediated cycloisomerization and by trapping the gold
cyclopropane carbene intermediate, an extended diene-yne 17
was employed. Our curiosity was to observe a novel mode of
addition of extended olefin that might happen either to
cyclopropane (a in 18) causing a ring-expansion or to the gold
carbene center (b in 18) leading to further complex and novel
molecular scaffolds. Under the catalysis of A or C, in DCM
and at room temperature, the dienyne 17 was cleanly
transformed into a pentacyclic indole scaffold embodying two
cyclopropane rings (19, Scheme 4b). Clearly, the reaction
happens via addition of terminal olefin to gold carbene that
further eliminates the gold catalyst forming another
cyclopropane ring. Thus, while addition of a relatively hard
O-nucleophile attacked the cyclopropane ring, the olefin
4.1.1. General procedure for the synthesis of 1,6-
enynes
To a freshly prepared solution of indole-2-carbaldehyde (5
mmol) in anhydrous DMF (35 mL) was added under argon
Cs2CO3 (15 mmol) and the corresponding allyl bromide (2
mmol). The mixture was stirred overnight at 65 °C. The
reaction mixture was diluted with EtOAc (35 mL) and washed
with water (5 x 50 mL). The combined organic layers were
dried (MgSO4), and the solvent removed under reduced
pressure. Purification by flash chromatography (petroleum
ether, 100%) afforded the desired products as oils. Then, CBr4
(11 mmol) was dissolved in dichloromethane (50 mL) and
cooled to 0 °C. PPh3 (22 mmol) was added and the color of
the reaction turned orange. After stirring the mixture for 10
minutes at 0 °C, the corresponding N-substituted indole 2-
carbaldehyde (5 mmol) was added dropwise at 0 °C. After
stirring for another 1.5 h, the reaction mixture was diluted
with pentane (50 mL), filtered through a Celite plug and the
solvent removed under reduced pressure to yield the
preferred the gold-carbene center indicating
a rather
carbocationic nature of the intermediate 18 (and 8). Further
experiments might be required to shed more light on the
nature of gold carbene complex 8.
corresponding
2-(2,2-dibromovinyl)-N-substituted-indole
(100% yield) that was directly used in the next step. 5 mmol
of this indole was dissolved in anhydrous THF (50 mL) under
argon atmosphere and cooled to -78 °C. nBuLi in hexane (10
mmol) was added dropwise. The color of the reaction turned
from yellow to orange. After stirring at -78°C for 2 h, the
reaction mixture was gradually warmed to room temperature
(5 h). The reaction was quenched by adding saturated aqueous
solution of NH4Cl (5 mL) at 0 °C, extracted with Et2O (3 x 50
mL), the combined organic layers dried (MgSO4) and the
solvent removed under reduced pressure. Purification by flash
chromatography (100:1, petroleum ether/ethyl acetate)
afforded the 1,6-enynes.
3. Conclusions
In conclusion, we have disclosed gold(I) mediated intra-
and intermolecular transformations of indole based 1,6-enynes
to build complex and novel indole scaffolds. A formal
[2+2+2] cycloaddition reactions of indole based 1,6-enynes 7
with various aldehydes was employed as a key reaction
leading to tetracyclic indoles supporting a dihydropyran ring.
Successful formation of natural product-like tetracyclic
indoles 15 was achieved by employing catalytic phosphine or
NHC-gold
cycloisomerization of enynes 7 afforded the tricyclic indoles
10 that support diene system amenable to further
complexes
A
and
C.
In
addition,
4.1.1.1. 2-Ethynyl-1-(3-methylbut-2-en-1-yl)-1H-
indole (7a)
a
cycloaddition reactions to deliver further complex indoles.
These gold(I) mediated divergent synthesis may find
applications in designing privileged structure based scaffold
synthesis.
1 H NMR (400 MHz, acetone-d6 ) δ 7.56 (dd, J =
8.0, 0.9 Hz, 1H), 7.37 (ddd, J = 8.3, 1.7, 0.8 Hz,
1H), 7.22 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.07
(tt, J = 10.4, 2.2 Hz, 1H), 6.80 (d, J = 0.6 Hz,
1H), 5.26 (ddd, J = 6.6, 4.1, 1.4 Hz, 1H), 4.91
(d, J = 6.7 Hz, 2H), 4.16 (s, 1H), 1.92 – 1.88 (m,
3H), 1.73 – 1.66 (m, 3H); 1 3 C NMR (101 MHz,
acetone-d6 ) δ 134.9, 130.1, 127.7, 126.2, 123.3,
4. Experimental Section
4.1. General

6
Tetrahedron
2.24 (s, 3H), 1.43 (s, J = 5.8 Hz, 4H), 1.38 (s, 4H); 13C NMR
123.1, 119.1, 118.2, 115.8, 113.3, 110.3, 109.8,
ACCEPTED MANUSCRIPT
26.1, 19.3. HRMS-ESI calcd. for C1 5 H1 6
N
(101 MHz, acetone-d6) δ141.6, 137.4, 136.9, 133.8, 133.5,
133.3, 129.9, 129.6, 121.4, 121.2, 121.1, 119.7, 119.2, 109.9,
91.4, 73.9, 69.7, 50.9, 45.0, 20.2, 19.8, 18.8; HRMS-ESI
calcd. for C25H28NO [M+H]+: 358.2165. Found: 358.2168.
[M+H]+ : 210.1283. Found: 210.13029.
4.1.1.2. 1-Cinnamyl-2-ethynyl-1H-indole (7c)
4.3.2. 3-(4-Methoxyphenyl)-1,1-dimethyl-
1,3,11,11a-tetrahydropyrano[4',3':3,4]pyrrolo-
[1,2-a]indole(15b)
1H NMR (400 MHz, acetone-d6): δ 7.59 (dd, J = 8.0, 0.8
Hz, 1H), 7.49 (dd, J = 8.4, 0.9 Hz, 1H), 7.38 (dd, J = 8.2, 1.2
Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.26 – 7.19 (m, 2H), 7.09
(ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 6.87 (d, J = 0.7 Hz, 1H), 6.54
– 6.39 (m, 2H), 5.09 (dd, J = 17.2, 5.0 Hz, 2H), 4.18 (s, 1H);
13C NMR (101 MHz, acetone-d6): δ 136.8, 136.7, 132.1,
128.7, 127.9, 127.4, 126.6, 125.1, 123.5, 121.2, 120.5, 110.5,
108.5, 85.1, 75.3, 46.1; HRMS-ESI calcd. for C19H16N
[M+H]+: 258.1277. Found: 258.1284.
1H NMR (400 MHz, acetone-d6): δ 7.53 (d, J = 8.0 Hz,
1H), 7.37 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.11 (t,
J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.4 Hz,
2H), 6.47 (s, 1H), 6.16 (s, 1H), 5.31 (s, 1H), 4.51 (t, J = 9.4
Hz, 1H), 3.80 (s, 3H), 3.76 (d, J = 9.8 Hz, 1H), 3.68 (t, J = 8.4
Hz, 1H), 1.44 (s, 3H), 1.34 (s, 3H); 13C NMR (101 MHz,
acetone-d6): δ 159.7, 154.4, 134.1, 133.4, 129.0, 125.7, 121.6,
121.4, 120.9, 119.9, 114.9, 114.0, 110.1, 91.8, 73.9, 73.5,
70.7, 55.0, 51.6, 45.1, 18.7; HRMS-ESI calcd. for C23H24NO2
[M+H]+: 346.1802. Found: 346.1805.
4.2. General procedure for cyclization of 1,6-enynes to
tricyclic indoles 10
To a round bottom flask and under argon atmosphere was
added 1,6-enyne 7 (1 mmol), in DCM (1 mL) followed by
addition of the catalyst A (5 mol%). The reaction mixture was
stirred at room temperature till completion (tlc, table 1). The
solvent was removed and the product was purified by flash
chromatography with pentane as eluent.
4.3.3. 3-(4-(Benzyloxy)phenyl)-1,1-dimethyl-
1,3,11,11a-tetrahydropyrano[4',3':3,4]pyrrolo-
[1,2-a]indole(15d)
1H NMR (400 MHz, acetone-d6): δ 7.53 (d, J = 7.9 Hz,
1H), 7.48 (d, J = 7.5 Hz, 2H), 7.43 – 7.35 (m, 4H), 7.32 (t, J =
7.9 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.03 - 6.99 (m, 3H), 6.47
(s, 1H), 6.16 (t, J = 3.0 Hz, 1H), 5.31 (t, J = 3.0 Hz, 1H), 5.15
(s, 2H), 4.51 (t, J = 9.3 Hz, 1H), 3.78 (t, J = 8.8 Hz, 1H), 3.67
4.2.1. 1-(2-Methylprop-1-en-1-yl)-3H-pyrrolo-
[1,2-a]indole (10a)
1H NMR (400 MHz, acetone-d6): δ 7.47 (d, J = 7.50 Hz,
1H), 7. 44 (d, J = 7.49 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.25
(d, J = 2.9 Hz, 1H), 7.11 (dt, J = 8.6, 4.3 Hz, 1H), 6.40 (d, J =
2.9 Hz, 1H), 6.10 (s, 1H), 3.81 (s, 1H), 1.88 (s, 3H), 1.87 (s,
3H); 13C NMR (101 MHz, acetone-d6): δ 134.9, 130.1, 127.7,
126.2, 123.3, 123.1, 119.1, 118.2, 115.8, 113.3, 110.3, 109.8,
26.1, 19.3; HRMS-ESI calcd. for C15H16N [M+H]+:
210.1283. Found: 210.1299.
(ddd, J = 11.7, 8.6, 3.1 Hz, 1H), 1.44 (s, 3H), 1.34 (s, 3H); 13
C
NMR (101 MHz, acetone) δ 159.4, 142.2, 138.5, 135.0,
134.5, 134.0, 130.0, 129.5, 129.3, 128.6, 128.6, 128.3, 122.1,
121.9, 121.3, 120.4, 115.6, 110.6, 92.3, 74.5, 74.0, 70.5, 52.1,
45.6, 19.2; HRMS-ESI calcd. for C29H28NO2 [M+H]+:
422.2115. Found: 422.2114.
4.4. Addition of methonol as nucleophile to Indole-enyne 1ª
To a dried schlenk and under argon atmosphere was added
the enyne (0.36 mmol, 1 eqv.) in methanol (1.5 mL) at room
temperature, followed by addition of catalyst A or C (5
mol%). The mixture was stirred for 4h when the reaction was
complete (tlc). The crude reaction mixture was directly
concentrated and product was purified by column
chromatography using pentane as eluent.
4.3. General procedure for the formal [2+2+2+] cyclo-
addition between indole enyne 7a and aldehydes
Method A: To a dried schlenk and under argon atmosphere
was added the enyne (0.36 mmol, 1 eqv.) and of the
corresponding aldehyde (3 eqv.) in DCM (2.0 mL). The
mixture was then cooled to -70 °C (15 min.) and catalyst A (5
mol%) was added. The mixture was stirred overnight and
warmed gradually to room temperature. The violet colored
crude reaction mixture was directly concentrated and product
was purified by column chromatography using pentane as
eluent.
4.4.1. 2-(2-Methoxypropan-2-yl)-1-methylene-
2,3-dihydro-1H-pyrrolo[1,2-a]indole (16)
1H NMR (400 MHz, acetone-d6): δ 7.51 (d, J = 7.9 Hz,
1H), 7.33 (d, J = 8.2 Hz, 1H), 7.08 (ddd, J = 8.2, 2.2, 1.0 Hz,
1H), 7.00 (tt, J = 7.1, 1.0 Hz, 1H), 6.46 (s, 1H), 5.69 (s, 1H),
5.30 (s, 1H), 4.25 (ddd, J = 10.9, 3.3, 1.1 Hz, 1H), 4.16 (ddd,
J = 9.6, 7.9, 1.1 Hz, 1H), 3.69 (d, J = 7.9 Hz, 1H), 3.25 (br s,
3H), 1.28 (s, 3H), 0.97 (s, 3H); 13C NMR (101 MHz,
acetone-d6) δ 140.2, 133.5, 133.3, 121.2, 121.1, 119.7, 114.9,
109.9, 108.4, 90.6, 76.7, 54.0, 48.6, 44.8, 21.6, 20.9; HRMS-
ESI calcd. for C16H20NO [M+H]+: 242.1542. Found:
242.1539.
Method B: To a dried schlenk and under argon atmosphere
was added the enyne (0.36 mmol,
1 eqv.) and the
corresponding aldehyde (5 eqv.) DCM (2.0 mL). The mixture
was then cooled to 0 °C (15 min.) and catalyst C (5 mol%)
was added. The mixture was stirred overnight and warmed
gradually to room temperature. The violet colored crude
reaction mixture was directly concentrated and product was
purified by column chromatography using pentane as eluent.
4.5. Synthesis of hexacyclic indole (19)
4.3.1. 3-Mesityl-1,1-dimethyl-1,3,11,11a-
tetrahydropyrano[4',3':3,4]pyrrolo[1,2-a]indole
(15a)
1H NMR (400 MHz, acetone-d6): δ 7.53 (dd, J = 8.0, 0.9
Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.11 (ddd, J = 8.2, 7.1, 1.1
Hz, 1H), 7.01 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 6.84 (s, 2H),
6.46 (s, 1H), 6.10 (t, J = 2.6 Hz, 1H), 5.80 (dd, J = 3.9, 2.5
Hz, 1H), 4.53 (dd, J = 9.6, 9.0 Hz, 1H), 3.79 (dd, J = 9.8, 8.8
Hz, 1H), 3.69 (ddd, J = 11.8, 7.8, 3.5 Hz, 1H), 2.40 (s, 7H),
To the enyne 17 (0.09 mmol) in a dried schlenk under
argon atmosphere was added catalyst A or C (5 mol%) in
DCM (1 mL) and orange colored reaction mixture was stirred
for 3-6 h. After completion of the reaction (tlc), the
concentrated mixture was purified by column chromatography
to obtain the product 19. Notably, we observed that freshly
purified starting material 17 performed better and any
impurity with enyne could drastically reduce the yield of the
product.

7
18.
Antonchick, A. P.; Lopez-Tosco, S.; Parga, J.;
Sievers, S.; Schurmann, M.; Preut, H.; Hoing, S.;
4.5.1. 1,1,3a-Trimethyl-1,1a,2,3,3a,3b,4,10c-
octahydrocyclopropa[5'',6'']benzo[1'',2'':1',3'] cy
ACCEPTED MANUSCRIPT
Scholer, H. R.; Sterneckert, J.; Rauh, D.; Waldmann, H.
Chem. Biol. 2013, 20, 500-509.
Antonchick, A. P.; Schuster, H.; Bruss, H.; Schurmann,
M.; Preut, H.; Rauh, D.; Waldmann, H. Tetrahedron
2011, 67, 10195-10202.
Correa, I. R., Jr.; Noren-Muller, A.; Ambrosi, H. D.;
Jakupovic, S.; Saxena, K.; Schwalbe, H.; Kaiser, M.;
Waldmann, H. Chem Asian J 2007, 2, 1109-26.
Dueckert, H.; Khedkar, V.; Waldmann, H.; Kumar, K.
Chem. Eur. J. 2011, 17, 5130-5137.
Eschenbrenner-Lux, V.; Duckert, H.; Khedkar, V.;
Bruss, H.; Waldmann, H.; Kumar, K. Chem. Eur. J.
2013, 19, 2294-2304.
clopropa[1',2':3,4]pyrrolo[1,2-a]indole (19)
1H NMR (400 MHz, acetone-d6): δ 7.43 (d, J = 7.6 Hz,
1H), 7.15 (d, J = 7.9 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.93 (t,
J = 7.4 Hz, 1H), 6.16 (s, 1H), 4.24 (dd, J = 11.2, 6.1 Hz, 1H),
3.96 (d, J = 11.0 Hz, 1H), 1.91 – 1.74 (m, 2H), 1.81 (s, 1H,
overlaped), 1.37 – 1.27 (m, 2H), 1.26 (s, 3H), 1.17 (s, 3H),
1.04 (d, J = 8.8 Hz, 1H), 0.85 (dd, J = 13.3, 8.3 Hz, 1H), 0.64
(s, 3H); 13C NMR (101 MHz, acetone-d6): δ147.4, 145.7,
133.2, 132.7, 120.1, 120.0, 118.9, 108.4, 93.9, 43.1, 40.0,
33.2, 30.5, 28.1, 23.1, 22.3, 18.2, 16.4, 13.7. HRMS-ESI
calcd. for C20H24N [M+H]+: 278.1902. Found: 278.1910.
19.
20.
21.
22.
Acknowledgements
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This work was supported by the Max Planck Gesellschaft
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Supplementary data
25.
26.
27.
28.
29.
30.
Supplementary data associated with this article can be
found in the online version, at http://.........
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