Accessing Polycyclic Terpenoids from Zerumbone via Lewis Acid Catalyzed Synthetic Strategies

Article abstract of DOI:10.1055/s-0039-1690840

We herein disclose an effective strategy for the synthesis of [5.3.0] and [6.3.0] fused polycyclic terpenoids, which are important structural elements of natural products and biologically active compounds. The method comprises of Lewis acid catalyzed interrupted Nazarov cyclization of zerumbone derivatives such as zerumbone epoxide, triazole-appended zerumbone, zerumbal, and zerumbenone with a wide substrate scope with different indoles. Zerumbone epoxide furnished [5.3.0] and [6.3.0] fused structurally diverse sesquiterpenoids and all other zerumbone derivatives furnished the [6.3.0] fused motifs.

Full text of DOI:10.1055/s-0039-1690840

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2020, 52, A–T
paper
A
en
Synthesis
P. Sharathna et al.
Paper
Accessing Polycyclic Terpenoids from Zerumbone via Lewis Acid
Catalyzed Synthetic Strategies
Puthiyaparambath Sharathna ‡ a,b
Murugan Thulasi Meenu ‡ a,b
Bhandara Purayil Dhanyaa
Greeshma Gopalana
O
H
O
CHO
O
In(OTf)3
Nu
H
H
Sc(OTf)3
Nu
OHC
H
O
+
O
O
O
[
6.3.0], 81%
CHO
H
H
SeO2
O
O
[5.3.0], 65%
[6.3.0], 25%
Parameswaran Sasikumara
Radhakrishnan Syam Krishnana
Kokkuvayil Vasu Radhakrishnan*a,b
0
0
0
0-0
0
0
2-
8
3
5
5-1
3
0
4
H
O
O
Ph
Sc(OTf)3
Nu
O
AlCl3
Nu
H
O
H
0
0
0
0-0
0
0
1-8
9
0
9-3
1
7
5
N
O
[
6.3.0], 85%
N
N
N
N
H
Diastereoisomers (1:0.8)
Ph
[6.3.0], 50%
a
N
Organic Chemistry Section, CSIR-National Institute for
Interdisciplinary Science and Technology (NIIST), Thiru-
vananthapuram-19, India
b
‡
Academy of Scientific and Innovative Research (AcSIR),
CSIR-NIIST, Thiruvananthapuram-19, India
radhu2005@gmail.com
These authors contributed equally.
9
Received: 23.12.2019
Accepted after revision: 05.02.2020
Published online: 27.03.2020
showing interesting biological activities. Zerumbone, the
marker compound present in the rhizome oil of this tropi-
cal ginger,10 comprises 3% of its dry weight. It is a crystal-
line achiral 11-membered monocyclic sesquiterpene with a
flexible skeleton structure with a conjugated dienone part
and an isolated olefin part. Within the last few decades, the
diverse reactivity of zerumbone was extensively explored
by various research groups. Mainly Kitayama and co-work-
ers established various synthetic modifications of zerum-
DOI: 10.1055/s-0039-1690840; Art ID: ss-2019-m0695-op
Abstract We herein disclose an effective strategy for the synthesis of
5.3.0] and [6.3.0] fused polycyclic terpenoids, which are important
[
structural elements of natural products and biologically active com-
pounds. The method comprises of Lewis acid catalyzed interrupted
Nazarov cyclization of zerumbone derivatives such as zerumbone epox-
ide, triazole-appended zerumbone, zerumbal, and zerumbenone with a
wide substrate scope with different indoles. Zerumbone epoxide fur-
nished [5.3.0] and [6.3.0] fused structurally diverse sesquiterpenoids
and all other zerumbone derivatives furnished the [6.3.0] fused motifs.
11
bone, including transannular ring contraction, cycliza-
tion,12 regio- and diastereoselective conjugate additions,
13
14
various regiospecific ring cleavage reactions, ring expan-
sion reaction,15 asymmetric epoxidation, and so forth.
Our interest in zerumbone chemistry began in 2013
with the report on transition metal catalyzed 1,4-conjugate
addition of boronic acids to zerumbone.1 In the very next
year, we reported a new synthetic methodology for Pd-
catalyzed decarboxylative reactions of arenecarboxylic acid
with zerumbone.1 Later we described the metal-free
trans-aziridation of zerumbone and the evaluation of their
antidiabetic properties.1 In the same year, our group re-
ported the synthesis of zerumbone pendant derivatives via
a palladium-catalyzed Tsuji–Trost coupling reaction for the
first time.1 Recently we have utilized Lewis acid chemis-
try for the synthesis of [5.7.0], [5.8.0], and [5.8.3] ring-fused
structurally diverse natural sesquiterpenoids.1 In continu-
ation of our interest in the Lewis acid catalyzed transforma-
tions of zerumbone towards highly functionalized sesquit-
erpenoids, we have extended our work to other zerumbone
derivatives, such as zerumbone epoxide and synthetically
prepared triazole-linked zerumbone, zerumbal, and zerum-
benone, where zerumbone epoxide is a naturally occurring
16
Key words zerumbone, zerumbone epoxide, zerumbal, zerumben-
one, Lewis acid catalysis, cyclization, polycyclic terpenoids
7a
Natural-product-based drug discovery, especially phy-
tochemical-focused drug development programs, holds an
undeniable position in the present drug research scenario.1
In between 1999–2013, only 34% of FDA approved drugs
were from natural product origin.7 Even though natural
products have high structural diversity and biological activ-
ity, further structural modifications are needed in many
cases to develop novel scaffolds with specific properties.
The structural reconstruction of natural products (NPs) de-
livers highly relevant molecular changes, which provide in-
sights into the bioactivities and structure–activity relation-
ships against specific targets that are critical for the explo-
ration of a still-unknown chemical space.
–6
7b
7c
7d
7e
Our group mainly focuses on the phytochemical investi-
8
gation of medicinal plants from Western Ghats of India and
the utilization of naturally abundant molecules to generate
structurally diverse bioactive molecules. Zingiber zerumbet
Smith is one among such plants having natural moieties
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synthesis
P. Sharathna et al.
Paper
O
O
O
formation of structurally diverse motifs. We already ob-
served the same while doing the zerumbone activation re-
mCPBA, 0 °C
17e
actions.
With this concept in mind, we synthesized
EtOAc
the epoxide 1 by following a reported procedure in which
mCPBA selectively reacted at the isolated double bond of
zerumbone (Z) to afford 97% of zerumbone epoxide 1
Z
1
(
Scheme 1).16 The structure of the epoxide was confirmed
Scheme 1 Epoxidation of zerumbone
by using various spectroscopic techniques and in compari-
son with previous reports.
7e
humulene epoxide, a component of Zingiber zerumbet
Smith, and have been reported as precursors for many nat-
urally relevant fused cyclic sesquiterpenoid motifs.1
We initiated our studies1 with the reaction of zerum-
bone epoxide and indole as nucleophile in the presence of
water and Yb(OTf) at room temperature. The reaction after
1,12
3
We hypothesized that, just like zerumbone, the zerum-
bone epoxide could also be activated with a Lewis acid, re-
sulting in transannular cyclization reactions leading to the
5 hours at 80 °C afforded a mixture of [5.3.0] (3a) and
[6.3.0] (3a′) fused ring systems (Scheme 2). The structures
of the products were confirmed by various spectroscopic
O
HN
HN
O
O
H
H
O
Yb(OTf)3, H2O
H
H
+
+
N
CH3CN, 80 °C, 5 h
H
O
OHC
1
2a
3a (29%)
3a' (5%)
Scheme 2 Lewis acid catalyzed transformation of zerumbone epoxide 1
Table 1 Optimization of Lewis Acid Catalyzed Transformation of Zerumbone Epoxide 1 with Indolea
O
HN
HN
O
O
H
H
Lewis acid, H2O
solvent, 5 h
+
H
+
H
N
H
O
OHC
3a
O
1
2a
Solvent
3a'
Entry
Lewis acid
Temp (°C)
Yield (%)b
3
a
3a′
NR
1
2
3
4
5
6
7
8
9
Yb(OTf)
Yb(OTf)
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
RT
80
NR
29
5
Sc(OTf)
In(OTf)
Cu(OTf)
Hf(OTf)
3
80
65
25
3
80
29
trace
trace
10
2
80
40
4
80
40
La(OTf)
3
80
32
trace
trace
trace
trace
trace
trace
trace
Zn(OTf)
2
80
trace
32
Sn(OTf)
Sn(OTf)
Sn(OTf)
Sn(OTf)
Sn(OTf)
2
2
2
2
2
80
10
11
12
13
DMF
153
66
trace
32
THF
DCE
83
32
toluene
110
38
a
2
Reaction conditions: 1 (1.0 equiv), 2a (1.0 equiv), Lewis acid (30 mol%), H O (10.0 equiv), solvent (2.0 mL), 5 h.
NR = no reaction.
b
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

C
Synthesis
P. Sharathna et al.
Paper
techniques and the stereochemistry of the molecules were
confirmed from NOE methods; this was similar to our own
previous reports.
mol%), and water (10 equiv) in MeCN (2.0 mL) at 80 °C for 5
hours; this led to the products being isolated in yields of
65% for 3a and 25% for 3a′.
17e
On the basis of the structural analysis of the product, we
confirmed that the transformation of zerumbone epoxide
to 3a′ had taken place via an interrupted Nazarov cycliza-
tion followed by a nucleophilic attack of indole, but the iso-
daucane system 3a was formed via an interrupted Nazarov
cyclization followed by a pinacol–pinacolone rearrange-
ment of the diol formed through the epoxide ring opening.
A similar type of rearrangement was reported by Luu et al.
in 1981, where they reported the acid-catalyzed transannu-
lar cyclization of zerumbone epoxide to bicyclic deriva-
With the optimal conditions in hand, we checked the
scope and generality of this reaction with indoles 2 featur-
ing both electron-withdrawing and -donating substituents.
The results are summarized in Table 2. In almost all cases
(entries 1–7 and 10–13), except in the case of hydroxy- and
amino-substituted indoles (entries 8 and 9), the reactions
proceeded smoothly and were completed within 5 hours at
80 °C. Indoles bearing electron-donating and -withdrawing
groups afforded comparable yields. In the case of substitut-
ed indoles, formation of two more side products resulted;
these include polymerized products of indole and indole–
acetonitrile products.
12
tives.
The reaction conditions were optimized further by ex-
amining various Lewis acids, solvents, and temperatures
We also checked the reactivity of C2-substituted indoles
(Table 2, entries 14–16); with 2-phenylindole, we obtained
the expected products 3n and 3n′ in 25% and 23% yield, but
2-formylindole and indole-2-carboxylic acid failed to afford
(Table 1). From the optimization studies, the best condi-
tions were found to consist of a combination of zerumbone
epoxide 1 (1.0 equiv), indole 2a (1.0 equiv), Sc(OTf) (30
3
Table 2 Generality of Lewis Acid Catalyzed Transformation of Zerumbone Epoxide 1 with Indoles 2a
R1
R1
O
HN
HN
O
R2
O
R2
R2
R1
H
H
Sc(OTf)3, H2O
H
+
H
+
CH3CN, 80 °C, 5 h
N
H
O
OHC
3a–m
O
1
2
3a'–m'
Entry
R1
R2
Products
Yield (%)b
3
3′
25
1
2
3
4
5
6
7
8
9
H
H
3a
3a′
3b′
3c′
3d′
3e′
3f′
65
33
27
32
31
31
20
NR
NR
35
37
34
25
25
NR
NR
NR
H
5-CH
5-Br
3
3b
22
23
20
20
11
15
NR
NR
20
15
13
18
23
NR
NR
NR
H
3c
H
5-NO
2
3d
H
5-CHO
5-CN
5-F
3e
H
3f
H
3g
3g′
3h′
3i′
H
5-OH
3h
H
5-NH
2
3i
10
11
12
13
14
15
16
17
H
5-OCH
3
3j
3j′
H
7-CH
6-CH
5-Cl
H
3
3
3k
3k′
3l′
H
3l
H
3m
3m′
3n′
3o′
3p′
3q′
2-Ph
2-CHO
2-COOH
3n
H
3o
H
3p
3-CH
3
H
3q
a
Reaction conditions: 1 (1.0 equiv), 2 (1.0 equiv), Sc(OTf)
NR = no reaction.
3
(30 mol%), H
2
3
O (10.0 equiv), CH CN (2 mL), 80 °C, 5 h.
b
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

D
Synthesis
P. Sharathna et al.
Paper
the corresponding products, possibly due to the lower nuc-
leophilicity at the C3 position. Reaction with C3-substituted
indole also failed to afford the expected products (entry
Table 3 Substrate Scope of CuAAC of Zerumbone Azide 4a with
Alkynesa
O
O
17).
Next, the scope of this reaction was explored with vari-
alkyne
ous nucleophiles such as pyrrole, thiophene, imidazole, sul-
fonamide, oxazolidine, and pyrazole, but the expected
products were not obtained under the optimized condi-
tions.
CuI, DIPEA
CH3CN, RT, 2 h
N
N
R
N3
N
4a
6a–g
Our next aim was to check the feasibility of Nazarov cy-
clization on zerumbone derivatives (functionalized at the
isolated double bond). Triazole is an important class of
nitrogen-containing heterocycles prevalent in many phar-
Entry
Alkyne
Product
Yield (%)b
1
2
Ph
6a
6b
44
41
18
maceuticals, agrochemicals, and so on. These compounds
exhibit various biological activities, such as antimicrobial,
antiviral, anti-histaminic, anti-tubercular, etc., and this has
attracted various research groups to develop promising
synthetic approaches towards these heterocycles.19 The
synthesis of these bioactive motifs can be achieved via the
p-Tol
3
6c
36
Ph
Ph
4
5
6
6d
6e
6f
38
89
48
NR
20
click chemistry approach. Herein, we describe the synthe-
sis of triazole-linked zerumbone derivatives.
HO
We commenced our investigation with the synthesis of
azido zerumbone derivative 4a via the activation of the al-
lylic methyl group of zerumbone by using N-bromosuccin-
imide, followed by azidation using sodium azide, which fur-
4
7
6g
Br
a
Reaction conditions: 4a (1.0 equiv), alkyne (1.5 equiv), CuI (20 mol%),
21
nished the product in 56% overall yield (Scheme 3). Azide
a was subsequently treated with phenylacetylene (5a; 1.5
DIPEA (3.0 equiv), CH
3
CN (2.0 mL), RT, 2 h.
b
4
NR = no reaction.
equiv), in the presence of CuI (20 mol%) as catalyst, and by
using DIPEA (3.0 equiv) as the base in acetonitrile (2 mL) at
room temperature for 2 hours. The reaction afforded the
corresponding triazole-linked product 6a in 44% yield
as catalyst in different solvents at 80 °C for 12 hours (Table
4). From the optimization studies, the best conditions were
found to consist of a combination of 6a (1.0 equiv), indole
2a (1.0 equiv), and AlCl (5 mol%), in CH CN at 80 °C for 12
(Scheme 3). The structure and stereochemistry of the prod-
3
3
uct was confirmed by various spectroscopic techniques
such as H NMR, C NMR, and HRMS analysis.
hours, delivering the triazole-appended [6.3.0] fused prod-
uct 7a in 50% yield (entry 10).
1
13
With the optimal conditions in hand, we investigated
the scope of reaction with substituted indoles 2 (Table 5).
Indoles bearing both electron-donating and electron-with-
drawing groups afforded the corresponding products in
moderate to good yields.
O
O
O
1
. NBS, CH3CN/H2O
Ph
5a
RT, 1 min
2. NaN3, DMF, RT
CuI, DIPEA
CH3CN, RT, 2 h
N
N
Next, we turned our attention to the oxidation reactions
of zerumbone (Z). In 2016, Kumar et al. reported the allylic
oxidation of the isolated olefin of Z when using selenium
N3
4a (56%)
Ph
N
Z
6a (44%)
dioxide (Scheme 4).22
They synthesized new zerumbone–
Scheme 3 CuAAC of zerumbone azide 4a with phenylacetylene (5a)
bicarbonyl analogues by selective oxidation of the methyl at
C13, leading to an aldehyde (zerumbal, 8) and a ketone
(zerumbenone, 9) with an exocyclic double bond between
the C13 and C6 positions.
With our persistent curiosity in constructing polycyclic
frameworks, here also we checked the possibility of Lewis
acid catalyzed cyclization reactions of the bicarbonyl
zerumbone derivatives 8 and 9. Reaction of zerumbal 8
The scope of the reaction was checked with various aro-
matic as well as aliphatic alkynes (Table 3). Variously sub-
stituted alkynes reacted smoothly with 4a affording the
corresponding triazole-linked products 6a–f in moderate to
good yields (Table 3). The reaction with propargyl alcohol
(
5e) gave the highest yield of 89% (entry 5), but the reaction
with propargyl bromide (5g) failed (entry 7).
To check our Nazarov cyclization hypothesis, we started
our investigations with the reaction of 6a with the external
nucleophile indole 2a in the presence of various Lewis acids
with indole (1.0 equiv) in the presence of In(OTf) (5 mol%)
in acetonitrile at room temperature resulted in the
formation of the 6–3 ring-fused system 10a in 81% yield
3
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

E
Synthesis
P. Sharathna et al.
Paper
Table 4 Optimization of Lewis Acid Catalyzed Transformation of
Triazole-Appended Zerumbone 6a with Indole
Table 5 Scope of Lewis Acid Catalyzed Transformation of Triazole-
Appended Zerumbone 6a with Indoles 2a
O
R
O
O
O
H
H
H
N
HN
HN
H
R
Lewis acid, solvent
12 h
AlCl3, CH3CN
80 °C, 12 h
+
+
N
H
N
N
N
N
H
N
N
N
N
N
N
N
N
6a
2a
7a
6a
2
7a–k
Entry
Lewis acid
Solvent
Temp (°C)
Yield (%)b
Entry
R
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
Sc(OTf)
Sc(OTf)
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
RT
80
NR
38
1
2
3
4
5
6
7
8
9
H
7a
7b
7c
7d
7e
7f
50
30
43
39
32
40
39
41
37
35
33
NR
NR
5-CH
5-Br
3
In(OTf)
Cu(OTf)
Hf(OTf)
3
80
45
2
80
NR
trace
NR
23
5-NO
2
4
80
5-CHO
5-OCH
La(OTf)
Zn(OTf)
Yb(OTf)
3
80
3
2
3
80
7-CH
6-CH
5-Cl
3
3
7g
7h
7i
80
38
Ag(OTf)
80
NR
50
1
1
1
1
0
1
2
3
4
AlCl
AlCl
AlCl
AlCl
AlCl
3
3
3
3
3
80
1
1
1
0
1
2
3
5-F
7j
DMF
153
66
trace
NR
NR
NR
5-CN
7k
7l
THF
5-NH
2
DCE
83.5
110
1
5-OH
7m
1
toluene
a
3 3
Reaction conditions: 6a (1.0 equiv), 2 (1.0 equiv), AlCl (5 mol%), CH CN
(2.0 mL), 80 °C, 12 h.
NR = no reaction.
a
Reaction conditions: 6a (1.0 equiv), 2a (1.0 equiv), Lewis acid (5 mol%),
solvent (2.0 mL), 12 h.
NR = no reaction.
b
b
6, entry 3). Since zerumbal contains two carbonyl groups,
(
Scheme 5), eventuated via the same interrupted Nazarov
we also performed the reaction with 2.0 equivalents of in-
dole, but no desired product was obtained.
cyclization followed by nucleophilic attack, as described
earlier. The structure and the stereochemistry were con-
firmed using various spectroscopic techniques.
In the detailed optimization studies, the catalytic activi-
ty of different Lewis acids and the effect of different sol-
vents and conditions for the reaction were studied; it was
found out that the reaction with In(OTf) (5 mol%) at room
temperature in acetonitrile (2.0 mL) for 12 hours under an
argon atmosphere gave the best yield of 81% for 10a (Table
To extend the scope and generality of the synthetic
methodology, we carried out the reaction with different
substituted indoles and the results are listed in Table 7. We
first studied the effect of substitution at the C2 position of
indole (10b, 10c). Interestingly, 2-phenylindole delivered
the expected product (entry 2) but 2-formylindole failed
(entry 3). Further, we checked the possibility of C2 activa-
tion using C3-substituted indoles (10d). Only a trace
amount of the desired product was obtained (entry 4). A
3
O
H
N
O
O
O
O
In(OTf)3
H
SeO2
+
+
N
CH3CN, RT, 12 h
O
1
,4-dioxane
H
OHC
100 °C, 12 h
H
CHO
CHO
8
2a
10a (81%)
Z
8
9
Scheme 5 Lewis acid catalyzed interrupted Nazarov cyclization of
zerumbal 8 with indole
Scheme 4 Allylic oxidation of zerumbone
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

F
Synthesis
P. Sharathna et al.
Paper
Table 6 Optimization of Lewis Acid Catalyzed Transformation of
Zerumbal 8 with Indole
Table 7 Scope of Lewis Acid Catalyzed Transformation of Zerumbal 8
with Indoles 2a
a
O
H
H
N
O
R1
N
R1
H
In(OTf)3
CH CN, RT, 12 h
H
Lewis acid
R2
+
R2
+
O
O
N
solvent, 12 h
N
3
H
OHC
H
OHC
H
H
CHO
CHO
8
2a
10a
8
2
10a–n
Entry
Lewis acid
Solvent
Temp (°C) Yield (%)b
Entry
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
Sc(OTf)
Sc(OTf)
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
RT
80
RT
RT
RT
RT
RT
RT
RT
RT
80
RT
80
RT
RT
RT
44
1
2
H
H
10a
10b
10c
10d
10e
10f
81
73
NR
NR
71
82
78
62
64
74
75
NR
NR
63
20
2-Ph
H
In(OTf)
Cu(OTf)
Fe(OTf)
3
81
3
2-CHO
H
2
trace
trace
NR
4
3-CHO
H
3
5
H
H
H
H
H
H
H
H
H
H
5-CHO
La(OTf)
Zn(OTf)
Yb(OTf)
3
6
5-NO
5-CN
2
2
3
NR
7
10g
10h
10i
trace
80
8
5-CH
3
AlCl
3
9
5-OCH
5-F
3
10
11
12
13
14
15
6
BF ·OEt
3
2
NR
10
11
12
13
10j
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
In(OTf)
3
78
5-Cl
10k
10l
3
3
3
3
3
DCE
trace
75
5-NH
5-OH
6-CH
2
DCE
10m
10n
THF
trace
NR
14
3
a
DMSO
DCE/toluene
Reaction conditions: 8 (1.0 equiv), 2 (1.0 equiv), In(OTf)
CN (2.0 mL), RT, 12 h.
NR = no reaction.
3
(5.0 mol%),
CH
b
3
1
trace
a
Reaction conditions: 8 (1.0 equiv), 2a (1.0 equiv), Lewis acid (5.0 mol%),
solvent (2 mL), 12 h.
NR = no reaction.
b
In the case of zerumbenone, we also started our investi-
gations with Sc(OTf) as the Lewis acid. To our dismay, the
3
detailed substrate scope was checked with C5- and C6-sub-
stituted indoles (10e–n); the products were obtained in
similar yield, which indicates that substitutions have no ef-
fect on the outcome of the reaction. The final confirmation
of the structure and stereochemistry was obtained from a
single-crystal X-ray structure of compound 10g (Figure 1).
reaction failed to proceed at room temperature. We noticed
that when the reaction temperature was increased to 80 °C,
a diastereoisomeric mixture (1:0.8) of a [6.3.0] ring-fused
system appended to two indole moieties was formed, prob-
ably via an interrupted Nazarov cyclization and allylic car-
bocation formation (Scheme 6).
O
O
NH
O
Sc(OTf)3
H
H
N
O
+
CH3CN, 80 °C, 12 h
N
H
H
9
2a
11a (diastereoisomers, 85%)
Scheme 6 Lewis acid catalyzed interrupted Nazarov cyclization of
zerumbenone 9 with indole
We have carried out detailed optimization studies for
the formation of the bis-indole derivative with different
Lewis acids, solvents, and reaction conditions. All the Lewis
acid tested furnished the desired product in good yield, but
Sc(OTf) emerged as the best Lewis acid in CH CN at 80 °C
Figure 1 Single-crystal X-ray crystal structure of compound 10g
3
3
under an argon atmosphere, with 85% yield (Table 8, entry
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

G
Synthesis
P. Sharathna et al.
Paper
2
). The structure of the product was established using vari-
Table 9 Scope and Generality of Lewis Acid Catalyzed Interrupted
1
13
Nazarov Cyclization of Zerumbenone 9 with Indolesa
ous spectroscopic techniques such as H, C, and other 2-D
NMR techniques and finally by HRMS analysis.
R2
O
NH
Table 8 Optimization Studies of Lewis Acid Catalyzed Interrupted
Nazarov Cyclization of Zerumbenone 9 with Indole
R2
R1
a
R1
R1
O
H
H
Sc(OTf)3
N
O
O
+
CH3CN, 80 °C, 12 h
N
H
H
O
O
NH
O
R2
9
2
11a–m
H
H
H
Lewis acid
N
O
+
R1
R2
Yield (%)b,c
Entry
Product
solvent, 12 h
N
H
1
2
3
4
5
6
7
8
9
H
H
11a
11b
11c
11d
11e
11f
85
9
2a
11a
2-Ph
H
trace
NR
50
Entry
Lewis acid
Solvent
Temp (°C)
Yield (%)b,c
2-COOH
H
H
H
H
H
H
H
H
H
H
H
5-CN
5-CHO
1
2
3
4
5
6
7
8
9
Sc(OTf)
Sc(OTf)
3
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
RT
80
RT
80
80
80
80
80
80
80
80
80
80
RT
NR
85
35
5-NO
2
56
AlCl
AlCl
3
3
NR
65
5-OCH
3
11g
11h
11i
55
5-CH
5-F
3
50
In(OTf)
3
79
53
Fe(OTf)
3
73
1
1
1
0
1
2
3
5-Cl
5-Br
11j
45
La(OTf)
Zn(OTf)
BF ·OEt
3
66
11k
11l
20
2
80
5-NH
2
NR
NR
3
2
NR
60
1
5-OH
11m
10
11
12
13
4
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
Sc(OTf)
3
3
3
3
3
DCE
a
3 3
Reaction conditions: 9 (1.0 equiv), 2 (2.0 equiv), Sc(OTf) (5mol%), CH CN
2.0 mL), 80 °C, 12 h.
NR = no reaction.
Diasteroisomers (1:0.8).
THF
trace
NR
NR
NR
(
b
c
DMSO
toluene
1
3
CH CN
a
carbocation is trapped by an external nucleophile (indole),
followed by tautomeric rearrangement to afford the prod-
uct 3a′ (Scheme 7). Product 3a′ again undergoes ring open-
ing by a water molecule to afford the diol intermediate C4,
which upon pinacol–pinacolone rearrangement affords
product 3a, which is a [5.3.0] fused ring system.
The formation of 4a follows the same mechanistic path-
way as 3a′, but for 5a, there is an interrupted Nazarov cy-
clization followed by conjugate addition of the nucleophile
which results in the formation of the bis-indole derivative
(Scheme 8).
Reaction conditions: 9 (1.0 equiv), 2a (2.0 equiv), Lewis acid (5.0 mol%),
solvent (2 mL), 12 h.
b
NR = no reaction.
Diastereoisomers obtained.
c
With the optimum reaction condition in hand, we
checked the feasibility of the reaction with different in-
doles; the results are listed in Table 9. The substrate scope
was tested with different indoles, both with electron-with-
drawing and electron-releasing groups, which afforded the
products in similar yields In the case of 2-phenyl indole
(
entry 2), only a trace amount of product was obtained,
possibly due to the steric hindrance. Indole-2-carboxylic
acid failed to form the product (entry 3), possibly due to the
lower nucleophilicity furnished by the carboxylic group at
the C3 position. Like in the previous case, here also C5-sub-
stituted aminoindole and hydroxyindole failed to deliver
the product (entries 12 and 13).
A plausible mechanism for the trans-annular cyclization
is shown in Scheme 7. The mechanism of formation of 3a′
can be explained by path A which follows the Nazarov-type
cyclization pathway (path A; Scheme 7). Initially, the Lewis
acid coordinates to the carbonyl oxygen atom of Z, thereby
In conclusion, we have described a straightforward
method for the preparation of polycyclic terpenoid systems
from the naturally abundant sesquiterpene zerumbone.
Lewis acid catalyzed transannular cyclization of zerumbone
derivatives furnished [5.3.0] and [6.3.0] fused ring systems
via interrupted Nazarov cyclization. Zerumbone epoxide
delivered biologically relevant [5.3.0] and [6.3.0] systems,
while all other derivatives, such as triazole-appended
zerumbone derivatives, zerumbenone, and zerumbal fur-
nished [6.3.0] fused sesquiterpenoid motifs. Furthermore,
the synthetic scope of the polycyclics prepared were tested
with a wide variety of substrates, which gave moderate to
creating an allylic carbocation intermediate C . Then, the
2
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

H
Synthesis
P. Sharathna et al.
Paper
Path A
Path B
H
Nu
H
H
H
OH
OH
O
O
O
LA
H
Nu
H2O
C4
3a'
LA
O
Nu
H
H
O
O
O
LA
Nu
H
H
O
C3
C1
C5
HO OH2
Nu
LA
H
O
O
H
C2
Nu
Nu
H
H
HO
O
OHC
O
OH
H
3a
C6
Scheme 7 Plausible mechanism for Lewis acid catalyzed transannular cyclization of zerumbone epoxide
Nu
Nu
H
H
O
O
O
O
O
Nu
OHC
H
H
4a
LA
5a
LA
LA
LA
O
O
Nu
H
O
LA
Nu
H
O
LA
O LA
H
A3
A1
OHC
CHO
H
LA
O
LA
O
Nu
Nu
LA
O
H
H
H
H
Nu
O
LA
A2 CHO
Scheme 8 Plausible mechanism for Lewis acid catalyzed transannular cyclization of zerumbal and zerumbenone
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

I
Synthesis
P. Sharathna et al.
Paper
good yields. Further, the biological evaluation of various
scaffolds is in progress in our laboratory, and will be report-
ed in due course.
H), 2.41–2.37 (m, 1 H), 2.33 (dd, J1 = 14.0, J2 = 7.2 Hz, 1 H), 2.17–
2.12(m, 2 H), 2.05 (d, J = 11.5 Hz, 1 H), 1.87–1.84 (m, 1 H), 1.75 (dd,
J = 17.5, J = 7.5 Hz, 1 H), 1.63 (s, 3 H), 1.23 (dd, J = 13.0, J = 5.0 Hz, 2
1
2
1
2
H), 1.12 (d, J = 7.0 Hz, 3 H), 1.04 (s, 3 H), 1.02 (s, 3 H), 0.88 (s, 3 H).
13
C NMR (125 MHz, CDCl ):  = 214.6, 134.7, 133.8, 131.0, 130.2,
3
1
3
29.9, 128.3, 112.1, 53.5, 52.4, 49.4, 49.3, 48.3, 41.2, 40.3, 39.6, 34.1,
1.2, 29.7, 25.1, 20.3, 18.8, 13.1.
All chemicals were of the best grade commercially available and were
used without further purification. All solvents were purified accord-
ing to standard procedures; anhydrous solvents were obtained ac-
cording to literature methods and stored over molecular sieves. Ana-
lytical TLC was performed with Merck TLC Silica gel F254 coated on
aluminum sheets. Gravity column chromatography was performed
using 100–200 or 230–400 mesh silica gel and mixtures of hexane–
EtOAc were used for elution. Melting points were determined on a
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO : 352.22711; found:
2
352.22712.
1,4,4,6-Tetramethyl-3-(5-methyl-1H-indol-3-yl)-2-oxodecahydro-
azulene-6-carbaldehyde (3b)
Yield: 26 mg (33%); brown viscous liquid; R = 0.35 (EtOAc–hexane,
f
1
13
Buchi melting point apparatus and are uncorrected. H and C NMR
spectra were recorded on a Bruker AMX 500 spectrophotometer
3.5:6.5).
IR (neat): 3370, 2962, 2927, 1730, 1691, 1583, 1460, 1374, 1343,
(
CDCl , CCl or their mixtures were used as solvent). Chemical shifts 
3 4
1
–1
1265, 1155, 1102, 920, 795, 735, 621 cm
.
13
of the H and C NMR spectra were referenced against SiMe ( = 0.0)
4
1
H NMR (500 MHz, CDCl ):  = 9.47 (s, 1 H), 7.98 (br s, 1 H), 7.29 (d, J =
or the signal of the NMR solvent. ESI-HRMS spectra were recorded at
3
0
6
2
.5 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.99 (dd, J = 7.0, J = 1.0 Hz, 1 H),
.91 (d, J = 2.0 Hz, 1 H), 3.38 (d, J = 11.0 Hz, 1 H), 2.44 (s, 3 H), 2.23–
.20 (m, 2 H), 2.19–2.09 (m, 2 H), 1.89 (d, J = 15.0 Hz, 1 H), 1.75–1.72
60,000 resolution by using a Thermo Scientific Exactive mass spec-
1 2
trometer. IR spectra were recorded on a Bruker FT-IR alpha spectro-
photometer.
(m, 2 H), 1.56–1.43 (m, 2 H), 1.16 (d, J = 7.0 Hz, 3 H), 1.08 (s, 3 H), 0.89
(
s, 3 H), 0.67 (s, 3 H).
Preparation of [5.3.0] and [6.3.0] Fused Cyclic Products 3 and 3′
from Zerumbone Epoxide 1; General Procedure
13C NMR (125 MHz, CDCl
1
2
):  = 216.6, 205.9, 134.8, 129.2, 124.3,
22.2, 121.0, 119.3, 110.8, 59.6, 52.3, 49.8, 48.7, 47.9, 39.7, 34.2, 31.1,
9.8, 25.4, 21.6, 20.0, 19.0, 13.0, 12.1.
3
Zerumbone epoxide 1 (1.0 equiv), indole 2 (1.0 equiv), Sc(OTf)3 (30
mol%), and H O (10.0 equiv) were placed in a reaction tube. CH CN (2
2
3
+
mL) was added and the reaction mixture was stirred at 80 °C for 5 h.
The solvent was evaporated in vacuo and the residue was purified by
column chromatography (silica gel, 230–400 mesh, hexane–EtOAc) to
yield the product.
HRMS (ESI): m/z [M + Na] calcd for C24H31NNaO : 388.22525; found:
388.22638.
2
1
a,4,7,7-Tetramethyl-6-(5-methyl-1H-indol-3-yl)decahydro-5H-
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3b′)
3
-(1H-Indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydroazulene-6-
Yield: 17 mg (22%); brown viscous liquid; R = 0.18 (EtOAc–hexane,
f
carbaldehyde (3a)
3.5:6.5).
Yield: 49 mg (65%); brown pasty mass; R = 0.37 (EtOAc–hexane,
f
IR (neat): 3386, 2924, 2855, 1701, 1577, 1458, 1377, 1263, 1180,
3.5:6.5).
–1
1099, 1071, 796, 708, 644, 622 cm
.
IR (neat): 3360, 2961, 2927, 1731, 1691, 1621, 1459, 1370, 1340,
1
H NMR (500 MHz, CDCl ):  = 7.80 (br s, 1 H), 7.60 (s, 1 H), 7.21 (d, J =
3
–1
1263, 1158, 1102, 1012, 653, 590 cm .
8
.0 Hz, 1 H), 7.00 (dd, J = 8.0, J = 1.2 Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H),
1 2
1
H NMR (500 MHz, CDCl ):  = 9.46 (s, 1 H), 8.15 (s, 1 H), 7.53 (d, J =
3.12 (d, J = 11.0 Hz, 1 H), 2.73 (d, J = 11.0 Hz, 1 H), 2.59 (d, J = 7.0 Hz, 1
H), 2.46 (s, 3 H), 2.07–1.99 (m, 2 H), 1.91 (dd, J = 14.0, J = 6.5 Hz, 2
H), 1.77–1.73 (m, 2 H), 1.32 (s, 3 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.10 (d,
3
8
7
2
.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.09 (t, J =
.5 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 3.40 (d, J = 11.0 Hz, 1 H), 2.25–
.21 (m, 2 H), 2.14–2.05 (m, 2 H), 1.88 (d, J = 15.5 Hz, 1 H), 1.74 (dd,
1
2
J = 7.0 Hz, 1 H), 1.03 (d, J = 7.0 Hz, 1 H), 0.95 (s, 3 H).
J = 14.5, J = 7 Hz, 1 H), 1.57 (d, J = 15.5 Hz, 1 H), 1.50 (dd, J = 23.0, J =
13
1
2
1
2
C NMR (125 MHz, CDCl ):  = 214.6, 123.7, 120.3, 119.0, 116.2,
3
12.0 Hz, 2 H), 1.17 (d, J = 6.5 Hz, 3 H), 1.07 (s, 3 H), 0.88 (s, 3 H), 0.65
110.5, 62.8, 60.9, 50.8, 50.0, 49.9, 47.0, 45.3, 37.9, 36.7, 36.6, 35.0,
(s, 3 H).
30.8, 29.9, 25.7, 23.5, 21.5, 19.8, 18.5, 14.3.
13
C NMR (125 MHz, CDCl ):  = 218.1, 206.1, 136.6, 126.4, 122.4,
+
3
HRMS (ESI): m/z [M + Na] calcd for C24H31NNaO : 388.22525; found:
2
1
3
22.1, 119.5, 119.1, 115.8, 111.4, 59.2, 50.8, 50.5, 49.5, 49.0, 47.7,
6.6, 33.1, 32.7, 27.3, 25.3, 21.5, 12.2.
388.22632.
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO : 352.22711; found:
2
3-(5-Bromo-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydro-
azulene-6-carbaldehyde (3c)
352.22712.
Yield: 25 mg (27%); brown viscous liquid; R = 0.27 (EtOAc–hexane,
f
6
-(1H-Indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-cyclopenta-
3.5:6.5).
[
5,6]cycloocta[1,2-b]oxiren-5-one (3a′)
IR (neat): 3346, 2964, 2930, 1730, 1688, 1457, 1375, 1266, 1154,
Yield: 19 mg (25%); brown pasty mass; R = 0.28 (EtOAc–hexane,
–1
f
1104, 884, 795, 734, 702, 636, 614 cm
.
3.5:6.5).
1
H NMR (500 MHz, CDCl ):  =  9.47 (s, 1 H), 8.29 (br s, 1 H), 7.61 (d,
3
IR (neat): 3337, 2964, 2930, 1696, 1574, 1464, 1437, 1376, 1340,
J = 1.0 Hz, 1 H), 7.22 (dd, J = 8.5, J = 1.5 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1
1
2
–1
1262, 1141, 1104, 1074, 750, 650 cm .
H), 6.85 (d, J = 2.0 Hz, 1 H), 3.33 (d, J = 11.0 Hz, 1 H), 2.22–2.18 (m, 1
H), 2.14–2.10 (m, 2 H), 1.89 (d, J = 15.0 Hz, 1 H), 1.74 (dd, J = 15.0, J =
1
H NMR (500 MHz, CDCl ):  = 8.13 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H),
3
1
2
7.33 (t, J = 8.0 Hz, 1 H), 7.21 (t, J = 7.0 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H),
6.5 Hz, 1 H), 1.58–1.49 (m, 2 H), 1.25 (d, J = 7.0 Hz, 2 H), 1.18 (d, J = 6.5
7.01 (d, J = 1.5 Hz, 1 H), 3.68 (d, J = 5.0 Hz, 1 H), 2.72 (d, J = 11.5 Hz, 1
Hz, 3 H), 1.08 (s, 3 H), 0.87 (s, 3 H), 0.62 (s, 3 H).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

J
Synthesis
P. Sharathna et al.
Paper
13
+
C NMR (125 MHz, CDCl ):  = 217.1, 206.1, 135.2, 128.1, 125.0,
HRMS (ESI): m/z [M + Na] calcd for C23H28N NaO : 419.19468; found:
2 4
3
1
2
23.7, 121.5, 115.3, 112.9, 59.4, 50.8, 50.5, 49.4, 48.9, 47.9, 36.6, 33.1,
7.1, 25.5, 21.4, 14.2, 12.2.
419.19447.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28BrNNaO : 452.12011;
3-(6-Formyl-3,6,8,8-tetramethyl-2-oxodecahydroazulen-1-yl)-1H-
2
found: 452.12076.
indole-5-carbaldehyde (3e)
Yield: 25 mg (31%); brown viscous liquid; R = 0.32 (EtOAc–hexane,
f
6-(5-Bromo-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-
3.5:6.5).
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3c′)
IR (neat): 3333, 2961, 2929, 1714, 1679, 1612, 1576, 1459, 1365,
1267, 1175, 1100, 896, 811, 735, 663 cm .
–1
Yield: 21 mg (23%); brown viscous liquid; R = 0.18 (EtOAc–hexane,
f
3.5:6.5).
1
H NMR (500 MHz, CDCl ):  = 10.03 (s, 1 H), 9.48 (s, 1 H), 8.36 (br s, 1
3
IR (neat): 3357, 2962, 2929, 1703, 1573, 1457, 1364, 1287, 1226,
H), 8.09 (s, 1 H), 7.75 (dd, J = 8.5 Hz, J = 1.5 Hz, 1 H), 7.42 (d, J = 8.5
1
2
–1
1101, 884, 797, 753, 703, 647 cm
.
Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 3.46 (d, J = 11.5 Hz, 1 H), 2.26–2.23
(m, 2 H), 2.26–2.23 (m, 2 H), 2.21–2.10 (m, 2 H), 1.92 (d, J = 15.5 Hz, 1
H), 1.79–1.74 (m, 1 H), 1.28–1.25 (m, 2 H), 1.18 (d, J = 6.5 Hz, 3 H),
1
H NMR (500 MHz, CDCl ):  = 8.28 (br s, 1 H), 7.89 (d, J = 12.0 Hz, 1
3
H), 7.26 (t, J = 4.0 Hz, 1 H), 7.17 (d, J = 8.5 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1
H), 3.59 (t, J = 5.0 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.52–2.38 (m, 1
H), 2.36–2.25 (m, 2 H), 2.12 (d, J = 11.5 Hz, 1 H), 1.96–1.80 (m, 2 H),
1.15–1.14 (m, 1 H), 1.08 (s, 3 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.65 (s, 3 H).
13
C NMR (125 MHz, CDCl ):  = 216.8, 206.0, 192.3, 140.0, 129.6,
3
1
.79–1.71 (m, 1 H), 1.65 (s, 2 H), 1.61–1.50 (m, 2 H), 1.13 (s, 3 H), 1.04
123.9, 118.1, 111.9, 59.6, 50.4, 49.3, 48.9, 47.9, 36.6, 33.0, 27.1, 25.5,
21.3, 12.2.
(s, 7 H), 0.99 (d, J = 7.5 Hz, 3 H).
13
HRMS (ESI): m/z [M + H]+ calcd for C24H30NO : 380.22202; found:
C NMR (125 MHz, CDCl ):  = 206.1, 135.2, 128.1, 125.0, 123.7,
3
3
1
2
21.5, 115.3, 112.9, 60.4, 59.4, 50.8, 50.5, 49.5, 48.9, 47.9, 36.6, 33.1,
7.1, 25.5, 21.3, 14.2, 12.2.
380.22328.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28BrNNaO : 452.12011;
found: 452.12076.
3-(3,3,6,8a-Tetramethyl-5-oxodecahydro-2H-cyclopenta[5,6]-
cycloocta[1,2-b]oxiren-4-yl)-1H-indole-5-carbaldehyde (3e′)
2
Yield: 16 mg (20%); brown pasty mass; R = 0.29 (EtOAc–hexane, 3:7).
f
1
,4,4,6-Tetramethyl-3-(5-nitro-1H-indol-3-yl)-2-oxodecahydro-
IR (neat): 3335, 2961, 2929, 1714, 1612, 1562, 1464, 1365, 1267,
azulene-6-carbaldehyde (3d)
–1
1175, 1100, 896, 811, 735, 663 cm
.
Yield: 27 mg (32%); yellow pasty mass; R = 0.33 (EtOAc–hexane,
1
f
H NMR (500 MHz, CDCl ):  = 10.06 (s, 1 H), 8.40 (s, 1 H), 8.33 (d, J =
3
3.5:6.5).
1
1.0 Hz, 1 H), 8.07 (t, J = 1.5 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.43 (d,
J = 7.5 Hz, 1 H), 3.72 (d, J = 5.5 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.53–
2.43 (m, 1 H), 2.39 (t, J = 6.0 Hz, 1 H), 2.32–2.28 (m, 1 H), 2.21–2.13
(m, 1 H), 2.09–2.03 (m, 1 H), 1.91 (d, J = 5.5 Hz, 1 H), 1.41 (d, J = 5.5 Hz,
IR (neat): 3335, 2961, 2928, 1728, 1696, 1623, 1519, 1470, 1373,
–1
1
332, 1248, 1106, 914, 816, 739, 651 cm .
1
H NMR (500 MHz, CDCl ):  = 9.48 (s, 1 H), 8.51 (s, 1 H), 8.11 (dd, J =
3
1
1
H), 1.25 (d, J = 7.5 Hz, 2 H), 1.13 (s, 3 H), 1.07 (s, 6 H), 1.02 (d, J = 8.5
9
.0, J = 2.0 Hz, 1 H), 8.00–7.95 (m, 1 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.13
2
Hz, 3 H).
(
2
d, J = 2.0 Hz, 1 H), 3.44 (d, J = 11.0 Hz, 1 H), 3.19–3.05 (m, 1 H), 2.95–
.74 (m, 1 H), 2.66–2.45 (m, 1 H), 2.26–2.20 (m, 1 H), 2.13–2.11 (m, 1
H), 1.93 (d, J = 15.0 Hz, 1 H), 1.26 (d, J = 3.0 Hz, 2 H), 1.19 (d, J = 6.5 Hz,
13
C NMR (125 MHz, CDCl ):  = 217.1, 192.5, 139.9, 133.7, 130.2,
3
129.8, 128.3, 122.5, 111.9, 53.3, 52.1, 50.1, 49.4, 48.6, 48.4, 31.1, 30.7,
29.7, 20.5, 18.7, 13.1.
3
H), 1.09 (s, 3 H), 0.91 (s, 3 H), 0.64 (s, 3 H).
13
HRMS (ESI): m/z [M + H]+ calcd for C24H30NO : 380.22202; found:
C NMR (125 MHz, CDCl ):  = 217.4, 205.9, 141.9, 139.4, 133.5,
3
3
130.2, 125.3, 118.1, 116.6, 111.4, 59.6, 50.7, 50.5, 49.3, 48.9, 47.9,
380.22333.
44.8, 40.2, 39.7, 36.6, 33.0, 30.9, 27.0, 25.5, 23.3, 21.3, 12.2.
+
HRMS (ESI): m/z [M + Na] calcd for C23H28N NaO : 419.19468; found:
3-(6-Formyl-3,6,8,8-tetramethyl-2-oxodecahydroazulen-1-yl)-1H-
2
4
419.19461.
indole-5-carbonitrile (3f)
Yield: 25 mg (31%); brown viscous liquid; R = 0.52 (EtOAc–hexane,
f
1a,4,7,7-Tetramethyl-6-(5-nitro-1H-indol-3-yl)decahydro-5H-
3:7).
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3d′)
IR (neat): 3325, 2962, 2931, 2220, 1728, 1691, 1619, 1469, 1370,
1265, 1173, 1102, 809, 736, 640 cm .
–1
Yield: 17 mg (20%); yellow viscous liquid; R = 0.24 (EtOAc–hexane,
f
3.5:6.5).
1
H NMR (500 MHz, CDCl ):  = 9.47 (s, 1 H), 8.52 (br s, 1 H), 7.87 (s, 1
3
IR (neat): 3077, 2963, 2926, 1728, 1624, 1575, 1520, 1471, 1432,
H), 7.38 (d, J = 1.5 Hz, 1 H), 7.35 (d, J = 0.5 Hz, 1 H), 7.06 (d, J = 2.5 Hz,
1 H), 3.39 (d, J = 11.5 Hz, 1 H), 2.20–2.09 (m, 5 H), 1.92 (d, J = 15.5 Hz,
1 H), 1.18–1.74 (m, 1 H), 1.54–1.49 (m, 3 H), 1.19 (d, J = 7.0 Hz, 3 H),
–1
1376, 1334, 1305, 1262, 1142, 1074, 898, 749, 721, 669 cm .
1
H NMR (500 MHz, CDCl ):  = 8.74 (dd, J = 15.0, J = 2.0 Hz, 1 H), 8.51
3
1
2
1.14 (s, 3 H), 1.09 (s, 3 H), 0.89 (s, 3 H), 0.61 (s, 3 H).
(s, 1 H), 8.15–8.11 (m, 1 H), 7.57 (s, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 3.69
13
(
d, J = 6.0 Hz, 1 H), 2.64 (dd, J = 11.5, J = 4.5 Hz, 1 H), 2.49 (dd, J =
C NMR (125 MHz, CDCl ):  = 216.4, 204.9, 137.2, 125.1, 124.2,
1
2
1
3
1
0.0, J = 3.0 Hz, 1 H), 2.41–2.36 (m, 1 H), 2.32–2.27 (m, 2 H), 2.23 (d,
123.9, 123.6, 115.8, 111.3, 101.9, 58.4, 49.7, 49.5, 48.5, 46.9, 35.6,
31.9, 31.9, 25.9, 24.5, 20.2, 11.2.
2
J = 11.5 Hz, 1 H), 1.94–1.88 (m, 5 H), 1.81 (dd, J = 13.0, J = 8.0 Hz, 3
1
2
H), 1.65–1.60 (m, 1 H), 1.49–1.39 (m, 1 H), 1.26 (s, 3 H), 1.09 (s, 6 H),
+
HRMS (ESI): m/z [M + Na] calcd for C24H28N NaO : 399.20485; found:
2
2
1.00 (d, J = 12.5 Hz, 3 H).
399.20572.
13
C NMR (125 MHz, CDCl ):  = 219.5, 134.7, 133.8, 130.2, 129.8,
3
1
2
28.3, 68.6, 64.2, 54.9, 52.8, 48.9, 41.7, 39.4, 34.1, 30.9, 29.4, 28.6,
1.3, 18.1, 14.1.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

K
Synthesis
P. Sharathna et al.
Paper
3
-(3,3,6,8a-Tetramethyl-5-oxodecahydro-2H-cyclopenta[5,6]-
IR (neat): 3360, 2962, 2930, 1733, 1689, 1625, 1583, 1485, 1459,
cycloocta[1,2-b]oxiren-4-yl)-1H-indole-5-carbonitrile (3f′)
1374, 1295, 1264, 1214, 1172, 1032, 925, 799, 735, 698, 632 cm–1
.
1
Yield: 9 mg (11%); brown viscous liquid; R = 0.41 (EtOAc–hexane,
H NMR (500 MHz, CDCl ):  = 9.46 (s, 1 H), 8.04 (br s, 1 H), 7.22–7.19
f
3
3
.5:6.5).
(m, 2 H), 6.99 (s, 1 H), 6.87–6.83 (m, 2 H), 3.85 (s, 3 H), 3.36 (d, J = 11.0
Hz, 1 H), 2.18 (t, J = 9.0 Hz, 2 H), 2.12–2.09 (m, 2 H), 2.06 (d, J = 10.0
Hz, 1 H), 1.89 (d, J = 15.5 Hz, 1 H), 1.76–1.72 (m, 1 H), 1.59–1.52 (m, 1
H), 1.49–1.46 (m, 2 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.07 (s, 3 H), 0.88 (s, 3
H), 0.66 (s, 3 H).
IR (neat): 3330, 2961, 2927, 2220, 1729, 1621, 1459, 1370, 1340,
–1
1263, 1158, 1102, 1012, 653, 640 cm .
1
H NMR (500 MHz, CDCl ):  = 8.43 (br s, 1 H), 8.15 (d, J = 13.0 Hz, 1
3
H), 7.44–7.42 (m, 1 H), 7.40 (s, 1 H), 7.14 (dd, J = 10.5, J = 1.5 Hz, 1 H),
1
2
13
C NMR (125 MHz, CDCl ):  = 218.3, 206.2, 153.9, 131.8, 126.9,
3.64 (dd, J = 8.5, J = 5.0 Hz, 1 H), 2.65 (d, J = 11.5 Hz, 1 H), 2.55–2.43
3
1
2
123.1, 115.5, 112.0, 111.8, 101.7, 59.2, 50.8, 50.4, 49.2, 49.0, 47.7,
(m, 2 H), 2.34 (dd, J = 11.0, J = 5.0 Hz, 1 H), 2.31–2.24 (m, 2 H), 2.19
1 2
36.6, 33.0, 32.8, 27.3, 25.4, 21.5, 12.2.
(d, J = 11.5 Hz, 1 H), 2.05 (d, J = 10.5 Hz, 1 H), 1.89 (d, J = 3.5 Hz, 1 H),
+
1
.44–1.39 (m, 1 H), 1.25 (s, 3 H), 1.05 (s, 6 H), 1.00 (d, J = 9.5 Hz, 3 H).
HRMS (ESI): m/z [M + Na] calcd for C24H31NNaO : 404.22016; found:
3
13
404.22034.
C NMR (125 MHz, CDCl ):  = 216.5, 143.4, 137.9, 133.5, 130.9,
3
129.1, 122.9, 111.8, 52.1, 49.6, 47.7, 41.5, 40.0, 29.7, 20.6, 17.6, 12.1.
+
6-(5-Methoxy-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3j′)
HRMS (ESI): m/z [M + Na] calcd for C24H28N NaO : 399.20485; found:
2
2
399.20517.
Yield: 16 mg (20%); brown viscous liquid; R = 0.82 (EtOAc–hexane,
f
3.5:6.5).
3-(5-Fluoro-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydro-
azulene-6-carbaldehyde (3g)
IR (neat): 3362, 2961, 2930, 1729, 1625, 1583, 1485, 1459, 1372,
–1
1296, 1214, 1170, 1038, 912, 832, 800, 731, 696, 645 cm .
Yield: 16 mg (20%); brown viscous liquid; R = 0.43 (EtOAc–hexane,
f
1
3.5:6.5).
H NMR (500 MHz, CDCl ):  = 8.05 (br s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1
3
H), 6.99 (s, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.62 (d, J = 4.0
Hz, 1 H), 2.72 (d, J = 11.5 Hz, 1 H), 2.40–2.37 (m, 1 H), 2.35–2.30 (m, 1
H), 2.18–2.13 (m, 2 H), 1.91–1.83 (m, 2 H), 1.77–1.70 (m, 2 H), 1.64 (s,
IR (neat): 3350, 2964, 2931, 2874, 1792, 1629, 1580, 1486, 1457,
–1
1375, 1292, 1233, 1168, 936, 843, 794, 735, 700 cm .
1
H NMR (500 MHz, CDCl ):  = 9.46 (s, 1 H), 8.33 (s, 2 H), 7.40 (dd, J =
3
1
3
H), 1.52–1.48 (m, 1 H), 1.13 (s, 3 H), 1.03 (d, J = 4.0 Hz, 6 H).
1
2.0, J = 8.5 Hz, 1 H), 7.15 (s, 1 H), 6.90 (d, J = 9.5 Hz, 1 H), 3.33 (d, J =
2
13
C NMR (125 MHz, CDCl ):  = 215.5, 154.3, 133.6, 130.2, 129.8,
11.0 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.49–2.41 (m, 1 H), 2.35–2.29
3
128.3, 121.7, 113.1, 112.0, 101.2, 55.9, 52.0, 49.8, 49.4, 48.8, 41.1,
(
m, 1 H), 2.21 (dd, J = 13.5, J = 7.0 Hz, 1 H), 1.88 (d, J = 14.0 Hz, 1 H),
1 2
39.7, 34.3, 31.1, 29.8, 20.1, 19.0, 13.0, 12.8.
1.76–1.72 (m, 1 H), 1.57 (d, J = 13.5 Hz, 1 H), 1.50–1.47 (m, 2 H), 1.07
+
(s, 3 H), 1.04 (s, 3 H), 1.00 (d, J = 6.5 Hz, 3 H), 0.88 (s, 3 H).
HRMS (ESI): m/z [M + Na] calcd for C24H31NNaO : 404.22016; found:
3
13
404.22034.
C NMR (125 MHz, CDCl ):  = 215.9, 206.4, 134.6, 133.5, 130.1,
3
129.8, 128.2, 123.1, 123.0, 116.7, 53.3, 52.2, 49.4, 48.8, 48.6, 48.3,
41.1, 40.1, 39.6, 34.0, 30.9, 29.7, 25.4, 20.3, 18.8, 13.2, 12.2.
1,4,4,6-Tetramethyl-3-(7-methyl-1H-indol-3-yl)-2-oxodeca-
+
hydroazulene-6-carbaldehyde (3k)
HRMS (ESI): m/z [M + Na] calcd for C23H28FNNaO : 392.20018; found:
2
3
92.20019.
Yield: 27 mg (37%); brown viscous liquid; R
.5:6.5).
IR (neat): 3368, 2960, 2924, 2854, 1733, 1689, 1617, 1458, 1375,
f
= 0.64 (EtOAc–hexane,
3
6
-(5-Fluoro-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-
–1
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3g′)
1266, 1156, 1102, 782, 738, 703 cm .
1
Yield: 12 mg (15%); brown viscous liquid; R = 0.40 (EtOAc–hexane,
H NMR (500 MHz, CDCl ):  = 9.46 (s, 1 H), 8.08 (s, 1 H), 7.98 (d, J =
f
3
3.5:6.5).
8.0 Hz, 2 H), 7.03–6.98 (m, 2 H), 3.40 (d, J = 11.0 Hz, 1 H), 2.47 (d, J =
4
.5 Hz, 1 H), 2.44 (s, 3 H), 2.23 (d, J = 10.0 Hz, 2 H), 2.08 (d, J = 13.5 Hz,
IR (neat): 3366, 2964, 2932, 1728, 1580, 1486, 1458, 1375, 1236,
–1
2 H), 1.88 (d, J = 15.0 Hz, 1 H), 1.74 (d, J = 7.5 Hz, 1 H), 1.56 (s, 1 H),
1167, 1101, 936, 844, 796, 734, 700, 614 cm .
1.47 (d, J = 11.0 Hz, 1 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.07 (s, 3 H), 0.89 (s,
1
H NMR (500 MHz, CDCl ):  = 8.30 (br s, 1 H), 8.08 (s, 1 H), 7.41 (dd,
3
3
H), 0.67 (s, 3 H).
J = 8.5, J = 6.5 Hz, 1 H), 7.21 (dd, J = 8.5, J = 4.0 Hz, 1 H), 6.93 (t, J = 9.0
1
2
1
2
13
C NMR (125 MHz, CDCl ):  = 218.2, 206.2, 134.7, 133.7, 131.1,
Hz, 1 H), 3.58 (d, J = 5.0 Hz, 1 H), 2.71 (dd, J = 21.0, J = 11.5 Hz, 1 H),
3
1
2
1
4
30.2, 129.8, 128.3, 122.8, 122.1, 120.5, 119.8, 116.9, 59.2, 50.5, 49.7,
9.0, 47.7, 36.6, 27.3, 25.3, 21.5, 16.6, 12.2.
2.53–2.39 (m, 1 H), 2.33–2.28 (m, 2 H), 2.10 (d, J = 11.5 Hz, 1 H), 1.88 (
d, J = 11.0 Hz, 1 H), 1.73 (dd, J = 17.0, J = 7.5 Hz, 1 H), 1.55–1.49 (m, 2
1
2
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO : 366.24276; found:
H), 1.11 (s, 3 H), 1.09–0.95 (m, 9 H).
2
13
366.24302.
C NMR (125 MHz, CDCl ):  = 216.2, 134.7, 133.7, 133.0, 130.2,
3
129.8, 128.3, 122.9, 112.0, 111.9, 52.2, 50.0, 49.4, 48.6, 48.3, 41.1,
3
9.6, 34.0, 31.1, 29.7, 20.3, 18.8, 13.2.
1a,4,7,7-Tetramethyl-6-(7-methyl-1H-indol-3-yl)decahydro-5H-
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3k′)
+
HRMS (ESI): m/z [M + Na] calcd for C23H28FNNaO : 392.20018; found:
2
3
92.20019.
Yield: 12 mg (15%); brown viscous liquid; R
.5:6.5).
IR (neat): 3366, 2962, 2930, 1724, 1617, 1457, 1436, 1372, 1230,
f
= 0.61 (EtOAc–hexane,
3
3-(5-Methoxy-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydro-
–1
azulene-6-carbaldehyde (3j)
1160, 1070, 784, 741 702, 673, 646 cm .
1
Yield: 28 mg (35%); brown viscous liquid; R = 0.84 (EtOAc–hexane,
H NMR (500 MHz, CDCl ):  = 8.01 (br s, 11 H), 7.62 (t, J = 8.5 Hz, 1 H),
f
3
3.5:6.5).
7.07 (t, J = 7.0 Hz, 1 H), 7.03 (d, J = 6.5 Hz, 1 H), 6.99 (d, J = 12.0 Hz, 1
H), 3.67 (d, J = 3.0 Hz, 1 H), 2.71 (d, J = 11.5 Hz, 1 H), 2.46 (s, 3 H),
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

L
Synthesis
P. Sharathna et al.
Paper
1
3
2
1
1
3
.42–2.36 (m, 2 H), 2.31 (dd, J = 15.0, J2 = 7.0 Hz, 1 H), 2.19 (dd, J1=
C NMR (125 MHz, CDCl ):  = 216.0, 209.1, 144.4, 135.4, 133.8,
1
3
6.0, J = 4 Hz, 1 H), 2.13 (d, J = 12.5 Hz, 1 H), 2.05 (s, 1 H), 1.86 (d, J =
133.1, 130.5, 127.8, 68.4, 66.1, 58.3, 51.9, 50.0, 48.3, 37.0, 36.8, 34.1,
29.8, 25.5, 24.2, 18.6, 14.3.
HRMS(ESI): m/z [M + H]+ calcd for C23H29ClNO : 386.18813; found:
2
0.5 Hz, 1 H), 1.74 (d, J = 13.5 Hz, 2 H), 1.26 (s, 6 H), 1.04 (d, J = 3.0 Hz,
H), 1.02 (s, 3 H).
2
13
C NMR (125 MHz, CDCl ):  = 216.6, 136.1, 123.1, 120.8, 120.3,
386.18806.
3
1
1
20.1, 117.4, 116.9, 52.4, 49.4, 48.9, 48.8, 48.3, 41.0, 34.3, 31.1, 20.1,
9.0, 16.5, 13.2.
6
-(5-Chloro-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO : 366.24276; found:
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3m′)
2
366.24302.
Yield: 15 mg (18%); brown pasty mass; R = 0.53 (EtOAc–hexane,
f
3.5:6.5).
1
,4,4,6-Tetramethyl-3-(6-methyl-1H-indol-3-yl)-2-oxodecahydro-
IR (neat): 3337, 2963, 2922, 1708, 1629, 1581, 1486, 1460, 1362,
azulene-6-carbaldehyde (3l)
–1
1291, 1222, 1184, 1102, 937, 799, 754, 701 cm
.
Yield: 27 mg (34%); brown viscous liquid; R = 0.78 (EtOAc–hexane,
1
f
H NMR (500 MHz, CDCl ):  = 8.16 (s, 1 H), 8.02–7.97 (m, 1 H), 7.59
3
3.5:6.5).
(ddd, J = 8.0, J = 2.0, J = 1.0 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.19–
1
2
3
IR (neat): 3370, 2962, 2930, 1733, 1690, 1630, 1548, 1459, 1375,
7.12 (m, 1 H), 3.60 (d, J = 5.0 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.54–
2.39 (m, 1 H), 2.37–2.30 (m, 1 H), 2.30–2.26 (m, 1 H), 2.24 (d, J = 11.5
Hz, 1 H), 2.11 (d, J = 11.5 Hz, 1 H), 2.09–1.99 (m, 1 H), 1.93–1.82 (m, 1
H), 1.74 (dd, J = 12.5, J = 8.5 Hz, 1 H), 1.59–1.50 (m, 1 H), 1.13 (s, 3 H),
–1
1339, 1156, 1101, 1032, 912, 800, 733, 648 cm .
1
H NMR (500 MHz, CDCl ):  = 9.45 (s, 1 H), 8.01 (br s, 1 H), 7.99 (s, 1
3
H), 7.08 (d, J = 13.0 Hz, 1 H), 6.80 (s, 1 H), 3.36 (d, J = 11.0 Hz, 1 H),
1
2
1.06 (m, 9 H).
2.71–2.67 (m, 1 H), 2.43 (s, 3 H), 2.22–2.16 (m, 2 H), 2.10 (d, J = 12.0
13
Hz, 2 H), 1.88 (s, 1 H), 1.76–1.71 (m, 1 H), 1.57 (s, 1 H), 1.48 (d, J = 11.0
C NMR (125 MHz, CDCl ):  = 214.6, 134.7, 133.8, 131.2, 129.9,
3
Hz, 1 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.06 (s, 3 H), 0.87 (s, 3 H), 0.65 (s, 3
H).
128.3, 112.1, 53.5, 52.4, 49.4, 49.4, 41.2, 40.3, 39.6, 34.1, 31.2, 29.7,
25.1, 20.3, 18.8, 13.1.
13
HRMS (ESI): m/z [M + H]+ calcd for C23H29ClNO : 386.18813; found:
C NMR (125 MHz, CDCl ):  = 216.7, 206.3, 137.0, 131.9, 124.2,
3
2
1
3
21.6, 121.2, 118.7, 111.4, 103.5, 59.2, 50.8, 50.5, 49.6, 49.0, 47.7,
6.6, 33.1, 32.6, 27.3, 25.3, 21.7, 12.2.
386.18806.
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO : 366.24276; found:
1,4,4,6-Tetramethyl-2-oxo-3-(2-phenyl-1H-indol-3-yl)decahydro-
2
366.24334.
azulene-6-carbaldehyde (3n)
Yield: 23 mg (25%); colorless liquid; R = 0.58 (EtOAc–hexane, 2.5:7.5).
f
1
a,4,7,7-Tetramethyl-6-(6-methyl-1H-indol-3-yl)decahydro-5H-
IR (neat): 3369, 2926, 2858, 1730, 1690, 1457, 1339, 1161, 1073, 923,
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3l′)
–1
765, 742, 703 cm
.
Yield: 10 mg (13%); brown viscous liquid; R = 0.89 (EtOAc–hexane,
1
f
H NMR (500 MHz, CDCl ):  = 9.36 (s, 1 H), 8.08 (s, 1 H), 7.57 (d, J =
3
3.5:6.5).
7
.0 Hz, 1 H), 7.45 (dd, J = 13.0, J = 5.5 Hz, 3 H), 7.41 (d, J = 7.0 Hz, 1
1 2
IR (neat): 3275, 2978, 2930, 1702, 1605, 1479, 1443, 1368, 1224,
H), 7.36 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.08 (t, J = 7.5 Hz, 1
H), 3.57 (d, J = 11.5 Hz, 1 H), 2.60–2.50 (m, 1 H), 2.27 (dd, J = 16.0, J =
–1
1166, 1105, 1011, 860, 736, 650 cm .
1
2
1
9.0 Hz, 1 H), 2.08 (dd, J
1 2
= 13.5, J = 7.0 Hz, 2 H), 2.02–1.96 (m, H),
H NMR (500 MHz, CDCl ):  = 7.92 (br s, 1 H), 7.57 (d, J = 8.0 Hz, 1 H),
.06 (t, J = 9.0 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 1 H), 3.57 (d, J = 4.5 Hz, 1 H),
.64 (d, J = 11.5 Hz, 1 H), 2.37 (s, 3 H), 2.32–2.28 (m, 1 H), 2.25 (dd, J1=
3
1.86–1.72 (m, 1 H), 1.70 (d, J = 15.0 Hz, 1 H), 1.42 (dd, J = 13.0, J = 7.6
7
1
2
Hz, 1 H), 1.26 (s, 3 H), 1.23 (d, J = 6.5 Hz, 3 H), 1.09 (d, J = 6.5 Hz, 1 H),
2
8
1
1
0.99 (s, 3 H), 0.40 (s, 3 H).
.5, J = 7.0 Hz, 1 H), 2.18–2.09 (m, 1 H), 2.07–2.02 (m, 1 H), 1.97 (d, J =
2
13
1.4 Hz, 1 H), 1.78 (d, J = 6.2 Hz, 1 H), 1.69–1.64 (m, 2 H), 1.26 (s, 1 H),
.04 (d, J = 7.0 Hz, 3 H), 0.95 (d, J = 6.0 Hz, 9 H).
C NMR (125 MHz, CDCl ):  = 219.9, 206.0, 128.9, 128.8, 128.4,
3
122.2, 119.7, 119.4, 111.4, 57.3, 51.2, 50.6, 49.7, 48.9, 47.9, 36.4, 33.0,
31.6, 27.3, 25.1, 21.5, 12.6.
HRMS (ESI): m/z [M + H]+ calcd for C29H34NO : 428.25841; found:
13
C NMR (125 MHz, CDCl ):  = 216.6, 137.0, 132.5, 124.1, 121.7,
3
1
3
20.4, 119.3, 116.3, 111.1, 52.6, 52.3, 50.5, 49.4, 48.8, 48.2, 41.0, 39.7,
5.2, 34.3, 31.2, 29.8, 21.7, 20.1, 19.0, 13.1.
2
428.25792.
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO : 366.24276; found:
2
366.24334.
1a,4,7,7-Tetramethyl-6-(2-phenyl-1H-indol-3-yl)decahydro-5H-
cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3n′)
3-(5-Chloro-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydro-
Yield: 21 mg (23%); colorless liquid; R
= 0.55 (EtOAc–hexane, 2.5:7.5).
f
azulene-6-carbaldehyde (3m)
IR (neat): 3369, 2927, 2874, 1730, 1607, 1456, 1338, 1371, 1310,
1160, 913, 843, 737, 702, 652 cm .
–1
Yield: 21 mg (25%); brown pasty mass; R = 0.56 (EtOAc–hexane,
f
3.5:6.5).
1
H NMR (500 MHz, CDCl ):  = 8.12 (s, 1 H), 7.58 (dd, J = 8.0, J = 1.3
3
1
2
IR (neat): 3337, 2963, 2922, 1708, 1689, 1629, 1574, 1433, 1289,
Hz, 2 H), 7.50–7.45 (m, 2 H), 7.44–7.41 (m, 3 H), 7.38 (d, J = 8.0 Hz, 1
H), 7.21–7.18 (m, 1 H), 7.14–7.10 (m, 1 H), 3.87 (d, J = 9.0 Hz, 1 H),
–1
1259, 1139, 1105, 1073, 896, 802, 752, 703, 672 cm .
1
2.54 (dd, J
1
= 9.0, J
2
= 7.0 Hz, 1 H), 2.46 (d, J = 11.5 Hz, 1 H), 2.40–2.32
H NMR (500 MHz, CDCl ):  = 9.47 (s, 1 H), 8.24 (br s, 1 H), 8.08 (t, J =
3
(m, 1 H), 2.27–2.22 (m, 1 H), 1.97 (s, 2 H), 1.81 (d, J = 11.0 Hz, 3 H),
2
.0 Hz, 1 H), 7.59–7.57 (m, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 6.91 (d, J = 2.5
Hz, 1 H), 3.34 (d, J = 11.5 Hz, 1 H), 2.69–2.64 (m, 1 H), 2.34–2.32 (m, 1
H), 2.30–2.28 (m, 1 H), 2.14–2.10 (m, 2 H), 1.89 (d, J = 15.5 Hz, 1 H),
1.67 (d, J = 11.0 Hz, 1 H), 1.59 (d, J = 2.0 Hz, 1 H), 1.20 (d, J = 7.0 Hz, 3
H), 1.06 (dd, J = 7.0, J = 2.5 Hz, 1 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.83 (s, 3
H), 0.51 (s, 3 H).
1
2
1
.77–1.72 (m, 1 H). 1.56–1.46 (m, 1 H), 1.20–1.25 (m, 1 H), 1.18 (d, J =
7.0 Hz, 3 H), 1.08 (s, 3 H), 0.88 (s, 3 H), 0.63 (s, 3 H).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

M
Synthesis
P. Sharathna et al.
Paper
13
13
C NMR (125 MHz, CDCl ):  = 217.5, 136.4, 132.9, 128.9, 128.8,
C NMR (125 MHz, CDCl ):  = 203.4, 158.9, 148.6, 148.2, 139.0,
3
3
128.4, 122.2, 119.7, 119.4, 111.3, 52.9, 50.6, 49.6, 48.9, 36.4, 33.1,
133.6, 131.7, 130.4, 128.9, 128.3, 127.7, 125.7, 119.3, 47.8, 42.3, 37.7,
31.7, 29.7, 27.4, 21.6, 12.6.
34.7, 24.3, 12.0.
+
+
HRMS (ESI): m/z [M + Na] calcd for C29H33NNaO : 450.24090; found:
HRMS (ESI): m/z [M + Na] calcd for C23H27N NaO: 384.20518; found:
2
3
450.24222.
384.20580.
(2E,6Z,10E)-6-(Azidomethyl)-2,9,9-trimethylcycloundeca-2,6,10-
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-p-tolyl-1H-1,2,3-triazol-1-
trienone (4a)
yl)methyl]cycloundeca-2,6,10-trienone (6b)
Allylic bromination of zerumbone: NBS (1.0 mmol) was added to a
Yield: 30 mg (41%); pale yellow solid: R = 0.48 (EtOAc–hexane, 3:7);
f
solution of zerumbone (0.92 mmol) and CH CN/H O (1:1, 15 mL), and
mp 205–208 °C.
3
2
the mixture was stirred vigorously at RT for 1 min. H O (30 mL) was
poured into the solution, which was filtrated immediately, and
2
IR (neat): 3407, 3138, 2959, 2925, 2861, 1716, 1647, 1497, 1453,
1
364, 1268, 1223, 1183, 1108, 1075, 1064, 973, 908, 820, 734, 699,
washed with H O several times; this afforded 7-bromo-2,9,9-trimeth-
–1
2
660 cm
.
yl-6-methylenecycloundeca-2,10-dienone as a colorless solid.
1
H NMR (500 MHz, CDCl ):  = 7.70 (d, J = 8.5 Hz, 2 H), 7.61 (s, 1 H),
3
Azidation: NaN3 (1.0 mmol) and Cs CO (5 mol%) were added to a
2
3
7.21 (d, J = 7.5 Hz, 2 H), 6.03 (d, J = 16.5 Hz, 1 H), 6.00–5.98 (m, 1 H),
solution of 7-bromo-2,9,9-trimethyl-6-methylenecycloundeca-2,10-
dienone (0.67 mmol) in DMF (20 mL) at RT and the mixture was
stirred for 12 h. The progress of the reaction was monitored by TLC
5.82 (d, J = 16.5 Hz, 1 H), 5.61–5.58 (m, 1 H), 5.06–5.03 (m, 1 H), 4.79
(br s, 1 H), 2.55–2.41 (m, 2 H), 2.40 (s, 3 H), 2.38–2.04 (m, 4 H), 1.87 (s,
3
H), 1.33 (s, 3 H), 1.16 (s, 3 H).
(
hexane–EtOAc, 3:2). The DMF solution was extracted with CH Cl (3
2 2
13
C NMR (125 MHz, CDCl ):  = 203.0, 158.6, 148.3, 139.1, 138.0,
3
×
30 mL) and the combined organic extracts were washed with brine
133.8, 131.5, 129.5, 127.8, 125.6, 118.7, 47.8, 42.3, 37.7, 34.8, 29.7,
(
2 × 30 mL), dried over anhydrous Na SO , and concentrated on a rota-
2 4
29.4, 24.3, 21.3, 12.0.
ry evaporator. Chromatography (silica gel, hexane–EtOAc, 2:1) afford-
ed 4a.
+
HRMS (ESI): m/z [M + Na] calcd for C24
H
N
NaO: 398.22083; found:
29
3
398.22180.
Yield: 245 mg (56%); colorless viscous liquid; Rf = 0.71 (EtOAc–
hexane, 3:7).
(
2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-phenethyl-1H-1,2,3-triazol-1-
IR (neat): 2960, 2924, 2854, 2095, 1653, 1451, 1386, 1364, 1265,
yl)methyl]cycloundeca-2,6,10-trienone (6c)
–1
1105, 968, 903, 831, 777, 698, 631 cm .
Yield: 27 mg (36%); amorphous viscous solid; Rf = 0.27 (EtOAc–
hexane, 3:7).
1
H NMR (500 MHz, CDCl ):  = 6.00 (s, 1 H), 5.96 (t, J = 7.0 Hz, 1 H),
3
5.76 (d, J = 8.0 Hz, 1 H), 5.50 (t, J = 8.5 Hz, 1 H), 4.06 (br s, 1 H), 3.44 (br
IR (neat): 3425, 2960, 2927, 2105, 1644, 1453, 1368, 1268, 1218,
1
1H NMR (500 MHz, CDCl
6
s, 1 H), 2.69 (s, 1 H), 2.55–2.21 (m, 5 H), 1.79 (s, 3 H), 1.25 (s, 3 H), 1.11
–1
053, 749, 701, 558 cm
.
(s, 3 H).
13
3
):  = 7.27–7.24 (m, 3 H), 7.19–7.14 (m, 2 H),
C NMR (125 MHz, CDCl ):  = 203.0, 159.3, 148.4, 138.9, 138.6,
3
.99 (s, 1 H), 6.02 (d, J = 16.5 Hz, 1 H), 6.00–5.96 (m, 1 H), 5.77 (d, J =
6.5 Hz, 1 H), 5.55–5.52 (m, 1 H), 4.97–4.90 (m, 1 H), 4.69–4.66 (m, 1
129.0, 127.4, 57.8, 48.8, 43.1, 38.3, 29.3, 25.8, 12.1.
1
+
HRMS (ESI): m/z [M + Na] calcd for C15H21N NaO: 282.15823; found:
3
H), 3.05–2.97 (m, 4 H), 2.42–2.37 (m, 1 H), 2.32–2.26 (m, 2 H), 2.10–
2
282.15758.
.07 (m, 3 H), 1.81 (s, 3 H), 1.27 (s, 3 H), 1.13 (s, 3 H).
13
C NMR (125 MHz, CDCl ):  = 202.9, 158.5, 148.2, 147.6, 141.0,
3
Triazole-Linked Zerumbones 6; General Procedure
1
39.0, 133.9, 131.1, 128.5, 128.4, 127.7, 126.1, 120.6, 47.5, 42.2, 37.7,
Zerumbone azide 4a (1.0 equiv), the appropriate alkyne (1.5 equiv),
CuI (20 mol%) as catalyst, and DIPEA (3 equiv) as base were weighed
35.5, 34.7, 27.5, 24.3, 12.0.
+
HRMS (ESI): m/z [M + Na] calcd for C25H31N NaO: 412.23648; found:
3
in a reaction tube. CH CN (2 mL) was added and the mixture was al-
3
412.24168.
lowed to stir at RT for 2 h. The solvent was evaporated in vacuo and
the residue was purified by column chromatography (silica gel, 100–
(2E,6Z,10E)-6-[(4-Benzyl-1H-1,2,3-triazol-1-yl)methyl]-2,9,9-
200 mesh, hexane–EtOAc).
trimethylcycloundeca-2,6,10-trienone (6d)
Yield: 27 mg (38%); pale yellow liquid; R = 0.28 (EtOAc–hexane, 3:7).
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-phenyl-1H-1,2,3-triazol-1-
f
yl)methyl]cycloundeca-2,6,10-trienone (6a)
IR (neat): 3410, 2185, 1645, 1454, 1362, 1267, 1210, 1054, 752, 712,
554 cm .
–1
Yield: 31 mg (44%); white solid; R = 0.42 (EtOAc–hexane, 3:7); mp
f
189–190 °C.
1
H NMR (500 MHz, CDCl ):  = 7.31–7.21 (m, 5 H), 7.12 (s, 1 H), 6.02
3
IR (neat): 3432, 3058, 2970, 2928, 2858, 2119, 1709, 1647, 1430,
(d, J = 16.5 Hz, 1 H), 6.00–5.97 (m, 1 H), 5.79 (d, J = 16.5 Hz, 1 H), 5.56–
5.29 (m, 1 H), 4.96 (br s, 1 H), 4.71 (br s, 1 H), 4.08–4.05 (m, 2 H),
2.46–2.44 (m, 2 H), 2.24–2.06 (m, 4 H), 1.79 (s, 3 H), 1.29 (s, 3 H), 1.16
(s, 3 H).
13C NMR (125 MHz, CDCl
):  = 203.5, 159.0, 148.7, 148.1, 139.0,
3
–1
1363, 1266, 1224, 1047, 973, 898, 739, 611, 557 cm .
1
H NMR (500 MHz, CDCl ):  = 7.84–7.76 (m, 2 H), 7.70 (s, 1 H), 7.44–
3
7.41 (m, 2 H), 7.35–7.27 (m, 1 H), 6.05 (d, J = 16.5 Hz, 1 H), 6.03–5.94
(m, 1 H), 5.85 (d, J = 16.5 Hz, 1 H), 5.63–5.60 (m, 1 H), 4.81 (br s, 1 H),
5
1
.06 (br s, 1 H), 2.56–2.42 (m, 2 H), 2.28–2.14 (m, 3 H), 1.90–1.86 (m,
H), 1.79 (s, 3 H), 1.29 (s, 3 H), 0.93 (s, 3 H).
138.9, 133.6, 131.5, 128.6, 128.4, 127.6, 126.5, 121.2, 47.6, 42.2, 37.7,
34.7, 32.2, 29.3, 24.3, 24.0, 12.0.
+
HRMS (ESI): m/z [M + Na] calcd for C24H29N NaO: 398.22083; found:
3
398.21868.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

N
Synthesis
P. Sharathna et al.
Paper
1
3
(
2
2E,6Z,10E)-6-[(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl]-
,9,9-trimethylcycloundeca-2,6,10-trienone (6e)
Yield: 54 mg (89%); colorless solid; R = 0.45 (EtOAc–hexane, 3:7); mp
C NMR (125 MHz, CDCl ):  = 215.8, 148.1, 136.9, 136.2, 130.7,
3
129.8, 129.1, 128.5, 126.2, 126.1, 122.4, 121.3, 119.7, 119.6, 116.7,
1
2
HRMS (ESI): m/z [M + H]+ calcd for C31H35N O: 479.28054; found:
479.27464.
10.9, 59.0, 48.0, 46.4, 43.7, 39.7, 38.5, 34.9, 31.9, 29.7, 29.3, 24.8,
2.7, 14.1, 12.0.
f
1
52–154 °C.
IR (neat): 3417, 2960, 2928, 2127, 1641, 1442, 1268, 1223, 1122,
1
4
–1
047, 1010, 971, 755, 699, 557, 538 cm .
1
H NMR (500 MHz, CDCl ):  = 7.48 (s, 1 H), 6.05 (d, J = 16.5 Hz, 1 H),
3
(
1
E)-1,4,4-Trimethyl-3-(5-methyl-1H-indol-3-yl)-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
6
4
2
.02–5.99 (m, 1 H), 5.80 (d, J = 16.5 Hz, 1 H), 5.62–5.59 (m, 1 H), 5.04–
.96 (m, 1 H), 4.80 (s, 2 H), 4.76–4.75 (m, 1 H), 2.47–2.41 (m, 2 H),
.28–2.27 (m, 1 H), 2.20–2.19 (m, 3 H), 1.83 (s, 3 H), 1.26 (s, 3 H), 1.15
penta[8]annulen-2-one (7b)
(s, 3 H).
Yield: 20 mg (30%); colorless viscous liquid; R = 0.69 (EtOAc–hexane,
f
13
2:3).
C NMR (125 MHz, CDCl ):  = 203.4, 158.8, 148.5, 139.0, 133.5,
3
1
31.8, 127.7, 121.3, 56.6, 47.6, 42.2, 37.7, 34.7, 24.3, 12.0.
IR (neat): 3332, 2957, 2925, 2856, 1732, 1623, 1464, 1372, 1265,
–1
+
1224, 1181, 1078, 1048, 975, 917, 798, 765, 737, 696 cm
1H NMR (500 MHz, CDCl
):  = 7.88 (d, J = 7.5 Hz, 2 H), 7.83 (s, 2 H),
.56 (s, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.06 (d, J =
.
HRMS (ESI): m/z [M + Na] calcd for C18H25N NaO : 338.18445; found:
3
2
338.18424.
3
7
4
5
2
1
.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.64 (s, H), 5.92 (t, J = 8.0 Hz, 1 H),
.06 (d, J = 13.5 Hz, 1 H), 4.98 (d, J = 14.0 Hz, 1 H), 3.49 (s, 1 H), 2.54–
.51 (m, 2 H), 2.43 (s, 3 H), 2.39–2.33 (m, 3 H), 2.22 (d, J = 5.0 Hz, 1 H),
.94–1.85 (m, 3 H), 1.26 (s, 6 H), 0.92 (s, 3 H).
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-pentyl-1H-1,2,3-triazol-1-
yl)methyl]cycloundeca-2,6,10-trienone (6f)
Yield: 33 mg (48%); colorless viscous liquid; R = 0.42 (EtOAc–hexane,
f
3:7).
13
C NMR (125 MHz, CDCl ):  = 215.9, 148.1, 134.5, 130.7, 129.8,
3
IR (neat): 3438, 2958, 2930, 2863, 2097, 1646, 1460, 1366, 1267,
1
1
29.1, 128.9, 128.5, 126.5, 126.1, 124.0, 121.4, 119.7, 119.2, 116.3,
10.6, 59.0, 48.0, 46.3, 38.6, 34.9, 31.9, 29.7, 29.4, 22.7, 21.5, 15.0,
–1
1217, 1048, 971, 780, 558 cm .
1
H NMR (500 MHz, CDCl ):  = 7.21 (s, 1 H), 6.04 (d, J = 16.5 Hz, 1 H),
3
14.1, 12.0.
6.02–6.00 (m, 1 H), 5.82 (d, J = 16.5 Hz, 1 H), 5.60–5.56 (m, 1 H), 4.99
HRMS (ESI): m/z [M + H]+ calcd for C32H37N O: 493.29619; found:
4
(br s, 1 H), 4.74 (br s, 1 H), 2.72–2.68 (m, 2 H), 2.52–2.23 (m, 4 H),
492.29605.
2.18–2.04 (m, 2 H), 1.88 (s, 3 H), 1.82–1.64 (m, 2 H), 1.40–1.20 (m, 7
H), 1.14 (s, 3 H), 0.92–0.86 (m, 3 H).
(
1
E)-3-(5-Bromo-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
13
C NMR (125 MHz, CDCl ):  = 203.2, 158.9, 148.8, 148.5, 138.9,
3
133.9, 131.2, 127.6, 120.2, 47.5, 42.2, 37.6, 34.7, 31.4, 29.6, 29.3, 29.1,
penta[8]annulen-2-one (7c)
25.6, 24.3, 24.0, 22.4, 14.0, 12.0.
Yield: 33 mg (43%); brown viscous liquid; R = 0.33 (EtOAc–hexane,
3:7).
f
+
HRMS (ESI): m/z [M + Na] calcd for C22H33N NaO: 378.25213; found:
3
378.25278.
IR (neat): 3331, 2958, 2926, 2856, 1732, 1613, 1459, 1362, 1265,
1
222, 1149, 1077, 1048, 976, 884, 797, 764, 735, 695, 655 cm–1
.
Triazole-Appended [6.3.0] Fused Cyclic Products 7; General Proce-
dure
1
H NMR (500 MHz, CDCl ):  = 7.92 (s, 1 H), 7.90–7.87 (m, 2 H), 7.85
3
(s, 1 H), 7.65 (s, 1 H), 7.52 (d, J = 6.5 Hz, 2 H), 7.47 (d, J = 7.0 Hz, 1 H),
Triazole-appended zerumbone 6a (1.0 equiv), indole 2 (1.0 equiv),
7
(
3
(
.22 (d, J = 8.5 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.78 (s, 1 H), 5.99–5.89
m, 1 H), 5.05 (d, J = 14.0 Hz, 1 H), 5.00 (d, J = 14.0 Hz, 1 H), 3.44 (d, J =
.5 Hz, 1 H), 2.57 (t, J = 13.0 Hz, 1 H), 2.39–2.34 (m, 2 H), 2.27–2.14
m, 3 H), 2.09–1.99 (m, 1 H), 1.94–1.87 (m, 2 H), 1.26 (s, 3 H), 0.93 (d,
J = 6.5 Hz, 3 H), 0.90 (s, 3 H).
and AlCl (5 mol%) were placed in a reaction tube. CH CN (2 mL) was
3
3
added and the reaction mixture was stirred at 80 °C for 5 h. The sol-
vent was evaporated in vacuo and the residue was purified by column
chromatography (silica gel, 100–200 mesh, hexane–EtOAc).
13
C NMR (125 MHz, CDCl ):  = 216.2, 148.0, 136.6, 134.9, 130.5,
3
(
E)-3-(1H-Indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-1,2,3-tri-
azol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta-
8]annulen-2-one (7a)
Yield: 33 mg (50%); brown viscous liquid; R = 0.66 (EtOAc–hexane,
1
1
29.2, 129.8, 128.5, 128.0, 126.0, 125.2, 122.8, 122.2, 120.1, 112.9,
12.5, 59.1, 47.8, 46.5, 39.6, 38.5, 34.8, 29.7, 22.8, 14.1, 12.0.
[
HRMS (ESI): m/z [M + H]+ calcd for C31H34BrN O: 557.19105; found:
4
f
557.19170.
2
:3).
IR (neat): 3327, 2959 2928, 2869, 1730, 1619, 1459, 1338, 1265, 1224,
–1
(E)-1,4,4-Trimethyl-3-(5-nitro-1H-indol-3-yl)-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
penta[8]annulen-2-one (7d)
1077, 1048, 764, 737, 696 cm .
1
1
H NMR (500 MHz, CDCl ):  = 7.88 (d, J = 7.0 Hz, 2 H), 7.84 (s, 1 H),
3
7
.78 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.48 (d, J = 7.0 Hz, 1 H),
.43 (s, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.14 (d, J = 7.0 Hz, 1 H), 7.09 (t, J =
.0 Hz, 1 H), 6.71 (s, 1 H), 5.93 (dd, J = 6.5, J = 10 Hz, 1 H), 5.06 (d, J =
Yield: 28 mg (39%); yellow viscous liquid; R = 0.30 (EtOAc–hexane,
f
7
8
1
2
3:7).
1
2
IR (neat): 3348, 2959, 2920, 2851, 1710, 1623, 1520, 1469, 1361,
4.0 Hz, 1 H), 4.75 (d, J = 14.0 Hz, 1 H), 3.53 (d, J = 3.5 Hz, 1 H), 2.58–
.52 (m, 1 H), 2.41–2.34 (m, 3 H), 2.26–2.20 (m, 2 H), 2.05–2.02 (m, 1
1
332, 1267, 1222, 1092, 1048, 975, 912, 815, 766, 733, 698, 649 cm–1
.
1
H), 1.95–1.85 (m, 2 H), 1.25 (s, 6 H), 0.92 (s, 3 H).
H NMR (500 MHz, CDCl ):  = 8.62 (br s, 1 H), 8.53 (s, 1 H), 8.10 (d, J =
3
9.0 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 2 H), 7.72 (s, 1 H), 7.43 (d, J = 7.0 Hz, 2
H), 7.38 (d, J = 9.0 Hz, 1 H), 7.35 (d, J = 7.0 Hz, 1 H), 7.20 (s, 1 H), 5.63–
5.55 (m, 1 H), 4.92 (d, J = 15.0 Hz, 1 H), 4.80 (d, J = 14.5 Hz, 1 H), 3.02
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

O
Synthesis
P. Sharathna et al.
Paper
(
d, J = 5.5 Hz, 1 H), 2.50–2.44 (m, 1 H), 2.26–2.22 (m, 1 H), 2.14–2.10
IR (neat): 3334, 2956, 2923, 2868, 1727, 1625, 1462, 1340, 1225,
1191, 1076, 1048, 910, 802, 765, 732, 695, 648 cm .
–1
(m, 2 H), 2.06–2.03 (m, 2 H), 1.93–1.86 (m, 2 H), 1.26 (s, 3 H), 0.89 (d,
J = 7.0 Hz, 1 H), 0.82 (s, 3 H), 0.36 (s, 3 H)..
1
H NMR (500 MHz, CDCl ):  = 7.88 (d, J = 7.5 Hz, 2 H), 7.83 (s, 1 H),
3
13
C NMR (125 MHz, CDCl ):  = 218.6, 148.0, 141.7, 138.8, 136.4,
7.56 (s, 1 H), 7.51 (t, J = 7.0 Hz, 2 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.29 (br s,
1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.64 (s, 1 H), 5.92
(t, J = 8.0 Hz, 1 H), 5.06 (d, J = 13.5 Hz, 1 H), 4.98 (d, J = 14.0 Hz, 1 H),
3.49 (s, 3 H), 2.57–2.51 (m, 2 H), 2.37 (s, 3 H), 2.35–2.31 (m, 3 H),
2.25–2.17 (m, 2 H), 1.94–1.85 (m, 3 H), 1.25 (s, 3 H), 0.92 (s, 3 H), 0.91
3
1
1
1
30.4, 128.9, 128.3, 127.8, 127.5, 126.4, 125.7, 119.8, 117.6, 115.9,
11.3, 56.6, 52.6, 39.8, 38.0, 35.1, 30.9, 29.7, 22.9, 21.9, 21.5, 15.0,
0.9.
HRMS (ESI): m/z [M + H]+ calcd for C31H34N O : 524.26562; found:
5
3
(s, 3 H).
524.265760.
13
C NMR (125 MHz, CDCl ):  = 216.2, 148.1, 134.5, 130.7, 129.8,
3
1
1
1
29.1, 128.9, 128.4, 126.5, 126.1, 124.0, 121.4, 119.7, 119.2, 116.3,
10.6, 59.0, 48.0, 46.3, 38.6, 34.9, 31.9, 29.7, 29.4, 22.7, 21.5, 14.1,
2.0.
(
E)-3-(3,9,9-Trimethyl-2-oxo-6-[(4-phenyl-1H-1,2,3-triazol-1-
yl)methyl]-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulen-
-yl)-1H-indole-5-carbaldehyde (7e)
Yield: 22 mg (32%); brown viscous liquid; R = 0.82 (EtOAc–hexane,
1
HRMS (ESI): m/z [M + H]+ calcd for C32
H N O: 493.29619; found:
37 4
f
2:3).
493.29605.
IR (neat): 3317, 2958, 2927, 2871, 1735, 1690, 1627, 1578, 1465,
367, 1316, 1226, 1177, 1078, 1048, 974, 920, 810, 766, 697, 625 cm–1
(E)-1,4,4-Trimethyl-3-(6-methyl-1H-indol-3-yl)-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
penta[8]annulen-2-one (7h)
1
.
1
1
H NMR (500 MHz, CDCl ):  = 9.96 (s, 1 H), 7.82 (s, 1 H), 7.81 (s, 1 H),
3
7
8
8
.77 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.69 (s, 1 H), 7.45 (t, J =
.0 Hz, 1 H), 7.36 (t, J = 7.0 Hz, 1 H), 7.28 (t, J = 7.0 Hz, 1 H), 5.76 (t, J =
.5 Hz, 1 H), 4.89 (d, J = 14.0 Hz, 1 H), 4.83 (d, J = 14.0 Hz, 1 H), 3.51 (d,
Yield: 28 mg(41%); colorless viscous liquid; R = 0.69 (EtOAc–hexane,
f
2:3).
J = 3.5 Hz, 1 H), 2.93 (t, J = 16.0 Hz, 1 H), 2.84 (d, J = 5.5 Hz, 1 H), 2.79–
IR (neat): 3338, 2958, 2930, 2863, 1719, 1625, 1460, 1366, 1267,
1217, 1048, 971, 780, 558 cm .
–1
2.75 (m, 1 H), 2.64–2.60 (m, 1 H), 2.27 (d, J = 6.0 Hz, 1 H), 2.24 (d, J =
6
.5 Hz, 1 H), 2.10–2.01 (m, 1 H), 1.87–1.83 (m, 2 H), 1.59 (s, 3 H), 0.95
1
H NMR (500 MHz, CDCl ):  = 7.81 (d, J = 7.0 Hz, 1 H), 7.76 (s, 2 H),
3
(s, 3 H), 0.86 (s, 3 H), 0.59 (s, 3 H).
7
.62 (d, J = 5.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.51 (s, 1 H), 7.46–7.41
(m, 2 H), 7.36 (t, J = 7.5 Hz, 2 H), 6.89 (s, 1 H), 6.00 (t, J = 16.0 Hz, 1 H),
4.97 (d, J = 14.0 Hz, 1 H), 4.90 (d, J = 13.5 Hz, 1 H ), 3.42 (s, 1 H), 2.48 (s,
1 H), 2.36 (d, J = 4.0 Hz, 1 H), 2.34 (s, 3 H), 2.26 (d, J = 7.5 Hz, 2 H), 2.15
(d, J = 5 Hz, 2 H), 1.98 (d, J = 10.5 Hz, 1 H), 1.53–1.46 (m, 2 H), 1.05 (s,
13
C NMR (125 MHz, CDCl ):  = 209.0, 192.2, 148.2, 138.4, 136.3,
3
130.4, 129.2, 128.9, 128.3, 127.1, 126.0, 125.7, 119.3, 111.7, 58.8, 47.1,
46.6, 39.2, 38.5, 38.3, 30.0, 28.3, 27.8, 22.4, 12.1, 8.2.
+
HRMS (ESI): m/z [M + Na] calcd for C32H34N NaO : 529.25795; found:
4
2
3
H), 1.01 (d, J = 7.0 Hz, 3 H), 0.83 (d, J = 6.5 Hz, 6 H).
529.25932.
13
C NMR (125 MHz, CDCl ):  = 216.2, 148.1, 134.5, 130.7, 129.8,
3
1
1
1
29.1, 128.9, 128.5, 126.5, 126.1, 124.0, 121.4, 119.7, 119.2, 116.3,
10.6, 59.0, 48.0, 46.3, 38.6, 34.9, 31.9, 29.7, 29.4, 22.7, 21.5, 14.1,
2.0.
(
1
E)-3-(5-Methoxy-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-
H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-
cyclopenta[8]annulen-2-one (7f)
HRMS (ESI): m/z [M + H]+ calcd for C32
493.29701.
H N O: 493.29610; found:
37 4
Yield: 28 mg (40%); blackish viscous liquid; R = 0.69 (EtOAc–hexane,
f
3:7).
IR (neat): 3398, 2958, 2928, 2869, 1732, 1626, 1583, 1485, 1464,
371, 1292, 1263, 1215, 1174, 1051, 912, 799, 766, 735, 696, 619 cm–1
(E)-3-(5-Chloro-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
penta[8]annulen-2-one (7i)
1
.
1
1
H NMR (500 MHz, CDCl ):  = 7.90 (d, J = 7.0 Hz, 2 H), 7.86 (s, 1 H),
3
7.51 (t, J = 7.5 Hz, 2 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.31 (s, 1 H), 7.23 (d, J =
Yield: 26 mg (37%); brownish viscous liquid; R = 0.63 (EtOAc–hexane,
2
6
1
1
.5 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 6.80 (dd, J = 8.5, J = 2.0 Hz, 1 H),
f
1
2
2:3).
.68 (s, 1 H), 6.03–5.89 (m, 1 H), 5.07 (d, J = 13.5 Hz, 1 H), 4.99 (d, J =
4.0 Hz, 1 H), 3.87 (s, 3 H), 3.46 (d, J = 3.5 Hz, 1 H), 2.54 (d, J = 13.5 Hz,
H), 2.43–2.31 (m, 2 H), 2.23 (dd, J = 10, J = 5.0 Hz, 2 H), 1.99–1.80
IR (neat): 3332, 2930, 2871, 1731, 1627, 1463, 1368, 1224, 1076,
–1
1048, 908, 799, 764, 730, 694, 648, 614 cm
.
1
2
(
0
m, 2 H), 1.29 (dd, J1 = 8.0, J2 = 3.0 Hz, 2 H), 1.26 (d, J = 1.0 Hz, 3 H),
.93 (d, J = 3.5 Hz, 3 H), 0.91 (s, 3 H).
1
H NMR (500 MHz, CDCl ):  = 7.88 (d, J = 7.0 Hz, 2 H), 7.85 (s, 1 H),
3
7
.76 (s, 1 H), 7.49 (d, J = 7.5 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.09 (s, 2
H), 6.82 (s, 1 H), 5.93 (t, J = 14.0 Hz, 1 H), 5.04 (d, J = 14.0 Hz, 1 H), 4.99
(d, J = 14.0 Hz, 1 H), 3.44 (d, J = 3.0 Hz, 1 H), 2.55 (t, J = 12.5 Hz, 1 H),
2.39 (t, J = 12.0 Hz, 1 H), 2.32–2.24 (m, 2 H), 2.19–2.15 (m, 1 H), 1.93–
1.88 (m, 1 H), 1.62–1.57 (m, 1 H), 1.42–1.25 (m, 2 H), 0.93 (d, J = 6.5
Hz, 3 H), 0.90 (s, 3 H).
1
3
C NMR (125 MHz, CDCl ):  = 218.9, 154.2, 148.1, 136.8, 129.8,
3
1
4
29.2, 128.5, 126.6, 126.1, 122.0, 112.9, 111.7, 101.1, 58.9, 55.9, 48.2,
6.2, 38.5, 35.1, 31.4, 29.6, 29.4, 22.9, 11.9.
+
HRMS (ESI): m/z [M + Na] calcd for C35H36N NaO : 531.27360; found:
5
4
2
31.27363.
13
C NMR (125 MHz, CDCl ):  = 216.2, 151.3, 148.0, 136.5, 134.6,
3
130.5, 129.8, 129.2, 128.6, 126.0, 125.8, 123.0, 122.6, 120.2, 119.1,
116.2, 112.1, 59.0, 51.8, 46.6, 41.2, 39.5, 38.5, 37.3, 34.8, 32.7, 29.1,
25.7, 20.2, 12.0, 7.8.
(
1
E)-1,4,4-Trimethyl-3-(7-methyl-1H-indol-3-yl)-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
penta[8]annulen-2-one (7g)
HRMS (ESI): m/z [M + H]+ calcd for C13
513.24171.
H34ClN O: 513.24157; found:
4
Yield: 27 mg (39%); colorless viscous liquid; R = 0.69 (EtOAc–hexane,
f
2:3).
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

P
Synthesis
P. Sharathna et al.
Paper
(
1
E)-3-(5-Fluoro-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-
,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclo-
H), 3.00–2.96 (m, 1 H), 2.73 (t, J = 11.0 Hz, 1 H), 2.41–2.35 (m, 1 H),
2.22–2.15 (m, 4 H), 1.76–1.70 (m, 1 H), 1.52–144 (m, 1 H), 1.05 (d, J =
7.0 Hz, 3 H), 1.03 (s, 3 H), 0.97 (s, 3 H).
penta[8]annulen-2-one (7j)
13
Yield: 24 mg (35%); brown viscous liquid; R = 0.63 (EtOAc–hexane,
C NMR (125 MHz, CDCl ):  = 216.0, 194.1, 152.7, 146.0, 136.4,
3
f
2:3).
126.2, 122.7, 120.9, 119.9, 119.7, 116.8, 111.2, 52.1, 48.2, 47.4, 44.0,
4
0.9, 39.5, 35.2, 27.3, 23.2, 22.7, 12.5.
IR (neat): 3323, 2960, 2928, 2869, 2097, 1731, 1693, 1602, 1485,
–1
+
1451, 1265, 1173, 1078, 937, 851, 799, 765, 738, 696, 619 cm
.
HRMS (ESI): m/z [M + Na] calcd for C23H27NNaO : 372.19398; found:
2
1
372.19468.
H NMR (500 MHz, CDCl ):  = 7.88 (d, J = 7.0 Hz, 1 H), 7.85 (s, 1 H),
3
7
.64 (s, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.44 (d, J = 11.5 Hz, 2 H), 7.08 (d,
J = 4.0 Hz, 1 H), 6.88 (t, J = 8.5 Hz, 1 H), 6.81 (s, 1 H), 5.97–5.90 (m, 1
H), 5.04 (d, J = 13.5 Hz, 1 H), 5.00 (d, J = 14.0 Hz, 1 H), 3.43 (s, 1 H),
(E)-3,9,9-Trimethyl-2-oxo-1-(2-phenyl-1H-indol-3-yl)-
2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carb-
aldehyde (10b)
2
2
.55 (t, J = 13.5 Hz, 1 H), 2.43–2.37 (m, 1 H), 2.34 (d, J = 8.0 Hz, 1 H),
.25 (s, 1 H), 2.18 (d, J = 10.5 Hz, 1 H), 2.06 (d, J = 10.0 Hz, 1 H), 1.88 (d,
Yield: 67 mg (73%); white solid; R = 0.17 (EtOAc–hexane, 1:4); mp
f
J = 14.0 Hz, 2 H), 1.62–1.53 (m, 1 H), 1.25 (s, 6 H), 0.90 (s, 3 H).
215–220 °C.
13
C NMR (125 MHz, CDCl ):  = 215.8, 158.9, 157.0, 148.0, 132.7,
3
IR (neat): 3350, 2961, 2931, 2336, 1736, 1681, 1640, 1459, 1374,
1
1
29.8, 129.1, 128.5, 126.0, 123.1, 119.9, 111.6, 111.5, 110.9, 110.7,
04.7, 104.5, 59.1, 47.9, 46.5, 38.5, 34.9, 29.7, 22.8, 14.1, 12.0.
–1
1281, 1207, 1168, 1112, 886, 799, 764, 670 cm
.
1
H NMR (500 MHz, CDCl ):  = 9.43 (s, 1 H), 8.05 (br s, 1 H), 7.86 (d, J =
3
HRMS (ESI): m/z [M + H]+ calcd for C31H34FN O: 497.27112; found:
4
1.5 Hz, 1 H), 7.21–7.19 (m, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 6.81 (d, J = 2.5
Hz, 1 H), 6.70–6.67 (m, 1 H), 3.46 (d, J = 4.5 Hz, 1 H), 2.93–2.89 (m, 1
H), 2.65 (t, J = 11.5 Hz, 1 H), 2.30–2.24 (m, 1 H), 2.15–2.11 (m, 2 H),
1.68–1.63 (m, 2 H), 1.41–1.34 (m, 2 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.95 (s,
3 H), 0.88 (s, 3 H).
497.27491.
(
E)-3-(3,9,9-Trimethyl-2-oxo-6-[(4-phenyl-1H-1,2,3-triazol-1-
yl)methyl]-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulen-
-yl)-1H-indole-5-carbonitrile (7k)
Yield: 23 mg (33%); brown viscous liquid; R = 0.93 (EtOAc–hexane,
1
13
C NMR (125 MHz, CDCl ):  = 217.4, 193.1, 151.5, 145.7, 136.5,
3
f
135.5, 133.9, 128.9, 128.6, 127.5, 121.8, 119.0, 119.0, 111.1, 109.8,
2:3).
56.0, 44.8, 43.1, 40.1, 39.0, 38.3, 35.9, 26.6, 24.2, 21.8, 21.6.
+
IR (neat): 3438, 2923, 2853, 1689, 1587, 1501, 1465, 1431, 1381,
HRMS (ESI): m/z [M + Na] calcd for C29H31NNaO : 448.22528; found:
448.21853.
2
–1
1328, 1224, 1114, 867, 804, 770, 721 cm
.
1
H NMR (500 MHz, CDCl ):  = 8.64 (br s, 1 H), 8.19 (s, 1 H), 7.88 (t, J =
3
5
.0 Hz, 2 H), 7.50 (t, J = 7.0 Hz, 2 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.36 (d, J =
(E)-3-(6-Formyl-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahy-
dro-1H-cyclopenta[8]annulen-1-yl)-1H-indole-5-carbaldehyde
(10e)
8.5 Hz, 2 H), 7.12 (s, 1 H), 5.97 (t, J = 9.5 Hz, 1 H), 5.05 (d, J = 14.0 Hz, 1
H), 5.01 (d, J = 14.0 Hz, 1 H), 3.49 (d, J = 3.0 Hz, 1 H), 2.59 (t, J = 14.0
Hz, 1 H), 2.48–2.35 (m, 2 H), 2.31–2.26 (m, 2 H), 2.14–2.10 (m, 1 H),
Yield: 70 mg (71%); white solid; R = 0.24 (EtOAc–hexane, 1:4); mp
f
1.67–1.61 (m, 2 H), 1.27–1.25 (m, 1 H), 0.93 (s, 3 H), 0.91 (s, 3 H), 0.89
190–194 °C.
(s, 3 H).
IR (neat): 3351, 2959, 2929, 2872, 1733, 1677, 1611, 1571, 1439,
13
C NMR (125 MHz, CDCl ):  = 215.8, 148.1, 136.9, 136.2, 130.7,
–1
3
1392, 1371, 1314, 1283, 1176, 1112, 809, 735 cm .
1
1
2
29.8, 129.1, 128.5, 126.2, 126.1, 122.4, 121.3, 119.7, 119.6, 116.7,
10.9, 59.0, 47.9, 46.4, 43.7, 39.7, 38.5, 34.9, 31.9, 29.7, 29.3, 24.8,
2.7, 14.1, 12.0.
1
H NMR (500 MHz, CDCl ):  = 10.23 (br s, 1 H), 9.61 (s, 1 H), 9.08 (s, 1
3
H), 7.96 (s, 1 H), 7.26 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 6.92
(d, J = 1.5 Hz, 1 H), 6.48–6.44 (m, 1 H), 3.32 (d, J = 4.5 Hz, 1 H), 2.72–
HRMS (ESI): m/z [M + H]+ calcd for C32H34N O: 504.27579; found:
5
2.61 (m, 1 H), 2.51–2.47 (m, 1 H), 2.00–1.96 (m, 1 H), 1.92 (t, J = 5.0
Hz, 1 H), 1.88–1.83 (m, 1 H), 1.83–1.77 (m, 2 H), 1.50–1.44 (m, 1 H),
504.28834.
1.15–1.08 (m, 1 H), 0.65 (s, 3 H), 0.60 (d, J = 7.0 Hz, 3 H), 0.59 (s, 3 H).
Synthesis of [6.3.0] Fused Ring System 10 from Zerumbal 8; Gener-
al Procedure
13
C NMR (125 MHz, CDCl ):  = 220.3, 198.7, 197.0, 157.1, 151.1,
3
145.4, 134.7, 131.7, 130.1, 129.2, 123.5, 119.8, 117.3, 57.1, 53.1, 52.6,
Zerumbal 8 (1.0 equiv), indole 2 (1.0 equiv), and In(OTf)3 (5 mol%)
48.9, 45.6, 44.4, 40.3, 31.8, 27.5, 27.2, 17.0.
were placed in a reaction tube. CH CN (2 mL) was added and the reac-
+
3
HRMS (ESI): m/z [M + Na] calcd for C24H27NNaO : 400.18889; found:
3
tion mixture was stirred at room temperature for 12 h. The solvent
was evaporated in vacuo and the residue was purified by column
chromatography (silica gel, 100–200 mesh, hexane–EtOAc).
400.18302.
(
E)-3,9,9-Trimethyl-1-(5-nitro-1H-indol-3-yl)-2-oxo-2,3,3a,4,5,8,9,9a-
octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10f)
(
E)-1-(1H-Indol-3-yl)-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octa-
Yield: 67 mg (82%); yellow solid; R = 0.28 (EtOAc–hexane, 1:4); mp
f
hydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10a)
210–215 °C.
Yield: 35 mg (81%); white solid; R = 0.20 (EtOAc–hexane, 1:4); mp
1
f
IR (neat): 3324, 2958, 2923, 2852, 1723, 1671, 1624, 1516, 1469,
45–150 °C.
–1
1
373, 1370, 1252, 1205, 1168, 1105, 1047, 811, 732 cm .
IR (neat): 3354, 2959, 2928, 2872, 1732, 1679, 1640, 1458, 1372,
1
1H NMR (500 MHz, CDCl
):  = 9.52 (s, 1 H), 8.79 (d, J = 1.5 Hz, 1 H),
–1
3
337, 1266, 1206, 1168, 1109, 1012, 739 cm .
8
.52 (br s, 1 H), 8.11 (dd, J = 9.0, J = 2.0 Hz, 1 H), 7.36 (d, J = 9.0 Hz, 1
1 2
1
H NMR (500 MHz, CDCl ):  = 9.50 (s, 1 H), 8.07 (br s, 1 H), 7.78 (d, J =
3
H), 7.04 (s, 1 H), 6.79–6.75 (m, 1 H), 3.64 (d, J = 4.5 Hz, 1 H), 2.99 (dd,
7
.5 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.20–7.17 (m, 1 H), 7.15–7.12 (m,
1
H), 6.89 (d, J = 2.5 Hz, 1 H), 6.77–6.73 (m, 1 H), 3.60 (d, J = 4.0 Hz, 1
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

Q
Synthesis
P. Sharathna et al.
Paper
J = 7.5, J = 5.5 Hz, 1 H), 2.75 (t, J = 11.5 Hz, 1 H), 2.36–2.30 (m, 1 H),
H), 2.85–2.81 (m, 1 H), 2.42–2.37 (m, 1 H), 2.32–2.28 (m, 2 H), 2.24–
1
2
2.22–2.17 (m, 3 H), 1.81–1.76 (m, 1 H), 1.51–1.41 (m, 2 H), 1.08 (d, J =
2.19 (m, 2 H), 1.87–1.83 (m, 1 H), 1.56–1.50 (m, 1 H), 1.06 (s, 3 H),
7.0 Hz, 3 H), 1.06 (s, 3 H), 0.97 (s, 3 H).
1.04–1.02 (m, 6 H).
13
13
C NMR (125 MHz, CDCl ):  = 214.9, 193.3, 151.7, 146.0, 141.5,
C NMR (125 MHz, CDCl ):  = 215.1, 193.4, 154.0, 151.9, 145.9,
3
3
1
39.8, 125.9, 125.5, 118.8, 117.1, 116.8, 111.7, 52.2, 47.8, 47.4, 43.7,
132.0, 126.8, 122.5, 115.9, 112.0, 101.0, 55.0, 52.3, 48.2, 47.3, 43.8,
40.5, 39.2, 35.1, 26.6, 22.4, 22.1, 11.9.
40.4, 39.2, 35.2, 26.6, 22.3, 22.0, 11.8.
+
HRMS (ESI): m/z [M + H]+ calcd for C24H29NHO : 380.22274; found:
HRMS (ESI): m/z [M + H] calcd for C23H26N HO : 395.19726; found:
2
4
3
395.19089.
380.21707.
(
E)-3-(6-Formyl-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahy-
dro-1H-cyclopenta[8]annulen-1-yl)-1H-indole-5-carbonitrile
10g)
Yield: 38 mg (78%); white solid; R = 0.24 (EtOAc–hexane, 1:4); mp
(E)-1-(5-Fluoro-1H-indol-3-yl)-3,9,9-trimethyl-2-oxo-
2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carb-
aldehyde (10j)
(
Yield: 49 mg (74%); white solid; R = 0.27 (EtOAc–hexane, 1:4); mp
f
f
210–214 °C.
214–216 °C.
IR (neat): 3348, 2961, 2930, 2873, 2220, 1734, 1678, 1640, 1619,
IR (neat): 3367, 2960, 2928, 2872, 1732, 1678, 1640, 1582, 1487,
1457, 1375, 1285, 1207, 1172, 1091, 1014, 937, 855, 798, 764, 737,
620 cm .
–1
1471, 1439, 1372, 1206, 1168, 1112, 810, 735, 634 cm .
–1
1
H NMR (500 MHz, CDCl ):  = 9.52 (s, 1 H), 8.58 (br s, 1 H), 8.19 (s, 1
3
1
H), 7.42–7.36 (m, 2 H), 7.00 (s, 1 H), 6.79–6.75 (m, 1 H), 3.58 (d, J = 4.5
Hz, 1 H), 3.03–2.97 (m, 2 H), 2.74 (t, J = 11.5 Hz, 1 H), 2.35–2.29 (m, 1
H), 2.22–2.15 (m, 4 H), 1.78–1.73 (m, 1 H), 1.47–1.40 (m, 1 H), 1.07 (d,
J = 6.5 Hz, 3 H), 1.04 (s, 3 H), 0.96 (s, 3 H).
H NMR (500 MHz, CDCl ):  = 10.10 (br s, 1 H), 9.37 (s, 1 H), 7.32 (dd,
3
J = 10.0, J = 2.5 Hz, 1 H), 7.22–7.20 (m, 1 H), 7.11 (d, J = 2.0 Hz, 1 H),
1
2
6.78–6.74 (m, 2 H), 3.45 (d, J = 4.0 Hz, 1 H), 2.80–2.76 (m, 1 H), 2.27–
2.21 (m, 1 H), 2.16–2.13 (m, 2 H), 2.10–2.03 (m, 2 H), 1.74–1.68 (m, 1
H), 1.40–1.33 (m, 1 H), 0.92 (s, 3 H), 0.88–0.87 (m, 6 H).
13
C NMR (125 MHz, CDCl ):  = 215.5, 194.1, 152.5, 146.0, 138.0,
3
13
126.2, 125.6, 125.6, 122.7, 120.6, 117.7, 112.1, 103.2, 60.4, 52.3, 47.8,
C NMR (125 MHz, CDCl ):  = 215.5, 193.5, 151.9, 145.9, 133.5,
3
47.5, 44.0, 40.8, 39.4, 35.3, 27.3, 23.1, 22.6, 21.1, 14.2, 12.4.
123.9, 112.3, 112.2, 109.9, 109.7, 104.1, 103.9, 52.4, 48.0, 47.1, 43.7,
+
40.4, 39.1, 35.2, 26.6, 22.3, 22.0, 11.7.
HRMS (ESI): m/z [M + H] calcd for C24H26N HO : 375.20743; found:
2
2
+
375.20224.
HRMS (ESI): m/z [M + H] calcd for C23H26FHNO : 368.20276; found:
2
368.19702.
(E)-3,9,9-Trimethyl-1-(5-methyl-1H-indol-3-yl)-2-oxo-
2
,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carb-
(E)-1-(5-Chloro-1H-indol-3-yl)-3,9,9-trimethyl-2-oxo-
2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carb-
aldehyde (10k)
aldehyde (10h)
Yield: 48 mg (62%); white solid; R = 0.55 (EtOAc–hexane, 1:4); mp
f
145–147 °C.
Yield: 59 mg (75%); brown solid; R = 0.48 (EtOAc–hexane, 1:4); mp
f
2
10–214 °C.
IR (neat): 3400, 2960, 2928, 2871, 1732, 1678, 1640, 1465, 1374,
–1
1267, 1180, 1150, 1111, 1049, 1003, 921, 796, 766, 736 cm .
IR (neat): 3347, 2960, 2930, 2872, 1732, 1678, 1625, 1578, 1518,
1470, 1373, 1330, 1108, 902, 815, 739 cm .
–1
1
H NMR (500 MHz, CDCl ):  = 10.01 (br s, 1 H), 9.52 (s, 1 H), 7.54 (d,
3
1
J = 1.0 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 2.5 Hz, 1 H), 6.95 (s,
H NMR (500 MHz, CDCl ):  = 10.19 (br s, 1 H), 9.37 (s, 1 H), 7.65 (d,
3
1
4
2
H), 6.94 (dd, J = 8.5, J = 1.5 Hz, 1 H), 6.91–6.87 (m, 1 H), 3.60 (d, J =
.0 Hz, 1 H), 2.95–2.90 (m, 1 H), 2.86–2.83 (m, 2 H), 2.40 (s, 3 H),
.31–2.29 (m, 2 H), 2.24–2.18 (m, 2 H), 1.88–1.82 (m, 1 H), 1.58–1.50
J = 2.0 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 2.5 Hz, 1 H), 6.94
(dd, J = 8.5, J = 2.0 Hz, 1 H), 6.77–6.74 (m, 1 H), 3.49 (d, J = 4.5 Hz, 1
H), 2.80–2.76 (m, 1 H), 2.71–2.66 (m, 1 H), 2.26–2.20 (m, 1 H), 2.17–
2.15 (m, 1 H), 2.10–2.03 (m, 1 H), 1.75–1.69 (m, 1 H), 1.40–1.33 (m, 1
H), 0.92 (s, 3 H), 0.88–0.87 (m, 6 H).
1
2
1
2
(m, 1 H), 1.06 (s, 3 H), 1.03–1.01 (m, 6 H).
13
C NMR (125 MHz, CDCl ):  = 216.0, 194.0, 152.6, 146.0, 134.8,
3
13
1
4
29.3, 126.5, 124.3, 120.9, 119.3, 116.4, 110.8, 52.1, 48.2, 47.2, 44.0,
0.9, 39.5, 35.2, 27.2, 23.1, 22.7, 21.5, 12.4.
C NMR (125 MHz, CDCl ):  = 214.9, 193.3, 151.8, 145.9, 135.3,
3
127.7, 124.3, 123.6, 121.8, 118.8, 116.1, 112.7, 52.3, 47.8, 47.1, 43.7,
40.4, 39.2, 35.1, 26.6, 22.3, 22.0, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C24H29NHO : 364.22783; found:
2
364.22223.
HRMS (ESI): m/z [M + H]+ calcd for C23H27ClNO : 384.17321; found:
2
384.16729.
(E)-1-(5-Methoxy-1H-indol-3-yl)-3,9,9-trimethyl-2-oxo-
2
,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbal-
Synthesis of [6.3.0] Fused Ring System 11 from Zerumbenone 9;
General Procedure
dehyde (10i)
Yield: 39 mg (64%); brown solid; R = 0.44 (EtOAc–hexane, 1:4); mp
A mixture of zerumbenone 9 (1.0 equiv), indole 2 (1.0 equiv), and
f
170–172 °C.
Sc(OTf)3 (5 mol%) in CH CN (2 mL) as solvent in a Schlenk tube was
3
stirred at 80 °C for 12 h. The completion of the reaction was con-
firmed by TLC, after which the reaction mixture was concentrated
and the crude product was purified by column chromatography (sili-
ca gel, 100–200 mesh, hexane–EtOAc), to give 11 as a diastereoiso-
meric mixture.
IR (neat): 3383, 2958, 2930, 2872, 1733, 1678, 1638, 1584, 1485,
–1
1457, 1374, 1287, 1214, 1173, 1032, 925, 799, 765, 736, 630 cm .
1
H NMR (500 MHz, CDCl ):  = 9.99 (br s, 1 H), 9.52 (s, 1 H), 7.25–7.24
3
(
m, 2 H), 7.14 (d, J = 2.0 Hz, 1 H), 6.91–6.87 (m, 1 H), 6.76 (dd, J = 8.5,
1
J2 = 2.5 Hz, 1 H), 3.81 (s, 3 H), 3.59 (d, J = 4.5 Hz, 1 H), 2.95–2.91 (m, 1
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

R
Synthesis
P. Sharathna et al.
Paper
13
7-[(1H-Indol-3-yl)methyl]-3-(1H-indol-3-yl)-1,4,4-trimethylocta-
C NMR (125 MHz, CDCl ):  = 216.7, 216.3, 215.2, 215.2, 192.3,
3
hydro-1H-cyclopenta[8]annulene-2,6-dione (11a)
140.0, 139.8, 129.8, 129.8, 129.4, 129.3, 127.6, 127.4, 126.3, 126.2,
1
5
3
24.4, 123.3, 122.9, 122.8, 118.3, 118.2, 115.8, 115.1, 112.0, 111.8,
5.9, 54.0, 53.7, 52.0, 51.2, 48.8, 48.5, 48.4, 42.3, 41.4, 39.8, 39.5, 33.3,
1.1, 30.3, 29.7, 28.4, 27.3, 20.6, 20.5, 13.1, 13.0.
Yield: 52 mg (85%); white solid; R = 0.33 (EtOAc–hexane, 3:7); mp
f
123–127 °C.
IR (neat): 3363, 2960, 2926, 1729, 1686, 1569, 1460, 1341, 1288,
HRMS (ESI): m/z [M + H]+ calcd for C33H34N O : 545.24166; found:
–1
1235, 1156, 1100, 892, 793 cm
.
2 4
545.24327.
1
H NMR (500 MHz, CDCl ):  = 8.19–8.11 (m, 4 H), 7.78–7.74 (m, 2 H),
3
7
.63–7.58 (m, 1 H), 7.36–7.29 (m, 4 H), 7.19–7.12 (m, 9 H), 7.00–6.93
1
,4,4-Trimethyl-3-(5-nitro-1H-indol-3-yl)-7-[(5-nitro-1H-indol-3-
(m, 4 H), 3.69 (d, J = 4.5 Hz, 1 H), 3.66 (d, J = 4.5 Hz, 1 H), 2.84–2.68 (m,
yl)methyl]octahydro-1H-cyclopenta[8]annulene-2,6-dione (11f)
4
1
H), 2.60 (d, J = 11.5 Hz, 1 H), 2.45–2.41 (m, 2 H), 2.38–2.34 (m, 5 H),
.76–1.67 (m, 3 H), 1.54–1.48 (m, 3 H), 1.07–0.99 (m, 16 H).
Yield: 40 mg (56%); yellow solid; R = 0.34 (EtOAc–hexane, 3:7); mp
f
13
238–245 °C.
C NMR (125 MHz, CDCl ):  = 217.4, 217.0, 216.2, 215.6, 139.3,
3
1
1
1
4
2
36.6, 136.4, 136.3, 127.5, 127.4, 126.2, 126.2, 122.6, 122.5, 122.0,
21.3, 121.3, 119.8, 119.6, 119.3, 118.8, 116.3, 114.1, 113.6, 112.7,
11.3, 111.3, 56.0, 53.9, 53.8, 53.7, 52.4, 51.3, 51.0, 48.8, 48.7, 48.4,
8.3, 42.2, 41.3, 40.0, 39.8, 34.3, 33.9, 33.2, 33.2, 32.0, 31.2, 31.0, 30.4,
7.1, 21.1, 20.1, 13.2, 12.9.
IR (neat): 3351, 2922, 2852, 1730, 1686, 1623, 1579, 1516, 1466,
–1
1372, 1330, 1099, 893, 813, 737 cm
.
1
H NMR (500 MHz, CDCl ):  = 10.77 (br s, 2 H), 10.66 (br s, 2 H), 8.67
3
(
(
d, J = 2.5 Hz, 1 H), 8.65 (d, J = 2.0 Hz, 1 H), 8.46 (d, J = 2.5 Hz, 1 H), 8.45
d, J = 2.0 Hz, 1 H), 7.92–7.90 (m, 2 H), 7.90–7.89 (m, 2 H), 7.46–7.42
+
HRMS (ESI): m/z [M + Na] calcd for C31H34N NaO : 489.25183; found:
(m, 5 H), 7.36 (d, J = 2.0 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 3.72–3.70 (m,
2
2
489.24449.
2 H), 2.99–2.94 (m, 1 H), 2.89–2.85 (m, 2 H), 2.50–2.48 (m, 2 H), 2.46–
2.44 (m, 1 H), 2.27–2.15 (m, 5 H), 1.80–1.74 (m, 2 H), 1.56–1.44 (m, 3
H), 0.96 (s, 2 H), 0.92–0.90 (m, 11 H), 0.84 (d, J = 7.0 Hz, 3 H).
3
-[(1-(5-Cyano-1H-indol-3-yl)-3,9,9-trimethyl-2,7-dioxodeca-
13
hydro-1H-cyclopenta[8]annulen-6-yl)methyl]-1H-indole-5-carbo-
C NMR (125 MHz, CDCl ):  = 215.5, 215.3, 214.0, 213.7, 141.4,
3
nitrile (11d)
141.2, 141.2, 139.9, 139.7, 127.0, 126.0, 125.8, 125.7, 118.6, 118.5,
1
5
2
17.1, 117.0, 116.9, 116.6, 115.7, 115.7, 111.7, 111.6, 56.1, 53.3, 51.5,
0.6, 48.3, 48.2, 48.1, 48.0, 41.4, 39.5, 39.1, 33.1, 30.4, 29.8, 27.9, 26.9,
0.3, 20.0, 12.3, 12.2.
Yield: 56 mg (50%); white solid; R = 0.28 (EtOAc–hexane, 2:3); mp
f
145–148 °C.
IR (neat): 3341, 2928, 2219, 1733, 1686, 1618, 1472, 1436, 1365 cm–1
.
+
HRMS (ESI): m/z [M + Na] calcd for C31H N NaO : 579.22198; found:
1
32
4
6
H NMR (500 MHz, CDCl ):  = 8.77 (br s, 1 H), 8.65 (br s, 1 H), 8.62 (br
3
579.21372.
s, 1 H), 8.14 (s, 1 H), 8.10 (s, 1 H), 7.96 (s, 1 H), 7.94 (s, 1 H), 7.42–7.36
(
2
2
m, 8 H), 7.16–7.11 (m, 4 H), 3.65–3.62 (m, 2 H), 2.87–2.83 (m, 1 H),
.80–2.72 (m, 3 H), 2.65 (d, J = 7.0 Hz, 1 H), 2.38–2.33 (m, 3 H), 2.29–
.18 (m, 4 H), 2.00–1.97 (m, 2 H), 1.61–1.51 (m, 4 H), 1.08–1.03 (m, 11
3
-(5-Methoxy-1H-indol-3-yl)-7-[(5-methoxy-1H-indol-3-yl)meth-
yl]-1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-di-
one (11g)
H), 0.99–0.98 (m, 5 H).
1
3
Yield: 62 mg (55%); white solid; R
85–189 °C.
IR (neat): 3410, 2925, 2855, 2098, 1643, 1457, 1367, 1291, 1211,
f
= 0.37 (EtOAc–hexane, 1:3); mp
C NMR (125 MHz, CDCl ):  = 216.6, 216.2, 215.0, 214.8, 138.2,
3
1
1
1
1
4
2
38.0, 137.9, 127.4, 127.3, 126.2, 126.1, 125.5, 125.4, 125.0, 124.8,
24.5, 123.4, 123.3, 120.9, 120.7, 120.6, 117.2, 117.1, 114.6, 114.0,
12.3, 103.0, 102.6, 102.5, 56.0, 54.2, 53.8, 51.8, 51.4, 50.9, 48.9, 48.5,
8.4, 48.3, 42.5, 41.5, 39.6, 39.4, 33.7, 33.2, 31.1, 30.2, 28.2, 27. 3, 21.4,
0.7, 13.1, 13.0.
–1
1167, 1098, 1043, 792, 735 cm
.
1
H NMR (500 MHz, CDCl ):  = 10.04 (br s, 2 H), 9.92 (br s, 2 H), 7.30–
3
7
.24 (m, 8 H), 7.16 (dd, J = 17.5, J = 2.5 Hz, 2 H), 7.09 (dd, J = 12.5, J
1
2
1
2
+
HRMS (ESI): m/z [M + Na] calcd for C33H32N NaO : 539.24233; found:
5
= 2.5 Hz, 2 H), 6.80–6.78 (m, 2 H), 6.78–6.77 (m, 2 H), 3.82 (s, 3 H,
OCH ), 3.82 (s, 3 H), 3.81 (d, J = 2.0 Hz, 6 H), 3.65 (d, J = 4.0 Hz, 2 H),
.88–2.82 (m, 2 H), 2.76–2.72 (m, 1 H), 2.56–2.49 (m, 3 H), 2.38–2.24
m, 5 H), 2.00–1.81 (m, 4 H), 1.66–1.59 (m, 1 H), 1.55–1.48 (m, 2 H),
4
2
39.24357.
3
2
(
3
-[(1-(5-Formyl-1H-indol-3-yl)-3,9,9-trimethyl-2,7-dioxodeca-
1.05–1.02 (m, 15 H), 0.95 (d, J = 7.0 Hz, 2 H).
hydro-1H-cyclopenta[8]annulen-6-yl)methyl]-1H-indole-5-carb-
aldehyde (11e)
13
C NMR (125 MHz, CDCl ):  = 215.8, 215.5, 214.7, 214.2, 154.0,
3
1
1
1
4
2
53.8, 153.8, 132.0, 132.0, 132.0, 128.1, 128.0, 126.9, 126.9, 123.9,
23.8, 122.7, 122.6, 115.7, 115.6, 112.6, 112.0, 111.9, 111.4, 111.3,
01.1, 100.5, 100.3, 56.0, 55.1, 55.0, 55.0, 53.4, 53.2, 51.9, 50.9, 50.4,
8.7, 48.7, 47.7, 47.6, 41.9, 41.3, 39.6, 39.2, 33.9, 32.6, 30.4, 29.8, 26.8,
0.3, 19.6, 12.2, 12.1.
Yield: 40 mg (35%); white solid; R = 0.65 (EtOAc–hexane, 2:3); mp
f
235–240 °C.
IR (neat): 3335, 2923, 2852, 2738, 1732, 1677, 1611, 1576, 1438,
–1
1
367, 1313, 1180, 1100 cm .
1
H NMR (500 MHz, CDCl ):  = 10.06 (s, 1 H), 10.05 (s, 1 H), 10.04 (s, 1
3
+
HRMS (ESI): m/z [M + Na] calcd for C33H38N NaO : 549.27296; found:
2
4
H), 10.04 (s, 1 H), 8.70 (br s, 2 H), 8.57 (br s, 1 H), 8.55 (br s, 1 H), 8.31
549.26495.
(d, J = 10.5 Hz, 2 H), 8.16 (d, J = 12.0 Hz, 2 H), 7.78–7.75 (m, 3 H), 7.46–
7
.43 (m, 2 H), 7.41–7.39 (m, 2 H), 7.13–7.09 (m, 3 H), 3.72–3.70 (m, 2
1
,4,4-Trimethyl-3-(6-methyl-1H-indol-3-yl)-7-[(6-methyl-1H-in-
H), 2.92–2.87 (m, 1 H), 2.83–2.81 (m, 1 H), 2.79–2.74 (m, 2 H), 2.68 (d,
J = 11.5 Hz, 1 H), 2.49–2.37 (m, 5 H), 2.31–2.27 (m, 2 H), 2.02–1.96 (m,
3
dol-3-yl)methyl]octahydro-1H-cyclopenta[8]annulene-2,6-dione
11h)
Yield: 61 mg (50%); white solid; R = 0.55 (EtOAc–hexane, 1:4); mp
(
H), 1.60–1.54 (m, 4 H), 1.09–1.00 (m, 16 H).
f
217–225 °C.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

S
Synthesis
P. Sharathna et al.
Paper
IR (neat): 3399, 2961, 2923, 2858, 1730, 1688, 1625, 1456, 1369,
1
3-(5-Bromo-1H-indol-3-yl)-7-[(5-bromo-1H-indol-3-yl)methyl]-
1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione
(11k)
337, 1241, 1153, 1098, 800 cm–1
.
1
H NMR (500 MHz, CDCl ):  = 7.92–7.88 (m, 4 H), 7.66–7.62 (m, 2 H),
3
7.51 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.17 (br s, 2 H), 7.12 (d,
Yield: 20 mg (20%); gummy brown mass; R = 0.48 (EtOAc–hexane,
f
J = 6.0 Hz, 2 H), 6.99–6.91 (m, 7 H), 3.63 (d, J = 4.5 Hz, 2 H), 2.78–2.70
3:7).
(
2
m, 4 H), 2.53 (d, J = 12.0 Hz, 1 H), 2.46 (s, 5 H), 2.44–2.43 (m, 5 H),
.38–2.26 (m, 7 H), 1.93–1.85 (m, 3 H), 1.51–1.44 (m, 3 H), 1.05–1.03
IR (neat): 3417, 2960, 2926, 1730, 1685, 1614, 1544, 1455, 1399,
–1
1369, 1331, 1236, 1156, 1099, 1051, 894, 801, 736 cm
.
(m, 7 H), 1.02–1.00 (m, 7 H), 0.98 (d, J = 7.0 Hz, 2 H).
1
H NMR (500 MHz, CDCl ):  = 8.30 (br s, 2 H), 8.21 (br s, 2 H), 7.60–
3
1
3
C NMR (125 MHz, CDCl ):  = 216.9, 216.5, 215.9, 215.3, 137.0,
3
7.56 (m, 2 H), 7.55–7.42 (m, 3 H), 7.40–7.39 (m, 2 H), 7.21–7.19 (m, 4
1
1
1
4
2
36.8, 136.8, 132.5, 132.0, 131.9, 125.4, 125.3, 124.1, 124.1, 121.8,
21.8, 121.7, 121.3, 121.2, 120.4, 119.4, 119.3, 118.5, 118.5, 116.5,
13.6, 112.8, 111.2, 111.1, 111.1, 55.9, 53.9, 53.6. 52.3, 51.3, 51.0,
8.8, 48.8, 48.4, 48.2, 42.1, 41.2, 39.9, 39.8, 34.4, 33.2, 31.2, 30.3, 29.7,
9.2, 27.2, 27.1, 21.7, 21.6, 21.0, 20.0, 13.1, 12.8.
H), 6.93–6.84 (m, 4 H), 3.59 (d, J = 5.0 Hz, 2 H), 2.81–2.74 (m, 2 H),
2.69–2.65 (m, 3 H), 2.46 (d, J = 12 Hz, 1 H), 2.32 (t, J = 6.0 Hz, 2 H),
2.30–2.22 (m, 3 H), 1.72–1.67 (m, 2 H), 1.53–1.47 (m, 4 H), 1.05–1.04
(m, 5 H), 1.02–0.99 (m, 6 H), 0.97–0.96 (m, 3 H).
13
C NMR (125 MHz, CDCl ):  = 216.9, 216.5, 215.6, 215.2, 137.3,
3
+
HRMS (ESI): m/z [M + Na] calcd for C 3H N NaO : 517.28313; found:
3
38
2
2
137.3, 137.1, 137.0, 129.6, 126.3, 125.2, 125.1, 123.3, 123.1, 123.0,
517.28496.
1
1
22.9, 122.7, 121.7, 121.6, 121.0, 120.9, 120.1, 120.0, 118.3, 116.6,
16.6, 116.3, 115.7, 115.7, 115.3, 114.2, 114.2, 114.1, 113.9, 113.1,
3
1
-(5-Fluoro-1H-indol-3-yl)-7-[(5-fluoro-1H-indol-3-yl)methyl]-
,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione
55.8, 53.8, 53.7, 52.2, 51.1, 48.6, 48.5, 48.4, 41.2, 39.8, 39.6, 34.0, 31.9,
31.8, 31.2, 31.0, 30.3, 30.0, 29.7, 29.4, 29.3, 28.8, 27.2, 22.7, 21.2, 20.2,
13.2, 12.9.
(11i)
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N Br NaO : 624.41700;
Yield: 52 mg (53%); gummy brown solid; R = 0.44 (EtOAc–hexane,
f
2
2
2
3:7).
found: 647.07138.
IR (neat): 3361, 3057, 2963, 2927, 1730, 1687, 1627, 1582, 1484,
–1
1
457, 1351, 1294, 1236, 1172, 1098, 935 796 cm .
1
Funding Information
H NMR (500 MHz, CDCl ):  = 8.33 (br s, 1 H), 8.32 (br s, 1 H), 8.23 (br
3
s, 1 H), 8.21 (br s, 1 H), 7.42–7.37 (m, 2 H), 7.25–7.16 (m, 6 H), 7.01 (d,
J = 2.0 Hz, 1 H), 6.99–6.98 (m, 2 H), 6.94 (d, J = 2.5 Hz, 1 H), 6.92–6.90
Financial assistance from the Science and Engineering Research Board
SERB), New Delhi (EMR/2017/002239) is gratefully acknowledged.
P.S., M.T.M., B.P.D., G.M.A., P.S., and S.K.R. thank the Council of Scientif-
ic and Industrial Research (CSIR) and the University Grants Commis-
(
(m, 2 H), 3.56 (d, J = 5.0 Hz, 2 H), 2.79–2.67 (m, 5 H), 2.39–2.23 (m, 6
H), 1.94–1.88 (m, 3 H), 1.51–1.46 (m, 3 H), 1.05–0.98 (m, 16 H).
13
C NMR (125 MHz, CDCl ):  = 217.2, 216.8, 215.7, 158.9, 158.7,
3
sion (UGC) for research fellowships.
S
c
i
e
n
c
e
a
n
d
E
n
g
i
n
e
eri
n
g
R
esearc
h
B
o
ard (E
M
R/2
0
1
7/0
0
2
2
3
9)C
o
u
n
c
i
l of
S
c
i
e
ntifi
c
a
n
dI
n
d
ustir
a
lResearc
h
,
I
n
d
i
a
()U
n
i
v
ersity Grants
C
o
m
m
i
si
o
n
()
1
1
1
5
3
58.7, 157.0, 156.9, 156.8, 133.0, 132.8, 132.7, 127.9, 127.8, 127.7,
26.6, 126.5, 126.5, 124.4, 124.4, 122.9, 122.9, 116.3, 113.8, 113.7,
13.0, 112.9, 112.0, 111.9, 111.1, 110.9, 110.6, 110.5, 110.4, 110.3,
5.9, 53.6, 52.1, 51.0, 48.7, 48.6, 48.6, 48.4, 41.3, 39.8, 39.6, 33.9, 31.2,
0.3, 28.9, 27.2, 20.2, 13.2, 13.0.
Acknowledgment
Authors acknowledge Dr. Jubi John for the help rendered during the
preparation of the manuscript. The authors also acknowledge Mrs.
Saumini Mathew and Mrs. S. Viji of CSIR-NIIST for recording the NMR
and HRMS spectra. Thanks are due to Dr. Sunil Varughese, for single-
crystal X-ray analysis.
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N F NaO : 525.23298;
found: 525.23212.
2
2
2
3
1
-(5-Chloro-1H-indol-3-yl)-7-[(5-chloro-1H-indol-3-yl)methyl]-
,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione
(
11j)
Supporting Information
Yield: 51 mg (45%); white solid; R = 0.20 (EtOAc–hexane, 1:4); mp
f
232–235 °C.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690840.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
IR (neat): 3363, 2960, 2926, 1729, 1686, 1569, 1460, 1341, 1288,
–1
1235, 1156, 1100, 892, 793 cm .
1
H NMR (500 MHz, CDCl ):  = 7.90 (br s, 2 H), 7.88 (br s, 2 H), 7.64 (d,
3
References
J = 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.17 (s, 2 H), 7.12 (s, 2 H),
6
3
2
1
.97–6.94 (m, 5 H), 6.91 (d, J = 2.0 Hz, 1 H), 3.63 (d, J = 4.5 Hz, 2 H),
.34 (d, J = 10.5 Hz, 1 H), 2.76–2.70 (m, 4 H), 2.53 (d, J = 12.0 Hz, 2 H),
.46 (s, 5 H), 2.43 (s, 6 H), 2.36–2.30 (m, 4 H), 2.20–2.14 (m, 3 H),
.91–1.85 (m, 2 H), 1.52–1.41 (m, 5 H), 1.05–1.03 (m, 11 H), 1.02 (s, 5
(
(
(
1) Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat. Prod. Rep. 2000,
17, 215.
2) Sneader, W. Drug Prototypes and their Exploitation; Wiley:
Chichester, 1996.
3) Buss, A. D.; Cox, B.; Waigh, R. D. In Burger’s Medicinal Chemistry
& Drug Discovery, 6th ed., Vol. 1; Abraham, D. J., Ed.; Wiley-
Interscience: Hoboken, 2003, 847–900.
H).
13
C NMR (125 MHz, CDCl ):  = 217.4, 217.1, 216.1, 215.7, 135.0,
3
134.8, 134.7, 134.5, 128.5, 127.2, 125.4, 125.0, 124.2, 124.1, 122.7,
122.6, 122.2, 122.1, 119.0, 118.9, 118.1, 115.6, 115.6, 112.4, 112.3,
56.0, 52.2, 51.0, 48.5, 48.3, 41.2, 39.7, 33.9, 31.1, 30.9, 29.7, 28.8, 27.1,
20.1, 13.1.
(4) Swann, J.; Weatherall, M. In Search of a Cure: A History of the
Pharmaceutical Industry, Vol. 8; Oxford University Press: Oxford,
1990, 224–225.
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N Cl NaO : 557.17388;
found: 557.16589.
(5) Grabley, S.; Thiericke, R. Drug Discovery from Nature; Springer:
Berlin, 2000, 3–37.
2
2
2
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T

T
Synthesis
P. Sharathna et al.
Paper
(
(
(
6) Mann, J. Murder, Magic, and Medicine, 2nd ed; Oxford University
(13) Kitayama, T.; Okamoto, T.; Hill, R. K.; Kawai, Y.; Takahashi, S.;
Yonemori, S.; Yamamoto, Y.; Ohe, K.; Uemura, S.; Sawada, S.
J. Org. Chem. 1999, 64, 2667.
(14) (a) Kitayama, T.; Yamamoto, K.; Utsumi, R.; Takatani, M.; Hill, R.
K.; Kawai, Y.; Sawada, S.; Okamoto, T. Biosci., Biotechnol., Bio-
chem. 2001, 65, 2193. (b) Kitayama, T.; Iwabuchi, R.; Minagawa,
S.; Shiomi, F.; Cappiello, J.; Sawada, S.; Utsumi, R.; Okamoto, T.
Bioorg. Med. Chem. Lett. 2004, 14, 5943.
(15) (a) Kitayama, T.; Masuda, T.; Sakai, K.; Imada, C.; Yonekura, Y.;
Kawai, Y. Tetrahedron 2006, 62, 10859. (b) Kitayama, T.;
Iwabuchi, R.; Minagawa, S.; Sawada, S.; Okumura, R.; Hoshino,
K.; Cappiello, J.; Utsumi, R. Bioorg. Med. Chem. Lett. 2007, 17,
1098.
(16) (a) Kitayama, T.; Masuda, T.; Kawai, Y.; Hill, R. K.; Takatani, M.;
Sawada, S.; Okamoto, T. Tetrahedron: Asymmetry 2001, 12,
2805. (b) Kitayama, T.; Furuya, A.; Moriyama, C.; Masuda, T.;
Fushimi, S.; Yonekura, Y.; Kubo, H.; Kawai, Y.; Sawada, S. Tetra-
hedron: Asymmetry 2006, 17, 2311. (c) Kitayama, T.; Nagao, R.;
Masuda, T.; Hill, R. K.; Morita, M.; Takatani, M.; Sawada, S.;
Okamoto, T. J. Mol. Catal. B: Enzym. 2002, 17, 75.
(17) (a) Ajish, K. R.; Nayana, J.; Radhakrishnan, K. V. Synthesis 2013,
45, 2316. (b) Ajish, K. R.; Dhanya, B. P.; Nayana, J.; Priya, M.;
Rani, B.; Raghu, K. G.; Vineetha, V. P.; Radhakrishnan, K. V. Tet-
rahedron Lett. 2014, 55, 665. (c) Gopalan, G.; Dhanya, B. P.;
Saranya, J.; Reshmitha, T. R.; Baiju, T. V.; Meenu, M. T.; Nair, M.
S.; Nisha, P.; Radhakrishnan, K. V. Eur. J. Org. Chem. 2017, 3072.
(d) Dhanya, B. P.; Gopalan, G.; Reshmitha, T. R.; Saranya, J.;
Sharathna, P.; Shibi, I. G.; Radhakrishnan, K. V. New J. Chem.
2017, 41, 6960. (e) Dhanya, B. P.; Gopalan, G.; Sasikumar, P.;
Neethu, S.; Meenu, M. T.; Sharathna, P.; John, J.; Varughese, S.;
Sabu, M.; Dan, M.; Radhakrishnan, K. V. Asian J. Org. Chem. 2018,
7, 471.
Press: Oxford, 1992, 232.
7) Ding, Y.; Ding, C. Y.; Ye, N.; Liu, Z.; Wold, E. A.; Chen, H.; Wild, C.;
Shen, Q.; Zhou, J. Eur. J. Med. Chem. 2016, 122, 102.
8) (a) Gopalan, G.; Prabha, B.; Joe, A.; Reshmitha, T. R.; Sherin, D.
R.; Abraham, B.; Sabu, M.; Manojkumar, T. K.; Radhakrishnan, K.
V.; Nisha, P. J. Sci. Food Agric. 2019, 99, 2521. (b) Sasikumar, P.;
Lekshmy, K.; Sini, S.; Prabha, B.; Anil Kumar, N.; Sivan, V. V.;
Jithin, M. M.; Jayamurthy, P.; Shibi, I. G.; Radhakrishnan, K. V.
J. Ethnopharmacol. 2019, 18, 31222. (c) Sasikumar, P.;
Sharathna, P.; Prabha, B.; Sunil, V.; Anil Kumar, N.; Sivan, V. V.;
Sherin, D. R.; Suresh, E.; Manojkumar, T. K.; Radhakrishnan, K.
V. Phytochem. Lett. 2018, 26, 1. (d) Sasikumar, P.; Prabha, B.;
Reshmitha, T. R.; Sheeba, V.; Pradeep, A. K.; Rohit, K. R.; Dhanya,
B. P.; Sivan, V. V.; Jithin, M. M.; Anil Kumar, N.; Shibi, I. G.; Nisha,
P.; Radhakrishnan, K. V. RSC Adv. 2016, 6, 77075.
(9) (a) Taha, M. M.; Abdul, A. B.; Abdullah, R.; Ibrahim, T. A.;
Abdelwahab, S. I.; Mohan, S. Chem.-Biol. Interact. 2010, 186, 295.
(b) Dai, J. R.; Cardellina, J. H.; McMahon, J. B.; Boyd, M. R. Nat.
Prod. Lett. 1997, 10, 115. (c) Szabolcs, A.; Tiszlavicz, L.; Kaszaki,
J.; Pósa, A.; Berkó, A.; Varga, I. S.; Boros, I.; Szüts, V.; Lonovics, J.;
Takács, T. Pancreas 2007, 35, 249. (d) Murakami, A.; Ohigashi, H.
Int. J. Cancer 2007, 121, 2357. (e) Murakami, A.; Miyamoto, M.;
Ohigashi, H. Biofactor 2004, 21, 95. (f) Murakami, A.; Takahashi,
M.; Jiwajinda, M. S.; Koshimizu, K.; Ohigashi, H. Biosci., Biotech-
nol., Biochem. 1999, 63, 1811. (g) Murakami, A.; Tanaka, T.; Lee,
J. Y.; Surh, Y. J.; Kim, H. W.; Kawabata, K.; Nakamura, Y.;
Jiwajinda, S.; Ohigashi, H. Int. J. Cancer 2004, 110, 481.
(
10) (a) Dev, S. Tetrahedron 1960, 8, 171. (b) Damodaran, N. P.; Dev,
S. Tetrahedron Lett. 1965, 6, 1977. (c) Dev, S.; Anderson, J. E.;
Cormier, V.; Damodaran, N. P.; Roberts, J. D. J. Am. Chem. Soc.
1968, 90, 1246. (d) Hall, S. R.; Nimgirawath, S.; Raston, C. L.;
Sittatrakul, A.; Thadaniti, S.; Thirasasana, N.; White, A. H. Aust. J.
Chem. 1981, 34, 2243. (e) Farnsworth, N. R.; Bunyapraphatsara,
N. Thai Medicinal Plants Recommended for Primary Health Care
System; Medicinal Plants Information Center (Faculty of Phar-
macy, Mahidol University): Thailand, 1992, 261. (f) Sawada, S.;
Yokoi, T.; Kitayama, T. Aroma Res. 2002, 3, 34.
(18) (a) Kharb, R.; Sharma, P. C.; Yar, M. S. J. Enzyme Inhib. Med.
Chem. 2011, 26, 1. (b) Nguyen, N. T.; Dang, P. H.; Yar, N. X. T.; Le,
T. H.; Nguyen, M. T. T. J. Nat. Prod. 2017, 80, 2151.
(19) (a) Kolb, H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8, 1128.
(b) Brik, A.; Alexandratos, J.; Lin, Y. C.; Elder, J. H.; Olson, A.;
Wlodawer, A.; Goodsell, D. S.; Wong, C. H. ChemBioChem 2005,
6, 1167.
(
11) Kitayama, T.; Yokoi, T.; Kawai, Y.; Hill, R. K.; Morita, M.;
Okamoto, T.; Yamamoto, Y.; Fokin, V. V.; Sharpless, K. B.;
Sawada, S. Tetrahedron 2003, 59, 4857.
(20) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org.
Lett. 2008, 10, 3081.
(
12) (a) Matthes, H. W. D.; Luu, B.; Ourisson, G. Tetrahedron 1982, 38,
(21) Kitayama, T.; Nakahira, M.; Yamasaki, K.; Inoue, H.; Imada, C.;
Yonekura, Y.; Awata, M.; Takaya, H.; Kawai, Y.; Ohnishi, K.;
Murakami, A. Tetrahedron 2013, 69, 10152.
(22) Kumar, S. C.; Negi, P. S.; Manjunatha, J. R.; Bettadaiah, B. K. Food
Chem. 2016, 141, 1097.
3129. (b) Ohe, K.; Miki, K.; Yanagi, S.; Tanaka, T.; Sawada, S.;
Uemura, S. J. Chem. Soc., Perkin Trans. 2000, 1, 3627. (c) Minassi,
A.; Pollastro, F.; Chianese, G.; Caprioglio, D.; Taglialatela-Scafati,
O.; Appendino, G. Angew. Chem. Int. Ed. 2017, 56, 7935. (d) Joshi,
B. N.; Chakravarti, K. K.; Bhattacharyya, S. C. Tetrahedron 1967,
23, 1251. (e) Chhabra, B. R.; Kalsi, P. S.; Dhir, B. S.; Shirahama,
H.; Dhillon, R. S. Indian J. Chem. 1985, 24, 499.
©
2020. Thieme. All rights reserved. Synthesis 2020, 52, A–T