Annulated oxa-cage frameworks via Claisen rearrangement and ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2020.131694

In our quest to design high-density fuels, we report a variety of structurally interesting new annulated oxa-cage frameworks. Here, we investigated a linear synthetic sequence, which relies on reductive C–C bond cleavage and ring-closing metathesis as key

Full text of DOI:10.1016/j.tet.2020.131694

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Annulated oxa-cage frameworks via Claisen rearrangement and ring-closing
metathesis
Sambasivarao Kotha, Subba Rao Cheekatla, Usha Nandan Chaurasia
PII:
S0040-4020(20)30907-8
https://doi.org/10.1016/j.tet.2020.131694
TET 131694
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To appear in: Tetrahedron
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Revised Date: 12 October 2020
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GRAPHICAL ABSTRACT
ANNULATED
OXA–CAGE
FRAMEWORKS
VIA
CLAISEN
REARRANGEMENT AND RING–CLOSING METATHESIS
Sambasivarao Kotha* Subba Rao Cheekatla and Usha Nandan Chaurasia
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai-400 076, India, Fax: +91(22)-2572 7152; E-mail: srk@chem.iitb.ac.in
Graphical Abstract
OH
10 Steps
O
O
OH
Claisen rearrangement
Cycloadditions
Transannular cyclization
Metathesis (RCM)
1

2

Graphical Abstract
Annulated oxa-cage frameworks via Claisen
rearrangement and ring-closing metathesis
Leave this area blank for abstract info.
Sambasivarao Kotha, Subba Rao Cheekatla and Usha Nandan Chaurasia
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai, Powai, India-400076

1
Tetrahedron
journal homepage: www.elsevier.com
Annulated oxa-cage frameworks via Claisen rearrangement and ring-closing
metathesis
a
Sambasivarao Kotha, ∗ Subba Rao Cheekatla and Usha Nandan Chaurasia
a
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai, India-400076
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In our quest to design high-density fuels, we report a variety of structurally interesting new annulated
oxa-cage frameworks. Here, we investigated a linear synthetic sequence, which relies on reductive C–
C bond cleavage and ring-closing metathesis as key steps. For this purpose, we utilized inexpensive
and readily available starting materials such as hydroquinone and endo-dicyclopentadiene.
Transannular cyclization during Grignard addition played a significant role in the design of intricate
caged compounds. The creation of these new oxa-cage systems is a challenging task by traditional
methods. The structure of the target compound has been unambiguously established by single-crystal
X-ray diffraction studies. These data indicate that density of the RCM compound is larger than the
Available online
Keywords:
Oxa-cages
Heterocycles
Cycloadditions
Transannular cyclization
Claisen Rearrangement
Ring-closing metathesis
cubane density
.
2
009 Elsevier Ltd. All rights reserved.
—
——
∗
Corresponding author. Tel.: +91 22 25767160; fax: +022-25767152; e-mail: srk@chem.iitb.ac.in

2
Tetrahedron
11
1
. Introduction
extraction. Interestingly, it was found that the oxa-cage crown
ether moieties increase the lipophilicity and complexation
properties of the host and these oxa-cage crown systems bind
Cage frameworks containing heteroatoms are useful in diverse
1
areas of chemical sciences. High symmetry, severe ring strain,
+
+
11
rigid and compact architecture of the cage systems has been
identified as suitable building blocks for the design of high-
density fuels. Moreover, the high nitrogen content within the
cage framework enriches its desirable energetic properties such
as detonation performance; positive heats of formation, low
ecological toxicity, good oxygen balance, high density,
hydrolytic and good thermal stability along with low impact
selectively with Li and Na ions (Figure 1). Kruger’s group
designed diverse oxa cage chiral bidentate ligands and studied
their binding properties. These PCUD ligands work as effective
1
2
catalysts with good enantioselectivities.
O
O
H3C
O
O
O
O
O
O
O
O
O
9
O
7
8
10
1
sensitivity and high burning rate. Also with these valuable
O
O
O
O
properties and lipophilicity of the cage moiety improve the
O
2
biological properties.
O
O
O
O
O
1
1
12
13
14
Several oxygenated cage systems 1-6 incorporating
pentacycloundecane (PCUD) framework are found to be
beneficial as supramolecules, application in medicinal and
pharmaceutical chemistry and also good ligands in the
Figure 2. Different types of oxa-cage frameworks designed by
various synthetic routes
2
. Results and discussion
3
asymmetric catalysis (Figure 1). Limited reports are available
4
dealing with the syntheses of oxa-cage systems. Interestingly,
To expand the synthetic routes to oxa-cage systems, ozonolysis
method has been used to design of tri-oxa, tetra-oxa, penta-oxa,
amino group present in the PCUD cage system 2, 4, 5, and 6
shows an interesting activities against tuberculosis,
13
acetal based oxa-cages, and oxa-peristylanes. Other methods to
5-7
neurodegenerative, and anti-viral diseases.
Additionally,
oxygenated cage compounds include: iodine induced cyclization,
hydride rearrangement, alkene-oxirane photocycloaddition,
tandem cyclizations, transannular cyclizations, base promoted
rearrangement, dehydration of diols, reduction of lactones,
oxidation-based methodologies, intramolecular etherification,
pentacycloundecylamine 5 (NGP1-01) reveals both N-methyl-d-
aspartate (NMDA) receptor channel blocking and L-type calcium
6-7
channel antagonist activity.
14-15
RCM, and radical cyclization.
Various examples to diverse
1
6
oxa-cage systems 7-14 reported are listed in Figure 2. Recently,
we have also assembled an interesting and synthetically
challenging cage compound 14 via ring-closing metathesis
(RCM) route. Interestingly, compound 14 contains three-, four-,
five-, six-, and seven-membered rings conjoined with in the
17
strained cage system.
Figure 1. PCUD containing oxa-cages 1-6 useful in different
arenas
NGP1-01 and similar types of aminated oxa-cage frameworks are
8
Scheme 1. Retrosynthesis to annulated cage compound 15 via
examined as a promising candidates for neuroprotective agents.
RCM
PCUD containing tetra-amine oxa-cages 4 show an excellent
18
9
In view of our interest in cage molecules, here, we report a
anti-TB activity against M-tuberculosis H37Rv (Figure 1). Also,
synthetic strategy to new cage framework containing oxygen
these studies have demonstrated that the crown ether-based oxa,
aza, and thia- cage frameworks exhibit interesting cation-binding
19
atoms via transannular cyclization and RCM
approach.
1
0
Moreover, cage molecules are useful synthons to design
cyclopentanoids. Our retrosynthetic plan to target compound 15
is illustrated in Scheme 1. In this context, the cage compound 15
properties. Marchand’s group assembled a series of bis
annulated cage crown ethers and tested for alkali metal picrate

3
may be derived from tetracyclic dione 16 through reductive
cleavage, Grignard addition, and RCM as key steps. Further, the
tetracyclic dione 16 could be obtained from quinone derivative
Figure 3. Single crystal X-ray structure of compound 15
(CCDC 2007824).
2
0
The hemiketal 25 was further treated with allyl bromide under
NaH/DMF condition to produce the tetraallyl compound 26.
Subsequently, the tetraallyl ether 26 was subjected to RCM under
1
7 via the Diels–Alder (DA) reaction followed by a [2+2]
photocycloaddition. Finally, the required quinone 17 was
prepared from commercially available hydroquinone 18 in three
steps via O-allylation, Claisen rearrangement followed by
nd
Grubb’s 2 generation catalyst (G-II) in dry DCM to deliver an
1
8e
interesting annulated oxa-cage framework 15. The structure of
RCM product 15 was firmly established on the basis of spectral
data and by single-crystal X-ray diffraction studies (Figure 3).
Finally, unsaturated oxa-cage compound 15 was subjected to
oxidation.
OH
OH
O
OH
Acetone, K
allylbromide,
5-60 °C, 85%
2
CO
3
,
Neat, 160-165 °
C
67%, (1:1)
5
OH
OH
O
OH
18
19
O
20
21
reduction with H in the presence of Pd/C to deliver the saturated
2
OH
O
O
MnO
acetone
2
,
[2+2], hv
125W lamp
cage ether 27 in 84% yield (Scheme 3). The structure of the oxa-
cage compound 27 was supported by spectroscopic data.
22
reflux, 66%
MeOH, rt,
2%
hv, EtOAc,
80%
7
H
O
O
OH
O
21
17
23
24
Scheme 2. Synthesis of diallyl cage dione 24
O
O
O
O
The quinone 17 was subjected to a [4+2] cycloaddition with
cyclopentadiene (22) at 0 ˚C to provide the endo DA adduct 23 in
d = 1.343 g/cm3
d = 1.340 g/cm3
d
= 1.290 g/cm3
d = 1.330 g/cm3
d
= 1.080 g/cm3
15
28
29
30
31
1
8e
7
2% yield. The cycloadduct 23 was exposed to UV irradiation
for 30 min in pyrex immersion well in dry EtOAc under nitrogen
Figure 4. Densities of various cage frameworks.
1
8e
gave the required cage system 24 in good yield (80%). Having
prepared the cage dione 24, next we attempted the metal-
catalyzed reductive cleavage of C–C bond of cyclobutane ring of
cage dione 24 under acidic conditions using activated zinc dust to
generate the tetracyclic system 16. Further, the compound 16 on
reaction with Grignard reagent (allyl magnesium bromide) gave
the transannular cage system 25 in good yield (Scheme 3).
These strained cage skeletons are promising as high energy
density materials (HEDMs) due to their outstanding explosive
performance as compred with the other traditional compounds.
Density is one of the positive factor, which induce the energetic
performance. More dense materials are better as potential fuels.
Here, we listed some of the selected cage compounds and their
3
densities (g/cm ) in Figure 4. Compound 15, 28, and 31 density
Allyl magnisium
Zn/AcOH
bromide
values has been determined by experimentally. The densities of
0 °
C to rt,
rt, 18 h, 84%
OH
O
O
O
O
1 h, 69%
O
2
5
24
16
Br
cubane 29 and hexaprismane 30 calculated from theoretically and
0 °
C to rt,
NaH, DMF
1i-m
N
N
3 h, 82%
Cl
experimentally.
The densities of the cubane 29, hexaprismane
Ru
Ph
Cl P(Cy)
3
3
0, and adamantane 31 were lesser than the oxa-cages such as
Pd/C, H
2
(1 atm)
G-II
O
rt, 5 h, 89%
O
G-II (5 mol%)
O
17
O
O
O
compound 15 and 28 synthesized in our laboratory.
CH
2 2
Cl
2
7
15
rt, 15 h, 94%
26
3
. Conclusions
In conclusion, we have successfully assembled new and
interesting oxa-cage framework via a transannular cyclization
and two-fold RCM protocol. The newly synthesized cage
heterocyclic system holds tetrahydrofuran and oxepane rings.
The methodology involved in this sequence is useful to design
other highly functionalized heterocyclic cage compounds. The
density of compound 15 as determined by X-ray studies and this
value is comparable to cubane 29 although one bond and
cyclopropane are missing as compared to compound 28 (Figure
Scheme 3. Synthesis of annulated oxa-cage system 27 via RCM
4
). These cage heterocycles may become valuable candidates for

4
Tetrahedron
1
3
pharmaceutics and high energy density materials useful in
5.64-5.75 (m, 2H); C NMR (125 MHz, CDCl ): δ (ppm) =
3
material science applications.
213.4, 212.3, 133.5, 132.8, 118.5, 118.2, 61.4, 60.0, 51.3, 47.7,
43.9, 41.8, 39.5, 35.4, 35.1, 33.5.
4
4
. Experimental section
.1. General methods
Synthesis of tetracyclic cage compound 16
Moisture-sensitive materials were transferred by using syringe-
septum technique and the reactions were maintained under
nitrogen atmosphere. The TLC (thin-layer chromatography) was
performed on (7.5×2.5 cm) glass plates coated with Acme’s silica
gel GF 254 (containing 13% calcium sulfate as a binder) by using
To a solution of pentacyclic cage dione 24 (850 mg, 3.34 mmol)
in glacial acetic acid (10 mL) added Zn dust (1.09 g, 16.7 mmol)
and stirred at rt for 24 hours. At the conclusion of the reaction
(TLC monitoring), the reaction mixture was neutralized, filtered
and then extracted with DCM. The solvent was evaporated and
the crude residue was purified by silica gel column
chromatography (5% EtOAc/petroleum ether) to give 16 as a
colourless liquid. Yield: 720 mg, 84%; IR (Neat): νmax 2955,
a
suitable mixture of EtOAc and petroleum ether for
development. Column chromatography was accomplished by
using Acme’s silica gel (100-200 mesh) with an appropriate
mixture of EtOAc and petroleum ether. Photochemical reaction
was carried out with 125W high-pressure mercury vapour lamp
and Pyrex vessel. The coupling constants (J) are given in hertz
-
1
1
1744, 1639, 1202, 1168, 1003, 917, 761 cm ; H NMR (400
MHz, CDCl ): δ (ppm) = 6.04-5.62 (m, 2H), 5.13-4.99 (m, 4H),
3
2.68-2.29 (m, 9H), 2.21-2.04 (m, 3H), 1.91 (d, J = 11.2 Hz, 1H),
1
3
(Hz) and chemical shifts are denoted in parts per million (ppm)
1.86 (d, J = 11.2 Hz, 1H); C NMR (100.6 MHz, CDCl ): δ
3
downfield from internal standard, tetramethylsilane (TMS). The
abbreviations, s, d, t, q, m, dd and dt refer to singlet, doublet,
triplet, quartet, multiplet, doublet of doublets, and doublet of
triplets, respectively. IR samples were recorded with DCM and
chloroform as solvents on Nicolet Impact-400 FTIR
(ppm) = 217.1, 216.8, 136.5, 133.6, 118.3, 116.0, 65.2, 62.2,
54.3, 51.2, 48.1, 42.6, 40.6, 37.3, 36.4, 33.5, 30.8; HRMS (ESI,
+
Q-ToF) m/z calcd for C H NaO [M + Na] 279.1356, found
1
7
20
2
279.1355.
Synthesis of cage hemiketal 25
1
spectrometer. Nuclear magnetic resonance (NMR) spectra ( H,
To a solution of tetracyclic compound 16 (600 mg, 2.34 mmol) in
dry THF (20 mL) was added freshly prepared allyl magnesium
bromide solution in ether (9.36 mmol) in a dropwise manner
under nitrogen at RT. At the conclusion of reaction (TLC
1
3
C and DEPT 135) have been recorded on 400 and 500 MHz
spectrometers (Bruker) with CDCl solvent and chemical shifts (δ
3
ppm) are reported relative to internal standard such as TMS. The
J values (coupling constants) are given Hz. Mass spectra
monitoring) the reaction mixture was quenched with saturated
°
(HRMS) have been recorded under positive ion electrospray
aqueous NH Cl solution at 0 C. Then aqueous layer was
4
ionization (ESI, Q-TOF) mode. X-ray crystal analysis was
performed on diffractometer equipped with graphite
monochromated Mo Kα radiation and structure was solved by
direct methods shelxl-97 and refined by full-matrix least-squares
extracted by EtOAc. The combined organic layer was washed
with brine and collected over anhydrous Na SO Solvent was
2
4.
evaporated under reduced pressure and the resulting residue was
purified by a silica-gel column chromatography (10% EtOAc in
2
against F using shelxl-97 software.
petroleum ether) to give the hemiketal 25 as a white crystalline
1
8e
°
Synthesis of the diallylated cage dione 24
The DA adduct 23 (1 g, 0.32 mmol) was dissolved in dry EtOAc
300 mL) and irradiated in a pyrex immersion well by using an
25 W UV Hg lamp (home-made) for 2 h under nitrogen
solid. MP 71-73 C; Yield: 485 mg, 69%; IR (Neat): ν 3413,
max
-
1 1
3074, 2966, 1457, 1434, 1308, 1281, 1129, 99, 910, 756 cm ; H
(
NMR (400 MHz, CDCl ): δ (ppm) = 6.02-5.92 (m, 1H), 5.87-
3
1
5.73 (m, 2H), 5.18-4.91 (m, 6H), 2.87 (brs, 1H), 2.47 (dd, J =
1
atmosphere at rt. At the conclusion of the reaction (TLC
monitoring), the solvent was evaporated under reduced pressure
and the crude residue was purified by silica gel column
chromatography (5% ethyl acetate-petroleum ether) to give cage
13.9 Hz, J = 6.0 Hz, 1H), 2.41-2.25 (m, 6H), 2.20-2.03 (m, 5H)
2
1
3
1.89-1.79 (m, 2H), 1.70, 1.60 (ABq, J = J = 10.7 Hz, 2H);
C
1
2
NMR (100.6 MHz, CDCl ): δ (ppm) = 138.8, 136.0, 135.1,
3
117.86, 117.82, 115.1, 114.9, 87.2, 62.1, 60.7, 54.3, 52.0, 48.3,
1
dione 24 as a colourless liquid. Yield: 795 mg, 80%; H NMR
44.8, 42.4, 41.3, 38.9, 37.7, 36.6, 31.2; HRMS (ESI, Q-ToF): m/z
+
(
500 MHz, CDCl ): δ (ppm) = 1.77 (d, J = 11.1 Hz, 1H), 2.01 (d,
calcd for C H NaO [M+Na] 321.1825, found: 321.1830.
3
20 26
2
J =11.1 Hz, 1H), 2.12-2.45 (m, 6H), 2.61 (d, J = 4.4 Hz, 1H),
.76 (d, J = 3.6 Hz, 1H), 2.84-3.01 (m, 2H), 4.97-5.05 (m, 4H),
Synthesis of O- allylated compound 26
2

5
The hemiketal 25 (400 mg, 1.34 mmol) dissolved in dry DMF
8mL), then washed and dried sodium hydride (4.34 mmol)
Yield: 135 mg, 89%; Mp 84-86 ˚C; IR (Neat): νmax 2935, 2854,
-
1 1
(
1461,1446,1183,1164,754 cm . H NMR (500 MHz, CDCl ): δ
3
added to the flask and allyl bromide (4.34 mmol) added dropwise
(ppm) = 4.29–4.24 (m, 1H), 3.62–3.59 (d, 1H), 2.14–2.07 (m,
5H), 2.00– 1.92 (m, 3H), 1.83–1.73 (m, 3H), 1.70–1.62 (m, 5H),
°
and stirred at 0 C to rt for 3 hours. After conclusion of the
1
3
reaction by TLC technique, water added to the reaction mixture
and extracted with EtOAc. Solvent was evaporated and residue
was purified by a silica-gel column chromatography (petroleum
ether) to give the allylated compound 26 as colourless liquid.
Yield: 375 mg, 82%; IR (Neat): νmax 3077, 2942, 2871, 1640,
1.55–1.51 (m, 6H), 1.41–1.34 (m, 1H), 1.27–1.15 (m, 1H);
C
NMR (125 MHz, CDCl ): δ (ppm) =117.1, 85.3, 65.8, 63.2, 61.7,
3
56.4, 54.6, 51.0, 45.8, 43.3, 39.5, 36.1, 35.8, 35.8, 33.7, 27.5,
25.0, 23.1, 22.9; HRMS (ESI): calcd for C H NaO [M+Na];
1
9
26
2
309.1825 found; 309.1827.
-
1 1
1
457, 1432, 1288, 1217, 1168, 1117, 997, 910, 717cm . H NMR
Acknowledgements
(
400 MHz, CDCl ): δ (ppm) = 6.03-5.91 (m, 2H), 5.86-5.75 (m,
The authors gratefully appreciate the Defense Research and
Development Organization (DRDO, NO.
3
2
4
2
H), 5.31-5.26 (m, 1H), 5.11-4.93 (m, 7H), 4.33-4.28 (m, 1H),
.12-4.07 (m, 1H), 2.47-2.39 (m, 2H), 2.36-2.25 (m, 5H), 2.14-
ARDB/01/1041849/M/1), New Delhi-India for the financial
assistance. S. K. thanks Department of Science and Technology
(DST, NO. SR/S2/JCB-33/2010), DST, New Delhi, India for the
award of a J. C. Bose fellowship and Praj industries for Chair
Professorship in Green Chemistry. S.R.C and U.N.C thanks
University Grants Commission (UGC), New Delhi, India for the
award of a doctoral fellowship.
1
3
.02 (m, 5H), 1.87-1.60 (m, 4H); C NMR (100.6 MHz, CDCl ):
3
δ (ppm) = 139.0, 137.3, 135.9, 135.5, 117.3, 116.3, 115.0, 114.8,
8
3
8.1, 65.4, 64.5, 60.8, 53.3, 51.8, 48.1, 44.9, 41.4, 40.8, 39.5,
7.6, 36.5, 31.3; HRMS (ESI, Q-ToF): m/z calcd for C H NaO
2
2
3
30
+
[
M+Na] 361.2138, found: 361.2140.
Synthesis of RCM product 15
To a solution of tetraallyl compound 26 (300 mg, 0.88 mmol) in
References
nd
dry DCM (25 mL) was added Grubb’s 2 generation catalyst (5
1. (a) W. J. Geldenhuys, S. F. Malan, J. R. Bloomquist, A. P.
Marchand, C. J. Van Der Schyf, Med. Res. Rev. 2005, 25,
21; (b) K. F. Biegasiewicz, J. R. Griffiths, G. P. Savage, J.
Tsanaktsidis, R. Priefer, Chem. Rev. 2015, 115, 6719; (c) Q.
Wu, W. Zhu, and H. Xiao, RSC Adv., 2014, 4, 3789; (d) E.
Osawa and O. Yonemitsu, Carbocyclic Cage Compounds;
VCH: New York, 1992; (e) G. A. Olah, Cage Hydrocarbons;
J. Wiley and Sons, Inc., New York, 1990; (f) R. T.
Vayalakkavoor, M. Vedachalam, J. H. Boyer, Heterocycles
1990, 31, 479 ; (g) S. J. Gharpure, S. K. Porwal, Org. Prep.
Proced. Int. 2013, 45, 81; h) P. E. Eaton, T. W. Cole Jr., J.
Am. Chem. Soc.,1964, 86, 3157; i) A. K. Sikder, N. Sikder,
J. Hazard. Mater. 2004, 112, 1; j) A. Sankaranarayanan, S.
Lal, I. N. N. Namboothiri, S. Rashmi, A. Chowdhury, N.
Kumbhakarna, Fuel 2019, 255, 115836; k) Q. Wu, W. Zu, H.
Xiao, RSC Adv. 2014, 4, 3789; l) L. Mallick, S. Lal, S. Reshmi,
I. N. N. Namboothiri, A. Chowdhury and N. Kumbhakarna,
New J. Chem. 2017, 41, 920; m) G. Ali mansoori, Adv.
Chemical Physics, 2007, 136, 207.
mol %) under nitrogen at rt. At the conclusion of the reaction (15
h, TLC monitoring), the solvent was evaporated and the resulting
residue was purified by a silica gel column chromatography (8%
EtOAc-petroleum ether) to give oxa-cage compound 15 as a
colourless crystalline needles. Yield: 235 mg, 94%; Mp 97-99
˚
C; IR (Neat): νmax 3020, 2928, 2857, 1447, 1190, 1125, 1081,
-
1 1
9
1
2
1
1
59 cm ; H NMR (400 MHz, CDCl ): δ (ppm) = 5.72-5.70 (m,
3
H), 5.62-5.59 (m, 1H), 5.53-5.49 (m, 1H), 5.37 (dd, J = 11.4,
.3 Hz, 1H), 4.60-4.55 (m, 1H), 4.23-4.18 (m, 1H), 2.66-2.62 (m,
H), 2.49-2.42 (m, 1H), 2.35-2.21 (m, 3H), 2.17-2.07 (m, 5H),
1
3
.98 (s, 1H), 1.89-1.72 (m, 4H), 1.57 (d, , J = 10.7 Hz, 1H);
C
NMR (100.6 MHz, CDCl ): δ (ppm) = 130.2, 128.1, 125.9,
3
1
3
23.1, 115.2, 85.0, 66.1, 64.8, 59.9, 55.4, 50.8, 49.7, 44.1, 43.1,
9.1, 37.0, 35.9, 30.2, 26.8; HRMS (ESI, Q-ToF): m/z calcd for
+
C H NaO [M+Na] 305.1512, found: 305.1511.
1
9
22
2
Oxa-cage compound 27
0% Palladium/charcoal (15 mg) was added to a solution of
1
RCM compound 15 (150 mg, 0.53 mmol) in dry EtOAc (10 mL)
under hydrogen (1 atm) at rt. At the conclusion of the reaction (5
h, TLC monitoring), the reaction mixture was filtered off by
using a Celite pad. The solvent was evaporated under vacuo and
the residue was purified by silica gel column chromatography
2
.
(a) I. A. Levandovskiy, D. I. Sharapa, O. A. Cherenkova, A.
V. Gaidai, T. E. Shubina, Russ. Chem. Rev. 2010, 79, 1005;
(b) D. I. Sharapa, I. A. Levandovskiy, T. E. Shubina, Curr.
Org. Chem. 2012, 16, 2632; (c) K. Gerzon, D. Kou, J. Med.
Chem, 1967, 10, 189; (d) K. Gerzon, R. J. Kraay, R. T.
Rapala, J. Med. Chem. 1965, 8, 580.
(
5% EtOAc-petroleum ether) to give 27 as a colourless solid.

6
Tetrahedron
3
. (a) K. Hayakawa, K. Kido, K. Kanematsu, J. Chem. Soc.,
O. C. Domingo, S. F. Malan, C. J. Van der Schyf, Arch.
Pharm. Chem. Life Sci., 2016, 349, 252
Chem. Commun. 1986, 268; (b) T. Govender, H. G. Kruger,
M. Makatini, O. K. Onajole, Struct. Chem. 2008, 19, 719;
8
.
(a) L. H. Prins, J. L. du Preez, S. van Dyk, S. F. Malan, Eur. J.
Med. Chem. 2009, 44, 2577; (b) J. Joubert, S. Van Dyk, I. R.
Green, S. F. Malan, Bioorg. Med. Chem. 2011, 19, 3935; (c)
D. K. Wilkes, A. de Vries, D. W. Oliver, S. F. Malan, Arch.
Pharm. 2009, 342, 73.
(
c) S. M. Williams, J. S. Brodbelt, A. P. Marchand, D. Cal,
K. Mlinarié-Majerski, Anal. Chem. 2002, 74, 4423; (d) C. L.
Sherman, J. S. Brodbelt, G. Srinivas, R. Sivappa, A. P.
Marchand, ARKIVOC 2005, 5; (e) T. G. Levitskaia, B. A.
Moyer, P. V. Bonnesen, A. P. Marchand, K. Krishnudu, Z.
Chen, Z. Huang, H. G. Kruger, A. S. Mckim, J. Am. Chem.
Soc. 2001, 123, 12099.
9
.
(a) M. D. Duque, C. Ma, E. Torres, J. Wang, L. Naesens, J.
Juárez-Jiménez, P. Camps, F. J. Luque, W. F. DeGrado, R. A.
Lamb, L. H. Pinto, S. Vázquez, J. Med. Chem. 2011, 54,
2
646; (b) O. K. Onajole, K. Govender, P. Govender, P. D. van
4
.
(a) D. Giomi, R. Nesi, S. Turchi, E. Mura, J. Org. Chem. 2000,
Helden, H. G. Kruger, G. E. M. Maguire, K. Muthusamy, M.
6
5, 360; (b) H. -C. Lin, H. -J. Wu, Tetrahedron 2000, 56, 341;
c) M. -Y. Chang, S. -T. Chena, N. -C. Chang, J. Chin. Chem.
Soc. 2001, 48, 1153; (d) H. -J. Wu, J. -H. Chern, Tetrahedron
997, 53, 17653; (e) F. A. Khan, V. Dwivedi, B. Rout,
Pillay, I. Wiid, T. Govender, Eur. J. Med. Chem. 2009, 44,
(
4
297.
1
0. (a) A. P. Marchand, H.S. Chong, S. Alihodzic, W. H. Watson,
S. G. Bodige, Tetrahedron 1999, 55, 9687; (b) A. P.
Marchand, H. S. Chong, Tetrahedron 1999, 55, 9697; (c) A.
P. Marchand, K. A. Kumar, A. S. McKim, K. Mlinarié-
Majerski, G. Kragol, Tetrahedron 1997, 53, 3467; (d) A. P.
Marchand, D. Cal, K. Mlinaric-Majerski, K. Ejsmont, W. H.
Watson, J. Chem. Crystallogr. 2002, 32, 447; (e) A. P.
Marchand, S. Alihodzic, A. S. McKim, K. A. Kumar, K.
Mlinarié-Majerski, G. Kragol, Tetrahedron Lett. 1998, 39,
1
Tetrahedron Lett. 2007, 48, 207; (f) N. C. Kong, Y. Zhang, S.
Gao, Y. Lu, Tetrahedron 2007, 63, 2132; (g) S. I. Kozhushkov,
T. Preuß, D. S. Yufit, J. A. K. Howard, K. Meindl, S. Rühl, C.
Yamamoto, Y. Okamoto, P. R. Schreiner, B. C. Rinderspacher,
A. De Meijere, Eur. J. Org. Chem. 2006, 2590; (h) R. Sharma,
J. Joubert, S. F. Malan, Molecules, 2018, 23, 308; (i) S. C. Suri,
J. Org. Chem. 1993, 58, 4153
5
.
(a) A. Mdzinarishvili, W. J. Geldenhuys, T. J. Abbruscato, U.
Bickel, J. Klein, C. J. Van der Schyf, Neurosci. Lett. 2005,
1
861; (f) S. M. Blair, J. S. Brodbelt, A. P. Marchand, K. A.
Kumar, H. -S. Chong, Anal. Chem. 2000, 72, 2433; (g) S. M.
Blair, J. S. Brodbelt, A. P. Marchand, K. A. Kumar, H.-S.
Chong, S. Alihodzic, J. Am. Soc. Mass Spectrom. 2000, 11,
3
83, 49; (b) A. van Dijk, C. Johnston, H. Allbutt, M. Kassiou,
J. Henderson, Behav. Brain Res. 2008, 190, 14; (c) J. Hao, A.
Mdzinarishvili, T. J. Abbruscato, J. Klein, W. J. Geldenhuys,
C. J. Van der Schyf, U. Bickel, Brain Res. 2008, 1196, 113;
8
84.
1
1. (a) A. P. Marchand, A. Hazlewood, Z. Huang, S. K.
Vadlakonda, J.-D. R. Rocha, T. D. Power, K. Mlinaric-
Majerski, L. Klaic, G. Kragol, J. C. Bryan, Struct. Chem.
(
d) J. Joubert, W. J. Geldenhuys, C. J. Van der Schyf, D. W.
Oliver, H. G. Kruger, T. Govender, S.F. Malan, Chem. Med.
Chem. 2012, 7, 375; (e) C. J. Van der Schyf, W. J.
Geldenhuys, Neurotherapeutics 2009, 6, 175.
2
003, 14, 279; (b) C. L. Sherman, J. S. Brodbelt, G. Srinivas,
R. Sivappa, A. P. Marchand, ARKIVOC 2005, 5; (c) A. P.
Marchand, S. A. McKim, K. A. Kumar, Tetrahedron 1998,
6
.
(a) J. Joubert, E. Kapp, D. Taylor, P. J. Smith, S. F. Malan,
Bioorg. Med. Chem. Lett. 2016, 26, 1151; (b) A. O. Egunlusi,
S. F. Malan, J. Joubert, Chem. Med. Chem. 2015, 10, 1259; (c)
F. T. Zindo, S. F. Malan, S. I. Omoruyi, A. B. Enogieru, O. E.
Ekpo, J. Joubert, Eur. J. Med. Chem. 2019, 163, 83; (d) O. K.
Onajole, Y. Coovadia, H. G. Kruger, G. E. M. Maguire, M.
Pillay, T. Govender, Eur. J. Med. Chem. 2012, 54, 1
5
4, 13421; (d) R. A. Bartsch, M. Eley, A. P. Marchand, R.
Shukla, K. A. Kumar, Tetrahedron 1996, 52, 8979; (e) S. M.
Williams, J. S. Brodbelt, A. P. Marchand, D. Cal, K. Mlinarié-
Majerski, Anal. Chem. 2002, 74, 4423.
1
2. (a) G. A. Boyle, T. Govender, H. G. Kruger, G. E. M.
Maguire, Tetrahedron: Asymmetry 2004, 15, 2661; (b) T.
Govinder, H. K. Hariprakasha, H. G. Kruger, A. P. Marchand,
Tetrahedron: Asymmetry 2003, 14, 1553; (c) A. P. Marchand,
H. S. Chong, B. Ganguly, Tetrahedron: Asymmetry 1999, 10,
7
.
(a) E. Grobler, A. Grober, C. J. Van der Schyf, S. F. Malan,
Bioorg. Med. Chem. 2006, 14, 1176; (b) H. J. R. Lemmer, J.
Joubert, S. van Dyk, F. H. van der Westhuizen, S. F. Malan,
Med. Chem. 2012, 8, 361; (c) O. K. Onajole, K. Govender, P.
Govender, P. D. van Helden, H. G. Kruger, G. E. M. Maguire,
K. Muthusamy, M. Pillay, I. Wiid, T. Govender, Eur. J. Med.
Chem. 2009, 44, 4297; (d) L. –M. Young, W. J. Geldenhuys,
4
695
1
3. (a) H. J. Wu, C. S. Chao, C. C. Lin, J. Org. Chem. 1998, 63,
7
687; (b) H. J. Wu, C. Y. Wu, C. C. Lin, Chin. Chem. Lett.
996, 7, 15; (c) H. C. Lin, C. Y. Wu, H. J. Wu, J. Chinese
1

7
Chem. Soc. 1997, 44, 609; (d) H. J. Wu, S. H. Tsai, W. S.
Chung, J. Chem. Soc., Chem. Commun. 1996, 375; (e) H. J.
Wu, S. H. Tsai, W. S. Chung, Tetrahedron Lett. 1996, 37,
Porwal, Synlett, 2008, 242.
16. (a) I. Chao, J. H. Shih, H. J. Wu, J. Org. Chem. 2000, 65,
7523; (b) H. -C. Lin, H. -J. Wu, J. Chin. Chem. Soc. 2009, 56,
1072; (c) G. Mehta, R. Vidya, J. Org. Chem. 2000, 65, 3497;
(d) H.-J. Wu, J. -H. Chern, C. -Y. Wu, Tetrahedron, 1997, 53,
2401; (e) A. P. Marchand, V. S. Kumar, H. K. Hariprakasha,
J. Org. Chem. 2001, 66, 2072; (f) G. Mehta, K. R. Reddy, J.
Org. Chem. 1987, 52, 460; (g) S. Kotha, S. R. Cheekatla, J.
Org. Chem. 2018, 83, 6315
8
4
2
209; (f) G. Mehta, R. Vidya, Tetrahedron Lett. 1997, 38,
173; (g) H. J. Wu, C. Y. Wu, Tetrahedron Lett. 1997, 38,
493; (h) C. C. Lin, H. J. Wu, Synthesis 1996, 715; (h) H. J.
Wu, C. Y. Wu, J. Org. Chem. 1999, 64, 1576; (i) H. J. Wu, J.
H. Chern, Tetrahedron 1997, 53, 17653.
1
4. (a) J. H. Chern, H. J. Wu, Tetrahedron, 1998, 54, 5967; (b) H.
J. Wu, J. H. Chern, J. Org. Chem. 1997, 62, 3208; (c) J. H.
Chern, H. J. Wu, J. Chin. Chem. Soc. 1997, 44, 71; (d) H. J.
Wu, S. H. Tsai, W. S. Chung, Tetrahedron Lett. 1996, 37,
17. (a) S. Kotha, S. R. Cheekatla, D. S. Mhatre, Synthesis 2017,
5339; (b) T. M. Swager, N. A. Romero, Synfacts 2018, 14(03),
0247.
8
209; (e) H. Prinzbach, M. Klaus, Angew. Chem. Int. Ed.
18. (a) S. Kotha, E. Manivannan, N. Sreenivasachary, J. Chem.
Soc., Perkin Trans. 1 1999, 2845; (b) S. Kotha, V. Seema, K.
Singh, K. D. Deodhar, Tetrahedron Lett. 2014, 51, 2301; (c)
S. Kotha, S. R. Cheekatla, Tetrahedron 2019, 75, 84; (d) G.
Lannoye, S. Kotha, S. Wehrli, J. M. Cook, J. Org. Chem.
1988, 53, 2327; (e) S. Kotha, M. K. Dipak, Beilstein J. Org.
Chem. 2014, 10, 2664.
Engl. 1969, 8, 276; (f) A. P. Marchand, G. M. Reddy, W. H.
Watson, R. Kashyap, Tetrahedron 1990, 46, 3409; (g) F. A.
Khan, G. H. M. Rao, R. Satapathy, K. Parasuraman, Org. Lett.
2
007, 9, 1581; (h) B. James, E. Suresh, M. S. Nair,
Tetrahedron Lett. 2007, 48, 6059; (i) G. Mehta, S. Kotha, J.
Org. Chem. 1985, 50, 5537.
1
5. (a) A. P. Marchand, B. E. Arney Jr., P. R. Dave, N.
Satyanarayana, W. H. Watson, A. Nagl, J. Org. Chem. 1988,
19. S. Kotha, N. Sreenivasachary, K. Mohanraja, S. Durani,
Bioorg. Med. Chem. Lett. 2001, 11, 1421.
5
3, 2644; (b) T. Sasaki, S. Eguchi, T. Kiriyama, O. Hiroaki,
20. (a) S. Kotha, S. Banerjee, RSC Adv. 2013, 3, 7642; (b) S.
Kotha, A. S. Chavan, D. Goyal, ACS Comb. Sci. 2015, 17,
253; (c) S. Kotha, A. Ghosh, Tetrahedron, 2004, 60, 10833.
21. S. Kotha, N. G. Krishna, S. Halder, S. Misra, Org. Biomol.
Chem. 2011, 9, 5597.
Tetrahedron 1974, 30, 2707; (c) A. P. Marchand, D. S. Reddy,
J. Org. Chem 1985, 50, 724; (d) W.-D. Fessner, H. Prinzbach,
Tetrahedron, 1986, 42, 1797; (e) A. P. Marchand, W. D.
LaRoe, G. V. M. Sharma, S. C. Suri, D. S. Reddy, J. Org.
Chem. 1986, 51, 1622; (f) A. P. Marchand, V. S. Kumar, H.
K. Hariprakasha, J. Org. Chem. 2001, 66, 2072; (g) G. Mehta,
H. S. P. Rao, K. R. Reddy, J. Chem. Soc., Chem. Commun.
1
987, 78; (h) S. Kotha, A. Saima, S. R. Cheekatla, M. K.
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Dipak, Tetrahedron, 2020, 79, 130856. (i) S. J. Gharpure S. K.

Highlights
•
Oxa-cage compounds were synthesized via cycloadditions and ring closing metathesis
(RCM).
•
•
Trans-annular cyclization was observed in the Grignard addition.
Novel dioxa cage compound was prepared by RCM.

Graphical Abstract
Annulated oxa-cage frameworks via Claisen
rearrangement and ring-closing metathesis
Leave this area blank for abstract info.
Sambasivarao Kotha, Subba Rao Cheekatla and Usha Nandan Chaurasia
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, India

1
Tetrahedron
journal homepage: www.elsevier.com
Annulated oxa-cage frameworks via Claisen rearrangement and ring-closing
metathesis
a
Sambasivarao Kotha, ∗ Subba Rao Cheekatla† and Usha Nandan Chaurasia†
a
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In our quest to design high-density fuels, we report a variety of structurally interesting new annulated
oxa-cage frameworks. Here, we investigated a linear synthetic sequence, which relies on reductive C–
C bond cleavage and ring-closing metathesis as key steps. For this purpose, we utilized inexpensive
and readily available starting materials such as hydroquinone and endo-dicyclopentadiene.
Transannular cyclization during Grignard addition played a significant role in the design of intricate
caged compounds. The creation of these new oxa-cage systems is a challenging task by traditional
methods. The structure of the target compound has been unambiguously established by single-crystal
X-ray diffraction studies. This data indicate that density of the RCM compound is better than the
Available online
Keywords:
Oxa-cages
Heterocycles
Cycloadditions
Transannular cyclization
Claisen Rearrangement
Ring-closing metathesis
cubane density
.
2
009 Elsevier Ltd. All rights reserved.
—
——
∗
†
Corresponding author. Tel.: +91 22 25767160; fax: +022-25767152; e-mail: srk@chem.iitb.ac.in
The authors contributed equally in this work

2
Tetrahedron
1
. Introduction
Cage frameworks containing heteroatoms are useful in diverse
1
areas of chemical sciences. Their compact molecular
architecture, strain, rigidity, and lipophilicity of the cage moiety
2
improves the biological properties. Several oxygenated cage
systems incorporating pentacycloundecane (PCUD) framework
are found to be beneficial as supramolecules, application in
medicinal and pharmaceutical chemistry and also good ligands in
Figure 2. Different types of oxa-cage frameworks designed by
various synthetic routes
3
the asymmetric catalysis (Figure 1). Limited reports are
4
available dealing with the syntheses of oxa-cage systems.
2
. Results and discussion
Interestingly, amino group present in the PCUD cage system
show
an
interesting
activities
against
tuberculosis,
To expand the synthetic routes to oxa-cage systems, ozonolysis
method has been used to design of tri-oxa, tetra-oxa, penta-oxa,
5-7
neurodegenerative, and anti-viral diseases. Additionally,
pentacycloundecylamine 5 (NGP1-01) reveal both NMDA
receptor channel blocking and L-type calcium channel antagonist
13
acetal based oxa-cages, and oxa-peristylanes. Other methods to
oxygenated cage compounds include: iodine induced cyclization,
hydride rearrangement, alkene-oxirane photocycloaddition,
tandem cyclizations, transannular cyclizations, base promoted
rearrangement, dehydration of diols, reduction of lactones,
oxidation-based methodologies, intramolecular etherification,
6
-7
activity.
NGP1-01 and similar types of aminated oxa-cage frameworks are
8
examined as a promising candidates for neuroprotective agents.
PCUD containing tetra-amine oxa-cages show an excellent anti-
9
TB activity against M-tuberculosis H37Rv (Figure 1). Also,
14-15
RCM, and radical cyclization.
Various examples to diverse
these studies have demonstrated that the crown ether-based oxa,
aza, and thia- cage frameworks exhibit interesting cation-binding
1
6
oxa-cage systems 7-14 reported are listed in Figure 2. Recently,
we have also assembled an interesting and synthetically
challenging cage compound 14 via RCM route. Interestingly,
compound 14 contains three-, four-, five-, six-, and seven-
1
0
properties. Marchand group assembled a series of bis-annulated
11
cage crown ethers and tested for alkali metal picrate extraction.
Interestingly, it was found that the oxa-cage crown ether moieties
increase the lipophilicity and complexation properties of the host
1
7
membered rings conjoined with in the strained cage system.
+
and these oxa-cage crown systems bind selectively with Li and
+
11
Na ions (Figure 1). Kruger’s group designed diverse oxa cage
chiral bidentate ligands and studied their binding properties.
These PCUD ligands works as effective catalysts with good
12
enantioselectivities.
Scheme 1. Retrosynthesis to annulated cage compound 15 via
RCM
18
In view of our interest in cage molecules, here, we report a
synthetic strategy to new cage framework containing oxygen
19
atoms via transannular cyclization and RCM
approach.
Moreover, cage molecules are useful synthons to design
cyclopentanoids. Our retrosynthetic plan to target compound 15
is illustrated in Scheme 1. In this context, the cage compound 15
may be derived from tetracyclic dione 16 through reductive
cleavage, Grignard addition, and RCM as key steps. Further, the
tetracyclic dione 16 could be obtained from quinone derivative
Figure 1. PCUD containing oxa-cages useful in different arenas
2
0
1
7 via the Diels–Alder (DA) reaction followed by a [2+2]
photocycloaddition. Finally, the required quinone 17 was
prepared from commercially available hydroquinone 18 in three

3
steps via O-allylation, Claisen rearrangement followed by
interesting annulated oxa-cage framework 15. The structure of
2
1
oxidation.
RCM product 15 was firmly established on the basis of spectral
data and by single-crystal X-ray diffraction studies (Figure 3).
Finally, unsaturated oxa-cage compound 15 was subjected to
OH
OH
O
O
OH
Acetone, K
2 3
CO ,
Neat, 160-165 °
C
allylbromide,
5-60 °C, 85%
67%, (1:1)
5
OH
OH
OH
reduction with H in the presence of Pd/C to deliver the saturated
2
18
19
O
20
21
cage ether 27 in 84% yield (Scheme 3). The structure of the oxa-
cage compound 27 was supported by spectroscopic data.
OH
OH
O
O
MnO
acetone
2
,
[2+2], hv
125W lamp
2
2
reflux, 66%
MeOH, rt,
2%
hv, EtOAc,
80%
7
H
O
O
O
21
17
23
24
Scheme 2. Synthesis of diallyl cage dione 24
O
O
O
O
d = 1.343 g/cc
d = 1.340 g/cc
d = 1.290 g/cc
d = 1.330 g/cc
d = 1.080 g/cc
The quinone 17 was subjected to [4+2] cycloaddition with
cyclopentadiene (22) at 0 ˚C to provide the endo DA adduct 23 in
15
28
29
30
31
7
2% yield. The cycloadduct 23 was exposed to UV irradiation
Figure 4. Densities of various cage frameworks.
for 30 min in pyrex immersion well in dry EtOAc under nitrogen
gave the required cage system 24 in good yield (80%). Having
prepared the cage dione 24, next we attempted metal-catalyzed
reductive cleavage of C–C bond of cyclobutane ring of cage
dione 24 under acidic conditions using activated zinc dust to
generate the tetracyclic system 16. Further, the compound 16 on
reaction with Grignard reagent (allyl magnesium bromide) gave
the transannular cage system 25 in good yield (Scheme 3).
Here, we listed some of the selected cage compounds and their
densities (g/cc) in Figure 4. The densities of the cubane 29,
hexaprismane 30, and adamantine 31 were lesser than the oxa-
cages such as compound 15 and 28 synthesized in our laboratory.
1
c, 1h, 17
3
. Conclusions
In conclusion, we have successfully assembled new and
interesting oxa-cage frameworks via a transannular cyclization
and two fold RCM protocol. The newly synthesized cage
heterocyclic system holds tetrahydrofuran and oxepane rings.
The methodology involved in this sequence is useful to design
other highly functionalized heterocyclic cage compounds. The
density of compound 15 as determined by X-ray studies and this
comparable to cubane 29 although one bond and cyclopropane is
missing as compared to compound 28 (Figure 4). These cage
heterocycles may become valuable candidates for pharmaceutics
and high energy density materials useful in material science
applications.
Allyl magnisium
Zn/AcOH
bromide
0 °
C to rt,
rt, 18 h, 84%
OH
O
O
O
O
1 h, 69%
O
25
24
16
Br
0 °
C to rt,
NaH, DMF
N
N
3 h, 82%
Cl
Ru
Cl P(Cy)
Ph
3
Pd/C, H
2
(1 atm)
G-II
O
rt, 5 h, 89%
O
G-II (5 mol%)
CH Cl
rt, 15 h, 94%
O
O
O
O
2
2
27
15
26
Scheme 3. Synthesis of annulated oxa-cage system 27 via RCM
4
4
. Experimental section
.1. General methods
Moisture-sensitive materials were transferred by using syringe-
septum technique and the reactions were maintained under
nitrogen atmosphere. The TLC (thin-layer chromatography) was
performed on (7.5×2.5 cm) glass plates coated with Acme’s silica
gel GF 254 (containing 13% calcium sulfate as a binder) by using
Figure 3. Single crystal X-ray structure of compound 15 (CCDC
007824).
2
a
suitable mixture of EtOAc and petroleum ether for
development. Column chromatography was performed by using
Acme’s silica gel (100-200 mesh) with an appropriate mixture of
EtOAc and petroleum ether. The coupling constants (J) are given
in hertz (Hz) and chemical shifts are denoted in parts per million
The hemiketal 25 was further treated with allyl bromide under
NaH/DMF conditions to produce the tetraallyl compound 26.
Subsequently, the tetraallyl ether 26 was subjected to RCM under
nd
Grubb’s 2 generation catalyst (G-II) in dry DCM to deliver an

4
Tetrahedron
(ppm) downfield from internal standard, tetramethylsilane
(ppm) = 217.1, 216.8, 136.5, 133.6, 118.3, 116.0, 65.2, 62.2,
(
TMS). The abbreviations, s, d, t, q, m, dd and dt refer to singlet,
54.3, 51.2, 48.1, 42.6, 40.6, 37.3, 36.4, 33.5, 30.8; HRMS (ESI,
+
doublet, triplet, quartet, multiplet, doublet of doublets, and
doublet of triplets, respectively. IR samples were recorded with
DCM and chloroform as solvents on Nicolet Impact-400 FTIR
Q-ToF) m/z calcd for C H NaO [M + Na] 279.1356, found
17
20
2
279.1355.
Synthesis of cage hemiketal 25
1
spectrometer. Nuclear magnetic resonance (NMR) spectra ( H,
To a solution of tetracyclic compound 16 (600 mg, 2.34 mmol) in
dry THF (20 mL) was added freshly prepared allyl magnesium
bromide solution in ether (9.36 mmol) in a dropwise manner
under nitrogen at RT. At the conclusion of reaction (TLC
13
C and DEPT 135) have been recorded on 400 and 500 MHz
spectrometers (Bruker) with CDCl solvent and chemical shifts (δ
3
ppm) are reported relative to internal standard such as TMS. The
J values (coupling constants) are given Hz. Mass spectra
monitoring) the reaction mixture was quenched with saturated
°
(HRMS) have been recorded under positive ion electrospray
aqueous NH Cl solution at 0 C. Then aqueous layer was
4
ionization (ESI, Q-TOF) mode. X-ray crystal analysis was
performed on diffractometer equipped with graphite
monochromated Mo Kα radiation and structure was solved by
direct methods shelxl-97 and refined by full-matrix least-squares
extracted by EtOAc. The combined organic layer was washed
with brine and collected over anhydrous Na SO Solvent was
2
4.
evaporated under reduced pressure and the resulting residue was
purified by a silica-gel column chromatography (10% EtOAc in
2
against F using shelxl-97 software.
petroleum ether) to give the hemiketal 25 as a white crystalline
2
1
°
Synthesis of the diallylated cage dione 24
The DA adduct 23 (1 g, 0.32 mmol) was dissolved in dry EtOAc
300 mL) and irradiated in a pyrex immersion well by using an
25 W UV Hg lamp (home-made) for 2 h under nitrogen
solid. MP 71-73 C; Yield: 485 mg, 69%; IR (Neat): ν 3413,
max
-
1 1
3074, 2966, 1457, 1434, 1308, 1281, 1129, 99, 910, 756 cm ; H
(
NMR (400 MHz, CDCl ): δ (ppm) = 6.02-5.92 (m, 1H), 5.87-
3
1
5.73 (m, 2H), 5.18-4.91 (m, 6H), 2.87 (brs, 1H), 2.47 (dd, J =
1
atmosphere at rt. At the conclusion of the reaction (TLC
monitoring), the solvent was evaporated under reduced pressure
and the crude residue was purified by silica gel column
chromatography (5% ethyl acetate-petroleum ether) to give cage
13.9 Hz, J = 6.0 Hz, 1H), 2.41-2.25 (m, 6H), 2.20-2.03 (m, 5H)
2
1
3
1.89-1.79 (m, 2H), 1.70, 1.60 (ABq, J = J = 10.7 Hz, 2H);
C
1
2
NMR (100.6 MHz, CDCl ): δ (ppm) = 138.8, 136.0, 135.1,
3
117.86, 117.82, 115.1, 114.9, 87.2, 62.1, 60.7, 54.3, 52.0, 48.3,
dione 24 as a pure white crystalline solid. Yield: 795 mg, 79%;
44.8, 42.4, 41.3, 38.9, 37.7, 36.6, 31.2; HRMS (ESI, Q-ToF): m/z
1
+
H NMR (400 MHz, CDCl ): δ (ppm) = 1.82 (d, J = 11.4 Hz,1H),
calcd for C H NaO [M+Na] 321.1825, found: 321.1830.
3
20 26
2
2
1
.12 (d, J =11.4 Hz,1H), 2.15-2.4 (m, 6H), 2.55 (dd, J = J =
Synthesis of O- allylated compound 26
1
2
Hz, 1H), 2.7 (dd, J = J = 1 Hz, 1H), 2.6-3.1 (m, 2H), 5.6-5.9
The hemiketal 25 (400 mg, 1.34 mmol) dissolved in dry DMF
(8mL), then washed and dried sodium hydride (4.34 mmol)
added to the RB and allyl bromide (4.34 mmol) added dropwise
1
2
13
(m, 2H); C NMR (100 MHz, CDCl ): δ (ppm) = 33.7, 35.3,
3
3
1
5.6, 39.7, 42.0, 44.0, 47.2, 51.5, 60.2, 61.6, 118.5, 118.7, 132.9,
33.6, 2125, 213.6.
°
and stirred at 0 C to rt for 3 hours. After conclusion of the
Synthesis of tetracyclic cage compound 16
reaction by TLC technique, water added to the reaction mixture
and extracted with EtOAc. Solvent was evaporated and residue
was purified by a silica-gel column chromatography (petroleum
ether) to give the allylated compound 26 as colourless liquid.
Yield: 375 mg, 82%; IR (Neat): νmax 3077, 2942, 2871, 1640,
To a solution of pentacyclic cage dione 24 (850 mg, 3.34 mmol)
in glacial acetic acid (10 mL) added Zn dust (1.09 g, 16.7 mmol)
and stirred at rt for 24 hours. At the conclusion of the reaction
(
TLC monitoring), the reaction mixture was neutralized, filtered
-
1 1
and then extracted with DCM. The solvent was evaporated and
the crude residue was purified by silica gel column
chromatography (5% EtOAc/petroleum ether) to give 16 as a
colourless liquid. Yield: 720 mg, 84%; IR (Neat): νmax 2955,
1457, 1432, 1288, 1217, 1168, 1117, 997, 910, 717cm . H NMR
(400 MHz, CDCl ): δ (ppm) = 6.03-5.91 (m, 2H), 5.86-5.75 (m,
3
2H), 5.31-5.26 (m, 1H), 5.11-4.93 (m, 7H), 4.33-4.28 (m, 1H),
4.12-4.07 (m, 1H), 2.47-2.39 (m, 2H), 2.36-2.25 (m, 5H), 2.14-
-
1
1
13
1
744, 1639, 1202, 1168, 1003, 917, 761 cm ; H NMR (400
2.02 (m, 5H), 1.87-1.60 (m, 4H); C NMR (100.6 MHz, CDCl3):
MHz, CDCl ): δ (ppm) = 6.04-5.62 (m, 2H), 5.13-4.99 (m, 4H),
δ (ppm) = 139.0, 137.3, 135.9, 135.5, 117.3, 116.3, 115.0, 114.8,
3
2
1
.68-2.29 (m, 9H), 2.21-2.04 (m, 3H), 1.91 (d, J = 11.2 Hz, 1H),
88.1, 65.4, 64.5, 60.8, 53.3, 51.8, 48.1, 44.9, 41.4, 40.8, 39.5,
13
.86 (d, J = 11.2 Hz, 1H); C NMR (100.6 MHz, CDCl ): δ
3

5
3
7.6, 36.5, 31.3; HRMS (ESI, Q-ToF): m/z calcd for C H NaO
2
Professorship in Green Chemistry. S.R.C and U.N.C thanks
23
30
+
[
M+Na] 361.2138, found: 361.2140.
University Grants Commission (UGC), New Delhi, India for the
award of a doctoral fellowship.
Synthesis of RCM product 15
To a solution of tetraallyl compound 26 (300 mg, 0.88 mmol) in
References
nd
dry DCM (25 mL) was added Grubb’s 2 generation catalyst (5
1. (a) W. J. Geldenhuys, S. F. Malan, J. R. Bloomquist, A. P.
Marchand, C. J. Van Der Schyf, Med. Res. Rev. 2005, 25,
21; (b) K. F. Biegasiewicz, J. R. Griffiths, G. P. Savage, J.
Tsanaktsidis, R. Priefer, Chem. Rev. 2015, 115, 6719; (c) Q.
Wu, W. Zhu, and H. Xiao, RSC Adv., 2014, 4, 3789; (d) E.
Osawa and O. Yonemitsu, Carbocyclic Cage Compounds;
VCH: New York, 1992; (e) G. A. Olah, Cage Hydrocarbons;
J. Wiley and Sons, Inc., New York, 1990; (f) R. T.
Vayalakkavoor, M. Vedachalam, J. H. Boyer, Heterocycles
1990, 31, 479 ; (g) S. J. Gharpure, S. K. Porwal, Org. Prep.
Proced. Int. 2013, 45, 81; h) P. E. Eaton, T. W. Cole Jr., J.
Am. Chem. Soc.,1964, 86, 3157.
mol%) under nitrogen at rt. At the conclusion of the reaction (15
h, TLC monitoring), the solvent was evaporated and the resulting
residue was purified by a silica gel column chromatography (8%
EtOAc-petroleum ether) to give oxa-cage compound 15 as a
colourless crystalline needles. Yield: 235 mg, 94%; Mp 97-99
˚
C; IR (Neat): νmax 3020, 2928, 2857, 1447, 1190, 1125, 1081,
-
1 1
9
1
2
1
1
59 cm ; H NMR (400 MHz, CDCl ): δ (ppm) = 5.72-5.70 (m,
3
H), 5.62-5.59 (m, 1H), 5.53-5.49 (m, 1H), 5.37 (dd, J = 11.4,
.3 Hz, 1H), 4.60-4.55 (m, 1H), 4.23-4.18 (m, 1H), 2.66-2.62 (m,
H), 2.49-2.42 (m, 1H), 2.35-2.21 (m, 3H), 2.17-2.07 (m, 5H),
13
.98 (s, 1H), 1.89-1.72 (m, 4H), 1.57 (d, , J = 10.7 Hz, 1H);
C
NMR (100.6 MHz, CDCl ): δ (ppm) = 130.2, 128.1, 125.9,
2. (a) I. A. Levandovskiy, D. I. Sharapa, O. A. Cherenkova, A.
V. Gaidai, T. E. Shubina, Russ. Chem. Rev. 2010, 79, 1005;
(b) D. I. Sharapa, I. A. Levandovskiy, T. E. Shubina, Curr.
Org. Chem. 2012, 16, 2632; (c) K. Gerzon, D. Kou, J. Med.
Chem, 1967, 10, 189; (d) K. Gerzon, R. J. Kraay, R. T.
Rapala, J. Med. Chem. 1965, 8, 580.
3
1
3
23.1, 115.2, 85.0, 66.1, 64.8, 59.9, 55.4, 50.8, 49.7, 44.1, 43.1,
9.1, 37.0, 35.9, 30.2, 26.8; HRMS (ESI, Q-ToF): m/z calcd for
+
C H NaO [M+Na] 305.1512, found: 305.1511.
19
22
2
Oxa-cage compound 27
0% Palladium/charcoal (15 mg) was added to a solution of
1
RCM compound 15 (150 mg, 0.53 mmol) in dry EtOAc (10 mL)
under hydrogen (1 atm) at rt. At the conclusion of the reaction (5
h, TLC monitoring), the reaction mixture was filtered off by
using a Celite pad. The solvent was evaporated under vacuo and
the residue was purified by silica gel column chromatography
3. (a) K. Hayakawa, K. Kido, K. Kanematsu, J. Chem. Soc.,
Chem. Commun. 1986, 268; (b) T. Govender, H. G. Kruger,
M. Makatini, O. K. Onajole, Struct. Chem. 2008, 19, 719;
(c) S. M. Williams, J. S. Brodbelt, A. P. Marchand, D. Cal,
K. Mlinarié-Majerski, Anal. Chem. 2002, 74, 4423; (d) C. L.
Sherman, J. S. Brodbelt, G. Srinivas, R. Sivappa, A. P.
Marchand, ARKIVOC 2005, 5; (e) T. G. Levitskaia, B. A.
Moyer, P. V. Bonnesen, A. P. Marchand, K. Krishnudu, Z.
Chen, Z. Huang, H. G. Kruger, A. S. Mckim, J. Am. Chem.
Soc. 2001, 123, 12099.
(5% EtOAc-petroleum ether) to give 27 as a colourless solid.
Yield: 135 mg, 89%; Mp 84-86 ˚C; IR (Neat): νmax 2935, 2854,
-
1 1
1
461,1446,1183,1164,754 cm . H NMR (500 MHz, CDCl ): δ
3
(ppm) = 4.29–4.24 (m, 1H), 3.62–3.59 (d, 1H), 2.14–2.07 (m,
5
1
H), 2.00– 1.92 (m, 3H), 1.83–1.73 (m, 3H), 1.70–1.62 (m, 5H),
13
.55–1.51 (m, 6H), 1.41–1.34 (m, 1H), 1.27–1.15 (m, 1H);
C
4. (a) D. Giomi, R. Nesi, S. Turchi, E. Mura, J. Org. Chem. 2000,
65, 360; (b) H. -C. Lin, H. -J. Wu, Tetrahedron 2000, 56, 341;
NMR (125 MHz, CDCl ): δ (ppm) =117.1, 85.3, 65.8, 63.2, 61.7,
3
(
c) M. -Y. Chang, S. -T. Chena, N. -C. Chang, J. Chin. Chem.
Soc. 2001, 48, 1153; (d) H. -J. Wu, J. -H. Chern, Tetrahedron
997, 53, 17653; (e) F. A. Khan, V. Dwivedi, B. Rout,
5
2
3
6.4, 54.6, 51.0, 45.8, 43.3, 39.5, 36.1, 35.8, 35.8, 33.7, 27.5,
5.0, 23.1, 22.9; HRMS (ESI): calcd for C H NaO [M+Na];
19
26
2
1
09.1825 found; 309.1827.
Tetrahedron Lett. 2007, 48, 207; (f) N. C. Kong, Y. Zhang, S.
Gao, Y. Lu, Tetrahedron 2007, 63, 2132; (g) S. I. Kozhushkov,
T. Preuß, D. S. Yufit, J. A. K. Howard, K. Meindl, S. Rühl, C.
Yamamoto, Y. Okamoto, P. R. Schreiner, B. C. Rinderspacher,
A. De Meijere, Eur. J. Org. Chem. 2006, 2590; (h) R. Sharma,
J. Joubert, S. F. Malan, Molecules, 2018, 23, 308; (i) S. C. Suri,
J. Org. Chem. 1993, 58, 4153
Acknowledgements
The authors gratefully appreciate the Defense Research and
Development Organization (DRDO, NO.
ARDB/01/1041849/M/1), New Delhi-India for the financial
assistance. S. K. thanks Department of Science and Technology
(DST, NO. SR/S2/JCB-33/2010), DST, New Delhi, India for the
award of a J. C. Bose fellowship and Praj industries for Chair
5
.
(a) A. Mdzinarishvili, W. J. Geldenhuys, T. J. Abbruscato, U.

6
Tetrahedron
Bickel, J. Klein, C. J. Van der Schyf, Neurosci. Lett. 2005,
Kumar, H. -S. Chong, Anal. Chem. 2000, 72, 2433; (g) S. M.
Blair, J. S. Brodbelt, A. P. Marchand, K. A. Kumar, H.-S.
Chong, S. Alihodzic, J. Am. Soc. Mass Spectrom. 2000, 11,
884.
3
83, 49; (b) A. van Dijk, C. Johnston, H. Allbutt, M. Kassiou,
J. Henderson, Behav. Brain Res. 2008, 190, 14; (c) J. Hao, A.
Mdzinarishvili, T. J. Abbruscato, J. Klein, W. J. Geldenhuys,
C. J. Van der Schyf, U. Bickel, Brain Res. 2008, 1196, 113;
11. (a) A. P. Marchand, A. Hazlewood, Z. Huang, S. K.
Vadlakonda, J.-D. R. Rocha, T. D. Power, K. Mlinaric-
Majerski, L. Klaic, G. Kragol, J. C. Bryan, Struct. Chem.
2003, 14, 279; (b) C. L. Sherman, J. S. Brodbelt, G. Srinivas,
R. Sivappa, A. P. Marchand, ARKIVOC 2005, 5; (c) A. P.
Marchand, S. A. McKim, K. A. Kumar, Tetrahedron 1998,
54, 13421; (d) R. A. Bartsch, M. Eley, A. P. Marchand, R.
Shukla, K. A. Kumar, Tetrahedron 1996, 52, 8979; (e) S. M.
Williams, J. S. Brodbelt, A. P. Marchand, D. Cal, K. Mlinarié-
Majerski, Anal. Chem. 2002, 74, 4423.
(
d) J. Joubert, W. J. Geldenhuys, C. J. Van der Schyf, D. W.
Oliver, H. G. Kruger, T. Govender, S.F. Malan, Chem. Med.
Chem. 2012, 7, 375; (e) C. J. Van der Schyf, W. J.
Geldenhuys, Neurotherapeutics 2009, 6, 175.
6
.
(a) J. Joubert, E. Kapp, D. Taylor, P. J. Smith, S. F. Malan,
Bioorg. Med. Chem. Lett. 2016, 26, 1151; (b) A. O. Egunlusi,
S. F. Malan, J. Joubert, Chem. Med. Chem. 2015, 10, 1259; (c)
F. T. Zindo, S. F. Malan, S. I. Omoruyi, A. B. Enogieru, O. E.
Ekpo, J. Joubert, Eur. J. Med. Chem. 2019, 163, 83; (d) O. K.
Onajole, Y. Coovadia, H. G. Kruger, G. E. M. Maguire, M.
Pillay, T. Govender, Eur. J. Med. Chem. 2012, 54, 1
12. (a) G. A. Boyle, T. Govender, H. G. Kruger, G. E. M.
Maguire, Tetrahedron: Asymmetry 2004, 15, 2661; (b) T.
Govinder, H. K. Hariprakasha, H. G. Kruger, A. P. Marchand,
Tetrahedron: Asymmetry 2003, 14, 1553; (c) A. P. Marchand,
H. S. Chong, B. Ganguly, Tetrahedron: Asymmetry 1999, 10,
4695
7
.
(a) E. Grobler, A. Grober, C. J. Van der Schyf, S. F. Malan,
Bioorg. Med. Chem. 2006, 14, 1176; (b) H. J. R. Lemmer, J.
Joubert, S. van Dyk, F. H. van der Westhuizen, S. F. Malan,
Med. Chem. 2012, 8, 361; (c) O. K. Onajole, K. Govender, P.
Govender, P. D. van Helden, H. G. Kruger, G. E. M. Maguire,
K. Muthusamy, M. Pillay, I. Wiid, T. Govender, Eur. J. Med.
Chem. 2009, 44, 4297; (d) L. –M. Young, W. J. Geldenhuys,
O. C. Domingo, S. F. Malan, C. J. Van der Schyf, Arch.
Pharm. Chem. Life Sci., 2016, 349, 252
13. (a) H. J. Wu, C. S. Chao, C. C. Lin, J. Org. Chem. 1998, 63,
7687; (b) H. J. Wu, C. Y. Wu, C. C. Lin, Chin. Chem. Lett.
1996, 7, 15; (c) H. C. Lin, C. Y. Wu, H. J. Wu, J. Chinese
Chem. Soc. 1997, 44, 609; (d) H. J. Wu, S. H. Tsai, W. S.
Chung, J. Chem. Soc., Chem. Commun. 1996, 375; (e) H. J.
Wu, S. H. Tsai, W. S. Chung, Tetrahedron Lett. 1996, 37,
8209; (f) G. Mehta, R. Vidya, Tetrahedron Lett. 1997, 38,
4173; (g) H. J. Wu, C. Y. Wu, Tetrahedron Lett. 1997, 38,
2493; (h) C. C. Lin, H. J. Wu, Synthesis 1996, 715; (h) H. J.
Wu, C. Y. Wu, J. Org. Chem. 1999, 64, 1576; (i) H. J. Wu, J.
H. Chern, Tetrahedron 1997, 53, 17653.
8
9
.
.
(a) L. H. Prins, J. L. du Preez, S. van Dyk, S. F. Malan, Eur. J.
Med. Chem. 2009, 44, 2577; (b) J. Joubert, S. Van Dyk, I. R.
Green, S. F. Malan, Bioorg. Med. Chem. 2011, 19, 3935; (c)
D. K. Wilkes, A. de Vries, D. W. Oliver, S. F. Malan, Arch.
Pharm. 2009, 342, 73.
(a) M. D. Duque, C. Ma, E. Torres, J. Wang, L. Naesens, J.
Juárez-Jiménez, P. Camps, F. J. Luque, W. F. DeGrado, R. A.
Lamb, L. H. Pinto, S. Vázquez, J. Med. Chem. 2011, 54,
14. (a) J. H. Chern, H. J. Wu, Tetrahedron, 1998, 54, 5967; (b) H.
J. Wu, J. H. Chern, J. Org. Chem. 1997, 62, 3208; (c) J. H.
Chern, H. J. Wu, J. Chin. Chem. Soc. 1997, 44, 71; (d) H. J.
Wu, S. H. Tsai, W. S. Chung, Tetrahedron Lett. 1996, 37,
8209; (e) H. Prinzbach, M. Klaus, Angew. Chem. Int. Ed.
Engl. 1969, 8, 276; (f) A. P. Marchand, G. M. Reddy, W. H.
Watson, R. Kashyap, Tetrahedron 1990, 46, 3409; (g) F. A.
Khan, G. H. M. Rao, R. Satapathy, K. Parasuraman, Org. Lett.
2007, 9, 1581; (h) B. James, E. Suresh, M. S. Nair,
Tetrahedron Lett. 2007, 48, 6059; (i) G. Mehta, S. Kotha, J.
Org. Chem. 1985, 50, 5537.
2
646; (b) O. K. Onajole, K. Govender, P. Govender, P. D. van
Helden, H. G. Kruger, G. E. M. Maguire, K. Muthusamy, M.
Pillay, I. Wiid, T. Govender, Eur. J. Med. Chem. 2009, 44,
4
297.
1
0. (a) A. P. Marchand, H.S. Chong, S. Alihodzic, W. H. Watson,
S. G. Bodige, Tetrahedron 1999, 55, 9687; (b) A. P.
Marchand, H. S. Chong, Tetrahedron 1999, 55, 9697; (c) A.
P. Marchand, K. A. Kumar, A. S. McKim, K. Mlinarié-
Majerski, G. Kragol, Tetrahedron 1997, 53, 3467; (d) A. P.
Marchand, D. Cal, K. Mlinaric-Majerski, K. Ejsmont, W. H.
Watson, J. Chem. Crystallogr. 2002, 32, 447; (e) A. P.
Marchand, S. Alihodzic, A. S. McKim, K. A. Kumar, K.
Mlinarié-Majerski, G. Kragol, Tetrahedron Lett. 1998, 39,
15. (a) A. P. Marchand, B. E. Arney Jr., P. R. Dave, N.
Satyanarayana, W. H. Watson, A. Nagl, J. Org. Chem. 1988,
53, 2644; (b) T. Sasaki, S. Eguchi, T. Kiriyama, O. Hiroaki,
Tetrahedron 1974, 30, 2707; (c) A. P. Marchand, D. S. Reddy,
J. Org. Chem 1985, 50, 724; (d) W.-D. Fessner, H. Prinzbach,
1
861; (f) S. M. Blair, J. S. Brodbelt, A. P. Marchand, K. A.

7
Tetrahedron, 1986, 42, 1797; (e) A. P. Marchand, W. D.
LaRoe, G. V. M. Sharma, S. C. Suri, D. S. Reddy, J. Org.
Chem. 1986, 51, 1622; (f) A. P. Marchand, V. S. Kumar, H.
K. Hariprakasha, J. Org. Chem. 2001, 66, 2072; (g) G. Mehta,
H. S. P. Rao, K. R. Reddy, J. Chem. Soc., Chem. Commun.
Manivannan, N. Sreenivasachary, J. Chem. Soc., Perkin
Trans. 1 1999, 2845; (c) S. Kotha , M. K. Dipak, Chem. Eur.
J. 2006, 12, 4446; (d) S. Kotha, S. R. Cheekatla, B. Mandal,
Eur. J. Org. Chem. 2017, 4277; (e) S. Kotha, V. Seema, K.
Singh, K. D. Deodhar, Tetrahedron Lett. 2014, 51, 2301; (f) S.
Kotha, S. R. Cheekatla, Tetrahedron 2019, 75, 84; (g) G.
Lannoye, S. Kotha, S. Wehrli, J. M. Cook, J. Org. Chem.
1988, 53, 2327.
1
987, 78; (h) S. Kotha, A. Saima, S. R. Cheekatla, M. K.
Dipak, Tetrahedron, 2020, 79, 130856. (i) S. Kotha, S. R.
Cheekatla, M. Meshram, Heterocycles 2018, 97, 1008; (j) S. J.
Gharpure S. K. Porwal, Synlett, 2008, 242.
19. S. Kotha, N. Sreenivasachary, K. Mohanraja, S. Durani,
Bioorg. Med. Chem. Lett. 2001, 11, 1421.
1
6. (a) I. Chao, J. H. Shih, H. J. Wu, J. Org. Chem. 2000, 65,
7
1
523; (b) H. -C. Lin, H. -J. Wu, J. Chin. Chem. Soc. 2009, 56,
072; (c) G. Mehta, R. Vidya, J. Org. Chem. 2000, 65, 3497;
20. (a) S. Kotha, S. Banerjee, RSC Adv. 2013, 3, 7642; (b) S.
Kotha, A. S. Chavan, D. Goyal, ACS Comb. Sci. 2015, 17,
253; (c) S. Kotha, A. Ghosh, Tetrahedron, 2004, 60, 10833.
21. (a) S. Kotha, N. G. Krishna, S. Halder, S. Misra, Org. Biomol.
Chem. 2011, 9, 5597; (b) S. Kotha, M. K. Dipak, Beilstein J.
Org. Chem. 2014, 10, 2664.
(d) H.-J. Wu, J. -H. Chern, C. -Y. Wu, Tetrahedron, 1997, 53,
2
401; (e) A. P. Marchand, V. S. Kumar, H. K. Hariprakasha,
J. Org. Chem. 2001, 66, 2072; (f) G. Mehta, K. R. Reddy, J.
Org. Chem. 1987, 52, 460; (g) S. Kotha, S. R. Cheekatla, J.
Org. Chem. 2018, 83, 6315.
1
1
7. (a) S. Kotha, S. R. Cheekatla, D. S. Mhatre, Synthesis 2017,
5
0
339; (b) T. M. Swager, N. A. Romero, Synfacts 2018, 14(03),
247 (C).
8. (a) S. Kotha, S. R. Cheekatla, A. K. Chinnam, T. Jain,
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Tetrahedron Lett. 2016, 57, 5605; (b) S. Kotha, E.

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☒
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
Sambasivarao Kotha
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6.08.2020