Design, synthesis, and rearrangement studies of gem-dimethyl containing cage systems

Article abstract of DOI:10.1016/j.tet.2019.130898

A variety of functionalized cage compounds and D₃-trishomocubane derivatives have been assembled via the Diels–Alder strategy, with reductive cleavage of the cyclopropane ring and metal promoted ring rearrangement as key steps. We have installed the gem-dimethyl moiety on the norbornane ring system containing a cage framework by a late-stage synthetic manipulation involving the hydrogenolysis of the cyclopropane ring with the aid of Adams’ catalyst (PtO₂). Several cage molecules containing methyl substituents were synthesized by starting with inexpensive and commercially available materials such as 2,3-dimethylhydroquinone, Zn/AcOH, and endo-dicyclopentadiene. These cage pentacycloundecane frameworks assembled here are difficult to synthesize by conventional routes. Some of these gem-dimethyl cage systems and D₃-trishomocubane derivative was firmly supported on the basis of single-crystal X-ray diffraction studies.

Full text of DOI:10.1016/j.tet.2019.130898

Journal Pre-proof
Design, synthesis, and rearrangement studies of gem-dimethyl containing cage
systems
Sambasivarao Kotha, Subba Rao Cheekatla
PII:
S0040-4020(19)31314-6
https://doi.org/10.1016/j.tet.2019.130898
TET 130898
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 November 2019
Revised Date: 6 December 2019
Accepted Date: 18 December 2019
Please cite this article as: Kotha S, Cheekatla SR, Design, synthesis, and rearrangement studies
of gem-dimethyl containing cage systems, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2019.130898.
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Design, Synthesis, and Rearrangement Studies of Gem-dimethyl
Containing Cage Systems
Sambasivarao Kotha* and Subba Rao Cheekatla
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, India
Fax: 022-25727152; Phone: +91(22)-2572 7160, E-mail: srk@chem.iitb.ac.in
Abstract
A variety of functionalized cage compounds and D3-trishomocubane derivatives have been
assembled via the Diels–Alder strategy, with reductive cleavage of the cyclopropane ring and
metal promoted ring rearrangement as key steps. We have installed the gem-dimethyl moiety on
the norbornane ring system containing a cage framework by a late-stage synthetic manipulation
involving the hydrogenolysis of the cyclopropane ring with the aid of Adams’ catalyst (PtO2).
Several cage molecules containing methyl substituents were synthesized by starting with
inexpensive and commercially available materials such as 2,3-dimethylhydroquinone, Zn/AcOH,
and endo-dicyclopentadiene. These cage pentacycloundecane frameworks assembled here are
1

difficult to synthesize by conventional routes. Some of these gem-dimethyl cage systems and D3-
trishomocubane derivative was firmly supported on the basis of single-crystal X-ray diffraction
studies.
Keywords
Adams’ catalyst; D3-trishomocubanes; hydrogenolysis; pentacycloundecane; cage
rearrangement; reductive cleavage
Introduction
The design and synthesis of theoretically interesting polycycles has been considered as a
challenging task in organic syntheses. In the beginning carbocyclic cage molecules were
assembled as academic curiosity.1-2 Many of these cage systems are useful synthons to assemble
complex natural products. Cage molecules act as useful precursors to design high-density fuels
and biologically active molecules.3-4 Special structural features such as deformation of bond
angles, rigid molecular architecture and inherent ring strain of these systems are general reasons
for their synthetic appeal.5 Synthesis of these molecules has become a worthwhile exercise
because of their utility as high energy materials.6
F
O
Cl
OH
N
NH
N
H
H
NH
1
2
3
OMe
F
H
N
Ph
N
O
NH2
4
5
6
Figure 1. Selected examples of biologically active cage molecules (1-6) containing PCUD and
D3-trishomocubyl moiety.
2

Moreover, due to the high strain energy associated with the cage propellanes they can be used as
suitable substrates for interesting molecular rearrangements. Rearrangement studies of cage
diones and cage propellanes have provided new synthetic routes to a variety of interesting
polycycles.7 Selected D3-trishomocubane frameworks prepared by rearrangement approaches
produced various biologically active as well as medicinally important compounds.8-9
Representative examples of biologically important cage molecules 1-6 containing
pentacycloundecane (PCUD) and D3-trishomocubane skeleton are shown in Figure 1.10
A variety of ring expansion, ring-contraction, ring-fragmentation, and ring-rearrangement
processes provide new cage frameworks in an unusual fashion.11 The rearrangement process
enable the relief of the ring strain.12-13 Some examples of polycycles 7-10 which are derived from
a metal-mediated reductive cleavage approach are illustrated in Figure 2.13 Our main objective in
this field is to expand the chemical space of unusual cage polycycles and D3-trishomocubanes
via the rearrangement strategy and in this regard, we studied metal-catalyzed (PtO2/H2) reductive
cleavage of the cyclopropane ring and rearrangements associated with the pentacycloundecane
system.
Figure 2. List of various polycycles 7-10 assembled via metal-mediated reductive cleavage.
Results and discussion
Here, our aim is to design new polycyclic cage molecules containing a gem-dimethyl moiety at
the C7 position of the norbornane ring system. These categories of methyl-substituted PCUD
frameworks are considered as suitable precursors to design high-density fuels. Also, some gem-
dimethyl cage frameworks containing amine groups were tested for anti-influenza activity.14
There are two possible synthetic routes to assemble gem-dimethyl substituted PCUD cage
frameworks as shown in Scheme 1. For example, compound 12 can be synthesized from 5,5-
3

dimethylcyclopentadiene (11) and spiro[2.4]hepta-4,6-diene (13). Preparation of the diene 1115
involves a multistep synthetic sequence. Whereas the preparation of the spiro diene 13 requires
only one step from readily accessible cyclopentadiene. Therefore, we chose a simple route to
synthesize gem-dimethyl substituted cage dione 12 from spirodiene 13. Late-stage metal-
mediated reductive cleavage of the cyclopropane ring was planned as a key step to introduce the
gem-dimethyl group. In this regard, reductive cleavage of cyclopropane rings may be
accomplished by use of PtO2/H2. The increased p-character of the cyclopropane C‒C bonds
shows a higher affinity towards the metal surface, which accelerates the reaction as compared
with simple alkane derivatives. The cleavage of the cyclopropane ring generally proceeds with
high regioselectivity. Hydrogenolysis of the cyclopropane ring is feasible because of the low
activation energy involved in the cleavage of the cyclopropane C–C bond. The relief of ring
strain provides the driving force for hydrogenolysis of C–C bonds in the strained systems
containing a cyclopropane ring.
Scheme 1. The synthetic plan of PCUD cage dione 12 constitutes gem-dimethyl moiety.
In view of our interest in designing new polycyclic cage frameworks, here we report the
synthesis of hexacyclic cage diones bearing cyclopropane and cyclopentane ring system with the
Diels–Alder (DA) reaction and [2+2] photocycloaddition as key steps. The synthesis of the target
cage compound commenced with the preparation of key building blocks such as 2,3-dimethyl-
1,4-benzoquinone 15 (Scheme 2). The quinone derivative 1516 was prepared by MnO2 oxidation
of the 2,3-dimethylhydroquinone 14 in acetone (81% isolated yield).
4

Scheme 2. Synthesis of spiro cage diones 19, 20, and 23.
Having the DA precursors 15 and 21 in hand, next our efforts were directed towards the
preparation of cage diones 19, 20, 23, and 27 using intramolecular [2+2] photocycloaddition as a
key step. In this context, the DA adduct 22 (72%) was prepared by [4+2] cycloaddition of freshly
prepared spirodiene 13 and 1,4-benzoquinone 21 under reflux conditions (Scheme 2).17 Along
similar lines, the other DA adducts 17 and 18 were assembled in good yields (74-76%) by
thermal cycloaddition of the quinone 15 with freshly generated spirodienes17such as 13 and 16.
Afterward, endo-adducts 17, 18, and 22 were prepared from quinones 15 and 21. They were then
subjected to intramolecular [2+2] photocycloaddition by irradiation with 125W UV light through
a pyrex immersion well for 30 min under N2 atmosphere to deliver the cage systems 19, 20, and
2317 in excellent yields. The structures of these cage diones 19, 20, and 2317 were fully supported
1
13
on the basis of IR, H NMR, C NMR, APT spectroscopy and further established using HRMS
data.
5

Scheme 3. Synthesis of PCUD cage frameworks 12 and 26 bearing gem-dimethyl group.
Scheme 4. Synthesis of cage hemiketal 29 bearing gem-dimethyl group.
Having the cage diones 19, 23, and 27 in hand, next we directed our efforts towards the metal-
catalyzed reductive cleavage of the cyclopropane ring18 to generate cage diones containing a
gem-dimethyl group. In this context, the cage diones such as 19 and 23 bearing cyclopropane
ring were treated with PtO2 in glacial acetic acid under hydrogen (balloon) atmosphere at room
temperature for 20 h produced the gem-dimethyl substituted cage diol 24 and cage hemiketal 25
in 84 and 87% yields respectively (Schemes 3). Steric strain associated with the presence of
methyl groups and the proximity of the two carbonyl groups in the cage dione facilitates the
formation of hemiketal 25.
Additionally, 19 also facilitates the formation of hemiketal 25. The structure of these compounds
1
13
24 and 25 were confirmed on the basis of IR, H NMR, and C NMR, APT, DEPT-135 and
HRMS data. Also, the structure of the transannular product 25 (hemiketal) was further confirmed
by single-crystal X-ray diffraction data (Figure 3).19 The ring-opened products 24 and 25 by
reductive C‒C bond cleavage with PtO2 on further treatment with PCC in DCM delivered the
6

cage diones 12 and 26 in excellent yields (Schemes 3). The structure of the cage dione bearing
gem-dimethyl group 12 was further established by single-crystal X-ray diffraction data (Figure
3). 19
Pentacyclic cage dione 23 bearing cyclopropane was also subjected to reductive C‒C bond
cleavage of the cyclobutane ring. To this end, the dione 23 was reacted with activated zinc
powder in glacial acetic acid at room temperature to give the tetracyclic cage dione 27 in 91%
yield (Scheme 4). Next, the tetracyclic dione 27 was further subjected to reductive cleavage with
PtO2 in glacial acetic acid under hydrogen (balloon) atmosphere at room temperature for 20 h to
produce the gem-dimethyl substituted tetracyclic cage dione 28 in 91% yield (Scheme 4).
Finally, the tetracyclic dione 28 was converted to the corresponding cage hemiketal 29 (82%) by
NaBH4 reduction in methanol at 0 °C to rt (Scheme 4). The hemiketal structure 29 was
1
13
characterized by spectroscopy (IR, H NMR, C NMR, and HRMS data). Subsequently, spiro
cage diones 19 and 20 were treated with NaBH4 in methanol to produce the cage diols 30 and 31
in good yields (Scheme 5). The structures of these cage diols 30 and 31 were confirmed by IR,
1H NMR, 13C NMR, APT, and DEPT spectroscopy followed by HRMS.
Scheme 5. Synthesis of hexacyclic cage diols bearing spiro systems 30-31.
7

Scheme 6. Zn/AcOH promoted rearrangement of spiro cage diones 19 and 20.
Cage PCUD systems containing a succinyl bonds are prone to undergo skeletal rearrangement to
produce unusual cage structures. To expand the rearrangement approach in cage frameworks, we
studied metal-mediated rearrangements starting with cage diones bearing methyl substituents. In
this context, we studied the zinc-mediated rearrangement of cage compounds 19, 20, and 26.
To design various functionalized D3-trishomocubane derivatives by Zn/AcOH catalyzed
rearrangement, we also examined the ring rearrangement approach in substituted cage diones
such as 19 and 20 bearing spiro linkages. In this context, the diones 19 and 20 containing a spiro
linkage were reacted with activated Zn dust in glacial acetic acid and this delivered the
rearranged cage hydroxyketones 32 and 33 in good yields (78-85%). The cage hydroxyketones
32 and 33 were then treated with NaBH4 in methanol to afford the desired D3-
trishomocubanediols 34 and 35 in excellent yields (Scheme 6). The structure of the cage diol 34
was further established by single-crystal X-ray diffraction data (Figure 3). 19
8

Figure 3. X-ray crystallographic structures of compounds 12, 25, and 34.
Scheme 7. Zn/AcOH promoted rearrangement of tetra substituted cage dione 26.
We also recognized that the cage dione 26 bearing gem-dimethyl group is also a useful candidate
for creating new functionalized D3-trishomocubane frameworks via the ring rearrangement
approach. Having tetramethyl cage dione 26 in hand, next, it was subjected to acid-catalyzed
rearrangement with activated zinc dust in glacial acetic acid to deliver the tetramethyl D3-
trishomocubane 36 in 75% yield (Scheme 7). Subsequent NaBH4 reduction of compound 36
produced the tetramethyl D3-trishomocubanediol 37. The structures of these D3-trishomocubane
1
13
derivatives 36 and 37 were confirmed by H NMR, C NMR, APT, DEPT spectroscopy and
HRMS data (Scheme 7).
Conclusions
To conclude, we have efficiently utilized a hydrogenolysis route to create gem-dimethyl
containing polycyclic cage frameworks involving reductive cleavage of the cyclopropane ring in
a PCUD system. Also, several D3-trishomocubane frameworks bearing cyclopropane and
cyclopentane ring systems, as well as substituted cage ketals, were synthesized successfully in
9

this sequence. The design and synthesis of gem-dimethyl substituents at the 7th position of the
norbornane ring in the PCUD framework requires a lengthy synthetic sequence by conventional
strategy. These gem-dimethyl substituted cage frameworks may function as promising candidates
for high-density fuels and also inspire further research in this area.
Experimental Section
General Experimental Details (methods/materials)
Essential reagents, required chemicals and solvents were used directly as obtained from
commercial suppliers. Thin-layer chromatography (TLC) plates were made on 10 × 5 glass plates
layered with commercial-grade Acme’s silica gel (GF-254) containing 13% CaSO4 which acts as
a binder. Reaction progress was analyzed by a chromatographic technique (TLC analysis) with
suitable solvent systems (ethyl acetate/pet ether) and observation was done by UV, iodine spray
and immersion in KMnO4 solution. All dry/anhydrous (moisture sensitive) reactions were done
in oven-dried glassware under nitrogen/argon atmosphere by using syringe-septum techniques.
Column purification was executed with 100-200 mesh silica gel in all cases with suitable solvent
systems. Dry benzene and DCM were distilled over CaH2 and ethyl acetate was dried with
anhydrous K2CO3. Spiro dienes 1317 and 1617 were prepared according to known literature
procedures.
IR samples were recorded with DCM and chloroform as solvents on a Nicolet Impact-400 FTIR
spectrometer. NMR spectra (1H, 13C, and DEPT 135) were recorded on 400 and 500 MHz
spectrometers (Bruker) with CDCl3 solvent and chemical shifts (δ ppm) are reported relative to
an internal standard such as TMS. The J values (coupling constants) are given in Hz. Mass
spectra (HRMS) have been recorded under positive ion electrospray ionization (ESI/Q-TOF)
mode. X-ray crystal analysis was performed on a diffractometer equipped with graphite
monochromated Mo Kα radiation and the structure was solved by direct methods shelxl-97 and
refined by full-matrix least-squares against F2 using shelxl-97 software.
10

Experimental procedures and characterization data
2,3-dimethylcyclohexa-2,5-diene-1,4-dione (15)16
To a stirred solution of the 2,3-dimethyl benzene-1,4-diol 14 (5.0 g, 36.2 mmol) in acetone (70
mL) was added an excess amount of MnO2 (25.2 g, 289.6 mmol) portion-wise. The resulting
reaction mixture was stirred at room temperature for 7 h and then manganese dioxide was
removed by filtration of the crude mixture through Celite pad and washed twice with acetone.
The solvent was evaporated under reduced pressure followed by purification (100-200 mesh,
silica gel) with 2% ethyl acetate in petroleum ether as an eluent to afford the compound 15 as a
yellow crystalline solid. Yield: 81% (4.13 g); Mp: 58-60 °C (lit. 54-55 °C);16 1H-NMR (CDCl3,
500 MHz): δ (ppm) = 6.70 (s, 2H); 2.01 (s, 6H), 13C NMR (125 MHz, CDCl3):
ꢀ (ppm) = 187.5,
141.1, 136.4, 12.3.
Synthesis of [4+2] cycloadducts 17, 18, and 22: General procedure7f, 12bfor the Diels–Alder
(DA) reaction
To a stirred solution of quinone derivatives such as 2,3-dimethyl-1,4-benzoquinone 15 (1 g, 7.34
mmol, 1 equiv for 17 and 18), 1,4-benzoquinone 21 (500 mg, 4.63 mmol for 22) was added
freshly made spiro[2.4]hepta-4,6-diene 13 (14.68 mmol, 2 equiv, 1.5 mL for 17 and 9.25 mmol,
1.0 mL for 22), spiro[4.4]nona-1,3-diene 16 (14.68 mmol, 2 equiv, 1.9 mL for 18) in dry
benzene/toluene (20 mL) and thus was kept under reflux for 5 h (reaction progress was
monitored by TLC). After completion of the reaction by TLC, the solvent was evaporated under
reduced pressure and the crude residue was purified by column chromatography (silica gel, 100-
200 mesh) using an appropriate mixture of ethyl acetate/petroleum ether as an eluent to deliver
the pure DA adducts 17, 18, and 22.
Diels–Alder (DA) adduct 17
Prepared according to the above general procedure using 2,3-Dimethyl-1,4-benzoquinone 15 (1
g, 7.34 mmol) and freshly made spiro[2.4]hepta-4,6-diene 13 (14.68, 1.5 mL) in dry benzene (20
mL) under reflux for overnight. Column chromatography (6% ethyl acetate in petroleum ether)
afforded the DA adduct 17.
Pale yellow solid: Yield: 76% (1.27 g); Mp: 120-122 °C; IR (neat, cm-1): υmax = 2958, 2850,
1658, 1622, 1440, 1373, 1284, 944, 765; 1H NMR (500 MHz, CDCl3):
ꢀ
(ppm) = 6.06 (t, J = 1.8
11

Hz, 2H), 3.36-3.35 (m, 2H), 2.85 (s, 2H), 1.90 (s, 6H), 0.58-0.55 (m, 2H), 0.48-0.45 (m, 2H); 13C
NMR (125.7 MHz, CDCl3): (ppm) = 198.6, 147.8, 135.4, 53.8, 49.2, 44.7, 13.2, 8.0, 6.9;
ꢀ
HRMS (ESI/Q-ToF): m/z calcd for C15H16NaO2 [M + Na]+ 251.1043; found: 251.1043.
Diels–Alder adduct 18
Prepared according to the above general procedure using 2,3-Dimethyl-1,4-benzoquinone 15 (1
g, 7.34 mmol) and freshly made spiro[4.4]nona-1,3-diene 16 (14.68 mmol, 1.9 mL) in dry
toluene (20 mL) under reflux for overnight. Column chromatography (5% ethyl acetate in
petroleum ether) afforded the DA adduct 18.
Pale yellow solid; Yield: 74% (1.39 g); Mp: 109-111 °C; IR (neat, cm-1): υmax = 3061, 2962,
1
2850, 1657, 1374, 1264, 1124; H NMR (400 MHz, CDCl3):
ꢀ
(ppm) = 5.92 (s, 2H), 3.23 (s,
(ppm) =
13
2H), 3.04 (s, 2H), 1.85 (s, 6H), 1.56-1.38 (m, 8H); C NMR (100.6 MHz, CDCl3):
ꢀ
199.1, 147.7, 136.1, 68.8, 56.3, 48.4, 31.9, 31.6, 25.9, 25.3, 13.1; HRMS (ESI/Q-ToF): m/z calcd
for C17H20KO2 [M + K]+ 295.1095; found: 295.1095.
Diels–Alder adduct 22 17
Prepared according to the above general procedure using 1,4-benzoquinone 21 (500 mg, 4.63
mmol) and freshly made spiro[2.4]hepta-4,6-diene 13 (1.0 mL, 9.25 mmol) in dry benzene (20
mL) under reflux for overnight. Column chromatography (30% ethyl acetate in petroleum ether)
afforded the DA adduct 22. Pale yellow solid; Yield: 72% (655 mg); Mp: 105-107 °C; (Lit. Mp:
110 °C).
Synthesis of cage diones 19, 20, and 23: General procedure7f, 12bfor [2+2]
photocycloaddition
The [4+2] cycloadducts (DA adducts) 17, 18, and 22 (500 mg to 1.0 g, 2.50-4.38 mmol) in 250
mL of dry ethyl acetate were degassed with nitrogen and then irradiated in a pyrex immersion
well by using 125W medium pressure UV mercury-vapor lamp (homemade) for 30 min at room
temperature under nitrogen atmosphere. The reaction progress was monitored by TLC, the
solvent was removed under reduced pressure and the crude reaction mixture was purified from
column chromatography (on 100-200 mesh silica gel) using appropriate mixture of ethyl acetate
in petroleum ether as an eluent to furnish the cage diones 19, 20, and 23.
12

Cage dione 19
Prepared according to the above general procedure using DA adduct 17 (1.0 g, 4.38 mmol) in dry
ethyl acetate under UV irradiation for 0.5 h. Column chromatography (6-8% ethyl acetate in
petroleum ether) afforded the pure cage dione 19.
Colourless crystalline solid; Mp: 152-154 °C; prepared from DA adduct 17 (1 g, 4.38 mmol);
Yield: 969 mg (96%); IR (neat, cm-1): υmax = 3062, 2970, 2929, 2866, 1747, 1732, 1455, 1381,
1
1302, 1227, 1184, 1158, 1104, 1049, 1016, 958, 903, 875, 864; H NMR (500 MHz, CDCl3):
ꢀ
(ppm) = 2.91 (d, J = 13.7 Hz, 4H), 2.15 (d, J = 1.4 Hz, 2H), 1.02 (s, 6H), 0.65-0.64 (m, 2H),
0.62-0.60 (m, 2H); 13C NMR (125.7 MHz, CDCl3):
(ppm) = 213.9, 55.2, 51.0, 49.1, 44.5, 37.8,
ꢀ
11.6, 5.4, 4.0; HRMS (ESI/Q-ToF): m/z calcd for C15H16NaO2 [M + K]+ 267.0782; found:
267.0780.
Cage dione 20
Prepared according to the above general procedure using DA adduct 18 (1.0 g, 3.90 mmol) in dry
ethyl acetate under UV irradiation for 0.5 h. Column chromatography (8-10% ethyl acetate in
petroleum ether) afforded the pure cage dione 20.
Colourless crystalline solid; Mp: 134-136 °C; Yield: 920 mg (92%); IR (neat, cm-1): υmax = 2976,
1
2945, 2854, 1747, 1730, 1452, 1446, 1383, 1268, 1232, 1119, 1053, 878; H NMR (500 MHz,
CDCl3):
ꢀ
(ppm) = 2.88 (d, J = 12.8 Hz, 4H), 2.38 (d, J = 1.5 Hz, 2H), 1.63-1.49 (m, 8H), 1.00
(s, 6H); 13C NMR (125.7 MHz, CDCl3):
ꢀ
(ppm) = 213.8, 65.4, 54.6, 51.1, 50.2, 44.4, 32.2, 28.4,
25.6, 25.5, 11.6; HRMS (ESI/Q-ToF): m/z calcd for C17H20NaO2 [M + Na]+ 279.1356; found:
279.1357.
Cage dione 2317
Prepared according to the above general procedure using DA adduct 22 (500 mg, 2.5 mmol) in
250 mL of dry ethyl acetate under UV irradiation for 0.5 h. Column chromatography (40% ethyl
acetate in petroleum ether) afforded the pure cage dione 23; Colourless crystalline solid; Yield:
445 mg (89%); Mp: 152-154 °C; (Lit. Mp: 152 °C); 1H NMR (500 MHz, CDCl3):
(s, 2H), 2.89 (s, 2H), 2.85-2.84 (m, 2H), 2.24 (s, 2H), 0.72-0.69 (m, 2H), 0.67-0.63 (m, 2H) ppm;
13C NMR (125.7 MHz, CDCl3):
(ppm) = 212.2, 55.3, 50.4, 44.6, 39.1, 37.3, 5.5, 4.2 ppm.
ꢀ (ppm) = 3.32
ꢀ
13

Reductive cleavage of cyclopropane ring with PtO2/AcOH: General procedure18
To a stirred solution of compounds 19, 23, and 27 (0.50-1.31 mmol) in 5 mL of glacial acetic
acid was added PtO2 (0.05-0.13 mmol). The resulting reaction mixture was stirred at room
temperature under H2 atmosphere (balloon pressure) for 20 h. After completion of the reaction by
TLC monitoring, the metal catalyst was removed through the Celite pad with ethyl acetate
washing. The solvent was diluted with water, quenched by aqueous NaHCO3 solution and
extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried
over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude residues
were purified by column chromatography (on 100-200 mesh silica gel) using an appropriate
mixture of ethyl acetate in petroleum ether as an eluent to deliver the gem-dimethyl cage
compounds 24, 25, and 28.
Cage diol 24
Prepared according to the above general procedure using cage dione 23 (200 mg, 1 mmol) and
Adams’ catalyst (22 mg, 0.1 mmol) in glacial acetic acid (5 mL) stirred under rt for 20 h.
Column chromatography (20% ethyl acetate in petroleum ether) afforded the cage diol 24.
White colour solid; Yield: 173 mg (84%); Mp: 116-118 °C; IR (neat, cm-1): υmax = 3314, 2952,
1
2867, 1450, 1277, 1168, 1145, 1087, 1042; H NMR (500 MHz, CDCl3):
ꢀ (ppm) = 3.89 (t, J =
4.1 Hz, 1H), 2.79 (q, J = 6.4 Hz, 1H), 2.72-2.59 (m, 3H), 2.55-2.46 (m, 2H), 2.31 (d, J = 11.9
Hz, 1H), 1.72 (t, J = 3.7 Hz, 1H), 1.66 (t, J = 3.7 Hz, 1H), 1.57 (s, 2H), 1.13 (s, 3H), 0.76 (s,
13
3H); C NMR (125.7 MHz, CDCl3):
ꢀ (ppm) = 74.7, 56.7, 52.5, 46.9, 45.5, 42.4, 41.4, 40.2,
38.3, 35.4, 29.1, 23.7, 21.5; HRMS (ESI/Q-ToF): m/z calcd for C13H18KO2 [M + K]+ 245.0938;
found: 245.0936.
Cage hemiketal 25
Prepared according to the above general procedure using cage dione 19 (300 mg, 1.31 mmol)
and Adams’ catalyst (30 mg, 0.13 mmol) in glacial acetic acid (5 mL) stirred under rt for 20 h.
Column chromatography (15% ethyl acetate in petroleum ether) afforded the cage hemiketal 25.
14

White solid; Yield: 267 mg (87%); Mp: 110-112 °C; IR (neat, cm-1): υmax = 3454, 2972, 2962,
1
2864, 1639, 1457, 1368, 1329, 1213, 1053, 1002; H NMR (400 MHz, CDCl3):
ꢀ (ppm) = 3.85
(d, J = 4.4 Hz, 1H), 3.39 (s, 1H), 3.00-2.96 (m, 1H), 2.65-2.62 (m, 1H), 2.45 (t, J = 2.3 Hz, 2H),
13
1.95 (t, J = 3.8 Hz, 2H), 1.09 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.79 (s, 3H); C NMR (125.7
MHz, CDCl3):
ꢀ (ppm) = 81.8, 54.3, 53.8, 52.9, 52.6, 51.7, 50.2, 48.0, 46.7, 44.9, 23.3, 20.4,
16.5, 11.6; HRMS (ESI/Q-ToF): m/z calcd for C15H20KO2 [M + K]+ 271.1095; found: 271.1093.
Cage dione 28
Prepared according to the above general procedure using cage dione 27 (100 mg, 0.5 mmol) and
Adams’ catalyst (11 mg, 0.05 mmol) in glacial acetic acid (5 mL) stirred under rt for 20 h.
Recrystallization of the crude mixture from ethyl acetate in petroleum ether afforded the pure
gem-dimethyl cage dione 28.
Colourless crystalline solid; Yield: 92 mg (91%); Mp: 148-150 °C; IR (neat, cm-1): υmax = 2966,
2949, 1749, 1722, 1463, 1422, 1265, 1180, 1120, 1081; 1H NMR (500 MHz, CDCl3):
ꢀ (ppm) =
13
2.90 (s, 4H), 2.28-2.24 (m, 4H), 2.16-2.13 (m, 2H), 1.21 (s, 3H), 1.04 (s, 3H); C NMR (125.7
MHz, CDCl3):
ꢀ (ppm) = 217.9, 58.4, 57.2, 46.3, 40.3, 38.2, 22.9, 20.1; HRMS (ESI/Q-ToF):
m/z calcd for C13H16NaO2 [M + Na]+ 227.1043; found: 227.1041.
Synthesis of gem-dimethyl cage diones 12 and 26: General procedure (PCC oxidation)
To a stirred solution of the cage diol 24 and cage hemiketal 25 (100 to150 mg, 0.48-0.64 mmol)
in anhydrous DCM (10 mL) was added pyridinium chlorochromate (PCC, 5 equiv). Then, the
reaction mixture was stirred for 8 h at room temperature under nitrogen atmosphere. After
completion of the reaction by TLC monitoring, the reaction mixture was filtered on a Celite bed
and washed twice with DCM (10 mL). The filtrate was evaporated under reduced pressure and
the crude product was purified by column chromatography (on 100-200 mesh, silica gel) using
an appropriate mixture of ethyl acetate in petroleum ether as an eluent system to furnish the gem-
dimethyl cage diones 12 and 26.
Cage dione 12
Prepared according to the above general procedure using cage diol 24 (100 mg, 0.48 mmol) and
PCC (521 mg, 2.42 mmol) in anhydrous DCM (10 mL) stirred under rt for 8 h. Column
chromatography (15% ethyl acetate in petroleum ether) afforded the cage dione 12.
15

Colourless crystalline solid; Yield: 89 mg (91%); Mp: 176-178 °C; IR (neat, cm-1): υmax = 2948,
1
2861, 1736, 1464, 1369, 1052; H NMR (500 MHz, CDCl3):
ꢀ (ppm) = 3.33 (s, 2H), 2.90 (s,
13
2H), 2.82 (s, 2H), 2.35 (s, 2H), 1.13 (s, 3H), 1.02 (s, 3H); C NMR (125.7 MHz, CDCl3):
ꢀ
(ppm) = 212.1, 54.4, 53.5, 53.4, 43.7, 39.0, 23.1, 18.2; HRMS (ESI/Q-ToF): m/z calcd for
C13H14NaO2 [M + Na]+ 225.0886; found: 225.0886.
Cage dione 26
Prepared according to the above general procedure using cage hemiketal 25 (150 mg, 0.64
mmol) and PCC (695 mg, 3.22 mmol) in anhydrous DCM (10 mL) stirred under rt for 8 h.
Column chromatography (8% ethyl acetate in petroleum ether) afforded the cage dione 26.
Colourless crystalline solid; Yield: 127 mg (85%); Mp: 135-137 °C; IR (neat, cm-1): υmax = 2983,
1
2935, 1742, 1730, 1461, 1386, 1369, 1300, 1232, 1169, 1075, 1059, 875, 782; H NMR (400
MHz, CDCl3):
ꢀ
(ppm) = 2.93 (d, J = 1.6 Hz, 4H), 2.27 (s, 2H), 1.09 (s, 3H), 1.03 (s, 6H), 1.00
(s, 3H); 13C NMR (125.7 MHz, CDCl3):
ꢀ
(ppm) = 213.9, 54.4, 54.1, 52.1, 50.1, 44.6, 22.9, 18.2,
11.7; HRMS (ESI/Q-ToF): m/z calcd for C15H18NaO2 [M + Na]+ 253.1199; found: 253.1200.
General procedure12b, 13bfor Zn/AcOH promoted rearrangement of cage diones 19, 20, 23,
and 26
A solution of cage ketones 19, 20, 23, and 26 (0.43-2.00 mmol, 1 equiv) and activated zinc dust
(20.0-1.73 mmol) in 5 ml glacial acetic acid was stirred at room temperature for overnight.
Insoluble zinc metal and salts were removed by filtration. The resulting filtrate was concentrated,
diluted with cold water and extracted with DCM. The combined organic layers were washed
with aqueous NaHCO3 solution, brine and dried over anhydrous Na2SO4. The organic layer was
concentrated under reduced pressure to give the crude rearranged cage hydroxy ketones. The
resulting crude residue was further purified by column chromatography on silica gel using an
appropriate mixture of ethyl acetate in petroleum ether as an eluent to deliver the cage dione 27
and hydroxy ketones 32, 33, and 36 in good to excellent yields.
Cage dione 2717
Prepared according to the above general procedure using cage dione 23 (400 mg, 2.00 mmol)
and activate Zn dust (1.30 g, 20.0 mmol) in glacial acetic acid (10 mL) under rt for overnight.
16

Recrystallization of the crude mixture from ethyl acetate in petroleum ether afforded the pure
cage dione 27.
1
Colourless crystalline solid; Yield: 328 mg (91%); Mp: 113-115 °C; (lit. 103-105 °C)17; H-
NMR (CDCl3, 500 MHz):
ꢀ (ppm) = 2.91-2.88 (m, 4H), 2.32-2.29 (m, 2H), 2.20-2.15 (m, 4H),
0.74-0.71 (m, 2H), 0.66-0.63 (m, 2H); 13C NMR (125 MHz, CDCl3):
ꢀ (ppm) = 217.8, 59.4,
53.8, 40.3, 39.5, 31.6, 5.6, 4.5.
Cage hydroxy ketone 32
Prepared according to the above general procedure using cage dione 19 (200 mg, 0.87 mmol)
and activate Zn dust (230 mg, 3.50 mmol) in glacial acetic acid (5 mL) under rt for overnight.
Column chromatography (15% ethyl acetate in petroleum ether) afforded the cage hydroxy
ketone 32.
Colourless crystalline solid; Yield: 172 mg (85%); Mp: 136-138 °C; IR (neat, cm-1): υmax = 3437,
1
3427, 2983, 2955, 2891, 1762, 1456, 1285, 1259, 1225, 1188, 1100, 1005, 983, 931, 865; H
NMR (500 MHz, CDCl3):
= 5.9 Hz, 2H), 2.08-2.06 (m, 2H), 1.90 (d, J = 4.3 Hz, 1H) 1.82 (s, 1H), 1.11 (s, 3H), 1.08 (d, J =
7.0 Hz, 3H), 0.59-0.51 (m, 2H), 0.48-0.41 (m, 2H); 13C NMR (125.7 MHz, CDCl3):
(ppm) =
ꢀ (ppm) = 2.55 (t, J = 5.6 Hz, 1H), 2.41 (t, J = 5.9 Hz, 1H), 2.33 (d, J
ꢀ
217.4, 84.8, 53.1, 52.7, 52.2, 50.3, 50.1, 49.2, 47.0, 45.7, 34.0, 12.7, 10.5, 6.0, 5.3; HRMS
(ESI/Q-ToF): m/z calcd for C15H18NaO2 [M + Na]+ 253.1199, found: 253.1199.
Cage hydroxy ketone 33
Prepared according to the above general procedure using cage dione 20 (150 mg, 0.58 mmol)
and activate Zn dust (153 mg, 2.34 mmol) in glacial acetic acid (5 mL) under rt for overnight.
Column chromatography (15% ethyl acetate in petroleum ether) afforded the cage hydroxy
ketone 33.
Colourless crystalline solid; Yield: 119 mg (78%); Mp: 118-120 °C; IR (neat, cm-1): υmax = 3432,
2956, 2943, 1759, 1267, 1050; 1H NMR (400 MHz, CDCl3):
2.27 (m, 3H), 2.14-2.04 (m, 3H), 1.73-1.62 (m, 4H), 1.52-1.38 (m, 5H), 1.11 (s, 3H), 1.07 (d, J =
7.0 Hz, 3H); 13C NMR (125.7 MHz, CDCl3):
(ppm) = 217.2, 84.6, 58.7, 56.0, 52.8, 52.3, 49.7,
ꢀ (ppm) = 2.46-2.42 (m, 1H), 2.32-
ꢀ
49.1, 49.0, 48.9, 45.9, 33.1, 31.3, 26.19, 26.15, 12.8, 10.5; HRMS (ESI/Q-ToF): m/z calcd for
C17H22NaO2 [M + Na]+ 281.1512, found: 281.1512.
17

Cage hydroxy ketone 36
Prepared according to the above general procedure using cage dione 29 (100 mg, 0.43 mmol)
and activate Zn dust (113 mg, 1.73 mmol) in glacial acetic acid (5 mL) under rt for overnight.
Column chromatography (15% ethyl acetate in petroleum ether) afforded the cage hydroxy
ketone 36.
Colourless crystalline solid; Yield: 76 mg (75%); Mp: 112-114 °C; IR (neat, cm-1): υmax = 3450,
3420, 2969, 2877, 1757, 1471, 1383, 1368, 1291, 1273, 1251, 1217, 1107, 1073, 1054, 949, 878;
1H NMR (400 MHz, CDCl3):
2H), 1.91 (s, 1H), 1.84 (s, 1H), 1.11 (s, 3H), 1.07 (d, J = 7.1 Hz, 3H), 0.97 (s, 3H), 0.92 (s, 3H);
13C NMR (125.7 MHz, CDCl3):
(ppm) = 217.5, 84.6, 56.4, 55.6, 53.0, 52.6, 50.1, 49.3, 48.4,
ꢀ (ppm) = 2.52-2.48 (m, 1H), 2.40-2.35 (m, 3H), 2.07-2.00 (m,
ꢀ
47.2, 45.6, 23.1, 20.9, 12.8, 10.5; HRMS (ESI/Q-ToF): m/z calcd for C15H20NaO2 [M + Na]+
255.1356, found: 255.1358.
Synthesis of cage hemiketal 29, cage diols 30, 31, 34, 35, and 37: General procedure12b, 13b
(NaBH4 reduction)
To a mechanically stirred solution of cage ketones 19, 20, 26, 32, 33, and 36 (0.49-0.21 mmol) in
dry methanol (10 mL), NaBH4 (4 equiv) was added at 0 °C in small portions over a period of 10
min. Later on, the reaction mixture was stirred for another 20-30 min at room temperature. The
progress of the reaction monitored by TLC, methanol was removed under vacuo and the crude
residue was quenched by addition of water and it was extracted with ethyl acetate. The combined
organic layers were washed with brine solution, dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The obtained crude residues were purified by column chromatography
(on 100-200 mesh silica gel) using an appropriate mixture of ethyl acetate in petroleum ether as
an eluent to deliver the cage hemiketal 29 and diols 30, 31, 34, 35, and 37.
Cage hemiketal 29
Prepared according to the above general procedure using cage dione 28 (100 mg, 0.49 mmol)
°
and NaBH4 (74 mg, 1.95 mmol) in methanol (10 mL) under 0 C to rt for 30 min. Column
chromatography (25% ethyl acetate in petroleum ether) afforded the cage hemiketal 29.
Colourless crystalline solid; Mp: 94-96 °C; Yield: 83 mg (82%); IR (neat, cm-1): υmax = 3349,
1
2955, 2942, 1463, 1339, 1280, 1246, 1166, 1129, 1071, 1003, 983, 937, 841; H NMR (400
18

MHz, CDCl3):
ꢀ (ppm) = 4.62 (t, J = 6.5 Hz, 1H), 3.08-3.02 (m, 1H), 2.99 (s, 1H), 2.56-2.52 (m,
1H), 2.44 (s, 2H), 2.08 (d, J = 13.4 Hz, 1H), 2.00 (d, J = 3.9 Hz, 1H), 1.90 (dd, J = 13.4, 4.5 Hz,
1H), 1.84 (d, J = 14.3 Hz, 1H), 1.73 (d, J = 3.9 Hz, 1H), 1.64-1.58 (m, 1H), 1.07 (s, 3H), 1.01 (s,
13
3H); C NMR (125.7 MHz, CDCl3):
ꢀ (ppm) = 115.3, 80.8, 59.0, 58.8, 56.7, 53.4, 49.9, 43.3,
41.8, 40.9, 37.8, 23.1, 22.5; HRMS (ESI/Q-ToF): m/z calcd for C13H18NaO2 [M + Na]+
229.1199; found: 229.1193.
Cage diol 30
Prepared according to the above general procedure using cage dione 19 (50 mg, 0.22 mmol) and
°
NaBH4 (33 mg, 0.87 mmol) in methanol (10 mL) under 0 C to rt for 30 min. Column
chromatography (15% ethyl acetate in petroleum ether) afforded the cage diol 30.
Colourless liquid; Yield: 41 mg (81%); IR (neat, cm-1): υmax = 3192, 2953, 2867, 1459, 1350,
1
1258, 1241, 1134, 1111, 1083, 1058, 990, 962; H NMR (400 MHz, CDCl3):
ꢀ (ppm) = 4.77 (s,
2H), 3.32 (s, 2H), 2.53 (s, 2H), 2.22 (s, 2H), 1.53 (s, 2H) 1.10 (s, 6H), 0.48-0.42 (s, 2H), 0.27-
0.20 (m, 2H); 13C NMR (125.7 MHz, CDCl3):
(ppm) = 77.9, 47.8, 46.7, 45.5, 45.4, 31.4, 18.2,
ꢀ
5.1, 4.4; HRMS (ESI/Q-ToF): m/z calcd for C15H20NaO2 [M + Na]+ 255.1356; found: 255.1358.
Cage diol 31
Prepared according to the above general procedure using cage dione 20 (75 mg, 0.29 mmol) and
°
NaBH4 (44 mg, 1.17 mmol) in methanol (10 mL) under 0 C to rt for 30 min. Column
chromatography (20% ethyl acetate in petroleum ether) afforded the cage diol 31.
Colourless liquid; Yield: 63 mg (83%); IR (neat, cm-1): υmax = 3345, 3244, 3162, 2936, 2853,
1
1463, 1216, 1107; H NMR (500 MHz, CDCl3):
ꢀ
(ppm) = 4.22 (s, 2H), 3.38 (s, 2H), 2.50 (s,
13
2H), 2.19 (s, 2H), 1.83 (s, 2H), 1.58-1.39 (s, 6H), 1.18-1.13 (m, 8H); C NMR (125.7 MHz,
CDCl3):
ꢀ (ppm) = 78.2, 57.5, 49.9, 46.0, 45.4, 44.8, 32.3, 29.8, 25.8, 25.6, 18.3 ppm; HRMS
(ESI/Q-ToF): m/z calcd for C17H24NaO2 [M + Na]+ 283.1669; found: 283.1668.
Cage diol 34 (D3-Trishomocubanediol)
19

Prepared according to the above general procedure using cage hydroxy ketone 32 (100 mg, 0.43
mmol) and NaBH4 (65 mg, 1.73 mmol) in methanol (10 mL) under 0 °C to rt for 30 min. Column
chromatography (30% ethyl acetate in petroleum ether) afforded the cage diol 34.
Colourless crystalline solid; Mp:181-183 °C; Yield: 89 mg (88%); IR (neat, cm-1): υmax = 3346,
1
3328, 2972, 2954, 1361, 1344, 1287, 1244, 1197, 1156, 1080, 1061, 1049, 1006; H NMR (500
MHz, CDCl3):
7.1 Hz, 1H), 1.60 (s, 3H), 1.16 (s, 3H), 1.07 (d, J = 7.1 Hz, 3H), 0.47-0.44 (m, 2H), 0.39-0.37
(m, 2H); 13C NMR (125.7 MHz, CDCl3):
(ppm) = 87.1, 80.1, 56.4, 52.4, 52.1, 51.6, 51.0, 49.1,
ꢀ (ppm) = 3.92 (s,1H), 2.37 (d, J = 4.9 Hz, 1H), 2.10-2.06 (m, 4H), 1.86 (q, J =
ꢀ
48.3, 45.1, 31.5, 13.4, 12.7, 5.7, 5.3; HRMS (ESI/Q-ToF): m/z calcd for C15H20NaO2 [M + Na]+
255.1356, found: 255.1353.
Cage diol 35 (D3-Trishomocubanediol)
Prepared according to the above general procedure using cage dione cage hydroxy ketone 33
°
(100 mg, 0.38 mmol) and NaBH4 (58 mg, 1.54 mmol) in methanol (10 mL) under 0 C to rt for
30 min. Column chromatography (25% ethyl acetate in petroleum ether) afforded the cage diol
35.
Colourless crystalline solid; Mp: 199-201 °C; Yield: 81 mg (80%); IR (neat, cm-1): υmax = 3363,
1
2928, 2851, 1456, 1402, 1185, 1050; H NMR (400 MHz, CDCl3):
ꢀ (ppm) = 3.90 (d, J = 1.9
Hz, 1H), 2.33 (t, J = 5.4 Hz, 2H), 2.05-1.96 (m, 3H), 1.86 (q, J = 7.1 Hz, 2H), 1.63-1.61 (m, 2H),
13
1.52 (s, 3H), 1.44-1.41 (m, 5H), 1.14 (s, 3H), 1.05 (d, J = 7.1 Hz, 3H); C NMR (125.7 MHz,
CDCl3):
ꢀ (ppm) = 86.8, 80.2, 55.9, 55.7, 55.49, 55.45, 51.2, 49.8, 48.5, 47.6, 45.1, 33.1, 32.4,
26.26, 26.21, 13.3, 12.7; HRMS (ESI/Q-ToF): m/z calcd for C17H24NaO2 [M + Na]+ 283.1669,
found: 283.1668.
Cage diol 37 (D3-Trishomocubanediol)
Prepared according to the above general procedure using cage hydroxy ketone 36 (50 mg, 0.21
mmol) and NaBH4 (32 mg, 0.86 mmol) in methanol (10 mL) under 0 °C to rt for 30 min. Column
chromatography (50% ethyl acetate in petroleum ether) afforded the cage diol 37.
Colourless crystalline solid; Mp: 163-165 °C; Yield: 39 mg (77%); IR (neat, cm-1): υmax = 3420,
1
3355, 2969, 1242, 1217, 1053, 1032; H NMR (400 MHz, CDCl3):
ꢀ
(ppm) = 3.91 (d, J = 2.2
20

Hz, 1H), 2.43-2.42 (m, 1H), 2.20-2.16 (m, 2H), 2.09 (t, J = 5.6 Hz, 1H), 2.03 (t, J = 5.5 Hz, 1H),
1.84 (q, J = 7.1 Hz, 1H), 1.75-1.74 (m, 1H), 1.14 (s, 3H), 1.06 (d, J = 7.3 Hz, 3H), 0.91 (d, J =
13
6.6 Hz, 6H); C NMR (125.7 MHz, CDCl3):
ꢀ (ppm) = 86.7, 80.2, 55.9, 55.86, 55.82, 51.4,
49.1, 48.7, 47.0, 44.8, 44.4, 23.2, 22.5, 13.4, 12.8; HRMS (ESI/Q-ToF): m/z calcd for
C15H22NaO2 [M + Na]+ 257.1512, found: 257.1511.
Notes
The authors declare no competing financial interests.
Acknowledgments
We gratefully acknowledge to the Defence Research and Development Organisation (DRDO,
NO. ARDB/01/1041849/M/1), New Delhi, for financial assistance. We thank Mr. Darshan S.
Mhatre and Ms. Saima for their help in single-crystal X-ray data collection and structure
refinement. S. K. thanks the Department of Science and Technology (DST, NO. SR/S2/JCB-
33/2010) for the award of a J. C. Bose fellowship and also Praj industries for Pramod Chaudhari
Chair Professorship (Green Chemistry). S. R. C. thanks University Grants Commission (UGC),
New Delhi for the award of a doctoral grant.
Appendix A. Supplementary data
The supporting information is available free of charge on the journal website. Copies of 1H, 13C,
13C-APT, DEPT-135 NMR spectral plots of all new products and X-Ray data of products 12, 25,
and 34 (refinement data and ORTEP diagrams) are available in supplementary information (SI)
file.
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CCDC 1908378 (12), CCDC 1908389 (25), and CCDC 1919869 (34) of rearranged
compounds contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. For ORTEPs of products 12, 25, and 34, please see
the SI file.
25

Design, Synthesis, and Rearrangement Studies of Gem-dimethyl
Containing Cage Systems
Highlights
•
•
A short synthetic route to Gem-dimethyl substituted cage frameworks and D3-
trishomocubane derivatives have been established by metal-mediated reductive
cleavage.
These PCUD cage frameworks were assembled by starting with commercially
available materials such as 2,3-dimethylhydroquinone, PtO2, Zn dust/AcOH, and
endo-dicyclopentadiene.
•
•
The design of gem-dimethyl substituents at 7th position of the norbornane ring in
PCUD system requires lengthy synthetic sequence by conventional approach.
These gem-dimethyl substituted cage frameworks may function as a promising
candidates for high energy density materials.

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