Synthesis of functionalized cage propellanes and D3-Trishomocubanes via the ring-closing metathesis and acid-promoted rearrangement

Article abstract of DOI:10.1016/j.tet.2018.11.027

Several functionalized cage propellanes and D₃-trishomocubanes containing spiro linkage have been reported starting with commercially available materials such as 1,4-hydroquinone and dicyclopentadiene. In this regard, Claisen rearrangement, Die

Full text of DOI:10.1016/j.tet.2018.11.027

Accepted Manuscript
Synthesis of functionalized cage propellanes and D -Trishomocubanes via the ring-
3
closing metathesis and acid-promoted rearrangement
Sambasivarao Kotha, Subba Rao Cheekatla
PII:
S0040-4020(18)31367-X
https://doi.org/10.1016/j.tet.2018.11.027
TET 29938
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 September 2018
Revised Date: 6 November 2018
Accepted Date: 13 November 2018
Please cite this article as: Kotha S, Cheekatla SR, Synthesis of functionalized cage propellanes and
D -Trishomocubanes via the ring-closing metathesis and acid-promoted rearrangement, Tetrahedron
3
(2018), doi: https://doi.org/10.1016/j.tet.2018.11.027.
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ACCEPTED MANUSCRIPT
Synthesis of Functionalized Cage Propellanes and D3-Trishomocubanes via
the Ring-Closing Metathesis and Acid-Promoted Rearrangement
Sambasivarao Kotha,* and Subba Rao Cheekatla
Department of Chemistry, Indian Institute of Technology-Bombay, Mumbai-400 076, India.
Abstract
Several functionalized cage propellanes and D3-trishomocubanes containing spiro linkage have
been reported starting with commercially available materials such as 1,4-hydroquinone and
dicyclopentadiene. In this regard, Claisen rearrangement, Diels–Alder reaction (DA), ring-
closing metathesis (RCM) and acid-promoted rearrangement have been used as key steps. The
strategies described here, opens up new opportunities to assemble intricate cage systems that are
difficult to construct by conventional methods. Carbocation intermediates generated during the
rearrangement process play a prominent role in designing unusual cage systems. One of the
rearranged cage compound’s structure was unambiguously established by single crystal X-ray
diffraction studies.
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Key words
Claisen rearrangement, Diels–Alder reaction, [2+2] photocycloaddition, ring-closing metathesis,
acid-catalyzed rearrangement, cage [4.4.2]propellane, and D3-trishomocubanes.
1. Introduction
D3-Trishomocubane 1 is a stable and chiral molecule with an empirical formula of C11H14. It is
made up of fused five membered rings with high degree of symmetry (Figure 1). Derivatives of
D3-trishomocubanes are useful frameworks for pharmaceutical applications, medicinal chemistry
and organocatalysis.1-6 Due to their distinctive properties such as high lipophilicity and
conformational rigidity, they are useful substrates in drug discovery.2-6
D3-Trishomocubane derivatives are important targets for synthetic as well as medicinal
chemists.2 Because of their inherent gyrochirality (e.g. D3-streoisomerism) these compounds
provides an opportunity for further investigations in chemical and biological sciences.3 D3-
trishomocubyl amines (Figure 2) shows interesting activities against tuberculosis,
neurodegenerative, and anti-viral diseases.4 For example, amino substituted trishomocubane
derivatives such as 4-amino-(D3)-trishomocubanes 2-3 exhibits significant anti-viral properties
against Herpes simplex I and II, Influenza A2/Taiwan and Rhino 1A virus when compared with
6
the standard drugs like acyclovir and amantadine.5 Trishomocubylamine 4 displays potential
anti-cataleptic and anti-cholinergic activity (Figure 2).
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Cage propellane containing succinyl bond is prone to skeletal rearrangement to produce unusual
cage structures.7 Moreover, strained propellanes undergo ring-rearrangement process providing a
variety of intricate cage systems that are difficult to design by direct synthetic approaches.8 The
stability of the carbocation intermediate generated during the ring-rearrangement play a crucial
role in assembling trishomocubane skeleton.9
Selected examples of D3-trishomocubane8,9 derivatives 5-9 prepared by rearrangement
approaches are shown in Figure 3.10 Recently, we reported a new synthetic approach to
functionalized D3-trishomocubane derivatives via acid-catalyzed rearrangement starting with
cage [4.3.2]propellane and cage [4.4.2]propellane system having methyl substituent in
cyclohexene ring. 10d, 11
2. Results and Discussions
Our retrosynthetic approach to cage [4.4.2]propellanes 10 and 11 containing spiro linkage is
depicted in Scheme 1. We anticipated that the required diones 10 and 11 could be constructed
from a di-allyl cage diones 12 and 13 by adopting a ring-closing metathesis (RCM) and
reduction. The heptacyclic diones 12 and 13 may be obtained from 2,3-diallyl-1,4-benzoquinone
14 via the Diels–Alder (DA) reaction followed by [2+2] photocycloaddition. The quinone
derivative 14 can be synthesized from a readily available 1,4-hydroquinone 15 by known
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methods12, 13 involving di O-allylation, double Claisen rearrangement followed by oxidation
(Scheme 1).
Several cage systems are used as high energy materials and in this context, we explored
rearrangement approach to trishomocubane derivatives containing spiro linkage starting with
cage [4.4.2]propellanes 10 and 11. To this end, we recognized cage diones such as 12 and 13 as
key precursors. These cage diones 12-13 were prepared12 via a quinone derivative 1413a by
adopting a two-step synthetic sequence involving DA reaction starting with suitable spiro-dienes
1913band 2013c and [2+2] photocycloaddition. 2,3-Diallyl-1,4-benzoquinone 14,13a readily
prepared from commercially available 1,4-hydroquinone 15 (Scheme 2).12, 13a
O
OH
OH
OH
OH
OH
Neat, 160-165 °C
Acetone, K2CO3,
allylbromide,
55-60 °C, 85%
67%, (1:1)
O
OH
15
16
17
18
Scheme 2. Synthesis of diallyl hydroquinones 17 and 18.
Cage propellanes containing cyclohexene ring may be assembled with dione units such as 23 and
24 via ring-closing metathesis (RCM) starting with a suitable synthons using [2+2] photoadducts
12 and 13 which are derived from DA adducts 21 and 22. In this context, ring-closing metathesis
(RCM)14 of di-allyl cage diones 12 and 13 was accomplished with the Grubbs first generation
(G-I) catalyst in dry DCM to produce the symmetrical diones 23 and 24 in good yields (84 and
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88%). Subsequent hydrogenation of the RCM products 23 and 24 in the presence of H2 with 10%
Pd/C in dry ethyl acetate furnished the saturated diones 10 (92%) and 11 (93%) (Scheme 3).
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6

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To assemble cage propellanes and D3-trishomocubanes containing spiro system, we attempted
acid-catalyzed rearrangement of cage [4.4.2]propellanes 10, 11, 23, and 24 with the aid of
.
BF3 OEt2 and Zn/AcOH. Having the cage diones 10, 11, 23 and 24 in hand, the reductive C-C
bond cleavage of cyclobutane ring present in the cage diones (10, 11, 23, and 24) was achieved
in the presence of activated zinc in glacial acetic acid at room temperature. Thus, the rearranged
cage hydroxyketones such as 25, 26, 27 and 28 were produced in good yields (Scheme 3). The
1
structures of these hydroxyketones 25, 26, 27, and 28 have been supported by H NMR, 13C
NMR, APT, DEPT spectroscopic data and HRMS details. Finally, the structure of ring
rearranged cage hydroxyketone 28 was confirmed by it’s single-crystal X-ray diffraction studies
(Figure 4).15
Based on Lewis acid-catalyzed rearrangements data of cage compounds, 10d, 11 we identified that
spiro dione 11 as a suitable substrate for carbocation rearrangement. In this regard, compound 11
(n = 4) was treated with BF3.OEt2 in dry benzene under reflux conditions to afford the solvent
(benzene) incorporated product 29 (23%) along with the rearranged cage dione 30 (41%). The
1
13
structures of these cage ketones 29 and 30 have been confirmed on the basis of H NMR, C
NMR, APT spectral parameters, and further supported by HRMS data (Scheme 4).
Ph
O
.
BF3 OEt2
+
Benzene, reflux
O
O
O
O
11
29 (
30
(42%)
23%)
.
Scheme 4. BF3 OEt2-Promoted rearrangement of cage dione 11
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We proposed a possible reaction mechanism for the formation of hydroxyketone 27 (Scheme
5).7,10d The reaction was initiated by activated Zn in AcOH to form a diradical species 10a. Later,
cleavage of the strained cyclobutane ring generates the dianion intermediate 10b. Then, the
dianion 10b is involved in enolization (keto-enol tautomerism) to produce the intermediate 10c,
which on transannular cyclization gave the hydroxyketone (internal aldol product) 27.
Figure 4. Single crystal X-Ray structure of 28 with thermal ellipsoids drawn at the 50%
probability level.
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The conversion of cage dione 11 to the rearranged ketone 29 is based on Lewis acid catalyzed
10,11
rearrangements with BF3.OEt2,
and the proposed mechanism is illustrated in Scheme 6.
Initially, coordination of the Lewis acid to the ketone of cage dione 11 would generate
carbocation intermediate 11a via the migration of cyclobutane bond adjacent to the carbonyl
carbon. The carbocation 11a captured with solvent (benzene) and subsequent aromatization
followed by hydrogen transfer gives the intermediate 11b. Afterward, elimination of BF3OH
from 11b will produce the carbocation 11c, and further hydride transfers from 11 (or from
benzene) delivers the rearranged molecule 29 (Scheme 6). The hydride transfers from solvent or
cage hydrocarbon 11 might be due to the disproportionation process under the reaction
conditions. At this stage, there is no strong supporting evidence for hydride transfer in the
mechanism (Scheme 6).
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O
.
BF3 OEt2
11
O
O
O
O
O
O
O
BF3
BF3
30
11x
.
Scheme7. Plausible mechanism for BF3 OEt2-promoted rearrangement of cage dione 11 to 30
Along similar lines, compound 11 can generate the rearranged product 29 which involves capture
of solvent (benzene) during the rearrangement along with the other rearranged trishomocubane
derivative 30. A plausible mechanism for the transformation of the cage dione 11 to the
rearranged dione 30 is depicted in Scheme 7. To start with compound 11, rearranged by
migration of cyclobutane bond which generates the carbocation intermediate 11x. Later on, a
second bond migration from 11x can give a rearranged dione 30 (Scheme 7)
.
(CH2)n
(CH2)n
(CH2)n
(CH2)n
dry EtOAc
[2+2], hv
G-I, 5 mol %
rt, 7 h
IBX, DMSO
60 C, 2 h
3 h
O
O
O
O
O
O
O
O
33: n = 2; 77%
34: n = 4; 82%
35: n = 2; 89%
36: n = 4; 91%
31: n = 2; 86%
32: n = 4; 89%
21: n = 2
22: n = 4
Scheme 8. Synthesis of hexacyclic cage dione 35 and 36
Having prepared the DA adducts 21 and 22, our attention has been shifted towards heptacyclic
diones such as 35 and 36 via RCM protocol, IBX mediated dehydrogenation followed [6+2]
photocycloaddition. In this regard, [4+2] cycloadducts 21 and 22 were subjected to ring-closing
metathesis (RCM) with Grubbs’ first generation catalyst (G-I, 5 mol%) to deliver the cyclized
products in high yields (up to 86-89%). Subsequently, IBX mediated dehydrogenation of RCM
°
products 31 and 32 in the presence of IBX in DMSO at 60 C gave the aromatized derivatives
3316 and 3416 in 77 and 82% yield respectively. Later on, photocycloaddition of aromatized
compounds 33 and 34 by irradiation of 125 W UV lamp in dry ethyl acetate for 3 h gave the
spiro cage diones 3516 and 3616 in excellent yields (Scheme 8).
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Next, we focused our attention on reduction sequence. In this regard, allyl cage derivatives 12
and 13 were subjected to hydrogenation in the presence of 10% Pd/C under hydrogen
atmosphere in dry ethyl acetate to produce the saturated cage diones 37 and 38 in 91 to 92%
yields respectively (Scheme 9). The structures of these diones 37 and 38 were established by 1H
NMR, 13C NMR, APT spectral parameters and further supported by HRMS data. Afterward,
reduction of cage diones 37 and 38 in the presence of NaBH4 in dry methanol at room
temperature for 0.5 h gave the alkylated cage diols 39 and 40 in excellent yields (Scheme 9).
85.06
86.08
84.75
HO
HO
HO
O
O
217.35
O
217.62
217.75
25
26
27
85.82
213.19
213.19
Ph
O
HO
O
217.75
O
O
217.22
28
29
30
Figure 5.
Comparison of 13C NMR value (s) of various D3-trishomocubanes with respect to carbonyl and
OH attached carbons.
We have compared chemical shifts of carbonyl groups and carbons attached to hydroxyl groups
of various D3-trishomocubane derivatives. Surprisingly, the δ value (ppm) of carbonyl carbon in
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symmetrical D3-trishomocubane 30 is of low value ( 213.19 ppm) as compared with carbonyl
group chemical shift value of other D3-trishomocubane derivatives (Figure 5).
3. Conclusions
In summary, we have successfully synthesized various functionalized cage
[4.4.2]propellanediones and D3-trishomocubane derivatives containing the spiro system from a
readily available 1,4-hydroquinone. In this context, RCM protocol and rearrangement reactions
are used as key steps. Solvent incorporation as well as ring rearrangement was observed in cage
propellane framework during acid promoted rearrangement. We have prepared various
functionalized cage hydroxy derivatives as well as alkylated cage diones in this sequence by
reduction strategy. Also, we have demonstrated synthetic route to cage [4.4.2]propellanes 35 and
36 using DA precursors such as 21 and 22 via RCM, IBX mediated aromatization followed by
[6+2] cycloaddition sequence.
4. Experimental section
4.1. General experimental details
Reagents, chemicals and solvents were purchased from the commercial suppliers and used as
without purification unless otherwise stated. Analytical TLC was performed on (10 × 5) glass
plates coated with Acme’s silica gel (GF-254) containing 13% calcium sulfate as a binder.
Reactions were monitored by TLC using suitable solvent system and visualization was done
under UV light, exposure to iodine vapour and by dipping in to a solution of KMnO4. Anhydrous
reactions were performed in oven dried glassware under nitrogen atmosphere by using standard
syringe-septum techniques. Acme’s silica gel (100-200 mesh size) was used for column
chromatography. Benzene and toluene were distilled from P2O5 or CaH2 and ethyl acetate was
dried over K2CO3.
IR spectra were collected on a Nicolet Impact-400 FTIR spectrometer and samples were
prepared as a thin film between CsCl plates by dissolving the compound in dichloromethane and
chloroform and then evaporating the solvent. 1H NMR (400 and 500 MHz), 13C NMR, 13C-APT
NMR, DEPT 135 NMR (100 and 125 MHz) spectra were recorded on Bruker spectrometer and
samples were prepared in CDCl3 solvent. The chemical shifts are reported in parts per million
(ppm) on delta scale with TMS as an internal standard and values for the coupling constants (J)
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are given in Hz. The standard abbreviations for 1H NMR spin couplings are given as s, d, t, q, dd,
dt, td, and m for singlet, doublet, triplet, quartet, doublet of doublet, doublet of triplet, triplet of
doublet and multiplet respectively. High-resolution mass spectra (HRMS) were recorded in a
positive ion electrospray ionization (ESI-Q-TOF). All melting points were recorded on Veego
VMP-CMP melting point apparatus and are uncorrected. spiro dienes such as spiro [2.4] hepta-
4,6-diene 19 and spiro[4.4]nona-1,3-diene 20 were prepared according to literature methods.13
General procedure for synthesis of Diels-Alder adducts 2112 and 2212
To a stirred solution of 2,3-diallylcyclohexa-2,5-diene-1,4-dione 14 (3.98-3.18 mmol, 1 equiv)
and freshly prepared spiro[2.4]hepta-4,6-diene 19 (0.7 mL, 7.17 mmol for 21) in dry benzene (10
mL) and spiro[4.4]nona-1,3-diene 20 (0.7 mL, 5.72 mmol for 22) in dry toluene (10 mL) was
kept reflux for overnight (progress of reaction monitored by TLC). After completion of the
reaction by TLC monitoring, the solvent was evaporated under reduced pressure and the crude
residue was purified by silica gel column chromatography (4-7% EtOAc/PE) to deliver the pure
21 as a yellow liquid and 22 as a yellow semi solid.
DA adduct 2112: viscous yellow liquid; obtained from compound 14 (750 mg, 3.98 mmol);
Yield: 877 mg (78%); IR (neat, cm-1) 3076, 3012, 2925, 1662, 1422, 1354, 1327, 1269,
1
1216,1127, 1011, 997, 667; H NMR (400 MHz, CDCl3): ꢀ 6.04 (t, J = 1.9 Hz, 2H), 5.72-5.62
(m, 2H), 4.99-4.94 (m, 4H), 3.36-3.35 (m, 2H), 3.13 (td, J = 4.0, 2.0 Hz, 4H), 2.84 (t, J = 1.8 Hz,
2H), 0.57-0.53 (m, 2H), 0.46-0.42 (m, 2H); 13C NMR (100.6 MHz, CDCl3): ꢀ 198.2, 149.2,
135.3, 133.5, 116.8, 53.9, 49.3, 44.7, 31.0, 8.0, 6.9.
DA adduct 2212: yellow semi solid; m.p. 47-49 °C; obtained from compound 14 (600 mg, 3.18
1
mmol); Yield: 687 mg (70%); IR (neat, cm-1): 3016, 2954, 1662, 1354, 1271, 1216, 918; H
NMR (500 MHz, CDCl3):
3.14 (d, J = 6.1 Hz, 4H), 3.08 (s, 2H), 1.57-1.61 (m, 2H), 1.50-1.42 (m, 6H) ppm; 13C NMR (125
MHz, CDCl3): = 198.8, 149.2, 136.2, 133.6, 116.8, 69.0, 56.6, 48.8, 32.0, 31.6, 31.0, 25.9, 25.4
ꢀ = 5.96 (s, 2H), 5.72-5.64 (m, 2H), 4.95-5.00 (m, 4H), 3.28 (s, 2H),
ꢀ
General procedure for [2+2] photocycloaddition of DA adducts 21 and 22
The [4+2] adducts 21 and 22 (1.42-2.59 mmol) was dissolved in dry EtOAc (250 mL) and
irradiated in a pyrex immersion well by using 125 W UV lamp for 1 h under nitrogen
atmosphere at room temperature. After completion of the reaction by TLC analysis, the solvent
was evaporated under reduced pressure and the crude residue was purified by silica gel column
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chromatography by using 7-10% EtOAc/petroleum ether as an eluent to afford the cage diones
12 and 13 as pure colourless crystalline solids.
Cage dione 1212: colourless crystalline solid; m.p. 81-83 ºC
; obtained from DA adduct 21 (400
mg, 1.42 mmol); Yield: 95% (379 mg); IR (neat, cm-1) 3082, 2982, 1736, 1415, 1273, 1223,
1
1182, 1080, 1010, 917, 875, 666; H NMR (400 MHz, CDCl3): ꢀ 5.56-5.46 (m, 2H), 5.05-4.97
(m, 4H), 3.05 (t, J = 1.3 Hz, 2H), 2.89 (d, J = 1.7 Hz, 2H), 2.47 (dd, J = 14.0, 5.7 Hz, 2H), 2.20
13
(dd, J = 14.0, 8.3 Hz, 2H), 2.10-2.07 (m, 2H), 0.63 (m, 4H); C NMR (100.6 MHz, CDCl3): ꢀ
213.0, 132.6, 118.6, 56.0, 54.7, 49.2, 41.6, 38.0, 30.2, 5.4, 4.0.
Cage dione 1312: colourless crystalline solid; m.p. 73-74 ºC
mg, 2.59 mmol); Yield: 92% (740 mg); IR (neat, cm-1): 3081, 2949, 2867, 1752, 1734, 1437,
1117, 918; 1H NMR (400 MHz, CDCl3):
= 5.49-5.59 (m, 2H), 5.01-5.07 (m, 4H), 2.99 (s, 2H),
; obtained from DA adduct 22 (800
ꢀ
2.85 (s, 2H), 2.51 (dd, J1 = 14.0 Hz, J2 = 5.6 Hz, 2H), 2.34-2.32 (m, 2H), 2.21 (dd, J1 = 14.0 Hz,
13
J2 = 8.4 Hz, 2H), 1.66-1.63 (m,4H), 1.53-1.62 (m, 4H) ppm; C NMR (100 MHz, CDCl3):
25.5, 25.7, 28.6, 30.3, 32.4, 41.5, 51.3, 54.0, 55.3, 54.0, 55.4, 65.6, 118.6, 132.7, 212.9 ppm
General procedure for synthesis of cage diones 23 and 24 via RCM protocol:
ꢀ =
To a stirred solution of RCM precursors 12 and 13 (1.78-1.29 mmol, 1 equiv) in dry DCM (10
mL) was degassed with nitrogen for 10 min was added G-I catalyst (5 mol%). Later on, the
reaction mixture was stirred at room temperature for 2-5 h. After completion of the reaction by
monitoring of the TLC, then the solvent was removed under reduced pressure and the crude
reaction mixture was purified by silica gel column chromatography using 3-5% EtOAc/PE as an
eluent to deliver the RCM products 23 and 24 as a colourless crystalline solids.
Cage dione 23: colourless crystalline solid; m.p. 128-130 ºC
;
started from [2+2] photo adduct 12
1
(500 mg, 1.78 mmol); Yield: 84% (380 mg); IR (neat, cm-1): 2962, 2865, 1763, 1270, 781; H
NMR (400 MHz, CDCl3):
Hz, 2H), 2.35 (d, J = 15.7 Hz, 2H), 2.19 (d, J = 1.7 Hz, 2H), 1.85-1.81 (m, 2H), 0.72-0.61 (m,
4H) ppm; 13C NMR (125 MHz, CDCl3):
= 212.9, 126.1, 55.2, 52.5, 49.1, 43.2, 37.7, 23.8, 5.5,
4.1; HRMS (ESI, Q-ToF): m/z calcd for C17H16NaO2 [M + Na]+ 275.1043; found: 275.1048.
ꢀ = 5.95 (d, J = 3.2 Hz, 2H), 2.95 (d, J = 1.6 Hz, 2H), 2.86 (d, J = 1.3
ꢀ
Cage dione 24: colourless crystalline solid; m.p. 145-147 ºC
; started from [2+2] photo adduct 13
(400 mg, 1.29 mmol); Yield: 88% (320 mg); IR (neat, cm-1): 2950, 2857, 1746, 1725, 1444,
1236, 1217, 1100; 1H NMR (400 MHz, CDCl3):
ꢀ
= 5.97-5.91 (m, 2H), 2.87 (d, J = 1.6 Hz, 2H),
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2.78-2.77 (m, 2H), 2.42-2.39 (m, 2H), 2.35 (d, J = 15.8 Hz, 2H), 1.85-1.79 (m, 2H), 1.68-1.50
(m, 8H) ppm; 13C NMR (100 MHz, CDCl3):
ꢀ = 212.8, 126.1, 65.3, 54.6, 51.8, 51.2, 43.1, 32.3,
28.5, 25.7, 25.6, 23.9; HRMS (ESI, Q-ToF): m/z calcd for C19H20NaO2 [M + Na]+ 303.1356;
found: 303.1356.
General procedure for synthesis of cage diones 10 and 12 via reduction:
To a stirred solution of RCM products 23 and 24 (0.53-0.79 mmol) in dry ethyl acetate (10 mL)
and 10% Pd/C (5 mg) was added. Afterwards, the resulting reaction mixture was stirred at room
temperature for 5 h under hydrogen atmosphere (1 atm). After conclusion of the reaction by TLC
monitoring, the reaction mixture was filtered through Celite pad and washed with ethyl acetate.
The combined washings and filtrate were evaporated under vacuo and the resulting crude residue
was purified by silica gel column chromatography using 2-4% ethyl acetate in petroleum ether as
an eluent to furnish the hydrogenated products 10 and 12 as white crystalline solids.
Cage dione 10: white crystalline solid; mp 171-173 ºC; started from RCM product 23 (200 mg,
0.79 mmol); Yield: 92% (187 mg); IR (neat, cm-1): 2964, 2833, 1748, 1732, 1438, 1379, 1297,
1277, 1230, 1195, 1168, 1134, 1097, 1066, 1028, 1005, 984, 948, 909, 854, 786; 1H NMR (400
MHz, CDCl3):
2H), 1.62-1.50 (m, 4H), 1.36-1.30 (m, 2H), 0.71-0.62 (m, 4H) ppm; 13C NMR (125 MHz,
CDCl3): = 213.7, 55.5, 50.3, 49.3, 44.4, 37.9, 22.8, 19.3, 5.5, 4.1; HRMS (ESI, Q-ToF): m/z
calcd for C17H18KO2 [M + K]+ 293.0938; found: 293.0936.
ꢀ = 3.0 (s, 2H), 2.93 (d, J = 1.3 Hz, 2H), 2.17 (d, J = 1.4 Hz, 2H), 1.98-1.91 (m,
ꢀ
Cage dione 11: white crystalline solid; m.p. 157-159 ºC
; started from RCM product 24 (150 mg,
0.53 mmol); Yield: 93% (140 mg); IR (neat, cm-1): 2955, 2939, 2858, 1743, 1728, 1449, 1217,
1095; 1H NMR (500 MHz, CDCl3):
ꢀ
= 2.94 (s, 2H), 2.84 (s, 2H), 2.39 (t, J = 1.7 Hz, 2H), 1.95-
13
1.90 (m, 2H), 1.67-1.62 (m, 4H), 1.58-1.47 (m, 8H), 1.33-1.28 (m, 2H) ppm; C NMR (125
MHz, CDCl3):
ꢀ = 213.5, 65.3, 54.8, 51.2, 49.5, 44.2, 32.3, 28.5, 25.7, 25.6, 22.8, 19.3; HRMS
(ESI, Q-ToF): m/z calcd for C19H22NaO2 [M + Na]+ 305.1512; found: 305.1510.
General procedure for the synthesis of cage hydroxy ketones 25, 26, 27 and 28 via
rearrangement
A solution of cage diones 10, 11, 23, and 24 (0.35-0.59 mmol, 1 equiv) and activated zinc dust
(1.41-2.36 mmol) in 5 ml glacial acetic acid was stirred at room temperature for overnight.
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Insoluble zinc metal and salts were removed by filtration. The resulting filtrate was concentrated,
diluted with cold water and extracted with dichloromethane (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 ketone. The resulting crude residue was further purified by column chromatography on
silica gel using 10-15% EtOAc/PE as an eluent to deliver the cage hydroxy ketones 25 and 26 as
a colourless liquids and 27 and 28 as a colourless crystalline solids.
Cage hydroxy ketone 25: colourless viscous liquid; prepared from cage dione 23 (150 mg, 0.59
mmol); Yield: 137 mg (90%); IR (neat, cm-1): 3442, 2937, 2862, 1758, 1449, 1305, 1269, 1245,
1
1159; H NMR (500 MHz, CDCl3):
ꢀ = 5.62 (t, J = 3.9 Hz, 2H), 2.65-2.63 (m, 1H), 2.44-2.38
(m, 2H), 2.34-2.24 (m, 4H), 2.17 (t, J = 3.8 Hz , 1H), 2.13-2.08 (m, 1H), 1.94-1.93 (m, 1H),
1.77-1.76 (m, 1H), 0.57-0.51 (m, 2H), 0.47-0.42 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3):
ꢀ
=
217.3, 129.5, 128.3, 85.0, 55.8, 53.4, 52.2, 50.2, 48.5, 48.4, 46.5, 46.0, 33.8, 26.0, 22.6, 6.0, 5.3
ppm; HRMS (ESI, Q-ToF): m/z calcd for C17H18NaO2 [M + Na]+ 277.1199; found: 277.1194.
Cage hydroxy ketone 26: colourless viscous liquid; prepared from cage dione 24 (150 mg, 0.53
mmol); Yield: 134 mg (88%); IR (neat, cm-1): 3421, 2962, 1763, 1270, 781; 1H NMR (400 MHz,
CDCl3):
2.30-2.24 (m, 4H), 2.17-2.01 (m, 4H), 1.95 (d, J = 3.0 Hz, 1H), 1.64-1.59 (m, 2H), 1.48-1.32 (m,
6H) ppm; 13C NMR (100 MHz, CDCl3):
= 217.7, 129.5, 128.3, 84.7, 58.5, 56.5, 55.5. 52.3,
ꢀ = 5.60 (t, J = 3.6 Hz, 2H), 2.82 (s, 1H), 2.52 (t, J = 5.6 Hz, 1H), 2.41-2.36 (s, 1H),
ꢀ
49.1, 49.0, 48.6, 47.2, 45.9, 32.9, 31.1, 26.1, 22.5 ppm; HRMS (ESI, Q-ToF): m/z calcd for
C19H22NaO2 [M + Na]+ 305.1512; found: 305.1518.
Cage hydroxy ketone 27: colourless crystalline solid; m.p. 113-115 ºC
dione 10 (150 mg, 0.59 mmol); Yield: 129 mg (85%); IR (neat, cm-1): 3399, 2975, 1749, 1422,
1226, 1164, 1015, 953, 781; 1H NMR (500 MHz, CDCl3):
= 2.53-2.50 (m, 1H), 2.37 (t, J = 5.9
; prepared from cage
ꢀ
Hz, 1H), 2.31-2.29 (m, 1H), 2.25-2.21 (m, 3H), 2.10 (ddd, J = 14.8, 6.4, 3.3 Hz, 1H), 1.92-1.91
(m, 1H), 1.85-1.73 (m, 3H), 1.69-1.63 (m, 2H), 1.49-1.40 (m, 1H), 1.35-1.22 (m, 2H), 0.58-0.51
(m, 2H), 0.49-0.41 (m, 2H) ppm; 13C NMR (125 MHz, CDCl3):
ꢀ = 217.6, 86.0, 57.0, 53.1, 53.0,
50.1, 50.0, 49.9, 48.6, 46.9, 33.6, 28.9, 26.2, 24.82, 24.80, 6.0, 5.3 ppm; HRMS (ESI, Q-ToF):
m/z calcd for C17H20NaO2 [M + Na]+ 279.1353; found: 279.1356.
16

ACCEPTED MANUSCRIPT
Cage hydroxy ketone 28: colourless crystalline solid; m.p. 122-124 ºC; prepared from cage
dione 11 (100 mg, 0.35 mmol); Yield: 87 mg (86%); IR (neat, cm-1) 3440, 2935, 2861, 1756,
1
1451, 1308, 1244, 1158; H NMR (500 MHz, CDCl3): ꢀ 2.41-2.39 (m, 1H), 2.26-2.16 (m, 5H),
2.14-2.06 (m, 2H), 1.99 (s, 1H), 1.82-1.71 (m, 2H), 1.68-1.62 (m, 4H), 1.52-1.34 (m, 7H), 1.31-
13
1.17 (m, 2H); C NMR (125 MHz, CDCl3): ꢀ 217.7, 85.8, 58.3, 56.6, 56.4, 53.2, 50.2, 50.1,
49.6, 48.7, 47.2, 33.0, 31.2, 28.9, 26.2, 26.1, 26.0, 24.85, 24.81; HRMS (ESI) m/z calcd for
C19H24NaO2 [M + Na]+ 307.1669; found: 307.1670.
.
BF3 OEt2-catalyzed rearrangement of cage dione 11
Spiro cage dione 11 (200 mg, 0.70 mmol) was added to a stirred solution of anhydrous BF3 OEt2
(1 mL) in dry benzene (10 mL) at room temperature. Later on, the resulting reaction mixture was
refluxed for 2 days. After completion of the reaction by TLC monitoring, the reaction mixture
was quenched with saturated aqueous NaHCO3 solution and this was extracted with benzene.
The combined organic layer was washed with water, brine solution and dried over anhydrous
Na2SO4. After removal of the solvent under vacuo, the resulting crude residue was subjected to
silica gel column chromatography by using 5% ethyl acetate/petroleum ether as an eluent to give
the desired rearranged cage ketone 29 (57 mg, 23%) containing a phenyl group as a colourless
liquid. After continuous elution with 10% ethyl acetate in petroleum ether delivered the
rearranged cage dione 30 (82 mg, 41%) as colourless crystalline solid.
Cage ketone 29: colourless liquid
mg (23%); IR (neat, cm-1): 2935, 2337, 1759, 1266; 1H NMR (400 MHz, CDCl3):
;
prepared from cage dione 11 (200 mg, 0.70 mmol); Yield: 57
= 7.31-7.15
ꢀ
(m, 5H), 2.82 (d, J = 1.9 Hz, 1H), 2.63-2.61 (m, 1H), 2.50-2.43 (m, 2H), 2.15-2.13 (m, 1H),
13
2.11-2.01 (m, 2H), 1.70-1.56 (m, 7H), 1.52-1.43 (m, 5H), 1.33-1.27 (m, 4H) ppm; C NMR
(100 MHz, CDCl3): ꢀ = 217.2, 149.6, 128.4, 126.8, 125.3, 60.0, 56.5, 55.3, 54.6, 54.2, 51.6, 50.4,
48.4, 48.1, 43.2, 42.2, 33.0, 32.8, 26.4, 26.2, 26.0, 25.4, 24.3 ppm; HRMS (ESI, Q-ToF): m/z
calcd for C25H28KO [M + K]+ 383.1772; found: 383.1778.
Cage dione 30: colourless crystalline solid; m.p. 136-138 ºC
;
prepared from cage dione 11 (200
1
mg, 0.70 mmol); Yield: 82 mg (42%); IR (neat, cm-1) 2926, 2857, 1751, 1450, 1294, 1076; H
NMR (500 MHz, CDCl3): 2.23-2.26 (m, 6H), 1.83 (d, J = 13.5 Hz, 2H), 1.69-1.62 (m, 2H), 1.49-
13
1.42 (m, 10H), 1.15-1.12 (m, 2H) ppm; C NMR (125 MHz, CDCl3,
ꢀ
213.1, 60.5, 50.6, 48.6,
17

ACCEPTED MANUSCRIPT
48.4, 42.8, 32.5, 26.1, 22.0, 21.9 ppm; HRMS (ESI, Q-TOF) m/z calcd for C19H22O2 [M + Na] +
305.1512; found: 305.1514.
General procedure for synthesis of RCM products 31 and 32:
To a stirred solution of RCM precursors 21 and 22 (0.97-1.24 mmol, 1 equiv) in dry DCM (10
mL) were degassed with nitrogen for 10 min was added G-I catalyst (5 mol%). Later on, the
reaction mixture was stirred at room temperature under nitrogen atmosphere for 2-5 h. After
completion of the reaction by TLC monitoring, then the solvent was removed under reduced
pressure and the crude reaction mixture was purified by silica gel column chromatography using
3-5% EtOAc/PE as an eluent to deliver the RCM products 31 and 32 as a colourless crystalline
solids.
Compound 31: colourless crystalline solid; m.p. 138-140 ºC
mg, 1.24 mmol); Yield: 86% (272 mg); IR (neat, cm-1): 2989, 1654, 1418, 1398, 1276, 1010,
771, 704; 1H NMR (400 MHz, CDCl3):
= 6.09 (t, J = 1.8 Hz, 2H), 5.73 (s, 2H), 3.39-3.38 (m,
; started from DA adduct 21 (350
ꢀ
2H), 3.00-2.89 (m, 6H), 0.61-0.57 (m, 2H), 0.51-0.47 (m, 2H) ppm; 13C NMR (125 MHz,
CDCl3): ꢀ 198.3, 146.0, 135.4, 122.7, 53.9, 49.0, 44.8, 24.7, 8.1, 7.0 ppm ; HRMS (ESI, Q-ToF):
m/z calcd for C17H16NaO2 [M + Na]+ 275.1043; found: 275.1045.
Compound 32: colourless crystalline solid; m.p. 143-145 ºC
;
started from DA adduct 22 (300
1
mg, 0.97 mmol); Yield: 89% (243 mg); IR (neat, cm-1): 2958, 2854, 1655, 1270, 1259, 772 ; H
NMR (500 MHz, CDCl3):
ꢀ
= 6.00 (t, J = 1.9 Hz, 2H), 5.73 (s, 2H), 3.30-3.29 (m, 2H), 3.11 (d, J
13
= 1.6 Hz, 2H), 2.96 (s, 4H), 1.63-1.58 (m, 4H), 1.53-1.44 (m, 4H) ppm; C NMR (100.6 MHz,
CDCl3): ꢀ 198.9, 146.0, 136.2, 122.8, 69.0, 56.6, 48.4, 32.1, 31.6, 26.0, 25.5, 24.7; HRMS (ESI,
Q-ToF): m/z calcd for C19H20NaO2 [M + Na]+ 303.1356; found: 303.1353.
General procedure for synthesis of aromatized derivatives 33 and 34 (IBX mediated
oxidative dehydrogenation):
To a stirred solution IBX (1.60-1.98 mmol, 2 equiv) in DMSO (5 mL) were added RCM
products 31 and 32 (0.80-0.99 mmol, 1 equiv) under nitrogen atmosphere and kept for heating at
75-85 0°C. After completion of the reaction by TLC monitoring (2 h), the reaction mixture was
quenched with water and extracted from ethyl acetate. Then the combined organic layers were
washed with saturated aqueous NaHCO3 solution followed by brine. The organic layer was dried
18

ACCEPTED MANUSCRIPT
over anhydrous Na2SO4 and removal of the solvent under reduced pressure produce the crude
products which was charged on silica gel column chromatography using 5-7% EtOAc/petroleum
ether as an eluent to affords the aromatized products 33 and 34 as white solids.
Compound 3316: white solid; m.p. 146-148 ºC
; started from RCM product 31 (250 mg, 0.99
mmol); Yield: 77% (192 mg); IR (neat, cm-1): 3067, 2959, 2861, 1676, 1603, 1569, 1451, 1325,
1
1298, 1273, 1195, 1122, 1020, 912, 883, 856, 836, 778; H NMR (400 MHz, CDCl3):
ꢀ = 8.02
(dd, J = 5.8, 3.3 Hz, 2H), 7.68 (dd, J = 5.8, 3.3 Hz, 2H), 6.06 (s, 2H), 3.62 (s, 2H), 3.01 (s, 2H),
0.65-0.61 (m, 2H), 0.57-0.53 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): ꢀ 197.6, 136.0, 135.5,
134.0, 126.8, 54.3, 50.3, 44.9, 8.1, 7.0 ppm.
Compound 3416: white solid; m.p. 149-151 ºC
; started from RCM product 32 (225 mg, 0.80
mmol); Yield: 82% (185 mg); IR (neat, cm-1): 2980, 2932, 2857, 1675, 1599, 1298, 1277, 1215,
1
1037, 915, 851, 837; H NMR (400 MHz, CDCl3):
ꢀ = 8.01 (s, 2H), 7.68 (s, 2H), 5.97 (s, 2H),
3.53 (s, 2H), 3.23 (s, 2H), 1.61-1.52 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3): ꢀ 198.3, 136.5,
136.2, 134.1, 126.9, 69.2, 57.1, 49.8, 32.2, 31.4, 26.0, 25.5 ppm
General procedure for synthesis of cage diones 35 and 36 via [2+2] photocycloaddition:
The aromatized derivatives 33 and 34 (0.53-0.69 mmol) was dissolved in dry EtOAc (250 mL)
and irradiated in a pyrex immersion well by using 125 W UV lamp for 3 h under nitrogen
atmosphere at room temperature. After completion of the reaction by TLC analysis, the solvent
was evaporated under reduced pressure and the crude residue was purified by silica gel column
chromatography by using 10-15% EtOAc/petroleum ether as an eluent to afford the symmetrical
cage diones 35 and 36 as pure colourless solids.
Cage dione 3516: colourless solid; m.p. 171-173 ºC
mg, 0.69 mmol); Yield: 89% (157 mg); IR (neat, cm-1) 2995, 2833, 1741, 1722, 1447, 1308,
1186, 1115; 1H NMR (400 MHz, CDCl3):
= 5.98-5.94 (m, 2H), 5.40-5.35 (m, 2H), 3.51-3.50
; obtained from aromatized derivative 33 (175
ꢀ
(m, 2H), 2.99 (d, J = 1.5 Hz, 2H), 2.30-2.28 (m, 2H), 0.75-0.71 (m, 2H), 0.65-0.61 (m, 2H)
ppm;13C NMR (100.6 MHz, CDCl3): ꢀ 210.3, 124.8, 119.9, 55.2, 52.0, 51.0, 49.9, 35.8, 5.3, 4.1.
Cage dione 3616: colourless solid; m.p. 164-166 ºC
;
obtained from aromatized derivative 34 (150
1
mg, 0.53 mmol); Yield: 91% (137 mg); IR (neat, cm-1): 2962, 2328, 1761, 1452, 1219; H NMR
(400 MHz, CDCl3):
ꢀ
= 5.97-5.95 (m, 2H), 5.39-5.37 (m, 2H), 3.43-3.40 (m, 2H), 2.91 (d, J =
19

ACCEPTED MANUSCRIPT
1.6 Hz, 2H), 2.53-2.50 (m, 2H), 1.68-1.60 (m, 8H) ppm; 13C NMR (100.6 MHz, CDCl3): ꢀ
210.3, 124.8, 120.0, 63.1, 54.5, 52.05, 52.01, 50.2, 32.5, 28.2, 25.7, 25.6.
General procedure for synthesis of di-alkyl cage diones 37 and 38 via reduction:
To a stirred solution of di-allyl cage diones 12 and 13 (0.48-0.71 mmol) in dry ethyl acetate (10
mL) and 10% Pd/C was added. Afterwards, the resulting reaction mixture was stirred at room
temperature for 3-5 h under hydrogen atmosphere (1 atm). After conclusion of the reaction by
TLC monitoring, the reaction mixture was filtered through Celite pad and washed with ethyl
acetate. The combined washings and filtrate were evaporated under vacuo and the resulting crude
residue was purified by silica gel column chromatography using 12-15% ethyl acetate in
petroleum ether as an eluent to furnish the di-alkyl cage diones 37 and 38 as white solids.
Di-alkyl cage dione 37: white solid; m.p. 99-101 ºC; obtained from di-allyl cage dione 12 (200
mg, 0.71 mmol); Yield: 92% (187 mg); IR (neat, cm-1) 3166, 2949, 1742, 1723, 1523, 1437,
1351, 1258, 1154; 1H NMR (400 MHz, CDCl3): ꢀ 3.06 (s, 2H), 2.90 (d, J = 1.5 Hz, 2H), 2.12 (d,
J = 1.4 Hz, 2H), 1.69-1.60 (m, 2H), 1.49-1.41 (m, 2H), 1.15-1.07 (m, 4H), 0.87 (t, J = 7.3 Hz,
6H), 0.68-0.64 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3): ꢀ 214.1, 56.3, 56.2, 49.5, 42.0, 38.1,
27.8, 17.1, 14.8, 5.5, 4.1; HRMS (ESI) m/z calcd for C19H24NaO2 [M + Na]+ 307.1669; found:
307.1664.
Di-alkyl cage dione 38: white solid; m.p. 81-83 ºC; obtained from di-allyl cage dione 13 (150
mg, 0.48 mmol); Yield: 91% (138 mg); IR (neat, cm-1) 3179, 2949, 2957, 2803, 2378, 1747,
1
1525, 1217,1131, 981, 768, 675; H NMR (400 MHz, CDCl3): ꢀ 2.97 (s, 2H), 2.82 (d, J = 1.4
Hz, 2H), 2.35-2.34 (m, 2H), 1.67-1.61 (m, 6H), 1.57-1.56 (m, 4H), 1.45-1.39 (m, 2H), 1.16-1.06
(m, 4H), 0.87 (t, J = 7.3 Hz, 6H) ppm;13C NMR (125 MHz, CDCl3): ꢀ 214.1, 65.7, 55.6, 55.4,
51.5, 41.8, 32.4, 28.7, 27.8, 25.7, 25.6, 17.0, 14.8; HRMS (ESI) m/z calcd for C21H28NaO2 [M +
Na]+ 335.1982; found: 335.1983.
General procedure for synthesis of di-alkyl cage diols 39 and 40 via reduction:
A solution of di-alkyl cage diones 37 and 38 (0.40-0.52 mmol) in dry methanol (10 mL), NaBH4
°
(1.60-2.08 mmol) was added at 0 C in small portions over a period of 10 min. Afterwards, the
reaction mixture was stirred for another 20 min at the room temperature. After completion of the
reaction (the progress of the reaction monitored by TLC), methanol was removed under vacuo
20

ACCEPTED MANUSCRIPT
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 crude products were obtained after evaporation of
solvent followed by purified by column chromatography on silica gel using 20-25% EtOAc in
petroleum ether as an eluent to deliver the cage diols 39 and 40 as a colourless solids.
Di-alkyl cage diol 39: white solid; m.p. 140-142 ºC; obtained from di-alkyl cage dione 37 (150
mg, 0.52 mmol); Yield: 80% (123 mg); IR (neat, cm-1) 3181, 2955, 1466, 1228, 1113, 1090,
1
1058, 993, 962, 806; H NMR (400 MHz, CDCl3): ꢀ 5.20 (s, 2H), 3.64 (s, 2H), 2.59 (s, 2H),
2.33 (s, 2H), 1.70-1.53 (m, 6H), 1.33-1.24 (m, 2H), 1.22-1.16 (m, 2H), 0.93 (t, J = 7.3 Hz, 6H),
13
0.51-0.48 (m, 2H), 0.29-0.26 (m, 2H) ppm; C NMR (125 MHz, CDCl3): ꢀ 72.8, 49.4, 48.2,
46.4, 43.4, 31.6, 31.5, 17.2, 15.1, 5.1, 4.4; HRMS (ESI) m/z calcd for C19H28NaO2 [M + Na]+
311.1982; found: 311.1985.
Di-alkyl cage diol 40: white solid; m.p. 137-139 ºC
;
obtained from di-alkyl cage dione 38 (125
1
mg, 0.40 mmol); Yield: 88% (112 mg); IR (neat, cm-1) 3369, 3186, 2951, 1496, 1269, 1017; H
NMR (500 MHz, CDCl3): ꢀ 5.37 (s, 2H), 3.63 (s, 2H), 2.50 (s, 2H), 2.23 (s, 2H), 1.76 (s, 2H),
1.68-1.62 (m, 2H), 1.59-1.52 (m, 6H), 1.49 (t, J = 6.9 Hz, 2H), 1.31-1.24 (m, 3H), 1.17 (t, J = 7.3
13
Hz, 3H), 0.92 (t, J = 7.3 Hz, 6H); C NMR (125 MHz, CDCl3): ꢀ 72.9, 57.6, 50.3, 48.7, 45.7,
43.3, 32.3, 31.6, 29.8, 25.8, 25.6, 17.1, 15.1; HRMS (ESI) m/z calcd for C21H32NaO2 [M + Na]+
339.2295; found: 339.2297.
Notes
The authors declare no competing financial interests.
Acknowledgements
We thank the Defence Research and Development Organisation (DRDO, NO.
ARDB/01/1041849/M/1), New Delhi, for financial assistance. The authors also thank Mr.
Darshan S. Mhatre for their help in collecting the X-ray data 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 we gratefully acknowledge Praj industries for Pramod
Chaudhari Chair Professorship (Green Chemistry). S. R. C. thanks University Grants
Commission (UGC), New Delhi for the award of a research fellowship.
21

ACCEPTED MANUSCRIPT
Appendix A. Supplementary data
The supporting information is available free of charge on the journal website. Characterization
1
13
data of H, C, 13C-APT, DEPT-135 NMR spectra of all new products (PDF) and X-Ray data
(ORTEP diagrams) are available in supplementary information (SI) file.
References
1. (a) Levandovsky, I. A.; Sharapa, D. I.; Cherenkova, O. A.; Gaidai, A. V.; Shubina, T. E.
Russ. Chem. Rev. 2010, 79, 1005; (b) Marchand, A. P. Chem. Rev. 1989, 89, 1011; (c)
Hopf, H. Classics in Hydrocarbon Chemistry; Wiley-VCH: Weinheim, 2000; (d)
Sharapa, D. I.; Levandovskiy, I. A.; Shubina, T. E. Curr. Org. Chem. 2012, 16, 2632; (e)
Underwood, R. G.; Ramamoorthy, B. Tetrahedron Lett. 1970, 11, 4125; (f) Kent, G. J.;
Godleski, S. A.; Osawa, E.; Schleyer, P. von R. J. Org. Chem. 1977, 42, 3852; (g)
Banister, S. D.; Moussa, I. A.; Beinat, C.; Reynolds, A. J.; Schiavini, P.; Jorgensen, W.
T.; Kassiou, M. Bioorg. Med. Chem. Lett. 2011, 21, 38.
2. (a) Bisetty, K.; Govender, T.; Kruger, H. G. Biopolymers, 2006, 81, 339; (b) Oliver, D.
W.; Dekker, T. G.; Snyckers, F. O. Eur. J. Med. Chem. 1991, 26, 375; (c) James, B.; Viji,
S.; Mathew, S.; Nair, M. S.; Lakshmanan, D.; Ajay Kumar, R. Tetrahedron Lett. 2007,
48, 6204; (d) van Dijk, A.; Johnston, C.; Allbutt, H.; Kassiou, M.; Henderson, J. Behav.
Brain Res. 2008, 190, 14; (e) Albericio, F.; Arvidson, P. I.; Bisetty, K.; Giralt, E.;
Govender, T.; Jali, S.; Kongsaeree, P.; Kruger, H. G.; Prabpai, S. Chem. Biol. Drug Des.
2008, 71, 125; (f) Liu, X.; Nuwayhid, S.; Christie, M. J.; Kassiou, M.; Werling, L. L.
Eur. J. Pharmacol. 2001, 422, 39.
3. (a) Helmchen, G.; Staiger, G. Angew. Chem. Int. Ed. 1977, 16, 116; (b) Gaidai, A. V.;
Volochnyuk, D. M.; Shishkin, O. V.; Fokin, A. A.; Levandovskiy, I. A.; Shubina, T. E.
Synthesis 2012, 44, 810; (c) Nakazaki, M.; Naemura, K.; Sugano, Y.; Kataoka, Y. J. Org.
Chem. 1980, 45, 3232; (d) Naemura, K.; Fujii, T.; Chikamatsu, H. Chem. Lett. 1986, 923;
(e) Eaton, P. E.; Leipzig, B. J. Org. Chem. 1978, 43, 2483; (f) Nakazaki, M.; Naemura,
K. J. Org. Chem. 1981, 46, 106.
4. (a) Sklyarova, A. S.; Rodionov, V. N.; Parsons, C. G.; Quack, G.; Schreiner, P. R.;
Fokin, A. A. Med. Chem. Res. 2013, 22, 360; (b) Oliver, D. W.; Malan, S. F. Med. Chem.
Res. 2008, 17, 137; (b) Van der Schyf, C. J.; Geldenhuys, W. J. Neurotherapeutics 2009,
22

ACCEPTED MANUSCRIPT
6, 175; (c) Banister, S. D.; Manoli, M.; Barron, M. L.; Werry, E. L.; Kassiou, M. Bioorg.
Med. Chem. 2013, 21, 6038; (d) Onajole, O. K.; Coovadia, Y.; Kruger, H. G.; Maguire,
G. E. M.; Pillay, M.; Govender, T. Eur. J. Med. Chem. 2012, 54, 1; (e) Wilkinson, S. M.;
Gunosewoyo, H.; Barron, M. L.; Boucher, A.; McDonnell, M.; Turner, P.; Morrison, D.
E.; Bennett, M. R.; McGregor, I. S.; Rendina, L. M.; Kassiou, M. ACS Chem. Neurosci.
2014, 5, 335; (f) Oliver, D. W.; Dekker, T. G.; Snyckers, F. O. Drug. Res. 1991, 41, 549
5. Geldenhuys, W. J.; Malan, S. F.; Bloomquist, J. R.; Marchand, A. P.; Van Der Schyf, C.
J. Med. Res. Rev. 2005, 25, 21.
6. Oliver, D. W.; Dekker, T. G.; Snyckers, F. O.; Fourie, T. G. J. Med. Chem., 1991, 34,
851.
7. (a) Mehta, G.; Rao, K. S.; Bhadbhade, M. M.; Venkatesan, K. J. Chem. Soc., Chem.
Commun., 1981, 755; (b) Mehta, G.; Rao, K. S. J. Org. Chem. 1985, 50, 5537; (c)
Marchand, A. P.; Chong, H. S.; Shukla, R.; Sharma, G. V. M.; Kumar, K. A.; Zope, U.
R.; Bott. S. G. Tetrahedron 1996, 52, 13531; (d) Mehta, G.; Singh, V. K.; Srikrishna, A.;
Cameron, T. S.; Chan, C. Tetrahedron Lett. 1979, 4595; (e) Yamamoto, H. Lewis Acids
in Organic Synthesis; Wiley–VCH: Weinheim, 2000.
8. (a) James, B.; Rath, N. P.; Suresh, E.; Nair, M. S. Tetrahedron Lett. 2006, 47, 5775; (b)
Nair, M. S.; Sudhir, U.; Joly, S.; Rath, N. P. Tetrahedron 1999, 55,7653; (c)Mehta, G.;
Rao, H. S. P.; Reddy, K. R. J. Chem. Soc., Chem. Commun. 1987, 78; (d) Tolstikov, G.
A.; Lerman, B. M.; Galin, F. Z.; Struchkov, Yu. T.; Andrianov, V. G. Tetrahedron Lett.
1978, 4145; (e) Dekker, T. G.; Oliver, D. W.; Venter, A. Tetrahedron Lett. 1980, 21,
3101; (f) Mehta, G.; Singh, V. K.; Srikrishna, A.; Rao, K. S. Tetrahedron Lett. 1980, 21,
1369; (g) Godleski, S. A.; Schleyer, P. v. R.; Osawa, E.; Kent, G. J. J. Chem. Soc., Chem.
Commun., 1974, 976; (h) Marchand, A. P.; Chou, T.-C.; Ekstrand, J. D.; Van der Helm,
D. J. Org. Chem. 1976, 41, 1438; (i) Mehta, G.; Reddy, D. S.; Reddy, A. V. Tetrahedron
Lett. 1984, 25, 2275; (c) Pecchioli, T.; Christmann, M. Org. Lett. 2018, 20, 5256; (d)
Dilmaç, A. M.; Spuling, E.; de Meijere, A.; Bräse, S. Angew. Chem. Int. Edit. 2017, 56,
5684; (e) Schneider, L. M.; Schmiedel, V. M.; Pecchioli, T.; Lentz, D.; Merten, T.;
Christmann, M. Org. Lett. 2017 19, 2310.
9. (a) Mehta, G.; Srikrishna, A. J. Chem. Soc., Chem. Commun., 1982, 218; (b) Smith, E.
C.; Barborak, J. C. J. Org. Chem. 1976, 41, 1433; (b) Rojas, C. M. Molecular
23

ACCEPTED MANUSCRIPT
Rearrangements in Organic Synthesis; Wiley: New York, 2016; (c) Lerman, B. M. Russ.
Chem. Rev. 1991, 60, 358; (d) Zhyhadlo, Y. Y.; Gaidai, A. V.; Sharapa, D. I.; Mitlenko,
A. G.; Shishkin, O. V.; Shishkina, S. V.; Levandovskiy, I. A.; Fokin, A. A. J. Chem. Res.
2017, 41, 718; (d) Sharapa, D. I.; Gayday, A. V.; Mitlenko, A. G.; Levandovskiy, I. A.;
Shubina, T. E. Eur. J. Org. Chem. 2011, 13, 2554; (e) Eaton, P. E.; Hudson, R. A.;
Giordano, C. J. Chem. Soc., Chem. Commun., 1974, 978; (f) Marchand, A. P.; Kumar, V.
S.; Hariprakasha, H. K. J. Org. Chem. 2001, 66, 2072; (g) Blum, J.; Zlotogorski, C.;
Zoran, A. Tetrahedron Lett. 1975, 16, 1117.
10. (a) Fessner, W. D.; Prinzbach, H. Tetrahedron 1986, 42, 1797; (b) Mehta, G.; Srikrishna,
A.; , K. S.; Reddy, K. R.; Acharya, K. A.; Puranik, V. G.; Tavale, S. S.; Guru Row, T. N.
J. Org. Chem. 1987, 52, 457; (c) Kozhushkov, S. I.; Preuß, T.; Yufit, D. S.; Howard, J. A.
K.; Meindl, K.; Rühl, S.; Yamamoto, C.; Okamoto, Y.; Schreiner, P. R.; Rinderspacher,
B. C.; de Meijere, A. Eur. J. Org. Chem. 2006, 2590; (d) Kotha, S.; Cheekatla, S. R. J.
Org. Chem. 2018, 83, 6315; (e) Tolstikov, G. A.; Lerman, B. M.; Galin, F. Z. Russ. J.
Org. Chem. 1977, 12, 1133.
11. Kotha, S.; Cheekatla, S. R.; Mandal, B. Eur. J. Org. Chem. 2017, 4277.
12. (a) Kotha, S.; Cheekatla, S. R.; Mhatre, D. S. Synthesis 2017, 49, 5339; (b) Kotha, S.;
Dipak, M. K.; Chem. Eur. J. 2006, 12, 4446; (c) Kotha, S.; Cheekatla, S. R. ChemSelect
2017, 2, 6877; (d) Kotha, S.; Seema, V.; Singh, K.; Deodhar, K. D. Tetrahedron Lett.
2010, 51, 2301.
13. (a) Fieser, L. F.; Campbell, W. P.; Fry, E. M. J. Am. Chem. Soc. 1939, 61, 2206; (b)
Amor, F.; Royo, P.; Spaniol, T. P.; Okuda, J. J. Organomet. Chem. 2000, 604, 126; (c)
Green, M.; L. H.; O´Hare, D. J. Chem. Soc., Dalton Trans. 1985, 1585.
14. (a) Kotha, S.; Dipak, M. K. Tetrahedron 2012, 68, 397; (b) Kotha, S.; Manivannan, E.;
Sreenivasachary, N.; Ganesh, T.; Deb, A. C. Synlett 1999, 1618; (c) Grubbs, R. H.;
Wenzel, A. G. Handbook of Metathesis, Wiley-VCH: Weinheim, 2015; (d) Nicolaou, K.
C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490; (e) Prunet, J. Angew.
Chem. Int. Ed. 2003, 42, 2826; (d) Kotha, S.; Lahiri, K. Synlett 2007, 2767; (e) Kotha, S.;
Mandal, K. Chem. Asian J. 2009, 4, 354; (f) Fürstner, A.; Grela, K.; Mathes, C.;
Lehmann, C. W. J. Am. Chem. Soc. 2000, 122, 11799; (g) Grubbs, R. H.; Miller, S. J.;
Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
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ACCEPTED MANUSCRIPT
15. (a) Kotha, S.; Cheekatla, S. R.; Gunta, R. IUCrData 2018, 3, x180090; (b) CCDC-
1586760 (for 28) 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 product 28, please see the
supporting information file.
16. Singh, V. K.; Raju, B. N. S.; Deota, P. T. Synth. Commun. 1987, 17, 1103.
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Synthesis of Functionalized Cage Propellanes and D3-Trishomocubanes via
the Ring-Closing Metathesis and Acid-Promoted Rearrangement
Highlights
1. Functionalized cage propellanes and D3-trishomocubanes have been reported by
Claisen rearrangement, Diels–Alder reaction (DA), ring-closing metathesis (RCM)
and acid-promoted rearrangement.
2. The strategies described here, opens up new opportunities to design intricate cage
systems via RCM and rearrangement approach.
3. Solvent incorporation as well as ring rearrangement was observed in cage
[4.4.2]propellane framework during the acid promoted rearrangement.
4. Functionalized cage hydroxy derivatives as well as alkylated cage diones have been
assembled by reduction.