Molecular Acrobatics in Polycyclic Frames: Synthesis of Functionalized D3-Trishomocubanes via the Rearrangement Approach

Article abstract of DOI:10.1021/acs.joc.8b00449

A new synthetic route to D₃-trishomocubanone and oxa- D₃-trishomocubane derivatives has been established by the rearrangement approach. A remotely located methyl substituent in the six-membered ring contributed to the acid-catalyzed rearrangement of the cage dione in an unusual fashion. This rearrangement approach provided an attractive route to extended D₃-trishomocubanes, which are not accessible by the conventional multistep synthetic sequence. For the first time, two phenyl groups were incorporated from the solvent into the strained trishomocubane skeleton in an unprecedented manner via carbocation-mediated rearrangement with the aid of BF₃·OEt₂. Interestingly, an oxa-bridged trishomocubane skeleton was also formed during acid-promoted rearrangement.

Full text of DOI:10.1021/acs.joc.8b00449

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Article
Molecular acrobatics in polycyclic frames: Synthesis of
functionalized D3-trishomocubanes via rearrangement approach
Sambasivarao Kotha, and Subba Rao Cheekatla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00449 • Publication Date (Web): 17 May 2018
Downloaded from http://pubs.acs.org on May 17, 2018
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Molecular acrobatics in polycyclic frames: Synthesis of functionalized D -
3
trishomocubanes via rearrangement approach
*
Sambasivarao Kotha , Subba Rao Cheekatla
Department of Chemistry, Indian Institute of Technology-Bombay, Powai, India
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Fax: 022-25727152; Phone: +91(22)-2572 7160, E-mail: srk@chem.iitb.ac.in
Abstract
A new synthetic route to D
3
-trishomocubanone and oxa- D -trishomocubane derivatives has been
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established by rearrangement approach. Remotely located methyl substituent in the six membered
ring contributed to the acid catalyzed rearrangement of cage dione in an unusual fashion. This
rearrangement approach provided an attractive route to extended D -trishomocubanes which are
3
not accessible by conventional multi-step synthetic sequence. For the first time, two phenyl groups
were incorporated from the solvent in strained trishomocubane skeleton in an unprecedented
manner via carbocation-mediated rearrangement with the aid of BF
3
.OEt
. Interestingly, oxa-
2
bridged trishomocubane skeleton was also formed during acid-promoted rearrangement.
Introduction
D -Trishomocubane 1 (C11H14) is known to be a stable hydrocarbon with a planar chiral cage
3
structure with a high degree of symmetry.1-2 Its enhanced lipophilicity, propeller chirality
combined with extended cage size (5.5 Å) and a rigid architecture makes it a worthwhile scaffold
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for further investigation. Several trishomocubane derivatives show improved pharmacokinetic
properties as drugs and they are also useful substrates for organocatalysis.3-5
Functionalized trishomocubane 6,7 has attracted the attention of synthetic chemists because of their
significant biological activities. For example, amino substituted trishomocubane derivatives show
prominent pharmacological properties against tuberculosis, neurodegenerative, and anti-viral
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diseases. 6,7 Moreover, amino derivatives, such as trishomocubyl 1-4-amine 2 acts as NMDA
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receptor antagonist, trishomocubyl derivative 3 shows potent anti-TB activity, D
3
-trishomocubyl
benzamide 4 10 acts as P2X7 receptor antagonist, and substituted trishomocubylamine 5 11 exhibits
anti-Parkinson activity (Figure 1).
Several methodologies have been developed to design D
3
-trishomocubane and its derivatives
1
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based on rearrangement strategies. Recently, Sharapa et al. reported chloro-D -trishomocubane
3
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derivatives via Diels–Alder (DA) reaction followed by chlorosulfation of Cookson’s dione. In
view of our continued interest in cage polycyclic systems,14 we developed a new synthetic
approach to D
3
-trishomocubane derivatives via Lewis acid-catalyzed rearrangement starting with
cage [4.3.2]propellane system.14d Additionally, we also described a unique method to oxa-cage
1
5
propellanes via ring-closing metathesis (RCM) strategy. Now, we report a new synthetic strategy
to functionalized trishomocubanes and oxa-trishomocubane by acid-promoted rearrangement. We
have included selected examples of recently reported oxa-cage frameworks 6-10 (Figure 2).16
In view of the ring strain and rigid architecture, cage moiety containing 1,4-dicarbonyl system is
a suitable substrate for ring-rearrangement, ring-fragmentation and ring-opening approaches by
acid, or metal catalysts. 17 Most of the acid-catalyzed rearrangements in polycyclic cage systems
are generally driven by a concomitant release of strain via formation of a stable carbocation
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intermediate which play a prominent role in assembling unusual cage frameworks in an
unprecedented manner.
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In view of our recent report on the rearrangement of the [4.3.2]propellane derivative 15 under
Lewis acid conditions, 14d now, we studied the rearrangement of the unsaturated cage
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[
4.4.2]propellane 17 containing methyl substituent in cyclohexene ring to generate the D -
3
trishomocubane derivative 18 involving a carbocation rearrangement.
Results and Discussion
Previously (Scheme 1, eq i), 18 the Lewis acid promoted rearrangement of the compound 11 was
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studied with BF .
OEt
in benzene to deliver compounds 12, 13 and 14. Recently, we also reported
14
3
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(Scheme 1, eq ii) a carbocation-mediated rearrangement of the cage [4.3.2]propellanedione 15
using BF in benzene under reflux conditions to produce the ketone 16 in a moderate to good
.OEt
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yield. Now, we disclose an interesting and unusual ring rearrangement approach to the
trishomocubane derivatives starting with a substituted cage dione 17 (Scheme 1, eq iii) with the
aid of Lewis acid such as BF .
OEt . Here, the methyl substituent located in one of the unsaturated
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cyclohexane ring in cage dione 17 play a critical role in the carbocation formation and
incorporation of two phenyl groups by the ring rearrangement process is unexpected with the aid
of Lewis acid.
Our retrosynthetic analysis to hexacyclic dione 17 is shown in Scheme 2. In this regard, the
synthesis of the cage dione 17 may be accomplished from dihydronaphthalene-1,4-dione 19 upon
Diels–Alder reaction (DA) followed by a [2+2] photocycloaddition of the cycloadduct. The DA
precursor 19 may be assembled from the tetrahydronaphthalene-1,4-dione 20 via aromatization
followed by oxidation. Finally, the required cycloadduct 20 could readily be prepared starting with
commercially available hydroquinone 21 in two steps involving a [4+2] cycloaddition and
oxidation sequence.
To realize the strategy shown in Scheme 2, our journey towards the synthesis of the hexacyclic
dione 17 was commenced with the preparation of the DA precursor such as the
dihydronaphthalene-1,4-dione 19 from inexpensive and commercially available hydroquinone
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119 (Scheme 3). In this context, [4+2] cycloaddition of 1,4-benzoquinone 22 prepared from the
hydroquinone 21 was treated with 2-methyl 1,3-butadiene 23 (isoprene) under reflux conditions in
anhydrous benzene to deliver the cycloadduct 20 in good yield (67%). Aromatization of the DA
adduct 20 in the presence of dil. HCl at room temperature furnished the 1,4-naphthalenediol 24 in
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9% yield. Alternatively, the diol 24 was also prepared from the enone 20 in 85% yield by
aromatization in the presence of NaOAc and AcOH under reflux conditions.19 Subsequently,
oxidation of the hydroquinone 24 in the presence of MnO delivered the quinone 19 in 72%
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isolated yield after column chromatography (Scheme 3).19
Having prepared the DA precursor 19, our attention was directed to assemble the cage dione 17
2
0
21
using [4+2] cycloaddition and intramolecular [2+2] photocycloaddition as key steps. To this
end, [4+2] cycloaddition of the quinone derivative 19 was accomplished by reacting with a freshly
cracked 1,3-cyclopentadiene 25 at 0 °C to furnish the desired cycloadduct 26 in 77% yield. The
1
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structure of the DA adduct 26 was established on the basis of H NMR, C NMR spectroscopic
evidence and further supported by the HRMS data. The stereochemistry of the cycloadduct 26 was
found to be endo and it was confirmed later by an intramolecular [2+2] photocycloaddition
reaction. The DA adduct 26 underwent intramolecular [2+2] photocycloaddition by irradiation
with UV light (125 W-homemade) gave the hexacyclic cage dione 17 in 90% yield (Scheme 3).
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The structure of the cage dione 17 was established on the basis of H NMR, C NMR, APT, and
further supported by HRMS data.
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Having the cage dione 17 in hand, we next attempted the synthesis of cage diol 27 as well as
saturated hexacyclic dione 28 by reduction. In this regard, the cage dione 17 was treated with
NaBH
of the cage dione 17 in the presence of 10% Pd/C in dry ethyl acetate delivered the saturated dione
8 in 85% yield (Scheme 4). Structures of the cage diol 27 and hexacyclic dione 28 were confirmed
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in methanol to produce the cage diol 27 in 81% yield. Along similar lines, hydrogenation
2
1
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by spectroscopic and analytical data ( H NMR, C NMR, APT and HRMS).
In view of our interest to design new polycyclic systems via rearrangement approach, the cage
dione 17 was treated with BF .
OEt in anhydrous benzene under reflux conditions. We found that
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the rearranged cage ketone 18 (trishomocubanone) was produced in moderate yield (Scheme 5).
The solvent incorporated product 18 was derived by an extensive reorganization of carbon skeleton
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of the strained [4.4.2]propellane framework 17 through the generation of carbocation
intermediates. The carbocation intermediate generated in the sequence incorporate the two phenyl
groups from the solvent (benzene). Initially, the structure of the rearranged ketone 18 (D -
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trishomocubanone) was indicated by the spectral data and later it was confirmed by its single-
crystal X-ray diffraction data (see the Supporting Information).22
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To create diverse frameworks by rearrangement approach, our efforts are also diverted towards
the synthesis of D -trishomocubane derivatives via a reductive C-C bond cleavage reaction. In this
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regard, the 1, 4-dicarbonyl system adjacent to the cyclobutane ring present in the cage dione 17
has a tendency to undergo rearrangement in the presence of metal/ acid media to release the ring
strain. Therefore, the reductive cleavage of C-C bond present in cage dione 17 was carried out
using activated zinc powder in glacial acetic acid at room temperature. After overnight stirring the
rearranged hydroxyketone 29 was formed in 88% yield (Scheme 5). The structure of the
1
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hydroxyketone 29 was established on the basis of H NMR and C NMR, APT, DEPT-135 and
HRMS data. Based on the spectroscopic data of the compound 29, it appears that, it is an
inseparable mixture of two compounds such as 29 and 34 (Schemes 5 & 7).
Later on, the hydroxyketone 29 was treated with 1:1 Conc.H
2
SO
4
+ Conc.HNO mixture to
3
produce the nitrito derivative 32. Unfortunately, the desired nitrito derivative 32 was not formed.
Interestingly, unexpected oxa-derivative 30 was obtained instead of the nitrito derivative 32 in
poor yield. Then the yield of oxa-cage compound 30 was improved (69%) by treatment with HNO
3
in anhydrous CH Cl . To the best of our knowledge, this is the first observation where oxa-bridged
2
2
cage frame work 30 was assembled by nitric acid (HNO
3
) treatment. The structure of the oxa-cage
1
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compound 30 was conformed on the basis of H NMR, C NMR, APT, and HRMS data. DEPT
1
8
35 NMR spectrum of cage ether 30 indicates the disappearance of two distinctive signals at δ =
9.9 and 96.3 which are quaternary carbons and both of them are connected to an oxygen atom
(ether linkage). This data indicates that the two carbons are joined through a bridgehead oxygen
atom. Further, we unambiguously confirmed the structure of the oxa derivative 30 by a single-
2
2
crystal X-ray diffraction studies (see the Supporting Information). Next, the hydroxyketone 29
was converted to the corresponding cage diol 31 in 87% yield by treatment with NaBH
4
in
methanol at 0 °C to rt (Scheme 5).
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Based on the earlier Lewis acid catalyzed rearrangements with BF
.OEt2,14d,18 the proposed
3
mechanism for the transformation of cage dione 17 to the rearranged ketone 18 is shown in Scheme
. Initially, coordination of the Lewis acid to the ketone of cage dione 17 would generate
6
carbocation intermediate 17A via the migration of cyclobutane bond adjacent to the carbonyl
carbon. The carbocation 17A is captured by solvent (benzene) and subsequent aromatization
affords the intermediate 17B. Later, elimination of AOH followed by involvement of the olefin
from methyl group in 17B in the presence of BF
3
.OEt gives another carbocation 17C. Intermediate
2
1
7C may cyclize in two different modes (path a & b) to form the carbocation 17D and 17F through
the migration of alternate C-C bonds as shown in Scheme 6. Intermediate 17D is a highly
resonance-stabilized benzylic carbocation, which follows the path a to generate the carbocation
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intermediate 17E and trapped with benzene to furnish the rearranged cage ketone 18. 17F is
expected to deliver the compound 33.
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Based on earlier studies, 17e and our experimental results, we have proposed a possible mechanism
for the formation of hydroxyketone 29 (Scheme 7). The reaction was initiated by activated Zn in
AcOH to form a diradical species 17X. Later, cleavage of strained cyclobutane ring generates the
dianion intermediate 17Y. In path a, the dianion 17Y involved in enolization (keto-enol
tautomerism) to produce the cage dione 34. In path b, the intermediate 17Y underwent enolization
gave 17Z followed by cyclization to afford the hydroxyketone (internal aldol product) 29.
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A proposed mechanism for the formation of cyclic ether 30 from compound 29 is illustrated in
Scheme 8. Initially, in the presence of nitric acid, a stable carbocation intermediate 29B is
generated. Further the intermediate 29B on cyclization gave the oxa-bicyclic cage system 30
through 29C.
Having established a new strategy to trishomocubanone 18, we next focused our attention to
prepare other D -trishomocubane derivatives such as 35 and 36. In this regard, compound 18 was
3
subjected to Wolff–Kishner reduction in the presence of hydrazine hydrate under basic condition
at 200 °C in diethylene glycol to produce the corresponding cage hydrocarbon 35 in 77% yield.
Finally, trishomocubanol 36 was obtained as a diastereomeric mixture in 82% yield from
trishomocubanone 18 by the treatment of NaBH
4
in methanol (Scheme 9). The structure of these
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two compounds 35 and 36 were established from H NMR and C NMR, APT, DEPT-135, and
further supported from HRMS data. The structure of the cage hydrocarbon (D
3
-trishomocubane)
3
5 has been firmely established from the DEPT-135 NMR spectrum, which clearly indicates the
presence of six -CH -groups in aliphatic region clearly indicate that the carbonyl group has been
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3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
reduced to methylene group.
Conclusions
In conclusion, we have successfully demonstrated a new synthetic strategy to functionalized D -
3
trishomocubane derivatives via carbocation-mediated rearrangement under acidic conditions such
as Zn/AcOH, fuming HNO OEt . For the first time, two phenyl groups were incorporated
and BF .
from the solvent in strained trishomocubanone system 18 in an unprecedented manner via Lewis
acid catalyzed rearrangement with the help of BF . Surprisingly, we also isolated oxa-
.OEt
3
3
2
3
2
trishomocubane derivative 30 through carbocation generation starting with cage dione 17.
Oxygenated trishomocubane system containing fused tetrahydropyran and tetrahydrofuran was
generated with the aid of fuming HNO . It looks like that, the ring-rearrangement of cage dione 17
3
to trishomocubane framework is driven by a concomitant release of strain due to involvement of
most stable carbocation intermediate through an acid-catalyzed rearrangement. In this strategy, we
reported six new substituted D -trishomocubane derivatives along with three cage compounds.
3
Further efforts to obtain interesting and unusual cage systems by rearrangement approach are
currently in progress.
EXPERMENTAL SECTION
General Experimental Details
All the required reagents, chemicals and solvents were purchased from the commercial suppliers
and used as without any further purification. Analytical TLC was performed on (10×5) glass plates
coated with Acme’s silica gel (GF-254) containing 13% calcium sulfate as a binder. All the
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 KMnO . Dry reactions were
4
performed in oven dried glassware under nitrogen atmosphere by using standard syringe-septum
techniques. Acme’s silica gel (100-200 mesh size) and neutral alumina was used for column
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2
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2
2
2
2
2
2
2
3
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3
4
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chromatography and solvents were concentrated under vacuo on rotary evaporator. Benzene and
DCM were distilled from P
2
O
5
or CaH
2
and ethyl acetate was dried by using K
2
CO .
3
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 DCM and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
13
chloroform and then evaporating the solvent. H NMR (400 and 500 MHz), C NMR, C-APT
NMR, DEPT 135 NMR (100 and 125 MHz) spectra were recorded on Bruker spectrometer and
samples were prepared in CDCl solvent. The chemical shifts are reported in parts per million
3
(ppm) on delta scale with TMS as an internal standard and values for the coupling constants (J)
1
are given in Hz. The standard abbreviations for H 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. All reported yields are isolated yields of
the products after column purification. X-ray data were recorded on diffractometer equipped with
graphite monochromated Mo Kα radiation and structure was solved by direct methods shelxl-97
2
and refined by full-matrix least-squares against F using shelxl-97 software.
-Methyl-4a,5,8,8a-tetrahydronaphthalene-1,4-dione (20)19
6
To a solution of 1,4-benzoquinone 22 (2g, 18.5 mmol) in anhydrous benzene (20 mL) was added
2-methyl-1,3-butadiene 23 (2.8 mL, 28 mmol) at room temperature. Later on, the resulting reaction
°
mixture was stirred at 50 C until all the starting material was consumed. After the reaction was
completed (2.5 h, TLC analysis), the solvent was evaporated under vacuo and the crude residue
was crystallized from petroleum ether and ethyl acetate (4:1) to afford the adduct 20 as a pure
yellow crystalline solid.
°
19
°
-1
Yield: 67% (2.2 g); mp 73-75 C; (lit. reported mp. 78-83 C), IR (neat, cm ) 2932,2352, 1686,
1
1659, 1451, 1307, 1268, 1090, 942, 883, 854; H NMR (500 MHz, CDCl
3
): = 6.62 (d, J = 5.1
Hz, 2H), 5.35 (d, J = 1.3 Hz, 1H), 3.22 (t, J = 5.27 Hz, 1H), 3.14 (t, J = 5.70 Hz, 1H), 2.42-2.34
1
3
(
m, 2H), 1.64 (s, 3H) ppm; C NMR (125 MHz, CDCl
3
): = 200.4, 200.0, 139.4, 136.6, 131.7,
1
18.4, 46.9, 46.2, 28.8, 24.7, 23.4 ppm.
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-Methyl-5,8-dihydronaphthalene-1,4-diol (24) 19
6
Method 1
To a stirred solution of compound 20 (1g, 5.7 mmol) in glacial acetic acid (10 mL), NaOAc (47
mg, 0.57 mmol) was added and the reaction mixture was heated at reflux for 1 h. After completion
of the reaction (monitored by TLC), the cooled reaction mixture was poured in water and extracted
with ethyl acetate. The combined organic layer was washed with water, brine solution and dried
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
over anhydrous Na
2
SO . Solvent was evaporated under reduced pressure and the resulting brown
4
colour residue was purified by column chromatography (silica gel, petroleum ether/EtOAc, 3:1)
to give aromatized hydroquinone 24 as a white colour solid. Yield: 85% (850 mg).
Method 2
To a stirred solution of compound 20 (1g, 5.7 mmol) in acetone was treated with dil. HCl (20 mL)
at room temperature for overnight. At the end of the reaction (monitored by TLC), the reaction
mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed
with brine solution, dried over anhydrous Na
obtained crude residue was purified by silica gel column chromatography (petroleum ether/EtOAc,
:1) to afford aromatized hydroquinone 24 as a white colour solid. Yield: 89% (890 mg).
2
SO and concentrated under reduced pressure. The
4
3
1
9
-1
Yield: 89% (2.2 g); mp 173-175 °C (lit. mp 177-178 °C), IR (neat, cm ): 3271, 2969,2325, 1485,
1
1
425, 1361, 1329, 1241, 1156, 1012, 807, 787; H NMR (500 MHz, DMSO-d6): = 8.50 (s, 1H),
8
.46 (s, 1H), 6.43 (s, 2H), 5.53 (s, 1H), 3.09 (br. s, 2H), 3.00 (d, J = 4.5 Hz, 2H), 1.75 (s, 3H) ppm;
13C NMR (125 MHz, DMSO-d6): = 146.8, 146.7, 130.2, 121.6, 121.2, 118.0, 115.5, 111.4, 29.1,
25.1, 23.1 ppm.
-Methyl-5, 8-dihydronaphthalene-1,4-dione (19) 19
6
To a stirred solution of hydroquinone 24 (500 mg, 2.83 mmol) in acetone (20 mL) manganese
dioxide (MnO ) was added in excess amount (8 equiv) at room temperature for overnight. After
completion of the reaction (monitored by TLC), the MnO in reaction mixture was filtered off
2
2
using Celite pad and filtrate was removed by vacuo to give the yellow colour solid 19. The crude
product 19 was purified by silica gel column chromatography (3% EtOAc/PE) to deliver the
quinone 19 as a yellow crystalline solid. Quinone 19 is sensitive to light and was immediately
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2
2
2
2
2
2
2
2
3
3
3
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5
5
5
5
5
5
5
5
6
subjected to next step [4+2] cycloaddition (Diels–Alder) reaction. Yield: 72% (355 mg): mp 133-
135 °C.
°
-1
Yield: 72% (355 mg); mp 133-135 C; IR (neat, cm ): 2891, 1647, 1634, 1444, 1418, 1296, 1115,
1
8
41, 782; H NMR (500 MHz, CDCl
3
): = 6.71 (s, 2H), 5.49 (t, J = 1.4 Hz, 1H), 3.06-3.04 (d, J
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
= 6.9 Hz, 2H), 2.95 (t, J = 7.98 Hz, 2H), 1.76 (s, 3H) ppm; C NMR (125 MHz, CDCl
87.2, 187.1, 139.7, 139.5, 136.4, 130.2, 116.9, 28.6, 25.1, 23.0 ppm.
3
):
=
1
Diels–Alder adduct (26)
To a stirred solution of Diels–Alder precursor (quinone) 19 (700 mg, 4.01 mmol) in anhydrous
dichloromethane (10 mL) was added freshly cracked cyclopentadiene 25 (0.5 mL, 6.0 mmol) in
dropwise manner at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the
reaction was complete (progress of the reaction monitored by TLC), the solvent was evaporated
under reduced pressure and the crude product was purified by silica gel column chromatography
(5% EtOAc/PE) to afford Diels–Adduct 26 as a pure yellow crystalline solid.
-1
Yield: 77% (750 mg); mp 103-105 °C; IR (neat, cm ) 2969, 1659, 1446, 1415, 1334, 1296, 1269,
1
7
05; H NMR (500 MHz, CDCl
3
): = 5.94 (s, 2H), 5.35 (d, J = 1.4 Hz, 1H), 3.46 (s, 2H), 3.16 (d,
J = 1.5 Hz, 2H), 2.85-2.98 (m, 2H), 2.72-2.84 (m, 2H),1.66 (s, 3H), 1.38, 1.46 (ABq, J = 8.7 Hz,
13
2H) ppm; C NMR (125 MHz, CDCl
3
): = 198.4, 198.3, 145.7, 145.5, 135.2, 129.9, 116.7, 48.95,
4
8.94, 48.93, 48.2, 48.1, 29.2, 25.7, 22.7 ppm; HRMS (ESI, Q-ToF): m/z calcd for C16 [M
H
16KO
2
+
+
K] 279.0782; found: 279.0781.
Hexacyclic Cage Propellanedione (17)
A solution of the Diels–Alder adduct 26 (500 mg, 2.08 mmol) in 250 mL of anhydrous EtOAc was
degassed with nitrogen and irradiated in Pyrex immersion well by using 125 W medium pressure
UV mercury-vapor lamp (homemade) for 1.5 h at room temperature. After completion of the
reaction (by TLC monitoring), the solvent was removed under vacuo and the crude product was
purified from column chromatography on silica gel using 5% EtOAc in petroleum ether as an
eluent to deliver cage dione 17 as a white crystalline solid.
-1
Yield: 90% (450 mg); mp 139-141 °C; IR (neat, cm ): 2959, 1747, 1730, 1440, 1295, 1227, 1098;
1H NMR (500 MHz, CDCl
): = 5.57-5.59 (m, 1H), 2.84 (t, J = 1.5 Hz, 2H), 2.71 (s, 2H), 2.60-
3
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2
.66 (m, 2H), 2.25-2.34 (m, 2H), 1.85, 2.00 (ABq, J = 11.0 Hz, 2H), 1.76 (s, 3H), 1.73 (s, 1H),
13
1.63 (d, J = 15.9 Hz, 1H) ppm; C NMR (125 MHz, CDCl ): = 213.3, 213.0, 133.9, 118.8, 54.9,
3
54.8, 52.3, 51.4, 43.5, 43.4, 42.88, 42.85, 41.1, 28.9, 24.4, 23.9 ppm; HRMS (ESI, Q-ToF): m/z
+
calcd for C16
H
17
O
2
[M + H] 241.1223; found: 241.1226.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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5
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5
5
6
0
1
2
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4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hexacyclic Cage Propellanediol (27)
To the stirred solution of cage dione 17 (50 mg, 0.20 mmol) in anhydrous methanol (5 mL), NaBH
4
°
(30 mg, 0.80 mmol) was added at 0 C in small portions over a period of 10 min. The resultant
reaction mixture was stirred for another 50 min at the room temperature. After completion of the
reaction (the progress of the reaction monitored by TLC, 1 h), 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 Na
2
SO and
4
concentrated under reduced pressure. The crude product obtained after evaporation of solvent was
purified from column chromatography on silica gel using 10% EtOAc in petroleum ether as an
eluent to deliver the cage diol 27 as a colourless liquid.
-1
1
Yield: 81% (41 mg); IR (neat, cm ): 3213, 2952, 2871, 2332, 2091, 1861, 1649, 1483, 1115; H
NMR (500 MHz, CDCl ): = 5.63 (d, J = 4.7 Hz, 1H), 5.03 (s, 2H), 3.46 (s, 2H), 2.23-2.38 (m,
H), 1.88-1.94 (m, 2H), 1.78 (s, 3H), 1.74 (d, J = 8.6 Hz, 1H), 1.63 (d, J = 15.4, 1H), 1.56 (d, J =
3
6
1
1
3
0.4 Hz, 1H), 1.01 (d, J = 10.2 Hz, 1H) ppm; C NMR (125 MHz, CDCl ): = 136.1, 120.8, 75.5,
3
75.3, 47.3, 46.4, 46.2, 46.1, 43.6, 43.5, 41.68, 41.63, 35.2, 34.9, 29.9, 24.7 ppm; HRMS (ESI, Q-
+
ToF): m/z calcd for C16
H20NaO
2
[M + Na] 267.1356; found: 267.1355.
Hexacyclic Cage Propellanedione (28) via catalytic hydrogenation
To a solution of cage dione 17 (50 mg, 0.20 mmol) in anhydrous EtOAc (5 mL) was added catalytic
amount of 10% Pd/C (9 mg). The dione was hydrogenated using hydrogen balloon at atmospheric
pressure at room temperature for 3-4 h. After completion of the reaction by TLC monitoring, the
reaction mixture was filtered off with the aid of Celite pad and filtrate was concentrated under
reduced pressure. The obtained crude residue was purified by column chromatography on silica
gel using 4% EtOAc in petroleum ether as an eluent to furnish the hydrogenated product 28 as a
colourless liquid.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
1
Yield: 85% (43 mg); IR (neat, cm ): 2952, 2335, 1740, 1456; H NMR (500 MHz, CDCl
3
): =
2
.83-2.89 (m, 2H), 2.72-2.78 (m, 4H), 2.11-2.16 (m, 1H), 1.89, 2.02 (ABq, J = 11.4 Hz, 2H), 1.67-
13
1.74 (m, 2H), 1.46 (td, J = 11.9, 1.6 Hz, 1H), 1.25-1.31 (m, 2H), 0.93 (d, J = 4.9 Hz, 4H) ppm; C
NMR (125 MHz, CDCl ): = 213.9, 213.5, 55.06, 55.01, 51.0, 48.6, 45.7, 43.5, 43.1, 41.3, 31.9,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[M + Na]+
2
8.6, 26.4, 25.1, 22.95, 22.92 ppm; HRMS (ESI, Q-ToF): m/z calcd for C18
91.1356; found: 291.1351.
H20NaO
2
2
BF
3
.OEt
2
-Catalyzed Rearrangement of Cage Propellanedione (17)
OEt ) in excess amount (5 mL) was added to a stirred solution of
Boron trifluoride etherate (BF .
3
2
cage dione 17 (300mg, 1.24 mmol) in anhydrous benzene (20 mL) under nitrogen atmosphere and
the reaction mixture was refluxed for 72 h. After conclusion of the reaction (progress of the
reaction monitored by TLC evident), the reaction mixture was cooled to room temperature.
Afterwards, it was quenched by the addition of saturated aqueous NaHCO
extracted with benzene. The combined organic layers were washed with water, brine solution and
dried with anhydrous Na SO . Evaporation of the solvent under reduced pressure followed by
3
solution, and was
2
4
silica gel column chromatography of the resultant crude residue using 3% ethyl acetate in
petroleum ether as an eluent furnished the desired rearranged caged molecule 18 (with two
phenyls) as a pure colourless crystalline solid.
-1
Yield: 53% (249 mg); mp 195-197 °C; IR (neat, cm ): 2938, 2315, 1762, 1468, 1274, 1032, 705;
1H NMR (500 MHz, CDCl
): = 7.32-7.36 (m, 4H), 7.27-7.31 (m, 4H), 7.19-7.22 (m, 1H), 7.14-
.18 (m, 1H), 2.61-2.62 (m, 1H), 2.53 (t, J = 5.5 Hz, 1H), 2.40-2.42 (m, 1H), 2.33 (dd, J = 12.8,
.0 Hz, 1H), 2.23-2.32 (m, 5H), 2.01-2.03 (m, 1H), 1.65-1.70 (m, 2H), 1.62 (dd, J = 10.3, 1.8 Hz,
3
7
3
2
13
H), 1.53 (dd, J = 13.1, 2.5 Hz, 1H), 1.47 (d, J = 10.7 Hz, 1H) ppm; C NMR (125 MHz, CDCl ):
3
= 216.8, 149.2, 148.2, 128.27, 127.1, 125.9, 125.69, 125.62, 62.0, 57.0, 54.2, 51.4, 50.4, 48.2,
4
8.0, 47.8, 44.7, 41.1, 37.7, 36.9, 33.2, 33.1, 20.5 ppm; HRMS (ESI, Q-ToF): m/z calcd for
+
C
28
H
27O [M + H] 379.2056; found: 379.2056.
Zn/AcOH reduction of cage propellanedione (17)
Mixture of hexacyclic cage propellanedione 17 (300 mg, 1.24 mmol) and activated zinc dust (300
mg, 4.55 mmol) in 5 ml glacial acetic acid was stirred at room temperature for 10 h. Insoluble zinc
metal and salts were removed by filtration. The resulting filtrate was concentrated, diluted with
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cold water and extracted with dichloromethane (DCM). The combined organic layers were washed
with aqueous NaHCO
3
solution, brine and dried over anhydrous Na
2
SO . The organic layer was
4
concentrated at reduced pressure to give the crude rearranged cage hydroxyketone. The resulting
crude residue was further purified by column chromatography on silica gel using 15% ethyl acetate
in petroleum ether as an eluent to afford the inseparable mixture of cage hydroxyketone 29 as a
colourless liquid.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
Yield: 88% (265 mg); IR (neat, cm ): 3413, 2976, 2966, 2332, 1752, 1442, 1308, 1288, 1246,
1
1
161, 858; H NMR (500 MHz, CDCl
3
): = 5.36 (dd, J = 16.4, 7.6 Hz, 1H), 2.56 (s, 1H), 2.27-
2.49 (m, 5H), 2.08-2.23 (m, 3H), 1.86-2.05 (m, 3H), 1.68 (s, 3H), 1.42, 1.54 (ABq, J = 10.6, 2H)
1
3
ppm; C NMR (125 MHz, CDCl
3
): = 217.9, 217.8, 137.2, 136.9, 122.9, 122.1, 84.5, 84.4, 55.3,
5
3
2
4.7, 51.36, 51.30, 49.7, 48.54, 48.50, 48.39, 48.32, 47.31, 47.2, 45.0, 40.5, 40.4, 37.07, 37.05,
1.0, 27.6, 27.1, 27.0, 25.1, 21.5 ppm; HRMS (ESI, Q-ToF): m/z calcd for C16
65.1199; found: 265.1196.
H
18NaO
[M + Na]+
2
Synthesis of Oxa Cage Compound (30)
To a stirred solution of cage hydroxyketone 29 (100 mg, 0.41 mmol) in dichloromethane (10 mL)
was added a solution of 98% fuming HNO (0.2 mL) in dropwise manner over a period of 5 min
3
under ice bath temperature. Then, the resulting reaction mixture was allowed to room temperature
and further stirred for 4 h. After reaction was complete (4 h, TLC), the reaction mixture was diluted
with water and extracted with dichloromethane (DCM). The organic layer was washed with water,
brine solution and dried with anhydrous Na
2
SO . Evaporation of the solvent under vacuo followed
4
by column chromatography of the crude mixture on silica gel using 5-7% EtOAc in petroleum
ether as an eluent afforded the oxa cage compound 30 as a pure colourless crystalline solid.
-1
1
Yield: 69% (69 mg): mp 102-104 °C; IR (neat, cm ): 2959, 1766, 1451, 1295; H NMR (500
MHz, CDCl ): = 2.68 (q, J = 5.9 Hz, 2H), 2.53-2.55 (m, 2H), 2.12-2.16 (m, 2H), 2.04 (d, J =
2.6, 1H), 1.80-1.88 (m, 2H), 1.62-1.69 (m, 2H), 1.46-1.60 (m, 3H), 1.38-1.44 (m, 1H), 1.32 (s,
3
1
3
4
13
H) ppm; C NMR (125 MHz, CDCl
3
): = 214.4, 96.3, 89.9, 61.7, 50.2, 47.4, 44.1, 43.6, 41.9,
1.1, 38.3, 35.4, 32.2, 25.7, 22.4 ppm; HRMS (ESI, Q-ToF): m/z calcd for C16
H18NaO
2
[M + Na]+
265.1199; found: 265.1193.
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NaBH Reduction of Cage Hydroxyketone (29)
4
A solution of cage hydroxyketone 29 (50 mg, 0.20 mmol) in anhydrous methanol (5 mL), NaBH
4
°
(
15 mg, 0.40 mmol) was added at 0 C in small portions over a period of 10 min. The resultant
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 and
the crude residue was quenched by the addition of water and was extracted with ethyl acetate. The
0
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combined organic layer was washed with brine solution, dried over anhydrous Na
2
SO and
4
concentrated under reduced pressure. The crude product obtained after evaporation of solvent was
purified from column chromatography on silica gel using 15% EtOAc in petroleum ether as an
eluent delivered the cage diol 31 as a white colour solid.
-
1
Yield: 87% (44 mg); mp 142-144 °C; IR (neat, cm ): 3359, 2938, 2966, 2833, 2515, 2040, 1454,
1
1
2
1
029, 680; H NMR (500 MHz, CDCl
3
): = 5.34-5.43 (m, 1H), 3.98 (s, 1H), 2.60 (s, 1H), 2.32-
.45 (m, 1H), 2.27-2.30 (m, 1H), 2.14-2.22 (m, 1H), 2.09-2.13 (m, 1H), 2.01-2.07 (m, 1H), 1.94-
1
3
.98 (m, 3H), 1.77 (s, 3H), 1.70-1.72 (m, 4H), 1.33 (q, J = 10.4, 2H) ppm; C NMR (125 MHz,
): = 137.7, 137.0, 123.2, 122.9, 87.2, 87.1, 78.6, 78.4, 58.6, 58.0, 51.38, 51.33, 49.79,
9.74, 48.2, 48.0, 47.3, 47.1, 46.76, 46.71, 44.68, 44.4, 44.3, 34.75, 34.71, 31.1, 30.1, 27.7, 27.5
CDCl
3
4
+
ppm; HRMS (ESI, Q-ToF): m/z calcd for C16
H20NaO [M + Na] 267.1356; found: 267.1354.
2
Wollf-Kishner reduction of cage ketone (18)
To a round bottom flask with a reflux condenser were added diethylene glycol (10 mL) and KOH
pellets and then heated at 80 °C until all of the KOH get dissolved. To this solution, cage ketone
18 (200 mg, 0.52 mmol) and hydrazine hydrate (169 mg, 5.28 mmol) were added sequentially.
The resultant reaction mixture was heated at 100-110 °C for 3 h. Afterwards, the round bottom
flask was fitted with a Dean-Stark apparatus, and water was removed from the reaction mixture by
azeotropic distillation. The Dean-stark set up was removed and the temperature of the reaction
mixture was increased to 190-200 °C. The reaction mixture was heated at the same temperature
for 10 h. After completion of the reaction by TLC monitoring, the reaction mixture was allowed
to room temperature, diluted with water and quenched by aqueous HCl. The aqueous layer was
extracted with ethyl acetate, and the combined organic layers were successively washed with
water, brine solution and dried with anhydrous Na
2
SO
4
. Evaporation of the solvent under reduced
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pressure followed by silica gel column chromatography of the resultant crude residue using 1%
ethyl acetate in petroleum ether as an eluent gave the desired cage hydrocarbon 35 as a pure
colourless solid.
-1
Yield: 77% (150 mg); mp 112-114 °C; IR (neat, cm ): 2955, 2938, 2328, 1495, 1473, 1036, 700;
1H NMR (500 MHz, CDCl
): = 7.32-7.34 (m, 2H), 7.23-7.30 (m, 6H), 7.12-7.16 (m, 2H), 2.22-
.30 (m, 4H), 2.05 (s, 2H), 2.03 (t, J = 2.2, 1H), 1.95-1.96 (m, 1H), 1.79-1.88 (m, 4H), 1.58-1.69
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
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6
7
8
9
0
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7
8
9
0
3
2
13
(
m, 3H), 1.49-1.53 (m, 1H), 1.28, 1.19 (ABq, J = 10.2 Hz, 2H) ppm; C NMR (125 MHz, CDCl
3
):
=
150.9, 149.5, 128.1, 127.8, 125.78, 125.71, 125.0, 61.0, 57.0, 55.7, 53.3, 50.7, 49.5, 47.96,
47.95, 47.4, 45.3, 40.6, 38.4, 37.3, 34.4, 33.9, 21.3 ppm; HRMS (ESI, Q-ToF): m/z calcd for
+
C
28
H
28K [M + K] 403.1823; found: 403.1828.
NaBH Reduction of Cage ketone (18)
4
A solution of cage ketone 18 (75 mg, 0.19 mmol) in anhydrous methanol (5 mL), NaBH (30 mg,
4
°
0
.40 mmol) was added at 0 C in small portions over a period of 10 min. The resultant 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 and the
crude residue was quenched by the addition of water and was extracted with ethyl acetate. The
combined organic layer was washed with brine solution, dried over anhydrous Na SO and
(
2
4
concentrated under reduced pressure. The crude product obtained after evaporation of solvent was
purified from column chromatography on silica gel using 5-7% EtOAc in petroleum ether as an
eluent delivered the cage alcohol 36 as a colourless solid.
-1
Yield: 82% (62 mg): mp 101-103 °C; IR (neat, cm ): 3461, 2952, 2861, 1427, 1357, 1266, 1224,
1
1
085, 734, 702; H NMR (500 MHz, CDCl
3
): = 7.33-7.34 (m, 4H), 7.24-7.30 (m, 4H), 7.13-7.17
(m, 2H), 4.03 (s, 1H), 2.68-2.74 (m, 1H), 2.43 (t, J = 5.6 Hz, 1H), 2.27-2.33 (m, 2H), 2.16-2.25
(m, 4H), 2.04 (d, J = 6.8 Hz, 1H), 1.90-1.96 (m, 2H), 1.67-1.77 (m, 3H), 1.55-1.62 (m, 1H), 1.21,
1
3
1
1
3
.29 (ABq, J = 10.3, 2H) ppm; C NMR (125 MHz, CDCl
3
): = 149.9, 149.5, 128.29, 128.2,
27.22, 127.8, 125.79, 125.77, 125.1, 79.7, 60.7, 56.9, 56.5, 54.1, 53.6, 50.8, 48.3, 47.7, 45.3, 42.2,
8.5, 37.6, 34.2, 33.8, 21.1 ppm; HRMS (ESI, Q-ToF): m/z calcd for C28
H
28NaO [M + Na]+
403.2032; found: 403.2037.
Associated content
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Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
1
13
13
ORTEP drawings as shown by X-ray crystallography and copies of H, C, C-APT, DEPT-135
NMR of all new products and GC spectra of compound 29 (PDF).
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Crystal data for 18 and 30 (CIF)
Author Information
Corresponding Author
*
E-mail: srk@chem.iitb.ac.in.
ORCID:
Sambasivarao Kotha: 0000-0002-7173-0233
Subba Rao Cheekatla: 0000-0002-2346-5930
Notes
The authors declare no competing financial interest.
Acknowledgement
We thank the Defence Research and Development Organisation (DRDO, NO.
ARDB/01/1041849/M/1), New Delhi, for financial assistance. The authors also thank Ms.
Gaddamedi Sreevani and 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 Praj industries for Chair
Professorship (Green Chemistry). We thank Prof. INN Namboothiri for his help in arriving the
mechanism for the formation of compound 18. We are also thankful to the reviewers for their
valuable suggestions to improve the manuscript. S. R. C. thanks University Grants Commission
(UGC), New Delhi for the award of a research fellowship.
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2. CCDC 1590575 (18) and 1586116 (30) contains supplementary crystallographic data for
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3
0, please see the SI file.
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