Cycloaddition of annulated cyclohexa-2,4-dienones and novel reduction of halogen at bridgehead: an expedient route to tetracyclo[6.5.2.02,7.09,13]pentadec-2(7),11-dien-14-one and framework of conidiogenol and conidiogenone

Article abstract of DOI:10.1016/j.tet.2009.07.051

An expedient route to tetracyclo[6.5.2.0^2,7.0^9,13]pentadec-2(7),11-dien-14-one and tetracyclic framework of conidiogenol have been reported. Cycloaddition of annulated cyclohexa-2,4-dienone with cyclopentadiene, photochemical oxa-di-π-methane reaction and a highly unusual dehalogenation of bridgehead halogen are the key features of our methodology.

Full text of DOI:10.1016/j.tet.2009.07.051

Tetrahedron 65 (2009) 7969–7974
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cycloaddition of annulated cyclohexa-2,4-dienones and novel reduction
of halogen at bridgehead: an expedient route to tetracyclo[6.5.2.02,7.09,13]-
pentadec-2(7),11-dien-14-one and framework of conidiogenol
and conidiogenone
,
a
b
Vishwakarma Singh a , Raj Bahadur Singh , Shaikh M. Mobin
*
a Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India
b National Single Crystal X-ray Diffraction Facility, Indian Institute of Technology Bombay, Mumbai 400076, India
a r t i c l e i n f o
a b s t r a c t
An expedient route to tetracyclo[6.5.2.02,7.09,13]pentadec-2(7),11-dien-14-one and tetracyclic framework
of conidiogenol have been reported. Cycloaddition of annulated cyclohexa-2,4-dienone with cyclo-
Article history:
Received 27 June 2009
Received in revised form 21 July 2009
Accepted 22 July 2009
Available online 25 July 2009
pentadiene, photochemical oxa-di-
p-methane reaction and
a
highly unusual dehalogenation of
bridgehead halogen are the key features of our methodology.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Diels–Alder cycloaddition
Photochemical reaction
Oxa-di-p-methane rearrangement
Spiroepoxycyclohexa-2,4-dienone
1. Introduction
conidiogenol 1 and the ketone 2 despite their potent conidiation
inducing activity, though there are a few routes to the tetracyclic
systems related to 1 and 2, which were developed earlier in context
of synthesis of megallanane family of alkaloids.2
Recently, Sterner and co-workers isolated two new diterpenes
from the extracts of fermentation broth of Penicillium cyclopium,
which were found to induce conidiogenesis in the producing
organism.1a These diterpenoids were identified as conidiogenol 1
and conidiogenone 2 (Fig. 1), which have a unique tetracyclic mo-
lecular architecture containing a linear triquinane annulated with
a six-membered ring in angular fashion. Most recently, several
analogues of 2 were isolated from marine microorganism Pen-
icillium sp.1b It seems, there are no synthetic approaches to
In continuation of our studies3 on development of new methods
from simple aromatics based on the chemistry of cyclohexa-2,4-
dienones, their cycloaddition and photochemical reaction we con-
sidered developing a route to the tetracyclic compound such as 3,
which contains carbocyclic network of conidiogenol and con-
idiogenone and wish to report our results herein.
Initially, we envisioned that the tetracyclic system of type 3
could be derived from 4 by a regioselective cleavage of the cyclo-
propane ring and that the intermediate 4 would be obtained from
the bridged tricyclic compound 5 via oxa-di-p-methane rear-
H
rangement or photochemical 1,2-acyl shift. The chromophoric
system 5 was thought to be derived from the ketoepoxide 6 and
that the ketoepoxide itself would be amenable from the hydroxy-
methyltetrahydronaphthol 8 via its oxidation to annulated cyclo-
H
O
O
HO
p4s
þ
p2s
cycloaddition
with
2
1
3
hexa-2,4-dienone
cyclopentadiene (Scheme 1).
7
and
OH
Figure 1.
OH
It is interesting to note that the pentacyclic system 4 would be
generated in a single stereoselective step. Further, all the carbon
atoms, which form the basic tetracyclic network of 3 are assembled
in a single step with correct connectivity and relative stereo-
chemical orientation, from a simple precursor 8. Moreover, the
* Corresponding author. Tel.: þ91 22 2576 7168; fax: þ91 22 2572 3480.
E-mail address: vks@chem.iitb.ac.in (V. Singh).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.051

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V. Singh et al. / Tetrahedron 65 (2009) 7969–7974
O
d 78.9, 61.2, 58.1, 54.0, 51.8, 34.0, 32.5, 27.2, 26.8, 22.15, 22.11 for
O
O
other carbons. These spectral features suggested that it is not the
expected adduct 13a, which may arise by the cycloaddition of 11
(formed as a result of oxidation of 10). Moreover, HRMS suggested
the presence of three oxygens in its molecular structure. The above
spectral features clearly indicated that a major structural re-
organization had occurred during the above reaction. However, it
was very difficult to ascertain the structure of the product from the
spectral data alone. Hence, X-ray structure was undertaken, which
established its formulation as 12 (Fig. 2).
hν
cleavage
5
3
4
OH OH
O
O
O
O
cyclo-
addition
6
8
7
Scheme 1.
b,g-enone moiety that is required for the transformation of bridged
structure into a ring fused structure is also generated in the very
first step of the synthetic sequence.
2. Results and discussion
In order to prepare the aromatic precursor 8, tetrahydronaph-
thol 9 was hydroxymethylated, which gave a mixture of 8 and 10
that was inseparable by chromatography.4 Therefore, we thought to
use the same mixture for the generation of cyclohexadienones and
interception with cyclopentadiene with a hope that the resulting
adducts would be easily separable. Thus, the mixture of 8 and 10
was oxidized with sodium metaperiodate5 in the presence of
cyclopentadiene following a procedure developed in our labora-
tory.6 Work-up gave a mixture of products from which the
unreacted cyclohexadienone 113b (derived from 10), a highly un-
usual product 12, and the desired adduct 6 were isolated by
a careful chromatography (Scheme 2).
Figure 2. ORTEP diagram of compound 12.
A probable mechanism of formation of 12 is shown below
(Scheme 3). It appears that the reaction of cyclohexadienone 11
arising from the oxidation of 10, with cyclopentadiene did not give
adduct of type 13a, instead it led to the formation of unusual regio-
isomer 13b. It may be mentioned that in general cycloaddition of
spiroepoxycyclohexa-2,4-dienones with cyclopentadiene gives the
adducts of type 13a (wherein the double bond of the cyclopentane
ring is closer to the carbonyl group).3 Presumably the steric in-
teraction between six-membered ring and methylene of the
cyclopentene ring in 13a led to the alternate mode of addition and
formation of 13b. The adduct 13b subsequently undergoes opening
of the oxirane ring under the reaction conditions (acidic) and a 1,2-
shift to give the allyl cation 14. Migration of the double bond in 14
gives the more stable carbocation 15 whose interception with
water gives the final product 12 (Scheme 3).
O
OH
OH OH
+
OH OH
O
HCHO
aq. NaIO4
CH3CN
NaOH
40%
6 (16.5%)
1:3
8
10
9
+
O
O
O
O
O
HO
+
HO
13a
11 (23%)
12 (18%)
Scheme 2.
While we could prepare the desired tetracyclic ketoepoxide 6 as
described above, we considered developing an alternate prepara-
tion of 8 (and hence 6). It was thought that tetrahydronaphthol 9
may be converted into bromo derivative 16, which upon hydroxy-
methylation would give 17 and removal of bromine would furnish
the desired precursor 8.
While, the structure of 6 was easily deduced from its spectral
data and comparison,3 structure of the unusual product 12 was
deduced as follows. The IR spectrum of compound 12 showed ab-
sorption bands at 3453, 3333, 1727 cmꢀ1 for hydroxyl and carbonyl
groups. Its 1H NMR (300 MHz) spectrum exhibited signals at
Thus, regioselective bromination of 9 with NBS as described7
gave 16 in excellent yield (92%). Hydroxymethylation of 16 also
proceeded well and gave compound 17 in good yield (78%). How-
ever, reduction of bromine in 17 proved to be difficult, as the
treatment of bromo compound 17 with Raney Ni gave an in-
separable mixture of products containing 8 in variable yields
(Scheme 4). Therefore, we considered preparing tricyclic com-
pound 19 with a hope to remove the halogen at later stages of the
sequence. Thus, a solution of compound 17 in acetonitrile con-
taining a freshly cracked cyclopentadiene was oxidized with NaIO4,
d
5.88–5.84 (ddd, J1¼6 Hz, J2¼3.3 Hz, J3¼2.5 Hz, 1H), 5.59–5.55
(ddd, J1¼6 Hz, J2¼4.2 Hz, J3¼2.5 Hz, 1H) for two olefinic protons.
Further signals were observed at
d
4.42 (d, J¼3.3 Hz, 1H), 3.94 (part
of an AB system, JAB¼12 Hz, 1H), 3.85 (part of an AB system,
JAB¼12 Hz, 1H), 3.18–3.12 (m, 1H), 2.99–2.88 (m, 1H), 2.73 (dd,
J1¼8 Hz, J2¼3.3 Hz, 1H), 2.49–2.22 (m, 6H), 2.20–2.05 (m, 1H), 1.90–
1.60 (m, 3H), 1.53–1.24 (m, 2H). Its 13C NMR (100 MHz) spectrum
displayed signals at
d 218.8, 137.0, 134.3, 133.4, 127.2 for carbonyl
group and four olefinic carbons. Further signals are observed at

V. Singh et al. / Tetrahedron 65 (2009) 7969–7974
7971
O
O
O
O
OH
OH
HO
O
aq.NaIO4
CH3CN-
H2O
OH
-
13a
12
10
11
+
H
H2O
+
O
H+
O
O
O
HO
+
+
OH
OH
13b
14
14
15
Scheme 3.
Br
showed a peak at m/z 267.1371 (MþNa)þ corresponding to molec-
ular formula C16H20O2. It also exhibited a peak at m/z 245.1537
[(MþNa)þ–H2O], a characteristic of primary alcoholic functional
group. Similarly, the mass spectrum of compound 22 also showed
peak at m/z 229.1581 (MþH)þ corresponding to the molecular
formula C16H20O.
R
OH
O
OH
iii
ii
mixture
OH
9, R = H
16, R = Br
17
i
iv
The
b-hydroxymethyl ketone 23 thus obtained was oxidized
O
O
Br
with Jones reagent and the resulting
b
-keto-acid was decarboxy-
O
lated to give the desired tetracyclic compound 5 whose structure
was deduced from the following spectral features. The IR spectrum
of 5 showed band at 1717 cmꢀ1 for carbonyl group. Its 1H NMR
Br
19 (77%)
18
(300 MHz) spectrum showed characteristic signals at
(m, 1H), 5.38–5.34 (m, 1H) for two olefinic protons. Other protons
exhibited signals at
d 5.66–5.62
Scheme 4. Reagents and conditions: (i) NBS, DMF, 92%; (ii) HCHO, NaOH, 78%; (iii)
Raney Ni, H2, KOH; (iv) aq NaIO4, CH3CN.
d
3.22–3.15 (m,1H), 2.85 (d, J¼2.6 Hz,1H), 2.65–
2.48 (m, 3H), 2.18–1.88 (m, 6H), 1.82–1.72 (m, 1H), 1.62–1.55 (m,
which furnished the adduct 19 in very good yield (77%) (Scheme 4).
The structure of adduct was revealed from its spectral data and
comparison with the structural features of the related compound
prepared earlier.
It was thought that the reduction of oxirane ring in 19 with zinc
would give the b-hydroxymethyl ketone 20, which upon oxidation
and decarboxylation would provide the bromoketone 21. Sub-
sequent reductive dehalogenation in 21 would then give desired
tetracyclic chromophoric system 5 (Scheme 5). Thus, the ketoep-
oxide 19 was subjected to reduction with activated zinc and am-
monium chloride in aq methanol according to the procedure
developed in our laboratory.3a Surprisingly, chromatography of the
b-keto alcohol 23 as major product
[syn:anti mixture] along with minor amounts of 22, which were
devoid of bromine (Scheme 5).
merged with signal due to water in CDCl3, 4H). The 13C NMR
(75 MHz) spectrum showed signals at
and 136.5, 132.4, 129.6, 129.1 for four olefinic carbons. Other
carbons showed signals at 57.6, 48.8, 42.0, 41.1, 40.0, 38.3, 30.0,
d 213.5 for carbonyl carbon
d
d
28.5, 22.9, 22.8 (all the 15 carbons). The HRMS showed a peak at
(m/z): 237.1262 (MþNa)þ corresponding to its molecular formula
C15H18O. This also confirmed the structure of the b-hydroxymethyl
ketone and that dehalogenation had occurred during reduction of
the bromoketoepoxide 19 with zinc–NH4Cl.
In order to further confirm the structures of 22, 23 and 5,
compound 5 was also prepared from adduct 6. Thus, the adduct 6
was treated with zinc–NH4Cl to give a
identical with 23 and the ketone 22. Oxidation of the
b
-keto alcohol, which was
-keto alcohol
product mixture gave the
b
23 and subsequent decarboxylation gave compound 5, which was
prepared earlier from the adduct 19 (Scheme 6).
OH
O
O
H
OH
O
O
O
H
O
O
O
1. Jones
oxidation
Zn-NH4Cl
Br
21
Br
19
Br
2. aq. THF
reflux
20
aq. MeOH
rt
23 (82%)
5 (51 %)
6
Zn, NH4Cl
+
aq. MeOH, rt
22 (8%)
OH
Me
O
H
H
Scheme 6.
O
O
1. Jones
+
These studies further confirmed that reductive dehalogenation
had occurred during the reaction of adduct 19 with zinc–NH4Cl in
addition to the reduction of the oxirane group. The aforementioned
dehalogenation though fortuitous was indeed highly surprising.
2. aq. THF
Δ
5 (44%)
23 (70%)
Scheme 5.
22 (4%)
While reduction of halogens a- to a carbonyl group by zinc is well
The spectral features (1H NMR and 13C NMR), and especially the
HRMS data of compounds 22 and 23 suggested that these com-
pounds do not contain bromine. The HRMS of keto alcohol 23
known,8 reduction of bridgehead halogen is generally not observed.
Having prepared the chromophoric system 5, its photochemical
reaction was explored. Photoreaction of
b,g-enones have

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V. Singh et al. / Tetrahedron 65 (2009) 7969–7974
stimulated interest for long time,9 which has enhanced recently by
virtue of its synthetic potential.10,11 In general,
-enones undergo
a 1,2-acyl shift or the oxa-di- -methane rearrangement, upon
triplet excitation and 1,3-acyl shift on singlet excitation, re-
spectively. However, it also depends upon the structure of the
chromophoric system and functional group in a subtle fashion.
Thus, a solution of the tetracyclic compound 5 in acetone (both
solvent and sensitizer) was irradiated with medium pressure
mercury vapour lamp (125 W) in a Pyrex immersion well. Removal
of solvent followed by chromatography of the photolysate gave the
desired photoproduct 4 in moderate yield (32%) as a result of oxa-
recorded on Varian VXR 300 instrument. 1H NMR (400 MHz) and
13C (100 MHz) NMR spectra were recorded on Mercury Varian
400 MHz instrument. The samples were dissolved in CDCl3 as
solvent and SiMe4 as internal standard. The high resolution mass
spectra were recorded on Q-Tof micro (YA-105) Mass Spectrom-
eter. Melting points were determined on a Veego apparatus of
Buchi type and are uncorrected. All the organic extracts were
dried over anhydrous sodium sulfate. Reactions were monitored
with thin layer chromatography and spots were visualized with
iodine vapour. Column chromatography was performed using SRL/
Thomas Baker silica gel (60–120 and 100–200 mesh). The elution
was done with petroleum ether (60–80 ꢁC) and ethyl acetate
mixture.
b,g
p
di-p-methane reaction, along with a minor amount of 24 (6%)
arising via a 1,3-acyl shift (Scheme 7).
4.1.1. 15-Spiroepoxytetracyclo[6.5.2.02,7.09,13]pentadec-2(7),11-dien-
O
hν
hν
O
24 (6%)
+
14-one (6), cyclohexa-2,4-dienone (11) and 8-hydroxy-1-hydroxy-
5
methyltetracyclo[7.5.1.02,7.010,14
]
pentadec-2(7),12-diene-15-one
acetone
Pyrex
benzene
1 h
(12). To a solution of compounds 8 and 10 (0.890 g, 5 mmol) in
acetonitrile (30 mL) was added freshly cracked cyclopentadiene
(5 mL, excess) followed by the addition of a saturated solution of
sodium metaperiodate (2.4 g, 11.2 mmol) drop wise (w15 min) at
w0 ꢁC. After stirring the reaction mixture in ice bath for additional
two and half hours, the reaction mixture was further stirred at
room temperature (w30 ꢁC) overnight. After which the reaction
mixture was saturated with sodium chloride and the organic layer
was separated and aqueous layer was extracted with ethyl acetate
(4ꢂ10 mL). The organic extract was combined and dried on anhy-
drous sodium sulfate. The solvent was removed under vacuum and
the residue was chromatographed on silica gel. Elution with pe-
troleum ether gave some impurities and unreacted cyclo-
pentadiene. Further elution with petroleum ether–ethyl acetate
(95:5) afforded adduct 6 (0.200 g, 16.5%). Continued elution with
petroleum ether–ethyl acetate (90:10) furnished known3b cyclo-
hexadienone 11 (0.200 g, 23%). Further elution with petroleum
ether–ethyl acetate (60:40) furnished compound 12 (0.234 g, 18%)
as a solid that was recrystallised from petroleum ether–ethyl
acetate.
4 (32%)
24 (40%)
Scheme 7.
The 1,3-acyl shift product 24 formed during sensitized irradia-
tion apparently arise from the excited singlet state, which may be
generated by direct absorption. In some cases, 1,3-acyl shift is also
known to occur from T2 state. Direct irradiation of a solution of 5 in
dry benzene gave the 1,3-acyl shift product 24 as a major product,
as expected (Scheme 7). However, the formation of compound 4
was not observed during direct irradiation (1S). Though, the effi-
ciency of oxa-di-p-methane reaction is only moderate, it provides
a stereoselective avenue to the pentacyclic product 4, which is not
readily accessible otherwise.
In order to prepare the tetracyclic system 3, compound 4 was
treated with tributyltin hydride–AIBN12 in refluxing benzene to
give the tetracyclic compound 3 in good yield (Scheme 8) whose
structure was clearly revealed from its spectral features.
O
Data for 6. Mp 100–102 ꢁC. Rf (20% EtOAc–petroleum ether) 0.6;
(Bu)3SnH
O
IR (KBr) nmax: 1736 cmꢀ1 1H NMR (300 MHz, CDCl3):
. d 5.74–5.68
AIBN
Benzene
reflux
(ddd, J1¼5.4 Hz, J2¼4.8 Hz, J3¼2.0 Hz, 1H), 5.42–5.37 (m of d,
J¼5.4 Hz, 1H), 3.38–3.32 (m, 1H), 3.12 (part of an AB system,
JAB¼6 Hz,1H), 3.05 (d, J¼2.7 Hz,1H), 3.02–2.93 (m,1H), 2.86 (part of
an AB system, JAB¼6 Hz, 1H), 2.66–2.53 (m, 1H), 2.24 (d, J¼2.7 Hz,
1H), 2.20–2.11 (m, 1H), 2.11–1.94 (m, 3H), 1.89–1.78 (m, 1H), 1.68–
4
3 (60%)
Scheme 8.
1.54 (m, 4H). 13C NMR (75 MHz, CDCl3):
d 206.3, 134.6, 133.1, 130.3,
3. Conclusion
129.0, 58.6, 57.0, 52.3, 49.6, 48.0, 37.9, 36.0, 30.1, 28.4, 22.6, 22.5.
HRMS (ESI) (m/z): found 265.1208 [MþNa]þ. C16H18O2Na requires
265.1204.
In summary, we have described an efficient stereoselective ap-
proach to a tetracyclic framework of conodiogenol from a simple
aromatic precursor. Our methodology involves transformation of
annulated o-hydroxymethylphenol into cyclohexadienone and its
cycloaddition with cyclopentadiene to give tetracyclic adduct
Data for 12. Mp 174–178 ꢁC. Rf (50% EtOAc–petroleum ether) 0.4;
IR (KBr) nmax: 3453, 3333, 1727 cmꢀ1 1H NMR (300 MHz, CDCl3):
.
d
5.88–5.84 (ddd, J1¼6 Hz, J2¼3.3 Hz, J3¼2.5 Hz, 1H), 5.59–5.55
containing a
b,g-enone chromophore. Further manipulation of
(ddd, J1¼6 Hz, J2¼4.2 Hz, J3¼2.5 Hz, 1H, olefinic proton), 4.42 (d,
J¼3.3 Hz, 1H), 3.94 (part of an AB system, JAB¼12 Hz, 1H), 3.85 (part
of an AB system, JAB¼12 Hz, 1H), 3.18–3.12 (m, 1H), 2.99–2.88 (m,
1H), 2.73 (dd, J1¼8 Hz, J2¼3.3 Hz, 1H), 2.49–2.22 (m, 6H), 2.20–2.05
(m, 1H), 1.90–1.60 (m, 3H), 1.53–1.24 (m, 2H). 13C NMR (100 MHz,
adduct followed by photochemical rearrangement and cleavage of
the peripheral cyclopropane bond furnished the tetracyclic net-
work of conidiogenol in stereoselective manner. In addition, un-
usual rearrangement and a novel dehalogenation with zinc have
also been described. The present methodology provides a nice ex-
ample of creating molecular complexity from simple precursors,
a desirable aspect of the development of new methods.13,14
CDCl3):
d 218.8, 137.0, 134.3, 133.4, 127.2, 78.9, 61.2, 58.1, 54.0, 51.8,
34.0, 32.5, 27.2, 26.8, 22.15, 22.11. HRMS (ESI) (m/z): found 283.1309
[MþNa]þ. C16H20O3Na requires 283.1310.
Crystal data of 12. C16H20O3, M¼260.32, triclinic, space group P-1,
4. Experimental section
4.1. General remarks
a¼7.6060(16) Å, b¼7.8830(9) Å, c¼12.5260(17) Å,
a
¼90.604(10)ꢁ,
b
¼107.024(14)ꢁ,
g
¼115.530(15)ꢁ, U¼639.82(18) Å3, Dc¼1.346 mg/
m3, Z¼2, F(0,0,0)¼278,
l
¼0.71073 Å,
m
¼0.092 mmꢀ1, total/unique
reflections¼2409/2225 [R(int)¼0.0174], T¼293(2) K, range¼1.72–
q
IR spectra were recorded on Nicolet Impact 400 FT-IR In-
strument. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
24.97ꢁ, final R[I>2
R1¼0.0847, wR2¼0.1288. The complete crystal data can be obtained
s(I)], R1¼0.0462, wR2¼0.1142, R (all data):

V. Singh et al. / Tetrahedron 65 (2009) 7969–7974
7973
free of charge from The Cambridge Crystallographic data Centre via
www.ccdc.cam.ac.uk/data_request/cif quoting the CCDC number
695219.
(m, 2H), 1.6–1.4 (m, 4H). 13C NMR (100 MHz, CDCl3):
d
218.0, 137.4,
132.8, 129.3, 62.3, 57.7, 50.9, 49.7, 44.1, 38.1, 34.8, 29.9, 28.4, 22.89,
22.82 (signals due to major isomer). HRMS (m/z): found 267.1371
[MþNa]þ. C16H20O2Na requires 267.1361.
4.1.2. 1-Bromo-5,6,7,8-tetrahydro-3-hydroxymethyl-2-naphthol
(17). To a solution of compound 16 (10.54 g, 46.4 mmol) in aq
NaOH (3.7 g, 92 mmol, in 100 mL), formaldehyde (37–40%, excess)
was added at w0–5 ꢁC. After 5 min ice bath was removed and re-
action mixture was stirred for 24 h at room temperature. After
completion of the reaction (TLC) the reaction mixture was neu-
tralized with ammonium chloride and the resulting solution was
extracted with ethyl acetate (4ꢂ50 mL). Combined organic extracts
were dried (anhydrous Na2SO4), evaporated under reduced pres-
sure and residue was chromatographed. Elution with petroleum
ether–ethyl acetate (85:15) gave compound 17 (9.4 g, 78%). Mp 84–
86 ꢁC. Rf (20% EtOAc–petroleum ether) 0.6; IR (KBr) nmax: 3543,
Data for 22. Mp 50–52 ꢁC. Rf (20% EtOAc–petroleum ether) 0.8; IR
(film) nmax: 1721 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d 5.67–5.63 (m,
1H, olefinic proton), 5.37–5.33 (m, 1H, olefinic proton), 3.11–3.04
(m, 1H), 2.83–2.75 (m, 2H), 2.56–2.45 (m, 1H), 2.41–2.31 (m, 1H),
2.20–1.90 (m, 5H), 1.82–1.73 (m, 1H), 1.72–1.50 (m, 4H), 1.12, 1.05
(two d, J¼7.3 Hz, total 3H). 13C NMR (75 MHz, CDCl3):
d 216.3, 137.4,
132.4, 129.4, 128.8, 57.3, 49.1, 47.6, 43.3, 37.8, 33.6, 29.8, 28.1, 22.7,
22.6, 14.1. HRMS (ESI) (m/z): found 229.1581 [MþH]þ. C16H21O re-
quires 229.1592.
4.1.5. Tetracyclo[6.5.2.02,7.09,13]pentadec-2(7),11-dien-14-one (5). To
a solution of
b-keto alcohol 23 (0.532 g, 2.18 mmol) in acetone
3478 cmꢀ1. 1H NMR (400 MHz, CDCl3):
2.71–2.67 (m, 4H), 1.82–1.69 (m, 4H). 13C NMR (100 MHz, CDCl3):
d
6.87 (s, 1H), 4.71 (s, 2H),
(30 mL) was added freshly prepared Jones reagent drop wise at
w5 ꢁC. After completion of the reaction (TLC) acetone was removed
under vacuum. The residue was diluted with water (10 mL) and
extracted with ethyl acetate (4ꢂ10 mL). The extract was combined,
dried over anhydrous sodium sulfate and the solvent was removed
d
148.7, 136.4, 130.7, 128.0, 124.4, 113.7, 62.6, 30.4, 29.3, 23.2, 22.8.
HRMS (ESI) (m/z): found 278.9999 [MþNa]þ. C11H13BrO2Na re-
quires 278.9997.
under vacuum to give the b-keto-acid, which was dissolved in the
4.1.3. 1-Bromo-15-spiroepoxytetracyclo[6.5.2.02,7.09,13]pentadec-
2(7),11-dien-14-one (19). A solution of compounds 17 (1.3 g,
5.07 mmol) in acetonitrile (30 mL) was cooled at w0–5 ꢁC. To this
were added freshly cracked cyclopentadiene (5 mL, excess) and
a saturated aq solution of sodium metaperiodate (2.4 g, 11.2 mmol,
50 mL H2O) drop wise. After stirring the reaction mixture in ice
bath for additional two and half hours, the reaction mixture was
stirred at room temperature overnight. The reaction mixture was
saturated with sodium chloride and the organic layer was sepa-
rated and aqueous layer was extracted with ethyl acetate
(4ꢂ20 mL). The combined extract was dried, solvent was removed
and residue was chromatographed on silica gel. Elution with pe-
troleum ether–ethyl acetate (90:10) afforded adduct 19 (1.25 g,
77%). Mp 106–108 ꢁC. Rf (20% EtOAc–petroleum ether) 0.6; IR (film)
THF–H2O mixture (1:1, 10 mL) and refluxed for 12 h. The reaction
mixture was saturated with NaCl and organic layer was separated.
The aqueous layer was extracted with ether (3ꢂ20 mL). The organic
layers were combined and dried over sodium sulfate. The solvent
was removed under reduced pressure and the crude product was
purified by column chromatography. Elution with petroleum
ether–ethyl acetate (90:10) gave compound 5 (0.204 g, 44%) as
a colourless solid. Mp 112–114 ꢁC. Rf (20% EtOAc–petroleum ether)
0.8; IR (KBr) nmax: 1717 cmꢀ1 1H NMR (400 MHz, CDCl3):
. d 5.66–
5.62 (m, 1H, olefinic proton), 5.38–5.34 (m, 1H, olefinic proton),
3.22–3.15 (m, 1H), 2.85 (d, J¼2.7 Hz, 1H), 2.65–2.48 (m, 3H), 2.18–
1.88 (m, 6H), 1.82–1.72 (m, 1H), 1.62–1.55 (m, merged with signal
due to water present in CDCl3, 4H). 13C NMR (75 MHz, CDCl3):
d
213.5, 136.5, 132.4, 129.6, 129.1, 57.6, 48.8, 42.0, 41.1, 40.0, 38.3,
nmax: 1743 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
d
5.85–5.80 (m, 1H),
30.0, 28.5, 22.9, 22.8. HRMS (ESI) (m/z): found 237.1262 [MþNa]þ.
5.69–5.63 (m, 1H), 3.57–3.53 (m, 1H), 3.22 (part of an AB system,
JAB¼6.4 Hz, 1H), 3.07–3.00 (m, 1H), 2.95 (part of an AB system,
JAB¼6.4 Hz, 1H), 2.72–2.62 (m, 1H), 2.28 (d, J¼2.8 Hz, 1H), 2.23–2.0
C15H18ONa requires 237.1255.
4.1.6. Tetracyclo[6.5.2.02,7.09,13]pentadec-2(7),11-dien-14-one (5) pre-
pared via adduct 6. To a solution of epoxy ketone 6 (0.650 g,
2.7 mmol) in methanol–water (6:1, 28 mL) were added zinc (acti-
vated, 6.0 g, excess) and ammonium chloride (1 g, 18.7 mmol). The
reaction mixture was stirred at ambient temperature for 8 h. The
reaction mixture was then filtered through a Celite bed and washed
with ethyl acetate (4ꢂ5 mL). The combined filtrate was concentrated
in vacuo and water was added to the residue and extracted with
ethyl acetate (4ꢂ25 mL). The combined extract was washed with
brine and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue was purified by
column chromatography. Elution with petroleum ether–ethyl ace-
tate (95:5) gave compound 22 (0.049 g, 8%), continued elution with
(m, 5H), 1.64–1.58 (m, 4H). 13C NMR (100 MHz, CDCl3):
d 197.8,
135.3, 134.7, 130.4, 128.6, 77.5, 59.1, 57.8, 53.0, 47.3, 39.0, 37.5, 30.9,
28.8, 23.1, 22.3. HRMS (ESI) (m/z): Found 343.0323 [MþNa]þ.
C16H17BrO2Na requires 343.0310.
4.1.4. 15-Hydroxymethyltetracyclo[6.5.2.02,7.09,13]pentadec-2(7),11-
dien-14-one (23) and 15-methyltetracyclo[6.5.2.02,7.09,13]pentadec-
2(7),11-dien-14-one (22). To a solution of epoxy ketone 19 (0.950 g,
w3 mmol) in methanol–water (6:1, 84 mL) were added zinc (acti-
vated, 6.0 g, excess) and ammonium chloride (1 g, 18.7 mmol). The
reaction mixture was stirred at ambient temperature for 8 h. The
reaction mixture was then filtered through a Celite bed and washed
with ethyl acetate (4ꢂ5 mL). The filtrate was combined and solvent
was removed in vacuo. Water was added to the residue and
extracted with ethyl acetate (4ꢂ25 mL). The combined extract was
washed with brine and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the residue
was purified by column chromatography. Elution with petroleum
ether–ethyl acetate (95:5) gave compound 22 (0.030 g, w4%),
petroleum ether–ethyl acetate (80:20) gave
b-keto alcohol 23
(0.536 g, 82%), which were identical with those obtained earlier.
To a solution of
b-keto alcohol 23 thus obtained (0.552 g,
2.3 mmol) in acetone (30 mL) at 5 ꢁC was added freshly prepared
Jones reagent drop wise. After completion of the reaction (TLC)
acetone was removed under vacuum. The residue was diluted with
water (10 mL) and extracted with ethyl acetate (4ꢂ10 mL). The
extract was combined, dried over anhydrous sodium sulfate and
elution with petroleum ether–ethyl acetate (80:20) gave
b-keto
alcohol 23 (0.510 g, 70%) as a mixture of syn–anti isomers.
the solvent was removed under vacuum to give the b-keto-acid,
Data for 23. Rf (20% EtOAc–petroleum ether) 0.3; IR (neat) nmax
:
which was dissolved in the THF–H2O mixture (1:1, 10 mL) and
refluxed for w12 h. The reaction mixture was saturated with NaCl
and the organic layer was separated. The aqueous layer was further
extracted with ether (3ꢂ20 mL) and dried over sodium sulfate. The
solvent was removed under reduced pressure and the crude
3429, 1715 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d
5.67–5.62 (m, 1H),
5.37–5.35 (m, 1H), 3.87–3.82 (m, 1H), 3.69–3.58 (m, 1H), 3.23–3.11
(m,1H), 2.87 (d, J¼2.4 Hz,1H), 2.78–2.62 (m,1H), 2.61–2.58 (m,1H),
2.58–2.40 (m, 1H), 2.27–2.14 (m, 2H), 2.07–1.77 (m, 3H), 1.80–1.60

7974
V. Singh et al. / Tetrahedron 65 (2009) 7969–7974
product was purified by column chromatography. Elution with
petroleum ether–ethyl acetate (90:10) gave compound 5 (0.248 g,
51%) as a colourless solid, which was found identical in all respect to
the compound prepared earlier.
60%). Rf (10% EtOAc–petroleum ether) 0.45; IR (neat) nmax
:
1738 cmꢀ1. 1H NMR (300 MHz, CDCl3):
d
5.68–5.65 (m, 1H), 5.57–
5.54 (m, 1H), 3.31–3.27 (m, 1H), 2.66–2.57 (m, 1H), 2.50–2.00
(complex m 7H), 1.84 (t, J¼8.4 Hz, 1H), 1.65–0.93 (complex m, 8H).
13C NMR (75 MHz, CDCl3):
d 219.9, 135.4, 127.5, 52.2, 52.1, 51.7, 50.1,
4.1.7. Pentacyclo[7.6.0.01,6.06,15.010,14]pentadec-12-en-7-one (4). A so-
lution of the enone 5 (0.074 g, 3.21 mmol) in degassed acetone
(100 mL, solvent as well as sensitizer) was irradiated with mercury
vapour lamp (125 W) in a Pyrex immersion well for 1.25 h under
nitrogen. Acetone was removed under vacuum and the residue was
chromatographed. Elution with petroleum ether–ethyl acetate
(95:5) first gave the minor compound 24 (0.004 g, 6%), which was
found to be identical with the compound prepared by direct irradi-
ation as described below.
48.3, 41.9, 41.3, 38.8, 35.4, 23.18, 23.13, 20.7. HRMS (ESI) (m/z):
found 217.1597 [MþH]þ. C15H21O requires 217.1592.
Acknowledgements
We are grateful to the Department of Science and Technology for
continuing financial support. We thank SAIF, IIT Bombay for spec-
tral facilities. One of us (R.B.S.) would like to thank CSIR, New Delhi
for a fellowship. Thanks are due to DST for creating a National single
crystal X-ray facility.
Continued elution with the same solvent furnished the desired
product 4 (0.024 g, 32%) as a colourless solid, mp 60 ꢁC. Rf (10%
EtOAc–petroleum ether) 0.5; IR (KBr) nmax: 1703 cmꢀ1 1H NMR
.
References and notes
(300 MHz, CDCl3):
d 5.76–5.70 (m, 2H), 3.08–3.06 (m, 1H), 2.77–
1. (a) Roncal, T.; Cordobes, S.; Ugalde, U.; He, Y.; Sterner, O. Tetrahedron Lett. 2002,
43, 6799; (b) Du, L.; Zhu, T.; Cai, S.; Wang, F.; Xiao, X.; Gu, Q. Tetrahedron 2009,
65, 1033.
2. (a) Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 10147; (b) Yen,
C.-F.; Liao, C.-C. Angew. Chem., Int. Ed. 2002, 41, 4090; (c) Hirst, G. C.; Johnson,
T. O., Jr.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 2992; (d) Mehta, G.; Reddy,
M. S. Tetrahedron Lett. 1990, 31, 2039.
3. (a) Singh, V. Acc. Chem. Res. 1999, 32, 324; (b) Singh, V.; Sahu, P. K.; Singh, R. B.;
Mobin, S. M. J. Org. Chem. 2007, 72, 10155.
4. Nilsson, J. L. G.; Selander, H.; Sievertsson, H.; Skanberg, I.; Svensson, K. Acta
Chem. Scand. 1971, 25, 94.
5. (a) Adler, E.; Brasen, S.; Miyake, H. Acta Chem. Scand. 1971, 25, 2055; (b) Becker,
H.-D.; Bremholt, T.; Adler, E. Tetrahedron Lett. 1972, 13, 4205.
6. Singh, V.; Porinchu, M.; Vedantham, P.; Sahu, P. K. Org. Synth. 2005, 81, 171.
7. Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.; Rettori, M.;
Renard, P.; Merour, J. J. Med. Chem. 2003, 46, 1962.
2.20 (m, 6H), 2.00–1.88 (m, 2H), 1.70–1.50 (m merged with signal
due to H2O present in CDCl3, 2H), 1.40–1.19 (m, 3H), 1.10–0.88 (m,
2H). 13C NMR (100 MHz, CDCl3):
d 216.9,133.4,131.8, 56.4, 51.3, 48.7,
48.2, 47.2, 46.8, 44.2, 38.2, 25.9, 25.7, 22.3, 21.2. HRMS (ESI) (m/z):
found 237.1254 [MþNa]þ. C15H18ONa requires 237.1255.
4.1.8. Tetracyclo[9.4.0.01,4.05,9]pentadeca-7,10-dien-2-one (24). A so-
lution of enone 5 (0.1 g, 0.43 mmol) in dry benzene (100 mL) was
irradiated for 1 h under nitrogen atmosphere in a Pyrex immersion
well. Removal of solvent followed by chromatography of the pho-
tolysate gave 1,3-acyl shift product 24 (0.04 g, 40%). Rf (10% EtOAc–
petroleum ether) 0.8; IR (neat) nmax: 1765 cmꢀ1. 1H NMR (300 MHz,
CDCl3):
d
5.84–5.82 (m,1H), 5.70–5.67 (m,1H), 5.30 (br s,1H), 3.15 (d,
8. House, H. O. Modern Synthetic Reactions; Benzamin/Cummings: Menlo Park,
California, 1972; pp 145.
J¼8.1 Hz, 1H), 2. 94 (d of part of an AB system, JAB¼16.5 Hz, J2¼12 Hz,
1H), 2.84 (d of part of an AB system, JAB¼16.5 Hz, J2¼12 Hz, 1H),
2.59–2.50 (m, 1H), 2.42–2.28 (m, 2H), 2.17–1.86 (m, 4H), 1.84–1.60
(m, merged with signal due to water, 2H),1.44–1.21(m, 3H). 13C NMR
9. (a) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065; (b) Demuth, M. In
Organic Photochemistry; Padwa, A., Ed.; Marcel-Dekker: New York, NY, 1991;
Vol. 11, pp 37–97 and references therein; (c) Demuth, M.; Hisken, W. Angew.
Chem., Int. Ed. Engl. 1985, 24, 973; (d) Schuster, D. I. In Rearrangements in Ground
and Excited States; De Mayo, P., Ed.; Academic: New York, NY, 1980; Vol. 3,
p 232.
10. (a) Reekie, T. A.; Austin, K. A. B.; Banwell, M. G.; Willis, A. C. Aust. J. Chem. 2008,
61, 94; (b) Banwell, M. G.; Edward, A. J.; Harfoot, G. J.; Jolliffe, K. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 2439; (c) Maiti, B. C.; Singh, R.; Lahiri, S. J. Photochem.
Photobiol. A: Chem. 1995, 91, 27.
11. (a) Armesto, D.; Ortiz, M. J.; Romano, S.; Agarrabeitia, A. R.; Gallega, M. G.;
Ramos, A. In CRC Hand Book of Organic Photochemistry and Photobiology;
Horspool, W. M., Lenci, F., Eds.; CRC: Boca Raton, 2004, Chapter 95; (b) Singh, V.
In CRC Hand Book Organic Photochemistry and Photobiology; Horspool, W. M.,
Lenci, F., Eds.; CRC: Boca Raton, 2004; Chapters 78 and 79.
(75 MHz, CDCl3):
d 209.6, 133.3, 130.6, 130.1, 120.6, 65.4, 47.5, 41.1,
37.2, 36.6, 35.5, 33.7, 32.8, 27.0, 23.9. HRMS (ESI) (m/z): Found
215.1428 [MþH]þ. C15H19O requires 215.1436.
4.1.9. Tetracyclo[7.6.0.01,6.010,14]pentadec-12-en-7-one (3). The pho-
toproduct 4 (0.066 g, 0.3 mmol), AIBN (0.02 g) was taken in ben-
zene (30 mL) and tributyltin hydride (0.1 mL, 0.11 g, 2 equiv) was
added under nitrogen atmosphere and the reaction mixture was
refluxed for 12 h. Solvent was removed under vacuum and residue
was chromatographed. Tin impurities were removed by elution
with petroleum ether. Further elution with petroleum ether–ethyl
acetate (98:2) furnished the product 3 as a colourless liquid (0.04 g,
12. Enholm, E. J.; Jia, Z. J. J. Org. Chem. 1997, 62, 174.
13. (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259; (b) Corey, E. J.; Cheng,
X.-M. The Logic of Chemical Synthesis; John Wiley & Sons: New York, NY, 1989.
14. Chanon, M.; Barone, R.; Baralotto, C.; Julliard, M.; Hendrickson, J. B. Synthesis
1998, 1559.