Molecular complexity from aromatics. Cycloaddition of spiroepoxycyclohexa- 2,4-dienones and intramolecular Diels-Alder reaction: A stereoselective entry into tetracyclic core of atisane diterpenoids

Article abstract of DOI:10.1016/j.tet.2012.10.051

A stereoselective approach to tetracyclic core of atisane diterpenoids is described. Oxidative dearomatization, intermolecular cycloaddition of spiroepoxycyclohexa-2,4-dieone with ethyl acrylate, and intramolecular inverse demand π⁴s+π²s cycloaddition are the key features of our design. Oxidation of appropriately appended o-hydroxymethyl phenols to corresponding 6,6-spiroepoxycyclohexadienones followed by cycloaddition with ethyl acrylate furnished bridged bicyclo[2.2.2]octanes disposed with appropriate functionality. Regioselective manipulation of functional groups led to highly embellished bicyclic systems endowed with appendages containing diene and dienophilic moieties that upon inverse electron demand intramolecular cycloaddition provide the tetracyclic framework of atisanes in stereoselective fashion. A remarkable effect of a remote functional group on intramolecular Diels-Alder reaction has also been described.

Full text of DOI:10.1016/j.tet.2012.10.051

Tetrahedron 69 (2013) 137e146
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Molecular complexity from aromatics. Cycloaddition of
spiroepoxycyclohexa-2,4-dienones and intramolecular DielseAlder
reaction: a stereoselective entry into tetracyclic core of atisane
diterpenoids
,
a
a
b,c
Vishwakarma Singh a , Pravin Bhalerao , Bharat Chandra Sahu , Shaikh M. Mobin
*
a Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400 076, India
b National Centre for Single Crystal X-ray Facility, Indian Institute of Technology Bombay, Mumbai 400 076, India
c School of Basic Sciences, Discipline of Chemistry, Indian Institute of Technology, Indore, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective approach to tetracyclic core of atisane diterpenoids is described. Oxidative dearoma-
tization, intermolecular cycloaddition of spiroepoxycyclohexa-2,4-dieone with ethyl acrylate, and in-
Received 25 September 2012
Accepted 17 October 2012
Available online 24 October 2012
tramolecular inverse demand
p
4sþ
p
2s cycloaddition are the key features of our design. Oxidation of
appropriately appended o-hydroxymethyl phenols to corresponding 6,6-spiroepoxycyclohexadienones
followed by cycloaddition with ethyl acrylate furnished bridged bicyclo[2.2.2]octanes disposed with
appropriate functionality. Regioselective manipulation of functional groups led to highly embellished
bicyclic systems endowed with appendages containing diene and dienophilic moieties that upon inverse
electron demand intramolecular cycloaddition provide the tetracyclic framework of atisanes in stereo-
selective fashion. A remarkable effect of a remote functional group on intramolecular DielseAlder re-
action has also been described.
Keywords:
Oxidative dearomatization
Cyclohexa-2,4-dienones
p
4sþ
p
2s cycloaddition
Atisane diterpenoids
Intramolecular DielseAlder reaction
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
neuroprotective activity.10 Similarly, several diterpenoids having
highly oxygenated ent-atisane framework were isolated from liv-
Creation of structural, functional, and stereochemical complexity
from simple precursors is an important aspect of contemporary
design and development of synthetic methodology.1 Cascade/tan-
dem reactions and multi-component reactions are some of the
methods to achieve this objective.2 Recently, there has been an up-
erwort Lepidolaena clavigera,11a Isodon albopilosus,11b and Euphorbia
nematocypha11c and some of these exhibit cytotoxic activity.11b
Though atisane diterpenoids are known for long time, only a few
synthetic routes have been developed.12e14 Iahara and co-workers
employed a novel double Michael addition methodology toward
the synthesis of atisane framework.12a Ghatak and co-workers de-
veloped a new method for the synthesis of atisane framework by
addition of diazo-ketone.12b,c Toyota and co-workers developed
a radical cyclization method to generate bridged bicyclo[2.2.2]oc-
tane framework.13 Recently, Abad and co-workers have also
surge of interest in the chemistry of reactive species such as
a,a-
dialkoxycyclohexa-2,4-dienone, -hydroxy-cyclohexa-2,4-dienone,
a
and spiroepoxycyclohexa-2,4-dienones generated by oxidative
dearomatization of arenols and reactions of these species have
proved to be an important tool for efficient creation of molecular
complexity.3e8 Atisane diterpenoids have generated significant in-
terest on account of their complex tetracyclic architecture contain-
ing spiro-fused bicyclo[2.2.2]octane ring system and important
biological properties exhibited by some members of this family.9e11
While atiserinic acid 1 and gummiferolic acid 2 (Fig. 1) are some of
the older members of this family,9c,d recently, many other diterpe-
noids have been isolated from various natural sources.10,11 For ex-
ample, serofendic acid A 3 was isolated from calf serum and exhibits
O
S
O
R
HO
Me
H
H
Me
H
H
R
Me
H
H
H
Me
HO2C
4
Me
CO2Et
3
1, R = H
CO2H
2, R = OCOC(Me)=CHMe
* Corresponding author. Tel.: þ91 22 2576 7168; fax: þ91 22 2576 7152; e-mail
address: vks@chem.iitb.ac.in (V. Singh).
Fig. 1. Atisane diterpenoids and tetracyclic compound 4.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.051

138
V. Singh et al. / Tetrahedron 69 (2013) 137e146
developed the synthesis of several atisane diterpenoids employing
diazo-ketone addition across a C]C bond and rearrangement of the
resulting cyclopropane derivative to create bridged bicyclo[2.2.2]
octane framework of atisanes.14b,c
In view of our continuing interest in creation of molecular com-
plexity from simple aromatics employing 6,6-spiroepoxycyclohexa-
2,4-dienones,8 and in order to expand the scope of our methodology,
we considered exploring a route for the synthesis of tetracyclic
network of atisanes such as 4 and wish to delineate our results
herein.
2. Result and discussion
In principle, bridged bicyclo[2.2.2]octanes of type 6 may be
prepared by
p
4sþ
p
2s cycloaddition between cyclohexa-2,4-
dienone I (Fig. 2) and acrylate. However, cyclohexadienone I is
a keto-tautomer of the corresponding phenol and there are no
suitable methods for its preparation. Hence, we considered
employing spiroepoxycyclohexa-2,4-dienone of type 8 as a syn-
thetic equivalent of I. We thought that oxidative dearomatization
of o-hydroxymethyl phenols would generate cyclohexadienone 8
that upon interception with acrylate followed by manipulation of
the resulting adduct would give a bicyclic compound of type 6. At
the outset, however, we were aware that spirocyclohexadienone
Our plan toward the synthesis of tetracyclic core structure 4 is
outlined in Scheme 1. We envisaged that tetracyclic compound of
type 4 would be accessible in a single step through intramolecular
p
4sþ
p
2s cycloaddition in the bridged bicyclic precursor 5 endowed
of type
8 has fleeting existence and readily undergoes
with appropriate tethers. The precursor of type 5 was thought to be
amenable from keto-ester 6 via the manipulation of ester func-
tionality. Keto-ester 6 would be derived from the keto-epoxide of
type 7, which in turn, was thought to be obtained from aromatic
precursor 9 via oxidative dearomatization to spiroepoxycyclohexa-
2,4-dienone of type 8 and intermolecular cycloaddition with ethyl
acrylate (Scheme 1).
dimerization.
O
R
O
R
O
COOR
I
8
O
O
O
Fig. 2. Cyclohexa-2,4-dienones and potential dienophile.
R
R
R
H
H
H
In order to realize the aforementioned objective, aromatic pre-
cursors 9a,b were prepared from readily available8d,e hydrox-
ymethyl phenols 10a,b as shown in Scheme 2. Thus, the protection
of the hydroxyl groups in 10a followed by hydroboration and
subsequent oxidation gave the known8e aldehyde 11a. Wittig ole-
fination of 11a followed by the removal of the protecting group
furnished the desired aromatic precursor 9a containing a butenyl
chain. Similarly, compound 10b was also converted into precursor
9b (Scheme 2).
CO2Et
O
H
6a,b
4a,b
5a,b
CO2Et
CO2Et
O
O
OH
OH
R
[O]
O
Toward the synthesis of adduct of type 7, we first attempted
oxidative dearomatization of 9a for in situ generation of cyclo-
hexadienone 8a and interception with ethyl acrylate. Thus,
a solution of o-hydroxymethyl phenol 9a in acetonitrile was
oxidized with aq NaIO4 in the presence of ethyl acrylate fol-
lowing an earlier procedure developed in our laboratory.15
However, it did not give adduct 7a, instead the dimer 12 was
obtained. It appeared that the failure to obtain adduct 7a during
oxidation of 9a under ambient conditions (0 ꢀCert) is pre-
sumably due to the greater propensity of cyclohexadienone 8a
toward dimerization as compared to the intermolecular cyclo-
addition with ethyl acrylate. Therefore, we contemplated that
the generation of cyclohexadienone 8a via retro-DielseAlder
reaction of dimer 12 at elevated temperature in the presence of
ethyl acrylate may lead to the desired adduct 7a. Indeed, py-
rolysis of epoxy dimer 12 in o-dichlorobenzene at 140 ꢀC in the
presence of ethyl acrylate gave endo adduct 7a in excellent yield
as a result of retro-DielseAlder/intermolecular DielseAlder cas-
cade reaction (Scheme 3).
CO2Et
CO2Et
R
8a,b
R
7a,b
9a,b
a, R = H; b, R = Me
Scheme 1. Retro-synthetic strategy for tetracyclic systems 4a,b.
Some interesting features of our strategy are as follows. The
bicyclo[2.2.2]octane ring system of atisane is generated from an
aromatic precursor in the very beginning of synthetic route. Fur-
ther, the four-carbon olefinic chain required at the bridgehead in
the crucial precursor 5 is derived from the aromatic precursor 9
itself, and the other olefinic tether containing diene moiety will be
introduced by manipulation of the endo ester group thus keeping
both the tethers in a cis-stereochemical disposition as required.
Moreover, mutually compatible functional groups in adduct 7
permit further manipulation in a regioselective manner so as to
prepare the key precursor for intramolecular inverse electron de-
mand DielseAlder reaction.
Me
Me
O
OH OH
O
OH OH
1. Ph3P=CH2
THF, rt
1. 2,2-dimethoxy-
propane, p-TSA
CHO
2. aq. HCl
2. NaBH4-I2
NaOH-H2O2
R
R
R
10a,b
3. PCC
a, R = H; b, R = Me
9a (73%), b (72%)
11a (67%), b (53%)
(3 steps)
(both steps)
Scheme 2. Preparation of aromatic precursors 9a,b.

V. Singh et al. / Tetrahedron 69 (2013) 137e146
139
glycol in the presence of p-TSA gave acetal 14a in excellent yield
that upon reduction with LiAlH4 gave alcohol 15a.
O
O
OH OH
aq. NaIO4
MeCN
oC to rt
O
CO2Et
X
O
O
OH
0
H
CO2Et
85%
8a
O
9a
O
O
7a
R
R
HO(CH2)2OH
R
1.Jones'
Zn
7a, b
p-TSA
2. aq. THF, Δ
CO2Et
13a (97%)
13b (92%)
NH4Cl
aq. MeOH
rt
O
EtO2C
CO2Et
14a (91%)
14b (64%)
O
benzene
CO2Et
O
Δ
6a (60%)
140 o
C
6b (60%)
LiAlH4
Ether
8a
a, R = H; b, R = Me
O
o-dichloro-
benzene
O
O
O
Triethyl-4-
phosphono-
crotonate
12 (78%)
O
O
R
R
Scheme 3. Synthesis of keto-epoxide 7a.
aq. HCl
acetone
nBuLi, THF
-78 o
C
On the other hand, oxidation of a solution of aromatic precursor
9b in acetonitrile containing ethyl acrylate directly furnished ad-
duct 7b in reasonably good yield (Scheme 4) as a consequence of
the in situ generation of cyclohexadienone 8b and subsequent cy-
cloaddition with ethyl acrylate under ambient conditions. It is in-
teresting to note the effect of C-4 methyl group on the reactivity of
8b (compared to 8a) toward cycloaddition with ethyl acrylate.
X
15a (93%),15b
CO2Et
(98%)
5a
17a (94%)
17b (80%)
TPAP
NMO
(96%), X = CH2OH
16a (98%), 16b
(96%), X = CHO
CO2Et
Scheme 5. Synthesis of precursors for IMDA reaction.
Similarly, adduct 7b was also converted into alcohol 15b. Oxi-
dation of 15a,b with TPAPeNMO gave aldehydes 16a,b, re-
spectively, in excellent yield. Subsequent olefination in 16a,b gave
compounds 17a,b having appropriate tethers in good yield. Re-
moval of the acetal group in 17a furnished the desired IMDA pre-
cursor 5a (Scheme 5). The structures of all the compounds were
deduced from their spectral data. The structure of keto-ester 5a was
further confirmed by single crystal X-ray structure determination
(Fig. 3) that also established structure of its progenitors.
O
OH OH
aq. NaIO4
MeCN
O
O
Me
O
CO2Et
0
oC to rt
CO2Et
8b
Me
Me
9b
7b (57%)
Scheme 4. Synthesis of keto-epoxide 7b.
The structure of both adducts was deduced from their spectral
features. The IR spectrum of the adduct 7a showed a broad ab-
sorption band at 1733 cmꢁ1 due to carbonyl groups. 1H NMR
(400 MHz) spectrum displayed characteristic signals at
J1¼8.2 Hz, J2¼7 Hz,1H) and 6.06 (m of d, J¼8.2 Hz,1H) for the
-proton of -enone moiety. Olefinic protons of butenyl chain
showed signals at 5.91e5.80 (m, 1H) and 5.08e4.94 (m, 2H).
Methylene protons of the oxirane moiety appeared as AB quartet at
3.16 (part of an AB system, JAB¼6.0 Hz, 1H) and 2.87 (part of an AB
system, JAB¼6.0 Hz, 1H). The methylene protons of the carboethoxy
group were observed at 4.21e4.08 (m, 2H). In addition, signals
were shown at 2.66e2.61 (m, 1H), 2.52e2.42 (m, 1H), 2.30e2.13
d
6.61 (dd,
g- and
b
b,g
d
d
d
d
(m, 2H), 1.95e1.75 (m, 3H), and 1.27 (t, J¼7.0 Hz, 3H) due to other
Fig. 3. X-ray crystal structure of compound 5a.
protons. The 13C NMR (100 MHz) spectrum exhibited signals at
d
204.0 and 173.1 for the carbonyl group of the ketone and ester
moiety, respectively. Further signals were observed at 138.5,
134.0, 131.1, and 114.6 for four olefinic carbons. In addition, signals
were observed at 61.0, 57.8, 54.6, 53.4, 43.5, 38.1, 29.3, 29.2, 28.6,
d
d
After having developed the synthesis of embellished bridged
bicyclo[2.2.2]octenones endowed with appropriate tethers, we set
out to explore an intramolecular DielseAlder reaction in 5a. Diel-
seAlder reaction, both inter- and intramolecular, is a powerful tool
and constitutes a versatile method for the synthesis of complex
molecular structures,16e19 the latter is often controlled by subtle
structural, stereochemical, and electronic factors. There are a large
number of intramolecular reactions between electron rich diene
and activated dienophiles, intramolecular DielseAlder reaction
between electron deficient diene and unactivated dienophiles is
rare.
Keeping the above in mind, we attempted IMDA reaction in
compound 5a. Thus, a solution of compound 5a in toluene was
heated in a sealed tube. Unfortunately, it did not give adduct, in-
stead a complex mixture was formed (Scheme 6). Lewis acid-me-
diated cycloaddition employing Sc(OTf)3 and TiCl4 as catalyst at low
temperature was also not fruitful.
and 14.3 for the other carbons. These spectral characteristics clearly
suggested the structure of adduct 7a. The endo stereochemical
disposition of the carboethoxy group was confirmed through
chemical transformation and crystal structure of a derivative of 7a
(vide infra). Stereochemistry of the oxirane ring, though it would be
lost during further transformation, was suggested on the basis of
the general tendency of the spiroepoxycyclohexa-2,4-dienones
during their cycloaddition. The adduct 7b also exhibited similar
spectral characteristics.
The presence of compatible functional groups in adducts 7a,b
provided a unique opportunity for regioselective manipulation and
synthesis of precursors for intramolecular DielseAlder (IMDA) re-
action. Thus, reduction of 7a with ZneNH4Cl in aq MeOH gave b-
hydroxymethyl keto-ester 13a in excellent yield. Oxidation of 13a
with Jones reagent followed by decarboxylation readily gave keto-
ester 6a (Scheme 5). Treatment of compound 6a with ethylene

140
V. Singh et al. / Tetrahedron 69 (2013) 137e146
with signal due to H2O present in CDCl3, 3H), 1.40e1.17 (m merged
O
O
with t, J¼7.0 Hz, total 6H), and 1.10e1.03 (m, 1H) for other protons.
The 13C NMR (100 MHz, CDCl3) spectrum of 18b showed signals at
Δ
X
d
174.3 for the CO group of the ester moiety. The presence of only
four signals at 143.5, 132.3, 125.7, 124.4 for olefinic carbons also
suggested that cycloaddition had taken place. Other carbons dis-
played signals at 114.7, 65.2, 64.7, 60.6, 46.6, 45.9, 42.3, 40.9, 38.4,
or
Lewis acids
d
d
36.7, 36.6, 31.45, 31.41, 29.3, 26.5, 20.2, and 14.4, thus accounting for
all the 22 carbons.
5a
CO2Et
CO2Et
Similarly, the keto-ester 4b displayed signals at
2H) and 5.39 (br s, 1H) for three olefinic protons in its 1H NMR
(400 MHz, CDCl3) spectrum. Further signals were shown at 4.14
(q, J¼7.1 Hz, 2H), 3.09e3.04 (m, 1H), 2.68e2.63 (m, 1H), 2.15e1.96
(complex m, total 4H), 1.86 (s, 3H), 1.84e1.68 (m, 3H), 1.63e1.53 (m
merged with the signal due to H2O in CDCl3, 1H), 1.52e1.18 (cluster
of m merged with t, J¼7.1 Hz, total 8H) for the other protons. The
13C NMR (100 MHz, CDCl3) spectrum of 4b also corroborated with
d 5.82e5.72 (m,
Scheme 6. Attempted IMDA reaction in compound 5a.
It was rather difficult to understand the aforementioned failure.
d
We surmised that the presence of carbonyl group in 5a at the
ethano-bridge, perhaps, controls the intramolecular DielseAlder
reaction in a subtle fashion (via geometrical constrains). At this
juncture, therefore, we considered exploring DielseAlder reaction
in the acetal 17a especially since it was thought that the presence of
five-membered ring acetal moiety in 17a may bring olefinic tethers
in closer proximity that might facilitate the desired intramolecular
DielseAlder reaction.
its structure as it showed signals at
ethano-bridge and CO of ester moiety, respectively. Further signals
were observed at 146.5, 131.3, 125.4, 122.4 due to four olefinic
carbons. In addition, signals were shown at 60.8, 53.3, 45.6, 40.8,
d 213.3,174.0 for CO group at the
d
Indeed, heating a solution of 17a in toluene at 175 ꢀC in a sealed
tube followed by removal of solvent and chromatography furnished
the desired adduct 18a as a sole product in excellent yield (Scheme 7).
Itwasdelightful to observe sucha rare and dramatic effectof a remote
functional group on the IMDA reaction. Subsequent treatment of 17a
with aq HCl in acetone gave the tetracyclic keto-ester 4a.
d
40.3, 39.3, 36.8, 36.3, 31.3, 31.2, 28.8, 27.4, 20.3, 14.3 for other car-
bons. The compounds 18a and 4a also exhibited similar spectral
characteristics.
The aforementioned spectral data of compounds 18b and 4b
clearly suggested their gross tetracyclic structures, however, it was
difficult to ascertain the stereochemistry of the newly generated
stereogenic centers from the spectral data alone. Therefore, a single
crystal X-ray analysis of compound 4b was undertaken (Fig. 4),
which confirmed its structure and stereochemistry. Hence, struc-
ture of the adduct 18b and its precursors was also established. The
structure and stereochemistry of adduct 18a and keto-ester 4a
were suggested on the basis of spectral data and comparison with
structural features of 18b and 4b, respectively.
O
O
O
O
O
toluene
sealed tube
aq. HCl
acetone
H
175 o
24 h
C
H
H
H
18a
4a (69%)
CO2Et
17a
CO Et
(80%)
2
CO2Et
O
O
Me
O
Me
175 o C, 18 h
175 o C, 18 h
H
17b
H
chromato-
graphy on
SiO2
chromatography
on SiO2
(prewashed with
triethyl amine)
H
H
4b
18b (90%)
CO2Et
(90%)
CO2Et
Scheme 7. Synthesis of tetracyclic compounds 4a,b.
Fig. 4. X-ray crystal structure of 4b.
Similarly, acetal 17b also underwent a smooth IMDA reaction
upon heating to give the corresponding adduct (1H NMR) that upon
chromatography on silica gel gave the keto-ester 4b as a result of
hydrolysis of acetal moiety. Subsequently, the reaction mixture was
chromatographed on silica gel (prewashed with triethyl amine)
that furnished adduct 18b in excellent yield (Scheme 7).
3. Conclusion
In summary, we have developed a stereoselective route to tet-
racyclic framework of atisane diterpenoids. The methodology in-
volves synthesis of functionalized and appended bridged bicyclo
[2.2.2]octane from simple aromatic precursors employing in situ
generation of spiroepoxycyclohexa-2,4-dienones and cycloaddition
with ethyl acrylate. The functional groups in cycloadducts readily
permitted selective manipulation that led to synthesis of advanced
precursors having bridged bicyclo[2.2.2]octane ring system
endowed with appropriate tethers for intramolecular DielseAlder
reaction. Heating the precursors 17a,b led to a smooth and ster-
eoselective inverse electron demand intramolecular DielseAlder
reaction to give the tetracyclic framework of atisane diterpenoids. A
highly remarkable effect of a remote functionality on the intra-
molecular cycloaddition is observed.
The structure of adducts and their derivative was deduced from
their spectral features and comparison with the spectral features of
4b whose structure and stereochemistry were further confirmed by
single crystal structure determination (vide infra).
Thus, 1H NMR (400 MHz, CDCl3) spectrum of adduct 18b dis-
played signals at
d 5.81e5.69 (m, 2H) and 5.58 (br s, 1H) for the
presence of only three olefinic protons, which clearly indicated that
intramolecular DielseAlder reaction had occurred. Further, signals
were observed at
oxymethylene protons of ester and acetal moieties, respectively. In
addition, resonances were observed at 3.12e3.00 (m, 1H),
d
4.13 (q, J¼7.0 Hz, 2H), 3.91e3.80 (m, 4H) for
d
2.38e2.32 (m, 1H), 2.04 (d, J¼12.0 Hz, 1H), 1.91e1.71 (m overlapped
The present methodology constitutes a nice example of creation
of molecular complexity from simple aromatics, which is an
with d, J¼1.5 Hz, total 5H), 1.68e1.62 (m, 2H), 1.60e1.50 (m merged

V. Singh et al. / Tetrahedron 69 (2013) 137e146
141
important aspect of synthesis design. Simplicity of the reagents and
4.2. 2-(But-3-enyl)-6-hydroxymethyl phenol (9a)
conditions employed in synthesis are additional interesting
features.
To a stirred suspension of methyltriphenyl phosphonium iodide
(8.20 g, 20.29 mmol) in dry THF (100 mL) was added t-BuOK (2.60 g,
23.00 mmol) at 0 ꢀC and the reaction mixture was stirred for 1 h at
ambient temperature. The resulting ylide was cooled to 0 ꢀC and
a solution of the aldehyde 11a (3.20 g, 14.54 mmol) in dry THF
(10 mL) was added dropwise. After complete addition, the reaction
mixture was stirred for 4 h at ambient temperature. After com-
pletion of reaction (TLC) the reaction mixture was quenched with
cold water and extracted with ether (3ꢂ30 mL). The combined
extract was dried on anhydrous Na2SO4. Removal of solvent under
reduced pressure gave the crude product that was purified by
column chromatography. Elution with petroleumether/ethyl ace-
tate (97:3) gave the desired product (2.5 g 79%) as a clear liquid
[Rf¼0.5 petroleum ether/EtOAc (95:5)] [IR (neat) nmax: 1638 cmꢁ1
4. Experimental section
4.1. 2,2,6-Trimethyl-8-(3-propanal)-1,3-benzodioxin (11b)
To a solution of dio1 10b (9.00 g, 50.56 mmol) in acetone
(150 mL) were added 2,2-dimethoxypropane (9.2 mL, 7.88 g,
75.76 mmol) and p-TSA (100 mg). The reaction mixture was stirred
at ambient temperature. After completion of reaction (TLC, 6 h),
solid sodium bicarbonate was added and the reaction mixture was
concentrated under reduced pressure. The residue was diluted with
water (100 mL) and extracted with diethyl ether (2ꢂ100 mL),
washed with brine (50 mL), and dried on anhydrous Na2SO4. Sol-
vent was removed under reduced pressure and the product was
chromatographed on silica gel. Elution with petroleum ether/ethyl
acetate (96:4) gave the protected compound (9.0 g, 81%). Rf¼0.5
petroleum ether/ethyl acetate (95:05) [IR (neat) vmax: 2942,
1H NMR (400 MHz, CDCl3):
d 7.04e6.98 (m, 1H), 6.84e6.78 (m, 2H),
5.93e5.82 (complex m, 1H), 5.02 (m of d, J¼16.3 Hz, 1H), 4.95 (m of
d, J¼10.9 Hz, 1H), 4.83 (s, 2H), 2.68e2.64 (m, 2H), 2.37e2.30 (m,
2H), 1.54 (s, partly merged with signal due to H2O present in CDCl3,
1511 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
6.83 (s, 1H), 6.66 (s, 1H),
6H). 13C NMR (100 MHz, CDCl3):
d 149.1, 138.7, 129.9, 128.3, 122.3,
6.01e5.90 (complex m, 1H), 5.09e4.99 (m, 2H), 4.80 (s, 2H), 3.29 (br
119.8, 119.0, 114.5, 99.3, 61.1, 33.9, 29.2, 24.9]. This product was
subjected to hydrolysis as follows.
d, J¼6.6 Hz, 2H), 2.23 (s, 3H), 1.51 (s, 6H). 13C NMR (100 MHz,
CDCl3):
d
146.7, 137.0, 129.3, 129.0, 128.1, 122.9, 119.0, 115.4, 99.4,
To a stirred solution of above product (2.50 g, 11.46 mmol) in
THF/H2O (1:1, 160 mL) was added concd HCl (6 mL 35%) at w5 ꢀC
and the reaction mixture was stirred at ambient temperature for
8 h. After which, some more HCl (2 mL 35%) was added and the
reaction mixture was further stirred for 2 h. After completion of
reaction (w2 h, TLC), the reaction mixture was cooled to 0 ꢀC and
quenched by the addition of excess solid sodium bicarbonate. The
organic solvent was removed under reduced pressure and the
aqueous solution was extracted with ethyl acetate (3ꢂ100 mL). The
combined organic layer was washed with brine (30 mL) and dried
on anhydrous Na2SO4 and concentrated in vacuo. The crude prod-
uct was chromatographed on silica gel. Elution with petroleum
ether/EtOAc (80:20) provided compound 9a (1.9 g, 93%) as a color-
61.1, 33.8, 24.9, 20.8]. This product was subjected to hydroboration
as described below.
To a suspension of sodium borohydride (2.35 g, 61.84 mmol) in
dry THF (50 mL) was slowly added a dilute solution of iodine
(5.80 g, 22.83 mmol) in dry THF (70 mL) under nitrogen atmo-
sphere at 0 ꢀC. The addition was complete in 2 h. It was further
stirred for 30 min. A solution of the above compound (5.00 g,
22.93 mmol) in THF (15 mL) was then added to the reaction mixture
and it was stirred for 2 h at ambient temperature. The reaction
mixture was cooled to 0 ꢀC and water (20 mL) followed by a solu-
tion of NaOH (3 N, 70 mL) were added to the reaction mixture at
0
ꢀC. Subsequently, H2O2 (30%, 70 mL) was added to the reaction
mixture slowly and stirred for 1 h. The organic layer was separated
and the aqueous layer was extracted with ether (3ꢂ100 mL). The
combined organic extract was washed with brine and dried on
anhydrous sodium sulfate and concentrated in vacuo. The crude
product was chromatographed on silica gel. Elution with petroleum
ether/EtOAc (80:20) provided an alcohol (5.3 g, 98%). Rf¼0.5 pe-
troleum ether/ethyl acetate (80:20) [IR (neat) nmax: 3399 cmꢁ1 1H
less liquid [Rf¼0.5 petroleum ether/EtOAc (80:20)]. IR (neat) vmax
:
3421, 2929 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
7.49 (br s, 1H), 7.10
(dd, J1¼6.0 Hz, J2¼2.0 Hz, 1H), 6.89 (dd, J1¼6 Hz, J2¼2 Hz, 1H), 6.79
(superimposed dd, J¼8 Hz, 1H), 5.96e5.84 (m, 1H), 5.06 (m of d,
J¼18.0 Hz, 1H), 4.98 (m of d, J¼10.0 Hz, 1H), 4.86 (s, 2H), 2.77e2.71
(m, 2H), 2.42e2.35 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 154.5,
138.7, 130.3, 129.5, 125.7, 124.2, 119.7, 114.8, 65.3, 34.0, 29.5. HRMS
NMR (400 MHz, CDCl3):
d
6.85 (s, 1H), 6.63 (s, 1H), 4.80 (s, 2H), 3.58
(ESI) (m/z): found 179.1072 [MþH]þ; calcd for C11H15O2 179.1069.
(dd, J1¼6.2 Hz, J2¼2.5 Hz, 2H), 2.65 (t, J¼7.5 Hz, 2H), 2.24 (s, 3H),
2.00 (br s, 1H), 1.86e1.79 (m, 2H), 1.54 (s, 6H). 13C NMR (100 MHz,
4.3. 2-(But-3-enyl)-4-methyl-6-hydroxymethylphenol (9b)
CDCl3):
d 146.9, 129.6, 129.4, 122.9, 188.9, 99.6, 61.7, 61.1, 33.1, 25.1,
24.8, 20.7. HRMS (ESI) (m/z): found 237.1492 [MþH]þ; calcd for
C14H21O3 237.1491]. This alcohol was then oxidized with PCC as
follows.
The reaction of compound 11b (3.00 g, 12.82 mmol) with
methyltriphenyl phosphonium iodide (8.20 g, 20.29 mmol) and t-
BuOK (2.80 g, 24.77 mmol) according to the aforementioned pro-
cedure followed by work-up and chromatography (elution with
petroleum ether/ethyl acetate 95:5) furnished an alkene as a clear
liquid (2.4 g, 80%) [Rf¼0.5 petroleum ether/EtOAc (95:5)] [IR (neat)
To a stirred solution of the above alcohol (5.0 g, 21.18 mmol) in
dichloromethane (100 mL) was cooled to 0 ꢀC and PCC (11.38 g,
52.93 mmol) was added in one portion. The reaction mixture was
stirred for 6 h at room temperature. The reaction mixture was fil-
tered through a column of dry silica gel and washed with
dichloromethane. The combined filtrate was dried on Na2SO4,
concentrated under reduced pressure, and the product was purified
by column chromatography on silica gel. Elution with petroleum
ether/EtOAc (95:5) provided the aldehyde 11b (3.3 g, 67%) [Rf¼0.5
petroleum ether/ethyl acetate (95:5)]. IR (neat) vmax: 1720 cmꢁ1 1H
vmax: 2921,1481 cmꢁ1 1H NMR (400 MHz, CDCl3):
d 6.83 (s,1H), 6.61
(s, 1H), 5.92e5.81 (m, 1H), 5.03 (d, J¼16.3 Hz, 1H), 4.95 (d,
J¼10.9 Hz, 1H), 4.80 (s, 2H), 2.62 (t, J¼14.8 Hz, 2H), 2.31 (dd,
J1¼14.8 Hz, J2¼8.8 Hz, 2H), 2.23 (s, 3H), 1.52 (s, 6H). 13C NMR
(100 MHz, CDCl3):
d 146.9, 138.9, 129.8, 129.3, 129.1, 122.7, 118.9,
114.6, 99.3, 61.2, 34.1, 29.4, 25.0, 20.8].
Hydrolysis of the above product (1.30 g, 5.60 mmol) by aq HCl as
described earlier followed by work-up and column chromatogra-
phy [elution with petroleum ether/ethyl acetate (85:15)] gave the
desired aromatic precursor 9b (0.970 g, 90%) as a clear liquid
[Rf¼0.5 petroleum ether/EtOAc (90:10)]. IR (neat) vmax: 3393,
NMR (400 MHz, CDCl3):
1H), 4.79 (s, 2H), 2.90e2.84 (m, 2H), 2.71e2.67 (m, 2H), 2.23 (s, 3H),
1.51 (s, 6H). 13C NMR (100 MHz, CDCl3):
202.6, 146.9, 129.39,
d
9.80 (t, J¼3.3 Hz, 1H), 6.83 (s, 1H), 6.64 (s,
d
129.32, 128.1, 123.3, 119.1, 99.5, 61.0, 43.9, 24.9, 22.9, 20.7. HRMS
(ESI) (m/z): found 257.1152 [MþNa]þ; calcd for C14H18O3Na
257.1154.
1481 cmꢁ1 1H NMR (400 MHz, CDCl3):
d 7.30 (s, 1H), 6.86 (s, 1H),
6.62 (s, 1H), 5.93e5.82 (m, 1H), 5.05 (m of d, J¼17.1 Hz, 2H), 4.96 (d,

142
V. Singh et al. / Tetrahedron 69 (2013) 137e146
J¼11.4 Hz, 1H), 4.68 (s, 2H), 2.86 (br s, 1H), 2.65 (t, J¼7.5 Hz, 2H),
2.35 (dd, J1¼7.5 Hz, J2¼6.7 Hz, 2H), 2.20 (s, 3H). 13C NMR (100 MHz,
The solvent was removed under reduced pressure and the residue
was chromatographed on silica gel. Elution with petroleum ether/
ethyl acetate (90:10) gave compound 7b (0.430 g, 57%) as a clear
liquid [Rf¼0.5 petroleum ether/EtOAc (90:10)]. IR (neat) nmax: 3393,
CDCl3):
d 151.8, 138.8, 130.7, 129.1, 128.9, 126.4, 124.3, 114.9, 64.8,
34.1, 29.5, 20.6. HRMS (ESI) (m/z): found 215.1048 [MþNa]þ; calcd
for C12H16O2Na 215.1056.
1715 cmꢁ1 1H NMR (400 MHz, CDCl3):
d 5.89e5.79 (m, 1H), 5.61 (br
s, 1H), 5.03 (m of d, J¼16.9 Hz, 1H), 4.95 (m of d, J¼10.7 Hz, 1H),
4.20e4.08 (m, 2H), 3.14 (part of an AB system JAB¼6.1 Hz, 1H),
2.92e2.87 (part of an AB system merged with another m,
JAB¼6.1 Hz, total 2H), 2.44e2.36 (m, 2H), 2.28e2.13 (m, 2H), 1.95 (s,
3H), 1.89e1.81 (m, 2H), 1.78e1.70 (m, 1H), 1.26 (t, J¼7.0 Hz, 3H). 13C
4.4. 6,9-Bis-spiroepoxy-1,4-bis-(buten-3-yl)-tricyclo[6.2.2.02,7
dodec-3,11-dien-5,10-dione (12)
]
To a stirred solution of compound 9a (10.00 g, 45.87 mmol) in
acetonitrile (150 mL) was added a solution of NaIO4 (24.54 g,
114.67 mmol) in water (150 mL) dropwise at 10 ꢀC (2 h). The re-
action mixture was then stirred for 3 h at ambient temperature. The
reaction mixture was filtered on a Celite bed to remove inorganic
salts. The organic layer was separated from the filtrate and the
aqueous layer was extracted with ethyl acetate (3ꢂ80 mL). The
organic extracts were combined and washed with brine (50 mL).
The solvent was evaporated under reduced pressure, dried on an-
hydrous Na2SO4 and the residue was chromatographed on silica gel.
Elution with petroleum ether/ethyl acetate (75:25) gave compound
12 (7.71 g, 78%) as a thick liquid [Rf¼0.5 petroleum ether/EtOAc
(75:25)]. IR (neat) nmax: 1733, 1689 cmꢁ1 1H NMR (400 MHz, CDCl3):
NMR (100 MHz, CDCl3): d 204.2,173.3,143.9, 138.7,123.1,114.5, 61.0,
57.8, 54.6, 52.6, 44.0, 43.4, 29.4, 28.7, 20.8, 14.3. HRMS (ESI) (m/z):
found 291.1589 [MþH]þ; calcd for C17H23O4 291.1596.
4.7. Ethyl-1-(but-3-en-yl)-6-oxo-bicyclo[2.2.2]oct-7-en-2-carbo-
xylate (6a)
To a solution of adduct 7a (3.9 g, 14.13 mmol) in MeOH/H2O (6:1,
50 mL) were added zinc (activated, 32 g, excess) and NH4Cl (4.00 g,
76.22 mmol). The reaction mixture was stirred at ambient tem-
perature (30 ꢀC) for 12 h. It was filtered on a Celite bed and washed
with ethyl acetate. The filtrate was concentrated under vacuum,
and the residue was diluted with water (15 mL) and extracted with
ethyl acetate (4ꢂ25 mL). The combined extract was washed with
brine and dried. The solvent was removed under reduced pressure
and the product was purified by column chromatography. Elution
with petroleum ether/ethyl acetate (65:35) gave a keto-alcohol 13a
(3.8 g, 97%, mixture of syn:anti isomers) as a colorless liquid [Rf¼0.5
petroleum ether/EtOAc (75:35)]. IR (neat) nmax: 3445, 1717 cmꢁ1 1H
d
6.59 (dd, J1¼8.2 Hz, J2¼6.8 Hz, 1H), 6.44 (d, J¼6.8 Hz, 1H),
5.96e5.81 (m, 2H), 5.78e5.67 (m, 1H), 5.11 (m of d, J¼16.5 Hz, 1H),
5.05e4.97 (complex m, total 3H), 3.31 (dd, J1¼9 Hz, J2¼6.3 Hz, 1H),
3.13 (part of an AB system JAB¼6.3 Hz, 1H), 2.91 (part of an AB
system JAB¼6.3 Hz, 1H), 2.88 (m of d, J¼7.2 Hz, 1H), 2.83 (s, 2H), 2.73
(dd, J1¼9 Hz, J2¼1.8 Hz, 1H), 2.41e2.34 (m, 2H), 2.29e2.16 (m, 4H),
2.01e1.88 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 204.9, 193.1, 143.0,
139.8, 138.1, 137.6, 133.8, 133.5, 115.8, 115.2, 59.1, 58.7, 58.4, 58.2,
54.0, 41.2, 40.6, 39.8, 32.4, 29.6, 28.9, 28.8. HRMS (ESI) (m/z): found
353.1756 [MþH]þ; calcd for C22H25O4 353.1753.
NMR (400 MHz, CDCl3):
d
6.70 (superimposed dd, J¼7.2 Hz, 1H),
6.00 (d, J¼7.2 Hz, 1H), 5.90e5.79 (m, 1H), 5.03 (m of d, J¼18.1 Hz,
1H), 5.15 (m of d, J¼10.9 Hz, 1H), 4.18e4.06 (m, 2H), 3.82 (dd,
J1¼11.4 Hz, J2¼5.7 Hz, 1H), 3.71e3.63 (m, 1H), 2.80e2.60 (m, total
2H), 2.23e2.05 (m, 4H), 2.00e1.80 (m, 2H), 1.65e1.59 (m merged
with signal due to H2O present in CDCl3, 1H), 1.30e1.20 (m, total
4H) (signals due to major isomer). 13C NMR (100 MHz, CDCl3):
4.5. Ethyl-1-(but-3-enyl)-5-spirooxirane-6-oxo-bicyclo[2.2.2]
oct-7-en-2-carboxylate (7a)
A mixture of the dimer 12 (8.0 g, 22.72 mmol) in o-di-
chlorobenzene (30 mL) and ethyl acrylate (15 mL, excess) was
heated at 110 ꢀC for 7 h. After which, the reaction mixture was
charged on a column of silica gel. Elution with petroleum ether/
ethyl acetate (96:4) removed the o-dichlorobenzene and unreacted
ethyl acrylate. Further elution with petroleum ether/ethyl acetate
(88:12) gave the epoxy ketone 7a (10.66 g, 85%) as a colorless liquid
[Rf¼0.5 petroleum ether/EtOAc (90:10)]. IR (neat) nmax: 1733 cmꢁ1
d 213.6, 173.3, 147.1, 138.9, 121.4, 114.4, 63.0, 60.9, 54.9, 49.2, 44.8,
39.9, 29.2, 27.7, 20.3, 12.3. HRMS (ESI) (m/z): found 279.1602
[MþH]þ; calcd for C16H23O4 279.1596. The
b-keto-alcohol was
subjected to oxidation and decarboxylation as presented below.
To a stirred solution of 13a (2.5 g, 8.99 mmol) in acetone (30 mL)
was added freshly prepared Jones reagent dropwise at 0 ꢀC and the
reaction mixture was stirred for 15 min. After that, isopropanol was
added to reaction mixture to quench excess Jones reagent. Solvent
was removed under reduced pressure, the residue was diluted with
water (10 mL) and aqueous layer was extracted with ethyl acetate
(3ꢂ30 mL). Organic extract was combined and dried over anhy-
drous Na2SO4. Removal of solvent gave a keto-acid that was directly
subjected for decarboxylation.
1H NMR (400 MHz, CDCl3):
d
6.61 (dd, J1¼8.2 Hz, J2¼7 Hz, 1H), 6.06
(m of d, J¼8.2 Hz, 1H), 5.91e5.80 (m, 1H), 5.08e4.94 (m, 2H),
4.21e4.08 (m, 2H), 3.16 (part of an AB system, JAB¼6.0 Hz, 1H), 2.92
(ddd, J1¼6.6 Hz, J2¼5.4 Hz, J3¼0.9 Hz, 1H), 2.87 (part of an AB sys-
tem, JAB¼6.0 Hz, 1H), 2.66e2.61 (m, 1H), 2.52e2.42 (m, 1H),
2.30e2.13 (m, 2H),1.95e1.75 (m, 3H), 1.27 (t, J¼7.0 Hz, 3H). 13C NMR
Thus, the carboxylic acid thus obtained was dissolved in THF/
H2O (1:1, 80 mL) and the reaction mixture was refluxed for 18 h.
After that it was saturated with NaCl, organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (3ꢂ20 mL).
Organic extract was combined and dried on anhydrous Na2SO4. The
solvent was removed under reduced pressure and the product was
purified by column chromatography. Elution with petroleum ether/
ethyl acetate (80:20) gave the keto-ester 6a (1.35 g, 60%) as a col-
(100 MHz, CDCl3): d 204.0, 173.1, 138.5, 134.0, 131.1, 114.6, 61.0, 57.8,
54.6, 53.4, 43.5, 38.1, 29.3, 29.2, 28.6, 14.3. HRMS (ESI) (m/z): found
299.1253 [MþNa]þ; calcd for C16H20O4Na 299.1259.
4.6. Ethyl-1-(but-3-enyl)-5-spirooxirane-6-oxo-bicyclo[2.2.2]
oct-7-en-8-methyl-2-carboxylate (7b)
To a stirred solution of the 9b (0.500 g, 2.60 mmol) in acetoni-
trile (70 mL) and ethyl acrylate (7 mL, excess) was added a solution
of NaIO4 (2.4 g, 11.21 mmol) in water (25 mL) dropwise at 0 ꢀC (4 h).
The reaction mixture was further stirred for 8 h at ambient tem-
perature. NaCl was added to the reaction mixture and filtered on
a Celite bed and washed with ethyl acetate. The organic layer was
separated from the filtrate and the aqueous layer was extracted
with ethyl acetate (3ꢂ50 mL). The organic extracts were combined
and washed with brine (50 mL) and dried on anhydrous Na2SO4.
orless liquid [Rf¼0.5 petroleum ether/EtOAc (80:20)]. IR (neat) nmax
:
2937, 1723, 1640 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
6.56 (dd,
J1¼8.7 Hz, J2¼6.2 Hz, 1H), 5.94 (d, J¼8.7 Hz, 1H), 5.91e5.80 (m, 1H),
5.03 (m of d, J¼16.9 Hz, 1H), 4.95 (m of d, J¼9.6 Hz, 1H), 4.16e4.05
(m, 2H), 3.05e2.99 (m, 1H), 2.78 (dd, J1¼9.2 Hz, J2¼5.1 Hz, 1H),
2.27e2.09 (m, 5H),1.86e1.75 (m, 3H),1.25 (t, J¼7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 210.1, 173.7, 139.0, 136.7, 129.8, 114.4, 60.9, 54.3,
42.7, 40.1, 32.9, 32.1, 29.2, 28.9, 14.3. HRMS (ESI) (m/z): found
249.1486 [MþH]þ; calcd for C15H21O3 249.1491.

V. Singh et al. / Tetrahedron 69 (2013) 137e146
143
4.8. Ethyl-1-(but-3-en-yl)-6-oxo-bicyclo[2.2.2]oct-7-en-8-
methyl-2-carboxylate (6b)
(50 mL) following aforementioned procedure and chromatography
(elution of petroleum ether/ethyl acetate 95:5) gave compound 14b
(0.150 g, 64%) [Rf¼0.5 petroleum ether/EtOAc (95:5)]. IR (neat) nmax
:
The reduction of adduct 7b (1.40 g, 4.82 mmol) with zinc (1.5 g,
excess) and NH4Cl (0.767 g, 14.47 mmol) in MeOH/H2O (6:1, 35 mL)
at ambient temperature (30 ꢀC) for 12 h, as described above fol-
lowed by work-up and chromatography (petroleum ether/ethyl
2927, 1695 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
5.87e5.76 (complex
m, 1H), 5.61 (br s, 1H), 4.99 (m of d, J¼18.0 Hz, 1H), 4.92 (m of d,
J¼10.0 Hz, 1H), 4.08 (q, J¼7.1 Hz, 2H), 3.94e3.86 (m, 4H), 3.13 (dd,
J1¼10.2 Hz, J2¼5.2 Hz, 1H), 2.48e2.44 (br m, 1H), 2.33e2.12 (m, 2H),
2.00e1.93 (m, 1H), 1.86 (d, J¼1.5 Hz, 3H), 1.84e1.72 (m, 2H),
1.69e1.66 (m, 2H), 1.60e1.52 (m, merged with signal due to H2O
present in CDCl3, 1H), 1.24 (t, J¼7.1 Hz, 3H). 13C NMR (100 MHz,
acetate 65:35) gave b-hydroxy-ketone 13b (1.3 g, 92%, mixture of
syn:anti isomers) as a clear oil [Rf¼0.5 petroleum ether/EtOAc
(75:25)]. IR (neat) nmax: 3475, 1718, 1640 cmꢁ1 1H NMR (400 MHz,
CDCl3):
d
5.90e5.78 (m, 1H), 5.55 (s, 1H), 5.02 (m of d, J¼16.8 Hz,
CDCl3): d 175.7, 143.2, 140.1, 124.8, 114.6, 113.7, 64.4, 60.3, 46.8, 42.7,
1H), 4.94 (d with str, J¼10.5 Hz, 1H), 4.18e4.04 (m, 2H), 3.80 (dd,
J1¼10.5 Hz, J2¼8.4 Hz, 1H), 3.70e3.61 (m, 1H), 2.78e2.73 (m, 1H),
2.70 (br s, 1H), 2.63 (dd, J1¼11.2 Hz, J2¼6.4 Hz, 1H), 2.27e2.06 (m,
4H), 1.94 (s, 3H), 1.91e1.78 (m, 2H), 1.67e1.58 (m, merged with
signal due to H2O present in CDCl3, 1H), 1.25 (t, J¼7 Hz, 3H). 13C
42.4, 36.4, 32.2, 29.8, 29.7, 20.2, 14.3. HRMS (ESI) (m/z): found
307.1915 [MþH]þ; calcd for C18H27O4 307.1909. Further elution with
petroleum ether/ethyl acetate (90:10) gave some unreacted 6b
(0.020 g, 10%).
NMR (100 MHz, CDCl3):
d
213.5, 173.4, 147.1, 138.9, 121.4, 114.4, 63.0,
4.11. 1-(But-3-enyl)-6-spiro(1,3-dioxalane)-2-hydroxymethyl-
bicyclo[2.2.2]oct-7-ene (15a)
60.9, 54.9, 49.4, 44.8, 39.9, 29.2, 29.0, 27.6, 20.3, 14.3. HRMS (ESI)
(m/z): found 293.1746 [MþH]þ; calcd for C17H25O4 293.1753.
The Jones oxidation of keto-alcohol 13b thus obtained (0.700 g,
2.39 mmol) in acetone (20 mL) followed by decarboxylation of the
To a stirred solution of ester 14a (1 g, 3.42 mmol) in dry ether
(50 mL) was added lithium aluminum hydride (0.195 g, 5.13 mmol)
at 0 ꢀC. After which, reaction mixture was stirred for 12 h at am-
bient temperature and the reaction was quenched by a careful
addition of water (w4 mL) dropwise at 0 ꢀC. It was filtered through
a Celite bed and washed with ethyl acetate (3ꢂ40 mL). Organic
extract was combined and dried on sodium sulfate. Removal of
solvent followed by column chromatography [elution with petro-
leum ether/ethyl acetate (75:25)] furnished the ketal-alcohol 15a as
a colorless liquid (0.800 g 93.45%) [Rf¼0.5 petroleum ether/EtOAc
(75:25)]. IR (neat) nmax: 3446, 1639 cmꢁ1 1H NMR (400 MHz,
resulting
b-keto-acid following aforementioned procedure and
chromatography (petroleum ether/ethyl acetate 80:20) gave the
keto-ester 6b (0.380 g, 60%) as a colorless liquid [Rf¼0.5 petroleum
ether/EtOAc (80:20)]. IR (neat) nmax: 1721, 1640 cmꢁ1 1H NMR
(400 MHz, CDCl3): d 5.91e5.80 (complex m,1H), 5.49 (br s,1H), 5.03
(m of d, J¼16.4 Hz, 1H), 4.94 (m of d, J¼10.2 Hz, 1H), 4.16e4.06 (m,
2H), 2.80e2.73 (m, 2H), 2.26e2.13 (m, 2H), 2.21e2.03 (m, 3H), 1.90
(d, J¼1.5 Hz, 3H), 1.81e1.72 (m, 3H), 1.25 (t, J¼7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 210.2, 173.7, 146.1, 139.1, 121.7, 114.2, 60.7, 54.2,
43.2, 39.7, 37.4, 32.2, 29.3, 28.8, 20.3, 14.3. HRMS (ESI) (m/z): found
CDCl3):
d
6.36 (dd J1¼8.0 Hz, J2¼6.6 Hz, 1H), 5.90e5.79 (merged m,
263.1653 [MþH]þ; calcd for C16H23O3 263.1647.
2H), 5.02 (m of d, J¼17.3 Hz, 1H), 4.94 (m of d, J¼9.3 Hz, 1H),
3.94e3.83 (m, 4H), 3.70 (dd, J1¼10.4 Hz, J2¼5.2 Hz, 1H), 3.31(dd,
J1¼10.4 Hz, J2¼8.6 Hz, 1H), 2.68e2.63 (br m, 1H), 2.45e2.38 (m, 1H),
2.32e2.22 (m, 2H), 1.99e1.86 (cluster of m, 2H), 1.71e1.59 (m, 3H),
4.9. Ethyl-1-(but-3-enyl)-6-spiro(1,3-dioxalane)-bicyclo[2.2.2]
oct-7-en-2-carboxylate (14a)
1.39e1.31 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 140.0, 135.4, 134.0,
A mixture of ethylene glycol (5 mL, excess), p-toluenesulphonic
acid (0.020 g, catalytic amount), and benzene (30 mL) was dried in
a DeaneStark apparatus. After that, a solution of the keto-ester 6a
(1.5 g, 6.04 mmol) in dry benzene was added to the reaction mixture
at ambient temperature and the reaction mixture was refluxed for
12 h. After which, it was cooled and poured into a cold solution of
sodium bicarbonate (30 mL) and stirred at ambient temperature. The
benzene layer was separated and the aqueous layer was extracted
with ether (3ꢂ20 mL). The combined organic layer was washed with
saturated sodium bicarbonate (2ꢂ20 mL) and dried on anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
product was chromatographed. Elution with petroleum ether/ethyl
acetate (95:5) gave the ketal-ester 14a as a colorless liquid (1.60 g,
114.9, 113.8, 65.3, 64.1, 64.0, 45.7, 43.2, 37.8, 31.0, 30.8, 29.8, 29.4.
HRMS (ESI) (m/z): found 251.1641 [MþH]þ; calcd for C15H23O3
251.1647.
4.12. 1-(But-3-enyl)-8-methyl-6-spiro(1,3-dioxalane)-2-hydrox-
ymethyl-bicyclo[2.2.2]oct-7-ene (15b)
The reaction of 14b (0.140 g, 0.457 mmol) with lithium alumi-
num hydride (0.034 g, 1.13 mmol) in dry diethyl ether (30 mL)
according to above procedure followed by chromatography (elution
of petroleum ether/ethyl acetate 75:25) gave the alcohol 15b
(0.114 g, 96.66%) [Rf¼0.5 petroleum ether/EtOAc (75:25)]. IR (neat)
nmax: 3397, 1639 cmꢁ1 1H NMR (400 MHz, CDCl3):
d 5.90e5.79
90.90%) [Rf¼0.5 petroleum ether/EtOAc (95:5)]. IR (neat) nmax
:
(complex m,1H), 5.46 (br s,1H), 5.02 (m of d, J¼17.1 Hz,1H), 4.93 (m
of d, J¼10.9 Hz, 1H), 3.95e3.82 (m, 4H), 3.69 (dd, J1¼10.4 Hz,
J2¼4.5 Hz, 1H), 3.34 (dd, J1¼10.4 Hz, J2¼7.8 Hz, 1H), 2.45e2.38 (m,
2H), 2.31e2.19 (m, 2H), 1.97e1.83 (m, 2H), 1.80 (d, J¼1.6 Hz, 3H),
1.71e1.54 (m, merged with signal due to H2O present in CDCl3, total
3H), 1.36 (m of d, J¼12.5 Hz, 1H), 1.20 (br s, 1H). 13C NMR (100 MHz,
1732 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
6.42 (dd, J1¼8.4 Hz, J2¼6 Hz,
1H), 6.03 (d, J¼8.4 Hz,1H), 5.86e5.74 (m,1H), 4.99 (m of d, J¼17.0 Hz,
1H), 4.91 (m of d, J¼11.0 Hz, 2H), 4.08 (q, J¼7.2 Hz, 2H), 3.93e3.85 (m,
4H), 3.13 (dd, J1¼15.1 Hz, J2¼8.8 Hz, 1H), 2.75e2.68 (m, 1H),
2.32e2.14 (m, 2H), 2.20 (merged ddd, J1¼13.3 Hz, J2¼10.6 Hz,
J3¼2.6 Hz, 1H), 1.89e1.74 (m, 2H), 1.72e1.64 (m, 2H), 1.58e1.50 (m,
CDCl3): d 144.8, 140.1, 126.0, 115.2, 113.8, 65.5, 64.2, 64.0, 46.0, 42.9,
1H), 1.23 (t, J¼7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
d
175.6, 139.9,
38.4, 36.4, 30.3, 29.8, 29.6, 20.2. HRMS (ESI) (m/z): found 265.1801
134.2, 132.9, 114.2, 113.8, 64.4, 64.3, 60.3, 46.2, 42.6, 42.0, 33.0, 30.8,
29.8, 29.6, 14.3. HRMS (ESI) (m/z): found 293.1762 [MþH]þ; calcd for
C17H25O4, 293.1753.
[MþH]þ; calcd for C16H25O3 265.1804.
4.13. 1-(Bute3-enyl)-6-spiro(1,3-dioxalane)-bicyclo[2.2.2]oct-
7-en-2-carboxaldehyde (16a)
4.10. Ethyl-1-(but-3-enyl)-6-spiro(1,3-dioxalane)-bicyclo[2.2.2]
oct-7-en-8-methyl-2 carboxylate (14b)
To a stirred mixture of alcohol 15a (0.350 g, 1.4 mmol), 4-
methyl-morpholine-N-oxide (NMO) (0.229 g, 1.95 mmol), and
powdered molecular sieves (4 A, 1.0 g) in dry dichloromethane
ꢀ
The treatment of 6b (0.200 g, 0.76 mmol) with ethylene glycol
(3 mL, excess) in the presence of p-TSA (0.01 g, catalytic) in benzene
(50 mL) was added TPAP (0.017 g, 0.09 mmol) at room temperature

144
V. Singh et al. / Tetrahedron 69 (2013) 137e146
under nitrogen atmosphere. The reaction mixture was further
stirred for 12 h (TLC) and filtered through a small pad of silica gel.
The filtrate was concentrated and the product was chromato-
graphed on silica gel (petroleum ether/ethyl acetate, 80:20) to give
the aldehyde 16a (0.340 g, 98%) as a colorless liquid [Rf¼0.5 pe-
troleum ether/EtOAc (80:20)]. IR (neat) nmax: 2925, 1740 cmꢁ1 1H
1.60 mmol) at ꢁ78 ꢀC. The reaction mixture was stirred for 30 min
after which a solution of the aldehyde 16b (0.060 g, 0.22 mmol) in
dry THF (5 mL) was added. The reaction mixture was further stirred
for 1 h at ꢁ78 ꢀC and it was quenched by careful addition of water
followed by brine. The organic layer was separated and aqueous
layer was extracted with ether (3ꢂ10 mL). Combined organic ex-
tract was washed with brine and dried. Removal of solvent followed
by chromatography (elution with petroleum ether/ethyl acetate
90:10) gave compound 17b (0.065 g, 80%) as a colorless liquid
[Rf¼0.5 petroleum ether/EtOAc (90:10)]. IR (neat) nmax: 1714,
NMR (400 MHz, CDCl3):
d
9.38 (d, J¼4.4 Hz, 1H), 6.47 (dd, J1¼8.0 Hz,
J2¼6.6 Hz, 1H), 6.04 (d, J¼8.0 Hz, 1H), 5.86e5.75 (m, 1H), 5.02 (m of
d, J¼17.3 Hz, 1H), 4.94 (m of d, J¼10.6 Hz, 1H), 3.95e3.85 (m, 4H),
3.06e3.00 (m, 1H), 2.80e2.76 (m, 1H), 2.31e2.23 (m, 2H), 1.95e1.86
(m, 2H), 1.83e1.71 (m, 2H), 1.68e1.58 (m, partly merged with signal
1638 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
7.24 (dd, J1¼14.6 Hz,
due to H2O in CDCl3, 2H). 13C NMR (100 MHz, CDCl3):
d
203.7, 139.3,
J2¼10.0 Hz, 1H), 6.12 (dd, J1¼14.6, J2¼10.0 Hz, 1H), 5.81e5.69
(merged m, total 3H), 5.54 (br s, 1H), 4.93 (m of d, J¼16.0 Hz, 1H),
4.87 (m of d, J¼10.6 Hz, 1H), 4.18 (q, J¼7.1 Hz, 2H), 3.94e3.83 (m,
4H), 2.93e2.84 (m, 1H), 2.41e2.37 (m, 1H), 2.23e2.14 (m, 2H),
2.01e1.92 (m, 1H), 1.84 (br s, 3H), 1.74e1.48 (m merged with signal
due to H2O in CDCl3, 3H), 1.32e1.25 (t merged with m, 4H),
136.3, 132.9, 114.3, 64.6, 64.5, 49.8, 45.9, 43.4, 30.8, 29.8, 29.7, 27.9.
HRMS (ESI) (m/z): found 249.1485 [MþH]þ; calcd for C15H21O3
249.1491.
4.14. Ethyl-5-[(but-3-enyl)-6-spiro(1,3-dioxalane)-bicyclo
[2.2.2]oct-7-en-2-yl]-penta-2,4-dienoate (17a)
1.14e1.11 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 167.4, 148.4, 145.1,
144.5, 140.2, 127.6, 125.1, 119.4, 114.9, 113.8, 64.3, 64.2, 60.3, 47.1,
42.9, 42.2, 36.5, 33.9, 30.4, 29.7, 20.3, 14.4. HRMS (ESI) (m/z): found
359.2225 [MþH]þ; calcd for C22H31O4 359.2222.
To a solution of triethyl phosphonocrotonate (0.36 g, 1.44 mmol)
in dry THF (5 mL) was added a solution of n-BuLi (0.8 mL,
1.28 mmol, 1.6 M) at ꢁ78 ꢀC. The mixture was stirred for 30 min at
ꢁ78 ꢀC after which a solution of the aldehyde 16a (0.2 g, 0.8 mmol)
in dry THF (5 mL) was added. The mixture was then stirred for 1 h at
ꢁ78 ꢀC and then it was quenched by careful addition of water and
extracted with ether (4ꢂ10 mL). The combined extract was washed
with brine (20 mL) and dried on anhydrous sodium sulfate. The
solvent was removed and the product was chromatographed on
silica gel. Elution with petroleum ether/ethyl acetate (90:10) gave
17a (0.26 g, 94%) as a colorless liquid [Rf¼0.5 petroleum ether/
EtOAc (90:10)]. IR (neat) nmax: 2927, 1714 cmꢁ1 1H NMR (400 MHz,
4.16. Ethyl-5 [1-(but-3-enyl)-6-spiro(1,3-dioxalane) bicyclo
[2.2.2]oct-7-en-2-yl]penta-2,4-dienoate (5a)
To a solution of 17a (0.100 g, 0.29 mmol) in acetone/water
(20 mL, 4:1) was added dil HCl (0.2 mL) at w10 ꢀC. The reaction
mixture was stirred at ambient temperature for 6 h. Acetone was
removed and aqueous residue was extracted with ethyl acetate
(3ꢂ15 mL). Combined extract was washed with sodium bi-
carbonate, brine, and dried on anhydrous sodium sulfate. The sol-
vent was removed and the product was chromatographed on silica
gel. Elution with petroleum ether/ethyl acetate (90:10) gave the
keto-ester 5a (0.085 g, 98%), which solidified after keeping in re-
frigerator, mp 64e65 ꢀC [Rf¼0.4, petroleum ether/EtOAc (90:10)]. IR
CDCl3):
d
7.21 (dd, J1¼15.5 Hz, J2¼11.1 Hz, 1H), 6.42 (dd, J1¼8.8 Hz,
J2¼6.6 Hz, 1H), 6.13 (dd, J1¼15.5 Hz, J2¼11.1 Hz, 1H), 5.96 (d,
J¼8.8 Hz, 1H), 5.80e5.69 (m, 2H), 4.93 (m of d, J¼15.5 Hz, 1H), 4.87
(m of d, J¼11.1 Hz, 1H), 4.19 (q, J¼7.1 Hz, 2H), 3.94e3.83 (m, 4H),
2.93e2.85 (m,1H), 2.68e2.60 (m, 1H), 2.25e2.16 (m, 2H), 2.04e1.94
(m, 1H), 1.77e1.53 (m, merged with signal due to H2O present in
CDCl3, 4H), 1.32e1.23 (t merged with m, J¼7.1 Hz, total 4H),
(neat) nmax: 1715 cmꢁ1 1H NMR (400 MHz, CDCl3):
d 7.22 (dd,
J1¼15.2 Hz, J2¼11.4 Hz, 1H), 6.62 (dd, J1¼9.5 Hz, J2¼7.6 Hz, 1H), 6.14
(dd, J1¼15.2 Hz, J2¼11.4 Hz, 1H), 5.89 (d, J¼7.6 Hz, 1H), 5.88e5.70
(m, 3H), 5.01 (m of d, J¼17.1 Hz, 1H), 4.92 (m of d, J¼9.5 Hz, 1H), 4.19
(q, J¼7.2 Hz, 2H), 3.00e2.92 (m, 1H), 2.62e2.52 (m, 1H), 2.24e2.00
(m, 5H), 1.70e1.60 (m, 2H), 1.40e1.35 (m, 1H), 1.28 (t, J¼7.2 Hz, 3H).
1.16e1.09 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 167.2, 147.8, 144.9,
139.8, 135.5, 132.8, 127.6, 119.4, 114.3, 113.7, 64.1, 64.0, 60.2, 46.7,
43.0, 41.3, 34.3, 30.8, 30.0, 29.6. HRMS (ESI) (m/z): found 345.2057
[MþH]þ; calcd for C21H29O4 345.2066.
13C NMR (100 MHz, CDCl3):
d 211.8, 167.1, 144.3, 144.1, 139.1, 137.6,
129.7, 129.0, 120.7, 114.4, 60.4, 55.5, 43.4, 40.8, 34.4, 32.1, 29.6, 28.9,
14.4. HRMS (ESI) (m/z): found 301.1810 [MþH]þ; calcd for C19H25O3
301.1804.
4.15. Ethyl-8-methyl-5-[(but-3-enyl)-6-spiro(1,3-dioxalane)-
bicyclo[2.2.2]oct-7-en-2-yl]-penta-2,4-dienoate (17b)
Crystal data for 5a: C19H24O3, mol. wt. 300.38. Crystal size
To a solution of alcohol 15b (0.100 g, 0.37 mmol) in CH2Cl2
0.33ꢂ0.23ꢂ0.18 mm. Space group: monoclinic P21/c, Z¼4,
¼90.00ꢀ,
ꢀ
(30 mL) was added TPAP (0.013 g, 0.0.037 mmol), NMO (0.066 g,
a¼16.541(2), b¼7.4877(15), c¼13. 6629(18) A,
a
0.56 mmol), and crushed molecular sieves (4 A, 0.500 g). The re-
b
¼16.983(16)ꢀ,
g
¼90.00ꢀ; Dc: 1.188 mg/m3; crystal volume
ꢀ
3
ꢀ
ꢀ
action mixture was stirred at ambient temperature for 12 h. It was
filtered on Celite pad and washed with dichloroethane. The filtrate
was concentrated and the product was chromatographed on silica
gel (petroleum ether/ethyl acetate, 80:20) to give the aldehyde 16b
(0.95 g, 96%) as a colorless liquid [Rf¼0.5 petroleum ether/EtOAc
(80:20)] [IR (neat) nmax: 1719,1641 cmꢁ1 1H MNR (400 MHz, CDCl3):
1679.6(5) A T¼150(2) K;
l
¼0.71073 A F(000)¼648. GOF¼1.093. Re-
flections collected/unique 7748/2947, [Rint¼0.1045], final R indices
[I>2
s(I)], R1¼0.0810, wR2¼0.2223. R indices all data¼R1¼0.1614,
wR2¼0.2555. Crystallographic data have been deposited with Cam-
bridge Crystallographic Data Centre, CCDC no. 892902. Copy of the
data can be obtained, free of charge, on application to CCDC. E-mail:
deposit@ccdc.cam.ac.uk.
d
9.39 (d, J¼4.5 Hz, 1H), 5.86e5.74 (m, 1H), 5.62 (br s, 1H), 5. 00 (m
of d, J¼16.4 Hz, 1H), 4.93 (m of d, J¼9.4 Hz, 1H), 3.99e3.83 (m, 4H),
3.03e2.97 (m, 1H), 2.55e2.49 (br m, 1H), 2.32e2.18 (m, 2H),
1.92e1.82 (m, merged with the signal due to Me, total 5H),
1.79e1.58 (cluster of m merged with signal due to H2O in CDCl3,
4.17. Ethyl-14-ethylenedioxy-tetracyclo[10.2.2.01,10.04,9]hex-
adec-15-ene-6-carboxylate (18a)
total 4H). 13C NMR (100 MHz, CDCl3):
d
204.2, 145.4, 139.4, 125.0,
A solution of compound 17a (0.075 g, 0.21 mmol) in dry toluene
(10 mL) was heated at 175 ꢀC sealed tube for 24 h. After which,
toluene was removed under reduced pressure and residue was
chromatographed on silica gel. Elution with petroleum ether/ethyl
acetate (85:15) gave compound 18a (0.056 g, 80%) as a thick col-
114.2, 64.6, 64.4, 50.5, 46.3, 43.0, 36.3, 30.0, 29.7, 27.3, 20.3]. The
aldehyde thus obtained was subjected to Wittig reaction as de-
scribed below.
To a stirred solution of triethyl phosphonocrotonate (0.120 g,
0.48 mmol) in dry THF (5 mL) was added n-BuLi (0.204 g, 0.300 mL,
orless liquid [Rf¼0.5 petroleum ether/EtOAc (90:10)]. IR (neat) nmax
:

V. Singh et al. / Tetrahedron 69 (2013) 137e146
145
2929, 1715 cmꢁ1 1H NMR (400 MHz, CDCl3):
d
6.36 (dd, J1¼8.2 Hz,
2.15e1.96 (complex m, 4H), 1.86 (s, 3H), 1.84e1.68 (m, 3H),
1.63e1.53 (m merged with signal due to H2O in CDCl3, 1H),
1.52e1.18 (cluster of m merged with t, J¼7.1 Hz, total 8H). 13C NMR
J2¼6.6 Hz, 1H), 5.95 (d, J¼8.2 Hz, 1H), 5.77e5.70 (br m, 2H), 4.14 (q,
J¼6.6 Hz, 2H), 3.90e3.81 (m, 4H), 3.06e3.01 (m, 1H), 2.63e2.58 (m,
1H), 2.05 (d, J¼11.6 Hz, 1H), 1.94e1.83 (m, 2H), 1.80e1.73 (m, 1H),
1.72e1.54 (m merged with signal due to H2O present in CDCl3, 3H),
1.40e1.16 (m merged with t, total 8H), 1.14e1.07 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 213.3,174.0,146.5,131.3,125.4,122.4, 60.8, 53.3,
45.6, 40.8, 40.3, 39.3, 36.8, 36.3, 31.3, 31.2, 28.8, 27.4, 20.3, 14.3.
HRMS (ESI) (m/z): found 315.1961 [MþH]þ; calcd for C20H27O3 re-
quires 315.1960.
(100 MHz, CDCl3): d 174.3,134.8, 133.7,132.2, 124.5,114.3, 65.2, 64.6,
60.7, 46.4, 46.0, 42.7, 40.9, 37.6, 36.7, 31.9, 31.4, 31.0, 29.3, 26.4, 14.4.
HRMS (ESI) (m/z): found 345.2053 [MþH]þ; calcd for C21H29O4
345.2066.
Crystal data for 4b: C20H26O3, mol. wt. 314.41. Crystal size
0.33ꢂ0.26ꢂ0.21 mm. Space group: monoclinic P21/n, Z¼4,
ꢀ
a¼10.8066(10), b¼9.1156(6), c¼17. 6322(13) A,
a
¼90.00ꢀ,
b
¼94.569(7)ꢀ,
g
¼90.00ꢀ; Dc: 1.206 mg/m3; Crystal volume
4.18. Ethyl-14-oxo-tetracyclo[10.2.2.01,10.04,9]hexadec-15-ene-
6-carboxylate (4a)
1731.4(2) A ; T¼293(2) K;
l
¼0.71073 A; F(000)¼680. GOF¼1.028.
3
ꢀ
ꢀ
Reflections collected/unique 14,256/3040, [Rint¼0.1258], final R
indices [I>2
s
(I)], R1¼0.0617, wR2¼0.1322. R indices all data-
To a stirred solution of compound 18a (0.042 g, 0.12 mmol) in
acetone/water (4:1, 20 mL), was added 1 N HCl (0.5 mL) at 0 ꢀC after
which reaction mixture was further stirred for 2 h at ambient
temperature. After completion of reaction (TLC), the reaction mix-
ture cooled to 0 ꢀC and NaHCO3 was added to it. Acetone was
evaporated under reduced pressure, water (10 mL) was added to
reaction mixture, and the aqueous layer was extracted with ethyl
acetate (3ꢂ30 mL). Combined organic extract was dried on anhy-
drous Na2SO4, solvent was removed, and product was chromato-
graphed. Elution with petroleum ether/ethyl acetate (85:15) gave
keto-ester 4a (0.025 g 69%) as a colorless liquid [Rf¼0.4 petro-
leum ether/EtOAc (90:10)]. IR (neat) vmax: 2931, 1718 cmꢁ1 1H NMR
¼R1¼0.1372, wR2¼0.1740. Crystallographic data have been de-
posited with Cambridge Crystallographic Data Centre, CCDC no.
893371. Copy of the data can be obtained, free of charge, on ap-
plication to CCDC. E-mail: deposit@ccdc.cam.ac.uk.
Acknowledgements
We are thankful to CSIR New Delhi for financial support. P.B. is
grateful to CSIR New Delhi and IRCC-IIT Bombay for a research
fellowship, B.C.S. is thankful to CSIR New Delhi for research fel-
lowship. V.S. is grateful to the Department of Science and Tech-
nology New Delhi for J C Bose fellowship. We also thank DST for the
creation of a National Centre for Single Crystal X-ray diffraction
facility at IIT Bombay.
(400 MHz, CDCl3):
d
6.52 (superimposed dd, J¼6.6 Hz, 1H), 5.82 (d,
J¼6.6 Hz, 1H), 5.80e5.73 (m, 2H), 4.14 (q, J¼7.4 Hz, 2H), 3.10e3.03
(m, 1H), 2.97e2.90 (m, 1H), 2.14e2.00 (m, 4H), 1.92e1.70 (m, 4H),
1.59e1.51 (m, 1H), 1.49e1.34 (m, 3H), 1.30e1.20 (m merged with t,
J¼7.4 Hz, 4H). 13C NMR (100 MHz, CDCl3):
d 212.9,173.9,137.2, 131.2,
Supplementary data
130.3, 125.4, 60.7, 53.5, 45.6, 40.8, 39.7, 39.6, 36.3, 31.6, 31.4, 31.2,
28.8, 27.3,14.3. HRMS (ESI) (m/z): found 301.1809 [MþH]þ; calcd for
C19H25O3 301.1804.
1H NMR and 13C NMR spectra of all new compounds and CIF data
of 5a and 4b. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2012.10.051.
4.19. Ethyl-16-methyl-14-ethylenedioxy-tetracyclo[10.2.2.01,10
4,9]hexadec-15-ene-6-carboxylate (18b)
.
0
References and notes
The solution of compound 17b (0.050 g, 0.139 mmol) in dry
toluene (10 mL) was heated at 175 ꢀC in a sealed tube for 18 h.
Toluene was removed under reduced pressure and residue was
chromatographed on neutral silica gel (100e200 mesh). Elution
with petroleum ether/ethyl acetate (90:10) gave (0.045 g, 90%)
compound 18b as a colorless liquid [Rf¼0.5 petroleum ether/EtOAc
(90:10)]. IR (neat) nmax: 2929,1732 cmꢁ1 1H NMR (400 MHz, CDCl3):
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Laurent Pouysegu, L.; Sylla, T.; Garnier, T.; Rojas, L. B.; Charris, J.; Deffieux,
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d
5.81e5.69 (m, 2H), 5.58 (br s, 1H), 4.13 (q, J¼7.0 Hz, 2H), 3.91e3.80
(m, 4H), 3.12e3.00 (m, 1H), 2.38e2.32 (m, 1H), 2.04 (d, J¼12.0 Hz,
1H), 1.91e1.71 (m overlapped with d, J¼1.5 Hz, total 5H), 1.68e1.62
(m, 2H), 1.60e1.50 (m merged with signal due to H2O present in
CDCl3, total 3H), 1.40e1.17 (m merged with t, J¼7.0 Hz, total 6H),
1.10e1.03 (m, 1H). 13C NMR (100 MHz, CDCl3):
d 174.3, 143.5, 132.3,
125.7, 124.4, 114.7, 65.2, 64.7, 60.6, 46.6, 45.9, 42.3, 40.9, 38.4, 36.7,
36.6, 31.45, 31.41, 29.3, 26.5, 20.2,14.4. HRMS (ESI) (m/z): found
359.2233 [MþH]þ; calcd for C22H31O4 359.2222.
4.20. Ethyl-16-methyl-14-oxo-tetracyclo[10.2.2.01,10.04,9]hex-
adec-15-ene-6-carboxylate (4b)
A solution of compound 17b (0.050 g, 0.139 mmol) in dry tolu-
ene (11 mL) was heated in a sealed tube at 175 ꢀC. After 18 h, tol-
uene was removed in vacuo and residue was chromatographed on
silica gel (100e200 mesh). Elution with petroleum ether/ethyl ac-
etate (90:10) gave compound 4b (0.039 g, 90%) as a colorless solid,
mp 63e64 ꢀC [Rf¼0.5 petroleum ether/EtOAc (90:10)]. IR (KBr) nmax:
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d
5.82e5.72 (m, 2H), 5.39 (br
s, 1H), 4.14 (q, J¼7.1 Hz, 2H), 3.09e3.04 (m, 1H), 2.68e2.63 (m, 1H),

146
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