Intramolecular cycloaddition in 6,6-spiroepoxycyclohexa-2,4-dienone: Simple aromatics to (±)-Platencin

Article abstract of DOI:10.1039/c004316h

A formal total synthesis of platencin from a simple aromatic precursor is described. Transformation of the aromatic compound into reactive spiroepoxycyclohexa-2,4-dienone and intramolecular cycloaddition are the key features of our methodology. 2-Hydroxymethyl-6-(3-hydroxy-hex-5-enyl)-phenol was oxidized with NaIO₄ to give a dimer that, upon a retro-Diels-Alder reaction, generated the spiroepoxycyclohexa-2,4-dienone that underwent intramolecular Diels-Alder reaction to give a tricyclic adduct having a core structure of platencin and appropriately disposed functional groups in a single step. Reduction of the double bond present in the ethano-bridge, manipulation of the oxirane ring and introduction of a double bond in the six-membered ring furnished a tricyclic intermediate which has already been converted into platencin.

Full text of DOI:10.1039/c004316h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Intramolecular cycloaddition in 6,6-spiroepoxycyclohexa-2,4-dienone: simple
aromatics to ( )-Platencin†
Vishwakarma Singh,*a Bharat Chandra Sahu,a Varsha Bansala and Shaikh M. Mobinb
Received 17th March 2010, Accepted 22nd June 2010
DOI: 10.1039/c004316h
A formal total synthesis of platencin from a simple aromatic precursor is described. Transformation of
the aromatic compound into reactive spiroepoxycyclohexa-2,4-dienone and intramolecular
cycloaddition are the key features of our methodology.
2-Hydroxymethyl-6-(3-hydroxy-hex-5-enyl)-phenol was oxidized with NaIO4 to give a dimer that, upon
a retro-Diels–Alder reaction, generated the spiroepoxycyclohexa-2,4-dienone that underwent
intramolecular Diels–Alder reaction to give a tricyclic adduct having a core structure of platencin and
appropriately disposed functional groups in a single step. Reduction of the double bond present in the
ethano-bridge, manipulation of the oxirane ring and introduction of a double bond in the
six-membered ring furnished a tricyclic intermediate which has already been converted into platencin.
and FabF and therefore exhibits a broad range antibacterial
Introduction
activity. Remarkably, platensimycin and platencin have different
Rapid generation of complex molecular structures is one of
carbocyclic networks but the same side chain. Platensimycin
the important aspects of synthesis design and development of
methodology.1,2 This objective is often accomplished by employing
has a tetracyclic structure containing a cyclic ether whereas
platencin has a tricyclic core of type 3 comprised of a bridged
a cascade of reactions,1,3 or multi-component reactions4 and
bicyclo[2.2.2]octane framework annulated with a six-membered
reactive species generated from aromatics.5-7 Recently, a group
ring in spiro fashion. The novel molecular architecture and
from Merck reported the isolation and structural elucidation of
promising therapeutic potential of platensimycin and platencin has
platensimycin 18 and platencin 29 (Fig. 1) which are metabolites of
Streptomyces platensis. Both of these compounds exhibit potent
antibacterial properties.
stimulated considerable interest in their synthesis. Platensimycin
received relatively greater attention since it was isolated earlier and
several elegant syntheses have appeared.10,11
The unique molecular structure and promising antibiotic prop-
erties of platencin have also stimulated a high level of interest
and several elegant synthetic routes were developed12,13 soon after
the reports by Nicolaou et al.12a and Rawal’s group.12b Various
types of strategies have been designed for the synthesis of the
tricyclic framework of platencin. However, the majority of the
approaches have employed radical-induced reactions to create the
bridged structure and generate the tricyclic framework of platencin
in a stepwise manner. Intramolecular Diels–Alder reaction of a,a
dialkoxycyclohexadienone and a cis-1,2-functionalized cyclohexa-
1,3-diene have been employed by Nicolaou et al.13c and Banwell
and co-workers13d, respectively, to generate the tricyclic framework
of platencin in a single step. Intermolecular Diels–Alder reaction
of (S)-(-)-perillaldehyde has also been utilized for efficient enan-
tioselective synthesis of platencin.12c,13b,h
Fig. 1 Structures of platensimycin, platencin and tricyclic core of
platencin.
We have a long standing and continued interest in the de-
velopment of new methodology involving in situ generation of
spiroepoxycyclohexa-2,4-dienones, cycloaddition and rearrange-
ments in excited states.6 In view of the above we considered
developing a synthesis of platencin from a simple aromatic
precursor in order to further demonstrate the versatility and
synthetic potential of our methodology.
Our plan for the synthesis of platencin is outlined in Scheme 1.
We also focused on the synthesis of the tricyclic dienone 3 which
has already been elaborated to platencin.12a,b It was contemplated
that the tricyclic dienone 3 may be easily obtained from the enone
4, which may be derived from the keto-epoxide 5.
Platensimycin is active against Staphylococcus aureus by block-
ing fatty acid biosynthesis via inhibition of the enzyme FabF. In-
terestingly, platencin inhibits action of both the enzymes FabH
aDepartment of Chemistry, Indian Institute of Technology Bombay, Mumbai
400 076, India. E-mail: vks@chem.iitb.ac.in
bNational Centre for Single Crystal X-ray diffraction, Indian Institute of
Technology Bombay, Mumbai, 400 076, India
† Electronic supplementary information (ESI) available: 1H NMR, 13C
NMR spectra of compounds 10, 11,7,12,13, 5a,5b, 14–21, 4, 3 and 22 and
CIF data of 5b and 18. CCDC reference numbers 770204–770205. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c004316h
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Towards the above objective, the aromatic precursor 7 was easily
prepared from readily available6c 3-allylsaligenin 8 as shown in
Scheme 2. Thus, protection of the 1,3-diol moiety in compound 8
followed by hydroboration-oxidation15 and subsequent oxidation
of the resulting alcohol furnished the aldehyde 10. Reaction of
allylmagnesium bromide on 10 gave the addition product 11 which
upon removal of the acetonide readily furnished the required
aromatic precursor 7 (Scheme 2).
Scheme 1
The keto-epoxide 5, in turn, was thought to be amenable from
the aromatic precursor 7 by its oxidative dearomatization to
spiroepoxycyclohexa-2,4-dienone 6 and subsequent intramolec-
ular p4s + p2s cycloaddition via an endo transition state. The
precursor 7 was thought to be prepared from readily available
2-allyl-(6-hydroxymethyl)phenol 8 (Scheme 1).
Scheme 2 Reagents and conditions: i, 2,2-Dimethoxypropane, p-TSA,
acetone, 87%; ii, NaBH4–I2, H2O2, NaOH, 96%; iii, IBX, ethyl acetate,
reflux 92%; iv, allylmagnesium bromide, THF, 96%; v, HCl, aq. acetone,
92%.
Some of the salient features of our strategy are as follows.
The tricyclic ring system of platencin is efficiently assembled with
correct relative stereochemistry and functional group disposition
from a simple aromatic precursor in the very beginning of the
synthetic route. Further, the juxtaposition of the functional group
in the ketoepoxide 5 provides a unique opportunity for selective
manipulation and transformation of the oxirane ring into an
exocyclic olefin moiety of the key precursor. Remarkably, all the
thirteen carbon atoms of the platencin core 3, the unique tricyclic
framework, and the requisite functionalities are present in the
aromatic precursor 7 in a latent fashion.
The hydroxymethyl phenol 7 was subjected to oxidative dearom-
atization with a view to generate the spiroepoxycyclohexa-2,4-
dienone 6 and explore the possibility of intramolecular cycload-
dition. Thus, a solution of 7 in acetonitrile was treated with aq.
NaIO4 following a procedure developed in our laboratory.16 How-
ever, the reaction did not lead to desired cycloadduct 5, instead
the dimer 13 was obtained due to intermolecular cycloaddition as
a major product along with a minor amount of the aldehyde 12
(Scheme 3).
It appeared that under the aforementioned reaction conditions
the dienophilic reactivity of the p-bond of the tether was not
sufficient to compete with the reactivity of the g,d-C C bond
of the cyclohexadienone moiety towards cycloaddition. Therefore,
we considered generating the cyclohexa-2,4-dienone 6 by a thermal
retro-Diels–Alder reaction of the dimer 13 with anticipation that
the dienone 6 generated under thermal activation may undergo
intramolecular cycloaddition to give the desired tricyclic keto-
epoxide 5. Hence, the dimer 13 was heated in o-dichlorobenzene
at 140 ◦C for 6 h. Indeed, it was gratifying to obtain the endo
adducts 5a and 5b in high yield, the latter being the major product
(Scheme 4).
Results and discussion
Conceptually, the tricyclic compound 4 may be prepared by
intramolecular cycloaddition in the species of type 9a and 9b
(Fig. 2). However, there are no methods for the preparation of
compound of type 9a as it is a keto-tautomer of the corresponding
phenol and the compound 9b also does not appear to be easily
accessible.
It may be interesting to note that the aforementioned cycload-
dition occurred with p-facial selectivity so as to give only one
stereoisomer at the spiro-oxirane centre and adducts of type I
were not observed.
The structure of both adducts was deduced from their spectral
features. Thus, the minor adduct exhibited the following spectral
features. The IR spectrum of the cycloadduct 5a showed absorp-
tion bands at 3442 and 1731 cm-1 for the hydroxyl and carbonyl
Fig. 2 Potential precursors for intramolecular Diels–Alder reaction.
1
We, therefore, considered employing intramolecular cycloaddi-
tion in 6,6-spiroepoxycyclohexa-2,4-dienone 6 for the synthesis
of tricyclo[6.2.2.0.2,6]dodecane framework of platencin, especially
since cyclohexa-2,4-dienones of type 6 can be generated by
oxidative dearomatization of the corresponding o-hydroxymethyl
phenol.14 Further, it was anticipated that the cyclohexa-2,4-
dienone 6 would undergo intramolecular p4s + p2s cycloaddition.
At the outset, however, we were aware that spiroepoxycyclohexa-
2,4-dienones have fleeting existence and readily dimerize in the
absence of a reactive 2p-partner.6,14
groups, respectively. The H NMR (400 MHz, CDCl3) spectrum
displayed highly characteristic signals at d 6.59 (superimposed dd,
J1 = J2 = 8.0 Hz, 1H) for the g- proton of the b,g-enone moiety
and at d 5.98 (d, J = 8.0 Hz, 1H) for the b-proton of the b,g-enone
moiety. The difference in the chemical shifts of these protons is a
manifestation of the homo-conjugation of the olefinic moiety with
the carbonyl group. This clearly indicated that the intramolecular
cycloaddition had indeed occurred. It further exhibited highly
characteristic AB patterns for methylene protons of the oxirane
ring at d 3.14 (part of an AB system, JAB = 6.4 Hz, 1H) and 2.83
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Scheme 3
Scheme 4
(part of an AB system, JAB = 6.4 Hz, 1H). In addition, signals were
observed at d 4.08–4.04 (m, 1H) for the methine proton attached
to the carbon bearing hydroxyl group, 2.54–2.48 (m, 1H), 2.44–
2.32 (m, 2H), 2.30–2.18 (m, 1H), 1.92–1.60 (m, 5H), 1.42–1.32 (m,
1H), 1.14–1.04 (m, 1H). The structure of the adduct 5a was also
supported by the 13C NMR spectrum that exhibited characteristic
signals at d 206.6 for the carbonyl carbon and d 134.5, 130.6 for
the olefinic carbons. It further exhibited signals at d 65.2, 57.8,
53.1, 52.7, 37.8, 37.5, 30.0, 29.3, 28.2 and 20.1 for other carbons.
The IR spectrum of the cycloadduct 5b showed absorption
bands at 3373 and 1728 cm-1 for the hydroxyl and carbonyl
1
groups, respectively. The H NMR (400 MHz, CDCl3) spectrum
Fig. 3 ORTEP diagram of compound 5b showing thermal ellipsoid at
50% probability. One of the disordered hydrogen atoms over O1 is omitted
for clarity.
displayed diagnostic signals at d 6.59 (dd, J1 = 8.0 Hz, J2
=
7.3 Hz, 1H) and 5.96 (d, J = 8.0 Hz, 1H) for the g- and b-proton
of the b,g-enone moiety, respectively. It further exhibited highly
characteristic AB patterns for the methylene protons of the oxirane
ring at d 3.13 (part of an AB system, JAB = 6.1 Hz, 1H), 2.84 (part
of an AB system, JAB = 6.1 Hz, 1H). In addition, signals were
observed at d 3.63–3.53 (m, 1H), 2.56–2.48 (m, 1H), 2.43–2.35
(m, 1H), 2.10–1.70 (complex m, 6H), 1.46–1.34 (m, 1H), 1.24–
1.12 (m, 2H) for other protons. The 13C NMR spectrum of 5b
exhibited characteristic resonances at d 206.4 and 134.3, 130.9 for
the carbonyl carbon and olefinic carbons, respectively. It further
exhibited signals at d 69.3, 57.8, 53.1, 52.2, 40.3, 37.7, 35.9, 31.1,
29.5 and 24.7 for other carbons.
The aforementioned spectral features clearly suggested the gross
structure of adducts; however, it was difficult to ascertain the
stereochemistry of the hydroxyl group and the oxirane moiety
(though both these stereocentres are inconsequential as it would
be manipulated later). Hence, a single crystal X-ray structure
determination of 5b was undertaken which confirmed its structure
(Fig. 3).
bicyclo[2.2.2]octane framework which also contains an oxirane
ring (C9, C11 and O3). It also clearly reveals the expected
relative stereochemical disposition of the hydroxyl group, oxirane
ring and six-membered ring (C1-C6) annulated to the bridged
bicyclo[2.2.2]octane framework.
The adducts 5a,b contain all the structural and stereochemical
features required in the desired tricyclic intermediate 3. The
elaboration of 5a,b to the compound 3 required some functional
group manipulation, such as reduction of the double bond and
deoxygenation of the oxirane ring into exocyclic olefin and
reduction of the carbonyl group present in the ethano bridge.
The unique functional group disposition in the adducts readily
permitted these transformations as presented below.
Both adducts 5a and 5b were oxidized with PDC to give the
same oxidation product 14 in good yield (Scheme 5). Reduction
of the epoxy-ketone 14 with Zn and NH4Cl in aqueous methanol
following a method developed in our laboratory17 furnished the
b-keto-alcohol 16 as a major product (62%) as a syn : anti mixture
The molecular structure of 5b consists of a tricyclic ring system
containing a six-membered ring (C1-C6) fused to a bridged
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Scheme 5 Reagents and conditions: i, PDC, CH2Cl2 (75% from 5a, 85% from 5b); ii, Zn, NH4Cl, MeOH–H2O (6 : 1) [15 (15%), 16 (62%)]; iii, Pd/C (5%),
H2, ethanol (84%); iv, (a) tosyl chloride, pyridine, RT, 12 h, (69%), (b) pyridine, 100 ◦C, 8 h (83%).
(1H NMR spectrum) in addition to the ketone 15 (as a syn : anti
mixture) as a minor product. The b-keto-alcohol 16 was readily
hydrogenated in the presence of Pd/C to give the alcohol 17.
Treatment of the b-keto-alcohol 17 with tosyl chloride–pyridine
followed by heating readily furnished the ene-dione 18 (Scheme 5).
The structure of compound 18 was deduced from the following
spectral features. The IR spectrum showed the absorption band
After synthesizing the tricyclic compound 18, selective deoxy-
genation of the keto group of the a,b-enone moiety was required.
Thus, the dienone 18 was converted into the keto acetal 19
in quantitative yield (Scheme 6). Reduction of 19 with sodium
borohydride in the presence of CeCl3·7H2O18 at 0 ◦C followed by
acylation gave the allylic acetate 20 in good yield. The acetate
20 was subjected to palladium-mediated reduction as developed
by Tsuji et al.19 Thus, treatment of 20 with [Pd2(dba)3]13b,19 and
PBu3 in the presence of Et3N/HCOOH gave compound 21, which
upon hydrolysis readily furnished the ketone 4 in excellent yield
(Scheme 6). The structure of ketone 4 is fully consistent with
its spectral features which are in excellent agreement with those
reported.13d
1
at 1707 cm-1 for the carbonyl groups. The H NMR (400 MHz,
CDCl3) spectrum of compound 18 displayed resonances at d 6.01
(d, J = 1.4 Hz, 1H) and 5.26 (d, J = 1.4 Hz, 1H) for olefinic
protons. Other protons appeared at d 2.82–2.76 (m, 1H), 2.50–
2.34 (m, 5H), 2.20–2.04 (m, 3H), 1.95–1.76 (m, 3H), 1.58–1.46
(m, 1H), 1.34–1.28 (m, 1H). The 13C NMR spectrum displayed
signals at d 210.2, 202.7 for two carbonyl groups and at d 146.8
and 117.8 for two olefinic carbons. Other signals were observed
at d 44.9, 44.2, 36.9, 35.7, 35.1, 34.6, 28.4, 26.0 and 21.3. The
structure of the ene-dione 18 was further confirmed by a single
crystal structure determination (Fig. 4).
Scheme 6 Reagents and conditions: i, ethylene glycol, p-TSA, benzene,
reflux (95%); ii, CeCl3·7H2O, NaBH4, MeOH (98%); iii, acetic anhydride,
DMAP, pyridine–CH2Cl2, (86%); iv, Pd2(dba)3, PBu3, HCOOH, Et3N,
THF, reflux, 18 h (56%); v, aq. HCl, acetone, (92%).
Completion of the synthesis of the key intermediate 3 for
platencin required introduction of a double bond in the precursor
4. Thus, the compound 4 was treated with triethylamine and
trimethylsilyl triflate and the resulting silyl enol ether was oxidized
with IBX employing a slightly modified procedure,13d which gave
the desired compound 3 in 50% yield along with the isomeric
dienone 22 (25%) in minor amounts (Scheme 7).
The structure of the enone 3 was deduced from its spectral
data which are in excellent agreement with those reported in the
literature.12b,13c,d The tricyclic dienone 3 has already been converted
into platencin.12a,b Thus, with the synthesis of the intermediate 3
as described above, a formal synthesis of platencin was complete.
Fig. 4 ORTEP diagram of compound 18 showing thermal ellipsoid at
30% probability
The X-ray structure of 18 depicts the tricyclic ring system
and clearly reveals the disposition of exocyclic methylene group
(C9–C12) and the carbonyl group (C13–O2) on the bridged
bicyclo[2.2.2]octane framework. It also clearly shows the desired
stereochemical orientation of the cyclohexanone ring (C1–C6),
especially its fusion with the bicyclo[2.2.2]octane framework at
C4 and C5.
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mixture at 0 ◦C. Subsequently, H2O2 (30%, 100 mL) was added to
the reaction mixture slowly and stirred for one hour. The organic
layer was separated and the aqueous layer was extracted with ether
(3 ¥ 100 mL). The combined organic extract was washed with brine
and dried on anhydrous sodium sulfate and concentrated in vacuo.
Removal of solvent followed by chromatography [petroleum
ether–EtOAc (85 : 15)] gave an alcohol (10.50 g, 96%) [IR (film)
n
max: 3408, 1596, 1463 cm-1. 1H NMR (400 MHz, CDCl3): d 7.06-
Scheme 7 Reagents and conditions: i, (a) TMSOTf, Et3N, CH2Cl2;
(b) IBX, MPO, DMSO
7.01 (m, 1H), 6.89-6.81 (m, 2H), 4.85 (s, 2H); 3.59 (t, J = 6.4 Hz,
2H), 2.68 (t, J = 6.9 Hz, 2H), 1.88-1.80 (m, 2H), 1.55 (s, 6H).
13C NMR (100 MHz, CDCl3): d 148.9, 129.5, 128.5, 122.3, 120.1,
118.9, 99.5, 61.5 60.9, 32.7, 25.0, 24.6] which was oxidized with
IBX as described below.
Conclusion
A formal total synthesis of platencin from a simple aromatic
precursor 7 has been reported. 2-Hydroxymethyl-6-(3-hydroxy-
hex-5-enyl)-phenol, readily prepared from 2-hydroxymethyl-6-
allylphenol, in a few simple steps and straightforward manner
was oxidized to give the dimer 13. In situ generation of 6,6-
spiroepoxycyclohexa-2,4-dienone by thermal activation of 13 and
a tandem intramolecular Diels–Alder reaction led to the formation
of adducts 5a,b endowed with the tricyclic framework of platencin
and requisite functionalities. Functional group manipulation of
5a,b provided the intermediate 3, which is a known precursor
of platencin. The present synthesis demonstrates the versatility
and synthetic potential of spiroepoxycyclohexa-2,4-dienones, and
constitutes a nice example of the creation of molecular complexity
from aromatics.
To a solution of the above alcohol (9.00 g, 40.54 mmol) in
ethyl acetate (300 mL) was added IBX (13.62 g, 48.64 mmol)
and refluxed for 6 h. The reaction mixture was filtered through a
sintered funnel and washed with EtOAc. The combined filtrate was
concentrated under reduced pressure and the product was purified
by column chromatography on silica gel. Elution with petroleum
ether–EtOAc (92 : 8) provided the compound 10 (8.22 g, 92%).
1
IR (film) nmax: 1724 cm-1. H NMR (400 MHz, CDCl3): d 9.81
(t, J = 1.3 Hz), 7.04-7.00 (m, 1H), 6.88-6.80 (m, 2H), 4.84 (s,
2H), 2.90 (t, J = 7.5 Hz, 2H), 2.75-2.70 (m, 2H), 1.54 (s, 6H).
13C NMR (100 MHz, CDCl3): d 202.3, 148.9, 128.3, 128.1, 122.8,
119.9, 119.1, 99.5, 60.8, 43.6, 24.7, 22.7. HRMS (ESI) (m/z): found
221.1173 [M+H]+; calcd for C13H17O3 221.1178.
1-(2,2-Dimethyl-4H-1,3-benzodioxin-8-yl)hex-5-ene-3-ol (11)
Experimental section
To a suspension of magnesium (freshly activated, 3.27 g,
136.25 mmol) in dry THF (150 mL), a crystal of iodine was added
3-(2,2-Dimethyl-4H-1,3-benzodioxin-8-yl)propanal (10)
◦
and it was cooled to 0 C. After which a dilute solution of allyl
To a solution of compound 8 (11.00 g, 67.07 mmol) in acetone
(100 mL) and 2,2-dimethoxypropane (25 mL) was added p-TsOH
(400 mg) and the reaction mixture was stirred at room temperature.
After completion of reaction (TLC, 6 h) the reaction mixture was
neutralized by the addition of excess solid sodium bicarbonate.
The mixture was concentrated under reduced pressure and the
residue was diluted with water (100 mL) and extracted with
diethyl ether (2 ¥ 100 mL), washed with brine (50 mL), dried on
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was chromatographed on silica gel. Elution with
petroleum ether–EtOAc (96 : 4) gave acetonide (12.00 g, 87%) [IR
bromide (5.9 mL, 8.26 g, 68.26 mmol) in THF (250◦mL) was
added very slowly over 4 h with vigorous stirring at 0 C. It was
further stirred for 2 h at ambient temperature. A solution of the
aldehyde 10 (5.00 g, 22.72 mmol) in dry THF (20 mL) was added
to the reaction mixture at 0 ◦C. The reaction mixture was further
stirred for 2 h at ambient temperature. After which it was cooled
in an ice bath and a saturated solution of ammonium chloride
(50 mL) was added and the reaction mixture was further stirred
for 0.5 h. The organic layer was separated and the aqueous layer
was extracted with diethyl ether (3 ¥ 75 mL) and the combined
organic extracts were dried on sodium sulfate and the solvent was
removed in vacuo, and the product was chromatographed on silica
gel. Elution with petroleum ether–ethyl acetate (90 : 10) gave the
1
(film) nmax: 1639, 1597,1463 cm-1. H NMR (400 MHz, CDCl3):
d 7.04-6.99 (m, 1H); 6.86- 6.81 (m, 2H); 6.02-5.90 (m, 1H); 5.09-
5.00 (m, 2H); 4.84 (s, 2H); 3.33 (d, J = 6.1 Hz, 2H); 1.55 (s, 6H).
13C NMR (100 MHz, CDCl3): d 149.0, 136.9, 128.39, 128.34,
122.7, 120.1, 119.2, 115.5, 99.5, 61.1, 33.8, 25.0]. The acetonide
thus obtained was subjected to hydroboration as described
below.
To a suspension of sodium borohydride (5.00 g, 131.57 mmol)
in dry THF (100 mL) was slowly added a dilute solution of iodine
(13.36 g, 52.59 mmol) in dry THF (100 mL) under nitrogen
atmosphere at 0 ◦C. The addition was complete in 2 h. It was
further stirred for 30 min. A solution of acetonide (10.00 g,
49.01 mmol) in THF (15 mL) was then added and the reaction
mixture was stirred for 2 h at ambient temperature. The reaction
mixture was cooled to 0 ◦C and water (20 mL) followed by a
solution of NaOH (3 N, 100 mL) was added to the reaction
compound 11 (5.71 g, 96%) as a colorless liquid. IR (film) nmax
:
3435 cm-1. H NMR (400 MHz, CDCl3): d 7.04-7.00 (m, 1H),
6.86-6.79 (m, 2H), 5.89-5.75 (m, 1H), 5.13-5.06 (m, 2H), 4.83 (s,
2H), 3.57 (brs, 1H), 2.76-2.61 (m, 2H), 2.32-2.15 (m, 3H), 1.75-
1.68 (m, 2H), 1.54 (s, 3H), 1.53 (s, 3H). 13C NMR (100 MHz,
CDCl3): d 149.0, 135.1, 129.9, 128.7, 122.5, 120.3, 119.1, 117.7,
99.7, 69.7, 69.6, 61.1, 41.7, 37.2, 25.4, 24.9. HRMS (ESI) (m/z):
found 285.1465 [M+Na]+; calcd for C16H22O3Na 285.1467.
1
2-Hydroxymethyl-6-(3-hydroxy-hex-5-enyl)-phenol (7)
To a solution of the acetal alcohol 11 (10.00 g, 38.16 mmol)
in acetone–water (1 : 1, 200 mL) was added conc. HCl (10 mL
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◦
35%) at ~10 C. and the reaction mixture was stirred at ambient
9-Spiroepoxy-4-hydroxy-tricyclo[6.2.2.01,6]dodec-11-ene-10-one
(5a and 5b)
temperature for 8 h. After which more HCl (2 mL 35%) was
added and the reaction mixture was further stirred for 6 h. After
completion of the reaction (TLC), the reaction mixture was cooled
to 0 ◦C and neutralized by the addition of excess solid NaHCO3.
The organic solvent was removed under reduced pressure and the
aqueous solution was extracted with ethyl acetate (3 ¥ 100 mL).
The combined organic extract was washed with brine (30 mL)
and dried on Na2SO4. Removal of solvent and chromatography
on silica gel [petroleum ether–EtOAc (75 : 25)] gave the compound
A solution of epoxy dimer 13 (4.20 g, 9.54 mmol) in o-
dichlorobenzene (30 mL) was heated at 140 ◦C for 6 h. The reaction
mixture was charged as such on silica gel. Dichlorobenzene was
eluted out in petroleum ether. Elution with petroleum ether–
EtOAc (60 : 40) first gave the less polar adduct 5a (1.40 g, 33%)
1
as a colorless liquid. IR (film) n max: 3442, 1731 cm-1. H NMR
(400 MHz, CDCl3): d 6.59 (superimposed dd, J1 = J2 = 8.0 Hz,
1H), 5.98 (d, J = 8.0 Hz, 1H), 4.08-4.04 (m, 1H), 3.14 (part of an
AB system, JAB = 6.4 Hz, 1H), 2.83 (part of an AB system, JAB
6.4 Hz, 1H), 2.54-2.48 (m, 1H), 2.44-2.32 (m, 2H), 2.30-2.18 (m,
1H), 1.92-1.60 (m, 5H), 1.42-1.32 (m, 1H), 1.14-1.04 (m, 1H). 13
NMR (100 MHz, CDCl3): d 206.6, 134.5, 130.6, 65.2, 57.8, 53.1,
52.7, 37.8, 37.5, 30.0, 29.3, 28.2, 20.1.
HRMS (ESI) (m/z): found 243.0998 [M+Na]+; calcd for
C13H16O3Na 243.0997.
Further elution with petroleum ether–EtOAc (50 : 50) furnished
the more polar adduct 5b (2.31 g, 55%) as a solid, mp. 123–125
◦C. IR (film) n max: 3373, 1728 cm-1. 1H NMR (400 MHz, CDCl3):
d 6.59 (dd, J1 = 8.0 Hz, J2 = 7.3 Hz 1H), 5.96 (d, J = 8.0 Hz,
1H), 3.63-3.53 (m, 1H), 3.13 (part of an AB system, JAB = 6.1 Hz,
1H), 2.84 (part of an AB system, JAB = 6.1 Hz, 1H), 2.56-2.48
(m, 1H), 2.43-2.35 (m, 1H), 2.10-1.70 (complex m, 6H), 1.46-
1.34 (m, 1H), 1.24-1.12 (m, 2H). 13C NMR (100 MHz, CDCl3):
d 206.4, 134.3, 130.9, 69.3, 57.8, 53.1, 52.2, 40.3, 37.7, 35.9, 31.1,
29.5, 24.7. HRMS (ESI)(m/z): found 243.0996 [M+Na]+; calcd
for C13H16O3Na 243.0997.
7 (7.80 g, 92%). IR (film) nmax: 3391, 1641, 1594, 1465 cm-1. H
1
=
NMR (400 MHz, CDCl3): d 8.35 (brs, 1H), 7.04-7.02 (m, 1H),
6.92-6.79 (m, 1H), 6.75 (superimposed dd, J1 = J2 = 8 Hz, 1H),
5.80-5.73 (m, 1H), 5.18-5.09 (m, 2H), 4.73 (brs, 1H), 3.80 (brs, 1H),
3.59-3.55 (m, 1H), 3.20 (brs, 1H), 2.84-2.75 (m, 1H), 2.70-2.60 (m,
1H), 2.30-2.10 (m, 2H), 1.77-1.70 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 153.9, 134.6, 130.2, 128.6, 126.2, 125.7, 120.1, 118.1,
69.6, 63.9, 41.8, 37.0, 25.5. HRMS (ESI) (m/z): found 245.1146
[M+Na]+; calcd for C13H18O3Na 245.1154.
C
5,8-Bis(3-hydroxy-hex-5-enyl)-3,10-bis(spiroepoxy)endo-tricyclo
[6.2.2.02,7]dodec-5,11-dien-4,9-dione (13) and the aldehyde (12)
To a solution of compound 7 (9.00 g, 40.54 mmol) in acetonitrile
(150 mL) was added a solution of NaIO4 (17.00 g, 79.47 mmol)
in water (150 mL) dropwise at 10 ◦C (~2 h). The reaction mixture
was then stirred for 3 h at ambient temperature. After which
it 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 (3 ¥ 80 mL). The organic
extracts were combined and washed with brine (50 mL) and dried
over sodium sulfate. The solvent was evaporated under reduced
pressure, and the residue was chromatographed on silica gel.
Elution with petroleum ether–ethyl acetate (90 : 10) first gave the
aldehyde 12 (0.800 g, 9%) as a colorless thick liquid. Further
elution with petroleum ether–ethyl acetate (60 : 40) gave the dimer
13 (5.95 g, 66%, a mixture of diastereoisomers) as a colorless thick
liquid.
Selected X-ray data for 5b: C13 H16 O3, M = 220.26, Monoclinic,
˚
˚
˚
-3
space grou◦p P21/c, a = 12.448(3) A, b = 6.840(3) A, c = 13.210(4) A,
◦
3
˚
a = g = 90 , b = 110.22(3) , V = 1055.5(6) A , Dc = 1.386 Mg m ,
3
˚
Z = 4, F(000) = 472, Size: 0.32 ¥ 0.28 ¥ 0.23 mm , l = 0.71073 A,
GoF = 1.053, m = 0.097 mm-1, Total/ unique reflections = 4908/
1844 [R(int) = 0.0477], T = 150(2) K, q range = 3.14 to 25.00◦,
Final R [I > 2s(I)]: R1 = 0.0546, wR2 = 0.0835, R (all data): R1 =
0.0978, wR2 = 0.0932.
Data for 12: IR (film) nmax: 3401, 1649 cm-1. 1H NMR (400 MHz,
CDCl3): d 11.36 (s, 1H), 9.88 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H),
6.97 (superimposed dd, J1 = J2 = 8.4 Hz, 1H), 5.89-5.76 (m, 1H),
5.16-5.09 (m, 2H), 3.67-3.59 (m, 1H), 2.81 (t, J = 8 Hz, 2H), 2.36-
2.06 (cluster of m, 3H), 1.84-1.70 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 196.9, 159.7, 137.6, 134.9, 131.9, 130.7, 120.4, 119.9,
118.1, 69.8, 42.0, 36.7, 25.3. HRMS (ESI) (m/z): found 243.0999
[M+Na]+; calcd for C13H16O3Na 243.0997.
9-Spiroepoxy-tricyclo[6.2.2.01,6]dodec-11-ene-4,10-dione (14)
To a solution of the compound 5a (1.40 g, 6.36 mmol) in CH2Cl2
(30 mL) was added PDC (4.78 g, 12.71 mmol) and the reaction
mixture was stirred at ambient temperature for 10 h. It was filtered
through a Celite bed, the filtrate was concentrated in vacuo and the
resulting product was chromatographed on silica gel. Elution with
petroleum ether–ethyl acetate, (60 : 40) furnished the diketone 14
(1.05 g, 75%) as a solid, mp. 130–132 ◦C. IR (film) n max: 1732,
1711 cm-1. 1H NMR (400 MHz, CDCl3): d 6.77 (dd, J1 = 8.2 Hz,
J2 = 6.7 Hz, 1H), 6.2 (d, J = 8.2 Hz, 1H), 3.19 (part of an AB
1
Data for 13: IR (film) nmax: 3487, 1731, 1693, 1640 cm-1. H
NMR (400 MHz, CDCl3): d 6.60-6.50 (m, 1H), 6.40-6.28 (m, 1H),
5.86-5.64 (m, 3H), 5.20-4.90 (m, 4H), 4.15-3.92 (m, 1H), 3.58-3.38
(m, 2H), 3.28 (s, 1H), 3.26 (d of part of an AB pattern, J = 5.5 Hz,
1H), 2.82-2.70 (m, merged with d of part of an AB pattern, J =
5.5 Hz, 3H), 2.62-2.42 (m, 2H), 2.34-1.84 (m, 9H), 1.76-1.66 (m,
1H), 1.60-1.40 (m, 3H).13C NMR (100 MHz, CDCl3): d 194.6,
194.1, 143.6, 141.7, 137.5, 134.9, 134.7, 129.2, 118.2, 116.8, 92.9,
69.9, 69.1, 66.2, 59.2, 58.6, 54.2, 48.0, 41.9, 41.3, 40.7, 38.5, 36.7,
26.5, 26.1 (major signals).
system, JAB = 6.2 Hz, 1H), 2.90 (part of an AB system, JAB
=
6.2 Hz, 1H), 2.66-2.62 (m, 1H), 2.54-2.34 (complex m, 5H), 2.27-
1.94 (m, 3H), 1.25-1.19 (m, 1H). 13C NMR (100 MHz, CDCl3): d
209.0, 205.3, 136.1, 129.9, 57.9, 53.4, 52.2, 45.9, 38.1, 37.8, 37.3,
30.0, 26.4. HRMS (ESI) (m/z): found 241.0846 [M+Na]+; calcd
for C13H14O3Na 241.0841.
Similarly, the compound 5b (2.32 g, 10.54 mmol) was oxidized
with PDC (7.93 g, 21.07 mmol) in CH2Cl2 (40 mL). Usual
work-up and chromatography furnished the diketone 14 (1.98 g,
HRMS (ESI) (m/z): found 441.2275 [M+H]+; calcd for
C26H33O6 441.2277.
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85%) as a solid which was identical to the compound prepared
above.
mixture was poured onto cold water (300 mL) and conc. HCl
(5 mL). The resulting mixture was extracted with ether (3 ¥ 80 mL)
and the organic layer was washed with aq. NaHCO3 (50 mL), H2O
(50 mL), aq. CuSO4 (2 ¥ 50 mL) and brine (50 mL). The organic
layer was dried and concentrated under vacuum. The product was
purified by column chromatography on silica gel. Elution with
petroleum ether–ethyl acetate (75 : 25) gave tosylate (0.49 g, 69%)
as a colorless liquid [IR (film) nmax: 1715, 1597, 1452 cm-1] which
was subjected to elimination reaction as described below.
9-Methyl-tricyclo-[6.2.2.01,6]dodec-11-ene-4,10-dione (15) and
9-hydroxymethyl-tricyclo[6.2.2.01,6] dodec-11-ene-4,10-dione (16)
To a solution of the compound 14 (0.90 g, 4.12 mmol) in MeOH–
H2O (5 : 1, 50 mL) was added zinc (activated 5.00 g, 79.36 mmol,
excess) and NH4Cl (1.00 g, 18.69 mmol, excess). The reaction
mixture was stirred at ambient temperature. After completion
of the reaction (TLC, 6 h), it was filtered on a Celite bed and
washed with methanol (30 mL). The filtrate was concentrated
under vacuum; the residue was diluted with water (50 mL) and
extracted with ethyl acetate (4 ¥ 30 mL). The combined extract
was washed with brine and dried over anhydrous Na2SO4. The
solvent was removed under vacuum, and the residue was purified
by column chromatography. Elution with petroleum ether–ethyl
acetate (85 : 15) first gave the compound 15 as a liquid (syn/anti
mixture, 0.135 g, 15%). IR (film) n max: 1718 cm-1. 1H NMR
(400 MHz, CDCl3): d 6.76 and 6.63 (each as superimposed dd,
J1 = J2 = 8.0 Hz, total 1H), 6.08 and 6.03 (each as d, J =
8.0 Hz, total 1H), 2.84-2.75 (m, 1H), 2.48-2.39 (m, 2H), 2.34-
2. 00 (m, 7H), 1.10 (d, J = 5.8 Hz, 3H), 1.00 - 0.96 (m, 1H). 13C
NMR (100 MHz, CDCl3): d 214.2, 209.8, 139.6, 128.2, 51.8, 46.2,
42.0, 37.7, 37.5, 37.3, 28.1, 26.9, 14.6. HRMS (ESI) (m/z): found
205.1228 [M+H]+; calcd for C13H17O2 205.1229.
A solution of the above tosylate (0.49 g, 1.30 mmol) in pyridine
(10 mL) was heated at 100 ◦C for 8 h, after which the reaction
mixture was poured onto cold water (300 mL) and conc. HCl
(5 mL). The resulting mixture was extracted with ether (3 ¥
80 mL) and the organic layer was washed with NaHCO3 (50 mL)
solution, H2O (50 mL), aq. CuSO4 (2 ¥ 50 mL) and brine (50 mL).
The organic layer was dried and the solvent was removed under
vacuum. The product was purified by column chromatography
on silica gel. Elution with petroleum ether–ethyl acetate (80 : 20)
gave the compound 18 (0.22 g, 83%) as a solid, mp. 70–72 ◦C. IR
1
(film) n max: 1707 cm-1. H NMR (400 MHz, CDCl3): d 6.01 (d,
J = 1.4 Hz, 1H), 5.26 (d, J = 1.4 Hz, 1H), 2.82-2.76 (m, 1H),
2.50-2.34 (m, 5H), 2.20-2.04 (m, 3H), 1.95-1.76 (m, 3H), 1.58-
1.46 (m, 1H), 1.34-1.28 (m, 1H). 13C NMR (100 MHz, CDCl3): d
210.2, 202.7, 146.8, 117.8, 44.9, 44.2, 36.9, 35.7, 35.1, 34.6, 28.4,
26.0, 21.3. HRMS (ESI)(m/z): found 227.1041 [M+Na]+; calcd
for C13H16O2Na 227.1048.
Further elution with petroleum ether–ethyl acetate (30 : 70)
furnished b-keto alcohol 16 as a liquid (syn/anti mixture, 0.560 g,
62%). IR (film) n max: 3500, 1712 cm-1. 1H NMR (400 MHz,
Selected X-ray data for 18: C13 H16 O2, M = 204.26, Orthorhom-
˚
˚
bic, space group Pbc, a = 6.5326(19) A, b = 16.022(7) A, c =
◦
3
˚
˚
21.032(6) A, a = b = g = 90 , V = 2201.3(13) A , Dc = 1.233 Mg
CDCl3): d 6.81 and 6.68 (each of these superimposed dd, J1
=
m-3, Z = 8, F(000) = 880, Size: 0.28 ¥ 0.23 ¥ 0.18 mm3, l = 0.71073
J2 = 6.6 Hz, total 1H); 6.13 and 6.05 (each as d, J = 6.6 Hz,
-1
˚
A, GoF = 0.827, m = 0.082 mm , Total/unique reflections = 9349/
1932 [R(int) = 0.0376], T = 293(2) K, q range = 3.20 to 25.00◦,
Final R [I > 2s(I)]: R1 = 0.0357, wR2 = 0.0793, R (all data): R1 =
0.0834, wR2 = 0.0871.
total 1H), 3.88-3.78 (m, 1H), 3.74-3.50 (m, 2H), 3.10-2.94 (m,
1H), 2.78-2.64 (m, 1H), 2.38-2.00 (m, 8H), 1.22-0.98 (m, 1H). 13
C
NMR (100 MHz, CDCl3): d 213.1, 209.2, 139.2, 128.2, 61.6, 51.9,
51.2, 49.3, 45.8, 37.7, 33.6, 28.5, 26.3 (major signals). HRMS
(ESI)(m/z): found 243.0998 [M+Na]+; calcd for C13H16O3Na
243.0997.
9-Methylenetricyclo[6.2.2.01,6]dodecanespiro[4.2¢]-1,3-dioxalan-10-
one (19)
9-Hydroxymethyl-tricyclo[6.2.2.01,6]dodec-4,10-dione (17)
To a mixture of ethylene glycol (0.5 mL), p-toluene sulfonic acid
(0.010 g, catalytic amount), and benzene (20 mL) dried in a Dean–
Stark apparatus was added a solution of the ene-dione 18 (0.30 g,
1.47 mmol) in dry benzene (10 mL). The reaction mixture was
refluxed for 4 h. It was cooled, and a saturated solution of sodium
bicarbonate (20 mL) was slowly added. The benzene layer was
separated, and the aqueous layer was extracted with ether (3 ¥
30 mL). The combined organic layers were washed with brine
and dried on anhydrous sodium sulfate. The solvent was removed
under vacuum, and the resulting product was chromatographed
on silica gel [petroleum ether–ethyl acetate (80 : 20)] to give the
To a solution of alcohol 16 (0.500 g, 2.272 mmol) in EtOH (25
mL) was added Pd on carbon (5% wt/wt, 0.150 g) at room
temperature. The resulting mixture was stirred under a hydrogen
atmosphere (balloon) for 1 h. The reaction mixture was filtered
on a pad of silica gel and the filtrate was concentrated in vacuo.
The resulting product was purified by column chromatography on
silica gel. Elution with petroleum ether–ethyl acetate (30 : 70) gave
the title compound 17 as a colorless liquid (0.420 g, 84%). IR (film)
n
max: 3425, 1710 cm-1. 1H NMR (400 MHz, CDCl3): d 4.10-3.86
(m, 1H), 3.78-3.62 (m, 1H), 2.96-2.80 (m, 1H), 2.60-2.30 (m, 6H),
2.28-1.64 (m, 7 H), 1.60-1.40 (m, 1H), 1.39-1.12 (m, 1H). 13C NMR
(100 MHz, CDCl3): d 218.3, 210.0, 62.2, 53.9, 44.8, 44.5, 36.9, 35.8,
30.2, 29.7, 28.4, 26.3, 21.8 (major signals). HRMS (ESI)(m/z):
found 223.1329 [M+H]+; calcd for C13H19O3 223.1334.
keto-ketal 19 (0.346 g, 95%) as a solid, mp. 120–122 ◦C. IR (film)
1
n
max: 1706 cm-1. H NMR (400 MHz, CDCl3): d 5.94 (d, J =
1.8 Hz, 1H), 5.18 (d, J = 1.8 Hz, 1H), 3.98-3.88 (m, 4H), 2.72-
2.66 (m, 1H), 2.34-2.22 (m, 1H), 2.08-1.90 (m, 3H), 1.84-1.60 (m,
merged with signal due to H2O in CDCl3, 6H), 1.56-1.46 (m, 1H),
1.34-1.14 (m, 2H). 13C NMR (100 MHz, CDCl3): d 204.0, 147.5,
116.7, 108.3, 64.4, 64.3, 44.0, 39.0, 35.8, 34.2, 32.0, 30.0, 26.35,
26.31, 21.0. HRMS (ESI)(m/z): found 249.1494 [M+H]+; calcd
for C15H21O3 249.1491.
9-Methylene-tricyclo[6.2.2.01,6]dodec-4,10-dione (18)
To a solution of alcohol 17 (0.42 g, 1.89 mmol) in pyridine (10 mL)
was added tosyl chloride (0.54 g, 2.83 mmol) and the reaction
mixture was stirred overnight at room temperature. The reaction
4478 | Org. Biomol. Chem., 2010, 8, 4472–4481
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9-Methylenetricyclo[6.2.2.01,6]dodecanespiro[4.2¢]-1,3-dioxalan-
10-yl acetate (20)
by column chromatography on silica gel. Elution with petroleum
ether removed some impurities. Continued elution with petroleum
ether–ethyl acetate (98 : 2) gave the compound 21 (0.045 g, 56%)
To a solution of compound 19 (0.100 g, 0.403 mmol) in methanol
(16 mL) was added CeCl3·7H2O (0.9 g) at 0 ◦C. Sodium borohy-
as a solid, mp. 59–61 ◦C. IR (film) nmax: 2923, 1648 cm-1. H
1
NMR (400 MHz, CDCl3): d 4.75-4.71 (m, 1H), 4.60-4.58 (m, 1H),
3.97-3.88 (m, 4H), 2.24-2.12 (m, 2H), 2.06-1.94 (m, 2H), 1.92-
1.82 (m, 1H), 1.78-1.28 (m, 9H), 1.08-0.96 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 152.2, 109.0, 104.7, 64.2, 64.0, 43.7, 39.6,
35.7, 35.3, 35.1, 34.5, 31.9, 30.5, 26.8, 23.8. HRMS (ESI) (m/z):
found 235.1707 [M+H]+; calcd for C15H23O2 235.1698.
◦
dride (0.012 g, 0.315 mmol) was then slowly added at 0 C and
the reaction mixture was stirred for 1 h. The reaction mixture was
diluted with water (5 mL) and extracted with diethyl ether (6 ¥ 20
mL). The combined extract was washed with brine and dried on
sodium sulfate. Removal of solvent followed by chromatography
on silica gel [petroleum ether–ethyl acetate] (75 : 25) gave an
alcohol (0.098 g, 98%) as a colourless liquid (as a mixture of
diastereoisomers) [IR (film) nmax: 3452 cm-1. 1H NMR (400 MHz,
9-Methylene-tricyclo[6.2.2.01,6]dodec-4-one (4)
CDCl3): d 5.11 and 5.05 (each of these superimposed dd, J1
=
To a solution of 21 (0.040 g, 0.170 mmol) in acetone–water (10 mL,
4 : 1) was added aq. HCl (10%, 0.5 mL) at 0 ◦C. The reaction
mixture was stirred at ambient temperature for 10 h. The reaction
mixture was neutralized with solid NaHCO3 and the organic
solvent was removed. The aqueous residue was extracted with
diethyl ether (3 ¥ 20 mL). The combined extract was washed with
brine (20 mL) and dried on anhydrous sodium sulfate. Removal
of solvent followed by chromatography on silica gel [petroleum
ether–ethyl acetate 96 : 4] gave 4 (0.030 g, 92%) as a thick colorless
J2 = 1.6 Hz, total 1H), 5.02-4.98 (m, 1H), 3.93 (s, 4H), 3.85 and
3.76 (each of these brs, total 1H); 2.30-2.22 (m, 1H), 2.14-1.96
(m, 2H); 1.94-1.32 (m, 8H), 1.30-1.24 (m, 1H), 1.20-0.08 (m, 3H).
13C NMR (100 MHz, CDCl3): d 156.7, 116.1, 108.9, 75.0, 64.2,
64.1, 39.5, 36.7, 35.6, 35.4, 34.3, 30.9, 28.7, 22.8, 16.9 (major
signals). HRMS (ESI) (m/z): found 273.1454 [M+Na]+; calcd for
C15H22O3Na 273.1467]. The alcohol thus obtained was subjected
to acetylation as described below.
To a solution of the above alcohol (0.100 g, 0.400 mmol) and
DMAP (0.004 g, 0.032 mmol) in CH2Cl2-pyridine (10 mL, 20 : 1)
at 0 ◦C was added acetic anhydride (0.20 g, 1.96 mmol). After
stirring for 5 min the reaction was stirred at ambient temperature
for 1 h. The reaction mixture was cooled to 0 ◦C and quenched with
saturated aq. NaHCO3 solution and the it was stirred vigorously at
room temperature for 30 min after which the reaction mixture was
diluted with CH2Cl2 (20 mL). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (3 ¥ 30 mL).
The combined organic layers were washed with aq. HCl (0.1 M,
20 mL), water (20 mL) and brine (30 mL), and dried on Na2SO4.
The solvent was removed under vacuum and the resulting product
was purified by column chromatography on silica gel. Elution
with petroleum ether–ethyl acetate (84 : 16) gave the acetate 20 as
a colourless liquid (as a mixture of diasteroisomers) (0.100 g, 86%).
IR (film) nmax: 1736 cm-1. 1H NMR (400 MHz, CDCl3): d 5.31 and
5.22 (each of these brm, total 1H), 4.99-4.88 (brm, 2H), 3.90 (s,
4H), 2.32-2.24 (m, 2H), 2.20-2.04 (m merged with two singlets,
total 5H), 2.00-1.80 (m, 2H), 1.78-1.40 (m merged with signal due
to H2O, 6H), 1.20-1.00 (m, 2H). 13C NMR (100 MHz, CDCl3): d
171.5, 151.4, 110.1, 108.6, 75.6, 64.4, 64.2, 39.7, 36.0, 35.6, 35.0,
30, 2, 28.8, 28.2, 25.8, 22.4, 21.4 (major signals). HRMS (ESI)
(m/z): found 315.1580 [M+Na]+; calcd for C17H24O4Na 315.1572.
1
liquid. IR (film) nmax: 1713 cm-1. H NMR (400 MHz, CDCl3):
d 4.78 (q, J = 2.1 Hz, 1H), 4.63 (q, J1 = 1.8 Hz, 1H), 2.50-2.10
(complex m, 7H), 2.06-1.92 (complex m, 2H), 1.90-1.78 (m, 1H);
1.78-1.64 (m, 3H), 1.53 (superimposed ddd, J1 = J2 = 13.5 Hz,
J3 = 5.4 Hz, 1H), 1.32-1.21 (m, 1H), 1.14 (ddd, J1 = 12.5 Hz, J2 =
5.7 Hz, J3 = 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 211.7,
150.8, 105.5, 46.2, 43.1, 38.8, 37.5, 36.7, 35.5, 35.4, 32.3, 26.5, 23.9.
HRMS (ESI) (m/z): found 191.1445 [M+H]+; calcd for C13H19O
191.1436. The above data are in excellent agreement with those
reported.13d
9-Methylene-tricyclo[6.2.2.01,6]dodec-2,3-diene-4-one (22) and
9-methylene-tricyclo[6.2.2.01,6]dodec-5,6-diene-4-one (3)
To a solution of ketone 4 (0.020 g, 0.105 mmol) in CH2Cl2 (3
mL) at 0 ◦C was added triethyl amine (0.350 g, 3.465 mmol)
and TMSOTf (0.380 g, 1.711 mmol). The reaction mixture was
stirred at 0 ◦C for 1.5 h, and further stirred at ambient temperature
for 2 h. It was then diluted with pentane (50 mL). The resulting
organic layer was separated and washed with saturated solution
of NaHCO3 (20 mL), brine (20 mL) and dried on Na2SO4 and
concentrated under reduced pressure to give a light-yellow oil.
This crude mixture of silyl enol ethers was dissolved in DMSO
(0.5 mL), then a solution of IBX (0.420 g, 1.500 mmol) and 4-
methoxypyridine N-oxide (MPO) (0.190 g, 1.520 mmol) in DMSO
(0.5 mL) was added. The resulting mixture was protected from
light and allowed to stir at ambient temperature for 18 h. The
reaction mixture was then poured into aq. NaHCO3 (5 mL) and
extracted with ethyl acetate (6 ¥ 10 mL). The combined organic
extract was washed with brine (20 mL) and dried on Na2SO4
and concentrated under reduced pressure to give a yellow liquid.
The product was purified by column chromatography on silica
gel. Elution with petroleum ether–ethyl acetate (95 : 5) gave the
desired compound 3 as a colorless liquid (0.010 g, 50%). Further
elution with petroleum ether–ethyl acetate (92 : 8) gave the isomeric
compound 22 as a liquid (0.005 g, 25%).
9-Methylenetricyclo[6.2.2.01,6]dodecane spiro[4.2¢]-1,3-dioxalane
(21)
To a solution of 20 (0.100 g, 0.342 mmol) in THF (5 mL) was
added a pre-mixed solution of Pd2dba3 (0.062 g, 0.067 mmol),
PBu3 (0.800 g, ~0.05 mL, 3.960 mmol), Et3N (0.400 g, 0.6 mL,
3.960 mmol) and formic acid (0.180 g, ~0.15 mL, 3.913 mmol) in
THF (2 mL) and the reaction mixture was refluxed. After 20 h the
reaction mixture was cooled to room temperature, diluted with
ether and the ether solution was washed with water (20 mL), aq.
HCl (2 M, 2 ¥ 20 mL), saturated aq. NaHCO3 (2 ¥ 30 mL) and
brine (30 mL). The organic layer was dried on Na2SO4, the solvent
was removed under reduced pressure and the product was purified
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Data for compound 3: IR (film) nmax: 1682 cm-1. 1H NMR
(400 MHz, CDCl3): d 6.57 (d, J = 9.8 Hz, 1H), 5.87 (dd, J1 = 9.8 Hz,
J2 = 0.9 Hz,1H), 4.83 (dt, J1 = 3.0 Hz, J2 = 1.8 Hz,1H), 4.69 (dd,
J1 = 3.7 Hz, J2 = 1.6 Hz,1H), 2.50-2.39 (m, 2H), 2.38-2.28 (m, 2H),
2.22-2.07 (m, 2H), 2.06-1.96 (m, 1H),1.82-1.66 (m, 3H), 1.56-1.48
(d) M. Malacria, Chem. Rev., 1996, 96, 289–306; (e) S. M. Sheehan, G.
Lalic, J. S. Chen and M. D. Shair, Angew. Chem., Int. Ed., 2000, 39,
2714–2715; (f) B. De Boeck, N. M. Harrington-Frost and G. Pattenden,
Org. Biomol. Chem., 2005, 3, 340–347; (g) D. P. Curran, Aldrichimica
Acta, 2000, 33, 104–110.
4 (a) I. Ugi, Pure Appl. Chem., 2001, 73, 187–191; (b) F. Bertozzi, B. V.
Gundersen, M. Gustafsson and R. Olsson, Org. Lett., 2003, 5, 1551–
1554; (c) M. A. Mironov, V. S. Mokrushin and S. S. Maltsev, Synlett,
2003, 943–946.
5 (a) S. Quideau, L. Pouysegu and D. Deffieux, Synlett, 2008, 467–495;
(b) D. Magdziak, S. J. Meek and T. R. R. Pettus, Chem. Rev., 2004,
104, 1383–1429; (c) C.-C. Liao and R. K. Peddiniti, Acc. Chem. Res.,
2002, 35, 856–866; (d) L. Pouysegu, S. Chassaing, D. Dejugnac, A.-
M. Lamidey, K. Miqueu, J.-M. Sotiropoulos and S. Quideau, Angew.
Chem., Int. Ed., 2008, 47, 3552–3555; (e) S.-Y. Luo, Y.-J. Jang, J.-Y. Liu,
C.-S. Chu, C.-C. Liao and S.-C. Hung, Angew. Chem., Int. Ed., 2008,
47, 8082–8085; (f) T. A. Wenderski, S. Huang and T. R. R. Pettus,
J. Org. Chem., 2009, 74, 4104–4109.
(m, 1H),1.22 (ddd, J1 = 12.5 Hz, J2 = 8.0 Hz, J3 = 1.3 Hz, 1H). 13
C
NMR (100 MHz, CDCl3): d 200.2, 156.7, 148.8, 127.7, 106.8, 41.6,
40.8, 35.9, 35.5, 35.4, 34.8, 26.3, 24.4. HRMS (ESI) (m/z): found
211.1090 [M+Na]+; calcd for C13H16ONa 211.1099. These spectral
features are in excellent agreement with the literature.12b,13c,d
1
Data for compound 22: IR (film) nmax: 1667 cm-1. H NMR
(400 MHz, CDCl3): d 5.85 (t, J = 2.0 Hz, 1H), 4.86 (dd, J1
3.5 Hz, J2 = 1.7 Hz, 1H), 4.69 (dd, J1 = 3.5 Hz, J2 = 1.7 Hz,
1H), 2.80-2.24 (m, 7H), 1.84-1.65 (m, 5H), 1.56-1.48 (m, 1H). 13
=
C
NMR (100 MHz, CDCl3): d 198.6, 170.0, 148.6, 124.1, 106.8, 39.7,
36.6, 36.3, 33.9, 32.1, 30.3, 29.6, 26.3. HRMS (ESI) (m/z): found
211.1109 [M+Na]+; calcd for C13H16ONa 211.1099. These features
are in agreement with those reported.13d
6 (a) V. Singh, Acc. Chem. Res., 1999, 32, 324–333; (b) V. Singh, J. D.
Praveena, K. Karki and S. M. Mobin, J. Org. Chem., 2007, 72, 2058–
2067; (c) V. Singh, P. K. Sahu, B. C. Sahu and S. M. Mobin, J. Org.
Chem., 2009, 74, 6092–6104.
7 (a) J. L. Wood, J. K. Graeber and J. T. Njardarson, Tetrahedron, 2003,
59, 8855–8858; (b) S. Quideau, M. Lebon and A.-M. Lamidey, Org.
Lett., 2002, 4, 3975–3978; (c) I. Drutu, J. T. Njardarson and J. L.
Wood, Org. Lett., 2002, 4, 493–496.
Crystal structure determination
8 (a) J. Wang, S. M. Soisson, K. Young, W. Shoop, S. Kodali, A. Galgoci,
R. Painter, G. Parthasarathy, Y. S. Tang, R. Cummings, S. Ha, K.
Dorso, M. Motyl, H. Jayasuriya, J. Ondeyka, K. B. Herath, C. Zhang,
L. Hernandez, J. Allocco, A. Basilio, J. R. Tormo, O. Genilloud, F.
Vicente, F. Pelaez, L. Colwell, S. H. Lee, B. Michael, T. Felcetto, C.
Gill, L. L. Silver, J. D. Hermes, K. Batizal, J. Barrett, D. Schmatz, J. W.
Becker, D. Cully and S. B. Singh, Nature, 2006, 441, 358–361; (b) S. B.
Singh, H. Jayasuriya, J. G. Ondeyka, K. B. Herath, C. Zhang, D. L.
Zink, N. N. Tsou, R. G. Ball, A. Basilio, O. Genilloud, M. T. Diez, F.
Vicente, F. Pelaez, K. Young and J. Wang, J. Am. Chem. Soc., 2006,
128, 11916–11920.
9 (a) J. Wang, S. Kodali, S. H. Lee, A. Galgoci, R. Painter, K. Dorso,
F. Racine, M. Motyl, L. Hernandez, E. Tinney, S. L. Colletti, K. B.
Herath, R. Cummings, O. Salazar, I. Gonzaa´lez, A. Basilio, F. Vicente,
O. Genilloud, F. Pelaez, H. Jayasuriya, K. Young, D. F. Cully and
S. B. Singh, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 7612–7616;
(b) H. Jayasuriya, K. B. Herath, C. Zhang, D. L. Zink, A. Basilio, O.
Genilloud, M. T. Diez, F. Vicente, I. Gonzalez, O. Salazar, F. Pelaez,
R. Cummings, S. Ha, J. Wang and S. B. Singh, Angew. Chem., Int. Ed.,
2007, 46, 4684–4688.
10 (a) K. C. Nicolaou, A. Li and D. J. Edmonds, Angew. Chem., Int. Ed.,
2006, 45, 7086–7090; (b) K. C. Nicolaou, D. J. Edmonds, A. Li and G. S.
Tria, Angew. Chem., Int. Ed., 2007, 46, 3942–3945; (c) P. Li, J. N. Payette
and H. Yamamoto, J. Am. Chem. Soc., 2007, 129, 9534–9535; (d) K. C.
Nicolaou, Y. Tang and J. Wang, Chem. Commun., 2007, 1922–1923;
(e) K. Tiefenbacher and J. Mulzer, Angew. Chem., Int. Ed., 2007, 46,
8074–8075; (f) G. Lalic and E. J. Corey, Org. Lett., 2007, 9, 4921–4923;
(g) Y. Zou, C.-H. Chen, C. D. Taylor, B. M. Foxman and B. B. Snider,
Org. Lett., 2007, 9, 1825–1828; (h) K. P. Kaliappan and V. Ravikumar,
Org. Lett., 2007, 9, 2417–2419; (i) A. K. Ghosh and K. Xi, Org. Lett.,
2007, 9, 4013–4016.
11 (a) K. C. Nicolaou, D. Pappo, K. Y. Tsung, R. Gibe and D. Y.-K. Chen,
Angew. Chem., Int. Ed., 2008, 47, 944–946; (b) C. H. Kim, K. P. Jang,
S. Y. Choi, Y. K. Chung and E. Lee, Angew. Chem., Int. Ed., 2008, 47,
4009–4011; (c) K. Tiefenbacher and J. Mulzer, Angew. Chem., Int. Ed.,
2008, 47, 2548–2555; (d) J. Matsuo, K. Takeuchi and H. Ishibashi, Org.
Lett., 2008, 10, 4049–4052.
Single crystal X-ray structural studies of 5b and 18 were performed
on a CCD Oxford Diffraction XCALIBUR-S diffractometer
equipped with an Oxford Instruments low-temperature attach-
ment. Data were collected at 150(2) K and 293(2) K for 5b and 18,
respectively, using graphite-monochromoated Mo-Ka radiation
˚
(la = 0.71073 A). The strategy for the data collection was evaluated
by using the CrysAlisPro CCD software. The data were collected
by the standard phi-omega scan techniques, and were scaled and
reduced using CrysAlisPro RED software. The structures were
solved by direct methods using SHELXS-9720 and refined by
full matrix least squares with SHELXL-97, refining on F2. The
positions of all the atoms were obtained by direct methods. All
non-hydrogen atoms were refined anisotropically. The hydrogen
atoms were placed in geometrically constrained positions and
refined isotropically. The hydrogen atom of the hydroxyl group
[(H101 and H102) over O1] in the structure of compound 5b was
found to be disordered and was refined by assigning 0.5 partial
occupancy. However, one of the disordered hydrogen atoms has
been removed for clarity in the ORTEP diagram (Fig. 3).
Acknowledgements
We thank the Department of Science and Technology, New Delhi
for continuing financial support. One of us (BCS) thanks CSIR
for a research fellowship. We are also thankful to DST for creating
a national centre for single crystal X-ray diffraction facility.
References
12 (a) K. C. Nicolaou, G. S. Tria and D. J. Edmonds, Angew. Chem., Int.
Ed., 2008, 47, 1780–1783; (b) J. Hayashida and V. H. Rawal, Angew.
Chem., Int. Ed., 2008, 47, 4373–4376; (c) K. Tiefenbacher and J. Mulzer,
Angew. Chem. Int. Ed., 2008, 47, 6199–6200.
13 (a) S. Y. Yun, J.-C. Zheng and D. Lee, Angew. Chem., Int. Ed., 2008, 47,
6201–6203; (b) D. C. J. Waalboer, M. C. Schaapman, F. L. van Delft and
F. P. J. T. Rutjes, Angew. Chem., Int. Ed., 2008, 47, 6576–6578; (c) K. C.
Nicolaou, Q.-Y. Toh and D. Y.-K. Chen, J. Am. Chem. Soc., 2008, 130,
11292–11293; (d) K. A. B. Austin, M. G. Banwell and A. C. Willis,
Org. Lett., 2008, 10, 4465–4468; (e) G. N. Varseev and M. E. Maier,
Angew. Chem., Int. Ed., 2009, 48, 3685–3688; (f) A. K. Ghosh and K.
Xi, Angew. Chem., Int. Ed., 2009, 48, 5372–5375; (g) K. Tiefenbacher
1 (a) K. C. Nicolaou and J. S. Chen, Chem. Soc. Rev., 2009, 38, 2993–3009;
(b) T. Newhouse, P. S. Baran and R. W. Hoffmann, Chem. Soc. Rev.,
2009, 38, 3010–3021; (c) J. Poulin, C. M. Grise´-Bard and L. Barriault,
Chem. Soc. Rev., 2009, 38, 3092–3101; (d) M. Juhl and D. Tanner,
Chem. Soc. Rev., 2009, 38, 2983–2992; (e) B. B. Toure and D. G. Hall,
Chem. Rev., 2009, 109, 4439–4486.
2 (a) M. Chanon, R. Barone, C. Baralotto, M. Julliard and J. B.
Hendrickson, Synthesis, 1998, 1559–1583; (b) E. J. Corey, X.-M.
Cheng, The Logic of Chemical Synthesis, John Wiley & Sons, New
York, 1989.
3 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115–136; (b) T. Hudlicky, Chem.
Rev., 1996, 96, 3–30; (c) J. D. Winkler, Chem. Rev., 1996, 96, 167–176;
4480 | Org. Biomol. Chem., 2010, 8, 4472–4481
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
and J. Mulzer, J. Org. Chem., 2009, 74, 2937–2941; (h) Synthesis of
(-)-norplatencin: O. V. Barykina, K. L. Rossi, M. J. Rybak and B. B.
Snider, Org. Lett., 2009, 11, 5334–5337.
17 (a) V. Singh, P. T. Deota and A. V. Bedekar, J. Chem. Soc., Perkin
Trans. 1, 1992, 903–912; (b) V. Singh and P. T. Deota, J. Chem. Res.,
1989, 390–391.
14 (a) E. Adler, S. Bransen and H. Miyake, Acta Chem. Scand., 1971, 25,
2055–2069; (b) E. Adler and K. Holmberg, Acta Chem. Scand., Ser. B,
1974, 28b, 465–472.
15 A. S. B. Prasad, J. V. B. Kanth and M. Periasamy, Tetrahedron, 1992,
48, 4623–4628.
16 V. Singh, M. Porinchu, P. Vedantham and P. K. Sahu, Organic Synthesis,
2005, 81, 171–177.
18 J.-L. Luche, L. Rodriguez-Hann and P. Crabbe, J. Chem. Soc., Chem.
Commun., 1978, 601–602.
19 J. Tsuji, I. Minami and I. Shimuzu, Synthesis, 1986, 623–
627.
20 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
64, 112–122; Program for Crystal Structure Solution and Refinement,
University of Goettingen, Germany, 1997.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4472–4481 | 4481
©