Synthetic studies towards bridgehead diprenyl-substituted bicyclo[3.3.1]nonane-2,9-diones as models for polyprenylated acylphloroglucinol construction

Article abstract of DOI:10.1002/ejoc.200700430

The synthesis of bridgehead diprenylated bicyclo[3.3.1]-nonane-2,9-dione, based on a reductive rearrangement of an enol lactone, is presented. The same target could be reached by a one-step sequence involving Michael addition of 2,6-diprenylcyclohexanone

Full text of DOI:10.1002/ejoc.200700430

FULL PAPER
DOI: 10.1002/ejoc.200700430
Synthetic Studies Towards Bridgehead Diprenyl-Substituted
Bicyclo[3.3.1]nonane-2,9-diones as Models for Polyprenylated
Acylphloroglucinol Construction
Thomas Pouplin,[a] Blanca Tolon,[a] Philippe Nuhant,[a] Bernard Delpech,*[a] and
Christian Marazano*[a]
Keywords: Enol lactones / Reduction / Rearrangement / Michael addition / Aldol reactions / Acylphloroglucinols
The synthesis of bridgehead diprenylated bicyclo[3.3.1]-
nonane-2,9-dione, based on a reductive rearrangement of an
enol lactone, is presented. The same target could be reached
by a one-step sequence involving Michael addition of 2,6-
diprenylcyclohexanone onto acrolein and intramolecular al-
dol reaction. The first method could be extended to the for-
mation of a compound with gem-dimethyl substituents adja-
cent to the bridgehead position, but the construction of a suit-
ably substituted enol lactone, with a view to polyprenylated
acylphloroglucinol elaboration, could not be achieved.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
thetic studies on these type B PPAPs, leading to the synthe-
sis of (Ϯ)-clusianone (2)[6] based on a Lewis acid catalyzed
Effenberger α,αЈ-annulation[7] of a suitably substituted cy-
clohexanone silyl enol ether with malonyl chloride.
Introduction
A
number of polyprenylated acylphloroglucinols
(PPAPs) with a bicyclo[3.3.1]nonane-2,4,9-trione core skel-
eton have been isolated from plants and trees of the family
Clusiaceae (Guttiferae), some of them presenting interest-
ing biological activities.[1] These compounds can be divided
principally into two classes: whereas type A PPAPs have a
bridgehead acyl group adjacent to a quaternary center,
those of type B have two bridgehead isoprenyl chains and
a C-3 acyl group (Figure 1).[2] The first total syntheses of a
compound of this class, garsubellin A (type A PPAP), have
been reported recently.[3]
Figure 2. Some examples of type B polyprenylated benzoylphloro-
glucinols.
Simpkins and co-workers published the synthesis of (Ϯ)-
clusianone (2) using a similar approach with a less-substi-
tuted cyclohexanone derivative and by bridgehead depro-
tonation and prenylation of a bicyclo[3.3.1]nonane-2,4,9-
trione enol methyl ether.[8]
The most direct route to the bicyclic core of type B pol-
yprenylated benzoylphloroglucinols, starting from a substi-
tuted cyclohexanone, is the Effenberger α,αЈ-annulation,[7]
but it is limited to compounds with a prenyl at C-7 in an
equatorial configuration (exo), such as 2, owing to the axial
attack of malonyl chloride on the enol derivative.[6,8] Thus,
we became interested in other methods for the construction
of the bridged bicyclic system of these natural products. As
we had already shown that C-benzoylation of the enolic β-
dicarbonyl moiety of a compound such as 4 can be achieved
using acyl cyanide,[6] we chose a potential precursor of 4 as
a target (Scheme 1). With this aim, bicyclo[3.3.1]nonane-
2,9-diones 3, with two isoprenyl chains at bridgehead posi-
tions, could be an interesting choice if the functionalization
Figure 1. Main types A and B polyprenylated acylphloroglucinols
(PPAPs).
Our interest in this field arose from the observation[4]
that xanthochymol (1) (Figure 2) was active in a tubulin
disassembly inhibition test and from the recent isolation of
the analogues oblongifolins A–D.[5] We also undertook syn-
[a] Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax: +33-1-69077247
E-mail: marazano@icsn.cnrs-gif.fr
delpech@icsn.cnrs-gif.fr
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T. Pouplin, B. Tolon, P. Nuhant, B. Delpech, C. Marazano
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at C-4 by further oxidation is easy. We also wanted to reach
Starting from 2,6-diprenylcyclohexanone (5), as a mix-
this goal directly starting from cyclohexanones substituted ture of isomers,[6] addition of ethyl acrylate followed by sa-
by prenyls, without protection of these groups[3a] and avoid- ponification and treatment of the intermediate acid with
ing olefin metathesis for their introduction.[3]
trifluoroacetic anhydride[13] gave enol lactone 7. Reduction
of 7, under the conditions described by Martin and co-
workers,[11] gave the bicyclic aldol product 8 in 82% yield,
essentially as a single exo isomer with the hydroxy group in
an axial position (Scheme 2). The efficiency and stereo-
chemistry of this aldol reaction could be attributed to the
generation of the ketone enolate close to the aldehyde ac-
cording to a mechanism illustrated in Scheme 3, as sug-
gested by Martin et al.[11b] Oxidation of alcohol 8 led to
1,5-diprenylbicyclo[3.3.1]nonane-2,9-dione (9) which could
be transformed into enone 10 by a bromination/dehydro-
bromination sequence.[10]
Scheme 1. Synthetic plan towards type B polyprenylated benzoyl-
phloroglucinols.
There are only a few methods for the synthesis of bicy-
clo[3.3.1]nonane-2,9-diones with alkyl groups at bridgehead
positions starting from the corresponding cyclohexanones.
When one of these positions is substituted by an acyl or
alkoxycarbonyl group, Michael addition onto α,β-unsatu-
rated aldehydes followed by intramolecular aldol reaction
can be used.[9] In the case of a 2,6-dialkylcyclohexanone,
indirect methods for the same type of cyclization have been
published,[10] but which are more difficult to apply with
acid-sensitive prenyl groups.
Scheme 3. Possible mechanism for the formation of the axial exo
alcohol 8.
An interesting way to reach the same target is the ef-
ficient reductive rearrangement of a enol δ-lactone, which
also implies intramolecular aldol reaction.[11] It should be
noted that this method has been recently applied to the syn-
thesis of a bicyclo[3.3.1]nonan-9-one derivative with only
one bridgehead prenyl group.[12]
Here, we report explorative work in this area and, in par-
ticular, our results concerning the evaluation of methods for
the synthesis of bridgehead diprenylated bicyclo[3.3.1]-
nonane-2,9-diones.
Surprisingly, we found that a mixture of 8 (major com-
pound) and its epimer could be directly obtained in 42%
yield from cyclohexanone 5 by a one-step sequence involv-
ing Michael addition onto acrolein in the presence of
tBuOK followed by intramolecular aldol reaction
(Scheme 4). It is worth noting that, to the best of our
knowledge, such a reaction has no precedent in the litera-
ture, acrolein leading usually, with ketone enolates, to com-
pounds resulting from addition onto a carbonyl rather than
from conjugate addition. A series of equilibria involving al-
dol and retroaldol reactions and proton transfers between
the different carbonyl derivatives and their enolates could
Results and Discussion
We first investigated the Martin reductive rearrange- explain this intriguing result. Moreover, direct oxidation of
ment[11] starting from the enol lactone 7 to evaluate this ketone 9 to enone 10 could be achieved by the method of
methodology for reaching the bicyclic structure with two Nicolaou et al. using 2-iodoxybenzoic acid (IBX) in the
prenyl groups at bridgehead positions (Scheme 1).
presence of NMO.[14]
Scheme 2. Formation of bicyclic aldol compound 8 by reductive rearrangement of 7.
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Bicyclononanediones as Models for Acylphloroglucinol
Scheme 4. α,αЈ-Annulation of 2,6-diprenylcyclohexanone with
acrolein and further oxidation.
Epoxidation of enone 10 with basic hydrogen peroxide
gave, as anticipated and without retroaldol reaction, the exo
derivative 11 in good yield, but its reduction to β-hydroxy
ketone 12 was more problematic. Miyashita conditions with
sodium phenylseleno(triethoxyborate) in the presence of
acetic acid[15] gave a disappointing 15% yield of 12 ac-
companied by 50% of enone 10. With SmI2 at a low tem-
perature,[16] 10 was the very major product (90%) and 12
was isolated in trace amounts. Aluminium amalgam gave
the best results (60% of 12), but only under sonication con-
ditions.[17] This result is of significance since this type of
reduction proved to be very difficult in an approach to ne-
morosone by Ciochina.[18] We ascribe the easy elimination,
leading to enone 10, to the axial position of the exo hydroxy
group in 12.
Unfortunately, we have not yet been able to oxidize the
β-hydroxy ketone 12 to the desired β-dicarbonyl derivative
under classical conditions (PDC, TPAP/NMO, Jones, Col-
lins, Swern and Dess–Martin reagents). Only Dess–Martin
periodinane, in the presence of 1 equivalent of water,[19]
gave minute amounts of the desired bicyclo[3.3.1]nonane-
2,4,9-trione 13.[6] This problem is not so trivial owing to the
axial position of the hydroxy group and it has already been
encountered in similar situations, but not with substituents
at the bridgehead positions.[20]
Scheme 5. Access to the 8,8-dimethyl-1,5-diprenyl bicyclic system.
Reduction of the lactone 19 was accompanied by an ef-
ficient aldol reaction, giving bicyclic compound 20 in an
excellent yield and as a single exo isomer which could be
oxidized with Dess–Martin periodinane to the bicyclo-
[3.3.1]nonane-2,9-dione 21 in 89% yield.
Finally, enol lactonization was attempted starting from
the cyclohexanone 22,[6] with the substitution pattern re-
quired for the synthesis of clusianone (2), according to
Scheme 6. Regio- and stereoselective introduction of the
ethoxycarbonylethyl chain (anti to the γ prenyl group)[3a,6]
by Michael addition onto ethyl acrylate gave 23 as a mix-
ture of isomers which could be separated. Formation of the
corresponding acids 24 by basic hydrolysis and conversion
into the acid chlorides proceeded in good yields.
We then examined if the reductive rearrangement of an
enol lactone could be applied to a compound with gem-
dimethyl substituents adjacent to a prenyl group to see if it
could be possible to reach, by this method, a bicyclic deriv-
ative with two contiguous quaternary carbons, as is re-
quired for the synthesis of PPAPs.
Enone 15[21] was obtained from 2-prenylcyclohexane-1,3-
dione (14)[6] via the vinylogous methyl ester[22] and conju-
gate addition of methyl copper onto enone 15, in the pres-
ence of BF3 etherate, followed by regioselective alkylation
of ketone 16[23] with prenyl bromide led to the tetrasubsti-
tuted cyclohexanone 17 as a mixture of isomers (Scheme 5).
Scheme 6. Failure of enol lactone 25 formation.
Unfortunately we could not obtain enol lactone 25 under
After carboxyethylation of 17, lactonization could not be the conditions described in Scheme 6 at 0 °C or at room
achieved using the trifluoroacetic-carboxylic mixed anhy- temperature or even under more classic conditions starting
dride shown in Scheme 2 for the lactonization of 6; the best from the acids 24 with acetic anhydride in the presence of
conditions were found starting from the acid chloride and sodium acetate at 140 °C.[11] We ascribe this failure to the
by activation with TMSOTf.
difficulty in obtaining the reactive conformation, that is,
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T. Pouplin, B. Tolon, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
reduced pressure. Column chromatography on silica gel (heptane/
ethyl acetate, 98:2) afforded 6 as a 1:1 mixture of the two diastereo-
isomers (227.2 mg, 65%) as a colorless oil. An analytical sample of
each epimer was obtained.
with the π bond of the chlorocarbonyl function in the direc-
tion of the lone pair of the ketone oxygen. Torsional strain
between the prenyl group adjacent to the carbonyl and the
gem-dimethyl substituents and the latter could disfavor
ring-conformation change.
A slightly different problem, relating to the aldol reaction
in the case of a compound with a prenyl at C-4, was en-
countered by Shibasaki and co-workers[3a] in their synthesis
of garsubellin A.
Thus, the enol lactone reductive rearrangement method-
ology could not be applied, in this case, to the preparation
of bicyclo[3.3.1]nonane-2,9-diones suitably substituted for
the synthesis of type B PPAPs. It should be also noted that
annulation of the pentasubstituted ketone 22 with acrolein
in the presence of tBuOK did not proceed.
Less Polar Epimer: 1H NMR (300 MHz, CDCl3): δ = 1.22 (m, 2
H), 1.22 (t, J = 7.2 Hz, 3 H), 1.52 (m, 1 H), 1.58 (s, 3 H), 1.58 (s,
3 H), 1.60 (m, 1 H), 1.66 (s, 3 H), 1.68 (s, 3 H), 1.70 (m, 1 H), 1.82
(m, 1 H), 1.85 (m, 1 H), 1.87 (m, 1 H), 1.90 (m, 1 H), 2.10 (m, 1
H), 2.20 (m, 1 H), 2.21 (m, 2 H), 2.36 (m, 1 H), 2.45 (m, 1 H), 4.08
(q, J = 7.2 Hz, 2 H), 5.03 (br. t, J = 7.6 Hz, 1 H), 5.06 (br. t, J =
7.6 Hz 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 17.7, 17.9,
20.9, 25.7, 26.1, 28.0, 28.9, 29.8, 32.3, 33.5, 37.6, 47.5, 51.5, 60.4,
119.6, 122.3, 132.8, 134.0, 173.3, 215.5 ppm. IR: ν = 2927, 1732,
˜
1702, 1450, 1375, 1182 cm–1.
1
More Polar Epimer: H NMR (300 MHz, CDCl3): δ = 1.21 (m, 2
H), 1.22 (t, J = 7.2 Hz, 3 H), 1.49 (m, 1 H), 1.57 (s, 3 H), 1.59 (s,
3 H), 1.66 (s, 3 H), 1.66 (s, 3 H); 1.68 (m, 1 H), 1.70 (m, 1 H), 1.80
(m, 1 H), 1.86 (m, 1 H), 1.87 (m, 1 H), 1.90 (m, 1 H), 2.12 (m, 1
H), 2.25 (m, 2 H), 2.36 (m, 1 H), 2.42 (m, 1 H), 2.47 (m, 1 H), 4.10
(q, J = 7.2 Hz, 2 H), 4.87 (br. t, J = 7.0 Hz, 1 H), 5.04 (br. t, J =
6.7 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 17.7,
18.0, 21.0, 25.7, 25.9, 27.9, 29.3, 29.9, 33.5, 33.6, 36.3, 47.4, 51.5,
Conclusions
We have shown that we can obtain bicyclo[3.3.1]nonane-
2,9-dione with two prenyl groups at bridgehead positions
starting from the corresponding 2,6-disubstituted cyclo-
hexanone and without protecting the olefinic double bonds.
This was achieved by either a reductive rearrangement of
an enol lactone or a one-step sequence involving Michael
addition onto acrolein and intramolecular aldol reaction.
Enol lactonization succeeded also with a gem-dimethyl de-
rivative, allowing, by reduction, the formation of a com-
pound with two contiguous quaternary carbon atoms in
good yield. The reaction failed with the suitably triprenyl-
substituted cyclohexanone that is necessary for the synthe-
sis of PPAPs such as clusianone. Oxidation of 1,5-diprenyl-
bicyclo[3.3.1]nonane-2,9-dione to a β-hydroxy ketone could
be achieved, but the major problem remaining to reach
PPAPs is the subsequent transformation into the enolic β-
dicarbonyl derivative. Investigations for finding prenyl-com-
patible oxidative conditions are currently underway and will
be reported in due course.
60.1, 118.0, 122.4, 132.6, 134.6, 174.1, 215.1 ppm. IR: ν = 2928,
˜
1732, 1702, 1445, 1376, 1176 cm–1.
3-[1,3-Bis(3-methylbut-2-enyl)-2-oxocyclohexyl]propanoic Acid:
A
mixture of esters 6 (1.134 g, 3.39 mmol) was solubilized in a solu-
tion of 85% KOH (291 mg, 4.41 mmol) in MeOH/H2O (2:1, 7 mL)
and stirred at room temperature for 24 h. Acetic acid (240 µL,
4.2 mmol) was added to the mixture and extraction was carried out
with dichloromethane (3ϫ5 mL). The organic layer was dried with
Na2SO4, filtered, and the solvent was removed under reduced pres-
sure to give acids as a colorless oil (1005 mg, 97%) and as a mixture
of epimers which could not be separated. 1H NMR (300 MHz,
CDCl3): δ = 1.20–1.22 (m, 1 H), 1.45–1.56 (m, 1 H), 1.58, 1.59,
1.60 (3ϫbr. s, 6 H), 1.67, 1.69 (2ϫbr. s, 6.5 H), 1.72–1.99 (m, 5
H), 2.04–2.53 (m, 7.5 H), 4.87 (br. t, J = 7.4 Hz, 0.5 H), 5.04 (m,
1 H), 5.06 (br. t, J = 7.4 Hz, 0.5 H), 10.16 (br. s, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 17.7, 17.7, 17.9, 18.0, 20.8, 21.1, 25.7,
25.9, 26.0, 27.9, 28.0, 28.7, 29.1, 29.5, 29.7, 32.3, 33.5, 33.6, 33.7,
36.4, 37.5, 47.4, 47.5, 51.4, 51.5, 117.8, 119.3, 122.2, 122.3, 132.7,
132.9, 134.2, 134.8, 179.4, 180.4, 215.2, 215.5 ppm. IR: ν = 3400–
˜
2400, 2926, 1702, 1445, 1376, 1221, 1113 cm–1. HRMS (EI): m/z
calcd. for C19H30NaO3 329.2093; found 329.2101.
Experimental Section
4a,8-Bis(3-methylbut-2-enyl)-3,4,4a,5,6,7-hexahydro-2H-chromen-2-
one (7): TFAA (1.43 mL, 10.1 mmol) was added dropwise during
10 min to a solution of a mixture of the above acids (2.613 g,
8.53 mmol) in dichloromethane at 0 °C (41 mL) containing dry
AcONa (704 mg, 8.58 mmol). The reaction mixture was vigorously
stirred at 0 °C for 2 h and at room temperature for 1 h. TEA
(3.3 mL, 23.7 mmol) was added and, after dilution with diethyl
ether (50 mL) and water (25 mL), the phases were separated and
the aqueous layer was extracted with diethyl ether (2ϫ20 mL). The
General Remarks: NMR spectra were recorded with the following
Bruker spectrometers: AC250 (250 MHz), AC300 (300 MHz), Av-
ance 300 (300 MHz), DPX 400 (400 MHz), and Avance 500
(500 MHz). FTIR spectra were recorded as a film on NaCl or dia-
mond (SensIR DurasampIRII) cell with a Perkin–Elmer Spectrum
BX FT-IR spectrometer. Mass spectra were recorded by electro-
spray ionization with a Micromass LCT (ESI-TOF) spectrometer.
Ethyl
3-[1,3-Bis(3-methylbut-2-enyl)-2-oxocyclohexyl]propanoate organic extracts were combined and dried with Na2SO4. Concen-
(6): A solution of 1.66  tBuOK in THF (120 µL, 0.2 mmol) and,
after 15 min at 0 °C, ethyl acrylate (113 µL, 1.04 mmol) were added
dropwise to a solution of a 85:15 cis/trans mixture of 2,6-diprenyl-
cyclohexanone[6] (243 mg, 1.04 mmol) in THF/dry tBuOH (1:1,
1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h
30 min and quenched at that temperature with saturated NH4Cl.
The aqueous layer was extracted with diethyl ether (3ϫ5 mL) and
the combined organic phases were washed with water (3 mL), brine
(3 mL), dried with Na2SO4, filtered, and the solvent removed under
tration and purification by silica gel chromatography (heptane/ethyl
acetate/TEA, 90:10:1) provided enol lactone 7 (1.637 g, 66%) as a
colorless oil. 1H NMR (300 MHz, CDCl3): δ = 1.30 (m, 1 H), 1.53
(m, 1 H), 1.57 (m, 1 H), 1.63 (s, 3 H), 1.65 (s, 3 H), 1.67 (m, 1 H),
1.69 (s, 3 H), 1.73 (s, 3 H), 1.80 (m, 1 H), 1.83 (m, 1 H), 2.03 (dd,
J = 7.1, 6.5 Hz, 2 H), 2.21 (br. d, J = 7.3 Hz, 2 H), 2.55 (dd, J =
8.5, 5.9 Hz, 2 H), 2.82 (m, 2 H), 5.04 (br. t, J = 7.3 Hz, 1 H), 5.06
(br. t, J = 7.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
17.8, 18.1, 18.5, 25.7, 26.1, 27.8, 28.0, 28.3, 30.0, 32.8, 33.9, 36.0,
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Bicyclononanediones as Models for Acylphloroglucinol
118.5, 118.6, 121.4, 132.7, 134.9, 147.1, 169.9 ppm. IR: ν = 2926,
(300 MHz, CDCl3): δ = 1.56 (m, 2 H), 1.60 (s, 3 H), 1.62 (m, 1 H),
1.63 (s, 3 H), 1.63 (s, 3 H), 1.73 (s, 3 H), 1.74 (m, 1 H), 1.90 (m, 1
H), 1.95 (m, 1 H), 2.04 (m, 1 H), 2.06 (m, 1 H), 2.24 (m, 1 H), 2.27
(m, 1 H), 2.32 (m, 1 H), 2.36 (m, 2 H), 2.55 (ddd, J = 14.5, 6.5,
2.7 Hz, 1 H), 5.07 (br. t, J = 7.1 Hz, 1 H), 5.18 (br. t, J = 6.9 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8, 18.0, 19.7, 25.9,
26.1, 26.5, 31.4, 35.7, 41.3, 42.0, 42.6, 49.2, 66.2, 119.0, 119.4,
˜
1750, 1686, 1451, 1247, 1146, 1115 cm–1. HRMS (EI): m/z calcd.
for C19H28NaO2 311.1987; found 311.1992.
(1R*,2R*,5R*)-2-Hydroxy-1,5-bis(3-methylbut-2-enyl)bicyclo-
[3.3.1]nonan-9-one (8): A 1  LiAlH(OtBu)3 solution in THF
(2.75 mL, 2.75 mmol) was slowly added to a solution of lactone 7
(582.5 mg, 2.02 mmol) in dry THF (1.2 mL) at –78 °C. The mixture
was stirred for 30 min at –78 °C, warmed up to room temperature
for 1 h, quenched by the addition of brine (6 mL), and filtered
through Celite. The aqueous phase was extracted with diethyl ether
(3ϫ10 mL) and the combined organic layers were washed with
water (5 mL), brine (5 mL), dried with Na2SO4, filtered, and the
solvent removed under reduced pressure. Column chromatography
on silica gel (heptane/ethyl acetate, 95:5) furnished 8 (480 mg, 82%)
134.3, 134.6, 212.9, 214.0 ppm. IR: ν = 2925, 1699, 1448 cm–1
.
˜
HRMS (EI): m/z calcd. for C19H28 NaO2 311.1987; found
311.1963.
(1S*,3S*,5S*)-3-Bromo-1,5-bis(3-methylbut-2-enyl)bicyclo-
[3.3.1]nonane-2,9-dione: A solution of ketone 9 (266.7 mg,
0.92 mmol) in THF (750 µL) was added dropwise to a suspension
of PhNMe3Br3 (346 mg, 0.92 mmol) in THF (7.5 mL) at 0 °C un-
der argon. The orange mixture was stirred for 30 min at 0 °C until
complete discoloration, and the resultant suspension was added to
a saturated brine/0.1  Na2S2O3 (1:1, 4 mL) mixture. The mixture
was filtered through Celite and extracted with dichloromethane
1
as a viscous oil. H NMR (300 MHz, CDCl3): δ = 1.52 (m, 1 H),
1.58 (s, 3 H), 1.65 (s, 3 H), 1.68 (m, 1 H), 1.70 (m, 1 H), 1.70 (s, 3
H), 1.71 (s, 3 H), 1.74 (m, 1 H), 1.84 (m, 1 H), 1.99 (m, 1 H), 2.00
(m, 1 H), 2.01 (m, 1 H), 2.03 (m, 1 H), 2.11 (m, 1 H), 2.13 (br. d,
J = 7.5 Hz, 2 H), 2.42 (m, 1 H), 2.52 (m, 1 H), 4.10 (br. s, 1 H), (3ϫ10 mL). The organic phases were washed with brine, dried with
5.16 (br. t, J = 7.4 Hz, 1 H), 5.18 (br. t, J = 7.6 Hz, 1 H) ppm. 13C
Na2SO4, filtered, and the solvent was removed under reduced pres-
NMR (75 MHz, CDCl3): δ = 17.8, 17.9, 21.1, 26.0, 26.1, 28.9, 31.8, sure to yield the bromo ketone (338 mg, 100%) as a crude oil which
34.1, 35.8, 35.9, 39.1, 49.5, 54.4, 78.1, 119.4, 120.2, 133.5, 134.6,
was used directly in the next step without any further purification.
1H NMR (300 MHz, CDCl3): δ = 1.60 (m, 2 H), 1.62 (s, 3 H), 1.64
(s, 3 H), 1.68 (s, 3 H), 1.70 (m, 1 H), 1.74 (s, 3 H), 1.78 (m, 1 H),
1.96 (m, 1 H), 2.28 (m, 1 H), 2.29 (m, 1 H), 2.39 (m, 1 H), 2.43
(m, 2 H), 2.50 (m, 1 H), 2.58 (m, 1 H), 4.48 (dd, J = 4.6, 2.6 Hz,
1 H), 5.21 (br. t, J = 7.7 Hz 1 H), 5.32 (br. t, J = 7.6 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 17.7, 18.0, 19.4, 25.9, 26.1, 32.9,
35.7, 35.8, 43.4, 44.6, 47.9, 48.8, 64.6, 119.1, 119.6, 133.9, 135.0,
219.1 ppm. IR: ν = 3494, 2915, 1703, 1448, 1375, 1103 cm–1
.
˜
HRMS (EI): m/z calcd. for C19H30NaO2 313.2144; found 313.2101.
Annulation of 5 with Acrolein: A 20% tBuOK solution in THF
(11 mL, 18.7 mmol) was added dropwise to a solution of an 85:15
cis/trans mixture of 2,6-diprenylcyclohexanone (5)[6] (4 g, 17 mmol)
in THF (57 mL) at room temperature and, after 30 min, the mix-
ture was cooled to –10 °C. A solution of acrolein (1.6 mL,
23.9 mmol) in THF (30 mL) was then added at that temperature
during 2 h through a syringe-drive. The reaction mixture was
stirred for 30 min between –5 °C and 0 °C and at room temperature
for 3 h and was then quenched with a pH 7 buffer. Extraction with
diethyl ether (3ϫ5 mL), followed by washing with brine, drying
with Na2SO4, and solvent removal under reduced pressure gave
a brown oil. Column chromatography on silica gel (heptane/ethyl
acetate, 9:1) afforded a 4:1 mixture of exo and endo alcohols 8 as
a colorless oil (2.05 g, 42%). An analytical sample of the minor
endo epimer (colorless oil) was obtained by column chromatog-
raphy on silica gel using the same eluent. 1H NMR (300 MHz,
CDCl3): δ = 1.25 (m, 1 H), 1.44 (m, 2 H), 1.50 (m, 1 H), 1.58 (s, 3
H), 1.67 (s, 3 H), 1.69 (m, 1 H), 1.70 (s, 3 H), 1.71 (s, 3 H), 1.72
(m, 1 H), 1.90 (m, 2 H), 1.93 (m, 1 H), 2.01 (m, 1 H), 2.09 (m, 2
204.6, 212.0 ppm. IR: ν = 2924, 1702, 1440, 1375, 1093 cm–1
.
˜
HRMS (EI): m/z calcd. for C19H27BrNaO2 389.1092; found
389.1107.
1,5-Bis(3-methylbut-2-enyl)bicyclo[3.3.1]non-3-ene-2,9-dione (10): A
solution of the above bromo ketone (326.9 mg, 0.89 mmol) in dry
DMF (500 µL) was added to a stirred suspension of dry LiBr
(309 mg, 3.56 mmol) and LiCO3 (255 mg, 3.45 mmol) in dry DMF
(2.9 mL) at 120 °C under argon. The reaction was stirred at 120 °C
for 75 min and the mixture was cooled to room temperature and
diluted with saturated brine. Then the aqueous solution was ex-
tracted with diethyl ether (2 ϫ 20 mL) and dichloromethane
(3ϫ10 mL). The organic layers were combined, washed with brine,
water, and brine, dried with Na2SO4, filtered, concentrated, and
purified by chromatography on silica gel (heptane/ethyl acetate,
H), 2.14 (m, 1 H), 2.43 (m, 1 H), 3.80 (dd, J = 11.2, 6.8 Hz, 1 H), 95:5) to give enone 10 (192 mg, 75%) as a slightly yellow oil. 1H
5.14 (br. t, J = 7.6 Hz, 1 H), 5.33 (br. t, J = 7.6 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 17.8, 17.9, 21.2, 26.1 (2 C), 29.6, 32.8,
33.1, 33.8, 35.9, 38.8, 48.8, 56.0, 77.0, 120.1, 121.4, 133.7, 134.2,
218.1 ppm. MS (EI): m/z = 313.2 [M + Na]+.
NMR (300 MHz, CDCl3): δ = 1.60 (m, 2 H), 1.61 (s, 3 H), 1.63 (s,
3 H), 1.63 (s, 3 H), 1.66 (m, 1 H), 1.66 (m, 1 H), 1.71 (s, 3 H), 1.86
(m, 1 H), 1.92 (m, 1 H), 2.30 (m, 1 H), 2.46 (m, 2 H), 2.51 (m, 1
H), 4.97 (br. t, J = 7.0 Hz, 1 H), 5.13 (br. t, J = 7.4 Hz, 1 H), 6.42
(d, J = 10.0 Hz, 1 H), 6.80 (d, J = 10.0 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.9, 18.0, 18.5, 25.9, 26.0, 29.5, 32.3, 36.5,
40.5, 53.3, 66.4, 118.5, 119.9, 132.3, 133.6, 135.3, 150.3, 200.9,
1,5-Bis(3-methylbut-2-enyl)bicyclo[3.3.1]nonane-2,9-dione (9): A
0.5  Dess–Martin periodinane solution in dichloromethane
(4.95 mL, 2.48 mmol) was added to a solution of alcohol 8
(480 mg, 1.65 mmol) in dry dichloromethane (3.75 mL) under ar-
gon at room temperature. The mixture was stirred for 3 h at room
temperature, quenched by the addition of a solution of saturated
NaHCO3 (75 mL) containing Na2S2O3 (15 g), and diluted with di-
ethyl ether (30 mL). The mixture was stirred under a normal atmo-
sphere until two limpid phases were obtained which were separated.
The organic layer was washed with water (2ϫ10 mL) and the aque-
ous phase extracted with diethyl ether (2ϫ10 mL) and, finally, the
combined organic phases were dried with Na2SO4, filtered, and
concentrated. Purification on silica gel (heptane/ethyl acetate, 95:5)
afforded dione 9 (433 mg, 91 %) as a colorless oil. 1H NMR
209.9 ppm. IR: ν = 2923, 1726, 1672, 1445, 1375, 1109 cm–1
.
˜
HRMS (EI): m/z calcd. for C19H26NaO2 309.1831; found 309.1847.
Oxidation of Ketone 9 to Enone 10 with IBX and NMO: A 60%
NMO solution in water (2.13 mL, 12.4 mmol) was added to a sus-
pension of IBX (3.45 g, 12.4 mmol) in DMSO (62 mL), protected
from the light and under argon, and the mixture was vigorously
stirred until dissolution. A solution of ketone 9 (1.19 g, 4.12 mmol)
in DMSO (4 mL) was added and the mixture was heated at 60–
70 °C for 60–72 h. After cooling to room temperature, aqueous 5%
NaHCO3 (50 mL) was added and the mixture was extracted with
diethyl ether. The organic phase was washed with saturated aque-
Eur. J. Org. Chem. 2007, 5117–5125
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5121

T. Pouplin, B. Tolon, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
ous NaHCO3, water, and brine, dried with Na2SO4, and the solvent
removed under reduced pressure. Column chromatography on silica
gel (heptane/ethyl acetate, 97:3) gave enone 10 (730 mg, 62%) as a
nearly colorless oil.
130.6, 171.3, 197.6 ppm. IR: ν = 2939, 1718, 1596, 1374, 1168 cm–1.
HRMS (ESI): m/z calcd. for C12H18NaO2 217.1204; found
217.1212.
˜
3-Methyl-2-(3-methylbut-2-enyl)cyclohex-2-enone (15): A 1.6 
MeLi solution in diethyl ether (10.75 mL, 17.2 mmol) was added
to a solution of the above vinylogous ester (2.30 g, 11.84 mmol)
in dry THF (41 mL) at 0 °C. After stirring for 30 min at room
temperature, the reaction mixture was cooled to 0 °C and treated
slowly with 1  HCl (29 mL, 29 mmol). After stirring for another
30 min at room temperature, the layers were separated and the
aqueous layer extracted with diethyl ether (3ϫ40 mL). The com-
bined organic layers were dried with Na2SO4 and the solvent was
removed under reduced pressure to give enone 15 (1.97 g, 93%) as
a pale yellow oil which was used without any further purification.
1H NMR (300 MHz, CDCl3): δ = 1.64 (s, 3 H), 1.68 (s, 3 H), 1.91
(quint., J = 6.3 Hz, 2 H), 1.91 (s, 3 H), 2.32 (t, J = 6.1 Hz, 2 H),
2.36 (t, J = 6.4 Hz, 2 H), 2.98 (d, J = 7.0 Hz, 2 H), 4.91 (br. t, J =
6.9 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7, 21.2,
22.2, 24.2, 25.6, 32.8, 37.7, 122.1, 131.2, 134.9, 155.6, 198.5 ppm.
(1S*,2R*,4R*,6S*)-1,6-Bis(3-methylbut-2-enyl)-3-oxatricyclo[4.3.1-
.02,4]decane-5,10-dione (11): Solutions of 35 % H2O2 (270 µL,
2.81 mmol) and 1.5  NaOH (120 µL, 0.18 mmol) were slowly
added to a solution of enone 10 (192 mg, 0.67 mmol) in MeOH
(2 mL) at 0 °C under argon . The mixture was stirred at 0 °C for
5 h and then ice (3 g) and cold saturated brine (4 mL) were added.
The mixture was extracted with dichloromethane (3ϫ10 mL), the
combined organic phases were washed with brine, dried with
Na2SO4, filtered, and the solvent was removed under reduced pres-
sure to furnish epoxy ketone 11 (187.9 mg, 93%) as a pure com-
1
pound. H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.58 (m, 1
H), 1.59 (m, 2 H), 1.59 (m, 1 H), 1.59 (s, 3 H), 1.63 (s, 3 H), 1.72
(s, 3 H), 2.09 (m, 1 H), 2.19 (m, 1 H), 2.33 (br. d, J = 6.9 Hz, 2
H), 2.37 (dd, J = 14.9, 8.6 Hz, 1 H), 2.59 (dd, J = 14.9, 7.2 Hz, 1
H), 3.40 (d, J = 3.9 Hz, 1 H), 3.44 (d, J = 3.9 Hz, 1 H), 4.87 (br.
t, J = 7.1 Hz, 1 H), 5.22 (br. t, J = 7.7 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.7, 17.8, 19.3, 25.6, 26.0, 30.3, 31.7, 35.2,
43.8, 50.8, 56.7, 56.9, 64.0, 117.8, 119.1, 133.7, 135.8, 207.1,
IR: ν = 2926, 1714, 1659, 1429, 1377, 1180, 1120 cm–1. HRMS
˜
(ESI): m/z calcd. for C12H18NaO 201.1255; found 201.1277.
3,3-Dimethyl-2-(3-methylbut-2-enyl)cyclohexanone (16): A 1.55 
MeLi solution in diethyl ether (19.35 mL, 30.0 mmol) was added
dropwise to a suspension of CuI (6.0 g, 31.5 mmol) in diethyl ether
(56 mL) at 0 °C. After cooling to –78 °C, freshly distilled BF3·Et2O
(3.8 mL, 30.0 mmol) was added dropwise and, after 10 min at that
temperature, a solution of enone 15 (534.8 mg, 3.0 mmol) in THF
(8 mL) was added. The reaction was stirred for 3 h 30 min at –78 °C
and quenched by the addition of saturated aqueous NH4Cl/20%
NH4OH (9:1, 80 mL). The mixture was brought to room tempera-
ture and stirring continued under a normal atmosphere until the
mixture turned deep blue. The suspension was filtered through Ce-
lite, the organic layer separated, and the aqueous layer extracted
with diethyl ether (3ϫ50 mL). The combined organic phases were
dried with Na2SO4, filtered, and the solvents evaporated. Column
chromatography on silica gel (heptane/ethyl acetate, 97:3) afforded
ketone 16 (367.2 mg, 63%) as a colorless oil and starting enone 15
207.5 ppm. IR: ν = 2927, 1701, 1447, 1256, 1147, 1037 cm–1
.
˜
HRMS (EI): m/z calcd. for C19H26NaO3 325.1780; found 325.1771.
(1R*,4S*,5S*)-4-Hydroxy-1,5-bis(3-methylbut-2-enyl)bicyclo-
[3.3.1]nonane-2,9-dione (12): Aluminium amalgam, prepared from
aluminium foils (1.56 g, 57.8 mmol) and a 0.19  aqueous solution
of mercuric chloride, was added to a solution of epoxy ketone 11
(350 mg, 1.16 mmol) in EtOH/H2O/THF/saturated NaHCO3
(87:48:30:3 v/v, 25 mL) under argon. The reaction mixture was son-
icated (TI-H-15Transsonic ultrasonic cleaning unit, 1250 W, max.
vol. 14.4/12.2 L) at 35 kHz and 80% of the power for 1 h 30 min
at room temperature. After decantation, the mixture was filtered
through a pad of Celite and the organic layer was washed with
brine, dried with Na2SO4, filtered, and concentrated. Column
chromatography on silica gel (heptane/ethyl acetate, 95:5) furnished
β-hydroxy ketone 12 (211.3 mg, 60 %) as a pure compound. 1H
NMR (300 MHz, CDCl3): δ = 1.64 (s, 6 H), 1.68 (s, 3 H), 1.72 (m,
2 H), 1.74 (s, 3 H), 1.83 (m, 1 H), 1.85 (m, 1 H), 2.04 (m, 1 H),
2.18 (m, 1 H), 2.25 (m, 1 H), 2.44 (br. d, J = 6.8 Hz, 2 H), 2.66
(m, 1 H), 2.74 (dd, J = 18.4, 2.5 Hz, 1 H), 3.02 (dd, J = 18.5,
4.9 Hz, 1 H), 4.13 (dd, J = 4.6, 2.8 Hz, 1 H), 5.00 (br. t, J = 6.9 Hz,
1 H), 5.26 (br. t, J = 7.7 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.9, 18.0, 20.4, 25.9, 26.2, 29.8, 31.7, 36.7, 41.6, 48.4,
1
(101.3 mg, 19%). H NMR (300 MHz, CDCl3): δ = 0.77 (s, 3 H),
1.04 (s, 3 H), 1.59 (s, 3 H), 1.61 (s, 3 H), 1.72 (m, 2 H), 1.81 (m, 2
H), 2.00 (m, 1 H), 2.12 (dd, J = 7.2, 3.0 Hz, 1 H), 2.25 (m, 1 H),
2.28 (m, 2 H), 5.00 (br. t, J = 7.1 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.6, 22.0, 22.9, 23.1, 25.6, 29.4, 39.0, 39.6,
41.1, 61.6, 123.4, 131.6, 213.0 ppm. IR: ν = 2962, 2921, 1711, 1460,
˜
1374, 1265 cm–1. HRMS (ESI): m/z calcd. for C13H22NaO
217.1568; found 217.1583.
54.2, 68.0, 69.8, 118.7, 120.2, 133.3, 135.8, 210.0, 211.5 ppm. IR: ν
˜
= 3506, 2916, 1727, 1691, 1442, 1376, 1032 cm–1. HRMS (EI): m/z
3,3-Dimethyl-2,6-bis(3-methylbut-2-enyl)cyclohexanone (17): A
1.1  BuLi solution in hexanes (1.89 mL, 2.08 mmol) was added to
a solution of DIPA (325 µL 2.32 mmol) in THF (4.2 mL) at 0 °C
under argon, and stirring was continued for 30 min at the same
temperature. At –78 °C a solution of ketone 16 (367.2 mg,
1.89 mmol) in THF (1.9 mL) was added dropwise and stirring was
continued for 1 h at the same temperature. Then a solution of 90%
prenyl bromide (224 µL, 1.75 mmol) in distilled HMPA (1.3 mL,
7.5 mmol) was added dropwise and the mixture was warmed up
slowly to room temperature overnight. A saturated solution of
NH4Cl and ether were added and the aqueous phase was extracted
with diethyl ether (2ϫ20 mL). The combined organic phases were
calcd. for C19H28NaO3 327.1936; found 327.1960.
3-Methoxy-2-(3-methylbut-2-enyl)cyclohex-2-enone: First DIPEA
(2.96 mL, 17.0 mmol) and, 5 min later, a solution of 2  TMS diaz-
omethane in hexanes (8.96 mL, 17.9 mmol) were added to a solu-
tion of 2-prenylcyclohexane-1,3-dione (14)[6] (2.31 g, 12.8 mmol) in
MeOH (5 mL) and CH3CN (45 mL) under argon at room tempera-
ture. The solution was stirred overnight at room temperature and
the solvent was removed under reduced pressure to provide a brown
oil (2.66 g). Purification on silica gel (heptane/ethyl acetate, 6:4 +
0.5% of TEA) afforded the methyl vinylogous ester (2.30 g, 92%)
1
as a colorless oil. H NMR (300 MHz, CDCl3): δ = 1.57 (s, 3 H), dried with Na2SO4, filtered, and the solvents evaporated. Column
1.63 (s, 3 H), 1.91 (quint., J = 6.5 Hz, 2 H), 2.26 (br. t, J = 6.4 Hz,
chromatography on silica gel (heptane/ethyl acetate, 98:2) afforded
2 H), 2.50 (t, J = 6.2 Hz, 2 H), 2.88 (d, J = 7.2 Hz, 2 H), 3.74 (s, ketone 17 (446.4 mg, 90%) as a colorless oil and as a 73:27 cis/trans
3 H), 4.98 (br. t, J = 7.2 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 17.3, 20.5, 20.9, 24.5, 25.4, 36.0, 54.8, 118.7, 122.5,
mixture. Only the less polar cis epimer was obtained as a pure com-
pound.
5122
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5117–5125

Bicyclononanediones as Models for Acylphloroglucinol
cis Epimer: 1H NMR (300 MHz, CDCl3): δ = 0.70 (s, 3 H), 1.10 (s,
3 H), 1.37 (m, 1 H), 1.52 (td, J = 13.6, 4.1 Hz, 1 H), 1.60 (s, 3 H),
1.63 (s, 3 H), 1.64 (s, 3 H), 1.68 (s, 3 H), 1.74 (dt, J = 13.7, 3.7 Hz,
1 H), 1.94 (m, 1 H), 1.95 (m, 1 H), 2.03 (m, 1 H), 2.18 (m, 1 H),
2.22 (m, 1 H), 2.37 (m, 1 H), 2.38 (m, 1 H), 5.05 (br. t, J = 7.3 Hz,
1 H), 5.07 (br. t, J = 7.5 Hz, 1 H) ppm. 13C NMR (75 MHz,
Minor Epimer: The minor ester 18 was saponified under the same
conditions as above and with the same yield. H NMR (300 MHz,
CDCl3): δ = 0.69 (s, 3 H), 1.10 (s, 3 H), 1.40 (m, 1 H), 1.60 (s, 3
H), 1.62 (s, 3 H), 1.63 (s, 3 H), 1.65 (m, 2 H), 1.66 (s, 3 H), 1.75
(m, 1 H), 1.90 (m, 1 H), 1.95 (m, 1 H), 1.97 (m, 1 H), 2.09 (m, 1
H), 2.29 (m, 1 H), 2.31 (m, 1 H), 2.32 (m, 1 H), 2.35 (m, 1 H), 2.59
1
CDCl3): δ = 17.6, 17.8, 20.5, 22.0, 25.7, 25.8, 27.7, 29.9, 30.1, 31.9, (m, 1 H), 4.82 (br. t, J = 7.3 Hz, 1 H), 4.99 (br. t, J = 7.3 Hz, 1
40.8, 51.0, 61.6, 122.2, 124.2, 131.3, 132.7, 212.8 ppm. IR: ν = 2923, H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.6, 18.0, 20.5, 21.9,
˜
1710, 1455, 1368 cm–1. HRMS (ESI): m/z calcd. for C18H30NaO 25.7, 25.9, 29.0, 29.8, 30.1, 32.0, 33.9, 36.5, 40.2, 50.4, 57.5, 118.0,
285.2194; found 285.2171.
124.0, 131.2, 134.6, 179.9, 214.7 ppm.
Ethyl 3-[4,4-Dimethyl-1,3-bis(3-methylbut-2-enyl)-2-oxocyclohexyl]-
propanoate (18): A 1.66  tBuOK solution in THF (560 µL,
0.93 mmol) and, after 15 min at 0 °C, ethyl acrylate (500 µL,
4.6 mmol) were added dropwise to a solution of ketone 17
(1214.2 mg, 4.63 mmol) in THF/dry tBuOH (1:1, 5 mL) at 0 °C.
The reaction mixture was stirred at 0 °C for 3 h 30 min and
quenched at that temperature with saturated NH4Cl. The aqueous
layer was extracted with diethyl ether and the combined organic
phases were washed with water, brine, dried with Na2SO4, filtered,
and the solvent removed under reduced pressure to yield esters 18
which were purified by column chromatography on silica gel (hep-
tane/ethyl acetate, 98:2) to afford, first, the major epimer (637.6 mg,
38%) and then the minor one (462.0 mg, 28%) as colorless oils.
HRMS (mixture of epimers) (ESI): m/z calcd. for C23H38NaO3
385.2719; found 385.2707.
Less Polar Epimer: 1H NMR (300 MHz, CDCl3): δ = 0.67 (s, 3 H),
1.09 (s, 3 H), 1.22 (t, J = 7.0 Hz, 3 H), 1.35 (m, 1 H), 1.58 (s, 3 H),
1.60 (br. s, 3 H), 1.61 (br. s, 3 H), 1.64 (m, 2 H), 1.68 (s, 3 H), 1.70
(m, 1 H), 1.77 (m, 1 H), 1.91 (m, 1 H), 1.93 (m, 1 H), 2.07 (m, 1
H), 2.18 (m, 1 H), 2.19 (m, 1 H), 2.20 (m, 1 H), 2.31 (m, 1 H), 2.37
(m, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 5.05 (m, 1 H), 5.06 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 17.6, 17.9, 20.5,
21.8, 25.5, 26.1, 28.7, 29.7, 30.0, 32.1, 33.0, 36.4, 40.2, 50.5, 57.8,
60.3, 119.5, 124.0, 131.6, 134.1, 173.4, 215.1 ppm.
7,7-Dimethyl-4a,8-bis(3-methylbut-2-enyl)-3,4,4a,5,6,7-hexahydro-
2H-chromen-2-one (19): Oxalyl chloride (51 µL, 0.58 mmol) was
added dropwise to a solution of the major above acid (163.0 mg,
0.49 mmol) in dichloromethane (5.3 mL) containing one drop of
dry DMF at room temperature. The reaction was stirred overnight
and the solvent and excess reagents were removed under reduced
pressure to yield the acid chloride (172.0 mg, quant.). IR: ν = 2926,
˜
1798, 1702, 1451, 1368, 1120 cm–1. TMSOTf (20 µL, 0.11 mmol)
was added to a solution of the acid chloride (100.0 mg, 0.28 mmol)
in dry dichloromethane (2 mL) at 0 °C and the mixture was stirred
for 3 h 30 min at 0 °C. TEA (70 µL, 0.5 mmol) was added to the
reaction and, after dilution with diethyl ether (4 mL) and water
(4 mL), the phases were separated and the aqueous layer was ex-
tracted with diethyl ether (2ϫ5 mL). The organic extracts were
combined and dried with Na2SO4. Concentration and purification
by silica gel chromatography (dichloromethane) provided the enol
1
lactone 19 (64.7 mg, 73%) as a colorless oil. H NMR (300 MHz,
CDCl3): δ = 0.76 (s, 3 H), 1.06 (s, 3 H), 1.36 (m, 1 H), 1.54 (m, 2
H), 1.60 (m, 1 H), 1.62 (s, 3 H), 1.65 (s, 3 H), 1.67 (s, 3 H), 1.72
(s, 3 H), 1.75 (m, 1 H), 1.77 (m, 1 H), 2.17 (m, 2 H), 2.51 (m, 2
H), 2.77 (d, J = 6.6 Hz, 2 H), 4.97 (br. t, J = 6.8 Hz, 1 H), 5.06
(br. t, J = 7.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
17.8, 18.1, 21.8, 24.5, 25.7, 26.0, 26.6, 27.9, 29.9, 30.3, 33.1, 34.9,
36.6, 43.3, 118.9, 123.6, 126.4, 130.4, 134.8, 148.1, 170.1 ppm.
More Polar Epimer: 1H NMR (300 MHz, CDCl3): δ = 0.68 (s, 3
H), 1.08 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.38 (m, 1 H), 1.59 (br.
s, 3 H), 1.60 (br. s, 3 H), 1.62 (br. s, 3 H), 1.63 (m, 2 H), 1.64 (br.
s, 3 H), 1.68 (m, 1 H), 1.92 (m, 1 H), 1.94 (m, 1 H), 1.94 (m, 1 H),
1.96 (m, 1 H), 2.07 (m, 1 H), 2.27 (m, 1 H), 2.34 (m, 1 H), 2.34
(m, 1 H), 2.59 (m, 1 H), 4.10 (q, J = 6.9 Hz, 2 H), 4.81 (br. t, J =
7.3 Hz, 1 H), 4.98 (br. t, J = 7.4 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.2, 17.6, 18.0, 20.5, 21.9, 25.6, 25.9, 29.2, 30.0, 30.1,
32.0, 33.8, 36.5, 40.1, 50.3, 57.5, 60.2, 118.2, 124.1, 131.0, 134.4,
174.1, 214.5 ppm.
(1S*,5R*,8R*)-8-Hydroxy-2,2-dimethyl-1,5-bis(3-methylbut-2-
enyl)bicyclo[3.3.1]nonan-9-one (20): A 1  LiAlH(OtBu)3 solution
in dry THF (0.15 mL, 150 µL) was slowly added to a solution of
lactone 19 (38.1 mg, 0.12 mmol) in dry THF (120 µL) at –78 °C.
The mixture was stirred for 30 min at –78 °C, warmed up to room
temperature for 1 h, quenched by the addition of cold brine (2 mL),
and filtered through Celite. The aqueous phase was extracted with
diethyl ether (3 ϫ 2 mL) and the combined organic layers were
washed with water (5 mL), brine (5 mL), dried with Na2SO4, fil-
tered, and concentrated. Column chromatography on silica gel
(heptane/ethyl acetate, 95:5) furnished alcohol 20 (37.6 mg, 98%)
3-[4,4-Dimethyl-1,3-bis(3-methylbut-2-enyl)-2-oxocyclohexyl]pro-
panoic Acid
1
as a very viscous oil. H NMR (300 MHz, CDCl3): δ = 0.87 (s, 3
Major Epimer: The major ester 18 (500.6 mg, 1.38 mmol) was solu-
bilized in a solution of 85% KOH (110 mg, 1.66 mmol) in MeOH/
H2O (2:1, 5.5 mL) and stirred at room temperature for 24 h. Acetic
acid (110 µL, 1.9 mmol) was added to the mixture and an extrac-
tion was carried out with dichloromethane. The organic layer was
dried with Na2SO4, filtered, and the solvent removed under re-
duced pressure to give the acid (452.4 mg, 98%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 0.68 (s, 3 H), 1.10 (s, 3 H), 1.37
(m, 1 H), 1.59 (s, 3 H), 1.62 (s, 6 H), 1.69 (m, 2 H), 1.70 (s, 3 H),
1.70 (m, 1 H), 1.87 (m, 1 H), 1.92 (m, 1 H), 1.97 (m, 1 H), 2.03
(m, 1 H), 2.20 (m, 1 H), 2.23 (m, 1 H), 2.30 (m, 1 H), 2.36 (m, 1
H), 1.11 (s, 3 H), 1.23 (m, 1 H), 1.47 (m, 1 H), 1.61 (s, 3 H), 1.62
(m, 1 H), 1.71 (br. s, 3 H), 1.718 (br. s, 3 H), 1.720 (br. s, 3 H),
1.78 (m, 1 H), 1.79 (m, 2 H), 1.96 (m, 1 H), 2.14 (m, 2 H), 2.26
(m, 1 H), 2.37 (dd, J = 15.6, 9.0 Hz, 1 H), 2.56 (br. d, J = 16.4 Hz,
1 H), 4.38 (br. s, 1 H), 5.16 (br. t, J = 7.0 Hz, 1 H), 5.41 (m, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8, 17.9, 25.2, 25.3,
26.07, 26.12, 26.5, 31.6, 31.9, 36.1, 36.1, 36.6, 43.5, 48.0, 61.6, 74.8,
120.2, 122.6, 133.7, 134.1, 218.1 ppm. IR: ν = 3510, 2922, 1705,
˜
1451, 1376 cm–1. HRMS (EI): m/z calcd. for C21H34NaO2
341.2457; found 341.2447.
H), 2.37 (m, 1 H), 5.05 (m, 1 H), 5.05 (m, 1 H) ppm. 13C NMR 8,8-Dimethyl-1,5-bis(3-methylbut-2-enyl)bicyclo[3.3.1]nonane-2,9-di-
(75 MHz, CDCl3): δ = 17.6, 17.9, 20.5, 21.8, 25.5, 26.0, 28.5, 29.4,
29.9, 32.1, 33.0, 36.3, 40.2, 50.4, 57.9, 119.3, 123.8, 131.9, 134.3,
one (21): Starting from alcohol 20, the procedure described for the
synthesis of 9 gave ketone 21 (89%) as a colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 0.83 (s, 3 H), 1.10 (s, 3 H), 1.33 (m, 1 H),
1.60 (s, 3 H), 1.63 (s, 6 H), 1.73 (s, 3 H), 1.74 (m, 1 H), 1.81 (m, 2
179.5, 215.1 ppm. IR: ν = 3400–2400, 2917, 1697, 1438, 1250,
˜
1108 cm–1.
Eur. J. Org. Chem. 2007, 5117–5125
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5123

T. Pouplin, B. Tolon, P. Nuhant, B. Delpech, C. Marazano
FULL PAPER
H), 1.82 (m, 2 H), 2.14 (m, 1 H), 2.26 (m, 2 H), 2.34 (m, 1 H), 2.51
(m, 1 H), 2.59 (m, 1 H), 4.84 (br. t, J = 7.1 Hz, 1 H), 5.20 (br. t, J
= 7.6 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.8, 18.0,
23.0, 25.3, 25.7, 25.9, 26.1, 28.2, 35.8, 36.0, 36.5, 41.3, 45.6, 47.9,
51.2, 56.8, 118.7, 123.2, 123.3, 131.9, 133.1, 134.2, 180.0,
217.0 ppm. IR: ν = 3400–2400, 2913, 1700, 1445, 1308, 1112 cm–1.
˜
HRMS (EI): m/z calcd. for C26H42NaO3 425.3032; found 425.3030.
73.1, 119.4, 119.8, 133.8, 134.5, 211.6, 213.2 ppm. IR: ν = 2967,
3-[(1R*,3S*,5S*)-4,4-Dimethyl-1,3,5-tris(3-methylbut-2-enyl)-2-
oxocyclohexyl]propanoic Acid (cis-24): Starting from the cis ester
23, the above procedure gave, with the same yield, the cis acid 24
˜
2926, 1694, 1453, 1373, 1264, 1152 cm–1. HRMS (ESI): m/z calcd.
for C21H32NaO2 339.2300; found 339.2292.
1
as a colorless oil. H NMR (300 MHz, CDCl3): δ = 0.57 (s, 3 H),
Ethyl 3-[(1R*,5S*)-4,4-Dimethyl-1,3,5-tris(3-methylbut-2-enyl)-2-
oxocyclohexyl]propanoate (23): A 1.66  tBuOK solution in THF
(464 µL, 0.77 mmol) and, after 15 min at 0 °C, ethyl acrylate
(425 µL, 3.9 mmol) were added dropwise to a solution of a 70:30
mixture of trans- and cis-22[6] (1267.2 mg, 3.83 mmol) in THF/dry
tBuOH (1:1, 4 mL) at 0 °C. The reaction mixture was stirred at
0 °C for 6 h and quenched at that temperature with saturated
NH4Cl. The aqueous layer was extracted with diethyl ether and the
combined organic phases were washed with water, brine, dried with
Na2SO4, filtered, and the solvent removed under reduced pressure.
The two epimers could barely be separated by column chromatog-
raphy on silica gel (heptane/ethyl acetate, 99:1) to afford cis-23
(179.4 mg, 11 %) and trans-23 (501.1 mg, 30 %) as colorless oils
(and 646.7 mg of a mixture of cis-23 + starting ketone). For the
1.14 (s, 3 H), 1.26 (m, 1 H), 1.29 (m, 1 H), 1.59 (s, 6 H), 1.62 (m,
2 H), 1.63 (s, 6 H), 1.70 (m, 1 H), 1.71 (s, 3 H), 1.72 (s, 3 H), 1.79
(m, 1 H), 1.82 (m, 1 H), 2.00 (m, 1 H), 2.10 (m, 1 H), 2.20 (m, 1
H), 2.23 (m, 2 H), 2.38 (m, 1 H), 2.39 (m, 1 H), 5.05 (m, 1 H), 5.06
(m, 1 H), 5.10 (m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
15.1, 17.6, 17.9 (2 C), 21.7, 25.5, 25.8, 26.1, 26.6, 28.4, 28.7, 30.2,
32.3, 39.8, 43.4, 43.5, 50.7, 58.4, 119.3, 123.5, 124.0, 132.0, 132.5,
134.3, 179.5, 215.0 ppm.
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mixture of epimers: IR: ν = 2917, 1729, 1446, 1318, 1189 cm–1.
˜
HRMS (EI): m/z calcd. for C28H46NaO3 453.3345; found 453.3338.
Ethyl 3-[(1R*,3S*,5S*)-4,4-Dimethyl-1,3,5-tris(3-methylbut-2-enyl)-
1
2-oxocyclohexyl]propanoate (cis-23): H NMR (300 MHz, CDCl3):
δ = 0.56 (s, 3 H), 1.12 (s, 3 H), 1.23 (t, J = 7.2 Hz, 3 H), 1.25 (m,
1 H), 1.58 (s, 6 H), 1.61 (s, 6 H), 1.69 (s, 3 H), 1.71 (s, 3 H), 1.72
(m, 2 H), 1.78 (m, 1 H), 1.79 (m, 1 H), 1.80 (m, 1 H), 2.00 (m, 1
H), 2.06 (m, 1 H), 2.18 (m, 1 H), 2.18 (m, 2 H), 2.22 (m, 1 H), 2.39
(m, 1 H), 2.40 (m, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 5.06 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 15.1, 17.6, 17.8,
17.9, 21.7, 25.5, 25.8, 26.1, 26.6, 28.7, 28.7, 30.5, 32.3, 39.8, 43.3,
43.4, 50.8, 58.3, 60.4, 119.5, 123.5, 124.1, 131.7, 132.4, 134.1, 173.5,
215.1 ppm.
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P. Nuhant, M. David, T. Pouplin, B. Delpech, C. Marazano,
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Ethyl 3-[(1R*,3R*,5S*)-4,4-Dimethyl-1,3,5-tris(3-methylbut-2-
enyl)-2-oxocyclohexyl]propanoate (trans-23): 1H NMR (300 MHz,
CDCl3): δ = 0.79 (s, 3 H), 0.94 (s, 3 H), 1.12 (m, 1 H), 1.23 (t, J =
7.1 Hz, 3 H), 1.54 (m, 2 H), 1.56 (s, 3 H), 1.59 (s, 3 H), 1.62 (s, 6
H), 1.66 (s, 3 H), 1.68 (m, 1 H), 1.69 (s, 3 H), 1.94 (m, 1 H), 1.94
(m, 1 H), 2.03 (m, 1 H), 2.08 (m, 2 H), 2.09 (m, 1 H), 2.19 (m, 2
H), 2.31 (m, 1 H), 2.36 (m, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 4.92
(m, 1 H), 4.94 (m, 1 H), 5.07 (br. t, J = 7.3 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.2, 17.6, 17.82, 17.85, 22.4, 22.9,
23.8, 25.66, 25.69, 25.9, 28.2, 28.2, 29.3, 34.2, 35.7, 40.3, 43.3, 51.2,
56.9, 60.2, 118.9, 123.3, 123.4, 131.8, 132.9, 134.0, 173.8,
217.0 ppm.
[8]
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3-[(1R*,3R*,5S*)-4,4-Dimethyl-1,3,5-tris(3-methylbut-2-enyl)-2-
oxocyclohexyl]propanoic Acid (trans 24): The trans ester 23
(267.0 mg, 0.62 mmol) was solubilized in a solution of 85% KOH
(54 mg, 0.8 mmol) in MeOH/H2O (2:1, 1.2 mL) and stirred at room
temperature for 24 h. Acetic acid (50 µL, 0.87 mmol) was added to
the mixture and an extraction was carried out with dichlorometh-
ane. The organic layer was dried with Na2SO4, filtered, and the
solvent removed under reduced pressure to give the trans acid 24
(243.9 mg, 98%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ
= 0.80 (s, 3 H), 0.95 (s, 3 H), 1.11 (m, 1 H), 1.57 (m, 2 H), 1.57 (s,
3 H), 1.60 (s, 3 H), 1.62 (br. s, 3 H), 1.63 (br. s, 3 H), 1.67 (s, 3 H),
1.70 (s, 3 H), 1.72 (m, 1 H), 1.76 (m, 1 H), 1.91 (m, 1 H), 1.93 (m,
1 H), 2.05 (m, 1 H), 2.10 (m, 2 H), 2.26 (m, 2 H), 2.32 (m, 1 H),
2.38 (m, 1 H), 4.92 (m, 1 H), 4.93 (m, 1 H), 5.07 (br. t, J = 7.2 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 17.7, 17.8, 17.9, 22.4,
22.8, 23.7, 25.7 (2 C), 25.9, 28.0, 28.1, 29.0, 34.3, 35.7, 40.4, 43.4,
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5124
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5117–5125

Bicyclononanediones as Models for Acylphloroglucinol
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Received: May 14, 2007
Published Online: August 17, 2007
Eur. J. Org. Chem. 2007, 5117–5125
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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