Enantiospecific synthesis and chiroptical properties of bicyclic enones

Article abstract of DOI:10.1002/ejoc.200700241

The enantiospecific synthesis of several bicyclic enones starting from enantiomerically pure (+)-(1S,5S)-bicyclo[3.3.1]-nonane-2,6-dione (1) was accomplished. The target enones 7-9 were obtained in high yield and purity by using a catalytic amount of benzeneselenic anhydride. (+)-(1S,5R)-bicyclo[3.3.1] nonane-2,3,6-trione was obtained from diketone 1 by α-hydroxylation involving the use of iodine under basic conditions. The reaction included a ring closure/reopening sequence via oxatricyclo[4.3.1.0^3,8]decane-10-one. It was shown that the latter triketone exists in enone/enol form. Chiroptical properties of the enantiomerically pure compounds were studied, and the sign of the Cotton effect was related to the absolute configuration of the enones. The positive Cotton effect in the bisignate CD curve is accounted for by the nonplanarity of the chromophore in enones (1S,5R)-4 and (1S,5S)-8. The circular dichroism spectra provided evidence for interchromophoric interaction in dichromophoric bis(enone) 9. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700241

FULL PAPER
DOI: 10.1002/ejoc.200700241
Enantiospecific Synthesis and Chiroptical Properties of Bicyclic Enones
[a]
[a]
[b]
[a]
ˇ
ˇ
Edvinas Orentas, Gintautas Bagdziunas, Ulf Berg, Albinas Zilinskas, and
¯
Eugenijus Butkus*[a]
Keywords: Chirality / CD spectroscopy / Chromophores / Enantiospecific synthesis / Enones
The enantiospecific synthesis of several bicyclic enones start-
ing from enantiomerically pure (+)-(1S,5S)-bicyclo[3.3.1]-
nonane-2,6-dione (1) was accomplished. The target enones
Chiroptical properties of the enantiomerically pure com-
pounds were studied, and the sign of the Cotton effect was
related to the absolute configuration of the enones. The posi-
7–9 were obtained in high yield and purity by using a cata- tive Cotton effect in the bisignate CD curve is accounted for
lytic amount of benzeneselenic anhydride. (+)-(1S,5R)-bicy-
clo[3.3.1]nonane-2,3,6-trione was obtained from diketone 1
by α-hydroxylation involving the use of iodine under basic
conditions. The reaction included a ring closure/reopening
sequence via oxatricyclo[4.3.1.03,8]decane-10-one. It was
shown that the latter triketone exists in enone/enol form.
by the nonplanarity of the chromophore in enones (1S,5R)-4
and (1S,5S)-8. The circular dichroism spectra provided evi-
dence for interchromophoric interaction in dichromophoric
bis(enone) 9.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
served CE with the absolute configuration of chiral mole-
cules containing various chromophores.[4] The α,β-unsatu-
rated ketone (enone) chromophore belongs to the group of
chromophores that have been investigated quite extensively
in recent years.[5] A number of sector and/or helicity rules
have been proposed to correlate the sign of the CEs ob-
served in the spectral region between 200 and 350 nm with
the absolute configuration of α,β-enone molecules.[6] These
rules are derived from the observation that the CD and UV
spectra of enones are affected by substituents located close
to this chromophore, which alter its electronic structure as
well as spatial dimension.[7] Moreover, there is considerable
interest in the chiroptical properties of molecules with sev-
eral chromophores at appropriate positions and spatial ar-
rangements in relevant molecules.
Therefore, well-designed molecules are needed for study-
ing these phenomena in more detail. The chiral bicy-
clo[3.3.1]nonane and related tricyclic skeletons derived from
this framework have been shown to be important structures
for the study of chiroptical properties.[8] These molecules
are structurally coherent and interconvertible by ring clo-
sure/reopening during chemical transformations, the appro-
priate chromophores could thus be introduced into a mole-
cule by using relevant synthetic methods.[9] Enantiomer-
ically pure compounds having this framework have been
synthesized and employed as suitable models to study the
effects of electronic interactions in the generation of rota-
tional strength in electronic transitions.
Introduction
A wide variety of natural products contain embedded in
their frameworks bicyclic motifs possessing the enone func-
tionality. This fragment is also essential in precursors for
the synthesis of natural or biologically important com-
pounds.[1] The majority of these compounds are chiral, as
they have substituents at appropriate positions. Thus the
question of establishing the absolute configuration of such
molecules arises when isolating minor quantities of natural
compounds and developing a range of methodologies for
their assembly.
Bicyclo[3.3.1]nonenones have attracted attention as a
synthetic goal, because polyfunctionalized derivatives of
this skeleton are key intermediates in natural product syn-
thesis.[2] We focused on the synthesis of chiral bicy-
clononane enones and the study of their chiroptical proper-
ties by circular dichroism (CD) spectroscopy.
CD spectroscopy today is a well-established technique in
studies of stereochemistry.[3] Various chromophores have
been investigated both experimentally and theoretically
over the past decade in order to correlate the sign of the
Cotton effects (CEs) to various sector and/or helicity rules.
The enormous number of applications of electronic CD
measurements led to the formulation of semiempirical rules
for the correlation of the sign and magnitude of the ob-
[a] Department of Organic Chemistry, Vilnius University,
Naugarduko 24, 03225 Vilnius, Lithuania
Fax: +370-5-2330987
In this work, we have accomplished the synthesis of sev-
eral bicyclo[3.3.1]nonanes possessing an α,β-enone moiety,
including a bicyclic triketone which was shown to exist in
enone/enol form, from enantiomerically pure (+)-(1S,5S)-
E-mail: eugenijus.butkus@chf.vu.lt
[b] Organic Chemistry, Department of Chemistry, Lund University,
P. O. Box 124, 22100 Lund, Sweden
E-mail: ulf.berg@organic.lu.se
Eur. J. Org. Chem. 2007, 4251–4256
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4251

ˇ
E. Orentas, G. Bagdziunas, U. Berg, A. Zilinskas, E. Butkus
ˇ
¯
FULL PAPER
bicyclo[3.3.1]nonane-2,6-dione (1). The chiroptical proper- enol OH group, and carbon signals at δ = 150.0 and
ties of these molecules were studied in order to correlate 117.0 ppm in the 13C NMR spectrum confirm the presence
the absolute configuration with the signs of the CD bands of the unsaturated bond.
and to verify existing rules.
Results and Discussion
Scheme 1. Reagents and conditions: (a) I2, KOH, MeOH, 0 °C; (b)
TsOH·H2O, acetone, room temp.; (c) DMSO, TFAA, TEA,
CH2Cl2, –60 °C.
Synthesis of Bicyclo[3.3.1]nonenones
The synthesis of the enantiomerically pure target bicy-
The above synthesis afforded the original dichromo-
clo[3.3.1]-nonane α,β-enones 4 and 7–9 was accomplished phoric enone/enol molecule, but related enones were re-
by using (+)-(1S,5S)-bicyclo[3.3.1]nonane-2,6-dione (1) as quired for a study of chiroptical properties. The synthesis of
the starting compound. The kinetic resolution of racemic racemic enones 7 and 9 described in the literature involves
2,6-dione 1 with baker’s yeast reduced the (–)-(1R,5R)-en- multistep procedures. We have developed a simpler and
antiomer, thus enriching the mixture with (+)-(1S,5S)-1. A higher-yielding synthesis of these enones.
modification of the procedure reported by Hoffmann and
Wiartalla[10] afforded the (+)-(1S,5S)-1 enantiomer with comprises a bromination-debromination sequence; how-
Ͼ99% ee after repeated fermentations. ever, the purification of the product from the monoenone
The reported synthesis of bis(enone) 9 from diketone 1
We developed a synthesis of triketone 4 by employing α- and brominated byproducts was very tedious because of the
hydroxylation of the initial 2,6-diketone 1, which involved nonselective bromination step.[14] An acetal-protected dike-
a ring closure/reopening reaction sequence. A powerful tone can be used for the same purpose; however, the synthe-
method for the preparation of α-hydroxy carbonyl com- sis requires many steps, and the overall yield is low.[13b]
A
pounds from the parent carbonyl compound involves the challenge was to develop a practical, one-step synthesis of
hydroxylation of preformed enolates or enol ethers with a enones 7–9 in enantiomerically pure form. Recently, Nico-
variety of oxidizing agents. However, the low stability of laou et al. reported unsaturation of aldehydes and ketones
diketone 1 monoenolate makes these methods difficult to mediated by a stoichiometric amount of 2-iodoxybenzoic
apply in our case and would necessitate the use of carbonyl acid (IBX) in DMSO.[15] In our hands, this one-step synthe-
protection-deprotection steps for selective monohy- sis of enones was quite successful with diketone 1, providing
droxylation.
bis(enone) 9 and enone 8 in 70% and 65% yield, respec-
On the other hand, the α-hydroxylation of diketone 1 tively. Nevertheless, it required a large excess of expensive
was successfully accomplished by following the reported IBX (4–8 equiv.) and long reaction times (38–48 h) for com-
procedure for the iodine-mediated α-hydroxylation of plete conversion.
ketones and aldehydes to α-hydroxyketals under basic con-
Another widely used method for introducing unsatura-
ditions in MeOH.[11] After treatment of (+)-1 with iodine tion in carbonyl compounds is based on selenoxide elimi-
in basic methanol solution, tricyclic acetal 2 was formed in nation.[16] The reaction between diketone (+)-1 and phen-
high yield instead of the expected α-hydroxyketone acetal ylselenyl chloride under various conditions failed to give the
(Scheme 1). This outcome can be explained by exo-selective diselenyl derivative in high yield. This could be explained by
iodination of the ketone in the first step and a subsequent unfavourable steric interactions between phenylselenyl
cascade addition–cyclization reaction initiated by meth- groups in positions 3 and 7 of the bicyclononane skeleton.
oxide anion attack on the carbonyl group. This reaction can We reasoned that introducing selenium in its higher oxi-
be regarded as analogous to a recently published synthesis dation state would ensure immediate selenoxide elimi-
of acetals under basic conditions.[12] The intramolecular nation, thus avoiding steric interactions between substitu-
acetal formation allowed us to obtain the monofunction- ents in the 3- and 7-positions.
alized product without protecting the carbonyl group. The
The Barton dehydrogenation procedure seemed very at-
analogous ring closure/reopening reaction strategy was suc- tractive and was thus subsequently examined, as benzene-
cessfully used earlier with the bicyclo[3.3.1]nonane skeleton selenic anhydride is generated in the reaction in situ from a
to effect carbonyl group transposition.[13] The tricyclic ring catalytic amount of diphenyl diselenide by using iodoxyben-
of 2 was readily converted to bicyclo[3.3.1]nonane by an zene as stoichiometric oxidant.[17] The unsaturation of dike-
acid-catalyzed transacetalization reaction with acetone, and tone (+)-1 under these conditions by using an excess of
subsequent Swern oxidation of the hydroxyketone 3 af- iodoxybenzene indeed afforded bis(enone) 9 in high yield
forded the corresponding (+)-(1S,5R)-2,3,6-trione 4. The (90%). The monounsaturation was achieved directly by
predictable existence of triketone 4 in the enol form was using 2 equiv. of iodoxybenzene giving enone 8 in 60%
confirmed by spectroscopic data. The intense band at ca. yield. By analogy, enone 7 was synthesized in 95% yield
3400 cm–1 in the IR spectrum clearly indicates O–H stretch- from monoketone 6, which was obtained by protection of
1
ing. The signal observed at δ = 6.25 ppm in the H NMR one carbonyl group in diketone 1 with a slight modification
spectrum can also be readily assigned to the proton of the of the reported procedure (Scheme 2).[18]
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Eur. J. Org. Chem. 2007, 4251–4256

Enantiospecific Synthesis and Chiroptical Properties of Bicyclic Enones
FULL PAPER
Table 1.Specific rotation and λmax for compounds 4 and 7–9.
Compound
[α]546, °cm2 g–1
CD, λmax, nm
(∆ε, dm3 mol–1 cm–1
)
(+)-(1S,5R)-4
(+)-(1S,5S)-7
(+)-(1S,5S)-8 +1569 (EtOH, c = 0.0204, 20 °C)
(+)-(1S,5S)-9 +2260 (EtOH, c = 0.37, 20 °C)
+350 (EtOH, c = 3.1, 20 °C)
+115 (EtOH, c = 0.76, 20 °C)
314 (+0.40), 273 (–0.37)
341 (+0.95)
313 (+5.4), 254 (–2.4)
342 (+10.2)
Scheme 2. (a) PhIO2, PhSeSePh, TsOH (cat.), toluene, reflux; (b)
Ra-Ni, EtOH, reflux; (c) Jones reagent, room temp.
CD Analysis
sign of the CEs that are observed in the spectral region
between 200 and 350 nm with the absolute configuration of
α,β-enone molecules have to be applied with caution. Re-
cently a study on the chiroptical properties of cisoid enones
showed that, in general, the positive (negative) sign of the
CE associated with the nǞπ* transition reflects the positive
(negative) enone helicity.[20] The sign of the torsional angles
in enones 4 and 8 correlates with the long-wavelength sign
of the CE in the bisignate CD curve (Figure 1).[21] The sign
of the shorter-wavelength band is opposite to that of the
longer-wavelength band.
Compound 4 possesses one band in the UV region be-
tween 200 and 360 nm (Figure 3b). The CD maximum is
shifted to a shorter wavelength relative to that of the UV
absorption of 4. The hypsochromic shift of the nǞπ* tran-
sition in triketone 4 and ketoenone 8 is associated with the
effect of neighbouring substituents. The marked difference
in intensity of this transition is accounted for by the elec-
tronic effects of the carbonyl group in the next six-mem-
bered ring of ketoenone 8, and more substantially, of the
hydroxy group attached directly to the enone double bond
in triketone 4.
The synthesized compounds possess enone chromo-
phores, and among them compounds 4, 8 and 9 are dichro-
mophoric. The CD spectra of enones usually have two CD
bands in the range 220 to 350 nm. The third short-wave-
length CD band, which is found in the 200 to 220 nm spec-
tral region, is of very small absorption intensity and is likely
to be due to a πǞπ* transition, though this assignment is
not unequivocal.[19] The long-wavelength band is due to an
nǞπ* transition which appears around 350 nm. The second
band, which appears between 230–260 nm, is due to a
πǞπ* transition polarized approximately along the line
connecting the oxygen and the most remote carbon atom
of the C=C bond.
The bands of the nǞπ* transition in the CD spectra of
the studied enones are observed at ca. 340 nm for enone 7
and bis(enone) 9, and at ca. 310 nm for ketoenone 8 and
triketone 4 (Figure 1). The λmax and specific rotation of
these enones are presented in Table 1. The CD spectra of
all compounds exhibited a positive Cotton effect. Enone 7,
containing the single chromophore, could be regarded as a
reference compound for this transition.
The intensity of the CD bands of enone 4 are ten times
weaker than those of ketoenone 8. This is due to the magni-
tude of the dipoles, although their orientation is nearly the
same in both molecules (Figure 2a). We calculated the angle
between the planes containing chromophores to be ca. 60°
for both compounds by the B3LYP/6-31G* method. How-
ever, the dipole moment is substantially smaller in molecule
4 because of the electronic effects of the hydroxy group at
the enone double bond, which decreases the electron den-
sity. The positive mesomeric effect of the hydroxy group
Figure 1. CD spectra of triketone (1S,5R)-4 (–·–), ketoenone
(1S,5S)-8 (···), enone (1S, 5S)-7 (– –), and bis(enone) (1S,5S)-9 (Ϫ)
in ethanol.
Conformational analysis by molecular mechanics and
B3LYP/6-31G* calculations revealed that the cyclohex-
enone ring of enones 4 and 8 exists in a distorted flattened
chair conformation.
The enone functionality is nonplanar, and the torsional
angles were found to be 4º and 5º, respectively, in minimized
Figure 2. (a) Distorted cyclohexenone chair conformation (in front)
and angle between planes containing chromophores in triketone
4; (b) Division of the C-6 carbonyl group in triketone (+)-4 into
structures. The sector and/or helicity rules correlating the octants.
Eur. J. Org. Chem. 2007, 4251–4256
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E. Orentas, G. Bagdziunas, U. Berg, A. Zilinskas, E. Butkus
ˇ
¯
FULL PAPER
and the intramolecular hydrogen bonding of the latter with
the enone carbonyl group (cf. the case of 1,2-cyclohexane-
dione)[22] considerably reduce the charge separation be-
tween the carbonyl oxygen atom and the terminal carbon
atom of the enone double bond, thus affecting the value
of the chromophore dipole moment in compound 4. This
conclusion is strongly supported by the 1H NMR signals of
the corresponding ethylene protons in molecules 4 and 8,
6.17 ppm and 7.12 ppm, respectively, which demonstrates
the strong deshielding of the enone double bond in 8. Ac-
cordingly, the bathochromic shift of the shorter-wavelength
band in the CD spectrum of compound 4 relative to that
of ketoenone 8 (Figure 1) is accounted for by the resulting
dipole as well.
We next examined the applicability of the octant rule for
the correlation of the sign of the observed Cotton effect
with the absolute configuration of enones containing a car-
bonyl chromophore in the next six-membered ring. The
band of an nǞπɆ transition is ascribed to the carbonyl
chromophore. In order to apply the octant rule, the trike-
tone molecule 4 was divided into octants. The cyclohex-
anone ring with the carbonyl group is in a conformationally
defined chair form in this molecule, and dividing it into
octants is straightforward. Figure 2b shows the division of
the minimized structure (1S,5R)-4 into octants. The hy-
droxy group of the enone functional group, the C-2 carbon
atom of the carbonyl group in the cyclohexenone ring and
the C-8 carbon atom of the next six-membered ring are lo-
cated in positive octants, while the enone carbonyl group is
Figure 3. (a) The orientation of dipoles in the minimized structure
of bis(enone) 9; (b) UV spectra of triketone 4 (Ϫ) and bis(enone)
9 (---).
connecting the oxygen atom and the most remote carbon
atom of the C–C double bond, and is observed for enones
4 and 8 (Figure 1). Interestingly, though the exciton chiral-
ity rule is not applicable to enones 4 and 8, a positive CD
couplet could be linked to a positive angle between planes
containing transition dipoles (Figure 2a) and vice-versa,[24]
thus relating positive chirality with the positive first and
negative second Cotton effects.
close to the nodal surfaces. Thus the major input in the top Conclusions
left and the bottom right positive octants leads to a positive
The synthesis of bicyclo[3.3.1]nonenones in enantiomer-
CE, which is in accordance with the experimental data. An
analogous unambiguous conclusion can be reached by di-
viding the carbonyl groups of ketoenone (1S,5S)-8 into oc-
tants.
The intensities of the nǞπ* transition bands of com-
pounds 4 and 7–9 are significantly different. For bis(enone)
9 the absorption of this transition is enhanced by an order
of magnitude in comparison to enone 7. This originates
from a transannular orbital interaction of chromophores in
dichromophoric bis(enone) 9.
The transannular interaction of enone chromophores in
this compound has been demonstrated earlier by photoelec-
tron spectroscopy[18] in comparison to enone 7 as well as
by their chemical reactivity leading to intramolecular ring
closure.[23] In addition, the molecular structure of 9 has a
slightly nonplanar arrangement of chromophores (calcu-
lated torsional angle 2º), and this helicity contributes to the
intensity of the CD absorption. In bis(enone) 9 the intensity
of the nǞπ* transition band is significantly higher as a re-
sult of the orientation of dipoles which are nearly parallel
(Figure 3a). Compound 9 possesses two bands in the UV
region, maxima occurring at 350 and 230 nm (Figure 3b).
The CD maximum corresponds to the absorption maxi-
mum in the UV spectrum. Interestingly, the polarimetric
rotation angle of the bis(enone) 9 is remarkably large.
The second band between 230 and 260 nm arises from
ically pure form afforded a series of novel derivatives of
this framework in high yield. A CD study of the molecules
possessing the α,β-enone chromophore was performed. The
positive Cotton effect in the bisignate CD curve is ac-
counted for by the nonplanarity of the enone chromophore
in enones (1S,5R)-4 and (1S,5S)-8. The octant rule was ap-
plied to both enones. The hypsochromic shift of the transi-
tion in ketoenone 8 and triketone 4 is associated with the
effect of neighbouring substituents. The marked difference
in intensity of this transition for ketoenone 8 is accounted
for by the electronic effects of the carbonyl group in the
next six-membered ring. The more substantial changes ob-
served in triketone 4 are attributed to the hydroxy group
attached directly to the enone double bond and the orienta-
tion of planes where transition dipoles are located. The sig-
nificant increase in the nǞπ* transition intensity in bis-
(enone) 9 relative to enone 7 is attributed to a transannular
orbital interaction of chromophores in the bis(enone).
Experimental Section
General: Melting points were determined with a Gallencamp melt-
ing apparatus in capillary tubes and are not corrected. IR spectra
were recorded in KBr pellets with a Perkin–Elmer Spectrum BX
spectrometer. NMR spectra were recorded with a Varian Inova 300
a πǞπ* transition polarized approximately along the line spectrometer in CDCl3. Chemical shifts are given in parts per mil-
4254 Eur. J. Org. Chem. 2007, 4251–4256
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Enantiospecific Synthesis and Chiroptical Properties of Bicyclic Enones
FULL PAPER
lion relative to TMS by using the residual solvent peak as internal
standard.
(+)-(1S,5R)-Bicyclo[3.3.1]nonane-2,3,6-trione (4): TFAA (0.14 mL,
1.0 mmol) was added dropwise to a stirred solution of dimethyl
sulfoxide (0.10 mL, 1.4 mmol) in dry CH2Cl2 (5 mL) under argon
at –60 °C. The resulting colourless, clear solution was stirred at
–60 °C for 10 min, and a solution of 3 (40 mg, 0.24 mmol) in
CH2Cl2 (2 mL) was then added dropwise. The mixture was stirred
at –60 °C for 1.5 h and triethylamine (0.28 mL, 2.0 mmol) was
added dropwise. The light yellow reaction mixture was stirred for
1.5 h at –60 °C, warmed to 5 °C, poured into water and extracted
with CH2Cl2. The combined organic extracts were dried (Na2SO4),
filtered, and the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography (CHCl3) to
afford 30 mg (80%) of 4 as a yellowish waxy solid: [α]54620 = +350 °
(c 3.1, EtOH). CD: λmax (∆ε/dm3 mol–1 cm–1) = 314 (+0.40), 273
(–0.37) nm. UV: λmax (lgε) = 275 (sh 2.26), 321 (3.06) nm. 1H
NMR: δ = 6.25 (s, 1 H, enol-OH), 6.17 (dd, J = 7.2, 1.5 Hz, 1 H),
3.25–3,22 (m, 1 H), 2.96–2.89 (m, 2 H), 2.70 (ddd, J = 13.2, 6.3,
3.1 Hz, 1 H), 2.35–2.08 (m, 5 H) ppm. 13C NMR: δ = 207.8 (C-6),
197.1 (C-2), 150.0 (C-4), 117.0 (C-3), 47.6 (C-5), 40.4 (C-1), 35.4
Mass spectra were run with a Hewlett–Packard 6980 instrument
having the mass selective detector 5975 inert XL and a Supelcowax
capillary column (30 mϫ0.25 µm). Chiral GC analysis was carried
out with a Perkin–Elmer Autosystem instrument by using a Beta-
Dex 120 fused silica capillary column.
Thin-layer chromatography was carried out on Kieselgel 60 F254
(Merck) sheets coated with silica gel. Column chromatography was
performed on silica gel (0.040–0.063 mm, Merck). The CD spectra
were recorded with a Jasco Model J-500A spectropolarimeter at
20 °C in 0.1-cm or 1.0-cm cells using spectral grade ethanol
(99.5%). The CD spectra were measured in millidegrees and nor-
malized into the units dm3 mol–1 cm–1 for ∆εmax and nm for λ. Op-
tical rotations were measured with a Polamat-A (Carl Zeiss) instru-
20
ment at 546 nm. [α]546 values are given in 10–1 °cm2 g–1, and con-
centrations are given in units of g/100 cm3.
The lowest energy conformational search was performed by using
the molecular mechanics MMFF94 force field, and the energy of
conformers was refined with ab initio B3LYP/6-31G* calculations
using the program package SPARTAN ’06 for Windows Version
1.0.2.[25]
(C-9), 33.8 (C-7), 28.8 (C-8) ppm. IR: ν = 3407 (OH), 1712 (6-
˜
C=O), 1676 (2-C=O), 1650 (C=C) cm–1. MS of the acetyl deriva-
tive: m/z (%) = 166 (100) [M – CH3CO]+, 148 (1), 138 (30), 111
(100).
(+)-(1S,5S)-Bicyclo[3.3.1]nonane-2,6-dione (1): Baker’s yeast (65 g)
and saccharose (100 g) were added to a preheated (36–38 °C) sus-
(+)-(1S,5S)-Bicyclo[3.3.1]nonane-2-one (6): The Lightner pro-
cedure[18] of monothioketalization was followed with 0.30 g of dike-
tone 1 to afford 0.38 g (83%) of 5.
pension of racemic bicyclo[3.3.1]nonane-2,6-dione
2 (20.2 g,
0.13 mol) in water (500 mL). The mixture was kept at the same
temperature for 6 d without stirring with daily addition of saccha-
rose (50 g). After this time, the yeast was centrifuged off, and the
resulting mixture was extracted with CHCl3. The combined organic
extracts were washed with brine, dried (MgSO4) and concentrated
to dryness. The residue was subjected to a second fermentation for
an additional 6 d, the products were then separated as above and
purified by flash chromatography (CHCl3) to yield 6 g (59%) of
(+)-(1S,5S)-diketone 1, ee Ͼ99% (GC).
Freshly prepared Ra-Ni (4.2 g) was added to a solution of mono-
thioketal 5 (0.38 g, 1.7 mmol) in EtOH (25 mL). The mixture was
heated under reflux for 0.5 h, cooled to room temperature and fil-
tered through Celite (CAUTION: Do not let the pyrophoric Raney
nickel get dry. The filter cake is washed several times with ethanol
and then destroyed with dilute hydrochloric acid). The filtrate was
concentrated under reduced pressure. The crude mixture, consisting
of monoketone 6 and the corresponding alcohol, was dissolved in
acetone (30 mL), and Jones reagent was added dropwise at room
temperature until the orange colour remained. After stirring for an
additional 30 min at room temperature, 2-propanol was added to
destroy excess Jones reagent. The mixture was filtered through a
short plug of silica gel and concentrated under reduced pressure.
The remaining solid was purified by flash chromatography (petro-
leum ether/ethyl acetate, 15:1) to afford 0.17 g (74%) of 6 as a white
(+)-(1R,3R,6S,8R)-3-Methoxy-2-oxatricyclo[4.3.1.03,8]decane-10-
one (2): A solution of 1 (52 mg, 0.34 mmol) in methanol (5 mL)
was cooled to 0 °C, and solid KOH (0.19 g, 3.4 mmol) was added.
After stirring the mixture for 5–10 min, a solution of I2 (0.17 g,
0.68 mmol) in MeOH (3 mL) was added dropwise over 30 min. The
reaction mixture was stirred for 1 h and then quenched by addition
of conc. Na2S2O3 and HCl (2 ). The aqueous phase was extracted
with CH2Cl2, which was washed with water and brine and dried
(Na2SO4). The solvent was evaporated under reduced pressure, and
the residue was purified by flash chromatography (CHCl3) to afford
1
waxy solid. H NMR: δ = 1.48–2.61 (m, 14 H) ppm. 13C NMR: δ
= 20.0 (C-7), 26.1 (C-6), 27.4 (C-4), 29.7 (C-8), 31.9 (C-5), 32.5 (C-
9), 38.9 (C-3), 45.0 (C-1), 216.9 (C-2) ppm.
20
(+)-(1S,5S)-Bicyclo[3.3.1]non-3-en-2-one (7): A mixture of ketone 6
(60 mg, 0.43 mmol), PhIO2 (0.28 g, 1.18 mmol), PhSeSePh (14 mg,
0.045 mmol) and a catalytic amount of TsOH in dry toluene
(10 mL) was heated under reflux for 3 h. The mixture was cooled
to room temperature, filtered, washed with saturated NaHCO3 and
brine and dried with MgSO4. After concentration under reduced
pressure, the residue was purified by flash chromatography (petro-
leum ether/ethyl acetate, 7:1) to afford 56 mg (95%) of 7 as a white
50 mg (81%) of 2 as a yellowish oil: [α]546 = +81 (c 2.0, EtOH).
1H NMR: δ = 4.33 (d, 1 H), 3.35 (s, 3 H, OMe), 1.73–2.65 (m, 10
H) ppm. 13C NMR: δ = 211.2 (C-10), 109.7 (C-3), 83.3 (C-1), 49.7,
44.8, 40.5, 38.3, 31.4, 26.6, 24.0 ppm. IR: ν = 1727 (C=O), 1045
˜
(O–C–O) cm–1. MS: m/z (%) = 182 (10) [M]+, 151 (100) [M –
CH3O]+, 123 (20) [M – CH3O – CO]+.
(–)-(1S,3R,5R)-3-Hydroxybicyclo[3.3.1]nonane-2,6-dione (3): To a
solution of 2 (50 mg, 0.27 mmol) in acetone (10 mL) was added
TsOH·H2O (60 mg, 0.32 mmol).The reaction mixture was stirred
under argon for 2 h at room temperature, then quenched with solid
NaHCO3, filtered and concentrated to dryness. The residue was
purified by column chromatography (chloroform/acetone, 9:1) to
20
waxy solid: [α]546 = +115 (c 0.76, EtOH). CD: λmax (∆ε/
1
dm3 mol–1 cm–1) = 341 (+0.95) nm. H NMR: δ = 1.50–1.70 (m, 6
H), 1.60–1.80 (m, 1 H), 2.17–2.26 (m, 1 H), 2.45–2.54 (m, 1 H),
2.57–2.68 (m, 1 H), 6.17–6.21 (d, J = 9.9 Hz, 1 H), 6.92–6.98 (ddd,
J = 9.9, 6.5, 1.8 Hz, 1 H) ppm. 13C NMR: δ = 203.3 (C-2), 152.8
(C-4), 132.0 (C-3), 42.9, 34.2, 30.9, 28.2, 25.2, 17.5 ppm.
20
afford 40 mg (90%) of 3 as a yellowish oil: [α]546 = –22 (c 1.35,
1
EtOH). H NMR: δ = 4.35 (dd, J = 6.3, 1.4 Hz, 1 H), 3.94 (br. s,
1 H, OH), 2.97 (m, 1 H), 2.80–1.68 (m, 9 H) ppm. 13C NMR: δ = (+)-(1S,5S)-Bicyclo[3.3.1]non-3-ene-2,6-dione (8): A mixture of di-
211.5 (C-6), 211.3 (C-2), 77.1 (C-3), 48.7 (C-5), 42.4 (C-1), 36.7, ketone 1 (0.1 g, 0.66 mmol), PhIO2 (0.34 g, 1.31 mmol), PhSeSePh
35.9, 32.7, 24.9 ppm. IR: ν = 3400 (OH), 1705 (6-C=O), 1714 (2-
(5 mg, 0.00165 mmol) and a catalytic amount of TsOH in dry tolu-
ene (10 mL) was heated under reflux for 3–4 h. The mixture was
˜
C=O) cm–1.
Eur. J. Org. Chem. 2007, 4251–4256
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4255

ˇ
E. Orentas, G. Bagdziunas, U. Berg, A. Zilinskas, E. Butkus
ˇ
¯
FULL PAPER
[5] J. Frelek, W. J. Szczepek, S. Neubrech, B. Schultheis, J. Brech-
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[6] J. K. Gawronski, “Conformations, Chiroptical and Related
Spectral Properties of Enones”, in The Chemistry of Enones
(Eds.: S. Patai, Z. Rappoport), John Wiley and Sons, 1989, pp.
55–105.
cooled to room temperature, filtered, washed with saturated
NaHCO3 and brine, and dried (MgSO4). After concentration under
reduced pressure, the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 7:1) to afford 58 mg (60%) of 9 as
20
a white solid, m.p. 80 °C (transition at 70 °C): [α]546 = +1569 (c
0.204, EtOH). CD: λmax (∆ε/dm3 mol–1 cm–1) = 313 (+5.4), 254
(–2.4) nm. 1H NMR: δ = 7.12–7.05 (ddd, J = 9.9, 6.8, 2.1 Hz, 1
H), 6.32 (d, J = 9.9 Hz, 1 H), 3.40–3.30 (ddd, J = 6.8, J = 3.1 Hz,
1 H), 2.39–2.77 (m, 2 H), 2.71–2.63 (ddd, J = 13.2, 3.1 Hz, 1 H),
2.37–2.11 (m, 4 H) ppm. 13C NMR: δ = 207 (C-6), 200.8 (C-2),
148.6 (C-4), 133.1 (C-3), 49.9 (C-5), 41.9 (C-1), 35.2 (C-7), 34.3 (C-
[7] a) P. J. Stephens, D. M. McCann, E. Butkus, S. Stoncˇius, J. R.
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2405–2413.
9), 29.3 (C-8) ppm. IR: ν = 3048 (=C–H), 1711 (C=O), 1673
˜
ˇ
[8] a) E. Butkus, U. Berg, A. Zilinskas, R. Kubilius, S. Stoncˇius,
(C=O), 1608 (C=C) cm–1. C9H10O2 (150.17): calcd. C 71.79, H
6.75; found C 71.98, H 6.71.
Tetrahedron: Asymmetry 2000, 11, 3053–3057; b) E. Butkus,
ˇ
A. Zilinskas, S. Stoncˇius, R. Rozenbergas, M. Urbanová, V.
Setnicˇka, P. Bourˇ, K. Volka, Tetrahedron: Asymmetry 2002, 13,
(+)-(1S,5S)-Bicyclo[3.3.1]nona-3,7-diene-2,6-dione (9): A mixture of
diketone 1 (50 mg, 0.33 mmol), PhIO2 (0.39 g, 1.64 mmol), PhSe-
SePh (5 mg, 0.0016 mmol) and a catalytic amount of TsOH in dry
toluene (10 mL) was heated under reflux for 3 h. The mixture was
cooled to room temperature, filtered, washed with saturated
NaHCO3 and brine, and dried (MgSO4). After concentration under
reduced pressure the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 4:1) to afford 44 mg (90%) of 9 as
a yellowish solid, m.p. 105 °C (transition at 98 °C), ref.[13] m.p. 81–
84 °C (for the racemate). [α]54620 = +2260 (c 0.37, EtOH). CD: λmax
(∆ε/dm3 mol–1 cm–1) = 342 (+10.2) nm. UV: λmax (lg ε) = 233 (2.95),
ˇ
633–638; c) A. Zilinskas, S. Stoncˇius, E. Butkus, Chirality 2005,
17, S70–S73.
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[11] M. J. Zacuto, D. Cai, Tetrahedron Lett. 2005, 46, 447–450.
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[13] a) E. Butkus, S. Stoncˇius, A. Zilinskas, Chirality 2001, 13, 694–
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698; b) E. Butkus, R. Kubilius, S. Stoncˇius, A. Zilinskas, J.
Chem. Soc. Perkin Trans. 1 1999, 1431–1436.
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1
260 (sh 2.23), 346 (1.82) nm. H NMR: δ = 7.03–6.98 (dd, J = 9.9,
6.75 Hz, 2 H), 5.88 (d, J = 9.9 Hz, 2 H), 3.36–3.32 (ddd, J = 6.75,
3 Hz, 2 H), 2.77 (t, J = 3 Hz, 2 H) ppm. 13C NMR: δ = 193.8 (C-
2, C-6), 146.7 (C-4, C-8), 126.4 (C-3, C-7), 45.9 (C-1, C-5), 34.6
(C9) ppm. IR: ν = 3040 (=C–H), 1676 (C=O), 1607 (C=C) cm–1.
˜
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Financial support from the Vilnius University Science Fund and
Nordforsk (Nordic Baltic Network in Crystal Engineering and
Supramolecular Materials) are acknowledged.
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Received: March 16, 2007
Published Online: July 10, 2007
4256
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4251–4256