Total Synthesis of (-)-13-acetoxymodhephene and (+)-14-acetoxymodhephene

Article abstract of DOI:10.1002/ejoc.200900713

Stereoselective epoxidation of [4.3.3]propellane 16 set the stage for the Lewis acid catalyzed stereospecific ring contraction to an oxygenated modhephene structure and eventually led to the total synthesis of (-)-13-acetoxymodhephene and (+)- 14-acetoxym

Full text of DOI:10.1002/ejoc.200900713

FULL PAPER
DOI: 10.1002/ejoc.200900713
Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
Hee-Yoon Lee,*[a] Ravichandran N. Murugan,[a] and Deuk Kyu Moon[a]
Keywords: Total synthesis / Epoxidation / Enantioselectivity / Polycycles / Radical reactions
Stereoselective epoxidation of [4.3.3]propellane 16 set the
stage for the Lewis acid catalyzed stereospecific ring contrac-
tion to an oxygenated modhephene structure and eventually
led to the total synthesis of (–)-13-acetoxymodhephene and
(+)-14-acetoxymodhephene.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
These natural products drew attention from the synthetic
organic chemistry community for their unique structural
features and biological activities. As a result, various syn-
thetic strategies to propellanes have been developed and ap-
plied to the total synthesis of modhephene.[9] Although
some of the total syntheses were elegant and highly ef-
ficient,[10] none were applied to the total synthesis of func-
tionalized modhephenes, probably due to the fact that selec-
tive introduction of an acetoxy group would require modifi-
cation of the synthetic strategies or development of new
ones.
Introduction
Propellanes are tricyclic compounds conjoined by a C–C
single bond. Propellanes appear to be highly congested and
are considered to be unstable. Contrary to their appearance,
however, propellanes with cyclopentanes or larger rings are
rather stable and have been the subject of theoretical chem-
istry as well as synthetic chemistry.[1] The unexpected sta-
bility of propellane was also observed in nature, as several
classes of propellane natural products were identified.[2]
Among them, modhephene with a [3.3.3]propellane struc-
ture was isolated from the rayless goldenrod plant (Isocoma
wrightii) in 1978 with toxicity to sheep and cattle.[3] Sub-
sequently, oxygenated derivatives of modhephene, 9-aceto-
xymodhephene,[4] 15-acetoxymodhephene,[5] 13-acetoxy-
modhephene,[6] and 14-acetoxymodhephene[7] were isolated.
Recently, taxane derivatives containing an embedded
[3.3.3]propellane structure were isolated (Figure 1).[8]
Results and Discussion
Herein, we report the first total synthesis of (–)-13-acet-
oxymodhephene and (+)-14-acetoxymodhephene in a stereo-
selective manner from the common intermediate obtained
through a tandem radical cyclization reaction. Our syn-
thetic strategy of acetoxymodhephenes focused on regiose-
lective introduction of the acetoxy group to modhephene.
Because the [3.3.4]propellane ring structure could be readily
constructed from a cyclopentane precursor through a tan-
dem radical cyclization reaction,[9a] oxygenated modheph-
enes could be obtained from [3.3.4]propellane 8 through
stereospecific ring contraction of the corresponding epox-
ides 6 and 7[11] (Scheme 1).
Because introduction of all stereocenters of acetoxy-
modhephenes would be controlled by the single quaternary
carbon center at the C-5 position of the modhephene struc-
ture, enantioselective introduction of the quaternary carbon
center was required. To create the quaternary carbon center,
diastereoselective alkylation of a chiral enamine was ex-
plored. Guingant reported[12] that the reaction of 2-meth-
oxycarbonylcyclopentanone with the enamine of (R)-phen-
ylethanamine produced alkylated compound in 41% yield
with 87%ee when alkylated with acrylonitrile. When we re-
peated the reaction, we were able to obtain a better yield
but a lower enantiomeric excess (Table 1, Entry 1). When
Figure 1. [3.3.3]Propellane natural products.
[a] Department of Chemistry, KAIST
Daejeon 305-701, South Korea
E-mail: leehy@kaist.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900713.
5028
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Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
This result strongly suggested that the bulkiness rather
than the stereostructure of menthol might be responsible
for the improvement in the selectivity. This explanation was
supported by the results obtained with various esters
(Table 1). As the bulkiness increased, the selectivity in-
creased from a ratio of 6:1 to 12.5:1 (85%ee) without a
decrease in the yield of the reaction. Another noteworthy
observation was that the enantioselectivity decreased with
an increase in product yield.
The total synthesis of hydroxymodhephenes started with
the introduction of the C-5 quaternary center enantioselecti-
vely by asymmetric alkylation of 21aЈ. Though the ratio of
selective alkylation improved with increasing bulkiness of the
ester, the optical purity of the product did not exceed 85%ee.
Therefore, 21aЈ was used for asymmetric induction and the
optical purity was further improved by eliminating undesired
enantiomer 22aЈ through the formation of chiral sulfoximine
of 22aЈ.[16] An alternative route to introduce the C-5 quater-
nary center was also explored, as the cinchona alkaloid cata-
lyzed alkylation of 24 was reported to produce 9 with high
enantioselectivity. The enantioselective conjugate addition re-
action of tert-butyl 2-oxocyclopentane carboxylate (24) to
acrolein by using quinidine-based organocatalyst 23 provided
9 with 93%ee.[13] Both carbonyl groups of 9 were treated with
Nysted reagent[14] to install the two alkene groups needed for
tandem radical cyclization reaction. The remaining append-
age for the tandem radical cyclization was introduced in a
five-step sequence starting from 10 in the same manner as the
previously reported total synthesis of modhephene.[9a] The es-
ter of 10 was converted into aldehyde 11 through a reduction–
oxidation sequence and sequential introduction of the methyl
group and the propargyl group furnished all the appendages
for the tandem radical cyclization reaction. The tin hydride
mediated tandem radical cyclization of 12 produced [4.3.3]-
propellane 13 stereoselectively (10:1 ratio) as an inseparable
mixture of diastereomers at the C-8 position bearing the
methyl group. This diastereomeric mixture of propellane
products was converted into enone 8 through oxidative cleav-
age of the exocyclic olefin followed by a dehydration reac-
tion[15] (Scheme 3).
Scheme 1. Synthetic analysis of (–)-13-acetoxymodhephene (2) and
(+)-14-acetoxymodhephene (3).
the methyl ester was replaced with a menthol ester in hope
to improve the selectivity of the alkylation, the product
showed improved selectivity with 82%ee When the enamine
of (S)-phenylethanamine with menthol ester was used to
find out which one was the better matched pair of isomers,
to our surprise the opposite isomer was obtained with same
selectivity (82%ee; Scheme 2).
Table 1. Asymmetric alkylation of chiral enamine esters.
[b]
Substrate
R
% Yield
Ratio[a]
[α]D
21a
21b
21c
21d
21e
21aЈ
Me
iPr
iBu
tBu
Ph2CH
Me
85
70
67
60
65
95
6:1
9:1
10.5:1
12:1
12.5:1
4:1
+18.22
+10.50
+9.41
+4.81
–
–15.73
At this stage, purity of enone 8 was further enhanced
through chiral sulfoximine adduct formation. The sulfox-
imine adduct of 8 was separable from other diastereomers,
and hydrolysis of the sulfoximine regenerated pure 8.[16]
Stereoselective functionalization of enone 8 to epoxy-
ketones 6 and 7 was one of the crucial steps in the total
synthesis. However, an earlier observation from the total
synthesis of modhephene from racemic 8 was not promis-
ing, as the cyanide addition reaction proceeded with low
selectivity, resulting in a 2.5:1 diastereomeric ratio of the
1,4-addition products. Direct epoxidation of enone 8
showed a similar selectivity of 2.5:1 for epoxyketones 7 and
6, as expected (Scheme 4). These outcomes were not sur-
prising, as the only possible discrimination of the two faces
of the enone ring is the existence of the methyl group on
one of the two five-membered rings. Even the methyl group
is positioned at the opposite side of the cyclohexenone ring
to provide no immediate facial discrimination.
[a] Determined by GC analysis. [b] Measured in EtOH with c =
3.05 (22a), 2.05 (22b), 6.00 (22c), 2.93 (22d), 1.2 (22aЈ).
Scheme 2. Alkylation of two diastereomeric enaminyl esters.
Eur. J. Org. Chem. 2009, 5028–5037
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H.-Y. Lee, R. N. Murugan, D. K. Moon
FULL PAPER
was obtained as the major product with 2.3:1 ratio of two
epimers. This result was quite surprising, because the facial
discrimination of enone 8 was not expected to be large
enough to override the stereoselectivity of the CBS reagents.
Luche reduction[18] of ketone 8 confirmed this intrinsic fa-
cial discrimination by hydride addition, as allylic alcohol 14
was obtained with 10:1 ratio.
Careful analysis of the structure of 8 indicated that the
cyclohexenone ring of 8 is not planar and two five-mem-
bered rings of 8 could not adopt the same conformation like
the five-membered rings of modhephenes (the modhephene
skeleton showed symmetric nature through the plane of the
five-membered ring containing the double bond as shown
in the X-ray crystallographic structure of 14-hydroxy-
modhephene[19]). On the basis of MM2 calculations
(Scheme 5),[20] the cyclohexenone ring of compound 8
adopts two half-chair conformations 8a and 8b, in which
the carbonyl group bends towards the methyl-substituted
and unsubstituted cyclopentane ring, respectively, thus ex-
posing either the β-face or α-face to the reducing agent.
From the calculations, conformer 8a was found to be far
more stable than 8b, as the latter displays a pseudoaxial
orientation for the methyl group. Hence, the more stable
conformer 8a provides better accessibility from the β-face.
Scheme 3. Asymmetric synthesis of 8.
Scheme 5. Two conformers of 8.
For the synthesis of 7, hydroxy group directed epoxid-
ation of allylic alcohol 14 through a Sharpless protocol[21]
was used to produce epoxy alcohol 15 with no detectable
amount of the other diastereomer. When the alcohol of 14
was protected and the olefin was oxidized with m-CPBA in
hope to obtain the opposite epoxide as the major prod-
uct,[22] the same selectivity as the alcohol-directed epoxid-
ation reaction was observed. This result indicated that the
Scheme 4. Stereoselective functionalization of 8.
If allylic alcohols 14 and 14Ј could be obtained selec- intrinsic facial selectivity of the allylic alcohol is even better
tively, they could be converted into 7 and 6, respectively, as than enone 8. Though this result hampered our original
the alcohol stereochemistry of 14 and 14Ј can direct the plan to obtain epoxide 6 through 14Ј, we could use this
epoxidation reaction. Reagent-controlled diastereoselective unexpected facial selectivity of allyl alcohol 14.[23] The ep-
reduction of ketone 8 by using Corey–Bakshi–Shibata oxide with opposite stereochemistry 16 was obtained
(CBS) reduction[17] could be applied to produce allylic stereoselectively through bromohydrin formation followed
alcohols 14 and 14Ј selectively. When (S)-2-methyl-CBS-ox- by epoxide formation. Because the facial selectivity of ini-
azaborolidine was used as the catalyst for asymmetric bor- tial bromonium ion formation should be similar to m-
ane reduction of ketone 8, as anticipated, allylic alcohol CPBA oxidation, hydroxide would add from the opposite
14 was obtained with 17.5:1 ratio of two epimers. When side of the bromonium ion and subsequent base treatment
(R)-2-methyl-CBS-oxazaborolidine was used as the catalyst would yield epoxide 16 selectively. When acetate-protected
for alcohol 14Ј, contrary to expectation, allylic alcohol 14 allyl alcohol 14b was treated with NBS in water/DME, ep-
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Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
oxide 16 was obtained after KHCO3 treatment. Hydrolysis ether was replaced by the acetate group, NaBH4 reduction
of the acetate followed by PCC oxidation produced epoxy of the ketone followed by dehydration reaction[25] produced
ketone 6. Epoxy alcohol 15 was also oxidized with PCC to (+)-14-acetoxymodhephene (Scheme 7). The total synthesis
provide 7 (Scheme 6).
of (–)-13-acetoxymodhephene was accomplished in the
same way as the total synthesis of (+)-14-acetoxym-
odhephene. Lewis acid catalyzed rearrangement of 6 pro-
duced desired hydroxy ketone 19 after selective reduction,
though the yield was not as high as in the rearrangement
of 7. Presumably, the conformational difference that dis-
criminated the faces of 8 played a similar role, and thus the
migrating aptitude of the desired C–C bond of 6 was not
as favorable as that of 7. Efficiency of the rearrangement
for the ring contraction did not change much by using
various Lewis acids[26] and BF3·THF provided the best re-
sult for the rearrangement of 6. Hydroxy ketone 20 was
converted into (–)-13-acetoxymodhephene through the
same four-step sequence as that used for the synthesis of
(+)-14-acetoxymodhephene. The 13C -NMR spectroscopic
data of synthetic acetoxymodhephenes were identical to the
Scheme 6. Stereoselective synthesis of epoxy ketones 6 and 7.
With the two desired epoxy ketones 6 and 7 in hand, the
total synthesis of (–)-13-acetoxymodhephene and (+)-14-
acetoxymodhephene was accomplished starting with the
crucial epoxide rearrangement to form the modhephene
skeleton stereospecifically. When epoxy ketone 7 was sub-
jected to BF3·Et2O-mediated rearrangement, the desired ke-
toaldehyde was obtained as the major product and the alde-
hyde was reduced selectively by using LiAl(tBuO)3H[9b] to
produce 17 in 50% yield over two steps. The alcohol of 17
was temporarily protected as ethoxyethyl ether to introduce
a methyl group next to the ketone.[24] After the ethoxyethyl
1
data reported for natural acetoxymodhephenes, and the H
NMR spectroscopic data of the synthetic ones had all the
data reported for the natural ones.
Conclusions
In summary, the stereoselective total synthesis of (–)-13-
acetoxymodhephene and (+)-14-acetoxymodhephene was
achieved from the common propellane intermediate 8 read-
ily obtained through a tandem radical cyclization reaction.
This work also demonstrated that a remote stereocenter
could provide enough bias to distinguish between the two
faces of the electrophilic sites of a cyclohexenone system.
Experimental Section
General Information: NMR spectra were recorded with a Bruker
1
DPX400 spectrometer (400 MHz for H NMR, 100 MHz for 13C
NMR) and measured in CDCl3. Chemical shifts were recorded in
ppm relative to the internal standard CDCl3. High-resolution mass
spectra were recorded with VG Autospec Ultima and JMS-700
spectrometers. The enantioselectivities were determined by HPLC.
HPLC measurements were done with a DIONEX model equipped
with P580G pump, UV 525 detector (Thermo Science, Waltham,
MA) measured at 254 nm, and chiral column DAICEL AD-H.
Eluting solvent was a mixture of 2-propanol and hexane. All reac-
tions were carried out in oven-dried glassware under a N2 atmo-
sphere. All solvents were distilled from the indicated drying rea-
gents right before use: Et2O and THF (Na, benzophenone),
CH2Cl2 (P2O5), and MeCN, 1,4-dioxane, and DMF (CaH2). The
normal workup included extraction, drying over Na2SO4, and
evaporation of volatile materials in vacuo. Purification by column
chromatography was performed using Merck (Darmstadt, Ger-
many) silica gel 60 (230–400 mesh).
Methyl 2-{[(R)-1-Phenylethyl]amino}cyclopent-1-ene-1-carboxylate
(21aЈ): To a stirred solution of methyl 2-oxocyclopentanecarboxyl-
ate (10.0 g, 70.3 mmol) and 4 Å molecular sieves in CH2Cl2
(100 mL) was added (R)-(+)-phenylethanamine (10.9 mL,
84.6 mmol). The reaction mixture was stirred under reflux for 1 d.
The mixture was filtered, and the resulting solution was concen-
Scheme 7. Total synthesis of (+)-14-acetoxymodhephene and (–)-
13-acetoxymodhephene.
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H.-Y. Lee, R. N. Murugan, D. K. Moon
FULL PAPER
trated in vacuo. The organic residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:20) to afford 15.9 g
139.2, 114.1, 105.8, 68.0, 50.5, 35.6, 34.6, 34.2, 28.8, 23.0 ppm. IR
(neat): ν = 3378, 3074, 2952, 1642, 1454, 1022, 909, 885 cm–1.
˜
(64.8 mmol, 92%) of the title compound. 1H NMR (400 MHz, HRMS (EI): calcd. for C11H18O 166.1358; found 166.1350. [α]2D0
=
CDCl3): δ = 7.81 (br. s, 1 H), 7.31–7.27 (m, 2 H), 7.23–7.18 (m, 3 –35.78 (c = 1.5, CHCl3)
H), 4.55–4.48 (m, 1 H), 3.68 (s, 3 H), 2.53–2.43 (m, 3 H), 2.23–2.15
(R)-1-(But-3-enyl)-2-methylenecylcopentanecarbaldehyde (11):
A
dry-ice cooled, magnetically stirred solution of oxalyl chloride
(5.3 mL, 60.2 mmol) in CH2Cl2 (50 mL) was treated with DMSO
(8.5 mL, 120.3 mmol) and stirred for 30 min. A solution of alcohol
(5.0 g, 30.1 mmol) in CH2Cl2 (10 mL) was introduced dropwise, fol-
lowed by Et3N (20 mL, 150.3 mmol) 1 h later. The reaction mixture
was poured into saturated aqueous NH4Cl (70 mL), and the aque-
ous layer was extracted with EtOAc (3ϫ50 mL). After the com-
bined organic extract was dried with anhydrous MgSO4 and con-
centrated, flash chromatography of the organic residue on silica gel
(Et2O/pentane, 1:30) produced 4.8 g (29.2 mmol, 97%) of aldehyde
(m, 1 H), 1.676–1.62 (m, 2 H), 1.48 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.8, 164.4, 145.0, 128.6, 126.9,
125.3, 93.0, 54.2, 50.0, 32.1, 28.7, 24.8, 20.9 ppm. IR (neat): ν =
˜
2956, 1752, 1724, 1641, 1456, 1408, 1389, 1369, 1179, 1023 cm–1.
HRMS (EI): calcd. for C15H19NO2 245.1416; found 245.1412
Methyl (R)-1-(2-Cyanoethyl)-2-oxocyclopentanecarboxylate (22aЈ):
To a solution of zinc chloride in Et2O (1 , 46.5 mL, 46.5 mmol)
and acrylonitrile (4.6 mL, 70.7 mmol) in Et2O (400 mL) was added
dropwise an ethereal solution (50 mL) of compound 21aЈ (11.4 g,
46.5 mmol) at 0 °C. Vigorous stirring was continued for 2 h. The
solvent was replaced with THF (500 mL) and then 10% aqueous
acetic acid (150 mL) was added to the mixture. The resulting solu-
tion was heated at 60 °C for 12 h. The reaction mixture was cooled
to room temperature and neutralized with saturated NaHCO3 solu-
tion and extracted with Et2O (3ϫ300 mL). The combined extracts
were dried with anhydrous MgSO4, filtered, and concentrated in
vacuo. Flash chromatography of the organic residue (EtOAc/hex-
ane, 1:3) afforded 8.6 g (44.2 mmol, 95%) of the title compound as
a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 3.63 (s, 3 H),
2.53–2.32 (m, 4 H), 2.27–2.18 (m, 1 H), 2.15–2.08 (m, 1 H), 2.01–
1.80 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 213.4, 170.5,
1
11 as a colorless oil. H NMR (400 MHz, CDCl3): δ = 9.25 (s, 1
H), 5.80–5.74 (m, 1 H),5.19–5.18 (m, 1 H), 5.02–4.97 (m, 1 H),
4.95–4.92 (m, 1 H), 4.87–4.86 (m, 1 H), 2.38–2.34 (m, 2 H), 2.28–
2.22 (m, 1 H), 2.00–1.91 (m, 2 H), 1.88–1.81 (m, 1 H), 1.73–1.66
(m, 1 H), 1.62–1.16 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3)
δ = 200.7, 152. 1, 138.1, 114.8, 109.4, 61.1, 34.3, 33.9, 31.3, 29.0,
23.6 ppm. IR (neat): ν = 3077, 2958, 1723, 1643, 1452, 994,
˜
911 cm–1. HRMS (EI): calcd. for C11H16O 164.1201; found
164.1201. [α]2D0 = + 197.05 (c = 1.5, CHCl3)
(R)-1-(1-But-3-enyl)-2-methylenecylcopentylethanol: To
a stirred
solution of aldehyde 11 (4.8 g, 29.2 mmol) in Et2O (30 mL) was
added dropwise a solution of methylmagnesium bromide (3  in
ether, 20 mL, 58.6 mmol) at 0 °C. After stirring for 30 min, the
solution was quenched with saturated aqueous NH4Cl (40 mL) and
extracted with EtOAc (3ϫ25 mL). The organic extracts were dried
with anhydrous MgSO4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (Et2O/pentane, 1:5) produced 5.02 g
(27.8 mmol, 95%) of the title compound as a colorless oil.
119.0, 58.4, 52.6, 37.5, 33.5, 29.1, 19.3, 12.8 ppm. IR (neat): ν =
˜
2959, 2248, 1750, 1727, 1451, 1264, 1237, 1166, 530 cm–1. HRMS
(EI): calcd. for C10H13NO3 195.0895; found 195.0895. [α]2D8
–15.73 (c = 1.2, EtOH)
=
tert-Butyl (R)-1-(But-3-enyl)-2-methylenecyclopentanecarboxylate
(10): A solution of TiCl4 (1  in CH2Cl2, 30 mL, 30 mmol) was
added by syringe to a solution of Nysted’s reagent (57 mL,
30 mmol) in THF (200 mL) at 0 °C, followed by a solution of com-
pound 9 (1.0 g, 4.27 mmol). The cooling bath was removed, and
the mixture was heated at reflux for 4 h. After cooling to room
temperature, the reaction mixture was quenched with 10% HCl
(200 mL) and transferred to a separatory funnel. The product was
extracted into ether (3ϫ300 mL), and the combined organic phase
was dried with anhydrous MgSO4 and concentrated to leave a resi-
due (726 mg, 72%) that was purified by flash chromatography (4%
(R)-1-(1-But-3-enyl)-2-methylenecylcopentylethanone: To a solution
of chromium oxide (16.7 g, 167 mmol) in CH2Cl2 (50 mL) was
added pyridine (24.7 mL, 306 mmol) at 0 °C. The reaction mixture
was stirred for 10 min. To the reaction mixture was added alcohol
(5.0 g, 27.8 mmol), and then the reaction mixture was stirred for
6 h. The mixture was filtered, and the resulting solution was con-
centrated in vacuo. The organic residue was purified by column
chromatography on silica gel (Et2O/pentane, 1:20) to afford 4.8 g
(26.7 mmol, 96%) of the title compound as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 5.83–5.73 (m, 1 H), 5.08–5.07 (m, 1
H), 5.01–4.96 (m, 1 H), 4.93–4.89 (m, 2 H), 2.41–2.36 (m, 2 H),
2.32–2.26 (m, 1 H), 2.10 (s, 3 H), 1.99–1.88 (m, 3 H), 1.73–1.65 (m,
2 H), 1.59–1.52 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
209.5, 154.7, 138.5, 114.5, 108.3, 63.1, 36.6, 34.2, 33.7, 29.6, 25.3,
1
Et2O/pentane). H NMR (400 MHz, CDCl3): δ = 5.84–5.74 (m, 1
H), 5.04–5.03 (m, 1 H), 5.01–4.95 (m, 2 H), 4.93–4.88 (m, 1 H),
2.37–2.30 (m, 3 H), 2.02–1.98 (m, 3 H), 1.64–1.46 (m, 4 H), 1.41
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.1, 155.5,
138.7, 114.2, 106.9, 79.9, 56.7, 38.4, 34.9, 33.8, 30.1, 27.8,
24.1 ppm.
23.5 ppm. IR (neat): ν = 3077, 2956, 1703, 1643, 1435, 1353, 1136,
˜
(R)-[1-(But-3-enyl)-2-methylenecylcopentyl]methanol: Compound
10 (726 mg, 3.1 mmol), dissolved in CH2Cl2 (30 mL), was cooled
to –15 °C and a solution of DIBAL (1  in CH2Cl2, 9.2 mL,
9.2 mmol) was added dropwise. After stirring for 4 h at –15 °C, the
excess amount of hydride was destroyed by the addition of EtOAc
(10 mL). H2O (10 mL) and 1  HCl (10 mL) were added. The re-
sulting solution was extracted with EtOAc (3ϫ30 mL), and the
combined organic extract was dried with anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The residue was purified by flash
910 cm–1. HRMS (EI): calcd. for C12H18O 178.1358; found
178.1363. [α]2D1 = + 127.29 (c = 1.4, CHCl3)
2-[(R)-1-(But-3-enyl)-2-methylenecyclopentyl]pent-4-yn-2-ol (12): To
a stirred solution of ketone (4 g, 26.7 mmol) in Et2O (40 mL) was
added dropwise 3-(trimethylsilyl)-1-propynylmagnesium bromide
[prepared from 3-bromo-1-(trimethylsilyl)-1-propyne and Mg] at
0 °C. After stirring for 30 min, the solution was quenched with sat-
urated aqueous NH4Cl (60 mL) and extracted with EtOAc
(3ϫ40 mL). The organic extracts were dried with anhydrous
chromatography to afford 482 mg (2.9 mmol, 95%) of the title
1
compound. H NMR (400 MHz, CDCl3): δ = 5.83–5.73 (m, 1 H), MgSO4, filtered, and concentrated in vacuo. Flash chromatography
5.04–5.03 (m, 1 H), 5.00–4.96 (m, 1 H), 4.91–4.88 (m, 1 H), 4.75–
4.74 (m, 1 H), 3.42 (d, J = 10.9 Hz, 1 H), 3.31 (d, J = 10.9 Hz, 1
on silica gel (EtOAc/hexane, 1:40) produced 7.1 g (24.6 mmol,
92%) as a colorless oil. TMS–dienyne 12 (7.1 g, 24.6 mmol) was
H), 2.38–2.33 (m, 2 H), 2.03–1.95 (m, 2 H), 1.65–1.53 (m, 6 H), dissolved in THF (20 mL) and treated with TBAF (1  in THF,
1.48–1.40 (1 H) ppm. 13C NMR (100 MHz, CDCl3) δ = 156.7, 27.1 mL). After stirring for 10 min, the reaction mixture was
5032
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5028–5037

Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
poured into saturated aqueous NH4Cl (40 mL) and extracted with
EtOAc (3ϫ25 mL). After the combined organic extract was dried
with anhydrous MgSO4, filtered, and concentrated in vacuo, the
organic residue was purified by flash chromatography on silica gel
2.48 mmol) was dissolved in CH2Cl2 (5 mL) and treated with meth-
anesulfonyl chloride (0.96 mL, 12.4 mmol) and Et3N (3.46 mL,
24.8 mmol) at 0 °C. After stirring overnight at room temperature,
the resulting mixture was poured into H2O (10 mL), and the aque-
(EtOAc/hexane, 1:20) to yield 4.9 g (22.6 mmol, 92%) of dienyne ous layer was extracted with EtOAc (3ϫ10 mL). The combined
12 as a colorless oil. NMR spectroscopic data of the major dia-
organic extract was dried with anhydrous MgSO4, filtered, and con-
centrated in vacuo. Flash chromatography of the residue on silica
gel (EtOAc/hexane, 1:10) afforded 441 mg (2.16 mmol, 87%) of 8
stereoisomer was extracted from the data of the diastereoisomeric
1
mixtures obtained above. H NMR (400 MHz, CDCl3): δ = 5.82–
1
5.72 (m, 1 H), 5.143–5.142 (m, 1 H), 4.99–4.95 (m, 1 H), 4.91–4.88
as a colorless oil. H NMR (400 MHz, CDCl3): δ = 5.68 (s, 1 H),
(m, 1 H), 4.84–4.80 (m, 1 H), 2.70 (dd, J = 16.2, 2.8 Hz, 1 H), 2.43 (d, J = 16.1 Hz, 1 H), 2.23 (d, J = 16.1 Hz, 1 H), 2.00–1.93
2.34–2.30 (m, 3 H), 2.06–2.03 (m, 1 H), 2.01–1.89 (m, 3 H), 1.75–
1.53 (m, 4 H), 1.44–1.36 (m, 1 H), 1.32 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 155.5, 139.4, 113.9, 108.2, 81.5, 75.7, 71.3,
(m, 1 H), 1.91 (s, 3 H), 1.75–1.60 (m, 8 H), 1.39–1.28 (m, 1 H),
1.25–1.19 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 199.4, 166.5, 123.3, 57.5, 55.0, 45.1, 41.7,
54.9, 37.6, 35.1, 34.2, 29.6, 28.1, 24.0, 23.0 ppm. IR (neat): ν =
39.2, 39.0, 34.3, 31.1, 23.9, 21.2, 13.6 ppm. IR (neat): ν = 2952,
˜
˜
3568, 3306, 3075, 2952, 2117, 1641, 1455, 1099, 909, 637 cm–1.
1670, 1622, 1455, 1378, 1273 cm–1. HRMS (EI): calcd. for C14H20O
HRMS (EI): calcd. for C15H22O 218.1671; found 218.1666. [α]1D5
+ 50.02 (c = 1.0, CHCl3)
=
204.1514; found 204.1521. [α]1D9 = +24.32 (c = 1.0, CHCl3)
Kinetic Resolution: To a solution of (+)-(S)-N,S-dimethyl-S-phenyl-
sulfoximine (439 mg, 2.59 mmol) in THF (7 mL) was added nBuLi
(2.4  in hexane, 1.08 mL, 2.59 mmol) at 0 °C. After stirring for
30 min, enone (441 mg, 2.16 mmol) was added to the resulting
anion solution at –78 °C and stirred for 3 h. The cold mixture was
quenched with NH4Cl (aq.), extracted with EtOAc, and concen-
trated in vacuo. Flash chromatography of the residue on silica gel
(EtOAc/hexane, 1:5) afforded 565 mg (1.51 mmol, 70%) of the sul-
foximine derivative. The sulfoximine derivative (565 mg,
1.51 mmol) was heated in toluene under reflux for 4 h. The reaction
mixture was concentrated and purified by silica gel column
chromatography (EtOAc/hexane, 1:10) to give 287 mg (1.40 mmol,
(1R,6S)-2,7-Dimethyl-4-methylenetricyclo[4.3.3.0]dodecan-2-ol (13):
A mixture of dienyne 12 (0.40 g, 1.83 mmol), Bu3SnH (0.59 mL,
2.2 mmol), and AIBN (82 mg, 0.5 mmol) in benzene (220 mL) was
heated for 3 h at 80 °C. The reaction mixture was cooled to room
temperature. Silica gel was added to the reaction mixture, which
was then stirred for 24 h. The reaction mixture was filtered and
concentrated in vacuo. Flash chromatography on silica gel (EtOAc/
hexane, 1:20) afforded 282 mg (1.28 mmol, 70%) of 13 as a color-
less oil. NMR spectroscopic data of the major diastereoisomer was
extracted from the data of the diastereoisomeric mixtures obtained
above. 1H NMR (400 MHz, CDCl3): δ = 4.78–4.77 (m, 1 H), 4.74–
4.73 (m, 1 H), 2.51–2.43 (m, 2 H), 2.24–2.11 (m, 3 H), 1.58–1.40
(m, 6 H), 1.32–1.22 (m, 4 H), 1.14 (s, 3 H), 0.82 (d, J = 6.5 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.7, 110.7, 75.3, 58.1,
54.5, 40.9, 40.0, 38.6, 37.6, 37.5, 35.7, 30.9, 26.7, 25.6, 13.2 ppm.
1
93%) of enone 8 as a colorless oil. H NMR (400 MHz, CDCl3):
δ = 5.68 (s, 1 H), 2.43 (d, J = 16.1 Hz, 1 H), 2.23 (d, J = 16.1 Hz,
1 H), 2.00–1.93 (m, 1 H), 1.91 (s, 3 H), 1.75–1.60 (m, 8 H), 1.39–
1.28 (m, 1 H), 1.25–1.19 (m, 1 H), 0.91 (d, J = 6.5 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 199.4, 166.5, 123.3, 57.5, 55.0,
IR (neat): ν = 3473, 3067, 2951, 1640, 1455, 1375, 1089, 874 cm–1.
˜
HRMS (EI): calcd. for C15H24O 220.1827; found 220.1823. [α]1D5
+ 16.82 (c = 1.0, CHCl3)
=
45.1, 41.7, 39.2, 39.0, 34.3, 31.1, 23.9, 21.2, 13.6 ppm. IR (neat): ν
˜
= 2952, 1670, 1622, 1455, 1378, 1273 cm–1. HRMS (EI): calcd. for
C14H20O 204.1514; found 204.1521. [α]1D9 = +24.32 (c = 1.0, CHCl3)
(1R,6S)-2,7-Dimethyl-2-hydroxytricyclo[4.3.3.0]dodecan-4-one: To a
stirred solution of 13 (700 mg, 3.18 mmol) in tBuOH/H2O/acetone
(3:20:12 mL) was added osmium tetraoxide (2.2 mL, 2.5 wt.-% in
2-methyl-2-propanol, 0.17 mmol) and 4-methylmorpholine N-oxide
(NMO; 447 mg, 3.81 mmol) at room temperature. The resulting
mixture was stirred for 12 h. The reaction mixture was poured into
H2O (20 mL), and the aqueous layer was extracted with EtOAc
(3ϫ15 mL), and the combined organic extract was dried with an-
hydrous MgSO4, filtered, and concentrated in vacuo. To the re-
sulting triol in 1,4-dioxane/H2O (16:6 mL) was added sodium per-
iodate (1.06 g, 4.96 mmol) at room temperature. The resulting mix-
ture was stirred for 2 h. The reaction mixture was poured into H2O
(20 mL), and the aqueous layer was extracted with EtOAc
(3ϫ15 mL), and the combined organic extract was dried with an-
hydrous MgSO4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel (EtOAc/hexane, 1:3) afforded 552 mg
(2.48 mmol, 78%) of the title compound as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 2.66 (d, J = 16.4 Hz, 1 H), 2.45 (d,
J = 18.5 Hz, 1 H), 2.35 (d, J = 16.4 Hz, 1 H), 2.28–2.26 (m, 1 H),
2.22 (d, J = 18.5 Hz, 1 H), 1.63–1.38 (m, 4 H), 1.31–1.24 (m, 6 H),
1.23 (s, 3 H), 0.86 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 213.1, 75.7, 58.3, 54.8, 48.3, 47.1, 44.0, 37.8, 37.6,
(1R,6S,4S)-2,10-Dimethyl-4-hydroxytricyclo[4.3.3.0]dodec-2-ene
(14): To a solution of (S)-2-methyl-CBS-oxazaborolidine and
BH3·Me2S in THF (5 mL) was added enone 8 (287 mg, 1.40 mmol)
at 0 °C. The reaction mixture was allowed to stir for 1 h at 0 °C.
H2O (10 mL) was added to the reaction mixture, and the aqueous
layer was extracted with EtOAc (3ϫ5 mL). The combined extract
was dried with anhydrous MgSO4, filtered, and concentrated in
vacuo. Flash chromatography on silica gel (EtOAc/hexane, 1:5) of
the residue produced 286 mg (1.39 mmol, 99%) of 14. 1H NMR
(400 MHz, CDCl3): δ = 5.26–5.25 (m, 1 H), 4.10–4.06 (m, 1 H),
2.03 (dd, J = 11.2, 5.2 Hz, 1 H), 1.87–1.82 (m, 1 H), 1.69 (s, 3 H),
1.67–1.46 (m, 7 H), 1.41–1.33 (m, 1 H), 1.28–1.19 (m, 1 H), 1.13–
1.08 (m, 2 H), 0.91 (d, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.6, 124.1, 65.7, 55.8, 54.0, 40.6, 40.0, 39.5, 39.2,
34.6, 31.1, 24.2, 20.3, 13.8 ppm. IR (neat): ν = 3320, 2945, 1659,
˜
1449, 1376, 1014 cm–1. HRMS (EI): calcd. for C14H22O 206.1671;
found 206.1665. [α]2D4 = –17.18 (c = 0.77, CHCl3)
(1R,2R,3S,4S,6S)-2,7-Dimethyl-2,3-epoxytricyclo[4.3.3.0]dodecan-
4-ol (15): To a stirred solution of 14 (286 mg, 1.39 mmol) in CH2Cl2
(4 mL) was added m-CPBA (80% in purified, 358 mg, 166 mmol)
at 0 °C. After stirring for 1 h, saturated aqueous NaHCO3 (5 mL)
was added to the reaction mixture and extracted with EtOAc
(3ϫ5 mL). The combined organic extract was dried with anhy-
drous MgSO4, filtered, and concentrated in vacuo. The residue was
subjected on flash chromatography (EtOAc/hexane, 1:3) to give
284 mg (1.28 mmol, 92 %) of epoxy alcohol 15. 1H NMR
35.4, 30.6, 26.5, 25.5, 12.9 ppm. IR (neat): ν = 3465, 2951, 1703,
˜
1456, 1377, 1456, 1377, 1085 cm–1. HRMS (EI): calcd. for
C14H22O2 222.1620; found 222.1617. [α]1D5 = + 65.80 (c = 1.4,
CHCl3)
(1R,6S)-2,7-Dimethyltricyclo[4.3.3.0]dodec-2-en-4-one (8): (1R,6S)-
2,7-Dimethyl-2-hydroxytricyclo[4.3.3.0]dodecan-4-one
(552 mg,
Eur. J. Org. Chem. 2009, 5028–5037
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5033

H.-Y. Lee, R. N. Murugan, D. K. Moon
FULL PAPER
(400 MHz, CDCl3): δ = 4.00 (dd, J = 11.4, 4.9 Hz, 1 H), 3.02 (s, 1 H), 1.26–1.12 (m, 2 H), 0.85 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR
H), 2.28–2.22 (m, 1 H), 1.71 (dd, J = 12.5, 4.8 Hz, 1 H), 1.56–1.43 (100 MHz, CDCl3): δ = 170.3, 69.3, 64.7, 61.7, 54.4, 52.1, 45.4,
(m, 5 H), 1.40–1.32 (m, 3 H), 1.30 (s, 3 H), 1.26–1.18 (m, 2 H), 39.7, 35.7, 35.5, 35.1, 32.6, 24.2, 21.2, 20.6, 14.6 ppm. IR (neat): ν
˜
1.14–1.08 (m, 1 H), 0.85 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 66.3, 66.1, 63.6, 55.2, 52.7, 41.3, 38.7, 38.6,
= 3456, 2954, 1661, 1473, 1112, 1058, 887 cm–1.
(1R,2S,3R,4S,6S)-2,7-Dimethyl-2,3-epoxytricyclo[4.3.3.0]dodecan-
4-ol: To a stirred solution of 16 (0.85 g, 3.2 mmol) in MeOH (6 mL)
was added potassium carbonate (885 mg, 6.4 mmol) at room tem-
perature. After stirring for 4 h, the mixture was poured into H2O
(7 mL), and the aqueous layer was extracted with EtOAc
(3ϫ10 mL). The combined extract was dried with MgSO4 and con-
centrated in vacuo. Flash chromatography of the residue on silica
gel (EtOAc/hexane, 1:3) afforded 662 mg (2.98 mmol, 93%) of the
36.6, 35.9, 30.7, 25.1, 20.8, 13.2 ppm. IR (neat): ν = 3398, 2952,
˜
1460, 1379, 1252, 1089, 1012, 883 cm–1. HRMS (EI): calcd. for
C14H22O2 222.1620; found 222.1620. [α]2D2 = + 10.45 (c = 0.7,
CHCl3)
(1R,2R,3S,6S)-2,10-Dimethyl-2-oxotricyclo[4.3.3.0]dodecan-4-one
(7): To a solution of epoxy alcohol 15 (284 mg, 1.28 mmol) dis-
solved in CH2Cl2 (4 mL) was added PCC (414 mg, 1.92 mmol) and
Celite. The reaction mixture was allowed to stir for 4 h at room
temperature. The mixture was filtered, and the resulting solution
was concentrated in vacuo. The organic residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:20) to af-
ford 257 mg (1.16 mmol, 91%) of 7. 1H NMR (400 MHz, CDCl3):
δ = 2.99 (d, J = 0.9 Hz, 1 H), 2.75 (d, J = 12.4 Hz, 1 H), 2.43–2.37
(m, 1 H), 2.03 (d, J = 12.4 Hz, 1 H), 1.80–1.69 (m, 1 H), 1.66–1.59
(m, 1 H), 1.56–1.50 (m, 2 H), 1.49–1.41 (m, 3 H), 1.38 (s, 3 H),
1.37–1.31 (m, 1 H), 1.26–1.20 (m, 2 H), 0.83 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 209.9, 72.8, 62.7, 60.6,
54.5, 43.7, 42.5, 38.9, 38.4, 36.3, 30.3, 25.4, 20.8, 12.7 ppm. IR
1
title compound as a colorless oil. H NMR (200 MHz, CDCl3): δ
= 4.14–4.10 (m, 1 H), 3.00 (s, 1 H), 2.21 (br. s, 1 H), 1.99–1.91 (m,
1 H), 1.85–1.57 (m, 7 H), 1.53–1.41 (m, 2 H), 1.34–1.29 (m, 1 H),
1.27 (s, 3 H), 1.24–1.11 (m, 2 H), 0.81 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 66.0, 65.6, 65.4, 54.3, 52.9, 42.6,
38.7, 38.4, 34.7, 34.5, 32.3, 23.3, 20.9, 14.6 ppm. [α]2D5 = –7.74 (c =
2.6, CHCl3)
(1R,2S,3R,6S)-2,7-Dimethyl-2,3-epoxytricyclo[4.3.3.0]dodecan-4-
one (6): To the epoxy alcohol (33 mg, 0.1484 mmol) dissolved in
CH2Cl2 (2 mL) was added PCC (64 mg, 0.2969 mmol) and Celite.
The reaction mixture was allowed to stir for 1 h at room tempera-
ture. The mixture was filtered, and the resulting solution was con-
centrated in vacuo. The organic residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:20) to afford
(neat): ν = 2962, 1709, 1460, 1391, 1299, 1233, 1071, 862 cm–1.
˜
HRMS (EI): calcd. for C14H20O2 220.1463; found 220.1458. [α]1D9
= + 16.80 (c = 0.7, CHCl3)
1
28.7 mg (0.13 mmol, 88%) of 6. H NMR (200 MHz, CDCl3): δ =
(1R,6S,4S)-2,7-Dimethyltricyclo[4.3.3.0]dodec-2-en-4-yl Acetate
(14b): To a solution of alcohol 14 (1.18 g, 5.72 mmol) dissolved in
CH2Cl2 (20 mL) was added Et3N (0.93 mL, 11.44 mmol) and Ac2O
(0.81 mL, 8.58 mmol) at 0 °C, and the reaction mixture was al-
lowed to stir for 4 h at room temperature. The mixture was poured
into H2O (10 mL), and the aqueous layer was extracted with EtOAc
(3ϫ10 mL). The combined extract was dried with MgSO4 and con-
centrated in vacuo. Flash chromatography of the residue on silica
gel (EtOAc/hexane, 1:20) afforded 1.34 g (5.38 mmol, 94%) of 14b.
NMR spectroscopic data of the major diastereoisomer was de-
duced from the data of the diastereoisomeric mixtures obtained
3.09 (s, 1 H), 2.71 (d, J = 12.4 Hz, 1 H), 2.10–2.00 (m, 2 H), 1.96–
1.88 (m, 1 H), 1.81–1.64 (m, 4 H), 1.60–1.54 (m, 1 H), 1.43–1.33
(m, 5 H), 1.28–1.15 (m, 2 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 211.1, 72.1, 64.0, 59.5, 55.7, 49.1,
48.6, 41.1, 37.0, 36.5, 33.6, 25.2, 20.5, 14.1 ppm. [α]2D5 = –41.89 (c
= 1.1, CHCl3)
(1R,2S,6S)-2-Hydroxymethyl-2,6-dimethyltricyclo[3.3.3.0]undecan-
3-one (17): To a solution of epoxy ketone 7 (50 mg, 0.23 mmol) in
CH2Cl2 (1 mL) was added BF3·Et2O (0.014 mL, 0.11 mmol) at
room temperature. The reaction mixture was stirred for 10 min.
The mixture was poured into saturated aqueous NaHCO3 (2 mL),
and the aqueous layer was extracted with EtOAc (3ϫ3 mL). The
combined organic layer was dried with anhydrous MgSO4. The
mixture was concentrated in vacuo. The crude product was dis-
solved in THF (1 mL) and treated with a solution of LiAl(OtBu)
3H (1  in THF, 0.23 mL, 0.23 mmol) at –78 °C. After stirring for
1 h, the mixture was poured into H2O (1 mL), and the aqueous
layer was extracted with EtOAc (3ϫ2 mL). The combined organic
layer was dried with anhydrous MgSO4 and concentrated. The resi-
due was purified by flash chromatography on silica gel (EtOAc/
1
above. H NMR (400 MHz, CDCl3): δ = 5.19–5.15 (m, 2 H), 2.03
(s, 3 H), 2.01–1.97 (m, 1 H), 1.89–1.83 (m, 1 H), 1.78–1.72 (m, 1
H), 1.69 (m, 3 H), 1.65–1.48 (m, 6 H), 1.43–1.35 (m, 1 H), 1.30–
1.20 (m, 2 H), 1.13–1.08 (m, 1 H), 0.91 (d, J = 6.8 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.9, 145.2, 119.8, 69.3, 55.8,
53.6, 39.8, 39.6, 39.2, 35.6, 34.6, 31.1, 24.2, 21.4, 20.3, 13.8 ppm.
[α]2D3 = + 6.64 (c = 1.0, CHCl3)
(1R,2S,3R,4S,6S)-2,7-Dimethyl-2,3-epoxotricyclo[4.3.3.0]dodec-4-yl
Acetate (16): To a stirred solution of 14b (1.34 g, 5.38 mmol) in
DME/H2O (10:5 mL) was added N-bromosuccinimide (1.15 g,
6.46 mmol) at 0 °C. After stirring for 4 h at that temperature, the
mixture was poured into H2O (20 mL), and the aqueous layer was
extracted with EtOAc (3ϫ15 mL). The combined extract was dried
with MgSO4 and concentrated in vacuo. Flash chromatography of
the residue on silica gel (EtOAc/hexane, 1:10) afforded 1.3 g
(3.77 mmol, 70 %). To a stirred solution of bromohydrin (1.3 g,
3.77 mmol) in 1,4-dioxane/H2O (10:5 mL) was added potassium bi-
carbonate (754 mg, 7.54 mmol) at room temperature. After stirring
for 12 h, the mixture was poured into H2O (15 mL), and the aque-
1
hexane, 1:3) to afford 25.6 mg (0.115 mmol, 50%) of 17. H NMR
(400 MHz, CDCl3): δ = 3.75 (d, J = 11.2 Hz, 1 H), 3.52 (d, J =
11.2 Hz, 1 H), 2.29 (s, 2 H), 2.08–2.03 (m, 1 H), 1.97 (br. s, 1 H,
OH) 1.71–1.53 (m, 5 H), 1.43–1.20 (m, 5 H), 1.15 (s, 3 H), 0.96 (d,
J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 223.7,
67.1, 62.1, 57.1, 55.5, 49.7, 46.1, 38.1, 35.3, 34.3, 32.7, 27.0, 18.3,
13.9 ppm. IR (neat): ν = 3459, 2955, 1731, 1456, 1040 cm–1. HRMS
˜
(EI): calcd. for C14H22O2 222.1620; found 222.1608. [α]2D6 = –4.67
(c = 1.2, CHCl3)
ous layer was extracted with EtOAc (3ϫ10 mL). The combined (1R,2S,6S)-2-[(1-Ethoxyethoxy)methyl]-2,6-dimethyltricyclo[3.3.3.0]-
extract was dried and concentrated in vacuo. Flash chromatog-
raphy of the residue on silica gel (EtOAc/hexane, 1:15) afforded
undecan-3-one: To a solution of alcohol 17 (25.6 mg, 0.115 mmol)
in CH2Cl2 (1 mL) was added ethyl vinyl ether (EVE) and pTosOH
0.85 g (3.2 mmol, 85%) of 16. 1H NMR (400 MHz, CDCl3): δ = at room temperature. After stirring for 1 h, the mixture was poured
5.22–5.19 (m, 1 H), 3.03 (d, J = 2.0 Hz, 1 H), 2.05 (s, 3 H), 2.01– into H2O (2 mL), and the aqueous layer was extracted with EtOAc
1.95 (m, 1 H), 1.89–1.51 (m, 9 H), 1.49–1.41 (m, 1 H), 1.29 (s, 3
(3ϫ3 mL). The organic extract was dried with MgSO4 and concen-
5034
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5028–5037

Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
trated. The residue was purified by flash chromatography (EtOAc/
hexane, 1:20) to give 32 mg (0.114 mmol, quant.) of the title com-
pound. 1H NMR (400 MHz, CDCl3): δ = 4.61–4.54 (m, 1 H), 3.61–
3.50 (m, 2 H), 3.43–3.30 (m, 2 H), 2.34 (dd, J = 17.6, 4.8 Hz, 1 H),
2.19 (dd, J = 17.6, 2.4 Hz, 1 H), 2.06–1.99 (m, 1 H), 1.77–1.56 (m,
39.4, 38.0, 35.1, 33.7, 32.7, 27.3, 21.0, 19.4, 15.2, 10.5 ppm. IR
(neat): ν = 3444, 2957, 1742, 1471, 1385, 1259, 1068, 1033,
˜
987 cm–1. HRMS (EI): calcd. for C17H28O3 280.2038; found
280.2025. [α]2D2
=
–39.88 (c
= 0.8, CHCl3). Data for the
(1R,2S,3S,6R)-isomer: 1H NMR (400 MHz, CDCl3): δ = 4.15 (d,
5 H), 1.44–1.13 (m, 11 H), 1.07 (s, 3 H), 0.95 (d, J = 6.7 Hz, 3 J = 11.0 Hz, 1 H), 4.04 (d, J = 11.0 Hz, 1 H), 3.38 (d, J = 11.0 Hz,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 221.8, 99.9, 70.6, 70.1,
1 H), 2.04 (s, 3 H), 2.03–1.94 (m, 1 H), 1.64–1.49 (m, 4 H), 1.45–
1.37 (m, 2 H), 1.34–1.21 (m, 3 H), 1.13–1.08 (m, 1 H), 1.02 (d, J
62.3, 61.0, 56.6, 54.9, 50.7, 46.1, 38.8, 36.0, 34.6, 33.0, 26.5, 19.5,
18.5, 15.2, 14.1 ppm. IR (neat): ν = 2953, 1734, 1458, 1377, 1136, = 7.6 Hz, 3 H), 0.99 (s, 3 H), 0.92 (d, J = 6.5 Hz, 3 H) ppm. 13C
˜
1058 cm–1. HRMS (EI): calcd. for C18H30O3 294.2195; found
NMR (100 MHz, CDCl3): δ = 171.4, 80.2, 72.1, 63.0, 60.7, 46.7,
45.9, 39.6, 37.6, 35.7, 32.5, 32.3, 27.2, 20.9, 15.2, 13.7, 11.9 ppm.
[α]2D0 = –5.04 (c = 0.7, CHCl3).
294.2181. [α]2D3 = –8.51 (c = 1.5, CHCl3)
(1R,2S,6R)-2-Hydroxymethyl-2,4,6-trimethyltricyclo[3.3.3.0]undec-
an-3-one: To a solution of ketone (32 mg, 0.114 mmol) in THF
(1 mL) was added lithium 2,2,6,6-tetramethylpiperidide(LiTMP;
2  in THF, 0.57 mL, 1.14 mmol) [prepared from 2,2,6,6-tet-
ramethylpiperidine and nBuLi in THF at 0 °C] at 0 °C. After stir-
ring for 30 min, CH3I (0.07 mL, 1.14 mmol) and HMPA (0.1 mL,
0.57 mmol) were added to the reaction mixture. Stirring was con-
tinued for 2 h at 0 °C. The mixture was poured into H2O (2 mL),
and the aqueous layer was extracted with EtOAc (3ϫ3 mL). The
mixture was concentrated in vacuo. The crude product was dis-
solved in THF (1 mL) and 1  HCl was added to the reaction mix-
ture at room temperature. After stirring for 1 h, the mixture was
poured into H2O (2 mL), and the aqueous layer was extracted with
EtOAc (3ϫ4 mL). The combined organic layer was dried with an-
hydrous MgSO4 and concentrated. Flash chromatography of the
residue on silica gel (EtOAc/hexane, 1:5) produced 12.7 mg
(0.054 mmol, 47%) of the title compound. 1H NMR (400 MHz,
CDCl3): δ = 3.80 (d, J = 11.5 Hz, 1 H), 3.51 (d, J = 11.5 Hz, 1 H),
2.42 (q, J = 6.9 Hz, 1 H), 2.30 (br. s, 1 H, OH), 2.13–2.09 (m, 1
H), 1.82–1.78 (m, 1 H), 1.70–1.47 (m, 6 H), 1.45–1.40 (m, 1 H),
1.36–1.31 (m, 1 H), 1.25–1.22 (m, 1 H), 1.21 (s, 3 H), 1.02 (d, J =
6.9 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 224.2, 66.5, 60.4, 60.0, 52.9, 49.3, 39.6, 37.2, 34.3,
(+)-14-Acetoxymodhephene (3): To a stirred solution of acetate
(13.4 mg, 0.048 mmol) in CH3CN (2 mL) was added triphenylphos-
phane (50.4 mg, 0.192 mmol) and carbon tetrachloride (18.5 µL,
0.192 mmol) at room temperature. The mixture was stirred under
reflux for 2 h. The reaction mixture was cooled to room tempera-
ture. The mixture was concentrated under the reduced pressure.
Flash chromatography of the residue (EtOAc/hexane, 1:40) af-
forded 10.3 mg (0.039 mmol, 82%) of 3 as a colorless oil. 1H NMR
(400 MHz, C6D6): δ = 4.71 (q, J = 1.4 Hz, 1 H), 4.11 (d, J =
10.8 Hz, 1 H), 3.90 (d, J = 10.8 Hz, 1 H), 2.09–2.02 (m, 1 H), 1.70
(s, 3 H), 1.60–1.45 (m, 2 H), 1.52 (d, J = 1.4 Hz, 3 H), 1.42–1.19
(m, 7 H), 1.06 (s, 3 H), 1.03–0.96 (m, 1 H), 0.92 (d, J = 6.5 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.2, 144.7, 129.6,
73.4, 71.8, 65.3, 49.4, 43.4, 39.0, 35.0, 34.1, 29.9, 26.9, 21.0, 15.3,
14.0 ppm. IR (neat): ν = 2950, 1741, 1656, 1462, 1376, 1241 cm–1.
˜
HRMS (EI): calcd. for C17H26O2 262.1933; found 262.1937. [α]2D3
= + 17.60 (c = 0.5, CHCl3).
(1R,2R,6S)-2-Hydroxymethyl-2,6-dimethyltricyclo[3.3.3.0]undecan-
3-one (19): To a solution of epoxy ketone 6 (70 mg, 0.32 mmol) in
CH2Cl2 (1 mL) was added BF3·THF (0.070 mL, 0.64 mmol) at
room temperature. The reaction mixture was stirred for 10 min.
The mixture was poured into saturated aqueous NaHCO3 (2 mL),
and the aqueous layer was extracted with EtOAc (3ϫ3 mL). The
combined organic layer was dried with anhydrous MgSO4. The
mixture was concentrated in vacuo. The crude product was dis-
solved in THF (1 mL), and a solution of LiAl(OtBu)3H (1  in
THF, 0.35 mL, 0.35 mmol) was added to the reaction mixture at
–78 °C. After stirring for 1 h, the mixture was poured into H2O
(2 mL), and the aqueous layer was extracted with EtOAc
(3ϫ3 mL). The combined organic layer was dried with anhydrous
MgSO4 and concentrated. Flash chromatography of the residue on
silica gel (EtOAc/hexane, 1:3) produced 8 mg (0.036 mmol, 11%)
of 19. 1H NMR (400 MHz, CDCl3): δ = 3.80 (d, J = 11.2 Hz, 1
H), 3.49 (d, J = 11.2 Hz, 1 H), 2.55 (d, J = 18.3 Hz, 1 H), 2.09 (d,
J = 18.3 Hz, 1 H), 1.91–1.82 (m, 2 H), 1.80–1.70 (m, 3 H), 1.64–
1.58 (m, 1 H), 1.40–1.29 (m, 5 H), 1.17 (s, 3 H), 0.98 (d, J = 6.5 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 224.4, 66.2, 62.6,
57.6, 55.5, 50.3, 47.2, 38.0, 35.9, 34.0, 33.7, 26.3, 20.8, 14.4 ppm.
[α]2D5 = –13.61 (c = 1.2, CHCl3).
32.9, 32.5, 27.3, 20.2, 15.2, 8.73 ppm. IR (neat): ν = 3500, 2953,
˜
1728, 1463, 1380, 1048, 989 cm–1. HRMS (EI): calcd. for C15H24O2
236.1776; found 236.1769. [α]2D2 = + 8.26 (c = 0.9, CHCl3)
(1R,2S,3S,6R)-3-Hydroxy-2,4,6-trimethyltricyclo[3.3.3.0]undec-3-yl-
methyl Acetate: To a solution of (1R,2S,6R)-2-hydroxymethyl-
2,4,6-trimethyltricyclo[3.3.3.0]undecan-3-one (12.7 mg,
0.054 mmol) dissolved in CH2Cl2 (1 mL) was added Et3N
(0.017 mL, 0.12 mmol) and Ac2O (0.01 mL, 0.11 mmol) at 0°C, and
the mixture was allowed to stir for 4 h at room temperature. The
mixture was poured into H2O (2 mL), and the aqueous layer was
extracted with EtOAc (3ϫ3 mL). The combined extract was dried
and concentrated in vacuo. Flash chromatography of the residue
on silica gel (EtOAc/hexane, 1:15) afforded 14.3 mg (0.051 mmol,
95%) of the title compound as a colorless oil. To a stirred solution
of acetate (14.3 mg, 0.051 mmol) in methanol (1 mL) was added
NaBH4 (2.2 mg, 0.056 mmol) at 0 °C. After stirring for 20 min,
H2O (2 mL) was added to the reaction mixture and extracted with
EtOAc (3ϫ2 mL). The combined organic extract was dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. The residue
was subjected to flash chromatography (EtOAc/hexane, 1:5) to give
13.4 mg (0.048 mmol, 94 %) of the products [3.2 mg of the
(1R,2R,6S)-2-[(1-Ethoxyethoxy)methyl]-2,6-dimethyltricyclo[3.3.3.0]-
undecan-3-one: To a solution of alcohol 19 (34 mg, 0.153 mmol) in
CH2Cl2 (1 mL) was added ethyl vinyl ether (EVE; 0.03 mL,
0.306 mmol) and pTosOH at room temperature. After stirring for
(1R,2S,3R,6R)-product and 10.2 mg of the (1R,2S,3S,6R)-product].
1
Data for the (1R,2S,3R,6R)-isomer: H NMR (400 MHz, CDCl3): 1 h, the mixture was poured into H2O (2 mL), and the aqueous
δ = 4.56 (d, J = 11.2 Hz, 1 H), 3.93 (d, J = 11.2 Hz, 1 H), 3.54 (d, layer was extracted with EtOAc (3ϫ3 mL). After the organic ex-
J = 3.8 Hz, 1 H), 2.56 (br. s, 1 H, OH), 2.32–2.26 (m, 1 H), 2.06
(s, 3 H), 1.99–1.94 (m, 1 H), 1.89–1.75 (m, 2 H), 1.64–.1.51 (m, 2
tract was dried and concentrated. Flash chromatography (EtOAc/
hexane, 1:20) of the residue gave 39.3 mg (0.141 mmol, 92%) of the
1
H), 1.43–1.29 (m, 4 H), 1.18–1.10 (m, 2 H), 1.07 (d, J = 7.2 Hz, 3 title compound. H NMR (400 MHz, CDCl3): δ = 4.61–4.54 (m, 1
H), 0.96 (s, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR H), 3.61–3.50 (m, 2 H), 3.43–3.30 (m, 2 H), 2.34 (dd, J = 17.6,
(100 MHz, CDCl3): δ = 172.3, 86.4, 68.1, 66.8, 65.7, 49.0, 44.5,
4.8 Hz, 1 H), 2.19 (dd, J = 17.6, 2.4 Hz, 1 H), 2.06–1.99 (m, 1 H),
5035
Eur. J. Org. Chem. 2009, 5028–5037
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

H.-Y. Lee, R. N. Murugan, D. K. Moon
FULL PAPER
1.77–1.56 (m, 5 H), 1.44–1.13 (m, 11 H), 1.07 (s, 3 H), 0.95 (d, J 62.0, 49.4, 48.2, 47.0, 39.6, 36.8, 35.0, 28.7, 27.3, 21.0, 16.3, 15.5,
= 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 221.8, 99.9,
13.8 ppm. [α]2D5 = –12.88 (c = 0.8, CHCl3).
70.3, 62.3, 61.0, 56.6, 54.9, 50.7, 46.1, 38.8, 36.0, 34.6, 33.0, 26.5,
(–)-13-Acetoxymodhephene (2): To a stirred solution of acetate
(1.3 mg, 0.0046 mmol) in CH3CN (1 mL) was added triphenylphos-
phane (4.83 mg, 0.0184 mmol) and carbon tetrachloride (1.8 µL,
0.192 mmol) at room temperature. The mixture was stirred under
reflux for 2 h. The reaction mixture was cooled to room tempera-
ture. The mixture was concentrated under the reduced pressure.
Flash chromatography of the residue (EtOAc/hexane, 1:40) af-
forded 1 mg (0.0038 mmol, 83%) of 13-acetoxymodhephene as a
19.5, 18.5, 15.2, 14.1 ppm. IR (neat): ν = 2953, 1734, 1458, 1377,
˜
1136, 1058 cm–1. HRMS (EI): calcd. for C18H30O3 294.2195; found
294.2181.
(1R,2R,6R)-2-Hydroxymethyl-2,4,6-trimethyltricyclo[3.3.3.0]undec-
an-3-one: To a solution of ketone (5 mg, 0.018 mmol) in THF
(1 mL) was added LiTMP (0.53  in THF, 0.340 mL, 0.18 mmol)
[prepared from 2,2,6,6-tetramethylpiperidine and nBuLi in THF at
0 °C] at 0 °C. After stirring for 30 min, CH3I (0.012 mL,
0.18 mmol) and HMPA (0.006 mL, 0.036 mmol) were added to the
reaction mixture. Stirring was continued for 2 h at 0 °C. The mix-
ture was poured into H2O (2 mL), and the aqueous layer was ex-
tracted with EtOAc (3ϫ3 mL). The mixture was concentrated in
vacuo. The crude product was dissolved in THF (1 mL) and 1 
HCl was added to the reaction mixture at room temperature. After
stirring for 1 h, the mixture was poured into H2O (2 mL), and the
aqueous layer was extracted with EtOAc (3ϫ3 mL). The combined
organic layer was dried with anhydrous MgSO4 and concentrated.
Flash chromatography of the residue on silica gel (EtOAc/hexane,
1
colorless oil. H NMR (400 MHz, C6D6): δ = 4.77 (q, J = 1.3 Hz,
1 H), 4.10 (d, J = 10.9 Hz, 1 H), 4.06 (d, J = 10.9 Hz, 1 H), 2.07–
2.01 (m, 1 H), 1.83–1.77 (m, 1 H), 1.70 (s, 3 H), 1.64–1.57 (m, 2
H), 1.52 (d, J = 1.2 Hz, 3 H), 1.50–1.45 (m, 1 H), 1.37–1.19 (m, 5
H), 1.08 (s, 3 H), 1.06–1.02 (m, 1 H), 0.92 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 171.4, 144.3, 129.7, 73.6, 70.5,
65.5, 49.6, 43.8, 38.3, 35.7, 34.5, 29.2, 27.0, 24.4, 21.0, 15.5,
14.0 ppm. HRMS (EI): calcd. for C17H26O2 262.1933; found
262.1937. [α]2D4 = –14.15 (c = 0.5, CHCl3).
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR and 13C NMR of the intermediates and synthetic
acetoxymodhephenes.
1
1:5) produced 2 mg (0.008 mmol, 47%) of the title compound. H
NMR (400 MHz, CDCl3): δ = 3.81 (d, J = 11.4 Hz, 1 H), 3.47 (d,
J = 11.4 Hz, 1 H), 2.52 (q, J = 7.0 Hz, 1 H), 2.36 (br. s, 1 H), 1.95–
1.87 (m, 2 H), 1.84–1.73 (m, 2 H), 1.55–1.40 (m, 4 H), 1.36–1.28
(m, 2 H), 1.26–1.19 (m, 4 H), 1.00 (d, J = 6.0 Hz, 3 H), 0.98 (d, J
= 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 225.8, 65.9,
61.0, 60.6, 52.9, 49.9, 49.8, 38.2, 34.5, 33.2, 29.1, 26.0, 23.1, 14.9,
10.1 ppm. [α]2D0 = –21.78 (c = 0.7, CHCl3).
Acknowledgments
This work was supported by the Korea Research Foundation (grant
KRF-2006-312-C00587).
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(1R,2R,3R,6R)-(3-Hydroxy-2,4,6-trimethyltricyclo[3.3.3.0]undec-2-
yl)methyl Acetate: To a solution of (1R,2R,6R)-2-hydroxymethyl-
2,4,6-trimethyltricyclo[3.3.3.0]undecan-3-one (7 mg, 0.030 mmol)
dissolved in CH2Cl2 (1 mL) was added Et3N (0.01 mL, 0.12 mmol)
and Ac2O (0.006 mL, 0.06 mmol) at 0 °C, and the mixture was al-
lowed to stir for 4 h at room temperature. The mixture was poured
into H2O (2 mL), and the aqueous layer was extracted with EtOAc
(3ϫ3 mL). The combined extract was dried and concentrated in
vacuo. Flash chromatography of the residue on silica gel (EtOAc/
hexane, 1:15) afforded 7.8 mg (0.028 mmol, 95%) of the acetate as
a colorless oil. To a stirred solution of acetate (7.8 mg, 0.028 mmol)
in methanol (1 mL) was added NaBH4 (1.21 mg, 0.031 mmol) at
0 °C. After stirring for 20 min, H2O (1 mL) was added to the reac-
tion mixture, which was then extracted with EtOAc (3ϫ2 mL). The
combined organic extract was dried with anhydrous MgSO4, fil-
tered, and concentrated in vacuo. The residue was subjected to
flash chromatography (EtOAc/hexane, 1:5) to give 7.2 mg
(0.026 mmol, 92%) of the products [3.7 mg of the (1R,2R,3R,6R)-
product and 3.4 mg of the (1R,2R,3S,6R)-product]. Data for the
1
(1R,2R,3R,6R)-isomer: H NMR (400 MHz, CDCl3): δ = 4.53 (d,
J = 11.1 Hz, 1 H), 3.93 (d, J = 11.1 Hz, 1 H), 3.70 (d, J = 4.4 Hz,
1 H), 2.47 (br. s, 1 H), 2.25–2.18 (m, 1 H), 2.05 (s, 3 H), 2.04–1.95
(m, 2 H), 1.83–1.75 (m, 2 H), 1.73–1.61 (m, 2 H), 1.46–1.30 (m, 4
H), 1.18–1.12 (m, 1 H), 1.01 (s, 3 H), 0.99 (d, J = 7.2 Hz, 3 H),
0.93 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
172.2, 87.7, 68.3, 68.2, 67.0, 50.2, 48.9, 46.5, 39.2, 38.5, 35.5, 29.1,
27.6, 22.3, 21.0, 16.2, 11.1 ppm. [α]2D5 = + 28.38 (c = 0.8, CHCl3).
1
Data for the (1R,2R,3S,6R)-isomer: H NMR (400 MHz, CDCl3):
δ = 4.07 (d, J = 11.0 Hz, 1 H), 4.00 (d, J = 11.0 Hz, 1 H), 3.44 (d,
J = 11.0 Hz, 1 H), 2.04 (s, 3 H), 2.00–1.94 (m, 1 H), 1.80–1.69 (m,
4 H), 1.47–1.42 (m, 3 H), 1.39–1.31 (m, 3 H), 1.20–1.14 (m, 1 H),
1.01 (s, 3 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.6 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.4, 84.0, 71.3, 64.7,
[13] F. Wu, R. Hong, J. Khan, X. Liu, L. Deng, Angew. Chem. Int.
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315.
5036
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5028–5037

Total Synthesis of (–)-13-Acetoxymodhephene and (+)-14-Acetoxymodhephene
[15] V. Van Rheenen, R. C. Kelly, D. Y. Cha, Tetrahedron Lett.
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[21]
[22]
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[23]
[24]
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[25]
[26]
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[20] The relative energies of conformations 8a and 8b calculated
with the use of the MM2 energy minimization program of
ChemBio3D indicated that conformer 8a is far more stable
than 8b.
TiCl4, TiF4, SnCl4, SnF4, TMSOTf, Sc(OTf)3, BBr3, BCl3,
BBu2OTf, BF3·SMe2, BF3·Et2O, FeF3, AlMe2Cl, and AlEtCl2
were tested, and none of them was as effective as BF3·THF.
Received: June 27, 2009
Published Online: September 2, 2009
Eur. J. Org. Chem. 2009, 5028–5037
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5037