Enantioselective syntheses of the proposed structures of kopeolin and kopeolone

Article abstract of DOI:10.1002/chem.201300711

The first total syntheses of the proposed structures of kopeolin (1) and kopeolone (3) have been achieved from a common enantiopure chiral building block obtained by a chemoenzymatic enantioconvergent methodology. The syntheses feature two key steps: a on

Full text of DOI:10.1002/chem.201300711

DOI: 10.1002/chem.201300711
Enantioselective Syntheses of the Proposed Structures of Kopeolin and
Kopeolone
Stꢀphanie Miquet,[a] Nicolas Vanthuyne,[b] Paul Brꢀmond,*[a] and Gꢀrard Audran*[a]
Abstract: The first total syntheses of
the proposed structures of kopeolin (1)
and kopeolone (3) have been achieved
highly diastereoselective addition of an
organocerate. The synthetic structures
were fully characterized and all stereo-
centers were confirmed. The results
show that the two previously reported
structures were not assigned correctly,
and suggest an initial structural misas-
signment during the isolation of the
natural products. Thus, two revised
structures, 1’ for kopeolin and 3’ for
kopeolone, are proposed.
from
a common enantiopure chiral
building block obtained by a chemoen-
zymatic enantioconvergent methodolo-
gy. The syntheses feature two key
steps: a one-pot reduction/diastereose-
Keywords: enantioselectivity · nat-
ural products · structure elucida-
tion · terpenoids · total synthesis
lective protonation followed by
a
Introduction
moiety (umbelliferone). Kopeolin (1) has three stereocen-
ters and an E-double bond, and is the aglycon part of ko-
peoside (2), the glycone part being the b-d-glucopyranose.
Their structures were established on the basis of their spec-
Monocyclic terpenoids are not very common metabolites in
nature and their biosynthetic processes are usually based on
polycyclization. However, during the last few years, identifi-
cation of several natural oxygenated monocyclic sesquiter-
penes suggests that they may be more prevalent within the
plant kingdom than previously assumed.[1] In 1973, the isola-
tion from roots of Ferula kopetdaghensis of the sesquiterpe-
noid coumarins kopeolin (1) and kopeoside (2), which are
ethers of umbelliferone, were reported (Figure 1).[2]
1
troscopic properties (IR, MS, H NMR spectroscopic data),
however, at that time, the stereostructures of 1 and 2 could
not be established with certainty. In 1982, kopeolone (3),[3]
another terpenoid coumarin, was also isolated from the
same species (Figure 1). The structure of kopeolone (3) is
similar to that of kopeolin (1) except that the secondary al-
cohol is oxidized to the ketone. The stereostructures of
these natural compounds were proposed based on chemical
transformations; indeed, NaBH4-mediated reduction of ko-
peolone (3) into kopeolin (1) followed by H2SO4 catalyzed
dehydration provided known farnesiferol C (4) as well as
three elimination products (Scheme 1). As reported, discus-
sions on the stereostructure of kopeolin (1) and kopeolone
Kopeolin (1) presents a six-membered ring carrying a
gem-dimethyl group, secondary and tertiary alcohol func-
tions, and a sidechain extended by a 7-hydroxycoumarin
1
(3) were only based on comparison of their H NMR spectra
(90 MHz).[3]
Figure 1. Structure of kopeolin (1), kopeoside (2), and kopeolone (3).
[a] S. Miquet, Dr. P. Brꢀmond, Prof. G. Audran
Aix-Marseille Universitꢀ, CNRS
Institut de Chimie Radicalaire UMR 7273
13397 Marseille Cedex 20 (France)
Fax : (+33)4.91.28.85.45
E-mail: paul.bremond@univ-amu.fr
g.audran@univ-amu.fr
[b] Dr. N. Vanthuyne
Aix-Marseille Universitꢀ, CNRS
Institut des Sciences Molꢀculaires de Marseille
UMR 7313, 13397 Marseille Cedex 20 (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300711.
Scheme 1. Chemical transformations conducted to elucidate the stereo-
structures of 1 and 3.
10632
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10632 – 10642

FULL PAPER
In 1991, kopeolin (1) was also isolated from the ethanol
extract of the resin of Ferula gummosa, which is widespread
in India.[4] Incidentally, the gum resin obtained by incision
from the stem is used as a traditional medicine in India.[5]
Kopeolin (1) was also isolated from Ferula assafoetida and
its antiproliferative properties were studied, showing strong
inhibition of the proliferation of cultured human cells.[6] To
date, no synthesis of kopeolin (1) or kopeolone (3) has been
described. Starting from an enantiopure building block for
the introduction and determination of the absolute stereo-
chemistry, we report herein the first enantioselective synthe-
sis of kopeolin (1) and kopeolone (3) to fully characterize
these natural compounds and to determine the absolute ster-
eochemistry of all the chiral centers.
tained from enone 11, as starting material, by the 1,4-addi-
tion of dimethyl cuprate, followed by quenching with methyl
cyanoformate. We have already reported the synthesis of
both enantiomers of the required enone 11 with good yields
and excellent enantiomeric excesses through a chemoenzy-
matic enantioconvergent methodology,[7] and demonstrated
the usefulness of these building blocks in the synthesis of
natural products.[8]
As shown in Scheme 3, enone 11 was converted into enol
ether 12 in 98% yield by the 1,4-addition of lithium dimeth-
Results and Discussion
Our retrosynthetic analysis of kopeolin (1) is outlined in
Scheme 2. Initial disconnection reduced kopeolin (1) to in-
Scheme 3. Preparation of b-ketoalcohol 9.
yl cuprate in diethyl ether followed by quenching of the in-
termediate enolate with chlorotrimethylsilane (TMSCl) in
the presence of hexamethylphosphoramide (HMPA) and
N,N,N’,N’-tetramethylethylenediamine (TMEDA). The eno-
late regenerated in situ from 12 by addition of methyllithi-
um was then quenched with methylcyanoformate (Manderꢂs
reagent) in a mixture of THF and HMPA in 85% yield.
Next, the transformation used to obtain b-ketoalcohol 9
from b-ketoester 10 involved a one-pot, three-step se-
quence: 1) regioselective formation of an enolate 2) chemo-
selective reduction of the ester function, and 3) stereoselec-
tive C-protonation of an ambident enolate. Chemoreduction
using alane (AlH3) as the reducing agent of the ester group
of a b-ketoester into an enolate salt of b-ketoalcohol has al-
ready been reported.[9] Moreover, diastereoselective proto-
nation of chiral enolates with proton donors has been re-
viewed.[10] Thus, attempts to realize this one-pot, three-step
sequence were made using NaH as the base and AlH3 as the
reductant with a range of proton donors (tert-BuOH,
MeOH, NH4Cl, HCl, ethyl salicylate). The best result was
obtained by using MeOH, giving pure b-ketoalcohol 9,
albeit in only 28% yield accompanied by a complex mixture
of byproducts.
Scheme 2. Retrosynthetic analysis of kopeolin (1).
termediate 5 and to the commercially available umbellifer-
one. The strategy then indicated that the sidechain of 5
could be prepared by its chemical transformation from ace-
tate 6, which could, in turn, arise by allylic rearrangement of
an intermediate stemming from ketone 7. The latter would
be prepared by Horner–Wadworth–Emmons (HWE) olefi-
nation from aldehyde 8. The critical point of the synthesis
involved the installation of the required stereogenic centers
of the alcohols. The stereocontrol of the tertiary alcohol
would be realized by diastereoselective addition of an orga-
nometallic to b-ketoalcohol 9, which would be prepared by
diastereoselective protonation of a chiral enolate generated
from b-ketoester 10. Finally, b-ketoester 10 could be ob-
Because the results were not satisfactory due to the insta-
bility of b-ketoalcohol 9 in this complex reaction mixture
containing many salts, we slightly changed the strategy to re-
alize the diastereoselective protonation from enol acetate 13
(Scheme 4).
Thus, treatment with acetic anhydride of the sodium eno-
late generated from b-ketoester 10 by NaH in THF occurred
Chem. Eur. J. 2013, 19, 10632 – 10642
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10633

Dr. P. Brꢀmond, Prof. G. Audran et al.
Scheme 4. Preparation of b-ketoalcohol 9.
Table 1. One-pot reduction/diastereoselective protonation to prepare
b-ketoalcohol 9.
Figure 2. Optimized conformation of the intermediate enolate for diaster-
eoselective protonation, calculated using the B3LYP/6-311G+ +(d,p)
method.
suitable alkylating reagent, which, due to its low basicity,
should prevent epimerization or elimination of the sensitive
hydroxymethyl moiety. Thus, MeCeCl2 reacted with 9 to
afford diol 14 as a single diastereomer in 76% yield
(Scheme 5).
To establish the stereochemistry of the newly generated
stereocenters, the TBS protecting group of diol 14 was re-
moved with tetrabutylammonium fluoride (TBAF) in THF
to give the crystalline triol 15 in 82% yield. The structure of
15, and therefore that of 14, was confirmed by X-ray crystal-
lography.[12]
Entry
Reductant
Proton donor
Yield of
Yield of
9 [%][a]
epi-9 [%][a]
1[b]
2[c]
3[c]
4[c]
AlH3
AlH3
DIBAL-H
LAH
MeOH/Rochelle salt
tert-BuOH/Rochelle salt
MeOH/Rochelle salt
MeOH/Rochelle salt
55
35
20
40
12
16
12
15
[a] Isolated yield after column chromatography. [b] These conditions
afford cleanly b-ketoalcohol 9 and epi-9. [c] Elimination product was also
isolated.
The diastereoselectivity was explained by calculation at
the B3LYP/6-311G+ +(d,p) level of the preferred chair
conformation of the b-ketoalcohol 9 (Figure 3). This confor-
mation is stabilized by a hydrogen bond between the ketone
and the hydrogen of the primary alcohol function, thus
forming a tethering six-membered ring. As a consequence,
exclusively by O-acetylation to give enol acetate 13 in excel-
lent yield. The next reaction involved reduction of 13 and
the reduced intermediate should be diastereoselectively pro-
tonated in situ. As shown in Table 1, three different reduc-
tants were tested (AlH3, diisobutylaluminum hydride
(DIBAL-H), lithium aluminum hydride (LAH)) with differ-
ent proton donors. The best result was observed when the
reaction was performed in THF at À808C with AlH3 as the
reductant, MeOH as the proton donor, and by quenching of
the reaction mixture with an aqueous solution of Rochelle
salt. Under these conditions, the reaction cleanly provided
the corresponding b-ketoalcohol 9 and epi-9 in 55 and 12%
yield, respectively, after separation by silica gel column
chromatography.
The observed stereoselectivity was explained by calcula-
tion at the B3LYP/6-311G+ +(d,p) level of the optimized
conformation of the intermediate enolate (Figure 2). The
low-energy twist conformation of the enolate, which mini-
mizes the steric interactions of the methyl groups and the
TBS ether in the pseudoequatorial position, presented a
less-hindered lower face, the
Figure 3. Optimized conformation [B3LYP/6-311G+ +(d,p)] of ketone 9
and the corresponding LUMO orbital showing the accessibility of the
lobe for the diastereoselective alkylation by MeCeCl2.
upper face being more crowded
due to the pseudoaxial position
of the b-methyl group. The
axial approach of the proton
donor to the a-face was thus
clearly favored and led to b-ke-
toalcohol 9.
Having obtained b-ketoalco-
hol 9, methylcerium dichloride
(MeCeCl2)[11] was selected as a Scheme 5. Formation of triol 15.
10634
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10632 – 10642

Synthesis of Kopeolin and Kopeolone
FULL PAPER
the approach of the organocerate occurred at the less-hin-
dered lower face of 9 in respect of the Bꢃrgi–Dunitz angle,
nicely illustrated by the lower lobe of the lowest unoccupied
molecular orbital (LUMO), the upper lobe of the LUMO
being inaccessible due to the proximity of the b-methyl
group. Consequently, this led to the formation of the tertiary
alcohol function cis to the CH2OH and TBS ether groups.
With the stereostructure of diol 14 confirmed, the synthe-
sis of kopeolin (1) was continued by elaboration of the cou-
marin sidechain. Careful oxidation of diol 14 with a catalytic
amount of tetrapropylammonium perruthenate (TPAP) and
N-methylmorpholine N-oxide (NMO) as the co-oxidant in
Scheme 6. Preparation of enone 16 and undesired dihydropyrane 17.
dichloromethane provided aldehyde
8 in 81% yield
(Scheme 6).[13] The Horner–Wadsworth–Emmons (HWE)
reaction is an efficient methodology for coupling of b-keto-
phosphonate, and numerous modifications have been report-
ed.[14] Among them, the Ba(OH)2 promoted HWE reaction
is a mild method for use with epimerizable aldehydes.[14c]
Thus, application of these conditions to aldehyde 8 in wet
THF afforded enone 16 in 88% yield as a single E isomer.
At this stage, hydrogenation of the double bond of enone 16
by a standard method (H2, Pd/C, MeOH) did not give the
desired reduced compound but instead gave dihydropyrane
17 as a unique product in 91% yield. The formation of the
undesired product 17 could be explained by reduction of the
double bond, followed by the
ladium catalyst.[15] Thus, subsequent exposure of 7 to vinyl-
magnesium bromide followed by treatment with acetic anhy-
dride/triethylamine in the presence of N,N-dimethyl-
AHCTUNGTREGaNNUN minopyridine (DMAP) yielded the tertiary allylic acetates
19 (79%) as a 60:40 diastereomeric mixture. To install the
umbelliferone to the side chain of 19 in one step, a palladi-
um-catalyzed cross-coupling reaction with allylic acetates 19
and the sodium or potassium salt of umbelliferone was first
investigated. However, no reaction was observed despite the
screening of several different conditions ([Pd
ACHTUNGTRENNUNG(PPh3)4],
K2CO3 or NaH, umbelliferone) and the unreacted starting
hemiketalization of the ketone
by the tertiary alcohol and fi-
nally b-elimination.
To circumvent this problem,
the tertiary alcohol was protect-
ed as the TBS ether, that is,
with the same protecting group
already used for the secondary
alcohol, to allow simultaneous
deprotection of both TBS
ethers at the final stage of the
synthesis. Treatment of the hin-
dered tertiary alcohol 16 with
TBS-OTf in the presence of
2,6-lutidine in CH2Cl2 afforded
the corresponding TBS ether
with concomitant formation of
the silyl enol ether of the
ketone, which was hydrolyzed
upon acidic aqueous workup
providing compound 18 in 89%
yield (Scheme 7). Hydrogena-
tion of 18 in ethyl acetate with
H2 in the presence of Pd/C oc-
curred smoothly to give ketone
7 in 87% yield. To obtain the
sidechain of kopeolin (1) with
high E stereoselectivity starting
from ketone 7, we selected a re-
arrangement of a tertiary allylic
acetate in the presence of a pal- Scheme 7. Completion of the synthesis of kopeolin (1).
Chem. Eur. J. 2013, 19, 10632 – 10642
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10635

Dr. P. Brꢀmond, Prof. G. Audran et al.
material was recovered. As a consequence, the umbellifer-
one was added using a linear methodology. Treatment of ter-
tiary allylic acetates 19 with dichlorobis(acetonitrile)palladi-
um afforded a 87:13 mixture of (E/Z)-6 (analyzed by
1H NMR spectroscopy) in 93% yield.
Separation of the geometric isomers on silica gel column
afforded pure acetate
(E)-6 in 80% yield. Treatment of (E)-6 with excess K2CO3
in methanol at room temperature cleaved the acetate group
and cleanly provided alcohol 20 as the precursor to the nat-
ural product in 82% yield. Reaction of alcohol 20 with PBr3
afforded the corresponding allylic bromide,[16] which was di-
rectly used in the next step without any further purification
due to its instability. Thus, coupling of the potassium salt of
umbelliferone and the crude allylic bromide in acetone
yielded coumarin derivative 21 in 70% yield over two steps.
To complete the synthesis of kopeolin (1), we needed to si-
multaneously remove both TBS protecting groups. The use
of several fluorine sources (TBAF, aq. HF or H2SiF6) to de-
protect 21 proved to be unworkable, leading only to a com-
plex mixture of products composed of starting material,
monodeprotected product, and the desired kopeolin (1) in
very poor yield along with extensive decomposition. To
solve this problem, the deprotections were carried out in
two separate steps. First, of the different attempts used to
remove the secondary TBS ether by using standard meth-
ods,[17] only the action of HF·pyridine complex[18] in THF at
408C cleanly afforded the monodeprotected derivative 22 in
79% yield. To remove the last TBS ether group of 22, the
same methods described before were used, but again with-
out any success. Fortunately, after extensive screening of
several deprotection conditions, desilylation was accomplish-
ed with KF in the presence of [18]crown-6 in DMSO at
1258C.[19] Under these conditions, 1 was obtained, after puri-
fication on silica gel column, as a foam in 52% yield togeth-
er with 45% yield of recovered 22. Attempts to reach full
conversion led only to decomposition of the reaction mix-
ture.
Figure 4. HPLC chromatogram of (Æ)-1 and (+)-1 and selected NOESY
correlations of 1.
kopeolin reported by Kamilov and Nikonov[2] or by Ryu.[6]
Indeed, the chemical shifts of the axial methyl of the gem-
À
dimethyl group, Meax C2 (reported: dH =0.80 ppm; synthet-
À
ic: dH =0.95 ppm) as well as the chemical shift of Hax C1
(reported: dH =1.19–1.11 ppm; synthetic: dH =0.86 ppm) dif-
fered significantly. Moreover, several carbon chemical shifts
were also quite different (see the Supporting Information).
In addition, the magnitude and the sign of the specific rota-
tion of our synthetic 1 ([a]2D5 =+7 (c 1.0, EtOH)) were not
consistent with the reported data ([a]2D5 =À16 (c 1.0,
EtOH)), and synthetic 1 was obtained as a foam and not as
a solid.[2] Thus, the differences in the spectral data and the
physical properties between 1 and natural kopeolin strongly
suggested a structural misassignment during the isolation of
kopeolin.
To investigate this possible misassignment in the structure
of natural kopeolin, we decided to examine the possibility
of a misattribution of the configuration of the secondary al-
cohol. To this end, we oxidized the secondary alcohol with
TPAP/NMO, which gave the proposed structure of kopeo-
lone 3 in 87% yield (Scheme 8). Moreover, reduction of 3
with NaBH4 afforded exclusively and cleanly 1, once again
as a foam, with 86% yield.
The high optical purity of 1 was confirmed by chiral
HPLC analysis by comparison with a racemic sample
1
(Figure 4). H and 13C NMR data for 1 were fully ascribed
by COSY and HMQC experiments, and the relative configu-
ration of the three stereocenters in 1 was assigned on the
basis of 1H NMR NOESY experiments; NOE effects be-
À
À
À
tween Hax C3 and Hax C1, and between Hax C1 and
À
Meeq C6 established the cis spatial orientation of these pro-
tons and the methyl group (Figure 4). Moreover, strong
À
À
NOE effects between the two protons of H C8 and H C10,
À
À
and between Me C9 and the two protons of H C11, estab-
lished the E double-bond configuration.
Kopeolin was also extracted recently from Ferula assafoe-
tida by Ryu[6] and the spectroscopic data were in agreement
with the NMR data previously reported in the literature[2]
1
(see H and 13C NMR data of natural kopeolin provided by
Ryu in the Supporting Information). Surprisingly, we ob-
1
served that the H and 13C NMR data of our synthetic com-
pound were not consistent with the reported data of natural
Scheme 8. Synthesis of kopeolone (3).
10636
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10632 – 10642

Synthesis of Kopeolin and Kopeolone
FULL PAPER
1
The structure of 3 was assigned on the basis of H, 13C,
COSY, HMQC and NOESY NMR analyses. The chemical
shifts and the large coupling constant of two signals resonat-
ing as a triplet of doublets at dH =3.07 (J=14.2, 5.8 Hz) and
1.82 ppm (J=14.2, 4.3 Hz) allowed us to identify anticopla-
À
À
nar orientation protons, Hax C4 and Hax C5, respectively.
À
À
Thus, NOE effects between Hax C4 and Meax C2 established
the cis spatial orientation of this proton and the methyl
À
group. In addition, strong NOE effects between Hax C5,
À
À
À
Meeq C6, Hax C1, and Meeq C2 established the cis orienta-
tion of these protons and this methyl group. The high optical
purity of 3 was also confirmed by chiral HPLC by compari-
son with a racemic sample (Figure 5).
Scheme 9. Revised structures for kopeolin and kopeolone.
signed, but the tertiary alcohol stereocenter C-6 remained
unknown. Our hypothesis is that, taking into account the
quite harsh conditions of the cyclization (conc. H2SO4 in
acetone at reflux), the intramolecular ether formation of far-
nesiferol C (4) follows an SN1 pathway with the intermediate
formation of carbocation 23. The latter can either react with
the secondary alcohol to give farnesiferol C (4), or can elim-
inate one of the three types of b-neighboring protons to give
the elimination products. Carbocation 23 can indeed be ob-
tained by loss of the tertiary hydroxyl group from the pro-
posed structure of kopeolin (1) after protonation, but it can
also be obtained from the diastereomer carrying the oppo-
site configuration of the tertiary alcohol. Thus, based on
these observations and according to our results, we postulate
that the configuration of the tertiary alcohol of the proposed
structure of kopeolin (1) and kopeolone (3) was missas-
signed and should be reassigned the opposite configuration.
As a consequence, the only remaining possible structures
for kopeolin and kopeolone that could explain these chemi-
cal transformations are compounds 1’ and 3’ depicted in
Scheme 9. To confirm the revised structures of kopeolin 1’
and kopeolone 3’, we plan to synthesize these molecules
using a new strategy that will permit the correct configura-
tion of the tertiary alcohol at C-6 to be obtained.
Figure 5. HPLC chromatogram of (Æ)-3 and (+)-3 and selected NOESY
correlations of 3.
Unfortunately, the spectral data of synthetic 3 were also
not consistent with the data reported for natural kopeolone,
confirming a structural misassignment of both kopeolin and
1
kopeolone. The chemical shifts in the H NMR spectrum of
the axial methyl of the gem-dimethyl group (reported: dH =
1.12 ppm; synthetic: dH =1.23 ppm) were also not in agree-
ment. Because no 13C NMR data were reported in the litera-
ture for kopeolone, we could not make any comparison.
However, the melting point of our synthetic 3 (m.p. 105–
1068C) was also not in agreement with that reported in the
literature (m.p. 125–1268C), nor was the magnitude of the
specific rotation (synthetic 3: [a]2D5 =+32 (c 1.0 in EtOH);
lit.: [a]2D5 =+70 (c 1.0, EtOH)[3]).
Previously, the determination of the stereostructure of the
isolated natural compounds, kopeolin and kopeolone, was
based on the dehydration of kopeolin with sulfuric acid into
known farnesiferol C (4) together with elimination products
(Scheme 9).[3] With this in mind, two of the three stereocen-
ters of kopeolin, C-1 and C-3, could undoubtedly be as-
Conclusion
The total syntheses of the proposed structures of kopeolin
(1) and kopeolone (3) have been completed in 17 and 18
steps, respectively. The synthetic materials 1 and 3 do not
correspond to the reported structure of natural kopeolin
Chem. Eur. J. 2013, 19, 10632 – 10642
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10637

Dr. P. Brꢀmond, Prof. G. Audran et al.
(R)-3-(tert-Butyldimethylsilanyloxy)-2,2-dimethyl-6-oxocyclohexane car-
boxylic acid methyl ester (10): MeLi (1.6m in Et2O, 10.50 mL, 16.8 mmol,
1.1 equiv) was added to a stirred solution of 12 (5.00 g, 15.2 mmol) in
Et2O (40 mL) at À788C. The reaction mixture was stirred for a further
2 h at À788C, HMPA (3.95 mL, 22.8 mmol, 1.5 equiv) was added drop-
wise under vigorous stirring, then methyl cyanoformate (1.80 mL,
22.8 mmol, 1.5 equiv) was added. The temperature of the solution was al-
lowed to rise to RT, then the solution was poured into water and extract-
ed with Et2O. The organic layers were combined, washed with brine, and
dried with MgSO4. Concentration and purification by flash chromatogra-
phy gave 10 as a mixture of diastereoisomers (4.06 g, 85% yield; trans/
cis, 4:1) as a colorless oil. 1H NMR (300 MHz, CDCl3): d=3.77 (s, 1H;
M), 3.72 (s, 3H; M), 3.70 (s, 3H; m), 3.64 (t, J=6.3 Hz, 1H; M), 3.43–
3.38 (m, 1H; m), 3.18 (s, 1H; m), 2.70–2.55 (m, 1H; M+m), 2.40–2.30
(m, 1H; M+m), 2.16–2.02 (m, 1H; M+m), 1.93–1.81 (m, 1H; M+m),
1.11 (s, 3H; m), 1.08 (s, 3H; M), 1.04 (s, 3H; M), 1.01 (s, 3H; m), 0.94 (s,
9H; M), 0.90 (s, 9H; m), 0.11 (s, 6H; M), 0.06 ppm (s, 6H; m); 13C NMR
(75 MHz, CDCl3): d=206.3 (C, M), 205.2 (C, m), 169.3 (C, M), 168.5 (C,
m), 75.4 (CH, m), 74.6 (CH, M), 64.5 (CH, m), 61.9 (CH, M), 51.6 (CH3,
m), 51.5 (CH3, M), 43.6 (C, M), 43.0 (C, m), 37.7 (CH2, m), 35.7 (CH2,
M), 30.0 (CH2, m), 29.3 (CH2, M), 26.5 (CH3, m), 25.8 (3ꢄCH3, M), 25.7
(3ꢄCH3, m), 24.7 (CH3, M), 22.6 (2ꢄCH3, M+m), 18.0 (C, M), 17.6 (C,
m), À4.2 (CH3, m), À4.3 (CH3, m), À4.5 (CH3, M), À4.9 ppm (CH3, M);
IR (neat): n˜ =1766, 1722, 1262, 1130, 1086, 834 cmÀ1; HRMS (ESI): m/z
calcd for C16H31O4Si+: 315.1992 [M+H]+; found: 315.1994.
and kopeolone, strongly suggesting a structural misassign-
ment during the isolation of the natural products. Based on
our current synthesis and the previously reported data, we
propose the structural revision of kopeolin to compound 1’
and kopeolone to compound 3’. Their total syntheses are
now under investigation and will be reported in due course.
Experimental section
General: All air- and/or water-sensitive reactions were carried out under
an argon atmosphere with anhydrous, freshly distilled solvents using
standard syringe/cannula/septa techniques. All corresponding glassware
were oven-dried (808C) and/or carefully dried in-line with a flameless
heat gun. All solvents were distilled under an argon atmosphere: THF
from a blue solution of sodium-benzophenone ketyl radical prior to use;
CH2Cl2 from CaH2; Et2O from LiAlH4. Routine monitoring of reactions
was performed using Merck Silica gel 60 F254, aluminum-supported TLC
plates; spots were visualized using UV light and ethanolic acidic para-
anisaldehyde solution or ethanolic phosphomolybdic solution, followed
by heating. Purifications by means of column chromatography were per-
formed with Silica gel 60 (230–400 mesh) and gradients of Et2O/petrole-
um ether (PE) or CH2Cl2/MeOH as eluent, unless otherwise stated. 1H
and 13C NMR spectra were recorded in CDCl3, CD3OD or C6D6 solutions
with Bruker Avance DPX-300 or Bruker AM-400 spectrometers. Chemi-
cal shifts (d) in ppm are reported using residual non-deuterated solvents
as internal reference. Optical rotations were measured with a PerkinElm-
er 241 polarimeter. Melting points are uncorrected. Infrared spectra were
obtained as films or KBr pellets with a Bruker Vertex 70 spectrophotom-
(R)-2-Acetoxy-5-(tert-butyldimethylsilanyloxy)-6,6-dimethylcyclohex-1-
ene carboxylic acid methyl ester (13): Sodium hydride (2.31 g, 57.3 mmol,
3.0 equiv, 60% dispersion in mineral oil) was added to an ice-cold stirred
solution of b-ketoester 10 (6.01 g, 19.1 mmol) in THF (300 mL), under
argon. The mixture was stirred at RT for 40 min and then acetic anhy-
dride (4.50 mL, 47.7 mmol, 2.5 equiv) was added dropwise. After stirring
for 18 h at RT, the mixture was poured into aqueous saturated NaHCO3
solution. The aqueous layer was extracted with Et2O, then the organic
layers were combined, washed with H2O, brine, and dried with MgSO4.
Concentration in vacuo and purification by column chromatography gave
compound 13 (6.47 g, 95% yield) as a yellow oil. [a]2D5 =À2.2 (c 1.0 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=3.73 (s, 3H), 3.58 (br t, J=
6.3 Hz, 1H), 2.45–2.25 (m, 2H), 2.09 (s, 3H), 1.85–1.78 (m, 2H), 1.16 (s,
3H), 1.12 (s, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=168.3 (C), 167.1 (C), 148.2 (C), 126.6 (C), 74.4
(CH), 51.3 (CH3), 38.7 (C), 26.3 (CH2), 25.8 (CH3), 25.7 (3ꢄCH3), 25.3
(CH2), 21.9 (CH3), 20.6 (CH3), 18.0 (C), À4.3 (CH3), À5.0 ppm (CH3); IR
(neat): n˜ =3024, 1768, 1613, 1125, 1083 cmÀ1; HRMS (ESI): m/z calcd for
C18H33O5Si+: 357.2091 [M+H]+; found: 357.2091.
eter. High-resolution mass spectra (HRMS) were performed with
a
SYNAPT G2 HDMS (Waters) mass spectrometer equipped with a pneu-
matically assisted atmospheric pressure ionization. The sample was ion-
ized in positive mode electrospray under the following conditions: elec-
trospray voltage (ISV): 2800 V; orifice voltage (OR): 20 V; nebulizing
gas flow (nitrogen): 800 LhÀ1. The mass spectrum was obtained with a
time of flight analyzer (TOF). The measurements were realized in tripli-
cate, with double internal standardization. The sample was dissolved in
CH2Cl2 (450 mL) then diluted (dilution factor 1/103) in a methanolic solu-
tion of ammonium acetate (3 mm). The sample solution was infused in
the ionization source at a 10 mLminÀ1 flow rate. Enantiomeric excesses
(ee) were determined by chiral HPLC by comparison with a racemic
sample: Chiralpak IA, hexane/ethanol (6:4), 1 mLminÀ1
.
AHCTUNGTERG(NNUN 2S,4R)-4-(tert-Butyldimethylsilanyloxy)-2-hydroxymethyl-3,3-dimethyl-
(R)-4-(tert-Butyldimethylsilanyloxy)-3,3-dimethyl-1-trimethylsilanyloxy-
cyclohexene (12): MeLi (1.6m in Et2O, 39.0 mL, 62.4 mmol, 3.0 equiv)
was added dropwise to a stirred suspension of copper(I) iodide (5.95 g,
31.2 mmol, 1.5 equiv) in Et2O (75 mL) at À158C, under an argon atmos-
phere. The mixture was stirred for 1 h at À158C and a solution of 11
(5.00 g, 20.8 mmol, 96% ee) in Et2O (15 mL) was added dropwise. The
reaction mixture was stirred for a further 1 h at À158C, HMPA (7.50 mL,
43.2 mmol, 2.1 equiv) was added dropwise under vigorous stirring, the
mixture was slowly cooled to À788C, then TMEDA (5.30 mL, 35.4 mmol,
1.7 equiv) and TMSCl (3.10 mL, 31.2 mmol, 1.5 equiv) were added drop-
wise. The temperature of the solution was allowed to rise to RT, then the
solution was poured into an aqueous ammonium hydroxide solution
(300 mL) and extracted with a Et2O/pentane (1:1) mixture. The organic
layers were combined, washed with brine, dried, and evaporated to fur-
nish 12 (6.70 g, 98% yield) as a yellow oil. This compound was used in
cyclohexanone (9) and epi-(2R,4R)-9: Freshly prepared AlH3 (0.5m in
THF, 35.00 mL, 16.8 mmol, 6.0 equiv) was slowly added dropwise, under
an argon atmosphere, to a stirred solution of enol acetate 13 (1.00 g,
2.8 mmol) in THF (50 mL) at À788C. The mixture was stirred for 3 h and
temperature was allowed to slowly rise to À208C. The reaction was then
quenched by the addition of MeOH (5 mL) and poured into an ice-cold
mixture of H2O/Et2O (1:1, 1 L) containing Rochelle salt (100 g). The mix-
ture was stirred for 3 h and the temperature was allowed to rise to RT.
The aqueous layer was extracted with Et2O, then the organic layers were
combined, washed with H2O, brine, and dried with MgSO4. Concentra-
tion in vacuo and purification by column chromatography gave pure
compound 9 (441 mg, 55% yield) and epi-9 (96 mg, 12% yield) as color-
less oils.
Compound 9: [a]2D5 =À20.6 (c 1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.01 (ddd, J=11.7, 8.3, 3.8 Hz, 1H), 3.73 (dd, J=9.8, 4.3 Hz,
1H), 3.66 (ddd, J=11.7, 10.0, 3.3 Hz, 1H), 2.72 (dd, J=10.0, 3.8 Hz, 1H),
2.50–2.32 (m, 3H), 2.06–1.99 (m, 1H), 1.89–1.79 (m, 1H), 1.06 (s, 3H),
0.92 (s, 9H), 0.81 (s, 3H), 0.12 (s, 3H), 0.11 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=213.4 (C), 75.6 (CH), 60.3 (CH), 59.0 (CH2), 42.2
(C), 38.6 (CH2), 30.3 (CH2), 26.3 (CH3), 25.8 (3ꢄCH3), 18.0 (C), 16.9
(CH3), À4.2 (CH3), À4.9 ppm (CH3); IR (neat): n˜ =3582, 1710, 1235,
1041 cmÀ1; HRMS (ESI): m/z calcd for C15H31O3Si+: 287.2037 [M+H]+;
found: 287.2037.
1
the next step without further purification. H NMR (300 MHz, C6D6): d=
4.73 (brs, 1H), 3.50 (dd, J=9.7, 3.4 Hz, 1H), 2.13 (brt, J=7.2 Hz, 2H),
1.82–1.58 (m, 2H), 1.11 (s, 3H), 1.05 (s, 3H), 0.99 (s, 9H), 0.20 (s, 9H),
0.05 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (75 MHz, C6D6): d=148.9 (C),
114.4 (CH), 76.1 (CH), 37.4 (C), 30.0 (CH3), 29.2 (CH2), 28.6 (CH2), 26.5
(3ꢄCH3), 24.8 (CH3), 18.7 (C), 0.75 (3ꢄCH3), À3.7 (CH3), À4.5 ppm
(CH3); IR (neat): n˜ = 3020, 1660, 1255, 834 cmÀ1; HRMS (ESI): m/z calcd
for C17H37O2Si2+: 329.2332 [M+H]+; found: 329.2333.
10638
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10632 – 10642

Synthesis of Kopeolin and Kopeolone
FULL PAPER
Compound epi-9: 1H NMR (300 MHz, CDCl3): d=3.93 (dd, J=11.4,
9.1 Hz, 1H), 3.59 (dd, J=11.4, 3.0 Hz, 1H), 3.44 (brs, 1H), 2.89 (dd, J=
9.1, 3.0 Hz, 1H), 2.68 (dt, J=13.6, 7.1 Hz, 1H), 2.20–1.82 (m, 2H), 1.66–
1.54 (m, 2H), 1.05 (s, 3H), 0.91 (s, 9H), 0.75 (s, 3H), 0.08 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=15.8 (C), 75.9 (CH), 58.7 (CH), 55.8
(CH2), 43.4 (C), 36.4 (CH2), 29.7 (CH2), 26.0 (3ꢄCH3), 25.7 (CH3), 22.7
(CH3), 18.2 (C), À4.3 (CH3), À4.8 ppm (CH3); IR (neat): n˜ =3585, 1708,
1237, 1035 cmÀ1; HRMS (ESI): m/z calcd for C15H31O3Si+: 287.2037
[M+H]+; found: 287.2038.
27.0 (CH2), 25.8 (3ꢄCH3), 18.1 (C), 16.6 (CH3), À4.0 (CH3), À5.0 ppm
(CH3); IR (KBr): n˜ =3370, 2731, 1716, 1014 cmÀ1; HRMS (ESI): m/z
calcd for C16H33O3Si+: 301.2194 [M+H]+; found: 301.2194.
4-[(1R,3R,6S)-3-(tert-Butyldimethylsilanyloxy)-6-hydroxy-2,2,6-trimethyl-
cyclohexyl]-but-3-en-2-one (16):
A mixture of diethyl 2-oxopropyl-
phosphonate (3.80 mL, 20.0 mmol, 4.0 equiv) and Ba(OH)2·8H2O (2.50 g,
8.0 mmol, 1.6 equiv, heated at 1408C for 2 h under a flux of argon before
use) in THF (60 mL) was stirred at RT for 45 min under an argon atmos-
phere. A solution of 8 (1.50 g, 5.0 mmol) in wet THF (40 mL, 40:1 THF/
H2O) was added at this temperature. After stirring for 18 h at RT, the re-
action mixture was diluted with Et2O, washed with aqueous NaHCO3,
and brine. The organic extract was dried with MgSO4, concentration in
vacuo, purified by flash chromatography and recrystallized (Et2O/
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(10.15 g, 27.3 mmol, 6.0 equiv) was placed in a three-necked flask con-
taining a stirring bar and evacuated (ca. 0.1 Torr). The apparatus was
heated at 808C for 4 h, then the temperature was increased slowly to
1408C and maintained for 5 h. The white solid was cooled to RT, the ap-
paratus was blanketed with argon, THF (25 mL) was added, and the mix-
ture was stirred for 12 h at RT. Methyllithium (1.6m in Et2O, 17.1 mL,
27.3 mmol, 6.0 equiv) was added dropwise at À788C to the resulting mix-
ture. After 1 h at À788C, a solution of 9 (1.30 g, 4.6 mmol) in THF
(10 mL) was added dropwise and the reaction mixture was allowed to
rise to RT. After 18 h, the reaction mixture was diluted with Et2O,
poured in aqueous saturated NH4Cl and extracted with Et2O. The organic
layers were combined, washed with H2O, brine, and dried with MgSO4.
Concentration in vacuo and purification by column chromatography gave
compound 14 (1.06 g, 76% yield) as a white powder. M.p. 103–1048C;
[a]2D5 =À9.0 (c 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=4.16–4.10
(m, 2H), 3.24 (dd, J=11.2, 3.9 Hz, 1H), 2.26 (brs, 2H), 1.99–1.81 (m,
1H), 1.70–1.62 (m, 1H), 1.55–1.41 (m, 2H), 1.35 (s, 3H), 1.15 (s, 3H),
1.01 (s, 3H), 1.01–0.96 (m, 1H; partially overlapped), 0.91 (s, 9H), 0.07
(s, 3H), 0.05 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=78.5 (CH),
73.2 (C), 60.8 (CH2), 52.6 (CH), 39.9 (C), 39.0 (CH2), 30.5 (CH3), 28.1
(CH3), 27.2 (CH2), 25.9 (3ꢄCH3), 18.1 (C), 17.2 (CH3), À3.9 (CH3),
À4.9 ppm (CH3); IR (KBr): n˜ =3381, 2921, 1227, 1036 cmÀ1; HRMS
(ESI): m/z calcd for C16H35O3Si+: 303.2350 [M+H]+; found: 303.2349.
hexane) to give 16 (1.50 g, 88%) as a white solid. M.p. 91–928C; [a]D25
=
1
+1.5 (c 1.0 in CHCl3); H NMR (300 MHz, CDCl3): d=6.97 (dd, J=16.2,
10.4 Hz, 1H), 6.03 (d, J=16.2 Hz, 1H), 3.27 (dd, J=11.3, 3.8 Hz, 1H),
2.32 (s, 3H), 1.95–1.70 (m, 2H), 1.73 (d, J=10.4 Hz, 1H), 1.60–1.45 (m,
2H), 1.35 (brs, 1H), 1.07 (s, 3H), 1.02 (s, 3H), 0.90 (s, 9H), 0.83 (s, 3H),
0.07 (s, 3H), 0.06 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=198.7 (C),
146.5 (CH), 135.0 (CH), 78.2 (CH), 71.1 (C), 58.1 (CH), 39.6 (C), 39.0
(CH2), 31.2 (CH3), 28.4 (CH3), 27.0 (CH2), 26.6 (CH3), 25.8 (3ꢄCH3),
18.0 (C), 15.6 (CH3), À4.0 (CH3), À5.0 ppm (CH3); IR (KBr): n˜ =3352,
3016, 1689, 1652, 1035 cmÀ1; HRMS (ESI): m/z calcd for C19H37O3Si+:
341.2507 [M+H]+; found: 341.2506.
(4aR,6R,8aS)-tert-Butyldimethyl-(2,5,5,8a-tetramethyl-4a,5,6,7,8,8a-hex-
ahydro-4H-chromen-6-yloxy)-silane (17): A catalytic amount of 10% pal-
ladium on activated charcoal was added to a stirred solution of 16
(26 mg, 0.08 mmol) in MeOH (5 mL). The mixture was stirred under a
hydrogen atmosphere for 12 h, then the reaction mixture was filtered and
the filtrate was concentrated under reduced pressure. Purification of the
residue by column chromatography gave 17 (23 mg, 91% yield) as a col-
orless oil. 1H NMR (300 MHz, CDCl3): d=4.40 (brd, J=5.1 Hz, 1H),
3.24 (dd, J=11.3, 3.5 Hz, 1H), 2.23–2.13 (m, 1H), 2.01–1.93 (m, 1H),
1.91–1.77 (m, 2H), 1.65 (brs, 3H), 1.52–1.37 (m, 2H), 1.14 (t, J=4.1 Hz,
1H; partially overlapped), 1.14 (s, 3H), 0.90 (s, 3H), 0.89 (s, 9H), 0.80 (s,
3H), 0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
148.8 (C), 94.9 (CH), 79.2 (CH), 74.1 (C), 43.9 (CH), 40.1 (C), 37.6
(CH2), 28.1 (CH3), 27.1 (CH2), 26.4 (CH3), 26.1 (3ꢄCH3), 20.6 (CH3),
19.9 (CH2), 18.3 (C), 14.4 (CH3), À3.7 (CH3), À4.7 ppm (CH3); IR (neat):
n˜ =3019, 2925, 1246, 1019 cmÀ1; HRMS (ESI): m/z calcd for C19H37O2Si+:
325.2563 [M+H]+; found: 325.2565.
A
(15):
TBAF (1.0m in THF, 0.58 mL, 0.58 mmol, 2.0 equiv) was added dropwise
to an ice-cold solution of silyl ether 14 (88 mg, 0.29 mmol) in THF
(5 mL), under argon. After stirring for 12 h at RT, the mixture was
poured into water (5 mL), the aqueous layer was extracted with EtOAc,
then the organic layers were combined, washed with water, brine, and
dried with MgSO4. Concentration in vacuo, purification by column chro-
matography, and recrystallization (Et2O/hexane) afforded triol 15 (45 mg,
82% yield) as white crystals. M.p. 149–1508C; 1H NMR (300 MHz,
CD3OD): d=3.94 (brt, J=3.5 Hz, 2H), 3.15 (dd, J=11.9, 3.9 Hz, 1H),
1.93–1.79 (m, 1H), 1.65–1.58 (m, 1H), 1.52–1.43 (m, 2H), 1.25 (s, 3H),
1.01 (s, 3H), 0.99 (s, 3H), 0.98 ppm (t, J=3.5 Hz, 1H; partially overlap-
ped); 13C NMR (75 MHz, CD3OD): d=79.0 (CH), 73.6 (C), 60.5 (CH2),
55.0 (CH), 40.4 (C), 40.0 (CH2), 30.7 (CH3), 27.9 (CH3), 27.7 (CH2),
16.3 ppm (CH3). IR (KBr): n˜ =3374, 2925, 1505, 1224, 1019 cmÀ1; HRMS
(ESI): m/z calcd for C10H21O3+: 189.1481 [M+H]+; found: 189.1480.
4-[(1S,3R,6S)-3,6-Bis-(tert-butyldimethylsilanyloxy)-2,2,6-trimethylcyclo-
hexyl]-but-3-en-2-one (18): 2,6-Lutidine (5.10 mL, 44.1 mmol, 10.0 equiv)
followed by TBSOTf (5.10 mL, 22.0 mmol, 5.0 equiv) were added to a
stirred solution of 16 (1.50 g, 4.4 mmol) in CH2Cl2 (60 mL) at À208C.
The mixture was stirred at RT for 18 h, then diluted with CH2Cl2 (60 mL)
and stirred with 1m HCl (60 mL) for 1 h. After extraction with CH2Cl2,
the organic layer was washed with water, brine, dried with MgSO4, and
concentrated under reduced pressure. Purification of the residue by
column chromatography and recrystallization (Et2O/hexane) gave 18
(1.78 g, 89% yield) as a white solid. M.p. 88–898C; [a]2D5 =+21.7 (c 1.0 in
ACHTUNGTRENNUNG(1R,3R,6S)-3-(tert-Butyldimethylsilanyloxy)-6-hydroxy-2,2,6-trimethylcy-
1
CHCl3); H NMR (400 MHz, CDCl3): d=7.00 (dd, J=16.5, 10.3 Hz, 1H),
clohexane carbaldehyde (8): A catalytic amount of tetrapropylammoni-
um perruthenate was added to a stirred solution of 14 (2.00 g, 6.6 mmol),
N-methylmorpholine N-oxide (3.01 g, 26.4 mmol, 4.0 equiv) and pow-
dered 4 ꢅ molecular sieves in CH2Cl2 (150 mL) at RT under an argon at-
mosphere. After 45 min stirring at RT, the reaction mixture was filtered
through a short pad of Celite, and the filtrate was poured into aqueous
Na2SO3 solution. The aqueous layer was extracted with CH2Cl2, then the
organic layers were combined, washed with H2O, brine, and dried with
MgSO4. Concentration in vacuo and purification of the residue by silica
gel column chromatography and recrystallization (Et2O/hexane) afforded
5.97 (d, J=16.5 Hz, 1H), 3.24 (dd, J=11.3, 3.8 Hz, 1H), 2.30 (s, 3H),
1.95–1.75 (m, 2H), 1.64 (d, J=10.3 Hz, 1H), 1.50–1.35 (m, 2H), 1.10 (s,
3H), 1.01 (s, 3H), 0.94 (s, 9H), 0.90 (s, 9H), 0.80 (s, 3H), 0.14 (s, 3H),
0.11 (s, 3H), 0.06 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=198.7 (C), 147.9 (CH), 134.8 (CH), 78.5 (CH), 74.3 (C), 60.2 (CH),
39.5 (C), 39.0 (CH2), 31.0 (CH3), 28.2 (CH3), 27.2 (CH2), 26.0 (CH3), 26.0
(3ꢄCH3), 25.9 (3ꢄCH3), 18.4 (C), 18.1 (C), 15.6 (CH3), À1.7 (CH3), À2.1
(CH3), À3.9 (CH3), À4.9 ppm (CH3); IR (KBr): n˜ =3027, 1676, 1637,
1250, 853 cmÀ1; HRMS (ESI): m/z calcd for C25H50O3Si2Na+: 477.3191
[M+Na]+; found: 477.3191.
aldehyde 8 (1.61 g, 81% yield) as a white solid. M.p. 50–518C; [a]D25
=
+55.7 (c 1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=10.04 (d, J=
2.8 Hz, 1H), 3.31 (dd, J=11.2, 3.8 Hz, 1H), 2.81 (brs, 1H), 2.15 (d, J=
2.8 Hz, 1H), 1.98–1.80 (m, 1H), 1.70 (dt, J=14.1, 3.8 Hz, 1H), 1.55–1.30
(m, 2H), 1.19 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H), 0.90 (s, 9H), 0.07 (s,
3H), 0.06 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=207.9 (CH), 78.8
(CH), 70.7 (C), 64.4 (CH), 39.6 (C), 38.1 (CH2), 30.6 (CH3), 27.7 (CH3),
4-[(1R,3R,6S)-3,6-Bis-(tert-butyldimethylsilanyloxy)-2,2,6-trimethylcyclo-
hexyl]-butan-2-one (7): A catalytic amount of 10% palladium on activat-
ed charcoal was added to a stirred solution of 18 (1.50 g, 3.3 mmol) in
ethyl acetate (70 mL). The mixture was stirred under a hydrogen atmos-
phere for 3 h, then the reaction mixture was filtered and the filtrate was
concentrated under reduced pressure. Purification of the residue by
Chem. Eur. J. 2013, 19, 10632 – 10642
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10639

Dr. P. Brꢀmond, Prof. G. Audran et al.
column chromatography gave 7 (1.32 g, 87%) as a colorless oil. [a]D25
=
(dd, J=11.4, 3.6 Hz, 1H), 2.14–1.98 (m, 2H; partially overlapped), 2.00
(s, 3H), 1.80 (brs, 3H), 1.77–1.58 (m, 3H), 1.42–1.26 (m, 3H), 1.21 (s,
3H), 0.89 (s, 12H), 0.88 (s, 12H), 0.70 (brt, J=3.2 Hz, 1H), 0.10 (s, 6H),
0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=171.2 (C),
144.0 (C), 118.6 (CH), 79.4 (CH), 75.8 (C), 61.2 (CH2), 56.0 (CH), 40.9
(C), 39.2 (CH2), 36.1 (CH2), 30.6 (CH3), 27.7 (CH3), 27.6 (CH2), 26.2 (3ꢄ
CH3), 26.1 (3ꢄCH3), 25.2 (CH2), 23.8 (CH3), 21.2 (CH3), 18.7 (C), 18.3
(C), 15.4 (CH3), À1.5 (CH3), À1.9 (CH3), À3.7 (CH3), À4.7 ppm (CH3);
IR (neat): n˜ =3077, 1766, 1641, 1246, 1028 cmÀ1; HRMS (ESI): m/z calcd
for C29H58O4Si2Na+: 549.3766 [M++Na]+; found: 549.3766.
1
À4.5 (c 1.0 in CHCl3); H NMR (400 MHz, CDCl3): d=3.18 (dd, J=11.5,
3.8 Hz, 1H), 2.55–2.35 (m, 2H), 2.15 (s, 3H), 1.90–1.55 (m, 4H), 1.45–
1.35 (m, 2H), 1.18 (s, 3H), 0.91 (s, 3H), 0.90 (s, 18H), 0.86 (s, 3H), 0.70
(dd, J=4.3, 3.0 Hz, 1H), 0.11 (s, 6H), 0.04 (s, 3H), 0.03 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=208.9 (C), 79.1 (CH), 75.6 (C), 55.2
(CH), 47.5 (CH2), 40.8 (C), 39.0 (CH2), 30.5 (CH3), 29.6 (CH3), 27.6
(CH3), 27.3 (CH2), 26.0 (3ꢄCH3), 25.9 (3ꢄCH3), 20.2 (CH2), 18.5 (C),
18.1 (C), 15.2 (CH3), À1.7 (CH3), À2.0 (CH3), À3.9 (CH3), À4.9 (CH3);
IR (neat): n˜ =2920, 1789, 1243, 1029 cmÀ1; HRMS (ESI): m/z calcd for
C25H52O3Si2Na+: 479.3347 [M+Na]+; found: 479.3348.
5-[(1R,3R,6S)-3,6-Bis-(tert-butyldimethylsilanyloxy)-2,2,6-trimethylcyclo-
Acetic acid 1-{2-[(1R,3R,6S)-3,6-bis-(tert-butyldimethylsilanyloxy)-2,2,6-
trimethyl-cyclohexyl]-ethyl}-1-methylallyl ester (19): Vinylmagnesium
bromide (1m in THF, 3.90 mL, 3.9 mmol, 1.8 equiv) was added dropwise
to a stirred solution of 7 (1.00 g, 2.2 mmol) in THF (50 mL) at À208C
under an argon atmosphere. The mixture was stirred at À208C for
15 min, allowed to warm to 08C and the reaction was quenched by addi-
tion of aqueous saturated NH4Cl solution. After warming to RT, the re-
action mixture was extracted with Et2O and the organic layer was dried
and concentrated to give crude allylic alcohols as a colorless oil, which
was used for the next step without further purification. The solution of
allylic alcohols in THF (50 mL) was treated with Et3N (4.60 mL,
32.8 mmol, 15.0 equiv), DMAP (53 mg, 0.4 mmol, 0.2 equiv), and Ac2O
(3.10 mL, 32.8 mmol, 15.0 equiv), and heated to reflux for 2 days. After
cooling to RT, the reaction mixture was diluted with Et2O, washed with
aqueous NaHCO3, and brine, and dried. Concentration and purification
by flash chromatography gave an inseparable 60:40 mixture of diaster-
eoisomers 19 (916 mg, 79% yield from 7) as a colorless oil. 1H NMR
(400 MHz, CDCl3): d=6.02–5.94 (m, 1H; m+M), 5.19–5.11 (m, 2H; m+
M), 3.17 (m, 1H; m+M), 2.02 (s, 3H; m+M), 1.90–1.60 (m, 4H; m+
M), 1.56 (s, 3H; m), 1.55 (s, 3H; M), 1.45–1.25 (m, 4H; m+M), 1.16 (s,
3H; m+M), 0.90 (s, 9H; m+M), 0.89 (s, 9H; m+M), 0.88 (s, 3H; m+
M), 0.84 (s, 3H; m+M), 0.64 (dd, J=6.7, 2.9 Hz, 1H; m+M), 0.10 (s,
6H; m+M), 0.04 (s, 3H; m+M), 0.03 ppm (s, 3H; m+M); 13C NMR
(75 MHz, CDCl3): d=169.9 (C, m+M), 142.1 (CH, m), 141.9 (CH, M),
113.1 (CH2, M), 113.0 (CH2, m), 83.3 (C, M), 83.2 (C, m), 79.2 (CH, m+
M), 75.8 (C, m+M), 55.4 (CH, m+M), 43.5 (CH2, M), 43.3 (CH2, m),
41.0 (C, m+M), 39.1 (CH2, m+M), 30.4 (CH3, m+M), 27.5 (CH3, m+
M), 27.4 (CH2, m+M), 26.0 (3ꢄCH3, M+m), 25.9 (3ꢄCH3, M+m), 23.6
(CH3, m+M), 22.2 (CH3, m+M), 19.7 (CH2, m+M), 18.5 (C, m+M),
18.1 (C, m+M), 15.3 (CH3, m+M), À1.7 (CH3, m+M), À2.0 (CH3, m+
hexyl]-3-methylpent-2-en-1-ol (20):
A solution of (E)-6 (700 mg,
1.33 mmol) in MeOH (50 mL) at 08C was treated with K2CO3 (367 mg,
2.66 mmol, 2.0 equiv) and stirred for 2 h. The mixture was concentrated,
diluted with Et2O, filtered, and concentrated in vacuo. Purification by
flash chromatography and recrystallization (Et2O/hexane) gave 20
(529 mg, 82% yield) as a white solid. M.p. 56–578C; [a]2D5 =+1.4 (c 1.0 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=5.43 (brt, J=6.6 Hz, 1H), 4.17
(t, J=6.6 Hz, 2H), 3.19 (dd, J=11.3, 3.5 Hz, 1H), 2.10–1.97 (m, 2H),
1.84–1.63 (m, 3H; partially overlapped), 1.71 (brs, 3H), 1.44–1.34 (m,
3H), 1.19 (s, 3H), 0.90 (s, 9H), 0.89 (s, 12H), 0.86 (s, 3H), 0.70 (brt, J=
3.5 Hz, 1H), 0.10 (s, 6H), 0.04 (s, 3H), 0.03 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=140.6 (C), 123.0 (CH), 79.3 (CH), 75.8 (C), 59.4
(CH2), 55.3 (CH), 43.4 (CH2), 40.8 (C), 39.1 (CH2), 30.4 (CH3), 27.6
(CH3), 27.4 (CH2), 26.0 (3ꢄCH3), 25.9 (3ꢄCH3), 24.7 (CH2), 18.5 (C),
18.1 (C), 16.3 (CH3), 15.3 (CH3), À1.6 (CH3), À2.0 (CH3), À3.9 (CH3),
À4.9 ppm (CH3); IR (KBr): n˜ =3521, 3077, 1646, 1250, 1016 cmÀ1; HRMS
(ESI): m/z calcd for C27H56O3Si2Na+: 507.3660 [M+Na]+; found:
507.3661.
7-{5-[(1R,3R,6S)-3,6-Bis-(tert-butyldimethylsilanyloxy)-2,2,6-trimethylcy-
clohexyl]-3-methyl-pent-2-enyloxy}-chromen-2-one (21): Phosphorous tri-
bromide (49 mL, 0.52 mmol, 0.50 equiv) and pyridine (33 mL, 0.41 mmol,
0.4 equiv) in CH2Cl2 (1 mL) were added to an ice-cold solution of 20
(500 mg, 1.03 mmol) in Et2O (13 mL). The reaction was stirred for 1 h at
this temperature, then the mixture was diluted with Et2O, and washed
with aqueous NaHCO3. The organic layer was dried and concentrated to
give the crude bromide as a yellow oil, which was directly used for the
next step without further purification. The above bromide was diluted in
acetone (4 mL) and added to an ice-cold mixture of 7-hydroxycoumarin
(234 mg, 1.44 mmol, 1.4 equiv) and K2CO3 (656 mg, 4.74 mmol, 4.6 equiv)
in acetone (8 mL). The reaction was stirred for 48 h at RT, then the mix-
ture was concentrated, diluted with EtOAc, and washed with H2O. The
organic layer was dried and concentrated. Purification by flash chroma-
M), À3.9 (CH3, m+M), À4.9 ppm (CH3, m+M); IR (neat): n˜ =3037,
1771, 1652, 1250, 1023 cmÀ1; HRMS (ESI): m/z calcd for C29H62NO4Si2
544.4212 [M+NH4]+; found: 544.4212.
:
+
tography gave 21 (453 mg, 70% yield from 20) as a yellowish oil. [a]D25
=
+3.7 (c 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.64 (d, J=
9.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 6.88–6.84 (m, 2H), 6.26 (d, J=
9.5 Hz, 1H), 5.48 (brt, J=6.3 Hz, 1H), 4.62 (d, J=6.3 Hz, 2H), 3.19 (dd,
J=11.6, 3.5 Hz, 1H), 2.17–2.01 (m, 2H), 1.80 (brs, 3H),1.79–1.62 (m,
3H), 1.45–1.34 (m, 3H), 1.19 (s, 3H), 0.90 (s, 9H), 0.89 (s, 3H), 0.88 (s,
9H), 0.87 (s, 3H), 0.71 (brt, J=3.5 Hz, 1H), 0.10 (s, 3H), 0.09 (s, 3H),
0.05 (s, 3H), 0.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=162.1
(C), 161.2 (C), 155.9 (C), 143.4 (CH), 143.2 (C), 128.6 (CH), 118.1 (CH),
113.2 (CH), 112.9 (CH), 112.4 (C), 101.6 (CH), 79.2 (CH), 75.7 (C), 65.5
(CH2), 55.3 (CH), 43.3 (CH2), 40.8 (C), 39.1 (CH2), 30.5 (CH3), 27.6
(CH3), 27.4 (CH2), 26.0 (3ꢄCH3), 25.9 (3ꢄCH3), 24.6 (CH2), 18.5 (C),
18.1 (C), 16.8 (CH3), 15.3 (CH3), À1.7 (CH3), À2.0 (CH3), À3.9 (CH3),
(E)- and (Z)-Acetic acid 5-[(1R,3R,6S)-3,6-bis-(tert-butyldimethylsilany-
loxy)-2,2,6-trimethylcyclohexyl]-3-methylpent-2-enyl ester (E)-6 and (Z)-
6:
A catalytic amount of dichlorobis(acetonitrile)palladium(II) was
added to a stirred solution of 19 (900 mg, 1.71 mmol) in THF (50 mL) at
RT under an argon atmosphere. After stirring for 5 h at RT, the solution
mixture was filtered through a short pad of silica gel, washed with Et2O,
and concentrated to give a yellow oil, which was purified by flash chro-
matography to give pure E-diastereoisomer (E)-6 (720 mg, 80% yield)
and pure Z-diastereoisomer (Z)-6 (107 mg, 12% yield) as a colorless oil.
Compound (E)-6: [a]2D5 =+2.3 (c 1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.35 (brt, J=7.0 Hz, 1H), 4.60 (d, J=7.0 Hz, 2H), 3.18 (dd,
J=11.5, 3.5 Hz, 1H), 2.12–1.98 (m, 2H; partially overlapped), 2.07 (s,
3H), 1.84–1.63 (m, 3H; partially overlapped), 1.74 (brs, 3H), 1.44–1.34
(m, 3H), 1.18 (s, 3H), 0.90 (s, 9H), 0.89 (s, 12H), 0.86 (s, 3H), 0.69 (dd,
J=3.9, 2.9 Hz, 1H), 0.10 (s, 6H), 0.04 (s, 3H), 0.03 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=171.1 (C), 143.1 (C), 118.0 (CH), 79.3
(CH), 75.8 (C), 61.4 (CH2), 55.3 (CH), 43.3 (CH2), 40.8 (C), 39.1 (CH2),
30.5 (CH3), 27.6 (CH3), 27.4 (CH2), 26.0 (3ꢄCH3), 25.9 (3ꢄCH3), 24.6
(CH2), 21.0 (CH3), 18.5 (C), 18.1 (C), 16.5 (CH3), 15.3 (CH3), À1.7
(CH3), À2.0 (CH3), À3.9 (CH3), À4.9 ppm (CH3). IR (neat): n˜ =3051,
1764, 1646, 1243, 1020 cmÀ1; HRMS (ESI): m/z calcd for C29H58O4Si2Na+:
549.3766 [M+Na]+; found: 549.3766.
À4.9 ppm (CH3); IR (neat): n˜ =3070, 1754, 1621, 1132 cmÀ1; HRMS
+
(ESI): m/z calcd for C36H64NO5Si2
:
646.4318 [M+NH4]+; found:
646.4315.
7-{5-[(1R,3R,6S)-6-(tert-Butyldimethylsilanyloxy)-3-hydroxy-2,2,6-trime-
thylcyclohexyl]-3-methyl-pent-2-enyloxy}-chromen-2-one (22): In
a
Teflon round-bottomed flask, HF·pyridine complex (70 wt.% HF,
0.20 mL, 7.95 mmol, 50.0 equiv) was carefully added to an ice-cold solu-
tion of silyl ether 21 (100 mg, 0.16 mmol) in THF (4 mL) under an argon
atmosphere and the mixture was heated at 408C for 24 h. The reaction
mixture was poured into a saturated aqueous NaHCO3 solution, then the
aqueous layer was extracted with Et2O, and the combined organic layers
were washed with saturated aqueous NaHCO3, water, brine, dried over
Compound (Z)-6: [a]2D5 =À4.8 (c 1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.34 (brt, J=7.1 Hz, 1H), 4.56 (brd, J=7.4 Hz, 2H), 3.18
10640
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10632 – 10642

Synthesis of Kopeolin and Kopeolone
FULL PAPER
MgSO4, and concentrated. After purification by column chromatography,
7.64 (d, J=9.3 Hz, 1H; H-C16), 7.37 (d, J=8.5 Hz, 1H; H-C14), 6.85 (dd,
J=8.5, 2.2 Hz, 1H; H-C13), 6.82 (d, J=2.2 Hz, 1H; H-C20), 6.25 (d, J=
9.3 Hz, 1H; H-C17), 5.51 (brt, J=6.5, 1H; H-C10), 4.60 (d, J=6.5 Hz, 2H;
H-C11), 3.07 (td, J=14.2, 5.8 Hz, 1H; Hax-C4), 2.19–2.14 (m, 2H; Heq-C4
and H-C8), 2.09 (td, J=12.1, 5.1 Hz, 1H; H-C8), 1.97 (ddd, J=14.2, 5.8,
2.8 Hz, 1H; Heq-C5), 1.82 (td, J=14.2, 4.3 Hz, 1H; Hax-C5, partially over-
lapped), 1.80 (brs, 3H, CH3-C9), 1.75 (ddt, J=14.6, 11.5, 5.1 Hz, 1H; H-
C7), 1.54 (dddd, J=14.6, 12.1, 5.6, 2.6 Hz, 1H; H-C7), 1.29 (s, 3H; CH3-
C6), 1.26 (dd, J=5.1, 2.6 Hz, 1H; H-C1), 1.23 (s, 3H; CH3ax-C2), 1.04 ppm
(s, 3H; CH3eq-C2); 13C NMR (100 MHz, CDCl3): d=215. 9 (C-3), 162.1
(C-12), 161.2 (C-18), 155.9 (C-19), 143.4 (CH-16), 142.6 (C-9), 128.7 (CH-
14), 118.8 (CH-10), 113.2 (CH-13), 113.0 (CH-17), 112.5 (C-15), 101.6
(CH-20), 72.2 (C-6), 65.4 (CH2-11), 54.3 (CH-1), 49.0 (C-2), 42.5 (CH2-8),
alcohol 22 (65 mg, 79% yield) was obtained as a yellowish foam. [a]D25
=
+8.1 (c 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.64 (d, J=
9.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.86 (dd, J=8.4, 2.4 Hz, 1H), 6.84
(d, J=2.4 Hz, 1H), 6.25 (d, J=9.4 Hz, 1H), 5.48 (brt, J=6.3 Hz, 1H),
4.62 (d, J=6.3 Hz, 2H), 3.23 (dd, J=11.4, 3.9 Hz, 1H), 2.18–2.04 (m,
2H), 1.80 (brs, 3H), 1.79–1.62 (m, 3H), 1.60–1.34 (m, 3H), 1.20 (s, 3H),
0.96 (s, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.74 (dd, J=4.3, 2.5 Hz, 1H), 0.10
(s, 3H), 0.09 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=162.1 (C),
161.3 (C), 155.9 (C), 143.4 (CH), 143.0 (C), 128.7 (CH), 118.2 (CH),
113.2 (CH), 112.9 (CH), 112.4 (C), 101.6 (CH), 78.7 (CH), 75.8 (C), 65.4
(CH2), 55.1 (CH), 43.2 (CH2), 40.2 (C), 39.1 (CH2), 30.3 (CH3), 27.0
(CH2), 26.9 (CH3), 26.0 (3ꢄCH3), 24.5 (CH2), 18.5 (C), 16.8 (CH3), 15.0
(CH3), À1.7 (CH3), À2.0 ppm (CH3); IR (KBr): n˜ =3464, 3035, 1729,
40.5 (CH2-5), 34.0 (CH2-4), 30.1 (CH3-C-6), 24.3 (CH2-7), 23.6 (CH3eq
-
1624, 1137, 890 cmÀ1 HRMS (ESI): m/z calcd for C30H46O5SiNa+:
;
C-2), 22.0 (CH3ax-C-2), 16.9 ppm (CH3-C-9); IR (KBr): n˜ =3475, 2910,
+
1730, 1705, 1603, 1128, 890 cmÀ1; HRMS (ESI): m/z calcd for C24H31O5
399.2166 [M+H]+; found: 399.2166.
:
537.3007 [M+Na]+; found: 537.3007.
7-{5-[(1R,3R,6S)-3,6-Dihydroxy-2,2,6-trimethylcyclohexyl]-3-methyl-
pent-2-enyloxy}-chromen-2-one (1) by deprotection of 22: In a Teflon
round-bottomed flask, KF (9 mg, 0.16 mmol, 4.0 equiv) and 18-crown-6
(42 mg, 0.16 mmol, 4.0 equiv) were carefully added to a stirred solution
of silyl ether 22 (20 mg, 0.039 mmol, 1 equiv) in anhydrous DMSO
(10 mL) under an argon atmosphere, and the mixture was heated at
1258C for 3 days. The reaction mixture was poured into saturated aque-
ous NaHCO3 solution, then the aqueous layer was extracted with EtOAc,
and the combined organic layers were washed with saturated aqueous
NaHCO3, water, brine, dried over MgSO4, and concentrated. After purifi-
cation by column chromatography, 1 (8.1 mg, 52% yield) was obtained as
Calculations: All calculations were performed with the Gaussian 09, revi-
sion C01, suites of program.[20] Structures of the compounds were calcu-
lated at the B3LYP[21] level using the 6-311G+ +(d,p) basis set.
Acknowledgements
1
We thank Prof. S. Y. Ryu for kindly providing copies of H and 13C NMR
spectra of natural kopeolin. S. M. thanks the Ministꢆre de l’Education
Nationale, de l’Enseignement Supꢀrieur et de la Recherchefor her Ph.D.
grant. The authors are thankful to Dr. R. Faure for 2D NMR analyses, to
Dr. M. Giorgi for X-ray diffraction analyses, to Prof. M. Santelli for cal-
culations, and to CNRS and Aix-Marseille Universitꢀ for their financial
support. P. Fournier is gratefully acknowledged for the English revision
of the manuscript.
a
yellowish foam. [a]2D5 =+7 (c 1.0 in EtOH); 1H NMR (400 MHz,
CDCl3): d=7.64 (d, J=9.4 Hz, 1H; H-C16), 7.36 (d, J=8.5 Hz, 1H; H-
C14), 6.86 (dd, J=8.5, 2.3 Hz, 1H; H-C13), 6.84 (d, J=2.3 Hz, 1H; H-C20),
6.25 (d, J=9.4 Hz, 1H; H-C17), 5.50 (brt, J=6.5 Hz, 1H; H-C10), 4.60 (d,
J=6.5 Hz, 2H; H-C11), 3.26 (dd, J=11.8, 3.9 Hz, 1H; H-C3), 2.17 (td, J=
12.7, 5.2 Hz, 1H; H-C8), 2.10 (td, J=12.7, 5.8 Hz, 1H; H-C8), 1.81 (brs,
3H; CH3-C9), 1.81 (qd, J=11.8, 3.9 Hz, 1H; partially overlapped,
Hax-C4), 1.69 (dt, J=13.9, 3.9 Hz, 1H; Heq-C5), 1.62 (m, 2H; H-C7 and
[1] a) A. F. Barrero, E. J. R. Alvarez-Manzaneda, R. Alvarez-Manzane-
da, Tetrahedron Lett. 1989, 30, 3351–3352; b) A. F. Barrero, E. A.
Manzaneda, R. A. Manzaneda, S. Arseniyadis, E. Guittet, Tetrahe-
dron 1990, 46, 8161–8168; c) J. A. Marco, J. F. Sanz, A. Yuste, M.
Carda, J. Jakupovic, Phytochemistry 1991, 30, 3661–3668; d) J. A.
Marco, J. F Sanz-Cervera, M. D. Morante, V. Garcia-Lliso, J. Valles-
Xirau, J. Jakupovic, Phytochemistry 1996, 41, 837–844; e) A. F. Bar-
rero, A. Haidour, M. MuÇoz-Dorado, M. Akssira, A. Sedqui, I.
Mansour, Phytochemistry 1998, 48, 1237–1240; f) T. Akihisa, K.
Arai, Y. Kimura, K. Koike, W. C. M. C. Kokke, T. T. Nikaido, J. Nat.
Prod. 1999, 62, 265–268; g) A. F. Barrero, E. J. Alvarez-Manzaneda,
M. M. Herrador, R. Alvarez-Manzaneda, J. Quilez, R. Chahboun, P.
Linares, A. Rivas, Tetrahedron Lett. 1999, 40, 8273–8276; h) T. Aki-
hisa, K. Akai, Y. Kimura, K. Koike, W. C. M. C. Kokke, T. Shibata,
T. Nikaido, Lipids 1999, 34, 1151–1157.
[2] K. M. Kamilov, G. K. Nikonov, Khim. Prir. Soedin. 1973, 9, 308–
313.
[3] A. A. Nabiev, T. K. Khasanov, V. M. Malikov, Khim. Prir. Soedin.
1982, 17, 48–51.
[4] A. I. Saidkhozhaev, D. U. Mukumova, K. M. Kamilov, V. M. Mali-
kov, M. G. Pimenov, Khim. Prir. Soedin. 1991, 27, 283–284.
[5] K. M. Nadkarni, India Materia Medica, Vol. 1 and 2, Popular Praka-
shan, Bombay, 1954.
H
eq-C4), 1.53 (td, J=13.9, 3.9 Hz, 1H; Hax-C5), 1.51–1.44 (m, 1H; H-C7),
1.19 (s, 3H; CH3-C6), 1.01 (s, 3H; CH3eq-C2), 0.95 (s, 3H; CH3ax-C2),
0.86 ppm (brt, J=2.8 Hz, 1H; H-C1); 13C NMR (100 MHz, CDCl3): d=
162.3 (C-12), 161.4 (C-18), 156.0 (C-19), 143.6 (CH-16), 142.7 (C-9), 128.9
(CH-14), 118.6 (CH-10), 113.4 (CH-13), 113.2 (CH-17), 112.6 (C-15),
101.7 (CH-20), 78.6 (CH-3), 72.6 (C-6), 65.6 (CH2-11), 53.2 (CH-1), 43.3
(CH2-8), 40.5 (C-2), 39.2 (CH2-5), 30.7 (CH3-C-6), 27.1 (CH3eq-C-2), 27.0
(CH2-4), 24.2 (CH2-7) 17.1 (CH3-C-9), 14.8 ppm (CH3ax-C-2); IR (neat):
n˜ =3461, 2923, 1718, 1628, 1141, 892 cmÀ1; HRMS (ESI): m/z calcd for
C24H33O5+: 401.2323 [M+H]+; found: 401.2319.
Synthesis of 1 by reduction of ketone 3: NaBH4 (5.6 mg, 0.15 mmol,
3 equiv) was added to a stirred solution of ketone 3 (20 mg, 0.050 mmol)
in MeOH (10 mL) at À788C under an argon atmosphere. The reaction
mixture was stirred for an additional 30 min before being concentrated
under reduced pressure to provide a residue that was partitioned be-
tween water and Et2O. The aqueous layer was extracted with Et2O and
the combined organic layers were dried over MgSO4 and concentrated in
vacuo. After purification by column chromatography, pure alcohol 1
(17.2 mg, 86%) was obtained as a yellowish foam. Physical data were
identical to those described above.
7-{5-[(1R,6S)-6-Hydroxy-2,2,6-trimethyl-3-oxocyclohexyl]-3-methylpent-
2-enyloxy}-chromen-2-one (3): A catalytic amount of tetrapropylammoni-
um perruthenate was added to an ice-cold solution of
1 (30 mg,
[6] Personal communication from Prof. Shi Yong Ryu.
0.07 mmol), N-methylmorpholine N-oxide (33 mg, 0.28 mmol, 4.0 equiv),
and powdered 4 ꢅ molecular sieves in CH2Cl2 (5 mL) under an argon at-
mosphere. After 40 min stirring at 08C, the reaction mixture was filtered
through a short pad of Celite, and the filtrate was poured into aqueous
Na2SO3 solution. The aqueous layer was extracted with CH2Cl2, then the
organic layers were combined, washed with water and brine, and dried
with MgSO4. Concentration in vacuo and purification of the residue by
silica gel column chromatography and recrystallization (Et2O/hexane) af-
forded kopeolone 3 (26 mg, 87% yield) as white crystals. M.p. 105–
1068C; [a]2D5 =+32.0 (c 0.8 in EtOH); 1H NMR (400 MHz, CDCl3): d=
[7] E. Palombo, G. Audran, H. Monti, Synlett 2006, 403–406.
[8] a) H. Monti, G. Audran, Mini-Rev. Org. Chem. 2005, 2, 265–281;
b) J.-P. Uttaro, G. Audran, H. Monti, J. Org. Chem. 2005, 70, 3484–
3489; c) E. Palombo, G. Audran, H. Monti, Synlett 2005, 2104–2106;
d) E. Palombo, G. Audran, H. Monti, Tetrahedron 2005, 61, 9545–
9549; e) P. Brꢀmond, G. Audran, T. Juspin, H. Monti, Eur. J. Org.
Chem. 2007, 2802–2807; f) P. Brꢀmond, G. Audran, H. Monti, J.
Org. Chem. 2008, 73, 6033–6036.
[9] K. Isobe, K. Mohri, H. Sano, J.-I. Taga, Y. Tsuda, Chem. Pharm.
Bull. 1986, 34, 3029–3032.
Chem. Eur. J. 2013, 19, 10632 – 10642
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10641

Dr. P. Brꢀmond, Prof. G. Audran et al.
[10] Diastereoselective protonation: N. Krause, S. Ebert, A. Haubrich,
Liebigs Ann. 1997, 2409–2418; enantioselective protonation: C.
Fehr, Angew. Chem. 1996, 108, 2726–2748; Angew. Chem. Int. Ed.
Engl. 1996, 35, 2566–2587.
[11] a) T. Imamoto, T. Kusumoto, Y. Tawarayama, Y. Sugiura, T. Mita, Y.
Hatanaka, M. Yokoyama, J. Org. Chem. 1984, 49, 3904–3912;
b) G. A. Molander, Chem. Rev. 1992, 92, 29–68; c) V. Dimitrov, K.
Kostova, M. Genov, Tetrahedron Lett. 1996, 37, 6787–6790; d) L. A.
Paquette in Encyclopedia of Reagents for Organic Synthesis, Vol. 2,
Wiley, Chichester, 1995, pp. 1031–1034; e) review: T. Imamoto in
Comprehensive Organic Synthesis, Vol. 1 (Eds.: B. M. Trost, I. Flem-
ing), Pergamon, Oxford, 1991, pp. 231–250.
Engl. 1984, 23, 579–587; e) J. Tsuji, Palladium Reagents and Cata-
lysts, Wiley, Chichester, 1999, pp. 399–404.
[16] a) C. Tsangarakis, E. Arkoudis, C. Raptis, M. Stratakis, Org. Lett.
2007, 9, 583–586; b) C. Tsangarakis, C. Raptis, E. Arkoudis, Adv.
Synth. Catal. 2008, 350, 1587–1600.
[17] T. W. Greene, P. G. M. Wuts, Protective Group in Organic Synthesis,
4th ed., Wiley, Hoboken, 2006, pp. 196–211.
[18] K. C. Nicolaou, S. P. Seitz, M. R. Pavia, N. A. Petasis, J. Org. Chem.
1979, 44, 4011–4013.
[19] M. E. Jung, P. Davidov, Angew. Chem. 2002, 114, 4299–4302;
Angew. Chem. Int. Ed. 2002, 41, 4125–4128.
[20] Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X.
Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Son-
nenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Ko-
bayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Po-
melli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzew-
ski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D.
Daniels, O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J.
Fox, Gaussian, Inc., Wallingford CT, 2010.
[12] CCDC- 902846 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[13] W. P. Griffith, S. V. Ley, Aldrichimica Acta 1990, 23, 13–19.
[14] a) M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masa-
mune, W. R. Rouch, T. Sakai, Tetrahedron Lett. 1984, 25, 2183–
2186; b) M. W. Rathke, M. Nowak, J. Org. Chem. 1985, 50, 2624–
2626; c) I. Paterson, K.-S. Yeung, J. B. Smaill, Synlett 1993, 774–776;
d) K. Ando, T. Oishi, M. Hirama, H. Ohno, T. Ibuka, J. Org. Chem.
2000, 65, 4745–4749; e) L. K. Blasdel, A. G. Myers, Org. Lett. 2005,
7, 4281–4283; reviews: f) S. E. Kelly in Comprehensive Organic Syn-
thesis, Vol. 1 (Eds: B. M. Trost, I. Fleming), Pergamon, New York,
1991, pp. 729–817; g) B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989,
89, 863–927.
[21] a) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[15] a) L. E. Overman, F. M. Knoll, Tetrahedron Lett. 1979, 20, 321–324;
b) L. E. Overman, F. M. Knoll, J. Am. Chem. Soc. 1980, 102, 865–
867 Reviews: c) R. P. Lutz, Chem. Rev. 1984, 84, 205–247; d) L. E.
Overman, Angew. Chem. 1984, 96, 565–573; Angew. Chem. Int. Ed.
Received: February 22, 2013
Published online: June 27, 2013
10642
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10632 – 10642