Revised structure, total synthesis, and absolute configuration of kopeolin and kopeolone

Article abstract of DOI:10.1021/jo402572b

An enantioselective total synthesis of two sesquiterpenoids, kopeolin and kopeolone, has been achieved. Using the diastereoselective addition of an organocerate as a key step, we controlled the absolute stereochemistry of a crucial stereocenter present in these natural products. This approach allowed us to confirm a structural revision that we previously proposed (Chem. - Eur. J. 2013, 19, 10632-10642) and to fully characterize these natural products while elucidating their absolute stereochemistry.

Full text of DOI:10.1021/jo402572b

Note
pubs.acs.org/joc
Revised Structure, Total Synthesis, and Absolute Configuration of
Kopeolin and Kopeolone
Stephanie Miquet, Paul Bremond,* Benjamin Ayela, Sylvain R. A. Marque, and Gerard Audran*
́
́
́
Aix Marseille Universite,
́
CNRS, ICR UMR 7273, 13397, Marseille, France
S
* Supporting Information
ABSTRACT: An enantioselective total synthesis of two
sesquiterpenoids, kopeolin and kopeolone, has been achieved.
Using the diastereoselective addition of an organocerate as a
key step, we controlled the absolute stereochemistry of a
crucial stereocenter present in these natural products. This
approach allowed us to confirm a structural revision that we previously proposed (Chem.Eur. J. 2013, 19, 10632−10642) and
to fully characterize these natural products while elucidating their absolute stereochemistry.
n 1973, the isolation of the sesquiterpenoid coumarins1
kopeolin and kopeolone from the roots of Ferula
kopetdaghensis was reported. In 1982, structures 1 and 2
(Figure 1) were proposed for these natural products on the
stereocenters. We planned to use an enantiopure building
block, (1R,5R)-8,8-dimethyl-2,7-dioxo-6-oxabicyclo[3.2.1]-
octane (4), for the introduction of the stereocenter at C-6, as
this key intermediate already contains two of the required
stereocenters present in the natural products. Moreover, the
bicyclo[3.2.1]octane skeleton of 4 presents a unique and rigid
conformation and could undergo a diastereoselective reaction
affording the formation of the required stereocenter of the
target compounds. DFT calculations supported this assumption
(see Figure 2 and the Supporting Information). Thus, the
I
Figure 1. Proposed structures 1 for kopeolin and 2 for kopeolone, the
structure of farnesiferol C (3), and the revised structures 1′ for
kopeolin and 2′ for kopeolone as determined in this work.
Figure 2. Optimized conformation of ketone 4 [calculated using the
B3LYP/6-311G++(d,p) method] showing the accessibility of the red
lobe for the diastereoselective alkylation by MeCeCl2.
1
basis of a comparison with the H NMR spectrum of the
known compound farnesiferol C (3), which was obtained after
dehydration of kopeolin with H2SO4.2 Recently, kopeolin
showed strong inhibition of the proliferation of cultured human
cells.3 In the course of our work directed toward the
enantioselective synthesis of sesquiterpene natural products,4
we recently developed a synthetic pathway to prepare these
proposed structures 1 and 2.5 However, the synthetic materials
1 and 2 did not match the reported data for natural kopeolin
and kopeolone, strongly suggesting a structural misassignment
during the isolation of the natural products.
We supposed that the misassignment occurred at the
stereocenter at C-6 bearing the tertiary alcohol present in
kopeolin and kopeolone.5 Consequently, this stereocenter in
the proposed structures 1 and 2 should be reversed to its C-6
epimer, as depicted in the revised structures 1′ and 2′ (Figure
1). Therefore, we focused our attention on proposing a new
synthetic strategy to synthesize 1′ and 2′ with full control of all
approach of the reagent to the bicyclic system would be realized
from the less-hindered endo face because of the presence of the
methyl substituent in the axial position on the exo face.
Moreover, possible Lewis acid/base interactions between the
organometallic reagent and a lone pair of the oxygen atom of
the lactone would also favor the approach on the endo face.
We previously reported a practical synthetic pathway for
synthesizing the required enantiopure building block 4 (nine
steps and 39% overall yield from commercially available 3-
methylanisole) or its enantiomer using a chemoenzymatic
process.6 Thus, starting from 4, addition of methylcerium
Received: November 21, 2013
Published: February 17, 2014
© 2014 American Chemical Society
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dichloride in THF proceeded with complete stereoselectivity,
Scheme 2. Synthesis of the Revised Kopeolin Structure 1′
affording alcohol 5 in 82% yield (Scheme 1).7 Protection of the
Scheme 1. Synthesis of Ketone 9
alcohol with chloromethyl methyl ether (MOMCl) in the
presence of Hunig’s base8 followed by reduction of the lactone
̈
with LiAlH4 afforded crystalline diol 6 in 84% yield over the
two steps. The structure of 6, and therefore the one of 5, was
secured by X-ray crystallography.9 Selective oxidation of the
primary hydroxyl function of 6 via the biphasic Anelli−
Montanari protocol using TEMPO/NaOCl as the oxidizing
agent gave exclusively the hydroxy aldehyde 7 in 85% yield.10
To elaborate the coumarin side chain, the Horner−Wads-
worth−Emmons (HWE) reaction was selected because it can
prevent epimerization as a result of its mild conditions.5,11
However, the reaction of 7 with diethyl 2-oxopropylphosph-
onate and Ba(OH)2 failed whether the OH group was
protected as a TBS ether or not, and the unreacted starting
material was recovered. As a consequence, we turned our
attention toward more reactive conditions. Aldehyde 7 was
then subjected to a Wittig reaction with 1-(triphenylphosphor-
anylidene)-2-propanone in refluxing toluene, which furnished
α,β-unsaturated ketone 8 in 85% yield as a single E isomer12
without any detectable amount of the epimerized compound.
Reduction of the double bond of 8 with H2 in the presence of
Pd/C in MeOH followed by protection of the alcohol with
TBSOTf in the presence of triethylamine in CH2Cl2 afforded
the corresponding TBS ether 9 in 96% yield over the two steps.
During the TBS-protection step, concomitant formation of the
silyl enol ether of the ketone was also observed, and this was
hydrolyzed upon acidic aqueous workup, providing exclusively
compound 9.
With 9 in hand, we planned to use the same methodology
employed for the synthesis of the structures 1 and 2 proposed
for the natural products, which is a Pd-catalyzed rearrangement
of a tertiary allylic acetate to elaborate the side chain of 1′ and
2′ with high E stereoselectivity.13 Thus, subsequent treatment
of 9 with vinylmagnesium bromide afforded tertiary allylic
alcohol 10 in 97% yield (Scheme 2). Treatment of 10 with
acetic anhydride/triethylamine in the presence of N,N-
dimethylaminopyridine (DMAP) in THF yielded the corre-
sponding tertiary allylic acetate. Unfortunately, treatment of the
tertiary allylic acetate with dichlorobis(acetonitrile)palladium
did not give the desired rearranged primary acetate but instead
led exclusively to the cyclic tetrahydropyran derivative 11 in
70% yield over the two steps as a 3:1 diastereomeric mixture.
The formation of the undesired product 11 could be explained
by intramolecular nucleophilic attack of the MOM group to the
π-allylpalladium intermediate, forming a stable six-membered
ring.
To circumvent this issue, reaction of the diastereomeric
mixture of tertiary allylic alcohol 10 with PBr3 in the presence
of pyridine in a mixture of Et2O/pentane resulted in the
formation of the unstable rearranged bromide 12, which was
immediately treated with umbelliferone and K2CO3 in acetone
(Scheme 2).14 Thus, the coupling reaction provided the two
coumarin derivatives (E)-13 and (Z)-13 in a 70:30 ratio in
favor of (E)-13. Fortunately, (E)-13 and (Z)-13 differ
significantly in polarity and therefore proved to be chromato-
graphically separable at this stage. A careful silica gel column
chromatography separation performed using a gradient of
petroleum ether/ethyl acetate gave a 21% yield of (Z)-13 (first
eluted) and 49% yield of (E)-13 (second eluted) over two
steps. The double-bond stereochemistries of (E)-13 and (Z)-13
were assigned using 2D NOESY experiments (see the
Supporting Information). To complete the synthesis of
kopeolin, desilylation of (E)-13 was accomplished with HF·
pyridine complex15 in THF, affording 14 in 84% yield.
Deprotection of the MOM group16 was then achieved by
treatment of 14 with a methanolic HCl solution, affording 1′ as
a solid in 80% yield. To optimize the synthesis, simultaneous
removal of the two protecting groups of (E)-13 was also
accomplished by methanolic HCl treatment with an extended
reaction time, affording 1′ in 85% yield.
The spectral data (IR, 1H and 13C NMR, HRMS) of
synthetic 1′ matched the data reported for natural kopeolin1,3
(see the NMR spectra of natural kopeolin provided by Prof.
Ryu and the comparison of the NMR data of natural kopeolin
and 1′ in Table 1 in the Supporting Information), and the
specific rotation was the same in sign and comparable in
magnitude {1′: [α]2D5 −12 (c 1.0, EtOH); lit. [α]2D5 −16 (c 1.0,
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raphy were performed with silica gel 60 (230−400 mesh) and
EtOH)}, confirming the synthesis of the natural enantiomer.
The high optical purity of 1′ was confirmed using chiral HPLC
by comparison with a racemic sample (see the Supporting
Information).17 Therefore, the absolute configuration of natural
kopeolin was determined to be (1R,3R,6R) as depicted for 1′ in
Scheme 3 and Figure 1.
gradients of Et2O/petroleum ether or CH2Cl2/MeOH as eluents,
1
unless otherwise stated. H and 13C NMR spectra were recorded in
CDCl3 or MeOH-d4 solutions on a 300 or 400 MHz spectrometer.
Chemical shifts (δ) in parts per million are reported using residual
nondeuterated solvents as internal references to calibrate the spectra
(CHCl3 7.26 ppm, MeOH 3.31 ppm for 1H NMR; CDCl3 77.16 ppm,
MeOH-d4 49.00 ppm for 13C NMR). Multiplicities are indicated by
one or more of the following: s (singlet), d (doublet), t (triplet), q
(quartet), quint (quintet), m (multiplet), br (broad). Optical rotations
were measured on a standard polarimeter. Melting points are
uncorrected. Infrared spectra were obtained from films or KBr pellets
using a standard IR spectrophotometer. High-resolution mass
spectrometry (HRMS) was performed using a high-resolution mass
spectrometer equipped with pneumatically assisted atmospheric
pressure ionization. Samples were ionized by positive-mode electro-
spray under the following conditions: electrospray voltage (ISV), 2800
V; orifice voltage (OR), 20 V; nebulizing gas flow (nitrogen), 800 L/h.
The mass spectra were obtained using a time-of-flight analyzer (TOF).
The measurements were realized in triplicate with double internal
standardization. Each sample was dissolved in CH2Cl2 (450 μL) and
then diluted (dilution factor 1/103) in a methanolic solution of
ammonium acetate (3 mM). The sample solution was infused into the
ionization source at a flow rate of 10 μL/min. Enantiomeric excesses
(ee) were determined by chiral HPLC (Chiralpak IA, hexane/ethanol
(6/4), 1 mL/min) by comparison with a racemic sample.
Scheme 3. Synthesis of the Revised Kopeolone Structure 2′
With 1′ in hand, our attention was then focused on the
synthesis of 2′. To this end, we oxidized the secondary alcohol
of 1′ with TPAP/NMO18 in CH2Cl2, which afforded 2′ in 91%
yield (Scheme 3). Reduction of 2′ with NaBH4 using the same
conditions described in the literature2 afforded exclusively and
cleanly kopeolin 1′ in 85% yield. The 1H NMR spectrum of 2′
was identical to the one reported for natural kopeolone (see the
comparison of the NMR data of natural kopeolone and 2′ in
Table 2 in the Supporting Information).2 The high optical
purity of 2′ was also confirmed using chiral HPLC by
comparison with a racemic sample (see the Supporting
Information). However, the magnitude and the sign of the
specific rotation of synthetic 2′ {[α]2D5 −7 (c 1.0, EtOH)}
disagreed with that reported for natural kopeolone {lit. [α]D18
+70 (c 1.0, EtOH)}. Nevertheless, as the natural products 1′
and 2′ are isolated from the same species,1 they are undoubtely
related and share common biosynthetic pathways. Conse-
quently, the absolute configuration of natural kopeolone is
most likely to be (1R,6R) as depicted for 2′ in Scheme 3 and
Figure 1.
In conclusion, we have accomplished the first total synthesis
of natural kopeolin 1′ and kopeolone 2′ from an enantiopure
keto lactone obtained by an enantioconvergent biocatalyzed
reaction. The key step of this strategy is the diastereoselective
addition of an organocerate while controlling the stereo-
chemistry of the reassigned stereocenter present in the natural
products. The achievements of this work are the confirmation
of the revised structures, the full characterization of these
natural products, and the elucidation of the absolute stereo-
chemistry of all chiral centers present in the natural products.
(1R,2R,5R)-2-Hydroxy-2,8,8-trimethyl-6-oxabicyclo[3.2.1]-
octan-7-one (5). Finely crushed cerium(III) chloride heptahydrate
(8.64 g, 23.2 mmol, 3.0 equiv) was placed in a 500 mL three-neck flask
containing a stirring bar and evacuated (ca. 0.1 Torr). The apparatus
was heated at 80 °C for 4 h, and then the temperature was increased
slowly to 140 °C and maintained for 5 h. The white solid was cooled
to rt, and the apparatus was blanketed with argon. THF (26 mL) was
added, and the mixture was stirred for 12 h. A 1.5 M solution of
methyllithium in Et2O (15.5 mL, 23.2 mmol, 3.0 equiv) was added
dropwise at −78 °C to the resulting mixture. After 1 h at −78 °C, a
solution of 4 (1.30 g, 7.71 mmol) in THF (10 mL) was added
dropwise, and the reaction mixture was allowed to warm to rt. After 12
h, the reaction mixture was diluted with ether, poured into an aqueous
solution of NH4Cl, and extracted with ether. The organic extracts were
combined, washed with brine, dried, filtered, and concentrated.
Purification by column chromatography afforded 5 (1.17 g, 82%
yield) as white crystals. Mp = 94−95 °C; [α]2D5 = −29.0 (c 1.0,
1
CHCl3); IR (KBr) ν = 3397, 1763, 1148, 1054 cm−1; H NMR (400
MHz, CDCl3) δ = 4.31 (br d, J = 4.8 Hz, 1H), 2.15 (br s, 1H), 2.06
(dddd, J = 14.5, 11.6, 7.4, 0.6 Hz, 1H), 1.91−1.84 (m, 2H), 1.75−1.71
(m, 2H), 1.39 (s, 2 × 3H), 1.13 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ = 178.0 (C), 85.7 (CH), 70.6 (C), 59.7 (CH), 42.4 (C),
32.1 (CH2), 30.8 (CH3), 28.1 (CH3), 22.3 (CH2), 21.7 (CH3) ppm;
HRMS (ESI) calcd for C10H16O3Na+ [M + Na]+ 207.0992, found
207.0992.
(1R,2R,5R)-2-(Methoxymethoxy)-2,8,8-trimethyl-6-
oxabicyclo[3.2.1]octan-7-one (5′). To a stirred solution of 5 (1.40
g, 7.6 mmol) in CH2Cl2 (30 mL) were added diisopropylethylamine
(15.9 mL, 91.2 mmol, 12.0 equiv) and chloromethyl methyl ether (4.1
mL, 53.2 mmol, 7.0 equiv) at 0 °C. After 48 h at rt, the reaction
mixture was diluted with CH2Cl2, and the organic layer was washed
with water. The aqueous washes were back-extracted, and the
combined organic layers were successively washed with 1 M HCl, a
saturated solution of NaHCO3, and brine. The organic layer was dried,
filtered, and concentrated to afford, after purification by column
EXPERIMENTAL SECTION
■
General Experimental Methods. All air- and/or water-sensitive
reactions were carried out under an argon atmosphere with dry, freshly
distilled solvents using standard syringe-cannula/septa techniques. All
of the corresponding glassware was oven-dried (80 °C) and/or
carefully dried in line with a flameless heat gun. All of the solvents
were distilled under an argon atmosphere as follows: THF from a blue
solution of sodium/benzophenone ketyl radical prior to use; CH2Cl2
from CaH2; and Et2O from LiAlH4. Routine monitoring of reactions
was performed using silica gel 60 F254 aluminum-supported TLC
plates; spots were visualized using UV light and ethanolic acidic p-
anisaldehyde solution or ethanolic phosphomolybdic solution,
followed by heating. Purifications by means of column chromatog-
chromatography, 5′ (1.58 g, 91% yield) as a solid. Mp = 77 °C; [α]D25
=
+14.2 (c 1.0, CHCl3); IR (KBr) ν = 1766, 1153, 1048 cm−1; 1H NMR
(400 MHz, CDCl3) δ = 4.75 and 4.58 (AB, J = 7.2 Hz, 2H), 4.29 (br d,
J = 4.5 Hz, 1H), 3.37 (s, 3H), 2.31 (br s, 1H), 2.08−1.83 (m, 3H),
1.63−1.55 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 1.11 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ = 177.5 (C), 91.1 (CH2), 85.4 (CH), 75.4
(C), 57.7 (CH), 55.7 (CH3), 42.2 (C), 30.3 (CH2), 28.2 (CH3), 25.5
(CH3), 22.4 (CH2), 21.4 (CH3) ppm; HRMS (ESI) calcd for
+
C12H24NO4 [M + NH4]+ 246.1700, found 246.1698.
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(1R,3S,4R)-3-(Hydroxymethyl)-4-(methoxymethoxy)-2,2,4-
trimethylcyclohexanol (6). A solution of 5′ (1.20 g, 5.3 mmol) in
ether (30 mL) was slowly added at 0 °C to a stirred slurry of LiAlH4
(503 mg, 13.3 mmol, 2.5 equiv) in ether (10 mL). The reaction
mixture was allowed to warm to rt. After 3 h, Celite (10 g) and
Na2SO4·10H2O (10 g) were added, and the solution was stirred for a
further 1 h. The mixture was filtered through a pad of MgSO4 and
concentrated. Column chromatography of the residue afforded 6 (1.12
g, 92% yield) as white crystals. Mp = 86 °C; [α]2D5 = −8.4 (c 1.0,
Hz, 1H), 2.51 (ddd, J = 16.7, 10.4, 5.5 Hz, 1H), 2.12 (s, 3H), 1.91 (dt,
J = 12.8, 3.3 Hz, 1H), 1.80−1.38 (m, 6H), 1.28−1.23 (m, 1H), 1.22 (s,
3H), 1.03 (s, 3H), 0.82 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ =
209.7 (C), 90.0 (CH2), 79.6 (C), 78.0 (CH), 55.2 (CH), 53.7 (CH3),
46.5 (CH2), 40.4 (C), 36.9 (CH2), 29.9 (CH3), 28.4 (CH2), 28.3
(CH3), 20.2 (CH2), 19.4 (CH3), 15.1 (CH3) ppm; HRMS (ESI) calcd
for C15H28O4Na+ [M + Na]+ 295.1880, found 295.1880.
4-((1R,3R,6R)-3-((tert-Butyldimethylsilyl)oxy)-6-(methoxy-
methoxy)-2,2,6-trimethylcyclohexyl)butan-2-one (9). To a
stirred solution of 8′ (560 mg, 2.06 mmol) in CH2Cl2 (35 mL) at
−20 °C was added triethylamine (720 μL, 6.18 mmol, 3.0 equiv)
followed by TBSOTf (710 μL, 3.09 mmol, 1.5 equiv). The mixture
was stirred at rt for 3 h and then diluted with CH2Cl2 (60 mL) and
stirred with a 1 M solution of HCl (40 mL) for 1 h. After extraction
with CH2Cl2, the organic layer was washed with water and brine, dried
with MgSO4, and concentrated under reduced pressure. Purification of
the residue by column chromatography gave 9 (779 mg, 98% yield) as
a clear oil. [α]2D5 = −12.6 (c 1.0, CHCl3); IR (neat) ν = 2951, 2855,
1716, 1093, 1033, 834 cm−1; 1H NMR (400 MHz, CDCl3) δ = 4.66 (s,
2H), 3.32 (s, 3H), 3.25 (dd, J = 10.7, 4.1 Hz, 1H), 2.69 (ddd, J = 16.5,
10.6, 5.8 Hz, 1H), 2.50 (ddd, J = 16.5, 10.3, 5.5 Hz, 1H), 2.12 (s, 3H),
1.87−1.82 (m, 1H), 1.77−1.41 (m, 5H), 1.25−1.21 (partially
overlapped m, 1H), 1.22 (s, 3H), 0.94 (s, 3H), 0.88 (s, 9H), 0.78
(s, 3H), 0.03 (s, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ = 209.6
(C), 90.0 (CH2), 79.7 (C), 78.6 (CH), 55.1 (CH), 53.6 (CH3), 46.6
(CH2), 41.0 (C), 36.8 (br, CH2), 29.9 (CH3), 28.8 (CH2), 28.7
(CH3), 25.9 (3 × CH3), 20.4 (CH2), 19.6 (CH3), 18.1 (C), 15.5
(CH3), −3.8 (CH3), −4.9 (CH3) ppm; HRMS (ESI) calcd for
C21H46NO4Si+ [M + NH4]+ 404.3191, found 404.3191.
1
CHCl3); IR (KBr) ν = 3391, 1141, 1069 cm−1; H NMR (300 MHz,
MeOH-d4) δ = 4.71 and 4.67 (AB, J = 7.3 Hz, 2H), 3.82 and 3.66 (br
ABX, J = 11.6, 3.8 Hz, 2H), 3.31 (s, 3H), 3.28 (partially overlapped br
t, J = 8.6 Hz, 1H), 1.88−1.65 (m, 2H), 1.65−1.58 (m, 1H), 1.53−1.44
(m, 2H), 1.26 (s, 3H), 1.14 (s, 3H), 0.88 (br s, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6, 335 K) δ = 89.3 (CH2), 78.1 (CH), 74.8 (C),
58.6 (CH2), 54.3 (CH3), 53.9 (CH), 38.3 (CH3), 34.3 (C), 28.9
(CH3), 27.2 (CH2), 21.3 (CH2), 18.3 (br, CH3) ppm; HRMS (ESI)
calcd for C12H24O4Na+ [M + Na]+ 255.1567, found 255.1566.
(1R,3R,6R)-3-Hydroxy-6-(methoxymethoxy)-2,2,6-trimethyl-
cyclohexanecarbaldehyde (7). To a stirred solution of 6 (200 mg,
0.86 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (15
mg, 0.06 mmol) in CH2Cl2 (10 mL) was added a saturated aqueous
solution of sodium bicarbonate (2 mL) containing potassium bromide
(15 mg, 0.13 mmol) and tetrabutylammonium chloride (15 mg, 0.05
mmol). To this cooled (0 °C) and well-stirred mixture was added
dropwise 2 mL of a solution containing household sodium
hypochlorite (2.8 mL, 4.47 mmol) in a mixture of saturated sodium
bicarbonate solution (5 mL) and brine (11 mL). This solution (1 mL)
was added every hour until the starting material was totally consumed,
as monitored by TLC. The aqueous phase was extracted with CH2Cl2,
and the combined extracts were washed with brine, dried over MgSO4,
filtered, and concentrated. Column chromatography afforded 7 (168
mg, 85% yield) as an oil. [α]D25 = −43.0 (c 1.0, CHCl3); IR (neat) ν =
5-((1R,3R,6R)-3-((tert-Butyldimethylsilyl)oxy)-6-(methoxy-
methoxy)-2,2,6-trimethylcyclohexyl)-3-methylpent-1-en-3-ol
(10). To a stirred solution of 9 (500 mg, 1.29 mmol) in THF (30 mL)
at −20 °C under an argon atmosphere was added dropwise
vinylmagnesium bromide (1 M in THF, 2.33 mL, 2.33 mmol, 1.8
equiv). The mixture was stirred at −20 °C for 15 min and then
allowed to warm to 0 °C, and the resulting solution was quenched with
aqueous saturated NH4Cl solution. After warming to rt, the reaction
mixture was extracted with Et2O, and the organic layer was dried and
concentrated to give crude allylic alcohols. Purification by column
chromatography gave an inseparable 60:40 mixture of diastereoisomers
10 (520 mg, 97% yield) as a colorless oil. IR (neat) ν = 3448, 2953,
1
3384, 2829, 1713, 1157 cm−1; H NMR (400 MHz, CDCl3) δ = 9.84
(d, J = 4.8 Hz, 1H), 4.76 and 4.64 (AB, J = 7.3 Hz, 2H), 3.55−3.46 (m,
1H), 3.35 (s, 3H), 2.34 (br d, J = 4.8 Hz, 1H), 2.11−2.03 (m, 1H),
1.92−1.84 (m, 2H), 1.77−1.70 (m, 1H), 1.66−1.59 (m, 1H), 1.30 (s,
3H), 1.16 (s, 3H), 0.99 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ =
205.3 (CH), 90.1 (CH2), 75.9 (C), 74.6 (CH), 65.4 (CH), 55.5
(CH3), 38.4 (C), 31.7 (br, CH2), 28.6 (CH3), 26.5 (CH2), 24.3 (br,
CH3), 22.4 (br, CH3) ppm; HRMS (ESI) calcd for C12H22O4Na+ [M
+ Na]+ 253.1410, found 253.1410.
1
2844, 1091, 1034, 834, 771 cm−1; H NMR (400 MHz, CDCl3) δ =
5.95−5.83 (m, 1H, m + M), 5.25−5.19 (m, 1H, m + M), 3.07−5.01
(m, 1H, m + M), 4.74−4.67 (m, 2H, m + M), 3.36 (s, 3H, M), 3.35 (s,
3H, m), 3.29−3.24 (m, 1H, m + M), 3.21 (br s, 1H, M), 2.36 (br s,
1H, m), 1.90−1.82 (m, 1H, m + M), 1.75−1.31 (m, 8H, m + M), 1.27
(s, 3H, m), 1.24 (s, 3H, M), 1.21 (s, 3H, m), 1.19 (s, 3H, M), 0.94 (br
s, 3H, m + M), 0.88 (s, 9H, m + M), 0.78 (s, 3H, m), 0.77 (s, 3H, M),
0.03 (s, 6H, m + M) ppm; 13C NMR (75 MHz, CDCl3) δ = 145.8
(CH, m), 145.7 (CH, M), 111.9 (CH2, M), 111.4 (CH2, m), 90.1
(CH2, m + M), 80.7 (C, M), 80.3 (C, m), 78.7 (CH, m), 78.6 (CH,
M), 74.3 (C, M), 73.6 (C, m), 55.5 (CH, M), 55.4 (CH, m), 55.2
(CH3, M), 54.2 (CH3, m), 44.7 (CH2, m), 44.2 (CH2, M), 41.5 (C,
M), 41.4 (C, m), 36.9 (CH2, M), 36.8 (CH2, m), 28.9 (CH2, m + M),
28.8 (CH3, m + M), 27.6 (CH3, m + M), 26.0 (3 × CH3, M + m), 20.4
(CH2, m), 20.0 (CH2, M), 19.7 (CH3, m), 19.3 (CH3, M), 18.2 (C, m
+ M), 15.7 (br, CH3, m + M), −3.8 (2 × CH3, m), −4.8 (2 × CH3, M)
ppm; HRMS (ESI) calcd for C23H46O4SiNa+ [M + Na]+ 437.3058,
found 437.3058.
tert-Butyldimethyl(((4aR,6R,8aR)-2,5,5,8a-tetramethyl-2-vi-
nyloctahydro-2H-chromen-6-yl)oxy)silane (11). To a solution of
allylic alcohols 10 (215 mg, 0.52 mmol) in THF (15 mL) were added
Et3N (850 μL, 7.78 mmol, 15.0 equiv), DMAP (13 mg, 0.10 mmol, 0.2
equiv), Ac2O (740 μL, 7.8 mmol, 15.0 equiv), and the mixture was
heated under reflux for 3 days. After being cooled to rt, the reaction
mixture was diluted with Et2O and washed with aqueous NaHCO3 and
brine. The organic layer was dried and concentrated to give the crude
allylic acetate as a colorless oil that was used in the next step without
further purification. A solution of allylic acetate in THF (20 mL) at rt
under an argon atmosphere was treated with a catalytic amount of
(E)-4-((1R,3R,6R)-3-Hydroxy-6-(methoxymethoxy)-2,2,6-
trimethylcyclohexyl)but-3-en-2-one (8). To a stirred solution of 7
(450 mg, 1.95 mmol) in toluene (30 mL) under an argon atmosphere
was added 1-(triphenylphosphoranylidene)propan-2-one (1.24 g, 3.90
mmol, 2.0 equiv). After 48 h at 130 °C, the solution was cooled to rt,
and toluene was removed in vacuo. Purification by column
chromatography gave 8 (448 mg, 85% yield) as a clear yellow oil.
[α]2D5 = −16.0 (c 1.0, CHCl3); IR (neat) ν = 3448, 2942, 1670, 1025
1
cm−1; H NMR (400 MHz, CDCl3) δ = 6.89 (dd, J = 15.7, 10.8 Hz,
1H), 6.07 (d, J = 15.7 Hz, 1H), 4.67 and 4.64 (AB, J = 7.4 Hz, 2H),
3.48−3.40 (m, 1H), 3.30 (s, 3H), 2.27 (s, 3H), 2.16 (br d, J = 10.8 Hz,
1H), 1.94−1.87 (m, 2H), 1.72−1.54 (partially overlapped m, 2H),
1.49 (br d, J = 4.5 Hz, 1H), 1.26 (s, 3H), 1.02 (s, 3H), 0.92 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ = 199.0 (C), 147.1 (br, CH),
134.7 (CH), 90.4 (CH2), 78.0 (C), 76.6 (CH), 58.3 (CH), 55.5
(CH3), 39.2 (C), 34.5 (br, CH2), 29.3 (CH3), 27.7 (CH2), 27.4
(CH3), 23.0 (br, CH3), 19.8 (br, CH3) ppm; HRMS (ESI) calcd for
C15H26O4Na+ [M + Na]+ 293.1723, found 293.1723.
4-((1R,3R,6R)-3-Hydroxy-6-(methoxymethoxy)-2,2,6-
trimethylcyclohexyl)butan-2-one (8′). To a stirred solution of 8
(700 mg, 2.59 mmol) in methanol (40 mL) was added a catalytic
amount of 10% palladium on activated charcoal. The mixture was
stirred under a hydrogen atmosphere for 3 h, and then the reaction
mixture was filtered and concentrated. Purification of the residue by
column chromatography gave 8′ (691 mg, 98% yield) as a colorless oil.
[α]2D5 = −7.5 (c 1.0, CHCl3); IR (neat) ν = 3450, 2938, 1672, 1028
1
cm−1; H NMR (400 MHz, CDCl3) δ = 4.66 (s, 2H), 3.32 (s, 3H),
3.35−3.28 (partially overlapped m, 1H), 2.71 (ddd, J = 16.7, 10.5, 5.5
2271
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Note
dichlorobis(acetonitrile)palladium(II). After being stirred for 12 h at
rt, the reaction mixture was filtered through a short pad of silica gel
and washed with Et2O. Concentration and purification by flash
chromatography gave an inseparable 75:25 mixture of diastereoisomers
11 (128 mg, 70% yield from 10) as a colorless oil. IR (neat) ν = 3015,
143.5 (CH), 128.7 (CH), 118.5 (CH), 113.2 (CH), 112.9 (CH),
112.4 (C), 101.5 (CH), 90.0 (CH2), 79.6 (C), 78.6 (CH), 65.3 (CH2),
55.0 (CH), 54.3 (CH3), 40.9 (C), 36.6 (br, CH2), 35.7 (CH2), 28.8
(CH2), 28.7 (CH3), 25.9 (3 × CH3), 25.4 (CH2), 23.7 (CH3), 19.7
(CH3), 18.1 (C), 15.8 (br, CH3), −3.9 (CH3), −4.9 (CH3) ppm;
HRMS (ESI) calcd for C32H54NO6Si+ [M + NH4]+ 576.3715, found
576.3715.
1
2923, 1646, 1252, 1023 cm−1; H NMR (300 MHz, CDCl3) δ = 6.00
(dd, J = 18.0, 11.4 Hz, 1H, m), 5.87 (dd, J = 17.4, 10.7 Hz, 1H, M),
5.14 (br d, J = 17.4 Hz, 1H, M), 4.96 (partially overlapped br d, J =
18.0 Hz, 1H, m), 4.92 (partially overlapped br d, J = 10.7 Hz, 1H, M
and J = 11.4 Hz, 1H, m), 3.30−3.24 (m, 1H, m + M), 2.27−1.41 (m,
9H, m + M), 1.29 (partially overlapped s, 3H, M), 1.27 (partially
overlapped s, 3H, M), 1.22 (s, 3H, m), 1.13 (s, 3H, m), 0.91 (partially
overlapped s, 3H, m), 0.88 (partially overlapped s, 12H M + 9H m),
0.72 (s, 3H, M), 0.66 (s, 3H, m), 0.04 (s, 6H, m + M) ppm; 13C NMR
(75 MHz, CDCl3) δ = 148.0 (CH, M), 147.7 (CH, m), 110.5 (CH2,
M), 109.8 (CH2, m), 79.1 (CH, m + M), 75.6 (C, m), 74.6 (C, M),
73.6 (C, m), 73.5 (C, M), 52.9 (CH, m), 50.1 (CH, M), 40.1 (CH2,
M), 39.9 (CH2, m), 39.3 (C, M), 39.1 (C, m), 35.7 (CH2, M), 35.0
(CH2, m), 32.8 (CH3, m), 29.4 (CH2, m), 29.3 (CH2, M), 28.7 (CH3,
M), 28.2 (CH3, m), 27.8 (CH3, M), 26.0 (3 × CH3, m + M), 24.5
(CH3, M), 22.9 (CH3, m), 18.2 (C, m + M), 17.1 (CH2, m), 16.4
(CH2, M), 15.6 (CH3, m), 15.2 (CH3, M), −3.7 (CH3, m + M), −4.8
(CH3, m + M) ppm; HRMS (ESI) calcd for C21H41O2Si+ [M + H]+
353.2870, found 353.2877.
7-(((E)-5-((1R,3R,6R)-3-Hydroxy-6-(methoxymethoxy)-2,2,6-
trimethylcyclohexyl)-3-methylpent-2-en-1-yl)oxy)-2H-chro-
men-2-one (14). In a Teflon round-bottom flask, HF·pyridine
complex (70 wt % HF, 440 μL, 24.16 mmol, 50.0 equiv) was carefully
added to an ice-cold solution of silyl ether (E)-13 (270 mg, 0.48
mmol) in THF (15 mL) under an argon atmosphere, and the mixture
was heated at 40 °C for 24 h. Then the reaction mixture was poured
into a saturated aqueous NaHCO3 solution. The aqueous layer was
extracted with ether, and the combined organic layers were washed
with saturated aqueous NaHCO3, water, and brine, dried over MgSO4,
and concentrated. After purification by column chromatography,
alcohol 14 (180 mg, 84% yield) was obtained as a foam. [α]2D5 = +1.0
(c 1.0, CHCl3); IR (KBr) ν = 3444, 2932, 1735, 1712, 1609, 1125
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.63 (d, J = 9.5 Hz, 1H), 7.35
(d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 6.83 (d, J = 2.5 Hz,
1H), 6.25 (d, J = 9.5 Hz, 1H), 5.47 (br t, J = 6.5 Hz, 1H), 4.72 and
4.66 (AB, J = 7.3 Hz, 2H), 4.59 (br d, J = 6.5 Hz, 2H), 3.33 (s, 3H),
3.32 (partially overlapped dd, J = 10.0, 4.3 Hz, 1H), 2.34−2.26 (m,
1H), 2.13−2.06 (m, 1H), 1.89 (dt, J = 12.6, 3.3 Hz, 1H), 1.78−1.71
(partially overlapped m, 1H), 1.78 (br s, 3H), 1.68−1.35 (m, 5H), 1.27
(t, J = 4.5 Hz, 1H), 1.22 (s, 3H), 1.04 (s, 3H), 0.82 (s, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ = 162.1 (C), 161.3 (C), 155.8 (C), 143.5
(CH), 143.3 (C), 128.7 (CH), 118.0 (CH), 113.2 (CH), 112.8 (CH),
112.4 (C), 101.5 (CH), 89.8 (CH2), 79.4 (C), 77.9 (CH), 65.5 (CH2),
55.0 (CH), 53.8 (CH3), 42.5 (CH2), 40.3 (C), 36.7 (CH2), 28.3
(CH2), 28.3 (CH3), 24.6 (CH2), 19.6 (CH3), 16.8 (CH3), 15.3 (CH3)
ppm; HRMS (ESI) calcd for C26H36O6Na+ [M + Na]+ 467.2404,
found 467.2404.
(E)- and (Z)-7-((5-((1R,3R,6R)-3-((tert-Butyldimethylsilyl)oxy)-
6-(methoxymethoxy)-2,2,6-trimethylcyclohexyl)-3-methyl-
pent-2-en-1-yl)oxy)-2H-chromen-2-one [(E)- and (Z)-13]. The
tertiary allylic alcohol 10 (500 mg, 1.21 mmol) was dissolved in 30 mL
of a mixture of pentane, diethyl ether, and pyridine (65:43:1). The
resulting solution was cooled to 0 °C and treated with a freshly
prepared 2.7 M solution of phosphorus tribromide (715 μL, 1.93
mmol, 1.5 equiv) in Et2O (2 mL). The reaction mixture was stirred at
0 °C for 30 min and then diluted with Et2O and washed with 1 M
HCl, aqueous NaHCO3, and brine. The organic layer was dried and
concentrated to give the crude bromide as a yellow oil that was
immediately dissolved in acetone (10 mL) to prevent degradation.
This solution was added to an ice-cold mixture of 7-hydroxycoumarin
(293 mg, 1.81 mmol, 1.4 equiv) and K2CO3 (820 mg, 5.93 mmol, 4.6
equiv) in acetone (20 mL). The mixture was stirred at rt for 24 h, and
then the residue was concentrated, diluted with AcOEt, and washed
with water. The organic layer was dried and concentrated. Purification
by flash chromatography gave pure compound (E)-13 (330 mg, 49%)
as a solid and (Z)-13 (142 mg, 21%) as a colorless oil. Data for (E)-
13: mp = 109−110 °C, [α]D25 = −14.8 (c 1.0, CHCl3); IR (KBr) ν =
Kopeolin (1′). Method A: To an ice-cold solution of 14 (108 mg,
0.24 mmol) in methanol (10 mL) was added 10 drops of a methanolic
solution of hydrochloric acid [10 drops of conc. HCl (35 wt % in
H2O) in 5 mL of methanol]. After 48 h of stirring at rt, the reaction
mixture was cooled, neutralized with Amberlyst IRA-67, filtered, and
concentrated. Purification of the residue by column chromatography
gave 1′ (78 mg, 80% yield) as a white solid. Method B: Starting from
(E)-13 (146 mg, 0.26 mmol), 1′ was prepared according to method A
with a reaction time of 72 h and was obtained as a white solid (89 mg,
85% yield). Method C: To a stirred solution of 2′ (30 mg, 0.07 mmol)
in MeOH (10 mL) at −78 °C under an argon atmosphere was added
NaBH4 (9.0 mg, 0.24 mmol, 3.0 equiv). The reaction mixture was
stirred for 30 min and then poured into a saturated aqueous NH4Cl
solution. The aqueous layer was extracted with AcOEt, and the
combined organic layers were washed with water and brine, dried over
MgSO4, and concentrated in vacuo. After purification by column
chromatography, pure alcohol 1′ (23 mg, 85%) was obtained as a
white solid. Mp = 120 °C; [α]D25 = −12.0 (c 1.0, EtOH); IR (KBr) ν =
3440, 2934, 1730, 1708, 1613, 1129 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 7.64 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.85
(dd, J = 8.5, 2.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.24 (d, J = 9.5 Hz,
1H), 5.50 (br t, J = 6.3 Hz, 1H), 4.59 (d, J = 6.3 Hz, 2H), 3.31 (dd, J =
11.0, 4.0 Hz, 1H), 2.29−2.12 (m, 2H), 1.78 (br s, 3H), 1.78−1.72
(partially overlapped m, 1H), 1.67−1.40 (m, 4H), 1.25−1.17 (partially
overlapped m, 1H), 1.17 (s, 3H), 1.13 (t, J = 4.3 Hz, 1H), 1.03 (s,
3H), 0.80 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ = 162.0 (C),
161.3 (C), 155.8 (C), 143.5 (CH), 143.4 (C), 128.7 (CH), 118.3
(CH), 113.2 (CH), 112.8 (CH), 112.4 (C), 101.5 (CH), 78.0 (CH),
73.4 (C), 65.4 (CH2), 55.2 (CH), 42.4 (CH2), 40.9 (CH2), 40.3 (C),
28.9 (CH2), 28.0 (CH3), 23.9 (CH2), 23.0 (CH3), 16.8 (CH3), 14.8
1
3051, 2858, 1738, 1612, 1093, 1031, 834 cm−1; H NMR (400 MHz,
CDCl3) δ = 7.63 (d, J = 9.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.85
(dd, J = 8.5, 2.5 Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.24 (d, J = 9.5 Hz,
1H), 5.47 (br t, J = 6.5 Hz, 1H), 4.72 and 4.64 (AB, J = 7.5 Hz, 2H),
4.58 (br d, J = 6.5 Hz, 2H), 3.33 (s, 3H), 3.28−3.24 (dd, J = 10.8, 4.0
Hz, 1H), 2.30−2.21 (m, 1H), 2.13−2.04 (m, 1H), 1.84−1.81 (m, 1H),
1.77 (br s, 3H), 1.63−1.40 (m, 5H), 1.27−1.20 (partially overlapped
m, 1H), 1.21 (s, 3H), 0.95 (s, 3H), 0.88 (s, 9H), 0.78 (s, 3H), 0.04 (s,
3H), 0.03 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ = 162.3 (C),
161.3 (C), 156.0 (C), 143.7 (C), 143.5 (CH), 128.8 (CH), 118.0
(CH), 113.3 (CH), 113.0 (CH), 112.5 (C), 101.7 (CH), 90.0 (CH2),
79.6 (C), 78.7 (CH), 65.7 (CH2), 55.1 (CH), 53.9 (CH3), 42.7
(CH2), 41.1 (C), 36.6 (br, CH2), 28.9 (CH2), 28.9 (CH3), 26.0 (3 ×
CH3), 24.9 (CH2), 19.9 (CH3), 18.1 (C), 17.0 (CH3), 15.4 (br, CH3),
−3.8 (CH3), −4.8 (CH3) ppm; HRMS (ESI) calcd for C32H54NO6Si+
[M + NH4]+ 576.3715, found 576.3716. Data for (Z)-13: [α]2D5
=
−15.3 (c 1.0, CHCl3); IR (neat) ν = 3050, 2857, 1735, 1610, 1090,
1030, 832 cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.63 (d, J = 9.5 Hz,
1H), 7.35 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.5, 2.5 Hz, 1H), 6.82 (d, J
= 2.5 Hz, 1H), 6.24 (d, J = 9.5 Hz, 1H), 5.45 (br t, J = 7.0 Hz, 1H),
4.65 (s, 2H), 4.59 (br d, J = 7.0 Hz, 2H), 3.30 (s, 3H), 3.25 (dd, J =
10.8, 4.3 Hz, 1H), 2.39−2.32 (m, 1H), 2.14−2.04 (m, 1H), 1.85−1.81
(partially overlapped m, 1H), 1.83 (br s, 3H), 1.62−1.36 (m, 5H),
1.27−1.20 (partially overlapped m, 1H), 1.20 (s, 3H), 0.95 (s, 3H),
0.87 (s, 9H), 0.77 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H) ppm; 13C NMR
(75 MHz, CDCl3) δ = 162.2 (C), 161.2 (C), 155.9 (C), 144.4 (C),
+
(CH3) ppm; HRMS (ESI) calcd for C24H33O5 [M + H]+ 401.2323,
found 401.2319.
Kopeolone (2′). A catalytic amount of tetrapropylammonium
perruthenate was added to an ice-cold solution of 1′ (24 mg, 0.060
mmol), N-methylmorpholine N-oxide (28 mg, 0.24 mmol, 4.0 equiv),
2272
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Note
and powdered 4 Å molecular sieves in CH2Cl2 (5 mL) under an argon
atmosphere. After 40 min of stirring at 0 °C, the reaction mixture was
filtered through a short pad of Celite, and the filtrate was poured into
an aqueous Na2SO3 solution. The aqueous layer was extracted with
CH2Cl2, and 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
(6) (a) Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron 2000, 56,
7477−7481. (b) Palombo, E.; Audran, G.; Monti, H. Synlett 2006,
403−406.
(7) Reviews: (a) Imamoto, T. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991;
Vol. 1, pp 231−250. (b) Molander, G. A. Chem. Rev. 1992, 92, 29−68.
(c) Paquette, L. A. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, U.K., 1995; Vol.
2, pp 1031−1034.
afforded 2′ (22 mg, 91% yield) as white solid. Mp = 116 °C; [α]D25
=
−7.0 (c 1.0, EtOH); IR (KBr) ν = 3445, 2928, 1735, 1712, 1610, 1134
cm−1; 1H NMR (400 MHz, CDCl3) δ = 7.57 (d, J = 9.5 Hz, 1H), 7.29
(d, J = 8.5 Hz, 1H), 6.77 (dd, J = 8.5, 2.3 Hz, 1H), 6.75 (d, J = 2.3 Hz,
1H), 6.18 (d, J = 9.5 Hz, 1H), 5.42 (br t, J = 6.5 Hz, 1H), 4.52 (d, J =
6.5 Hz, 2H), 2.45−2.41 (m, 2H), 2.21 (ddd, J = 14.0, 10.0, 6.0 Hz,
1H), 2.10 (ddd, J = 14.0, 10.0, 5.3 Hz, 1H), 1.94 (dt, J = 13.5, 5.8 Hz,
1H), 1.74 (partially overlapped ddd, J = 13.5, 8.8, 6.8 Hz, 1H), 1.71
(br s, 3H), 1.67−1.56 (m, 1H), 1.53 (dd, J = 5.0, 4.3 Hz, 1H), 1.48−
1.36 (m, 1H), 1.32 (s, 3H), 1.10 (s, 3H), 0.99 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ = 215.2 (C), 162.2 (C), 161.4 (C), 156.0 (C),
143.6 (CH), 142.9 (C), 128.9 (CH), 119.0 (CH), 113.3 (CH), 113.2
(CH), 112.7 (C), 101.7 (CH), 73.0 (C), 65.5 (CH2), 55.8 (CH), 48.4
(C), 41.4 (CH2), 40.1 (CH2), 35.4 (CH2), 26.3 (CH3), 25.2 (CH2),
24.5 (CH3), 21.9 (CH3), 17.0 (CH3) ppm; HRMS (ESI) calcd for
(8) Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275−1276.
(9) Details of the X-ray structure can be obtained from the
Cambridge Crystallographic Data Centre as entry CCDC 271219.
(10) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559−2562. (b) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici,
S. J. Org. Chem. 1989, 54, 2970−2972.
́
(11) (a) Alvarez-Ibarra, C.; Arias, S.; Fernandez, M. J.; Serrano, D.;
Sinisterra, J. V. J. Chem. Soc., Perkin Trans. 2 1989, 503−508.
(b) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774−776.
(c) Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem.
2000, 65, 4745−4749. Review: (d) Maryanoff, B. E.; Reitz, A. B.
Chem. Rev. 1989, 89, 863−927.
(12) (a) Harris, T. M.; Harris, C. M. Org. React. 1969, 17, 155−212.
(b) Baoyu, M.; Maleczka, R. E., Jr. Org. Lett. 2001, 3, 1491−1494.
(c) Oritani, T.; Yamashita, K. Agric. Biol. Chem. 1987, 51, 1271−1275.
(13) Reviews: (a) Lutz, R. P. Chem. Rev. 1984, 84, 205−247.
(b) Overman, L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579−587.
(c) Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons:
Chichester, U.K., 1999; pp 399−404.
+
C24H31O5 [M + H]+ 399.2166, found 399.2166.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 5, 5′, 6, 7, 8, 8′, 9, 10,
11, (E)-13, (Z)-13, 14, 1′, 2′, and natural kopeolin; 2D
NOESY spectra of (E)- and (Z)-13; comparison tables;
ORTEP view and X-ray data (CIF) for 6; and calculation
details. This material is available free of charge via the Internet
at http://pubs.acs.org.
(14) Demnitz, F. W. J.; Philippini, C.; Raphael, R. A. J. Org. Chem.
1995, 60, 5114−5120.
(15) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R.; Petasis, N. A. J. Org.
Chem. 1979, 44, 4011−4013.
(16) Auerbach, J.; Weinreb, S. M. J. Chem. Soc., Chem. Commun.
1974, 298−299.
(17) Racemic samples of 1′ and 2′ were prepared from racemic 4
AUTHOR INFORMATION
■
using the synthetic pathway described in this article.
Corresponding Authors
*E-mail: paul.bremond@univ-amu.fr.
*E-mail: g.audran@univ-amu.fr.
(18) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Chem. Soc., Chem. Commun. 1987, 1625−1627. (b) Griffith, W. P.;
Ley, S. V. Aldrichimica Acta 1990, 23, 13−19.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. S. Y. Ryu for kindly providing copies of the 1H
and 13C NMR spectra of natural kopeolin. S.M. thanks the
̀
Ministere de l′Education Nationale, de l′Enseignement Super-
ieur et de la Recherche for her Ph.D. grant. The authors are
thankful to Dr. N. Vanthuyne for HPLC analyses, Dr. R. Faure
́
for 2D NMR analyses, and Aix-Marseille Universite and CNRS
for their financial support. P. Fournier is gratefully acknowl-
edged for the English revision of the manuscript.
REFERENCES
■
313.
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