Asymmetric total synthesis of rugulactone, an α-pyrone from Cryptocarya rugulosa

Article abstract of DOI:10.1055/s-0029-1218836

A total asymmetric synthesis of rugulactone, a naturally occuring -pyrone isolated from Cryptocarya rugulosa, is reported. The synthesis involved a cross-metathesis coupling reaction to construct the internal E-olefin group, a Still-Gennari olefination to

Full text of DOI:10.1055/s-0029-1218836

PAPER
2787
Asymmetric Total Synthesis of Rugulactone, an a-Pyrone from Cryptocarya
rugulosa
Total
S
ynthesi
l
s
of Ru
o
gulactone rent Allais,* Mahoulo Aouhansou, Amel Majira, Paul-Henri Ducrot*
INRA/AgroParisTech UMR1318, Institut Jean-Pierre Bourgin, INRA, route de Saint-Cyr, 78026 Versailles Cedex, France
Fax +33(01)30833119; E-mail: florent.allais@versailles.inra.fr
Received 19 March 2010; revised 21 April 2010
subtropics.11 The most common secondary metabolites re-
Abstract: A total asymmetric synthesis of rugulactone, a naturally
ported from this genus are alkaloids, flavonoids, and a-
occuring a-pyrone isolated from Cryptocarya rugulosa, is reported.
pyrones.12–14 The 6-substituted 5,6-dihydro-2H-pyran-2-
The synthesis involved a cross-metathesis coupling reaction to con-
one group is a prominent structural feature among natural
struct the internal E-olefin group, a Still–Gennari olefination to con-
struct the Z-configured a,b-unsaturated ester group, and a one-pot products of this group that display a broad range of bio-
logical activities.15,16 Rugulactone (1) belongs to a family
of Cryptocarya a-pyrone-containing natural products iso-
lated from C. rugulosa extract that exhibit up to a fivefold
induction of IC50 at 25 mg/mL.1 Because of these interest-
ing inhibition properties, rugulactone has recently attract-
ed a considerable degree of attention, and three total
deprotection and intramolecular lactonization reaction. The stereo-
chemistry at C5 was controlled by the use of a chiral pool.
Key words: total synthesis, natural products, pyrones, metathesis,
olefination
Rugulactone (1) is a naturally occurring a-pyrone recently syntheses have been published.17
isolated from extracts of the plant Cryptocarya rugulosa.1
As part of the development of efficient and rapid total syn-
Biological tests showed that this lactone is a potent inhib-
itor of the activation pathway of nuclear factor kappa-
light-chain enhancer of activated B cells (NF-kB), and
therefore a potential anticancer therapeutic target. NF-kB
is a protein complex that acts as a transcription factor that
is found in almost all types of animal cell and is involved
in cellular responses to stimuli such as stress, cytokines,
free radicals, ultraviolet irradiation, oxidized low-density
lipoproteins, and bacterial or viral antigens.2–6 NF-kB
therefore plays a key role in regulating the immune re-
sponse to infection. Consistent with this role, incorrect
regulation of NF-kB has been linked to cancer, inflamma-
tory, and autoimmune diseases, septic shock, viral infec-
tion, and improper immune development. NF-kB has also
been implicated in processes of synaptic plasticity and
memory.7 Defects in NF-kB result in an increase in sus-
ceptibility to apoptosis, leading to increased cell death.
Because NF-kB controls many genes involved in inflam-
mation, it is not surprising that NF-kB is found to be clin-
ically active in many inflammatory diseases, such as
inflammatory bowel disease, arthritis, sepsis, and asthma.
Many natural products (including antioxidants) that have
been promoted as having anti-cancer and anti-inflamma-
tory activity have also been shown to inhibit NF-kB. Re-
cent work by Karin,8 Pikarsky and Ben-Neriah,9 and
others has highlighted the importance of the connection
between NF-kB, inflammation, and cancer, and has un-
derscored the value of therapies that regulate the activity
of NF-kB.10
theses of natural phenylpropanoids,18 we have been work-
ing on the use of cross-metathesis to build internal olefins.
Because of the presence of such an olefin group in the
structure of rugulactone, and because of its potent biolog-
ical activities, we put our efforts into a total synthesis of
this compound. Our original convergent retrosynthetic
route (Scheme 1) was based on a cross-metathesis cou-
pling reaction and a Still–Gennari olefination to construct,
respectively, the internal E-olefin 3 and the Z-configured
a,b-unsaturated ester 2. We also wanted to take advantage
of the chiral pool of sugars and glycidol derivatives for the
control of the C5 stereocenter to avoid the use of any
atom-consuming or expensive enantioselective steps.
The first plan for a synthesis of rugulactone (1) began
from the known silylated homoallylic alcohol 419 and vi-
nyl ketone 5 (Scheme 1). Compound 4 was easily ob-
tained in five steps (Scheme 2) from commercially
available (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-
dioxolane (7). The hydroxy group in 7 was protected
through formation of the corresponding p-methoxybenzyl
ether 8 (94%). Subsequent cleavage of the acetonide 8 by
using cerium(III) chloride20a gave the diol 9 (97%). One-
pot formation of the epoxide 10 from the 1,2-diol 9 was
realized by using 1-[(2,4,6-triisopropylphenyl)sulfonyl]-
1H-imidazole (TPSI)20b (53%). Finally, opening of the ep-
oxide 10 by copper-catalyzed Grignard vinylation gave
the homoallylic alcohol 11 (87%), which was then con-
verted into the required silyl ether 4 (98%).
As shown in Scheme 3, vinyl ketone 5 was synthesized
from the commercially available 3-phenylpropanal (6) in
two steps by alkylation of the aldehyde through Grignard
vinylation (92%) followed by Dess–Martin periodinane
oxidation of the resulting allylic alcohol (96%).
The plant genus Cryptocarya consists of a large number
of species that are distributed throughout the tropics and
SYNTHESIS 2010, No. 16, pp 2787–2793
x
x.
x
x
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2
0
1
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Advanced online publication: 25.06.2010
DOI: 10.1055/s-0029-1218836; Art ID: P04310SS
© Georg Thieme Verlag Stuttgart · New York

2788
F. Allais et al.
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O
of the silyl ether. Cleavage using 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ) did not provide the expect-
ed free alcohol, but resulted in the formation of
tetrahydropyran 13 as the major product22b through a dia-
stereoselective 1,4-Michael addition of the transient alco-
holate to the vinyl ketone. Unfortunately, even the use of
buffered conditions did not prevent that reaction.
1
2
3
O
O
7
11
8
9
5
10
6
4
1
MeO2C
TBSO
O
Though undesired in the total synthesis of rugulactone,
this Michael addition onto a vinyl ketone appears to be a
useful method for preparing tetrahydropyrans directly
from PMB-protected hydroxy compounds without prior
deprotection. This method will be studied and optimized
in due course. A similar formation of a tetrahydropyran
was observed on treating tert-butyl(dimethyl)silyl-pro-
tected hydroxy groups with tetrabutylammonium fluoride
in a preparation of diospongin A (14).23
2
O
TBSO
O
3
At this point, because we were unable to obtain the free
hydroxy compound efficiently, we had to devise an alter-
native route to the desired aldehyde 3, so we chose to use
the masked aldehyde 15 instead of the protected hydroxy
compound 4 (Scheme 5).
O
OTBS OPMB
+
5
4
The second plan for a synthesis of rugulactone (1) began
from commercially available (2S)-glycidyl tosylate (16)
and 3-phenylpropanal (6) (Scheme 5). Compound 15 was
easily obtained in three steps from 16 (Scheme 6).24 First,
the tosylate moiety in 16 was displaced by using lithiated
1,3-dithiane (n-BuLi, 1,3-dithiane, THF, –78 °C) to give
the corresponding thioacetal 17. The epoxide ring in 17
was then opened by copper-catalyzed Grignard vinylation
(vinylMgBr, CuI, THF, –60 °C; 65% from 16), which
gave the secondary homoallylic alcohol 18. Finally, pro-
tection of 18 as its triethylsilyl ether (TESCl, imidazole,
DMAP, DMF; 98%) gave the cross-metathesis precursor
15.
O
OH
O
H
O
6
7
Scheme 1 First retrosynthetic pathway
O
OH
O
OPMB
OPMB
PMBCl, NaH
CeCl3, H2C2O4
O
O
THF–DMF, r.t.
94%
MeCN
97%
7
8
TPSI
NaH, DMF
H2C=CHMgBr
OH OPMB
The cross-metathesis coupling reaction of 15 and 5 (5
mol% Grubbs II catalyst, CH2Cl2, reflux) gave the desired
intermediate 19 in 72% yield (Scheme 7).21 In fact, this re-
action was the crucial step of our synthesis, as sulfur is of-
ten problematic in transition metal-catalyzed reactions
because its high affinity with the soft metal center can re-
sult in poisoning of the catalyst. Indeed, there have been
several cases of olefin metathesis in which sulfides were
detrimental. For example, in Fürstner’s synthesis of the
macrocycle zeranol, in a key step involving ring-closing
metathesis of a molecule containing a 1,3-dithiane unit,25
cyclization was not observed in the presence of the first-
generation Grubbs catalyst as a result of chelation of the
proximal sulfur atom to the ruthenium. Furthermore, the
decreased reactivities of butenyl and pentenyl sulfides
may be due to the unproductive formation of five- or six-
membered chelates. In our case, however, it was fortunate
that the sulfide was sufficiently distant from the olefin
group to avoid the formation of such chelates with the
Grubbs second-generation catalyst.
O
HO
53%
CuI, THF, –60 °C
87%
10
9
OH OPMB
TBSCl
OTBS OPMB
imidazole, DMF
98%
11
4
Scheme 2 Synthesis of precursor 4
O
1) H2C=CHMgBr
THF, 0 °C
CHO
2) Dess–Martin, CH2Cl2
88%
6
5
Scheme 3 Synthesis of vinyl ketone 5
With compounds 4 and 5 in hand, the cross-metathesis21
coupling reaction was carried out (5 mol% Grubbs II cat-
alyst, refluxing CH2Cl2) to give the desired intermediate
1222a in 72% yield (Scheme 4). However, cleavage of the
PMB ether moiety proved troublesome. Conventional
methods using a variety of acids (e.g., p-TsOH, TFA, Am-
berlyst resin) had to be ruled out because of the sensitivity
Removal of the thioacetal group from dithiane 19 was
then performed cleanly (methyl iodide, calcium carbon-
ate, aqueous acetonitrile) to give the crude aldehyde 3¢,
Synthesis 2010, No. 16, 2787–2793 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Rugulactone
2789
4
O
O
OTBS OPMB
O
O
A (5 mol%)
DDQ
R
R
R
OTBS
CH2Cl2, Δ
72%
5
12
13
R = (CH2)2Ph
OH
Mes
N
N
Mes
O
Cl
O
Ru
Cl
PCy3
14
A
diospongin A
Scheme 4 Cross-metathesis and an unexpected diastereoselective 1,4-Michael addition
O
5
A (5 mol%)
O
OTES S
OTES S
1
2
3
O
O
CH2Cl2, Δ
72%
7
11
8
R
S
S
9
5
19
15
10
6
4
1
CaCO3, MeI
MeCN–H2O (9:1)
R = (CH2)2Ph
MeO2C
O
TESO
O
TESO
O
MeO2C
TESO
B, KHMDS
O
O
R
18-crown-6
THF, –78 °C
52%
R
3'
2
2
86% 80% AcOH, Δ
CF3
O
O
O
TESO
O
O
O
P
O
F3C
O
3'
+
1
OMe
B
O
TESO
S
Scheme 7 Cross-metathesis, Still–Gennari Z-olefination, and com-
pletion of the synthesis
S
5
6
15
tetrahydrofuran, –78 °C) to give the Z-a,b-unsaturated
ethyl ester 2 in 52% overall yield from 19, with a Z/E ratio
of 97:3.26,27 Finally, one-pot deprotection and intramolec-
ular lactonization of 2 (80% AcOH) gave rugulactone 1 in
86% yield (30% overall yield from 15).18a The analytical
and spectral data of the synthetic product were in good
agreement with those reported in the literature.1,17
O
O
H
OTs
16
Scheme 5 Second retrosynthetic pathway
In summary, a total asymmetric synthesis of rugulactone
1 was realized in seven steps from commercially available
(2S)-glycidyl tosylate (16) with an overall yield of 19%. It
is noteworthy that the stereogenic center at C5 was con-
trolled by using the chiral pool, that the internal olefin was
built by using a cross-metathesis coupling, and that the Z-
configured unsaturated lactone was formed by a Still–
Gennari olefination/lactonization. The absence of expen-
sive chiral reagents in stoichiometric quantities and the
use of only a single catalytic step make this synthesis cost-
efficient and green. Furthermore, the synthetic pathway is
highly flexible and will be used to synthesize isomers and
analogues of rugulactone for in-depth biological tests; this
work will be published in due course.
O
n-BuLi, dithiane
S
O
OTs
THF, –78 °C
S
16
17
H2C=CHMgBr, CuI
THF, –40 °C
65%
TESCl, imidazole
OTES S
OH
S
DMAP, DMF
98%
S
S
15
18
Scheme 6 Synthesis of cross-metathesis precursor 15
which was immediately subjected to Still–Gennari olefi-
nation [methyl P,P-bis(2,2,2-trifluoroethyl)phosphono-
acetate, potassium hexamethyldisilazide, 18-crown-6,
CH2Cl2 (stabilized with 2-methylbut-2-ene) was purified by distil-
lation from CaH2 under N2 immediately before use. THF and Et2O
Synthesis 2010, No. 16, 2787–2793 © Thieme Stuttgart · New York

2790
F. Allais et al.
PAPER
were purified by distillation from sodium/benzoquinone under N2.
Moisture and O2-sensitive reactions were carried out in flame-dried
glassware under N2. Evaporations were conducted under reduced
pressure at a temperature below 35 °C unless otherwise noted. Col-
umn chromatography was carried out under a positive pressure of
N2 on 40–63 m silica gel. Melting points are uncorrected. 1H NMR
spectra of samples in the indicated solvent were recorded at 300
MHz at 20 °C (1H NMR: CDCl3 residual signal at 7.26 ppm). 13C
NMR spectra of samples in the indicated solvent were recorded at
75 MHz at 20 °C (13C NMR: CDCl3 residual signal at 77.26 ppm).
High-resolution mass spectra were recorded on a Tof-MS spectrom-
eter operating in the ESI (+) mode. All reported yields are uncor-
rected and refer to the purified products.
quenched with sat. aq NH4Cl, and the mixture was extracted with
Et2O (3 × 100 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash column chromatography
[cyclohexane–EtOAc (7:3)] gave a thick colorless oil; yield: 5.74 g
21
25
(53%); [a]D –15.8 (c 0.1, CHCl3) {Lit.20b [a]D –13.1 (c 0.58,
CHCl3)}. The spectral data agreed well with literature values.20b
IR (neat): 2924, 2862, 1612, 1586, 1512 cm–1
1H NMR (300 MHz, CDCl3): d = 7.24 (d, J = 8.7 Hz, 2 H, 7-H), 6.86
(d, J = 8.7 Hz, 2 H, 8-H), 4.45 (s, 2 H, 5-H), 3.79 (s, 3 H, 10-H), 3.58
(m, 2 H, 4-H), 3.04 (m, 1 H, 2-H), 2.75 (ddapp, J = 5.0 and 4.4 HZ,
1 H, 1-H), 2.50 (ddapp, J = 5.0 and 2.7 Hz, 1 H, 1-H), 1.88 (m, 1 H,
3-H), 1.76 (m, 1 H, 3-H).
13C NMR (75 MHz, CDCl3): d = 159.5 (s, 9-C), 130.0 (s, 6-C),
129.4 (d, 7-C), 114.1 (d, 8-C), 73.0 (t, 5-C), 67.0 (t, 4-C), 55.5 (q,
10-C), 50.3 (s, 2-C), 47.3 (t, 1-C), 33.2 (t, 3-C).
(4S)-2,2-Dimethyl-4-{2-[(4-methylbenzyl)oxy]ethyl}-1,3-diox-
olane (8)
A 60% dispersion of NaH (4.21 g, 0.105 mol) was added to a soln
of alcohol 7 (10.25 g, 70 mmol) in THF (25 mL) and DMF (25 mL)
at r.t., and the mixture was stirred for 30 min. PMBCl (14.25 mL,
0.105 mol) and Bu4NI (1.3 g, 3.5 mmol) were added sequentially,
and the mixture was stirred for a further 12 h. The reaction was
quenched with sat. aq NH4Cl and extracted with Et2O (3 × 100 mL).
The combined organic extracts were dried (MgSO4) and concentrat-
ed in vacuo. Flash column chromatography [cyclohexane–EtOAc
(3R)-1-[(4-Methoxybenzyl)oxy]hex-5-en-3-ol (11)
A 1.0 M soln of CH2=CHMgCl in THF (5.3 mL, 5.3 mmol) was
added to a stirred suspension of CuI (44 mg, 0.23 mmol) in THF (12
mL) at –50 °C, and the mixture was stirred for 30 min. A soln of the
epoxide 10 (417 mg, 2.3 mmol) in THF (5 mL) was added by can-
nula. The resulting mixture was stirred at –40 °C for 40 min then al-
lowed to warm to –10 °C over 30 min. The reaction was quenched
by addition of sat. aq NH4Cl. The residue was extracted with Et2O,
dried (MgSO4), and concentrated. The residue was purified by flash
column chromatography [cyclohexane–EtOAc (6:4)] to give a thick
25
(9:1)] gave a yellow oil; yield: 17.5 g (94%); [a]D –7.9 (c 0.1,
MeOH) [Lit.20b –8.4 (c 0.8, MeOH)]. The spectral data agreed well
with literature values.20b
20
IR (neat): 2984, 2865, 1612, 1513 cm–1.
colorless oil; yield: 470 mg (87%); [a]D +5.8 (c 1.37, CHCl3)
{Lit.28 [a]D25 +3.2 (c 1.0, CHCl3)}. The spectral spectral data agreed
1H NMR (300 MHz, CDCl3): d = 7.24 (d, J = 8.4 Hz, 2 H, 7-H), 6.87
(d, J = 8.4 Hz, 2 H, 8-H), 4.43 (s, 2 H, 5-H), 4.20 (ddtapp, J = 8.0, 6.3
and 5.7 Hz, 1 H, 1-H), 4.05 (dd, J = 8.0 and 6.0 Hz, 1 H, 2-H), 3.80
(s, 3 H, 10-H), 3.59–3.50 (m, 3 H, 4-H + 1-H), 1.96–1.79 (m, 2 H,
3-H), 1.40 (s, 3 H, 11-H, acetonide), 1.35 (s, 3 H, 12-H acetonide).
13C NMR (75 MHz, CDCl3): d = 159.5 (s, 9-C), 130.0 (s, 6-C),
129.4 (d, 7-C), 114.1 (d, 8-C), 108.8 [s, C(OMe)2], 74.2 (d, 2-C),
73.0 (t, 5-C), 69.9 (t, 1-C), 67.0 (t, 4-C), 55.5 (q, 10-C), 34.1 (t, 3-
C), 27.2 (q, 11-C), 26.0 (q, 12-C).
well with literature values.28
IR (neat): 3445, 3072, 2930, 2861, 1612, 1513, 1461, 1362, 1300,
1247, 1175, 1089, 1033 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.22 (d, J = 8.2 Hz, 2 H, 9-H), 6.84
(d, J = 8.2 Hz, 2 H, 10-H), 5.80 (ddt, J = 6.3, 10.5 and 17.1 Hz, 1 H,
2-H), 5.07 (d, J = 17.1 Hz, 1 H, 1-H trans), 5.06 (d, J = 10.5 Hz, 1
H, 1-H cis), 4.42 (s, 2 H, 7-C), 3.77 (s, 3 H, 12-H), 3.89–3.55 (m, 3
H, 4-H + 6-H), 2.97 (br s, 1 H, OH), 2.21 (tapp, J = 6.3 Hz, 2 H, 3-
H), 1.73 (tapp, J = 5.4 Hz, 2 H, 5-H).
13C NMR (75 MHz, CDCl3): d = 159.4 (s, 11-C), 135.1 (d, 2-C),
130.3 (s, 8-C), 129.5 (d, 9-C), 117.6 (t, 1-C), 114.0 (d, 10-C), 73.1
(t, 7-C), 70.5 (d, 4-C), 68.8 (t, 6-C), 55.4 (q, 12-C), 42.1 (t, 3-C),
36.0 (t, 5-C).
(2S)-4-[(4-Methylbenzyl)oxy]butane-1,2-diol (9)
Oxalic acid (16.9 mg, 0.188 mmol) was added to a soln of 8 (1.0 g,
3.75 mmol) and CeCl3·7H2O (2.79 g, 7.5 mmol) in MeCN (18.8
mL) at r.t., and the mixture was stirred for 90 min at r.t. The mixture
was then cooled to 0 °C and the reaction was quenched with sat. aq
NaHCO3 (5 mL). The mixture was extracted with EtOAc (3 × 10
mL), and the extracts were dried (MgSO4), filtered, and concentrat-
ed in vacuo. The crude product was purified by flash chromatogra-
phy [cyclohexane–EtOAc (8:2)] to give a thick yellow oil; yield:
823 mg (97%); [a]D23 +3.9 (c 0.1, CHCl3) {Lit.20b [a]D25 +4.4 (c 0.8,
CHCl3)}. The spectral data agreed well with literature values.20b
tert-Butyl[((1R)-1-{2-[(4-methoxybenzyl)oxy]ethyl}but-3-en-1-
yl)oxy]dimethylsilane (4)
TBSCl (244 mg, 1.62 mmol) was added to a stirred soln of the alco-
hol 15 (318 mg, 1.35 mmol) and imidazole (230 mg, 3.38 mmol) in
DMF (1 mL) at r.t., and the mixture was stirred for 12 h until the re-
action was complete (TLC). Sat. aq NaHCO3 (6 mL) was added, and
the mixture was extracted with Et2O, dried (MgSO4), and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography [cyclohexane–EtOAc (6:4)] to give a thick colorless oil;
IR (neat): 3373, 2932, 2863, 1612, 1586, 1512 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.24 (d, J = 8.4 Hz, 2 H, 7-H), 6.88
(d, J = 8.4 Hz, 2 H, 8-H), 4.45 (s, 2 H, 5-H), 3.90 (m, 1 H, 1-H), 3.80
(s, 3 H, 10-H), 3.70–3.60 (m, 3 H, 2-H + 4-H), 3.52–3.48 (m, 1 H,
1-H), 3.11 (d, J = 3.3 Hz, 1 H, OH), 2.31 (t, J = 6.0 Hz, 1 H, OH),
1.87–1.70 (m, 2 H, 3-H).
13C NMR (75 MHz, CDCl3): d = 159.3 (s, 9-C), 130.1 (s, 6-C),
129.5 (d, 7-C), 114.0 (d, 8-C), 72.8 (t, 5-C), 70.7 (d, 2-C), 67.5 (t,
1-C), 66.6 (t, 4-C), 55.3 (q, 10-C), 33.0 (t, 3-C).
20
yield: 462 mg (98%); [a]D –16.9 (c 0.8, CHCl3) [Lit.24a –15.7 (c
1.65, CHCl3)]. The spectral data agreed well with literature val-
ues.24a
IR (neat): 3076, 2956, 2930, 2858, 1614, 1515, 1250 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.26 (d, J = 8.4 Hz, 2 H, 9-H), 6.87
(d, J = 8.1 Hz, 2 H, 10-H), 5.81 (m, 1 H, 2-H), 5.03 (dapp, J = 12.9
Hz, 2 H, 1-H), 4.44 (B of AB system, d, J = 11.1 Hz, 1 H, 7-H), 4.38
(A of AB system, d, J = 11.1 Hz, 1 H, 7-H), 3.89 (m, 1 H, 4-H), 3.80
(s, 3 H, 12-H), 3.51 (tapp, J = 6.3 Hz, 2 H, 6-H), 2.23 (m, 2 H, 3-H),
1.74 (m, 2 H, 5-H), 0.88 (s, 9 H, Si-t-Bu), 0.05 (d, J = 2.1 Hz, 6 H,
SiMe2).
(2S)-2-{2-[(4-Methylbenzyl)oxy]ethyl}oxirane (10)
A soln of diol 9 (11.68 g, 51.6 mmol) in THF (200 mL) was added
to a suspension of NaH (60% dispersion, 5.16 g, 0.129 mol) in DMF
(50 mL) at 0 °C, and the mixture was stirred for 30 min. 1-[(2,4,6-
Triisopropylphenyl)sulfonyl]-1H-imidazole (19 g, 56.8 mmol) was
added and the soln was stirred at r.t. overnight. The reaction was
13C NMR (75 MHz, CDCl3): d = 159.4 (s, 11-C), 135.2 (d, 2-C),
131.0 (s, 8-C), 129.5 (d, 9-C), 117.2 (t, 1-C), 114.0 (d, 10-C), 72.8
Synthesis 2010, No. 16, 2787–2793 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Rugulactone
2791
(t, 7-C), 69.2 (d, 4-C), 67.0 (t, 6-C), 55.5 (q, 12-C), 42.5 t, 3-C), 37.0
(t, 5-C), 26.1 [q, SiC(CH3)3], 18.3 [s, SiC(CH3)3], –4.1 (q, SiMe2),
–4.5 (q, SiMe2).
{[(1R)-1-(1,3-Dithian-2-ylmethyl)but-3-en-1-yl]oxy}(triethyl)si-
lane (15)
TESCl (1.6 mL, 9.5 mmol) was added to a stirred soln of the alcohol
18 (1.4 g, 6.8 mmol), imidazole (1.83 g, 27 mmol), and DMAP (200
mg, 1.6 mmol) in DMF (5 mL) at 0 °C. The mixture was then stirred
at r.t. for 12 h until the reaction was complete (TLC). Aq NaHCO3
(20 mL) was added and the mixture was extracted with Et2O (3 × 40
mL), dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash column chromatography (cyclohexane–EtOAc
95:5) to give a thick colorless oil; yield: 2.1 g (98%); [a]D21 –26.0
(c 0.128, CHCl3) {Lit.24b [a]D22 –28.8 (c 0.13, CHCl3)}. The spectral
data agreed well with the literature values.24b
(4E,7R)-7-{[tert-Butyl(dimethyl)silyl]oxy}-9-[(4-methoxyben-
zyl)oxy]-1-phenylnon-4-en-3-one (12)22a
A soln of alkene 4 (84 mg, 0.24 mmol) and vinyl ketone 5 (115.3
mg, 7.2 mmol) in CH2Cl2 (12 mL) was bubbled with a N2 flow be-
fore Grubbs type II catalyst A (10.2 mg, 0.012 mmol) was added at
once. The mixture was then heated under N2 at 40 °C for 12 h. After
completion of the reaction, the solvent was removed under reduced
pressure and the residue was purified by column chromatography
[silica gel; cyclohexane–EtOAc (95:5)] to give a thick clear oil;
yield: 83.4 mg (72%).
IR (neat): 742, 915, 1005, 1088, 1240, 1275, 1373, 1422, 1458,
1640, 2876, 2904, 2953 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42–7.07 (m, 7 H, aromatic-H),
6.98–6.72 (m, 3 H, aromatic-H + 5-H), 6.09 (d, J = 15.9 Hz, 1 H, 4-
H), 4.43 (B of AB system, d, J = 11.4 Hz, 1 H, 10-H), 4.34 (A of AB
system, d, J = 11.4 Hz, 1 H, 10-H), 3.98 (m, 1 H, 7-H), 3.79 (s, 3 H,
15-H), 3.48 (m, 2 H, 9-H), 2.89 (m, 4 H, 1-H + 2-H), 2.36 (m, 2 H,
6-H), 1.71 (m, 2 H, 8-H), 0.87 [s, 9 H, SiC(CH3)3], 0.03 (s, 6 H,
SiMe2).
13C NMR (75 MHz, CDCl3): d = 199.4 (s, 3-C, C=O), 159.5 (s, 14-
C), 144.1 (d, 5-C), 141.5 (s, Ph), 132.7 (d, 4-C), 130.7 (s, 11-C),
129.5 (d, 12-C), 128.7 (d, Ph), 128.6 (d, Ph), 126.3 (d, Ph), 114.0 (d,
13-C), 72.9 (t, 10-C), 68.7 (d, 7-C), 66.6 (t, 9-C), 55.5 (q, 15-C),
41.7 (t, 2-C), 41.0 (t, 6-C), 37.4 (t, 8-C), 30.3 [t, 1-C), 26.0
SiC(CH3)3], 18.3 [s, SiC(CH3)3], –4.2 (q, SiMe2), –4.4 (q, SiMe2).
1H NMR (300 MHz, CDCl3): d = 5.85–5.71 (m, 1 H, 2-H), 5.09–
5.03 (m, 2 H, 1-H), 4.11 (dd, J = 6.0 and 8.4 Hz, 1 H, 6-H), 3.98–
4.06 (m, 1 H, 4-H), 2.93–2.78 (m, 4 H, 7-H), 2.27–2.22 (m, 2 H, 8-
H), 2.15–2.05 (m, 1 H, 3-H), 1.94–1.79 (m, 3 H, 3-H + 5-H), 0.97
(t, J = 8.1 Hz, 9 H, SiCH2CH3), 0.63 (q, J = 8.1 Hz, 6 H,
SiCH2CH3).
13C NMR (75 MHz, CDCl3): d = 134.5 (d, 2-C), 117.8 (t, 1-C), 68.4
(d, 4-C), 44.2 (t, 5-C), 42.6 (d, 6-C), 30.8 (t, 3-C), 30.3 (t, 7-C), 26.4
(t, 8-C), 7.2 (t, SiCH2CH3), 5.4 (q, SiCH2CH3).
HRMS: m/z [M + H]+ calcd for C15H30OS2Si: 319.1586; found:
319.1587.
5-Phenyl-pent-1-en-3-one (5)
HRMS: m/z [M + Na]+ calcd for C29H42NaO4Si: 505.2750; found:
505.2742.
A soln of Ph(CH2)2CHO (6; 1.0 g, 7.462 mmol) in THF (20 mL)
was added dropwise to a stirred 1 M soln of CH2=CHMgBr in THF
(11.2 mL, 11.18 mmol) at 0 °C, and the mixture was brought to r.t.
and stirred for 1 h. When the reaction was complete (TLC), it was
quenched with sat. aq NH4Cl, and the mixture was extracted with
Et2O (3 × 50 mL). The combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by column chromatography [silica gel, cyclohexane–
EtOAc (7:3)] to give the corresponding homoallylic alcohol as a
clear liquid; yield: 1.12 g (92%).
(2R)-1-(1,3-Dithian-2-yl)pent-4-en-2-ol (18)
A 1.4 M soln of BuLi in hexane (17 mL, 23.8 mmol) was added to
a soln of 1,3-dithiane (2.8 g, 23.3 mmol) in THF (31 mL) at –10 °C.
The soln was stirred at –10 °C for 2 h and then cooled to –78 °C. A
soln of (2S)-glycidyl tosylate (16; 5 g, 22.0 mmol) in THF (8 mL)
was added by cannula, and the soln was kept at –78 °C for 4 h then
allowed to warm to r.t. over 2 h. Sat. aq NaHCO3 was added and the
mixture was extracted with Et2O (3 × 50 mL), dried (MgSO4), and
concentrated in vacuo. The residue was purified to flash column
chromatography [cyclohexane–EtOAc (9:1)] to give the epoxide 17
as a colorless oil; yield: 2.6 g (14.9 mmol).
IR (neat): 3349, 1604, 1498, 1455, 1428, 1403, 750, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.14 (m, 5 H, aromatic-H),
5.92 (ddd, J = 6.3, 10.2 and 17.1 Hz, 1 H, 2-H), 5.27 (d, J = 17.1 Hz,
1 H, 1-H trans), 5.16 (d, J = 10.2 Hz, 1 H, 1-H cis), 4.14 (dt, J = 6.0
and 6.3 Hz, 1 H, 3-H), 2.74 (m, 2 H, 5-H), 1.97 (br s, 1 H, OH),
1.94–1.80 (m, 2 H, 4-H).
13C NMR (75 MHz, CDCl3): d = 142.1 (s, 6-C), 141.2 (d, 2-C),
128.7 (d, 8-C), 128.6 (d, 7-C), 126.0 (d, 9-C), 115.0 (t, 1-C), 72.6
(d, 3-C), 38.7 (t, 5-C), 31.8 (t, 4-C).
A 1.0 M soln of CH2=CHMgBr in THF (22 mL, 22 mmol) was add-
ed to a stirred suspension of CuI (500 mg, 2.6 mmol) in THF (70
mL) at –50 °C, and the mixture was stirred for 30 min. A soln of the
epoxide 17 (2.6 g, 14.9 mmol) in THF (10 mL) was then added by
cannula, and the mixture was stirred at –40 °C for 40 min then al-
lowed to warm to –10 °C over 30 min. The reaction was quenched
by the addition of sat. aq NH4Cl. The residue was extracted with
Et2O, dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash column chromatography [cyclohexane–EtOAc
(9:1)] to give secondary alcohol 18 as a thick colorless oil; yield: 2.8
A soln of the homoallylic alcohol obtained above (800 mg, 4.92
mmol) in CH2Cl2 (10 mL) was added to a stirred soln of Dess–Mar-
tin periodinane (2.3 g, 5.41 mmol) in dry CH2Cl2 (10 mL) at r.t., and
the mixture was stirred for 3 h. When the reaction was complete, the
mixture was filtered, diluted with H2O (10 mL), and extracted with
CH2Cl2 (2 × 30 mL). The combined organic layers were washed
with brine (20 mL), dried (MgSO4), and concentrated in vacuo. The
crude product was purified by column chromatography [silica gel,
cyclohexane–EtOAc (8:2)] to give the pure vinyl ketone 5 as a col-
orless liquid; yield: 757.0 mg (96%).
22
26
g (63%); [a]D +22.4 (c 0.2, CHCl3) {Lit.24a [a]D +24.2 (1.0,
CHCl3)}.
IR (neat): 3432, 1640, 1422, 1275, 1244 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.89–5.74 (m, 1 H, 2-H), 5.14 (d,
J = 12.9 Hz, 2 H, 1-H), 4.27 (t, J = 7.3 Hz, 1 H, 6-H), 3.99 (br, 1 H,
4-H), 2.97–2.81 (m, 4 H, 7-H), 2.33–2.20 (m, 2 H, 3-H), 2.18–2.10
(m, 2 H, 8-H), 2.03 (br, 1 H, OH), 1.89 (t, J = 6.8 Hz, 2 H, 5-H).
13C NMR (75 MHz, CDCl3): d = 133.9 (d, 2-C), 118.2 (t, 1-C), 67.4
(d, 4-C), 44.4 (t, 5-C), 42.1 (d, 6-C), 41.9 (t, 3-C), 30.3 (t, 7-C), 30.0
(t, 8-C).
IR (neat): 3061, 3027, 2925, 2856, 1709, 1605, 1495, 1450, 1403,
750, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.31–7.11 (m, 5 H, aromatic-H),
6.33 (dd, J = 10.2 and 17.7 Hz, 1 H, 2-H), 6.18 (d, J = 17.7 Hz, 1 H,
1-H trans), 5.79 (d, J = 10.2 Hz, 1 H, 1-H cis), 3.00–2.80 (m, 4 H,
4-H + 5-H).
HRMS: m/z [M]+ calcd for C9H16OS2: 204.0643; found: 204.0651.
Synthesis 2010, No. 16, 2787–2793 © Thieme Stuttgart · New York

2792
F. Allais et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 199.8 (s, 3-C, C=O), 141.3 (s, 6-
C), 136.7 (d, 2-C), 128.9 (d, 8-C), 128.5 (t, 7-C), 126.3 (t, 1-C), 41.4
(t, 4-C), 30.0 (t, 5-C).
132.8 (d, 4-C), 128.7 (d, Ph), 128.6 (d, Ph), 126.3 (d, Ph), 121.4 (d,
10-C), 70.8 (d, 7-C), 51.3 (q, 12-C), 41.7 (t, 2-C), 40.7 (t, 6-C), 36.7
(t, 8-C), 30.3 (t, 1-C), 7.1 (t, SiCH2CH3), 5.2 (q, SiCH2CH3).
HRMS: m/z [M + Na]+ calcd for C24H36NaO4Si: 439.2281; found:
439.2295.
(4E,7R)-8-(1,3-Dithian-2-yl)-1-phenyl-7-[(triethylsilyl)oxy]oct-
4-en-3-one (19)
A soln of alkene 15 (663 mg, 2.08 mmol) and vinyl ketone 5 (1.0 g,
6.24 mmol) in CH2Cl2 (104 mL) was bubbled with a N2 flow before
Grubbs type II catalyst A (88.3 mg, 0.104 mmol) was added at once.
The resulting mixture was heated under N2 at 40 °C for 12 h. When
the reaction was complete, the solvent was removed under reduced
pressure and the residue was purified by column chromatography
[silica gel, cyclohexane–EtOAc (95:5)] to give a thick clear oil;
yield: 675 mg (72%); [a]D21 –3.4 (c 0.1, CHCl3).
Rugulactone (1)
Enone 2 (129.2 mg, 0.31 mmol, 1 equiv) was dissolved in 80%
AcOH (1.5 mL) and the soln was stirred at 60 °C for 24 h. The re-
action was quenched with sat. aq NaHCO3 and the mixture was ex-
tracted with EtOAc (3 × 15 mL). The organic layer was washed
with brine, dried (MgSO4), filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography [cyclohexane–
25
EtOAc (6:4)]; yield: 72.1 mg (86%); [a]D –47.0 (c 0.3, CHCl3)
IR (neat): 3024, 2952, 2901, 2875, 1673, 1630, 1454, 1371, 1238,
1084, 1046, 724 cm–1.
[Lit.17a –46.5 (c 0.7, CHCl3)]. The spectral data agreed well with the
literature values.17
1H NMR (300 MHz, CDCl3): d = 7.31–7.11 (m, 5 H, aromatic-H),
6.80 (dt, J = 7.2 and 15.9 Hz, 1 H, 5-H), 6.13 (d, J = 15.9 Hz, 1 H,
4-H), 4.20–4.05 (m, 2 H, 7-H + 9-H), 3.10–2.71 (m, 8 H, 1-H + 2-
H + 10-H), 2.45–2.30 (m, 2 H, 6-H), 2.19–2.01 (m, 2 H, 8-H), 1.95–
1.77 (m, 2 H, 11-H), 0.97 (t, J = 8.1 Hz, 9 H, SiCH2CH3), 0.63 (q,
J = 8.1 Hz, 6 H, SiCH2CH3).
13C NMR (75 MHz, CDCl3): d = 199.3 (s, 3-C, C=O), 143.0 (d, 5-
C), 141.5 (s, Ph), 133.0 (d, 4-C), 128.7 (d, Ph), 128.6 (d, Ph), 126.3
(d, Ph), 67.9 (t, 7-C), 44.0 (t, 8-C), 43.1 (d, 9-C), 41.9 (t, 2-C), 41.0
(t, 6-C), 30.8 (t, 1-C), 30.3 (t, 10-C), 26.2 (t, 11-C), 7.2 (t,
SiCH2CH3), 5.3 (q, SiCH2CH3).
IR (neat): 3448, 2922, 2852, 1720, 1671, 1632, 1457, 1382, 1247,
1042 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32–7.11 (m, 5 H, aromatic-H),
6.88 (ddd, J = 3.9, 4.8 and 9.6 Hz, 1 H, 7-H), 6.80 (dt, J = 7.2 and
16.2 Hz, 1 H, 3-H), 6.20 (d, J = 16.2, 1 H, 2-H), 6.05 (d, J = 9.6 Hz,
1 H, 8-H), 4.55 (quintapp, J = 6.6 Hz, 1 H, 5-H), 2.94–2.86 (m, 4 H,
10-H + 11-H), 2.64 (dtapp, J = 6.6 and 7.2 Hz, 2 H, 4-H), 2.33 (m, 2
H, 6-H).
13C NMR (75 MHz, CDCl3): d = 199.2 (s, 9-C, C=O ketone), 163.9
(s, 1-C, C=O ester), 144.8 (d, 3-C), 141.3 (s, 12-C), 140.2 (d, 7-C),
133.8 (d, 8-C), 128.7 (d, 14-C), 128.6 (d, 13-C), 126.4 (d, 15-C),
121.8 (d, 2-C), 76.3 (d, 5-C), 42.0 (t, 10-C), 37.8 (t, 6-C), 30.2 (t,
11-C), 29.2 (t, 4-C).
HRMS: m/z [M + Na]+ calcd for C24H38NaO2S2Si: 473.1980; found:
473.1985.
HRMS: m/z [M + Na]+ calcd for C17H18NaO3: 293.1154; found:
293.1163.
Methyl (2Z,5R,7E)-9-Oxo-11-phenyl-5-[(triethylsilyl)oxy]un-
deca-2,7-dienoate (2)
A stirred mixture of enone 19 (225 mg, 0.5 mmol), MeI (0.32 mL,
5.1 mmol), and CaCO3 (100 mg, 2.6 mmol) in 9:1 v/v MeCN–H2O
(16.7 mL) was heated at 45 °C for 2.5 h then cooled to r.t. and the
bulk of the MeCN was removed. The mixture was then extracted
with Et2O (3 × 30 mL), dried (Na2SO4), and concentrated to provide
the crude aldehyde 3¢, which was used directly in the next step.
Acknowledgment
F.A. would like to thank Julien Pons for his help at the bench and
the INRA for financial support.
Methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate (B;
0.25 mL, 381 mg, 1.19 mmol) and a 0.5 M soln of KHMDS in tol-
uene (2.4 mL, 1.19 mmol) were added sequentially to a stirred soln
of 18-crown–6 (330 mg, 1.25 mmol) in dry THF (5.2 mL) at –40 °C
under argon. After 15 min, the mixture was cooled to –78 °C and
stirred for an additional 30 min. Crude aldehyde 3¢ (0.5 mmol) in
dry THF (2.6 mL) was added, and the resulting mixture was stirred
at –78 °C for 4 h. When the starting material 3¢ was completely con-
sumed (TLC), the reaction was quenched with sat. aq NaHCO3 (10
mL) at –78 °C. The cooling bath was removed and then the mixture
was extracted with EtOAc (3 × 25 mL). The combined extracts
were washed with brine (5 mL), dried (MgSO4), filtered, and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy [cyclohexane–EtOAc (9:1)] to give ester 2; yield: 108.4 mg
(52% isolated yield from 19); [a]D22 +109.4 (c 0.1, CHCl3).
References
(1) Meragelman, T. L.; Scudiero, D. A.; Davis, R. E.; Staudt, L.
M.; McCloud, T. G.; Cardellina, J. H. II.; Shoemaker, R. H.
J. Nat. Prod. 2009, 72, 336.
(2) Gilmore, T. D. Oncogene 2006, 25, 6680.
(3) Brasier, A. R. Cardiovasc. Toxicol. 2006, 6, 111.
(4) Perkins, N. D. Nat. Rev. Mol. Cell Biol. 2007, 8, 49.
(5) Gilmore, T. D. Oncogene 1999, 18, 6842.
(6) Tian, B.; Brasier, A. R. Recent Prog. Horm. Res. 2003, 58,
95.
(7) Albensi, B. C.; Mattson, M. P. Synapse (Hoboken, NJ, U. S.)
2000, 35, 151.
(8) Karin, M. Cell Res. 2008, 18, 334.
(9) Pikarsky, E.; Ben-Neriah, Y. Eur. J. Cancer 2006, 42, 779.
(10) Mantovani, A.; Marchesi, F.; Portal, C.; Allavena, P.; Sica,
A. Adv. Exp. Med. Biol. 2008, 610, 112.
IR (neat): 2960, 2909, 2877, 1721, 1675, 1634, 1437, 1174, 1089,
1002, 737 cm–1.
(11) Rali, T.; Wossa, S. W.; Leach, D. N. Molecules 2007, 12,
1H NMR (300 MHz, CDCl3): d = 7.31–7.11 (m, 5 H, aromatic-H),
6.84 (dt, J = 7.2 and 16.0 Hz, 1 H, 5-H), 6.35 (dt, J = 7.5 and 11.4
Hz, 1 H, 9-H), 6.12 (d, J = 16.0 Hz, 1 H, 4-H), 5.89 (d, J = 11.4 Hz,
1 H, 10-H), 4.00 (quintapp, J = 5.7 Hz, 1 H, 7-H), 3.68 (s, 3 H, 12-
H), 3.05–2.80 (m, 6 H, 1-H + 2-H + 6-H), 2.37 (tapp, J = 6.3 Hz, 2
H, 8-H), 0.95 (t, J = 7.8 Hz, 9 H, SiCH2CH3), 0.61 (q, J = 7.8 Hz, 6
H, SiCH2CH3).
149.
(12) Toribio, A.; Bonfils, A.; Delannay, E.; Prost, E.; Harakat, D.;
Henon, E.; Richard, B.; Litaudon, M.; Nuzillard, J.-M.;
Renault, J.-H. Org. Lett. 2006, 8, 3825.
(13) Davies-Coleman, M. T.; Rivett, D. E. A. Prog. Chem. Org.
Nat. Prod. 1989, 55, 1.
(14) Cavalheiro, A. J.; Yoshida, M. Phytochemistry (Elsevier)
13C NMR (75 MHz, CDCl3): d = 199.4 (s, 3-C, C=O ketone), 166.8
(s, 11-C, C=O ester), 145.9 (d, 9-C), 143.7 (d, 5-C), 141.5 (s, Ph),
2000, 53, 811.
(15) Murga, J.; García-Fortanet, J.; Carda, M.; Marco, J. A.
J. Org. Chem. 2004, 69, 7277; and references therein.
Synthesis 2010, No. 16, 2787–2793 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Rugulactone
2793
(16) Maxwell, A.; Dabideen, D.; Reynolds, W. F.; McLean, S.
J. Nat. Prod. 1998, 61, 815.
(17) (a) Reddipalli, G.; Venkataiah, M.; Fadnavis, N. W.
Tetrahedron: Asymmetry 2010, 21, 320. (b) Mohapatra, D.
K.; Das, P. P.; Reddy, D. S.; Yadav, J. S. Tetrahedron Lett.
2009, 50, 5941. (c) Kumar Reddy, D.; Shekhar, V.;
Srikhanth Reddy, T.; Purushotham Reddy, S.;
Venkateswarlu, Y. Tetrahedron: Asymmetry 2009, 20, 2315.
(18) (a) Allais, F.; Ducrot, P.-H. Synthesis 2010, 1649.
(b) Allais, F.; Martinet, S.; Ducrot, P.-H. Synthesis 2009,
3571. (c) Quentin, M.; Allasia, V.; Pegard, A.; Allais, F.;
Ducrot, P.-H.; Favery, B.; Levis, C.; Martinet, S.; Masur, C.;
Ponchet, M.; Roby, D.; Schlaich, N.-L.; Jouanin, L.; Keller,
H. PLoS Pathog. 2009, 5, e1000264.
(19) Li, D.-R.; Khang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.;
Chen, J.; Liu, B.; Su, C.; Zhou, X.-S.; Lin, G.-Q. Chem. Eur.
J. 2006, 12, 1185.
(20) (a) Xiangshu, X.; Donghu, B. Synlett 2001, 535. (b) Gaunt,
M. J.; Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D. F.;
Ley, S. V. Org. Lett. 2003, 5, 4819.
(21) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(22) (a) As the first pathway did not operate as predicted,
compound 12 was not thoroughly characterized.
(b) Compound 13 was identified among other products in the
crude mixture and was not purified.
(23) Bressy, C.; Allais, F.; Cossy, J. Synlett 2006, 3455.
(24) (a) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001,
57, 6311. (b) Jin, M.; Taylor, R. E. Org. Lett. 2005, 7, 1303.
(25) Fürstner, A.; Seidel, G.; Kindler, N. Tetrahedron 1999, 55,
8215.
(26) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(27) The Z/E ratio was determined from the 1H and 13C NMR
spectra of compound 2 and confirmed by GC/MS.
(28) Karuturi, R.; Vangaru, S.; Jondoss, J. P. S.;
Chitturi Bhujanga, R.; Yenamandra, V. Helv. Chim. Acta
2009, 92, 1866.
Synthesis 2010, No. 16, 2787–2793 © Thieme Stuttgart · New York