Rapid synthesis of taxifolione and taxifolial D, two metabolites from the Marine alga caulerpa taxifolia

Article abstract of DOI:10.2174/157017809787003179

The synthesis of two natural products - Taxifolione and Taxifolial D - isolated from the marine alga Caulerpa taxifolia invading the Mediterranean Sea was performed. Coupling reactions allowed for a rapid synthesis. The surprising Z configuration of Taxif

Full text of DOI:10.2174/157017809787003179

Letters in Organic Chemistry, 2009, 6, 65-70
65
Rapid Synthesis of Taxifolione and Taxifolial D, Two Metabolites from the
Marine Alga Caulerpa taxifolia
Fabien Fécourt, Cédric Carlier and Patrick Pale*
Laboratoire de synthèse et réactivité organiques, associé au CNRS, Institut de Chimie, Université Louis Pasteur, 4 rue
Blaise Pascal, 67000 Strasbourg, France
Received December 28, 2007: Revised October 19, 2008: Accepted October 23, 2008
Abstract: The synthesis of two natural products - Taxifolione and Taxifolial D – isolated from the marine alga Caulerpa
taxifolia invading the Mediterranean Sea was performed. Coupling reactions allowed for a rapid synthesis. The surprising
Z configuration of Taxifolial D was confirmed after synthesis and comparison of each synthetic stereoisomer.
Keywords: Terpenoids, enynes, cross-coupling, antitumor agents.
INTRODUCTION
are probably oxidation products derived from the other me-
tabolites or from a common biogenic precursor. Surprisingly,
Taxifolial D was reported as a Z stereoisomer while all other
related metabolites exhibit the E stereochemistry for the
same double bond (Fig. 1). This led us to synthesize both
isomers in order to check its stereochemistry.
Tropical algae usually living in herbivore-rich tropical
waters have set up various defense systems against grazing
fishes and invertebrates. One of the most efficient systems is
based on the release of repulsive and toxic metabolites [1]. A
tropical green seaweed, Caulerpa taxifolia, was accidentally
introduced in the Mediterranean Sea more than a decade ago
[2], and after adaptation [3], this alga started spreading, now
covering thousands of sea floor square kilometers, and lead-
ing to modifications in the Mediterranean ecosystem with a
notable decrease in the biodiversity [4]. Due to its origin, this
alga is releasing a cocktail of toxic and repellent metabolites
and this has been proposed to explain its rapid proliferation
[5]. The major metabolite Caulerpenyne (Fig. 1) exhibits
several biological activities [3, 6], among which are anti-
proliferative activity and modification of the cell microtu-
bule network [7]. The activities of the other metabolites so
far remain unknown.
RESULTS AND DISCUSSION
Synthesis of Taxifolione
A rapid and convergent access to Taxifolione can be en-
visaged through either acylation of 4-methylpent-3-en-1-yne
or coupling reaction [9] between 1-bromo-2-methylpropene
and but-1-yn-3-ol, both being commercially available,
(Scheme 1, routes a and b respectively). Both routes were
explored to find the more appropriate on large scale.
O
b
AcO
a
OAc
b
a
OAc
OH
Caulerpenyne
O
m
X
O
X
O
Scheme 1.
O
Indeed, based on the Holmes procedure [10], we were
able to exchange the silyl group of 1-trimethylsilyl-4-
methylpent-3-en-1-yne 1 by lithium (Scheme 2). However,
the so formed lithium acetylide could not be trapped by con-
ventionnal acetylating agents and only N-methoxy-N-
methylacetamide [11] proved to be effective enough, but at
room temperature. The starting enyne 1 was obtained from
the commercially available 1-bromo-3-trimethylsilylprop-2-
yne by phosphonylation and Wadsworth-Emmons condensa-
tion with acetone [12].
IsoTaxifolial D
Taxifolione
Taxifolial D
Fig. (1).
In order to learn more on the bioactivity of each metabo-
lites, we embarked on the synthesis of each of them [8], and
we reported here the first total synthesis of two of them, i. e.
Taxifolione and Taxifolial D (Fig. 1). These natural products
*Address correspondence to this author at the Laboratoire de synthèse et
réactivité organique, associé au CNRS, Institut de Chimie, Université Louis
Pasteur, 4 rue Blaise Pascal, 67000 Strasbourg, France; Fax: (33) (0)390 241
517; E-mail: ppale@chimie.u-strasbg.fr
Alternatively, but-1-yn-3-ol was coupled with 1-bromo-
2-methylpropene in the presence of catalytic amounts of
bis(triphenylphosphine)palladium dichloride and copper io-
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Fécourt et al.
dide in Sonogashira conditions [13] (Scheme 2). The enynol
2 was isolated in good yields. Although propargylic, this
alcohol was best oxidized with pyridinium dichromate in
dichloromethane.
4E were then deprotonated with n-BuLi in THF at -78°C,
and the corresponding acetylides were trapped by isobu-
tyraldehyde, giving the corresponding alcohols 5Z or 5E in
good yields. The elimination step proved to be far from ob-
vious and eventually, we found that treatment with triflic
anhydride in the presence of pyridine at low but controlled
temperature gave the expected dienynes 6Z or 6E with rea-
sonable yields. Deprotection by tetrabutylammonium fluo-
ride treatment followed by manganese dioxide oxidation
provided Taxifolial D and Isotaxifolial D. These compounds
were thus obtained in 5 steps with respectively 38 and 36 %
overall yields.
Br
SiMe3
i, ii, 58 %
SiMe3
1
O
OMe
iii, 56 %
N
O
OH
OH
i, 92 %
Taxifolione
v, 97 %
3Z
3E
i, 90 %
OH
OH
Br
OSiPh2tBu
iv, 72 %
2
OSiPh2tBu
4Z
4E
Scheme 2. i) HP(O)(OEt)2, THF, LiHMDS, -78°C; ii) LiHMDS,
THF, then Me2CO, -78°C; iii) MeLi.LiBr, THF, rt; iv) PdCl2(PPh3)2
5 mol%, CuI 10 mol%, HNEt2; v) PDC, CH2Cl2, rt.
ii, 80 %
ii, 75 %
The enynone so obtained proved identical with the natu-
ral compound. Taxifolione was thus obtained in either 2
steps with an excellent overall yield (69%) or in 3 steps but
less effectively (31% overall yield). The coupling route was
thus the best and more scalable. However, the acetylation
route allows introducing labels at various locations into the
structure for biological studies.
OSiPh2tBu
OSiPh2tBu
OH
OH
5Z
5E
iii, 60 %
iii, 62 %
Synthesis of Taxifolial D and Isotaxifolial D
The synthesis of Taxifolial D and its stereoisomer
Isotaxifolial D can also be envisaged through either
alkylation (Scheme 3, route a) or coupling reactions (route b)
[9], and again, both routes were explored for the same
reasons.
OSiPh2tBu
OSiPh2tBu
6Z
6E
iv, 88 %
iv, 92 %
O
OH
a
b
OH
7Z
7E
v, 95 %
v, 96 %
OR
OR
X
O
O
Scheme 3.
O
IsoTaxifolial D
Taxifolial D
The alkylation route was based on the addition of the an-
ion derived from Z or E 3-methylpent-2-en-3-yn-1-ol, 3Z or
3E respectively [14, 14c], to isobutyraldehyde, followed by
elimination (Scheme 4). Each alcohol 3Z or 3E was first
protected as tert-butyldiphenylsilyl ether. These ethers 4Z or
Scheme 4. i) tBuPh2SiCl, imidazole, CH2Cl2; ii) n-BuLi, THF-
78°C, then iPrCHO; iii) Tf2O, pyridine, CH2Cl2, -30°C; iv)
nBu4NF, CH2Cl2, rt; v) MnO2, CH2Cl2, rt.

Rapid Synthesis of Taxifolione and Taxifolial D
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
67
Pd-catalyzed coupling reactions usually are tolerant to
hydroxyl groups. We thus performed these reactions with 1-
bromo-2-methylpropene and 3Z or 3E without protecting
group (Scheme 5). Under the original Sonogashira condi-
tions [13], the expected dienynols 7Z or 7E were indeed
stereospecificaly obtained. However, the yield was very
good for the Z isomer (79%) but surprisingly low for the E
isomer (45%). These dienynols were then independently
oxidized with manganese dioxide providing Taxifolial D and
Isotaxifolial D in respectively 76 % and 43 % yield over 2
steps.
CONCLUSION
In conclusion, two metabolites isolated from the alga
Caulerpa taxifolia were synthesized with good overall yields
and various routes were evaluated. By synthesizing the Z and
E isomers of Taxifolial D, we were able to confirm the stere-
ochemistry of the natural compound. We are currently evalu-
ating the bioactivity of these compounds.
EXPERIMENTAL SECTION
1H and 13C NMR spectra were recorded on Bruker AC-
1
With no protection-deprotection steps, the coupling route
proved to be faster and more efficient than the alkylation
route, especially for the Z isomer, the natural one (76 vs 38
% overall yield).
300 spectrometers. For H NMR, TMS was used as internal
standard, for 13C NMR, solvent peak at 77.00 (CDCl3) were
used. Column chromatography was performed with Merck
silica gel (0.040–0.063 mesh). TLC used MERCK Art 5554
DC Alufolien Kieselgel 60 PF254 with detection by UV-
absorption (254 nm) and appropriate staining. All reactions
involving air and moisture sensitive materials were con-
ducted under an atmosphere of dry argon. All solvents were
freshly distilled by standard procedures.
OH
OH
3Z
Br
3E
Br
i, 45 %
i, 79 %
Taxifolione Synthesis Through Cross-Coupling
6-Methylhept-5-en-3-yn-2-ol (2)
To a solution of 1-bromo-2-methylpropene (1.20 g, 8.89
mmol, 1.1 eq.) in anhydrous and degassed Et2NH (10 mL)
were successively added at 0°C, PdCl2(PPh3)2 (0.104 g 0.148
mmol, 0.02 eq.), CuI (0.141 g, 0.740 mmol, 0.10 eq.) and a
solution of butyn-3-ol (0.571 g, 8.15 mmol, 1 eq.) in anhy-
drous and degassed Et2NH (20 mL). The initially slightly
yellow solution gradually darkened. After disappearance of
the starting material as judged from TLC (3 to 4 h), a satu-
rated aqueous solution of ammonium chloride was added at
0°C. After extraction with diethyl ether, the combined or-
ganic layers were washed with water, dried over Na2SO4,
filtrated and concentrated. The orange oil was purified by
flash-chromatography (cyclohexane/EtOAc: 4/1) to give
pure product 2 (0.725 g, 72%).
OH
OH
7Z
7E
v, 95 %
v, 96 %
O
O
IsoTaxifolial D
Taxifolial D
Scheme 5. i) PdCl2(PPh3)2 5 mol%, CuI 10 mol%, HNEt2; ii)
1H-NMR (300 MHz) CDCl3: 1.47 (d, 3H, J = 6.6 Hz);
1.79 (br d, 3H, J = 1.4 Hz); 1.87 (br s, 3H); 2.01 (s, 1H);
4.66 (qd, 1H, J = 1.4, 6.5 Hz); 5.23-5.26 (m, 1H). 13C-NMR
(75 MHz) CDCl3: 20.9 (CH3); 24.6 (CH3); 24.8 (CH3); 58.9
(CH); 82.0 (Cq); 93.1 (Cq); 104.5 (CH); 149.1 (Cq). MS
(EI): m/z (%) = 124.1 ([M]+, 50); 109.1 (100); 79.1 (35). IR
(NaCl; cm-1): 1055; 1215; 1633; 2206; 2922; 2933; 2991;
3015; 3388.
MnO2, CH2Cl2, rt.
Comparison of 1H and 13C NMR spectra of synthetic
Taxifolial D and Isotaxifolial D revealed some key differ-
ences.
For the synthetic Z isomer, NMR spectra proved to be
identical to those described by Pietra and al [5] for the natu-
ral Taxifolial D. Surprisingly, the H NMR spectra of the
1
synthetic E isomer were very similar to the Z isomer. Only
the signals corresponding to the vinylic H2 proton and the
methyl group ꢀ to the carbonyl group were significantly
shifted (from 6.09 ppm in the Z to 6.16 ppm in the E isomer,
and from 2.12 ppm in the Z to 2.31 ppm in the E isomer,
respectively). In contrast, the 13C NMR spectra were quite
different with the signals of the enynal system shifted. The
most significant shift was observed for the same methyl
group (from 25.1 ppm for the Z to 18.6 ppm for the E iso-
mer). NOE experiments revealed a clear relation between
this methyl group and the vinylic H2 proton for the Z isomer
and between this methyl group and the aldehyde proton for
the E isomer. All these data confirmed the surprising stereo-
chemistry of the natural Taxifolial D.
Taxifolione (= 6-methylhept-5-en-3-yn-2-one)
To a solution of enynol 2 (0.500 g, 4.03 mmol) in anhy-
drous CH2Cl2 (20 mL) was added anhydrous PDC (3.18 g,
8.45 mmol, 2.1 eq.). The mixture was stirred overnight, fil-
tered through a pad of Celite® and rinsed with EtOAc. After
evaporation, the yellow-brown oil was purified by flash-
chromatography (cyclohexane/EtOAc: 7/3) providing pure
Taxifolione (0.477 g, 97%) as slightly yellow oil.
1H-NMR (300 MHz) CDCl3: 1.90 (br d, 3H, J = 1.5 Hz);
1.99 (br s, 3H); 2.36 (s, 3H); 5.39-5.42 (m, 1H). 13C-NMR
(75 MHz) CDCl3: 21.8 (CH3); 25.5 (CH3); 32.7 (CH3); 89.7
(Cq); 91.6 (Cq); 103.5 (CH); 158.2 (Cq); 184.7 (Cq). MS

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Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Fécourt et al.
(EI): m/z (%) = 122.1 ([M]+, 51); 107.1 (100); 77.1 (43). IR
(CH); 133.5 (Cq); 135.6 (CH); 138.2 (CH). IR (NaCl; cm-1):
1057; 1115; 1427; 1589-1620; 2188; 3073.
(NaCl; cm-1): 755; 1249; 1360; 1618; 1654; 2913-3016.
1-Trimethylsilyl-4-methylpent-3-en-1-yne (1)
(2E)-1-tert-Butyldiphenylsilyloxy-3-methylpent-2-en-4-yne
(4E)
A solution of LiHMDS (13.55 mL, 1.06 M, 14.36 mmol,
1.1 eq.) in THF was slowly added to a solution of diethyl (3-
trimethylsilylprop-2-ynyl)phosphonate (3.24 g, 13.05 mmol)
in THF (25 mL) at –78 °C. The resulting red solution was
stirred for 30 min. at -78°C. At this temperature, acetone
(1.44 mL, 9.60 mmol, 1.5 eq.) was then added. The resulting
yellow solution was stirred at -78 °C for a further 30 min.
and then at room temperature for 18 h. The mixture was then
diluted with hexane (100 mL) and water (50 mL). The aque-
ous layer was decanted and extracted twice with hexane (50
mL). The organic layer was washed twice with brine (100
mL). The combined organic layers were then dried over
MgSO4, filtered and evaporated in an ice-bath. The residue
was purified by flash-chromatography on silica gel (pentane)
and the solvent was evaporated in an ice bath to give 1 as a
colourless and volatile liquid (1.43 g, 72%).
To a solution of freshly distilled (2E)-3-methylpent-2-en-
4-ynol 3E (1.85 g, 19.2 mmol) in DMF (20 mL) were added
at room temperature tert-butyldiphenylchlorosilane (6.5 mL,
25.0 mmol; 1.3 eq.) and imidazole (3.39 g, 49.8 mmol; 2.6
eq.). After overnight stirring, 20 mL of H2O were added and
the resulting mixture was stirred for 30 min. The aqueous
layer was extracted with dichloromethane. The combined
organic layers were then dried over Na2SO4, filtered and
concentrated. Flash chromatography (cyclohexane/EtOAc:
97/3) gave pure product 4E (5.78 g, 90%).
1H-NMR (300 MHz) CDCl3: 1.14 (s, 9H); 1.91 (q, 3H, J
= 1.4 Hz); 3.05 (s, 1H); 4.52 (dq, 2H, J = 1.4, 6.3 Hz); 6.00
(tq, 1H, J = 1.5, 6.3 Hz); 7.41-7.80 (m; 10H). 13C-NMR (75
MHz) CDCl3: 19.3 (Cq); 23.0 (CH3); 27.0 (CH3); 63.0
(CH2); 82.0 (CH and Cq); 117.9 (Cq); 127.8 (CH); 129.7
(CH); 133.8 (Cq); 135.7 (CH); 136.4 (CH). IR (NaCl; cm-1):
1056; 1112; 1427; 1589-1620; 1822-1990; 2188; 2857-2959;
3071.
1H-NMR (300 MHz) CDCl3: 0.09 (s, 9H); 1.61 (br d, 3H,
J = 1.9 Hz); 1.72 (br d, 3H, J = 1.3 Hz); 5.08-5.11 (m, 1H).
13C-NMR (75 MHz) CDCl3: 0.1 (CH3); 21.1 (CH3); 24.7
(CH3); 95.9 (Cq); 103.4 (Cq); 105.3 (CH); 150.2 (Cq).
(2Z)-1-tert-butyldiphenyl-silyloxy-3,7-dimethylocta-2-en-4-
yn-6-ol (5Z)
Taxifolione Via Weinreb Amide Coupling
To a solution of 1-trimethylsilyl-4-methylpent-3-enyne 1
(105 mg, 0.69 mmol, 1 eq.) in anhydrous THF (4.5 mL) was
added at room temperature MeLi-LiBr (0.51 mL, 1.5 M in
diethylether; 0.76 mmol, 1.1 eq.). The resulting yellow-
orange mixture was stirred 3h at this temperature. At -78°C,
a solution of N-methoxy-N-methylacetamide (142 mg, 1.38
mmol, 2 eq.) in THF (5 mL) was added. The mixture was
stirred for 2h at -78°C and 2h at room temperature. The reac-
tion was then quenched by addition of aqueous saturated
NH4Cl solution. The organic layer was extracted with diethyl
ether, washed twice with a saturated solution of NH4Cl and
once with water. The organic layer was dried over MgSO4,
filtrated and concentrated to give the slightly yellow liquid
Taxifolione (47 mg, 56%).
To a solution of (2Z)-1-tert-butyldiphenylsilyloxy-3-
methylpent-2-en-3-yn-1-ol 4Z (1.00 g, 2.99 mmol) in anhy-
drous THF (20 mL) at -78 °C under argon were added n-
BuLi (2.40 mL, 1.48 M in hexane; 3.55 mmol, 1.2 eq.). After
stirring for 1h at -78 °C, isobutyraldehyde (0.33 mL, 3.62
mmol, 1.2 eq.) was added. The yellow solution was further
stirred for a further 2 h at -78°C. The reaction was then
quenched by an aqueous saturated NH4Cl solution. The
aqueous layer was extracted with dichloromethane. The
combined organic layers were then dried over Na2SO4, fil-
tered and concentrated. Flash-chromatography (cyclohex-
ane/EtOAc: 9/1) provided pure product 5Z (0.915 g, 75%) as
yellowish viscous oil.
1H-NMR (300 MHz) CDCl3: 0.87 (d, 3H, J = 6.8 Hz);
0.87 (d, 3H, J = 6.7 Hz); 1.05 (s, 9H); 1.52 (s, 1H); 1.70-1.81
(m, 1H); 1.84 (br d, 3H, J = 1.4 Hz); 4.16 (d, 1H, J = 5.5
Hz); 4.40 (dq, 2H, J = 1.3, 6.3 Hz); 5.87 (tq, 1H, J = 1.5, 6.3
Hz); 7.35-7.71 (m, 10H). 13C-NMR (75 MHz) CDCl3: 17.4
(CH3); 18.1 (CH3); 19.2 (Cq); 23.0 (CH3); 26.9 (CH3); 34.5
(CH); 63.2 (CH2); 68.3 (CH); 83.9 (Cq); 93.6 (Cq); 118.4
(Cq); 127.7 (CH); 129.6 (CH); 133.8 (Cq); 135.6 (CH);
136.7 (CH). MS (ESI): m/z = 429.22 [M+Na]+. IR (NaCl;
cm-1): 705, 774, 1064, 1110, 1381, 1427, 1470, 3074, 3047,
3407.
Taxifolial and Isotaxifolial D Synthesis Through Alkyla-
tion
(2Z)-1-tert-Butyldiphenylsilyloxy-3-methylpent-2-en-4-yne
(4Z)
To a solution of freshly distilled (2Z)-3-methylpent-2-en-
4-ynol 3Z (1.83 g, 19.4 mmol) in DMF (15 mL) were added
at room temperature tert-butyldiphenylchlorosilane (6.5 mL,
25.0 mmol; 1.3 eq.) and imidazole (3.39 g, 49.8 mmol; 2.6
eq.). After overnight stirring, water (20 mL) was added and
the resulting mixture was stirred for 30 min. The aqueous
layer was extracted with dichloromethane. The organic lay-
ers were then combined, dried over Na2SO4 and concen-
trated. A flash-chromatography (cyclohexane/EtOAc: 97/3)
gave pure product 4Z (5.97 g, 92%).
1H-NMR (300 MHz) CDCl3: 1.05 (s, 9H); 1.62 (dt, 3H, J
= 1.1, 2.5 Hz); 2.80 (s, 1H); 4.27 (dq, 2H, J = 1.0, 6.2 Hz);
6.12 (tq, 1H, J = 1.5, 6.2 Hz); 7.36-7.71 (m, 10H). 13C-NMR
(75 MHz) CDCl3: 17.4 (CH3); 19.2 (Cq); 26.8 (CH3); 60.7
(CH2); 74.6 (Cq); 86.2 (CH); 117.8 (Cq); 127.7 (CH); 129.7
(2E)-1-tert-butyldiphenyl-silyloxy-3,7-dimethylocta-2-en-4-
yn-6-ol (5E)
To a solution of (2E)-1-tert-butyldiphenylsilyloxy-3-
methylpent-2-en-3-yn-1-ol 4E (1.00 g, 2.99 mmol) in anhy-
drous THF (20 mL) at -78 °C under argon, was added n-
BuLi (2.40 mL, 1.48 M in hexane, 3.55 mmol, 1.2 eq.). After
stirring for 1h at -78 °C, isobutyraldehyde (0.33 mL, 3.62
mmol, 1.2 eq.) was added. The yellow solution was stirred
for a further 2 h at -78°C. The reaction was then quenched
by an aqueous saturated NH4Cl solution. After decantation,

Rapid Synthesis of Taxifolione and Taxifolial D
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
69
the aqueous layer was extracted with dichloromethane. The
combined organic layers were then dried over Na2SO, fil-
tered and evaporated. Flash-chromatography (cyclohex-
ane/EtOAc: 9/1) provided pure product 5E (0.969 g, 80%)as
yellowish viscous oil.
1H-NMR (300 MHz) CDCl3: 1.01 (d, 3H, J = 6.7 Hz);
1.03 (d, 3H, J = 6.7 Hz); 1.05 (s, 9H); 1.62 (dt, 3H, J = 1.0,
1.4 Hz); 1.76 (d, 1H, J = 5.6 Hz); 1.90 (m, 1H); 4.27 (dq,
2H, J = 1.1, 6.3 Hz); 4.29 (d, 1H, J = 5.4 Hz); 6.02 (tq, 1H, J
= 1.4, 6.2 Hz); 7.37-7.72 (m, 10H). 13C-NMR (75 MHz)
CDCl3: 17.6 (CH3); 17.8 (CH3); 18.2 (CH3); 19.2 (Cq); 26.8
(CH3); 34.7 (CH); 60.8 (CH2); 68.4 (CH); 86.4 (Cq); 88,1
(Cq); 118.4 (Cq); 127.8 (CH); 129.7 (CH); 133.6 (Cq); 135.6
(CH); 136.7 (CH). MS (ESI): m/z = 429.22 [M+Na]+. IR
(NaCl; cm-1): 705, 775, 1064, 1110, 1381, 1427, 1470, 1050,
3407.
1H-NMR (300 MHz) CDCl3: 1.06 (s, 9H); 1.65 (br d, 3H,
J = 1.3 Hz); 1.83 (br d, 3H, J = 1.6 Hz); 1.91 (br s, 3H); 4.27
(dq, 2H, J = 1.0, 6.3 Hz); 5.36-5.38 (m, 1H); 5.99 (tq, 1H, J
= 1.5, 6.4 Hz); 7.36-7.71 (m; 10H). 13C-NMR (75 MHz)
CDCl3: 17.8 (CH3); 19.2 (Cq); 21.0 (CH3); 24.9 (CH3); 26.8
(CH3); 60.9 (CH2); 85.3 (Cq); 94.1 (Cq); 105.3 (CH); 119.5
(Cq); 127.7 (CH), 129.6 (CH); 133.6 (Cq); 135.1 (CH);
135.6 (CH); 148 (Cq). MS (CI/Isobutane): m/z (%) = 389.2
([M+H]+,19); 331.1 (65); 311 (21); 199.1 (56); 133.2 (100).
IR (NaCl; cm-1): 1057; 1115; 1427; 1589-1620; 2188; 3073.
(2Z)-3,7-dimethylocta-2,6-dien-4-ynol (7Z)
In a solution of (2Z)-1-tert-butyldiphenylsilyloxy-3,7-
dimethylocta-2,6-dien-4-yne 6Z (0.210 g, 0.54 mmol) in
anhydrous THF (5 mL) was added tetrabutylammonium
fluoride (0.65 mL, 1M in THF, 0.65 mmol, 1.2 eq.). The
mixture was stirred 3h and was hydrolyzed by an aqueous
saturated NH4Cl solution. The aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered and evaporated. The desired product 7Z
(0.075 g, 92%) was obtained after flash chromatography
(cyclohexane/EtOAc: 4/1) as a yellowish oil.
(2Z)-1-tert-butyldiphenylsilyloxy-3,7-dimethylocta-2,6-
dien-4-yne (6Z)
At -30°C in CH2Cl2 (5 mL) were successively added
pyridine (35 μL, 0.434 mmol, 1.05 eq.) and triflic anhydride
(75 μL, 0.445 mmol, 1.07 eq.). The resulting yellow solution
containing a white precipitate was stirred over 30 min. A
solution of (2Z)-1-tert-butyl-diphenylsilyloxy-3,7-dimethyl-
octa-2-en-4-yn-6-ol 5Z (169 mg, 0.416 mmol) in CH2Cl2 (5
mL) was added. When the solution began to turn brown (5
min.), pyridine (340 μL, 4.21 mmol, 10 eq.) were added. The
solution was further stirred for a further 3h at -30°C. The
reaction was then hydrolyzed by addition of water. The
aqueous layer was extracted with dichloromethane. The
combined organic layers were then dried over Na2SO4, fil-
trated and evaporated. A flash-chromatography (cyclohex-
ane/EtOAc: 9/1) gave the product 6Z (101 mg, 62%).
(2E)-3,7-dimethylocta-2,6-dien-4-ynol (7E)
In a solution of (2E)-1-tert-butyldiphenylsilyloxy-3,7-
dimethylocta-2,6-dien-4-yne 6E (0.210 g, 0.54 mmol) in
anhydrous THF (5 mL) was added tetrabutylammonium
fluoride (0.65 mL, 1M in THF, 0.65 mmol, 1.2 eq.). The
mixture was stirred 3h and was hydrolyzed by an aqueous
saturated NH4Cl solution. The aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried over
Na2SO4, filtered and evaporated. The desired product 7E
(0.071 g, 88%) was obtained after flash chromatography
(cyclohexane/EtOAc: 4/1) as slightly yellow oil.
1H-NMR (300 MHz) CDCl3: 1.07 (s, 9H); 1.72 (br s,
3H); 1.79 (br d, 3H, J = 1.5 Hz); 1.88 (br d; 3H; J = 1.4 Hz);
4.46 (dq, 2H, J = 1.3, 6.3 Hz); 5.30-5.32 (m, 1H); 5.81 (tq;
1H; J = 1.5, 6.2 Hz); 7.35-7.72 (m; 10H). 13C-NMR (75
MHz) CDCl3: 19.3 (Cq); 20.9 (CH3); 23.2 (CH3); 24.9
(CH3); 26.9 (CH3) 63.3 (CH2); 90.0 (Cq); 92.5 (Cq); 105.4
(CH); 119.3 (Cq); 127.6 (CH); 129.5 (CH) 133.9 (Cq); 135.2
(CH); 135.6 (CH); 148.4 (Cq). MS (CI/Isobutane): m/z (%) =
389.2 ([M+H]+,18); 331.1 (65); 311 (21); 199.1 (56); 133.2
(100). IR (NaCl; cm-1): 1056; 1112; 1427; 1589-1620; 1822-
1990; 2188; 2857-2959; 3071.
Taxifolial and Isotaxifolial D Synthesis Through Cross-
Coupling Reactions
(2Z)-3,7-dimethylocta-2,6-dien-4-ynol (7Z)
To a solution of 1-bromo-2-methylpropene (0.750 g, 5.55
mmol, 1.1 eq.) in anhydrous and degassed Et2NH (10 mL)
were successively added at 0°C PdCl2(PPh3)2 (0.080 g 0.11
mmol, 0.02 eq.), CuI (0.107 g, 0.56 mmol, 0.10 eq.) and a
solution of (2Z)-3-methylpent-2-en-3-ynol 3Z (0.587 g, 6.11
mmol, 1 eq.) in 20 mL of anhydrous and degassed Et2NH.
The initially slightly yellow solution gradually darkened.
After disappearance of the starting material as judged from
TLC (3 to 4 h), a saturated aqueous solution of ammonium
chloride was added at 0°C. After extraction with diethyl
ether, the combined organic layers were washed with water,
dried over Na2SO4, concentrated. The dark oil was purified
by flash chromatography (cyclohexane/EtOAc: 4/1) to give
pure product 7Z (0.724 g, 79%).
1H-NMR (300 MHz) CDCl3: 1.73 (s, 1H); 1.83 (br d, 3H,
J = 1.5 Hz); 1.90-1.92 (m, 6H); 4.33 (dq, 2H, J = 1.1, 6.8
Hz); 5.38-5.41 (m, 1H); 5.82 (tq, 1H, J = 1.5, 6.8 Hz). 13C-
NMR (75 MHz) CDCl3: 21.1 (CH3); 23.4 (CH3); 24.9 (CH3);
61.4 (CH2); 89.6 (Cq); 92.9 (Cq); 105.2 (CH); 121.6 (Cq);
134.1 (CH); 149.1 (Cq). MS (EI): m/z (%) = 150.2 ([M]+,
92); 135.1 (83); 107.2 (70); 91.1 (100); 79.1 (58). IR (NaCl;
cm-1): 1048; 1376; 1440; 2928; 3358.
(2E)-1-tert-butyldiphenylsilyloxy-3,7-dimethylocta-2,6-
dien-4-yne (6E)
At -30°C in CH2Cl2 (5 mL) were successively added
pyridine (35 μL, 0.434 mmol, 1.05 eq.) and triflic anhydride
(75 μL, 0.445 mmol, 1.07 eq.). The resulting yellow solution
containing a white precipitate was stirred for 30 min. A solu-
tion of (2E)-1-tert-butyldiphenylsilyloxy-3,7-dimethylocta-
2-en-4-yn-6-ol 5E (169 mg, 0.416 mmol) in CH2Cl2 (5 mL)
was then added. When the solution began to turn brown (5
min.), pyridine (340 μL, 4.37 mmol, 10 eq.) were added. The
solution was still stirred for a further 3h at –30 °C. The reac-
tion was then hydrolyzed by addition of water. The aqueous
layer was extracted with dichloromethane. The combined
organic layers were then dried over Na2SO4, filtrated and
evaporated. A flash-chromatography (cyclohexane/EtOAc:
9/1) gave the product 6E (98 mg, 60%).

70
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Fécourt et al.
(2E)-3,7-dimethylocta-2,6-dien-4-ynol (7E):
1H-NMR (300 MHz) CDCl3: 1.87 (br d, 3H, J = 1.7Hz);
1.93 (br s, 3H); 2.31 (d, 3H, J = 1.4 Hz); 5.44-5.47 (m, 1H);
6.16 (dq, 1H, J = 1.4, 8.0 Hz); 10.01 (d, 1H, J = 8.0 Hz). 13C-
NMR (75 MHz) CDCl3: 18.6 (CH3); 21.4 (CH3); 25.2 (CH3);
93.5 (Cq); 98.1 (Cq); 104.9 (CH); 132.4 (CH); 141.5 (Cq);
153.4 (Cq); 190.2 (CH). MS (CI/isobutane): m/z (%) = 149.1
([M+H]+, 100), 133.2 (17). IR (NaCl; cm-1): 1140; 1216;
1585; 1664; 2182; 2849-3019.
To a solution of 1-bromo-2-methylpropene (1.02 g, 7.55
mmol, 1.1 eq.) in anhydrous and degassed Et2NH (10 mL)
were successively added at 0°C PdCl2(PPh3)2 (0.096 g 0.137
mmol, 0.02 eq.), CuI (0.131 g, 0.688 mmol, 0.10 eq.) and a
solution of (2E)-3-methylpent-2-en-3-ynol 3E (0.660 g, 6.87
mmol, 1 eq.) in anhydrous and degassed Et2NH (20 mL).
The initially slightly yellow solution gradually darkened.
After disappearance of the starting material as judged from
TLC (3 to 4 h), a saturated aqueous solution of ammonium
chloride was added at 0°C. After extraction with diethyl
ether, the combined organic layers were washed with water
dried over Na2SO4, concentrated. The crude orange-brown
oil was purified by flash chromatography (cyclohex-
ane/EtOAc: 4/1) to give pure 7E (0.473 g, 45%) as slightly
yellow oil.
1H-NMR (300 MHz) CDCl3: 1.35 (s, 1H); 1.82 (br d, 3H,
J = 1.6 Hz); 1.86 (dt, 3H, J = 0.8, 1.5 Hz); 1.90 (br s, 3H);
4.23 (d, 2H, J = 6.9 Hz); 5.35-5.37 (m, 1H); 5.95 (tq, 1H, J =
1.5, 6.9 Hz). 13C-NMR (75 MHz) CDCl3: 17.8 (CH3); 21.0
(CH3); 24.9 (CH3); 59.3 (CH2); 86.2 (Cq); 93.7 (Cq); 105.2
(CH); 121.6 (Cq); 133.9 (CH); 148.8 (Cq). MS (EI): m/z (%)
= 150.2 ([M]+, 80); 135.1 (83); 107.2 (72); 91.1 (100); 79.1
(52). IR (NaCl; cm-1): 1050, 1375, 1432, 2930, 3358.
ACKNOWLEDGEMENTS
We thank CNRS and MESR for providing financial sup-
port. PP also thanks the Roche, now DSM, company for a
generous gift of the alcohols 3E and 3Z.
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Taxifolial D (= (2Z)-3,7-dimethylocta-2,6-dien-4-ynal)
To a solution of dienynol 7Z (0.130 g, 0.865 mmol) in
anhydrous CH2Cl2 (5 mL), was added anhydrous MnO2
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1H-NMR (300 MHz) CDCl3: 1.87 (br d, 3H, J = 1.4 Hz);
1.93 (br s, 3H); 2.12 (d, 3H, J = 1.4 Hz); 5.45-5.58 (m, 1H);
6.09 (dq, 1H, J = 1.4, 8.3 Hz); 10.03 (d, 1H, J = 8.3 Hz). 13C-
NMR (75 MHz) CDCl3: 21.6 (CH3); 25.1 (CH3); 25.2 (CH3);
88.7 (Cq); 99.3 (Cq); 104.7 (CH); 133.6 (CH); 143.2 (Cq);
153.3 (Cq); 192.9 (CH). MS (CI/isobutane): m/z (%) = 149.1
([M+H]+, 100), 133.2 (19). IR (NaCl; cm-1): 1140; 1216;
1585; 1664; 2182; 2849-3019.
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IsoTaxifolial D (= (2E)-3,7-dimethylocta-2,6-dien-4-ynal)
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To a solution of dienynol 7E (0.129 g, 0.859 mmol) in
anhydrous CH2Cl2 (5 mL), was added anhydrous MnO2
(0.649 g, 7.465 mmol, 8.7 eq.). The solution was stirred
overnight in the absence of light. The mixture was filtrated
through a pad of Celite®. Solvent evaporation gave Isotaxi-
folial D (0.121 g, 95%) as slightly yellow oil.