Studies towards the total synthesis of (-)-caulerpenynol, a toxic sesquiterpenoid of the green seaweed caulerpa taxifolia

Article abstract of DOI:10.1002/ejoc.200900101

The first diastereoselective synthesis of the antimicrobial and cytotoxic agent (-)-caulerpenynol (2) was achieved in relatively few steps from, commercially available (S)-malic acid, Highlights of this synthesis include the nonracemization. of the sensitive a-hydroxy ketone moiety and the proper choice of the protecting groups for critical last deprotection step. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009.

Full text of DOI:10.1002/ejoc.200900101

FULL PAPER
DOI: 10.1002/ejoc.200900101
Studies towards the Total Synthesis of (–)-Caulerpenynol, a Toxic
Sesquiterpenoid of the Green Seaweed Caulerpa taxifolia
Laurent Commeiras,*[a] Jérôme Thibonnet,[b] and Jean-Luc Parrain*[a]
Dedicated to Prof. Maurice Santelli on the occasion of his 70th birthday
Keywords: Natural products / Total synthesis / Biological activity / Terpenoids
The first diastereoselective synthesis of the antimicrobial and
cytotoxic agent (–)-caulerpenynol (2) was achieved in rela-
tively few steps from commercially available (S)-malic acid.
Highlights of this synthesis include the nonracemization of
the sensitive α-hydroxy ketone moiety and the proper choice
of the protecting groups for critical last deprotection step.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
rial and cytotoxic activities of 2 were evaluated against pro-
karyotic marine bacteria and unicellular eukaryotes ciliate
protists, and 2 proved to be the most active of the terpenes
of C. taxifolia with the exception of two bacteria.[6]
Introduction
Some metabolites from tropical algae have been impli-
cated in the chemical defense against grazing fish and inver-
tebrates in herbivore-rich tropical waters[1] and have been
proposed as an explanation for the unhindered proliferation
of Caulerpa taxifolia, a tropical green seaweed, accidentally
introduced into the Mediterranean. In comparison to other
Caulerpa species in the tropics, Caulerpa taxifolia contains
a large amount of caulerpenyne (1), a sesquiterpene isolated
from 10 different species of Caulerpa and first identified
from Caulerpa prolifera.[2] Among its biological activities,
which are attributed to the diacetoxybutadiene moiety, cau-
lerpenyne (1) inhibits the proliferation of the fibroblastic
cell line BHK 21/C13 from baby hamster kidney and the
division of sea urchin eggs.[3] The cytotoxicity was also
demonstrated in various tumor cell lines,[4] and it was re-
cently shown that caulerpenyne (1) has antiproliferative ac-
tivity against the tumor cell line SK-N-SH and modifies
the microtubule network.[5] In addition, several secondary
metabolites were identified and could contribute to the tox-
icity of C. taxifolia from the Mediterranean (Figure 1).
Among these metabolites, caulerpenynol (2) was isolated
and identified in 1993 by Guerriero et al.[6] The antibacte-
Figure 1. Caulerpenyne (1) and caulerpenynol (2).
Inspired by the pronounced biological activities of 2 and
to provide material for a more extensive biological evalu-
ation, we have undertaken the total synthesis of caulerpeny-
nol (2). To the best of our knowledge, only a few synthetic
transformations (epoxidation) from 1 to caulerpenynol (2)
have been reported in the literature[6,7] but no total synthe-
sis of 2 has been realized.
Herein is a full account of our preliminary communica-
tion, and we disclose results obtained during different ap-
proaches of the synthesis of 2.[8]
Results and Discussion
The main structural features of 2 are a terminal 1,4-di-
acetoxybutadiene moiety, an enynene moiety, two chiral
centers, and a 1,3-anti-diol moiety in which one alcohol
function is protected as an acetate. As outlined in Scheme 1,
our retrosynthetic scheme for synthesizing 2 called for the
initial preparation of three fragments referred to as west,
central, and east. We considered that the assembly of the
three fragments could be obtained through two C–C cou-
pling reactions. The first coupling was realized between alk-
[a] Aix-Marseille Université, Institut des Sciences Moléculaires de
Marseille iSm2 UMR 6263,
équipe STeRéO, Campus Scientifique de Saint Jérôme,
13397 Marseille CEDEX 20, France
Fax: +33-4-91289187
E-mail: laurent.commeiras@univ-cezanne.fr;
jl.parrain@univ-cezanne.fr
[b] Laboratoire PCMB Physicochimie des matériaux et des biomo-
lécules, EA 4244, Faculté des Sciences et Techniques de Tours,
Parc de Grandmont,
32 avenue Monge, 37200 Tours, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900101.
ynyllithium
3 (west fragment obtained from Fritsh–
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Buttenberg–Wiechell rearrangement) and aldehyde 4 (cen- dibromoalkene,[12] which after treatment with nBuLi
tral fragment). The carbon skeleton was achieved through (2 equiv.) generated alkynyllithium 3 through a Fritsch–
a second coupling between vinyllithium reagent 5 (east frag- Buttenberg–Wiechell rearrangement.
ment obtained from a tin–lithium exchange reaction) and
the corresponding west–central fragment.
Construction of the carbon skeleton of (–)-caulerpenynol
(2) started by a coupling reaction between central segment
7 and alkynyllithium 3 to furnish desired alcohol 8 in an
8:2 mixture of diastereomers. This mixture was then oxid-
ized with Dess–Martin periodinane[13] to corresponding
ketone 9, which was then subjected to olefination under
standard conditions to afford dienyne 10. Regioselective re-
duction of p-methoxybenzylidene acetal 10 with DIBAL-H
at –40 °C predominantly (78:22, 92%) gave p-methoxyben-
zyl ether 11 of the more-hindered secondary alcohol func-
tion. It is noteworthy that DIBAL-H must be cooled down
to –78 °C before it is added to give better regioselectivity.
The primary alcohol function of 11 was then oxidized with
Dess–Martin periodinane into aldehyde 12.
Scheme 1. Retrosynthetic scheme of (–)-caulerpenynol (2).
The remaining east fragment 13 was prepared in two
steps from commercially available but-2-yn-1,4-diol through
a palladium-catalyzed hydrostannation reaction to give
quantitatively the known (E)-vinyltin reagent.[14,15] Subse-
quent selective protection of the less-hindered primary
alcohol as a tert-butyldimethylsilyl ether furnished 13 in
64% overall yield for the two-step transformation.[15]
With the west–central and east fragments in hand, the
Synthesis of the central fragment (Scheme 2) started
from commercially available (S)-butan-1,2,3-triol [or pre-
pared on a large scale by reduction of (S)-malic acid], which
was transformed in two steps, in high yield on a multigram
scale into known ketal compound 6.[9] First, (S)-butan-
1,2,3-triol was protected as the tris-OTMS derivative fol-
lowed by treatment with trimethylsilyl triflate and p-anisal- carbon skeleton of caulerpenynol was achieved through a
dehyde to furnish acetal 6. The alcohol function of 6 was second coupling reaction between 12 and the vinyllithium
then oxidized with Dess–Martin periodinane into unstable reagent generated from the tin–lithium exchange reaction
aldehyde 7, which was immediately used for the next step of 13[16] to give diol 14 as a 6:4 mixture of diastereomers
without further purification.[10] Synthesis of the western (64%). The diastereomers were separated by semiprepar-
fragment was performed by Corey–Fuchs alkynylation.[11] ative HPLC, and the stereochemistry of major diastereomer
Commercially available 3,3-dimethylacrolein was first con- 14 was determined by NOESY experiments conducted on
verted quantitatively into the known corresponding gem- the corresponding p-methoxybenzylidene acetal (obtained
Scheme 2. First approach to caulerpenynol (2). Reagents and conditions: (a) i. CBr4, PPh3, Zn, ii. nBuLi –78 °C; (b) –78 °C to r.t. (66%
from 6); (c) Dess–Martin periodinane, CH2Cl2 (91%); (d) CH2=PPh3, –40 to 0 °C (77%); (e) DIBAL-H, hexane, –80 to –40 °C (71%);
(f) Dess–Martin periodinane, CH2Cl2 (82%); (g) i. Bu3SnH, PdCl2(PPh3)2, THF (99%); ii. TBDMSCl, DMF, 0 °C (65%); (h) MeLi·LiBr,
–40 to –35 °C; (i) –78 °C, THF (64%); (j) Ac2O, DMAP, pyridine (92%); (k) HF·pyridine, THF (77%); (l) Dess–Martin periodinane,
CH2Cl2 (85%); (m) Ac2O, DMAP, NEt3, 80 °C (89%).
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Studies towards the Total Synthesis of (–)-Caulerpenynol
in 85% yield by oxidation of p-methoxybenzyl ether 14 with gave predominantly (9:1, 79%) p-methoxybenzyl ether 11Ј
DDQ in anhydrous CH2Cl2).[17] At this stage, both hydroxy of the less-hindered primary hydroxy group. Protection of
groups of the major anti isomer 14 were acylated by using the secondary hydroxy group by TBSOTf followed by oxi-
acetic anhydride and a catalytic amount of DMAP in pyr- dative deprotection of the p-methoxybenzyl ether function
idine to give bisacetate 15. Desilylation of primary TBS furnished desired alcohol 22 in a mixture with residual p-
alcohol by HF·pyridine furnished desired alcohol 16, which methoxybenzaldehyde. The primary alcohol function of 22
was then oxidized into aldehyde 17. To generate the diace- was then oxidized by using Dess–Martin periodinane into
toxybutadiene moiety, we employed conditions developed aldehyde 23. Addition of the vinyllithium reagent generated
in our group[18] (NEt3, DMAP, Ac2O at 80 °C) and pro- by a tin–lithium exchange reaction on 13 gave desired diol
tected PMB caulerpenynol 18 was obtained as a 1:1 insepa- 24 as a (6:4) mixture of diastereomers separable by column
rable mixture of diastereomers. In order to complete the chromatography (30%). At this stage, both hydroxy groups
synthesis of caulerpenynol (2), the last step involved the re- of major anti isomer 24 were protected as the acetates to
moval of the PMB group. Unfortunately, the oxidative give bisacetate 20.
(DDQ or CAN) conditions failed to selectively provide cau-
Selective removal (Scheme 4) of the primary allylic TBS
lerpenynol (2), which was never observed. Numerous un- group in the presence of the hindered secondary TBS group
identified byproducts were obtained that we attributed to was accomplished with a stock solution of HF·pyridine/
the uncontrolled oxidation or cycloaddition reactions of the THF/pyridine to furnish desired alcohol 25.[20] The end of
enynene and/or diacetoxybutadiene moieties.
the synthesis was identical to the one previously described.
As the p-methoxybenzyl protecting group does not seem Oxidation of primary alcohol 25 followed by transforma-
to be the adequate protecting group for the last deprotec- tion of aldehyde 26 into the diacetoxybutadienyl derivative
tion step of our synthesis, we decided to replace it by a tert- led to a 45:55 mixture of TBS-protected caulerpenynol and
butyldimethylsilyl group that could be more readily re- TBS-protected iso-caulerpenynol (27). At this stage, we
moved. Replacement (Scheme 3) of the p-methoxybenzyl found that the cleavage of the TBS group of 27 also caused
group by a tert-butyldimethylsilyl group was realized from considerable problems. All attempts[21] to deprotect it with
15 by routine protecting group interconversions. First of all, diluted HCl in THF, PPTS in ethanol, or TBAF in THF
p-methoxybenzyl ether was deprotected by using DDQ in led only to starting material. In view of these difficulties,
5% aqueous CH2Cl2 to give corresponding secondary we were pleased to find that aqueous HF in CH3CN gave
alcohol 19, which was then protected as the silyl ether by better results. A 1:1 inseparable mixture of caulerpenynol
TBSOTf and 2,6-lutidine at low temperature to furnished (2) and iso-caulerpenynol (iso-2) was formed in low yield
20.
(40%). Along with the caulerpenynol derivatives, an alde-
Another synthesis scheme (Scheme 3) was also used for hyde resulting from the hydrolysis of one enol acetate was
the synthesis of TBS analog 20. The tert-butyldimethylsilyl obtained in 16% yield.
protecting group was introduced before the coupling be-
Even if the natural product was obtained, the last step is
tween the west–central and east segments. The synthesis be- unsatisfactory and it is essential to consider the option for
gan with p-methoxybenzylidene acetal 10, which can be re- the ultimate deprotection very prudently. So we turned our
duced with NaBH3CN/TMSCl in CH3CN.[19] In compari- attention to a triethylsilyl protecting group, which is more
son to reduction with DIBAL-H, the reduction reaction labile than the corresponding TBS group for the hydroxy
Scheme 4. Second approach to caulerpenynol (2). Reagents and conditions: (a) HF·pyridine/THF/pyridine, THF (86%); (b) Dess–Martin
periodinane, CH2Cl2 (100%); (c) Ac2O, DMAP, NEt3, 80 °C (98%); (d) HF in water, CH3CN.
Scheme 3. Synthesis of TBS analog 20. Reagents and conditions: (a) DDQ, H2O, CH2Cl2 (35–62%); (b) TBSOTf, 2,6-lutidine, CH2Cl2,
0 °C (71%); (c) NaBH3CN/TMSCl, CH3CN (79%); (d) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C (97%); (e) DDQ, H2O, CH2Cl2; (f) Dess–
Martin periodinane, CH2Cl2 (85% over two steps), (g) 13, MeLi·LiBr, –40 to –35 °C; (j) –78 °C, THF (30%); (h) Ac2O, DMAP, pyridine
(81%).
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Scheme 5. Successful approach to caulerpenynol (2). Reagents and conditions: (a) TESCl, imidazole, DMAP, DMF (100%); (b) 3, –78 °C
to r.t. (73%); (c) Dess–Martin periodinane, CH2Cl2 (85%), (d) i. Bu3SnH, PdCl2(PPh3)2; ii. TESCl, NEt3, –20 °C (53%); (e) MeLi·LiBr
–78 to –40 °C; (f) –78 °C (43%, 7:3 mixture of diastereomers); (g) Ac2O, DMAP, pyridine (81%); (h) CH2=PPh3, –80 to 0 °C (53%); (i)
2:1:10 mixture of AcOH/H2O/THF,40 °C (88%); (j) Dess–Martin periodinane, CH2Cl2 (90%); (k) Ac2O, DMAP, NEt3, 80 °C (73%); (l)
3:2:1 mixture of AcOH/H2O/THF, 45 °C (81%).
group needing protection. The beginning of the synthesis THF at 45 °C was used to remove the triethylsilyl protect-
(Scheme 5) was slightly different and started from known ing group to afford cleanly a 52:48 diastereomeric mixture
lactone 28.[22] First, (S)-malic acid was protected as an ace- of caulerpenynol (2) and iso-caulerpenynol (iso-2) separable
tonide (2,2-dimethoxypropane, p-TsOH), and the carbox- by HPLC.[26] The physical and spectroscopic data (mass, 1H
ylic acid was then reduced to the alcohol by using BH3– NMR, 13C NMR, optical rotation) of our synthetic mate-
THF. This unstable product immediately rearranged into rial are in complete agreement with those reported for the
(S)-3-hydroxybutyrolactone (28) in the presence of p-TsOH. naturally derived caulerpenynol,[6,27] confirming our predic-
Lastly, the alcohol function of 28 was protected as the tri- tion of the relative and absolute configuration of anti dia-
ethylsilyl ether to give new central fragment 29 (71% yield stereomer 33.
over four steps).
Construction of the carbon skeleton of (–)-caulerpenynol
(2) started by a coupling reaction between central fragment
29 and alkynyllithium 3 to furnish corresponding alcohol
Conclusions
In summary, the first diastereoselective synthesis of the
30, which was then oxidized by using Dess–Martin
antimicrobial and cytotoxic agent (–)-caulerpenynol (2) was
periodinane to afford aldehyde 31. The carbon skeleton of
achieved in relatively few steps from commercially available
caulerpenynol was achieved through a second coupling re-
(S)-malic acid. Highlights of this synthesis include the non-
action between 31 and a vinyllithium reagent generated by
racemization of the sensitive α-hydroxy ketone moiety and
tin–lithium exchange reaction on 32 (obtained by selective
the proper choice of the protecting groups for the critical
last deprotection step.
protection of the less-hindered primary alcohol as triethylsi-
lyl ether) to give diol 33 in 43% yield as a 7:3 mixture
(based on 13C NMR) of diastereomers separable by flash
chromatography in favor of the anti diastereomer.[23] The
Experimental Section
stereochemistry of anti-diol 33 was confirmed by our pre-
1
vious results. H and 13C NMR spectra of 34, obtained by
1-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-5-methylhex-4-en-
2-yn-1-ol (8): To a solution of 1,1-dibromo-4-methylpent-1,3-
diene[12] (6.4 g, 26.75 mmol) in THF (100 mL) was added nBuLi
(2.5 , 21.4 mL, 53.5 mmol) dropwise at –78 °C. The clear yellow
solution was stirred at –78 °C for 1.5 h and then crude aldehyde 7
diluted in a minimum amount of THF was added by cannula. After
warming to room temperature, the mixture was quenched with
NH4Cl/NH4OH (8:2). The aqueous layer was extracted with
EtOAc, and the combined organic layers were dried with Na2SO4,
filtered, and then concentrated under vacuum. The crude alcohol
was purified by column of chromatography (SiO2; 4% NEt3, petro-
leum ether/Et2O, 5:5) to give a mixture (8:2) of two diastereomers
protection of both hydroxy groups of major anti isomer 33
as the acetates, exactly matched those of TBS analog 20
(excepted alkyl silyl chain).[24]
Bisacetate 34 was subjected to an olefination reaction by
using standard conditions to afford 35. Selective cleavage
of the primary allylic triethylsilyl ether in the presence of
the secondary allylic triethylsilyl ether was performed with
a 2:1:10 mixture of AcOH/H2O/THF at 40 °C, furnishing
desired primary alcohol 36,[25] which was further oxidized
with Dess–Martin periodinane into aldehyde 37. The diace-
toxybutadiene moiety was generated under basic conditions
to give TES-protected caulerpenynol 38 in a 53:47 E/Z dia-
1
(3.59 g) in 66% yield over two steps from 6. H NMR (300 MHz,
CDCl3): δ = 1.62 (br. d, J = 13.4 Hz, 1 H, CH2), 1.80 (s, 3 H, CH3),
stereomeric mixture. At last, a 3:2:1 mixture of AcOH/H2O/ 1.90 (s, 3 H, CH3), 2.15 (qd, J = 13.4, 5.1 Hz, 1 H, CH2), 2.71 (m,
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Studies towards the Total Synthesis of (–)-Caulerpenynol
1 H, OH), 3.78 (s, 3 H, CH3), 3.85–4.01 (m, 2 H, CH2 and CH),
quenched with a few drops of methanol and then by a saturated
4.31 (dd, J = 11.1, 5.1 Hz, 1 H, CH2), 4.65 (br. s, 1 H, CH), 5.28 aqueous Rochel salt solution and diluted with EtOAc. The aqueous
(br. s, 1 H, CH), 5.50 (s, 1 H, CH), 6.87 (br. d, J = 8.8 Hz, 2 H,
layer was extracted with EtOAc, and the combined organic layers
were dried with MgSO4 and then concentrated under vacuum. The
2ϫCH), 7.42 (br. d, J = 8.8 Hz, 2 H, 2ϫCH) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 21.2 (CH3), 24.8 (CH3), 25.2 (CH2), 55.3 crude product was purified by column of chromatography (SiO2;
(CH3), 65.2 (CH), 66.7 (CH2), 79.2 (CH), 84.4 (C), 87.9 (C), 101.3 petroleum ether/Et2O, 7:3 to 0:10) to give a 78:22 separable mixture
(CH), 104.6 (CH), 113.6 (2ϫCH), 127.6 (2ϫCH), 130.9 (C), 149.8
(C), 160.1 (C) ppm. HRMS (ESI): calcd. for C18H23O4 [M + H]+
303.1590; found 303.1596.
of two isomers (555 mg) in 91% yield. Major isomer 11: [α]2D1
=
1
–102.8 (c = 1, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 1.83 (s,
3 H, CH3), 1.92 (s, 3 H, CH3), 1.87–2.08 (m, 2 H, CH2), 2.43 (m,
1 H, OH), 3.67–3.80 (m, 2 H, CH2), 3.79 (s, 3 H, CH3), 4.05 (dd,
J = 8.5, 4.3 Hz, 1 H, CH, H2), 4.28 (d, J = 11.3 Hz, 1 H, CH2),
4.60 (d, J = 11.3 Hz, 1 H, CH2), 5.40 (br. s, 1 H, CH), 5.46 (br. s,
1 H, CH2), 5.53 (br. s, 1 H, CH2), 6.87 (br. d, J = 8.5 Hz, 2 H,
2ϫCH), 7.26 (br. d, J = 8.5 Hz, 2 H, 2ϫCH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.3 (CH3), 25.0 (CH3), 37.2 (CH2), 55.3
(CH3), 60.7 (CH2), 70.2 (CH2), 80.6 (CH), 89.0 (C), 89.8 (C), 105.1
(CH), 113.9 (2 ϫ CH), 121.3 (CH2), 129.7 (2 ϫCH), 130.0 (C),
132.1 (C), 149.8 (C), 159.3 (C) ppm. HRMS (ESI): calcd. for
C19H25O3 [M + H]+ 301.1798; found 301.1810.
1-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-5-methylhex-4-en-
2-yn-1-one (9): To a stirred solution of alcohol 8 (6.57 g,
21.72 mmol) in CH2Cl2 (200 mL) at 0 °C was added Dess–Martin
periodinane (11 g, 26.07 mmol) and pyridine (2.6 mL, 30.41 mmol).
The reaction mixture was stirred at room temperature and followed
by TLC. After disappearance of the starting material, the mixture
was poured into a saturated aqueous Na2S2O3/NaHCO3 solution
(1 L, 1:1). After stirring for 10 min, the layers were separated and
the aqueous layer was extracted with EtOAc. The combined or-
ganic layers were washed with saturated aqueous NaHCO3 solu-
tion, dried with Na2SO4, and then concentrated under vacuum.
The crude product was purified by column of chromatography
(SiO2; 4% NEt3, petroleum ether/Et2O, 5:5) to give 9 (5.95 g) in
91% yield. [α]2D1 = –14.2 (c = 1, CH2Cl2). M.p. 95–100 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.89 (br. s, 3 H, CH3), 1.91 (s, 3 H, CH3),
1.94–2.12 (m, 2 H, CH2), 3.81 (s, 3 H, CH3), 4.01 (td, J = 11.5,
3.0 Hz, 1 H, CH2), 4.34 (ddd, J = 11.5, 4.9, 1.3 Hz, 1 H, CH2),
4.44 (dd, J = 11.5, 3.0 Hz, 1 H CH), 5.45 (br. s, 1 H, CH), 5.55 (s,
1 H, CH), 6.88 (br. d, J = 8.8 Hz, 2 H, 2ϫCH), 7.47 (br. d, J =
8.8 Hz, 2 H, 2ϫCH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 22.1
(CH3), 25.6 (CH3), 27.8 (CH2), 55.4 (CH3), 66.8 (CH2), 81.6 (CH),
89.3 (C), 95.2 (C), 101.2 (CH), 103.7 (CH), 113.6 (2ϫCH), 127.7
(2ϫCH), 130.6 (C), 160.2 (C), 160.3 (C), 185.3 (C) ppm. HRMS
(ESI): calcd. for C18H21O4 [M + H]+ 301.1434; found 301.1434.
(3S)-3-(4-Methoxybenzyloxy)-8-methyl-4-methylenenon-7-en-5-yn-
1-al (12): To a stirred solution of alcohol 11 (2.4 g, 7.99 mmol)
in CH2Cl2 (190 mL) at 0 °C was added Dess–Martin periodinane
(4.04 g, 9.59 mmol). The reaction mixture was stirred at room tem-
perature and followed by TLC. After disappearance of the starting
material, the mixture was poured into a saturated aqueous
Na2S2O3/NaHCO3 solution (400 mL, 1:1). After stirring for
10 min, the layers were separated and the aqueous layer was ex-
tracted with EtOAc. The combined organic layers were washed
with saturated aqueous NaHCO3 solution, dried with Na2SO4, and
then concentrated under vacuum. The crude aldehyde was purified
by column of chromatography (SiO2; petroleum ether/Et2O, 7:3) to
give 12 (1.95 g) in 82% yield. [α]2D3 = –74.6 (c = 1, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = 1.84 (s, 3 H, CH3), 1.92 (s, 3 H,
CH3), 2.68 (ddd, J = 16.4, 4.3, 1.7 Hz, 1 H, CH2), 2.84 (ddd, J =
16.4, 8.5, 2.5 Hz, 1 H CH2), 3.79 (s, 3 H, CH3), 4.32 (d, J = 11.3 Hz,
1 H, CH2), 4.35 (dd, J = 8.5, 4.3 Hz, 1 H, CH2), 4.59 (d, J =
11.3 Hz, 1 H, CH2), 5.40 (br. s, 1 H, CH), 5.52 (s, 1 H, CH2), 5.55
(br. s, 1 H, CH), 6.86 (br. d, J = 8.7 Hz, 2 H, 2ϫCH), 7.25 (br. d,
J = 8.7 Hz, 2 H, 2ϫCH), 9.74 (br. d, J = 2.5, 1.7 Hz, CH, 1 Hd)
ppm. 13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 25.0 (CH3),
48.6 (CH2), 55.3 (CH3), 70.3 (CH2), 76.3 (CH), 88.5 (C), 90.3 (C),
105.0 (CH), 113.9 (2ϫCH), 121.7 (CH2), 129.7 (2ϫCH), 129.9
(C), 131.2 (C), 150.0 (C), 159.4 (C), 200.7 (CH) ppm. HRMS (ESI):
calcd. for C19H23O3 [M + H]+ 299.1641; found 299.1642.
(2S,4S)-2-(4-Methoxyphenyl)-4-(5-methyl-1-methylenehex-4-en-2-
ynyl)-1,3-dioxane (10): To a solution of CH3PPh3I (215 mg,
0.53 mmol) in dry THF (2 mL) was added, at –40 °C, dropwise
nBuLi (2.5  in hexanes, 0.192 mL, 4.8 mmol). The solution was
warmed up to 0 °C for 2 h and recooled to –50 °C. Ketone 9
(80 mg, 0.27 mmol) dissolved in a minimum amount of THF was
added by cannula. The mixture was warmed up to room tempera-
ture and quenched with saturated aqueous NH4Cl solution. The
aqueous layer was extracted with Et2O. The combined organic lay-
ers were washed with saturated aqueous NaCl solution, dried with
Na2SO4, and then concentrated. The crude product was purified
by column of chromatography (SiO2; 4% NEt3, petroleum ether/
Et2O, 8:2) to give 10 (61.3 mg) in 77% yield. [α]2D1 = –32.3 (c = 1,
(3S,5S,E)-2-[2-(tert-Butyldimethylsilyloxy)ethylidene]-5-(4-meth-
oxybenzyloxy)-10-methyl-6-methyleneundec-9-en-7-yne-1,3-diol
(14): To a solution of (E)-vinyltin reagent 13[15] (2.7 g, 5.49 mmol)
in THF (85 mL) at –40 °C was added dropwise MeLi·LiBr (2.2 ,
5 mL, 10.99 mmol). The reaction mixture was warmed to –35 °C
and stirred until disappearance of the starting material (1 h). The
mixture was cooled to –90 °C, aldehyde 12 (1.366 g, 4.58 mmol)
diluted in a minimum amount of THF was then added dropwise.
The solution was kept at –90 °C for 2 h and then quenched with a
saturated aqueous NH4Cl solution. The aqueous layer was ex-
tracted with ethyl acetate. The combined organic layers were dried
with Na2SO4 and concentrated under vacuum. The crude product
was then purified by flash chromatography (petroleum ether/Et2O,
4:6) to give a 6:4 mixture of diastereomers (1.456 g) in 64% yield.
1
CH2Cl2). M.p. 41 °C. H NMR (300 MHz, CDCl3): δ = 1.84 (br.
s, 3 H, CH3), 1.93 (s, 3 H, CH3), 1.89–2.04 (m, 2 H, CH2), 3.80 (s,
3 H, CH3), 4.01 (td, J = 11.5, 3.2 Hz, 1 H, CH2), 4.27–4.38 (m, 2
H, CH2 and CH), 5.40 (br. s, 1 H, CH), 5.47 (br. s, 1 H, CH2), 5.55
(s, 1 H, CH), 5.63 (br. s, 1 H, CH2), 6.89 (br. d, J = 8.8 Hz, 2 H,
2ϫCH), 7.46 (br. d, J = 8.8 Hz, 2 H, 2ϫCH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.2 (CH3), 25.0 (CH3), 31.1 (CH2), 55.4
(CH3), 67.1 (CH2), 78.2 (CH), 89.2 (C), 89.4 (C), 101.2 (CH), 105.2
(CH), 113.6 (2 ϫ CH), 119.5 (CH2), 127.6 (2 ϫCH), 131.2 (C),
132.0 (C), 149.4 (C), 160.0 (C) ppm. HRMS (ESI): calcd. for
C19H23O3 [M + H]+ 299.1641; found 299.1641.
(3S)-3-(4-Methoxybenzyloxy)-8-methyl-4-methylenenon-7-en-5-yn- The two diastereomers were separated by chiral semipreparative
1-ol (11): To a stirred solution of dioxane 10 (600 mg, 2.01 mmol)
in hexane (85 mL) was added at –80 °C, DIBAL-H (1.5  in tolu-
ene, 8.04 mL, 12.06 mmol) precooled to –80 °C. The solution was
HPLC. Major diastereomer 14: [α]2D5 = –41.8 (c = 1, CH2Cl2). M.p.
40–44 °C. 1H NMR (300 MHz, CDCl3): δ = 0.10 (s, 6 H, 2ϫCH3),
0.92 (s, 9 H, 3ϫCH3), 1.85 (s, 3 H, CH3), 1.93 (s, 3 H, CH3), 2.02–
warmed to –40 °C and stirred overnight. The mixture was carefully 2.07 (m, 2 H, CH2), 2.87 (m, 1 H, OH), 2.97 (m, 1 H, OH), 3.82
Eur. J. Org. Chem. 2009, 2987–2997
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2991

L. Commeiras, J. Thibonnet, J.-L. Parrain
FULL PAPER
(s, 3 H, CH3), 4.13–4.18 (m, 3 H, CH and CH2), 4.25–4.28 (m, 3 solution of alcohol 16 (45 mg, 0.0956 mmol) in CH2Cl2 (3 mL) was
H, CH2 and CH2), 4.43–4.47 (m, 1 H, CH), 4.60 (d, J = 11.1 Hz, added at 0 °C Dess–Martin periodinane (48 mg, 0.115 mmol). The
1 H, CH2), 5.41 (br. s, 1 H, CH), 5.51 (s, 1 H, CH2), 5.55 (br. s, 1 mixture was stirred at room temperature and followed by TLC.
H, CH2), 5.73 (t, J = 6.0 Hz, 1 H, CH), 6.90 (br. d, J = 8.7 Hz, 2 After disappearance of the starting material (2 h), the solution was
H, 2ϫCH), 7.29 (br. d, J = 8.7 Hz, 2 H, 2ϫCH) ppm. 13C NMR
(75 MHz, CDCl3): δ = –5.1 (2ϫCH3), 18.4 (C), 21.3 (CH3), 25.0
poured into a saturated aqueous Na2S2O3/NaHCO3 solution
(5 mL, 1:1). After stirring for 10 min, the layers were separated and
(CH3), 26.0 (3ϫCH3), 40.0 (CH2), 55.4 (CH3), 58.7 (CH2), 59.6 the aqueous layer was extracted with EtOAc. The combined or-
(CH2), 70.6 (CH2), 73.0 (CH), 79.0 (CH), 89.2 (C), 89.9 (C), 105.1
(CH), 114.0 (2ϫCH), 121.0 (CH2), 128.3 (CH), 129.8 (2ϫCH),
ganic layers were washed with saturated aqueous NaHCO3 solu-
tion, dried with Na2SO4, and then concentrated under vacuum.
130.0 (C), 131.9 (C), 142.7 (C), 149.8 (C), 159.5 (C) ppm. MS The crude aldehyde was purified by column of chromatography
(ESI+): m/z = 518 [M + NH4]+. HRMS (ESI): calcd. for
(SiO2; petroleum ether/ether, 1:1) to give 17 (38 mg) in 85% yield.
1
C29H45O5Si [M + H]+ 501.3030; found 501.3030.
[α]2D6-56.5 (c = 1, CH2Cl2). H NMR (300 MHz, CDCl3): δ = 1.83
(br. s, 3 H, CH3), 1.85–1.95 (m, 1 H, CH2), 1.90 (br. s, 3 H, CH3),
1.92 (br. s, 3 H, CH3), 2.01–2.10 (m, 1 H, CH2), 2.03 (br. s, 3 H,
CH3), 3.79 (s, 3 H, CH3), 3.85 (dd, J = 10.0, 2.6 Hz, 1 H, CH),
4.19 (d, J = 11.5 Hz, 1 H, CH2), 4.56 (d, J = 11.5 Hz, 1 H, CH2),
5.00 (d, J = 14.0 Hz, 1 H, CH2), 5.09 (d, J = 14.0 Hz, 1 H, CH2),
5.39 (br. s, 1 H, CH), 5.45–5.52 (m, 3 H, CH and CH2), 6.05 (d, J
= 7.2 Hz, 1 H, CH), 6.85 (br. d, J = 8.5 Hz, 2 H, 2ϫCH), 7.21
(br. d, J = 8.5 Hz, 2 H, 2ϫCH), 10.04 (d, J = 7.2 Hz, 1 H, CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 20.7, 20.8, 21.2, 25.0, 39.7,
55.4, 59.4, 70.0, 71.0, 76.3, 88.9, 90.0, 105.1, 113.9 (2 C), 121.4,
128.1, 129.9, 130.0 (2 C), 131.9, 149.9, 156.1, 159.4, 169.9, 171.4,
190.5 ppm.
(3S,5S,E)-2-[2-(tert-Butyldimethylsilyloxy)ethylidene]-5-(4-meth-
oxybenzyloxy)-10-methyl-6-methyleneundec-9-en-7-yne-1,3-diyl Di-
acetate (15): A solution of trans-diol 14 (0.660 g, 1.32 mmol), acetic
anhydride (0.495 mL, 5.27 mmol), and DMAP (80 mg, 0.65 mmol)
in pyridine (14 mL) was stirred overnight. The mixture was
quenched with saturated aqueous NaHCO3 solution. The aqueous
layer was extracted with diethyl ether, and the organic layers were
washed with saturated aqueous CuSO4 solution and water, dried
with MgSO4, and concentrated under vacuum. The crude product
was purified by column of chromatography (SiO2; petroleum ether/
Et2O, 8:2) to give 15 (0.720 g) in 93% yield. [α]2D1 = –54.7 (c = 1,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.03 (s, 6 H, 2ϫCH3),
0.87 (s, 9 H, 3ϫCH3), 1.83 (s, 3 H, CH3), 1.90 (s, 3 H, CH3), 1.91
(s, 3 H, CH3), 1.96–2.00 (m, 2 H, CH2), 2.00 (s, 3 H, CH3), 3.79
(s, 3 H, CH3), 3.79–3.86 (m, 1 H, CH), 4.20 (d, J = 11.3 Hz, 1 H,
CH2), 4.27 (br. d, J = 5.9 Hz, 2 H, CH2), 4.54 (d, J = 11.3 Hz, 1
H, CH2), 4.58 (s, 2 H, CH2), 5.39 (br. s, 1 H, CH), 5.42 (br. s, 1 H,
CH2), 5.45 (m, 1 H, CH), 5.50 (br. s, 1 H, CH2), 5.81 (t, J = 5.9 Hz,
1 H, CH), 6.84 (br. d, J = 8.5 Hz, 2 H, 2ϫCH), 7.23 (br. d, J =
8.5 Hz, 2 H, 2ϫCH) ppm. 13C NMR (75 MHz, CDCl3): δ = –5.1
(2 ϫ CH3), 18.3 (C), 20.8 (CH3), 21.1 (CH3), 21.2 (CH3), 24.9
(CH3), 25.9 (3ϫCH3), 39.8 (CH2), 55.3 (CH3), 59.6 (2ϫCH2), 70.0
(CH2), 72.5 (CH), 77.0 (CH), 89.1 (C), 89.7 (C), 105.3 (CH), 113.8
(2ϫCH), 121.1 (CH2), 129.9 (2ϫCH), 130.2 (C), 132.3 (C), 133.3
(C), 133.8 (CH), 149.5 (C), 159.3 (C), 169.9 (C), 170.7 (C) ppm.
MS (ESI+): m/z = 602 [M + NH4]+. HRMS (ESI): calcd. for
C33H52NO7Si [M + NH4]+ 602.3507; found 602.3504.
(4S,6S,Z)-3-(Acetoxymethylene)-6-(4-methoxybenzyloxy)-11-
methyl-7-methylenedodeca-1,10-dien-8-yne-1,4-diyl Diacetate (18):
In a dry Schlenk tube, a solution of 17 (36 mg, 0.0768 mmol),
DMAP (9.3 mg, 0.0768 mmol), NEt3 (1 mL), and acetic anhydride
(21.6 µL, 0.23 mmol) was stirred at 80 °C and monitored by TLC.
After disappearance of the starting material (3 h), the mixture was
concentrated under vacuum. The crude product was purified by
flash chromatography (SiO2; petroleum ether/EtOAc, 8:2) to give a
52:48 mixture (35 mg) of 18 and iso-18 in 89% yield. Data for 18:
1H NMR (500 MHz, C6D6): δ = 1.44 (br. s, 3 H, CH3), 1.45 (br. s,
3 H, CH3), 1.50 (s, 3 H, CH3), 1.55 (s, 3 H, CH3), 1.56 (s, 3 H,
CH3), 1.59 (s, 3 H, CH3), 1.61 (s, 3 H, CH3), 1.64 (s, 3 H, CH3),
1.71 (s, 3 H, CH3), 1.82 (br. s, 3 H, CH3), 1.86 (br. s, 3 H, CH3),
2.24–2.30 (m, 2 H, 2ϫCH2), 2.41–2.46 (m, 1 H, CH2), 2.60–2.66
(m, 1 H, CH2), 3.31 (s, 3 H, CH3), 3.32 (s, 3 H, CH3), 4.11 (dd, J
= 9.8, 3.0 Hz, 1 H, CH), 4.14 (dd, J = 10.0, 2.8 Hz, 1 H, CH),
4.30–4.34 (m, 2 H, 2ϫCH2), 4.65 (m, 2 H, 2ϫCH2), 5.08 (d, J =
7.2 Hz, 1 H, CH), 5.37–5.41 (m, 4 H, 2ϫCH and CH2), 5.52 (br.
s, 1 H, CH2), 5.56 (br. s, 1 H, CH2), 5.75 (d, J = 12.7 Hz, 1 H,
CH), 6.61 (dd, J = 10.6, 3.1 Hz, 1 H, CH), 6.65 (dd, J = 10.4,
3.3 Hz, 1 H, CH), 6.81 (br. d, J = 8.0 Hz, 4 H, 2ϫCH2), 7.30–7.34
(m, 6 H), 7.93 (d, J = 12.7 Hz, 1 H, CH), 8.12 (s, 1 H, CH) ppm.
(3S,5S,E)-2-(2-Hydroxyethylidene)-5-(4-methoxybenzyloxy)-10-
methyl-6-methyleneundec-9-en-7-yne-1,3-diyl Diacetate (16): To a
stirred solution of 15 (92 mg, 0.157 mmol) in THF (2 mL) was
added HF·pyridine complex (140 µL). The reaction mixture was
stirred at room temperature and followed by TLC. After disappear-
ance of the starting material (3 h), the mixture was concentrated
under vacuum and then purified by column of chromatography
(SiO2; petroleum ether/EtOAc, 6:4) to give 16 (57 mg) in 77% yield.
[α]2D4 = –64.5 (c = 1, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ =
1.83 (br. s, 3 H, CH3), 1.90 (br. s, 3 H, CH3), 1.91 (br. s, 3 H, CH3),
1.91–2.03 (m, 2 H, CH2), 2.01 (s, 3 H, CH3), 3.78 (s, 3 H, CH3),
3.78–3.85 (m, 1 H, CH), 4.18–4.22 (m, 3 H, CH2 and CH2), 4.54
(d, J = 11.5 Hz, 1 H, CH2), 4.58 (d, J = 12.5 Hz, 1 H, CH2), 4.70
(d, J = 12.5 Hz, 1 H, CH2), 5.39 (br. s, 1 H, CH), 5.43 (m, 2 H,
CH and CH2), 5.50 (br. s, 1 H, CH2), 5.91 (J = 6.7 Hz, 1 H, CH),
6.85 (br. d, J = 8.5 Hz, 2 H, 2ϫCH), 7.23 (br. d, J = 8.5 Hz, 2 H,
2ϫCH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0 (CH3), 21.1
(CH3), 21.2 (CH3), 25.0 (CH3), 40.0 (CH2), 55.4 (CH3), 58.5 (CH2),
59.5 (CH2), 70.0 (CH2), 72.4 (CH), 76.9 (CH), 89.1 (C), 89.8 (C),
105.2 (CH), 113.8 (2ϫCH), 121.2 (CH2), 130.0 (2ϫCH), 130.2
(C), 132.1 (C), 132.3 (C), 135.6 (CH), 149.7 (C), 159.3 (C), 170.1
(C), 171.2 (C) ppm.
(3S,5S,E)-2-[2-(tert-Butyldimethylsilyloxy)ethylidene]-5-hydroxy-10-
methyl-6-methyleneundec-9-en-7-yne-1,3-diyl Diacetate (19): To a
stirred solution of 15 (82 mg, 0.0141 mmol) in 5% aqueous CH2Cl2
(2.9 mL) was added DDQ (31.9 mg, 0.0141 mmol) at 0 °C. The
solution was stirred at room temperature and followed by TLC.
After disappearance of the starting material (3 h), the mixture was
filtered through Celite and concentrated under vacuum. The crude
product was purified by column of chromatography (SiO2; petro-
leum ether/Et2O, 7:3) to give 19 (41 mg) in 62% yield. [α]1D9 = –34.1
(c = 1, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.05 (s, 6 H,
2ϫCH3); 0.88 (s, 9 H, 3ϫCH3), 1.82 (br. s, 3 H, CH3), 1.82–1.90
(m, 1 H, CH2), 1.90 (br. s, 3 H, CH3), 2.03 (s, 3 H, CH3), 2.06 (s,
3 H, CH3), 2.06–2.18 (m, 1 H, CH2), 2.52 (m, 1 H, OH), 4.12 (br.
d, J = 8.9 Hz, 1 H, CH), 4.30 (d, J = 5.9 Hz, 2 H, CH2), 4.63 (s, 2
H, CH2), 5.38 (br. s, 1 H, CH), 5.40 (br. s, 1 H, CH2), 5.48–5.52
(3S,5S,E)-5-(4-Methoxybenzyloxy)-10-methyl-6-methylene-2-(2-oxo- (m, 2 H, CH and CH2), 5.86 (t, J = 5.9 Hz, 1 H, CH) ppm. 13C
ethylidene)undec-9-en-7-yne-1,3-diyl Diacetate (17): To a stirred NMR (75 MHz, CDCl3): δ = –5.2 (2ϫCH3), 18.2 (C), 20.8 (CH3),
2992
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2987–2997

Studies towards the Total Synthesis of (–)-Caulerpenynol
21.0 (CH3), 21.1 (CH3), 24.8 (CH3), 25.9 (3ϫCH3), 40.7 (CH2),
59.5 (2ϫCH2), 70.5 (CH), 72.7 (CH), 88.9 (C), 90.0 (C), 105.1
(CH), 119.2 (CH2), 133.1 (C), 134.0 (CH), 134.5 (C), 149.3 (C),
δ = 21.0 (CH3), 24.8 (CH3), 35.2 (CH2), 55.1 (CH3), 67.8 (CH2),
72.8 (CH2), 73.1 (CH), 89.4 (C), 89.5 (C), 105.1 (CH), 113.8
(2ϫCH), 119.2 (CH2), 129.3 (2ϫCH), 130.0 (C), 134.5 (C), 149.0
170.6 (C), 170.7 (C) ppm. MS (ESI+): m/z = 482 [M + NH4]+. (C), 159.2 (C) ppm. HRMS (ESI): calcd. for C19H25O3 [M + H]+
HRMS (ESI): calcd. for C25H44NO6Si [M + NH4]+ 482.2932; 301.1798; found 301.1799.
found 482.2930.
(S)-tert-Butyl[1-(4-methoxybenzyloxy)-8-methyl-4-methylenenon-7-
en-5-yn-3-yloxy]dimethylsilane (21): To a stirred solution of alcohol
11Ј (712 mg, 2.37 mmol) in dry CH2Cl2 (21 mL) was added, at 0 °C,
2,6-lutidine (0.552 mL, 4.74 mmol) then TBDMSOTf (0.628 mL,
2.84 mmol). The mixture was stirred at 0 °C until disappearance of
the starting material (2 h) and then quenched with saturated
NaHCO3 aqueous solution. The aqueous layer was extracted with
Et2O, and the combined organic phases washed with saturated
aqueous NaCl solution, dried with MgSO4, and concentrated. The
crude product was purified by column of chromatography (SiO2;
petroleum ether/Et2O, 9:1) to yield 957 mg (97%). [α]2D3 = –16.7 (c
= 1, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.06 (s, 3 H, CH3),
0.08 (s, 3 H, CH3), 0.92 (s, 9 H, 3ϫCH3), 1.83 (s, 3 H), 1.92 (s, 3
H, CH3), 1.94–2.08 (m, 2 H, CH2), 3.48–3.64 (m, 2 H, CH2), 3.81
(s, 3 H, CH3), 4.34 (dd, J = 7.7, 4.3 Hz, 1 H, CH), 4.41 (d, J =
11.3 Hz, 1 H, CH2), 4.46 (d, J = 11.3 Hz, 1 H, CH2), 5.36 (br. s, 1
H, CH), 5.39 (br. s, 1 H, CH2), 5.44 (s, 1 H, CH), 6.89 (br. d, J =
8.7 Hz, 2 H, 2ϫCH), 7.28 (br. d, J = 8.7 Hz, 2 H, 2ϫCH) ppm.
13C NMR (75 MHz, CDCl3): δ = –5.0 (CH3), –4.5 (CH3), 18.3 (C),
21.2 (CH3), 24.9 (CH3), 25.9 (3ϫCH3), 37.3 (CH2), 55.3 (CH3),
66.5 (CH2), 72.3 (CH2), 72.7 (CH), 89.5 (C), 89.8 (C), 105.4 (CH),
113.8 (2ϫCH), 119.0 (CH2), 129.4 (2ϫCH), 130.9 (C), 135.8 (C),
148.9 (C), 159.2 (C) ppm. MS (ESI+): m/z = 432 [M + NH4]+.
HRMS (ESI): calcd. for C25H39O3Si [M + H]+ 415.2663; found
415.2660.
(3S,5S,E)-5-(tert-Butyldimethylsilyloxy)-2-[2-(tert-butyldimethylsil-
yloxy)ethylidene]-10-methyl-6-methyleneundec-9-en-7-yne-1,3-diyl
Diacetate (20)
Method A: To a stirred solution of alcohol 19 (54 mg, 0.115 mmol)
in CH2Cl2 (2 mL) was added at 0 °C 2,6-lutidine (27 µL,
0.230 mmol) followed by TBSOTf (32 µL, 0.138 mmol). After stir-
ring for 1 h at room temperature, the mixture was quenched with
saturated aqueous NaHCO3 solution. The aqueous layer was ex-
tracted with Et2O. The combined organic layers were washed with
saturated aqueous NaCl solution, dried with Na2SO4, and then
concentrated under vacuum. The crude product was purified by
column of chromatography (SiO2; petroleum ether/Et2O, 9:1) to
give 20 (47 mg) in 71% yield.
Method B: A solution of diol 25 (15 mg, 0.0303 mmol), acetic anhy-
dride (12 µL, 0.0.121 mmol), and DMAP (0.185 mg, 1.51 µmol) in
pyridine (0.5 mL) was stirred at room temperature. After disap-
pearance of the starting material (4 h), the mixture was quenched
with saturated aqueous NaHCO3 solution. The aqueous layer was
extracted with diethyl ether, and the organic layers were washed
with saturated aqueous CuSO4 solution and water, dried with
MgSO4, and then concentrated under vacuum. The crude product
was purified by column of chromatography (SiO2; petroleum ether/
Et2O, 9:1) to give 20 (16.1 mg) in 92% yield. [α]2D2 = –30.8 (c = 1,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.01 (s, 6 H, 2ϫCH3),
0.05 (s, 6 H, 2 ϫ CH3), 0.88 (s, 9 H, 3 ϫ CH3), 0.90 (s, 9 H,
3ϫCH3), 1.76–1.87 (m, 1 H, CH2), 1.83 (s, 3 H, CH3), 1.92 (s, 3
H, CH3), 1.96–2.13 (m, 1 H, CH2), 2.03 (br. s, 6 H, CH3), 4.20 (br.
d, J = 8.9 Hz, 1 H, CH), 4.29 (d, J = 5.7 Hz, 2 H, CH2), 4.58 (d,
J = 12.5 Hz, 1 H, CH2), 4.63 (d, J = 12.5 Hz, 1 H, CH2), 5.30 (br.
d, J = 10.4 Hz, 1 H, CH), 5.35 (br. s, 1 H, CH2), 5.38 (br. s, 1 H,
CH), 5.43 (br. s, 1 H, CH2), 5.79 (t, J = 5.7 Hz, 1 H, CH) ppm.
13C NMR (75 MHz, CDCl3): δ = –5.3 (CH3), –5.0 (2ϫCH3), –4.3
(CH3), 18.2 (C), 18.4 (C), 21.0 (CH3), 21.2 (CH3), 21.3 (CH3), 25.0
(CH3), 25.9 (6ϫCH3), 42.6 (CH2), 59.7 (CH2), 60.0 (CH2), 71.9
(CH), 72.6 (CH), 89.6 (C), 89.9 (C), 105.4 (CH), 119.2 (CH2), 133.0
(CH), 134.0 (C), 135.7 (C), 149.2 (C), 170.1 (C), 170.8 (C) ppm.
MS (ESI+): m/z = 596 [M + NH4]+. HRMS (ESI): calcd. for
C31H58NO6Si2 [M + NH4]+ 596.3797; found 596.3797.
(3S)-3-(tert-Butyldimethylsilyloxy)-8-methyl-4-methylenenon-7-en-
5-ynal (23): To a stirred solution of 21 (423 mg, 1.02 mmol) in 5%
aqueous CH2Cl2 (4 mL) was added DDQ (255 mg, 1.12 mmol) at
0 °C. The solution was stirred at 0 °C and followed by TLC. After
disappearance of the starting material (4 h), the mixture was fil-
tered through Celite and concentrated. The crude product was
purified by column chromatography (SiO2; petroleum ether/Et2O,
8:2) to yield 380 mg of an inseparable mixture of 22 and anisal-
dehyde. To a stirred solution of alcohol 22 and anisaldeyde
(380 mg) in CH2Cl2 (31 mL) was added at 0 °C Dess–Martin
periodinane (545 mg, 1.29 mmol). The mixture was stirred at room
temperature and followed by TLC. After disappearance of the
starting material (2 h), the solution was poured into a saturated
aqueous Na2S2O3/NaHCO3 solution (55 mL, 1:1). After stirring for
10 min, the layers were separated, and the aqueous layer was ex-
tracted with Et2O. The organic layers were washed with saturated
aqueous NaHCO3 solution, dried with Na2SO4, and concentrated
under vacuum. The crude aldehyde was purified by column of
chromatography (SiO2; petroleum ether/Et2O, 9:1) to give 23
(254 mg) in 85% yield over two steps. [α]2D3 = –50.7 (c = 1, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 0.07 (s, 3 H, CH3), 0.08 (s, 3 H,
CH3), 0.89 (s, 9 H, 3ϫCH3), 1.83 (s, 3 H, CH3), 1.91 (s, 3 H, CH3),
2.65 (ddd, J = 15.9, 4.4, 2.3 Hz, 1 H, CH2), 2.77 (ddd, J = 15.9,
6.8, 2.6 Hz, 1 H CH2), 4.65 (br. d, J = 6.8, 4.4 Hz CH, 1 Hd), 5.38
(br. s, 1 H, CH), 5.44 (br. s, 1 H, CH2), 5.56 (s, 1 H, CH), 9.79 (t,
J = 2.3 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = –5.1
(CH3), –4.6 (CH3), 18.2 (C), 21.2 (CH3), 25.0 (CH3), 25.8
(3ϫCH3), 50.4 (CH2), 70.9 (CH), 89.0 (C), 90.4 (C), 105.1 (CH),
119.6 (CH2), 134.2 (C), 149.7 (C), 201.5 (CH) ppm. MS (ESI+):
m/z = 342 [M + NH4+ MeOH]+. HRMS (ESI): calcd. for
C17H29O2Si [M + H]+ 293.1931; found 293.1926.
(3S)-1-(4-Methoxybenzyloxy)-8-methyl-4-methylenenon-7-en-5-yn-
3-ol (11Ј): To a stirred solution of 10 (1 g, 3.35 mmol) in CH3CN
(67 mL) was added molecular sieves (4 Å, 433 mg). The solution
was stirred at room temperature for 5 min. After cooling to 0 °C,
NaBH3CN (1.26 g, 20.1 mmol) followed by TMSCl (2.55 mL,
20.1 mmol) was added. The mixture was stirred at 0 °C until disap-
pearance of the starting material and then concentrated under vac-
uum. The mixture was diluted with water, extracted with EtOAc,
dried with MgSO4, and then concentrated. The crude product was
purified by column of chromatography (SiO2; petroleum ether/
Et2O, 6:4) to give a 1:9 separable mixture of two isomers (11/11Ј,
787 mg) in 79% yield. Major isomer 11Ј: [α]2D1 = –17.5 (c = 1,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.82 (s, 3 H, CH3),
1.90 (s, 3 H, CH3), 1.90–2.14 (m, 2 H, CH2), 3.40 (br. d, J = 4.5 Hz,
1 H, OH), 3.57–3.73 (m, 2 H, CH2), 3.78 (s, 3 H, CH3), 4.35 (m, 1
H, CH), 4.43 (s, 2 H, CH2), 5.38 (br. s, 1 H, CH), 5.43 (br. s, 1 H,
CH2), 5.54 (s, 1 H, CH), 6.87 (br. d, J = 8.5 Hz, 2 H, 2ϫCH), 7.24
(br. d, J = 8.5 Hz, 2 H, 2ϫCH) ppm. 13C NMR (75 MHz, CDCl3):
(3S,5S,E)-5-(tert-Butyldimethylsilyloxy)-2-[2-(tert-butyldimethylsil-
yloxy)ethylidene]-10-methyl-6-methyleneundec-9-en-7-yne-1,3-diol
Eur. J. Org. Chem. 2009, 2987–2997
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2993

L. Commeiras, J. Thibonnet, J.-L. Parrain
FULL PAPER
(24): To a solution of vinyltin reagent 13[15] (584 mg, 1.19 mmol) in
THF (18.4 mL) was added at –40 °C MeLi·LiBr (2.2 , 1.08 mL,
2.38 mmol). The mixture was stirred at –35 °C until disappearance
of the starting material. The mixture was then cooled to –80 °C and
aldehyde 23 (365 mg, 1.25 mmol), diluted in a minimum amount of
THF, was added at –80 °C. The reaction was followed by TLC
(2 h). The mixture was quenched with saturated NH4Cl aqueous
solution. The aqueous layer was extracted with EtOAc. The com-
bined organic layers were dried with Na2SO4 and concentrated un-
der vacuum. The crude product was purified by column of
chromatography (SiO2; petroleum ether/Et2O, 9:1 to 6:4) to yield
117 mg (30%). Major isomer: [α]2D4 = –7.5 (c = 1, CH2Cl2). M.p.
65 °C. 1H NMR (300 MHz, CDCl3): δ = 0.06 (s, 6 H, 2ϫCH3),
0.08 (s, 3 H, CH3), 0.12 (s, 3 H, CH3), 0.88 (s, 9 H, 3ϫCH3), 0.92
(s, 9 H, 3ϫCH3), 1.81 (s, 3 H, CH3), 1.88 (s, 3 H, CH3), 1.95–2.05
(m, 2 H, CH2), 3.02 (br. s, 1 H, OH), 3.66 (br. s, 1 H, OH), 4.17
(br. s, 2 H, CH2), 4.27 (d, J = 6.0 Hz, 2 H, CH2), 4.47 (br. d, J =
8.3 Hz, 1 H, CH), 4.53 (m, 1 H, CH), 5.35 (br. s, 1 H, CH), 5.49
(s, 1 H, CH2), 5.55 (br. s, 1 H, CH2), 5.69 (t, J = 6.0 Hz, 1 H, CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = –5.2 (CH3), –5.1 (2ϫCH3),
–4.7 (CH3), 18.3 (C), 18.4 (C), 21.3 (CH3), 25.0 (CH3), 25.9
(3ϫCH3), 26.0 (3ϫCH3), 40.8 (CH2), 58.9 (CH2), 59.7 (CH2), 73.1
(CH), 74 (CH), 89.4 (C), 90.0 (C), 105.2 (CH), 119.8 (CH2), 128.0
(CH), 133.5 (C), 142.5 (C), 149.4 (C) ppm. MS (ESI+): m/z = 512
[M + NH4]+. HRMS (ESI): calcd. for C27H51O4Si2 [M + H]+
495.3320; found 495.3320.
NMR (300 MHz, C6D6): δ = 0.06 (s, 3 H, CH3), 0.10 (s, 3 H, CH3),
1.01 (s, 9 H, 3ϫCH3), 1.47 (br. s, 3 H, CH3), 1.63 (s, 3 H, CH3),
1.73 (s, 3 H, CH3), 1.85 (br. s, 3 H, CH3), 2.01 (dd, J = 7.4, 5.3 Hz,
2 H, CH2), 4.37–4.41 (m, 1 H, CH), 4.58 (d, J = 14 Hz, 1 H, CH2),
4.95 (d, J = 14 Hz, 1 H, CH2), 5.39–5.42 (m, 3 H, CH and CH2),
5.56–5.60 (m, 1 H, CH), 6.11 (d, J = 7.2 Hz, 1 H, CH), 9.93 (d, J
= 7.2 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, C6D6): δ = –5.3
(CH3), –4.2 (CH3), 18.4 (C), 20.26 (CH3), 20.3 (CH3), 21.1 (CH3),
24.6 (CH3), 26.0 (3ϫCH3), 42.6 (CH2), 59.0 (CH2), 71.0 (CH),
72.2 (CH), 89.9 (C), 90.9 (C), 105.8 (CH), 119.4 (CH2), 128.1 (CH),
136.1 (C), 149.4 (C), 156.0 (C), 169.4 (C), 169.6 (C), 189.6 (C) ppm.
MS (ESI+): m/z = 482 [M + NH4]+.
(4S,6S,Z)-3-(Acetoxymethylene)-6-(4-tert-butyldimethylsiloxy)-11-
methyl-7-methylenedodeca-1,10-dien-8-yne-1,4-diyl Diacetate (27):
In a dry Schlenk tube, a solution of 26 (16.5 mg, 0.0357 mmol),
DMAP (4.4 mg, 0.0357 mmol), NEt3 (1 mL), and acetic anhydride
(10 µL, 0.107 mmol) was stirred under an atmosphere of argon at
80 °C and monitored by TLC. After disappearance of the starting
material (1 h), the mixture was concentrated under vacuum. The
crude product was purified by flash chromatography (SiO2; petro-
leum ether/EtOAc, 9:1) to give a 45:55 mixture (17.6 mg) of 27 and
iso-27 in 98% yield. 1H NMR (300 MHz, C6D6): δ = 0.14–0.17 (m,
12 H, 12H, 6ϫCH3), 1.05 (s, 9 H, 3ϫCH3), 1.06 (s, 9 H, 3ϫCH3),
1.44 (br. s, 3 H, CH3), 1.46 (br. s, 3 H, CH3), 1.57 (s, 3 H, CH3),
1.60 (s, 3 H, CH3), 1.70 (s, 3 H, CH3), 1.73 (s, 3 H, CH3), 1.75 (s,
3 H, CH3), 1.82 (m, 6 H, 2ϫCH3), 1.86 (br. s, 3 H, CH3), 2.01–
2.11 (m, 2 H, 2ϫCH2), 2.39–2.48 (m, 1 H, CH2), 2.61–2.70 (m, 1
H, CH2), 4.48 (dd, J = 9.6, 2.6 Hz, 1 H, CH), 4.53 (dd, J = 9.8,
2.5 Hz, 1 H, CH), 5.06 (d, J = 7.4 Hz, 1 H, CH), 5.36–5.46 (m, 6
H, 2ϫCH and 2ϫCH2), 5.73 (d, J = 12.8 Hz, 1 H, CH), 6.32–
6.40 (m, 2 H, 2ϫCH), 7.30 (d, J = 7.4 Hz, 1 H, CH), 7.34 (s, 1 H,
CH), 7.92 (d, J = 12.8 Hz, 1 H, CH), 8.17 (s, 1 H, CH) ppm. 13C
NMR (75 MHz, C6D6): δ = –4.14 (CH3), –4.10 (CH3), 18.43 (2 C),
20.0 (2ϫCH3), 20.1 (CH3), 20.2 (CH3), 20.6 (CH3), 20.7 (CH3),
21.0 (CH3), 21.1 (CH3), 24.6 (2 ϫ CH3), 26.16 (3 ϫ CH3), 41.7
(CH2), 42.0 (CH2), 66.9 (CH), 67.1 (CH), 72.2 (CH), 72.4 (CH),
90.11 (C), 90.13 (C), 90.7 (C), 90.8 (C), 103.6 (CH), 106.0 (2ϫCH),
110.1 (CH), 118.1 (C), 119.2 (CH2), 119.3 (CH2), 120.0 (C), 128.4
(CH), 134.5 (CH), 135.4 (CH), 136.3 (C), 136.5 (C), 137.1 (CH),
137.7 (CH), 148.9 (C), 149.0 (C), 166.6 (C), 166.7 (C), 166.8 (C),
167.2 (C), 169.1 (C), 169.2 (C) ppm. MS (ESI+): m/z = 522 [M +
NH4]+.
(3S,5S,E)-5-(tert-Butyldimethylsilyloxy)-2-(2-hydroxyethylidene)-
10-methyl-6-methyleneundec-9-en-7-yne-1,3-diyl Diacetate (25): To
a stirred solution of 20 (62 mg, 0.107 mmol) in THF (4 mL) was
added HF·pyridine/pyridine/THF (4 mL, 1:2:4). The mixture was
stirred for 1 h at room temperature and then quenched with a satu-
rated aqueous NaHCO3 solution. The aqueous layer was extracted
with EtOAc, and the combined organic layers were dried with
Na2SO4 and then concentrated under vacuum. The crude product
was purified by flash chromatography (petroleum ether/EtOAc, 8:2)
to give 25 (1.456 g) in 86% yield. [α]2D2 = –35.8 (c = 1, CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ = –0.01 (s, 3 H, CH3), 0.00 (s, 3 H,
CH3), 0.89 (s, 9 H, 3ϫCH3), 1.73–1.82 (m, 1 H, CH2), 1.81 (s, 3
H, CH3), 1.90 (s, 3 H, CH3), 1.96–2.09 (m, 1 H, CH2), 2.03 (br. s,
6 H, 2ϫCH3), 2.36 (m, 1 H, OH), 4.14–4.27 (m, 3 H, CH and
CH2), 4.55 (d, J = 12.5 Hz, 1 H, CH2), 4.75 (d, J = 12.5 Hz, 1 H,
CH2), 5.28 (br. d, J = 10.8 Hz, 1 H, CH), 5.33 (br. s, 1 H, CH2),
5.36 (br. s, 1 H, CH), 5.42 (br. s, 1 H, CH2), 5.88 (t, J = 6.9 Hz, 1
H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = –5.4 (CH3), –4.3
(CH3), 18.2 (C), 21.0 (CH3), 21.1 (CH3), 21.2 (CH3), 25.0 (CH3),
25.9 (3ϫCH3), 42.7 (CH2), 58.3 (CH2), 59.8 (CH2), 71.7 (CH),
72.3 (CH), 89.5 (C), 89.9 (C), 105.3 (CH), 119.1 (CH2), 130.9 (CH),
135.6 (C), 136.3 (C), 149.3 (C), 170.2 (C), 171.3 (C) ppm. MS
(ESI+): m/z = 482 [M + NH4]+.
(3S)-3-Triethylsilanyloxydihydrofuran-2(3H)-one (29): To a stirred
solution of alcohol 28 (2.5 g, 24.48 mmol) in DMF (23 mL) was
added imidazole (3.67 g, 53.87 mmol), DMAP (299 mg,
2.45 mmol), and TESCl (4.98 mL, 29.38 mmol). The solution was
stirred at room temperature for 5 h and then quenched with satu-
rated aqueous NaHCO3 solution. The aqueous layer was extracted
with EtOAc. The combined organic layers were washed with satu-
rated aqueous NaCl solution, dried with Na2SO4, and then concen-
trated under vacuum. The crude product was purified by column
of chromatography (SiO2; 3% NEt3, petroleum ether/Et2O, 7:3 to
6:4) to give 29 (5.3 g) in quantitative yield. [α]2D2 = –36.3 (c = 1,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.60–0.69 (m, 6 H,
3ϫCH2), 0.90–0.98 (m, 9 H, 3ϫCH3), 2.11–2.25 (m, 1 H, CH2),
2.39–2.49 (m, 1 H, CH2), 4.11–4.20 (m, 1 H, CH2), 4.30–4.40 (m,
2 H, CH2 and CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 4.7
(3 ϫ CH2), 6.6 (3 ϫ CH3), 32.5 (CH2), 64.8 (CH2), 68.00 (CH),
176.00 (C) ppm. HRMS (ESI): calcd. for C10H24NO3Si [M +
NH4]+ 234.1519; found 234.1515.
(3S,5S,E)-5-(tert-Butyldimethylsilyloxy)-10-methyl-6-methylene-2-
(2-oxoethylidene)undec-9-en-7-yne-1,3-diyl Diacetate (26): To a
stirred solution of alcohol 25 (43 mg, 0.0925 mmol) in CH2Cl2
(2.6 mL) was added at 0 °C Dess–Martin periodinane (47 mg,
0.111 mmol). The mixture was stirred at room temperature and fol-
lowed by TLC. After disappearance of the starting material (2 h),
the solution was poured into a saturated aqueous Na2S2O3/
NaHCO3 solution (5 mL, 1:1). After stirring for 10 min, the layers
were separated and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
NaHCO3 solution, dried with Na2SO4, and then concentrated un-
der vacuum. The crude aldehyde was purified by column of
chromatography (SiO2; petroleum ether/EtOAc, 8:2) to give 26
(42.6 mg) in quantitative yield. [α]2D2 = –16.3 (c = 1, CH2Cl2). 1H
(3S)-1-Hydroxy-8-methyl-3-(triethylsilyloxy)non-7-en-5-yn-4-one
(30): To a solution of 1,1-dibromo-4-methylpent-1,3-diene[12]
2994
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2987–2997

Studies towards the Total Synthesis of (–)-Caulerpenynol
(7.31 g, 30.46 mmol) in THF (130 mL) was added dropwise, at (7S,9S,E)-9-Hydroxy-10-(hydroxymethyl)-2-methyl-7,12-bis(tri-
–78 °C, n-butyllithium (2.5  in hexanes, 24.4 mL, 61 mmol). The
solution was stirred at –78 °C for 1.5 h and then transferred by
ethylsilyloxy)dodeca-2,10-dien-4-yn-6-one (33): To a solution of vi-
nyl tin 32 (1.08 g, 2.21 mmol) in THF (31 mL) at –78 °C was added
cannula to lactone 7 (6 g, 27.73 mmol) in THF (130 mL) at –78 °C. dropwise MeLi·LiBr (2.0 mL, 4.41 mmol, 2.2  in Et2O). The reac-
After warming to –20 °C, the mixture was quenched with a 9:1
mixture of saturated aqueous NH4Cl solution and aqueous 33%
NH4OH solution. The aqueous phase was extracted with EtOAc.
The combined organic layers were dried with Na2SO4, filtered, and
then concentrated under vacuum. The crude alcohol was purified
by column of chromatography (SiO2; 3% NEt3, petroleum ether/
Et2O, 7:3 to 6:4) to give 30 (5.04 g) in 61% yield. [α]2D2 = –56.3 (c
tion mixture was warmed to –35 °C. The mixture was then cooled
to –78 °C and aldehyde 31 (620 mg, 2.1 mmol) diluted in minimum
of THF was added dropwise at –78 °C. The solution was kept at
–78 °C for 1 h and then quenched with a 9:1 mixture of saturated
aqueous NH4Cl solution and aqueous 33% NH4OH solution. The
aqueous layer was extracted with ethyl acetate. The combined or-
ganic layers were dried with Na2SO4 and concentrated under vac-
= 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.63 (q, J = 7.9 Hz, uum. The crude product was purified by flash chromatography
6 H, 3ϫCH2), 0.95 (t, J = 7.9 Hz, 9 H, 3ϫCH3), 1.89 (br. s, 3 H, (SiO2; 3% NEt3, petroleum ether/Et2O, 6:4) to give a 7:3 separable
CH3), 1.99 (br. s, 3 H, CH3), 1.97–2.05 (m, 2 H, CH2), 2.24 (m, 1 mixture of diastereomers 34 (444 mg) in 43% yield. Major dia-
H, OH), 3.76 (t, J = 5.6 Hz, 2 H, CH2), 4.39 (br. d, J = 5.1, 6.8 Hz,
CH, 1 Hd), 5.42 (br. s, 1 H, CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 4.8 (3ϫCH2), 6.8 (3ϫCH3), 22.0 (CH3), 25.6 (CH3),
stereomer 33: [α]2D1 = –32.8 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.55–0.68 (m, 12 H, 6ϫCH2), 0.91–0.99 (m, 18 H,
6ϫCH3), 1.90 (s, 3 H, CH3), 2.00 (s, 3 H, CH3), 2.00–2.15 (m, 2
36.9 (CH2), 59.4 (CH2), 77.5 (CH, C3), 89.6 (C), 94.3 (C), 103.7 H, CH2), 4.17 (br. d, J = 2.5 Hz, 2 H, CH2), 4.25 (d, J = 5.6 Hz,
(CH), 159.2 (C), 189.8 (C) ppm. HRMS (ESI): calcd. for
2 H, CH2), 4.41 (d, J = 9.2 Hz, 1 H, CH), 4.51 (br. d, J = 4.3,
6.6 Hz, CH, 1 Hd), 5.43 (br. s, 1 H, CH), 5.71 (t, J = 5.6 Hz, 1 H,
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 4.4 (CH2), 4.8 (CH2),
6.8 (3ϫCH3), 22.0 (CH3), 25.6 (CH3), 40.1 (CH2), 58.6 (CH2), 59.1
(CH2), 72.8 (CH), 77.4 (CH), 89.7 (C), 94.5 (C), 103.7 (CH), 128.5
(CH), 142.4 (C), 159.4 (C), 189.4 (C) ppm. MS (ESI+): m/z = 514
[M + NH4]+. HRMS (ESI): calcd. for C26H52NO5Si2 [M + NH4]+
514.3378; found 514.3378.
C16H29O3Si [M + H]+ 297.1880; found 297.1879.
(3S)-8-Methyl-4-oxo-3-(triethylsilyloxy)non-7-en-5-ynal (31): To a
stirred solution of alcohol 30 (1.5 g, 5.06 mmol) in CH2Cl2 (45 mL)
was added at 0 °C Dess–Martin periodinane (2.55 g, 6.04 mmol).
The mixture was stirred at room temperature and followed by TLC.
After disappearance of the starting material (2 h), the solution was
poured into a saturated aqueous Na2S2O3/NaHCO3 solution
(255 mL, 1:1). After stirring for 10 min, the layers were separated (3S,5S,E)-10-Methyl-6-oxo-5-(triethylsilyloxy)-2-[2-(triethylsilyl-
and the aqueous layer was extracted with EtOAc. The combined
organic layers were washed with saturated aqueous NaHCO3 solu-
tion, dried with Na2SO4, and then concentrated under vacuum.
The crude aldehyde was purified by column of chromatography
(SiO2; 3% NEt3, petroleum ether/Et2O, 8:2) to give 31 (1.27 g) in
85% yield. [α]2D0 = –46.4 (c = 1, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 0.63 (q, J = 8.0 Hz, 6 H, 3ϫCH2), 0.94 (t, J = 8.0 Hz,
9 H, 3ϫCH3), 1.91 (s, 3 H, CH3), 2.00 (s, 3 H, CH3), 2.80–2.83
(m, 2 H, CH2), 4.68 (br. t, J = 5.8 Hz, 1 H, CH), 5.43 (br. s, 1 H,
oxy)ethylidene]undec-9-en-7-yne-1,3-diyl Diacetate (34): A solution
of diol 33 (70 mg, 0.141 mmol), acetic anhydride (53 µL,
0.563 mmol), and DMAP (1.7 mg, 0.014 mmol) in pyridine (2 mL)
was stirred at room temperature. After disappearance of the start-
ing material (4 h), the mixture was quenched with saturated aque-
ous NaHCO3 solution. The aqueous layer was extracted with di-
ethyl ether and the organic layers were washed with saturated aque-
ous CuSO4 solution and water, dried with MgSO4, and then con-
centrated under vacuum. The crude product was purified by col-
CH), 9.78 (br. t, J = 1.4 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, umn of chromatography (SiO2; 3% NEt3, petroleum ether/Et2O,
CDCl3): δ = 4.8 (3ϫCH2), 6.8 (3ϫCH3), 22.1 (CH3), 25.6 (CH3),
48.2 (CH2), 74.3 (CH), 89.4 (C), 95.0 (C), 103.6 (CH), 159.8 (C),
188.0 (C), 199.08 (CH) ppm. MS (ESI+): m/z = 295 [M + H]+.
HRMS (ESI): calcd. for C16H27O3Si [M + H]+ 295.1723; found
295.1723.
85:15) to give 34 (66 mg) in 81% yield. [α]1D9 = –31.5 (c = 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 0.53–0.63 (m, 12 H, 6ϫCH2),
0.92 (t, J = 7.9 Hz, 9 H, 3 ϫ CH3), 0.93 (t, J = 7.9 Hz, 9 H,
3ϫCH3), 1.74–1.87 (m, 1 H, CH2), 1.91 (s, 3 H, CH3), 2.01–2.02
(m, 9 H, 3ϫCH3), 2.06–2.20 (m, 1 H, CH2), 4.23 (dd, J = 9.8,
2.8 Hz, 1 H, CH), 4.27 (d, J = 5.9 Hz, 2 H, CH2), 4.57 (d, J =
12.7 Hz, 1 H, CH2), 4.62 (d, J = 12.7 Hz, 1 H, CH2), 5.31 (br. d,
J = 10.6, 1.9 Hz, CH, 1 Hd), 5.44 (br. s, 1 H, CH), 5.83 (t, J =
5.9 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 4.5 (CH2),
4.8 (CH2), 6.8 (3ϫCH3), 20.9 (CH3), 21.1 (CH3), 22.0 (CH3), 25.6
(CH3), 39.6 (CH2), 59.2 (CH2), 59.7 (CH2), 71.9 (CH), 76.0 (CH),
89.4 (C), 94.2 (C), 103.7 (CH), 133.4 (C), 133.7 (CH), 159.3 (C),
169.9 (C), 170.7 (C), 189.4 (C) ppm. MS (ESI+): m/z = 598 [M +
NH4]+. HRMS (ESI): calcd. for C30H56NO7Si2 [M + NH4]+
598.3589; found 598.3584.
(E)-4-Triethylsilyloxy-2-tributylstannylbut-2-en-1-ol (32): To a solu-
tion of (E)-2-tributylstannylbut-2-en-1-ol[15] (9.66 g, 25.61 mmol) in
THF (105 mL) at –20 °C was added NEt3 (7.13 mL, 51.22 mmol)
and TESCl (4.33 mL, 25.61 mmol). The solution was stirred at
–20 °C and followed by TLC. After disappearance of the starting
material (4 h) the reaction was quenched with water, and the aque-
ous layer was extracted with Et2O. The combined organic layers
were dried with Na2SO4, filtered, and concentrated under vacuum.
The crude alcohol was purified by column of chromatography
(SiO2; 3% NEt3, petroleum ether/Et2O, 9:1) to give 32 (6.62 g) in
1
53% yield. H NMR (300 MHz, CDCl3): δ = 0.62 (q, J = 7.7 Hz,
(3S,5S,E)-10-Methyl-6-oxo-5-(triethylsilyloxy)-2-[2-(triethylsilyl-
oxy)ethylidene]undec-9-en-7-yne-1,3-diyl Diacetate (35): To a stirred
solution of CH3PPh3Br (307 mg, 0.860 mmol) in THF (0.7 mL)
was added tBuOK (77 mg, 0.69 mmol) in THF (0.7 mL). The solu-
tion was stirred at 0 °C for 30 min and then cooled to –78 °C.
Ketone 34 (100 mg, 0.172 mmol) diluted in THF (1 mL) was then
added. The solution was warmed up to 0 °C and then quenched
with water. The aqueous layer was extracted with Et2O, and the
combined organic layers were dried with Na2SO4 and then concen-
trated under vacuum. The crude product was purified by column
of chromatography (SiO2; 3% NEt3, petroleum ether/Et2O, 9:1) to
6 H, 3ϫCH2), 0.86–0.99 (m, 24 H, 6ϫCH3, 3ϫCH2), 1.25–1.37
(m, 6 H, 6ϫCH2), 1.44–1.55 (m, 6 H, 6ϫCH2), 1.82 (br. t, J =
4
5.4 Hz, 1 H, OH), 4.22 (br. d, J = 5.5 Hz, JSn,H = 16 Hz, 2 H,
3
CH2), 4.34 (m, JSn,H = 37 Hz, 2 H, CH2), 5.72 (br. t, J = 5.4 Hz,
3JSn,H = 69 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
4.6 (3ϫCH2), 6.9 (3ϫCH3), 7.9, (1JSn,C = 332 Hz, 3ϫCH2), 13.8
(3ϫCH2), 27.2 (3JSn,C = 58 Hz, 3ϫCH2), 29.3 (2JSn,C = 19 Hz,
3ϫCH2), 60.5 (CH2), 63.8 (2JSn,C = 24 Hz, CH2), 138.9 (2JSn,C
=
19 Hz, CH), 147.5 (C) ppm. HRMS (ESI): calcd. for C22H49O2SiSn
[M + H]+ 493.2522; found 493.2534.
Eur. J. Org. Chem. 2009, 2987–2997
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2995

L. Commeiras, J. Thibonnet, J.-L. Parrain
FULL PAPER
give 35 (52 mg) in 53% yield. [α]1D9 = –34.0 (c = 1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.57 (q, J = 8.12 Hz, 12 H, 6ϫCH2),
0.93 (t, J = 8.1 Hz, 9 H, 6ϫCH3), 1.74–1.87 (m, 1 H, CH2), 1.81
71.1 (CH), 72.3 (CH), 89.9 (C), 90.9 (C), 105.8 (CH), 119.4 (CH2),
128.1 (CH), 135.2 (C), 149.4 (C), 156.0 (C), 19.4 (C), 169.6 (C),
189.5 (CH) ppm. MS (ESI+): m/z = 480 [M + NH4]+. HRMS
(s, 3 H, CH3), 1.90 (s, 3 H, CH3), 1.95–2.08 (m, 1 H, CH2), 2.01 (ESI): calcd. for C25H42NO6Si [M + NH4]+ 480.2775; found
(m, 6 H, 2ϫCH3), 4.20 (dd, J = 9.1, 2.7 Hz, 2 H, CH), 4.27 (d, J
= 6.0 Hz, 2 H, CH2), 4.56 (d, J = 12.5 Hz, 1 H, CH2), 4.62 (d, J =
12.5 Hz, 1 H, CH2), 5.29–5.37 (m, 3 H, CH2 and 2ϫCH), 5.43 (br.
s, 1 H, CH2), 5.80 (t, J = 6.0 Hz, 1 H, CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 4.5 (3ϫCH2), 4.9 (3ϫCH2), 6.8 (3ϫCH3),
6.9 (3ϫCH3), 20.9 (CH3), 21.1 (CH3), 21.2 (CH3), 25.0 (CH3),
42.32 (CH2), 59.3 (CH2), 59.8 (CH2), 72.0 (CH), 72.7 (CH), 89.5
(C), 89.9 (C), 105.4 (CH), 119.1 (CH2), 133.1 (CH), 133.9 (C),
135.7 (C), 149.2 (C), 170.0 (C), 170.8 (C) ppm. MS (ESI+): m/z =
596 [M + NH4]+. HRMS (ESI): calcd. for C31H58NO6Si2 [M +
NH4]+ 596.3797; found 596.3790.
480.2774.
(3S,5S,Z)-2-(2-Acetoxyvinyl)-10-methyl-6-methylene-5-(triethylsil-
yloxy)undeca-1,9-dien-7-yne-1,3-diyl Diacetate (38): In a dry
Schlenk tube, a solution of 37 (50 mg, 0.108 mmol), DMAP
(13 mg, 0.108 mmol), NEt3 (0.67 mL), and acetic anhydride (30 µL,
0.324 mmol) was stirred under an atmosphere of argon at 80 °C
and monitored by TLC. After disappearance of the starting mate-
rial (3 h), the mixture was concentrated under vacuum. The crude
product was then purified by flash chromatography (SiO2; 3 %
NEt3, petroleum ether/EtOAc, 7:3) to give a 53:47 mixture (40 mg)
of 38 and iso-38 in 89% yield. 1H NMR (300 MHz, C6D6): δ =
0.68–0.77 (m, 12 H, 6ϫCH2), 1.05–1.11 (m, 18 H, 6ϫCH3), 1.43
(br. s, 3 H, CH3), 1.45 (br. s, 3 H, CH3), 1.56 (s, 3 H, CH3), 1.59
(s, 3 H, CH3), 1.67 (s, 3 H, CH3), 1.73 (br. s, 6 H, 2ϫCH3), 1.81
(br. s, 6 H, 2ϫCH3), 1.86 (br. s, 3 H, CH3), 2.00–2.16 (m, 2 H,
2ϫCH2), 2.42–2.51 (m, 1 H, CH2), 2.62–2.72 (m, 1 H, CH2), 4.50–
4.58 (m, 2 H, 2ϫCH), 5.08 (d, J = 7.4 Hz, 1 H, CH), 5.35–5.48
(m, 6 H, 6ϫCH), 5.74 (d, J = 12.7 Hz, 1 H, CH), 6.36–6.44 (m, 2
H, 2ϫCH2), 7.31 (d, J = 7.4 Hz, 1 H, CH), 7.34 (s, 1 H, CH), 6.10
(br. d, J = 7.4 Hz, 1 H, CH), 7.93 (d, J = 12.7 Hz, 1 H, CH), 8.17
(s, 1 H, CH) ppm. 13C NMR (75 MHz, C6D6): δ = 5.32 (3ϫCH2),
5.34 (3ϫ CH2), 7.3 (6 ϫCH3), 20.0 (3 ϫCH3), 20.1 (CH3), 20.5
(CH3), 20.7 (CH3), 21.0 (CH3), 21.1 (CH3), 24.6 (2ϫCH3), 41.7
(3S,5S,E)-2-(2-Hydroxyethylidene)-10-methyl-6-methylene-5-(trieth-
ylsilyloxy)undec-9-en-7-yne-1,3-diyl Diacetate (36): To a stirred
solution of 35 (89 mg, 0.154 mmol) in THF (7 mL) was added a
mixture of H2O (700 µL) and AcOH (1.4 mL) dropwise. The mix-
ture was warmed to 40 °C and stirred for 12 h. The mixture was
then cooled to 0 °C and poured slowly into a suspension of
NaHCO3 (3 g) in water (20 mL). The aqueous layer was extracted
with EtOAc, and the combined organic layers were washed with
saturated aqueous NaHCO3 solution, dried with Na2SO4, and then
concentrated under vacuum. The crude product was purified by
column of chromatography (SiO2; 3 % NEt3, petroleum ether/
EtOAc, 1:1) to give 36 (63 mg) in 88% yield. [α]1D8 = –36.9 (c = 1,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.52–0.60 (m, 6 H, (CH2), 42.0 (CH2), 67.0 (CH), 67.2 (CH), 72.5 (CH), 72.6 (CH),
3ϫCH2), 0.93 (t, J = 7.9 Hz, 9 H, 3ϫCH3), 1.74–1.87 (m, 1 H, 90.11 (C), 90.14 (C), 90.7 (C), 90.8 (C), 103.7 (CH), 106.1 (CH),
CH2), 1.81 (s, 3 H, CH3), 1.90 (s, 3 H, CH3), 1.96–2.09 (m, 1 H, 110.2 (CH), 118.2 (C), 119.2 (CH2), 119.3 (CH2), 120.1 (C), 128.4
CH2), 2.02 (br. s, 6 H, 2ϫCH3), 2.37 (m, 1 H, OH), 4.14–4.27 (m, (CH), 134.6 (CH), 135.3 (CH), 136.4 (C), 136.6 (C), 137.2 (CH),
3 H, CH and CH2), 4.55 (d, J = 12.5 Hz, 1 H, CH2), 4.74 (d, J = 137.7 (CH), 148.9 (C), 149.0 (C), 166.6 (C), 166.8 (C), 166.9 (C),
12.5 Hz, 1 H, CH2), 5.28 (dd, J = 10.4, 1.8 Hz, 1 H, CH), 5.34 (br. 167.2 (C), 169.1 (C), 169.2 (C) ppm. MS (ESI+): m/z = 522 [M +
s, 1 H, CH2), 5.36 (br. s, 1 H, CH), 5.43 (br. s, 1 H, CH2), 5.88 (t, NH4]+. HRMS (ESI): calcd. for C27H44NO7Si [M + NH4]+
J = 6.8 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 4.9
(3ϫCH2), 6.9 (3ϫCH3), 21.0 (CH3), 21.1 (CH3), 21.2 (CH3), 25.0
(CH3), 42.5 (CH2), 58.4 (CH2), 59.7 (CH2), 71.9 (CH), 72.5 (CH),
89.5 (C), 89.9 (C), 105.3 (CH), 119.1 (CH2), 131.2 (CH), 135.6 (C),
136.1 (C), 149.3 (C), 170.2 (C), 171.2 (C) ppm. MS (ESI+): m/z =
482 [M + NH4]+. HRMS (ESI): calcd. for C25H44NO6Si [M +
NH4]+ 482.2932; found 482.2929.
522.2881; found 522.2880.
Caulerpenynol (2): To a stirred solution of 38 (20 mg, 0.0396 mmol)
in THF (640 µL) was added a mixture of AcOH (2 mL) and H2O
(1 mL). The solution was then heated at 45 °C and followed by
TLC. After disappearance of the starting material (2 h) the mixture
was poured into an aqueous solution of NaHCO3 (3 g). The aque-
ous layer was extracted with EtOAc. The combined organic layers
were washed with saturated aqueous NaHCO3 solution, dried with
Na2SO4, and then concentrated under vacuum. The crude product
was purified by column of chromatography (SiO2; 3% NEt3, petro-
leum ether/EtOAc, 1:1) to give a 52:48 mixture of 2 and iso-2
(12.5 mg) in 81% yield separable by HPLC.[26] Caulerpenynol (2):
[α]2D5 = –48.6 (c = 0.105, EtOH), ref.[6] [α]2D0 = –53.7 (c = 0.095,
EtOH). 1H NMR (500 MHz, C6D6): δ = 1.46 (br. s, 3 H, CH3),
1.57 (s, 3 H, CH3), 1.59 (s, 3 H, CH3), 1.71 (s, 3 H, CH3), 1.84 (br.
s, 3 H, CH3), 2.00 (ddd, J = 14.5, 9.6, 3.4 Hz, 1 H, CH2), 2.69
(ddd, J = 14.5, 10.4, 3.2 Hz, 1 H, CH2), 4.30 (br. d, J = 9.6 Hz, 1
H, CH), 5.39 (br. s, 1 H, CH), 5.46 (br. s, 1 H, CH), 5.53 (br. s, 1
H, CH), 5.77 (d, J = 12.7 Hz, 1 H, CH), 6.53 (dd, J = 10.4, 3.4 Hz,
1 H, CH), 7.30 (s, 1 H, CH), 7.92 (d, J = 12.7 Hz, 1 H, CH) ppm.
(3S,5S,E)-10-Methyl-6-methylene-2-(2-oxoethylidene)-5-(triethylsil-
yloxy)undec-9-en-7-yne-1,3-diyl Diacetate (37): To a stirred solution
of alcohol 36 (58 mg, 0.125 mmol) in CH2Cl2 (4 mL) was added at
0 °C Dess–Martin periodinane (63 mg, 0.15 mmol). The mixture
was stirred at room temperature and followed by TLC. After disap-
pearance of the starting material (2 h), the solution was poured
into a saturated aqueous Na2S2O3/NaHCO3 solution (7 mL, 1:1).
After stirring for 10 min, the layers were separated, and the aque-
ous layer was extracted with EtOAc. The combined organic layers
were washed with saturated aqueous NaHCO3 solution, dried with
Na2SO4, and then concentrated under vacuum. The crude aldehyde
was purified by column of chromatography (SiO2; 3% NEt3, petro-
leum ether/EtOAc, 7:3) to give 37 (51 mg) in 89% yield. [α]1D9
=
1
–18.7 (c = 1, CH2Cl2). H NMR (300 MHz, C6D6): δ = 0.60–0.68 13C NMR (125 MHz, C6D6): δ = 19.87 (CH3), 19.98 (CH3), 20.46
(m, 6 H, 3ϫCH2), 1.01 (t, J = 7.9 Hz, 9 H, 3ϫCH3), 1.46 (br. s,
(CH3), 21.07 (CH3), 24.59 (CH3), 40.74 (CH2), 67.15 (CH), 70.92
3 H, CH3), 1.64 (s, 3 H, CH3), 1.72 (s, 3 H, CH3), 1.84 (br. s, 3 H, (CH), 89.95 (C), 90.72 (C), 105.91 (CH), 109.93 (CH), 119.15
CH3), 2.00–2.04 (m, 2 H, CH2), 4.40–4.44 (m, 1 H, CH), 4.62 (d, (CH2), 119.92 (C), 134.46 (CH), 135.48 (C), 137.34 (CH), 149.06
J = 13.6 Hz, 1 H, CH2), 4.93 (d, J = 13.6 Hz, 1 H, CH2), 5.39– (C), 166.73 (C), 167.24 (C), 170.00 (C) ppm. iso-2: [α]2D5 = –33.2 (c
1
5.44 (m, 3 H, CH and CH2), 5.58–5.62 (m, 1 H, CH), 6.10 (br. d,
= 0.295, EtOH), H NMR (500 MHz, C6D6): δ = 1.45 (br. s, 3 H,
J = 7.4 Hz, 1 H, CH), 9.93 (d, J = 7.4 Hz, 1 H, CH) ppm. 13C CH3), 1.62 (s, 3 H, CH3), 1.64 (s, 3 H, CH3), 1.66 (s, 3 H, CH3),
NMR (75 MHz, C6D6): δ = 5.2 (3 ϫ CH2), 7.1 (3 ϫ CH3), 20.2 1.80 (br. s, 3 H, CH3), 1.98 (ddd, J = 14.2, 9.6, 3.4 Hz, 1 H, CH2),
(CH3), 20.3 (CH3), 21.1 (CH3), 24.6 (CH3), 42.5 (CH2), 59.0 (CH2), 2.53 (ddd, J = 14.2, 10.4, 3.0 Hz, 1 H, CH2), 4.30 (br. d, J = 9.6 Hz,
2996
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2987–2997

Studies towards the Total Synthesis of (–)-Caulerpenynol
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1 H, CH), 5.12 (d, J = 7.3 Hz, 1 H, CH), 5.36 (br. s, 1 H, CH),
5.48 (br. s, 1 H, CH), 5.58 (br. s, 1 H, CH), 6.57 (dd, J = 10.4,
3.4 Hz, 1 H, CH), 7.31 (d, J = 7.3 Hz, 1 H, CH), 8.10 (s, 1 H, CH)
ppm. 13C NMR (125 MHz, C6D6): δ = 20.00 (CH3), 20.57 (CH3),
21.04 (CH3), 24.57 (CH3), 40.99 (CH2), 67.13 (CH), 70.89 (CH),
90.03 (C), 90.57 (C), 103.83 (CH), 105.88 (CH), 118.07 (C), 119.30
(CH2), 135.33 (CH), 135.52 (C), 137.73 (CH), 149.10 (C), 166.84
(C), 166.97 (C), 170.14 (C) ppm.
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Supporting Information (see footnote on the first page of this arti-
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synthesized compounds, comparison of NMR spectroscopic data
for original and synthesized caulerpenynol (2).
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[17]
Acknowledgments
The authors thank Roselyne Rosas for NMR spectroscopic studies
and Nicolas Vanthuyne for HPLC separations. Sarah Chaibi and
Sophie Delestic are also thanked for their beneficial contribution.
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[23] Each diastereomer was obtained as a mixture of keto-alcohol
and the corresponding lactol.
[24] See Supporting Information for a NMR superimposition of
compound 34 and its TBS analogue 20.
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[26] Semipreparative separations were performed by successive in-
jections on a Knauer unit composed of a Smartline 1000 pump,
a Smartline 3900 autosampler, a Smartline 2500 UV-detector,
and a valve to collect separately the different isomers. Chi-
ralpak AD (250ϫ10 mm) was used with hexane/ethanol (95:5)
as mobile phase, 5 mLmin–1 as flow rate, and UV at 220 nm.
[27] See Supporting Information for an NMR spectroscopic com-
parison between natural and synthetic caulerpenynol.
Received: January 29, 2009
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20, 3455–3464.
Published Online: May 7, 2009
Eur. J. Org. Chem. 2009, 2987–2997
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2997