Total synthesis of dolatrienoic acid: A subunit of dolastatin 14

Article abstract of DOI:10.1021/jo962217a

The (7R,15R)- and (7S,15R)-diastereomers of dolatrienoic acid were synthesized using a convergent strategy. Fragment C5-C9 was obtained through enantiodifferentiation of racemic pentane-1,3,5-triol as the key step, fixing the chirality at C7 of fragments 4 and ent-4. The chirality at C15 of the fragment C10-C16 was introduced from L-glutamic acid. Coupling of these two fragments led to the aldehydes (7R,15R)- and (7S,15R)-2 which were homologated by Horner-Wadsworth-Emmons condensation to give (7R,15R)- and (7S,15R)-dolatrienoic acids.

Full text of DOI:10.1021/jo962217a

3332
J . Org. Chem. 1997, 62, 3332-3339
Tota l Syn th esis of Dola tr ien oic Acid : A Su bu n it of Dola sta tin 14
Sylvie Moune´, Gilles Niel,* Magali Busquet, Ian Eggleston, and Patrick J ouin
UPR 9023, Me´canismes Mole´culaires des Communications Cellulaires 141, rue de la Cardonille,
34094 Montpellier Cedex 5, France
Received November 26, 1996X
The (7R,15R)- and (7S,15R)-diastereomers of dolatrienoic acid were synthesized using a convergent
strategy. Fragment C5-C9 was obtained through enantiodifferentiation of racemic pentane-1,3,5-
triol as the key step, fixing the chirality at C7 of fragments 4 and ent-4. The chirality at C15 of
the fragment C10-C16 was introduced from L-glutamic acid. Coupling of these two fragments led
to the aldehydes (7R,15R)- and (7S,15R)-2 which were homologated by Horner-Wadsworth-
Emmons condensation to give (7R,15R)- and (7S,15R)-dolatrienoic acids.
In tr od u ction
(7R,15R) diastereoisomers of DTA and a suitable meth-
odology for the preparation of the other diastereoisomeric
pair.
The Indian Ocean sea hare Dolabella auricularia is a
rich source of pseudopeptide metabolites with potent
antiproliferative activity.1 By 1980, Pettit and co-work-
ers had isolated, identified, and evaluated seven major
compounds named dolastatins, among which only the
cyclic dolastatin 3 and the two linear dolastatins 10 and
15 have been fully characterized and synthesized. Due
to their in vitro and in vivo antineoplastic properties, both
dolastatin 10 and dolastatin 15 have received much
attention. In the series of cyclic dolastatins, dolastatin
14 presents the highest antiproliferative activity against
a human tumor cell line minipanel from the NCI primary
screen. This macrocyclic depsipeptide is a remarkable
association composed of a heptapeptide and an unsatur-
ated hexadecanoic acid called dolatrienoic acid (1) (DTA)
(Scheme 1).2 Several other macrolactones of marine
origin with promising pharmacological activity are com-
posed of a peptide and a lipid moiety such as jasplaki-
nolide,3 cryptophycin A,4 doliculide,5 dolastatin G,6 and
aurilide.7 G. Pettit assumed that the heptapeptide
residues were (S) configured by comparison with other
metabolites extracted from this marine organism.2 Be-
cause of the very small amounts of dolastatin 14 avail-
able, neither the absolute nor the relative configuration
of the two asymmetric carbons C7 and C15 (DTA num-
bering) could be determined in the natural compound.
This would only be possible after total synthesis of
dolastatin 14, which necessitates the synthesis of the four
possible diastereoisomers of DTA and subsequent cou-
pling with the heptapeptide. We present herein our
results on the stereocontrolled synthesis of (7S,15R) and
Retr osyn th etic An a lysis of Dola tr ien oic Acid (1)
Retrosynthetic analysis of 1 (Scheme 2) led us to an
initial disconnection between positions C4 and C5 which
imposed the construction of the conjugated diene in the
final steps of the synthesis starting from the aldehyde
2. The stereochemistry of the isolated (E) double bond
between C10 and C1 in 2 should be secured after hydride
reduction of the corresponding alkyne 3, allowing a
second disconnection between the carbon atoms C9 and
C10. The resulting new subtargets 4 and 5 allowed
independent control of the stereocenters at positions C7
and C15, respectively. Stereodifferentiation of the triol
6, using Harada’s methodology,8 served to obtain the
iodide intermediates (R)- or (S)-4. The natural L-Glu was
chosen from the chiral pool as the starting material for
the synthesis of the alkyne 5 since the preparation of the
chiral intermediate 16 is well documented. Such a
versatile approach was found to be suitable for the
preparation of the four possible diastereoisomers of DTA
since L-Glu could be replaced by its D-form to obtain the
(15S)-isomer.
Syn th esis of th e F r a gm en ts C5-C9 a n d C10-C16
Enantiodifferentiation of prochiral diols was efficiently
promoted by Harada’s group and was successfully applied
to obtain the spiroketals 7 and 88a using (-)-menthone
as a chiral template (Scheme 3). We have simplified the
original procedure by using a more conventional ketal-
ization step (catalytic TsOH at ambient temperature) and
starting from unprotected pentane-1,3,5-triol 69 instead
of the persilylated derivatives described by Harada.8a The
use of an excess of trimethyl orthoformate was crucial
to complete the reaction. Under these conditions we
observed the formation of 7 and 8 as the major products
together with their corresponding formate esters as
assessed by 1H NMR spectroscopy analysis. These latter
esters were saponified in situ to give alcohols 7 and 8 as
an inseparable mixture (62% combined yield). Tosylation
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Pettit, G. R.; Kamano, Y.; Herald, C. L.; Fujii, Y.; Kizu, H.; Boyd,
M. R.; Boettner, F. E.; Doubek, D. L.; Schmidt, J . M.; Chapuis, J . C.;
Michel C. Tetrahedron 1993, 49, 9151-9170.
(2) Pettit, G. R.; Kamano, Y.; Herald, C. L.; Dufresne, C.; Bates, B.
R.; Schmidt, J . M.; Cerny, R. L.; Kizu, H. J . Org. Chem. 1990, 55,
2989-2990.
(3) (a) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986,
27, 2797-2800. (b) Zabriskie, T. M.; Klocke, J . A.; Ireland, C. M.;
Marcus, A. H.; Molinski, T. F.; Faulkner, D. J .; Xu, C.; Clardy, J . J .
Am. Chem. Soc. 1986, 108, 3123-3124.
(4) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.;
Corbett, T. H.; Valeriote, T. H.; Demchik, L. J . Am. Chem. Soc. 1994,
116, 4729-4737.
(5) Ishiwata, H.; Nemoto, T.; Ojika, M.; Yamada, K. J . Org. Chem.
1994, 59, 4710-4711.
(8) (a) Harada, T.; Kurokawa, H.; Kagamihara, Y.; Tanaka, S.;
Inoue, A.; Oku, A. J . Org. Chem. 1992, 57, 1412-1421. (b) Harada,
T.; Oku, A. Synlett 1994, 95-104.
(9) The triol 6 was readily prepared by reduction of diethyl 3-hy-
droxyglutarate according to: Thiam, M.; Slassi, A.; Chastrette, F.;
Amouroux, R. Synth. Commun. 1992, 22, 83-95.
(6) Mutou, T.; Kondo, T.; Ojika, M.; Yamada, K. J . Org. Chem. 1996,
61, 6340-6345.
(7) Suenaga, K.; Mutou, T.; Shibata, T.; Itoh, T.; Kigoshi, H.;
Yamada, K. Tetrahedron Lett. 1996, 37, 6771-6774.
S0022-3263(96)02217-7 CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of Dolatrienoic Acid
J . Org. Chem., Vol. 62, No. 10, 1997 3333
Sch em e 1
corresponding 1-heptyne-6-one13 or starting from (S)-
propylene oxide.14 We decided to follow another route
consisting of the condensation of a lithio acetylide with
an activated (R)-pentane-1,4-diol, obtained from L-Glu.
This procedure can alternatively give the (S)-enantiomer
of 5, starting from D-Glu. The (R)-pentane-1,4-diol 16
was prepared (Scheme 4) according to Barbier’s proce-
dure.15 Regioselective tritylation of the primary alcohol
and then silylation of the secondary one afforded 18 (80%
over the two steps). Compound 18 was selectively
deprotected (PPTS in hot ethanol), and the resulting
primary hydroxyl group of 19 was tosylated to give 20
(68% over the two steps). Finally, the tosylate group was
displaced by means of the lithium acetylide-ethylene-
diamine complex16 in good yield (86%) to give the C10-
C16 intermediate 5.
Sch em e 2
Syn th esis of th e Ald eh yd es (7R,15R)-2 a n d
(7S,15R)-2
The C5-C16 fragment was obtained by condensation
of the C5-C9 and the C10-C16 fragments prepared
above. Nucleophilic displacement of the iodide (S)-4 was
done by the lithio derivative of the alkyne 5 (Scheme 5).
Reduction of the alkyne 3 by LiAlH4 in refluxing di-
glyme17 furnished the diol 22 directly but in low yield.
To overcome this difficulty, the protecting groups were
first removed (TBAF in THF) to yield 21 which in turn
was reduced to the alkene 22 (64% over the two steps).
1H NMR spectroscopy revealed the presence of a pure
(E) double bond by homodecoupling irradiation at the
allylic position (J 10,11 ) 15.7 Hz). The following steps to
obtain the key aldehyde (7R,15R)-2 were straightforward
and involved a sequence of protection-deprotections
before the final oxidation of the alcohol 25 using Swern’s
protocol.18 The same sequence of reactions was per-
formed starting from the alkyne 5 and the iodo derivative
(R)-4 as the key intermediates and allowed the prepara-
tion of the aldehyde (7S,15R)-2.
of the crude mixture afforded spiroketals 9 and 10 in a
ratio of 69:31 and a 57% yield from racemic 6. After
chromatographic separation, the complete assignment of
the stereoisomers 9 and 10 was made by comparison with
Harada’s spiroketals 7 and 8.10 The synthesis was
pursued on enantiomerically pure compound 9, using
Conia's procedure11 for the deprotection of the spiroketal.
The diol 11 was submitted without purification to a
regioselective silylation12 (TBDMSCl, DIEA, cat. DMAP).
Under these conditions we observed the formation of the
TBDMS ether 12 together with the chloro derivative 13
(70%, 60:40). Compounds 12 and 13 could either be
separated and then methylated (NaH, MeI, DMF) or
more conveniently used as a mixture for methylation,
since the resulting methyl ethers 14 and 15 led to the
same iodide derivative (S)-4 after treatment with sodium
iodide in refluxing acetone. The same sequence of
reactions was applied to the spiroketal 10 to give the
isomer (R)-4.
P r ep a r a tion of Dola tr ien oic Acid (1)
For homologation of the aldehyde 2 into dolatrienoic
acid (1), we explored two distinct pathways: first vinylo-
gous Mukaiyama aldol condensation of a silyl dienol ether
The preparation of the alkyne 5 has already been
described either through baker’s yeast reduction of the
(13) Le Drian, C.; Greene, A. E. J . Am. Chem. Soc. 1982, 104, 5473-
5483.
(14) Nokami, J ; Ohkura, M; Dan-Oh, Y.; Sakamoto, Y. Tetrahedron
Lett. 1991, 32, 2409-2412.
(15) Barbier, P.; Benezra, C. J . Med. Chem. 1982, 25, 943-946.
(16) Smith, N.; Beumel, O. F. Synthesis 1974, 441-442.
(17) Rossi, R.; Carpita, A. Synthesis 1977, 561-562.
(18) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-185.
(10) 1H NMR spectroscopic data for compounds 9 and 10 are in full
agreement with Harada's results.8a
(11) Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J . M. Synth.
Commun. 1978, 8, 63-65.
(12) Chaudary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 2, 99-
102.

3334 J . Org. Chem., Vol. 62, No. 10, 1997
Moune et al.
Sch em e 3
Sch em e 4
Sch em e 5
followed by dehydration of the resulting allylic alcohol
(Scheme 6), and secondly the Horner-Wadsworth-
Emmons (HWE) condensation using ethyl (E)-4-(dimeth-
oxyphosphonyl)-2-methyl-2-butenoate (Scheme 7).19
Vinylogous Mukaiyama Aldol Condensation. We first
synthesized the silylketene acetal20a 27 (Scheme 6)
derived from ethyl tiglate starting from ethyl (E)-croto-
nate through successive methylation and trimethylsi-
lylation in a one-pot procedure. In our hands, this
protocol gave better results than direct trimethylsilyla-
tion of ethyl tiglate. After distillation, the acetal 27,
obtained as a mixture of (E)- and (Z)- isomers (45:55),
was allowed to react with the aldehyde (7R,15R)-2 under
Mukaiyama’s conditions,21 giving the expected aldol 28
in only 18% isolated yield together with related but
unidentified compounds. 1H NMR analysis of the aldol
28 showed the presence of two epimers (65:35) at the
newly created stereocenter which were directly submitted
to mesylation and subsequent elimination (DBU, tolu-
ene). Isomerization of the resulting mixture of conju-
gated (E,E) and (E,Z) dienes, obtained in a ratio of 71:
29, was done using catalytic amounts of iodine and led
to isomerically pure protected dolatrienoic acid ethyl ester
(7R,15R)-30 in an 8% yield from the aldehyde (7R,15R)-
2. This low overall yield led us to follow a different
strategy.
Horner-Wadsworth-Emmons (HWE) Condensation.
We prepared the phosphonate 34 starting from 2-hy-
droxy-2-methyl-3-butenoic acid 32 (Scheme 7).22 Esteri-
fication with benzyl bromide under basic conditions
afforded the corresponding benzyl ester 33, which is more
easily purified than its volatile methyl counterpart. The
ester 33 was chlorinated (SOCl2) and the resulting chloro
compound was converted to the desired phosphonate 34
by Arbuzov displacement in refluxing trimethyl phos-
phite. Under NaH treatment, the anion of 34 reacted
cleanly with the aldehyde (7S,15R)-2 to furnish the
(19) Alternatively, we also tried the double homologation starting
with a Wittig reaction using (formylmethylene)triphenylphosphorane
followed by the HWE reaction on the R,â-unsaturated aldehyde with
ethyl (diethoxyphosphonyl) propionate, but with no clean reaction.
(20) (a) Fleming, I.; Chow, H. F. Tetrahedron Lett. 1985, 26, 397-
400. (b) Hertler, W. R.; Reddy, G. S.; Sogah, D. Y. J . Org. Chem. 1988,
53, 3532-3539.
(21) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973,
1011-1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J . Am. Chem.
Soc. 1974, 96, 7503-7509. (c) Heathcock, C. H. In Asymmetric
Synthesis; Morrison, J . D., Ed.: Academic Press: San Diego, CA, 1984;
Vol. 3, Chapter 2.
(22) Kitahara, I.; Horiguchi, A.; Mori, K. Tetrahedron 1988, 44,
4713-4720.

Total Synthesis of Dolatrienoic Acid
J . Org. Chem., Vol. 62, No. 10, 1997 3335
Sch em e 6
synthesis of dolastatin 14 and are essential for the
assignment of the absolute configuration of the C7 and
C15 stereocenters present in the natural compound. The
proposed synthesis involves a convergent assembling of
three fragments. Fragment C5-C9 was obtained by
stereodifferentiation of a functionalized pentane-1,3,5-
triol. L-Glu was chosen to fix the chirality of fragment
C10-C16. These two fragments were coupled to give
(7S,15R)- and (7R,15R)-2. These aldehydes were then
homologated by Horner-Wadsworth-Emmons conden-
sation to give (7S,15R)- and (7R,15R)-1. Coupling of
these two acids with the heptapeptide included in dola-
statin 14 and the macrocyclization of the resulting amides
are in progress.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H-NMR spectra were recorded
either at 200 or 360 MHz and chemical shifts are reported in
ppm and referenced to CHCl3 (7.24 ppm) unless otherwise
noted. NMR correlation experiments were recorded at 400
MHz in C6D6. 31P-NMR spectra were recorded at 81 MHz, and
chemical shifts are reported in ppm and referenced to H3PO4.
Mass spectra were performed in the FAB+ mode unless
otherwise noted, by the Department of Physical Measurements
of the University of Montpellier II. Elemental analyses were
performed by the CNRS, at the Ecole Nationale Supe´rieure
de Chimie de Montpellier. Optical rotations were run at 20
°C. Column chromatography was conducted by using silica
gel (70-230 or 240-400 mesh) as the stationary layer.
Analytical TLC was performed on silica gel 60F254 aluminum
sheets. Analytical HPLC was carried out with a Kromasil C8
column (5 µm, 4.6 × 150 mm) using a gradient of acetonitrile
+ 0.1% TFA (solvent B) in water + 0.1% TFA (solvent A) at a
1.5 mL/min rate (conditions A) or with an Ultrasphere Si
column (5 µm, 4.6 × 250 mm) using a gradient of ethyl acetate
(solvent B) in hexane (solvent A) at the same rate (conditions
B). Semipreparative HPLC was carried out with an Ultra-
sphere ODS column (10 µm, 10 × 250 mm) using a gradient
of acetonitrile + 0.1% TFA in water + 0.1% TFA at 4 mL/min
(conditions C).
Sch em e 7
(2RS,6S,7S,10R)-7-Isop r op yl-10-m et h yl-2-[(4-m et h yl-
ben zen esu lfon yl)oxy]-1,5-dioxaspir o[5.5]u n decan e (9 an d
10). To a stirred solution of 610 (6.04 g, 50 mmol), (-)-
menthone (8.4 mL, 55 mmol), and TsOH (475 mg, 2.5 mmol)
in dry CH2Cl2 (250 mL) was added trimethyl orthoformate
(16.4 mL, 0.15 mol) at rt. The solution was stirred overnight,
and then additional trimethyl orthoformate (5.3 mL, 0.05 mol)
was added. Stirring was continued for another 4 h. At 0 °C
a solution of 1 N NaOH (55 mL) in MeOH (200 mL) was added
to the mixture and was stirred for 12 h at rt. The aqueous
layer was extracted with diethyl ether (3 × 100 mL), and then
the combined organic layers were washed with brine (100 mL)
and dried over Na2SO4. Filtration and concentration of the
solvent under vacuum yielded a mixture of diastereoisomeric
alcohols 7 and 8 (7.94 g, 62% combined yield). This mixture
was used as such for the next step.
To the preceding mixture of alcohols 7 and 8 dissolved in
dry CH2Cl2 (200 mL) was added DMAP (5.23 g, 42.9 mmol) at
rt. To the resulting solution cooled to -5 °C was slowly added
TsCl (7.1 g, 37.2 mmol) dissolved in dry CH2Cl2 (40 mL). The
solution was stirred at rt overnight and then washed succes-
sively with 1 N HCl (2 × 60 mL), saturated aqueous NaHCO3
(60 mL), and brine (60 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum to afford a mixture
of diastereoisomeric tosylates 9 and 10 in the ratio 69:31 (11.68
g, 57% overall yield) as colorless oils after purification by flash
column chromatography (pentane/EtOAc, 95:5).
dolatrienoic benzyl ester as a mixture of (E,E)- and (E,Z)-
dienes in a ca. 50/50 ratio. This mixture was isomerized
as above with iodine crystals yielding the pure (E,E)-
diene (7S,15R)-35 in a 70% yield. The last deprotection
steps were conducted on the ester 35 using sequentially
an aqueous solution of HF in hexane/acetonitrile then
methanolic KOH to furnish the desired (7S,15R)-1 in 33%
yield. The ester (7R,15R)-30 gave (7R,15R)-1 in 37%
yield under the same conditions of deprotection.
The structure of the final compound (7S,15R)-1 was
ascertained by NMR correlation experiments. Absence
of migration of the C10-C11 (E) double bond during the
synthesis was confirmed from both COSY-DQF and
HMQC-TOCSY experiments which showed unambiguous
connections from H10 to H7 protons. The correct geom-
etry of the conjugated (E,E) diene was deduced from the
J 4,5 coupling constant (15.0 Hz). Moreover, on the basis
of a NOESY experiment, the spatial proximities of the
H3 and H5 protons on the one hand and the C2-methyl
and H4 protons on the other hand confirm this geometry.
Ma jor 9: Rf 0.22 (pentane/EtOAc, 95:5); 1H-NMR δ 7.77
(d, J 8.3 Hz, 2H), 7.33 (d, J 8.3 Hz, 2H), 4.20-4.07 (m, 2H),
4.03 (td, J 11.5, 2.7 Hz, 1H), 3.88 (ddt, J 11.7, 9.1, 2.6 Hz,
1H), 3.75 (ddd, J 11.5, 5.3, 1.4 Hz, 1H), 2.61 (ddd, J 13.6, 3.4,
1.9 Hz, 1H), 2.44 (s, 3H), 2.32 (hept.d, J 7.0, 1.8 Hz, 1H), 1.84-
1.10 (m, 9H), 0.85 (d, J 6.6 Hz, 3H), 0.84 (d, J 7.0 Hz, 3H),
Con clu sion
We have synthesized (7S,15R)- and (7R,15R)-dola-
trienoic acids, which are key intermediates in the total

3336 J . Org. Chem., Vol. 62, No. 10, 1997
Moune et al.
0.76 (d, J 7.0 Hz, 3H), 0.64 (dd, J 13.5, 12.6 Hz, 1H); MS m/ e
(rel intens) 411 (M + H+, 50), 353(33), 325(58), 257(20),
239(13), 211(13), 173(38), 155(64), 137(33), 67(100), 55(92); [R]D
) +3 (c 0.67, MeOH).
purification by flash column chromatography (cyclohexane/
EtOAc, 90:10): Rf 0.42 (cyclohexane/EtOAc, 80:20), H-NMR
1
δ 7.77 (d, J 8.3 Hz, 2H), 7.32 (d, J 8.3 Hz, 2H), 4.12 (m, 2H),
3.62 (m, 2H), 3.38 (m, 1H), 3.21 (s, 3H), 2.43 (s, 3H), 1.92-
1.82 (m, 1H), 1.79-1.64 (m, 2H), 1.61-1.53 (m, 1H), 0.86 (s,
9H), 0.017 (s, 6H); MS m/ e (rel intens) 403 (M + H+, 40),
345(15), 287(13), 229(59) 145(22), 89(100), 73(99), 55(68); [R]D
) +5 (c 1.1, MeOH). Anal. Calcd for C19H34O5SiS: C, 56.68;
H, 8.51. Found: C, 56.96; H, 8.52.
(S)-5-[(ter t-Bu t yld im et h ylsilyl)oxy]-1-ch lor o-3-m et h -
oxyp en ta n e (15). By the same procedure, the alcohol 13 (1.71
g, 6.8 mmol) yielded 15 (1.50 g, 83%) as a pale-yellow oil: Rf
0.7 (cyclohexane/EtOAc, 80:20), 1H-NMR δ 3.71-3.60 (m, 4H),
3.55 (m, 1H), 3.35 (s, 3H), 1.95-1.88 (m, 2H), 1.78-1.60 (m,
2H), 0.88 (s, 9H), 0.04 (s, 6H); MS (EI) no molecular ion,
231(12), 185(21), 95(72), 55(100); [R]D ) +5 (c 1.1, CHCl3).
Anal. Calcd for C12H27O2ClSi: C, 54.01; H, 10.20. Found: C,
54.17; H, 10.32.
(S)-5-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-iod o-3-m eth oxy-
p en ta n e (4). A solution of 14 (1.64 g, 4 mmol) and sodium
iodide (1.84 g, 12 mmol) in acetone (40 mL) was refluxed for
16 h. Acetone was removed by vacuum evaporation, and the
resulting white precipitate was suspended in diethyl ether (200
mL). Filtration and concentration under vacuum yielded 4
(1.36 g, 98%) as a pale-yellow oil: Rf 0.54 (cyclohexane/EtOAc,
80:20), 1H-NMR δ 3.72-3.62 (m, 2H), 3.41 (m, 1H), 3.36 (s,
3H), 3.24 (m, 2H), 2.04-1.97 (m, 2H), 1.77-1.58 (m, 2H), 0.88
(s, 9H), 0.04 (s, 6H); MS m/ e (rel intens) 359(M + H+, 13),
327(8), 301(19), 231(13), 185(12), 95(85), 55(100); HRMS m/ e
calcd for C12H27O2SiI: ([M + H]+), 359.0903; found: ([M + H]+)
359.0901.
1
Min or 10: Rf 0.31 (pentane/EtOAc, 95:5); H-NMR δ 7.78
(d, J 8.2 Hz, 2H), 7.32 (d, J 8.2 Hz, 2H), 4.17-4.08 (m, 2H),
4.03 (tdd, J 11.5, 8.1, 3.4 Hz, 1H), 3.79 (td, J 12.2, 2.6 Hz,
1H), 3.71 (ddd, J 11.6, 5.5, 1.3 Hz, 1H), 2.55 (ddd, J 13.5, 3.3,
1.9 Hz, 1H), 2.44 (s, 3H), 2.21 (hept.d, J 7.0, 2.5 Hz, 1H), 1.84-
1.24 (m, 8H), 0.99 (ddd, J 12.6, 3.9, 2.6 Hz, 1H), 0.86 (d, J 6.6
Hz, 3H), 0.81 (d, J 7.0 Hz, 6H), 0.47 (dd, J 13.5, 12.6 Hz, 1H);
MS m/ e (rel intens) 411(M + H+, 45), 353(13), 325(22), 257(6),
239(5), 211(5), 173(14), 155(22), 137(15), 67(100), 55(49); [R]D
) -35 (c 1.23, MeOH).
(S)-5-[(4-Met h ylb en zen esu lfon yl)oxy]p en t a n e-1,3-d i-
ol (11). Silica gel (70-230 mesh) was suspended in CH2Cl2
(14 mL) containing 6 N HCl (0.4 mL) and stirred for 5 min.
To this suspension was slowly added a solution of 9 (1.6 g, 4
mmol) in CH2Cl2 (14 mL). The reaction mixture was stirred
overnight at rt. Solid NaHCO3 (0.8 g) was then added and
the suspension stirred for 15 min. After filtration over a plug
of silica gel, the reaction mixture was washed with pentane
(100 mL), and the pentane washings were discarded. The
silica gel was then washed with a mixture of CH2Cl2/MeOH
(150 mL, 90:10). Concentration under vacuum of the filtrate
afforded 11 as a pale-yellow oil (0.85 g, 98%): Rf 0.43 (CH2Cl2/
1
MeOH, 95:5), H-NMR δ 7.76 (d, J 8.1 Hz, 2H), 7.33 (d, J 8.1
Hz, 2H), 4.24 (ddd, J 10.0, 8.6, 5.2 Hz, 1H), 4.12 (ddd, J 10.0,
5.4, 5.4 Hz, 1H), 4.00 (m, 1H), 3.87-3.77 (m, 2H), 2.43 (s, 3H),
1.90-1.69 (m, 2H), 1.66 (q, J 5.8 Hz, 2H); MS m/ e (rel intens)
275(M + H+, 73), 257(21), 173(35), 155(32), 85(49); [R]D ) +9.8
(c 2.5, CHCl3). Anal. Calcd for C12H18O5S: C, 52.32; H, 6.53.
Found: C, 52.54; H, 6.61.
(R)-5-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-iod o-3-m eth oxy-
p en ta n e (4). HRMS m/ e calcd for C12H27O2SiI: ([M - I]+),
231.1801; found: ([M - I]+) 231.1780.
(S)-5-[(ter t-Bu t yld im et h ylsilyl)oxy]-1-[(4-m et h ylb en -
zen esu lfon yl)oxy]p en ta n -3-ol (12). To a solution of diol 11
(2.65 g, 9.67 mmol) in dry CH2Cl2 (40 mL) were added DIEA
(2 mL, 10 mmol) and DMAP (58 mg, 0.4 mmol) at rt. The
solution was cooled to 0 °C, and then TBDMSCl (1.65 g, 10
mmol) was added to the reaction mixture which was stirred
for 24 h at rt. CH2Cl2 (20 mL) was added to the crude mixture,
and the organic layer was treated successively with a 5%
KHSO4 solution (75 mL), saturated NaHCO3 (100 mL), and
brine (100 mL). The organic layer was dried over Na2SO4 and
concentrated under vacuum to afford a mixture of the oily
compounds 12 (1.6 g, 42%) and 13 (0.7 g, 28%) after purifica-
tion by flash column chromatography (cyclohexane/EtOAc, 90:
10).
(R)-1-[(Tr ip h en ylm eth yl)oxy]p en ta n -4-ol (17). A solu-
tion of diol 1615 (3.00 g, 28.8 mmol), DMAP (161 mg, 1.32
mmol), and Et3N (6.1 mL, 43.8 mmol) in CH2Cl2 (25mL) was
treated with TrCl (8.84 g, 31.7 mmol). The mixture was stirred
for 24 h, then it was poured into cold H2O (25 mL) and it was
extracted with CH2Cl2 (2 × 50 mL). The combined organic
extracts were washed with brine (100 mL), then dried over
Na2SO4 and the solvent was evaporated to give 17 (8.3 g, 83%)
as a colorless oil after purification by flash column chroma-
tography (pentane/EtOAc, 70:30): Rf 0.50 (pentane/EtOAc, 50:
50); 1H-NMR (DMSO-d6) δ 7.40-7.23 (m, 15H), 4.30 (d, J 4.7
Hz, 1H), 3.49-3.54 (m, 1H), 2.95 (t, J 6.5 Hz, 2H), 1.50-1.66
(m, 2H), 1.32-1.38 (m, 2H), 1.01 (d, J 6.2 Hz, 3H); MS no
molecular ion, 243(95), 199(12), 165(21), 154(100), 136(80),
105(20), 89(29), 77(36); [R]D ) -3.1 (c 1.3 EtOH). Anal. Calcd
for C24H26O2: C, 83.2; H, 7.56. Found: C, 83.54; H, 7.79.
(R)-4-[(ter t-Bu tyld ip h en ylsilyl)oxy]-1-[(tr ip h en ylm eth -
yl)oxy]p en ta n e (18). A solution of 5 (7.41 g, 21.4 mmol) and
imidazole (3.24 g, 47.6 mmol) in anhydrous DMF (30 mL) was
treated with TBDPSCl (6.2 mL, 23.8 mmol). The mixture was
stirred for 17 h, and then it was diluted with EtOAc (75 mL)
and washed with H2O and brine (3 × 75 mL each). The
organic layer was dried over Na2SO4 and concentrated to give
18 (12.0 g, 96%) which was purified by flash column chroma-
tography (pentane/EtOAc, 98:2) as a colorless oil: Rf 0.74
12. Rf 0.33 (cyclohexane/EtOAc, 80:20), 1H-NMR δ 7.76 (d,
J 8.3 Hz, 2H), 7.33 (d, J 8.3 Hz, 2H), 4.20 (ddd, J 9.8, 8.1, 6.0
Hz, 1H), 4.15 (ddd, J 9.8, 6.0, 5.4 Hz, 1H), 3.91 (m, 1H), 3.86
(ddd, J 10.1, 4.6, 4.6 Hz, 1H), 3.76 (ddd, J 10.1, 8.4, 4.2 Hz,
1H), 3.45 (bs, 1H), 2.42 (s, 3H), 1.81 (dddd, J 14.4, 6.5, 4.1,
4.1 Hz, 1H), 1.74 (dddd, J 14.4, 8.4, 5.6, 5.6 Hz, 1H), 1.64 (dddd,
J 14.4, 8.4, 8.4, 4.2 Hz, 1H), 1.57 (dddd, J 14.4, 4.6, 3.6, 3.6
Hz, 1H); MS m/ e (rel intens) 389(M + H+, 82), 331(18),
275(94), 257(21), 229(73), 154(51), 120(42), 91(76), 73(100),
57(39); [R]D ) +8 (c 1, MeOH). Anal. Calcd for C18H32O5SiS:
C, 55.64; H, 8.30. Found: C, 55.48; H, 8.31.
13. Rf 0.67 (cyclohexane/EtOAc, 80:20), 1H-NMR δ 4.05 (m,
1H), 3.88 (ddd, J 10.2, 4.6, 4.6 Hz, 1H), 3.83 (ddd, J 10.2, 6.4,
4.2 Hz, 1H), 3.71 (ddd, J 10.7, 8.7, 6.3 Hz, 1H), 3.65 (ddd, J
10.7, 6.9, 5.3 Hz, 1H), 3.52 (bs, 1H), 1.99-1.79 (m, 2H), 1.75-
1.60 (m, 2H), 0.89 (s, 9H), 0.07 (s, 6H); MS m/ e 253(M + H+,
100), 235(29), 189(22), 139(33), 131(49), 123(51), 115(78),
97(100), 65(24); [R]D ) +36 (c 0.41, MeOH). Anal. Calcd for
C11H25O2ClSi: C, 52.25; H, 9.97. Found: C, 51.88; H, 9.54.
(S)-5-[(ter t-Bu t yld im et h ylsilyl)oxy]-3-m et h oxy-1-[(4-
m eth ylben zen esu lfon yl)oxy]p en ta n e (14). To a solution
of 12 (1.94 g, 5 mmol) in anhydrous DMF (20 mL) was added
NaH (0.45 g, 11 mmol) at -5 °C. After being stirred for 15
min, MeI (5 mL, 80 mmol) was added to the resulting
suspension and stirred for 1 h at -5 °C, and then allowed to
reach rt for 3 h. CH2Cl2 (50 mL) was added to the reaction
mixture which was washed with brine (3 × 500 mL). The
organic layer was dried over Na2SO4 and concentrated under
vacuum to afford 14 (1.93 g, 93%) as a pale-yellow oil after
1
(pentane/EtOAc, 95:5); H-NMR (DMSO-d6) δ 7.62-7.22 (m,
25H), 3.83-3.78 (m, 1H), 2.91-2.82 (m, 2H), 1.57-1.40 (m,
4H), 1.07-0.93 (m, 12H); [R]D ) +9.8 (c 1.1 EtOH). Anal.
Calcd for C40H44O2Si: C, 82.14; H, 7.58. Found: C, 81.93; H,
7.37.
(R)-4-[(ter t-Bu tyld ip h en ylsilyl)oxy]p en ta n -1-ol (19). A
solution of 18 (9.05 g, 15.5 mmol) and PPTS (1.25 g, 5 mmol)
in absolute EtOH (350 mL) was stirred at 55 °C for 6 h. The
solvent was evaporated under vacuum, and the residue was
dissolved in EtOAc (150 mL). The organic layer was succes-
sively washed with H2O (60 mL) and brine (60 mL), and then
dried over Na2SO4. Filtration and concentration under vacuum
yielded 19 (4.66 g, 88%) as a pale-yellow oil which was purified
by flash column chromatography (cyclohexane/EtOAc, 80:20):
Rf 0.22 (cyclohexane/EtOAc, 80:20); 1H-NMR (DMSO-d6) δ 7.61
(m, 4H), 7.48-7.38 (m, 6H), 4.32 (t, J 5.1 Hz, 1H), 3.85 (m,
1H), 3.28 (m, 2H), 1.47-1.36 (m, 2H), 1.00 (d, J 6.0 Hz, 3H),

Total Synthesis of Dolatrienoic Acid
J . Org. Chem., Vol. 62, No. 10, 1997 3337
0.99 (s, 9H); MS m/ e (rel intens) 343 (M + H+, 71), 285(13),
265(11), 239(28), 199(100), 135(57), 87(37), 69(38); [R]D ) +10.3
(c 1 EtOH). Anal. Calcd for C21H30O2Si: C, 73.64; H, 8.83.
Found: C, 73.63; H, 8.90.
The organic phases were washed with brine (2 × 10 mL), and
then dried over Na2
SO4. The solvents were evaporated under
high vacuum to afford 22 containing traces of diglyme.
Crude 22 was protected as for compound 17 to give 23 (449
mg, 60% over the two steps) after purification by flash column
chromatography (cyclohexane/EtOAc/NEt3, 70:30:0.5): Rf 0.71
(CH2Cl2/MeOH, 90:10); 1H-NMR δ 7.43-7.20 (m, 15H), 5.39-
5.36 (m, 2H), 3.76 (dd, J 5.9, 5.9 Hz, 1H), 3.35 (quint, J 5.9
Hz, 1H), 3.22 (s, 3H), 3.15 (m, 2H), 2.00-1.90 (m, 4H), 1.74
(m, 2H), 1.53 (m, 6H), 1.15 (d, J 5.9 Hz, 3H); MS m/ e (rel
intens) 495(M + Na+, 3), 243(100); [R]D ) -6.0 (c 0.8 CHCl3)
(3R,11R)-11-[(ter t-Bu tyld ip h en ylsilyl)oxy]-3-m eth oxy-
d od ec-6(E)-en -1-ol (25). Compound 23 (396 mg, 0.84 mmol)
was silylated as for 18 giving the fully protected triol 24. This
latter derivative was then treated with PPTS (64 mg, 0.24
mmol) in absolute EtOH (15 mL) as for compound 19 to give
25 as an oil (252 mg, 64%): Rf 0.10 (cyclohexane/EtOAc, 90:
(R)-4-[(ter t-Bu t yld ip h en ylsilyl)oxy]-1-[(4-m et h ylb en -
zen esu lfon yl)oxy]p en ta n e (20). To the alcohol 19 (5.56 g,
17.5 mmol) dissolved in dry CH2Cl2 (120 mL) was added DMAP
(3.42 g, 28 mmol) at rt. To the solution cooled to -5 °C was
slowly added TsCl (4.01 g, 21 mmol) dissolved in dry CH2Cl2
(30 mL). The solution was stirred at rt overnight and then
washed successively with 1 N HCl (2 × 40 mL), saturated
NaHCO3 (40 mL), and brine (40 mL). The organic layer was
dried over Na2SO4 and concentrated under vacuum to afford
20 (5.62 g, 77%) as a colorless oil after purification by flash
column chromatography (cyclohexane/EtOAc, 90:10): Rf 0.72
1
(cyclohexane/EtOAc, 80:20); H-NMR (DMSO-d6) δ 7.72 (d, J
8.1 Hz, 2H), 7.58-7.38 (m, 12H), 3.93 (m, 2H), 3.76 (m, 1H),
2.40 (s, 3H), 1.62-1.53 (m, 2H), 1.41-1.28 (m, 2H), 0.96 (s, 9H),
0.93 (d, J 6.2 Hz, 3H); MS m/ e (rel intens) 497 (M + H+, 11),
297(20), 239(55), 199(100), 135(77), 73(29), 57(18); [R]D ) +7.2
(c 1.2 EtOH). Anal. Calcd for C28H36O4SiS: C, 67.70; H, 7.31.
Found: C, 67.95; H, 7.45.
1
10); H-NMR δ 7.64 (m, 4H), 7.42-7.32 (m, 6H), 5.36 (dd, J
15.7, 5.8 Hz, 1H), 5.29 (dd, J 15.7, 5.8 Hz, 1H), 3.82 (m, 1H),
3.80-3.70 (m, 2H), 3.39 (m, 1H), 3.33 (s, 3H), 2.46 (bs, 1H),
2.00-1.96 (m, 2H), 1.85-1.75 (m, 2H), 1.76-1.63 (m, 4H),
1.52-1.29 (m, 2H), 1.04 (d, J 5.7 Hz, 3H), 1.03 (s, 9H); MS
m/ e (rel intens) 469 (M + H+, 3), 229(8), 197(40); [R]D ) +6.0
(c 0.6 CHCl3). Anal. Calcd for C29H44O3Si: C, 74.31; H, 9.46.
Found: C, 74.45; H, 9.63.
(R)-7-[(ter t-Bu tyld ip h en ylsilyl)oxy]h ep t-1-yn e (5). To
a suspension of lithium acetylide-ethylenediamine complex
(1.84 g, 20 mmol) in dry DMSO (30 mL) was slowly added a
solution of 20 (4.72 g, 10 mmol) in dry DMSO (10 mL) at rt.
Stirring was maintained at rt for 1 h, and then H2O (150 mL)
was cautiously added to the brownish reaction mixture. The
aqueous layer was extracted with pentane (3 × 50 mL), and
the pentane extracts were washed with brine (2 × 50 mL) and
dried over Na2SO4. Filtration and concentration under vacuum
yielded 5 (3.01 g, 86%) as a pale-yellow oil which was purified
by filtration over a plug of silica gel: Rf 0.80 (cyclohexane/
EtOAc, 98:2); 1H-NMR (DMSO-d6) δ 7.61 (d, J 7.0 Hz, 4H),
7.47-7.40 (m, 6H), 3.85 (m, 1H), 2.70 (t, J 2.4 Hz, 1H), 2.05
(td, J 6.6, 2.4 Hz, 2H), 1.57-1.39 (m, 4H), 1.00 (d, J 6.0 Hz,
3H), 0.99 (s, 9H); MS m/ e (rel intens) 351 (M + H+, 3), 321(4),
295(10), 240(7), 200(100), 138(56), 75(32); [R]D ) +13.1 (c 1.1
(3S,11R)-11-[(ter t-Bu tyld ip h en ylsilyl)oxy]-3-m eth oxy-
dodec-6(E)-en -1-ol (25). This compound was obtained through
the same sequence of reactions starting from the alkyne 5 and
the iodide derivative (R)-4: Rf 0.10 (cyclohexane/EtOAc, 90:
1
10); H-NMR δ 7.65 (m, 4H), 7.40-7.25 (m, 6H), 5.30 (dd, J
15.7, 5.8 Hz, 2H), 3.87-3.65 (m, 3H), 3.36 (m, 1H), 3.33 (s,
3H), 2.00-1.80 (m, 4H), 1.78-1.13 (m, 8H), 1.04 (d, J 5.7 Hz,
3H), 1.03 (s, 9H); [R]D ) +29 (c 1.0 CHCl3). Anal. Calcd for
C29H44O3Si: C, 74.31; H, 9.46. Found: C, 74.60; H, 9.56.
(3R,11R)-11-[(ter t-Bu tyld ip h en ylsilyl)oxy]-3-m eth oxy-
d od ec-6(E)-en -1-a l (2). To a solution of oxalyl chloride (35
µL, 0.41 mmol) in dry CH2Cl2 was added at -78 °C dry DMSO
(0.58 µL, 0.8 mmol) dissolved in 2 mL of dry CH2Cl2. After
being stirred at -78 °C for 30 min, a solution of the alcohol
25 (128 mg, 0.27 mmol) dry CH2Cl2 was added to the precedent
mixture which was stirred for 30 min. At -78 °C triethyl-
amine (1.14 mL, 8 mmol) was added to the reaction mixture
which was allowed to reach rt. Water (15 mL) was added, the
aqueous phase was extracted with CH2Cl2 (2 × 10 mL), and
the combined organic phases were successively washed with
1 N HCl (10 mL) and a saturated NH4Cl aqueous solution (10
mL). The organic phase was dried over Na2SO4 and then
concentrated under high vacuum to give the title compound 2
(125 mg, 98%) as an oil. This aldehyde was used without
further purification. Rf 0.8 (cyclohexane/EtOAc, 80:20); 1H-
NMR δ 9.78 (t, J 2.0 Hz, 1H), 7.67-7.64 (m, 4H), 7.39-7.24
(m, 6H), 5.39-5.26 (m, 2H), 3.86-3.78 (m, 1H), 3.69 (m, 1H),
3.32 (s, 3H), 2.58 (ddd, J 15.7, 6.8, 2.6 Hz, 1H), 2.50 (ddd, J
15.7, 4.8, 1,8 Hz, 1H), 2.01 (q, J 6.5 Hz, 2H), 1.85 (q, J 6.6 Hz,
2H), 1.70-1.41 (m, 2H), 1.39-1.24 (m, 4H), 1.03 (d, J 5.9 Hz,
3H), 1.03 (s, 9H); MS m/ e (rel intens) no molecular ion 465(1),
243(45), 239(18), 199(86), 197(42), 165(19), 135(100), 109(24),
91(36), 67(42).
EtOH). Anal. Calcd for
Found: C, 78.94; H, 8.58.
C23H30OSi: C, 78.80; H, 8.63.
(3R,11R)-3-Meth oxyd od ec-6-yn e-1,11-d iol (21). To an
ice-cooled solution of the alkyne 5 (2.13 g, 6.1 mmol) in
anhydrous THF (20 mL) was added dropwise n-BuLi (1.5 M
in hexane, 4.26 mL, 6.4 mmol), and the mixture was stirred
for 1 h at rt. At 0 °C a solution of the iodide 4 (2.25 g, 6.3
mmol) in HMPT (10 mL) was slowly added, and the reaction
mixture was stirred for 16 h at rt. This mixture was
hydrolyzed with a 5% KHSO4 solution (100 mL), and the
aqueous layer was extracted with diethyl ether (3 × 50 mL).
The combined organic layers were washed with brine (3 × 70
mL) and dried over Na2SO4. Filtration and concentration
under vacuum yielded 3 (2.20 g, 71%) as a pale-yellow oil which
was used as such in the next step.
To the crude 3 was added TBAF (1 M in THF, 20 mL, 20
mmol), and the mixture was stirred 16 h at rt. To this were
successively added diethyl ether (150 mL) and brine (50 mL).
The aqueous layer was extracted with diethyl ether (3 × 30
mL), and the ethereal extracts were washed with brine (3 ×
30 mL) and were dried over Na2SO4. Filtration and concen-
tration under vacuum yielded 5 (890 mg, 64%) after purifica-
tion by flash column chromatography (CH2Cl2/MeOH, 95:5):
Rf 0.2 (CH2Cl2/MeOH, 95:5); 1H-NMR δ 3.83-3.69 (m, 3H),
3.53 (quint, J 5.9 Hz, 1H), 3.36 (s, 3H), 2.24-2.14 (m, 4H),
1.81-1.49 (m, 8H), 1.18 (d, J 5.9 Hz, 3H); MS m/ e (rel intens)
229(M + H+, 100), 197(20), 179(11), 161(12); HRMS m/ e calcd
for C13H24O3: (M + H+), 229.1804; found: (M + H+), 229.1849;
[R]D ) -9.0 (c 1.1 CHCl3).
(3R,11R)-1-[(Tr ip h en ylm et h yl)oxy]-3-m et h oxyd od ec-
6(E)-en -11-ol (23). To the alkyne 21 (380 mg, 1.65 mmol)
was slowly added LiAlH4 (0.5 M in diglyme, 13 mL, 6.5 mmol)
at 0 °C. The mixture was refluxed 24 h. At rt the reaction
was quenched with a piece of crushed ice, 1 N HCl (0.7 mL),
and H2O (0.7 mL). The aqueous phase was treated with 1 N
HCl (pH 1) and was extracted with diethyl ether (3 × 10 mL).
(3S,11R)-11-[(ter t-Bu tyld ip h en ylsilyl)oxy]-3-m eth oxy-
d od ec-6(E)-en -1-a l (2). 1H-NMR δ 9.78 (t, J 2.2 Hz, 1H),
7.69-7.63 (m, 4H), 7.38-7.29 (m, 6H), 5.30 (m, 2H), 3.85-
3.74 (m, 1H), 3.71-3.62 (m, 1H), 3.32 (s, 3H), 2.59 (ddd, J 16.2,
6.8, 2.5 Hz, 1H), 2.49 (ddd, J 16.2, 5.3, 2.0 Hz, 1H), 2.02 (m,
2H), 1.85 (m, 2H), 1.73-1.23 (m, 6H), 1.03 (d, J 5.9 Hz, 3H),
1.03 (s, 9H). Anal. Calcd for C29H42O3Si: C, 74.63; H, 9.07.
Found: C, 73.73; H, 9.12.
(5RS,7R,15R)-15-[(ter t-Bu t yld ip h en ylsilyl)oxy]-5-h y-
d r oxy-7-m et h oxy-2-m et h ylh exa d eca -2(E),10(E)-d ien oic
Acid Eth yl Ester (28). To a stirred solution of 2 (100 mg,
0.2 mmol) in a mixture of dry dichloromethane/diethyl ether
(2 mL, 90/10), cooled to -78 °C, was added the silyl ketene
acetal 2720 (133 mg, 0.72 mmol) and then boron trifluoride
etherate (63 mL, 0.4 mmol). Stirring was maintained over 36
h at rt, and then water (1 mL) was added at -78 °C followed
by diethyl ether (5 mL) to the reaction mixture. The aqueous
phase was extracted with CH2Cl2 (3 × 30 mL), and the

3338 J . Org. Chem., Vol. 62, No. 10, 1997
Moune et al.
combined organic phases were dried over Na2SO4. After
evaporation of the solvent under high vacuum, the crude
product was purified by flash column chromatography (cyclo-
hexane/EtOAc, 80:20) to give 28 as an inseparable mixture of
diastereoisomers (24 mg, 20%): Rf 0.3 (cyclohexane/EtOAc, 80:
20); 1H-NMR δ 7.72-7.63 (m, 4H), 7.39-7.28 (m, 6H), 6.80
(tq, J 7.4, 1.3 Hz, 1H), 5.33 (m, 2H), 4.16 (q, J 7.0 Hz, 2H),
4.11-3.96 (m, 1H), 3.95-3.72 (m, 1H), 3.53-3.40 (m, 1H), 3.34
and 3.33 (2s, 3H), 2.33 (m, 2H), 1.83 (s, 3H), 2.00-1.20 (m,
12H), 1.22 (t, J 7.0 Hz, 3H), 1.02 (d, J 5.9 Hz, 3H), 1.02 (s,
9H); MS m/ e (rel intens) 617(M + Na+, 3), 595(M + H+,4),
563(2), 537(2), 505(2), 339(6), 307(8), 289(6), 243(17), 239(18),
199(100), 197(45), 91(27), 67(37).
enoic acid phenylmethyl ester (673 mg, 3 mmoL) after puri-
fication by flash column chromatography (cyclohexane/EtOAc,
90:10) as a yellow oil.
The preceding chloride compound was dissolved in trimethyl
phosphite (15 mL), and the solution was heated at 120 °C for
3 h. The trimethyl phosphite was evaporated under high
vacuum, and the residue was purified by flash column chro-
matography (cyclohexane/EtOAc, 50:50) to give the desired
phosphonate 34 (885 mg, 82%): Rf 0.10 (cyclohexane/EtOAc,
50:50); 1H-NMR δ 7.33-7.24 (m, 5H), 6.74 (tdq, J 8.2, 6.8, 1.5
Hz, 1H), 5.14 (s, 2H), 3.73 (d, J 11.0 Hz, 1H), 2.73 (ddd, J 23.4,
8.2, 0.8 Hz, 2H), 1.87 (dd, J 1.5, 0.8 Hz, 3H); 31P-NMR δ 29.19;
MS m/ e (rel intens) 299(MH+, 72), 209(2), 191(55), 109(5),
91(95). Anal. Calcd for C14H19O5P: C, 56.38; H, 6.42.
Found: C, 55.78; H, 6.61.
(7R,15R)-15-[(ter t-Bu tyld ip h en ylsilyl)oxy]-7-m eth oxy-
2-m eth ylh exa deca -2(E),4(E),10(E)-tr ien oic Acid Eth yl Es-
ter (30). The mixture of diastereoisomeric alcohols 28 and
triethylamine (0.15 mL, 1 mmol) were dissolved in dry CH2Cl2
(1 mL). To this solution was added methanesulfonyl chloride
(10 mL, 0.13 mmol) at -78 °C. The mixture was stirred at rt
overnight and then diluted with CH2Cl2 (5 mL). The organic
phase was successively washed with a 5% KHSO4 aqueous
solution (5 mL), a 5% NaHCO3 aqueous solution (5 mL), and
a saturated NH4Cl aqueous solution (10 mL). The organic
phase was dried over Na2SO4 and then concentrated under
high vacuum. The resulting mesylate 29 was directly treated
with DBU (19 mL, 0.15 mmol) in chloroform (2 mL) at rt over
24 h. The same workup as above yielded a mixture of (2E,4E)
and (2E,4Z) expected esters after purification by flash column
chromatography (cyclohexane/EtOAc, 95:5). The mixture of
dienes was isomerized after being stirred with some freshly
sublimed crystals of iodine in CHCl3 for 6 h. Iodine was
eliminated after washing the organic phase with a 10%
NaHSO3 aqueous solution. The organic phase was dried over
Na2SO4 and then concentrated under high vacuum to give the
protected dolatrienoic acid ethyl ester 30 (8 mg, 46%) as an
oil: Rf 0.3 (cyclohexane/EtOAc, 95:5); 1H-NMR δ 7.65 (m, 4H),
7.44-7.27 (m, 6H), 7.15 (d, J 10.8 Hz, 1H), 6.37 (dd, J 15.1,
10.8 Hz, 1H), 6.05 (td, J 15.1, 7.3 Hz, 1H), 5.33-5.25 (m, 2H),
4.18 (q, J 7.2 Hz, 2H), 3.82 (m , 1H), 3.33 (s, 3H), 3.23 (m,
1H), 2.37 (t, J 7.3 Hz, 2H), 2.03-1.97 (m, 2H), 1.92 (s, 3H),
1.89-1.85 (m, 2H), 1.48-1.24 (m, 11H), 1.03 (d, J 5.9 Hz, 3H),
1.03 (s, 9H); MS m/ e (rel intens) 599(M + Na+, 2), 577(M +
H+, 2), 575(3), 520(12), 519(28), 321(8), 239(21), 199(100);
HRMS m/ e calcd for C36H49O4Si: (M-H+), 575.3537; found:
(M-H+), 575.3625; calcd for C36H52O4Si: (M-tBu+), 519.3061;
found: (M-tBu+), 519.2996; HPLC (conditions B) tR 2.3 min
(30% B isocratic).
2-Hyd r oxy-2-m et h ylb u t en -3-oic Acid P h en ylm et h yl
Ester (33). 2-Hydroxy-2-methylbuten-3-oic acid22 (3.54 g, 30.5
mmol) was dissolved in dry DMF (120 mL). To this solution
were added NaHCO3 (5.12 g, 61 mmol) and then benzyl
bromide (18.1 mL, 152.5 mmol) dissolved in dry DMF (120
mL). Stirring was continued overnight at rt then water (1 L)
was added. The aqueous phase was extracted with ethyl
acetate (3 × 200 mL). The combined organic phases were
washed with brine (200 mL) and dried over Na2SO4. After
evaporation of the solvents, the crude product was purified
by flash column chromatography (cyclohexane/EtOAc, 90:10)
to give the desired ester 33 (9.0 g, 53%) as an colorless oil: Rf
0.3 (cyclohexane/EtOAc, 90:10); 1H-NMR δ 7.33 (m, 5H), 5.99
(dd, J 17.0, 10.5 Hz, 1H), 5.48 (dd, J 17.0, 1.0 Hz, 1H), 5.18 (s,
2H), 5.14 (dd, J 10.5, 1.0 Hz, 1H), 3.25 (bs, 1H), 1.48 (s, 3H);
MS m/ e (rel intens) 207(M + H+, 32), 181(9), 91(100). Anal.
Calcd for C12H14O3: C, 69.89; H, 6.84. Found: C, 69.75; H,
7.01.
(7S,15R)-15-[(ter t-Bu tyld ip h en ylsilyl)oxy]-7-m eth oxy-
2-m eth ylh exa d eca -2(E),4(E),10(E)-tr ien oic Acid P h en yl-
m eth yl Ester (35). Sodium hydride (20.1 mg, 0.87 mmol) was
suspended in dry THF (1.5 mL) and cooled in an ice-bath. To
this suspension was added phosphonate 34 (260 mg, 0.87
mmol) dissolved in THF (1.5 mL), and the mixture was stirred
for 2 h at 0 °C. This solution was added dropwise to a
precooled (-30 °C) solution of the aldehyde 2 (140 mg, 0.3
mmol) in THF (2 mL), and the mixture was stirred for 1.5 h
until the temperature reached -15 °C. Water (10 mL) was
poured into the reaction mixture, and then the aqueous phase
was extracted with diethyl ether (3 × 15 mL). After evapora-
tion of the solvent, the crude product was purified by flash
column chromatography (cyclohexane/EtOAc, 95:5). The re-
sulting dienes were isomerized and worked-up as for compound
30 to give the protected dolatrienoic acid phenylmethyl ester
35 (133 mg, 70%) as an oil: Rf 0.7 (cyclohexane/EtOAc, 80:
1
20); H-NMR δ 7.65 (m, 4H), 7.39-7.30 (m, 6H), 7.18 (dd, J
11.2, 1.2 Hz, 1H), 6.38 (dd, J 15.0, 11.2 Hz, 1H), 6.07 (td, J
15.0, 7.2 Hz, 1H), 5.34-5.27 (m, 2H), 5.18 (s, 2H), 3.81 (m ,
1H), 3.31 (s, 3H), 3.22 (m, 1H), 2.37 (t, J 6.4 Hz, 2H), 2.02-
1.83 (m, 4H), 1.93 (d, J 1.2 Hz, 3H), 1.52-1.33 (m, 6H), 1.03
(d, J 5.9 Hz, 3H), 1.03 (s, 9H); MS m/ e (rel intens) 661(M +
Na+, 2), 639(M + H+, 2), 581(2), 505(11), 473(1), 423(3), 393(6),
307(5), 239(18), 199(100), 91(58); HRMS m/ e calcd for C41H54
-
O4Si: (M + H+), 639.3870; found: (M + H+), 639.3917; HPLC
(conditions B) tR 2.2 min (30% B isocratic).
(7R,15R)-15-H yd r oxy-7-m et h oxy-2-m et h ylh exa d eca -
2(E),4(E),10(E)-tr ien oic Acid (1). To a solution of (7R,15R)-
30 (8 mg, 13.8 µmol) in hexane/acetonitrile (0.48 mL, 50:50),
cooled to -60 °C, was added fluorhydric acid (0.35 mL of a
50% aqueous solution). Stirring was pursued over 2 days at
0 °C. Hexane (3 mL) was added, and the organic phase was
washed successively with a saturated KHCO3
solution (3 × 1
mL) and a saturated NH4Cl solution until neutral. Drying
over Na2SO4 and evaporative distillation of the solvents
afforded the desired hydroxy ester which was directly saponi-
fied with a methanolic (1.3 mL) solution of KOH (0.82 mL of
a 1 M aqueous solution) during 3 days at 0-10 °C. An ice-
cooled 5% aqueous solution of KHSO4 (2.2 mL) was added to
the preceding mixture, and then methanol was evaporated
under vacuum. The aqueous residue was extracted with
EtOAc (3 × 3 mL), and the combined organic phases were
washed with a saturated NH4
Cl solution (until pH 5) and dried
over Na2SO4. Evaporation of the solvent led to the expected
(7R,15R)-dolatrienoic acid (1) (1.4 mg, 33%) as a pale-yellow
oil after chromatographic purification (hexane/EtOAc, 60/40):
1
Rf 0.1 (cyclohexane/EtOAc, 60:40); H-NMR δ 7.24 (d, J 11.2
Hz, 1H), 6.39 (dd, J 15.0, 11.2 Hz, 1H), 6.10 (dt, J 15.0, 7.2
Hz, 1H), 5.39 (m, 2H), 3.78 (m , 1H), 3.33 (s, 3H), 3.25 (quint,
J 5.6 Hz, 1H), 2.39 (t, J 6.2 Hz, 2H), 2.05 (m, 4H), 1.92 (s,
3H), 1.65-1.31 (m, 6H), 1.16 (d, J 6.2 Hz, 3H); MS m/ e (rel
intens) 333(M + Na+, 84%), 311(M + H+, 30), 293(27), 262(30),
245(24), 135(84), 79(85); HRMS m/ e calcd for C18H31O4: (M
+ H+), 311.2222; found: (M + H+), 311.2198; HPLC (conditions
A) tR 7.2 min (20% to 100% B).
[3-Meth yl-3-[(p h en ylm eth oxy)ca r bon yl]bu t-2(E)-en yl]-
p h osp h on ic Acid Dim eth yl Ester (34). To a cooled (-78
°C) solution of alcohol 33 (760 mg, 3.6 mmol) in dry CH2Cl2
(25 mL) was added SOCl2 (0.9 mL, 12.4 mmol) in dry CH2Cl2.
Stirring was continued overnight at reflux. The reaction
mixture was poured onto an ice-cooled 5% NaHCO3 aqueous
solution (20 mL), and the aqueous phase was extracted with
CH2Cl2 (20 mL). The combined organic phases were succes-
sively washed with a 5% NaHCO3 solution (20 mL) and a
saturated NH4Cl solution (20 mL) then dried over Na2SO4.
Evaporation of the solvent yielded 4-chloro-2-methyl-but-2(E)-
(7S,15R)-15-H yd r oxy-7-m et h oxy-2-m et h ylh exa d eca -
2(E),4(E),10(E)-tr ien oic Acid (1). By a similar procedure,
(7S,15R)-35 gave the desired (7S,15R)-1 in a 37% overall
yield: 1H-NMR δ 7.25 (d, J 11.2 Hz, 1H), 6.39 (dd, J 14.7, 11.2
Hz, 1H), 6.10 (dt, J 14.7, 7.3 Hz, 1H), 5.38 (m, 2H), 3.76 (m ,

Total Synthesis of Dolatrienoic Acid
J . Org. Chem., Vol. 62, No. 10, 1997 3339
1H), 3.33 (s, 3H), 3.25 (quint, J 5.8 Hz, 1H), 2.38 (t, J 6.3 Hz,
2H), 2.02 (m, 4H), 1.91 (s, 3H), 1.54-1.38 (m, 6H), 1.16 (d, J
6.1 Hz, 3H); HRMS m/ e calcd for C18H31O4: (M + H+),
311.2222; found: (M + H+), 311.2141; HPLC (conditions A) tR
7.2 min (20% to 100% B).
Dr. A. Aumelas for kindly supplying to us NMR cor-
relation experiments.
Su p p or tin g In for m a tion Ava ila ble: 1H, 1H-1H COSY-
DQF, HMQC, HMQC-TOCSY, and NOESY spectra for (7S,-
15R)-1 (8 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. This work was supported by the
CNRS as a postdoctoral fellowship (I.E.) and the MESR
for a doctoral research grant (S.M.). We are grateful to
Dr. S. L. Salhi for the revision of the manuscript and
J O962217A