Synthesis of elenic acid, an inhibitor of topoisomerase II from the sponge Plakinastrella sp.

Article abstract of DOI:10.1039/a801122b

(R)-(-)-Elenic acid 1, an inhibitor of topoisomerase II isolated from the marine sponge Plakinastrella sp., has been synthesized starting from hexadecane-1,16-diol 2 and methyl (S)3-hydroxy-2-methylpropanoate 6.

Full text of DOI:10.1039/a801122b

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Synthesis of elenic acid, an inhibitor of topoisomerase II from the
sponge Plakinastrella sp.
Shin-ichi Takanashi, Masanori Takagi, Hirosato Takikawa and Kenji Mori*
Department of Chemistry, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku,
Tokyo 162-8601, Japan
(R)-(؊)-Elenic acid 1, an inhibitor of topoisomerase II isolated from the marine sponge Plakinastrella
sp., has been synthesized starting from hexadecane-1,16-diol 2 and methyl (S)-3-hydroxy-2-
methylpropanoate 6.
Elenic acid 1, an inhibitor of topoisomerase II, was isolated
from the Indonesian sponge Plakinastrella sp. and character-
ized by Scheuer and co-workers in 1995.1 Elenic acid has a
rather unusual structure, in which its phenol portion and β,γ-
unsaturated carboxylic acid moiety are linked with a long
hydrocarbon chain. Scheuer and co-workers also determined
the absolute configuration at C-2 to be R by employing
Kusumi’s method.2 According to them, its inhibitory activity
for topoisomerase II is very strong with an IC50 value of 0.1 µg
mlϪ1.1 Since topoisomerase II is considered to be an indicator
enzyme in the treatment of lung cancer,3 elenic acid offers much
promise for clinical use. We became interested in the unique
structure and strong activity of elenic acid, and undertook a
project to synthesize it stereoselectively.
intermediate B is obtainable from D and E, while C can be
prepared from F (>99.8% ee).
The above synthetic plan was realized as follows (Scheme 2).
First, hexadecane-1,16-diol (2, = E) was converted into the
corresponding bromohydrin 3 in 57% yield. This was treated
with an excess of p-methoxybenzylmagnesium chloride (D) in
the presence of dilithium tetrachlorocuprate (Li2CuCl4) to give
alcohol 4 in 77% yield. Treatment of 4 with hydrobromic acid
afforded 17-p-hydroxyphenyl-1-bromoheptadecane 5a in 76%
yield. Tetrahydropyranyl (THP) protection of the phenolic
hydroxy group of 5a gave THP ether 5b (= B) in 97% yield. The
overall yield of 5b was 32% based on 2 in four steps.
Methyl (S)-3-hydroxy-2-methylpropanoate 6 (= F, >99.8%
ee) was converted to the ester 7a by the known procedure (81%,
1
three steps).4 The H NMR spectrum of 7a suggested the E:Z
ratio of 7a to be 19:1. For determination of the enantiomeric
purity of 7a, it was deprotected to the corresponding alcohol 7b
in the conventional manner. GLC Analysis of 7b employing a
chiral stationary phase allowed the enantiomeric purity of 7b
to be estimated as 94.0% ee (see Experimental). The regio-
isomeric and enantiomeric purities of 7a were in accord with
those reported4 and judged as sufficient for the purpose of our
Results and discussion
Synthetic plan
Elenic acid 1 is composed of a phenol, a long chain and a β,γ-
unsaturated carboxylic acid portion. Our synthetic plan is
shown in Scheme 1. The target compound 1 is easily obtained
from A, which can be prepared by the coupling of B and C. The
CO2H
Elenic acid 1
HO
OH
THPO
A
(CH2)17Br
PhSO2
OTBDMS
THPO
C
B
MgCl
HO(CH2)16OH
OH
MeO2C
MeO
F
D
E
Scheme 1 Structure and retrosynthetic analysis of elenic acid
J. Chem. Soc., Perkin Trans. 1, 1998
1603

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ation. After several recrystallizations from methanol, the
(CH2)17OH
(b)
(a)
unwanted (Z)-isomer and the double bond positional isomer(s)
could be removed completely, and pure 10b was obtained in
70% yield. Purified 10b was then oxidized with Dess–Martin
periodinane7 followed by sodium chlorite8 to afford carboxylic
acid 11b (67%, two steps). Finally, removal of the THP group
was achieved by treatment with hydrochloric acid to give (R)-
elenic acid 1 as a white amorphous powder, [α]D25 Ϫ30 (c 0.38,
CHCl3) {lit.,1 Ϫ27.2 (c 2.2, CHCl3)}, in 74% yield. The overall
yield of 1 was 7.6% based on 2 in 10 steps or 16% based on 6 in
12 steps. The enantiomeric purity of synthetic 1 was estimated
to be 87.3% ee by means of HPLC analysis (see Experimental).
The reason for the partial loss of enantiomeric purity (94.0%
ee at the stage of 7a to 87.3% ee at 1) might be due to partial
racemization in the course of the final three steps. Unfortun-
ately, all attempts to enrich the enantiomeric purity of synthetic
1 by recrystallization were unsuccessful. The 1H and 13C NMR
spectra of synthetic 1 were in good accord with those of the
natural product.
HO(CH2)16OH
Br(CH2)16OH
MeO
2 (= E)
3
4
(c)
(CH2)17Br
RO
(d)
5a R = H
5b R = THP
ref. 4
OH
OR
MeO2C
6 (= F)
EtO2C
3 steps
7a R = TBDMS
(7b R = H)
(e)
( )17
SO2Ph
OTBDMS
(h)
X
OTBDMS
Experimental
THPO
9
All bps and mps were uncorrected. IR Spectra were measured
as films for oils and as KBr disks or Nujol suspensions for
solids on a JASCO A-102 spectrometer or a Perkin-Elmer 1640
spectrometer. 1H NMR spectra were recorded at 90 MHz on a
JEOL EX-90A spectrometer, at 270 MHz on a JEOL JNM EX
270L spectrometer, or at 300 MHz on a Bruker DPX 300 spec-
trometer. The peak for SiMe4 or solvent (CHCl3: δ 7.26) was
used as the internal standard. J Values are given in Hz. 13C
NMR spectra were recorded at 67.8 MHz on a JEOL JNM EX
270L spectrometer or at 75.5 MHz on a Bruker DPX 300
spectrometer with the solvent peak (CDCl3: δ 77.0) used as
an internal standard. Optical rotations were measured on a
JASCO DIP-1000 polarimeter. Mass spectra were recorded on
a JEOL JMS-SX102A mass spectrometer. Refractive indexes
were measured on an ATAGO Abbe refractometer 1T.
8a X = OH
(f)
(i)
8b X = Br
(g)
8c X = SO2Ph
( )17
OR
( )17
R
(l)
O
THPO
THPO
10a R = TBDMS
10b R = H
11a R = H
(j), (k)
(m)
11b R = OH
(n)
( )17
OH
O
HO
16-Bromohexadecan-1-ol 3
1
To a solution of hexadecane-1,16-diol 2 (1.00 g, 3.87 mmol) in
benzene (30 cm3), hydrobromic acid (48%; 0.78 cm3, 6.9 mmol)
was added and the mixture was stirred for 5 h under reflux. This
mixture was poured into water and extracted with CHCl3. The
extract was washed successively with water, saturated aq.
NaHCO3 and brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was chromatographed over SiO2
to give the bromo alcohol 3 (713 mg, 57%) as a white solid, mp
48–50 ЊC; νmax(Nujol)/cmϪ1 3300m (OH); δH(90 MHz; CDCl3)
1.20–1.90 (29 H, m, 2–15-H, OH), 3.41 (2 H, t, J 7, 16-H), 3.64
(2 H, t, J 6, 1-H). This was employed in the next step without
further purification.
Scheme 2 Synthesis of elenic acid. Reagents, conditions and yields: (a)
aq. HBr, C6H6 (57%); (b) p-MeOC6H4CH2MgCl, Li2CuCl4, THF
(77%); (c) aq. HBr, AcOH (76%); (d) DHP, TsOH (97%); (e) DIBAL,
hexane, CH2Cl2 (quant.); (f) BunLi, TsCl, LiBr, Et2O, HMPA (quant.);
(g) PhSO2Naؒ2 H2O, DMF (84% yield based on 8a); (h) BunLi, THF,
HMPA, 5b (78%); (i) PdCl2(dppp), LiEt3BH, THF (93%); (j) TBAF,
THF (94%); (k) Recrystallization from MeOH (70%); (l) Dess–Martin
periodinane, C5H5N, CH2Cl2 (quant.); (m) NaClO2, NaH2PO4, DMSO,
MeCN, H2O (67% based on 10b); (n) aq. HCl, THF (74%).
synthesis. Reduction of the ester 7a with diisobutylaluminium
hydride (DIBAL) gave the known alcohol 8a4 (quant.), which
was converted to the corresponding bromide 8b under Stork’s
conditions.5 It was then treated with sodium benzenesulfinate to
afford the phenyl sulfone 8c (= C) in 84% yield based on 8a. The
overall yield was 68% based on 6 in six steps.
17-(p-Methoxyphenyl)heptadecan-1-ol 4
A THF solution of p-methoxybenzylmagnesium chloride was
prepared from p-methoxybenzyl chloride (0.58 g, 3.7 mmol)
and magnesium (90 mg, 3.7 mmol) in THF (3 cm3) in the usual
manner. The resulting Grignard reagent and an Li2CuCl4 solu-
tion (0.10 mol dmϪ3 in THF; 0.3 cm3, 0.03 mmol) was added
successively to a suspension of bromo alcohol 3 (296 mg, 921
µmol) in THF (3 cm3) at Ϫ78 ЊC under Ar. This mixture was
allowed to warm to room temperature with stirring overnight.
After quenching with saturated aq. NH4Cl, it was extracted
with diethyl ether. The extract was washed with water, saturated
aq. NaHCO3 and brine, dried (MgSO4), and concentrated
under reduced pressure. The residue was chromatographed over
SiO2 and then recrystallized from hexane to give the alcohol 4
(257 mg, 77%) as colorless plates, mp 77–78 ЊC (Found: C,
79.10; H, 11.49. C24H42O2 requires C, 79.50; H, 11.67%);
νmax(Nujol)/cmϪ1 3250m (OH), 1610w (Ar), 1580w (Ar), 1515m
The resulting sulfone 8c was treated with BunLi and bromide
5b successively to furnish the coupled product 9 in 78% yield.
Reductive cleavage of the phenylsulfonyl group was carried out
by employing LiEt3BH and PdCl2(dppp)2 in THF according to
Inomata and co-workers to give 10a in 93% yield.6 However, the
1H NMR spectrum of the resulting compound 10a suggested it
to be contaminated with inseparable by-product(s) (<20%). The
most probable structure of the by-product(s) was the double
bond isomer(s) with unsaturation at C-4. Compound 10a could
not be purified further. The TBDMS protecting group of 10a
was then removed by treatment with tetrabutylammonium
fluoride (TBAF) to give alcohol 10b (= A) in 94% yield. Fortu-
nately, 10b was a solid and could be purified by recrystalliz-
1604
J. Chem. Soc., Perkin Trans. 1, 1998

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(Ar), 1115m, 1070m, 1025m, 815m; δH(90 MHz; CDCl3) 1.25
(30 H, br s, 2–16-H), 2.17 (1 H, s, OH), 2.54 (2 H, t, J 7, 17-H),
3.64 (2 H, q-like, J 6, 1-H), 3.79 (3 H, s, OMe), 6.81 (2 H, d, J 9,
3Ј- and 5Ј-H), 7.10 (2 H, d, J 9, 2Ј- and 6Ј-H).
(R)-5-tert-Butyldimethylsilyloxy-2,4-dimethylpent-2-enyl phenyl
sulfone 8c
A mixture of 8b (1.24 g, ~3.77 mmol), NaHCO3 (50 mg, 0.60
mmol) and NaSO2Phؒ2 H2O (1.56 g, 7.79 mmol) in dry DMF
(12 cm3) was stirred for 3 d at room temperature. It was then
poured into water and extracted with diethyl ether. The extract
was washed with water, saturated aq. NaHCO3 and brine, dried
(MgSO4), and concentrated under reduced pressure. The resi-
due was chromatographed over SiO2 to give the sulfone 8c (1.17
g, 84%basedon 8a)asacolorlessoil; nD25 1.5001(Found:C, 61.71;
H, 9.09. C22H44OSi requires C, 61.91; H, 8.75%); [α]D27 ϩ6.9
(c 0.21 in CHCl3); νmax(film)/cmϪ1 1585w (Ar), 1445m (Ar),
1320s (SO2), 1310s, 1250m (Si᎐Me), 1150s (SO2), 1085s (SO2),
835m, 690m (C᎐S); δH(90 MHz; CDCl3) 0.00 (6 H, s, SiMe),
0.75 (3 H, d, J 7, 4-Me), 0.85 (9 H, s, But), 1.79 (3 H, br d, J 1.5,
2-Me), 2.41 (1 H, m, 4-H), 3.20 (2 H, m, 5-H), 3.73 (2 H, s, 1-H),
4.76 (1 H, br d, J 8, 3-H), 7.45–7.90 (5 H, m, Ar-H).
17-p-Hydroxyphenyl-1-bromoheptadecane 5a
To a solution of 4 (2.28 g, 6.29 mmol) in acetic acid (60 cm3),
hydrobromic acid (48%; 75 cm3) was added and the stirring was
continued for 8 h under reflux. This mixture was then concen-
trated under reduced pressure. The residue was diluted with
water and extracted with diethyl ether. The extract was washed
with water, saturated aq. NaHCO3, water and brine, dried
(MgSO4), and concentrated under reduced pressure. The resi-
due was chromatographed over SiO2 to give the bromide 5a
(1.97 g, 76%) as a white crystalline solid, mp 87 ЊC; νmax(KBr)/
cmϪ1 3400m, (OH), 1620m (Ar), 1600w (Ar), 1520s (Ar), 820m
(Ar); δH(90 MHz; CDCl3) 1.10–2.00 (30 H, m, 2–16-H), 2.53 (2
H, t, J 7, 17-H), 3.41 (2 H, t, J 7, 1-H), 4.67 (1 H, br s, OH), 6.74
(2 H, d, J 8, 3Ј- and 5Ј-H), 7.04 (2 H, d, J 8, 2Ј- and 6Ј-H). This
was employed in the next step without further purification.
(2R,5RS)-1-tert-Butyldimethylsilyloxy-2,4-dimethyl-5-phenyl-
sulfonyl-22-(p-tetrahydropyranyloxyphenyl)docos-3-ene 9
To a stirred solution of 8c (223 mg, 605 µmol) in dry THF
(3 cm3) and HMPA (0.5 cm3), BunLi (1.54 mol dmϪ3 in n-
hexane; 0.394 cm3, 608 µmol) was added dropwise at Ϫ78 ЊC
under Ar. After stirring for 30 min at Ϫ78 ЊC, a solution of 5b
(250 mg, 504 µmol) in dry THF (3 cm3) was added dropwise to
this solution. It was stirred for 2 h at Ϫ78 ЊC and 15 h at 4 ЊC,
diluted with water, and extracted with diethyl ether. The extract
was washed with water and brine, dried (MgSO4) and con-
centrated under reduced pressure. The residue was chromato-
graphed over SiO2 to give the sulfone 9 (308 mg, 78%) as a
colorless oil; nD25 1.5070; [α]D25 ϩ3.3 (c 0.29 in CHCl3); νmax(film)/
cmϪ1 1610w (Ar), 1510s (Ar), 1305s (SO2), 1250w (Si᎐Me),
1145s (SO2), 1085s (SO2), 835s, 690m (C᎐S); δH(90 MHz;
CDCl3) Ϫ0.02 and 0.00 (total 6 H, each s, SiMe), 0.53 (3 H,
d, J 7, 2-Me), 0.84 and 0.86 (total 9 H, each s, But), 1.10–2.00
(38 H, br s 6–21-H, 3Љ-, 4Љ- and 5Љ-H), 1.68 (3 H, br s, 4-Me),
2.40–2.70 (3 H, m, 2- and 22-H), 2.90–4.10 (5 H, m, 1-, 5- and
6Љ-H), 4.66–4.90 (1 H, m, 3-H), 5.38 (1 H, br s, 2Љ-H), 6.95 (2 H,
d, J 9, 3Ј- and 5Ј-H), 7.10 (2 H, d, J 9, 2Ј- and 6Ј-H), 7.45–7.90
(5 H, m, SO2-ArH). This was employed in the next step without
purification.
17-(p-Tetrahydropyranyloxy)phenyl-1-bromoheptadecane 5b
A mixture of 5a (85.5 mg, 0.208 mmol), 2,3-dihydro-2H-pyran
(0.10 ml, 1.1 mmol) and TsOHؒH2O (~3 mg, catalytic amount)
in dry diethyl ether was stirred for 19 h at room temper-
ature. This mixture was poured into water and extracted
with diethyl ether. The extract was washed with saturated aq.
NaHCO3, water and brine, dried (MgSO4), and concentrated
under reduced pressure. The residue was chromatographed over
SiO2 to give the THP ether 5b (99.7 mg, 97%). This was
employed in the next step without further purification. A small
amount of 5b was further purified by recrystallization from
hexane to give colorless plates, mp 59–60 ЊC (Found: C, 67.93;
H, 9.81. C28H47O2Br requires C, 67.86; H, 9.56%); νmax(KBr)/
cmϪ1 1610w (Ar), 1515s (Ar), 1230s, 990s; δH(90 MHz; CDCl3)
1.10–2.00 (36 H, br s, 2–16-H, 3Љ-, 4Љ- and 5Љ-H), 2.55 (2 H, t,
J 7, 17-H), 3.41 (2 H, t, J 7, 1-H), 3.55–4.10 (2 H, m, 6Љ-H), 5.38
(1 H, br s, 2Љ-H), 6.95 (2 H, d, J 9, 3Ј- and 5Ј-H), 7.10 (2 H, d,
J 9, 2Ј- and 6Ј-H).
Enantiomeric purity of 7a
A small amount of the TBDMS ether 7a was converted to the
corresponding alcohol 7b by treatment with TBAF in THF. The
resulting compound 7b was analyzed by GLC to determine its
enantiomeric purity. GLC analysis [column: Chirasil DEX-CB
(0.25 mm × 25 m, 120 ЊC, ϩ1 ЊC minϪ1; carrier gas: He, pres-
sure 110 kPa)]: tR/min 15.0 [97.0%, (R)-7b], 16.5 [3.0%, (S)-7b].
The anantiomeric purity of 7b was estimated to be 94.0% ee.
The enantiomeric purity of 7a should be equal to that of 7b.
(R)-1-tert-Butyldimethylsilyloxy-2,4-dimethyl-22-(p-tetra-
hydropyranyloxyphenyl)docos-3-ene 10a
To a mixture of 9 (200 mg, 255 µmol) and PdCl2(dppp) (15.1 mg,
25.6 µmol) in dry THF (3 cm3), LiEt3BH (1.0 mol dmϪ3 in
THF; 0.384 cm3, 384 µmol) was added at 0 ЊC. The mixture was
stirred for 15 h at 4 ЊC, diluted with water and extracted with
diethyl ether. The extract was washed with water, aq. NaCN
(10%) and brine, dried (Na2SO4), and concentrated under
reduced pressure. The residue was chromatographed over SiO2
to give the title compound 10a (153 mg, 93%) as a colorless oil;
nD23 1.4855 (Found: C, 76.33; H, 11.91. C22H44OSi requires C,
76.57; H, 11.60%); [α]D25 Ϫ2.2 (c 0.22 in CHCl3); νmax(film)/cmϪ1
1610w (Ar), 1510s (Ar), 1250w (Si᎐Me), 970s, 835s, 775s;
δH(300 MHz, CDCl3) 0.04 (6 H, s, SiMe), 0.82 (~0.6 H, d, J 6.4,
2-Me of 4-ene isomer), 0.89 (9 H, s, But), 0.91 (3 H, d, J 5.7,
2-Me), 1.25 (32 H, br s, 6–21-H), 1.55–2.15 (8 H, m, 5-, 3Љ-,
4Љ- and 5Љ-H), 1.61 (3 H, d, J 1.2, 4-Me), 2.54 (2 H, t, J 7.6,
22-H), 2.61 (1 H, m, 2-H), 3.31 (1 H, dd, J 9.7 and 7.7, 1-Ha),
3.44 (1 H, dd, J 9.7 and 5.9, 1-Hb), 3.60 and 3.93 (total 2 H,
each m, 6Љ-H), 4.87 (1 H, dd, J 9.2 and 1.1, 3-H), 5.10 (~0.2 H, t,
J 7.7, 5-H of 4-ene isomer), 5.38 (1 H, t, J 3.2, 2Љ-H), 6.96 (2 H,
d, J 8.6, 3Ј- and 5Ј-H), 7.08 (2 H, d, J 8.6, 2Ј- and 6Ј-H).
(R)-1-Bromo-5-tert-butyldimethylsilyloxy-2,4-dimethylpent-2-
ene 8b
BunLi (1.59 mol dmϪ3 in n-hexane; 2.4 cm3, 3.8 mmol) was
added dropwise to a solution of 8a (922.5 mg, 3.77 mmol) in
dry diethyl ether (10 cm3) and dry HMPA (10 cm3) at 0 ЊC under
Ar, and the mixture was stirred for 10 min at 0 ЊC. To this
solution, TsCl (934 mg, 4.90 mmol) was added portionwise.
After stirring for 1 h at 0 ЊC, LiBr (1.64 g, 8.78 mmol) was
added to this mixture portionwise. The reaction mixture was
allowed to warm to room temperature with stirring during 2 h
and poured into saturated aq. NaHCO3. It was then extracted
with pentane–diethyl ether (1:2). The extract was washed with
water and brine, dried (MgSO4), and concentrated under
reduced pressure to give the bromide 8b (1.24 g, quant.) as a
colorless oil. δH(90 MHz; CDCl3) 0.03 (6 H, s, SiMe), 0.80–
0.95 (12 H, m, 4-Me, But), 1.77 (3 H, br s, 2-Me), 2.43 (1 H, m,
4-H), 3.42 (2 H, d, J 7, 5-H), 3.98 (2 H, d, J 4, 1-H), 5.20–5.45
(1 H, m, 3-H). This was employed in the next step without
purification.
(R)-2,4-Dimethyl-22-(p-tetrahydropyranyloxyphenyl)docos-3-
en-1-ol 10b
TBAF (1.0 mol dmϪ3 in THF; 0.3 cm3, 0.3 mmol) was added to
a solution of 10a (320 mg, 519 µmol) in dry THF (1.3 cm3) at
room temperature, and the stirring was continued for 5 h. It was
J. Chem. Soc., Perkin Trans. 1, 1998
1605

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then poured into water and extracted with diethyl ether. The
extract was washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was chrom-
atographed over SiO2 to give the alcohol 10b (247 mg, 94%) as
a white solid. For the removal of the minor isomers, (Z)-10b
and the 4-ene-isomer, the crude product 10b was purified by
recrystallization from methanol to give pure (E)-10b (70%) as
colorless leaflets, mp 48.5–49.5 ЊC (Found: C, 79.06; H, 11.42.
C35H60O3 requires C, 79.49; H, 11.44%); [α]D26 ϩ11.9 (c 0.52
in CHCl3); νmax(KBr)/cmϪ1 3380s (O᎐H), 1610w (Ar), 1230m,
980m; δH(300 MHz; CDCl3) 0.93 (3 H, d, J 6.7, 2-Me), 1.26 (32
H, br s, 6–21-H), 1.45–2.03 (9 H, m, 5-, 3Љ-, 4Љ-, 5Љ-H and OH),
1.65 (3 H, d, J 1.1, 4-Me), 2.54 (2 H, br t, J 7.6, 22-H), 2.62
(1 H, m, 2-H), 3.33 (1 H, m, 1-Ha), 3.46 (1 H, m, 1-Hb), 3.60
and 3.93 (total 2 H, each m, 6Љ-H), 4.88 (1 H, dd, J 9.4 and 0.9,
3-H), 5.38 (1 H, t, J 3.2, 2Љ-H), 6.96 (2 H, d, J 8.6, 3Ј- and 5Ј-H),
7.08 (2 H, d, J 8.6, 2Ј- and 6Ј-H).
washed with brine, dried (MgSO4) and concentrated under
reduced pressure. The residue was chromatographed over SiO2
to give elenic acid 1 (39 mg, 74%) as a white amorphous solid.
An analytical sample was obtained by recrystallization from
CHCl3 to give a white amorphous powder, mp 90.5–92.5 ЊC
[Found: (HREI-MS) Mϩ, 458.3760. C30H50O3 requires M,
458.3752]; [α]D25 Ϫ30 (c 0.38, in CHCl3); νmax(CHCl3)/cmϪ1
3600m (OH), 3015w (CH), 2925s (CH), 2850s (CH), 1740m
(C᎐O), 1705s (C᎐O), 1650w, 1510s (Ar), 1460m (CH), 1170w;
᎐
᎐
δH(300 MHz; CDCl3) 1.22 (3 H, d, J 7.0, 2-Me), 1.25 (28 H, br s,
7–20-H), 1.36 (2 H, quintet-like, J 7.5, 6-H), 1.56 (8 H, br
quintet, J 7.2, 21-H), 1.66 (3 H, d, J 0.8, 4-Me), 1.98 (2 H, t,
J 7.5, 5-H), 2.52 (2 H, t, J 7.5, 22-H), 3.36 (1 H, dq, J 9.2 and
7.0, 2-H), 5.14 (1 H, br d, J 9.2, 3-H), 6.74 (2 H, d, J 8.4, 3Ј- and
5Ј-H), 7.03 (2 H, d, J 8.4, 2Ј- and 6Ј-H); δC(75.5 MHz; CDCl3)
16.3, 17.9, 27.7, 29.2, 29.5, 29.6, 29.7, 31.7, 35.0, 38.5, 39.5,
115.0, 122.7, 129.4, 135.2, 138.8, 153.3, 180.4; m/z 458 (Mϩ,
47.6%), 440 (Mϩ Ϫ H2O, 29.9), 412 (Mϩ Ϫ CO, 27.9), 330 (7.0),
107 (100).
(R)-2,4-Dimethyl-22-(p-tetrahydropyranyloxyphenyl)docos-3-
enal 11a
Dess–Martin periodinane (517 mg, 1.22 mmol) and pyridine
(0.4 cm3) were dissolved in CH2Cl2 (8 cm3) under Ar. To this
solution, a solution of 10b (130 mg, 246 µmol) in CH2Cl2 (1.5
cm3) was added slowly at room temperature. This mixture was
stirred for 2 h, diluted with saturated aq. NaHSO3–saturated
aq. Na2S2O3 (1:1) and extracted with diethyl ether. The extract
was washed with water and brine, dried (Na2SO4), and concen-
trated under reduced pressure to give the crude aldehyde 11a
Enantiomeric purity of elenic acid 1
The synthetic (R)-elenic acid 1 was converted to the corre-
sponding (R)-naphthylethylamide by the conventional manner
using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride. For comparison, the (S)-naphthylethylamide was
also prepared. These amides were analyzed by HPLC analysis
[column, Pegasil Silica 60-5 (4.6 mm φ × 250 mm); solvent,
n-hexane–THF (150:1); flow, 0.5 cm3 minϪ1; detection at 254
nm]: tR/min 14.5 [6.35%, (R)-naphthylethylamide of (S)-1], 16.7
[93.65%, (R)-naphthylethylamide of (R)-1]. The enantiomeric
purity of synthesized 1 was determined to be 87.3% ee.
(130 mg, quant.); νmax(Nujol)/cmϪ1 1725m (C᎐O). This was
᎐
employed in the next step without further purification.
(R)-2,4-Dimethyl-22-(p-tetrahydropyranyloxyphenyl)docos-3-
enoic acid 11b
Acknowledgements
A mixture of 11a (97.5 mg, ∼185 µmol), NaH2PO4 (114 mg,
1.54 mmol), NaClO2 (80%; 53 mg, 0.47 mmol), DMSO (1.9 cm3),
CH3CN (0.9 cm3) and water (2.4 cm3) was stirred for 2 d at
room temperature. It was then diluted with brine and extracted
with CHCl3. The extract was washed with brine, dried (Na2SO4)
and concentrated under reduced pressure. The residue was
chromatographed over SiO2 to give the carboxylic acid 11b
(67 mg, 67% based on 10b) as a colorless amorphous solid, mp
46–48 ЊC; [α]D24 Ϫ28 (c 0.35, in CHCl3); νmax(KBr)/cmϪ1 1700s
We thank Professor P. J. Scheuer (University of Hawaii at
Manoa) for copies of the IR, 1H and 13C NMR and mass spec-
tra of natural elenic acid. This work was financially supported
by Kyowa Hakko Kogyo Co. and Nissan Chemical Co.
References
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(C᎐O), 1510s (Ar), 1235m, 1110m; δ (300 MHz; CDCl ) 1.18–
᎐
H
3
1.45 (33 H, m, 2-Me and 6–21-H), 1.50–1.87 (8 H, m, 5-, 3Љ-, 4Љ-
and 5Љ-H), 1.66 (3 H, d, J 1.1, 4-Me), 1.99 (2 H, t, J 7.5, 5-H),
2.53 (2 H, t, J 7.6, 22-H), 3.36 (1 H, dq, J 9.2 and 7.0, 2-H), 3.60
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(2 H, d, J 8.6, 2Ј- and 6Ј-H); m/z 542 (Mϩ). This was employed
in the next step without purification.
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(R)-2,4-Dimethyl-22-(p-hydroxyphenyl)docos-3-enoic acid
(elenic acid) 1
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To a solution of 11b (62 mg, 0.11 mmol) in THF (1 cm3), hydro-
chloric acid (4.0 mol dmϪ3; 1 cm3, 4 mmol) was added. After
stirring for 30 min at room temperature, this mixture was
diluted with brine and extracted with CHCl3. The extract was
Paper 8/01122B
Received 9th February 1998
Accepted 10th March 1998
1606
J. Chem. Soc., Perkin Trans. 1, 1998