Synthesis of elenic acid, an inhibitor of topoisomerase II

Article abstract of DOI:10.1021/jo982260t

A short, efficient synthesis of elenic acid, a marine natural product with interesting biological activity, has been completed. Critical features of the synthesis are the development of methodology for the one-pot elaboration of an alkyne to an (E)-β,γ-unsaturated ester with a stereocenter at the α-position and the use of the zipper reaction of a 1- arylalkyne. This reaction has not been previously reported with aromatic substrates. The synthesis strategy provides considerable flexibility for the preparation of structural analogues.

Full text of DOI:10.1021/jo982260t

2450
J . Org. Chem. 1999, 64, 2450-2453
Syn th esis of Elen ic Acid , a n In h ibitor of Top oisom er a se II
Rebecca C. Hoye,* Alejandro S. Baigorria, Michael E. Danielson, Alexa A. Pragman, and
Hemaka A. Rajapakse
Department of Chemistry, Macalester College, St. Paul, Minnesota 55105
Received November 13, 1998
A short, efficient synthesis of elenic acid, a marine natural product with interesting biological
activity, has been completed. Critical features of the synthesis are the development of methodology
for the one-pot elaboration of an alkyne to an (E)-â,γ-unsaturated ester with a stereocenter at the
R-position and the use of the zipper reaction of a 1-arylalkyne. This reaction has not been previously
reported with aromatic substrates. The synthesis strategy provides considerable flexibility for the
preparation of structural analogues.
Sch em e 1
Elenic acid (1) is an attractive synthetic target due to
its unusual structure among marine natural products
and its potent biological activity. Elenic acid was isolated
from the Indonesian sponge Plakinastrella sp. (0.012 wt
%) and characterized by Scheuer and co-workers in 1995.1
Elenic acid has been shown to display impressive cyto-
toxicity with an IC50 of 5 µg/mL in P-388, A-549, and
MEL-28 bioassays. In addition it inhibits topoisomerase
II, an indicator enzyme in the treatment of lung cancer,2
at 0.1 µg/mL. Such activity compares favorably with the
currently used clinical agents doxorubicin and etoposide.3
The first synthesis of elenic acid was reported recently
by Mori and co-workers.4 We have chosen a different
route for the enantiospecific construction of elenic acid
as shown in Scheme 1. Our synthesis is short and offers
potential for the preparation of analogues by varying any
of the four readily available building blocks used in the
preparation of the natural product itself, namely 4-io-
dophenol (2), 1-eicosyne (3), a metalated methane reagent
4, and methyl (R)-(+)-lactate (5). The synthesis is de-
signed to construct the alkynylphenol (6) and to elaborate
the â,γ-unsaturated acid moiety directly from this sub-
strate. The terminal three-carbon unit of elenic acid thus
originates from methyl (R)-(+)-lactate, available com-
mercially with 96% enantiomeric excess.
adduct 10 in 96% yield. Whitesell7 has shown that a
vinylalanate can displace a primary alkyl triflate for
effective carbon-carbon bond formation. Vinylalanates
have also been used as nucleophiles in carbon-carbon
bond formation with epoxides,8 enones,9 and carbonyl-
containing substrates.5 We have demonstrated for the
first time that this reaction can be used for the construc-
tion of a â,γ-unsaturated ester containing a stereocenter
at the R- and allylic position. Only the desired (E)-â,γ-
unsaturated ester was observed by 1H NMR and GC/MS
analyses. Isomerization of the double bond and/or epimer-
ization of the stereocenter was not observed (vide infra).
Hydrolysis of the ester 10 to the carboxylic acid 11 and
coupling of this acid with (S)- or (R)-R-methylbenzy-
lamine in the presence of dicyclohexylcarbodiimide and
dimethylaminopyridine gave the two expected amide
A model study was initially undertaken to assess the
feasibility and enantioselectivity of the proposed alkyne
elaboration sequence. (2S,3E)-Methyl 2,4-dimethyltet-
radec-3-enoate (10) was prepared as shown in Scheme
2. Negishi’s zirconium-catalyzed carboalumination of
1-dodecyne, 7, followed by treatment of the resulting
vinylalane with methyllithium generated the vinylalan-
ate 8 in situ.5 Reaction with triflate (S)-9,6 derived from
methyl (S)-(-)-lactate (97% ee), afforded the desired
1
diastereomers, (S,S)-12 and (S,R)-12. H NMR analysis
of the crude reaction products did not reveal the presence
of a minor diastereomer. GC/MS analysis definitively
(1) J uagdan, E. G.; Kalindindi, R. S.; Scheuer, P. J .; Kelly-Borges,
M. Tetrahedron Lett. 1995, 36, 2905-2908.
(2) D’Arpa, P.; Liu, L. F. Biochim. Biophys. Acta 1989, 989, 163-
177.
(3) Kasahara, K.; Fujiwara, Y.; Sugimoto, Y.; Nishio, K.; Tamura,
T.; Matsuda, T.; Saijo, N. J . Natl. Cancer Inst. 1992, 84, 113-118.
(4) Takanashi, S.; Takagi, M.; Takakawa, H.; Mori, K. J . Chem. Soc.,
Perkin Trans. 1 1998, 1603-1606.
(5) Okukado, N.; Negishi, E. I. Tetrahedron Lett. 1978, 2357-2360.
Negishi, E. I. Pure Appl. Chem. 1981, 53, 2333-2356.
(6) Feenstra, R. W.; Stokkingreef, E. H. M.; Nivard, R. J . F.;
Ottenheijm, H. C. J . Tetrahedron Lett. 1987, 28, 1215. Effenberger,
F.; Burkard, U.; Willfahrt, J . Liebigs Ann. Chem. 1986, 314. Vedejs,
E.; Engler, D. A.; Mullins, M. J . J . Org. Chem. 1977, 42, 3109.
(7) Whitesell, J . K.; Fisher, M.; J ardine, P. D. S. J . Org. Chem. 1983,
48, 1556-1557.
(8) Smith, A. B.; Hale, K. J . Tetrahedron Lett. 1989, 30, 1037-1040.
Matthews, R. S.; Milhelichm, E. D.; McGowan, L. S.; Daniels, K. J .
Org. Chem. 1983, 48, 409. Pfalz, A.; Mattenberger, A. Angew. Chem.,
Int. Ed. Engl. 1982, 21, 71.
(9) Wipf, P.; Smitrovich, J . H.; Moon, C. W. J . Org. Chem. 1992, 57,
3178-3186. Lipshutz, B. H.; Dimrock, S. H. J . Org. Chem. 1991, 56,
5761-5763. Ireland, R. E.; Wipf, P. J . Org. Chem. 1992, 57, 3178-
3186.
10.1021/jo982260t CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

Synthesis of Elenic Acid
Sch em e 2a
J . Org. Chem., Vol. 64, No. 7, 1999 2451
the presence of CuII and diisopropylamine proceeded
smoothly to give the internal alkyne 13 in 88% yield.
Isomerization to the terminal alkyne 6 was effected in
41% yield with KAPA in 1,3-diaminopropane.11 Alkyne
“zipper” reactions of an alkyne that is conjugated to an
aromatic ring are previously unreported.
Protection of the phenol 6 as the TBDPS ether afforded
the key intermediate 14 in 93% yield for elaboration of
the remaining functionality of elenic acid. Zirconium-
catalyzed carboalumination of 14, addition of methyl-
lithium, and alkylation with triflate (R)-9 afforded the
desired adduct 15 in 95% yield. Treatment of ester 15
with lithium hydroxide in aqueous tetrahydrofuran af-
forded elenic acid (1) directly. The synthetic elenic acid
was identical by comparison of 1H and 13C NMR, IR,
melting point, and optical rotation data to that reported
by Scheuer1 and by Mori.4 The (S)-(-)-enantiomer of
elenic acid ((S)-1) was also prepared by the reaction of
alkyne 14 with the triflate derived from methyl (S)-(-)-
lactate ((S)-9). It exhibited identical spectral properties
and the expected opposite sign of rotation.
A stereospecific synthesis of elenic acid has been
accomplished in five steps with an overall yield of 26%
from 1-eicosyne (3) and 4-iodophenol (2). The synthesis
involves a novel zipper reaction of a 1-arylalkyne and a
one-pot elaboration of a terminal alkyne to an (E)-â,γ-
unsaturated ester containing an R-stereocenter. This is
an attractive route for the preparation of structural
analogues.
a
Reagents, conditions, and yields: (a) (i) (CH3)3Al, Cp2ZrCl2,
(ii) CH3Li; (b) (i) (S)-9, (ii) saturated NaHCO3 (96%); (c) (i) LiOH,
THF, H2O, (ii) H3O+ (73%); (d) (i) DCC, DMAP, (ii) (S)-R-
methylbenzylamine (99% ee) (61%); (e) (i) DCC, DMAP, (ii) (R)-
R-methylbenzylamine (96% ee) (75%).
Sch em e 3a
Exp er im en ta l Section
Gen er a l Exp er im en ta l Deta ils. Flash chromatography
was performed using the indicated solvent system on EM
reagent silica gel 60 (230-400 mesh).12 THF was distilled from
sodium/benzophenone ketyl. Hexanes, DMF, CH2Cl2, and 1,2-
dichloroethane were distilled from CaH2. Diethylamine, diiso-
propylamine, 1,3-diaminopropane, and pyridine were distilled
from KOH and stored over 4 Å molecular sieves. Air- and/or
moisture-sensitive reactions were carried out under N2 or Ar
using oven-dried glassware and standard syringe/septa tech-
niques.
Met h yl
(S)-2-[[(Tr iflu or om et h yl)su lfon yl]oxy]p r o-
p a n oa te ((S)-9). Pyridine (1.42 mL, 17.6 mmol, 1.1 equiv) in
30 mL of CH2Cl2 was cooled to 0 °C, trifluoromethanesulfonic
anhydride (2.8 mL, 16.2 mmol, 1.05 equiv) was added, and the
resulting mixture was stirred 10 min. Methyl (S)-(-)-lactate
(1.53 mL, 16.0 mmol, 1 equiv) was added dropwise. The
reaction mixture was stirred at 0 °C for 30 min and then
warmed to room temperature. The mixture was filtered, and
the filter cake was washed with ether. The filtrate was
evaporated in vacuo (<25 °C), and the residue was triturated
with ether and filtered. The solvent was evaporated, and the
residue was passed through a short flash column (∼4 cm) with
ether. Evaporation of the solvent gave a colorless oil (2.68 g,
11.4 mmol, 71%).6 Molecular sieves were added to the product,
and it was stored at -10 °C.
(2S,3E)-Meth yl 2,4-Dim eth yltetr a dec-3-en oa te (10). Tri-
methylaluminum (2 M in hexanes, 1.2 mL, 2.4 mmol, 2.4
equiv) and zirconocene dichloride (292 mg, 1 mmol, 1 equiv)
were combined in 3 mL of 1,2-dichloroethane in a 25 mL
modified Schlenk flask, and the pale yellow solution was
stirred for 15 min. Dodecyne (7) (166 mg, 213 µL, 1 mmol, 1
equiv) was added, and the reaction mixture was stirred
overnight. Volatile material was removed in vacuo (0.5 mmHg),
and the residue was heated in vacuo at 50 °C for 30 min. The
yellow residue was washed twice with hexanes (2 and 1 mL
portions), and the hexane-soluble vinylalane was cannulated
a
Reagents, conditions, and yields: (a) (Ph3P)4Pd,CuI, i-Pr2NH,
RT, 15 h (88%); (b) KAPA, H2N(CH2)3NH2, 65 °C, 20 h (41%); (c)
TBDPSCl, DMAP, imidazole, RT, 15 h (93%); (d) (i) (CH3)3Al,
Cp2ZrCl2, 12 h; (ii) CH3Li, -40 °C; (iii) (R)-9, RT, 48 h; (iv)
NaHCO3 (95%); (f) LiOH, THF, H2O, 16 h (79%).
confirmed the enantiospecificity of the displacement
reaction.10
The success of the model study encouraged its applica-
tion to the synthesis of elenic acid (Scheme 3). 1-Eicosyne
(3) was prepared in 71% overall yield from 1-eicosene.
Bromination and dehydrobromination of the crude 1,2-
dibromoeicosane with LDA yielded 1-eicosyne (3). Pal-
ladium-catalyzed coupling of 3 with 4-iodophenol (2) in
(10) The two diastereomeric amides have the following GC retention
times: (S,S), 20.17 min; (S,R), 20.39 min. Examination of the TIC (total
ion chromatogram) of the crude amide (S,S)-12 showed the presence
of 1.2% of the (R,S) diastereomer. Examination of the TIC of the crude
amide (S,R)-12 showed the presence of 3.8% of the (S,S) diastereomer.
Considering the advertised enantiomeric purity of the starting materi-
als, this diastereomeric ratio confirms the absence of product racem-
ization under the reaction conditions.
(11) Abrams, S. R. Can. J . Chem. 1984, 62, 1333-1334.
(12) Still, W. C.; Lahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

2452 J . Org. Chem., Vol. 64, No. 7, 1999
Hoye et al.
into a 15 mL pear-shaped flask. The hexane solution was then
cooled to -40 °C, and methyllithium (1.4 M in ether, 0.75 mL,
1 equiv) was added. After stirring for 5 min, (S)-9 (510 mg,
2.5 mmol, 2.5 equiv) was added dropwise, and the solution was
allowed to warm gradually to room temperature. The reaction
mixture was stirred at room temperature for 48 h, then
quenched by the careful addition of 5 mL of saturated sodium
bicarbonate solution. The precipitated aluminum salts were
removed by vacuum filtration, and the filtrate was diluted with
10 mL of water and extracted with ether. The combined ether
extracts were washed with brine, dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatog-
raphy (SiO2, 2% ethyl acetate/hexanes) to yield the product
48.3, 40.0, 39.4, 31.7, 31.4, 29.4, 29.3, 20.2, 20.1, 29.0, 27.7,
22.4, 21.7, 17.7, 16.1, 13.8; GC/MS (m/ z) 357 (M+), 177, 105
(base), 69.
(R)-N-(r-Meth ylben zyl)-(2S,3E)-2,4-d im eth yltetr a d ec-
3-en a m id e [(S,R)-12]. By a similar procedure, the acid 11
(25 mg, 0.10 mmol, 1 equiv), dimethylaminopyridine (25 mg,
0.20 mmol, 2 equiv), dicyclohexylcarbodiimide (41 mg, 0.20
mmol, 2 equiv), and (R)-R-methylbenzylamine (30 µL, 0.20
mmol, 2 equiv) afforded after purification the corresponding
amide (S,R)-12 (27 mg, 0.075 mmol, 75%) as a colorless oil
that solidified on standing (mp 40.5-42.0 °C): IR (neat) 3286,
1
1641 cm-1; H NMR (300 MHz, CDCl3) δ 7.28 (m, 5H), 5.95
(d, J ) 7.3 Hz, 1H), 5.17 (d, J ) 8.8 Hz, 1H), 5.09 (quintet, J
) 7.4 Hz, 1H), 3.14 (dq, J ) 7.1, 8.7 Hz, 1H), 2.02 (t, J ) 7.7
Hz, 2H), 1.59 (s, 3H), 1.45 (d, J ) 6.8 Hz, 3H), 1.38 (m, 2H),
1.26 (br s, 14H), 1.14 (d, J ) 7.1 Hz, 3H), 0.88 (t, J ) 6.3, 3H);
13C NMR (75 MHz, CDCl3) 174.1, 143.7, 140.0, 128.8, 127.3,
126.2, 124.9, 48.4, 40.0, 39.4, 31.7, 31.3, 29.43, 29.40, 20.3, 29.1,
29.0, 27.7, 22.5, 21.6, 17.6, 16.1, 13.8; GC/MS (m/ z) 357 (M+)
177, 105 (base), 69.
RT
(258 mg, 0.96 mmol, 96%) as a colorless oil: [R]D ) +76.4 (c
) 11.67, CHCl3); IR (neat) 1742 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 5.14 (d, J ) 8.5 Hz, 1H), 3.67 (s, 3H), 3.34 (dq, J )
7.1, 9.1 Hz, 1H), 1.98 (t, J ) 7.8 Hz, 2H), 1.64 (s, 3H), 1.38
(quintet, J ) 7.0 Hz, 2H), 1.26 (s, 14H), 1.20 (d, J ) 7.1 Hz,
3H), 0.88 (t, J ) 6.2 Hz, 3H); 13C NMR (57 MHz, CDCl3) 176.4,
138.1, 123.6, 51.5, 39.3, 38.6, 31.7, 29.4, 29.3, 29.1, 28.9, 27.5,
22.4, 17.8, 15.9, 13.8; GC/MS (m/ z) 268 (M+), 236, 209, 181,
124, 88, 69 (base). Anal. Calcd for C17H32O2: C, 76.06; H, 12.02.
Found: C, 76.37; H, 12.11.
1-Eicosyn e (3). A solution of 1-eicosene (10.0 g, 0.036 mol,
1 equiv) in 150 mL of anhydrous ether was cooled to 0 °C.
Bromine (6.9 g, 2.2 mL, 0.043 mol, 1.2 equiv) was added
dropwise, and the reaction mixture was stirred at 0 °C for 30
min. It was then allowed to warm to room temperature and
was quenched by the addition of saturated aqueous sodium
bisulfite solution. The organic layer was separated, washed
with water and brine, dried (MgSO4), and concentrated to
afford 1,2-dibromoeicosane (15.82 g, 0.035 mol, 99%) as a white
solid that was subsequently used without purification. 1,2-
Dibromoeicosane (15.80 g, 0.035 mol, 1 equiv) in 100 mL of
THF at 0 °C was treated with a solution of lithium diisopro-
pylamide [prepared from diisopropylamine (40.2 mL, 0.288
mol, 8 equiv) and n-BuLi (2.5 M in THF, 57.6 mL, 0.144 mol,
4 equiv) in 50 mL of THF]. The reaction mixture was stirred
at 0 °C for 3 h and then gradually warmed to room temper-
ature and stirred overnight. The reaction was then quenched
with water (100 mL) and extracted with ether. The combined
ether extracts were washed with 1 M HCl, water, and brine,
dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography in three batches (SiO2, hexanes)
gave the product (7.11 g, 0.025 mol, 71%) as a colorless oil.13
1-(4-Hyd r oxyp h en yl)-1-eicosyn e (13). Tetrakis(triphe-
nylphosphine)palladium(0) (500 mg, 0.43 mmol, 0.02 equiv)
and copper(I) iodide (250 mg, 1.3 mmol, 0.07 equiv) were added
to 25 mL of diisopropylamine in a 100 mL round-bottomed
flask. The solution was stirred for 5 min, then 4-iodophenol, 2
(4.75 g, 21.6 mmol, 1.2 equiv), was added in one portion. After
stirring for an additional 15 min, a solution of eicosyne (3) (5.00
g, 18 mmol, 1 equiv) in 25 mL of diisopropylamine was added
dropwise. The reaction mixture was stirred overnight at room
temperature, quenched by the addition of 10 mL of saturated
aqueous potassium carbonate and 10 mL of saturated aqueous
ammonium chloride, and diluted with 50 mL of water. The
resulting solution was extracted with ether. The combined
organic extracts were washed with 10% HCl, water, and brine,
dried (MgSO4), filtered, and concentrated. Chromatography
(SiO2, 10% ethyl acetate/hexanes) in three batches gave the
internal alkyne 13 (5.86 g, 15.8 mmol, 88%) as a white solid:
mp 71-72 °C; IR (KBr) 3418, 1607 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.29 (d, J ) 8.5 Hz, 2H), 6.75 (d, J ) 8.5 Hz, 2H),
2.38 (t, J ) 7, 2H), 1.59 (quintet, J ) 7, 2H), 1.26 (br s, 30H),
0.88 (t, J ) 7, 3H); 13C NMR (75 MHz, CDCl3) 155.9, 139.2,
133.2, 115.5, 88.6, 80.3, 31.9, 29.5, 29.4, 29.1, 29.0, 28.7, 22.5,
19.9, 19.2 , 13.9; GC/MS (m/ z) 370 (M+), 187, 174, 133 (base),
131, 107, 77, 55. Anal. Calcd for C26H42O: C, 84.26; H, 11.42.
Found: C, 84.17; H, 11.77.
(2R,3E)-Meth yl 2,4-Dim eth yltetr a d ec-3-en oa te. By a
similar procedure, trimethyl aluminum (2 M in hexanes, 3.6
mL, 7.2 mmol, 2.4 equiv) and zirconocene dichloride (876 mg,
3 mmol, 1 equiv) were combined in 5 mL of 1,2-dichloroethane.
Dodecyne (834 mg, 3 mmol, 1 equiv) was added. The resulting
vinylalane was transferred from the solid residue using
hexanes (2 × 2 mL). The hexane extracts were cooled to -40
°C and treated with methyllithium (1.4 M in diethylether, 2.14
mL, 3 mmol, 1 equiv), and (R)-9 (800 mg, 3.9 mmol, 1.3 equiv).
Workup and chromatography gave the desired product as a
25
colorless oil (767 mg, 2.2 mmol, 73%), [R]D ) -74.23 (c )
9.38, CHCl3).
(2S,3E)-2,4-Dim eth yltetr a d ec-3-en oic Acid (11). A solu-
tion of the ester 10 (181.0 mg, 0.67 mmol, 1 equiv) and LiOH
(274 mg, 6.70 mmol, 10 equiv) in aqueous THF (2 mL THF, 1
mL H2O) was stirred overnight at room temperature. After
removal of the THF on the rotovap, the reaction mixture was
diluted with 10 mL of water and acidified with 10% HCl. The
aqueous solution was extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried
(MgSO4), filtered, and concentrated. The residue was purified
by MPLC (SiO2, 10% ethyl acetate/hexanes) to afford 11 as a
RT
colorless oil (123.8 mg, 0.48 mmol, 73%): [R]D ) +70.81 (c
) 9.71, CHCl3); IR (neat) 3500-2500 (br), 1708 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.15 (d, J ) 9.1 Hz, 1H), 3.36 (dq, J )
7.1, 9.1 Hz, 1H), 1.99 (t, J ) 7.1 Hz, 2H), 1.66 (s, 3H), 1.39
(quintet, J ) 6.2 Hz, 2H), 1.26 (br s, 14H), 1.23 (d, J ) 7.1 Hz,
3H), 0.88 (t, J ) 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
182.4, 138.9, 123.0, 39.4, 38.6, 31.8, 29.5, 29.3, 29.2, 29.0, 27.5,
22.5, 17.6, 16.1, 13.9; GC/MS (m/ z) 254 (M+), 181, 128, 97, 83
(base). Anal. Calcd for C16H30O2: C, 75.54; H, 11.89. Found:
C, 75.76; H, 11.95.
(S)-N-(r-Meth ylben zyl)-(2S,3E)-2,4-d im eth yltetr a d ec-
3-en a m id e [(S,S)-12]. Acid 11 (47 mg, 0.18 mmol, 1 equiv),
dimethylaminopyridine (44 mg, 0.36 mmol, 2 equiv), and
dicyclohexylcarbodiimide (74 mg, 0.36 mmol, 2 equiv) were
dissolved in 1.0 mL of CH2Cl2 and treated with (S)-R-methyl-
benzylamine (50 µL, 0.36 mmol, 2 equiv). The reaction mixture
was stirred overnight at room temperature, then eluted
through a plug of SiO2 with additional CH2Cl2. Evaporation
of the solvent and purification of the residue by flash chro-
matography (SiO2, 10% ethyl acetate/hexanes) gave the amide
(40 mg, 0.11 mmol, 61%) as a colorless oil that solidified on
standing (mp 43.5-44.0 °C): IR (neat) 3286, 1636 cm-1 1H
;
20-(4-Hyd r oxyp h en yl)-1-eicosyn e (6). Lithium wire (567
mg, 81 mmol, 30 equiv) was added to 40 mL of 1,3-diamino-
propane in a 100 mL two-necked pear flask. The solution was
heated at 80 °C for 2 h until the blue color had discharged
NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 5.95 (d, J ) 7.4 Hz,
1H), 5.15 (d, J ) 8.1 Hz, 1H), 5.09 (quintet, J ) 7.4 Hz, 1H),
3.18 (dq, J ) 7.1, 8.7 Hz, 1H), 2.02 (t, J ) 7.4 Hz, 2H), 1.65 (s,
3H), 1.45 (d, J ) 7.0 Hz, 3H), 1.38 (m, 2H), 1.25 (br s, 14H),
1.20 (d, J ) 8.1 Hz, 3H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) 174.0, 143.6, 139.9, 128.8, 127.3, 126.1, 124.9,
(13) Huang, H. C.; Rehmann, J . K.; Gray, G. R. J . Org. Chem. 1982,
47, 4018-4021.

Synthesis of Elenic Acid
J . Org. Chem., Vol. 64, No. 7, 1999 2453
and the white lithium salt was evident. The reaction mixture
was cooled to room temperature, and potassium tert-butoxide
(7.90 g, 64.8 mmol, 24 equiv) was added in one portion. The
resulting yellow solution was stirred for 15 min. A solution of
the internal alkyne (1.00 g, 2.7 mmol, 1 equiv) in 5 mL of 1,3-
diaminopropane was added dropwise, and the blood-red solu-
tion was heated at 65 °C overnight. The resulting brown
solution was cooled to room temperature and then in an ice
bath and quenched with saturated aqueous ammonium chlo-
ride. The resulting mixture was poured into 100 mL of water
and acidified with 105 mL of concentrated HCl. This mixture
was then extracted with chloroform. Evaporation of the
chloroform, addition of 100 mL of benzene, and subsequent
evaporation afforded a tan solid that was adsorbed onto SiO2
and added to the top of a chromatography column. Flash
chromatography (10% ethyl acetate/hexanes) gave the product
(408 mg, 1.10 mmol, 41%) as a white solid: mp 70.3-70.6 °C;
IR (KBr) 3414, 3300 cm-1; 1H NMR (300MHz, CDCl3) 7.17 (d,
J ) 8.5 Hz, 2H), 6.76 (d, J ) 8.5 Hz, 2H), 4.66 (br s, 1H), 2.54
(t, J ) 7.0 Hz, 2H), 2.19 (dt, J ) 2.5, 7.0 Hz, 2H), 1.95 (t, J )
2.5 Hz, 1H), 1.57 (m, 4H), 1.26 (br s, 28H); 13C NMR (75 MHz,
CDCl3) 130.8, 129.6, 127.6, 115.7, 115.2, 67.9, 34.9, 31.6, 29.5,
28.93, 28.59, 28.3, 18.2; GC/MS (m/ z) 370 (M+), 354, 281, 207,
133, 120, 107 (base). Anal. Calcd for C26H42O: C, 84.26; H,
11.42. Found: C, 84.29; H, 11.79.
20-(4-ter t-Bu tyld ip h en ylsiloxyp h en yl)-1-eicosyn e (14).
The phenol 6 (426 mg, 1.15 mmol, 1 equiv), imidazole (156
mg, 2.3 mmol, 2 equiv), and 4-dimethylaminopyridine (140 mg,
1.15 mmol, 1 equiv) were combined in 5 mL of DMF. tert-
Butylchlorodiphenylsilane (397 µL, 1.72 mmol, 1.5 equiv) was
added dropwise. The reaction mixture was stirred overnight
and then quenched by the addition of 5 mL of saturated
aqueous sodium bicarbonate. The reaction mixture was diluted
with 30 mL of water and extracted with ether. The combined
ether extracts were washed with water and brine, dried
(MgSO4), filtered, and evaporated. Purification of the residue
by MPLC (hexanes) afforded the product as a colorless oil (682
mg, 1.11 mmol, 97%) that crystallized on standing: mp 52-
53 °C; IR (neat) 3311, 1608 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.71 (d, J ) 6.4 Hz, 4H), 7.45 (m, 6H), 6.88 (d, J ) 8.4 Hz,
2H), 6.60 (d, J ) 8.4 Hz, 2H), 2.45 (t, J ) 7.6 Hz, 2H), 2.18
(dt, J ) 2.5, 7.0 Hz), 1.94 (t, J ) 2.5 Hz), 1.54-1.33 (m, 4H),
1.24 (br s, 24H), 1.09 (s, 9H); 13C NMR (75 MHz, CDCl3) 153.72,
135.79, 135.57, 133.47, 129.96, 129.15, 127.88, 119.49, 84.84,
67.98, 34.94, 31.41, 29.51, 29.34, 29.10, 28.95, 28.61, 28.35,
26.39, 18.20. Anal. Calcd for C42H60OSi: C, 82.83; H, 9.93.
Found: C, 83.12; H, 10.03.
temperature. The reaction mixture was stirred at room tem-
perature for 20 h, then quenched by the careful addition of
saturated sodium bicarbonate solution. The precipitated alu-
minum salts were removed by vacuum filtration, and the
filtrate was diluted with 10 mL of water and extracted with
ether. The combined ether extracts were washed with brine,
dried (MgSO4), filtered, and concentrated. The residue was
purified by chromatography (SiO2, 2% ethyl acetate/hexanes)
to yield the product (407 mg, 0.57 mmol, 95%) as a colorless
RT
oil: [R]D ) -27.7 (c ) 10.48, CHCl3); IR (neat) 1749 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.69 (d, J ) 6.5 Hz, 4H), 7.36
(m, 6H), 6.86 (d, J ) 8.3 Hz, 2H), 6.64 (d, J ) 8.3 Hz, 2H),
5.12 (d, J ) 9.1 Hz, 1H), 3.64 (s, 3H), 3.31 (dq, J ) 7.1, 9.1
Hz, 1H), 2.43 (t, J ) 7.5 Hz, 2H), 1.95 (t, J ) 7.1 Hz, 2H), 1.58
(s, 3H), 1.48 (quintet, J ) 6.0 Hz, 2H), 1.35 (quintet, J ) 6.1
Hz, 2H), 1.22 (br s, 28H), 1.17 (d, J ) 6.9 Hz, 3H), 1.07 (s,
9H); 13C NMR (75 MHz, CDCl3) 153.7, 138.0, 135.5, 133.4,
129.9, 129.1, 128.1, 127.8, 123,7, 119.5, 51.5, 39.3, 38.6, 34.9,
31.4, 29.5, 29.3, 29.1, 28.9, 27.5, 26.4, 19.2, 17.8, 15.9. Anal.
Calcd for C47H70O3Si: C, 79.38; H, 9.92. Found: C, 79.59; H,
10.10.
(R)-(-)-Elen ic Acid (1). Ester 16 (210 mg, 0.29 mmol, 1
equiv) was dissolved in 2 mL of THF under argon. Lithium
hydroxide, monohydrate (237 mg, 5.8 mmol, 20 equiv), and 2
mL of water were added, and the reaction mixture was stirred
overnight at room temperature. THF was removed in vacuo,
and the remaining solution was diluted with 5 mL of water,
acidified with 10% HCl, and extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried
(MgSO4), filtered, and evaporated to yield a crude product that
was purified by flash chromatography (SiO2, 30% ethyl acetate/
hexanes). Elenic acid was obtained as a white amorphous solid
25
(105 mg, 0.22 mmol, 79%), [R]D ) -31 (c ) 0.31, CHCl3),
whose mp, IR, 1H NMR, and 13C NMR data duplicate that
reported by Mori4 and by Scheuer.1
(S)-(+)-Elen ic Acid . Alkyne 15 (320 mg, 0.53 mmol, 1
equiv) was treated in a manner analogous to the preparation
of ester 17, with trimethylaluminum (2 M in hexanes, 0.53
mL, 2 equiv), zirconocene dichloride (154.7 mg, 0.53 mmol, 1
equiv), methyllithium (1.4 M in ether, 0.38 mL, 0.53 mmol, 1
equiv), and (S)-9 (270 mg, 1.32 mmol, 2.5 equiv). The crude
product was purified by chromatography (SiO2, 2% ethyl
acetate/hexanes) to yield the desired ester (233 mg, 0.33 mmol,
61%) as a colorless oil, [R]D25 ) +28.7 (c ) 8.73, CHCl3), which
1
was identical to 16 by H and 13C NMR and IR spectroscopy.
The (S)-ester (121 mg, 0.17 mmol, 1 equiv) was treated with
lithium hydroxide monohydrate (139 mg, 3.4 mmol, 20 equiv)
in 2 mL of 1:1 aqueous tetrahydrofuran to afford (S)-(+)-elenic
acid (59.5 mg, 0.13 mmol, 76%) as a white amorphous solid,
(2R,3E)-Meth yl 22-(4-ter t-Bu tyld ip h en ylsiloxyp h en yl)-
2,4-d im eth yld ocos-3-en oa te (15). Trimethylaluminum (2 M
in hexanes, 0.72 mL, 1.44 mmol, 2.4 equiv) and zirconocene
dichloride (175.2 mg, 0.60 mmol, 1 equiv) were combined in 2
mL of 1,2-dichloroethane in a 25 mL modified Schlenk flask,
and the pale yellow solution was stirred for 15 min. Alkyne
15 (370 mg, 0.60 mmol, 1 equiv) dissolved in 1 mL of
1,2-dichloroethane was added via cannula, and the reaction
mixture was stirred overnight. Volatile material was removed
in vacuo (0.5 mmHg), and the residue was heated in vacuo at
50 °C for 30 min. The yellow residue was washed twice with
hexanes (2 and 1 mL portions). The hexane-soluble vinylalane
was cannulated into a 15 mL pear-shaped flask. The hexane
solution was then cooled to -40 °C, and methyllithium (1.4 M
in ether, 0.43 mL, 0.60 mmol) was added. After stirring for 5
min, (R)-9 (388 mg, 1.9 mmol, 3.1 equiv) was added dropwise,
and the solution was allowed to warm gradually to room
25
[R]D ) +32 (c ) 0.36, CHCl3), otherwise spectroscopically
identical to (R)-(-)-elenic acid.
Ack n ow led gm en t. This research was financially
supported by a Bristol-Myers Squibb Company Award
of Research Corporation. M.E.D. and H.A.R. thank
Macalester College for a summer stipend from the Violet
Olson Beltmann Fund. A.A.P. thanks the Howard
Hughes Medical Institute for a summer stipend (Grant
No. 71196-5044020). We thank Professor P. J . Scheuer
for copies of the 1H and 13C NMR spectra of natural
elenic acid.
J O982260T