Studies on the synthesis of elegan-type linear diterpenes: The efficient total syntheses of eleganolone, eleganolone acetate, elegandiol, eleganonal, and epoxyeleganolone

Article abstract of DOI:10.1021/np970227g

The first total syntheses of five elegan-type linear diterpenes- eleganolone (1), eleganolone acetate (2), elegandiol (3), eleganonal (4), and epoxyeleganolone (5)-were accomplished starting from (E,E)-farnesol (6) via four to six steps, successively, with high overall yield. The key step was the alkylation reaction of silyl cyanide with allylic iodide.

Full text of DOI:10.1021/np970227g

92
J . Nat. Prod. 1998, 61, 92-95
Stu d ies on th e Syn th esis of Elega n -Typ e Lin ea r Diter p en es: Th e Efficien t Tota l
Syn th eses of Elega n olon e, Elega n olon e Aceta te, Elega n d iol, Elega n on a l, a n d
Ep oxyelega n olon e
J ing Li, J iong Lan, Zuosheng Liu, and Yulin Li*
National Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University,
Lanzhou 730000, People’s Republic of China
Received May 2, 1997X
The first total syntheses of five elegan-type linear diterpenesseleganolone (1), eleganolone
acetate (2), elegandiol (3), eleganonal (4), and epoxyeleganolone (5)swere accomplished starting
from (E,E)-farnesol (6) via four to six steps, successively, with high overall yield. The key step
was the alkylation reaction of silyl cyanide with allylic iodide.
Previous studies on the pharmacological activity of
Cystoseira brachycarpa (J . Agardh) var. balearica
(Sauv.) Giaccone,1 Cystoseira elegans, and Bifurcaria
bifurcata2 have found that these Mediterranean Sea
algae demonstrate many significant biological activities
such as antiviral and antimicrobial activities, vasodi-
lating effects, and antihypertensive activity. For this
reason, chemical studies on these marine algae have
developed rapidly, and since eleganolone (1) was first
isolated nearly 20 years ago,3 many more such elegan-
type acyclic diterpenes or sesquiterpenes have been
isolated as natural products.3-7 Five typical compounds
of this kind have been isolated: eleganolone (1) from
C. elegans,3 B. bifurcata,5 and Cystoseira balearica;4
eleganolone acetate (2) from C. balearica;4 elegandiol
(3) from B. bifurcata;5 eleganonal (4) from C. balearica;6
and epoxyeleganolone (5) from B. bifurcata.5
Furthermore, 1 and 2 dose dependently relaxed the
same preparations precontracted with 300 mM BaCl2
(pIC50 ) 4.34 ( 0.18 for 1, and pIC50 ) 4.34 ( 0.02 for
2) or with 60 mM KCl (pIC50 ) 4.73 ( 0.18 and 4.47 (
0.06, respectively).1 These pharmacological results sup-
port the hypothesis of an antihypertensive activity of
the brown alga C. balearica as found in other algae
belonging to different genera. This effect could be the
result of a direct relaxing effect on arterial smooth
muscle together with an inhibitory activity on the
cardiac inotropism stimulated by adrenergic agonists.
It was further proved that these diterpenoids show a
higher efficiency with respect to the previous fractions
because the active principles in the crude mixture are
diluted with other compounds.2
The geometrical configurations of these compounds
have been elucidated by spectral analysis and chemical
correlations, but the absolute stereochemistry of elegan-
diol 3 and epoxyeleganolone 5 has not yet been deter-
mined, and no synthetic work on these significant
compounds has yet been reported. To verify the struc-
tures of these compounds and to determine their
absolute configuration, and furthermore, to do further
research on the pharmacological activities of these
compounds, we explored the total synthesis of com-
pounds 1-5, and herein provide details of this work.
Our strategy started with (E,E)-farnesol (6). Acyla-
tion of 6 with Ac2O,8 followed by selective oxidation of
the terminal E methyl group, gave alcohol 7,9 which can
be transformed into iodide 8.10 The key step was the
alkylation reaction11 of allylic iodide 8 with silyl cyanide
9, which was conveniently prepared from 3-methyl-2-
buten-1-ol (10) through two steps (oxidation with active
12
MnO2 and cyanosilation with Me3SiCN13 in the pres-
The pharmacological tests indicated that these com-
pounds exhibited significant bioactive effects, such as
blocking the isoprenaline inotropic activity,2 inhibiting
the contractile activities of acetylcholine and histamine
on ileum musculature. The relative pIC50 values of 1
were found to be 4.60 ( 0.03 and 4.84 ( 0.20, while
those of 2 were 4.71 ( 0.18 and 5.18 ( 0.01, respectively.
ence of a catalytic amount of KCN/18-crown-6). Depro-
tection of silyl cyanide 11 with a catalytic amount of
n-Bu4N+F- afforded the first title compound (2), which
was hydrolyzed to obtain compound 1. Finally, com-
pounds 3, 4, and 5 were easily prepared from compound
1 by reduction with NaBH4 to give 3, oxidation with
active MnO2 to give 4, and asymmetric Sharpless
epoxidation to give 5. In the asymmetric Sharpless
epoxidation of compound 1, we used D-(-)-DET as the
chiral inducer. Therefore, the absolute configuration of
* To whom correspondence should be addressed. Phone: (+86) 931-
8912595. FAX: (+86) 931-8911100. E-mail: liyl@lzu.edu.cn.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
S0163-3864(97)00227-9 CCC: $15.00
© 1998 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/23/1998

Notes
J ournal of Natural Products, 1998, Vol. 61, No. 1 93
Sch em e 1a
a
Key: (a) Ac2O, Py, DMAP, room temperature, 30 min, 100%; (b) SeO2, t-BuOOH, room temperature, 2 h, 37%; (c) Ph3P, imidazole, I2,
Et2O/CH3CN, 0 °C, 100%; (d) MnO2, n-hexane, 20 h, 70%; (e) Me3SiCN, 18-crown-6/KCN, CH2Cl2, 0 °C, 100%; (f) (Me3Si)2NLi, 9, -78 °C,
40 min, then 8, -78 °C, 2 h, 39%; (g) catalytic amount of n-Bu4N+F-, 10% aqueous THF, Ar, room temperature, 15 h, 50%; (h) K2CO3,
MeOH, room temperature, 2 h, 100%; (i) MnO2, n-hexane, 10 h, 92%; (j) NaBH4, MeOH, 80%; (k) Ti(OiPr)4, D-(-)-DET, TBHP, CH2Cl2,
76%.
the final product 5, whose optical rotation has been
determined as [a]D -101 (c 0.055, CHCl3), should be
(2R, 3R). See Scheme 1.
In summary, we succeeded in obtaining eleganolone
(1), eleganolone acetate (2), elegandiol (3), eleganonal
(4), and epoxyeleganolone (5) in four to six steps from
(E,E)-farnesol. We have also determined that the
absolute configuration of (-)-epoxyeleganolone is (2R,
3R).
Ac2O (5 mL) was added dropwise at 0 °C with vigorous
stirring. Stirring was continued at room temperature
for 30 min until the reaction was complete. The
resulting mixture was diluted with H2O (10 mL) and
extracted with Et2O (50 mL × 3), the combined organic
layer was washed with 10% HCl aqueous solution, H2O,
and brine, then dried. Evaporation of the solvent
followed by purification on Si gel afforded farnesol acetyl
acetate (13 g, 100%), which was dissolved in CH2Cl2 (20
mL) and added dropwise to a clear solution of SeO2 (555
mg, 5 mmol) and t-BuOOH (70%, 13.7 mL, 100 mmol)
in CH2Cl2 (150 mL) at 0 °C. After being stirred at room
temperature for 2 h, the reaction mixture was diluted
with Et2O (200 mL) and washed sequentially with 10%
aqueous KOH, H2O, and brine, then dried and concen-
trated. The resulting oil was purified by flash column
chromatography on Si gel to yield alcohol 7 (4.88 g, 37%)
as a colorless oil: IR (film) νmax 3446 (s, OH), 1740 (s,
CdO) cm-1; 1H NMR (CDCl3, 80 MHz) δ 4.95-5.35 (3H,
m, CHd), 4.59 (2H, d, J ) 7.1 Hz, CH2OAc), 3.98 (2H,
s, CH2O), 2.00-2.45 (8H, m, 4CH2), 2.04 (3H, s, CH3-
CO), 1.71 (3H, s, CH3), 1.67 (3H, s, CH3), 1.61 (3H, s,
CH3); anal. C 72.70%, H 10.10%, calcd for C17H28O3, C
72.82%, H 10.06%.
3-Meth yl-2-bu ten a l (12). A suspension of 3-methyl-
2-butenol (10) (2 mL, 20 mmol) and MnO2/SiO2 (2:1, 13
g) in n-hexane (50 mL) was vigorously stirred at room
temperature for 20 h before being diluted with Et2O (50
mL). The mixture was filtered through a short column
on Si gel to remove MnO2, and the resulting filtrate was
concentrated and purified to give enal 12 (1.17 g, 70%)
as a clear oil: 1H NMR (CDCl3, 80 MHz) δ 9.89 (1H, d,
J ) 5.6 Hz, CHO), 5.93 (1H, d, J ) 8.2 Hz, dCH), 2.25
(3H, s, CH3), 2.05 (3H, s, CH3).
20
Exp er im en ta l Section
Gen er al Exper im en tal P r ocedu r es. 1H-NMR spec-
tra were recorded on a Varian FT-80A or Bruker AM-
400 spectrometer, and 13C-NMR spectra were recorded
at 100 MHz in CDCl3 solution using TMS as internal
reference. IR spectra were obtained as films using a
FT-170SX spectrophotometer. Mass spectra were mea-
sured on a VG ZAB-HS spectrometer by direct inlet at
70 eV, and signals are given in m/z with relative
intensity (%) in brackets. Optical rotation measure-
ments were carried out on a Perkin-Elmer 141 pola-
rimeter. All solvents were freshly purified and dried
by standard techniques prior to use. All reactions were
routinely carried out under an inert atmosphere of Ar
and monitored by TLC. Purification of products were
conducted by flash column chromatography on Si gel
(200-300 mesh) purchased from Qing Dao Marine
Chemical Co. (E,E)-Farnesol and 3-methyl-2-buten-1-
ol were purchased from Aldrich Chemical Co. In the
workup, all organic phases were washed with H2O and
brine, respectively, then dried (MgSO4) and filtered prior
to rotary evaporation of the solvent under reduced
pressure.
3,7,11-Tr im eth yl-12-h ydr oxy-2(E),6(E),10(E)-dode-
ca tr ien -1-ol Acetyl Aceta te (7). To a solution of
(E,E)-farnesol 6 (11.1 g, 50 mmol) and a catalytic
amount of DMAP in pyridine (2.15 mL), freshly distilled
3,7,11,15-Tetr a m eth yl-13-cya n o-13-(tr im eth ylsi-
loxy)-2(E),6(E),10(E),14-h exadecatetr aen -1-ol Acetyl
Aceta te (11). A catalytic amount of KCN and 18-

94 J ournal of Natural Products, 1998, Vol. 61, No. 1
Notes
crown-6 complex was first added to enal 12 (84 mg, 1
mmol) in CH2Cl2 (1 mL) with stirring, then Me3SiCN
(0.18 mL, 1.2 mmol) was added dropwise to the suspen-
sion at 0 °C under argon atmosphere. The reaction was
complete within 30 min and gave silyl cyanide 9, which
was used in situ without further purification. To a
stirred clear solution of 7 (280 mg, 1 mmol), Ph3P (393
mg, 1.5 mmol) and imidazole (102 mg, 1.5 mmol) in a
mixed solvent of CH3CN (2 mL) and Et2O (3 mL) was
added iodine crystals portionwise at 0 °C (ice-water
bath) until the reaction was complete. After being
stirred for an additional 30 min at room temperature,
the reaction mixture was diluted with Et2O (20 mL) and
washed with saturated Na2S2O3 aqueous solution, H2O,
and brine, then dried. The solvent was removed in
vacuo and the crude oil was purified by chromatography
to afford iodide 8, which was dissolved in anhydrous
THF (2 mL) and used for the followed procedure. To a
clear solution of LiN(SiMe3)2 (1.5 mmol) in anhydrous
THF (5 mL) was syringed dropwise a solution of silyl
cyanide 9 (183 mg, 1 mmol) in anhydrous THF (2 mL)
at -78 °C under an argon atmosphere, and the reaction
mixture was stirred at that temperature for a further
40 min. The above solution of allylic iodide 8 in THF
(2 mL) was then added dropwise to the reaction mixture
with efficient stirring. The stirring was continued for
2 h at -78 °C before the reaction was quenched by the
addition of saturated aqueous NH4Cl and Et2O (30 mL).
The organic phase was washed with H2O and brine,
then dried and concentrated. The residue was purified
on Si gel to afford silyl cyanide 11 (173 mg, 39%) as a
clear oil: 1H NMR (CDCl3, 80 MHz) δ 4.95-5.50 (4H,
m, dCH), 4.62 (2H, d, J ) 6.5 Hz, CH2OAc), 1.40-2.50
(10H, m, 5CH2), 2.10 (3H, s, COCH3), 2.17 (3H, s, CH3),
2.09 (3H, s, CH3), 1.75 (6H, s, 2CH3), 1.65 (3H, s, CH3),
0.18 (6H, s, 2CH3), 0.12 (3H, s, CH3); anal. C 70.29%,
H 9.65%, calcd for C26H43O3SiN, C 70.06%, H 9.72%.
purification of the crude residue by flash column chro-
matography afforded eleganolone (1) (42 mg, 100%) as
a clear oil: IR (film) νmax 3427 (s), 3382 (s), 2965 (s),
2919 (s), 1736, 1683 (s), 1618, 1442, 1380, 1004 (s), 841
1
cm-1; H NMR (CDCl3, 400 MHz) δ 6.12 (1H, s, dCH),
5.42 (1H, t, J ) 7.1 Hz, dCH), 5.24 (1H, t, J ) 7.1 Hz,
dCH), 5.12 (1H, m, dCH), 4.16 (2H, d, J ) 6.9 Hz,
CH2O), 3.03 (2H, s, CH2CO), 2.14 (3H, s, CH3), 1.95-
2.14 (8H, m, 4CH2), 1.88 (3H, s, CH3), 1.68 (3H, s, CH3),
1.62 (3H, s, CH3), 1.60 (3H, s, CH3); 13C NMR (CDCl3,
100 MHz) δ 198.2, 154.6, 139.8, 135.1, 129.2, 128.4,
124.1, 123.5, 122.9, 59.4, 55.4, 39.5, 39.4, 27.8, 26.8,
26.3, 20.8, 16.3, 16.1, 16.0; EIMS m/z 304 [M]+ (1), 286
(1), 205 (1), 188 (2), 149 (3), 121 (4), 83 (100), 67 (6), 55
(11); anal. C 79.08%, H 10.54%, calcd for C20H32O2, C
78.90%, H 10.59%.
Elega n on a l (4). A suspension of eleganolone (1) (15
mg, 0.05 mmol) and MnO2/SiO2 (2:1, 65 mg, 0.5 mmol)
in n-hexane (2 mL) was stirred at room temperature
for 10 h and then diluted with Et2O. The mixture was
filtered through a short column of Si gel, and the
resulting filtrate was concentrated on a rotatory evapo-
rator in vacuo to give the crude oil that was purified on
Si gel to yield eleganonal (4) (13 mg, 92%) as a colorless
oil: IR (film) νmax 2920 (s), 1676 (s), 1620 (s), 1516, 1438,
1381, 1110, 1049, 981 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 10.00 (1H, d, J ) 8.0 Hz, CHO), 6.11 (1H, s, dCH),
5.89 (1H, d, J ) 8.1 Hz, dCH), 5.23 (1H, m, dCH), 5.10
(1H, t, J ) 6.7 Hz, dCH), 3.04 (2H, s, CH2CO), 2.17
(3H, s, CH3), 2.15 (3H, s, CH3), 2.00-2.45 (8H, m, 4CH2),
1.88 (3H, s, CH3), 1.70 (3H, s, CH3), 1.62 (3H, s, CH3);
13C NMR (CDCl3, 100 MHz) δ 193.8, 191.3, 163.9, 156.5,
136.7, 128.7, 128.1, 127.5, 123.0, 122.9, 55.4, 40.6, 39.5,
27.8, 26.8, 25.7, 20.8, 17.6, 16.4, 16.1; EIMS m/z 302
[M]+ (1), 219 (1), 186 (2), 151 (2), 121 (1), 109 (2), 91
(2), 83 (100), 67 (4), 55 (9); anal. C 79.21%, H 10.06%,
calcd for C20H30O2, C 79.42%, H 10.00%.
Elega n olon e Aceta te (2). Silyl cyanide 11 (155 mg,
0.35 mmol) was dissolved in 10% aqueous THF (5 mL)
and a catalytic amount of n-Bu4N+F- was added. The
reaction mixture was stirred at room temperature under
an argon atmosphere for 15 h. The resulting mixture
was extracted with Et2O (20 mL × 3), and the combined
organic phases were washed with H2O and brine, then
dried. Evaporation of the solvent followed by purifica-
tion by chromatography gave ketone 2 (60 mg, 50%) as
a colorless oil: IR (film) νmax 2965 (s), 2932 (s), 1739
Elega n d iol (3). To an ice-cooled solution of 1 (9 mg,
0.03 mmol) in dry MeOH (0.5 mL) was added NaBH4
portionwise at 0 °C with stirring until the reaction was
complete. The resulting mixture was diluted with H2O
and extracted with Et2O (10 mL × 4). The organic layer
was washed with H2O and brine and dried. Evaporation
of the solvent in vacuo gave an oily residue, which was
chromatographed on Si gel to yield diol 3 (7 mg, 80%)
as a clear oil: IR (film) νmax 3322 (s), 2963 (s), 2923 (s),
1720, 1669, 1449, 1378, 1006, 838 cm-1 1H NMR
;
(s), 1687 (s), 1620, 1449, 1380, 1232, 1024, 954 cm-1
;
(CDCl3, 400 MHz) δ 5.42 (1H, m, dCH), 5.21 (1H, m,
dCH), 5.11 (2H, m, 2CHd), 4.44 (1H, m, CHOH), 4.15
(2H, d, J ) 6.9 Hz, CH2OH), 1.99-2.11 (10H, m, 5CH2),
1.75 (3H, s, CH3), 1.73 (3H, s, CH3), 1.69 (3H, s, CH3),
1.68 (3H, s, CH3), 1.60 (3H, s, CH3); 13C NMR (CDCl3,
100 MHz) δ 139.2, 135.2, 135.0, 131.6, 128.5, 127.4,
124.5, 123.6, 65.6, 59.4, 48.2, 39.8, 39.5, 26.4, 26.2, 25.8,
18.2, 16.2, 16.1, 16.0; EIMS m/z 222 (1), 204 (4), 189
(21), 175 (4), 161 (9), 136 (9), 121 (17), 107 (15), 93 (22),
85 (100), 68 (15); anal. C 78.53%, H 11.14%, calcd for
C20H34O2, C 78.38%, H 11.18%.
1H NMR (CDCl3, 400 MHz) δ 6.12 (1H, s, dCH), 5.34
(1H, t, J ) 7.24 Hz, CHd), 5.25 (1H, t, J ) 7.0 Hz,
dCH), 5.11 (1H, m, dCH), 4.59 (2H, d, J ) 7.30 Hz,
CH2O), 3.04 (2H, s, CH2CO), 2.14 (3H, s, CH3), 2.05 (3H,
s, CH3), 1.98-2.15 (8H, m, 4CH2), 1.88 (3H, s, CH3), 1.70
(3H, s, CH3), 1.60 (3H, s, CH3), 1.58 (3H, s, CH3); EIMS
m/z 346 [M]+ (1), 286 (1), 203 (2), 188 (3), 149 (3), 135
(3), 121 (4), 107 (3), 83 (100), 67 (5), 55 (8); anal. C
76.46%, H 9.83%, calcd for C22H34O3, C 76.26%, H
9.89%.
Elega n olon e (1). K2CO3 powder (14 mg, 0.10 mmol)
was added to a solution of eleganolone acetate (2) (50
mg, 0.14 mmol) in dry MeOH (1 mL). The mixture was
stirred at room temperature for 2 h, then extracted with
Et2O (10 mL × 3). The Et2O layer was washed with
H2O and brine and dried. Removal of the solvent and
Ep oxyelega n olon e (5). To a suspension of Ti(Oi-
Pr)4 (0.01 mL, 0.03 mmol), CaH2 (4 mg), 4-Å sieve (4
mg), and Si gel (2 mg) in anhydrous CH2Cl2 (1 mL) was
syringed dropwise a solution of D-(-)-DET (8 mg, 0.04
mmol) in anhydrous CH2Cl2 (1 mL) at -20 °C with
stirring. After being stirred for an additional 10 min

Notes
J ournal of Natural Products, 1998, Vol. 61, No. 1 95
at -20 °C, the solution of alcohol 1 (10 mg, 0.03 mmol)
in anhydrous CH2Cl2 (1 mL) was added dropwise to the
above reaction mixture. The mixture was further
stirred for 15 min at that temperature and then cooled
to -40 °C, followed by the addition of a solution of TBHP
in toluene (3.1 M, 0.02 mL, 0.06 mmol). The resulting
mixture was stirred for a further 5 h at that tempera-
ture before being allowed to warm to -30 °C. The
reaction was then quenched by the addition of 10%
aqueous tartaric acid (0.1 mL). The mixture was
allowed to warm to room temperature gradually and
was stirred for 1 h further prior to extraction with Et2O
(20 mL × 3). The ether layer was washed with H2O
and brine and then dried. Evaporation of the solvent
followed by purification on Si gel gave compound 5 (8
the Special Research Grant for Doctoral Sites in Chinese
Universities for financial support.
Refer en ces a n d Notes
(1) Pieta, F. D.; Breschi, M. C.; Scatizzi, R.; Cinelli, F. Planta. Med.
1995, 61, 493-496, and references therein.
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Planta. Med. 1993, 59, 135-138, and references therein.
(3) Francisco, C.; Combaut, G.; Teste, J .; Prost, M. Phytochemistry
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(4) Amico, V.; Oriente, G.; Piattelli, M.; Ruberto, G.; Tringali, C.
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(7) Combaut, G.; Piovetti, L. Phytochemistry 1983, 22, 1787-1789.
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mg, 76%) as a colorless oil: [R]20 -101° (c 0.055,
D
CHCl3); IR (film) νmax 3470 (s), 2982 (s), 2937 (s), 1744
(s), 1618, 1447, 1370, 1267 (s), 1220 (s), 1131 (s), 1031
1
(S), 1021, 920, 853 cm-1; H NMR (CDCl3, 400 MHz) δ
6.11 (1H, s, dCH), 5.23 (1H, m, dCH), 5.12 (1H, t, J )
6.9 Hz, dCH), 3.81 (1H, m, CH2OH), 3.68 (1H, m, CH2-
OH), 3.04 (2H, s, CH2CO), 2.98 (1H, t, J ) 4.5 Hz, epoxy
H), 2.14 (3H, s, CH3), 2.02-2.17 (8H, m, 4CH2), 1.89
(3H, s, CH3), 1.63 (3H, s, CH3), 1.58 (3H, s, CH3), 1.31
(3H, s, CH3); EIMS m/z 320 [M]+ (1), 237 (1), 218 (2),
151 (2), 123 (3), 109 (3), 93 (4), 83 (100), 67 (4), 55 (7);
anal. C 74.72%, H 10.13%, calcd for C20H32O3, C
74.96%, H 10.06%.
(11) (a) Takayanagi, H.; Kitano, Y.; Morinaka, Y. Tetrahedron Lett.
1990, 31, 3317-3320; (b) Takayanagi, H.; Kitano, Y.; Morinaka,
Y. J . Org. Chem. 1994, 59, 2700-2709.
(12) Xiao, X. Y.; Prestwich, G. D. Synth. Commun. 1990, 20, 3125-
3130.
(13) Evans, D. A.; Hoffman, J . M.; Truesdale, L. K. J . Am. Chem.
Soc. 1973, 95, 5822-5823.
Ack n ow led gm en t. We thank the National Nature
Science Foundation of China (grant no. 29672015) and
NP970227G