First total synthesis of (±) Hedaol B

Article abstract of DOI:10.1081/SCC-120018704

Hedaol B, a new bisnorditerpene isolated from the Japanese brown alga Sargassum. sp., was first synthesized starting from geranyl acetone, alkylation of silyl cyanide as the key step.

Full text of DOI:10.1081/SCC-120018704

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 8, pp. 1417–1423, 2003
First Total Synthesis of (1)Hedaol B
2
*
Ying Li, Biao Lu, Chunhong Li, and Yulin Li
National Laboratory of Applied Organic Chemistry and
Institute of Organic Chemistry, Lanzhou University,
Lanzhou, P.R. China
ABSTRACT
Hedaol B, a new bisnorditerpene isolated from the Japanese brown
alga Sargassum. sp., was first synthesized starting from geranyl
acetone, alkylation of silyl cyanide as the key step.
Key Words: Hedaol B; Alkylation; Total synthesis.
*Correspondence: Ying Li, National Laboratory of Applied Organic Chemistry
and Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000,
P.R. China; E-mail: liying@lzu.edu.cn.
1417
DOI: 10.1081/SCC-120018704
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Li et al.
In the course of investigations on the Japanese brown alga Sargassum.
sp., many marine natural products bearing terpenic skeletons have been
found.[1–3] Takada et al.[3] recently isolated a new class of bisnordi-
terpenes, named hedaol A, B, C. Numerous biological activities such as
antitumor, cytotoxic properties have been found among these compounds.
For example, hedaol B (1) showed a toxicity against P388 cells, with
IC50 value of 2.2 (50 mg/mL).
In this communication, we report the first synthesis of (ꢀ)hedaol B (1)
involving the alkylation key-step reaction of silyl cyanide with allylic
iodide, starting from geranyl acetone via six steps, successively, with
high overall yield. Since the reaction of TMSCN with a variety of alde-
hydes and ketones was first shown by Evans et al.[4] and Lidy and
Sundermeyer[5] and alkylation of silyl cyanide was reported by Deuchert
et al.,[6] the reaction has been so favorable in organic synthesis.[7] We wish
to apply it to the facile synthesis of (ꢀ)hedaol B (1) and herein provide
details of this work.
Geranyl acetone 2 was reducted with NaBH4 to give the correspond-
ing alcohol, which can be transformed acetate 3 by treatment with Ac2O,
followed by regoselectively oxidized the
E methyl group using
SeO2/tBuOOH[8] at 0ꢁC gave the terminal alcohol 4, which can be trans-
formed into iodide 5. The key step was the alkylation of allylic iodide[9]
with silyl cyanide 8, which was conveniently prepared from 3-methyl-2-
buten-1-ol 6 through two steps (oxidation with PCC and cyanosilation
with Me3SiCN in the presence of a catalytic amount of KCN/18-crown-6),
deprotection of silyl cyanide 9 with a catalytic amount of TBAF afforded
the ketone 10, which was hydrolyzed to obtain (ꢀ)hedaol B (1), with
spectroscopic data identical to those of literature. Our synthetic route
is shown in Sch. 1.
EXPERIMENTAL
IR spectra were recorded on a Nicolet 170 FT-IR spectrophotometer
in KBr dics.1H NMR spectra were measured on AM-200 spectrometer

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First Total Synthesis of (1)Hedaol B
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Scheme 1. Reagents and conditions: (a) NaBH4, MeOH, 0ꢀC, 30 min, 98%.
(b) AC2O, Py, DMAP, 0ꢀC, 30 min, 100%. (c) SeO2, tBuOOH, 0ꢀC, 2 h, 50%.
(d) Ph3P, imidazole, I2, Et2O/CH3CN, 0ꢀC, 100%. (e) PCC, CH2Cl2, r.t., 80%.
(f ) Me3SiCN, 18-crown-6/KCN, CH2Cl2, 0ꢀC, 100%. (g) (Me3Si)2NLi, 5, À78ꢀC,
1 h, then 8, À78ꢀC, 2 h, 63%. (h) a catalytic amount of TBAF, 10% aqueous
THF, r.t., 15 h, 63%. (i) K2CO3, MeOH, r.t. 4 h, 80%.
with TMS as internal standard in a solution of CDCl3. Mass spectra were
determined on a MAT-44S spectrophotometer (EI, 70 eV). All used
reagents are of commercial origin and used without further purification.
Unless otherwise indicated all reaction products were purified by flash
chromatography on silica gel (200–300 mesh), purchased from Qing Dao
Marine Chemical Co. (Qingdao, China) and eluting with a solvent
mixture (v/v) of petroleum ether (60–90ꢁC) and ethyl acetate.
6,10-Dimethyl-5(E ),9-undecadien-2-ol Acetyl Acetate (3)
To a clear solution of geranyl acetone 2 (1.94 g, 10 mmol) in anhy-
drous MeOH (20 mL) was added sodium borohydride (380 mg, 10 mmol)
portionwise at 0ꢁC with stirring. The reaction completed after 0.5 h, then,
was quenched with H2O. The reaction mixture was extracted with Et2O
(100 mL), and washed sequentially with H2O and brine, then dried and
concentrated. The residue was purified on silica gel to afford a pale yellow

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1420
Li et al.
oil (1.92 g, 98%), which was dissolved in pyridine ꢁ(3 mL) and added to a
catalytic amount of DMAP and Ac2O (2 mL ) at 0C. After being stirred
vigorously for 0.5 h at that temperature, the reaction mixture was diluted
with H2O (10 mL) and extracted with Et2O (3 ꢂ 30 mL), the combined
organic layer was washed 10% aqueous HCl, H2O, brine, then dried and
concentrated, purified by chromatography to give acetate 3 (2.28 g,
100%) as a colorless oil. IR ꢀmax: 2927, 2925, 1773, 1447, 1375, 1249,
912, 734; ꢁH (200 MHz, CDCl3): 5.08 (2H, m, 2HC¼), 4.89 (1H, m,
CHOAc), 2.04 (3H, s, CH3CO–), 2.03–2.00 (6H, m, 3CH2), 1.68 (3H, s,
CH3), 1.60 (3H, s, CH3), 1.59 (3H, s, CH3), 1.56 (2H, m, CH2), 1.22
(3H, d, J ¼ 6.4 Hz). m/z: 238 (1), 195 (3), 178 (8), 163 (6), 135 (17), 109
(84), 69 (100), 43 (92).
6,10-Dimethyl-11-hydroxy-5(E ),
9(E )-undecadien-2-ol Acetyl Acetate (4)
t
To a clear solution of SeO2 (111 mg, 1 mmol) and BuOOH (70%,
1.71 mL, 12.5 mmol) in CH2Cl2 (30 mL) at 0ꢁC was added compound 3
(1.19 g, 5 mmol) in CH2Cl2 (100 mL). After being stirred at 0ꢁC for 2 h,
the reaction mixture was diluted with Et2O (100 mL) and washed
sequentially with 10% aqueous KOH, H2O, and brine, then dried and
concentrated. The resulting oil was purified by flash column chromato-
graphy on silica gel to yield the terminal alcohol 4 (0.64 g, 50%) as
a colorless oil. IR ꢀmax: 3412, 3385, 2927, 1734, 1247, 1023. ꢁH
(200 MHz, CDCl3): 5.40 (1H, t, HC¼), 5.12 (1H, t, HC¼), 4.89
(1H, m, CHOAc), 4.00 (2H, s, CH2O), 2.04 (3H, s, CH3CO–),
2.00–2.08 (6H, m, 3CH2), 1.70 (3H, s, CH3), 1.68 (3H, s, CH3), 1.56
(2H, m, CH2), 1.22 (3H, d, J ¼ 6.4 Hz). m/z: 236 (M À 18) (1), 194 (1),
161 (18), 109 (77), 67 (62), 43 (100).
3-Methyl-2-butenal (7)
To the suspension of PCC (646.5 mg, 3 mmol) in CH2Cl2 (15 mL) was
added 3-methyl-2-buten-1-ol 6 (172 mg, 2 mmol) in CH2Cl2 (5 mL) with
stirring at room temperature for 3 h, the reaction mixture was Et2O
(100 mL) diluted and filtered through a short column on silica gel to
remove the black solid, then the resulting filtrate was concentrated and
purified to give enal 7 (135 mg, 80%) as a clear oil.
ꢁH (200 MHz, CDCl3): 9.89 (1H, d, J ¼ 5.6 Hz, CHO), 5.93 (1H, d,
J ¼ 8.2 Hz, HC¼), 2.25 (3H, s, CH3), 2.05 (3H, s, CH3).

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First Total Synthesis of (1)Hedaol B
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2
6,10,14-Trimethyl-12-cyano-12-trimethylsiloxy-5(E ),
9(E ),13-tetradecatrien-2-ol Acetyl Acetate (9)
A catalytic amount of KCN and 18-crown-6 complex was first added
to aldehyde 7 (168 mg, 2 mmol) in CH2Cl2 (2 mL), with stirring, then
Me3SiCN (0.36 mL, 2.4 mmol) was added dropwise to the suspention at
0ꢁC under argon atmosphere. The reaction was complete within 1 h and
gave silyl cyanide 8, which was used in situ without further purification.
To a stirred clear solution of 4 (508 mg, 2 mmol), Ph3P (786 mg,
3 mmol), and imidazole (204 mg, 3 mmol) in a mixed solvent of CH3CN
(4 mL) and Et2O (6 mL) was added iodine crystals (762 mg, 3 mmol)
portionwise at 0ꢁC, until the reaction was complete with TLC monitor-
ing. The reaction mixture was diluted with Et2O (60 mL) and washed with
saturated Na2S2O3 aqueous solution, H2O, and brine, then dried. The
solvent was removed in vacuo below 40ꢁC, the crude oil was purified by
chromatography to afford ioide 5, which was dissolved in anhydrous
THF (2 mL) and used for the followed procedure.
To a clear solution of HN(SiMe3)2 (3 mmol) in anhydrous THF
(5 mL) was added BuLi (1 mL, 3 N) at 0ꢁC under argon atmosphere.
After the reaction mixture was stirred 0.5 h, silyl cyanide 8 (2 mmol) in
the anhydrous THF (2 mL) was added dropwise at À78ꢁC and stirring
was continued for 1 h at that temperature, then, the above solution of
allylic ioide 5 (2 mmol) in THF (2 mL) was added by syringe and the
reaction mixture was stirred at À78ꢁC for a further 2 h before the reaction
was quenched by the addition of saturated aqueous NH4Cl and Et2O
(50 mL). The organic phase was washed H2O and brine, then, dried
and concentrated. The residue was purified on silica gel to afford silyl
cyanide 9 as a colorless 503 mg (60%). IR ꢀmax: 2964, 1740, 1251, 1089,
848; ꢁH (200 MHz, CDCl3): 5.32 (1H, t, HC¼), 5.24 (1H, s, HC¼), 5.12
(1H, t, HC¼), 4.89 (1H, m, CHOAc), 2.49 (2H, d, CH2), 2.03 (3H, s,
CH3CO–), 2.14–1.48 (8H, m, 4CH2), 1.89 (3H, s, CH3), 1.76 (3H, s, CH3),
1.73 (3H, s, CH3), 1.63 (3H, s, CH3), 1.22 (3H, d, J ¼ 6.4 Hz), 0.21 (6H, s,
2CH3), 0.08 (3H, s, CH3); m/z: 419 (1), 310 (1), 260 (1), 182 (39), 83 (100).
6,10,14-Trimethyl-12-oxo-5(E ),9(E ),13-tetradecatrien-2-ol
Acetyl Acetate (10)
Silyl cyanide 9 (210 mg, 0.5 mmol) was dissolved in 10% aqueous
THF (5 mL) and a catalytic amount of n-Bu4NþFÀ was added. After
being stirred at room temperature for 15 h, the reaction mixture was
extracted with Et2O (30 mL) and the combined organic phase was

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1422
Li et al.
washed with H2O and brine, then dried and concentrated, purified by
chromatography to afford ketone 10 100 mg as a colorless oil (63%). IR
ꢀ
max: 3409, 2925, 1735, 1621, 1446, 1245, 1065; ꢁH (200 MHz, CDCl3):
6.13 (s, 1H, CH¼), 5.24 (1H, t, HC¼), 5.10 (1H, t, HC¼), 4.89 (1H, m,
CHOAc), 3.05 (2H, s, CH2), 2.15 (3H, s, CH3), 2.04 (3H, s, CH3),
2.16–1.48 (8H, m, 4CH2), 1.89 (3H, s, CH3), 1.60 (6H, s, 2CH3), 1.22
(3H, d, J ¼ 6.4 Hz); m/z: 320 (1), 260 (1), 205 (1), 109 (37), 83 (100).
(1)Hedaol B (1)
2
To a solution of ketone 10 (50 mg, 0.16 mmol) in dry MeOH (3 mL)
was added anhydrous K2CO3 (18 mg, 0.16 mmol). The mixture was stir-
red at room temperature for 4–5 h, then extracted with Et2O (15 mL). The
ether layer was washed with H2O and brine, then dried and concentrated,
purified by chromatography to afford (ꢀ)hedaol B (1) 35 mg as a color-
less oil (80%). IR ꢀmax: 3420, 2921, 2965, 1682, 1619, 1443, 1112; ꢁH
(200 MHz, CDCl3): 6.12 (s, 1H, CH¼), 5.23 (1H, t, HC¼), 5.15 (1H, t,
HC¼), 3.82 (1H, m, CHOH), 3.05 (2H, s, CH2), 2.15 (3H, s, CH3),
2.17–1.50 (8H, m, 4CH2), 1.89 (3H, s, CH3), 1.63 (6H, s, 2CH3), 1.20
(3H, d, J ¼ 6.4 Hz); m/z: 278 (1), 260 (1), 209 (1), 180 (1), 83 (100).
ACKNOWLEDGMENT
The research was financially supported by foundation for University
Key Teacher by the Ministry of Education.
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Received in Japan February 18, 2002

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