The first total synthesis of (-)-sinulariol-B and three other cembranoids

Article abstract of DOI:10.1016/S0957-4166(99)00194-9

The first total synthesis of (-)-sinulariol-B, a marine cembrandiol, was achieved from geraniol. Three other cembranoids were also synthesized from (- )-sinulariol-B.

Full text of DOI:10.1016/S0957-4166(99)00194-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1877–1885
The first total synthesis of (−)-sinulariol-B and three other
cembranoids
Jiong Lan,a Jing Li,a Zuosheng Liu,a Yulin Li a,∗ and Albert S. C. Chan b
aNational Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, People’s Republic of China
bDepartment of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
Received 1 March 1999; accepted 10 May 1999
Abstract
The first total synthesis of (−)-sinulariol-B, a marine cembrandiol, was achieved from geraniol. Three other
cembranoids were also synthesized from (−)-sinulariol-B. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Cembranoids, a 14-membered cyclic diterpene family, have become of interest to synthetic chemists
and biologists because of their unusual structures and wide range of biological activities.1,2 Sinulariol-B
1, sinulariol-D 2, sinularial-A 3 and sinularic acid-A 4 were isolated in 1987 and 1988 from the southern
Japan soft coral Sinularia mayi.3,4 Their geometrical structures and configurations were confirmed to be
3E, 7E, 11E and 1R, respectively, but the absolute configuration C15 of sinulariol-B was not determined.
In our previous work,5 we have reported the synthesis of (ꢀ)-sinulariol-B. For determining the absolute
configuration and finding a new method to synthesize sinulariol-D, sinularial-A and sinularic acid-A, the
total synthesis of (−)-sinulariol-B 1 was studied. Herein we wish to describe the details of their total
syntheses.
∗
Corresponding author. E-mail: liyl@lzu.edu.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00194-9

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2. Results and discussion
Our strategy involved three key steps: (1) the Sharpless asymmetric epoxidation of 10; (2) the
coupling of sulfone 11 with allylic chloride 8 by sulfone-stabilized carbanionic alkylation; and (3) the
macrocyclization of precursor 15 by intramolecular thioether-stabilized carbanionic alkylation.
The synthesis began with geraniol 5. Acetylation of 5 with Ac2O in pyridine6 gave the acetate 6 in 98%
yield, which was converted into the alcohol 7 in 73% yield by selective oxidation with SeO2/t-BuOOH
according to the Sharpless procedure.7 Reaction of the alcohol 7 with the insoluble complex of NCS and
Ph3P in dry THF8 yielded the allyl chloride 8. The sulfone 9 was prepared in 75% yield from geraniol
using the Grieco procedure9 and then transformed into the sulfonyl alcohol 10 in 78% yield. Using the
Sharpless asymmetric epoxidation,10 sulfonyl alcohol 10 was converted to the epoxide 11 in 98% yield
and 99% ee (determined by 1H NMR with its (R)-(−)-acetylmandelic acid derivative).
Alkylation of the anion of sulfone 11 with the allylic chloride 8 took place smoothly in anhydrous
THF at −78°C, and the acetyl group was removed from the product without damage to the rest of the
molecule by treatment with anhydrous K2CO3 in dry MeOH to give the sulfonyl diol 12 in 85% yield.
The sulfonyl group was reductively removed from 12 by the reaction with 6% Na(Hg) at 20°C to yield
the diol 13 in 76% yield.11,12 We found that removal of the sulfonyl group with 6% Na(Hg) was better
than by Li–EtNH2.5 It did not need low temperatures for a long time. The yield was high, and most
importantly, the double bonds did not rearrange. From the alcohol 13, the cyclization precursor 15 was
conveniently obtained after two steps.
The next key step was cyclization by intramolecular thioether-stabilized carbanionic alkylation. Slow
addition of 15 over 48 h in dry THF to a cooled (−78°C), well-stirred solution of LDA and DABCO13 in
dry THF gave the intermediate 16. After deprotection of 16 in the usual way, the thiophenyl diol 17 was

J. Lan et al. / Tetrahedron: Asymmetry 10 (1999) 1877–1885
1879
obtained in 54% yield after two steps and then reduced with Li–EtNH2 at −78°C to yield (−)-sinulariol-B
in 70% yield.
The spectral data and specific rotation of synthetic compound 1 showed good agreement with natural
products.3 The absolute stereochemistry of the synthetic compound at C1 and C15 should be 1R,15S,
and therefore the absolute stereochemistry of the naturally occurring material should have the 15S-
configuration too.
From (−)-sinulariol-B, sinulariol-D was obtained by treatment with SOCl2 in pyridine. Oxidation of
sinulariol-D with MnO2 gave sinularial-A, which was converted into sinularic acid-A in 65% yield by
treatment with Ca(ClO)2.14
In summary, we have accomplished the total synthesis of natural products (1R,15S)-(−)-1, (R)-(+)-2,
(R)-(+)-3 and (R)-(+)-4 from geraniol, and the absolute configuration C15 of sinulariol-B was assigned to
be 15S.
3. Experimental
3.1. General
Melting points were determined on a Kofler apparatus, and are uncorrected. IR spectra were recorded
1
on a FT-170SX (film) spectrometer. H NMR spectra were measured on a Bruker AC-80 or AM-400
spectrometer using CDCl3 as a solvent and TMS as an internal standard. Mass spectra were measured on
a VG ZAB-HS spectrometer by direct inlet at 70 eV, and signals given in m/z with relative intensity (%) in
brackets. Elemental analyses were determined on a Vario EL instrument. Optical rotation measurements
were carried out on a Perkin–Elmer 141 polarimeter. All solvents were distilled prior to use. All
anhydrous solvents were prepared by standard methods. All reactions were conducted under an argon
atmosphere unless otherwise noted, and monitored by TLC. All products prepared were purified by
flash column chromatography on silica gel (200–300 mesh) purchased from Qingdao Marine Chemical
Company. Geraniol was purchased from Aldrich Chemical Company, Inc.
3.2. 3,7-Dimethyl-2E,6-octadien-1-yl acetate 6
A mixture of geraniol 5 (4.00 g, 26.0 mmol) and acetic anhydride (2.7 mL, 28.6 mmol) and a catalytic
amount of 4-(dimethylamino)pyridine in pyridine (5 mL) was stirred at 20°C for 6 h, then poured into
water and extracted with ether (3×50 mL). The combined ether layer was washed successively with 2N
HCl, 10% aqueous NaHCO3, water and brine, then dried over MgSO4 and concentrated. The resulting
oil was purified by flash column chromatography on silica gel using petroleum ether:acetone (25:1, v/v)
as an eluent to yield the acetate 6 (5.00 g, 98%) as a colorless oil. 1H NMR (80 MHz, CDCl3): δ 1.67 (s,
6H, 2CH3), 1.71 (s, 3H, CH3), 2.04 (s, 3H, CH3CO), 2.00–2.40 (m, 4H, 2CH2), 4.59 (d, 2H, J=7.2 Hz,

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CH2OAc), 4.95–5.30 (m, 2H, 2CH_). Anal. calcd for C12H20O2: C, 73.43; H, 10.27; found: C, 73.56;
H, 10.34.
3.3. 3,7-Dimethyl-8-hydroxy-2E,6E-octadien-1-yl acetate 7
To a suspension of SeO2 (550 mg, 5.0 mmol) and 70% t-BuOOH (6.8 mL, 50 mmol) in CH2Cl2 (30
mL) was added the acetate 6 (4.90 g, 25.0 mmol) in CH2Cl2 (20 mL). After being stirred at 20°C for 15 h,
the reaction mixture was diluted with ether (150 mL) and washed successively with 10% aqueous KOH,
saturated aqueous NaHSO3, water and brine, then dried over MgSO4, and concentrated. The resulting oil
was purified by flash column chromatography on silica gel using petroleum ether:acetone (15:1, v/v) as
an eluent to give the alcohol 7 (3.87 g, 73%) as a colorless oil. IR (film): νmax 3437, 1738, 1670, 1021;
1H NMR (80 MHz, CDCl3): δ 1.67 (s, 3H, CH3), 1.70 (s, 3H, CH3), 2.03 (s, 3H, CH3CO), 2.00–2.40
(m, 4H, 2CH2), 3.95 (s, 2H, OCH2), 4.58 (d, 2H, J=7.2 Hz, CH2OAc), 5.00–5.35 (m, 2H, 2CH_). Anal.
calcd for C12H20O3: C, 67.89; H, 9.50; found: C, 67.67; H, 9.45.
3.4. 3,7-Dimethyl-8-chloro-2E,6E-octadien-1-yl acetate 8
Triphenylphosphine (5.42 g, 20.7 mmol) in THF (25 mL) was added dropwise to a stirring solution
of N-chlorosuccinimide (2.76 g, 20.7 mmol) in THF (20 mL) under an atmosphere of argon. After 30
min the alcohol 7 (3.85 g, 18.2 mmol) in THF (15 mL) was added slowly over 10 min to the resulting
suspension of solids, and the mixture was stirred at 20°C until it became clear and homogeneous
(about 5 h). The resulting dark mixture was diluted with ether (200 mL), washed successively with
saturated aqueous NaHCO3, water and brine, then dried over MgSO4, and concentrated. Flash column
chromatography over silica gel using petroleum ether:acetone (20:1, v/v) as an eluent gave the chloride
8 (3.56 g, 85%) as a colorless oil. 1H NMR (80 MHz, CDCl3): δ 1.69 (s, 3H, CH3), 1.74 (s, 3H, CH3),
2.03 (s, 3H, CH3CO), 1.80–2.20 (m, 4H, 2CH2), 3.97 (s, 2H, CH2Cl), 4.58 (d, 2H, J=7.2 Hz, CH2OAc),
5.05–5.40 (m, 2H, 2CH_). Anal. calcd for C12H19ClO2: C, 62.47; H, 8.30; found: C, 62.32; H, 8.25.
3.5. 3,7-Dimethyl-1-(phenylsulfonyl)-2E,6-octadiene 9
Phosphorus tribromide (2.4 mL, 25.0 mmol) was added dropwise into an anhydrous ether solution (65
mL) of geraniol 5 (3.50 g, 22.7 mmol) under ice-bath cooling, and then the mixture was stirred for 3 h
at 20°C. After the reaction was quenched with saturated aqueous NaHCO3, the ether layer was washed
twice with brine, dried over MgSO4, and concentrated to give an oil. The oil was added into sodium
benzenesulfonate (3.72 g, 22.7 mmol) dissolved in dry DMF (45 mL), and the mixture was stirred at
room temperature under argon in the dark for 24 h. After addition of brine, the organic substances were
extracted with ether, and the usual workup gave an oil. Flash column chromatography on silica gel using
petroleum ether:acetone (12:1, v/v) as an eluent gave the sulfone 9 (4.73 g, 75%) as a colorless oil. IR
(film): νmax 1655, 1585, 1300, 1140; 1H NMR (80 MHz, CDCl3): δ 1.31 (s, 3H, CH3), 1.57 (s, 3H, CH3),
1.67 (s, 3H, CH3), 1.95–2.20 (m, 4H, 2CH2), 3.80 (d, 2H, J=7.9 Hz, CH2SO2), 5.07 (t, 1H, J=7.2 Hz,
CH_), 5.17 (t, 1H, J=7.8 Hz, CH_), 7.45–8.00 (m, 5H, ArH). Anal. calcd for C16H22SO2: C, 69.03; H,
7.96; found: C, 69.43; H, 7.90.

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3.6. 3,7-Dimethyl-1-(phenylsulfonyl)-8-hydroxy-2E,6E-octadiene 10
To a suspension of SeO2 (367 mg, 3.31 mmol) and 70% t-BuOOH (4.5 mL, 33.1 mmol) in CH2Cl2
(30 mL) was added the sulfone 9 (4.60 g, 16.5 mmol) in CH2Cl2 (15 mL). After being stirred at 20°C
for 25 h, the reaction mixture was poured into water and extracted with ether (3×60 mL). The combined
organic layers were washed successively with 10% aqueous KOH, saturated aqueous NaHSO3, water
and brine, then dried over MgSO4, and concentrated to give an oil. Flash column chromatography on
silica gel using petroleum ether:acetone (10:1, v/v) as an eluent yielded the alcohol 10 (3.78 g, 78%) as
1
a colorless oil. IR (film): νmax 3440, 1658, 1587, 1312, 1150; H NMR (80 MHz, CDCl3): δ 1.39 (s,
3H, CH3), 1.69 (s, 3H, CH3), 1.90–2.40 (m, 4H, 2CH2), 3.85 (d, 2H, J=7.9 Hz, CH2SO2), 4.02 (s, 2H,
OCH2), 5.00–5.45 (m, 2H, 2CH_), 7.35–8.00 (m, 5H, ArH); EIMS m/z: 294 (M+, 2%), 279 (5), 276 (3),
212 (73), 77 (100). Anal. calcd for C16H22SO3: C, 65.28; H, 7.53; found: C, 65.12; H, 7.49.
3.7. 3,7-Dimethyl-1-(phenylsulfonyl)-6R,7R-epoxy-8-hydroxy-2E-octene 11
To a suspension of Ti(OiPr)4 (2.85 g, 10 mmol), CaH2 (150 mg), powdered and freshly activated 4 Å
molecular sieves (400 mg) and silica gel (200 mg) in anhydrous CH2Cl2 (20 mL) was added dropwise
a solution of D-(−)-DET (2.47 g, 12 mmol) in anhydrous CH2Cl2 (20 mL) at −20°C with stirring. After
being stirred for an additional 10 min at −20°C, the solution of the alcohol 10 (2.94 g, 10.0 mmol) in
anhydrous CH2Cl2 (20 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
tert-BuOOH in toluene (3.2 M, 6.3 mL, 20 mmol). The resulting mixture was stirred for a further 5 h at
that temperature before being allowed to warm to −30°C. The reaction was then quenched by the addition
of 10% aqueous tartaric acid (40 mL). The mixture was allowed to warm to room temperature gradually
and was stirred for a further 1 h prior to extraction with CH2Cl2 (3×40 mL). The combined organic phase
was washed with water and brine, then dried over MgSO4. Evaporation of the solvent followed by flash
column chromatography on silica gel using petroleum ether:acetone (5:1, v/v) as an eluent afforded the
epoxide 11 (3.04 g, 98%) as a colorless oil. [α]D20=+8.3 (c 1.0, CHCl3); IR (film): νmax 3400, 1650,
1
1250, 1150; H NMR (400 MHz, CDCl3): δ 1.26 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.80–2.20 (m, 4H,
2CH2), 2.94 (t, 1H, J=6.1 Hz, epoxy H), 3.47 (d, 2H, J=12.1 Hz, OCH), 3.64 (d, 2H, J=12.1 Hz, OCH),
3.76 (d, 2H, J=7.8 Hz, CH2SO2), 5.22 (t, 1H, J=7.8 Hz, CH_), 7.40–7.65 (m, 5H, ArH); EIMS m/z: 310
(M+, 1%), 295 (5), 292 (3), 151 (19), 141 (85), 77 (100). Anal. calcd for C16H22SO4: C, 61.91; H, 7.14;
found: C, 61.75; H, 7.18.
3.8. Determination of the enantiomeric excess of 11
To a solution of dicyclohexylcarbodiimide (DCC, 16 mg, 78 µmol) and the epoxide 11 (20 mg, 65
µmol) in 0.5 mL of dry CH2Cl2 was added (R)-(−)-acetylmandolic acid (15 mg, 77 µmol) and a catalytic
amount of 4-(dimethylamino)pyridine. After stirring at room temperature for 24 h, the solution was
evaporated in vacuo and the residue was directly chromatographed using petroleum ether:acetone (4:1)
to yield the ester (31 mg, 98%). 1H NMR (400 MHz, CDCl3): δ 1.21 (s, 3H, CH3), 1.34 (s, 3H, CH3),
1.80–2.20 (m, 4H, 2CH2), 2.21 (s, 3H, CH3CO), 2.84 (t, 1H, J=6.1 Hz, epoxy H), 3.81 (d, 2H, J=7.8 Hz,
CH2SO2), 4.02 (d, 1H, J=12.0 Hz, OCH), 4.19 (d, 1H, J=12.0 Hz, OCH), 5.20 (t, 1H, J=7.8 Hz, CH_),
5.93 (s, 1H, CH), 7.40–7.90 (m, 10H, ArH).

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3.9. 2,6,10,14-Tetramethyl-2R,3R-epoxy-8-(phenylsulfonyl)-6E,10E,14E-hexadecatrien-1,16-diol 12
To a cooled (−78°C), well-stirred solution of 1.6 M LDA in hexane (7.5 mL, 12.0 mmol) in anhydrous
THF (40 mL) was added dropwise the sulfone 11 (1.77 g, 5.71 mmol) in dry THF (12 mL) under an
argon atmosphere. After 40 min, the allylic chloride 8 (1.32 g, 5.71 mmol) in dry THF (12 mL) was
added. The reaction mixture was allowed to warm to room temperature in 2 h and then saturated aqueous
NH4Cl (20 mL) was added. The usual workup gave an oil, which was added to anhydrous K2CO3 (480
mg) suspended in dry methanol (40 mL), and the mixture was stirred at 20°C for 2 h. After addition of
water, the organic substances were extracted with ethyl acetate (3×50 mL). The extracts were washed
with water and brine, then dried over MgSO4, and concentrated. The resulting oil was passed through a
short pad of silica gel using petroleum ether:acetone (2:1, v/v) as an eluent to give the sulfonyl diol 12
(2.24 g, 85%) as a colorless oil. [α]D20=+7.8 (c 1.0, CHCl3); IR (film): νmax 3421, 1640, 1252, 1151; 1H
NMR (400 MHz, CDCl3): δ 1.27 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.60 (s, 3H, CH3), 1.68 (s, 3H, CH3),
1.80–2.30 (m, 10H, 5CH2), 2.98 (t, 1H, J=5.9 Hz, epoxy H), 3.53 (d, 2H, J=12.0 Hz, OCH), 3.69 (d, 2H,
J=12.0 Hz, OCH), 3.78 (m, 1H, CHSO2), 4.13 (d, 2H, J=7.1 Hz, OCH2), 4.95 (t, 1H, J=6.9 Hz, CH_),
5.10 (t, 1H, J=6.8 Hz, CH_), 5.36 (t, 1H, J=6.9 Hz, CH_), 7.30–7.60 (m, 5H, ArH); EIMS m/z: 462
(M+, 1%), 477 (2), 444 (2), 135 (65), 93 (67), 43 (100). Anal. calcd for C26H38O5S: C, 67.50; H, 8.28;
found: C, 67.32; H, 8.25.
3.10. 2,6,10,14-Tetramethyl-2R,3R-epoxy-6E,10E,14E-hexadecatrien-1,16-diol 13
To a solution of the sulfonyl diol 12 (2.20 g, 4.76 mmol) and sodium hydrogenphosphate (2.70 g,
19 mmol) in dry methanol (20 mL) was added portionwise 6% Na(Hg) powder (9.13 g, 23.8 mmol)
at 20°C. After the reaction was complete, the reaction mixture was diluted with water and extracted
with Et2O. The organic layer was washed with saturated aqueous NH4Cl, water and brine, then dried
over MgSO4. Evaporation of the solvent followed by flash column chromatography on silica gel using
petroleum ether:acetone (4:1, v/v) as an eluent yielded the diol 13 (1.16 g, 76%) as a colorless oil.
1
[α]D20=+8.1 (c 2.3, CHCl3); IR (film): νmax 3440 (br), 1644, 1250, 1020, 920; H NMR (400 MHz,
CDCl3): δ 1.28 (s, 3H, CH3), 1.62 (s, 6H, 2CH3), 1.67 (s, 3H, CH3), 1.80–2.45 (m, 12H, 6CH2), 2.97
(t, 1H, J=6.0 Hz, epoxy H), 3.58 (d, 2H, J=12.1 Hz, OCH), 3.72 (d, 2H, J=12.1 Hz, OCH), 4.10 (d,
2H, J=7.0 Hz, OCH2), 5.08 (t, 1H, J=6.8 Hz, CH_), 5.14 (t, 1H, J=6.7 Hz, CH_), 5.39 (t, 1H, J=6.9
Hz, CH_); EIMS m/z: 322 (M+, 1%), 135 (32), 123 (15), 95 (72), 69 (45), 43 (100). Anal. calcd for
C20H34O3: C, 74.49; H, 10.63; found: C, 74.28; H, 10.69.
3.11. Preparation of 13 by Li–Et2N
Sulfonyl diol 12 (700 mg, 1.52 mmol) in dry THF (2 mL) was added at −78°C to a solution of lithium
wire (630 mg, 91 mmol) in dry EtNH2 (10 mL, dried over sodium). The mixture was stirred at −78°C
for 4 h and some solid NH4Cl and some methanol were added. The solution was allowed to warm to
room temperature, then poured into water, and extracted with Et2O (3×20 mL). The combined organic
layers were washed with water and brine, then dried over MgSO4, and concentrated to give an oil, which
was purified by flash column chromatography on silica gel using petroleum ether:acetone (4:1, v/v) as an
eluent to yield diol 13 (380 mg, 78%) as a colorless oil.

J. Lan et al. / Tetrahedron: Asymmetry 10 (1999) 1877–1885
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3.12. 2,6,10,14-Tetramethyl-2R,3R-epoxy-16-(thiophenyl)-6E,10E,14E-hexadecatrien-1-ol 14
Triphenylphosphine (1.02 g, 3.90 mmol) in THF (10 mL) was added dropwise to a stirring solution of
N-chlorosuccinimide (520 mg, 3.90 mmol) in THF (8 mL) under an argon atmosphere. After 30 min, the
diol 13 (1.10 g, 3.42 mmol) in THF (8 mL) was added dropwise in 10 min to the resulting suspension,
the mixture was stirred at 20°C until it became clear and homogeneous (about 5 h), and then PhSLi (500
mg, 3.78 mmol) in THF (5 mL) was added. After 3 h, the reaction mixture was poured into water and
extracted with ether (3×40 mL). The combined organic layers were washed successively with 2N KOH,
water and brine, then dried over MgSO4, and concentrated to yield an oil, which was purified by flash
column chromatography on silica gel using petroleum ether:acetone (25:1, v/v) as an eluent to give the
alcohol 14 (1.08 g, 76%) as a colorless oil. [α]D20=+11.8 (c 1.7, CHCl3); IR (film): νmax 3640 (br), 1644,
1450, 1390, 1160, 720, 690; 1H NMR (400 MHz, CDCl3): δ 1.26 (s, 3H, CH3), 1.58 (s, 3H, CH3), 1.63
(s, 3H, CH3), 1.66 (s, 3H, CH3), 1.80–2.40 (m, 12H, 6CH2), 3.00 (t, 1H, J=6.1 Hz, epoxy H), 3.51 (d,
2H, J=7.6 Hz, CH2S), 3.56 (d, 2H, J=12.0 Hz, OCH), 3.68 (d, 2H, J=12.0 Hz, OCH), 5.08 (t, 1H, J=6.8
Hz, CH_), 5.14 (t, 1H, J=6.7 Hz, CH_), 5.35 (t, 1H, J=6.9 Hz, CH_), 7.20–7.50 (m, 5H, ArH); EIMS
m/z: 414 (M+, 1%), 287 (7), 161 (13), 135 (42), 107 (52), 93 (100), 81 (89). Anal. calcd for C26H38SO2:
C, 75.32; H, 9.24; found: C, 75.40; H, 9.16.
3.13. 2,6,10,14-Tetramethyl-1-(trimethylsiloxy)-2R,3R-epoxy-16-(thiophenyl)-6E,10E,14E-hexadeca-
triene 15
To a mixture of the alcohol 14 (1.05 g, 2.54 mmol) and imidazole (345 mg, 5.07 mmol) in dry DMF
(5 mL) was added trimethylchlorosilane (303 mg, 2.79 mmol). After being stirred at 50°C for 10 h under
an atmosphere of argon, the reaction mixture was cooled to room temperature, then diluted with brine,
and extracted with ether (3×40 mL). The combined organic layers were washed successively with 10%
aqueous NaHCO3, water and brine, then dried over MgSO4, and concentrated. The resulting oil was
purified by flash column chromatography on silica gel using petroleum ether:acetone (30:1, v/v) as an
eluent to yield 15 (1.21 g, 98%) as a colorless oil. [α]D20=+4.8 (c 1.8, CHCl3); IR (film): νmax 2940,
1
1650, 1458, 1401, 1150, 720, 690; H NMR (400 MHz, CDCl3): δ 0.03 (s, 9H, 3CH3), 1.31 (s, 3H,
CH3), 1.62 (s, 3H, CH3), 1.66 (s, 6H, 2CH3), 1.70–2.24 (m, 12H, 6CH2), 2.98 (t, 1H, J=6.1 Hz, epoxy
H), 3.54 (d, 2H, J=7.9 Hz, CH2S), 3.60 (d, 2H, J=12.3 Hz, OCH), 3.74 (d, 2H, J=12.3 Hz, OCH), 5.07
(t, 1H, J=6.9 Hz, CH_), 5.15 (t, 1H, J=6.8 Hz, CH_), 5.31 (t, 1H, J=6.8 Hz, CH_), 7.25–7.45 (m, 5H,
ArH); EIMS m/z: 486 (M+, 2%), 471 (5), 456 (2), 377 (7), 161 (27), 135 (42), 93 (100). Anal. calcd for
C29H46O2SSi: C, 71.55; H, 9.53; found: C, 71.67; H, 9.48.
3.14. 4,8,12-Trimethyl-1R-(15S,16-dihydroxyl-isopropyl)-2-(thiophenyl)-cyclotetradeca-3E,7E,11E-
triene 17
To a mixture of 1.6 M LDA–hexane solution (1.36 mL, 2.18 mmol) and DABCO (80 mg, 0.74 mmol)
in anhydrous THF (40 mL) was added the precursor 15 (300 mg, 0.62 mmol) in anhydrous THF (40
mL) at −78°C via syringe pump over 48 h under an atmosphere of argon. After 3 h, the cooling bath
was removed and the reaction mixture was allowed to warm to room temperature, and then poured into
saturated aqueous NH4Cl and extracted with ether (3×100 mL). The extracts were washed with water
and brine, then dried over MgSO4, and concentrated to give crude product 16, to which was added n-
Bu4N+F− in THF (1N, 2 mL). After being stirred at 15°C for 24 h under argon, the reaction mixture
was diluted with ethyl acetate (100 mL), and washed with water and brine, then dried over MgSO4,

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and concentrated. The resulting oil was purified by flash column chromatography on silica gel using
petroleum ether:acetone (10:1, v/v) as an eluent to yield 17 (139 mg, 54% from 15) as colorless needles.
1
Mp 92–93°C; IR (KBr): νmax 3360–3100 (br), 1665, 1385, 890, 840, 690, 660; H NMR (400 MHz,
CDCl3): δ 1.12 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.70–2.10 (m,
13H, CH, 6CH2), 3.55 (d, 1H, J=11.8 Hz, CH2O), 3.66 (d, 1H, J=11.8 Hz, CH2O), 3.81 (dd, 1H, J=8.6
and 10.8 Hz, CHSPh), 4.89 (t, 1H, J=6.6 Hz, CH_), 4.99 (t, 1H, J=6.7 Hz, CH_), 5.08 (t, 1H, J=6.7 Hz,
CH_), 7.25–7.50 (m, 5H, ArH); EIMS m/z: 414 (M+, 2%), 305 (8), 304 (4), 287 (5), 153 (20), 93 (48),
81 (100), 71 (74). Anal. calcd for C26H38O2S: C, 75.31; H, 9.24; found: C, 75.55; H, 9.18.
3.15. 4,8,12-Trimethyl-1R-(15S,16-dihydroxyl-isopropyl)-cyclotetradeca-3E,7E,11E-triene 1
A mixture of 17 (130 mg, 0.31 mmol) in dry THF (1 mL) was added at −78°C to a solution of lithium
(130 mg, 18.7 mmol) in dry EtNH2 (10 mL). The mixture was stirred at −78°C for 3.5 h and a small
amount of NH4Cl and methanol were added. The solution was allowed to warm to room temperature,
then poured into water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were
washed with water and brine, then dried over MgSO4, and concentrated to give a crude product, which
was purified by flash column chromatography on silica gel using petroleum ether:acetone (5:1, v/v) as
an eluent to yield (−)-sinulariol-B 1 (66 mg, 70%) as colorless needles. Mp 60–62°C [lit.3, 61–63°C];
[α]D15=−50 (c 0.24, CHCl3) [lit.3, −52 (c 1.12, CHCl3)]; IR (KBr): νmax 3260 (br), 1650, 1384, 1370;
1H NMR (400 MHz, CDCl3): δ 1.15 (s, 3H, CH3), 1.58 (s, 3H, CH3), 1.60 (s, 3H, CH3), 1.61 (s, 3H,
CH3), 1.50–2.30 (m, 15H, 7CH2, CH), 3.43 (d, 1H, J=11.1 Hz, OCH), 3.55 (d, 1H, J=11.1 Hz, OCH),
4.91 (t, 1H, J=6.8 Hz, CH_), 4.99 (t, 1H, J=6.7 Hz, CH_), 5.10 (t, 1H, J=6.8 Hz, CH_); EIMS m/z:
306 (M+, 8%), 291 (15), 288 (6), 275 (45), 257 (42), 189 (35), 93 (70), 40 (100).
3.16. 2-[1R,4,8,12-Trimethyl-3E,7E,11E-cyclotetradecatrien-1-yl]-prop-2-en-1-ol 2
To a solution of the diol 1 (60.0 mg, 0.20 mmol) in pyridine (10 mL) at 15°C was added dropwise
SOCl2 (0.29 mL, 4.0 mmol). The reaction mixture was stirred at that temperature for 3 h. After addition
of 10% aqueous NaCl, the organic substance was extracted with ether (3×20 mL). The combined organic
layers were washed with 2N HCl, water and brine, then dried over MgSO4. Evaporation of the solvent
followed by flash column chromatography on silica gel using petroleum ether:acetone (12:1, v/v) as an
eluent yielded (+)-sinulariol-D 2 (18.3 mg, 49%) as a colorless oil. [α]D15=+13.2 (c 0.60, CHCl3) [lit.4,
1
+14 (c 0.84, CHCl3)]; IR (KBr): νmax 3348, 1644, 895; H NMR (400 MHz, CDCl3): δ 1.57 (s, 6H,
2CH3), 1.60 (s, 3H, CH3), 1.45–2.35 (m, 15H, 7CH2, CH), 4.09 (s, 2H, CH2O), 4.92 and 5.09 (br s, each
1H, CH2_), 4.97 (t, 1H, J=5.7 Hz, CH_), 5.07 (t, 1H, J=6.1 Hz, CH_), 5.18 (t, 1H, J=6.5 Hz, CH_);
EIMS m/z: 288 (M+, 16%), 273 (16), 270 (6), 257 (41), 255 (14), 147 (25), 93 (75), 40 (100).
3.17. 2-[1R,4,8,12-Trimethyl-3E,7E,11E-cyclotetradecatrien-1-yl]-propenal 3
To a suspension of active MnO2 (151 mg, 1.74 mmol) in n-hexane (5 mL) was added dropwise a
solution of the alcohol 2 (25.0 mg, 0.087 mmol) in n-hexane (2 mL) at 15°C. After the reaction mixture
was stirred for an additional 12 h, ether (30 mL) was added to the mixture which was then filtered through
a short column of silica gel. Evaporation of the solvent followed by flash column chromatography on
silica gel using petroleum ether:acetone (20:1, v/v) as an eluent yielded aldehyde 3 (22.9 mg, 92%) as a
colorless oil. [α]D15=+11.5 (c 0.46, CHCl3) [lit.4, +12.5 (c 0.64, CHCl3)]; IR (KBr): νmax 2701, 1696,
1
1620, 940; H NMR (400 MHz, CDCl3): δ 1.54 (s, 3H, CH3), 1.58 (s, 3H, CH3), 1.60 (s, 3H, CH3),

J. Lan et al. / Tetrahedron: Asymmetry 10 (1999) 1877–1885
1885
1.40–2.40 (m, 14H, 7CH2), 2.61 (m, 1H, CH), 4.97 (t, 1H, J=6.7 Hz, CH_), 5.07 (t, 1H, J=6.9 Hz,
CH_), 5.17 (t, 1H, J=6.9 Hz, CH_), 6.03 and 6.24 (s, each 1H, CH2_), 9.56 (s, 1H, CHO); EIMS m/z:
286 (M+, 21%), 271 (8), 255 (40), 147 (21), 93 (79), 40 (100).
3.18. 2-[1R,4,8,12-Trimethyl-3E,7E,11E-cyclotetradecatrien-1-yl]-propenoic acid 4
To a solution of 67% Ca(ClO)2 (14.8 mg, 0.070 mmol) in water (1 mL) and a drop of glacial acetic
acid was added the aldehyde 3 (20 mg, 0.070 mmol) in acetonitrile (4 mL) at 15°C. After the reaction
mixture was stirred for 20 h at that temperature, the mixture was extracted with Et2O (3×50 mL). The
combined organic layers were washed with water and brine, then dried over MgSO4. Evaporation of the
solvent followed by flash column chromatography on silica gel using petroleum ether:acetone (4:1, v/v)
as an eluent yielded the acid 4 (13.7 mg, 65%) as a colorless oil. [α]D15=+18.2 (c 0.25, CHCl3) [lit.4,
+19.7 (c 0.71, CHCl3)]; IR (KBr): νmax 3600–2700 (br), 1698, 1624, 951; 1H NMR (400 MHz, CDCl3):
δ 1.56 (s, 3H, CH3), 1.58 (s, 3H, CH3), 1.60 (s, 3H, CH3), 1.40–2.40 (m, 14H, 7CH2), 2.60 (m, 1H, CH),
4.98 (t, 1H, J=6.5 Hz, CH_), 5.07 (t, 1H, J=6.7 Hz, CH_), 5.18 (t, 1H, J=7.0 Hz, CH_), 5.64 and 6.35
(s, each 1H, CH2_); EIMS m/z: 302 (M+, 1%), 287 (3), 257 (30), 219 (14), 119 (53), 93 (74), 40 (100).
Acknowledgements
We are grateful for financial support from the National Science Foundation of China (Grant No.
29672015) and from the Special Research Grant for Doctoral Sites in the Chinese University.
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