A synthetic study on antiviral and antioxidative chromene derivative

Article abstract of DOI:10.1248/cpb.54.391

An efficient synthesis of the antiviral and antioxidative chromene (1) was achieved. A small amount of chromene 1 could be derived from plastoquinones 2 and 3, the major constituents of the brown alga, Sargassum micracanthum. By the following synthetic sc

Full text of DOI:10.1248/cpb.54.391

March 2006
Notes
Chem. Pharm. Bull. 54(3) 391—396 (2006)
391
A Synthetic Study on Antiviral and Antioxidative Chromene Derivative
b
Jun MORI,a,b Makoto IWASHIMA, ,a Makoto TAKEUCHI,b and Haruo SAITO
*
a Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University; 2630 Sugitani, Toyama 930–0194,
Japan: and b Department of Pharmaceutical Research, Lead Chemical Co., Ltd.; 77–3 Himata, Toyama 930–0912, Japan.
Received October 17, 2005; accepted November 18, 2005
An efficient synthesis of the antiviral and antioxidative chromene (1) was achieved. A small amount of
chromene 1 could be derived from plastoquinones 2 and 3, the major constituents of the brown alga, Sargassum
micracanthum. By the following synthetic scheme involving its application, many kinds of analogs can be synthe-
sized for evaluation of their biological activity and mechanistic study. The total synthesis of 1, started from ger-
anyl acetate and protected 2-bromo-6-methylhydroquinone, was executed with Sharpless asymmetric dihydroxy-
lation for introduction of the terminal diol system and base-catalyzed sigmatropic rearrangement for construc-
tion of the chromene skeleton as the crucial steps. The stereochemistry at C-11ꢀ was reconfirmed by this synthe-
sis.
Key words chromene; plastoquinone; antiviral activity; cytotoxic activity; Sargassum micracanthum
The chromene derivative 1 was initially found as a mixture the structure–activity relationship. In the first stage for the
of diastereomers at C-2 from the brown alga, Sargassum mi- chemical synthesis, we chose compound 1, which comprises
cracanthum (KUETZING) ENDLICHER (Sargassaceae, Fucales) inseparable diastereomers at C-2, as the target molecule, be-
by our group, and was also obtained from plastoquinone 2 by cause the antioxidative activity of the tocopherol/tocotrienol
chemical conversion in two steps via 3.1,2)
analogs was observed essentially at the same level.3) In the
Chromene 1 shows strong antioxidant activity, such as the next stage for evaluation of their biological activity and
inhibitory effect of NADPH-dependent lipid peroxidation mechanistic study, we planned to prepare a number of
in rat microsomes at IC50 0.28 mg/ml (in the case of vita- analogs including each diastereomer at C-2, stereoselectively.
min E as a positive control: IC50 34 mg/ml), as well as re-
The synthetic strategy shown in Chart 1, comprised the
markable antiviral activity against human cytomegalovirus construction of the chromene skeleton from D to C, and of
(HCMV).1,2) Focusing on its cytotoxicity, weak and/or no the diterpene side chain stereoselectively, that is, the connec-
lethal activity was found toward various cells. Therefore, 1 tion formed between A and B. It also contained Sharpless
could be a candidate of a new supplement for anti-aging and asymmetric diol formation3) on the side chain terminal using
of a new antiviral agent; however, it is difficult to obtain suf- geranyl acetate followed by introduction of the sulfone group
ficient amounts of these compounds by isolation from the to prepare B. The small segments E and F can be obtained by
alga. For the above reasons, we decided to prepare 1 effi- modified methods of the known procedures. This paper de-
ciently for further biological investigation and evaluation of scribes the synthesis of 1 in detail.
Along with the above strategy, the synthetic intermediate
D possessing a short-length side-chain was prepared. The
side-chain segment F was obtained from geranyl acetate in
seven steps to give the protected allyl bromide 6 (Chart 2).
Olefin selective dihydroxylation of geranyl acetate, periodate
oxidation, and hydride reduction with NaBH4 provided the
primary alcohol 4 in 46% yield for three steps. The obtained
alcohol 4 was protected with a tert-butyldimethylsilyl (TBS)
group followed by hydrolysis of the acetate protection under
basic condition to give 5 in 100% yield for two steps. The
allyl bromide 6 was obtained by treatment of 5 with
methanesulfonyl chloride and triethylamine to give an allyl
chloride intermediate, followed by bromination with lithium
bromide in 44% yield for two steps. Compound 6 easily de-
Chart 1
∗ To whom correspondence should be addressed. e-mail: iwashi@ms.toyama-mpu.ac.jp
© 2006 Pharmaceutical Society of Japan

392
Vol. 54, No. 3
Chart 2
Chart 3
composed at room temperature or by silica gel separation. from 9). After oxidation to the corresponding aldehyde, three
For these reasons, the obtained compound 6 was immediately carbons were introduced by Horner–Emmons reaction to
1
used for the next reaction.
give 11 (E : Zꢁ5 : 1 by H-NMR analysis). Chromatographic
Readily available 2-bromo-6-methyl-1,4-hydroquinone de- separation of the mixture of isomers and further transforma-
rivative 7 was converted from o-cresol by the known proce- tions with two steps were executed to obtain the E-allyl bro-
dure.4,5) Bromide 7 was treated with butyl lithium in ether at mide 12 in 53% yield from 10.
ꢀ78 °C followed by addition of an ethereal solution of a
The remaining side chain was prepared from geranyl ac-
cuprous iodide–tributylphosphine complex at ꢀ60 °C to pre- etate (Chart 3). The terminal diol involving the chiral sec-
pare the phenyl cuprate species. After the mixture was stirred ondary hydroxyl group was introduced by Sharpless asym-
for 1 h at the same temperature, allyl bromide 6 was added, metric dihydroxylation3) using AD-mix b (46% yield), and
then the reaction mixture was allowed to warm to 0 °C over the diol unit was then converted to the acetonide 13 in good
2 h to obtain 8 in 75% yield. In this alkylation reaction, the yield. After basic hydrolysis of the primary acetate to the
use of a cuprous iodide–tributylphosphine complex, instead corresponding alcohol 14, sulfone 15 was prepared via the
of cuprous iodide itself, resulted in better yield due to the ho- unstable allyl chloride by a standard reaction sequence (34%
mogenous condition.4,5) The primary protective group of yield, three steps).
TBS was changed to the corresponding acetate, and subse-
The coupling reaction between 12 and the lithium salt of
quent acid treatment to remove two phenolic methoxymethyl 15 proceeded to give the desired coupling products as a mix-
(MOM) protections following cerium(IV) ammonium nitrate ture of diastereomers (37% yield from 12). Pd-catalyzed sul-
(CAN) oxidation gave quinone 9 in 50% yield for four steps.
fone removal cleanly occurred to provide 16 in 80% yield.
The chromene forming reaction of 9 was carried out by Finally, acid treatment for deprotection of TBS and acetonide
treatment with pyridine for 15 h at rt.2) In this case, com- afforded chromene 1 in 63% yield. The spectral data includ-
pound 10 was obtained as a racemic mixture at C-2; however, ing the optical rotation value ([a]D ꢂ12.5°) of the synthetic
the target molecule was also a mixture. The resulting pheno- chromene 1 was identical with those of our reported com-
lic hydroxyl was protected by TBS, then hydrolysis of the pound ([a]D ꢂ11.0°). The present synthesis of the chromene
primary acetate under basic condition afforded 10 (48% yield 1 has clearly established the absolute configuration at C-11ꢃ

March 2006
393
as assigned as (R).
tained alcohol 4 (1.28 g, 7.44 mmol) was converted to the corresponding
tert-butyldimethylsilyl (TBS) ether by treatment with TBSCl (2.82 g,
18.7 mmol), triethylamine (3.80 ml, 27.3 mmol) and 4-dimethylaminopyri-
dine (DMAP, 5 mg, 0.04 mmol) in dichloromethane (20 ml) at 20 °C for 4 h.
The mixture was diluted with a solution of hexane–EtOAc (1 : 1, 300 ml).
The organic layer was washed with water and saturated NaCl solution, dried
over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography [hexane–EtOAc (10 : 1)];
TBS ether (2.13 g, 100% yield) was obtained as colorless oil. To a mixture
Synthetic studies toward both optically pure chromene de-
rivatives having C-2 chirality and other analogs for evaluat-
ing the structure–bioactivity relationship are currently under
preparation. In addition, the biological aspects will be re-
ported near future.
Experimental
Optical rotations were measured with a JASCO DIP-1000 automatic po- of the resulting TBS ether (2.13 g, 7.44 mmol) in methanol (30 ml) was
larimeter. IR spectra were recorded with a Perkin-Elmer FT-IR 1600 spec- added potassium carbonate (200 mg, 1.45 mol) at 0 °C. The reaction mixture
trophotometer and UV spectra with a JASCO V-530 spectrophotometer. was stirred for 1 h at 0 °C, and then saturated ammonium chloride solution
NMR spectra were recorded with a Varian Unity-500 (1H, 500 MHz; 13C, (3 ml) was added to neutralize the mixture. After concentrated under re-
125 MHz) in CDCl3. 1H–1H correlation spectroscopy (COSY) and nuclear
duced pressure, the residue was extracted twice with EtOAc (2ꢄ200 ml).
Overhauser effect spectroscopy (NOESY) were measured with a Varian The combined extracts were washed with saturated NaCl solution, dried over
Unity-500 using standard Varian pulse sequences. Chemical shifts are given Na2SO4, filtered, and concentrated. The residue was separated by silica gel
on a d (ppm) scale with CHCl3 (1H, 7.26 ppm; 13C, 77.0 ppm) as the internal
column chromatography [hexane–EtOAc (5 : 1)] to give alcohol 5 (1.81 g,
standard (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad). 100% yield) as colorless oil.
Mass spectra were taken with a JEOL JMS-AX505HAD spectrometer. Col-
umn chromatography was carried out on Kanto Chemical silica gel 60N
Compound 5: IR (dry film) cmꢀ1: 3347 (br), 1668, 1471. 1H-NMR
(CDCl3) d ppm: 0.05 (6H, s), 0.90 (9H, s), 1.64 (2H, m), 1.68 (3H, br s),
(100—210 mm). Normal and reversed phase flash column chromatography 2.11 (2H, br t, Jꢁ7.3 Hz), 3.62 (2H, t, Jꢁ6.4 Hz), 4.56 (2H, d, Jꢁ6.8 Hz),
was performed on Kanto Chemical silica gel 60N (40—100 mm, normal
5.35 (1H, qt, Jꢁ1.2, 6.8 Hz). 13C-NMR (CDCl3) d ppm: ꢀ5.4, 16.4, 16.6,
phase) and Fuji Silysia Chemical ODS DM1021T (100—200 mesh, reversed 25.9 (3C), 30.9, 35.7, 59.4, 62.7, 123.3, 139.7. EI-MS m/z: 244 (M)ꢂ. HR-
phase), respectively. Thin layer chromatography (TLC) was carried out on EI-MS m/z: 244.1842 [Calcd for C13H28O2Si: 244.1859 (M)ꢂ].
Merck Kieselgel 60F254 TLC plate. Diethyl ether (Et2O) and THF was dried
over sodium using benzophenone as indicator. Chloroform, dichloro-
(2E)-1-Bromo-6-tert-butyldimethylsilyloxy-3-methyl-2-hexene (6)
The obtained alcohol 5 (5.15 g, 21.1 mmol) was treated with methanesul-
methane, N,N-dimethyl formamide (DMF), dimethylsulfoxide (DMSO) and fonyl chloride (3.50 ml, 45.5 mmol), triethylamine (9 ml, 64.7 mmol) in
toluene were dried over CaH2. Methanol, 2-methyl-2-propanol, water, and chloroform (50 ml) at 0 °C for 30 min. The reaction mixture was diluted with
the eluants for chromatography except for hexane were distilled before use. a solution of hexane–Et2O (1 : 1, 100 ml). The organic phase was washed
Hexane was used as purchased. Geranyl acetate was made by acetylation of with water and saturated NaCl solution, dried over Na2SO4, filtered, and con-
geraniol, purchased from Kanto chemical, and was distilled before use. 2- centrated. The crude product containing unstable allyl chloride was sepa-
Bromo-6-methyl-1,4-hydroquinone dimethoxymethyl ether was also pre- rated by passing through a short silica gel column [hexane–Et2O (9 : 1)] very
pared by the known procedure according to the references.
(4E)-6-Acetoxy-4-methyl-4-hexen-1-ol (4) To a mixture of potassium
quickly, then the solvent was removed under reduced pressure. The resulting
allyl chloride was immediately converted to the corresponding allyl bromide
hexacyanoferrate(III) (42.3 g, 128 mmol), potassium carbonate (17.8 g, (6) by treatment with lithium bromide (8.60 g, 99.0 mmol) in DMF (50 ml)
129 mmol) and potassium osmate(VI) dihydrate (4 mg, 0.01 mmol) in a
at 20 °C for 1 h. The same work up described in the formation of allyl chlo-
combined solution of water and 2-methyl-2-propanol (each 250 ml) was ride was carried out to provide 6 (2.85 g, 44% yield for two steps from 5) as
added geranyl acetate (12.6 g, 64.2 mmol) at 4 °C. The reaction mixture was a pale yellowish oil. Compound 6 was immediately used for the next reac-
stirred for 72 h at 4 °C, Na2S2O3 solution (50 ml) was added to quench the
active oxidizer, and the mixture was concentrated under reduced pressure.
The residue was extracted twice with ethyl acetate (2ꢄ300 ml), and the com-
tion due to unstableness.
Compound 6: H-NMR (CDCl3) d ppm: 0.05 (6H, s), 0.89 (9H, s), 1.66
(2H, m), 1.71 (3H, br s), 2.14 (2H, br t, Jꢁ7.5 Hz), 3.63 (2H, t, Jꢁ6.5 Hz),
1
bined extracts were washed with saturated NaCl solution, dried over 4.59 (2H, d, Jꢁ6.7 Hz), 5.46 (1H, br t, Jꢁ6.7 Hz).
Na2SO4, filtered, and concentrated under reduced pressure. The oily residue
2-[(2ꢀE)-6ꢀ-tert-Butyldimethylsilyloxy-3ꢀ-methyl-2ꢀ-hexen-1ꢀ-yl]-6-
was purified by silica gel column chromatography [hexane–ethyl acetate methyl-1,4-hydroquinone 1,4-Dimethyl Ether (8) To a mixture of 7
(EtOAc, 2 : 1)] to afford diol (6.90 g, 47% yield) as pale yellowish oil. The (1.33 g, 4.57 mmol)4,5) in Et2O (10 ml) was added butyllithium (1.58 M in
resulting diol (1.77 g, 7.69 mmol) was dissolved into acetone (70 ml), fol- hexane, 3.80 ml, 6.00 mmol) at ꢀ78 °C under N2. The reaction mixture was
lowed by adding the solution of sodium periodate (2.47 g, 11.5 mmol) in stirred for 1 h at ꢀ78 °C. The ethereal solution (5 ml) of copper(I) iodide–
water (70 ml) at 0 °C over 20 min. The reaction mixture was stirred for 2 h at tributylphosphine complex, prepare from copper(I) iodide (450 mg,
20 °C, and then extracted thrice with a mixture of hexane–EtOAc (1 : 1, 2.36 mmol) and tributylphosphine (2.10 ml, 8.43 mmol), was added to the re-
3ꢄ200 ml). The combined extracts were washed with saturated NaCl solu- action mixture at ꢀ60 °C over 15 min via canula, and the mixture was stirred
tion, dried over Na2SO4, filtered, and concentrated under reduced pressure.
for additional 1 h at this temperature to prepare the aryl cuprate species. Fi-
The residue was separated by passing over a small plug of silica gel column nally, the ethereal solution (10 ml) of ally bromide 6 (1.68 g, 5.47 mmol) was
[hexane–EtOAc (5 : 1), as an eluant] to give aldehyde (1.28 g, 98% yield). added at ꢀ60 °C over 20 min. The reaction mixture was allowed to warm to
1
The NMR data of this aldehyde are shown as follows; H-NMR (CDCl3) d
ppm: 1.69 (3H, br s), 2.02 (3H, s), 2.35 (2H, br, Jꢁ7.3 Hz), 2.55 (2H, dt,
Jꢁ1.7, 7.3 Hz), 4.55 (2H, d, Jꢁ6.8 Hz), 5.33 (1H, qt, Jꢁ1.2, 6.8 Hz), 9.57
0 °C over 2 h, and then a mixture of saturated ammonium chloride solution
and 6 N ammonia solution (1 : 1, 40 ml) was added to terminate the reaction.
After diluted with Et2O (200 ml), the mixture was washed with water and
(1H, t, Jꢁ1.7 Hz). 13C-NMR (CDCl3) d ppm: 16.5, 20.9, 31.3, 41.6, 61.0, saturated NaCl solution, dried over Na2SO4, filtered, and concentrated under
119.2, 139.9, 171.0, 201.7.
reduced pressure. The oily residue was purified by silica gel column chro-
The aldehyde (1.28 g, 7.52 mmol) obtained above was reduced with matography [hexane–EtOAc (20 : 1)] to give 8 (1.50 g, 75% yield) as color-
sodium borohydride (168 mg, 4.44 mmol) in methanol (35 ml) at 0 °C. After
quenched by saturated ammonium chloride solution, the mixture was con-
centrated, and then extracted thrice with EtOAc (3ꢄ100 ml). The combined
less oil.
1
Compound 8: IR (dry film) cmꢀ1: 2930, 1596, 1471. H-NMR (CDCl3) d
ppm: 0.04 (6H, s), 0.89 (9H, s), 1.65 (2H, m), 1.70 (3H, br s), 2.06 (2H, m),
extracts were washed with saturated NaCl solution, dried over Na2SO4, fil- 2.28 (3H, s), 3.35 (2H, d, Jꢁ7.3 Hz), 3.47 (3H, s), 3.60 (2H, q, Jꢁ6.4 Hz),
tered, and concentrated under reduced pressure. The residue was purified by 3.61 (3H, s), 4.91 (2H, s), 5.10 (2H, s), 5.30 (1H, br t, Jꢁ0.8, 7.3 Hz), 6.67
silica gel column chromatography [hexane–EtOAc (4 : 1)] to provide alcohol (1H, d, Jꢁ3.0 Hz), 6.72 (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) ꢀ5.3, 16.2,
4 (1.28 g, 99% yield) as colorless oil.
17.2, 18.3, 25.9 (3C), 28.6, 31.2, 35.8, 55.9, 57.4, 62.9, 94.7, 99.5, 115.3,
1
Compound 4: IR (dry film) cmꢀ1: 3408 (br), 1739, 1668, 1237. H-NMR 116.0, 122.5, 132.1, 135.8, 136.3, 149.0, 153.5. EI-MS m/z: 438 (M)ꢂ. HR-
(CDCl3) d ppm: 1.68 (2H, m), 1.70 (3H, br d, Jꢁ1.2 Hz), 2.04 (3H, s), 2.11 EI-MS m/z: 438.2778 [Calcd for C24H42O5Si: 438.2802 (M)ꢂ].
(2H, br t, Jꢁ7.3 Hz), 3.62 (2H, t, Jꢁ6.4 Hz), 4.56 (2H, d, Jꢁ6.8 Hz), 5.35
2-[(2ꢀE)-6ꢀ-Acetoxy-3ꢀ-methyl-2ꢀ-hexen-1ꢀ-yl]-6-methyl-1,4-benzo-
(1H, qt, Jꢁ1.2, 6.8 Hz). 13C-NMR (CDCl3) d ppm: 16.3, 21.0, 30.4, 35.7, quinone (9) To a mixture of 8 (1.50 g, 3.42 mmol) in THF (5 ml) was
61.3, 62.4, 118.5, 141.8, 171.2. EI-MS m/z: 172 (M)ꢂ. HR-EI-MS m/z:
172.1110 [Calcd for C9H16O3: 172.1100 (M)ꢂ].
added tetrabutylammonium fluoride (TBAF, 1 M in THF, 4.1 ml, 4.1 mmol) at
20 °C. The reaction mixture was stirred for 1 h at 20 °C to remove TBS
group, and then diluted with a mixture of hexane–EtOAc (1 : 1, 100 ml). The
(2E)-6-tert-Butyldimethylsilyloxy-3-methyl-2-hexen-1-ol (5) The ob-

394
Vol. 54, No. 3
mixture was washed with water and saturated NaCl solution, dried over 18.1, 21.0, 23.4, 25.9, 37.1, 64.7, 77.4, 114.9, 120.9, 121.8, 123.5, 126.0,
Na2SO4, filtered, and concentrated under reduced pressure. The oily residue 129.7, 145.0, 148.4, 171.2.
was purified by passed over a small plug of silica gel [hexane–EtOAc (2 : 1)]
To a mixture of TBS ether (848 mg, 2.17 mmol) in methanol (50 ml) was
to give the primary alcohol (750 mg, 68% yield) as pale yellowish oil. The added potassium carbonate (300 mg, 2.17 mmol) at 0 °C. The reaction mix-
spectral data of this alcohol are shown as follows; 1H-NMR (CDCl3) d ppm: ture was stirred for 1 h at 0 °C, and then saturated ammonium chloride solu-
1.70 (2H, m), 1.71 (3H, br s), 1.34 (3H, s), 2.12 (2H, br t, Jꢁ7.5 Hz), 2.27
tion (10 ml) was added to neutralize the mixture. After concentrated under
(3H, s), 3.36 (2H, d, Jꢁ6.8 Hz), 3.46 (3H, s), 3.60 (3H, s), 3.63 (2H, t, reduced pressure, the residue was extracted twice with EtOAc (2ꢄ100 ml).
Jꢁ6.4 Hz), 4.90 (2H, s), 5.10 (2H, s), 5.34 (1H, dt, Jꢁ0.8, 6.8 Hz), 6.67
The combined extracts were washed with saturated NaCl solution, dried over
(1H, d, Jꢁ3.0 Hz), 6.71 (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) d ppm: 16.0, Na2SO4, filtered, and concentrated. The residue was purified by silica gel
17.2, 28.6, 30.5, 35.8, 55.9, 57.3, 62.4, 94.6, 99.5, 114.8, 116.2, 123.0, column chromatography [hexane–EtOAc (4 : 1)] to give 10 (620 mg, 82%
132.1, 125.6, 136.0, 149.0, 153.4. EI-MS m/z: 324 (M)ꢂ.
The alcohol derivative (1.64 g, 5.06 mmol) was converted to the corre-
sponding acetate by treatment with acetic anhydride (4.0 ml, 42.3 mmol) and ppm: 0.16 (6H, s), 0.97 (9H, s), 1.35 (3H, s), 1.72 (4H, m), 1.92 (1H, br s),
yield).
1
Compound 10: IR (dry film) cmꢀ1: 3348 (br), 1588. H-NMR (CDCl3) d
pyridine (6.0 ml, 74.2 mmol) at 20 °C for 7 h. After concentration and purifi-
cation by passing through a short silica gel column [hexane–EtOAc (5 : 1)],
the primary acetate was obtained (1.85 g, 100% yield) as colorless oil. The
2.11 (3H, s), 3.62 (2H, dd, Jꢁ6.4, 6.9 Hz), 5.54 (1H, d, Jꢁ9.8 Hz), 6.25 (1H,
d, Jꢁ9.8 Hz), 6.31 (1H, d, Jꢁ3.0 Hz), 6.47 (1H, d, Jꢁ3.0 Hz). 13C-NMR
(CDCl3) d ppm: ꢀ4.6, 15.4, 18.0, 25.6, 25.8, 27.2, 37.0, 62.9, 77.7, 114.8,
spectral data of this acetate are shown as follows; 1H-NMR (CDCl3) d ppm: 120.9, 121.7, 123.2, 125.9, 129.9, 144.9, 148.4. EI-MS m/z: 348 (M)ꢂ. HR-
1.71 (3H, br s), 1.76 (2H, m), 2.04 (3H, s), 2.09 (2H, t, Jꢁ7.5 Hz), 2.28 (3H,
s), 3.35 (2H, d, Jꢁ6.8 Hz), 3.46 (3H, s), 3.60 (3H, s), 4.05 (2H, dt, Jꢁ0.8,
EI-MS m/z: 348.2094 [Calcd for C20H32O3Si: 348.2121 (M)ꢂ].
Methyl (2E)-5-[6-(tert-Butyldimethylsilyloxy)-2,8-dimethyl-2H-
7.3 Hz), 4.90 (2H, s), 5.10 (2H, s), 5.31 (1H, dt, Jꢁ0.8, 6.8 Hz), 6.66 (1H, d, chromen-2-yl]-2-methyl-2-pentenoate (11) To a mixture of 10 (620 mg,
Jꢁ3.0 Hz), 6.72 (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) d ppm: 16.0, 17.2, 1.78 mmol), DMSO (12.7 ml, 179 mmol), and triethylamine (2.0 ml,
21.0, 26.8, 28.6, 35.8, 55.9, 57.4, 64.2, 94.7, 99.5, 115.2, 116.1, 123.3, 14.3 mmol) was portionwisely added sulfur trioxide–pyridine complex
132.1, 135.3, 135.5, 149.0, 153.4, 171.2. EI-MS m/z: 366 (M)ꢂ.
(1.70 g, 10.7 mmol) over 10 min at 0 °C under N2 atmosphere. The mixture
The above acetate (2.54 g, 6.93 mmol) was treated with 80% acetic acid was stirred for 1 h at 20 °C. After diluted with a solution of hexane–Et2O
solution (20 ml) at 60 °C for 12 h to remove MOM group. Concentration and (1 : 1, 100 ml), the mixture was washed with water and saturated NaCl solu-
purification by silica gel column chromatography [hexane–EtOAc (4 : 1)] tion, dried over Na2SO4, filtered, and concentrated under reduced pressure.
gave the hydroquinone derivative (1.66 g, 86% yield) as pale yellow oil. The The oily residue was separated by passed over a small plug of silica gel
NMR spectral data of this hydroquinone are shown as follows; 1H-NMR [hexane–EtOAc (10 : 1)] to give the product mainly containing the aldehyde
(CDCl3) d ppm: 1.72 (3H, br s), 1.81 (2H, m), 2.06 (3H, s), 2.16 (2H, t,
Jꢁ7.6 Hz), 2.20 (3H, s), 3.29 (2H, d, Jꢁ7.3 Hz), 4.10 (2H, t, Jꢁ6.8 Hz),
4.52 (1H, s, OH), 5.32 (1H, dt, Jꢁ0.8, 7.3 Hz), 6.45 (1H, d, Jꢁ3.0 Hz), 6.52
(1H, d, Jꢁ3.0 Hz).
derivative (616 mg, quantitative yield), which was directly used without fur-
ther purification. THF solution (10 ml) of the obtained aldehyde (616 mg,
1.78 mmol) was added to a mixture of methyl diethylphosphono-2-propioate
(2.40 g, 10.7 mmol) and potassium tert-butoxide (850 mg, 7.58 mmol) in
THF (20 ml) at ꢀ78 °C under N2. After adding ammonium chloride solution
To a mixture of hydroquinone (1.66 g, 5.96 mmol) in acetonitrile (50 ml)
was added a solution of ammonium cerium(IV) nitrate (CAN, 4.19 g, (15 ml) and a solution of hexane–Et2O (1 : 1, 100 ml), the mixture was
7.64 mmol) in water (6.4 ml) at 0 °C. The reaction mixture was stirred for
30 min at 0 °C, and saturated Na2S2O3 solution (1 ml) was added to quench
washed with water and saturated NaCl solution, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The oily residue was purified by
active CAN, and the reaction mixture was concentrated under reduced pres- column chromatography [hexane–EtOAc (20 : 1)] to provide 11 (440 mg,
sure. The residue was extracted twice with EtOAc (2ꢄ50 ml), and the com- 59% yield). The Z ester of 11 (164 mg, 22% yield) and the mixture of them
1
bined extracts were washed with saturated NaCl solution, dried over (140 mg) were also obtained both as colorless oil. H-NMR analysis of the
Na2SO4, filtered, and concentrated. The oily residue was purified by silica crude product showed the E/Z ratio to be about 5 : 1.
gel column chromatography [hexane–EtOAc (2 : 1)] to provide quinone 9
Compound 11: IR (dry film) cmꢀ1: 2929, 1715, 1644, 1470. 1H-NMR
(CDCl3) d ppm: 0.16 (6H, s), 0.97 (9H, s), 1.37 (3H, s), 1.76 (2H, m), 1.79
(1.40 g, 85% yield) as pale yellowish oil.
Compound 9: IR (dry film) cmꢀ1: 2956, 1738, 1651, 1614, 1242. 1H- (3H, br d, Jꢁ1.7 Hz), 2.12 (3H, s), 2.31 (2H, m), 3.71 (3H, s), 5.53 (1H, d,
NMR (CDCl3) d ppm: 1.64 (3H, br s), 1.76 (2H, m), 2.05 (3H, s), 2.06 (3H, Jꢁ9.8 Hz), 6.28 (1H, d, Jꢁ9.8 Hz), 6.31 (1H, d, Jꢁ2.6 Hz), 6.47 (1H, d,
d, Jꢁ1.3 Hz), 2.10 (2H, t, Jꢁ7.5 Hz), 3.13 (2H, d, Jꢁ7.3 Hz), 4.04 (2H, t,
Jꢁ6.8 Hz), 5.18 (1H, qt, Jꢁ0.8, 7.3 Hz), 6.66 (1H, qd, Jꢁ1.3, 3.0 Hz), 6.72
Jꢁ2.6 Hz), 6.77 (1H, qt, Jꢁ1.7, 7.2 Hz). 13C-NMR (CDCl3) d ppm: ꢀ4.5,
15.5, 18.1, 23.6, 25.7, 26.1, 39.5, 51.6, 77.5, 114.9, 120.8, 121.9, 123.6,
(1H, qd, Jꢁ1.3, 3.0 Hz). 13C-NMR (CDCl3) d ppm: 16.0, 21.0, 26.8, 27.6, 125.9, 127.5, 129.4, 142.3, 145.0, 148.5, 168.6. EI-MS m/z: 416 (M)ꢂ. HR-
35.8, 64.0, 118.7, 132.3, 133.1, 138.7, 145.9, 148.2, 171.2, 187.9, 188.0. EI- EI-MS m/z: 416.2400 [Calcd for C24H36O4Si: 416.2383 (M)ꢂ].
MS m/z: 276 (M)ꢂ. HR-EI-MS m/z: 216.1160 [Calcd for C14H16O2:
216.1150 (MꢀCH3CO2H)ꢂ].
cis-Isomer of 11: IR (dry film) cmꢀ1: 2929, 1718, 1649, 1471. H-NMR
1
(CDCl3) d ppm: 0.16 (6H, s), 0.97 (9H, s), 1.37 (3H, s), 1.77 (2H, m), 1.86
3-[6-(tert-Butyldimethylsilyloxy)-2,8-dimethyl-2H-chromen-2-yl]- (3H, br d, Jꢁ1.3 Hz), 2.11 (3H, s), 2.59 (2H, m), 3.71 (3H, s), 5.56 (1H, d,
propan-1-ol (10) Compound 9 (1.40 g, 5.07 mmol) was treated with pyri- Jꢁ9.8 Hz), 5.95 (1H, qt, Jꢁ1.3, 7.5 Hz), 6.26 (1H, d, Jꢁ9.8 Hz), 6.30 (1H,
dine (50 ml) at 20 °C for 15 h under N2 atmosphere. After concentration and d, Jꢁ3.0 Hz), 6.46 (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) d ppm: ꢀ4.5,
separation by silica gel column [hexane–acetone (3 : 1)], the 2H-chromene 15.5, 18.1, 20.6, 24.6, 25.7, 25.8, 40.2, 51.2, 77.7, 114.9, 121.0, 121.7,
1
derivative (820 mg, 59% yield) was obtained as pale yellowish oil. H- and
123.3, 126.0, 126.8, 129.9, 143.2, 145.1, 148.4, 168.4. EI-MS m/z: 416
13C-NMR spectral data of chromene are shown as follows; 1H-NMR (M)ꢂ.
(CDCl3) d ppm: 1.34 (3H, s), 1.68 (2H, t, Jꢁ6.7 Hz), 1.77 (2H, m), 2.03
(2E)-1-Bromo-5-[6-(tert-butyldimethylsilyloxy)-2,8-dimethyl-2H-
chromen-2-yl]-2-methyl-2-pentene (12) Diisobutylaluminum hydride
(0.95 M in hexane, 4.0 ml, 3.80 mmol) was added to a mixture of 11 (440 mg,
(3H, s), 2.10 (3H, s), 4.07 (2H, d, Jꢁ6.4 Hz), 5.53 (1H, d, Jꢁ9.8 Hz), 6.23
(1H, d, Jꢁ9.8 Hz), 6.33 (1H, d, Jꢁ3.0 Hz), 6.48 (1H, d, Jꢁ3.0 Hz). 13C-
NMR (CDCl3) d ppm: 15.4, 20.9, 23.2, 25.7, 36.9, 64.9, 77.3, 110.3, 117.2, 1.06 mmol) in dichloromethane (20 ml) at ꢀ78 °C under N2. The reaction
121.0, 123.3, 124.8, 126.2, 130.0, 144.2, 148.9, 171.8. mixture was stirred for 1 h, quenched with Rochelle salt solution (8 ml), di-
The above chromene (600 mg, 2.17 mmol) was converted to the corre- luted with Et2O (200 ml) and stirred additional 1 h at 20 °C. The ethereal so-
sponding TBS ether by treatment with TBSCl (981 mg, 6.51 mmol), imida-
zole (665 mg, 9.77 mmol) and DMAP (5 mg, 0.04 mmol) in DMF (25 ml) at
lution was dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The oily residue was purified by passed over a small plug of silica gel
20 °C for 16 h. The reaction mixture was diluted with a mixture of [hexane–EtOAc (4 : 1)] to afford the primary alcohol (410 mg, 100% yield)
hexane–EtOAc (1 : 1, 100 ml). The obtaining mixture was washed with water as colorless oil. The spectral data of this acetate are shown as follows; IR
and saturated NaCl solution, dried over Na2SO4, filtered, and concentrated. (dry film) cmꢀ1: 3347 (br), 1588, 1470. 1H-NMR (CDCl3) d ppm: 0.16 (6H,
The oily residue was purified by silica gel column chromatography s), 0.97 (9H, s), 1.35 (3H, s), 1.69 (2H, m), 1.76 (3H, br d, Jꢁ1.3 Hz), 2.12
[hexane–EtOAc (10 : 1)] to provide TBS ether (848 mg, quantitative yield) as (3H, s), 2.18 (2H, m), 4.01 (2H, br s), 5.29 (1H, dt, Jꢁ1.3, 7.7 Hz), 5.52
colorless oil. The NMR spectral data of this TBS ether are shown as follows; (1H, d, Jꢁ9.8 Hz), 6.25 (1H, d, Jꢁ9.8 Hz), 6.30 (1H, d, Jꢁ3.0 Hz), 6.47
1H-NMR (CDCl3) d ppm: 0.15 (6H, s), 0.96 (9H, s), 1.35 (3H, s), 1.70 (2H, (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) d ppm: ꢀ4.5, 15.5, 18.1, 21.2, 22.4,
t, Jꢁ6.6 Hz), 1.78 (2H, m), 2.02 (3H, s), 2.11 (3H, s), 4.06 (2H, d, 25.7, 26.1, 41.2, 61.5, 77.7, 114.9, 121.3, 121.8, 123.3, 125.9, 128.3, 129.9,
Jꢁ6.8 Hz), 5.53 (1H, d, Jꢁ9.7 Hz), 6.26 (1H, d, Jꢁ9.7 Hz), 6.30 (1H, d, 134.3, 145.1, 148.4.
Jꢁ3.0 Hz), 6.47 (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) d ppm: ꢀ4.5, 15.5,
The obtained alcohol (42 mg, 0.11 mmol) was treated with triphenylphos-

March 2006
395
phine (143 mg, 0.55 mmol) and carbon tetrabromide (289 mg, 0.87 mmol) in
toluene (3 ml) at 20 °C under N2 atmosphere for 1 h. The reaction mixture
yield) as colorless viscous oil.
Compound 15: [a]D25 ꢀ5.4° (cꢁ5.35, CHCl3). IR (dry film) cmꢀ1: 2364,
1
was diluted with a solution of hexane–EtOAc (5 : 1, 50 ml), which was then 1597, 1370. H-NMR (CDCl3) d ppm: 1.07 (3H, s), 1.23 (3H, s), 1.31 (3H,
filtered though a small plug of silica gel [hexane–EtOAc (5 : 1)]. The filtrate s), 1.40 (3H, s), 1.38 (1H, m), 1.54 (1H, m), 1.37 (3H, s), 2.04 (1H, m), 2.23
was concentrated under reduced pressure to give unstable allyl bromide 12 (1H, m), 2.43 (3H, s), 3.60 (1H, dd, Jꢁ3.0, 9.9 Hz), 3.79 (2H, d, Jꢁ8.1 Hz),
(45 mg, 92% yield) as pale yellowish oil. It was immediately used for the 5.29 (1H, dt, Jꢁ1.3, 8.1 Hz), 7.30 (2H, d, Jꢁ6.8 Hz), 7.73 (2H, d,
next reaction. The NMR spectral data of this bromide are shown as follows; Jꢁ6.8 Hz). 13C-NMR (CDCl3) d ppm: 16.3, 21.6, 22.9, 26.0, 26.8, 27.4,
1H-NMR (CDCl3) d ppm: 0.16 (6H, s), 0.97 (9H, s), 1.35 (3H, s), 1.70 (2H, 28.5, 36.8, 56.0, 80.0, 82.7, 106.6, 110.7, 128.4, 129.6, 144.5, 145.7. EI-MS
m), 1.80 (3H, br d, Jꢁ1.3 Hz), 2.12 (3H, s), 2.17 (2H, m), 3.94 (2H, br s),
5.52 (1H, d, Jꢁ9.8 Hz), 5.59 (1H, br t, Jꢁ7.3 Hz), 6.26 (1H, d, Jꢁ9.8 Hz),
6.30 (1H, d, Jꢁ3.0 Hz), 6.47 (1H, d, Jꢁ3.0 Hz).
m/z: 366 (M)ꢂ. HR-EI-MS m/z: 366.1829 [Calcd for C20H30O4S: 366.1865
(M)ꢂ].
(3E,7E)-10-[6-(tert-Butyldimethylsilyloxy)-2,8-dimethyl-2H-chromen-
(2E)-3-Methyl-5-{(4R)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl}-2-pen- 2-yl]-3,7-dimethyl-1-{(4R)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl}-deca-
tenyl Acetate (13) To a mixture of potassium hexacyanoferrate(III) 3,7-diene (16) To a mixture of 15 (69 mg, 0.188 mmol) in THF (1 ml) at
(29.8 g, 90.5 mmol), potassium carbonate (12.5 g, 90.4 mmol), methanesul-
ꢀ78 °C under N2 atmosphere was added butyllithium (1.58 M in hexane,
fonamide (4.30 g, 45.2 mmol) and AD-mix b (4.0 g) in a combined solution
0.20 ml, 0.316 mmol) dropwisely over 10 min. The mixture was stirred at
of water and 2-methyl-2-propanol (each 250 ml) was added geranyl acetate ꢀ78 °C for 1 h. To a reaction mixture was added THF solution (0.2 ml) of
(9.0 g, 45.9 mmol) at 4 °C. The reaction mixture was stirred for 6 d at 4 °C,
allyl bromide 12 (45 mg, 0.100 mmol) over 10 min, and the reaction temper-
Na2S2O3 solution (50 ml) was added to quench the active oxidizer, and the ature was gradually warmed to 20 °C over 1 h. After stirred for 1 h at 20 °C,
mixture was concentrated under reduced pressure. The residue was extracted ammonium chloride solution (0.5 ml) to quench the reaction, and a mixture
twice with ethyl acetate (2ꢄ300 ml), and the combined extracts were washed of hexane–Et2O (1 : 1, 100 ml) was added to the reaction mixture. The or-
with saturated NaCl solution, dried over Na2SO4, filtered, and concentrated ganic phase was washed with water and saturated NaCl solution, dried over
under reduced pressure. The oily residue was purified by silica gel column Na2SO4, filtered, and concentrated under reduced pressure. The oily residue
chromatography [hexane–EtOAc (2 : 1)] to afford diol (4.82 g, 46% yield) as was purified by silica gel column chromatography [hexane–EtOAc (8 : 1)] to
colorless oil. The resulting diol (4.0 g, 17.4 mmol) was dissolved into 2,2-
dimethoxypropane (30 ml) and methanol (10 ml), followed by addition of p- as colorless oil. The physical data of the products are shown as follows; IR
toluenesulfonic acid hydrate (TsOH, 20 mg, 0.11 mmol) at 20 °C. After
(dry film) cmꢀ1: 1597, 1470. 1H-NMR (CDCl3) d ppm: (major signals) 0.16
give a diastereomeric mixture of the coupling products (27 mg, 37% yield)
standing for 2 h at 20 °C, pyridine (0.1 ml) was added and the mixture was (6H, s), 0.97 (9H, s), 1.07 (3H, s), 1.21 (3H, s), 1.25 (3H, s), 1.31 (3H, s),
concentrated under reduced pressure. The residue was purified by silica gel 1.41 (3H, s), 1.42 (2H, m), 1.52 (3H, s), 2.10 (3H, s), 2.21 (2H, m), 2.43
column chromatography [hexane–EtOAc (6 : 1)] to give acetonide 13 (3H, s), 2.80 (2H, m), 3.60 (1H, m), 3.68 (1H, m), 4.92 (1H, t, Jꢁ6.8 Hz),
(4.34 g, 92% yield) as colorless oil.
5.12 (1H, t, Jꢁ6.8 Hz), 5.49 (1H, d, Jꢁ9.8 Hz), 6.23 (1H, d, Jꢁ9.8 Hz), 6.28
Compound 13: [a]D25 ꢀ16.0° (cꢁ3.77, CHCl3). IR (dry film) cmꢀ1: 1732, (1H, d, Jꢁ3.0 Hz), 6.45 (1H, d, Jꢁ3.0 Hz), 7.29 (2H, d, Jꢁ7.7 Hz), 7.70
1243. 1H-NMR (CDCl3) d ppm: 0.99 (3H, s), 1.13 (3H, s), 1.21 (3H, s), 1.30 (2H, d, Jꢁ7.7 Hz). EI-MS m/z: 583 [MꢂHꢀC7H7SO2]ꢂ.
(3H, s), 1.40 (1H, m), 1.53 (1H, m), 1.63 (3H, s), 1.94 (3H, s), 2.00 (1H, m),
To
a solution of compounds obtained above (12 mg, 0.016 mmol)
2.18 (1H, m), 3.54 (1H, dd, Jꢁ3.0, 9.8 Hz), 4.49 (2H, d, Jꢁ6.8 Hz), 5.29
and [1,3-bis(diphenylphosphino)propane]palladium(II) dichloride (5.0 mg,
(1H, br t, Jꢁ6.8 Hz). 13C-NMR (CDCl3) d ppm: 16.3, 20.8, 22.7, 25.8, 26.6, 0.0085 mmol) in THF (0.1 ml) was added lithium triethylborohydride
27.1, 28.3, 36.4, 61.0, 79.8, 82.4, 106.3, 118.5, 141.2, 170.7. EI-MS m/z:
(1.05 M in THF, 1.0 ml, 1.05 mmol) at 0 °C under N2 atmosphere. After
stirred for 1 h at 0 °C, ammonium chloride solution (0.2 ml) to terminate the
270 (M)ꢂ.
(2E)-3-Methyl-5-{(4R)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl}-2-pen- reaction, and a mixture of hexane–Et2O (1 : 1, 50 ml) was added to the reac-
tene-1-ol (14) The obtained acetonide (4.0 g, 14.8 mmol) was dissolved tion mixture. The organic layer was washed with water and saturated NaCl
into methanol (50 ml) and potassium carbonate (415 mg, 3.0 mmol) was
added to the mixture at 20 °C. The reaction mixture was stirred for 3 h, and
then neutralized with saturated ammonium chloride solution (2 ml). After
concentration under reduced pressure, the residue was diluted with EtOAc
(200 ml). The organic layer was washed with water and saturated NaCl solu- 1603, 1470. H-NMR (CDCl3) d ppm: 0.16 (6H, s), 0.97 (9H, s), 1.01 (3H,
tion, dried over Na2SO4, filtered, and concentrated. The crude product was s), 1.24 (3H, s), 1.32 (3H, s), 1.36 (3H, s), 1.42 (3H, s), 1.47 (1H, m), 1.57
purified by silica gel column chromatography [hexane–EtOAc (5 : 1)] to give (3H, br s), 1.60 (3H, s), 1.63 (1H, m), 1.68 (2H, m), 1.96 (2H, m), 2.00 (1H,
solution, dried over Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatography
[hexane–EtOAc (10 : 1)] to give 16 (7.6 mg, 80% yield) as colorless oil.
Compound 16: [a]D25 ꢂ2.2° (cꢁ0.495, CHCl3). IR (dry film) cmꢀ1: 2929,
1
14 (3.24 g, 96% yield) as colorless oil.
m), 2.06 (3H, m), 2.10 (1H, m), 2.12 (3H, s), 2.17 (1H, m), 3.65 (1H, dd,
Compound 14: [a]D25 ꢂ4.3° (cꢁ0.285, CHCl3). IR (dry film) cmꢀ1: 3407 Jꢁ3.4, 9.4 Hz), 5.11 (1H, dt, Jꢁ1.3, 6.9 Hz), 5.15 (1H, dt, Jꢁ1.3, 6.9 Hz),
(br), 2980, 1671, 1370. 1H-NMR (CDCl3) d ppm: 1.01 (3H, s), 1.16 (3H, s),
5.55 (1H, d, Jꢁ9.8 Hz), 6.24 (1H, d, Jꢁ9.8 Hz), 6.30 (1H, d, Jꢁ3.0 Hz),
1.25 (3H, s), 1.33 (3H, s), 1.42 (1H, m), 1.56 (1H, m), 1.61 (3H, br s), 1.99 6.46 (1H, d, Jꢁ3.0 Hz). 13C-NMR (CDCl3) d ppm: ꢀ4.5, 15.5, 15.9, 16.0,
(1H, m), 2.17 (1H, m), 2.42 (1H, br s, OH), 3.58 (1H, dd, Jꢁ3.0, 9.4 Hz), 18.1, 22.6, 22.9, 25.7, 25.9, 26.0, 26.5, 26.8, 27.7, 28.5, 39.6, 40.8, 77.7,
4.07 (2H, d, Jꢁ6.8 Hz), 5.35 (1H, dt, Jꢁ1.3, 6.8 Hz). 13C-NMR (CDCl3) d 80.1, 82.8, 106.4, 114.8, 121.1, 121.7, 123.1, 124.2, 124.7, 126.0, 130.2,
ppm: 16.2, 22.7, 25.8, 26.7, 27.3, 28.3, 36.4, 58.8, 80.0, 82.7, 106.4, 123.7, 134.2, 135.1, 145.3, 148.3. EI-MS m/z: 582 (M)ꢂ. HR-EI-MS m/z: 582.4094
138.2. EI-MS m/z: 228 (M)ꢂ. HR-EI-MS m/z: 228.1700 [Calcd for
[Calcd for C36H58O4Si: 582.4104 (M)ꢂ].
(3R,6E,10E)-13-(2,8-Dimethyl-6-hydroxy-2H-chromen-2-yl)-2,6,10-
C13H24O3: 228.1726 (M)ꢂ].
(2E)-1-(p-Toluenesulfonyl)-3-methyl-5-{(4R)-2,2,5,5-tetramethyl- trimethyltrideca-6,10-diene-2,3-diol (1) Compound 16 (7.6 mg, 0.013
[1,3]dioxolan-4-yl}-2-pentene (15) The resulting alcohol 14 (1.27 g, mmol) was treated with 80% acetic acid solution at 40 °C under N2 at-
5.56 mmol) was converted to the corresponding allyl chloride by treatment mosphere for 20 h. After the solvent was removed under reduced pressure,
with methanesulfonyl chloride (1.30 ml, 16.8 mmol) and triethylamine the residue was purified by silica gel column chromatography
(4.0 ml, 28.7 mmol) in chloroform (20 ml) at 0 °C. The reaction mixture was
stirred for 1 h at 20 °C. After dilution with a mixture of hexane–Et2O (1 : 1,
[hexane–EtOAc (2 : 1)] to afford 1 (3.5 mg, 63% yield) as pale yellowish oil:
The spectral data obtained for the product were identical to those of both
200 ml), the organic phase was washed with water and saturated NaCl solu- isolated 1 and chemically converted 1 from 2.1)
tion, dried over Na2SO4, filtered, and concentrated under reduced pressure.
Compound 11): [a]D25 ꢂ12.5° (cꢁ0.385, CHCl3). IR (dry film) cmꢀ1: 3400
The oily residue was purified by passed over a small plug of silica gel (br), 1592, 1250. 1H-NMR (500 MHz, CDCl3) d ppm: 1.16 (3H, s), 1.20
[hexane–EtOAc (10 : 1)] to provide an unstable allyl chloride (670 mg, 49% (3H, s), 1.36 (3H, s), 1.41 (1H, m), 1.56 (1H, m), 1.57 (3H, s), 1.59 (3H, s),
yield) as pale yellowish oil. This compound is directly used for the next re- 1.66 (2H, m), 1.96 (2H, m), 2.02 (1H, m), 2.07 (2H, m), 2.11 (2H, m), 2.14
action without further purification. To a mixture of allyl chloride (670 mg, (3H, s), 2.22 (1H, m), 3.36 (1H, dd, Jꢁ2.1, 10.5 Hz), 5.10 (1H, br t,
2.71 mmol) and sodium iodide (2.03 g, 13.5 mmol) in DMF (25 ml) was
added sodium p-toluenesulfinate (1.21 g, 6.79 mmol) at 20 °C. The reaction
mixture was stirred for 3 h at 60 °C. After cooled to 20 °C, 1 : 1 mixture of
Jꢁ6.1 Hz), 5.15 (1H, br t, Jꢁ6.3 Hz), 5.58 (1H, d, Jꢁ9.9 Hz), 6.24 (1H, d,
Jꢁ9.9 Hz), 6.33 (1H, d, Jꢁ2.7 Hz), 6.49 (1H, d, Jꢁ2.7 Hz). 13C-NMR
(125 MHz, CDCl3) d ppm: 15.4, 15.5, 15.9, 22.5, 23.3, 25.8, 26.4, 26.4,
hexane–EtOAc (100 ml) was added and the organic layer was washed with 29.6, 36.8, 39.5, 40.7, 73.2, 77.8, 78.3, 110.3, 117.1, 121.3, 122.9, 124.2,
water and saturated NaCl solution, dried over Na2SO4, filtered, and concen- 125.0, 126.3, 130.7, 134.8, 135.0, 144.7, 148.7. EI-MS m/z: 428 (M)ꢂ, 410
trated under reduced pressure. The oily residue was purified by silica gel [(MꢀH2O)ꢂ]. HR-EI-MS m/z: 428.2945 [Calcd for C27H40O4: 428.2927
column chromatography [hexane–EtOAc (5 : 1)] to give 15 (727 mg, 73%
(M)ꢂ].

396
Acknowledgments The authors express their appreciation to Ms.
Vol. 54, No. 3
(2005), and references cited therein.
Kazuko Sawaya, Toyama Medical and Pharmaceutical University, for con-
ducting MS measurements. This work was supported in part by a Grant-in-
Aid for Scientific Research (15590097, M. I.) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
2) Mori J., Matsunaga T., Takahashi S., Hasegawa C., Saito H., Phytother.
Res., 17, 549—551 (2003).
3) Kolb H. C., VanNieuwenhze M. S., Sharpless K. B., Chem. Rev., 94,
2483—2547 (1994).
4) Terashima K., Takeya Y., Niwa M., Bioorg. Med. Chem., 10, 1619—
1625 (2002).
References and Notes
1) Iwashima M., Mori J., Ting X., Matsunaga T., Hayashi K., Shinoda D.,
Saito H., Sankawa U., Hayashi T., Biol. Pharm. Bull., 28, 374—377
5) Mori K., Uno T., Tetrahedron, 45, 1945—1958 (1989).