Total synthesis of both enantiomers of dictyochromenol and their (Z)-isomers.

Article abstract of DOI:10.1271/bbb.66.1915

Total syntheses of both enantiomers of dictyochromenol (1) and its (Z)-stereoisomer (2) were achieved with high enantiomeric purity. The results of this study reveal the relationship between the optical rotation of the resolved 1 enantiomers.

Full text of DOI:10.1271/bbb.66.1915

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Total Synthesis of Both Enantiomers of
Dictyochromenol and their (Z)-Isomers
Kota AOKIa, Mihoko TAKAHASHIa, Masaru HASHIMOTOa, Toshikatsu OKUNOa, Kazuya
KURATAb & Minoru SUZUKIc
a Faculty of Agriculture and Life Science, Hirosaki University Bunkyo- Cho 3, Hirosaki
036-8561, Japan
b Department of Material and Environmental Engineering, Hakodate National College of
Technology Hakodate 042-8501, Japan
c Laboratory of Biofunctional Chemistry, Graduate School of Enviromental Earth Science,
Hokkaido University Sapporo 060-0810, Japan
Published online: 22 May 2014.
To cite this article: Kota AOKI, Mihoko TAKAHASHI, Masaru HASHIMOTO, Toshikatsu OKUNO, Kazuya KURATA & Minoru
SUZUKI (2002) Total Synthesis of Both Enantiomers of Dictyochromenol and their (Z)-Isomers, Bioscience, Biotechnology,
and Biochemistry, 66:9, 1915-1924, DOI: 10.1271/bbb.66.1915
To link to this article: http://dx.doi.org/10.1271/bbb.66.1915
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Biosci. Biotechnol. Biochem., 66 (9), 1915–1924, 2002
Total Synthesis of Both Enantiomers of Dictyochromenol
and their (Z )-Isomers
Kota AOKI,1 Mihoko TAKAHASHI,1 Masaru HASHIMOTO
,
† Toshikatsu OKUNO
1,
,
1
3
Kazuya KURATA,2 and Minoru SUZUKI
1Faculty of Agriculture and Life Science, Hirosaki University, Bunkyo- Cho 3, Hirosaki 036-8561, Japan
2Department of Material and Environmental Engineering, Hakodate National College of Technology,
Hakodate 042-8501, Japan
3Laboratory of Biofunctional Chemistry, Graduate School of Enviromental Earth Science,
Hokkaido University, Sapporo 060-0810, Japan
Received March 22, 2002; Accepted May 16, 2002
Total syntheses of both enantiomers of dic-
tyochromenol (1) and its ( )-stereoisomer (2) were
achieved with high enantiomeric purity. The results of
this study reveal the relationship between the optical
rotation of the resolved 1 enantiomers.
studies on enantiomeric pairs of dictyochromenol
were performed with the objective of developing
novel antifeedants from the related compounds. We
report here total syntheses of both enantiomers of 1
Z
and (Z )-dictyochromenol (2) in optically pure forms
which features the introduction of an asymmetric
center utilizing Sharpless epoxidation and the con-
struction of a tetrahydropyran ring by 6-endo cycli-
zation of an epoxyalcohol system. These syntheses
disclose the assignment of the optical rotation of 1.
Key words: dictyochromenol; total synthesis; optical
rotation; feedingdeterrent
Continuing studies on feeding deterrents against
marine herbivores from brown algae of the family
Dictyotaceae have resulted in Kurata reporting the
isolation of such sesquiterpene-substituted quinones
as zonarol, zonarone and cyclozonarone from Dic-
tyopteris undulata Holmes collected in Tobi (Akita
Prefecture, Japan).1,2) Further investigation of the
newly collected sample yielded a new antifeedant
with potent activity comparable to that of zonarol
and zonarone. This substance was identiˆed as dic-
tyochromenol (1), which had previously been isolated
from the same alga collected in Izu-Shimoda (Shizuo-
ka Prefecture, Japan),3) by independent 1D and 2D
NMR spectra.4) Although Kakisawa et al. have
reported that the optical rotation of dictyochromenol
Our syntheses commenced with commercial
p-
hydroquinone (3) (Scheme 1). After protecting one
hydroxyl group of 3 in the form of a MOM ether by
i
MOMCl in the presence of Pr2NEt in CH3CN, the
other phenol was converted into allyl ether 4 by using
allyl bromide and K2CO3 in acetone under re‰uxing
9
temperature. Heating 4 at 220 C in N, N-diethylani-
line in an argon atmosphere resulted in Claisen rear-
rangement5) to give phenol 5 in an 88
yield. The
hydroxyl group of 5 was then protected as a TBDMS
ether by TBDMSCl imidazole in DMF, aŠording 6
z
W
in a 94
z
yield. The oleˆn moiety of 6 was successive-
ly oxidized with OsO4 NMO6) and sodium periodate
W
to give the corresponding aldehyde which, without
puriˆcation, was subjected to a Wittig reaction em-
ploying (carbomethoxyethylidene)triphenylphospho-
which they isolated was +4
9
, the [
a]D value for our
dictyochromenol was 0
9
, indicating that it was ra-
cemic. We resolved isolated 1 by chiral HPLC to
reveal enantiomers showing [
rane,7) giving (
E a,b-unsaturated ester 7 in a 96
z
)-
yield in three steps. The stereochemistry of the in-
29
a
]
9
„94.4 (c 0.55,
D
＝ ×
(tR 12.0 min, Chiralcel OD 0.45 cm
CHCl3)
25.0 cm, hexane 2-propanol (25:1), 1.0 ml min
W
W
29
D
＝
‰ow), and [
a
]
+94.1
9
(
c
0.58, CHCl3) (tR
14.0 min, under the same conditions).4) However, the
absolute stereochemistries of the isomers was not
identiˆed. In order to assign the absolute stereoche-
mistry of the resolved enantiomers of 1, synthetic
Fig. Structures of Dictyochromenol and Its (Z )-Isomer.
†
To whom correspondence should be addressed. Fax: +81-172-39-3782; E-mail: hmasaru
-dimethylformamide; DMSO, dimethylsulfoxide;
-toluenesulfonyl; DET, diethyl tartrate; TBHP, tert-butyl-
hydroperoxide; CSA, dl-camphorsulfonic acid; Ms, methanesulfonyl; DBU, 1.8-diazabicyclo[5.4.0]undec-7-ene
＠
cc.hirosaki-u.ac.jp
Abbreviations: MOM, methoxymethyl; TBDMS, tert-butyldiemethylsilyl; DMF,
THF, tetrahydrofuran; TBAF, tetrabutylammonium‰uoride; Ac, acetyl; -Ts,
N, N
p
p

1916
K. AOKI et al.
Scheme 2.
Scheme 1. Reagents and conditions
:
(a) MOMCl, iPr2NEt,
); (c)
); (d) TBDMSCl, imidazole,
); (e) i) OsO4, NMO, THF-H2O, ii) NaIO4,
MeOH–H2O, iii) Ph3P C(CH3)COOMe, CH2Cl2 (96
steps); (f) LiAlH4, THF, „78 C (99 ); (g) for 9, L-(+)-DET,
TBHP, Ti(O-iPr)4, CH2Cl2, „20
C (87 ); for 9 , mCPBA,
CH2Cl2 (81 ); (h) (S)-MTPACl, DMAP, CH2Cl2.
CH3CN (65
-diethylaniline, 220
DMF (94
z
); (b) K2CO3, allyl bromide, acetone (85
z
N
,
N
9
C (88
z
z
＝
z
, 3
9
z
9
z
?
z
troduced double bond in 7 was established by observ-
ing an oleˆnic proton signal at 6.90 ppm (br, t,
＝
J
7.3 Hz; calcd. for E-isomer, 6.6 ppm; Z-isomer,
1
6.0 ppm) in its H-NMR spectrum. Reduction of 7
with lithium aluminum hydride in THF at „78
produced allyl alcohol 8 in 99 yield. In preliminary
experiments, asymmetric dihydroxylation of 8 with
ADmix- was quite slow and aŠorded the desired
products in almost racemic forms. On the other
hand, Sharpless epoxidation of 8 with (+)-DET
Scheme 3. Reagents and conditions: (a) Swern ox.; (b) Ph3P
＝
9
C
CHCOOMe, CH2Cl2 (83
z
, 2 steps); (c) TBAF, AcOH, THF;
Pd C, H2, MeOH (92
z
); (f) MsCl, TEA, CH2Cl2; (g) DBU, xylene, re‰ux (92 , 2
z
(d) CSA, CH2Cl2 (83 , 2 steps); (e) 10
z
z
W
z
b
steps); (h) LiAlH4, THF (98
z
); (i) Dess-Martin reagent.
W
titanium tetraisopropoxide TBHP took place to give
tetrahydrofuran 12 (through 5-exo) in an 80z yield.
W
(„)-epoxide 9 in an 87
into MTPA9) ester 10. As a reference, 8 was oxidized
by mCPBA, and resulting racemic 9 was also trans-
z
yield8) which was converted
The ratio between 11 and 12 could not be improved
with the acids and solvents employed. Interestingly,
the selective formation of a tetrahydropyran ring
?
1
formed into MTPA ester 10
?
. In the H-NMR spec-
trum of 10 prepared from racemate 9
could be achieved by adding of p-TsOH to the reac-
?
?
, signals due
tion mixture in one pot, after completely removing
TBDMS group under the same conditions as these
to the methyl group of the side chain appeared at
1.35 and 1.38 ppm in a 1:1 peak ratio. On the other
hand, the ratio of those signals in 10 was 2.7:100
which revealed the diastereomeric excess of 10 to be
above, to give 11 in a 95
z
yield. Resulted 11 could be
converted into aldehyde 13 by several steps.
However, the coupling reaction of 13 with geranyl
magnesium bromide did not proceed, and only
reduction of the aldehyde moiety of 13 was observed.
We thus needed to choose an alternate synthetic
route.
95
the Sharpress epoxidation reaction proceeded with
high enantioselectivity (ca. 95 ee).
zde. The results of these experiments suggest that
z
Construction of the tetrahydropyran ring was next
examined in the 6-endo mode (Scheme 2).10)
Deprotection of the TBDMS group of 9 was achieved
by treating with TBAF in the presence of acetic acid11)
to give an epoxyphenol after silica gel column chro-
matography. When the reaction was performed
without acetic acid in the deprotection step, the
resulting phenol was decomposed and no epoxy-
phenol was obtained.12) It was found that treating the
We investigated the 6-endo type of tetrahydropy-
ran ring formation by taking advantage of the stable
allylic cations reported by Nicolaou (Scheme 3).13)
Swern oxidation14) of alcohol 9 gave an aldehyde
which was subjected, without puriˆcation, to Wittig
oleˆnation with methyl (triphenylphosphoranyli-
dene)acetate to stereoselectively produce (
saturated ester 14 in an 83 yield in two steps. The
coupling constant of the newly introduced double
bond was 15.6 Hz, indicating ( )-sterochemistry.
The TBDMS group of 14 was removed with a TBAF
E )-a,b-un-
z
epoxyphenol with p-toluenesulfonic acid in CH2Cl2
produced an inseparable 7:3 mixture of desired tetra-
E
hydropyrane derivative 11 (through 6-endo) and
W

Synthesis of Dictyochromenol and Isomers
1917
isomer 2. The 1H-and 13C-NMR data and IR spectral
data of synthesized 1 were identical with those
reported. The
Z-stereochemistry of 2 was conˆrmed
by observing the C-11? methyl (natural product num-
bering)3) signal at 23.3 ppm in the 13C-NMR spec-
trum, whereas that of 1 appeared at 15.9 ppm. The
speciˆc rotation values of 1 and 2 were „82.49(c
9
0.89, CHCl3) and „71.6 (c 0.71, CHCl3), respec-
tively. It could thus be concluded that the enantiomer
showing the negative optical rotation value in chlo-
roform carried the
R conˆguration. Employing
(„)-DET in an asymmetric epoxidation reaction on 8
Scheme 4. Reagents and conditions: (a) 25, n BuLi, THF, „78
(81 ); (b) Ac2O, pyridine (96 ); (c) 5 Na–Hg, NaH2PO4,
MeOH, „20 C (82 ); (d) HCl, MeOH.
9C
and almost the same procedure as that described,
S
-dictyochromenol (ent-1), [
CHCl3), and -isomer (ent-2), [
CHCl3), were also successfully synthesized.
In conclusion, we prepared both enantiomers of 1
as well as ( )-isomer 2. These studies reveal the
natural 1, which indicated an optical rotation value
a
]1D9+83.1
9
(
c
0.15,
0.25,
z
z
z
9
a (c
]1D9+74.7
9
z
S
-
Z
AcOH THF system to give phenol 15. Similar to the
Z
W
conditions used for 9, the addition of acetic acid was
necessary to avoid decomposition of resulting 15. As
of „94.4
9
carried the R conˆguration. The an-
anticipated, treatment of crude 15 with CSA CH2Cl2
tifeedant activities of 2 are under investigation in our
W
selectively constructed the 3,4-dihydro-2
H
-benzo-
laboratories.
[b]pyran framework, giving 16 as a single di-
astereomer in an 83
z yield in two steps. The
Materials and Methods
stereochemistry of 16 was conˆrmed by NOE be-
tween Ha (5.14 ppm, t,
oleˆnic Hb (5.97 ppm, d,
ing to corresponding diacetate 16
J
J
3.9 Hz, Scheme 3) and
15.6 Hz) after convert-
. After the double
1H-NMR spectra were measured by a JEOL
ALPHA 400 Spectrometer in chloroform-d. Chemi-
＝
＝
?
cal shifts are reported in ppm downˆeld from the
peak of tetramethylsilane as an internal standard.
Splitting patterns are designed as s, d, t, q, and br;
these symbols mean singlet, doublet, triplet, quartet,
and broad, respectively. IR spectra were measured by
a JASCO FT-IR 7000 instrument in a KBr cell.
bond of 16 had been reduced with catalytic 10
Pd C and H2 in methanol, dehydration was per-
z
W
formed by treating with methansulfonyl chloride in
the presence of triethylamine in CH2Cl2 and then by
heating with DBU in xylene at 140
90 yield in two steps. Once the ester part of 19 had
been reduced with lithium aluminum hydride to alco-
9
C, giving 19 in a
z
Optical rotation values were obtained with
a
HORIBA SEPA-300 HIGH-SENSITIVITY
hol 20 in a 98
z
yield, it was re-oxidized by em-
POLARIMETER. Low- and high-resolution-mass
spectra were obtained with a JEOL JMS AX-500
mass spectrometer.
Analytical and preparative thin layer chro-
matography were carried out on precoated silica gel
plates (MERCK 60 F254 Silica gel), and the Silica gel
used for column chromatography was Wakogel}
C-200. Analytical and preparative HPLC were car-
ried out with a WatersTM 600 system equipped with a
ploying Dess-Martin periodinane15) to aŠord alde-
hyde 21 which was subjected to the next step without
chromatographic puriˆcation.
The side chain was introduced by employing the
Julia protocol (Scheme 4).16,17) The addition of a THF
solution of crude aldehyde 21 at „789C to the solu-
tion of a lithio-sulfone, which had been generated by
butyllithium from 25, introduced a coupling reaction
to aŠord adduct 22 in an 81
z
yield as a mixture of
Waters 2487 Dual l Absorbance Detector.
THF was dried and distilled from sodium ben-
zophenone ketyl before use. Molecular sieves were
four possible diastereomers. These were subjected to
the next step without separation. After the hydroxyl
group of 22 had been acetylated, the diastereomeric
ˆnely powered and activated at 200
cuo
9
C for 2 hr in va-
mixture of acetates 23 was treated with 5
z
sodium
.
amalgam in methanol at „20 C in the presence of
9
sodium dihydrogen phosphate to give MOM-protect-
ed dictyochromenol 24 as a 1:1 inseparable mixture
around the newly introduced double bond. Deprotec-
tion of the MOM group in 24 by acidic methanol and
Allyl 4-(methoxymethoxy)phenyl ether (4). p-
Hydroquinone 3 (5.00 g 45.5 mmol) was stirred
with chloromethyl methyl ether (5.18 ml, 5.49 g,
68.2 mmol) in the presence of
N, N-diisopropyl-
subsequent HPLC puriˆcation (
m
-BONDASPHERE
150 mm, CH3CN:H2O (68:32)
TFA, 10.0 ml min ‰ow, detected at
ethylamine (15.8 ml, 11.7 g, 90.9 mmol) in CH3CN
×
5
m
C18 100 Å, 19(
containing 0.1
235 nm) aŠorded dictyochromenol (1) and its (
q
)
9
(150 ml) at 0 C, and the mixture was allowed to
z
warm to room temperature. After stirring for 8 hr,
W
Z
)-
MeOH (ca. 2.0 ml) was added to decompose the ex-

1918
K. AOKI et al.
1
cess reagent while stirring for an additional 1 hr at
room temperature. The mixture was concentrated
under reduced pressure, dissolved in AcOEt (150 ml),
1505, 1435, 1150, 1015; H-NMR (CDCl3)
d
: 3.35
＝
＝
(2H, br d,
J
6.4 Hz, C
H
2CH CH2), 3.46 (3H, s,
OC 3), 4.68 (1H, O
H
H
), 5.08 (2H, s, OC
H2OCH3),
＝
CH H), 5.15
and poured into a 1
M
aqueous HCl solution
5.12 (1H, dt,
J
＝
11.2, 1.5 Hz, CH2CH
(150 ml), before the organic layer was separated. The
(1H, dt, J 16.0, 1.5 Hz, CH2CH CH H), 5.98
＝ ＝
×
＝
＝
6.4, 11.2, 16.0 Hz, CH2CH CH2),
aqueous layer was extracted with AcOEt (100 ml 3).
(1H, ddt,
J
The combined organic solution was successively
washed with H2O (200 ml) and brine (200 ml), dried
over anhydrous MgSO4, and concentrated under
reduced pressure. The residue was puriˆed by silica
gel column chromatography with hexane:AcOEt
(85:15) to give 4-(methoxymethoxy)phenol (4.55 g,
6.40 (3H, m, aromatic protons); EIMS (relative in-
tensity,
z
)
m z: 194 (M+, 34), 164 (24), 149 (13), 45
W
(100); HREIMS: calcd. for C11H14O3, 194.0943;
found, 194.0970.
1-(tert-Butyldimethylsilyloxy)-2-(2-propenyl)-4-
methoxymethoxybenzene (6). A solution of 5 (3.97 g,
29.6 mmol, 65
z
) as a pale yellow oil. IR (ˆlm) cm„1
:
1
3370, 1505, 1225, 1190, 1150, 1080, 1010, 825; H-
20.0 mmol) in DMF (15 ml) was stirred with
TBDMSCl (4.00 g, 26.7 mmol) and imidazole
(4.50 g, 66.0 mmol) at room temperature for 3 hr.
The mixture was poured into H2O (200 ml) and ex-
NMR (CDCl3)
s, O ), 5.08 (2H, s, OC
(each 2H, br d,
(relative intensity,
d
: 3.46 (3H, s, OC
H3), 4.71 (1H, br,
H
H
2OMe), 6.73 and 6.90
＝
J
9.2 Hz, aromatic protons): EIMS
z
)
m z: 154 (M+, 26), 124 (21),
tracted with ether (100 ml 3). The combined organ-
×
W
103 (12), 45 (100); HREIMS: calcd. for C8H10O3,
154.0630; found, 154.0597.
ic solution was washed with brine (100 ml), dried
over MgSO4, and concentrated under reduced
pressure. Puriˆcation by silica gel column chro-
A suspension of a mixture of 4-(methoxymethoxy)
phenol (358 mg, 2.33 mmol) and K2CO3 (640 mg,
4.66 mmol) in acetone (10 ml) was stirred with allyl
matography with hexane:AcOEt (98:2) gave
(5.82 g, 18.8 mmol, 94 ) as a colorless oil. IR (ˆlm)
cm„1: 2950, 2350, 1500, 1220, 1150, 1020, 1075, 920,
840, 775; 1H-NMR (CDCl3)
: 0.18 (6H, s, Si(C 3)2),
0.98 (9H, s, SiC(C 3)3), 3.31 (2H, br d, 6.3 Hz,
6
z
bromide (845 mg, 600 ml, 7.00 mmol) under re‰ux
temperature for 10 hr. After H2O (ca. 30 ml) had
been added to the suspension to dissolve the solid
material, the mixture was concentrated under
reduced pressure to half the original volume. The
resulting mixture was successively extracted with
d
H
＝
J
H
＝
＝
C
H
2CH CH2), 3.45 (3H, s, OC
H
3), 5.03 (2H, m,
CH2CH
C
H
2), 5.07 (2H, s, OC
H
2OCH3), 5.93
＝
＝
8.8 Hz,
(1H, m, CH2C
H
CH2), 6.67 (1H, d,
J
ether (20 ml
×
3) and brine (20 ml), dried over anhy-
aromatic proton), 6,75 (1H, dd, J 8.8, 2.9 Hz, aro-
＝
＝
2.9 Hz, aromatic pro-
drous MgSO4 and concentrated in vacuo to give a
residue which was puriˆed by silica gel column chro-
matography. Elution with hexane:AcOEt (92:8)
matic proton), 6.80 (1H, d,
ton); EIMS (relative intensity,
J
z
)
m z: 308 (M+, 81),
W
251 (100), 73 (60), 45 (56); HREIMS: calcd. for
C17H28O3Si, 308.1808; found, 308.1821.
aŠorded 4 (387 mg, 2.00 mmol, 85
oil. IR (ˆlm) cm„1: 2900, 1505, 1220, 1195, 1150,
1080, 1010, 1100 920, 825: 1H-NMR (CDCl3)
: 3.47
z) as a colorless
d
Methyl
(E)-4-[2-(tert-Butyldimethylsilyloxy)-5-
＝
(3H, s, OC
OC 2CH
H
3), 4.49 (2H, dt,
J
5.6, 1.6 Hz,
2OMe), 5.27
(methoxymethoxy)phenyl]-2-methyl-2-butenoate (7).
H
＝
CH2), 5.10 (2H, s, OC
10.4, 1.2 Hz, OCH2CH
H
To a solution of 6 (993 mg, 3.22 mmol) and 4-
＝
＝
＝
(1H, dq,
(1H, dq,
J
J
C
C
H
H
H), 5.40
H), 6.04
CH2), 6.85
methylmorphorine-4-oxide (870 mg, 6.45 mmol) in a
＝
17.2, 1.2 Hz, OCH2CH
mixture of THF (10 ml) and H2O (2.0 ml), a 0.1
z
＝
＝
(ddt,
and 6.97 (each 2H, br,d,
tons); EIMS (relative intensity,
J
10.4, 17.2, 5.6 Hz, OCH2C
H
aqueous OsO4 solution (100 ml) was added at room
＝
J
9.6 Hz, aromatic pro-
temperature under an Ar atmosphere. After stirring
for 12 hr at the same temperature, the mixture was
poured into H2O (100 ml) and extracted with AcOEt
z
)
m z: 194 (M+,
W
22), 153 (5), 123 (13), 45 (100); HREIMS: calcd. for
C11H14O3, 194.0943; found, 194.0944.
(80 ml
×
3). The combined organic solution was suc-
aqueous Na2S2O3 solution
cessively washed with 10
z
2-(2-Propenyl)-4-(methoxymethoxy)phenol (
solution of 4 (379 mg, 1.95 mmol) in -diethylani-
line (3.0 ml) was heated at 220 C for 5 hr under an
5
).
A
(100 ml) and brine (100 ml), dried over Na2SO4, and
concentrated in vacuo. Puriˆcation by silica gel
column chromatography with hexane:AcOEt
(50:50) aŠorded 3-[2-(tert-butyldimethylsilyloxy)-5-
(methoxymethoxy) phenyl]propane-1,2-diol (1.09 g,
N, N
9
Ar atmosphere. After cooling to room temperature,
the mixture was poured into a 1
M
aqueous HCl solu-
z :
) as a colorless oil. IR (ˆlm) cm„1
×
tion (50 ml) and extracted with ether (30 ml 3). The
combined organic solution was washed with brine
(30 ml), dried over anhydrous MgSO4 and concen-
trated under reduced pressure. Puriˆcation was per-
formed by silica gel column chromatography with
hexane:AcOEt (85:15) to give 5 (334 mg, 1.72 mmol,
2.90 mmol, 98
3400, 2950, 1490, 1250, 1220, 1150, 1080, 1020, 940,
885, 840, 780; 1H-NMR (CDCl3)
: 0.20 (6H, s,
3)3), 2.22 (2H, br s,
d
Si(C
H
3)2), 0.98 (9H, s, SiC(C
H
×
＝
7.4, 12.7 Hz,
O
H
2), 2.74 (1H, dd,
J
＝
C
H
HCHOHCH2OH), 2.75 (1H, dd,
HCHOHCH2OH), 3.45
J
6.0, 12.7
(3H, s,
88
z
) as a colorless oil. IR (ˆlm) cm„1: 3400, 2900,
Hz,
CH

Synthesis of Dictyochromenol and Isomers
1919
＝
OCH2OC
H
3), 3.46 (1H, dd,
HOH), 3.61 (1H, dd,
CH2CHOHC HOH), 3.91
OHCH2OH), 5.07 (2H, s, OC
J
6.3, 11.2 Hz,
NMR (CDCl3)
d
: 0.19 (6H, s, Si(C
H
3)2), 0.98 (9H, s,
＝
＝
CH2CHOHC
H
J
3.4, 11.2
SiC(C 3)3), 1.74 (3H, s, C2C
H
H
3), 3.31 (2H, d,
J
Hz,
H
(1H,
m,
7.1 Hz, C4H2), 3.45 (3H, s, OCH2OC
br s, C1 2OH), 5.06 (2H, s, OC
br t, 6.1 Hz, C2 ), 6.67 (1H, d,
matic proton), 6.74 (1H, dd,
H3), 4.02 (2H,
CH2C
H
H
2OCH3),
H
＝
H
2OCH3), 5.57 (1H,
8.8 Hz, aro-
＝
2.9, 8.8 Hz, aromat-
6.71 (1H, d,
J
＝
8.8 Hz, aromatic proton), 6.78 (1H,
J
H
J
＝
＝
dd,
J
2.9, 8.8 Hz, aromatic proton), 6.83 (1H, d,
J
＝
＝
2.9 Hz, aromatic proton);
J
2.9 Hz, aromatic proton); EIMS (relative inten-
ic proton), 6.77 (1H, d,
EIMS (relative intensity,
(28), 245 (51), 75 (65), 73 (85), 45 (100); HREIMS:
calcd. for C19H32O4Si, 352.2070; found, 352.2079.
J
sity,
z
)
m z: 342 (M+, 25), 253 (85), 73 (74), 45
z
)
m z: 352 (M+, 96), 263
W
W
(100); HREIMS: calcd. for C17H30O5Si, 342.1863;
found, 342.1826.
A suspension of the resulting diol (963 mg,
2.81 mmol) and sodium periodate (686 mg, 3.20
mmol) in a mixture of methanol (15 ml) and H2O
(1.5 ml) was stirred vigorously at room temperature
for 1 hr. The mixture was then poured into H2O
(2S,3S) - 4 - [2 - (tert - Butyldimethylsilyloxy) - 5-
(methoxymethoxy)
butan-1-ol (
(251 mg, 711
phenyl]-2-methyl-2,3-epoxy-
9
). A suspension of a mixture of
mol), -(+)-DET (292 mg,
8
m
L
×
(100 ml) and extracted with ether (80 ml 3). The
1.42 mmol) and freshly activated and ˆnely pow-
dered 4A molecular sieves (100 mg) were stirred in
combined organic solution was washed with brine
(100 ml), dried over anhydrous MgSO4, and
concentrated in vacuo to give a crude aldehyde
which was dissolved in CH2Cl2 (10 ml). (Carbo-
CH2Cl2 (15 ml) at „20
tetraisopropoxide (222 mg, 782
3.6 solution in CH2Cl2, 595
added at the same temperature. After stirring for
3 hr, a 10 aqueous tartaric acid solution (3.0 ml)
was added to the mixture, and it was stirred for
9
C for 30 min. Titanium
mol) and TBHP (a
l) were successively
m
m
M
methoxyethylidene)triphenylphosphorane
3.20 mmol) was added to the solution at 0
(1.10 g,
C under
9
z
an Ar atmosphere, and the mixture was allowed to
warm to room temperature. After stirring for 10 hr,
the mixture was concentrated in vacuo. The residue
thus obtained was puriˆed by silica gel column chro-
matography with hexane:AcOEt (90:10) to aŠord 7
15 min at „209C and then for 1 hr at room tempera-
ture. After the mixture had been ˆltered through a
Celite pad in vacuo, the ˆltrate was poured into H2O
×
(20 ml) and extracted with ether (20 ml 3). The
(1.05 g, 2.76 mmol,98
cm„1: 2950, 2350, 1710, 1490, 1250, 1220, 1150,
1020, 890, 840, 770; 1H-NMR (CDCl3)
: 0.20 (6H, s,
Si(C 3)2), 0.97 (9H, s, SiC(C 3)3), 1.90 (3H, d,
1.0 Hz, C2C 3), 3.42 (2H, d,
3.45 (3H, s, OCH2OMe), 3.70 (3H, s, COOMe), 5.06
(2H, s, OC 2OMe), 6.75 (3H, m, aromatic protons),
6.90 (1H, br t,
z
) as a colorless oil. IR (ˆlm)
combined organic solution was stirred with a 2
M
aqueous NaOH solution (10 ml) for 1 hr at room
temperature, and then separated. The organic layer
was washed with brine (50 ml), dried over anhydrous
MgSO4, and concentrated under reduced pressure.
Puriˆcation was performed by silica gel column chro-
matography with hexane:AcOEt (87:13) to aŠord 9
d
＝
J
H
H
＝
7.3 Hz, C4H2),
H
J
H
J
W
＝
7.3 Hz, C3
H
); EIMS (relative
(228 mg, 619
z 9
mmol, 87 ) as a colorless. [a
]2D5„5.15
intensity,
z
)
m z: 380 (M+, 67), 323 (28), 89 (45), 73
(c
1.98, CHCl3); IR (ˆlm) cm„1: 3450, 2930, 1490,
1
(66), 45 (100); HREIMS: calcd. for C20H32O5Si,
380.2019; found, 380.2007.
1250, 1220, 1150, 1020, 890, 840; H-NMR (CDCl3)
d
: 0.22 (6H, s, Si(C
H
3)2), 1.00 (9H, s, SiC(C
H
3)3),
6.8, 14.6 Hz,
H), 3.31
3),
H), 3.69 (1H, br d,
H), 5.09 (2H, s, OC 2OCH3), 6.72
8.8 Hz, aromatic proton), 6.80 (1H, dd,
2.9, 8.8 Hz, aromatic proton), 6.89 (1H, d,
＝
1.39 (3H, s, C2C
C4
(1H, t,
3.64 (1H, br d,
11.7 Hz, C1
H
3), 2.78 (1H, dd,
J
(E)-4-[2-(tert-Butyldimethylsilyloxy)-5-(methoxy-
H H), 2.94 (1H, dd, J 6.8, 14.6, C4H
＝
＝
methoxy) phenyl]-2-methyl-2-buten-1-ol (
8
). Lithium
mol) was added to a
mol) in THF (2.0 ml) at
C under an Ar atmosphere. The mixture was
J
6.8 Hz, C3
H
), 3.45 (3H, s, OCH2OC
H
＝
H
aluminum hydride (5.1 mg, 134
solution of 7 (26.2 mg, 67
„78
m
J
11.7 Hz, C1
H
m
J
＝
H
＝
(1H, d, J
9
stirred for 1 hr at the same temperature, the cooling
bath was removed, and it was stirred for a further
J
＝
J
＝
2.9 Hz, aromatic proton); EIMS (relative intensity,
1 hr. After cooling to „78
9
C again, methanol
z)
m z: 368 (M+, 67), 253 (66), 89 (45), 73 (78), 45
W
(50 l), H2O (50 l), and ether (5.0 ml) were succes-
m
m
(100); HREIMS: calcd. for C19H32O5Si, 368.2019;
found, 368.1999.
sively added. The mixture was allowed to warm to
room temperature over 1 hr while stirring, Celite
(200 mg) was added to the suspension, and the whole
mixture was stirred for an additional 1 hr. After
ˆltration in vacuo, the ˆltrate was concentrated un-
der reduced pressure. The obtained residue was puri-
ˆed by silica gel column chromatography with hex-
(2R,3R) - 4 - [2 - (tert - Butyldimethylsilyloxy) - 5-
(methoxymethoxy)
phenyl]-2-methyl-2,3-epoxy-
butan-1-ol (ent-9). A similar treatment to that used
for 9, employing 8 (298 mg, 847 mol), -(„)-DET
(349 mg, 1.70 mmol), titanium tetraisopropoxide
m
D
ane:AcOEt (85:15) to give 8 (23.3 mg, 66
m
mol, 99
z
)
(265 mg, 932
CH2Cl2, 706
m
mol), TBHP (a 3.6
l) and CH2Cl2 (15 ml), and similar
mol, 90 ) as a
M
solution in
as a colorless oil. IR (ˆlm) cm„1: 3400, 2900, 1490,
m
1
1250, 1220, 1150, 1020, 940, 900, 880, 840, 780; H-
puriˆcation gave ent-9 (285 mg, 770
m
z

1920
K. AOKI et al.
colorless oil.. The 1H-NMR and EIMS spectra of this
silyloxy)-5-(methoxymethoxy)phenyl]-4-methyl-4,5-
epoxy-2-hexenoate (14). Oxalyl chloride (354 mg,
2.80 mmol) was added to a solution of DMSO
sample were identical with those of 9. [
a
]
25 +5.86
9(
c
D
1.84, CHCl3); HREIMS: calcd. for C19H32O5Si,
368.2019; found 368.2017.
(436 mg, 5.56 mmol) in CH2Cl2 (8.0 ml) at „789C.
After the mixture had been stirred at the same tem-
*
*
(2S ,3S ) - 4 - [2 - (tert - Butyldimethylsilyloxy) - 5-
(methoxymethoxy)phenyl] - 2 - methyl - 2,3 - epoxy-
perature for 10 min, a solution of 9 (206 mg,
559
ture. After stirring at „78
„45 C for an additional 45 min, the mixture was
cooled again to „78 C. Triethylamine (566 mg,
mmol) in CH2Cl2 (2.0 ml) was added to the mix-
butan-1-ol (
was stirred in CH2Cl2 (2.0 ml) with mCPBA (70
purity, 22.8 mg) at „10 C for 1 hr. The mixture was
then poured into a 10 Na2S2O3 solution (1.0 ml)
and extracted with AcOEt (20 ml 3). The combined
organic solution was washed with brine (25 ml), dried
over anhydrous Na2SO4 and concentrated in vacuo
9?
). A mixture of 8 (23.3 mg, 66
m
mol)
9
C for 30 min and then at
z
9
9
z
9
5.56 mmol) was then added to the mixture. After the
mixture had been allowed to warm to room tempera-
ture, it was poured into H2O (50 ml) and extracted
×
×
.
with AcOEt (80 ml 3). The combined organic solu-
The obtained residue was puriˆed by silica gel
column chromatography with hexane:AcOEt (82:18)
tion was washed with brine (100 mL), dried over
Na2SO4, and concentrated in vacuo to give a crude al-
dehyde which was then dissolved in CH2Cl2 (10 ml).
Methyl (triphenylphosphoranylidene) acetate
(373 mg, 1.12 mmol) was added to the solution at
to aŠord 9? (23.2 mg, 62.9 mmol, 95z) as a colorless
oil. The 1H-NMR spectrum of this sample was identi-
cal with that of 9.
9
0 C under an Ar atmosphere, and the mixture was al-
Determination of the enantiomeric excess of 9: An
lowed to warm to room temperature. After stirring
for 20 hr at room temperature, the mixture was con-
centrated in vacuo. The residue was puriˆed by silica
gel column chromatography with hexane:AcOEt
(
S
)-MTPACl solution (210
added to a mixture of racemic 9
and DMAP (8.0 mg) in CH2Cl2 (200
m
M
in benzene, 14
(1.9 mg, 5.16
l) at room tem-
m
l) was
?
mmol)
m
perature. After 10 min, the mixture was diluted with
ether (1.0 ml) to give a suspension which was ˆltered
through a Celite pad in vacuo. Concentration under
(87:13) to aŠord 14 (194 mg, 461
colorless oil. [ 1.96, CHCl3); IR (ˆlm)
]2D5+18.8
cm„1: 2950, 1720, 1495, 1260, 1220, 1150, 1010; H-
NMR (CDCl3) : 0.21 (6H, d, 2.9 Hz, Si(C 3)2),
1.00 (9H, s, SiC(C
(1H, dd, 6.4, 14.9 Hz, C6
5.8, 14.9 Hz,C6
C5
COOMe), 5.09 (2H, s, OC
15.6 Hz, C2 ), 6.80 (3H, m, aromatic protons),
6.82 (1H, d,
intensity,
z
mmol, 83 ) as a
a
9
(c
1
reduced pressure aŠorded crude 10
?
as a 1:1 di-
d
J
＝
H
astereomeric mixture. NMR spectra were observed
without silica gel column chromatography to avoid
H3)3), 1.53 (3H, s, C4Me), 2.81
J
＝
H
H), 2.97 (1H, dd,
J
＝
diastereoselective decomposition. 1H-NMR
d
:
H
H), 3.12 (1H, dd,
J
5.8, 6.4 Hz,
＝
×
×
(CDCl3) 0.176 (3H 0.5, s, Si(C
0.5, s, Si(C 3) (2), 0.188 (3H
H
3)), 0.183 (6H
0.5, s, Si(C 3)),
3)3), 1.35, 1.38
H
), 3.47 (3H, s, OCH2OMe), 3.73 (3H, s,
2OMe), 6.02 (1H, d,
H
×
H
H
J
＝
×
0.963, 0.971 (each 9H 0.5, s, SiC(C
H
H
(each 3H
6.0 Hz, C4
C4H ), 3.16 (1H, q,
(each 3H
×
0.5, s, C2C
H
3), 2.75 (1H, dt,
J
＝
14.5,
J 15.6 Hz, C3H ); EIMS (relative
＝
H
H), 2.87 (1H, dt,
J
14.5, 6.0 Hz,
z
)
m z: 422 (M+, 27), 365 (8), 333 (15),
＝
H
W
＝
H
J
6.0 Hz, C3
), 3.43, 3.45
252 (44), 73 (83), 45 (100); HREIMS: calcd. for
C22H34O6Si, 422.2125; found, 422.2136.
×
0.5, s, OCH2OC
H
3), 3.48, 3.50 (each 3H
＝ ×
1.2 Hz, CH3O), 4.13, 4.16 (each 1H 0.5,
(0.5, d,
d, 11.7 Hz, C1
J
J
＝
H
H), 4.407, 4.413 (each 1H, d,
Methyl
(2E,4R,5R)-4-[2-(tert-butyldimethyl-
＝
×
J
J
11.7 Hz, C1
H
H
H), 5.045, 5.050 (each 1H 0.5, d,
silyloxy)-5-(methoxymethoxy)phenyl]-4-methyl-4,5-
＝
×
＝
6.8 Hz, OC
2OCH3), 5.075, 5.080 (each 1H
2OCH3), 6.70 (1H, br d,
epoxy-2-hexenoate (ent-14). A similar treatment to
that used for 14 employing ent-9 (275 mg, 747 mmol),
0.5, d,
J
＝
6.8 Hz, OC
H
J
8.8 Hz, aromatic proton), 6.80 (2H, m, aromatic
proton), 7.35 (3H, m, aromatic proton), 7.48 (1H,
m, aromatic proton). A similar treatment was
performed by employing optically active 9 (1.9 mg,
oxalyl chloride (475 mg, 3.74 mmol), DMSO
(583 mg, 7.47 mmol), Et3N (1.11 g, 7.47 mmol),
CH2Cl2 (15 ml), methyl (triphenylphosphoranyli-
dene) acetate (468 mg, 1.49 mmol), and CH2Cl2
51.6
the (
m
mol), DMAP (8.0 mg), CH2Cl2 (200
m
l), and
(5 ml) and similar puriˆcation gave ent-14 (261 mg,
1
S
)-MTPACl solution (14 l). The diastereomeric
m
619
m
mol, 83
z
) as a colorless oil. The H-NMR and
excess was determined without chromatographic
EIMS data for this sample were identical with those
puriˆcation to be 95
z
de by comparing the intensity
9
of 14. [a (c 1.85, CHCl3). HREIMS: calcd.
]2D5„12.7
of the signals corresponding to C2CH3 (1.35,
1.38 ppm, 0.27:10) and C1H (4.13, 4.16 ppm,
for C22H34O6Si, 422.2125; found, 422.2141.
1
0.27:10) in its H-NMR spectrum. The ratio could
(2R,3S)-3,4-dihydro-3-hydroxy-2-[2(E)-(methoxy-
carbonyl)ethenyl]-6-methoxymethoxy-2-methyl-2H-
not be determined for the other signals due to peak
overlapping.
benzo[b]pyran (16). AcOH (53.2 mg, 886
TBAF (a 1.0 solution in THF, 885 l) were succes-
sively added to a solution of 14 (185 mg, 443 mol) in
mmol) and
M
m
Methyl
(2E,4S,5S)-6-[2-(tert-butyldimethyl-
m

Synthesis of Dictyochromenol and Isomers
1921
THF (5.0 ml) at room temperature under an Ar at-
1010, 1H-NMR (CDCl3)
d
: 1.23 (3H, s, C2C
H
3), 1.87
＝
mosphere. After stirring for 3 min, the mixture was
poured into H2O (30 ml) and extracted with AcOEt
(1H, dt,
J
6.3, 6.8, 14.6 Hz, C
H
HCH2COOMe),
＝
2.17 (1H,
ddd,
J
6.3,
6.8,
14.6 Hz,
×
＝
6.3, 6.8, 17.6
(15 ml 3). The combined organic solution was
C
H
HCH2COOMe), 2.47 (1H, dt,
Hz, CH2C
J
washed with brine (30 ml), dried over Na2SO4, and
concentrated in vacuo to give a crude alcohol which
was then dissolved in CH2Cl2 (5.0 ml) without puriˆ-
cation.
H
HCOOMe), 2.62 (1H, ddd,
J 6.3, 6.8,
＝
＝
17.6 Hz, CH2C
H
HCOOMe), 2.76 (1H, dd,
J
8.8,
), 2.96
5.9, 16.7 Hz, C4H H), 3.47 (3H, s,
＝
5.9 Hz, OH
16.7 Hz, C4
H
H), 2.91 (1H, d,
J
＝
(1H, dd,
OCH2OC
J
CSA (10.0 mg, 44.3
m
mol) was added to the solu-
H
3), 3.68 (3H, s, COOMe), 3.74 (1H, dt,
OH), 5.08 (2H, s, OC 2OCH3),
8.8 Hz, aromatic proton), 6.74 (1H,
tion at room temperature under an Ar atmosphere.
After stirring for 6 hr, the mixture was neutralized by
adding Et3N until litmus paper indicated the basic
condition. The mixture was poured into H2O (50 ml)
J
＝
5.9, 8.8 Hz, C3
H
H
＝
J
6.70 (1H, d,
＝ ＝
2.9 Hz, aromatic proton), 6.80 (1H, dd, J
d,
J
2.9, 8.8 Hz, aromatic proton); EIMS (relative inten-
and extracted with AcOEt (30 ml 4). The combined
sity,
z)
m z: 310 (M+, 3), 278 (29), 45 (100);
×
W
organic solution was washed with brine (30 ml), dried
over Na2SO4, and concentrated under reduced
pressure. Puriˆcation by silica gel column chro-
HREIMS: calcd. for C16H22 O6, 310.1416; found,
310.1397.
matography with hexane:AcOEt (75:25) gave 16
(2S,3R)-3,4-dihydro-3-hydroxy-2-[2-(methoxycar-
bonyl)ethyl] - 6 - methoxymethoxy - 2 - methyl - 2H-
benzo[b]pyran (ent-17). A similar treatment to that
25
(113 mg, 367 mmol, 83z) as a colorless oil. [a]
D
9
„63.5 (
c
1.33, CHCl3); IR (ˆlm) cm„1: 3450, 2950,
1720, 1490, 1310, 1200, 1150, 1070, 1010; H-NMR
1
used for 17 employing ent-16 (22.0 mg, 71.0
10 Pd C (2.0 mg) and MeOH (500 l) and similar
puriˆcation gave ent-17 (19.8 mg, 64.0 mol, 90
as a colorless oil. The H-NMR and EIMS data for
mmol),
(CDCl3)
d
: 1.45 (3H, s, C2C
8.8 Hz, O ), 2.77 (1H, dd,
H), 2.92 (1H, dd,
3.47 (3H, s, OCH2OC
3.92 (1H, br, C3 OH), 5.08 (2H, s, OC
H
3), 1.87 (1H, d,
＝
4.2, 17.2 Hz,
z
m
W
＝
J
H
J
m
z
)
1
＝
C4
H
J
4.4, 17.2 Hz, C4
3), 3.70 (3H, s, COOC
H
H
H),
3),
2OCH3),
25
H
this sample were identical with those of 17. [
+16.1 2.37, CHCl3). HREIMS: calcd. for
310.1416, C16H22O6; found, 310.1447.
a]
D
H
H
9
(c
＝
＝
CH
5.98 (1H, d,
J
15.6 Hz, CH
COOMe), 6.84
(3H, m, aromatic protons), 6.93 (1H, d,
J
＝
15.6 Hz,
＝
C
H
CHCOOMe); EIMS (relative intensity,
z)
(2R)-2-[2-(methoxycarbonyl)ethyl]-6-methoxy-
m z: 308 (M+, 43), 167 (31), 45 (100); HREIMS:
methoxy-2-methyl-2H-benzo[b]pyran (19). A solu-
W
calcd. for C16H20O6, 308.1260; found, 308.1254.
tion of 17 (64.0 mg, 206 mmol) in CH2Cl2 (3.0 ml)
was stirred with MsCl (94.4 mg, 82.4 mmol) in the
presence of Et3N (126 mg, 1.24 mmol) at 0 C, and
the mixture allowed to warm to room temperature.
After stirring for 1 hr, methanol (100 l) was added
(2S,3R)-3,4-dihydro-3-hydroxy-2-[2(E)-(methoxy-
carbonyl)ethenyl]-6-methoxymethoxy-2-methyl-2H-
benzo[b]pyran (ent-16). A similar treatment to that
9
m
used for 16 employing ent-14 (19.1 mg, 45.2
TBAF (90 l), AcOH (5.42 mg, 90 mol), THF
(1.5 ml), CSA (2.1 mg, 9.04 mol), and CH2Cl2
(1.0 ml) and the same puriˆcation gave ent-16
(12.7 mg, 41.2 mol, 91
) as a colorless oil. The 1H-
NMR and EIMS data for this sample were identical
with those of 16. [ 1.72, CHCl3).
]2D5+63.6
m
mol),
in order to decompose the excess reagent, and the
mixture was then stirred for 1 hr at room tempera-
ture. The mixture was poured into H2O (30 ml) and
m
m
m
×
extracted with AcOEt (30 ml 3). The combined
m
z
organic solution was washed with brine (30 ml) and
dried over Na2SO4 and concentrated in vacuo. Puriˆ-
cation of the residue by silica gel column chro-
matography with hexane:AcOEt (75:25) gave the cor-
responding mesylate which contained a small amount
of impurities. Without further puriˆcation, this was
diluted with xylene (3.0 ml) and then re‰uxed with
a
9 (c
HREIMS: calcd. for 308.1260, C16H20O6; found,
308.1238.
(2R,3S)-3,4-dihydro-3-hydroxy-2-[2-(methoxycar-
bonyl)ethyl] - 6 - methoxymethoxy - 2 - methyl - 2H-
benzo[b]pyran (17). A suspension of 16 (103 mg,
DBU (41.1 mg, 270 mmol) for 10 hr. After the mix-
ture had been cooled to room temperature, xylene
was removed under reduced pressure. The residue
was puriˆed by silica gel column chromatography
with hexane:AcOEt (90:10) to give 19 (48.5 mg,
335 mmol) and 10z Pd C (15.5 mg) in methanol
W
(2.0 ml) was vigorously stirred at room temperature
under an H2 atmosphere for 10 hr. The suspension
was ˆltered through a Celite pad in suction to give a
ˆltrate which was then concentrated under reduced
pressure. The obtained residue was puriˆed by silica
gel column chromatography with hexane:AcOEt
166 mmol, 92z) as a colorless oil. [a 9(c
]2D5„37.7
2.43, CHCl3); IR (ˆlm) cm„1: 2950, 1740, 1490,
1
1150, 1075, 1050; H-NMR (CDCl3)
d
: 1.37 (3H, s,
2CH2COOMe), 2.47 (2H,
2COOMe), 3.47 (3H, s, OCH2OC 3),
3.65 (3H, s, COOC 3), 5.08 (2H, s, OC 2OCH3),
5.52 (1H, d, 9.8 Hz, C3 ), 6.32 (1H, d,
C2C
H3), 2.00 (2H, m, CH
(80:20) to give 17 (95.6 mg, 308
colorless oil. [ 2.63, CHCl3) IR (ˆlm)
]2D5„16.8
cm„1: 3450, 2950, 1740, 1490, 1220, 1150, 1080,
m
mol, 92
z
) as a
m, CH2C
H
H
a
9(
c
H
H
J
＝
H

1922
K. AOKI et al.
＝
＝
J
9.8 Hz, C4
H
), 6.65 (1H, d,
J
8.8 Hz, aromatic
CHCl3); HREIMS: calcd. for C15H20O4, 264.1362;
found 264.1388.
＝
proton), 6.68 (1H, d,
J
2.9 Hz, aromatic proton),
＝
2.9, 8.8 Hz, aromatic proton);
6.78 (1H, dd,
J
EIMS (relative intensity,
z)
m z: 292 (M+,14), 277
(R)-dictyochromenol
chromenol ( ). A solution of 20 (40.9 mg, 155
in CH2Cl2 (2.0 ml) was stirred with the Dess-Martin
reagent (131 mg, 310 mol) at room temperature
under an Ar atmosphere. After 3 hr of stirring, a 2
aqueous NaOH solution (315 l) was added to the
(
1
)
and (R)-(Z)-dictyo-
W
(8), 261 (6), 205 (100), 161 (22); HREIMS: calcd. for
C16H20O5, 292.1311; found, 292.1291.
2
m
mol)
m
(2S)-2-[2-(methoxycarbonyl)ethyl]-6-methoxy-
methoxy-2-methyl-2H-benzo[b]pyran
M
(
ent-19).
A
m
similar treatment to that used for 19 employing
ent-17 (29.8 mg, 96.0 mol), MsCl (44.0 mg,
384 mol), Et3N (48.6 mg, 480 mol), CH2Cl2
(2.0 ml), DBU (44.0 mg, 288 mol) and xylene
(1.5 ml) and similar puriˆcation gave ent-19
(22.7 mg, 77.7 mol, 81
) as a colorless oil. The 1H-
NMR and EIMS data for this sample were identical
with those of 19. [ 2.16, CHCl3);
]2D5+37.7
mixture which was then stirred for an additional
10 min. The mixture was poured into H2O (25 ml)
m
×
m
m
and extracted with ether (20 ml 3). The combined
m
organic solution was washed with brine (30 ml), dried
over Na2SO4, and concentrated in vacuo to give
crude aldehyde 21.
m
z
Under an Ar atmosphere, buthyllithium (1.55
hexane, 213 l) was added to a solution of 6-phenyl-
sulfonyl-2-methyl-2-heptene (25; 100 mg, 396 mol)
in THF (3.0 ml) at „78 C while stirring. After stir-
M
in
a
9
(c
m
HREIMS: calcd. for C16 H20O5, 292.1311; found,
292.1306.
m
9
ring for 10 min, a solution of crude aldehyde 21 thus
obtained in THF (2.5 ml) was added to the mixture at
the same temperature and was stirred for 15 min. The
mixture was warmed to room temperature over
20 min, poured into H2O (25 ml), and extracted with
(2R)-2-(3-hydroxypropyl)-6-methoxymethoxy-2-
methyl-2H-benzo[b]pyran (20). Lithium aluminum
hydride (17.8 mg, 480
19 (70.0 mg, 240
mmol) added to a solution of
m
mol) in THF (3.0 ml) at „789C
under an Ar atmosphere. After the cooling bath had
been removed, the mixture was warmed to room tem-
perature and stirred for 1 hr. The mixture was then
ether (30 ml 3). The combined organic solution was
×
washed with brine (30 ml), dried over Na2SO4, and
concentrated in vacuo. Puriˆcation of the residue by
silica gel column chromatography with hexane:
cooled to „78
9
C again, and methanol (30 ml), H2O
(20 l), and ether (5.0 ml) were successively added.
m
AcOEt (90:10) gave 22 (55.0 mg, 107
mmol, 81z) as
The mixture was allowed to warm to room tempera-
ture over 1 hr, and Celite (200 mg) was added to the
suspension. The resulting suspension was ˆltered in
suction to give a ˆltrate which was concentrated un-
der reduced pressure. The residue was puriˆed by sili-
ca gel column chromatography with hexane:AcOEt
a mixture of four diastereoisomers. A mixture of 22
(55.0 mg, 107
pyridine (500
m
mol) and acetic anhydride (300
ml) in
m
l) was stirred at 40 C for 12 hr. After
9
the volatile substances had been removed under
reduced pressure, the residue was puriˆed by silica
gel column chromatography with benzene:AcOEt
(75:25) to give 20 (62.1 mg, 235
colorless oil. [ 2.05, CHCl3); IR (ˆlm)
]2D5„20.4
cm„1: 3400, 2950, 1480, 1150, 1075, 1050; H-NMR
(CDCl3) : 1.38 (3H, s, C2Me), 1.62 (1H, br s, O ),
1.73 (4H, m, 2C 2CH2OH), 3.48 (3H, s,
OCH2OC 3), 3.64 (2H, br t, CH2CH2C 2OH),
5.08 (2H, s, OC 10.3 Hz,
C3 ), 6.31 (1H, d, ), 6.67 (1H, d,
m
mol, 98
z
) as a
(97:3) to give 23 (60.5 mg, 103
ture of four diastereoisomers. Under an Ar at-
mosphere, 5 sodium amalgam (400 mg) was added
to the suspension of 23 (60.5 mg, 103 mol) and
NaH2PO4 2H2O (64.3 mg, 400 mol) in methanol
(3.0 ml) at „20 C while stirring. After 2 hr, the mix-
ture was poured into H2O (30 ml) and extracted with
ether (15 ml 3). The combined organic solution was
z
mmol, 96 ) as a mix-
a
9(c
1
z
d
H
m
C
H
H
・
m
H
H
9
＝
J
H
2OCH3), 5.57 (1H, d,
10.3 Hz, C4
8.8 Hz, aromatic proton), 6.68 (1H, d,
2.9 Hz, aromatic proton), 6.78 (1H, dd, 2.9,
＝
H
J
＝
H
×
＝
＝
J
J
washed with brine (30 ml), dried over MgSO4, and
concentrated in vacuo. The residue was puriˆed by
silica gel chromatography with hexane:AcOEt (97:3)
J
8.8 Hz, aromatic proton); EIMS (relative intensity,
z
)
m z: 264 (M+, 13), 249 (8), 205 (100), 161 (24), 45
to aŠord 24 (30.0 mg, 84.0 mmol, 82z) as a mixture
W
(16); HREIMS: calcd. for C15H20O4, 264.1362;
found, 264.1337.
of geometrical isomers around the newly produced
double bond. A solution of the mixture of 24
(30.0 mg, 84.0
with a 12
room temperature. After the mixture had been neu-
tralized by adding of Et3N (21 l), it was concentrat-
mmol) in methanol (1.0 ml) was stirred
aqueous HCl solution (6.0 ml) for 18 hr at
(2S)-2-(3-hydroxypropyl)-6-methoxymethoxy-2-
methyl-2H-benzo[b]pyran (ent-20). A similar treat-
ment to that used for 20 employing ent-19 (30.0 mg,
M
m
103
154
m
m
mol), lithium aluminum hydride (6.0 mg,
mol) and THF (1.5 ml) and similar puriˆcation
ed under reduced pressure to give a residue which was
puriˆed by silica gel column chromatography. Suc-
cessive elution with 90:10 and 85:15 hexane:AcOEt
gave a geometrical mixture of dictyochromenols
gave ent-20 (26.1 mg, 99.0
m
mol, 97
z
) as a colorless
1
oil. The H-NMR and EIMS data for this sample
were identical with those of 20. [ 2.33,
a
]2D5+20.3
9
(
c
z
(25.4 mg, 81.0 mmol, 96 ). This mixture was further

Synthesis of Dictyochromenol and Isomers
1923
puriˆed by HPLC (
m
-BONDASPHERE 5
m
C18
as colorless oils.
×
100 Å, 150 19 mm, CH3CN:H2O (68:32) contain-
(S)-dictyochromenol (ent-1).
[
a
]1D9+83.1
9(
c
0.15,
ing 0.1
235 nm) to give (
27.2 mol) and
10.7 mg, 34.3 mol) as colorless oils.
z
TFA, 10.0 ml min ‰ow, detected at
CHCl3); HREIMS: calcd. for C21H28 O2, 312.2089;
found, 312.2123.
W
R
)-dictyochromenol (1; 8.5 mg,
)-( )-dictyochromenol (2;
m
(
R
Z
m
(S)-(Z)-dictyochromenol (ent-2). [a 9 (c
]2D5+74.7
0.25, CHCl3). HREIMS: calcd. for C21 H28O2,
1
＝
(R)-dictyochromenol (
conditions); [
]2D5„82.4
cm„1: 3400, 1500, 1450, 1200; 1H-NMR (CDCl3,
natural product numbering) : 1.37 (3H, s, C2C 3),
1.57, 1.58, 1.67 (each, 3H, br s, C9 3, C10 CH3,
C11 CH3), 4.39 (1H, s, OH), 5.09 (2H, m, oleˆnic
proton), 5.60 (1H, d,
d, 9.8 Hz, C4 ), 6.48 (1H, d,
matic proton), 6.57 (1H, dd,
1
(
). tR 43.0 min (foregoing
312.2089; found, 312.2079. The H-NMR and IR
a
9
c
0.89, CHCl3); IR (ˆlm)
data for these samples were identical with those of 1
and 2, respectively.
d
H
?
C
H
?
References and Notes
?
1) Taniguchi, K., Yamada, J., Kurata, K., and Suzuki,
M., Feeding Deterrents from the Brown Alga Dic-
tyopteris undulata against the Abalone Haliotis dis-
cus hannai. Bull. Japan. Soc. Sci. Fish. (in Japanese),
59, 339–343 (1993).
2) Kurata, K., Taniguchi, K., and Suzuki, M.,
Cyclozonarone, a sesquiterpene-substituted benzo-
quinone derivative from the brown alga Dictyopteris
undulata. Phytochemistry, 41, 749–752 (1996).
3) Dave, M.-N., Kusumi, T., Ishitsuka, M., Iwashita,
T., and Kakisawa, H., A Piscicidal Chromanol and A
Chromenol from the Brown Alga Dictyopteris un-
dulata. Heterocycles, 22, 2301–2307 (1984).
4) Suzuki, M., Kurata, K., and Taniguchi, K., unpub-
lished results.
5) Tarbell, S. D., The Claisen Rearrangement. In ``Or-
ganic Reactions,'' 2, ed. Adams, R., John Wiley &
Sons, New York, pp. 1–48 (1962).
6) Schroder, M., Osmium Tetraoxide Cis Hydroxylation
of Unsaturated Substrates. Chem. Rev., 80, 187–213
(1980).
＝
J
9.8 Hz, C3-C
H
), 6.27 (1H,
2.9 Hz, aro-
2.9, 8.3 Hz, aromat-
8.3 Hz, aromatic proton),
: 15.9, 17.7, 22.6, 25.7, 26.0,
J
＝
H
J
＝
＝
J
＝
J
ic proton), 6.64 (1H, d,
13C-NMR (CDCl3)
d
26.7, 39.7, 40.9, 78.1, 112.8, 115.4, 116.7, 122.0,
122.6, 124.0, 124.3, 131.0, 131.3, 135.3, 147.0,
149.2; EIMS (relative intensity,
z
)
m z
:
312
W
(M+,11), 161 (100); HREIMS: calcd. for C21H28O2,
312.2089; found, 312.2082. These NMR spectral data
were identical with those of the natural product
reported by Professor Kusumi.
＝
(R)-(Z)-dictyochromenol (
going conditions); [
]2D5„71.6
(ˆlm) cm„1: 3400, 2950, 1480, 1450, 1200; H-NMR
(CDCl3, natural product numbering) : 1.36 (3H, s,
C2C 3), 1.59, 1.66, 1.68 (each, 3H, br s, C9 H3
C10 3, C11 CH3), 5.09 (2H, m, oleˆn proton),
5.58 (1H, d, 10.0 Hz, C3 ), 6.27 (1H, d,
10.0 Hz, C4 ), 6.47 (1H, d,
2
). tR 38.0 min (fore-
a
9
(c 0.71, CHCl3); IR
1
d
H
?
C
,
?
C
H
?
＝
J
H
H
J
J
＝
7) Maercker, A., The Wittig reaction. In ``Organic
Reactions,'' 14, eds. John Wiley & Sons, New York,
pp. 270–490 (1965).
8) Hanson, R. M., and Sharpless, K. B., Procedure for
the Catalytic Asymmetric Epoxidation of Allylic alco-
hol in the Presence of Molecular Sieves. J. Org.
Chem., 51, 1925–1926 (1986).
＝
2.9 Hz, aromatic
2.9, 8.8 Hz, aromatic pro-
8.8 Hz, aromatic proton); 13C-
proton), 6.56 (1H, dd,
ton), 6.63 (1H, d,
J
＝
＝
J
NMR (CDCl3) d: 17.6, 22.4, 23.4, 25.7, 26.0, 26.5,
31.9, 41.1, 78.0, 112.8, 115.4, 116.7, 122.0, 122.5,
124.3, 124.8, 131.0, 131.5, 135.4, 147.0, 149.2; EIMS
9) Dale, A. D., and Mosher, H. S., Nuclear Magnetic
Resonance Enantiomer Reagents. Conˆgurational
(relative intensity,
z
)
m z: 312 (M+,17), 161 (100);
W
HREIMS: calcd. for C21 H28O2, 312.2089; found,
312.2097.
Correlation Shifts of Diastereomeric Mandelate,
Methylmandelate, and -Methoxy-
phenylacetate (MTPA) Esters. J. Am. Chem. Soc.
95:2, 512–519 (1973).
O
-
a
a
-tri‰uoromethyl-
,
(S)-dictyochromenol
tyochromenol (ent-2). A similar treatment to that
used for 1 and 2 employing ent-20 (43.2 mg, 164
(
ent-1
)
and (S)-(Z)-dic-
10) Baldwin, J. E., Rules for Ring Closure. J. Chem.
Soc. Chem. Commun., 734–736 (1976).
,
11) Smith, III, A. B., and Ott, G. R., Total Synthesis of
m
mol), the Dess-Martin reagent (208 mg, 492
CH2Cl2 (2.5 ml), 2 NaOH (250 l; for oxidation),
25 (150 mg, 595 mol), BuLi (328 l), THF (7.0 ml;
for coupling), pyridine (500 l), Ac2O (300 l; for
acetylation), NaH2PO4–2H2O (48.2 mg, 309 mol),
sodium amalgam (310 mg), MeOH (2.0 ml; for
desulfonylation), a 12 aqueous HCl solution
(5.0 l), and MeOH (1.0 ml; for deprotection) and
mmol),
(„)-Macrolactin. J. Am. Chem. Soc.
13095–13096 (1996).
,
118,
N
m
m
m
12) Clark, J. H., Floride Ion as a Base in Organic Synthe-
sis. Chem. Rev., 80, 429–452 (1980).
13) Nicolaou, K. C., Duggan, M. E., Hwang, C.-K., and
Somers, P. K., Activation of 6-endo over 5-exo
Epoxide Openings. Ring-selective Formation of
Tetrahydropyran Systems and Stereocontrolled Syn-
thesis of ABC Ring Framework of Brevetoxin B. J.
Chem. Soc., Chem. Commun., 1359–1362 (1985).
14) Mancuso, A. J., Huang, S.-L., and Swern, D., Oxi-
dation of Long-Chain Alcohols to Carbonyls by
m
m
m
5
z
M
m
similar puriˆcation gave ent-1 and ent-2 (10.9 mg) as
colorless oils. Further HPLC separation under the
above mentioned conditions aŠorded pure ent-1
(5.5 mg, 17.6 mmol) and ent-2 (3.9 mg, 12.5 mmol)

1924
K. AOKI et al.
Dimethyl Sulfoxide ``Activated'' by Oxalyl Chloride.
J. Org. Chem., 43, 2480–2482 (1978).
15) Dess, D. B., and Martin, J. C., Readily Accessible
12-I-5 Oxidation for the Conversion of Primary and
Secondary Alcohols to Aldehydes and Ketones. J.
Org. Chem., 48, 4155–4156 (1983).
16) Julia, M., and Marc, J., Syntheses a L'aide de
Sulfones V(+)-Methode de Synthese General de
Doubles Liaisons. Tetrahedron Lett., 49, 4833–4836
(1973).
17) Trost, B. M., Arndt, C., and H. Strege, P. E., Tetra-
hedron Lett., 3477 (1976).