SYNTHESIS OF (+/-)-ASCOCHLORIN, (+/-)-ASCOFURANONE AND LL-Z1272α

Article abstract of DOI:10.1016/S0040-4020(01)96890-5

Three antibiotics with a common structural feature as prenylated phenols were synthesized: (+/-)-ascochlorin (5-chloro-2,4-dihydroxy-6-methyl-3-<(2'E,4'E)-5'-(1",2",6"-trimethyl-3"-oxocyclohexyl)-3'-methyl-2',4'-pentadienyl>benzaldehyde), (+/-)-ascofurano

Full text of DOI:10.1016/S0040-4020(01)96890-5

Vol.
No. 14, pp. 2711 to 2720, 1984
$3.00
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Printed in the U.S.A.
1984
Ltd.
SYNTHESIS OF
(
)-ASCOFURANONE AND LL-Z
and
Department of Agricultural Chemistry, The University of Tokyo, Yayoi l-l-l, Bunkyo-ku, Tokyo 113,
Japan
(Received in Japan 30 August 1983)
antibiotics with a common structural feature as prenylated phenols were synthesized:
(+)-ascochlorin (5
dihydroxy
6
methyl
3
5’
trimethyl
oxocyclohexyl) 3’ methyl
(5 chloro
dihydroxy
6
methyl
3
7’
and
4”
(5 chloro
2” oxacyclopentyl)
dihydroxy 6 methyl
3
trimethyl
To confirm the applicability of our syn-
Many prenylated phenols are known as microbial
metabolites. Among them, LL-Z1272a 1,’
thetic method for prenylated phenols,’ we carried out
the preparation of
Alkylation of
1 as shown in Fig. 2.
methyl
cofuranone
and ascochlorin
are of special
dimethoxy
3
interest because of their unique properties as anti-
biotics. The peculiar structural feature of these me
cyclohexadiene 7 with famesyl bromide 6 yielded 8 in
as the base. This was
to give
tabolites is the combination of a fully substituted 67% yield employing
benzene ring with a sesquiterpenoidal side-chain. The treated with N-chlorosuccinimide
crude 9 in 61% yield. Dehydrochlorination of 9 with
gave 10 in
73% yield. For the introduction of the CHO group,
challenges posed by the structures 2 and 3 are there-
fore (i) the construction of the
zene ring; (ii) the construction of the
ben-
moiety; and (iii) the coupling of the two building 10 was treated with
in
followed by
blocks. The early phase of our work was focused on
the construction of the fully substituted benzene ring reaction previously employed by us for the same
under mild conditions and culminated in the syn-
thesis of colletochlorin B We now report the full
This procedure was superior to the
purpose.’ Finally treatment of the crude product with
dil effected the hydrolysis of to
yielding 1, m.p. 6869” (lit.’ m.p.
whose spectral data were identical to
details of the synthesis of LL-Z1272a 1,
ascofuranone
compounds such as
)-ascochlorin and some related
(Fig. 1).
those reported by Ellestad et al.’
Recently Chen and
reported a’synthesis of
Synthesis of LL-Z 1272a and colletochlorin B
colletochlorin D 13 by the direct alkylation of
12 with isoprenyl bromide
lla in the presence of KOH aq in a yield of
previously reported the m.p. of 12 to be
Further purification of our crude 12 by
LL-Z1272a 1 is a metabolite from an unidentified
species isolated by Ellestad
al.’ It is a
growth-inhibitor of the protozoan, Tetrahymena
chromatography and
with m.p.
yielded pure 12
microbial chemistry-IV. This work was
presented by K.M. as a part of his lecture at the 10th
(from
m.p.
Application of this method to the
Conference on
Czechoslovakia (Octo-
3107 (1983).
synthesis of colletochlorin B 4 was attempted so as to
the scope and limitation of their short-cut
procedure. Colletochlorin B 4, m.p.
ber 1983). Part III, K.
Fellow on leave from Otsuka Pharmaceutical
Co. Ltd., Tokushima Research Institute (1981-83).
m.p.
Fig. 1. Structures of the target molecules.
2711

K.
and T.
2712
10
LL-Z1272
1
1 3
4
b
Fig. 2. Synthesis of
and colletochlorin B.
ists. Indeed an attempted synthesis of 2 had been
reported by et
Our successful synthesis of (+)-2 started from
geraniol 14 to build up the sesquiterpene part of the
molecule (Fig. 3). The aldehyde 15 was prepared from
was obtained in 16.5% yield by alkylating 1 2
with geranyl bromide llb. However, the alkylation of
12 with famesyl bromide 6 could not give any useful
result. We therefore decided to employ our own
procedure of prenylating the cyclohexadiene 7 for the
synthesis of more complicated compounds such as
ascofuranone 2 and ascochlorin 3.
14 as previously described by
reaction between 15 and
A cross-aldol
butanone gave
in 73% yield in the presence of
as the base (see Ref. 15). However, when
was employed as the base, the major product
(-)-Ascofuranone 2 is a hypolipidemic antibiotic
was i and the yield of the desired 16 was only 15%.
isolated from the mycelium of
et
configuration was established by an X-ray crys-
by
Cyclization of 16 to the furanone
tially attempted with
was ini-
Its structure including the (S)-absolute
or
as the dehydrating agents, but the yield of
tallographic analysis of
Re-
was at best
the simple dehydration product i
cently its antitumor protective effect on L-1210 leuke-
mia was discovered when it was administered once
having been the major product. We therefore tried to
protect the CO group in 16 prior to the cyclization to
seven days before tumor
The
prevent the /?-elimination of the
OH group. To
structure 2 coupled with its unique bioactivity makes
ascofuranone an attractive target for synthetic
our pleasure, instead of the acetalization of the CO
group, the desired cyclization to (+)-17a was effected
in 53% yield by the treatment of 16 with
containing a small amount of
in
our preliminary
we erroneously
was
stated that the absolute configuration of
Removal of the THP protective group in
unknown. This is untrue. We thank Dr. Y. Nawata,
Pharmaceutical Co. Ltd., for drawing our attention to their
X-ray
gave
whose homogeneity as the desired
was confirmed by its
and
15
G e r a n i o l
16
Fig. 3. Synthesis of

2713
Synthesis of
and
partment, we initiated our synthetic work on
cochlorin. In this case, the structure of the
HPLC analyses. This means that no isomerization of
the
bond took place either in the course
terpene part of the molecule is rather complicated
and hence is more to synthesize than that of
the required alkylating reagent, was ascofuranone.
As shown in Fig. 4, we chose
cyclohexenone and
as our starting materials. Hydrostannation of
23b with was followed by metal exchange
of the aldol reaction or at the stage of the furanone
formation. Conversion of to the bromide
straight-forward. Acetylation of
was followed by Noyori’s
to
Thus the
CO group in
acetal to give
was protected as an ethylene
in yield by treatment with
and
with
to give a lithiated
A mixed
to give
to
in
Al-
This was
upon suc-
derived from the lithiodiene and
was reacted with
kaline hydrolysis of
converted to the desired bromide
cessive treatments with
gave
in
in
yield after quenching with aq
and
Conjugate addition of this mixed
The later stages leading to (f)-ascofuranone 2
followed the route employed for the synthesis of
failed to give
gave the same
Both
and
LL-Z1272a 1. Alkylation of 7 with
was
(+)-24 as a mixture of geometrical isomers at C-2
with
effected with
as the base to give (+)-19 in 33%
ratio = 2: 1. The
of 23b
yield. Treatment of (+)-19 with NCS yielded
in 63% yield. Aromatization of (+)-20 with DBU
was therefore employed as the starting material.
Unfortunately, the trapping experiments with Me1 of
an enolate anion generated by the conjugate addition
gave
(50% yield). Finally formylation of
with
hydrolysis of the product gave (+)-ascofuranone 2,
m.p. in 21% yield. Its IR and
and
followed by acid
of the
reagent to
gave poor results of
directly. So
low reproducibility in securing
as to achieve the regioselective introduction of a Me
group at C-2’, the sterically less crowded
was blocked by the formylation of (+)-24 with
‘H-NMR spectra were identical with those of
(-)-ascofuranone kindly provided by Prof. G.
Tamura.
to give
This was converted to
Although the overall yield of (f)-ascofuranone
a dianion by treatment with 2 eq of
alkylation with 1.1 eq of Me1 yielded (
whose
Hydro-
in
was 0.82% from 15 in 11 steps, the
synthesis of
this interesting antibiotic was thus completed, mak-
ing it possible to synthesize various analogs of
cofuranone.
lysis of
with 2%
aq gave
55% yield from (+)-24. Treatment of
with
aq gave
in
whose acetylation
Synthesis of
afforded
yield from
The
3 is an antiviral antibiotic isolated
ethylene acetal (+)-%a was obtained in 86% yield
by Tamura from by treatment with
from the mycelium of
et
Its structure including absolute stereochemistry
and
This was hydrolyzed with
in 96% yield. Separation of the desired
of from the was
to give
was determined by an X-ray analysis as depicted in
Later biosynthetic studies on 3 by
et al.
definitely proved its dual biosynthetic origin as a carried out by medium pressure LC. In their
Mainly because of its structural
prenylated phenol.
novelty coupled with potentially useful bioactivity due to
and partly because it was discovered in our
‘H-NMR spectra,
showed a
at 1.71, while
showed it at 6 1.80. The
28b was
Fig. 4. Synthesis of

K. MORI and T.
2714
bromide
in the conventional manner.” This is now in progress in our laboratory.
synthesis of the moiety
converted
concluded
to
the
corresponding
of the optically active forms of these two antibiotics
of the target molecule. There was no trouble in
establishing the required stereochemistry around the
cyclohexane ring with three equatorial substituents at
C-l’, C-2’ and C-6’.
EXPERIMENTAL
were uncorrected. IR spectra refer to
All b.ps and
films for oils and Nujol mulls for solids and were measured
on a Jasco IRA 102 spectrometer. NMR spectra were
recorded at 60 MHz with TMS as an internal standard on
a Hitachi R-24A spectrometer, unless otherwise stated. The
To complete
and reliable route.
synthesis, we followed our general
of 7 with
numbering systems
compounds described below.
dimethoxy
8. To a stirred and cooled
(2.6 M in n-hexane. 4.2 ml. 10.9 mmole) in THF ml) was
added (1.5 g, at 78” under Ar. The stirring
was continued for 1 hr at 78”. HMPA (2 ml) was added
The crude to the mixture at -78”. The stirring was continued for
in Fig. 1 were used in naming
yielded
with
in
yield. Treatment of (
of NCS in DMF aq in the presence of
in 43% yield. Aromatization of
was achieved in 43% yield by
6
3
methyl 1.4
gave
to
heating (f )-30 with DBU in THF. Finally the CHO
group was introduced to
7
by treatment with
to give
in
followed by
10 min at -78”. To the stirred and cooled mixture was
added 6 (4.0 g) gradually. At the end of the addition the red
color of the anion of 7 faded. The mixture was left to stand
for a while with gradual raise of the reaction temp to room
temp. It was then poured into brine and extracted with
ether. The ether soln was washed with brine, dried
product was treated with 35%
3, m.p. 142-146”. The IR and
400 MHz ‘H-NMR data of our product were identi-
cal to those of
3 kindly provided by
Prof. G. Tamura. In entirely the same manner,
yielded the
3, m.p.
and concentrated in
to give 5.7 g of a crude oil. This
of
It should be added that
was chromatographed over
(Mallinckrodt
g).
gave 2.33 g
(+)-3 and its
could not be separated by
Elution with n-hexane-EtOAc (100:
(66.8% from of 8,
prep TLC. Although the overall yield of our synthesis
This was employed in
the next step without further purification.
is rather unsatisfactory
this completed the
3.
from 22 in steps),
synthesis of
Dichloro
9.
2
5
met hyl
(184 mg, 1.84 mmole) was added
to a soln of 8 (1.2 g, 3.35 mmole) in DMF (17 ml) and
To prove the generality of our approach, an analog
(+)-bisnorascochlorin 5 was also synthesized. The
route shown in Fig. 5 is exactly similar to the route
Ar was bubbled into the mixture for
to
remove any dissolved
NCS (983 mg, 7.36 mmole) was
added to the stirred mixture at O-5”. After the addition, the
mixture was stirred overnight at room temp. then poured
into water. The aq mixturewas stirred for min, acidified
developed for the syntheses of
except that the ethoxyethyl
itself
protective group was
employed in protecting the OH group in the enyne
with N-HCl to
soln was
concentrated
and extracted with ether. The ether
and brine, dried and
to give 1.55 g of a semi-solid. This was
(Mallinckrodt CC-7, 45 g).
with
alcohol
Starting from
32 and via the intermediates
chromatographed over
and
5, m.p.
were
Elution with n-hexane-EtOAc (100: l-2: 1) gave 810 mg
100” and its
m.p.
(60.6%) of 9,
3225 (m), 1610 (s) cm-‘. This was em-
ployed in the next step without further purification.
obtained as the racemates. In this case these two
geometrical isomers were separable by prep TLC.
In conclusion, the fist total syntheses of both
DBU (1.5 ml, 10.6 nunole)
was added to a soln of 9 (810 mg, 2.03 mmole) in THF (5 ml)
)-ascofuranone 2 and
)-ascochlorin 3 were ac-
under Ar. The soln was stirred and heated under
for
complished. The syntheses were flexible enough to
enable the preparation of their analogs which might
possess useful bioactivity as antibiotics. The synthesis
4hr. After cooling, the mixture was poured into water,
acidified with N-HCl to
4-5, and extracted with ether.
The ether soln was washed with water and brine, dried
Cl
Fig. 5. Synthesis of

2715
Synthesis of
)-ascofuranone and
1020
mj,
1.26
This was
s),
br. s),
sj,
(MgSO,) and concentrated in
The residual semi-solid
m), 4.55
(681 mg) was chromatographed over
60, Art 7734, 5 g). Elution with
gave 536mg (72.8%) of
(Merck Kieselgel
in the next
without further purification.
1.5221;
7
4’
2’
THP
3450 (m), 1620
1.55
1580 (m), 1455 (s), 1410 (s) cm-‘;
oxacyclopentyl)
ether
heptadien
1
and
s), 1.63
s), 1.76
s), 1.80-2.30
br.
s); MS: m/z 362
(24
(162
0.12
to a soln of 16
The soln was stirred for
m), 2.20
m), 5.47
s), 3.35
s), 5.68
d, J =
s), 6.20
0.049 mole) in
‘8 h at room
of
that period additional amounts
(24 mg x 2) and (0.5 ml) were ad-
chloro
dihydroxy 6 methyl
- -
ded to the mixture. It was then diluted with ether. The ether
1. One-third of an ether soln of
was washed with sat
aq and brine, dried
The residue was
prep from
(0.53 ml) and Mg
of 10 (464 mg,
(MgSO,) and concentrated in
(187 mg) was added
to a stirred
matographed over
(Merck Kieselgel 60, Art 7734,
1.28
30
in ether (4 ml) at room temp. After stirring for
(0.85 ml, 5.12 mmole) was added to the
350 g). Elution with n-hexane-EtOAc (50: l-5: 1) gave 8.8 g
of
1.4854;
1.15 s), 1.22
m), 3.14-4.09
1755 (s), 1110 (s), 1020 (s)
mixture and the reaction
was gradually raised to
s), 1.64
4.34-4.57
br. s),
m),
remove ether. The residue was heated at
After cooling, the mixture was acidified with
for
and
m). (Found: C, 70.87; H, 9.55.
for
extracted with ether. The ether
was washed with water
to give
This was chromatographed over
60, Art 7734, 9g). Elution with
and brine, dried (MgSO,) and concentrated
C, 71.39; H,
7
4’
2’
crude 1
oxacyclopentyl)
A soln of 17a (8.6 g) in
was stirred and heated at 50” for 2 h. It was then poured into
heptadien
1
(Merck
(3 1: 1: 1,200
hexane-ether
259me
of 1. This was
mg of 1,
recrystallized from n-hexane to
and extracted with ether. The ether
with sat and brine, dried
trated in
1460 (w), 1425 (m), 1375 (m), 1330 (w), 1290 (m), 1250 (s), (Merck Kieselgel 60, Art 7734, 70g). Elution with
was washed
and concen-
Further recrystallization of this from
gave 65 mg of pure 1, 68-69” (lit.’
3520 (w), 2975 (w), 2910
The residue was chromatographed over
2850 (w), 1630 (s),
1110 (m), 960 (w), 905 (w) cm-‘;
1.55
m), 2.54
s), 1.64
s), 3.36
s), 10.12
(10: l-l 1) gave 6.2 g (96.1%) of
s), 1.76
s), 1.80-2.20
3425 (m). 1755 (vs), 1665 (w), 1170 (s), 1110 (s),
d, J = 7 Hz),
s), 12.66
br. m), 6.42
995 (s)
‘H-NMR
1.15
1.20
3.94
br),
s); MS: m/z 390
The IR and NMR
was identical to those
1.61
s), 1.86-2.43
4.42
“C-NMR (25
2.68
spectral data of our synthetic
reported by Ellestad
1
t.
5.09-5.70
16.18,
(Found: C, 70.55; H. 7.96.
70.66; H,
1
for
25.92, 38.82, 39.93, 58.82, 77.72, 80.62, 124.35, 128.12,
Colletochlorin B (5 chloro
[(E)
The crude 12
6
133.27,
MS: m/z 252
HPLC (Column,
= 4: 1;
3
4.
was purified by prep TLC.
Partsil-5, 25 cm x 4.6 mm; Eluent,
1
13.2 min (single peak).
7
Further recrystallization of the sample from
n-hexane gave the pure 12, 170-172” (lit.”
W-170”) (25 MHz, 14.74, 102.26,
114.31, 114.43, 152.57, 161.46, 165.04, 194.93. (Found: C,
51.70; H, 3.88. for C, 51.50; H, 3.78%). This room temp. It was then poured into dil
4’
2’
acetate
(271 mg) in
oxacyclopentyl)
(0.15 ml) was added to a
of
and the mixture was stirred overnight at
and extracted
was alkylated with 2 eq of llb in the presence of 2 eq of 10%
KOH aq for two days at room temp. The mixture was poured
into water and extracted with ether. Further workup and the
purification of the product by
TLC gave 4 in 16.5% yield, m.p. 90-96” (lit.’
with ether. The ether
dried (MgSO,) and concentrated
was washed with water and brine,
residue was
Art 7734,
chromatographed over
5 g). Elution with
of
(Merck
chromatography and prep
(100: 8) gave 285 mg
1755 (s), 1740 (s), 1665 (w),
3520 (m), 2970
2910 (m), 2840 (m), 1630 (s),
1230
1170 (m), 1110
1.14 Sj, 1.20
1.86-2.45
1020
1.62
4.42
995
S),
cm-‘:
1455 (m), 1420 (m), 1375
1325 (m), 1285
s), 1.66
1250
1105
s),
(m) cm-‘;
2.02
1.58
3.42
s), 10.20
s), 1.80
J
=
7
Hz). 4.46
t.
1.95
br), 2.60
d, J = 7 Hz), 4.9-5.5
m), 6.54
s), 12.72
These
(Found: C, 69.43; H, 8.86.
for
C, 69.36; H,
spectral data were identical with those of an authentic sam-
ple.’ The identity was moved bv HPLC analvsis under the
condition described in Ref. 7.
7
2’ oxacyclopentyl)
heptadienyl acetate
Trihydroxy
trimethyl
A
soln of
and
(2 ml)
of
dodecadien
3
one
ether 16.
A
of
(1.58 g, 7.6 mmole) in
to a stirred and ice-cooled
under Ar. After
the reaction was quenched by the
The mixture was poured into sat
(14.2 g, 0.14 mole) in dry
to a stirred and cooled
was added
THF (150 ml) was added
of
in
(prep from 177 ml of 1.57 M
in
stirring for 7 h at
addition of
n-hexane and 58.5 ml of
at -20 to -30” under Ar. The
4
in THF (650 ml)
(22
was continued for
NaHCO, aq and extracted with ether. The ether
was
and concentrated in
The residue was chromatographed over
linckrodt CC-7, Elution with n-hexane-EtOAc
gave (80.4%) of 1.4832;
1 h at -20 to -30”. The mixture was then cooled to -78
and a soln of15 (17.5 g, 0.07 mole) in dry THF (250 ml) was
washed with brine, dried
added
over 90min to the mixture. After stirring
the reaction was quenched with sat
for 30min at
aq. The mixture was poured into brine and extracted
1740 (s), 1670 (w), 1230 (s), 1145 (s), 1025 (s) cm-‘; 6
with ether. The ether
was washed with brine, dried
and concentrated in
The residue was
m). 3.86
J = 7 Hz), 5.10-5.55
C, 67.50; H, 8.98.
7
4.22
t, J = 7 Hz), 4.49
C, 67.43; H,
d,
matographed over
with
1.4859;
(Mallinckrodt CC-7,300 g). Elution
(20: l-l 1) gave 18.0 g (73.2%) of 16,
1710 (s), 1115 (s), 1070 (s), 1050 (s),
m); MS: m/z 338
(Found:
for
3450

K. Mom and T.
2716
soln of (177 mg) in THF (0.9 ml) and the mixture was
stirred and heated under for 4 h under Ar. After
cooling, the mixture was poured into water, acidified
N-HCl to 4-5 and extracted with ether. The ether soln
was washed with water and brine, dried and
concentrated in The residue was chromatographed
over (Mallinckrodt CC-7, 5g). Elution with
(50: 1) gave 80 mg of 21, 3550
2’ oxacyclopentyl)
A soln of
heptadien 1 01
(1.41 g) in
(0.7 ml) and
was added
to a stirred soln of
The stirring was continued
(691 mg) in
overnight at room temp. The mixture was then poured into
water and extracted with ether. The ether
with brine, dried and concentrated
residue was chromatographed over
7, Elution with n-hexane-ether
was washed
The
(Mallinckrodt
gave 563mg
(m), 3380 (m), 3320 (m), 1655 (w), 1610 (m), 1585 (m), 1140
(s),
1025 (m)
s),
6
1.19
s), 1.51
s), 3.23
(93.1%) of
1.4937;
3425 (m), 1670 (w), 1150 (s),
s), 1.68
m), 2.20
1030 (s) cm-‘; (Ccl,), 1.11
s), 1.53
s),
s), 1.62
d, J = 7 Hz), 3.85
5.65
s), 4.29
br. s), 6.16
for
t, J = 7 Hz), 4.91-5.51
s), 6.36
s),
m), 3.85
m); MS: m/z 296
m),
br); MS:
(Found: C, 68.46: H,
m/z 436.2002.
436.2016.
dihydroxy 6
9.46.
for
C, 68.89; H,
Dimethvl-
7
ethvlenedioxv-
Ascofuranone (5 chloro
2’ oxacyclopentyl)
bromide A soln of
1.88 mmole) was added
soln of 1 8 b (5 5 7 mg, 1.88 mmole) in dry ether (1.9 ml) and wise to a soln of
(1.50 M in n-hexane, 1.25 ml,
2. A soln
to a stirred and ice-cooled of 21 (79 mg, 0.18 mmole) in ether (1 ml) was added drop
in ether at room
at room temp.
temp. The stirring was continued for
HMPA (0.66 ml). A soln of pTsCl(376 mg, 1.97 mmole) in
dry ether (1.9 ml) was then added
and ice-cooled mixture. After stirring for
(330 mg, 3.8 mmole) was added to the mixture. The stirring
to the stirred Subseauentlv
(0.12 ml. 0.72 mmole) was added to
off from the mixture and the
the
residue was heated at 100” for
After cooling, the
was continued overnight at room temp. The mixture was residue was acidified with N-HCl and extracted with ether.
diluted with ether and poured into sat aq. The
ether soln was separated, washed with water and brine,
dried and concentrated in uacuo to give 600mg
(quantitative) of
(Cdl,) 1.10
m l . 3 . 8 2
was
The residue was chromatographed over
(Mallinckrodt
CC-7, 3.5 g). Elution with n-hexane-ether (20: 1) gave a
crude product (73 mg) with the intact ethylene
group.
1655 (w), 1145
s),
1030
step
This was. dissolved in
12 2 ml) and the soln
30 min. After
was stirred and heated under
cooling, the mixture was diluted with water and extracted
with ether. The ether soln was washed with water,
aq and brine, dried
5.20-5.70
in the
further purification.
and concentrated in oacuo.
3
7’
The residue was purified by prep TLC (Merck, developed
with = 2: 1) to give 38 mg of an oil. This
was dissolved in ether, filtered to remove insoluble im-
ethvlenedioxv 2”
-- ‘ 6
clohexadiene 1 9 . A soln of 7 (3 19 mg, 2.07 mmole) in THF purities and concentrated in oacuo. Crystallization of the
(1.5 ml) was added to a stirred and cooled soln of residue (33 mg) from n-hexane-ether gave 24 mg (3 1.5%) of
(2.6 M in n-hexane, 0.9 ml, 2.3 mmole) in THF (8 ml) crystalline 2. Recrystallization from acetone-n-hexane gave
at 78” under Ar. The stirring was continued for 45 min at
78”. Then HMPA (0.42 ml) was added to the mixture and
the stirring was continued for 10 min at -78”. To this
16 mg (21.0%) of 2 as colorless fibrous needles,
87-91”;
3520 (m), 2970 (m), 2925 (m), 1755 (s), 1630
1460
(vs), 1220 (sh. m), 1165 (m), 1110 (m), 990 (m),
1.22
1420
1375
1325
1285
1250
(w)
1.63
m),
stirred and cooled mixture was added a soln of
(600 mg,
ca. 1.88 mmole) in THF (2 ml). The mixture was further
stirred for 30min at -78”. The temp was then raised to
and the reaction was quenched by the addition of sat
aq. The mixture was poured into brine and extracted
with ether. The ether soln was washed with brine, dried
and concentrated in oacuo. The residue was
1.28
1.79
dd, J= 10,
s), 3.39
5.21
s), 10.14
2.35
2.60
2.42
dd, J= 7, 18 Hz),
d, J =
t, J = 7 Hz), 5.51
s), s); MS:
4.52
dd, J = 7,
t, J = 7 Hz), 6.46
The
matographed over
with
(Mallinckrodt CC-7, 25g). Elution spectral data (IR and NMR) were identical to those of an
authentic
(Found: C, 65.66, H, 6.94.
C, 65.63; H,
for
A cata-
with
(100:
gave 270mg (33.2%
from
of 1 9 ,
1.5040;
1690 (s), 1655 (m), 1225 (s),
THP ether
was added to a soln of
and dihydropyran in ether
1200 (s), 1145 (s), 1050 (s), 1025 (s), 810 (m) cm-‘; MS: m/z
432
This was employed in the next step without lytic amount of
further purification.
3
stirring and ice-cooling. The mixture was stirred overnight
at room temp, washed with 5% aq and brine, dried
7’
ethylenedioxy 2” oxacyclopentyl)
methyl
(33 mg, 0.33 mmole) was added to
and concentrated in uacuo. The residue was dis-
tilled to give
(86.9%) of
3290 2090
b.p.
1640
1.82
t.
hexanedione 20.
a soln of 19 (256 mg, 0.59 mmole) in DMF (3 ml) and
Ar was bubbled into this mixture for
1.4820;
(w). 1120 (s), 1025
m). 4.56
= 7 Hz). This was employed
further purification. In the same manner
were also prepared.
to
1.61
br.
5.98
remove 0, comnletelv. NCS (174 ma. 1.3 mmole) was
ually add&i to
and ice-c&led mixture under Ar.
the
and
The stirring was continued overnight at room temp. The
mixture was then poured into water, acidified to by
adding and extracted with ether. The ether soln was
washed with water and brine, dried (MgSO,) and concen-
trated in uacuo. The residue was chromatographed over
(Mallinckrodt CC-7, 9 g). Elution with n-hexane-EtOAc
5
3’
3
methyl
pentadien
1
01 THP ether 24. A catalytic
amount of AIBN and
(4.4 ml, 16.5 mmole) were
added to 2 3 b (2.0 g, 11
under
and the mixture
(50: l-2: 1) gave 177 mg (63.2%) of crude
3200 (m), was heated at
for 30min. The excess was
1725 (s), 1620 (s), 1140
This was employed in the distilled off in oacuo at 100”. The residue
dissolved in
(1.50 M
THF (20 ml) and cooled to 78”. A soln of
next step without further purification.
4
Chloro
2
7’
in n-hexane, 8.8 ml, 13.2 mmole) was added over 20 min to
the mixture and the stirring was continued for 40min at
ethylenedioxy 2” oxacyclopentyl)
DBU (0.28 ml) was added to a
2’6’
-78”. To this was added a soln of
(1.2 g,

Synthesis of (f)-ascochlorin,
9.2 mmole) in ether (15 ml) and
and LL-Zl272a
2717
employed in the next step without further purification
in spite of the rather unsatisfactory elemental analytical
data.
18.4 mmole) over 15 min with stirring and cooling at -78”.
The stirring was continued for 2 h at 78”. A soln of (
(0.8 6.4
in ether (10 ml) was added
to
5
Trimethyl 3’
pentadienyl acetate
the stirred and cooled dark green-colored soln of the mixed
at 78” and the stirring was continued for 1.5 h at
-78”. The reaction was quenched by the addition of sat
and the mixture was extracted with ether. The
cyclohexyl)
3
methyl
(3 ml) was added to a soln of
in dry ml). The mixture was stirred overnight at
room temp, poured into iced-dil and extracted with
ether. The ether
and concentrated in
(6.1 g, 25.8 mmole)
ether soln was washed with water and brine, dried
was washed with water and brine, dried
and concentrated
matographed over
Elution with
The residue was
(Merck Kieselgel 60, Art 7734,
(SO: l-10: 1) gave
The residue was
over
Elution with
of 1.5116;
(Merck Kieselgel 60, Art 7734,
150
(10: l-3:
1710
6.3
1.17 g
22 was recovered after chromatography),
or 81.3% on the basis of consumed 22. Some
1.5095:
1740
1235 (s), 1020 (m), 970 (m) cm-‘;
0.72
s), 0.82
1715
1025
J =
1640
970
0.92
1200
890
1135 (m), 1120 (m), 1075 (m),
1.81
m), 4.58
1.98
d, J = 7 Hz),
cm-‘;‘
0.92
m). 2.00-2.53
d,
2.1-2.5
5.7-6.5
m),
for
(Found: C, 72.79; H, 9.37.
m),
4.53
C, 73.35; H,
m). (Found: C, 74.23; H, 10.09.
C, 74.47; H,
5
for
5
Ethylenedioxy
methyl pentadienyl acetate
3
3’
(0.45 ml) was added to a boln of
22.6 mmole) in
was ml of a soln anhydrous
(6.3
(31 ml). To this
(100 mg) in
cyclohexyl)
27a. (i)
washed with n-pcntane and
3
methyl
in mineral oil
was suspended in dry
pentadien
1
01 THP ether
was
dry C&-I, (30 ml). The mixture was stirred for 4 days at room
During that period (0.3 ml x 3) and
(5 ml x 3) were added to the soln. It was then
(8 ml). To this suspension was added a soln of (1.74
5.7 mmole) and (0.7 ml, 8.7 mmole) in dry
(8ml) in one portion with stirring and ice-cooling. The
mixture was stirred for 2 h at The excess was
destroyed by the addition of water and the mixture was
acidified with N-HCI to 4. It was then extracted with
ether. The ether soln was washed with dil
and brine, dried (MgSO,) and concentrated in uacuo to give
1640 (s), 1590 (s) cm-‘. This was
in
poured into dil
aq and extracted with ether. The
ether soln was washed with water and brine, dried
and concentrated in uacuo. The residue was
matographed over
(Mallinckrodt CC-7, 160 g). Elution
water with n-hexane-EtOAc (100: 3-50: 3)
6.3 (86.3% of
1
v
1740 (S), 1656
(S)
of crude
(Found: C. 70.78: H. 9.43.
employed in the next step without further purification.
for
C, 70.77;
5
(ii) A soln of
addition of
(13.2 mmole) was prepared by the
(1.50 M in n-hexane, 8.5 ml) to a of
Ethylenedioxy
pentadien
trimethylcyclohexyl)
3
methyl
A soln of
(18 ml) was added to a soln of
1
in
(1.7 ml) in THF (12 ml). To this was added bln
(i)
(3.5
of 25 (1.7 g) in THF (6 ml) gradually at
After stirring for 20 min at
with
(3.0 g) in
(0.4 ml, 6.4 mmole)
(10 ml). The mixture was stirred overnight at room
and HMPA (2.2 ml) were added to the mixture. The stirring
was continued for 1.5 h at 20”. The reaction was quenched
temp. It was then poured into water and extracted with
ether. The ether soln was washed with water and brine, dried
by the addition of sat
with N-HCI to
aq. The mixture was acidified
5 and extracted with ether. The ether
and concentrated
The residue was
matographed over
with
(Mallinckrodt CC-7, 30 g). Elution
soln was washed with water and brine, dried (MgSO,) and
gave
3400
(96.2%) of
1640 (w). 1065 (s)
concentrated in uacuo to give 1.75 g of crude 26,
1590 0.7-1.2 m). This was
employed in the next step without further purification.
1640
1 5170 v
MS: m/z
(ii) Separation of the two geometrical isomers. The above
(iii) (1.75 was dissolved in 2%
and heated
ml) and
h. It was Merck
5 and Elution with
described mixture
column (Li Chroprep Si 60,
(2: 1) gave
was chromatographed over a
reflux
then diluted with water, acidified with N-HCl to
(64%) of
extracted with ether. The ether soln was washed with water
The
1.5170;
3420 (m), 1640 (w), 1620 (w),
and brine, dried (MgSO,) and concentrated
1175 (m), 1150 (m), 1095 (m), 1070 (s), 1010 (m), 995 (m),
residue was chromatographed over
60, Art 7734, 60 g). Elution with
(Merck Kieselgel
(25: 1)
965 (m), 900 (m)
4.12 d, J =
6
m), 1.71
m), 5.95
and 0.8 g (32%) of
3420 (m), 1640 (w). 1175 (m),
5.0-5.7
d,
J =
MS: m/z 280
1.5137;
(m), 1095 (m), 1065 (s), 1010 (m), 990 (m), 965 (m), 900
gave l.Og
from 24) of
1.5154;
1715 (s),
1615 (w), 15 (s), 1075 (m), 1025 (s), 975 (m) cm-‘;
0.72
s), 0.78
d, J = 6 Hz), 0.82
d, J = 6 Hz),
m, signals at 1.78 and
(m)
m), 1.80
m), 6.26
s), 4.17
d, J=
m),
10.14.
s),
for
m). (Found: C, 74.43; H, d,
C. 74.96: H. 10.07% MS: m/z 280
5.10-5.59
5
3’
5
Ethylenedioxy
cyclohexyl)
3
methyl
pentadien
1
A soln
30ml) was
for 3 h. It was then poured into
water and extracted with ether. The ether was washed
with dil aq, water and brine, dried (MgSO,) and
methylcyclohexyl)
3
methyl
A soln of
pentadienyl bromide
(1.53 in
to a stirred
(0.96 g, 3.4 mmole) in
ether (3.4 ml)-HMPA (1.2 ml) under Ar. To this was added
a soln of (666 mg, 3.5 mmole) in ether
of
(1.1 g) in
(i)
hexane, 2.2 ml, 3.4 mmole) was added
and ice-cooled soln of
stirred and heated at
concentrated in uacuo. The residue was chromatographed
over
(3.4 ml). The mixture was stirred for 20 min at 0”. Then
(700 mg, 8.1 mmole) was added and the mixture was stirred
overnight at room temp. The mixture was poured into dil
and extracted with ether. The ether soln was
(Merck
Art 7734, 10 g). Elution with
(20: l-l 1) gave 0.8 g of
1.5261;
3410 (m), 1710 (s), 1015 (s), 970 (s) cm-‘; 6 0.71
s), 0.74
d, J =
0.76
d, J =
0.92-1.11
2.65
m),
br. s), 4.11
m), 2.11-2.51
m), washed
trated in
(w), 1610 (w), 1070 (s) cm-‘;
s), 3.85 br.),
water and brine, dried (MgSO,) and concen-
to give 1.04 g of crude
1640
m), 1.82
d, J = 7 Hz), 5.1 l-5.69
m),
m); MS: m/z 236
for
(Found: C, 74.84; H,
10.01.
C, 76.23; H,
This was
m). This was employed

Synthesis of (+)-ascochlorin,
- 1 was prepared
and
2719
dichloro - 6 - methyl -
manner as described for the synthesis of 30,
3.3 mmole) was treated with NCS (970 mg, 7.2 mmole) in the
cyclohexanedione 36. In the same
3 - methyl -
in the same manner as described for the synthesis of
employing the following materials:
(1.28 g,
presence of
(13 (1.48 ml). Subsequent work-up was followed
by chromatographic purification (Mallinckrodt g)
3200 (m), 2650 (w), 1620
(91 mg,
in DMF
(19 ml, 71 mmole), AIBN (trace),
(1.55 M in n-hexane, 46 ml, 71.6 mmole),
(6.6 g,
51 mmole),
88mmole) and 32
45 mmole). The crude product (12.5 g) obtained after
to give 720 mg
of 36,
matographic purification over
(Merck
Art
(s). 1080 (s) cm-‘; MS: m/z 432, 430, 428
M.W. = 429.384).
1:
7734, 300 g) was dissolved in 75%
aq (100 ml).
It was then
-
- 4 -
2 -
-
soln was stirred and heated at 40” for
diluted with water and extracted with ether. The ether soln
oxy - 1” - methylcyclohexyl) - 3’ methyl -
In the same manner as described for the
synthesis of 31, 36 (720 1.68 mmole) was heated under
with DBU (1.3 ml) in THF Subsequent
work-up was followed by chromatographic
(Mallinckrodt CC-7,24 g) to give 435 mg (66.5%) of 37,
3350 (m), 1615 (m), 1595 (m), 1460 (s), 1420 (s), 1355
1170 (s), 1085 (s) cm-‘;
-
was washed with dil
soln, water and brine, dried
The residue was
and concentrated in
matographed over
with
(Merck
g). Elution
(10: l-2: 1) gave 7.01 g (60.3% from
32 or 75.4% basing on the amount of the consumed 32) of
1.5210;
970 (s)
2.062.46
5.26-5.74 (2H; m), 5.98 and 6.33 (total
J = 15 Hz); MS: m/z 208
3425 (m), 1705 (s), 1220 (m), 1000 (m),
1.06
s),
m),
d, J = 7 Hz),
each d,
1.02 and 1.10 (total
m), 3.44
br. s), 4.11
each 1.50
s),
br. 1.73 and 1.81 (total
d, J =
MS: m/z 392
each br.
s),
3.80
s),
This was employed in the
next step without further purification.
- 5
-
- methyl - 3 -
-
-
(1” - methyl - 3” - oxocyclohexyl) - 3’ - methyl -
-
- 5 - (1’ - Methyl - 3’ -
- pentadienyl acetate 33b. Acetylation of 33a
(3.7 ml) and (50 ml) was followed
-
3 - methyl
(5.34 g) with
5 . ( i )
In the same manner as described for
syn-
by the usual work-up. The chromatographic purification thesis of 3, 37
(Merck Kieselgel 60, Art 7734, 30 g) of the crude product
0.32 mmole) was treated with
in ether and
(0.1 ml,
0.62 mmole) to give 59 mg (43.7%) of a crude product with
the intact ethylene acetal group. This (178 mg) was dissolved
gave
(91.9%) of
1.5057;
1.07
4.58
1740 (s), 1710 (s),
1230 (s)
s), 1.76
br. s), 1.96
d, J = 7 Hz), 5.21-5.72
each d, J = 15 Hz); MS:
2.01-2.41
in ice-cooled
stirred for
(1:
ml). The mixture was
at O-5”. The conventional work-up gave
m), 5.99 and 6.39 (total
m/z 250
(94.5% from the acetal or 41.3% from 37) of a
and These (83 mg) were
(Found: C, 71.41; H, 8.80.
for
mixture of
C, 71.97; H,
- 5 -
separated by prep TLC (Merck Kieselgel G; developed with
-
-
Ethylenedioxy - 1’ - methyl-
= 4:1) to give
100” (sinter at 65”) (from
(31 mg), m.p.
cyclohexyl) - 3 methyl
- pentadienyl acetate
In the
33b
3650 (w),
same manner as described for the synthesis of
3525 (m), 2980 (m), 1705 (s), 1630 (s), 1420 (m), 1285 (s),
(2.59 g, 10.3 mmole),
103 mmole),
(9.9 ml,
1250 (s) cm-‘; 6
1.01
s), 1.50-2.00
s), 3.39
d, J=
m),
d,
7.12
(0.3 ml, 7.5 mmole) and
(10 mg) yielded 2.7 g (88.6%) of
1.80
m), 2.00-2.37
m), 2.51
after chromatographic
1645 1230
1.05 and 1.09 (total
br. s), 1.93 s).
m), 5.81
purification,
1.5090;
1735
s), 9.97
s), 12.52
s); MS: m/z 376.1431.
1085 (s), 1020 (s), 960 (s) cm-‘;
for
for
of
376.1441. (Found: C, 64.21; H, 7.12.
C, 64.62; H, The presence
in the crystals was proved by the MS showing the
(ii) From less
each s), 1.48
br. s), 1.75
and 6.26 (total
(Found: C, 69.30; H, 8.85.
each d, J = 15 Hz; MS: m/z 294 (M+).
presence of M+ due to
for
C, 69.36; H,
polar zone of the prep TLC,
obtained, m.p. 147-152” (from
(22mg) was
3525
- 5 -
- Ethylenedioxy - 1’ - methyl-
- pentadien - 1 - In the
same manner as described for the synthesis of
(m). 2960 (m), 1785 (w), 1705 (s), 1630 (vs), 1455 (m), 1420
(m), 1375 (m), 1285 (s), 1250 (vs), 1110 (m), 970 (m)
cyclohexyl) - 3 - methyl
(11.5 g) was hydrolyzed with
in
aq to give
1.11
s), 3.44
s), 1.72
br. s), 2.10-2.35
m),
m), 5.43
s),
10.3 a
of
after chromatoaraphic purification.
2.52
d, J = 7 Hz), 5.15-5.61
3400 (m), 1080 (s)
br. s), 1.72 and 1.80 (total
d, J = 7 Hz),
1.08
d, J=
10.00
6.72
d, J=
7.15
1.50
s), 4.10
each s), 3.80
s), 12.55
s); MS: m/z 376.1438.
for
for
m). This was
376.1441. (Found: C, 66.28; H, 6.66.
C, 66.92; H,
employed in the next step without further purification.
-
- 5 -
Ethylenedioxy - 1’ - methyl-
cyclohexyl) - 3 - methyl
- pentadienyl bromide In
Acknowledgements-We thank Prof. G. Tamura, this De-
partment, for his gift of the authentic samples of
cofuranone and ascochlorin. Financial support by Otsuka
Pharmaceutical Co. Ltd. is gratefully acknowledged. This
work was partly supported by a Grant-in-Aid for Special
Project Research, Japanese Ministry of Education, Science
and Culture.
the same manner as described for the synthesis of
(2.22 8.3 mmole) gave 2.6 g (quantitative) of crude
l.lOand 1.15
br. 3.78
(total 3H. each s). 1.52
3.95 and
br. 1.80
each J =
m). This was employed in the next step without further
purification.
-
- 3 -
methylcyclohexyl) 3’ - methyl -
dimethoxy - 6 - methyl -
manner as described for the synthesis of 29,
7 (1.4 yielded 1.38 from of after
-
-
Ethylenedioxy - 1”
- pentadienyl] -
-
-
cyclohexadiene
In the same
(2.6 g) and
‘G. A. Ellestad, R. H. Evans, Jr. and M. P. Kunstmann,
Tetrahedron
1323 (1969).
Sasaki, T. Okutomi, T. Hosokawa, Y. Nawata and K.
(s), 1655 (m),
Tetrahedron Letters 2541 (1972).
1225
1205
1150
1085
MS:
the next step.
Ethylenedioxy 1” -
- pentadienyl] -
388
Sasaki, T. Hosokawa, M.
Antibiotics 26, 676 (1973).
and K.
directly
-
- 3
-
H. Sasaki, T. Hosokawa, Y. Nawata and Y.
Iitaka, Tetrahedron Letters 887 (1975).
methylcyclohexyl) - 3’ - methyl -
-

K.
and T.
2120
J. Jenis, P. M. Wovkulich and A. B. Smith, III,
Tamura, S. Suzuki, A. Takatsuki, K.
and K.
Tetrahedron Letters 4517 (1979).
Tsunoda, M. Suzuki and ‘Noyori,
Stork, P. A. and M.
Arima, Antibiotics 21, 539 (1968).
1357 (1980).
1393 (1969).
Nawata, K.
G. Tamura, K. Arima and Y. Iitaka,
Ibid. 22, 511 (1969).
and K. T. Suzuki,
and K. Sato, Tetrahedron 38, 1221 (1982).
445 (1974).
communication: K.
Tetrahedron Letters 24, 1547 (1983).
communication: K.
and T. Fujioka,
J. Birch, J. Chem.
430 (1944).
M. Ohki, A. Sato and M. Matsui,
and T. Fujioka,
3739 (1972).
J. Corey and R. H. Wollenberg, J. Am.
5581 (1974); J. Corey and R. H. Wollenberg, J. Org.
Chem. 40, 2265 (1975).
L. Chen, R. E. Schaub and C. V.
Ibid. 43, 3450 (1978).
Ibid. 23, 5443 (1982).
Casnati, M.
and A. Ricca, Ibid. 243 (1965).
“K.-M. Chen and M. M.
23, 4567 (1982).
K.
Magae, T. Hosokawa, K.
and G.
Tamura, Antibiotics 35, 1547 (1982).
E.
J. E. Semple and M. M.
Org.
47, 2369 (1982).
M. Ohki and M. Matsui, Tetrahedron 30, 715
(1974).