Preparation of 2,6-difluoromanoalogues derivatives

Article abstract of DOI:10.1016/S0022-1139(99)00246-8

Design of the inhibitors for the phospholipase A₂ modified with fluorine(s) and total synthesis of 2,6-difluoromanoalogues derivatives, are described.

Full text of DOI:10.1016/S0022-1139(99)00246-8

Journal of Fluorine Chemistry 102 (2000) 61±67
Preparation of 2,6-di¯uoromanoalogues derivatives
*
Yuzo Komatsu, Tomoya Kitazume
Department of Bioengineering, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8501, Japan
Received 5 June 1999; received in revised form 19 July 1999; accepted 20 August 1999
Dedicated to Professor Paul Tarrant on the occasion of his 85th birthday
Abstract
Design of the inhibitors for the phospholipase A modi®ed with ¯uorine(s) and total synthesis of 2,6-di¯uoromanoalogues derivatives,
2
are described. # 2000 Elsevier Science S.A. All rights reserved.
2
Keywords: Bioactive materials; Inhibitor; Phospholipase A ; Fluorine
1
. Introduction
Since the discovery of the anti-in¯ammatory activity of
2. Results and discussion
A convenient synthetic route to the desired materials is
shown in Scheme 3 and/or Scheme 4. To obtain the desired
¯uoromanoalogues (9a and 9b) derivative possessing ¯uor-
ine atom(s), we required the cis- and/or trans-acetal deri-
vatives (4a and 4b) as a precursor.
manoalide [1] and/or manoalogues [2], research into the
modi®cation of those materials with functional group(s)
and/or halogen atom(s), thus generating effective inhibitor
of the phospholipase A (PLA ) [3±5], has been extensive in
2
2
recent years. It is well known that the irreversible inactiva-
tion of cobra venom phospholipase A by manoalide and
manoalide analogues requires the opening of the lactone ring
and the presence of the a,b-unsaturated aldehyde moiety
At ®rst, compound 1 was sought to undergo a Horner±
Emmons reaction upon treatment with NaH±(EtO)2-
P(O)CHFCO Et system in THF, giving satisfactory conver-
2
2
sion of desired cis- and trans-compound 2, and then the
mixture was transformed into its thioacetal derivative by the
reaction of ethanthiol in the presence of BF ÁEt O. Then, for
(
shown in Schemes 1 and 2) [2,6,7]. Recently, we reported
that carbon±carbon double bond modi®ed by a ¯uorine atom
has signi®cantly lower LUMO energy level than the corre-
sponding non¯uorinated counterpart and has the similar
3
2
the purpose of obtaining either stereoisomer selectively,
compound 3 was treated with DIBAL-H in diethyl ether
at 08C followed by quenching the reaction with 1 N HCl or
values for the corresponding p orbital coef®cients at the
z
reaction sites, which demonstrates the higher electrophilic
reactivity of those materials [8,9]. As a continuation of our
interest in the synthesis of biological active materials mod-
i®ed with ¯uorine(s), which often exhibit unique physio-
chemical properties, we were intrigued by modi®cation of 2-
and/or 6-position on the manoalogues with a ¯uorine atom to
increasethereactivityofa,b-unsaturatedcarbonylcompound.
Our basic strategy is based on the concept that ¯uorine-
containing molecules might be constructed more easily by
employing building blocks with appropriate functionalities.
Herein, we report the synthesis of a di¯uorinated analog of
manoalogues. Especially, we aimed to introduce ¯uorine
atom(s) at position for the purpose of increasing the reac-
tivity of aldehyde group in manoalogues.
saturated NH Cl aq. The ®nal puri®cation with column
4
chromatography on silica gel using a mixture of n-hex-
ane±ethyl acetate (3:1) as eluent, giving 4a (13% yield) and
4b (56% yield).
Pawson and Lovey have reported the preparation of the
geometrical isomers of compound 6 by the reaction of triethyl
¯uorophosphonoacetate and pyruvaldehyde dimethyl acetal
[10]. Their NMR spectral data shown in Table 1 suggest that
the four-bond coupling constants (4JF;H) between the C-2
¯uorine and C-3 methyl protons in compound A follow the
pattern 4JF;H (E-isomer) >4JF;H (Z-isomer) [11,12]. From
this result, it seems that comparison of the coupling con-
stants (JF,H) supports the assignment of the geometrical
isomers. The comparison of their NMR spectral data has
led to the assignment of 4a (E-isomer; JF,H ˆ 2.4 Hz) and 4b
(Z-isomer; JF,H ˆ 1.2 Hz) (shown in Table 1).
*
Corresponding author.
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 4 6 - 8

6
2
Y. Komatsu, T. Kitazume / Journal of Fluorine Chemistry 102 (2000) 61±67
nucleophilic attack by the nucleophile derived from LDA±
CH (=NNMe )CH(OMe) in THF and hydrolysis led pre-
dominantly to the formation of compounds 5a and 5b. Then,
3
2
2
Horner±Emmons reaction with (EtO) P(O)CHFCO Et in
2
2
THF was carried out, giving satisfactory conversion into
the crude mixture of desired cis- and trans-compounds 6a
and 6b. Treatment of the acetal derivatives with CF CO H
3
2
in CH Cl led to the ¯uorinated closed type of manoalogue
2
2
derivatives 7a and 7b. Employment of Ag O±BF ÁEt O
2
3
2
system followed by the hydrolysis with 40% H SO furn-
2
4
ished the desired 6-cis-2,6-di¯uoromanoalogue (9a) and 6-
trans-2,6-di¯uoromanoalogue (9b).
3
. Experimental
At the next stage, transformation of the obtained com-
pounds 4a and 4b into 6-cis-2,6-di¯uoromanoalogue 9a
and/or 6-trans-2,6-di¯uoromanoalogue 9b was investigated
in detail (Schemes 3 and 4). After protecting the hydroxy
group of compounds 4a and 4b with a mesyl moiety, the
3.1. General procedure
All commercially available reagents were used without
1
further puri®cation. Chemical shifts of H (500 MHz) and
Scheme 1. Proposed schemes for the reaction of manoalide and manoalogue with cobra venom phospholipase A2: (a) involving two conjugate additions or
b) involving conjugate addition following Schiff base formation.
(

Y. Komatsu, T. Kitazume / Journal of Fluorine Chemistry 102 (2000) 61±67
63
‡ �
2 4 2 2 2
, Bu N I , CH Cl , 08C; (c) DIBAL-H, Et O, 08C.
Scheme 2. (a) NaH, (EtO)
2
P(O)CHFCO
2
Et, THF, 258C, Y, 93%; (b) (CH
2
SH) , BF
2
3
ÁOEt
1
3
C NMR spectra were recorded in ppm (d) down®eld from
the following internal standard (Me Si, d 0.00, or CHCl , d
hexane. On removal of the solvent under high vacuum, the
crude oily material is used in the next step.
4
3
1
.24). The F (470 MHz) NMR spectra were recorded in
9
7
ppm down®eld from the external tri¯uoroacetic acid (TFA)
To a solution of lithium diisopropylamide (2.43 g,
24 mmol) in dry THF (20 ml) at � 108C under an argon
atmosphere, dimethylhydrazone of 1,1-dimethoxy-2-propa-
none (3.53 g, 22 mmol) in dry THF (10 ml) was added, and
then the mixture was stirred for 30 min at 08C. Geranyl-
bromide in dry THF (10 ml) was added into the mixture at
that temperature, and then the whole was stirred for 6 h at
room temperature. After the whole was cooled with ice-
water, the reaction mixture was quenched with saturated aq.
in CDCl . Yields quoted are those of the products actually
3
isolated.
3
.1.1. 1,1-Dimethoxy-6,10-dimethyl-5(E),9-undecadien-2-
one (1)
To a solution of N-bromosuccinimide (3.91 g, 22 mmol)
in dry CH Cl (80 ml), dimethylsul®de (1.49 g, 24 mmol)
2
2
was added dropwised at � 408C under an argon atmosphere.
NH Cl. The organic materials were extracted with diethyl
4
After stirring the whole at 08C for 5 min, geraniol (3.09 g,
ether. On removal of the solvent, the crude intermediate
hydrazone was taken up in cold THF (100 ml) and shaken
together with 40 ml of 2.0 N HCl. The mixture was then
diluted with diethyl ether, and then the organic layer was
separated. The organic materials were extracted with diethyl
2
0 mmol) in dry CH Cl (10 ml) was added to the mixture at
2 2
� 408C. After stirring of 2 h at 08C, the mixture was allowed
to warm to room temperature. The mixture was poured into
water (10 ml), and then oily materials were extracted with
Scheme 3. (a) MsCl, EtN, DMAP, LiCl/CH
2
Cl
2
, 258C; (b) LDA, CH
3
C(=NNMe
O, BF
2
)CH(OMe)
2
, THF, � 158C to 258C; (c) 2 N HCl, THF, 258C, 4a ! 5a; (d)
O, 08C; (g) 40%, H SO , 1,4-dioxane, 258C.
NaH, THF, (EtO )P(O)CHFCO Et, 258C; (e) TFA, CH
2
2
2
Cl , 08C; (f) Ag
2
2
3
ÁOEt , THF, H
2
2
2
4

6
4
Y. Komatsu, T. Kitazume / Journal of Fluorine Chemistry 102 (2000) 61±67
Scheme 4. (a) MsCl, EtN, DMAP, LiCl, CH
2
Cl
2
, 258C; (b) LDA, CH
3
C(=NNMe
2
)CH(OMe)
2
, THF, � 158C to 258C; (c) 2 N HCl, THF, 258C, 4b ! 5b; (d)
NaH, THF, (EtO )P(O)CHFCO Et, 258C; (e) TFA, CH
2
2
2
Cl , 08C to 258C; (f) Ag
2
2
O, BF
3
ÁOEt
2
, THF, H O, 08C; (g) 40%, H SO , 1,4-dioxane, 258C.sc4
2
2
4
ether, and the extract was washed with brine, dried over
MgSO , and concentrated. Chromatography (silica gel, 10:1
39.70, 55.52 (2 C), 61.61, 101.51 (d, J ˆ 10.0 Hz), 123.60,
124.38, 131.31, 132.91 (d, J ˆ 11.5 Hz), 135.96, 146.54 (d,
4
1
9
n-hexane±ethyl acetate) afforded compounds 1 in 76% yield
(
J ˆ 260.1 Hz), 160.77 (d, J ˆ 34.8 Hz); F NMR (CDCl ):
3
3.87 g).
1
d 49.3 (d, J ˆ 2.4 Hz); IR (neat): 1726 (C=O), 1654 (C=C)
� 1
H NMR (CDCl ): d 1.59 (3 H, s), 1.62 (3 H, d,
cm
.
3
1
J ˆ 1.0 Hz), 1.68 (3 H, d, J ˆ 1.2 Hz), 1.93±1.98 (2 H,
Z-isomer (2b): H NMR (CDCl ): d 1.35 (3 H, t,
3
m), 2.01±2.07 (2 H, m), 2.24±2.30 (2 H, m), 2.58 (2 H, t,
J ˆ 7.3 Hz), 1.60 (3 H, s), 1.62 (3 H, s), 1.68 (3 H, d,
J ˆ 1.5 Hz), 1.94±2.00 (2 H, m), 2.02±2.09 (2 H, m), 2.13±
2.24 (2 H, m), 2.44±2.52 (2 H, m), 3.41 (6 H, s), 4.31(2 H, q,
J ˆ 7.1 Hz), 5.07±5.12 (1 H, m), 5.15±5.20 (1 H, m), 5.19 (1
1
3
J ˆ 8.1 Hz), 4.47 (1 H, s), 5.05±5.11 (2 H, m); C NMR
(
CDCl ): d 15.99, 17.67, 21.58, 25.69, 26.63, 37.65, 39.65,
3
5
4.60 (2 C), 103.92, 122.53, 124.20, 131.41, 136.39, 205.50.
1
3
H, d, J ˆ 1.5 Hz); C NMR (CDCl ): d 14.12, 15.96, 17.69,
3
3
2
.1.2. Ethyl 3-dimethoxymethyl-7,11-dimethyl-2-fluoro-
(E), 6(E), 10-dodecatrienoate (2a), ethyl 3-
24.85, 25.71, 26.74, 28.37 (d, J ˆ 3.4 Hz), 39.73, 55.28 (2
C), 61.54, 101.18 (d, J ˆ 13.1 Hz), 123.78, 124.42, 131.27,
131.64 (d, J ˆ 5.5 Hz), 135.71, 145.72 (d, J ˆ 256.0 Hz),
dimethoxymethyl-7,11-dimethyl-2-fluoro-2(Z),6(E),10-
dodecatrienoate (2b)
To a solution of triethyl-2-¯uoro-2-phosphonoacetate
19
160.69 (d, J ˆ 35.7 Hz); F NMR (CDCl ): d 45 (s); IR
3
�
1
(neat):1732 (C=O), 1654 (C=C) cm .
(
(
1.54 g, 6 mmol) in dry THF (2.5 ml), a mixture of NaH
0.14 g, 6 mmol) in THF (10 ml) was added at 08C under an
3.1.3. Ethyl 7,11-dimethyl-2-fluoro-3-(1,3-dithiolan-
2-yl)-2(Z),6(E),10-dodecatrienoate (3a), ethyl
7,11-dimethyl-2-fluoro-3-(1,3-dithiolan-2-yl)-
2(E),6(E),10-dodecatrienoate (3b)
argon atmosphere. After stirring of 30 min at room tem-
perature, a mixture of acetal trienone 1 (1.27 g, 5 mmol) in
dry THF (5 ml) was added, and then was stirred for 8 h at
room temperature. After quenching with cold saturated aq.
To a solution of acetal ester 2 (mixture of E- and Z-
isomers, 1.78 g, 5.6 mmol) and n-Bu NI (0.206 g,
NH Cl, oily materials were extracted with ethyl acetate, and
4
4
the extract was washed with brine, dried over MgSO , and
4
0.56 mmol) in CH Cl2 (10 ml), BF ÁEt O (0.024 g,
2
3
2
concentrated. Chromatography (silica gel, 20:1 n-hexane±
ethyl acetate) afforded E/Z mixture (ratio 2.4:1) of 2 in 93%
yield (1.59 g).
0.28 mmol) and ethanedithiol was added at 08C. The reac-
tion mixture was stirred for 1 h, then poured into ice-water.
Organic materials were extracted with ethyl acetate. The
1
E-isomer (2a): H NMR (CDCl ): d 1.37 (3 H, t,
extract was washed with brine, dried over MgSO , and
4
3
J ˆ 7.1 Hz), 1.60 (3 H, s), 1.61 (3 H, s), 1.68 (3 H, d,
concentrated. Chromatography (silica gel, 1:2ꢀ1:1 n-hex-
J ˆ 1.5 Hz), 1.97±2.00 (2 H, m), 2.03±2.09 (2 H, m), 2.17±
ane±benzene) afforded E/Z mixture (ratio 4.2:1) of 3 in 73%
yield (1.47 g).
2
.25 (2 H, m), 2.26±2.31 (2 H, m), 3.41 (6 H, s), 4.31 (2 H, q,
1
J ˆ 7.1 Hz), 5.07±5.12 (1 H, m), 5.16±5.21 (1 H, m), 5.82 (1
E-isomer (3a): H NMR (CDCl ): d 1.36 (3 H, t,
3
1
3
H, d, J ˆ 2.4 Hz); C NMR (CDCl ): d 14.09, 15.90, 17.67,
J ˆ 7.3 Hz), 1.61 (3 H, s), 1.64 (3 H, s), 1.69 (3 H, s),
3
2
5.01 (d, J ˆ 4.7 Hz), 25.70, 26.72, 27.38 (d, J ˆ 2.6 Hz),
1.96±2.01 (2 H, m), 2.04±2.11 (2 H, m), 2.26±2.37 (4 H, m),

Y. Komatsu, T. Kitazume / Journal of Fluorine Chemistry 102 (2000) 61±67
65
3
.27±3.34 (2 H, m), 3.34±3.41 (2 H, m), 4.30 (2 H, q,
ture, the whole was poured into water. Oily materials were
extracted with ethyl acetate, The whole was stirred room
temperture for 4 h, then poured into water. The mixture was
extracted with ethyl acetate, and then the extract was
J ˆ 7.1 Hz), 5.07±5.14 (1 H, m), 5.17±5.23 (1 H, m), 6.66 (1
19
H, d, J ˆ 3.2 Hz);
F NMR (CDCl ): d 41.7 (d,
3
J ˆ 2.8 Hz).
1
Z-isomer (3b): H NMR (CDCl ): d 1.35 (3 H, t,
washed with brine, dried over MgSO , and concentrated.
4
3
J ˆ 7.2 Hz), 1.61 (3 H, s), 1.64 (3 H, s), 1.69 (3 H, s),
Chromatography (silica gel, 10: 1 n-hexane±ethyl acetate)
afforded allyl chloride. This was used in the next step
without further puri®cation.
2
3
.04±2.11 (4 H, m), 2.28±2.36 (2 H, m), 2.50±2.55 (2 H, m),
.27±3.34 (2 H, m), 3.34±3.41 (2 H, m), 4.98 (2 H, q,
J ˆ 7.1 Hz), 5.07±5.13 (1 H, m), 5.16±5.22 (1 H, m), 5.88 (1
To a solution of lithium diisopropylamine (5.0 mmol) in
THF (10 ml) at � 108C under argon atmosphere, dimethyl-
hydrazone of 1,1-dimethoxy-2-propanone (5.5 mmol) in
THF (10 ml) was added, and then the mixture was stirred
for 30 min at 08C. Allyl chloride in THF (10 ml) was added
into the mixture at that temperature, and then the whole was
stirred for 6 h at room temperature. After the whole was
cooled with ice-water, the reaction mixture was quenched
1
9
H, s); F NMR (CDCl ): d 37.7 (s).
3
3
2
7
2
.1.4. 7,11-Dimethyl-3-(1,3-dithiolan-2-yl)-
-fluoro-2(Z),6(E),10-dodecatrien-1-ol (4a),
,11-dimethyl-3-(1,3-dithiolan-2-yl)-2-fluoro-
(E),6(E),10-dodecatrien-1-ol (4b)
To a solution of ditioacetal ester 3 prepared from 2
3.36 g, 9.8 mmol) in dry Et O (20 ml), DIBAL-H
1.0 M, 22 ml, 22 mmol) was added at 08C under an argon
(
(
with saturated aq. NH Cl. The organic materials were
4
2
extracted with diethyl ether. On removal of the solvent,
the crude intermediate hydrazone was taken up in cold THF
(20 ml) and shaken together with 10 ml of 2.0 N HCl. The
mixture was then diluted with diethyl ether, and then the
organic layer was separated. The organic materials were
extracted with diethyl ether, and the extract was washed
atmosphere. After the starting material was consummed, the
reaction mixture was quenched with saturated aq. Na SO .
2
4
Oily materials were extracted with diethyl ether, and then
the extract was washed with brine, dried over MgSO , and
4
concentrated. Chromatography (silica gel, 4:1ꢀ3:1 n-hex-
ane±ethyl acetate) afforded 4a (0.42 g, yield 13%) and 4b
(
with brine, dried over MgSO , and concentrated. Chroma-
4
1.81 g, yield 56%).
1
tography (silica gel, 5: 1 n-hexane±ethyl acetate) afforded
compound 5a (1.20 g) in 63% yield.
Compound 4a: H NMR (CDCl ): d 1.61 (3 H, s), 1.63 (3
3
1
H, s), 1.69 (3 H, d, J ˆ 1.0 Hz), 1.97±2.02 (2 H, m), 2.04±
H NMR (CDCl ): d 1.61 (3 H, s), 1.63 (3 H, s), 1.67 (3 H,
3
2
3
6
.11 (2 H, m), 2.16±2.22 (2 H, m), 2.23±2.30 (2 H, m), 3.23±
.30 (2 H, m), 3.33±3.39 (2 H, m), 4.23 (2 H, dd, J ˆ 22.0,
.4 Hz), 5.07±5.11 (1 H, m), 5.15±5.18 (1 H, m) 5.89 (1 H,
d, J ˆ 0.8 Hz), 1.94±2.00 (2 H, m) 2.04±2.09 (2 H, m),
2.09±2.15 (2 H, m), 2.19±2.25 (2 H, m), 2.54 (2 H, dt,
J ˆ 22.0, 7.3 Hz), 2.80 (2 H, t, J ˆ 7.1 Hz) 3.20±3.26 (2 H,
m), 3.31±3.36 (2 H, m), 3.41 (6 H, s), 4.48 (1 H, s), 5.07±
1
3
s); C NMR (CDCl ): d 16.20, 17.71, 25.71, 26.50 (d,
3
13
J ˆ 3.0 Hz), 26.62, 30.44 (d, J ˆ 2.8 Hz), 39.65, 39.95 (2
5.12 (1 H, m), 5.13±5.18 (1 H, m), 5.89 (1 H, s); C NMR
(CDCl ): d 16.14, 17.69, 22.87 (d, J ˆ 28.1 Hz), 25.70,
C), 49.29 (d, J ˆ 10.7 Hz), 58.28 (d, J ˆ 30.0 Hz), 117.43
3
(
d, J ˆ 7.1 Hz), 123.32, 124.18, 131.48, 136.35, 155.98 (d,
26.66, 26.77, 29.83 (d, J ˆ 2.7 Hz), 33.96, 39.67, 39.82 (2
C), 49.69 (d, J ˆ 11.5 Hz), 54.76 (2 C), 103.89, 114.28 (d,
19
1
9
J ˆ 254.5 Hz); F NMR (CDCl ): d 45.4 (t, J ˆ 22.0 Hz);
3
�
1
IR (neat): 3385 (OH), 1684 (C=C) cm
.
J ˆ 8.8 Hz), 123.59, 124.29, 131.32, 135.77, 157.05 (d,
1
Compound 4b: H NMR (CDCl ): d 1.61 (3 H, s),1.64 (3
J ˆ 253.7 Hz), 204.06; F NMR (CDCl ): d 52.9 (t,
3
3
�
1
H, s), 1.69 (3 H, d, J ˆ 1.0 Hz), 1.96±2.01 (2 H, m), 2.04±
J ˆ 21.4 Hz); IR (neat): 1734 (C=O) cm
.
2
3
.12 (2 H, m), 2.18±2.29, (4 H, m), 3.24±3.30 (2 H, m),
.36±3.41 (2 H, m), 4.32 (2 H, dd, J ˆ 22.7, 6.4 Hz), 5.11 (1
1
3
H, m), 5.20 (1 H, m), 5.51 (1 H, d, J ˆ 2.2 Hz); C NMR
3.1.6. 1,1-Dimethoxy-10,14-dimethyl-6-(1,3-dithiolan-
2-yl)-5-fluoro-5(E),9(E),13-pentadecatrien-2-one (5b)
In the above reaction, compound 4b was used to give
(
CDCl ): d 16.09, 17.70, 25.71, 26.53 (d, J ˆ 3.5 Hz),
3
2
6.70, 28.63 (d, J ˆ 2.5 Hz), 39.67, 40.11 (2 C), 52.66
d, J ˆ 8.3 Hz), 57.65 (d, J ˆ 31.0 Hz), 118.57 (d,
J ˆ 17.8 Hz), 123.83, 124.38, 131.31, 135.71, 156.58 (d,
(
compound 5b in 64% yield.
1
H NMR (CDCl ): d 1.61 (3 H, s), 1.62 (3 H, s), 1.67 (3 H,
3
1
9
J ˆ 254.9 Hz); F NMR (CDCl ): d 53.5 (dt, J ˆ 22.9,
d, J ˆ 1.0 Hz), 1.95±2.00 (2 H, m), 2.04±2.10 (2 H, m),
2.13±2.18 (2 H, m), 2.18±2.24 (2 H, m), 2.61 (2 H, dt,
J ˆ 23.4, 7.1 Hz), 2.81 (2 H, t, J ˆ 7.6 Hz), 3.22±3.27 (2 H,
m), 3.32±3.37 (2 H, m), 3.42 (6 H, s), 4.48 (1 H, s), 5.12±
5.08 (1 H, m), 5.16±5.20 (1 H, m), 5.54 (1 H, d, J ˆ 3.2 Hz);
3
�
1
.1 Hz); IR (neat): 3386 (OH), 1684 (C=C) cm .
3
3
2
.1.5. 1,1-Dimethoxy-10,14-dimethyl-6-(1,3-dithiolan-
-yl)-5-fluoro-5(Z),9(E),13-pentadecatrien-2-one (5a)
To a solution of compound 4a (1.469 g, 4.44 mmol) in dry
1
3
C NMR (CDCl ): d 16.05, 17.68, 22.35 (d, J ˆ 28.3 Hz),
3
25.71, 26.14 (d, J ˆ 4.0 Hz), 26.73, 28.88, 34.42, 39.67,
39.98 (2 C), 53.47 (d, J ˆ 9.2 Hz), 54.79 (2 C), 103.92,
115.45 (d, J ˆ 18.9 Hz), 124.12, 124.41, 131.24, 135.38,
CH Cl
2
(
(20 ml),
.67 mmol), chloride (0.661 g, 5.78 mmol), triethylamine
0.495 g, 4.89 mmol), and LiCl (0.282 g, 6.66 mmol) were
added sequentially. After stirring of 4 h at room tempera-
dimethylaminopyridine
(0.326 g,
2
2
19
157.02 (d, J ˆ 252.7 Hz), 204.08; F NMR (CDCl ): d 60
3
1
�
(dt, J ˆ 22.9, 3.0 Hz); IR (neat): 1734 (C=O) cm
.

6
6
Y. Komatsu, T. Kitazume / Journal of Fluorine Chemistry 102 (2000) 61±67
3
1
2
.1.7. Ethyl 2,6-difluoro-3-dimethoxymethyl-
1,15-dimethyl-7-(1,3-dithiolan-2-yl)-
3.1.9. 4-[8,12-Dimethyl-4-(1,3-dithiolan-2-yl)-3-fluoro-
3(Z),7(E),11-tridecatrienyl]-3-fluoro-5-methoxy-2(5H)-
furanone (7a)
,6(Z),10(E),14-hexadecatetraenoate (6a)
To a solution of triethyl-2-¯uoro-2-phosphonoacetate
1.54 g, 6 mmol) in dry THF (2.5 ml), a mixture of NaH
To a solution of compound 6a (0.739 g, 1.43 mmol) in dry
CH Cl (5.0 ml), under argon and cooled to 08C tri¯uor-
(
(
2
2
0.14 g, 6 mmol) in THF (10 ml) was added at 08C under an
oacetic acid (1.1 eq) was added at 08C under an argon
atmosphere. After stirring of 6 h at room temperature, the
mixture was poured into water. Oily materials were
extracted with diethyl ether, and then the extract was washed
argon atmosphere. After stirring of 30 min at room tem-
perature, a mixture of acetal trienone 5a (5 mmol) in dry
THF (5 ml) was added, and then the whole was stirred for
8
rated aq. NH Cl, oily materials were extracted with ethyl
h at room temperature. After quenching with cold satu-
with brine, dried over MgSO , and concentrated. Chroma-
4
tography (silica gel, 4:1 n-hexane±ethyl acetate) afforded 7a
(0.47 g, yield 72%).
4
acetate, and the extract was washed with brine, dried over
MgSO , and concentrated. Chromatography (silica gel, 20:1
1
H NMR (CDCl ): d 1.61 (3 H, s), 1.63 (3 H, s), 1.69 (3 H,
4
3
n-hexane±ethyl acetate) afforded E/Z mixture (ratio 2.3:1)
of 6a in 86% yield.
d, J ˆ 0.7 Hz), 1.96±2.00 (2 H, m), 2.04±2.12 (4 H, m),
2.18±2.25 (2 H, m), 2.53±2.65 (4 H, m), 3.23±3.28 (2 H, m),
3.32±3.38 (2 H, m), 3.61 (3 H, s), 5.06±5.12 (1 H, m), 5.12±
1
E-isomer: H NMR (CDCl ): d 1.37 (3 H, t, J ˆ 7.1 Hz),
3
1
3
1
2
2
3
5
.60 (3 H, s), 1.63 (3 H, s), 1.68 (3 H, s), 1.95±2.00 (2 H, m),
.03±2.12 (4 H, m), 2.20±2.28 (2 H, m), 2.42±2.48 (2 H, m),
.48±2.54 (2 H, m), 3.20±3.26 (2 H, m), 3.30±3.37 (2 H, m),
.40 (6 H, s), 4.31 (2 H, q, J ˆ 7.1 Hz), 5.07±5.12 (1 H, m),
.12±5.20 (1 H, m), 5.83 (1 H, d, J ˆ 2.4 Hz), 5.91 (1 H, s);
5.17 (1 H, m), 5.66 (1 H, d, J ˆ 5.1 Hz) 5.88 (1 H, s);
C
NMR (CDCl ): d 16.12, 17.69, 20.81 (d, J ˆ 3.0 Hz), 25.70,
3
26.12 (d, J ˆ 2.4 Hz), 26.62, 26.79 (d, J ˆ 3.4 Hz), 29.84
(d, J ˆ 2.7 Hz), 39.65 (2 C), 39.92 (2 C), 49.39 (d,
J ˆ 11.1 Hz), 57.36, 100.83 (d, J ˆ 11.5 Hz), 115.78 (d,
J ˆ 8.2 Hz), 123.24, 124.16, 131.45, 134.53 (d,
1
9
F NMR (CDCl ): d 53.7 (1 F, t, J ˆ 21.4 Hz), 40.7 (1 F, d,
3
J ˆ 3.1 Hz).
J ˆ 5.2 Hz), 136.12, 146.66 (d, J ˆ 279.0 Hz), 155.95 (d,
1
19
J ˆ 254.1 Hz), 162.58 (d, J ˆ 31.9 Hz); F NMR (CDCl ):
Z-isomer: H NMR (CDCl ): d 1.36 (3 H, t, J ˆ 7.3 Hz),
3
3
1
2
2
3
5
.61 (3 H, s), 1.63 (3 H, s), 1.68 (3 H, s), 1.95±2.00 (2 H, m),
.03±2.12 (4 H, m), 2.19±2.28 (2 H, m), 2.48±2.54 (2 H, m),
.67±2.72 (2 H, m), 2.68±2.73 (2 H, m), 3.18±3.25 (2 H, m),
.31±3.38 (2 H, m), 3.39 (6 H, s), 4.31 (2 H, q, J ˆ 7.1 Hz),
.05±5.12 (1 H, m), 5.16±5.21 (1 H, m), 5.21 (1 H, d,
d 16.4 (1 F, d, J ˆ 6.1 Hz), 52.1 (1 F, t, J ˆ 21.4 Hz); IR
�
1
(neat): 1793 (C=O), 1719 (C=C) cm
.
3.1.10. 4-[8,12-Dimethyl-4-(1,3-dithiolan-2-yl)-3-fluoro-
3(E),7(E),11-tridecatrienyl]-3-fluoro-5-methoxy-2(5H)-
furanone (7b)
19
J ˆ 1.5 Hz), 5.91 (1 H, s); F NMR (CDCl ): d 53.9 (1 F, t,
3
J ˆ 22.7 Hz), 36.5 (1 F, s).
In the above reaction, compound 6b was used to give
compound 7b in 65% yield.
1
H NMR (CDCl ): d 1.61 (3 H, s), 1.63 (3 H, s), 1.69 (3 H,
3
3
.1.8. Ethyl 2,6-difluoro-3-dimethoxymethyl-11,15-
d, J ˆ 0.9 Hz), 1.96±2.01 (2 H, m), 2.04±2.11 (2 H, m),
2.14±2.24 (4 H, m), 2.54±2.71 (4 H, m), 3.22±3.28 (2 H, m),
3.34±3.39 (2 H, m), 3.62 (3 H, s), 5.08±5.13 (1 H, m), 5.16±
5.21 (1 H, m), 5.36 (1 H, d, J ˆ 2.9 Hz), 5.67 (1 H, d,
dimethyl-7-(1,3-dithiolan-2-yl)-2,6(E),10(E),14-
hexadecatetraenoate (6b)
In the above reaction, compound 5b was used to
give compound 6b in 89% yield (2.5:1 mixture of E-/Z-
isomers).
1
3
J ˆ 5.1 Hz); C NMR (CDCl ): d 16.05, 17.69, 21.13 (d,
3
J ˆ 3.2 Hz), 25.71, 26.26, 26.33, 26.71, 28.77, 39.65 (2 C),
40.13 (2 C), 53.16 (d, J ˆ 8.8 Hz), 57.31, 100.80 (d,
J ˆ 11.5 Hz), 116.97 (d, J ˆ 18.6 Hz), 123.86, 124.36,
131.30, 134.15 (d, J ˆ 5.6 Hz), 135.64, 147.02 (d,
J ˆ 279.1 Hz), 155.89 (d, J ˆ 252.8 Hz), 162.64 (d,
1
E-isomer: H NMR (CDCl ): d 1.36 (3 H, t, J ˆ 7.1 Hz),
3
1
2
.60 (3 H, s), 1.63 (3 H, s), 1.68 (3 H, s), 1.97±2.00 (2 H, m),
.07±2.11 (2 H, m), 2.12±2.19 (2 H, m), 2.19±2.27 (2
H, m), 2.50±2.55 (2 H, m), 2.55±2.60 (2 H, m) 3.18±3.25
2 H, m), 3.30±3.37 (2 H, m), 3.43 (6 H, s), 4.30 (2 H, q,
J ˆ 7.1 Hz), 5.05±5.12 (1 H, m), 5.16±5.22 (1 H, m), 5.50 (1
1
9
(
J ˆ 31.5 Hz); F NMR (CDCl ): d 16.8 (1 F, d, J ˆ 6 Hz),
3
59.5 (1 F, dt, J ˆ 22.9, 3.1 Hz); IR (neat): 1792 (C=O), 1718
19
� 1
H, d, J ˆ 3.2 Hz), 5.87 (1 H, d, J ˆ 2.5 Hz); F NMR
(C=C) cm
.
(
CDCl ): d 61.6 (1 F, dt, J ˆ 5.9, 3.1 Hz), 40.7 (1 F, d,
3
J ˆ 3.1 Hz).
3.1.11. 4-[8,12-Dimethyl-3-fluoro-4-formyl-3(Z),7(E),11-
tridecatrienyl]-3-fluoro-5-methoxy-2(5H)-furanone (8a)
To a mixture solution of Ag O (0.18 g, 0.8 mmol),
2
1
Z-isomer: H NMR (CDCl ): d 1.37 (3 H, t, J ˆ 7.3 Hz),
3
1
2
2
3
5
.61 (3 H, s), 1.63 (3 H, s), 1.68 (3 H, s), 1.97±2.00 (2 H, m),
.07±2.11 (2 H, m), 2.12±2.19 (2 H, m), 2.19±2.27 (2 H, m),
.50±2.55 (2 H, m), 2.68±2.73 (2 H, m), 3.18±3.25 (2 H, m),
.30±3.37 (2 H, m), 3.42 (6 H, s), 4.32 (2 H, q, J ˆ 7.1 Hz),
.05±5.12 (1 H, m), 5.16±5.22 (1 H, m), 5.22 (1 H, d,
BF ÁEt O (0.11 g, 0.8 mmol), and 15% aqueous THF
3
2
(3.0 ml), compound 7a (0.183 g, 0.4 mmol) was dissolved
in THF (1.5 ml) and was added dropwise at 08C. The
reaction mixture was stirred for 5 min at this temperature
1
9
J ˆ 1.5 Hz), 5.58 (1 H, d, J ˆ 3.4 Hz); F NMR (CDCl ): d
under argon. Et O then added, the precipitated salts were
2
3
6
2.9 (t, J ˆ 24.4, 3.1 Hz), 57.2 (s).
®ltered, and the solution was washed with brine, then dried

Y. Komatsu, T. Kitazume / Journal of Fluorine Chemistry 102 (2000) 61±67
67
over MgSO , and the solution was concentrated. The crude
4
m), 2.66±2.72 (2 H, m), 2.80±3.89 (2 H, m), 5.05±5.11 (2 H,
19
product was puri®ed by column chromatography on silica
gel, eluting with hexane/ethyl acetate (2:1) to give 8a
m), 5.88 (1 H, d, J ˆ 4.5 Hz), 10.43 (1 H, s); F NMR
(CDCl ): d 57.2 (1 F, t, J ˆ 22.8 Hz), 15.3 (1 F, d,
3
(
0.029 g, yield 19%).
1
J ˆ 3.6 Hz). HRMS calculated for C H O F 368.1797,
20 26 4 2
H NMR (CDCl ): d 1.57 (3 H, s), 1.60 (3 H, s), 1.68 (3 H,
found m/e 368.1794.
3
d, J ˆ 0.8 Hz), 1.95±2.00 (2 H, m), 2.02±2.09 (4 H, m),
2
3
1
.14±2.20 (2 H, m), 2.66±2.71 (2 H, m), 2.77±3.86 (2 H, m),
.64 (3 H, s), 5.05±5.10 (2 H, m), 5.67 (1 H, d, J ˆ 5.1 Hz),
3.1.14. 4-[8,12-Dimethyl-3-fluoro-4-formyl-3(E),7(E),11-
tridecatrienyl]-3-fluoro-5-hydroxy-2(5H)-furanone (9b)
In the above reaction, compound 8b was used to afford
1
9
0.14 (1 H, s); F NMR (CDCl ): d 57.5 (1 F, t,
3
J ˆ 21.4 Hz), 17.2 (1 F, d, J ˆ 4.6 Hz). HRMS calculated
compound 9b in 40% yield.
1
for C H O F 382.1954, found m/e 382.1945.
1
H NMR (CDCl ): d 1.57 (3 H, s), 1.60 (3 H, s), 1.68 (3 H,
2
28
4
2
3
s), 1.94±2.00 (2 H, m), 2.03±2.11 (4 H, m), 2.29±2.31 (2 H,
m), 2.66±2.80 (2 H, m), 3.00±3.15 (2 H, m), 5.04±5.13 (2 H,
3
.1.12. 4-[8,12-Dimethyl-3-fluoro-4-formyl-3(E),7(E),11-
1
9
tridecatrienyl]-3-fluoro-5-methoxy-2(5H)-furanone (8b)
In the above reaction, compound 7b was used to give
compound 8b in 24% yield.
m), 5.67 (1 H, d, J ˆ 4.6 Hz), 9.88 (1 H, d, J ˆ 1.7 Hz);
F
NMR (CDCl ): d 81.7 (1 F, t, J ˆ 22.9 Hz), 15.1 (1 F, d,
3
J ˆ 4.3 Hz). HRMS calculated for C H O F 368.1797,
20 26 4 2
1
H NMR (CDCl ): d 1.57 (3 H, s), 1.60 (3 H, s), 1.68 (3 H,
found m/e 368.1788.
3
d, J ˆ 0.8 Hz), 1.94±1.99 (2 H, m), 2.02±2.09 (4 H, m),
2
3
9
.29±2.32 (2 H, m), 2.66±2.79 (2 H, m), 2.98±3.10 (2 H, m),
.64 (3 H, s), 5.06±5.13 (2 H, m), 5.67 (1 H, d, J ˆ 5.1 Hz),
References
1
9
.82 (1 H, d, J ˆ 1.7 Hz); F NMR (CDCl ): d 81.8 (1 F, t,
3
[
[
1] E.D. De Silva, P.J. Sheuer, Tetrahedron Lett. 21 (1980) 1611.
2] L.J. Reynolds, B.P. Morgan, G.A. HiteE, D. Mihelich, E.A. Dennis,
J. Am. Chem. Soc. 110 (1988) 5172.
J ˆ 22.9 Hz), 17.4 (1 F, d, J ˆ 4.6 Hz). HRMS calculated
for C H O F 382.1954, found m/e 382.1967.
2
1 28 4 2
[
[
3] W.W. Wilkerson, Drugs of the Future 15 (1990) 140.
4] M. Waite, J. Lipid Res. 26 (1985) 1379.
3
.1.13. 4-[8,12-Dimethyl-3-fluoro-4-formyl-3(Z),7(E),11-
tridecatrienyl]-3-fluoro-5-hydroxy-2(5H)-furanone (9a)
To a solution of compound 8a (0.016 g, 0.042 mmol) in
[5] I. Kudo, H.W. Chang, S. Hara, M. Murakami, K. Inoue,
Dermatologica 179 (1989) 72.
[
[
6] K.B. Glaser, R.S. Jacobs, Biochem. Pharmacol. 36 (1987) 2079.
7] R.A. Deems, D. Lombardo, B.P. Morgan, E.D. Mihelich, E.A.
Dennis, Biochem. Biophys. Acta 917 (1987) 258.
1
,4-dioxane (2 ml), H SO (40%, 20 ml) was added. After
2 4
stirring of 2 h at room temperature, the mixture was poured
into water. Oily materials were extracted with diethyl ether,
and then the extract was washed with brine, then dried over
[
[
8] N. Shinohara, J. Haga, T. Yamazaki, T. Kitazume, J. Org. Chem. 60
(1995) 4363.
9] N. Shinohara, T. Yamazaki, T. Kitazume, Bioorg. Med. Chem. Lett. 5
MgSO , and the solution was concentrated. Chromatogra-
4
(
1995) 923.
phy (silica gel, 1:1 n-hexane±ethyl acetate) afforded 9a
(
[
[
10] A.J. Lovey, B.A. Pawson, J. Med. Chem. 25 (1982) 71.
11] G.L. Pattenden, B.C.L. Weedon, J. Chem. Soc. (1968) 1984.
0.0075 g, yield 47%).
1
H NMR (CDCl ): d 1.57 (3 H, s), 1.60 (3 H, s), 1.68 (3 H,
3
[12] C.D. Poulter, J.C. Argyle, E.A. Mash, J. Am. Chem. Soc. 99 (1977)
957.
s), 1.96±2.03 (2 H, m), 2.03±2.10 (4 H, m), 2.13±2.20 (2 H,