Note: Descriptions are shown in the official language in which they were submitted.
1 7 64 ~ 157
7-Oxabicycloheptane- and 7-Oxabicycloheptene Compounds
This invention relates to a group of compounds
o~ the ~GH2 type and intermeaiates therefor which are
cardiovascular agents use~ul, for example, in the
treatment of thrombolytic disease. The~e compQu~ds ~ye
the structural formula
CH2-CH=CH-lower alkylene-COOR
~ ~2
wherein Rl is hydrogen or lower alkyl; R is -CHO,
-CH20H or -CH=CH-R -lower alkylene-CH3; R is keto
(C=O) or hyaroxymethyl (~HOH); and the dotted line is an
optional double bond.
The intermediates have the formulas
(II)
~ CH=CH-O-lower alkyl
~ CH20H
and
(II~)
~ ~
wherein R has the same meaning as above and x is 0 or
', 1. .
The aotted line in each of the foregoing
structural formulas represents an optional double bond.
~ ' ~`.
1 16~381
HA157
The symbols in the foregoing formulas and
throughout this specification have the meanings defined
above. The lower alkyl and lower alkylene groups are
straight or branched chain aliphatic hydrocarbon
radicals having up to seven carbon atoms, e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl,t butyl, amyl
and the like. The Cl-C4 and especially the C3-C4
members are preferred.
Preferred compounds are compounds of formulas
I, II and III; wherein R is hydrogen or lower alkyl,
particularly Cl-C4 lower alkyl and espec~ally methyl, R
is -C~2O~ or especially -CH=CH-R -lower alkylene- CH3,
particularly wherein the lower alkylene group has 3 or
4 carbons in a linear chain; and R3 is hydroxymethyl.
Compounds of formula I, and especially those having the
applicable foregoing characteristics, are preferred over
compounds of formulas II and III.
The compounds of this invention are cardiovascular
agents useful as platelet aggregation inhibitors e.g.,
for treatment of thrombolytic disease such as coronary
or cerebral thromboses. They are also selective
thromboxane A2 synthetase inhibitors, e.g., having a
vasodilatory effect for treatment of myocardial ischemic
disease such as angina pectoris. They can ~e administered
orally or parenterally to various mammalian species known
to be subject to such maladies, e.g., cats, dogs, and
the like in an effective amount within the dosage range
of about 1 to 100 mg./kg., preferably about 1 to 50 mg./
kg. and especially about 2 to 25 mg./kg. on a regimen in
single or 2 to 4 divided daily doses.
=
6~t~(~t
HA157
The active substance can be utilized in a
composition such as tablet, cap~ule, solution or
suspension containing about 5 to about 500 mg. per
unit of dosage of a compound or mixture of compounds
of formula I. They may be compounded in convention~l
manner with a physiologically acceptable vehicle or
carrier, excipient, ~inder, preservative, stabilizer,
flavor, etc. as called for by accepted pharmaceutical
practice. Also as indicated in the discussion above,
certain members additionally serve as intermediates
for other members of the grollp.
The sequence of reactions described below yields
a series of 7-oxabicycloheptane- and 7-oxabicycloheptene
derivatives of the PGH2 type.
Not only can members of the group be derived from
other members and thus have utility as intermediates, but
they also have physiological activity themselves.
Thus, when maleic anhydride is made to react with
furan which has the formula0 (IV) ~CH
fH
~CH /
e.g. in ether solution at room temperature, this results5 in a compound having the formula
(V) ~0
CH-CH-CH-C~
Il b I \o
CH-CH-CH-C /
~0
I 1 fi~88 ~
HA157
Reduction of the compound of formula V, e.g.,
catalytically, for example, in the presence of
palladium-carbon, provides a reduced product having
the formula
(VI)
CH2-~H-fH-C
1o 1 ~. O
CH2-CH-CH-C
~he compound of formula VI can then be con-
verted to a compound having the formula
(VII)
CH2- ~CH-CH-C\
I ~0 I ~o
CH2-CH-CH-CH
e.g., by reduction in tetrahydrofuran with a boro---
hydride like sodium borohydride or zinc borohydride.
Treatment of the compound of formula VII with
diisobutylaluminum hydride or diisobutylborane yields
a compound having the formula
(VII~
CH2-CH-CH-CHOH
I \ O
CH2--CH-CH-CH2
which then is submitted to Wittig reaction conditions
e.g., with an (alkoxymethyl)triphenylphosphonium
1 164~8~
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s
halide like (methoxymethyl)triphenylphosphonium
chloride in the presence of an alkali metal alkylamide
like lithium diisopropylamide, a lithium alkyl like
n-butyl lithium in an inert organic medium like
S toluene, tetrahydrofuran or the like, at a
temperature in the range of about -10 to 25C.
This reaction produces a compound having the
formula
(IX)
- CH2-CH-CH-CH=CH-O-lower alkyl
I ~1
CH2- H- H-CH2OH
This product of formula IX is acylated, e.g.,
with an acylpyridinium halide like N-acetylpyridinium
chloride in the presence of an acid acceptor like
pyridine, oxidized with an oxidizing agent like
mercuric acetate in an organic medium like tetra-
hydrofuran, then demetalated with a reducing agent
like potassium iodide to yield a product having the
formula
(X)
CH 2--,CH - CH -CH 2 -CHO
1 IO I IO
CH2-CH-CH CH2-O-C-lower alkyl
Alternatively, the product of formula IX
can be treated with an acid like formic acid or
trifluoroacetic acid to yield a product having the
formula
1 3 6~8 1
HAl 5 7
. (XI)
~ CH 2 ~ OH
CH 2 - CH- CH CH
1 1
S CH2-CH-CH O
CH2
~hese products of formulas X or XI are
subjected to a Wittig reaction, e.g., with a
carboxyalkyl triphenylphosphonium halide to obtain
a product having the formula
(XII)
fH2-CH-CH-CH2-CH=CH-lower alkylene-COOH
CH2-cH-cH-cH2oH
By esterifying the product of formula XII,
e.g., with a diazoalkane like diazomethane in an
2~ inert organic solvent like ether, or with a sub-
stituted diazoalkane like diphenyldiazomethane,
the lower alkyl ester or substituted lower alkyl
ester of that compound (i.e., Rl is lower alkyl) is
obtained.
The hydroxymethyl group in the 3-position of
this ester is next oxidized, e.g., with chromium
trioxide in pyridine, to obtain the aldehyde compound
having the formula
~XIII)
- CH2-CH-CH-CH -CH=CH-lower alkylene-COOR
I O 1 2
CH2-CH-CH-CHO
wherin R is lower alkyl.
) 1 6~88 t
HA157
Subjecting the compound of formula XIIIto a
Horner-Wittig reaction using an alpha ketophosphonate
such as dimethyl 2-oxoheptylphosphonate and a base
such as sodium hydride in an inert organic solvent
such as dimethoxyethane or alternatively a Wittig
reaction using an alpha keto phosphorous ylide such
as tributyl or triphenyl 2-oxoheptylidine phosphorane
iD an organic solvent such as tetrahydrofuran provides
a product having the formula
(XIV)
CH2-CH-fH-CH2-CH=CH-lower alkylene-COOR
CH2-CH-CH-CH=CH-C-lower alkylene-CH3
O
1~ -
wherein ~1 is lower alkyl.
This product is then reduced, e.g., with
lithium diisobutyl aluminum hydride, with zincborohydride,
sodium borohydride with cerium chloride or sodium cyano-
20 ~orohydride to yield a product having the formula
(XV) *
CH2-CH-CH-CH2-CH=CH-lower alkylene-COOR
0 1 *
~ CH2-CH-CH-CH=CH-CH-lower alkylene-CH3
OH
which can be converted to the free acid, i.e., a
compound having the formula
i 1 fi~8 ~
H~157
(XVI) *
CH2-CH-CH-CH2-CH=CH-lower alkylene-COOH
O I *
CH2-CH-CH-CH=CH-CH-lower alkylene-CH3
OH
by treatment with a base such as lithium hydroxide
followed by neutralization with an acid such as dil~te
hydrochloric acid.
If, instead of reacting maleic anhydride with
the unsubstituted or substituted furan of formula IV,
it is made to react with maleic acid, e.g., in water
at room temperature, the unsaturated product having
the formula
- 15 (XVII)
CH-CH-CH-COOH
llo I
CH-CH-CH-COOH
is obtained. ~
This can then be converted by reaction with an
acid anhydride such as trifluoroacetic acid anhydride
followed by treatment with a reducing agent such as
sodiu,m borohydride to the 5,6-unsaturated analog of
a compound of formula VII above, i.e., a compound
having the formula
~VIIa)
CH-CH-CH-C~
~ \0
CH-CH-CH-CH2
I 1 fi4~8 1
HA157
Starting with this compound instead of with the
compound of formula VII and following the same sequence
of steps as described above with respect to the latter
compound and its successor compounds, there are
obtained compounds corresponding to those of formulas
VIII and XVI inclusive but having a double bond in the
5,6-position.
Additionally, the compound of formula VIIa can be
reduced e.g., with hydrogen over palladium on carbon
to obtain a compound of formula ~II and this
intermediate processed as described aboye.
The compounds of this invention ha~e three centers
of asymmetry as indicated by the asterisks in formulas
X~ and XVI. The various stereoisomeric forms are within
the scope of the invention.
Thus when the first sequence of reactions described
above are followed, i.e., reacting maleic anhydride with
a furan of formula I~, compounds are obtained wherein
both side chains, i.e., those residues attached to the
2 and 3 positions on the 7-oxabicyclo~2,2,1]heptane
ring system, are cis to the 7-oxa bridge.
These can be shown by the common method of de-
picting steric structure as follows with respect to a
compound of formula VIII, for example
(XVIII)
OH
~b
8 ~ ~
HA157
the right hand ring being in the exo position. When
the keto group in the side chain of the compound of
formula XIV is reduced as first descri~ed above, a
mixture of stereoisomeric compounds in which the
S hydroxy group is either R (~) or S (~) is usually ob-
tained. They can be graphically described as follows:
(XIX)
o
~ COO-lower alkyl
10 ~
OH
15 (XXI
/ ~ ~ / COO-lower alkyl
~/~
OH ~
The same considerations apply to the acids which are
obtained by hydrolysis. The stereoisomeric pairs can
be resolvea by conventional techniques, such as
chromatography on silica gel.
On the other hand, when the alternate procedures
described above are used, e.g., reacting a furan with
maleic acid and optionally reducing the double bond,
stereoisomeric compounds are obtained wherein the
lactole ring and subsequent compounds are in the endo
position as depicted graphically with respect to
a compound of formula XVIII:
1 3 ~8 t
HA157
11
(XVIIIa ) O
~0
The ~ollowing examples are illustrati~e of the
invention. The products o~ the examples constitute
preferred embodiments as well as provide additional
experimental details and serve as models for
additional mem~ers of the group. All temperatures
are in degrees Celsius.
6 ~
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12
Example l
(Exo)Hexahydro-4,7-epoxyisobenzofuran-1(3H)-one
(a) (Exo)Hexahydro-4,7-epoxyisobenzofuran-1,3-dione
A mixture containing 30.0 g. (0.18 mole) of
7-oxabicyclo E2 . 2.1~-5-heptene-2,3-dicarboxylic
anhydride [Ber. 62, 554 (1~29); Ann. 460, ~8(1928)],
1.5 g. of 5% Pd/C and 1.5 1. of ethyl acetate is
hydrogenated in an atmospheric hydrogenator. The
reaction is stopped after uptake of 4~518 1. of
hydrogen. The catalyst is filtered from the
reaction mixture and the solvent is stripped off
under vacuum to yield 29.8 g. of (exo)hexahydro-4,7-
epoxyisobenzofuran-1,3-dione, m.p. 112-114.
(b) (Exo)Hexahydro-4,7-epoxyisobenzofuran-1(3H)-one
To a slurry of 6.7 g. (0.18 mole) of sodium
borohydride in 50 ml. of dry tetrahydrofuran is
added a solution of 29.8 g. (0.18 mole) of (exo)-
hexahydro-4,7-epoxyisobenzofuran-1,3-dione in 500 ml.
of dry tetrahydrofuran over a 10 minute period with
stirring and ice-bath cooling. The resulting mixture
is stirred under nitrogen for 5 hours and then
stripPed of solvent under vacuum. The residue is
treated with 100 ml. of 10% hydrochloric acid solution
while being cooled in an ice-bath. The resulting
slurry is extracted with dichloromethane (5 x 100 ml.),
dried over sodium sulfate and concentrated to yield
crystalline crude material. This is recrystallized
from benzene-hexane to yield 20.1 g. of (exo)hexahydro-
4,7-epoxyisobenzofuran-1(3H)-one, m.p. 112-118.
Example 2
(Exo)Octahydro-4,7-epoxyisobenzofuran-1-ol
.
A solution of (exo)hexahydro-4,7-epoxyisobenzo-
furan-1(3H)-one (3 g., 0c02 moles) in 100 ml. of
~ 3 6 ~
HA157
13
anhydrous toluene is chilled to -78 and treated
dropwise over ten minutes with a solution of
diisobutyl aluminum hydride in toluene (1.5 molar,
26 ml., 0.04 moles). The resulting slurry is
stirred at -78 for twenty minutes (a solution results).
The reation is quenched by adding dropwise 24 ml. of
10% acetic acid and allowing the reaction mixture to
warm to room temperature. The mixture is then poured
into 100 ml. of 10% hydrochloric acid saturated with
sodium chloride. The product is exhaustively extracted
with dichloromethane (8 x 100 ml.). The combined
dichloromethane extracts are washed with 50 ml. of
5% sodium bicarbonate, dried over sodium sulfate,
and concentrated in vacuo. The resultant crystalline
product is recrystallized from benzene to yield 2.4 g.
of ~exo)octahydro-4,7-epoxyisobenzofuran-1-ol, m.p.
125-127.
Example 3
(Exo)-3-(2-Methoxyethenyl)-7-oxabicyclo[2.2.1]heptane-
2-methanol
A slurry of ~methoxymethylJ-triphenylphosphonium
chloride (123.47 g., 0.36 moles) in anhydrous toluene
(1700 ml.) is chilled in an ice bath and treated
dropwise over ten minutes with a solution of lithium
diisopropylamide (38.6 g., 0.36 moles) in anhydrous
tetrahydrofuran. The resulting red solution is
stirred at 0 for ten minutes then treated via a
solid addition device with (exo)octahydro-4,7-
epoxyisobenzofuran-l-ol (18.7 g., 0.12 moles). The
mixture is then stirred at room temperature for two
hours. The mixture is poured into brine (1000 ml.)
and treated with 10% hydrochloric acid to pH 6.8.
I 1 64~ ~
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14
The mixture is extracted several times with diethyl
ether. The combined ether extracts are dried over
sodium sulfate and concentrated in vacuo. The residue
i5 dissolved in diethyl ether (500 ml.) and chilled
overnight. The solid precipitate is filtered off and
the filtrate concentrated in vacuo. The residue is
chromatographed on silica gel (1500 ml.) eluting
with 1) dichloromethane and 2) ethyl acetate. The
crude product contained in the ethyl acetate fractions
is distilled in vacuo to yield 14.5 g. of (exo)-3-(2-
methoxyethenyl)-7-oxabicyclo[2.2.1]heptane-2-methanol,
b.p. 100-105/0.001 mm.
Example 4
(Exo)Octahydro-5,8-epoxy-lH-benzopyran-3-ol
(Exo)-3-(2-Methoxyethenyl)-7-oxabicyclo-
12.2.1]heptane-2-methanol (10.2 g., 0.055 moles) is
dissolved in cold 88% formic acid (166 ml.) at 0 then
left stirring without cooling under nitrogen for
thirty minutes. The reaction mixture is then chilled
in an ice bath and treated dropwise over forty-five
minutes with 10% sodium hydroxide to pH 7.5. The
solution is saturated with sodium chloride and
extracted several times with dichloromethane. The
combined extracts are dried over sodium sulfate and
concentrated to yield eight grans of crude product.
The solid product is recrystallized from cyclohexane
to yield 5.9 g. of (exo)octahydro-5,8-epoxy-lH-
benzopyran-3-ol, m.p. 101-103.
Example 5
[lR~ ,2B(Z),3B,4~)]-7-[3-(Hydroxymethyl)-7-oxab'cyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid
a) A mixture of N-acetylpyridinium chloride
is prepared by adding 9.6 ml. (136 mmole) of acetyl
I ~ 64~8 1
~IA157
chloride dropwise to 56 ml. of pyridine. To this is
added 5.0 g. (27 mmole) of (exo)-3-(2-methoxyethenyl)-
7-oxabicyclo[2.2.1]-heptane-2-methanol dissolved
in 5 ml. of pyridine. The resulting mixture is
stirred at room temperature for 1.5 hours and poured
into brine. The product is extracted into ether
(3 x 200 ml.), the ether extracts are washed with 5~
hydrochloric acid (2 x400 ml.) and brine ~1 x 200 ml.)
and dried over sodium sulfate. Concentration yields
a yellow oil which is purified by passage through a
short column of silica gel (150 ml.) with dichloro-
methane, yield 4.42 g. of an oil.
b) To a solution of 4.42 g. (19.6 mmole) of
the oil in S00 ml. of tetrahydrofuran containing
50 ml. of water is added 31.1 g. (97.8 mmole) of
mercuric acetate. The yellow suspension which
forms is stirred for 10 minutes and then the entire
mixture is poured into a solution containing 200 g.
of potassium io~de in 2 1. of water. Upon shaking,
the yellow color disappears and the mixture is
extracted with benzene (3 x 500 ml.). The combined
benzene estracts are washed with potassium iodide
solution and brine and dried over sodium sulfate.
Concentration yields 3.7 g. of material which5 crystallizes on standing in an ice box.
c) A Wittig reagent is prepared in dimethyl
sulfoxide (dried over calcium hydride) by adding a
solution of sodium methylsulfinylmethide (prepared
by heating 300 mg. of sodium hydride in 60 ml. of
dimethyl sulfoxide at 75 until hydrogen evolution
stops) dropwise to a solution of 5.32 g. (12 mmole)
of 4-carboxybutyl triphenylphosphonium bromide in
100 ml. of dimethyl sulfoxide. After the first
1 3 6~81
HA157
16
orange color, lasting more than 10 seconds forms, an
equivalent amount of base is added to form the ylide.
To this deep orange solution is added a solution of
the product of part b in 20 ml. of dimethyl sulfoxide
and the resulting mixture stirred at room temperature
for 45 minutes. The reaction is quenched by addition
of 24 mmole of acetic acid and the mixture poured into
brine (30Q ml.) and extracted with ether (3 x 200 ml.~.
Concentration of these extracts gives an oil which
is stirred with saturated sodium bicarbonate solution
until crystalline triphenylphosphine oxide forms in
the mixture. This mixture is washed with benzene
and acidified with 10% hydrochloric acid. The
aqueous layer is saturated with salt and extracted
with ether which on drying (sodium sulfate) and
concentration gives 2.43 g. of crude product. The
mixture is stirred 24 hours with 10% aqueous sodium
hydroxide and reisolated by acidification and ether
extraction. The product is purified on 500 g. of
silica gel with 50/50 ethyl acetate-hexane as the
eluant which gives 600 mg. of acid which crystallizes
on standing. This is recrystallized twice from
ethyl acetate-cyclohexane to yield 320 mg. of
[lR-(la,2B(Z),3B,4~)~-7-[3-(hydroxymethyl)-7-
oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid, m.p.
59-63.
Example 6
11R- (la, 2B(5Z),3B,4a) ~ droxymethyl)-7-
oxabicyclo-[2.2.1]hept-2-yll-5-heptenoic acid,
methyl ester
A solution of diazomethane in ether is
prepared from 3 g. of N-methylnitro-nitroso~uanidine
in 50 ml. of ether with dropwise addition at 0 of
1 3 64~81 HA157
17
9 ml. of 40% potassium hydroxide water solution.
This solution (dried over potassium hydroxide pellets~
~s added dropwise to a stirring solution of 11R-
(1~,2B(Z),3B,4~)]-7-[3-(hydroxymethyl)-7-oxabicyclo-
t2.2.1]hept-1-yl-5-heptenoic acid (254 g., 10 mmole
in ether (lS0 ml.) over a ten minute period. Stirring
~ 8 continued for one hour. The excess diazomethane
i~ destroyed by the addition of acetic acid (1.5 ml.).
The solution is washed with 5% sodium bicarbonate
solution, brine, dried over sodium sulfate, and
concentrated in vacuo to yield 2.6 g. of product
(one spot by TLC - silica gel; ethyl acetate;
Rf=0.5). The residue is chromatographed on silica
gel (200 ml.) eluting with 1) ethyl acetate/pentane
(1:9), 2) ethyl acetate~pentane (1:4), a~d 3) ethyl
acetate/pentane (2:3) to yield 2.23 g. of [lR-
(la,2B,(5Z),3B,43)]-7-[3-(hydroxymethyl)-7-oxabicyclo-
~2.2~1]hept-2-yl]-5-heptenoic acid, methyl ester as
an oil.
Example 7
[lR- (la,2B(5z)~3B~4~)]-7-[3-formyl-7-oxabicyclo-
2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester
A solution of chromium trioxide/pyriaine is
prepared in anhydrous dichlormethane (from 5.38 g.,
-54 mmoles of chromium trioxide, 8.~ ml., 108 mmoles
of pyridine and 200 ml. of dichloromethane) and
stirred at room temperature for twenty minutes.
Eight grams of dry*Celite(diatomaceous earth
dried at 100 overnight) are then added ~ollowed
by a solution of 11R~ ,2B~5Z) ,3B,4~)]-7-13-
(hydroxymethyl)-7-oxa~icyclo[2.2.1-]hept-2-yl]-5-
heptenoic acid,methyl ester (2.38 g., 8.94 mmoles
in 15 ml. of dichloromethane). The resulting mixture
* Trade Mark
. . .
.
1 16~81
HA157
18
. .
is stirred under nitrogen ~or fifteen minutes and
then filtered. The filtrate is washed with 5%
~odium bicarbonate solution (2 x 100 ml.), 10%
hydr~chloric acid (2 x 100 ml.),~5% sodium bicarbonate
solution (2 x 100 ml.), water (l x 200 ml.) and brine
(2 x 100 ml.). After drying over sodium sulfate,
the dichloromethane solution is concentrated in
vacuo to yield 2.6 g. of crude product. The crude
product is purified by column chromatography on
*Silicar CC-7 silica gel (300 ml.) eluting with 10%
ethyl acetate/hexane to yield 2.1 g. of llR-tl,2B(5Z~,
3B,4)]-7-13-formyl-7-oxabicyclo~2.2.1]hept-2-yl~-5-
heptenoic acid, methyl ester as an oil.
Example 8
11R- ~1, 2B(5Z),3B(lE),4a~ 7-~3-(3-oxo-1-octenyl)-
7-oxabicyclo 12.2.i]hept-?-~1]-5-heptenoic acid,
methyl ester
A solution of llR-(la,2B(5Z),3B,4~)]-7-~3-
formyl-7-oxabicyclot2.2.1]hept-2-yi]-5-heptenoic acid,
methyl ester (l.lB g., 0.0044 moles) and tributyl-2-
oxoheptylidenephosphorane (1 g., 0.0044 moles)
in anhydrous ether (50 ml.) is heated at reflux
for three days. The reaction mixture is concentrated
in vacuo~ The residue is purified by column
chromatography on Silicar CC-7 silica gel eluting
with 5% ethyl acetate/chloroform to yield 1.3 g.
of oil. The oil is dissolved in pentane ~25 ml.)
and chilled to yield 1.2 g. of [lR-(1,2B(5Z),
3~(lE~,4~)]-7-13-(3-oxo-1-octenyl)-7-oxabicyclo
~2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, -
m.p. 32-34.
.
* Trade Mark
.. . .
1 3 64~8t HA157
19
.
Example 9
-[lR~ ,2B(~),3B(lE,3R*),4~)]-7-~3-(3-hydroxy-1-
o~ l)-7-oxabic~clo[2.2.1]he~t-2-yl]-5-heptenoic
acid, methyl ester
and
[lR~ ,2B(SZ),3B(lE,3S*),4~)]-7-[3-(3-hydroxy-1-
-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester
A solution of [lR~ ,2B(5Z),3B(lE),4~)]-7-
[3-(3-oxo-1-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5-heptenoic acid, methyl ester (1.26 g., 0.0035
moles) in anhydrous dimethoxyethane (20 ml.) is
chilled to -78 and treated dropwise with a solution
of lithium tri-sec. butylborohydride (3.8 ml.,
0.0038 moles) over two minutes. The reaction mixture
is stirred at -78 for 30 minutes. The reaction
mixture is then quenched with saturated ammonium
chloride solution (10 ml.) and extracted several
times with ethyl acetate (3 x 100 ml.). The combined
ethyl acetate extracts are dried over magnesium
sulfate and concentrated in vacuo. The residue is
purified on a 1" x 24" silica gel column eluting
with 1) benzene, 2) 2.5% ethyl acetate/benzene and
3) 5% ethyl acetate/benzene to yield 550 mg. of
a) tlR- (la, 2~(5Z),3~(lE,3R*),4a)]-7-[3-(3-hydroxy-
l-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester and 370 mg. of b) [lR-~1,23(5Z),
3~(lE,3S*), 4a)]-7-[3,(3-hydroxy-1-octenyl)-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.
22H364 C,72.49; H,9.96
Found: C,72.24; H, 10.01
b) Analysis Calc'd. for C22H3604: C,72.49; H, 9.96
Found: C,72.22; H, 9.92
I 1 6 ~
~A157
_
Example 10
[lR~ ,2Bt5Z),3B(lE,3R*),4~)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl~-5-heptenoic
acia ~ -
and
[lR-(1~,2B(5Z),3B(lE,~S*),4a)]-7-r3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1~hept-2-yl~-5-heptenoic
aci~
a) A solution of chromium trioxide~pyridine
`is prepared in anhyarous dichloromethane (from 5.9 g.,
59 mmole, of chromium trioxide, 9.5 ml. 118 mmole, of
pyridine and 200 ml. of dichloromethane) and stirred
at room temperature for 25 minutes. Eight grams of
dry*Celite (dried at 100 overnight) is then added
followed by 2.61 g. (9.8 mmole) of [lR-(1~,23(5Z),
3B,4a)]-7-[3-(hydroxymethyl)-7-oxabicyclo12.2.1]hept-
2-yl~-5-heptenoic acid, methyl ester dissolved in
5 ml. of dichloromethane; The resulting mixture is
stirred under nitrogen for 15 minutes and then worked
up. The Celite-chromium trioxide mixture is removea
by filtration and the filtrate is washed sequentially
with saturated sodium bicarbonate solution (2 x 100
ml.), water (200 ml.) and brine (100 ml.). After
drying over sodium sulfate, the mixture is concentrated
under ~acuum to give 2.34 g. of 11R-(1~,2B(5Z),3~,4)]-
7-13-formyl-7-oxabicyclo12.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester.
b) A mixture of Horner-Wittig reagent is
prepared from sodium hydride (washed free of oil
with hexane) 1470 mg., 9.8 mmole) and dimethyl(2-
oxoheptyl)phosphonate (1.82 g., 8.2 mmole) in dry
dimethoxyethane .(* 5 ml.)~ After combining these
reagents, stirring is continued under nitrogen for
.
* Trade Mark
-
I 1 64~ ~
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21
30 minutes during which time a white paste-like
material forms. A solution o~ the product of part
a (2.09 g., 8.2 mmole) in dimethoxyethane (40 ml.)
i6 added and stirring continued for three hours
during which time the mixture becomes homogeneous
and yellow. The solvent is then removed under
vacuum and the residue partitioned between ether
and saturated sodium bicarbonate solution. The ether
layer is washed with brine, dried over sodium sulfate
and concentrated to yield 3.4 g. of crude material.
This is purified by HPLC chromatography on a 1"
by 24 n column of silica gel using 0.5~ ethyl
acetate/benzene as the eluent. This yields 0.79
g. of pure [lR-(1,2B(5Z),3~(lE),4)]-7-[3-(3-oxo-
1-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester and 1.67 g. of mixed fractions.
The mixed fractions are rechromatographed on the
same column with 30% hexane/benzene as the eluent
yielding an additional 0.83 g. of pure trans-ketone.
The pure fractions are combined for a total yield
of 1.62 g.
c) A solution of lithium tri-sec.butylborohydride
~3.8 ml., 3.8 mmole) is added dropwise under nitrogen
to a solution of the product of part b (1.26 g., 3.5
mmole) in lS ml. of dry dimethoxyethane at -78. The
reaction is allowed to proceed at -78 for 30 minutes
and then quenched by the addition of 9 ml. of
saturated ammonium chloride sol~tion. The mixture
is then poured into brine (20 ml.) and extracted
with ethyl acetate. The extracts are washed with
ethanolamine-water solution (S0/50) to remove
borane side products, then dried over magnesium
1 1 64~8 ~
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22-
sulfate and concentrated to yield the crude product.
The two diastereomers are separated by HPLC on a
silica gel colum (1" x 24") using 2.5~ ethyl
acetate/benzene to elute the less polar isomer
~-OH) and 5% ethyl acetate/benzene to elute the
more polar isomer (a-OH). In this way 449 mg. of
llR-(la,2B(5Z),3B(lE,3R*),4)]-7-~3,(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester (~~OH isomer) and 300 mg. of
11R- (la,2~(5Z),3~(lE,3S*3,4a)]-7-r3-(3-hydroxy-1-
octenyl)-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester (a-OH isomer) are obtained.
d) A mixture of the B-OH isomer from part c
(449 mg., 1.2 mmole) in tetrahydrofuran (65 ml.)
and water (13 ml.) and lithium hydroxide-water
(504 mg., 12 mmole) in water ~3 ml.) is prepared
and stirred at 0 under nitrogen for three hours,
then kept at 0 overnight. During this time the
mixture becomes homogenous and is acidified to pH3 with
a 10% oxalic acid solution. The mixture is saturated
with salt and extracted with ether (3 x 100 ml.). The
ether extracts are dried over sodium sulfate and
concentrated yielding an oil containing water. This
is dried by solution in dichloromethane and drying
over sodium sulfate. Removal of the solvents under
vacuum yields 425 mg. of crude acid. This is
purified by dissolving in 10% potassium carbonate
solution, treatment of this solution with carbon,
acidification with hydrochloric acid and re-extraction
with ether. Removal of the solvent gives 302 mg. of
[lR-(1,2~(5Z)~3~(1E~3R*),4a]-7-~3-(3-hydrOxy-l-
octenyl)-7-oxabicyclol2.2.1]hept-2-yl]-5-heptenoic
acid as an oil.
I 1 64~
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23
Analysis calc'd: C, 71.96; H, 9.78
Found: C, 71.85; H, 9.66
e) A mixture of the ~-OH isomer from part c
~398 mg., 1.1 mmole) in tetrahydrofuran (60 ml.)
and water (12 ml.) and lithium hydroxide/water
(462 mg. llmmoles) in water (12 ml.) is prepared
and stirred at room temperature for three hours.
The mixture is diluted with brine (100 ml.) and
aciaified to pH 3 with 10% hydrochloric acid solution.
The product is removed by extraction with ether.
The ether extracts are dried over magnesium sulfate
and concentrated to yield the crude acid. This is
purified by dissolvin~ in dilute potassium carbonate,
washing the aqueous layer with pentane and acidifying
with dilute hydrochloric acid followed by extraction
with ether as before. The purified material is
dried under vacuum over phosphorus pentoxide at
room temperature for five days to yield 100 mg. of
11R- (la,2B(5Z)~3B(lE, 3S*), 4a) ] -7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid.
Analysis Calc'd. for C21~34O4: C, 71.96; H, 9.78
Found: C, 71.68; H, 9.49
Example 11
(endo)-3a,4,7,7a-Tetrahydro-4,7-epoxyisobenzofuran-
1(3H)-one
a) ~1R- (endo,cis)]-7-Oxabicyclo[2.2.1]hept-5-ene-
?, 3-dicarboxylic acid
A solution of maleic acid (982 g., 8.5 moles)
in water (2100 ml.) is treated with furan (618 ml.,
8.5 moles) and stirred at room temperature in a sealed
flask for forty-eight hours. The unreacted furan is
removed and the aqueous solution treated with charcoal
1 16~81
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~24
and filtered. The filtrate is chilled in the
refrigerator overnight. The resultant precipitate
is collected by filtration and dried over phosphorus
pentoxide to yield 250 g. of [lR-(endo,cis)]-7-
oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid,
m.p. 149-150.
b) (endo)-3a,4,7,7a-Tetrahydro-4,7-epoxyisobenzofuran-
1(3H)-one
,
Trifluoroacetic anhydride (90 ml.) is chilled
to D and treated with 11R- (endo,cis)]-7-oxabicyclo-
[2.2.1]hept-5-ene-2,3-dicarboxylic acid (10 g., 0.0543
moles). The slurry is stirred at 0 until solution
occurs (~ 10 minutes). The mixture is then concentrated
in vacuo at 0. The resultant solid is added to a
slurry of sodium borohydride (2.35 g., 0.062 moles)
in tetrahydrofuran (250 ml.) at 0. The reaction
mixture is then stirred at room temperature for
two hours. The mixture is concentrated in vacuo The
solid residue is chilled in an ice bath and treated
dropwise with 75 ml. of 10% hydrochloric acid. The
mixture is then extracted with dichloromethane
(3 x 200 ml.). The combined dichloromethane
extracts are washed with 5% sodium bicarbonate
solution, dried over sodium sulfate, and concentrated
in vacuo to yield 3.3 g. of (endo)-3a,4,7,7a-tetrahydro-
4,7 epoxyisobenzofuran-1(3H)-one which is recrys~lized
from benzene/pentane to yield 2.1 g., m.p. 121 .
Example 12
~endo)-1,3,3a!4,7,7a-Hexahydro-4,7-epoxyisobenzofuran-
l-ol
A solution of (endo)-3a,4,7,7a-tetrahydro-
4,7-epoxyisobenzofuran-1~3H)-one ~3 g., 0.0197 moles)
I ~64~81 `
HA157
ln toluene (100 ml.) is chilled to -78 and treated
dropwise over five minutes with a solution of diisobutyl
aluminum hydride in toluene (26.3 ml., 0;0395 moles).
The reaction mixture is stirred at -78 for 20 minutes
then quenched with the dropwise addition of 10%
acetic acid (20 ml.). The reaction mixture is al~owed
to warm to room temperature. The mixture is poured
into 50 ml. of 10%`hydrochloric acid and extracted
with dichloromethane (7 x 200 ml.). The combined
dichloromethane extracts are washed with saturated
sodium bicarbonate solution, dried over soaium sulfate
and concentrated in vacuo. The residue is chromato-
graphed on Silicar CC-7 (200 ml. silica gel) eluting
with 10% ethyl acetate/dichloromethane to yield 1.6
15- - g. of product which is recrystallized from benzene/
pentane to yield 1.5 g. of (endo)-1,3,3a,4,7,7a-
hexahydro-4,7-epoxyisobenzofuran-1-ol, m.p. 108-110.
Example 13
(endo)-3-(2-Methoxyethenyl)-7-oxabicyclo12.2.1]he~t-
_
5-ene-2-methanol
By substituting ~endo)-1,3,3a,4,7,7a-hexahydro-
4,7-epoxyisobenzofuran-1-ol in the procedure of
Example 3,-(endo)-3-(2-methoxyethenyl)-7-oxabicyclo-
12.2.1]hept-~-ene-2-methanol is obtained.
Example 14
(endo)-3,4,4a,5,7,7a-Hexahydro-5,8-epoxy-lH-benzopyran-
l-ol
By substituting (endo~-3-(2-methoxyethenyl)-7-
- oxabicyclot2.2.1]hept-5-ene-2-methanol in the pro-
cedure of Example 4, (endo)-3,4,4a,5,7,7a-hexa~.ydro-
5,8-epoxy-lH-benzopyran-l-ol is obtained.
....
* Trade Mark
. .
I :~ fi ~ t
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26^
Example 15
11R- (1, 2a (Z),3,4)1-7-(3-Hydroxymethyl)-7-oxabicyclo-
[2.2.1]hept-5-en-2-yl]-5-heptenoic acid
By substituting (endo)-3-(2-methoxyethenyl)-7-
S oxabicyclo~2.2.1]hept-5-ene-2-methanol in the
procedure of Example 5, [lR-(1,2(Z),3,4)]-7-
(3-hydroxymethyl)-7-oxabicyclo~2.2.1]hept-5-en-2-yl]-
5-heptenoic acid is obtained.
Example 16
[lR-(1~,2a(Z),3,4a)]-7-(3-Hydroxymethyl)-7-oxabicyclo-
2.2.Uhept-5-en-2-yl]-5-heptenoic acid, methyl ester
By substituting [lR-(1,2(Z),3a,4)]-7-
oxabicyclo[2.2.1]hept-5-en-2-yl]-5-heptenoic acid
in the procedure of Example 6, [lR-(la,2a(Z),3,4)]-
7-~3-hydroxymethyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-
5-heptenoic acid, methyl ester is obtained.
Example 17
llR-(1,2~5Z),3,4)]-7-(3-formyl)-7-oxabicyclo-
[2.2.1]hept-5-en-2-yl]-5-heptenoic acid, methyl
ester
By substituting [lR-(1,2(Z),3,4)]-7-
(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-
5-heptenoic acid, methyl ester in the procedure of
Example 7, [lR-(1,2(5Z),3,4a)]-7-(3-formyl)-7-
oxabicyclor2.2.1]hept-5-en-2-yl-5-heptenoic acid,
methyl ester is obtained.
Ex mple 18
~lR-(1,2(5Z~,3(1E),4a]-7-[3-(3-oxo-1-octenyl)-7-
oxabicyclo[2.2.1]hept-5-en-2-yl]-5-h ptenoic acid,
methyl ester
By substituting [lR-(1,2al5Z),3,4a]-7-
(3-formyl-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5-
heptenoic acid, methyl ester in the procedure of
1 1 6~
H~157
27
Example 8, 1lR-(1,2(5Z),3(lE),4]-7-~3,(3-oxo-1-
octenyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5-heptenoic
acid, methyl ester is obtained.
Example 19
[lR-(1,2(5Z),3(lE,3R ),4)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1~hept-5-en-2-yl]-5-
heptenoic acid, methyl ester
and
[lR-(1,2(5Z),3(lE,3S ),4)]-7-[3-(3-hydroxy-1-
1~ octenyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5-
heptenoic acid, methyl ester
By substituting the product of Example 18
in the procedure of Example 9, [lR-(la,2a(5Z),
3,(lE,3R ),4a)]-7-[3-(3-hydroxy-1-octenyl)-7-
15- oxabicyclo[2.2.1]hept-5-en-2-yl]-5-heptenoic acid,
methyl ester and [lR-(1,2a(5Z),3(1E,3S ),4a)]-
7-[3-~3-hydroxy-1-octenyl)-7-oxabicyclo[2.2.1]-
hept-5-en-2-yl]-5-heptenoic acid, methyl ester,
respectively, are obtained.
Example 20
[lR-(1~2~5Z),3a(1E,3R ),4)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5-
heptenoic acid
and
[lR-(la,2a(5Z),3a(lE,3S ),4a)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5-
hePtenoic acid
By substituting the product of Example 18
in the procedure of Example 10 c and continuing
as in parts d and e, [lR~ 2(5Z),3a(1E,3R ),4)]-
7-13-(3-hydroxy-1-octenyl)-7-oxabicyclo[2.2.1]hept-
5-en-2-yl]-5-heptenoic acid and [lR,(1,2a(5Z),3a-
(lE,3S ),4a)]-7-[3-(3-hydroxy-1-octen~1)-7-oxabicyclo
I ~ 6 ~
HA157
28
i2.2.1]hept-5-~n-2-yl]-5-heptenoic acid, respectively
are obtained.
Example 21
(endo)-Hexahydro-4,7-epoxyisobenzofuran-1(3H)-one
a) [lR-(endo,cis)]-7-Oxabicyclo[2.2.1]heptane-2,3-
dicarboxylic acid
A slurry of [lR-(endo,ci~)-7-oxabicyclo[2.2.1~-
hept-5-ene-2,3-dicarboxylic acid (33.8 g., 0.18 moles),
and 10~ palladium/carbon (800 mg.) in absolute ethanol
(1000 ml.) is stirred vigorously under one atmosphere
of hydrogen until the uptake of hydrogen has ceased
(4460 ml.!. The reaction mixture is then filtered
and the filtrate concentrated in vacuo to yield
34 g. of [lR-(endo,cis)]-7-oxabicyclo[2.2.1]heptane-
2,3-dicarboxylic acid. An analytical sample is
prepared by recrystallizing 3 g. of the diacid from
ethyl acetate/pentane to yield 2.9 g., m.p. 169-170.
b) (endo)-Hexahydro-4,7-epoxyisobenzofuran-1,3-dione
A slurry of 11R- (endo,cis)~-7-oxabicyclo-
[2.2.1]heptane-2,3-dicarboxylic acid (8.4 g., 0.045
moles) in acetyl chloride (80 ml.) is heated at
reflux for thirty minutes. The resultant solution is
concentrated in vacuo. The resultant solid is
rec~ystallized from benzene to yield 6 g. of (endo)-
hexahydro-4,7-epoxyisobenzofuran-1,3-dione, m.p.
154-155.
c) (endo)-Hexahydro-4,7-epoxyisobenzofuran-1~3H)-
one
-
Sodium borohydride (3.48 g., 0.092 moles~
is slurried in anhydrous tetrahydrofuran (150 ml.),
chilled to 0 and treated dropwise over ten minutes
~ 1 6L~381
HA157
29
with a solution of (endo)-hexahydro-4,7-epoxyisobenzo-
furan-1,3-dione (14.8 g., 0.088 moles) in anhydrous
tetrahydrofuran (250 ml.). The reaction mixture is
stirred at room temperature for one hour, then
concentrated in vacuo. The residue is chilled in
an ice bath and treated dropwise with 10% hydrochloric
acid (50 ml.). The mixture is diluted with brine
(100 ml.) and extracted several times with dichloro-
methane (5 x 200 ml.). The combined dichloromethane
extracts are dried over magnesium sulfate and con-
centrated in vacuo. The residue is dissolved in
dichloromethane and filtered through silica gel. The
filtrate is concentrated in vacuo. The residue is
recrystallized from heptane to yield 6.8 g. of
(endo)-hexahydro-4~7-epoxyisobenzofuran-l(3H)-one~
m.p. 153-155.
Example 22
~endo)-Octahydro-4,7-epoxyisobenzofuran-1-ol
A solution of tendo)-hexahydro-4,7-expoxy-
isobenzofuran-1(3H)-one (8.03 g., 0.052 moles) in
anhydrous toluene (250 ml.) is chilled to -78 and
treated dropwise over five minutes with a solution
of diisobutyl aluminum hydride (70 ml., 0.105 moles)
in toluene. The reaction mixture is stirred at
-78~ for twenty minutes. The reaction mixture is
then quenched with 10% acetic acid (50 ml.) and
allowed to come to room temperature. The mixture
is treated with 10% hydrochloric acid (25 ml.) and
extracted several times with dichloromethane
t7 x 200 ml.). The combined dichloromethane
extracts are dried over solid sodium bicarbonate
and concentrated in vacuo. The solid residue is
1~6~t~8~
HA157
recrystallized from heptane to yield 7.5 g. of
(endo)-octahydro-4,7-epoxyisobenzofuran-1-ol, m.p.
132-13~.
Example 23
(endo)-3-(2-Methoxyethenyl)-7-oxabicyclo[2.2.1]-
heptane-2-methanol
Lithium diisopropyl amide is prepared by
dissolving diisopropyl amine (140 ml., 1.0 moles)
in pentane (600 ml.), chilling the solution in an
ice bath, and adding n-butyl lithium (311 ml. of
2.42M in hexane, 0.753 moles) dropwise over 15
minutes. The reaction mixture is concentrated in
vacuo to ~ield the desired lithium diisopropyl
amide which is then dissolved in anhydrous tetrahydro-
furan (300 ml.) and added dropwise over ten minutes
to a slurry of (methoxymethyl)-triphenylphosphonium
chloride (259 g., 0.755 moles) in anhydrous toluene
(3700 ml.) chilled in an ice bath. The dark red
mixture is stirred at 4 for 15 minutes. (endo)-
Octahydro-4,7-epoxyisobenzofuran-1-ol (39.2 g.,
0.251 moles) is added and the reaction mixture
stirred at room temperature for three hours. The
reaction mixture is then poured into brine (2000 ml.)
and treated with concentrated hydrochloric acid to
pH 7. The mixture is extracted with ether ~3 x 800
ml.). The combined ether extracts are dried over
sodium sulfate and concentrated. The residue is
dissolved in ether (1000 ml.) and chilled overnight.
The precipitated phosphine oxide is removed and
the ether solution concentrated in vacuo. The
residue is chromatographed on silica gel (2000 ml.)
eluting with 1) dichloromethaneJ 2) 10% ethyl acetate/
dichloromethane and 3) 50~ ethyl acetate/dichloro-
i 364~81 HA157
31
methane. The fractions containing the pxoduct are
concentrated in vacuo. The resultant residue is
d~stilled ln vacuo to yield 17 g. of (endo)-3-
t2-methoxyethenyl)-7-oxabicyclo-12.2.1]heptane-2-
methanol, b.p. 110/0.001 mm.
Example 24
(endo)-Octahydro-5,8-epoxy-lH-benzopyran-3-ol
(endo)-3-(2-Methoxyethenyl)-7-oxabicyclo-
2.2.1]heptane-2-methanol (~.3 g., 0.013 moles)
is dissolved in cold 88~ formic acid (25 ml.). The
solution is stirred at room temperature for 30
minùtes. The solution is then chilled in a salt/
ice bath and treated dropwise with 10% sodium
hydroxide to pH 7Ø The mixture is saturated with
sodium chloride and extracted with dichloromethane
(4 x 100 ml.). The combined org~nic extracts are
dried over sodium sulfate and concentrated in vacuo.
The residue is chromatographed on*Silicar CC-7
(neutral silica gel) (200 ml.) eluting with 1)
dichloromethane, 2) 5% ethyl acetate/dichloromethane,
3) 20% ethyl acetate/dichloromethane and 4) ethyl
acetate. The factions containing the desired hemi-
acetal are combined and concetrated. An analytical
sample is obtained by distilling the residue in vacuo
to yield 1 g. of (endo)-octahydro-5,8-epoxy-lH-
benzopyran-3-ol, m.p. 37-40; b.p. 125-130~0.001 mm.
Example 25
[lR-(la,2~(Z),3~,4~]-7-13-(Hydroxymethyl)-7-oxabicyclo -
[2.2.1~hept-2-yl]-5-heptenoic acid
A solution of t4-carboxybutyl)triphenyl- -
phosphonium bromide (9.17 g., 0.021 moles) in
anhydrous dimethyl sulfoxide (8Q ml.) is treated
dropwise with dimsyl ion (from 0.1 moles of sodium
.
* Trade Mark
_ _ ;
i16~t~
HA157
32
hydride in 60 ml. of dimethylsulfoxide heated
at 75 until hydrogen evolution ceases) until an
orange color persists. A second amount of dimsyl
ion equaling the fixst ls then added. The reaction
is stirred at room temperature for 15 minutes then
treated with a solution of (endo)-octahydro-5,8-
epoxy-lH-benzopyran-3-ol (1.76 g., 0.01 moles) in
dimethyl sulfoxide (5 ml.). The reaction mixture
is stirred at room temperature for one hour then
quenched by the dropwise additon of a solution of
glacial acetic acid (1.7 g.) in ether (10 ml.).
The reaction mixture is poured into brine (100 ml.),
adjusted to pH 4 with 10~ hydrochloric acid, and
extracted with ether (4 x 100 ml.). The combined
ether extracts are dried over sodium sulfate and
concentrated. The residue ts treated with 5%
sodium bicarbonate solution (100 ml.) and stirred
for 15 minutes. The mixture is then extracted
with benzene (10 x 50 ml.), acidified with
10% hydrochloric acid, saturated with sodium
chloride, and extracted with ether (4 x 100 ml.).
The combined ether extracts are dried
over sodium sulfate and concentra~ed. The residue
is dissolved in ether (25 ml.) and chilled over-
night. The resultant phosphine oxide is removedby filtration. The filtrate is concentrated
in vacuo. The residue is dissolved in 10 ml. of
ethyl acetate and treated with dicyclohexylamine
until basic. The resultant solid is recrystallized
from ethyl acetate. The precipitate is filtered,
dissolved in water, acidified with 10% hydrochloric
acid and extracted with ethyl acetate. The ethyl
acetate extract is dried over sodium sulfate and
concentrated. The residue is chromatographed on
IJ~ 8~
~A15 7
33
Silicar CC-7 (100 ml.) ~neutral R~lica gel, pH 7)
eluting with ethyl acetate to yield 2 g. of tlR-
(lu,2(Z),3,4~-7-13-(hydroxymethyl)-7-
oxabicyclo[2.2.1~hept-2-yl]-S-heptenoic acid.
Analysis Calc'd. for C14H2204; C, 66~12; H, 8.72
F~und: C, 66,23; H, 8.60
Example 26
11R- (1, 2a (Z), 3,4~)]-7-(3-Hydroxymethyl)-7-
oxabicyclol2.2.11hept-2-yll-5-heptenoic acid,
methyl ester
By substituting [lR-(1~,2(Z),3~4)]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid in
`the procedure of Example 6, [lR-(1,2~(Z),
3,4a)]-7-(3-hydroxymethyl)-7-oxabicyclol2.2.1]hept-
2-yl]-5-heptenoic acid, methyl ester is obtained.
- Example 27
[lR-(1,2(5Z),3a,4a)]-7-(3-formyl)-7-oxabicyclo-
l2.2.1~hept-2-yl]-5-heptenoic acid, methyl ester
,
By substituting [lR- (la, 2~(Z),3a,4a)]-7-
(hydroxymethyl)-7-oxabicyclo12.2.1~hept-2-yl]-
5-heptenoic acid, methyl ester in the procedure
of Example 7, tlR-[la,2(5Z), 3~,4a)]-7-(3-formyl)-
7-oxabicyclo12.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester is obtained.
Example 28 - --
¦lR-(1~,2~(5Z),3(1E),4~]]-7-[3-(3-oxo-1-octenyl)-
7-oxabicyclol2.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester -
By substituting [lR- (la, 2(5Z),3,4]-7-
(3-formyl-7-oxabicyclo12.2.1]hept-2-yl)-5-heptenoic
acid, methyl ester in the procedure-of Example 8,
- 11R-(1~ ,2a(5Z)~3(1E)~4~-7-[3-(3-oxO-l-octenyl)
7-oxatricyclol2.2.1]hept-2-yl]-S-heptenoic acid,
methyl ester is obtained.
* Trade Mark
_
) 1 6~t
HA157
34
Example 29
.
[lR-(1,2(5Z),3~(1E,3R ),4)]-7~[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo12.2.1]hept-2-ylj-5-heptenoic
acid, methyl ester
and
11R~ , 2~t5Z),3~(lE,3S ),4~)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester
.
By substituting the product of Example 18
in the procedure of Example 10, t1R-(1 ,2(5Z),
3~lE,3R ),4)]-7-[3-(3-hydroxy-1-octenyl)-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester and [lR-(1,2(5Z),3(1E,3S ),
4)]-7-~3-(3-hydroxy-1-octenyl)-7-oxabicyclo~2.2.1]-
hept-2-yl]-5-heptenoic acid, methyl ester,
respectively, are obtained.
Exam~le 30
¦lR-(la,2~(5Z),3a(lE,3R ),4)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicYclo[2.2.1]hept-2-yl)-5-heptenoic
acid
and
[lR-(1~,2(5Z),3a(1E,3S ),4)]-7-[3-(3-hydroxy-1-
octenYl)-7-oxabicYclo[2~2~l]hept-2-yl]-5-he-ptenoic
_
acid
By substituting the product of Example 18
in the procedure of Example llc and continuing as
in parts d and 3, [lR-(1,2~(5Z),3(1E,3R ),4~)]-
7-13-(3-hydroxy-1-octenyl)-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid and [lR-(1,2~(5Z),3~(lE,3S ),
4)]-7-[3-(3-hydroxy-1-octenyl)-7-oxabicyclo[2.2.1]-
hept-2-yl]-5-heptenoic acid, respectively are
obtained.
