Note: Descriptions are shown in the official language in which they were submitted.
~6~7~ HA157
This invention relates to a yroup o~ compounds
o~ the Pe~2 type and intermediates therefor which are
cardiovascular agents use~ul, for example, in the
treatment of throm~olytic d;sease. TheRe compau~ds ~e
the structural formula
~ C~2-CH~CH-lower alkylene-COOR
~ ~2
wherein Rl is hydrogen or lower alkyl; R2 is -C~O,
-C~2OH or -CH=CH-R -lower alkylene-CH3; R is keto
(C=O) or hyaroxymethyl (C~O~); and the ~otted line is an
optional dou~le bond.
The intermediates ha~e the formulas
: (II)
CH=CH-O-lower alkyl
~ ~ CH2O~
and
(III) .
: 25 ~ ~3
wherein R3 has the same meanin~ as abo~e and x is 0 or
1~ ,
: The ~otted li~e ~n each o~ the fore~oing
structural ~ormulas represent~ an optional double bond.
.
' ' .
=
HA157
1167~
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 se~en carbon atoms, e.g., methyl,
ethyl, propyl, isopropyl, butyl, isobutyl,t~utyl, 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 especially methyl, R
is -CH2O~ or especially -CH=C~-R -lower alkylene- CH3,
particularl~ 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 a.g.,
for treatment of thrombolytic disease such as coronary
or cerebral thromboses. T~ey are also selective
thromboxane A2 synthetase inhi~itor~, e.gO, having a
~asodilatory 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.
.
~746~ H~157
The active substance can be utllized in a
composition such as tablet, capsule, svlution or
suspension containing about 5 to about 500 mg. per
unit of dosage o~ a compound or mixture o~ c~npounds
o~ formula ~. They may be compounded in conventional
manner with a physiologically acceptable vehicle or
carrier, excipient, binder, preservative, stabilizer,
fla~or, etc. as called for by accepted pharmaceutical
practice. Also as indicated i~ the discussion above,
lQ certain members additionally sexve as intermediates
for other members of the group.
The sequence of reactions described below yields
a series o~ 7-oxabicycloheptane- and 7-oxabicycloheptene
derivatives of the PG~2 type.
lS No~ only can members of the group be derived from
other members and thus have utility as intermediates, but '
they also have physiological activity themselves.
~ hus, when maleic anhydride is made to react with
furan which has the formula
~IV) ~CH
\O
CH
~CH ~
e.g. in ether solution at room temperature, this results
in a compound having the formula
~V) ~0
CH-CH-CH-C
CH- H-CH-C
~0
~167'~ HA157
Reduction of the compound o~ formula V, e.g.,
catalytically, for example, in the presence of
palladium-carbon, provides a reduced product having
the formula
(VI) ~ O
f
I I ~
CH2-Ck-CH-C~
o
~ he compound of formula VI can then be con-
verted to a compound having the fonmula
(VII~ O
CH2-CH-CH-C \
1 O I ~ O
CH2-CH-CH-C'H
e.g., by reduction in tetrahydrofuran with a boro- --
hydride like ~odium borohydride or zinc borohydride~
Treatment of the compound of formula VII with
:: : diisobutylaluminum hydride or diisobutylborane yields
a compound having the formula
(YII~
CH2-CH-CH-CHOH
1o 1 \ O
CH2-CH-CH-CH
which then is submitted to Wittig reaction conditions
e.g., with an (alkoxymethyl)triphenylphosphonium
11674~ HA157
halide ].ike (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
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
CH -~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- -~
2a hydrofuran, then demetalated with a reducing agent
like potassium iodide to yield a product having the
formula
(X)
CH2-1~H-CH-CH2-CHO
1 ~ I O
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
i'7~
HA157
(XI~
/ CH2 ~ OH
CH2-CH-CH C~
CH2 CH~CH o
CH2
These 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 fvrmula
(XII)
CH2-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 à sub-
stituted diazoalka~e 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-CH2-CH=CH-lower alkylene-COOR
O I
CH2-CH-CH-CHO
wherin ~ is lower alkyl.
.
'
.
~6~74~
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
~s tributyl or triphenyl~2-oxoheptylidine phosphorane
in an organic solvent such as tetrahydrofuran provides
a product having the formula
(xn7)
C~2-CH-CH-CH2-CH=CH-lower alkylene-COOR
O
CH2-~H-CH-CH=CH-C-lower alkylene-CH3
O
~herein Rl is lower alkyl.
This product is then reducea, e~g., with
lithium diisobutyl aluminum hydride, with zinc~orohydride,
~odium borohydride with ce~rium ~hloride or sodi~m cyano- ^~
20 b~Iohydride to yield a product having the formula
(XV) *
C~2~CH-CH-CH2-CH=CH-lower alkylene-COOR
0 1 *
~ CH2-CH-CH-CH=CH-CH-lower alkylene-CH3
2~ OH
: ~hich can be converted to the free acid, i.e., a
c~mpound having the formula
3~
'4~
H~157
(XVI) *
CH2-CH-CH-CH2-CH=CH-lower alkylene-COOH
~ I *
CH2-CH-CH-CH=CH-CH lower alkylene-CH3
OH
by treatment with a base such as lithium hydroxide
followed by heutralization with an acid such as dilute
hydrochloric acid.
1~ 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
tXVII)
CH-CH-CH-COOH
11 1 1
CH-CH-CH-COO~
:: : '
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
sodium borohydride to the 5,6-unsaturated analog of
a compound of formula VII above, i.e., a compound
having the formula
VIIa)
CH-CH-C~-C
; 30 ~ \
CH-C~-CH-CH2
::
:
:~
'
.
~16746~ HA157
Starting with this compound instead o~ with the
compound of formula VII and ~ollowing the same sequence
of steps as described abo~e with respect to the latter
compouna 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 oYer palladium on carbon
lQ to obtain a compound of formula VII and this
intermediate processed as described aboYe.
The compounds of this in~ention ha~e three centers
o~ asymmetry as indicated b~ the asterisks in formulas
X~ and XVI. The various stereoisomeric forms are ~Jithin
the scope of the invention.
Thus when the first sequence of reactions described
abo~e are followed, i.e., reacting maleic anhydride with
a furan of formula IV, compounds are obtained wherein
both side chains, i.e., those residues attached to the
2 and 3 positions on the 7-oxabicyclol2,2,1]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
::
\~
~ 4~ 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 described above, a
mixture of stereoisomeric compounds in which the
hydroxy group is either R (~) or S (a) is usually ob-
tained. They can be graphically described as follows:
(XIX)
~ / ~ ~ `COO-lower alkyl
~
OH
(XX~
~ ~ ~ / COO-lower alkyl
G~
~o o~ ~
The same considerations apply to t~e acids which are
obtained by hydrolysis. The stereoisomeric pairs can
be resol~ed by conven~ional 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 dou~le bond,
stereoisomeric compounds are obtained wherein the
lactole ring and subsequent compounds are in the endo
3Q position as depicted graphically with respect to
a compound of formula XVIII:
.
~6~6~ ~157
11
(XVIIIa) O
~, j4
HO~/
The following examples are illustrative o~ the
invention. The products o~ the examples constitute
pre~erred embodiments as well as provide additional
experimental ae~ails and serve as models for
additional mem~ers of the group, All temperatures
are in degrees Celsius.
.
~'
: ` -
.
-
::
~67 '~ HA157
12
xample 1
(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[2.2.13-5--heptene-2,3-dicarboxylic
anhydride [Ber. 62, 554 (1929); Ann. 460, 98(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.pO 112-114.
tb~ (Exo)Hexahydro-4,7-epoxyisobenzofuran-1(3H)-one
To a slurry of 6.7 g. t0.18 mole) of sodium
borohydride in 50 ml. of dry tetrahydrofuran is
added a solution of 29.8 g. (0.18 mole1 of (exo)-
hexahydro-4,7-epoxyisobenzofuran-1,3-dione in 500 ml.
~f dry tetrahydrofuran o~er 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 ?-1 g. of (exo)hexahydro~
4,7-epoxyisobenzofuran-1(3H)-one, m.pO 112-118.
Example 2
(Exo)Octahydro-4,7-epoxyisobenzofuran-1-ol
.
A solution of (exo)hexahydro-4,7-epoxyisobenzo-
furan-1(3H)-one t3 g., 0.02 moles~ in 100 ml. of
.
116 ~46~ HA157
13
anhydrous toluene is chilled to -78 and treated
dropwise over ten minutes with a soJution 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. ~f 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 benæene to yield 2.4 g.
of (exo)octahydro-4,7-epoxyisobenzofuran-1-ol, m.p.
125-127.
xample 3
(Exo)-3-(2-Methoxyethenyl)-7-oxabicyclo[2.2.1]heptane-
2-methanol
A slurry of (methoxymethyl)-triphenylphosphonium
chloride (123.47 g., 0.36 moles) in anhydrous toluenè
(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
- 30 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.
.. .
.
~ 7~6~ ~157
1~
The mixture is extracted several times with diethyl
ether. The combined ether extracts are dried over
sodium sulfate and concentrated in vacuo. The residue
is 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-
r2.2.1]heptane-2-methanol ~10.2 g., 0.055 moles) is
dissoIved 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 ~orty-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 gran~ 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 S
[lR~ ,2~(Z),3~, 4a) ~ -7- [3- (Hydroxymethyl)-7 oxabicyclor
12.2.1ihept-2-yl]-5-heptenoic acid
. . . ~ . _ .
a) A mixture of N-acetylpyridinium chloride
is prepared by adding 9.6 ml. (136 mmole) of acetyl
116 7L~6;~ . ~
HA157
chloride dropwise to 56 ml. of pyridine. To this is
added 5.0 g. (~7 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 ~ver 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 500 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 iodide 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
~olution and brine and dried ov~r sodium sulfate.
Concentration yields 3.7 g. of material which5 crystallizes on standing in an ice box.
c) A Wittig reagent is prepared in d;methyl
sulfoxide (dried over calcium hydride) by adding a
solution of sodium methylsulfinylmethide (pr~pared
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
.
~746~ 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 produc~ of part b in 20 ml. of dimethyl sulfoxide
S 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 (300 ml.) and extracted with ether t3 x 200 ml.).
Concentration of these extracts gives an oil which
ls ~tirred 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 acet~te-cyclohexane to yield 320 mg. of
11R- (1, 2~ (Z), 3~,4)]-7-[3-(hydroxymethyl)-7-
oxabicyclo- [2 . 2.1]hept-2-yl]-5-heptenoic acid, m.p.
59-63a~ o
Example 6
[lR~ ,2~5Z),3~,4~)3-7-~3-(hydroxymethyl) 7-
oxabicyclo-~2.2.1]hept-2-yl]-5-heptenoic acid,
methy-l ester
A solution o~ diazomethane in ether is
prepared from 3 g. of N-methylnitro-nitrosoquanidine
in 50 mlu of ether with dropwise addition at 0 o~
.
116746~ HA157
17
9 ml. of 40~ potassium hydroxidc water solution.
This solution (dried o~er potassium hydroxide pellets)
is added dropwise to a stirring solution of llR-
(1~,2~Z),3R,4~)]-7-[3-(hydroxymethyl)-7-oxabicycl~-
[2.2.1]hept-1-yl-5-heptenoic acid (254 g~, 10 mmole
iD ether (150 ml.) over a ten minute period. Stirring
i8 continued-~or 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 t~ yield 2.6 g. of product
(one spot ~y TLC - silica gel; ethyl acetate;
Rf=0.5). The residue is chromatographed on silica
gel (200 ml.) eluting with 1) ethyl acetate/pentane
lS (1:9), 2) ethyl acetate/pentane (1:43, and 3) ethyl
acetate/pentane (2:3) to yield 2.23 g. of [lR-
(1~,2B,(5Z),3B,4~)]-7-[3-(hydroxymethyl)-7-oxabicyclo-
12.2.1]hept-2-yl]-5-heptenoic acid; methyl ester as
an oil.
Example 7
11R- (la, 2~ r5Z), 3B, 4 ~ ]-7- [3-formyl-7-oxabicyclo
: 12.2.1]hept-2-yl]-5 heptenoic acid, methyl ester
A solution of chromium trioxide/pyridine 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 ~or twenty minutes.
Eight grams of dry*Celite(diatomaceous earth
: dried at 100 o~ernight) are then added ~ollowed
by a solution o~ ~lR~ ,2~5Z)~3~,4~)]-7-[3- -
~hydroxymethyl)-7-oxahicyclo[2.2.1]hept-2-yl3-5-
heptenoic acid,methyl ester (2.38 g., 8.94 mmoles
: . in 15 ml. of dichloromethane). The resulting mixture
* Trade Mark
.
, _ . . .. . .
116~46~ HA157
18
.
i~ stirred under nitrogen fo~ fifteen minutes and
then filtered. The filtrate is washed with 5~
~od~um bicarbonate s~lution ~2 x 100 ml.), 10%
hydrochloric aci~ (2 x 100 ml.),-5% sodium ~icar~onate
~olution (2 x 100 ml.) r water ~1 :x 200 ml.) and brine
(2 x 100 ml.). After drying over sodlum 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 11R~ ,2~ (5Z~,
3B,4~l~-7-t3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-
heptenoic acid, methyl ester as an oil.
Example 8
ilR-(l~, 2B (5Z), 3~ (lE),4~-7-[3-(3-oxo-1-octe~yl)-
7-oxabicyclo [2.2.i]hept-2-yl]-5-heptenoic acid,
methyl ester
A solution of 11~ ,2~5Z)~3B~4a)]-7-[3-
formyl-7-oxabicyclor2.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester (1.18 g., 0.0044 moles~ and tributyl-2-
oxoheptylidenephosphorane (1 g.~ 0.0044 moles3
in anhydro~s ether (50 ml.) is heated at reflux
for three days.. The xeaction 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 (2~ ml.j
and chilled to yield 1.2 g. of IlR-(l~?~r5z)~ , .-
3~1E),4~ 7-[3-(3-oxo-1-octenyl)-7-oxabicyclo
[2.2.1]hept-2-yl] 5-heptenoic acia~ methyl ester~ -
-m.p. 32-34.
.
* Trade Mark
~- . ' ; ..
~ 7'~ HA157
19
Example 9
~lR~ ,2~(~Z),3B(lE,3R*),4a)]-7-[3-(3~hydroXy-l-
octenyl)-7-oxabicyclo[2.2.1~hept-2-yl]-5-he~tenoic
acid, methyl ester
and
[lR- ~la, 2B (5Z), 3~ (lE, 3S*), 4a) ] -7- L3-(3-hydroxy-1-
octenYl)-7~oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
ac_d, methyl ester
A solution of [lR-(la,2~(5Z),3~(1E), 4a) ] -7-
[3-(3-oxo-1-octenyl)-7-oxabicyclo[2.2.1]h~pt-2-yl]-
5-heptenoic acid, methyl ester (1.26 g., 0.0035
moles) in anhydrous dimethoxyethane t20 mlO) is
chilled to -78 and treated dropwise with a solution
of lithium tri-sec~ butylborohydride (3.8 ml.,
15- 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) ~lR~ ,2~(5Z),3e(1E,3R*)~4a)~-7-t3-(3-hydroxy-
l-octenyl)-7-oxabicyclo[2.2.1~hept-2-yl3-5-heptenoic
acid, methyl es~er and 370 mg. of b) [lR~ 2~(5Z),
3~ (lE, 3S*), 4a) ]-7 [3, (3-hydroxy-1-octenyl)-7-
oxabicyclo[2.2~1~hept-2-yl]-5-heptenoic acid.
~) Analysis Calc'd. for C22H3~G4: C,72.49; H,9-96
Found: C,72.24; H, 10.01
b3 Analysis Calc'd- for C22H3604: C,72.49; H, 9.96
Found: C,72.22; H, 9~92
f~ 157
Example 10 ~
[lR-¦1,2~52),3B(lE,3R*),4~)]-7-~3~[3-hydroxy-1-
octenyl) -7~oxabicyclo [2 ~ 2. l]hept-2-yl] -5-heptenoic
acid
_
and
[lR- (la, ?~ (SZ), 3R (lE, 3S*), ~a? ~ [3- (3-hydroxy-1-
octenyl ) - 7-oxabicyclo 12 . 2 . 1 ] hept-?-yl ~ - 5-heptenoic
acid
a) A solution o~ chromium trioxide~pyriaine
is prepared in anhydrous dichloromethane (from 5O9 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-(1,2~(5z),
3~,4a 3]-7-13-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-
2-yl~-5-heptenoic acid, methyl ester dissol~ed in
S ml. of dichloromethane. The resulting mixture is
stirred under nitrogen for 15 minutes and then worked
up. The Celite-chromium-trioxide mixture is removed
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 concentratea
under vacuum to give 2.34 g. of llR~ ,2~5Z),3~,4a~]-
7-[3-formyl-7-oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic
acid, methyl ester.
b) A mixture of Horner-Wittig reagent i9
prepared from sodium hydride (washed free of oil
with hexane~ (470 mg., 9.8 mmole) and dimethylS2-
oxoheptyl)phosphonate Sl. 82 g. ~ 8.~ mmole) in dry
dime~hoxyethane (175 ml.~. After combining these
reagents~ stirring is continued under nitrogen for
-- . .
.. . . .
- * Trade Mark : -
.
~ a6 7L~
HA157
21
30 minutes during which time a white paste-like
material forms. A solution of 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 mix~ure 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 cxude material.
This is purified by HPLC chromatography on a 1"
by 24" column of silica gel using 0.5% ethyl
acetate/benzene as ~he eluent. This yields 0.79
g. of pure [lR~ ,2~(5Z),3~(lE),4~)]-7-[3-(3-oxo-
1-octenyl)-7-oxabicyclol2.2.11hept-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
o~ 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 o~ the product of part b (1.26 g., 3.5
mmole) in 15 ml. of dry dimethoxyethane at -7B. The
reaction is allowed to proceed at -78 for 30 minutes
and then quenched by the addition of 9 ml. of
saturated ammonium chloride solution. The mixture
is then poured into brine (20 ml.) and extracted
3~ with ethyl acetate. The extracts are washed with
Pthanolamine-water solution (50/50) to remove
borane side products, then dried over magnesium
~ 74~ HAl57
22-
sulfate and concentrated to yield the crude product.
The two dias~ereomers are separated by HPLC on a
silica gel colum (l" x 24'l) using 2.5~ ethyl
acetate/benzene to elute the less polar isomer
(B-OH) and 5% ethyl acetate/benzene to elute the
more polar isomer (a OH). In this way 449 mg. of
11R~ ,2 B ( S Z ) , 3 B ( lE,3R*),4~ 7- [ 3 , ( 3-hydroxy-l-
octenyl)-7-oxabicyclo[2~2.1]hept~2-yl]-5 heptenoic
acidt methyl ester (~-OH isomer) and 300 mg. of
11R- (la,2~ ~5Z) ~3B (lE,3S*) ~4a) ]-7- [3- (3-hydroxy-l-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acld, methyl ester (~-OH isomer) are obtained.
d) A mixture of the ~-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 lOO ml.). The
ether extracts are dried over sodium sulfate and
concentrated yielding an oil containing water. This
is dried by solution in dichIoromethane and drying
~5 over sodium sulfate. Remo~al 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
11R~ , 2~ (5Z), 3~(1E,3R*),4u]-7-l3-(3-hydroxy-l-
octenyl~-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid as an oil.
~16746~ HA157
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 tetrahydrouran (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 dissolving 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 oYer phosphorus pentoxide at
room temperature for five days to yield 100 mg. of
tlR-tl,2~(5Z),3~(1E~3S*),4a)]-7-[3~13-hydroxy-1-
~0 octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid.
Analysis Calc'd- for C21H34O4: C, 71.96; H, 9.78
, Found: C, 71.68; H, 9.49
E~
(endo)-3a,4,7,7a-Tetrahydro-4,7-epoxyisobenzofuran-
1(3H)-one
_ .
a) [lR-(endo,cis)]-7-Oxabicyclo[2.2.1]hept-5-ene-
2,3-dicarboxylic acid
. .
A solution of maleic acid (982 g.l 8.5 moles)
in water (2100 ml.) is treated with furan ~618 ml.,
B.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
~1674~ ~IA157
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~dicaxboxylic acid,
m.p. 149-150.
b) (endo)-3a,4,7,7a-Tetrahydro 4,7~epoxyisobenzofuran
1 (:3H) -Dne
Trifluoroacetic anhydride (90 ml.) is chilled
to D and treated with [lR~(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 minutes3. 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
~5 in vacuo to yield 3.3 g. of (endo)-3a,4,7,7a-tetrahydro-
4,7 epoxyisobenzofuran-lt3H)-one which is recrys~lized
from benzene/pentane to yield 2 0 1 g., m.p. 121 .
Example 12
~endo3-1,3,3a,4,7,7a-Hexahydro-4 7-epoxyisobenzofuran-
3~ l-ol
~ so~tion o~ ~an~o)-3a,4,7,7a-tetrahydro-
4,7-~poxyisobenzofuran-1~3H)-one (3 g., 0.0197 moles)
HA157
..
in toluene (100 ml.) is chilled to -78 and treated
dropwi~e over five minutes with a solut~on of d~isobut~l
aluminum hydride iD toluene (26~3 ml.0 0.0395 moles).
The reaction mixture is stirred at ~78 for 20 minute~
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 p~ured
i~to 50 ml. of lO~ hydrochloric acid and extractea
with dichloromethane 17 x 200 ml.). The combined
dichloromethane extracts are washed with saturated
sodium bicarbonate solution, dried over sodium sul~ate
and concentrated in vacuo. The residue is chromato-
graphed on Silicar CC-7 (200 mln silica gel~ éluting
with 10% ethyl acetate/dichl,oromethane to yield 1~6
- 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-epoxylsobenzofuran-1-ol~ m.p. 108-110~
Example 13
(endo)-3-~2-Methoxyethenyl)-7-oxabicyclol2,2.1]he~t-
.. _ .. ~ .. . . . _ . _ . _ ... _
20 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-
.~2.2~lJhept-5-ene-2-methanol is obtainedO
Example 14 : . ~
.. _ .. . . .
(endo~-3,~,4a,5,7,~a-Hexahydro-5,8-epoxy-lH-benzopyran-
. _
l-ol
: By substituting (endo~-3-(2-methoxyethenyl)-7-
~ oxabicyclo~2.2.1]hPpt-5-ene-2-methanol in the pro-
3~ cedure of Example 4, (endo)-3,4,4a,5,7,7a-hexahydro-
5,8-epoxy-lH-benzopyran l-ol is obtained.
. * Trade Mar~
- . . ............................... .
.
7~ HA157
26-
Example 15
[lR-(1,2a(Z),3~,4)]-7-(3-Hydroxymethyl)-7-oxabicyclo-
[2.2.1]hept-5-en-2-yl]~5-heptenoic acid
-
By substituting (endo)-3-(2-methoxyethenyl)-7-
oxa~icyclo[2.2.1]hept-5-ene-2-methanol in the
procedure of Example 5, ~lR-(la,2a(Z),3a,4a)]-7~
(3-hydroxymethyl)-7-oxabicyclo[2.2.1~hept-5-en-2-yl]-
5-heptenoic acid is obtained.
Exam~le 16
` [ lR= ( la, 2~ ( Z ), 3a, 4 a ) ] - 7-(3-Hydroxymethyl)-7-oxabicyclo-
t2.2.Uhept-5-en-2-yl]-5-heptenoic acid, methyl ester
By substituting [lR-(la,2a(Z),3,4a)]-7-
oxabicyclo[2.2.1]hept-5-en-2-yl]~5-heptenoic acid
in the procedure o~ Example 6, [lR-(la,2a(Z),3a,4a)]-
7-(3-hydroxymethyl)-7-oxabicyclo[2.2.1~hept-5-en-2-yl]
5-heptenoic acid, methyl ester is obtained.
Example 17
.
rlR-(la/2a~5z)~3~4u)]-7-(3-formyl)-7-oxabi
[2 2.1]hept-5-en-2-y1]-5-heptenoic acid, methyl
ester
_
By substituting llR-(la,2a(Z),3a,4a~]-7-
(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-
5-heptenoic acid, methyl ester in thQ procedure of
Example 7, ~lR-(1,2~5Z),3~,4)]-7-(3-formyl)-7-
oxabicyclo[2.2.1~hept-5-en-2-yl-5-heptenoic acid,
methyl ester is obtained.
Example 18
.
[lR- (1~, 2~ ( 5Z ) ~ 3 (lE), 4a ] -7- [3- ( 3-oxo-1-octenyl)-7-
- oxabicyclo[2.2.1]hept-5-en-2-yl]-5-heptenoic acid,
methyl ester
By ubstituting [lR- ~la,2a (5Z) ,3a,4~]-7-
(3-formyl-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5-
heptenoic acid, methyl ester in the pxocedure of
~6~'~6'~ ~157
27
Example 8, [lR~ ,2~(5Z),3atlE),9~-7-[3,(3-oxo~l-
octenyl)-7-oxabicyclo[2.2.1]hept-5~en-2~yl~-5-heptenoic
acid, methyl ester is obtained.
Example 19
[lR~ ,2(5Z),3~(1E,3R ),4~)]-7-[3-(3-hydrox~-1-
octenyl) 7-oxabicyclo[2.2~1]hept-5-en-2-yl]-5-
heptenoic acid, methyl ester
and
[lR-(1~,2~(5Z),3~(1E,3S ),4a) ]~7~[3-(3~hydroxy-1-
. . _ . .
octenyl)-7~oxabicyclo[2.2.1]hept-5-en-2-yl]-5-
hepte~oic acid, methyl ester
By substituting the product of Example 18
in the procedure of Example 9, [lR~ , 2a (5Z),
3,(1E,3R ),4a)]-7 [3-(3-hydroxy-1-octenyl)-7-
oxabicyclo[2.2.1]hept-5-en-2-yl]-5-heptenoic acid,
methyl ester and [lR-(1~,2a(5Z),3~(1E,3S ),4~)]-
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-~1~2a(5Z),3~(1E,3R ),4~]-7-[3-(3-hydroxy-1-
octenx1)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]-5
heptenoic acid
and
~lR- (la, 2~ (5Z), 3a (lE,3S ),4)]-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~ 2a(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, ~la~2a(5Z) ,3a-
(lE,3S ),4)]-7-[3-(3-hydroxy-1-octenyl)-7-oxabicyclo
l~G74~ HA157
28
[2.2~1]hept-5-en-2-~1]-5-heptenoic acid, respectively
are obtained.
(endo)~Hexahydro-4,7-epo~sobenzofuran-1(3H)-one
a) 11R- (endo,cis)]-7-Oxabicyclo[2.2.1]heptane-2,3-
.
dicar _ ylic 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 reactior. mixture is then filtered
and the filtrate concentrated in vacuo to yield
34 g. of [lR-(endo,cis)3-7-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 [lR-(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.
I54-155.
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 dropwlse over ten minutes
. .
1~746~ HA157
~9
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
~tirred at room temperature for one hour, then
concentrated in vacuo. The residue is chilled in
an ice bath and treated dropwise with 10% hydrochloric
a~id (50 ml.). The mixture is diluted with brine
(100 ml.) and extracted seYeral times with dichloro-
methane ~5 x 200 ml.). The combined dichloromethane
extracts are dried over magnesium sulate 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 q. of
(endo)-hexahydro-4,7-epoxyisobenzofuran-1~3H)-one,
m.p. 153-155.
(e do)-Octahydro-4,_7-epoxyisobenzofuran-1-ol
A solution of (endo)-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
o~ diisobutyl aluminum hydride (70 ml., 0.105 moles)
in toluene. The reaction mixture is stirred at
25~ -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
(7 x 200 ml.~. The combined dichloromethane
extracts are dried over SOlia sodium bicarbonate
and concentrated in vacuo. The solid residue is
.
.
~ 4~ HA157
3~
recxystallized from heptane to yield 7.5 g. of
(endo)-octahydro-4,7-epoxyisobenzofuran-1-ol, m.p.
132-133.
Example 23
(endo)-3-(2-Methoxyethenyl)-7-oxabicyclo[2.2.1]-
. . . ~
he~tane-2-methanol
Lithium diisopropyl amide is prepared by
dissolving diisopropyl amine (140 mlO, 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 yield 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 molesj 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
sQdium 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~ dichloxomethane, 2) 10% ethyl acetate/
dichloromethane and 3) 50% ethyl acetate/dichloro-
.
~ 746~ ~A157
31
. .
methane. The fractions containing the product are
~oncentrated -in vac~o. The resultant residue i8
d~stilled in vacuo to yield 17 g. of (endo~ 3-
(2-me~hoxyethenyl)-7-oxabicyclo-12.2.1]heptane-2-
me~hanol, ~.p. 110/0.001 mm.
Exam le 24
(endo~-Octahydro-5,~-epoxy~l~ benzopyran-3-ol
(endo)-3-(2-Methoxyethenyl)-7-oxabicyclo-
2.2.1]heptane-2-methanol ~2.3 g., 0.013 m~les)
'i~ dissolved in cold 88% formic acid (25 ml.~. The
solution is stirred at room temperature for 30
minutes. The solution is then chilled in a salt/
ice bath and treated dropwise with 10% sodium
hydroxide to p~ 7.0~ The mixture is saturated with
sodium chloride and extracted with dichloromethane
(4 x 100 ml.). 'The combined organic extracts are
dried over sodium sulfate and concentrated in vacuo.
The residue is chromatographed on*Sili'car CC-7
' ~neutral silica gel) (200 ml.) eluting with 1)
dichloromethan~, 2~ 5~ ethyl acetate/dichloromethane,
3) 20% ethyl acetate/dichloromethane and 4) ethyl
acetate. The factions containing the desired hemi-
acetal are combined an~ concetrated. An analytical
sample is obtained by distilling the residue in vacuo
to yield 1 g. of (endo)-octahydro-5,8-epoxy-1~-
benzopyran-3-ol, m.p. 37-4Q; b.p. 125-130~0.001 mm.
Example 25
.
[lR- (1 ,2a (Z~ ,3a,4~]-7- [3- SHydroxymethyl)-7-oxabicyclo ~
t2.2.1~hept-2-yl]-5- eptenoic acid
A solution o* ~4-carboxybutyl)triphenyl- -
phosphonium bromide S9.17 g., 0.0~1 moles? in
anhydrous dimethyl sulfoxide '~80 ml.) is treated
dropwise with dimsyl ion (from 0.1 moles of sodium
:
* Trade ~ark
.
~157
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 first is 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 gO, 0.01 moles) in
dimethyl sul~oxide (5 ml.). The reaction mixture
is stirred at xoom temperature for one hour then
'quenched by the dropwise additon of a solution of
glacial acetic acid (1.7 g.) in ether (lO ml.3.
The reaction mixture is poured into brine tlOO ml.),
adjusted to pH 4 with 10% hydrochloric acid, and
extracted with ether (4 x lOO ml.). The combined
ether extracts are dried over sodium sulfate and
concentrated. The residue is treated with 5%
sodium bicarbonate solution (lOO ml.) and stirred
for 15 minutes. The mixture is then extracted
with benzene (lO 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 concentrat,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 prPcipitate is filtered,
dissolved in water, acidified with 10% hydrochloric
acia and extracted with ethyl acetate. The ethyl
acetate extract is dried over sodium sulfate and
concentrated. The residue is chromatographed on
l~i 746~ HAl 5 7
33
Silicar CC-7 (100 ml.) (neutral sllica gel, pH 7)
eluting with ethyl acetate to yield 2 g. of [1~-
~ 2a (Z) ~ 3a ~ 4a] -~ [3-(hydroxymethyl)-7-
oxabicyclo[2~2.1]hept-2-yl]-5-heptehoic acid.
S Analysis Calc'd. for C14H2204, C, 66~12; ~, B.72
Found: C, 66~23; H, 8.60
ExamPle ?~ `
11R-(1~2tZ3 ,3~,4~)]-7-13 Hydxoxymethyl)-7- -
oxabicyclo[2.2.1]hept-2-yl~5-heptenoic acid,
methyl ester
By substituting [lR-(lu, 2a (Z) ~ 3a ~ 4a) ~ -7-
- oxabicyclo[2.2.1]hept-2-yl]~5-heptenoic acid in
`the procedure of Example 6, tlR-(l a ~2a(Z),
3,4a)]-7-(3-hydroxymethyl3-7 oxabicyclo[2.2.1]hept-
2-yl]-5-heptenoic acid, methyl ester is obtained.
Example 27
~lR-(1~,2at5Z),3a,4a) ] -7-(3-formyl)-7-oxabicyclo-
~2.2.1]hep~-2-yl]-5-heptenoic acid, methyl ester
By substituting [lR-(l~, 2a ~Z), 3a, 4a) ~ -7-
(hydxoxymethyl~-7-oxabicyclo[~.2.1~hept-2-yl]-
5-heptenoic acid, methyl ester in the procedure
of Example 7, [lR-~la,~(5Z), 3a,4a)]-7-t3-~ormyl)- :
: 7-oxabicyclo 12. 2. l]hept 2-yl] -5-heptenoic acid,
methyl ester.is obtained.
.. Example ~8
¦1R=(1, 2a (5Z), 3~ (lE),4)]-7-13-13-oxo-1-octenyl)-
7-oxabicycl~[2 . 2. l~hept-2~1] -5-heptenoic acid,
methyl ester
: . By substituting 11R-11~, 2~ (5Z~ ~3a,4~-7-
(3-formyl-7-oxabicyclo[2.2.1]hept-~-yl3-5-heptenoic
acid, methyl ester in the pxocedure of Example B,
[lR-tl~2t5Z~,3~[1E),4]-7-~3-(3-oxo-1-octenyl)-
7 oxatricyclo[2~2.1]he~t-2-yl~-5-heptenoic acid,
methyl ester is obtained.
* Trade Mark . -
=
~7~6~ ~A157
3q
~e~
11R- (la,2~(5Z),3~(1E,3R ~,43]-7-[3-_3-hydroxy~l-
_
octen~l ? -7-oxabicyclo[2.2.1]he~t-2-yl]-5-heptenoic
acid, methyl ester
and
[lR-(la,2a($Z),3~(1E,3S_),4a)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept~2~ 5-heptenoic
_ _ _
acid, methyl ester
By substituting the product of Ex~mple 18
in the procedure of Example 10, [lR-(la,2a~5Z),
3a(lE,3R ), 4a) ] -7-[3-(3-hydroxy-1-octenyl)~7-
oxabicyclo[2.2.1]hept-2-yl]-5 heptenoic acid,
methyl ester and ElR~ 2a(5z)~3~(lE~3s ),
4)]-7-~3-(3-hydroxy-1-octenyl~-7-oxabicyclo[2.2.1]-
15- hept-2-yl]-5-heptenoic acid, methyl ester,
respectively, are obtained.
Example 30
~lR-(1,2(5Z),3~(lE,3R ),4a)]-7-[3-(3-hydroxy-1-
octenyl)-7-oxabic~clo[2. ?.1]hept-2-yl) -5-hep~enoic
acid
and
[lR-(la,2a(5Z) ,3a(1E,3S ) ,4a) ]-7-[3-~3-hydroxy-1-
octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
... . . _
acid
By substituting the product of Example 18
in the procedure of Example llc and continuing as
in parts d and 3, [lR~ ,2a~5Z),3a(1E,3R ),4a)]-
7-13-(3~hydroxy 1-octenyl)-7-oxabicyclo[2.2.1~hep~-
2-yl]-5-heptenoic acid and ~lR-(la,2a~5Z),3a(1E,3S ),
4~)~-7-[3-(3-hydroxy-1-octenyl~-7-oxabicyclo[2.2.1]-
hept-2-yl3-5-heptenoi~ acid, respectively are
obtained.
.
