Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~.~7Q~
HA363
--1--
SUBSTITUTED PROSTAGLANDIN ANALOGS
The present invention relates to 5,6-
epoxy-7-oxabicycloheptane substituted prostaglandin
analogs which are cardiovascular agents useful, for
example, in the treatment of thrombotic disease.
These compounds have the structural formula
I * C~2 CH=CH-(CH2)m-CO2R
*)~/ 1 /* *
1/ ~ A-~-R
O *\ ¦ OH
and including all stereoisomers tAereof, wherein
m is 1 to 5; R is hydrogen, lower alkyl,
alkali metal salt or polyhydroxylamin~ salt; A is
-C~=C~ or -(C~2)2-; and Rl is lower alkyl, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl or lower
al~enyl.
7~ 8~
HA363
--2--
The present invention also includes
intermediates for preparing the above compounds of
the invention which have the structure
IA ~ _CH2-CHo
1< 1 ~
0/ ~ \CH2-O
and
IB ~ CH2-C~=C~-(cH2)m-cO
f~ 1
1/~\
O \ I X
O
wherein X is -CH2-O ~ , -CH2OH, -CHO or
-C~=C~-C-Rl wherein m and Rl are as defined
o
above.
The term "lower alkyl" or "alkyl" as employed
herein by itself or as part of a~other group
includes both ~traight and branch~d chain radicals
of up to 12 carbons, preferably 1 to 8 carbons,
such as methyl, ethyl, propyl, isopropyl, butyl,
t-butyl, isobutyl, pentyl, hexyl, heptyl,
4,4-dimethylpentyl, octyl, 2,2,4-trimetnylpentyl,
nonyl, decyl, undecyl, dodecyl, the various
7~
HA363
-3~
branched chain isomers thereof, and the llke as
well as such groups including a halo-substituent,
such as F, Br, Cl or I or CF3, an alkoxy substi-
tuent, an aryl substituent, an alkyl aryl substi-
tuent, a haloaryl substituent, a cycloalkyl sub-
stituent, an alkylcycloalkyl substituent, hydroxy,
an alkylamir.o substituent, a nitro substituent, an
amino substituent, a cyano substituent, a thiol
substituent or an alkylthio sub-stituent.
The term "cycloalkyl" by itself or as part
of another group includes saturated cyclic
hydrocarbon groups containing 3 to 12 carbons,
preferably 3 to 8 carbon~, which include cyclo-
propyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl and cyclodo-
decyl, any of which groups may be substituted with
1 or 2 halogens, 1 or 2 lower alkyl groups and/or
lower alkoxy groups, an aryl group, 1 or 2 hydroxy
groups, 1 or 2 alkylamino groups, 1 or 2 amino
groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1
or 2 thiol groups or 1 or 2 alkylthio groups.
The term "aryl" or "Ar" as employed herein
by itself or as part of another group refers
to monocyclic or bicyclic aromatic groups
containing from 6 to 10 carbons in the ring
portion, such as phenyl, naphthyl, substituted
phenyl or æubstituted naphthyl wherein the
substituent on ei~her the phenyl or naphthyl may be
1 or 2 lower alkyl groups, 1 or 2 halogens (Cl,
Br or F), an aryl group, 1 or 2 lower alkoxy
groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino
groups, l or 2 amino groups, 1 or 2 nitxo groups, 1
7~
_4_ HA363
or 2 cyano groups, 1 or 2 thiol groups or 1 or 2
alkylthio groups~
The term "aralkyl", "aryl-alkyl" or
"aryl-lower alkyl" as used herein by itself or a~
part of another group refers to lower alkyl groups
as discussed above having an aryl substituent, such
as benzyl.
The term "lower alkenyl" or "alkenyl"
includes straight or branched chain radicals of
from 2 to 12 carbons, preferably 2 to 6 carbons in
the normal chain, which include one double bond in
the normal chain, such as ethenyl, 2-propenyl,
3-butenyl, 2-butenyl, 1-pentenyl, 3-pentenyl,
2-hexenyl, 3~hexenyl, 2-heptenyl, 3-heptenyl,
4~heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl,
3-undecenyl, 4-dodecenyl and the like.
The term "lower alkoxy", "alkoxy" or
"aralko~y" includes any of the above lower alkyl,
alkyl or aralkyl groups linked to an oxygen atom.
The term "halogen" or "halo" as used herein
refers to chlorine, bromine, fluorine or iodine
with chlorine being preferred.
The term "polyhydroxylamine" refers to
glucamine salt, tri(hydroxymethyl)aminomethane
salt and the like.
The term "(CH2)m" includes a straight
or branched chain radicals having from 1 to
S carbons in the normal chain and may
contain one or more lower alkyl or halo
substituents. Examples of (C~)m
groups include C~2, CH2CH2, (CH2)3, ( 2)g
0~
_5_ HA363
(~H3 ~H3 l H3 ~H3
C , CH-, -HC-CEI2 -, -C-CH2 -, ( CE12 ) ( CH
H3 CH3
l H3
2 7' ( ~2)2 IH ~ -I-cH-, -cH2-cH--CH-cH2_,
CH3 CE13 C~3 CH3
CH2 1~ C~2-CH-, and the like.
CH3 CH3
Preferred are those compounds of formula I
wherein A is CH=CH, and m is 2 or 4, R
is ~, and R1 is lower alkyl, aryl, such as phenyl,
or aralkyl su~h as benzyl, or benzyl-l-methyl or
cycloalkyl, sucb as cyclohexyl.
The various compounds of the invention may
be prepared as outlined below.
The compounds of formula I of the invention
- may be prepared as described below.
The starting compounds of the invention II
may be prepared as follows.
20Dione-A having the structure
-- /~
~,
O O
that is, 7-oxabicyclo~2.2.1]-5-heptene-2,3-
dicarboxylic anhydride [Ber. 62, 554 (1929); Ann.
460, 98 (1928)], is reduced, for example, by
~7(~
HA363
reacting with lithium aluminum hydride or
diisobutyl aluminum hydride in the presence of
an inert organic solvent such as tetrahydrofuran,
ether or toluene at reduced temperatures of from
about -78C to about 67C to form diol B of the
structure
B ~ CH2-OH
10 <~
\ I C~I20E~ ,
The diol B is subjected to a chloroformylation
reaction by reacting B dissolved in an inert organic
solvent as described above, with phosgene in the
presence of a solvent such as tetrahydrofuran,
toluene, benzene or xylene, to form an alcohol of
the structure
C ~f ~2-0oC~Cl
~ ~
~\ I CH20H
The alcohol C is dissolved in an inert organic
solvent such as methylene chloride, tetrahydrofuran
or ether and then reacted with an organic base,
such as pyridine, triethylamine, N,N-dimethyl-
aminopyridine or diazabicycloundecane (DBU) at
4~
_7_ ~A363
reduced temperatures of from about ~78C to about
25 C, to form cyclic carbonate D
D ~\CH2 ~C=O
C~2
o
The cyclic carbonate D is the~ subjected to
alcoholysis by reacting D with.an alkanol
(alkyl-O~) having from 1 to 12 carbons, such as
ethanol, n-propanol, isopropanol, butanol,
pentanol, hexanol, heptanol, octanol, nonenol or
decanol, including all the various isomers thereof,
preferably isopropyl alcohol, employing a molar
ratio o~ ~:alkanol of within the range of from
about l:10 to about 1:100 to form hydroxycarbonate
E (which itself is a novel compound)
E ~ C~2_o~
C~2-OIlOalkyl
O O
(wherein alkyl contains 1 to 12 carbons a~ defined
herein).
Thereafter, the hydroxy carbonate E is
tosylated (or otherwise protected) by reacting E
lX7~
-8- HA363
(dlssolved in methylene chloride, and a basic
solvent such as pyridine~ triethylamine or
dimethylaminopyridine) with tosyl chloride or other
protecting agent, such as methane sulfonyl chloride
(mesyl chloride) and trifluoromethanesulfonic
anhydride, to form the tosylate F or other
protected compound
p ~ CH2-OTs (or other protect.ng group)
¦ C~2-OIO-alk
O o
Then, the tosylate F dissolved in an inert solvent
such as dimethylsulfoxide, or dimethylformamide is
cyanated by reacting F with an alkali metal
¦ cyanide such as NaCN or KCN employing a molar ratio
of IV: cyanide of within the range of from about 1:1
to about 10:1, at elevated temperatures of from
about 80C to about 130C, in an inert a~mosphere,
such as an argon atmosphere, to form the cyano-
carbonate G (which itself is a new compound)
G ~ CH2-CN
2-o6o-alkyl
7~
~9_ HA363
Cyanocarbonate G is dissolved in an alcohol
such as methanol or ethanol and treated with
aqueous alkali metal carbonate such as potassium
carbonate at reduced temperature to form
cyano-alcohol H
CH2 -CN
10 \ ~
\ I CH2 ~
which is made to undergo tetrahydropyranyl ether
formation by reacting cyano alcohol H with
dihydropyran in the presence o~ an inert organic
solvent such as ~ethylene chloride or ether and
catalytic amount of p-toluene sulfonic acid at
reduced temperatures of from about 0C to about
10C, to form the tetrahydropyranyl ether of
formula J
~ ~ C~2-CN
~ ~
~ \ C~2
O I ,_,
O~
Compound J is then made to undergo epoxide
formation by treating a solution of J in methylene
7~
HA363
--10--
chloride or other appropriate solvent with
m-chloroperoxybenzoic acid at reduced temperatures
to form epoxy nitrile II ~which itself is a novel
compound)
II ~ C~2-CN
/ ~ ~2- ~
(which is a novel compound).
The compounds of formula I of the invention
may be formed starting with compound II in
accordance with the following reaction sequence.
~70~4~
363
_, .
~ T ,, _~
~ N U Ç
0 y
~0 ~ U
~,0
a a~ ~ ~
T~ , D"~o~
~o~
_ 12- HA36 3
8~ ~
C
_, ~
o X
U o
_,
.Y g
' e
3~
_ 13 HA363
Y6 1 6
N ,~ ~ ~ X
0 3: 1
1~ ~ ~ c~ o
:S~ ~ X
~3 ~o
G
,0 ,GO
Z ~ C~
C~
O=c~
0=~
~ ~ I
+
~ .
~7~V~
_ 14- HA363
O
~o
t
o
~ ~ .
~, O X
7~
HA363
-15~
As seen from the reaction sequence set out
above, compounds of the invention may be formed by
treating II with diisobutyl aluminum hydride
(DIBAL~ in the presence of an inert solvent such
a~ toluene or tetrahydrofuran at reduced
temperatures of from about -70 to about -85C to
form epoxy aldehyde III (which itself is a new
compound)
III ~ ,CH2-CHO
I /~\C~20 {~
O
Epoxy aldehyde III in appropriate solvent
such as tetrahydrofuran is then reacted with a
suspension formed by mixing dry carboxyalkyltri-
phenylphosphonium halide K
K + B -(CH ) COOH
in tetrahydrofuran with potassium t-amylate
in toluene at reduced temperature and the reaction
product treated with ethereal diazoalkane to form
the ester IV (which also is a novel compound)
4~
HA363
. -16-
IV ~ ~ C~ (C~z)m-COOR
(wherein R is lower alkyl)
Compound IV is dissolved in methanol and is
then hydrolyzed by treatment with strong acid such
as ~Cl, Amberlyst resin or acetic acid to form
alcohol v (which also is a novel compound)
V ~ C~2 C~ OE-(c~)~-cozR
O ¦ C~2-OH
O
(wherein R is lower alkyl)
which also is a novel compound.
The epoxy ester V containing the hydroxy-
methyl group is used to form epoxy aldehyde VI
by subjecting epoxy ester V to Collins oxidation,
for e~ample, by reacting V with chromium oxide in
pyridine.
Aldehyde VI of the structure
* Trade Mark
7~
HA363
-17-
VI ~ ~2 C~ ~H-~c~2)m-cooR
S ~o
wherein R is lower alkyl (which also is a novel
compound) is reacted with a dialkoxy phosphonate,
such as of the structure
O O
L (C~30)2P-CH2-~-R1
employing a molar ratio of V:L of within the
range of from about 1:1 to about O.5:1, under
ba~ic conditions, such as triethylamine,
diazabicyclo undecene (DBu~ in the presence of
ZO anhydrous lithium bromide and an inert organic
solvent, such as methylene chloride or acetonitrile
to form epoxy compound VII of the structure
VII ~ C~2 C~ C'-(C~2)~-COOR
O ¦ C~-C~ R
O
(wherein R is lower alkyl)
l~t:~lU8~,4
H~3 63
--18--
which also is a novel compound.
Compound VI I may then be reduced by two
different ways as outlined above to form compounds
of the invention VI I I or IX
~CH2 -CH=CH- ( CH ~ -COOR
/~
0 ~ I A-CH-Rl
o OH
(wherein R is lower alkyl)
VIII - A is (CH2)2
IX - A is -CH=CH-
or compounds of the invention of the general
formula X
X ~ C112-CE=CH-(C1}2)m-COOR
2 5 0 ¦ A-CH-R
0 0~
(wherein R is lower alkyl)
Compounds of formula I
7~4~
HA363
-;L9-
IA /\~ CH2-CH=CH- ( CH2 )m-COOR
5 \
` ~ I A-CH-R
O 1H
(wherein R is hydrogen)
ld
may be prepared by hydrolyzing ester VIII or IX by
treatment with a strong base such as sodium
hydroxide or lithium hydroxide in the presence of
an iner~ solvent such as tetrahydrofuran, methanol
or dimethoxyethane-water to form the corresponding
alkali metal salt which iæ the~ treated with
strong acid such as ~Cl to for~ the acid compound
of the i~vention IF.
The compounds of this invention have seven
centers of asymmetry as indicated by the asterisks
in formula I. However, it will be apparent that
each of the formulae set out above which do not
include asterisks still represent all of the
possible stereoisomers thereof. All of the various
stereoisomeric forms are within the scope of the
invention.
The various stereoisomeric forms of the
compounds of the invention, namely, cis-exo,
cis-endo and all trans forms and stereoisomeric
pairs may be prepared as shown in the working
Examples which follow and by employing starting
materials and following the procedures as outlined
~7~
HA363
-20-
in U. S. Patent No. 4,143,054. Examples of such
stereoisomers are set out below.
Ia f 2 CH CH-(CH2)m-CO
~ H
J\~ A_CH_Rl
(cis-endo)
Ib
~ --CH2-CH=CH-(CH2) -CO R
O \ I I .
O A-5CH-R
OH
(cis-exo~
~27~
HA363
-21-
Ic
CH2-C~=C~I- ( C~2 ) -C02R
0~ gH
O ~
~trans)
Id C~2-C~-CH-(CH2)m-CO2R
~ --H
O A-SCH-R
OH
(trans)
The wavy line ~ 5 ) in the ~bove formulae
indicates that the hydroxy group in each of the
compounds of formulae Ia-Id is either R(~) or S~
The nucleus in each of the compounds of the
invention is depicted as
~: 7C~1 ~ t~,
HA363
-22-
S 0~
for matter of co~venience; it will also be
appre~-iated that the nucleus in the compou~ds of
the invention may be depicted as
~1'
The compounds of this invention are
cardiovascular agents useful as platelet aggre-
gation inhibitors, such as inhibiting arachidonic
acid-induced platelet aggregation (e.g., for
treatment of thrombotic disease, such as coronary
or cerebral thromboses) and in inhibiting broncho-
constriction as induced by asthma. They are also
selective thromboxane A2 receptor antagonists and
synthetase inhibitors, e.g., having a vasodilatory
effect for treatment of myocardial ischemic
disease, such as angina pectoris.
The compounds of this invention may also be
used in combination wi~h a-cyclic AMP phosphodi-
esterase (PDE) inhibitox such as theophylline orpapaverine in the preparation and storage of
platelet conc~ntrates.
H~363
-23-
The compounds of the invention can be
administered orally or parenterally to various
mammalian species known to be subject to such
maladles, e.g., humans, cats, dogs, and the like in
an effective amount wi~hin 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.
The compounds of the invention may also be
10 administered topically to any of the above
mammalian species in amounts of from about 0.1 to
10 mg/kg in single or 2 to 4 divided daily doses.
The active substance can be utilized in a
composition such as tablet, capsule, 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
conventional matter with a physiologically
acceptablo vehicle or carrier, excipient, binder,
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 group.
~'7~
HA363
-24-
The following Examples represent preferred
embodiments of the invention. Unless otherwise
indicated, all temperatures are expressed in
degrees Centigrade.
Example 1
[1~,2~(5Z),3~(1E,35),4a,5~,6a]-7-[5,6-Epoxy-3-(3-
hydroxy-l-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5 he~tenoic acid,_methYl ester
A. 7-Oxabicyclo[2.2.1]-5-hepten-2,3-
dimethanol
To a suspension of 6.84 g of lithium
aluminum hydride (180 mmol) in 200 ml of freshly
distilled T~F, cooled in an ice-water bath was
added dropwise, a solution of 20 g of
7-oxabicyclo[2.2.1~-5-heptene-2,3-dic~rboxylic
anhydride (120 mmol) in 150 ml o~ dry THF, over a
period of 1 hour. After the addition, the cooling
bath was removed and the reaction mixture was
stirred at room temperature for 24 hours. The
reaction mixture was now cooled in an ice-water
bath and excess of hydride was destroyed by slow
addition of freshly prepared saturated sodium
sulfate solution. Addition was continued until all
the inorganic salts were precipitated as white
granular solids. Anhydrous magnesiu~ sulfate was
added to the reaction mixture and it was fil~ered.
~ The residue was thoroughly washed with m~thylene
chloride. The residue was taken up in 500 ml of
10% acetonitrile in ethyl acetate, stirred for 30
minutes and finally was filtered. The combined
filtrate was concentrated under reduced pressure.
The crude residue was chromatographed on a silica
7~3~
HA3~3
_ ~I S _
gel column. Elution with 50% ethyl acetate in
hexane followed by ethyl acetate and finally with
10% methanol in ethyl acetate afforded 17.25 g of
title diol as a colorless viscous oil.
B . 7 -oxabicyclot2~2~ 5-heptene-2~3
dimethanol carbonate
.. . . _ _
To a solution of 16.73 g of Part A diol
(107.4 m~ole) in 200 ml of freshly distilled THF,
cooled in an ice-water bath was added dropwise 90
ml of a 12.5% by weight solution of phosgene in
toluene (112.5 mmol), over a period of 45 minutesO
The reaction mixture was stirred for an additional
15 minutes, whereupon argon was bubbled through to
remove excess of phosgene and hydrogen chloride
formed during ~he reaction. The reaction mixture
was now concentrated under reduced pressure. The
crude monochloroformate was now dissolved in 250 ml
of methylene chloride and cooled at -50C in a dry
ice-acetone bath. A solution of 25 ml of pyridine
in 50 ml of methylene chloride was now added
dropwise over a period of 20 minutes. An immediate
white precipitate was formed upon addition. .The
reation mixture was left at -50C for an additional
30 minutes, whereupon the cooling bath was removed
and the reaction mixture was washed thoroughly
with water. The methylene chloride layer was
dried over anhydrous magnesium sulfate, filtered
and the filtrate was concentrated u~der reduced
pressure. The crude residue was triturated with
ether, cooled at 0C and the precipitated title
carbonate was filtered off. 15.25 g of white
crystalline title carbonate was obtained.
7(~
H~363
-26-
C. 2-Hydroxymethyl-3-isopropyloxycarbonyl-
ox~ yl-7-oxablcyclo[2.2.11hePtene
To a suspension of 15.25 g of Part B cyclic
carbonate (83.8 mmole) in 200 ml of isopropyl
alcohol was added with stirring 1 g of p-toluene
sulfonic acid. The reaction mixture was heated
under reflux for 8 hours whereupon it was cooled
and isopropanol was removed by distillation under
reduced pressure. The crude residue was dissolved
in methylene chloride and washed with aqueous
sodium bicarbonate solution. The aqueous layer
was extracted several times wi~h methylene
chloride. The combined methylene chloride extract
was dried over anhydrous magnesium sulfate and was
then concentrated under reduced pxessure to obtain
22.53 g of title isopropyloxycarbonate as a
viscous oil.
D. 2-p-Toluenesulfonyloxymethyl-3-isopro-
pyloxycarbonyloxymethyl-7-oxabicyclo-
[2.2.11heptene
To a solution of 22.53 g of Part C isopropyl-
oxycarbonate ~84 mmole) in 100 ml of pyridine was
added with stirring 19.2 g of p-toluene sulfonyl
chloride ~101 m~ole) at 0-5C. The reaction
~ixture was stirred at room temperature for 24
hours, whereupon it was diluted with methylene
chloride and washed thoroughly with water,
saturated copper sulfate solution and finally with
water. The combined aqueous layer was extracted
with two 200 ml portions of methylene chloride.
The combined methylene chloride extract was dried
over anhydrous magnesium ~ulfate and finally was
HA363
-27-
concentrated under reduced pressure. The crude
residue was ~riturated with ether, cooled at 0C
and the precipitate title tosylate (28.3 g) was
filtered off. The mother liquor was concentrated
and chromatographed on a silica gel column to
obtain additional 5.2 g of crystalline title
tosylate (eluting solvent 15-30% ethyl acetate in
hexane).
E. 2-Cyanomethyl-3-isopropyloxycarbonyl-
oxym~t~ --abicYclo[2~2. 11 he~tene
To a solution of 5.3 g ~f Part D tosylate
(12.99 mmole) in 50 ml of dry dimethylsulfoxide
was added with stirring 1.28 g of powdered sodium
cyanide (26 mmole). The reaction mixture was
placed on an oil bath (bath temperature 90-95~C)
and heated for 2 hours. It was now cooled and
diluted with 200 ml of ether. The reaction
mixture was now thoroughly washed with water. The
combined aqueous extract was extracted with two
150 ml of ether. The ether layer was now dried
over anhydrous magnesium sulfate and concentrated
under reduced pressure. The crude residue was
chromatographed on a silica gel column. Elution
with 25-50% ehtyl acetate in hexane afforded 2.58
g of title cyano-carbonate.
F. 2-Cyanomethyl-3-hyro~ymethyl-7-oxabi-
c~clo[2.2.1lheptene
To a solution of 1 g of potassium carbonate
in 25 ml of water and 75 ml of methanol, cooled in
an ice-water bath was added with stirring a
solution of 2.58 g of Part E cyano-carbonate (9.8
HA363
-28-
~mol) in 10 ml of methanol. After 15 minutes, the
cooling bath was remo~ed and the reaction mixture
was allowed to stand at room temperature for
additional 6 hours, whereupon it was acidified
with lN a~ueous hydrochloric acid ~olution. Most
of methanol was now removed by distillation under
reduced pre sure. The residue was now
exhaustively extracted with methylene chloride
(X12) (after saturating it with sodium chloride).
The combined organic extract was dried over
anhydrous magnesium sulfate and concentrat~d under
reduced pressure. The crude residue was
chromatographed on a silica gel column and eluted
with 25-50% ethyl acetate in hexane, followed by
ethyl acetate to obtain 1.23 g of title cyano
alcohol.
G. 2-Cyanomethyl-3-tetrahydropyranyloxy-
methyl-7-oxabicyclo~2.2.1Lhe~tene
A solution of 1.23 g of Part F
cyano-alcohol (7.36 mmole) in 20 ml of dry
methylene chloride was treated with 800 ml of
dihydropyran (8.89 mmole) and catalytic amount of
p-toluene sulfonic acid at 0-5C. After 4 hours,
the reaction mixture was diluted with ether and
washed with agueous sodium bicarbonate solution.
The aqueous layer was reextracted twice with
ether. The com~ined organic extract was dried
over anhydrous magnesium sulfate and concentrated
- 30 under reduced pressure. The crude residue was
chromatographed on a silica gel column and eluted
with 20-25% ~thyl acetate in hexane to obtain 1.61
g of title tetrahydropyranyl ether.
~7(3B4
HA3 6
--2g--
H. 5,6-Epoxy-2~cyanomethyl-3-tetrahydro-
pyranyloxymethyl-7-oxabicyclo[2.2.1]-
heDtene
~ solution of 1.61 g of Part G cyano ether
(6.4 mmole) in 20 ml of dry methylene chloride wastreated with 1.66 g of 80% pure m-chloroperoxy-
benzoic acid (9.6 mmole) at 0-5C. After a few
minutes, the cooling-bath was removed and the
reaction mixture was let stand at room temperature
for 6 hour~. The reaction mixture was now diluted
with ether and excess of peracid was decomposed by
addition of aqueous sodium met~-bisulite
solution. After stirri~g for 30 minutes, the
organic layer was separated and the aqueous layer
was extracted twice with methylene chloride. The
combined organic extract was dried over anhydrous
magnesium sulfate and co~centrated under reduced
pressure. Purification by chromatography on a
silica gel column (eluting solvent 25-67% ethyl
acetate in hexane) afforded 1.57 g of title epoxide.
J. 5,6-Epoxy-2-formylmethyl-3-tetrahydro-
pyranyloxymethyl-7-oxabicyclo~2.2.1]-
heDtene
To a solution of Part ~ epoxy-nitrile (1.57
g, 5.88 mmole) in 25 ml of toluene, cooled at
-78C in a dry ice-acetone bath was added with
stirring, 6.8 ml of a 25% by weight solu~ion of
diisobutylaluminum hydride in toluene (~12 mmole),
dropwise over a period of 5 minutes. After 4
hours at -78C, excess of hydride was destroyed by
dropwise addition of 1 ml of glacial acetic acid.
The cooling bath was removed and 20 g of silica
1~7~3~
HA363
-30-
gel was added to the reaction mixture with
stirring, followed by 1.5 ml of water dropwise.
Stirring was continued for 30 minutes, whereupon
the reaction mixture was filtered and the residual
silica gel was washed successively with THF, 5%
acetonitrile in ethyl acetate and finally with
acetone. The combined filtrate was concentrated
under reduced pressure and the crude residue was
chromatographed on a silica gel column. Elution
with 50% ethyl acetate in hexane, followed by
ethyl acetate afforded 1.16 g of title
epoxyaldehyde which crystallized on standing at
-20C.
K. [la,2~(5Z~,3~,4a,5~,6a]-7~[5,6-Epoxy-3-
(tetrahydropyranyloxymethyl)-7-oxabi-
cyclo[2.2.1]hept-2-yl]-S-heptenoic
acid, methYl ester
A suspension of 5.77 g of freshly dried
carboxybutyltriphenylphosphonium bromide (13.03
mmol), in 50 ml of freshly distilled THF, cooled
in an ice-water bath was trea~ed dropwise with 12
ml of a l.S M solution of K-t-amylate in toluene
(19.2 mmole~. The yellow-orange suspension was
stirred at 0C for 30 minutes and finally at room
temperature for 1 hour, whereupon it was cooled
to -20C and a solution of 2.33 g of Part J epoxy
aldehyde (8.69 mmole) in 10 ml of dry L~ was
added dropwise over a period of several minutes.
An instant discolorization of the ylide solution
was observed. The reaction mixture was stirred at
-20C for 2 hours, whereupon it was warmed to 0C
and left for 15 minutes, prior to addition of
1~7~*~
HA363
-31~
glacial acetic acld. The reaction mixture was now
dil~ted with ether and washed wlth water. The
ether extract was washed several times with
saturated sodium bicarbonate solution. The
combined aqueous extract was now washed with ether
(X2). The agueous layer was now carefully
acidified with lN aqueous hydrochloric acid to p~
2. It was now extracted with ether and then with
methylene chloride. The combined ether and
methylene chloride extract was dried over
anhydro-ls magnesium sulfate and concentated under
reduced pressure. The crud~ residue was diluted
with 75 ml of e~her, cooled in an ice-water bath
and an etheral diazomethane solution was added
dropwise until the color persisted. After 30
minutes, excess diazomethane was removed by
bubbling ar~on through the reaction mixture. It
was now concentrated and the crude residue was
chromatographed on a silica gel column. Elution
with 15-40% ethyl acetate in hexane afforded 1.27
~ of title SZ-ester (contaminated with 10-15% of
undesired 5E ester).
L. [la,2~(5Z),3~,4a,5a,6a]-7-[5,6-
Epoxy-3-hydroxymethyl-7-oxabicyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid,
methYl ester
To a solution of 1.27 g of Part K tetrahydro-
pyranyl ether (3.46 mmole) in 30 ml of methanol
was added with stirring 250 mg of powdered and
dried Amberlyst-15. After 6 hours at room
temperature, the reaction mixture was diluted with
ether and anhydrous magnesium sulfate was added.
E ~
~A~63
-32-
It was now filtered and ~e residual solid w~s
washe~ thoroughly wi~h ethe~. The combined
organic e~tract W2S drie~ over anhydrous maSnesium
sulfate a~d conce~tratad under reduced pressure
S The crude residue was c.~romatographed on a silica
gel colu~n and eluted with 50-75% e~hyl acetate ln
hexane to obtain 892 mg of title alcohol ester.
M. [la,2~(5Z),3~,4a,5a,6a]-7-r5,6-
Epo~y-3-formyl-7-~abicyclo[2.2.~]~
hept-2-yL]-5-heptenoic acid, methyl
ester
To a suspeQsion of 325 mg of pyridinium
chl~rochromate and 325 mg of Celite in 20 ml of
dry m~thylene chloride was added wi~h stirrlng a
solutlon of 211 mg Part L alco~ol ester (O.75
mmole) in 2 ml of methylene chloride. A~te_ 4
hours at room te~perature, the reaction mixture
was diluted with 100 ml of ether and filte_ed
through a pad of Florisil. Florisil was washed
se~Jeral times with ether and ethyl acetate. The
com~ined organic e~tract was washed with water,
dried over anhydrous maqnesium sulfate and was
then conce~trated under reduced pressure to obtain
174 mg of title aldehyde.
N, [la,2~(5Z),3~(1E),4~,5a,6a]-7-[5,6-
Epoxy-~-(3-oxo-1-octe~yl)-7~
oxabicyclo[2.2.1]he~t-2-yl]-5-
he~tenoic acid, methvl ester
To a suspension of 90 mg of dry li~hium
~romide in 5 ml of dry methylene chloride was
added with stirring lao ~1 of t~iethylamine,
* Trade Mark
7~4~
HA363
-33-
followed by a solution of .222 mg dimethyl-(2-
oxoheptyl3 phosphona~e (1 mmole) in 1 ml of
methylene chloride. After stirring for 15 minutes
at room temperature, a solution of 174 mg Part M
aldehyde (O.6~ mmole) in 3 ml of methylene
chloride was added dxopwise. The reaction was
stirre~ overnight, whereupon it was diluted with
ether and wa~hed with water. The aqueous layer
was e~txacted with ether (X2). The combined ether
extract was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The
crude oily residue was chromatographed on a silica
gel column and eluted with 15-30% ethyl acetate in
hexane to obtain 175 mg of title enone.
O. [1~,2~(5Z),3~(1E,3S~,4a,5a,6a]-7-~5,6-
Epoxy-3-(3-hydroxy-1-octenyl)-7-oxabi-
cyclo[2.2.1]hep~-2-yl]-5-heptenoic
acid, methy ~ fast movinq isomer ?
and
P. ~la,2~5Z),3~(1E,3R),4a,5a,6a]-7-[5,6-
Epoxy-3-(3-hydroxy-1-octenyl)~7-oxabi-
cyclo[2.2.1]hept-2-yl]-5-heptenoic
- acid, methyl ester (slow movinq isomer)
To a solution of 170 mg of Part N enone
(0.45 mmole3 in 5 ml of methanol and 'l'~k' each, was
added with stirring 170 mg of ceric chloride
hydrate. Aftex 10 minutes at room temperature,
the homogeneous solution was cooled to -50C in a
dry ice-acetone bath and 20 mg of solid sodium boro
hydride (O.5 mmole) was added. The reaction
mixture was stirred at -50C for 1 hour, whereupon
it was treated with aqueous ammonium chloride
3~
HA363
-3~-
solution. The cooling bath was removed and the
reaction mixture was diluted with ether. The
organic layer was separated and the aqueous layer
was reextracted successively with ether and
methylene cloride. The combined organic extract
was dried over anhydrous magnesium sulfate and
concentrated. Purification by chromatography on a
silica gel column and elution with 30-50% ethyl
acetate in hexane afforded 130 mg of title
lo fast-moving alcohol epimer and 40 mg of
slow-moving isomer.
Example 2
[la,2~(5Z),3~(1E,3S~,4a,5a,6a]-7-[5,6-Epoxy-3-(3-
hydroxy-1-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
S-heE~enoic acld (fast movinq ester)
A soiution of 130 mg of Example 1
fast-moving alcohol epimer (0.35 mmole) in 5 ml of
distilled TKF was treated with 2 ml of a lN
aqueous lithium hydroxide solution. ~fter 8 hours
at room temperature, the reaction mixture was
diluted with ether and acidified to pH 1 by
addition of lN aqueous hydrochloric acid
solution. The ether layer was separated and the
aqueous layer was extracted with methylene
chloride (X2). The combined organic extract was
dried over anhydrous magnesium sulf~e and
concentrated under reduced pressure to obtain 120
mg o~ crude acid (contaminated with 10 15% of
presumably SE-isomer~. Chromatography on a silica
gel column and elution with 2-3% methanol in
methylene chloride afforded 8~ mg of pure title
acid.
7~
HA363
-35-
21H325 C, 69.20; H, 8.85
Found: C, 69.24; H, 8.84
Example 3
[la,2~(5Z3,3~(1E,3R),4a,5a,6a]-7-[5,6-Epoxy-3-(3-
hydroxy-l-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5-heptenoic acid (slow movin isomer? _
To a solution of 40 mg [la,2~(5Z),3~(lE,35),-
4a, 5a, 6a ] -7-[5,6-epoxy-3-(3-hydroxy-octenyl)-
7-oxabicyclo~2.2.1]hept-2-yl3 S-heptenoic acid,
methyl ester slow-moving alcohol epimer (prepared
as described in Example 1 Part P~ (O.11 mmole~ in
3 ml of distilled THF was added with stirring 1 ml
of a lN aqueou~ lithium hydroxide solution. After
8 hours at room temperature, the reaction mixture
was diluted with ether and acidified with lN
aqueous hydrochloric acid solution of p~ 1.
The organic layer was separated and th~ agueous
layer was extracted with methylene chloride. The
combined organic extract was dried with anhydrous
magnesium sulfate and then concentrated under
reduced pressure to obtain 33 mg of title acid as
an oil.
lcd for C~lH32O5, 0.96 mole of ~2
C, 66.06; ~, 8.95
Found: C, 66.06: ~, 8.47
Exam~le 4
[la,2~(5Z),3~1E,35),4a,5a,6a]-7-~5,6-Epoxy-3-(3-
cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid (fast moving
isomer~
.
7~
HA363
-36-
A. [la,2~5Z),3~(1E),4a,5a,6a]-7-[5,6-
Epoxy-3-(3-oxo-3-cyclohexyl-1-propenyl)-
7-oxabicyclo[2.2.1]hept-2-yl]-5-
heptenoic acid, methyl ester
To a suspension of 135 mg of dry lithium
bromide in 5 ml of methylene chloride was added
with stirring 200 ~1 of triethylamine, followed by
a sol!tion of 350 mg 2-oxo-cyclohexyl(dimethyl)-
phosphonate (1.5 mmole) in 2 ml of methylene
chloride. After stirring for 15 minutes at room
temperature, a solution of 220 mg of [la,2~(5Z),-
3~(1E,35),4a,5a,6a]-7-t5,6-epoxy-3-formyl-7-
o~ybicyclo[2.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester prepared as described in Example 1
lS Part M in 3 ml of methylene chloride was added
dropwise. The reaction mixture was stirred at
room temperature for 3 hours whereupon it was
diluted with ether and washed with water. The
aqueous layer was extracted with ether (X2). The
20 combined ether eXtraCt was dried over anhydrous
magnesium sulfate and was then concentrated under
reduced pressure. Chromatographic purification on
a silica gel column (eluting solvent 10-30% ethyl
acetate in hexane) gave 235 mg of desired title
25 enone~
B. tla,2~(5Z),3~(1E,3S),4a,5a,6a]-7-[5,6-
Epoxy-3-(3-cyclohexyl-3-hydroxy~
propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5-heptenoic acid, methyl ester ( fas~
movinq isomer)
and
7(~
XA363
37-
C. ~1~,2~5Z),3~(1E,3R~,4~,5~,6~]-7 [5,6-
Epoxy~3 (3-cyclohexyl-3-hydroxy-1-
propenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5-heptenoic acid, methyl ester (slow
movinq isomer) _ _
To a solution of 235 mg of Part A enone
(O.61 mmole) in 5 ml of methanol and THF was
added with stirring 235 mg ceric (111) chloride
hydrate. After stirring or 10 minutes at room
temperature, the reaction mixture was cooled to
-50C and 25 mg of solid sodium borohydride (O.66
mmole~ was added. After 1 hour at -50C, the
reaction mlxture was quenched b~ addition of
aqueous ammonium chloride solution. It was now
warmed to room temperature and diluted with
ether. The organic layer was separated and the
agueous layer was extracted with methylene
chloride. The combined organic extract was dried
over anhyd~ous magnesium sulfate and concentrated
under reduced pressure. The crude residue was
chromatographed on a silica gel column and eluted
with 30-67% ethyl acetate in hexane to obtain 175
mg of title B fast-moving alcohol epimer and 35 mg
of title C slow-moving alcohol epimer.
ExamPle 5
[1,2,B(5Z),3~(1E,3S),4a,5~,6a]-7-t5,6-Epoxy-3-(3-
cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid (fast moving
isomer~ _
A solution of 175 mg of Example 4, Part B,
alcohol-ester (fast moving isomer) in 5 ml of dry
THF was treated with 2 ml of lN aqueous lithium
7~4~
HA363
-38-
hydroxide solution. The reaction mixture was
stirred at room temperature for 8 hours, whereupon
it was acidified with lN aqueous hydrochloric acid
solution. It was then diluted with ether and the
organic layer was separated. The aqueous layer
was extracted with methylene chloride twice. The
combined organic extract was dried over anhydrous
magnesium sulfate and was then concentrated under
reduced pressure to obtain 163 mg of crude acid.
Chromatography on a silica gel colum~ and elution
with 3-5% methanol in methylene chloride afforded
110 mg of title acid.
Anal Calcd for C22H325 C~ 70-18; H~ 8-57
Found: C, 70.03; H, 8.59
Example 6
[la,2~(5Z),3~(1E,3R),4a,5~,6a]-7-[5,6-Epoxy-3-(3-
cyclohexyl-3~hydroxy-1-propenyl) 7-oxabicyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid (slow moving
isomer~
,
To a solution of 35 mg Example 4 Part C
slow-moving alcohol epimer (O.09 mmole) in 3 ml of
distilled THF was added with stirring 1 ml of a lN
aqueous lithium hydroxide solution. After 8 hours
at room temperature, the reaction mixture was
diluted with ether and acidified to p~ 1 with
lN aqueous hydrochloric acid solution. The
organic layer was separated and the aqueous layer
was extracted with methylene chloride. The
combined organic extract was dried over anhydrous
magnesium sulfate and finally was concentrated
~7~4~
HA363
-39-
-
under reduced pressure to obtain 28 mg of title
acid.
22 32 5~ 27 mole of water
C, 69.28; H, 8.60
Found: C, 69.28; H, 8.71
Example 7
[la,2~(5Z),3~(1E,3R,4S),4a,5a,6~Y]-7-t5,6-Epoxy-
10 3 (3-hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo-
[2.2.1~he~t-2-yll-5-he~t noic acid, methyl ester
A. [la,2~(5Z~,3~(1E,3R,4S),4a,5~,6aJ-7-
[5,6-Epoxy- L 3-(3~oxo-4-phenyl-l-
! pentenyl)-7-oxabicy~1O[2.2.1]hept-2-
yllL-5-he~tenoic acid, methyl e~ter
To a suspension of 90 mg of anhydrous
lithium bromide 51 mmole) in 5 ml of dry methylene
chloride was added with stirring 140 ~l triethyl-
amine (1 mmole). 256 mg of (+) dimethyl(2-oxo-3-
methyl-3-phenyl) propyl phosphonate was then added
dropwise. After 15 minutes at room temperature, a
solution of ~xample 1 Part M 5,6-e~o epoxy aldehyde
(170 mg, 0.62 mmole) in 3 ml of methylene chloride
was added slowly. The reaction mixture was stirred
at room temperature overnight, whereupon it was
diluted with ather and washed with water. The
organic layer was dried over anhydrous magnesium
sulfake, filtered and concentratred under reduced
pre~sure. The c N de oily residue was chromato-
graphed on a silica gel column and eluted with15-30% ethyl acetate in hexane to obtain 177 mg of
title enone.
HA363
-4~-
B. [la,2~(5Z),3~(1E,3R,4S),4~,5a,6a]-7-
[5,6-Epoxy~ hydroxy-4-phenyl-1-
pentenyl)-7-oxabicyclo[2.2.l]hept-2-yl]-
5-heptenoic acid! methYl_ester
To a solution of 177 mg of Part A enone in
5 ml of dry methanol and s ml of distilled THF was
added with stirring 175 mg of ceric (III) chloride
hydrate. After 10 minutes at room temperature,
the homogeneous solution was cooled to -50OC in
dry ice-acetone bath and 20 mg of solid sodium boro-
hydride was added with tirring. A~ter 1 hour at
-50C, the reaction mixture was quenched by
addition of aqueous ammonium chloride solution,
warmed to room temperature and was then diluted
with ether. The organic layer was separated and
the aqueous layer was extracted twice wi~h ether
and twice with methylene chloride. The combined
organic extract was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure.
The crude residue was chromatographed on a silica
gel column and eluted with 20-50% ethyl acetate in
hexane to obtain 133 mg of title alcohol~ester as
an oil.
ExamPle 8
[1~,2~5Z),3~(1E,3R,4S),4a,5a,6a]-7-[5,6-Epoxy-3-
(3-hydroxy-4-phenyl-1-pentenyl)-7-oxa~icyclo-
[2.2.1 ~
A solution of 133 mg Example 7 alcohol-ester
(O.32 mmole) in 5 ml of distilled lk~ was treated
with 2 ml of lN aqueouC lithium hydroxide solution.
The reaction mixture was stirred at room tempera-
ture for 16 hours, whereupon it was carefully
HA363
-4:L-
acidified to pH 1 by addition of lN aqueous
hydrochloric acid solutloIl. It was now diluted
with ether and the organic layer was separated.
The aqueous layer was extracted with methylene
chloride ~X2). The combined organic extract was
dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to obtain 124
mg crude acid, contaminated with ~15% of a-side
chain olefin isomer. Chromatogxaphy on a silica gel
column and elution with 1-3% methanol in methylene
chloride afforded 51 mg of title acid as an oil.
Anal Calcd for C24H305 ~ 72-33; ~ 7-59
Found: C, 72.32; H, 7.57
Fxam~le 9
[la,2~(5Z),3~(1E,3S),4a,5a,6a~-7-t5,6-Epoxy-
3-~3-hydroxy-3-phenyl-1-propenyl)-7-oxabicyclo-
t2-2-1lhePt-2-yll-s-heDtenoic acid
Following the procedure of Examples 7 and 8
except substituting dimethyl(2-oxo-~-phenyl~-
ethyl phosphonate for (+)dimethyl(2-oxo-3-methyl-
3-phenyl)propyl phosphonate, acid, the title
compound is obtained.
[la,2~(5Z),3~1E,35),4a,5a,6a]~-7-[5,6- poxy-
3-(3-hydroxy-4-phenyl-1-butenyl)-7-oxabicyclo-
L~ 1 hept-2-yll-s-hlp~c~ acid
Following the procedure of E~amples 7 and 8
except substituting dimethyl(2-oxo-4-phenyl)-
butyl phosphonate for (+)dimethyl(2-oxo-3-
1~7(~8~
HA363
42-
methyl 3-phenyl)propyl phosphonate, the title
compound is obtained.
Example 11
[1~,2~(5Z),3~(1E,3S~4a,5a,6a]-7-[5,6-Epoxy-
3-~3-hydroxy-5-phenyl-1-pentenyl)-7-oxabi-
cyclo[2.2.1~hept-2-yl~-5-heptenoic acid,
methyl ester
A. [la,2~(5Z),3~(1E),4a,5~,6a]-7-[5,6-
Epoxy-3-(3-oxo-5-phenyl-1-pentenyl~-
7-oxabicyclo[2.2.1~hept-2-yl]-5-
heptenoic acid, met~yl ester
To a suspension of 135 mg anhydrous lithium
bromide (1.56 mmole) in 3 ml of dry methylene
-chloride was added with stirring 198 ~l
triethylamine (1.42 mmole). 386 mg dime~hyl-
(2-oxo-4-phenyl)butyl phosphonate (1.51 mmole) in
1 ml of methylene chloride was now added
dropwise. After 30 minutes at room temperature, a
solution of Example 1 Part M 5,6-exo-epoxy
aldehyde (200 mg, 0.7 mmole) in 3 ml of methylene
chloride was added dropwise. The reaction mixture
was stirred at room temperature overnight,
whereupon it was diluted with ether and washed
with water. The organic layer was dried over
anhydrous magneisum sulfate and concentrated under
reduced pressure. The crude residue was
chromatographed on a silica gel column and eluted
wi~h 40% ethyl acetate in hexane to obtain 208 mg
of title enone.
7~
H~363
-43-
B. [la,2~(5Z~,3~(1E,3S3,4~,5~,6~]-7-[5,6-
Epoxy-3-(3-hydroxy-5-phenyl-1-pentenyl)-
7-oxabicyclo[2.2.1]hept-2-yl]-5-
hoL~ Lid, methx~-~ster
To a solution of 208 mg of Part A enone
(0.5 mmole) in 1 ml of methanol and 1 ml of
methylene chloride was added with stirring 124 mg
ceric chlorid~ hydrate. ~fter 10 minutes at room
temperature, the homogeneous solution was cooled
to ~50C and 19 mg of solid sodium borohydride
~O.5 mmole) was added. The reaction mixture was
let stand at -50C for 3 hours, whereupon it was
treated with aqueous ammonium chloride ~olution.
The cooling bath was removed and the reaction
mixture was diluted with ether. The organic layer
was separated and the agueous layer was extracted
successively with ether and methylene chloride.
The combined organic e~tract was dried over
anhydrous magnesium sulfate and concentrated. The
crude residue was chromatographed on a silica gel
column and eluted with 40% ethyl acetate in hexane
to obtain 114 mg of title fast moving alcohol
epimer and 40 mg of slow moving isomer.
Exam~le llA
[1~,2~(5Z),3~(1E,3S),4a,5~,6a]-7-[5,6-Epoxy-3-(3-
hydroxy-5-phenyl-1-pentenyl)-7-oxabicyclo[2~2.1~-
hePt-2-Y11-5-heptenoic cid
A solution of 114 mg of Example 11 ester
(0.27 mmole) in 1 ml of THF and 1 ml of lN aqueous
lithium hydroxide was stirred at 25~C for 2 hours.
The reaction mixture was concentrated and then
7~
HA363
-44-
acidified with oxalic acicl solution to p~ 3. It
was now extracted with ether (X3). The combined
ether extract was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to
give 100 mg crude oil. Purifications on
preparative silica gel plates (eluting solvent 10%
in methylene chloride) gave 37 mg of title acid.
Anal Calcd for C2~H3005: C, 72-33; H, 7-59
Found: C, 72.10; H, 7.54
Exam~le 12
[la,2~5~),3~(1E,3S)4a,5a,6a]-7-[5,6-Epoxy-
3-~3-hydroxy-4-cyclopentyl-1-butenyl~-7-o~abi-
cvclo[2.2.1lhept-2-yl]-5-he~tenoic acid
Following the procedure of Examples 7 and 8
except substituting dimethyl(2-oxo 3-cyclo-
pentyl) propyl phosphonate for ( + ) dimethyl(2-oxo-3-
methyl-3-phenyl )propyl phosphonate, the title
compound is obtained.
Exam~le 13
[la,2~(5Z),3~(1E,3~)4~,5a,6~]-7-[5,6-Epoxy-
3-(3-hydroxy-1,5-hexadienyl)-7-oxabicyclo[2.2.1]-
he~t-2-yll-5-heptenoic acid __
Following the procedure of Examples 7 and 8
except substituting dimethyl(2-oxo-4-pentenyl)-
phosphonate for ( + ) dimethyl (2 oxo-3-methyl-3-
phenyl)propyl phosphonate, the title compound is
obtained.
7~
aA363
~45-
Example 14
[1~,2~(5Z),3~1E,3S)4~,5~,6~]-7-[5,6-Epoxy-
3-(3-hydroxy-1-nonenyl)-7-oxabicyclo[2 .2.1]hept-
2-vll~5-heptenoic acid
Following the procedure of Examples 7 and 8
except substituting dimethyl(2-oxo-octyl)phos-
phonate for (+)dimethyl(2-oxo-3 methyl-3-phenyl)-
propyl phosphonate, the title co~pound is obtained.
ExamPle 15
[1~,2~(5Z),3~(1E,3S)4a,5a,6a]-7-[5,6-Epoxy-
3-(3-hydroxy-1-pentenyl)-7-oxabicyclo[2.2.1]hept-
2-yll-5-heptenoic acid
Following the procedure of Examples 7 and 8
except substituting dimethyl(2-oxo-butyl)phos-
phonate for (~)dimethyl(2-oxo-3-methyl-3-phenyl)-
propyl phosphonate, the title compound is obtained.
Exam~le 16
[la,2~(5Z),3~3R,4S),4a,5a,6~]-7-[5,6-Epoxy-3~
(3-hydroxy-4-phenyl-1-pentyl)-7-oxabicyclo[2.2.1]-
he~t-2-yll-5-he~tenoic acid
A. [la,2~(5Z),3~(3R,4S),4a,5a,6a]-7-[5,6-
Epoxy-3~(3~hydroxy-4-phenyl-1-pentyl)-
7-oxabicyclo[2.2.1]hept-2-yl]-5-
heptenoic acid, methyl ester
To a suspension of 686 mg of purified
cuprous bromide (4.8 mmole) in 12 ~1 of dry ~
cooled at 0-5~C is added with stirring 1.35 ml of
a 3.5 M solution of red-~l (sodium bis(2-methoxy-
ethoxy)aluminum hydride) in toluene dropwise. The
solution is stirred at 0-5C for 30 minutes,
whereupon it is cooled to -78C and 2 ml of
n-butanol (18 mmole) is added rapidly, followed
by a solution of 672 mg of Example 7 Part A enone
70 ~
HA363
-46-
(2 mmole) in 4 ml of dry THF. After 10 minutes at
-78C, the reaction mixture is warmed to -20C and
left for an additional 1 hour. The reaction
mixture is quenched by addition of 70 ml of water
and then poured into saturated ammonium chloride
solution and extracted with ether (X3). The ether
extract is dried over anhydrous magnesium sulfate,
filtered and the filtrate is concentrated under
reduced pressure. 675 Mg of desired title ketone
is obtained.
To a solution of 338 mg of ketone
(1 mmole) (prepared aR described above) in 2 ml of
methanol and 2 ml of dry THF is added with stirring
400 mg of ceric (III) chloride hydrate (1 mmole).
After stirring at room temperature for 10 minutes,
the reaction mixture is cooled to -50C and 38 mg
of solid sodium borohydride (~1 mmole) is added to
the reaction mixture. The reaction mixture is
stirred at -50C for 45 minutes, whereupon 5 ml of
acetone is added to destroy excess of borohydride.
The mixture is stirred for an additional 5 minutes
at -50C. The cooling bath is removed and the
reaction mixture is evaporated to dryness. The
crude residue is diluted with ether and washed
with 1 N aqueous hydrochloric acid solution. The
ether extract is dried over anhydrous MgS04 and
concentrated under reduced pressure. The crude
residue is chromatographed on a silica gel column
and eluted with ethyl acetate (30-50~) in hexane
to obtain the desired title alcohol.
B. [la,2~(5Z~,3~(3R,4S),4a,5a,6~]-7-
[5,6-Epoxy-3-(3-hydroxy-4-phenyl-1-
pentyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5-hePtenoic acid
H~363
-47-
Following the procedure of Example 8 except
substituting the above Part A alcohol ester for
the Example 7 aicohol ester, the title compound is
obtained.
ExamDle 17
rla,2~3(5Z),3~(3S),4~,Sr~,6a]--7--t5,6--Epoxy--3--(3--
hydroxy-3-phenyl-1-propyl)-7-oxabicyclot2.2.1]-
Following the proc~dure of Example 16 and
E~amples 7 and 8 except subs~ituting benzoic acld
for 2-phenylpropionic acid, the title compound is
obtained.
Exam~le 18
[la,2~(5Z),3~(3S~,4~,5~,6a]-7-~5,5-Epoxy-3~(3-
hydroxy 4-phenyl-1-butyl)-7-oxabicyclo[2.2.1]-
hept-2-Y11-5-he~tenoic acid
Following the procedure of Example 16 and
Examples 7 and 8 except substituting phenylacetic
acid for 2-phenylpropionic acld, the title compound
is obtained. -
Exa~ple 19
tla,2~(5Z~,3~(3S),4a,5a,6a~]-7-[5,6-Epoxy-3-(3-
hydroxy-3-cyclohexyl-1-propyl~-7-oxabicyclo[2.2.1]-
h~ 2-Y11-5-heptenoic acid
Following the procedure of Example 16 and
Examples 7 and 8 except substituting cyclohexyl-
carboxylic acid for 2~phenylpropionic acid, the
title compound is obtained.
70 ~
HA363
-4B-
Examples 20 to 29
Following the procedure of Examples 7 and 8
(where A is CH=CH) and Example 16 (where A is
( CH2 )2 ), except substitut.ing for carboxybutyl-
5 triphenylphosphonium bromide, the compound shown in
Column I of Table I set out below and substituting
for (+)dimethyl(2-oxo-3 -methyl-3-phenyl)propyl
phosphonate, the compound shown in Column II,
the compound of the invention ~hown in Column III
10 is obtained.
1~7~
--49-- HA363
a' ''~ C b
~o~
~o
-s
~3~ ~ rr',~aSrO b~
-
~ 21 q ~ ~ ~ `J Ui
~7~
EIA36 3
--50--
t- ~ E ¦ ~ ~
X
zl o~
E~A3 63
Example 3 0
[la,2~(5Z),3~1E),4~,5a,6~]-7-[5,6-~poxy-3-[3-
hydroxy-3~(1-methylcyclohexyl)~1-propenyl]-
7-oxabicyclo[2.2.1]hept-2-yl]~5-heptenoic acid,
methyl ester
_ .
A. [la,2~(5Z),3~(1E),4a,5a,6a]-7-[5,6-
Epoxy-~-[3-oxo-3-(1-methylcyclohexyl)-
1-propenyl]-7-oxabicyclot2.2.1]hept-2-
yll-5-heptenoic acid, me~hYl ester
To a sl~rry of 135 m~ of lithium bromide
(1.56 mmole, 2.2 equiv.) in 3 ml of dry methylene
chloride at 25C was added a solution of 293 mg of
dimethyl t2-~l-methylcyclohexyl)]-2-oxo-ethyl
phosphonate (1.5 mmole, 2.1 equiv.) in 1 ml of
methylene chloride and 198 ml of triethylamine
(1.42 mmole, 2.01 equiv.). After stirring for 30
minutes, a solutio~ Of ca. 0.70 mmole of ~la,2~-
(5Z),3,B(lE:),4~,5a,6c~3-7-tS,6-epoxy- -formyl-
7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid,
20 methyl ester (prepared as described in Example 1
Part M) in 1 ml of methylene chloride was added.
The stirring was continued at 25C for 18 hours.
The reaction mixture was then treated with S ml of
lM NaE~2P04 solution and diluted with 30 ml of
25 ether. The layers were separated. The organic
layer was washed with 10 ml of a saturated K~CO3
solution, 10 ~1 of ~2 and 10 ml of brine. The
or~anic layer was then dried (MgSO4~ and
concentrated.
The residue was purified on a silica gel
colu~ul. Elution with 25% EtOAc/hexane gave 170 mg
of title enone as a clear oil.
1~7~
~A363
-52-
B. [1~,2~(5Z),3~(1E,3S),4a,5~,6~] 7-~5,6-
Epoxy-3-~3 hydroxy-3-(l-methylcyclo-
hexyl) l-propenyl]-7-oxabicyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid,
methYl ester _ _
To a solution of 170 mg of Part A enone
~0.42 mmole~ in 1 ml of methanol and 1 ml of THF
at 25c was added 102.9 mg of cerium trichloride
~0.42 mmole, 1 equiv.). After stirring at 25c
for 15 minutes, the mixture was cooled to -50c
and 15.9 mg of sodium borohydride 6.42 mmole, 4
eguiv. was added, The mixture was stirred at
-50C for 3 hours, then poured into 30 ml of a
saturated solution of ammonium chloride. The
aqueous solution was extracted with three 15 ml
portions of ether. The combined extract was
wsahed with 10 ml of H20, dried (MgS04) and
concentrated. The residue was purified on a
silica gel column. Elution with 25% of
EtOAc/hexane gave 128 mg of title alcohol ester.
Example 31
la,2~(5Z),3~(1E,3S),4a,5~,6a]-7-[5,6-Epoxy-3-[3-
hydroxy-3-(1-methylcyclohexyl)-1-propenyl]-
7 oxabicvclo[2.2.1lheDt-2-yll-5-heptenoic acid
A mixture of 128 mg of Example 30 alcohol
ester (O.31 mmole), 1 ml of lN LiOH (l.O mmole, 3
equiv.) in 1 ml of THF was stirred a~ 25C for 2
hours and then concentrated. The residue was
diluted with 5 ml of H20, acidifying to pH 3 with
a saturated solution of oxalic acid, then
extracted with three 15 ml portions of ether. Th~
combined ethereal extract was washed with 15 ml of
7~ ~4 ~
HA363
-53-
H20, dried (MgS04) and concentrated ~o give 112 mg
of a crude oil,
This oil was purified on a silica gel
preparative plate (50 mg batches, 0.5 mm silica
gel plate, 10~ MeOH/CH2C12) to yield a total Of
49.6 mg of clean acid product.
TLC: silica gel; 10% MeOH/C~2Cl2; Rf ~ 0.60
Anal Calcd for C23H345- 5 H20
H, 8.82
Found: C, 69.10; H, 8.51
Example 32
[la,2~(5Z),3~(1E,35),4a,5~,6~]-7-[5,6-Epoxy-3-(3-
hydroxy-4,4-dimethyl-1-octenyl)-7-oxabicyclo~2.2.13-
he~t-2-Yll-5-heptenoic_acid, methvl ester
A. [la,2~(5Z),3~(1E),4a,5a,6a]-7-[5,6-
Epoxy-3-(3-oxo-4,4-dimethyl-1-octenyl)-
7-oxabicyclo[2.2.1]hept-2-yl]-5-
heptenoic acid, methYl ester
To a sluxry of 102 mg of lithium bromide
(1.17 mmol, 2.2 equiv.) in 3 ml of dry CH2C12 at
25C was added a solution of 293 mg of
3,3-dimethyl-2-oxo-heptyldimethylphosphonate
(1.11 ~mole, 2.1 eguiv.) in 1 ml of CH2C12 and 14B
ml of triethyl~mine (1.06 mmole, 2.01 eguiv.).
After stirring at 25C for 30 minutes~ a solution
of ca. 0.53 mmole of [la,2~(5Z),3~(1E),4a,5a,6a]-
7-[5,6-epoxy-3-formyl-7-oxabicyclo[2.2.1]hept-2-
yl]-5-heptenoic acid, methyl ester (prepared as
described in Example 1 Part M) in 1 ml of CH2Cl2
was added. The stirring was continued at 25C for
1i~7(3~
HA363
-54-
18 houxs. The reaction mixture was then treated
with 5 ml of lM NaH2P04 solution, and diluted with
30 ml of ether. The layers were separated. The
organic layer was washed with 1 ml of a saturated
KHC03 solution, 10 ml o H20 and 10 ml of brlne.
The organic layer was then dried (MgS04) and
concentrated.
The residue was purified on a silica gel
column. Elution with 25~ EtOAc/hexane gave 130 mg
of title enone as a clear oil.
B. [la,2~(5Z),3~(1E,3S),4a,5a,6a]-7-[5,6-
Epoxy-3-(3-hydroxy-4,4-dimethyl-1-
octenyl)-7-oxabicyclo[2.2.13hept-2-yl]-
5-hePtenoic acid, methyl ester
To a solution of 130 mg of Part A enone
(0.32 mmole) in 1 ml of methanol and 1 ml of THF
at 25C was added 78.4 mg of cerium trichloride
0.32 mmole, 1 eguiv.). After stirring at 25C for
15 minutes, the mixture was cooled to -50C and
12.1 mg of sodium borohydride (0.32 mmole, 4
equiv.) was added. The mixture was stirred at
-50C for 3 hours, then poured into 30 ml of a
saturated solution of ammonium chloride. The
aqueous solution was extracted with three 15 ml
portions of ether. The combined extract was
washed with 10 ml of H20, dried (MqS04) and
concentrated. Ths residue was purified on a
silica gel column. Elution with 25% EtOAc/hexane
gave 96 mg of title alcohol ester.
L~
HA363
-55
Exam~le 33
[la,2~(5Z~,3~(1E,~S),4a,5~,6~]-7-[5,6-Epoxy-3-(3-
hydroxy-4~ 4-dimethyl-1-octenyl)-7-oxabicyclo-
r2.2.11he t-2-yll-5-he tenoic acid
P
A mixture ~f 96 mg of Example 31 alcohol
ester (~.23 mmole), 1 ml of lN Lio~ (l.o mmole, 4
eguiv.) in 1 ml of THF was stirred at 25C for 2
hours, then concentrated. The residue was diluted
with S ml of ~2~ acidifying to pH 3 with a
10 saturated solu~ion of oxalic acid, then extracted
with three 15 ml portions of ethex. The combined
ethereal extract was washed with 15 ml of H20,
dried ~MgSO4) and concentrated to give 75 mg of a
crude oil.
This oil was purified on ~ilica gel
preparative plate~ (50 mg batches; 0.5 mm plates;
10% MeOH (CH2C12) to yield a total of 49.8 mg of
clean acid product.
TLC: silica gel; 10% MeOH/CH2CH2; Rf ~ 0.55
Anal Calcd for C23H3605: C, 70.37; H~ 9.~4
Found: C, 70.34; H, 9.43
