Note: Descriptions are shown in the official language in which they were submitted.
~25~887 - _~A290/280
_
; . 7-O~ABICYCLOHEPTA~E SUBSTITUTED
PROSTAGLANDIN ~NALOGS
,
., .
; 5 The present invention relates to
7-oxabicycloheptane prostaqlandin analogs which
are cardiovascular agents us~eul, ~or example, in
the treat~ent o~ thrombolytic disease. These
compounds have the structura1 formula
I ~ CH2-A-(CH2)m-cOOR
< ~ I
(C~2)n-B-R
0
wherein B is oxygen (-O-) or -~- w,herein n' is 0
to 2, R is hydrogen, lower alky~, alkali metal or
trihydroxymethylaminomethane, Rl is alkyl, alkenyl,
alkynyl, aryl, aralkyl, aralkenyl, aralkynyl,
cycloalkylalkyl, cycloaLkylalkenyl or cycloalkynyl.
~ A is -CH=CH- or -(C~2)2-, n is l to 4, and m is l to
; 8, and including all stereoisomers thereof.
The term "lo~er alkyl" or "alkyl" as employed
herein includes both st~aight and beanched chain
: 25 radicals of-up to 12 carbons, preferably l to 8
, .
.ar
~25~
i HA2~0/2~0
-2~
. carbons, such as methyl, ethyl, propyl, isopcopyl,
- butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl,
heptyl, 4,4-dimethylpentyl, octyl,
2,2,4-trimethylpentyl, nonyl, decyl, undecyl,
dodecyl, the ~arious branched chain isomers
thereo~, and ~he like as well as such srouPs
; incl~ding a halo-sub~tituent, such as F, Br, Cl o~
I OL CF3, an alkoxy substituent, a haloaryl
substituent, a cycloalkyl substituent (that is,
cycloalkylalkyl3 or an alkylcycloalXyl substituent.
The terms "alkenyl" and "alkynyl" as used
herein contemplate simllar hydrocarbon groups
bearing therein a carbon-carbon double or
triple hond such as for example, 2-propenyl,
2-hexenyl, 3-hexenyl, 3-hexynyl and in the case
of an aryl substituent or cycloalkyl substituent
as defined below, 3-phenyl-2-propenyl, 3-phenyl-
2-propynyl, 3-cyclohexyl-2-propenyl and 3-cyclo-
hexyl 2-propynyl.
The ter~ "cycloalkyl" includes saturated
cyclic hydrocarbon groues containing 3 to 12
carbans, pre~erably 3 to 8 carbons, which include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl ~nd
cyclododecyl, any of which groups may be
substituted with l or 2 halogen, l or 2 lower alkyl
groups and/or lower alkoxy groups.
The term ~aryl~ or ~Ar~' as employed herein
refers to monocyclic or bicyclic aro~atic groups
containing ~rom 6 to lO carbons in the ring
portion, such a~ phenyl, naphthyl, substituted
phenyl or substituted naph~hyl wherein the
substituent on either the phenyl or naphthyl may be
lower alXyl, halogen (Cl, 8r or F~, or lower alkoxy.
~25~ HA2 5 0 / 2 8 0
. 3 .~ .
. .
The term ~aralkyl~ aryl-alkyl~ or
"aryl-lower alkyl~ as used herein Lefers to lower
alkyl groups as discussed above having an acyl
substitu~nt, such as benzyl.
The terms "(CH2)n~" and "(CH2~n" includes
a straight or branched chain radic:al having from 1
to 8 carbons in the normal chain i.n th~ cas~ of
" (CH2),1," and 1 to 4 carbons i~ th~ rlormal chain
in ~he cas~ of " (CH2)n" and may contain one or
more lower alkyl substituents. E~ca~npl~s of
(CH;~)m and (CEI2)n groups include CH2.
CH2CEI~, ( CH2 ) 3, ( CE~2 ) 4 ~ ( CH2 ) 5 ' ( 2 6
ICH3
10 ( CEI2 ) 7 - ( CEI2 ) 2 -Cl H- . -CH2 -Cl E~-, -CH2 - ICEI--~H-CEI2 -,
C~I3 C~3 CE~3 CH3
-CH2- IH-CH2-ClEI-, and ~he likQ.
CH3 , CE~3
. .
~8~ ~
HA290/280
_4_
The compounds of Formula I (wherein R is
alkyl) are prepared by etherifying or thioether-
ifying a compound of the Form~la II:
~ 2-A-(C~)m 2
(C~2)n_} 2
q with the desired Rl-oH or R~SH groups or thelr
equivalents according to conventional methods.
TXe synthesis of ethers an-d thioethers is
based on the Williamson Synthesis (J. Chem. Soc.
4, 229 (1852)) wherein ethers (and later thio-
ethers) were synthesized by alkylation ofalkoxides with alkyl halides:
R'(O or S)Na ~ R"X-~ R'(O or S)R" + NaX
.
The modern version of this synthesis envisions
use of other leaving groups in addition to halides.
Thus with respect to Formula II above, the ether-
ification or thioetherification reaction comprehends
reaction of a Formula IIa compound of the formula
~H 2-A-(ca2)m-co2alkyl IIa
~ (CH2) n-~ ca2X
wherein X in addition to hydroxy can also be -SH or
their sodium or potassi~um salts, chloro, bromo, iodo
and alkyl, aryl- and aralkyl-sulfonyloxy groups with
a complementary RlX compound to form the following
type compounds of Formula I:
HA290/280
_5 _ .
(C~ ) -A- ~C~ ) -CO alkyl
~/ ~f 2 2 in 2 ~ j CH2 -A- (CH2 ) CO alkyl
~ C~2) n~~R \~~~ (CH2 ) -S-R
III IV
The thioethers of Formula IV can then be oxidized
to the sulfinyl and sulfonyl derivatives
~n'=l or 2 in Formula I~ having the formulae~
10 ~C82-A~(c~2)mco2alkyl CH2~A~(C~i2)m~C2
(CH2) n~~~R \~;~ (C~2) n O R
V VI .,
15 ' ' '
The compounds o Formula I wherein R ls an
alkali metal or hydrogen (free acid) can then be
prepared from the above products where R is alkyl
by conventional basic hydrolysis with sodium or
potassium hydroxide to form the sodium and potassium
; salts followed by acidification to the free acid.
Etherification is usually accomplished by
reacting the Formula II compound with a compound
of the formula RlX wherein X is chloro, bromo, or
iodo or methylsulfonyloxy or toluenesulfonyloxy,
in the presence of a strong base such as sodium or
potassium hydroxide in an appropriate solvent. In
carrying out the reaction a molar excess of the
RlX reactant varying from .25 mole excess to a 5
mole excess is used employing a solvent such as
xylene, tetrahydrofuran, dimethylsulfoxlde or
dimethylformamide. In the case where X is bromo
or chloro, a phase transfer etherification can be
- employed in which case tetrahydrofuran is used as
the solvent and a phase transfer reagent such as
.
~:256~7
~ ---H~290/2~0
--6
Bu4NHS04 or (C6H5CH2)~CH3)3NHS04 is employ~d- In
the case wherein Rl is aryl it is convenient to
first react the alcohol group of the Formula II
compound with triphenylphosphine and diethylazo-
dicarboxylate in solution with an inert solventsuch as tetrahydrofuran and then with an Rl(aryl)
alcohol such as phenol. As is generally known in
the art, the sequence of reacting the Formula II
alcohol with the RlX compound to achieve ether-
ification can be reversed by converting the FormulaII alcohol into a Formula II compound wherein the
alcohol group has been replaced with another radical
from the group X and then reacting with an
Rl-alcohol or al~oxide to form the Formula I product.
Thioetherification is usually accomplished by
flrst converting the Formula II alcohol to another
Formula II-X derivative as indicated above and
thioetherifying with an RlS~ mercaptan in the
presence of a base or with an alkali metal sal~
thereof.
Oxidation of the sulfide product where n'=O
to the sulfinyl and sulfonyl analogs where n' is
1 or 2 is readily accomplished by reacting with
sodium periodate in the presence of methanol and
tetrahydrofuran to form the sulfinyl and sulfonyl
derivatives which may then be separated by
chromatography or other conventional separation
procedures.
The starting materials of Formula II wherein
n is 1 (hydroxymethyl group) are known from U.S.
; Patent 4,143l054 and can be prepared as described
therein. These compounds can be used to prepare
starting materials of Formula II wherein n is 2 to
4 by oxidation of the hydroxymethyl group to an
aldehyde by way of a Collins oxidation, for example,
HA290/280
--7
by reacting Compound II with chromium trioxide
in pyridine, to form a intermediate of the
formula
~CH2 A- (CH2) mC02~11kyl
C~O
VII
The Formula VII aldehyde is subjected to a
homologation sequence by way of a Wittig reaction
using (C6H5)3P=CHOCH3 folIowed by hydrolysis
5n-1) times followed by reduction of the aldehyda
to the alcohol employing a reducing agent such as
sodium borohydride or sodium cyanoborohydride in
a solvent such as methanol to fbrm the Formula II
starting material:
.
~25~7
- ` HA290/280
.
. , .
a) I r~
_I
o
,.,
/1`. ~,
~o~
o~ ~;o
~) o ~ ~
3~
~0
~7
O
~!
_~
. ,~
3 C~ I .
. , .
,
- ~ ~ HA290/280
_g _ .
Th.e tris(hydroxymethyl)aminomethane salt of
any of the acids of focmula I of the present
invention i~ formed by reacting a solution of such
acid in an inert solvent such as methanol with
tristhydroxymethyl)aminomethane and thereafter ~he
solvent is re~oved by evaporation to leave the
desired salt.
The compounds o~ this invention have ~our
centers o~ asymmetry as indicated by the asterisks
i~ ~ormula I. However, i~ ~ill 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 YariOUs
stereoisomeric forms are within the scope of the
in~ention.
The ~arious stereoisomeric forms of the
compounds of the invention. namely, cis-exo,
: cis-endo and all trans forms and stereoisomeriF
.~
- ~256~7
HA2so/280
,
pairs may be prepared as shown in the working
Examples which follow and by employing starting
materials and following the procedures as ouelined
in U. S. Patent No. 4.143.054. Examples of such
stereoiso~e~s are set out below.
CH2-A-~CH2)m-C02R
CH2)n-~-R
O E~
~cis endo) . ..
I~ . ~ ~ _-C~2-A-(c~2~m
O (CH;~)n-B-R
(cis-exo)
HA290/280
'
I g \~¦ ~ ~ C~2 -A- ( CHz ) m-C2
<~1~ ( C~2 ) n~ B -R
O ~1
(trans)
I ~I2-A-tC~2)m-cO2
Ih
\ ~H
O (CE[ ) B
ttrans)
The nucleus in each of the comp~unds of the
invention is depicted as
/~
O
. HA290/280
-12-
for matter of convenience: it will also beappreciated that the nucleus in the c:ompounds of
the invention may be depicted as
0
~b
The eomp~unds of this invention are
cardio~ascular agents useful as platelet
ag~regation inhibitors, e.g., for treatment of
t~ro~bolytic disease, such as coronary or cerebral
thrombo~es. They are also selective thromboxane
A2 receptor antagonists and syn~hetase
inhibitors, e.g., having a vasodilatory effec~ for
treatment o~ myocardial ischemic disease, such as
~ angina pectoris. The compounds of the invention
; 20 are also arachidonic acid cyclooxygenase
inhibitors. ~hey can be 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 ~ithin the dosage
25 range of about 1 to 100 mg/ky, preerably about 1
to 50 mg/kg a~d especially about 2 to 25 ~g/kg on a
regimen in single or 2 to 4 divided daily doses.
The active substance can be u~ilized in a
composition such as tablet, capsule, solution or
suspension containing about 5 to about 500 mg per
.
~i@5~
HA290/280
. 13-
unit of dosage of a compound oc mix~ure ofcompounds o~ ~ormula I. They ~ay be compounded in
conventional matter with a physiologically
acceptable vahicle or carrier, excipient, binder,
preservative, stabilizer. ~lavor, etc. as called
for by ac~epted pharmaceutical p actice. Also as
indicated in the discussion above, certain members
additionally ser~e as intermediates ~or other
~embers of the group.
HA2so/280
-14-
.
The following Examples represent preferred
embodimen~s of the invention.
Exampl e
LlB.2~5Z),3~ 4~1-?- r~3- L(HexYlox~lme-thyll=7-
oxabicyclor2._.llhePt-2-vl~5-he~tenoic acid. hexyl
ester
A. ~ 2~(5Z).3~.4BL-7-L3-(HY~roxYmethYl)-
7-oxab_yclo~2.2.11he~t-2-yll-5-heptenoic
acid, methyl_ester
(a) A mixture of N-acetylpyridinium chloride
was pcepared by adding 9.6 ml (136 mmole) of acetyl
chlo ide dropwise to 56 ml of pyridine. To thls was
added 5.0 g (27 mmole) of ~qxo)-3-(2-methoxy-
ethenyl)-7-oxabicyclot2.2.1]heptanq-2-methanol
dl~solved in 5 ml af py~idlne. The resulting
mixture was stirred at room temperature ~or 1.5
hours and poured into brine. The product was
extrac~ed into ether (3 x 200 ml); the ether
extracts were washed with S~ hydrochloric acid (2 x
20 400 ml) and brine (1 x 200 ml) and dried over sodium
sulfate. Concentration yielded a yellow oil which
was purified by passage through a short column of
silica gel (150 ml) with dichloromethane: 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 was added 31.1 g (97.8 mmole) of
mercuric acetate. T~e yellow suspension which
formed was stirred for 10 minutes and then the -
HA~90/280-15-
entire mixture was poured into a solution containing200 g of potassium iodide in 2 l. of water. Upon
shaking, the yello~ color disappeared and the
mixture was extracted with benzene (~ x 500 ml).
S The combined benzene extracts were washed with
potassium iodide solution and brine and dried over
sodium sulfate. Concentration yielded 3.7 g of
~aterial which crystallized on standing in an ice
box,
(c) A Wittig reagent was prepared in dimethyl
sulfoxide (dried over calciu~ hydride) by adding a
solution of sodiu~ methylsulfinylmethide (prepared
by heating 300 mg of sodium hydride in 60 ml of
dimethyi sulfoxide at ~5 until hydrogen evolution
itopa) dropwise to a solution of 5~32 g (12 mmole~
of 4-carboxybutyl triphenylphosphonium bromide in
100 ~1 o~ dimethyl sulfoxide. After the first
orange color lasting more than 10 seconds formed, an
equivalent amount o~ base was added to ~orm the
ylide. To this deep orange solution was added a
solution of the product of part (b) in 20 ml of
dime~hyl sulfoxide and the resulting mixture stirred
at room temperature for 45 minutes. The reaction
was quenched by addition of 24 mmole of acetic acid
a~d the mixture poured into brine (300 ml) and
extracted with ether (3 x 200 ml). Concentration of
these extracts gives an oil which was stirred with
saturated sodium bicarbonate solution until
crystalline triphenylphosphine oxide formed in the
HA29~/280
-16-
- . mixture. This mixture was washed with benzene and
acidified with 10% hydrochloric acid. The aqueous
layer was saturated with salt and extrac~ed with
ether which on drying (sodiu~ sulfate) and
~oncentration ga~e 2.43 g o~ crude product. The
mixture was stirred 24 hours with 10'~ aqueous sodiu~
hydroxide and reisolated by acidification and ether
extraction. The produet was purified on 500 q o
silica gel with 50/50 ethyl acetate-hexane as the
eluant ~hich ga~e 600 mg of acid ~hich crystallized
on standing. This was recrystallized twice fsom
ethyl acetate-cyclohexane to yield 320 mg of
tl~.2~(5Z),3~,4R~-7-~3-(hydroxymethyl)-7-oxabi-
cyclot2.2.~lhept-2-yl]-5-heptenoic acid,m.p. 59-63C.
Anal. Calc'd ~or C14H2204: C,66~ H,8-72
Found: C,66.06i H,8.79
The acid is then converted to the correspondiny
methyl ester by treating with diazomethane.
B. Ll~ ~2~t5Z),3~,4~1-7-~3-~HexYloxy)-
~ethyll-7-oxabicYclo~2.2.llhe~t-2-Yll-5-
he~tenoic acid, hexYl ester
A suspension of 0.56 g of powdered KOH in
15 ml of dry xylene was heated to reflux and 7 ml of
xylene was distilled ofE. To this mixture was added
a solution of 300 mg (1.12 mmol) of alcohol ester
from part A in 10 ml of dry xylene. The resulting
mixture was heated to reflux and 9 ml of xylene was
distilled off. To this mixture was added 1.0 g
.
.
. -
6~3~7 - -
' 'HA290/280
-17-
(5.6 mmol) of n-hexylmethanesulf,onate and the
resulting mixture was heated at reflux for 1-1/2
hours. The reaction mixture was cooled to ambient
temperature and diluted with CH2C12 (~0 ml).
The resulting solution was poured into 50 ml
satura~ed NaHC03. The layers were separated and
the aqueous phase was extracted (2 x 60 ml) with
CH2C12. The combined CH2C12 extracts were
dried over MgSO4, then concentrated in vacuo to
yield 0.9 g of crude prod,uct. The crude product was
chromatogr~phed on 33.4 g of silica gel 60 with
hexane:~ther (5:1) to yield 390 mg ~83~) of the
title hexyl ester.
ExamPl~ 2
~1~,2~t$Z~,3~,4~1-7-~3-t~HexYloxy)methvll-7-
oxabicYclot2.2.llhept-2-~ll-s-heptenoi-c--acid
To a st~red solu~ion of'115 mg (0.27 mmol) of
the Example 1 hexyl ester in 12.0 ml of dis~illed
THF and 1.60 ml f ~2 under argon was added 2.40
~1 of lN aqueous lithium hydroxide solution. This
mixture was purged with argon for 40 minutes and
stirred at room temperature for 24 hours. At this
time, TLC analysis showed that the reaction was not
co~plete so an additional 1 ml of methanol and 1 ml
of lN aqueous lithium hydroxide was added. The
reaction mixture was kept stirring for another 4
hours and then was acidified to pH 4 by the addition
of lN aqueous HCl solution. The resulting solution
was poured into 25 ml of saturated NaCl solution and
was saturated wth s~lid NaCl. The aqueous layer was
extracted with EtOAc (4 x 40 ml). The combined
EtOAc extracts ~ere dried over anhydLous MgS04,
. .
~A290/230
-18-
filtered and concentrated in vacuo to gi~e 124 mg of
crude oil. This was chromatographed on 20.6 g of
silica gel 60 using hexane:ether (2:3) as eluant to
giYe 102 mg Q~ desired product contaminated with a
small a~ount of hexyl alcohol. The mixture was put
in high ~acuum overnight at room temperature to giv~
77 mg (84%) of pure title acid. TLC: silica gel, a~
C~3~H~C~2C12. Rfl0.74. iodine-
~nal. Calc d for C~oH3404
Found: C, ~70.60: H, 9.89
CNMR (CDC13, l5.0mHz)tau 33.4, 22.6, 24.6,
129.4, 130.1, 26.7, 46.4, 79.4, 29.5,
- 80.1, 46.8, 71.3, 69.8, 31.7, 25.7, 29.7,
22.6, 14Ø
.
Example 3
~lB.2~(5Z).3~,4~1-7-~3-~HexYloxY)methyll-7-
oxa~icvclor2.2.11hePt-2-Yll-5-he~tenoic acid, hexYl
ester
503 mg (1.83 mmol) o~ tlB,2~(5Z),3~,4~l-
?-t3-(hydroxymethyl)-7-oxabicyclot2.2.1~hept-2-yl]-5-
heptenoic acid, methyl ester (prepared as described
in E~ample 1) ~as dissolved in 2.17 ml tetcahydro-
uran. ThereaSter 2.17 ml (15.46 mmol) of n-hexyl
bromide, 173.4 mg (0.51 mmol) te~rabutylammoniumbi-
sulfate (Bu4NHS04), and 2.17 ml of a 50~ NaOH
solution were added and the mixture vigorously
stirred at room temperature. A slightly
yellowish-brown solution formed which upon stirring
o~ernight for~ed a white precipitate.
The reaction mixture ~as poured into 25 ml of
saturated NaHC03. The mixture was extracted with
CH2C12 (4 x 25 ml). The combined CH2C12
,
HA290/2~0
--19--
extracts were dried (MgS04), f~ltered and
concenerated in va~uo to give tlfl,2l~(5Z),3~,4~-
7-E3-~hexyloxy)methyl~-7-oxabicyclol2.2.1~hept-2-yl~-
5-heptenoic acid, hexyl .ester (1272 ~g). This ~as
chroma~ogr~phed on 40 g ~llica gel using
hexane:et~er (4:1) a~ eluant to give f~nal product.
ExamPle 4
~lB,2~,3~4~)-7-~3-LtHexYl xy~meth~ll-7-oxa-
bic~clot2~2~llhept-2-yl~heptanoic acid, hexyl ester
A. ~lB,2~.3~.4~) 7-~3~ ydr~xxlmethyll-7
oxabicYclo~2.2.11he~t-2-YllhePtanoiC acid
methYl ester
To 800 mg ~3.0 m~ole) o~ the El~.2~(5Z).-
3~,4~]-7-t3-thydroxy~ethyl)-7-oxabicyclot2.Z.l]-
hept-2-yl]-5-heptenoic acid, met~yl ester as
prepared in Example L, dissolved i~ 120 ml of ethyl
aceCate wa~ added, und~r a3 argo~ at~os~here, 160 mg
of 5% Pd on carbon. The arqon atmosphere was
exchanged for a slight ~osit~ve pressure of hydrogen
and the reaction was stirred for 8 hours at 25 ,
~iltered through a Celite plug and evaporated to
provide 730 mg (90~) o~ the title ~ compound.
B. ~1~;2~,3~,4~L~L Ll L~_exYloxylmethyll-7-
oxabicy~lo~2.2.11hePt-2-Yll-S-hePtano~c
aeid, hexYl ester
Following the procedure of Exa~ple 1 except
subs~ituting ~he Part A alcohol-ester for the
Examp~e lA alcohol ester. the title product is
obtained.
* Trade Mark
HA290/280
_ -20-
Example 5
(1~,2a,3a,4~)-7-[3-~(Hexyloxy)methyl~-7-oxabi-
cyclo~2.2.1]hept-2-yl]heptanoic acid
Following the procedure of Example 2 except
substituting the Example 4 hexyl ester for the
Example 1 hexyl ester, the title acid is obtained
as an oil [a~25= -3.1(c=1.37, CHC13); TLC(silica
gel, 8% CH30H)CH2C12 , Rf=0.74.
Anal. Calcd. for C2oH36O4: C,70.55; H,10.66
Found: C,70.30; H,10.70
CNMR (CDC13, 15-0MHz)tau 179.1, 33.9, 24.6,
27.6, 29.2, 29.3, 29.0, 47.0, 79.1, 29.7,
29.6, 80.1, 46.4, 71.2, 69.8, 29.3, 25.a,
31.6, 22.6, 1~.0
.. ~ .
[1~,2a(5Z),3~,4~]-7-[3-[(Hexyloxy)methyl]-7-
oxabicyclo[2.2.11hept-2-yll-5-heptenoic acid
Following the procedure of Examples 3 and 2
20 except substituting [1~,2a(5Z), 3~,4~]-7-[3-
(hydroxymethyl)-.7-oxabicyclo[2.2.1l-hept-2-yl]-
S-heptenoic acid, methyl ester for ~1~,2(5Z),
3a,4~]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-
hept-2-yl]-5-heptenoic acid,. methyl ester, the
title compound is obtained as an oil.
Anal. Calcd. for C20H34O4
Found: C, 70.93; H, 10.33
3C NMR (C3C13, 15.0MHz)tau 178.7, 33.4, 24.6,
26.6, 128.7, 129.9, 32.6, 47.9, 79.1,
29.5, 23.8, 80.5, 49.1, 71.7, 71.2, 31.6,
25.8, ~9.9, 22.6, 13.9
:`
'
` HA290/280
- -21~
Example 7
[1-~,2a(5Z),3a,4~]-7-[3-Methyloxy)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 1 and
2 except substituting methyl methanesulfonate
for n-hexyl methanesulfonate, the title compound
- is obtained as an oil, [a]25= ~10.4
(C=2.21, CHC13~.
Anal. Calcd. for.C~5X24O4: C, 67.14; H, 9.01
Found: C, 67.03; H, 9.14
3C NMR ~CDC13, 15 0MHz) tau 178.3, 33.2, 24.4,
25.5, 129.5, 129.8, 26.5, 46.5, 79.:L,
29.3, 29.3, 79.g, 46.2, 71.7, 58.6.
~ HA~90/280
-22-
Example 8
Ll~._a(5Zl.3~.4Rl-7-[3-~tProPYloxY)m~hy~
oxabicycloL2.2.11hePt-2-v~ 5-heptenoic acid
Follo~ing the procedure of Example 6, excep~
subs~ituting n-propylbromide for n-hexylbromide, the
title c~mpound is obtained.
~ xample 9
(lR.2~.3~4~)-7-~(3utyloxy)methY11-7-
10. oxabicYclol2.2.llhe~t-2-~llheptano-ic acid
Following the procedure of Examples 4 and S
eXcept subatituting n-butyl methanesulConate for
n-hexyl m~thanesul~onate. the title compound is
obtal~d.
-15
ExamPle 10
~lB.2~5Z),3~.4~1-7-t3-1(OctYloxY)methvll-7-
oxabicvclot2.2.Llhe~t-2-yll-S-heptenoic_acid
Pollowing the procedure of Examples 1 and 2
e~cept sub6tituting n-octyl methanesulfonate for
n-hexyl methanesulfonate, the title compound is
obtained.
ExamP-le 11
~,2~5Z),3~,~81-7-~3-~(PhenYloxy)methyll-7
oxabicYclot2.2.1lhePt-2-vll-s-he~tenoic acid
(a) Phenol (1 mmol) is added to a solution of
triphenylphosphine (1 m~ol), diethylazodicarboxy}ate
(1 mmol) and title A alcohol from Example 1 ~1 mmol)
in 25 ml THF and is stirred under an argon
.
HA290/280
. -23~
atmosphere for 48 hours at 23C. The reaction
mix~ure is concentrated in vacuo. The residue is
triturated with ether and the solids are removed.
The filtrate i5 concentrated in vacuo and
~j chromatographed OEl silic3 gel to give
tlB,2~(5Z),3~.4B~-7-t3-t(phenyloxy)~ethyl]-7-
oxabicyclol2.2.1]hept-2-yl3-5-heptenoic acid, methyl
ester.
(b) Pollowing the procedure as set ou~ in
Example 2. the ester ~ro~ part (a) is convereed to
the title compound.
Exa~Ple 12
15 J~ g(SZ) ~3~.4Rl-7~ t (PhenYlox~r)meth~
7-oxab~cYcloL2.2~11he~-2-Yll-5-he~tenoic acid
(a) Phenol (1 mmol~ i5 added to a so}ution of
. triphenylphosphine (1 mmol~, diisopropylazodi-
carboxylate (1 mmol) and title A alcohol fro~
Example 1 (1 mmol) in 25 ml THP and is stirred under
an argon atmosphere for 48 hours at 23C. The
reaction mixture is concentrated in vacuo. The
resiaue is triturated with ether and the solids are
removed. The ~iltrate is concentrated in vacuo and
chromatogra~hed on si}ica qe} to give
tl~2~(5z)~3B~4A]-7-t3-t(phenyloxy)methyli-7-
oxabicyclot2.2.1]hept-2-y}]-5-heptenoic acid, methy}
ester.
~;æs6ss~
HA290/280
. -24-
tb) Following the Procedure as set out inExample 2, the ester from part (a) is converted to
the title compound.
S Exampls L3
llB,2~(5Z)~3~,4~1-7-t3 t(Ethvlox~lmethY11-7-
ox~bic~clot?.2.11heue-2-Yll-s-heQtenoic acid
Following the procedure of Examples 3 and 2
except substituting ethylbromide ~or n-hexylbromide,
the title compound is obtained..
Exa.mPle 14
Ll~.2~ AL-7-t3-L~phenyloxylmQthyll-7-
oxabicvcloL2.~ ept-2-~llheptanoic acid
Following the, procedure o~ Example 11 exc~pt
substituting (1~,23.3~.4~)-7-~3-~(hydeoxy)-
methyl]-7-oxabicyclo~2.2.1~hep~-2-yl~heptanoic.a.cid,
methyl ester ~or the alcohol o~ part (a) of
Exam~le 11, the title compound is obtained.
Example 15
tlR.2~(5Z~.3~.4~1-7- r 3 r (~enzyloxYlmethyll-7=
oxabic~clor2.2.Llhept-2-vll-5-heptenoic acid
Following the peocedure o~ 2xample 6 except
~ub~tituting benzylbromide ~o~ n-hex~ylbeomide, the
title compound is ob~ained.
.~.. i .
5~
_ HA290/280
_ .
-25- - .
Example 16
(1~,2l,3~L~)-7:[3-[(~enzYloxyimethyll-7-
oxabicvclo~2.2.11he~t-2-vllhePtanoic acid
Following the procedure of ~xamples 4 and 5
S except substitu~ing benzyl methanesulfonate fo~
n-hexyl methanesulfonate, the ~itle compound is
obtained.
~xam~le L7
t~ 25~s2~3~4Rl-7-~3-L~clohexylox~r)methyll-7
oxabicYclo~2.2.~1hePC-2-Y11-5-hePtenoic acid
Following the procedure of Examples 1 and 2
except subætituting cyclohexyl methanesulfonate for
n-hexyl methanesulfonate, the title compound is
obtained.
Exam~le la
tl~.2~(5Z) I~.4~1-7-13-L(CvcloPentyloxy)methyll-7
oxabicyclo~2.2.11he~t-2-~11-5-heptenoic acid
Following the procedure of Examples 1 and 2
except substituting cyclopentyl methanesulfonate for
n-hexyl methanesulfonate, and substituting
tl~ (5Z).3~.4~]-7-~3-(hydroxymethyl)-7
oxabicyclot2.2.1]hept-2-yl]-5-heptenoic acid, methyl
ester (prepared as described in U. S. Patent No.
4,143,054) for tl~.2~(5Z),3~.4~]-7-t3-
(hydroxymethyl)-7-oxabicyclotZ.2.1]hept-2-yl]-5-
heptenoic acid. methyl ester, the title compaund is
obtained.
~2~7
HA290~280 `
-26-
Example l9
(1~,2c~3~,4~1-7-L3-~(CYclohexyloxylmethYl]-7-
oxabic~cloL2,2.llhe~-2-~llhe~tanoic acid
Pollowing the procedure of Examples 4 and 5
except substituting cyclohexyl methanesulfonate for
~-~exyL ~e~hanesu~nate. the tit~e com~o~nd is
oh ta ined .
~1~,2~Z~.3~,4~1-7-~3-12-~HexYloxY-ethYll-7-
oxabicyclc~Z.2~L1hept-2-Yll-5-heQtenoic- acid
A. LlB .2~(5Z).3~,4RI-7-~3-(2-Oxo) ethYIl-7-
oxabi~Yalo t 2 . 2 . 11 hQPt-2-Yl 1 -S-hePteno~c
~n~o a dry 100 ml round bot~om 3-n~cked
containing a stir bar was added dried 12.9 g t37.7
mmoles) methoxymethyltriphenylphosphonium chloride
(~ 6~5)3P -CB20~3Cl ) and Z35 ml
distilled toluene (stored over molecular sie~es).
The resulting suspension ~as stirred in an ice-bath,
under argon. until cold and then a L.SS ~ solution
of 18.3 ml t28.3 mmol) of potassium t-amylate in
toluene was added dropwise. A bright red solution
formed Which was stirred at 0C for an additional
35 minutes. Thereafter, a solution of 4.97 g (18.8
m~ol) ~,2~t5Z),3~,48]-7-t3-formyl-7-oxabi-
; cyclot2.2.l]hept-2-yl~-5-heptenoic acid, methyl
ester in 60 ml toluene was added by means o~ a
dropping ~unnel over a 35 minute period with the
ice-bath still in place. The reaction was then
quenched by addieion of 2.3 g t39 mmol) acetic acid
HA2so/280
-27-
ln 5 ~1 ethe~. The reaction ~ixture immed~ately
tu~ned pale yellow and was immediat~aly pou~ed into
200 ml satura~ed NH~Cl. and ext~acted ~lth e~he~
(4 x 200 ml). ~he oo~bined ether plases ~ere washed
with NaCl saturated solution, and dried (MgSO4)
and concentra~ed to yiela a yellow oil in a white
crystalline solid 5phosphine oxide). The white
~olid wa6 triturated with ~tOAo and the mo~her
liquo~ wa~ purifiea by chromatography on an LPS-l
sillca colu~n. ~he fractions obtained were (A)
tlB,2~(5Z).3~.4B]-7-t3-t2-oxo)ethyl-7-oxabi-
cyelot2.2.1]hept-2-yl]-5-heptenoic acid, methyl
ester, (B) tlB,2~5Z),3~.4~]-7-t3-(2-methoxy~-
ethendiyl~~7-oxabicyclo~2.2.1~hept-2-yl]-5-hepterloic
acid,. methyl eaterj and (C)' tlH.2~$Z).3~.4~]~
7-t3-(2,2-di~ethoxy)ethyl-7-oxabicyclot2.2.1~hept-2-
yl]-S-heptenoic aci~, methyl ester.
Compounds (~) and (C) a~e each trea~ed with
trifluoroacetic acid to convert each to oompound (A).
B. tl~.2~5Z-.3~.4~1-7-r3-(2-~Ydr~xvethYll-
7-oxabic~clor2.2.11hept-2-Yll-5-hePtenoi
acid, methYl ester
The aldehyde (1.4 g, 5 ~ol) ~rom part A in
25 methanol (50 ml) was treated with Na~Hg (0.19 ~,
5 mmol) in an argon at~osphere at 0C. After
st~ring at 0 ~o~ 1 hour. the ~eaction was
quenched by addition of 2N HCl (to p~ 2). The
methanol was ~e~oved in vacuo and the reaction
- 30 mixture was taken up in ether. The ethe~ solutlon
* Trade Mark
HA290/280
_ -28-
.
was washed with saturated KHC03, saturated NaCl
and d~ied (~gS04). The ether was e~aporated to
yield the title B compound.
C. ~LB,2~5Z)L3n~4~ 3-t2-tHex~loxY~-
sth~rll-7-oxabicYelor2.2011hePt-2-Yll-S-
he~tenoic acid
Following the procedure of Examples 1 and 2
- excep~ substituting ~he above part B alcohol for Che
alcohol us~d in Example 1, the titl.e compound is
obtained.
tl~.20t~5Z)..3~9..4~1-7-t3-L~-(H~xYlox~,r)ethYl1-7-
oxabicvclot2.2.11hePt-2--Yll-$-hePtenoiC acid
Following the procedure of Example 20, except
; substituting tl~,2~(5Z),3R,4~]-7-t3-formyl-
7-oxabicyclo[2.2.1]hept-2-yll-5-heptenoic acid,
methyl es~er for tl~2~(5z)~3~4B~-7-E3-
formyl-7-oxabicyclo~2.2.1~-hept-2-yl]-5-heptenoic
acid, methyl ester, the ~itle compound is obtained.
~xam~le 22
2~L3c~ 4B) -7- r 3- r z- ~Hexyloxy~ ethyl l -7 -
oxabicvclot2.2.1~ePt-2-Yll-5-hepta-oic acid
Following ~he procedure o~ Example 21 except
substituting (l~,Z~,3a,4~)-7-t3-formyl-7-
oxabicyclot2.2.1]hept-2-yl]heptanoic acid, methyl
ester ~or tlB,2~(5Z),3~,4~]-7-t3-formyl-7-
oxabicyclot2.2.1lhept-2-yl]~-5-heptenoic acid, methyl
ester, the title compound is obtained.
, .
5~37
HA290/280
-29-
Example 23
rL~2(sz)~3R~4~l-7-l3-~2-~phen~lox~ethvll-7
oxabicyclor2.2.11hept-2~yll-5-he~tenoic acid
Follo~ing the procedure of Example 11 except
substituting tl~,2c(52),3~,4~-7-t3-[2-
(hydroxy)ethyl]-7-oxabicyclot2.2.1~hept-2-yl]-5-
heptenoic acid, methyl ester for tlB,2~(5Z),-
3~,4B]-7-[3-(hydroxymethyl)-7-oxabicyclo~2.2.1]hept-
2-yl~-S-heptenoic acid, methyl ester, the title
compound i~ obtained.
ExamPle 24
5~,2~(5Z~,3B,4Bl-7-~3-L2-~PhenYlox~ethY}]--7
oxabicYalo~2.2~1~he~t-2-Yll-5-hep-tenoic-acid
' Followinq the ~cocedure of Example 12 except
~ubs~i~uting tl~.2~(5Z).3~.4~-7-~3-t2-(hydroxy)-
ethyl~-7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic
acid, methyl ester ~or t1~,2~5Z),3~,4~]-1-~3-
(hydroxy~ethyl)-7-oxabicyclo~Z.2.1~hept-2-yl)-S-
heptenoic acid, methyl ester, the titl~ compound is
obtained.
Exam~le 25
(1~L2~.3~-4B)-7- r 3-~2-~PhenvloxY)eth~11-7-
oxabic~clo~2.2.11hept-2-~Llhe~tanoic acid
Following the procedure of Example 11 exGept
substituting (1~,2~,3~,4~)-7-t3-t2-(hydroxy)-
ethyl~-7-oxabicyclot2.2.1]hept-2-yl]heptanoic acid,
me~hyl e6ter for tl~2~tsz)~3~J4~]-7-t3-
(hydroxymathyl)-7-oxabicyclot2.2.1]hep~-Z-yl~-S-
heptenoic acid, ~ethyl ester, the title compound is
obtained.
.
_ - HA290/280
-30-
Exam~le 26
rlB~2~(5z2~3~4Rl-7-~3-~2-(Benzyloxy)ethyll-7
oxabicyclo~2.2.11he~t-2-~11-5-heptenoic acid
Following the ~rocedure of Exan~ple 20 except
substituting benzyl methanesulfonate for n-hexyl
methanesulfonate, the title comp~und is obtained.
ExamPle 27
r L~,2~(5Z),3~,4~1-7-~3- r 2-~enzYloxY)ethyll-7
oxabicYclot2.2.11hePt-2-Y11-5-hePtenoic acid
Followin~ the p~ocedure of Example 21 except
aubstltuting benzyl methanesul~onat3 for n~hexyl
~ethanesul~onate, the title com~ound is obtained.
ExamPle 2
rl~.2~tsz) ,3e~4~l-7~L3-~2-(~cloPe-ntvloxy)eth
7-oxabicyclor2.2.11hePt-2-~11-5-heP_enoic acid
Following the procedure of Example 20 except
substitutinq cyclopentyl ~ethanesulfonate for
n-hexyl methanesulfonate, the title compound is
o~tained.
Example 29
SlB,2~(5ZI,3~,4131-7-~3-L2-tC~clohe~loxY)ethYl'1-7-
oxabicYclo~2.2 11hePt-2~ 5-hePtenoic aci~
Following the procedure of Example 20 except
substituting cyclohexyl methanesulfonate for n-hexyl
methanesulfonate, the title compound is obtained.
~25~
. HA290/280
31
.
Example 30
r 1~ . 2~(5Z).3~,4~1-7-t3-t4-(HexyloxYlbutY11-7-
oxabicYclot2.2.11he~t-2-Yll-S-hePterloic acid
~ ,2~(5Z~,3~,4~1-7-~3-(3-Oxo)pro~Yl-7-
S oxabicyclor2.2.11he~t-2-yll-5-hePtenoic
acid, ~ethvl_ester
Following the procedure o~ Example 20,
part A except substituting tl~,2~(5Z),3~,4A]-7-
13-(2-oxo)-ethyl-7-oxabicyclot2.2.1~hept-2-yl~-S-
hep~enoic acid, methyl ester for tl~,2~(5Z),3~,-
4R]-7-~3-~ormyl-7-oxabicyclot2:2.1~hept-2-yl]-5-
heptenoic acid. methyl ester, the title A compound
~ ~bta~ne~l.
B . ~ 2~ (5 Z l . 3~ . q~ 1~7 - ~ 3 - ( 4 -~xo l~u tY1~7 ~
oxablc~lot2~2-llhept-2-vll-5-heptelloi~
ac d~th~l ester .
: ~oll~wing the p~o~edure of~~xa~ple zo ~ part A,
except substiCuting the aldehyde from part A a~o~e,
~or tl~,2Q~5Z).3~,4B~-7-t3-for~yl-7-oxabicyclo-
2.2.1~hept-2-yl~-$-heptenolc acid, methyl ester,
the title B aldehyde is obtained.
c . r lB 2~t SZ~ . 3~. 4R~ 3- (~-HYdroxYbutYl) -
7-oxabicYclor2~2~11hept-2-Yll-S-heptenoic
acid, m~thYl ester
Following the procedure of E~ample 20, part B,
exc~pt substiCuting the title B aldehyde ~o~
~1~,,2~(5Z) ,3~"4~1-7-~3-(2-oxo)ethyl-7-oxabi-
cyclo[2.2.1]hept-2-yll-S-heptenoic acid, methyl
ester, the title C alcohol is obtained.
' ''~ A2 gO/ 2 8 0
~ -32-
I)-. r 1~, 2~ ( 5Z ) . 3~, 4~1-7 13 - ~ 4- ( Hex~loxY ) -
but~ll-7-oxabic~clot2.2.1lhe~t-2-Yl]-5-
hePtenoic acid
Following the procedure of Examples l and 2.
except substituting the above part C alcohol for the
alcohol used in Example l, the title compound is
obtained.
.
Example 31
o .r 1~, 2~(5Z)~3~,4~l-7-r3- r 4=tCYclohexYloxv)butYl~-7-
oxabicvclol2.2.11he~t-2-Yll-S-heptenoic,acid
Following the procedure oS Example 30 except
substituting cyclohexyl methanesul~onate ~or n-hexyl
~ methaneaul~onat~, the ti~l~ com~ound is obtained.
ExamPle 32 .
~lB,2c~(5Z~.3~.,4Rl-7-r3-r4-(PhenYloxyLbutyll-7- .
oxabicYclor2.2 llhe~t-2-Yll-5-he~enoic acid
Following the procedure of Example 11 except
subatituting ~lB,2~(5Z),3~,4~]-7-t3-(9-
hydroxybutyl)-7-oxabicyclot2.2.1]hept-2-yl]-5-
heptenoic acid, ~eChyl ester for ~lR,2(5Z),-
3~4~]-7-t3-(hydroxymethyl)-7-oxabicycloE2.2~l]hept
2-yl]-S-heptenoic acid, methyl ester, the title
compound is obtained.
.
Example 33
~}B,2~(5Z~,3~,4~1-7-~3-~4-(BenzvloxY~butY11-7-
oxabicYclot2.2.1lhept-2-Yll-s--heptenoic acid
~ollowing the procedure of Example 30 except
substituting benzyl methanesulfonat for n-hexyl
~ethanesulfonate, the title compound is obtained.
.
~ 35
.
, ~ , ,
'
HA290/280
-33- -
Example 34
Tris~h~dromethYl~aminomethane salt of
2Q(SZ~.3~.4~l-7-r3~ exYloxY)methY1~-7-
oxabicvclo[2.2.11hePt-~-ylt-5-heptenoic acid
A solution of the compound formed in Example 2
in methanol is treated with an equivalent amount of
tris(hydromethyl)a~inomethane. The solvent is
removed by eva~oratio~ to yield the title compound
as a solid, m.~. 68.5-70C. TLC (silica ~el,
10 8~ CH30H/CH2C12)Rf=0,74,
Anal. Calcd. for C24H4507N: C,62.72; H,9.87; N,3.04
Found: C,62.71; H,3.80; M,3.10
Exam~le 35
15 ~lA.2~5Z)L3~.4~1-7-~3-L2~(PentYloxY)ethYll-7
oxabicycloL2.2.11hept-2-Yll-5-heptenoic acid
A. ~1~,2~(5Z),3~,4~L-7-t3-~2-(PentYlox~)
ethYl1-7-oxabicYclo~2.2~1lhePt-2-yll-5
he~tenoic acid,_~_nt~l ester
A mixture of powdered KOH (0.36 g) in 15 ml
of dry xylene was heated to re~}ux under argon
atmosphere and 6 ml of xylene was removed by
distillation. To this mixture was added a solution
of 200 mg (0.71 mmol) of Example 20, part B,
alcohol methyl ester in 17 ml of dry xylene. The
volume of the reaction mixture was reduced 15 ml by
distillative removal of xylene. To the reaction
mixture ~as then added a solution of 0.5 g (3.55
mmol) pentylmesylate in 10 ml of dry xylene. This
30 ~ixture ~as refluxed for 2 hours and 30 minutes.
The cooled reaction mixture was diluted ~ith 50 ml
of saturated Na~C03 solution and extracted with
CH2C12 (3 x 60 ml). The combined C~2C12
HA290/28
-34-
extracts were dried (MgSO4), filte~ed and
concentrated ln vacuo. Purification was ~ffected
by fla h chromatography on 33 g of silica gel 60
usin~ hexane:ether ~5:1) as eluant. This gave
238 ~g of title pentyl ester (83~) a~; a colorless
oil. TLC: silica gel, hexane:ether (1:1).
B. ~ 2~5Z~.3~4~1-7-L3-12-(Pent~lox~-
ethY11-7-oxabic~cloL2.2.LlhePt-2-~11-5-
hePtenoic acid
To a stirred solution of 238 mg (0.58 mmol)of pentyl ester from Part A, 26 ml of distilled
THF, 2.1 ~1 of CH3OH and 3.4 ml of H2O under
argon was added 6.4 ml o~ lN aqueous lithium
lS hyd~oxid~ solution. This mixturo was purg~d ~ith
a~gon vigorously ~o~ 30 mlnutes and stirred at coom
temperatur~ ~oc 7 hou~. The reaction mixture was
~cidified to pH 3 b~ the addition of lN aqueous HCl
solution. The ~esulting solution was poured into
50 ml of saturated NaCl solution and was saturated
with solid NaCl. The aqueous layer was extracted
w~th EtOAc (4 x 60 ~1). The combined E~OAc
extracts were dried (MgSO4), filtered and
concentrated in vacuo. This was chromato~raphed on
24 g of silica gel 60 using 3% CH30H in
CH2C12 as eluant to give 181 m~ (92~) of title
pur~e acid, T~C: silica gel, 4% CH3OH/CH2C12,
R~0.30, vanillin.
Anal. Calcd. for C20 34 4
C20H34O4 0.22 H2O: C, 70.16; H, 10-14
- Found: C, 70.16; H, 9.87
CNMR ~CDC13, 15.0MHz)tau 173.5, 33.8, 24.7, 26.7,
; 129.5, 130.1, 28.0, 43.8, 79.8, 29.5, 29.5, 30.3,
47.3, 29.7, 71.0, 70.3, 28.7, 22.4, 28.3, 13.9,
64.3, 28.3, 22.2, 28.3, 13.9
HA290/`280
_
-- ~xamPle 36
LlB~2~(sz)~3~4Bl-7-~ u~o~)-
ethY11-7-oxabicyclo~2.2,.1lhePt-2-~l1-S-he~tenolc
acid
A. r 1~ .2~5Z~.3~4~l-7- U3-Phen~lpro~oxy)-
meth~ 7-o~abicYclor2.2.;1he~t-2-yl]-5-
hepte~oic acid, Phenylpro~ ester
A mixture of powdered KOH (~.59 g) in 16 ml
of d~y xyle~e was heated tG reflux under argon
atmosphere and 9 ~l of xylese was removed by
distillation. To this m~xture was added a solu~ion
o~ 410 mg (1.53 mmol) oS Exa~ple l. part A, alcohol
~ethyl est~r in 10 ml o~ dry xylene. The volume of
the reaction ~i~ture was ~educed 6 ml by
di~tillati~e removal o~ xylene. To the reacton
mixture was then added a solution of 1.66 g (7.58
~mol) of 3-phenylpropylmesylate in 36 ml of dry
~ylene. Thi~ mixture was refluXed for 1 hour. The
cooled reaction mixture was diluted with 50 ml of
~atu~ated NaHC03 solution and extracted with
C~2C12 (3 x 50 ~l). The combined CH2C12
extracts were dried (MgS0~), filtered. and
concentrated ln vacuo. P~rification was effected
by flaah chromatography on 40 g of silica gel 60
using hexane:ether ~3:1) as eluant. This gave
0.61 q of ~itle phenylpropyl ester (al~) as a
colorles~ oil. TLC: silica gel, 2
C~3OH/C~2Cl2, Rf: .60, iodine.
HA290/.
~36-
B. LL~2~ L~3~.4~l-7-~(3-PhenYlpro~oxY)-
me~hYl1-7-oxabicyclo~2.2.11hePt
heptenoic acid
: To a sti~red solution of 610 mg (1.24 mmole)
S o~ title A phenyl~ropyl efiter, 55 ml o~' distilled
. T~F, 4.40 ml of C~30~ and 7.30 ml of H20 under
a~gon was added 13.7 ml o' lN aqueous lithium
hydroxide solution. This ~ixture was purged with
argon vigo~ously for 30 minutes and stirred at room
te~pe~atu~e foE 14 hours. The rea~tion mixture was
dlluted with 100 ml o~' 0.1 N aqueous lithium
hyd~oxide solution and ~ashed once with lOO ml of
hexane. The eeactio~ mixture was acidi'ied ~o pH 3
by the a~dition of lN aqueoua HCl ~olution and was
pour~d into 100 ml o' saturated NaCl solution. rrhe
resulting mixtu~e was satu~ated with solid NaC1 and
ext~acted with EtOAc (4 x 150 ml). The combined .
EtOAc extracts were d~ied (~gS04), filtered and
concentrated in va~uo. This was ch~oma~ographed on
44 g o' silica gel 60 using 4~ C~30H in
C~2C12 as eluant to give 3ao mg (a2%) of pu~e
title acid. TLC: silica gel, 4
CH30H/CHzCl2, Rf30.30. iodine.
Anal Calcd fo~ C23H3204
23~324 0 35 K20: C, 72.94; H, 8.70
Found: C, 72.94; H, a . 49
3C NMR (C~C13, 15.0MHz)tau 17~.7, 33.4, 24.5,
25.7, 129.5, 130.1, 26.6, 46.3, 7q.3, 29.5,
30.1, 46.8, 70.2, 69.9, 31.2, 32.3, 141.9,
128.4, 128.4.
,
- HA290/280
-37-
ExamPle 37
~lfl,Z~SZl,3~.4~1-7-[3-t(Octyloxy)methyll-
7-o~abicyGlot2.2.11hept-2-yll-S-heptlnoi _acid
A. ~l~,2~tSZ),3~,4fll-7- r 3- ~ ~OC tYlox~- `
methyll-7-oxabicYclO~2.2.11hePt-2-Y11-5-
To a sti~red solution o~ 50~ mg (1.89 mmol)
of Examele 1, Part A, ester alcohol in 2.69 ml THF
was added in order 2.69 ~1 (L5.6 m~ol) of n-octyl
bromide, 642 mg ~L.89 mmol) o~ te~rabutylammonium
hydrogen sulfate and 2.69 ml of 50~ aqueous sodium
hydroxide solutio~. This mixture was stirred aC
roo~ temperature in dar~naas for l9 hours. The
reaction mixture was poured lnto 25 ml of saturatQd
lS sodiu~ bicarbonate solution and extracted with fo~r
25 ml portions of C~2Cl2. The co~bined
C~2C12 extracts were dried (MgSO4), filtered,
and concen~rated ln vacuo. Purlication was
effected by flash chromatography on 39.6 g of
silica gel 60 using hexane:ether (3:1) as eluant to
gi~e 333 m~ ~37~) of octyl ester and 250 mg of a
~ixed band of octyl ester and corresponding methyl
ester. TLC: silica gel, 3~ C~3OH/C~2Cl2,
Rf:octyl este~, 0. a5; me~hyl ester, 0.80, iodine.
B~ ,2~(5Z),3~ 7~ (OctYlox~l-
met~ -7-oxablcYclo~2.2.llhePt-2-vll-5-
he~tenoic acid
To a stirred solution of 333 mg (0.70 mmol)
of Part A octyl eseec in 31 ml of distilled THF,
~ HA290/280
-38-
2.50 ml of CH30H and 4.1 ~1 o~ H20 under argonwas added 7.70 ml of lN aqueous lith;.um hydroxide
solu~ion. This mixture was purged with argon
vigorously for 20 minutes and stirred at room
temperatu~e for 16 hours and 30 minutes. The
~ixture of octyl ester a~d corresponding methyl
es~er was hydrolyzed in the exact sa~e manner. To
a stirred solution of this mixture (250 mq) in
29 ~1 of distilled THF, 2.40 ml of C~30R and
3.9 ml of H20, ~as added 7.30 ml of lN aqueous
lithium hydroxide. This mixture was purgsd with
argon vigorously ~or 20 minutes and stirred at room
tempe ature for 16 hours and 30 minutes.
These 2 reaction mixtures were com~ined and
dlluted with a solutlon of 120 ~l of 0.1 N aqU~ous
lithium hydroxide solution and 50 ~1 of H20. The
resulting mixture was extracted once with 220 ml of
hexane. The aqueous layer was acidified to pH 3 by
the addition of lN aqueous HCl solution ~aturated
with solld NaCl, and extracted with EtOAc
(4 x 150 ml). The hexane extract and EtOAc
ex~racts (hexane extract contained the desired
- acid) were combined, dried (~gS04), filtered and
concen~rated in vacuo to give 0.53 g of c~ude
product. This was chromatographed on 4~ g of
silica gel 60 using 3~ CH30H in CH2C12 to
gi~e 222 mg (45%) of desired ti~le acid. TLC:
silica gel, 4~ CH30H/CH2C12, Rf=0.40.
vanillin
~nal CalCd for C22H3804: C. 72-09; H- LO-45
C22H3804 0.24 H20: C. 7L.25: H, 10.45
; Found: C, 7L.25: H, 10.20
.
HA290/280
-39-
3C NMR ~CDCl , 15.0mHz)tau 178.7, 33.8, 24.9,
26.2, 129.6, 130.0, 26.8, ~6.5, 79.3,
29.5, 29.5, 80.1, 46.9, 71.2,~69.9, 31.7,
29.7, 29.2, 28.7, 25.9, 22.6, 14.0, 64.4,
31.7, 29.7, 29.2, 28.2, 25.8, 22.6, 14Ø
. ~
- methvll-7-oxabic~clo~2.2.11hept-2-yl~-5- heQtepoic
acid
A. LlB,2~1sZ),3~,4Bl-7-L3-~yclohexYl-
meehoxY~meth~ Z~ xabicYclo~2.2.11he2t-2-
YlL-5- heptenoic acid, cYclohexylmeth
estQr
A mixture o~ powde~ed KO~ (0.56 g) in 15 ml
o~ dry xylene was heated to reflu~ unde~ argon
atmosphere and 7 ml of xyle~e was removed by
distillation. To this mixture was added a solution
of 300 mg (1.12 mmol) of Example 1, Part A, alcohol
methyl ester in 10 ml of dry xylene. The volume of
the reaction ~ixture was reduced to 11 ml by
distillative removal of xylene. To the reacton
mixture was then added a solution of 2.47 g (12.9
mmol) cyclohexylmethylmesylate in 10 ml of dry
xylene. This mixture was refluxed for 5 hours.
The cooled reaction mixture was diluted with 50 ml
of saturated NaHCQ~ solution and extcacted with
CH2C12 (3x50 ml). The combined CH2C12
extracts were dried (~gSO4), filtered a~d
concentrated in vacuo. Purification was affected
by flash chro~atography on 35 g of silica ge} 60
using 1~ CH30H in C~2Cl2 aa eluant. This
gave 0.46 g o~ title hexyl es~er (93%) as a
colorless oil. TLC: silica gel, 2
; 35 C~3OH/C82C12, Rf , 0.80, iodine.
~2~
HA290/280
-40-
B. r~,2n(5Z~,3~,4~l-7-r3-tCYclohexYl-
me~hoxy~methyll-7-oxabicyclo[2.2.1lhePt-2-
yll-5- heptenoic acid
To a stirred solution of 460 mg ~1.03 mmol)
of Part A cyclohexylme~hyl ester, 45 ml of
distilled THF, 3.80 ml of CH30H and 6.10 ml of
H20 under argon was added 11.~ ml of lN aqueous
lithium hydroxide solution. This mixture was
purged with argon vigorously for 20 minutes and
stirred at room temperature for 16 hours. The
reaction mixture was diluted with 83 ml of 0.1 N
aqueous lithium hydroxide solution and washed once
with 83 ml of hexane. The aqueous layer was
acidi~ied to pH 3 by the addition of l~ aqueous EICl
solution and saturated with solid NaCl. The
resulting aqueous layer was extracted with EtOAc
(4x120 ml). The combined EtOAc extracts were dried
(MgS04~. filtered and concentrated in vacuo to
give 0.32 g of crude product. This was
chromatographed on 34.6 g of silica gel 60 usiny 3%
CH30H in CH2Cl2 as eluant to give 278 mg
~77%) of pure title acid. TLC=silica gel, 4%
CH30HtCH2Cl2, Rf=O. 2a ~ iodine.
~nal. Calcd for C2lH3404: C. 71.g6; H. 9-78
C2lH3404 0.31 H20: C, 70.84, H, 9.80
Found: C, 70.B4: H, 9.68
C NMR (CDC13, 15.0MHz)tau 173.5, 33.7, 24.9, 25.3,
129.5, 129.9, 26.0, 46.4, 79.2, 29.6, 29.6,
79.~, 46.8, 70.0, 77.~, 37.9, 30.0, 2607,
~5.8, 26.7, 30.0, 69.3, 37.1, 29.1, 26.3,
25.6, 26.3, 29.1
..~
~5~ HA290/280
41-
Example 39
l[a,2~(Z),3~,4al-7-[3-[[(l-methylhexyl)oxy]-
methyl]-7-oxobicyclo[2.2.lJhept-2-yl]-5-
heptenoic acid
By following the procedures of Examples 1
and 2 except substituting l-methylhexyl methane
sulfonate for n-hexylmethanesulfonate, the titled
compound is obtained, TLC (selica gel,
4% CH3OH/CH2C12) Rf = 0-47- .
Anal. Calc 21 36 4
~ Found: C, 71.73; H, 10.21
3C NMR tCDCl , l5.0MHz)tau 178.8, 33.4, 24.6,
25.7, 129.4, 130.2, 26.7, 46.4, 79.5,
29.5, 80.1, 47.1, 67.5, 75.9, 36.7, 25.3,
lS 31.g, 22.6, 1~.0, 19.7
Example 40
{la,2~(Z),3~,4]-7-[3-[(3-hexynyloxy)methyl-7-
oxabicvclo[2.2.1]hept-2-vl]-5-heptenoic acid
By followlng the procedures of Examples 1
and 2 except substituting 3-hexynylmethane-
sulfonate, the titled compound is obtained as an
oil, TLC (silica gel, 4~ CH3OH/CH2C12) Rf 0-32
Anal. calcd for C20H30O4: C,
Found: C, 71.66; H,9.21
C NMR (CDC13, 15.0MHz)tau 178.9, 33.4, 22.0,
24.5, 129.5, 130.0, 26.7, 46.4, 79.4,
~9.4, 29.5; ~0.0, 46.7, 69.0, 58.8, 76.1,
86.8, 22.0, 25.8, 13.4
~ ` HA290/280
-42-
Example 41
[1~,2a(Z),3(Z),4~]-7~[3 [(3-hexenyloxy)methyl~-
-- . _
7-oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid
By following the procedure of Examples 1 and
2 except substituting cis-3-hexen-1-mesylatè for
the n-hexylmethanesulfonate, the titled compound
is obtained as an oil. TLC ~silica gel,
4~ CH3OH/CH2C12) Rf = 0-3-
Anal. calcd. for C20H32O4: C,
Found: C, 71.10; H, 9.59
C ~MR ~DC13, 15.0~IHz)tau 178.9, 33.4, 24.5,
25.6, 129.5, 130.1, 27.7, 46.3, 79.3,
29.4, 80.1, 46.7, 70.7, 69.8, 26.6,
133.6, 124.8, 20.6, 14.2
Example 42
[1~,2~(Z),3a(Z),4~]-7-[3-[(2-hexenyloxy)methyl]-
7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
By following the procedure of Examples l
and 2 and substituting 2-1-hex-2-enyl-mesylate
for n-hexylmethanesulfonate, the ~itled compound
is prepared as an oil, TLC (silica gel,
2~ CH3OH/CH2C12~ Rf = 0.22, vanlllin.
Anal. calcd. for C20H32O4
Found: C, 70.97; H, 9.64
13C NMR (CDC13, 15.0MHz)tau 178.8, 33.4, 24.5,
25.8, 129.5, 130.1, 26.7, 46.4, 79.5,
29.5, 29.5, 80.1, 46.9, 69.3, 66.6, 133.5,
126.2, 29.5, 22.6, 13.6
-
EIA290/280
-43-
Example 43
[1~,2a(Z),3a,4a]-7-[3-[2-propenyloxy)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid,
and methyl ester
To a stirred solution of 310 mg (1.16 mmol)
of [ 1 ~ , 2a ( 5 Z ) , 3a,4~]-7-[3-(hydroxymethyl)-7-
oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic
acid, methyl ester in 1.34 ml
of tetrahydrofuran was added in order,
1.34 ml of allyl bromide, 107 mq of
tetrabutylammonium hydrogen sulfate and 1.34 ml
of 50~ aqueous sodiu~ hydroxide solution. The
mixture was stirred at room tempera~ure in darkness
for 23 hours and then poured into 30 ml of saturated
lS sodium bicarbonate solution and extracted twice
with 30 ml portions of methylene chloride. The
combined extracts were dried over magnesium sulfate,
filtered and concentrated to dryness in vacuo.
Purification was effected by flash chromatography
on 35 g of silica gel 60 using hexane-ether (2:1)
as eluant to give 220 mg of the methyl ester product,
~LC (sillca gel, hexane-ether ~l:l) Rf = 0.4, iodine.
The ester was dissolved in 36 ml of tetra-
hydrofuran along with a small amount of hydroquinone,
6 ml of water and 7 ml of lN aqueous lithlum
hydroxide solution and stirred at room temperat~ure
for 5.5 hours whereupon the reaction mixture was
poured into 80 ml of saturated aqueous sodium
chloride solution and was saturated with additicnal
solid sodium chloride. The aqueous layer was
extracted with 4 portions of ethyl acetate (125 ml
each), dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was chromato-
gxaphed on 30 g of silica gel using 4~ CH3OH/CH2C12
as eluant to give l90 mg of the acid product, TLC
(silica gel, hexane-ether (1:1)) Rf = 0.15.
r HA290/280
~44~
Anal. Calcd for Cl7 264
Found: C, 69.72; H, 9.05
C NMR (CDCl3, 15.0MHz)tau 178.9, 33.4, 24.5,
25.7, 129~5~ 130.0, 26~6~ 46~3~ 79.3,
29.4, gO.l, 46~7~ 69~3~ 72~0~ 134.7,
117.0
E~ample 44
[lB ,2a(5Z), 3a,4~] -7- ~3- ~ (Hexylthio)methyll -7
oxabicyclo [2.2. l~hept-2-yl]-5-heptenoic acid,
methyl ester
A. [1~,2~tSZ), 3a, 4~ ] -7- ~3- ~Hydro~ymethyl) -
7 oxabicyclo[2.2.11hept-2-yl]-5-heptenoic
acid
(a) A mixture of N-acetylpyridinium chloride
was prepared by addin~ 9.6 ml (136 mmole) of acetyl
chl~ride dropwise to 56 ml o~ pyridine. To thi~
was added S.0 g (27 mmole) of (exo)-3-~2-methoxy-
ethenyl)-7-axabi.cyclo[2.2.1]heptane-2-methanol
dissolved in 5 ml of pyridine. The resulting
mixture was stirred at room temperature for 1.5 hours
and poured into brine. The product was extracted
into ether (3 x 200 ml), the ether extracts were
washed with 5~ hydrochloric acid ~2 x 400 ml) and
brine (1 x 200 ml) and dried over sodium sulfate.
Concentration yielded a yellow oil whic~ was
purified by passage through a short column of
~ilica gel (150 ml) with dichloromethane, 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 was added 31.1 g (97.8 mmole) of
mercuric acetate. The yellow suspension which
formed was stirred for 10 minutes and then the
entire mixture was poured into a solution containing
200 g of potassium iodide in 2 1. of water. Upon
,
,
HA290/2~0
-45-
shaking, the yellow color disappeared and themixture was extracted with benzene (3 x 500 ml).
The combined benzene extracts were washed wi-th
potassium iodide solution and brine and dried
over sodium sulfate. Concentration yielded 3.7 g
of material which crystallized on ~tanding in an
ice box.
(c) A Wittig reagent was prepared in
lG dimethyl sulfoxide (dried over calcium hydride) by
adding a solution of sodium methylsulfinylmethide
~prepared by heating 300 mg of sodium hydride in
60 ml of dimethyl sulfoxide at 75 untll 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 orange color lasting more than 10 seconds
forme~jan equivalent amount of base was added to
orm the ylide. To this deep orange solution was
added a solution of the product of part (b) in 20 ml
of dimethyl sulfoxide and the resulting mixture
stirred at room temperature for 45 minutes. The
reaction was quenched by addition of 24 mmole of
acetic acid and the ~ixture poured into brine
(300 ml) and extra~ted with ether (3 x 200 ml).
Concentration of these extracts gives an oil which
was stirred with saturated sodium bicarbonate solution
until crystalline triphenylphosphine oxide formed
in the mixture. This mixture was washed with
benzene and acidified with 10% hydrochloric acid.
.
~25~
` HA2 9 n /~
-46- . ,
.
The aqueous layer was saturated with salt and
extracted with ether which on drying (sodium sulfate)
and concentration gave 2.43 g of crude product.
The mixture was stirred 24 hours with 10~ aqueous
sodium hydroxide and reisolated by acidification and
ether extraction. The product was purified on
- 500 g of silica gel with 50/50 ethyl acetate-hexane
as the eluant which gave 600 mg of acid which
crystallized on standing. This was recrystallized
twice from ethyl acetate-cyclohexana to yield 320 mg
of [1~,2a(5Z),3a,4~]-7-[3-~'hydroxymethyl)-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.
~. [1~,2a(5Z),3a,4S]-7-[3-(~-ToluenesulfonYI-
oxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-
5-heptenoic acid, methyl e5ter
To a solution of 300 mg (1.12 mmol) of
alcohol ester from Part A in 4 ml of dry pyridine
was added 427 mg ~2.24 mmolj of tosyl chloride.
The mlxture was stirred at room temperature under
an argon atmosphere for 10hours. The reaction
mixture was diluted with 300 ml of ether, washed
with lN aqueous HCl solution (3 x 100 ml), and
0.5 N aqueous NaOH solution (3 x 100 ml). The
ether layer was dried over anhydrous magnesium
sulfate and concentrated ln vacuo. Purification
3~ was effected by flash chromatography on 30 g of
. H.-~2so/2~a
-47- .
.
silica gel 60 using 50~ hexane in ether as eluant
to give 450 mg of title compound (95~). TLC~silica
gel, 4~ C~30H in C~2C12, Rf=0.80, iodine.
S C. [1~,2a(5Z),3a,4~]-7-[3-[~exylthio)methyl]-
?-oxabicy~o~[2_______Pt-2-yl]-5 heptenoic
acid, me~hyl ester
To a solution of 132 mg (1.17 ~mol) of
potassium t-butoxide in 10 ml of dry THF under argon
was added 378 mg (3.21 mmol) of l-hexanethiol. To
. this.mixture was added a solution of 450 mg
(1.07 mmol) of Part B tosylate in 5 ml of THF. The
reaction mixture was stirred at room temperature
under argon ror 2.5 hours and then heated to reflux
lS for 5.5 houxs. The cooled reaction was diluted
with 300 ml of ether and poured into lO0 ml of
saturated NaHC03 solution. The aqueous layer was
extracted with ether ~2 x 100 ml). The combined
ether extracts (S00 ml) were washed with O.SN
aqueous sodium hydroxl~e ~2 x 100 ml), brine (lO0 ml),
and then dried (MgS04), filtered and concentrated
ln vacuo to give 0.55 g of crude oil. Purification
was ef~ected by chromatography on 25.2 g of silica
gel 60 using 5:1 pet ether:ether as eluant to give
328 mg of title product as an oil (84~). TLC=silica
gel, petroleum ether:ether 3;2, Rf=0.55, iodine.
Example 45
,2a(5Z),3a,4~]-7-[3-[(Hexvlthio)methyl]-7-o~abicy-
c13 ~2.2 l]hept-2-vl]-5-he~tenoic acid
3 0 ~
To a stirred solution of 328 mg (0.89 mmol)
. . .
.
HA290/2~0
-48
of the Example 1 methyl ester in 43.8 ml of THF
~nd 6.67 ml of H2O under argon was added 8.40 ml
of lN aqueous lithium hydroxide solution. Thi-
~. mixture was purged with argon vigorously for
20 minutes and ~tirred at room temperaturA for
12.5 hours. The reaction mixture was acidi~ied
to pH 4 by the addition of lN aqueous HCl solution
and poured into 50 ml of saturated NaCl solution.
The resulting solution wa3 saturated with solid
NaCl and extracted with Et~Ac (4 x 50 ml). The
combined EtOAc extracts were dried (MgSO4~,
~iltered and concentrated in vacuo to give 295 mg of
crude acid. Purification was effected by flash
chromatogr~phy on 25 g of SiliCAR CC-7 using 2:3
petroleum ether:ether as eluant to give title
product (250 mg, 79%) as an oil. TLC:9ilica yel,
2:3 petroleum ether:ether, Rf~ 0.25, iodine.
Anal Calc'd for C20H3403S: C, 67.80; H, 9.61;
S, g.04
Found: C, 67.80; H, 9.85;
S, ~.14
3C NMR (CDCl3, lS.0MHz)tau 173.5, 33.1, 24.5,
25.6, 129.~, 128.8, 26.5, 45.9, 79.9,
~9.2, 28.8, 78.3, 45.9, 69.5, 144.5,
i29.7, 127.6, 132.1, 127.6, I29~7,
21.3,. Sl.l
Ex mple 46
(1~,2a,3a,4~)-7-t3-~(Hexylthio)meth~1]-7-oxabicyclo-
t2.2Ol]hep~-2-yl]-S-heptenoic acid, methyl ester
A.
acid, meth~l ester
: . To 800 mg (3.0 mmole~ of the tl~,2a(52) ,-
3a,4~]-7-13-(hydroxymethyl) -7-oxabicyc~o[2.2.1~-
* Trade Mark
l;~S~!3'7
H~29n~280
-49-
hept-2-yl]-5-heptenoic acid, methyl ester as
prepared in Example 1, dissolved in 120 ml of
ethyl acetate W~5 added, un~er a~l argon atmosphere,
160 mg of 5% Pd on carbon. ~he zlrgon atmosphere
was exchanged fsr a slight posit;~ve pressure of
hydrogen and the reaction was stirred for 8 hours
at 25, filtered through a Celite plug and evaporated
to provide 730 mg (90%) of the title A compound
B. (1~ ,2a, 3a,43) -7- t3-t(~ex~lthio)methyl~-7
oxabicyclot2.2.1]hept-2-yl~ hept~noic
acid, methyl ester
Following the procedure of Example 1
except substituting the Part A alcohol-ester for
the Example lA alcohol ester, the title product is
obtained.
Exam~le 47
~lB,2,3a,4~) -?- [3-[(Hexylthio)meth~1]-7-oxabicyclo-
[2.2.1]he~t-2-yl]-heptanoic acid_
Following the procedure of Example45 except
substituting the Example 46methyl ester ~or the
Example 45methyl ester, the title acid is obtained~
Exam~le 48
[lB,2~(5Z),3B,4~]-7-[3-[(PeIItylthio)methyl]-7-
oxabicvclo~2 2.1]he~t-2-Y1~-5-heptenoîc acid,
methyl ester
tl~ , 2a t 5 Z ) , 3~ , 4B 1 -7- [ 3- hydroxy-
_
3 methyl)-7-oxabicyclo[2.2.1]hept-2-vl}-
o
5-heptenoic acid, methvl ester
_
* Trade Mark
:,;`1,
HA2~0/280
-50-
To a solution of 2.6S g of [1~,2~(5Z),3,4~]-
7-[3-(hydroxymethyl~-7-oxabicyclo-[2.2.1]hept-2-
yl]-S-heptenoic acid in 175 ml of dimethylformamide
was added 13.16 g of pyridinium di.chromate. This
mixture was stirred at room temperature for ~9
hours at which time an additional 8 g of pyridinium
dichromate was added. This mixture was allowed to
: stir an additional 24 hours. The reaction mixture
was diluted with 500 ml of ether a~d the xesultant
black gummy precipitate was removed by filtration
through a pad of Celite. The filtrate was
concentrated in vacuo. The resulting dark brown
oil was passed through 60 g of silica gel 60 and
eluted with 5% MeOH/CH2C12 to give 1.86 g of brown
oil.
This was purified by chromat~graphy on 150 g
of silica gel 60 using 1:1:0.01 pentane-ether-
acetic acid as eluant. This gave 0.63 g of ~1~,2,-
(SZ) ,3a,4~]-7-13- (carboxy)-7-oxabicyclo12.2.1~ hept-
2-yl]-5-heptenoic acid methyl ester and 0.31 ~ of
[1~,2,(5Z~,3~,4~-7-t3-tcarboxy~-7-oxabicyclo-
~ [2.2.1lhept-2-yll-$-heptenoic acid methyl ester.
3C NMR (CDC13 ,15 . OMHz) tau 177 . O, 174 . O, 130 . 6,
127.7, 8}.5, 77.9, 54.7, 51.3, 46.2, 33.4,
32.3, 29.2, 26.6, 25.~, 24.7.
A salution of 350 mg of tlB~2a~sz) ,3~,4~1-7-
[3-(carboxy)-7-oxabicyclo[2.2.1]hept-2-yl~-S,
heptenoic acid methyl ester and 0. 35 ml of triethyl-
amine in 3.0 ml of dry THF under argon was cooled
to 0C. To this stirred solution was added dropwise
0.24 ml of ethylchloroformate. The resulting
mixture was stirred at ~C for 50 minutes and then
diluted with 20 ml of anhydrous ether. The mixture
was filtered through a pad of MgSO4 and concentrated
in vacuo. The rPsidue was dissolved in 2~ml of
* Trade Mark
~2~6~37 H~2 9 0/2 8 o
-51-
absolute EtOH and 3.3 ml of dry THF. This
solutlon was cooled in an ice bath and then
80 mg of NaBH4 was added. The mixture was
stirred for 30 min. at 0C and then the ice bath
was removed. After 15 minutes, the reaction
mixture was poured into 25 ml of ice-cold lN HCl.
The aqueous layer was extracte~ with three 25 ml
portions of ether. The ether layers were combined
dried over MgS04, filtered, and concentrated
ln vacuo to afford the crude product. Purification
was effected by flash chromatography of 22 g o~
silica gel using 2~ MeOH/CH2C12 as eluant. This
gave 250 mg of [1~,2a~5Z),3~,4~]-7-[3-(hydroxy-
methyl)-7-oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic
acid methyl ester;
15 13C NMR ~CDC13, 15.OMHz)tau 174.1, 130.0, 128.5,
80.6, 78.7, 63.4, 51;7; 51.4, 47.8, 33.4,
32.7, 29.8, 26.6, 24.7, 23.7
B. [1~,2a(5Z),3~,4~]-7-[3-(p-Toluenesulfonyl-
oxymethyl)-7-oxobicyclo[2.~.1]hept-2-yl-
5-heotenoic acid, methYl ester
~25~
- HA290/280
-52-
To a solution of 300 mg (1.12 mmol) of
[1~,2~(5Z),3~,4~]-7-[3-(hydroxymet:hyl)-7-oxa-
bicyclo[2~2.11hept-2-yl]-S-heptenoic acid,
methyl ester from part A in 4 ml of dry pyridine
is added 427 mg (2.24 mmol) of tosyl chloride.
The mixture is stirred at room temperature
under argon atmosphere for 10 hours. The
reaction mixture is diluted with 300 ml of ether,
washed with lN aqueous HCl solution (3 x 100 ml),
and 0.5 N aqueous NaOH solution (3 x 100 ml). The
ether layer is dried over anhydrous magnesium sulfate
and concentrated ln vacuo; Purification is effected
by flash chromatography on 30 g of silica gel 60
using 50% hexane in ether as eluant to give 450 mg
Of title B compound.
C. [l~2a(5z)r3~l4a]-7-~3~(pentylthio)methyl]
7-oxabicyclo~2.2.1]hept-2-yl]-S eptenoic
acid, methyl ester
To a soLution of 132 mg (1.17 mmol) of
potassium t-butoxide in 10 ml of dry THF under argon
is added 318 mg (3.21 mmol) of l-pentanethiol.
To this mixture is added a solution of 4S0 mg
(1.07 mmol) of Part B tosylate in 5 ml of THF. The
reaction mixture is stirred at room temperature
under argon for 2. 5 hours and then heated to reflux
for 5.5 hours. The cooled reaction is diluted with
~2568~7 H~290/280
300 ml of ether and poured into 100 ml of saturated
NaHCO3 solution. The aqueous layer is extracted
with e~her (2 x 100 ml). The co~bined ether
extracts (500 ml) are washed with 0.5 N aqueous
sodium hydroxide (2 x 100 ml), brine ~100 ml~, and
then driad (MgSO4~, filtered and concentrated
in vacuo to give 0.55 g of crude oil. Purification
was effected by chromatography on 25.2 g of
sllica gel 60 using 5:1 pet. ether:ether as
eluant to givc 328 mg of ti le compoundO
Exam~le 4g
[lB, 2a (5Z), 3~, 4B 1-7- ~3-[(Pentylthio)me~hyl]-7
oxabicvclot2.2.1]he~t-2~Yl]-S-hePten~ic acid
To a stirred solution of 328 mg ~0.89 mmol)
of Example 4~methyl ester in 43.8 ml of THF and
6~67 ml of H20 under argon is added 8.40 ml of lN
aqueou~ lithium hydroxide solution. This mixture
~g purged with argon vigorously fox 20 minutes and
stirred at room temperature for 12.5 hours. The
reaction mixture is acidified to pH 4 by the
addition of l~ aqueous HCl solution and poured into
50 ml of saturated NaCl solution. The resulting
solution is saturated with solid NaCl and extracted
2S with EtOAc ~4 x 50 ml). The co~bined EtOAc
extracts are dried (~gSO4), filtered a~d concentrated
in vacuo to give 295 mg of crude acid. Purification
*is effected by flash chromatography on 25 g of
Sili~A~ CC-7 using 2:3 petroleum ether:ether
as eluan~ to give the acid.
Example50
a~5Zl,3a,4B]-7-[3-[~Methylthio)methyl]-7-
oxabicyclo[2.2.1]hept-2-~1]-5-heptenoic acid
Following the procedure of Examples~4 and 45
except substituting methyl mercap~an for l-hexane-
thiol the title compound is obtained.
* Trade Mark
~æs~7 -
HA290/280
-54
Example 51
[1~,2a(5Z),3~,4~]-7-[3~ropylthio)methyl]-7-
oxabicvclo[2.2.1]hept-2-yl]-5-heptenoic acid
~ _
Following the procedure of Examples 48 and 49
except substituting propylmercaptan for l-pentanethiol,
the title compou~d is obtained.
~ ple52
(1~,2a,3a,4~-7-~3-(Bu~lthio)methyl]-7-oxabicyclo-
- 10 [2.2.1]hept-2-yl]he~tanoic acid
Following t~e procedure of ~xamples 46 and 47
except substituting butylmercaptan for l-hexanethiol,
the title compound is obtained.
E~ ele_53
~1~,2a(5Z)~3a,4~]-7-[3-~(Octylthio)methyl}-7-
oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acld
Following the procedure of Examples 44 and 45
except substituting l-octanethiol for l-hexanethiol,
the title compound is obtained.
Anal. Calcd. for C22H38O3S: C, 69.0~; H,10.01; S, 8.38
Found: C, 69.08; H, 9.75;S,8.20
C NMR (CDCl , 15.0MHz)tau 178.7, 32.6, 29.1, 29.4,
129.8, 129.8, 29.4, 46.9, 80.6, 29.7, 31.7,
80.4, 47.5, 33.4, 32.1, 29.1, 28.8, 26.7,
26.2, 24.5, 22.5, 13.9
. , .
Example 54
[1~,2a(5Z),3a,43]-7-~3-~Phenylthio)methyl]-?-
oxabicyclo~2.2.1]he~t-2-yl]-5-heptenolc acid
Following the procedure of Examples 44 and 45
except substituting phenylmercaptan for l-hexanethiol,
the title compound is obtained.
'
. HA290/28~ ~
_
O Example 55
(1~,2a, 3a, 4~) -7-~3-[(Phenylthio)methyl]-7-oxabicyclo-
[2 2 l]he t-2- l]he~tanoic acid
P Y ._ _ ~
Following the procedure of Examples 46 and47
except substituting phenylmércaptan for l-hexanethiol,
the title compound is obtained.
Example 56
[1~,2a~5Z~,3a,4~]-7-[3-~(Ethylthio)meth~1]-7-
oxabicyclo[2.2.1~hept-2-yl}-5-heptanoic acid
Follow mg the procedure of Examples 44 and 45
except substituting ethylmercaptan for l-hexanethiol,
the title compound is obtained.
Example 57
~1~,2a(5Z),3~,4~]-7-[3~(Phenylthio)methyl]-7-
oxabicvclo [2~2~1]heDt-2-Yl~-5-he~tenoic acid
Following the procedure of ExampLes 48 and 49
except substituting phenylmercaptan for l-pentane-
thiol, the title product is obtained.
Exa~le 58
[1~,2a(5Z),3~,4~]-7-[3-[(Benzylthio)methyl]-7-
oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acld
Following the procedure of Examples 48 and 49
except substituting.benzylmercaptan for l-pentanethiol,
the title product is obtained.
Example 59
3 ~1~,2a 3a 43)-7-[3-[(Benzvlthio)methyl]-
O
7-oxabicyclo[2.2.1]he~t-2-yl]heptanoic acid
Following the procedure of Examples 46 and 47
except substituting benzylmercap~an for l-hb~anethiol,
the title product is obtained
'' " ' .
HA290/2~30
-56-
.
Example 60
[1~,2a(5Z),3a,4~]-7-[3-[(Cyclohexylthio)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid
Following the procedure of Examples 44 and 45
except subs~ituting cyclohexylmercaptan for l-hexane-
thiol, the title product is obtained.
Example 61 - ~
[1~,2a(5Z),3~,4~]-7-[3-[(Cyclopentylthio)me_hyl]-7-
oxabicyclo~2.2.1]he~t-2-yl~-5-heptenoic acid
Following the procedure of ExampI~s 48 and 49
except substituting cyclopentylmercaptan for
l-pentanethiol, the title product is obtained.
Example 62
(1~,2a,3a,4~)-7-[3-~(Cyclohex~ o)methyl]-7-
oxabic~clo[2.2.1]hept-2-yl]heptanoic acid
Following the procedure of Examples 46 and 47
except substituting cyclohexylmercaptan for
l-hexanethiol, the title product is obtained.
.
Example ~3
[1~,2a(5Z),3a,4~]-7-[3-E2-(Hexylthio)ethyl]-7-
oxabicyclo[2 2.1]hept-2-yl]-S-heptenoic acid
A. [1~,2a(5Z),3a,43]-7-~3-(2-Oxo)ethyl-
7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, meth~l ester
Into a dry 100 ml round bottom 3-necked flask
containing a stir bar was added dried 12.9 g
(37.7 mmoles) methoxymethyltriphenylphosphonium
chloride ((C6H5)3P+-CHzOCH3Cl ) and 235 ml distilled
~2~ HA290/280
-57-
toluene (stored over molecular sieves~O The resulting
suspension was stirred in an ice-bath, under argon,
until cold and then a 1.55 M solution of 18.3 ml
(28.3 mmol) of potassium t-amylate in ~oluene
was added dropwise. A bright re,d solutio~ formed
which was stirred at 0C ~or an additional 35 minute~.
Thereafter, a solution of 4.97 g (18. 8 m~ol)
[1~,2a(5Z),3a,4~]-7-[3-formyl 7-oxabicyclo[2.2.1~-
hept-2-yl~-5 heptenoic acid, methyl ester in
60 ml toluene was added by maans of a dropping
funnel ovar a 35 minute period with the ice-bath
still in placeO The reaction was then quenched
by additio~ of 2.3 g ~39 mmol) acatic acid in 5 ml
ether. The reaction mixture immediately turned
lS pale yellow and was immediately poured into 200 ml
saturated NH4Ci, and extracted with ether (4 x 200 ml).
The combined ether phases were washed with NaCl,
saturated solution, and dried ~MgSOi) and concen~
tra~ed to yield a yellow oil in a white crystalline
solid (ph~ne cxide). The white solid wa~ triturated with
EtCAc and the m~er liquor was p~ied by ch3~hx~aphy
on an LPS-l silica column. The fractions obtained
were (~) [1~,2a(5Z),3a,4~]-7-[3-(2-oxo)ethyl-7-
oxabicyclol2.2.1]hept-2-yl]-5-heptenoic acid,
25 methyl ester, (B) [1~,2a(5Z),3a,4~]-7-[3-(2-methoxy)-
ethendiyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester, and (C) [1~, 2a(5z),3a,4~J-7-E3~
(2,2-dimethoxy)ethyl-7-oxabicyclo[2.2.1]hept-
2-yl]-S-heptenoic acid, methyl ester.
Compounds (B) and (C) are each treated with
trifluoroacetic acid to convert each to compound (A).
* Trade Mark
~, .
` ~256~7 - HA290/280
- -58-
B. ~1~,2a(5Z),3a,4~]-7-[3-(2-Hydroxyethyl)-
7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester
The aldehyde (1.4 g, 5 mmol~ from part A
in methanol (50 ml) is treated with ~aBH4 (0.19 g,
5 mmol) in an argon atmosphere at 0 C. After
stirring at 0 for 1 hour, the reac~ion is quenched
by addition of 2N HCl (to pH 2). The methanol is
removed in vacuo and the reaction mixture is taken
up in ether. ~he ether solution is washed with
satu~ated KHC03, saturated NaCl and dried (MgS04~.
The ether LS evaporated to yield the title B compound.
C. ~1~,2a~5Z),3a,4~]-7-~3-E2-~exylthio)-
ethyl]-7-oxabic~clo[2.2 1 ~ t-2-yl]-
5-heE~noic acid
-
Following the procedure of Examples 44 and 45
except substitu~Lng the above part B alcohol for the
alcohol used in Example 44,the title compaund is
obtained.
Example 64
[1~,2a(SZ),3~,4~]-7-[3-[2~Hexylthio)ethyl~-7-
oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid
2~ Following the procedure of Example 63, except
substituting [1~,2a(5Z) ,3~,4~]-7-[3-formyl-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl
ester for [1~,2a(52~,3a,4~]-7-~3-formyl-7-oxabicyclo-
[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester,
the title compound is obtained.
- ~% ~ ~ ~ HA290/280
59
Example 65
(1~,2a,3~,4~)-7-[3-[2-(Hexylthio)ethyl]-7-oxabicyclo-
[2.2.1]hept-2-yl]heptanolc acid
Following the procedure of Example 64 except
substituting (1~,2a,3a,4~)-7-[3-formyl-7-oxabicyclo-
[2.2.1]hept-2-yl]heptanoic acid, ~ethyl ester for
[1~,2a(52),3a,4~]-7-[3-formyl-7-oxabicyclo[2.2.1]-
hept~2-yl]-5-heptenoic acid, methyl ester, the title
compound is obtained.
Æxam~ le 6 6
[1~, 2a ~ 5Z ), 3a,4~]-7-E3-[2-(Phenylthlo)ethyl]-7-
oxablcyclo[2.2.1]hept-2-yl]-5-heptenoic acid
; Following the procedure of Example 63
lS except substituting phenyl~ercaptan for l-hexanethiol,
the title compound i9 obtained.
Example 67
[1~,2a(5Z),3~,43]-7-[3-[2-(Phenylthio)ethyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Example 64
except substituting phenylmercaptan for l-hexanethiol,
the title compound is obtained.
Example h8
(1~,2a,3a,4~)-7-[3-[2-~Phenvlthio)ethYl]-7-oxabic~clo-
.
~2.2.1]hept-2-yl]heptanoic_acld
Following the procedure of Example 65
except substituting phenylmercaptan for l-hexanethlol,
the title compound is obtained.
.
:~ .
~:
.
- ~2~ HA290/280
,
Example 69
[1~,2a(5Z),3,4~}7-[3-[2-(-Benzylthio)ethyl~-7-
oxabicycl_[2.2.1]hept-2-yl]-5-heptenoic acld
Following the procedure of Example 63
except substituting benzylmercaptan for l-hexanethiol,
the title compound is obtained.
Example 70
[1~,2a(5Z),3~,4~-7-[3-t2-(Benzylthio)ethyl]-7-
oxabicycloE2.2.11hept-2-yl]-5-heptenoic aci_
Following the procedure of Example 64
except substituting benzylmercaptan for l-hexanethiol,
the title compound is obtained.
Exam~le 71
[1~,2(5Z),3a,4~}7-~3-[2-( Cyclopentyl)thio) e~hyl]-
7-oxabic~vclo~2.2.1]hept-2-yl]heptenoic acid
Following the procedure of Example 63
except substituting cyclopentylmercaptan for
l-hexanethiol, the title compound is obtained.
Example 72
[1~,2a(5Z),3a,4~}7 [3-[2-(Cyclohexylthio)ethyl]-7-
oxabicvclo[2.2.l]hept-2-Yl]-5-hePtenoic acid
Following the procedure of Example 63
except substituting cyclohexylmercaptan for
l~hexanethiol, the title product is obtained.
Example 73
[ 1~ , 2a ( 52 ) , 3a,4~}7-[3-[4-(Hexylthio)butyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
A. [1~,2a(5Z),3a,4~]-?-[3-(3-Oxo)~ropyl-7-
oxabicvclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester
~ ~ ~ HA290/280
-61- -
Following the procedure of Example 63, part A
except substituti~g [1~,2a(5Z),3a,4~] 7 ~3-(2-oxo)-
ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester for [1~, 2(5Z), 3a, 43 ] -7 [3-formyl-7-
oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid, methyl
ester, the title A compound is obtained.
B. [1~,2a(5Z),3a,4~]-7-[3-(4-Oxo)butyl-7-
oxabicyclo[2.2.1]hept-2-yl]-5-hep~enoic
acid, methyl ester
Following the procedure o~ Example 63, par~ A,
except substituting the aldehyde from part A above,
~or ~1~,2a(5Z) ,3a,4~ 7- [3-formyl-7-oxabicyclo[2.2.1]-
hspt-2-yl]-5-heptenoic acid, methyl ester, the title B
15 aldehyde is obtained.
C. [1~,2(5Z),3a,4a]-7-~3-(4-Hydroxybutyl)-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid, methyl ester
Following the procedure of Example 63, part B,
except substituting the title ~ aldehyde for
[1~,2a~5Z),3a,4~]-7-[3-(2-oxo)ethyl]-7-oxabicyclo-
[2.2.1]hept-2-yll-5-heptenoic acid, methyl ester,
the title C alcohol is obtained.
D. [1~,2a(5Z),3~,4~}7-[3-[4-(Hexylthio)-
butyll-7-oxabi yclo[2 2 l]hept 2 yl]-
5-heptenoic acid
Following the procedure of Examples 44 and 4~,
30 except substituting the above part C alcohol for
the alcohol used in Example 44, the title compound
is obtained.
,
; 35
.
, . .
~ HA290/2~0
-62- -
Example 74
[1~,2a(5 ~ [3-[4-(Cyclohe~ylthio)butyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Followins the procedure of Example 73
except substituting cyclohexylmercaptan for
l-hexanethiol, the title compound is obtained.
Example 75
[1~,2a(5Z),3a,4~]-7 [3-[4-(Phenylthio)buty~l-?-
oxabicyclo[2.2.l]hept-2-yl]-s-heptenoic acid
-Following the procedure of Example 73
except substituting phenylmercaptan for l-hexanethiol,
the title compound is obtained.
ExamD~le 76
~1~,2a(5Z),3a,4~]-7-[3-~4-(Benzylthio)butyl]-7-
oxabicycloE2.2.1]hept-2-yl]heptenolc acid
Following the procedure of Example 73
except substituting benzylmercaptan fox l-hexanethiol,
the title compound is obtained.
Examples 77 78 and 79
[13,2a(5Z),3a,4~]-7-[3-[(He~ylsulfinyl)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl
ester (~ast movin~Lisomer), [13,2a(5Z),3a,4~]-7-
_
~3-[(Hexylsulflnyl)methyl]-7-oxabicyclo[2.2.1]he~t-
2-yl]-5-he~tenoic acid, _ethyl ester (slow movlng
isomer) and ~1~,2a(5Z),3a,4~]-7-[3-[(Hexylsulfonyl)-
methyl]-7-oxabicyclo[2.2.1lhept-2-yI]-5-heptenoic
~ acid, methyl ester
To a solution of 634 mg (1.72 mmol) of
.
~ HA290/280
-~3-
[13,2a(5Z),3,4~]-7-[3-[(hexylthio)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid,
methyl ester (prepared as describ~ed in ~xam~le 4,~)
in 6.78 ml of methanol at 0C was added dropwise
over 4 minutes 8.37 ml of 0.5M aqueous sodlum
periodate solution. Tetrahydrofuran t2 ml) was
then added and the resulting reaction mixture was
stirred at room temperature for 15 hours. A
white precipitate was removed by filtration and
washed with ether (3 x 50 ml)~ The filtrate was
washed with 60 ml of saturated aqueous NaHC03
solution and dried over anhydrous magnesium sulfate.
Concentration in vacuo afforded 648 mg of an oily
crude produc~. This was chromatographed on
lS 54.16 g of silica gel 60 using O.S-l. a~ CH30H
in CH2C12 as eluent. This gave FMI ~East moving
isomer) sulfoxide (Example 77) (211 mg, 32~), SMI
(slow moving isomer) sulfoxide (Example 78)
~142 mg, 21~) and sulfone (Example 79) (165 mg,
24%). These products were oils which so~idified on
storage in the freezer. TLC = silica gel, 2%
(CX3O~CH2C12, Rf: Example 77 sulfoxide, 0.28;
Example 78 sulfoxide, 0.21; Example 79 ;ulfone,
0.74; iodine.
Example 80
[1~,2a(5Z),3a,43]-7-~3-[~Hexylsulfonyl)methyl]-7-
oxablcyclo[2.2.1]hept-2-yll-5-heptenoic acid
To a stirred solution of 165 mg ~0.41 ~mol)
of [1~,2a(5Z),3a,4~]-7-[3-[(hexylsulfonyl~methyl]-7-
oxabicyclo[2.2.1]hep~-2-yl]-5-heptenoic acid,
.~
.
- HA290/280
-64- _
me~hyl ester (Example 79 in 20.3 ml of THF and
3.09 ml of H20 under argon ~as added 3.90 ml of lN
aqueous lithium hydroxide solution. This mixture
was purged with argon vigorously for 10 minutes and
stirred at room temperature for 6 hours. The
reaction mixture was acidi~ied to pH 4 by addition
of lN a~ueous HCl solution and pollred into 30 ml
of saturated NaCl solution. The resulting solution
was saturated with solid NaCl and extracted with
EtOAc (4 x 50 ml). The combined EtOAc extracts
~ were dried (MgS04), filtered and concentrated
; in vacuo to give 165 mg of crude acid. Purification
was effected by flash chromatography on 2Q g of
silica gel 60 using 3~ C~30H in C~2C12 as eluant.
This aorded title acid (145 mg, 91%) which
solidified on storage in the free7er. TLC~silica
gel, 4~ CH30H/CH2C12, Rf 0.32, iodine.
Anal. Calcd for C20H3405S: C, 62.18; H, 8-31; S, 8-29
Found: C, 61.99; H, 9.01; S, 8.33
13C NMR (CDC13, 15.OMHz)tau 178.4, 33.1, 24.3,
26.7, 12a.9, 130.3, 28.0, 39.9, 79.8,
31.1, 28.8, 80.9, 47.0, 54.1, 51.7, ~9.4,
27.1, 22.2, 21.9, 13.7
Example 81
~1~,2a (5Z?,3a,4~]-7-E3-E(Hexylsulfinyl)methyl]-7-
oxabicycloE2.2.1]hept-2-yl]-5-heptenoic acid (fast
movin~ isomer)
To a stirred solution of 211 mg (0.55 mmol)
of [1~,2a(5Z),3a,4~]-7-[3-[(hexylsulfinyl)methyl]-7-
oxabicyclo[2.2.1]hept-2-yll-5-heptenoic acid,
methyl ester (fast moving isomer) prepared in
Example 77 in 27.0 ml of T~F and 4.11 ml of H20
under argon was added 5.19 ml of lN aqueous lithium
.
z~
HA290/280
-65-
hydroxide solution. This mixture was purged with
argon vigorously for ten mlnutes and stirred at
room temperature for 6 hours. The reaction mixture
was acidified to pH 4 ~y addition of lN aqueous
HCl solution and poured into 50 ml of saturated NaCl
solution. The resulting solution was saturated
with solid NaCl and extracted with EtOAc (4 x 100 ml).
The combined EtOAc extracts were dried (MgSO4),
filtered and concentrated ln vacuo.to give 216 mg of
crude acid. ,Purification was effected by flash
chromatography ~n 20.2 g of silica gel 60 using
3% CH30H in CH2C12 as eluant to give the title
acid (17~ mg, 85~) as a white solid. TLC = silica
gel, 4% CH3OEI/CH2C12, R~ 0!10, iodine.
Anal. Calcd for C20H3404S: C, 64-83; H~ 9.25t, ~, 8-65
Found: C, 64.7~; H, 9.17; S, 3.55
13
C NMR (CDC13, 15,0MHz)tau 176.8, 33,3, 24,5,
26.9, 129.0, 130.2, 28.4, 41.1, 80.1,
31.2, 28.3, 80.4, 47.1, 52.7, 52.7, 29.6,
; 20 26.7, 22.6, 22.3, L3.8
Example 82
[lB,2alSZ),3a,4~]-7-[3-[(Hexylsulfinyl)methyl]-7-
oxa~icyclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow
moving.isomer)
To a stirred solution of 142 mg
(0,37 mmol) of [1~,2a(5z),3a,4~]-7-[3-[(hexyl-
sulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-
heptenoic acid, methyl ester (slow moving isomer)
prepared as described in Example 78 in 18.2 ml
of THF and 2.77 ml of H2O under argon was added
3.50 ml of lN aqueous lithium hydroxide solution,
This mixture was purged with argon vigorously for
15 minutes and stirred at room temperature for
~; 35
HA29Q/~80
- -66-
4 hours and 40 minutes. The reaction mixture was
acidified to pH 4 by addition of lN aqueous HCl
solution and poured into 30 ml of saturated NaCl
solution. The resulting solution was saturated with
S solid NaCl and extracted with EtOAc (3 x 70 ml).
The combined ~tOAc extracts were dried (MgSO4),
filtered and concentrated ln vacuo to give 152 mg
of crude acid. Purification was effected by flash
chromatography on 20.8 g of silica gel 60 using
4% CH30H in CH2C12 as eluant to give title acid
(116 mg, 85~). TLC: silica gel, 4~ CH3OH/CH2C12,
Rf 0.6, iodine.
Anal. Calcd for C20H34O4S: C, 64.83; H, 9.25; S, 3-65
Found: C, 64~44; H, 9.1S; S; 8.58
13C NMR (CDCl , 15.0MHz)tau 33.4, 24.6, 26.7,
129.0, 130.3, 27.1, 41.8, 80.0, 31.3,
28.4, 81.7, 47.3, 52.8, 52.8j 29.4,
27.1, 22.4, 22.4, 13.8
Example 83
[1~,2a(5Z),3,4~]-7-[3-[(Methylsulfinyl)methyl]-7-
oxablcyclo[2.2.1]h_pt-2-yl]-5-heptenoic acid
(fast moving isomer)
Following the procedure of Examples 44, 77 and
81 except substituting methyl mercaptan for
l-hexanethiol, the title compound is obtained.
Example 84
2a(5Z),3a,4~]-?-~3-[(Oct}~ulfinyl)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic_acid
(slow movlng isomer)
- Following the procedure of Examples 44
77 and 82 except substituting l-octanethiol for
l-hexanethiol, the title compound is obtained.
. . HA290/280
-67-
Example 85
[1~,2a(5g),3~,43]-7-[3-[(Phenylsulfinyl)methyl]-?-
oxabicyclo[2.2.11hept-2-yl~ ~-heptenoic acid (fast
moving isomer)
Follow mg the procedure of Examples 48, 77
and 81 except substituting phenylmercaptan for
l-pentanethiol,-the title compound is obtained.
Example 86
[1~ ! 2a (SZ), 3,4~]-7-[3-~(Ethylsulfinyl)methyl]-7-
oxabi~yclo[2.2.1]hept-2-yl]-5-heptenoic acid
(slow movin~ isomer)
~ollowing the procedure of Example 48, 77and
82 except substituting ethylmercaptan for l-pentane-
thiol, the ~itle compound is obtained.
Example 87
(13, 2a, 3a, 4~) -7- [3- [ (Heptylsulfinyl~methyl] -7-
oxabicyclo[2.2.1]hept-2-yll-5-heptanoic acid
(fast moving isomer)
Following the procedure of Examples 46, 77
and 81 except substituting l-heptanethiol for
l-hexanethiol, the tltle compound is obtained.
Example 88
[l~,~a(5Z) ,3a,4~l-7-~-[(Benzylsulfinyl)methyl]-7-
oxabicyclo [2 . 2.11hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 44, 77
and 81 excep~ substituting benzylmercaptan for
l-hexanethlol, the title compound is obtained.
:, , .
r . ~ HA290/2~.0
--68--
Example 89
[lB,2a(5Z),3~,4~]-7-[3~[(Benzylsulfinyl)methyl]-7-
oxabicyclo[2.2.1]hept-2~yl]-5-heF)tenoic acid
(slow moving isomer)
Following the procedure of Examples 48, 77
and 82 except substituting benzy].mercaptan for
l-pen~anethiol, the title compound is obtained.
Example 90
~1~,2a(5Z),3a,4~]-7-[3-~(Cyclohexylsulfinyl)methyl]-
7-o~abicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
~fast moving isomer)
Following the procedure of Examples 44, 77
and 81 except substituting cyclohexylmercaptan
for l-hexanethiol, the title compound is obtained.
Example 91
[1~,2a(5Z),3a,4~]-7-[3-[(Cyclopentylsulfi ~ )-
methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic
acid (fast movin~ isomer)
Following the procedure of Examples 44, 77
and 81except substituting cyclopentylmercaptan
for l-hexanethiol, the title compound is obtained.
Example 92
[1~,2a(5Z),3a,4~]-7-[3-[(Octylsulfonyl)methyl]-7-
oxabicyclo~2.2.1]hept-2-yl]-5~heptenoic acid
Following the procedure of Examples 44, 77
and 80except substituting octylmercaptan for
l-hexanethiol, the title compo nd is obtained.
,
~25~3~ HA2 9 o / ~ 8 o
_ -69-
O Example 93
[1~,2a(5Z),3a,4~]-7-[3-[(Propylsulf~nyl)methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 44, 77
and 80 excep~ substituting propylmercaptan for
l-hexanethiol, the title compound is obtained.
Example 94
[1~,2a(5Z),3a,4~]-7-[3-[(Phenylsulfonyl)methyl]-7-
19 oxabicyclo~2.2.1~hept-2-yl]-5-heptenoic acid
Foll~wing the procedure of Examples 44, 77
and 80 except substituting phenylmercaptan for
l-hexanethiol, the title compound is obtained.
Exam~le 95
[1~,2a(5Z),3a,4~]-7-[3-[(Benzyl~ul~onyl)methyl]-7-
oxabicyclot2.2.1]hept-2-yl]-S-heptenoic acid
Following the procedure of Examples 44, 77
and 80 except substituting benzylmercaptan for
l-hexanethiol, the title compound is obtained.
Example 96
[1~,2~(5Z),3a,4B]-7-[3-[(Cyclohexylsu~fonyl)methyl]-
7-oxabicyclo[2.2.1]hep~-2-yl]-5-heptenoic acid
Following the-procedure of Examples 44, 77
and 80 except substituting cyclohexylmercaptan for
l-hexanethiol, the title compound is obtained.
Example 97
[1~,2~(5Z),3~,4~]-7-[3-[(Heptylsulfonyl?methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 48, 77
and 80 except substituting l-heptanethiol for
l-pentanethiol, the title compound is obtained.
3S
:~2~
. HA290~280
.-70-
Example 98
Cl3,2a(5z) ,3~,4~]-7-[3-[(Benz~lsulfonyl)methyl]-7-
oxabicyclo [2 . 2 .1 ] hept-2-yl]-5-hep _noic acid
Foll~wing the procedure of Examples 48, 77
and 80 except substituting benzylmercaptan for
l-pentanethiol, the title compound is obtained.
.
~9
[1~,2a(5Z?,3~,4~]-7-~3-[(Cyclopentylsulfonyl)methyl]-
7-oxabicyclo[2.2.1]hept-2-yl].-S heptenoic acid
Following the procedure of Examples 48, 77
and 80 except substituting cyclopentylmercaptan
for l-pentanethiol, th.e title compound is obtained.
Example lon
[1~,2a(5Z),3~,4B]-7-[3-[(Phenylsulfonyl)methy~-7-
oxabicyclo~2.2.1]hept-2-yl]-5_heptenoic acid
. Following the procedure of Examples 48, 77
and 80 except substituting phenylmercaptan for
; 20 l-pentanethiol, the title compound is obtained.
.
Example 101
(1~,2,3a,4~)-7-[3-[(Cyclopropylsulfinyl)methyl]-7-
oxabicyclo[2.2 l]hept-2-yl]-5-heptanoic acid
Following the procedure of Examples 46, 77 and 80
except substituting cyclopropylmercaptan for
l-hexanethiol, the title compound is obtained.
~'
- ~2:;6~187
. HA290/280
-71-
.
Example 102
(1~,2a,3a,4~)-7-[3-[(Benzylsulfirlyl?methyl]-7-
oxabicyclo[2.2.1]hept 2-yl]-5-heptanoic acid
Following the procedure of Examples 47, 77 and 81
S except substituting benzylmercaptan for l-hexanethiol,
the title compound is obtained.
Example 103
.
[i~2~sæ) ,3a,4~}7-[3-[2-(Pentylsulfinyl)ethyl]-7-
oxabicyclo~2.2.1]hept~2-yl]-5-heptenoic acid
Following the procedure of Examples 63, 44, ~ 77
and 81 except sub~tituting l-pentanethiol for
l-hexanethiol, the title compound is obtained.
Exam~le 104
~1~,2a(5Z),3~,4~}1-~3-~2-(Phenylsulfonyl)ethyl] 7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic aci.d
Following the procedure of Examples 63, 44,
77 and 80 except substituting phenylmercaptan for
2~ l-hexanethiol, the title compound is obtained.
.
Example 105
[la, 2a(5Z),3a,4~}7-[3-[2-(Cyclohexylsulfonyl)ethyl]-
7-oxabicyclo[2 2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63, 44, 77
and 80 except substituting cyclohexylmercaptan
for l-hexanethiol, the title compound is obtained.
ExamDle 106
[1~,2a(5Z),3a,43~7-[3-[2 (Be~ lsulfinyl)ethyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63, 44, 77
and 81 except substituting benzylmercaptan for
l-hexanethol, the title compound is obtained
3S
., .
' HA2~0/280
-72-
OExample 107
[13,2~5Z), 3a, 4~]-7-~3-[2-(Bu ylsulfonyl)ethyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63, 48, 77
and 80 except substituting butylmercaptan for
l-pentanethiol, the title compound is obtained.
Exam~ 8
[1~!2a(sZ),3~,4~7-E3-E2-(Phenylsulfinyl)ethyl]-7-
oxabicycloE2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63, 48, 77
and 81 except substituting phenylmercaptan for
l-pentanethiol, the title compound is obtained.
Example 109
[1~,2a(5Z) ,3~,4~}7-E3-[2-(Benzylsulflnyl)ethyl]-7-
oxabicycloE2.2.1]~hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63, 48, 77
and 81 except substituting benzylmercaptan for
l~pentanethiol, the title compound is obtained.
Example llD
[1~,2a(5Z),3~,4B}7-[3-[2-(Cycloheptylsulfonyl)-
ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63, ~8
77 and 80 except substituting cycloheptylmercaptan
for l-pentanethiol, the title compound is obtained.
Example 11~
(1~,2a,3a,4~)-7-E3-E2-(Pentylsulfonyl)ethyl]-7-
oxabicyclo[2.2._1]hept-2-yl]-5-heptanolc acid
Following the procedure of Examples 63, ~ 77
and 80 except subs~ituting l-pentanethiol for
l-hexanethiol, the title compound is obtained.
:3.2~i;~3~7
290~280
~ 73-
Example 112
(1~,2a,3a,4~7-[3-[2-(Phenylsulfinyl)ethyl] ?_
oxabicyclo~2.2.1]hept-2-yl]-5-heptanoic acid
Following the procedure of Examples 63, 46, 77
S and 81 except subs~ituting phenylmercaptan for
l-hexanethiol, the title compo~nd is obtained.
Example 113
, 2a, 3a, 4 ~ ~7- [3- ~2-(Benz~lsulfinyl)ethyl]-7~
oxablcyclo~2.2.1]hept-2-yl]-5-heptanoic acid
Following the procedure of Examples 63, 46
77 and 81 except substituting benzylmercaptan
for l-hexanethiol, the title compound is obtained.
~ 4
, 2a, 3a, 4~ ~7-~3-~2-(Cyclohexylsulfonyl)ethyl]-7-
oxabicyclo[2.2.1]he~t-2-yl]-5-hepta~oic acid
Following the procedure of Examples 6 3, 4 8
77 and 8n except substituting cyclohexylmercaptan
for l-hexanethiol, the title compound is obtained.
'; ' .
Example_115
_~,2a~5Z),3a,4~}7-[3-[4-(Pentylsulfonyl)butyl~-7-
oxabicyclo[2.2.1]hept-2-yl]~S-h~ptenoic acid
Following the procedure of E~ples 73, 63, 44
77 and 80 except substituting pentylmercaptan for
l-hexanethiol, the title compound is obtained.
Example 116
[1~,2a(5Z),3a,4~}7-[3-[4-(Cyclohexylsulfinvl)butyl]-
-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 73, 63
44, 77 and 81eXcePt substituting cyclohexylmercaptan
for l-hexanthiol, the title compound is obtained.
~ ~ HA290/280
_ -74-
Example 117
[13,2a(5Z),3a,4~]-7-[3-[4-lPhenylsulfin~but~1]-7-
oxabicyclo[2.2.1]hept-2-yll-5-heptenoic acid
Following the procedure of Examples 73, 63,
44, 77 an~ 81except substituting phenylmercaptan
: for l-hexanethiol, the title compound i5 obtained.
. Example 1.1~
[1~,2~(5Z),3a,4~7-[3-~4-(Benzylsulfonyl~butyl]-7-
oxabicvclo[2.2.1~hept-2-vl]-5-heptenoic acid
~ . . . _ _ .
Following the procedure of Examples 73, 63
44, 77 and 80eXcept substituting benzylmercaptan
for l-hexanethiol, the title compound is obtained.
Example~
[1~,2a(5Z),3~,4~}7-~3-[4-(Cyclopentylsulfinyl)butyl]-
7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 73, 53
48, 77 and 8] except substituting cyclopentylmercaptan
for l-pentanethiol, the title compound is obtained.
Example 120
[1~,2a(5Z),3~,4~}7-[3-[4-(Benzylsulfinyl)butyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-5-he~tenoic acid
~ollowing the procedure of Examples 73, 63
48, 77 and 80 except substituting benzylmercaptan
for l-pentanethiol, the title com~ound is obtained.
.
Example 121
~; 30 [1~,2a(5Z),33,4~}7-[3-[4-(Propylsulfinyl)butvl]-7-
o abicyclo[2.2.1]hept-2-yl]-5-he~tenoic acid
Followi~g the procedure of Examples 73, 63, 48,
77 and 81 except substituting propyl~ercaptan
for l-pentanethiol, the title compound is obtained.
- 35
,
~A290/280 '' V
-7~
Example 122
[1~,2a(5Z?,3~,4B}7-[3-[4-t~henylsulfonyl?butyl]-?-
oxabic clo[2.2.l]hept-2-yl]-5-he~tenoic acid
Following the procedure of Examples 73, 63
48, 78 and 80 except substituting phenylmercaptan
for l-pentanethiol, the title comDound is obtained.
Examp le 12 3
, 2a, 3a, 4B)-7-~3-[4-(Nonylsulfinyl)butyl]-7-
oxabicyclo~2.2.1]hept-2-y~-5-heptanoic acid
Following the procedure of Examples 73, 63
46, 77 and 8lexcept substituting l-nonanethiol for
l~hexanethiol, the title compound is obtained.
Example 124
(13,2a, 3a, 4~)-7- ~3-[4-(Pentylsulfonyl)butyl]-7-
oxabicyclo~'2.2.1]he~t-2-yl]-5-heptanoic acid
; Following the procedure of Examples 73, 63, 46
7i and 80 except substituting l-pentanethiol for
l-hexanethiol, the title compound is obtained.
Example 125
(1~,2a,3a,4~)-7-~3-[4-(Phenvlsulfinyl)butyl]-7-
.
oxabicyclo[2.2.1]hept-2-yl}-5-heptenoic acid
Following the procedure of Examples 77, 63
46, 77 and 81except substituting phenylmercaptan
for l-hexane~hiol, the title compound is obtained.
Example 126
,2a,3a,4~)-7-[3-[4-(CYclohexylsulfonyl)butyl]-7-
- -
oxablcvclo[2.2.1]hept-2-yl]-5-heptanoic acld
Following the procedure of Examples 73, 63, 46
77 and 8C except substituting cyclohexylmercaptan
for l-hexanethiol, the title compound is obtained.
~ ~5~
- ~ HA290/280
-76- -
xample 127
[1~,2a(5Z),3a,4~]-7-[_-[[(Cyclohexylmethyl)thio]-
methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
A. [1~,2~(5Z),3a,4~]-7-[3-[[(Cyclohexyl-
me~h~l)thio]methyl]-7-oxabicyclo[2.2.1]-
hept-2-yl]-5-heptenoic acid, methyl ester
To a solution of 88 mg (0.78 mmol) of
potassium t-butoxIde in S ml of dry THF under argon
was added 277 mg (2.13 mmol) of cyclohexylmethane-
thiol (prepared from cyclohexylmethanol by the
method of Volante: Tetrahedron Letters 1981, 22,
3119). To this m~xture was added a solution of
300 mg (0.71 mmol) of ~1~,2~sZ),3,4~]-7-E3-
(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1~-
hept-2-yl]-S-heptenoic acid, methyl ester,prepared
as described in ExampLe 44B, in S.5 ml of dry THF.
The reaction mixture was heated to reflux for 7 hours.
The cooled reaction mixture was dilu~ed with 250 ml
of ether and poured into 100 ml of saturated
NaHCO3 solution. The a~ueous layer was extracted
with ether ~2 x 100 ml). The combined ether
extracts ~450 ml) were washed with 0.5 N aqueous
sodium hydroxide solution (2 x 100 ml) and brine
(100 ml). The ether extxacts were dried over
anhydrous MgSO4 and corlcentrated ln vacuo to give
an oily product. Purification was effected by
chromatography on 20.2 g of silica gel 60 using
hexane:ether (3:1) as eluant to give 253 mg of
tit}e ~ methyl ester as an oil (94~). TLC:silica
gel, petroleum ether:ether (3:2), Rf=0.70; iodine.
. - ~ HA290/28
_ _77_
~ Bo [1~,2(5Z),3a,4~]-7-[3 [[(Cyclohexyl-
,
methyl)thio]methyl]-7-oxabicyclo[2.2.1]-
hept-2-yl ~ acid
~; To a stirred solution of 243 mg (0.64 mmol)
S of Part A methyl ester in 31.4 ml of THF and
4.80 ml of H20 under argon was added 6.00 ml of
lN aqueous lithium hydroxide solution. This mixture
was purged with argon vigorously for 2S minutes
and stirred at room temperature for 16 hours. The
react~on mixture was acidified to pH 5 by addition
o lN aqueous HCl solution and poured into 40 m~l
of saturated NaCl solution. The resulting solution
was saturated with solid NaCl and extracted with
EtOAc (4 x 50 ml). The combined EtOAc extracts
lS were dried (MgSO4), filtered and concentrated ln vacuo
to give 253 mg of crude acid. Purification
was effected by flash chromatography on 20.6 g
of silica gel 60 using ~etroLeum-ether:ether (2:3)
as eluant to give pure title product (117 mg, 50~)
along with 108 mg (46~) of mixed fractions of which
title product was the major component. TLC:silica
gel, Pet-ether:ether (2:3), Rf = 0.32, iodine.
Anal. Calcd for C~lH34O3S: C, 68.85; H, 9-29; S, 3-74
Found: C, 68.90; H, 9.43; S, 8.66
3C NM~ (CDC13, 15.0MHz)tau 178.7, 32.9, 24.6, 26.1,
129.7, 129.9, 29.5, 47.1, 80.4, 25.7, 26.3,
80.7, 47.6, 33.4, 40.4, 38.0, 32 . a, 29.5,
26.1, 29.5, 32.9
290/2~0
-78-
.
Example 128
~1~, 2a (5Z), 3a, 43] -7- ~3- ~ [ (2-Phenylethyl)thlo]methyl]-
7-oxabicyclo[2.2.1]hept-2 vl]-5-h~ptenoic acid
A. [ 1~, 2a ( 5 Z ~, 3a, 4~ ] -7-~3-[[~2-Phenylethyl)-
thio]methyl]-7-oxablcyclo[2.2.1]hept-
~ 2-ylJ-5-heptenoic acid, methyl ester
To a solution of 55.7 mg (0 50 mmol) of
potassium t-butoxide in 5 ml of dry THF under argon
was added 185 mg (1.35 mmol) of phenylethanethiol.
1~ To this mixture was added a solution of 189 mg
(0.45 mmol) of [1~,2~(5Z),3a,4~-7-~3-~p toLuene-
sulfonyloxymethyl)l-7-oxabicyclo[2.2.1}hept-2-yl~-5-
heptenoic acid, methyl ester,prepared as described
in Example 44B, in 6 ml of dry THF. The reacti~n
15 mixture was heated to reflux for 4 hours and
30 minutes. The cooled reaction mixture was diluted
with 160 ml of ether and poured into Ç0 ml of~
saturated ~aHCO3 solution. The aqueous layer ~as
extracted with ether (2 x 60 ml). ~he combined
20 ether extracts (280 ml) were washed with 0.5 N
aqueous sodium hydroxide solution (2 x 60 ~1) and
brine ( 75 ml). The ether extracts were dried over
MgSO4 and concentrated ln vacuo to give an oily
product. Purification ~as effected by chromatography
25 on 21.6 g of silic gel 60 using petroleum ether:ether
(5:1) as eluant to give 157 mg of title A compound
as an oil (90%). TLC:silica gel, petroleum ether:ether
; (2:1), Rf = 0.60, iodine.
~ % S ~ ~ HA290/280
-79~
B. [1~, 2a ( 5z ?, 3a,43]~7- E 3~[[(2-Phenylethyl)-
thio]methyl~-7-oxabicyclo[2.2.1]hept-
2-yl]-5-heptenolc acid
-
To a stirred solution of lS0 mg ~0.39 mmol)
of Part A methyl ester in 19 ml of freshly distilled
THF and 2.91 ml of H20 under argc,n was added
3.64 ml of lN aqueous lithi~m hyc~oxide solution.
This mixture was purged with argon vigorously Eor
25 minutes and stirred at room temperature for
6 hours. The reaction mixture was acidified to
pH 5 ~y additio~ of lN aqueous HCl solution and.
poured into 40 ml of saturated NaCl solution.
The resulting solution was saturated with ~solid
NaCl and extracted with EtO~c (4 x 60 ml). The
combined EtOAc extracts were dried (MgSO~), filtered
and concentrated in ~acuo to give 147 mq o
-
crude acid. Purification was effected by flash
chromatography on 20 g of silica gel 60 using
2~ CH30H in CH2C12 as eluant to give title product
(122 mg, 84~) as an oil. TLC:silica gel, 6
CH3OH in CH2C12, Rf = 0.32, iodine.
A~al. Calcd for C22H3003S: C, 70.55; ~, 8.07; S, 8-56
Found: C, 70.54; H, 8.08; S, 8.48
13C NMR (CDC13, 15.0MHz)tau 179.0, 33.4, 24.5,
26.2, 129.9, 129.7, 26.7, 46.9, 80.4~
29.5, 80.6, 47.5, 32.3, 34.1, 36.4, 140.5,
128.4, 126.3, 128.4, 12~.4
Example 129
[lB,2a($Z),3,43]-7-[3-[[(3-Phenylpropyl)thio]-
met yll-7 oxabicyclo[2.2.1]hept-2-yl]-S-heptenolc acid
A. [lB,2~(5Z),3a,4B]-7-[3-[~(3-Phenvl~ro~Yl)-
,, ~ ~
thlo]methyl~-7-oxabicyclo[2.2.1]hept-2-~tl]-
S-heptenoic acid, methyl ester
To a solution of 88 mg (0.78 mmol) of
3~ potassium t-butoxide in 5 ml of dry THF under argon
: . .
HA290/280-
- -80-
.
was added 324 mg (2.13 mmol) of 3--phenylpropyl-
mercaptan. To this mixture was added a solution of
300 mg (0 71 mmol) of [1~,2a(5Z),3a,4~]-7-~3-
(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1]-
S hept-2-yl]-5-heptenoic acid, methyl ester in 7 ml
of dry THF. The reaction mixture was heated to
- - raflux for 6 hours and 30 minutes. The cooled
reaction mixture was diluted with 25C ml of ether
and poured into 100 ml of saturated NaHC03 solution.
The aqueous layer was extracted with ether
(2 x 100 ml). The combined ether extracts (4;0 ml)
was washed with 0~5 N a~ueous sodium hydroxide
solution (2 x 100 ml) and brine (100 ml)~ The
ether extracts were dried over MgS04 and concentrated
ln vacuo to give a~ 4ily product. Purification
was efected by chromatography on 25 g of silica
gel 60 using hexane:ether (3:1) as eluant to give
280 mg of title A compound as an oil (98%).
TLC:silica gel, petroleum ether:ether t2:1),
Rf 0.60, io*ine.
B. [1~,2a(5Z),3a,4~]-7-[3-~[(3-Phen~lpro~yl)-
thiolmethyl]-7-oxabicyclo~2.2.1]hept-2-yl]-
5-heptenoic acid
To a stirred solution of 280 my (0.70 mmol)
of Part A methyl ester in 34.4 ml oP freshly dlstiiled
THF and 5.30 ml of H20 under argon was added 6.60 ml
of lN aqueous lithium hydroxide solution. This
mixture was purged with argon for an hour and stirred
3~ at room temperature for 3 hours. The reaction
mixture was acidified to p~ 5 by addition of lN
aqueous HCl solution and poured into 50 ml of
saturated NaCl solution. The resulting solution
was saturated with solid NaCl and extracted with
EtOAc (4 x 60 ml). The combined EtOAc extracts
`
.
~ ~ HA290/280
-81- -
were dried (MgSO4), filtered and concentrated
n vacuo to give 280 mg of crude acid. Purification
was effected by flash chromatography on 29 g of
silica gel 60 using 2~ CH3OH in CH2Cl2 eluant to
give title product (205 mg, 76~). TLC:silica gel,
6% CH3OH/CH2C12, Rf=0.34, iodine.
Anal. Calcd for C23~32Q3S: C, ~1.09; H, 8-30; S, 8.25
Found: C, 70.81; H, 8.36; S, 8.14
13C NMR (CDC13, 15.0MHz)tau 179.0, 33.4, 24.7,
26.7, 129.7, 129.8~ 29.5, ~6.9, 80.4,
29.5, 80.6, 47.5, 32.1, 31.9, 26.2, 34.7,
141.4, 128.4, 128.4, 125.8, 128.4, 128.4
Example 130
~1~,2a~5Z),3~,4~]-7-~3-~(C~clohexylmethyl)_
thio]methyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5-
heptenoic acid
Following the procedure of ExampIes 48 and 49
except suhstituting cyclohexylmethanethiol for
l-pentanethiol, the title compou~d is obtained.
Example 131
[1~,2a(5Z),3~,43]-7-[3-~[~3-Cyclohexylpropyl)thio]-
methyl]-7-oxabicyclo[2.2.1Jhept-2-yl]-5-heptenoic acid
Following the procedure of Exa~ples 48 and 49
except substituting 3-cyclohexylpropanethiol for
l-pentanethiol, the title compound is obtained.
Example ]~2
(13,2a,3a,4~)-7-[3-[[(2-Cyclohexylethyl)~hio]methyl]-
7-oxabicyclo[2.2.1]hept-2-yl~-5-heptanoLc acid
Following the procedure of Examples 46 and 47
except substituting 2-Cyclohexylethanethiol for
l-hexanethiol, the title compound is obtained.
HA290/280
82- ~ _
Example 133
[lB,2a(5Z),3~,4B]-7-[3~[[(2-Phenylethy~thio~ methyl]-
7-oxabic ~1 _2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 48 and 49
except substituting 2-phenylethanethiol for l-pentane-
thiol, the title compou~d is obtained.
~ 4
[1~,2a(5Z),3~,4~-7-~3-[[(3-Phenylpropyl)thio]methyl]-
7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acid
Followiny the procedure of Examples 48 and 49
except substituting 3-phenylpropanethiol for l-pentane-
thiol, the title compound is obtained.
Example 135
(l~,Zd,3a,4~)-7-~3-~(2-Phenylethyl)thio]meth~1]-7-
oxabicyclo~2.2.1]hept-2-yl]-5 heptanoic acid
Following the procedure of Examples 46 and 47
except substituting 2-phenylethanethiol for l hexane-
thiol, the title compound is obtained.
; Example 1~
(1~,2a,3a,43)-7-~3-[~(3-Phenylpropyl)th~,Q]methyl]-7-
oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic a~id
Following the procedure of Examples 46 and ~5
except substit~i~g 3-phenylpnopanethiol for l-hexane~iol,
the title compound is obtained.
Example 137
[1~,2a(5Z),3a,43]-7-[3-[~(Cyclohe~ylmethyl)sulfinyl]-
methyl]-7-oxabicyclo[2.2 l]hept-2-yl]-S-heptenoic
acid (slow moving isomer)
Following the procedure of Examples 44, 77
and 81except substituting cyclohexylmethanethiol for
l-hexanethiol, the title compound is obtained.
' . HA2gO/280
-83-
Example 138
[1~,2a(5Z),3~,4~]-7-[3-[[(_yclohexylmethyl)sulfinyl]-
meth~]-7-oxa~icyclo[2.2.1~hept-Z-yl]-5-heptenoic
acid (fast moving isomer)
Following the procedure of Examples 48, 77
and 81 except substituting cyclohexylmethanethiol
for l-pentanethiol, the title compound is obtained.
Example 139
[1~,2a(5Z),3~,4~]-7-[3-~[(2-Phenylethyl)sulfinyl]-
methyl]-7 oxabic~clo~2.2.1]hept-2-yl~-5-heptenoic
acid (fast moving isomer~
Following the procedure of Examples '44, 77
and 81 except substituting 2~henylethanethiol for
l-pentanethiol, the title compound ls obtained.
Exam~le 1~0
~1~,2a(5Z),3a,4~]-7-[3-[1(3-Phenylpropyl)sulfinyl]-
methyl~-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenolc
2~ acid (slow moving isomer?
Following the procedure of Examples 48, 77
and 82 ~xcept substituting 3-~henyl~ropanethiol for
l-pentanethiol, the title compound is obtained.
.
Example 141
(1~,2a,3a!4~)-7-~3-[[(2-Phenylethyl)sulfinyl]methyl]-
7-oxablcyclo[2.2.1]hept-2-yl]-5-heptano~c acid
(fast movin~ isomer)
Following the procedure of Examples 46, 77
and 81 except substituting 2-phenylethanethiol for
l-hexanethiol, the title compound is obtained.
. HA290/280
- 84-
Example 142
[13~ 5~ 3a~43]_7_[3-[[~Cyclohe ylmet_yl)sulfonyl]-
meth~l]-7-oxabicyclo[2.2_.1 h_p -_-yl]-5-heptenoic acid
Following the procedure of Examples 44,.77
and 80 except substituting cyclohexylmethane~hiol
for l-hexanethiol, the title compound is obtained.
Example _43
[1~,2a~5Z),3a,4~]-7-~3-~[(2-Phenylethyl)sulfonyl]-
methyl]-7 oxabicyclo~2.2.1]hept-2-yl~-5-heptenoic acid
Following the procedure of Examples 44, 77
and 80 except substitutiny 2-~henyle~ethiol for
l-hexanethiol, the title compound is obtained.
lS Example 144
[1~,2~5Z),3~,43]-7-~3-~(3-Phenylpropyl)sulEonyl]-
meth ~]-7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acid
Following the procedure of Examples 44, 77
and 80 except substituting 3-phenylpropanethiol for
l-hexanethiol, the title compound i5 obtained.
ExampIe 145
[1~,2a(5Z),3a,4~]-7-[3-[2-[(Cyclohexylmethyl)thio]-
ethyl~-7-oxabicyclo[2.2.1]hept-2-yl~-5-heptenoic acid
Following the procedure of Examples 63 and 44
except substituting cyclohexylmethanethiol for
l-hexanethiol, the title compound is obtained.
Example 146
[1~,2a(5Z),3a,43]-7-~3-[2-[(Cyclohexylmethyl)sulfinyl]-
ethyl]-7-oxablcyclo[2.2.1]hept-2-yl~-5-heptenolc acid
Following the procedure of ~xamples 63, 44
77 and 81 except substituting cyclohexylmethanethiol
for l-hexanethiol, the title compo~nd ls obtàined.
'
`HA290/280 ~ -
-85-
Example 14~7
[1~,2a(5Z),3a,4~]-7-~3-[2_1(Cyclohexylmethyl)
sulfonyl ethyl~-7-oxabicyclo[2.2.
heptenoic acid
Following the procedure of Examples 63, 44,
77 and 80 except subs~ituting cyclohexylmethanethiol
for l-hexanethiol, the title compound is obtained.
Exam~le 143
[1~,2a(5Z),3a,4~]-7-~3-[2-~(2-Phen~lethyl)thio]-
ethyl]-7-oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic acid
Following the procedure o~ Examples 63 and
44 except substituting 2-phenylethanethiol for l-hexane-
thiol, the title compound is obtained.
lS
Example 143
[1~,2(5Z),3~,4~]-7-[3-~2-[(2-Phenylethyl)sulfinyl]-
ethyl]-7-oxabicycl_[2 2.1]hept-2-yl]-5- ~enoic a~id
Following the procedure of Examples 63, 44, 77
and 81 except substitutins 2-phenylethanethiol for
l-hexanethiol, the title compound is obtained.
Example 150
[13 ,2a(5Z), 3a,43]-7-[2-~(3-Phenylpropvl)thio]ethyl]-
7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Following the procedure of Examples 63 and 44
except substituting 3-phenylpropanethiol for l-hexane-
thiol, the title compound is obtained.
Example 151
[1~,2a(5Z),3a,4~]-7-[3- ~-r(3-Phenylpropyl)sulfinyl~-
ethyl]-7-oxabicvclo[2. 2 .1 ] he~t-2-y]l-5-he~tenoic acid
Following the procedure of Examples 63, 44
77 and 81 except substituting 3-phenylpropanethiol fer
l-hexanethiol, the title compound is obtained.
3iL~Sf i~7 ~ ,
HA290~230
- 86-
Example 152[1~,2a(sZ),3a,43]-7-E3-[2-~(2-Phenylethyl)sulfonyl]-
ethyl] 7-oxabicycloE2.2.1}hept-2-yl]-5-heptenoic acid
-Following the procedure of Examples 63, 44
77 and 80 except substituting 2-phenyleth~nethiol for
l-hexanethiol,'the title compound is obtained.
Example 15'3
[1~2a(5Z)~3a,4~]-7-[3-[2-[(3-Phenylpropyl)sulfonyl]-
ethylj-7-oxabicyclo[2.2.1]hept-2-~1]-5-heptenoic acid
' Following the procedure of Examples 63, 44, 77
and 80 except substituting 3-phenylpropanethiol for
l-hexanethiol, the title compound'is obtained.
Example 154
~13,2a(SZ),3a,4~]-7-~3-[4-~(Cyclohexylmethyl)thio]-
butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
Eollowing'the proce'dure of Examples 73,
63 and 44 except substituting cyclohexylmethanethiol
for l-hexanethiol, the title compound is obtained.
Example 15~
[13,2a(5Z),3,4~]-7-[3-[4-[(Cyclohexylmethvl)-
sulinyl tyl]-7-oxabic~ycloE2.2.1]hept-2-yl]-5-
heptenoic acid
Following the procedure of Examples 73, 63, 44,77 and 81except s~stituting cyclohexylmethanethiol
for l-hexanethiol, the title compound is obtained.
Example 156
[1~, 2 (5S), 3a, 4~ ] -7-[3-[4-[(Cyclohexylmethyl)-
sulfonyl]butyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5-
heptenoic acid
Following the procedure of Examples 73,63
'~A290/?80
44, 77and 80 except substituting cyclohexylmethane~ol
for l-hexanethiol, the title compound is obtained.
Example 157
[1~,2(5Z),3a,4~]-7-[3-[4-[(2-Phenylethyl)thio]-
butyl]-7-oxabicyclo[2.2.1lhept-2-yl]-5-heptenoic acid
Followins the procedure of Examples 73, 63.
and 44except substituting 2-phenyleth~nethiol for
l-hexanethiol, the title compound is obtained.
E mple 158
[1~,2a(5Z),3a,43]-7-[3-[4-~2~Phenylethyl)sulfinyl]-
buty~1]-7-oxabicyclo[2.2 llhept-2-yl]-5-heptenoic acid
Following the procedure of Examples 73, 63,
44,77 and 81 except substitutinq 2-PhenY1et~ethiol
for 1-hexanethiol, the title compound is obtained.
Example lS9
[1~,2a(5Z),3a,4~] 7-[3-[4-~(2-Pheny~ethyl)sulfonyl]-
butyl] 7-oxabicyclo~2.2.1]hept-2-yl]-S-he~tenoic acid
Following the procedure of Examples 73, 63,
44, 77and 80 except substituting 2-2henvlet~nethiol
for 1-hexanethlol, the title compound is obtained.
~56~ -HA290/280
-88- -
Example 160
[1~,2a(5Z?,3a,4~)-7-[3-[2-(hepty:Lthio)eth~1]-7-
oxabicyclo[2.2.11hept~2-yl~-5-heptenoic acid
and me hyl_ester
By reacting [1~,2a(5Z),3a,4~]-7-[3-(2-
hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-
heptenoic acid, methyl ester (sec example 20B~
with tosyl chloride as per Example 44B and with
heptanethiol according to the procedure of 44C,
the titled product is obtained as the methyl
ester as a colorless oil, TLC(silica gel,-
hexane:ether~2:1) Rf - 0.45. Hydrolysis
according to the procedure of example 45 affords
the free acid as an oil, TLC(silica gel, 3
lS CH3OH/CH2cl2) Rf - 23-
Anal. calcd. for C22H38O3S: C,69-06; H,10-01; S,8-38
Found: C,68.80; H, 9.99; S,8.24
3C NMR (CDC13, 15.0MH~)tau 178.8, 33.4, 22.5, 24.5,
129.5, 130.1, 26.6, 46;1, ~30.1, 29.7, 29.7, 80.1,
47.3, ~2.3, 31.7, 31.7, 29.5, 28.8, 32.3,
28.8, 26.6, 13.9
Example 161
[1~,2~(5Z),3a(E),4~]-7-[3-[~(3-phenyl-2-propenyl)-
thiolmethyl]oxabicycloj2.2.1]hept-2-yl]-5-heptenoic
acid and methyl ester
By following the procedure of exam~le 44 and
. substituting 3-phenyl-2-propenylthiol for the 1-
; hexanethiol used in example 44(C), the titled
methyl ester is obtained, TLC~silica gel, hexane:
30 ether(2:1)) Rf = 0.35; and continuing on with the
hydrolysis procedure outlined in example 45 affords
the titled free acid, TLC(silica gel, 3
CH3OH/CH2C12), Rf - 0.25
Anal. calcd. for C23H30O3S: C,71.46; H,7.82; S,8.30
Found: C,71.31; H,7.87; S,8.26
