CA1271198A - 5,6-epoxy-7-oxabicycloheptane substituted prostaglandin analogs - Google Patents

Abstract

ABSTRACT

A novel intermediate compound having the structure which is useful in the preparation of 5,6-epoxy-7-oxabicycloheptane substituted prostaglandin analogs having the structural formula

Description

~7~ 8 ~A3~3 S The pres~nt invention relat~s to 5,6-epo~y-7-oxabicycloheptane subs~ituted pxo~taglandin analogs which are cardiovascular agents useful, for example, in the treatment of thrombotic disease.
:~ These compounds hav~ th~ structural fonmula *~ 2~ 2 )m-C02R

~ A-~H-Rl ~ 15 o *\ I 0~
O

and incl~ading all stereoisomers thereof, wherein m is 1 to 5; R is hydros~en, lower alkyl, : 20 alkali metal sallt or E~olyhydroxylamine salt; A is -C~=~ or -(C:EI2)2-; and Rl is lower alkyl, aryl, ;~ aralkyl, cycloal~yl, cycloalkylalkyl or lowex ~ alXenyl.

:
, .
: ' , : -.
-~ .

~L~;:71198

-2- HA363 The present invention also includes intermediates for preparing the above compounds of the invention which have the structure IA ~ CH2-C~O

\ I, ~ C~2-and IB ~ C~2 c~=C~-(C~2)m-C02alkYI

O I X

/~
wherein X is CH2 ~ ~ , -CH2OH, -CH0 or -C~=CH-C R1 wherein m and Rl are as defined above~
The term "lower alkyl" or l'alkyll' as employed h~r~in by i~self or as par~ of anothex group i~cludes both str~ight and branched chain radicals of up to 12 carbons, preferably 1 to 8 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various , ' ' .

.

7~3~

branched chain isomers thereof, and the like as well as such groups including a halo-sukstituent, such as F, Br, Cl or I or CF3, an alkoxy substi-tuent, an aryl substituent, an alkyl~aryl substi-tuent, a haloaryl substituen~, a cycloalkyl sub-s~ituent, an alkylcycloalkyl substituent, hydroxy, an alkylamino substituent, a nitro substitue~t, an amino subs~itue~, a cyano substi~uent, a ~hiol substituen~ or an alkylthio substituent~
: 10 The term "cycloalkyl" by itself or as part o~ arlother group includes saturate~ cyclic hydrocarbon groups containing 3 to i 12 carbons, preferably 3 to 8 carbons, which include cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclodo-decyl, any of which groups may be substituted with 1 or 2 halogens, 1 or 2 lower alkyl groups and/or : lower alkoxy groups, an aryl group, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups or 1 or 2 alkylthio groups.
Th~ term "aryl" or 'IAr" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ringportion, such as phenyl, naphthyl, substltuted phenyl or substituted naphthyl wherein th~
substituen~ on either the phenyl or naph~hyl may be 1 or 2 lower alkyl groups, 1 or 2 haloyens (Cl, ~r or F), an aryl group, 1 or 2 lower alkoxy : groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups,.1 or 2 amino groups, 1 or 2 nitro groups, 1 ' ' :, .
.

_ ~ "

or 2 cyano groups, 1 or 2 thiol groups or 1 or 2 alkylthio groups.
The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein by itself or as part of another group refers to lower alkyl groups as discus~ed above having an aryl substitue~t, such as benzyl.
The term "lower alkenyl" or "alkenyl"
: includes straight or branched chain radicals of fxom 2 to 12 carbons, preferably 2 to 6 carbons in the normal chain, which includ~ one double bond in the normal chain, such as ethenyl,~2-propenyl,

3-butenyl, 2-butenyl, 1-pentenyl, 3-pentenyl, 2-hexenyl, 3-h~xenyl, ~-heptenyl, 3-heptenyl,

4-h~ptenyl, 3-oc~enyl, 3-nonenyl, 4 decenyl, 3-undecenyl, 4 dodecenyl and the like.
The ter~ "lowar alkoxy", "alkoxy" or "aralkoxy" include~ any of the above lower alkyl, alkyl or ar~lkyl groups li~ked to a~ oxygen atom.
The term "halog~n" or "halol' as used herein refers to chlorine, bromine, fluorine or iodine ~ with chlorine being preferred. ~-`: The term "polyhydroxylamine" ref~rs to gluca~ine salt, tri(hydroxyme~hyl)aminomethane salt and the like.
The term 1l (C~2)ml~ includes a straight or branched chain radicals having from 1 to S carbon~ in the normal chain and may contain on~ or more lower alkyl or halo subs~ituents. Examples of (C~2)m groups include CH2, CH2CH~, (CH2~3, (CH2)4, `~ , -~7~

~5- ~363 ~H3 ~H3 IH3 ~H3 C- CH~ CwCH2-, -C-C~2 ~ (CH2~5~ ( 2 6 2 7' ( ~2~2 tH , _I_CH_, C~2-FH ~ C~ CH2~, C~3 CH3 C~3 CH3 -C~ H~CH2-C~I-, a~d the like.
~H3 ~3 . Preferred are those compound~ of formula I
wherein A i~ CH~CH, and m is 2 or 4, ~
is ~, and R1 is lower alkyl, aryl,lsuch as phenyl, or ~ralkyl such as b~nzyl, or b~zyl-l~methyl or cycloalkyl, such as cyclohexyl.
The various compounds of the invention may be prepared as outlined below.
The co~pounds of fonmula I of the invention may be pxepared as describ~d below.
The startlng compounds of the invention II
may be prepared as follows.
Dione-A having the structure ~ O O
: 30 that is, 7-oxabicyclo[2.2.1]-5-hepten~-2,3-- dicarboxylic anhydride [Ber. 62, 554 (1929); Ann.
; 460, 98 (19283]~ is reduced, for exampl~, by .
.~ .
. .

. ~ .

:: ' 7~

reacting with lithium aluminum hydride or diisobutyl aluminum hydride in the presence of an inext organic solvent such as tetrahydrofuran, ether or toluene at reduced temperatures of from S about -78C to about 67C to fonm diol B of the structure 10- ~

¦ CH~OH
O

The diol B is subjected to a chloroformylation reaction by reacting B dissolvad in an inert organic solvent as descri~ed above, with phos~ene in the presence of a solvent such as tetrahydrofuran, toluene, benzene or xyl~ne, ~o form an alcohol of the structure ~f H2-0CC

\ I CEI20 o The alcohol _ is dissolved in an inert organic solvent such as methylene chloride, tetrahydrofuran or ether and then reacted with an organic base, ; such as pyridine, triethylamine, N,N-dimethyl-aminopyridine or diazabicycloundecane (DBU) at .

~A363 reduced temperatures of from about -78C to about 25 C, to form cyclic carbonate D
.

D ~ C~2 o 1~

The cyclic caxbona~e D i~ then subj!ected ~o alcoholysis by reacti~g D with a~ alkanol (alkyl-OH) having from 1 to 12 carbons, such as ethanol, n-propa~ol, isopropanol, butanol, pentanol, hexanol, heptanol, octanol, no~enol or decanol, including all the Yariou~ isomers thereof, pr~ferably isopropyl alcohol, ~mploying a molar ratio of D:alkanol of within the range of from about 1:10 to about 1:100 to form hydroxycarbo~ate E (which itself is a novel compound) ~ ~

:. ~

12-OIlOalkyl o o ~; 30 (wherein alkyl contains 1 to 12 carbons as defined herein).
Thereafter, the hydroxy carbonate E is tos~lated (or otherwise protected) by reacting E

, ~ . . .

', - ' ' .

~8- HA363 (dissolved in methylene chloride, and a basic solvent such as pyridine, triethylamine or dimethyl~linopyridine) with tosyl chloride or other protecting agent, such as methane sulfonyl chloride (mesyl chloride) and trifluorometh~nesulfonic anhydride, to form the tosylate F or other protected compound ~ CH2-OTs (or other protecting group) F ~/ ~

CH2-OCO-alkyl O O
Then, the tosylate F dissolved in an inert solvent such as dimethylsulfoxide, or dimethylformamide is cya~ated by reacting F with an alkali m~tal cyanide such as NaCN or KCN employing a molar ratio of IV:cyanide of within the range of from about 1:1 to about 10:1, at elevated temperatures of from about 80C to about 130C, in an inert atmosphere, such a~ an argon atmosphere, to form the cyano-: carbonate G (which itself is a new compound3 : 25 C~2-CN

\ ¦ C~-0~0-alkyl , ~, , 7~ 8 _g_ HA363 CyaIlocarbonate G is dissolved in an alcohol such as methanol or ethanol and treated with agueous alkali metal carbonate such as potassium carbonate at reduced temperature to form cyano-alcohol H

~ ~ C~2-S:N
~ .
\ ~ CH2 OEI
O

which is made to underyo tetrahydropyranyl ether fonmation by reacting cyano alcohol H with dihydropyran in ~he presence of an inert organic I solvent ~uch as methylene chloride or ether and catalytic amount of p-toluene sulfonic acid at reduced tempera~ures of from about O~C to about 10C, to form the tetrahydropyranyl ether of formula J

C~CN

\O
~- ~

Compound J is then mad~ to undergo epoxide formation by treating a solution o J in methylene . .

. ' , .
: .

~_ ~D ~ L ~ 3 ~

chloride or other appropriate solvent with m-chloxoperoxybenzoic acid at reduced temperatures to form epoxy nitrile II (which itself is a novel compound) ~ IC~;2-C~

10 Ot~\C~2-0 ~
O O

(which is a novel compound).

ThA compounds of formula I of the invention may be formed starting with compound II in accordance wi~h the following reaction sequence.

~ . .
.

.

.
:

Ul ~' ~
.~
o :s:

I H N
u :c C' I~
~ 0 ~
~
~\--O

~ oU
a B ~ ~ ~ ~}
:~
~ ~ u $ ~+=~ 3'`~ ~ ~

C o ~ H

.

., e71~

,.12- HA363 C
,, .x ~6 'e .~ ' .

: ' ' 7~
. 13- HA36 3 `

~.

U1~ ~ H
U I H t.) ~' 2 ^~, g ~ y~o U

~ ~
ns

5 U=O

h Z
a ~ , O=
O= ',~
_ C~

H
`

, , . ' ' "~,' '~ ' ' ' .. ' ' ' ' ~ . ~,.
: `, ' . ' ' , . . .

~:7~

_ 14- HA363 . 8 ~`:

H
O
~

`

r~
:~ ~ O
:~

Il H
. H O X
H
o , . .
~:, ' ~ ' ' ' ' .

.
. ..

3~3 -15~ H~36~

As seen from the reaction seq~ence set out above, compounds of the invention may be formed by treating I I with diisobutyl aluminum hydride ( DIBAL ) in the pre~ence of an inert solvent such 5 as toluene or tetrahydrofuran at reduced temperatures of from abou~ -70 ~o about -~5C to form epoxy aldehyde III (which itself is a new compound ) III ~CE~2-C~O

O I C~I20 ~
0 ~

Epoxy aldehyde I I I in appropriate solvent such a~ te~xahydrofuran is then react~d wi~h a susp0nsis:~n ~ormed by mixing dry carboxyalkyltri-20 phenylphosphonium halide K
.
K ( C H ) P+ B ~ ( (::~I ) COOH.~ :
in tetrahydrofuran with potassium t-a;nylate 25 in toluen~ at reduc:ed temperature and the reaction produclt treated with ethereal diazoalkane to form th~ ester IV (which also is a novel compound ) . , : .. . .

~ a3 7~ 3~3 ~IA3 63 lV f~ 2 CE C}~-(C~2)m-COOR

O ~ OE~2 ~>
O o (wherein R is lower alkyl ) Compound IV is dissol~ed i~ Ime~thanol and is the~ hydrolyzed by ~reat~en~ with ~trong acid such as E~Cl, ~mberlyst r~si~ or ac~tic acid ~o ~orm al~ohol V ~which also is a ~ovel compound~

2 CEI-(C52)~1~-C02R

O I C~12-0 -.: O

(wherein R is lower alkyl ) 2S which also i5 a nov~l co~pou~d.
The e~o:cy e ter V containiIlg the hydroxy-lue!thyl grouE~ is used to form epoxy aldehyde VI
by subjee~ing epoxy ~s~er V to Collins oxidation, for ~ aple, by ~e~cting V with chromium oxide in 30 pyridine.
Aldeh~d~ VI of the st~ ture ~ !

* Trade Mark . ~

.- : -: -3L~7 ~L~Le~3 VI ~ H2-CH=C~- ( CH~ )m-COOR

5 O/\~CHO

wherein R is lower ~lkyl (which also is a novel 10 compound3 is reacted with a dialkoxy phosphonate, such as of the s~ructure O O
L ( 30 ) 2P-CH2-~-R
employin5~ a mol2lr ra~io of V:L of within ~e raIlge of fro~ about 1:1 to about 0 . 5 :1, under h~sic: cotlditions, such as triethylamine, diazabicyclo u~decene (DBu) in t::he presen~e of 20 anhydrous lithi~Ln bromide and an inert organic ~olvent, such as methylene chloride or acetonitrile to orm ~po~cy compound V~I o~ the structure ,~ CH2-CEl-CEI-~C~I2)m-COOR
~5 VII ~

O ~ C~I=C~ R
O, O
. (wherein R is lower alkyl ) ~ ' , .

.

i ~ ` , ' -: .

~7~

H~363 -la-which also is a novel compound.
Compound VII may then be reduced by two different ways as outlined above to form compounds of the invention VIII or IX

~ CE12-C~=C~(CE12) -COOR

Ol ~ A-CH-R
O OH

(wherein R is lower alkyl) VIII - A is (~2)2 IX - A is -C~=CH-or compound~ o th~ invention of th~ general formula X

X ~ 12 C~ CEI-(C~2)~-COOR

: /
O \ I A-CE-Rl ~' ~ .
- ~wherein ~ i~ lower alkyl3 Compounds of formula I
~;

, .
, ~A363 ~ CH2-CH=C~I-(CH2)m-COOR
IA / ~

\ I A~CH-R

(wherein R is hydrogen3 may be prepared by hydrolyzing ester YIII or IX by trea~ment wi~h a strong base such as sodium hydroxide or lithium hydroxide in the ~resence o~
an inert solve~t such as tetrahydrofuran, methanol or dimetho~ye~hane~water to form ~he corresponding alkali metal salt which i~ then tr~ated wi~h strong acid such as HCl to form ~he acid compound of the inv~ntion IF.
The compounds of this invention have seven cent~rs of asymmetry as indicated by the asterisks in formula I. ~owever, it will be apparent that : each of the formulae set out ahove which do not include asterisks still represent all of the possible stere~iso~ers thereof. ~11 o~ the v~rious ~ 25 stereoiso~ ric forms are within the scop~ of ~he inv~nti~n.
The various s~ereoisomeric forms of th~
compou~ds of the invention, namely, cis-exo, cis-endo and all trans forms ~nd st~reoisomeric pairs may be prepared as shown in ~he working Exampl~s which follow and by ~mploying starting materials a~d following the procedures a outlined ~L~7~1~3~3 ~A3 63 in U. 5 ~ Patent No. 4, 143, 054. Ex~nples of such stereoisomers axe set out below.

Ia TH2~CH=CH~(CH2 )m~C2R

O I t ( cis-endo ) Ib ~ - ~ C~2-cE~=cEi- ( C~2 )I C2 10 ~ ' O~ A-~I R
` OE~

~ ~ ( cis-axo ) .

.

, ' ~ ' .

--21~

Ic ~L--cH2-cH=cH~(c~2)m C2R

A-~

O ~

( trans ) Id ~E~2 C~-CH-(C~2 )m-C02R

~}I

O A-~ R~
OH

( trans ) The wavy line ( ~ ) in the absve formulae indica~es that ~he hydroxy ~roup in each of the compc~unds of fo~ulae Ia-Id is either R(~ 3 or S~a ) .
Th~ nucleus in each of the compounds of the invention is depi ::ted as . ~ .
:~;' ' ' , . : -7~19~3 S o~

for matter of con~eni~nce; it will al~o b~
appreciated that the rlucleus in the compounds of 10 the invention may be depicted as The compounds of this invention are ~: cardiovascula~ agents useful as platelet aggre-gation inhibitors, suc:h a~ inhibiting aras:hidonic:
20 acid-indu ed platelet aggregation ( e . g ., for trea~nent of thrombotic disease, such as coronary or cer~bral thromboses) and iI~ inhibiting bronc:ho-- . constrictiorl as induced by asl:hma. They are also selectiv~ ~hromboxane ~ receptor antagonists and 25 ~ he~ase ir~hibi~ors, e.g., having a vasodilatory ef~ct for ~r~a~en~ of myocardial ischemic diseas~, such ~s angina pectoris.
The compou~d~ o this invention may also be u~ed in combination wi~h a cyclic AMP phosphodi-30 es~era~ (PD13) ir~ibitor such s theophylline or ~- ~ papaverine in the preparation and storage of platelet concentrates.

.

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.
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3~3 The compounds of the invention can be administered orally or paxenterally to various ~nammalian species known to be subject to such maladies, e.g., humans, cat5, dogs, and the like in S an effective amount within the dosage range of about 1 to 100 mg/kg, preferably about 1 to 50 mg/kg and especially abc: ut 2 to 25 mg/kg on a regim~an in single or 2 to 4 divided daily doses.
The compounds of the inventiorl may also be 10 admini~tered topic:ally to any of the above mammalian species in amounts of ~rom about 0.1 to 10 mg/kg in single or 2 to 4 divided daily doses.
The artive substance can be utilized in a compo~ition such as ta3~1et, capsule, solution or 15 suspenslon containing about 5 ~o about 500 mg per unit of dosage of a compound or mixture o~
compounds of formula I. They may be compounded in conve~tional matter with a phy iologically accsptable vehicle or carrier, excipient, binder, 20 preservati~re, stabilizer, flavor, etc. as called for by accepted phannaceutical practice. Also as indi ::ated in the discussio~ above, certain members additionally s~rve as intennediates for other members of the yroup.

, . .
.~. ~ . - ' .

~7~

H~363 The following Examples represent preferred embodiments of the invention. Unless otherwise indicated, all temperatures are expressed in degrees Centigrade.

[1~,2~(5Z),3~(1E,3S),4a,5~,6a3-7-~5,6 Epo~y-3-(3-hydroxy-1-oc~enyl~-7-oxabicyclo r 2.2.1~hept~2-yl]

A. 7-O~abicyclo[2.2.1~.5-hepten-2,3-To a ~usl?ension of 6 . 84 g of lit:hium alun~inum hydride ( ï80 mmol ) in 200 ml of freshly distilled ~, cooled in an ica-water bath was 15 added dropwise, a solution o~ 20 g of 7-oxabicyclo [ 2 . 2 . l J -5-heptene 2, 3 -dicarboxylic anhydride (120 mmol) in 150 ml o:E dry q~F, over a period o 1 hour. Ater the addition, the cooliny :i bath was r~moved and the reac~ion mixture was 20 stirred at room ~emperature for 2~ hours. The t reaction mixtur~ was now cooled in an ice-water ba~ a~d excess of hydride was destroyed by slow addition of freshly prepared saturated sodium sulfate solution. Addition was corltinued until all 25 th~ organic salts were pres:ipitat~d as white gr~ular solids. Anhydrous r~agne~ium sulfate was added to the.reac~ion mix~ure and it was filtered.
:: Th~ residue was thoroughly washed with methylene chloxide. The residu~ was taken up in 500 ml of 10% acetoni~rile in ethyl aceta~e, stirred for 30 minutes and fina}ly was filtered. The combined filtrate was concentrated under reduced pressure.
The crude residue was chromatographed on a silica ~' ' , ...
, :

:~ ' ' ' ' ,' ~ ' .

gel column. Elution with 50% ethyl acetate in hexane followed by ethyl a~etate and finally with 10% methanol in ethyl acetate afforded 17.25 g of title diol as a colorless viscous oil.

B. 7-Ox~bicy~1O[2.2.1]-5-h~ptene-2,3 To a solutio~ of ~6.73 g of Part A diol (107.4 mmole) in 200 ml of freshly distilled T~F, cool~d in an ic~-water ba~h was added dxopwise 90 ml of a 12.5% by weight solution o~ phosgene in toluene (112.5 mmol), over a period of 45 minutes.
Th~ reac~ion ~ixture was s~irred for an additional 15 minut~s, wh~reupon argon was bubbled thxough to r~move excess of phosgene and hydrogen chloride formed during the reaction. The reaction mi~ture was ~ow con¢e~trated u~der reduced pressure. The crude monochloroformate was now dissolved in 250 ml of m~thylen~ chloride a~d cooled at 50C in a dry ice-acetone bath. A solution of 25 ml of pyridine in 50 ml of methylene chloride was now adde~
dropwise ~ver a period of 20 minutes. An immediate ~ white precipitate was ormed upon addition. .The - reatio~ ~ixture was left at -50C for a~ additional 30 minutes, whexeupon ~he cooling ba~h was remo~ed and the reac~io~ mixture wa~ washed thoroughly : . with water. Th~ me~hylene chloride layer was ~ drie~ ov~r ~nhydrous magnesium sul~ate, filtered : and the filtrate was concentrated u~der reduçed :~ 30 pr~ssurs. The crude residue was triturated with e~her, cooled at 0C and the precipitated title carbo~at~ was filtered off. 15.25 g of white - crystalline title carbonate was obtained.

~ .

.`.~' , .
.

:', , . , :
- .
' ' . ' .
'' ' . . , :

~L~7~

H~363 -26~

C. 2-Hydrox~methyl-3-isopropyloxycarbonyl-oxymeth~l-7-oxabicyclo[2.2.11heptene To a suspension o~ 15.25 g of Part B cyclic carbonate (83.8 mmole) in 200 ml of isopropyl S alcohol was added wi~h stirring 1 g of p-toluene sulfonic acid. The reaction mix~ure was hea~ed und~r re1ux for 8 hours whereupon it was cooled and isopropanol wa~ remov~d by distillation under reduced pressur~. The crude r~sidue was dissol.ved in methylene chloride and washed with aqueous sodium bicarbonate solution. The ~queou~ layer was e~tracted several time~ wi~h m~thylen~
chloride. The combined methylene chloride extract was dried over anhydrous ~agnesium sulfate and was then co~centra~ed under reduced pressure ~o obtain 22.53 g of title i~opropyloxycarbonate as a viscous oilO
:~ .
D. 2~p~Toluene~ulfonyloxyme~hyl-3-isopro~
pyloxycarbonyloxyme~hyl-7 oxabicyclo-~_ ,.;~
- To a solution of 22.53 g of P~rt C isopropyl-` oxycarbonate (~4 ~ole) in 190 ~1 of pyridine wa~
added with stirri~g 19.2 g of p-toluene sulfonyl chloride (101 mmole) at 0-5C. The reaction ~ix~ure wa~ s~irred at xoom ~emp~rature for 24 hours, whereupoM it was dilu~ed with methylene chloride and wash~d ~horou~hly with water, saturated copper sulfate solu~ion and finally with water~ The combined aqueous layer was extracted with two 200 ml portions of methylene chloride.
The combined methylene chloride ~xtract was dried over anhydrous magnesium sulfate and finally was ~ ' 7~

~A3~3 -~7-concentrated under reduced pressure. The crude residue was triturated with ethex, cooled at 0C
and th~ precipitate title tosylate (28.3 g) was filtered off. The mother liquor was con~entrated and chromatographed on a silica gel column to obtain addi~ional S.~ g of crystalline title tosylate ~eluting solvent 15-30% ethyl acetate in hexane).

E. 2-Cyano~ethyl 3 isopropylo~ycarbonyl-To a solution of 5.3 g o.f Part D tosylate (12.99 ~ol~) in S0 ml o dry dimethylsulfoxide : was added with ~tirring 1.28 g of powdered sodium cya~ide (26 mmole). The reaction mixture was placed on a~ oil bath (bath temperature 90-95C) and heated ~or 2 hours. It wa~ now cooled and diluted with 200 ~1 of ether. The rea~tion : mixtur~ was now thoroug~ly washed with water~ The combined aqueous extract was extracted with two 150 ml of ether. The e~her layer was now dried over anhydrous magnesiu~ sulate and concentrated under reduced pr~s~ure. The crude residue was chromatoyraphed o~ a silica gel column. Elution 25 with 25-50% ehtyl aceta~e i~ hexane aforded 2.~8 g of title cyano-carbonate.

F. 2-Cyanomethyl,-3Dhyroxymeth~1-7-oxabi To a ~olution of 1 g of jotassium carbonate . in 25 ml of watex a~d 75 ml of methanol, cooled in -` an ice-water ba~h wa~ added with stirring a ;~ solution of 2.58 g of Part E cyano~carbonate (9.8 ' , ' ' , '.

' ' ' .
' ~'7~

~A363 ~28-mmol) in lO ml of methanol. After 15 minutes, the cooling bath was removed and the reaction mixture was allowed to stand at room temperature for additional 6 hours, whereupon it was cidified with lN aqueous hydrochloric acid solution. Most of me~hanol was now removed by dis~illation under red~ced pressuxe. The residue was now exhaustively extracted with methylene chloride SXl2~ ~ater saturating it with sodium chloride).
The combined organic extract was dried over anhydrous magn~sium ~ulfate and co~centrated under reduced pressure. The crude resid~e was chromatographed on a silica gel column and eluted with 25-50% ethyl acetate in hexane, followed by ethyl acetate to obtain 1.23 g of ~itle cyano alcohol.

G. 2-Cyanomethyl-3-tetrahydropyranyloxy-A solution of 1.23 g of Part F
:~ cyano-alcohol (7.36 mmole) in 20 ml of dry methylene chloride was tr~ated with 800 ml of dihydropyra~ (8.89 mmole) and catalytic amou~t of p-toluene sulfonic acid at 0-5C. After 4 hours, ~h~ reaction ~ixture was diluted with e~her and washed wi~h aqu~ous sodium bicarbonate solution.
- Th~ agueous layer was reextracted twice with ether. Th~ co~bined organic ex~rac~ was dried ~; over anhydrou~ maqnesium sulfate and conce~tra~ed under reduced pressure. The crude residu~ was cAro~atogxaphed on.a silica gel column and eluted with 20-25% ethyl acetate i~ hesane to obtain 1.61 g of title tetr~hydropyranyl ether.

:

. ~ , . 5,6-Epoxy-2 cyanomethyl-3-tetrahydro-pyranyloxymethyl-7-oxabicycls[2.2.1]-A solution of 1.61 g of P~rt G cyano ether (6.4 mmole~ i~ 20 ml of dry m~thylene chloride wastreated with 1.66 g of ~0% pur~ m-chloroperoxy-benzoic acid (9.6 l~ole) at 0-5~C~ Af~er a few mi~utes, ~he cooling-bath was re~oved and ~he reactioD mi~ure wa~ l~t ~tand at roo~ temperature 10 for 6 hours. The reaction mix~ure was now diluted wi~h e~her and e~cess of peracid w~s de~omposed by addition of ~queous sodiu~ meta-bi~ulfits solution. After stirring for 30 minute~, the ~ organic layer was ~eparated and the agueous layer .~ 15 wa~ e~tracted t~ir~ with methylene chloride. The co~bined organic extract was dried over anhydrous ~agne~iu~ sulfa~e and conc~trated under reduced pressure. Purifica~io~ by chromatography o~ a silica gel colu~n (eluting solve~t 25 67% e~hyl acetate i~ hexane) ~forded 1.57 g of title epoxide.
.
~ J. 5,6-~poxy-2-formyIme~hyl-3-tetrahydro-;~ ~ pyranylo~ymethyl-7-oxabicyclo[2.2.1]-: 25 To a solution o Par~ Y epoxy-ni~rile (1.57 g, 5.88 m~ole) in 25 ml of toluene, cooled at -78C i~ a d~y ic~-acetone bath was added with tirring, 6.a ~l o a 25% by wei~h~ ~olution of ~` diisobu~ylaluminum hydrid~ in ~oluene (~12 mmole), dropwi~e over a period of 5 minutes. After 4 :~ hour~ a~ -78C, exces of hydride was destxoyed by dropwise addition of 1 ml of glacial acetlc acid.
~ The cooling bath was removed and 20 g of silica :' .
- .: . . . .

. ' :. ' , - :

: -, , .

~30-gel was added to the reaction mixture with stirring, followed by 1.5 ml of water dropwise.
Stirring was sontinued for 30 minutes, whereupon the reaction mixture was filtered and the residual S silica gel was washed successively with THF, 5%
acetonitrile in ethyl acetate and finally with acetone. The combined filtrate was conce~trated under reduced pressure and the crude residue was chromatographed on a silica gel column. Elution with 50% e~hyl aceta~e in hexane, followed by e~hyl acata~e afforded 1.16 g of title epoxyaldehyde which crys~allized on s~anding at _20C .

K. [la,2~(5Z~,3~,4a,5a,6a]-7-[5,6-Epoxy-3-~tetrahydropyranyloxymethyl)-7-oxabi~
cyclo[2.2.1~hept-2-yl]-5-heptenoic acid, methyl ester ,~
A suspension of 5.77 g of freshly dried carboxybutyltriphenylphosphonium bromide (13.03 mmol), in 50 ml of freshly distilled THF, cooled in a~ ice~water ba~h was ~reated dropwise with 12 ml of a l.S M solution of K-t-amylate in toluene (19.2 mmol~). The yellow-orange suspe~sion was : 25 s~irred at 0C ~or 30 ~inute~ and finally at room temperature for 1 hour, whereupon it was cooled to -20C and a solution.of 2.33 g of Part J epoxy ald~hyde (8.69 mmole) in 10 ml of dry T~F was : added dropwise over a p~riod of several minutes.
An instant discolorization of the ylide solution was observed. The reaction mi~ture was stirred at -20C for 2 hours, whereupon it was warmed to 0C
and left for 15 minutes, prior to addition of , ~:

glacial acetic acid. The rea ::tion mixture was now diluted with e ther and washed with water . The ether extract was washed several times with saturated ~odium bicarbonate solution. The S combined aqueous extract was now washed with ether ~X2 ) . The aqueous layer was now care~ully acidified with lN aqueous hydrochloric acid to pH
2. It was now extracted with ether and then with me~thylerle chloride. Th~ combined ether alld methylene chloride extract was dried over anhydrous magnesium sulfate and co~centatad under reduced pressure. The crude residue was diluted with 75 ml of ether, cooled in an ice-water bath and an etheral diazometharle solution was added dropwise until 'che color persisted. After 30 minutes, exces diazomethane was remov~d by bubbling argon through th~ reaction mixture. It was ~ow concentrated arld the crude residue was chromatographed on a silica gel column. Elution with 15-40% ethyl acetate in hexane afforded 1.27 q of title 5Z~ester (contaminated with 10-15% of ~` undesired 5E ester).

Lo [1~,2~l5Z),3~,4a,5a,6a3-7~[5,6~
Epoxy-3-hydroxymethyl 7-oxabicyclo-~2.2.1]hept-2-yl~-5-heptcnoic acid, : m ~
To a solution of 1.27 g of Part K tetrahydro-pyranyl ether ( 3 . 46 mmol~ 30 ml of methanol was added with stirri~g 250 mg of powdered and dried Amberlyst-15. After 6 hours at room temperature, the reaction mixture was diluted with ether and anhydrous ma~nesium sulfate was added.
~dE

.,' ~ ,'-' ' ~ ' ~ ' ~ A363 -3~-It w~s ncw filtered and the residual solid was washed ~horoughly wi~ ether. The combined organic extract was dried over anhydrous magnesium sulfate and conc~ntrated undar reduced pressure.
The crude residue was c.~romatographed on a siLica gel colu~n a~d eluted with 50-75~ e~yl ~cetat~ in hexa~ to obtain 892 mg of title alcohol ester.

M. ~la,2~(5Z),3~,4a,5a,6a~-7-[5,6-a Fpoxy ~ 3 ~ for~yl-7-~abi~ycLo[2.2.1~-he~t-2-yl]-5 hept~oic acid, methyl To a ~uspe~sion of 325 mg of pyridinium chlorochromate and 325 mg of Celite in 20 ml of d~y methylene chloride was added with stirri~g a s~lution o~ 211 mg Part ~ alcohol ester (0.75 mmole) in ~ ml of ~eth~l~n~ chlorida. A ter 4 hours at room temperature, ~he r~action mi~ture wa~ diluted with 100 ml of ether and filter~d through a pad of Florisil. Florisil was washed ~everal times with ether and ethyl acotat~. The combined organic e~tract was washed with water, d~ied over ~nhydrous m~qnesium sulfate and w~s then co~centrated under reduced pressure to obtain 2S 174 mg of title aldehyda.

N. [la,2~(5Z),3~(1E~,4~,5,6a]-7-~5,6-~poxy-3~(3-~xo-l-octe~yl~-7-oxabicyclo~2.2.1]hept~2-yl]-5-To a suspe~sion o~ 90 mg of dry li~ium :~: bromide in 5 ml of dry methylene chloride was added with stirring 140 ~1 of triethylamine, * Trade Mark :
.

.~ .

7~

followed by a solution of 222 mg dimethyl-l2-oxohep~yl) phosphonate (1 mmole) in 1 ml of methylene chloride. After stirring for 15 minutes at room temperature, a solution of 174 mg Part M
5 aldehyde (O.62 mmole) in 3 ml of methylene chloride was added ~ropwise. The reaction was stirred overnight, whereupon it was diluted with ether and washed with water. The aqueous layer was extracted with ether ~X2). The co~bined ether extract was dried over a~hydrous magnesium sulfat~
and concentrated under reduced preslsure. The crude oily residue was chromatographed on a silic~
gel column and eluted with 15~30% ekhyl acetate in hexane to obtain 175 mg of titla enone.
O. ~1~,2~(5Z),3~(1E,3S),4~,5a,6~]-7-[5,6-Epoxy-3-(3~hydroxy-1-octenyl) -7oxabi-cyclo[2.2.1~hept-2-yl]-5-heptenoic and P. {1~,2~5Z),3~(1E,3R),4~,5a,6~]-7~[5,6~
Epoxy~3-~3-hydroxy-1-oct~nyl)-7-oxabi-cyclo~2.2.13hept 2-yl~-5-heptenoic To a solutio~ of 170 ~g of Part N enone :~ (0.45 mmole) in 5 ml of methanol and THF each, was added wi~h s~irring I70 mg of ceric chloride hydrate. After 10 minutes at room temperablre, the homogeneous solution was cooled ~o ~50C in a - 30 dry ice-acetone bath and 20 mg of solid sodium boro-hydride (O.S mmole) was added. The reaction mixture was stirred at -50C for 1 hour, whereupon t was treated with aqueous ammonium chloride - :' HA3~3 solution. The cooling bath was removed and the reaction mixture was diluted with ether. The organic layer was separated and the aqueous layer was reextracted successively with ether and methylene ~loride. The combi~ed or~anic extract was dried over anhydrous magnesium sulfate and concentrated. Purification by chromatography on a ~ilica gel colu~n and ~lution with 30-50% ethyl acetate in hexane afforded 130 mg of title fast-moving alcohol epimer and 40 mg of slow-moving isomer.

Example 2 [1~,2~(5Z),3~ ,3S),4~,5u,6~ 7-[5,6-~poxy-3-(3-: 15 hydroxy-1-octenyl~-7 oxabicyclot2.2.13hept-~-yl]-A solution of 130 mg of Example 1 :~ fast-moving alcohol epimer (0.35 mmole) in 5 ml of distilled lnF was treated with 2 ml of a lN
. 20 aqueou~ lithium hydroxide solution. After B hours ; at room temperatur~, the reaction mixture was diluted with ether and acidified to pH 1 by additio~ of lN agueous hydrochloric acid ~ solution. The ether layer was separated and the - 25 aqueous layer was extracted with methylene chloride (X2). The combined organic extract was dri~d over anhydrous magnesium sulf~te a~d conce~trated under reduced pressure to obtain 120 .~ mg of crude acid (contaminated with 10-15% of io presumably 5E-isomer~. Chroma~ography on a silica gel col~unn and elution with 2-3% me~hanol in me~hylene chloride af~orded 80 mg of pure title .~ acid.

. .

~ .

', ~ .
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7~1~8 -35~

Anal calcd for C21~325 C~ 69-20; ~ 8-85 Found: C, 69.24; ~, 8.84 xam~le 3 [la,2~(5Z~,3~(1E,3R),4a,5a,6a]~7-[5,6-Epoxy-3-(3-hydroxy-1-octenyl)-7-oxabicyclo[2.2.1]hept-2-yl]
5-heE~tenoic acid (s _ _ _ To a sslution of 40 mg ~la,2~(5Z),3~(1E,3S),-4a,5a,~a] 7-[5,6-epoxy 3-~3-hydroxy-oct~nyl)-7-oxabicyclo~2.2.1]hept~2-yl]-5-heptenoic acid, me~hyl ester slow-~oving alcohol ep~mer (prepared a~; described i~ ~xample 1 Paxt P) (0.11 m~ole) in 3 ml of distilled THF was added with stirring 1 ml of a lN aqueous lithium hydroxide solution. After 8 hours at room temperature, the reaction mixture was diluted with e~her and acidified with lN
agueou~ hydrochloric acid solution of p~ 1.
The organic layer was separated and the aqueous layer was ~x~racted with methylene chloxide. The ; 20 combined organic extract was dried with anhydrous magnesium sulfat~ and then concentrated under reduced pressure to obtain 33 mg of title acid as - an oil.

25Anal Calcd for C21H325~ 0-96 mole of ~2 ; C, 66~06; ~, 8.95 ~ Found: C, 66.06~ .47 ~ .
[1~,2~(5Z),3~(1E,3S),4a,5a,6a]-7-[5,6-Epoxy-3~(3-cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo-[2.2.1]hept-2-yl]-5-hept~noic acid (fast moving isomer) - --~7~1~8 ~A3 63 A. [la,2~(5Z),3~(1E),4a,5a,6a]-7-[5,6-Epoxy-3-(3-oxo-3-~yclohexyl-1-propenyl)-7~oxabicyclo[2.2.1]hept 2-yl]-5-heptenoic acid, meth~l ester To a suspension of 135 mg of dxy lithium bromide in 5 ml of methylene chloxide was added with stirring 200 ~l of triethylamine, followed by a solution of 350 mg 2-oxo-cyclohexyl~dimethyl)-phospho~ate ~1.5 mmole) in 2 ml of methylene chloxide. After stirring for 15 minutes at room temperature, a solution of 220 mg of ~1~,2~(5Z~,-3~(1E,3S),4~,5a,6a]-7-~5,6-epoxy-3+formyl-7-oxybicyclo[2.2.1]hep~ 2-yl]~5-heptenoic acid, methyl ester prepared as described in Example 1 Part M in 3 ml of methylene chloride was added dropwise~ Th~ reaction mixture was stirred at room tamperature for 3 hours whereupon it was diluted wi~h ether and washqd wi~h water. The aqueous layer was extracted with e~her (X~). The combined e~her extract was dried over anhydrous ma~nesium sulfat~ and was then concentrated under reduced pressure. Chromatographic pur.ification on ; a silica gel col~mn (eluting sol~ent 10 30% ethyl acetate i~ he~an23 gave 235 mg of desired title eno~e.

B. [la,2~(52),3~(1E,3S),4a,5a,Sa]-7-[5,6-Epoxy-3-~3 cy~lohe~yl-3-hydxoxy~
:~ propenyl3-7-o~abicyclo[2.2.1]hept-2 yl]-:~ ~ 30 5-he~tenoic acid, methyl ester (fast movina isomerl and ::
- ~ .

' : : ' . '. .
.

~ ' ~7~

~A363 C. [la,2~(5Z),3~(1E,3R),4a,5~,6a]-7 [5,6-Epoxy-3-~3-cyclohexyl-3-hydroxy-1-propenyl)-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (slow To a solu~ion of 235 mg of Part A enone (O.61 mmole) ~n 5 ml of methanol and T~F was added with stirring 235 mg ceric (111~ chloride hydra~e. Aftar ctirring or lO minut~s at room temperature, the reactio~ mixture was cooled to -50C and 25 mg of solid sodium borohydride (O.66 mmole) was added. After 1 hour at! 50C, the reaction mixture was quenched b.y addition of aqueous ammonium chlorid solution. It was now warmed to room temper~ture and diluted with ether. The organic layer was separated and the agueous layex was extracted with methylene chloride. The combined organic extract was dried over anhyd~ous magnesium sulfate and concentrated : 20 und~r r~duced pr~ssure. The crude residue was ~ chromatograph~d on a silica gel column and eluted : with 30-67% ethyl acetate in hexane to obtain 17S
mg of title B fast-moving aIcohol epimer and 35 mg of title C slow-moving alcohol epimer.
: 25 : [la,2~(5Z),3~(1E,35~,4~,5a,6a]-7-[5,6-Epoxy-3~(3-cyclohexyl-3-hydroxy-1-prope~yl)-7-oxabicyclo-[2.2.1]he~t-2-yl]-5 h~ptenoic acid (fast moving ~
A solution of 175 mg of E~ample 4, Part B, alcohol-ester (fast moving isomer) in ~ ml of dry T~F was trea~ed with 2 ml of lN aqueous lithium ~ ' ' ' .

:
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~' ' ' ' ~ ~7~

hydroxide solution. The reaction mixture was stirred at room temperature for 8 hours, whereupon it was acidified with lN aqueous hydrochloric acid solution. It was then diluted with ether and the organic layer was separated. The aqueous layer was extracted with methylene chloride twice. The combined organic ex~rac~ was dried over anhydrous mag~esium sulfate and was then concentrated under reduced pressure to obtain 163 mg of crude acid.
Chromatography on a silica gel column and elution with 3-5~ methanol in methylene chloride afforded 110 mg.of title acid.

for C22H3205: C, 70.18; H, 8.57 15 Found: C, 70.03; H, 8~59 Exam~le 6 [la,2~(5Z3,3~(1E,3R),4a,5a,6a]-7-[5,6-Epoxy-3-(3-cyclohe~yl-3-hydroxy-1-propenyl)~7-o~abicyclo-2Q ~2.2.1]hept-~yl]-5-hept~noic acid ~slow moving isomer 2 ,.. , : To a ~olution of 35 mg Example 4 Part ~
slow-moving alcohol epimer (O.09 mmole) in 3 ml of distilled THF was added wi~h stirring 1 ml of a lN
aqueous li~hium hydroxide solution. After 8 hours at room temperature, the reactio~ mi~ture was dilu~ed with ether a~d acidifiad to p~ 1 with : lN aqueous hydrochloric acid solution. Th~
organlc layer was separated and th~ agueous layer was extracted wi~h methylene chlorideO The combined organic extract was dried over anhydrous : magnesium sulfate and finally was concentrated . ~ .

H~363 under reduced pressure ~o obtain 2a mg of title acid.

A~al Calcd for C22H3205, 0.27 mole of water:
S C, 69.28; H, 8.60 Fou~d: C, 69.28; H, 8.71 ~la,2~(5Z),3~(1E,3R,4S),4a,5~,6a]-7-[5,6~Epoxy-: 10 3 ~3-hydroxy-4-phenyl-1-pentenyl)-7-oxabi yclo-. [1~,2~(5Z),3~(1E,3R,4S),i~,5a,6a]-7-[5,6-Epoxy-[3-~3-oxo-4-phenyl-1-pent~nyl~-7-oxabicyclo[2.2.1]hept-2 ~ ~
To a suspension of 90 my of anhydrous li~hi~ bromide (1 mmole) in 5 ml of dry methyle~e chloride was added with stirring 140 ~l triethyl-amine (1 mmol~). 256 mg of S+) dimethyl(2-oxo-3-methyl~3-phen~lj propyl phosphonate was then added dropwise. After 15 minutes at room temperature, a }
solution of Example 1 Part ~ 5,6-exo epo~y aldehyde (170 mg, 0.62 mmole) in 3 ml of methylene chloride was add~d slowly. The reaction mixture was stirred at room te~peratuxe overni~ht, whereupon it was diluted wi~h e~her and washed with wa~er. The org~nic layer ~as dried over anhydrou~ ~agnesium sul~ate, filtered and concentratred und~x reduced pressure. The crude oily residue was chromato-: 30 graphed on a silica gel column and eluted with 15-30% ethyl acetate in hexane to obtain 177 mg o title enone.

~2 ~

~40-B. [1~,2~(5Z),3~(1E,3R,4S),4~,5a,6a]-7-[5,6-Epoxy-3~ hydroxy-4-phenyl-1-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester To a solution of 177 mg of Part A e~one in 5 ml of dry me~hanol and 5 ml of distilled THF was added wi~h stirring 175 mg of ceric (III) chloride hydrate. After 10 minutes at room temperature, the homogeneous solution was cooled to -50C in dry iceacetone bath and 20 mg of solid sodium boro-hydride was added with stirring. ~fter 1 hour at -50C, the reac~io~ mixture was quënched by addition of aqueous ammonium chloride solution, wa~med to room temperature and w~s then diluted with e~her. The organic lay~r was separated and the agueous layer was ex~racted twice with ether and ~wice with methyl~ne chloride. The combined organic extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
: 20 The cru~e residue was chromatographed on a silica gel column and eluted with 20-50% ethyl ac~tate in hexane to obtain 133 mg of title alcohol-ester as an oil.

Ex~mç~
[la,2~(5Z),3~1E,3R,4S),4a,5a,6a]-7-[5,6-Epoxy-3-(3-hydroxy-4-phe~yl-1-p~ntenyl)-7-oxabicyclo-A solutio~ o~ 133 mq Example 7 alcohol-ester (0.32 mmole) in 5 ml of distilled THF was ~reated with 2 ml of lN aqueous lithium hydro~ide solution.
The reaction mixture was stirred at room tempera-- ture for 16 hours, whereupon it was carefully : ., .. . .

` ' :' .
.

7~

acidified to pH 1 by addition of lN aqueous hydrochloric acid solution. It was now diluted with ether and the organic layer was separated.
The aqueous layer was e~tracted with methylene chloride (X2). The combined organic extract was dried over anhydrous magnesium sulfate and co~centrated under reduced pres~ure to obtain 124 mg crude acid, contaminated with ~15% of ~-side chain ol~fin isomer. Chromatography on a silica gel column and elution with 1-3% m~hanol in methylene chloride afforded 51 mg of title afid as an oil.

Anal Calcd for C24H305 C~ 72 33; ~ 7-59 Found: C, 72.32; H, 7.57 : 15 Exam~le 9 ~1~,2~(5Z) 3~(1E,3S~,4a,5a,6a]-7-[5,6-Epoxy-3-~3-hydro~y3-phenyl-l~propenyl)-7-oxabicyclo-Following the procedure of Examples 7 and 8 excep~ substituting dimethyl(2-oxo-~-phenyl)-ethyl phosphonate for (+)dimethyl(~-o~o 3-methyl-3-phenyl)propyl phosphonate, acid, the title compound is obtained.

tl~,2~(5Z~,3~(113,35),4a,5a,6a]]-7-[5,6-Epoxy-3 (3-hydroxy-4-phenyl-1-butenyl)-7-oxabicyclo Following the procedure of Ex~mples 7 and 8 except substituting dimethyl(2-oxo-4-phenyl)-butyl phosphona~e or (+)dimethyl(2-oxo-3-.

: :`
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methyl-3-phenyl)propyl phosphonate, the title compound i5 obtained.

~e~
[la,2~(5æ~,3~(1E,3S~4~,5~,6~]-7-[5,6 Epoxy-3-(3-hydro~y-5-phe~yl-1-pe~tenyl)-7-oxabi-cyclo~2.2.1~hept-2-yl]-5-heptenoic acid, m ~
A. ~la,2~(5Z),3~(1E),4~,5a,6a~-7-[5,6-Epo~y-3-~3-oxo~5-phenyl-1-pentenyl)-7-oxabicyclo[2~2.13heptT2-yl]-5-To a suspension of 135 mg anhydrous li~hium bxomide (1.56 mmole) in 3 ml of dry methylene chloride was added wi~h stirring 198 ~l triethylamin~ ~1.42 mmol~. 386 mg dimethyl (2-oxo-4-phenyl)butyl phosphona~e (1.51 mmole) in 1 ml o me~hylene chloride wa~ now add~d dropwise. After 30 minutes at room temperature, a solution of Example 1 Part M 5~6-exo~epoxy aldehyde (200 mg, 0.7 mmole) in 3 ml of methylene chloride was added dropwise. The reaction mixture : wa~ s~irred at room tempera~ure overnight, whereupo~ it was diluted with ether and washed wi~h water. The organic layer was dried over anhydrou~ ~agnei~um sulate and concentrated under re~uced pres~ure. The crude residue was chroma~ographed on a silica gel col~mn a~d elu~ed ; wi~h 40% ethyl acetate in h~xane to obtain 208 mg of title e~one.

. :
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.

H~363 B. [la,2~(5Z),3~(1E,3S),4a,5~,6a]-7-[5,6-Epo~y-3-~3-hydroxy-5-phenyl-1-pentenyl)-7 oxabicyclo~2.~ hept-2-yl]~5-heptenoic acid, meth~l ester ~o a solution of 20~ mg of Part ~ enone (0~5 mmole) in 1 ml of methanol and 1 ml of methylene chloride was added with stirring 124 mg ceric chloride hydrate. After 10 minu~es at room temperatur , the homogeneous solution was cooled to -50C and 19 mg of solid sodium borohydride (0.5 mmole) was added. The reacti~n mixture was let stand at -50C ~or 3 hours, wh~reupon it was treated with aqueous ammonium chloride solution.
The cooling bath was removed and the reaction mix~ure was diluted with ether. The organic layer was separated and the aqueous layer W~8 extracted ~ucce~sively with ether and me~hylene chloride.
The combined organic extract was dxied over anhydrous magnesium sulfate and co~centrat~d. The ~ 20 crude residue was chromatographed on a silica gel :; column and eluted with 40% ethyl acetat~ in hexane to o~tain 11~ mg of ~itle fast moving alcohol epimer and 40 mg of slow movi~g isomer.

`~ 25 ~
[1~,2~(5Z~,3~(1E,3S),4a,5~,6a]~7-~5,6-Epoxy-3-(3-~ . hydroxy-5~phenyl-1-pentenyl3-7 o~abicyclo[2.2.1]-; . . ~ solution of 114 mg of ~xam~le 11 ester 30 (0.27 mmole) in 1 ml o f THF and 1 ml o f lN aqueous hium hydroxide was stirred at 25C for 2 hours.
The reaction mix~ure was concen~rated and ~h4n :~.

. ~

: .

$~3~

H~363 -44~

acidified with oxalic acid solution to pH 3. It was now e~tracted with ether (X3). The combined ether extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 100 mg crude oil. Purifications on preparative ilica gel plates (elu~ing solven~ 10%
in methylene chloride) gave 37 mg of title acid.

alcd for C24H305 C~ 72-33; ~ 7.59 Fo~lnd: C, 72.10; ~, 7.5g ~ i r~ 2~(5z3~3~(lE~3s)4a~5a~6a]-7-[5~6oEpoxy-3-(3-hydroxy-4-cyclope~tyl-1-butenyl)-7-oxabi-cyclor~2.Z~Ih ~ _ Following the procedure of Exa~ples 7 and 8 ~xcept substituting dimethyl(2~oxo-3-cyclo-pentyl)propyl phosphonate for (~dimethyl(2~oxo-3-methyl-3 phe~yl)propyl phosphonate, the title 29 compound i5 obtained.

[1~,2~(5Z),3~(1E,35~4a,5a,6a]-7-[5,6-Epo~y-3-(3-hydroxy-1,5-hexadienyl)-7-oxabicyclot2.2.1]-Following ~he pxocedur~ of Examples 7 and B
except subs~i~uting di~ethyl(2-oxo4-pentenyl)-phosphonate for (~)dime~hyl(2-oxo-3-methylQ3-phe~yl)propyl phosphonate, the title compound is obtained.

-~5-[la,2~(5Z),3~(1E,3S)4~,5a,6a]-7-~5,6-Epoxy-3 (3-hydroxy-1 nonenyl)-7-o~abicyclo[2.2.1]hept-Following the procedure of Ex~mples 7 and 8 e~cept substitu~i~g dimethyl(2 oxo-octyl)phos phona~e for (~dime~hyl(2-oxo=-3-~ethyl-3-phenyl)~
propyl phosphonate, ~he title compou~d is obtained.
~
[la,2~(5Z),3~1E,3S)4a,5a,6a]-7-[5,6-Epoxy-3-(3-hy~roxy1-pentenyl)~7-oxabicy~10[2.2.1~hept-2~ 5-heptenols acid Following the procedure of Examples 7 and 8 except substituti~g dimethyl(2-oxo-butyl)phos-pho~ate for (~)dimethyl(2-oxo-3-methyl 3-phenyl) propyl phosphonat~, the titl~ co~pound is obtained.

Example 1~
[la,2~5Z~,3~3R,4S),4a,5a,6a] 7-[5,6-Epoxy-3-(3-hydro~y-4-phenyl-1-pentyl)-7-oxabicyclo[2.2.1]-~' _ . A. [la,2~(5Z),3~(3R,4S),4~,5~,6a]-7-[5,~-~ Epoxy3-(3-hydroxy-4~phenyl-1-pentyl)-:~ 25 7-oxabicy~10[2~2.1Jhept-2-yl]-5-,~:
:~; To a suspension of 686 mg of purified cuprous bromide (4.8 mmole) in 12 r~l of dry TH~, ~: cooled at 0-5C is added with ~tirring 1.35 ml of 3û a 3 . 5 M solution of red-A1 ( sodium bis ( 2-methoxy-ethoxy)aluminum hydride) in toluene dropwise. The ;~ solution is stirred at 0-5C for 30 minutes, whereupon it is c::ooled to 78C and 2 ml of butanol ( 18 mmole ) ls added rapidly~ followed 35 by A solutliDn of 672 mg of Example 7 Part A enone .

.

-~6-t2 mmole) in 4 ml of dry THF. After 10 minutes at -78C, the reaction mixture is warmed to -20C and left for an additional 1 hour. The reaction mixture is quenched by addition of 70 ml of water and then poured into saturated ammonium chloride solution and e~tracted with e~her ~X3). The ether extract is dried over anhydrous magnesium sulfate, filtered and the filtrat~ is co~centrated under reduced presæure. 675 ~g of desired title keton~
0 i5 obtained.
To a solution of 338 mg of ketone ~1 mmol~) (prepared as described a~ove) in 2 ml of me~thanol and 2 ml of dry T~F is added with stirring 400 mg of ceric (III) chloride hydrate (1 mmole).
After stirring at room temperature or 10 minutes, ~he reaction mixture is cooled to -50C a~d 38 mg : of solid sodiu~ borohydride (~1 mmole~ is added to the reaction ~ixture. The reactio~ mixture is stirred at ~50C for 45 minutes, whereupon 5 ml of acetone is added to destroy excess of borohydride.
The mixture is stirred for an additional S minutes a~ -50C. The cooling bath is removed and the reaction mix~ure is evaporated to dryness. The ; crude residue is diluted wi~h ether and washed with 1 N aqueous hydrochloric acid solution. The ether ex~rac~ is dried over anhydrous MgS04 and concen~rated under reduced pressure. The crude residu~ is chromatographed on a silica gel column and eluted with ethyl acetate (30-50%) in hexane to obtain the desired title alcohol.

B. [1~,2~(5Z),3~(3R,4S),4a,5a,6u]-7~
~5,6-Epoxy-3~(3-hydxoxy-4-phenyl-1-pentyl)-7~o~abicyclo[~.2.1]hept-2-yl]-~
.

, Following the procedure of Example 8 except substituting the above Part A alcohol ester for the Example 7 alcohol ester, the title compound is obtained.

~1~,2~(5Z),3~(3S),4~,5~,6~]-7-~5,6-Epoxy-3-(3- -hydroxy-3 phenyl-1-propyl)-7 oxabicyclo[2.2ul]-~ L~L-~L~ acid Following the proc~dure of ~xample 16 and E~amples 7 and 8 exc~pt substituti~g benzoic acid for 2-phenylpro~ionic acid, the title compound is obtai~ed.
~ .
{la,2~(5Z),3~(3S~,4~,5a,6a~-7-~5,6-Epoxy-3-(3-hydroxy~-phenyl1-buty})-7-oxabicyclo[2.2.1J-Follswing the procedure of Example 16 and E~mples 7 and 8 except substituting phenylacetic acid for 2-ph~nylpropionic acid, the title compound ~: is obtained.
~;
2~ ~3~Ee~
[1~,2~(5Z~,3~(3S),4~,5a,6a] 7-[5,6-Epoxy-3-~3-~y~ro~y 3-cyd ohexyl-1-propyl) 7-oxabicyclo[2.2.1~-- Following the procedure o~ Exampl~ 16 and Examples 7 aIld 8 exc:ept ~ubstitutirlg cyclohexyl-car}:~oxylic acid for 2-phenylpropionic acid, the title compound is obtained.
.
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, lX7~1"3B

Examples 20 to 29 Following the proceduxe of Examples 7 and 8 (where A is C~=CH~ and Example 16 (where A is (CH2)2)~ except ~ubstituting for carboxybutyl-triphenylphosphonium bromide, the compound shown inColumn I of Table I set out below and substituting for (~3dim~thyl(2-oxo-3-methyl-3-phenyl)propyl phospho~ate, the compound shown in Column II, the compound of the invention shown in Column III
is obtained~

' ~, , - , ' ~, .. .

~7~L9f~

~49- HP.363 o a ~ u~ ~ ,, - ~ X~ X~ J ~ ~
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W ~ ~1 ~¦ ~ o= IL~ ~ t~ 11 ~ O
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~ ~1 ot, ~: 3: ,_ W ~, ~ ~1 ~ i~l~
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~7~C~
~A363 Example 30 [la,2~(5Z),3~(1E),4a,5a,6a]-7-[5,6-Epoxy-3-[3-hydroxy-3~ methylcyclohexyl)-1-propenyl]-7-oxabicyclo[2.2.1~hept-2-yl];5-heptenoic acid, S m A. [la,2~5Z),3~(1E),4u,5a,6a]-7-[5,6-Epoxy-3 [3-oxo-3-(1-me~hylcyclohexyl)-1-propenyl3 7-oxabicyclo[2.2.1]hept-2-y~lL5~ noic acid~ tky~_c~e~
To a slurry of 135 mg of lithium bromide ~1.56 mmole, 2.2 egui~.) in 3 ml of dry methylene chloxide at 25C was added a solu~ion of 293 mg of dimethyl [2~ methylcyclohexyl)]-2-oxo ethyl phosphonate (loS mmole, 2.1 equiv.) i~ 1 ml of methylene chloride ~nd 198 ml of triethylamine (1.42 ~mole, 2.01 equiv.). After stirring for 30 minutes, a solution of ca. 0.70 mmole of [la,2~-' ~ (5Z),3~(1E),4a,5a,6a]-7-t5,6~epoxy-3-formyl-7-o~abicyclo[2.2.1]hept~2-yl]-5-h~pt~noic acid, ~ 20 methyl ester (prepared as describ~d in Example 1 -~ Part M) in 1 ml of methylene chloride was added.
~: The stirring was continued a~ 2SC for 18 hours.
The reaction mixture was then treated with 5 ml of lM Na~2P04 solution and diluted with 30 ml of ~25 ether. The layers were separated. The organic : layer was was~ed wi~h 10 ml of a saturated K~C03 solution, lO ~l f ~2 and 10 ml of brine. The organic layer was then dried (MgS04) and concentrated.
The residue wa~ purifi~d on a silica gel .~ coIumn. Elution wi~h 25% EtOAc/hexane gave 170 mg of title enone as a clear oil.

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127~ g~3 .

-52~

B. [1~,2~5Z),3~(1E,3S),4a,5a,6a]-7-[5,6-Epoxy-3-[3-hydroxy~3-(1-methylcyclo-hexyl)-l propenyl]~7~oxabicyclo-f2.2.1]hept 2-yl~-5-heptenoic acid, m~th l ester To a solution of 170 mg of Part A enone (0.42 mmole) in 1 ml of me~hanol and 1 ml of THF
a~ 25C was added 102.9 mg of c~rium trichloride (0.42 ~nole, 1 equiv.). ~f~er stirring at 25C
for 15 minutes, the mixture was cooled to -50C
a~d 15.9 mg of sodium borohydride ~.42 mmole, 4 equi~. was added. The mix~ure waslstirred at -50C for 3 hours, then poured into 30 ml of a saturated solution of ammonium chloride. The agueous solution was extracted with three 15 ml portlons of ether. The combined extract was wsahed with 10 ml f ~2~ dried (MgSO4) and concentrated. The residue was purified on a silica gel column. Elution with 25% of EtOAc/hexane gave 12a mg of title alcohol ester.

: 1~,2~(5Z~,3~(1E,35),4~,5a,6a]-7-[5,6-Epoxy-3-[3-hydroxyw3-~l methylcyclohexyl3-1-propenyl3-~
A mix~ure of 128 mg of Exampl~ 30 alcohol :~ e~ter (O.3~ mmol~), 1 ml of lN LiO~ ~1.0 mmole, 3 eguiv.) in 1 ml o~ T~F was stirred at 25~C for 2 hours and ~hen concentrat~d. Th~ residu~ was dilut~d with 5 ml of H20, acidifyiny to p~ 3 with a saturat~d solution o~ oxalic acid, then extract0d with three 15 ml portions of ether. The combined ethereal e~tract was washed with 15 ml of :
- . . . . .
.
' - . : , 7 ~

H~0, dried (MgSO4) and concentrated to give 112 mg of a crude oil.
This oil was purified on a silica gel preparative plate (50 mg batchPs, O.5 mm silica gel plate, 10% MeOH/CH2C12~ to yield a total of 49.6 mg of clean acid product.

TLC: silica gel; 10% MeOH/C~2C12; R~ ~ 0.60 Anal Calcd fo~ C23H345~5 ~2 ~'l 8.82 Found: C, 69.10; H,' 8.51 [la,2~(5Z),3~(1E,3S),4u,5~,6~]-7-[5,6-Epoxy 3-(3-hydroxyw4,4-dimethyl-l-octenyl)-7-oxabicyclo[2.2.1J-A. [la,2~(5Z),3~(1E3,4~,5a,6~]~7~[5,6-: Epoxy-3-(3-oxo-4,4-dimethyl-1-oc~enyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-e~e~noic acid, methyl ester To a slurry of 102 mg of lithium bromide ; - (1.17 mmol, 2.2 equiv.) in 3 ml of dry CH2C12 at 25C was added a solution of 293 mg of ~:~ 25 3,3-dimethyl-2-oxo-heptyldimethylphosphonate (1.11 mmole, 2.1 equiv.) in 1 ml of C~2C12 and 148 ~1 o~ triethylamine (1.06 ~mol~, 2.01 eguiv.).
~f~er ætirring a~ 25C for 30 minutes, a solution -~ of c~. 0.53 mmole of [1~,2~(5Z~,3~(1E),4~,5a,6a]-~ 30 7-~5,6-epoxy-3-formyl 7-oxabicyclo[2.2.1]hept-2-:~ yl]-5-heptenoic acid, methyl ester (prepared as described in Example ~ Part M~ in 1 ml of CH~C12 ~as added. The stirring was contlnued at 25C for ~ ~ ' ' , ` .

~ ~ 7~
.

18 hours. The reaction m1xture was then treated with 5 ml of lM NaH2PO4 solution, and diluted with 30 ml of ether. The layers were separated. The oxganic lay~r was washed with 1 ml of a saturated KHCO3 solution, 10 ml of H2O and 10 ml of brine.
The organic layer was th~ dried (MgS04) and co~c~ntrated.
The residue was purified on a silica gel column. Elution with 25% EtOAc/hexane gave 130 mg of title enone as a clear oil.

B. ~la,2~(5Z),3~(1E,3S),4aJ5a,6a]-7-[5,6-Epoxy~3-(3-hydroxy 4,4-dimethyl-1-octe~yl3 7-oxabicyclo[2.2.1]hept-2-yl]-~
To a solution of 130 ~g o Part A enone (0.32.mmole) in 1 ml of methanol and 1 ml o~ THF
at 25UC was added 78.4 mg of cerium trich~oride 0~32 mmole, 1 ~quiv.~. After stirring at 25~C for 15 minutes, ~he mixture was cooled to -50C and 12.1 mg of sodium borohydride (O.32 mmole, 4 equiv.) was added. ~he mi~ture was s~irred at 50C for 3 hours, ~hen poured into 30 ml of a saturated ~olutio~ of ammonium chloride. The aqueous solution was extracted with three 15 ml . portio~s of e~her. The combined ex~ract was washed with 10 ml of ~2~ dried (MgS04) and co~centrated. The residue wa~ purified on a silica gel col~m~. ~lu~ion with 25% EtOAc/hexane gave 96 ng of title alcohol ester.

.

. .

.. ..

7~
~A363 -55~

Example 33 [la,2~(5Z~,3~(1E,3S),4a,5a,6a]~7-[5,6-Epoxy-3~3-hydroxy-4,4-dimethyl~l octenyl)-7-oxabicyclo-[2.2.1~hept-2-yll-5-heptenolc acld _ A mixtuxe of 96 mg of Example 31 alcohol ester (O.23 mmole), 1 ml of lN LioH (1.O mmol~l 4 eguiv.) in 1 ~l of T~F was stirred at 25C for 2 hours, the~ concentrated. The residue was diluted with 5 ml of H2O, acidifying to p~ 3 with a saturated solution of oxalic acid, the~ extracted with three 15 ml portions of etherl The combined ethereal extract was washed with lg ml f ~2~
dried (MgSO4) and concentrated to give 75 mg of a crude oil.
This oil was purified on silica gel preparative plates (50 mg batches; 0.5 mm pla~es;
10% MeO~ 2C12) to yield a ~o~al of 49.8 mg of clean acid product.

20 TLG: silica gel; 10% MeOH/CH2C~2; Rf ~ 0.55 1 Calcd for C23~36O5: C, 70.37; H, g.24 Found: C, 70.34; H, 9.43 :

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Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are de-fined as follows:

1. A compound having the structure