CA1041495A - Process for preparing a 15-substituted-w-pentanorprostaglandins - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A process for preparing .omega.-pen?anorprostaglandins having at the 15-position a hydrogen or lower alkyl group and one sub-stituent of the formula:

Ar-(CH2)n-wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl;
3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; and n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1, and various intermediates employed in their preparation is described.
The novel prostaglandins of the invention have been found to have activity profiles comparable to the parent prostaglandins but exhibit a greater tissue specificity of action.

Description

This invention relates to certain novel analo~s of the naturally occurring prostaglandins. In particular, .
lt relakes to novel 15-substituted- ~ pentanorprostaglandins and various novel intermediates useful in their preparation.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, khe prostaglandins of the E and A series are potent vasodilatorq (Bergskrom, et al., Acta. Physiol. Scand.
64:332-33, 1965 and Bergstrom, ek al., Life Sci. 6:449-455, 1967) and lower systemic arterial blood pressure (vasode- `
pression) on intravenous administration (Weeks and King, ~ `~
Federation Proc. 23:327, 1964; Bergstrom, et al., 1965, op.
cit.; Carlson, et al., Acta. Med. Scand. 183:423-430, 1968;
and Carlson, et al., Acta. Physiol. Scand. 75:161-169, 1969).
Another well known physiological action for PGE1 and PGE2 is as a bronchodilator ~Cuthbert, Brit. Med. J. 4:723- `
: : 726, 1969).
Still another important physiological role for the , ~
natural prostaglandins is in connection with the repro~uctive 20~ cycle. PGE2 is known to possess the ability to induce labor (Karim, et al., J:. Obstet. ~ . Brit. Cwlth. 77: 200-210, 1970), to induce therapeutic abortion ~Bygdeman, et al., , 4, 293, 1971) and to be use~ul for control of .: ; .
~ ertility~Karim~ Contraceptionl 33 173 (1971). Patents have ~ , : , ~
; 25 ; been obtained ~or~several pros~aglandins o~ the E and F series

2~
~ , ' , ~ , : ~ ~ ':.', ':

4~
as inducers of labor in mammals (Belgian Patent 754,158 and West German Patent 2,0343641) and on PGFl, F2 and F3 for control of the reproductive cycle (South African Patent 69/6089). It has been shown that luteolysis can take place as a result of administration of PGF2~ [Labhsetwar~ Nature 230 528 (1971)] and hence prostaglandins have utility ~or fertility control by a process in Nhich smooth muscle stimula-tion is not necessary.
Still other known physiological actlvities for PGEl are in the inhibition of gastric acid secretion ~Shaw and Ramwell, In: Worcester Symp. on Prosta~landins, New York, Wiley, 1968, pp. 55-64) and also of platelet aggrega-tion (Emmons, et al., Brit. Med. J. 2:468-472, 1967).
It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. A substantial body of evldence lndicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by ~ -oxidation o~ the carboxylic acid side-chain and by oxidation of the 15~ -hydroxyl group (Anggard, et al., Acta. Ph~siol. Scand., 81a 396 (1971) and references cited therein). It has been shown that placing a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action possibly by ;25 preventing the oxidation of the C-15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972)], ~Kirton and Forbes, Prosta-glandins~ 1, 319 (1972)].
~; It was~ of course, considered desirable to create analogs of the prostaglandin~ which would have physiological activities equivalent to the natural compounds, but in which ~ .

the selectivlty o~ action and the duration o~ the activity would be increased. Increased selectivity of action would be expected to alleviate the severe side e~fects, particular-ly ga~trointestinal side effects, frequently observed follow-ing systemic administration of the natural prostaglandins .
(Lancet, 536, 1971).
These needs are met by the novel compounds o~ this invention, the 15-substituted- ~-pentanorprostaglandins in which the substituent in question is of the structure:
Ar-(CH2)n~
wherein Ar is ~-, or p-~uryl; c~- or ~-thlenyl; ~- or ~-naphthyl; phenyI; 3,4-dimethoxyphenyl, 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl or mono-substituted phenyl wherein said substituent ls halo, trifluoromethyl, phenyl, :
lower alkyl or lower alkoxy; n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substltuted phenyl or naphthyl n is 0 or 1, and in which the remaining 15-hydro-gen may be replaced by a 15-lower alkyl group if desired.
In addition to the 15-substituted- _-pentanor- .
prostaglandins wherein the prostaglandin is PGFl~, PGF ~, . .
PGEl, PGAl: 13,14-dihydro PGF~X, PGF ~, PGEl, and PGAl;
PaF2~, PGF2~, PGE~, PGA2; 13,14-dihydro PGF2~, PGF2~, PGE2, and P~A2; 15-lower alkyl derivatives of the above compounds, ...
: thi~ invention further comprises a compound o~ the structure~
O O
~ OCH3 : 25 Ar~(CH2)n~C~CH2~P OCH3 : wherein Ar is ~ - or ~ -furyl; ~ - or ~ -thienyl; ~- or naphthyl; 3,4-methylenedioxy phenyl; 3,4-dimethoxy phenyl;

3,4,5-trimethoxy phenyl or mono-substltuted phenyl wherein

-4-.,, sald substituent is halo9 trifluoromethyl, phenyl, lower alkyl or lower alkoxyl, and n is an integer from O to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is O or 1, and useful intermediates for these prostaglandins as follows:
a compound of the structure ~. , ~ C~O~ CH2)n-Ar whereln Z ls a single bond or trans double bond;

a compound of the structure:
. ~C5 0 ~
CH2)n-Ar '.
QO' H~- ~
wherein R is hydrogen or lower alkyl; and Q ls hydrogen or parabiphenylcarbonyl, n ls an integer from O to 5; z ls a H
single bond or a trans double bond and X is -O or ~
: ~ H
a compound of the structure:

. . .:' ..

~icH2)rl-Ar R ~ OTHP : .:
- ,,:

~ -5- . ~
'';~ ~ .,- .
' ~ ~" 7~
::; ' ' :"

wherein THP is tetrahydropyranyl, and X ls =O or <
OH
a compound of the structure:
OH
O ..
-OH

THPO- ~ C~12)n~Ar R "OTHP
wherein W is a single bond or a cis double bond;
5a compound of the sturcture:
O ~ .`.,'.~.'.

~ ~"` ~ -OH .....

THPO,' ~ CH2)n-Ar R "OTHP
wherein W, Z, THP, R, Ar and n are as previously de~ined; and ~:
especially 16-phenyl-~J-tetranor PGE2;
16-phenyl-~J-tetranor PGF2~;
16-phenyl- ~J-tetranor PGEl;
16-p-methoxyphenyl- ~-tetranor PGE2; ~.
: : 16-_-biphenyl- ~-tetranor PGE2; . :
16~ -naphthyl-~)~tetranor PGE2;
16~ -naphthyl- ~-tetranor PGE2;
: 15 16-o-methylphenyl-~J-tetranor PGE2; . , : .
16-~-methylphenyl- _-tetranor PGE2;
13,14-dihydro-15-phenyl-~J-pentanor PGE2;
16-phenyl-13,14-d1hydro-15-methyl~
tetranor PGE2; ~:
16-~-biphenyl-lJ-tekranor PGF2~;
16-o-methylphenyl-1~-tetranor PGF2~; . ::
: ~ 16~ -naphthyl- ~-tetranor PGF2~; ~ :
16~ -naphthyl- -tetranor PGF2~; :

. . :

16-phenyl~13,14 dihydro~-tetranor PGA2;
13,14-dih~dro-16-phenyl~ tetranor PGE2;
16-phenyl~ ~-tetranor-13,14~dihydro PGEl;
16 ~ -thianyl-~ -tetranor PGE2;
16~ -thienyl~ -tetranor PGE2;
17c~ thi9nyl-~ ~tris-nor PGE2;
170<-ruryl~ -tris-nor PGE2;
17~uryl- ~tris-nor PG~2~ and 17O~-thienyl_~ -tri~-nor PGE2, 17~ ~uryl-~ -trisnor PGE2;
17~ -~uryl-~ -trisnor PGF2~ , 17~ -thienyl- W-trisnor PG~2~ ;
17~ -thienyl-~-trisnor PGE2 and the Cls epi~ers o~ these compounds, such a9 15 epi-16 phenyl-13,14 dihydro-~ -tetranor PGE2.
It will be und3rstood by those skilled in tho art that in qtructures depicting hemiacetals, no sterochemi~try ::
i~ implied at the lactol carbon. ~
It will b~ ~urther understood that as herein used, :: :
the axpression "prostaglandin o~ the ~zerot series", ~or example PGEo , re~ers ~o prostaglandins in which the 5-6 :
: ; and 13-14 double bonds have been saturated9 i.e~: PGEo i9 5-6~ 13~14, tetrahydro PGE2~ In addition, the phrase~
: : "zoro seri;es'i~ "on~ serie~" or "two serie~ herein em~
ployed r~rer~to the dogroe o~un~aturation in the sid~
hain~, e~g., PGE2, PGA2 and PGF2C~, are prosta~landin~ o~
: the "two serie~" wherea~ PGEl, PGFl~ and PGAl are pro ta-glandins o~ the "one seria~". Furth0rmore as haroin employad :
the~ phrase low~r "alkyl group~ rerers to alk~l greups ¢on-~taining ~rom 1 to 4 carbon atoms. : : .
. ~ .
~ : 7~

- , ~
: `

~34~
An aspect o~ tha invsntion is concorned with a process ~or prsparing a compound o~ the structure:
M

L ~ ~ OH

N ~ C~I2)n_Ar .............................. I .
wherein Ar i~ ~ - or ~-furyl; ~- or ~ -thienyl;
or ~-naphthyl; phenyl; 3,4-di~ethoxyphenyl, 3,4 methylene~ ;
dioxyph3nyl; 3,4,5-trimethoxyphenyl; or mono-sub~tituted ~henyl wherein said sub~tituent i9 halo, tri M uoromethyl, phenyl, lower al~l or lower alkoxy; ;.
n is an integer ~rom O to 5 with the provi~o that wh~n Ar is phenyl, ~ubstituted phenyl or naphthyl n i O or l;
R i9 hydrogen or low~r alkyl; ;::
W is a single bond or cis double bond; ;:
Z is a ~ingla bond or tran3 double bond;.~.
.
~ /~ ~OH
: 15 M i~ koto, ~ or ~OH `H ; .;~
N and L whan taken together .~orm a ~ingle bond, or -:
N is o~-hydroxyl when L i~ hyarogen, and wher~in : L,~ M and N are ~o se1ected as to complete the : 20 ~truoture o~ ~ prost~glandin o~ the ~, E or F series, the :10ws~alkanoJl~ rormy1 or benzoyl esters o~ an~ free hydro~
;groups ~t the C9~ Cl1- and Cls-positions, and the pharma ceutically aeoep~able ~alts thereor3 characterizad b~ the t t~it-;

. ~
.

::: ~: :

a) when N is ~ hydroxy and L is h~drogen, and Ar9 n, M, W and Z are as darined above, said compound iq prepar~d by treating the 11 , and ll- and 15-tetrah~dropyranyl ethers o~ a compound o~ Formula I above, with a suitable acid;
b) whon N and L~ ~hen taken tog~th~r form a single bond, M i9 keto and Ar, n, R, W and Z are as de~ined above, said oompound i9 prepared by reacting a compound o~ Formula I, ~bove, wherein N is C~ -hydroxy and L is hydrogen, M is keto and Ar, n~ R, W and Z are as d~ined above, with a suitable dehydrating agent;
c) when H
N is ~ -hydroxy and L is hydrogen, M is ..

H
or < and Ar~ n, R, W and Z are as de~ined above, `H
said compound is pr0p~red bg reacting a compound Or the ~ormula ~ :
I, above, wherein N is C~ hydroxy and L is hydrogen, M is koto, Ar, n, R, W and Z are a~ de~ined above, with a suitable reduoing agent, and, i~ desiredJ separating the 9 ~ - and 20 9p- isomers;
d) when N i9 os~hydro~, L i~ hydrogen~ Ar, R, n and M are as derinsd abovo, and W and Z are singl0 bond~, said oompound:~s pr~parsd by catalytic reduction o~ a compound o~
25~: Formula I~ above, wher~in Ar7 R, n and M are as d~in~d above, W is a ~ingle bond or cis doubla bond when Z i9 ~ trans double bond and Z is a 9ingl9 bond when W is a ¢i9 double bond;
;9~ .:
;: : .

~ : .

9~
e) when N is ~ -hydroxy, L is hydrogen5 Ar, R, n and M are as de~ined above, W is a singlo bond and Z is ~ trans double bond, ~aid compound is prepared by selective roduction Or a compound o~ Formula I, above~ wherein Ar, R, n and M :
are a3 dorin~d above and W and Z are double bonds~
and, i~ desired, preparing the 9~ -, 11~ - ;
and 15~ lower alkanoyl, ~ormyl or benzoyl ester~ o~ any free h~dro~yl groups by reacting said compound~ with the appro-10 priat~ acylating agents and, i~ desired, preparing the pharma- . ;
ceutically acceptabl0 salt3 o~ the3e oQmpounds. ~ ~:
More speci~ically, an a3pect o~ the in~ention reside~ in a process ~or preparing a compound o~ the 3tructure:
~. ~. .
OE ~ :

OOH
~ CH2)n Ar HO~ R "OH ~.. IA :.
whsrein A~ i3 ~ -, or ~ -~uryl; o~or ~-thienyl; ~ -or ~ naphth~l, phenyl; 3,4~dimethox~phenyl~ 3,4-meth~lene-dioxyph~nyl; 3,4,5~trimethoxyphenyl or mono-sub~tituted phenyl wherein said substituent i3 halo, trifluoromethyl, phenyl, ~, .
~ ; 20: lower alkyl or lower alko~, : ~ n is an intege~ ~rom O to 5 with the proviso that when Ar i3 ph~nyl, substituted phenyl or naphth~l n i~ O or l;
R i~ hydrogen or lowor alkyl;
W i3 a singl~ bond or ci~ doublo bond; and Z i~ a singl~ bond or tran~ double bond;
~he lower alkanoyl, ~ormyl or benzoyl es~3:rs o~
lQ -~

'','.: ' 4~S
any ~ree hydroxyl group~ at the C9-, Cll and Cl~- po~itions, and the pharmaceutically acceptable ~al.t~ thereof, ch~rac terized by the ~act that a) the 11-, and 11- and 15-tetrahydropyranyl ether3 o~
a ¢ompound o~ Formula I, above, i9 treated with a suibabla acid;
b) a compound of tha ~ormula:

~ OH

HO\~ CH2 )n-Ar ~ "OH ... IB
wherein Ar, nl R, W and Z are as de~ined above, is reduced with a suitable reducing agent and th0n 9eparating the 9c~ -Qnd 9 y -i~omers;
c) a compound o~ the ~ormula~
,0 '` "~ .
O C~CH3 OOR

~" ~ ~ ~ CH2)n;~r :
HO~ R
OH
wherein W i~ a ~in~l~ boncl, and whorein Ar, n, R and ~ are 15as d~ined abovo, and R~ i:s h~drogen or lower alkyl, i9 ~ :
treated with a suitable base;
:
:d) a compound o~ Formula IA, above, wharein Ar, R and ~:
n are a3 de~ined above, W is a single bond or ci~ double bond ~` .
when Z il3.~a ~r~n~ doubl~ bond and Z i3 a single bond when W
20 i3 ~ cis doubl~ bond, i9 Gatal~tioally reduced to a compound ~: :
of Formu1~ IA, abovo, whe~ein Ar, R and N are as de~inad . ~ . , 9~
above and W and Z are ~ingle bond~;
e) the dimethyli~opropyl~ilyl derivative o~ a compound Or Formula IA, above9 who~ei~ Ar, R and n are a~ de~ined above, W is a cis double bond and Z i~q a trans double bondg i~ selectively oatalytically reduoed to a compound of Formula IA, above, wherein Ar, R and n are as de~ined above, W is a~ :
single bond and Z is a tran~ double bond;
and, i~ de~ired, preparing the 9c~ ~, llc~ -, and 15c~ lowar alkanoyl, ~ormyl or benzoyl ester~ o~ any ~ree :.
hydro~yl group~ by reacting ~aid comp~unds with the appro~
prlAts acylating agsnts, and, i~ d~qired~ praparing tho pharmaceutioally acosptab:le salt9 Or th~se oompound9.
More sp0ci~ically, an aspect Or ths invantion reside~ in a process ~or preparing a compound o~ the 8tructure:

O

~ ~OOEI
H0~ 2)n-Ar ...IB
wherein Ar i.q ~- or ~ ~uryl, G<- or ~ -thienyl; o~-or ~ -naphthyl; phenyl; 3,4-dimethoxyphen~l; 3,4-methylene-dioxyphonyl; 3,4,5-trimethoxyphenyl; or mono-substituted 20 ~ phenyl whorein said 3ubstituant is h~log tri~luoromethyl, ~ .;
phenyl, lower alkyl or lower alkoxy;
. n i~ an integer ~rom 0 to 5 ~ith th0 pr-oviso that when~Ar i~q phenyl, substituted phanyl or naphthyl n i~ O or l;
R is hydrogen or lower alkyl; . :~
: 2~ W is a singlo bond or cis double bond; and ;
12- : :

~ (34~L~9S
Z i~ a single bond or tran~ double bond;
the lower alkanoyl, ~ormyl or benzo~l e~ter~ o~
any ~ree hydroxyl group~ at the Cll- and Cls-pvsition~9 and tha pharmaceutica'lly acceptable salts thereo~, characterized by a) treating the 11- or 11- and 15-te~rah~drop~rainyl ether~ o~ a compound o~ ~qrmula IB9 ab~ve3 wherein Ar, R, : ' n, W and:Z are as de~ined above~ with a ~itable acid;
b) catalytically rsducing a compound o~ Formula IB, above, wherein Ar, R and n ar~ as de~ined abovo, W i~ a single bond or a cis doubis bond wh~n Z is a trans double'bond and' Z i9 a 9in~1e bond when''W i9 a Ci9 doubla bond, to a~ord a compound or'Formula IB wherein Ar, n and R are a~ de~ined above and W and Z are ~ingle bond~
~ 15 ~ c ) . selsctivel~ catalytically ~educing the dimsth~ o-- propylsilyl derivat1ve o~ a compound o~ ~ormula IB, abov~g .; ., whersin Ar, R and n are as d~in3d~abo~e, W~is a ci~ double . .' bond and Z i9 a tran~ double bond, to a~ord a compo~nd Or Formula IB, above, wh0roi~ Ar, R and n are as de~ined abov3, W is~a single bond and Z i~ a tran~ double bond;
~nd, i~ dosirodJ preparing the lowsr alkanoyl, .': '':
rormyl or benzoyl esters o~ any ~re~ and 15-hydroxyl groups b~ reacting sa~d compounds with the appropriate acyl~
.
~ ~ ~ ating ag~nts, and, i~ desired, pr~paring the ph~rmaceutically '' : :
: ~ h 25 ~ accopta~ble salts o~ th0~e co~pound~
.
Mo~e speci~ically, an aspeot o~ th~ invontie~ r3 ' '-9id~s in a process ~or preparine a compound o~ the structure~
.: ., .

13~

'' ' :, -OOE

~ ~ ICE2)rl-Ar ...IC
wharein Ar i9 o~ or ~ -~ur~ or ~ -thianyl;
or ~ -naphthyl; phenyl; 3,4-dimothoxyphenyl; 3,4~methylene-dio~yphenyl; 3,4,5-trimethoxyphen~l; or mon'o-9ub9tituted ` phenyl'wherein said'substituont~is halo, tri~luoromethyl,~
phenyl, lower alkyl or lower alkoxy;
n is an integer from O to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is O or l;

: . .
~ 10 R is hydrogen or lower alk~
.
W is a single bond or ci~ double bond3 ~ .' Z is a ~ingle bond or trsns double bond9 the lower alkano~ orm~l~or benzoyl estars o~

: ' the Cls-h~droxy group, and t.he pharmaceutically acceptable salts thareo~, charaot~rized by . :.

; ~ . treating a compound o~'~ormula IB, ' .;.

.. .

OOH

2~n ~
XO~ : R ~"OH ~.~IB

~hs~in Ar, R, n, W and Z ar~ as dsi~ined above"

20 ~ ~ with~ a~ ~;uitab:L0 dehydrating ~agerlt; ~
and, ir de~ir~d, pr~paring the el5-low~r alkanoyl" .' .: ~
, .. ... . .. .... . .. .. . .. ... .. .

~ormyl or benzoyl estars by reactin~ ~aid compound with the appropriate acylating agent~, and, i~ desired, preparing the ph~rmaceutically acceptable ~alts o~ these compound~.
FurtherJ an aspect o~ tho invention i9 ¢oncerned with a proces~ for preparing a compoum~ of the ~tructure:
,. ,~0 )n~Ar - ........... II :
wherein Ar i8 ~- or ~ -~uryl; ~ or ~ -thienyl; ~ ~ or ~ -naphthyl; phenyl; 3~ dimetho~yphenyl; 3,4-methylenedioxy- :
phenyl; 3,4,5-trimethoxyphenyl; or ~ono-substituted phenyl whercin said sub~tituent is halo~ tri~l~orometh~l, phenyl, . ~: ;
lower alkyl or loNer alkoxy and n i~ an integer from 0 to 5 with the proviso that : :~
~hen Ar i~ phenyl9 subqtituted ph~nyl or naphthyl n i9 0 or 1, :~
charaoterized by . reaoting a compot~d o~ the ~ormula ~'' \~C~O ~ ~

~ with dialkylmethylketophosphonate o~ the ~ormula ~
...
o o ~ . , t~
: Ar (CH2)nC-GH2-p(o-lower alk~l)2 :
~ 20 wherein :~ Ar ~nd n are a~ de~ined above. :
. ' : ~ , ' '. ":
. . ~, ~`
. . . : .

4~S
Additionally, an aspect o~ ~he invention is con-cerned with a proces~ for preparing a compound o~ the struc-ture:
~P

~`~
CH2 )n-A.r Q0~ ~o~r R ... III
5wherein Ar is ~ - or ~uryl; ~- or ~ -thienyl; ~-or ~ -naphthyl7 phsnyl; 3J4-dimethoxyphanyl; 3,L~_methylene-dioxyphenyl; 3,~,5-trimethoxyphenyl; or mono substituted phenyl wherein said substituant i3 halo, tri~luoromethyl, 10 p~enyl, lower alkyl or lower alko~y;
n i~ an integer rrom 0 to 5 with the provi~o that ~:~
when Ar i9 ph0nyl, sub9titut~d phonyl or naphthyl n is 0 or ;
R is hydrogen or lower alkyl; and Q is hydrogen or ~-biphanylcarbonyl~
¢haracterized by aj reducin~ ~ compound o.~ the Formula IIA
O ~P ,'' : ~ ~ CH ) _Ar : Q0 '~ :
where~n Ar, n and Q are a~ d~in0d above, to a~rorcl a GOm~ : .
:: : :
: 20 pound o~ For~ùla III, above, wher0in Arg n and Q ara as 16.
.. ~,, .

derined above and ~ ~ hydrogen, and, i~ desired, ~eparating th~ 15 ~ - and 15 ~ ers;
b) treating a compound o~ Formu:la IIA~ a~ de~ined above, with a quitabl0 alkylating agent to ar~ord a cQmpound o~ Formula III, wherein Ar, n and Q are aq de~ined above and R i~ lower alkyl;
andJ i~ de~ired treating a compound o~ ~or-mula III, above, wherein Ar, n and R are a~ derined abovo and Q is bi phenylcarbonyl with K2C03 to a~ord a compound o~ Formula 10 . III wher~in Q i~ hydrogen; and, i~ desir0d, qeparating the 15c~ r and 15 ~ -isomer~.
Furth~r, an aspect o~ the invention concarn~ it~el~
with a proce9~ ror preparing a ¢ompound Or the ~tructure:

~ ` ~ C~2)n~Ar THP0" R THP ................................... IV :
wherein Ar is ~- or ~ -ruryl; o<- or ~ -th-ienyl; ~ -or ~ -naphthyl; phenyl; 3,4 dimetho~yphenyl; 3~4-methylene dloxyphenyl; 3~4~5-trimethoxyph2nyl; or mono-substituted phen~l wherein ~aid ~qub~tltuent i~ halo, tri~luoromethyl, phenyl~ lower alk~l or lowor alkoxy;
n i9 an intager ~rom 0 to 5 with the provi~qo that when A~ i~ phenyl, 3ub~qtituted phen~l o~ n~phthyl n i3 0 or 1; :
R i~ h~drogan or lower alkyl;

: THP i~ 2~t~trah~dropyranyl; : ~ .
: ~25 : ~ Z i~ a ~ingle bond or a tran~ double bond; and ;"
~ : ~17- . l ~.. : ,, ,. , .. : . ,, .. , . . . . , . . . . .. . - . ..... . . .

H
X is =O or <
\ OH
characterized by a) reacting a compound Or the Formula IIIA
X

~ ~ .
HO` ~ CH2)n;Ar ... IIIA ~ ~
wher~in Ar, R, n and Z are as d~rined above and X i~ =O .
with Z,3-dihydropyran in the preqonce o~ An acid ¢atalyst to a~rord a compound o~ Formula IV wherein Ar, R, n and Z
are as de~n~d above and X i~ -0;
b) reacting a compound Or Formul~ IV, above, whorein .
:~ 10 Ar~ R, n and Z are as de~ined above and X i~ =O with dii~o~
butylaluminum hydride to a~ord a compound o~ Formula IV
wherein Ar~ R, n and Z are as defined above, and X i~

- ~ , , ~; , OH
c) by oatalyticall~ r~ducing a compound o~ Formula III
~ abov~ wherein Ar, R and n are a3 de~ined above, Z is a tr~n doublo~bond~and X 1s -0~ to a~ord a compound o~ Formula IV
whsrein Ar,:R and N are a~ de~ined above, X i~ =O a~d Z i~
a ~ingle bond.
:: Wlthln the ambit o~ the invention i~ a proo~s3 rOr 20~ p~par1ng a compound o~ the t~uctur~:

OH
O

" ; .
~ ~( CH2 )n~Ar THPO~ R OTHP ... V
whersin :
Ar i~ O<- or ~-~uryl~ ~ - or ~ thienyl, c~-or ~ -naphthyl; phenyl; 3,4-dimethoxyphen~l; 3,4 meth~lene~
dioxyphenyl; 3,4,5-trimethoxyphenyl; or mo~o-~ubstituted phen71 wh3rein said substituent i9 halo, tri~luoromethyl9 ph9nyl, lower alkyl or lowsr alkoxy;
n is an integer ~rom O to 5 with the provi~o that when Ar i~ phenyl, sub~tituted phen~l or naphth~l n i~ O or 1, R i~ h~drogen or lower alkyl; ~ ::
THP i~ 2-t~trahydropyranyl3 ~ :
. W i9 a single bond or a Ci9 doublo bond; and ~;
Z i~ a ~ingle bond or .tran~ double bond;
characterizad by reaoting a compo~d o~ the Formula IVA
OH

CH2)n-Ar~
TXPO` R THP IVA `~
wherein ~ `.
:Ar j R, ~ and Z are a~ de~insd above :with an ylide o~ the ~ormula ..
20~ (a6~5)3p=cH~cH2-cH2-cH2 COO( ) to ~X~ord a compound o~ Formula V wherein Ar, R9 n and Z .:
19- .

: r~;

s are as de~inad above and W i~ a cis doubl~ bond, and, when required, ~ubsequently reducing th~ co~pound thus ~orm~d to a~ord a compound o~ Formula V wherein Ar9 R, n and Z are a~ de~ined above and W i~ a single bond;
b) by reducing a compound Or Formula V above, wheroin Arl R and n are as de~ined abov~, W i~ a cis doubl~ bond and ,Z i~ a trans doublo bond, to ~orm a compound o~ Formula V
. -- . .
above wherein Ar, R and n are as de~ined above and W and Z
are ~ingle bonds;
c) by solectivsly reducing a compound Or Formula V
above, wherein Ar~ R and n ar0 a~ de~ined above~ W i~ ~ Ci9 double bond and Z i9 a tran9 double bond, to ~orm a compound o~ Formula V wher~in Ar, R and n are as de~ined abovo, W is a ~ingle bond and Z i3 a trans double bond.
Additionally, the ambit o~ th~ invention con~0rn3 itsel~ with a prooe~s ~or proparing a compound o~ the struc~
tur~, -O
-OH

~ ~ CH2)n_Ar THPO~ R OTHP .. OVI
~: :; whsrein Ar i3 ~ - or ~-~ur~ or p ~thîenyl, ~ -or ~ -naphthyl; phsnyl; 3,4-dimethoxyphenyl; 3,4-~thyle~o-diox~ph~nyl; 334,5-trimethox~phen~l; or mono sub9titut~d phenyl ~her2in said 9ub9tituont i~ halo, tri~luoro~0th~1, phen~l, low~r alkyl or low~r alkoxy; ;~
25 ~ n i:~ an int~g~r rrom 0 to 5 with the provi~o that - whan ~r ~is phenyl3 ~ub~titut~d ph~n~l or naphth~l n :L~ O or 19 ~:, .20-. . ' 9 ~
i~ hydrogen or lower ~lkyl;
THP i~ 2 tetrahydropyranyl;
W is a ~ingle bond or a cis double bond; and Z i~ a single bond or a trans double bo~d;
characterized by reacting a compound o~ Formula V

OH
. .
~ oOX .'''' .' L ~ ~ CH ) Ar THPO~ R~r"9THP ,.,V : .
wherein Ar, R, n, W and Z are a~ de~ined above with ch~omic acid in aquaou~ ~ul~uric aoid and ace~one. ~ : .
10Further, th0 ambit o~ the invcntion conce~n~ it~el~ :~
with a proce~s ~or pr~paring a comp~und o~ the ~ormula~
O
. .'l . . .: .
: : O~C-R"
~ ~ ~"` 6 : ~L ~ CH2)n Ar THPO~ ,.VII
'.,.

whorein ~ Ar i~ ~ ~ or ~-ruryl; PC- or ~ -thienyl; ~
15~ or ~ _naphthyl, phenyl; 3~L~dimethoxyphenyl, 3,4-methylene- :
. dioxyphen~l; 3,4,5-trimeth~yphanyl, or mono-~ub~titutad :
phenyl wh~rein ~aid ~ub~tituent is halo, tri~luoromethyl, : phenyl, lower alk~l or lower alkoxy~ .:
n i~ an integer ~rom O to 5 with th~ provi30 that when Ar i~ phonyl, ~ub tit~ted phenyl or naphthyl n i9 0 or 21- ~ ' :. ;,~,.

49~;
THP i~ 2-t~trahydropyranyl;
Rl is lower alkyl; and R" is lower alkyl, aralkyl o.~ fro~ 7 to lO carbo~
a~oms, phen~l and ~ubstituted phenyl wherain ~aid sub~tituent i9 lowsr alkyl, lower alko~y, halo, tri~luoromethyl or phenyl;
characterized by ..
r~acting a compound o~ the ~ormula ~ ~, O
ooc_ ~ ~ / GOOR7 THPO" CXO
with a compound o~ th0 ~ormul~

Ar(CH2)n-CCH2-P-(O~lower alkyl)2 . .
; wheroin Ar, Rt, R" and n are as de~inad above.
~: An aspect o~ the invention r~sides in a proces~ for : preparing a compound o~ the ~ormula: :
~ ''. , . ' O " :'..... ' ~7 ~ .
O~C~R"

THPO ~ H2)~-Ar R X VIII :-; 15:~:wheroin Ar i~ , or ~ ~uryl; ~ -or ~ -thienyl;
or~ ~ -na~phthyl::phenyl; 3,4-dimethoxyphenyl, ~,4-msthyl~n~

_22-~ . .
~ . . .. : .
..... ;,, 9S ::
dioxyphanyl; 3,495-trimethoxyphen~l or mono s.ubstitut9d phan~l wherein said sub~tituent i9 halo5 tri~:Luoromethyl, phflnyl, lower alkyl or low~r alkoxy; ......
n i9 an integer from 0 to 5 with the proviqo that . -~
when Ar i~ phenyl, sub~tituted phenyl or naphthyl n i~ 0 or l; : -THP is 2-tstrahydrop~ranyl;
Rl i~ lower alkyl;
R~ is lower alkyl, aralkyl o~ ~rom 7 to lO carbon ..
atomsl phenyl or sub~tituted phenyl wherein ~aid substituent 0 i9 halog tri~luoromethyl, lower alkyl, lower alko~yl or phenyl; :
charAoterized by a) reducing a compound o~ ~ormula VII

O ......
t . .;
O a-R" . ' : ~ \\\~ ~ 2 n THP0\\\ 11 .....
~ ... VII
wherein Ar~ R~, R" and n are a~ de~ined above, to a~rord a oompound o~ F'ormula VIII wherein Ar9 Rl, R" and n ara as ~:
de~inad above and R is hydrogen;
. .. .
b) treating a compound o~ Formula VII, above, with : . .
: a ~uitabla alkylating agent to af~ord a compound o~ Formula .
VIII, wherein Ar, Rl, R~ and n ar~ a~ de~ined above and R : :
lower alk~
and, i~ desired, separaking tho 15 C~- and 15~
omers~ ;
: : Further~ an aspect o~ th~ invention re~lide3 in a :
.
~: -23 :
.~"

- :

4~
proce~s ror preparing a compound o~ the ~ormula:

O
O-C -Rl' -( CH2 )6COOR I

C~2) -Ar THPO~ ~ "
R OTHP IX
: wherein Ar i9 ~ or p -~uryl; ~ or ~ -thieny:L; ~ -or ~ -naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4 methylene-dlox~phenyl; 3,4,5~trimethoxyphenyl; or mono-substituted phenyl whersin ~aid sub3titutent is halo, tri~luoromethyl, phenyl, lower alkyl or lowar alkoxy; ~ :
n is an integer ~rom O to 5 with the pro~iso that wh~n Ar is phenyl, substituted phenyl or naphthyl n is O or 1, THP is 2-tetrahydropyranyl;
Rl is lower alkyl;
R" is lower alkyl, aralkyl o~ ~rom 7 to 10 carbon atom~, phenyl or substituted phenyl wherein said substituent ..
is lower alkyl~ lower alkoxyl, halo, tri~luoromethyl or phenyl;
and .
: R is hydro~en or lowar alk~l;
characterized by ,: :
~ reacting a compound o~ the ~ormula .
: : O : ..
~. . .
O-C-R"

OOR

~20:
R30 _ ~ CH2)n-Ar - : -24~
~.

~ 4~ S
wherein Ar, R, R~, R" and n are a~ d~3~inad above; and R3 i9 hydrogen or THP, with 29 3-dihydrop~ran in the presenc~ o~ ~-toluen0qul~0nic acid.
Additionally, ~n aspect o~ tho invention resides in a proce g for preparing a compound o~ the ~ormula:

OX
( CH2 ) 6C OOH ' ' ' ' ~ / ~ ~ CH2)n-Ar THPO R OTHP .. ,X ~.

wherein .
Ar iq c~_ or ~ ~ur~ C-or ~ -thi~nyl; c~
- 10 or ~ -naphthyl; phenyl; 3~4-dimethoxyphenyl; 3,4-msth~lsne- -dio~yphenyl; 3,4,5-trimethoxyph~nyl; or mono-~ub~tituted phenyl wherein ~aid substituent is halo, trifluoromethyl, ~ phenyl, lower alkyl or lowor alkoxy;
:: ~ n i9 an integer ~rom O to 5 with the proviso that : 15 when Ar is phenyl, substitutod phsnyl or naphthrl n i~ O or l; . ,:
~HP i~ 2 t~trah~drop~ranyl; and :~
: ~ R ~q hydrogen or lowor alkyl, ::.
charDotorizod b~
20 ~ reacting a compound of Formula IX

: ~: : : ~ O
"
:: ~ :
~: O_C_R"
( a~ ~6COOR
~ L_~ ~(CH2)n~Ar ~ THPO~ : R~OTHP ,.. :IX
~ ~ .
~ 250 .
:~ ;,. ;~ ' - ' .

wherein Ar, R and n are a~ derinad above;
R7 is lower alkyl;
R" i~ lower alkyl, aralkyl of' ~ro~ 7 to 9 carbon atoms, phenyl or ~ubstituted phenyl wherein said sub~tituent i~ halo, lower alkyl3 low~r alkoxyl, ~rirluorom~thyl or ~ .
phenyl;
with a 3uitable base.
An a~pect o~ th~ invention is concarned wi~h a pro- ~:
oo~ ror preparing a compound o~ the ~tructure:
0 Q :
" ~ 0 low~r alkyl Ar-(CH2)n_C.. CH2_p ~ ~.
0 lower A lkyl .,~XI
wher~in , . , Ar i~ c<- or ~uryl; C~- or ~-thienyl; ~ ~ or ~ -naphthyl; phenyl; 3~4~dimatho~yphenyl; 3,4 methylene-dioxyphenyl; 3,4J5~trimethoxyphen~1; or mono-~ubstituted pheny1 wharein ~aid ~ub~tituent i~ halo, tri~luorom~thyl~ :
phenyI, lower alkyl or lower alkoxy; and n i~ an inte~er ~rom 0 to 5 with the proviso that ..
when Ar i8 phenyl, subqtituted ph~nyl or naphthyl n is O or l;
ohara~teriz~d b~
reacting a lowor alkyl e~qter o~ the ~ormula Ar ( CH2 )n-C-O-low~r alkyl with a dialkylm~thylpho~phonato o~ ths ~ormula 25 ~ ; (lowor alk~l-0)2P~H

26~

~4~ as As shown in scheme A, the ~ir~t step ~ 2) is the condensation o~ the appropriate a~ter with a dialkyl msthylphosphonate to produco ketophosphonak~ 2~ Typicall~, the desired methyl ~ster i3 conden~ed with dimethyl methyl phoqphonate.
In 2 ~ the k~topho3phonate 2 is caussd to re~
act with the known /Corey et al., J ~. ChamO, 3~J 3043 ~1972 ~ aldohyde H to produce arter chromatography or cr~stal~
lization, the enone 3.
The 0none ~ can be ¢onverted to a mixture o~ -tertiary alcohol3 ~ and 14 by reaction with the appropriate lithium alkyl or Grignard reagent and th~ isomeric 13 and 14 oan be separated by column or high pressure liquid chroma~
tography. The enonc ~ can b~ reducod with zinc boroh-~dride to a mixture o~ alcohols, 4 and 5 which can be 3eparated as above. Lithium triethyl borohydride is e~pacially pre~erred when 1~2 reduction ls desir~d. In this reaction ethers such AS tetrahydro~uran or 1,2-dimetho~y ethana are usually em-plo~d as solvents, although ocoasionally methanol is pre-rerred to ensure speciricity o~ r0duction. ~urther trans~rormation~ Or ~ are shown on scheme B.
4 -~ 6 is a ba~e catal~zed transeskeri~ication in which the p-biphenyl-carbonyl prot~cting group is removed.
This is most conveniently conduct~d with potassium carbonate in mothanol or msthanol-tetrah~droruran solvent. 6~
involve the protaction o~ the two ~ree hydroxyl groups with An a¢id-labile protecting group~ Any sufriciently acid labile group is ~ati~ac~ory; howflv~r, the most usual one is tetrah~dropyranyl, which can bs incorporated in thls molecule ; 30 by treatmont with dihydropyran and an acid catal~t in an anhydrous medium. The catalyst ls usually p--toluenesulronic acid.

s SCHEME A
R ~
Ar-(CH2)n-COOCH3 ~ (CH2)r~ ~CH2~P(OCH3)2 :, ~ ~ .
~ 2 ~:
~_o~ '~
~ ~ I I ~ .
H ~ 0~ 3 ~CN2)n ~ .
' ' '.''.

I I I , 2 ~

M2)D-,.

o~--cl-o ~ ~c~2 )n-Ar HO~r H ~

O~ H2 ) SCHEME B
~ . '.

HO~ ~ CH2 )Ar ~.

~ (CH ) Ar ~ ~ CH2)n-Ar THPO~ H' "'OTHP THPO~ H ~OTHP

HO
COOH ~ ~`
~ tCH2)n-Ar ---~ ~ /AcH2)n H
THPO~ H ~OTHP THPO~
H OTHP
0 : '' ~.' COOH ~ ~ \ - ~ OOH
~ CH2)n Ar ~ ~ /tcH2)n-Ar .:
HO~ . H ~ ~OH HO~ H ~ "OH . :: :
.:

:~ \~

COOH : .

)n-Ar :: ~:: :: ~ ; : , . .

- .

: ~ :: : :

~ b~ ;

,,,,, , ,, ,, ,, , ,,,, ,,, , . . . ... -- -- --~ - , 7 ~8 i~ a redu¢tion o~ the lactone 7 to ths hemi~
acatal ~ using diisobutyl alwminum hydride in an inert solvent.
Low reaction temperature~ are pre~erre~ and ~60 ~o -70C.
are u~ual~ However, higher te~peratur~ may be employed i~
over_reduction doe~ not occurO ~ i~ puri~ied, i~ desired, b~ column ¢hromatography.
8 --~ 9 i~ a Wittig condensation in which hemiacetal 8 is reacted with (4-carbohydroxy~n-butyl)triphenylphosphonium bro~id~ in d~methyl sul~oxide7 in the pre~ence o~ ~odium methyl~ul~inyl methide. 9 i~ puri~ied as abovo.
The conv0rsion 9 ---p 12 i~ an acidic hydrolysi~ Or the tetrahydropyranyl groups. Any a¢id may be us~d which does not oau9e destruction o~ the mole~ule in the cour~e Or the ramoval o~ the protecting group; however, this i9 a¢¢om-1~ pli~ed mo~t o~ten by u~e o~ 65% aqu00us aceti¢ flcid. The pro-du¢t i9 puri~ied a~ above.
:: :
9~ 10 i9 an oxidation o~ the 3e¢0ndary al¢ohol 9 to the ketone 10. This may b~ ac¢ompli~had using any o~idizing agent which does not OEttaGk double bond~; however, the Jones reagent is u~ually pre~erredO The product î~ puri~ied a~
above.
carried out in the ~am0 manner as ~ 12.
The produ¢t i9 puri~ied a9 above~
~ an acid catalyzed dah~dration. Any acid ma~ be used ~or the pro¢e~s whi¢h does not ¢aus~ e~ten-9ivo de¢omposition o~ the productg but the most u~ual pro~
¢adura ¢on~i~t~ Or di~solving 11 i~ an a~c~3s o~ 97~ ~ormi¢
:. ., ~¢id rollowed by dilution with ic0 watsr and a~traction of tha produot artor th~ ~tarting mRt~rial h~ been ¢onsumed.
The produ¢t ig puri~iad a~ abov~.
_30_ As is illustrated in scheme C, ~, 13 and ll~ may be substituted ror 4 in ~chema B to provide pro~taglandin deri~rativ~s 12 ~ l8 ~ .

:

.
: .

~ .

. .

~~c1~:35 OH
OOH
(CH2)n-Ar 121 :
HO\~ HO ~ H :~
' 11 '.,' ~ COOH
_ ¦_I~.~ICH2 )n~Ar 111 ~ . . . . . .

~OOH
2 n ;

OH :. :
~COOH

HO~ ~CH2)n COOH

3 ~~HO~ ~ CH2)n-Ar COOH
~C~2)n-Ar 18 R ~'OH . ~ :.
. ~
. .
~ ' .' ~:' .
: .
,: : :
:: : .. : --.:. ., , . :.
~ ~: : 3 :: . ~, .

~;~ ~ : '.' ' ;' : ',,. ~ ' , ' '' . .:
, OH

~ ~ OOH

/~ HO ~ ~ ' R 16 ' fJ~ ~OOH
4 - . ,~, HO~ . . ~CH2 )n~Ar 17 li~ .
~COOH

)n Ar , HO : R
: ....... :
~ ' ' ' ' : ' "
-" ,, ' . - ' ., : .
: , .~ ~,:

9~ii Scheme D illustrates the synthe~qi~ o~ precursors to the 13,14-dihydro 15-3ubstituted~ pentanorpro~taglandin~
In 3 19 197 the enone ~ i~ reduced to the tetra~
.... ...
hydro compound through the u~qe o~ any of the complex metal h~dride reducing agent~3 LiAlH4, NaBH4, KBHL~, LiB~ and Zn~BH4)2. Especially pro~rred is NaBH4, The products, 19 and 19~~ are qeparated ~rom each other by oolu~n or high pres9ure liquid chromatographyO
Furthermore~ the compounds 4 and ~ o~ scheme A can ba r~duced catalytically with hydrogen to 19 and 1~7 r~sp~c-tively, The stage at which the doubl0 bond i3 redlAced is not critioal, and hydrogenation o~ 6 or 7 o~ scheme B will al~o a~ord use~ul interm~di~tes ~or the 13,14 dihydro prostaglandin analogs o~ the pre~nt inv0ntion. This reduction may b~ achi~ved with eith~r a homogenous catalyst ~uch as tristriph3nylpho~phinerhodium_0hloride, or with a h3tarogan~0us oatalyst 3uch a3 platinum, palladium or rhodium. In a similar way th~ precur~ors to th~ 15-low~r alk~l-15 substituted- -pentanorprost~glandin~ are qynthe~ized by subqtituting com-pound~ ~ and ~ ~or 4 and 5 respectiv~ly, in the synthesis Just de3cribedO The oonv~rsion o~ 19~, 20~ and 20 to - . .
their respective prostaglandin3 ~ollow3 the rou~ shown in .-. .
~sch~me B when LL is replac0d by ~ 207 and 20 to yield ~:
th~ 13~14-dihydro:PGE2, PGA2 and PGF2 ~eris~ o~ pro3taglandin 25 ~ d~rivatives contain~ng h~drogen or lower alkyl group at carbon ` :
15 ~, :
::
; ~

' ~ 3l~

,.

",~ l ~
'~ol ~, ~ '~ ',.
o~/' ,' , ., . -R :

: ~, ' '' .

: :

. , Scheme E illustrates the preparation Or the various reduced 15-sub~tituted-~lJ-pentanorprostaglandin pro'cursor~; :
19 -~ 22 is ca:rried out as i:Llustrated on ~cheme B
~or ~ 9. 22 can be used as both a precursor to a 13,14~
dih~dro 15-sub~tituted- pentanorprosliaglandin o~ the "2- :
series" or as an intermediate to ?~, a precursor to a 13,140- ~:
dih~dro-15-substituted-~-pentanorprosta~;landin o~ the "1- :
~eries"0 22~ 23 is carried out by catalytic hydrogarlation u~in~ the catalyst described ~or the reduction o:E 4.~19 o~ Scheme D. Intermediates o~ the type 21 are prepared b~
sslective reduction o~ the 5-6 cis double bond at low tem~
perature usi~g catalysts such as thoss described ror 1~19 and ;LZ. ~ 13spe¢ially prererred ~or this reduotion is .: .
the use o~ palladium on carbon as a catalyst and a reaction ~:
tomp0rature of -20o Intermediates o~ the tgpe 21 are not onl~ p~eoursors to 15-substitut~d~ -pentanorprostaglandins o;E the "1-3eries" through the route 9 ~15 o~ ~cheme B, but al~o as a preoursor to oornpounds of' the type ~ thx~ough the route alread~ discussed ~or 22--t ~o Furthermora9 the .: ,.
15-~ubstituted~ pentanorprostaglandins o~ the El and F
series may be obtained direotly ~rom the corresponding prosta~landin analog o~ the "2-saries" by ~irst proteotirlg ~:
.

the hydrox~rl by introducing dim0thyl isopropgl 9ilyl ~;roup~, :reducing 3electivel~r the ci~ doubl~ bond, and r~moving ~he :: :
25 protaoting group.
he int;roduction o~ the prot~otin~ group is usually aoco~plished b~ traatmant o~ th~3 pro3ta~ 1andin analog with ;~
dimsthyl~ isopropyl chloro3ilane and triethylamine5, th~ re-duotion i9 acco~plished ~9 di~cusæed abovs ~or 5~,21 and :30 r~moval o~ the protecting group i3 accompli3hed b~ contaotin~

' .

4~
ths roduced protected co~pound with 3~:1 acatic acid:water ~or 10 minutes or until roaction i9 ~llbstantially complete, Tha Cls epimers o~ 22 and ~ can be u~ed as prec~rsors to the 15~epi serieq o~ pro~ta~landin derivatives de~cribed above, and 15-loweP-alkyl-15-substituted-~ -penta-norpro~taglandins reduced at the 5,6 and/or the 13,14 po~
tion and their Cls epimers can ba prepared rrom th~ appro priatoly ~ubstituted analogs o~ ~ and 1~ who3e syntheses ~ollow those o~ Scheme A and B.
13,14-Dihydro-15-lowerialk~1-15-substitut~d~
pentanorprostQglandins are avallable ~rom the appropriately ~ubstitutHd precur~or~ v~a Scheme E, ~ , .. .

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

; ' ' ..:
. . .. . .

: ~ ~37_ . ::
.. , ... , , .. ... . . . ... . ... ~ . . .. . . . . ... . ..... . . . . . . .

.9,9~
SCHEME E

OH OH

~" \ \COOH ~--~

~( CH2 )n-Ar ~ CH2 )~) - H
~HPO ~` H ~OTHP ` ~ 5 ~HPO H OTHP

.:' ` :' 22 2 /
.'.' ~": ' ., .:
~` . .
OH : :: .
.

L, /CH2 )n-~

T}IPO H 'OTHP
' .
~ ` ~

:: : ~ : i ` .
:
: : :

~: : ' In the ~or~going procedures, where puri~ication by chromato~raphy is de~ired, appropriate chromatographic 9Up port~ include n~utral alumina and ~ilica gel and 60~200 me~h silica gel i~ generally pre~erred, Tha chromatography i~
~uitably conducted in reaction-inert solv~nt~ such a~ eth0rg ethyl acotQt0, benzene~ chloroform~ methylen~ chloride, cyclohe~ana and n-hexane, as further illu~trated in the append- . :
ed exam~le In numerou~ in vivo and in vitro tests we have de -monstrated that th~ new pro~taglandin analogs pO9ige93 physio-logical activities comparabl~ to those exhibited by the natural prostaglandins (see above). Theso test~ include, among others, a te~t ~or er~eot on i~olated smooth muscle ~rom guinea pig uterus, guinea pig ileum and rat utsrus, inhibition : .
o~ norapinephrine-induced lipoly~is in i~olat~d rat rat cellis~
inhibition Or histamine-induc~d bronchospasm in ~he guinea pig e~ect, on dog blood prjessure, inhibition o~ str~ss-induced ulceration in th0 rat, inhibitlon of pentagastrin induced hydrochlorlc acid secretion 1n:bhe rat and dog, and inhibi-tion of ADP- or collagen~induced aggregatlon of blood platelets.
, .. ., . . .: : :
The ph~siological re3ponses ob~erved in these te~ts are use~ul in determinin~ khe utility o~ the test sub~ance ~or the tr~atmo~t o~ variou~ natural and pathological condi-tions. Such determined utilities includ~: antihyperten~iv~
; ~ 25 a¢tivity~ bronchodilator activity, vasodilator act~vit~, anti-: thromboge~ic activity, ~ntiarrh~thmic activity~ cardiac b~mula~t activity, antiulcer actlvity, ~mooth mu~cle activit~
/u~e~ul a~ an anti-~ertilit~ agent, ~or the induction o~
labor9 and a~ an aborti~acien ~, and anti-rertility activity : 39~ ~ `~

~ 5 through a mechanism not a~ecting smooth muscle~ ~or example, luteolytic mechani~ms.
Tha novel compounds o~ this inv0ntion possess hi~hly selectivc aotivit~ proriles compar~d with the c~rresponding naturally o~currin~ pro~taglandins and, in ma~y ca~es, exhibit a longer duration o~ action. A prime example o~ the thera-peutic importancs Or thess pro~taglandin analogs i9 the er~i~
cacy o~ 13,14-dihydro 16-phenyl-~ -tetranorpro~taglandin E2 ~hich exhibits hypotensive activit~ o~ greatly ~nhanced poteno~
and duration a9 co~pared with P~E2 itsel~ At the same tim~, the smooth muscla stimulatin~ activity i~ markedly deprassed in compariso~ with PGE2.
In a similar mann3r) the othsr 13,1L~-dih~dro 16 Ar_substituted PGE2 analogs, the novel 15-substituted~
pentanorprostaglandin~ o~ the A seri~s and the 16-Ar;;subski-tuted PGEo (tetrahydro PGE2) and 16-Ar-substituted PGE2 prosta-glandins o~ the present invontion and partioularlg 16 ~-thie~
tetranor PGE2 and 16-~ -naphthyl~ ~ -tetranor PGE2 exhibit d3sirable hypotensive activity. In addition, the 16~Ar sub stituted prostaglandins o~ ths E a~d A series are particularly potsnt inhibition Or ga~tric acid secretion. On oral ad-mini~tration, and a~ a con~equ~nce are use~ul ~or tho treat-;~ ment o~ peptic ul¢~rs or ~astric hyparactivit~. It should be noted~that~the 15-substitut~d-13,14 dih~dro-6J-pent~norprosta~
~glsndins o~ this invontion sr~ e~pecially u~ul owing to -.
th~ir inorea~ed se1ecti~ity. For oxa~ple, th~ 16~Ar~ubsti-t ut~d- ~-tetranor 13,14-dihydro PGE2, hav~ highl~r s~lective hypot~n~ive activity wherea~ th~ 17 Ar-~ub~tituted~ -tri~- :
nor~l3,14-dih~dro have hig~ly ~elective smooth muscl~ activity.
30 ~ Fhr~harmor~, tha 15~Ar~ bstituted- ~ pentanor 13,14~dihydro _40~

. ,. . ~ .
.
, ~ : : .. .. . . .. . .. ... . . . ..

E2 prostaglandins o~ tha present invention have highly selec-tive bronchodilator a~tivityO
Similarly, 17-~uryl- ~-trisno:rprostaglandin F2~
and E2 e~hibit outstanding smooth muscle stimulating activity .. :
use~ul ~or ~ertility control, abortion and induction o~ labor, while at the same time having reducad blood pressure er~ects~
Furthermore, the other novel 17 ~ubstituted trisnorprosta-glandins o~ the E and ~ seri~s7 o~ this invontion, i.~. the 173-18,19 and 20-Ar-substituted prostaglandins o~ the E and F
series of this invention, axhibit des,irablo ~mooth muscle -~
stimulating activity. The novel 15-hr-substituted- ~-penta-norprostaglandins Or the F serias also are o~ usc in thc in-du¢tion o~ labor and abortion, and control o~ ~ertility, while the 16-Ar-substituted- ~-tetranorprostaglandins of the F series ~
are us~ul ~or fertilit~ control via me¢hanisms not a~ecting ;:-smooth muscle.
Furthermore, 16thienyl-~ tetranorprostaglandin ::
E2 and 16~-biphen~l-w ~tetranorprostaglandin E2 e~hibit high bronchodilator activi~ with reduced non-vascular ~mooth musole aotivity. In similar ~ashion, the other 16 Ar-s~bstitut3d~
tetranorpro~taglandin El ancl ~2 analogs o~ the present inven-tion display dasirable bronchodilator activity. ~.
The novel 15 lower alkyl compounds o~ this invsn~tion hav~ th~ ~ame pro~ile o~ aotivity a~ the prostaglandin 25 . analogs o~ this invent~on, wher~ R i~ hydrogen, ~rom which ~ .
they are~derived, Their ~pecial utility is concern~d with : th0 ~act that th~ir duration o~ action i~ much incr~ased over th~ above ~ald compounds, wh~r~ R is h~drogan, and in ~uch ca30~ where thi~ is essontiAl the 15 lower alkyl compound~
;~ are u~uall~ pr~arred~
_41- :
.:~

- - . . ... . . . . . . . . ..

4~a~
All o~ the prostaglandin~ Or thi~ inven~ion are al90 u~erul in the ~orm~ o~ their salt~l with pharmaceutically acceptable cations, Furthermor~, s~tor~ at C9, Cll and Cls in which tha acyl group i3 lower alkanoyl~ ~o~m~l, or benzoyl likewise share the utilities o~ the pro~taglandin from which thay are derived. In soms ca~e~ a lower incidence o~ un-desirable side ~ects accompani~s ths use o~ these est3rs as compared with tha corresponding uneYt~ri~ied prostaglandin~.
It is obvious to one skilled in the art that the~e compounds . .
include mono esters in the ca~e Or a prostaglandin o~ the ~
serie3, diester~ in the case o~ prostaglandins Or the E ~erieY
and triesters in the case o~ the F ssries. Such e~ters are readily prepared by standard methods well know.n in the art.
Tha prostagl~ndin analogs which have a beta hydroxyl at Cls and pos3ess a C15 lower alkyl group havo action which i~
similar to their epimers. In some ca~es, howevar, tha ~elec tivity that these compounds display exceeds that o~ the epi-meric compounds.
The new compounds o~ this invention can be used in a variety o~ pharmaceutical pr3parations which oontain the compound or a pharmaceutically acceptable salt thoreo~, and the~ may be admini~tered in the same manner as nAtural pro~ta- . .
glandins by a variety o~ routes7 such as intravenous, extra ~ . , .
and intra-amniotically, oral and topical, including ~erosol, . -; ~ 25 ~ intravaginal, and intranasal, amon~ others~
For induct~on o~ abortion an a~ueous suspen3ion o~
a 1.7 9ub~tituted- ~trisnorprostaglandin o~ the E or F series : :or tablets would appropriate~y be administered at oral doses . :~
.
o~ about 1-20 mgO ~ with 1 7 doses per day boing employed.
For intravaginal administration a sui~able ~ormulation would : ~2- : .
.~ . ' .:

.be lactose tablsts or an impregnated tampon o~ the ~ame agentO
For such treatments 3uitable dosas would be ~ro~ about 1-20 mg./dose ~or the 17~ uryl PGF2~ derivative or ~rom about 10-200 mg./do~e ror the 17 ~ ~uryl PGE2 derivative~ with 1 to 7 dose3 being employadO
Alternatively, ~or abortion, the 17~sub~tituted- :
-tri~norprostaglandins can be admini~terad intra~amnioti cally at doses o~ 5~40 m~o3 1~5 tim~ per day, or in:~used intravenouqly at dose3 o~ 5~500 ~g/minute ~or a period o~ . :
~rom about 1-24 hoursl .
Alternatively, ~or abortion, tho 17-substituted ~ .:
trisnor prostaglandins can be administored by extra~amniotic ..
inrusion at doses o~ 005~50 ~g/minute ~or a period ~rom 1-2L~
hour~.
Anot~er suitable uso ~or the 17,18,19 and 20~Ar-substituted prostaglandin analogs o~ this invention i3 as in~
ducers o~ laborO For this purpose an ethanol~saline solution o~ a 17 substituted ~ ~ ~tri~nor PGF2~ or PGE2 d0rivative can be employed as an intravenous in~usion in the amount o~ ~rom about 0,05 50Jug/minute ~or ~rom about 1 10 hours or orally in th~ ~orm o~ capsules, tablets9 solutions or su9pansions ~: ;
at do~os Or 0~005-5 mgO with 1~7 dosos baing employed. ..
The produce bronchodilationg an appropriate dosaga ~orm would b~ an a~uaous ethanolic solution o~ 16~Ar-substi tutod tetranor PGEl or PGE2 employed as an aerosol u~in~
~luorinated hydrocarbons a~ propellant in the amount o~ ~rom about 3_500 ~/dose.with up to 16 do~e~ per dayO To increase na al potency, an appropriate dosage ~orm would be an a~ueou~
solut~on o~ 16~Ar~substituted~tetra~or PGEl or PGEz~ employed in:the ~orm o~ no~e drops in th~ amount o~ 1~100 ~g/do~ as s needed.
The 16-Ar~3ubstituted~ ~ tetranorprostaglandin~ o~
-the E2; 13,1l~-dihydro E2 and A2 series are use~ul antiulcer agents. For the treatmant Or peptio ulcers~ th~so dosage~
ara appropriately administ~red orally in the ~orm o~ aqueous suspen~ions, solutions or pre~erably in the ~orm o~ capsules or tablet3 at do.~s Or OoOOl to 0~10 mgO/kgO per do3e with up to 12 dos~s per dayO ~-The abov~ n.amsd 15~substituted~w~p~ntanorprosta~
glandin o~ the "one" series may be prepared by the syntheti¢
route outlined in Scheme Fo In the ~irst step the h~miacetal U is caused to r~act with the L~oarbohydro~y~n~butyl triphen~l-phosphoniwm bromide to produce intermediate WO
W --~X involves treatment with diazomethane; ~ollowed ~ :
by a¢etic anhydride and pyridine; ~ollowed by r~duotion with palladiwm in carbon in ethanol~acetic acid; ~ollow~d by . .
oxidation with dimoth~l ~ul~oxido, dicyclohexylcarbodiimid~, :
and pyridinium tri~luoroacetataO :
X --~Y involv~s tr~atment with the sodium or lithium~ ..
20 salt o~ th0 appropriate phosphonate (2) and puri~ication by .
column chromatography Y-~ Z involves reduction with zinc borohydride or lithium triethylborohydridel hydrolysis, and separation o~
the Cls epimers b~ column chromatographyO
: 2~ Z--~Zl involveq trsatment with dihydropyran with an acid catal~st ~ollowed b~ mild aqueous ba~ hydrol~sisO
PG~ PGE1, and PGAl 15~substituted pentanorprostaglanains.~ollows ~actly th~ same method as ;~
~; outlin~d ~or the PGF2~ ~ PGE2~ PG~2 seria3 abov~-~: :
~44 .. ~;,`~
.~ ` . , .
- `. ` - `,. .. ; .. ` .. . ; ;` `~ - . - .... , ; ~ - . ` . . . ` . . . ` . - . .. .

s ~:

:
~:
~:~
~ o > <~
"~, o , . o ,.; .

Pl~ < .

<~ 1 ~ I xl ~;
; ~o ~ .
45~

~ f ~ ~- ' ' ,' ' ... ,.~ ., . ,... ~ .. .,, ... , . -.-, ` - . , . ` -O~
_R
~CI .
~> ~ ~ ' ~ <\
~ .
~"~"~
\~" ,~ ' ' ''~ '' ' O ~ .
~3 al , ........ .
~ ~ ' ', .
O ,~ , .
V ~ .':,',':.. ', ' 'a o~
~ ~~ ~' ,. . .

~ . ~:

o ~ ; . . . ~
...
. ...

~ ................................................................. . . .

Yi5 Each of the novel compounds of the present invention are also useful in the form of their Cl esters. ~xamples of preferred esters are those wherein the esterifying group is alkyl of from one to twelve carbon atoms, cycloalkyl of from three to eight carbon atoms; aralkyl of from seven to nine carbon atoms; phenyl or ~ -naphthyl or mono substituted phenyl or ~naphthyl wherein said substituent is:
halo, lower alkyl~ low~r alkoxyl or phenyl.
Especially preferred are the p biphenyl esters. These specific esters are valuable because they are very easily crystal- -lized, thereby a~fording the opportunity to recover them in highly pure form and outstanding yield whereas prostaglandlns in general ordinarily present se~ere crystallization problems.
The new para-biphenyl esters exhibit the activities of the corresponding parent novel compounds and in addition possess the advantage of a flatkened activity ver~us time cu~ve which is often advantageous. They furthermore have reduced effects on gastrointestinal smooth muscle as evidenced by the reduc-tion side e~fects such as diarrhea. The new compounds ln the ~orm of the para-phenylphenol esters are prepared by procedures already described wlth appropriate ~ubstitution of correspond-ing intermediates employed in the foregoing reaction schemes.
Thus, for example, compounds 9 and 10 may be esterified with para~phenylphenol in the presence of dicyclohexylcarbodiimide to~provide para-phenylphenol esters of precursors to 15 omega pentanorprostaglandin para-phenylphenol esters. These can, through steps 9-12, 10-11 and 11-12, be converted to the :
novel para-phenylphe~l esters mentioned above. Further, compounds 11, 12 and 15 can likewise be esterified with para-, . . .
~ ~30 phenylphenol and dicyclohexyicarbodiimide to provide the ', ~ ' .

lr~ 4 i 4~ ~
desired esters. In addition, the para-biphenyl ester moiety can be introduced at an earlier stage by using in step 8-9 a tri-para-phenylphenol ortho ester phosphonium bromide of the structure [(C6H5)3POCH2CH2CH2CH2C(OR3]Br~ wherein R equals para-phenylphenol to provide the corresponding ortho ester of 9 which can be carried through steps 9-15 to yield the desired para-phenylphenol esters.
15 Substituted- -pentanorprostaglandins of the A
series as well as 16-Ar substituted-~ -tetranorprostaglandins o~ the El, E2, Eo and 13,14 dehydro E2 and A2 series, are useful hypotensive agents, (as are the 15-Ar-substituted-~ -pentanorprostaglandins o~ the E series). For treatment of hypertension these drugs could appropriately be administered as an intravenous in~ection at doses o~ about 0.5-10 ~g/kg or pre~erably in the form of capsules or tablets at doses of 0.005 to 0.5 mg/kg/day.
To prepare any of the above dosage forms or any of ~the numerous other rorms pos~ible, various reaction-inert diluents, excipients or carriers may be employed. Such sub-stance~ include, for example, water, ethanol~ gelatins,lactose 5 starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum ~elly, cholesterol, and other known carriers for medicaments. I~
desired, these pharmaceutical compositions may contain ` 25 ausiliary subetances such as preserving agents, wetting agents~ stabilizlng agents, or other therapeutlc agents such as antibiotics. -, ~ The following examples are merely illustrative, : ~ , ~ ~ ~ and in no way limit the scope of the appended claims. In .
~ 30~ ~these examples it will be appreciated that a~l temperatures --.

"' ~, ' ' :''.
:

s are expressed in Centigrade, all melting and boiling points are uncorrected and all biological test data is expressed ln terms of % activity of PGE2 or administered at the same level (i.e., PGE2 = 100) unless otherwise noted.
Dog Blood Pressure.
Mongrel dogs were anesthetized with sodium pentobarbitol, 30 mg/kg/i.v. Femoral artery blood pressure was measured with a mercury manometer and recorded on smoked paper and heart rate was determined from electrocardlograms recorded ; -from subcutaneous electrodes. Drugs were given through a cannula in a ~emoral vein. -Isolated Gastrointestinal and Reproductive Tlssue All measurements were made in a 2 ml. tissue bath using a Phipps-Bird Linear Motion Transducer model ST-2. Tissues were allowed to respond to a stable maximum3 at which point they were washed and allowed to return to baseline condition. ;~ -All determinations, are an average of at least three lndividual tissues at each reported dose. Data for analogs were compared to the dose response obtained for a natural PG in a given tissue. For purposes of potency comparisons, a standard dose o~ natural PG was selected; and all responses were calculated as a percentage of its response. Addl~ional data were re-corded as minlmum e~fective dose (MED) and a consistently . . .
effective dose (CED) to estab~lish compound de~ection levels : ~ .
for each tissue. A standard equivalent dose (SED) was determin~d. This value was deflned as the amount of compound ~ -tng/ml) which yielded a response that was equivalent to the tlssue'-s response to a given dose of standard PG.
The biological data given below was obtained using the following test procedures:
_49_ . . :-:
~ '.'' . ~ ' ' : ~, ~ -.' S
Histamine Induced Bronchoconstriction - Guinea Pi~s.
Bronchodilator activities were evaluated in conscious female Reed-Willet guinea pigs (200 to 250 g.) fasted overnight accordlng to the method o~ Van Arman~ Miller and O'Malley (1).
At a pre~selected interval (pre-challenge interval) following oral or aerosol administration of water or the test clrug in water, each animal was challenged with histamine aerosol as ~ollows: a 0.4% aqueous solution of hlstamine was placed in a Vaponephrine Standard Nebulizer (Vaponephrine Company, Edison, New Jersey) and sprayed under an air pressure of 6 lb/in2 lnto a closed 8 x 8 x 12 inch transparent plastic container ~or one min. Immediately thereafter~ the guinea pig was pIaced in the container. The respiratory status ta reflection of bronchoconstrlction) of the guinea pig after one min. in the container was scored as ~ollows: 0, normal breathing; 1, slightly deepened breathing; 2, labored breath~
ing5 3, severely labored breathing and ataxia; 4, unconscious- t ness. The scores for a control group and a test group (8 animals/group) were summed and compared and the dlfference expressed as per cen~ protection. (1) 1. VAN ARMAN, C.G., Miller, L.M. and O'Malley, M.P.: SC-10,049: a catacholamine bronchodilator and hyperglycemic agent. J.- Pharmacol. Exp. Ther. 133 9Q-97~ 1961.
Gu1_ a Pig Ileum: The lleum was dissecbed from 200-300 g.
:: :
male guinea pigs sacrificed by cervical dislocation. The tissue was su3pended in 2 ml. Tyrode solution (2) at 37C.
PGE2 (30 ng/ml and/or PGF2~ (30 ng/ml) were used to estab ;
:
lish tissue actlvity. ~ -.
~ Guinea Pi~_Uterus (3): Nulliparous females (300-400 ~.) -: .
which were not in estrus were sacrificed by cervical disloca-_50_ -. '' . ' ' .

- ::

tion. The dissected uteri were incubated in 2 ml. of a modi-fied Krebs solution (12) at 37C. Uterine activity was established using PGE2 (1.0 ng/ml) and~or PGF2~ (10 ng/ml).
2. Hale, L.J. ed. Biol. Lab Data. p. 92, 1958.
3. Clegg, P.C.~ P. Hopkinson and V.R. Pickles. J. Physiol.
67:1, 1963.
4. W.S. Umbreit, R.H. Burris and J.F. Stauffer. Monometric Techniques 148, 1957.

Dimethyl 2-Oxo-3-phenylpropylphosphonate (2a~:
-- _ . . ; . .
A solution o~ 6.2 g. (50 mmoles) dimethyl methyl-phosphonate (Aldrlch) in 125 ml. dry tetrahydro~uran was cooled ko -78 ln a dry nitrogen atmosphere. To the stirred pho~phonate ~olution was added 21 ml. of 2.37 M n-butyllithium in hexane solution (Al~a Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction tempera-ture never rose above w65. After an additional 5 minutes -~
stirring at -78, 7.5 g. (50.0 mmole) methyl phenylacetate was added dropwise at a rate that kept the reaction tempera- ;~ture les~ than -70 (20 minutes). After 3.5 hours at -78, the reaction mixtùre was allowed to warm to ambient tempera- :
ture, neutrallzed with 6 ml. acetic acid and rotary evaporated (wate~r aspirator~) to a white gel. The gelatinous material was taken up in 75 mlO water, the aqueous phase extracted ~;
with lGO ml. portions o~ chloro~orm (3x), the comblned organlc extracts were backwashed (50 cc. H2O)~ dried tMgSO4), and concentrated (water aspirator) to a crude resldue and distllled, b.p. 134-5 (~0.1 mm.) to give 3.5 g. (29%) di- ~;
methyl 2-oxo~3-phenylpropyl~hosphonate (2a).
~ ~he nmr spectrum (CDC13) showed a doublet centered .. ~.'~; ' 4~
o . ~;
at 3.72 ~ (J = 11.5 cps, 6H) for (CH30)-P-, a doublet centered O O
"
at 3.14~ (J = 23 cps, 2H)~C-CH2-P-, a singlet at 3.88~ (2H) o for CH2-C- and a broad singlet at 7.22 ~ (5H) for C6H5 .
In the manner described above dimethyl 2-oxo-3tp-chlorophenyl)propylphosphonate, dimethyl 2-oxo-3(m-phenyl-phenyl) propylphosphonate and dimethyl 2-oxo-3(o-trifluoro- -methylphenyl) propylpho~phonate may be prepared ~rom the ... . .
appropriately substituted methyl phenyl acetates. These pro-~ucts are sultable for conversion to the corresponding 16-lo substituted- -tetranorproskaglandins by the sequence described below.
,-. ' ~.: .
EXAMPLE 2 `

2-[3~ -n-Phenylbenzoyloxy-5OC-hydroxy-2~-(3-oxo-4-phenyl-.. ..
trans-l-buten-l-yl) cyclopent-l~ -yl]Acetic Acid, r-lactone .
15 (3a): ;
Method_A:
Dimethyl 2-oxo-3-phenylpropylphosphonate (2a) (3.4 ~., 14.2 mmole) in 200 ml. anhydrous ether was treated with 5.0 ml. (12.5 mmole) 2.5 M _~butyllithium in n-hexane ;-2U~ (Al~a Inorganics, Inc.) in a dry nitrogen atmosp~ere at room temperature. After 5 min. of stirring, an additional 400 ml.
o~ anhydrous~ether wae added followed by 3.85 g. (11 mmole) 2-[3 ~-p-phenylbenzoyloxy-5~-hydroxg-2~ -~ormylcyclopentan~
1~ yl~ac~etic acld, r-lactone ln one portion and 50 ml.
` 25~ anhydrous ether, A~ter 35 minutes the reaction m~xture was quenched with 5 ml. glacial acetic acid, washed with lOO ml.

, ~ .
saturated odium bicarbonate solution (4 x), lOO ml. water ~ ~ ~ ' "' ' :

(2 x), lOO ml. saturated brine (1 x), dried (MgS04) and evaporated to yield 2.908 g. (57%) 2-[3~ -~-phenylbenzoyloxy-5Oc-hydroxy-2~ -(3-oxo-4-phenyl-trans-1-buten-1-yl)cyclopent-lc<-yl]acetic acid, y -lactone (3a) as a foam after column chromatography (silica gel, Baker, 60-200 mesh)3 m.p. 107-8 (ether).
Method B:
Dimethyl 2-oxo-3-phenylpropylphosphonate (2a) (2.9 g., 12 mmole) in 20 ml. anhydrous dimethoxyethane wa~ -treated with 4.7 ml. (11 mmole) 2.34 M n-butyllithium in n- ;
hexane (Alfa Inorganics, Inc.) in a dry nitrogen atmosphere at room temperature. After 40 min. of stirring, 3.5 g. (10 mmole) 2-~3~ -~-phenylbenzoyloxy-5 ~-hydroxy-2~ ~formylcyclo-pentan-lo~-yl]acetlc ac~d, y -lactone was added In one portion ~ollowed by 15 ml. anhydrous 1,2-dimethoxy ethane. After 30 minutes the reaction mixture was quenched with 1 ml. glacial ;
acetic acid, filtered, washed with 20 ml. saturated sodium bicarbonate solution (2 x), 20 ml. saturated brine (1 x), dried (Na2S04) and evaporated to yieId 2 g. (43%) 2-[3~ -p-phenyl-benzoyloxy-5~C-hydroxy-2~ -(3-oxo-4-phenyl-trans-1-buten~
. .. .
yl)cyclopent-l~ -yl]acetl¢ acid, y-lactone (3a) as a Foam after column~chromatography (silica gel, Baker, 60-200 mesh).
The ir spectrum (CHC13) of the product (3a) ex-hiblted~adsorption bands at;l775 cm~1 (strong), 1715 cm~
25~ (strong),~1675 cm-l (medium) and 1630 cm~l (medium) attri-butable~to the carbony1 groups and at 973 cm~l ~or the trans double bond. The nmr spe~trum (CDC13) exhibited a multiplet at~7.23-8.1a ~ (9H) for the ~-biphenyl group, a doublet of doùblets~centered at 6.75~ (lH, J = 16 cps) and a doublet ;30 ~oentered at 6.27 ~ (lH, J = 16cps) for the olefinic protons3 ~53~

~ :
~: : .

o a broad singlet at 7.20 ~ (5H) for C6H5-CH2-C-g a slnglet O
at 3.84 ~ (2H) for C6H5-CH2-C, and multiplets at 4.90-5.50 ~ (2H) and 2.21-3.07 ~ (6H) for the remainder o~ the protons.

2-~3~ -p-Phenylbenzoyloxy-5~-hydroxy-2~ -(3~-hydroxy-4--- phenyl-trans-l-buten-l-yl)cyclopent-l~ -yl]acetic acid, y- -Iactone (4a) and 2-~3~ -p-Phenylbenzoyloxy-5~ -hydroxy-2~
(3~ -hydroxy-4-phenyl-tran6-1-buten-1-yl)cyclopent-1~ -yl]-acetic acid y -lactone (5a) To a solutlon of 2908 mg. (6.2 mmole) 2-[35~
phenylbenzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-phenyl-trans-1-buten- :
l-yl)cyclopent 1~ -yl]ace~ic acid, y-lactone (3a) in 30 ml.
dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient ~ -~
temperature was added dropwise 2.0 ml. of a 1.0 M zinc boro~
hydride solution in 1,2-dimethoxyethane. After stirring at 0 for 2 hours~ a saturated sodium bitartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was allowed to stir for 5 mlnutes at which time 250 ml. dry methylene chloride was added. After drying (MgSO4) and concentrating (water aspirator) the resultant semisolid ~ i was purified by c~T~umn chromatography on silica gel (Baker "Analyzed" Reagent~ 60-200 mesh) using ether as eluent. After .
elution of Ieæs polar impurities a frac~ion contalning 658 mg. 2-~3 ~ phenylbenzoyloxy 5O~-hyclroxg-2~ -hydroxy- -4-phenyl-trans-1-buten-1-yl)cyclopent~ yl}acetic acid, -lactone (4a)~ a 480 mg. frQctlon of mixed 4a ancl 5a and finally a fraction (671 mg.) of 2-[3O~-_-phenylbenzoy:Loxy-_54_ - \

5~ -hydroxy-2~ (3~ -hydroxy-4-phenyl- rans-l~buten-yl)cyclo-pent-l~ -yl]acetic acid, y-lactone (5a) The ir spectrum (CHC13) of 4a and 5a had strong carbonyl adsorptions at 1770 and 1715 cm~l and an adsorption at 970 cm~1 ~or the trans double bond. The NMR spectrum (CDCl ) of 4a and 5a was consistent with the assigned struc-ture.
. . ... .

2-~3~ ,50<-Dihydroxy-2~ -(3~ -hydroxy 4-phenyl-trans-1-buten-_ _ _ _ _ . _ . . .. . . . ~
l-yl)cyclopent-lc~-yl]acetic acid, y-lactone (6a):

A heterogeneQus mixture o~ 658 mg. (1.35 mmole) o~
2~~3~ -~-phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-4-phenyl-trans-l-buten-l-yl)cyclopent~ yl]acetlc acid, r- :
lactone (4a), 7.1 ml. of absolute methanol and 188 mg. o~
finely powdered3 anhydrous potassium carbonate was stirred at room temperature ~or one hour, then cooled to 0. To the ¢ooled solution was added 2.8 ml. (2.8 mmole) of l.ON aqueous hydrochloric acid. After stirring at 0 ~or an additional 10 minutes, 5 ml. o~ water was added with concomitant formation o~ methyl p-phenylbenzoate which was collected by filtration.
~he ~iltrate was saturated with solid sodium chloride, extrac-ted with ethyl acetate (4 x 10 ml.), the combined organic extract~ were washed with saturated sodium b~carbonate (10 ml.), dried (MgS04) and concentrated ko give 381 mg of viscous, oily 2-~3~ ,5~ -dihydroxy-2~ -(3~ -hydroxy-4-phenyl-trans-1-buten-l-yl)cyclopent-lo~Yyl]acetic acid, y -lactone (6a).
he ir spectrum (CHC13) exhiblted a strong adsorp~
tion at~1770 cm~l ~or the lactone carbonyl and medium adsorp-; tion at 965 cm~l ~or the trans-double bond.

, . , .

. ~' 2-[3 ~,5 ~-Dihydroxy-2~ -(3~ -hydroxy-4--phenyl-trans-1-buten-.
l~yl) cyclopent~ yl]acetic acid, y-lactone (6'a):
A heterogeneous mixture of 761 mg. (1.57 mmole) of 2-[3~ -~-phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-4-phenyl-trans-l-buten-l-yl)cyclopen~-lc~ yl]acetic acid, y-lactone (5a)3 7.1 ml. of absolute methanol and 216 mg. of ;~
~lnely powdered, anhydrous potassium carbonate was stirred at room temperature for one hourj~ then cooled to 0. To the aooled solutlon was added 3.2 ml. (3.2 mmole) of l.QN aqueous ~ ;
hydrochlorl¢ acid. After stirring at 0 for an additlonal `
10 minute9, 5 ml. o~ water was added with concomitant ~orma- ;
tion of methyl ~-phenylbenzoate whlch was collected by filtra-tion. The filtrate was saturated with solid sodium chloride, extracted with ethyl acetate (4 x 10 ml.), the combined ~`
organic extrac~s were washed wikh saturated sodium bicarbonate (10 ml.) dried (MgS04) and concentrated to give 382 mg. (85%) of viscousjl oily 2-[3~ ,5Or dihydroxy-2~ -(3 ~-hydroxy-4-phenyl-trans-l-buten-l-yl)cyclopent-l ~ -yl~acetic acid~ r-lactone (6'a).
The ir spectrum (CHC13) exhibited a strong adsorp-tion at 1770 cm~l for the lactone carbonyl and medium adsorp-tion at 965 cm~l ~or the trans-double bond : ~ :

2-~5~ -Hydroxy-3D~-(tetrahydropyran-2-yloxy)-2 ~-(3~<_[tetra_ hydropyran-2~yloxy] 4-phenyl-trans~l-buten-1-yI)cyclopen~-lo<-yl]acetic acidj~ y-lactonQ (7a):
. .
To a solution of 38 mg. (1.33 mmole) 2-[3~ ,5~ ~
dlhydroxy-2~ -(3 ~-hydroxy-4-phenyl~trans-1~-buten yl~cyclo pent~ yl]acetic acid, y -lac~one (6a) in 5 ml. anhydrous :, , methylene chloride and 0.4 ml. of 2,3-dihydropyran at 0 in a dry nitrogen atmosphere was added 5 mg. p-toluenesulfonic acid monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml. ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml.) then saturated brine (1 x 15 ml.), dried (MgS04) an~ concentrated ~ -to yieId 615 mg. ~ 100%) crude 2-[5~ -hydroxy-3~-(tetra-hydropyran-2-yloxy)~2~ -(3G~-~tetrahydropyran-2-yloxy]-4-phenyl-trans-1-buten-1-yl)cyclopent-lo~-yl]acetlc acid, y -lactone (7a).
The product of this example (7a) may be converted to 13,14-dlhydro-16-phenyl-~ -tetranorprostaglandins of the ;`
A, E or F serles through the procedures of examples 16, 18J
20-24.
~15 EXAMPLE 7 2-C5~ -Hydroxy-3c~-(tetrahydropyran-2-yloxy)-2~ -(3~ -ctetra-. .
~ hydropyran-2-yloxy]-4-phenyl-trans-1-buten-1-yl)cyclopent- ~ -.
lo~-yl3acetlc acid, y lactone (7?a):

To a solution of 382 mg. (0.71 mmole) 2-~3~ ,5~ -dihydroxy-2~ -(3~ -hydroxy-4-phenyl-trans-1-buten-yl)cyclo-pent~ yl~aoetlc acid, y -lactone (6'a) ln 5 ml. anhydrous methylene chloride and 0.4 ml. of 2,3-dihydropyran at 0 in a ~dry nltrogen atmosphere was added 5 mg. p-toluenesulfonic acid monohydrate~ A~ter stirring fQr 15 minutes, the reactlon 25~ ;miXture was oombined w1th 100 ml. etherg the ether solution washed with saturated sodium bicarbonate (1 x 15 ml.) then saturated brine (1 x 15 ml.), dried (MgS04) and concentrated ~-to yield 621 mg. (> 100%) crude 2-[5 ~-hydroxy-3~ -(tetra-hydropyran-2-yloxy)-2~ -(3~ -CtetrahYdroPyran-~-yloxy]-4 ; 30 phenyl-trani-l-buten-1-yl)cyclopent-lo<-yl]acetic aclcl, r- ~:

~: . , .
~.~ ~i ' ' .

~ . .. , . . ~ . .... .. .. .... . . .. .

lactone (7'a).
The nmr spectrum (CDC13) of 7a and 7'a exhibited a multlplet at 5.30-5.62~ (2H) for the olefinic protons, a singlet at 7.2 ~ (5H) for the phenyl protons, and multiplets at 4.36-5.18 ~ (4H), 3.22-4.24 ~ (9H), and 1.18-2.92 ~
(16H) for the remaining protons. The ir (CHC13) spectrum had a medium adsorption at 970 cm~l for the trans-double bond.

2-[5c<-Hydroxy-3c~-(tetrahydropyran-2-yloxy)-2~ -(3~ -[tetra-hydropyran-2-yloxy]-4-phenyl-trans-1-buten-1-yl)cyclopent-1~ -yl]acetaldehyde, r-hemiacetal (8a): ;
A ~olution o~ 605 mg. (1.33 mmole) 2-[5~ -hydroxy-3~ -(tetrahydropyran~2-yloxy)-2~ -3~-[tetrahydropyran-2-yloxyJ-4-phenyl-trans-1-buten-1-yl)cyclopent-1~ -yl]acetic acid~ y -lactone (7a) in 8 mlO dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled solution was ;~
added 3.0 ml. of 20% dlisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never ro~e above -65 (15 minutes). After an additlonal 45 minute8 of Btirring at -78Q, anhydrous methanol wa~ added until gas evolukion ceased and the reaction mixture ~- . "
wa8 allowed to warm to room temperature. The reaction mix-ture was combined with 100 ml. ether, washed with 50% sodium pota sium~tartrate solution (4 x 20 mlO), dried (Na2S04) and ooncentrated to yield 615 mg. (100%) 2 C5~ -hydroxy-3~ -(tetrahydropyra~n-2-yloxy)-2~ -(3~-[tetrahydropyran-2-yloxy)-4-phenyl-trans-1-buten-1-yl)cyclopent-1 yl~acetaldehyde, hemiacetal t8a)~
:

:

2-C50~-Hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~-(3~ -[tetra-hydropyran-2-yloxy]-4-phenyl-trans-1-buten-1)-ylcyclopent lo~-yl] acetaldehyde, y-hemiacetal (8'a): -,-A solution of 621 mg. (1.34 mmole) 2-[5~ -hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3~ -[tetrahydropyran-2-yloxy~-4-phenyl-trans-1-buten-1-yl)cyclopent~ yl]acetic acid, y-lactone (7'a) in 8 ml. dry toluene was cooled to ~78 in a dry nitrogen atmosphere. To this cooled solution was added 3.0 ml. of 20% diisobutylaluminum hydride in n- ~ , hexane (Al~a Inorganics) dropwlse at such a rate so that the internal temperature never rose above -65 (15 minutes).
A~ter an additional 45 minutes o~ stirring at -78, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml. ether, washed with 50% sodium potassium tartrate solution (4 x 20 ml.), dried (Na2S04) and concentrated to yield 621 mg. (100%) 2-[5 ~-hydroxy-30~- , (tetrahydropyran-2-yloxy)-2~ -(3~ -[tetrahydropyran-2 yloxy]-4-phenyl-trans-1-buten-1-yl)cyclopent-1-yl~acetaldehyde, ~-hemiacetal (8'a). ' EXAMPLE 10 ,~
9~ -Hydroxy-110c,15 ~ bis-(tetrahydropyran-2-yloxy)-16-phenyl-, ; cis-5~trans-13- ~ -tetranor prostadienoic,acid (9a): '~
. - .:
~ To a solutlon of 1760 mg. (4.0 mmole) (4-carbo- - ~
hydroxy-n-butyl) triphenylphosphonium bromide in a dry nitro- -gen atmosphere in 500 ml. dry dimethyl sulfoxide was added ' 3.2 ml. (7~.0 mmole) of a 2.2M solution o~ sodium methyl-sul~inylmethide ln dimethyl sulfoxide~ To this red ylide ,~

_59_ :

solution was added dropwise a solution of 615 mg. (1.34 mmole) 2-[5~ -hydroxy-3c~-~tetrahydropyran-2-yl.oxy)-2~ -(3~-[tetra-hydropyran-2-yloxy]-4~phenyl-trans-1-buten-1-yl)cyclopent- `
1 ~-yl]acetaldehyde, ~-hemiacetal (8a) in 5.0 ml. dry dimethyl sulfoxlde over a period of 20 minutes. Af~er an additional 2 hours stirring at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (20 ml.) and acidified to ` ~-pH23 with 10% aqueous hydrochloric acid. The acidic soluti~n was extracted with ethyl acetate (3 x 20 ml.) and the combined organlc extracts washed once with water (10 ml.) J dried (MgS04) and evaporated to a solid resldue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by coRrumn chromatography on silica gel (Baker B 15 "Analyzed" Reagent~60-200 mesh) uslng ethyl acetate as eluent. ~`
After removal of high Rf lmpurities, 150 mg. of 9~ -hydroxy-11c~,15~-bis-(tetrahydropyran 2-yloxy)-16-phenyl-cis-5-trans- -13-~ -tetranor prostadienoic acid (9a) was collected.

- .... - ::
20 9~ -Hydroxy-11O~,15~ -bls-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13- ~-tetranor prostadienoic acid (9'a):

T~ a solution of 1760 mg. (4.0 mmole) (4-carbo~
hy~roxy-n-butyl) triphenylphosphonium bromide in a dry nitro-gen atmosphere in 5.0 ml. dry aimethyl sulfoxide was added 25~ ~3~i2 ml. (7.~ mmole) of a 2.2M solution of sodium methyl- : `
sulfinylmethide in dlmethyl sulfoxi~e~ To thls red ylide olution wa~ added dropwise a solution of 621 mg. (1.34 mmole) 2-~5G~-hydroxy-3~ ~ etrahydropyran-2-yloxy)-2~ - ;
(3p -~tetrahydropyran-2-yloxy]-4~phenyl-trans-1-buten~

. -~ :.'', ::

.. ~ :, . ,, ,; . . .: . . ., - . . . ~ ; . . ..

yl)cyclopent~ yl]acetaldehyde, y -hemiacetal ~8'a) in 5.0 ml. dry dimethyl sulfoxide over a period of 20 minutes. After an additional 2 hours stirring at room temperature, the re- ~
aotion mixture was poured into ice water. The basic aqueous ;
solution was washed twice with ethyl acetate (20 ml.) and acidified to pH23 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml.) and the combined organic extracts washed once with water (10 ml.), dried (MgSO4) and evaporated to a solid residue. The solid residue was triturated with ethyl acetate and filtered.
The ~lltrate was purlfied by column chromatography on silica ~el (Baker "Analyzed" Reagent~60-200 mesh) using ethyl acetate a~ eluent. A~ter removal of high Rf impurities, 300 mg. o~
9~ -hydroxy-ll~ ,15~ -bis-(tetrahydropyran-2~yloxy)-16-phenyl-cis-5-tran -13- -tetranor prostadienoic acid (9'a) was collected.

9-Oxo-11~ ,15~ -bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13~ tetranor prostadienoic acid (10a):
, To a eolution cooled to -10 under nitrogen of 2300 mg. (4.24 mmole) 9~ -hydroxy-ll~ ,15~ -bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-~-tetranor prostadienolc acld t9~) ln 50 ml. reagent grade acetone was added dropwlse to 11.3 ml. (29.6 mmole) of Jones' reagent. After 20 ~-.
minutes at -10, 10 ml. 2-propanol was added and the reaction mixture was allowed to ~tir an additional 5 minutes at which time lt was combined with 300 ml. ethyl acetata~ washed with water (3 x 50 ml.)g dried (MgSO~) and concentrated to give 1983 mg. of 9-o~o-11 ~ ,15~ -bis-(t~trahydropyran~2--yloxy)- -: , .
, . ... ... . .. ,. ... .. , . ,, .. .. ..... , " .. . .,.. ,. ~.. .. . . . . .. .. . . ..

16-phenyl-cis~5-trans-13-~J-tetranor prostadienoic acid (10a).

. . . . .
9-Oxo-ll~ ,1 ~ -bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-~ . ",.
5-trans-13-~ -tetranor prostadienoic acid (lO'a):
. . ... _ _ .
To a solution cooled to -10 under nitrogen o~ 300 mg. (0.551 mmole) 9c~-hydroxy-11~ ~15~ -bis-(tetrahydropyran- -2-yloxy)-16-phenyl-cis-5-trans-13- ~-tetranor prostadienoic acid (9'a) in 9.2 ml. reagent grade acetone was added dropwlse to 0.262 ml. (o.655 mmole) of Jones' reagent. After 20 minu~es at -10, 0.260 ml. 2-propanol was added and the reaction mix-ture was allowed to stir an addltional 5 minutes at which time it was combined with 75 ml. ethyl acetate, washed with water (3 x 10 ml.), dried (MgSO4) and concentrated to give 220 mg. of 9-oxo~ ,15~ -bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13- ~ -tetranor-prostadienoic acid (10'a).

9-Oxo-11~ ,15~-dihydroxy 16-phenyl-cis-5-trans-13-u~tetranor-prostadienoic acid (lla):
.
A solution o~ 1637 mg. (3.02 mmole) 9-oxo-11 ~,15~ -bis-tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13- ~~ ! ''`'~''" ' ' tetranor-prostadienoic acid (10a) in 20 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at room~temperature for 24 hours and then was concentrated by rotary evaporation. The resultant crude oil was purified ~ : ~ :
~ ~ 25~ by column chromatography on silica gel (Mallinckrodt CC 4~ ~
..
lo0-?00 mesh) using ethyl acetate-cyclohexane as eluent.
APter elution o~ less polar impurities, the oily 9-oxo-11~ ,15~ -dihydroxy-16-phenyl~cis-5-trans-13- ~tetranor-prostadienoic acid (lla) weighing 365 mg. was collected.

: ': ~ . - "
: ' :.

..

Biological activity: guinea pig uterus 3, guinea pig ileum 1, guinea pig Histamine aerosol test lOO, dog blood pressure 3O0-400.

9-Oxo-11O~,15~ -dihydroxy-16-phenyl-cis~5-trans-13- -tetranor-~, , _ .
prostadienoic acid (ll'a):
A solution of 220 mg. (0.334 mmole) 9-oxo-11~ ,&rl5~-bis-tetrahydropyran-2-yloxy~-16-phenyl-cis-5-trans-13 tetranor-prostadienoic acid (lO'a) in 3.0 ml. o~ a 65:35 mix- .
ture of glacial acetic acid:water was stirred under nitrogen ~ ;
at 38 for 5 hours and then was concentrated by rotary evapora-tion. The resultant crude oil was purified by column chroma `
B tography on silica gel (Mallinckrodt CC-4~100-200 mesh) using ethyl acetate as eluent. After elution o~ less polar impuri-ties the semisolid 9-oxo~ c~15~ -dihydroxy-16-phenyl~ci3-5-tr -13- ~-tetranor prostadienoic acld tll'a) weighing 8 mg.
was collected.

9O¢~,11~ ,15~ -Trihydroxy-16-phenyl-cis-5-trans-13- W-tetranor-.
prostadienoic acid (12a):
A mixture of 0.7 g. of 9 ~-hydroxy-ll~ ,15~ -bis-ttetrahydroPyran-2-yloxy)-l6-phenyl-cis-5-trans-l3- W-tetranor-prostadienoic acid (9a) in 5 ml. of a 65:35 mix~ure of acetic aoid:water was stirred under nitrogen at room temperature ;25~ overnight, then was concentrated under reduced pressure to a Vi6~CQUS oil. The crude product was purifie~ by column ~ ;
chromatography on Mallinckrodt CC-4~s11ica gel using ethyl ~ -acetate a~ eluent. ~After elution of less polar impurlties, ~i~
the desired 9~ ,11~ jl5~ -trihydroxy-16-phenyl-cis-5~tran -9~
13-~tetranor-prostadienoic acid (12a) was obtained as a viscous, colorless oil welghing 51 mg.
The ir spectrum (CHC13) of 12a showed a strong absorption at 1710 cm~l for the carbonyl group and a medium absorption at 970 cm~l for the trans double bond.
The product obtai~ed above (12a) may be converted to 16-phenyl-~3-tetranor prostaglandin Fl~ via the process of Example 26. 12a may also be converted to 16-phenyl- ~-tetranor prostaglandin FoX , via the proce~s of Example 25.

EX~MPLE 17 2-[3~-~-Phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-3~ -.
methyl-4-phenyl-trans-1-buten-1-yl)cyclopent~ yl]acetic .:
acid, p lactone (13a) and 2-~3 ~-p-Phenylbenzoyloxy-5~-.
hydroxy-2~ -~3~ -hydroxy-3~ -methyl-4-phenyl~trans-1-buten-1-yl)cyclopent~ yl]acetic acid y -lactone (14a).

To a solution of 2908 mg. (6.2 mmole) 2-[3~ ~
phenylbenzoyloxy-so~ -hydroxy-2~ -(3-oxo-4-phenyl-trans-1-buten-l-yl) cyclopent-l~ -yl]acetic acld, y lactone (3a) in 26 ml. anhydrous ether and 20 ml. of tetrahydrofuran (distilled from LAH) in a dry nitrogen atmosphere at ~78 i~ added dropwise 6.8 ml. of (0.92M) methyllithium ln ether (Alfa). After skirring at -78 for 15 mlnutes the reaction is quenched by the dropwise addition of glacial acetic acid until the pH of the reaction is approximately 7. The mixture is then diluted with methylene chloride and the diluted organic so]ution is washed wlth water (lX) and with saturated brine ~-~(lX), is drled (anhydrous magneslum sulfate)~ and is concen~
trated to af~ord the epimeric alcohols.

he crude product is purlfied by column chroma~o~ `

.
-64- ~

. ' .

B graphy on 108 g. of silica gel t~aker "Analyzed" Reagen~ 60 200 mesh) using a mixture of benzene:ethyl acetate as eluent to provide the 2-[3O~-p-phenylbenzoyloxy-5~-hydroxy-2~ -(3~ -hydroxy-3~ -methyl-4-phenyl-trans-1-buten-1-yl)cyclo-pent-~ -yl]acetic acid, ~-lactone (13a), and 2-[3 ~-~-phenyl-benzoyloxy-5~ -hydroxy-2~ -(3~--hydroxy-3~ -methyl-4-phenyl-trans-1-buten-yl)cyclopent 1~ -yl]acetic acid, y -lactone (14a).
This material (14a) may be converted to the 15~ -methyl-16-phenyl-~ -tetranorprosta~landins of the A, E, and F series by the procedures outlined in Examples 4 16 and 18-26.
Other lower alkyl derivatives of the type tl4a) may be prepared by substituting the appropriate alkyl lithium derivative for methyl lithium ln the above procedure. These derivatives are suitable for conversion to 15-lower alkyl-16-phenyl- ~ -tetranorprostaglandins of the A, E, and F series through the sequences of Examples 3-16 and 18-26.

9-Oxo-15~ -hydroxy-16-phenyl-cis-5- ~ 1~11-trans-13~ ~_ ;
tetranor-prostatrienoic acid (15a):
A solution of 50 mg. of 9-oxo-11~ ,15 ~-dihydroxy-16-phenyl-cis-5-trans-13-~J-tetranor~prostadienoic acid (lla) ~ ~ in lO ml. dry methylene chloride and 10 ml. ~ormic acid is ; ~ 25 stirred at room temperature for 5 hours. The reaction mix-ture is diluted with 50 ml. toluene and evaporated to yield :: :
~ ~ (after chromatography) 9-oxo-11 ~-hydroxy-16-phenyl-cis-:: ~
5~ ~ 10~11 trans~l3-~J-tetranor prostadienoic acid (15a).
In the same way 15-substituted- w-pçntanor prosta-glandlns o~ the Al, Ao and 13,14 dihydro A2 series may be ~0~ $
prepared from 15-substituted -pentanorprostaglandins of the El, Eo and 13,14-dihydro series respectively.

The procedure of example 3 in which sodium boro-hydride is substituted for zinc borohydride may be used to produce l9a, l9a may then be converted to 24a via the pro-cedure of example 4 and 6, which is further converted to 13,14 dihydro-16-phenyl-~-tetranor prostaglandins of the A
E or F series by the procedures of examples 21-24~ 16, and 18. -~

2-~5O<-Hydroxy-3 ~ (tetrahydropyran-2-yloxy)-2~ -t3~ -~tetra-hydropyran-2-yloxy~ 4-phenylbut-1-yl)cyclopent-1~ -yl]acetlc ;
acid, ~ -lactone t24a):
A stirred heterogeneous solution o~ 1.555 g. (3.4 mmole) 2-t5~-hydroxy-3~ (tetrahydropyran-2-yloxy)-2~ -(3~ ~tetrahydropyran-2-yloxy~ -4-phenyl-tran~ buten-1-yl)- -cyclopent-l~ -yl~acetic acid, y -lactone (7a) and 300 mg. 5%
. .
palladium on carbon in 35 ml. at absolute methanol was hydro- -genated for 90 minutes. The reaction mixture was filtered through filter aid and concentrated (in vacuo) to yield 1.457 g. o~ 2-~5~ -hydroxy-3~ (tetrahydropyran-2-yloxy)-2~

(3~ ~tetrahydropyran-2-yloxy~ -4-phenylbut-1-yl)cyclopentan-1~ -yl]acetic acid, ~-lactone (24a). The ir spectrum (CHC13) .. . -of 24a exhibl~ed a lactone carbonyl adsorption at 177Q cm~

. .
2-~5O~-Hydroxy-3~ -(tetrahydropyran-2-yloxy~-2 ~ (3~ - ~ ~ -. . .
~tetrahydropyran-2-yloxy ~-4-phenylbut-1-yl)cyclopen~

;~ yl]acetaldehyde~ ~-hemiacetal (25a): -~

; A olution of 1457 mg. (3.2 mmole) 2-[5~ -hydroxy 30~ 3 ~-~tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetrahydropyran-2-~66-....:

yloxy~ -4 phenylbut-l-yl)cyclopent-l~ yl] acetic acid, ~-lactone (24~) in 15 ml. dry toluene was cooled to -78 ln a dry nitrogen atmosphere. To this cooled solution was added 5.0 ml. of 20% dlisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal tem-perature never rose above -65 (3 minutes~. After an addition al 30 minutes of stirring at -78, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 150 ml. ether, washed with 50% sodium potassium tartrate solution (1 x 50 ml.), dried (Na2SO4) concentrated, and chromatographed to yield 1200 mg. (81.5%) 2-[5~ -hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3c~{tetrahydropyran~2-yloxy~ -4-phenylbut-1-yl)cyclopent-1-yl]acetaldehyde, y-hemiacetal (25a).

9~ -Hydroxy-11~ ~15 ~-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-~ -tetranor prostenoic acid (22a):
To a solution of 5150 mg. (11.6 mmole) (4-carbo-hydroxy-n-butyl) triphenylphosphonium bromide in a dry nitro-gen atmosphere in 10.1 ml. dry dimethyl sulfoxide was added10.8 ml. (21.1 mmole) of a 1.96M solution of sodium methyl sulfinylmethide in dimethyl sulfoxide. To this red ylide solution was~added dropwlse a solution o~ 1200 mg. (2.6 mmole) 2-[5~ -hydroxy-3~-(tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetrahydropyran 2-yloxy } -4-phenyl-but-1-yl)cyclo-pent-l~ -yl]acetaldehyde, y -hemiacekal (25a) in 7.0 ml. dry dlmethyl sulfo~ide over a period of 20 minutes. After an addltional 2 hours stirring at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution ~;~

was acidified to pH 3 with 10% aqueous hydrochloric acid. The acidic solution ~as extracted with ethyl acetate (3 x 100 ml.) and the combined organic extracts washed once with water (50 ml.), dried (MgSO4) and evaporated to a solid residue. Thls solid residue was triturated with ethyl acetate and filtered.
The filtrate was purified byR~olumn chromatography on silica B gel (Baker "Analyzed" Reagent~60-200 mesh) using et~yl acetate as eluent. After removal of high R~ impurities, 880 mg. of 9~ -hydroxy-ll ~ ,15 ~-bis-(tetrahydropyran-2-yloxy)-16-phenyl- ;
cis-5-~J-tetranor prostenolc (22a) acid was collected. The ir spectrum (CHC13) of 22a exhibited a carbonyl adsorption at 1715 cm~l.
The product obtained above (22a) may be converted to 16-phenyl- W-tetranor-13,14 dihydro PGF2~ via the process of Example 16.

9-Oxo-11~ ,15~ -bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-~ -tetranor prostenoic acid (26a):
_ . . . . .
To a solukion cooled to -10 under nitrogen of 880 mg. (1.68 mmole) 9 ~-hydroxy-11 ~c,15O<-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis 5- ~-tetranor-prostenoic acid (22a) in 15 ml. reagent grade acetone was added dropwise 0.75 mmole) of `:
~;~ Jones' reagent. After 20 minutes at -10, 0.75 ml. 2-propanol was added and the reaction mixture was allowed to stir an ~ , Qdditional 5 mlnutes at which time it was combined with 100 ml. ethyl acetate, washed with water (3 x 25 ml.), drled (MgSO4) and concentrated to give 775 mg. of 9-oxo-11O~l5~ - :
bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5 _~tetranor ., prostenoic acid (26a). The ir spectrum (CHC13) had carbonyl adsorptions at 1710 and 1735 cm~
-68- ~
: ' ' . . .
: :~
'~i'~`' : ~ '' ~ `: ' 9-Oxo-11O~,15~ -dihydroxy-16-phenyl-cis 5- ~-tetranor prostenoic acid (27a):

A solution of 772 mg. 9-oxo-11~ ,15~ -bis-(tetra-hydropyran-2~yloxy)-16-phenyl-cis-5-~ -tetranor-prostenoic acid (26a) in 7.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25 for 20 hours and then was concentrated by rotary evaporation. The resultant crude oil was purified by column chromatography on silica gel ~ RrM
~3 10 (Mallinckrodt CC-4¦100-200 mesh) using ethyl acetate as eluent.

A~ter elution of less polar impurities, the oily 9-oxo-llo~, ~

15O~-dihydroxy-16-phenyl-cis-5- ~-tetranor prostenoic acid (27a) weighing 361 mg. was collected. The ir spectrum (CHC13) exhibited carbonyl bands at 1710 and 1735 cm~l.

Biological Activity: guinea pig u~erus~ 1, guinea pig histamine aerosol test, 0; dog blood pressure, 400 (long dura~

; tion of action).

9-Oxo-llo<,15~-dihydroxy-16-phenyl- ~ -tetranor prostanoic -acid (28a):
:
A heterogeneous solution of 34 mg. (. o8g mmole) 9-oxo-11~ ,15~ -dihydroxy-16-phenyl-cis-5-trans-13~~ -tetranGr prostadienoic acid (lla) and 13 mg. of 5% palladium on carbon in 3 ml. absolute methanol was hydrogenated (1 atm.) Z5 ~ at 0 for 2 hours. The reaction mixture was filtered and ; evaporated to yield 30 mg. of 9-oxo-11,15~ -dihydroxy-16-phenyl- _-tekranor prostanoic acid (28a). The lr (CHC13) of 28a exhibited carbonyl absorptions at 1715 cm~l and . .
~ 1735 cm~l, a broad OH region and no trans double bond absorp-:

, . : .

tion.
EXAMPL~ Z6 9-Oxo-11~ ,15~<-dihydroxy-16-phenyl-trans-13-~ -tetranor prostenoic acid (29a):
A solution of 46 mg. 9-oxo-11~ ,15~-dihydroxy-16-phenyl-cis-5-trans-13- w-tetranor prostadienoic acid (lla) .
in 5 ml. of dry ether was treated with 448 mg. (3.6 mmole) dimethyl isopropyl chlorosilane and 360 mg. (3.6 mmole) tri-ethylamine at 25 ~or 48 hours. The reaction m~xture was cool-ed to 0, methanol was added and the resulting solution was washed with water (3 x 2 ml.), dried (MgS04) and evaporated to a residue (67 mg.). The cru~e residue was then taken up in 6 ml. methanol and 30 mg. o~ 5% Pd/C and the resultant slurry was hydrogenated ~or 4 hours at -22 (CC14/Dry Ice).
After filtration through super cell and evaporation, the hydrogenated product was hydrolyzed in 2 ml. of acetic acid-water (3:1) for 10 minutes, diluted with water (20 ml.) and extracted with ethyl acetate (4 x 15 ml.!). The combined organlc extracts were washed with water (2 x 10 ml.), dried (MgS04) and evaporated to yield ll4 mg. of 9-oxo-lloC,15~ -dihydroxy-16-phenyl-trans-13- ~-tetranor prostenolc acid (29a) EXAMPLE 27 ;
2-~3~ -p-Phenylbenzoyloxy-5 ~-hydroxy-2~ -(3-hydroxy-4-phenyl-l-butyl cyclopent-l~ -yl]acetic acid, y lactone: (19a) A solution of 14.5 g. ~3.10 mmole) of 4a in 195 ml.
absolute methanol containing 0.5 g. 5~ palladium on carbon was hydrogenated at atmospheric pressure at room temperature for 5.5~hours. The reaction mixture was filter~d through _70_ . ~.
.~ .

~r~ ~0~ 5 Celite~and evaporated to yield 14.0 g. (95.5%) of desired 19a.
The ir (CHC13) spectrum of l9a exhibited carbonyl adsorptions at 1775 cm~l (S, lactone) and 1715 cm~l (S, ester) and no adsorption for a trans double bond.

2-[30C-_-Phenylbenzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-phenyl-1-butyl)cyclopent-lo~-yl]acetic acid, y ~lactone: ~50a) To a solution of 14.0 g. (30.0 mmole) l9a in 150 ml.
dry acetone at 0 was added 11.9 ml. (31.0 mmole) 2.6 M Jones' reagent dropwise over a period of 7 minutesO After an addi-tional 10 mlnutes 11 ml. of 2~propanol was added and the re-actlon mixture was combined with 1 ml. of ethyl acetate. The ethyl acetate layer was washed successively with water (3 x 100 ml.), sodium bicarbonate (1 x 100 ml.), brine (1 x 100 ml.), dried (MgS04) and evaporated to yield 9.5 g~ of desired 50a, m.p. 84-86.

2-[3G~,5~ -Dihydroxy-2~ -(3-oxo-4-phenyl-1-butyl)cyclopent-_ ~ -yl]acetic acid, y-lactone (51a) .
A heterogeneous mixture of 9.5 g. (20.4 mmole) of 2-~30~-p-phenylbenzoyloxy--5 ~-hydroxy-2~ -(3-oxo-4-phenyl-1-butyl)cyclopent-l~ -yl]acetic acid, y -lactone(50a), 100 ml~
of absolute methanol 100 ml. dry THF 3.7 g. of finely powdered, anhydrous potassium carbonate was stirred at room temperature for 3.5 hours, then cooled to 0. To the cooled solution was added 53.2 ml. (53.2 mmole) of l.ON aqueous hydrochlorlc acid. After stirring at 0 for an additional 10 minutes 9 50 ml. of water was added with concomitant formation of methyl p-phenylben~oate which was collected by filtration~

' ' The filtrate was saturated with solid sodium chloride, ex-kracted with ethyl acetate (2 x 400 ml.~, the combined organic extracts were washed with saturated sodium bicarbonate (2 x 50 ml.) dried (MgS04) and concentrated to give 2.3 g. (39%) of viscous, oily 2-[3 ~,5O~-dihydroxy-2~ -(3-oxo-4-phenyl-1-bukyl)cyclopent-l~ -yl]acetic acid, y -lactone (51a ).
The ir spectrum (CHC13) exhibited a strong adsorp-tion at 1770 cm~l for the lactone carbonyl, a strong adsorp- -tion at 1915 cm 1 for the ketone carbonyl, and no adsorption at 965 cm~l for a trans-double bond.

2-[5O~-Hydroxy-30~-(tetrahydropyran-2-yloxy)-2~ -(3-oxo-4-phenyl-butyl)cyclopent-l~ -yl]acetic acid, y -lactone: (52a) ~ , . , ~o a solukion o~ 2.2 g. (7.65 mmo~e) 2-~ ~ ,6 ~di-hydroxy-2~ -l3-oxo-4-phenyl-1-butyl)cyclopent-1~ -yl~acetic acid, p-lactone (51a) in 35 ml. anhydrous chloroform and 0.5 ml. of 2,3-dihydropyran at 0 in a dry nitro~en atmosphere was added 5 mg. p-toluene-sulfonic acidg monohydrate. After stir-ring for 80 minutes~ the reaction mixkure was combined with 350 ml. ether, the ekher solution washed with saturated sodium bicarbonate (2 x 100 ml.) then saturated brine (1 x 100 ml.)g dried (MgS04) and concentrated to yield 2.8 g. crude 2-[5~ -hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3-oxo-4-phenyl-1-~ butyl)cyclopent-l~ -yl]acetic acid, y-lactone, (52a).
; i 25 EXAMPLE 31 2-[5~ -Hydroxy-3~ (tekrahydropyran-2-yloxy)-2~ -(3-hydroxy-3-methyl-4-phenyl-1-~utyl)cyclopent~ yl]acetic acid, lactone (53a) B: ~ To a solution of 2.8 g. (7.6 mmole)(52a~ ln 100 ml.
INSTA START TM (Baker) ether in a nitrogen atmosphere was .

added 2.8 ml. (8.4 mmole) of 3M methyl magnesium bromide drop-wise over 8 minutes. A~ter 1 hour of stirring an additional 1 ml. of methyl magnesium bromide was added. After 25 minutes the reaction was diluted with 250 ml. of ether, quenched with 25 ml. saturated ammonium chloride, dried (MgS04), evaporated and chromatographed (Baker, 60-200 mesh) using ether as eluent to yield 940 mg. of the deslred (53a).
EXAMPLE 32 ~`
2-[5s<-Hydro~y-3c~-(tetrahydropyran-2-yloxy)-2~ -(3--hydroxy-. ... _ _ _ _ .
3-methyl-4-phenyl-l-butyl)cyclopent-lc~-yl~acetaldehyde, ~-_ . . .
hemiacetal (54a) A solution o~ 1.113 g. (2.87 mmole) 2-[5~ -hydroxy 3~ -(tetrahydropyran-2-yloxy)-2~ -(3-hydroxy-3-methyl-4-phenyl-but-l-yl) cyclopent~ yl]acetic acid, Y -lactone(53a) in 15 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. ~-To this cooled solution was added 5.0 ml. of 20% diisobutyl- `~-alumi.num hydride inin-hexane (Alfa Inorganics) dropwise at such `
.
a rate s~ that the internal temperature never rose above -65 (7 minutes). After an additional 30 minutes of stirring at -78, anhydrous mekhanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room tempera-ture. The reaction mixture was combined with 150 ml. ether, washed with 50% sodlum potassium tartrate solution (50 ml.), dried (Na2SO4) and concentrated to yleld 798 mg. 2-[5 ~-hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3-hydroxy-4-methyl-4-phenyl-but-1-yl)cyclopent-l-yl~acetaldehyde, y-hemiacetal-(54a) after column chromatography.

~, ~ 73~ ~ ~
: : ~.
f ~
~: ' .

.
2 [2~ -benzyloxymethyl-3~ -(tetrahydropyran-2-yloxy)-5D(-, .
hydroxy-cyclopent-l ~-yl]acetaldehyde, ~-hemiacetal To a stirred solution, cooled to -78, of the 2-[2~ -benzyloxymethyl-3~ -(tetrahydropyran-2~yloxy)-5~ - -hydroxycyclopent-l~-yl]acetic acid~ Y-:Lactone in 78.8 ml. of toluene was added 13.4 ml. (10.8 mmoles) of a 0.805M solution ~ -;
of diisobutyl-aluminum hydride in hexane dropwise. I'he solu-tion was stlrred in the cold under nitrogen for 1.0 hour then was quenched by the dropwise addition of methanol until gas evolution ceased. The quenched mixture was warmed to room temperature, was diluted with ether (79 ml.~, was washed with 50% sodium potassium tartrate (3x) and saturated brine (lx), was dried (anhydrous magnesium sulfate), and was concentrated to afford the crude, colorless, oily 2-[2~ ~benzyloxymethyl-3~ -(tetrahydropyran-2-yloxy)-5O<-hydroxycyclopent-1~-yl]-; acetaldehyde, y -hemiacetal weighing 3.15 g. (92.0% yield).
The ir, nmr, and mass spectra of the oil were consistent with the assigned structure.
20Spectra:
ir (CHCl3):
no carbonyl nmr (CDCl3):
7.31 ~ singlet 5H aromatic 255.32-5.75c~ broad lH OH
singlet 4.50~ ~ singlet 2H ~CH2-O

4.45 4.98 S multiplet 2H O~CH-O
3.44 ~ quartet 2H -CH2O-BZ-= 9 cps ~ J ~ 4 cps .
;~ ~30 1.20-4.40 S multiplets 16H remaining protons ~ ~ _74 :
.. . . . ..

7-[2 ~ -benzyloxyrnethyl-3~ -(tetrahydroE?yran-2-yloxy)-5~ -hydroxy-cyclopent-l~ -yl]-cis-5-heptenoLc acid To a solution of 4.96 g. (11.2 mmoles) of (4-carboxy-n-butyl)-triphenylphosphonium bromide in 8.85 ml. of dimethyl sulfoxide was added dropwise 9.73 ml. (21.2 mmoles) of a 2.18 M solution of sodium methylsulfinylmethide in di-methyl sulfoxide. To the resultant red ylide solution was added dropwise over a period of ].0 hour a solution of 1.57 g.
(4.50 mmoles) of the crude hemiacetal prepared in Example 33 ln 13.7 ml. o~ dimethyl sulfoxide. After being stirred ~or an additional 45 minutes the reaction was poured onto ice-water. The basic aqueous solution was extracted with a 2:1 mixture o~ ethyl acetate:ether (2 x 60 ml. was then covered with ethyl acetate, and was acidified with 1.0 N hydrochloric acid to pH r~3. The aqueous layer was extracted further with ethyl acetate, the combined ethyl acetate extracts were washed w1th water, were dried (anhydrous magnesium sulfate), and were concentrated to a viscous yellow oil. The crude oil was purified by chromatography on 30 g. o~ silica gel using ethyl acetate as eluent. After elution of high Rf impurities the desired 7-~2~ -benzyloxymethyl-30c-(tetrahydropyran-2-yloxy)-50~-hydroxycyolopent~ -yl]-cis-5 heptenoic acid was collect~
ed weighing 1.75 g. (90.0% yield).
25Spectra:
ir (CHC13):
5.82 ~ acid carbonyl -nmr (CDC13):
.
7.30 S singlet 5H aromatic ~ 6 . ~4 7 . oo ~ broad singlet 2H -OH

:

5.28-5.58 c~ multiplet 2H oleflnic ,~ . .
4.62-4.79 ~ broad singlet lH -O-CH-O
4.51 c~ singlet 2H ~-C_2-0 ;
3.23-4.38 S multiplets 8H -CH-O &
-CH-O
51.22-2.53 ~ multiplets 16H remaining protons Optical Rotation:
[~]D5 =~15.1 (C 9.94, HCC13).
_AMPLE 35 Methyl 7-[2~-benzyloxymethyl-3O~-(tetrahydropyran-2-yloxy)-5G~-hydroxycyclopent-l~ -yl]-cis-5-heptenoate A solution of 1.75 g. (4.06 mmoles) of the chromato-graphed acid prepared in Example 34 in 17.5 ml. of' anhydrous ether was titrated at room temperature with an ethereal diazo-methane solution until the yellow color persisted for 5 minutes. The reaction was then decolorized by the dropw~se additlon of glacial acetic acid. The ethereal solution was then washed with saturated sodium bicarbonate (lx) and satu-rated brine (lx), was dried (anhydrous mggnesium sulfate), and was concentrated to afford the faintly-yellow, oil methyl 7-~2~ -benzyloxymethyl-3~-(tetrahydropyran-2-yloxy)-5~ -hydroxycyclopent-l~ -yl]-cis-5-heptenoate weighing 1~80 g.
(99.0% yield).

ir (CHCl ):

255.77~u Ester carbonyl :. .
nmr (CDC13):
7-31 S singlet 5H aromakic 5.62-5.30 ~ multiplet 2H olefinic 4.81~4.63 ~ broad singlet lH -O-CH-O

: : , . .:' , 4.53 ~ singlet 2H ~-CH2-0 3O66 d~ singlet 3H --C_3 4.42-3.67 ~ multiplets 9H -CH2-0 &

2.55-1.36 ~ multiplets 12H remaining protons Methyl 7-[2~ -benzyloxymethyl-3~-(tetrahydropyran-2-yloxy)-~X wacetoxycyclopent-l~ -yl]-cis-5-heptenoate .
A mixture of 1.58 g. (3.54 mmoles) of the crude hydroxyester prepared in Example 35, 5.0 ml. of pyridine and o.736 ml. (7.78 mmoles) of acetic anhydride was stirred under nitrogen at 50 overnight. The mlxture was then cooled to room temperature and was diluted with ether (75 ml.). ~he etheral solution was washed with water (lx) and with saturated copper sul~ate (3x), was dried (anhydrous magnesium sulfate), and was ooncentrated to afPord the colorless, oily methyl 7-[2p -benzyloxymethyl-36~-(tetrahydropyran-2-yloxy)~5~ -acetoxycyclopent 1~ -yl]-cis-5-heptenoate weighing 1.61 g.
,: . :: .' (93.5% yield).
20 Spectra:
ir (CHC13):
1750 cm~l ester carbonyls -nmr (CDC13):
7.30 ~ singlet 5H aromatic 5.51-5.23 ~ multiplet 2H olefinic 5.22-4.91 ~ multiplet lH -CH-0-Ac ~ : ~ . :. 4.52 ~ slnglet 2H ~-CH2--; 3.63 ~ singlet 3H -0-CH

4.67-3.20 ~ multiplets 8H -0-CH &

-77- ;
: .., . .,:
:~ : ~: ., ~ ...

o 2. o6 ~ singlet 3H _3 2.55-1.22 S multiplets 16H remaining protons Methyl 7-[2~ -hydroxymethyl~ (tetrahydropyran-2-yloxy)-5~ -. _ _ _ _ acetoxycyclopent 1~ -yl]heptanoate -A heterogeneous mixture of 1.53 g. (3.14 mmoles) o~
the crude acetoxy ester prepared in Example 369 305 mg. of 5%
palladium on carbon, and 15.3 ml. of a 20:1 mixture of absolute ethanol:glacial acetic acid was stirred at room temperature under one atmosphere o~ hydro~e~ for 48 hours. The mixture B wa~ then ~iltered through Celite~545 and the filtrate was con-centrated to a~ord the colorless, oily methyl 7-~2~ -hydroxy-methyl-3~ -(tetrahydropyran-2-yloxy)-5~ -acetoxycyclopent-l~ -yl]heptanoate weighing 1.10 g. (87.5% yield).
Spectra:
.. ~ .
ir (CHC13):
1750 cm-l esker carbonyls nmr~(CDC13):
5.23-4.92 ~ multiplet lH -CH-OAc 4.83-4.46 ~ multiplet lH -O-CH-O
; 3.65 S singlet 3H -O-CH3 4.32-3.18 ~ multiplets 7H -O-CH &

3~06-2.70 ~ broa~ singlet 3H

. .
2.58-1.00 ~ multiplets 2CH remaining protons ... : . "., ,.,., ,,., " ., . , , . : . .

3t5 Methyl 7-[2~ -formyl-3~ -(tetrahydropyran-2-yloxy)-5~ -acetoxy-cyclopent-l~ -yl]heptanoate To a mechanically stirred solution of 3.37 ml.
(41.7 mmoles) of pyridine in 50 ml. of methylene chloride cooled to 10 to 15 under nitrogen was added portionwise over a period of 30 minutes 1.89 gO (18.9 mmoles) of chromium trioxide. The dark burgundy solution was then let warm to room temperature then was cooled to 0. To the cold solution was added a solution of 0.947 g. (2.37 mmole) of the orude alcohol prepared in Example 37 in 7.0 ml. of methylene chloride with the concomitant formakion of a dense black precipitate.
The suspension was stirred in the cold for 15 minutes then 7.21 g. t52.2 mmoles) of finely ground sodium bisulfate mono hydrate was added. After being stirred for 10 minutes 6.25 g.
(52.2 mmoles) of anhydrous magnesium sulfate was added. A~ter being skirred for 5 minutes the dark suspension was filtered ~
'E~ ~TI'q .
through a pad of Celitek was washed with methylene chloride, then was concentrated by rotary evaporation (bath <10) to afford the crude, dark brown, oily methyl 7-[2~ -formyl-3~ -(tetrahydropyran-2-yloxy)-5~ -acetoxycyclopent-l~ -yl]heptano-ate which was used without purification.

Methyl 9o<-acetoxy-11~ (tetrahydropyran-2-yloxy)-15-oxo-~25 tr -13-16-phenyl- ~-tetranorprostenoate.
. . , :
To a suspension of 110 mg. (2.61 mmoles) o~ a 57.0% dispersion of sodium hydride in mineral oil in 20 ml.
of dimethoxyethane is added 631 mg. (2.61 mmoles) of dimethyl-2-oxo-3-phenylpropylphosphonake. The mixture is stirred at room temperature for 1 hour under nitrogen. To this suspen-~ 79 ~ ~ .
.,. ~, sion is added a solution of 0.947 g. (2.37 mmoles) of the crude aldehyde prepared in Example 38 in 4 ml. of dimethoxyethane.
The resultant slightly turbid~ brown solution is stirred at room temperature for 2.0 hours under nitrogen. The reaction is then quenched by the addition of glacial acid to pH 7 and is concentràted by rotary evaporation. The crude product is puri~ied by column chromatography on silica gel to a~ord the desired methyl 9~ -acetoxy~ (tetrahydropyran-2-yloxy)-15-oxo-trans-13-16-phenyl-~ -tetranorprostenoate.
EXAMPLE 40 :
Methyl 9~ -acetoxy-ll ~-(tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16-phenyl- w -tetranorprostenoate.

To a solution o~ 1.1 g. (2.17 mmoles) of the enone prepared in Example 39 in 6.5 ml. of dimethoxyethane is added dropwise 2.17 ml. (1.08 mmoles) of a 0.5M Zn(BH4)2 solution in dimethoxyethane. After being stirred at room temperature under nitrogen for 3 hours the reaction is quenched by the dropwise addition o~ a saturated aqueous solution o~ sodium bitartrate until gas evolution ceased. The quenched hetero-geneous solution is stirred at room ~emperature for 5 minutes, is diluted with methylene chloride, is dried (anhydrous magnesium sulfate), and is concentrated to af~ord methyl 9~ -acetoxy-11~ (tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16-phenyl- ~-tetranorprostenoate.

:: :
25 ~ EXAMPLE 41 ~; Methyl-9 ~ -acetoxy-11O~,15~-dihydroxy trans-13-16~-phenyl~
tetranorprostenoate and methyl 9o<-acetoxy~ ,15~ -dihydroxy-trans-13~16-phenyl- w -tetranorprostenoate.
.

A solution of 1~l gO (2~16 mmoles) of the crude THP

-80~
.

.

ether prepared in Example 40 in 10.7 ml. of a 65:35 mixture of acetic acid:water is stirred at 40 + 2 under nitrogen for 2.5 hours. The reaction mixture is then concentrated to af~ord the crude epimeric diol mixture. The crude product is purified by column chromatography on silica gel to provide the desired methyl-9~ -acetoxy-ll~ ,15~ -dihydroxy-trans-13-16-phenyl-~J-tetranorprostenoate and the epimeric methyl 9~ -acetoxy-llc~,15O~-dihydroxy-trans-13-16-phenyl- -tetranor-prostenoate. -;

Methyl g~ -acetoxy-ll ~,15c~-bis~(tetrahydropyran-2-yloxy)-~n~-13-16-phenyl- ~ -tetranorprostenoate A mixture of 220 mg. (0.510 mmole) of the chromato- ;
graphed diol of Example 41, 0.14 ml.(1.53 mmoles) of dihydro-pyran, 4.2 ml. of methylene chloride, and 1 crystal of p~
toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 minutes. The reaction mixture is then diluted with ether, is washed with saturated aqueous sodium ........ .... ... ................................................................. ... . ~.
bicarbonate, is dried tanhydrous magnesium sulfate), and is ;~
concentrated to give the desired methyl 9 ~-acetoxy-11~ ,15~<-bis-(tetrahydropyran-2-yloxy)-trans-13-16-phenyl-W -tetranor- ~ ; -prostenoate.

9~ ,11c~,15OC-trihydroxy-trans-13-16-phenyl- ~-tetranor- -prostenoic acid.

; ~ A mixture o~ 55 mg. (0.15 mmoles) of the chromato-graphed diol prepared in Example 41, 0.45 ml. (0.45 mmole) of : :
1.0 N aqueous sodium hydroxide, 0.45 ml. of tetrahydrofuran, ~
and 0.45 ml. of absoluke methanol ls stirred unde:r nitrogen ~ -~at room temperature for 1.5 hours. The solution is then , -81- ~
.' .
': ~ ~' ' ' ~: ' ': .
.. . , . . . .. . ... . . , .. . .. .. . . . . . .. ... . . ~ . .... . .

acidified by the addition of 0.45 ml. of 1.0 N aqueous hydro-chloric acid (pH of acidified solution was ca. 5). The acidi-fied solution is extracted with ethyl acetate (4 x 2 ml.).
The combined extracts are dried (anhy~rous magnesium sulfate) and concentrated to afford the desired 90<,110~,15~ -tri-hydroxy-trans-13J16-phenyl~ ~-tetranorprostenoic acid.

9 ~ -Hydroxy-110~,15~ -bis-(tetrahydropyran-2-yloxy)-trans-13~16-phenyl-~ -tetranorprostenoic acidO ~`

A homogeneous solution of 262 mg. (0.436 mmole) of the crude bis-THP ester prepared in Example 42, 1.3 ml. (1.30 mmoles) of the l.ON aqueous sodium hydroxide solution, 1.3 ml.
of methanol, and 1.3 ml. of tetrahydrofuran is stirred under nitrogen overnight. The reaction is then quenched by the addi-tion of 1.30 ml. (1.30 mmoles) o~ a l.ON aqueous hydrochloric acid solution. The quenched solution ls diluted with ethyl -acetate. The organic layer is dried (anhydrous magnesium ; sulfate) and concentrated to afford the crude product. The crude product is purified by column chromatography on Baker . ~
"Analyzed'~ silica gel (60-200 mesh) to provide the 9~ -hydroxy-11~ ,15~ rbis-(tetrahydropyran-2-yloxy~-trans-13~16-phenyl- ~-tetranorprostenoic acid.

9-Oxo-11~ ,15~ bis-(tetrahydropyran-2-yloxy)-13 trans-16-phenyl-~ -tetranorprostenoic acid.
To a solution, cooled under nitrogen to -15 to 20, of 195~mg. (00371 mmole) of the chromatographed acid : ~ . ..
prepared in Example 44 in 4.0 ml. of acetone is added drop-wise 0~163 ml. (0.408 mmole) o~ 30nest reagent. The reaction : ~ .
~ -82-is stirred in the cold for 15 minutes then is quenched by the addition of 0.194 ml. o~ isopropanol. The quenched reaction is stirred in the cold for 5 minutes then is diluted with ethyl acetate. The organic solution is washed with water (2x~ and saturated brine (lx), is dried (anhydrous magnesium sulfate), and is concentrated to a~ford the desired 9-oxo-11~ ,15~-bis-(tetrahydropyran-2-yloxy) 13-trans-16-phenyl- w tetranor-prostenoic acid. ~ ;

9-Oxo-11~ ,15~ -dihydroxy-13-trans-16-phenyl- ~-tetranor--.
prostenoic acid.
A homogeneous solution of 178 mg. (0.328 mmole) o~
the crude THP ether o~ Example 45 in 2 ml. Or a 65:35 mixture of acetic acid:water is stirred under nitrogen at 40 ~ 2 for ..: : .
5 hours. The reaction is concentrated by rotary evaporation followed by oil pump. The crude product is purified by column ~ ~7M ~ -chromatography on silica gel (Mallinckrodt CC-7)~to provide the desired 9-oxo-11~ ,15~ -dihydroxy-13-trans-16-phenyl-~ -tetranorprostenoic acid.
. ,. . -Dimethyl 2-Oxo-3-(p-methylphenyl-propylphosphonate (2e):
. .
.:. ~ . . .
A solution of 74.5 g. (oo6 mole) dimethyl methyl-; phosphonate (Aldrich) in 700 ml. dry tetrahydro~uran was cooled to -78 in a dry nitrogen atmosphere. To the stirred Z5 phosphona-te~solution was added 386 ml. of 1.6 M n-butyllithium in hexane solutlon (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction tem-perature never rose above -65. After an additional 5 . .
minutes stirring at -78, 49.1 g. (0.3 mole) methyl ~-methyl-phenylacetate was added dropwise at a rate that kept the re-: : ' '' ,- ", ~: :.,;, ~ -'. :

action temperature less than -70 (20 minutes). After 3.5 hours at -78 the reaction mixture was allowed to warm to ambient temperature, neutralized with 30 ml. ace~ic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3x), the combined organic ex-tracts were backwashed (50 cc H20), dried (MgS04~, and con-centrated (water aspirator) to a crude resldue and distilled, b.p. 145-7 (< 0.2 mm) to give 36.5 g. (47.7%) dimethyl 2-oxo-3-(p-methylphenyl)propylphosphonate (2e).
The nmr spectrum (CDC13) showed a doublet centered ~
;.~ .," . o .: .' at 3.75 S (J=11.5 cps, 6H) for (CH30)2-P-, a doublet centered O O
at 3.14 S (J = 23 cps, 2H) -C-CH2-P-, a singlet at 3.8~ (2H) "
for -CH2-C-, broad singlet at 7.15 (4H) for p-C6H4 and a singlet at 2.3 ~ (3H) ~or p-CH3-C6H4-. The ir (CHC13) ex-hibited a carbonyl absorption at 5.79~u.

2-[3~ -p-Phenylbenzoyloxy-5~ -hydroxy-2~-(3-oxo-4-(p-methyl-.
phenyl)-trans-l-buten-l-yl)-cyclopent-l ~-yl]Acetic Acid, . . , y -lactone (3e):
Dimethyl 2-oxo-3(p-methylphenyl)propylphosphonate (2e) (5.7 g., 22.3 mmole) in 40 ml. anhydrous 1,2-dimethoxy-ethane (DME) was treated with 9.2 ml. (21.7 mmole) 2.34 M n-butyllithium in n-hexane (Alfa Inorganics, Inc.) in a dry ;~ 25 ~ nitrogen atmosphere at icy water temperature. A~ter 25 min.
of stirring, 7.1 g. (20.3 mmole) 2-[3 ~-p-phenylbenzoyloxy-5P~-hydroxy-2~ -formylcyclopentan-l~ -yl] acetic acid, y-: :
~ 84-. .
. .:

lactone was added in one portion followed by 30 ml. anhydrous DME. The reaction was warmed to room temperature and after 35 minutes the reaction mlxture was quenched with 15 ml.
glacial acetic acid, combined with 50 ml. CH2C12 and washed successively with 100 ml. saturated sodium bicarbonate solu-tion (2x), 100 ml. water t2X), 100 ml. saturated brine (lx), dried tMgSO4) and evaporated to yield 7.7 g. (79%) 2-[3~-p-phenylbenzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-(p-methylphenyl)-trans-l-buten-l yl) cyclopent-l~ -yl]acetic acid, r -lactone (3e) as a solid after column chromatography (Silica gel, Baker, 60-200 mesh), m.p. 145-146.
The ir spectrum (CHC13) of the product exhibited ad-sorption bands at 1777 cm~l (strong), 1717 cm 1 (strong), 1680 cm~l (medium) and 1630 cm 1 (medium) attributable to the carbonyl groups and at 973 cm~l for the trans double bond.
The nmr spectrum (CDC13) exhibited a multlplet at 7.23-8.18 S
(9H) ~or the _-biphenyl group, a doublet of doubIets centered at 6.75 (lH~ J a 7, 16 cps) and a doublet centered at 6.25 S
(lH, J = 16 cps) for the olefinic protons, a broad singlet at O . ,: -~, .
7.09 ~ (4H) for C6Hs-CH2-C-, a singlet at 3.74 ~ (2H) for O ~
C6H5-~CH2-C, a singlet at 2.27S (3H) for ~-CH3-C6H4~ and multiplets at 4.85-5.47 ~ (2H) and 2.21-3.07 ~ ~6H) for the remainder of the protons.
The product of this example (3e) may be converted .
; 25 to 13,14-dihydro-16-p-methylphenyl- ~ tetranorprostaglandins of the A, E or F series through the procedures of e~amples 14, 163 18-19 and 21-24.
.
The product (3e) may also be converted to 15-lower : '' ~.'," . .~"'."'.';' '.: , ' . :

4~
alkyl-16-p-methylphenyl- ~-tetranorprostaglandins of the A, E
or F series by the procedures of examples 4-26.
13,14-Dihydro-15-lower alkyl-16-p-methylphenyl- ~-tetranorprostaglandins of the A, E or F series may be obtained from ~3e) via the procedures of examples 16-19 and 21-24.

2-[3 ~-p-Phenylbenzoyloxy-5 ~-hydroxy-2 ~-(3 ~-hydroxy-4-(p-methylphenyl)-trans-l-buten-l-yl)cyclopent-l ~ -yl]acetic acid, , y -lactone3 (4e), and 2[3 ~-p-Phenylbenzoyloxy-5~ -hydroxy-._ 2~ -(3/~-hydroxy-4-(p-methylphenyl)-trans-1-buten-1-yl)cyclo-pent-lc~-yl]acetic acid, y -lactone t5e).

To a solution of 17.7 g. (16 mmole) 2-[3~ -~-phenyl-benzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-(p-methylphenyl)-trans-1-buten-l-yl)cyclopent-l~ -yl]acetic acid, ~ -lactone (3e) in ;
65 ml. dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at 0 was added dropwise 14.6 ml. of a 0.5 M zinc borohydride solution. After stirring at room temperature for 40 minutes~
a saturated sodium bitartrate solution was added dropwise at 0 until hydrogen evolution ceased. The reaction mixture was allowed to stir for 5 minutes at which time 200 ml. dry methyl-ene chloride was added. After drying (Na2S04) and concen-trat1ng (water aspirator) the resultant semi-solid was puri-fied by column chromatography on silica gel (Baker "Analyzed"
~TM -Reagent~60-200 mesh) using ether as eluent. After elution ` of less polar impuritles a fraction containing 1.3 gO 2-[3 ~-p-phenylbenzoyloxy-5 ~-hydroxy-2~ -(3 ~-hydroxy-4-(p=methyl-; ~ phenyl) trans-l-buten-l-yl)cyclopent~lo<-yl]acetic acid, r-.
lactone ~4e), a 0031 g. fraction of mixed 4e and 5e and ~inall~ a fraction (105 g.) of 2-C3~ -p-phenylbenzoyloxy-5~ -; -86-~: ~ : .. ,.' .
: ' .

:

' - :

hydroxy-2~ -(3~ -hydroxy-4-(p-methylphenyl)-trans l-buten-yl)-cyclopent-lo~-yl]acetic acid, ~ -lactone (5e).
The ir spectrum (CHC13) of 4 had strong carbonyl adsorptions at 1770 and 1710 cm~l and an adsorption of 965 cm~l for the trans double bond.
EXAMPLE 50 i;
2-~3c~,5~ -Dihydroxy-2~ -(3O<-hydroxy-4~-(p-methylphenyl)-trans- -l-buten-l-yl~cyclopent-l~ -yl]acetic ac'Ld, y -lactone (6e):

A heterogeneous mixture o~ 1.7 g. (3.5 mmole) of 10 2-[3~ -p-phenylbenzoyloxy-5 ~-hydroxy-2~ -(3~ -hydroxy-4-(p-methylphenyl)-trans-l-buten-l-yl)cyclopent-l~ ~yl]acetic acld, y -lactone (4e), 25 ml. of absolute methanol, 25 ml. dry tetrahydrofuran, and 514 mg. o~ ~inely powdered, anhydrous i, pota8sium carbonate was stirred at room temperature for one hour, then cooled to 0. To the cooled solution was added 7.4 ml. (7.4 mmole) of l.ON aqueous hydrochloric acid. After stirring at 0 ~or an additional 10 minutes, 5 ml. of water was ~ -added with concomitant formation of methyl p-phenylbenzoate which was collected by filtration. The filtrate was saturated with solid sodlum chloride, extracted with ethyl acetate (3 x 200 ml.), the combined organic extracts were washed with saturated sodium bicarbonate (25 ml.), dried (MgS04) and con-centrated to give 1.0 g. (95.5% of viscous, oily 2-[3c<~5~ -dlhydroxy-2~ -(3~ -hydroxy-4-(p-methylphenyl)-trans-1-buten-25~ yl)oyelopent~ yl]acetic acid, y -lactone (6e). :
The ir spectrum (CHC13) exhibited a strong adsorp-;tion at 1770 cm~l for the lactone carbonyl and medium adsorp-tion at 97Q cm~l ~or the trans-double bond. ;~

, .. : .. .
.-:

2-[~X -Hydroxy 3c~-(tetrahydropyran-2-yloxy)-2~ -(3~ -[tetra-_ hydropyran-2-yloxy]-4-(p-methylphenyl)-trans-1-buten-1-yl)--cyclopent-1~ -yl]acetic acid, ~ -lactone (7e):
To a solution of 1.0 g. (3.3 mmole) 2 ~3 ~,5~-di-hydroxy-2~ -(3~ -hydroxy-4-(_-methylphenyl)-trans-1-buten-yl)-cyclopent-l~ -yl] acetic acid~ ~-lactone (6e) in 15 ml. an-hydrous methylene chloride and 2.0 ml. o~ 2,3-dihydropyran at 0 in a dry nitrogen atmosphere was added 10 mg. p-toluene-sul~onic acid, monohydrate~ After stirring for 15 minutes, the reaction mixture was combined with 150 ml. ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml.) then saturated brine (1 x 15 ml.), dried (MgS04) and concen-trated to yield 1.6 g. (100%) crude 2-[5O<-hydroxy-3O<-(tetra-hydropyran-2-yloxy)-2~ -(3~ -[tetrahydropyran-2-yloxy]-4-(~-methylphenyl)-trans~l-buten l-yl)cyclopent-lG~-yl] acetic acid, y -lactone (7e).
The ir ~CHC13) spectrum had a medium adsorption at 970 cm 1 for the trans-double bond.
The product of this example (7e) may be converted to 13,14-dihydro-16-(p-methylphenyl)-~-tetranorprostaglandins of the A, E or F series through the procedures o~ examples 16, -`
18, 20-24.
EXAMPLE 52 ~-2-[5O~-Hydroxy-3~c-(tetrahydropyran-2-yloxy)-2~ -(3 -[tetra- ~
. ~
hydropyran-2-yloxy]-4-(p-methylphenyl)-trans-1-buten-1-yl)-~_~ .
~,. .
:~ ~ , ~:
A solution of 1.6 g. (3.3 mmole) 2-[5~ ~hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -3 ~-[tetrahydropyran-2- -,~: ' . ' , '' .
.. . . .
:.'``"''~''` ' ' ....

~4~4~S ~;
yloxy]-4-(p-methylphenyl)trans-1-buten-l-yl)cyclopent-l~_-yl]-acetic acid, Y -lactone (7e) in 20 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled solwtion was added 8. o ml. of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that theinternal temperature never rose above -65 (15 minutes). After an additional 45 minutes of stirring at -78, anhydrous `~
methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 200 ml. ether, washed with 50% sodium potassium tartrate solution (2 x 50 ml.), dried (Na2S04) and concentrated to yield 1.4 g. (87.5%) 2-[5~ -hydroxy-3~ -(tetra-hydropyran-2-yloxy)-2~ -(3~ -[tetrahydropyran-2-yloxy]-4-(p-methylphenyl)-trans-l-buten-1-yl)cyclopent-l-yl]acetaldehyde, ~ -hemiacetal (8e).
EXAMPLE 53 ~ -9~ -Hydroxy-11O~,15c~-bis-(tetrahydropyran-2-yloxy)-16-(p-methylphenyl)-cis 5-trans-13- ~ -tetranor-prostadienoic acid .
(9e)-To a solution of 5.3 mg. (12.0 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry ni.trogen atmosphere in 10 ml. dry dimethyl sulfoxide was added 9.5 ml.
(21.0 mmole) of a 2.2M solution of sodium methylsulfinylmethide ln dimethyl sulfoxide. To this red ylide solution was added 25~ dropwise a aolution of 1.2 g. (2.54 mmole) 2-[5~C-hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ (3~-[tetrahydropyran-2~
yloxy]-4-(~-methylphenyl)-trans-l-buten-1-yl)cyclopent-1~ - -yl]acetaldeh~de, Y -hemiacetal (8e) ln 5.0 ml. dry dimethyl ~: , sul~oxide over a period of 20 minutes. After an additional ~ ;

30 ~ 2 hours~stirring at room temperatureg the reaction mtxture ~i~

. . .
. .-: . .

~ ' 4~i was poured into ice water and acidified to pH 3 with 10%
aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 100 ml.) and the combined organic ex-tracts washed with water (3 x 50 ml.), dried (MgS04) and evaporated to a solid residue. This solid residue was tri-turated with ethyl acetate and filtered. The filtrate was purified by column chromatography on sllica gel (Baker B "Analyzed" Reagent~60-200 mesh) using chloroform then ethyl acetate as eluent. After removal o~ high Rf impurities, 1.2 g.
of 9 ~-hydroxy-ll~ ,15 ~-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13- ~-tetranor-prostadienoic acid (9e) was collected.
The ir (CHC13) had a carbonyl absorption at 1710 cm~
and a trans double bond absorption at 965 cm~l.
The product of thls example (9e) can be converted to 16-p-methylphenyl- ~-tetranorprostagiandins of the F series (F2~, Fl~, Fo~) via the procedures of examples 169 24 and 25.
EXAMPLE 54 ~ -9-Oxo-11 ~,15~-bis-(tetrahydropyran-2-yloxy)-16-(p-methyl-: . . , phenyl)-cis-5-trans-13 ~-tetranor-prostadienoic acid (lOe):

To a solution cooled to -10 under nitrogen o~ 1.2 : .
g. (2.0 mmole) 9c~-hydroxy-llo~l5o<-bis-(tetrahydropyran-2 yloxy)-16-(p-methylphenyl)-cis 5-trans-13-~J-tetranor-prosta- '-dlenoic acid (9e) in 9.2 ml. reagent grade acetone was addeddropwise 1.0 ml. (2.67 mmole) of Jones' reagent. After 20 minutes at -10, 1.0 ml 2-propanol was added and the reaction .
mixture was alIowed to stir an additional 5 minutes at which time it was comblned with 75 ml. ethyl acetate, washed with ~: : : : .
~9~ : . .' `' ' '' ~'' ' ' ' ' water (3 x 10 ml.), drled (MgS04) and concentrated to give 1 g. of 9-oxo~ ,15~ -bis-(tetrahydropyran-2-yloxy)-16-(p-methylphenyl)-cis-5-trans 13-~ -tetranor-prostadienoic acid (lOe). Puri~ication by column chromatography yie].ded 575 mg. of pure 10.
The ir (CHC13) had carbonyl absorptions at 1735 cm~
and 1710 cm~1 and a trans double bond at 965 cm~1.

9-~xo-11~ ,15O5-dihydroxy-16-(p-methylphenyl)-cis-5-trans-13-~-tetranor-prostadienolc acid (lle):

A solution o~ 5.75 mg. (1.04 mmole) 9-oxo-11O~,15~ -bis-tetrahydropyran-2-yloxy)-16-(p-methylphenyl)~cis-5-trans-13-~ -tetranor-prostadienoic acid (lOe) in 5.7 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitro- ;
gen at room temperature for 20 hours then was concentrated by ;

rotary evaporation. The resultant crude oil was puri~ied by -~2 RT~ ' .'`' ~, column chromatography on silica gel (Mallinckrodt CC-4~100-200 mesh) using ethyl acetate~cyclohexane as eluent. A~ter elu -~
tion of less polar impurities the semisolid 9-oxo-11~15O~-dihydroxy-16-(p-methylphenyl)-cis-5-trans-13- ~ -tetranor-prostadlenoic acid (l1e) weighing 250 mg. was collected.
The lr (CHC13) of lle exhibited a broad OX band, carbonyl ab-orptions at 1735 cm~l and 1710 cm~l and a trans double bond absorption at 965 cm~1. -;25 The product of thls example (lle) can be converted to 16-p-methylphenyl-~ ~tetranQrprostaglandins El, EoA2~ A

and Ao via the procedures of examples 25, 26, and 18.
:

.

. :' ' Dimethyl 2~0xo-2-phenylethylphosphonate (2f):

A solution of 74.5 g. t600 mmoles) dimethyl methyl-phosphonate (Aldrich) in 750 ml. dry tetrahydrofuran was cooled to ~78 in a dry nitrogen atmosphere. To the stirred phos-phonate solution was added 265 ml. of 2.34 M _-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction tempera- -ture never rose above -65. After an additional 5 minutes stirring at -78, 41 g. (300 mmole) of methyl benzoate was added dropwise at a rate that kept the reaction temperature ;
less than -70 (10 minutes). After 1 hour at -78 the reaction mixture was allowed to warm to ambient temperature, neukralized with 35 ml. acetic acid and rotary evaporated to a white gel.
The gelatinous material was taken up in 75 ml. water, the aqueous phase e~tracted with 300 ml. portions of ether (3x), ~--the combined organic extracts were backwashed (50 cc H20), ~ ;
dried (MgS04), and concentrated (water aspirator) to a crude residue and distilled, b.p. 130-5 (.04 mm) to give 35 g.
(29%) dimethyl 2-oxo-2-phenylethylphosphonate (2f).
The nmr spectrum (CDC13) showed a doublet centered -:
" - .:
~ at 3.78 ~ (J = 11.5 cps, 6H) for (CH30)2-P-, a doublet .
::: o o : " " . . - :
centered at 3.63 ~ (J = 23 cps, 2H) -0-CH2-P-, and a multi-plet 7.3-8.2 ~ ~5H) for ~ -.
: ' , . ' .

~; -92~ ~

,,.,~,~ :
. . .
.... . .. ... .... ... , , .. . .. . . . . . .. . . . . . . ........ ... ... . :: ..

S '' 2-[3 ~-p-Phenylbenzoyloxy-5~ -hydroxy-2~ -(3-oxo-3-phenyl-.
trans-l-propen-l-yl)-cyclopent-l~ -yl]acetic acid, ~-lactone .
(3f):
Method A:
Dimethyl 2-oxo-2-phenylethylphosphonate (2f) (3.4 g., 14.2 mmole) in 225 ml. anhydrous ether was treated with 5.9 ml.
(9.5 mmole) 1.6 M n-butyllithium in n-hexane (Foote) in a dry nitrogen atmosphere at room temperature. After 5 min. of stir- ;
ring, an addltional 400 ml. of anhydrous ether was aclded, followed by 3.08 g. (8.8 mmole) 2-[3 ~-p-phenylbenzoyloxy-5~-hydroxy-2~ -formylcyclopentan-l~ -yl]acetic acid, y-lactone ~ ~ ;
in one portlon followed by 75 ml. anhydrous ether. After 2 hours, 30 ml. anhydrous 1,2-dimethoxyethane was added and the reaction was stirred overnight. The reaction mixture was quenched with 5 ml. glacial acetic acid and filtered to yield 2.375 g. (69%) 2-[3~-p-phenylbenzoyloxy-5c~-hydroxy-2~ -(3-oxo-3-phenyl-trans-1-propen-1-yl)cyclopent-1~ -yl] acetic acid, ~ -lactone (3f) as a solid (mOp. 145-9).
The ir spectrum (CHC13) of the product (3f) ex~
hlbited adsorption bands at 1775 cm~1 (strong), 1715 cm~
(medium) and 1625 cm~l (medium) attributable to the carbonyI
groups and at g75 cm~l (medium) for the ~rans double bond.
13,14 Dihydro-15-lower alkyl-5-phenyl- ~-pentanor-prostaglandins of the A, E or F series may be obtained from (3f) vla the procedures of examples 16-19 and 21-24.
Method B:
.
Dimethyl 2-oxo-2-phenylpropylphosphonate (2f) (5.17 g., 22.6 mmole) in 30 ml. anhydrous 1,2-dimethoxyethane was treated wikh 9~4 ml. (22 mmole) 2.34 M n-butyllithium in : .

.'' ~ ' n~hexane (Al~a Inorganics, Inc.) in a dry nitrogen atmosphere at 0. After 45 min. of stirring at room temperature, 7.6 g.
(21.4 mmole) ?-[3~ -p-phenylbenzoyloxy-5c<-hydroxy-2 ~-formyl-cyclopentan~ yl]acetic acid, ~ -lactone was added in one portion ~ollowed by 15 ml. anhydrous 1,2-dimethoxyethane.
After 30 minutes, the reaction mixture was quenched with 2 ml.
glacial acetic acid, combined with 200 ml. CH2C12 and extracted successively with 75 ml. water (2 x), 75 ml. saturated sodium blcarbonate solution (2 x), 75 ml. saturated brine (1 x), dried --(Na2S04) and evaporated to yield 8.2 g. (85%) 2-[3c~ phenyl-benzoyloxy-5 ~-hydroxy-2~ -(3-oxo-3-phenyl-trans-1-propen-1-yl)cyclopent-l~ -yl}acetic acid, y-lactone (3f) as a solid.
The product of this example 3f may be converted to 15-phenyl- -pentanorprostaglandins of the A, E or F series through the procedures o~ examples 4-18, 25 and 26.
The product (3f) may also be converted to 15-lower alkyl-5-phenyl-~ -pentanorprostaglandins of the A, E or F
series by the procedures of examples 4-26. ~ -2-[3~-p-Phenylbenzoyloxy-5 ~-hydroxy-2~ (3-hydroxy-3-phenyl-l-prop-l-yl)cyclopent~ l]acetic acid, ~ -lactone (19f):
To a solution of 7.6 g. (16.8 mmole) 2-[3~-p-phenyl-benzoyloxy-5 ~-hydroxy-2~ -(3-oxo-3-phenyl-trans-1-propen-1-yl)cyclopent-lo<-yl] acetic acid, ~ -lactone (3f) in 100 ml.
dry tetrahydrofuran in a dry nitrogen atmosphere at ambient .
temperature was added dropwise 16.8 ml~ of a 0.5 M zinc boro~
hydride solution. After stirring at 25 for 2 hours, a ~saturated sodium bltartrate solution was added dropwise until hydrogen evolution ceased. The reactlon mixture was allowed ~; 30 ~ to stlr for 5~mlnutes, at which time 250 ml. dry methylene _ 9 11 _ . - . . .
: ; ~ : ''' ' ' :~ ,. ~:

'' ' '.~.

~ o~
chloride was added. After drying (MgSO4) and concentrating (water aspirator) the resultant semisolid was purified by RT~
column chromatography on silica gel (Baker "Analyzed" Reagen~
60~200 mesh) using chloroform as eluent. After elution of less polar impurities, a fraction containing 2.8 g. of 2-[3~
p-phenylbenzoyloxy-5~-hydroxy^2~ -(3-hydroxy-3-phenyl-1-prop- ' l-yl)cyclopent-l~-yl]acetic acid, y-lactone (19f) was obtain-ed.
The ir spectrum (CHC13) of 19f had strong carbonyl ~' adsorptions at 1770 and 1715 cm~l. ' ;
If the 2-[3~-_-phenylbenzoyloxy-5~ -hydroxy-2 (3--hydroxy-3-phenyl-1-propen-1-yl)cyclopent-1 ~-yl]acetic acid, ~ -lactone is desired, the reaction is run at -78 sub-stituting lithium triethyl borohydride for zinc borohydride.
The product of this example (19f) may be converted ~ "
to 13,14-dihydro-15-phenyl-~ -pentanorprostaglandins of the A, E or F series through the procedures of examples 16, 18-19 and 21-24.

Dimethyl 2-Oxo-3-(p-methoxy-phenyl)propylphosphonate (2h):

A solution of 74.5 g. (600 mmo~les) dimethyl methyl-phosphonate ~Aldrich) in 700 ml. dry tetrahydrofuran was cooled to -78 in a dry nltrogen atmosphere. To the stirred phosphonate solution was added 385 mlO of 1.6 M n-b'utyl- ' ;' lithium in hexane solution (Foote~ Inc.) dropwise over a period of 10 minutes at such a rate that the reaction tem-perature never rose above -65. After an additional 5 minutes stirring at -78, 54 g. (300 mmole) methyl p-methoxy phenyl acetate was added dropwise at a rate that kept the _95_ - :
,',,: `

reaction temperature less than -70 (20 minutes). After 3.5 hours at -78 the reaction mixture was allowed to warm to ambient temperature, neutralized with 55 ml. acetic acid and rotary evaporated to a white gelO The gelatinous material was taken up in 75 ml. water, the aqueous phase extracted with 300 ml. portions of chloroform (3x), the combined organic ex-tracts were backwashed (50 cc H2O), dried l(MgS04), and concen-trated (water aspirator) to a crude residue and distilled, b.p.
167-195 (0.2-0.3 mm) to give 3906 gO (49.4%) dimethyl 2-oxo-3-(p-methoxyphenylpropylphosphonate (2h).
The nmr spectrum (CDC13) showed a doublet centered O
at 3.83 ~ (J = 11.5 cps, 6H) for (CH3O)2-P-, a doublet O
centered at 3.14 S (2H) for -CH2-C-, a singlet at 3.84 S (3H) for CH3O-C6H4 and a multiplet at 6.82-7.41 ~ (IIH) for C6H4.

Dimethyl 2-oxo-3-(3,4 methylenedioxy)-phenylpropyl~
phosphonate, dimethyl 2-oxo-3-(3,4 dimethoxy3-phenylpropyl-phosphonate, and dimethyl 2~oxo-3-(3,4,5 trimethoxy)-phenyl-propylphosphonate may be prepared following the above pro-cedure and may be converted to the correspond-sng 16 substi-20 ~ tuted_~J-tetranorprostaglandins of the A, E or F series via the procedures of examples 2-26.

2-C3~ -~-Phenylbenzoyloxy-5G~-hydroxy-2~ -(3-oxo-4-~p-methoxy- -phenyl]-trans-1-buten-1-yl)-cyclopènt-1~ -yl]Acetic Acid, ~- -lactone (3h):
:: :
~ ~ Dimethyl 2-oxo-3-~p-methoxyphenyl]propylphosphonate :: : :
(2h) (3.2 g., 11.7 mmole) 1n 200 ml. anhydrous ether was -g6--treated with 5.6 ml. (9 mmole) 2.5 M n-butyllithium in n-hexane (Foote) in a dry nitrogen atmosphere at room temperature.
After 5 min. of stirring9 an additional 100 ml. of anhydrous ether was added followed by 2.5 g. (7.15 mmole) 2 [3 ~-p-phenylbenzoyloxy-5G~-hydroxy-2~ -formylcyclopentan-l~ -yl~- f`~
acetic acid, y-lactone in one portion and 75 ml. anhydrous ether. After 35 minutes the reaction mixture was quenched with 5 ml. glacial acetic acid and extracted successfully with 100 ml. saturated sodium bicarbonate solution (4 x), 100 ml. water t2 x), 100 ml. saturated brine (1 x), dried (MgS04) and evaporated to yield 10641 gc (46.5%) 2-[3~ -_-phenylbenzoyl ; --oxy-5~ -hydroxy-2~ -(3-oxo-4-(p-methoxyphenyl)-trans-1-buten-1-yl) cyclopent~ yl]acetic aci.d, ~-lactone (3h) as an oil after column chromatography (Silica gel, Baker, 60-200 mesh).
The NMR (CHC13) was consistent for (3h).
The product of this example (3h) may be converted to -13,14-dihydro-16-p-methoxyphenyl- ~-tetranorprostaglandins ~ . .. . .
of the A, E or F series through the procedures of examples 16, 18-19 and 21-24.
The product (3h) may also be conver~ed to 15-lower alkyl-16-p-methoxyphenyl-~ ~tetranorprostaglandins of the A~ ~ f ' E or F series by the procedures of examples 4-26.
13,14-Dihydro-15-lower alkyl-16-p-methoxyphenyl- -tetranorprostaglandins o~ the A, E or F series may b~
obtalned~ from (3h~ via the prooedures of examples 16-19 and 21-24.
.

,. .. . ..
, _97 ;
.... ..
: "" ' '':, ' ' ' : '' '' ' : f .

2-[3~ -~-Phenylbenzoyloxy-5~-hydroxy-2~ -(3~ -hydroxy~4-(p methoxyphenyl)-trans-l-buten-l-yl)cyclopent-l~ yl]acetic acid, ~ -lactone (4h); and 2-[3~-_-Phenylbenzoyloxy-5~C-hydroxy-2~ -(3~ -hydroxy-4~(p-methoxyphenyl)-trans-l-buten l-yl)cyclopent-lo<-yl]acetic acid, y lactone (5h).

To a solution of 5.5 g. (11.1 mmole) 2-[3~ -p-phenyl- -benæoyloxy-5~-hydroxy-2~ -(3~oxo-4~ methoXyphenyl)-tra~_-l~bu~en-l-yl) cyclopent-l~ -yl]acetic acid, y -lactone (3h) in 50 ml.
dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 10.0 ml. of a 0.5 M zinc boro-hydride solution. After stirring at 0 for 2 hours, a saturat-ed sodium bitartrate solution was added dropwise until hydrogen evolution ceased. The reaction mixture was allowed to stir for 5 minutes at which time 200 ml. dry methylene chloride was added. After drying (MgSO4) and concentrating (water aspirator) the resultant oll was purified by column chromato-RT~
graphy on silica gel (Baker "Analyzed" Reagent~60-200 mesh) using ether as eluent. After elution of less polar impurities a fraction containing 1.09 g. 2-[3~--p-phenylbenzoyloxy-5~ -hydroxy-2~ -(3 ~-hydroxy-4-(~-methoxyphenyl)-trans-1-buten-1-yl) cyclopent-lr~-yl]acetic acid, y -lactone (4h), a 0.75 g.
fraction of mixed 4h and 5h and finally a ~ractlon (2O05 g.~
of 2-~3~ -p-phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-4- ;
~25 (p-methoxyphenyl)-trans-l-buten-yl)cyclopent-1~ -yl]acetic acld, y -lactone (5hj.
The ir spectra (CHC13) of 4h and 5h were super-,: :
imposable and had strong carbonyl adsorptionæ at 1775 and 1720 cm~l and an adsorptlon at g65 cm 1 for the trans double bond.
-98- ~

~: :

3~;

2~[3O<~5O<-Dihydroxy-2~ -(3c~-hydroxy-4-(p-methoxy)phenyl-trans-l-buten-l-yl) cyclopent-lc~-yl]acetic acid, ~ -lactone (6h) A heterogeneous mixture of 1091 mg. (2.2 mmole) of 2-[3~<-p-phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-4-(p- ;
methoxyphènyl)-t-rans-l-buten-l yl)cyclopent~ yl]acetic acid, - ;
~ -lactone (4h), 30 ml. of absolute methanol and 306 mg. o~
finely powdered, anhydrous potassium carbonate was stirred at room temperature for one hour~ then cooled to 0. To the ...
cooled solution was added 4.4 mmole) of l.ON aqueous hydro-chlorlc acid. After stirring at 0 for an additional 10 ~ -. .
minutes, 5 ml. of water was added with concomitanb formation ~ o~ methyl ~-phenylbenzoate which was collected by filtration.
The :Ei!~tra~e! was saturated with solid sodium chloride, ex-. - :~. . .
tracted with ethyl acetate (3 x 100 ml.), the combined organic .....
extracts were washed with saturated sodium bicarbonate (25 ml.), dried (MgSO4) and concentrated to give 700 mg. (100%) of viscous, oily 2-[3~ ,5O~-dihydroxy-2~ -(3O<-hydroxy-4 (_- ~-~; 20 methoxyphenyl)-trans-l-buten-l-yl)cyclopent-l ~~yl]acetic -~
acid, ~ -lactone (6h).
The ir spectrum (CHC13) exhibited a strong adsorp-tion~at 1770 cm~l for the lactone carbonyl and medium adsorp-tion at 970 cm~l for the trans-double bond.
25~ EXAMPLE 63 2-[3~ ,5D<-Dihydroxy-2~ -(3~ -hydroxy-4-(p-methoxy)phenyl- - ;:
trans-l-buten-l-yl) cyclopent~l~ -yl]acetic acid, ~-lactone ~ ~ :
(6'h)~
A heterogeneous mixture of 2.05 g. (4.04 mmole) o~ '~

~: , . .. ..

.

9~ -2-[3~ -p-phenylbenzoyloxy-5 ~-hydroxy-2~ -(3~ -hydroxy-4-(p-methoxyphenyl)-trans-l-buten-l-yl)cyclopent-lo~-yl]acetic acid, ~ -lactone (5h), 50 ml. of absolute methanol and 560 mg. of finely powdered, anhydrous potassium carbonate was stirred at room temperature for one hour, then cooled to 0. To the cooled solution was added 8.2 ml. (8.2 mmole) of l.ON aqueous hydrochloric acid. After stirring at 0 ~or an additional 10 minutes, 5 ml. of water was added with concomitant formation of methyl p-phenylbenzoate whlch was collected by filtration.
The filtrate was saturated with solid sodium chloride, ex-tracted with ethyl acetate (4 x 150 ml.), the combined organic ' extracts were washed with saturated sodium bicarbonate (25 ml.) dried (MgSO4) and concentrated to give 990 mg. (76%) of viscous, oily 2~3 ~,5 ~-dihydroxy-2~ -(3~ -hydroxy~ (p-methoxyphenyl)-trans-l-buten-l-yl)cyclopent~ yl~acetic acld, y-lactone (6'h).
The ir spectrum (CHC13) exhibited a strong adsorp-tion at 1770 cm~l for the lactone carbonyl and medium adsorp- ~' tion at 970 cm~l for the trans-double bond. ~' 2-[5~ -Hydroxy-3 ~-(tetrahydropyran-2-yloxy ~ '-(3 ~-~tetra-, . - .
~ ~ cyclopent-l~ -yl] acetic acid, ~-lactone (7h): ~ ' ~: :
To a solution of 700 mg. (2.2 r~mole) 2-[3~ ,5c~-dihydroxy~2~ -(3O~-hydroxy-4-(p-methoxyphenyl)-trans l-buten- -.
yl]cyclopent~ yl~ acetic acid, ~ -lactone ~6h) in 15 ml.
anhydrous methylene chloride and 1.5 ml. of 2,3-dihydropyran ~' at 0 in a dry nitrogen atmosphere was added 10 mg. p-' toluenesulfonlc acid, monohydrate. After stirring for 25 minutes, the reaction mixture was combined with 100 ml.

,,~,~ ' ' ether, the ether solution washed with saturated sodium bicarbo-nate (2 x 20 ml.) then saturated brine (1 x 20 ml.), dried (MgS04) and concentrated to yield 1200 mg. ( > 100%) crude 2-[5O~-hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetra-hydropyran-2-yloxy} -4-(~-methoxyphenyl)-trans-1-buten-1-yl)-cyclopent-l~ -yl]acetic acid, ~-lactone (7h).
The ir (CHC13) spectrum had a medium adsorption at 970 cm~l ~or the trans-double bond and a lactone-carbonyl ad-sorption (strong) at 1770 cm~l.
The product o~ this example (7h) may be converted to 13,14-dihydro-16-p-methoxyphenyl- ~-tetranorprostaglandins of the A, E or F serles through the procedures of examples 14, 16, 1~, 20-24.

2-~5~ -Hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3 ~- ~tetra~
hydropyran-2-yloxy~ ~4-(p-methox~phenyl)-trans l buten_l_yl)_ cyclopent-lo<-yl} acetic aci~ lactone (7'h):
To a solution o~ 990 mg. (3.12 mmole) 2-[3 ~,5~-dihydroxy-2~ -(3~ -hydroxy-4-(p-methoxyphenyl)-trans-1-buten-yl)cyclopent-l~ -yl] acetic acid, ~-lactone (6'h) in 20 ml.
anhydrous methylene chloride and 2.0 ml. o~ 2,3-dihydropyran at 0~ in a dry nitrogen atmosphere was added 10 mg. p-toluene-sul~onic acld, monohydrlde. After stirring for 15 minutes, the reaction mixture was combined with lQ0 ml. ether, the ~ ether solut~ion~washed with saturated sodium bicarbonate ; (1 x 25 ml.) then saturated brlne (1 x 25 ml.), dried (MgS04) and concentrated to yield 1700 mg. (> 100%) crude 2-[5~
hydroxg-3~ -(tetrahydropyran-2-yloxy)-2~ -(3~ - {tetrahydro-pyran-2-yloxy} -4-(p-methoxyphenyl)-trans-1-buten-1-yl)~ ;
cyclopent~ yl~ acetic acid~ y-lactone (7'h).

. .. : ~ " ,' ,:

The ir (CHC13) spectrum had a medium adsorption at 970 cm~l for the trans-double bond and a lactone carbonyl adsorption (strong) at 1770 cm-l.

2-[5~ -Hydroxy-3~ (tetrahydropyran-2-yloxy)-2~ -(3O~- ~tetra-hydropyran-2-yloxy } -4-(~-methoxyphenyl)-trans-1-buten-1-.
yl)cyclopent--lcC-yl] acetaldehyde, y-hemiacetal (8h):
.
A solution of 2.2 mmole 2-[5~ -hydroxy-3~ -(tetra-hydropyran~2-yloxy)-2~ -3~ ~tetrahydropyran-2-yloxy ~ -4-(_-methoxyphenyl)-trans-l-buten-l-yl)cyclopent-l~ -yl]acetic acid, ~-lactone (7h) in 15 ml. dry toluene was cooled to -78 ~ -ln a dry nitrogen atmosphere. To this cooled solution was added 5.0 ml. of 20% diisobutylaluminum hydride in _-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65 ~15 minutes). A~ter an additional 45 minutes of stirring at ~78, anhydrous methanol ,. ..
was added until gas evolution ceased and the reaction mixture ~-was allowed to warm to room temperature. The reaction mixture :
; . . . .
was combined with 100 ml. ether, washed with 50% sodium pokassium tartrate solution (4 x 20 ml O ) ~ dried ~Na2S04) and concentrated and chromatographed to yield gO0 mg. (84%) 2-[5~ -hydroxy-3cx-(tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetra-hydropyran-2-yloxy } -4-(p-methoxyphenyl)-trans-1-buten~
yl)oyclopent-l-yl]acetaldehyde, Y hemiacetal (8h).

2-[5~ -Hydroxy-3 ~-(te :: : :
ten-l-yl)cyclopent~ yl] acetaldehyde, ~-hemiacetal (8'h): j-A solution of 2.68 mmole 2-[5~-hydroxy-3G~-(tetra-~30 ~ hydropyrsn-2-yloxy3~2~ -(3~ - ~tetrahydropyran-2-yloxy } _LI_ .
~ .

4~
(_-methoxyphenyl)-trans-1-buten l-yl)cyclopent-~-yl]acetic acid, y-lactone (7'h) in 15 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled solution ~
was added 8.o ml. of 20% diisobutylaluminum hydride in n- ~ -hexane (Al~a Inorganics) dropwise at such a rate so that the internal temperature never rose above 65 (15 minutes).
After an additional 45 minutes of stirring at -78, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction ' '~
mixture was combined with 100 ml. ether, washed with 50%
sodium potassium tartrate solution (4 X 20 ml.), dried ~ ' ' (Na2S04), concentrated and chromato~raphed to yield 1150 mg. ' (87%) 2-[50~-hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3~
'~tetrahydropyran-2-yloxy~ -4- (~methoxyphenyl)-trans-l-buten- ~ ;
l-yl)cyclopent-l-yl] acetaldehyde, ~ -hemiacetal (8''h). ;
E_ M~LE 6~ ''" ' ' 9~ -Hydroxy-11 ~,15~ -bis-(tetrahydropyran-2-yloxy)-16-(~
-- -- -- -- . , .
mehtoxyphenyl)-cis-5-trans-13-~ -tetranor-prostadienoic acid (9h): '' To a solution of 3720 mg. (8.55 mmole) (4-carbo~
hydroxy-n-butyl) triphenylphosphonium bromide in a dry nitro- '"
gen atmosphere in 7.4 ml. dry dimethyl sulfoxide was added ' '~;' 7.9 ml. (15.3 mmole) of a I.96 M solution of sodium methyl- ' '' sul~inylmethide in dimethyl sulfoxide. To this red ylide '" ' 25~ solution was added dropwise a solution of 900 mg. (1.84 " ~''' mmole) 2~[5~ -hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~
(3~ - ~tetrahydropyran~2-yloxy} -4-(p-methoxyphènyl~)-trans-`' '~' ' buten-l-yl) cyclopent-l-yl]acetaldehyde3 y-hemiacetal (8h) in 5!0 ml. dry dimethyl sulfoxide over a period o~ 20 minutes. ; ~ ' ;-103- ~
: : ~

`:: :
., .

~4~
After an additional 2 hours stirring at room temperature9 the reaction mixture was poured lnto ice water. The basic aqueous solution was acidified to pH ~3 with 10% aqueous hydrochloric acid. The acidic solution was exkracted with ethyl acetate (3 x 100 ml.) and the combined organic extracts washed once with water (50 ml.)~ dried (MgS04) and evaporated to a solid residue. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by column chromato~
graphy on silica gel (Baker "Analyzed" Reagent~60-200 mesh) ;
using chloroform then ethyl acetate as eluents. After re-mo~al of high Rf impurities, 762 mg. of 9 ~-hydroxy-11 ~,15v~- -bis-(ketrahydropyran-2-yloxy)-16-(p-methoxyphenyl)-cis-5-trans-13-~J-tetranor-prostadienoic(9h)acid was collected. The ir spectrum (CHC13) had a carbonyl adsorption at 1715 cm~l and a trans-double bond adsorption at 970 cm~l.
The produck of this example (9h) can be converted to 16-p-methoxyphenyl-~ -tetranorprostaglandins of the F series (F2~ , Fl~, Fo ~) via the procedures of examples 16, 24 and 25.
EXAMPLE 69 ; -96~-Hydroxy-ll~ ,15~--bis-(tetrahydropyran-2-yloxy)-16-(p-,_ _ methoxyphenyl)-cis-5-trans-13- ~-tetranor-prostadienoic acid Tc a solution of 4876 mgO (10.95 mmole) (4-carbo-hydroxy-_-butyl) triphenylphosphonium bromide in a dry nitro-gen atmosphere in 9.7 ml. dry dimethyl sulfoxide was added 10.3 ml. (20.0 mmole) of a 1.96M solutlon of sodium methyl- ~ -sul~inylmethide~in dimethyl sul~oxide. To this red ylide solution was added dropwise a solution of 1150 mg. (2.34 mmole) 2-[5~ -hydroxy-3C~-(tetrahydropyran-2-yloxy)-2~ - ;

(3~ - ~tetrahydropyran-2-yloxy} -4-(p-methoxyphenyl)-trans-l-buten-l-yl)cyclopent-l ~-yl]acetaldehyde, ~-hemiacetal (8'h) in 7.0 ml. dry dimethyl sul~oxide over a period o~ 20 minutes. After an additional 2 hours stirring at room tempera-ture, the reaction mixture was poured onto ice water. The basic aqueous solution was acidified to pH ~3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with -~
ethyl acetate (3 x 100 mlO) and the combined organic extracts washed once with water (50 ml.), dried (MgS04) and evaporated , to a solid residueO This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by ~:
B column chromatography on silica gel (Baker "Analy~ed" Reagent 60-200 mesh) using chloroform then ethyl acetate as eluent.
After removal of high Rf impurlties, 898 mg. of 9~-hydroxy-11 ~ ,15~ ~bis-(tetrahydropyran-2-yloxy)-16-(p-methoxyphenyl)- ~:
cis-5-trans-13- ~-tetranor-prostadienoic acid (91h) was collected. The ir spectrum (CHC13) had a carbonyl adsorption ~ -at 1715 cm~l and a trans-double bond adsorption at 970 cm~1.

9-Oxo lld~,15O<-bis-(tetrahydropyran-2-yloxy)-16-(p-methoxy-~ _ , .
phenyl)-cis-5-trans-13-~ -tetranor-prostadienoic acid (lOh): ;
To a solution cooled to ~10, under nitrogen of ~;~ 762 mg. ~1.3 mmole) 9~ -hydroxy~ ,15O~bis-(tetrahydro-pyran-2-yloxy)-16-(_-methoxyphenyl)-cis-5-trans-13-~J-tetra-nor-prostadienoic acid (9h) ln 15 mlD reagent grade acetone ~ ~ was added dropwise to o . 6 ml O ( 1.6 mmole) of Jones' reagent.
; After 20 minutes at -10j 0.6 ml 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 100 ml. ethyl ~
., ` .

:

~4~
acetate, washed with water (3 x 25 mlO)~ dried (MgS04) and concentrated to give 617 mg. of 9-oxo~ ,15~-bis-(tetra-hydropyran-2-yloxy)-16-(p-methoxyphenyl)-cis-5-trans-13- ~-tetranor-prostadienoic acid (lOh)o The ir spectrum (CHC13) had strong carbonyl adsorptions at 1710 and 1740 cm~l and a trans-double bond adsorption at 970 cm~l.

9-Oxo-llc<,15 ~-bis-(tetrahydropyran-2-yloxy)-16-(p-methoxy-phenyl)-cis-5-trans-13-~ ~tetranor-prostadienoic acid (lO'h):
-To a solution cooled to -10 under nitrogen of 898 ~ ;~
mg. (1.57 mmole) 9 ~-hydroxy-11~,15~ -bis-(tetrahydropyran-2-yloxy)-16-(p-methoxyphenyl)-cis-5-trans-13- W-tetranor-prostadienoic acid (9'h) in 15 ml. reagent grade acetone was added dropwlse to o.64 ml. (1.7 mmole) of Jones' reagent.
After 20 minutes at 10, o.64 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which time it was combined with 125 ml. ethyl acetate, washed with water (3 x 25 mlO), dried (MgS04) and concentrated to give 823 mg. of 9-oxo-llc~,15~ -bis-(tetra-hydropyran-2-yloxy)-16-(_-methoxyphenyl)-cis-5-trans-13- ~-tetranor-prostadienoic acid (lO'h). The ir spectrum (CHC13) exhibited strong carbonyl adsorptions at 1710 and 1740 cm~l , and a trans-double bond adsorption at 970 cm~l.
.

~;~ 25 9-Oxo-110~,15~ -dihydroxy-16-(p-methoxyphenyl)~cis-5-trans-13-~J-tetranor-prostadienoic acid (llh):
A solution o~ 617 mg. 9-oxo-110<,15C~-bis tetra-hydropyan-2-yloxy)-16-(p-methoxyphenyl)-cis-5-trans-13-~ -tetranor-prostadienoic acid (lOh) in 6.1 ml. o~ a 65:35 mix-.

: -` ~ ,, ,' ,~

gs ~
ture of glacial acetic acid:water was stirred under nitrogen at 25 Por 20 hours then was concentrated by rotary evapora-, tion. The resultant crude oil was purified by column chromato-graphy on silica gel (Mallinckrodt CC-4A100-200 mesh) using ethyl acetate as eluent. After elution of less polar impuri-ties the oily 9-oxo-11 ~,15O~-dihydroxy-16-(_-methoxyphenyl)-cis-5-trans-13-~)-tetranor-prostadienoic acid (llh) weighing 230 mg. was collected. The ir spectrum (CHC13) exhibited carbonyl adsorptions at 1715 and 1745 cm 1 and a trans-double `
bond adsorption at 970 cm~l.
The product of this example (llh) can be converted ~ -to 16-p-methoxyphenyl-~-tetranorprostaglandins El, EoA2~ A
and Ao via the procedures of examples 25, 26, and 18.

9-Oxo-llG~,15~ -dihydroxy-16-(p-methoxyphenyl) cis-5-trans- -13- ~ -tetranor-prostadlenoic acid (ll'h):
.:
A solution of 8?3 mg. 9-oxo-11O~,15~ -bis-tetrahydro-pyran-2-yloxy)-16-(~-methoxyphenyl)-cis 5-trans-13- ~-tetranor-prostadienoic acid (10'h) in 8.2 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25 Por 20 hours then was concentrated by rotary evaporation.
The resultant crude oil was pur ~ied ~y column chromatography on silica gel (Mallinckrodt CC-4~100-200 mesh) using ethyl acetate as eluent. After elution of less polar impurities . .
~25~ the semisolid 9-oxo~ ,15~ ~dihydroxy-16-(p-methoxyphenyl)-cis-5-trans-13-~J~tetranor-prostadienoic acid (lllh) weighing 300 mg. was collected. The ir spectrum (CHC13) of ll'h ex~
hibited carbonyl adsorption at 1740 and 1715 cm~l and a tranR-double bond adsorption at g70 cm-l.

-107- :
::. .

' 1 ~ i'd'~ ' ' . ,. , . ... , . .~,~ . : , . , . . . ,.. - . . . . , . , . :

Dimethyl 2-Oxo-3-(~ -naphthyl)propylphosphonate (2m):
.
A solution of 74.5 g. (o.6 mole) dimethyl methyl-phosphonate (Aldrich) in 750 ml. dry tetrahydrofuran was cooled to -78 in a dry nitrogen atmosphere. To the stirred phos-phonate solution was added 265 ml. of 2.34 M _-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction tempera- ;~
ture never rose above -65. After an additional 5 minutes ~-stirring at -78, 60 g. (0.3 mole) methyl-2-(~ -naphthyl) acetate was added dropwise at a rate that kept, the reaction temperature less than -70 (10 minutes). A~ter 3.5 hours at -78 the reaction mixture was neutralized with 35 ml. acetic ~ ;
acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml. water3 the aqueous phase ex-tracted with 200 ml. portions of methylene chlorlde (3~), the combined organlc extracts were backwashed (50 cc H20), dried (MgS043, and concentrated (water aspirator) to a crude residue and dlstilled, b.p. 195-200 (~ 0.1 mm) to give dimethyl 2-oxo-3-(~ -naphthyl) propylphosphonate (2m).
The nmr speotrum (CDC13) showed a doublet centered O ~ .:
" . ~
~ at 3072 ~ (J = 11.5 cps~ 6H) for (CH30)2-P-, a doublet ~ centered at 3.09~ ~J = 22 cps, 2H) C-CH2-P-, a slnglet at O ;
4.0 ~ (2H) ~or -CH2-C- and a multlplet at 7.I8-7.~2 ~ (7H) ~;~ 25 rr~ClOH7~-This is a suitable starting material for the ; ~ ~ -108- ,~

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

synthesis of 16-(~ -naphthyl)- ~-tetranorprostaglandins of the A, E or F series via the procedures of examples 2-26. Dimeth~
2-oxo-(c~-naphthyl)propyl phosphonate is synthesized as ~"
descrlbed above, substituting methyl-2-(o~-naphthyl)acetate for methyl-2-(~ -naphthyl)acetate. This material is a suitable starting material for the synthesis of 16-(C~-naphthyl)-~J- . :
tetranorprostaglandins of the A, E or F series via the pro-cedures of examples 2-26.

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9-Oxo-11~,15O~-dihydroxy-16-p-biphenyl- ~-tetranorprostanoic acid .
A heterogeneous solution of 9-oxo-1~ ,15~_-dihydroxy-~

16-p-biphenyl-cis-5-trans-13- ~-tetranorprostadienoic acid and . ~ . , 5% palladium on carbon in absolute methanol was hydrogenated ~
(1 atm.) at 25 for 2 hours. The reaction mixture was filtered -and evaporated to yield 9-oxo-lld~,15 ~dihydroxy-16-p-biphenyl- ~-tetranorprostanoic acid, m.p. 120-123. The IR
~KBr3) of exhibited carbonyl absorptions at 1715 cm~L and 1735 cm~l, a broad OH region and no trans double bond absorp-tion.

9-9~ ,15s~-trihydroxy-16-phenyl-cis-5-trans-13-~ -tetranor-prostadienoic acid: ~ ;
To a solution of 74 mg. (0.2 mmole) 9-oxo-11~,15K~- ~
dihydroxy-16-phenyl-cis-5-trans 13- w-tetranorprostadienoic ;
acid in 10 ml. absolute methanol at 0 was added a chilled ~ -~
-solution of 300 mg. sodium borohydride in 35 ml. absolute;~
methanol. After 20 minutes at 0, the reaction was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was then cooled to C and 2 ml.
of water was added, the resultant solution stripped of solvent (ln vacuo), taken up in 10 mls. ethyl acetate and acidified to pHrJ 3 wlth 10%~ HCl in an ice bath. This mixture was ex-tracted with ethyl acetate (4 x 5 ml.), dried (NA2 SO4~, con- :
oentrated and chromatographed on silica gel (CC-7) using 97%
methylene chloriùe-methanol and 95% methylene chloride-methanol `
as eluents yielding flrst 22 mg. of 9 ~,11DC,15 ~-trihydroxy-: ~ : . .
30~ ~ ~16-phenyl-cis-5-trans-13- ~-te~ranorprostadienoic acid and -120~ ~

,;' .: .' :

-then 18 mg. of the desired 9~ ,11 ~,15 ~-dihydroxy-16-phenyl-cis-5 trans-13- -tetranorprostadienoic acid.

Dimethyl 2-Oxo-3-(2-thienyl)propylphosphonate (2d):

A solution of 37.2 g. (0.3 mole) dimethyl methyl-phosphonate (Aldrich) in 400 ml. dry tetrahydrofuran was cooled to -78 in a dry nitrogen atmosphere. To the stirred phos-phonate solution was added 194 ml. of 1.6 M n-butyllithium in hexane solution (Alfa Inorganlcs, Inc.) dropwise over a period -o~ 18 minutes at sucih a rate that the reaction temperature never rose above -65. After an additional 5 minutes stirring at -78, 23.4 g. (0.15 mole) methyl 2-(2-thienyl)acetate was added dropwise at a rate that kept the reaction temperature less than -70 (20 minutes). After 3.5 hours at -78 the re-action mixture was allowed to warm to ambient temperature, neutralized with 6 ml. acekic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml.
water, the aqueous phase extracted with 100 ml. portions o~
chloroform (3x) the combined organic extracts were backwashed (50 ml. H2O), dried (MgSO4), and concentrated (water asplrator) to a crude residue and distilled, b.p. 150-52 (C 0.5 mm) to give 4.8 g. dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2d).
The nmr spectrum (CDC13) showed a doublet centered o .::
at 3.7~ (J ~ 11.0 cps~ 6H) for (CH30)2-P-, a singlet at ~ -4.12 ~ (2H) for Ar-CH2-CO-, a doublet centered at 3.16 ~ -o -" ,, ~
(J - 22 cps~ 2H~ -C-CH2 and a multiplet at 6.8 - 703 ~ (3H) : ~ ' . :

s for the thienyl protons. In the same manner the corresponding ~ -thienyl compound was prepared. NMR data 3.65 S (J - 11 cps) 3.1 ~ (J = 24 cps).

2-[3~ -~-Phenylbenzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-(2-~thienyl)-buten-l-yl)-cyclopent-l~ -yl]acetic acid, y-lactone (3d):
.
Dimethyl 2-oxo-3-(2-thienyl)propylphosphonate (2d) (6.4 g., 25.7 mmole) in 300 ml. anhydrous ether was treated - 10 with 7.7 ml. (18 mmole) 2.34 M n-butyllithium in n-hexane (Alfa Inorganic~, Inc.) in a dry nitrogen atmosphere at room temperature. After 5 min. of stirring, an a~ditional 300 ml. `
of anhydrous ether was added, followed by 6.0 g. (17 mmole) 2-~3c~-p-phenylbenzoyloxy-5c~-hydroxy-2~ -formylcyclopent~
yl~acetic acid, ~ -lactone in one portion and 50 ml. anhydrous ether. After 35 minutes, khe reactlon mixture was quenched with 5 ml. glacial acetic acid and washed with 100 ml. saturat-ed brine (lx)3 dried (MgS0l~) and evaporated to yield 3.28 g.
2-[3~ p-phenylbenzoyloxy-5c<-hydroxy-2~ -(3-oxo-4-(2-thienyl)-trans-l-buten-l-yl)cyclopent-l~ -yl]acetic acid, ~-lactone (3d) as an oil after column chromatography (sillca gel, Baker, ,........... .................................................................... .~, .
6Q-200 mesh).
The ir spectrum (CHC13) of the product exhibited adsorpti~on bands at 1770 cm~l (strong), 1705 cm~l (strong), 25~ ~1675 cm~l (mediumjand 1625 cm~l (medium) attributable to the carbonyl group and at 970 cm~l for the trans double ; bond. The nmr spectrum (CDC13) exhibited a doublek centered at 6.27 (lH3 J ~ 16 cps) for the olefinic proton~ a singlet at 4.01 (2H) for Ar-CH2-C, and multiplets at 4.90-5.50 (2H~
: .. .
an~ 2.05-3.20 (6H) for the remainder of the protons. In the --122- ~
:, ~ ' ' ,::

same manner the corresponding ~-thienyl compound was prepared having IR bands at 1715, 1775, 1630, 1670 and 970 cm~l.
The product of this example (3d) may be converted to 13,14-dihydro-16-(2-thienyl)- w -tetranorprostaglandins of the A, E or F series through the procedures herein described.
The product (3d) may also be converted to 15-lower alkyl-16-(~-thieny~ J-te~ranorprostagliandins of the A, E
or F series by the procedures of examples 80-102.
13,14 Dihydro-15-lower alkyl-16-(2-thienyl)~
tetranorprostaglandins o~ the A, E or F series may be obtained ~rom (3d) via the procedures o~ examples 10-13 and 15-18. -~

2-[3~-~-Phenylbenzoyloxy-5~ -hydroxy 2~ -(3~y-hydroxy-4~(2-thlenyl)-trans-l-buten-l-yl]acetic acid, ~-lactone (4d) and 2-~3 ~-~-Phenylben~oyloxy-5 ~-hydroxy-2~ -(3 ~-hydroxy-4-(2-thienyl)-trans-l-buten-l-yl)cyclopent-l~-yl]acetic acid, y-lactone (5d). -~ -To a solution of 4.7 g. (10 mmole) 2-[3 ~-p-phenyl- ~
benzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-(2-thienyl)-tran:-1-buten- ;
;20;~;l-yl~)oyclopent-1~ -yl]acetic acid,~ ~-lactone (3d) in 30 ml.
dry~ 2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was adcled dropwise 10 ml. of a 0.5 M `~
-zinc borohydride solution. A~ter stirring at room tempera- ;~
ture for l hour, a saturated sodium bitartrate solution was -~
`25~ added dropwise until hydrogen evolu~ion oea:ed.~ The reaction ;~
mixture~wa~s~allowed to stir for 5~minutes at whioh time 200 ml.~dry~methylene chloride was~added. After~drying (MgSO4) and~;oonoentrating (water~a:pirator), the resulting semisolid wa~purifled~by c~oIumn chromatography~on slllca gel; (Baker ~ ;

123- ~ ~

~ ,~, 104~1L49S
"Analyzed" Reagent~ 60-200 mesh) using ether as eluent. After elution of less polar impurities, a fractlon containing 710 mg.
2-[3~ -p-Phenylbenzoyloxy 5O~-hydroxy-2~,-(3~ -hydroxy-4-(2-thienyl)-trans~l-buten-l-yl)cyclopent-lo~-yl]acetic acid, ~ -lactone (5d), a 50 mg. fraction of mixed 4 and 5 and finally a fraction (862 mg.) of 2-[3~ -p-phenylbenzoyloxy-5~-hydroxy-4-(2-thienyl)-trans-1-buten-yl)cyclopent-1~ -yl]acetic acid, ~-lactone (4d).
The ir spectrum (CHC13) of 4 had strong carbonyl adsorptions at 1770 and 1710 cm~l and an adsorption at 965 cm~l for the trans double bond. In the same manner the corresponding ~ -thienyl compound was prepared from the appropriate starting material. ~ -Hydroxyl epimer (less polar on TLC) m.p. 101.5-102.5C. ~ -Hydroxyl epimer (more polar on TLC) m.p. 109-111C. The compounds were crystallized from EtOAc-pentane.

~- 3~<,5~-Dih~drc~y-2~ oY-hydroxy-4-(2-thienyl)-tranS-l-buten-l-yl) cyclopent~ yl]acetic acid~ ~ -lactone (6d3.
, A heterogeneous mixture o~ 1.35 g. (2.85 mmole) of 2-[3O~-p-phenylbenzoyloxy-5~<-hydroxy-2~ -(3~-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1~ -yl]acetic acid~
r -lackone (4d~, 13 ml. of absolute methanol and 394 mg. of finely powdered, anhydrous potassium carbonate was stirred at room temperature for one hour, then cooled to 0. To the cooled solution was added 5.6 ml. of 1.0N aqueous hy~ro-chloric acld. After stirring at 0 for an additional 10 minutes, 15 ml. of water was added with concomitant forma-tlon of methyl p-phenylbenzoate which was collected by filtration. The filtrate was saturated with solid sodium :

chlorlde, extracted with ethyl acetate (4 x 20 ml.), the com-bined organic extracts were washed with saturated sodium bi~
carbonate (10 ml.), dried (MgSO4) and concentrated to gi~e 738 mg. of viscous, oily 2-[3~ ,5O~-dihydroxy-2~ -(3OC-hydroxy-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-lo~-yl]
acetic acid, ~-lactone (6d).
The ir spectrum (CHC13) exhibited a strong adsorp-tion at 1755 cm~l for the lactone carbonyl and medium adsorp-tion at 965 cm~l ~or the trans-double bond. In the same manner the corresponding ~ -thienyl compounds were prepared.
15-o~OH IR 1774, 970 cm~l 15-~ OH IR 1775, 970 cm~l.

2-[5~-Hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~-(3 ~-(tetra-hydropyran-2-yloxy)-4-(2-thienyl)-trans-1-buten-1-yl)cyclo-~ nt~ yl]acetlc acid, ~ -lactone (7d):

To a solution of 738 mg. (2.5 mmole) 2-[3~ ,5 ~--dihydroxy-2~ -(3 ~-hydroxy-4-(2-thienyl)-trans-1-buten-yl)-cyc1Opent-l~< yl]acetic acid, y -lactone ~6d) in 5 ml. an-hydrous methylene chloride and 0.5 ml. of 2,3-dihydropyran Z0 at 0 in a dry nitrogen atmosphere was added 7 mg. p-toluene-sul~onic acld, monohydrate. A~ter stirring for 15 minutes, the reaction mixture was combined with 100 ml. ether, the ether solution washed with saturated sodium bicarbonate (l x 15 ml~) then saturated brine (1 x 25 ml.)~ dried (MgSO4) 25 ~ and o~onoentrated to yield 1..2 g. (~100%) crude 2-~5~ -hydroxy-3~-(tetrahydr~pyran-2-yloxy)-2~ -(3~ -(tetrahydro-pyran-2-yloxy)-4-(2-thieny~)-trans-1-buten-1-yl)cyclopent-yl]acetic aoid, ~ -lactone (7d).

The ir (CHC13) spectrum displayed a medium absorp-~ L04 tion at 970 cm~l ~or the trans-double bond and at 1772 cm 1 for the lactone carbonyl.
The product of this example (7d) may be converted ~o 13,14-dihydro-16-(2-thienyl)- ~ -tetranorpros~aglandins of the A, E or F series through the procedures of examples 86, 88, 90-94. In the same manner the corre~ponding ~-thienyl compound~ were prepared. 15 ~--OTHP IR 17703 970 cm''l.
15~ -OTHP IR 1770~ 970 cm~l.

102 [50~ Hydroxy-3~ -(tetrahydropyran-2-yloxy)-2 -(30~ S tetra-hydropyran-2-yloxy } -4-phenyl-trans l-buten-l-yl)cyolopent-1~ -yl]acetaldehyde, ~ -hemlacetal (8d):
.
A ~olution of 1~2 g. (2.5 mmole) 2-~5 ~-hydroxy-3~ - j (tekrahydropyran-2-yloxy)-2~ -(3~ - ~tetrahydropyran-2- ~ ;

yloxy ~ -4-(2-thlenyl)-br~n~-1-buten~l-yl)cyclopent~ yl]
: acetia aaid, ~-laotone (~) in 25 ml. dry toluene was aooled t~ -78 in a dry nitro~en atmosph0re. To this cooled ~olution was a~ 3.4 ml. o~ 0-.8 M dii~obutylalumInum hydrlde in n-hQxane ~Alra Inor~Qnic~) ~ropwl~e at such a ra~e ~o that the 20~ ~ in~q~n~I bomp~ratur~ never ro~e abov~ -65 (15 mlnutes).
: ~ Arbor ~n a~4ibional 45 minute~ o~ ~tirrln~ at ~78, anhydrou~ ;
~bh~nol WaQ ~ until ~aEl evolution cea~ed ~nd the reaction ~ ~ :
, ~ixtur~ wa~ ~114w~ ~0 warm to ~oom temperature. The reaotion mlx~ur~ WQ~ comb~ne~ w~th 150 ml. ether, washed wi~h 50%
25~ o~lum po~a~lum~tartrab~ ~lution (4 x 20 ml.), dried tNa:2~ a~ oon~entrak~d t~ a quantitative yield Or oily 2- ;
C5~ ~hydrox~3d -t~s~rahY~roPYran-2-yloxy)~2~ -(3 ~- ~ t~ra~
hy~opy~n~2~yloxy~ -4-(2-thienyl)-tran~ buten-1-yl)- .
oyal~p~t-l-yl~aootaldehyde, ~-h~ml~oe~al ~8d). The lr 9Q~ op~o:~rum ~isplay~d a broad ab~orption at 3400 om-l ~or the j:

, , :
:

~, ~

9~ -hydroxyl group. In the same manner the corresponding ~ -thienyl compound~ were prepared.
15 ~-OTHP IR: 970 cm~
15~ -OTHP IR: 970 cm~
~
90~-Hydroxy-110<,150~-bis-(tetrahydropyran-2-yloxy) 16-(2 thienyl)-cis-5-trans-13~ tetranor-prostadienoic acid (9d):
To a solution of 2.6 g. (6 mmole) (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in a dry nltrogen atmo~
sphere in 5.0 ml. dry dimethyl sulfoxide was added 5.7 ml. `-(11.4 mmole) of a 2.2M ~olution o~ sodium methylsufinylmethide ln dimethyl sulfoxide. To this red ylide solution was added `
dropwise a solution of 1.03 g. (2.2 mmole) 2-~5~ -hydraxy-3 ~tetrahydropyran-2-yl~xy)-2~ -(3c~- ~tetrahydropyran-2-yloxy~-4-(2-thienyl)-trans-1-buten l-yl)cyclopent~ -yl]acetaldehyde, -hemlacetal (8d) in 5.0 ml. dry dlmethyl sul~oxide over a perlod o~ 20 mlnutes. After an additional 2 hours stirring .
at room temperature, the rea¢tion mixture was poured into ioe water. ~he ba~ic aqueous solutlon was washed twice wlth ; 20;;~ éthyl acetate (20 ml.) and aaldl~ied to pH ~3 with 10%
a~ueou~ hydrochlori¢ aold. The a¢ldic solution wa~ extracted Wlth ethyl aoetate (3 x 20 ml.) and the comblned organlc ex-tra¢k~ wash~d onoe with water (10 ml.), dried (MgS04) and evaporated to a ~olid residue~ This ~olld resldue was tri-25~ tura~ed~with ethyl acetate and ~he ~iltrate ¢oncentrated to gield~ .02 ~.; o~9~-hydroxy-l~l~ ,150C-bi 8- (tetrahydropyran-2-ylox~)-l6-~2-thienyl)-¢1 -5-trans-13- W-tetranor-Prosta~
dienolc~ao~id~9d.~ ~The ir spe¢trum~displayed a strong band ~ ~
at~1700~om l along~wlth absorptlons between 2800 to 2600 ~ -30~ om~l ~r~the~carboxyl~group.
~ 127--.

~0~ 5 ;:

The product of this example (9d) can be converted to 16-(2-thlenyl)-1~tetranorprostaglandins of the F series (F2~ ~ Fl~, Fo~) via the procedures of examples 86, 94 and 95. In the same manner the corresponding ~ -thienyl com-pounds were prepared.
15~ -OTHP IR: 1710, 970 cm~
15~-OTHP IR: 1710, 970 cm 1 EXAMPLE 84 ;
9-Oxo-11~,15~-bls-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-1~ cis-5-trans-13-~-tetranor prostadienoic acid (lOd): ~:
To a solution cooled to -10 under nitrogen of 1.02 g. (1.86 mmole) 9 ~-hydroxy-ll ~,150~-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-trans-13- -tetranor-prostadienoic acid (9d) in 18 ml. reagent grade acetone was added dropwise to 0.82 ml. (2.04 mmole) of Jones' reagent. A~ter 20 minutes at -10~, 0.260 ml. 2-propanol was added and the reaction mix- `-ture was allowed to stir an additional 5 minutes at which time it~was combined with 75 ml. ethyl acetate, washed with water (3 x 10 ml.), dried tMgS04) and concentrated to give 952 mg.
of7 9-oxo~ ,150C-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-cis-5-tran~-13-~J-~tetranor-prostadienoic acid (lOd), whioh was~chromatographed on silica gel using ethyl acetate as eluent to af~ord 760 mgO of pure lOd. In the same manner :,, ~
both the corresponding ~-thienyl compounds epimeric at C15 25~ were prepared.
EXAMP~ 85 9-Oxo-11~ ,15~ -dihydroxy-16-(2-thienyl)-cis-5-trans-13 tetranor-prostadienoic acid (lld): -;A solution o~ 769 mg. (1~39 mmole) 9-oxo-110<,15 -128 ;~

~: .. . .

~o~9~ :
bis-tetrahydropyran~2-yloxy)-16-(2-thienyl)-cis-5-trans-13~ ~
tetranor-prostadienoic acid (10d) in 3.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25 for 18 hour then was concentrated by rotary evaporation. The resultant crude oil was puri~ied by column chromatography on ~ilica gel (Mallinckrodt CC-4A100-200 mesh) using ethyl acetate as eluent. A~ter elution of less polar impurities the semi- -solid 9-oxo-llOy,15~ -dihydroxy-16-phenyl-cis-5-trans-13-~J-tetranor-prostadienoic acid (lld) weighing 369 mg. was collect~
ed.
IR displayed:
carbonyl absorptions at 1730 and 1705 cm~l, and a weak band at 972 cm~1 for the 13,14-trans double bond.
The product of this example (lld) can be converted to 16-(2-thienyl)-~J-tetrarlorprostaglandins El, Eo~A2~ Al and Ao via the procedures of examples 95, 96 and 880 In the same manner the corresponding ~ -thienyl compounds were prepared. -15C~-OH IR: 1715, 1740, 970 cm~
}5~ -OH IR: 1715, 1740, 970 cm~
2~ XAMPLE 86 .
~ ~ 9O<~11O~15c~-Trihydroxy-16-(2-thienyl)-cis-5-trarls-13- ~- ~
, ~ tetranor-prostadienoic acid (12d):
- . ~
A mixture of 0.76 g. of 9~ -hydroxy-11~ ,15~ -bis~
tetrahydropyran-2-yloxy)-16-t2-thienyl)-c -5-trans-13~
25~ ;tetranorprosta~ienolc acid (9d) in 5 ml. of a 65:35 mixture o~aoetlo acid:water 1s~stirred under nitrogen at room tem-perature overnight, then is concentrated under reduced pres- ;
sure to a viscous oll. ~he crude productRis purified by oolumn~ohromatography on Mallinckrodt~CC-4~silica gel using ~O~ 5 ~ .. .- .
ethyl acetate as eluent. After elutlon of less polar impuri-ties, the desired 9 ~lloC,15~-trihydroxy-16-(2-thienyl)- ;" "
cis-5-trans-13- ~ tetranorprostadienoic acid (12d) is obtained as a viscous, colorless oil weighing 51 mg.
The product obtained above (12d) may be converted to 16-(2-thienyl)-~ -tetranorprostaglandin Fl~ via the pro- ' '' ' cess of Example 96. 12d may also be converted to 16-(2~
thienyl)- -tetranorprostaglandin Fo~ ~ via the process of ;;
Example 95. ~
.~: ~ ..

2-t3 ~-~-Phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-3~
methyl-4-(2-thienyl)-trans~l-buten-1-yl)cyclopent-1~ -yl]- ' ' . .
acetia acid, ~ -lactone (~) and 2-C3~-p-Phenylbenzoyloxy~
5O~-hydroxy-2~ -(3~ -hydroxy-3 ~-methyl-4-(2-thienyl)-trans-1-buten-l-yl)cyclopent-l~ -yl.]acetlc acld ~ -lactone (14d): ' To a solution of 3190 mg. (6.2 mmole) 2-~3O~
phenylbenzoyloxy-5~ -hydroxy-2~ -(3-oxo-4-(2-thienyl)-trans~
buten-l-yl)cyclopent-l ~-yl]acetic acid, ~-lactone (3d) in ~ , ; 26 ml. anhydrous ether and 20 ml. of tetrahydrofuran (distilled ,; ', from LAH) ln a dry nitrogen atmosphere at -78 is added drop- ~' wise 6.8 ml. of (0.92M) methyllithium in ether (Alfa). After .
stlrring at -78 for 15 minutes the reaction is quenched by the dropwise additlon o~ glaclal acetic acid until the pH of ~ ,~
;the rea~ctlon is approximately 7. The mixture is then diluted ''' 5~ wlth~methylene chlorlde and the diluted organic solution is '~ ;
wa~hed~with~water (lx)~and with sa~turated brlne (lx), is ,';, '~;
dried (anhydrous magnesium sulfate), and is concentrated to af~ord the~epimerlc alcohols. ,;;'- ;
The~crude~product is purified by column chromato~
'~graphy on 108 g. of silica gel (Baker "Analyzed~' Reagent~ `' ' .: . ~ : ;, , :, ~: .,. .: , ::: ~ '- :.

... , . " .. . . . . . .. . ~ . . . . . . .

~0~
60-200 mesh) using a mixtu:re of benzene:ethyl acetate as eluent to provide the 2-[3~ -p-phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ - ~-hydroxy-3~ -methyl-4-(2-thienyl)-trans-1-buten-1-yl)cyclopent-1 ~-yl]acetic acid3 ~ -lactone (13d), and 2-[3~ -p-phenyl-benzoyloxy-5~-hydroxy-2~ -(3~ -hydroxy-3~ -methyl-4-(2-thienyl)-trans-l-buten-yl)cyclopent-l~ -yl]acetic acid, y -lactone (14d)~
This material (14d) may be converted to the 15~-methyl-16-2(thienyl)- -tetranorprostaglandins o~ the A, E, and F series by the procedures outlined in Examples 80-86 and 88-96.
Other lower alkyl derivatives o~ the type (14d) may be prepared by substituting the appropriate alkyl lithium deri-vative for methyl lithium ~n the above procedure. These deri-vatives are suitable ~or conversion to 15-lower-alkyl 16-2-(thienyl)- -tetranorprostaglandins of the A, E, and F series through the seq~ences o~ Examples79 86 and 88-96. -9-oxo-l5o~-hydroxy-l6-2(thienyl)-cis-5- ~ l0~11 tranS_13_~
tetranor-prostatrienoic acid (15d):

A solution o~ 55 mg. of 9-oxo-11~ ,15~-dihydroxy- ;
16-2(thienyl)-cis-5-trans-13- ~-tetranorprostadienoic acld ; (lld) in 1~ ml. dry methylene chloride and 10 ml. ~ormic acid is stirred~at room temperature for 5 hours. The reaction mix-2;5~ ture is dlluted with 50 ml. toluene and evaporated to yield (a~ter chromatography) 9-oxo~ hydroxy-16-2(thienyl)-cis~
5- ~ 1~ll-trans-13- -tetranorprostatrienolc acid (15d).
In the same way 16~substituted- ~-pentanorprosta-glandlns Or the Al, Ao anù 13914-ùihydro A2 series may be pre-pared~from 16-substltuted~ -pen~anorprostaglandlns of the ~, .

El, Eo and 13,14-dihydro series respectively.
EXAMPLE 8g The procedure of example 3 in which sodium boro-hydride is substituted for zinc borohydride may be used to produce l9d. l9d may then be converted to 24d via the pro-cedure of example ~, which is further converted to 13,14 dihydro-16-2(thienyl)-~J-tetranorprostaglandins of the A, E
or F series by the procedures o~ examples 91-94, 86, and 88.

a _ .
hydropyran-2-yloxy -4-(2-thienyl)but-1-yl)cyclopent-1~ -yl]- -.
acetic acid, ~ -lactone t24d):
A stlrred heterogeneous solution of 1.7 g. (3.4 mmole) 2-[5OC-hydroxy 3O~tetrahydropyran-2-yloxy)~2~ -(3~ -~tetrahydropyran-2-yloxy~ -4-2(thienyl)-trans-1-buten-1-yl)-cyclopent-l~ -yl]acetic acid, ~ -lactone (7d) and 300 mg. 5%
. ~:
palladium on carbon in 35 ml. at absolute methanol is hydro-; genated for 90 minutes. The reaction mixture is filtered through filter aid and concentrated (in vacuo) to yield 2-[5~ -hydroxy-3~ (tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetra-hydropyran-2-yloxy~ -4-2(thienyl)but-1-yl)cyclopentan-1~ -yl]acetlc acid, ~ -lactone (24d).

2-~5~ -Hydroxy-3O6-(tetrah~dropyran-2-yloxy)-2~ -(3~- ~tetra-25~ ~;hydropyran-2-yloxy ~ -4 2(thienyl)but 1-yl3cyclopent-1~ -yl]- ~:
aoetaldehyde~ hemiacetal (25d): ~;
A~s~lu~lon o~ 1600 mg. (3.2 mmole) 2-[5~ hydroxy-3~ -(;tetrahydropyran-2-yloxy)-2~ -(3~ tetrahydropyran-2-yloxy;~ -4-2~(thienyl)~but-1-yl3cyclopent-1~ -yl}acetic acid, 30~ lactone~(24d) in 15 ml. dry toluene is cooled to -78 in ;~

~:

~0~149~i ~

a dry nitrogen atmosphere. To this cooled solution ls added 5.0 ml. of 20% diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so khat the internal temperature never rises above -65 (3 minutes). After an additlonal 30 minutes of stirring at -78, anhydrous methanol is added until gas evolution ceases and the reaction mixture is allowed to warm to room temperature. The reaction mixture is combined with 150 ml. ether, washed with 50% sodium potas- ~ -sium tartrate solution (1 x 50 ml.), dried (Na2S04) concen-trated, and chromatographed to yield 2-C5~ -hydroxy-30~-(tetra-hydropyran-2-yloxy)-2~ -(3~ - ~tetrahydropyran-2-yloxy ~-4-2(thienyl)but-1-yl)cyclopent-l-yl]acetaldehyde, ~-hemiace*al ~ -(25d)-9~ -Hydroxy 11~ ,15~ -bis-ttetrahydropyran-2-yloxy)-16-(2-.
thienyl)-cis-5-~J~tetranorprostenoic acid (22d): ~ ~
- - :::,: :. : . .
~o a solution o~ 5150 mg. (11.6 mmole) (4-carbo-hydroxy-n-butyl)triphenylphosphonium bromide in a dry nitro-gen atmosphere in 10.1 ml. dry dimethyl sulfoxide is added ~10.8 ml. (21.1 mmole) of a 1.96M solution of sodium methyl-9ulflnylmethide in dimethyl sul~oxide. To thls red ylide solu~
tion is added dropwise a solution of 1300 mg. (2.6 mmole) 2-~5~<~hydroxy-3~-(tetrahydropyran-2-yloxy)-2~ -(3O< ~tetra-hydropyran-~-yloxy} -4-(2-thienyi)but-l-yl) cyclopent-loC- ~
25~ ~ yl]acetaldehyde, ~-hemiacetal (25d) in 7.0 ml. dry dimethyl ;~ -sulfoxlde over a period o~ 20 minutes. After an addltional 2 hours stirring at room temperature, the reaction mixture le~poured lnto ice water. The basic aqueous solutlon is aaidi~ied to pH ~3 with 10% aqueous hydrochloric acid. ~ -~
. .. , : .
. , .
~ 133 ~ , : . ::

~LO~ 5 ;;
The acidlc solution is extracted with ethyl acetate (3 x 100 ml.) and the combined organic extracts washed once with water (50 ml.), dried (MgS04) and evaporated to a solid residue.
This solid residue is triturated with ethyl acetate and filter-ed. The filtrate is puri~ied by column chromatography on ~T~
B silica gel (Baker "Analyzed" Reagent~60--200 mesh) uslng ethyl acetate as eluent. A~ter removal of high Rf impurities, 9~ -hydroxy-ll ~,15 ~-bis-(tetrahydropyran-2-yloxy)-16~(2-thienyl)-CiS-5-L~-tetranor-prO~tenoic (22d) acid is collected.
The product obta~ned above (22d) may be converted to 16-(2-thienyl)-~ -tetranor-13,14-dihydro PGF2~ via the pro- ~ ~ ;
cess o~ Example 86~

9-Oxo-11~ ~15 ~-bis-(tetrahydropyran-2-yloxy)-16-(2-thienyl)-~ .
~ 15 cis-5-~ -tetranorprostenoic acid (26d):

To a solution cooled to -10 under nitrogen of 950 ~;
mg. (1~68 mmole) 9~ -hydroxy~ l5c<-bis-tetrahydropyran-2~
yloxy)-16-(2-thienyl)-cis-5- ~ -tetranorprostenoic acid (2?d) ;-in 15~ml. reagen~ Brade acetone is added dropwise 0.75 ml. -;20 ~(2~mmole~ o~ Jones' reagent. A~ter 20 minutes at -10, 0.75 ml. 2-propanol is added and the reaction mixture is allowed - ~-to ~tir an additional 5 minutes at whlch time it is combined ;~ with lOO ml. e*hyl acetate, washed with water t3 x 25 ml.), dried~(MgS04) and concentrated to æive of 9-oxo 110~150f-2~5~ bis-(t~trahydropyran-2-yloxy)-16 (2~thienyl)-cis-5~ tetra-norproetenolc aold (26d).

9-Oxo~ 15~-dihydroxy-16-(2-thienyl3-c -5~ etranor- -olut~ion o~ 800 m 9-oxo-11~ ,15c~-bis-(tetra-hydropyran-2-yloxy)-16-(2-thienyl)-cis-5-~ -tetranorprostenoic acid (26d) in 7.0 ml. of a 65:35 mixture of glacial acetic acid:water is stirred under nitrogen at 25 ~or 20 hours and then is concentrated by rotary evaporation. The resultant crude oil is purified by column chromatography on silica gel B (Mallinckrodt CC-4~100~200 mesh) using ethyl acetate as eluent.
After elution of less polar impurities, the oily 9-oxo~ ,15~ -dihydroxy-16-(2-thienyl)-cis-5-~ -tetranorprostenoic acid (27d) is collected.

9-Oxo-11~ 915~-dlhydroxy-16 (2-thienyl)-~-tetranorprostanoic acid (28d)~
A heterogeneous solutlon o~ 37 mg. (.089 mmole) 9-oxo-11O<,15~-dihydroxy-16-(2-thienyl)-cis-5-trans-13- ~-tetra- -norprostadienoic acid tlld) and 13 mg. o~ 5~ palladium on carbon in 3 ml. absolute methanol is hydrogenated (1 atm.) at ~ -0 ~or 2 hours. The reaction mixture is ~iltered and evaporat- ~ -ed to yield 9-oxo-11O~,15~<-dlhydroxy-16-(2-thienyl)-~ -tetra-norprostanoic acid (28d).
20~ EXAMPLE 96 9-Oxo-llO<,15~ -dihydroxy-16-(2-thienyl)-trans-13- ~ -tetranor-. .
prostenoic acid (29d):
A solution of 50 mg. 9-oxo-11~ ~lSo~-dihydroxy-16-(2-thienyl)-cis-5-trans-13-~-tetranorprostadienoic acid (lld) ~-~
25~ in 5~ml. o~ dry ether ls treated with 448 m~. (3.6 mmole) di-; methyl isopropyl chlorosilane and 360 mg. (3.6 mmole) triethyl-amine at 25 ~or 48 hours. The reaction mixture is cooled to 0,~ methanol was added and the resulting solution is washed wlth water (3 x 2 ml.), dried (MgSO4) and evaporated < .

5`
to a residue. The crude residue is then taken up in 6 ml.
methanol and 30 mg. of 50% Pd/C and the resultant slurry is hydrogenated for 4 hours at -22 (CC14/Dry ICE). Afker filtra-tlon through super cell and evaporation, the hydrogenated product is hydrolyzed in 2 ml. of acetic acid-water (3:1) for 10 minutes, diluted with water (20 ml.) and extracted with ethyl acetate (4 x 15 ml.). The combined organic extracts are washed with water (2 x 10 ml.), dried (MgS04) and evaporated to yield 9-oxo-11~ ,15 ~-dihydroxy-16-(2-thienyl)-trans-13-~ -tetranor-prostenoic acid (29d).
.

Methyl 9~ -acetoxy-llo~ (tetrahydropyran-2-yloxy)-15-oxo-tran~-13-16-(3-thienyl)-~-tetranorprostenoate.

.
To a suspension of 110 mg. (2.61 mmoles) of a 57.0%
dispersion of sodium hydride in mineral oil in 20 ml. of di-methoxyethane is added 646 mg. (2.61 mmoles) of dimethyl-2-oxo-3-(3-thienyl)propylphosphonate. The mlxture is stirred at room temperature for 1 hour under nitrogen. To this suspen-sion is added a solution of 0.947 g. (2.37 mmoles) of the crude aldehyde prepared in Example 38 in 4 ml. of dimethoxy-ethane. The resultant slightly turbid, brown solution is stirred at room temperature ~or 2.0 hours under nitrogen.
The reaction is then quenched by the addition of glaclal acid to pH ~ 7 and 1s concentrated by rotary evaporation. The crude product is purified by column chromatography on silica gel to afford the desiréd methyl 9~ -acetoxy~lL~ -(tetrahydro-pyran-2-yloxy)-15-oxo~trans-13-16 (3-thienyl)-~ -tetranor-prostenoate.
, ...

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

Methyl 9~ -acetoxy-ll~ -(tetrahydropyran-2-yloxy)-15-hydroxy- ;
.
trans-13-16-(3-thienyl)- ~-tetranorprostenoate.

To a solution of 1.60 g. (2.17 mmoles) of the enone prepared in Example 39 in 6.5 ml. of dimethoxyethane is added dropwise 2.17 ml. (1.08 mmoles) of a 0.5M Zn(BH4)2 solution in '' ; '' dimethoxyethane. After being stirred at room temperature under ~ ' nitrogen for 3 hours the reaction is quenched by the dropwise addition of a saturated aqueous solution of sodium bitartrate , ~;,, 10 until gas evolution ceased. The quenched heterogeneous solu- -~
tlon is stirred at room temperature for 5 minutes~ is diluted with methylene chloride~ is dried (anhydrous magnesium `
sulfate), and is concentrated to afford methyl 9~-acetoxy- ',;~
11~ -(tetrahydropyran-2-yloxy)-15-hydroxy-trans-13-16-(3- >' '~' thienyl)- ~-tetranorprostenoate.

Methyl-9~ -acetoxy-ll ~,15~-dihydroxy-trans-13-16-~3-thienyl)- ',~
-tetr~norprostenoate and methyl 9 ~-acetoxy-l~X ,15~ i-hydroxy-~E3~-13-16-(3-thienyl)- W-tetranorprostenoate.
..
; A solution of 1.60 g. (2.16 mmoles) of the crude THP
ether prepared in Example 98 in 10.7 ml. of a 65:35 mixture ' o~ acetic acid:water is ~tirred at 40 ~ 2 under nikrogen for 2.5 hours. The reaction mixture is then concentrated to af~ord the crude epimeri,c diol mixture. '' , ' ~ The crude product is purified by column chromato- "' graphy on silioa gel to provide the desired~methyl-9 ~-acetoxy- ' '' 11~ 915~ -dihydro~y-trans-13-16-(3-thienyl)- ~-tetranor~
.
; ~ proskenoate and the epimeric methyl 9~ -acetoxy-ll ~,15~ - '' "

dihydroxy-trans-13-16-(3-~hi~nyl)-~ -tetranorprostenoate.,- ,~,', :: . ... ..
- , . :..
-137- , -Methyl 9~ -acetoxy~ ,15O~-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-~J-tetranorprostenoate.

A mixture of 0.223 g. (0.510 mmole) of the chromato-graphed diol of Example 99, 0.14 ml. (1.53 mmoles) of dihydro-pyran, 4.2 ml. of methylene chloride, and 1 crystal o~ p-toluenesulfonic acid monohydrate is stirred at room temperature under nitrogen for 20 minutes. The reaction mixture is then diluted with ether, is washed with saturated aqueous sodium :, . -bicarbonate, is dried (anhydrous magnesium sulfate)~ and isconcentrated to give the desired methyl 9~ -acetoxy-ll~ ,15~ -bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-~ -tetranorprostenoate.

9C~11O~15 ~-trihydroxy-trans-13-16-(3-thienyl)-~J-tetranor-. .
; prostenoic acid.

A mixture of 65 mg. (0.15 mmoles) of the chromato~graphed dlol prepared in Example 99, 0.45 ml. (0.45 mmole) of l.O N aqueous sodium hydroxide, 0.45 ml. of tetrahydrofuran, and 0.45 ml. of absolute methanol is stlrred under ~itrogen at ~;~ room temperature for 1.5 hours. The solution is then acidified by the addition of 0.45 ml. of 1.0 N aqueous hydrochloric acid `
(pH ~Qr ao1di~ied solution was ca. 5). The acidified solution is~extracted with ethyl acetate ~4 x 2 ml.). The combined ex~racts are dried (anhydrous magnesium sulfate) and concen-trated to af~ord the deslred 9~ ,11~ ,15~c-trihydroxy~trans 13-16-(3-th1enyl)-~ -tetranorprostenoic aci~.

~o~

9~ -Hydroxy-11 ~,15 ~-bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-~-tetranorprostenoic acid.
A homogeneous solution of 0.263 g. (0.436 mmole) of the crude bis THP ester prepared in Example 100, 1.3 ml. (1.30 mmoleæ) of the l.ON aqueous soidum hydroxide solution, 1.3 ml.
of methanol, and 1.3 ml. of tetrahydrofuran is stirred under nitrogen overnight. ~he reaction is then quenched by the a~di-tion of 1.30 ml. (1.30 mmoles) of a l.ON aqueous hydrochloric acid solution. The quenched solution is diluted with ethyl ~ ~
acetate. The organic layer is dried (anhydrous magnesium ~ -sulfate) and concentrated to afford the crude product. The ~;
crude product is puri~ied by column chrornatography on Baker B "Analyzed"~silica gel (60-20~ mesh) to Provide the 9~-hydroxy-110~,15~ -bis-(tetrahydropyran-2-yloxy)-trans-13-16-(3-thienyl)-~-tetranorprostenoic acid. - ;

:
9-Oxo-11~ ,15~ -bis-(tetrahydropyran-2-yloxy)-13-trans-16 (3-thieny~ J-tetranorprostenoic acid.

To a solution, cooled under nitrogen to -15 to -20~ :
. .
of 0.201 g. (0.371 mmole) of the chromatographed acid prepared in Example 102 in 4.0 ml. of acetone is added dropwise 0.163 .
ml. (o.408 mmole) of Jones' reagent. The reaction is stirred in the cold for 15 minutes then is quenched by the addition ^
25~ of 0.194 ml. of isopropanol. The quenched reaction is stirred in the cold for 5 minutes then is diluted with ethyl acetate.
The organic~solution ls washed with water (2x) and saturated brine (lx), i5 dried (anhydrous magnesium sulPate~), and is ;~
concentrated to a~ford the desired 9-oxo-llocgl~ -bis-(tetra- ~-30~ hydropyran-2-yloxy)-13-trans-16-(3-thienyl)- w -tetranor-39- i ~:: :

~, ~i~, . ' .

~04~45a5 : ~ ~
pro~tenoic acid.

9-Oxo~ 15~ -dihydrox~ 13~ n~-16-_3-thienyl)- ~-tetranor prostenoic acid.
.:
A homogeneous solution of 0.179 g. (0.328 mmole) of the crude THP ether o~ Example 103 in 2 ml. o~ a 65:35 mixture of aceklc acid:water is stirred under nitrogen at 40 ~ 2 for 5 hours. The reaction is concentrated by rotary evaporation followed by oil pump. The crude product is purified by column chromatography on silica gel (Mal~inckrodt CC~ o provide the desired 9-oxo-llcc,15~ -dihydroxy 13-trans-16-(3--thienyl)-~-tetranorprostenoic acid.
; EXA~PLE 105 Dimethyl 2-Oxo-4-(2-thienyl)bu~y~phosphonate (2b):
A solution of 11.6 g. (94 mmoles) dimethyl methyl-phosphonate (Aldrich) in 130 ml. dry tetrahydro~uran was cooled .
to -78 in a dry nitrogen atmosphere. To the stirred phos-phon&te solution was added 43 ml. of 2.26 M n-butyllithium in hexane~solution (Alfa Inorganics, Inc.) dropwlse~over a perio~
of 18 minutes at such a rate that the reaction temperature ;never rose above -65. After an additional 5 minutes stirring at -780, 8.o g. (47 mmole~ methyl 3-(2-thienyl)propionate was added dropwise at a rate that kept the reaction temperature less than~-70 (20 minutes). After 3.5 hours at -78, the 25;;~reactlon mlxture was allowed bo warm to ambient temperature, neutral1~zed~with S ml. aoetic acld~and rotary evaporated to a whibe~gel. ~The gelatlnous materlal was taken up in;75 ml.
water, the agueous phase extracted with 100 ml. portions o~
chloro~orm (3x),~the comblned organic extracts were backwashed 30~ 0~c~c~H~O),~dr1ed (MgSOIl), an~ concentra~ed (water aRpirator) .3LO~ S
to a crude residue and distilled, b.p. 156 (0.2mm) to give 9.7 g. dimethyl 2-oxo-4-(2-thienyl)butylphosphonate.
The nmr spectrum (CDC13) showed a doublet centered O
at 3-75S (J=11.5 c.ps. 6H) for (CH30)-P~, a triplet centered at 3.11 ~ (4H) ~or -CH2-CH2-, a doublet centered at 3.14 O O , ., , .
- (J=23 cps, 2H)~C-CH2-P- and a multlplet 6.7-7.4 ~ (3H) ~or thienyl rlng protons.
In the same manner dimethyl 2-oxo-4~(3-thienyl) butyl pho~phonate may be prepared from methyl 3-(3-thienyl) ;;
propionate. This is also a suitable starting material in the preparatlon o~ 17-(3-thienyl)-~ -trisnorprostaglandins of the ~ ;
A, E and F ~eries via example~ 112-125. In the same manner starting materlals suitable for conversion to 18, 19 or 20 o~ or ~ -thienyl substltuted prostaglandins by the procedure o E~amples 111-125, can be synthesized from the appropriate esters. ,:
~ .
EXAMPLE 106 `
2 -[3~ -~-Phenylbenzoyloxy-5~ hydroxy~2~ -(3-oxo-5-(2-thienyl)-trans-l-penten-l-yl)-cyclopent-lo~-yl] acetic acid3 ~ ~ -Iactone ( _):
.: , .
Dimethyl 2-oxo-4-(2-thienyl)butylphosphonate (2b) (2.81g., 7.5 mmole) in 100 ml. anhydrous ether was treated with~3.~3~2~ml~.~(7.5 mmole) 2.26 M n butyllithium~in n-hexane Alfa~Inorganics3 Ino.3 in a dry nltrogen atmosphere at room ;29~ temperature~.; After 5 min. o~ stirring, an additional 200 ml.
o~anhDdrous ether was added followed by 2.0 g. (5.7 mmole) 2-~3~ phenylben~zoyloxy-5~ -hydroxy-2~ -~ormylcyclopentan-10~ 5 ~ ~
l~-yl]acetic acid, ~-lactone in one portion and 20 ml. an-hydrous ether. After 35 minutes the reaction mixture was quenched ~ith 0.5 ml. glacial acetic acid and washed with 100 ml. saturated sodium bicarbonate solution (4 x), 100 ml. water (2 x), 100 ml. saturated brine (1 x), dried (MgS04) and evapo-rated to yield an oil which crystallized from CH2C12-hexane to give 2.4 g. 2-[3~-p-phenylbenzoyloxy-5~-hydroxy-2~ -(3-oxo-5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1~ -yl]acetic acid, ~ -lactone (3b) m.p. 121-123.
The ir spectrum (KBr) of the product exhibited ad-sorption bands at 1776 cm~l (strong), 1710 cm~l (strong), 1676 cm~l (medium) and 1636 cm~l.
The product o~ this example (3b) may be converted ~O 13,~ }ydYo~17-(2~h~enyl)~ rl~norpro~t~glan~n~
the A, E or F series through the procedurea c~ examples 86, .
88 - 89 and 91 - 94. The product (3b) may also be converted to 15-lower alkyl-17-(2-thlenyl)-~ -trisnorprostaglandins of the A, E or F series by the procedures o~ examples 80-96. 15-Lower-alkyl-13,14-dihydro-17-(2-thienyl)- ~ -trisnorprosta-glandins of the A, E or F series may be obtained from (3b) by the procedures o~ examples 86 - 89 and 91 - 94.

2-C3D~ Phenylbenzoyloxy-50~-hydroxy-2~g -(3c~-hydroxy-5-(2- . '.
thienyl)~trans-l-penten~l-yl)cyclopent-lc~-yl]acetic acid3 ~ ,.
~ -y -lactone (4b) and 2~3c~-p-Phenylbenzoyloxy-5~ -hydroxy-2B -(3 ~ -hydroxy-5-(2-thlenyl)-trans-1-penten-1-yl)cyclopent-yl~ acetic acid, ~-lactone-(5b).
, . ...
To a solution o~ 4.53 g. (9.3 mmole) 2-~3~ -p-phenyl- ~ -benzoyloxy-5~ -hydroxy-2~ -(3-oxo-5-(2-thienyl)-trans-1-penten-30; ~l-yl)cyclopent-l~ ~l]acetic acid, ~ -lactone (3b) :Ln 28 ml.

:: ~

49~ ~:
dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 9.3 ml. of a 0.5 M zinc boro-hydride solution. After stirring at room temperature for 45 minutes, a saturated sodium bitartrate solution was added drop~
wise until hydrogen evolution ceased. The reaction mixture : .
was allowed to stir for 5 minutes at which time 300 ml. dry methylene chlorlde was added. After drying (MgS04) and con-centrating (water aspirator)~ the resultant semisolid was purified by column chromatography on silica gel (Baker lR R~P1 .. :
"Analyzed" Reagent~60-200 mesh) using ether as eluent. After elution of less polar impurities, a fraction containing 1.44 g. 2-[3~ -~-phenylbenozyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-5- -~2-thienyl)-trans-1-penten-1-yl)cyclopent-1~ -yl]acetic acid, ~-lactone ~4b), a 200 mg. fraction of mixed (4b) and (5b) and flnally a fractlon (1.72 g.) of 2-[3O~-p-phenylbenzoyloxy-5~-hydroxy-2~ (3~ -hydroxy-5-(2~thienyl)-trans-l-penten-l-yl)-~ ,.,:.,.
cyclopent-lo~-yl]acetic acid, Y-lactone t5b) was obtained.
The ir spectrum (CHC13) of 4b and 5b had strong carbonyl adsorptions a~ 1765 and 1709 cm~l and an adsorption at 970 cm~~ for the trans double bond.
EXAMPLE_108 , ~ .' '.
.~ ,.... . .
2-~3~ ,5 ~-Dihydroxy-2~-(3 ~-hydroxy-5-(2-th~enyl)-trans- `
penten-l-yl)cyclopent-lo<-yl~acetic acid, ~ -lactone (6b):

A heterogeneous mixture of 1.44 e (2.95 mmole) of 25~ Z-[3 ~-~phenylbenzoyloxy-5~ -hydroxy-2~ -~3~ -hydroxy-5-(2-thlenyl~-trans-l-penten-l-yl)cyclopent-l~ -yl~ace~ic acid, -laotone~(4b),;16~ml. of abeolute methanol and 75 mg. of ; finely;powdered, anhydrous potasslum carbonate was stlrred at~room temperature~overnight, then cooled to 0. To the cooled solution was added 1.0 ml. (1.0 mmole) of l.ON aqueous hydrochloric acid. After stirring at 0 for an additional 10 minutes, 10 ml. of water was added with concomitant formation of methyl p-phenylbenzoate which was co:Llected by filtration.
The filtrate was saturated with solid ~odium chloride, extract-ed wikh ethyl acetate (4 X 20 ml.), the combined organic ex-tracts, were washed with saturated sodium bicarbonate (10 ml.), dried (MgS04) and concentrated to give 839 mg. t92%) of crystalline, 2-[30~,5~C-dihydroxy-2~ -(30~-hydroxy-5-(2-thienyl)-trans-l-penten-l-yl)cyclopent-l~ -yl]acetic acid, y -lactone (6b), mp. 98-100.
The ir spectrum (CHC13) exhibited a strong adsorption at 1765 cm~l ~or the lactone carbonyl and medium adsorption at 970 cm~l for the trans-double bond.

2-[3~ ,5~ -Dihydroxy-2~ -(3~ -hydroxy-5-(2-thienyl)-trans-1-penten-l-yl)cyclopent-l ~ -yl]acetic acld, ~ -lactone (6'b): -A heterogeneous mixture of 1.72 g. (3.52 mmole~ o~
2-[3~ -~-phenylbenzoyloxy~5 ~-hydroxy-2 ~-(3~ -hydroxy-5 (2-2G thienyl)-trans-l-penten-l-yl)cyclopent-lv~-yl]acetic acld, Y -lactone t4b), 20 ml. of absolute methanol and 90 mg. of flnely powdered, anhydrous potasslum carbonate was stirred at room ~ temperature ~or 18 hours, than cooled to 0. To the cooled ; ~ solution waB added 1.0 mI. t2.0 mmole) of l.ON aqueous hydro~
~ ;25 chloric acid. After stirring at 0 for an additional 10 .
; minute~ 15 ml. of water was added with concomitant forma-tlon of mekhyl p-phenylbenzoate which was collected by filtra~
~;; tion. The filtrate was saturate~ with solid sodium chloride, : ~ ~
extracted with ethyl acetate t4 x 10 ml.), khe combined organic ~

~: ., , .
: : ,.
. . .

~ ; , ' : '.: .
' ~ 1 ! '1 . . . : . ' . . ' . ' . ; . . '. ' ' . ' . ' ' ' ' . ' extracts were washed with saturated sodium bicarbonate (10 ml.) ~;
dried (MgS04) and concentrated to give 967 mg. (90%) of vis-cous, oily 2-[3~ ,5O~-dihydroxy-2~ -(3~ -hydroxy-5~(2-thienyl)-trans-l-penten-l-yl)cyclopent-l~ yl]acetic acid, y -lactone (6'b).
` The ir spectrum (CHC13) exhibited a strong adsorp-tion at 1768 cm~l for the lactone carbonyl and medium adsorp-tion at 968 cm~l for the trans~double bond.

2-[5~-Hydroxy-3 ~ -(tetrahydropyaan-2-yloxy)-2~ -~3~C~-(tetra-hydropyran-2-yloxy }-5-(2-thienyl)-trans-1-penten-1-yl)cyclo-pent-l~ -yl]acetic acid, ~-lactone (7b):

To a solution o~ 839 mg. (2.72 mmole) 2~-~3~ ,5O~-dihydroxy-2~ -(3~ -hydroxy-5-(2-thienyl)-trans-1-penten-1-yl) cyclopent-l~ -yl]acetic acid, ~ -lactone t6b) in 15 ml. an-hydrous methylene chlorlde and 0.75 of 2,3-dihydropyran at 0 in a dry nitrogen atmosphere was added 9 mg. p-toluenesulfonlc acid monohydrate. A~ter stirring ~or 15 minutes, the reaction mixbure was combined with 200 ml. ether, the ether solution 20~ washed with saturated sodium bicarbonate (1 x 25 ml.) and then ~: ~ . .. ." ..
saturated brine (1 x 25 ml.)~ ~ried (MgS04) and concentrated to yleld 1.28 (~ 100%) crude 2-~5~ -hydroxy-3s~-(tetrahydro-pyran-2-yloxy)-2~ -(3 ~{tetrahydropyran-2-yloxy~ -5-(2-thlenyl1-trans-1-penten-1-yl)cyclopent-1 ~ -yl]acetic acid, 25 ~ la~ctone (7b).
The ir (CHC13) spectrum has a strong adsorption at 965~cm 1 ~or the trans-double bond.
The product o~ thls example (7b) may be converted t~o~13,~14-dihy~dro-17-(2-thienyl)~ -trisnorprostaglandins of ~:
30~ the A~,~E or F series through the procedures of examples 86, ~;

:: : : ~: . . :, : . . .: .

~0 ~ ~ ~9 S
88, 90-94-2-[50~-Hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3~ -(tetra-hydropyran-2-yloxy)-5-(2-thienyl)-trans-1-penten-1-yl)cyclo-. ~
pent-l~ -yl]acetic acid, ~-lactone (7'b):
To a solution o~ 967 mg. (3.14 mmole) 2-[3~ ,5~ -dihydroxy-2~-(3~ -hydroxy-5-(2-thienyl trans-l-penten-l-yl)-cyclopent-l~ -yl]acetic acid, ~ -lactone (6'b) in 10 ml. an-hydrous methylene chloride and oO85 ml of 2,3-dihydropyran at 0 in a dry nitrogen atmosphere was added 10 mg. p-toluene-sulfonic acld monohydrateO After stirring for 15 minutes, the reaction mixture was comblned with 100 ml. ether, the ether solution washed with saturated sodium bicarbonate (1 x 15 ml.), then saturated brine (1 x 15 ml~), dried (MgS04) and concen-trated to yield 1.47 g. (~ 100%) 2-r5 ~-hydroxy-3~ -(tetra-; ~ hydropyran-2-yloxy)-~ -(3~ -(tetrahydropyran-2-yloxy)-5-(2-thienyl)-trans-l-penten-l-yl)cyclopent-lc~-yl]acetic acid, y -ctone (7'b), which after crystallization from ether-hexane had mp. 80-82.
The ir (CHC13) spectrum has a strong adsorption at 960 cm~l for the trans-double bond.

2-[5c~-Hydroxy-30C-(tetrahydropyran-2-yloxy)-2~ -~3~ tetra- ` -hydropyran-2-yloxy ~ -5-(2-thienyl)-trans-1-penten-yl)cyclo- ~
25~ pent-lc~-yl]acetaldehyde, ~-hemiacetal (8b): ;
~, , ~:: : .. ,::
A~solution of 1.28 g~ (2.7 mmolej of 2-~5~ -hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetrahydropyran-Z-yloxy 3 -5-(2-thienyl)-trans-1-penten-1-yl)cyclopent~
ylj acetlc acid, ~ -lactone (7b) ln 13 ml. dry toluene was ~: ~ ~:: :: :

.:
~:~ ~ 3 ~ ~
;yS~
~ .

:.
~0~ 3~ :
cooled to -78 in a dry nitrogen atmosphere. To this cooled solution was added 3.7 ml. of o.8 M diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above ~65 (15 minutes).
After an additional 45 minutes of stirring at -78, anhydrous methanol was added until gas evolution ceased and the reactlon mixture was allowed to warm to room temperature. ~he reaction mixture was combined with 150 ml. ether, washed with 50% sodium potassium tartrate solution (ll x 20 ml.), dried (Na2SO4) and concentrated to a quantitative yield of oily 2-[5 ~-hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3 ~- ~tekrahydropyran-2-yloxy3 -5-(2-thienyl)-trans-1-penten~l-yl)cyclopent-1-yl]
acetaldehyde, y -hemiacetal (8b).
EXAMPLE 113 ;
2-~5 ~-Hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ -(3~ -(tetra-hydropyran-2-yloxy)-5-(2-thienyl)-tran~ penten-1-yl)cyclo-pent-l ~-yl]acetaldehyde, y -hemiacetal (8'b) ~ -. .
A solution of 1.47 g. (3.1 mmole) 2-[5 ~-hydroxy-(tetrahydropyran-2-yloxy)-2~ -(3~ -(tetrahydropyran-2-yloxy)-5-(2-thienyl) trans-l-penten-l-yl)cyclopent-l ~-yl]
acetic acid, ~ -lactone (7'b) in 15 ml. dry toluene was cooled to -78, in a dry nitrogen atmosphere. To this cooled solu-tion was added 4.25 ml. of o.8M diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal temperature never rose above -65 (15 minutes).
Aft~er an additional 45 minutes of stlrring at -78, anhydrous ;
methanol was added until gas evolution ceased ~nd the reac-tion m1xture was allowed to warm to room temperature. The reactlon mixture was combined with 100 ml. ether, washed with ;30 ~50% sodium potassium tartrate soIution (4 x 20 ml.), dried., . ~ , ~1'' ' .: : : --'~LO~ 5 (Na2S04) and concentrated to yield 1.38 g. 2 [5 ~-hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3~ ~ tetrahydropyran-2-yloxy -5-(2-thienyl)-trans-1 penten-l-yl)cyclopent~ yl]acetaldehyde, ~ -hemiacetal (8'b).

9 ~-Hydroxy 11 ~,15 ~-bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13- ~-trisnor prostadienolc acid (9b):
. ~
To a solution of 1.8 g~ (4.04 mmole) (4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmo-sphere in 8. o ml. dry dimethyl sulfoxide was added 3.5 ml. -(7.8 mmole) of a 2.2M solution of sodium methylsulfinylmethide in dlmethyl sulfoxide. To this red ylide solution was added dropwise a solution of 717 mg. (1.5 mmole) 2-[5 ~-hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3 ~- ~tetrahydropyran-2-yloxy~
5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1 ~-yl]acetalde-hyde, ~-hemiacetal (8b) in 5.0 ml. dry dimethyl sulfoxide over ~ -a period of 20 minutes. After an additional 2 hours stirring at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (20 ml.) and acidif'Led to pH 3 with 10% aqueous hydro-¢hloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml.) and the ¢ombined organic extracts washed ~ -once with water (10 ml.), dried (MgS04) and evaporated to a ~solid residue. This solid residue was triturated with ethyl acetate and ~iltered. The filtrate was purified by column ohromatography on sillca gel (Baker "Analyzed't Reagent~60-200 mesh) using ethyl acetate as eluent. ~fter removal of high R~ impurities, 260 mg. of 9 ~-hydroxy~ ,15 ~-bis-(tetra-hydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13 ~)-trisnor : ~ :
prostadienoic acid tgb) was collected.
-~148-". ' ' ' .

~4~
The product of this example (9b) can be converted to 17-(2-thienyl)-~ -trisnorprostaglandins of the F series (F2~ ~ ~l~ ,Fo~ ) via the procedures of examples 86~ 94 and 95.

9o~-Hydroxy-11O~,15~ -bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13- ~-trisnor prostadienoic acid (9~b):
To a solution of 1.8 g. (4.05 mmole~ t4-carbohydroxy-n-butyl)triphenylphosphonium bromide in a dry nitrogen atmo-sphere in 5.0 ml. dry dimethyl sulfoxide was added 3.2 ml. ;
(7.0 mmole) of a 2.2M solution of sodium methylsufinylmethide in dimethyl sulfoxide. To this red ylide solution was added dropwise a solution o~ 717 mg. (1.34 mmole) 2-[5 ~-hydroxy-3~ -(tetrahydropyran-2-yloxy)-2~ ~(3~tetrahydropyran-2-yloxy } -5-(2-thienyl)-trans-1-penten-1-yl)cyclopent-1~ -yl]-acetaldehyde, ~-hemiacetal (8'b) in 5.0 ml. dry dimethyl sulfoxide over a period of 20 minutes. After an additlonal ~
2 hours stirring at room temperature, the reaction mixture was ~ : -; .'. . : -poured into ice water. The baslc aqueous soIution was washed twice with ethyl acetate (20 ml.) and acldlfied to pH ^~3 with 20~ 10% aqueous~hydrochloric aold. The acidic solution was ex- ;
traoted with ethyl acetate (3 x 20 ml.) and the combined organlc extracts washed once with water (10 ml.), dried (MgS04) and evaporated to a solid residue. This solid resldue was triturated~with ethyl acetate and fiItered. The filtrate 5~ w~as~purlfied~by co~lumn chromatography on silica gel (Baker "Analyzed"~Reagent~60-2Q0 mesh) using ethyl acetate as eluent.
A~ber removal of high Rf impurities, 740 mg. of 9~-hydroxy-11O~,~15 ~-bis-~(tetrahydropyran-2-yloxy)-17 - (2-thienyl)-cis-5-tr -13-~J-trisnor prostadienoic acid ~9'b) was collected.

~: .

9-Oxo~ 15~ -bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-~J-trisnor prostadienoic acid (10b):
To a solution cooled to -10 under nitrogen of 250 mg. (.445 mmole) 9O~-hydroxy-116~,15~ -bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13- ~-trisnor prostadienoic ~acid (9b) in 10 mlO reagent grade acetone was added dropwise 0.18 ml. (.487 mmole) of Jones' reagent. After 20 minutes at -10, 0.2 ml. 2-propanol was added and the reaction mixture was allowed to stir an additional 5 minutes at which ~ime it `
was combined with 75 ml. ethyl acetate, washed with (3 x 10 ml.), dried (MgSO4) and concentrated to give 240 mg. of 9-oxo-11O~,15~ -bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13- W-trisnor prostadienoic acid (10b).
EXAMPLE 117 `
. .
, 9-Oxo-11~ ,15~ -bis-(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13- ~ -trisnor prostadienoic acid (10'b):
o a solution cooled to -10 under nitrogen of 640 mg. (1.14 mmole) 9o~-hydroxy-11~ ,15~ -bis~(tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-~ -krisnor prostadienoic acid (9'b) in 9.2 ml. reagent grade acetone was added dropwise .
.. . .
to 0.502 ml. (1.25 mmole) of Jones' reagent. After 20 minutes at~-10, O.5 ml. 2-propanol was added and the reaction mixture aB~allowed~to stir an addltional 5 minu~es, at Nhlch time 25~ it was combined with 75 ml. ethyl acetate, washed with water (3 x 10 ml.)~ dried (MgSO4) and concentrated to give 500 mg. ~ -O~9-oxo-lls~l5~-bis-(tetrahydropyran-2-yloxy)~l7-(2- `~
thlenyl)-cis-5-trans-13~~ -trisnor prostadienoic acid (10'b).

9-Oxo-11~ ,150~-dihydroxy-17-(2-thienyl)-cis-5-trans-13-~ -trisnor prostadienoic acid (llb): :
A solution of 240 mg. (0.334 mmole) 9-oxo-11~ ,15~-bis-tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13~
trisnor prostadienoic acid (lOb) in 3.0 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25 ;
~or 18 hours and then was concentrated by rotary evaporation.
The resultant crude oil was puri~ied by column chromatography 'l on silica gel (Mallinckrodt CC-4~100-200 mesh) using ethyl acetate as eluent. Aft0r elution of less polar impurities, the oily 9-oxo-110~,150~-dihydroxy-17-(2-thienyl)--cis-5-trans-13- ~ -trisnor prostadienoic acid (llb~ weighing 100 mg. was collected.
The product o~ this example (llb) can be converted to 17-(2-thienyl)- ~ trisnorprostaglandln El, Eo~ A2, Al and Ao via the procedures of examples 95, 96, an~ 88.

', ' trlsnor-prostadienoic acid (ll'b):
A solution o~ 500 mg. (.893 mmole~ 9-oxo~ ,15~ -bis-tetrahydropyran-2-yloxy)-17-(2-thienyl)-cis-5-trans-13-~ -tetranorpro8tadienoic acld (lO'b) in 7.0 ml. of a 65:35 m~x-ture o~ glacial acetic acid:water was stirred under nitrogen ~25 at 25 ~or 18 hours and then was concentrated by rotary evaporation. The result~nt crude oil was puri ~ d by column chromatography on silica gel (Mallinckrodt CC-4~100-200 mesh) , uslng ethyl acetate as eluent. A~ter elution o~ less polar impurities, ~he semisolld 9-oxo-11~ ,15~ -dihydroxy-17-(2-.
: , 151- - `
~ .

S .
thlenyl)-cis-5-trans-13- ~-trisnorprostadienoic acid (ll'b) weighing 215 mg. was collected.

Dimethyl 2 Oxo-4-(2-furyl)butylphosphonate (2~):
..
A solution of 25 g. ~0.21 mole) dimethyl methyl-pho9phonate (Aldrich) in 300 ml. dry tetrahydro~uran was cooled to -78 in a dry nitrogen atmosphere. To the stirred phos- - -phonate solution was added 80 ml. o~ 2.67 M n-butyllithium in :

hexane solution (Alfa Inorganics, Inc.) dropwise over a period . .;
o~ 18 mlnutes at such a rate that the reactlon temperature never rose above -65. After an additlonal 5 minutes stirring at -78, 16.0 g. (.104 mole) methyl 3-(2-furyl)propionate wa~ added dropwise at a rate that kept the reaction temperature ~ ., .
le8~ than 70 (20 minutes). After 3.5 hours at -78 the re-action mixture was allowed to warm to ambient temperature, neutralized with 6 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml.
` water, the aqueous phase extracted with 100 ml. portions of ehloroform ~3x), the combined organic extracts were backwashed ;2~a (50~ cc~. H20), dried (MgS04), and concentrated (water aspirator) o a crude residue and distilled, ~.p. 148-50 (0.5 mm) to give 8.4 g. dimethyl 2-oxo-4-(2-furyl)butylph~osphonate (2~
; The nmr spectrum (CDC13) showed a doublet centered O
" : - ,, ab~ 3.73~ (J - 11.5 cps, 6H) ~or (CH30)2-P-, a singlet oentered ;;
Z5~ a~ 2.~9~(2H) for;CH2 CH2 , a doublet centered at 3.12~ (J =

2-3~cps, 2H)~ -C-CH2- , and multiplets at 5.96, 6.23 and 7.23 (lH~:eaoh);~or furan ring protons.

In a manner similar to the above, dimethyl 2-oxo-4- ; ' (3-~uryl)butylphosphonate may be obtained by substituting methyl 3-(3-furyl)propionate for methyl 3-(2-furyl) propionate in the above example. This compound is a suitable starting material for the synthesis of 17-(3-furyl)~-trisnorprostaglandins of the A, E or F series by the procedures Or examples 121-129.
In the same manner the dimethyl 2-oxo-2(~ -furyl)ethyl phos-phonate was prepared BP 140C. (0.2 mm.). This is a suitable starting material ~or the preparation of 15-(~ -furyl)-~ -10 pentanorprostaglandins of the A, E or F series by the procedure :
of examples 121-129. ~ ;
In the same manner the ~imethyl-2-oxo-2~ -thienyl ethyl phosphonate can be prepared. This is a suitable start~ng materlal for the synthesis of 15~<-thienyl-~-pentanorprosta-glandins of the A, E or F series by the procedure of examples 112-125.
i In a simllar manner dimethyl 2-oxo-3(G~-ruryl)propyl phosphonate, dimethyl-2-oxo-5-(o<-~uryl)pentylphosphonate, ; dimethyl-2-oxo-6(o~-furyl)-_hexylphosphonate and dimethyl-2-oxo-7-(o~-~uryl)-heptylphosphonate may be prepared from the appropriat~e starting materials. These are suitable starting materials for the preparation o~ the 16,`18, 19 and 20 o~- ;
furyl substituted prostaglandin of this invent10n by the pro-oedure o~ examples 121-129. The ~-~uryl derivatives are pre-25~ pared in the same manner as the ~ -~uryl derlvatives from the -appropriate~starting materials.

:~ ~ . ., . ~ .

~ 153-.
.: : , . .. .: ,. .. . " ,.~ .. ,. , , , ., . . , . ,. . .. - , . -.. . . . .. . . .... .. ... . .... . . . . . . . . . . . . . . .

2-[3O~-p-Phenylbenzoyloxy-5~<-hydroxy-2~ -(3-oxo-5-(2-furyl)-trans-l-penten-l-yl)-cyclopent-l~ -yl]Acetlc Acid, y lactone _ _ _ _ , (3j):
Dimethyl 2-oxo-4-(2-furyl)-butylphosphonate (2~) (5.2 g., 21.1 mmole) was added to a mixture of 230 ml. an-hydrous DME and 57% NaH (860 mg., 20 mmole), and heated to re- -~lux until no hydrogen was given off (1 hour). After cooling, 5.2 g. (21 mmole) 2-[3O~-p-phenylbenzoyloxy-5~ -hydroxy~2~ -formylcyclopenta~-l~ -yl~acetic acid, y-lactone was added in one portion, followed by 100 ml. DME. After 1 hour the reac~
tion mixture was quenched with 2 ml. glacial acetic acid, filtered and concentrated to dryness. The residue dissolved .
in ethyl acetate and was washed with 100 ml. eaturated sodium bicarbonate solution (4 x), 100 ml. water (2x), 100 ml.
saturated brine (1 x), dried (MgSO4) and evaporated to yield

6.02 g. 2-[3O~-p-phenylbenzoyloxy-5c~-hydroxy-2~ -(3-oxo-5-(2-~uryl)-trans-1-penten-1-yl)cyclopent-lcC-yI]acetic acld, ~ ;
-laotone (3~) as an oil after column chromatography (Silica 20~ ~ ~ge~1, Baker, 60-200 mesh~
The ir spectrum (CHC13) o~ the product exhibited ad- -~
sorption bands at 1774 cm-1 (strong), 1710 om~1 (strong), 1670 ~ -om~1 (medium~ and 1625 cm 1 (medium) attributable to the carbonyl groups and at 973 cm~l for the trans double bon*.
25~ ; The produot~of this example (3~) may be converted to 13,14-dihydro-17-~(2-~uryl~ trisnorpro3taglandins of the A~ E or F~series through the procedures o~ examples 77, 88-89, ;
an~ 91-94~ ?r-~
The product (3j) may also be converted to 15-1Ower~
30~ àlkyl-17-(2-~uryl)-~ -trisnorpro~staglandins of the A, E or F

4~5 ~
series by the procedures of examples 80-96.
15 lower-alkyl-17-(2~furyl)~ tetranorprostaglandins of the A, E or F series may be obtained from (3~) via the pro- ''-' cedures of examples 86-89 and 91-94. In a similar manner the 2-~3~-p-phenylbenzoyloxy-5O~-hydroxy-2~ -t3-oxo-3~ uryl-t-rans-l-propen-l-yl)-cyclopent-lo~-yl]acetic acid, r-lactone was prepared, m.p. 140-141C. IR 1715~ 1775, 16259 1675, 9~5 cm~l. Thls is a suitable starting material for~the synthe''si's of the 15O~-furyl-~J-pentanorprostaglandins o~ this invention ' ' by the methods of examples 79-96. ~ -EXAMPLE_122 2-[3O~-~-Phenylbenzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-5-(2- ' furyl)-trans-l-penten-l-yl)cyclopent-~ -yl]acetic acid~ -lactone ( ~ ) and 2-[3c~-p-phenylbenzoyloxy-5 ~-hydroxy-2~ -(3~ -- .- , : .
hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1~ -yl]acetic '' acid, y -lactone (5J).
' To a solution of 5.97 g. (12.7 mmole) 2-[3~ -p-phenyl-:
benzoyloxy-5~-hydroxy-2~ -(3oxo-5-~2-furyl)~trans-1-penten~
l-yI)-~c~yclopent-J~ -yl]acetlc acid~ y-lactone (3J) in 3 ml. dry 1,2-dimethoxyethane in a dry nitrogen atmosphere at ambient temperature was added dropwise 12.7 ml. of a 0.5 M zinc boro~
hydride solution. After stirring at room temperature for 45 ~' minutes, a saturated sodium bitartrate solution was added ~;
dropwise until hydrogen evolution ceased. The reaction mix~
25~ ture~was allowed to stlr for 5 minutes, at which time 300 ml. ~ ~' dry~methylene chloride was added. After drying (MgS04) and cono~entrating (~ater aspirator), the resultant semisolid was purlied~by column chromatography on silica gel (Baker ~' ~ :~ : RTI~
I ~ Analy~ed~ Reagent~60-200 mesh) using ether as eluent.
30~ Aftar elution of less polar impurities, a ~rackion containing . . .

: : :

- ~ `
~ ``

~g~49S ~`
2.26 g. 2-[3~ -p-phenylbenzoyloxy-5 ~-hydroxy-2~ -(3O~-hydroxy-5-(2-furyl)-trans-1-penten-1-yl)cyclopent-1~ -yl]-acetic acid, ~-lactone (4~), a 270 mg. fraction of mixed 4 and 5~ and finally a fraction (2.2 g.) of 2-[3~ -~phenyl-benzoyloxy-5~ -hydroxy-2~ -(3~ -hydroxy-5-(2-furyl)-trans-1 penten-yl) cyclopent-l~ -yl]acetic acid, ~-lactone (5J).
The ir spectrum (CHC13) of 4~ and 5~ had strong carbonyl absorptions at 1770 and 1710 cm~l and an absorption at 97O cm~l for the trans double bond.

2-[3O<,5 ~-Dihydroxy-2~ (3~ -hydroxy-5-(2-furyl)~trans~
penten-l-yl)cyclopent~ yl]acetic acid, ~-lactone (6 A heterogeneous mixture of 2.26 g. (4.8 mmole) of 2-~3~ phenylbenzoyloxy-5~ -hydroxy-2~ -(3 ~-hydroxy-5-(2-furyl)-trans-l~penten-l-yl)cyclopent-lP<-yl]acetic acid, y-lactone (4J), 26 ml. of absolute methanol and 660 mg. of fi~ely powdered, anhydroua~p~otassium carOonate was~stirred at room~
temperature for one hour, ~hen cooled to 0. To the cooled : .. : j.
; solution was added 9.6 ml. of l.ON aqueous~hydrochloric acid.
~;~After stirring at 0 for an additlonal 10 minutes, 20 ml. of water was added with concomitant formation of methyl p-phenyl- ~;~
ben oate which was collected by filtration. The flltrate was ;saturated wlth solid sodium chloride, extracted wlth ethyl Bcetate~(4~ x 20 ml~ , the comblned organlc extracts were washed S~ with~saturated sodium bicarbonate (10 ml.), dried (MgSO4) and concent~rated~to give 1.02 g. of viscous, oily 2-[3 ~,5~ -di- ;
hydroxy-2~ -(3~ -hydroxy-5-(2-furyl)-trans-1-penten-1-yl)- ~-cyclopent~ yl]a~stlc acid, y-~lactone t6J). --;Ths~ir 9psctrum (CHC13)~sxh1blted a strong absorp~
3w ~ tIon at l765~om~l~r~r ths lact;ons carbonyl 3nd medlum absorp-~(;1 4~9~9~ :
tion at 960 cm~1 ~or the trans-double bond. ~i 2-[5O~-Hydroxy-3O~-(tetrahydropyran-2-yloxy) ~ -(3 ~- ~ tetra-hydropyran-2-yloxy ~ -5-(2-furyl)-trans-l-penten-l-yl)cyclo-pent-l~-yl]acetic acid, ~ -lactone (7~):
, To a solution of l gm. (3.42 mmole) 2-[3 ~,5~ -dl-hydroxy-2~ -(3 ~-hydroxy-5-(2-furyl)-trans-l-penten-yl)cyclo-pent-lo~-yl] acetic acid, r-lactone (6~) in 5 ml. anhydrous methylene chloride and 0.93 ml. of 2~3-dihyaropyran at 0 in a dry nitrogen atmosphere was added lO mg. p-toluenesulfonic acid, monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 100 ml. ether, the ether solution washed with saturated sodium bicarbonate (l x 15 ml.) then saturated brine (1 x 20 ml.), drled (MgS04) and concentrated to yield 1.63 g. (~ 100%) crude 2-C5~-hydroxy-3~-(tetra-hydropyran-2-yloxy)-2~ -(3 ~- ~tetrahydropyran-2-yloxy ~ -5- ;
2-furyl)-trans-l-penten-1-yl3cyclopent-l~< yl]acetic acid, y -lactone (7~). ` `
; The ir (CHC13) spectrum has a strong absorption at ~ 20 960 cm~l, for trans double bond.
; The product of this example (7~) may be converted to 13,14-dihydro~17-(2-furyl)-~J~trisnorprostaglandins o~
the A~ E or F series through the procedures of examples 86, 25~ ~ EXAMPLE 125 2~-[5O~-Hydroxy-3~ -(tetrahydropyran-2-yloxy)- ~ -(3D~- ~tetra-hydropyran-2-yloxy~ -5-(2-furyl)-trans-l-penten-1-yl)cyclopent-yl] acetaldehyde; y -hemiacetal (8~):
.
A solution of 1.6 g. (3.4 mmole) 2-~50~-hydroxy-3 ~ :
: : .
.

(tetrahydropyran-2-yloxy)-2~ -(3~ -tetrahydropyran-2-yloxy-5 (2-furyl)-trans-1-pentene-l yl)cyclopent-1~ -yl] acetic acid, ~ -lactone (7j) in 16 ml. dry toluene was cooled to -78 in a dry nitrogen atmosphere. To this cooled solution was added 4.68 ml. of o.8M diisobutylaluminum hydride in n-hexane (Alfa Inorganics) dropwise at such a rate so that the internal tem-perature never rose above -65 (15 minutes). After an addi-tional 45 minutes of stirring at -78g anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture .
was cornbined with 150 ml. ether, washed with 50% sodium potassium tartrate solution (4 x 20 ml.), dried (Na2S04) and concentrated to a quantitative yield of oily 2-[5 ~-hydroxy-3 ~-(tetrahydropyran-2-yloxy)-2~ -(3O~- ~tetrahydropyran-2-yloxy ~ -5-(2-furyl)~trans-1-penten-1-yl)cyclopent~l-yl~-acetaldehyde, ~ -hem1acetal (8~

9O~-Hydroxy-11~ ,15~-bis-(tetrahydropyran-2-yloxy)-17-(2-~uryl)-cis-5-trans-13-~J-trisnor-prostadienoic acid t9~):

To a solution of 3.36 g. (7.6 mmole) (4-carbohydroxy-n-butyl) triphenylphosphonium bromide in a dry nitrogen atmo-sphere in 15.0 ml. dry dimethyl sulfoxide was added 7.0 ml.
(14 0 mmole) of a 2.0M soluklon o~ sodium methylsu~inylmethide in dimethyl sulfoxlde. To this red ylide solution was added dropwlse a solution of 1.3 g. (2.81 mmole) 2-[5 ~-hydroxy-3K - -(tetrahydropyran-2-yloxy)-2~ -(3~ - ~tetrahydropyran-2-yloxy~ -5-(2-~uryl)-trans-1-penten-1-yl)cyclopent~ yl]acetaldehyde, hemiacetal (8~) in 5.0 ml. dry dimethyl sulfoxide over a ~period o~ 20 minutes. A~ter an additional 2 hours stirring ~ ;
at~ room kemperature, the reackion mixture wa~ poured onko ice -158- ~`
' - , .

:

~o~ s water. The basic aqueous solution was washed twice with ethyl acetate (20 ml.) and acidified to pH ^~3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (3 x 20 ml.) and the combined organic extracts washed once with water (10 ml.)~ dried (MgS04) and evaporated to a solid residue. This solld residue was triturated with ethyl acetate and filtered. The ~iltrate was purified by column B chromatography on silica gel (Baker "Analyzed" Reagent~60-200 mesh) using ethyl acetate as eluent. After removal of` high Rf impurities, 1.53 g. of 9GC-hydroxy-lloc,15c~-bis-(tetra-hydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13- ~-trisnor-prostadienoic acid (9J) was collected.

.. . . .
9-Oxo-11~ ,150<-bis-(tetrahydropyran~2-yloxy)-17-(2-furyl)-cis-5-trans-13- ~ -trisnor-prostadienoic acid (10~):
.
To a solution cooled to -10 under nitrogen of 1.1 g.
(2.01 mmole) 50<-hydroxy-ll~ ~15 ~-bis-(tetrahydropyran-2-yloxy) ~ `
17-(2-furyl)-cis-5-trans-13- ~-trisnor-prostadienoio acid ~-( I ) in 20 ml. reagent grade acetone was added dropwise to 0.88 ml. (2.2 mmole) of Jones' reagent. After 20 minutes at -10, 0.260 ml. 2-propanol was added and the reaction mix- :
ture was allowed to stir an additional 5 minutes at which time it was combined with 75 ml. ethyl acetate, washed with water (3 x 10 ml.), dried (MgS04) and concentrated to give 25 ~ 425~;mg. o~9 oxo-11~ ,15 ~-bis-(tetrahydropyran-2 yloxy)-17-~2-furylj-cis-5-trans-13-~ -triænor-pros~adienoic acid ; .

~ 159-~4~35 9-Oxo-11~ ,15O~-dihydroxy-17-(2-furyl)-cis-5-trans-13-4)-_ _ trisnor-prostadienoic acid (~
A solution of 425 mg. (0.782 mmole) 9-oxo-11 ~,15~ -bis-tetrahydropyran-2-yloxy)-17-(2-furyl)-cis-5-trans-13- ~-trisnor-prostadienoic acid (10~) in 3.0 ml. o~ a 65:35 mixture ~`
o~ glacial acetic acid:water was stirred under nitrogen at ~ ~
25 for 18 hours, then was concentrated by rotary evaporation. `
~he resultant crude oil was purRfied by column chromatography B 1~ on sllica gel (Mallinckrodt CC-4A100-200 mesh) using ethyl acetate a~ eluent. After elution of less polar impurities, the crystalline 9-oxo~ C,15~-dihydroxy-17-(2-~uryl)-cis- ~ -5-trans-13- ~-trisnor-prostadienoic acid (~1) mp.98-99 weighing 204 mg. was collected.
The product of this example (11~) can be converted to 17-(2-furyl)- W-trisnorprostaglandins-El, Eo A2, Al and A
vi& the procedures of examples 95, 96, and 88.

9~ ,llo~, 15~-Trihydroxg-17-(2-~uryl)-cis-5-trans-13- ~J-20~ ~ ~trl9nor-pro~stadlenoic acid (12~
; A solution of 700 mg. (0.334 mmole) 9~ -hydroxy-llbc915~ -bis-tetrahydropyran-2-yloxy)-17-(2-~uryl)-cis-5-trans-13-~ -trisnorprostadienoic acid (9~) in 5 ml. of a 65:35 - .
mixture of glaclal ~cet~c acid:water was stirred under nitrogen 25~ at 25C~or 20 hours,; then was concentrated by rotary evapora-tion.~ he resultant crude~oil was puri~ied by column chromato- ^
graphy on silica gel (Malllnckrodt~ CC-4~100-200 mesh) uslng ; ~ ethyl~acetate as eluent. After elution of less polar impuri-tie;~, the olly 9~ ,11~ ,15~ -trihydroxy-17-(2-furyl)-cis-5-. ~ . ,:
::

9~
trans-13-~J-trisnorprostadienoic acid (12~) weighing 108 mg.
was collected.
The ir (CHC13) had a carbonyl absorption at 1710 cm~l and a trans double bond absorption at 965 cm~l.
The product of this example (12;) can be converted to 17-t2-furyl)-~J~trisnorprostaglandins Fl~ and Fo~ via the procedures of examples 94 and 95. ~ :

' . ' ~'':

. . .
'' ' "~;~

- , :
.
.

~ 161- ~

: : ,

Claims (59)

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

1. A proces for preparing a compound of the struc-ture:

...I

wherein Ar is .alpha. - or .beta. -thienyl; .alpha.-or .beta. -naphthyl; phenyl; 3,4-dimethoxyphenyl, 3,4-methylene-dioxyphenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl;
W is a single bond or cis double bond;
Z is a single bond or trans double bond;
M is keto, or ;
N and L when taken together form a single bond, or N is .alpha. -hydroxyl when L is hydrogen; and wherein L, M and N are so selected as to complete the structure of a prostaglandin of the A, E or F series, the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups at the C9-, C11- and C15-positions, and the pharma-ceutically acceptable salts thereof, characterized by the fact that a) when N is .alpha. -hydroxy and L is hydrogen, and Ar, n, M, W and Z are as defined above, said compound is prepared by treating the 11-, and 11- and 15-tetrahydropyranyl ethers of a compound of Formula I above, with a suitable acid;
b) when N and L, when taken together form a single bond, M is keto and Ar, n, R, W and Z are as defined above, said compound is prepared by reacting a compound of Formula I, above, wherein N is .alpha.-hydroxy and L is hydrogen, M is keto and Ar, n, R, W and Z are as defined above, with a suitable dehydrating agent;
c) when N is .alpha.-hydroxy and L is hydrogen, M is or and Ar, n, R, W and Z are as defined above, said compound is prepared by reacting a compound of the Formula I, above, wherein N is .alpha.-hydroxy and L is hydrogen, M is keto, Ar, n, R, W and Z are as defined above, with a suitable re-ducing agent, and, if desired, separating the 9.alpha.- and 9.beta.-isomers;
d) when N is .alpha.-hydroxy, L is hydrogen, Ar, R, n and M
are as defined above, and W and Z are single bonds, said compound is prepared by catalytic reduction of a compound of Formula I, above, wherein Ar, R, n and M are as defin-ed above, W is a single bond or cis double bond when Z is a trans double bond and Z is a single bond when W is a cis double bond;
e) when N is .alpha.-hydroxy, L is hydrogen, Ar, R, n and M
are as defined above, W is a single bond and Z is a trans double bond, said compound is prepared by selective reduc-tion of a compound of Formula I, above, wherein Ar, R, n and M are as defined above and W and Z are double bonds, and, if desired, preparing the 9.alpha.-, 11.alpha.- and 15.alpha.- lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups by reacting said compounds with the appro-priate acylating agents and, if desired, preparing the pharmaceutically acceptable salts of these compounds.

2. A process for preparing a compound of the structure:

...IA

wherein Ar is .alpha.-, or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl, 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;

R is hydrogen or lower alkyl;
W is a single bond or cis double bond; and Z is a single bond or trans double bond;
the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups at the C9-, C11- and C15-positions, and the pharmaceutically acceptable salts thereof, charac-terized by the fact that a) the 11-, and 11- and 15-tetrahydropyranyl ethers of a compound of Formula I, above, is treated with a suitable acid;
b) a compound of the formula ...IB

wherein Ar, n, R, W and Z are as defined above, is reduced with a suitable reducing agent and then separating the 9.alpha.-and 9.beta.-isomers;
c) a compound of the formula wherein W is a single bond, and wherein Ar, n, R and Z are as defined above, and R' is hydrogen or lower alkyl, is treated with a suitable base;
d) a compound of Formula IA, above, wherein Ar, R and n are as defined above, W is a single bond or cis double bond when Z is a trans double bond and Z is a single bond when W
is a cis double bond, is catalytically reduced to a compound of Formula IA, above, wherein Ar, R and N are as defined above and W and Z are single bonds;
e) the dimethylisopropylsilyl derivative of a compound of Formula IA, above, wherein Ar, R and n are as defined above, W is a cis double bond and Z is a trans double bond, is selectively catalytically reduced to a compound of Formula IA, above, wherein Ar, R and n are as defined above, W is a single bond and Z is a trans double bond;
and, if desired, preparing the 9.alpha.-, 11.alpha.-, and 15.alpha.-lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups by reacting said compounds with the appro-priate acylating agents, and, if desired, preparing the pharmaceutically acceptable salts of these compounds.

3. A process for preparing a compound of the structure:

...IB

wherein Ar is .alpha. - or .beta. -furyl; .alpha. - or .beta.-thienyl; .alpha.-or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylene-dioxyphenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl;

W is a single bond or cis double bond; and Z is a single bond or trans double bond;
the lower alkanoyl, formyl or benzoyl esters of any free hydroxyl groups at the C11- and C15-positions, and the pharmaceutically acceptable salts thereof, characterized by a) treating the 11- or 11- and 15-tetrahydropyranyl ethers of a compound of Formula IB, above, wherein Ar, R, n, W and Z are as defined above, with a suitable acid;
b) catalytically reducing a compound of Formula IB, above, wherein Ar, R and n are as defined above, W is a single bond or a cis double bond when Z is a trans double bond and Z is a single bond when W is a cis double bond, to afford a compound of Formula IB wherein Ar, n and R are as defined above and W and Z are single bonds;
c) selectively catalytically reducing the dimethyliso-propylsilyl derivative of a compound of Formula IB, above, wherein Ar, R and n are as defined above, W is a cis double bond and Z is a trans double bond, to afford a compound of Formula IB, above, wherein Ar, R and n are as defined above, W is a single bond and Z is a trans double bond;
and, if desired, preparing the lower alkanoyl, formyl or benzoyl esters of any free 11- and 15-hydroxyl groups by reacting said compounds with the appropriate acyl-ating agents, and, if desired, preparing the pharmaceutically acceptable salts of these compounds.

4. A process for preparing a compound of the structure:

...IC

wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl;
W is a single bond or cis double bond; and Z is a single bond or trans double bond, the lower alkanoyl, formyl or benzoyl esters of the C15-hydroxy group, and the pharmaceutically acceptable salts thereof, characterized by treating a compound of Formula IB, ...IB

wherein Ar, R, n, W and Z are as defined above, with a suitable dehydrating agent;
and, if desired, preparing the C15-lower alkanoyl, formyl or benzoyl esters by reacting said compound with the appropriate acylating agents, and, if desired, preparing the pharmaceutically acceptable salts of these compounds.

5. A process for preparing a compound of the structure:

...II
wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy and n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1, characterized by reacting a compound of the formula with dialkylmethylketophosphonate of the formula wherein Ar and n are as defined above.

6. A process for preparing a compound of the structure:

...III

wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluormethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl; and Q is hydrogen or p-biphenylcarbonyl, characterized by a) reducing a compound of the Formula IIA

...IIA

wherein Ar, n and Q are as defined above, to afford a compound of Formula III, above, wherein Ar, n and Q are as defined above and R is hydrogen, and, if desired, separating the 15.alpha.-and 15.beta.-isomers;
b) treating a compound of Formula IIA, as defined above, with a suitable alkylating agent to afford a compound of Formula III, wherein Ar, n and Q are as defined above and R
is lower alkyl;
and, if desired treating a compound of Formula III, above, wherein Ar, n and R are as defined above and Q is bi-phenylcarbonyl with K2CO3 to afford a compound of Formula III
wherein Q is hydrogen; and, if desired, separating the 15.alpha.-and 15.beta.-isomers.

7. A process for preparing a compound of the structure:

...IV

wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl;
THP is 2-tetrahydropyranyl;
Z is a single bond or a trans double bond; and I is =O or characterized by a) reacting a compound of the Formula IIIA

...IIIA

wherein Ar, R, n and Z are as defined above and X is =O
with 2,3-dihydropyran in the presence of an acid catalyst to afford a compound of Formula IV wherein Ar, R, n and Z
are as defined above and X is =O;
b) reacting a compound of Formula IV, above, wherein Ar, R, n and Z are as defined above and X is =O with diisobutyl-aluminum hydride to afford a compound of Formula IV wherein Ar, R, n and Z are as defined above; and X is ;
c) by catalytically reducing a compound of Formula III
above wherein Ar, R and n are as defined above, Z is a trans double bond and X is =O, to afford a compound of Formula IV
wherein Ar, R and N are as defined above, X is =O and Z is a single bond.

8. A process for preparing a compound of the structure:

...V

wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is pheny, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl;
THP is 2-tetrahydropyranyl;
W is a single bond or a cis double bond; and Z is a single bond or trans double bond;
characterized by reacting a compound of the Formula IVA

IVA

wherein Ar, R, n and Z are as defined above with an ylide of the formula (C6H5)3P=CH-CH2-CH2-CH2-COO(-) to afford a compound of Formula V wherein Ar, R, n and Z are as defined above and W is a cis double bond, and, when re-quired, subsequently reducing the compound thus formed to afford a compound of Formula V wherein Ar, R, n and Z are as defined above and W is a single bond;
b) by reducing a compound of Formula V above, wherein Ar, R and n are as defined above, W is a cis double bond and Z
is a trans double bond, to form a compound of Formula V
above wherein Ar, R and n are as defined above and W and Z
are single bonds;
c) by selectively reducing a compound of Formula V above, wherein Ar, R and n are as defined above, W is a cis double bond and Z is a trans double bond, to form a compound of Formula V wherein Ar, R and n are as defined above, W is a single bond and Z is a trans double bond.

9. A process for preparing a compound of the structure:

...VI

wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
R is hydrogen or lower alkyl;
THP is 2-tetrahydropyranyl;
W is a single bond or a cis double bond; and Z is a single bond or a trans double bond;
characterized by reacting a compound of Formula V

...V

wherein Ar, R, n, W and Z are as defined above with chromic acid in aqueous sulfuric acid and acetone.

10. A process for preparing a compound of the formula:

...VII
wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
THP is 2-tetrahydropyranyl;
R' is lower alkyl; and R" is lower alkyl, aralkyl of from 7 to 10 carbon atoms, phenyl and substituted phenyl wherein said substituent is lower alkyl, lower alkoxy, halo, trifluoromethyl or phenyl;
characterized by reacting a compound of the formual with a compound of the formula wherein Ar, R', R" and n are as defined above.

11. A process for preparing a compound of the formula:

VIII

wherein Ar is .alpha.-, or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl, 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
THP is 2-tetrahydropyranyl;
R' is lower alkyl;
R" is lower alkyl, aralkyl of from 7 to 10 carbon atoms, phenyl or substituted phenyl wherein said substituent is halo, trifluoromethyl, lower alkyl, lower alkoxyl or phenyl;
characterized by a) reducing a compound of Formula VII

...VII

wherein Ar, R', R" and n are as defined above, to afford a compound of Formula VIII wherein Ar, R', R" and n are as de-fined above and R is hydrogen;
b) treating a compound of Formula VII, above, with a suit-able alkylating agent to afford a compound of Formula VIII, wherein Ar, R', R" and n are as defined above and R is lower alkyl;
and, if desired, separating the 15.alpha.- and 15.beta.-isomers.

12. A process for preparing a compound of the formula IX
wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from O to S with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
THP is 2-tetrahydropyranyl;
R' is lower alkyl;
R" is lower alkyl, aralkyl of from 7 to 10 carbon atoms, phenyl or substituted phenyl wherein said substituent is lower alkyl, lower alkoxyl, halo, trifluoromethyl or phenyl; and R is hydrogen or lower alkyl;

chacterized by reacting a compound of the formula wherein Ar, R, R', R" and n are as defined above; and R3 is hydrogen or THP, with 2,3-dihydropyran in the presence of p-toluenesulfonic acid.

13. A process for preparing a compound of the formula X
wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl: phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy;
n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
THP is 2-tetrahydropyranyl; and R is hydrogen or lower alkyl;
characterized by reacting a compound of Formula IX

IX
wherein Ar, R and n are as defined above;
R' is lower alkyl;
R" is lower alkyl, aralkyl of from 7 to 9 carbon atoms, phenyl or substituted phenyl wherein said substitu-ent is halo, lower alkyl, lower alkoxyl, trifluoromethyl or phenyl;
with a suitable base.

14. A process for preparing a compound of the structure XI
wherein Ar is .alpha.- or .beta.-furyl; .alpha.- or .beta.-thienyl; .alpha.- or .beta.-naphthyl; phenyl; 3,4-dimethoxyphenyl; 3,4-methylenedioxy-phenyl; 3,4,5-trimethoxyphenyl; or mono-substituted phenyl wherein said substituent is halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; and n is an integer from 0 to 5 with the proviso that when Ar is phenyl, substituted phenyl or naphthyl n is 0 or 1;
chacterized by reacting a lower alkyl ester of the formula Ar(CH2)n-?-O-lower alkyl with a dialkylmethylphosphonate of the formula .

15. A process according to claim 3, for preparing 16-phenyl-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

16. A process according to claim 2, for preparing 16-phenyl-.omega.-tetranor PGF2.alpha., characterized by hydrolyzing the precursor9.alpha.-hydroxy-11a,15.alpha.-bis-(tetrahydropyran-2-yloxy)-116-phenyl-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

17. A process according to claim 3, for preparing 16-phenyl-.omega.-tetranor PGE1, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-phenyl cis-5-.omega.-tetranorprostenoic acid with aqueous acetic acid.

18. A process according to claim 3, for preparing 16-p-methoxyphenyl-.omega.-tetranor PGE2, characterized by hydro-lyzing the precursor 9 oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-16-(p-methoxyphenyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

19. A process according to claim 3, for preparing 16-p-biphenyl-.omega.-tetranor PGE2, characterized by hydro-lyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-16-(p-biphenyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

20. A process according to claim 3, for preparing 16.alpha.-naphthyl-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11a,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-(.alpha.-naphthyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

21. A process according to claim 3, for preparing 16.beta.-naphthyl-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-(.beta.-naphthyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

22. A process according to claim 3, for preparing 16-p-methylphenyl-.omega.-tetranor PGE2, characterized by hydro-lyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-16-(p-methylphenyl)-cis-5-trans-13-.omega.-tetranorprostadi-enoic acid with aqueous acetic acid.

23. A process according to claim 3, for preparing 15-phenyl-13,14-dihydro-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-(p-methylphenyl)-cis-5-.omega.-tetranorprostenoic acid with aqueous acetic acid.

24. A process according to claim 3, for preparing 16-phenyl-13,14-dihydro-15-methyl-.omega.-tetranor PGE2, character-ized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetra-hydropyran-2-yloxy)-15-methyl-16-phenyl-cis-5-.omega.-tetranor-prostenoic acid with aqueous acetic acid.

25. A process according to claim 2, for preparing 16-p biphenyl-.omega.-tetranor PGE2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-16-(p-biphenyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

26. A process according to claim 3, for preparing 16-o-methylphenyl-.omega.-tetranor PGE2, characterized by hydrolyz-ing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-(o-methylphenyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

27. A process according to claim 2, for preparing 16.alpha.-naphthyl-.omega.-tetranor PGF2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-16-(.alpha.-naphthyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

28. A process according to claim 2, for preparing 16.beta.-naphthyl-.omega.-tetranor PGF2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-16-(.beta.-naphthyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

29. A process according to claim 4, for preparing 16-phenyl-13,14-dihydro-.omega.-tetranor PGA2, characterized by treating the precursor 9-oxo-11.alpha.,15.alpha.-dihydroxy-16-phenyl-cis-5-trans-13-.omega.-tetranorprostadienoic acid with formic acid in methylene chloride.

30. A process according to claim 3, for preparing 16-phenyl-.omega.-13,14-dihydro-tetranor PGE1, characterized by re-ducing the precursor 9-oxo-11.alpha.,15.alpha.-dihydroxy-16-phenyl-cis-5-trans-13-.omega.-tetranorprostadienoic acid with hydrogen in the presence of a palladium-on-carbon catalyst.

31. A process according to claim 3, for preparing 16.alpha.-thienyl-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-(.alpha.-thienyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

32. A process according to claim 3, for preparing 16.beta.-thienyl-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-(.beta.-thienyl)-cis-5-trans-13-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

33. A process according to claim 3, for preparing 17.alpha.-thienyl-.omega.-trisnor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-17-(.alpha.-thienyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

34. A process according to claim 3, for preparing 17.alpha.-furyl-.omega.-trisnor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-17-(.alpha.-furyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

35. A process according to claim 2, for preparing 17.alpha.-furyl-.omega.-trisnor PGF2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-17-(.alpha.-furyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

36. A process according to claim 2, for preparing 17.alpha.-thienyl-.omega.-trisnor PGF2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-17-(.alpha.-thienyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

37. A process according to claim 2, for preparing 17.beta.-furyl-.omega.-trisnor PGF2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-17-(.beta.-furyl)-cis--5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

38. A process according to claim 3, for preparing 17.beta.-furyl-.omega.-trisnor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-17-(.beta.-furyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

39. A process according to claim 2, for preparing 17.beta.-thienyl-.omega.-trisnor PGE2.alpha., characterized by hydrolyzing the precursor 9.alpha.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-17-(.beta.-thienyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

40. A process according to claim 3, for preparing 17.beta.-thienyl-.omega.-trisnor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-17-(.alpha.-furyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

41. A process according to claim 2, for preparing 17.alpha.-furyl-.omega.-trisnor PGF2.beta., characterized by hydrolyzing the precursor 9.beta.-hydroxy-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yl-oxy)-17-(.alpha.-furyl)-cis-5-trans-13-.omega.-trisnorprostadienoic acid with aqueous acetic acid.

42. A process according to claim 3, for preparing 16-phenyl-13,14-dihydro-.omega.-tetranor PGE2, characterized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetrahydropyran-2-yloxy)-16-phenyl-cis-5-.omega.-tetranorprostadienoic acid with aqueous acetic acid.

43. A process according to claim 3, for preparing 15-epi-16-phenyl-13,14-dihydro-.omega.-tetranor PGE2, character-ized by hydrolyzing the precursor 9-oxo-11.alpha.,15.alpha.-bis-(tetra-hydropyran-2-yloxy)-16-phenyl-cis-5-.omega.-tetranorprostanoic acid with aqueous acetic acid.

44. Compounds of Formula I, as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

45. Compounds of the Formulas .IA, IB and IC, as defin-ed in claims 2, 3 and 4, whenever prepared by the processes of claims 2, 3 or 4, respectively, or by an obvious chemical equivalent thereof.

46. Compounds of the Formulas II, III and IV, as defin-ed in claims 5, 6 and 7, whenever prepared by the processes of claims 5, 6 or 7, respectively, or by an obvious chemical equivalent thereof.

47. Compounds of the Formulas V, VI and VII, as defin-ed in claims 8, 9 and 10, whenever prepared by the processes of claims 8, 9 or 10, respectively, or by an obvious chemical equivalent thereof.

48. Compounds of the Formulas VII and IX, as defined in claims 11 and 12, whenever prepared by the processes of claims 11 or 12, respectively, or by an obvious chemical equivalent thereof.

49. Compounds of the Formulas X and XI, as defined in claims 13 and 14, whenever prepared by the processes of claims 13 or 14, respectively, or by an obvious chemical equivalent thereof.

50. 16-Phenyl-.omega.-tetranor PGE2, 16-phenyl-.omega.-tetranor PGF2.alpha., and 16-phenyl-.omega.-tetranor PGE1, whenever prepared by the process of claims 15, 16 or 17, respectively or by an obvious chemical equivalent thereof.

51. 16-p-Methoxyphenyl-.omega.-tetranor PGE2, 16-p-biphenyl-.omega.-tetranor PGE2, and 16.alpha.-naphthyl-.omega.-tetranor PGE2, whenever prepared by the process of claims 18, 19 or 20, respectively or by an obvious chemical equivalent thereof.

52. 16.beta.-Naphthyl-.omega.-tetranor PGE2, 16-p-methylphenyl-.omega.-tetranor PGE2, and 15-phenyl-13,14-dihydro-.omega.-tetranor PGE2, whenever prepared by the process of claims 21, 22 or 23, re-spectively or by an obvious chemical equivalent thereof.

53. 16-Phenyl-13,14-dihydro-15-methyl-.omega.-tetranor PGE2, 16-p-biphenyl-.omega.-tetranor PGF2.alpha., and 16-o-methylphenyl-.omega.-tetra-nor PGE2, whenever prepared by the process of claims 24, 25 or 26, respectively or by an obvious chemical equivalent thereof.

54. 16.alpha.-Naphthyl-.omega.-tetranor PGF2.alpha., 16.beta.-naphthyl-.omega.-tetranor PGF2.alpha., and 16-phenyl-13,14-dihydro-.omega.-tetranor PGA2, whenever prepared by the process of claims 27, 28 or 29, re-spectively or by an obvious chemical equivalent thereof.

55. 16-Phenyl-.omega.-13,14-dihydro-tetranor PGE1, 16.alpha.-thienyl -.omega.-tetranor PGE2, and 16.beta.-thienyl-.omega.-tetranor PGE2, whenever prepared by the process of claims 30, 31 or 32, respectively or by an obvious chemical equivalent thereof.

56. 17.alpha.-Thienyl-.omega.-trisnor PGE2, 17.alpha.-furyl-.omega.-trisnor PGE2, and l7.alpha.-furyl-.omega.-trisnor PGF2.alpha., whenever prepared by the process of claims 33, 34 or 35, respectively or by an obvious chemical equivalent thereof.

57. 17.alpha.-Thienyl-.omega.-trisnor PGF2.alpha., 17.beta.-furyl-.omega.-trisnor PGF2.alpha., and 17.beta.-furyl-.omega.-trisnor PGE2, whenever prepared by the process of claims 36, 37 or 38, respectively or by an obvious chemical equivalent thereof.

58. 17.beta.-Thienyl-.omega.-trisnor PGF2.alpha., 17.beta.-thienyl-.omega.-trisnor PGE2, and 17.alpha.-furyl-.omega.-trisnor PGF2.beta., whenever prepared by the process of claims 39, 40 or 41, respectively or by an obvious chemical equivalent thereof.

59. 16-Phenyl-13,14-dihydro-.omega.-tetranor PGE2, and 15-epi-16-phenyl-13,14-dihydro-.omega.-tetranor PGE2, whenever prepared by the process of claims 42, or 43, respectively or by an obvious chemical equivalent thereof.