CA1075250A - Preparation of prostaglandin intermediates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Process for preparing bicyclic lactone ketones of the formula wherein R12 is (1) (2)

Description

~075ZS0 BACKG~ROUND OF THE INVENTION
I-his invent10n relates to intermediates usefui In the preparation of prostagland1ns and to a process for pre-paring them.
Each of the known prostaglandins Is a derivative of prostanoic acid which has the following structure and atom : numbering;

~COO~

' ~l~i~o A systematic name for prostanotc acid is 7-~(2~-octyl)-cyclopent -la -y l]heptanoic acid.
Prostaglandin Ez, "PGE2", has the following structure:
O
~ ~ OOH

HO H OH
Prostaglandin F2a, "PGF2a", has the following struc-20 ture: HO

~r ^~== ~ OOH
~~/ '~ .
. ~0 H OH
.

The prostaglandtn formulas mentioned above each have several centers of asymmetry. Each formula represents a molecule of the parsicular opttcally active form of the prostaglandin obtained from certatn mammalian ttssues, for example, sheep vesic~lar glands, swine lung, and human seminal plasma, or by reduction or dehydration of a prosta-

-2- ~ ~

~230 ~075;~:50 glandin so ob~ained. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein.
The mirror image of each formula represents a molecule of the other enantiomeric form of that prostaglandin. The racemic form of the prostaglandins consists of equal num-bers of two types of molecules, one represented ~y one of the above formulas and the other represented by the mirror image of that formula. Thus, both formulas are needed to define a racemic prostaglandin See Nature 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.
In the formulas above, as well as in the formulas given hereinafter, broken line attachments to the cyclo-pentane ring indicate substit~ents in alpha configuration, i.e., below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e. above the plane of the cyclopentane ring In the formulas above, the hydroxyl attachment to carbon 1~ is in the alpha configura-tion, as indicated by the broken line. In formulas below, this convention is also used for intermediates having hydroxyl substituted at the corresponding position on the side chain. A wavy line ~ indicates optional attachment to carbon 15 in either alpha or beta configuration.
The various optically active and racemic prostaglandins 2~ and thei~ alkyl esters are useful for various pharmacological purposes. With particular regard to P~F2a s~e, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and refer-ences cited thereln, Wlqvist et al., The Lancet, 889 (1970), and ~arlm et al., J. Obstet. Gynaec. Brlt. Cwlth., 76, 769

3~ (1969). As to the other prostaglandTns, see, for example Ramwell et al., Nature 221, 1251 (1969).

Previously, the preparation of an inter-mediate bicyclic lactone ketone of the formula ~0~

)~ C5Hll wherein R4 is acetyl was reported by E.J. Corey et al., J. Am.
Chem. Soc. 91, 5675 (1969), and later disclosed in an optically active form by E.J. Corey et al., J. Am. Chem. Soc. 92, 397 (1970) Conversion of this intermediate to PGE2 and PGF2a either in racemic (di-) or optically active form, was disclosed in those publications. For that compound wherein R4 is benzoyl see U.S.
Patent 3,778,450.
Related compounds of the formula o, ~

~ G

wherein R4 is acetyl or benzoyl have been disclosued as follows:
(1) wherein G is alkyl of one to 10 carbon atoms, inclusive, substituted with zero to 3 fluoro, U.S. Pate~t No.
3,936,487 (The Upjohn Company, Feb. 3/76);
(2) wherein G is tS

-C-~CH2)3-CH3 ~075Z50 wherein R5 and R6 are hydrogen, methyl, or ethyl, provided that at least one of R5 and R6 is not hydrogen, Canadian Patent No. 984,387 ~The Upjohn Company, Feb. 24/76);
(3) wherein G is f n 2n 3 wherein CnH2n is alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive, in the chain between -CFR7- and terminal methyl and wherein R7 is hydrogen, methyl, ethyl, or fluoro, British Specification No. 1,396,206; and

(4) wherein G is - I - ~ S

wherein R8 and Rg are hydrogen, methyl, or ethyl, wherein T
is alkyl of one to 3 carbon atoms, inclusive, fluoro, chloro, trifluoro, or -ORlo wherein Rlo is alkyl of one to 3 carbon atoms, inclusive, and wherein s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl, British Specification No. 1,409,~41.
Also disclosed is a compound of the formula:

P ~

~ XR `
AcO

- 5 -iO75250 wherein Ac represents an acyl radical, either acetyl or p-phenylbenzoyl, X is an alkylene radical of 2 or 3 carbon atoms, optionally bearing as substituent or substituents one or two alkyl radicals each of 1 to 4 carbon atoms, and Rll is an aryl or thienyl radical, which is unsubstituted or which is substituted by halogen atoms, nitro radicals, alkyl, halogenoalkyl or alkoxy radicals each of 1 to 3 carbon atoms or dialkylamino radicals wherein each alkyl is of 1 to 3 carbon atoms, British Specification No. 1, 372,541.
' A related disclosed compound is O

N~ ~C~cHz~c ~C2H5 lV
THPO HO~ \H H ~ ~H

wherein THP is tetrahydropyranyl, useful in the synthesis of PGF3~ E.J. Corey et al. J. Am. Chem. Soc, 93, 1490 (1971).
` SUMMARY ` OF THE INVENTION
It is the purpose of this invention to provide novel intermediates useful in the preparation of prostaglandins commerically in substantial amount, with high purity, and ~230 - ~075250 at reasonable cost. It is a further purpose to provide processes tor preparing these intermediates and for utitizing them.
Thus there is provided a process for preparing an optically active bicyclic lactone ketone of the formula O 4~ ' ~'' V
~,Rl2 1~ 0~
or a mixture of that compound and the enantiomer thereof, wherein Rl2 is Rl3 (1 ) -C-C9H2g-CH3J

(2) -CH2 j C2Hs, or H ~ C C ~ H

20(~) ~13 I_z~( )S
., I ' R1 4 wherein ~gH29 is alkylene of one to 9 carbon atoms, inclu-sive, with one to 5 carbon atoms, inclusive, in the chain ~ between -CRI9R~4- and terminal methyl; wherein R19 and R
.~ are hydrogen, alkyl of one to 4 carbon atoms, lnclusive, or fluoro, being the same or different, wtth the provlso that R~3 is fluoro only when R14 ts hydrogen or fluoro;
wherein T is alkyl of one to 4 carbon atoms, Inclusive, _7 fluoro, chloro, `trifluoromethyl, or -ORl5, wherein R15 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl; and wherein Z represents an oxa atom (-0-) or CjH2j, wherein CjHzj Is a valence bond or alkylene of one to 9 carbon atom , incluslve, sub-stltuted with zero, one, or 2 fluoro, with one to 6 carbon atoms, Inclusive, between -CRl~R1~- and the rTng; which comprises (a) starting with a tricyclic lactone aldehyde of the formula 0 O \
~' Vl ~ ~ CH0 ;: 15 or a mixture of that compound and the enantiomer thereof, wherein ~ indicates attachment to the cyclopropane ring in endo or exo configuratlon, and reacting sald aldehyde with a nitrlle of the formula I a 1 CN

: 25 wherein ~al is chloro, bromo, or lodo, the two Hal's belng the same or different, and whereln Rl2 Is deflned as above, to form an optically active cyanoepoxide of the formula o~ Vl I

or a mixture of that compound and the enantiomer thereof, wherein R,2 and ~ are as defined above;
(b) reacting said cyanoepoxide with formic acid to produce an optically active cyanohydrin monoformate of the formula O
0 4~ :
~ ~ , Vl I I
. ~ '- .

OCHO Ll or a mixture of that compound and the ena.ntiomer thereof, ' wherein R~2 is as defined above and wherein L1 represents either HO CN or HO CN; and (c) transforming the product of step (b) to said bicyclic lactone ketone by (d) removing hydrocyanic acid by dehydrocyanation to convert the -fi R12 moiety to -If - Rl2 Ll O

and (e) replacing formyl with hydroxyl, said steps (d) and (e) being performed either in the order (d)-(e) or (e)-(d).
There is further provTded a process for prepartng an _g_ optically ac~ive bicyclic lactone k~tone o~ the formula O
C~

S ' ¢~ Xl OH
or a mixture of that compound and the enanttomer thereof, which comprises (a) starting with a tricyclic lactone cyanoepox;de of the formula o ~1 ~' X I I
COOc2Hs CN
or a mixture of that compound and the enantiomer thereof, wherein ~ indicates attachment to the cyclopropane ring in endo or exo configuration, and reacting said cyano-epoxide with formic acid to produce an optically active cyanohydrin monoformate of the formula ~ :

X l I I

or a mixt~Jre of that compound and the enantiomer thereof, wherein Ls represents either ~ ~ or ,'~
H~ CN HO ~N;

(b) replacing ~ormyl with hydroxyl to produce an opti-cally actlve cvanohydrin of the formula '10-Q~\ . xlV

~COOC2H5 r~ O~H

or a mixture of that compound and the enantiomer thereof, wherein Ll is as defined above;
(c) transforming the product of step ~b) to form a diether of the formula O
0~
X V I I . - -15 . OR1~ L2 or a mixture of that compound and the enantiomer thereof, wherein L2 represents either ~ ~ or R~O CN
, ~ and wherein Rl~ is 1-ethoxyethyl, tetra-; Rl~O CN
hydropyranyl, tetrahydrofuranyl, or a group of the formula . H

R~8 wherein Rl7 ts alkyl of one to 18 carbon atoms, Inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusTve, aralkyl of 7 to 12 carbon atoms, inc1usive, phenyl, or phenyl sub-stituted w;th one, 2, or 3 alkyl of one to 4 carbon atoms, : inctusive, wherein Rl8 and R~ are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, Inclustve, : 30 phenyl or phenyl substituted wlth one, ?, or 3 alkyl of one iO75Z50 to 4 carbon atoms, inclusive, or, when Rl8 and R18 are ; taken together, ^(CH2)a- or -(CH2)b-0-(CH2)c- wherein a Ts 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 wlth the proviso that b plus c is 2, 3, or 4, and whereln R20 Ts hydrogen or phenyl; by (d) replacing the hydrogen of the hydroxyl groups wtth Rl~ groups wheretn Rl~ is as defined above, and (e) replacing the -COOC2H5 moiety with hydrogen, said steps (d) and (e) being performed either in the order (d)-(e) or (e)-(d);
(f) transforming the product of step (c) to a compound of the formula XV I

~H

or a mixture of that compound and the enantiomer thereof, wherein ~1 ts as defined above, by the steps of deprotonatlng, alkylating wlth 1-bromo-cis-2-pentene, and deblocklng, and (g) removing hydrocyanlc acid by dehydrocyanatlon to convert the . .
~ mo~ety to ,., ., ~~.

,,, O
There Is further provlded a process for preparlng an opttcally actlve btcycllc lactone ketone of the formula ~075250 ~\
~' Xl . ~ .
OH

or a mixture of that compound and the enantiomer thereof, which comprises (a) starting with a tr7cyclTc lactone aldehyde of the 10 formula O
.. 0~
., ~~ . Vl : CHO

:
or a mixture of that compound and the enantiomer thereof, : wherein indicates attachment to the cyclopropane ring . in endo or exo configuratton, and reacting said aldehyde with a nitrile of the formula l1al Hal-C-(CH2)2-O-R
CN

- 25 wherein Hal is chloro, bromo, or ~odo, the two Hal's belng the same or different, and wherein R2l is (1`) Rl~> defined as 1-ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, or rj a group of the formula H

Rl7-O-l -C-Rzo .. - I
Rla R

~)75250 wherein R17 is alkyl of one to 18 carbon atoms, inclusive,cycloalky~ of 3 to 10 carbon atoms, inclusTve, aralkyl of 7 to 12 carbon atons, incluslve, phenyl, or phenyl substituted with onc, 2, or 3 alkyl of one to 4 carbon dtoms, inclusive, wherein Rl8 and R~g are ~he same or di.~e.ent, being hydro-gen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 car-bon atoms, inclusive, or, when R,8 and Rl~ are taken together, -(CH2)a- or -(CH2)b-O-(C~2)c- wherein a is 3,- 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R20 is . hydrogen or phenyl; or (2) carboxyacyl -C(O)Rz2 wherein R22 is hydrogen or alkyl of one to 17 carbDn atoms, inclu-. sive, to form an optically active cyanoepoxide of the .15 formula O
.' ' ' ~' X I X
' .0 .. ~ ~ ~ OR
CN
or a mixture of that compound and the enantTomer thereof,.
wherein R?, and ~ are as def;ned above;
(b) transforming the produc.t of step (a) to a compound . of the formula ,, o4~

~ ~ CHO

or a mlxture of that compound and the enantiomer thereofJ
whereln ~ is as defined above, by hydrolyzing -CH2CH2-O-R2l to -CH2CH2-OH and thereafter oxldlzlng ~075250 -CH2CH2-OH to -CH2CHO;
: (c) transforming the product of step (b) to a cyano-~ epoxide of the formula o4 XXI
~

:: N
, . .or a mixture of that compound and the enant;omer thereof, wherein ~ is as defined above;
i 10(d) reacting said cyanoepoxide with formic acid to produce an optically active cyanohydrin monoformate of the :.~ formula ~ ! O
.~. _/1 ~ ~ XXII

OCHO L
~3 or a mlxture of that compound and the enantlomer thereof, ~1) wherein L~ represents either ~ " or ,~\
. HO CN HO CN;
and : (e) transforming the product of step (d) to said blcyclic lactone ketone by :, (f) removing hydrocyanic acld by dehydrocyanat;on to ' convert the molety to ~ ; and (g) replaclng formyl wlth hydroxyl, sald steps (f) ; and (g) being performed elther In the order ~f)-(g) or (9)-;: 30 (f).
,.

-~07 5ZS0 There is ~urther provided a process for preparlng an optically active bicyclic lactone ketone of the formula o ~, XXIII
~ R23 ~ o~(T~s or a mixture of that compound and the enantiomer thereof, wherein T is alkyl of one to 4 carbon atoms, ;nclusive, fluoro, chloro, trifluoromethyl, or -ORls, wherein R1s is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than t~Jo T's are other than alkyl and when s is 2 or ~ the T's are either the same or different; and wherein R23 ;s hydrogen or alkyl of one to 4 carbon atoms, inclusive; which comprises (a) starting with a bicyclic lactone cyanohydrin di-ether of the formula ~, ~
~ ~ ~ XVI I
<
: ~ H
0~ 11 or a mixture of that compound and the enantiomer thereof, wherein R~ is 1-ethoxyethyl, tetrahydropyranyl, tetrahydro- `~
furanyl, or a group o~ the formula H
R~7 O~ -R20 - , ~ ¦ , . . .

~8 ~1 wherein R~7 is alkyl of one to 17 carbon atoms, Inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, Tncluslve, phenyl, or phenyl substi-tuted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein Rl8 and Rl9 are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R18 and Rl9 are taken together, -(CH2)a- or -(CH2)b--(CH2)C- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, ~, or 4, and wherein R20 is hydrogen or phenyl; and wherein L2 represents either / " or ,'~ ; and transforming said diether : R~0 CN R1~0 CN
into an alkoxide of the formula //
' 1~ XXIV

~Rl~ L2 wherein R23 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein Rl~ and L2 are as defined above, - by successively-deprotonating and reacting the carbanion of sa;d diether with an aldehyde of the formula R23-CH0 wherein R23is as defined above;
(b) arylating the product of step (a) to form a com-` pound of the formula _~ 3230 1(~75~50 ~
~ Z 3 OR~ 2 or a mixture of that compoun~ and the enantiomer thereof, where;n R1~J R23. s, T, and L2 are as defined above;
(c) replacing the Rl6 groups with hydrogen; and (d) removing hydrocyallic acid by dehydrocyanation to convcrt the (T)s moiety to 23 ~ (T)s O
Accordingly, from the above processes there are pro^
vided new intermediates corresponding to formulas Yll, Vlll J
Xll, XIV, XVII, XVIIIJ XIX, XXJ XXI, XXII, XXIVJ and XXV
above, wherein R~2, R1~, R2l, R23, s, T, Ll, L2, and are as de~ined above.
With regard to lormulas Y to XXYI herein, alkyl groups of one to 4 carbon atoms, inclusive, include methylJ ethyl, propyl, butyl, and isomeric forms thereof. Alky1 groups of one to 17 carbon atoms, inclusive, include those given 2~ above, and pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-decyl, heptadecyl J and isomeric forms thereof. Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, which Includes. a)kyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dlmethylcyclopropyl, 2,~-dlethyl`-~' ' ' ' ~075Z50 cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclo-butyl, 3-propylcyclobutyl, 2,3,4-tr;ethylcyclobutyl, cyclo-pentyl, 2~2-dimethylcyclopentyl, 2-pentylcyclopentyl, ~-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl.
3-lsopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, 1-phenyiethyl, 2-phenylpropyl, 4-pherylbutyl, 3-phenylbutyl, 2-(1-naphthylethyl), and 1-(2-naphthyl-methyl). Examples of phenyl substituted by one to 3 chloroor alkyl of one to 4 carbon atoms, inclusive, are (o-, m-, or p-)chlorophenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, (o-, m-, or p-)tolyl, p-ethylphenyl, ; p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methyl-phenyl, and 2,4-dichloro-3-methylphenyl.
Examples of alkylene of one to 9 carbon atoms, inclu-sive, with one to 5 carbon atoms inclusive, in the chain, - within the scope of CgH2g as defined above, are methylene, ethylene, trimethylene, tetramethylene, and pentamethylene, and those alkylene with one or more alkyl substituents on one or more carbon atoms thereof, e.g. -CH(CH9)-, -C(CH3)2-, -CH(CH2CH3)-, -CH2-CH(CH3)-, -CH(CH3)-CH(CH3)-, -CHz-C(CH3 )2 -~ -CHz-CH(CH3)-CH3-~ -CH2-CH2-CH(CH2CHzCH9)-, -CH(CH3)-CH(CH3)-CH2-CH2-, -CH2-CH2-CH2-C(CH3 )2 -CH2, and 2~ -CH2-CH2-CH2-CH2-CH(CH3)-. Examples of alkylene of one to 9 carbon ato~s, inclus;~e, substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms in the cha;n, with-in the scope of Cj~2j as tefined above, are those given - - above for CgH29 and hexamethylene, including hexamethylene with one or more alkyl substituents on one or more carbon _ atoms thereof, and includlng those alkylene groups with one or 2 fluoro substituents on one or 2 carbon atoms thereof, e.g -CHF-CH2-, -CHF-CHF-, -CHz-CH2-CF2-~ -CH2-CHF-CH2-, -CH2-CH2-CF(CH3)-, -CH2-CH~-CF2-CH2-, -C~(CH9)-CH2-CH2-CHF-, -CH2-C~2-CH2-CH2-CF2-, -CHF-CH2-CH2-CH2-CH2-CHF-, -CF2-CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CF2-CH2-CH2-, and -CH2-CH2-CH2-CH2-CH2-CF2.
Examples of ~(T )s aS defined above are phenyl, (o-, m-, or p-)tolyl, (o-, m-~
or p-)ethylphenyl, (o-, m-, or p-)propylphenyl, (o-, m-, or p-)butylphenyl, (o-, m-, or p-)isobutylphenyl, (o-, m-, or p-)tert-butylphenyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-xylyl, 3,4-xylyl, 2,6-diethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-: o-tolyl, 5-ethyl-m-tolyl, 2-propyl-(o-, m-, or p-)tolyl, 4-butyl-m-tolyl~ 6-tert-butyl-m-tolyl, 4-isopropyl-2,6-.Y~ylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or - 20 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-fluoro-(o-, m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-, m-, or p-)-chlorophenyl, 2-chloro-p-tolyl, (3-, 4 -? 5-. or 6-)chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chloro-phenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3-, or 4-)chloro-2-fluorophenyl, a, a, a - trifluoro-(o-, m-, or p-)-tolyl, (o-, m-, or p-)methoxyphenyl, (o-, m-, or p-)e~hoxy-phenyl, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dTchloro-~5- or b-Jmethoxyphenyl.

-The processes descrlbed herein and the intermediates produced in the course of those processes lead to bicycllc lactone ketones V, Xl, and XXIII which are useful in ~re-paring prostaglandins or prostaglandin analogs having pharmacological activity. See the references cited above under "Background of the Invention".
~ he processes are useful for preparing said ketones within the scope of the substituent groups R,2, R23, and T
as defined herein. However, certain of said ketones are ' 10preferred for the reason that they are especially useful in preparing prostaglandins or prostagl'andin analogs having especially desirable biological response specificity, potency, and duration of activity, as well as advantageous qualities for administration by oral, sublingual, intra-vaginal, buccal or rectal methods.
For example, considering ketone Y, wherein Rl2 is ~13 "
-C-CgHzg~CH9 , it is preferred that ~gH29 be ethylene, tri~ethylene, or tetramethylene, and that Rl3 and Rl4 be hydrogen or methyl or that both R~ 3 and R1 4 be methyl or fluoro. When Rl2 in ketone V is 2~~R~3 -C-Z- ~ T)s 1 ~

- - and when Z is -oxa- (as also Tn ketone XXIII) it Is pre~
ferred that Rl'9 and R~4 be hydrogen or methyl, that "s" be zcro or one, anc~ that T be methyl, fluoro, chloro, trl-fluoromethyl, or methoxy; when Z is CjH2j, It is preferred that CjH2j be a valence bond or a chaln of one to 3 carbon atomsJ that R13 and Rl 4 be hydrogen or methyl, or that both R13 and Rl4 be methyl or fluoro, that "s" be zero or one, ; and that ~ be methyl, fluoroJ chloro, trifluoromethyl, or methoxy. In ketone XXIII it is preferred that R23 be hydro-gen or methyl.
Reference to Charts A, B, C, and D will make clear : 10 the steps by which these processes are performed and by which these compounds are obtained. In these charts, Rl2, R1~, R2~, R2s~ s, T, Ll, L2, and ~ are as defined above, namely: R12 is . (1 ) IR~ ,3 -C-Cg~29-CH3 . Rl4 (2) ~ C=C or H'' ~ H

(3) Rls -~( T ) s - Rl4 wherein CgH29 is alkylene of one to 9 carbon atoms, ;nclu-sive, with one ~o 5 carbon atoms, inc1usive, in the chain between -CRI9Rl4- and terminal methyl; wherein Rl3 and R~4 are hydrogen, alkyl of one to 4 carbon atoms, tncluslve, or fluoro, being the same or dlfferent, with the proviso _ that R~3 is f!uoro only when Rl4 is hydrogen or fluoro;
wherein ~ is alkyl of one to 4 carbon atoms, Inclusive, ~ 1075ZS0 3230 CHAR~ A

,0~ , .
- 5 ~,~ Vl CHO

1 step a .~ o O~< .
~ Vll ~R l 2 CN
~¦ step b ~"; ,~ Vlll ''' ~ , ?~Rl2 OCHO L

,0~ tep I step~ X

RI Z ¢~ RIZ
O~HO oh L 1 2~ \ step step/
~d O f L~
0'~ V

._ _ ~R~2 . .
OH . o CHART B

C,~

~COOC2Hs N

step j o~
~ ~' XIV
~COOC2Hs OH L

~Sk ep s te~

0~ q~

¢~ XV ~_~ cOXOcVlHs OH L 1 OR 1 ~ L2 tep s tep/
n ~

,C~' . ' .
/~
H X Y ~ ( ~Rl~L2 ¦ step p ~075250 ÇHART ~ (cont i nued ) l step O P
o_l~> xvl I ~

OH L

. s tep ,,., ' O ~ ~ , J~ X l ~ ., ?~ .
OH o - .

.

. _ . _ . . . . _ . . . .. , . _ . .

.. 30 -~5 -~075250 CHART C

0~
~_ Vl l step r O
,o ,4~ , ~ ' X I X

OR
CN

¦ s tep s ,o~

~CH0 CN

O ~
<~-I XX I

CN

s tep u .

~ 1075250 CHART C (cont I nued ) s tep u o '~ XXII
?~

l 5 tep v o ~ . .
~ ~ Xl f~
. OH

.

, CllAR T D
0~
~ ~ XVI I
~ H
~R~e 2 step w O, 4~ XXIV ' ~--1 R2-~
10 \~

dR le L2 o ¦ step x ' ' o~~4( \~
XXV
~3 ~ Rle L2 ~ ¦ s tep y : O ~
~ XXYI
~ ~T~5 OH Ll l s~ep 2~ O

~ R23 XXI
<~0 ~( T )s . . . . dH O

1075'~50 32~0 fluoro, chloro, trifluoromethyl, or -ORl5, wherein Rs5 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3, with the proviso that not more than two T's are other than alkyl; and wherein Z represents an oxa atom (-0-) or CjH2j, wherein CjHzi ;s a valence bond or alkylene of one to 9 carbon atoms, inclusive" substituted with zero, one, or 2 fluoro, with one to 6 carbon atoms, inclusive, between -CR13R~4- and the ring; R1~ is 1-ethoxy-ethyl, tetrahydropyranyl, ~etrahydrofuranyl, or a group of the formula I H

Rl8 R~9 wherein R~7 is alkyl of one to 17 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of ; 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substi-tuted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R18 and R~9 are the same or different, being hydrogen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R18 and R~
are taken to4ether, -(CH2)a- or -(CH2)b-0-(CH2)C- wherein a is 3, 4, or 5,-b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R20 is hydrogen or phenyl; R~ is (1) R1~ as defined above or (2) carboxyacyl -C(O)R22 wherein R22 is hydrogen or alkyl of one to 17 carbon atoms, inclusive; R23 is hydro-- gen or alkyl of one to 4 carbon atoms, lnclus1ve; L~ repre-~- ~~~~~
~0 sents / " or ,' \ ; L2 represents ~
H0 CN H0 CN R~0 CN
.

-~ 1075ZS0 3230 or ,'\ , wherein Rto is as defined above; and ~
r~. "r, ;ndicates at~achment to thc cyclopropane ring in cndo or exo configuration.
The formulas as depicted herein are intended to repre-sent those specific stereoisomers which will lead to prosta-glandins or prostaglandin analog products having the same or similar pharmacological activity as correspondtng prosta-glandins obtained from natural sources. In Charts A-D the formulas as drawn represent speci~ic optical isomers, fol-l~ lowing that convention. However, for purposes of conven-ience and brevity it is intended that such representations of the process steps for the optically active intermediates are also ap~licable to those same process steps as used for the corresponding racemic intermediates or mixtures of the - 15 enantiomeric forms of the intermediates.
Referring to Chart A, there are shown the steps by which tricyclic lactone aldehyde VI is transformed to bi-cyclic lactone ketone V. Starting material Vl is readily available. See U.S. Patent No. 3,816,462. That isomer is used which 1eads to prostaglandins having the same config-uration as prostaglandins obtained from mammalian tissues:
for example, for the endo form of aldehyde VI, m.p. 61-64 C., D-30 (see R.C. Kelly et al., J. Am. Chem. Soc. 95, 2746 (1973)). Either the endo or exo form may be used. In step "a" aldehyde VI is reacted with dihalonitrile of the formula I a 1 Hal-f _ R 12 wherein Hal is chloro, bromo, or iodo, the two Hal's being -3o-~230 ~075250 the same or different, and wherein R~2 is defined above, to form cyanoepoxide Vll.
The reagent dihalonitrile is available by methods known in the art, for example halogenation of a nitrile. Thus, 2,2-dibromoheptanenitrile is obtained ~y bromination of heptanenitrile. Alterna~ely, a dihaloaldehyde i~ converted ~o the dihalonitrile by methods known in the art, following the seguence:
c~Ja-dihaloaldehyde ~,a-dihaloacid ,`~' , ; . .
a,~-dihaloacid chloride ., ~,, .

a,a-dihaloamide ;"
a,a -dihalonitrile-Thus, 2,2-dibromo-4-phenyl-butanal is converted to 2,2-dibromo-4-phenylbutyronitrile, Br ~- ( CH2 )2 -C -CN
Br ' ' Similarly, 2,2-di-bromo-cis-4-heptenal is converted to 2,2-dibromo-cis-4-heptenenitrile, C2H5~ ~CH2-CBr2-CN
,C=C~

... _ . _ . _ . .. ... . .. . .......... .. . .
` 30 Examples of dthalonitriles useful for the purposes of `` 1075'~0 this in~en~ion as depicted in Chart A are:
2,2-dibromohexanenitrile 2,2-dichlorooctanenitrile 2,2-diiodo-3-methylhexanenitrile 2,2-dibromo-3,3-dimethylheptanenitrile 2,2-diiodo-3-fluorooctanenitrile 2,2-dibromo-3J~-difluoroheptanenitrile 2,2-dibromo-cis-4-heptenenitrile ~,2-dibron~-3-phenylpropionitrile 0 2,2-dibromo-4-phenylbutyronitrile 2,~-dichloro-4-(4-chlorophenyl)butyronitrile 2,~-dibromo-4[(3-trifluoromethyl)phenyl]butyronitrile 2,2-diiodo-4-(2-fluorophenyl)butyronitrile 2,2-dibromo-4-(4-methoxypheny)butyronitrile 2,2-dibromo^~-phenoxypropionitrile.
In "a" , the reaction o~ aldehyde V! with the dihalo-nitrile is done in the presenc~ of a reducing agent in an inert (aprotic) solvent such as tetrahydrofuran at about Q
to -15 C. For the reducing agent, trivalent phosphorus compounds are useful, including phosphines, phosphites, and phosphorous triamides. Particularly useful is hexamethyl-phosphorous triamide, ~(CH3)2N]3P. Certain metals or com- -binations of metals are also useful, including magnesium, strontium, barium, caicium, and zinc. The dihalon;trile and reduc;ng agent are used in slight excess, 5-10% over the theoretical amounts based on aldehyde Vl.
In step "b", the cyanoepoxide Vll is solvolyzed in sub-stantially anhydrous formic ac;d at about 25 C. Advan-tageously-the formic acid may be rendered anhydrous by con-tact with acet;c anhydride prior to use. An inert solvent -~2-lV75Z50 such as dichloromethane, ben~ene, or diethyl ether may be employed.
The product of step "b" is converted to the formula-V
ketone either by steps c-d or e-f. In step "c", hydrocyanic acid is removed by dehydrocyanation, e~loving a has~ stJch as an alkali metal carbonate, hydroxide or alkoxide, pre-ferably potassium carbonate, at about 25 C. either in water or in an inert liquid medium such as tetrahydrofuran or benzene In step "d" the monoformate is hydrolyzed under either acidic or basic conditions, using aqueous mineral acids or sulfonic acids, for example p-toluene-sulfonic acid, or aqueous weak bases such as alkaii metal carbonates, b;carbonates, or phosphates, preferably sodium or potassium bicarbonate, together with a lower alkanol for improved solubility. For this hydrolysis, a temperature range of 10 C. to 50 C. is operable, preferably about 25 C.
In step "e", the hydrolysis of the monoformate precedes the dehydrocyanation and for this hydrolysis acidic condi-tions are employed using aqueous mineral acids or sulfonicacids, preferably p-toluenesulfonic acid at about 10-50 C., preferably about 25 C. Finally in step "f" the dehydro-cyanation is effected as in step "c" above, for example with potassium carbonate in tetrahydrofuran or benzene or mixtures thereof at about 25 C.
In the processes of Chart A as well as Charts B, C, and D, the intermediate.products are separated from the starting materials and impurities by methods described herein or known .
in the art, tncluding partitlon extractlon, fractional crys-tallization, and silica gei column chromatography. For con ~33-venience the product of an intermed;ate step may generally be used directly without isolation or purification.
Intermediates VII, VIII and X are obtalned as various diastereomers or mixtures thereof. Although these may be separated by methods kn~wn in the art, for example ~y silica gel chromatography, such separation is generally not neces--sary for the purposes of this process as any or all of said diastereomers are useful for the purposes disclosed herein. i Thus, from optical1y active aldehyde Yl as 5 tarting material, - 10 the product V of Chart A is obtained in an optically active form. Similarly, from racem;c aldehyde VI, product V ;s obtained as a racemic mixture.
Referring to Chart B, there are shown the steps by which cyanoepoxide Xll is transformed into ketone XI. The start-ing material XII is prepared from aldehyde VI similar1y to step "a" of Chart A but replacing the dihalonitrile reagent w;th the ethyl ester of dibromocyanoacetic acid:
0 Br .' 1~ ~ .
C2HsO-C-C-CN . . . -.
Br The react~on is carried out in an inert solvent in the pres-ence of a reducing agent, preferably hexamethylphosphorous triamide, at about 0 to -15 C.
In step "j", the cyanoepoxide XI1 is solvo~yzed in formic acid as discussed above for step "a" of Chart A.
The product of step "j" is converted to cyanohydrin diether XVII either by steps k-l or m-n. In step "k", carb-ethoxy cyanohydrin XIV is hydrolyzed to effectively cleave the ester and decarboxylate to compound XV. Dllute mlneral ~0 acld and a mtscible solvent such as tetrahydrofuran are -34 ~

---- 3~30 used. In step "l" cyanohydrin XV is converted to diether XVII as follows.
When R~ is tetrahydropyranyl or tetrahydrofuranyl, the appropriate reagent, e.g. 2,3-dihydropyran or 2,3-di-hydrofuran, is used in an inert solven~. such as dichloro-methane, in the presence of an acid condensing agent such as p-toluenesulfonic acid or pyridine hydrochloride. ~he reagent is used in slight excess, preferably 1.0 to 1.2 times theory. The reaction is carried out at about 20-50 C.
When Rl~ is of the formula Rl7-0-~(RlB)-CHRl~R~o~ as defined above, the appropriate reagent is a vinyl ether, e.g. ethyl vinyl ether or any vinyl ether of the formula Rl7-0-C(Rl8)=CR19R20 wherein Rl7, Rl8, Rl9, and R20 are as defined above; or an unsaturated cyclic or heterocyclic compound, e.g. 1-cyclchexen-1-yl methyl ether CH30 ~
or 5,6-dihydro-4-methoxy-2H-pyran CH30- ~
See C.B. Reese et al., J. Am~ Chem. Soc. 89, ~66 (1967).
The reaction conditions for such vinyl ethers and unsatu-rates are similar to those for dihydropy~an above.
In step "m", the etherification precedes the decarboxy-lation using the conditions and reagents for step "l" above.
In step "n'~, the conversion to compound XVII ts done con-veniently in dimethyl sulfoxide in the presence of sodium cyanide at temperatures above 120 C., preferably at about - -- - ---- 160 C. ~ ~-~~ ~~ ~ ~~
3 In step "p", the three successive reactions of depro-~35~

--` 1075250 tonating, alkylating with 1-bromo-cis-2-pentene, and de-blocking are carried out. Deprotonation to form a carbanion is done with an alkali metal amide, preferably lithium di-isopropylamide, in an inert (aprotic) sol~ent such as tetra-hydrofuran at below about -40 C. Alkyldtion occurs readi'y on addition of 1-bromo-cis-2-pentene. Deblocking (for example, replacement of 1-ethoxy-ethoxy groups with hydroxy) is done under midly acidic conditions using for example aqueous organic acids such as acetic or citric acid at pH
2.0 at about 25-~0 C.
In step "q", dehydrocyanation is achieved as for steps "c" and "f" in Chart A, for example by contacting the formula-XVIII compound with dilute aqueous sodium bicarbonate at about 25 C.
Referring to Chart C, there are shown the steps for an alternate process by which aldehyde VI is transformed into ketone XI. In this process the key intermediate XX is an aldehyde which is subjected to a Wittig alkylation at step "t" to extend the side chain.
In step "r", aldehyde Vl is reacted with a dihalobutyro-nitrile of the formu~a ~Hal Hal-C-(CHz )2 - -R2 1 .
CN
wherein R2~ is (1) R~ as defined above or (2) carboxyacyl -C(0)~22 wherein R22 is hydrogen or alky1 of one to 17 car-bon atoms, inclusive. Examples of the reagent are the 2l2-dibromo-4-hydroxybutyronitri)e ester of acetic actd:
,, . - .
- __ , 0 8r 3o CH9C-0-(CH2 )2 -t -CN
Br 32~0 10752~0 and the 1-ethoxyethyl ether of 2~2-dibromo-4-hydroxybutyro-nitrile:
Ir C2~5-CH2-0-(CH2 )2 -C -CN
CH3 Pr The conditions for this reaction, done in the presence of a reducing agent such as hexamethylphosphorous triamide, are essentially the same as for step "a" of Chart A.
In step "s", cyanoepoxide XIX is hydrolyzed to replace R2~ with hydro~en, using conditions suitable for hydrolysis of esters or ethers. See, for example, step "d" and step "p", above, as to deblocking. The alcohol moiety thus formed is then oxidized to an aldehyde moiety by methods known in the art, for example with Collins reagent (Tetra-hedron Lett. 3366~ (1968)).
In step "t", the aldehyde compound XX is alkylated with an ylid by the Wittig reaction. The ylid is preferably formed from propyltriphenylphosphonium bromide and butyl1ithium using methods known in the art.
In step "u", cyanoepoxide XXI is solvolyzed in formic acid. See step "b" of Chart A above.
In step "v", monoformate XXII is converted to ketone Xl either by first dehydrocyanating and then hydrolyzing the monoformate or by the reverse order. See steps c-d and e-f of Chart A discussed above.
Referring to Chart D, there are shown the steps by wh~ch cyanohydrin XVII (of Chart 8) is transformed ~o ~ ketone XXIII. Ketone XXIII Is a useful intermedlate In ~ ~~~~
preparing 16-phenoxy-PGF2~-type analogs.

:~2~0 1075;~50 In step "w" two successive reactions are carried out:
deprotonating and reacting the carbanion thus produced with an aldehyde of the formula R23CHO wherein R23 is hydrogen or alkyl of one to 4 carbon atoms, inclusive. The condi-tions for deprotonating are those used above in ste~ "p"of Chart B. The reaction with the aldehyde is done under anhydrous conditions, generally in an inert solvent such as tetrahydrofuran at about 25 C.
- In step "x", alkoxide anion XXIV of step "w" is arylated, - 10 for example by reaction with diphenyliodonium bromide or other suitable substituted phenyliodonium halide to provide the terminal group:
`'' ~--(T)S

wherein T and s are as defined above. See for example Fieser et al., Reagents for Organic Synthesis, Vol. 1, p. 340, Wiley, New York, (1967).
In step "y", cyanohydrin diether XXV is deblocked to replace R1~ groups with hydrogen, preferably using mildly 2G acidic conditions. See step "p" of Chart B.
Finally, in step "z" the cyanohydrin XXVI i~ converted by dehydrocyanation to ketone XXIII. See step "q" of Chart B. Those formula-XXIII ketones wherein R23 is not hydrogen exist as two epimers, both having the same configuration at the other asymmetric cent~rs. These are separable by methods commonly applied to diastereomers, for example silica gel chromatography.
In the processes of Charts B, C, and D, as for Chart A, the-products~XI and XXIII are optically actlve tf derlved from optlcally actlve aldehyde Vl, and racemtc If dertved from racemic aldehyde Vl.
For convenience herein, names of racemic intermediates or products include the prefix "racemlc" ("rac" or "dl");
when ~hat prefix is absent, the intent is to designate an optically active compound.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention can be more fully understood by the fol-lowing examples.
All temperatures are in degrees centigrade.
Infrared absorption spectra are recorded on a Perkin-Elmer Model 257 infrared spectrophotometer. Except when specified otherwise, chloroform solutions are used.
NMR spectra are recorded on a Varian A-60, A-60D, or T-60 spectrophotometer using deuterochloroform solutions with tetramethylsilane as an internal standard (downfield).
Mass spectra are recorded on a Varian Model MAT CH7 mass spectrometer or an LKB Model 9000 Gas Chromatograph-Mass Spectrometer (ionization voltage 70 ev) "Brine", herein, refers to an aqueous saturated sodium chloride solution.
Silica gel chromatography, as used herein, is under-stood to include elution, collection of fractions, and com-bination of those fractions shown by TLC (thin layer chroma-tography) to contain the desired product free of starting material and impurities.
Ske1lysolve~ consists of mixed isomeric hexanes.
Example 1 2,2-Dibromoheptanenitrile 8romine (14 ml.) is added to heptanenltrlle, CH9(CH2)sCN
(26.64 9.) at 16-38 C., followed by phosphorus trlbromide (3.75 ml.) added in four portions. The mixture Is heated ~39-3~30 ~075Z50 at 60-80 C. for 45 min. Additional bromine (24 ml.) is ad<~e~ within 1() nlin. The heating bath temperature is ra;sed so that the reaction tcmperature is 88 C. for about 30 min. Th~ mixture is coole~ and shciken with a mixture of 5 cold 9% sodium sulfite solution and Skellysolve 8. The organic phase is washed with 20% aqueous su1fate, dried ov~r sodium sul~ate, and concentrated. Distillation yields the title compound, 36.47 9., b.p. 52-~7~ C.
Example 2 Tricyclic Lactone Cyanoepoxide (Formula Vll wherein Rl2 is n-pentyl and ~ is endo).
Refer to Chart A, step "a". The formula-VII tricyclic lactone cyanoepoxide, name!y 6-endo-(3-cyano-3-pentyl -2-oxiranyl)-3-exo-hydroxybicyclo[3.1.0]hexane-2-exo-acetic acid, y-lactone, is prepared as follows. A mixture of the formula-Vl endo tricyclic lactone aldehyde (U.S. Patent 3,816,462, 4.0 9.), 2,2-dibromoheptanenitrile (Example 1, 7.75 9. ), and 35 ml. of tetrahydrofuran is cooled to -~5 C. and treated with hexamethylphosphorous triamide (5.26 ml. ) in portions of about 0.5 ml. every 5 min., with the reaction temperature at -8 to -14Q C. The mixture Ts stirred 2 hr.
at a temperature of -10 to 0 C. The mixture is then shaken with 180 ml. of toluene and ~0 ml. of brine. The organic phase is concentrated under reduced pressure to the formula-VII title compound, an oil, 8.54 9., having ~ 0.42 (TLC on silica ~el in ethyl acetate-benzene ~1:4));
mass spectral peaks at 275, 246, and 217; infrared a~sorp-tion at 2960, 2935, 2B62, 2253, 1770, 1460, and 1190 cm ';
and NMR peaks at 4.9, 3.2-2.5, 2.3, 2.0-1.2, and 1.0 ~;
Example 3 Bicyclic Lactone Cyanohydrin Monoformate ~ (Formula Vlll wherein Rl2 Is n-pentyl) ~2~0 Refer to Ch~r~ A, step "b". The formula-VIII bicyclic cyanohydrin ~nonororn~tc, namely 2~-(3-cyano-3-hydroxy-1-octenyl)-3~-(formyloxy)-5a-hydroxy -la -cyC lopentaneacetic acid, y-lactone~ is pr~pared as follows. A soiu~ion of the formula-Vll cyanoepoxide (Example 2, 148 mg.) in C,2 ml. of d7chloro methane is added to a mixture of anhydrous formic dCi d (0.95 ml ) and acetic anhydride (0.05 ml.) previously stir-red for 0.5 hr. The reaction mixture is then stirred at about 25 C. for one hr. whereupon water (2.0 ml.) sodium carbonate (o.685 g ) and ethyl acetate ~15 ml.) are added.
The upper organic phase is washed with lN.sodium bicarbonate (4.0 ml.) and both aqueous layers are washed with additional ethyl acetate (10 ml.). The combined organic extracts are dried and concentrated to yield the formula-VIII title com-pound in about 80~ purity, 150 mg. Fureher purification by silica gel chromatography, eluting with ethyl acetate-benzene (1:4), yields the title compound, 75 mg.; having infrared absorption at 3580 -3210, 3013, 2960, 2941, 2872, 2263, 1771, 1724, 1182, and 925 cm 1 ~nd NMR peaks at 8.oo, 5.45-5.42, 5.25-4.90, 2.46-2.40, 2.40-1.08, and 0.91 6, Example 4 Bicyclic Lactone Monoformate (Formula IX
wherein R12 is n-pentyl).
Refer to Chart A, step "c". The formula-lX bicyclic lactone monoformate, namely 3a-(formyloxy)-5a-hydroxy-2~--(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid, y-lactone, is prepared as follows.
A mixture of the formula-~lll bicycltc lactone cyano-hydrin monoformate ~xample 3, 200 mg.) in tetrahydrofuran ~4.0 ml.) is treated with 200 mg. of potassium carbonate and stirred at about ~5 C. for 3.5 hr. The mixture is diluted with benzene (7 ml.), filtered, and concentrated to yield the formula-lX title compound, an oil, 190 mg., having infrared absorption at 2987, 2937, 1773, 1725, 1671, 1630, 1240, and 1178 cm 1; and NMR peaks at ~.0, 6.6, 6.2, 5.1, 4.7-3.5, 3.5-1.9, and 3.6 ~.
The formula-lX bicyclic lactone monoformate of Example 4 is converted to PGF2~ by (a) reducing with excess z;nc borohydride in dimethoxyethane at about 20 C. for 0.5 hr., (b) separating the 3-hydroxy epimers thereby formed, using silica ~el chromatography, (c) deformylating by contacting the appropriate 3a-hydroxy epimer with water and p-toluene-sulfonic acid in tetrahydrofuran at about 25-40 C. to yield the corresponding bicyclic lactone diol, and (d) transforming the diol to PGF2a by methods known in the art. See E.J.
Corey et al , J. Am. Chem. Soc. 92, 397 (1970).
Example 5 Bicyclic Lactone Ketone (Formula V wherein R~2 i s n-pentyr ) .
Refer to Chart A, step "d". The formula-V brcyclic lactone ketone, namely 3aJ5a-dihydroxy-2B-(3-oxo-trans-1-octenyl)-la-cyclopentaneacetic acid, y-lactone, is prepared as follows. A mixture of the formul3-lX bicyclic lactone monoformate (Example 4, 0.10 g.), 1 ml. of tetrahydrofuran, 0.05 ml. of water, and p-toluenesulfonic acid monohydrate -~
(0.010 g.) is stirred at about 25 C. for i7 hr. Then 0.05 ml. of water is added and stirring ts continued at 40 C.
for 7 hr. The mixture is diluted with benzene and washed with dilute aqueous sodium bicarbonate. The organic phase is dried and concentrated to yield the title compound, o.o8 g., having Rf 0.27 (TLC on si)ica gel in ethyl acetate-benzene (1 1)); in~rared absorption at 3605-3250, 3030, 3000, 2962, 2938, 28~, 1768, 1691, 1626! 1180, 1092, and 993 cm mass spectral peaks (TMS derivative) at 338, 323, 295, 281, 267, 248, 239, 221, 166, 145, 99, and 73; and NMR peaks at

6.99. 6.17, 4.95, 4.14, 3.25-2.9, 2.83-1.85, 1.76-1.07, and 5 o.88 ~.
The formula-V bicyclic lactone ketone of Example 5 is converted to PGF2a by (a) benzoylating with benzoyl chloride in pyridine at about 20-40 C. thereby forming 3~-benzoxy-5a-hydroxy-2~3-(3-oxo-trans-1-octenyl )-la-cyc'lopentaneactic acid, y-lactone, (b) forming the corresponding bicyclic lactone diol, and ~c) transforming the diol to PGF2a. See U.S. Patent No. 3,778,450.
Example 6 Bicyclic Lactone Cyanohydrin (Formula X
wherein R 12 is n-pentyl).
Refer to Chart A, step "e". The formula-X bicyclic lactone cyanohydrin, namely 2a-(3-cyano -3 -hydroxy-1-octenyl)-3a,5a-dihydroxy-1a-cyclopentaneacetic acid, y-lactone, is prepared as follows. ~he formula-VIII bicyclic lactone cyano-hydrin monoformate (Example 3, 150 mg.) is dissolved in acetone (2 ml.), water (0.05 ml.) and p-toluenesulfonic acid (1 mg.), and the mixture is stirred at about 25 C. for 19 . hr. Thereafter the mixture is extracted with ethyl acetate, dried, and concentrated to yield the formula-X title compound, an oil, 120 mg., having mass spectral peaks (TMS derivative) at 437, 442, 410, 367, 239, and 197; infrared absorption at 3600-3150, 3012, 2960, 2941, 2872, 1769, 1460, 1180, 984, and 922 cm ~; and NMR peaks at 5.78, 4.95, 3.90-4.45, 2.51-2.70, 1.14-2.35, and 0.91 ~.
Example 7 Bicyclic Lactone Ketone (Formula V where;n R~2 is n-pentyl).
~43-~30 10'7S250 Re~er to Chart A, steps "b", "c", and "d". The formula-V bicyclic lactone ketone, namsly ~a,5a-dlhydroxy-2~-(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetlc acid, y-lactone, is prepared as follows.
I. The formula-VIII bicycllc lactone cyanohydrin mono-formate wherein R~2 is n-pentyl is first ptepared. A solu-tion of the formula-VII cyanoepoxide (Example 2, 8.54 9.) in

7 ml. dichloromethane is added to a mixture of anhydrous formic acid (44.4 ml.) and acetic anhydride (1.16 ml.) pre-viously stirred for 0.5 hr. The reaction mixture is then stirred at about 25 C. for 23 hr., concentrated, and the resulting cyanohydrin monoformate used directly.
Il. The product of part I is taken up in tetrahydro-furan (72 ml.) and treated with 24 ml. of 10~ sulfuric acid, with stirring continued at about 25 C. for 21 hr.
Thereafter sodium carbonate (2.18 9.) is added and the tetrahydrofuran removed under reduced pressure. The resi-due is extracted with ethyl acetate and the resulting ethyl acetate solution is backwashed with water (60 ml.) and then lN. sodium bicarbonate solut;on. The aqueous phases are backwashed with ethyl acetate and all of the ethyl ace~ate extracts are combined, stirred with lN. sodium bicarbonate solu~ion and separated. The upper (organic) layer is washed w;th brine, dried.over sodium sulfate, and concentrated to yield the formula-Y title compound, 7.19 g. in about 65%
purity.
The formula-V product is further-purified either by silica gel chromatography, or, preferably, by liquid-ltqu;d extraction followed by crystallization, as follows.
~0 Ill. A solutton of ~he formula-V ketone ofpart I

(6.~8 g.) in 1(~ ml. of ethyl acetate is subjected to a multi-stage liquid-l;quid extraction. Each stage contains a lower phase (412 ml.) and an upper phase (206 ml.) from equilibrated acetone-Skellysolve B (isomeric hexanes)-water (1:1:1).
The impurities are concentrated in the upper phase.
The product is obtained by concentrating the lower phase and extracting with ethyl acetate (washing each extract with brine). The ethyl acetate solution is dried over sodium sulfate and concentrated to yield the formula-V title com-pound, 5.707 9. in about 80~ purity.
IV. Further purification is achieved by crystallization as follows. A solution of the formula-V compound from part lll (5.626 9.) in tetrahydrofuran (4.0 ml.) and isopropyl ether (15 ml.) is cooled to -15 C. and seeded. Additional isopropyl ether (25 ml.) is added slowly while cooling at -25 C. The resulting solid is washed with cold ;sopropyl ether (5 ml.) and dried. The resulting semisolid product (4.688 9.) is recrystallized from tetrahydrofuran (2.4 ml.) and isopropyl ether (5.0 ml.) as above to yield the formula-V
title compound, 4.1147 9. Additional product is obtained ~rom the mother liquors by silica gel chromatography, eluting with ethyl acetate-benzene (1:4) 0.514 9.
Example 8 Bicyclic Lactone Ketone (Formula V wherein Rl2 is n-pentyl).
Refer to Chart A, step "f". The formula-V bicyclic lactone ketone, namely 3a,5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-la-cyclopentane-acetic acid, y-1actone, Is pre-pared as follows. A mixture of the ~ormula-X bicycllc lactone cyanohydrin (Example 6, 4.35 9.) in 45 ml. o~

1075'~50 tetrahydrofuran and 45 ml. of benzene, with potassium carbonate (4.5 9.), is stirred at about 25 C. for 21 hr.
The mixture is diluted with benzene (100 ml.), flltered, and concentrated to an cil, 3.618 9. The oil is subjected to silica gel chromatography, eluti~g with ethyl acetate-benzene (1:4), and concentrating to yield the fo.rmula-V
title compound, an oil, 1.4753 9., having the same properties as reported above ;n Example 5.
Following the procedures of Examples 1-8 but replacing heptanenitrile with 3,3-dimethylheptanenitrile, there is first obtained 2,2-dibromo-3,3-dimethylheptanenitrile which is further reacted as in Example 2 to yield the formula-VII 6-endo{3-cyano-3-(1,1-dimethylpentyl)-2-oxiranyl]-3-exo-hydroxybicyclo-[3.1.0lhexane-2-exo-acetic acid, y-lactonei there is finally obtained the corresponding formula-V bicyclic lactone ketone wherein R12 is -e -(CH2) 3 -CHs name1y 3a,5a-dihydroxy-2~-(4,4-dimethyl-3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid, y-lactone. That ketone is useful in preparing 16,16-dimethyl-PGF2a by methods known in tHe art.
Likewise following the procedures of Examples 1-8 but replacing heptanenitrile with 3,~-difluoroheptanenitrlte, there is finally obtained the corresponding formula-V
bicyclic lactone ketone wherein Rl2 is -CF2-(CH2)9-CH3, nameIy 3a,~a-dihydroxy-2~-(4,4-difluoro-3-oxo-trans-1-octenyl3-1~-cyclopentaneacetic acid, y-lactone, use~ul for 3 prepartng 16~16-d;fluoro-PGF2a by methods known In the art.

~230 10'75Z~O

Following the procedures o~ Example 2-8 but replacing 2,2-dibromoheptanenitrile with 2,2-dibromo-4-phenylbutyro-nitrile, there is obtained the corresponding formula-V bi-cyc)ic lactone ketone whcrein Rl2 is -(CH2)2- ~ , namely 3a)5~-dihydroxy-2~-(3-oxo-5-pheny)-trans-1-pentenyl)-l~-cyclopentaneacetic acid, y-lactone, useful for preparing 17-phenyl-18,19,20-trinor-PGF2~ by methods known in the art.
Likewise ~o)lowing the procedures of Examples 2-8 but replacing 2,2-dibromoheptanenitrile with each of the fol-lowing dihalonitriles:
(a) 2,2-dibromohexanenitrile (b) 2,2-dichlorooctanenitrile (c) 2,2-diiodo-3-methylhexanenitrile (d ) 2,2 -di i odo-3-fluorooctanenitrile (e) 2,2-dibromo-cis-4-heptenenitrile (f ) 2,2-di bromo-3-phenylpropionitrile (9) 2,2-dichloro-4-(4-chlorophenyl)butyronitrile (h) 2,2-dibromo-4-r(3-trifluoromethyl)phenyl~butyro-nitrile (i) 2,2-diiodo-4-(2-fluorophenyl)butyronitrile (~) 2,2-dibromo-4-(4-methoxyphenyl)butyronitrile (k) 2,2-dibromo-3-phenoxypropionitrile, there are obtained the corresponding formula-Y blcyclic lactone ketones wherein R12 is, respective)y:
(a) -(CH2~3-CH9 (b ~ - (CH2 )5 -Cff3 3 (c) -CH(CH3)-(CHz )2 -CH9 ~47-~075250 (d) -CHF-~CH2)~-CH3 (e) -CH2~ C C~ C2Hs H~ ` H

tf) -CH

(g) -CH2 )2 -~-C 1 (h ) - (C~2 )2 - ~ F3 (j) -(CH2 )2-~

(j ) -(cH2)2-~o-cH3 (k) -CH2-0 ~

Following the procedures of Examples 2-8 and of the paragraphs following Example 8 but replacing the endo form of the formula-VI aldehyde with the exo form, the correspond-ing formula-VII exo tricyclic lactone cyanoepoxides are.
obtained which are finally converted to the formula-V
bicyclic lactone ketones.
Also following the procedures of Examples 2-8 and of the paragraphs following Example 8, but replacing the opti-cally active formula-VI aldehyde with the racemic m7xture of either the endo or exo form, there are obtained the racemic mixtures corresponding to the compounds of formulaS
V, Vll, Vlll, IX, and X.
Example~ Tricyclic Lactone Cyanoepoxide (Formula Xll whereTn ~ Is endo).

Re~er to Chart B, The formula-XII trlcyclic lactone cyanoepoxide, namely 6-endo-(3-carbethoxy-3-cyano-2-oxiranyl)-3-exo-hydroxybicyclo[3.1.0]hexane-2-exo-acetic aci4 y-lactone, is prepared as follows. A mixture of the formula-VI (Chart A) endo tricyclic lactone aldehyde (U,S.
Patent 3,816,462, 166 9.), the ethyl ester of dibromocyano-acetic acid (2.98 9.), and 35 ml. of tetrahydrofuran pre-viously cooled to -10 C. is treated dropwise with hexa-methylphosphorous triamide (1.79 9.) added ~ropwise.- After complete reaction, as shown by TLC, the mixture is worked up to yie;d the title compound, as isomeric epoxides.
Example 10 Bicyclic Lactone Carbethoxy Cyanohydrin -(Formula XIV).
Refer to Chart B, step "j". The formula-XlV bicyclic lactone carbethoxy cyanohydrin, namely ?~-(3-carbethoxy-3-cyano-3-hydroxy-1-propenyl)-3a,5a-dihydroxy -la-cyc 10pentane-acetic acid, y-lactone, is prepared as follows. ~The formula-Xll tricyclic lactone cyanoepoxide (Example 9) is dissolved in a minimum volume of dichloromethane and, using a mixture of anhydrous formic acid and acetic anhydride following the procedure of Example 3, transformed to the 3-monoformate of the title compound. After replacement of formyl with hydroxyl by hydrolysis with dilute sulfuric acid in tetra-hydrofuran solution and work-up as Tn Example 6, the t;tle compound is obtained.
Example 11 Bicycl;c Lactone Cyanohydrin (Formula XV).
Refer to Chart 8, step "k", The formula-XV bicyclic lactone cyanohydrin, namely 2~-(3-cyano-3-hydroxy-1-pro-penyl~-3a,5a-dihydroxy-la-cyclopentaneacetic acid, y-3 lactone, is prepared as follows, The formula-XlV bicyclic , ;1075250 lactone carbethoxy cyanohydrin (Example 10) is hydrolyzed under vigorous conditions in dilute sulfuric acid and tetrahydrofuran so that ester cleavage and decarboxylation occur to yield the title compound. Example 12 Bicyclic Lactone Cyanohydrin Diether (Formula XVII wherein R~ is 1-ethoxyethyl).
Refer to Chart B. The formula-XVII bicyclic lactone cyanohydrin diether namely2~-L3-cyano-3-(1-ethoxyethoxy)-i-propenyl]-3a-(1-ethoxyethyl)-5a-hydroxy-1a-cyclopentane-acetic acid, y-lactone, is prepared as follows.
I. Refer to step "l". The formula-XV bicyclic lactone cyanohydrin (Example 11, 2.2 9. ) in 72 ml, of toluene is cooled to -10 C. and treated with 9.6 ml. of ethyl vinyt ether and p-toluenesulfonic acid (5 mg.). After the reaction is complete, after about 18 hr. at -10 to 0 C., excess reagent is removed under reduced pressure and the catalyst is neutralized with triethylamine. The mixture is concen-trated to yield the title compound.
Il. Refer to step "m". Alternately, there is first prepared the formula-XVI bicyclic lactone carbethoxy cyano-hydrin diether, namely 2B-~3-carbethoxy 3-cyano-(1-3-ethoxy-ethoxy)-1-propenyl~ -(1-ethoxyeth~xy)-5~-hydroxy -la-cyc 1 o-pentaneacetic acid, y-lactone as follows. The formula-XIV
bicyclic lactone-carbethoxy cyanohydrin (Example 10) is 2~ treated with ethyl vinyl ether, following the procedure in part I above.
lil. Refer to step "n". Next, the title compound is prepared by decarboxylation as follows. The formula-XVI di-ether of Part ll above (1.0 9.) is treated in dimethyl sul-3 foxide (10 ml.) with sodium cyanide (0.2 9.) and heated to -5o-la 75~50 3230 160 C. The reaction mixture is diluted with 30 ml. of water and extracted with benzene. The organic extract is backwashed with brine, dried, and concentrated under re-duced pressure to yield the title compound.
Example 1~ Bicyclic Lactone Cyanohydrin (Formula XVIII).
Re~er to Chart B, step "p". The formula-XVII bicyclic lactone cyanohydrin, namely 2~-(3-cyano-3-hydroxy-trans-1, cis-5-octadienyl)-3a,5~-dihydroxy-la-cyclopentaneacetic acid, y-lactone is prepared as follows.
I. Deprotonation.
The formula-XVII bicyclic lactone cyanohydrin diether (Example 12, 3.67 9.) in tetrahydrofuran is treated at about -78 C. with lithium diisopropylamide (10 mmole) and the mixture warmed to -40 C.
Il. Alkylation and Deblocking.
The anion of part I above in tetrahydrofuran solution is treated with 1-bromo-cis-2-pentene (1.48 9.). After reaction is complete as shown by TLC, aqueous citric acid is added to pH 2.0 and the mixture is stirred at 30 C. for about 4 hr. to effect deblocking (replacement of 1-ethoxy-ethoxy groups with hydroxy). The mixture is concentrated under reduced pressure to remove tetrahydrofuran. Ethyl acetate (10 ml.) is added, the phases are separated, and the aqueous layer again extracted with ethyl acetate. The combined organic extracts are concentrated under reduced pressure to yield the t;tle compound.
xamp1e 14 8icyclic ~actone Ketone (Formula Xl).
Refer to Chart B, step "q". The formula-XI bicyclic lactone ketone, namely 3a,5a-dihydroxy-2~-(3-oxo-trans-1, 3 cis-5-octadienyl)-1~-cyclopentaneacetic acid, r-lactone, is prepal-ed as follows. The formula-XVIII bicyclic lactone cyanohydrln (Example 13)in ethyl acetate is sti~rred with lN. sodium bicarbonate (10 ml.) at about 25 C. for 4 hr.
to effect dehydrocyanation. The organic phase is separate(~, dried over sodium sulfate, and concèntrated to obtain the title compound.
Example 15 Bicyclic Lactone Ketone (Formula Xl) Refer to Chart C. The formula-XI bicyclic lactone ketone, namely 3~,5~-dihydroxy-2~-(3-oxo-trans-1,cis-5-octadienyl)-la-cyclopen~aneacetic acid, y-lactone, is pre-pared as follows.
I. Refer tO step "r". A mixture of the formula-VI
endo tricyclic lactone aldehyde (4.0 g.), the 2,2-dibromo-~-hydroxybutyronitrile ester of acetic acid (8.2 9.), and ~5 ml. of tetrahydrofuran is cooled to -15 C. and treated with hexamethylphosphorous triamide (5.26 ml.) in portions at about -10 C~J continuing stirring for an additional 2 hr. at 10 C. The mixture is worked up to yield the formula-XIX cyanoepoxide.
Il. Refer to step "s". The product of part I is -hydrolyzed in d;lute sulfuric acid to replace thP acetyl group (R2l) with hydrogen. Thereafter, using Collins reagent (Tetr. Lett. 336~ (1968)) in dichloromethane at about 0 C., the formula-XX aldehyde is obtained.
Ill. Refer to step "t". The product of part ll ;s subjected to Wittig alkylation, adding it to a suspension of propyltriphenylphosphonium bromide in benzene containing the equivalent amount of n-butyllithium. The mixture is finally heated at about 50-70 C. for 2.5 hr. The mixture is cooled and filtered, and the solids washed with benzene.

, 107525~D 32~0 The combined filtrate and washes are concentra~ed somewhat, then washed with dilute hydrochloric acid and water. The organic phase is dried and concentrated to yield the formula-XXI cyanoepoxide.
9 IV. Refer to step "u". The product of part lll is added to a mixture of anhydrous formic acid (2.0 ml.) and acetic anhydride (0.1 ml.) previously stirred for 0.5 hr.
The mixture is then stirred at about 25 C. for one hr. and quenched with aqueous sodium carbonate. The product is ex-~10 tracted into ethyl acetate and worked up to yield the formula-XXII cyanohydrin monoformate.
Y. Refer to step "v". Thereafter, the product of part IV is first hydrolyzed in tetrahydrofuran wTth 10~
sulfuric acid at about 40 C. The solvent is removed and the residue extracted with ethyl acetate. The formyl-free cyanohydrin obtained by concentration is then contacted wtth potassium carbonate in tetrahydrofuran and benzene at about 25 C. for 21 hr. to produce the formula-XI ketone.
Example 16 B;cyclic Lactone Ketone (Formula XXIII
wherein R23 is hydrogen and "s" is zero).
Refer to Chart D. The formula-XXIII bicyclic lactone ketone, namely 3a,9a-d;hydroxy-2~-(3-oxo-4-phenoxy-trans-l-butenyl)-la-cyclopentaneacetic acid, y-lactone is pre-pared as follows.
I. Refer to step "w". The formula-XYII b;cyclic lactone cyanohytrin diether (Example 12, 3.67 9.) is de-protonated following the procedure of Example 13, part 1.
Then, to a solution of the an;on in tetrahydrofuran is added gaseous formaldehyde formed by pyrolyzing paraform-3 aldehyde. The resulttng formula-XXlV al~oxide wherein R

1075'~50 is hydrogen and "s" is zero is used directly without iso-lation.
,I. Refer to step "x". The reaction mixture of part I is arylated by treatment with diphenyliodonium bromide.
See Fieser et al., Rea~ents for Organic Synthesis, Vol. 1, p. 340, Wiley, New York (1967). The formula-XXV diether is isolated, either by extraction or chromatography.
Ill. Refer to step "y". The formula-XXVI cyanohydrin is obtained by deblocking the product of part ll. A mixture of the formula-XXV diether (0.5 9.) in tetrahydrofuran (10 ml. with aqueous citric acid (ca. 2N.) added to pH 2.0 is stirred at about 30 C. until the reaction is complete as shown by TLC. The tetrahydrofuran is removed under reduced pressure, and the remainder is extracted repeatedly with ethyl acetate. The combined extracts contain the formula-XXVI cyanohydrin wherein R23 is hydrogen and "s" is zero.
IV. Refer to step "z". Finally, the title compound is obtained by dehydrocyanation of the product of part lll in aqueous sodium bicarbonate (10 ml.,lN) for 4 hr. at about 25 C. The phases are separated and the organic phase is dried and concentrated under reduced pressure to yield the formula-XXIII bicyclic lactone ketone.
Following the procedures of Example 16 but replacing formaldehyde in step I with acetaldehyde, there is obtained the corresponding formula-XXIII bicyclic lactone ketone in which R29 is methyl, namely 3a~5a-dihydroxy-2~-(3-oxo-4-meth 4-phenoxy-trans-1-butenyl)-la-cyclopentaneacetic acid, y-lactone.
Likewise following the procedures of Example 16 but replacing the optically active formula-XVII start;ng mate ~ -54-~ 3230 ria1 with the corrcsponding raccmic mixture, there are ob-tained the racemic mixtures corresponding to the compounds of formulas XXIII, XXIV, XXV, and XXVI.
This application is a division of copending Canadian application Serial No. 247,284, filed March 5, 1976.

Claims (2)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing an optically active bicyclic lactone ketone of the formula (XXIII) or a mixture of that compound and the enantiomer thereof, wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or -OR15, wherein R15 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; and wherein R23 is hydrogen or alkyl of one to 4 carbon atoms, inclusive; which comprises (a) starting with a bicyclic lactone cyanohydrin diether of the formula or a mixture of that compound and the enantiomer thereof, wherein L2 is or ; and wherein R16 is 1-ethoxyethyl, tetrahydropyranyl, tetrahydro-furanyl, or a group of the formula wherein R17 is alkyl of one to 17 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, inclusive, wherein R18 and R19 are the same or different, being hydro-gen, alkyl of one to 4 carbon atoms, inclusive, phenyl or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive, or, when R18 and R19 are taken together, -(CH2)a- or -(CH2)b-0-(CH2)c- wherein a is 3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with the proviso that b plus c is 2, 3, or 4, and wherein R20 is hydrogen or phenyl;
and transforming said diether into an alkoxide anion of the formula wherein R23 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and wherein L2 and R16 are as defined above, by successively deprotonating the diether to form a carbanion and reacting said carbanion with an aldehyde of the formula R23-CHO wherein R23 is as defined above;
(b) arylating the product of step (a) to form a compound of the formula or a mixture of that compound and the enantiomer thereof, wherein L2, R16, R23, s, and T are as defined above;
(c) replacing the R16 groups with hydrogen; and (d) removing hydrocyanic acid by dehydrocyanation to convert the thus-formed moiety wherein L1 represents or ; to

2. An optically active bicyclic lactone ketone of the formula wherein R23, T and s are as defined in claim 1, whenever pre-pared or produced by the process defined in claim 1 or by the obvious chemical equivalent.