The present specification provides novel intermediates and novel processes for the synthesis of Thromboxane B.sub.2 (11a-homo-11a-oxa-PGF.sub.2.sub..alpha.), its 15-epimer, and various carboxyl derivatives thereof. In particular, there are disclosed various bicyclic tetrahydropyran-containing lactones useful in the above processes, and corresponding acyclic lactones.

BACKGROUND OF THE INVENTION 
The present invention provides novel intermediates and chemical processes 
which are useful in the preparation of Thromboxane B.sub.2 (TXB.sub.2). 
Thromboxane B.sub.2 has the structure: 
##STR1## 
and can be considered as a derivative of thromboxanoic acid or 
11a-homo-11a-oxa-prostanoic acid which has the following structure and 
carbon atom numbering: 
##STR2## 
A systematic name for thromboxanoic acid is 
7-[2.beta.-octyltetrahydropyran-3.alpha.-yl]-heptanoic acid. 
Alternatively Thromboxane B.sub.2 is named as an analog of 
PGF.sub.2.sub..alpha., i.e., 11a-homo-11a-oxa-PGF.sub.2.sub..alpha.. 
In the above formulas, as well as in the formulas hereinafter given, broken 
line attachments to the tetrahydropyran ring indicate substituents in 
alpha configuration i.e., below the plane of the tetrahydrofuran ring. 
Heavy solid line attachments to the tetrahydropyran ring indicate 
substituents in beta configuration, i.e., above the plane of the 
cyclopentane ring. The use of wavy lines (.about.) herein will represent 
attachment of substituents in either the alpha or beta configuration or 
attachment in a mixture of alpha and beta configurations. 
The side-chain hydroxy at C-15 in the above formulas is in S configuration. 
See, Nature 212, 38 (1966) for discussion of the stereochemistry of the 
prostaglandins, which discussion applies hereto with respect to TXB.sub.2. 
Expressions such as C-15, and the like, refer to the carbon atom in 
Thromoxane B.sub.2 which is in the position corresponding to the position 
of the same number in thromboxanoic acid. 
Molecules of the known prostaglandins each have several centers of 
asymmetry, and can exist in racemic (optically inactive) form and in 
either of the two enantiomeric (optically active) forms, i.e. the 
dextrorotatory and levorotatory forms. Likewise TXB.sub.2, which as 
discussed above is alternatively nominated as 
11a-homo-11a-oxa-PGF.sub.2.sub..alpha., has similar centers of asymmetry, 
and thus, likewise can exist in optically active or racemic form. As 
drawn, the above formulas each represent the particular optically active 
form of the TXB.sub.2 as is obtained biosynthetically, for example, as 
obtained by Samuelsson below. The mirror image of each of these formulas 
represents the other enantiomer of TXB.sub.2. The racemic form of 
TXB.sub.2 contains equal numbers of both enantiomeric molecules, and one 
of the above formulas and the mirror image of that formula is needed to 
represent correctly racemic TXB.sub.2. For convenience hereinafter, use of 
the term, thromboxane or "TX" will mean the optically active form of that 
thromboxane thereby referred to with the same absolute configuration as 
TXB.sub.2 obtained biosynthetically by Samuelsson. When reference to the 
racemic form of TXB.sub.2 is intended, the word "racemic" or "dl" will 
precede the name, i.e. dl-TXB.sub.2. 
The term "thromboxane intermediate" as used herein, refers to any 
cyclopentane or tetrahydrofuran derivative or acyclic compound which is 
useful in preparing TXB.sub.2. 
When a formula, as drawn herein, is used to depict a thromboxane 
intermediate each such formula represents the particular stereoisomer of 
the thromboxane intermediate which is useful in preparing TXB.sub.2 of the 
same relative stereochemical configuration as TXB.sub.2 obtained 
biosynthetically. 
With respect to the asymmetric C-11 position of TXB.sub.2, the hemiacetal 
structure about this carbon atom results in the presence of two 
diastereiomeric forms: the .alpha.-hydroxyl and .beta.-hydroxy anomers. 
Due to the mutoratation resulting from the conversion of TXB.sub.2 to its 
hydroxy-aldehyde form, e.g. 
##STR3## 
in, for example, aqueous and other solutions, the 11-hydroxyl represents 
an equilibrium mixture of alpha and beta hydroxy anomers, depicted by a 
.about. OH, herein. 
In formulas herein (e.g., formula IV) where a cyclopentane or 
tetrahydropyran ring is not present, such a ring having been cleaved or to 
be introduced in subsequent reaction steps, the convention by which 
substituents about asymmetric centers are depicted as alpha or beta is as 
defined above, but with respect to the plane of the various atoms which 
comprised said ring before its cleavage or will comprise said ring as 
synthesized in subsequent reaction steps. Thus, for example, in formula IV 
the oxygen atom of the 12-hydroxy substituent, having formerly been or 
successively to be the 11a-oxa of the tetrahydropyran ring is viewed as 
planar with C-8 to C-11 and C-12. Accordingly the C-12 side chain is beta 
to this plane and thus rendered by a heavy solid line, while the C-12 
hydrogen is alpha to this plane and thus rendered by a dotted line. 
Thromboxane B.sub.2 is known in the art. This compound was prepared 
biosynthetically from arachadonic acid by B. Samuelsson, Proc. Nat. Acad. 
Sci. U.S.A. 71, 3400-3404 (1974). This compound alternately is named by 
him as 8-(1-hydroxy-3-oxopropyl)-9,12L-dehydroxy-5,10-heptadecadienoic 
acid, hemiacetal or PHD. 
TXB.sub.2 is produced biosynthetically from arachadonic acid, employing the 
cyclic oxygenase system which is responsible for the production of 
prostaglandins from arachadonic acid. 
TXB.sub.2, 15-epi-TXB.sub.2, their esters and pharmacologically acceptable 
salts have been discovered to be extremely potent in causing various 
biological responses. For that reason, these compounds have been found to 
be useful for pharmacological purposes. 
These biological responses include: 
a. stimulating smooth muscle (as shown by tests on guinea pig ileum, rabbit 
duodenum, or gerbil colon); and more especially and particularly 
b. affecting the reproductive organs of mammals as labor inducers, 
abortifacients, cervical dilators, regulators of the estrus, and 
regulators of the menstral cycle. 
Because of these biological responses, these TXB.sub.2 compounds are useful 
to study, prevent, control, or alleviate a wide variety of diseases and 
undesirable physiological conditions in birds and mammals, including 
humans, useful domestic animals, pets, and zoological specimens, and in 
laboratory animals, for example, mice, rats, rabbits, and monkeys. 
These TXB.sub.2 compounds, being extremely potent in causing stimulation of 
smooth muscle, are also highly active in potentiating other known smooth 
muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the 
various ergot alkaloids including derivatives and analogs thereof. 
Therefore, these compounds for example, are useful in place of or in 
combination with less than usual amounts of these known smooth muscle 
stimulators, for example, to relieve the symptoms of paralytic ileus, or 
to control or prevent atonic uterine bleeding after abortion or delivery, 
to aid in expulsion of the placenta, and during the puerperium. For the 
latter purpose, the TXB.sub.2 compound is administered by intravenous 
infusion immediately after abortion or delivery at a dose in the range 
about 0.01 to about 50.mu.g. per kg. of body weight per minute until the 
desired effect is obtained. Subsequent doses are given by intravenous, 
subcutaneous, or intramuscular injection or infusion during puerperium in 
the range 0.01 to 2 mg. per kg. of body weight per day, the exact dose 
depending on the age, weight, and condition of the patient or animal. 
The TXB.sub.2 compounds, being useful in place of oxytocin to induce labor, 
are used in pregnant female animals, including man, cows, sheep, and pigs, 
at or near term, or in pregnant animals with intrauterine death of the 
fetus from about 20 weeks to term. For this purpose, the compound is 
infused intravenously at a dose of 0.01 to 50 .mu.g. per kg. of body 
weight per minute until or near the termination of the second stage of 
labor, i.e., expulsion of the fetus. These compounds are especially useful 
when the female is one or more weeks post-mature and natural labor has not 
started, or 12 to 60 hours after the membranes have ruptured and natural 
labor has not yet started. An alternative route of administration is oral. 
The compounds are further useful for controlling the the reproductive cycle 
in menstruating female mammals, including humans. Menstruating female 
mammals are those mammals which are mature enough to menstruate, but not 
so old that regular menstruation has ceased. For that purpose the 
TXB.sub.2 compound is administered systemically at a dose level in the 
range 0.01 mg. to about 20 mg. per kg. of body weight of the female 
mammal, advantageously during a span of time starting approximately at the 
time of ovulation and ending approximately at the time of menses or just 
prior to menses. Intravaginal and intrauterine routes are alternate 
methods of administration. Additionally, expulsion of an embryo or a fetus 
is accomplished by similar administration of the compound during the first 
or second trimester of the normal mammalian gestation period. 
These compounds are further useful in causing cervical dilation in pregnant 
and nonpregnant female mammals for purposes of gynecology and obstetrics. 
In labor induction and in clinical abortion produced by these compounds, 
cervical dilation is also observed. In cases of infertility, cervical 
dilation produced by these compounds is useful in assisting sperm movement 
to the uterus. Cervical dilation by thromboxanes is also useful in 
operative gynecology such as D and C (Cervical Dilation and Uterine 
Curettage) where mechanical dilation may cause performation of the uterus, 
cervical tears, or infections. It is also useful in diagnostic procedures 
where dilation is necessary for tissue examination. For these purposes, 
the TXB.sub.2 compound is administered locally or systemically. 
TXB.sub.2, for example, is administered orally or vaginally at doses of 
about 5 to 50 mg. per treatment of an adult female human, with from one to 
five treatments per 24 hour period. Alternatively TXB.sub.2 is 
administered intramuscularly or subcutaneously at doses of about one to 25 
mg. per treatment. The exact dosages for these purposes depend on the age, 
weight, and condition of the patient or animal. 
These compounds are further useful in domestic animals as an abortifacient 
(especially for feedlot heifers), as an aid to estrus detection, and for 
regulation or synchronization of estrus. Domestic animals include horses, 
cattle, sheep, and swine. The regulation or synchronization of estrus 
allows for more efficient management of both conception and labor by 
enabling the herdsman to breed all his females in short pre-defined 
intervals. This synchronization results in a higher percentage of live 
births than the percentage achieved by natural control. The TXB.sub.2 
compound is injected or applied in a feed at doses of 0.1-100 mg. per 
animal and may be combined with other agents such as steroids. Dosing 
schedules will depend on the species treated. For example, mares are given 
the prostaglandin 5 to 8 days after ovulation and return to estrus. 
Cattle, are treated at regular intervals over a 3 week period to 
advantageously bring all into estrus at the same time. 
SUMMARY OF THE INVENTION 
The present invention provides novel intermediates and processes for the 
production of Thromboxane B.sub.2, its 15-epimer, and various carboxyl 
derivatives thereof. In particular, there are disclosed herein novel 
processes in Charts A-F. 
With respect to Chart A the transformation of the formula XXIV compound to 
the formula XXV or XXVIII compound and each successive transformation or 
series of transformations thereafter represents a novel element of the 
present disclosure. Likewise, in Chart B transformation of the formula 
XLII compound to the formula XLIII compound and each successive 
transformation or series of transformations thereafter represent a novel 
element of the present disclosure. Further, each of the transformations 
and series of transformations in Charts C and D represent novel elements 
of the present disclosure. 
In addition to the processes depicted by the Charts herein, various 
intermediates of Charts A-D represent novel elements of the present 
disclosure. In particular, formulas XXV to XXXVa or XXXVb of Chart A, 
formulas XLIII-LII of Chart B, formulas LXII-LXIV of Chart C, and formulas 
LXXII-LXXV of Chart D represent novel elements of the present disclosure. 
Finally, 15-epi-TXB.sub.2 depicted by formula LXXVII and the various 
compounds of formula LXXVII wherein R.sub.1 is not hydrogen represent 
novel derivatives or isomers of known TXB.sub.2. 
With respect to Charts E and F, the transformation of the formula XCI 
compound to the formula XCII compound and each successive transformation 
or series of transformations thereafter represents a novel element of the 
present disclosure. 
In addition to the processes depicted by Charts E and F, various 
intermediates of Charts E and F represent novel elements of the present 
disclosure. In particular, formulas XCII-XCIV of Chart F represent novel 
elements of 
##STR4## 
the novel disclosure. 
The following symbols, as used herein are defined as follows: M.sub.9 is 
##STR5## 
R.sub.1 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl 
of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, 
inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkyl of 
one to 4 carbon atoms, inclusive, or a pharmacologically acceptable 
cation. 
R.sub.9 is an acyl protecting group. Acyl protecting groups according to 
R.sub.9, include: 
a. benzoyl; 
b. benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms, 
inclusive, phenylalkyl of 7 to 12 carbon atoms, inclusive, or nitro, with 
the proviso that not more than 2 substituents are other than alkyl, and 
that the total number of carbon atoms in the substituents does not exceed 
10 carbon atoms, with the further proviso that the substituents are the 
same or different; 
c. benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms, 
inclusive; 
d. naphthoyl; 
e. naphthoyl substituted with one to 9, inclusive, alkyl of one to 4 carbon 
atoms, inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, or 
nitro, with the proviso that not more than 2 substituents on either of the 
fused aromatic rings are other than alkyl and that the total number of 
carbon atoms in the substituents on either of the fused aromatic rings 
does not exceed 10 carbon atoms, with the further proviso that the various 
substituents are the same or different; or 
f. alkanoyl of 2 to 12 carbon atoms, inclusive. 
In preparing these acyl derivatives of a hydroxy-containing compound 
herein, methods generally known in the art are employed. Thus, for 
example, an aromatic acid of the formula R.sub.9 OH, wherein R.sub.9 is as 
defined above (e.g., benzoic acid), is reacted with the hydroxy-containing 
compound in the presence of a dehydrating agent, e.g. sulfuric acid, zinc 
chloride, or p-toluenesulfonic acid; or alternatively an anhydride of the 
aromatic acid of the formula (R.sub.9).sub.2 O (e.g., benzoic anhydride) 
is used. 
Preferably, however, the process described in the above paragraph proceeds 
by use of the appropriate acyl halide, e.g., R.sub.9 Hal, wherein Hal is 
chloro, bromo, or iodo. For example, benzoyl chloride is reacted with the 
hydroxyl-containing compound in the presence of a hydrogen chloride 
scavenger, e.g. a tertiary amine such as pyridine, triethylamine or the 
like. The reaction is carried out under a variety of conditions, using 
procedures generally known in the art. Generally mild conditions are 
employed: 0-60.degree. C., contacting the reactants in a liquid medium 
(e.g., excess pyridine or an inert solvent such as benzene, toluene, or 
chloroform). The acylating agent is used either in stoichiometric amount 
or in substantial stoichiometric excess. 
As examples of R.sub.9, the following compounds are available as acids 
(R.sub.9 OH), anhydrides ((R.sub.9).sub.2 O), or acyl chlorides (R.sub.3 
Cl): benzoyl; substituted benzoyl, e.g., 2-, 3-, or 4-)-methylbenzoyl, 
(2-, 3-, or 4-)-ethyl benzoyl, (2-, 3-, or 4-)-isopropylbenzoyl, (2-, 3-, 
or 4-)-tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 
2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, 
alphaphenyl-(2-, 3-, or 4-)-toluyl, (2-, 3-, or 4-)-phenethylbenzoyl, (2-, 
3-, or 4-)-nitrobenzoyl, (2,4-, 2,5-, or 2,3-)-dinitrobenzoyl, 
2,3-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 
2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl, 
2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; mono esterified 
phthaloyl, isophthaloyl, or terephthaloyl; 1- or 2-naphthoyl; substituted 
naphthoyl, e.g., (2-, 3-, 4-, 5-, 6-, or 7-)-methyl-1-naphthoyl, (2- or 4 
-) ethyl-1-naphthoyl, 2-isopropyl-1-naphthoyl, 4,5-dimethyl-1-naphthoyl, 
6-isopropyl-4-methyl-1-naphthoyl, 8-benzyl-1-naphthoyl, (3-, 4-, 5-, or 
8-)-nitro-1 -naphthoyl, 4,5-dinitro-1-naphthoyl, (3-, 4-, 6-, 7-, or 
8-)methyl-1-naphthoyl, 4-ethyl-2-naphthoyl, and (5- or 
8-)nitro-2-naphthoyl; and acetyl. 
There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl 
chloride, 3,5-dinitrobenzoyl chloride, or the like, i.e. R.sub.9 Cl 
compounds corresponding to the above R.sub.9 groups. If the acyl chloride 
is not available, it is prepared from the corresponding acid and 
phosphorus pentachloride as is known in the art. It is preferred that the 
R.sub.9 OH, (R.sub.9).sub.2 O, or R.sub.9 Cl reactant does not have bulky 
hindering substituents, e.g. tert-butyl on both of the ring carbon atoms 
adjacent to the carbonyl attaching cite. 
The acyl protecting groups, according to R.sub.9, are removed by 
deacylation. Alkali metal carbonate are employed effectively at ambient 
temperature for this purpose. For example, potassium carbonate in methanol 
at about 25.degree. C. is advantageously employed. 
R.sub.10 is a blocking group which is herein defined to be any group which 
replaces a hydroxy hydrogen and is neither attacked nor is reactive to the 
reagents used in the transformations used herein as an hydroxy is and 
which is subsequently replaceable with hydrogen in the preparation herein 
of TXB.sub.2. Several such blocking groups are known in the art, e.g. 
tetrahydropyranyl and substituted tetrahydropyranyl. See for reference E. 
J. Corey, Proceedings of the Robert A. Welch Foundation Conference on 
Chemical Research, 12, Organic Synthesis, pgs. 51-79 (1969). Those 
blocking groups which have been found useful include 
a. tetrahydropyranyl; 
b. tetrahydrofuranyl; and 
c. a group of the formula 
EQU --C(OR.sub.11) (R.sub.12) --CH(R.sub.13) (R.sub.14), to 
wherein R.sub.11 is alkyl of one to 18 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 to 3 alkyl of one to 4 
carbon atoms, inclusive, wherein R.sub.12 and R.sub.13 are alkyl of one to 
4 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 
alkyl of one to 4 carbon atoms, inclusive, or when R.sub.12 and R.sub.13 
are taken together --(CH.sub.2).sub.a --or --(CH.sub.2).sub.b 
--O--(CH.sub.2).sub.c, wherein a is 3, 4, or 5, or 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, with the 
further proviso that R.sub.12 and R.sub.13 may be the same or different, 
and wherein R.sub.14 is hydrogen or phenyl. 
When the blocking group R.sub.10 is tetrahydropyranyl, the 
tetrahydropyranyl ether derivative of any hydroxy moieties of the PG-type 
intermediates herein is obtained by reaction of the hydroxy-containing 
compound with 2,3-dihydropyran in an inert solvent, e.g. dichloromethane, 
in the presence of an acid condensing agent such as p-toluenesulfonic acid 
or pyridine hydrochloride. The dihydropyran is used in large 
stoichoimetric excess, preferably 4 to 10 times the stoichoimetric amount. 
The reaction is normally complete in less than an hour at 20.degree. to 
50.degree. C. 
When the blocking group is tetrahydrofuranyl, 2,3-dihydrofuran is used, as 
described in the preceding paragraph, in place of the 2,3-dihydropyran. 
When the blocking group is of the formula 
EQU --C(OR.sub.11)(R.sub.12)--CH(R.sub.13)(R.sub.14), 
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are as defined above, 
the appropriate reagent is a vinyl ether, e.g. isobutyl vinyl ether or any 
vinyl ether of the formula 
EQU C(OR.sub.11)(R.sub.12)=C(R.sub.13)(R.sub.14), 
wherein R.sub.11, R.sub.12, R.sub.13, and R.sub.14 are as defined above; or 
an unsaturated cyclic or heterocyclic compound, e.g. 1-cyclohexen-1-yl 
methyl ether, or 5,6-dihydro-4-methoxy-2H-pyran. See C. B. Reese, et al., 
Journal of the Chemical Society 89, 3366 (1967). The reaction conditions 
for such vinyl ethers and unsaturated compounds are similar to those for 
dihydropyran above. 
The blocking groups according to R.sub.10 are removed by mild acidic 
hydrolysis. For example, by reaction with (1) hydrochloric acid in 
methanol; (2) a mixture of acetic acid, water, and tetrahydrofuran; or (3) 
aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran, at 
temperatures below 55.degree. C., hydrolysis of the blocking groups is 
achieved. 
R.sub.32 is --Si(G.sub.1).sub.3, wherein G.sub.1 is alkyl of one to 4 
carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl, or phenyl 
substituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbon 
atoms, with the proviso that in the --Si--(G.sub.1).sub.3 moiety the 
various G.sub.1 's are the same or different. Preferably R.sub.32 is 
trimethylsilyl, or some other conveniently available, readily hydrolysable 
silyl group. 
R.sub.33 is alkyl of one to 5 carbon atoms, inclusive. Preferably R.sub.5 
is methyl or ethyl. 
R.sub.34 is an arylmethyl hydroxyhydrogen replacing group, which is defined 
as any arylmethyl group which replaces the hydroxy hydrogen of the 
intermediates in the preparation of TXB.sub.2 herein which is subsequently 
replaceable by hydrogen in the processes herein for preparation of 
TXB.sub.2, being stable with respect to the various reactions to which 
R.sub.34 -containing compounds are subjected and being introduced and 
subsequently hydrolysed by hydrogenolysis under conditions which yield to 
substantially quantitative yields of desired products (e.g., the primary 
alcohol). 
Examples of arylmethyl hydroxy-hydrogen replacing groups are 
a. benzyl (i.e., 
##STR6## 
b. benzyl substituted by one to 5 alkyl of one to 4 carbon atoms, 
inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 
carbon atoms, inclusive, with the further proviso that the various 
substituents are the same or different; 
c. benzhydryl (i.e., 
##STR7## 
d. benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms, 
inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 
carbon atoms, inclusive, with the further proviso that the various 
substituents are the same or different on each of the aromatic rings; 
e. trityl (i.e., 
##STR8## 
f. trityl substituted by one to 15 alkyl of one to 4 carbon atoms, 
inclusive, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 
carbon atoms, inclusive, with the further proviso that the various 
substituents are the same or different on each of the aromatic rings. 
The introduction of such ether linkages to the hydroxy-containing compounds 
herein, particularly the benzyl or substituted benzyl ether proceeds by 
methods known in the art, for example by reaction of the 
hydroxy-containing compound with the benzyl or substituted benzyl halide 
(chloride or iodide) corresponding to the desired ether. This reaction 
proceeds in the presence of an appropriate condensing agent (e.g., silver 
oxide). The mixture is stirred and heated to 50.degree.-80.degree. C. 
Reaction times of four to 20 hours are ordinarily sufficient. 
These arylmethyl groups are subsequently removed by hydrogenolysis, for 
example by catalytic hydrogenation over a 5-10% palladium-on-carbon 
catalyst. 
R.sub.31 is a hydroxy hydrogen replacing group which is stable to the 
reagents employed herein in the preparation of TXB.sub.2, and 
subsequently, readily hydrolyzed orhydrogenolysed as required herein. 
Those hydroxy-hydrogen replacing groups useful for this purpose include 
any acyl protecting group according to R.sub.9, blocking group according 
to R.sub.10, or arylmethyl hydroxy-hydrogen replacing group according to 
R.sub.34. 
With respect to Chart A, a method is provided whereby the formula XXI 
compound, known in the art in optically active form or as a mixture of 
isomers is transformed to either of the formula XXXV intermediates, which 
are useful according to processes of Charts C and D for preparing the 
TXB.sub.2 -type compounds of formula LXVII. 
With respect to Chart A, the formula XXII compound is known. See, for 
example, Yankee, et al., Journal of the American Chemical Society 96, 5865 
(1974). The formula XXII compound is otherwise available by methods known 
in the art. 
The transformation of the formula XXI compound to the formula XXII compound 
proceeds by methods known in the art. For example, the formula XXI 
compound is dissolved in a suitable organic solvent (ethyl acetate, 
tetrahydrofuran, benzene, methylene chloride, chloroform, and the like), 
and thereafter treated with a weak base. For this purpose a base such as 
Florisil or various tertiary amines, e.g., triethylamine, are conveniently 
employed. The reaction proceeds at or about room temperature and is 
ordinarily complete within about 6 to 24 hr. Pure formula XXII product is 
then obtained by any suitable conventional procedure. For example, 
filtration or solvent extractions are employed, or alternatively and 
preferably column chromatography on Florisil employing ethyl acetate as a 
eluant provides a convenient method of recovering pure product. 
Thereafter the formula XXII compound thus obtained is selectively reduced 
to the formula XXIII primary alcohol using reducing agents known to 
provide selective reduction of aldehydes in the presence of lactones. For 
this purpose, lithium tri-t-butoxyaluminum hydride in tetrahydrofuran is 
conveniently employed. Other reducing agents, for example, sodium 
potassium, zinc, or lithiumborohydride in various alkanol solvents are 
further employed. The formula XXIII compound is then transformed to the 
formula XXIV compound by replacing the hydroxy hydrogen with an acyl 
protecting group, a blocking group, or an aryl methyl hydroxy hydrogen 
replacing group. For the introduction of any of these groups in the 
formula XXIII compound, methods described hereinabove for such a 
transformation are employed. 
The formula XXIV compound is then transformed directly to the formula 
XXVIII compound by ozonolysis and reduction or alternatively transformed 
to the formula XXVIII compound by transformation successively to the 
formula XXV, XXVI, and XXVII compounds. 
The transformaton of the formula XXIV compound to the formula XXV compound 
proceeds by glycolization. Glycolization proceeds by methods known in the 
art. Thus, for this purpose osmium tetroxide is employed catalytically 
while N-methylmorpholine N-oxide is employed in slight stoichiometric 
excess. The mixture of these reactants is maintained with stirring at 
about 0.degree.-50.degree. C., but for convenience is preferably run at 
about ambient temperature. The reaction is ordinarily complete within 
about one to 3 hr. and the formula XXV glycol is then isolated by 
conventional means. For example, solvent extraction is employed or 
chromatographic purification and/or crystallization techniques are used. 
In place of N-methylmorpholine, N-oxide, there are for example used other 
known oxidants such as potassium chlorate, hydrogen peroxide, and the 
like. 
The formula XXV compound is oxidatively cleaved to the formula XXVI 
compound employing concentrated aqueous periodic acid (H.sub.5 lO.sub.6) 
in the presence of an amine base (e.g. pyridine). About one and one-half 
molecular equivalents of the periodic acid and amine base are conveniently 
employed per equivalent of formula XXV starting material. The reaction is 
run at about -5.degree. to 30.degree. C. preferably at or about 0.degree. 
C. The reaction proceeds by vigorous stirring and ordinarily is complete 
within about 2 to 20 min. The reaction mixture is then diluted with ethyl 
acetate and product recovered by filtration from the filtrate. Since the 
formula XXVI compound is relatively unstable, particularly in acidic or 
especially basic environments, it is ordinarily used without further 
purification in preparation of the formula XXVII and formula XXVIII 
compounds. 
Alternatively, in place of periodic acid other reagents known to cleave 
glycol linkages, such as sodium periodate, manganese dioxide and lead 
tetraacetate are employed. 
The formula XXVI compound is reduced to the formula XXVII and thereafter 
the formula XXVIII compound. This reduction is achieved employing reducing 
agents described above for the transformation of the formula XXII compound 
to the formula XXIII compound. In particular, sodium borohydride is 
particularly useful reagent for this purpose thus, the formula XXVI 
compound in a solvent (e.g. methanol: methylene chloride, 7:3) is treated 
with excess sodium borohydride with stirring at about 0.degree. C. for 
between 10 min. and one hr. Where recovery of the formula XXVII compound 
is desired the course of the reaction is followed by silica gel 
chromatography and when reduction of the formula XXVI compound to the 
formula XXVII compound is complete the reaction conditions are terminated 
by cautious destruction of the reducing agent, for example, by addition of 
acetic acid. The formula XXVII compound is then concentrated and isolated 
by conventional means as described above. This formula XXVII compound is 
then useful in the preparation of the formula XXVIII compound or if the 
reaction conditions are maintained the formula XXVI compound is ultimately 
reduced directly to the formula XXVIII compound. This compound is obtained 
as an (1'RS) epimeric mixture which is separated into pure (1'R) or (1'S) 
isomers. 
In identifying the stereochemistry about the asymmetric centers of the 
formula XXVIII compound (and likewise the corresponding formula XXIX, XXX, 
and XXI compounds) the convention described hereinabove is employed. Thus, 
for example, in each case the 5 carbon atoms which formerly comprised the 
cyclopentane ring and oxygen of the secondary hydroxyl are depicted as 
planar, since these are the latent tetrahydrofuran ring atoms of formula 
XXII. Accordingly, various substituents of asymmetric carbon atoms are 
depicted as either alpha or beta, or mixture thereof, to this plane. 
However, in naming each of the formula XXVIII-XXXI compounds (and like 
acyclic compounds in successive charts), "R" and "S" nomenclature about 
asymmetric centers is employed. See R. S. Cahn, J. Chem. Ed., 41; 116-125 
(1964). 
Accordingly, the isomer of the formula XXVIII compound which leads to the 
formula XXXIV 2.beta.-compound is of the S configuration at the asymmetric 
carbon atom containing the secondary hydroxyl. The formula XXVIII compound 
is then transformed to the formula XXX compound by silylation. Methods and 
reagents generally known in the art are employed. For discussion of the 
various silylating agents employed herein see Post, Silicones and Other 
Organic Silicone Compounds, Reinhold Publishing Co., New York, New York 
(1949). For procedures in effecting the instant silylation see Pierce, 
Silylation of Organic Compounds, Pierce Chemical Co., Rockford, Ill. 
(1968). 
Since no special stability requirements are demanded of the silyl 
containing intermediates herein, readily available silylating agents are 
preferably employed. For example, the silylation herein proceeds by 
treating the formula XXVIII compound, dissolved in a suitable organic 
solvent, such as tetrahydrofuran, with trimethylsilyl chloride and 
hexamethyldisilane. This reaction is run for convenience at or near 
ambient temperature and is ordinarily complete within about 15 to 20 hr. 
The course of the reaction is conveniently monitored by silica gel thin 
layer chromatography using for example ethyl acetate in hexane. In the 
preparation of the formula XXVIII compound the reaction proceeds first by 
the partial silylation of the hydroxyl in the position .epsilon. to the 
lactonized carboxyl (formula XXIX) and thereafter to the formula XXX 
product. Since in the employment of the process herein, recovery of the 
formula XXIX partially silylated product is not required, ordinarily, 
silylation of the formula XXVIII compound is allowed to proceed to 
completion. 
The formula XXXI compound is prepared from the formula XXX compound by a 
selective oxidation of the silyl ether at the carbon atom .epsilon. to the 
lactonized carboxyl to the corresponding aldehyde. For this purpose, the 
Collins reagent is employed by methods known in the art. See R. Ratcliffe, 
et al., Journal of Organic Chemistry 35, 4000 (1970). For this purpose 
about 8 to 9 equivalents of oxidizing reagent are employed for each 
equivalent of formula XXX compound. The reaction is run at room 
temperature and is ordinarily complete in about 15 to 45 min. The product 
is then recovered by filtration of crude product through a mixture of 
Celite and acid-washed silica gel (1:2). The filtrate and diethyl ether 
washings are then combined, washed and concentrated to yield the formula 
XXI aldehyde. 
This formula XXXI aldehyde is then transformed to the formula XXXII 
hemiacetal by desilylation, followed by hemiacetal formation. Thus, the 
formula XXXI product is dissolved in methanol or an aqueous methanol 
mixture sufficient to yield a homogeneous reaction mixture and allowed to 
react at 0.degree. to 50.degree. C. for about 1-5 hr. Preferably, however, 
reaction temperatures of between 20.degree. and 40.degree. C. are 
employed. Thereupon, the formula XXXII compound is isolated, by solvent 
extraction or silica gel chromatography, employing conventional methods. 
The formula XXXIV compound is then prepared from the formula XXXII compound 
(when R.sub.31 is not a blocking group according to R.sub.10) by reaction 
of the formula XXXII compound with hydrogen chloride in an alkanol 
corresponding to the alkyl group to be introduced into formula XXXII. The 
reaction proceeds at temperatures of about 0.degree.-40.degree. C., 
although it is preferred for convenience to allow the reaction to proceed 
at ambient temperature. The reaction is ordinarily complete within one to 
24 hr. and thereafter the reaction mixture is diluted with excess organic 
solvent (e.g. ethyl acetate, diethyl ether, and methylene chloride). 
Thereafter pure formula XXXIV product is recovered by conventional means. 
For example, crude reaction mixture may be washed with basic brine and 
brine and thereafter chromatographed on silica gel. There are thereby 
recovered two isomeric alkyl acetals depicted by formula XXXIV. 
When R.sub.31 in the reaction sequence of Chart A is a blocking group 
according to R.sub.10, then the procedure described above for the 
introduction of the alkyl group on the formula XXXII compound yields a 
hydrolyzed 2.beta.-hydroxymethyl compound according to formula LXIII of 
Chart C. 
Further, when R.sub.31 is not a blocking group according to R.sub.10, then 
the reaction described for the transformation of the formula XXXII 
compound to the formula XXXIV compound is optionally and preferably 
employed on the formula XXXI compound. Accordingly, by this optional 
method the formula XXXI compound is transformed directly to the formula 
XXXIV compound. 
Thereafter, the formula XXV compounds are prepared by separation of 
diastereomeric mixtures of the formula XXXIV compound. For example, 
suitable conventional techniques for such a separation include silica gel 
chromatography. 
Chart B provides an alternate method for the preparation of one species of 
the formula XXXIV compound (i.e., wherein R.sub.31 is an arylmethyl 
hydroxy hydrogen replacing group according to R.sub.34) from the formula 
XLI compound. 
The formula XLI compound is known in the art or prepared by methods known 
in the art. This compound is transformed to the formula XLII compound by 
oxidation. Acidic oxidation reagents known in the art are employed in this 
transformation. For example, a Jones oxidation or Moffatt is employed. 
Reaction temperatures of between -10.degree. and +10.degree. C. are 
employed. Preferably, however, temperatures of 0.degree. C. are used. This 
reaction is ordinarily complete within several minutes to several hr. and 
the formula XLII compound so produced is preferably transformed directly 
to the formula XLIII compound without chromatographic purification after 
normal extractive separation. 
Accordingly, crude formula XLII compound is transformed to the formula 
XLIII dilactone by methods known in the art for the oxidation of ketones 
to lactones. Accordingly, a Baeyer-Villiger oxidation is employed. 
Accordingly, this oxidation proceeds by the use of any one of a number of 
peracids. For convenience, it is preferred to use peracids which are 
commercially available, such as perphthallic, peracetic, or 
m-chloroperbenzoic acid. The reaction can be conveniently carried out at 
ambient temperature, in which case the oxidation is ordinarily complete 
within 2-5 days. Thereafter, the formula XLIII compound is isomerized to 
the formula XLIV unsaturated lactone. This isomerization proceeds under 
basic conditions. For example, preferred bases are tertiary amines, and 
particularly convenient and useful tertiary amine for this purpose is 
1,5-diazobicyclo[5.4.0]undec-5-ene (DBU). The formula XLIV compound is 
acidified, and then recovered by conventional means, e.g., solvent 
extraction. The formula XLIV compound is then transformed to the formula 
XLV compound by reduction of the formula XLIV lactone to a lactol. This 
reduction proceeds by conventional methods for such reductions, for 
example, the use of diisobutylaluminum hydride at or about -70.degree. C. 
Other reducing, agents useful for this purpose, are alternately employed. 
For example, lithium-tri-tert-butoxy aluminum hydride or sodium 
bis-(2-methoxyethoxy)aluminum hydride are optionally employed. 
The formula XLV lactol is then transformed to the formula XLVI methyl ester 
by alkyl esterification. Methods known in the art for the transformation 
of carboxylic free acids to corresponding alkyl esters, particularly and 
especially the use of the appropriate diazoalkane in a solvent such as 
diethyl ether, are employed. The formula XLVI compound is thereafter 
recovered in crude form by concentration under reduced pressure. The 
residue so obtained thereafter spontaneously lactonizes to formula XLVII 
compound. 
However, for the succeeding steps herein either the formula XLVII lactone 
is employed as depicted (i.e., transformation to either the formula XLVIII 
or formula L compound) or its formula XLVI methyl ester precursor is 
employed. In any event, either the formula XLVI or formula XLVII compound 
is transformed to the formula XLVIII and formula L compounds by treatment 
with a dry alkanol, corresponding to the R.sub.33 alkyl group to be 
introduced in the formula XLVII compound and a catalytic amount of acid. 
For this purpose, hydrogen chloride gas in dry diethyl ether or a Lewis 
acid, such as boron trifluoride etherate are employed. Additionally, a 
trialkyl orthoalkanoate corresponding to the R.sub.33 alkyl group to be 
introduced is added to the reaction mixture in a quantity sufficient to 
prevent any water present from interfering with the reaction. This 
reaction is preferably run for convenience at about ambient temperature 
and is ordinarily complete within several hours. The formula XLVIII and 
formula L compounds thereby produced are then recovered and separated by 
conventional means, e.g. chromatographic methods. 
Thereafter, the formula XLVIII compound is converted to the formula XLIX 
iodo lactone by methods known in the art for this purpose. For example, 
the formula XLVIII lactone is treated with base (e.g., sodium hydroxide, 
followed by treatment with solid carbon dioxide, potassium iodide, and 
molecular iodine). The formula XLIX dialkyl acetal is then converted to 
the formula LI lactone methyl acetal by refluxing in a solution of benzene 
containing a catalytic amount of a condensing agent, such as 
p-toluene-sulfonic acid. 
Alternatively, the formula L compound product from the formula XLVIII 
compound is transformed to the formula LI compound by the iodo 
lactonization method described above in the preparation of the formula 
LXIX compound from the formula LXVIII compound. 
Thereafter, the formula LI or LII compound in either of its diastereomeric 
forms (i.e., 6.alpha.-alkoxy, 6.beta.-alkoxy, 5.alpha.-iodo or 
5.beta.-iodo) is transformed to the formula LIII compound by deiodination. 
A particularly convenient method for achieving this deiodination employs 
the method of Corey, et al., Journal of Organic Chemistry 40, 2554 (1975). 
Thus, by this method the formula LI or LII compound, tri-n-butylchloride, 
and sodium borohydride, are combined while irradiating with a tungsten 
Lamp. 
Chart C provides a method whereby the formula LXI compound, as prepared in 
Charts A or B is transformed to the formula LXlV bicyclic lactone acetal 
aldehyde. 
The formula LXI compound is transformed to the formula LXII compound when 
R.sub.3, is an acyl protecting group, or the LXIII compound by hydrolysis 
or hydrogenolysis of the R.sub.31 group. When R.sub.31 is a acyl 
protecting group according to R.sub.9, methods described above, e.g. the 
use of sodium methoxide, are employed. When R.sub.31 is a blocking group 
according to R.sub.10, hydrolysis proceeds by methods described 
hereinabove for removing blocking groups according to R.sub.10, or 
alternatively the reaction conditions described for the transformation of 
the formula XXXI to formula XXXII compound are employed. Finally, when 
R.sub.31 is an aryl methyl hydroxy hydrogen replacing group according to 
R.sub.34, the transformation proceeds by hydrogenolysis. For this purpose, 
for example, as described above a palladium-on-catalyst is employed. 
As indicated above, hydrolysis of the acyl protecting group results in a 
mixture of the formula LXII .delta.-lactone and the formula LXIII 
.gamma.-lactone. This formula LXII .delta.-lactone can be recyclized to 
the formula LXIII lactone by treatment with sodium methoxide, followed by 
neutralization. 
The formula LXIII alcohol is then oxidized to the corresponding aldehyde by 
oxidation. For this purpose the Collins oxidation (see R. Ratcliffe, 
Journal of Organic Chemistry, 35, 4000 (1970); E. W. Yankee, et al., 
Journal of the American Chemical Society 96, 5865 (1974); or Moffatt 
oxidation, (see Journal of the American Chemical Society, 85, 3027 (1963) 
or Journal of the American Chemical Society 87, 5661, 5670 (1965), is 
employed. 
Chart D provides a method whereby the formula LXXI bicyclic lactone acetal 
aldehyde, prepared according to Chart C, is transformed to Thromboxane 
B.sub.2, its 15-epimer, or carboxyl derivatives thereof. The procedure 
described in Chart D is analogous to procedures known in the art for the 
preparation of PGF.sub.2.sub..alpha., its 15-epimer, or carboxyl 
derivatives thereof from the formula XXI compound of Chart A. See Corey, 
et al., Journal of the American Chemical Society 91, 5675-5677 (1969), 
particularly the transformation of the formula 8 compound to the formula 
14 compound. 
The formula LXXII compound is prepared from the formula LXXI compound 
employing a Wittig alkylation. Reagents known in the art are employed. The 
trans-enone lactone acetal is obtained stereospecifically. See for 
reference D. H. Wadsworth, Journal of Organic Chemistry 30, 680 (1965). In 
the preparation of the formula LXXII compound, certain phosphonates are 
employed in the Wittig reaction. These phosphonates are of the general 
formula 
##STR9## 
wherein R.sub.15 is alkyl of one to 8 carbon atoms, inclusive. 
Phosphonates of the above general formula are prepared by methods known in 
the art. See Wadsworth, et al., as cited above. 
The formula LXXII 3-oxo-bicyclic lactone acetal is transformed to a 
corresponding 3.alpha.- or 3.beta.-hydroxy compound by reduction of the 
3-oxo moiety, followed by separation of 3.alpha.- and 3.beta.-epimers. For 
this reduction the known ketonic carbonyl reducing agents which do not 
reduce ester or acid groups or carbon carbon double bonds are employed. 
Examples of these reagents particularly useful for the present purposes 
are the metal borohydrides, especially sodium, potassium, and zinc 
borohydride. For the production of C-15 epimerically pure compounds, 
separation proceeds by methods known in the art. For example, silica gel 
chromatography is employed. 
The formula LXXIII compound is then reduced to the formula LXXIV bicyclic 
lactol acetal by employing methods described above herein for reduction of 
lactones to lactols. Thus, diisobutylaluminum hydride is about -78.degree. 
C. is advantageously employed herein. 
Thereafter the formula LXXV compound is prepared from the formula LXXIV 
compound employing a Wittig alkylation with 
4-carboxybutyltriphenylphosphonium bromide. The reaction proceeds as is 
generally known in the art, by first mixing 
4-carboxybutyltriphenylphosphonium bromide with sodio 
dimethylsulfinylcarbanide, at ambient temperature, and thereafter adding 
the formula LXXIV bicyclic lactone acetal to this mixture. 
The formula LXXV compound is then employed in the preparation of the 
formula LXXVI compound, Thromboxane B.sub.2, by hydrolysis of the alkyl 
ether. For this purpose, mineral or organic acids, such as phosphoric 
acid, hydrochloric acid or trifluoroacetic acid are employed. Suitable 
reaction diluents are those which yield homogeneous reaction mixtures, for 
example, mixtures of water and tetrahydrofuran. The formula LXXVI product 
is then isolated and purified by conventional means. For example, solvent 
extraction is employed and thereafter purification by silica gel 
chromatography is used. 
Thereafter, the carboxy hydrogen of the formula LXXVI compound is 
transformed to an R.sub.1 moiety of the formula LXXVII compound by methods 
and procedures hereinbelow described. Accordingly, there is prepared the 
formula LXXVII compound: Thromboxane B.sub.2 or its 15-epimer, or carboxyl 
derivatives thereof. 
With respect to Chart E, a method is provided whereby the formula LXXXI 
PGF.sub.2.sub..alpha., 11,15-bis-ether, and carboxyl derivatives thereof 
are transformed to the formula LXXXIV compound: a PGF.sub.2.sub..alpha., 
9,15-diacylate, or carboxyl derivatives thereof. With respect to Chart E, 
the various reaction steps are known in the art. 
The formula LXXXI compound is acylated, preparing the formula LXXXII 
compound according to procedures hereinabove described. Thus, methods 
described above for the introduction of acyl protecting groups according 
to R.sub.9 are employed. Thereafter, the formula LXXXII compound is 
transformed to the formula LXXXIII compound by selective hydrolysis of the 
R.sub.10 blocking groups in the presence of the acyl protecting group 
according to R.sub.9. For this purpose, methods described above for the 
hydrolysis of R.sub.10 blocking groups are employed. Accordingly, a 
mixture of acetic acid, water, and tetrahydrofuran is useful in this 
transformation. 
The formula LXXXIII compound is then selectively acylated at the C-15 
position, preparing the formula LXXXIV compound. This selective acylation 
proceeds by reacting one equivalent of acylating agent (e.g., the acyl 
anhydride) with the formula LXXXIII compound at low temperature. 
Preferably, the reaction is run at or below 0.degree. C. Acylation is 
ordinarily complete within one to 3 hr. and formula LXXXIV product is 
recovered by conventional means from the mixture of 9,11- and 
9,15-acylated products. Conventional separation techniques, e.g. 
chromatographic techniques, are employed. 
Chart F provides a method whereby Thromboxane B.sub.2, its 15-epimer, or 
carboxyl derivatives thereof are prepared from the formula XCI compound 
(as prepared in Chart E). 
The formula XCI compound is transformed to the formula XCII aldehyde by 
reaction with lead-tetraacetate in benzene. The reaction proceeds rapidly 
at temperatures of about 40.degree. to 60.degree. C., and is ordinarily 
complete within about 45 min. to 2 hr. The resulting formula XCII product 
is unstable (e.g. subject to loss of R.sub.9 OH) and is accordingly 
converted to the formula XCIII acetal without further purification. 
The preparation of the formula XCIII dialkyl acetal proceeds by methods 
described hereinabove for the preparation of acetals from aldehydes, e.g. 
reaction with an alkanol in the presence of a trialkyl orthoalkanoate and 
catalytic amount of an acid. Thus, when R.sub.33 is methyl, the present 
reaction proceeds by treatment of the formula XCII compound with methanol, 
methylorthoformate, and pyridine hydrochloride. Pure formula XCIII product 
is thereafter isolated by conventional methods, such as chromatography. 
The formula XCIV compound is then prepared from the formula XCIII compound 
by removal of the acyl protecting groups. Methods described hereinabove 
are employed. Accordingly, sodium methoxide in methanol is employed in 
stoichiometric amounts, yielding the formula XCIV trihydroxy acetal. 
Optionally, the use of aqueous methanolic sodium hydroxide removes both 
the acyl protecting groups and R.sub.1 ester. 
The formula XCV compound is then prepared from the formula XCIV compound by 
hydrolysis of the acetal group. Methods described above for the hydrolysis 
of tetrahydropyranyl ethers (i.e. acetic acid, water, and tetrahydrofuran 
mixtures) yield the formula XCIV product. More vigorous conditions of 
hydrolysis of the formula XCIV compound yield the formula XCVI product 
directly. 
Optionally, however, the formula XCV compound is prepared directly from the 
formula XCII compound by treatment of the formula XCII compound with an 
alkanol and anhydrous mineral acid in diethyl ether. When R.sub.33 is 
methyl, for example, methanol and ethereal 2N hydrochloric acid yield the 
formula XCV compound directly from the formula XCII product. 
In the reaction sequence described by Charts E and F, the use of C-1 
esters, particularly and especially lower alkyl esters, is preferred. 
Diastereomeric mixtures, other than anomeric mixtures, when produced by any 
reaction step herein, are separated immediately by isolation and 
conventional separation techniques, e.g., chromatography. However, when 
isolation of any intermediate, which is produced as a nonanomeric 
diastereomeric mixture, is not required, then optionally the separation of 
such mixture is deferred to succeeding reactions, or if such a separation 
is not required due to a subsequent removal of centers or assymmetry 
(e.g., transformation of XXV to XXVI) or preparation of anomeric products 
(e.g., transformation of LXXV to LXXVI), then it is deleted entirely. 
Optically active Thromboxane B.sub.2 and related products are obtained from 
optically active intermediates, according to the process steps of the 
above charts. Likewise racemic TXB.sub.2 compounds are obtained from 
corresponding racemic TXB.sub.2 intermediates following the procedures in 
the above charts, e.g. when racemic intermediates are used in the 
reactions above, racemic products are obtained. These products may be used 
in their racemic form or if preferred they may be resolved as optically 
active enantiomers following procedures known in the art. For example, 
when a TXB.sub.2 free acid is obtained, the racemic form thereof is 
resolved into d and l forms by reacting said free acid by known procedures 
with an optically active base (e.g., brucine or strychnine) thereby 
yielding a mixture of 2 diastereomers which are separable by procedures 
known in the art (fractional crystallization to yield the separate 
diastereomeric salts). The optically active acid may then be prepared from 
the salt by general procedures known to the art. 
In all of the above described reactions, the products are separated by 
conventional means from starting material and impurities. For example, by 
use of silica gel chromatography monitored by thin layer chromatography 
the products of the various steps of the above charts are separated from 
the corresponding starting materials and impurities. 
As discussed above, the processes herein described lead variously to acids 
(R.sub.1 is hydrogen) or to esters. 
When the alkyl ester has been obtained and an acid is desired, 
saponification procedures, as known in the art for PGF-type compounds are 
employed. Optionally, however, free acids are prepared by enzymatic 
process for transformation of PGE-type esters to their acid forms. Thus 
the TXB.sub.2 methyl ester is combined with prepared enzyme powder and 
hydrolyzed. See for reference E. G. Daniels, Process For Producing An 
Esterase, U.S. Pat. No. 3,761,356. 
When an acid has been prepared and an alkyl, cycloalkyl, or aralkyl ester 
is desired, esterification is advantageously accomplished by interaction 
of the acid with the appropriate diazohydrocarbon. For example, when 
diazomethane is used, the methyl esters are produced. Similar use of 
diazoethane, diazobutane, and 1-diazo-2-ethylhexane, and diazodecane, for 
example, gives the ethyl, butyl, and 2-ethylhexyl and decyl esters, 
respectively. Similarly, diazocyclohexane and phenyldiazomethane yield 
cyclohexyl and benzyl esters, respectively. 
Esterification with diazohydrocarbons is carried out by mixing a solution 
of the diazohydrocarbon in a suitable inert solvent, preferably diethyl 
ether, with the acid reactant, advantageously in the same or a different 
inert diluent. After the esterification reaction is complete the solvent 
is removed by evaporation, and the ester purified if desired by 
conventional methods, preferably by chromatography. It is preferred that 
contact of the acid reactants with the diazohydrocarbon be no longer than 
necessary to effect the desired esterification, preferably about one to 
about ten minutes, to avoid undesired molecular changes. Diazohydrocarbons 
are known in the art or can be prepared by methods known in the art. See, 
for example, Organic Reactions, John Wiley and Sons, Inc., New York, N.Y., 
Vol. 8, pp. 389-394 (1954). 
An alternative method for alkyl, cycloalkyl or aralkyl esterification of 
the carboxy moiety of the acid compounds comprises transformation of the 
free acid to the corresponding silver salt, followed by interaction of 
that salt with an alkyl iodide. Examples of suitable iodides are methyl 
iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, 
cyclopropyl iodide, cyclopentyl iodide, benzyl iodide, phenethyl iodide, 
and the like. The silver salts are prepared by conventional methods, for 
example, by dissolving the acid in cold dilute aqueous ammonia, 
evaporating the excess ammonia at reduced pressure, and then adding the 
stoichiometric amount of silver nitrate. 
Various methods are available for preparing phenyl or substituted phenyl 
esters within the scope of the invention from corresponding aromatic 
alcohols and the free acid TXB-type compounds, differing as to yield and 
purity of product. 
Thus by one method, the PG-type compound is converted to a tertiary amine 
salt, reacted with pivaloyl halide to give the mixed acid anhydride and 
then reacted with the aromatic alcohol. Alternatively, instead of pivaloyl 
halide, an alkyl or arylsulfonyl halide is used, such as p-toluenesulfonyl 
chloride. See for example Belgian Pat. Nos. 775,106 and 776,294, Derwent 
Farmdoc Nos. 33705T and 39011T. 
Still another method is by the use of the coupling reagent, 
dicyclohexylcarbodiimide. See Fieser et al., "Reagents for Organic 
Synthesis", pp. 231-236, John Wiley and Sons, Inc., New York, (1967). The 
PG-type compound is contacted with one to ten molar equivalents of the 
aromatic alcohol in the presence of 2-10 molar equivalents of 
dicyclohexylcarbodiimide in pyridine as a solvent. 
One preferred novel process for the preparation of these esters, however, 
comprises the steps: 
a. forming a mixed anhydride with the TXB-type compound and 
isobutylchloroformate in the presence of a tertiary amine and 
b. reacting the anhydride with an appropriate aromatic alcohol. 
The mixed anhydride described above is formed readily at temperatures in 
the range -40.degree. to +60.degree. C., preferably at -10.degree. to 
10.degree. C. so that the rate is reasonably fast and yet side reactions 
are minimized. The isobutylchloroformate reagent is preferably used in 
excess, for example 1.2 molar equivalents up to 4.0 per mole of the 
TXB-type compound. The reaction is preferably done in a solvent and for 
this purpose acetone is preferred, although other relatively nonpolar 
solvents are used such as acetonitrile, dichloromethane, and chloroform. 
The reaction is run in the presence of a tertiary amine, for example 
triethylamine, and the co-formed amine hydrochloride usually crystallizes 
out, but need not be removed for the next step. 
The aromatic alcohol is preferably used in equivalent amounts or in 
substantial stoichiometric excess to insure that all of the mixed 
anhydride is converted to ester. Excess aromatic alcohol is separated from 
the product by methods described herein or known in the art, for example 
by crystallization. The tertiary amine is not only a basic catalyst for 
the esterification but also a convenient solvent. Other examples of 
tertiary amines useful for this purpose include N-methylmorpholine, 
triethylamine, diisopropylethylamine, and dimethylaniline. Although they 
are effectively used, 2-methylpyridine and quinoline result in a slow 
reaction. A highly hindered amine such as 2,6-dimethyllutidine is, for 
example, not useful because of the slowness of the reaction. 
The reaction with the anhydride proceeds smoothly at room temperature 
(about 20.degree. to 30.degree. C.) and can be followed in the 
conventional manner with thin layer chromatography (TLC). 
The reaction mixture is worked up to yield the ester following methods 
known in the art, and the product is purified, for example by silica gel 
chromatography. 
Solid esters are converted to a free-flowing crystalline form on 
crystallization from a variety of solvents, including ethyl acetate, 
tetrahydrofuran, methanol, and acetone, by cooling or evaporating a 
saturated solution of the ester in the solvent or by adding a miscible 
nonsolvent such as diethyl ether, hexane, or water. The crystals are then 
collected by conventional techniques, e.g. filtration or centrifugation, 
washed with a small amount of solvent, and dried under reduced pressure. 
They may also be dried in a current of warm nitrogen or argon, or by 
warming to about 75.degree. C. Although the crystals are normally pure 
enough for many applications, they may be recrystallized by the same 
general techniques to achieve improved purity after each 
recrystallization. 
The compounds of this invention prepared by the processes of this 
invention, in free acid form, are transformed to pharmacologically 
acceptable salts by neutralization with appropriate amounts of the 
corresponding inorganic or organic base, examples of which correspond to 
the cations and amines listed hereinabove. These transformations are 
carried out by a variety of procedures known in the art to be generally 
useful for the preparation of inorganic, i.e., metal or ammonium salts. 
The choice of procedure depends in part upon the solubility 
characteristics of the particular salt to be prepared. In the case of the 
inorganic salts, it is usually suitable to dissolve an acid of this 
invention in water containing the stoichiometric amount of a hydroxide, 
carbonate, or bicarbonate corresponding to the inorganic salt desired. For 
example, such use of sodium hydroxide, sodium carbonate, or sodium 
bicarbonate gives a solution of the sodium salt. Evaporation of the water 
or addition of a water-miscible solvent of moderate polarity, for example, 
a lower alkanol or a lower alkanone, gives the solid inorganic salt if 
that form is desired. 
To produce an amine salt, an acid of this invention is dissolved in a 
suitable solvent of either moderate or low polarity. Examples of the 
former are ethanol, acetone, and ethyl acetate. Examples of the latter are 
diethyl ether and benzene. At least a stoichiometric amount of the amine 
corresponding to the desired cation is then added to that solution. If the 
resulting salt does not precipitate, it is usually obtained in solid form 
by addition of a miscible diluent of low polarity or by evaporation. If 
the amine is relatively volatile, any excess can easily be removed by 
evaporation. It is preferred to use stoichiometric amounts of the less 
volatile amines. 
Salts wherein the cation is quaternary ammonium are produced by mixing an 
acid of this invention with the stoichiometric amount of the corresponding 
quaternary ammonium hydroxide in water solution, followed by evaporation 
of the water. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The invention can be more fully understood by the following examples and 
preparations. 
All temperatures are in degrees centigrade. 
IR (infrared) absorption spectra are recorded on a Perkin-Elmer Model 421 
or 137 infrared spectrophotometer. Except when specified otherwise, 
undiluted (neat) samples are used. 
UV (Ultraviolet) spectra are recorded on a Cary Model 15 spectrophotometer. 
NMR (Nuclear Magnetic Resonance) spectra are recorded on a Varian A-60, 
A-60D, or T-60 spectrophotometer in deuterochloroform solutions with 
tetramethylsilane as an internal standard (downfield). 
Mass spectra are recorded on an CEC model 21-110B Double Focusing High 
Resolution Mass Spectrometer on an LKB Model 9000 Gas-Chromatograph-Mass 
Spectrometer. Trimethylsilyl derivatives are used, except where otherwise 
indicated. 
"Brine", herein, refers to an aqueous saturated sodium chloride solution. 
The A-IX solvent system used in thin layer chromatography is made up from 
ethyl acetate-acetic acid-cyclohexane-water (90:20:50:100) as modified 
from M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257 (1966). 
Skellysolve-B (SSB) refers to mixed isomeric hexanes. 
Silica gel chromatography, as used herein, is understood to include 
elution, collection of fractions, and combination of those fractions shown 
by TLC (thin layer chromatography) to contain the pure product (i.e., free 
of starting material and impurities). 
Melting points (MP) are determined on a Fisher-Johns or Thomas-Hoover 
melting point apparatus. 
Preparation 1 
5.alpha.-Hydroxy-2-carboxaldehyde-1.alpha.-cyclopent-2-eneacetic acid 
.gamma.-lactone (Formula XXII). 
Refer to Chart A. 
A mixture of 136 g. of Florisil and 13.6 ml. of water is shaken until the 
mixture becomes homogeneous. Thereafter, this mixture is purged with 
nitrogen, removing any residual oxygen. Thereafter, a solution of 13.6 g. 
of 
3.alpha.,5.alpha.-dihydroxy-2.beta.-carboxaldehyde-1.alpha.-cyclopentaneac 
etic acid, .gamma.-lactone, benzoate (Formula XXI) in 240 ml. of ethyl 
acetate is added to the nitrogen purged mixture. This second mixture is 
then allowed to stand for 12 hr. at ambient temperature and thereafter 
transferred to a wet-packed column of 400 g. of Florisil and ethyl 
acetate. Eluting with ethyl acetate, fractions shown to contain pure 
formula XXII product are combined and concentrated under reduced pressure 
to yield 5.6 g. of title product. The melting point is 72.degree. to 
73.5.degree. C. Silica gel TLC R.sub.f is 0.69 in ethyl acetate. 
Characteristic NMR absorptions are observed at 2.5-3.2, 3.5-4.0, 5.1-5.3, 
6.8-7.0, and 9.8 .delta.. 
Preparation 2 
5.alpha.-Hydroxy-2-hydroxymethyl-1.alpha.-cyclopent-2-eneacetic acid 
.gamma.-lactone. (Formula XXIII). 
Refer to Chart A. 
To the solution of 15.6 g. of the reaction product of Preparation 1, 65 ml. 
of methylene chloride, and 65 ml. of methanol at -15.degree. C. is added 
with stirring, in small portions, sodium borohydride powder (2.5 g.). The 
addition proceeds over a period of about 5 min. The mixture is then 
stirred at about 0.degree. C. for 5 min. at which time 3.8 ml. of acetic 
acid is cautiously added, with evolution of hydrogen gas. The resulting 
mixture is then concentrated under reduced pressure. Brine is added to the 
residue thusly produced and the resulting mixture is extracted with ethyl 
acetate. The organic extract is then washed with brine containing sodium 
bicarbonate, dried over magneisum sulfate, and concentrated under reduced 
pressure to afford 3.2 g. of essentially pure formula XXIII title product. 
The aqueous layers obtained above are then extracted with 200 ml. of 
tetrahydrofuran. The organic extract is then dried and concentrated under 
reduced pressure to afford an additional 2.7 g. of essentially pure 
formula XXIII product, thereby obtaining a total yield of 5.9 g. Silica 
gel TLC R.sub.f is 0.42 in ethyl acetate. NMR absorptions are observed at 
2.5-2.8, 3.2-3.7, 4.15, 5.0-5.3, and 5.62 .delta.. 
Preparation 3 
5.alpha.-Hydroxy-2-(p-phenylbenzoyloxymethyl)-1.alpha.-cyclopent-2-eneaceti 
c acid .gamma.-lactone (Formula XXIV: R.sub.31 is p-phenylbenzoyl). 
Refer to Chart A. 
To a solution of 15.4 g. of the reaction product of Preparation 2, 75 ml. 
of dry tetrahydrofuran, and 75 ml. of dry pyridine at 0.degree. C. is 
added over a 2 min. period 22 g. of p-phenylbenzoyl chloride with 
stirring. Thereafter the mixture is cooled in an ice methanol bath, 
maintaining the reaction temperature below 10.degree. C. When the 
exothermic reaction has ceased, the cooling-bath is removed and the 
mixture is stirred at about ambient temperature for 30 min. Thereafter, 
additional 1.0 g. portions of p-phenylbenzoyl chloride are added at 10 
min. intervals until the starting material is completely consumed. Water 
(5 ml.) is then added with cooling, thereby destroying excess acid 
chloride. The mixture is then stirred for an additional 10 min., diluted 
with 500 ml. of ethyl acetate, and washed with a mixture of 80 ml. of 
concentrated hydrochloric acid in 800 ml. of an ice-water mixture. 
Thereafter, the resulting mixture is washed successively with water, 
dilute potassium bicarbonate, and brine; dried with magnesium sulfate; and 
concentrated under reduced pressure to yield 38.3 g. of crude product. 
This crude material is then chromatographed on 2 kg. of silica gel, 
deactivated by addition of 400 ml. of ethyl acetate. Elution with 4 l. of 
1:1 ethyl acetate in Skellysolve B yields crude title product which is 
combined and concentrated and thereafter washed with dilute potassium 
bicarbonate and brine and thereafter dried and concentrated under reduced 
pressure to yield 32.7 g. of pure product. Melting point is 
84.degree.-85.degree. C. Silica gel TLC R.sub.f is 0.58 in a mixture of 
ethyl acetate and hexane (1:1). NMR absorptions are observed at 2.6-2.85, 
2.34-3.8, 4.89, 5.0-5.3, 5.83, and 7.38-8.2 .delta.. Infrared absorptions 
are observed at 745, 1100, 1175, 1190, 1270, 1280, 1610, 1720, and 1775 
cm..sup.-.sup.1. The mass spectrum shows a parent peak 334.1219 and other 
peaks at 152, 153, 181, and 198.

EXAMPLE 1 
2.alpha.,3.alpha.,5.alpha.-Trihydroxy-2.beta.-(p-phenylbenzoyloxymethyl)-1. 
alpha.-cyclopentaneacetic acid 5.gamma.-lactone and its 
2.beta.,3.beta.-dihydroxy epimer (Formula XXV: R.sub.31 is 
p-phenylbenzoyl). 
Refer to Chart A. 
To a solution of 32.7 g. of the reaction product of Preparation 3, 300 ml. 
of acetone, and 40 ml. of water is added a solution of 500 mg. of osmium 
tetroxide in 25 ml. t-butanol. Thereafter there is added to the resulting 
solution 17.5 g. of N-methylmorpholine, N-oxide, dihydrate in 25 ml. of 
water. The mixture thereby produced is stirred at ambient temperature for 
1.5 hr. Acetic acid is then added to the mixture and the acetone removed 
under reduced pressure. To the residue is added 300 ml. of tetrahydrofuran 
and 1 l. of ethyl acetate and the resulting mixture is washed with (a) a 
cold mixture of 250 mg. of brine and 15 ml. of concentrated hydrochloric 
acid, (b) brine, (c) 200 ml. of brine and 25 ml. of saturated aqueous 
sodium bicarbonate, and (d) brine. The organic layer is then dried over 
sodium sulfate, and concentrated under reduced pressure. The residue 
thusly obtained is diluted with 200 ml. of ethyl acetate, cooled, and the 
resulting precipitate collected to yield 19.13 g. of a crystalline isomer 
of the title product. (Isomer A; melting point is 166.degree.-167.degree. 
C.). The filtrate is then concentrated and the residue (16.5 g.) 
chromatographed on 1 kg. of silica gel, deactivated by addition of 200 ml. 
of ethyl acetate. Eluting with 2 l. of a mixture of ethyl acetate and 
hexane (3:1), and thereafter with 2 l. of ethyl acetate, 13.6 g. of a semi 
solid mixture of isomer A and its 2,3-diepimer (Isomer B) are obtained. 
Isomer B is obtained in pure form by fractional crystallization of the 
isomeric mixture from ethyl acetate. Isomer B exhibits melting point of 
144.degree.-146.degree. C. For Isomer A infrared absorptions are observed 
at 745, 1135, 1180, 1215, 1270, 1295, 1610, 1750, and 3500 
cm..sup.-.sup.1. The mass spectrum shows a parent peak at 497.1821 and 
other peaks at 512, 331, 301, 209, 255, 198, 181, 89, 68, and 59. For 
isomer B the mass spectrum shows a parent peak at 497.1821 and other peaks 
at 512, 422, 331, 301, 181, 153, and 145. 
EXAMPLE 2 
(3S,4S)-4-hydroxy-6-oxo-3-(p-phenylbenzoyloxyacetyl)hexanoic acid 
.gamma.-lactone (Formula XXVI: R.sub.31 is p-phenylbenzoyl). 
Refer to Chart A. 
To a solution of 15.5 g. of the reaction product of Example 1 (Isomer A), 
300 ml. of methanol, and 22.5 ml. of pyridine at 0.degree. C. is added 
with stirring and cooling in an ice methanol bath a solution of 14.4 g. of 
periodic acid (H.sub.5 10.sub.6) in 40 ml. of water. The aqueous acidic 
mixture is added at about 20 ml. per minute, so as to maintain the 
reaction temperature at or below 8.degree. C. A thick precipitate forms 
quickly and the resulting mixture is stirred vigorously for 15 min. at 
0.degree. C. The mixture is then diluted with ethyl acetate, filtered and 
the precipitate washed with 300 ml. of ethyl acetate. The filtrate and 
washings are then combined; washed vigorously with (a) 700 ml. of brine, 
(b) one l. of brine containing 20 ml. of concentrated hydrochloric acid, 
and (c) 500 ml. of brine; dried briefly over magnesium sulfate; and 
concentrated under reduced pressure to yield a paste, maintaining bath 
temperature below 35.degree. C. The resulting crude product, being 
unstable to mild bases (e.g., silica gel) is therefore used without 
further purification in succeeding examples herein, e.g. Example 3. Silica 
gel R.sub.f is 0.50 in 7.5 percent methanol in chloroform. 
EXAMPLE 3 
(3R,4S)-4,6-Dihydroxy-[(1'S)-1-hydroxy-2-(p-phenylbenzoyloxy)ethyl]hexanoic 
acid 4.gamma.-lactone and its (1'R)-epimer (Formula XXVIII: R.sub.31 is 
p-phenylbenzoyl). 
Refer to Chart A. 
Crude title product of Example 2 (15.5 g.) as obtained from Isomer A is 
mixed with 150 ml. of methylene chloride, followed by addition of 300 ml. 
of methanol. This mixture is cooled to about -5.degree. C. and sodium 
borohydride powder (4 g.) is added in small portions with stirring over 
about one min. The resulting mixture is then stirred at 0.degree. C. for 
an additional minute, following the course of the reaction with silica gel 
thin layer chromatography, developing with ethyl acetate. An intermediate 
reduction yields the formula XXVII compound: 
(2RS)-2,4-dihydroxy-2-(p-phenylbenzoyloxymethyl)-3.alpha.-tetrahydrofurana 
cetic acid .gamma.-lactone. Silica gel R.sub.f is 0.78 in ethyl acetate. 
When the reduction is complete, acetic acid (10 ml.) is cautiously added, 
causing hydrogen evolution. The resulting mixture is then concentrated 
under reduced pressure to a volume of about 50 ml. and the residue mixed 
with 400 ml. of tetrahydrofuran and 600 ml. of ethyl acetate. The 
resulting mixture is then washed with (a) 500 ml. of brine containing 10 
ml. of concentrated hydrochloric acid, (b) 400 ml. of brine containing 15 
g. of sodium bicarbonate, and (c) brine. This washed mixture is then dried 
over magnesium sulfate and concentrated under reduced pressure to yield 
13.8 g. of crude title product as a mixture of isomers. This material is 
then combined with 11.8 g. of an essentially identical isomeric mixture 
obtained from 15.5 g. of the reaction product of Isomer B of Example 2. 
The combined isomeric mixture (25.6 g.) is then chromatographed on 2.5 g. 
of silica gel, deactivated by addition of 375 ml. of acetone and 125 ml. 
of methylene chloride. The column is then wetted with one l. of a mixture 
of acetone and methylene chloride (3:7). Crude product is then dissolved 
in warmed tetrahydrofuran and elution proceeds with mixtures of ethyl 
acetate and methylene chloride as follows: 8 l. of 3:7 mixture; 4 l. of 
2:3 mixture; 4 l. of 1:1 mixture, and 4 l. of 3:2 mixture by volume. 
Thereupon, 2.34 g. of the (1'R) title product and 13.65 g. of the (1'S) 
title product are obtained. For the (1'R) isomer, melting point is 
159.degree.-160.degree. C. Silica gel R.sub.f is 0.39 in a mixture of 
acetone and methylene chloride (3:7). Infrared absorptions are observed at 
745, 955, 1005, 1045, 1105, 1180, 1285, 1605, 1695, 1760, and 3480 
cm..sup.-.sup.1. The mass spectrum exhibits a parent peak at 499.1984 and 
other peaks at 313, 303, 255.0845, 213, 198, 181, 103. For there (1'S) 
epimer, melting point is 135.degree.-136.degree. C. Silica gel R.sub.f is 
0.31. Infrared absorptions are observed at 740, 745, 1040, 1115, 1205, 
1260, 1270, 1295, 1610, 1710, 1755, 1770, 3320, 3440, and 3540 
cm..sup.-.sup.1. The mass spectrum exhibits a parent peak at 499.1993 and 
other peaks at 514, 313, 303, 301, 255, 213, 198, and 181 cm..sup.-.sup.1. 
For the formula XXVII intermediate, a melting point is observed at 
176.degree.-178.degree. C. and characteristic infrared absorptions are 
observed at 1725, 1780, and 3610 cm..sup.-.sup.1. The mass spectrum 
exhibits a parent peak at 440.1655 and other peaks at 425, 313, 299, 198, 
and 181 cm..sup.-.sup.1. 
EXAMPLE 4 
(3S,4S)-4-hydroxy-6-trimethylsilyloxy-3-[(1'S)-2'-(p-phenylbenzoyloxy)-1'-t 
rimethylsilyloxyethyl]hexanoicacid .gamma.-lactone (Formula XXX: R.sub.31 
is p-phenylbenzoyl, and R.sub.32 is trimethylsilyl). 
Refer to Chart A. 
To a solution of 21.3 g. of the reaction product of Example 3, 190 ml. of 
tetrahydrofuran, and 100 ml. of hexamethyldisilizane at ambient 
temperature is added with stirring 25 ml. of trimethylsilyl chloride. The 
mixture is then allowed to stand at ambient temperature for about 20 hr. 
During this period the formula XXIX monosilyl compound is formed: 
(3R,4S)-4-hydroxy-6-trimethylsiyl-3[(1'S)-2-(P-phenylbenzoyloxy)-1'-hydrox 
yethyl]-hexanoic acid .gamma.-lactone. Silica gel TLC R.sub.f is 0.58 in 
ethyl acetate and hexane (1:1). At the conclusion of this period crude 
title product is prepared. Silica gel TLC R.sub.f is 0.87 with a mixture 
of ethyl acetate and hexane (1:1). This mixture containing crude title 
product is then concentrated to a volume of about 100 ml. under reduced 
pressure and the residue diluted with 250 ml. of dry benzene. This benzene 
containing mixture is then filtered and the filtrate washed with benzene. 
The filtrate and washings and then combined and concentrated under reduced 
pressure and the residue diluted with 200 ml. of xylene and again 
concentrated under reduced pressure to yield 29.6 g. of pure title 
product. 
EXAMPLE 5 
4.alpha.,6-Dihydroxy-2.beta.-(p-phenylbenzoyloxymethyl)-3.alpha.-tetrahydro 
pyranacetic acid .gamma.-lactone (Formula XXXII: R.sub.31 is 
p-phenylbenzoyl). 
Refer to Chart A. 
To a solution of 100 ml. of dry methylene chloride and 6.22 ml. of pyridine 
at 15.degree. C. is added with stirring 3.9 g. of dried chromium trioxide. 
This mixture is then stirred at 20.degree.-23.degree. C. for 30 min. and 
thereafter cooled to 15.degree. C. To this cooled mixture is added a 
solution of 2.3 g. of the reaction product of Example 4 in 15 ml. of 
methylene chloride. The resulting mixture is then stirred at ambient 
temperature for 30 min. Benzene (25 ml.) and 3 g. of Celite are added to 
the mixture. This resulting mixture is then filtered through a bed of 
Celite and acid-washed silica gel. Resulting solids are washed with ethyl 
acetate and the filtrate and washings are combined and concentrated under 
reduced pressure (at about 25.degree. C.) to a residue which is mixed with 
ethyl acetate and filtered by the method described above. This second 
filtrate and ethyl acetate washings and then combined and concentrated 
under reduced pressure at about 25.degree. C. Accordingly, there is 
prepared crude formula XXXI compound: 
(3S,4S)-4-hydroxy-6-oxo-3-[(1'S)-2'-(p-phenylbenzoyloxy)-1'-trimethylsilyl 
oxyethyl]hexanoic acid .gamma.-lactone. 
The residue of this crude formula XXXI compound is then dissolved in 25 ml. 
of tetrahydrofuran, 10 ml. of water, and 5 ml. of acetic acid. The 
resulting mixture is stirred at ambient temperature for one hr. and the 
resulting mixture shaken with 75 ml. of ethyl acetate and brine containing 
excess sodium bicarbonate. The resulting organic layer is then washed with 
brine, dried over magnesium sulfate, and concentrated under reduced 
pressure. The residue is then chromatographed on 200 g. of silica gel, 
deactivated by addition of 40 ml. of ethyl acetate. The column is eluted 
with ethyl acetate and yields 0.55 g. of crude product which on 
trituration with ethyl acetate yields 250 mg. of pure title product. 
Melting point is 172.degree.-174.degree. C. The product recrystallized 
from ethyl acetate exhibits a melting point of 176.degree.-177.5.degree. 
C. Silica gel TLC R.sub.f is 0.52 in ethyl acetate and hexane (3:1). The 
mass spectrum exhibits a parent peak at 440.1633 and other peaks at 425, 
284, 283, 271, 255, 243, 230, 198, and 181. 
EXAMPLE 6 
4.alpha.-Hydroxy-6.beta.-methoxy-2.beta.-(p-phenylbenzoyloxymethyl)-3.alpha 
.-tetrahydropyranacetic acid .gamma.-lactone and its 6.alpha.-methoxy 
epimer. (Formula XXXIII, XXXIV, or XXXVa and XXXVb: R.sub.31 is 
p-phenylbenzoyl and R.sub.33 is methyl). 
Refer to Chart A. 
To a mixture of 500 ml. of dry methylene chloride and 31.1 ml. of pyridine 
at 15.degree. C. is added with stirring 19.5 ml. of dry chromium trioxide 
over a period of about 30 seconds. The resulting mixture is then stirred 
at ambient temperature for 30 min. and thereafter cooled to 10.degree. C. 
Celite (5 g.) is added, followed by the immediate addition of a solution 
of 11.9 g. of the reaction product of Example 4, in 40 ml. of dry 
methylene chloride. The resulting mixture is then stirred at 25.degree. C. 
for 30 min. and thereafter filtered through a bed of 40 g. of Celite and 
80 g. of acid-washed silica gel, moistened with methylene chloride. The 
filtrate is washed with one l. of diethyl ether and the filtrate and 
washings are combined and washed quickly with a mixture of 20 ml. of 
concentrated hydrochloric acid, 200 g. of ice and 250 ml. of brine, and 
finally with 500 ml. of brine. The washed mixture is then dried over 
magnesium sulfate and concentrated under reduced pressure, maintaining a 
bath temperature below 30.degree. C. Accordingly, as in Example 5, crude 
formula XXXI product is obtained. 
The residue of this crude formula XXXI product is then immediately mixed 
with 150 ml. of ice cold 0.25 N methanolic hydrogen chloride prepared by 
cautious addition of 4.45 ml. of freshly distilled acetyl chloride to 
anhydrous methanol and diluting the mixture to a volume of 250 ml. by 
further addition of methanol. The resulting mixture is then stirred at 
room temperature for 18 hr. and thereafter diluted with 750 ml. of ethyl 
acetate. The resulting solution is then washed with a cold mixture of 750 
ml. of brine, 200 ml. of water and 7.5 g. of sodium bicarbonate, followed 
by a further brine wash. The organic phase is then dried over magnesium 
sulfate and concentrated under reduced pressure to yield 10.3 g. of a 
residue. This residue is then chromatographed on one kg. of silica gel, 
deactivated by addition of 200 ml. of ethyl acetate. The residue, diluted 
in a mixture of Skellysolve B and ethyl acetate (1:1) with addition of 
sufficient methylene chloride to effect a homogeneous solution, is then 
applied to the column and the column is eluted with 6 l. of a one to one 
mixture of ethyl acetate and Skellysolve B followed by 2 l. of ethyl 
acetate. There is thereby obtained 910 mg. of the title product (formula 
XXXVa) and 4.03 g. of its 6.alpha.-methoxy epimer (formula XXXVb). For the 
6.beta.-methoxy epimer silica gel TLC R.sub.f is 0.49 in a mixture of 
ethyl acetate and hexane (1:1). A characteristic NMR absorption is 
observed at 3.49.delta.. For the 6.alpha.-methoxy-epimer m.p. is 
149.5.degree.-150.degree. C. on crystallization from methylene chloride 
and methanol. Silica gel TLC R.sub.f is 0.36 in ethyl acetate and hexane 
(1:1). A characteristic NMR absorption is observed at 3.38 .delta.. 
Infrared absorptions are observed at 705, 755, 1050, 1105, 1115, 1185, 
1280, 1610, 1705, and 1755 cm..sup..sup.-1. The mass spectrum exhibits a 
parent peak at 482.1411 and other peaks at 367, 351, 240, 198, 181, 171, 
and 153. 
EXAMPLE 7 
3.alpha.-Hydroxy-6-oxo-2.beta.-benzyloxymethyl-3.alpha.-tetrahydropyranacet 
ic acid .gamma.-lactone (Formula XLIII: R.sub.34 is benzyl). 
Refer to Chart B. 
A. A solution of 30.2 g. of 
3.alpha.,5.alpha.-dihydroxy-2.beta.-benzyloxymethyl-1.alpha.-cyclopentanea 
cetic acid .gamma.-lactone is dissolved in 500 ml. of acetone and the 
solution cooled to less than 5.degree. C. To this cooled solution is added 
dropwise, with stirring, 15 ml. of a 2.5 M solution of Jones reagent over 
a period of 10-15 min. The reaction is stirred for an additional 30 min. 
and then poured into one l. of dichloromethane and 2 l. of water. The 
aqueous layer is then separated and extracted with dichloromethane. The 
combined dichloromethane solutions are then dried over sodium sulfate and 
concentrated under reduced pressure to yield 30.7 g. of crude formula XLII 
compound: 
3.alpha.-hydroxy-5-oxo2.beta.-benzyloxymethyl-1.alpha.-cyclopentaneacetic 
acid .gamma.-lactone. 
B. The crude reaction product of part A (30.7 g.), an oil, is dissolved in 
200 ml. of dichloromethane, and this solution is treated with 40 g. of 
(0.198 M) m-chloroperbenzoic acid. After stirring for 88 hr. at 25.degree. 
C., the resulting mixture is diluted with dichloromethane and then 
extracted with aqueous sodium thiosulfate (Na.sub.2 S.sub.2 O.sub.3), 
about one l., and with aqueous sodium bicarbonate, about 600 ml. The 
dichloromethane layer is then dried over sodium sulfate and concentrated 
under reduced pressure yielding 28 g. of an oil. This oil is then 
crystallized from ethyl acetate yielding 14.85 g. in a first crop of 
crystals (melting point 108.degree.-111.degree. C.) and 3.97 g. of a 
second crop of crystals (melting point 105.degree.-108.degree. C.) These 
crystals represent pure title product. NMR absorptions are observed at 
2.2-3.4, 3.68, 4.2-4.15, and 7.28 .delta.. Infrared absorptions are 
observed at 2900, 2850, 1770, 1750, 1460, 1450, 1370, 1260, 1250, 1190, 
1040, and 740 cm.sup..sup.-1. Silica gel TLC R.sub.f is 0.58 in ethyl 
acetate and benzene (1:1). 
EXAMPLE 8 
4,5-Didehydro-6-oxo-2.beta.-benzyloxymethyl-3.alpha.-tetrahydropyranacetic 
acid (Formula XLIV: R.sub.34 is benzyl). 
Refer to Chart B. 
The reaction product of Example 7 (18.8 g.) is suspended in 200 ml. of 
benzene and the resulting mixture treated dropwise with 11.4 g. of 
1,5-diazobicyclo[5.4.0]-undec-5-ene (DBU). After stirring 10 min., the 
reaction is diluted with ethyl acetate and the resulting solution 
extracted with aqueous 1.0 N hydrochloric acid. The aqueous layer is then 
separated and extracted twice with additional ethyl acetate. The combined 
ethyl acetate solutions are then dried over magnesium sulfate and 
concentrated under reduced pressure yielding 19.2 g. of an oil which on 
standing yields a waxy solid. Melting point 65.degree.-70.degree. C. This 
crude title product is then used directly in succeeding examples, e.g., 
Example 9, without further purification. NMR absorptions are observed at 
2.4-2.7, 2.7-3.5, 3.68, 4.3-4.7, 5.97, and 6.80 .delta.. Silica gel TLC 
R.sub.f is 0.50 in ethyl acetate in Skellysolve B (1:1). 
EXAMPLE 9 
4,5-Didehydro-6-hydroxy-2.beta.-benzyloxymethyl-3.alpha.-tetrahydropyranace 
tic acid (Formula XLV: R.sub.34 is benzyl). 
Refer to Chart B. 
The reaction product of Example 8 (19.2 g.) is dissolved in 400 ml. of dry 
tetrahydrofuran and the resulting solution treated dropwise at -78.degree. 
C. for 2 hr. with a solution of 24 ml. of diisobutylaluminum hydride in 
250 ml. of toluene. The resulting mixture is then treated dropwise at 
-78.degree. C. with 100 ml. of a 1.0 N hydrochloric acid solution. The 
reaction mixture is then warmed to 25.degree. C. and poured into one l. of 
ethyl acetate. The aqueous layer is then acidified with hydrochloric acid 
to pH one and separated and extracted twice with ethyl acetate. The 
combined ethyl acetate solutions are then dried over magnesium sulfate and 
concentrated under reduced pressure yielding 20.4 g. of crude title 
product as an oil. This crude product is used without further purification 
in succeeding examples herein, e.g. Example 10. NMR absorptions are 
observed at 2.2-3.1, 3.2-4.1, 4.4-4.6, 4.7-5.3, 5.8-6.4, and 7.3 .delta.. 
Silica gel TLC R.sub.f is 0.43 in ethyl acetate and Skellysolve B (1:1). 
EXAMPLE 10 
(3R)-6,6-Dimethoxy-4,5-didehydro-3-(2'-benzyloxy-1'-hydroxyethyl) hexanoic 
acid .gamma.-lactone (Formula XLVIII: R.sub.33 is methyl and R.sub.34 is 
benzyl) and 
6.alpha.-methoxy4,5-didehydro-2.beta.-benzyloxymethyl-3.alpha.-tetrahydrop 
yranacetic acid, methyl ester (Formula L: R.sub.33 is methyl and R.sub.34 
is benzyl) or its 6.beta.-methoxy-epimer. 
Refer to Chart B. 
A. Crude reaction product of Example 9 (20.4 g.) is dissolved in diethyl 
ether and the resulting solution treated with ethereal diazomethane until 
the methane color persists. This solution is then concentrated under 
reduced pressure, yielding the formula XLVI compound: 
4,5-didehydro6-hydroxy-2-benzyloxymethyl-3.alpha.-tetrahydropyranacetic 
acid, methyl ester which on standing lactonizes to 
4,5-didehydro6.alpha.-hydroxy-2.beta.-benzyloxymethyl-3.alpha.-tetrahydrof 
uranacetic acid, methyl ester, .gamma.-lactone. 
B. The crude residue from part A (either in methyl ester of lactone form or 
as a mixture thereof) is dissolved in 200 ml. of dry methanol. This 
solution is treated with 30 ml. of trimethylorthoformate and 5 ml. of 2N 
hydrogen chloride gas in dry diethyl ether. After stirring for 2.5 hr. at 
25.degree. C. the reaction mixture is then treated with 2 ml. of pyridine 
and concentrated under reduced pressure. The residue is then dissolved in 
ethyl acetate and extracted with a 5 percent aqueous sodium bicarbonate 
solution. After drying over magnesium sulfate, the ethyl acetate 
containing solution is then concentrated under reduced pressure yielding 
19.5 g. of an oil, crude title product. This oil is then chromatographed 
on 1.2 kg. of silica gel, eluting with mixtures of ethyl acetate and 
Skellysolve B: 3 l. of a 3:7 mixture, 2 l. of a 9:11 mixture; 3 l. of 3:2 
mixture, and 2 l. of 3:1 mixture. Accordingly, there is obtained 3.2 g. of 
the lactone title product XLVIII, 7.7 g. of the 6.alpha.-methoxy title 
product L, and 0.84 g. of the 6.beta.-methoxy title product L. For the 
lactone title product LXVIII, NMR absorptions are observed at 2.3-2.8, 
3.26, 3.62, 4.50, 4.4-4.8, 5.3-6.2, and 7.31 .delta.. Infrared absorptions 
are observed at 2900, 1780, 1740, 1450, 1360, 1165, 1130, 1070, 1045, and 
740 cm..sup..sup.-1. Silica gel TLC R.sub.f is 0.29 in ethyl acetate and 
Skellysolve B (2:3). The 6.beta.-methoxy title product exhibits NMR 
absorptions at 1.8-3.2, 3.42, 3.65, 3.6-4.0, 4.60, 4.90, 5.6-6.1, and 7.37 
.delta.. Infrared absorptions are observed at 2850, 1740, 1450, 1430, 
1360, 1225, 1185, 1025, and 960 cm..sup.-1. Silica gel TLC R.sub.f is 0.60 
in ethyl acetate and Skellysolve B (2:3) and 0.48 in ethyl acetate and 
Skellysolve B (3:7). For the 6.alpha.-methoxy title product NMR 
absorptions are observed at 2.0-3.0 3.43, 3.65, 3.5-4.1, 4.56, 4.90, 
5.6-6.15, and 7.33 .delta.. Silica gel TLC R.sub.f is 0.63 and ethyl 
acetate in Skellysolve B (2:3) and 0.53 in ethyl acetate and Skellysolve B 
(3:7). 
EXAMPLE 11 
6.alpha.-Methoxy-5.alpha.-iodo-4.alpha.-hydroxy-2.beta.-benzyloxymethyl-3.a 
lpha.-tetrahydropyranacetic acid .gamma.-lactone (formula LI: R.sub.33 is 
methyl and R.sub.34 is benzyl). 
Refer to Chart B. 
The 6.alpha.-methoxy reaction product of Example 10 (7.2 g.) is dissolved 
in 120 ml. of tetrahydrofuran. This solution is then treated with 235 ml. 
of a 1.0 N aqueous sodium hydroxide solution and the resulting 2 phase 
system is stirred at 25.degree. C. for 2.5 hr. Solid carbon dioxide is 
then added until a pH of 10 is obtained. The reaction mixture is then 
concentrated to about two-thirds of the original volume under reduced 
pressure, thereby removing the tetrahydrofuran. Thereafter, 10.1 g. of 
potassium iodide and 15.9 g. of molecular iodine are added to the aqueous 
residue. The reaction mixture is then stirred for 20 hr. at 25.degree. C. 
and then poured into dichloromethane. Solid sodium thiosulfate is added 
and the resulting mixture stirred until the dark iodine color has faded. 
The aqueous layer is then separated and extracted twice with 
dichloromethane and the combined organic extracts are then dried over 
sodium sulfate and concentrated under reduced pressure yielding 8.92 g. of 
a crystalline product. Recrystallization from ethyl acetate yields 5.48 g. 
of pure title product as colorless crystals. Melting point is 
126.degree.-127.degree. C. NMR absorptions are observed at 2.2-3.2, 3.38, 
3.4-4.0, 4.1-4.4, 4.5-5.3, and 7.32 .delta.. Infrared absorptions are 
observed at 2900, 1780, 1500, 1450, 1360, 1260, 970, 840, and 780 
cm..sup..sup.-1 Silica gel TLC R.sub.f is 0.55 in ethyl acetate and 
Skellysolve B (2:3). 
EXAMPLE 12 
6.alpha.-Methoxy-4.alpha.-hydroxy-2.beta.-benzyloxymethyl-3.alpha.-tetrahyd 
rofuranacetic acid .gamma.-lactone (Formula LII: R.sub.33 is methyl and 
R.sub.34 is benzyl). 
Refer to Chart B. 
The crystalline reaction product of Example 11 (7.51 g.) is dissolved in 90 
ml. of dry glyme and 90 ml. of dry ethanol. (See E. J. Corey, et al., 
Journal of Organic Chemistry 40, 2554 (1975)). This solution is then 
treated with 0.9 ml. of tri-n-butyltin chloride dissolved in 9 ml. of 
ethanol. The resulting solution is then cooled in an ice bath under an 
argon atmosphere. The mixture is then irradiated with a 150 watt tungsten 
lamp. While irradiation is proceeding a solution of 0.98 g. of sodium 
borohydride in 70 ml. of dry methanol is added over 15 min. Bubbling of 
the reaction mixture is visible throughout the addition. The reaction 
mixture is then treated with 115 mg. of oxalic acid. The resulting 
solution is then poured into dichloromethane and a 5 percent aqueous 
solution of sodium bicarbonate. The aqueous layer is then separated and 
extracted with dichloromethane and the organic extracts are then dried 
over magnesium sulfate and concentrated under reduced pressure. The crude 
residue thereby obtained is then chromatographed on 500 g. of silica gel, 
eluting with 20 percent ethyl acetate and dicloromethane. Pure title 
product is thereby obtained (5.37 g.). Melting point is 
80.degree.-81.degree. C. NMR absorptions are observed at 2.1-2.9, 3.32, 
3.5-4.0, 4.57, 4.50-5.0, and 7.32 .delta.. Infrared absorptions are 
observed at 2875, 1775, 1450, 1420, 1360, 1340, 1320, 1240, 1220, 1160, 
1100, 1060, 1020, and 920 cm..sup..sup.-1. The mass spectrum exhibits 
parent peak 292.1314. Silica gel TLC R.sub.f is 0.25 in ethyl acetate and 
Skellysolve B (2:3) and 0.55 in ethyl acetate and dichloromethane (1:4). 
EXAMPLE 13 
6.alpha.-Methoxy-5.alpha.-hydroxy-2.beta.-hydroxymethyl-3.alpha.-tetrahydro 
pyranacetic acid 4.gamma.-lactone (Formula LXII: R.sub.33 is methyl) or its 
6.beta.-methoxy epimer. 
Refer to Chart C. 
A. Preparation of the 6.beta.-methoxy isomer from the reaction product of 
Example 6: 
To a mixture of 2.0 g. of the 6.beta.-methoxy isomer of the reaction 
product of Example 6, 25 ml. of anhydrous methanol and 3 ml. of dry 
tetrahydrofuran under a nitrogen atmosphere is added with stirring 1.0 ml. 
of a 4.40 N solution of methanolic sodium methoxide. The resulting mixture 
is then stirred at ambient temperature for 25 min. and thereafter acetic 
acid is added and the mixture cooled and filtered and the filtrate 
concentrated under reduced pressure. The residue is then chromatographed 
on 100 g. of silica gel, deactivated with 15 ml. of acetone and 10 ml. of 
methylene chloride, eluting with one l. of acetone and methylene chloride 
(3:7). Accordingly, there is obtained 0.90 g. of 6.beta.-methoxy title 
product. Silica gel TLC R.sub.f is 0.48 in acetone and methylene chloride 
(3:7). The mass spectrum exhibits a parent peak at 202.0852 and other 
peaks at 201, 185, 171, 142, 113, and 87. 
B. Preparation of the 6.alpha.-methoxy epimer from the reaction product of 
Example 6: 
A solution of 5.53 g. of the 6.alpha.-methoxy reaction product of Example 6 
and 30 ml. of methylene chloride are added to 90 ml. of 0.15 N methanolic 
sodium methoxide solution under a nitrogen atmosphere with stirring. The 
mixture is then stirred at room temperature for 30 min. and thereafter 
acidified with acetic acid and concentrated under reduced pressure. The 
residue is then dissolved in ethyl acetate and the mixture filtered and 
the filtered solid washed thoroughly with ethyl acetate. The filtrate and 
washings are then combined and concentrated under reduced pressure and the 
residue chromatographed on 500 g. of silica gel, deactivated by addition 
of 75 ml. of acetone and 50 ml. of methylene chloride. Eluting with 
mixtures of acetone and methylene chloride (1.25 l. of 3:7 mixture, 1.25 
l. of 2:7 mixture, and 1.25 l of a 1:1 mixture by volume) yields 2.25 g. 
of 6.alpha.-methoxy title product and 100 mg. of the formula LXII 
compound: 6.alpha.-methoxy-4.alpha.-hydroxy-2.beta.-hydroxymethyl-tetrahyd 
rofuranacetic acid .delta.-lactone, which compound is relactonized to title 
product. For the 6.alpha.-methoxy title product, silica gel TLC R.sub.f is 
0.42 in acetone and methylene chloride (3:7). A characteristic NMR 
absorption is observed at 4.80 .delta. (t,J 3.8) and 3.31 .delta.. 
Characteristic infrared absorptions are observed at 1780, 3560, and 3690 
cm..sup..sup.-1. The mass spectrum exhibits parent peak at 202.0848 and 
other peaks at 201, 185, 171, 142, 113, and 87. 
For the formula LXII .delta.-lactone silica gel TLC R.sub.f is 0.55 in 
acetone and methylene chloride (3:7). Characteristic NMR absorptions are 
observed at 4.90 and 3.37 .delta.. Characteristic infrared absorptions are 
observed at 1730 and 3550 cm..sup..sup.-1. 
C. Preparation of the 6.alpha.-methoxy title product from the reaction 
product of Example 12 by hydrogenolysis: 
The reaction product of Example 12 (1.39 g.) is dissolved in 100 ml. of 95 
percent ethanol and 100 ml. of absolute ethanol. A 1.5 g. quantity of 5 
percent palladium on carbon catalyst is added and the mixture hydrogenated 
at 3 atmospheres pressure. After 1.5 hr. the reaction mixture is filtered 
and the filtrate concentrated under reduced pressure. The residue is then 
dissolved in dichloromethane, dried over sodium sulfate, and concentrated 
under reduced pressure to yield 1.03 g. of pure 6.alpha.-methoxy title 
product as a colorless oil, essentially identical to the reaction product 
of Part B. NMR absorptions are observed at 2.0-3.1, 3.34, 3.4-3.9, and 
4.5-5.0 .delta.. Infrared absorptions are observed at 3500, 2900, 1775, 
1420, 1340, 1320, 1220, 1190, 1160, 1130, 1105, 1060, 1010, 980, 965, 945, 
and 920, cm..sup..sup.-1. The mass spectrum exhibits an M.sup.+-OCH.sub.3 
peak at 171.0660. Silica gel TLC R.sub.f is 0.49 in acetone and 
dichloromethane (2.3). 
EXAMPLE 14 
2.beta.-Carboxaldehyde-4.alpha.-hydroxy-6.alpha.-methoxy3.alpha.-tetrahydro 
pyranacetic acid .gamma.-lactone (Formula LXIV: R.sub.33 is methyl). 
Refer to Chart C. 
A. Oxidation employing the Collins reagent: 
Chromium trioxide (4.18 g.) is added in portions to 6.75 ml. of pyridine in 
70 ml. of dichloromethane at a temperature of about 20.degree. C. The 
mixture is then stirred for two hr. under an argon atmosphere. To this 
stirred mixture is there is added rapidly 1.05 g. of the reaction product 
of Example 13 (6.alpha.-methoxy epimer) dissolved in 7 ml. of 
dichloromethane. After about 25 min. the entire reaction mixture is 
chromatographed on 100 g. of silica gel, eluting with a mixture of 25 
percent acetone in methylene chloride. Evaporating fractions containing 
pure title product there is obtained 425 mg. of the title aldehyde. 
B. Oxidation employing a Moffatt reagent: 
The reaction product of Example 13 (101 mg.) is dissolved in 1.5 ml. of 
dichloromethane and the resulting solution treated with 300 mg. of 
dicyclohexylcarbodiimide in 1.5 ml. of benzene, 0.5 ml. of dimethyl 
sulfoxide, and 20 ml. of dichloroacetic acid in 0.5 ml. of benzene. After 
20 min. the reaction is treated with 127 mg. of oxalic acid, dissolved in 
0.3 l. of methanol. After evolution of carbon dioxide ceases, about 10 
min., the reaction is filtered and the filtrate chromatographed on 10 g. 
of silica gel, eluting with acetone and methylene chloride (1:4). 
Concentrating fractions containing pure title product under reduced 
pressure yields the title aldehyde. 
EXAMPLE 15 
Thromboxane B.sub.2, 11.alpha.-methyl acetal (Formula LXXV: M.sub.9 is 
##STR10## 
or its 15-epimer. 
Refer to Chart D. 
A. The entire residue from the reaction product of Example 14, part A (425 
mg.) is dissolved in 20 ml. of diethyl ether and the solution treated with 
4.8 ml. of 0.5 M 2-oxo-heptylidine-tri-n-butyl phosphorane in diethyl 
ether. After 20 min., the reaction mixture is evaporated and the residue 
chromatographed on 80 g. of silica gel. The column is eluted with ethyl 
acetate in n-hexane (1:1) and fractions containing pure 
3.alpha.-hydroxy-5.alpha.-methoxy-2.beta.-(3-oxo-trans-1-octenyl)-3.alpha. 
-tetrahydrofuranacetic acid .gamma.-lactone, a formula LXXII compound, are 
combined (524 mg.) NMR absorptions are observed at 0.6-1.9, 1.9-3.0, 3.33, 
4.25, 4.5-5.0, 6.4, and 6.80 .delta.. Infrared absorptions are observed at 
2900, 1780, 1670, 1160, 1130, 1070, 1050, and 1025 cm..sup.-.sup.1. The 
mass spectrum exhibits parent peak at 296.1589. Silica gel TLC R.sub.f is 
0.43 in ethyl acetate and Skellysolve B (1:1). 
Alternatively, a solution of 13.09 g. of dimethyl-2-oxoheptyl phosphonate 
in 30 ml. of dry tetrahydrofuran is added with stirring to a cold solution 
of 5.98 g. of potassium t-butoxide in 250 ml. of dry tetrahydrofuran under 
a nitrogen atmosphere. The mixture is then stirred at ambient temperature 
for about 1.5 hr. and the residue of the reaction product of Example 14 
from 3.6 g. of LXIII (.alpha.-methoxy isomer) diluted with 70 ml. of 
methylene chloride is added. This hetereogeneous reaction mixture is then 
stirred at ambient temperature for 2 hr. at which time 3.15 ml. of acetic 
acid is added. The resulting mixture is then concentrated under reduced 
pressure and the residue diluted with ethyl acetate and the mixture washed 
with acidified (hydrochloric acid) brine, basified (sodium bicarbonate) 
brine, and then dried over magnesium sulfate and concentrated under 
reduced pressure. The resulting residue (about 12.7 g.) is then 
chromatographed on 500 g. of silica gel, deactivated by addition of 100 
ml. of ethyl acetate. The column is eluted with ethyl acetate and hexane 
(1:1), yielding 1.17 g. of 
4.alpha.-hydroxy-6.alpha.-methoxy-2.beta.-(3-oxo-trans-1-octenyl)-3.alpha. 
-tetrahydrofuran acetic acid .gamma.-lactone. 
B. To a mixture of 2.18 g. of anhydrous zinc chloride and 15 ml. of 
1,2-dimethoxyethane under a nitrogen atmosphere is added with stirring 
0.61 g. of sodium borohydride. The resulting mixture is then stirred at 
ambient temperature for 2 hr. and thereafter cooled to -15.degree. C. A 
solution of 1.17 g. of the reaction product of part A in 10 ml. of 
1,2-dimethoxyethane is then added dropwise over about 2 min. The mixture 
is then stirred at -15.degree. C. for 2 hr., thereafter at 0.degree. C. 
for one hr. and finally at ambient temperature for about 1.5 hr. The 
mixture is then cooled to 0.degree. C. and 4.4 ml. of water is added 
dropwise, with caution (hydrogen gas evolution). The resulting mixture is 
then diluted with 75 ml. of ethyl acetate and filtered through Celite. The 
filtrate is then washed with 30 ml. of brine and the organic layer dried 
over magnesium sulfate and concentrated under reduced pressure. The 
resulting residue (1.24 g.) is then chromatographed on 125 g. of silica 
gel, deactivated by addition of 25 ml. of ethyl acetate. Eluting with 500 
ml. of ethyl acetate and hexane (3:1) and 500 ml. of ethyl acetate affords 
1.05 g. of 
4.alpha.-hydroxy-6.alpha.-methoxy-2.beta.-[(3RS)-3-hydroxy-trans-1-octenyl 
]-3.alpha.-tetrahydropyranacetic acid .gamma.-lactone (formula LXXIII). 
Epimeric alcohols are then separated employing silica gel thin layer 
chromatography, eluting with methanol and chloroform (1:19). 
Alternatively, the epimeric mixture of alcohols is employed directly in 
succeeding parts of the present Example. For the epimeric mixture, a 
characteristic NMR absorption is observed at 3.27 .delta.. The mass 
spectrum exhibits a parent peak 370.2194 and other peaks at 369, 345, 329, 
327, 323, 229, 267, 257, 241, 199, 185, 173, and 129. 
C. To a stirred solution of 1.05 g. of the epimeric mixture of the reaction 
product of part C in 15 ml. of toluene and 10 ml. of dry tetrahydrofuran 
at -78.degree. C. under a nitrogen atmosphere is added 15 ml. of a 10 
percent solution of diisobutylaluminum hydride in toluene over a 5 min. 
period. The mixture is stirred for 20 min. and thereafter a solution of 3 
ml. of water and 10 ml. of tetrahydrofuran is added cautiously with 
vigorous stirring. The resulting mixture is allowed to warm to ambient 
temperature and then filtered through Celite, rinsing with ethyl acetate. 
The filtrate is then shaken with 30 ml. of brine and the resulting mixture 
filtered through Celite. The filtrate is then washed with brine, and 
concentrated under reduced pressure to yield 1.0 g. of 
4.alpha.-hydroxy-6.alpha.-methoxy-2.beta.-[(3RS)-3-hydroxy-trans-1-octenyl 
]-3.alpha.-tetrahydropyran acetic acid .gamma.-lactol, an oil. Silica gel 
TLC R.sub.f is 0.21 and 0.24 in methanol and chloroform (1:19). 
The reaction product of part C is prepared directly from the reaction 
product of part A as follows: 
The reaction product of part A (500 mg.) is dissolved in 10 ml. of 
tetrahydrofuran and the solution cooled to -78.degree. C. under an argon 
atmosphere. This stirred solution is then treated over 30 min. with 0.7 
ml. of diisobutylaluminum hydride, diluted to 2.8 ml. with toluene. The 
reaction mixture is then treated dropwise with 2 ml. of water and allowed 
to warm to ambient temperature. Ethyl acetate in 0.25 N aqueous 
hydrochloric acid are added to the reaction mixture, and the mixture 
partitioned between organic and aqueous phases. The organic phase is 
washed with brine, dried over magnesium sulfate and concentrated under 
reduced pressure to yield 0.364 g. of a crude oil, the (3RS)-3-hydroxy 
formula LXXIV compound, as above. 
D. A mixture of 1.69 g. of 57 percent sodium hydride in mineral oil and 45 
ml. of dry dimethylsulfoxide are stirred slowly under nitrogen at 
65.degree.-70.degree. C. for one hr. This solution is then cooled to 
15.degree. C. and 8.87 g. of 4-carboxybutyltriphenylphosphonium bromide is 
added. The resulting orange mixture is then stirred for 30 min. at ambient 
temperature, cooled to 15.degree. C. and the solution of 1.0 g. of the 
reaction product of part C in 5 ml. of dimethyl sulfoxide is added. The 
resulting mixture is then stirred at ambient temperature for 2.5 hr. and 
is then cooled to 15.degree. C. Water is added with cooling, yielding a 
solution of about pH 9. This solution is then extracted with diethyl ether 
to remove neutral materials. To the aqueous layer is added a suspension of 
10 g. of ammonium chloride in 60 ml. of brine and the resulting mixture 
extracted with ethyl acetate. The ethyl acetate extract is then washed 
with brine, dried over magnesium sulfate, and concentrated under reduced 
pressure. The resulting residue (1.5 g.) is chromatographed on 100 g. of 
acid-washed silica gel, deactivated by addition of 20 ml. of ethyl 
acetate. Eluting with one l. of ethyl acetate and hexane (1:1) yield 0.43 
g. of 11-deoxy-11.alpha.-methoxy-15-epi-Thromboxane B.sub.2 as an oil, and 
0.32 g. of 11-deoxy-11.alpha.-methoxy-Thromboxane B.sub.2. For the 15-epi 
compound silica gel TLC R.sub.f is 0.73 in ethyl acetate and hexane (3:1) 
containing one percent acetic acid. The mass spectrum exhibits parent peak 
585.3449 and other peaks at 569, 568, 529, 439, 425, 416, 355, 334, 314, 
280, 199, 173, 159, and 117. For the (15S)-epimer silica gel TLC R.sub.f 
is 0.62 in ethyl acetate and hexane (3:1) containing one percent acetic 
acid. The mass spectrum exhibits a parent peak at 585.3437 and other peaks 
at 569, 568, 529, 439, 199, 173, 169, and 117. 
EXAMPLE 16 
Thromboxane B.sub.2 (Formula LXXVII: R.sub.1 is hydrogen). 
Refer to Chart D. 
A solution of one ml. of 85 percent aqueous phosphoric acid and 10 ml. of 
water is added with stirring to a solution of 220 mg. of the reaction 
product of Example 15, the (15S)-epimer in 10 ml. of tetrahydrofuran. The 
resulting solution is then heated to 40.degree. C. for 6 hr. and sodium 
chloride is thereafter added to the mixture. The resulting mixture is 
extracted with ethyl acetate and the ethyl acetate extract washed with 
brine until the aqueous layer is neutral. The organic phase is then dried 
over magnesium sulfate and concentrated to a residue. The residue (210 
mg.) is then chromatographed on 20 g. of acid-washed silica gel, 
deactivated by addition of 4 ml. of ethyl acetate. Eluting with 70 ml. of 
ethyl acetate and hexane (3:1), and 100 ml. of ethyl acetate yields 170 
mg. of thromboxane B.sub.2. Silica gel TLC R.sub.f is 0.38 in acetic acid 
and ethyl acetate (1:99). The mass spectrum for the methyl ester, tris TMS 
derivative exhibits a peak at 585 and other peaks at 529, 510, 495, 439, 
429, 256, and 225. 
Following the procedure of Examples 1-6, but employing in place of the 
2-(p-phenylphenylbenzoyloxymethyl) starting material of Preparation 3, 
each of the various corresponding hydroxy hydrogen replacing groups 
according to R.sub.31, there are obtained respective products 
corresponding to those of Examples 1-6. Accordingly, employing 
5.alpha.-hydroxy-2.beta.-benzoyloxymethyl-1.alpha.-cyclopent-2-eneacetic 
acid .gamma.-lactone, there are obtained the corresponding 
benzoyloxy-containing compounds as follows: 
2.alpha.,3.alpha.,5.alpha.-Trihydroxy-2.beta.-benzoyloxymethyl-1.alpha.-cyc 
lopentanceacetic acid 5.gamma.-lactone and its 2.beta.,3.beta.-dihydroxy 
epimers; 
(3S,4S)-4-Hydroxy-6-oxo-3-benzoyloxyacetylhexanoic acid .gamma.-lactone; 
(3R,4S)-4,6-Dihydroxy-[(1'S)-1-hydroxy-2-benzoyloxyethyl]-hexanoic acid 
.gamma.-lactone and its (1'R)-epimer; 
(3S,4S)-4-Hydroxy-6-trimethylsilyloxy-3-[(1'S)-2'-benzoyloxy-1'-trimethylsi 
lyloxyethyl]-hexanoic acid .gamma.-lactone; 
3.alpha.,6-Dihydroxy-2.beta.-benzoyloxymethyl-3.alpha.-tetrahydropyranaceti 
c acid .gamma.-lactone; and 
4.alpha.-Hydroxy-6.beta.-methoxy-2.beta.-benzoyloxymethyl-3.alpha.-tetrahyd 
ropyranacetic acid .gamma.-lactone and its 6.alpha.-methoxy epimer. 
Likewise, following the procedure of Examples 1-6, but employing 
5.alpha.-hydroxy-2-tetrahydropyranyloxymethyl-1.alpha.-cyclopent-2-eneacet 
ic acid .gamma.-lactone in place of the starting material of Preparation 3, 
there are prepared the corresponding tetrahydropyranyloxy-containing 
compounds, as follows: 
6.alpha.,3.alpha.,5.alpha.-Trihydroxy-2.beta.-tetrahydropyranyloxymethyl-1. 
alpha.-cyclopentaneacetic acid 5.gamma.-lactone and its 
2.beta.,3.beta.-dihydroxy epimers; 
(3S,4S)-4-Hydroxy-6-oxo-3-tetrahydropyranyloxyacetylhexanoic acid 
.gamma.-lactone; 
(3R,4S)-4,6-Dihydroxy-[(1'S)-1-hydroxy-2-tetrahydropyranyloxyethyl]hexanoic 
acid 4.gamma.-lactone and its (1'R)-epimers; 
(3S,4S)-4-Hydroxy-6-trimethylsilyloxy-3-[(1'S)-2'-tetrahydropyranyloxy-1'-t 
rimethylsilyloxyethyl]hexanoic acid .gamma.-lactone; 
3.alpha.,6-Dihydroxy-2.beta.-tetrahydropyranyloxyacetic acid 
.gamma.-lactone; and 
4.alpha.-Hydroxy-6.beta.-methoxy-2.beta.-tetrahydropyranyloxymethyl-3.alpha 
.-tetrahydropyranacetic acid .gamma.-lactone and its 6.alpha.-methoxy 
epimer. 
Further, following the procedure of Examples 1-6, but employing 
5.alpha.-hydroxy-2-benzyloxymethyl-1.alpha.-cyclopent-2-eneacetic acid 
.gamma.-lactone in place of the starting material of Preparation 3, there 
are obtained the corresponding benzyloxy-containing compounds, as follows: 
2.alpha.,3.alpha.,5.alpha.-Trihydroxy-2.beta.-benzyloxymethyl-1.alpha.-cycl 
opentaneacetic acid 5.gamma.-lactone and its 2.beta.,3.beta.-dihydroxy 
epimers; 
(3S,4S)-4-Hydroxy-6-oxo-3-benzyloxyacetyl-hexanoic acid .gamma.-lactone; 
(3R,4S)-4,6-Dihydroxy-[(1'S)-1-hydroxy-2-benzyloxyethyl]-hexanoic acid 
4.gamma.-lactone and its (1'R)-epimers; 
(3S,4S)-4-Hydroxy-6-trimethylsilyloxy-3[(1'S)-2'-benzyloxy-1'-trimethylsily 
loxyethyl]hexanoic acid .gamma.-lactone; 
3.alpha.,6-Dihydroxy-2.beta.-benzyloxyacetic acid .gamma.-lactone; and 
4.alpha.-Hydroxy-6.beta.-methoxy-2.beta.-benzyloxymethyl-3.alpha.-tetrahyd 
ropyranacetic acid .gamma.-lactone and its 6.alpha.-methoxy epimer. 
Following the procedures of Examples 7-12, but employing in place of the 
Formula XLI benzyloxyether, each of the various other 
arylmethyl-containing compounds according to formula XLI wherein R.sub.34 
is not benzyl, there are obtained each of the various R.sub.34 -ethers 
corresponding to each of the reaction products of Examples 7-12. 
Further, following the procedures of Examples 6, 10, 11, and 12, but 
employing in Example 6 and Example 10 an homologous alkyl reagents to the 
methyl-containing reagents employed therein, there are obtained each of 
the various 6.alpha.- or 6.beta.-alkoxy products of one to 5 carbon atoms, 
inclusive, corresponding to the 6.alpha.- or 6.beta.-methoxy reaction 
products of these Examples. Further, employing these homologous alkyl 
reagents in conjunction with each of the various R.sub.31 - or R.sub.34 
-containing compounds corresponding to starting material for Examples 6, 
10, 11, or 12, there are obtained corresponding products. 
Further, following the procedure of Examples 13 and 14, but using the 
6.alpha.- or 6.beta.-alkoxy reactant of formula LXI, in place of the 
6.alpha.- or 6.beta.-methoxy starting material of Example 13, there are 
obtained the corresponding 6.alpha.-or 6.beta.-alkoxy products, of one to 
5 carbon atoms, inclusive. 
Finally, following the procedure of Example 15, but employing in place of 
the 6.alpha.- or 6.beta.-methoxy starting material therein the various 
6.alpha.- or 6.beta.-formula LXXI reactants, of one to 5 carbon atoms, 
inclusive, of Formula LXXI there are obtained the corresponding 
Thromboxane B.sub.2 11.alpha.-alkyl acetals, of one to 5 carbon atoms, 
inclusive, or their respective 15-epimers. Accordingly, there is obtained 
Thromboxane B.sub.2, 11.alpha.-ethyl acetal or its 15-epimer. 
Preparation 4 
PGF.sub.2.sub..alpha., methyl ester, 9,15-diacetate (Formula LXXXIV: 
R.sub.1 is methyl and R.sub.9 is acetal). 
Refer to Chart E. 
A. To a solution of PGF.sub.2.sub..alpha., 
11,15-bis(tetrahydropyranylether), methyl ester (0.77 g.) in pyridine (5 
ml.) is added acetic anhydride (2 ml.). The mixture is stirred for about 4 
hr. under a nitrogen atmosphere and thereafter water (50 ml.) is added and 
the resulting mixture stirred for an additional one hr. The resulting 
mixture is then extracted with ethyl acetate and the combined organic 
extracts are then washed, dried, and concentrated to yield 
PFG.sub.2.sub..alpha., 11,15-bis-(tetrahydropyranyl ether), methyl ester, 
9-acetate (a formula LXXXII compound). 
B. The reaction product of part A is treated with a mixture of water, 
tetrahydrofuran, and acetic acid, and thereafter freeze-dried. The residue 
thusly obtained is then chromatographed on silica gel, yielding pure 
PGF.sub.2.sub..alpha., methyl ester, 9-acetate, a formula LXXXIII 
compound. 
C. A solution of 3.28 g. of PGF.sub.2.sub..alpha., methyl ester, 9-acetate 
in 82 ml. of pyridine is then cooled to about 0.degree. C. and with 
stirring 16.4 ml. of acetic anhydride is added. Stirring at 0.degree. C. 
is then continued for 90 min. and thereafter ice and water are added. The 
resulting mixture is then partitioned by addition of ethyl acetate and the 
organic layer thusly obtained is washed with 3N hydrochloric acid, 
saturated sodium bicarbonate, and brine. The resulting mixture is then 
dried over sodium sulfate and concentrated under reduced pressure. The 
residue so obtained is then chromatographed on 400 g. of silica gel 
eluting with 20 to 100 percent ethyl acetate in Skellysolve B. 
Thereby, 0.742 g. of PGF.sub.2.sub..alpha., methyl ester, 9,15-diacetate 
are obtained. Silica gel TLC R.sub.f is 0.59 employing the A-IX solvent 
system. 
EXAMPLE 17 
TXB.sub.2, methyl ester (Formula XCVI: R.sub.1 is methyl). 
Refer to Chart F. 
A. A solution of 800 mg. of PGF.sub.2.sub..alpha., methyl ester, 
9,15-diacetate in 32 ml. of dry benzene is treated with 1.21 g. of 
lead-tetraacetate (recrystallized from acetic acid and dried under reduced 
pressure over potassium hydroxide) at 50.degree. C. under a nitrogen 
atmosphere. Reaction conditions are maintained for about 70 min. The 
resulting mixture is then filtered through Celite and the filtrate washed 
with brine. The process of filtration is repeated and the second such 
filtrate is washed with brine, dried over sodium sulfate, and evaporated 
under reduced pressure at ambient temperature to yield a crude light 
yellow oil (900 mg.), 
(8S,9R,12S)-8-[(1'S)-3'-oxo-1'-hydroxypropyl]-9,12-dihydroxy-5-cis-9-trans 
-heptadecadienoic acid, methyl ester, 9,12,1'-triacetate, a formula XCII 
compound. Characteristic infrared absorptions are observed at 2750, 1745, 
1370, 1230, 1150, 1050, 1020, and 970 cm..sup.-.sup.1. NMR absorptions are 
observed at 9.9, 5.9, 5.0, 3.7, 2.05, and 0.97 .delta.. 
The entire crude reaction product from part A is then dissolved in 16 ml. 
of dry methanol, 2.5 ml. of trimethyl orthoformate, and 175 mg. of 
pyridine hydrochloride. This mixture is then stirred over a nitrogen 
atmosphere for about 60 hr. at ambient temperature. Thereafter about 30 
ml. of dry benzene is added and the methanol removed by concentration 
under reduced pressure. The resulting benzene-containing solution is then 
washed twice with brine, dried over sodium sulfate, and concentrated, 
yielding a residue of about 950 mg. This residue is then chromatographed 
on silica gel, eluting with 50 to 75 percent ethyl acetate in hexane. 
Fractions containing pure 
(8S,9R,12S)-8-[(1'S)-3'-oxo-1'-hydroxypropyl]-9,12-dihydroxy-5-cis-10-tran 
s-heptadecadienoic acid, methyl ester, 9,12,1'-triacetate, dimethylacetal 
(436mg.) are combined, yielding the formula XCIII thromboxane 
intermediate. Infrared absorptions are observed at 1750, 1175, 1240, 1210, 
1130, 1050, 1020, and 975 cm..sup.-.sup.1. The mass spectrum exhibits 
peaks at 556, 525, 497, 465, 404, 362, 344, 311, 139, 75, and 43. 
C. A solution of 110 mg. of sodium and 10 ml. of dry methanol is prepared 
under a nitrogen atmosphere and to this mixture is added a solution of 420 
mg. of the reaction product of part B and 5 ml. of dry methanol. The 
resulting mixture is then stirred at ambient temperature for 1.5 hr. and 
thereafter 0.5 ml. of acetic acid is added, followed by addition of 
benzene. Thereafter, the methanol is substantially removed by evaporation 
under reduced pressure. This benzene containing solution is then washed 
with brine, dried over sodium sulfate, and evaporated to yield 360 mg. of 
a pale yellow oil. This oil is then chromatographed on silica gel eluting 
with two percent methanol and ethyl acetate. Fractions containing pure 
(8S,9R,12S)-7-[(1'S)-3'-oxo-1'-hydroxypropyl]-9,12-dihydroxy-5-cis-10-tran 
s-heptadecadienoic acid methyl ester dimethylacetal (218 mg.) are obtained. 
Silica gel TLC R.sub.f is 0.19 in the A-IX solvent system. Infrared 
absorptions are observed at 3350, 1740, 1370, 1310, 1240, 1190, 1125, 
1045, and 975 cm..sup.-.sup.1. The mass spectrum exhibits peaks at 380, 
362, 349, 184, 99, and 75. 
D. A mixture of 187 mg. of the reaction product of part C under a nitrogen 
atmosphere is treated with a mixture of 4 ml. of acetic acid, 2 ml. of 
water, and 1 ml. of tetrahydrofuran for about 4 hr. Thereupon, the 
resulting mixture is stirred at ambient temperature under vacuum for about 
one hr. and the mixture then freeze dried and chromatographed on silica 
gel eluting with one percent methanol and ethyl acetate. There are thereby 
obtained 49 mg. of 11-deoxy-11.alpha.- and 11.beta.-methoxy-TXB.sub.2, 
methyl ester and 0.44 g. of TXB.sub.2, methyl ester. For the 
11-methoxy-compounds silica gel TLC R.sub.f is 0.66 in one percent 
methanol in ethyl acetate. For TXB.sub.2 methyl ester silica gel TLC 
R.sub.f is 0.44 in one percent methanol and ethyl acetate. 
E. The reaction product of part A in dry methanol is allowed to stand for 
several days in the presence of 2N ethereal hydrochloric acid yielding 
11-deoxy-11.alpha.- and 11.beta.-methoxy-TXB.sub.2 methyl ester. 
F. The reaction product of part C (258 mg.) dissolved in 12 ml. of 
tetrahydrofuran and treated under a nitrogen atmosphere with 10 ml. of 
water and one ml. of 85 percent phosphoric acid are stirred at ambient 
temperature for about 35 hr. Thereafter the mixture saturated with sodium 
chloride and extracted with ethyl acetate. The ethyl acetate extracts are 
then washed with brine, dried over sodium sulfate, and concentrated to a 
232 mg. residue. This residue is then chromatographed on silica gel 
yielding 59 mg. of 11-deoxy-11.alpha.- and 11.beta.-methoxy TXB.sub.2, 
methyl ester and 110 mg. of TXB.sub.2, methyl ester. 
Following the procedure of Example 17, but employing PGF.sub.2.sub..alpha., 
methyl ester, 9,15-dibenzoate in place of the 9,15-diacetate starting 
material, there are obtained the corresponding formula XCII 
8,11-dibenzoate, formula XCIII 8,11-dibenzoate, and formula XCIV-XCVI 
products as in Example 17. Likewise, employing each of the various 
diacylates according to R.sub.9 in place of the 9,15-diacetate starting 
material for Example 17, there are obtained the corresponding 
8,11-diacylate TXB.sub.2 intermediates of formula XCII and formula XCIII. 
EXAMPLE 18 
TXB.sub.2 and 11-deoxy-11.alpha.- or 11.beta.-methoxy-TXB.sub.2 
Refer to Chart F 
A. A solution of 300 mg. of the reaction product of part B of Example 17 in 
5 ml. of dry methanol under nitrogen is treated at room emperature with 10 
ml. of a sodium methoxide solution (120 mg. sodium dissolved in 10 ml. of 
methanol) for 45 min. Then 6 ml. of water is added and stirring is 
continued for 135 min. to hydrolyze the methyl ester. A solution of 2.5 
ml. of 85 percent phosphoric acid in water is added and some of the 
methanol is removed at reduced pressure. The aqueous residue is then 
extracted with ethyl acetate. The extracts are dried over sodium sulfate 
and evaporated, yielding 260 mg. of the residue: formula XCIV, R.sub.1 is 
hydrogen and R.sub.33 is methyl R.sub.f is 0.17 in the A-IX system. NMR 
absorptions are observed at 5.45, 4.61, 4.0, 3.38, and 0.96 .delta.. 
B. The 260 mg. residue of part A is dissolved in 12 ml. tetrahydrofuran and 
treated with 9 ml. of water and 1 ml. of 85 percent phosphoric acid for 
4.5 hr. at room temperature as in part F. The reaction mixture is worked 
up as in part F of Example 17 and chromatographed on silica gel to give 
11-deoxy-11.alpha.- and 11.beta.-methoxy TXB.sub.2, 50 mg. and TXB.sub.2, 
100 mg.