IL38080A - Octhaydro-2-oxocyclopropa(3,4)cyclopenta(1,2-b)furan-4-carboxaldehyde and process for its preparation - Google Patents

Description

38080/2 (3a^ .3b , 4tf , 4a h, 5a^) - 0GTAHYDR0 - 2-0X0-CYCLOPROPA /3,4_7 CYCLOPENTA /"l ,2-b7 FURAN - 4 -CARBOXALDEHYDE AND PROCESSES FOR ITS PREPARATION 38080/3 BACKGROUND OF THE INVENTI ON This Invention relates to a process for preparing the 3a a » 3b β, 4a, 4a β , 5a These compounds are Intermediates In the preparation of compounds presently claimed in our application No. 49500, which latter are themselves Intermediates for the important class of prostaglandins, described herewithin.

It is well known that the prostaglandin structures have several centers of asymmetry and therefore exist as stereoisomers (see Nugteren et al., Nature 212, 38-39 (1966); Bergstrom et al, Pharmacol. Rev. 20, 1 (1968)). Each formula for PGE2> PGF2a » PGE3» and PGF3a nerein represents a molecule of the optically active naturally-occurring form of the prostaglandin.

PGE, has the following structure: PGF2a has the fol lo i ng structure : — identi ca 1 — to the abovo formu-los whon - «.< < rcffcres ft-frs attachment of hydroxy 1 — in the ¾ (S) conf i gurati on. The mirror image of each formula represents a molecule of the enantiomorphic form of that prostaglandin. Thus, for example, "ent-PGEa" refers to the enantiomorph of PGE3.

The racemic or "d 1 " form of the prostaglandin consists of equal numbers of two types of molecules, e.g., a natural- con iguration prostaglandin and its enantiomorph* If one of the optical ly active isomers has dextro opti ca 1 rotatory power, the other has an equal degree of laevo optical rotatory power. A racemic mixture of equa 1 quantities of d- and 1-isomers exhibits no optical rotation. The reaction of the components of a racemic mixture with an optically-active substance results in the formation of diastereomers having different physical properties, e.g. degree of solubi li ty in a solvent. Another term used herein is "15-epimer". When referred to one of the above prostaglandins, it identifies a molecule having the opposite configuration at the C -15. a torn. Thus, "153-PGE3" refers to the product having the β (R) configuration at carbon 15 as compared wi th the α (S) configuration for PGE3.

GEE, PGF2ct, PGF2 , and PGA2, and their esters, acylates, and pha rmacologi ca 1 ly acceptab le salts, are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of the PGE2, PGF≥ , and PGA2 compounds as measured, for example, in anesthetized (pentobarbital sodium) pentol i nium-trea ed rats with indwelling aortic and right heart cannulas; pressor activity, simi larly measured, for the PGF20; compounds; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig i leum, rabbit duodenum, or gerbi 1 colon; potentiation of other smooth muscle st i mu lants ; ant i 1 i poly ti c activity as shown by antagonism of epi nephri ne- induced mobi lization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of the PGE2 and PGA2 compounds as shown in dogs with secretion stimulated by food or histamine infusion; activi ty on the central nervous system; decrease of blood platelet adhesiveness as shown by p late let- to-g lass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various bi ochemi ca 1 stimu 1 i , e.g., ADP, ATP, serotonin^ thrombi n, and collagen; and in the case of the PGE2 compounds, stimulation of epidermal proliferation and kerati nizati on as shown when applied in culture to embryonic chick and rat ski n segments .

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or al leviate a wide variety of diseases and undesirable physio-logical 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.

For example, these compounds, and especially the PGE2 compounds, are useful in mammals, including man, as nasal decongestants. For this purpose, the compounds are used in a dose range of about 10 g. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

The PGE2 and PGA2 compounds are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or i nf used intravenously, subcutaneous ly, or i nt ramuscu lar 1 y i n an infusion dose range about 0.1 g. to about 500 g. per kg. of body weight per minute, or in a total dai ly dose . by i nj eeti on or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condi tion of the patient or animal, and on the frequency and route of administration.

The PGE2, PGF2a, and GF^ compounds are useful when-ever it is desi red to i nh i b i t p la te let aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts following surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipemia> and other clinical conditions in which the unde r 1 y i ng etiology is associated with lipid imbalance or hype r 1 i p i demi a . For these purposes, these compounds are administered systemi- cally, e.g., intravenously, subcutaneous 1 y, intramuscularly, and in the form of steri le implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of . admi ni strati on is preferred. Doses in the range about 0.005 to about 20 mg. per kg. of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

The PGE2, PGF2a, and P F2p compounds are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal ci rculation and perfusion of isolated body portions, e.g., limbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the ci rcu la ti on apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradua 11 y or in single or multiple portions to the ci rculating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or a 11 of those at a total steady state dose of about 0.001 to 10 mg. per liter of ci rcu lati ng fluid . I t is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and limb transplants.

PGE2 compounds are extremely potent in causing stimulation of smooth muscle, and are also highly acti e in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. There-fore P6E2J for example, is 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 i leus, or to control or prevent atonic uterine b leed i ng -a ter abortion or delivery, to aid in expulsion of the placenta, and during the puerperiurrT. For the latter purpose, the PGE2 compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 0 g. per kg. of body weight per minute unti l the desi red effect is obtai ned. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion du ri ng pue rpe r i urn 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 PGE2, PGF2p, and PGA2 compounds are useful as hypotensive agents to reduce blood pressur in mammals including man. For this purpose, the compounds are administered by intravenous infusion at the rate of about 0.01 to about 50 ng..per kg. of body weight per minute, or in single or multiple doses of about 25 to 500 μ . per kg. of body weight total per day.

The PGE≥j PGF20;, and PGF^ compounds are useful in place of oxytocin to i nduce labor in pregnant f ema le an i ma 1 s, including man,1 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 0.01 to 50 ^g. per kg. of body weight per minute unti l 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.

The PGE2, PGF2a* and PGF^ compounds are useful for controlling the reproductive cycle in ovulating female mammals, including humans and other animals. For that purpose, PGF2a> f°r example, is administered systemi ca 1 ly at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight, 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.

Additional ly, expulsion of an embryo or a fetus is accomplished by simi lar administration of the compound during the first third of the normal mammalian gestation period. Because the PGE2 compounds are potent antagonists of epi neph r i ne- i nduced mobi lization of free fatty acids, they are useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, prevention, symptom al leviation, and cure of diseases involving abnormal lipid mobi lization and high free fatty acid levels, e.g., diabetes mellitus, vascular diseases, and hyperthyroidism.

The PGE 2 compounds promote a nd acce le rate the growth Of epidermal cells and keratin in animals, including humans, and other animals. For that reason, these compounds are useful to promote and accelerate healing of skin which has been damaged, for example, by burns, wounds, and abrasions, and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts, especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and to retard rejection of homograf ts .

For these purposes, these compounds are preferably administered topically at or near the site where cell growth and keratin formation is desi red, advantageously as an aerosol liquid or micronized powder spray, as an isotonic aqueous solution in the case of wet dressings, or as a lotion, cream, or ointment in combination with the usual pharmaceutical ly acceptable di luents. In some instances, for example, when there is substantial f luid loss as in the case of extensive burns or skin loss due to other causes, systemic administration is advantageous, for example, by intravenous injection or infusion, separate or in combi nation with the usual infusions of blood, plasma, or substitutes thereof . Alternative routes of administration are subcutaneous or intramuscular near the site, oral, sublingual, buccal, rectal, or vaginal . The exact dose depends on such factors as the route of administration, and the age, weight, and condi tion of the subject. To i l lustrate, a wet dressing for topical application to second and/or thi rd degree burns of skin area 5 to 25 square centimeters would advantageously involve use of an isotonic aqueous solution . containing 5 to 1000 μg./ml . of the PGE^ compound. Especially for topical use, these prostaglandins are useful in combination wi th antibiotics, for example, gentamycin, neomycin, polymyxin B, bacitracin, spect i nomyci n, and oxy-tetracyc 1 i ne, wi th other ant i bacte r i a 1 s , for example, mafenide hydrochloride, sulfadiazine, furazolium chloride, and n i t rof u razone , and wi th corticoid steroids, for example, hydrocortisone, prednisolone, me th y 1 p red n i so 1 one , and f lupredni solone, each of those bei ng used in the combination at the usual concentration sui table for its use alone. \ • ' 38080/2 SUMMARY OF THE INVENTION It is the purpose of this Invention to provide an optically active compound of the formula or the mirror image thereof, or a racemic compound of that formula and the mirror image thereof, -wherein f^-^ indicates attachment of the moiety to the cyclopropane ring in exo or endo configuration, and a process for preparing such compounds which comprises. converting optically active or racemic bicyclo or the mirror image thereof, or a racemic compound of that formula and the mirror image thereof, wherein ¾ and R2 are alkyl of one to carbon atoms, inclusive, or, inclusive, or phenyl, with the proviso that not more than one of the R'e is phenyl and the total number of carbon atoms is from 2 to 10, inclusive; x is zero or one, and is as defined above} b) transforming said optically active or racemic acetal to an optically active tricyclic mono or dihalo-ketone of the formula or the mi rror image thereof, or a racemic compound of that formula and the mi rror image thereof, wherein Ri, R≤, and ~ are as defined above, and wherein io is bromo or chloro and Rii is hydrogen, bromo, or chloro; c) transforming said optically active or racemic tri cyclic mono or dihaloketone to an optically active tricyclic ketone of the formula or the mirror image thereof, or a racemic compound of that formula and the mirror image thereof, whe re i n Ri , ≥ , and ~ are as defi ed above; d) oxidizing said optically active or racemic tricyclic ketone to an opti ca 1 ly active tricycli c lactone acetal of the formula or the mi rror image thereof, or a racemic compound of that formula and the mirror image thereof, wherein Ri, R2, and are as defined above j e ) hydrolyzing said optically active or racemic tricyclic lactone acetal to an optically active tricyclic lactone aldehyde of the formula or the mirror image thereof, or a racemic compound of that formula and the mirror image thereof, wherein is as defined above; Reference to Chart A, herein, will make clear the transformation from bicyclic aldehyde 1 to the lactone aldehyde VI by steps a-e, inclusive. Formulas I - VI, inclusive, hereinafter referred to, are depicted in Chart A, wherein and are al^Y1 of one to carbon atoms, inclusive, or, when taken together, -C- -C-. wherein ILj, RZ f I «8 38080/2 Rg, Rg, Ry, and Rg are hydrogen, alkyl of one to 4 carbon atoms, Inclusive, or phenyl, with the proviso that not more than one of the R's 1s phenyl and the total number of carbon atoms 1s from 2 to 10, Inclusive; and x 1s zero or one; wherein is bromo or chloro, and ^ 1s hydrogen, bromo, or chloro; and wherein ^Indicates attachment of the moiety to the cyclopropane ring 1n exo or endo configuration, or attachment of the hydroxyl to the side chain 1n alpha or beta configuration.

In the formulas herein, the broken line attachments to a ring represent substltuents 1n alpha configuration, i.e., below the plane of the paper. The wavy line Indicates attachment of a group to a cyclopentane or lactone ring 1n alpha or beta configuration, or It Indicates attachment to a cyclopropane ring 1n exo or endo configuration, or 1t Indicates attachment to the C-15 carbon of the prosta-mo1c add skeleton in α (S) or^ (R) configuration. The formula of each Intermediate as drawn herein 1s Intended to represent the particular optical Isomer which can be transformed by the processes herein to an optically active prostaglandin having the natural configuration of posta-glandlns obtained from mammalian tissues. The mirror Image of each formula then represents a molecule of the enantlo-morphic form of that Intermediate. The expression "racenrfc compound" refers to a mixture of the optically active Isomer which yields the natural configuration prostaglandin and the optically active isomer which 1s Its enantlomorph.

The blcicycHc aldehyde of Formula I in Chart A exists in 38080/2 a number of Isomeric forms. With respect to the attachment of the -CH0 group, 1t exists 1n two Isomeric forms, exo and endo. Also, with respect to the position of the cyclo-pentene double bond relative to the -CHO group, each of the exo and endo forms exists 1n two optically active (d- or 1-) forms, making 1n all four Isomers. Each of those Isomers separately or mixtures thereof undergo the reactions of Step "a of Chart A to produce compounds of Formula II. For racemic products the unresolved Isomers are used. For the optically active prostaglandins, the aldehyde or subsequent Intermediate isomers are resolved by the novel process claimed 1n our application No. 47791, and are used for preparing the optically active products. The preparation of the exo and endo aldehydes is discussed below under "Preparations".

In carrying out step a, b1 cyclic aldehyde S 1s transformed to acetal II by methods known 1n the art. Thus aldehyde I is reacted with either an aleShol of one to 4 carbon atoms, e.g., methanol, ethanol, propanol, or butanol in their Isomeric forms, or mixture of such alcohols, or preferably, a glycol having the formula wherein R3, R4, Rg, Rg, R7» and Rg are hydrogen, alk l of one to 4 carbon atoms, Inclusive, or phenyl, with the proviso that not more than one of the R's 1s phenyl and the total number of carbon atoms 1s from 2 to 10, Inclusive; and x 1s zero or one. Examples of suitable glycols are ethylene glycol, 1 ,2-propanediol , 1 ,2-hexaned1ol , 1,3- 3,5",nonaned i ol, 2,2-dimethy 1-1,3-propanedi ol, 3,3~d ϊ methy 1 -2 i 4 -hep taped i ol , 4-ethy 1 - -methy 1 -3i5"Theptaned i ol , pheny 1 -1,2-ethanedi ol , and 1-pheny 1 -1,2-propaned i o 1.

The step-a reaction is carried out under a variety of conditions using procedures general ly known, i n the art.

Thus, the reactants are dissolved in benzene and the mixture heated to remove the water formed azeotropica 1 ly. To accelerate the reaction, there may be added an acid catalyst such as p- to luenesu 1 f on i c aci d, tr i ch loroace t i c acid, zinc chloride, and the like. Alternati ely, the reactants, together with the acid catalyst and a water scavenger such as trimethyl or thoformate are warmed to 40-100° C. in an inert solvent such as benzene, toluene, chloroform, or carbon tetrachloride. The ratio of the aldehyde to the glycol is preferably between 1:1 and 1:4.

In transforming acetal I I to ketone IV, reactions known i n the art for analogous compounds are employed. In carrying out step b, acetal I I is reacted with a ketene or Cl2p- =0. For convenience, ketene Cl2C=C=0 is preferred. It is preferably generated in situ by the reaction of a 0.5~to-2.0-fold excess of dichloroacetyl chloride i n the presence of a tertiary amine, e.g., triethy lami ne, tri-butylamine, pyridine, or 1 ,4-d i azab i eye 1 o[2.2.2 Joctane, in a solvent such as n-hexane, cyclohexane, or mixture of isomeric hexanes (Skellysolve B) at a temperature of from 0° to 70° C. (See, for example, Corey et a 1. , Te t rahedrop Letters No. 4, pp. 307-310, 1970). Alternatively, the ketene C12C=C=0 is generated by adding a tri ch loroacy 1 halide to zinc dust suspended in the reaction vessel, omitting the tertiary amine.

In carrying out step c, mono- or di ha loketone l i t is reduced wi th a 2-to-5~fold excess of. zinc dust over the stoichiometric ratio of Zn:2 CI in methanol, ethanol, ethylene, glycol, and the like, in the presence of acetic acid, ammonium chloride, sodium bicarbonate or sodium di -hydrogen phosphate. Alternatively, the reaction is carried out with aluminum amalgam in a water-containing solvent such as me t hano 1 -d i e thy 1 ether-water, tet rahyd rof uran-wate r, or d ? oxane-wate r, at about 0-50° C.

In carrying out step d, tricyclic acetal ketone I is converted to a lactone by methods known in the art, for example by reaction with hydrogen peroxide, peracetic acid, perbenzoic acid, m-ch lorope rbenzoi c acid, and the like, in the presence of a base such as alkali hydroxide, bicarbonate, or orthophospha te , using a preferred molar ratio of oxidizer to ketone of 1:1.

In carrying out step e, lactone acetal V is converted to aldehyde VI by acid hydrolysis, known in the art, using di lute mineral acids, acetic or formic acids, and the like. Solvents such as acetone, dioxane, and tet rahyd rof u ran are used.

In our Patent App. o.47791 there is described Ti^i¾-4*-f tH--½te -4Wov4£l d a process for resolving a race mi c mixture of an oxo compound of the formula hyd rogen, a 1 Ky I one to carbon atoms, inclusive, or phenyl, wi th the proviso that not more than one of the R's is phenyl and the total number of carbon atoms is from 2 to 10, inclusive; x is zero or one, and ~ indicates attach-ment of the moiety to the cyclopropane ring in exo or endo configuration, which comprises the steps of a) converting the oxo compound by reaction with an optically active ephedrine to a mixture of oxazolidine d iaste reome rs, b) separating at least one oxazolidine diastereomer from said mixture, c) hydrolyzing said oxazolidine to free the optically active oxo compound, and d) recovering said optically active oxo compound .

In carrying out the resolution of the aldehyde, there is prepared an oxazolidine by reaction of the aldehyde with an optically active ephedrine, e.g. d- or 1 -ephedrine, or d- or 1-pseudoephedr i ne . Approximately equi-molar quantities of the reactants are employed in a solvent such as benzene, isopropyl ether, or dichloro- methane. Although the reaction proceeds smoothly over a wide range in temperature, e.g.. > 10-80° C, it is preferred that it be done in the range 20° to 30° C. to minimize side reactions. With the Formula-I compound, it occurs quickly, within minutes, whereupon the solvent is removed, preferably under vacuum. The product consists of the d iastereomers of the a ldehyde-ephed ri ne product, i .e. the oxazoli dines. At least one of the d iastereomers is separated by methods known in the art, including crystallization and chrpmato-graphy. In this instance, crystallization is used as the preferred method . Repeated recrysta 11 izati on of the thu,s-obtained solid oxazolidine from a sui table solvent, e.g., isopropyl ether, yields one of the d iaste reome rs in substantially pure form. The oxazolidine is then hydro lyzed by procedures known in the art to release the aldehyde.

However, I have found si lica gel wet with water surprisingly effective, using the si lica gel in a column, with the further beneficial effect that the column acts as a means of separating the ephedrine from the aldehyde. The e luted fractions are then evaporated to yield the desired resolved Formu la -VI aldehyde.

The mother liquor from the recrysta 11 i zed diastereomer contains the optical isomer having opposite configuration. , A preferred method for isolating this second d iastereomer* however, is to prepare the oxazolidine of the racemi c a Ide-hyde using ephedrine of the opposite configuration to that f i rst emp loyed above, and thereafter recr ysta 11 iz i ng as above. Finally, hydrolysis and recovery yield the resolved Formu I a -/1 aldehyde in opposite configuration to that fi rst obtained above. 38080/3 We have further found that this method 1s generally applicable for resolving aldehydes and ketones .

DESCRIPTION OF THE PREFERRED EMBODIMENTS The Invention 1s further I llustrated by, but not limited to, the following examples.

All temperatures are 1n degrees centigrade.

Infrared absorption spectra are recorded on a Perkln-Elmer model 421 Infrared spectrophotometer.

Except when speci f i ed otherw i se, undi luted (neat) samples are used.

The NMR spectra are recorded on a Varian A -60 spectrophotometer i n deuteroch lorof orm solutions with tetramethyl-si lane as an internal standard (downfield).

Circular dichroism curves are recorded on a Cary 60 recording spectropolarimeter.

The collection of chromatographic eluate fractions starts when the eluent front reaches the bottom of the column.

"Brine" herein, refers to an aqueous saturated sodium chloride solution.

Preparation 1 Endo-bi eye 1o[3.1.0]hex-2-ene-6-carboxa lde- hyde (Formula I : ~ is endo).

To a rapidly stirred suspension of anhydrous sodium carbonate (3l8.g.) in a solution of bi eye lo[2 *2.1 Jhepta- 2,5-diene (225.5 g.) in d i eh lorome thane (1950 ml.) is added I77 ml . of 2 .6^ peracetic acid containing 6 g. of sodium acetate. The addition time is about 5 min,, and the reaction temperature is 20^26° C. The mixture is stirred for an additional 2 hrs. The reaction mixture is fi ltered and the fi lter cake washed with d i ch loromethane . The fi ltrate and washings are concentrated under vacuum. About 8l g. of the resulting liquid is stirred with 5 ml. of acetic acid in 200 ml. of di ch loromethane for 5·5 hrs., then concentrated and disti lled. The fraction boi ling at 69- 75° C*/30 mm. represents the desi red Formu la- I aldehyde, 73 g. NMR peaks at 5.9 and 9.3 (doublet) 6.

Vi The various Formu la- 1 - to- # intermediates, hereinafter, exist in exo as well as endo forms. A preferred route to the exo form of the Formula-! bicyclic aldehyde is by the steps shown in Chart G, us i ng; methods known in the art. See South African Patent 69/4809 issued July 3, 1970.: In Formulas XXVI I to XXX^ t≡l, the attachment to the cyclopropane ring by a straight line extended downward at an angle to the right indicates the exo configuration. Thus, diazoacetic acid is added to a double bond of eye 1 opentad iene to give an exo-endo mixture of the Formu la-XXVI I I b i eye 1 o[3.1.0]-hexene substituted at the 6-position with a carboxyl. The exo-endo mixture is treated with a base to isomerize the endo isomer in the mixture to more of the exo isomer. Next the carboxyl group at 6 is transformed to an alcohol group and thence to the exo ldehyde of the Formula XXX.

Example 1 d l~Endo-b i eye lo[ .1.0]hex-2-ene -6-ca rboxa ldeh yde Acetal of Ethylene Glycol (Formula I I : Ri and R2 taken together are -CH2CH2- and ~ is endo).

Refer to Chart A. A solution of Formula-I endo-bicyclo [3.1.0]hex-2-ene-6-carboxa ldehyde (216 g., Preparation 1), ethylene glycol (1 0 g.), and p- to luene su 1 f oni c acid (0.5 g) in benzene (l 1.) is heated under ref lux. The azeotrop-ical ly disti lled water (29 ml. after 20 hrs.) is collected in ¾ Dean-Stark trap. The reaction mixture is cooled, treated with sodium carbonate (0.3 g.), and disti lled at reduced pressure. The fraction collected at *60° C. 3-mm. is partitioned between ether and water. The ether layer is extracted with water, dried over anhydrous magnesium sulfate, and concentrated to the Formu la- I I bi eye 1 i c aceta 1 , a light tan oi l (70 g.); NMR peaks at 1.1, 1.6-2.9, 3. - .2, 4.42, and 5-3-6.0 6.

Following the procedures of Example 1 but using the exo Formula-I (XXX) compound, there is obtained the cor res - CHART G ponding exo Formula- 1 I acetal.

Following the procedures of Example 1 but using either the endo or exo. form of the Formula- 1 aldehyde and substituting for the ethylene glycol one of the following glycols: 1,2-propaned i ol , 1,2-hexanedi ol , l,3~butanedi o I , 2,3-pentane diol, 2, -hexaned i ol , 3, -octaned i o 1 , 3.»5-nonaned i ol, 2,2-di me thy 1 -l,3_propaned ί o 1 , 3j3-dimethyl -2, -heptanedi ol , 4-ethy 1 -4-me thy 1 -3,5"heptaned i ol , pheny 1 -1,2-ethaned i ol and 1-pheny 1 -1,2-propaned i ol , there are obtained the correspond- i ng Formula-l | acetals.

Following the procedures of Example 1 but using either the endo or exo form of the Formula-I aldehyde and substituting for the ethylene glycol one of the fol lowing alcohols methanol, ethanol, 1-propanol, or 1-butanol, there are ob-tained the corresponding Formula-I I acetals.

Example 2 dl-Tricycl ic D i ch 1 oroketone (Formula I I I : i and R≥ taken together are -CH2CH2- and ~ is endo). Refer to Chart A. A solution of the Formijla-l l bicyclic acetal of Example 1, ( 6 g.) and triethylami ne (80 g.) in 300 ml. of isomeric hexanes (Skellysolve B) is heated at ref lux, wi th sti rring, and treated dropwise with di ch loroacety 1 chloride (100 g.) in Skel lysolve B over a 3-hour period. The mixture is cooled and fi ltered to remove solids. The fi ltrate and combined Skellysolve B washes of the fi ltered solid is washed wi th water, $ aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate and concentrated to the title compound, a dark brown oi l (91 g.). An additional quantity (13 g.) is recovered from the fi lter cake and aqueous washes. Alter-natively, the triethy lami ne is added to a solution of the bicyclic acetal and the di ch loroacety 1 chloride, or the triethy lami ne and the d i ch loroacety 1 are added separately but simultaneously to a solution of the b i cycl i c ace ta 1 in Ske 11 yso lve B .

Fol lowing the procedures of Example 2 but using the exo Formula-l l compound, there is obtained the corresponding exo Formu la - 1 I I t r i eye 1 i c d i ch 1 oroke tone .

Fol lowing the procedures of Example 2, but using the Formula-l l compounds disclosed fol lowing Example 1, there are obtained the corresponding Formula-I l l compounds.

Example 3 di=Tri cycl ic Ketone (Formula IV: Ri and R∑ are methyl and ~ is endo) .

A solution of the Formula-I l l d i ch loroketone of Example 2 (10k g.) in dry methanol (1 1.) is treated wi th ammonium chloride (lOO g.) and smal l portions of zinc dust. The o temperature is al lowed to rise to 60 C. After 200 g. of zi nc have been added, the mixture i s heated under ref lux for an addi tional 80 min. The mixture i s cooled, the solids fi ltered off , and the fi ltrate concentrated. The residue is treated wi th d i ch 1 orome tha ne and 5$ aq ueous sod i urn bi carbonate and the mixture is fi ltered. The d i ch 1 orome tha ne layer is washed wi th $ aqueous sodium bicarbonate and water dried, and concentrated to the ti tle compound, a dark brown oi l (56 g.); infra-red absorption at 1760 cm" 1.

Fol lowi ng the procedures of Example 3 but usi ng the exo Formula-I l l compound, there is obtai ned the correspondi ng exo Formu la- I V tricyclic ketone.

Fol lowi ng the procedures of Example 3 but using the Formula-I l l compounds disclosed fol lowi ng Example 2, there are obtai ned the correspondi ng Formu la- IV compounds.

Example 4 d 1 - Tr ί eye 1 i c Lactone Acetal (Formula V: Ri and R2 are methyl and ~ is endo), and Tricyclic Lactone Aldehyde (Formula VI : ~ is endo) .

Refer to Chart A. A solution of the Formula-I V product of Example 3 ( 6 g.) in di ch loromet hane (400 ml .) is treated wi th potassium bicarbonate (40 g.) and cooled to 10° C. A solution of meta-ch loroperbenzoi c acid (55 « of 85$) in di ch loromethane (600 ml .) is added over 40 min. The mixture i s sti rred at 10° C. for 1 hr., then warmed to ref lux for 40 min. The mixture is cooled and fi ltered, and the fi ltrate is washed with 5$ sodium bicarbonate containi ng 60 g/1. sodium thiosulfate, and water. The d i ch loromethane layer is dried over anhydrous sod i urn su 1 fa te , and concentrated to the Formula-V acetal (6l g.). A portion (58 g.) is chromato-graphed on 2 kg. of si lica gel packed in ethyl acetate- Skel lysolve B (50-50) . E lution wi th 50-50, 70-30 and 80-20 ethyl acetate-Ske 1 lyso Ive B yields a fraction (24.9 g.) shown by NMR to be a mixture of dimethyl acetal (v) and aldehyde (Vl ). A portion (22.6 g.) of the mixture is dis-solved i n 100 ml. of (6θ-4θ) formic acid-water and al lowed to stand 1 hr. at 25° C. The solution is then concentrated under vacuum and the residue taken up in di ch loromethane .

The di ch loromethane solution is washed with 5^ aqueous sodium bicarbonate and water, dried over sodium sulfate, and concentrated to a brown oi l (17·5 9>) which crystal lizes on seeding. Trituration of the crystals wi th benzene leaves crystals of the Formula-VI aldehyde (9.9 g.). An analytical sample is obtai ned by recrysta 11 iza ti on from tetrahydrof uran, m.p. 72-74° C (corr.); infrared absorption peaks at 2740, 1755, 1710, I695, 119 , II 5, 1020, 955, and 910, cm" 1; NMR peaks at 1,8—3. 9 5.0-5,¾t and 9.92 o.

Following the procedures of Example k but using the exo Formula-IV lactone acetal compound, there is obtained the corresponding exo Forraula-V lactone acetal Likewise, following the procedures of Example k using the exo Formula—V compound, there is obtained the corresponding exo Formula-IV lactone aldehyde.

Following the procedures of Example but using the Formula-IV, compounds disclosed following Example 3 there are obtained the corresponding Formula-V compound and, thence, the corresponding Formula-VI lactone aldehydes.

Claims (8)

38080/2 WHAT IS CLAIMED IS:

1. . An optically active compound of the formula CHO or the mirror Image thereof, or a racemlc compound of that formul a and the mirror image thereof, wherein Indicates attachment of the moiety to the cycl opropane ring 1n exo or endo configuration .

2. An optical ly active compound of claim 1 having the formul a shown.

3. A racemlc compound of claim 1 .

4. A compound of claim 1 In the endo configuration.

5. A process for preparing an optically active tricycl ic lactone aldehyde of the formula or the mirror Image thereof, or a racemlc compound of that formul a and the mirror Image thereof, wherein ^ Indicates attachment of the aldehyde group to the cyclopropane ring 1n exo or endo configuration, which comprises the steps of a) converting optical ly active or racemlc b1cyclo-¾ ,l .0]hex 2-ene-6-carboxaldehyde to an optical ly active acetal of the formul a -73-- 38080/2 or the mi rror image thereof, or a racemic compound of that formula and the mi rror image thereof, wherei n Ri and R2 are phenyl, wi th the provi so that not more than one of the R 's is phenyl and the tota l number of carbon atoms i s from 2 to 10, i nclusive, x is zero or one, and ~ is as defi ned above; b) transformi ng said optical ly acti ve or racemic acetal to an optica l ly active tri cycli c mono or dihalo-ketone of the formu la or the mi rror image thereof, or a racemic compound of that formu la and the mi rror image thereof, wherei n Ri, R2, and ~ are as def ined above, and wherei n Rio is bromo or chloro, and 11 is hydrogen, bromo, or chloro; c) transforming said optical l y active or racemic tri eye 1 i c mono or diha loketone to an opti ca l l y active tri cycl i c ketone of the formu la or the mi rror image thereof, or a racemic compound of that formula and the mi rror image thereof, wherei n Ri, Kz» and ~ are as defi ned above; 38080/2 d) oxidizing said opt i ca 11 y act i ve or racemic tricyclic ketone to an optical ly acti e tricycli c lactone acetal of the formula or the mi rror image thereof, or a racemic compound of that formula and the mi rror image thereof, wherein Ri, 2 i and ~ are as defined above; and e) hydrolyzing said optical ly active or racemic tricyclic lactone acetal to said optica l ly active or racemic tricyclic lactone aldehyde.

6. A process of claim 5, wherein Ri and Ra taken together are -CH2-C (CH3)2-CH2- .

7. c . icyclo A process accordi ng to claim b, wherein said/nexene car box a ldehyde is in the endo configuration.

8. A process for prepari ng an optical ly active tricyclic lactone aldehyde of the formula or the mirror image thereof, or a racemic compound of that formula and the mi rror image thereof, wherein ~- indicates attachment of the aldehyde group to the cyclopropane ring 38080/2 in exo or endo configuration, which compri ses the steps of a) transforming an optical ly active aceta i of the formu la or the mi rror image thereof, or a racemic compound of that formula and the mi rror image thereof, wherein i and Ra are alkyl of taken together, Ra hydrogen, alkyl : one to 4 carbon atoms, inclusive, or phenyl, wi th the proviso that not more than one of the R's is phenyl and the total number of carbon atoms is from 2 to 10, inclusive; x is zero or one, and ~ is as defined above, to a racemic or optical ly active tricyclic mono or dihalo-ketone of the formula wherein Ri, R2, and ~ are as defined above; b) transforming said racemic or optical ly active tricyclic mono or dihaloketone to a racemic or optical ly active tri eye 1 i c ketone of the formula wherein Ri, R2, and are as defined above; c) oxidizi ng said optical ly active or racemic tri - 38080/2 cyc l ic ketone to an optica l ly active tri cyc li c lactone aceta l of the formula or the mi rror image thereof , or a racemic compound of that formu la and the mi rror image thereof^ wherein Ri , R2, and ~ are as def ined above; and d) hydrolyz i ng said racemi c or opti ca l l y acti ve tri ¬ cyclic lactone acetal to said racemic or optically active tricyclic lactone aldehyde. A process of claim 8 wherein Ri and R2 taken together are -CH2-C (CH3 )2-CH2- . A process according to claim 8 wherein said acetal in the endo configuration. Attorneys fo Applicants