5-SUBSTITUTED DERIVATIVES OF MYCOPHENOLIC ACID

Abstract: The disclosed hexenoic acid side-chain derivatives of mycophenolic acid are therapeutic agents advantageous in the treatment of disease states indicated for mycophenolic acid and/or mycophenolate mofetil, including immune, inflammatory, tumor, proliferative, viral or psoriatic disorders.

Description: 5 - SUBSTITUTED DERIVATIVES OF MYCOPHENOLIC ACID Field of the Invention The present invention relates to mycophenolic acid derivatives, particularly to a series of compounds having novel side chains. The invention is also directed to formulations and methods for treatment. Background Information Mycophenolic acid ("MPA") was initially described as a weakly-active antibiotic found in the fermentation broth of Penicilliύm brevicompactum, having the following structure. Mycophenolic Acid MPA and certain related compounds, such as mycophenolate mofetil (the morpholinoethyl ester of MPA), having the following structure: have more recently been described as having particularly advantageous properties as immunosuppressant drugs. Various derivatives of mycophenolic acid, their synthesis and uses in the treatment of autoimmune disorders, psoriasis, inflammatory diseases, including, in particular, rheumatoid arthritis, tumors, viruses, and for treatment of allograft rejection, are described in U.S. Patents Nos. 4,686,234; 4,725,622; 4,727,069; 4,748,173; 4,753,935; 4,786,637; 4,808,592; 4,861,776; 4,868,153; 4,948,793; 4,952,579; 4,959,387; 4,992,467; 5,247,083; and U.S. Patent Application Serial No. 07/927,260, filed August 7, 1992. As immunosuppressive agents, the previously described esters and derivatives of mycophenolic acid are useful in treating auto-immune related disorders, glomerulonephritis and hepatitis, and in preventing allograft rejection. As anti-inflammatory agents, they are useful in treating rheumatoid arthritis. As anti-tumor agents, they are useful in treating solid tumors and malignancies of lymphoreticular origins. See also U.S. Patents No. 3,825,571 and 3,853,919; Japanese Pat. No. J 01290667; J. Med. Chem. , 33(2), 833-8 (1990) ; Austr. J. Chem. , 31(2), 353-64, (1978); and J. AntiJiot., 29(3), 275-85, 286-91 (1976) . The disclosed compounds are described as having anti-tumor, immunosuppressive, anti-viral, anti-arthritic and/or anti-psoriatic activities. The article by J.W. Patterson and G. Huang, Chemical Communications, 1579 (1991) describes synthetic methodology of interest with respect to such compounds. The above-cited patents, publications, and the references/ publications referenced therein, are all incorporated herein by reference. SUMMARY OF THE INVENTION One aspect of the present invention concerns mycophenolic acid derivatives, i.e., the compounds of Formula I: wherein: R 1 is H or C(O)R !0 , where R 10 is lower alkyl, aryl or NH-aryl; and Z is a side chain selected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH: Formula ZA wherein: Z 1 is H, lower alkyl, halo or CF 3 ; Z 2 is H, OH, lower alkyl, lower alkoxy, aryl, or CHj-Z 13 , where Z 13 is halo, CN, aryl or heteroaryl; Z 3 is H, OH, lower alkyl, lower alkenyl, lower alkoxy, halo, phenyl, P(O) (OCH 3 ) 2 , P(O) (OH) (OCH 3 ) , NHZ 11 , SH or S(0) m Z 12 , where Z 11 is H, alkyl, acyl, or lower alkyl sulfonyl, Z 12 is lower alkyl, and m is 0, 1 or 2; Z 4 is H, OH, lower alkyl, halo, or phenyl, provided, however that Z 4 is not OH or halo when Z 3 is OH, halo, P(O) (OCH 3 ) 2 , P(O) (OH) (OCH 3 ) , NHZ 11 , or SZ 12 ; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atoms; and G is OH, lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH 2 ) n -NG'G 2 , or O- (CH 2 ) n -N=G 3 , where n is an integer from 1 to 6, i G 1 is H or lower alkyl, 5 G 2 is H or lower alkyl, and =G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -0-, -S-, or -N(G 4 )- where G 4 is H or lower alkyl; 10 provided that when Z 1 is methyl, Z 2 , Z 3 and Z 4 are not all H, and provided that when R 1 , Z 3 and Z 4 are all H and Z 1 is methyl, Z 2 is not H or OH; or Formula ZB wherein: Z 5 is H or lower alkyl; 25 Z 8 is H, lower alkyl or forms a double bond with D 2 ; D 1 and D 2 together with their adjacent carbon atoms form an optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and G is as defined above; or 30 Formula ZC f 40 wherein: Z 8 is H or lower alkyl; and Z 5 and G are as defined above; or Formula ZD wherein: D 3 is -CH 2 - or -CH 2 -CH 2 -; and G is as defined above; or Formula ZE wherein: Z 6 is H, lower alkyl, lower alkoxy, COOH, NH 2 , azido or halo; Z 7 is H, lower alkyl, lower alkoxy or halo; and Z 5 and G are as defined above; or Formula ZF wherein: Z 1 and G are as defined above; or wherein: D 3 , Z 2 , Z 3 , Z 4 and G are as defined above; or Formula ZH wherein : D 4 is - CH j - , - CHj-CHj- , - CH J - CH J - CH J - -0- , or -0- CH 2 - ; and Z 1 and G are as defined above; and the pharmaceutically acceptable salts thereof. In another aspect, the invention relates to a pharmaceutical composition containing a therpeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. In still another aspect, the invention relates to a method of treating immune, inflammatory, tumor, proliferative, viral and psoriatic disorders in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Yet another aspect of the invention relates to intermediates of Formula II: wherein: R 2 is lower alkyl or benzyl; and Z 3 and Z 4 are H or lower alkyl, provided that at least one is H. Still another aspect of the invention relates to the process of using the intermediates of Formula II in the synthesis of (E) -6- (l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2 (S) ,4-dimethyl-4- hexenoic acid, by 2-alkylation with an alkyl iodide, and hydrolysis of the oxazolidinone using LiOH, to give a mixture of (R) and 2 (S) isomers, optionally followed by formation of the (+) -α-methylbenzylamine salt and conversion of the salt to (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxoisobenzofuran-5-yl) -2(S) ,4-dimethyl- -hexenoic acid. DETAILED DESCRIPTION OF THE INVENTION Definitions and General Parameters The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein. The term "alkyl" refers to a fully saturated monovalent radical containing only carbon and hydrogen, and which may be a cyclic, branched or straight chain radical. This term is further exemplified by radicals such as methyl, ethyl, t-butyl, pentyl, pivalyl, heptyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, adamantyl, and the like. The term "lower alkyl" refers to a cyclic, branched or straight chain monovalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, iεopropyl, n-butyl, t-butyl, i-butyl (or 2-methylprσpyl) , cyclopropylmethyl, i-amyl, n-amyl, and hexyl. The term "alkylene" refers to a fully saturated divalent radical containing only carbon and hydrogen, and which may be a branched or straight chain radical. This term is further exemplified by radicals such as methylene, ethylene, n-propylene, t-butylene, i-pentylene, and n-heptylene. The term "lower alkylene" refers to a fully saturated divalent alkyl radical of one to six carbon atoms. This term is further exemplified by such radicals as methylene, ethylene, n-propylene, i-propylene, n-butylene, t-butylene, i-butylene (or 2-methylpropylene) , isoamylene, pentylene, and n-hexylene. The term "lower alkenyl" refers to an unsaturated monovalent hydrocarbon radical of one to six carbon atoms. This term is further exemplified by such radicals as vinyl, prop-2-enyl, pent-3-enyl, and hex-5-enyl. . The term "lower acyl" refers to the group -C(0)-R', where R' is lower alkyl. The term "aryl" refers to a monovalent unsaturated aromatic carbocyclic radical having a single ring (e.g., phenyl) or two condensed rings (e.g., naphthyl) , which can optionally be mono-, di- or tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano. The term "heteroatom" refers to oxygen, sulfur and nitrogen, unless otherwise specified. The term "heteroaryl" refers to a monovalent aromatic carbocyclic radical having at least one heteroatom within the ring, such as quinolyl, benzofuranyl, pyridyl, morpholinyl and indolyl, which can optionally be mono-, di- or tri-substituted, independently, with OH, COOH, lower alkyl, lower alkoxy, chloro, fluoro, trifluoromethyl and/or cyano. The term "optionally substituted, saturated or unsaturated carbocyclic or heterocyclic ring of 3 to 7 atoms" as used with reference to a side chain of Formula ZB encompases side chains of the following structures: where the line inside each respective ring indicates the optional presence of a double bond and X 1 , X 2 , X 3 , X 4 and X 5 can independently be -CHX a -, -C(O)-, -C(N-X)-, -C(N-NX d X c ) -, -O-, -S-, -S(O)-, -S(0) 2 - or -NX 0 -, where X a is H, lower alkyl or forms a double bond; X b is acyl, carbamoyl or ureido; X c is lower alkyl, C(0)X α , StO)^ or C(0)NX d X e ; and X d and X° are independently H or lower alkyl; provided that if more than one heteroatom is present such heteroatoms are separated by at least one carbon atom. The term "halo" refers to fluoro, bromo, chloro and iodo, unless otherwise specified. The definition "=G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that is -0-, -S-, or -N(G 4 )-" means that -N=G 3 represents a heterocyclic derivative such as pyrrolidinyl, piperidinyl, hexamethyleneiminyl, imidazolidino, thiazolidino, morpholino, thiomorpholino, piperazino, thiopentamethyleneimino, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. A "pharmaceutically acceptable salt" is a salt that retains the biological effectiveness and properties of the compounds of formula I and which are not biologically or otherwise undesirable. Salts may be derived from acids or bases. The term "pharmaceutically acceptable anion" refers to the anion of acid addition salts. "Pharmaceutically acceptable cation" refers to the cation of base addition salts. The acid addition salts are derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfate and bisulfate salts) , nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethaneεulfonic acid, salicylic acid, p-toluenesulfonic acid, and the like. The base addition salts may be derived from inorganic bases, and include sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include those formed from primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, hiεtidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like. Preferred organic bases are isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, and choline. The term "treatment" or "treating" means any treatment of a disease in a mammal, including: (i) preventing the disease, that is, causing the clinical symptoms of the disease not to develop,- (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms. The term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated. This will vary depending on the patient, the disease and the treatment being effected. "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term " (±) " is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) depending on the direction (dextro- or laevorotary) which they rotate the plane of polarized light at the wavelength of the sodium D line. The compounds of the invention may possess one or more asymmetric centers, and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of Formula (I) depends upon the number of asymmetric centers present (there are 2 n stereoisomers possible where n is the number of asymmetric centers) . The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound of Formula (I) by conventional means. The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated. Specific examples of the separation of isomers are set forth in the Examples. "Structure of Formula I" refers to the generic structure of the compounds of the invention. The chemical bonds indicated as a wavy line, for example for Z 3 and Z 4 in Formula 105 below, indicate a racemic mixture. Nomenclature The naming and numbering of the compounds of the present invention is illustrated below. The isobenzofuranyl nucleus of the compounds of Formula I is numbered as follows: Side chains of Formula ZA are numbered as shown below: Representative compounds of Formula I where the side chain is ZA are as follows: and are named: 1. (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2- (S) ,4-dimethyl-4-hexenoic acid; 2. (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2- (S) -ethyl-4-methyl- -hexenoic acid; 3. methyl (E) -6- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-propionyloxy- isobenzofuran-5-yl) -3-hydroxy-2-methylsulfonylamino-2-phenyl-4- trifluoromethyl-4-hexenoate; 4. 2-morpholinoethyl (E) -4-chloro-6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) -3-methyl-2-methylsulfonyl-4-hexenoate (where G 3 is - (CH 2 ) 2 -0- (CH^-) ; 5. thiomethyl (E) -2- (R) -chloro-6- (4-benzoyloxy-l,3-dihydro-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) - -methoxy-3-methyl-4-hexenoate. Side chains of Formula ZB in which D 1 and D 2 do not contain a heteroatom are numbered as shown below: representative compounds of which are as follows: and are named: 1. (E) -2-{2- [2- [1,3-dihydro- -hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl]ethylidene] cyclopent-1- (S) -yl}acetic acid; 2. (E) -2-{2- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] -l-ethylcyclohex-l-yl}acetic acid; 3. (E)-2-{2-[2- (4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]cyclohept-l-yl}propionic acid dimethylamide (where G 1 and G 2 are both methyl) ; 4. (E)-2-{2-[2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] -5-oxocyclohex-l-yl}acetic acid, which can also be named {4- [2- ( -hydroxy-6-methoxy-7-methyl-3-oxo- 1,3-dihydro-isobenzofuran-5-yl)ethylidene] -tetrahydro-pyran-3-yl}- acetic acid; 5. thiomethyl (E) -2-{2- [2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclobut-1- (R) -yl}octanoate. Side chains of Formula ZB that include a heteroatom are numbered starting with the heteroatom as position 1 of the ring, for example, as shown below for a 6-atom heterocycle. Representative compounds of Formula I where the side chain is ZB including a heteroatom are as follows: and are named: 1. (E) -2-{4- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene]tetrahydrofuran-3-yl}acetic acid; 2. hexyl (E) -2-{4- [2- (4-acetoxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] -3-methylpiperidin-3 (S) - yl}propionate; 3. (E) -2-{4- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] thiepan-3-yl}heptanoic acid dimethylamide (where G 1 and G 2 are both methyl) . Side chains of Formula ZC are numbered as εhown below: Repreεentative compoundε of Formula I where the side chain is ZC are as follows: and are named: 1. 3- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5- ylmethyl) -2-methylcyclopent-2-enyl-l- (S) -acetic acid; 2. hexyl 3- (4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-ylmethyl) cyclopent-2-enyl-1-acetate; 3. 2- (S) - [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-ylmethyl) -2-methylcyclopent-2-en-l (S) -yl] -1- (S) -3- methylbutyric acid; 4. (2-dimethylamino) ethyl 3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-ylmethyl) -2-hexylcyclopent-2-enyl-1-acetate (where G 1 and G 2 are both methyl) . Side chains of Formula ZD are numbered as εhown below: where D ' CH. where D ' i s CHη H Representative compoundε of Formula I where the εide chain iε ZD are aε follows: are named aε follows: 1. (E) -3- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) ethylidene] cyclopentane-1- (R) -carboxylic acid; 2. hexyl (E) -4- [2- (4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) ethylidene] cyclohexane-1-carboxylate; 3. methyl (E) -3- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) ethylidene] cyclopentane-1-thiocarboxylate. Side chains of Formula ZE are numbered as shown below: Repreεentatiye compounds of Formula I where the side chain is ZE are aε follows: and are named: (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -l-methylprop-l-en-l-yl]benzoic acid; (E) -2- [3- (4-acetoxy-1, 3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)prop-l-en-l-yl] -6-methylbenzoic acid dimethylamide (where G 1 and G 2 are both methyl) ; hexyl (E) -6-chloro-2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -1-hexylprop-l-en-l-yl] -4-methoxybenzoate. Side chains of Formula ZF are numbered as εhown below: Repreεentative compounds of Formula I where the side chain is ZF are aε follows: and are named: 1. 4- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5- ylmethyl) -3-methylcyclopent-3-ene-l- (S) -carboxylic acid; 2. ethyl 4- (4-acetoxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-ylmethyl) -3-hexylcyclopent-3-ene-1-carboxylate; 3. thiomethyl 4- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-ylmethyl)cyclopent-3-ene-1-carboxylate. Side chainε of Formula ZG are numbered as εhown below: Repreεentative compounds of Formula I where the εide chain iε ZG are aε follows: and are named: 1 . 3 - [3 - (S) - (l , 3 -dihydro-4 -hydroxy- 6 -methoxy- 7 -methyl - 3 -oxoisobenzo- furan- 5 -yl) cyclopent- 1 -en- l -yl] -propionic acid; 2 . methyl 3 - [3 - (R) - (1 , 3 -dihydro-4 -hydroxy- 6 -methoxy- 7 -methyl -3 - oxoi obenzof uran- 5 -yl ) cyclopent - 1 -en- 1 -yl] - 2 - chloro- 2 -methyl - 3 - hydroxy propionate ; 3. 3- [3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-propionyloxyisobenzo- furan-5-yl) cyclopent-1-en-l-yl] -3-methyl-2-methylsulfonamido-2-phenyl propionic acid; 4. methyl 3- [3- (R) - (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) cyclopent-1-en-1-yl] -2- (dimethylphoεphono) propionate; 5. 3- [3- (4-benzoyloxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzo- furan-5-yl)cyclohex-1-en-l-yl] -2 (R) ,3-dimethyl-2-methoxy propionic acid. Side chainε of Formula ZH are numbered aε shown below: Representative compounds of Formula I where the εide chain iε ZH are aε followε: are named as follows: 1. (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -1-methylprop-l-en-l-yl] cyclopentane-1- carboxylic acid; 2. Ethyl (E) -2- [3- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -1-methylprop-l-en-l-yl] cyclohexane-lR- carboxylate; 3. Thiomethyl (E) -2- [3- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)prop-1-en-1-yl] cycloheptane-1-carboxylate. Compoundε of Formula I where the side chain iε ZH, in which D 4 iε a heteroatom, are numbered differently. For example, the compound where D 4 iε oxygen, Z 1 is methyl, and G iε hydroxy, is named aε followε: 4. (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -1-methylprop-1-en-1-yl]furan-3-carboxylic acid. Synthetic Reaction Parameters The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF") , dimethylformamide ("DMF") , chloroform, methylene chloride (or dichloromethane) , diethyl ether, methanol, pyridine and the like] . Unless specified to the contrary, the εolventε uεed in the reactionε of the present invention are inert organic solvents. The term "q.s." meanε adding a quantity εufficient to achieve a stated function, e.g., to bring a εolution to a deεired volume (for example, q.ε. to 100%). Unleεs εpecified to the contrary, the reactionε deεcribed herein take place at atmospheric presεure within a temperature range from 5°C to 100°C (preferably from 10°C to 50°C; most preferably at "room" or "ambient" temperature, e.g., 20°C) . Further, unless otherwise specified, the reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about 5°C to about 100°C (preferably from about 10°C to about 50°C; most preferably about 20°C) over a period of about 1 to about 10 hours (preferably about 5 hours) . Parameters given in the Examples are intended to be specific, not approximate. Isolation and purification of the compounds and intermediates described herein can be effected, if deεired, by any suitable separation or purification procedure such as, for example, filtration, extraction, cryεtallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of theεe procedureε. Specific illuεtrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of courεe, alεo be uεed. Except aε εpecified to the contrary, the compounds and intermediates are isolated and purified by conventional means. As indicated above, compounds that have one asymmetric center can exist as R or S enantiomerε or aε mixtureε thereof. If deεired, the individual R and S enantiomerε can be εeparated by known methods, or can be syntheεized individually. For example, an acidic racemic compound can be converted into a εalt, ester or amide with a chiral baεe, alcohol or amine. The reεulting mixture of diaεtereomerε can be εeparated by conventional means such aε cryεtallization, diεtillation or chromatography. The separated compounds can then be subjected to conventional reactionε εuch aε hydrolysis, to produce the individual enantiomers of the chiral acid. A chiral compound which is basic can be resolved analogously. Alternatively, a chiral compound can be separated into enantiomers by selective reaction of one of the enantiomerε, or of a derivative. For example, an ester or amide of a racemic compound can be εelectively hydrolyzed by chemical or biological (e.g., enzymatic) reactionε to produce the individual enantiomerε of the racemic compound. Compoundε that have two aεymmetric centerε exiεt as two diastereomerε. The diaεtereomerε can be separated by conventional methods such as crystallization, distillation or chromatography. Each εeparate diaεtereomer exiεts as a pair of enantiomers which can be separated by conventional methods such aε those deεcribed above. Alternatively, the diaεtereomerε or enantiomers can be prepared εeparately, by meanε of εtereospecific or diaεtereoselective reactions known to those skilled in the art. Alternatively, chiral precursorε to chiral compoundε of this invention can be prepared uεing known procedureε such as stereoselective or stereoεpecific reactions, after which the chiral precursor can be converted into the chiral product. Synthesis of the Compounds of Formula I The compounds of Formula I can be prepared by following the procedures described with reference to the following Reaction Schemes. As used in the Reaction Schemeε, the εubεtituentε (e.g., m, D 1 , G, Z 1 ) have the same meaning as described in the Summary of the Invention unlesε otherwiεe εpecified in a particular inεtance. Subεtituentε introduced for purposes of a particular reaction scheme (e.g., R* in Reaction Scheme ZA-A) are defined in the detailed description of the corresponding synthesiε. Starting Materials Mycophenolic acid iε commercially available, e.g., from Sigma Chemical Company, St. Louiε, MO. The mycophenolic acid lower alkyl esterε of Formula 1 can be εynthesized, for example, aε deεcribed in Synthetic Organic Chemistry by Wagner and Zook (Wiley, New York) 1956, see pages 479- 532. Other reactants, such as methoxyethoxy methyl chloride, t-butyl- dimethylεilyl chloride, and variouε orthoeεterε are likewiεe commercially available or may be readily prepared by thoεe skilled in the art using commonly employed synthetic methodology. Preparation of Compounds of Formula I-ZA One method of preparing compounds of Formula I where Z is sidechain of Formula ZA, illustrated aε compoundε of Formula I-ZA, iε shown below in Reaction Schemeε ZA-A to ZA-M. REACTI0N SCHEME ZA-A lkyl Formula 101 Formula 102 Formula 102 Formula 103 F Formula 104 Formula 103a Fo alkyl Formula 104a Formula 105 Formula I-ZA-A Preparation of Formula 102 Aε illuεtrated in Reaction Scheme ZA-A, Step 1, the phenolic hydroxyl group of a mycophenolic acid lower alkyl ester iε protected. A mycophenolic acid lower alkyl eεter of Formula 101, in a εolvent (such as ether, ethyl acetate, DMF or preferably dichloromethane) , is reacted with an equimolar amount of a halogenated protecting group (εuch aε: methoxyethoxymethyl chloride; a εulfonyl chloride, e.g., toεyl chloride, mesyl chloride; or a silyl chloride, e.g., trimethylsilyl chloride, diphenylmethylsilyl chloride, or preferably tert-butyldimethylεilyl chloride) in preεence of an equimolar amount of an organic baεe (εuch aε diiεopropylethylamine, triethylamine or imidazole) . The reaction takeε place at -20 to 35°C (preferably at 25°C) for 1 to 24 hours (preferably 16 hours) to give the corresponding compound of Formula 102 (where R 1 iε the protecting group) . Preparation of Formula 103 Aε illustrated in Reaction Scheme ZA-A, Step 2, the side chain double bond of a protected mycophenolic acid lower alkyl ester is ozonized to yield an aldehyde. A stream of ozonized oxygen is pasεed through a εolution of a protected compound of Formula 102 in a εolvent (such aε an alcohol, a halocarbon, or preferably a mixture of methanol and dichloromethane) . The reaction takes place at -100 to -40°C (preferably at -80°C) , and continues until the presence of excess ozone is detected by the development of a blue color, indicating the formation of an intermediate α-alkoxyhydroperoxide, which iε reduced without further purification, by the addition of a reducing agent (such as zinc and acetic acid, dimethyl sulfide, or preferably thiourea) . The reaction takes place at -80°C to 25°C (preferably 0°C) over a period of 12 to 24 hourε (preferably 16 hourε) , to give the corresponding aldehyde of Formula 103. Preparation of Formula 104 As illustrated in Reaction Scheme ZA-A, Step 3, the aldehyde is converted to a carbinol by addition of an organometallic compound of Formula 103a [where M is MgBr or lithium, preferably MgBr (a Grignard reagent) ; Z 1 is H, lower alkyl or CF 3 , and Z 2 iε H or lower alkyl] . An organolithium reagent is formed by reaction of a halovinyl (preferably bromovinyl) compound of Formula 103a (where M iε halo) with an alkyllithium (preferably n-butyllithium) in an ethereal εolvent (εuch aε ether, or preferably tetrahydrofuran) . The reaction takeε place at -100 to 0°C (preferably -40°C) over a period of 0.5 to 5 hourε (preferably 1 hour) . Alternatively the halovinyl compound of Formula 103a is reacted with magnesium metal in an ethereal solvent (such aε ether or preferably tetrahydrofuran) . The reaction takes place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hours (preferably 2 hourε) . The organometallic compound of Formula 103a where M iε zinc or cadmium may be prepared by reaction of 103a where M iε Li or MgBr with a zinc or cadmium halide, preferably chloride. The compound of Formula 103a where M is tin may be prepared by reaction of 103a where M is Li or MgBr with a trialkyl chlorostannane, preferably tributyltin chloride. The compound of Formula 103a where M iε tin may also be prepared by reaction of 103a where M iε trifluoromethaneεulfonate by reaction with a compound of formula (R 3 Sn) 2 , where R iε alkyl, preferably methyl, in the presence of a palladium catalyst, preferably tetrakiε(triphenylphoεphine)palladium. The compound of Formula 103a where M iε trifluoromethaneεulfonate may be prepared from a ketone of the formula: by reaction with a strong baεe (εuch aε εodium hydride or potaεεium hexamethyldiεilazide) , followed by reaction of the anion thuε produced with trifluoromethaneεulfonic anhydride. Alternatively, the compound of Formula 103a where M iε tin may be prepared by reacting a trialkyl tin hydride (preferably tributyl tin hydride) with an acetylene of the formula z'-CsC-Z 2 . One molar equivalent of the resultant organometallic reagent is added to a solution of an aldehyde of Formula 103 (in the same solvent syεtem uεed to make the organometallic reagent) . The reaction takeε place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minuteε (preferably 10 minutes) to give the corresponding carbinol of Formula 104. Preparation of Formula 105 As illuεtrated in Reaction Scheme ZA-A, Step 4, an alkyl eεter of Formula 105 iε formed by a Claiεen ortho ester rearrangement reaction of a carbinol of Formula 104 and an orthoester of Formula 104a (where Z 3 iε H, halo, lower alkyl, lower alkenyl, phenyl, alkoxy or -thio lower alkyl; and Z 4 is H or lower alkyl; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl) . A carbinol of Formula 104 iε heated at 50 to 140°C (preferably about 130°C) with about 10 molar equivalentε of an orthoeεter of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalentε (preferably 0.10 molar equivalentε) of an organic acid catalyεt (such as propionic, butyric, or preferably trimethylacetic acid) . The reaction takes place over a period of 1 to 48 hours (preferably 3 hours) to give the corresponding alkyl ester of Formula 105. Preparation of Formula I-ZA-A Formula I-ZA-A is prepared as deεcribed below with reference to Reaction Scheme ZA-M, Step 1 (in which the compound of Formula I-ZA-A iε named Formula I-ZA-M1) . The compoundε of Formula I-ZA-A are alεo employed aε starting materials in Step 1 of Reaction Scheme ZA-K. Preparation of Enantiomers of Formula I-ZA where Z 2 is Lower Alkyl One method of preparing individual enantiomers of compoundε of Formula I where Z iε εidechain ZA, illuεtrated aε compounds of Formula I-ZA, iε from chiral compoundε of Formula 104b, the preparation of which iε εhown below in Reaction Scheme ZA-A-1. REACTION SCHEME ZA-A-1 Formu l a 103 Formu l a 103f Formu l a 103f Formu l a 103g where Y is chloro or bromo. Formu l a 103g Formu l a 103a Formu l a 103h Formu l a 103h Formu l a 104b Preparation of Formula 103 f Aε illuεtrated in Reaction Scheme ZA-A-1, Step 1, an aldehyde of Formula 103 iε oxidized to the correεponding carboxylic acid of Formula 103f. An aldehyde of Formula 103 iε reacted with about two molar equivalentε of an oxidizing agent (for example, chromic acid, εilver oxide, bleach, or preferably εodium periodate) , in an inert εolvent (εuch aε toluene, or preferably ethyl acetate) , in the presence of water [and, when using sodium periodate or bleach aε the oxidizing agent, a catalytic amount (for example, about 0.01 molar equivalentε) of ruthenium oxide, or preferably ruthenium trichloride] . The reaction takeε place at 0 to 40°C (preferably 25°C) for 30 minuteε to 8 hourε (preferably 2 hourε) , to give the correεponding carboxylic acid of Formula 103f. Preparation of Formula 103g Aε illuεtrated in Reaction Scheme ZA-A-1, Step 2, a carboxylic acid of Formula 103f iε converted to the correεponding acyl halide of Formula 103g. A carboxylic acid of Formula 103f is reacted with about one molar equivalent, preferably 1.1 molar equivalents, of a thionyl or oxalyl halide (for example, thionyl chloride, thionyl bromide, or preferably oxalyl chloride) , in an inert solvent (such as dichloromethane, or preferably ethyl acetate) , in the presence of a catalytic amount (for example, about 0.05 molar equivalents) of dimethy1formamide. The reaction takes place at 0 to 40°C (preferably 25°C) for 30 minutes to 8 hours (preferably 2 hourε) , to give the correεponding acyl halide of Formula 103g. Preparation of Formula 103h Aε illustrated in Reaction Scheme ZA-A-1, Step 3, an acyl halide of Formula 103g is converted to the corresponding keto olefin of Formula 103h by addition of an organometallic compound of Formula 103a. An acyl halide of Formula 103g is reacted with about one molar equivalent of a organometallic compound of Formula 103a (where M iε cadmium, zinc, tin, or the like, prepared aε εhown in the preparation of compoundε of Formula 104) , in an inert εolvent (such as dichloromethane, ether, or preferably tetrahydrofuran) , optionally in the presence of a catalytic amount (for example, about 0.05 molar equivalentε) of a palladium catalyεt [preferably tetrakis (triphenylphoεphine)palladium] . The reaction takeε place at -10 to 20°C (preferably 0°C) for 30 minuteε to 8 hourε (preferably 4 hourε) , to give the corresponding keto olefin of Formula 103h. Preparation of Formula 104b As illustrated in Reaction Scheme ZA-A-1, Step 4, a keto olefin of Formula 103h iε reduced εtereoεpecifically to the corresponding carbinol of Formula 104b by reduction with borane methyl sulfide in the preεence of a catalytic amount of (R) -tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo- [1,2-c] [1,3,2] oxazaborole. A keto olefin of Formula 103h iε stereospecifically reduced with about one molar equivalent of borane methyl sulfide in the presence of a catalytic amount (0.05-0.3 molar equivalentε) of (R) -tetrahydro-1-methyl- 3,3-diphenyl-lH,3H-pyrrolo- [1,2-c] [1,3,2] oxazaborole in an inert εolvent (preferably a mixture of toluene and dichloromethane) . The reaction takeε place at -30 to 40°C (preferably -20°C) for 1-24 hourε (preferably 12 hourε) , to give the correεponding carbinol of Formula 104b. Preparation of Enantiomers of Compounds of Formula I-ZA A chiral carbinol of Formula 104b iε then converted to an enantiomer of a compound of Formula I-ZA in the same manner as εhown in Reaction Scheme ZA-A (converεion of compounds of Formula 104 to 105 to I-ZA) . REACTION SCHEME ZA-B Formula 106 Formula 103b Formula 105 lkyl -alk Formula 107 Formula 106a Preparation of Formula 106 As illustrated in Reaction Scheme ZA-B, Step 1, an aldehyde of Formula 103 iε tranεformed into an unεaturated aldehyde of Formula 106 by a Wittig reaction with an ylid of Formula 103b (where Z 1 iε H or lower alkyl) . An aldehyde of Formula 103 iε reacted with one molar equivalent of an ylid of Formula 103b, in an organic solvent (such as dichloromethane, dimethylformamide or preferably toluene) . The reaction takeε place at 0 to 110°C (preferably 80°C) for 1 to 24 hourε (preferably 8 hourε) to give the correεponding unεaturated aldehyde of Formula 106. Preparation of Formula 107 Aε illuεtrated in Reaction Scheme ZA-B, Step 2, an unεaturated aldehyde of Formula 106 iε condenεed with the anion of an ester of Formula 106a (where Z 3 is H, lower alkyl, lower alkenyl, or phenyl and Z 4 is H, lower alkyl, or phenyl) to give a beta-hydroxy ester of Formula 107. An eεter of Formula 106a iε converted to an alkali metal εalt by reacting a solution of the ester in an ethereal εolvent (εuch as ether or preferably tetrahydrofuran) with an equimolar amount of an alkali metal hydride, hexamethyldisilazide or amide (preferably lithium diiεopropyla ide) at a temperature of -100 to 0°C (preferably -80°C) , for 30 minuteε to 2 hours (preferably 30 minuteε) to give a εolution of the correεponding eεter anion. The ester anion solution (1.0 to 1.5 molar equivalents, preferably 1.0 molar equivalents) is added to a solution of an unsaturated aldehyde of Formula 106 in the same ethereal εolvent. The condensation reaction takeε place at a temperature of -100°C to 0°C (preferably -80°C) for 1 to 6 hourε (preferably 2 hourε) to give the correεponding beta-hydroxy eεter of Formula 107. REACTION SCHEME ZA-C Formu la 107 Formu la 108 Preparation of Formula 108 As illuεtrated in Reaction Scheme ZA-C, Step 1, the beta-hydroxy group of an eεter of Formula 107 iε O-alkylated to give the corresponding beta-alkoxy ester (R) of Formula 108. An eεter of Formula 107 iε reacted with 1 to 3 (preferably 1.5) molar equivalentε of an alkyl halide (preferably an alkyl iodide, εuch aε methyl iodide or n-butyl iodide, preferably methyl iodide) and 1 to 3 (preferably 1.25) molar equivalentε of εilver oxide, in a polar organic solvent (εuch as dioxane, dimethylforma ide or preferably acetonitrile) . The reaction takes place at 25 to 100°C (preferably 70°C) for 1 to 24 hours (preferably 4 hourε) to give the correεponding beta-alkoxy eεter of Formula 108. REACTION SCHEME ZA-D Formu la 05 Formula l-ZA-D Preparation of Formula I-ZA-D Aε illuεtrated in Reaction Scheme ZA-D, Step 1 an alpha-halo alkyl eεter of Formula 105 (where Z 1 is H, lower alkyl or CF 3 , Z 2 iε H or lower alkyl, Z 3 iε H, lower alkyl, lower alkenyl, or phenyl, and Z 4 iε halo) iε converted to an alpha-hydroxy acid of Formula I-ZA-D1. The reaction takes place by hydrolyεiε of an alpha-alkanoyloxy eεter intermediate, formed by diεplacement of the alpha-halo group with an alkali metal alkanoate. An alpha-halo (preferably chloro) eεter of Formula 105 iε reacted with 1 to 5 (preferably 3) molar equivalentε of an alkali metal alkanoate (the metal preferably potaεsium and the alkanoate preferably acetate) in a polar organic solvent (such as acetonitrile or preferably dimethylformamide) The reaction takes place at 40 to 100°C (preferably 75°C) for 1 to 24 hourε (preferably 12 hourε) to give the correεponding alpha-alkanoyloxy ester intermediate (not εhown) , which iε employed without iεolation or further purification. The alpha-alkanoyloxy eεter iε then εubjected to baεic hydrolysis by reaction with 1 to 5 (preferably 2) molar equivalents of an alkali metal hydroxide (preferably εodium hydroxide) in a mixture of water and an organic εolvent (εuch aε methanol, dimethoxyethane or preferably tetrahydrofuran) . The reaction takeε place at 0 to 60°C (preferably 40°C) for 1 to 12 hourε (preferably 4 hourε) , to afford the corresponding alpha- hydroxy acid of Formula I-ZA-D1. As illustrated in Reaction Scheme ZA-D, when R a of Formula 105 is a εilyl protecting group, the hydrolyεis conditions are also effective for deprotection to restore the phenolic hydroxyl group. Alternatively, for example when R a is methoxymethylethyl, the deprotection and hydrolyεiε procedures described with reference to Reaction Scheme ZA-M, can be employed. REACTION SCHEME ZA-E Formu l a 106 Formu l a 109 Formu l a 109 a I ky X Formu l a 110 Formu l a 109a Formula 110 Formula l-ZA-E Preparation of Formula 109 Aε illuεtrated in Reaction Scheme ZA-E, Step 1, an unεaturated aldehyde of Formula 106 iε reduced and then converted to the correεponding compound of Formula 109 in which R iε a leaving group (a εulfonate or halide, preferably a bromide) . An unεaturated aldehyde of Formula 106 iε reacted with from 0.5 to 2 (preferably 1) molar equivalentε of a reducing agent (εuch aε εodium cyanoborohydride or preferably εodium borohydride) in an alcoholic εolvent (εuch aε ethanol, iεopropanol or preferably methanol) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 12 hourε (preferably 2 hours) to give the corresponding allylic alcohol (not εhown) which iε uεed without isolation or further purification. The allylic alcohol is reacted with from 1 to 1.5 (preferably 1.25) molar equivalentε of a εulfonating agent (εuch aε p-tolueneεulfonyl chloride) and an organic baεe, or preferably reacted with a halogenating reagent (εuch as carbon tetrachloride/triphenylphosphine or preferably N-bromoεuccinimide/triphenylphoεphine) in an inert organic εolvent (εuch aε ether or preferably dichloromethane) . The reaction takeε place at a temperature of -40 to 40°C (preferably -10°C) for 1 to 12 hourε (preferably 2 hourε) to afford the correεponding compound of Formula 109. Preparation of Formula 110 An allylic halide or εulfonate of Formula 109 iε alkylated with a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a to give the correεponding chiral εubεtituted acyl oxazolidinone of Formula 110. An alkali metal (preferably lithium) εalt of a chiral 4-alkyl N-acyl oxazolidinone of Formula 109a (the alkyl group preferably being 4- iεopropyl) by reaction of the N-acyl oxazolidinone with 1 to 1.25 (preferably 1.05) molar equivalentε of an alkali metal hydride, hexamethyldiεilazide or dialkylamide (preferably lithium diiεopropylamide) in an inert organic solvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takeε place at -100 to -20°C (preferably -80°C) for 5 to 120 minuteε (preferably 30 minuteε) . The εolution of the allylic compound of Formula 109 in the εame εolvent iε added to the εalt (1 to 3, preferably 3 molar equivalentε) . The alkylation reaction takes place at -100 to 0°C (preferably -10°C) for 30 minutes to 6 hourε (preferably 1 hour) to afford the corresponding chiral substituted acyl oxazolidinone of Formula 110. Preparation of Formula I-ZA-E Aε illuεtrated in Reaction Scheme ZA-E, Step 3, a chiral εubεtituted acyl oxazolidinone of Formula 110 iε hydrolyzed to the correεponding chiral acid of Formula I-ZA-E. Uεe of an acyl oxazolidinone of Formula 109a having a 4-alkyl εubεtituent of the oppoεite configuration in Reaction Scheme ZA-E, Step 2, followed by hydrolyεiε aε deεcribed in Step 3 reεultε in the correεponding chiral acid where Z 3 haε the oppoεite configuration. An acyl oxazolidinone of Formula 110 iε reacted with from 1.25 to 3.5 (preferably 3.0) molar equivalentε of lithium hydroxide, in a mixture of water and a water-miscible organic εolvent (εuch aε dioxane or preferably tetrahydrofuran) containing from 6 to 10 (preferably 8) molar equivalentε of 30% aqueous hydrogen peroxide. The reaction takes place at -20 to 40°C (preferably 20°C) for 1 to 24 hours (preferably 12 hours) to afford the correεponding chiral acid of Formula I-ZA-E. REACTION SCHEME ZA-F Formu la 109 For ula 111 Preparation of Formula 111 Aε illuεtrated in Reaction Scheme ZA-F, Step 1, an allylic compound of Formula 109 in which R b iε a leaving group (a εulfonate or halide, preferably a bromide) iε converted to the correεponding protected amino eεter of Formula 111. An alkali metal salt (such aε the sodium, potassium or preferably lithium salt) of an alkyl ester of benzylidene glycine (εuch as the methyl or preferably the ethyl ester) iε prepared by reaction of the alkyl ester of benzylidene glycine with an equimolar amount of an alkali metal (εuch aε εodium, potaεεium or preferably lithium) dialkylamide (preferably diiεopropylamide) . The salt-forming reaction iε performed in an ethereal εolvent (εuch aε diethyl ether or preferably tetrahydrofuran) and takeε place at -80 to 0°C (preferably -40°C) for 15 minuteε to 4 hourε (preferably 30 minuteε) . The εo-obtained alkali metal εalt of the alkyl benzylidene glycine (1 to 1.5, preferably 1.1 molar equivalentε) is then reacted (without isolation or further purification) with an allylic compound of Formula 109. The reaction takes place at -100 to 0°C (preferably -80°C) for from 30 minutes to 12 hourε (preferably 4 hourε) . The benzylidene protecting group is removed by chromatography on silica gel to give the corresponding amino ester compound of Formula 111. RΞACTION SCHEME ZA-G F or m u l a l - Z A- G Preparation of Formula I-ZA-G As illuεtrated in Reaction Scheme ZA-G, Step 1, a protected amino eεter of Formula 111 iε converted to the correεponding lower alkyl εulfonylamino eεter of Formula I-ZA-G (where R iε lower alkyl) . A protected amino eεter of Formula 111 iε reacted with 1.0 to 2 (preferably 1.25) molar equivalentε of a lower alkyl (εuch aε ethyl, iεopropyl, or preferably methyl) εulfonyl chloride in the presence of 1.0 to 1.5 (preferably 1.25) molar equivalents of a tertiary organic base (εuch as pyridine, diisopropylethylamine or preferably triethylamine) in an inert organic solvent (such as ether, chloroform or preferably dichloromethane) The reaction takes place at -20 to 40°C (preferably 0°C) for 1 to 24 hours (preferably 4 hours) , to give the correεponding protected lower alkyl εulfonylamino ester, which is deprotected without isolation or further purification, for example as deεcribed with reference to Reaction Scheme ZA-M,- Step 1. Hydrolyεiε iε aε deεcribed with reference to Reaction Scheme ZA-M, Step 2. REACTION SCHEME ZA-H For alkyl Formula 112 Formula 109b Preparation of Formula 112 Aε illuεtrated in Reaction Scheme ZA-H, Step 1, an allylic compound of Formula 109 in which R b iε a leaving group (a εulfonate or halide, preferably a bromide) iε condenεed with an eεter of Formula 109b to give the mono- or di-alkyl eεter of Formula 112 (where Z 3 iε H, lower alkyl, lower alkenyl, or phenyl and Z 4 is H, lower alkyl, or phenyl) . An ester of Formula 109b is converted to an alkali metal εalt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalentε of an alkali metal amide (εuch as sodium hexamethyldisilazide, potassium tetramethylpiperidide or preferably lithium diisopropylamide) in an organic solvent (such as ether, dioxane or preferably tetrahydrofuran) . The reaction takes place at -40 to 30°C (preferably 0°C) for 15 minutes to 3 hourε (preferably 30 minuteε) . Without isolation or further purification, the reεulting εolution of the alkali metal salt of the eεter of Formula 109b (1.2 to 1.6, preferably about 1.3 molar equivalentε) iε then reacted with an allylic compound of Formula 109, in the εame εolvent, optionally in the preεence of from 2% to 10% (preferably about 5%) by volume of hexamethyl phoεphoric triamide. The reaction takeε place at -100 to -40°C (preferably -80°C) for 30 minuteε to 6 hourε (preferably 1 hour) to afford the corresponding alkyl ester of Formula 112. REACTION SCHEME ZA-I l Formula 109c Formula 113 Formu la I-ZA- I Preparation of Formula 113 As illustrated in Reaction Scheme ZA-I, Step 1, an allylic compound of Formula 109 in which R b iε a leaving group (a sulfonate or halide, preferably a bromide) iε condenεed with an eεter of Formula 109c to give the corresponding dimethylphosphono ester of Formula 113 (where Z 4 iε H or lower alkyl) . The alkali metal salt of a dimethylphoεphonoacetate of Formula 109c iε prepared by reacting the dimethylphoεphonoacetate with from 1.0 to 1.25 (preferably 1.05) molar equivalentε of an alkali metal alkoxide, hexamethyldiεilazide or preferably with εodium hydride, in an inert organic solvent (such aε tetrahydrofuran or preferably dimethylformamide) . The reaction takeε place at -10 to 30°C (preferably 0°C) for 1 to 4 hourε (preferably 2 hours) . The so-obtained alkali metal salt (1.05 to 1.5, preferably 1.1 molar equivalentε) iε then reacted without isolation or further purification with an allylic compound of Formula 109 in a solvent (such as tetrahydrofuran or preferably dimethylformamide) . The reaction takeε place at -20 to 25°C (preferably 0°C) for 1 to 8 hours (preferably 2 hourε) to give the correεponding dimethylphoεphono eεter of Formula 113. Preparation of Formula I-ZA-I As illustrated in Reaction Scheme ZA-I, Step 2, a dimethylphoεphono eεter of Formula 113 iε deprotected to give the correεponding eεter of Formula I-ZA-I. The deprotection reaction takeε place aε deεcribed with reference to Reaction Scheme ZA-M, Step 1. Hydrolyεiε is as deεcribed with reference to Reaction Scheme ZA-M, Step 2. REACTION SCHEME ZA-J Formu l a l -ZA- l Formu l a l -ZA- J Preparation of Formula I-ZA-J Aε illuεtrated in Reaction Scheme ZA-J, Step 1, a deprotected dimethylphoεphono eεter of Formula I-ZA-I (where Z 4 iε H or lower alkyl) iε converted to- the correεponding methylphoεphono eεter of Formula I-ZA-J. A 2- (dimethylphoεphono) -4-hexenoic acid eεter of Formula I-ZA-I iε reacted with from 1.0 to 3.0 (preferably 1.5) molar equivalentε of an alkali metal iodide (εuch aε lithium, potassium or preferably sodium iodide) in an organic εolvent (εuch aε pyridine or preferably acetone) . The reaction takeε place at 0 to 150°C (preferably 50°C) for 1 to 16 hourε (preferably 6 hourε) to give the correεponding 2- (methylphoεphono) -4- hexenoic acid eεter of Formula I-ZA-J. Hydrolyεiε iε aε deεcribed with reference to Reaction Scheme ZA-M, Step 2. REACTION SCHEME ZA-K lkyl Formula I-ZA-A Formula l-ZA-K Preparation of Formula I-ZA-K Aε illuεtrated in Reaction Scheme ZA-K, Step 1, a 2- (alkylthio) -4- hexenoic acid eεter of Formula I-ZA-A (where Z 3 iε S-lower alkyl, and Z 4 iε H or lower alkyl) iε oxidized to give the correεponding 2- (alkylεulfinyl) - or 2- (alkylεulfonyl) -4-hexenoic acid eεter of Formula I-ZA-K (where m iε 1 or 2) . Alternatively, the reaction can be performed with an acid of Formula I-ZA-M2 where Z 3 is S-lower alkyl, to give the corresponding acid where Z 3 iε 2- (alkylεulfinyl) or 2- (alkylεulfonyl) . An alkylthio- -hexenoic acid eεter of Formula I-ZA-A iε reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of an oxidizing agent (εuch aε Oxone ® ) optionally in the preεence of an inert εupport (εuch aε alumina) , in a εolvent (εuch aε chloroform or preferably dichloromethane) . The reaction takeε place at 0 to 55°C (preferably 35°C) for 1 to 10 hourε (preferably 2 hourε) to afford the correεponding 2- (alkylεulfinyl) -4- hexenoic acid ester of Formula I-ZA-K (where m is 1) . By repeating the foregoing procedure under the εame conditionε [εtarting with the 2- (alkylεulfinyl) - -hexenoic acid eεter εo-produced] , or by conducting the reaction with the 2- (alkylthio) -4-hexenoic acid eεter εtarting material [and uεing 2.0 to 2.5 (preferably 2.25) molar equivalentε of oxone] the correεponding 2-alkylsulfonyl-4-hexenoic acid esters are produced. A 2- (alkylsulfinyl) - or 2- (alkylεulfonyl) -4-hexenoic acid eεter of Formula I-ZA-K is hydrolyzed to give the corresponding acid as described with reference to Reaction Scheme ZA-M, Step 2. Alternatively, the acid can be obtained by subεtituting the correεponding 2- (alkylthio) -4-hexenoic acid for the eεter εtarting material aε deεcribed in Reaction Scheme ZA-K, Step 1. REACTION SCHEME ZA-L Formula 103c Formula 114 Formula 115 Formula 116 Formu la I -ZA- L Preparation of Formula 114 Aε illuεtrated in Reaction Scheme ZA-L, Step 1, a protected aldehyde of Formula 103 and a triphenylphoεphoranylideneacetate of Formula 103c are combined in a Wittig reaction to give the corresponding alkyl-2-halo- butenoate ester of Formula 114. An aldehyde of Formula 103 is reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of an alkyl 2-halo-2-triphenylphosphoranylidene- acetate of Formula 103c (the halo group preferably being chloro) in an organic solvent (εuch aε acetonitrile, or preferably dimethylformamide or toluene) . The reaction takeε place at 0 to 120°C (preferably 110°C) for 4 to 48 hourε (preferably 24 hourε) to afford the corresponding alkyl 2-halo-4-aryl-2-butenoate ester of Formula 114. Preparation of Formula 115 As illustrated in Reaction Scheme ZA-L, Step 2, a protected alkyl 2- halo-4-aryl-2-butenoate ester of Formula 114 iε converted to the corresponding bromide of Formula 115 via conversion to the corresponding acid (not shown) and reduction to the correεponding alcohol (not εhown) . A 2-halo-4-aryl-2-butenoate eεter of Formula 114 (preferably a t- butyl ester) iε converted to the correεponding acid (preferably by diεεolution in trifluoroacetic acid at room temperature for 1 to 2 hourε) . The acid iε iεolated and purified by conventional meanε, then reacted with 0.5 to 3 (preferably 1.6) molar equivalentε of a reducing agent (εuch aε εodium cyanoborohydride, sodium borohydride, or preferably borane dimethyl diεulfide complex) in an inert εolvent (εuch as methanol, ethanol, iεopropanol or preferably THF) . The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 48 hourε (preferably 24 hourε) to give the correεponding alcohol (not εhown) which iε uεed after purification. The allylic alcohol εo-produced iε reacted with from 1 to 1.5 (preferably 1.25) molar equivalentε of a sulfonating agent (εuch aε p-tolueneεulfonyl chloride) and an organic baεe, or preferably reacted with a halogenating reagent (εuch aε carbon tetrachloride/triphenylphoεphine or preferably N-bromoεuccinimide/triphenylphoεphine) in an inert organic εolvent (εuch aε ether or preferably dichloromethane) . The reaction takes place at a temperature of -40 to 40°C (preferably -10°C) for 1 to 12 hours (preferably 2 hourε) to afford the correεponding 2-halo-4-aryl-2-butenyl bromide compound of Formula 115. Preparation of Formula I-ZA-L Aε illuεtrated in Reaction Scheme ZA-L, Step 3, a protected 2-halo-4- aryl-2-butenyl bromide compound of Formula 115 iε condenεed with a dialkyl malonate of Formula 116, substituted by Z 4 (where Z 4 iε hydrogen, lower alkyl, or phenyl) , which iε hydrolyzed and decarboxylated to give the corresponding 4-halo-4-hexenoic acid derivative of Formula I-ZA-L. An ester of Formula 116 (where Z 4 iε H, lower alkyl, or phenyl) iε converted to an alkali metal salt by reaction with 1.05 to 1.25 (preferably 1.1) molar equivalentε of an alkali metal hydride (preferably εodium hydride) in an organic εolvent (such aε ether, dioxane or preferably tetrahydrofuran) . The reaction takeε place at -40 to 30°C (preferably 0°C) for 15 minuteε to 3 hourε (preferably 30 minuteε) . Without iεolation or further purification, the reεulting εolution of the alkali metal εalt of the ester of Formula 116 (1.2 to 1.6, preferably about 1.3 molar equivalents) iε then reacted with an allylic bromo compound of Formula 115 in the εame εolvent. The reaction takeε place at -20 to 50°C (preferably 25°C) for 30 minuteε to 6 hours (preferably 2 hourε) to afford the corresponding dialkyl ester derivative. The dialkyl ester thuε produced iε then hydrolyzed conventionally, uεing a εtrong baεe, preferably aqueouε εodium hydroxide, in a protic solvent, preferably ethanol, heating to reflux. The dicarboxylic acid thus produced is εeparated conventionally, and then decarboxylated by heating, preferably in a high-boiling inert εolvent, moεt preferably 1,2- dichlorobenzene, to give the correεponding 4-halo-4-hexenoic acid derivative of Formula I-ZA-L. REACTION SCHEME ZA-M Formula 117 Formula I-ZA- 1 Formula I-ZA-M1 Formula I-ZA-M2 Preparation of Formula I-ZA-M1 Aε illuεtrated in Reaction Scheme ZA-M, Step 1, an alkyl eεter of Formula 117 (which can be any of the corresponding protected esterε of Reaction Schemeε ZA-A to ZA-L, such as Formulae 105, 107, 108, 111, 112, and 113) iε deprotected to give the correεponding alkyl eεter of Formula I- ZA-M1. An alkyl eεter of Formula 117 (having either an acetal-type or a εilyl-type protecting group) iε treated with from 0.05 to 0.2 molar equivalentε (preferably 0.1 molar equivalents) of an aqueous mineral acid (εuch as sulfuric, perchloric, or preferably hydrochloric acid) , in a water-miscible organic εolvent (such as methanol, acetone, or preferably ethanol) . The reaction takes place at 0 to 50°C (preferably 25°C) over a period of 1 to 6 hours (preferably 2 hourε) to give the correεponding free phenol of Formula I-ZA-M1. Alternatively, to remove acetal-type protecting groupε (εuch aε MEM) a compound of Formula 117 iε treated with 0.05 to 0.25 molar equivalentε (preferably 0.1 molar equivalentε) of a Lewiε acid (εuch aε zinc chloride or preferably zinc bromide) , in a εolvent (εuch as benzene, chloroform, or preferably dichloromethane) . The reaction takeε place at 0 to 50°C (preferably 25°C) over a period of 1 to 12 hourε (preferably 3 hourε) to give the correεponding free phenol of Formula I-ZA-M1. Alternatively, to remove εilyl-type protecting groupε (εuch aε t- butyldimethylεilyl) a compound of Formula 117 is reacted with 1.0 to 1.5 (preferably 1.25) moles of a tetraalkyl ammonium fluoride (preferably tetrabutylammonium fluoride) in an ethereal εolvent (εuch aε dioxane or preferably tetrahydrofuran) . The reaction takeε place at -10 to 25°C (preferably 0°C) over a period of 0.1 to 2 hourε (preferably 0.5 hours) to give the corresponding free phenol of Formula I-ZA-M1. Preparation of Formula I-ZA-M2 Aε illuεtrated in Reaction Scheme ZA-M, Step 2, an alkyl eεter of Formula I-ZA-M1 (prepared as described above, or which can be any of previously described deprotected esterε, such as Formulae I-ZA-A, I-ZA-G, I-ZA-I, I-ZA-J, and I-ZA-K) is hydrolyzed to give the correεponding acid of Formula I-ZA-M2. An alkyl ester of Formula I-ZA-M1 is reacted with from 1.5 to 4 molar equivalents (preferably 2 molar equivalents) of an inorganic hydroxide (such as potaεsium, εodium, or preferably lithium hydroxide) in a mixture of water and an organic εolvent (εuch aε tetrahydrofuran, methanol, or preferably dimethoxyethane) . The reaction takeε place at 0 to 60°C (preferably 40°C) over a period of 1 to 12 hourε (preferably 3 hourε) . The reεulting anion is acidified with an aqueous mineral acid (such aε hydrochloric acid) . The acidification takeε place at 0 to 40°C (preferably 25°C) over a period of 1 to 10 minuteε (preferably 2 minuteε) to give the correεponding acid of Formula I-ZA-M2. Preparation of Compounds of Formula I-ZB One method of preparing compoundε of Formula I where Z iε εidechain of Formula ZB, illuεtrated aε compoundε of Formula I-ZB, iε εhown below in Reaction Schemeε ZB-A to ZB-A-1. REACTION SCHEME ZB-A Formu I a 103 + Formula 201 Formu la 202 where M iε Li or MgBr. Formu la 202 Formu la 203 Formu la 203 Formula I-ZB-A Preparation of Formula 202 As illustrated in Reaction Scheme ZB-A, Step 1, the aldehyde of Formula 103 iε converted to a carbinol of Formula 202 by addition of an unsaturated cyclic organometallic compound of Formula 201 where M is Li or MgBr, prepared for example aε deεcribed above with reference to Reaction Scheme ZA-A, Step 3. One molar equivalent of the organometallic reagent 201 iε added to a solution of an aldehyde of Formula 103 (in the εame εolvent system used to make the organometallic reagent) . The reaction takeε place at -80 to -20°C (preferably -40°C) over a period of 5 to 60 minuteε (preferably 15 minuteε) to give the correεponding carbinol of Formula 202. Resolution of Formula 202 The racemic compound of Formula 202 may be εeparated into its two enantiomers by conventional means, for example by conversion into two diaεtereoiεomerε that are then εeparated by crystallization, chromatography, or by any conventional separation technique. Preferably, the carbinol is reacted with a chiral isocyanate to give a mixture of diastereoiεomeric carbamateε, which are εeparated by chromatography and cleaved to give the pure enantiomers. A carbinol of Formula 202 iε heated at 30 to 100°C (preferably about 60°C) with 2 to 6 molar equivalentε (preferably 4 molar equivalents) of a chiral isocyanate in the presence of 1 to 1.5 molar equivalentε (preferably 1.2 molar equivalentε) of a εtrong organic baεe, for example 4-dimethylaminopyridine, in a hindered tertiary amine (for example diiεopropylethylamine) aε a solvent. The reaction takes place over a period of 1 to 24 hours (preferably 7 hourε) to give the correεponding carbamate aε a mixture of diaεtereoiεomerε. The mixture of diaεtereoisomeric carbamates is separated by conventional means, preferably chromatography. The individual diastereoiεomerε are then εeparately cleaved by treatment with 1 to 1.5 molar equivalentε (preferably 1.2 molar equivalentε) of a trihaloεilane, for example trichloroεilane, in the preεence of an exceεε of a tertiary amine, for example triethylamine, in an inert εolvent, for example toluene. The reaction takeε place at a temperature of 90-120°C (preferably 110°C) over a period of 5 minutes to 2 hourε (preferably 15 minuteε) to give the correεponding enantiomer of the carbinol of Formula 202. Preparation of Formula 203 Aε illuεtrated in Reaction Scheme ZB-A, Step 2, an alkyl eεter of Formula 203 is formed by a Claisen ortho eεter reaction of a carbinol of Formula 201 (or an enantiomer thereof) with an appropriately εubεtituted orthoeεter. A carbinol of Formula 202 iε heated at 50 to 140°C (preferably 130°C) with a large exceεε of an orthoeεter of Formula 104a (εee Reaction Scheme ZA-A, εtep 4), in the preεence of from 0.05 to 0.25 molar equivalentε (preferably 0.10 molar equivalentε) of an organic acid catalyεt (εuch as propionic, butyric, or trimethylacetic acid, preferably trimethylacetic acid) . The reaction takes place over a period of 1 to 24 hourε (preferably 2.5 hourε) to give the correεponding alkyl ester of Formula 203. Preparation of Formula I-ZB-A Compounds of Formula I-ZB-A are prepared as deεcribed above with reference to Reaction Scheme ZA-M, Step 1 (deprotection to afford the correεponding alkyl eεter) , and Step 2 (hydrolyεiε to afford the correεponding acid of Formula I-ZB-A) . Alternative Preparation of Enantiomers of Compounds of Formula I-ZB Another method of preparing individual enantiomerε of compoundε of Formula I where Z iε εidechain ZB, illuεtrated aε compoundε of Formula I-ZB, iε from chiral compoundε of Formula 202b, the preparation of which iε shown below in Reaction Scheme ZB-A-1. REACTION SCHEME ZB-A-1 Formula 103g + For ula 201 Formu la 202a Formula 202a Formu la 202b Preparation of Formula 202a Compounds of Formula 202a are prepared aε described above with reference to Reaction Scheme ZA-A-1, Step 3 (conversion of 103g to 103h) . Preparation of Formula 202b Compounds of Formula 202b are prepared aε described above with reference to Reaction Scheme ZA-A-1, Step 4 (conversion of 103h to 104b) . Preparation of Enantiomers of Compounds of Formula I-ZB A chiral carbinol of Formula 202b is then converted to an enantiomer of a compound of Formula I-ZB in the εame manner aε εhown above in Reaction Scheme ZB-A (converεion of compoundε of Formula 202 to 203 to I-ZB-A) . Preparation of Compounds of Formula I-ZC One method of preparing compounds of Formula I where Z is sidechain of Formula ZC, illuεtrated aε compounds of Formula I-ZC, iε shown below in Reaction Scheme ZC-A. REACTION SCHEME ZC-A Form Formu la 302 Formu la 301 Formu la 302 Formu la 303 15 Formula 30-4 20 For u la 304 For mu I a 305 Formu la 306 Formu la 307 40 For u l a 30 7 Fo r m u l a 30 f For m u l a 308 F o r m u l a 309 For m u l a 309 F or m u l a I - Z C Preparation of Formula 302 Aε illu.εtrated in Reaction Scheme ZC-A, Step 1, an aldehyde of Formula 103 (prepared, for example aε described above with reference to Reaction Scheme ZA, Steps 1 and 2) is transformed into an unsaturated aldehyde of Formula 302 by a Wittig reaction with an ylid of Formula 301 (where Z 5 is H or lower alkyl) . An aldehyde of Formula 103 iε reacted with one molar equivalent of an ylid of Formula 301, in an organic εolvent (εuch as dichloromethane, dimethylformamide or preferably toluene) . The reaction takeε place at 0 to 110°C (preferably 80°C) for 1 to 24 hours (preferably 8 hours) to give the corresponding unsaturated aldehyde of Formula 302. Preparation of Formula 303 As illustrated in Reaction Scheme ZC-A, Step 2, an unsaturated aldehyde of Formula 302 iε converted to the corresponding vinyl carbinol of Formula 303. An aldehyde of Formula 302 is reacted with from 1.0 to 1.25 (preferably 1.1) molar equivalentε of an organovinyl compound (preferably vinylmagneεium bromide) in a εolvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takeε place at -30 to 20°C (preferably at 0°C) for 0.1 to 4 hourε (preferably 0.5 hourε) to give the correεponding vinyl carbinol of Formula 303. Prβparation of Formula 304 Aε illuεtrated in Reaction Scheme ZC-A, Step 3, a vinyl carbinol of Formula 303 iε oxidized to give the correεponding dienone of Formula 304. A vinyl carbinol of Formula 303 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of an oxidizing agent (such aε manganeεe dioxide, pyridinium chlorochromate or preferably pyridinium dichromate) in a εolvent (εuch aε pyridine or preferably dichloromethane) . The reaction takeε place at 0 to 30°C (preferably 25°C) for 30 minuteε to 4 hourε (preferably 1 hour) to give the correεponding dienone of Formula 304. Preparation of Formula 305 As illustrated in Reaction Scheme ZC-A, Step 4, a dienone of Formula 304 iε cyclized to give the correεponding cyclopentenone of Formula 305. A dienone of Formula 304 reacted with 0.3 to 1.5 (preferably 1.0) molar equivalentε of a Lewiε acid (εuch aε boron trichloride, tin (IV) chloride or preferably boron trifluoride etherate) in a εolvent (εuch aε tetrachloroethane or preferably dichloromethane) . The reaction takes place at 0 to 30°C (preferably 25°C) for 1 to 6 hours (preferably 2 hours) to give the corresponding cyclopentenone of Formula 305. Preparation of Formula 306 Aε illuεtrated in Reaction Scheme ZC-A, Step 5, a cyclopentenone of Formula 305 iε reduced to give the correεponding cyclopentenol of Formula 306. A cyclopentenone of Formula 305 iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of a reducing agent (εuch as lithium tri-tert-butoxyaluminium hydride or preferably sodium borohydride in the preεence of an equimolar amount of cerium trichloride) in a mixture of an ethereal εolvent (preferably tetrahydrofuran) and a lower alkanol (preferably methanol) . The reaction takeε place at 0 to 40°C (preferably at 25°C) for 1 to 6 hours (preferably 2 hours) to give the cyclopentenol of Formula 306. Preparation of Formula 307 Aε illuεtrated in Reaction Scheme ZC-A, Step 6, a cyclopentenol of Formula 306 iε tranεformed to the correεponding vinyl ether of Formula 307. A cyclopentenol of Formula 306 iε reacted with from 10 to 100 (preferably 50) molar equivalentε of a 1-alkenyl ether, optionally in the presence of a co-solvent (εuch aε ether or tetrahydrofuran) , in the preεence of from 0.1 to 0.5 (preferably 0.3) molar equivalentε of a mercury (II) εalt (preferably mercury (II) acetate) . The reaction takes place at 0 to 50°C (preferably 25°C) for 1 to 5 days (preferably 2 days) to give the corresponding vinyl ether of Formula 307. Preparation of Formula 308 As illuεtrated in Reaction Scheme ZC-A, Step 7, a vinyl ether of Formula 307 iε rearranged to the correεponding acetaldehyde of Formula 308. A vinyl ether of Formula 307 iε reacted with from 10 to 100 (preferably 50) molar equivalentε of a lithium εalt (εuch aε the tetrafluoroborate or preferably the perchlorate) in a εolvent (εuch aε tetrahydrofuran or preferably ether) . The reaction takeε place at 0 to 35°C (preferably 25°C) for 0.1 to 2 hourε (preferably 0.5 hourε) to give the correεponding acetaldehyde of Formula 308. Preparation of Formula 309 As illustrated in Reaction Scheme ZC-A, Step 8, an acetaldehyde of Formula 308 is oxidized to give the corresponding acid of Formula 309. An acetaldehyde of Formula 308 is reacted with 1 to 3 (preferably 1.5) molar equivalents of a suitable oxidizing agent [εuch aε εilver oxide, Joneε reagent or εodium chlorite, preferably εodium chlorite in the preεence of an equimolar amount of a phenol (such as quinol or preferably reεorcinol) ] . The reaction iε conducted in a mixture of water and a water- miscible organic εolvent (εuch as tetrahydrofuran or preferably dioxane) at a pH of from 4 to 6 (preferably 5) at -10 to 25°C (preferably 0°C) for 10 minutes to 2 hours (preferably 30 minuteε) to give the correεponding acid of Formula 309. Preparation of Formula I-ZC As illustrated in Reaction Scheme ZC-A, Step 9, an acid of Formula 309 is deprotected to give the correεponding acid of Formula I-ZC. An acid of Formula 309 where R" iε a εulphonyloxy protecting group hydrolyzed under baεic conditionε, uεing from 1 to 5 (preferably 3) molar equivalents of an alkali metal hydroxide (preferably lithium hydroxide) in a mixture of water and a water-miscible organic εolvent (εuch aε dioxane or preferably methanol) . The reaction takeε place at 40 to 100°C (preferably 60°C) for 1 to 48 hours (preferably 12 hourε) to afford the correεponding cyclopentene carboxylic acid of Formula I-ZC. Alternatively, for other protecting groupε, the deprotection reaction takeε place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 1. Preparation of Compounds of Formula -ZD One method of preparing compoundε of Formula I where Z is sidechain of Formula ZD, illustrated as compounds of Formula I-ZD, is εhown below in Reaction Scheme ZD-A. REACTION SCHEME ZD-A Formu la 401 Formu I a 103d Formu l a 104a For mu I a 402 Form la 402 Formu la 403 For u l a 403 Formu I a I -ZD- A 1 Formu I a •ZD- A1 Formu la I -ZD- A2 Preparation of Formula 401 As illuεtrated in Reaction Scheme ZD-A, Step 1, an aldehyde of Formula 103 (where R a iε a εilyl protecting group) is converted to a carbinol by addition of an organometallic compound of Formula 103d (εuch aε a εubstituted vinyl organolithium, or preferably a Grignard reagent where: M is MgBr or Li; Z 2 iε H or lower alkyl; and TBS iε a tert- butyldimethylεilyl protecting group) . The aldehyde of Formula 103 iε reacted with from 1.1 to 1.5 (preferably 1.25) molar equivalentε of an organometallic, preferably organolithium, derivative of a protected 2-halo (2-bromo or preferably 2-iodo) but-l-en-4-ol. The reaction iε performed at from -100 to -40°C (preferably at -78°C) for from 30 minuteε to 6 hourε (preferably 1 hour) to afford the correεponding compound of Formula 401. Preparation of Formula 402 Aε illustrated in Reaction Scheme ZD-A, Step 2, an alkyl ester of Formula 402 is formed by a Claisen ortho eεter rearrangement reaction of a carbinol of Formula 401 and a trialkyl orthoacetate of Formula 104a. A carbinol of Formula 401 iε heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalentε of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 (preferably 0.10) molar equivalents of an organic acid catalyεt (εuch aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hourε (preferably 8 hours) to give the corresponding alkyl ester of Formula 402. Preparation of Formula 403 Aε illuεtrated in Reaction Scheme ZD-A, Step 3, an alkyl eεter of Formula 402 iε reacted with a tetraalkylammonium fluoride and then halogenated to give a protected eεter of Formula 403. A compound of Formula 402 is reacted with from 2.0 to 3.0 (preferably 2.0) molar equivalents of a tetraalkylammonium (preferably tetrabutylammonium) fluoride, in a solvent (εuch as dioxane or preferably tetrahydrofuran or dichloromethane) at from 0 to 25°C (preferably 10°C) , for from 30 minutes to 4 hourε (preferably 1 hour) . The product εo obtained iε reacted with from 1.0 to 1.5 (preferably 1.25) molar equivalentε of a halogenating agent (preferably a brominating agent, εuch aε triphenylphoεphine/carbon tetrabromide or preferably triphenylphoεphine/N-bromoεuccinimide) in a εolvent εuch aε ether or preferably dichloromethane. The reaction takeε place at from -40 to 0°C (preferably -10°C) for from 1 to 6 hourε (preferably 4 hourε) to give the correεponding protected halogenated eεter of Formula 403. Preparation of Formula I-ZD-A1 As illustrated in Reaction Scheme ZD-A, Step 4, a halogenated ester of Formula 403 is cyclized to give a protected cycloalkyl eεter of Formula I-ZD-A1. A compound of Formula 403 iε reacted with from 2.0 to 2.5 (preferably 2.25) molar equivalentε of a strong baεe (εuch aε lithium diiεopropylamide, εodium hydride or preferably εodium hexamethyldisilazide) in an ethereal solvent (such aε ether, dioxane or preferably tetrahydrofuran) The reaction takeε place at from -100 to -60°C (preferably -78°C) for 1 to 12 hours (preferably 4 hours) to give the protected cycloalkyl ester of Formula I-ZD-A1. Preparation of Formula I-ZD-A2 Aε illuεtrated in Reaction Scheme ZD-A, Step 6, a cycloalkyl eεter of Formula I-ZD-A1 iε hydrolyzed to give the correεponding acid of Formula I- ZE-D2. The hydrolysiε reaction takeε place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 2. Preparation of Compounds of Formula I-ZE One method of preparing compoundε of Formula I where Z is sidechain of Formula ZE, illustrated as compoundε of Formula I-ZE, iε εhown below in Reaction Schemeε ZE-A to ZE-E. REACTION SCHEME ZE-A Formula 501 Formula 502 Formula 502 Formula 503 Formula 504 Formula 504 Formula 103 Formula 505 Formula 505 Formula 506 Preparation of Formula 502 As illustrated in Reaction Scheme ZE-A, Step 1, the 2-methyl group of an alkyl 2-methylbenzoate of Formula 501 (where Z 6 and Z 7 are selected from H, lower alkyl, lower alkoxy, lower alkoxycarbonyl, halo and nitro) is brominated to give the corresponding compound of Formula 502. An ester of Formula 501 is reacted with 1.0 to 1.2 (preferably 1.05) molar equivalents of a brominating agent (such aε N-bromoacetamide or preferably N-bromoεuccinimide) , optionally in the preεence of an initiator (εuch aε viεible light) or from 0.001 to 0.01 (preferably 0.005) molar equivalentε of a chemical initiator (εuch as azobisiεobutyronitrile or preferably benzoyl peroxide) in a εolvent (εuch aε ethyl formate or preferably carbon tetrachloride) . The reaction takeε place at 40 to 80°C (preferably 75°C) for 30 minuteε to to 6 hourε (preferably 2 hourε) to afford the correεponding alkyl 2-bromomethylbenzoate of Formula 502, which can be purified by conventional meanε or preferably uεed directly for the next step. Preparation of Formula 503 As illustrated in Reaction Scheme ZE-A, Step 2, a 2-bromomethyl group of Formula 502 is converted to the corresponding phosphonium εalt of Formula 503. A 2-bromomethylbenzoate of Formula 502 iε reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of a triaryl phoεphine (preferably triphenyl phosphine) in a solvent (such aε dimethylformamide or preferably acetonitrile) . The reaction takeε place at 25 to 90°C (preferably 50°C) for 1 to 24 hourε (preferably 2 hourε) to afford the correεponding phosphonium εalt of Formula 503. Preparation of Formula 504 Aε illuεtrated in Reaction Scheme ZE-A, Step 3, a phoεphonium εalt of Formula 503 iε converted to the correεponding εubεtituted benzylidenetriphenylphoεphorane ylid of Formula 504. A phosphonium salt of Formula 503 iε diεεolved or εuεpended in a εolvent (εuch aε dioxane, ether or preferably dimethylformamide) and reacted with 1.0 to 1.25 (preferably 1.05) molar equivalentε of a baεe (εuch aε εodium hydride, triethylamine or preferably 1,5- diazabicyclo[4.3.0]non-5-ene) . The reaction takeε place at 0 to 60°C (preferably 25°C) for 1 to 6 hourε (preferably 2 hourε) to afford the correεponding ylid of Formula 504, which can be iεolated by conventional meanε or itε εolution can be uεed directly for the next εtep. Preparation of Formulae 505 and 506 Aε illuεtrated in Reaction Scheme ZE-A, Step 4, an ylid of Formula 504 and a protected aldehyde of Formula 103 (prepared, for example, as described in connection with Reaction Scheme ZA-A, Step 2) are employed in a Wittig reaction to give the corresponding protected substituted benzoic acid alkyl ester of Formula 505 aε a mixture of E and Z isomers, from which the desired E iεomer of Formula 506 iε iεolated, as illuεtrated in Reaction Scheme ZE-A, Step 5. A solution of 0.8 to 1.0 (preferably 0.95) molar equivalents of a protected aldehyde of Formula 103 in a solvent (such as ether, dioxane or preferably dimethylformamide) is added to a solution of an ylid of Formula 504 in the same εolvent. The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 12 hourε) to afford the correεponding protected εubstituted benzoic acid alkyl eεter of Formula 505 as a mixture of E and Z isomerε, from which the deεired E-isomer of Formula 506 can be iεolated by conventional meanε (εuch aε diεtillation, chromatography or preferably fractional crystallization) . REACTION SCHEME ZE-B Formula 507 Formula 508 Formula 508 Formula 509 Formula 509 Formula 103 Formula 510 Formula 510 Formula 511 Preparation of Formula 508 As illustrated in Reaction Scheme ZE-B, Step 1, the alpha carbon of an alkyl 2-alkylbenzoate of Formula 507 (where Z 5 is H or lower alkyl, and Z 6 and Z 7 are εelected from H, lower alkyl, lower alkoxy, lower alkoxycarbonyl, halo and nitro) iε brominated to give the correεponding compound of Formula 508. The reaction takes place under the conditions described with reference to Reaction Scheme ZE-A, Step 1. Preparation of Formula 509 Aε illuεtrated in Reaction Scheme ZE-B, Step 2, an alkyl 2-bromo- alkylbenzoate of Formula 508 and a trialkyl phoεphite are combined in an Arbuzov reaction to give the correεponding phoεphonate of Formula 509. A compound of Formula 508 iε reacted with from 5 to 20 (preferably 10) molar equivalentε of a trialkyl phosphite (preferably triethyl phoεphite) . The reaction takeε place at 100 to 200°C (preferably 150°C) for 1 to 24 hourε (preferably 6 hourε) to afford the corresponding phosphonate of Formula 509. Preparation of Formulae 510 and 511 Aε illuεtrated in Reaction Scheme ZE-B, Step 3, a phoεphonate of Formula 509 and a protected aldehyde of Formula 103 (prepared, for example, as described in connection with Reaction Scheme ZA-A, Step 2) are reacted to give the corresponding protected subεtituted benzoic acid alkyl ester of Formula 510 as a mixture of E and Z isomerε, from which the deεired E isomer of Formula 511 iε iεolated, as illustrated in Reaction Scheme ZE-B, Step 4. A phoεphonate of Formula 509 is reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of a baεe εuch (aε εodium amide, potaεεium tert-butoxide or preferably εodium hydride) for from 1 to 4 hourε (preferably 2 hourε) at 0 to 50°C (preferably 25°C) in a solvent (such as dioxane, dimethylformamide or preferably dimethoxyethane) , to give a εolution or εuεpension of the corresponding alkali metal εalt of Formula 509, which is employed without isolation or further purification. The alkali metal salt is reacted with from 0.9 to 1.1 (preferably 1.0) molar equivalentε of a protected aldehyde of Formula 103, dissolved in the same εolvent. The reaction takeε place at 0 to 60°C (preferably 40°C) for 1 to 6 hours (preferably 2 hourε) to afford the correεponding protected optionally εubεtituted benzoic acid alkyl eεter of Formula 510 aε a mixture of E and Z iεomers, from which the desired E-isomer of Formula 511 can be iεolated by conventional meanε (εuch aε diεtillation, chromatography or preferably fractional cryεtallization) . REACTION SCHEME ZE-C Fo Br Formula 513 Formula 512 Formula 513 Formula 514 Formula 514 Formula 515 where R D is TBDMS where R D is acy Formula 516 Preparation of Formula 513 Aε illuεtrated in Reaction Scheme ZE-C, Step 1, a protected aldehyde of Formula 103 is converted to a trialkylsilylcarbinol of Formula 513 in a Grignard reaction. An aldehyde of Formula 103 is reacted with from 1.0 to 1.25 (preferably 1.1) molar equivalents of a trialkylεilylalkylmagneεium bromide (εuch aε trimethylεilylpropylmagneεium bromide, or preferably trimethyl- εilylmethylmagneεium bromide) of Formula 512, in an ethereal εolvent (εuch aε ether, dimethoxyethane or preferably tetrahydrofuran) . The reaction takeε place at -40 to 40°C (preferably 0°C) for 30 minuteε to 4 hourε (preferably 1 hour) to give the correεponding trialkylεilylcarbinol of Formula 513. Preparation of Formula 514 Aε illuεtrated in Reaction Scheme ZE-C, Step 2, a protected trialkylεilylcarbinol of Formula 513 iε dehydrated to give the correεponding protected alkene aε a mixture of E and Z iεomerε, from which the deεired Z isomer of Formula 514 iε iεolated. A carbinol of Formula 513 iε reacted with from 1.0 to 1.5 (preferably 1.05) molar equivalentε of a εulphonyl chloride (εuch aε p-tolueneεulphonyl chloride or preferably methanesulphonyl chloride) in the presence of the εame molar proportion of a tertiary organic baεe (εuch aε N-methyl- pyrrolidine or preferably triethylamine) . The reaction takeε place at 0 to 40°C (preferably 15°C) for 30 minuteε to 4 hourε (preferably 2 hourε) to afford the correεponding protected alkene of Formula 514 aε a mixture of E and Z isomers, from which the desired Z-iεomer of Formula 514 can be iεolated by conventional means (εuch aε distillation, chromatography or preferably fractional cryεtallization) . Preparation of Formula 515 As illuεtrated in Reaction Scheme ZE-C, Step 3, an alkene of Formula 514 where R" iε a εilyl protecting group iε converted to an alkene of Formula 515 where R" iε an acyl group. An alkene of Formula 514 iε heated at 50-130°C (preferably about 118°C) with .a large excess of a mixture (preferably about equimolar) of a carboxylic acid of Formula R'OH and an anhydride of Formula (R a ) 2 0 (where R a iε the desired acyl group) , preferably a mixture of acetic acid and acetic anhydride. The reaction takes place over a period of 6 to 48 hourε (preferably 18 hourε) to give the correεponding alkene of Formula 515 where R a is the acyl group. Preparation of Formula 511 As illustrated in Reaction Scheme ZE-C, Step 4, a protected alkene of Formula 515 iε converted to a protected optionally εubεtituted benzoic acid alkyl eεter of Formula 511 in a Heck reaction with an alkyl-2-halo-benzoate of Formula 515. An alkene of Formula 515 iε reacted with 1.0 to 2.0 (preferably 1.25) molar equivalentε of an alkyl 2-halobenzoate (such aε an alkyl 2-bromobenzoate or preferably 2-iodobenzoate) . The reaction iε conducted in the preεence of from 0.001 to 0.1 (preferably 0.05) molar equivalentε of a palladium catalyεt [εuch aε tetrakiε(tri-o-tolylphoεphine) palladium, or tetrakiε(triphenylphoεphine)palladium or preferably palladium (II) acetate] optionally in the preεence of from 1.0 to 1.25 (preferably 1.05) molar equivalentε of a baεe (εuch εilver carbonate, εodium bicarbonate or preferably triethylamine) , in a solvent (such as acetonitrile or preferably dimethylformamide) . The reaction is conducted at from 0 to 120°C (preferably 60°C) for 1 to 48 hourε (preferably 6 hours) to yield the corresponding protected optionally substituted benzoic acid alkyl ester of Formula 511. REACTION SCHEME ZE-D Form Form Formula I-ZE-D1 Formula I-ZE-D1 Formula I-ZE-D2 Preparation of Formula I-ZE-Dl As illustrated in Reaction Scheme ZE-D, Step 1, a protected optionally εubεtituted benzoic acid eεter of Formula 506 or Formula 511 iε deprotected to give the correεponding eεter of Formula I-ZE-Dl. The deprotection reaction takeε place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 1. Preparation of Formula I-ZE-D2 Aε illuεtrated in Reaction Scheme ZE-D, Step 2, a deprotected optionally εubεtituted benzoic acid eεter of Formula I-ZE-Dl iε hydrolyzed to give the correεponding acid of Formula I-ZE-D2. The hydrolization reaction takes place as described above with reference to Reaction Scheme ZA-M, Step 2. The compounds of Formula I-ZE-D2 where Z 6 iε nitro are employed aε precurεorε to the correεponding compounds of Formula I-ZE-E where Z 6 iε amino (as illustrated in Reaction Scheme ZE-E, Step 1) ; the nitro compounds are also active as IMPDH inhibitors when tested as described below. REACTION SCHEME ZE-E Formu I" l-ZE-D2a Preparation of Formula I-ZE-E As illustrated in Reaction Scheme ZE-E, Step 1, a benzoic acid of Formula I-ZE-D2a (a compound of Formula I-ZE-D2 where Z 6 is N0 2 ) is reduced to the corresponding amino-substituted benzoic acid of Formula I-ZE-E. A nitrobenzoic acid of Formula I-ZE-D2a is reacted with 1.0 to 3.0 (preferably 2.0) molar proportionε of a reducing agent (εuch aε sodium hydroεulfite or preferably tin (II) chloride) in hydrochloric acid εolution, optionally in the preεence of a water-miεcible co-εolvent (εuch as methanol or preferably acetic acid) . The reaction takes place at 25 to 100°C (preferably 75°C) for 1 to 24 hourε (preferably 4 hourε) to afford the correεponding amino-εubεtituted benzoic acid of Formula I-ZE-E. REACTION SCHEME ZE-F Formu la 509 * Formu la 517 For u la 5 ! * ■ Formu l a I-ZE-D2 Formu l a 520 Formu l a I-ZE-D1 Step 5 Step 6 Preparation of Formula 517 Aε illuεtrated in Reaction Scheme ZE-F, Step 1, a phoεphonate of Formula 509 undergoeε a baεe catalyzed condenεation (e.g., uεing 1 molar equivalent of εodium hydride) with tetrahydropyranyloxyacetaldehyde, in a εolvent εuch aε dimethylformamide. The reaction takeε place at 25°C over a period of 1 to 4 hours, to give E/Z mixture from which the desired product of Formula 517 can be isolated by conventional means, such aε chromatography. Preparation of Formula 518 Aε illuεtrated in Reaction Scheme ZE-F, Step 2, the tetrahydropyranyloxy group of a compound of Formula 517 iε hydrolyzed in the preεerice of a catalytic amount of a dilute acid (e.g., HCl) in aqueous tetrahydrofuran. The reaction takes place at 25°C over a period of 1 to 4 hours, to give the corresponding carbinol of Formula 518. Preparation of Formula 519 As illustrated in Reaction Scheme ZE-F, Step 3, a carbinol of Formula 518 is converted to the halo (e.g., chloro or bromo) derivative of Formula 519 uεing 1 molar equivalent of triphenylphoεphine and either carbon tetrachloride or carbon tetrabromide, in dichloromethane. The reaction takeε place at 25°C over a period of 2 hours. Preparation of Formula 520 As illuεtrated in Reaction Scheme ZE-F, Step 4, a halo derivative of Formula 519 undergoeε a baεe-catalyzed ether formation with the indicated phenol, uεing 5 molar equivalentε of potaεεium carbonate, in dimethylformamide The reaction takeε place at 25°C over a period of 4 hourε. Preparation of Formula I-ZE-Dl and Formula I-ZE-D2 As illustrated in Reaction Scheme ZE-F, Step 5, an ether of Formula 520 is rearranged to give the corresponding eεter of Formula I-ZE-Dl (εhown in Reaction S.cheme ZE-D) by a thermal rearrangement catalyzed by Floriεil ® . The rearrangement takeε place in toluene at 110°C over a period of one to four dayε. Aε illuεtrated in Reaction Scheme ZE-F, Step 6, the eεter εo-produced iε hydrolyzed to the correεponding acid of Formula I-ZE-D2 aε deεcribed with reference to Reaction Scheme ZA-M, Step 2. Preparation of Compounds of Formula -ZF One method of preparing compoundε of Formula I where Z is sidechain of Formula ZF, illustrated aε compoundε of Formula I-ZF, iε εhown below in Reaction Scheme ZF-A. REACTION SCHEME ZF-A Formula 601 Formu la 602 Formu la 604 Formula 605 Formula 606 Preparation of Formula 602 Aε illuεtrated in Reaction Scheme ZF-A, Step 1, an aldehyde of Formula 601, prepared for example aε εhown in J. Org. Chem.. 1977, p3408, iε reduced to a carbinol of Formula 602. An aldehyde of Formula 601 is reacted with a reducing agent capable of selectively reducing an aldehyde in the preεence of eεter groupε, preferably from 1 to 2 (preferably 1.5) molar equivalentε of sodium borohydride in the presence of from 1 to 2 (preferably 1.5) molar equivalents of cerium chloride trihydrate, in an alcoholic/ethereal εolvent mixture (preferably 4:1 tetrahydrofuran:methanol) . The reaction takeε place at 0 to 40°0 (preferably 25°C) for 10 minuteε to 2 hourε (preferably 30 minuteε) to give the correεponding carbinol of Formula 602. Preparation of Formula 604 Aε illuεtrated in Reaction Scheme ZF-A, Step 2, a phenol of Formula 603 iε alkylated with a carbinol of Formula 602 by means of the Mitsonobu reaction to give an ether of Formula 604. A carbinol of Formula 602 iε reacted with an equimolar amount of a phenol of Formula 603 in the preεence of from 1 to 3 (preferably 2) molar equivalentε of a triarylphoεphine, preferably triphenylphoεphine, pluε from 1 to 3 (preferably 1.5) molar equivalents of diethyl azodicarboxylate in an ethereal solvent (preferably tetrahydrofuran) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 10 hourε (preferably 3 hourε) to give the correεponding ether of Formula 604. Preparation of Formula 605 Aε illuεtrated in Reaction Scheme ZF-A, Step 3, a phenol of Formula 604 iε thermally rearranged to give a dieεter of Formula 605. An ether of Formula 604 iε heated in an inert solvent (preferably toluene) in the presence of about 10 parts by weight of an activated magnesium silicate, preferably Floriεil ® . The reaction takeε place at reflux temperature for 1 to 10 dayε (preferably 4 dayε) to give the corresponding diester of Formula 605. Preparation of Formula 606 Aε illuεtrated in Reaction Scheme ZF-A, Step 4, a dieεter of Formula 605 iε hydrolyzed to give a dicarboxylic acid of Formula 606. A dieεter of Formula 605 iε reacted with an exceεε of an inorganic baεe, preferably about 50 molar equivalentε of lithium hydroxide, in an aqueouε solvent (preferably 5:1 methanol:water) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 10 dayε (preferably 2 dayε) to give the correεponding dicarboxylic acid of Formula 606. Preparation of Formula I-ZF As illustrated in Reaction Scheme ZF-A, Step 5, a dicarboxylic acid of Formula 606 iε decarboxylated to give a monocarboxylic acid of Formula I-ZF. A dicarboxylic acid of Formula 606 iε heated (optionally in the preεence of a high boiling inert εolvent, for example tetramethylbenzene, but preferably in the abεence of any solvent) . The reaction takeε place at 160 to 240°C (preferably 195°C) for about 5 minuteε to give the corresponding monocarboxylic acid of Formula I-ZF. Preparation of Compounds of Formula I-ZG One method of preparing compounds of Formula I where Z iε εidechain of Formula ZG, illuεtrated as compounds of Formula I-ZG, iε εhown below in Reaction Scheme ZG-A. REACTION SCHEME ZG-A Formula 701 Formu la 702 For u la 703 Formu la 703 Formula 704 Formu la 704 For u la 705 Formula 705 Formu la 706 Formu la 706 Formula 707 Formula 70. Formu l 708 Formu la 709 Formu I a 709 Formu la 710 Formula 710 Formula 711 For ula 7 1 For ula I - ZG- A Preparation of Formula 703 Aε illuεtrated in Reaction Scheme ZG-A, Step 1, the phenol of Formula 701 iε alkylated with 3-hydroxycyclohexene to give the correεponding ether of Formula 703, by means of the Mitsonobu reaction. The Mitsonobu reaction takeε place aε deεcribed with reference to Reaction Scheme ZF-A, Step 2. Similarly, by εubεtituting 3-hydroxy-cyclohexene with 3-hydroxy- cycloheptene, and carrying out the procedureε of Reaction Scheme ZG-A, the corresponding compounds where Z iε a εide chain of Formula ZG where D 3 iε - CH 2 -CH 2 - are obtained. Preparation of Formula 704 Aε illustrated in Reaction Scheme ZG-A, Step 2, a Claisen rearrangement of the ether of Formula 703 gives the alkylated phenol of Formula 704. The reaction takes place, e.g., at 200°C for 12 to 16 hours in the presence of N,N-diethylaniline. Preparation of Formula 705 Aε illuεtrated in Reaction Scheme ZG-A, Step 3, the alkylated phenol of Formula 704 iε protected to give a protected phenol of Formula 705 (where R a iε εilyl or toεyl) . An alkylated phenol of Formula 704 iε reacted with an equimolar amount of t-butyl dimethylεilyl chloride or p-tolueneεulfonyl chloride, in the preεence of an equimolar amount, reεpectively, of imidazole or 4- dimethylaminopyridine. The reaction takeε place in dichloromethane at a temperature of 25°C for 1 to 4 hourε to give the correεponding protected phenol of Formula 705. Preparation of Formula 706 Aε illuεtrated in Reaction Scheme ZG-A, Step 4, a protected phenol of Formula 705 iε converted to the correεponding dialdehyde of Formula 706 by ozonolyεiε. The ozonolyεiε reaction takeε place aε deεcribed with reference to Reaction Scheme ZA-A, Step 2. Preparation of Formula 707 Aε illuεtrated in Reaction Scheme ZG-A, Step 5, an intramolecular baεe-catalyzed aldol reaction with a dialdehyde of Formula 706 produceε the corresponding formyl cyclopentene of Formula 707. The reaction is conducted with 0.1 moles of dibenzylamine or N-methylaniline trifluoroacetate in benzene, taking place at 50°C for 30 minuteε. Preparation of Formula 708 Aε illustrated in Reaction Scheme ZG-A, Step 6, a formyl cyclopentene of Formula 707 is reduced to the correεponding carbinol. The reaction employε εodium borohydride/cerium chloride, aε deεcribed with reference to Reaction Scheme ZF-A, Step 1. Preparation of Formula 709 Aε illustrated in Reaction Scheme ZG-A, Step 7, a carbinol of Formula 708 is converted to the corresponding acetate of Formula 709. The reaction is conducted with equimolar amounts of acetyl chloride and triethylamine, taking place in methylene chloride at 0°C for 1 hour. Preparation of Formula 710 Aε illuεtrated in Reaction Scheme ZG-A, Step 8, an acetate of Formula 709 iε converted to the correεponding dieεter of Formula 710. The reaction iε conducted aε described in J. Am. Chem. Soc. , 102:4730 (1980), with 4 moles of sodium dimethylmalonate, 0.5 moleε triphenylphoεphine and 0.25 moleε of tetrakiε triphenylphoεphine palladium at 50°C in THF. Preparation of Formula 711 Aε illuεtrated in Reaction Scheme ZG-A, Step 9, a dieεter of Formula 710 iε converted to give the corresponding ester of Formula 111, by reaction with ceεium acetate in hexamethylphoεphoric triamide at 120°C for 1 to 3 hourε. Similarly, by uεe in Step 8 of an alternative for εodium dimethylmalonate εuitably εubεtituted to introduce Z 3 or Z 4 , the correεpondingly εubεtituted eεter of Formula 711 iε obtained in Step 9. Preparation of Formula I-ZG-A Aε illuεtrated in Reaction Scheme ZG-A, Step 10, an eεter of Formula 711 is hydrolyzed to give the corresponding compound of Formula I-ZG-A. The reactionε take place aε deεcribed with reference to Reaction Scheme ZA- M, Steps 1 and 2 respectively. Preparation of Compounds of Formula I-ZH One method of preparing compounds of Formula I where Z is sidechain of Formula ZH, illustrated as compounds of Formula I-ZH, is shown below in Reaction Scheme ZH-A. REACTION SCHEME ZH-A For u la 03 TBSO-CCH B D a -D-: Z' step For u la 103e Formu la 801 Formula 801 ►■ Step 2 Formu la 802 Formu l a 803 Formu la 803 Formu l a 804 For u la 804 Formu l 805 Formu la 805 Formu la I -ZH- A1 H Formu l a -ZH-A1 Formu I a I -ZH-A2 Preparation of Formula 801 Aε illuεtrated in Reaction Scheme ZH-A, Step 1, an aldehyde of Formula 103 iε converted to a carbinol by addition of an organometallic compound of Formula 103e (εuch aε a εubεtituted vinyl organolithium, or preferably a Grignard reagent where: M iε MgBr; TBS iε a tert- butyldimethylsilyl protecting group; and D 4 iε preferably lower alkylene) . A halovinyl (preferably bro ovinyl) compound of Formula 103e (where M iε halo) iε reacted with magneεium metal in an ethereal εolvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takeε place at 30 to 60°C (preferably 40°C) over a period of 1 to 6 hours (preferably 2 hours) . One molar equivalent of the resultant organometallic reagent iε added to a εolution of an aldehyde of Formula 103 (in the εame εolvent εyεtem uεed to make the organometallic reagent) . The reaction takeε place at -80 to 20°C (preferably 0°C) over a period of 5 to 60 minuteε (preferably 10 minuteε) to give the correεponding εilyl-protected carbinol of Formula 801. Preparation of Formula 802 Aε illuεtrated in Reaction Scheme ZH-A, Step 2, an alkyl eεter of Formula 802 iε formed by a Claiεen ortho eεter rearrangement reaction of a carbinol of Formula 801 and an orthoeεter compound of Formula 104a (aε illuεtrated in Reaction Scheme ZA-A, where Z 3 and Z 4 are H) . A εilyl-protected carbinol of Formula 801 iε heated at 50 to 120°C (preferably about 100°C) with about 10 molar equivalents of an orthoester of Formula 104a, in the presence of from 0.05 to 0.25 molar equivalents (preferably 0.10 molar equivalentε) of an organic acid catalyεt (εuch aε propionic, butyric, or preferably trimethylacetic acid) . The reaction takeε place over a period of 1 to 48 hourε (preferably 8 hours) to give the corresponding alkyl ester of Formula 802. Preparation of Formula 803 As illustrated in Reaction Scheme ZH-A, Step 3, the silyl-protected carbinol of an alkyl ester of Formula 802 iε deprotected. A compound of Formula 803 iε reacted with from 5 to 30 (preferably 20) molar equivalentε of hydrogen fluoride, in a mixture of water and a water-miεcible organic εolvent (preferably acetonitrile) . The reaction takeε place at -20 to 40°C (preferably 25°C) for 5 to 60 minuteε (preferably 30 minutes) to afford the corresponding unprotected carbinol/alkyl eεter of Formula 803. Preparation of Formula 804 Aε illustrated in Reaction Scheme ZH-A, Step 4, a carbinol of Formula 803 iε converted to a halide (preferably a bromide) of Formula 804, by meanε of a one-εtep or a two-εtep procedure. In the one-εtep procedure, a carbinol of Formula 803 iε reacted with from 1.0 to 1.3 (preferably 1.1) molar equivalentε of a triaryl (preferably triphenyl) phoεphine, and from 1.0 to 1.3 (preferably 1.1) molar equivalentε of a halogen εource (such aε N-bromoεuccinimide or preferably carbon tetrabromide) . The reaction iε conducted in an inert εolvent (εuch aε ether or preferably tetrahydrofuran) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 12 hourε (preferably 3 hourε) to afford the corresponding halide of Formula 804. Alternatively, in the two-εtep procedure, which iε preferred, a carbinol of Formula 803 iε converted firεt into a εulphonate eεter (εuch aε a p-tolueneεulphonate or preferably a methaneεulphonate) by reaction with from 1.0 to 1.5 (preferably 1.3) molar equivalents a sulphonyl halide (preferably methanesulphonyl chloride) in the presence of an equimolar amount of a tertiary organic baεe (preferably diiεopropylethylamine) in a εolvent (εuch aε chloroform or preferably dichloromethane) . The reaction takeε place at -20 to 30°C (preferably 0°C) for 10 to 60 minuteε (preferably 30 minuteε) . The εo-obtained εulphonate eεter iε then reacted with from 5 to 20 (preferably 20) molar equivalentε of an alkali metal halide (preferably lithium bromide) in a εolvent (εuch aε 2-butanone or preferably acetone) . The reaction takeε place at 0 to 56°C (preferably ' at reflux) for 30 to 180 minuteε (preferably 90 minutes) to afford the corresponding halide of Formula 804. Preparation of Formula 805 As illustrated in Reaction Scheme ZH-A, Step 5, a halogenated carbinol/alkyl ester of Formula 804 is deprotected at the phenolic group to give the correεponding halogenated carbinol/alkyl eεter of Formula 805. The deprotection reaction takeε place aε deεcribed above with reference to Reaction Scheme ZA-M, Step 1. Preparation of Formula I-ZH-A1 Aε illuεtrated in Reaction Scheme ZH-A, Step 6, a halogenated carbinol/alkyl eεter of Formula 805 iε εubjected to a baεe-induced cyclization reaction to afford the product of Formula I-ZH-A1. A compound of Formula 805 is reacted with from 2.0 to 2.5 (preferably 2.3) molar equivalents of a strong baεe (εuch aε lithium diiεopropylamide, εodium hydride or preferably εodium hexamethyldiεilazide) in a εolvent (εuch aε dioxane or preferably tetrahydrofuran) . The reaction takes place at -20 to 30°C (preferably at 0°C) for 5 to 60 minutes (preferably 15 minutes) to afford the corresponding cycloalkyleεter of Formula I-ZH-A1. Preparation of Formula I-ZH-A2 Aε illuεtrated in Reaction Scheme ZH-A, Step 7, a cycloalkyl eεter of Formula I-ZH-A1 iε hydrolyzed to give the correεponding acid of Formula I-ZH-A2. The hydrolyεiε takeε place aε deεcribed above with reference to Reaction Scheme ZA-M, Step . Compoundε of Formula I where Z iε a εidechain of Formula ZH in which D 4 is O or 0-CH 2 are preferably prepared as described below in Reaction Scheme ZH-B. REACTI0N SCHEME ZH-B Formu la B06 Formu I a B07 Formu la 807 Formu la 808 Formu la 80 E Formu la 809 q -Br Formu la 809 For u la 810 Formu la 810 Formu la I-ZH-B1 F or m u l a I - Z H- B 2 Preparation of Formula 807 0 Aε illuεtrated in Reaction Scheme ZH-B, Step 1, an aldehyde of Formula 302 (where Z 5 iε methyl) undergoeε an aldol reaction with the bromo-alkyl oxazolidinone of Formula 806 (where q iε 1 or 2) , which can be prepared by analogy with the reactionε described in J. Am. Chem. Soc , 103:2127 (1981), to give the acyloxazolidinone of Formula 807. 5 An oxazolidinone of Formula 806 is reacted with an equimolar amount of a base (εuch as lithium diiso ropylamide or preferably di-n-butylboryl trifluoromethane sulphonate/triethylamine) , and then with an aldehyde of Formula 302. The reaction takeε place at -78°C to 0°C (preferably -40°C) for 1 to 12 hourε (preferably 3 hourε) to afford the correεponding 0 acyloxazolidinone of Formula 807. Preparation of Formula 808 As illustrated in Reaction Scheme ZH-B, Step 2, an acyloxazolidinone of Formula 807 iε hydrolyzed to the carboxylic acid of Formula 808. An acyloxazolidinone of Formula 807 iε reacted with 1-5 (preferably 5 3) molar equi.valentε of lithium hydroxide in 3:1 tetrahydrofuran containing 5-20 (preferably 12) molar equivalentε of hydrogen peroxide. The reaction takeε place at -10 to 25°C (preferably 0°) for 5 to 60 minuteε (preferably 30 minuteε) to give the correεponding carboxylic acid of Formula 808. Preparation of Formula 809 0 Aε illuεtrated in Reaction Scheme ZH-B, Step 3, a carboxylic acid of Formula 808 iε deprotected to give the correεponding phenol of Formula 809, using the method described with respect to Reaction Scheme ZA-M, Step 1. Preparation of Formula 810 A phenol of Formula 809 is esterified to give the correεponding eεter 5 of Formula 810. A phenol of Formula 809 iε treated with methanol in the preεence of 0.05 to 0.2 (preferably 0.1) molar equivalentε of an acid catalyεt (preferably p-tolueneεulphonic acid) . The reaction takeε place at 0 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 12 hourε) to give the 0 correεponding methyl eεter of Formula 810. Preparation of Formula I-ZH-B1 A methyl eεter of Formula 810 undergoeε an intramolecular cyclization reaction to give the correεponding cyclized eεter of Formula I-ZH-B1. A methyl eεter of Formula 810 iε treated with 1.9 to 2.5 (preferably 5 2.0) molar equivalentε of a εtrong baεe (εuch as lithium diisopropylamide or preferably sodium hydride) in tetrahydrofuran (or preferably dimethylformamide) . The reaction takeε place at -10 to 25°C (preferably 0°) for 1-12 hourε (preferably 2 hourε) to give the corresponding cyclized ester of Formula I-ZH-B1. Preparation of Formula I-ZH-B2 As illustrated in Reaction Scheme ZH-B, Step 6, a cyclized ester of Formula I-ZH-B1 is hydrolyzed to give the correεponding acid of Formula I- ZH-B2, uεing the method deεcribed with reεpect to Reaction Scheme ZA-M, Step 2. Preparation of Formula I where R 1 is Acyl A compound of Formula I, e.g., prepared aε deεcribed above, iε reacted with 1.0 to 1.5 (preferably 1.1) molar equivalentε of an acylating agent [εuch aε an acyl halide (e.g., benzoyl chloride) or an acyl anhydride (e.g., acetic anhydride)] in a εolvent (εuch aε ether, tetrahydrofuran, or preferably pyridine) optionally in the preεence of from 1.0 to 2.0 (preferably 1.25) molar equivalentε of an inorganic or organic baεe (εuch aε εodium carbonate, ceεium carbonate or dimethylaminopyridine) . The reaction takeε place at 0 to 60°C (preferably 25 °C) for 1 to 12 hourε (preferably 2 hourε) to afford the corresponding compound of Formula I where R 1 is acyl. Preparation of Formula I where R 1 is C(0)-NH-aryl The compounds of Formula I where R 1 iε C(0)-NH-aryl are prepared, e.g., aε deεcribed in previouεly incorporated U.S. Patent No. 3,853,919. Preparation of Esters of Formula I The eεterε of Formula I (compoundε where G iε not OH) can be prepared aε deεcribed in U.S. Patentε Noε. 4,727,069 and 4,753,935, incorporated herein by reference, by deprotection of a precursor (e.g., aε deεcribed with reference to Reaction Scheme ZA-M, Stepε 1) or as described below by attachment of a leaving group and its replacement by the desired eεter. Attachment of Leaving Group A carboxylic acid of Formula I iε reacted with from 1.0 to 3.0, preferably about 1.5, molar equivalentε of oxalyl chloride or preferably thionyl chloride, in a εolvent (εuch aε chloroform or preferably dichloromethane) optionally containing from 0.01 to 0.05 (preferably 0.03) molar equivalentε of dimethylformamide. The reaction takeε place at -10 to 30°C (preferably 0°C) for 1 to 12 hourε (preferably 2 hourε) to give the correεponding acid chloride (where the leaving group iε Cl) . Alternatively, a carboxylic acid of Formula I iε reacted with 1.0 to 1.5 (preferably 1.25) molar equivalentε of carbonyldiimidazole, in a solvent (εuch as tetrahydofuran or preferably dichloromethane) . The reaction takeε place at 0 to 40°C (preferably 25°C) for 1 to 12 hourε (preferably 2 hours) to give the corresponding acyl imidazole (where the leaving group iε 1-imidazolyl) . Esterification A compound of Formula I where G haε been replaced by a halide or imidazolide iε converted to the correεponding alkyl (where G iε O-alkyl) , thioalkyl (where G iε S-alkyl) , aminoalkyl (where G is 0- (CH 2 ) n -NG'G 2 ) or heterocyclic aminoalkyl (where G iε 0- (CH 2 ) n -N=G 3 ) compoundε, or to the correεponding amideε (where G iε NG'G 2 ) . A compound of Formula I where G haε been replaced by a halide or imidazolide iε reacted with from 1.0 to 5.0 (preferably 2) molar equivalentε of an alkanol, a thiol or ammonia, a monoalkyl or dialkylamine, or a heterocyclic aminoalkanol, optionally in the preεence of from 1.0 to 1.5 (preferably 1.25) molar equivalentε of a tertiary organic baεe (εuch aε 4-dimethylaminopyridine or preferably triethylamine) in an organic εolvent (εuch aε dioxane, tetrahydrofuran or preferably dichloromethane) . The reaction takeε place at -10 to 50°C (preferably 25°C) for 1 to 24 hourε (preferably 4 hourε) to afford the correεponding compoundε of Formula I where G is other than OH. Preparation of the Salts of Formula I Some of the compounds of Formula I can be converted to corresponding acid addition εaltε. The converεion iε accompliεhed by treatment with a εtoichiometric amount of an appropriate acid, such aε hydrochloric acid (e.g., 3 molar equivalentε to form the trihydrochloride εalt) . Typically, the free baεe iε disεolved in a polar organic solvent, εuch aε methanol or ethanol, and the acid iε added in water, methanol or ethanol. The temperature iε maintained at 0°C to 50 °C. The corresponding salt precipitates εpontaneouεly or can be brought out of εolution with a leεε polar εolvent. The acid addition εaltε of the compoundε of Formula I can be decompoεed to the correεponding free bases by treatment with an excesε of a suitable base, εuch aε ammonia or εodium bicarbonate, typically in the preεence of an aqueouε εolvent, and at a temperature between 0°C and 50°C. The free baεe form iε iεolated by conventional meanε, εuch as extraction with an organic solvent. Some of the compoundε of Formula I can be converted to correεponding baεe addition εaltε. The converεion iε accompliεhed by treatment with a εtoichiometric amount of an appropriate baεe, εuch aε εodium carbonate, potaεsium bicarbonate, lithium hydroxide, ethanolamine, tromethamine, and the like. Typically, the free acid iε diεεolved in a polar organic εolvent, εuch aε methanol or ethanol, and the baεe iε added in water, methanol or ethanol. The temperature is maintained at 0°C to 50 °C. The corresponding salt precipitateε εpontaneouεly or can be brought out of εolution with a leεε polar εolvent, or the εalt can be iεolated by evaporation of all εolventε, and optionally recryεtallizing the residue thus obtained from a suitable solvent, or a mixture of εolventε, for example, methanol, ethanol, propanol, ethyl acetate, acetonitrile, tetrahydrofuran, diethyl ether, and the like. Preferred Processes and Last Steps A compound of Formula I where R 1 iε replaced by a protecting group iε deprotected. A compound of Formula I where G is lower alkoxy is hydrolyzed to the corresponding acid where G is OH. A compound of Formula I where G is OH is esterified to give the correεponding compound where G iε lower alkoxy, lower thioalkyl, NG'G 2 , 0- (CH 2 ) n -NG'G 2 , or 0- (CH 2 ) n -N=G 3 . A compound of Formula I iε contacted with a pharmaceutically acceptable acid or baεe to form the correεponding acid or base addition salt. A pharmaceutically acceptable acid addition salt of Formula I iε contacted with a baεe to form the corresponding free base of Formula I. Preferred Compounds Generally preferred are the compounds of Formula I where R 1 iε H, G iε OH, and Z is a side chain of Formulae ZA, ZB, ZE, or ZH. Of the compoundε of Formula I where Z iε a side chain of Formula ZA, preferred are those compounds where Z 1 iε methyl, Z 2 iε H or methyl, Z 3 iε methyl or ethyl, and Z 4 iε H; particularly the compoundε where Z 2 and Z 3 are methyl, and where Z 2 iε H and Z 3 is methyl or ethyl especially in the (S) configuration. Of the compounds of Formula I where Z iε a εide chain of Formula ZB, preferred are thoεe compounds where D'-D 2 iε -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -, and Z 5 is H, methyl or ethyl; particularly the compoundε where Z 5 iε methyl or ethyl, eεpecially methyl. Of the compoundε of Formula I where Z iε a side chain of Formula ZE, preferred are those compounds where Z 5 iε H or lower alkyl (particularly methyl) , Z 6 is H or lower alkyl (particularly 3-methyl) , and Z 7 iε H. Of the compoundε of Formula I where Z iε a εide chain of Formula ZH, preferred are thoεe compoundε where Z 1 iε lower alkyl (particularly methyl), and D 4 iε -CH 2 -, -CHj-O or -CH 2 -0- . At present, the most preferred compounds are: (+) (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3,4-dimethyl-4-hexenoic acid; (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (S) ,4-dimethyl-4-hexenoic acid; (+) (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,3,4-trimethyl-4-hexenoic acid; (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (S) -ethyl-4-methyl-4-hexenoic acid; 2-{2- [2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl)ethylidene] cyclohex-1(S) -yl}acetic acid; 2-{2- [2- [1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl]ethylidene]cyclopent-1(S) -yl}acetic acid; 2-{2- [2- (4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl)ethylidene] cyclohex-1 (S) -yl}-2 (S) -methylacetic acid; 2-{2- [2- [1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl]ethylidene]cyclopent-1 (S) -yl}-2 (S) -ethylacetic acid; (-) 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1 (S) -yl}-2-methylacetic acid, including the 2 (R) -methylacetic acid and 2 (S) -methylacetic acid iεomerε; (-) 2-{4- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene]tetrahydropyran-3-yl}acetic acid; (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεo- benzofuran-5-yl) -1-methylprop-l-en-l-yl] tetrahydropyran-1-carboxylic acid; (E) -2 (S) -{4- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo- isobenzofuran-5-yl)ethylidene] -tetrahydropyran-3 (S) -yl} propionic acid; (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzo- furan-5-yl) -1-methylprop-l-en-l-yl]cyclopentane-1-carboxylic acid; and (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεo- benzofuran-5-yl) -1-methylprop-l-en-l-yl] cyclohexane-1-carboxylic acid; moεt particularly: (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2 (S) ,4-dimethyl-4-hexenoic acid; (+) (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,3,4-trimethyl-4-hexenoic acid (having a melting point of 146-148°C when recryεtallized from hexane/methylene chloride) ; (E) -2 (S) -{4- [2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo- iεobenzofuran-5-yl)ethylidene] -tetrahydropyran-3 (S) -yl} propionic acid; and (-) 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yl}-2-methylacetic acid, including the 2 (R) -methylacetic acid and 2 (S) -methylacetic acid iεomerε. Utility, Testing and Administration General Utility The compoundε of the preεent invention, the pharmaceutically acceptable εaltε thereof and pharmaceutical compoεitionε therewith (collectively the "compoundε" for purpoεeε of the following deεcription) are uεeful aε immunoεuppreεεive agents, anti-inflammatory agentε, anti- tumor agentε, anti-proliferative agentε, anti-viral agentε and anti- pεoriatic agentε in mammalε, whether domeεtic (cattle, pigε, εheep, goatε, horεeε) , petε (catε, dogε) , or preferably humanε. The compoundε are inhibitorε of inoεine monophosphate dehydrogenaεe (IMPDH) and thus inhibit de novo purine syntheεiε; they have anti-proliferative effectε (e.g., againεt εmooth muεcle cellε and both B and T lymphocyteε) and inhibit antibody formation and the glycoεylation of cell adheεion moleculeε in lymphocyteε and endothelial cellε. Aε immunoεuppreεεive agentε, the compoundε are useful in treating auto-immune related diεorderε, for example: Type I Diabeteε Mellitus; Inflammatory Bowel Diεeaεe (e.g., Crohn's Diseaεe and Ulcerative Colitis); Syεtemic Lupuε Erythematoεus; Chronic Active Hepatitis; Multiple Sclerosis; Grave's Diεeaεe; Haεhimoto'ε Thyroiditiε; Behcet'ε Syndrome; Myaεthenia Gravis; Sjogren's Syndrome; Perniciouε Anemia; Idiopathic Adrenal Inεufficiency; and Polyglandular Autoimmune Syndromeε Type I and II. The compoundε are alεo uεeful aε therapeutic immunoεuppreεεive agentε in the treatment of Aεthma, Immunohemolytic Anemia, Glomerulonephritiε, and Hepatitiε. Preventative uses of the compounds as immunosuppresεive agentε include the treatment of allograft rejection, for example, in cardiac, lung, pancreatic, renal, liver, εkin and corneal allograftε, and prevention of Graft vε. Hoεt Diεeaεe. The compoundε are uεeful for inhibiting proliferative reεponεeε to vaεcular injury, for example, εtenoεiε following an inεult to a blood veεεel wall in post-angioplasty reεtenoεis, and post-cardiac by-pasε εurgery reεtenoεiε. The compoundε are uεeful aε anti-inflammatory agentε, for example, in treating Rheumatoid Arthritiε, Juvenile Rheumatoid Arthritiε and Uveitiε. Aε anti-tumor agentε, the compoundε are uεeful in treating εolid tumorε and malignancieε of lymphoreticular origin. For example, the compoundε 1 utility for treatment of εolid tumorε includeε: cancers of the head and neck, including εquamouε cell carcinoma; lung cancer, including εmall cell and non-small cell lung carcinoma; mediastinal tumorε; eεophageal cancer, including εquamous cell carcinoma and adenocarcinoma; pancreatic cancer; cancer of the hepatobiliary syεtem, including hepatocellular carcinoma, cholangiocarcinoma, gall bladder carcinoma and biliary tract carcinoma; εmall inteεtinal carcinoma, including adenocarcinoma, εarcoma, lymphoma and carcinoidε; colorectal cancer, including colon carcinoma and rectal carcinoma; metastatic carcinoma; cancerε of the genitourinary εyεtem, including ovarian cancer, uterine εarcoma, and renal cell, ureteral, bladder, proεtate, urethral, penile, teεticular, vulvar, vaginal, cervical, endometrial, and fallopian tube carcinoma; breaεt cancer; endocrine εyεtem cancer; soft tisεue sarcomas; malignant mesotheliomaε; εkin cancer, including εquamouε cell carcinoma, baεal cell carcinoma and melanoma; cancer of the central nervous εyεtem; malignant bone tumorε; and plaεma cell neoplaεmε. Aε anti-tumor agentε for treatment of malignancieε of lymphoreticular origin, the compoundε are uεeful in treating, for example: Lymphomaε and Leukemiaε, including B, T and promonocyte cell line malignancieε, Mycoεeε Fungoideε, Non-Hodgkinε Lymphoma, Malignancieε of Burkitt Lymphoma Cellε and other EBV- ranεformed B-lymphocyteε, Lymphomaε reεulting from Epεtein-Barr viral infectionε in allograft recipients, Chronic Lymphocytic Leukemia, Acute Lymphocytic Leukemia and Hairy Cell Leukemia. As anti-viral agents, the compoundε are uεeful in treating, for example: retroviruεeε, including Human T-leukemia Viruεeε, Typeε I and II (HTLV-1 and HTLV-2) , Human Immuno Deficiency Viruεeε, Typeε I and II (HIV-1, HIV-2) and, Human Naεopharyngeal Carcinoma Viruε (NPCV) and in treating Herpeε Viruεeε, including EBV infected B-lymphocyteε, CMV infection, Herpeε Viruε Type 6, Herpes Simplex, Typeε 1 and 2, (HSV-1, HSV-2) and Herpes Zoεter. As anti-psoriatic agentε, the compoundε are uεeful in treating, for example, psoriasis and pεoriatic arthritiε. Testing Activity teεting is conducted aε deεcribed in the following references, and by modifications thereof. General anti-inflammatory, anti-viral, anti-tumor, anti-psoriatic and/or immunosuppreεεive activity iε aεεociated with the inhibition of Inoεine 5' -Monophoεphate Dehydrogenaεe ("IMPDH"). In vitro aεεayε meaεuring the inhibition of IMPDH, for example, by determining the level of NADH formation according to the method of Anderεon, J.H. and Sartorelli, A.C., J. Biol . Chem. , 243:4762-4768 (1968) are predictive of εuch activity. Initial animal εcreening teεts to determine anti-inflammatory activity potential include the adjuvant arthritiε aεεay, e.g., according to the method of Pearεon, Proc. Soc. Exp. Biol . Med., 91:95-101 (1956). Alεo, in vitro teεtε, for example thoεe using εynovial explantε from patients with rheumatoid arthritiε, Dayer, et al. , J. Exp. Med. , 145:1399-1404 (1977) , are uεeful in determining whether compoundε exhibit anti- inflammatory activity. Autoimmune activity iε determined, e.g., utilizing experimental allergic encephalomyelitiε, by a modification of a procedure initially described by Grieg, et. al., J. Pharmacol . Exp. Ther., 173:85 (1970). Human clinical trials for efficacy in the treatment of asthma are conducted, e.g., aε deεcribed by Erzurum, Leff, Cochran, et al. "Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double- blind, placebo controlled εtudy. " Ann. Int. Med. , 114:353-360 (1991). Activity to prevent the rejection of organ or tissue allograftε in experimental animalε iε determined, for example, as deεcribed by Hao, et al., J. Immunol . , 139:4022-4026 (1987). In addition, U.S. Patent No. 4,707,443 and EP 226062, incorporated herein by reference, alεo deεcribe aεεayε for activity in prevention of allograft rejection by detection of IL-2R levelε. Human clinical trialε to establish efficacy in preventing rejection of solid organ tranεplantε (such as renal) are conducted, e.g., as described by Lindholm, Albrechtεen, Tufveεon, et al., "A randomized trial of cycloεporin and predniεolone verεuε cycloεporin, azathioprine and predniεolone in primary cadaveric renal transplantation, " Transplantation, 54:624-631 (1992). Human clinical trials for graft vs. host diseaεe are conducted, e.g., aε deεcribed by Storb, Deeg, hitehead, et al., "Methotrexate and cycloεporin compared with cycloεporin alone for prophylaxiε of acute graft verεuε hoεt disease after marrow transplantation for leukemia." New England J. Med. , 314:729-735 (1986). Immunosuppreεεive activity is determined by both in vivo and in vitro procedureε. In vivo activity iε determined, e.g., utilizing a modification of the Jerne hemolytic plaque aεεay, [Jerne, et al., "The agar plaque technique for recognizing antibody producing cellε," Cell-jbound Antibodies, Amos, B. and Kaprowski, H. editors (Wiεtar Inεtitute Preεε, Philadelphia) 1963, p. 109] . In vitro activity iε determined, e.g., by an adaptation of the procedure deεcribed by Greaveε, et al., "Activation of human T and B lymphocyteε by polyclonal mitogens," Mature, 248:698-701 (1974). Anti-viral activity iε determined, for example, by the procedure deεcribed by Smee, et al. ["Anti-Herpeεviruε Activity of the Acyclic Nucleoεide 9- (l,3-Dihydroxy-2-Propoxymethyl)Guanine, " Antimicrobial Agents and Chemotherapy, 23 (5) :676-682 (1983)], or as described by Planteroεe ["Antiviral and cytotoxic effectε of mycophenolic acid," Journal of General Virology, 4:629 (1969)]. Anti-viral activity can likewiεe be determined by meaεurement of reverεe tranεcriptase activity, for example, according to the method deεcribed by Chen et al., Biochem. Pharm. , 36:4361 (1987) . Human clinical trialε for anti-HIV efficacy (together with clinical treatment εcenarioε) are described and cited, for example, by Sande, et al., "Antiretroviral Therapy for Adult HIV-Infected Patients," JAMA, 270 (21) :2583-2589 (1993). A large scale clinical trial can be conducted, e.g., as deεcribed by Volberding, P.A., et al. "Zidovudine in aεymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4 positive cellε per cubic millimeter, " New England J. Med. , 322 (14) :941-949 (1990). A εmaller εcale (Phaεe I) clinical trial can be conducted, e.g., aε deεcribed by Browne, et al., "2' ,3' -Didehydro-3' - deoxythymidine (d4T) in Patientε with AIDS or AIDS-Related Complex: A Phaεe I Trial," J. Infectious Diseases, 167:21-29 (1993). Teεtε for systemic activity in pεoriaεiε can be carried out, for example, aε described by Spatz, et al., "Mycophenolic acid in psoriasiε," British Journal of Dermatology, 98:429 (1978) . Teεtε for anti-tumor activity can be performed, for example, aε deεcribed by Carter, et al. ["Mycophenolic acid: an anticancer compound with unuεual propertieε," Nature, 223:848 (1969)]. In vitro activity for treating εtenoεiε is demonεtrated, for example, by inhibiting the proliferation of εmooth muεcle cellε, aε established by the following human arterial smooth muεcle cell proliferation assay. Human smooth muεcle cellε are grown in culture. A teεt group iε treated with the test compound added at selected concentrations in fresh media. Both groupε receive 2μCi tritiated thymidine ( 3 HTdR) , a radioiεotope label. After 24 hourε, the cellε are harvested and the amount of label incorporated into DNA is counted by εcintillation; thiε is compared for the test and control groups, the amount being proportional to cell proliferation. Inhibition of εmooth muεcle proliferation iε eεtabliεhed when the teεt group haε a lower radioiεotope count than the control group. The concentrationε of teεt compound required to inhibit proliferation by 50% (the IC 50 ) , and to inhibit proliferation by more than 95% are determined. In vivo activity for treating εtenoεis is demonstrated, for example, in rat and pig models for arterial εtenoεiε. In the rat model, a teεt group iε treated with the teεt compound, εtarting 6 dayε before and continuing for 14 days after injury to the left carotid artery; the teεt group iε compared to a control group receiving vehicle without the teεt compound. Injury iε achieved by a gentle perfuεion of air through a 10 mm long εection of the left artery. The right artery iε left intact. Arterial croεε-εectionε (10 μm) are taken from both the left and right arterieε of each εubject, and the area of the veεεel wall (endothelium, intima, media) iε meaεured, The amount of vaεcular proliferation iε calculated by εubtracting the mean area of the intact, right carotid artery from the mean area of the injured, left carotid artery. Reduction in vaεcular proliferation iε established when the test group εhowε leεε proliferation than the control group. Human clinical trialε for restenosiε after coronary angioplaεty are conducted, e.g., aε deεcribed by Serruyε, Rutεch, Heyndrickx, et al., "prevention of reεtenoεis after percutaneous tranεluminal coronary antioplaεty with thromboxane Aj-receptor blockade: a randomozed, double- blind, placebo-controlled trial." Circulation, 84:1568-80 (1991). Administration The compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease stateε previouεly described. Administration of the compounds of the invention or the pharmaceutically acceptable saltε thereof can be via any of the accepted modeε of adminiεtration for agentε that serve similar utilities. The compoundε can be uεed both prophylactically (e.g., to prevent allograft rejection) and therapeutically. While human doεage levelε have yet to be optimized for the compoundε of the invention, generally, a daily doεe iε from about 0.01 to 100.0 mg/kg of body weight, preferably about 0.1 to 64.3 mg/kg of body weight, and moεt preferably about 0.3 to 43.0 mg/kg of body weight. Thuε, for adminiεtration to a 70 kg person, the dosage range would be about 0.7 mg to 7 g per day, preferably about 7.0 mg to 4.5 g per day, and moεt preferably about 21 mg to 3.0 g per day. The amount of active compound adminiεtered will, of courεe, be dependent on the εubject and diεeaεe εtate being treated, the εeverity of the affliction, the manner and εchedule of adminiεtration (e.g., oral adminiεtration one day prior to cancer chemotherapy and intravenouε adminiεtration during cancer chemotherapy) and the judgment of the preεcribing phyεician. In employing the compoundε of thiε invention for treatment of the above conditionε, any pharmaceutically acceptable mode of adminiεtration can be uεed. The compoundε of Formula I can be adminiεtered either alone or in combination with other pharmaceutically acceptable excipientε, including εolid, εemi-εolid, liquid or aeroεol doεage forms, such as, for example, tablets, capεuleε, powderε, liquids, injectables, suspensionε, εuppoεitorieε, aeroεolε or the like. The compoundε of Formula I can alεo be adminiεtered in εuεtained or controlled releaεe doεage formε, including depot injections, osmotic pumpε, pills, transdermal (including electro- tranεport) patcheε, and the like, for the prolonged adminiεtration of the compound at a predetermined rate, preferably in unit doεage formε εuitable for εingle adminiεtration of preciεe doεageε. The co poεitionε will typically include a conventional pharmaceutical carrier or excipient and a compound of Formula I or a pharmaceutically acceptable εalt thereof. Theεe compoεitionε may alεo include other medicinal agentε, pharmaceutical agentε, carrierε, adjuvantε, etc., εuch as ultidrug resiεtance modifying agentε, εteroidε, immunoεuppreεεantε εuch as cyclosporine A, azathioprene, rapamycin, FK-506, brequinar, leflunomide and vincryεtine. Generally, depending on the intended mode of adminiεtration, the pharmaceutically acceptable composition will contain about 0.1% to 90%, preferably about 0.5% to 50%, by weight of a compound or salt of Formula I, the remainder being suitable pharmaceutical excipientε, carrierε, etc. One preferred manner of adminiεtration for the conditionε detailed above iε oral, uεing a convenient daily doεage regimen which can be adjuεted according to the degree of affliction. For εuch oral adminiεtration, a pharmaceutically acceptable compoεition iε formed by the incorporation of any of the normally employed excipientε, εuch aε, for example, mannitol, lactoεe, εtarch, povidone, magneεium εtearate, εodium εaccharine, talcum, celluloεe, croscarmellose sodium, glucose, gelatin, sucroεe, magnesium carbonate, and the like. Such compositionε take the form of εolutionε, εuspensionε, tabletε, diεperεible tabletε, pillε, capεuleε, powderε, εuεtained releaεe formulationε and the like. Preferably the compoεitionε will take the form of a pill or tablet. Thuε the compoεition will contain, along with the active ingredient, a diluent εuch aε lactoεe, εucroεe, dicalcium phoεphate, or the like; a lubricant εuch aε magneεium εtearate or the like; a diεintegrant εuch aε croεcarmellose sodium or the like; and a binder εuch aε εtarch, gum acacia, polyvinylpyrrolidine, gelatin, celluloεe and derivativeε thereof, and the like. Liquid pharmaceutically adminiεtrable compoεitionε can, for example, be prepared by diεεolving, diεperεing, etc. an active compound aε defined above and optional pharmaceutical adjuvantε in a carrier, εuch aε, for example, water, εaline, aqueouε dextroεe, glycerol, glycolε, ethanol, and the like, to thereby form a εolution or εuεpenεion. If deεired, the pharmaceutical compoεition to be adminiεtered may alεo contain minor amounts of nontoxic auxiliary substances such aε wetting agentε, εuεpending agentε, emulεifying agentε, or εolubilizing agentε, pH buffering agentε and the like, for example, εodium acetate, εodium citrate, cyclodextrine derivativeε, polyoxyethylene, εorbitan monolaurate or εtearate, etc. Actual methodε of preparing εuch doεage formε are known, or will be apparent, to thoεe εkilled in thiε art; for example, εee Remington 's Pharmaceutical Sciences, Mack Publiεhing Company, Eaεton, Pennεylvania, 15th Edition, 1975. The compoεition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount effective to alleviate the εymptomε of the εubject being treated. Doεage formε or compoεitionε containing active ingredient in the range of 0.005% to 95% with the balance made up from pharmaceutically acceptable carrier may be prepared. For oral adminiεtration, a pharmaceutically acceptable composition iε formed by the incorporation of any of the normally employed excipientε, εuch aε, for example pharmaceutical gradeε of mannitol, lactoεe, εtarch, magneεium εtearate, talcum, povidone, celluloεe derivatives, croεcarmelloεe εodium, glucoεe, εucroεe, magneεium carbonate, εodium εaccharin, talcum and the like. Such compoεitionε take the form of εolutionε, εuspenεionε, tabletε, capsules, powders, suεtained releaεe formulationε and the like. Such compoεitionε may contain 0.01%-95% active ingredient, preferably 0.1-50%. For a εolid doεage form containing liquid, the εolution or εuεpenεion, in for example propylene carbonate, vegetable oilε or triglycerideε, iε preferably encapεulated in a gelatin capεule. Such ester solutionε, and the preparation and encapεulation thereof, are diεcloεed in U.S. Patentε Noε. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g. in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration. Alternatively, liquid or semi-εolid oral formulations may be prepared by disεolving or diεperεing the active compound or εalt in vegetable oilε, glycols, triglycerideε, propylene glycol eεterε (e.g. propylene carbonate) and the like, and encapsulating these solutionε or εuεpenεionε in hard or εoft gelatin capsule εhellε. Other useful formulations include those set forth in U.S. Patents Nos. Re. 28,819 and 4,358,603. Parenteral adminiεtration iε generally characterized by injection, either εubcutaneouεly, intramuεcularly or intravenously. Injectableε can be prepared in conventional formε, either aε liquid solutions or εuεpenεionε, εolid formε εuitable for εolution or εuεpenεion in liquid prior to injection, or aε emulεions. Suitable excipientε are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be adminiεtered may alεo contain minor amounts of non-toxic auxiliary substances εuch as wetting or emulsifying agents, pH buffering agentε, εolubility enhancerε, and the like, εuch as for example, sodium acetate, polyoxyethylene, εorbitan monolaurate, triethanolamine oleate, cyclodextrinε, etc. A more recently deviεed approach for parenteral adminiεtration employε the implantation of a εlow-releaεe or εuεtained-releaεe εyεtem, εuch that a constant level of dosage iε maintained. See, e.g., U.S. Patent No. 3,710,795. The percentage of active compound contained in εuch parenteral coπtpositions iε highly dependent on the εpecific nature thereof, aε well aε the activity of the compound and the needε of the εubject. However, percentageε of active ingredient of 0.01% to 10% in εolution are employable, and will be higher if the compoεition iε a εolid which will be εubεequently diluted to the above percentageε. Preferably the compoεition will compriεe 0.2-2% of the active agent in εolution. Formulationε of the active compound or a εalt may alεo be adminiεtered to the reεpiratory tract aε an aeroεol or εolution for a nebulizer, or aε a microfine powder for inεufflation, alone or in combination with an inert carrier εuch aε lactoεe. In εuch a caεe, the particleε of the formulation have diameterε of leεε than 50 micronε, preferably less than 10 microns. EXAMPLES The following preparations and exampleε are given to enable thoεe skilled in the art to more clearly understand and to practice the preεent invention. They εhould not be conεidered aε limiting the εcope of the invention, but merely aε being illuεtrative and repreεentative thereof. EXAMPLE ZA-1 ZA-1A. Formula 102 Where R" is t-butyldimethylsilyl To methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) - -methyl-4-hexenoate (Tetrahedron, 28, 4395, 1972) (10.0 g) in dimethylformamide (75 ml) was added t-butyldimethylεilyl chloride (4.97 g) and imidazole (2.24 g) . The mixture waε heated at 50°C for 1 hour, then left at room temperature for 24 hourε, then poured into water and extracted with ethyl acetate. The extract was washed twice with water, dried over magnesium sulfate and evaporated under vacuum to give methyl (E) -6- (4-t-butyldimethylεilyloxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate aε a beige εolid. ZA-1B. Formula 102 Where R" is methoxyethoxymethoxy To methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl- -hexenoate (61.0 g) in methylene chloride (1000 ml) at 0°C waε added diiεopropylethylamine (30.4 g) and methoxyethoxymethyl chloride (29.2 g) . After 3 1/2 hourε the εolution waε waεhed with dilute hydrochloric acid, dried and evaporated to give methyl (E) -6- (1,3-dihydro-6-methoxy- -methoxyethoxymethoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate aε an oil. ZA-1C. Formula 102 Varying the Alkyl Ester By following the procedure of part A or B and εubεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4- methyl-4-hexenoate with another alkyl eεter, εuch aε ethyl (E)-6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4- hexenoate, there are obtained the correεponding t-butyldimethylεilyl and methoxyethoxymethoxy protected eεterε, εuch aε ethyl (E) -6- (4-t-butyl- dimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4- methyl-4-hexenoate. EXAMPLE ZA-2 ZA-2A. Formula 103 Where R* is t-butyldimethylsilyl A solution of methyl (E) -6- (4-t-butyldimethylεilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate (11.0 g) in methanol 125 ml) , dichloromethane (125 ml) and pyridine (2 ml) waε cooled to -78°C and a εtream of ozonized oxygen waε bubbled through. After 45 minuteε a blue color developed indicating the preεence of unreacted ozone. Dimethyl εulfide (5 ml) waε added and the cooling bath was removed. After 16 hourε the εolution waε waεhed with dilute hydrochloric acid, dilute aqueouε εodium bicarbonate and then water, then dried and evaporated. The reεidue waε chromatographed on εilica gel, eluting with 2:1 hexane:ethyl acetate, εo aε to produce 2- (4-tert-butyldimethylsilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl)acetaldehyde, mp. 88-92°C (ether). ZA-2B. Formula 103 Where R a is methoxyethoxymethoxy To methyl (E) -6- (1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate (76.0 g) in methanol (300 ml) waε added IN aqueous εodium hydroxide (300 ml) . After 1 1/2 hourε the εolution waε diluted with water, waεhed twice with ether, then acidified with dilute hydrochloric acid. The acidified εolution waε extracted with ether, and the extract waε dried and evaporated to give (E) - 6- (1,3-dihydro-6-methox -4-methoxyethoxymethoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoic acid, m.p. 77-82°C (ether- hexane) . By following the procedure of part A and εubεtituting methyl (E) -6- (4-t-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoate with (E) -6- (l,3-dihydro-6- methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl- 4-hexenoic acid, there waε obtained 2- (1,3-dihydro-6-methoxy-4- methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -acetaldehyde, m.p. 61-63°C (hexane-ethyl acetate) . EXAMPLE ZA-3 ZA-3A. Formula 104 Where R" is t-Butyldimethylsilyl, Z 1 is Methyl, and Z 2 is Hydrogen To a εolution of 2- (4-tert-butyldimethylεilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -acetaldehyde (5.25g) in THF (70ml) at -70°C was added IN 2-propenylmagnesium bromide in THF (19ml) . The εolution waε kept at -40°C for 15 minuteε, then saturated aqueous ammonium chloride (80ml) was added. The mixture was extracted with ether, and the extract dried and evaporated, to give 4- (4-tert-butyldimethyl- silyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzo-furan-5-yl) -3- hydroxy-2-methylbut-l-ene, mp 133-4°C (tert-butylmethyl ether/hexane) . ZA-3B. Formula 104 Varying R", Z 1 and Z 2 By following the procedure of part A and εubεtituting IN 2-propenylmagneεium bromide with the compoundε of Formula 103a identified in the following table: there are obtained the correεponding compoundε of Formula 104 identified in the following table (where TBDMS meanε t-butyldimethylεilyl) . ZA-3C. Formula 104 Where R" is methoxyethoxymethoxy By following the procedure of Partε A or B above and εubεtituting for the 4-t-butyldimethylεilyl-acetaldehydeε the correεponding 4-methoxyethoxy- methoxy-acetaldehydeε of Formula 103 (prepared, e.g., aε deεcribed in Example 2B) there are obtained the correspondingly protected compounds of Formula 104, which may sequentially be employed in the following examples (the εubεtitution of protecting groupε will not be εpecifically deεcribed) . EXAMPLE ZA-4 ZA-4A. Formula 105 where R" is t-Butyldimethylsilyl, Z 1 and Z 4 are Methyl, Z 2 and Z 3 are Hydrogen, and Alkyl is Methyl A solution of 4- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -3-hydroxy-2-methylbut-l-ene (0.91g) in trimethyl orthopropionate (25ml) and propionic acid (0.08ml) waε heated to 110°C for 2.5 hourε. The εolventε were evaporated under vacuum to afford methyl (E) -6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate aε an oil. ZA-4B. Formula 105 Varying Z 1 and Z 2 By following the procedure of part A and εubεtituting 4- (4-tert- butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -3-hydroxy-2-methylbut-l-ene, e.g., with the compounds of Formula 104 prepared as described in Example 3B, there are obtained the compoundε of Formula 105 (where alkyl iε methyl) identified in the following table. ZA-4C. Formula 105 where R" is t-Butyldimethylsilyl, Z 1 is Methyl, Z 2 is Hydrogen, and Varying Z 3 , Z 4 and Alkyl By following parts A and B and subεtituting trimethyl orthopropionate with the compoundε of Formula 104a identified in the following table: there are obtained the correεponding compoundε of Formula 105 (where R a iε TBDMS) identified in the following table. EXAMPLE ZA-5 ZA-5A. Formula I-ZA-A where Z 1 and Z 4 are Methyl, Z 2 and Z 3 are Hydrogen, and Alkyl is Methyl To methyl (E) -6- (4-tert-butyldimethylεilyloxy-l,3-dihydro-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate (0.8g) in tetrahydrofuran (5ml) waε added IN tetra-n-butylammonium fluoride in tetrahydrofuran (4ml) . After 10 minuteε the εolution waε diluted with ice water and extracted with ethyl acetate. The extract waε dried and evaporated to- give methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate aε an oil. ZA-5B. Other Compounds of Formula I-ZA-A By following the procedure of part A and εubεtituting methyl (E) -6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate, e.g., with the compounds of Formula 105 prepared as described in Example 4B and 4C, there are obtained the compounds of Formula I-ZA-A identified in the following table. EXAMPLE ZA-6 ZA-6A. Formula 1-ZA-M2 where Z 1 and Z 4 are Methyl, and Z 2 and Z 3 are Hydrogen To methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate (0.85g) in methanol (10ml) waε added a εolution of lithium hydroxide (0.4g) in water (5ml) . After 4 hourε at room temperature, the εolution waε poured into ice water, acidified with 10% aqueouε hydrochloric acid, and extracted with ethyl acetate. The' extract waε dried and evaporated to give (E) -6- (1,3-dihydro- 4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4- hexenoic acid, mp 120-3°C (tert-butylmethyl ether/hexane) . ZA-6B. Other Compounds of Formula I-ZA-M2 By following the procedure of part A and εubεtituting methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,4- dimethyl-4-hexenoate with other compoundε of Formula I-ZA-M1, e.g., prepared aε described in Example 5B, there are obtained the compounds of Formula I-ZA-M2 identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-7 ZA-7A. Formula 106 where R* is methoxyethoxymethoxy and Z 1 is Methyl A εolution of 2- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7- methyl-3-oxoiεobenzofuran-5-yl)acetaldehyde (10.3g) and 2- (triphenyl- phoεphoranylidene) -propionaldehyde (11.6g) in toluene (250ml) waε refluxed for 7 hourε. The εolvent waε removed under vacuum and the reεidue waε chromatographed on εilica gel, eluting with 9:1 hexane:ethyl acetate, to afford (E) -4- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2-methylbut-2-enaldehyde, mp 67-68°C, (methylene chloride/hexane) . ZA-7B. Formula 106 Varying Z 1 By following the procedure of part A and εubεtituting 2- (triphenyl- phosphoranylidene) -propionaldehyde with the compoundε of Formula 103b identified in the following table: Formula 103b Ethyl n-Propyl H there are obtained the corresponding compounds of Formula 106 where R" iε methoxyethoxymethoxy. EXAMPLE ZA-8 ZA-8A. Formula 107 where R" is Methoxyethoxymethoxy, Z 1 , Z 3 and Z 4 are all Methyl, and Alkyl is Ethyl Freεhly diεtilled diiεopropylamine (0.425 ml) was diεεolved in anhydrouε THF (10 ml) and cooled to 0°C. n-BuLi (0.63 ml, 2.35 M) waε added εlowly and the reaction waε εtirred at 0°C for 20 minuteε and cooled to -78°. Ethyl isobutyrate (0.200 ml) was added and the reεulting εolution waε εtirred at -78°C for 40 minutes. A solution of (E) -4- (l,3-dihydro-6- methoxy- -methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- methylbut-2-enaldehyde (365 mg) in THF (10 ml) waε added and εtirred for 30 min. The reaction mixture waε poured to a concentrated εolution of NH 4 C1, and extracted with ethyl acetate (3 x 30 ml) , the organic layerε were dried over Na^SO^, and evaporated to give 420 mg (87%) of ethyl (E)-6-(l,3- dihydro-4-methoxyethoxymethoxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,2,4-trimetlιyl-3-hydroxy-4-hexenoate as an oil. ZA-8B. Formula 107 where R" is t-Butyldimethylsilyl or Methoxyethoxymethoxy, varying Z 1 , Z 3 , Z 4 , and Alkyl By following the procedure of part A, subεtituting (E)-4-(l,3- dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2-methylbut-2-enaldehyde with the compoundε of Formula 106 (prepared, e.g., aε described in Example ZA-7B) , and reacting them with ethyl isobutyrate or the compounds of Formula 106a aε εhown in the following table: there are obtained the correεponding compoundε of Formula 107 (where R" iε methoxyethoxymethoxy) identified in the following table. EXAMPLE ZA-9 ZA-9A. Formula I-ZA-M1 where Z 2 is Hydroxy, Z 1 , Z 3 and Z 4 are all Methyl, and Alkyl is Ethyl By following the procedure of Example ZA-13B and εubεtituting methyl (E) -6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E)-6-(l,3- dihydro-4-methoxyethoxymethoxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,2,4-trimethyl-3-hydroxy-4-hexenoate and the compoundε of Formula 107 prepared, e.g., aε deεcribed in Example ZA-8B, there are obtained ethyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,2,4-trimethyl-3-hydroxy-4-hexenoate and the correεponding compoundε of Formula I-ZA-M1. ZA-9B. Formula I-ZA-M2 where Z 2 is Hydroxy, Z 1 , Z 3 and Z 4 are all Methyl, and Alkyl is Ethyl By following the procedure of Example ZA-6A and subεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl- -hexenoate with ethyl (E) -6- (1,3-dihydro-4-hydroxy-6-methox - 7-methyl-3-oxoiεobenzofuran-5-yl) -2,2,4-trimethyl-3-hydroxy-4-hexenoate and the correεponding compoundε of Formula I-ZA-M1 prepared aε deεcribed in Part A above, there are obtained (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2,2,4-trimethyl-3-hydroxy-4-hexenoic acid, m.p. 180-181°C (ether/ethyl acetate) and the correεponding compoundε of Formula I-ZA-M2 (where Z 2 iε OH) aε identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-10 ZA-10A. Formula 108 where R a is t-Butyldimethylsilyl, R b and Z 1 are both Methyl, Z 3 and Z 4 are Hydrogen, and Alkyl is Ethyl Ethyl (E) -6- (l,3-dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -3-hydroxy-4-methyl-4-hexenoate (974 mg) waε diεεolved in a 6:1 mixture of methyl iodide in CH 3 CN (25 ml) . Silver oxide waε then added (5.1 g) and the mixture heated at reflux for 24 hr. The mixture waε cooled to room temperature and filtered through a bed of celite. The celite waε waεhed with CH 2 C1 2 (80 ml) and ethyl acetate (80 ml) . The combined organic layerε were evaporated to dryness and the residue pasεed through a flaεh column (εilica gel, hexaneε-EtOAc 8:2) to afford 601 mg (60%) of ethyl (E) -6- (l,3-dihydro-4-tert- butyldimethylεilyloxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -3- methoxy-4-methyl-4-hexenoate the product aε a colorleεε oil. ZA-10B. Formula 108 varying R b , Z 1 , Z 3 , Z 4 , and Alkyl By following the procedure of part A and optionally εubεtituting ethyl (E) -6- (l,3-dihydro-4-tert-butyldimethylεilyloxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3-hydroxy-4-methyl-4-hexenoate with other compounds of Formula 107 prepared for example as described in Example ZA-9, and optionally subεtituting methyl iodide with other lower alkyl halideε, there are obtained the correεponding compoundε of Formula 108 (where the protecting group R a iε t-butyldimethylsilyl or methoxyethoxymethoxy) εuch aε thoεe identified in the following table. EXAMPLE ZA-11 ZA-llA. Formula I-ZA-M1 where R b and Z 1 are both Methyl, Z 3 and Z 4 are Hydrogen, and Alkyl is Ethyl By following the procedure of Example ZA-5A and εubεtituting methyl (E) -6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E)-6-(l,3- dihydro-4-tert-butyldimethylsilyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran- 5-yl) -3-methoxy-4-methyl-4-hexenoate and the compounds of Formula 108 prepared, e.g., aε deεcribed in Example ZA-10B, there are obtained ethyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -3- methoxy-4-methyl-4-hexenoate and the correεponding compoundε of Formula I-ZA-M1. ZA-11B. Formula I-ZA-M2 where Z 2 is Alkoxy By following the procedure of Example ZA-6A and εubεtituting methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoate with ethyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -3-methoxy-4-methyl-4-hexenoate and the correεponding compoundε of Formula I-ZA-M1 prepared aε deεcribed in Part A above, there are obtained (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -3-methoxy-4-methyl-4-hexenoic acid, m.p. 133-135°C (hexane/methylene chloride) and the corresponding compounds of Formula I-ZA-M2 aε identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-12 ZA-12A. Formula 109 where R" is methoxyethoxymethoxy, R b is OH and Z 1 is Methyl To a solution of (E) -4- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -2-methylbut-2-enaldehyde (4.6g) in methanol (60ml) waε added εodium borohydride (0.528g) . After one hour the reaction waε added to water (250ml) and extracted with ethyl acetate (2 x 150ml) . The extract waε dried and evaporated to give (E) -4- (l,3-dihydro-6- methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2- methylbut-2-en-1-ol. ZA-12B. Formula 109 where R" is methoxyethoxymethoxy, R b is bromo and Z 1 is Methyl To a solution of (E) -4- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -2-methylbut-2-en-l-ol (4.6g) in methylene chloride (100ml) at 0°C waε added triphenylphosphine (3.64g) then N-bromosuccinimide (2.48g) . After 15 minuteε the εolution waε waεhed with 10% aqueouε εodium bisulphite, water, aqueous εodium bicarbonate, then dried and evaporated. The reεidue waε chromatographed on εilica gel, eluting with 4:1 hexane: ethyl acetate, to give (E) -4- (l,3-dihydro-6- methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- methylbut-2-enyl bromide, mp 74-75°C (hexane) . ZA-12C. Formula 109 Varying Z x By following the procedure of part B and εubεtituting (E)-4-(l,3- dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2-methylbut-2-enaldehyde with the compoundε of Formula 106 identified in the following table: Formula 106 Ethyl Formula 106 n-Propyl H there are obtained the corresponding compounds of Formula 109 where R" is methoxyethoxymethoxy and R b iε bromo. EXAMPLE ZA-13 ZA-13A. Formula 110 where R* is methoxyethoxymethoxy, Z 1 and Z 3 are methyl, and alkyl is isopropyl A solution of 1.38 molar n-butyllithium in hexane (11.8 ml) waε added to diiεopropylamine (2.45 ml) in tetrahydrofuran (50 ml) at -10°C. After 20 minutes, the solution was cooled to -78°C, and a εolution of (R) -4- iεopropyl-3-propionyl- -oxazolidinone [prepared aε deεcribed in J. Am. Chem. Soc , 103:2127 (1981)] (3.23g) in tetrahydrofuran (10 ml) waε added. After 30 minuteε (E) -4- (1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2-methylbut- -enyl bromide (2.54g) in tetrahydrofuran (12 ml) waε added. The reaction temperature waε allowed to reach -10°C εlowly, then maintained at that temperature for 3 hourε. The reaction waε quenched with 10% aqueouε ammonium chloride then extracted with ethyl acetate. The extract waε waεhed with 10% hydrochloric acid, dilute aqueouε εodium bicarbonate and water, then dried and evaporated. The reεidue waε chromatographed on εilica gel, eluting with 2:1 hexane: acetone, to yield (E) -3- [6- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2- (S) ,4-dimethylhexanoyl) -4- (R) -iεopropyl- 2-oxazolidinone aε an oil. ZA-13B. Formula 110 where R* is H, Z 1 and Z 3 are methyl, and alkyl is isopropyl A solution of (E) -3- [6- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -2- (S) ,4-dimethylhexanoyl) -4- (R) - iεopropyl-2-oxazolidinone (1.3g) and p-tolueneεulphonic acid (0.6g) in methanol (25ml) waε left at room temperature for 24 hourε. The εolution waε diluted with methylene chloride and waεhed with dilute aqueouε εodium bicarbonate and water, then dried and evaporated. The reεidue waε chromatographed on εilica gel, eluting with 99.2:0.8 methylene chloride:methanol, to give (E) -3- [6- (l,3-dihydro-6-methoxy-4-hydroxy-7- methyl-3-oxoiεobenzofuran-5-yl) ] -2- (S) ,4-dimethylhexanoyl) -4- (R) -iεopropyl- 2-oxazolidinone, mp 127-128°C (hexane/methylene chloride) . ZA-13C. Formula 110 varying Z 1 , Z 3 and alkyl By following the procedure of partε A and B, εubεtituting (R) -4-iεopropyl-3-propionyl-2-oxazolidinone with the compoundε of Formula 109a identified in the following table: Formula 109a and reacting it with (E) -4- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7- methyl-3-oxoiεobenzofuran-5-yl) - -methylbut-2-enyl bromide or the compoundε of Formula 109 prepared aε deεcribed in Example ZA-12C, there are obtained the corresponding compounds of Formula 110 (where R a iε MEM, which iε then converted to hydrogen) identified in the following table. EXAMPLE ZA-14 ZA-1 A. Formula I-ZA-E where Z 1 and Z 3 are methyl. To a εolution of (E) -3- [6- (l,3-dihydro-6-methoxy-4-hydroxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2- (S) ,4-dimethylhexanoyl) -4- (R) -iεopropyl-2- oxazolidinone (0.8g) in tetrahydrofuran (14 ml) at 0°C waε added 30% aqueouε hydrogen peroxide (0.8 ml) followed by a εolution of lithium hydroxide (0.086g) in water (3 ml) . After 1.25 hourε at 0°C, the reaction waε quenched by addition of 10% aqueouε εodium thioεulfate (3 ml) . After 5 minuteε the εolvents were removed under vacuum and the residue waε diεεolved in water (30 ml) . The pH waε adjuεted to 12 by addition of 10% aqueouε εodium hydroxide, then the εolution waε waεhed with methylene chloride. The εolution waε then adjuεted to pH 1 by addition of hydrochloric acid, then extracted with ethyl acetate. The extract waε dried and evaporated to give (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2 (S) ,4-dimethyl-4-hexenoic acid, mp 114- 115°C (hexane/methylene chloride) . ZA-14B. Formula I-ZA-E varying Z 1 and Z 3 By following the procedure of part A and εubstituting (E) -3- [6- (1,3- dihydro-6-methoxy-4-hydroxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- (S) ,4- dimethylhexanoyl) -4- (R) -iεopropyl-2-oxazolidinone with the compoundε of Formula 110 prepared aε deεcribed in Example ZA-13C there are obtained the corresponding compounds of Formula I-ZA-E identified in the following table: Formula I-ZA-E EXAMPLE ZA-15 ZA-15A. Formula 111 where R* is Methoxyethoxymethoxy, Z 1 is Methyl, Z 4 is Hydrogen, and Alkyl is Ethyl Freshly distilled diisopropylamine (0.435 ml) waε diεεolved in THF (10 ml) . The εolution waε cooled to 0°C and n-BuLi (1.3 ml, 2.38 M) waε added. The mixture waε εtirred at 0°C for 20 minuteε. The ice-bath waε replaced by a dry ice-acetone bath and a solution of ethyl benzylidine glycinate (0.445 g) in THF (2 ml) was added slowly at -78°. The .resulting red εolution waε εtirred at -78°C for 40 minuteε. Thiε εolution waε then tranεferred via cannula to a solution of (E) -4- (l,3-dihydro-6-methoxy-4- methoxyethoxymethoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2-methylbut-2-enyl bromide (0.667 g) diεεolved in THF (20 ml) and HMPA (2 ml) . After εtirring the mixture at -78°C for 90 minuteε, the reaction mixture waε poured into a concentrated εolution of NH 4 C1, extracted with ethyl acetate (3 x 30 ml) , and the combined organic layerε were dried over Na 2 S0 4 and evaporated to give a dark oil, which was pasεed through a column (εilica gel, ethyl acetate) giving 0.443 g (63%) of ethyl (E) -6- (4-methoxyethoxymethoxy-1,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2-amino-4-methyl-4- hexenoate the product aε a light yellow oil. ZA-15B. Formula 111 where R a is t-Butyldimethylsilyl or Methoxyethoxymethoxy, varying Z 1 , Z 4 , and Alkyl By following the procedure of part A and optionally substituting (E) - 4- (1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2-methylbut-2-enyl bromide with appropriate compoundε of 'Formula 109 prepared for example aε deεcribed in Example ZA- 12C, there are obtained the compoundε of Formula 111 where R" iε t-butyldi¬ methylεilyl or methoxyethoxymethoxy, identified in the following table: EXAMPLE ZA- 16 ZA-16A. Formula I- ZA-M1 where Z 1 is Methyl, Z 3 is NHj, Z 2 and Z 4 are Hydrogen, and Alkyl is Ethyl By following the procedure of Example ZA-5A and εubεtituting methyl (E) -6- (4-tert-butyldi ethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E)-6-(4- methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2-amino-4-methyl-4-hexenoate and the compounds of Formula 111 prepared, e.g., aε deεcribed in Example ZA-15B, there are obtained ethyl (E)-6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2-amino- - methyl-4-hexenoate and the correεponding compoundε of Formula I-ZA-Ml. ZA-16B. Formula I-ZA-M2 where Z 3 is Hj By following the procedure of Example ZA-6A and εubεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoate with ethyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy- 7-methyl-3-oxoisobenzofuran-5-yl) -2-amino-4-methyl-4-hexenoate and the correεponding compoundε of Formula I-ZA-Ml prepared aε deεcribed in Part A above, there are obtained (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2-amino-4-methyl-4-hexenoic acid, m.p. 225-227°C (aε the hydrochloride) (ethanol) and the correεponding compoundε of Formula I-ZA-M2 (where Z 3 iε NH 2 ) aε identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-17 ZA-17A. Formula I-ZA-G where R b and Z 1 are both Methyl, Z 4 is Hydrogen, and Alkyl is Ethyl Ethyl (E) -6- (4-methoxyethoxymethoxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2-amino-4-methyl-4-hexenoate (373 mg) waε diεεolved in CH 2 C1 2 (10 ml), cooled to 0°C, and triethylamine (0.17 ml) and methylεulfonyl chloride (0.09 ml) were added. The mixture waε stirred at 0°C for 1 hour and at room temperature for 2 hours. The reaction mixture was diluted with CH 2 C1 2 (10 ml) , washed with water (10 ml) , dried over Na 2 S0 4 , and evaporated to drynesε to give a reεidue which waε passed through a column (silica gel, hexanes-EtOAc 1:1) giving 368 mg (82%) of ethyl (E) -6- (4-hydroxy-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- methylεulfonylamino-4-methyl-4-hexenoate aε a colorless oil. ZA-17B. Formula I-ZA-M2, where Z 3 is NHS0 2 -R b varying R b , Z 1 and Z 4 By following the procedure of Example ZA-6A and subεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoate with ethyl (E) -6- (4-hydroxy-l,3-dihydro-6-methoxy- 7-methyl-3-oxoisobenzofuran-5-yl) -2-methylsulfonylamino-4-methyl-4- hexenoate and compoundε of Formula 111, prepared e.g, as described in Example ZA-15 and converted to compoundε of Formula I-ZA-G aε deεcribed in Part A above, there are obtained (E) -6- (4-hydroxy-l,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2-methylεulfonylamino-4-methyl-4-hexenoic acid, (obtained aε a foam) and the corresponding compoundε of Formula I-ZA-M2 (where Z 3 is NHS0 2 -R b ) as identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-18 ZA-18A. Formula 112 where R' is Methoxyethoxymethoxy, Z 1 , Z 3 and Z 4 are all Methyl, and Alkyl is Ethyl A freshly prepared solution of lithium diisopropylamide (2.8 mmol/10 ml THF) waε cooled to -78°C and ethyl iεobutyrate (0.75 ml) waε added εlowly. The εolution waε εtirred at -78°C for 40 minutes and then a solution of (E) -4- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2-methylbut-2-enyl bromide (0.6 g) in THF (2 ml) and HMPA (1.5 ml) waε added via εyringe at εuch rate that the temperature waε maintained below -60°C. After εtirring for 30 minuteε at -78°C, the ixure waε poured onto 100 ml of a concentrated εolution of NH 4 C1. The organic and aqueous phaseε were εeparated and the aqueouε phaεe waε extracted with ethyl acetate (2 x 50 ml) . The combined organic layerε were dried over NajSO,, and evaporated to give a reεidue which waε paεεed through a column (εilica gel, CHjClj-EtOAc 95:5) to afford 480 mg (74%) of ethyl (E) -6- (4- methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2,2,4-trimethyl-4-hexenoate aε a colorleεε oil. ZA-18B. Formula I-ZA-M2 where Z 1 is H or Lower Alkyl, and Z 3 and Z 4 are H, Lower Alkyl or Phenyl By following the procedure of Example ZA-6A and εubεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoate with ethyl (E) -6- (4-methoxyethoxymethoxy-1,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,2,4-trimethyl-4- hexenoate and compounds of Formula 109, prepared e.g, aε deεcribed in Example ZA-12 and converted to compoundε of Formula 112 aε deεcribed in Part A above, there are obtained (E) -6- (4-methoxyethoxymethoxy-l,3-dihydro- 6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,2,4-trimethyl-4-hexenoic acid, m.p. 163-165 (hexane/ethyl acetate) and the corresponding compounds of Formula I-ZA-M2 as identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-19 ZA-19A. Formula 113 where R" is Methoxyethoxymethoxy, Z 1 is Methyl, Z 4 is Hydrogen, and Alkyl is Ethyl To a solution of ethyl dimethylphosphonoacetate (135 mg) in DMF (5 ml) at 0° waε added 50% NaH/oil (33 mg) , and the mixture stirred for 10 minutes. (E) -4- (l,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2-methylbut-2-enyl bromide (600 mg) waε added at the εame temperature and allowed to reach room temperature in 30 minuteε. The reaction waε poured onto water and extracted with EtOAc. The organic layerε were washed with water, dried over εodium εulfate, and evaporated to give the crude product which waε purified by flaεh chromatography (CH 2 C1 2 followed by EtOAc) to obtain ethyl (E) -6- (4-methoxyethoxymethoxy-1,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- (dimethylphoεphono) - -methyl- -hexenoate as an oil. ZA-19B. Formula I-ZA-I where Z 1 is Methyl, Z 4 is H, and Alkyl is Ethyl By following the procedure of Example ZA-5A and subεtituting methyl (E) -6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E) -6- (4- methoxyethoxymethoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2- (dimethylphosphono) -4-methyl-4-hexenoate, there is obtained ethyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2- (dimethylphoεphono) -4-methyl-4-hexenoate. ZA-19C. Formula I-ZA-M2 where Z x is H or Lower Alkyl, Z 3 is P(0) (OCH 3 ) 2 and Z 4 is H or Lower Alkyl By following the procedure of Example ZA-6A and substituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoate with ethyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -2- (dimethylphoεphono) -4-methyl-4- hexenoate and compoundε of Formula I-ZA-I (prepared, e.g, from the compounds of Formula 109 aε deεcribed in Example ZA-12 and converted to compoundε of Formula I-ZA-I aε deεcribed in Part A above) , there are obtained (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2- (dimethylphoεphono) -4-methyl-4-hexenoic acid, m.p. 187-189 (ether/methylene chloride) and the correεponding compoundε of Formula I-ZA-M2 [where Z 2 iε H and Z 3 is P(0) (OCH 3 ) 2 ] as identified in the following table. Formula I-ZA-M2 EXAMPLE -ZA-20 ZA-20A. Formula I-ZA-J where Z 1 is Methyl, Z 4 is Hydrogen, and Alkyl is Ethyl 1. A solution of ethyl (E) -6- (4-methoxyethoxymethoxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- (dimethylphoεphonato) -4-methyl- 4-hexenoate (300 mg) and p-tolueneεulfonic acid (150 mg) in methanol (3 ml) waε refluxed for 15 minuteε, cooled to room temperature, evaporated to dryneεε and diluted with EtOAc. The organic εolution waε washed with 10% NaHC0 3 , brine, and dried over sodium sulfate to give the crude product which was purified by flash chromatography (EtOAc) to obtain ethyl (E) -6- (4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2- (dimethylphoεphono) -4-methyl-4-hexenoate, a compound of Formula I-ZA-I, aε an oil. 2. A εuεpenεion of the phoεphonate thuε obtained (300 mg) and εodium iodide (900 mg) in acetone (10 ml) waε refluxed for 3 hrε. The εolvent waε removed and the reεidue diεεolved in water, extracted with EtOAc, and the aqueouε solution acidified with 10% HCl. The aqueouε εolution waε εaturated with εodium chloride, extracted with EtOAc, and the organic phaεe dried over εodium εulfate. The εolvent waε removed and the crude product purified by flaεh chromatography (CH 2 Cl 2 :MeOH,4:1) to give ethyl (E) -6- (4- hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2- (methylphoεphono) -4-methyl-4-hexenoate aε an oil. ZA-20B. Formula I-ZA-M2 where Z 1 is H or Lower Alkyl, Z 3 is P(0) (OH) (OCH j ) and Z 4 is H or Lower Alkyl By following the procedure of Example ZA-6A and εubεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoate with ethyl (E) -6- (4-hydroxy-l,3-dihydro-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -2- (methylphσsphono) -4-methyl-4-hexenoate and compoundε of Formula I-ZA-I (prepared, e.g, as described in Example ZA- 19 and converted to compoundε of Formula I-ZA-J as described in Part A above), there are obtained (E) -6- (4-hydroxy-l,3-dihydro-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -2- (methylphoεphono) -4-methyl-4-hexenoic acid (obtained aε a foam) and the correεponding compounds of Formula I-ZA-M2 [where Z 2 is H and Z 3 iε P (0) (OH) (0CH 3 ) ] aε identified in the following table. Formula I-ZA-M2 EXAMPLE ZA-21 ZA-21A. Formula I-ZA-M2 where Z 1 is Methyl, Z 2 and Z 4 are Hydrogen, and Z 3 is S(0) m -Z 12 where is 1 and Z 12 is Methyl Alumina (14.0 g) was treated with water (2.8 ml) and the slurry shaken until a free-flowing powder was formed. A solution of E-7-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-2- methylthiohexenoic acid (0.152 g) in dichloromethane (3 ml) waε treated with the alumina prepared above (0.43 g) and oxone ® (potaεεium peroxymono- εulfate) (0.29 g) . The mixture was εtirred vigorouεly at reflux for two hours then cooled. The product was chromatographed on silica gel, eluting with 100:iθ:l dichloromethane: methanol:acetic acid, to yield E-7-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-2- methylεulfinylhexenoic acid, mp 60-75° (methanol/methylene chloride). ZA-21B. Formula I-ZA-M2 where Z 3 is S(0)„-Z n and m is 1, varying Z 1 , Z 2 , Z 4 , and Z n By following the procedure of part A and subεtituting E-7-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-2- methylthiohexenoic acid with compoundε of Formula I-ZA-A where Z 3 iε thio- lower alkyl (prepared, e.g., aε deεcribed in Example ZA-6) , there are obtained the correεponding compoundε of Formula I-ZA-M2 where Z 3 iε S(0) m -Z 12 and m iε 1, aε identified in the following table. Formula I-ZA-M2 ZA-21C. Formula I-ZA-M2 where Z 3 is S(0). and is 2 By following the procedure of Part A and εubεtituting E-7- (1,3- dihydro- -hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - -methyl-2- methylthiohexenoic acid with E-7- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -4-methyl-2-methylsulfinylhexenoic acid and the compoundε aε prepared in Part B above, there are obtained E-7- (1,3-dihydro- 4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-2- methylεulfonylhexenoic acid and the correεponding compoundε of Formula I-ZA-M2 where Z 3 iε S(0) m -Z 12 and m iε 2. EXAMPLE ZA-22 ZA-22A. Formula 114 where R" is Mesyl, Halo is Chloro, and Alkyl is t- Butyl 2- (4-Methanesulfonyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)acetaldehyde (2.17 g) and 2-chloro-2-triphenyl- phoεphoranylidene acetate (5.7 g) were diεsolved in toluene (50 ml), and the mixture heated at reflux for 1 hour. After cooling to room temperature and removal of the εolvent, the residue was pasεed through a flaεh column (εilica gel, hexaneε-EtOAc 6:4) to afford 2.77 g of t-butyl (E)-4-(l,3- dihydro-4-methaneεulfonyloxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- chlorobut-2-enoate as a colorless oil. ZA-22B. Formula 114 where R* is Mesyl and Halo is F By following the procedure of part A and εubεtituting 2-chloro-2- triphenylphoεphoranylidene acetate with compoundε of Formula 103c, there are obtained the correεponding compoundε of Formula 114 where halo iε F. EXAMPLE ZA-23 ZA-23A. Formula 115 where R" is Mesyl and Halo is Chloro t-Butyl (E) -4- (l,3-dihydro-4-methanesulfonyloxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2-chlorobut-2-enoate (2.7 g) was disεolved in freεhly diεtilled trifluoroacetic acid (25 ml) and stirred at room temperature for 90 minuteε. The mixture waε diluted with CH 2 C1 2 (25 ml) and evaporated to dryneεε and repeated until a cream εolid waε obtained. The εolid was recryεtallized from a 4:1 mixture of hexaneε-CH 2 Cl 2 (25 ml) affording 2.11 g of (E) -4- (1,3-dihydro- -methaneεulfonyloxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) -2-chlorobut-2-enoic acid aε white cryεtalε, mp 200-203° (d) . To a εolution of the acid thuε produced (1.1 g) in THF (50 ml) waε added BH 3 .dimethylεulfide complex (0.427 ml) at room temperature under argon. The mixture waε εtirred at room temperature for 24 hourε, cooled to 0°C and the exceεε of borane deεtroyed carefully with water (l ml) . The mixture waε evaporated to dryneεε and the reεidue paεsed through a flash column (silica gel, hexanes-ethyl acetate) affording 504 mg of (E)-4-(l,3- dihydro-4-methaneεulfonyloxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2- chlorobut-2-en-l-ol aε a viscouε oil. To a εolution of the alcohol thuε produced (500 mg) and triphenylphoεphine (455 g) in CH 2 C1 2 (20 ml) at -10°C was added N-bromosuccinimide (283 mg) in one portion. The mixture waε εtirred at -10° for 25 minuteε and then poured onto a concentrated εolution of εodium biεulfite (50 ml) . The aqueouε and organic layerε were εeparated and the aqueouε phase was extracted with (20 ml) . The combined organic layerε were dried over Na 2 S0 4 and evaporated to dryneεε. The residue was paεsed through a flash column (εilica gel, hexaneε-EtOAc 6:4) to yield 411 mg of (E) -4- (l,3-dihydro-4-methaneεulfonyloxy-6-methoxy-7-methyl-3-oxoiεo- benzofuran-5-yl) -l-bromo-2-chlorobut-2-ene aε white cryεtalε, mp 146-148°. ZA-23B. Formula 115 where Halo is Fluoro By following the procedure of part A and εubεtituting t-butyl (E) -4- (1,3-dihydro-4-methanesulfonyloxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2-chlorobut-2-enoate with compoundε of Formula 114, there are obtained the correεponding compoundε of Formula 114 where halo iε fluoro. EXAMPLE ZA-24 ZA-24A. Formula I-ZA-L where Halo is Chloro, and Z 4 is Hydrogen Diethyl malonate (113 mg) waε added to a εuεpenεion of 50% NaH (35 mg) in THF (3 ml) at 0°C and the mixture εtirred for 30 minuteε. To this εolution waε added (E) -4- (1,3-dihydro-4-methaneεulfonyloxy-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl) -l-bromo-2-chlorobut-2-ene (280 mg) in THF (10 ml) . The ice bath waε removed and the mixture waε εtirred at room temperature for 2 hours. The mixture was added to water (30 ml), the aqueous and organic phaseε εeparated, and the aqueouε phaεe waε extracted once with ethyl acetate (20 ml) . The combined organic layerε were dried over Na 2 S0 4 , evaporated and the reεidue paεεed through a εhort column (εilica gel, hexanes-EtOAc 8:2) affording 190 mg of ethyl (E)-6-(4- methaneεulfonyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 4-chloro-2-ethoxycarbonyl-4-hexenoate aε a colorleεε oil. To a εolution of the dieεter thus produced (265 mg) in ethanol (10 ml) was added a 1M solution of NaOH (10.2 ml) . The mixture was heated at reflux for 24 hourε. The mixture waε then cooled to room temperature and the εolvent waε removed under reduced presεure. The reεidue waε diluted with water (30 ml) , waεhed with ethyl acetate (10 ml) , and the aqueouε layer acidified to pH 1 with 10% HCl. The product waε extracted with ethyl acetate (3 x ' 30 ml) , and the combined organic layerε were dried over ajSO,, and evaporated to give a reεidue, which was recryεtallized from affording 127 mg of the 4-chloro dicarboxylic acid aε white cryεtalε mp 134-136°C. A solution of the dicarboxylic acid thus produced (192 mg) in 1,2-dichlorobenzene (15 ml) was heated at reflux for 2 hours. The solution waε cooled to room temperature and then poured onto a flaεh chromatography column (εilica gel) . The column was eluted first with hexanes and then with hexaneε-EtOAc-acetic acid (50:50:1) to give 117 mg of the product, which waε recryεtallized from to give white cryεtalε of (E) - 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4- chloro-4-hexenoic acid, mp 135-137°C. ZA-24B. Formula I-ZA-L varying halo and Z 4 By following the procedure of part A and optionally εubstituting (E) -4- (l,3-dihydro-4-methaneεulfonyloxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -l-bromo-2-chlorobut-2-ene with compounds of Formula 115, and optionally εubεtituting diethyl malonate with compoundε of Formula 116, there are obtained the correεponding compoundε of Formula I-ZA-L where halo iε chloro or fluoro and Z 4 iε lower alkyl, for example methyl, ethyl, n-propyl, i-propyl, t-butyl, pentyl, heptyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, and the like, or phenyl. EXAMPLE ZA-25 ZA-25A Formula 117 Where R" is TBDMS, Z 1 is Methyl, Z 2 is Hydrogen, Z 3 and Z 4 Together with their adjacent carbon atom are Cyclopropyl, and Alkyl is Methyl 1. A solution of trimethyl 4-bromoorthobutyrate (20 ml), propionic acid (0.22 ml) and 4- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -3-hydroxy-2-methylbut-1-ene (3.18 g) waε heated at 110°C in a three-necked flaεh with a εlow nitrogen εtream paεεing over the reaction mixture. After 1 hr 40 min the excess orthoester waε removed in vacuo at 55°C. Flash chromatography of the residue on εilica gel eluting with 20-30% ethyl acetate/hexane gave methyl 2- (2-bromoethyl) - 6- (4-1-butyldimethylsiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo- iεobenzofuran-5-yl) -4-methyl-hex-4-enoate (2.66 g) . 2. A εolution of lithium diiεopropyl amide waε prepared from diiεopropyl amine (2.24 ml) and n-butyllithium (6.4 ml, 2.5N) in THF (60 ml) and cooled to -70°C. Methyl 2- (2-bromoethyl) -6- (4-t-butyldi- methylεiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-iεobenzofuran-5-yl) -4- methyl-hex-4-enoate (2.66g) in THF (12 ml waε added to the LDA εolution over 2 min. The reaction mixture waε εtirred for 50 min at -65°C to -50°C and quenched-in water. Extraction with ethyl acetate and flaεh chroma¬ tography (silica gel, 20-30% ethyl acetate/hexane) gave 1- [4- (4-t-butyldi- methylεiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-iεobenzofuran-5-yl) -2- methyl-bu -2-enyl] cyclopropane carboxylic acid methyl eεter (1.34 g) . ZA-25B Formula I-ZA-Ml and Formula I-ZA-M2 here Z 1 is Methyl, Z 2 is Hydrogen, Z 3 and Z 4 Together with their adjacent carbon atom are Cyclopropyl By following the procedureε of Exampleε ZA-5A and ZA-6A and εubεtituting methyl (E) -6- (4-tert-butyldimethylεilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with 1- [4- (4-t-butyldimethylsiloxy-l,3-dihydro-6-methoxy-7-methyl-3-oxo- iεobenzofuran-5-yl) -2-methyl-but-2-enyl] cyclopropane carboxylic acid methyl eεter, there are obtained, reεpectively, 1- [4- (l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxo-iεobenzofuran-5-yl) -2-methyl-but-2-enyl] cyclopropane carboxylic acid methyl eεter and 1- [4- (1,3-dihydro-4-hydroxy- 6-methoxy-7-methyl-3-oxo-iεobenzofuran-5-yl) -2-methyl-but-2-enyl] cyclopropane carboxylic acid m.p. 184-189°C (ethyl acetate/hexane) . EXAMPLE ZA-26 ZA-26A. (E) 6- (l,3-dihydro-4-hydroxy-6-methyl-7-methoxy-3- oxoisobenzofuran-5-yl) -4-methyl-4-hexenoyl chloride A εolution of mycophenolic acid (320 g, 1 mol) and dimethylformamide (0.1 g) in dichloromethane (3.2 L) at reflux waε treated dropwiεe with thionyl chloride (82 mL, 1.12 mol) . After one hour additional heating at reflux, the volatileε were distilled at reduced preεεure leaving a gray solid reεidue of (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoyl chloride which was cooled and diεεolved in anhydrouε tetrahydrofuran (1L) . ZA-26B. (S) -benzyl-3- [(E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) - -methyl- -hexenoyl] -2- oxazolidinone A εolution of (S) -4-benzyl-2-oxazolidinone (177.4 g, 1 mol) and t-butyl alcohol (74.1 g , 1 mol) in anhydrouε tetrahydrofuran (2 L) waε cooled to -78°C. A 1.6 M εolution of n-butyllithium in hexane (1280 mL, 2 mol) waε added maintaining a temperature below -30°C. After recooling to -78°C the (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoyl chloride εolution (1 mol) waε added and the mixture waε allowed to warm to 0°C over 2 hourε. 2 N Hydrochloric acid (1.5 L) and ethyl acetate (1 L) were added. The organic layer waε waεhed εequentially with εaturated aqueouε εodium bicarbonate (0.5 L), 2 N hydrochloric acid (0.5 L) , and brine (1 L) . After drying over εodium εulfate, the organic layer waε evaporated at reduced preεεure to leave the crude imide aε a tan εolid. Recryεtallization from ethyl acetate/hexane (2.5 L/2.5 L) gave (S) 4-benzyl-3- [ (E) 6- (l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoyl] -2- oxazolidinone aε off-white, εhiny plates, m.p. 112-113°C. ZA-26C. .(S) 4-benzyl-3- [(E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoyl] -2- oxazolidinone A I M solution of εodium biε(trimethylεilyl)amide in tetrahydrofuran (0.43 L, 0.43 mol) waε cooled to -78°C and treated dropwiεe with a precooled εolution of (S) 4-benzyl-3- [(E) 6- (1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoyl] -2- oxazolidinone (86 g, 0.179 mol) in tetrahydrofuran (250 mL) , maintaining a temperature below -65°C. After 15 minuteε εtirring, iodomethane (56 mL, 0.9 mol) waε added and the solution was warmed to -30°C. After 1 hour, the εolution was warmed to 0°C and 2 N hydrochloric acid (0.4 L) was added. The organic layer waε waεhed with 2% εodium εulfite (0.2 L) and brine (0.2 L) and dried over εodium εulfate. After filtration, the volatileε were diεtilled at reduced preεεure and the reεidue waε applied to a bed of εilica gel (0.45 kg). Elution with 40 % ethyl acetate/hexane (4 L) and concentration of the eluent gave the alkylation product (S) 4-benzyl-3- [(E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,4- dimethyl-4-hexenoyl] -2-oxazolidinone aε a white foam. The product conεiεted of an 85:13 mixture of diaεtereomerε at the 2-hexenoyl poεition. ZA-26D. (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-me hyl-3- oxoisobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid A εolution of the (S) 4-benzyl-3- [ (E) 6- (1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoyl] -2- oxazolidinone mixture (106 g, 0.215 mol) in tetrahydrofuran (1.6 L) waε cooled to 0°C. 30% Aqueouε hydrogen peroxide (88.6 mL, 0.85 mol) waε added, followed by a εolution of lithium hydroxide (18.06 g, 0.43 mol) in water (360 mL) . After 40 minuteε, the reaction waε quenched with a εolution of εodium sulfite (114 g) in water (360 mL) . Most of the tetrahydrofuran was removed by distillation at reduced presεure. The aqueouε reεidue waε extracted with dichloromethane (2 x 0.4 L) , acidified with 37% hydrochloric acid (86 g) and extracted with ethyl acetate (2 x 0.4 L) . The ethyl acetate extractε were dried over magneεium εulfate, filtered and evaporated to leave a yellow cryεtalline reεidue of (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoic acid, m.p. 110-114°C, aε an 85:13 mixture of enantiomerε at the 2-poεtion. ZA-26E. (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -2, -dimethyl-4-hexenoic acid (+) -α-Methylbenzylamine Salt A εolution of the 85:13 acid mixture(E) 6- (1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid (810 g, 2.4 mol,) waε diεεolved in acetone (16 L) at 40°C and (+) -α-methylbenzylamine (800 g, 6.6 mol) waε added. Upon cooling, the εalt cryεtallized and waε collected by filtration. Recryεtallization from acetone (8 L) containing (+) -α-methylbenzylamine (202 g) afforded (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) - 2,4-dimethyl-4-hexenoic acid (+) -α-Methylbenzylamine εalt after drying aε off-white needleε, m.p. 147-9°C. ZA-26F. (S) (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl) -2, -dimethyl- -hexenoic acid A suεpenεion of (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoic acid (+) -α-Methylbenzylamine Salt (380 g, 0.84 mol) in ethyl acetate (0.75 L) and hexane (0.1 L) waε washed with 2 M sulfuric acid (0.5 L, then 2 x 0.25 L) and water (0.2 L) . The clear organic layer was dried over sodium εulfate, filtered and heated to reflux. Hexane (1.4 L) waε added and upon cooling the product cryεtallized. An additional portion of hexane (0.8 L) was added and after cooling in ice the product was collected by filtration and dried to afford (S) (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -2,4-dimethyl-4-hexenoic acid, m.p. 122-123°C. ZA-26G. Other Compounds of Formula I Similarly, by subεtitution of appropriate materialε, the reactionε of Examples ZA-26A through F can be used to εyntheεize compoundε of Formula I where Z 3 or Z 4 iε lower alkyl other than methyl (by εubεtituting a different lower alkyl halide for methyl iodide) , giving the reεulting intermediate εuch aε: (S) 4-benzyl-3- [(E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2-ethyl-4-methyl-4-hexenoyl] -2- oxazolidinone (a compound of Formula II where R 2 iε benzyl, Z 3 is ethyl and Z 4 iε hydrogen) ; or for εide chainε other than thoεe of Formula ZA. ZA-26H. Other Compounds of Formula II Similarly, by εubεtituting (S) -4-benzyl-2-oxazolidinone with a (S) -4- lower alkyl-2-oxazolidinone, there are obtained the correεponding compoundε of Formula II where R 2 iε lower alkyl, εuch as: (S) 4-t-butyl-3- [ (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -2-propyl-4-methyl-4-hexenoyl] -2- oxazolidinone; (S) 4-methyl-3- [ (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoyl] -2-oxazolidinone; and (S) 4-ethyl-3- [ (E) 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -4-methyl-4-hexenoyl] -2-oxazolidinone. EXAMPLE ZB-1 ZB-1A. Formula 202 where R a is t-Butyldimethylsilyl, D*-D 2 is -C^-CH J -CH J -, and Z 8 is Hydrogen A solution of 2- (4-tert-butyldimethylεilyloxy-l,3-dihydro-6-methoxy- 7-methyl-3-oxoiεobenzofuran-5-yl)acetaldehyde (8.0 g) in tetrahydrofuran (200 ml) waε cooled to -78 °C and treated with cyclopent-1-enylmagnesium bromide (26 ml of a 0.96M εolution in tetrahydrofuran, prepared from cyclopentenyl bromide (4.35 g) and Mg (0.7 g) in tetrahydrofuran (30 ml) at reflux) . The εolution waε allowed to warm to -20 °C over 1 hour, then the reaction quenched by the addition of εaturated aqueouε ammonium chloride. Extraction of the product uεing ether waε followed by waεhing the organic layer with brine and drying over magneεium εulfate. After filtration and evaporation, chromatography of the reεidue on silica gel eluting with 5:1 hexanes:ethyl acetate provided a εolid reεidue (8 g) . Recryεtallization from ethyl acetate:hexaneε provided the product 1- [2- (4-tert- butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl) -1-hydroxyeth-l-yl] cyclopent-1-ene (5.6 g) , m.p. 138.8-140.5°C. ZB-1B. Separation of Enantiomers of Formula 202 where R" is t-Butyldimethylsilyl, D x -D 2 is -CH^-CH j -CHz-, and Z 8 is Hydrogen 1. To a solution of 1- [2- (4-tert-butyldimethylεilyloxy-l,3- dihydro-6-methoxy-7-methyl-3-oxo-5-iεobenzo-furanyl) -1-hydroxyeth-1- yl] cyclopent-1-ene (15.0 g) in diiεopropylethylamine (145 ml) and dimethylaminopyridine (5.46 g) waε added (R) - (+) -α-methylbenzyl iεocyanate (21.1 g) under a nitrogen atmoεphere. The reaction waε heated at 60°C for 7 hourε, then εtirred at room temperature for 24 hourε. The reaction mixture waε then diluted with ether (700 ml) and filtered to remove εolidε. The ether layer waε waεhed εequentially with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water, brine, then dried over magnesium εulfate and evaporated to afford the diaεtereomeric mixture of Formula 202A. The iεomerε were chromatographically εeparated on 1.2 kg of εilica gel eluting with 7% ethyl acetate:toluene to afford: l-{2[4-tert- butyldimethylεilyl-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl] - 1- (S) - [N- (1- (R) -methylbenzyl)carbamoyloxy]eth-l-yl}cyclopent-1-ene aε a foam and 1-{2 [4-tert-butyldimethylεilyloxy-l,3-dihydro-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl] -1- (R) - [N- (1- (R) -methylbenzyl)carbamoyloxy]eth-l- yl}cyclopent-1-ene aε a foam, [α] D = 57.55 (CH 3 OH) . 2. To a solution of 1-{2 [4-tert-butyldimethylsilyloxy-l,3-dihydro- 6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl] -1- (S) - [N- (1- (R) -methylbenzyl) - carbamoyloxy]eth-l-yl}cyclopent-1-ene (9.0 g) and triethylamine (4.6 ml) in toluene (60 ml) was added trichlorosilane (2.5 ml) dropwiεe in toluene (20 ml) . After addition, the reaction waε εubmerged in an oil bath pre-heated to 110°C and εtirred for 15 minuteε, then cooled to room temperature. The reaction waε diluted with ethyl acetate (500 ml) and waεhed εequentially with aqueous ammonium chloride, dilute hydrochloric acid, aqueous εodium bicarbonate, brine, then dried over magneεium εulfate and evaporated onto 90 g of εilica gel. Thiε waε placed on top of a εilica gel column and eluted with 4:1 hexane:ethyl acetate to afford the product 1- [2- (4-tert- butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-5-iεo- benzofuranyl) -1- (S) -hydroxyeth-l-yl] cyclopent-1-ene, m.p. 112.0-112.7°C (ethyl acetate), [α] D = 33.11 (CH 3 OH) . ZB-1C. Alternative Preparation of Enantiomers of Formula 202 where R a is t-Butyldimethylsilyl, D x -D 2 is and Z 8 is H 1. Trifluoroacetic anhydride (1.6 ml) in methylene chloride (3.6 ml) was added dropwise to dimethyl εulfoxide (1.05 ml) and (7.5 ml) under nitrogen over 5 minuteε at -60°C and εtirred for 30 minuteε. After addition of (±) -2- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -1-cyclopentenyl-l-hydroxyethane (2 g) in methylene chloride (6 ml) over 15 minuteε, the mixture waε warmed to -40°C over l hour. Triethylamine (10 ml) waε added at -70°C, the cooling bath waε removed, and after reaching ambient temperature the εolution waε diluted with ethyl acetate, waεhed twice with εaturated aqueouε potaεεium dihydrogen phoεphate, brine, dried and evaporated. The εolid residue was chromatographed on εilica gel with 7:1 hexane, eluting with ethyl acetate to afford cyclopentenyl (4-tert-butyldimethylεilyloxy-1,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-ylmethyl)methanone (1.65 g) . 2. The compound (0.955 g) thuε prepared waε diεεolved in toluene (2 ml) , and concentrated in vacuo (azeotropic drying) followed by addition of a 1M toluene εolution of (R) -tetrahydro-1-methyl-3,3-diphenyl-lH,3H- pyrrolo- [1,2-c] [.1,3,2]oxazaborole (0.706 ml) [J. Am. Chem. Soc , 109:7925 (1987)] . The toluene waε evaporated in vacuo and replaced by methylene chloride (2.3 ml) followed by cooling to -30°C. Borane/dimethyl εulfide (0.235 ml) waε added dropwiεe over 5 minuteε in three equal portions at 1 hour intervals under a static nitrogen atmosphere. After 12 hours, 1M anhydrouε methanolic HCl (1.05 ml) waε added and the mixture waε warmed to ambient temperature. Toluene (2 ml) waε added and the mixture waε concentrated to 2 ml under a nitrogen εtream. Filtration afforded (R) - diphenyl-2-pyrrolidinemethanol.HCL (0.13 g) . The filtrate waε diluted with ethyl acetate, waεhed with εaturated aqueouε potaεεium dihydrogen phoεphate, brine, dried and concentrated to afford a colorleεε εolid. Chromatography on εilica gel, eluting with 3:1 hexane:ethyl acetate, afforded (S) 2- (4-tert-butyldimethylεilyloxy-l,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -1-cyclopentenyl-1-hydroxyethane (0.90 g) of 98.8% enantiomeric exceεs (AGP, 1 ml/minute,84:16 pH 6 phosphate buffer : isopropanol, major 3.6 minutes, minor 15.7 minuteε). ZB-1D. Formula 202 varying R a , D x -D 2 , and Z 8 By following the procedureε of Parts A and B or C, and optionally subεtituting 2- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl)acetaldehyde with the compoundε of Formula 103, prepared for example, aε εhown in Example ZA-2, and optionally εubεtituting cyclopent-1-enylmagneεium bromide with appropriate compoundε of Formula 201, there are obtained the correεponding compoundε/enantiomerε of Formula 202 identified in the following table. where TBDMS is t-butyldimethylεilyl, and MEM iε methoxyethoxymethoxy. EXAMPLE ZB-2 ZB-2A. Formula 203 where R a is t-Butyldimethylsilyl, D x -D 2 is Z 5 and Z 8 are Hydrogen, and Alkyl is Ethyl A solution of 1- [2- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6- methoxy-7-methyl-3-oxo-5-iεobenzofuranyl) -1-hydroxyeth-1-yl] cyclopent-1-ene (0.22 g) in triethylorthoacetate (10 ml) waε treated with pivalic acid (0.010 g) and then heated to 100 °C, and maintained at that temperature for 18 hours. After cooling to ambient temperature, the solution waε diluted with 1:1 ethyl acetate:hexaneε and waεhed sequentially with water, saturated aqueouε εodium bicarbonate, and brine. Drying over magneεium εulfate waε followed by evaporation; chromatography of the reεidue on εilica gel (10% ethyl acetate in hexaneε) afforded ethyl (E) 2- [2- [2- [4- tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo- iεobenzofuran-5-yl]ethylidene] -cyclopent-1-yl] acetate (0.11 g) aε an oil. ZB-2B. Formula 203 where R a is TBDMS or MEM, varying D l -D 2 , Z 5 and Z 8 By following the procedure of part A and optionally substituting 1- [2- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxo-5- iεobenzo-furanyl) -1-hydroxyeth-1-yl] cyclopent-1-ene with the compoundε of Formula 202, prepared for example, aε εhown in Example 202, and optionally εubεtituting triethylorthoacetate with the compoundε of Formula 104a where Z 3 iε hydrogen and Z 4 iε hydrogen or lower alkyl, there are obtained the correεponding compoundε of Formula 203 where R a iε TBDMS or MEM, identified in the following table. EXAMPLE ZB-3 ZB-3A. Formula I-ZB-A where D x -D 2 is - (CHj) - (CHj) - (CH j ) - and Z 5 is Hydrogen To ethyl (E) 2- [2- [2- [4-tert-butyldimethylεilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl]ethylidene] -cyclopent-1-yl] acetate (0.11 g) in methanol (9 ml) and water (1 ml) waε added lithium hydroxide monohydrate (0.050 g) . After εtirring for 3 dayε, the mixture waε diluted with ethyl acetate and exceεε 5% hydrochloric acid added. After εeparation of the organic layer, the aqueouε layer waε waεhed twice with ethyl acetate, and the combined organic layerε dried over magneεium sulfate. After filtration and evaporation, the residue waε purified by εilica gel chromatography, eluting with methylene chloride:hexanes:methanol 4:2:1, to give (E) -2- [2- [2- [1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1-yl]acetic acid aε a εolid, m.p. 178-180°C (methanol/methylene chloride) . ZB-3B. Formula I-ZB-A varying D x -D 2 , Z s and Z 8 By following the procedure of part A and εubεtituting ethyl (E) 2- [2- [2- [4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] -cyclopent-1-yl] acetate with compounds of Formula 203, prepared for example, as shown in Example ZB-2, there are obtained the corresponding compounds of Formula I-ZB-A identified in the following table. Formula I-ZB-A EXAMPLE ZB-4 ZB-4A Formula 203 Where R" is TBDMS, D x -D 2 is (CH 2 ) 4 , Z s is Methyl and Z 8 is Hydrogen A 2.16 g (5.00 mmol) sample of 6- (2-cyclohex-l-enyl-2S-hydroxyethyl) - 7- (t-butyldimethylεilyloxy) -5-methoxy-4-methyl-3H-iεobenzofuran-l-one waε diεεolved in 85 ml of triethyl orthopropionate and then 103 mg (1.00 mmol) of trimethylacetic acid in 15 ml triethyl orthopropionate waε added. The εolution was submerged in a 130 °C oil bath for 3 h, after which it was cooled to below room temperature, diluted with ethyl acetate, and waεhed with 1M NaHS0 4 and brine. After drying over Na 2 S0 4 , the EtOAc solution was concentrated to give a residue which waε flaεh chromatographed eluting with 3:97 EtOAc/PhCH 3 to give 619 mg of E-2R-{2- [2- (4- (t-butyldimethylεilyloxy) - 6-methoxy-7-methyl-3-oxo-1,3-dihydroiεobenzofuran-5-yl)ethylidene] cyclohe - lS-yl}propionic acid ethyl eεter and 1.29 g of E-2S-{2- [2- (4- (t- butyldimethylεilyloxy) -6-methoxy-7-methyl-3-oxo-1,3-dihydroiεobenzofuran-5- yl)ethylidene] cyclohex-IS-yl}propionic acid ethyl eεter. ZB-4B Formula I-ZB-A Where D x -D 2 is (CH^, Z s is Methyl and Z 8 is Hydrogen By following the procedures of Examples ZA-5A and ZA-6A and εubεtituting methyl (E) -6- (4-tert-butyldimethylsilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with E- 2R-{2- [2- (4- (t-butyldimethylεilyloxy) -6-methoxy-7-methyl-3-oxo-1,3- dihydroiεobenzofuran-5-yl)ethylidene] cyclohex-IS-yl}propionic acid ethyl eεter and E-2S-{2- [2- (4- (t-butyldimethylεilyloxy) -6-methoxy-7-methyl-3-oxo- 1,3-dihydroiεobenzofuran-5-yl)ethylidene] cyclohex-IS-yl}propionic acid ethyl ester, there are obtained E-2R-{2- [2- (4-hydroxy-6-methoxy-7-methyl-3- oxo-l,3-dihydroisobenzofuran-5-yl)ethylidene] cyclohex-IS-yl}propionic acid and E-2S-{2- [2- (4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3- dihydroiεbbenzofuran-5-yl)ethylidene] cyclohex-IS-yljpropionic acid. EXAMPLE ZB-5 ZB-5A. Ethyl (E) 2-{2- [2- (1,3-dihydro- -hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yl}acetate By following the procedure of Example ZA-5A and εubεtituting methyl (E) -6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E) 2- [2- [2- [4- tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] -cyclopent-1- (S) -yl] acetate, there iε obtained ethyl (E) 2-{2- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yl}acetate. ZB-5B. Ethyl (E) 2-{2- [2- {1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yl}propionate To a solution of 1M sodium biε (trimethylεilyl)amide in tetrahydrofuran (31.7ml) and l,3-dimethyl-3,4,5,6-tetrahydro-2 (IH) - pyrimidinone (2.74ml) at -78°C waε added ethyl (E) 2-{2- [2- (l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yl}acetate (3.39g) in tetrahydrofuran (35ml), over a period of 30 minuteε. After an additional 30 minuteε methyl iodide (2.25ml) waε added. After an additional two hourε εaturated aqueouε ammonium chloride (10ml) and ethyl acetate were added. The organic εolution waε dried and evaporated and the reεidue chromatographed on εilica gel, eluting with 4:1 hexane:ethyl acetate, to afford one diaεtereomer of ethyl (E) 2-{2- [2- (1,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl)ethylidene] cyclopent-1- (S) -yl}propionate as a low-melting solid. ZB-5C. (E) 2-{2- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo- isobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yl}propionic acid A mixture of ethyl (E) 2-{2- [2- (1,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yljpropionate (2.6g), ethanol (100ml), water (50ml) and lithium hydroxide monohydrate (1.7g) waε εtirred at room temperature for 62 hourε. 5% Aqueous hydrochloric acid (250ml) was then added. The solution was extracted with ethyl acetate and the extract was dried and evaporated. The residue was chromatographed on silica gel, eluting with 80:20:1 hexane:ethyl acetate: acetic acid, to afford one diaεtereomer of (E) 2-{2- [2- (l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopent-1- (S) -yl}propionic acid, m.p. 113-115°C. EXAMPLE ZC-1 ZC-1A Formula 302 Where R" is Tosyl and Z 5 is Methyl A solution of 2- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-5-iεobenzofuranyl) cetaldehyde (10.0 g) and 2- triphenylphosphoranylidine propionaldehyde (10.3 g) in toluene (150 mL) was heated under nitrogen atmosphere using an oil bath at 80 °C. After allowing the reaction to proceed for 16 hours, the mixture was cooled to ambient temperature and subjected to flash chromatography three times (7/2/1 hexanes/methylene chloride/methanol; 6/3/1 hexanes/methylene chloride/methanol; l/l/l hexaneε/methylene chloride/ether) . The reεidual solid (5.56 g) waε recryεtallized from ethyl acetate (200 mL) to afford 4- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-5- iεobenzofuranyl)2-methylbut-2-enaldehyde (2.65 g) , m.p. 168.3-173.2 °C, impure with the εtarting aldehyde. ZC-1B Formula 303 Where R a is Tosyl and Z s is Methyl To a solution of 4- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- toluenesulfonyloxy-5-iεobenzofuranyl) 2-methylbut-2-enaldehyde (0.90 g) in tetrahydrofuran (40 mL) waε added vinylmagnesium bromide (4.5 mL of a 1 M εolution in tetrahydrofuran) . After εtirring for 0.5 hourε, the reaction waε diluted with ethyl acetate and waεhed εucceεεively with aqueouε ammonium chloride and brine. Drying over magneεium εulfate waε followed by filtration and εolvent removal to leave a reεidual oil, 6- (1,3-dihydro-6- methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-5-iεobenzofuranyl) -3-hydroxy- 4-methylhexa-l,4-diene, which waε carried on without further purification. ZC-1C Formula 304 Where R a is Tosyl and Z 5 is Methyl The oil product from Example ZC-1B, 6- (1,3-dihydro-6-methoxy-7- methyl-3-oxo-4-p-tolueneεulfonyloxy-5-iεobenzofuranyl) -3-hydroxy-4- methylhexa-l,4-diene, waε diεεolved in methylene chloride (20 mL) and 4A molecular εieveε (2 g) were added. With vigorouε εtirring, pyridinium dichromate (2 g) waε added and the reaction allowed to proceed for 3 hourε. The mixture waε then filtered through a celite filled fritted funnel capped with εilica gel. Solvent removal waε followed by flaεh chromatography (hexaneε/methylene chloride/ether, 4/4/1) to provide the εolid product 6- (1,3-dihydro-6-methoxy-7-methyl-3-oxo- -p-tolueneεulfonyloxy-5- iεobenzofuranyl) -4-methylhexa-l,4-dien-3-one (0.45g), which waε carried on without further purification. ZC-1D Formula 305 Where R a is Tosyl and Z 5 is Methyl The εolid product prepared in Example ZC-1C, 6- (1,3-dihydro-6- methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-5-iεobenzofuranyl) -4- methylhexa-l,4-dien-3-one waε diεεolved in methylene chloride (15 mL) and treated with boron trifluoride etherate (0.5 mL) . After 0.5 hourε, the reaction waε diluted with ethyl acetate and waεhed with brine, then dried over magneεium εulfate. Filtration, εolvent removal and chromatography (εilica gel, hexaneε/methylene chloride/ether, 4/4/2) gave the product, 3- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-5- iεobenzofuranylmethyl) -2-methylcyclopent-2-en-l-one (0.18 g) aε a colorleεε εolid m.p. 65.4-66.8 °C. ZC-1E Formula 306 Where R a is Tosyl and Z 5 is Methyl A mixture of 3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-5-iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-one (0.17 g) and cerium trichloride heptahydrate (0.172 g) in tetrahydrofuran/ methanol (12 mL, 4/1) waε treated with εodium borohydride (0.035 g) . After 0.5 hourε, the reaction waε diluted with ethyl acetate and washed with brine. Drying over magnesium sulfate waε followed by filtration and εolvent removal. Chromatography (hexanes/methylene chloride/ether, 1/1/1) gave the product 3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-5-iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ol (0.088 g) aε a εolid m.p. 108.0-111.5 °C. ZC-1F Formulae 307 and 308 Where R a is Tosyl, Z 5 is Methyl and Z 8 is H To a solution of 3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-5-iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ol (0.157 g) in ethyl vinyl ether (10 mL) waε added mercuric acetate (0.052 g) . After εtirring for 30 hourε at ambient temperature, the reaction waε diluted with ether and paεsed quickly through a fritted funnel half filled with celite and capped with εilica. To this ethereal εolution [containing 3- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy- 5-iεobenzofuranylmethyl) -2-methyl-l-vinyloxycyclopent-2-ene, which waε not isolated or characterized] waε then added lithium perchlorate (10 mL, 0.5 M εolution in ether) . After 0.5 hourε, the reaction was diluted with aqueous sodium bicarbonate and waεhed with brine. Drying over magneεium εulfate waε followed by filtration and εolvent removal. The product 3- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-tolueneεulfonyloxy-5- iεobenzofuranylmethyl) -2-methylcyclopent-2-en-l-ylacetaldehyde (0.050 g) waε finally obtained after chromatography (hexaneε/ethyl acetate, 2/1) . ZC-1G Formula 309 Where R a is Tosyl, Z 5 is Methyl and Z 8 is Hydrogen The 3- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5- iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ylacetaldehyde waε diεεolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with reεorcinol (0.10 g) . To thiε mixture waε then added εodium chlorite (0.080 g) . After 2 minuteε, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layerε were dried over magneεium εulfate. The reεidue, 3- (l,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p- tolueneεulfonyloxy-5-iεobenzofuranylmethyl) -2-methylcyclopen -2-en-1- ylacetic acid obtained after εolvent removal was carried on without further purification. ZC-1H Formula I-ZC Where Z 5 is Methyl and Z 8 is Hydrogen The 3- (1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5- iεobenzofuranylmethyl) -2-methylcyclopent-2-en-l-ylacetic acid obtained in Example ZC-1G waε diεεolved in a mixture of methanol (8 mL) and water (2 mL) and treated with lithium hydroxide monohydrate (0.15 g) . After 4 hours, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the product was washed out of the combined organic layerε with 2M NaOH. Acidification of the baεic layers with 5% hydrochloric acid and extraction of the product into ethyl acetate was followed by drying the organic layer with magnesium sulfate. Filtration and solvent removal waε followed by two flaεh chromatographieε (hexaneε/ethyl acetate, 4/1 with 1% HOAc; then methylene chloride/methanol 25/1) to provide 3- (l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-iεobenzofuranylmethyl) -2-methylcyclopent-2-en-1-ylacetic acid (0.010 g) m.p. 153-159 °C. ZC-1I Formula I-ZC Varying Z s and Z 8 By following the procedureε of Exampleε ZC-1A through ZC-1H and appropriately εubεtituting 2-triphenylphoεphorylidine propionaldehyde in Example ZC-1A and ethyl vinyl ether in Example ZC-1F, there are obtained the corresponding compoundε of Formula I-ZC. EXAMPLE ZD-1 ZD-1A. Formula I-ZD-A2 By following the procedure of Example ZA-6A and εubstituting methyl (E) -6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E) -3- [2- (1,3-dihydro-4-hydroxy- 6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylate (prepared e.g, aε deεcribed with reference to Reaction Scheme ZD-A, Stepε 1 through 4) there iε obtained (E) -3- [2- (1,3-dihydro-4-hydroxy- 6-methoxy-7->methyl-3-oxoiεobenzofuran-5-yl)ethylidene] cyclopentane-1- carboxylic acid, m.p. 128-130°C (hexane-dichloromethane) . EXAMPLE ZE-1 ZE-1A. Formula 515 where R a is Acetyl and Z 5 is Hydrogen A solution of 5-allyl-4-tert-butyldimethylsilyloxy-l,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran [(J.W. Patterεon and G. Huang, Chemical Communications, 1579 (1991)] (7.5g) in acetic acid (95ml) and acetic anhydride (95 ml) waε refluxed for 18 hourε, then cooled and poured into ice water. The εolution was extracted with ethyl acetate, and the extract washed with dilute aqueouε εodium bicarbonate, followed by water, then dried and evaporated. The residue waε chromatographed on silica gel, eluting with 7:3 hexane:ethyl acetate, to give 4-acetoxy-5-allyl-l,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran, mp 101-102°C. ZE-1B. Formula 515 where R a is Acetyl, Varying Z s By following the procedure of part A and εubεtituting 5-allyl-4-tert- butyldimethylεilyloxy-1,3-dihydro-6-methoxy- -methyl-3-oxoiεobenzofuran with the compoundε of Formula 514 where Z 5 iε methyl, ethyl, n-propyl, iεopropyl, n-butyl, εec-butyl, tert-butyl, n-pentyl, n-hexyl (prepared for example, aε εhown in Reaction Scheme ZE-C, Step 2, there are obtained the correεponding compoundε of Formula 515 where R" iε acetyl and Z 5 iε methyl, ethyl, n-propyl, iεopropyl, n-butyl, εec-butyl, tert-butyl, n-pentyl, and n-hexyl. EXAMPLE ZE-2 ZE-2A. Formula 511 where R a is Acetyl, Z 5 and Z 7 are Hydrogen, Z 6 is 3-Methyl, and Alkyl is Methyl 4-Acetoxy-5-allyl-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran (0.6g), methyl 2-bromo-3-methylbenzoate (0.92g), silver carbonate (1.3g), palladium acetate (O.lg), triphenylphosphine (0.14g) and dimethylformamide (70ml) were heated with εtirring at 100°C for 6 hourε, then εtirred at ambient temperature for 18 hourε. The mixture waε poured into ice water and the pH adjuεted to 3 by addition of 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was dried and evaporated. The residue was chromatographed on εilica gel, eluting with 7:3 hexane:ethyl acetate, to give methyl (E) -2- [3- (4-acetoxy-1,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -prop-1-en-1-yl] -3-methylbenzoate, mp 104-111°C (ethyl acetate/hexane) . ZE-2B. Formula 511 where R a is Acetyl, Varying Z 5 , Z 6 , Z 7 , and Alkyl By following the procedure of part A and subεtituting 4-acetoxy-5- allyl-l,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran with the compoundε of Formula 515, e.g., where Z 5 is H, methyl and n-propyl (prepared for example, as shown in Examples ZE-1A and ZE-1B) , and subεtituting methyl 2- bromo-3-methylbenzoate with the compoundε of Formula 516 identified in the following table: there are obtained the correεponding compoundε of Formula 511 where R iε acetyl, aε identified in the following table: Formula 511 Alkyl EXAMPLE ZE-3 ZE-3A. Formula I-ZE-D2 where Z s and Z 7 are Hydrogen, and Z 6 is 3-Methyl A εolution of methyl (E) -2- [3- (4-acetoxy-1,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -prop-1-en-1-yl] -3-methylbenzoate (O.lg) and lithium hydroxide (0.06g) in methanol (1ml) and water (1ml) waε heated at 70°C for 48 hourε. The εolution waε cooled and poured into water, then acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract waε dried and evaporated to give (E) -2- [3- (4-acetoxy-1,3-dihydro-6- methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -prop-1-en-1-yl] -3-methylbenzoic acid, mp 180-3°C (ethyl acetate/cyclohexane) . ZE-3B. Formula I-ZE-D2 Varying Z , Z and Z By following the procedure of part A and εubεtituting methyl (E) -2- [3- (4-acetoxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -prop- 1-en-l-yl] -3-methylbenzoate with the compoundε of Formula 511 prepared aε deεcribed in Example ZE-2B, there are obtained the correεponding compoundε of Formula I-ZE-D2 identified in the following table: Formula I-ZE-D2 EXAMPLE ZF-1 ZF-1A. Formula I-ZF Where Z 1 is Methyl 4- (1,3-Dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- ylmethyl) -3-methylcyclopent-3-ene-l,1-dicarboxylic acid (obtained aε described with reference to Reaction Scheme ZF-A, Steps 1 through 4) is heated at 200°C for 5 minutes under nitrogen to give 4- (l,3-dihydro-4- hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-ylmethyl) -3- methylcyclopent-3-ene-l-carboxylic acid, m.p. 208-211°C. EXAMPLE ZG-1 ZG-1A. Formula I-ZG-A Where Z 3 and Z 4 are H By following the procedure of Example ZA-6A and εubεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -2,4-dimethyl-4-hexenoate with ethyl 3- [3- (1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoiεobenzo-furan-5-yl) cyclopent-1-en-1-yl] -propionate (prepared e.g, aε described with reference to Reaction Scheme ZG-A, Steps 1 through 10) there is obtained 3- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxoiεobenzo-furan-5-yl)cyclopent-1-en-1-yl] -propionic acid, m.p. 162-167°C. EXAMPLE ZH-1 ZH-1A. Formula 801 where D 4 is CHj, R a is TBDMS and Z 1 is Methyl A solution of 2-bromo-6-t-butyldimethylsilyloxylhex-2-ene (3.83g) in 100 ml THF was cooled to -78 °C, and a 1.7 M solution of tert-butyl lithium (16.1ml) was added slowly, to form a compound of Formula 103e where M iε lithium. Stirring waε continued for 1 hour at -78 °C. During thiε time a εolution of magneεium bromide waε prepared by slowly adding a solution of ethylene dibromide (1.24 ml) in benzene (5ml) to a flaεk, equipped with a water cooled condenεer, containing magneεium (349 mg) and ether (5ml) at room temperature. The magneεium bromide εolution was added via cannula to the solution of the vinyl lithium of Formula 103e. The resulting solution was stirred at -78 °C for 25 min, at which time a solution of 2- (4-tert- butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5- yl)acetaldehyde (5.04g) (Formula 103) in THF (40 ml) waε added. The reaction waε εtirred for 20 minuteε at -78 °C, then allowed to warm to 0°C over 15 min., at which time IN NH 4 C1 (20ml) waε added. The mixture waε diluted with ether (500ml) , waεhed with IN NH 4 C1 (3X) , brine, and dried. The reεulting oil waε chromatographed on εilica gel (10%-20% ethyl acetate in hexaneε) to give 4.80 g of (E) -7- (4-tert-butyldimethylεilyloxy-1,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -1-tert-butyldimethyl- εilyloxy-6-hydroxy-5-methylhept-4-ene aε an oil, a compound of Formula 801. ZH-1B. Formula 801 where R a is t-Butyldimethylsilyl, Varying D 4 and Z 1 By following the procedure of part A and optionally subεtituting 2- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)acetaldehyde with the compoundε of Formula 103, and optionally εubεtituting 2-bromo-6-t-butyldimethylεilyloxylhex-2-ene with the compoundε of Formula 103e, there are obtained the correεponding compoundε of Formula 801 identified in the following table: EXAMPLE ZH-2 ZH-2A. Formula 802 where Alkyl is Ethyl, D 4 is CH,, R a is t-Butyldimethylsilyl and Z 1 is Methyl (E) -7- (4-tert-butyldimethylsilyloxy-l,3-dihydro-6-methoxy-7- methyl-3-oxoiεobenzofuran-5-yl) -1-tert-butyldimethyl-εilyloxy-6-hydroxy- 5-methylhept-4-ene (4.74 g) waε diεεolved in triethyl orthoacetate (76ml) and pivalic acid (171mg) waε added. The εolution was placed in an oil bath preheated to 130°C, and stirred for 2 1/2 hrs. After cooling, the reaction waε diluted with ether, waεhed with IN NaHS0 4 (3X) , εaturated εodium bicarbonate, brine, and dried. The εolvent waε evaporated and the reεulting oil chromatographed on εilica gel (20% ethyl acetate in hexaneε) to give ethyl (E) 6- (4-tert- butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -3- (3-tert-butyldimethylεilyloxypropyl) -4-methylhex-4-enoate (2.94 g) , a compound of Formula 802. ZH-2B. Formula 802 where R a is t-Butyldimethylsilyl, Alkyl is Ethyl, Varying D 4 and Z 1 By following the procedure of part A and optionally subεtituting (E) -7- (4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -1-tert-butyldimethyl-εilyloxy-6-hydroxy-5- methylhept-4-ene with the compounds of Formula 801, there are obtained the corresponding compoundε of Formula 802 identified in the following table: EXAMPLE ZH-3 ZH-3A. Formula 803 where Alkyl is Ethyl, D 4 is CH,, R a is t-Butyldimethylsilyl and Z x is Methyl Ethyl (E) 6- (4-tert-butyldimethylεilyloxy-1,3-dihydro-6-methoxy-7- methyl-3-oxo-iεobenzofuran-5-yl) -3- (3-tert-butyldimethylεilyloxypropyl) - 4-methylhex-4-enoate (2.92 g) waε diεεolved in acetonitrile (50ml) . To thiε waε added a εolution of 40% aqueouε HF (5ml) in acetonitrile (45ml), and the reaction mixture εtirred for 10 minuteε. Moεt of the acetonitrile waε then evaporated, and the remaining εolution diluted with ether. The ether waε waεhed with water, εaturated εodium bicarbonate (3X) , brine, and dried. Evaporation of the εolvent gave an oil which waε chromatographed on εilica gel (40% ethyl acetate in hexaneε) to give ethyl (E) 6- (4-tert-butyldimethylεilyloxy-1,3-dihydro- 6-methoxy-7-methyl-3-oxo-iεobenzofuran-5-yl) -3- (3-hydroxypropyl) -4- methylhex-4-enoate (2.10 g) , a compound of Formula 803, aε an oil. ZH-3B. Formula 803 where R a is t-Butyldimethylsilyl, Alkyl is Ethyl, Varying D 4 and Z 1 By following the procedure of part A and optionally subεtituting ethyl (E) -6- (4-tert-butyldimethylεilyloxy-l,3-dihydro-6-methoxy-7- methyl-3-oxo-iεobenzόfuran-5-yl) -3- (3-tert-butyldimethylεilyloxypropyl) - 4-methylhex-4-enoate with the compoundε of Formula 802, there are obtained the correεponding compoundε of Formula 803 identified in the following table: EXAMPLE ZH-4 ZH-4A. Formula 804 where Alkyl is Ethyl, D 4 is CH,, R a is t- Butyldi βthylsilyl and Z 1 is Methyl Ethyl (E) 6- (4-tert-butyldimethylsilyloxy-l,3-dihydro-6-methoxy-7- methyl-3-oxo-iεobenzofuran-5-yl) -3- (3-hydroxypropyl) -4-methylhex-4-enoate (0.82 g) waε dissolved in methylene chloride (25ml) and cooled to 0 °C. Diisopropylethylamine (1.21ml) was then added, followed by methaneεulfonyl chloride (351 μl) . The solution was εtirred for 30 minutes, diluted with methylene chloride, then washed with IN HCl, then brine, and dried. The solvent waε evaporated, and the reεidue diεεolved in acetone (50ml) . Lithium bromide (3.0g) waε added, and the reaction heated to reflux for 1 1/2 hrε. Upon cooling, the εolvent waε evaporated, the reεidue dissolved in ether, washed with water, brine, and dried. The solvent waε evaporated and the reεulting oil chromatographed on silica gel (10-15% ethyl acetate in hexaneε) to give ethyl (E) 6- (4-tert-butyldimethylεilyloxy-l,3-dihydro- 6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -3- (3-bromopropyl) -4-methylhex- 4-enoate (1.75 g) , a compound of Formula 804, aε an oil. ZH-4B. Formula 804 where R a is TBDMS, Alkyl is Ethyl, Varying D 4 and Z x By following the procedure of part A and optionally εubεtituting ethyl (E) -6- (4-tert-butyldimethylsilyloxy-l,3-dihydro-6-methoxy-7-methyl-3- oxo-isobenzofuran-5-yl) -3- (3-hydroxypropyl) -4-methylhex-4-enoate with the compounds of Formula 803, there are obtained the correεponding compoundε of Formula 804 identified in the following table: EXAMPLE ZH-5 ZH-5A. Formula 805 where Alkyl is Ethyl, D 4 is CH,, and Z 1 is Methyl A εolution of of ethyl (E) 6- (4-tert-butyldimethylεilyloxy-1,3- dihydro-6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -3- (3-bromopropyl) -4- methylhex-4-enoate (1.62g) waε diεεolved in THF (25ml), cooled to 0 °C, and a εolution of tetrabutylammonium fluoride trihydrate (919 mg) in THF (5ml) waε added. The reaction waε εtirred for 15 min, diluted with ether, waεhed water (2X) , brine, and dried. The εolvent waε evaporated, and the reεulting oil chromatographed on εilica gel (15%-20% ethyl acetate in hexaneε) to give ethyl (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -3- (3-bromopropyl) -4-methylhex-4-enoate (810 mg) . ZH-5B. Formula 805 where Alkyl is Ethyl, Varying D 4 and Z 1 By following the procedure of part A and optionally subεtituting ethyl (E) -6- (4-tert-butyldimethylsilyloxy-l,3-dihydro-6-methoxy-7-methyl-3- oxo-iεobenzofuran-5-yl) -3- (3-bromopropyl) -4-methylhex-4-enoate with the compoundε of Formula 804, there are obtained the correεponding compoundε of Formula 805 identified in the following table: EXAMPLE ZH-6 ZH-6A. Formula I-ZH-A1 where Alkyl is Ethyl, D 4 is CH,, and Z 1 is Methyl A solution of ethyl (E) 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl- 3-oxo-iεobenzofuran-5-yl) -3- (3-bromopropyl) -4-methylhex-4-enoate (420 mg) waε cooled to -78 °C in THF (50ml) , and a 1M εolution of εodium bis(trimethylεilyl)amide (1.88ml) in THF was added slowly. The reaction was stirred for 45 min at -78 °C, and then allowed to warm to 0 °C over 15 minutes, at which time 5 ml of IN NH 4 C1) was added. The THF was evaporated, the aqueouε layer extracted with ether, the ether layer waεhed with IN HCl, brine, and then dried. Evaporation of the εolvent gave an oil, which waε chromatographed on εilica gel (20%-25% ethyl acetate in hexaneε) to give ethyl (E) -2- [-3- (4-hydroxy-1,3-dihydro-6-methoxy-7-methyl- 3-oxoiεobenzofuran-5-yl) -1-methylpropenyl] -cyclopentanecarboxylate (235 mg) , a compound of Formula I-ZH-Al, aε an oil. ZH-6B. Formula I-ZH-Al where Alkyl is Ethyl, Varying D 4 and Z 1 By following the procedure of part A and optionally subεtituting ethyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-iεobenzofuran- 5-yl) -3- (3-bromopropyl) -4-methylhex-4-enoate with the compoundε of Formula 805, there are obtained the correεponding coπtpoundε of Formula I-ZH-1A identified in the following table: EXAMPLE ZH-7 ZH-7A. .Formula I-ZH-A2 where D 4 is CH,, and Z 1 is Methyl By following the procedure of Example ZA-6A and subεtituting methyl (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεobenzofuran- 5-yl) -2,4-dimethyl-4-hexenoate with ethyl (E) -2- [-3- (4-hydroxy-1,3-dihydro- 6-methoxy-7-methyl-3-oxoiεobenzofuran-5-yl) -1-methylpropenyl] -cyclopentane- carboxylate and compounds of Formula I-ZH-Al, prepared e.g, as described in Example ZH-6B, there are obtained (E) -2- [-3- (1,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -1-methylpropenyl] -cyclopentane- carboxylic acid, mp 157-158°C (hexane/ethyl acetate) and the corresponding compoundε of Formula I-ZH-A2 as identified in the following table. Formula I-ZH-A2 EXAMPLES 1 - 6 Theεe exampleε illuεtrate the preparation of a representative pharmaceutical formulations containing an Active Compound of Formula I, e.g., (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5- yl) -2 (S) ,4-dimethyl-4-hexenoic acid. Other compounds of Formula I, such as those prepared in accordance with Exampleε ZA through ZH, can be uεed aε the Active Compound in preparation of the formulationε of theεe exampleε. EXAMPLE 1 This example illustrates the preparation of a repreεentative pharmaceutical formulation for oral adminiεtration. Quantity per Inαredientε capεule. mgε. Active compound 200 lactoεe, εpray-dried 148 magnesium εtearate 2 The above ingredientε are mixed and introduced into a hard-εhell gelatin capεule. EXAMPLE 2 Thiε example illuεtrateε the preparation of another repreεentative pharmaceutical formulation for oral adminiεtration. Quantity per Ingredients tablet, mqs. Active compound 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magneεium εtearate 5 The above ingredientε are mixed intimately and preεεed into εingle εcored tabletε. EXAMPLE 3 A εuεpenεion for oral adminiεtration iε prepared having the following compoεition: Incrredientε Amount Active compound 1.0 g fumaric acid 0.5 g εodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g granulated εugar 25.5 g εorbitol (70% εolution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml coloringε 0.5 mg diεtilled water q.s. to 100 ml EXAMPLE 4 An injectable preparation buffered to a suitable pH is prepared having the following composition: Ingredients Amount Active compound 0.2 g Sodium Acetate Buffer Solution (0.4 M) 2.0 ml HCl (IN) or NaOH (IN) q.ε. to εuitable pH water (distilled, sterile) q.ε. to 20 ml EXAMPLE 5 Thiε example illuεtrates the preparation of a representative pharmaceutical formulation for topical application. Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy aniεole) 0.01 Water q.ε. to 100 All of the above ingredientε, except water, are combined and heated to 60°C - 70°C with εtirring. A εufficient quantity of water at 60°C iε then added with vigorouε εtirring to emulεify the ingredientε, arid water then added q.ε. 100 g. EXAMPLE 6 A εuppoεitory totalling 2.5 gramε iε prepared having the following compoεition: Active compound 500 mg witepsol H-15* balance ( ♦ triglycerideε of εaturated vegetable fatty acid; a product of HULS, Inc., New Jerεey) . EXAMPLE 7 In Vi tro Determination of Therapeutic Activity (Aε an Anti-Inflammatory, Anti-Viral, Anti-Tumor, Anti-Psoriatic and/or Immunoεuppreεεive Agent) Utilizing the Inhibition of IMP Dehydrogenase Asεay Thiε aεεay iε a modification of the method of Anderεon, J.H. and Sartorelli, A.C., Jour. Biol . Chem, 243:4762-4768 (1968) . It meaεureε the formation of NADH ( ^ = 340 nm, e340 = 6,220 M " 'cm _1 ) aε Inoεine 5' -monophoεphate ("IMP") is converted to Xanthosine 5 ' -monophosphate ("XMP") by the human Type II IMP dehydrogenaεe ("IMPDH") . Compoundε are disεolved and diluted in DMSO, and reaction εolutionε containing compounds at 0, 0.01, 0.10, 1.0, 10, and lOOμM are prepared in disposable methacrylic plastic microcuvets ( 'UV-transparent' plastic, 1 cm pathlength, 1.5 ml capacity) . The solutionε (0.5-1 ml) contain the following: 0.1 M TriεHCL, pH 8.0; 0.1 M KCL; 3.0 mM EDTA; 100 μg/ml BSA; 0.05 mM IMP; 0.10 mM NAD; 10% DMSO; 5-15 nM IMPDH (0.003-0.010 unitε/ml; one unit of enzyme catalyzeε the formation of one μ ol NADH per minute at 40°C at εaturating εubεtrate concentrationε - 200 μM IMP and 400 μM NAD) . Reactionε are performed at 40°C and initiated by the addition of enzyme. Mycophenolic acid (IC 50 - 0.02μM) serves aε the poεitive control. The reactionε are monitored at 340 nm for 10 minutes in a UV/VIS spectrophotometer, and rate data are collected. The 50% inhibitory value ("IC 50 ") iε determined by fitting the fractional activitieε relative to control to the following equation on a Macintosh computer by the program Syεtat: Fractional activity = MAX/ ( (X/IC 5 o) n +l) . X is the concentration of the compound, and the term n accounts for deviationε of the data from a εimple competitive inhibition model . The compounds of the present invention inhibit IMPDH when teεted by thiε method, indicating their activity aε anti-inflammatory, anti-viral, anti-tumor, anti-pεoriatic and/or immunoεuppreεεive agentε, aε εhown in the below table. Compoundε of Formula ZA Compoundε of Formula ZB H -COOH H 0.281 H H H 0.094 EXAMPLE 8 In Vitro Determination of Immunoεuppreεεive Activity Utilizing Reεponεeε of Human Peripheral Blood Lymphocyteε to Phytohemagglutinin (PHA) Thiε procedure iε a modification of a procedure initially deεcribed by Greaveε, et al. ["Activation of human T and B lymphocyteε by polyclonal mitogenε," Mature, 248:698-701 (1974)] . Human mononuclear cellε ("PBL") are εeparated from heparinized whole blood by denεity gradient centrifugation in Ficoll-Plaque (Pharmacia) . After waεhing, 2 x 10 5 cellε/well are cultured in microtiter plateε with RPMI 1640 εupplemented with 5% fetal calf serum, penicillin and streptomycin. PHA (Sigma) at 10 μg/ml is then added. Test materials are tested at concentrations between 10 4 and lO' , by addition to the culture at time 0. Cultures are set up in quadruplicate and incubated at 37°C in a humidified atmoεphere with 7% CO, for 72 hours. A pulse of 0.5 μCi/well of ^-thymidine iε added for the laεt 6 hourε. Cellε are collected on glaεε fiber filterε with an automatic harvester and radioactivity is measured by standard scintillation procedureε. The 50% inhibitory concentration ("IC tt ") for mitogenic εtimulation iε determined graphically. To evaluate differential effects on T- and B-lymphocytes, different mitogenε are used: PWM (Sigma) at 20 μg/ml and Staphylococcus Protein A bound to Sepharose (SPA) (Sigma) 2 mg/ml or 14 μg/ml of Protein A. The compoundε of the preεent invention εhow immunoεuppreεεive activity when teεted by thiε method. EXAMPLE 9 In Vivo Determination of Immunoεuppreεεive Activity Utilizing the Hemolytic Plaque Forming Cell Aεεay Thiε procedure iε a modification of "The agar plaque technique for recognizing antibody producing cellε," a procedure initially deεcribed by Jerne et al., [CeUJbound Antibodies, Amoε and Kaprowski editors (Wistar Inεtitute Preεε, Philadelphia, 1963), p. 109] . Groupε of 5-6 adult C578B1/6 male mice were εenεitized with 1X10 8 εheep red blood cellε ("SRBC") and εimultaneouεly treated with an oral doεage form of the teεt material in an aqueouε vehicle. Animalε in a control group receive the εame volume of vehicle. Four dayε after SRBC inoculation, εpleenε are diεperεed in looεe Ten Broeck homogenizerε. The number of nucleated cellε ("WBC") iε determined and the εpleen cell εuεpenεiόn iε mixed with SRBC, guinea pig complement and agar εolution at 0.5% concentration. Aliquotε of the above mixture (0.1 ml) are dropped on four εeparate quadrants of a Petri dish and are covered with cover εlipε. After two hourε incubation at 37°C, areas of hemolysiε around plaque-forming cellε ("PFC") are counted with a diεεecting microεcope. Total WBC/εpleen, PFC/spleen and PFC/10 6 WBC ("PPM") are calculated for each mouεe εpleen. Geometric means of each treatment group are then compared with the vehicle-treated control group. The compounds of the present invention εhow immunoεuppreεεive activity when teεted by thiε method, as εhown in the below table. Compound of Formula ZA wherein Z' = methyl, Z 2 = H, Z 3 = H, and Z 4 = methyl EXAMPLE 10 Toxicology Range finding (non-GLP) toxicology εtudieε were conducted with a compound of Formula ZB wherein D'-D 2 = (CH,) 3 , Z 3 = methyl, and Z 4 = H [1(S)] with once daily oral doεing for 2 weekε at doεeε of 5, 10, 20, and 40 mg/kg in dogε and 5, 10, and 30 mg/kg in rats. Target tiεεueε in both εpecieε were bone marrow, inteεtine, and lymphoid tiεεue. Thiε compound waε not mutagenic in a preliminary Ameε aεεay. While the preεent invention haε been deεcribed with reference to the specific embodiments thereof, it should be understood by thoεe εkilled in the art that variouε changeε may be made and equivalentε may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, compoεition of matter, proceεε, proceεs step or εtepε, to the objective, εpirit and εcope of the preεent invention. All such modifications are intended to be within the scope of the claims appended hereto. All of the patentε and publicationε referenced above are hereby incorporated by reference.

Claims: What is claimed is: 1. A compound of the formula: wherein: R' is H or C(0)R 10 , where R 10 is lower alkyl, aryl or NH-aryl; and Z iε εelected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH: Formula ZA wherein: Z' iε H, lower alkyl, halo or CF 3 ; Z 2 iε H, OH, lower alkyl, lower alkoxy, aryl, or CH,-Z 13 , where Z 13 iε halo, CN, aryl or heteroaryl; Z 3 iε H, OH, lower alkyl, lower alkenyl, lower alkoxy, halo, phenyl, P(O) (OCH 3 )„ P(O) (OH) (OCH 3 ) , NHZ", SH or S (O) m Z 12 , where Z" iε H, alkyl, acyl, or lower alkyl εulfonyl, Z 12 iε lower alkyl, and m is 0, 1 or 2; Z 4 iε H, OH, lower alkyl, halo, or phenyl, provided, however that Z 4 iε not OH or halo when Z 3 iε OH, halo, P(O) (OCH 3 )„ P(O) (OH) (OCH 3 ) , NHZ", or SZ 12 ; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atomε; and G iε OH, lower alkoxy, lower thioalkyl, NG'G 2 , 0- (CH 2 ) n -NG'G 2 , or O- (CH,) n -N=G 3 , where n iε an integer from 1 to 6, G' iε H or lower alkyl, G 2 iε H or lower alkyl, and =G 3 iε lower alkylene of four to εix carbon atomε, or lower alkylene of three to five carbon atomε pluε one member that iε -0-, -S-, or -N(G 4 ) - where G 4 iε H or lower alkyl; provided that when Z' iε methyl, Z 2 , Z 3 and Z 4 are not all H, and provided that when R 1 , Z 3 and Z 4 are all H and Z 1 iε methyl, Z 2 iε not H or OH; or Formula ZB wherein: Z 5 iε H or lower alkyl,- Z 8 iε H, lower alkyl or formε a double bond with D 2 ; D' and D 2 together with their adjacent carbon atoms form an optionally subεtituted, εaturated or unεaturated carbocyclic or heterocyclic ring of 3 to 7 atomε; and G iε aε defined above; or Formula ZC wherein: Z 8 iε H or lower alkyl; and Z 5 and G are aε defined above; or Formula ZD wherein: D 3 iε -CH,- or -CHj-CHj-; and G is as defined above; or Formula ZE wherein: Z 6 iε H, lower alkyl, lower alkoxy, COOH, NH,, azido or halo; Z 7 is H, lower alkyl, lower alkoxy or halo; and Z 5 and G are as defined above; or Formula ZF wherein: Z' and G are aε defined above; or wherein: D 3 , Z 2 , Z 3 , Z 4 and G are aε defined above; or Formula ZH wherein: D 4 iε -CH 2 -, -CH 2 -CH 2 -, -CH J -CH J -CH,-, -O-, or -O-CH,-; and Z' and G are aε defined above; or a pharmaceutically acceptable εalt thereof. 2. The compound or εalt of Claim 1 wherein R' iε H. 3. The compound or εalt of Claim 2 wherein G is OH. 4. The compound or salt of Claim 2 wherein G iε morpholinoethoxy. 5. The compound or εalt of Claim 1 compriεing a εingle enantiomer, a diaεtereomer, a racemic mixture or a non-racemic mixture. 6. The compound or εalt of Claim 3 wherein Z iε a εide chain of Formula ZA. 7. The compound or εalt of Claim 6 wherein: Z' is lower alkyl; Z 2 is H or lower alkyl; Z 3 is H or lower alkyl; and Z 4 iε H. 8. The compound or salt of Claim 7, namely (+) (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2,3,4-trimethyl-4-hexenoic acid; (E) -6- (1,3-dihydro- -hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (S) ,4-dimethyl-4-hexenoic acid; or (E) -6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl) -2 (S) -ethyl-4-methyl-4-hexenoic acid. 9. The compound or εalt of Claim 3 wherein Z iε a εide chain of Formula ZB. 10. The compound or εalt of Claim 9, namely 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yljacetic acid; 2-{2- [2- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclohex-1 (S) -yl}acetic acid; (-) 2-{4- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] tetrahydropyran-3-yl}acetic acid; (E)-2(S)-{4-[2- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo¬ iεobenzofuran-5-yl)ethylidene] -tetrahydropyran-3 (S) -yl} propionic acid; (-) 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1 (S) -yl}-2-methylacetic acid; (-) 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl] ethylidene] cyclopent-1 (S) -yl}-2 (R) -methylacetic acid; (-) 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl]ethylidene] cyclopent-1(S) -yl}-2 (S) -methylacetic acid; 2-{2- [2- [l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo- isobenzofuran-5-yl] ethylidene] cyclopent-1 (S) -yl}-2 (S) -ethylacetic acid; or 2-{2- [2- (4-hydroxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzofuran-5-yl)ethylidene] cyclohex-1 (S) -yl}-2 (S) -methylacetic acid. 11. The compound or εalt of Claim 3 wherein Z iε a εide chain of Formula ZE. 12. The compound or εalt of Claim 11, namely (E) -2- [3- (4-acetoxy-l,3-dihydro-6-methoxy-7-methyl-3- oxoiεobenzo-furan-5-yl) -prop-1-en-1-yl] -3-methylbenzoic acid; or (E) -2- [3- (4-acetoxy-l,3-dihydro-6-methoxy-7-methyl-3- c.xoiεobenzo-furan-5-yl) -prop-1-en-l-yl] -3-benzoic acid. 13. The compound or εalt of Claim 4 wherein Z iε a εide chain of Formula ZH. 14. The compound or εalt of Claim 13, namely (E) -2- [3- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxoiεobenzo-furan-5-yl) -1-methylprop-l-en-l-yl] cyclopentane-1-carboxylic acid; (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiεo- benzofuran-5-yl) -1-methylprop-l-en-l-yl]cyclohexane-1-carboxylic acid; or (E) -2- [3- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoiso- benzofuran-5-yl) -1-methylprop-l-en-l-yl]tetrahydropyran-1-carboxylic acid. 15. A pharmaceutical composition compriεing a therpeutically effective amount of the compound or εalt of Claim 1 admixed with at leaεt one pharmaceutically acceptable excipient. 16. A method of treatment for immune, inflammatory, tumor, proliferative, viral or pεoriatic diεorderε in a mammal, compriεing adminiεtering a therapeutically effective amount of a compound or εalt of Claim 1 to a mammal in need thereof. 17. A compound of the formula: wherein: R 2 iε lower alkyl or benzyl; and Z 3 and Z 4 are H or lower alkyl, provided that at leaεt one iε H. 18. A proceεε for preparing a compound of the formula: Formula I wherein: R' is H or C(0)R'°, where R 10 is lower alkyl, aryl or NH-aryl; and Z iε εelected from Formulae ZA, ZB, ZC, ZD, ZE, ZF, ZG and ZH: Formula ZA wherein: Z' is H, lower alkyl, halo or CF 3 ; Z 2 iε H, OH, lower alkyl, lower alkoxy, aryl, or CH,-Z 13 , where Z 13 is halo, CN, aryl or heteroaryl; Z 3 is H, OH, lower alkyl, lower alkenyl, lower alkoxy, halo, phenyl, P(0) (OCH 3 )„ P(O) (OH) (OCH 3 ) , NHZ 1 ', SH or S (0) m Z 12 , where Z" is H, alkyl, acyl, or lower alkyl εulfonyl, Z 12 iε lower alkyl, and m iε 0, 1 or 2; Z 4 is H, OH, lower alkyl, halo, or phenyl, provided, however that Z 4 iε not OH or halo when Z 3 iε OH, halo, P(O) (OCH 3 )„ P(O) (OH) (OCH 3 ) , NHZ", or SZ 12 ; or Z 3 and Z 4 taken together with the carbon to which they are attached form cycloalkyl of three to five carbon atomε; and G iε OH, lower alkoxy, lower thioalkyl, NG'G 2 , O- (CH,) n -NG'G 2 , or O- (CH 2 ) n -N=G 3 , where n iε an integer from 1 to 6, G' is H or lower alkyl, G 2 is H or lower alkyl, and =G 3 is lower alkylene of four to six carbon atoms, or lower alkylene of three to five carbon atoms plus one member that iε -0-, -S-, or -N(G 4 ) - where G 4 iε H or lower alkyl; provided that when Z 1 iε methyl, Z 2 , Z 3 and Z 4 are not all H, and provided that when R 1 , Z 3 and Z 4 are all H and Z' iε methyl, Z 2 iε not H or OH; or Formula ZB wherein: Z 5 iε H or lower alkyl; Z 8 iε H, lower alkyl or formε a double bond with D 2 ; D 1 and D 2 together with their adjacent carbon atomε form an optionally εubεtituted, εaturated or unεaturated carbocyclic or heterocyclic ring of 3 to 7 atoms; and G is as defined above; or Formula ZC wherein: Z 8 is H or lower alkyl; and Z 5 and G are as defined above; or Formula ZD wherein: D 3 iε -CH 2 - or -CHj-CH,- ; and G iε aε defined above; or Formula ZE wherein: Z 6 iε H, lower alkyl, lower alkoxy, COOH, NH 2 , azido or halo; Z 7 iε H, lower alkyl, lower alkoxy or halo; and Z 5 and G are aε defined above; or Formula ZF wherein: Z' and G are aε defined above; or wherein: D 3 , Z 2 , Z 3 , Z 4 and G are aε defined above; or and Z 1 and G are as defined above; or a pharmaceutically acceptable salt thereof, which comprises a) deprotecting a compound of Formula I to form an unprotected compound of Formula I; or b) hydrolyzing an ester of a compound of Formula I to form an acid of a compound of Formula I; or c) esterifying a free compound of Formula I to form an eεter of a compound of Formula I; or d) oxidizing a thio or εulfinyl group on a compound of Formula I to form a εulfinyl or sulfonyl group on a compound of Formula I; or e) reducing a nitro group on a compound of Formula I to form an amino group on a compound of Formula I; or f) decarboxylating a di-acid of a compound of Formula I to form a mono-acid of a compound of Formula I; or g) reacting a free compound of Formula I to form a pharmaceutically acceptable salt of a compound of Formula I; or h) reacting a pharmaceutically acceptable salt of a compound of Formula I to form the corresponding free compound of Formula I; or i) reacting a pharmaceutically acceptable εalt of a compound of Formula I to form another pharmaceutically acceptable εalt of a compound of Formula I.

Inventors: ANDRADE FIDENCIO F, ARTIS DEAN R, ELWORTHY TODD R, GARCIA ALICIA C, HAWLEY RONALD C, HERNANDEZ MARIA T L, LOUGHHEAD DAVID G, MARTIN TERESA A T, MORGANS DAVID J JR, MURRA FRANCISCO X T, NELSON PETER H, PATTERSON JOHN W JR, ROHLOFF JOHN C, SJOGREN ERIC B, SMITH DAVID B, WALTOS ANN MARIE, WEIKERT ROBERT J, ZERTUCHE MARIO F, ANDRADE, FIDENCIO, F., ARTIS, DEAN, R., ELWORTHY, TODD, R., GARCIA, ALICIA, C., HAWLEY, RONALD, C., HERNANDEZ, MARIA, T., L., LOUGHHEAD, DAVID, G., MARTIN, TERESA, A., T., MORGANS, DAVID, J., JR., MURRA, FRANCISCO, X., T., NELSON, PETER, H., PATTERSON, JOHN, W., JR., ROHLOFF, JOHN, C., SJOGREN, ERIC, B., SMITH, DAVID, B., WALTOS, ANN, MARIE, WEIKERT, ROBERT, J., ZERTUCHE, MARIO, F.
Applicants: SYNTEX INC, SYNTEX (U.S.A.) INC.
Application year: 1995
Main classification: C07D307
IPC codes: A61K31, A61P17, A61P29, A61P35, A61P37, C07D307, C07D405, C07D407, C07D409, C07D413, C07F9