6(R)-(2-(8'-ACYLOXY-2'-METHYL-6'-METHYL (OR HYDROGEN)-POLYHYDRONAPHTHYL-1')-ETHYL)-4(R)-HYDROXY-3,4,5,6-TETRAHYDRO-2H-PYRAN-2-ONES, THE HYDROXY ACID FORM OF SAID PYRANONES, THE PHARMACEUTICALLY ACCEPTABLE SALTS OF SAID HYDROXY ACIDS, AND THE LOWER ALKYL, AND PHENYL, DIMETHYLAMINO OR ACETYLAMINO SUBSTITUTED LOWER ALKYL ESTERS OF SAID HYDROXY ACID, PROCESSES FOR PREPARING THE SAME, AND A PHARMACEUTICAL ANTIHYPERCHOLESTEROLEMIC COMPOSITION CONTAINING THE SAME

Abstract: 6(R)-[2-(8′-acyloxy-2′-methyl-6′-methyl (or hydrogen)­ polyhydronaphthyl-1′)-ethyl]-4(R) -hydroxy-3,4,5,6-­ tetrahydro-2H-pyran-2-ones are prepared by acylation of the corresponding 8′-hydroxy compounds. The products are strong inhibitors of the biosynthesis of cholesterol. The 8′-hydroxy compounds are prepared by hydrolysis of the corresponding, naturally occurring 8′-(2(S)-­ methylbutyryloxy) compounds with a strong base at elevated temperatures to remove the acyl group.

Description: TITLE OF THE INVENTION 6(R)-/2-(81-acyloxy-2'-methyl-6'-methyl(or hydrogen) polyhydronaphtyl-1')-ethyl/-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-ones, The Hydroxy Acid Form Of Said Pyranones, The Pharmaceutically Acceptable Salts Of Said Hydroxy Acids, And The Lower Alkyl, And Phenyl, Dimethylamino Or Acetylamino Substituted Lower Alkyl Esters Of Said Hydroxy Acid, Processes For Preparing The Same, And A Pharmaceutical Antihypercholesterolemic Composition Containing The Same SUStARY OF THE INVENTION This invention relates to a group of 6(R)-[2 (8'-acyloxy-2'-methyl-6'-methyl(or hydrogen)-polyhydro naphthyl-l')-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-ones and to the hydroxy acid form of said pyranones, the pharmaceutically acceptable salts of said hydroxy acids and to the lower alkyl and phenyl, dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid. More specifically, this invention relates to a compound of the structure I in Table I, in which the dotted lines X, Y and Z represent possible double bonds, said double bonds being, when any are present, either X and Z together in combination or X, Y or Z alone; R represents C1-10 straight or branched chain alkyl (except (S)-2-butyl), C3-10 cycloalkyl, C210 alkenyl, C1-10 CF3substituted alkyl, phenyl, halophenyl, phenyl-C13 alkyl or substituted phenyl-Cl 3 aikyl, in which the substituent is halo, C13 alkyl or C13 alkoxy; and the free hydroxy acids of formula II formed by opening the lactone ring of formula I in Table I. The invention also relates to the 6(R)-12 (8'-hydroxy-2',6l-dlmethylpolyhydronaphthyl-l)ethyl]-4(R) hydroxy-3,4 ,5,6-tetrahydro-2H-pyran-2-ones as intermediates for the above-described 8'-acyloxy compounds BACKGROUND OF THE INVENTION It is known that certain mevalonate derivatives inhibit the biosynthesis of cholesterol, cf. F.M. Singer et al, Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F.H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971). Nevertheless, the activity of these known compounds has not always been found to be satisfactory, i.e. to have practical application. Recently, Endo et al, reported (U.S. Letters Patent 4,049,495, Patent 4,137,322 and Patent 3,983,140) the production of fermentation products which were quite active in the inhibition of cholesterol biosynthesis. The most active member of this group of natural products, now called compactin, IITa(R'=H) was reported by Brown et al [J.Chem.Soc.Perkin I 1165 (1976)3 to have a complex mevalonolactone structure. More recently, Monaghan et al in U.S. Patent 4,231,938, which is incorporated herein by reference, reported an inhibitor, designated MK-803 and having the structure 111a (R'=CH3) in Table I, which was isolated from an entirely different fermentation. Albers-Schonberg et al (European patent application 80,103,286) described a dihydro MK-803, designated 111d (R'=CH3) in Table I, of equal potency to MK-803 isolated from the same fermentation as was MK-803. Patchett et al (European patent application filed February 2, 1981, Merck case no. 16448Y) > describe dihydro and tetrahydro derivatives of MK-803 of different structures (III b,c and e (R =CH3) in Table I), prepared by the catalytic hydiogenation of MK-803. A tetrahydro analog 111e (R'=H), of compactin was reported in published Japanese Application (Kokai) 55009-024. The preparation of the starting materials, 111a and IIId, (R'=CH3) are the products of fermentation with a strain of Aspergillus terreus, ATCC No. 20542, designated MF-4845 in the culture collection of MERCK & CO., Inc., Rahway, New Jersey, deposited at the American Type Culture Coilection, 12301 Parklawn Drive, Rockville, Maryland USA. Preparation of Compounds IIIa and IIId (R'=CH3) A. Fermentation A tube of lyophilized culture MF-4845 was opened aseptically and the contents suspended in an unbaffled 250 ml Erlenmeyer flask (seed flask) containing approximately 10 ml of the Medium which has the following composition: Medium Corn steep liquor 5 g Tomato paste 40 g Oatmeal 10 g Glucose 10 g Trace Element Solution 10 g Distilled water 1000 ml pH 6.8 with NaOH Trace Element Solution: : FeSO4.7H2O 1000 mg MnS 4 4H2O 1000 mg CuCl2.2H2O 25 mg CaCl2.2H2O 100 mg H 3BO3 56 mg (NH4)6Mo7O24.4H2O 19 mg ZnSO4. 7H2O 200 mg Distilled Deionized Water 1000 ml The inoculated flask was incubated for 24 hours at 280C on a 220 rpm shaker (2 inch throw). An unbaffled 2 liter Erlenmeyer flask containing 500 ml of the medium was then inoculated with 10 ml of the first stage fermentation growth from the seed mixture. This too was shaken 24 hours at 280C. A 200 gallon stainless steel fermentation vat was then charged with 485 liters of a medium comprising: Cerelose 4.5% wt/vol Peptonized Milk 2.5% wt/vol Autolyzed yeast 0.25% wt/vol Polyglycol P2000 0.25% vol/vol whose pH was adjusted to 7.0. This was sterilized 15 minutes at 121oC. One liter of the second stage above was then charged and the mixture was incubated at 85 rpm for 12 hours then at 130 rpm for 84 hours at 280C with an air flow of 5 cfm for 12 hours then 10 cfm for 84 hours. B. Isolation 1. Extraction Two batches of one hundred gallons of whole broth were combined, acidified with stirring to pH 4.1 by careful addition of 800 ml of concentrated hydrochloric acid, and extracted by addition of 75 gal of ethyl acetate and further stirring for two hours. About 25 lbs of a silicaceous filter aid was then added and the total slurry was pumped through a 24-inch filter press. An additional 75 gal of ethyl acetate was used to wash the press cake and continue the extraction, by reversing the direction of pumping through the press four times. Then all of the wash solvent was discharged from the press and combined with the first filtrate. The two-phase filtrate was allowed to settle, and the water layer removed. The ethyl acetate layer was washed with 10 gal of deionized water, the phases were allowed to separate and the ethyl acetate extracts were concentrated under vacuum to a residue of about 10 gal. 2. Lactonization Ethyl acetate extracts from an additional three hundred gal of broth were added to the above extract and the volume was reduced to about thirty gal by vacuum distillation. About fifty gal of toluene was added, and the batch was concentrated under vacuum to 32 gal; this step was repeated; then sufficient new toluene was added to bring the volume to 75 gal. Without vacuum, the batch was brought to reflux and maintained there for two hours, with a temperature over 1060C. This solution was then concentrated under vacuum to a small volume, which was further concentrated to an oily residue in a large rotary evaporator under vacuum. 3. Chromatography on Silica Gel The extract obtained above was flushed free of other solvents by addition of 2 gal of methylene chloride and reconcentration to an oil. The oily residue was dissolved in about 5 gal of ethyl acetate-methylene chloride (30/70; v/v) mixture, and a slurry was made by addition of 2.8 kg of silica gel. The slurry was loaded as a level layer on the top of a 12 in. x 50 in. silica gel column packed in the same solvent mixture. Elution was with ethyl acetate-methylene chloride (40/60; v/v) at 800 ml/min. A forerun of 10 gal, then further fractions of 4 gal each were collected. Fractions 6-10 inclusive were concentrated under vacuum to an oily residue which was dissolved in hot ethyl acetate, treated with decolorizing carbon, filtered hot, and cooled. Crystals of Compound 111a (R'=CH3) were filtered off and the mother liquors were concentrated to an oil for further chromatography. Pure 111a (R'=CH3) has m.p. 170-1710C. 4. Rechromatography on Silica Gel Mother liquor residues from similar broth extract work-ups equivalent to an additional 600 gal of fermentation production were combined with the above in methylene chloride solution. One-half of this solution was taken for further silica gel chromatography. A small aliquot showed a total solids content of 325 g. The solution was treated with 40 g of decolorizing carbon, filtered, and the cake rinsed with methylene chloride. The combined filtrate and washings were concentrated under vacuum to an oily residue. This was redissolved in 800 ml of ethyl acetate/methylene chloride (30/70; v/v) and slurried with 225 g of silica gel. The slurry was loaded on top of a 14 x 36 cm column bed of silica gel packed in the same solvent mixture. Development was with ethyl acetate/methylene chloride (40/60; v/v). A forecut of three liters was set aside; then fractions of 800 ml each were collected. 5. Chromatography on Reverse-phase Packing Forty ml from fraction 12 of the above chromatography were concentrated to an oil weighing 500 mg and the oil redissolved in 5 ml acetonitrile. This acetonitrile solution was charged to a 5/8" OD by 6 ft long stainless steel chromatography column packed with preparative reverse-phase liquid chromatography column packing material "Bondapak Cl8/PorasilB" (Waters Associates, Inc., Milford, Mass. 01757). The column was eluted with a mixture consisting of (v/v) 55% acetonitrile and 45% 0.05 M ammonium phosphate pH3. The elution volume between 1360 ml and 1700 ml was combined on the basins of refractive index detection. The organic solvent was removed in vacuo and the residual aqueous solution extracted with ethyl acetate. In vacuo removal of the ethyl acetate left 120 mg of compound which crystallized from a concentrated acetonitrile solution yielding crystals of Compound IIId (R'=Ci3), m.p. 129-131"C. Preparation of Compounds 111b, c, e Starting materials IIIb, III and 111e c c are prepared in accordance with the following Flow Sheet and preparative methods. The desmethyl analogs, IIIb, IIIc and 111e (R'=H) are obtained substantially as described by Patchett et al. (European application, filed February 2, 1981, Merck case 16448Y) but starting with III (R'=H) in each case. a For the preparation of 111e it is advantageous to reduce IIId inasmuch as the desired trans fusion of the perhydronaphthalene ring, present in the starting materials, is retained in the final product, and the need to separate isomers is avoided. FLOW SHEET EMI8.1 Reactions and Reagents l. Hydrogenation at about 20-750C and about atmospheric pressure to about 4 atmospheres over tris (triphenylphosphine)chlororhodium in an aromatic solvent such as benzene, toluene or xylene, preferably toluene. Preferred conditions are about 400C and about 2-7 atmospheres in toluene. 2. Hydrogenation at about 20-250C and about atmospheric pressure over 5% palladium on calcium carbonate in a lower alkanol such as a C13 alkanol, especially ethanol. 3. Hydrogenation at about 20-250C and atmospheric pressure over platinum oxide in ethyl acetate. 4. Hydrogenation at 20-250C and atmospheric pressure over 10% Palladium on charcoal in ethyl acetate. Preparation of 6a12- (.8B-2-(S) -methylbutyryloxy-2'B,6"a-di- methyl-1',2',3',4',6'.7',8',8'a-octahydronaphthyl-1)ethyl- 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, 111b (R' -CH3) A mixture of 50 mg (0.1236 mmol) of Compound 111a (R'=CH3) and an equal molar amount (114.35 mg, 0.1236 mmol) of tris(triphenylphosphine)chlororhodium in 10 ml of dry toluene was hydrogenated at room temperature for 6 days, with a total uptake of 14.6 ml of hydrogen. The mixture was evaporated in vacuo to dryness. The red residue was subjected to preparative thin-layer chromatography on silver nitrate impregnated silica plates and was developed twice in the 10% ethyl acetateether system. The yield of Compound IIIb (R'=CH3) was 22.3 mg. Mass spectrum (M/# ) 406 (m+) 304 (m-102) 286 (m-102-18) nmr (CDCl3, 300MHz) 4.37 (m,lH) 4.60 (m,lH) 5.34 (d of t, J=2.5 Hz, lH) 5.41 (m,lH) Preparation of 6&alpha;[2-(8&beta;-2-(S)-methylbutyryloxy-2'&beta;,6'&alpha;- dimethyl-l', 2', 3', 5', 6', 7', 8', 8'a-octahydronaphthyl-1) ethyl] -4- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, IIIc (R'=CH3) A solution of 80.91 mg (0.2 mmol) of Compound 111a (R'=CH3) in 10 ml of absolute ethanol, in the presence of an equal weight of 5% Pd on CaCO3 was hydrogenated at 1 atmosphere until an uptake of one mole equivalent of hydrogen was observed. The catalyst was then removed by filtration and the filtrate was evaporated to dryness (81 mg). After a purification by preparative thin-layer chromatography to remove a small amount of by-product tetrahydro compound, 72 mg of the 1,4 reduction product IIIc (R'=CH3) was isolated. Mass spectrum (M/e) 406 (m+) 304 (m-102) 286 (304-H20) nmr (CDCl3, 300MHz) 6 4.38 (m,lH) 4.64 (m,lH) 5.28 (d of t, J=3.5Hz, lH) 5.48 (m,lH) Preparation of 6&alpha;-[2-(8'&beta;-2 (S)-methylbutyryloxy-2&alpha;,6'&beta;- dimethyl-l,Z',3 2',3',4',4'a&alpha;,5',6',7',8',8'a-decahydronaphthyl-1)- ethyl]-4ss-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, IIIe (R'=CH3) A solution of 80.91 mg (0.2 mmol) of Compound 111a (R'=CH3) in 10 ml of ethyl acetate was hydrogenated in the presence of an equal weight of platinum oxide at one atmosphere. An exact 2 mole equivalent of hydrogen was consumed within 1 hour. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give an oil. The cis and trans isomers were separated by preparative thin-layer chromatography on silica gel plates (10% ethyl acetate - ether system, bands detected by water spray). The trans isomer 111e (R'=CH3) appears as the more polar spot, compared to the cis isomer, and 60 mg was isolated. Mass spectrum (M/e ) 408 (m+) 323 (m-85) 306 (m-102) nmr (CDCl3, 300MHz) S 4.36 (broad singlet, lH) 4.59 (m,lH) 5.19 (d of t, J=2.5Hz, lH) Fermentative Production of Compound IIId (R'=H) A. Fermentation: A natural isolate of Penicillium citriunum, NRRL 8082, deposited at Northern Regional Research Center, Peoria, Illionois, USA, was used to prepare a yeast-malt extract (YME) slant which was incubated for 2 weeks at 280C. A portion (1/5) of the slant (MF-4870a) was used to inoculate each of 5 unbaffled seed flasks (250 ml) containing 44 ml of KF seed medium with CaCl2. They were incubated for 3 days at 280C, and 220 rpm. A portion of the seed growth (about 1.5 ml) was used to inoculate each of 100 production medium flasks (250 ml unbaffled) containing 40 ml of LM Production Medium Without Malt Extract. The production flasks were incubated for 4 days at 250C. Another group of production medium flasks (140), each containing 40 ml of LM Production Medium Without Modification were inoculated and incubated under the same conditions as previously described. The broths from both fermentations were combined. The various media employed in the foregoing fermentations are: YME Slant Dextrose 4 g./l. Malt Extract 10 g./l. Yeast Extract 4 g./l. Agar 20 g./l/ Dist. Water to 1 liter pH 7.0 KF Seed Medium with CaCl2 CaCl2 10 g. Corn steep liquor 5 g. Tomatoe Paste 40 g. Oatmeal 10 g. Cerelose 10 g. Trace Element Mix 10 ml. Distilled Water 1000 ml. pH 6.8 Trace Element Mix FeSO4.7H2O 1 g. MnSO4.4H2O 1 g. CuCl2.2H2O 25 mg. CaCl2 100 mg. H3B03 56 mg. (NH4)6Mo7O24.4H2O 19 mg. ZnSO4.7H2O 200 mg. Distilled Water 1000 ml. LM Production Medium Without Malt Extract Dextrose 20 g. Glycerol 20 ml. Ardamine pH 10 g. CoCl2.6H2O 8 mg. Polyglycol p 2000 0.25% Distilled Water 1000 ml. pH 7.0 LM Production Medium Without Modification Dextrose 20 g. Glycerol 20 ml. Ardamine pH 10 g. Malt Extract 20 g. CoCl2.6H2O 8 mg. Polyglycol p 2000 0.25% Distilled Water 1000 ml. pH 7.0 B. Isolation The combined whole broth (10.3 liters) was filtered and the mycelia cake was washed with 2.5 liters of deionized water. The combined filtrate and wash was adjusted to pH 4.0 with lN hydrochloric acid. The aqueous solution was extracted with 7 liters of ethyl acetate and the extract was back-extracted with 3 x 2 liters of aqueous sodium hydroxide solution. The combined sodium hydroxide extract was adjusted to pH 3.8 with lN hydrochloric acid and extracted with 2 liters and 1 liter of ethyl acetate. The combined ethyl acetate solution was dried over anhydrous Na2SO4, filtered and concentrated to dryness. The oily residue was dissolved in toluene and refluxed for 1 hour. The toluene solution was concentrated to dryness and the residue was dissolved in 18 ml of a mixture of n-hexane/toluene/methanol (4/1/1 by volume). This solution was loaded onto a 30 mm (ID) x 40 cm. Sephadex LH-20 column equilibrated in the same solvent system. After eluting with 300 ml of solvent, a 10 ml fraction was obtained which was concentrated to an oil. High performance liquid chromatography (HPLC) on an ES Industries column (9 mm x 50 cm) using a mixture of acetonitrile/water (60/40 by volume) as the eluting solvent yielded 45 mg of dihydrocompactin (Compound IIId, R'=H), m.w. 392.2560 by mass spectrum (calculated for C23H3605, 392.2558). In KBr, the major IR peaks obtained from a Fourier Transform -IR (FTIR, Nicolet, Model 7199) are at 1724, 1704, 1258, 1078 and 1070 -I -l cm l. or significance is a peak at 3005 cra and the absence of a peak at 3030 cm l. A nuclear magnetic resonance spectrum was obtained in CDCl3, (tol mg/0.5 ml) on a Varian SC-300 superconducting nmr spectrometer. The following are the peak positions given in ppm (b) relative to internal tetramethylsilane (TMS). EMI16.1 <tb> <SEP> J <SEP> Assignment <tb> 5.62 <SEP> d,d,d <SEP> (2.17, <SEP> 4.5, <SEP> 10.0) <SEP> H3,(or <SEP> 4') <tb> 5.43 <SEP> d <SEP> (10) <SEP> H4,(or <SEP> 3') <tb> 5.20 <SEP> m <SEP> H8, <tb> 4.63 <SEP> m <SEP> H6 <tb> 4.39 <SEP> m <SEP> H4 <tb> 2.75 <SEP> d,d <SEP> (17.5, <SEP> 5.5) <tb> 2.63 <SEP> d,d,d <SEP> (17.5, <SEP> 4.0, <SEP> 1.5) <SEP> 3-CH2 <tb> 2.39 <SEP> m <SEP> CH3H <SEP> C <tb> 2.29 <SEP> m <SEP> H4al <SEP> + <SEP> H21 <tb> 1.14 <SEP> d <SEP> CH3CHCzJP <tb> 0.90 <SEP> t <SEP> CH3CH2 <tb> 0.84 <SEP> d <SEP> 2 <tb> d: doublet; m: multiplet; t: triplet The evidence indicates the structure to be: EMI16.2 DESCRIPTION OF THE INVENTION We have found that the a-methylbutyryl group in Compound 111a (R'=CH3) and hydro-derivatives, IIIb e can be removed cleanly to produce a family of 6(R)-[2 (8-hydroxy-2,6-dimethylpolyhydronaphthyl-l)ethyS4(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones which are themselves hypocholesterolemic agents and which are extremely useful as intermediates for the preparation of novel esters which are even more potent in this use. The preparation of the novel alcohols of this invention is carried out by heating the esters III a-e (R'=CH3) with an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a protic solvent such as water or alcohols for extended periods. Preferred is lithium hydroxide in water at reflux for about 50-72 hours or under pressure at higher temperatures of 120-180"C for shorter times of 8-24 hours. The pyranone ring readily opens but the removal of the side chain acyl group is not easily effected. The heating must be prolonged and/or pressure must be used. An inert atmosphere is also helpful. It is quite unexpected that molecules with so many highly sensitive functional centers can withstand the harsh conditions necessary for removal of the highly hindered a-methylbutyryl ester. It is especially unexpected to find the yields high. In the case of Compounds 111a-e (R'=H) the saponification of the 8'-esters is much more facile proceeding to completion in about 20 hours to give IVa,e (R'=H). The Compound IV (R'=H) is known as ML-236A a as reported by Endo et al. in U.S. Patent 3,983,140. The products are isolated by acidification and extraction with organic solvents which provides the trihydroxy acid form of compounds IVa e. These trihydroxy acids can be relactonized by heating a solution of the acid in an appropriate organic solvent such as toluene or benzene in an apparatus permitting continuous separation of the water formed. The alcohols which form part of this invention comprise Structures IVa e (R'=CH3) as well as the trihydroxy acids resulting from opening of the lactone rings. An alternate synthetic route to the Compounds IVb, c e comprises the steps of hydrolysis of 111a to IVa as described herein followed by hydrogenation of IVa under the conditions described previously for the preparation of 111b, c e to produce IVb, IVC or IVe depending on those reaction conditions. Preparation of Compounds IV a-e The starting materials, the 8hydroxy compounds IV (R'=CH3) are prepared from the various 8'-esters described by Monaghan et al (IIIa, R'=CH3), Albers-Schonberg et al (IIId, R'=CH3) and Patchett et al (IIIb c e' R'=CH3) by heating them with lithium hydroxide solution for extended periods. The pyranone ring readily opens but the removal of the side chain acyl group is not easily effected. The heating must be prolonged and/or pressure must be used. An inert atmosphere is also helpful. In the case of the Compounds IIIa e (R'=H) the saponification of the 8-esters is much more facile proceeding to completion in about 20 hours. The 8hydroxy products are isolated by acidification and extraction with organic solvents which provides the hydroxy acid form, in which the pyranone ring is still opened. These hydroxy acids are relactonized by heating a solution of the acid in an appropriate organic solvent such as benzene or toluene in an apparatus permitting continuous separation of the water formed. The Compound IV (R'=H) is known as ML-236A as a reported by Endo et al in U.S. Patent 3,983,140. In their lactone form, these alcohols are the compounds of Formula IVae in Table I and are prepared as described in the following preparations. Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(R)- dimethyl-1' 2' 6',7', 8 'a (R) -hexahydronaphthyl-l ' (S))- ethyl] -4(R) -hydroxy-3 '4,5, 6-tetrahydro-2H-pyran-2-one, IVa (R'=CH3) A mixture of 8.0 g. (19.78 mmole) of MK-803 (IIIa, R'=CH3) and 8.31 g (197.8 mmole) of LioH.H2O in 600 ml of water was stirred at reflux under a nitrogen atmosphere for 56 hours. The reaction mixture was cooled to 0 and treated, with stirring, with 20 ml of concentrated hydrochloric acid. The mixture was then extracted with three 250-ml portions of ether and the combined extracts were washed successively with three 200-ml portions of water and then 200 ml of saturated brine. After drying over MgSO4, this organic solution was filtered and the solvent evaporated in vacuo to give an oily residue. This residue was dissolved in 200 ml of toluene and heated at reflux under a nitrogen atmosphere for 2 hours with-continuous separation of water to effect relactonization. Evaporation of the toluene and trituration of the residue with hexane gave 5.15 g (81%) of the title compound IVa (R'=CH3) as a white solid which did not require further purification. An analytical sample was prepared by recrystallization of a portion of this material from butyl chloride to give white clusters: m.p. 128-131 (vacuum); NMR(CDC13) s 0.87 (d,3,J=7Hz, CH3), 1.16 (d,3,J=7Hz, CH3), 2.64 (m,2,pyran C3H's), 4.27 (brm,l, naphthalene C8H), 4.37 (m,l,pyran C4H), 4.71 (m,l,pyran C6H), 5.56 (m,l, naphthalene C5H), 5.79 (dd,l, J=6,10 Hz, naphthalene C3H), 6.03 (d,l,J=lO Hz, naphthalene C4H); IR (CHCl3) 3400 (OH), 1725 (C=O), 1240, 1120, 1080cm Anal. Calcd for ClgH2804.O.lC4HgCl C, 70.67; H, 8.84. Found: C,70.77; H, 8.75. Alternative preparation of 6(R) - j2-181 (S)-hydroxy-21 (S), 6' (R)-dimethyl-l' ,2' ,6' 17' ,8' ,8'a (R)-hexahydronaphthyl- 1' (S)) ethyl)-4 (R) -hydroxy-3 '4,5, 6-tetrahydro-2H-pyran- 2-one, IVa (R' =CH3) A suspension of 188 mg (0.463 mmol) of MK-803 (IIIa, R'=CH3) in 5 ml (5 mmol) of aqueous 1N LioH solution is shaken for 12 hours at 1350 in a 30 ml stainless steel pressure vessel. The cooled reaction mixture is acidified with 1M H3P 04 and extracted with ethyl acetate. The ethyl acetate solution is dried (MgSO4) and filtered and the solvent is evaporated. The residue is dissolved in 20 ml of toluene which is heated to reflux for 4 hours in a Dean-Stark apparatus to effect relactonization. Evaporation of the toluene gives the title compound. Preparation of alcohols IVa (R'=H) and IVb, IVC, IVd, and IVe (R'=H or CH3) Following essentially either procedure described above but substituting an equivalent amount of esters IIIa(R'=H) or IIIb, IIIC, IIId, or 111e (R'=H or CH3), for III (R'=CH3) used therein the corresponding alcohols a IVa (R'=H), IVb, IVcl IVd and IVe (R1=H or CH3) are respectively obtained. We have found that the 8'-hydroxy compounds of Structure IV can be acylated to give a new class of 8-acyloxy compounds of the structure defined by Formulas I and II and the definitions thereunder. These new compounds are inhibitors of cholesterol synthesis in vivo. The absolute configuration of these compounds is known from X-ray diffraction. Table I provides a convenient tabulation of these structures and their stereochemical relationship. The reference numerals to the various compounds, including those of the various series of polyhydronaphthyl structures, remain the same throughout these specifications and are so used. Each of the esters Ia e (R'=CH3), of this invention contains seven or eight chiral centers. The relative and absolute configuration of these asymmetric centers is as depicted in Table I. More specifically, for ester 1a (R' =CH3), the Cahn, Ingold, Prelog designations for the absolute configurations are 4(R), 6(R), 1' (S), 2' (S), 6' (R) , 8' (S) and 8a1 (R) [R.S. Cahn, C.Ingold and V. Prelog, Angew.Chem.Int.Ed.,5, 385 (1966)]. EMI22.1 As is indicated in the formulas 1a-e' all of these compounds have the same spatial orientation of groups at each chiral carbon atom and therefore belong to the same stereochemical series. The R-S designation for each center may not be identical to that found for the ester 1a (R'=CH3) because of the details of the sequence rules used for determining that designation. In the two esters 1d and Ie which have an additional chiral carbon atom not present in ester Ia, the hydrogen atom at 4a' is in the down (or a) orientation as depicted in Table I, giving a trans ring junction. TABLE I THE COMPOUNDS OF THIS INVENTION AND THEIR STEREO-RELATIONSHIP EMI23.1 R'=H or CH3 STEREOCHEMISTRY OF THE HYDRONAPHTHYL SERIES EMI23.2 <tb> Series <SEP> Double <SEP> Bonds <SEP> Present <SEP> Structure <tb> <SEP> a <SEP> X <SEP> and <SEP> Z <SEP> w <tb> <SEP> b <SEP> x <tb> <SEP> c <SEP> R <SEP> W <tb> <SEP> d <SEP> Z <SEP> R <SEP> 4 <tb> <SEP> e <SEP> None <tb> The 8'-acyloxy compounds of this invention are useful as antihypercholesterolemic agents for the treatment of atherosclerosis, hyperlipemia and like diseases in humans. They may be administered orally or parenterally in the form of- a capsule, a tablet, an injectable preparation or the like. It is usually desirable to use the oral route. Doses may be varied, depending on the age, severity, body weight and other conditions of human patients but daily dosage for adults is within a range of from about 2 mg to 2000 mg (preferably 10 to 100 mg) given in three or four divided doses. Higher doses may be favorably applied as required. The compounds of this invention also have useful anti-fungal activities. For example, they may be used to control strains of Penicillium sp., Aspergillus niger, Cladosporium sp., Cochliobolus miyabeanus and Helminthosporium cynodnotis. For those utilities they are admixed with suitable formulating agents, powders, emulsifying agents or solvents such¯ as aqueous ethanol and sprayed or dusted on the plants to be protected. The preparation of the compounds of this invention is described in Flow Sheet A. FLOW SHEET A EMI25.1 Definitions - X,Y,Z,R and R' as defined in specification and series a-e as defined in Table I. Reactions 1) Lithium hydroxide, heat, acidify and lactonize 2) t-Butyldimethylchlorsilane and imidazole in DMF at ambient temperatures in an inert atmosphere. 3) Treatment with RCOC1 and 4-dimethylamino pyridine in pyridine solution preferably under inert atmosphere. 4) Treatment with RCOOH and N,N'-dicyclohexyl carbodiimide and 4-pyrrolidinopyridine in dichloromethane, preferably under an inert atmosphere. 5) Three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of ester in THF, preferably in an inert atmosphere. 6) Aqueous alkali followed by careful acidification with dilute acid. 7) See Reactions and Reagents and Flow Sheet for synthesis of IIIb c, e In the novel process of this invention the 4-hydroxyl on the pyranone ring, of alcohols IVa e is first protected with a t-butyldimethylsilyl group by reaction with t-butyldimethylchlorosilane in an inert atmosphere at ambient temperatures in the presence of an acid acceptor such as imidazole to provide the protected alcohols Va e. The 8-hydroxyl on the polyhydronaphthyl ring is then acylated in one of two ways. The first comprises treatment with the acid chloride of the desired acyl group in pyridine in the presence of 4-dimethylaminopyridine as a catalyst. The second comprises treatment of the 8'-polyhydronaphthol with the free acid of the desired acryl group and a carbodiimide such as N,N'-dicyclohexylcarbodiimide with 4pyrrolidinopyridine as a catalyst in dichloromethane. These procedures give the protected esters VIa e. The removal of the silyl protecting group from the 4-hydroxyl of the pyranone ring is then carried out, using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of esters VI a-e' to give the desired compounds 1a-e The ratio of reagents in this last reaction is critical to the yield of the process and the purity of the products. The acyl groups thus put on the 8'-hydroxyl are those in which R in Ia e is: 1) C1 10 straight, or branched chain alkyl except (S)-2-butyl, 2.) C3-10 cycloalkyl, 3) C2-10 alkenyl, 4) C1-10 CF3-substituted alkyl, 5) phenyl, 6) halophenyl, wherein halo is chloro, fluoro, bromo or iodo, 7) phenyl-C13 alkyl, 8) substituted phenyl-C13 alkyl in which the substituent is halo, such as fluoro, chloro, bromo, or iodo, C1-3 alkyl or C13 alkoxy. It is preferred that R' be CH3 Preferred definitions of R, are: C25 straight chain alkyl, C3 10 branched chain alkyl except (S)-2-butyl, C3-10 cycloalkyl, C3-10 alkenyl in which the unsaturation is not in conjugation with the carbonyl, especially C3-10 branched chain alkyl except (S)-2-butyl. Preferred species are those wherein R is l,l-diethylpropyl or l-ethyl-l-methylpropyl. And it is especially preferred that none of X, Y or Z is a double bond. Compounds Ia e can be hydrolyzed with bases such as NaOH to yield the salts such as the sodium salt of Compounds 11a-e The use of bases with other pharmaceutically acceptable cations affords salts of those cations. Careful acidification of the salts affords the hydroxy acids 11a-e which revert to Compounds 1a-e at acidic pH. Treating Compound Ia-e under acidic or basic catalysis with methanol, ethanol, propanol, or butanol or with phenyl-, dimethylamino-, or acetylamino-alkanols yields the corresponding esters of Compounds 11a-e which also form a part of this invention. The pharmaceutically acceptable salts of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, l-p-chlorobenzyl-2-pyrrolidine-l' -yl-methylbenzimidazole, diethylamine, piperazine, and tris(hydroxymethyl)aminomethane. EXAMPLE 1 6(R)- [2-(8' (S)-211,2'1-dimethylpropanoyloxy-21 (S) ,6' (R)- dimethyl-1',2',6',7',8',8'a(R)-hexahydronaphthyl-l'(S))- ethyl] -4(R) -hydroxy-3 '4,5, 6-tetrahydro-2H-pyran-2-one Step A: Preparation of 6(R)- [2-(8' (S)-hydroxy-2' (S)-6' (R)- dimethyl-1' ,2' ,6' ,7' ,8' ,8'a(R)-hexahydronaphthyl l'(S))ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)- 3,4,5,6-tetrahydro-2H-pyran-2-one, V a (R'=CH3) A mixture of the alcohol IVa (R'=CH3) (18.3 g, 57.1 mmol), 21.5 g (142.8 mmol) of tert-butyldimethylchlorosilane and 19.4 g (285.6 mmol) of imidazole in 200 ml of N,N-dimethylformamide was stirred at 200 under a nitrogen atmosphere for 18 hours. The reaction mixture was then diluted with 1500 ml of ether and washed successively with water, 2% aqueous hydrochloric acid, water and saturated sodium bicarbonate. The ether solution was dried over MgSO4, filtered and reduced to a volume of 1 L. After addition of 600 ml of hexane, the volume was reduced to 600 ml on a steam bath. The product crystallized at room temperature; after isolation and air drying this provided 13.7 g of a white cottony solid. The mother liquors were reduced to 250 ml and a second crop of crystals was isolated after this solution stood at 0 overnight. The combined yield was 17.13 g (69%) of the title compound as a white cottony solid: mp 142-1440(vac); NMR (CDC13) d 0.10 (s,6,(CH3)2Si),0.90 (s,9,(CH3)3CSi), 1.19 (d,3,J=7Hz, CH3), 2.58 (d, 2,J=4Hz,pyran C3H's), 4.3 (m,2,pyran C4H and naphthalene C8H) 4.70 (m, 1, pyran C6H), 5.57 (m,l,naphthalene C5H), 5.58 (dd,l, J=6,10Hz, naphthalene C3H),6.03 (d,l, J=lOHz, naphthalene C4H). Anal. Calcd. for C25H4204Si: C, 69.08, H, 9.74. Found: C, 69.46; H, 9.83. Step B: Preparation of 6(R)-[2-(8' (S)-2",2"-dimethyl propanoyloxy-2'(S),6'(R)-dimethyl-1',2',6',7', 8',8'a(R)-hexahydronaphthyl-1'(S))ethyl]-4(R)- (dimethyl-tert-butylsilyloxy) -3,4,5, 6-tetrahydro- 2H-pyran-2-one, VIa (R' =CH3) A solution of 6.0 g (13.8 mmol) of the alcohol Va( (R'=CH3) from Step A and 200 mg of 4-dimethylamino- pyridine in 50 ml of pyridine was cooled to 0 under a nitrogen atmosphere. To this stirred solution was added 6.8 ml (6.65 g, 55.2 mmol) of pivaloyl chloride over 15 minutes. The reaction mixture was stirred at 0 for 1 hour and then at 200 for 4 days. The reaction mixture was diluted with 750 ml of ether and washed with 2% aqueous hydrochloric acid until the wash was acidic and then with saturated NaHC03 solution. After drying over MgS04 the solution was filtered and evaporated to give 7.81 g of the title compound as a light orange oil: NMR (CDCl3) # C 0.09 (s,6(CH3)2Si), 0.88 (s,9,(CH3)3CSi), 1.28 (s,9, (CH3)3CC02-), 2.57 (d,2,J=4Hz, pyran C3H's), 4.32 (m, 1, pyran C4H), 4.63 (m,l, pyran C6H), 5.34 (m, 1, naphthalene C8H), 5.54 (m,l, naphthalene C5H), 5.78 (dd, 1, J=6, 10Hz, naphthalene C3H), 6.03 (d,l,J=lOHz, naphthalene C4H). Employing the procedure substantially as described in Example 1, Step B, but substituting for the pivaloyl chloride used therein, an equimolecular amount of the acid chloride of structure R-COC1 described in Table II, there are prepared the esters of structure Via (R'=CH3) also described in Table II. TABLE II EMI30.1 <tb> NMR(CDCl3 <SEP> ,) <tb> <SEP> 7.10(t,2,J=8Kz,p-FPh-) <tb> <SEP> 0""' <SEP> 8,03(dd,2,J=5,8Hz,p-FPh-) <tb> F <tb> CH3CO2- <SEP> 2.02(s,3,CH3CO2-) <tb> <SEP> 0 <tb> CH3 <SEP> 0- <SEP> -1.19 <SEP> (d,J=7Hz,a-CH3 <SEP> ester) <tb> <SEP> CH3 <SEP> 1.21(d,J=7Hz,a-CH3 <SEP> ester) <tb> <SEP> Total <SEP> 3H <tb> (CH3)2CHCH2CO2- <SEP> O.83(d,6,J=6Hz,(CH3)2CH-) <tb> (CH3)2CHCO2- <SEP> 1.13 <SEP> (d,6,J=6Hz(CH3)2CH) <tb> CH3(CH2)3CO2- <SEP> 0.95 <SEP> (t,3,J=7Hz,CH3-(CH2)3 <tb> <SEP> g <SEP> 2- <SEP> 1.60-2.08 <SEP> (m,15,Adamantyl) <tb> CH3 <SEP> (CH2) <SEP> 6CO2 <tb> C6H11 <SEP> CO2 <tb> CH2=CH- <SEP> C02 <tb> CF3 <SEP> (CH2) <SEP> 2CO2 <tb> C6H5C 2 <tb> 4-ClC6H4CO2 TABLE II (Cont'd.) EMI31.1 <tb> <SEP> 0 <tb> R-0-O <SEP> NMR(CDC13, <SEP> 6) <tb> 2 <SEP> , <SEP> 4-F2C6H3CO2 <tb> C6H5 <SEP> (CH2) <SEP> 3CO2 <tb> 4-FC6H4CH2CO2 <tb> 2,4-F2C6H3CH2C02 <tb> 4-ClC6H4CH2C02 <tb> 4-FC6H4 <SEP> (CH2) <SEP> 3C02 <tb> <SEP> CF <tb> CH,3 <tb> CH3CH-CH2C02 <tb> CH3 <SEP> CO2 <tb> CH <tb> <SEP> 3 <tb> <SEP> Dy <SEP> CO2 <tb> <SEP> CH3 <tb> CH3 <SEP> (CH2) <SEP> 8CO2 <tb> <SEP> CO <SEP> <tb> <SEP> ¹¸H32 <tb> Step C: Preparation of 6(R)- f2-(8' (S)-2",211-diraethyl- propanoyloxy-2'(S),6'(R)-dimethyl-1',2',6',7',8', 8' a (R) -hexahydronaphthyl-l' (S) ) ethyl]-4 (R) -hydroxy 3,4,5,6-tetrahydro-2H-pyran-2-one, Ia (R'=CH3) To a solution of 10.0 g (31.7 mmol) of Bu4N+F.3H2O and 2.4 ml (2.5 g, 42.3 mmol) of-acetic acid in 50 ml of tetrahydrofuran was added 7.81 g (13.8 mmol) of the silyl ether VIa (R'=CH3) from Step B in 50 ml tetrahydrofuran. This mixture was stirred at 200 under a nitrogen atmosphere for 18 hours. The reaction mixture was diluted with 700 ml of ether and washed successively with 2% aqueous hydrochloric acid, water and saturated aqueous NaHC03. The organic solution was dried (MgSO4) and filtered. Evaporation of the solvent left 6.45 g of an off-white solid. This material was crystallized from 100 ml of butyl chloride and the isolated crystals were dried at 350/0.01 mm for four hours to give 4.0 g (72%) of the title compound as nearly white needles: mp 167.5-170.5 (vac); NMR (CDCl3) d 0.88 (d,3,J=7Hz,CH3), 1.08 (d,3,J=7Hz, CH3), 1.19 (s,9,(CH3)3C), 2.67 (d,2,J=4Hz, pyran C3H's), 4.39 (m,l,pyran C4H), 4.65 (m,l,pyran C6H), 5.36 (m,l, naphthalene C8H) 5.55 (m,l,naphthalene C5H), 5.80 (dd,l,J=6,10Hz, naphthalene C3H), 6.04 (d,l,J=lOHz, naphthalene C4H); HPLC (4.6 mm. x 25 cm Partisil 10 PAC, 10% isopropanol/hexane, 4 ml/min) retention time 4.4 min. Anal. Calcd. for C24H36O5: C,71.25; H, 8.97. Found: C,71.40; H, 8.93. Employing the procedure of Example 1, Step C, but substituting for the 2,2-dimethylpropanoyloxy-silyl ether Compound VI a (Rr=CH3) used therein, an equimolecular amount of the other esters of structure via (R'=CH3) described in Table II, there are prepared the esters of structure 1a (R' =CH3), described in Table III. TABLE III EMI33.1 <tb> RCO2- <SEP> Formula <SEP> MP(OC) <tb> <SEP> CO2- <SEP> C24H36O5 <SEP> 139-148 <tb> <SEP> CH3 <tb> <SEP> CO <SEP> <tb> <SEP> C26H31FO5 <SEP> 119.5-120.5 <tb> <SEP> (vac) <tb> (CH3)2CHCH2CO2- <SEP> C24 <SEP> 36 <SEP> 5 <SEP> 126-128 <tb> (CH3)2CHC02- <SEP> C23 <SEP> 34 <SEP> 5 <SEP> 144-147 <tb> CH3(CH2)3C02- <SEP> 24 <SEP> 36 <SEP> 5 <tb> CH3CO2- <SEP> C21H30O5.O.1C4H9 <SEP> 153-156 <tb> <SEP> (vac) <tb> <SEP> /r <SEP> COa <tb> <SEP> C3 <SEP> OHq <SEP> 205 <SEP> ' <SEP> 0. <SEP> 05C,H, <SEP> 2 <SEP> 155-158 <tb> CH3 <SEP> (CH2) <SEP> 6C02 <tb> C6H11CO2 <tb> CH2=CH-C02 <tb> CF3 <SEP> (CH2) <SEP> 2C 2 <tb> TABLE III (Cont'd.) EMI34.1 <tb> RC02- <SEP> Formula <SEP> MP <SEP> COC) <tb> C6H5CO2 <tb> 4-C1C6H4CO2 <tb> 2, <SEP> 4-F2 <SEP> C6H3 <SEP> CO2 <tb> C6H5 <SEP> (CH2) <SEP> 3CO2 <tb> 4 <SEP> -FC6H4 <SEP> CH2 <SEP> CO2 <tb> 2,4-F2C6H3CH2C02 <tb> 4-ClC6fl4CH2CO2 <tb> 4-FC6H4 <SEP> (CH2) <SEP> 3CO2 <tb> <SEP> CF3 <tb> CH3H-CH2CO2 <tb> CH3 <SEP> H-CH2C02 <tb> CHM <tb> <SEP> 3 <tb> <SEP> ;¸CO2 <SEP> <tb> <SEP> CH3 <tb> CH3 <SEP> (CH2) <SEP> 8CO2 <tb> <SEP> co2 <tb> CH3 <SEP> < <SEP> CH3 <tb> <SEP> H <tb> EXAMPLE 2 6(R)- L2-(8' (S)-phenylacetoxy-2' (S) ,6' (R) -dimethyl-l', 2' ,6' ,7',8' ,8a' (R)-hexahydronaphthyl-l' (S))ethyl]-4-(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-on Step A: Preparation of 6(R)-12-(8' (5)-phenylacetoxy- 2'(S),6'(R)-dimethyl-1' ,2 ,6',7',8',8'a (R)- hexahydronaphthyl-l' (S))ethyl]-4(R)-dimethyl- tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H- pyran-2-one, via (R' =CH3) A solution of 434 mg (1.0 mmol) of the alcohol V a (R'=CH3) from Example 1, Step A, 204 mg (1.5 mmol) of phenylacetic acid, and 309 mg (1.5 mmol) of N,N'-dicyclohexylcarbodiimide in 10 ml of dichloromethane was treated with 22 mg (0.15 mmol) of 4-pyrrolidinopyridine and stirred at 200 under a nitrogen atmosphere. After 3 days the solvent was removed in vacuo and the residue was suspended in 25 ml of ether and filtered. Evaporation of the filtrate gave a viscous oil which was chromatographed on a 3 x 15 cm. column of silica gel (230-400 mesh). Elution (under air pressure) with ether-hexane (l:l,v:v) gave 460 mg (83%) of the title compound as a viscous oil: NMR (CDC13) 6 0.10 (s,6,(CH3)2Si), 0.90 (s,9,(CH3)3CSi) 3,58 (s,2,PhCH2-) 5.34 (m,l,naphthalene C8H), 7.30 (s,5,Ph). Employing the procedure of Example 2, Step A, but substituting for the phenylacetic acid used therein, an equimolecular amount of the organic acids of structure R-COOH described in Table IV there are produced the esters of structure via (R' =CH3) also described in Table IV. TABLE IV EMI36.1 <tb> <SEP> 0 <tb> R-C-O- <SEP> NMR(CDC13, <SEP> ) <tb> <SEP> CO2 <SEP> 0.78-1.02(m,4,cyclopropane) <tb> <SEP> CF3 <SEP> 1.04(d,3,J=7Hz,CH3CHCF3) <tb> <SEP> CH3CH-CH2CO2 <tb> <SEP> CH3 <SEP> CO2- <SEP> 1.88(s,3,CH3C=C) <tb> <SEP> 2.17(d,3,J=2Hz,CH3C=C) <tb> <SEP> g <SEP> 5.68 <SEP> (brs,l,C=CH-) <tb> <SEP> CH3 <tb> <SEP> CH, <tb> <SEP> < <SEP> CO2- <SEP> 1.80 <SEP> (s,3,CH3C=C) <tb> <SEP> CH3 <SEP> 4.86,4.92(s,2,CH2=C) <tb> <SEP> 0 <SEP> 87(mt3tCH3(CH2)8C02-) <tb> <SEP> CH3(CH2)8CO2 <SEP> 1.25(mtl4cH3(cH2)7cH2co2-) <tb> <SEP> CO2 <tb> <SEP> CH33"! <tb> <SEP> H <SEP> CH3 <tb> TABLE IV (Cont'd.) EMI37.1 <tb> <SEP> 0 <tb> R- <SEP> NMR(CDC13, <SEP> 6 <tb> <SEP> C02 <tb> C <SEP> 3C <SEP> 2 <tb> <SEP> 0 <tb> CHffi·O <tb> <SEP> CH3 <tb> (CH3) <SEP> 2CHCH2CO2 <tb> (CH3) <SEP> 2CHCO2 <tb> CH3(CH2)3Co2 <tb> <SEP> C <tb> <SEP> XC- <SEP> -CO2 <tb> <SEP> DC-C02 <tb> <SEP> & CO2 <tb> <SEP> C'C02 <tb> <SEP> 1 <tb> <SEP> 7 <tb> <SEP> CFCO2 <tb> CH3 <SEP> (CH2) <SEP> 6CO2 <tb> C6 <SEP> 11 <SEP> 2 <tb> CH2=CH- <SEP> C02 <tb> CF3 <SEP> (CH2) <SEP> 2C02 <tb> C6H5C02 TABLE IV (Cont'd) EMI38.1 <tb> R-lOC-O <SEP> NMR <SEP> (CDCL3, <SEP> J <SEP> ) <tb> 4-ClC6H4CO2 <tb> 2,4-F2C6H3C02 <tb> C6H5 <SEP> (CH2)3C02 <tb> 4-FC6H4CH2CO2 <tb> 2,4-F2C6H3CH2C02 <tb> 4-ClC6H4CH2CO2 <tb> 4-FC6H4 <SEP> (CH2) <SEP> 3C 2 <tb> Step B: Preparation of 6(R)-[2-(8' (S)-phenylacetoxy 2' (S) ,6' (R) -dimethyl-l' , 2',6',7',8',8' a(R)- hexahydronaphthyl-1'(S)) ethyl] -4(R) -hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one, 1a (R'=CH3) Employing the procedure substantially as described in Example 1, Step C, but substituting for the propanoyloxy compound used therein an equimolar amount of the phenylacetoxy compound from Example 2, Step A, there is produced the title compound, m.p. 109 1120C. Employing the other esters, via (R'=CH3) described in Example 2, Step A, (Table IV) and following the procedure of Example 2, Step B, there are produced the esters of structure Ia (R'=CH3) described in Table V. TABLE V EMI38.2 <tb> RC02 <SEP> Formula <SEP> rap. <SEP> (C0) <tb> <SEP> -CO2- <SEP> C23H32 5 <SEP> 116-119 <tb> <SEP> CF <tb> <SEP> J <tb> CE3CHCH2C02- <SEP> C24H33F3O5 <SEP> 110-113 <tb> TABLE V (Cont'd.) EMI39.1 <tb> RC02 <SEP> Formula <SEP> m.p.( C) <tb> CHMuCO2 <SEP> C24H34O5 <SEP> 113-118 <tb> CIE <tb> <SEP> CH, <tb> <SEP> ; ;¸C02 <SEP> <tb> CH3 <SEP> C24H3405 <SEP> 116-119 <tb> CH3(CH2)8C02 <SEP> C29H4605 <SEP> (wax) <tb> <SEP> CO2 <tb> CH <SEP> / <SEP> x, <SEP> C24 <SEP> 36 <SEP> 5 <SEP> 126-129 <tb> <SEP> L <tb> <SEP> F <tb> CH3C02 <tb> <SEP> 0 <tb> CH¹ <tb> <SEP> CH3 <tb> (CH3) <SEP> 2CHCH2CO2 <tb> (CH3) <SEP> 2CHCO2 <tb> CH3(CH2)3C02 <tb> TABLE V (Cont'd.) EMI40.1 <tb> RC02 <SEP> Formula <SEP> m.p.(OC) <tb> cvF- <SEP> C02' <tb> RC- <SEP> CO <SEP> <tb> C- <SEP> CO2 <tb> & BR< <tb> <SEP> C1 <SEP> -CO <SEP> <SEP> 2 <tb> <SEP> .c- <SEP> <SEP> 2 <tb> CH3 <SEP> (CH2) <SEP> 6CO2 <tb> C6H11CO2 <tb> CH2=CH- <SEP> CO2 <tb> CF3(CH2)2C02 <tb> C6H5 <SEP> CO2 <tb> 4-ClC6H4CO2 <tb> 2,4-F2C6H3C02 <tb> C6H5 <SEP> (CH2) <SEP> 3CO2 <tb> 4-FC6H4CH2C02 <tb> 2,4-F2C6H3CH2C02 <tb> 4-ClC6H4CH2C02 <tb> 4-FC6H4 <SEP> (CH2) <SEP> 3CO2 EXAMPLE 3 6(R)-f2-(8' (s)-2'1-ethyl-2"-raethylbutyryloxy-2' (S)-6' (R)- dimethyl-1' 2' 6' r7',8',8' a(R) -hexahydronaphthyl-1 ' (S))- ethyl] -4(R) -hydroxy-3, 4,5, 6-tetrahydro-2H-pyran-2-one Step A: Preparation of 6(R)-[2-(8'(S)-2"-ethyl-2" methylbutyryloxy-2' (S)-6 (R) -dimethyl-l ',2',6', 7',8',8'a(R)-hexahydronaphthyl-l'(S))ethyl]-4(R)- (dimethyl-tert-butylsilyloxy)-3,4,5,6-tetra- hydro-2H-pyran-2-one Via (R'=CH3) 3.0 g of 2-ethyl-2-methylbutyryl chloride (20 mmol) was added to a magnetically stirred solution of 2.17 g (5 mmol) of alcohol Va (R' =CH3) and 74 mg of 4pyrrolidino pyridine in 20 ml of pyridine. This reaction mixture was stirred at 1000C under an atmosphere of N2 for nine hours. The reaction mixture was diluted with 500 ml ether and washed with 1N HC1 until the wash was acidic and then with brine (3 x 50 ml). After drying over MgS04, the solution was filtered and evaporated to give 4.2 g of a brown oil. This oil was chromatographed on a 6 x 15 cm column of silica gel (230-400 mesh). Elution (under air pressure) with ether-hexane (1:1, v:v) gave 2.6 g (95%) of the title compound as a viscous yellow oil: NMR (CDCl3) d 0.08(s,6,(CH3)2Si), O.9(s,9,(CH3)3 CSi), 2.57(d,2,J=4Hz, pyran C3H's), 4.30(m,l,pyran C4H), 4.63(m,l,pyran C6H), 5.42(m,l,naphthalene C8H), 5.53(m,1, naphthalene C5H), 5,78(dd,l,J=6,Hz,lOHz, naphthalene C3H), 6.03(d,l,J=10Hz, naphthalene C4H). Employing the procedure substantially as described in Example 3, Step A, but substituting for the 2-ethyl-2-methylbutyryl chloride used therein, an equimolecular amount of the acid chlorides of structure R-COC1, described in Table VI, there are produced the esters of structure VIa (R'=CH3) also described in Table VI. TABLE VI EMI42.1 <tb> <SEP> 0 <tb> R <SEP> NMR(CDC13, <tb> <SEP> U <SEP> C-C02- <SEP> 0.87(m,91CH3CH2CH2(CH3CH2) <SEP> 2CCO2) <tb> <SEP> C-Co2- <SEP> 0.78(t,9,J=7Hz,(CH,CH,)3CC02) <tb> <SEP> --J <tb> <SEP> 1.48(q,6,J=7Hz, <SEP> (CH3CH2) <SEP> 3CCO2) <tb> <SEP> )·CO2 <tb> <SEP> )¯c¯C02¯ <SEP> 1.28(s,6,(CH3)2CC02) <tb> <SEP> 2.20(s,3,CH3-C-CH2) <tb> <SEP> 3.86(m,2,CH2=C) <tb> <SEP> m <tb> <SEP> -¯C-C02- <SEP> 1.l2(s,6, <SEP> (CH3)2CCO2) <tb> <SEP> 0.83(t,3,(CH3CH2CC02) <tb> Step B: Preparation of 6 CR)- I2-(8' (S) -2"-ethyl-2"-methy1- butyryloxy-2'(S)-6'(R)-dimethyl-1',2',6',7',8',- 8 'a-(R)-hexahydronaphthyl-1' (S) )ethyl]-4 (R) hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one Employing the procedure substantially as described in Example 1, Step C, or Example 2, Step B, but employing as starting material the silyl ether compound from Example 3, Step A, there is produced the title compound, m.p. lll-1130C (C26H4005). Similarly prepared are the esters of structure 1a described in Table VII, employing as starting materials the other esters Via (R'=CH3) described in Table VI. TABLE VII EMI43.1 <tb> RC02- <SEP> Formula <SEP> m.p. <SEP> (0C) <tb> <SEP> C-CO2- <SEP> C28H4405 <SEP> 81-83 <tb> -CO <SEP> 2 <SEP> C27H42O5 <SEP> 129-132 <tb> <SEP> ,xC-C02- <SEP> C26H3805 <SEP> 75-78 <tb> <SEP> -C-C02- <SEP> C25 <SEP> 38 <SEP> 5 <SEP> 135-138 <tb> Employing the procedures of Example 1, Step A, followed by Example 1, Steps B and C, or Example 2 or 3, Steps A and B, but substituting for the diol of structure IVa (R'=CH3) in Example 1, Step A, the corresponding diols of structure IVa (R'=H) or IVb,c,d, or e (R'=H, or CH3), there are produced in sequence the silyl ethers of structures V a (R'=H) or V,c,d, and e (R'=H, or CH3), the esters of structure via (R'=H) or VIb,c,d1 and e (R'=H, or CH3), and the novel esters of structures 1a (R'=H) or Ib,c,d and e (R'=H or CH3) in accordance with Flow Sheet A, wherein EMI43.2 of the 8'-alkanoyl group is: : EMI44.1 4-ClC6H4CO2- 2,4-F2C6H3C02 C6H5(CH2)3CO2- (CH3)2CHCH2C02 4-FC6H4CH2C02 (CH3) 2CHCO2- 2,4-F2C6H3CH2CO2- CH3 (CH2) 3CO2- 4-ClC6H4CH2CO2- EMI44.2 CH3(CH2)6C02- C6H11CO2- CH2=CH- CO2- CF3 (CH2) 2CO2- C6H5CO2- 4-FC6H4 (CH2) 3CO2- EMI44.3 EMI45.1 EXAMPLE 4 Preparation of 6 (R)- #2- [ 6(R)-t2-t8(S)(2"-ethyl-2"-methylbutyryl- oxy)-2'(S),6'(S)-dimethyl-1',2',3',4',4'a(S),5',6',7',8', 8'a(S)-decahydronaphthyl-l'(S)]ethyl3-4(R)hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one, 1e (R'=CH3) Step A. Preparation of 6(R)- f2-(8' (S)hydroxy-2' (S), 6'(S)dimethyl-1',2',3',4',4'a(S),5',6't7',8', 8'a(S)-decahydronaphthyl-l'(S))ethyl]-4(R)- hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one IVe (R' =cH3) A solution of 2.0 g (6.2 mmol) of the alcohol IVa (R' =CH3) in 100 ml of ethyl acetate was hydrogenated in the presence of platinum oxide (1 g) at 40 lbs. pressure until an uptake of two mole equivalents of hydrogen was observed. The catalyst was removed by filtration and the filtrate was evaporated to dryness to provide a white solid (1.9 g) which was chromatographed on a 6 x 20 cm column of silica gel (230-400 mesh). Elution (under air pressure) with acetone-methylene chloride (3:7, v:v) gave 1.0 g (50%) of the title compound as a colorless solid. An analytical sample was prepared by recrystallization of a portion of the material from chloroform to give a white cottony solid: m.p. 166-8 . Step B: Preparation of 6(R)-[2-(8' (S)-hydroxy-2' (S), 6'(S)-dimethyl-1',2t,3',4',4'a(S),5',6',7', 8' ,8'a(S)-decahydronaphthyl-l' (S)-ethyl]-4 (R) - (dimethyl-tert-butylsilyloxy) 3,4,5, 6-tetrahydro- 2H-pyran-2-one, Ve (R'=CH3) A solution of the alcohol IVe (R'=CH3) (1.0 g, 3.1 mmol), imidazole (1.05 g, 15.4 mmol) and tert-butyldimethylchlorosilane (1.16 g, 7.7 mmol) in 20 ml of N,Ndimethyl formamide was stirred at 200 under a nitrogen atmosphere for 18 hours. The reaction solution was diluted with 200 ml of ether and washed successively with water, 2% aqueous hydrochloric acid and brine. The ether solution was dried over MgS04 and evaporated to provide a white solid (1.8 g) which was chromatographed on a 6 x 20cm column of silica (230-400 mesh). Elution under air pressure with acetone:methylene chloride (1:19, v:v) gave 1.0 g (748) of the title compound as a white solid: m.p. 136 1380C. Step C: Preparation of 6(R)-i2t8'(S)(2"-ethyl-2"- methylbutyryloxy)-2' (S) ,6' (S)-dimethyl-l' ,2', 3',4',4'a(S),5',6',7',8',8'a(S)-decahydro- naphthyl-l'(S)]ethyl}-4(R)(dimethyl-tert- butylsilyloxy) -3,4,5, 6-tetrahydro-2H-pyran-2- one VI (R'=CH3) e CH3) By substituting an equimolar amount of alcohol V (R'=CH3) for alcohol V a (R'=CH3) in Step A of Example 3 and following the procedure for Step A there was obtained a corresponding amount of the title compound, VIe (R'=CH3) as a yellow oil. NMR(CDC13) 0.08(S,6,(CH3)2Si) , 0.90 (S,9,(CH3)3)CSi), 1.13 (S,6,(CH3)2C02), 2.63(m,2,pyran C3H's), 4.33 (m,lfpyran C4H), 4.60(m,l,pyran C6H), 5.23 (m,l,naphthalene C8H1. Step D: Preparation of 6(R)-2-f8'(S)(2'1-ethyl- 2"-methylbutyryloxy)-2'(S),6(S)-dimethyl-1',2',3', 4,4'a(S),5',6',7',8',8'a(S)-decahydronaphthyl- 1'(S)]ethyl} -4 (R)-hydroxy-3,4 ,5,6-tetrahydro- 2H-pyran-2-one, 1e (R' =CH3) By substituting an equimolar amount of the silyl ether Vle (R'=CH3) from Example 4, Step C for the silyl ether in Step C of Example 1 and following the procedure for Step C of Example 1 there was obtained a corresponding amount of the title compound as a solid. An analytical sample was prepared by recrystallization of the material from hexane to obtain white needles: m.p. 146-1470C. Employing the procedure substantially as described in Example 4 Steps A through D, but substituting for the diol of structure IVa (R'=CH3) in Step A, an equimolecular amount of the diol of structure IVa (R'=H) there are produced in sequence the compounds: IVe (R'=H) in Step A; V (R'=H) in Step B; Vie (R'=H) in Step C; and 1e (R'=H) in Step D. EXAMPLE 5 6(R)-2-i8' [8'(S)- (2"-ethyl-2"-methylbutyryloxy)-2' (S), 6'(R)-dimethyl-1',2',3',4',6',7',8'atS)-octahydro- naphthyl-l' (S) J ethyl -4 (R)-hydroxy-3 '4,5, 6-tetrahydro- 2H-pyran-2-one, Ib (R'=CH3) Step A: Preparation of 6(R)- [2-(8' (S)-hydroxy-2' (S), 6'(R)-dimethyl-1'2',3',4',6',7',8'a(S)- octahydronaphthyl-1'(S)-ethyl] -4(R) hydroxy- 3,4,5,6-tetrahydro-2H-pyran-2-one, IVb (R'=CH3) Employing the procedure substantially as described for the preparation of the starting material IVa (R'=CH3) by hydrolysis of MK-803 with refluxing aqueous LioH.H2O for 56 hours but substituting for the MK-803 an equimolecular amount of compound IIIb (R'=CH3) there is produced, in comparable yield, the title compound IVb (R'=CH3), m.p. 136-1390C. Following the procedure of Example 4, Steps B, C, and D, but substituting for the compound IVe (R'=CH3) used in Step B thereof, an equimolecular amount of compound IVb (R'=CH3) from Step A of this example, there is produced in comparable yields to those experienced in Example 4, the following compounds: Step B: 6(R)-f2-(8'(S)-hydroxy-2' (S),6' (R)-dimethyl- 1',2',3',4',6',7',8'a(S)-octahydronaphthyl- 1'(S)-ethyl]-4 (R)- (dimethyl-tert-butylsilyloxy) - 3,4,5,6-tetrahydro-2H-pyran-2-one, Vb (R' =CH3), m.p. 140-1420C. Step C: Hz2 " - 6(R)-%2- (S)-(2"-ethyl-2"-methylbutyryloxy) 2'(S),6' (R)-dimethyl-1',2',3',4',6',7',8'a(S)- octahydronaphthyl-l'(S)]ethyi5) -4(R)-(dimethyl tert-butylsilyoxy)-3,4,5,6-tetrahydro-2H-pyran- 2-one, VI(b) (R'=CH3) wherein EMI49.1 Step D: 6(R) -2- [8' (S) (2"-ethy-2"-raethy1butyryloxy)- 2' CS),6' (R)-dimethyl-1',2' ,3',4',6',7' ,8'a(S) octahydronaphthyl-l' (S) j ethyl -4(R) hydroxy- 3,4 ,5,6-tetrahydro-2H-pyran-2-one, Ib (R'=CH3) m.p. 129-1310C. wherein EMI49.2 Following the procedure substantially as described in Example 5, but using 111b (R'=H) or IIIC, IIId, or IIIc (R'=H or CH3) as starting material in place of IIIb (R'=CH3) there are produced in turn compounds IVb (R'=H) or IVc, d, e (R'=H or CH3), Vb (R'=H) or V (R'=H or CH3), vib (R'=H) or VIc,d,e (R'=H or CH3), and 1b (R1=H) or 1c,d,e (R'=H or CH3) wherein EMI49.3 EXAMPLE 6 Typical formulations for filling a size 0 hard gelatin capsule comprise 3.125, 6.25, 12.5, 25 or 50 mg of one of the novel compounds of this invention such as the products of Example 3, Step B, Example 1, Step C, or Example 2, Step B and sufficient finely divided lactose to provide a total capsule content of about 580-590 mg.

Claims: WHAT IS CLAIMED IS: 1. A process for the preparation of a compound of structural formula: EMI50.1 wherein R' is H or CH3; R is (1) C1-10 straight or branched chain alkyl except 2-(S)-butyl, (2) C3¯10 cycloalkyl, (3) C2-10 alkenyl, (4) C1-10 CF3- substituted alkyl, (5) phenyl, (6) halophenyl, (7) phenyl-Cl 3 alkyl, (8) substituted phenyl-Cl 3 alkyl in which the substituent is halo, C13 alkyl or C1-3 alkoxy; the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or X, Y or Z alone; and the corresponding dihydroxy acids of the formula: EMI51.1 or a pharmaceutically acceptable salt of said acids, a C14 alkyl ester of said acids or a phenyl-, dimethylamino-, or acetylamino-substituted-Cl 4 alkyl esters of said acids, which comprises 1) heating a compound of formula: EMI51.2 with an alkali metal hydroxide in a protic solvent followed by acidification and lactonization to give compound IVa¯e; 2) reacting the compound of the structure: EMI51.3 IV a-e with t-butyldimethylchlorosilane under an inert atmosphere at ambient temperature in the presence of an acid acceptor; 3) acylating the resulting 4-t-butyldimethylsilyloxy compound by: : a) stirring it in solution with an acid chloride, RCOCl, in pyridine in an inert atmosphere in the presence of an acylation catalyst, or b) stirring it in solution at ambient temperature with an acid, RCOOH, and N,N dicyclohexylcarbodiimide in the presence of an acylation catalyst, and 4) removing the silyl group by stirring at ambient temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of silyl compound J and, if desired, treating the resulting compound I e with a base, it desired, followed by a-e careful acidification with dilute acid, or, if desired w treating the resulting compound Ia e with. a C1 -alkanol or with a phenyl-, dimethyl-amino-, or acetylamino C 1-4 alkanol. 2. The process of Claim 1 wherein R' is CH3. 3. The process of Claims 1 or 2 wherein R is C310 branched alkyl except 2(S)-butyl, especially 1-ethyl-1-methyl propyl or 1,1-diethylpropyl. 4. The process of Claims 1,2 or 3 wherein none of X,Y or Z is a double bond. The process of Claim 2 for the preparation of a compound of formula: EMI52.1 6. The process of Claim 1 for the preparation of a compound of structural formula: EMI53.1 in which R is (1) C1 10 straight or branched chain alkyl except 2-(S)-butyl, (2) C3-10 cycloalkyl, (3) C2-10 alkenyl, (4) C1-10 CF3-substituted alkyl, (5) phenyl, (6) halophenyl, (7) phenyl-C13 alkyl, (8) substituted phenyl-Cl 3 alkyl in which the substituent is halo, C1-3 alkyl or C13 alkoxy; and the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or X, Y or Z alone; and the corresponding dihydroxy acids of the formula. EMI53.2 or a pharmaceutically acceptable salt of said acids, a C14 alkyl ester of said acids or a phenyl-, dimethylamino-, or acetylamino-substituted-Cl 4 alkyl esters of said acids, which comprises 1) reacting a compound of the structure: EMI54.1 with t-butyldimethylchlorosilane under an-inert atmosphere at ambient temperature in the presence of an acid acceptor, 2) acylating the resulting 4-t-butyldimethylsilyloxy compound by: : a) stirring it-in solution with an acid chloride, RCOC1, in pyridine in an inert atmosphere in the presence of an acylation catalyst, or b) stirring it in solution at ambient temperature with an acid, RCOOH, and N,N dicyclohexylcarbodiimide in the presence of an acylation catalyst, and 3) removing the silyl group by stirring at ambient temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of silyl compound, and, if desired, treating the resulting compound Ia e with a base, if desired, followed by careful acidification with dilute acid, or, if desired, treating the resulting compound Ia e with a C 1-4 -alkanol or with a phenyl-, dimethyl-amino-, or acetylamino C1 4 alkanol. 7. The process of Claim 6 wherein R' is CH3 8. The process of Claims 6 or 7 wherein R is C3-10 branched alkyl except 2(S)-butyl, especially l-ethyl-l-methyl propyl or l,l-diethylpropyl. 9 The process of Claims 6,7 or 8 wherein none of X, Y or Z is a double bond. 10. A compound of the formula: EMI55.1 wherein R' is H or CH3; R is (1) C1-10 straight or branched chain alkyl except 2-(S)-butyl, (2) C3-10 cycloalkyl, (3) C2¯10 alkenyl, (4)C1-10 CF3-substituted alkyl, (5) phenyl, (6) halophenyl, (7) phenyl-cl 3 alkyl, (8) substituted phenyl-Cl 3 alkyl in which the substituent is halo, C1-3 alkyl or C13 alkoxy; the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or X, Y or z alone; and the corresponding dihydroxy acids of the formula: EMI56.1 or a pharmaceutically acceptable salt of said acids, a C1-4 alkyl ester of said acids or a phenyl-, dimethyl-amino-, amino-, or acetylamino-substituted-Cl 4 alkyl esters of said acids. 11. The compound of Claim 10 wherein R' is CH3. 12. The compound of Claims 10 or.11 wherein R is C3-10 branched chain alkyl except 2tS)-butyl, especially is 1-ethyl-1-methylpropyl or 1,1-diethylpropyl. 13. The compound of Claims 10 11 or12 wherein none of X, Y or Z is a double-bond. 14. A compound of the formula: EMI57.1 in which the dotted lines X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or one of X, Y or Z alone. 15. A pharmaceutical antihypercholesterolemic composition comprising a pharmaceutical carrier and an antihypercholesterolemic effective amount of a compound of any one of claims 10 to 14. Claims for Austria 1. A process for the preparation of a compound of structural formula: EMI58.1 wherein R' is H or CH3; R is (1) C1 10 straight or branched chain alkyl except 2-(S)-butyl, (2) C3 10 cycloalkyl, (3) C2¯10 alkenyl, (4) C1-10 substituted alkyl, (5) phenyl, (6) halophenyl, (7) phenyl-C1-3 a lkyl, (8) substituted phenyl-Cl 3 alkyl in which the substituent is halo, C1-3 alkyl or C13 alkoxy; the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or X, Y or Z alone; and the corresponding dihydroxy acids of the formula: EMI59.1 or a pharmaceutically acceptable salt of said acids, a C1 4 alkyl ester of said acids or a phenyl-, dimethylamino-, a C14 or acetylamino-substituted-Cl 4 alkyl esters of said acids, which comprises 1) heating a compound of formula: EMI59.2 with an alkali metal hydroxide in a protic solvent followed by acidification and lactonization to give compound IV 2) reacting the compound of the structure: EMI59.3 iCh t-butyldimethylchlorosil2ne under an inert atmosphere at ambient temperature in the presence of an acid acceptor; 3) acylating the rcsulting 4-t-butyldimethylsilyloxy compound by: : a) stirring it in solution with an acid chloride, RCOC1, in pyridine in an inert atmosphere in the presence of an acylation catalyst, or b) stirring it in solution at ambient temperature with an acid, RCOOH, and N,N dicyclohexylcarbodiimide in the presence of an acylation catalyst, and 4) removing the silyl group by stirring at ambient temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of silyl compound, and, if desired, treating the resulting compound I e with a base, if desired, followed by a-e careful acidification with dilute acid, or, if desired, treating the resulting compound 1a-e with a C 1-4 alkanol or with a phenyl-, dimethyl-amino-, or acetylamino C1 alkanol. 2. The process of Claim 1 wherein R' is CH3. 3. The process of Claims 1 or 2 wherein R is C3-10 branched alkyl except 2(S)-butyl, especially 1-ethyl-1-methyl propyl or 1,1-diethylpropyl. 4. The process of Claims 1, 2 or 3 wherein none of X, Y or Z is a double bond. 5. The process of Claim 2 for the preparation of a compound of formula: EMI60.1 6. The process of Claim 1 for the preparation of a compound of structural formula: EMI61.1 in which R is (1) C1-10 straight or branched chain alkyl except 2-(S)-butyl, (2) C,-10 cycloalkyl, (3) C2-10 alkenyl, (4) C1-10 CF3-substituted alkyl, (5) phenyl, (6) halophenyl, (7) phenyl-Cl 3 alkyl, (8) substituted phenyl-C1-3 alkyl in which the substituent is halo, C13 alkyl or C13 alkoxy; and the dotted lines at X, Y and Z represent possible double bonds, said double bonds, when any are present, being either X and Z in combination or X, Y or Z alone; and the corresponding dihydroxy acids of the formula: EMI61.2 or a pharmaceutically acceptable salt of said acids, a C1 alkyl ester of said acids or a phenyl-, dimethylamino-, or acetylamino-substituted-Cl 4 alkyl esters of said acids, which comprises 1) reacting a compound of the structure: EMI62.1 with t-butyldimethylchlorosilane under an inert atmosphere at ambient temperature in the presence of an acid acceptor, 2) acylatingxthe resulting 4-t-butyldimethylsilyloxy compound by: : a) stirring it-in solution with an acid chloride, RCOC1, in pyridine in an inert atmosphere in the presence of an acylation catalyst, or b) stirring it in solution at ambient temperature with an acid, RCOOH, and NtN- dicyclohexylcarbodiimide in the presence of an acylation catalyst, and 3) removing the silyl group by stirring at ambient temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylamonium fluoride and 4 equivalents of acetic acid per equivalent of silyl compound , and, if desired, treating the resulting compound Ia-e with a base, if desired, followed by careful acidification with dilute acid, or, if desired, treating the resulting compound I with a C1 -alkanol or with a phenyl-, a-e 1-4 dimethyl-amino-, or acetylamino C 1-4 alkanol. 7. The process of Claim 6 wherein R' is CH3. 8. The process of Claims 6 or 7 wherein R is C3 10 branched alkyl except 2(S)-butyl, especially 1-ethyl-1-methyl propyl or 1,1-diethylpropyl. 9. The process of Claims 6, 7 or 8 wherein none of X, Y or Z is a double bond.

Inventors: HOFFMAN, WILLIAM F., SMITH, ROBERT L., WILLARD, ALVIN K.
Applicants: MERCK & CO. INC.
Application year: 1981
Main classification: C07D309
IPC codes: C07D309