Title of Invention

PROCESS FOR THE PREPARATION OF VITAMIN D ANALOGUES

Abstract

A stereospecific method for accomplishing the below reaction: results in the compound of formula 2 having the same stereochemistry at both carbon 1 and carbon 3 as that in the compound of formula 1. Thus, if carbon 3 is in the R- configuration in the compound of formula 1, then carbon 3 will be in the R-configuration in the compound of resulting formula 2. In the above process, R<sub>1</sub> is C<sub>1</sub>-C<sub>6</sub> alkyl that can be straight-chain or branched. The process functions using a fluorinated alcohol having a P<sup>K</sup <sub>a</sub> less than about 9, in the presence of a palladium catalyst. The compounds of formula 1, as well as novel intermediates in this process, are useful in manufacturing vitamin D analogs.

Full Text

The invention relates to a process useful to produce vitamin D analogs, such as calcitriol, sold under the brand name Realtor . Processes for manufacturing vitamin D analogs typically require multiple steps and chromatographic purification. See, Norman, A. W.; Okamura, W. H. PCT Int. Apples. WO 9916452 Al 990408; Chem. Aster. 130:282223. Batch, A. D.; Bryce, G. R; Hennessy, B. M.; lacobelli, J. A.; Uskokovic, M. R. Euro. Pat. Apples. EP 808833,1997; Chem., Absorb. 128:48406. Nestor, J. J.; Manchand, R S.; Uskokovic, M. R. Vickery, B. H. US 5872113,1997; Chem. Absorb. 130:168545. The present invention seeks to provide an efficient synthesis of the A-ring portion of such vitamin D analogs. The subject invention provides a method of stereo specifically producing a compound of formula: wherein R is alkyl and is a hydroxy protecting group, which comprises for the preparation of compounds of formula 2AA and 2AA*reacting a compound of formula: Kj/So 16.05.2000 wherein R^ and R'^ are as above and the stereochemistry of both the compound of formula lAA and the compound of formula 2AA is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula 1AA"*" and the compound of formula 2AA' is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pKa lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2AA or Laa , respectively; and for the preparation of compounds of formula 2BB and 2BB*reacting a compound of formula: and the stereochemistry of the compound of formula IBB, and the compound of formula 2BB is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula IBB"*" and the compound of formula ZBB'*' is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pKa lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2BB or 2BB respectively. The reacting is preferably in the presence of a palladium catalyst that is palladium-phosphine catalyst, such as a palladium-triarylphosphine, especially when selected from the group consisting of palladium-triphenylphosphine, palladium-tris(2-methoxyphenyl)-phosphine, palladium-tris(3-methoxyphenyl)phosphate, palladium-tris(4-methoxy-phenyl)phosphine, palladium-tris(o-tolyl)phosphine, palladium-tris(m-tolyl)phosphine, palladium-tris(p-tolyl)phosphine, palladium-tris(4-fluorophenyl)phosphine, palladium-tris(p-trifluoromethylphenyl)phosphine, and palladium-tris(2-furyl)phosphine. Another preferred palladium catalyst is palladium-l,2-bis(diphenylphosphino) ethane. The fluorinated alcohol is favorably selected from the group consisting of: The present invention also provides novel intermediates used in the process for the preparation of the compounds of formulae 2AA, 2AA' 2BB and 266 the invention is 5 thus related to compounds having the structure preferably to the compound having the structure: to intermediates having the structure: wherein R is alkyl; preferably to the compound having the structure: to novel intermediates including the compounds having the formula wherein R is alkyl; preferably a compound of the structure: to novel intermediates having the structure: R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, f-butyldimethylsilyl ("TBS"), dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl. to the compounds having the structure: R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; preferably to a compound of the structure: wherein R is alkyl, phenyl, 4-nitrophenyl, or CF3; preferably to the intermediates of formulae )r Further the invention relates to the compound having the structure: and to the compounds having the structure: wherein R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; and preferably to the compound having the structure: Further novel intermediates provided by the present invention are the compounds having the structure: wherein R is alkyl and R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, f-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or the compounds having the structure: wherein R is alkyl; or the compound having the structure: wherein R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or the compound having the structure: Further novel compounds include the compound having the structure: wherein R is alkyl and R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, f-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and r-butyldiphenylsilyl; examples of such compounds are the compounds having the structure: wherein R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, f-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; preferably the compound having the structure: The enantiomeres of the novel intermediates and compounds mentioned above are also part of the present invention. The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting. The subject invention is concerned generally with a stereo specific and regioselective process for converting compounds of formula 1 to compounds of formula 2. However, as explained below, there are certain differences between the processes involving compounds of formula 1 wherein the substituents at the 1 and 3 carbons are attached cist i.e. on the same side of the plane of the six-membered ring, and compounds of formula 1 wherein the substituents at the 1 and 3 carbons are attached trans-., i.e. on opposite sides of the plane of the six-membered ring. The process results in the compound of formula 2 having the same relative and absolute stereochemistry at both carbon 1 and carbon 3 as that in the compound of formula 1. Thus, if carbon 1 is in the R-configuration in the compound of formula 1, then carbon 1 will be in the R-configuration in the compound of resulting formula 2. In the above process, R is alkyl that can be straight-chain or branched. For example, methyl, ethyl, propyl, isopropyl, butyl (primary, secondary or tertiary), lentil (primary, secondary or tertiary), or hexyls (primary, secondary or tertiary). R is a hydroxy protective group. The choice of protective group is readily determinable by the skilled artisan. However, a silyl protective group, such as tert-butyldimethylsilyl ("TBS") is preferred. The bonds forming the peroxide ring may be above the plane or below the plane of the molecule. When the epoxide ring is below the plane, the adjacent methyl group is above the plane. Likewise, when the epoxide ring is above the plane, the adjacent methyl is below the plane. For example, when the substituents at carbons 1 and 3 are the following situations can occur: When the substituents at carbons 1 and 3 are trans, the following situations can occur: Compounds of formula 2A-D are useful for the preparation of Vitamin D analogs, for example, for compound 2A, see: Shiuey, S. J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic, M, R. /. Org. Chem. 1990,55,243; for compound 2B, see: Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I. Tetrahedron Let. 1991,32,4937. Nagasawa, K.; Zako, Y.; Ishihara, H.; Shimizu, I. /. Org. Chem. 1993,58,2523; for compound 2C, see: Hatakeyama, S.; Iwabuchi, Y PCT Int. Apples. WO 9915499 Al 990401; Chem. Aston 130:252533; and. for compound 2D, see: Shimizu, N. Japan. Kaka Tokyo Kohl JP 04305553 A2 921028; Chem. Aster. 118:191249. Shimizu, N. Jon. Koki Tokyo Coho JP 04305548 A2 921028; Chem. Aster. 118:212477. Minojima, T.; Tomimori, K.; Kato, Y Japan. Koki Tokyo Coho JP 02286647 A2 901126; iem.A&str. 114:184872. Compounds of formula lA and IC are enantiomers, and can be prepared from known compounds. For example, the starting material may be (+)-Carvone for the preparation of lA, and the starting material may be (-)-Carvone for the preparation of IC [Liu, H. J.; Zhu, B. Y Can. J. Chem. 1991, 69, 2008]. The compound of formula 3 or its enantiomer may be obtained by reacting (+)-carvone or (-)-carvone, respectively, with an acetic acid ester, such as methylacetate, ethylacetate, propylacetate, isopropylacetate, t-butyl, zoo-butyl, or sec-butyl acetate, pentyl (primary, seconadry or tertiary) acetate, or hexyls (primary, seconadry or tertiary) acetate, according to procedures set forth in the above publication. A skilled chemist having read the present specification would know how to produce a given enantiomer by choosing the corresponding enantiomeric starting material. the compounds of the above scheme, R^ is CpCe alkyl that can be straight-chain or branched. For example, methyl, ethyl, propyl, isopropyl, butyl (primary, secondary or tertiary), pentyl (primary, secondary or tertiary), or hexyl (primary, secondary or tertiary). R is a hydroxy protective group, for example a silyl protective group. The choice of hydroxy protective group is readily apparent to the skilled artisan, see for example T. W. Greene, R G. M. Wuts, Protective Groups in Organic Synthesis, 2" Ed., John Wiley 8c Sons, 1991. Acceptable hydroxy protective groups for use in connection with the subject invention include silyl ethers such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, f-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl. Step A of the above process is the highly regio- and stereo selective epoxidation of the known [Liu, H. J.; Zhu, B. Y. Can. /. Chem. 1991, 69, 2008] ally alcohol of formula 3 catalyzed by vandal acetylacetonate to obtain the epoxide of formula 4. The side chain double bond is then ionized to give the ketones of formula 5. A Baeyer-Villiger oxidation of the ketones of formula 5, followed by hydrolysis of the resulting acetate 6 gave alcohol 7. Selective illation of the secondary alcohol and dehydration of the tertiary alcohol gave unsaturated ester of formula 1A in the (E) configuration. Step A The alkyl alcohol of formula 3 can be deoxidized in ethylene chloride using a catalytic amount of vandals acetylacetonate and a neonate solution of tert-hotly hydro peroxide in the presence of molecular sieves. Alternatively, the reaction can be carried out in refluxing cyclopean with constant removal of water by a Dean-Stark condenser, using 1.5 mol% of the vanadium complex and about 1.2 equiv. of the hydro peroxide to give a complete reaction after five hours and product in a good yield. The epoxide of formula 4 tends to be unstable. Accordingly, it is advisable to quench the excess hydroperoxide with sodium bisulfate, wash the reaction mixture several times with saturated sodium bicarbonate solution, concentrate it at 30 under reduced pressure, and dried it at room temperature under high vacuum. The resulting mixture of the crude product and nonane (from the hydroperoxide solution) can then be subjected to ozonolysis in step B. Step A methanolic solution containing the epoxide of formula 4 can be agonized in the presence of sodium bicarbonate, with dry ice-acetone cooling. A Polymeric Laboratory Ozonator Model T-816 (Polymetrics, Inc.) can be used to generate the ionized air (shell pressure 6 PSIG; flow rate 4 LPM; 110 V). This is followed with a reduction with diethyl sulfide to obtain the ketone of formula 5. Sodium bicarbonate should be removed by filtration prior to concentration below 30°C. Step The compound of formula 5 can be oxidized under modified Baeyer-Villiger oxidation conditions (excess meta-chloroperbenzoic acid in the absence of base) in a mixure of hexane and ethyl acetate. Greater amounts of hexane in the mixture accelerate the reaction. However, a too high ratio of hexane to ethyl acetate causes an additional layer in the reaction mixture and the production of by-products. A 3:1 mixture of hexane to ethyl acetate was found particularly suitable. Stepped The acetate of formula 6 can be hydrolyzed in methanol with a catalytic amount of sodium methoxide (15 mol%) with ice-water cooling. The product of formula 7 can then be crystallized from ethyl acetate-hexane and isolated. StepE Selective protection of the secondary alcohol over the tertiary alcohol in formula 7 can be achieved using known protection technology, such as t-butyldimethylsilyl chloride and imidazole in tetrahydrofuran. Other silyl protective groups, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl protective groups can be similarly used, when a corresponding silylchloride is reacted with the compound of formula 7 in the presence of base, such as imidazole, pyridine, or other aromatic or aliphatic tertiary amine. Imidazole hydrochloride that precipitates from the reaction mixture can be removed by filtration. The filtrate can be concentrated and then introduced to the next step without further purification. Alternatively, silylation maybe performed in pyridine and the reaction mixture can then be added directly to the dehydration mixture (i.e., pyridine/thionyl chloride) in Step F. StepF The protected (for example silyl) ether of formula 8 can be dehydrated to give the compound of formula 1A on treatment with thionyl chloride in pyridine. Adding a THF solution of the compound of formula 8 into a preformed, cold thionyl chloride/pyridine mixture minimizes formation of by-product. The product can be used in the next step without purification. Although this crude product may contain protective group (for example silyl) by-products, the protective group should be stable under these dehydration conditions. Compounds of formula IB and ID are enantiomers, and can be prepared from known compounds. For example, the starting material may be (-h)-Carvone [Okamura, W. H.; Aurrecoechea, J. M.; Gibbs, R. A.; Norman, A. W. /. Org, Chem. 1989, 54,4072] for the preparation of IB, and the starting material maybe (-)-Carvone [Jones, Joel, Jr.; Kover, W. B. Synchs. Common. 1995, 25y 3907] for the praparation of ID. Thus, compound 9 or its enantiomer maybe obtained from (+)-Carvone or (-)-Carvone, respectively, by diastereoselective approximation according to procedures set forth in the above publications. A skilled chemist having read the present specification would know how to produce a given enantiomer by choosing the corresponding enantiomeric starting material. The compound of formula 9 is known [Klein, E.; Hoff, G. Tetrahedron 1963, J9, 1091. Okamura, W. H.; Aurrecoechea, J. M.; Gibbs, R. A.; Norman, A. W. /. Org, Chem, 1989,54,4072]. At low temperature (-70°C) a 1,3-dipolar cycloaddition of ozone to the compound of formula 9 occurs to give an ozonide, which at a higher temperature (e.g., room temperature) releases formaldehyde via a retro-1,3-dipolar cycloaddition to form carbonyl oxide. In the presence of methanol as a co-solvent, the carbonyl oxide is efficiently trapped by the alcohol to give the desired hydroperoxide of formula IDA (Step Gl) which is then acierated to the compound of formula lOB (Step G2). Variations on common acylation are readily apparent to one of ordinary skill of the art. In the compound of formula lOB, R1 can be alkyl, phenyl, 4-nitrophenyl, or CF3. Such variations are readily made by the skilled artisan. Excess methanol may interfere with this acylation. However, a clean reaction can be achieved with 4 equivalents of methanol. Then, the hydroperoxide can be acetylated in situ with 7 equivalents of acetic anhydride and triethylamine in the presence of a catalytic amount of DMAP at -S^'C to obtain peroxyacetate lOB, where R is a methyl group. Other acylating agents may be similarly used and the resulting peroxyester subjected to the Cringe rearrangement as described below. Such appropriate acylating agents are aliphatic and aromatic acid halides (chlorides or bromides) and acid anhydrides, such as acetyl chloride, acetic anhydride, propionylchloride, benzoylchloride, 4-nitrobenzoyl-chloride, and trifluoroacetic anhydride. These acylating agents may react with hydroperoxide loan in the presence of base such as triethylamine, as above, to give the corresponding peroxyesters lOB, where R is methyl, ethyl, phenyl, 4-nitrophenyl, trifluoromethyl. However, a peroxyacetate lOB where R is methyl, is preferred. Step HI The peroxyester of formula lOB is immediately subjected to the Cringe rearrangements to yield the alcohol of formula 11, preferably in methanol. The peroxyacetate of formula lOB tends to be unstable. Accordingly, sodium acetate may be added to prevent acid-catalyzed solvolysis of the compound of formula 10 to the corresponding diethyl acetyl and Step HI preferably follows Step G immediately. An aqueous workup of the reaction mixture should be used to remove acidic and basic byproducts in order to obtain purified compound of formula 11. Step H2 After solvent exchange with acetonitrile, the product of formula 11 can be protected (for example, silylated) to give the ketone of formula 12. The relatively volatile protective group (for example, silyl) by-products can be removed at 45°C under high vacuum and the crude product of formula 12 obtained. Protection of the secondary alcohol in formula 11 can be achieved using known protection technology, for example using t-butyldimethylsilyl chloride and imidazole. Other silyl protective groups, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl protective groups can be similarly used, when a corresponding silylchloride is reacted with 7 in the presence of base, such as imidazole, pyridine, or other aromatic or aliphatic tertiary amine under controlled conditions to minimize elimination of the willowy group. It is noteworthy that the product of the Carriage rearrangement in methanol is the alcohol of formula 11 and that the corresponding acetate ester has never been observed in the course of the reaction. This contrasts to the typical Carriage rearrangement procedure (one-pot acetylating and rearrangement in dichloromethane: Schreiber, S. L.; Liew, W. R Tetrahedron Lett 1983,24, 2363), where an acetate is usually obtained as the major product together with a smaller amount of the corresponding alcohol. Subsequent hydrolysis of the acetate to the alcohol is problematic due to elimination of the acetoxy group. Step I A Witting-Horner reaction of the compound of formula 12 can be carried out using 2.2 equiv. of tri-R phosphonoacetate (where R is a alkyl that can be straight-chain or branched) and 1.8 equiv. of lithium hydride in a relatively small amount of THF, at a relatively low temperature (11°C), for a longer reaction time (20 h) to minimize elimination of the protecting (for example, silyloxy) group. The desired compound of formula IB is thus obtained in approximately a 7-9:1 mixture with its Z-isomer (the compound of formula l'*'B). To illustrate the inventive aspects of the subject reaction, the reaction will be discussed with reference to the reaction of a species of formula 1A (formula lA') to form the corresponding species of formula 2A (formula 2A'). The same principles hold true with its enantiomer — compound IC, as well as the reactions of compound IB to form 2B, and of its enantiomer — compound ID to form 2D. The above reaction, when using a palladium(O) triphenylphosphine catalyst [Suzuki, M.; Ode, Y.; Koori, R. /. Am. Chem. Soc. 1979,101,1623] in THF at 65°C, results in the summarizations of epoxide lA' to yield a mixture of the desired alkyl alcohol of formula 2A' and isomeric neon of formula 13 in a ratio of 1:3 (HPLC area% at 220 nm). It has been discovered that phosphine legends [for example, triarylphosphines, such as triphenylphosphine, tris(2-methoxyphenyl)phosphine, tris(3-methoxyphenyl)phosphine, tris(4-methoxyphenyl) phosphine, tris(o-tolyl)phosphine, tris(m-tolyl)phosphine, tris(p-tolyl)-phosphine, tris(4-fluorophenyl)phosphine, tris(p-trifluoromethylphenyl)phosphine, and tris(2-furyl)phosphine, and aryl phosphines such as l,2-bis(diphenylphosphino)ethane] in combination with palladium(O) catalyze the isomerization and that adding a fluorinated alcohol [for example 1,1,1,3,3,3-hexafluoro-2-phenyl-2-propanol and l,3-bis(l,1,1,3,3,3-hexafluoro-2-hydroxypropyl)benzene, perfluoro-r-butanol] increases the yield of the desired alkyl alcohol of formula 2A' versus the undesired ketone of formula 13 and also improves catalyst turnover for the palladium-triphenylphosphine catalyst. The palladium-phosphine catalyst can be prepared in situ prior to the reaction from commercial palladium sources, such as Pd2dba3(CHCl3) ("dabs" stands for dibenzylideneacetone), and an excess (typically 4-5 equivalents) of the corresponding phosphine legend, such as triphenylphosphine. Other palladium sources maybe used as well, such as palladium(O) complexes Pd2dba3, Pddba2, and palladium(n) salts Pd(Oaks)2, PdCl2, [allylPdCl]2, and Pd(aced)2 ("aced" stands for acetylacetonate). Alternatively, a palladium(0)-phosphine catalyst, such as retraces(triphenylphosphine)palladium(0), may be separately prepared and used in the reaction. However, generation of the catalyst in situ from Pd2dba3(CHCl3) and phosphine is preferred. With 1 mol% of the palladium-triphenylphosphine catalyst even a catalytic amount of the appropriate fluorinated alcohol was sufficient to increase the selectivity for alkyl alcohol of formula 2A' to 10:1. Increasing the amount of fluorinated alcohol of formula 15c further to 50 mol% and 100 mol% gave a 16:1 and 19:1 ratio of allyl alcohol of formula 2A' to isomeric ionone of formula 13, respectively. where X is CH3 (formula 15a), H (formula 15b), phenyl (formula 15c), or CF3 (formula 15d). It has been discovered that selectivity correlated to the pKa of the fluorinated alcohols. Fluorinated alcohols with pKa Although the most acidic perfluoro-tert-butanol (formula 15d) gave abettor selectivity (ratio of allyl alcohol of formula 2A' to isomeric neon of formula 13 = 95:5) than the less acidic fluorinated alcohols of formulas 15c and 16, the reactions run with the alcohols of formulas 15c and 16 were cleaner than those with 15d. Using the fluorinated alcohol of formula 16, better results (ratio of ally alcohol of formula 2A' to isomeric neon of formula 13 > 99:1) were obtained by carrying out the reaction with 1 mol% of the palladium catalyst [prepared in situ from 0.5 mol% of Pd2dba3(CHCl3) and 5 mol% of triphenylphosphine] and 2 mol% of the alcohol of formula 16 in a less polar solvent, toluene, at the lower temperature of 35°C. This lower reaction temperature also increased the purity of the product. The 7:1 mixture of the compound of formula IB' (formula IB' is the formula IB wherein R is t-Bu and R is TBS) and the compound of formula l'*'B' (the Z-isomer of the compound of formula IB') was subjected to the palladium catalyzed isomerization reaction as described above to yield a 88:12 mixture of the desired allelic alcohol of formula 2B' (formula 2B' is the formula 2B wherein R is t-Bu and R is TBS) and its corresponding ketone (see the following Table). Thus, the regioselectivity depends on the stereochemistry of tweediness oxide double bond. Isomers IB (E-isomer) and I' 'B (Z-isomer) can be separated by chromatography. From pure E-isomers IB the desired allelic alcohols (2B' and 2B") were obtained with high selectivity (>99%). On the other hand, (Z)-dynes oxides l B gave ketones 13 and 14 selectively (see the table below). Both ethyl and t-butyl esters gave similar results. Although a high selectivity (>99%) was achieved with the pure E-isomers of formula IB, under commercial conditions it may not be practical to separate the E-isomers IB from the Z-isomers 1*B. Thus, in practice a mixture of E/Z-isomers will typically be subjected to the epoxide opening and, after solvent exchange with DMF, the resulting mixture of allelic alcohol 2BV2B" and ketone 14/13 will be subjected to silylation. Silylation is typically achieved using t-butyldimethylsilyl chloride and imidazole using known protection technology. Other silyl protective groups, such as trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl protective groups can be similarly used, when a corresponding silylchloride is reacted with alcohol 2B. Since alcohol 2B72B" is converted to a non-polar product by silylation, while the polar ketone remains unchanged, pure silylated product can be easily isolated by a simple silica gel filtration. The following examples were actually performed and are illustrative of the invention. Modifications of these examples to produce related compounds as shown in the various schemes herein are obvious chemical modifications to a person of ordinary skill in the art. The product of this reaction may undergo a Delis-Alder tenderization as a concentrated solution and in the solid phase, at room temperature. Thus, it should be stored at -20°C. A 500 mL, three-necked, round-bottomed flask equipped with a magnetic stirrer, septum stoppers and a thermometer was charged with 570 mg (0.551 mmol) of tris-(dibenzylideneacetone)dipalladium(0)-chloroform adductand 1.45 g (5.55 mmol) of triphenylphosphine. The flask was evacuated and refilled with nitrogen three times, then charged with 35 mL of toluene via a syringe. The resulting deep purple mixture was stirred at ambient temperature for 1 h to give a yellow slurry. Then, 0.54 mL (2.18 mmol) of l,3-bis-(l,l,l,3,3,3-hexafluoro-2-hydroxypropyl) benzene was added. The slurry became red-orange. After three minutes of stirring at ambient temperature (19*'C), a solution of 40.7 g (110 mmol, in theory) of crude compound of formula lA' in 160 mL of toluene, prepared in a similar manner described above for the catalyst solution (i.e., the flask containing the crude compound of formula 1 A' was evacuated and refilled with nitrogen three times, then the toluene was added via a syringe), was added to the resulting catalyst solution, via a canola using a slight positive pressure of nitrogen. After ten minutes of stirring at ambient temperature under a slight positive pressure of nitrogen, the reaction mixture was heated to 32 overnight (15 hours), then to 35°C for 2 h. The reaction mixture was quickly concentrated on a rotary evaporator at 25°C (bath temperature) under reduced pressure (oil pump) and the residue was dried under high vacuum for 30 min to give 44.8 g (overweight) of crude compound of formula 2A' as a reddish oil. This material was used immediately without flirtier purification in subsequent reactions, as described in prior work: Shiuey, S.-J.; Kulesha, I.; Baggiolini, E. G.; Uskokovic M. R. /. Org, Chem. 1990,55y 243. HPLC analysis indicated this material to be about 87% pure with about 3% of the starting material compound of formula 2A', less than 1% of the ketone by-product and about 3% of the dimmer present. In-process controls: NMR (CDCI3), TLC (3:1 hexane: ethyl acetate; short-wave UV detection and PMA stain; Fro compound of formula lA' = 0.74, Ruff compound of formula 2A = 0.45 and Ruff of the ketone = 0.50) and HPLC. Reaction at 35 overnight is preferred as the described procedure resulted in incomplete reaction (about 3% of the starting material was observed after stirring at 32°C for 15 h, then at 35°C for 2h). The percentages given are the area percentages of the corresponding peaks at 220 nm. The HPLC conditions are as follows: Column: Nucleoli 5 |Am, 4.6 x 250 mm Mobile Phase: 2% isopropanol in hexanes at 0.5 mL/min Retention Times: 7.6 min (the compound of formula lA'), 8.8 min (the ketone by-product), 8.9 min (dibenzylidene-acetone), 12.1 min (the compound of formula 2A') and 18 min (the dimmer). A 250 mL round-bottomed flask equipped with a magnetic stirrer, septum stopper, thermocouple and nitrogen bubbler was charged with 388 mg (0.375 mmol) of tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct and 985 mg (3.75 mmol) of triphenylphosphine. The flask was evacuated and refilled with nitrogen three times, then charged via syringe with 23 mL of toluene. The resulting deep purple mixture was stirred at ambient temperature for 30 min to give a light orange suspension. Then, 370 all (1.5 mmol) of l,3-bis-( 1,1,1,3,3,3-hexafluoro-2-hydroxypropyl)benzene was added. The mixture turned red-orange and most of the solids dissolved. After three minutes of stirring at ambient temperature (19°C), to the resulting catalyst solution was added, via canella using a slightly positive nitrogen pressure, a solution of 24.4 g (74.9 mmol) of crude compound of formula I’ve B' (E/Z 8.5:1) in 100 mL of toluene, prepared in a similar manner to that described above for the catalyst solution (the flask containing the crude compound of formula IB' was evacuated and refilled with nitrogen three times, then the toluene was added via canella). After ten minutes of stirring at ambient temperature under slightly positive nitrogen pressure, the reaction mixture was heated to 40°C overnight (16 hours). TLC analysis indicated complete reaction. The mixture was concentrated on a rotary evaporator at analysis indicated complete reaction. The reaction mixture was diluted with 300 mL of hexanes and washed with 2x150 mL = 300 mL of water. The combined aqueous washes were back-extracted with 2x100 mL = 200 mL of hexanes and the combined back-extracts were washed with 2x50 mL = 100 mL of water. All the organic layers were combined, dried over magnesium sulfate and concentrated to dryness to give a yellow, viscous oil (35.6 g, overweight). This material was dissolved in 100 mL of hexanes and the resulting solution was filtered through 200 g of TLC silica gel. The silica gel pad was then washed with 1.5 L of 98:2 hexane: ethyl acetate, and the combined filtrate and washes were concentrated to dryness under reduced pressure to give 27.7 g (84.0%) of the compound of formula 3B' as a colorless oil. In-process controls: HPLC, NMR (CDCI3) and TLC (3:1 pet.ether:diethyl ether; short-wave UV detection and PMA stain; Ruff 3B' = 0.9, Ruff IB' = 0.85, Ruff 2B' = 0.45, Ruff 14 = 0.6 and Ruff of dibenzylideneacetone = 0.7, 19:1 hexane: ethyl acetate; short-wave UV detection and PMA stain; Rf of the compound of formula 3B' = 0.4 and Rf of the compound of formula 2B' = 0.1) A 2 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, Dean-Stark condenser, addition funnel and nitrogen bubbler was charged with 207 g (776 mmol) of the compound of formula 3\ 3.09 g (11.7 mmol) of vandal acetylacetonate and 770 mL of cyclopean. After the mixture was heated to gentle reflux, 170 mL (850-1020 mmol) of 5.0-6.0M tert-hexyls hydroperoxide in nonane was added over 90 min. The green solution turned deep red upon addition and a mild exothermic ensued. After completion of the addition, the resulting orange-green solution was heated to reflux for 3 h. The volume of the water in the trap increased by about 4 mL. TLC analysis indicated the presence of only a small amount of starting material. After cooling to below room temperature with an ice-water bath, 77 mL of IM sodium bisulphate solution and 150 mL of saturated sodium bicarbonate solution were added. After 5 min, an iodine-starch paper test indicated no I peroxide to be present. The organic layer was separated, then washed with 3 x 150 mL = 450 mL of saturated sodium bicarbonate solution and 150 mold saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure at A 3 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, nitrogen inlet-tube and gas outlet-tube was charged with 247 g {about 776 mmol) of the compound of formula 4\ 24 g (286 mmol) of sodium bicarbonate and 1.8 L of methanol. After the mixture was cooled with a dry-ice/acetone bath, the nitrogen inlet-tube was replaced with a gas dispersion tube with porous fritted glass tip (25-50 |l), and the gas outlet-tube was connected, through a trap, to a tube (4 mm I.D.) immersed in a IM solution of potassium iodide (2 L). Then, odorized air (4 LPM) was continuously passed through the reaction mixture at -70°C. The reaction turned pale blue after 5 h. After agonized air was passed for an additional 15 min through the mixture at a reduced flow rate of 1 LPM, excess ozone was removed by purging with air (4 LPM) for 25 min. The resulting white suspension was treated with 75 mL (1.02 mol, about 1.3 equiv.) of methyl sulfide and allowed to warm to room temperature overnight. An iodine-starch paper test indicated no peroxide to be present. The insoluble inorganic salts were removed by filtration and washed with 100 mL of ethyl acetate. The combined filtrate and washes were concentrated under reduced pressure (bath temperature room temperature to give 155.9 g (68.5% over 3 steps) of formula 5 as a white solid (mp 92-94*^0). The combined mother liquor and washes were washed with 3 x 100 mL = 300 mL of saturated sodium bicarbonate solution and 100 mL of saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure (bath temperature In-process controls: NMR (CDCI3) and TLC (1:1 hexane: ethyl acetate; PMA stain; Rf the compound of formula 4' = 0.70 and Rf the compound of formula 5' = 0.50) A 2 L, three-necked, round-bottomed flask equipped with a mechanical stirrer, nitrogen bubbler and thermometer was charged with 82.2 g (289 mmol) of the compound of formula 5', 115 g (606 mmol, 2.1 equiv.) of 91% m-chloroperoxybenzoic acid and 840 mL of 3:1 hexane-ethyl acetate. The white suspension was stirred at room temperature (about 20°C) for 3 days. NMR analysis indicated about 98% conversion. After cooling to 5°C with an ice-water bath, 145 mL (435 mmol) of 2.5M potassium carbonate solution was added drop wise at layer was washed with 30 mL of 10% potassium bicarbonate solution and dried over magnesium sulfate. The combined aqueous layers were extracted with 200 mL of ethyl acetate. The organic layer was washed with 20 mL of 10% potassium bicarbonate solution and dried over magnesium sulfate. The combined aqueous layers were again extracted with 200 mL of ethyl acetate. The organic layer was washed with 20 mL of 10% potassium bicarbonate solution and dried over magnesium sulfate. The combined aqueous layers were extracted one more time with 200 mL of ethyl acetate. The organic layer was washed with 20 mL of 10% potassium bicarbonate solution and dried over magnesium sulfate. All the organic layers were combined and concentrated at In-process controls: NMR (CDCI3) and TLC (1:1 hexane: ethyl acetate; PMA stain; Rf compound of formula 5' = 0.50 and Rf compound of formula 6' = 0.55). AIL round-bottomed flask equipped with a magnetic stirrer, nitrogen bubbler and addition funnel was charged with 81.3 g (270 mmol) of the compound of formula 6' and 270 mL of methanol. The resulting solution was stirred with ice-water cooling for 30 min and 9.3 mL (40.5 mmol, 15 mol%) of 25% sodium methoxide in methanol was added drop wise over 10 min. After stirring at 0*^C for 4 h, TLC analysis indicated complete reaction. The reaction mixture was quenched with 3.0 mL (52.6 mmol, 1.3 equiv. To sodium methoxide) of acetic acid and concentrated at of ethyl acetate and crystallization was induced by the addition of seed crystals. Then, 350 mL of hexane was gradually added. The resulting suspension was allowed to stand at room temperature overnight. The solid was collected by filtration, washed with 2 x 70 mL = 140 mL of 5:1 hexane: ethyl acetate and dried by suction, then under high vacuum at room temperature to give 54.8 g (78.4%) of the compound of formula T as a white solid (mp 91-92°C). The combined mother liquor and washes were diluted with 300 mL of hexane and stored in a freezer overnight. The supernatant was removed by decantation, and the residue was dissolved in 100 mL of ethyl acetate. The solution was washed with 20 mL of 5% potassium bicarbonate solution and 20 mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure (bath temperature In-process controls: NMR (CDCI3) and TLC (1:1 hexane:ethyl acetate; PMA stain; Rf the compound of formula 6' = 0.55 and Rf the compound of formula T - 0.25) Preparatory Example 5 - Preparation of the Silyl Ether of formula 8' A 250 mL, three-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer and nitrogen bubbler was charged with 28.6 g (111 mmol) of the compound of formula 7', 20.5 g (301 mmol) of imidazole, 19,6 g (130 mmol) of t-butylchloro-dimethylsilane and 170 mL of tetrahydrofuran. An initial mild isotherm (10 to \TC) subsided quickly. The mixture was stirred under nitrogen overnight. TLC analysis indicated complete reaction. The solids were removed by filtration using a sintered glass funnel and washed thoroughly with 200 mL of tetrahydrofuran. The combined, colorless I filtrate and wash were concentrated under reduced pressure at 25°C, then under high vacuum for 30 min to yield 48.7 g (overweight) of crude compound of formula 8' as a white solid. H NMR analysis indicated the presence of about one equivalent of proton Ted imidazole. This material was used directly in the next step without further purification. In-process controls: NMR (CDCI3) and TLC (1:1 hexane:ethyl acetate; PMA stain; Rf the compound of formula 7' = 0.16 and Rf compound of formula 8' = 0.79). Preparatory Example 6 - Preparation of the Unsaturated Ester of formula lA' A 500 mL, three-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer and nitrogen bubbler was charged with 136 mL (1.68 mol) of pyridine. Then, 13.6 mL (186 mmol) of thionyl chloride was added in one portion. The initial exotherm to 27°C was allowed to subside and the solution was stirred at ambient temperature for 40 min. The resulting yellow solution was then cooled to -34°C and a solution of 48.7 g (111 mmol, in theory) of crude compound of formula 8' in 86 mL of tetrahydrofuran was added dropwise over 1 h at such a rate as to maintain the temperature of the reaction at less than -25°C. The reaction mixture was allowed to warm to 0°C over 100 min, then poured into a mixture of 700 mL of saturated sodium bicarbonate solution and 350 mL of hexanes. The resulting mixture was stirred for 30 min until there was no noticeable gas evolution occurring. The hexane layer was separated, washed with 350 mL of IM citric acid solution, dried over sodium sulfate and concentrated to dryness under reduced pressure to yield 40.7 g (overweight) of compound of formula lA' (about 90% pure by ^H NMR analysis) as a colorless oil. This material was used directly in the next step without further purification. In-process controls: NMR (CDCI3) and TLC (9:1 hexane; ethyl acetate; short-wave UV detection and PMA stain; Rf the compound of formula 8' = 0.04 and Rf the compound formula' = 0.21). A 500 mL, three-necked, round-bottomed flask equipped with a mechanical stirrer, thermometer, nitrogen inlet-tube and gas outlet-tube was charged with 20.0 g (120 mmol) of the compound of formula 9, 20 mL (494 mmol) of methanol and 200 mL of dichloromethane. After the mixture was cooled to -68*^C with a dry-ice/acetone bath, the nitrogen inlet-tube was replaced with a gas dispersion tube with porous fritted glass tip (25-50 |x), and the gas outlet-tube was connected, through a trap, to a tube (4 mm I.D.) immersed in a IM solution of potassium iodide (2 L). Then, odorized air (4.5 LPM) was continuously passed through the reaction mixture at -68 ± 3°C. The reaction turned pale blue after 65 min, indicating complete reaction. Excess ozone was removed by purging with nitrogen for 30 min to give a colorless solution. The gas dispersion and outlet tubes were replaced with a nitrogen bubbler and an addition funnel. The mixture was allowed to warm to 14°C over 40 min. After cooling to -25°C with a dry-ice/acetone bath, 117 mL (839 mmol) of triethylamine was added over 5 min, while maintaining the temperature of the mixture below-25°C. Then, 2.0 g (16.4 mmol) of dimethylaminopyridine (DMAP) was added in one portion and 79.6 mL (843 mmol) of acetic anhydride was added slowly over 10 min, while maintaining the reaction temperature between -25*^0 and -38°C. The mixture was allowed to warm to -8°C over 30 min and stirred at -7 ± 1°C for 1.5 h. TLC analysis indicated complete reaction. The reaction mixture was quenched by the slow addition (over 7 min) of 33 mL of methanol, while maintaining the temperature of the mixture below 10°C. After stirring for 5 min at 5°C, the mixture was diluted with 220 mL of hexane, washed with 2x150 mL = 300 mL of 10% citric acid solution and 2x80 mL = 160 mL of saturated potassium bicarbonate solution, dried over sodium sulfate and concentrated to dryness at 35°C under reduced pressure to give 38.2 g (overweight) of crude the compound of formula 10 as a yellow oil. This material was immediately used in the next step without further purification. In-process controls: NMR (CDCI3) and Tics (2:1 hexane:ethyl acetate; PMA stain; Rf the compound of formula 9 = 0.80 and Rf the compound of formula 9C = 0.45,40:2:1 dichloromethane:ethyl acetate:methanol; PMA stain; RY take compound of formula 9C = 0.40 and Rf the compound of formula 10 = 0.80). A 500 mL round-bottomed flask equipped with a magnetic stirrer, thermometer and nitrogen bubbler was charged with 38.2 g (120 mmol, theoretical) of crude compound of formula 10. 2 g (24.4 mmol) of sodium acetate and 245 mL of methanol. After stirring at 37°C overnight, TLC analysis indicated complete reaction. Thus, the mixture was concentrated to dryness at 39°C and the residue (29 g) was dissolved in 40 mL of acetonitrile. The resulting solution was concentrated to dryness at 35°C under reduced pressure and 40 mL of acetonitrile was added. The resulting solution was again concentrated to dryness at 35°C under reduced pressure, and 35 mL of acetonitrile and 29.5 g (433 mmol) of imidazole were added. After cooling with an ice-water bath, 32.6 g (217 mmol) of tert-butylchlorodimethylsilane was added. The cold bath was removed and the mixture was stirred at room temperature for 4 h. TLC analysis indicated the presence of only a trace amount of starting material. The reaction mixture was quenched by the addition of 10 mL of methanol. A mild exotherm ensued that raised the temperature of the mixture by 2°C. After stirring for 5 min, 55 mL of ice water was added and the mixture was extracted with 2x50 mL = 100 mL of hexane. The combined organic layers were washed with 50 mL of 2:3 methanol water, dried over sodium sulfate and concentrated to dryness at 40°C under reduced pressure. Further drying of the residue at 46°C and 0.4 mmHg for 1 h gave 25.2 g of crude compound of formula 12' as a pale yellow oil. This material was used directly in the next step without fritter purification. In-process controls: NMR (CDCI3) and Tics (40:2:1 dichloro-methane:ethyl acetate:methanol; PMA stain; Rf the compound of formula 10 = 0.8, Rf the compound of formula 11 = 0.4 and Rf compound of formula 12' = 0.95,8:1 hexane:ethyl acetate; PMA stain; Rf the compound of formula 12' = 0.6 and Rf of tert-butyldimethylsilanol = 0.5) A 250 mL, three-necked, round-bottomed flask equipped with a magnetic stirrer, condenser, thermometer and nitrogen bubbler was charged with 1.41 g (177 mmol) of Atrium hydride, 43.3 mL (216 mmol) of diethyl phosphonoacetate and 45 mL of The mixture was slowly heated to 55 and the heating bath was removed. An exotherm ensued that raised the temperature of the mixture to 69 over 5 min. The temperature of the mixture slowly came down to 66*'C over 55 min and a clear solution resulted. Approximately 25 mL of the THF was then removed by distillation at 50-55°C under a slightly reduced pressure. After cooling the resulting mixture to 3°C with an ice water bath, 25.2 g (98.4 mmol) of crude the compound of formula 12'was added in one portion. The funnel was rinsed with 15 mL of THF and the rinse was added to the reaction mixture. The mixture was stirred at 5-6°C for 90 min, at for 18 h, then at 24°C for 2 h. TLC analysis indicated complete reaction. Thus, the mixture was diluted with 100 mL of 8:1 hexane:ethyl acetate, washed with 3x36 mL = 108 mL of water and concentrated to dryness at 38°C under reduced pressure. The residue was dissolved in 115 mL of hexane and filtered through 50 g of TLC silica gel. The silica gel pad was then washed with 191 mL of 8:1 hexane:ethyl acetate, and the combined filtrate and washes were concentrated to dryness at 37°C under reduced pressure. The residue was further dried under high vacuum for 1 h to give 24.4 g (76.1%) of crude compound of formula IB' as a yellow oil. H NMR analysis indicated this material to be a 8.5:1 mixture of the compound of formula IB' and its corresponding Z-isomer, the compound of formula l'*"B'. This material was used directly in the next step without further purification. In-process controls: NMR (CDCI3) and TLC (3:1 dichloromethane: hexane; short-wave UV detection and PMA stain; Rf the compound of formula 12' = 0.55, Rf the compound of formula IB' = 0.45 and Rf of the Z-isomer (compound of formula 1*B' = 0.35) ) Upon reading the present specification, various alternative embodiments will become obvious to the skilled artisan. These variations are to be considered within the scope and spirit of the subject invention that is only to be limited by the claims that follow and their equivalents. Claims 1. A method of stereospecifically producing a compound of formula: wherein R is C1-C6 alkyl and R is a hydroxy protective group, which comprises reacting a compound of formula: wherein R' and R" are as above and the stereochemistry of both the compound of formula lAA and the compound of formula 2AA is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula lAA* and the compound of formula lAA"^ is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pKa lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2AA or 2AA'*", respectively. 2. A method of stereospecifically producing a compound of formula: which comprises reacting a compound of formula: wherein R and R are as above and the stereochemistry of the compound of formula IBB, and the compound of formula 2BB is the same at carbons 1 and 3, respectively, and the stereochemistry of both the compound of formula IBB'*' and the compound of formula 2BB* is the same at carbons 1 and 3, respectively, with a fluorinated alcohol having a pKa lower than about 9, in the presence of a palladium catalyst to yield the compound of formula 2BB or 2BB'*' respectively. 2. The method of claim 1 or 2, wherein the reacting is in the presence of a palladium catalyst that is palladium-phosphine catalyst, 4. The method of claim 3, wherein the reacting is in the presence of a palladium-phosphine catalyst that is a palladium-triarylphosphine. 5. The method of claim 4, wherein the reacting is in the presence of a palladium-triarylphosphine catalyst selected from the group consisting of palladium-triphenyl-phosphine, palladium-tris(2-methoxyphenyl)phosphine, palladium-tris(3-methoxy-phenyl)phosphine, palladium-tris(4-methoxyphenyl)phosphine, palladium-tris(o-tolyOphosphine, palladium-tris(m-tolyl)phosphine, palladium-tris(p-tolyl)phosphine, palladium-tris(4-fluorophenyl)phosphine, palladium-tris(p-trifluoromethylphenyl)-phosphine, and palladium-tris(2-furyl)phosphine. 6. The method of claim 1 or 2, wherein the reacting is in the presence of a palladium catalyst that is palladium-l,2-bis(diphenylphosphino) ethane. 7. The method of claim 1 or 2, wherein the reacting is with a fluorinated alcohol selected from the group consisting of: 9. The method of claim 7, wherein the reacting is with a fluorinated alcohol selected which is: 10. The method of claim 7, wherein the reacting is with a fluorinated alcohol which is: 11. A compound having the structure: wherein R is C1-C6 alkyl; or its enantiomer. 12. The compound of claim 11 having the structure: or its enantiomer. 13. A compound having the structure: wherein R^ is C1-C6 alkyl and R^ is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or its enantiomer. 14. The compound according to claim 13 having the structure: or its enantiomer. 15. A compound having the structure: wherein R^ is Ci-Cg alkyl, phenyl, 4-nitrophenyl, or CF3; or its enantiomer. 16. A compound according to claim 15 having the structure: or its enantiomer. 17. A compound having the structure: or its enantiomer. 18. A compound having the structure: or its enantiomer. 19. A compound having the structure: wherein R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethyhhexylsilyl, triphenylsilyl, and f-butyldiphenylsilyl; or its enantiomer. 20. A compound having the structure: wherein R is C1-C6 alkyl and R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or its enantiomer. 21. The compound according to claim 20 having the structure: wherein R^ is C1-C6 alkyl and R is a hydroxy protective group selected from the group consisting of trimethylsilyl, triethylsilyl, tripropylsilyl, triisopropylsilyl, t-butyldimethylsilyl, dimethylthexylsilyl, triphenylsilyl, and t-butyldiphenylsilyl; or its enantiomer. 23. The compound according to claim 17 having the structure: or its enantiomer. 24. A compound having the structure: wherein R1 is C1-C6 alkyl; or its enantiomer. A compound having the structure: wherein R1 is C1-C6 alkyl; or its enantiomer. A compound having the structure: wherein R1is C1-C6 alkyl; or its enantiomer.

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666-mas-2000-abstract.pdf

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666-mas-2000-claims filed.pdf

666-mas-2000-claims granted.pdf

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