In Reaction Scheme II, the compound of formula (V), a 3: 1  mixture of 3R- and 3S-enantiomers, may be prepared by  mixing an aldehyde ketonide of formula (VII) with a difluoro  compound of formula (VI), and allowing the mixture to  undergo Reformatsky reaction using zinc.  Further, a 3R-carboxylate of formula (III) can be prepared  from the compound of formula (V), as shown in Reaction  Scheme III.  nyl ( or substituted biphenylcarbonyl) chloride, bromide, cya› nide or azide, which may be commercially obtained or chemi› cally synthesized in accordance with conventional methods.  Also, the base used in the neutralization process of step (i)  may be selected from the group consisting of pyridine, tri› ethylamine, tributylamine, diisopropylethylamine and meth› ylpiperidine, preferably triethylamine; a catalyst used in the  acylation may be 4-dimethylaminopyridine or 4-pyrolidi› nopyridine; and the acylationmay be conducted at -25 to 50°  C.  In the hydrolysis of step (ii), the base may be selected from  the group consisting of gaseous ammonia, aqueous ammonia,  sodium carbonate, sodium bicarbonate, sodium hydroxide,  potassium carbonate, potassium bicarbonate, potassium  hydroxide and a mixture thereof, preferably potassium bicar› bonate, which may be employed in an amount of 1 equivalent  or more, preferably ranging from 1.5 to 5 equivalents based  on the compound of formula (IV).  Also, the mixed solvent essentially comprising water may  be a mixture of water and an organic solvent selected from the  group consisting of tetrahydrofuran, dioxane, acetonitrile,  acetone, methylisobutylketone, methylethylketone, metha› nol, ethanol, propanol, isopropanol, dimethylacetamide, dim› ethylformamide, dimethylsulfoxide, ethyl acetate and a mix- ture thereof, preferably a mixture of tetrahydrofuran and  methanol; and the water may be employed in an amount  ranging from 3 to 15 ml, preferably from 5 to 11 ml, and the  organic solvent, from 3 to 30 ml, preferably from 6 to 18 ml,  based on 1.0 g of the compound of formula (IV). Thehydroly- sis may be conducted at 5 to 50°  C., preferably 10 to 30°  C. for  30 min to 2 hours.  The compound of formula (III) may be isolated easily from  the reaction mixture obtained in step (ii), by removing the  organic solvent under a reduced pressure, and filtering the  resulting mixture; or by extracting the reaction mixture with  an organic solvent, and recrystallizing the product in a mixed  solvent essentially comprising water.  wherein, R, R1, R 2  and M have the same meanings as  defined above.  In Reaction Scheme III, the 3R-carboxylate of formula  (III) can be obtained as a solid by; (i) protecting the 3-hydroxy  group of the compound of formula (V) with a biphenylcar› bonyl protecting group to obtain the compound of formula  (IV); and (ii) hydrolyzing the compound of formula (IV) with  a base.  In the inventive method, the protecting group used in step  (i) may be a biphenylcarbonyl group which is a benzoyl group  substituted with benzene ring optionally the benzene ring is  substituted with one or more substituents selected from the  group consisting ofhydrogen, cyano, halo, carboalkoxy, tolu› oyl, nitro, alkoxy, alkyl and dialkylamino. Representative  examples ofbiphenylcarbonyl include such as 2-phenylben› zoyl (2-biphenylcarbonyl), 4-phenylbenzoyl ( 4-biphenylcar› bonyl) and substituted 2-(or 4-) phenylbenzoyl, preferably  2-phenylbenzoyl and 4-phenylbenzoyl.  In the inventive method, the 3R-carboxylate of formula  (III) may be obtained from the compound of formula (V) in a  high yield of 60 to 70% via a potassium or sodium salt, or  about 40% when an ammonium salt is used as a base in step  (ii). Further, the compound of formula (III) obtained in the  inventive method has a 3R-carboxylate content of more than  99.7% while the 3S-carboxylate content is less than 0.3%  (consequently, e.e value over 99.4%).  The compound of formula (I) having the erythro structure  may be obtained from the compound of formula (III) in a  highly enantioselective manner, as shown in Reaction  Scheme IV.  Increased hydrophobicity due to the two benzene ring of  biphenylcarbonyl group makes it possible to separate 3R-car› boxylate of formula (III) as a solid even in the water or water  containing mixed solvent.  On the other hand, in case of using a conventional benzoyl  group as a hydroxy protecting group, it is impossible to get a  3R-carboxylate salt as a solid in the water or water containing  mixed solvent.  In contrast, in case of introducing a conventional hydroxy 60  protecting group such as 1-naphtoyl, 2-naphtoyl, pivaloyl or  acetyl for the 3-hydroxy group of the compound of formula  (V), it is very difficult to selectively isolate the 3R-carboxy› late of formula (III) as a solid from the resulting reaction  mixture.  65  The biphenylcarbonyl-based compound used in step (i)  may be selected from the group consisting ofbiphenylcarbo- US 7,638,642  B2  7  8  Reaction Scheme TU  10‰  R  F  F  R 1 ~ 1 ,,,...  OR 7  protecting  hydroxy group  OH  0  (V)  hydrolysis  R  F  F  10‰  R’~"’"’’  j  0-M’  OR  0  (III)  R  eactian  Scheme TV  R1vo1  FvF  R 1 ’\,,••yyO•M+  HO  OR  0  (III)  OR  (II)  F  HO  1-- F F  ,•  OH  HO‰  OR  0  0  (VIII)  protecting  hydroxy group 