Title of Invention

A NOVEL PROCESS FOR THE PREPARATION OF OPTICALLY ENRICHED SUBSTITUTED R(+)BETA-BENZYL-GAMMA- BUTYROLACTONES

Abstract

The present invention relates to a novel process for the preparation of substituted ß benzyl-γ- butyrolactones .The invention particularly relates to a novel synthetic process for the preparation of substituted ß-benzyl-y-butyrolactone with a micro-organism or an enzyme to produce optically enriched R (-) primary alcohol and cyclisation of the dihydro product with dilute mineral acid to produce substituted ß-benzyl-γ- butyrolactone alternatively bio-reduction of the unsaturated formyl ester with a micro-organism or enzyme to directly produce optically enriched substituted p-benzyl-y-butyrolactone.

Full Text

A NOVEL PROCESS FOR THE PREPARATION OF OPTICALLY ENRICHED SUBSTITUTED R(+) ß-BENZYL-γ-BUTYROLACTONES Field of the Invention The present invention relates to a novel process for the enriched preparation of substituted R (+)ß-benzyl-γ- butyrolactones of the formula (1) (Formula Removed) wherein, R1 and R2 independently represent the following groups R1 = R2 = H, OH, -OC„H2n+1 (n = 1 to 8), NH2, and/or CF3 R1 and R2 together represents -O(CH2)mO- where m = 2 to 4. Background and Prior art References Substituted ß-benzyl-γ-butyrolactones are known for their biological properties such as anticancer activities, and they are also the key intermediates in the synthesis of butyrolactone lignans as well as other natural products. Due to various pharmacological and medicinal properties associated with butyrolactones and related lignans, the chemical synthesis of the intermediate butyrolactones has been the major target of several synthetic schemes. One of the more common synthetic strategies utilizes Stobbes condensation of an aromatic aldehyde with alkyl succinates followed by selective reduction (Banerji, J., Biswanath, D. Heterocycles, 1985, 23(3), 661-5 (b) Shao.L., Miyato, S., Muramatsui, H., Kawano, H, Ishi,Y.,Soburi,M., Uchida.Y. J. Chem. Soc. Perkin Trans. (I), 1990, 5, 1441-5 (c) Marimoto,T.,Chiba,M., Achiwa.K. Tetrahedron , 1993, 49(9), 1793-806). Besides, several novel synthetic methodologies have also been reported for the asymmetrisation of the butyrolactones and the lignans [(a) Vanderlei, J. M. de. L., Coelho, F, and Almeida, W. P. Synth. Comm. 1998, 28(16), 3047-55. (b) Carlton, J. L. Can. J. Chem. 1997, 75(8), 1076-83. (c) Filho,H.C.A.,Filho, U.F.L., Pinheiro, S., Vasconcells, M.L.L.A., Costa, P.R.R. Summary of the invention Accordingly, the present invention provides a novel synthetic process for the enriched preparation of substituted R(+)P-benzyl-y-butyrolactone (1 ) as shown below wherein R and R2 independently or in combination represent the following groups: i.e. R1 = R II -OCnH2n+1 (where n = 1 to 8) ; R1 and R2 together represents -O(CH2)mO- (where m 2 to 4) (Formula Removed) Detailed Description of the accompanying drawing: Figure 1 depicts structure of various compounds obtained in the process of preparation of substituted R(+)P-benzyl-y-butyrolactones,wherein: (1) represents R(+)P-benzyl-y-butyrolactones, (2) represents substituted alkoxybenzene, (3) represents 4-keto-4-phenyl-butync acid, (4) represents 4-keto-4-phenyl-butyrate, (5) represents 4-hydroxy-4-phenyl-butyrate, (6) represents 4-phenyl-3-formyl-3ene-butyrate,and (7) represents optically enriched R(-) dihydro primary alcohol. Detailed description of the invention The present invention therefore discloses a novel, facile and enriched process for the synthesis of substituted R(+)p-benzyl-y-butyrolactones with moderate to high overall yield. The present invention is directed to chemo-enzymatic process of preparation of optically ennchcd substituted R(+)P-benzyl-γ- butyrolactones (1). The process particularly relates to a novel chemo- enzymatic process for the preparation of optically enriched 4-(alkoxy phenyl)-methyl-γ butyrolactones. Accordingly, the present invention relates to a novel process for the preparation of optically enriched substituted R(+)P-benzyl-y- butyrolactones of the general 1 as shown below Summary of the invention Accordingly, the present invention provides a novel synthetic process for the enriched preparation of substituted R(+)P-benzyl-γ-butyrolactone (1 ) as shown below wherein R and R; independently or in combination represent the following groups: i.e. R1- R 11. -OCnH2n+1 (where n = 1 to 8) ; R, and R2 together represents -O(CH2)mO- (where m 2 to 4) (Formula Removed) Detailed Description of the accompanying drawing: Figure 1 depicts structure of various compounds obtained in the process of preparation of substituted R(+)P-benzyl-y-butyrolactones,wherein: (1) represents R(+)ß-benzyl-γ-butyrolactones, (2) represents substituted alkoxybenzene, (3) represents 4-keto-4-phenyl-butyric acid. (4) represents 4-keto-4-phenyl-butyrate, (5) represents 4-hydroxy-4-phenyl-butyrate, (6) represents 4-phenyl-3-formyl-3ene-butyrate,and (7) represents optically enriched R(-) dihydro primary alcohol. Detailed description of the invention The present invention therefore discloses a novel, facile and enriched process for the synthesis ot substituted R(+)ß-benzyl-γ-butyrolactones with moderate to high overall yield. The present invention is directed to chemo-enzymatic process of preparation of optically enriched substituted R(+)ß-benzyl-γ- butyrolactones (1). The process particularly relates to a novel chemo-enzymatic process for the preparation of optically enriched 4-(alkoxy phenyl )-methyl-butyrolactones. Accordingly, the present invention relates to a novel process for the preparation of optically enriched substituted R(+)ß-benzyl-γ- butyrolactones of the general 1 as shown below Chemo-enzymatic process for the preparation of optically enriched p-benzyl-ybutyrolactones The present application claims priority from US Provisional application serial no 60/366,577 filed on March 25, 2002. Field of the Invention The present invention relates to a novel process for the enriched preparation of substituted R (+)p-benzyl-y- butyrolactones of the formula (1) wherein, RI and R2 independently represent the following groups Ri = R2 = H, OH, -OCnH2n+i (n = 1 to 8), NH2, and/or CF3 RI and R2 together represents -O(CH2)mO- where m = 2 to 4. Background and Prior art References Substituted (3-benzyl-y-butyrolactones are known for their biological properties such as anticancer activities, and they are also the key intermediates in the synthesis of butyrolactone lignans as well as other natural products. Due to various pharmacological and medicinal properties associated with butyrolactones and related lignans, the chemical synthesis of the intermediate butyrolactones has been the major target of several synthetic schemes. One of the more common synthetic strategies utilizes Stobbes condensation of an aromatic aldehyde with alkyl succinates followed by selective reduction (Banerji, J., Biswanath, D. Heterocycles, 1985, 23(3), 661-5 (b) Shao.L., Miyato, S., Muramatsui, H., Kawano, H, Ishi,Y.,Soburi,M., Uchida.Y. J. Chem. Soc. Perkin Trans. (I), 1990, 5, 1441-5 (c) Marimoto,T.,Chiba,M., Achiwa,K. Tetrahedron , 1993, 49(9), 1793-806). Besides, several novel synthetic methodologies have also been reported for the asymmetrisation of the butyrolactones and the lignans [(a) Vanderlei, J. M. de. L., Coelho, F, and Almeida, W. P. Synth. Comm. 1998, 28(16), 3047-55. (b) Carlton, J. L. Can. J. Chem. 1997, 75(8), 1076-83. (c) Filho,H.C.A.,Filho, U.F.L., Pinheiro, S., Vasconcells, M.L.L.A., Costa, P.R.R. Tetrahedron Asymm. 1994, 5(7), 1219-20 9 (d) Costo Paulo,R.R..V.Ferreiro J. Braz. Chem Soc. ,1996, 7(1), 67-73. Chem.Abstr. 124:260681y]. In recent years asymmetric syntheses of optically active butyrolactones and corresponding lignans have also been achieved using the chemo-enzymatic methods [(a) Vanderlei, J. M. de. L., Coelho, F. and Almeida, W. P. Synth. Cornm. 1998, 28(16), 3047-55. (b) Carlton, J. L. Can. J. Chem. 1997, 75(8), 1076-83. (c) Filho,H.C.A.,Filho, U.F.L., Pinheiro, S., Vasconcells, M.L.L.A., Costa, P.R.R. Tetrahedron Asymm. 1994, 5(7), 1219-20 9 (d) Costo Paulo,R.R..V.Ferreiro J. Braz. Chem Soc. ,1996, 7(1), 67-73. Chem.Abstr. 124:260681y ]. Most of the known processes or synthesis of substituted (3-benzyl-ybutyrolactones are either inconvenient to carry out on higher scale because of the complexity of the reactions or due to the unavailability of the starting materials. These methods also suffer from low over all yields. They also involve complex experimental conditions, which are lacking reproducibility. Objects of the Invention The main object of the invention is to provide a synthetic process for the enriched preparation of R(+)p-benzyl-y-butyrolactone (1) as shown in the accompanying drawing. Another object of the invention is to provide a economical and environmental friendly process for the preparation of R(+)(3-benzyl-y-butyroIactone Still another object of the invention is to provide a chemo-enzymatic reduction for generation of chirality. Yet another object of the invention is to provide chemo-enzymatic reduction and cyclization process for the intermediates to achieve enriched optically active form of the final compound. Summary of the invention Accordingly, the present invention provides a novel synthetic process for the enriched preparation of substituted R(+)p-benzyl-y-butyrolactone (1 ) as shown below wherein R[ and R2 independently or in combination represent the following groups: i.e. R[ = R2 = H, -OCnH2n+i (where n = 1 to 8) ; RI and R2 together represents - O(CH2)mO- (where m = 2 to 4) (1) Detailed Description of the accompanying drawing: Figure 1 depicts structure of various compounds obtained in the process of preparation of substituted R(+)(3-benzyl-Y-butyrolactones, wherein: (1) represents R(+)(3-benzyl-y- butyrolactones, (2) represents substituted alkoxybenzene, (3) represents 4-keto-4-phenyl- butyric acid, (4) represents 4-keto-4-phenyl butyrate, (5) represents 4-hydroxy-4-phenyl butyrate, (6) represents 4-phenyl-3-formyl-3ene-butrylate, and (7) represents optically enriched R (-) dihydro primary alcohol. Detailed description of the invention The present invention discloses a novel, facile and enriched process for the synthesis of substituted R(+)3-benzyl-Y-butyrolactones with moderate to high overall yield. The present invention is directed to chemo-enzymatic process of preparation of optically enriched substituted R(+)p-benzyl-Y- butyrolactones (1). The process particularly relates to a novel chemo-enzymatic process for the preparation of optically enriched 4-(alkoxy phenyl)-methyl-Y-butyrolactones The present invention relates to a novel process for the enriched preparation of substituted R(+)f3-benzyl-Y- butyrolactones of the general 1 as shown below, wherein, RI and R2 independently represent the following groups R, = R2 = H, OH, -OCnH2n+1 (n = 1 to 8), NH2, and/or CF3 RI and R2 together represents -O(CH2)mO- where m = 2 to 4, and said process comprises the steps of: a) reacting the requisite substituted alkoxybenzene (2) where Rj and R2 having the same meaning as mentioned earlier with succinic anhydride in presence of a Lewis acid in an inert solvent, b) esterification of the resulting product 4-keto-4-phenyl- butyric acid (3) of step (a) to yield 4-keto-4-phenyl butyrate (4), c) reducing the keto group of compound (4) obtained in step (b) to yield the corresponding secondary alcohol 4-hydroxy-4-phenyl butyrate (5), d) reacting the compound (5) of step (c) with a reagent prepared from equimolar mixture of phosphoryl chloride and dimethyl formamide to produce 4-phenyl-3- formyl-3ene-butrylate (6), e) bio-reduction of the unsaturated formyl ester (6) (when RI and R2 substituents are other than H) of step (d) with a micro-organism or an enzyme to produce an optically enriched R (-) dihydro primary alcohol (7) or to obtain a compound of formula 1 (when R2 substituent is H); and f) cyclizing the dihydro primary alcohol (7) of step (e) with dilute mineral acid to produce substituted R(+) (3-benzyl-y- butyrolactone (1) where RI and R2 are as defined above. In an embodiment of the invention, the microorganism or enzyme used in step (e) is selected from a group consisting of Baker's yeast, Candida sp., and Pichia sp. Another embodiment, the substituted alkoxybenzene (2) in step (a), wherein RI and R2 has the same definition as mentioned earlier, is reacted with succinic anhydride in presence of a Lewis acid selected from a group consisting of anhydrous aluminum trichloride, aluminum tribromide, zinc chloride and boron trifluoride ethereate. Still another embodiment, the Lewis acid used is anhydrous aluminum chloride. In an embodiment of the present invention, alternatively optically enriched substituted R(+)p-benzyl-y- butyrolactone (1) is directly obtained by bio-reduction of the unsaturated formyl ester (6) obtained from step (e) with a micro-organism or enzyme selected from Baker's yeast, Candida sp., Pichia sp. In another embodiment of the present invention wherein, RI and R2 substituents of alkoxy benzene (2) have the same meaning as mentioned earlier, which is reacted with succinic anhydride in presence of a Lewis acid selected from a group consisting of anhydrous aluminum trichloride, aluminum tribromide, zinc chloride and boron trifluoride ethereate preferably aluminum chloride. Yet another embodiment of the invention wherein in step (a), the reaction of succinic anhydride is carried out using an inert organic solvent selected from the group consisting of nitromethane, carbon disulfide and/or benzene. Yet another embodiment of the invention wherein in step (b), the esterification of (3) is carried out with an alcohol in presence of an acid selected from a group consisting of sulfuric acid, hydrochloric acid and phosphoric acid and alcohol selected from methanol, ethanol, propanol or mixture thereof. Yet another embodiment of the invention wherein in step (c), the reduction of the keto ester is performed in presence of hydrogen gas using metal catalyst supported on activated charcoal selected from a group consisting of palladium, platinum and nickel. Yet another embodiment of the invention wherein in step (c), the reduction of the keto function may also be carried out using metal hydride reagents selected from a group consisting of sodium borohydride, and sodium cyanoborohydride preferably in an aqueous medium or lithium aluminum hydride in an inert organic solvent selected from diethyl ethrr, tetrahydrofuran or mixtures thereof. Yet another embodiment of the invention wherein in step (d), formylation of the hydroxy ester (4) is carried out at a temperature ranging between -5°C to 50°C using formylating reagent prepared from equimolar mixture of phosphoryl trichloride and dimethyl formamide. Yet another embodiment provides bio-reduction of the unsaturated formyl ester (6) (when Rl and R2 substituents are other than H) with a microorganism or an enzyme to produce an optically enriched R (-) dihydro primary alcohol (7) or to obtain a compound of formula 1 (when R2 substituent is H). Yet another embodiment of the invention wherein in step (e), bioreduction of the prochiral a,(3-unsaturated formyl ester is effected by an microorganism or yeast enzyme selected from group consisting of Baker's yeast, Candida sp., Pichia xp. Yet another embodiment of the invention wherein in step (f), the optically enriched dihydrohydroxymethyl ester (7) is cyclised to produce (1) with a dilute mineral acid selected from a group consisting of sulfuric acid, hydrochloric acid and phosphoric acid. The Lewis acid may be selected preferably from anhydrous aluminum chloride, aluminium tribromide, boron trifluoride, zinc chloride but more preferably aluminium trichloride in an inert organic solvent selected from nitrobenzene, carbon disulphide, benzene but more preferably nitrobenzene. The esterification of the acid (3) is carried out with an anhydrous alcohol preferably methanol, ethanol, propanol more preferably methanol in presence of an acid such as concentrated hydrochloric acid, sulphuric acid, phosphoric acid but more preferably sulphuric acid. Alternatively, the esterification may also be effected by freshly prepared diazomethane to produce methyl ester (4) in quantitative yield. The conversion of substituted 4-keto-4-phenyl butyrate (4) 3 to hydroxy ester (5) is preferably carried out by catalytic reduction using 5% to 10% palladium or platinum on activated charcoal in an alcoholic solvent in presence of hydrogen gas. Alternatively, reduction may also be effected using metal hydride reagents such as sodium borohydride, preferably in an inert or an alcoholic or aqueous medium. It is further preferred that metal hydride such as lithium aluminum hydride reagent is used in an inert solvent such as diethyl ether, tetrahydrofuran or admixture thereof. The formylating reagent prepared from one mole each of phophoryl chloride and dimethyl formamide is reacted with the compound (5) at -10 C to 50 C more preferably at -5°C to +50°C to furnish prochiral a,P-unsaturated aldehyde (6). The bioreduction of the compound (6) where R\ and Ra has same definition as described above, is performed using a bio-catalyst or an enzyme which stereoselectively reduces the double bond as well as capable of simultaneously converting aldehyde function to a primary alcoholic function. The more preferred bio-catalyst to produce optically enriched in R(-) enantiomer (7) is the use of Baker's yeast in which the bioreduction is carried out at!0°C to 50°C preferably at 20°C to 35°C. The pH of the aqueous medium containing D-glucose for bio-reduction is maintained between 6 to 8 more preferably between 6.5 to 7.3. The cyclisation of the intermediate hydroxymethyl ester (7) is prepared as above where the substitiuents R-, and RI have the same meaning as mentioned earlier., preferably effected by a using a mineral acid in an aqueous medium. The preferred acid for cyclisation of compound (7) is hydrochloric acid (20%). Alternatively, the bio-reduction as well as cyclisation to furnish the optically enriched final compound is completed in a single step. In the preferred embodiment use of the term optically enriched R-(+)- (3-benzyl-ybutyrolactone (1) 1 is intended to signify the formation of both (R) and (S) stereoisomers of (3-benzyl-y- butyrolactone (1) wherein one of the stereoisomer i.e. R(+) optical isomer is in large excess, therefore the mixture has overall +ve sign of optical rotation with (R) configuration. The invention is described in examples given below which are given by way of illustration only and therefore these examples should not be construed as to restrict the scope of the invention. EXAMPLE-1 Stey-1 Preparation of 4-(3,4-dimethoxyphenyl)-4-oxo-butyric acid (3) R: = R2 = OCH3) In a three necked flask fitted with a guard tube, a mixture of veratrole (3,4-dimethoxy benzene, 2) (7.0g, (50ml) stirred at 0-5°C and to the mixture is added drop wise a solution of succinic anhydride (6g, 60mmol) in nitrobenzene (60 ml). After the addition is over, the stirring mixture is allowed to attain room temperature and heated up to 60°C for further three hours till the evolution of hydrochloric acid subsides. The reaction mixture is cooled, poured into ice cold water (200ml) and the resulting precipitate is filtered, washed with water. The dried crude acid 3 (10.6g. 89%) is crystallized from methanol: ethyl acetate (1:9) as colorless powder mp 162-63°C, it is analyzed for Cia H,4O5 (found C, 61.44%, H, 5.88% requires C60.49%; H 5.92%). 'H NMR (CD3OD): 2.67 (2H, t, J=6.6 Hz, H-2), 3.27(2H, t, J=6.6 Hz, H-3), 3.86 & 3.89(6H, 2xs, 2xOCH3), 7.02(1H, d, J=8.5 Hz, Ar-H), 7.65(1H, d, J=2.0 Hz, Ar-H), 7.68(1H, dd, J=8.5 & 2.0 Hz, Ar-H). IR (KBr): 3382, 2940, 1730, 1660, 1592, 1504, 1444, 1414, 1332, 1264, 1240, 1140, 1018,874cm'1. Stey-2 Preparation of methyl [4-(3,4-dimethoxyphenyl)-4]-oxo-butyrate (4) Rj = R2 = OCH3) The 4-(3,4-dimethoxyphenyl)-4-oxo-butyric acid (5g.) in diethyl ether is esterified with a freshly prepared ethereal solution of diazomethane to furnish the corresponding ester in quantitative yield, which on crystallization from ethyl acetate/n-hexane gave colorless needles of 4 mp 87°C, analyzed for C]3 H]6 O5 (found C 62.14, H 6.41 requires C 61.89, H 6.39). 'H NMR (CDC13): 2.76 (2H,t,J=7.0 Hz , H-2), 3.22 (2H, t, J=7.0Hz, H-3), 3.56 (3H,s, OCH3), 3.96 (6H, s, 2x OCH3), 6.94 (1H, d, J=8.5Hz, Ar-H), 7.68 (2H, m, Ar-H). 13C NMR: 27.7, 32.2, 51.58, 55.3, 55.4, 109.7, 122.1, 129.3, 148.3,152.7, 174.2, 196.3. IR(KBr): 2876, 1714, 1666, 1592, 1446, 1412, 1380, 1314, 1244, 1210, 1178, 1148, 1088,1020,988,914,872,794cm'1. M+ at m/z : 252 ( 16), 221(7), 206 ( 8), 179 ( 5), 165 (61), 132 (49), 119 (100),91 (36), 89 (79), 74 ( 91). Stev-3 Synthesis of methyl [4-(3,4-dimethoxyphenyl)-4-hydroxy] butyrate (5) To a stirring solution of 4 (3.3g, 13 mmol) in DME (40ml) at 0-5°C is added sodium borohydride (250mg) in small installments and monitored the reaction by TLC. After the completion of the reaction the contents poured in ice cold saturated brine solution (80ml) and extracted with ethyl acetate (5x30ml). The combined organic layer washed with water, dried over anhydrous sodium sulphate and concentrated in vacuum. The obtained semi solid mass on column chromatography on silica gel and elution with dichloromethane/ethyl acetate furnished the alcohol 5, a semi-solid (2.6g) analyzed for C|3H,8O5 (found C 62.31,H 7.22; requires C 61.40, H 7.13). 'H NMR (CDCI3): 2.08(2H, m, CH2-), 2.53(2H, t, J=7.4Hz, CH2COO), 3.65(3H, s, OCH3), 3.89(6H, s, 2x OCH3 ),4.69(1H, t, J=6.6Hz, H-4), 6.82-6.89 (3H, m, Ar-H). I3C NMR: 30.4, 33.8, 51.9,55.8, 55.9, 73.2, 108.9, 111.0, 118.0, 136.8, 148.4, 149.1, 174.3. IR (KBr): 3256, 2880,1718,1594, 1496, 1356, 1332, 1250, 1236, 1144, 1030, 940, 858,812,760cm-'. M+ at m/z : 254 (6), 236(1), 234 (5), 218 (7), 216 (4), 204(5), 188(6), 182(8), 174 (10), 164 (22), 162 (17), 137(22), 136 (100), 121 (17), 105 (18), 90(27). Step-4 Synthesis of methyl [4-(3,4-dimethoxyphenyI)-3-formyl-3-ene]-butyrate (6) To a stirring solution of hydroxy ester 5 (2.3g, 9mmol) in dimethyl formamide (9 ml) at 0-5 C is added phosphoryl chloride (5ml) slowly for 30 minutes. The contents further stirred for one hour maintaining the temperature. The temperature is then raised to 35-40°C and stirring is continued for 36 hours till the completion of the reaction. The contents are then poured in cold water (200 ml) and the resulting precipitate filtered. The aqueous layer extracted with ethyl acetate (3x20 ml). The combined solid and organic layer washed with water, dried, concentrated and chromatographed over silica gel using ethyl acetate: chloroform (1:4) as eluent to give a light yellow compound 6 (1.4g, 59.5%). mp 61°C, analyzed for CH Hi6 Os ( found C 64.11, H 6.09%; requires C 63.62, H 6.10). 'H NMR (CDC13): 3.56 (2H, s, CH2-), 3.64 (3H, s, OCH3), 3.86 (6H, 2xs, 2x OCH3), 6.88 (1H, d, J=8.5 Hz, Ar-H), 7.00 (3H, m, Ar-H), 7.05(1H, s, Ar-H), 7.37 (1H, s, =CH), 9.56 (1H, s, CHO). 13C NMR: 30.7, 52.2, 55.9, 55.9, 111. 2, 112.3, 124.1, 126.9, 133.2,149.1, 150.9, 152.2, 172.2, 193.2. IR (KBr): 2832, 1752, 1590, 1512, 1456, 1424, 1352, 1266, 1240, 1152, 1022, 864, 808 cm'1. M+ at m/z : 264 (26), 263 (91), 248 (11), 235 (41), 232 (25), 204 (39), 176 (100), 160 (92), 145 (60), 131 (25), 115 ( 25), 103(24), 91(28), 89 (28). Stev-5 Synthesis of optically enriched R(-)methyl-[4-(3,4-dimethoxyphenyl)-3- hydroxymethyl]-butyrate (7) ( R! = R2 = OCH3) A mixture of Baker's yeast (3g, dry powder) and D-glucose (3g) in distilled water (60ml) was stirred ar 30°C in a fermentation flask with a bubbler for 10 minutes after which an ethanolic solution of formyl ester 6 (173 mg, 3 ml) is added to it. The mixture stirred at 30°C for 50 hours with TLC, monitoring and after the consumption of 6, filtered through a pad of celite (2 g) and extracted with chloroform (5x20 ml). The combined chloroform layer washed and dried (Sod. sulphate), concentrated under reduced pressure. The concentrated material is purified over silica gel using chloroform: ethyl acetate (9:1). The purified product 7 (100 mg, 62.5%) a semi-solid is analyzed for C14 H20 O5 (found C 62.92 , H 7.55% ; requires C 62.67, H 7.50%).[a] D 2 5 -3.4° (c, 1.4,CHC13). Step-6 Preparation of optically enriched R(+)4-(3,4 dimethoxybenzyl) -y- butyrolactone )- - (1) ( RI = RI = -OCHa) A suspension of 7 (60 mg) and dilute hydrochloric acid (10%, 5 ml) heated at 70°C for 20 minutes with stirring. The product processed as described for the preparation of racemic lactone above to furnish optically enriched 1, mp 108-109°C, analysed for d3 Hi6 O4 (found C 66.12, H 6.87; requires C 66.08, H 6.82) [a] D 2 5 + 10.5° (c, 0.24,CHC13); reported [a] D 2 5 +23.8° (ee, 94%)3b. EXAMPLE-2 Step-1 Preparation of 4-(4-methoxyphenyl)-4-oxo-butyric acid (3) (Riand R:= OCHs and H): The title compound was prepared from anisole (llg, 102 mmol) and succinic anhydride (12g, 120 m mol) in presence of anhydrous aluminum chloride (30g) by the same method as described for 2 above to furnish 4-(4-methoxyphenyl)-4-oxo-butanoic acid in 84.6% yield, which on purification and crystallization from methanol/ethyl acetate (1:9) produced white crystals of 3 , mpl42-43°C , analyzed for Cn Hi2 O4 (found C64.21, H5.86 ; requires C63.45, H5.80%). 'H NMR (CDCb+DMSO-de): 2.70 ( 2H, t, J=6.5 Hz, H-2), 3.26 (2H, t, J=6.5 Hz, H- 3), 3.93 (3H, s, OCH3), 7.04 (2H, d,J=8.5 Hz, Ar-H), 8.05 ( 2H, d, J= 8.5, Ar-H). 13C NMR (CDCb+DMSO-da): 28.1, 32.9 , 55.4, 114.2, 129.7, 130.1, 162.7, 174.6, 196.7. IR (KBr): 2844, 1670, 1600, 1574, 1426, 1358, 1316, 1246, 2120, 1026, 930, 830 cm' M+ at m/z, 208 (40), 135 (83), 120 (12), 106 (69), 91 (100), 77 (!00). Stev-2 Preparation of methyl[4-(4-methoxyphenyl)-4-oxo]butyrate (4) (Ri and RI = OCH3 and H) The 4-oxo-4-phenyl butyric acid derivative (3) (10.16g) was esterified in dry methanol (25 ml) in presence of concentrated sulfuric acid (0.5ml) and refluxing the contents on a water bath for an hour and removing the solvent at reduced pressure after neutralization of the acid followed by column chromatography over silica gel to furnish 4 (10.90 g), which is crystallized from ethyl acetate: hexane (1:4) mp 46°C analyzed for C12 H14 O4 (found C65.46, H 6.42; requires C 64.85, H 6.34%). 'H NMR (CDC13): 2.75 ( 2H, t, J=6.5 Hz, H-2), 3.28 (2H, t, J=6.5 Hz, H-3), 3.75 (2H, t, COOCH3), 3.90 (3H, s, OCH3), 7.00 (2H, d,J=8.5 Hz, Ar-H), 8.05 ( 2H, d, J= 8.5, Ar-H). 13C NMR: 28.1, 33.0, 51.8,55.45.5,113.8129.6,130.3163.6,173.5,196.6. IR (KBr): 2844, 1704, 1670, 1600, 1516, 1426, 1358, 1310, 1*240, 1174, 1120, 1060, 1022,986,944,830cm'1. M+ at m/z, 222 (13), 191(19), 135 (100), 107 (18), 97 (27), 92(27), 77 (37). Step-3 Synthesis of methyl [4-(4-methoxyphenyl)-4-hydroxy] butyrate (5) Reduction of (4) was carried out with sodium borohydride (7.0g, 31 mmol) by a similar process as described in example 1, the reduced product purified by column chromatography over silica gel using dichloromethane: ethyl acetate (19:1) as eluant to give a semi-solid 5 (6.4g) which is analyzed for C\% Hi6 di (found C 64.93, H 7.23; requires C64.27, H 7.19%). 'H NMR (CDC13): 1.98-2.10 (2H, m, H-3), 2.40(2H, t, J=7Hz, H-2), 3.65 (3H, s, COOCH3), 3.83 (3H, s, OCH3), 4.66 (1H, t, J=6.5 Hz, H-4), 6.94(2H, d, J= 8.5 Hz, Ar-H), 7.33(2H, d, J= 8.5 Hz, Ar-H). I3C NMR: 30.3, 33.7, 51.5, 55.07, 72.6, 113.6, 126.9, 131.0, 136.3, 158.8, 174.2.IR (KBr): 3392, 2884, 1712, 1678, 1604, 1512, 1440, 1362, 1240, 1172, 1114,1060, 1026,944,888cm-'. M+ at m/z : 224 (2), 223 (6), 206(3), 205 (7), 191 (15), 149 (21), 136 (100), 134 (21), 108 (28), 93 (12), 76 (29). Stev-4 Synthesis of methyl[4-(4-methoxyphenyl)-3-formyl-3-ene]-butyrate (6) Formylation of 5 (4.5g, 20 mmol) was carried out with Vilsmeiers reagent as described in example 1. The product purified by column chromatography with petroleum ether: ethyl acetate (9:1) to furnish 6 as a light yellow solid (2.38g, 51%), mp 54-56°C, analyzed for d3 H14 O4 (found C 67.13, H 6.09; requires C66.65, H 6.02). 'H NMR (CDC13): 3.59 (2H, s,CH2), 3.72(3H, s, COOCH3), 3.89 (3H, s, OCH3 ), 7.03 (2H, d, J= 8.5 Hz, Ar-H), 7.53(1H, s, =CH), 7.56 (2H, d, J= 8.5 Hz, Ar-H), 9.66 (1H, s, CHO). 13C NMR: 30.7, 52.3, 55.5, 114.6, 126.8, 131.3, 133.3, 148.3, 161.4, 171.0, 194.3. IR (KBr) : 2828, 1722, 1666, 1632, 1602, 1494, 1452, 1438, 1416, 1380, 1340, 1316, 1306, 1254, 1200, 1166, 1066, 1018, 1004, 942, 912, 878, 834, 772 cm'1. M+ at m/z : 234(6), 233 (42), 205 (96), 202 (31), 174 (31), 159 (24), 146 (100), 134 (14), 107(17). Synthesis of optically enriched R (+) 4-(4-methoxybenzyl)-y butyrolactone (1) (R,and R2= -OCH3 and H): An ethanolic solution of 6 (160 mg, 3 ml) is added to a stirring mixture of Baker's yeast (dry powder, 2.5g) and D-glucose (2.1g) in distilled water (80 ml, pH 6.8) and the contents stirred at 30°C under anaerobic conditions using a bubbler. The reaction is monitored by TLC and after the consumption of the starting material the contents worked up by the method as described in example 1 to furnish crude bio-product 12 (0.13g) which on chromatographic purification on silica gel column and elution with petroleum ether: ethyl acetate (9:1) gave (+)-! (80 mg, 57%) analyzed for C\2 Hu O3 (found C 70. 13, H 6.18; requires C 69.89, H 6.84). 'H NMR (CDCI3): 2.27 (1H, dd, J=6.7 & 17.45 Hz, H-2), 2.52-2.72(4H, m, 2x CH2), 3.80 (3H, s, OCH3 ), 4.04 (lH,dd, J=5.90 & 8.17 Hz, CH2O), 4.31(lH,dd, J=6.65 & 9.03 Hz, -OCH2), 6.81(2H, d, J= 8.5 Hz, Ar-H), 7.08 (2H, d, J= 8.5 Hz, Ar-H). I3C NMR: 34.3, 37.3, 38.0, 55.2. 72.7, 1 13.8, 130.0, 130-3, 158.5, 177.0. IR (KBr): 2884, 2848, 1732, 1614, 1510, 1460, 1378, 1356, 1302, 1248, 1176, 1030, 846,834,752cm"1. M+ at m/z : 206 (8), 192(3), 147 (6), 121 (100), 103 (8), 91 (20), 78 (35). Advantages: 1. The synthetic process for the preparation of optically enriched substituted (3- benzyl-y- butyrolactone is novel. 2. The synthetic process is facile and economical 3. The yield of the final product optically enriched substituted (3-benzyl-ybutyrolactone is moderate to good. 4. Use of enzymes is being made for generation of chirality at the intermediate stage, which makes the process environmental friendly. 5. The final product itself possess biologically active or can easily be as a intermediates for the preparation of other class of biologically active compounds. We Claim : 1 A novel process for the preparation of optically enriched substituted R(+)β-benzyl-γ- butyrolactones of the general formula 1 as shown below, (Formula Removed) wherein, R1 and R2 independently or in combination represent the following groups R1= R2 = H, -OCnH2n+1 where n = 1 to 8, NH2 and /or CF3 R1 and R2 together represents -O(CH2)mO- where m = 2 to 4 and said process comprises the steps of: a) reacting the requisite substituted alkoxybenzene (2) where R1 and R2 having the same meaning as mentioned earlier with succinic anhydride in presence of a Lewis acid in an inert solvent; b) esterification of the resulting product 4-keto-4-phenyl- butyric acid (3) of step (a) to yield 4-keto-4-phenyl butyrate (4); c) reducing the keto group of compound (4) obtained in step (b) to yield the corresponding secondary alcohol 4-hydroxy-4-phenyl butyrate (5); d) reacting the compound (5) of step (c) with a reagent prepared from equimolar mixture of phosphoryl chloride and dimethyl formamide at -5 to 50°C to produce 4-phein lo-formyl-3ene-butrylate (6); e) bio-reduction of the unsaturated formyl ester (6) (where R| and R2 of substituents are other than H ) step (d) with a micro-organism or an enzyme to produce optically enriched R (-) dihydro primary alcohol (7) or to obtain a compound of formula 1 when R2 substituents is H ); and f) cyclizing of the dihydro primary alcohol (7) of step (e) with dilute mineral acid to produce substituted R(+) ß-benzyl-γ- butyrolactone (1) where R1 and R2 are as defined above. 2. The process as claimed in step (f) of claim 1 wherein,in step (e), the microorganism or enzyme is selected from Baker's yeast, Candida sp., Pichia sp. 3. The process as claimed in claim 1,wherein in step (a) the substituted alkoxyben/cnc (2) wherein R1 and R2 has the same definition as mentioned earlier, is reacted with succinic anhydride in presence of a Lewis acid selected from a group consisting of anhydrous aluminum trichloride, aluminum tribromide, zinc chloride and boron trifluoride ethereate. 4. The process as claimed in claim 3, wherein the Lewis acid used is anhydrous aluminium chloride. 5. The process as claimed in claim 1, wherein in step (a) the reaction of succinic anhydride is carried out in an inert organic solvent selected from the group consisting of nitromethane, carbon disulfide and benzene. 6. The process as claimed in claim 1, wherein, in step (b) the esterification of (3) is carried out with an alcohol in presence of an acid selected from a group consisting of sulfuric acid, hydrochloric acid and phosphoric acid and alcohol is selected from methanol, ethanol, propanol or mixtures thereof. 7. The process as claimed in claim 1 in step (c) wherein, the reduction of the keto ester is performed in presence of hydrogen gas using metal catalyst supported on activated charcoal selected from a group consisting of palladium, platinum and nickel. 8.The process as claimed in claim 1, wherein in step (c) the reduction of the keto function may also be carried out using metal hydride reagents selected from a group consisting of sodium borohydride, and sodium cyanoborohydride preferably in an aqueous medium or lithium aluminum hydride in an inert organic solvent selected IVom dimethyl ether, tetrahydrofuran or admixtures thereof. 9. The process as claimed in claim 1, wherein, in step (e) bioreduction of the proclural a,p-unsaturated formyl ester(6) is effected by an microorganism or yeast en/yme selected from group consisting of Baker's yeast, Candida sp., Pichia spcies, 10. The process as claimed in claim 1, wherein, in step (f) the optically enriched hydroxymethyl ester (7) is cyclised with a dilute mineral acid selected from a group consisting of sulfuric acid, hydrochloric acid and phosphoric acid. 11 .A novel process for the preparation of optically enriched substituted R(+)ß-benzyl-γ-butyrolactones substantially as herein described with reference to the examples and drawings accompanying the specification .

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