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Title:
DIPHENYLOXIRANES, PROCESS FOR PREPARATION THEREOF, AND ITS USE IN AN ENANTIOSELECTIVE SYNTHESIS OF (+)-SERTRALINE
Document Type and Number:
WIPO Patent Application WO/2016/088138
Kind Code:
A1
Abstract:
The present invention discloses substituted diphenyloxiranes and process for synthesis thereof. The present invention also provides a process for production of enantiomerically pure anti-3,3'-diphenylmethyloxirane and anti-3,3'-diphenylpropan- 1,2-diol from racemic anti-3,3'-diphenylmethyloxirane using hydrolytic kinetic resolution. Further it provides a process for preparation of enantioselective (+)- Sertraline from anti-3,3'-diphenylpropan-1,2-diol.

Inventors:
SURYAVANSHI, Gurunath Mallappa (National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 8, 411008, IN)
SUDALAI, Arumugam (National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 8, 411008, IN)
KAMBLE, Rohit Balkrishna (National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 8, 411008, IN)
Application Number:
IN2015/050182
Publication Date:
June 09, 2016
Filing Date:
December 01, 2015
Export Citation:
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Assignee:
COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH (Anusandhan Bhawan, Rafi Marg, New Delhi 1, 110001, IN)
International Classes:
C07D301/02; C07B57/00; C07C33/46; C07C211/41; C07C211/42; C07D303/08
Foreign References:
EP0093526A21983-11-09
US4211549A1980-07-08
US4629492A1986-12-16
Other References:
SHIJUN ZHANG ET AL: "Discovery of Novel Trisubstituted Asymmetric Derivatives of (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol, Exhibiting High Affinity for Serotonin and Norepinephrine Transporters in a Stereospecific Manner", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 48, no. 15, 22 June 2005 (2005-06-22), pages 4962 - 4971, XP008128170, ISSN: 0022-2623, DOI: 10.1021/JM049021K
JUDITH A. CLARK ET AL: "Substituted 3-Amino-1,1-diaryl-2-propanols as Potential Antidepressant Agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 11, 1 January 1979 (1979-01-01), pages 1373 - 1379, XP055252264, Retrieved from the Internet [retrieved on 20160223]
CHITTARANJAN BHANJA ET AL: "Asian Journal of Biochemical and Pharmaceutical Research Synthesis Design of TOP-selling Anti-Depressant Drug "Sertraline": A Retrosynthetic Approach", ASIAN JOURNAL OF BIOCHEMICAL AND PHARMACEUTICAL RESEARCH ISSUE, 1 January 2012 (2012-01-01), XP055252330, Retrieved from the Internet [retrieved on 20160223]
ALEXANDRE ALEXAKIS ET AL: "Iridium-Catalyzed Asymmetric Allylic Substitution with Aryl Zinc Reagents", ORGANIC LETTERS, vol. 9, no. 17, 1 August 2007 (2007-08-01), US, pages 3393 - 3395, XP055252513, ISSN: 1523-7060, DOI: 10.1021/ol0713842
JULIO CEZAR PASTRE ET AL: "Remarkable Electronic Effect on the Diastereoselectivity of the Heck Reaction of Methyl Cinnamate with Arenediazonium Salts: Formal Total Synthesis of ( )-Indatraline and ( )-Sertraline", ADVANCED SYNTHESIS & CATALYSIS, vol. 351, no. 9, 1 June 2009 (2009-06-01), DE, pages 1217 - 1223, XP055252428, ISSN: 1615-4150, DOI: 10.1002/adsc.200900032
BHASKAR GOPISHETTY ET AL: "An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2,4,5)-2-benzhydryl-5-((4-methoxybenzyl)amino)tetrahydro-2-pyran-4-ol (D-142)", TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 22, no. 10, 17 May 2011 (2011-05-17), pages 1081 - 1086, XP028260504, ISSN: 0957-4166, [retrieved on 20110527], DOI: 10.1016/J.TETASY.2011.05.012
R S REDDY ET AL.: "Co(III)(salen)-catalyzed HKR of two stereocentered alkoxy- and azido epoxides: a concise enantioselective synthesis of (S,S)-reboxetine and (+ )-epi-cytoxazone", CHEM. COMMUN., vol. 46, 2010, pages 5012 - 5014
TOKUNAGA ET AL.: "Asymmetric catalysis with water: efficient kinetic resolution of terminal epoxides by means of catalytic hydrolysis", SCIENCE, vol. 277, no. 5328, 15 August 1997 (1997-08-15), pages 936 - 8
SCHAUS SE ET AL.: "Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols", J AM CHEM SOC., vol. 124, no. 7, 20 February 2002 (2002-02-20), pages 1307 - 15
KURESHY RI ET AL.: "Improved catalytic activity of homochiral dimeric cobalt-salen complex in hydrolytic kinetic resolution of terminal racemic epoxides", CHIRALITY, vol. 17, no. 9, November 2005 (2005-11-01), pages 590 - 4
HITOSHI TANAKA ET AL.: "Two Diphenylpropan-1,2-diol Syringates from the Roots of Erythrina variegate", J. NAT. PROD., vol. 65, no. 12, 2002, pages 1933 - 1935
PASTREA, J. C.; CORREIA, C. R. D: "Remarkable Electronic Effect on the Diastereoselectivity of the Heck Reaction of Methyl Cinnamate with Arenediazonium Salts: Formal Total Synthesis of (±)-Indatraline and (±)-Sertraline", ADV. SYNTH. CATAL., vol. 351, 2009, pages 1217
EBNER, C.; PFALTZ, A: "Chiral dihydrobenzo[1,4]oxazines as catalysts for the asymmetric transfer-hydrogenation of a,p-unsaturated aldehydes", TETRAHEDRON, vol. 67, 2011, pages 10287
ALOKE DUTTA ET AL.: "An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (2S,4R,5R)-2-benzh.ydryl-5-((4-methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142", TETRAHEDRON ASYMMETRY, vol. 22, no. 10, 31 May 2011 (2011-05-31), pages 1081 - 1086
SARGES, R.; TRETTER, J.R.; TENEN, S.S.; WEISSMAN, A: "5,8-Disubstituted 1-aminotetralins. Class of compounds with a novel profile of central nervous system activity", J. MED. CHEM., vol. 16, 1973, pages 1003
Attorney, Agent or Firm:
KOUL, Sunaina et al. (RCY House, C-235 Defence Colony, New Delhi 4, 110024, IN)
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Claims:
We claim

1. A compound of formula I

Formula I

wherein

Ri, R2 and R3 are selected from group consisting of H, CI, F or Br with the proviso that R2 and R3 are not H at the same time;

R4 is selected from (a) or (b)

(a) (b)

2. The compound as claimed in claim 1, wherein representative compound of

Formula I is selected from the group consisting of:

(S)-2-((S)-(4-bromophenyl)(phenyl)methyl)oxirane[(-)-I(la)];

(R)-2-((R)-(4-chlorophenyl)(phenyl)methyl)oxirane [(-)-I(2a)] ;

(R)-2-((R)-(4-fluorophenyl)(phenyl)methyl)oxirane [(+)-I(3a)] ;

(R)-2-((R)-(2-fluorophenyl) (phenyl)methyl)oxirane [(-)-I(4a)];

(S)-2-((S)-(3,4-Dichlorophenyl)(phenyl)methyl) oxirane (-)-I(5a)];

(2R,3R)-3-(4-bromophenyl)-3-phenylpropan- 1 ,2-diol [(-)-I( lb)] ;

(2S,3S)-3-(4-chlorophenyl)-3-phenylpropan-l,2-diol [(+)-I(2b)]; (2S,3S)-3-(4-fluorophenyl)-3-phenylpropan-l, 2-diol [(-)- I(3b)]; (2S,3S)-3-(2-fluorophenyl)-3-phenylpropan-l,2-diol [(+)-I(4b)]; and (2R,3R)-3-(3,4-dichlorophenyl)-3-phenylpropan-l ,2-diol [(-)-I(5b)].

3. A process for the preparation of the compound of Formula I as claimed in claim 1, wherein said process comprises: a) reacting phenyl methyl cinnamate (A) with arenediazonium tetrafluoroborate (B) in presence of Pd(OAc)2 to get the {Ε)-β, ? '-diphenyl cinnamate; b) reducing the (Ε)-β, β '-diphenyl cinnamate of step (a) using Diisobutylaluminium hydride (DIBAL-H) to get allylic alcohol; c) hydroborating the allylic alcohol of step (b) using borane -dimethyl sulphide and hydrogen peroxide (H202) to get racemic anti- β, T-diphenylpropan- 1 , 2-diol; d) monotosylating the racemic anti- β, β '-diphenylpropan- 1 ,2-diol of step (c) using dibutyltinoxide and 4-Dimethylaminopyridine (DMAP) followed by epoxidation using potassium carbonate in methanol to get desired racemic anti- ? ,β '- diphenylmethyloxiranes ; e) adding acetic acid to a solution of (S, 5)-Co-salen in toluene followed by stirring at a temperature ranging from 20 to 25 °C in open air for a period ranging from 20 to 30 minutes to get a dark brown colored solution; f) adding water and racemic anti-3,3 '-diphenylmethyloxirane obtained in step (d) to the dark brown colored solution of step (e) at 0°C to get a reaction mixture, followed by stirring the reaction mixture for 12-13 hours at a temperature ranging from 20-25°C to obtain chiral anti-3,3'-diphenylpropane-l, 2-diol compound of formula (Ia-Ie) and anti-3,3'-diphenylmethyloxirane compound of formula (Ila-IIe).

4. The process as claimed in claim 3, wherein the yield of racemic anti-β ,β'- diphenylmethyloxiranes in step (d) is greater than 85%.

5. The process as claimed in claim 3, wherein the yield of compound of formula

(Ila-IIe) in step (f) is greater than 45 % with upto 98% ee.

6. A process for preparation of enantioselective (+)-Sertraline (III)

e

Formula III

using anti-3, 3 '-diphenylpropan- 1 ,2-diol (He) as claimed in claim 2, said process comprising:

a. stirring a solution of compound lie, a solvent, and sodiumperiodate at a temperature ranging from 15-20°C for 4 hours to obtain (R)-2-(3,4- Dichlorophenyl)-2-phenylacetaldehyde;

b. refluxing the solution of (R)-2-(3,4-Dichlorophenyl)-2-phenylacetaldehyde obtained in step (a) in dry benzene and Pli3P=CHC02Me at 20-25°C for 8-10 hours to obtain Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate;

c. stirring the solution of Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate obtained in step (b) in methanol followed by addition of Pd/C under hydrogen atmosphere at a temperature ranging from 25-30°C for 6-8 hours to obtain Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate; d. refluxing the solution of Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate obtained in step (c) in a mixture of alcohol: water and sodium hydroxide for 20-24 hours to obtain (R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid;

e. stirring the solution of t(R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid obtained in step (d) in dichloromethane and chlorosulfuric acid at a temperature ranging from 20-25°C for 2-3 hours to obtain (S)-4-(3,4-Dichlorophenyl)-3,4- dihydronaphthalen-l(2H)-one;

f. adding methylamine in THF and titanium tetrachloride to the solution of (S)-4-(3,4- Dichlorophenyl)-3,4-dihydronaphthalen-l(2H)-one obtained in step (e) in a diethyl ether at -78°C to obtain a reaction mixture, followed by stirring the reaction mixture at a temperature ranging from 25-30°C for overnight to obtain desired (+)- Sertraline compound of formula III.

7. The process as claimed in claim 6, wherein the solvent used in step (a) is ethanol or water.

8. The process as claimed in claim 6, wherein the yield is more than 11 % with upto 98% ee.

AMENDED CLAIMS

received by the International Bureau on 03 May 2016 (03.05.16)

We claim

1. A compound of formula I

Formula I

wherein

R 1= CI

R2 = C1

R3 = H

R4 is selected from (a) or (b) having anto stereochemistry with adjacent streocentre.

(a) (b)

2. The compound as claimed in claim 1, wherein compounds of Formula lare: (S)-2-((S)-(3,4-Dichlorophenyl)(phenyl)methyl) oxirane (-)-I(5a)];

AMENDED SHEET (ARTICLE 19) (2R,3R)-3-(3,4-dichlorophenyl)-3-phenylpropan- 1 ,2-diol [(-)-I(5b)].

3. A process for the preparation of the compound of Formula I as claimed in claim 1, wherein said process comprises: a) reacting methyl cinnamate (A) with arenediazonium tetrafluoroborate (B) in presence of Pd(OAc)2 to get the (Ε)-β, iphenyl methyl cinnamate; b) reducing the (Ε)-β, -phenyl methylcinnamate of step (a) using Diisobutylaluminium hydride (DIBAL-H) to get allylic alcohol; c) hydroborating the allylic alcohol of step (b) using borane-dimethyl sulphide and hydrogen peroxide (H202) to get racemic anti- β, ? '-diphenylpropan-l ,2-diol; d) monotosylating the racemic anti- β, ? '-diphenylpropan-r l,2-diol of step (c) using dibutyltinoxide and 4-Dimethylaminopyridine (DMAP) followed by epoxidation using potassium carbonate in methanol to get desired racemic anti- ? ,β '- diphenylmethyloxiranes; e) adding acetic acid to a solution of (S, S)-Co-salen in toluene followed by stirring at a temperature ranging from 20 to 25°C in open air for a period ranging from 20 to 30 minutes to get a dark brown colored solution; f) adding water and racemic anti-3,3'-diphenylmethyloxirane obtained in step (d) to the dark brown colored solution of step (e) at 0°C to get a reaction mixture, followed by stirring the reaction mixture for 12-13 hours at a temperature ranging from 20-25°C to obtain chiral anti-3,3 '-diphenylpropane-l,2-diol compound of formula (5b) and anti-3,3'-diphenylmethyloxirane compound of formula (5a).

AMENDED SHEET (ARTICLE 19)

R 1=C1 R2 = C1 R3 = H

The process as claimed in claim 3, wherein the yield of racemic anti-β ,β'- diphenylmethyloxiranes in step (d) is greater than 85%.

The process as claimed in claim 3, wherein the yield of compound of formula (Ila-IIe) in step (f) is greater than 45 % with upto 98% ee.

A process for preparation of enantioselective (+)-Sertraline (III)

e

Formula III

AMENDED SHEET (ARTICLE 19) using anti-3,3 '-diphenylpropan-l,2-diol (5b) as claimed in claim 2, said process comprising:

a. stirring a solution of compound 5b, a solvent, and sodiumperiodate at a temperature ranging from 15-20°C for 4 hours to obtain (R)-2-(3,4- Dichlorophenyl)-2-phenylacetaldehyde; b. refluxing the solution of (R)-2-(3,4-Dichlorophenyl)-2-phenylacetaldehyde obtained in step (a) in dry benzene and Ph3P=CHC02Me at 20-25°C for 8-10 hours to obtain Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate; c. stirring the solution of Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate obtained in step (b) in methanol followed by addition of Pd/C under hydrogen atmosphere at a temperature ranging from 25-30°C for 6-8 hours to obtain Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate; d. refluxing the solution of Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate obtained in step (c) in a mixture of alcohol:water and sodium hydroxide for 20-24 hours to obtain (R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid; e. stirring the solution of t(R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid obtained in step (d) in dichloromethane and chlorosulfuric acid at a temperature ranging from 20-25°C for 2-3 hours to obtain (S)-4-(3,4-Dichlorophenyl)-3,4- dihydronaphthalen- 1 (2H)-one;

AMENDED SHEET (ARTICLE 19) f. adding methylamine in THF and titanium tetrachloride to the solution of (S)-4-(3,4- Dichlorophenyl)-3,4-dihydronaphthalen-l(2H)-one obtained in step (e) in a diethyl ether at -78°C to obtain a reaction mixture, followed by stirring the reaction mixture at a temperature ranging from 25-30°C for overnight to obtain imine.desired (+)- Sertraline compound of formula III. g. imine obtained in step (f) hydrogenated over Raney-Ni catalyst using methanol as solvent to obtain compound of formula III.

7. The process as claimed in claim 6, wherein the solvent used in step (a) is ethanol or water.

8. The process as claimed in claim 6, wherein the yield is more than 11 % with upto 98% ee.

AMENDED SHEET (ARTICLE 19)

Description:
DIPHENYLOXIRANES, PROCESS FOR PREPARATION THEREOF, AND ITS USE IN AN ENANTIOSELECTIVE SYNTHESIS OF (+)-SERTRALINE

FIELD OF THE INVENTION

The present invention relates to compounds of formula 1 and process for synthesis thereof. Particularly the present invention relates to the process for production of enantiomerically pure anti-3, 3 '-diphenylmethyloxirane and anti-3, 3 '-diphenylpropan- 1,2-diol from racemic anti-3, 3 '-diphenylmethyloxirane using hydrolytic kinetic resolution. More particularly, the present invention relates to a process for preparation of enantioselective (+)-Sertraline from anti-3, 3 '-diphenylpropane- 1 ,2-diol.

BACKGROUND OF THE INVENTION

The substituted diphenylmethyl moiety is an important core structure for number of natural products and biologically active pharmaceutical agents. Due to their interesting biological activity in medicinal chemistry, an efficient catalytic method for their enantiopure synthesis of substituted β,β '-diphenylpropan- 1 ,2-diol and β,β '- diphenylmethyloxiranes is of current interest.

EP 0093526 A2 relates to a process for the production of epoxides of the formula in which the benzene ring A is substituted with 1 to 3 halogen atoms, which are the same or different, and optionally carries other substituents, and R' is

which is the same as or different from the other group or Ci-6 alkyl.

Article titled, "Nucleophilic Cleavage of (25,35)-3-Phenylglycidol" by Seiichi Takano, Masashi Yanase, and Kunio Ogasawara in Heterocycles, 1989, 29, 249 reports the synthesis of P,P'-diphenylpropane-l,2-diol from a nucleophillic attack of Gillman reagent at the benzylic position of (25,35)-3-phenylglycidol. This method suffers from the drawback of use of stoichiometric amounts of organometalic reagent and low diastereoselectivity of formed diol.

US 4,211,549 relate to novel substituted oxirane compounds, useful as herbicidal agents and in the control of green foxtail in the presence of corn, sorghum and soybeans.

US 4629492 A relates to novel substituted oxirane compounds, useful as herbicidal compounds.

Article titled, "Co(III)(salen)-catalyzed HKR of two stereocentered alkoxy- and azido epoxides: a concise enantioselective synthesis of (5,5)-reboxetine and (+)-epi- cytoxazone" R S Reddy et al. in Chem. Commun., 2010, 46, 5012-5014 reports the HKR of racemic syn- or anti- alkoxy- and azido epoxides catalyzed by Co(salen) complex affords a practical access to a series of enantioenriched syn- or anti- alkoxy- and azido epoxides and the corresponding 1,2-diols. This strategy has been successfully employed in the concise, enantioselective synthesis of bioactive molecules such as (5,5)-reboxetine and (+)-ep -cytoxazone.

Article titled, "Asymmetric catalysis with water: efficient kinetic resolution of terminal epoxides by means of catalytic hydrolysis" by Tokunaga M et al. in Science. 1997 Aug 15, 277(5328):936-8 reports that readily accessible synthetic catalysts (chiral cobalt - based salen complexes) have been used for the efficient asymmetric hydrolysis of terminal epoxides. This process uses water as the only reagent, no added solvent, and low loadings of a recyclable catalyst (<0.5 mole percent), and it affords highly valuable terminal epoxides and 1 , 2-diols in high yield with high enantiomeric enrichment.

Article titled, "Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioennched terminal epoxides and 1, 2-diols" by Schaus SE et al. in J Am Chem Soc. 2002 Feb 20;124(7): 1307-15 reports the hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. The reaction has several appealing features from a practical standpoint, including the use of H 2 0 as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2- diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)0. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.

Article titled "Optically pure γ-butyrolactones and epoxy esters via two stereocentered HKR of 3-substituted epoxy esters: a formal synthesis of (-)-paroxetine, Ro 67-8867 and (+)-eldanolide" by DA Devalankar et al. published in Org. Biomol. Chem., 2013, 11, 1280-1285 reports the HKR of racemic anti- or syn-3 -substituted epoxy esters catalyzed by a Co(III)salen complex provides ready access to the corresponding enantioenriched 3,4-disubstituted γ-butyrolactones and 3-substituted epoxy esters. This strategy has been successfully employed in the formal synthesis of biologically active 3,4-disubstituted piperidine derivatives, (-) -paroxetine and Ro 67-8867 and a natural product, (+)-eldanolide.

1 ^

Article titled, "Improved catalytic activity of homochiral dimeric cobalt-salen complex in hydrolytic kinetic resolution of terminal racemic epoxides" by Kureshy RI et al. in Chirality. 2005 Nov; 17(9): 590-4 reports Enantiomerically pure epoxides (99%, ee) and diols (98%, ee) from racemic epichlorohydrin, 1 ,2-epoxypropane, 1 ,2-epoxyhexane, 1 ,2-epoxyoctane, and 1,2-epoxydodecane were obtained in 2-12 h by hydrolytic kinetic resolution (HKR) using the recyclable dimeric homochiral Co(III)-salen complex Γ (0.2 mol %) derived from 5,5-(2',2'-dimethylpropane)-di-[(R,R)-{N-(3-tert- butylsalicylidine)-N'-(3',5'-di-tert-butylsalicylidine) } - 1 ,2-cyclohexanediamine] with cobalt(II) acetate.

Article titled, "Two Diphenylpropan-l,2-diol Syringates from the Roots of Erythrina variegate " by Hitoshi Tanaka et al. in . Nat. Prod., 2002, 65 (12), pp 1933-1935 reports that two new diphenylpropan- 1 ,2-diols, eryvarinols A (1) and B (2), were isolated from the roots of Erythrina variegata. Their structures were elucidated as l-(4- hydroxy-2-methoxyphenyl)-2-(4-hydroxy-3,5-dimethoxybenzoylox y)-3-(4- hydroxyphenyl)propan-l-ol (1) and its 3' '-prenyl derivative (2) on the basis of spectroscopic and chemical evidence. Both these compounds are unusual diphenylpropan- 1,2-diols with a syringyl group.

Article titled, "Remarkable Electronic Effect on the Diastereoselectivity of the Heck Reaction of Methyl Cinnamate with Arenediazonium Salts: Formal Total Synthesis of (±)-Indatraline and (±)-Sertraline" by Pastrea, J. C; Correia, C. R. D. in Adv. Synth. Catal., 2009, 351, 1217 reports an efficient and stereoselective protocol for the preparation of β,β-disubstituted acrylates in good to high yields by means of a Heck- Matsuda arylation was accomplished. The method employs a base- and ligand-free Heck arylation reaction of methyl cinnamate using both electron-deficient and electron- rich arenediazonium salts as electrophiles. The overall methodology provides a convenient route to 3-arylindanones and 4-aryltetralones allowing the concise formal total syntheses of the therapeutically important psychoactive compounds (±)-indatraline and (±)-sertraline.

Article titled, "Chiral dihydrobenzo[l,4]oxazines as catalysts for the asymmetric transfer-hydrogenation of α,β-unsaturated aldehydes" by Ebner, C; Pfaltz, A. in Tetrahedron, 2011, 67, 10287 reports a new class of organocatalysts based on the structure of 2,3-dihydrobenzo[l,4]oxazine was prepared and applied in the enantioselective transfer-hydrogenation of α,β-unsaturated aldehydes with Hantzsch ester as hydride donor. These catalysts proved to be particularly effective for the conjugate reduction of β,β-diaryl-substituted acrylaldehydes leading to saturated aldehydes bearing a stereogenic center with two different aryl groups with enantioselectivities of up to 91 % ee.

Hydroboration-oxidation reaction is shown below:

Reduction of Esters via Aldehydes to Alcohols using DIBAL H is shown below:

Article titled, "An improved asymmetric synthetic route to a novel triple uptake inhibitor antidepressant (25,4i?,5i?)-2-benzhydryl-5-((4- methoxybenzyl)amino)tetrahydro-2H-pyran-4-ol (D-142)" by Aloke Dutta et al. in Tetrahedron Asymmetry, 2011 May 31 ; 22(10): 1081-1086 reports an alternative efficient synthetic route for triple monoamine reuptake inhibitor D-142 in 18.5% overall yield in 11 steps starting from diphenylmethane. The key step of the present synthetic strategy is the preferential formation of a bromohydrin from olefin via a c/s-bromoinum intermediate, which introduced significant efficiency in the overall synthesis. Furthermore, we have developed an efficient way to recycle the optically active intermediate diol back to the desired chiral epoxide.

i. -s. s ) X ··-,. ■») 1 ..„

W γ" " OH · * Ph' j" ' OTBDMS * p(¾- ' γ' "QTBDMS

OH OH OMs

8 9 tfl

>h' y : ΌΗ Ph ""

" U

11

Article titled, "5,8-Disubstituted 1-aminotetralins. Class of compounds with a novel profile of central nervous system activity" by Sarges, R.; Tretter, J.R.; Tenen, S.S.; Weissman, A. in . Med. Chem., 16, 1973, 1003 reports that (+)- Sertraline 1 is a selective serotonin reuptake inhibitor (SSRI).

Due to the less steric difference between the two phenyl groups it is difficult to maintain the enantioselectivity as well as diastereoselectivity. Most of the reports contain asymmetric hydrogenation reaction using transition metals. The methods suffer from the use of stoichiometric amount of organometalallic reagents and stereo selectivity.

(+)-Sertraline is a selective serotonin reuptake inhibitor (SSRI), is an important antidepressant drug discovered by Pfizer chemist Reinhard Sarges in 1970. It is one of the highest selling drugs, sold under the trade name Zoloft® 2. Medicinally, (+)- Sertraline is also prescribed for the treatment of post-traumatic stress disorder and panic disorder. Administration of sertraline comes with side effects such as gastrointestinal complaints, nervousness and sexual dysfunction on long-term users. As can be seen from synthetic studies, the literature methods in the synthesis of (+) -sertraline employ either chiral starting materials or expensive reagents involving longer reaction sequences, often resulting in poor product selectivities. The enantioselective synthesis of (+)-sertraline is thus undertaken to overcome some of the disadvantages associated with the reported methods. The literature methods in the synthesis of (+)-Sertraline employ either chiral starting materials or expensive reagents involving longer reaction sequences, often resulting in poor product selectivity.

The existing methods to synthesize functionalized 3, 3'-diphenylpropane-l,2-diol involves multistep reaction sequences thereby limiting the overall yield and the enantioselectivity as well as regioselectivity of the process particularly unsuitable for the atom economic synthesis. Therefore there is need to develop a flexible and novel method that employs hydrolytic kinetic resolution of racemic arat/-3,3'- diphenylmethyloxiranes to generate two stereocentres of high optical purities in a single step.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide compound of formula (I)

Formula I

wherein

Ri, R 2 and R 3 are selected from group consisting of H, CI, F or Br with the proviso that Ri, R 2 and R 3 are not H at the same time;

R4 is selected from (a) or (b)

Another objective of the present invention is to provide a process for the synthesis of formula 1 from phenyl methyl cinnamate.

Yet another objective of the invention is to provide a process for the resolution of substituted racemic diphenyloxiranes using Co (III) salen to obtain chiral oxirane and diol.

Still another objective of the present invention is to provide an enantioselective process for the synthesis of (+)-Sertraline from anti-3,3 '-diphenylpropane-l,2-diol.

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

Fig. 1 represents process for the synthesis of substituted diphenyloxiranes from phenyl methyl cinnamate wherein reaction conditions are (i) Pd(OAc) 2 , MeOH, Reflux, 3 h; (ii) DIBAL-H, CH 2 C1 2 , 0°C, 1 h; (iii) BH 3 .DMS, THF, 0°C to RT 4 h, H 2 0 2 , NaOH, 3 h; (iv) a) TsCl, NEt 3 , Bu 2 SnO, DMAP, 0°C, 1 h; b) K 2 C0 3 , MeOH;

Fig. 2 represents a process for the resolution of substituted racemic diphenyloxiranes using Co(III) salen to obtain chiral oxirane and diol wherein reaction conditions are (v) (S, S)-Co m (salen)(0.5 mol %), H 2 0 (0.49 equiv), 0 to 25°C, 12 h.

Fig. 3 represents a process for the synthesis of (S)-2-((S)-(3,4- Dichlorophenyl)(phenyl)methyl) oxirane (-)-(Ie) and (2i?,3i?)-3-(3,4-dichlorophenyl)-3- phenylpropan-l,2-diol (-)-(IIe) wherein reaction conditions are (i) DIBAL-H, CH 2 C1 2 , 0°C, 1 h, 95%; (ii) BH 3 .DMS, THF, 4 h, 30% aq. H 2 0 2 , NaOH, 5 h, 84%; (iii) TsCl, Et 3 N, Bu 2 SnO, DMAP, CH 2 C1 2 , 0°C, 3 h, 95%; (iv) K 2 C0 3 , MeOH, 25°C, 85%, (v) (S, 5)-Co m (salen) (0.5 mol %), H 2 0 (0.49 equiv), 0 to 25°C, 12 h. Fig. 4 represents process for the synthesis of sertraline from methyl cinnamate and 3,4- dichlorobenzenediazonium tetrafluoroborate wherein reaction conditions are (vi) NaI0 4 , CH 2 C1 2 , 25°C, 30 min, 82%; (vii) Ph 3 P=CHC0 2 Et, dry benzene, 25°C, 12 h, 92%; (viii) 10% Pd/C, H 2 (20 psig), MeOH, 25°C, 94%; (ix) 6 N HC1, reflux, 23 h, 89%; (x) C1S0 3 H, CH 2 CI 2 , 25°C, 2 h, 82%; (xi) . TiCl 4 , excess MeNH 2 , then Raney-Ni, H 2 (1 atm).

SUMMARY OF THE INVENTION

Accordingly, present invention provides a compound of formula I

Formula I

wherein

Ri, R 2 and R 3 are selected from group consisting of H, CI, F or Br with the proviso that Ri, R 2 and R 3 are not H at the same time;

R4 is selected from (a) or (b)

(a) (b)

In an embodiment of the present invention, representative compound of formula I are sleeted from group consisting of: (S)-2-((S)-(4-bromophenyl)(phenyl)methyl)oxirane[(-)-I(la)] ;

(R)-2-((R)-( 4-chlorophenyl)(phenyl)methyl)oxirane [(- )-I( 2a ) ];

(R)-2-((R)-( 4-fluorophenyl)(phenyl)methyl)oxirane [(+ )-I( 3a ) ];

(R)-2-((R)-(2-fluorophenyl) (phenyl)methyl)oxirane [(- )-I(4a)];

(S)-2-( (S)-( 3,4-Dichlorophenyl)(phenyl)methyl) oxirane ( - )-I( 5a ) ];

(2R,3R)-3-(4-bromophenyl)-3-phenylpropan-l,2-diol [(- )-I( lb)];

(2S,3S)-3-(4-chlorophenyl)-3-phenylpropan-l,2-diol [(+ )-I(2b)];

( 2S,3S)-3-( 4-fluorophenyl)-3-phenylpropan-l, 2-diol [ ( - )-I( 3b ) ];

( 2S,3S)-3-( 2 -fluorophenyl)- 3 -phenylpropan-1, 2-diol [(+ )-I( 4b ) ];

(2R,3R)-3-(3,4-dichlorophenyl)-3-phenylpropan-l, 2-diol [(-)-I(5b)].

In another embodiment, present invention provides a process for the preparation of compound of formula I and the process comprises the following steps: a) reacting phenyl methyl cinnamte (A) with arenediazonium tetrafluoroborate (B) in presence of Pd(OAc) 2 to get the (Ε)-β, ? '-diphenyl cinnamate;

b) reducing (Ε)-β, T-diphenyl cinnamate of step (a) using Diisobutylaluminium hydride

(DIBAL-H)to get allylic alcohol; c) hydroborating the allylic alcohol of step (b) using borane -dimethyl sulphide and hydrogen peroxide (H 2 0 2 ) to get racemic anti- β, β '-diphenylpropane- 1 , 2-diol; d) monotosylating the racemic anti- β, β '-diphenylpropane- 1 ,2-diol of step (c) using dibutyltinoxide and 4-Dimethylaminopyridine (DMAP) followed by epoxidation using potassium carbonate in methanol to get desired racemic anti- ? ,β '- diphenylmethyloxiranes ; e) adding acetic acid to a solution of (S, 5)-Co-salen in toluene followed by stirring at a temperature ranging from 20 to 25 °C in open air for a period ranging 20 to 30 minutes to get a dark brown colored solution; f) adding water and racemic anti-3,3'-diphenylmethyloxirane obtained in step (d) to the dark brown colored solution of step (e) at 0°C to get a reaction mixture, followed by stirring the reaction mixture for 12- 13 hours at a temperature ranging 25°C to obtain chiral anti-3, 3' -diphenylpropane- 1,2-diol compound of formula (Ia- Ie) and anti-3, 3 '-diphenylmethyloxirane compound of formula (Ila-IIe).

In yet another embodiment of the present invention, the yield of racemic anti- ? ,β '- diphenylmethyloxiranes in step (d) is greater than 85%.

In yet another embodiment of the present invention, the yield in step (f) is greater than 45 % with upto 98% ee.

In yet another embodiment a process for the preparation of (+) -Sertraline (III) using anti-/? ,β '-diphenylpropan- 1 ,2-diol and the said process comprising the steps of:

a. stirring solution of compund He in solvent and sodiumperiodate at a teamperature ranging from at 15-20°C for 4 hours to obtain (R)-2-(3,4-Dichlorophenyl)-2- phenylacetaldehyde; b. refluxing the solution of (R)-2-(3,4-Dichlorophenyl)-2-phenylacetaldehyde as obtained in step (a) in dry benzene and Ph 3 P=CHC0 2 Me at 20-25°C for 10-12 hours to obtain Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate; c. stirring the solution of Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate obtained in step (b) in methanol followed by addition of Pd/C under hydrogen atmosphere at at a teamperature ranging from 25-30°C for 6-8 hours to obtain Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate; d. refluxing the solution of Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate obtained in step (c) in a mixture of alcohol/water and sodium hydroxide for 20-24 hours to obtain (R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid; e. stirring the solution of (R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid obtained in step (d) in dichloromethane and chlorosulfuric acid at a temperature ranging from 20-25°C for 2-3 hours to obtain (S)-4-(3,4-Dichlorophenyl)-3,4- dihydronaphthalen-l(2H)-one; f. adding methylamine in THF and titanium tetrachloride to the solution of (S)-4-(3,4- Dichlorophenyl)-3,4-dihydronaphthalen-l(2H)-one obtained in step (e) in a diethyl ether at -78°C to obtain a reaction mixture followed by stirring the reaction mixture at a temperature ranging from 25-30°C for overnight to obtain desired (+)- Sertraline compound of formula III.

e

In yet another embodiment of the present invention, solvent used is selected from ethanol or water or mixture thereof.

In yet another embodiment of the present invention, the yield is more than 1 1 % with upto 98% ee. ABBREVIATIONS USED

HKR- Hydrolytic Kinetic Resolution

DIBAL-H-Diisobutylaluminium hydride

DMAP-4-Dimethylaminopyridine

Pd(OAc) 2 -Palladium (II) acetate

AcOH - Acetic acid

CH 2 Cl 2 -Dichloromethane

THF - Tetrahydrofuran

K 2 C0 3 -Potassium carbonate

Ph 3 P=CHC0 2 Me - Methyl (triphenylphosphoranylidene)acetate

DETAILED DESCRIPTION OF THE INVENTION

Present invention provides diphenyloxiranes, preparation and its use in an enantioselective synthesis of (+)-Sertraline.

The present invention provides compound of formula (I)

Formula I

wherein

Ri, R 2 and R 3 are selected from group consisting of H, CI, F or Br with the proviso that Ri, R 2 and R 3 are not H at the same time; R4 is selected from (a) or (b)

(a) (b)

The present invention provides a process for the synthesis of formula (I) from phenyl methyl cinnamate comprising the steps of: a) reacting phenyl methyl cinnamte (A) with arenediazoniumtetrafluoroborate(B) in presence of Pd(OAc) 2 to give the {Ε)-β, ? '-diphenylcinnamate; b) reduction of diphenylcinnamate of step (a) using DIBAL-H to give allylic alcohol; c) hydroboration of allylic alcohol of step (b) using borane -dimethyl sulphide and hydrogen peroxide (H 2 0 2 ) to give racemic anti- β, ? '-diphenylpropan-l,2-diol; d) monotosylation of diol of step (c) under classic reaction condition using dibutyltinoxide and DMAP; e) epoxidation of compound of step (d) reaction using potassium carbonate in methanol to give recemic anti- ? ,β '-diphenylmethyloxirane.

The process for the synthesis of substituted diphenyloxiranes from phenyl methyl cinnamate is in Fig. 1.

The synthesis of racemic Άΐΐύ-β,β '-diphenylmethyloxirane ( ld-4d) commences (Fig. 1) with the Heck reaction of phenyl methyl cinnamte (A) with arenediazoniumtetrafluoroborate (B) in presence of Pd(OAc) 2 to give the (Ε)-β, β '- diphenylcinnamte ( la-4a) in 80-90% yield. The diphenylcinnmate then subjected to reduction using DIBAL-H to give allylic alcohol (lb-4b) 93-95%. Then this allylic alcohol subjected to hydroboration reaction using borane -dimethyl sulphide and hydrogen peroxide (H 2 0 2 ) to give racemic anti- β, T-diphenylpropane-l,2-diol (lc-4c) in 62-67 % yield. The formed diol then subjected to monotosylation reaction under classic reaction condition using dibutyltinoxide and DMAP. Subsequently subjected epoxidation reaction using potassium carbonate in methanol to give recemic anti - ?, ? '- diphenylmethyloxirane (ld-4d).

The epoxide resolved under reaction parameters to give the enantiopure epoxide (la-Id) and diol (Ila-IId) as shown in table 1.

The present invention provide a process for the resolution of substituted racemic diphenyloxiranes using Co(III) salen to obtain chiral oxirane and diol comprising the steps of:

a) Adding Acetic acid to a solution of (S, 5)-Co-salen in toluene followed by stirring at 25 °C in open air for 30 min to get dark brown colored solution;

b) Adding racemic anti-3,3 '-diphenylmethyloxirane and water to a solutions from step (a) at 0°C followed by stirring the reaction mixture for 12 h at 25°Cto obtain chiral anti-3,3'-diphenylpropan-l,2-diol (Ila-IId) and anti-3,3 '-diphenylmethyloxirane (la-Id).

The above process is shown in Fig. 2.

In an aspect the present invention provides compound of formula I selected from: (S)-2-( ( S)-( 4-bromophenyl)(phenyl)methyl)oxirane[ ( - )-I(la)];

(R)-2-((R )-(4-chlorophenyl)(phenyl jmethyl joxirane [(-)-I(2a)];

(R)-2-((R)-(4-fluorophenyl)(phenyl)methyl)oxirane [(+ )-I(3a)];

(R)-2-((R)-(2-fluorophenyl) (phenyl)methyl)oxirane [(-)-I(4a)];

(S)-2-((S)-( 3,4-Dichlorophenyl)(phenyl)methyl)oxirane [(- )-I(5a)].

(2R,3R)-3-(4-bromophenyl)-3-phenylpropan-l, 2-diol [(-)-I(lb)];

( 2S, 3S)-3-(4-chlorophenyl)-3-phenylpropan-l,2-diol [(+ )-I( 2b ) ];

(2S,3S)-3-(4-fluorophenyl)-3-phenylpropan-l, 2-diol [(-)- I(3b)];

(2S,3S)-3-(2-fluorophenyl)-3-phenylpropan-l,2-diol [(+ )-I(4b)];

( 2R,3R )-3-( 3,4-dichlorophenyl)-3-phenylpropan-l, 2-diol [(- )-I( 5b)].

In yet another aspect the present invention provides a process for the synthesis of (5)-2- ((5)-(3,4-Dichlorophenyl)(phenyl)methyl) oxirane (-)-[I(5a)] and (2Z?,3Z?)-3-(3,4- dichlorophenyl)-3-phenylpropan-l, 2-diol (-)-(-)-[I(5b)] comprising the steps of:

a) Adding 3,4-dichlorobenzenediazonium tetrafluoroborate and Pd(OAc) 2 to a solution of methyl cinnamate in methanol followed by stirring the reaction mixture at 25°C for 4 h to obtain Methyl (E)-3-(3,4-dichlorophenyl)-3-phenylacrylate (7); b) Adding a solution of diisobutylaluminium hydride in toluene to a solution of the ester 7of step (a)in dry CH 2 Cl 2 at 0°C followed by stirring for the period of 2-5 h to obtain (E)-3-(3,4-Dichlorophenyl)-3-phenylprop-2-en-l-ol (8);

c) Adding borane dimethylsulfide to a solution of homoallyl alcohol 8 of step (b) in THF and stirring the mixture at 25 °C for 2 h followed by diluting with THF/MeOH and adding solution of NaOH and H 2 0 2 with further stirring for 1 h to obtain 3-(3,4-Dichlorophenyl)-3-phenylpropane-l, 2-diol (9);

d) Stirring the solution of diol 9 of step (c) in dichloromethane with p-toluenesulfonyl chloride, dibutyltin oxide, trimethylamine and dimethylaminopyridine at 0°C for 1 h to obtain 3-(3,4-Dichlorophenyl)-2-hydroxy-3-phenylpropyl-4-methylbenz ene- sulfonate (10);

e) Stirring the solution of tosylatelOof step (d) in methanol and K 2 CO 3 at 0 °C for 30 min to obtain (3,4-dichlorophenyl)(phenyl)methyl)oxirane (11).

The above process is shown in Fig. 3.

The present invention provides the process for the synthesis of sertraline comprising the steps of:

a) stirring the solution of diol He in ethanol/water at 20°C and sodiumperiodate for 4 h to obtain (R)-2-(3,4-Dichlorophenyl)-2-phenylacetaldehyde (12);

b) reflux the solution of aldehyde 12of step (a) in dry benzene and Pli 3 P=CHC0 2 Me at 25°C for 10 h to obtain Methyl (R, E)-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate (13);

c) stirring the solution of ester 13 of step (b)in methanol followed by addition of Pd/C under hydrogen atmosphere at 25°C for 6 h to Methyl (R)-4-(3,4-dichlorophenyl)- 4-phenylbutanoate (14);

d) reflux the solution of ester 14 of step (c) in ethanol/water and sodium hydroxide for 24 h to obtain (R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid (15);

e) stirring the solution of the carboxylic acid 15 of step (d) in dichloromethane and chlorosulfuric acid at 25°C for 2 h to obtain (S)-4-(3,4-Dichlorophenyl)-3,4- dihydronaphthalen- 1 (2H)-one (16);

f) adding methylamine in THF and titanium tetrachloride to a solution of tetralonel6 of step

(e) in a diethyl ether at -78°C followed by stirring the reaction mixture at 25°C for overnight to obtain (+)-Sertraline (III).

The process for the synthesis of sertraline from methyl cinnamate and 3,4- dichlorobenzenediazonium tetrafluoroborate is shown in Fig. 4. The synthetic scheme for the synthesis of (+)-sertraline (III) is shown in Fig. 4. The diol (-)-IIe, on oxidation with NaI0 4 gave the corresponding aldehyde 12. Then Aldehyde 12 was then subjected to Wittig olefination to give the corresponding a, β-unsaturated ester 13. The, β-unsaturated ester 13 on catalytic hydrogenation (10% Pd/C, H 2 (20 psig), MeOH) gave the saturated ester 14. This Ester 14 subsequently hydrolyzed to obtain carboxylic acid 15 which on further cyclization under acidic conditions to give tetralone 16. Finally, reductive amination of tetralone 16 (TiCl 4 , excess MeNH 2 , then Raney-Ni, H 2 (1 atm) afforded (+)-sertraline (III).

EXAMPLES

Following examples are given by way of illustration therefore should not be construed to limit the scope of the invention.

Example 1

General Procedure for hydroboration of allylic alcohol (lc-4c)

To a stirred solution of homoallyl alcohol (lb-4b) (9.4 mmol) in THF (5 mL) at 0°C, BH 3 .SMe 2 (5.8 mL, 4.5 mmol) was added and the reaction mixture was stirred at 25°C for 2 h. After dilution with THF/MeOH (14 mL, 1: 1) followed by the addition of 3 M solution of NaOH (4 mL) and an aq. solution 30% H 2 0 2 (4 mL), the reaction was stirred for 1 h and quenched with a saturated solution of Na 2 S0 3 (20 mL). The reaction mixture was then cooled to 0°C, diluted with sat. NaHC0 3 (35 mL) and Et 2 0 (35 mL). The organic layer was separated and the aqueous layer extracted with Et 2 0 (2 x 30 mL). The combined organic extracts were washed with brine and dried over anhyd. Na 2 S0 4 and concentrated under reduced pressure to give the crude product, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (5:5) as eluent gave pure (lc-4c) diol. Example 2

General procedure for Synthesis of Racemic oxiranes (ld-4d)

A solution of diol lc-4c (1.18 mmol) in CH 2 C1 2 ( 10 mL) was treated with TsCl (1.18 mmol), Bu 2 SnO (30 mol%), Et 3 N (30 mmol) and DMAP (cat.) at 0 °C. After being stirred for 1 h, the mixture was extracted with CH 2 C1 2 (3 x 20 mL), washed with water and the combined organic phases were dried over anhydrous Na 2 S0 4 and concentrated to give the crude tosylate. To a solution of crude tosylate in MeOH (20 mL) was added K 2 C0 3 (13 mmol) and the mixture was stirred at 0°C for 30 min. After the reaction was complete (monitored by TLC), solvent was evaporated and the residue was extracted with diethyl ether (3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 S0 4 and concentrated to give the crude product which was then purified by column chromatography using petroleum ether/EtOAc (8:2 v/v) to give epoxide (le- 4e) (2.5 g) as a colorless oil.

Example 3

General Procedure for Hydro kinetic resolution

To a solution of (5,5)/(R,R)-Co-salen (0.5 mol%) in toluene (2 mL), AcOH (0.036 mmol) was added. It was allowed to stir at 25°C in open air for 30 min. During this time the color changed from orange-red to a dark brown, it was then dried under vacuum. To this racemic anti-3,3 '-diphenylmethyloxirane (1 mmol) and H 2 0 (0.5 mmol) was added at 0°C. Then the reaction was allowed to stir for 12 h at 25°C. After completion of reaction (monitored by TLC), the crude product was purified by column chromatography over silica gel to give chiral anti-3,3'-diphenylpropane-l,2-diol (Ila- Ild) and anti-3,3 '-diphenylmethyloxirane (la-Id), [solvent system; petroleum ether: ethyl acetate (95:5)] and [solvent system; petroleum ether: ethyl acetate (6:4)] in pure form. Example 4

Synthesis of Methyl-(E)-3-(4-bromophenyl)-3-phenylacrylate (la)

Yield: 84%, Colorless thick liquid; IR: (CHC13, cm "1 ) - 1738; 1H NMR: (200 MHz, CDC13) δ 3.60 (d, s, 1H), 6.32 (s, 1H), 7.15 (m, 5H), 7.46 (m, 4H); 13 C NMR (50 MHz, CDC13): δ 51.2, 117.1, 124.0, 128.0, 128.4, 129.8, 131.6, 138.2, 139.7, 155.7, and 165.9.

Example 5

Synthesis of (E)-3-(4-bromophenyl)-3-phenylprop-2-en-l-ol (2a)

Yield: 96%, White solid, IR: (CHC13, cm "1 )- 3340; 1H NMR: (200 MHz, CDC1 3 ) δ 1.55 (bs, 1H), 4.18-4.21 (d, 2H, J= 6Hz), 6.18-6.25 (t, 1H, J=6Hz), 7.08 (m, 4H), 7.34- 7.42 (m, 5H); 13 C NMR (50 MHz, CDC1 3 ) δ 60.6, 12.8, 127.8, 128.0, 128.4, 129.2, 129.7, 131.3, 140.8 and 147.2.

Example 6

Synthesis of (4-bromophenyl)-3-phenylpropan-l,2-diol (3a):

Yield: 62%, colorless gummy, IR(CHC1 3 , cm "1 )- 3351 (broad), 1488, 1453, 1009, 698; 1H NMR: (200 MHz, CDC1 3 ) δ 3.21-3.46 (m, 4H), 3.83-3.87 (d, lHJ=8Hz), 4.22-4.28 (t, IH, J= 6Hz), 7.13-7.29 (m, 7H), 7.35-7.40 (d, 2H, J=10Hz); 13 C NMR (50 MHz, CDC1 3 ) δ 54, 64.7, 73.6, 120.6, 126.9, 128.0, 128.8, 130.4, 131.6, 140.5, 141.

Example 7

Synthesis of (4-bromophenyl)(phenyl)methyl)oxirane (4a):

Yield: 92%, colorless gummy, 1H NMR: (200 MHz, CDC1 3 ) δ 2.46-2.50 (q, IH, =4Hz), 3.40 (3.47 (m, IH), 3.74-3.78 (d, IH, J=8Hz), 7.11-7.26 (m,6H), 7.30-7.35 (m, IH), 7.38-7.45 (dt, J=8Hz, 2H); 13 C NMR (50 MHz, CDC13) δ 46.4, 52.9, 54.6, 120.9, 127.1, 128.4, 128.7, 131.4, 131.6, 140.1, 140.5.

Example 8

Synthesis of (2R,3R)-3-(4-bromophenyl)-3-phenylpropan-l,2-diol [(-)-I(lb)]

Yield: 48%, colorless oil; [a] 25 D +30.46 (c 1, CHC1 3 ); Optical purity: 97% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (95:05), 0.5 mL/min, 254 nm); Retention time: t minor = 21.30 and t major = 35.84 min.

Example 9

Synthesis of (S)-2-((S)-(4-bromophenyl)(phenyl)methyl)oxirane[(-)-I(lba)]

Yield: 50%, [a] 25 D -22.18 (c 0.5, CHC1 3 ); Optical purity: 95% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (97.5:2.5), 0.5 mL/min, 254 nm); Retention time: t minor = 13.92 and t major = 15.03 min.

Example 10

Synthesis of Methyl-(E)-3-(4-chlorophenyl)-3-phenylacrylate (lb):

Yield: 88%, greenish gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 3.60 (s, 3H), 6.32 (s, 1H), 7.15-7.25 (m, 6H), 7.37-7.40 (t, 3H, J=4Hz); 13 C NMR (50 MHz, CDC1 3 ) δ 51.2, 117.2, 128.0, 128.4, 128.6, 129.1, 129.6, 135.7, 138.3, 139.3, 155.6, 166.

Example 11

Synthesis of (E)-3-(4-chlorophenyl)-3-phenylprop-2-en-l-ol (2b):

Yield: 89%; Gummy; X H NMR: (200 MHz, CDC1 3 ) δ 1.69 (bs, 1H), 4.22-4.23 (d, 2H, J=4Hz), 6.22-6.25 (t, 1H, J=8Hz), 7.15-7.21 (m, 4H), 7.28-7.25 (m, 2H), 7.35-7.41 (m, 3H); 13 C NMR (50 MHz, CDC1 3 ) δ 60.6, 127.8, 127.9, 128.4, 128.9, 129.7, 133.6, 140.2, 143.1. Example 12

Synthesis of (4-chlorophenyl)-3-phenylpropan-l,2-diol (3b):

Yield: 63%; Colorless gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 3.21-3.48 (m, 4H), 3.80- 3.84 (d, 1H, J=8Hz), 4.20 (bs, 1H), 7.18 (s, 9H); 13 C NMR (50 MHz, CDC1 3 ) δ 54.0, 64.7, 73.1, 127.0, 128.1, 128.7, 128.9, 130.1. 132.5, 140.0, 141.2.

Example 13

Synthesis of (4-chlorophenyl)(phenyl)methyl)oxirane (4b):

Yield: 93%; colorless oil; 1H NMR: (200 MHz, CDC1 3 ) δ 2.48-2.52 (q, 1H, J=4Hz), 2.82-2.86 (q, lHJ=8Hz),3.42-3.48 (m, 1H), 3.77-3.80 (d,lH, /=6Hz), 7.14-7.22 (m, 5H), 7.25-7.35 (m, 4H); 13 C NMR (50 MHz, CDC1 3 ) δ 46.4, 52.8, 54.7, 127.1, 128.4, 128.6, 128.7, 130.0, 132.8, 139.5, 140.6.

Example 14

Synthesis of (2S,3S)-3-(4-chlorophenyl)-3-phenylpropan-l,2-diol [(+)-I(2b)

Yield: 47%, [a] 25 D + 19.23 (c 1, CHC1 3 ); Optical purity: 97% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (95.5:5), 0.5 mL/min, 254 nm); Retention time: t minor = 49.88 and t major = 55.56 min. Example 15

Synthesis of (R)-2-((R)-(4-chlorophenyl)(phenyl)methyl)oxirane [(-)-I(2a)]

Yield: 48%, [a] 25 D -16.14 (c 0.5, CHC1 3 ); Optical purity: 98% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (97.5:2.5), 0.5 mL/min, 254 nm); Retention time: t major = 9.94 and t minor = 11.41 min.

Example 16

Synthesis of Methyl-(E)-3-(4-fluorophenyl)-3-phenylacrylate (lc):

Yield: 82%; Gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 3.69 (s, 3H), 4.34 (s, 1H), 7.02- 7.20 (m, 3H), 7.27-7.35 (m, 5H); 13 C NMR (50 MHz, CDC1 3 ) δ 51.6, 115.3 (d, J= 21.2 Hz, CH), 116.4 (d,7= 1.6 Hz), 128.1, 128.3, 129.2, 130.5 (d, = 8.3 Hz), 136.8 (d, J= 3.1 Hz), 138.9, 155.9, 163.3(d, = 250.3 Hz), 166.3

Example 17

Synthesis of (E)-3-(4-fluorophenyl)-3-phenylprop-2-en-l-ol (2c):

Yield: 92%, Colorless gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 1.77 (bs, 1H), 4.16-4.19 (d, 2H, J=6Hz), 6.15 (t, 1H, J=8Hz), 6.90-6.99 (t, 2H, J=8Hz), 7.10-7.25 (m,4H), 7.30- 7.39 (m, 3H); 13 C NMR (50 MHz, CDC1 3 ) δ 60.6, 115.0-115.5 (d, J=21 Hz), 127.6- 127.8 (d, J=7Hz), 128.3, 131.4-131.5 (d, J=8Hz), 141.7, 143.4. Example 18

Synthesis of (4-fluorophenyl)-3-phenylpropan-l,2-diol (3c):

Yield: 68%; Colorless gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 3.01(bs, 2H), 3.26-3.52 (m,2H), 3.89-.394 (d,lH, J=10Hz), 4.26-4.32 (t, IH, J=6Hz), 6.91-6.99 (m. 4H), 7.16- 7.29 (m, 5H); 13 C NMR (50 MHz, CDC1 3 ) δ 53.9, 64.7, 74.0, 115.3-115.8 (d, /=21Hz), 126.9, 128.1, 128.8, 130.1-130.2 (d, =8Hz), 136.9, 141.4, 164.1.

Example 19

Synthesis of (4-fluorophenyl)(phenyl)methyl)oxirane (4c):

Yield: 86%; Colorless oil; 1H NMR: (200 MHz, CDC1 3 ) δ 2.47-2.51 (q, IH, J=4Hz), 2.82-2.86 (q, IH, J=4Hz), 3.42-3.48 (m,lH), 3.78-3.82 (d,lH, J=8Hz), 6.94-7.03 (t, 2H, J=10Hz), 7.16-7.23 (m, 5H), 7.25-7.31 (m, 2H); 13 C NMR (50 MHz, CDC1 3 ) δ45.2,52.6, 63.0, 115.2-115.8 (d, J=21Hz), 126.6, 128.2, 129.4, 130.1-130.4 (d, J=8Hz), 137.0, 141.2, 164.5.

Example 20

Synthesis of (2S,3S)-3-(4-fluorophenyl)-3-phenylpropan-l, 2-diol [(-)- I(3b)]:

Yield: 49%, [a] 25 D -123.41 (c 1, CHCl 3 );Optical purity: 96% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (90: 10), 0.5 mL/min, 220 nm); Retention time: t major = 25.14 and t minor = 28.13 min.

Example 21

Synthesis of (R)-2-((R)-(4-fluorophenyl)(phenyl)methyl)oxirane [(+)-I(3a)]:

Yield: 50 %, colorless oil; [a] 25 D +2.82 (c 0.5, CHCl 3 );Optical purity: 98% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (97.5:2.5), 0.5 mL/min, 220 nm); Retention time: t major = 10.87 and t minor = 11.46 min.

Example 22

Synthesis of Methyl-(E)-3-(2-fluorophenyl)-3-phenylacrylate (Id):

Yield: 91%; Gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 3.6 (s, 3H), 6.32 (s, 1H), 7.05- 7.11 (m, 3H), 7.19-7.24 (m, 1H), 7.30 (m, 5H); 13 C NMR (50 MHz, CDC1 3 ) δ 51.2, 116.1-116.3 (d, J= 23Hz), 120.8 (d, J= 5.76 Hz), 124.0 (d, J=4 Hz), 127.8, 128.3, 128.5, 128.7, 130.4 (d, J=8.62 Hz), 131.4, 138.6, 150.8, 158.9, 161.4, 166.0. Example 23:

Synthesis of 3-(2-fluorophenyl)-3-phenylprop-2-en-l-ol (2d):

Yield: 91%; White Solid; 1H NMR(200MHz, CDC1 3 ) δ 1.53 (bs, IH), 4.31-4.35 (m, 2H), 6.17(t, J=7Hz, IH), 7.03 (ddd, J=10.8, 8.4, 1.2Hz, IH), 7.09 (td, J=7.8 Hz, IH), 7.16-7.21 (m,3H), 7.23-7.27 (m, IH), 7.30-7.36 (m, 3H); 13 C NMR (50 MHz, CDC1 3 ) δ 600.4, 115.9-116.1 (d, J=23 Hz), 123.9 (d, J=2.88), 127.7, 128.2, 129.2, 131.3-131.4 (d, J=3.84), 131.7-131.8 (d, J=3.84), 138.7, 159.0, 161.5.

Example 24:

Synthesis of (2-fluorophenyl)-3-phenylpropan-l,2-diol (3d):

Yield: 65%; Colorless gummy; 1H NMR: (200 MHz, CDC1 3 ) δ 2.88 (bs, IH), 2.97 (bs, IH), 3.28-3.33 (q, IH, J= 6Hz), 3.46-3.49 (d, IH, J= 11.4 Hz), 4.29-4.31 (d, IH, J=9 Hz), 4.35-4.39 (t, IH, J= 7Hz), 6.93-6.96 (dt, IH, J=10 Hz), 7.02-7.08 (m, IH), 7.11- 7.23 (m, 5H), 7.27-7.33 (m, IH), 7.41-7.45 (dt, IH, J= 1.83, 7 Hz); 13 C NMR (50 MHz, CDC1 3 ) δ 47.0, 64.8, 73.2, 115.6 (d, J= 23 Hz), 124.1 (d, J= 3.84 Hz), 126.9, 128.2, 128.3, 128.1, 128.9, 129.3 (d, J= 3.84), 140.6, 159.9, 162.4. Example 25

Synthesis of (2-fluorophenyl)(phenyl)methyl)oxirane (4d):

Yield: 89%; Colorless Oil; 1H NMR: (200 MHz, CDC1 3 ) δ 2.52-2.56 (q, 1H, J= 2.66 Hz), 2.88-2.92 (q, 1H, J= 3.91 Hz), 3.56-3.63 (m, 1H), 4.25-4.28 (d, 1H, J= 6.4 Hz), 7.03-7.10 (m, 1H), 7.13-7.18 (m, 1H), 7.31-7.43 (m, 7H); 13 C NMR (50 MHz, CDC1 3 ) δ 46.2, 46.6, 53.8, 115.4 (d, J= 23 Hz), 124.1 (d, J= 2.87 HZ), 127.0, 128.3, 128.5, 128.6, 129.9, (d, J= 3.83 Hz), 140.1.

Example 26

Synthesis of (2S,3S)-3-(2-fluorophenyl)-3-phenylpropan-l,2-diol [(+)-I(4b)]:

Yield: 48%, [a] 25 D +6.25 (c 1, CHCI 3 ), 97% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (90: 10).

Example 27

(R)-2-((R)-(2-fluorophenyl) (phenyl)methyl)oxirane [(-)-I(4a)]:

Yield: 49%, colorless oil; [a] 25 D -26.85 (c 0.5, CHCI 3 ), 95% ee determined from HPLC analysis (Chiral AD-H column, n-hexane/ 2-propanol (90: 10).

Example 28

Synthesis of Methyl (E)-3-(3,4-dichlorophenyl)-3-phenylacrylate (7):

To a solution of methyl cinnamate(1.6 g, 10 mmol) in methanol (60 mL), Pd(OAc) 2 (240 mg, 10 mol%) and 3,4-dichlorobenzenediazonium tetrafluoroborate(3.12 g, 12 mmol) was added. The reaction mixture was stirred at 25 °C for 4 h. After completion of reaction (monitored by TLC), it was filtered through a pad of Celite and washed with methanol (3 x 15 mL). The combined filtrates were concentrated to give crude product, 7which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (3:7) as eluent gave pure 7 as colorless oil.

Yield: 82%, colorless oil; IR (CHC1 3 , cm "1 ): O max 699, 823, 874, 1190, 1275, 1549, 1620, 1727, 2948; X H NMR (200 MHz, CDC1 3 ): δ 3.61 (s, 3H), 6.32 (s, 1H), 7.07-7.19 (m, 3H), 7.37-7.41 (5H); 13 C NMR (50 MHz, CDC1 3 ): δ 51.3, 118.1, 127.4, 128.1, 128.7, 129.0, 130.0, 130.3, 132.9, 133.7, 137.7, 140.9, 154.3, 165.7; Anal. Calcdfor C16H12O2CI2 requires C, 62.56; H, 3.94; found C, 62.50; H, 3.95%.

Example 29

Synthesis of (£')-3-(3,4-Dichlorophenyl)-3-phenylprop-2-en-l-ol (8):

To a stirred solution of the ester 7 (1 g, 3.26 mmol), in dry CH 2 CI 2 (25 mL), a solution of diisobutylaluminium hydride (1 M solution in toluene, 3.6 mL, 7.18 mmol)) was added drop wise at

0°C and the reaction mixture was stirred at this temperature for 2 h. After completion of reaction (monitored by TLC), it was diluted with a saturated solution of Rochelle salt and stirred for further 3 h. The organic phase was separated and the aqueous phase extracted twice with CH 2 CI 2 . The combined organic layers were washed with brine, dried over anhyd. Na 2 S0 4 and concentrated under reduced pressure to give crude product 8, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (8:2) as eluent gave pure 8 as colorless oil.

Yield: 95%, colorless oil; IR (CHCI 3 , cm "1 ): rj max 1055, 1130, 1430, 1520, 2847, 2956, 3430; 1H NMR (200 MHz, CDC1 3 ): δ 4.22 (d, = 6.8 Hz, 2H), 6.22 (t, = 6.6 Hz, 1H), 7.04 (m, 3H), 7.32-73.39 (m, 5H); 13 C NMR (50 MHz, CDC1 3 ): δ 60.4, 126.8, 128.0, 128.5, 129.0, 129.4, 129.6, 130.1, 132.5, 137.9, 141.8, 141.9; Anal. Calcdfor C 15 H 12 OCI 2 requires C, 64.54; H, 4.33; found C, 64.66; H, 4.38%.

Example 30

Synthesis of 3-(3,4-Dichlorophenyl)-3-phenylpropan-l,2-diol (9):

To a stirred solution of homoallyl alcohol 8(2.6 g, 9.4 mmol) in THF (5 mL) at 0°C, BH3.SMe 2 (5.8 mL, 4.5 mmol) was added and the reaction mixture was stirred at 25°C for 2 h. After dilution with THF/MeOH (14 mL, 1: 1) followed by the addition of 3 M solution of NaOH (4 mL) and an aq. solution 30% ¾(¾ (4 mL), the reaction was stirred for 1 h and quenched with a saturated solution of Na 2 SC>3 (20 mL). The reaction mixture was then cooled to 0°C, diluted with sat. NaHC0 3 (35 mL) and Et 2 0 (35 mL). The organic layer was separated and the aqueous layer extracted with Et 2 0 (2 x 30 mL). The combined organic extracts were washed with brine and dried over anhyd. Na 2 S0 4 and concentrated under reduced pressure to give the crude product, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (5:5) as eluent gave pure 9 as colourless oil.

Yield: 67%, colorless oil; IR (CHC13, cm "1 ): O max 749, 850, 1011, 1236, 1462, 1620, 2844, 3456; 1H NMR (200 MHz, CDC1 3 ): δ 1.62 (br s, 1H), 2.28 (br s, 1H), 3.43 (dd, = 6.3, 11.1 Hz, 1H), 3.61 (dd, / = 3.0, 11.1 Hz, 1H), 4.00 (d, = 9.2 Hz, 1H), 4.40 (m, 1H), 7.19-7.47 (m, 8H); 13 C NMR (50 MHz, CDC1 3 ): δ 54.1, 64.3, 73.3, 127.2, 128.0, 129.0, 130.4, 130.6, 130.7, 132.5, 140.5, 141.8; Anal. Calcd for Ci 5 Hi 4 0 2 Cl 2 requires C, 60.63; H, 4.75; found C, 60.75; H, 4.70%.

Example 31

Synthesis of 3-(3,4-Dichlorophenyl)-2-hydroxy-3-phenylpropyl-4-methylbenz ene- sulfonate (10):

A solution of diol9(3.5 g, 11.8 mmol) in CH 2 C1 2 (50 mL) was treated with TsCl (2.25 g, 11.8 mmol), Bu 2 SnO (883.8 mg, 30 mol%), Et 3 N (4.21 mL, 30 mmol) and DMAP (cat.) at 0 °C and stirred for 1 h. After the reaction was complete (monitored by TLC), it was quenched with water (10 mL) and product was extracted with CH 2 C1 2 (3 x 100 mL). The combined organic phases were dried over anhydrous Na2S04 and concentrated to give the crude product 10, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (7:3) as eluent gave pure lOas colorless oil. Yield: 95%, colorless oil; IR (CHQ 3 , cm "1 ): O max 3407, 3019, 2927, 1518, 1454, 1364, 1215, 1176, 1047, 928; 1H NMR (200 MHz, CDC1 3 ): δ 2.45 (s, 3H), 3.80-4.07 (m, 3H), 4.45-4.56 (m, 1H), 7.06-7.40 (m, 10H), 7.68-7.72 (m, 2H); 13 C NMR (50 MHz, CDC1 3 ): δ 21.7, 53.1, 71.5, 71.8, 127.5, 128.0, 128.1, 129.1, 129.9, 130.5, 130.7, 132.5, 132.6, 139.7, 140.5, 145.0; Anal. Calcd for C22H20O4CI2S requires C, 58.54; H, 4.47; found C, 58.60; H, 4.50%.

Example 32

Synthesis of (3,4-dichlorophenyl)(phenyl)methyl)oxirane (11):

To a solution of tosylatelO (5.3 g, 11.8 mmol) in MeOH (50 mL) was added K 2 C0 3 (1.79 g, 13 mmol) and the mixture was stirred at 0 °C for 30 min. After the reaction was complete (monitored by TLC), solvent was evaporated and the residue was extracted with diethyl ether (3 x 100 mL). The combined organic phases were dried over anhydrous Na 2 S0 4 and concentrated to give the crude product which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (8:2) as eluent gave pure 11 as colorless oil.

Yield: 85%, colorless oil; IR (CHC1 3 , cm "1 ): O max 690, 810, 904, 1081, 1209, 1371, 1443, 3062, 3390, 756,; 1H NMR (200 MHz, CDC1 3 ): δ 2.50-2.53 (m, 1H), 2.83-2.87, (m, 1H), 3.42-3.46 (m, 1H), 3.74-3.77 (m, 1H), 7.10-7.39 (m, 8H) ; 13 C NMR (50 MHz, CDC1 3 ): δ 46.3, 52.6, 54.4, 127.4, 128.0, 128.3, 128.8, 130.3, 130.5, 131.0, 132.6, 139.9, 141.3; Anal. Calcdfor Ci 5 H 12 OCl 2 requires C, 64.54; H, 4.33; found C, 64.55; H, 4.35%. Example 33

HKR of racemic (3,4-Dichlorophenyl)(phenyl)methyl)oxirane:

To a solution of (S, 5)-Co-salen (0.027g, 0.5 mol%) in toluene (2 mL), acetic acid ( 0.02 g, 0.36 mmol) was added. It was allowed to stir at 25 °C in open air for 30 min. During this time the colour of the solution changed from orange -red to a dark brown, it was then dried under vacuum. To this, racemic epoxide (±)-ll (2.5 g, 9.13 mmol) and H 2 0 (0.08 mL, 4.47 mmol) were added at 0 °C. Then the reaction was allowed to stirred for 12 h at 25°C. After completion of reaction (monitored by TLC), the crude product was purified by column chromatography over silica gel to give chiral epoxide (-)-Ie, [solvent system; petroleum ether: ethyl acetate (95:5)] and chiral diol (-)-IIe solvent system; petroleum ether: ethyl acetate (2:8)] in pure form.

(5)-2-((5)-(3,4-Dichlorophenyl)(phenyl)methyl) oxirane [(-)-(I(5a)]

Yield: 50%, colorless oil; [a] D 25 = -23.6 (c 1, CHC13); Optical purity: 97% ee determined from HPLC analysis (OD-H column, n-hexane/ 2-propanol (95:5), 0.5 mL/min, 254 nm); Retention time: t minor = 13.70 and t major = 14.95 min.

(2R,3R)-3-(3,4-dichlorophenyl)-3-phenylpropan-l,2-diol [(-)-(I(5b)]

Yield: 48%, colorless oil; [a] D 25 = -28.5 (c 1 , CHCI 3 ); Optical purity: 98% ee determined from HPLC analysis (Chiral OD-H column, n-hexane/ 2-propanol (90: 10), 0.5 mL/min, 254 nm); Retention time: t minor = 27.00 and t major = 30.59 min.

Example 34

Synthesis of (R)-2-(3,4-Dichlorophenyl)-2-phenylacetaldehyde (12):

To stirred solution of diol (-)-IIe (1 g, 3.3 mmol) in ethanol/H 2 0 (15 mL, 2: 1) at 20°C, NaI0 4 (0.863 g, 4.0 mmol) was added and the reaction mixture was stirred for 4 h. After completion of reaction (monitored by TLC), it was quenched with water (10 mL) and product was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na 2 S0 4 and concentrated to give the crude product 12 which was taken up for further reaction without purification.

Yield: 82%, colorless oil; [a] D 25 = +4.2 (c 1, CHC1 3 ); IR (CHC1 3 , cm "1 ): rj max 698, 1030, 1136, 1178, 1380, 1448, 1466, 1720, 2853, 2929 ; 1H NMR (200 MHz, CDC1 3 ): δ 4.85 (d, = 1.3 Hz, 1H), 7.24 -7.52 (m, 8H), 9.92 (d, = 1.2 Hz, 1H); 13C NMR (50 MHz, CDC13): δ 45.4, 126.7, 127.2, 128.9, 129.1, 129.4, 130.7, 132.9, 133.3, 138.8, 139.5, 197.2; Anal. Calcdfor Ci 4 Hi 0 OCi 2 requires C, 63.42; H, 3.80; found C, 63.45; H, 3.81%.

Example 35

Synthesis of Methyl (R, £')-4-(3,4-dichlorophenyl)-4-phenylbut-2-enoate (13):

To a solution of aldehyde 12(0.9 g, 3.55 mmol) in dry benzene (25 mL), was added Ph 3 P=CHC0 2 Me (1.42 g, 4.26 mmol) at 25°C. The reaction mixture was refluxed for 10 h, and then quenched with water (5 mL). The product was extracted with EtOAc (3 x 20 mL) and washed with water (3 x 15 mL). The combined organic phases were dried over anhydrous Na 2 S0 4 and concentrated to give the crude products which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (8:2) as eluent gave pure 13as colorless oil.

Yield: 92%, colorless oil; [a] D = +1.2 (c 1, CHC1 3 ) {lit. [a] D +1.0 (c 1.12, CHC1 3 )}; IR (CHC1 3 , cm "1 ): rj max 636, 700, 818, 918, 983, 1030, 1130, 1170, 1377, 1652, 1713, 2946; 1H NMR (200 MHz, CDC1 3 ): δ 3.75 (s, 3H), 4.84 (d, J = 7.3 Hz, 1H), 5.75 (d, = 15.6 Hz, 1H), 7.09 (m, 1H), 7.26-7.42 (m, 8H); 13 C NMR (50 MHz, CDC1 3 ): δ 51.6, 52.3, 123.1 , 127.2, 127.8, 128.4, 128.9, 130.3, 130.9, 133.3, 140.2, 141.6, 148.6, 165.2; Anal. Calcd for Ci 7 H 14 0 2 Cl 2 requires C, 63.57; H, 4.39; found C, 63.60; H, 4.40%.

Example 36

Synthesis of Methyl (R)-4-(3,4-dichlorophenyl)-4-phenylbutanoate (14):

To a solution of ester 13 (0.85 g, 2.66 mmol) in methanol (20 mL), was added 10% Pd/C (60 mg) and stirred under hydrogen atmosphere ( 1 atm) at 25 °C. The reaction mixture was further stirred at 25°C for 6 h, and the progress monitored by TLC. After completion of reaction, it was filtered through a Celite pad and washed with EtOAc (3 x 20 mL). The combined organic phase was concentrated under vacuum. The crude product thus obtained was purified by column chromatography on silica gel using petroleum ether: ethyl acetate (8:2) as eluent to give pure Has colorless oil.

Yield: 94%, colorless oil; [a] D = -6.0 (c 1 , CHC13) {lit. [a] D -6.1 (c 1.12, CHC13) } ; IR (CHC1 3 , cm "1 ): rj max 680, 2970, 1202, 1365, 1494, 1600, 1722, 2930; 1H NMR (200 MHz, CDC1 3 ): δ 2.21 -2.38 (m, 4H), 3.64 (s, 3H), 3.85-3.94 (m, 1H), 7.15-7.31 (m, 8H); 13C NMR (50 MHz, CDC13): δ 30.2, 32.0, 50.4, 51.4, 126.3, 127. 1 , 127.6, 127.8, 128.4, 128.7, 129.7, 130.4, 132.5, 142.6, 144.5, 173.0; Anal. Calcdfor Ci 7 H 16 0 2 Cl 2 requires C, 63.17; H, 4.99; found C, 63.21 ; H, 4.87 %. Example 37

Synthesis of (R)-4-(3,4-Dichlorophenyl)-4-phenylbutanoic acid (15):

To a solution of the ester 14 (0.3 g, 0.92 mmol) in ethanol/ H 2 0 (5 mL, 5: 1), sodium hydroxide (0.07 g, 1.85 mmol) was added and the solution was heated at reflux for 24 h. After completion of reaction (monitored by TLC), it was cooled and the resulting solution was neutralized by adding with dil.HCl and the acidified solution extracted with EtOAc (3 x 10 mL). The combined organics were dried over anhyd. Na 2 S04 and concentrated under reduced pressure to give corresponding acid 15, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (6:4) as eluent gave pure 15 as colorless solid.

Yield: 89%, colourless solid, mp 117°C; [a] D 25 = -4.5 (c 1, CHC1 3 ) {lit. [a] D 25 -4.9 (c 1.02, CHC1 3 )} ; IR (CHC1 3 , cm "1 ): rj max 1406, 1470, 1715, 2664, 2975; X H NMR (200 MHz, CDC1 3 ): δ 2.22-2.44 (m, 4H), 3.85-3.99 (m, 1H), 7.02- 7.29 (m, 8H); 13 C NMR (50 MHz, CDC13): δ 30.2, 32.2, 49.7 , 126.4, 126.6, 127.9, 128.8, 129.9, 130.4, 130.5, 132.5, 132.3, 143.3, 144.6, 178.6; Anal. Calcd for C16H1402 C12 requires C, 62.16; H, 4.56; found C, 62.15; H, 4.60 %.

Example 38

Synthesis of (5)-4-(3,4-Dichlorophenyl)-3,4-dihydronaphthalen-l(2H)-one (16) :

To a solution of the carboxylic acid 15(0.184 g, 0.60 mmol) in CH 2 C1 2 (11 niL) was added CISO 3 H (0.20 mL; 3.0 mmol; 5.0 equiv.) and the reaction mixture was stirred at 25°C for 2 h. After 2 h, the reaction mixture was added to a saturated NaHC0 3 solution (75 mL) and extracted with CH 2 C1 2 (2 x 30 mL) followed by diethyl ether (2 x 30 mL). The combined organic layers were dried over anhyd. Na 2 S0 4 and concentrated under reduced pressure to give tetralone 16, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (6:4) as eluent gave pure 16 as colorless solid.

Yield: 82%, colorless solid, mp 84 °C; [a] D 25 = +65.0 (c 1, benzene) {lit. [ ] D 24 +65.8 (c 1.2, benzene)}; IR (CHC1 3 , cm "1 ): rj max 676, 730, 756, 823, 1030, 1132, 1284, 1329, 1469, 1599, 1683, 1715, 2984, 3019; 1H NMR (200 MHz, CDC1 3 ): δ 2.20-2.34 (m, 1H), 2.42 (m, 1H), 2.63-2.72 (m, 2H), 4.25-4.31 (m, 1H), 6.93 (dd, = 2.1, 8.4 Hz, 2H), 7.22-7.26 (m, 1H), 7.38-7.48 (m, 3H), 8.14 (dd, = 1.7, 7.7 Hz, 1H); 13 C NMR (50 MHz, CDC1 3 ): δ 31.4, 36.3, 44.2, 127.0, 127.2, 127.8, 129.0, 130.3, 130.6, 132.4, 133.6, 143.6, 144.6, 196.9; Anal. Calcdfor Ci 6 Hi 2 OCl 2 requires C, 66.00; H, 4.15; found C, 66.10; H, 4.17 %. Example 39

Synthesis of (+)-Sertraline (III)

e

A stirred solution of tetralone 16 (0.6 g, 2.06 mmol) in a dry diethyl ether (10 mL) was cooled to -78°C. Then, methylamine in THF (1.5 mL, excess) was introduced dropwise via syringe, followed by the addition of T1CI 4 (1 M in CH 2 CI 2 , 3 mL, 3.09 mmol). The reaction mixture was allowed to warm to 25°C slowly and stirred overnight. After the reaction was complete, it was filtered through a pad of Celite and washed with ether (3 x 15 mL). The combined filtrates were concentrated to give imine, which was taken up for further reaction without purification. Formed Imine (0.109 g, 0.35 mmol) was dissolved in methanol (5 mL) and hydrogenated (1 atm) over Raney-Ni. After completion of the reaction (monitored by TLC), it was filtered over Celite and the filtrate was concentrated under reduced pressure to provide 17, which upon column chromatographic purification with silica gel using petroleum ether: ethyl acetate (5:5) as eluent gave pure III as colourless oil.

Yield: 88%, colorless oil; [a] D 25 = +36.7 (c 1, MeOH) {lit. [a] D 26 +36.5 (c 1, MeOH)} ; IR (CHCI 3 , cm "1 ): rj max 669, 1028, 1134, 1215, 1401, 1468, 1589, 2749, 2926, 3019, 3438; 1H NMR (200 MHz, CDC1 3 ): δ 1.38 (m, 1H), 1.80 (m, 1H), 1.98 (m, 2H), 2.07 (m, 1H), 2.53 (s, 3H), 3.71 (m, 1H), 3.97 (m, 1H), 6.77 (d, = 7.6 Hz, 1H), 6.95 (d, = 8.2 Hz, 1H), 7.09 (m, 1H), 7.19 (m, 1H), 7.24 (m, 1H), 7.32 (m, 2H); 13 C NMR (50 MHz, CDCI 3 ): δ 25.7, 28.4, 34.4, 45.4, 57.4, 126.6, 127.2, 128.2, 129.2, 129.8, 130.1, 130.3, 130.7, 132.3, 138.6, 139.4, 147.4; Anal. Calcdfor Ci 7 Hi 7 NCl 2 requires C, 66.68; H, 5.60; N, 4.57; found C, 66.70; H, 5.65; N, 4.59%. ADVANTAGES OF THE INVENTION

Method that employs hydrolytic kinetic resolution of racemic anti- , '- diphenylmethyloxiranes to generate two stereocentres of high optical purities in a single step.

It is the catalytic method of synthesis of chirally pure anti-3, 3 ' -diphenylmethyloxiranes and anti -3, 3' -diphenylpropan- 1, 2-diol which is being developed for the first time using hydrolytic kinetic resolution technique.

The chiral anti-3, 3 '-diphenylmethyloxiranes and nn ' -3,3'-diphenylpropan-l, 2-diol are valuable "building blocks" for the bioactive pharmaceuticals

This method has been successfully applied to the asymmetric synthesis of antidepressant drug (+)-Sertraline.