Single step enantioselective process for the preparation of 3-substituted chiral phthalides

1. Single step, asymmetric dihydroxylation (AD) and nitrile accelerated catalytic oxidative cyclization for synthesis of 3-substituted chiral phthalides of Formula II, comprising,

(a) reacting o-cyano substituted aryl alkenes of Formula I with AD-mix-β in presence of a solvent at room temperature ranging between 25-35° C. for a period ranging between 3-7 h

to form a cyclic amino ether

(b) hydrolyzing the cyclic amino ether with water to form the lactone of Formula II;

wherein AD-mix-β comprises potassium osmate K 2 OsO 2 (OH) 4 ; potassium ferricyanide K 3 Fe(CN) 6 ; potassium carbonate; and chiral ligand (DHQD) 2 PHAL; and

wherein R1, R2, R3 and R4 are independently same or different groups selected from hydrogen, C1-C7 straight or branched alkyl, C1-C7 alkoxide, —OTs, —OBn, C6-C10 aryls, C3-C6 cycloalkyl, C3-C6 cycloalkenes, heteroaryls, —NR6R7, —CN, —CONR8R9, —CO—R10; and —COOR11;

R5 is selected from hydrogen, C1-C7 straight or branched, and C2-C7 alkyl alkoxy where alkyl is C1-C3 and alkoxy is C1-C4, C6-C10 aryl, —COO R12, where R12 is C1-C4alkyl;

when R5 is —COOR12, R1 and R4 is hydrogen, R2 and R3 together may represent —O—CH2—O or a phenyl ring, R12 is C1-C4alkyl;

when R5 is C1-C7 straight or branched alkyl, R1 is —O-alkyl, R4 is H, R2 and R3 together represent a heteroarly.

2. The single step, asymmetric dihydroxylation process according to claim 1 , wherein the compound of Formula II is selected from;

a) (S)-Ethyl-2-((R)-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIa)

b) (S)-Ethyl-2-((R)-1,3-dihydro-5-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy acetate (IIb);

c) (S)-Ethyl-2((R)-1,3-dihydro-5,6-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy acetate (IIc);

d) (S)-Ethyl-2((R)-1,3-dihydro-6,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy acetate (IId);

e) (S)-Ethyl-2-((R)-1,3-dihydro-5,7-dimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy acetate (IIe);

f) (S)-Ethyl-2-((R)-1,3-dihydro-5,6,7-trimethoxy-1-oxoisobenzofuran-3-yl)-2-hydroxy acetate (IIf);

g) (S)-Ethyl-2-((R)-5-(p-toluenesulfonoyloxy)-1,3-dihydro-6-methoxy-1-oxo iso benzo furan-3-yl)-2-hydroxyacetate (IIg);

h) (S)-Ethyl-2-((R)-5-(benzyloxy)-1,3-dihydro-6-methoxy-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIh);

i) (S)-Ethyl-2-((R)-5-fluoro-1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-hydroxy acetate (IIi);

j) (S)-Ethyl-2-((R)-1,3-dihydro-5-nitro-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIj);

k) (S)-Ethyl 2-((R)-5-1,3-dihydro-5,6-dioxomethyl-1-oxoisobenzofuran-3-yl)-2-hydroxyacetate (IIk);

l) (S)-Ethyl 2-((R)-1,3-dihydro-1-oxonaphtho[2,1-c]furan-3-yl)-2-hydroxyl acetate (II 1);

m) (R)-3-(Hydroxymethyl)isobenzofuran-1(3H)-one (IIm);

n) (R)-3-(Hydroxymethyl)-5-methoxyisobenzofuran-1(3H)-one (IIn);

o) (R)-3-(Hydroxymethyl)-5,6-dimethoxyisobenzofuran-1(3H)-one (IIo);

p) (R)-3-(Hydroxymethyl)-6,7-dimethoxyisobenzofuran-1(3H)-one (IIp);

q) (R)-3-(Hydroxymethyl)-5,7-dimethoxyisobenzofuran-1(3H)-one (IIq);

r) (R)-3-(Hydroxymethyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one (IIr);

s) (R)-1,3-Dihydro-1-(hydroxymethyl)-5-methoxy-3-oxoisobenzofuran-6-yl-4-methyl benzenesulfonate (IIs);

t) (R)-5-(Benzyloxy)-3-(hydroxymethyl)-6-methoxyisobenzofuran-1(3H)-one (IIt);

u) (R)-5-Fluoro-3-(hydroxymethyl)isobenzofuran-1(3H)-one (IIu);

v) (R)-3-(Hydroxymethyl)-5,6-dioxomethylisobenzofuran-1(3H)-one (IIv);

w) (R)-3-((R)-1-Hydroxy(butyl) isobenzofuran-1(3H)-one (II w);

x) (R)-3-((R)-1-Hydroxy-2-tertiarybutyldimethylsilylethyl)-5,6 dimethoxyisobenzofuran-1(3H)-one (II x);

y) (R)-3-((R)-Hydroxy(phenyl)methyl)-5,6-dimethoxyisobenzofuran-1(3H)-one (IIy); and

z) (R)-3-((R)-1-Hydroxyheptyl)-5,6,7-trimethoxyisobenzofuran-1(3H)-one (IIz).

3. The process as claimed in claim 1 , wherein the solvent is selected from (a) polar protic solvents selected from water, methanol, ethanol, n-propanol, isopropanol, n-butyl alcohol and t-butyl alcohol; (b) polar aprotic solvents selected from THF, DMF, DMSO, and ethyl acetate; (c) nonpolar organic solvent selected from benzene, toluene, hexane, and chloroform; and (d) a combination thereof.

4. The process as claimed in claim 1 , wherein the solvent is a mixture of t-BuOH, THF, water in the ratio of 0.5:0.5:1.

5. The process as claimed in claim 1 , wherein yields and enantiomeric excess (ee) of chiral phthalides is in the range of 92-97% and 97-99% respectively.