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

Patent metadata

Field	Value
Publication number	US-9505733-B2
Application number	US-201514694588-A
Country	US
Kind code	B2
Filing date	Apr 23, 2015
Priority date	Nov 18, 2011
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

The present invention discloses single step, highly enantioselective catalytic oxidative cyclization process for the synthesis of 3-substituted chiral phthalides. In particular, the invention discloses asymmetric synthesis of chiral phthalides via synergetic nitrile accelerated oxidative cyclization of o-cyano substituted aryl alkenes in high yield and enantiomeric excess (ee) in short reaction time. Also, disclosed herein is “one-pot” asymmetric synthesis of biologically important natural compounds having 3-substituted chiral phthalide structural framework in the molecule.

First claim

The invention claimed is:

1. A synthesis of compound (3)

comprising
(a) reacting an o-cyano substituted aryl alkene of Formula I with AD-mix-β in the 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 R 1 , R 2 , R 3 and R4 are hydrogen; and R 5 is C 4 H 9
to form compound (21)

(c) carrying out Barton-Mccombie deoxygenation of compound (21) with 1,1-thiocarbonyl diimidazole in the presence of dichloromethane as solvent at 25-35° C. for 10-14 h followed by treatment with tributyltinhydride in the presence of catalytic amount of azobisisobutyronitrile for 20-40 min to obtain compound (3).

2. A synthesis of compound (2a)

comprising
(a) reacting an o-cyano substituted aryl alkene of Formula I with AD-mix-β in the 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 osmate K 2 OsO 2 (OH 4 ); potassium ferricyanide K 3 Fe(CN) 6 ; potassium carbonate; and chiral ligand (DHQD) 2 PHAL; and
wherein R 1 and R 3 are hydrogen, R 2 and R 4 are —OMe, and R 5 is unsubstituted phenyl; to form compound (19)

(c) adding BBr3 and an organic solvent to compound (19) followed by stirring at 10° C. to 25° C. for 6-8 h to obtain compound (2a).

3. A synthesis of compound (20)

comprising
(a) reacting an o-cyano substituted aryl alkene of Formula I with AD-mix-β in the 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 R 1 and R 3 are hydrogen, R 2 and R4 are —OMe and R 5 is —Me; to form compound (18)

(c) adding BBr3 and an organic solvent to compound (18), followed by stirring at 10° C. to 25° C. for 6-8 h to obtain compound (20).

Assignees

• Council Scient Ind Res

Inventors

• Reddy Rekula Santosh
• Naga Chithanya Kiran Indukuru
• Arumugam Sudalai

Classifications

• C07D307/92

  Naphthofurans; Hydrogenated naphthofurans · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title

• C07D307/88 Primary

  with one oxygen atom directly attached in position 1 or 3 · CPC title

• C07B53/00

  Asymmetric syntheses · CPC title