Process for producing wine lactone

Abstract

The present invention relates to a method comprising (A) reacting a β-keto ester with a 2-halo ester under basic conditions to obtain a 2-aceto-3-methyl-succinic acid ester; (B) reacting the resulting 2-aceto-3-methyl-succinic acid ester with methyl vinyl ketone under basic conditions, optionally followed by a decarboxylation reaction and hydrolysis, etc., to obtain an α-methyl-γ-keto acid; and (C) reducing the resulting α-methyl-γ-keto acid to obtain wine lactone or a stereoisomer thereof or a mixture thereof. Alternatively, the present invention relates to a method comprising step (A) as recited above; (B) reacting the resulting 2-aceto-3-methyl-succinic acid ester with methyl vinyl ketone under basic conditions, followed by decarboxylation reaction to obtain an α-methyl-γ-keto acid ester; and (E) reducing the resulting α-methyl-γ-keto acid ester in the presence of a ruthenium complex having a specific structure and in the presence of a hydrogen donor to obtain wine lactone or a stereoisomer thereof or a mixture thereof.

1 . A process for producing a compound represented by formula (a), which is wine lactone or a stereoisomer thereof or a mixture thereof: 
       
         
           
           
               
               
           
         
       
       wherein said process comprises:
 A) the step of reacting a β-keto ester represented by formula (1): 
 
       
         
           
           
               
               
           
         
         [wherein R 1  is an alkyl group containing 1 to 4 carbon atoms] 
         with a 2-halo ester represented by formula (2): 
       
       
         
           
           
               
               
           
         
         [wherein R 2  is an alkyl group containing 1 to 4 carbon atoms, and X is a chlorine atom or a bromine atom] 
         under basic conditions to obtain a 2-aceto-3-methyl-succinic acid ester represented by formula (3): 
       
       
         
           
           
               
               
           
         
         [wherein R 1  is as defined in formula (1), and R 2  is as defined in formula (2)]; 
         B-2) the step of reacting the 2-aceto-3-methyl-succinic acid ester obtained in step A) with methyl vinyl ketone under basic conditions, followed by decarboxylation reaction to obtain an α-methyl-γ-keto acid ester represented by formula (5): 
       
       
         
           
           
               
               
           
         
         [wherein R 2  is as defined in formula (2)]; 
         B-3) the step of hydrolyzing the α-methyl-γ-keto acid ester obtained in step B-2) to obtain an α-methyl-γ-keto acid represented by formula (4): 
       
       
         
           
           
               
               
           
         
       
       and
 C) the step of reducing the α-methyl-γ-keto acid obtained in step B-3) to obtain the compound represented by formula (a). 
 
     
     
         2 . The process according to  claim 1 , wherein step C) comprises causing asymmetric reduction reaction in the presence of an optically active form of a ruthenium complex selected from compounds represented by formula (6) or (7) and in the presence of a hydrogen donor: 
       
         
           
           
               
               
           
         
       
       [wherein * represents an asymmetric carbon atom,
 R 31  is an alkyl group containing 1 to 10 carbon atoms; a halogenated alkyl group containing 1 to 10 carbon atoms; a 10-camphoryl group; an amino group which may be substituted with one or two alkyl groups each containing 1 to 10 carbon atoms; or an aryl group which may be substituted with at least one substituent selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms, a halogenated alkyl group containing 1 to 10 carbon atoms, a halogen atom, a cyano group (—CN), an amino group, an alkylamino group (—NR 20 R 21 ) a 5- or 6-membered cyclic amino group, an acylamino group (—NH—CO—R 20 ), a hydroxyl group, an alkoxy group (—OR 20 ), an acyl group (—CO—R 20 ), a carboxyl group, an alkoxycarbonyl group (—COOR 20 ), a phenoxycarbonyl group, a mercapto group, an alkylthio group (—SR 20 ), a silyl group (—SiR 20 R 21 R 22 ) and a nitro group (—NO 2 ), wherein R 20 , R 21  and R 22  are each independently a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a cycloalkyl group containing 3 to 10 carbon atoms, 
 Y is a hydrogen atom, 
 W is a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a benzenesulfonyloxy group, a hydrogen atom, or a halogen atom, 
 j and k are each independently 0 or 1, provided that j+k is not 1, 
 R 32  and R 33  are each independently a hydrogen atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl group which may be substituted with at least one substituent selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon atoms, or alternatively, R 32  and R 33  may together form a ring, 
 R 11 , R 12 , R 13 , R 14  and R 15  each independently represent a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon atoms, 
 R 16 , R 17 , R 18  and R 19  are each independently a hydrogen atom, a hydroxyl group, an alkyl group containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon atoms, or alternatively, R 16  and R 17  may form a carbonyl group together with their adjacent carbon atom and/or R 18  and R 19  may form a carbonyl group together with their adjacent carbon atom, 
 Z is an oxygen atom or a sulfur atom, 
 n 1  is 1 or 2, and n 2  is an integer of 1 to 3] 
 
       
         
           
           
               
               
           
         
       
       [wherein * represents an asymmetric carbon atom,
 R 31  is an alkyl group containing 1 to 10 carbon atoms; a halogenated alkyl group containing 1 to 10 carbon atoms; a 10-camphoryl group; an amino group which may be substituted with one or two alkyl groups each containing 1 to 10 carbon atoms; or an aryl group which may be substituted with at least one substituent selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms, a halogenated alkyl group containing 1 to 10 carbon atoms, a halogen atom, a cyano group (—CN), an amino group, an alkylamino group (—NR 20 R 21 ) a 5- or 6-membered cyclic amino group, an acylamino group (—NH—CO—R 20 ), a hydroxyl group, an alkoxy group (—OR 20 ), an acyl group (—CO—R 20 ), a carboxyl group, an alkoxycarbonyl group (—COOR 20 ), a phenoxycarbonyl group, a mercapto group, an alkylthio group (—SR 20 ), a silyl group (—SiR 20 R 21 R 22 ) and a nitro group (—NO 2 ), 
 R 20 , R 21  and R 22  are each independently a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or a cycloalkyl group containing 3 to 10 carbon atoms, 
 Y is a hydrogen atom, 
 R 32  and R 33  are each independently a hydrogen atom; an alkyl group containing 1 to 10 carbon atoms; a phenyl group which may be substituted with at least one substituent selected from the group consisting of an alkyl group containing 1 to 10 carbon atoms, an alkoxy group containing 1 to 10 carbon atoms and a halogen atom; or a cycloalkyl group containing 3 to 8 carbon atoms, or alternatively, R 32  and R 33  may together form a ring, 
 R 11 , R 12 , R 13 , R 14  and R 15  are each independently a hydrogen atom, an alkyl group containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon atoms, 
 R 16 , R 17 , R 18  and R 19  are each independently a hydrogen atom, a hydroxyl group, an alkyl group containing 1 to 10 carbon atoms, or an alkoxy group containing 1 to 10 carbon atoms, or alternatively, R 16  and R 17  may form a carbonyl group together with their adjacent carbon atom and/or R 18  and R 19  may form a carbonyl group together with their adjacent carbon atom, 
 Z is an oxygen atom or a sulfur atom, Q −  is a counter anion, 
 n 1  is 1 or 2, and n 2  is an integer of 1 to 3]. 
 
     
     
         3 . The process according to  claim 2 , wherein the ruthenium complex represented by formula (6) is a compound represented by the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The process according to  claim 1 , which further comprises the step of distilling the compound obtained in step C) under basic conditions to obtain a diastereomeric isomer mixture composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The process according to  claim 2 , which further comprises the step of distilling the compound obtained in step C) under basic conditions to obtain a diastereomeric isomer mixture composed of (3S,3aS,7aR) and (3R,3aR,7aS) isomers represented by the following formulae: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The process according to  claim 5 , which further comprises the step of recrystallization to obtain the (3S,3aS,7aR) isomer represented by the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The process according to  claim 3 , wherein in step E), the ruthenium complex selected from compounds represented by formula (6) or (7) is an optically active ruthenium complex and is used to cause asymmetric reduction reaction.