Cyclic ketones, their preparation and their use in the synthesis of amino acids

Abstract

A method is provided for making an enantiomerically pure compound of the formula: in which R and R′ represent C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C 3 -C 10 cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents in compound (II) being trans. Conjugate addition is carried out between an organometallic nucleophile that provides a group R as defined above and (R)-4-acetoxycyclopent-2-en-1-one, (S)-4-acetoxycyclopent-2-en-1-one or a similar compound in which acetoxy is replaced by another leaving group to give, e.g. in the case of the acetoxy compound, a trans 3,4-disubstituted addition product of formula III or IV;

1 - 29 . (canceled)  
   
   
       30 . A method of making an enantiomerically pure compound of the formula (I) or (II):  
     
       
         
         
             
             
         
       
     
     wherein R and R′ represent C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 3  -C 10  cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents in compound (II) being trans, which method comprises: 
 conjugate addition of an organometallic nucleophile that provides a group R as defined above to a compound of the formula (III) or (IV):  
                     
 wherein X represents a leaving group to give a trans 3,4-disubstituted addition product of formula (V) or (VI) in which R and X are as previously defined;  
                     
 eliminating the leaving-group X from the addition product of formula (V) or (VI) to give an (R)- or (S)-4-alkyl or 4-alkenyl cyclopent-2-en-1-one of formula (VII) or (VIII)  
                     
 and either  
 (i) hydrogenation of the compound of formula (VII) or (VIII) to give a cyclopentanone of formula (I) or  
 (ii) conjugate addition of a second organometallic nucleophile that provides a group R′ as defined above to the compound of formula (VII) or (VIII) to give a trans 3,4-disubstituted addition product of formula (II).  
 
   
   
       31 . The method of  claim 30 , when used to make an (S)-compound of formula (I).  
   
   
       32 . The method of  claim 30 , when used to make an (R)-compound of formula (I).  
   
   
       33 . The method of  claim 30 , when used to make a (3S,4S)-compound of formula (II).  
   
   
       34 . The method of  claim 30 , when used to make a (3R,4R)-compound of formula (II).  
   
   
       35 . The method of  claim 30 , when used to make a compound in which R and R′ (if present) represent methyl, ethyl or n-propyl.  
   
   
       36 . The method of  claim 30 , when used to make any of the following compounds: 
 (S)-3-methylcyclopentanone;    (R)-3-methylcyclopentanone;    (S)-3-ethylcyclopentanone;    (R)-3-ethylcyclopentanone;    (S)-3-n-propylcyclopentanone;    (R)-3-n-propylcyclopentanone;    (3S,4S)-3,4-dimethyl-cyclopentanone;    (3R,4R)-3,4-dimethyl-cyclopentanone;    (3S,4S)-3,4-diethyl-cyclopentanone;    (3R,4R)-3,4-diethyl-cyclopentanone;    (3S,4S)-3-ethyl-4-methyl-cyclopentanone;    (3R,4R)-3-ethyl-4-methyl-cyclopentanone;    (3S,4S)-3-methyl-4-propyl-cyclopentanone;    (3R,4R)-3-methyl-4-propyl-cyclopentanone;    (3S,4S)-3-ethyl-4-propyl-cyclopentanone;    (3R,4R)-3-ethyl-4-propyl-cyclopentanone.    
   
   
       37 . The method of  claim 30 , wherein the elimination product of formula (VII) or (VIII) is treated with hydrogen at a pressure of 1-30 atmospheres at a temperature in the range 0-60° C. in a solvent and in the presence of a hydrogenation catalyst to give a compound of formula (I).  
   
   
       38 . The method of  claim 30  wherein the elimination product of formula (VII) or (VIII) is treated with hydrogen at a pressure of 1-30 atmospheres at a temperature in the range 0-60° C. in a solvent and in the presence of a hydrogenation catalyst to give a compound of formula (I); and wherein 
 the hydrogenation catalyst is selected from palladium on charcoal, platinum oxide, Raney nickel, and rhodium on alumina.    
   
   
       39 . The method of  claim 30 , wherein the elimination product of formula (VII) or (VIII) is treated with hydrogen at a pressure of 1-30 atmospheres at a temperature in the range 0-60° C. in a solvent and in the presence of a hydrogenation catalyst to give a compound of formula (I); and wherein 
 the solvent is ethyl acetate or methanol.    
   
   
       40 . The method of  claim 30 , wherein the conjugate addition is carried out by treating the elimination product of formula (VII) or (VIII) with a second organo-Grignard reagent or with a second an organo-lithium reagent in the presence of a dialkylzinc or zinc chloride or a copper (I) salt or a trialkylaluminium in a solvent at a temperature from −100° C. to 0° C. to produce a compound of formula (II).  
   
   
       41 . The method of  claim 40 , wherein the solvent is selected from tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether and t-butyl methyl ether.  
   
   
       42 . The method of  claim 30 , wherein the leaving group X in the compound of formula (III) or (IV) is acetoxy.  
   
   
       43 . The method of  claim 30 , wherein the leaving group X in the compound of formula (III) or (IV) is halogen or sulfonic acid ester group.  
   
   
       44 . An enantiomerically pure compound made by the method of  claim 30 .  
   
   
       45 . The compound of  claim 44 , whose enantiomeric purity is 98% or above.  
   
   
       46 . A method of producing a compound of one of the formulae shown below:  
     
       
         
         
             
             
         
       
     
     in which the substituents R and R′ and the wedges have the meanings indicated in  claim 30 , which comprises providing a compound of formula (I) or (II) produced by the method of  claim 30 , converting said compound to a compound of formula (XI), (XII), (XIII) or (XIV), and optionally further converting said compound into a pharmaceutically acceptable salt.  
   
   
       47 . The method of  claim 46 , wherein said conversion is via an intermediate (XV)-(XVIII) shown below:  
     
       
         
         
             
             
         
       
     
     in which the substituents R and R′ and the wedges have the meanings indicated above.  
   
   
       48 . The method of  claim 47 , wherein the intermediate of formula (XV)-(XVIII) is converted to a compound of formula (I) or (II) by transforming the phenyl ring to a carboxylic acid and then to an amine.  
   
   
       49 . The method of  claim 47 , wherein the intermediate of formula (XV)-(XVIII) is converted to a compound of formula (I) or (II) by transforming the carboxylic acid group into an amine and oxidizing the phenyl group to an acid.  
   
   
       50 . The method of  claim 47 , wherein the intermediate of formula (XV)-(XVIII) is converted to a compound of formula (I) or (II) by protecting the carboxylic acid group, oxidizing the phenyl ring to a second carboxylic acid group, protecting the second carboxylic acid group, selectively de-protecting the first carboxylic acid group, transforming the first carboxylic acid group to an amine, and de-protecting the second carboxylic acid group.  
   
   
       51 . A method of producing a compound of the formula (XV)-(XVIII) shown below:  
     
       
         
         
             
             
         
       
     
     in which the substituents R and R′ and the wedges have the meanings indicated in  claim 30 , which comprises providing a compound of formula (I) or (II) produced by the method of  claim 30 , and converting said compound to a compound of formula (XV)-(XVIII).  
   
   
       52 . An enantiomerically pure compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein R and R′ represent C 1 -C 10  alkyl, C 2 -C 10  alkenyl or C 3 -C 10  cycloalkyl and the wedges signify (S)- or (R)-stereochemistry, the substituents being trans, and at least one of R and R′ not being methyl.  
   
   
       53 . Any of the following compounds 
 (3S,4S)-3,4-diethyl-cyclopentanone;    (3R,4R)-3,4-diethyl-cyclopentanone;    (3S,4S)-3-ethyl-4-methyl-cyclopentanone;    (3R,4R)-3-ethyl-4-methyl-cyclopentanone;    (3S,4S)-3-methyl-4-propyl-cyclopentanone;    (3R,4R)-3-methyl-4-propyl-cyclopentanone;    (3S,4S)-3-ethyl-4-propyl-cyclopentanone;    (3R,4R)-3-ethyl-4-propyl-cyclopentanone.