Cyclohexenone Compositions and Process for Making Thereof

Abstract

Provided herein are processes of preparing cyclohexenone compounds useful for cancer treatments and/or diseases.

What is claimed is: 
     
         1 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising a step of reacting a compound of formula II, 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula (III), Ph 3 PCHR b R c L (III) in the presence of a base, wherein
 L is a leaving group, P1 is a hydroxyl protecting group; 
 each of X and Y independently is a bond, oxygen, NR 5  or sulfur;
 R is H, C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , C(═O)SR 5 , C(═S)R 5 , or C(═S)NR 5 R 6 ; 
 each of R 1 , R 2  and R 3  independently is H, or an optionally substituted C 1 -C 12 alkyl; 
 each of R b  and R c  independently is an optionally substituted C 1 -C 12 alkyl or (CH 2 CH═C(CH 3 )(CH 2 )) m —R 4 , wherein 
 R 4  is H, NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, and C 1 -C 8  haloalkyl; 
 each of R 5  and R 6  is independently H or C 1 -C 8 alkyl; 
 R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; 
 m=0-11. 
 
 
     
     
         2 . The process of  claim 1 , X is an oxygen, Y is an oxygen. 
     
     
         3 . A process for preparing a compound of formula IV: 
       
         
           
           
               
               
           
         
         comprising reacting an enol or enolate compound of formula V, 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula (VI), 
       
         
           
           
               
               
           
         
       
       under suitable conditions, wherein
 each of X and Y independently is oxygen, NR 5  or sulfur;
 R p  is an oxo protecting group; 
 L is a leaving group; 
 each of R 1 , R 2  and R 3  independently is H, or an optionally substituted C 1 -C 12 alkyl; 
 R 4  is NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, and C 1 -C 8  haloalkyl; 
 each of R 5  and R 6  is independently H or C 1 -C 8 alkyl; 
 R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; and 
 n=1-12. 
 
 
     
     
         4 . The process of  claim 3 , X is an oxygen, Y is an oxygen. 
     
     
         5 . The process of  claim 1 , wherein each of R 1 , R 2  and R 3  independently is H, methyl, ethyl, propyl, butyl, pentyl or hexyl. 
     
     
         6 . The process of  claim 1 , wherein said base is a lithium salt. 
     
     
         7 . The process of  claim 6 , wherein said lithium salt is n-butyllithium. 
     
     
         8 . The process of  claim 3 , wherein said enolate compound is prepared under basic conditions. 
     
     
         9 . The process of  claim 3 , wherein said enol compound is prepared under acidic conditions. 
     
     
         10 . The process of  claim 3 , wherein R p  is an acyclic or cyclic acetal, acyclic or cylic ketal, dithio acetal, dithio ketal, cyclic dithio acetal, cyclic dithio ketal, substituted hydrazone, oxime, oxime derivative, or oxazolidine. 
     
     
         12 . A process for preparing a compound of formula X: 
       
         
           
           
               
               
           
         
         comprising a step of reacting an in situ generated compound of formula XI, 
       
       
         
           
           
               
               
           
         
       
       with a compound of formula (III), Ph 3 PCHR b R c L (III) in the presence of a base, wherein
 L is a leaving group, P 1  is a hydroxyl protecting group; 
 each of X and Y independently is a bond, oxygen, NR 5  or sulfur;
 R is H, C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , C(═O)SR 5 , C(═S)R 5 , or C(═S)NR 5 R 6 ; 
 each of R 1 , R 2  and R 3  independently is H, or an optionally substituted C 1 -C 12 alkyl; 
 each of R b  and R c  independently is an optionally substituted C 1 -C 12 alkyl or (CH 2 CH═C(CH 3 )(CH 2 )) m —R 4 , wherein 
 R 4  is H, NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , halogen, 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, glucosyl, wherein the 5 or 6-membered lactone, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, and glucosyl are optionally substituted with one or more substituents selected from NR 5 R 6 , OR 5 , OC(═O)R 7 , C(═O)OR 5 , C(═O)R 5 , C(═O)NR 5 R 6 , C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 8  cycloalkyl, and C 1 -C 8  haloalkyl; 
 each of R 5  and R 6  is independently H or C 1 -C 8 alkyl; 
 R 7  is a C 1 -C 8 alkyl, OR 5  or NR 5 R 6 ; 
 m=0-11. 
 
 
     
     
         13 . The process of  claim 12 , wherein X is an oxygen, Y is an oxygen. 
     
     
         14 . The process of  claim 12 , wherein R 1  is methyl substituted with phenyl. 
     
     
         15 . The process of  claim 12 , wherein R 2  is methyl substituted with phenyl. 
     
     
         16 . The process of  claim 12 , wherein said base is a lithium salt. 
     
     
         17 . The process of  claim 16 , wherein said lithium salt is n-butyllithium.