Synthetic techniques and intermediates for polyhydroxy dienyl lactones and mimics thereof

Abstract

Synthetic methods and intermediates useful in the preparation of lactone containing compounds such as discodermolide and compounds which mimic the chemical or biological activity of discodermolide are provided.

1 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 11  and R 12  are each independently C 1 -C 10  alkyl;  
 R 14  and R 15  are each independently an acid labile hydroxyl protecting group; and  
 R 16  is H or C 1 -C 6  alkyl.  
 
     
     
         2 . The compound of  claim 1  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
       wherein TBS is tert-butyldimethylsilyl and TES is triethylsilyl.  
     
     
         3 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 7  and R 8  are independently C 1 -C 10  alkyl;  
 R 6  and R 16  are independently H or C 1 -C 6  alkyl;  
 R 9  is an acid labile hydroxyl protecting group; and  
 J is:  
                     
 wherein:  
 R 32  is H or C 1 -C 6  alkyl; and  
 R 33  is an acid labile hydroxyl protecting group.  
 
     
     
         4 . The compound of  claim 3  of formula:  
       
         
           
           
               
               
           
         
       
       wherein TBS is tert-butyldimethylsilyl and TES is triethylsilyl.  
     
     
         5 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1 , R 2 , R 7 , and R 8  are independently C 1 -C 10  alkyl;  
 R 3  and R 6  are independently selected from hydrogen and C 1 -C 6  alkyl;  
 R 4  and R 9  are independently an acid labile hydroxyl protecting group;  
 R 18  is C 6 -C 14  aryl;  
 R 25  is an acid stable hydroxyl protecting group; and  
 X is halogen.  
 
     
     
         6 . The compound of  claim 5  of formula:  
       
         
           
           
               
               
           
         
       
       wherein TBS is tert-butyldimethylsilyl, Ph is phenyl and PMB is para-methoxybenzyl.  
     
     
         7 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 6  is H or C 1 -C 10  alkyl;  
 R 7  and R 8  are independently C 1 -C 10  alkyl;  
 R 9  is an acid labile protecting group;  
 R 18  is C 6 -C 14  aryl; and  
 X is halogen.  
 
     
     
         8 . The compound of  claim 7  of formula:  
       
         
           
           
               
               
           
         
       
       wherein TBS is tert-butyldimethylsilyl and Ph is phenyl.  
     
     
         9 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 6  is C 1 -C 4  alkyl;  
 R 7  and R 8  are independently C 1 -C 10  alkyl;  
 R 9  is an acid labile hydroxyl protecting group;  
 R 10  is an acid stable hydroxyl protecting group; and  
 X is halogen.  
 
     
     
         10 . The compound of  claim 9  of formula:  
       
         
           
           
               
               
           
         
       
       wherein TBS is tert-butyldimethylsilyl and PMB is para-methoxybenzyl.  
     
     
         11 . A compound of formula:  
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1 , R 2  and R 3  are independently, C 1 -C 10  alkyl;  
 X is a halogen;  
 Z 1  and Z 2  are independently, O, S or NR′;  
 R 4  is an acid labile hydroxyl protecting group;  
 R 5  is C 6 -C 14  aryl; and  
 each R′ is independently hydrogen or C 1 -C 6  alkyl.  
 
     
     
         13 . The compound of  claim 12  wherein R 1 , R 2  and R 3  are methyl; X is iodo; Z 1  and Z 2  are each O; R 4  is tert-butyldimethylsilyl; and R 5  is para-methoxyphenyl.