Intermediates for the preparation of analogs of halichondrin B

Abstract

Intermediates and methods of their use in the synthesis of analogs of halichondrin B are provided.

The invention claimed is: 
     
       1. A compound of formula F-2d: 
       
         
           
           
               
               
           
         
         wherein: 
         R′ is —CH═CH 2  or —C(O)H; 
         Alk is a C 1-4  straight or branched aliphatic group; and 
         PG 5  is a suitable hydroxyl protecting group. 
       
     
     
       2. The compound of  claim 1 , wherein PG 5 , taken with the oxygen atom to which it is bound, is an ester, silyl ether, alkyl ether, arylalkyl ether, or alkoxyalkyl ether. 
     
     
       3. The compound of  claim 1 , wherein PG 5 , taken with the oxygen atom to which it is bound, is a silyl ether. 
     
     
       4. The compound of  claim 1 , wherein PG 5  is t-butyldimethylsilyl. 
     
     
       5. The compound of  claim 1 , wherein Alk is methyl. 
     
     
       6. The compound of  claim 1  of formula F-2d′: 
       
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 1  of formula: 
       
         
           
           
               
               
           
         
       
     
     
       8. A method of synthesizing a compound of formula F-2, the method comprising reacting a compound of formula F-2d: 
       
         
           
           
               
               
           
         
         wherein: 
         R′ is —CH═CH 2  or —C(O)H; 
         Alk is a C 1-4  straight or branched aliphatic group; and 
         PG 5  is a suitable hydroxyl protecting group 
         with a compound of formula F-2e: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R″ is OH, OPG 3 , or LG 4 ; 
         LG 4  is a suitable leaving group; and 
         each PG 3  is independently a suitable hydroxyl protecting group 
         to produce a compound of formula F-2f: 
       
       
         
           
           
               
               
           
         
          and 
         converting the compound of formula F-2f into the compound of formula F-2: 
       
       
         
           
           
               
               
           
         
         wherein: 
         each   is independently a single or double bond, provided that both   groups are not simultaneously a double bond; 
         LG 1  is a suitable leaving group; 
         X is halogen or —OSO 2 (R y ); 
         R y  is C 1-6  aliphatic or a 5-7 membered saturated, partially unsaturated, or fully unsaturated ring, wherein R y  is optionally substituted with up to 3 groups selected from halogen, R, NO 2 , CN, OR, SR, or N(R) 2 ; and 
         each R is independently hydrogen, C 1-4  haloaliphatic, or C 1-4  aliphatic. 
       
     
     
       9. The method of  claim 8 , wherein the compound of formula F-2 is 
       
         
           
           
               
               
           
         
       
     
     
       10. A method for preparing a compound of formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         the method comprising producing the compound of formula B-1939 or a pharmaceutically acceptable salt thereof from a compound of formula F-2d: 
       
       
         
           
           
               
               
           
         
         wherein: 
         R′ is —CH═CH 2  or —C(O)H; 
         Alk is methyl; and 
         PG 5  is a suitable hydroxyl protecting group. 
       
     
     
       11. The method of claim 10, wherein PG 5 , taken with the oxygen atom to which it is bound, is an ester, silyl ether, alkyl ether, arylalkyl ether, or alkoxyalkyl ether. 
     
     
       12. The method of claim 10, wherein PG 5 , taken with the oxygen atom to which it is bound, is a silyl ether. 
     
     
       13. The method of claim 10, wherein PG 5  is t-butyldimethylsilyl. 
     
     
       14. The method of claim 10, wherein the compound of formula F-2d is of formula F-2d′: 
       
         
           
           
               
               
           
         
        
       
     
     
       15. The method of claim 10, wherein the compound of formula F-2d is of formula: