Intermediates for the preparation of analogs of Halichondrin B

Abstract

The present invention provides macrocyclic compounds, synthesis of the same and intermediates thereto. Such compounds, and compositions thereof, are useful for treating or preventing proliferative disorders Formula (F-4).

We claim: 
     
       1. A compound of formula F-4: 
       
         
           
           
               
               
           
         
       
       wherein:
 each of PG 1 , PG 2 , and PG 3  is independently hydrogen or a suitable hydroxyl protecting group; 
 R 1  is R or —OR; 
 each R is independently hydrogen, C 1-4  haloaliphatic, benzyl, or C 1-4  aliphatic; and 
 LG 1  is a suitable leaving group. 
 
     
     
       2. The compound according to  claim 1 , wherein said compound is of formula F-4′: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       3. The compound according to  claim 2 , wherein R 1  is OR wherein R is hydrogen, methyl, or benzyl. 
     
     
       4. The compound according to  claim 2 , wherein PG 1  and PG 2  are both hydrogen. 
     
     
       5. The compound according to  claim 2 , wherein each of PG 1  and PG 2  is independently a suitable hydroxyl protecting group. 
     
     
       6. The compound according to  claim 5 , wherein one or both of PG 1  and PG 2 , taken together with the oxygen atom to which each is bound, is a silyl ether or an arylalkyl ether. 
     
     
       7. The compound according to  claim 6 , wherein PG 1  and PG 2  are both t-butyldimethylsilyl. 
     
     
       8. The compound according to  claim 5 , wherein PG 1  and PG 2  are taken together, with the oxygen atoms to which they are bound, to form a diol protecting group. 
     
     
       9. The compound according to  claim 8 , wherein said diol protecting group is a cyclic acetal or ketal, a silylene derivative, a cyclic carbonate, or a cyclic boronate. 
     
     
       10. The compound according to  claim 2 , wherein LG 1  is sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or halogen. 
     
     
       11. The compound according to  claim 10 , wherein LG 1  is mesyloxy tosyloxy, chloro, iodo, bromo, or triflate. 
     
     
       12. The compound according to  claim 2 , wherein said compound is: 
       
         
           
           
               
               
           
         
       
       
        
       
     
     
       13. The compound according to  claim 1 , wherein said suitable hydroxyl protecting group, taken with the oxygen atom to which it is bound, is selected from an ester, an ether, a silyl ether, an alkyl ether, an arylalkyl ether, and an alkoxyalkyl ether. 
     
     
       14. The compound according to  claim 13 , wherein
 said ester is a formate, acetate, carbonate, or sulfonate;   said silyl ether is a trialkylsilyl ether; or   said alkoxyalkyl ether is an acetal.   
     
     
       15. The compound according to  claim 13 , wherein said ester is formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate, p-benzylbenzoate, 2,4,6-trimethylbenzoate, methyl carbonate, 9-fluorenylmethyl carbonate, ethyl carbonate, 2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, vinyl carbonate, ally! carbonate, or p-nitrobenzyl carbonate;
 said silyl ether is trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl ether;   said alkyl ether is methyl, trityl, t-butyl, allyl, or allyloxycarbonyl ether;   said alkoxyalkyl ether is methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers; or said arylalkyl ether is benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, 2- picolyl, or 4-picolyl.   
     
     
       16. The compound according to  claim 1 , wherein LG 1  is mesyloxy or tosyloxy. 
     
     
       17. The compound according to  claim 9 , wherein
 said cyclic acetal or ketal is methylene, ethylidene, benzylidene, isopropylidene, cyclohexylidene, or cyclopentylidene; or   said silylene derivative is di-t-butylsilylene or a 1,1,3,3-tetraisopropyldisiloxanylidene derivative.   
     
     
       18. The compound according to  claim 1 , wherein LG 1  is sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, or halogen. 
     
     
       19. A compound of formula: 
       
         
           
           
               
               
           
         
       
       and/or a pharmaceutically acceptable salt thereof. 
     
     
       20. A composition comprising a compound: 
       
         
           
           
               
               
           
         
       
       and/or a pharmaceutically acceptable salt thereof, and 
       a compound of formula: 
       
         
           
           
               
               
           
         
       
       and/or a pharmaceutically acceptable salt thereof.