Compounds, processes and intermediates for synthesis of mixed backbone oligomeric compounds

Abstract

Synthetic processes are provided wherein mixed backbone oligomeric compounds are prepared having at least one phosphodiester internucleoside linkage in addition to one or more phosphorothioate, phosphoramidate and boranophosphate internucleoside linkages. Novel H-phosphonate intermediates are also disclosed that are useful in the synthetic processes. The synthetic processes use a novel oxidation step to oxidize H-phosphonate internucleoside linkages to phosphodiester internucleoside linkages without degradation of adjacent phosphorothioate, phosphoramidate and boranophosphate internucleoside linkages. Also provided are synthetic intermediates useful in such processes.

What is claimed is:  
     
         1 . A chimeric oligomeric compound having the formula:  
       5′—Nu—(L 4 —Nu) z1 —(L 5 —Nu) z2 —(L 6  -Nu) z3 —3′  
       wherein: 
 each L 4 , L 5 , and L 6  is, independently, an internucleoside linkage selected from phosphodiester, phosphorothioate, secondary phosphoramidate, tertiary phosphoramidate or boranophosphate, with the provision that L 4  and L 6  are different from L 5  and that one of L 4 , L 5  and L 6  are other than phosphodiester and phosphorothioate;  
 each z 1 , z 2 , and z 3  is, independently, an integer greater than 1;  
 each Nu is a nucleoside having the formula:  
                     
 wherein:  
 Bx is a heterocyclic base moiety;  
 each R 1  is, independently, H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group; and  
 said 5′- and said  -3 ′ ends of said chimeric oligomeric compound are, independently, hydroxyl, a protected hydroxyl, a linkage to a solid support, an activated phosphate group, an activated phosphite group, a reactive group for forming an internucleotide linkage, a nucleotide, a nucleoside, or an oligonucleotide  
 with the proviso that when one or both of said L 4  and L 6  is independently a phosphoramidate then at least one R 1  is other than H.  
 
     
     
         2 . The chimeric oligomeric compound of  claim 1  wherein each L 4  and L 6  is a phosphoramidate internucleotide linkage and each L 5  is a phosphorothioate internucleoside linkage.  
     
     
         3 . The chimeric oligomeric compound of  claim 1  wherein each L 4  and L 6  is a phosphoramidate internucleotide linkage and each L 5  is a phosphodiester internucleoside linkage.  
     
     
         4 . The chimeric oligomeric compound of  claim 1  wherein each L 4  and L 6  is a boranophosphate internucleotide linkage and each L 5  is a phosphodiester internucleoside linkage.  
     
     
         5 . The chimeric oligomeric compound of  claim 1  wherein each L 4 , L 5  and L 6  is a phosphoramidate, phosphorothioate or phosphodiester internucleoside linkage.  
     
     
         6 . The chimeric oligomeric compound of  claim 1  wherein each L 4  and L 6  is a phosphodiester internucleotide linkage and each L 5  is a phosphorothioate internucleoside linkage.  
     
     
         7 . The chimeric oligomeric compound of  claim 1  wherein each L 4  and L 6  is a boranophosphate internucleotide linkage and each L 5  is a phosphorothioate internucleoside linkage.  
     
     
         8 . The chimeric oligomeric compound of  claim 1  wherein each R 1  is independently —O—CH 2 CH 2 —O—CH 3 , —O—CH 2 CH 2 —O—N(R 6 )(R 7 ) or —O—CH 2 CH 2  —O—CH 2 CH 2 —N(R 6 )(R 7 ), wherein each of R 6 and R 7  is, independently, H or C 1 -C 10 alkyl.  
     
     
         9 . The chimeric oligomeric compound of  claim 8  wherein each R 6  and R 7  is —CH 3 .  
     
     
         10 . A chimeric oligomeric compound having the formula:  
       5′—Nu—(L 4 -Nu) z1 —(L 5 —Nu) z2 —(L 6  —NU) z3 —(L 7 —Nu) z4 —3′  
       wherein: 
 each L 4 , L 5 , L 6 , and L 7  is, independently, an internucleoside linkage selected from phosphodiester, phosphorothioate, secondary phosphoramidate, tertiary phosphoramidate or boranophosphate, with the provision that L 4  and L 6  are different from L 5  and that one of L 4 , L 5  and L 6  are other than phosphodiester and phosphorothioate;  
 each z 1 , z 2 , z 3 , and z 4  is, independently, an integer greater than 1;  
 each Nu is a nucleoside having the formula:  
                     
 wherein:  
 Bx is a heterocyclic base moiety;  
 each R 1  is, independently, H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group; and  
 said 5′- and said  -3 ′ ends of said chimeric oligomeric compound are, independently, hydroxyl, a protected hydroxyl, a linkage to a solid support, an activated phosphate group, an activated phosphite group, a reactive group for forming an internucleotide linkage, a nucleotide, a nucleoside, or an oligonucleotide with the proviso that when one or both of said L 4  and L 6  is independently a phosphoramidate then at least one R 1  is other than H.  
 
     
     
         11 . The chimeric oligomeric compound of  claim 10  wherein L 4  is a phosphoramidate internucleotide linkage, L 5  and L 7  are, independently, a phosphodiester internucleotide linkage and L 6  is a phosphorothioate internucleotide linkage  
     
     
         12 . A chimeric oligomeric compound having the formula:  
       5′—Nu—(L 4 —Nu) z1 —(L 5 —Nu) z2 —(L 6 —Nu) z3 —(L 7 —Nu) z4 (L 8 —Nu) z5 —3′  
       wherein: 
 each L 4 , L 5 , L 6 , L 7 , and L 8  is, independently, an internucleoside linkage selected from phosphodiester, phosphorothioate, secondary phosphoramidate, tertiary phosphoramidate or boranophosphate, with the provision that L 4  and L 6  are different from L 5  and that one of L 4 , L 5  and L 6  are other than phosphodiester and phosphorothioate;  
 each z 1 , z 2 , z 3 , z 4  and Z 5  is, independently, an integer greater than 1;  
 each Nu is a nucleoside having the formula:  
                     
 wherein:  
 Bx is a heterocyclic base moiety;  
 each R 1  is, independently, H, hydroxyl, a protected hydroxyl, a 2′-substituent group or a protected 2′-substituent group; and  
 said 5′- and said  -3 ′ ends of said chimeric oligomeric compound are, independently, hydroxyl, a protected hydroxyl, a linkage to a solid support, an activated phosphate group, an activated phosphite group, a reactive group for forming an internucleotide linkage, a nucleotide, a nucleoside, or an oligonucleotide  
 with the proviso that when one or both of said L 4  and L 6  is independently a phosphoramidate then at least one R 1  is other than H.  
 
     
     
         13 . The chimeric oligomeric compound of  claim 12  wherein L 4  is a phosphoramidate internucleotide linkage, L 5  and L 7  are, independently, a phosphodiester internucleotide linkage, L 6  is a phosphorothioate internucleotide linkage and L 8  is a phosphoramidate internucleotide linkage.