Synthesis of Protected 3'-Amino Nucleoside Monomers

Abstract

Orthogonally protected 3′-amino nucleoside monomers and efficient methods for their synthesis are described. The methods employ selective protection of the 3′-amino group in the presence of the unprotected nucleoside base.

1 . A method of preparing an adenosine, guanosine or cytosine monomer having a protected nucleoside base and a protected 3′-amino group, wherein said base and said 3′-amino group are orthogonally protected, the method comprising:
 (a) providing a 3′-amino-3′-deoxy adenosine, cytosine, or guanosine monomer in which the 5′-hydroxyl group, nucleoside base, and 3′-amino group are unprotected; 
 (b) selectively reacting said 3′-amino group with a first protecting group; 
 reacting said 5′-hydroxyl group with a second protecting group; and 
 reacting said nucleoside base with a third protecting group; 
 wherein said first protecting group can be removed from said 3′-amino group under conditions which do not deprotect said nucleoside base, and said second protecting group can be removed from said 5′-hydroxyl group under conditions which do not deprotect said nucleoside base or said 3′-amino group. 
 
     
     
         2 .- 16 . (canceled) 
     
     
         17 . An adenosine or a guanosine monomer having a protected 3′-amino group and a nucleoside base which is (i) unprotected or (ii) protected such that said protected 3′-amino group can be deprotected under conditions which do not deprotect said nucleoside base. 
     
     
         18 .- 32 . (canceled) 
     
     
         33 . The monomer of  claim 17 , wherein said nucleoside base is unprotected. 
     
     
         34 . The monomer of  claim 17 , wherein said nucleoside base is protected. 
     
     
         35 . The monomer of  claim 34 , wherein said nucleoside base is protected with an acyl group. 
     
     
         36 . The monomer of  claim 34 , wherein said nucleoside base is protected with a dialkyl-, di(cycloalkyl)-, or di(aralkyl)-formamidinyl group. 
     
     
         37 . The monomer of  claim 36 , wherein said nucleoside base is protected with a dialkylformamidinyl group. 
     
     
         38 . The monomer of  claim 37 , wherein said nucleoside base is protected with a dimethylformamidinyl group. 
     
     
         39 . The monomer of  claim 36 , wherein said nucleoside base is protected with a di(aralkyl)-formamidinyl group. 
     
     
         40 . The monomer of  claim 39 , wherein said nucleoside base is protected with a dibenzylformamidinyl group. 
     
     
         41 . The monomer of  claim 40 , wherein said 3′-amino group is protected with an acid labile protecting group, or a fluorenylmethoxycarbonyl group or a derivative of a fluorenylmethoxycarbonyl group. 
     
     
         42 . The monomer of  claim 41 , wherein said 3′-amino group is protected with an acid labile protecting group. 
     
     
         43 . The monomer of  claim 42 , wherein said acid labile protecting group is a triarylmethyl group. 
     
     
         44 . The monomer of  claim 41 , wherein said 3′-amino group is protected with a fluorenylmethoxycarbonyl group or a derivative of a fluorenylmethoxycarbonyl group. 
     
     
         45 . The monomer of  claim 17 , comprising an unprotected 5′-hydroxyl group. 
     
     
         46 . The monomer of  claim 34 , comprising a protected 5′-hydroxyl group. 
     
     
         47 . The monomer of  claim 46 , wherein the protected 5′-hydroxyl group can be deprotected under conditions which do not deprotect said nucleoside base or said 3′-amino group. 
     
     
         48 . The monomer of  claim 46 , wherein the protected 5′-hydroxyl group is a trialkyl silyl ether group. 
     
     
         49 . The monomer of  claim 48 , wherein the protected 5′-hydroxyl group is a trimethyl silyl ether group. 
     
     
         50 . The monomer of  claim 17 , wherein said monomer comprises a 2′ group selected from hydrogen, hydroxy, lower alkoxy, lower alkyl, and fluoro.