Guanidinylation reagents

Abstract

Trisubstituted N-protected guanidines and methods for use as guanidinylating reagents to yield N-protected guanidine derivatives.

What is claimed is:  
     
         1 . A protected guanidine of the structure  
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2 , and P 3  are the same or different urethane protecting groups, and salts and solvates thereof.  
     
     
         2 . A protected arginine homologue of the structure  
       
         
           
           
               
               
           
         
       
       wherein Q, P 1 , P 2 , and P 3  are the same or different urethane protecting groups, and n is an integer of 0-3, and salts and solvates thereof.  
     
     
         3 . The protected molecules of claims  1 - 2  wherein the urethane protecting groups are selected from the group consisting of 
 (a) tert-butyloxycarbonyl (Boc)  
 (b) benzyloxycarbonyl (Cbz),  
 (c) allyloxycarbonyl (Alloc)  
 (d) 2,2,2-trichloroethyloxycarbonyl (Troc),  
 (e) 2-chlorobenzyloxycarbonyl; and  
 (f) 4-methoxy-benzyloxycarbonyl (Moz).  
 
     
     
         4 . N-,N′-,N″-Tri-tert-butyloxycarbonyl-guanidine  
     
     
         5 . N-,N′-,N″-Tri-benzyloxycarbonyl-guanidine  
     
     
         6 . N-Methyl-N-,N′-,N″-tri-tert-butyloxycarbonyl-guanidine  
     
     
         7 . N-Methyl-N-,N′-,N″-tri-tert-benzyloxycarbonyl-guanidine  
     
     
         8 . A protected guanidine of the structure  
       
         
           
           
               
               
           
         
       
       wherein P 1  and P 2  are the same or different urethane protecting groups, and R is a substituted or unsubstituted alkyl or aryl group or a heterocyclic group, and salts and solvates thereof.  
     
     
         9 . A protected guanidine of the structure  
       
         
           
           
               
               
           
         
       
       wherein P 1  and P 2  are the same or different urethane protecting groups, and salts and solvates thereof.  
     
     
         10 . N-N′-Di-Boc-N″-trifluoromethanesulfonyl-guanidine  
     
     
         11 . N-N′-Di-Cbz-N″-Trifluoromethanesulfonyl-guanidine  
     
     
         12 . N-Boc-N′-Cbz-N″-Trifluoromethanesulfonyl-guanidine  
     
     
         13 . A method for guanidinylation comprising reacting a protected guanidine of the structure  
       
         
           
           
               
               
           
         
       
       wherein P 1 , P 2  and P 3  are the same or different urethane groups, with an alcohol of the structure  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are selected from the group consisting of H, substituted or unsubstituted alkyl, alkenyl, aryl, arylalkyl or R 1 , and R 2  are members of a 3-6 member cycloalkyl structure,  
         to yield a product of the structure  
         
           
             
             
                 
                 
             
           
         
       
     
     
         14 . A method according to  claim 13 , further comprising the step of reacting a primary or secondary alcohol having the structure  
       
         
           
           
               
               
           
         
         wherein R 3  and R 4  are independently the same as or different from R 1  or R 2  with the product of the method of  claim 13  to yield a compound having the structure  
         
           
             
             
                 
                 
             
           
         
       
     
     
         15 . A method for preparing arginine homologs, comprising reacting a protected guanidine of the structure  
       
         
           
           
               
               
           
         
         wherein P 1 , P 2  and P 3  are the same or different urethane groups with a protected amino acid of the structure  
         
           
             
             
                 
                 
             
           
         
         wherein R 1  is a substituted or unsubstituted alkyl or aryl group, Q is a urethane protecting group and n is 0-3, to yield a product of the structure  
         
           
             
             
                 
                 
             
           
         
       
     
     
         16 . A method for guanidinylating amines, comprising reacting a protected guanidine of the structure  
       
         
           
           
               
               
           
         
         wherein P 1 , P 2  and P 3  are the same or different urethane groups, and R 1  is a substituted or unsubstituted alkyl group, and a primary or secondary amine of the structure  
         
           
             
             
                 
                 
             
           
         
         wherein R 2  and R 3  are independently H, or a substituted or unsubstitued alkyl group, or an amino acid or a polypeptide, or R 2  and R 3  are part of a cyclic structure as in piperidine, pyrrolidine, or morpholine, to yield a product of the structure  
         
           
             
             
                 
                 
             
           
         
       
     
     
         17 . The method of  claim 16  wherein the sulfonyl guanidinylating group has the structure  
       
         
           
           
               
               
           
         
       
     
     
         18 . Guanidinylated compounds prepared by the method of any one of claims  15 - 17 .  
     
     
         19 . Guanidinylated compounds prepared by reacting a guanidinylating reagent selected from the group consisting of 
 N-N′-di-Boc-N″-trifluoromethanesulfonyl-guanidine,    N-N′-di-Cbz-N″-trifluoromethanesulfonyl-guanidine, and    N-Boc-N′-Cbz-N″-trifluoromethanesulfonyl-guanidine    with a primary amine.    
     
     
         20 . Guanidinylated compounds prepared by reacting a guanidinylating reagent selected from the group consisting of 
 N-N′-di-Boc-N″-trifluoromethanesulfonyl-guanidine,    N-N′-di-Cbz-N″-trifluoromethanesulfonyl-guanidine, and    N-Boc-N′-Cbz-N″-trifluoromethanesulfonyl-guanidine    with a secondary amine.    
     
     
         21 . A method for the solid phase synthesis of a peptide comprising one or more arginine homologs, comprising the steps of: 
 (a) assembling a sequence (Xaa) n  of amino acids on a solid phase peptide synthesis resin, where Xaa denotes any appropriately protected amino acid.    (b) attaching an amino acid having the structure                          wherein Q is Boc or Fmoc and P is any protecting group that can be selectively removed, and n=0-3, to the amino terminus of the product of step (a);    (c) coupling any sequence of suitably protected amino acids to the amino terminus of the product of step (b);    (d) selectively removing all the protecting groups P as defined in (b) from the product of step (c)    (e) reacting a protected guanidine having the structure                          with the product of step (d) to guanidinylate all unprotected amino functions present; and    (f) removing all protecting groups and cleaving the peptide from the resin to yield the product