Cyclic amino acid molecules and methods of preparing the same

Abstract

Macrocyclization of amino acids or linear peptides upon reaction with amphoteric amino aldehydes and isocyanides is provided.

The invention claimed is: 
     
       1. A cyclic compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein
 n=0 or 1, and R1, R2, R3, R4 and R5 are independently selected from H; lower alkyl; aryl; heteroaryl; alkenyl; heterocycle; cyckoalkyl; esters of the formula C(O)OR* wherein R* is selected from alkyl and aryl; amides of the formula C(O)NR**R***, wherein R** and R*** are independently selected from alkyl and aryl; —CH 2 C(O)R, wherein R is selected from —OH, lower alkyl, aryl, -lower alkyl-aryl, or —NR a R b , where R a  and R b  are independently selected from H, lower alkyl, aryl or -lower alkyl-aryl; —C(O)R c , wherein R c  is selected from lower alkyl, aryl or -lower alkyl-aryl; or -lower alkyl-OR d , wherein R d  is a suitable protecting group or OH group; 
 bonds [a] and [b] are syn or antito each other; 
 R′ is an amino acid side chain of the amino terminus amino acid; 
 R″ is an optionally substituted amide; and 
 R 6  is a nucleophilic moiety of a compound having the formula R 6 —H, wherein R 6 —H is selected from the group consisting of 7-mercapto-4-methyl-coumarin, thiobenzoic acid, thioacetic acid, biotin, aromatic thiols, aliphatic thiols; and is capable of nucleophilic opening of the aziridine ring of a compound of formula (II) 
 
       
       
         
           
           
               
               
           
         
         
           to form the compound of formula (III); 
           and the linear molecule is an amino acid, a linear peptide comprising 2-9 amino acids, or a salt of the amino acid or the linear peptide, wherein N′ is the nitrogen at the amino terminus end of the linear molecule and C′ is the carbon at the carboxy terminus end of the linear molecule, and provided that if the linear molecule is a linear peptide, bonds [a] and [c] are anti—to each other. 
         
       
     
     
       2. The cyclic compound of  claim 1 , wherein R 6  is a fluorescent moiety. 
     
     
       3. The cyclic compound of  claim 1 , wherein any one of R 1 -R5 is H. 
     
     
       4. The cyclic compound of  claim 1 , wherein n=0 and R 1 -R 3  are H. 
     
     
       5. The cyclic compound of  claim 3 , wherein n=0 and R 2  and R 3  are H. 
     
     
       6. The cyclic compound of  claim 1 , wherein R 1  is CH 2 OTBDMS or CH 2   i Pr. 
     
     
       7. The cyclic compound of  claim 1  wherein the linear molecule is a peptide. 
     
     
       8. The cyclic compound of  claim 1 , wherein the amino terminus amino acid of the peptide is selected from the group consisting of proline and an amino acid with an amino group substituted with NHCH 3 , NHBn, NHCH 2 CH 2 SO 2 Ph or NHCH 2 CH 2 CN. 
     
     
       9. The cyclic compound of  claim 1 , wherein the linear molecule is a D- or L-amino acid selected from the group consisting of: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, selenocysteine, serine, tyrosine, threonine, tryptophan and valine. 
     
     
       10. The cyclic compound of  claim 1 , wherein the linear molecule is an alpha-amino acid. 
     
     
       11. The cyclic compound of  claim 1 , wherein the linear molecule is a beta-amino acid. 
     
     
       12. The cyclic compound of  claim 1 , wherein the linear molecule is a gamma-amino acid. 
     
     
       13. The cyclic compound of  claim 1 , wherein R″ is tert-Butyl amide. 
     
     
       14. The cyclic compound of  claim 1 , wherein the linear peptide consists of 2 amino acids. 
     
     
       15. The cyclic compound of  claim 1 , wherein the linear peptide consists of 3 amino acids. 
     
     
       16. The cyclic compound of  claim 1 , wherein the linear peptide consists of 4 amino acids. 
     
     
       17. The cyclic compound of  claim 1 , wherein the linear peptide consists of 5 amino acids. 
     
     
       18. The cyclic compound of  claim 1 , wherein the linear peptide consists of 6 amino acids. 
     
     
       19. The cyclic compound of  claim 1 , wherein the linear peptide consists of 7 amino acids. 
     
     
       20. The cyclic compound of  claim 1 , wherein the linear peptide consists of 8 amino acids. 
     
     
       21. The cyclic compound of  claim 1 , wherein the linear peptide consists of 9 amino acids. 
     
     
       22. The cyclic compound of  claim 1 , wherein the nucleophilic moiety is bonded to XH, wherein X is S. 
     
     
       23. The cyclic compound of  claim 1 , wherein R6-H is 7-mercapto-4-methyl-coumarin or thiobenzoic acid. 
     
     
       24. The cyclic compound of  claim 1 , wherein if the amino acid molecule is an amino acid then the amino terminus is a primary amino group or a secondary amino group but wherein the amino acid molecule is a linear peptide, then the amino terminus is a secondary amino group.