9-Amino-4,5-diazafluorene-9-carboxylic Acid (Daf), a New C-alpha,alpha-Disubstituted Glycine Containing a Spatially Constrained Bipyridine-Like Ligand for Transition Metals - Synthesis and Evaluation of Peptide-Coupling Conditions at its C- and N-Termini

Acylation of the anion of N-benzyl-8,5-diazafluorene-9-methyleneamine with methyl or benzyl chloroformate, followed by acidic hydrolysis, resulted in 9-amino-4,5-diazafluorene-9-carboxylic acid methyl ester (H-Daf-OMe) and benzyl ester (H-Daf-OBz1), respectively N-alpha-protection with Boc(2)O at 60 degreesC gave Boc-Daf-OMe and Boc-Daf-OBz1, saponification or hydrogenolysis of which resulted in complete decarboxylation. However, hydrazinolysis of the ester function afforded Boc-Daf-NHNH2, which was efficiently coupled with H-Ala-OMe by the acylazide method. Coupling of Boc-Ala-OH at the N-terminus of Daf could also be performed by the mixed anhydride method. However, coupling of the crowded Aib residue required the use of Boc-Aib-NCA. Daf, a new C-alpha,C-alpha-disubstituted glycine, is the first alpha -amino acid containing a rigid bipyridine ligand in a totally controlled spatial disposition relative to the C-alpha atom.