Position 6, 8 or others BAZ

The benzodiazepine moiety has proven its high pharmacological activity in many respects as the examples in Fig. 37 show [12]. Therefore it seemed attractive to incorporate the benzodiazepine structure also in a peptide chain so that the heterocycle has a defined orientation with respect to the peptide backbone and may interact with a suitable receptor protein. In principle the distance of the benzodiazepine from the peptide strand may be regulated by the number of the carbon atoms between the nitrogen atoms in the peptide bond and the endocyclic N-4. We chose the 1,3-distance and took BAZ (Z enzodmzepino alanine 101) as 

The differentiation was achieved by starting from L-glutamate and protecting the C-H-acidic 2-position against deprotonation by Rapoport s 9-phenylfluo-renyl (9-Phf)-amino protective group [14]. If the adjacent ester is fer -butoxy, most superbases are too bulky to attack the corresponding hydrogen (Fig. 39). 

Indeed, glutamate 104 (Fig. 40) can be selectively deprotonated at the 4-position and treated with Evans trisylazide [4] to give 105 as a 2 l-diastereomeric mixture which is converted into the a-azido-pyroglutamates 107/108. 

These cyclic derivatives can be separated by chromatography. 108 is crystalline and submitted to an X-ray crystal structure analysis (Fig. 41). 

One can see very clearly how the 9-Phf-group blocks the 2-H. Also, the azide function and the ester are rigidly fixed in an antiperiplanar conformation which can be incorporated in a peptide chain. Analogously the cis-isomer 107 could be used for generating a rigid P-tum in a peptide. 

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