Azaamino acids

The synthesis of pyrazolidine-2-carboxylic acid containing peptides is carried out following the standard procedures established for azaamino acid peptides as described in Section 10.4. Accordingly, l-(/< rt-butoxycarbonyl)pyrazolidine (which is the equivalent of 2-azaproline tert-butyl ester) is treated with 4-nitrophenyl chloroformate to generate (/ert-butoxy-carbonyl)pyrazolidine-2-carboxylic add 4-nitrophenyl ester.1 60 This active ester is then used... 

The generation of azaamino add residues and their incorporation into the peptide chain can be accomplished by different methods that closely resemble the methods used for peptide coupling but are derived from the chemistry of semicarbazides. In principle, the formation of an azaamino acid residue takes place by the reaction of a hydrazine derivative (hydrazine or hydrazide) with carbonyl donors , different types of activated TV-carboxylic acid derivatives (Scheme 2). 

Scheme 2 Methods for the Generation of an Azaamino Acid Residue...

Use of hydrazine hydrate and alkyl hydrazines results in azapeptides with the corresponding N-terminal unprotected azaamino acid residues. 11 Reaction at the substituted amino group of the hydrazine is favored, affording predominantly the correct (a-sub-stituted) product. 

Compounds with an N-terminal protected azaamino acid residue can be produced by using acylated hydrazines, those with Boc and Z groups being favored. 319 Tosyl-protected compounds can likewise be prepared however, attempts to remove the tosyl protecting group using sodium in liquid ammonia were unsuccessful. 19 ... 

Reaction of an isocyanate with an amino acid or peptide hydrazide affords products with a central azaamino acid residue 3,10,19 20 (Scheme 3). 

The use of activated esters provides a relatively high degree of synthetic flexibility. Thus, it is possible, for example, not only to synthesize any mixed peptide analogue required, but also to link azaamino acid residues directly in almost any desired number and sequence, enabling the preparation of pure azapeptides. 

C-Activated esters 6 are prepared by reacting hydrazides 4 with aryl chloroformates 5 (X=Q) or carbonic diesters 5 (X=OAr),M whereas N-activated esters 9 are obtained by reaction of the free amino group of N-terminal amino acid 7 or azaamino acid residues with the same reagents. 

Scheme 8 Coupling of /V-Carboxylic Acid Chlorides with Amino and Azaamino Acid Derivatives 7-9-35 381...

This coupling method seems to be equally suited to the synthesis of normal azaamino acid compared to the activated ester method. 

Special azapeptides are those with C-terminal azaamino acid residues that can only be obtained as esters or amides the corresponding free acids are not available because of their lability that results in decarboxylation to hydrazides. 

The use of activated azaamino or amino acid derivatives of the ester type has rendered the synthetic strategy for azapeptides considerably more independent of the sometimes difficult to access and unstable isocyanates. 

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