Tetrasubstituted Amino Acids-Containing Peptides

Another means of overcoming the sterically very demanding coupling reactions is to reduce the bulkiness of the residues, inherent to the presence of both the C ra-disubstitu-tion, and the urethane protecting group. This has been demonstrated by the use of a-azi-do acids in which the azide is the precursor of the amino function [113]. These monomers can be activated as acid chlorides, and their preparation is also compatible with the presence of the side chain protecting group used in Fmoc-based peptide synthesis. This approach has been exploited in the solid-phase synthesis of a-aminoisobutyric acid (Aib)-rich peptides [114]. 

This mild procedure for the solid-phase synthesis of peptides containing sterically hindered residues can be easily extended to generate combinatorial libraries of unnatural peptides, which may display biological properties superior to those of natural counterparts. 

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Further discussion and additional references to the synthesis of peptides containing dide-hydro-a-amino acids, reduced peptide isosteres, TV-hydroxy amides and hydrazides, and Ca-tetrasubstituted amino acids including 2,3-methano amino acids can be found in Sections 11.1,10.7,10.8, and 10.3, respectively. 

Since the first systematic synthetic effort of Leplawy et al)22 the preparation of peptides containing the slow-reacting C -tetrasubstituted a-amino acids has been achieved mainly by solution procedures. However, recent improvements in activation methodologies make solid-phase peptide synthesis (SPPS) an attractive tool as well, at least with the less sterically hindered Ca-tetrasubstituted a-amino acids. 

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