If ammonia is used as amine component in Ugi reactions, the desired peptide sometimes is obtained only as the minor product or in traces. Side reactions such as six-component couplings are responsible for this observation. These side reactions can be suppressed by using non-nucleophilic alcohols, such as trifluoroethanol, sterically demanding aldehydes and carboxylic acids.Non proteinogenic amino acids are found in a wide range of peptides and cyclopeptides produced by marine organisms and microorganisms. 1 Many of these structures, especially the cyclic peptides, are highly interesting from a pharmaceutical point of view. 2 Unfortunately, the quantities isolated from natural resources are often very small, and therefore for therapeutic applications and/or for structure/activity investigations efficient synthetic concepts are necessary to provide enough material. Especially for the later point, the improvement of the biological activity of a lead structure, peptide modifications in a side chain 3 or on the backbone 4 are very efficient tools. In addition, multicomponent reactions such as the Ugi reaction allow a straightforward approach towards peptide fragments containing unnatural amino acids. 5 In most cases good results are obtained with primary amines, giving rise to a wide range of N-alkylated peptides. In contrast, only a few examples are described where ammonia was used as a nitrogen source. 6 This is quite surprising, because the 'more natural' NH amide bonds are formed in this case. But in general the yields obtained with ammonia are significantly lower, compared to other amines, and in addition, the new formed stereogenic center is obtained in racemic form. Therefore several attempts have been undertaken to solve these problems by using chiral primary amines, especially those, which can be cleaved after the reaction providing the unsubstituted NH bond. First investigations were carried out with chiral b-alanine derivatives, 7 phenylethylamine 8 and a-ferrocenylalkylamines. 9 Meanwhile, best results are obtained with amines derived from carbohydrates, where the amino functionality is located at the anomeric position. 10 These auxiliaries can be cleaved under acidic conditions. The same approach can also be applied to solid phase synthesis of peptides. 11Recently, we reported a straightforward approach towards the synthesis of cyclic peptides using the Ugi reaction in combination with a ring closing metathesis (RCM). 12 As described by Grubbs and others, RCM is a very powerful tool for the synthesis of cyclic peptide structures. 13During these investigations we became interested in Ugi reactions with ammonia, because from a combinatorial point of view, the formation of diastereomers in similar amounts is convenient and the stereoisomeric cyclopeptides can easily be separated by chromatography. As a model reaction we investigated the reaction of isobutyraldehyde with the isonitrile obtained from glycine methylester and the ammonium salt of various carboxylic acids in methanol. No product was obtained with...