Preparation of achiral and of enantiopure geminally disubstituted beta-amino acids for beta-peptide synthesis

While geminally disubstituted cc-amino acids are helix-inducing residues in cr-peptides, gem-disubstituted beta-amino acids are predicted not to fit i nto any of the three major secondary structures of beta-peptides recognized to date [the 3(14) helix, the 12/10/12 helix, and the pleated sheet (Figur e 1)]. In order to be able to synthesize and structurally identify beta-pep tides containing such building blocks, or consisting entirely of them, and in order to establish the chirality of secondary structures they may form, achiral and chiral gem-disubstituted beta-amino acids must be readily avail able. The methods of preparation of 3-amino carboxylic acids with two carbo n substituents at the 2-or 3-position (beta(2.2)-/beta(3.3)-amino acids, Fi gure 2) are reviewed. While there are numerous essentially classical routes to achiral and rac-beta-amino acids of this type (Schemes 1-4), their EPC synthesis is currently the subject of investigations. These chains. include the nucleophilic addition to (R)- or (S)-N-sulfinimines (Schemes 6-10) and other Mannich-type transformations (Schemes 19-221, stereoselective alkyla tions of various chiral hydropyrimidines (Schemes 11, 12, 18), of esters or amides of 2-cyano-alkanoic acids (Schemes 13, 14, 16), and of Li-2 derivat ives of non-racemic N-protected 3-amino-alkanoates (Scheme 17), as well as sequences of reactions involving enantiopure gem-disubstituted succinic aci d derivatives and a Curtius degradation (Schemes 23-26). Oligomers of the a chiral gem-disubstituted compounds 1-(aminomethyl)- cyclopropane and -cyclo hexane carboxylic acid have already been shown to form 8- and l0-membered h ydrogen-bonded rings, respectively (Figure 5), which provide novel motifs f or the possible construction of turns, Links, or steps in beta-peptidic cha ins.