Wiley InterScience Backfile Collection 1832-2000
Chemistry and Pharmacology
---While geminally disubstituted α-amino acids are helix-inducing residues in α-peptides, gem-disubstituted β-amino acids are predicted not to fit into any of the three major secondary structures of β-peptides recognized to date [the 314 helix, the 12/10/12 helix, and the pleated sheet (Figure 1)]. In order to be able to synthesize and structurally identify β-peptides 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 β-amino acids must be readily available. The methods of preparation of 3-amino carboxylic acids with two carbon substituents at the 2- or 3-position (β2,2-/β3,3-amino acids, Figure 2) are reviewed. While there are numerous essentially classical routes to achiral and rac-β-amino acids of this type (Schemes 1-4), their EPC synthesis is currently the subject of investigations. These include the nucleophilic addition to (R)- or (S)-N-sulfinimines (Schemes 6-10) and other Mannich-type transformations (Schemes 19-22), stereoselective alkylations of various chiral hydropyrimidines (Schemes 11, 12, 18), of esters or amides of 2-cyano-alkanoic acids (Schemes 13, 14, 16), and of Li2 derivatives of non-racemic N-protected 3-amino-alkanoates (Scheme 17), as well as sequences of reactions involving enantiopure gem-disubstituted succinic acid derivatives and a Curtius degradation (Schemes 23-26). Oligomers of the achiral gem-disubstituted compounds 1-(aminomethyl)-cyclopropane and -cyclohexane carboxylic acid have already been shown to form 8- and 10-membered hydrogen-bonded rings, respectively (Figure 5), which provide novel motifs for the possible construction of turns, links, or steps in β-peptidic chains.
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