Preparation of Achiral and of Enantiopure Geminally Disubstituted β-Amino Acids for β-Peptide Synthesis

• Published in: European journal of organic chemistry Vol. 2000; no. 1; pp. 1 - 15
• Main Authors: Abele, Stefan, Seebach, Dieter
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag GmbH 01.01.2000; WILEY‐VCH Verlag GmbH
• Subjects: Amino acids; Chirality; Peptides; Stereoselectivity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/(SICI)1099-0690(200001)2000:1<1::AID-EJOC1>3.0.CO;2-6

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.