Preparation and Structure of β ‐Peptides Consisting of Geminally Disubstituted β 2,2 ‐ and β 3,3 ‐Amino Acids: A Turn Motif for β ‐Peptides

We report on the synthesis of new and previously described β ‐peptides ( 1  –  6 ), consisting of up to twelve β 2,2 ‐ or β 3,3 ‐geminally disubstituted β ‐amino acids which do not fit into any of the secondary structural patterns of β ‐peptides, hitherto disclosed. The required 2,2‐ and 3,3‐dimethyl derivatives of 3‐aminopropanoic acid are readily obtained from 3‐methylbut‐2‐enoic acid and ammonia ( Scheme 1 ) and from Boc‐protected methyl 3‐aminopropanoate by enolate methylation ( Scheme 2 ). Protected (Boc for solution‐, Fmoc for solid‐phase syntheses) 1‐(aminomethyl)cycloalkanecarboxylic‐acid derivatives (with cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings) are obtained from 1‐cyanocycloalkanecarboxylates and the corresponding dihaloalkanes ( Scheme 3 ). Fully 13 C‐ and 15 N‐labeled 3‐amino‐2,2‐dimethylpropanoic‐acid derivatives were prepared from the corresponding labeled precursors (see asterixed formula numbers and Scheme 4 ). Coupling of these amino acids was achieved by methods which we had previously employed for other β ‐peptide syntheses (intermediates 18  –  23 ). Crystal structures of Boc‐protected geminally disubstituted amino acids ( 16a  –  d ) and of the corresponding tripeptide ( 23a ), as well as NMR and IR spectra of an isotopically labeled β ‐hexapeptide ( 2a* ) are presented ( Figs. 1 – 4 ) and discussed. The tripeptide structure contains a ten‐membered H‐bonded ring which is proposed to be a turn‐forming motif for β ‐peptides ( Fig. 2 ).