Preparation and structure of beta-peptides consisting of geminally disubstituted beta(2,2)- and beta(3,3)-amino acids: A turn motif for beta-peptides

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