β2‐ and β3‐Peptides with Proteinaceous Side Chains: Synthesis and solution structures of constitutional isomers, a novel helical secondary structure and the influence of solvation and hydrophobic interactions on folding

Abstract Enantiomerically pure β‐amino‐acid derivatives with the side chains of Ala, Val, and Leu in the 2‐ or 3‐position (β 2 ‐ and β 3 ‐amino acids, resp.), as well as with substituents in both the 2‐ and 3‐positions (β 2,3 ‐amino acids, of like ‐configuration) have been prepared (compounds 8 – 17 ) and incorporated (by stepwise synthesis and fragment coupling, intermediates 24 – 34 ) into β‐hexa‐, β‐hepta‐, and β‐dodecapeptides ( 1 – 17 ). The new and some of the previously prepared β‐peptides ( 35 – 39 ) showed NH/ND exchange rates (in MeOH at room temperature) with τ 1/2 values of up to 60 days, unrivalled by short chain α‐peptides. All β‐peptides 1 – 7 were designed to be able to attain the previously described 3 1 ‐helical structure ( Figs. 1 and 2 ). CD Measurements ( Fig. 4 ), indicating a new secondary structure of certain β‐peptides constructed of β 2 ‐ and β 3 ‐amino acids, were confirmed by detailed NMR solution‐structure analyses: a β 2 ‐heptapeptide ( 2c ) and a β 2,3 ‐hexapeptide ( 7c ) have the 3 1 ‐helical structure ( Figs. 6 and 7 ), while to a β 2 /β 3 ‐hexapeptide ( 4 ) with alternating substitution pattern H‐(β 2 ‐Xaa‐β 3 ‐Xaa) 3 ‐OH a novel, unusual helical structure (in (D 5 )pyridine, Fig. 8 ; and in CD 3 OH, Figs. 9 and 10 ) was assigned, with a central ten‐membered and two terminal twelve‐membered H‐bonded rings, and with CO and NH bonds pointing alternatively up and down along the axis of the helix ( Fig. 11 ). Thus, for the first time, two types of β‐peptide turns have been identified in solution. Hydrophobic interactions of and hindrance to solvent accessibility by the aliphatic side chains are discussed as possible factors influencing the relative stability of the two types of helices.