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

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