Bridging between (i)‐ and (i+3)‐positions in a β3‐peptide with a tether of appropriate length is expected to prevent the corresponding 314‐helix from unfolding (Fig. 1). The β3‐peptide H‐β3hVal‐β3hLys‐β3hSer(All)‐β3hPhe‐β3hGlu‐β3hSer(All)‐β3hTyr‐β3hIle‐OH (1; with allylated βhSer residues in 3‐ and 6‐position), and three tethered β‐peptides 2–4 (related to 1 through ring‐closing metathesis) have been synthesized (solid‐phase coupling, Fmoc strategy, on chlorotrityl resin; Scheme). A comparative CD analysis of the tethered β‐peptide 4 and its non‐tethered analogue 1 suggests that helical propensity is significantly enhanced (threefold CD intensity) by a (CH2)4 linker between the β3hSer side chains (Fig. 2). This conclusion is based on the premise that the intensity of the negative Cotton effect near 215 nm in the CD spectra of β3‐peptides represents a measure of ‘helical content’. An NMR analysis in CD3OH of the two β3‐octapeptide derivatives without (i.e., 1) and with tether (i.e., 4; Tables 1–6, and Figs. 4 and 5) provided structures of a degree of precision (by including the complete set of side chain–side chain and side chain–backbone NOEs) which is unrivaled in β‐peptide NMR‐solution‐structure determination. Comparison of the two structures (Fig. 5) reveals small differences in side‐chain arrangements (separate bundles of the ten lowest‐energy structures of 1 and 4, Fig. 5, A and B) with little deviation between the two backbones (superposition of all structures of 1 and 4, Fig. 5, C). Thus, the incorporation of a CH2-O-(CH2)4-O-CH2 linker between the backbone of the β3‐amino acids in 3‐ and 6‐position (as in 4) does accurately constrain the peptide into a 314‐helix. The NMR analysis, however, does not suggest an increase in the population of a 314‐helical backbone conformation by this linkage. Possible reasons for the discrepancy between the conclusion from the CD spectra and from the NMR analysis are discussed.
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