β-thiopeptides: synthesis, NMR solution structure, CD spectra, and photochemistry

To test the effect of NH-C(=S) groups on the stability of beta-peptide secondary structures, the authors have synthesized three beta-thiohexapeptide analogs I (X = S, Y = Z = O; X = Z = S, Y = O; X = Y = Z = S) of H-(beta-HVal-beta-HAla-beta-HLeu)2-OH I (X = Y = Z = O). The first C=S group was introduced selectively by treatment with Lawesson reagent of Boc-beta-dipeptide esters II and III. A series of fragment-coupling steps (with reagents for the corresponding sulfur-free building blocks) and another thionation reaction led to the beta-thiohexapeptides. The sulfur derivs., esp. those with three C=S groups, were much more sol. in org. media than the sulfur-free analogs ( > 1000-fold in CHCl3). The UV and CD spectra (in CHCl3, MeOH, and H2O) of the three new beta-thiopeptides were recorded and compared with those of the parent beta-hexapeptide I (X = Y = Z = O); they indicate the presence of more than one secondary structure under the various conditions. Most striking is a pronounced exciton splitting (Deltalambda ca. 20 nm, amplitude up to +121000) of the pipi*C=S band near 270 nm with the beta-trithiohexapeptide (with and without terminal protecting groups), and strong, so-called "primary solvent effects", in the CD spectra. The CD spectrum of the beta-dithiohexapeptide I (X = Z = S, Y = O) undergoes drastic changes upon irradn. with 266-nm laser light of a MeOH soln. The NMR structure in CD3OH of the unprotected beta-trithiohexapeptide I (X = Y = Z = S) was detd. to be an (M)-314-helix, very similar to that of the non-thionated analog. NMR and mass spectra of the beta-hexapeptides with C=S and with C=O groups are compared.