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

Thierry Sifferlen, Magnus Rueping, Karl Gademann, Bernhard Jaun, Dieter Seebach*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

To test the effect of NH-C=S groups (Scheme 1) on the stability of β- peptide secondary structures, we have synthesized three β-thiohexapeptide analogues of H-(β-HVal-β-HAla-β-HLeu)2-OH (1) with one, two, and three C=S groups in the N-terminal positions (cf 2-4 and model in Fig. 1). The first C=S group was introduced selectively by treatment with Lawesson reagent of Boc-β-dipeptide esters (6 and 8). A series of fragment-coupling steps (with reagents as for the corresponding sulfur-free building blocks) and another thionation reaction led to the title compounds with a C=S group in residues 1, 1, and 3, as well as 1, 2, and 3 of the β-hexapeptide (Schemes 2 and 3). The sulfur derivatives, especially those with three C=S groups, were much more soluble in organic media than the sulfur-free analogues (> 1000- fold in CHCl3; Table 1). The UV and CD spectra (in CHCl3, MeOH, and H2O) of the new compounds were recorded and compared with those of the parent β- hexapeptide 1 (Figs. 2-4); they indicate the presence of more than one secondary structure under the various conditions. Most striking is a pronounced exciton splitting (Δλ ca. 20 nm, amplitude up to + 121000) of the ππ*(c=s) band near 270 nm with the β-trithiohexapeptide (with and without terminal protecting groups), and strong, so-called 'primary solvent effects', in the CD spectra. The CD spectrum of the β-dithiohexapeptide 3 undergoes drastic changes upon irradiation with 266-nm laser light of a MeOH solution (Fig. 5). The NMR structure in CD3OH of the unprotected β- trithiohexapeptide 4 was determined to be an (M)-314-helix (Fig. 7), very similar to that of the non-thionated analogue (cf. 1). NMR and mass spectra of the β-hexapeptides with C=S and with C=O groups are compared (Figs. 6 and 8).

Original languageEnglish (US)
Pages (from-to)2067-2093
Number of pages27
JournalHelvetica Chimica Acta
Volume82
Issue number12
DOIs
StatePublished - Dec 1 1999

ASJC Scopus subject areas

  • Catalysis
  • Biochemistry
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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