Preparation ofβ2-Homotryptophan Derivatives forβ-Peptide Synthesis

Abstract

In view of the prominent role of the 1H-indol-3-yl side chain of tryptophan in peptides and proteins, it is important to have the appropriately protected homologs H-β2HTrpOH and H-β3HTrpOH (Fig.) available for incorporation in β-peptides. The β2-HTrp building block is especially important, because β2-amino acid residues cause β-peptide chains to fold to the unusual 12/10 helix or to a hairpin turn. The preparation of Fmoc and Zβ2-HTrp(Boc)OH by Curtius degradation (Scheme 1) of a succinic acid derivative is described (Schemes 2–4). To this end, the (S)-4-isopropyl-3-[(N-Boc-indol-3-yl)propionyl]-1,3-oxazolidin-2-one enolate is alkylated with BrCH2CO2Bn (Scheme 3). Subsequent hydrogenolysis, Curtius degradation, and removal of the Evans auxiliary group gives the desired derivatives of (R)-Hβ2-HTrpOH (Scheme 4). Since the (R)-form of the auxiliary is also available, access to (S)-β2-HTrp-containing β-peptides is provided as well.