Collect. Czech. Chem. Commun. 2002, 67, 1305-1319

Parallel Solid-Phase Synthesis of Partially Modified Retro and Retro-Inverso ψ[NHCH(CF3)]-Gly Peptides

Monica Sania, Pierfrancesco Bravoa,b, Alessandro Volonterioa,* and Matteo Zandaa,*

a C.N.R.-Istituto di Chimica del Riconoscimento Molecolare, sezione "A. Quilico", via Mancinelli 7, I-20131 Milano, Italy
b Dipartimento di Chimica, Materiali, e Ingegneria Chimica "Giulio Natta", Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy


The parallel solid-phase synthesis of small libraries of molecules belonging to a novel class of retro and retro-inverso peptides having a ψ[NHCH(CF3)] surrogate of the conventional retro-peptide bond (NH-CO) has been accomplished. Key step for the synthesis of the -NHCH(CF3)- unit is a Michael-type N-addition of resin bound α-amino acid esters H-AA1-OWang (1), dipeptide H-Val-Gly-OWang (8), and tripeptide H-Val-Val-Ala-OWang (12) to (S)-3-(E-enoyl)-1,3-oxazolidin-2-one (3), which took place very effectively under mild condition. Chemoselective exocyclic oxazolidinone cleavage, followed by parallel couplings of the resulting polymer-bound pseudopeptides WangO-AA1-ψ[NHCH(CF3)]-Gly-OH (5), WangO-Gly-Val-ψ[NHCH(CF3)]-Gly-OH (10), and WangO-Ala-Val-Val-ψ[NHCH(CF3)]-Gly-OH (14) with different α-amino acid esters afforded, after release from the resin, a representative set of ψ[NHCH(CF3)] retro and retro-inverso tripeptides HO-AA1-ψ[NHCH(CF3)]-Gly-AA2-OX1 (7), tetrapeptides HO-Gly-Val-ψ[NHCH(CF3)]-Gly-AA3-OX2 (11), and pentapeptides HO-Ala-Val-Val-ψ[NHCH(CF3)]-Gly-AA4-OX3 (15), respectively, with good to excellent purity in all cases.

Keywords: Solid-phase synthesis; Combinatorial synthesis; Peptide mimetics; Michael reactions; Trifluoromethyl group.

References: 27 live references.