A Novel Route to Pseudoproline (ΨH,HPro)-Containing Dipeptides Building Blocks

• Published in: International journal of peptide research and therapeutics 2005-12, Vol.11 (4), p.267-270
• Main Authors: Sélambarom, Jimmy, Smadja, Jacqueline, Thomas, Olivier, Parrot, Isabelle, Martinez, Jean, Pavia, André A.
• Format: Article
• Language: English
• Subjects: Amino acids; Biosynthesis; Peptides; Pharmacology
• ISSN: 1573-3149; 1573-3904
• DOI: 10.1007/s10989-005-8114-0

In view of the synthetic and biological interest of pseudoproline (Ψ^sup R,R^Pro)-containing peptides, we have investigated a new strategy to these target compounds, taking into account the existence of the well-known ring-chain tautomerism occurring in the NH-free pseudoproline unit. Indeed, the NH-free oxaprolines derived from β-hyroxyamino acid (Ser, Thr) are rarely isolable in contrast to the cysteine-derived thiaproline. The strategy developed herein is based on the use of 2:3 adducts (amino acid-formaldehyde) resulting from the condensation of amino acids (Ser, Thr, Cys) with paraformaldehyde. The latter may exist as an equilibrium mixture of 1,4-diaza-3,9-dioxabicyclo[4.4.1]undecane (2) and isomeric N,N-methylenebis (oxazolidine) or -(thiazolidine) (3). Coupling these 2:3 adducts with a C-activated amino acid using conventional procedure afforded C2-unsubstituted pseudoproline (Ψ^sup H,H^Pro)-containing dipeptides. This strategy was applied to both oxa- and thiaprolines. Such result clearly established the usefulness of these 2:3 adducts in peptide synthesis as they allow to trap the non isolable NH-free oxaprolines. The isomerization process (ProQuest: Formulae and/or non-USASCII text omitted; see image) appeared to play a major role in this procedure, as illustrated by the peculiar case of the serine-derived 2:3 adduct 2a where no coupling occurred.[PUBLICATION ABSTRACT]