Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere

Abstract

Summary. d-Amino acids are very attractive in drug discovery, especially in the peptidomimetic area, because of their capability to act as dipeptide isosteres and reverse turn mimetics. Herein we report the synthesis of a rigid d-amino acid constrained by a 3-aza-6,8-dioxabicyclo[3.2.1]octanebased scaffold, which can be considered as a Gly-Asn dipeptide mimetic. Key steps are the condensation of glycidol and tartaric acid derivatives, and the intramolecular trans-acetalization of the oxidized adduct to give the bicyclic d-amino acid. Starting from L-tartaric acid derivative, it was achieved the corresponding Gly-D-Asn isostere, whereas from the enantiomeric D-tartaric acid derivative the corresponding Gly-L-Asn isostere could be obtained, thus giving access to both enantiomeric dipeptide sequences.

Selective, Catalytic, and Dual C(sp3)–H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions

“…Numerous naturally occurring bioactive products are DKP derivatives, and another great number of synthetic DKPs have been prepared for the purpose of mimicking the conformational and biological properties of peptides . On the other hand, although 3-morpholinones (3-MPs) are not common in nature, they are frequently prepared in the laboratory as key precursors for pharmaceutical drugs . A representative example of each DKP and 3-MP is showcased in Figure .…”

1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid and Derivatives As Chiral Constrained Bridged Scaffolds for Foldamers and Chiral Catalysts

“…substituted by dipeptide mimics and to a lesser extent by β-amino acids. 23,[35][36][37] Therefore, we have evaluated the ability of the ABOC motif to induce a turn in peptide sequences. For that purpose, following the Boc standard peptide strategy in solution, we have synthesized two model peptides, incorporating the ABOC motif in central position and varying the capping groups, i.e.…”

“…The carboxylic acid and amino groups of the ABOC residue were locked in a synclinal position that could potentially favor a turn within peptides. Reverse turns that are key structural motifs in biologically active peptides and proteins have been often substituted by dipeptide mimics and to a lesser extent by β-amino acids. ,− Therefore, we have evaluated the ability of the ABOC motif to induce a turn in peptide sequences. For that purpose, following the Boc standard peptide strategy in solution, we have synthesized two model peptides, incorporating the ABOC motif in central position and varying the capping groups, i.e., Z-Ala-( S )-ABOC-Phe-NHiPr 18 and iPrCO-Ala-( S )-ABOC-Phe-OCH 3 19 .…”

Peptidomimetic Small-Molecule Inhibitors of 3CLPro Activity and Spike–ACE2 Interaction: Toward Dual-Action Molecules against Coronavirus Infections

“…Thus, starting from our expertise in the preparation of dipeptide isosteres, − we envisioned to develop a short and versatile synthetic strategy for the formation of differently substituted piperazinones and diazepanones VIII starting from N -(2,2-dimethoxyethyl)­acetamides VII (Figure b). These constrained dipeptide isosteres were then inserted in the selected ACE2 epitope EDLFYQ to evaluate their potential activity as inhibitor of the ACE2–spike S1 interaction and as inhibitor of the activity of 3CLPro viral enzyme, based on a terminal glutamine in the peptide sequence essential for molecular recognition…”