Development and Conformational Analysis of a Pseudoproline-Containing Turn Mimic

Abstract

The liquid-phase synthesis and the conformational analysis of a small library of fully protected tetramers containing L-pyroglutamic acid (L-pGlu), (4S,5R)-4-methyl-5-carboxybenzyloxazolidin-2-one (L-Oxd), or (4R,5S)-4-methyl-5-carboxybenzyloxazolidin-2-one (D-Oxd) as residue i + 1 are reported to test the tendency of these oligomers to assume a -hairpin conformation. The most promising molecule is Boc-L-Val-D-Oxd-Gly-L-Ala-OBn, which assumes a preferential -turn conformation in CDCl3, as shown by IR and 1H NMR analysis. These findings have been confirmed by DFT calculations, which provide an interpretation for the available experimental data and agree with the reported observations.

Asymmetric Access to Peptidyl β3‐Aldehydes by Coupling of N‐Phthalyl α‐Amino Acids with a Synthetic Heterocyclic β‐Amino Aldehyde Precursor

“…Only a few reports described the coupling reaction of amino acids with five-membered cyclic carbamates [11] and, to the best of our knowledge, no example involving sixmembered carbamates have been reported. The peptide-like coupling of adducts 5 was particularly challenging since it required the finding of activating conditions that could offset the low nucleophilicity of 5 with respect to its hemiacylal functionality and to the stereogenicity of the amino acid moiety.…”

“…[11] Applying this method to Cbz-Gly-OPfp (8-Pfp) proved to be efficient with 2-oxazolidinone 6, but gave no results with tetrahydrooxazinone 7 (entries 1, 2). The direct model coupling reaction was then tested with N-protected amino acids [8 and (±)-9c] by using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI·HCl) as the coupling reagent (see Figure 1).…”

Foldamers Based on Oxazolidin‐2‐ones

“…[74] In naturally occurring reverse-turns this position is often occupied by l-Pro (Pro = proline), so the introduction of an oxazolidin-2-one moiety could favour the formation of a β-hairpin secondary structure. To study and to compare their conformational preferences, conformation analysis and DFT calculations have been performed on the most interesting molecules.…”

Occurrence of the d-Proline Chemotype in Enzyme Inhibitors

“…In particular, while Apicidin B showed a 5-fold selectivity between the HDAC of the parasite and the HDAC of the liver of the chicken host, its synthetic analogue Apicidin C (12), where the (R)-proline ring is substituted with a (R)-piperidine ring, did not show any selectivity. D-and L-proline have long attracted the interest of the medicinal chemistry community, and many papers are present in the literature focusing on the generation of proline derivatives as molecular scaffolds for the synthesis of peptidomimetics and enzyme inhibitors [36,37], also in a combinatorial chemistry [38] and Diversity-Oriented Synthesis perspective [39]. In this review paper, d-and l-proline have long attracted the interest of the medicinal chemistry community, and many papers are present in the literature focusing on the generation of proline derivatives as molecular scaffolds for the synthesis of peptidomimetics and enzyme inhibitors [36,37], also in a combinatorial chemistry [38] and Diversity-Oriented Synthesis perspective [39].…”

“…D-and L-proline have long attracted the interest of the medicinal chemistry community, and many papers are present in the literature focusing on the generation of proline derivatives as molecular scaffolds for the synthesis of peptidomimetics and enzyme inhibitors [36,37], also in a combinatorial chemistry [38] and Diversity-Oriented Synthesis perspective [39]. In this review paper, d-and l-proline have long attracted the interest of the medicinal chemistry community, and many papers are present in the literature focusing on the generation of proline derivatives as molecular scaffolds for the synthesis of peptidomimetics and enzyme inhibitors [36,37], also in a combinatorial chemistry [38] and Diversity-Oriented Synthesis perspective [39]. In this review paper, an insight into the different biological outcomes of d-proline and l-proline in enzyme inhibitors is presented, considering as case studies the matrix metalloprotease (MMP) and metallo-β-lactamase (MBL) enzymes.…”