To obtain key sugar derivatives of making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H-tX-OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H-cX-OH) from D-glucose is described here. The present synthetic route elaborated is i) appropriate for large-scale synthesis, ii) reagent costs reduced (e.g. by a factor of 400), iii) yields optimized are ~80% or higher for all six consecutive steps concluding -tX-or -cX-and iv) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for D-xylo and D-riboamino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous flow reactor). Multigram scale syntheses of these β-sugar amino acids, β-SAAs, now available on a larger scale made possible to test and optimize coupling reactions and conditions of making α/β-chimera peptides. Our study encompasses necessary building blocks (e.g. -X-OMe, -X-O i Pr, -X-NHMe, Fmoc-X-OH) and key coupling reactions making -Aaa-tX-Aaa-or -Aaa-tX-tXAaa-type "inserts". Completed for both stereoisomers of X, including the newly synthetized FmoccX-OH, producing longer oligomers for drug design and discovery is more of a reality than a wish. 2Graphical abstract: From D-glucose in 6 (7) steps both C-3 epimers of an azido-furanuronic acid (cAFU and tAFU) are obtained. Yield optimized, scalable and robust reactions made possible to get β-sugar amino acids in a more environment-friendly way. Useful derivatives were synthesized and probed as key intermediates of foldameric "Lego element" now ready to be built in into α/β-chimera peptides supporting drug design and discovery.3

We report the solid phase synthesis of -GG-X-GG-type α/β-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc deriva-tive (e.g., Fmoc-RibAFU(ip)-OH) and the azido deriva-tive (e.g., N 3 -RibAFU(ip)-OH) via Staudinger reaction with nBu 3 P can be successfully applied. Both X-ray dif-fraction, 1 H-and 31 P-NMR, and theoretical (QM) data support and explain why the application of Ph 3 P as Staudinger reagent is "ineffective" in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (-CONH-) bond. The failure of the poly-peptide chain elongation with N 3 -cX originates from the "coincidence" of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack dur-ing the hydrolysis of a quasi penta-coordinated triph-enylphosphinimine. Nevertheless, the synthesis of the above α/β-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo-and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts.

New enantiopure crown ethers containing either an ethyl diarylphosphinate moiety [(S,S)‐4 to (S,S)‐7] or a proton‐ionizable diarylphosphinic acid unit [(S,S)‐8 to (S,S)‐11] have been synthesized. Electronic circular dichroism (ECD) studies on the complexation of these new enantiopure crown ethers with the enantiomers of α‐(1‐naphthyl)ethylammonium perchlorate (1‐NEA) and with α‐(2‐naphthyl)ethylammonium perchlorate (2‐NEA) were also carried out. These studies showed appreciable enantiomeric recognition with heterochiral [(S,S)‐crown ether plus either (R)‐1‐ or (R)‐2‐NEA] preference. Theoretical calculations found three significant intermolecular hydrogen bonds in the complexes of (S,S)‐9. Furthermore, preference for heterochiral complexes was also observed, in good agreement with ECD results. Complex formation constants were determined by NMR titration for four selected crown ether/NEA pairs.

Here we present folding‐associated aggregation propensity of three Trp‐cage foldamers: E0 (20 aa), E5 (25 aa) and E10 (30 aa), models of different sizes but comparable molecular properties. Electronic circular dichroism (ECD), vibrational circular dichroism (VCD) and FT‐IR spectroscopic measurements were used to monitor their concentration‐dependent, heat‐induced (5 °C → 65 °C) “α→β” fold transition. The ECD curves of E0 display an ensemble of highly dynamic structures. ECD of both E5 and E10 foldamers show the expected Trp‐cage fold, dominated by their α‐helical properties. No sign of β‐structures was revealed by ECD at any conditions (5 °C < T < 65 °C, 5 < pH < 7, c ≈ 30 μM) for any of these miniproteins. However, at higher concentration (c ≈ 1–30 mM) both VCD and FT‐IR spectral features of E5 as well as E10 resemble that of a β‐strand (ca. 1615 cm–1), accompanied with “free β‐edges”, or native β‐sheets (ca. 1635 cm–1). E5 at lower concentrations (c ≈ 1–3 mM), and E10 at higher concentration (c ≈ 30 mM) display the α→native‐β→β‐sheet folding transitions, monitored by the characteristic C=O vibrational normal mode frequency shift as follows: ca. 1650 cm–1 → ca. 1635 cm–1 → ca. 1615 cm–1, respectively. The latter folding path is irreversible. The shortest polypeptide E0 has an “unordered” fold, while E10 presents the most tightly packed Trp‐cage 3D‐structure. We have found that both high dynamicity and/or tight molecular core packing are different in nature, but common in efficacy in preventing the polypeptide backbone chain against self‐aggregation. However, E5 is intermediate in size and stability, and thus among these three polypeptides it is the quickest to aggregate. The present molecular triad, E0, E5 and E10, serves as a good example of larger globular proteins for which aggregation and amyloid fiber‐like nanoparticle formations are often associated with Alzheimer's, Creutzfeldt–Jakob, or prion diseases.