ABSTRACT
Invited for the cover of this issue is the group of Gilles Guichard at the University of Bordeaux. The image depicts sketches and technical drawing tools to illustrate the creation and precise characterization of foldamer tertiary structures. Read the full text of the article at 10.1002/chem.202300087.
ABSTRACT
Oligomers designed to form a helix-turn-helix super-secondary structure have been prepared by covalently bridging aliphatic oligourea foldamer helices with either rigid aromatic or more flexible aliphatic spacers. The relative helix orientation in these dimers was investigated at high resolution using X-ray diffraction analysis. In several cases, racemic crystallography was used to facilitate crystallization and structure determination. All structures were solved by direct methods. Well-defined parallel helical hairpin motifs were observed in all cases when 4,4'-methylene diphenyl diisocyanate was employed as a dimerizing agent, irrespective of primary sequence and chain length.
ABSTRACT
Substantial progress has been made toward the development of metal-free catalysts of enantioselective transformations, yet the discovery of organic catalysts effective at low catalyst loadings remains a major challenge. Here we report a novel synergistic catalyst combination system consisting of a peptide-inspired chiral helical (thio)urea oligomer and a simple tertiary amine that is able to promote the Michael reaction between enolizable carbonyl compounds and nitroolefins with excellent enantioselectivities at exceptionally low (1/10â¯000) chiral catalyst/substrate molar ratios. In addition to high selectivity, which correlates strongly with helix folding, the system we report here is also highly amenable to optimization, as each of its components can be fine-tuned separately to increase reaction rates and/or selectivities. The predictability of the foldamer secondary structure coupled to the high level of control over the primary sequence results in a system with significant potential for future catalyst design.
ABSTRACT
Nearly isosteric oxo to thioxo substitution was employed to interrogate the structure of foldamers with a urea backbone and explore the relationship between helical folding and hydrogen-bonding interactions. A series of oligomers with urea bonds substituted by thiourea bonds at discrete or all positions in the sequence have been prepared and their folding propensity was studied by using a combination of spectroscopic methods and X-ray diffraction. The outcome of oxo to thioxo replacements on the helical folding was found to depend on whether central or terminal ureas were modified. The canonical helix geometry was not affected upon insertion of thioureas close to the negative end of the helix dipole, whereas thioureas close to the positive pole were found to increase the terminal flexibility and cause helix fraying. Perturbation was amplified when a selenourea was incorporated instead, leading to a structure that is only partly folded.
Subject(s)
Organoselenium Compounds/chemistry , Thiourea/chemistry , Urea/analogs & derivatives , Urea/chemistry , Circular Dichroism , Models, Molecular , Molecular StructureABSTRACT
Aliphatic oligoureas−(NH−CH(R)−CH2−NH−CO)n− and oligocarbamates −(NH−CH(R)−CH2−O−CO)n− are two classes of synthetic peptidomimetic oligomers whose backbone is isosteric to that of γ-peptides. We have shown recently that the constituent units of these backbones (i.e., amide (A), carbamate (C) and urea (U) units) can be combined in various ways to generate new heterogeneous oligomers with well-defined secondary structures. For example, oligomers consisting of urea (U) and carbamate (C) linkages arranged in a 1:1 pattern adopt a helical conformation akin to that of urea homoligomers and γ-peptide foldamers. In this case, helix formation is mainly driven by U units whose propensity for folding surpasses that of C units. Here, we have investigated further the influence of the U/C ratio on the folding preference of such heterogeneous oligomers. We report the synthesis and the structural analysis of a short oligomer with a 2:3 U/C ratio and two consecutive carbamate linkages. X-ray diffraction analysis reveals a helical structure that unwinds at one end. In contrast, a cognate oligomer prepared for comparison and containing four contiguous urea units adopts a fully helical conformation in the crystalline state. These results which are supported by data in solution indicate that the balance between U and C units should be carefully adjusted and that consecutive C linkages should be avoided for optimal helix formation.
