Assignment of Vibrational Circular Dichroism Cross‐Referenced Electronic Circular Dichroism Spectra of Flexible Foldamer Building Blocks: Towards Assigning Pure Chiroptical Properties of Foldamers

Abstract

Assignment of the most established electronic circular dichroism (ECD) spectra of polypeptides and foldamers is either “evidence based” or relies on the 3D structures of longer oligomers of limited internal dynamics, which are derived from NMR spectroscopy (or X‐ray) data. Critics warn that the use of NMR spectroscopy and ECD side by side has severe limitations for flexible molecules because explicit knowledge of conformational ensembles is a challenge. Herein, an old–new method of comparing ab initio computed and measured vibrational circular dichroism (VCD) data is presented to validate both the structures (conf(i)) and their relative weights (c(i)) that make up the conformational ensemble. Based on the array of {conf(i), c(i)}, the pure ECD spectra, g(i)conf(i), can be ab initio calculated. The reconstructed spectrum Σc(i)g(i)conf(i) can thus help to assign any experimental ECD counterparts. Herein, such a protocol is successfully applied to flexible foldamer building blocks of sugar β‐amino acid diamides. The epimeric pair of the model system was selected because these molecules were conformationally tunable by simple chemical modification, and thus, the robustness of the current approach could be probed. The initial hydrogen bond (NH⋅⋅⋅O) eliminated by N‐methylation reorients the amide plain, which influences the chiroptical properties of the foldamer building block; this structural change is successfully monitored by changes to the VCD and ECD transitions, which are now assigned to pure conformers. The current method seems to be general and effective without requiring extensive CPU and spectroscopic resources.

Foldamers controlled by functional triamino acids: structural investigation of α/γ-hybrid oligopeptides

“…The here found spiro/bridged hydrogen bond network is unknown. So far, five-membered hydrogen bonds have been recognized as conformationally constraining in planar arrangements between amide N-H and adjacent pyridyl nitrogen atoms in aromatic sp 2 -oligoamide foldamers 6 , 59 , in so-called hydrazino turns between amide N-H functions and adjacent hydrazine nitrogen atoms 60 – 63 , as well as in “fused-ring” hydrogen bonds between amide N-H functions and adjacent Lewis-basic oxygen atoms in the backbone 64 , 65 . Larger six-membered hydrogen bonds are more common, e.g.…”

Computational methods and points for attention in absolute configuration determination

“…In some cases, flexible chiral compounds, such as β-peptides and foldamers, could be analyzed by careful conformational study (Farkas et al, 2019)-for example, compounds 85 (Santoro et al, 2019) to 98 (Mazzeo et al, 2017a;Taniguchi et al, 2017;Gimenesa et al, 2019). Typical structures are 86 (Gimenesa et al, 2019) and 87 (Taniguchi et al, 2017), boron-containing chiral compound 88 (Mazzeo et al, 2017a), chiral thiophene sulfonamide 89 , chiral Sicontaining compound 90 (Xia et al, 2018), pseudoenantiomeric atropisomers anti-(S)-streptorubin B (91A) and syn-(S)streptorubin (91B) (Andrade et al, 2015), axial chiral ligand 92 , 93 (Qiu et al, 2013), bioactive compound 94 (Junior et al, 2015), axial N-BF 2 compound 95 (Abbate et al, 2017), Mo€bius-shaped cycloparaphenylenes 96 (Nishigaki et al, 2019), and Frontiers in Natural Products frontiersin.org axial 3,3′-bithiophene atropisomeric scaffold 97 (Gabrieli et al, 2016).…”