Vibrational circular dichroism as a probe of solid‐state organisation of derivatives of cyclic β‐amino acids: Cis‐ and trans‐2‐aminocyclobutane‐1‐carboxylic acid

Abstract

Peptide models built from cis‐ and trans‐2‐aminocyclobutane‐1‐carboxylic acids (ACBCs) are studied in the solid phase by combining Fourier‐transform infrared spectroscopy (FTIR) absorption spectroscopy, vibrational circular dichroism (VCD), and quantum chemical calculations using density functional theory (DFT). The studied systems are N‐tert‐butyloxycarbonyl (Boc) derivatives of 2‐aminocyclobutanecarboxylic acid (ACBC) benzylamides, namely Boc−(cis‐ACBC)−NH−Bn and Boc−(trans‐ACBC)−NH−Bn. These two diastereomers show very different VCD signatures and intensities, which of the trans‐ACBC derivative being one order of magnitude larger in the region of the ν (CO) stretch. The spectral signature of the cis‐ACBC derivative is satisfactorily reproduced by that of the monomer extracted from the solid‐state geometry of related ACBC derivatives, which shows that no long‐range effects are implicated for this system. In terms of hydrogen bonds, the geometry of this monomer is intermediate between the C6 and C8 structures (exhibiting a 6‐ or 8‐membered cyclic NH⋯O hydrogen bond) previously evidenced in the gas phase. The benzyl group must be in an extended geometry to reproduce satisfactorily the shape of the VCD spectrum in the ν (CO) range, which qualifies VCD as a potential probe of dispersion interaction. In contrast, reproducing the IR and VCD spectrum of the trans‐ACBC derivative requires clusters larger than four units, exhibiting strong intermolecular H‐bonding patterns. A qualitative agreement is obtained for a tetramer, although the intensity enhancement is not reproduced. These results underline the sensitivity of VCD to the long‐range organisation in the crystal.

Unambiguous Stereochemical Assignment of Cyclo(Phe-Pro), Cyclo(Leu-Pro), and Cyclo(Val-Pro) by Electronic Circular Dichroic Spectroscopy

“…Although VCD requires more sample materials than ECD, VCD provides a wealth of structural information associated with individual functional groups, which could be useful for differentiation of complex DKP stereoisomers. In fact, VCD has been used for stereochemical assignment of cyclic peptides, including DKP [ 24 , 25 , 26 ].…”

Recent Trends in Chiroptical Spectroscopy: Theory and Applications of Vibrational Circular Dichroism and Raman Optical Activity

“…Two polymorphic crystal forms of linezolid could be distinguished by VCD due to the differences in the carbonyl absorption spectral region . Relatively weak VCD spectra were reported for several α and cyclic β‐amino acids, and indazoles …”

“…[110] Two polymorphic crystal forms of linezolid could be distinguished by VCD due to the differences in the carbonyl absorption spectral region. [111] Relatively weak VCD spectra were reported for several α [112] and cyclic β-amino acids, [113] and indazoles. [114] AIMD simulations were conducted to understand VCD spectra of l-alanine crystals (Figure 2).…”

Vibrational optical activity: From discovery and development to future challenges

“…Corresponding calculations assume the solid‐state conformation of a single molecule with some accounting of nearest neighbor weak interactions, but currently, software is not commercially available to calculate VCD for the full infinite lattice approximation. For ROA, measurements of dispersed solids are just beginning to appear, which previously have been hampered by large background scattering from particle scattering…”