Nonplanar Tertiary Amides in Rigid Chiral Tricyclic Dilactams. Peptide Group Distortions and Vibrational Optical Activity

Abstract

We investigate amide nonplanarity in vibrational optical activity (VOA) spectra of tricyclic spirodilactams 5,8-diazatricyclo[6,3,0,0(1,5)]undecan-4,9-dione (I) and its 6,6',7,7'-tetradeuterio derivative (II). These rigid molecules constrain amide groups to nonplanar geometries with twisted pyramidal arrangements of bonds to amide nitrogen atoms. We have collected a full range vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectra including signals of C-H and C-D stretching vibrations. We report normal-mode analysis and a comparison of calculated to experimental VCD and ROA. The data provide band-to-band assignment and offer a possibility to evaluate roles of constrained nonplanar tertiary amide groups and rigid chiral skeletons. Nonplanarity shows as single-signed VCD and ROA amide I signals, prevailing the couplets expected to arise from the amide-amide interaction. Amide-amide coupling dominates amide II (mainly C'-N stretching, modified in tertiary amides by the absence of a N-H bond) transitions (strong couplet in VCD, no significant ROA) probably due to the close proximity of amide nitrogen atoms. At lower wavenumbers, ROA spectra exhibit another likely manifestation of amide nonplanarity, showing signals of amide V (δ(oop)(N-C) at ~570 cm(-1)) and amide VI (δ(oop)(C'═O) at ~700 cm(-1) and ~650 cm(-1)) vibrations.

Structure of Condensed Phase Peptides: Insights from Vibrational Circular Dichroism and Raman Optical Activity Techniques

“…Some efforts have been made to model β-turns with designed peptides and to determine if they have characteristic VCD spectra. IR spectra of turns are highly variable, and although some trends have been proposed as diagnostic, unique assignments for turn determination are not reliable. − One approach has been to construct cyclic peptides and try to sort out the overlapping components of the spectra, or prepare sequences that favor turn formation. ,− Paralleling IR, little unique characteristic VCD has developed from these studies, but due to their small size, turn sequences have been subject of detailed theoretical modeling. ,, Turns that are promoted and stabilized by disulfide links have been studied, which can also allow some analyses of the chiral disulfide. ,,, Various other studies of short peptides have been interpreted in terms of turn formation, but the populations of such structures are unclear so that establishing a unique spectral pattern remains difficult. ,,,,,,,, An alternative approach has explored VCD of constrained structures that have cis -amides or are based on cyclic dipeptides, often termed diketopiperazines. ,− Since proteinic peptides are almost universally trans , these studies have been mostly equivalent to small molecule conformational studies, with little impact on more general peptide and protein conformational studies. An unusual aspect of bridged peptides is their potential for constraint-induced nonplanar amide formation, but this also has had little carry-over to “normal” peptides beyond theoretical modeling. ,,, …”

“…An unusual aspect of bridged peptides is their potential for constraintinduced nonplanar amide formation, but this also has had little carry-over to "normal" peptides beyond theoretical modeling. 250,346,478,480 Nonproteinic peptides (e.g., β-peptides) have also been studied but due to their variant backbone structures correlation with normal (α-amino acid based) peptides is difficult. 451,481−483 Such residues substituted into other sequences can stabilize various forms.…”

Electronic Circular Dichroism of the Chiral Rigid Tricyclic Dilactam with Nonplanar Tertiary Amide Groups

“…Because of the unique nature of our dilactams (mainly the rigid geometry and sample availability) such a model might be built with more confidence using simultaneously a wider selection of spectroscopic techniques including vibrational optical activity (VOA). These vibrational chiroptical properties of the spirodilactam I have been already investigated and provided interesting parallels to preliminary electronic CD, , like the bathochromic shift of the amide I vibration (first observed by Smolı́ková et al). Therefore, it appears important to find out whether detection of several inherently chiral nonplanar amide groups in one molecule can be achieved using experimentally simple electronic circular dichroism spectroscopy.…”

“…As racemates, these compounds are known since the 1970s; however, preparation of pure enantiomers in quantities sufficient for thorough physicochemical investigation succeeded only recently . Nowadays the synthesis can be achieved in both enantiomeric forms by chromatographic resolution of the racemates using commercial columns and enantiomer separating instrumentation.…”

Relative intensity correction of Raman optical activity spectra facilitates extending the spectral region

“…in 1975 using an instrument recording one spectral point at a time. There are also recent ROA data on C–H and C–D vibrations . With current multichannel spectrometers, measurements in the extended spectral range can be realized by either compressing the spectrum along the CCD detector or by combining data from several shorter spectral subregions, each of them measured separately with a region‐optimized arrangement, particularly grating .…”