(1S,7S)-7-Methyl-6,9-diazatricyclo[6,3,0,01,6]tridecane-5,10-dione, a tricyclic spirodilactam containing non-planar amide groups: Synthesis, NMR, crystal structure, absolute configuration, electronic and vibrational circular dichroism

Abstract

The title spirocyclic dilactam (1S,7S)-7-methyl-6,9-diazatricyclo[6,3,0,01,6]tridecan-5,10-dione (I), a molecule designed to contain non-planar amide groups, has been synthesized from an optically active precursor of known absolute configuration. The relative and absolute configuration have been determined by X-ray diffraction. The conformation of the compound has been investigated by X-ray, 1H and 13C NMR, electronic and vibrational circular dichroism. The compound possesses moderately non-planar amide groups in the two rings of nonequal geometry. The electronic CD is dominated by inherent chirality of the amide chromophores. The dilactams I and II ((1S,6S)-6-methyl-5,8-diazatricyclo[6,3,0,01,5]undecan-4,9-dione – having five-membered rings) exhibit monosignate amide I VCD and strong VCD bands in the mid-ir region.

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

“…Initial oligopeptide VCD studies sampled blocked amino acids and dipeptides and other short variants, investigating mostly VCD of the amide I mode but in some cases the amide II and III. ,,− Since each peptide bond in such short oligomers is actually part of an end group, the lack of degeneracy caused the spectral patterns to be distinct, but not necessarily characteristic of conventional (longer) polypeptide secondary structure. More recently, a large number of studies of tripeptides in aqueous solution by Schweitzer-Stenner and co-workers have been interpreted in terms of the role of PLP-II conformations with variations of other conformer populations as the sequence is altered using Ala-Xxx-Ala and similar models. − Such tripeptides have two nondegenerate amide groups that couple in a manner dependent on the conformation.…”

“…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.…”

Discriminating 310‐ from α‐helices: Vibrational and electronic CD and IR absorption study of related Aib‐containing oligopeptides

“…In infrared (IR) absorption, 3 10 ‐model helical peptides containing C α ‐tetra‐substituted α‐amino acids have an amide I band at higher frequencies (1658–1666 cm −1 )12, 28–30 than do α‐helices (1650–1658 cm −1 )31–33 in nonaqueous solutions. This small frequency shift of the amide I band cannot uniquely determine the conformation, as both distortions and irregularities in the helix,13, 34, 35 different types of residues,36 helix length,37, 38 solvent effects,39–42 and strain in the amide bond43 can result in higher (or lower) frequencies for either structure. Reports of a low amide I′ frequency for 3 10 ‐helical segments in proteins dissolved in D 2 O44 will be addressed in the Discussion section.…”

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

“…Nowadays the synthesis can be achieved in both enantiomeric forms by chromatographic resolution of the racemates using commercial columns and enantiomer separating instrumentation. As a further advantage the absolute configuration of the spirodilactam system is known on the basis of a correlation to corresponding 6-methyl and 6-isobutylderivatives, which were prepared from precursors of known absolute configurations ( l -alanine and l -leucine). These derivatives introduce an additional chiral center at C 6 , which is in the known diastereomeric relation (determined by both NMR and X-ray) with the spirodilactam moiety.…”