Configurational Assignment of D‐ and L‐Isovalines in Intact, Natural, and Synthetic Peptides by 2D‐NMR Spectroscopy

Abstract

We investigated, by means of 2D-NMR, the naturally occurring and chemically synthesized 16-mer integramides A and B, which belong to a group of bioactive, fungal peptides (peptaibiotics), that are characterized by an abundance of Aib as well as D- and L-Iva residues. The chemical shifts of the C(alpha)-alkyl groups in the Iva enantiomers depend on the alpha-C-atom configuration and on the helical screw sense of the peptides, the latter determined by CD. In the full-length, right-handed helical integramides, as well as in the partial sequences exploited for their total chemical syntheses, the gamma-Me H-atoms of the Et side chain of the D-Iva residues located near the C-terminus are significantly more shielded (delta<0.90 ppm) than those of the L-Iva residues (delta>0.95 ppm). The opposite behavior is observed for the left-handed, synthetic, intermediate Z-Aib-L-Hyp-L-Iva(14)-D-Iva(15)-O(t)Bu. Here, the gamma-Me H-atoms of L-Iva(14) are more shielded (0.838 ppm) than those of D-Iva(15) (0.905 ppm). The chemical-shift difference between the diastereotopic beta-CH(2) H-atoms of the Iva side chains in the right-handed helical peptides is much larger for D-Iva than for L-Iva. For D-Iva(14/15), the values range from 0.38 to 0.63 ppm, whereas, for D-Iva(1), the value is in the range of 0.26-0.31 ppm. In each case, the difference is always larger for the d-Iva than for the l-Iva residues (which is always <or=0.19 ppm). Again, an opposite behavior is seen for the left-handed tetrapeptide. Overall, our method enables the nondestructive assignment of the configuration of each Iva residue in peptides of known helical screw sense.

Microbacterins A and B, New Peptaibols from the Deep Sea Actinomycete Microbacterium sediminis sp. nov. YLB-01(T)

“…The occurrence of two negative maxima at 210 and 225 nm and a positive maximum near 195 nm in the CD curve ( Figure 3) reflected the right-handed helical conformation of 1. 22 Thus, the chemical shifts of γ-H 3 (δ H 0.81 for Iva-7, δ H 0.69 for Iva-13, <0.89 ppm), Δδ βHb-βHa (0.34 ppm for Iva-7, 0.23 ppm for Iva-13, >0.20 ppm), and βC (δ C 28.7 for Iva-7 and δ C 29.7 for Iva-13, <30 ppm) ( Table 1) were in agreement with the R-configuration for the Iva residue. 23 Acidic hydrolysis of compound 1 and semipreparative HPLC separation resulted in the isolation of 3-amino-2-hydroxyvaline (AHV).…”

Isolation and Total Synthesis of Albu­peptins A–D: 11‐Residue Peptaibols from the Fungus Gliocladium album

“…The stereochemistry of the Iva residues in albupeptins A-D (1-4) was investigated using an approach based on 2D NMR spectroscopy (Table 2, Figure 5), [33] which, unlike Marfey's analysis, is nondestructive. This approach is based on analysis of 1 H chemical shift differences between the diastereotopic β-methylene protons of Iva residues.…”

“…In righthanded helical peptaibols, these protons have large chemical shift differences for d-Iva (Δδ H Ͼ 0.28 ppm) and low values for l-Iva (Δδ H Ͻ 0.20 ppm) residues, whereas the opposite behavior is observed for left-handed helicity. [33] Table 2). …”

Screening the Biosphere: The Fungicolous Fungus Trichoderma phellinicola, a Prolific Source of Hypophellins, New 17‐, 18‐, 19‐, and 20‐Residue Peptaibiotics

“…These are attributed to the presence of high proportions of peptide-bound α-aminoisobutyric acid (Aib), frequently accompanied by d - and/or l-isovaline (Iva) [16], and, in a few sequences, l -α-ethylnorvaline (EtNva), or 1-aminocyclopropane-1-carboxylic acid (Acc) [17]. The presence of these α,α-dialkyl-α-amino acids (Fig.…”