Isotopically labelled and unlabelled β-peptides with geminal dimethyl substitution in 2-position of each residue: Synthesis and NMR investigation in solution and in the solid state

The preparation of (S)-β2.2.3-amino acids with two Me groups in the α-position and the side chains of Ala, Val, and Leu in the β-position (double methylation of Boc-β-HAla-OMe, Boc-β-Val-OMe, and Boc-β-Leu-OMe, Scheme 2) is described. These β-amino acids and unlabelled as well as specifically ¹³C- and ¹⁵N-labelled 2,2-dimethyl-3-amino acid (β^2.2-HAib) derivatives have been coupled in solution (Schemes 1, 3 and 4) to give protected (N-Boc, C-OMe), partially protected (N-Boc/C-OH, N-H/C-OMe), and unprotected β^2.2- and β^2.2.3.-hexapeptides, and β^2.2- and β^2.2.3-heptapeptides 1-7. NMR Analyses in solution (Tables 1 and 2, and Figs. 2-4) and in the solid state (2D-MAS NMR measurements of the fully labelled Boc-(β^2.2-HAib)₆-OMe ([¹³ C₃₀, ¹⁵N₆]-1e; Fig. 5), and TEDOR/REDOR NMR investigations of mixtures (Fig. 6) of the unlabelled Ac-(β^2.2-HAib)₇-OMe (4) and of a labelled derivative ([¹³C₄,¹⁵N₂]-5; Figs. 7-11, and 19), a molecular-modeling study (Figs. 13-15), and a search in the Cambridge Crystallographic Data Base (Fig. 16) allow the following conclusions: i) there is no evidence for folding (helix or turn) or for aggregation to sheets of the geminally dimethyl substituted peptide chains in solution; ii) there are distinct conformational preferences of the individual β^2.2- and β^2.2.3-amino acid residues: close to eclipsing around the C(O)-C(Me₂(CHR)) bond (τ_1.2), almost perfect staggering around the C(2)-C(3) ethane bond (τ_2.3), and antiperiplanar arrangement of H(C3) and H(N) (τ_3,N; Fig. 12) in the solid state; iii) the β^2.2-peptides may be part of a turn structure with a ten-membered H-bonded ring; iv) the main structure present in the solid state of F₃CCO(β^2.2-HAib)₇-OMe is a nonfolded chain (> 30 Å between the termini and > 20 Å between the N-terminus and the CH₂ group of residue 5) with all C=O bonds in a parallel alignment (± 10°). With these structural parameters, a simple modelling was performed producing three (maybe four) possible chain geometries: one fully extended, two with parallel peptide planes (with zick-zack and crankshaft-type arrangement of the peptide bonds), and (possibly) a fourth with meander-like winding (D - G in Figs. 17 and 18).