Insight into the structure of antitubercular Callyaerins: conformational studies and synthesis of a unique dehydroamino acid, β-aminodehydroalanine

β-Aminodehydroalanine, ΔAla(β-NH), (2,3-diaminoprop-2-enoic acid), is a unique dehydroamino acid and a central component of Callyaerins A-M and Callynormine A. The presence of this unusual structural element containing an enamine functional group may be related to the antitubercular activity of Callyaerins. According to The WHO Global Tuberculosis Report tuberculosis is the second leading cause of death worldwide caused by a single infectious agent. Therefore, it is essential to understand the molecular structure of these peptides in more detail. To investigate the conformational properties of the ΔAla(β-NH) residue, a series of model compounds: Ac-(Z/E)-ΔAla(β-NHMe)-NHMe, Ac-(Z/E)-ΔAla(β-NHMe)-NMe₂, Boc-Gly-(Z)-ΔAla(β-NHMe)-OMe, and Boc-Gly-(Z)-ΔAla(β-Leu-OMe)-OMe, were selected for quantum chemical calculations and/or synthesized. Two conformations, β2 (φ,ψ ~ - 120°, 20°) and α (φ,ψ ~ - 70°, - 15°) are predicted as the most preferable, regardless of the geometry of isomer (Z/E), polarity of environment, and order (2°/3°) of C-terminal amide group. The N-H⋯O hydrogen bond involving the N-H group in the β position of the side chain as a donor is a significant stabilizing factor. The Z isomer is predicted to be the most stable and has been synthesized. The following synthesis method is proposed: Ser → ΔAla → ΔAla(β-Br) → ΔAla(β-NH). The advantages of the proposed method are: (i) serine as the starting substrate, (ii) mild alkaline conditions, (iii) avoidance of the reactive intermediate α-formylglycine.