Alpha-hydroxymethylserine as a peptide building block: synthetic and structural aspects

A synthetic methodology has been developed for peptide bond formation with alpha-hydroxmethylserine as the carboxyl or amino component and also for the preparation of homo-sequences. The key intermediate, O,O-protected alpha-hydroxymethylserine in the form of an isopropylidene derivative, is easily accessible and represents the first example of a heterocyclic C(alpha,alpha)-disubstituted amino acid containing an 1,3-dioxane ring. The use of this intermediate facilitates protection of the sterically hindered amino and carboxyl groups and is advantageous for the coupling and deprotection steps. X-ray structure determination of Z-HmS(Ipr)-Ala-OMe revealed that the two crystallographically independent molecules present in the asymmetric unit adopt an S-shaped conformation. In the one molecule the achiral HmS(Ipr) residue has the torsion angle values (phi = 61.4 degrees, psi, = 40.8 degrees) in the left-handed helical region of the Ramachandran map, while in the second molecule the negative torsion angles (phi = -60.1 degrees, psi = -44.4 degrees) are associated with the right-handed helix.