By exploiting the chemo-enzymatic synthesis
developed by DSM Pharmaceutical Products (Sonke et al., 1999), we prepared enantiomerically pure isovaline and Cα-methylvaline in large amounts. The corresponding racemic α-amino amides, synthesized by partial Strecker synthesis, were enzymatically resolved with appropriate α-amino amidases. Then, homo-peptides (di- and tetra-) from the sterically hindered isovaline and Cα-methylvaline were synthesized step-by-step in solution. The highly effective EDC/HOAt or acyl fluoride C-activation procedures EPZ-6438 in vivo were employed in peptide bond formation. Results of the catalysis experiments showed MAPK inhibitor the all Cα-methylated peptides exhibit significant chiral influence on the synthesis of tetroses
and mimic the effect of the L-Val-L-Val catalyst in having a larger erythrose ee than threose ee, as well as in their configuration relationship with the sugars (the product erythrose acquires ee of configuration opposite to that of the catalyst in case of peptides, while it is the same for amino acids). Interestingly, the largest ee (45% for erythrose) was obtained with the homo-tetrapeptide of isovaline under mild conditions (sodium acetate buffer, pH 5.4, 25°C, 18 h). The homo-dipeptides of both isovaline and Cα-methylvaline also produced a significant ee (41% for erythrose) that appears to increase with time. Because Cα-methylated amino acids are non-racemic in meteorites, do not racemize in aqueous environments, and are known to be (310)-helix (Toniolo and Benedetti, 1991) Flavopiridol (Alvocidib) formers in peptides with as few as four residues (Toniolo et al., 2001),
these results suggest that meteoritic, Cα-methylated, α-amino acids may have contributed to molecular evolution upon delivery to the early Earth by catalytically transferring their asymmetry to other prebiotic molecules. Pizzarello, S., Weber, A. (2004). VS-4718 Meteoritic amino acids as asymmetric catalysts. Science, 303:1151. Sonke, T., Kaptein, B., Boesten, W. H. J., Broxterman, Q. B., Schoemaker, H. E., Kamphuis, J., Formaggio, F., Toniolo, C., Rutjes, F. P. J. T. (1999). In Patel, R. N., editor, Stereoselective Biocatalysis, pages 23–58. Dekker, New York, NY. Toniolo, C., Benedetti, E. (1991) The polypeptide 310-helix. Trends Biochem. Sci., 16:350–353. Toniolo, C., Crisma, M., Formaggio, F., Peggion, C. (2001). Control of peptide conformation by the Thorpe-Ingold effect (Cα-tetrasubstitution). Biopolymers (Pept. Sci.), 60:396–419. Weber, A., Pizzarello, S. (2006). The peptide catalyzed stereospecific synthesis of tetroses: a possible model for prebiotic molecular evolution. Proc. Natl.