There is a great interest in developing peptidomimetic libraries of oligomeric compounds displayed on a solid support in order to facilitate the rapid and inexpensive discovery of bioactive compounds. Peptoids, oligomers of N-alkylated glycines, had been widely used for their better serum stability and/or cell permeability than peptide libraries. However, most ligands identified from peptoid libraries rarely displayed high affinity towards protein targets, possibly due to lack of stereogenic centers and conformational constraints. To get away from using “floppy” molecules, we have reported construction of chemical libraries using chiral oligomers of pentenoic amides (COPAs) and peptide tertiary amides (PTAs). As an extension of making building blocks with “stiffness”, β-amino acids (BAAs) with substituents at both the alpha and the beta position were considered attractive as highly conformationally constrained by gauche interaction. However, we anticipated that α-branched acid building blocks could not meet requirements for coupling with secondary amines often used in libraries. Therefore, we focused on the syntheses of vinylogous β-amino acids (VBAAs) in which the α-stereocenter is separated from the carboxylic acid by a sterically undemanding vinyl unit. Herein, we report expedient syntheses of VBAAs using enantioselective Mannich reactions of aldehydes with in situ generated N-carbamoyl imines followed by a Wittig-type olefination reaction. Comparison of the coupling efficiency between VBAAs and BAAs with different moieties on the C- and N-terminal sides suggests that VBAAs as useful building blocks for the construction of combinatorial libraries of peptidomimetic compounds.

Asymmetric syntheses of conformationally constrained vinylogous β-amino acids and their incorporation into mixed backbone oligomers

255th National Meeting (2018)

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