Sustainable electrochemical synthesis of a new isoxazoline scaffold as turn inducer to build parallel β-hairpins

Abstract

New diastereoisomeric isoxazoline scaffolds bearing two amino-alkyl chains were synthesized using a 1,3-dipolar cycloaddition reaction, with the aim to prepare N-to-N parallel ß-hairpins. Two approaches were employed, both starting from methyl(azidomethyl)acrylate as dipolarophile, and an enantiopure chloroxime or oxime as dipoles derived from cheap L-phenylalanine. In the first method the chloroxime was treated with a base to in situ generate the corresponding nitrile oxide which then reacted with the dipolarophile. In the second approach, a more sustainable electrochemical cycloaddition was performed, enabling direct nitrile oxide generation from the oxime, avoiding one synthetic step. The regioselective cycloaddition allows the formation of two diastereoisomeric isoxazoline scaffolds, both used for the synthesis of model peptidomimetics. Comprehensive computational and NMR studies revealed that the R,S-isoxazoline more effectively stabilizes the desired parallel β-hairpin conformation.