Stereoselective Synthesis of Unnatural Spiroisoxazolinoproline-Based Amino Acids and Derivatives

A route to spiroisoxazolinoproline-based amino acid derivatives is reported in which exo-methyleneprolinate 4 (tert-butyl ester) reacts as a dipolarophile with nitrile oxides to generate spiroisoxazolinoprolinates 7/10/11 in good yields (70-75%) and with ca. 1:4 cis:trans diastereoselectivity. tert-Butyl spiroisoxazolinoprolinates were separable by column chromatography and amenable to scale-up leading to single diastereoisomers of N-Boc and N-Fmoc protected spiroisoxazolinoproline amino acids.