Synthesis of 4-hydroxy-2-methylproline derivatives via pyrrolidine ring assembly: chromatographic resolution and diastereoselective synthesis approaches

Abstract

4-Hydroxy-2-methylproline diastereomers are successfully prepared without the use of an external chiral auxiliary. Dihydroxylation of the key intermediate 2 resulted in lactone 4 as a mixture of diastereomers in good yield. Mesylation, hydrogenation and concomitant intramolecular cyclization of 4 led to the formation of both (2R,4R)- and (2R,4S)-4-hydroxy-2-methylprolines as a mixture of diastereomers. Appropriate protection followed by chromatographic separation resulted in isolation of both cis- and trans-diastereomers in enantiomerically pure form and in equal quantity. In subsequent experiments, the synthesis of the more challenging diastereomers (2R,4R)- and (2S,4S)-4-hydroxy-2-methylproline was achieved by diastereoselective iodolactonization of (R)- or (S)-allylalanine obtained after hydrolysis of intermediate 2, followed by pyrrolidine ring closer under mild alkaline conditions. After selective protection and deprotection, Fmoc-(2R,4R)-α-Me-Hyp(tBu)-OH 14, a building block suitable for solid phase peptide synthesis was obtained.