Synthesis of 4-hydroxy-β3-homoprolines and their insertion in α/β/α-tripeptides

The stereoselective syntheses of 2-cyclopropyl and (2S)-2-hydroxymethyl-(3R,4S)-4-hydroxy-beta3-homoproline are described. The reported amino acids were constructed through 1,3-dipolar cycloaddition of strained alkylidenecyclopropanes with enantiopure pyrroline N-oxides derived from malic acid followed by thermal rearrangement of the adducts in the presence of trifluoroacetic acid. The two-step sequence afforded the homoprolines suitably protected to be directly used as building blocks in peptidomimetic synthesis as proved by the synthesis of the two model mixed alpha/beta/alpha tripeptides Phe-beta3-HPro-Val