Diastereoselective Synthesis of (3 R ,5 R)-γ-Hydroxypiperazic Acid.

We report an asymmetric synthesis of the (3 R ,5 R)-γ-hydroxypiperazic acid (γ-OHPiz) residue encountered in several bioactive nonribosomal peptides. Our strategy relies on a diastereoselective enolate hydroxylation reaction and electrophilic N-amination to provide the acyclic γ-OHPiz precursor. This orthogonally protected α-hydrazino acid intermediate is amenable to late-stage diazinane ring formation following incorporation into a peptide chain. We determined the N-terminal amide rotamer propensity of the γ-OHPiz residue and showed that the γ-OH substituent enhances trans -amide bias relative to piperazic acid. [ABSTRACT FROM AUTHOR]