A Short Synthesis of Partially Protected l- and d-β-Hydroxyenduracididines and a Structurally Simplified Dipeptide Analogue

Abstract

A short synthesis of the C2-epimeric amino acids Land D-β-hydroxyenduracididine (βhEnd) was developed. Both amino acids are part of the cyclopeptide portion of the mannopeptimycin antibiotics. The synthetic route comprises eight steps starting from Garner's aldehyde and provides partially protected derivatives in good overall yields. Key steps are a stereodivergent olefinationbishydroxylation sequence and a regioselective guanidine cyclization reaction. In addition, precursor amino acids that contain a protected amino alcohol instead of the cyclic guanidine could be efficiently coupled to provide a structurally simplified analogue of the L-βhEnd-D-βhEnd dipeptide portion of the mannopeptimycin aglycone.

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

“…Synthesis of β-hydroxyenduracididine by Oberthür et al: In 2014, Oberthür et al reported a second generation synthesis of β-hydroxyenduracididine using a more concise route to orthogonally protected amino acids 46 and 47 (Scheme 7) [58]. Installation of the C-2 stereocentre again began with Garner’s aldehyde 48 and Wittig olefination, followed by Sharpless dihydroxylation to stereoselectively afford diol 49 [59–60].…”

“…An alternative route to L-β-hydroxyenduracididine based on the synthesis reported by Oberthür et al [58] afforded L-β-hydroxyenduracididine 98 in 7% yield over twelve steps from 99 (Scheme 20). …”