Gram-scale total synthesis of (+)-pseudoephedrine

Abstract

Based on the requirements of natural product total synthesis and medicinal chemistry research, we have developed a gram-scale total synthesis of (+)-pseudoephedrine [(1S,2S)-2-(methylamino)-1-phenylpropan-1-ol]. The strategy involves the construction of two chiral centers through Sharpless asymmetric dihydroxylation (AD) and establishment of the molecular skeleton via configuration inversion. Starting from ethyl cinnamate, (+)-pseudoephedrine was prepared on gram-scale through 11 straightforward steps with 40 % overall yield. This synthetic route features multiple one-pot reactions, requiring only two intermediate purifications throughout the entire process. The purity and absolute configuration of the target compound were confirmed by melting point analysis, specific rotation measurement, and NMR characterization.