Concise Total Synthesis of Phenylethanoid Glycoside Acteoside.

Acteoside is a prominent phenylethanoid glycoside (PhG) with diverse pharmacological activities. However, its chemical synthesis has been challenging due to the reliance on extensive protection/deprotection strategies, leading to lengthy routes and low overall yields. Herein, we present a streamlined and efficient synthetic approach that minimizes synthetic complexity while improving overall efficiency. The strategy, which gave acteoside in 18.6% overall yield over just 6 steps, employs key regio- and chemoselective transformations, including β-glycosylation, selective caffeoylation, regioselective silylation, α-rhamnosylation, and a one-pot global deprotection. By exploiting the inherent differences in hydroxyl reactivity, this method significantly reduces the need for protecting groups, ensuring a more direct synthetic pathway. Importantly, the approach prevents E:Z isomerization of the caffeoyl moiety, preserving the structural integrity of the final product. This methodology can be extended to a broader class of phenylethanoid glycosides, facilitating access to these bioactive natural products for further applications.