Total Synthesis of Phallusialide A Using Palladium-Catalyzed Asymmetric Hydroalkoxylation

Abstract

One of the biggest concerns in terms of health worldwide is bacterial strain resistance. To overcome the problem, the research and development of new antibiotics is urgently needed. One natural product that exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) is Phallusialide A. From the structural viewpoint, Phallusialide A represents unique 𝛼-4-epivancosamine linked with 2,3,6-trideoxysaccharide 𝛽-amicetose and the rare aglycone 2- carboxy-pyrrole. The assembly of those monosaccharides has tremendously become a challenging task. The classical glycosylation method is unsuitable, especially for the substrate-bearing acid-sensitive compound like Phallusialide A. To overcome the challenge, this research emphasized Palladium-catalyzed asymmetric hydroalkoxylation as a de novo strategy for glycosylation. The highlighted feature of this approach was high regioselectivity, stereoselectivity, and atomic efficiency, which was achieved by coupling the alkoxyallenes with alcohols followed by subsequent ring-closing metathesis. The disaccharide was connected to the aglycone through the classical Steglich esterification reaction. The first synthesic approach towards Phallusialide A was completed in a total of 28 steps and 2.2% overall yield.