Scalable and sustainable synthetic study towards the rubriflordilactones Pavle Kravljanac, Edward A. Anderson* Chemistry Research Laboratory, University of Oxford, UK
Rubriflordilactones A and B, triterpenes from the Schisandraceae family, have attracted the attention of the synthetic community due to their intricate structures and potential anti-HIV bioactivity. However, the previous two syntheses of these molecules were hampered by lengthy routes (34 and 37 steps), inefficient strategies, toxic and hazardous chemicals and excessive protecting groups and chromatographic purifications. Here we describe efforts to address these limitations by employing strategies that achieve efficient, scalable and sustainable syntheses of key building blocks towards the rubriflordilactones. Our optimised AB ring synthesis introduces a novel paradigm for tetrahydrofuran ring formation through a strategic ring expansion rearrangement of a cyclobutanol, which is derived from a cyclobutene-containing terpene chiral pool starting material. This approach leverages the bridged nature of this biorenewable building block to achieve complete stereocontrol of a challenging quaternary stereocentre adjacent to a tertiary one. This resulted in a highly efficient scalable synthesis of the AB rings in only 7 steps, devoid of chromatographic separations, with just two crystallisations required. Our projected FG ring synthesis explores the reactivity and stereoselectivity of an unusual vinylogous ester within a locked cis-decalin system, obtained via concise and stereoselective synthetic sequence from a carbohydrate chiral pool starting material. However, the unanticipated challenges of ketone alpha-methylation in this bicyclic system hindered the continuation of this approach; ongoing strategies to overcome this will be described.
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© The Author(s), 2023
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