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A Unifying Bioinspired Synthesis of (−)-Asperaculin A and (−)-Penifulvin D

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posted on 2021-04-08, 16:46 authored by Ian R. George, Miguel López-Tena, Anders P. Sundin, Daniel Strand
The first syntheses of the isomeric dioxafenestrene natural products (−)-asperaculin A and (−)-penifulvin D are reported. Each target is formed selectively by choice of oxidant in a final divergent bioinspired Baeyer–Villiger (BV) reaction. Density functional theory calculations reveal that electrostatic interactions between the oxidant leaving group and the lactone motif accounts for a reversal of selectivity with H2O2/H3O+ compared to peracids. Synthetic features include forging the polycyclic carbon framework with a diastereoselective meta-photocycloaddition biased by an ether substituent at the aryl α-position. The encumbered tertiary alcohol was installed by cyanation of a ketone intermediate followed by nonaqueous hydrolysis of the resulting delicate cyanohydrin.