Bioinspired Asymmetric Total Synthesis of Emeriones A–C

22 April 2022, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

We report an asymmetric bioinspired total synthesis of the fungal metabolites emeriones A–C via stereoselective late-stage epoxidation or endoperoxidation of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffold is synthesized in an 8pi/6pi electrocyclization cascade of a stereodefined (E,E,Z,Z,E)-pentaene, which contains the fully assembled and unprotected side chains of the natural products. The pentaene is constructed convergently through Stille cross-coupling of two similarly complex polyenes. The anti-aldol side chain of the emeriones is made using a Paterson-aldol approach, and the epoxide of the dioxobicyclo[3.1.0] side chain is synthesized via ring-closure onto an oxidized para-methoxyphenyl acetal. Our total synthesis has enabled the revision of the structure of emerione C and the synthesis of a “missing” family member, which we hereby call emerione D. DFT calculations indicate the two methyl groups that reside on the cyclobutene ring are critical for the stereochemical outcome of 8pi/6pi electrocyclization.

Keywords

biomimetic synthesis
electrocyclizations
isomerization
natural product total synthesis
reaction cascade

Supplementary materials

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Supporting Information
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Experimental details, compound characterization data, NMR spectra, and supplementary tables, figures, and schemes.
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X-ray crystallographic data file
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CIF with all crystallographic data for the three solved X-ray crystal structures
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