Total synthesis of chrysophaentin F and approaches to related natural products

Abstract

The chrysophaentins are a new family of natural products first isolated from the marine algae Chrysophaeum taylori in 2010.1,2 They have been found to have strong antibiotic activity, particularly against methicillin resistant Staphylococcus aureus (MRSA), multiple drug resistant SA (MDRSA) and vancomycin resistant Enterococcus faecium (VREF). Chrysophaentin A was identified as the most active member of the family with MIC50 values of 1.5 ± 0.7 and 1.3 ± 0.4 μg/mL against MRSA and MDRSA and 2.9 ± 0.8 μg/mL towards VREF, closely followed by chrysophaentins F and H.

This thesis describes the total synthesis of chrysophaentin F and progress towards the synthesis of chrysophaentins A and E. The synthetic strategy described herein is designed to give access to all chrysophaentins with minimal modification. It takes advantage of common building blocks and symmetry elements present throughout the chrysophaentin family and uses these to proceed via related intermediates. It uses a variety of transition metal catalysed C-C and C-O bond forming reactions to conjoin these building blocks, including Cu-catalysed Chan-Evans-Lam couplings, Pd- and Ni-catalysed sp-sp3 couplings and a Mo-catalysed RCAM. Furthermore, a late-stage hydrozirconation is used to install the (E)-vinyl chloride groups present in the natural products. This has resulted in the total synthesis of chrysophaentin F as a 2:1 mixture with a regioisomer and the preparation of a protected derivative of chrysophaentin E. Significant progress towards chrysophaentin A is also described.

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ORCID for David C. Harrowven: orcid.org/0000-0001-6730-3573

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