*3.3. Diterpenes*

3.3.1. Darwinolide

(+)-Darwinolide (**54**) (Figure 13) is a diterpene isolated in 2016 by Baker from the Antarctic Dendroceratid sponge *Dendrilla membranosa* [49]. It presents fourfold selectivity against a biofilm phase of methicillin-resistant *Staphylococcus aureus* (IC50 of 33.2μM), compared to the planktonic phase (with the higher MIC of 132.9 μM). This interesting property and its low mammalian cytotoxicity (IC50 of 73.4 mM) against a J774 macrophage cell line turn darwinolide into a possible scaffold for antibiofilm-specific antibiotics. Additionally, it was found to have modest activity (11.2 μM) against *L. donovani*-infected macrophages [50].

Its total synthesis was reported in 2019 by Christmann [51]. The required tetrahydrofuranyl ring is installed starting from the commercially available anhydride **55**, which is converted to the 2,5-dimethoxylated tetrahydrofuran **56** in four steps. A sequence of oxidation (with o-iodoxybenzoic acid), saponification, and Criegee oxidation with Pb(OAc)4 is then used to convert **56** into **57** in 61% yield over three steps (Scheme 7). A further 14 linear steps are needed to complete the total synthesis of **54**, with an overall yield of 1.4%.

**Scheme 7.** Synthesis of the key THF-containing intermediate in Christmann's total synthesis of darwinolide.
