2.1.1. Amphidinolides

Amphidinolides belong to the macrolide family and more than forty members have been isolated from marine dinoflagellates of the genus *Amphidinium* sp. In the last thirty years. Within these structurally rich compounds, only a few contain tetrahydrofuran units embedded in the macrolactone ring. The studies published in the literature about tetrahydrofuran-containing amphidinolides up to 2013 have been already reviewed by Álvarez and coworkers [10].

#### Amphidinolides C and F

Amphidinolides C (**1**), C2 (**2**), C3 (**3**), and F (**4**) are structurally similar (Figure 1), bearing a complex 25-membered macrolide core, which contains 11 chiral carbons and a functionalized side chain. The nature of this chain drastically affects biological activity. Amphidinolide C, which possesses an (*S*)-hydroxyl group, is active against murine lymphoma L1210 (IC50 = 5.8 ng/mL) and human epidermoid carcinoma KB cell lines (IC50 = 4.6 ng/mL). Strikingly, compounds **2**-**4** are three orders of magnitude less toxic to the same cell lines.

**Figure 1.** Structure of amphidinolides C, C2, C3, and F.

In 2016, a new amphidinolide C4 (**5**) was isolated from octocoral *Stragulum bicolor* (Figure 2). Toxicity was tested against the colon adenocarcinoma cell line HCT-116, finding an IC50 of 10.3 μM. Compound **5** is therefore surprisingly inactive, although it contains a hydroxyl group in the side chain [14].

**Figure2.**Structure of amphidinolideC4.

The interesting biological properties of these compounds have attracted the attention of different authors who have described either total syntheses [15,16] or synthetic approaches to various molecular fragments [17–19]. For instance, Fürstner and coworkers took advantage of the structural similarity of **1** and **4** to perform an elegant total synthesis of both compounds [15]. In these syntheses, the formation of the trisubstituted tetrahydrofuran unit was performed using a TBAF-mediated oxa-Michael addition, which selectively led to the desired 1,4-*trans* tetrahydrofuran ring **7**. Parallelly, a chemoselective cobaltcatalyzed cyclization of an appropriate bishomoallylic alcohol **8** provided the required *trans*-disubstituted tetrahydrofuran **9** (Scheme 1).

**Scheme 1.** Synthesis of the THF moiety in amphidinolides C and F by Fürstner.
