Akaeolide

Akaeolide (Figure 23) is another polycyclic polyketide isolated from a culture extract of a marine-derived actinomycete, *Streptomyces* sp., in 2013 [102]. Its 15-membered carbocyclic structure possesses a five-membered cyclic ether and a β-keto-δ-lactone unit. The biological essays of this compound have shown modest cytotoxicity against 3Y1 rat fibroblasts with an IC50 of 8.5 μM [103].

**Figure 23.** Structure of akaeolide.

## *2.4. Acetogenin Metabolites*

Acetogenins are secondary metabolites derived from polyketides. Acetogenins from marine algae are mostly halogenated and are thought to have a common C15 precursor derived from a C16 fatty acid. The majority of these marine C15 acetogenins are differentsized cyclic ethers with a terminal enyne or bromoallene. Among them, tetrahydrofuran and bis-tetrahydrofuran acetogenins are quite abundant. Acetogenins are known to be chemotaxonomic markers from red algae to the genus *Laurencia*. A general overview of C15 acetogenins from 1965 till 2015 was provided by Falkenberg [104].

In 2016, three new tetrahydrofuran-containing acetogenins with potent and selective antiproliferative activity against human nasopharyngeal carcinoma (NPC) cell lines and their methotrexate-resistant counterparts have been described [105].

In 2019, a synthetic route for the bis-tetrahydrofuran core of acetogenins based on a chemoenzymatic cascade reaction was reported [106]. Catalytic hydrogenation of benzylidene acetal **153** produces the inside-out cyclization to afford bis-tetrahydrofuran-ditosylate **154** in 66% yield. It was also possible to obtain a different stereochemistry on the bistetrahydrofuran moiety **156**, through a double Payne rearrangemen<sup>t</sup> of epoxide **155** followed by 5-*exo*-tet cycloetherification (Scheme 29).
