2.1.11. Phormidolides

The first member of this family, Phormidolide A (**142**) (Figure 19), was isolated in 2002 from the marine cyanobacterium *Leptolyngbya* sp. [88]. Although it was an inactive metabolite in cell line essays, phormidolide A showed high toxicity to brine shrimp (LC50 = 1.5 μM). At that moment, a complex structure was proposed on the basis of spectroscopic techniques. Eleven stereocentres, a tetrahydrofuran-embedded macrolactone, a polyol side chain and a terminal bromomethoxydiene motif composed the polyketide. Almost 20 years later, the assignment of eight chiral centers was corrected thanks to the contribution of Gerwick, Paterson, Britton, and Piel and colleagues, who used synthetic methods [89], computational information, and anisotropic NMR studies [90].

**Figure 19.** Structure of phormidolide A.

In 2015, the study of an active organic extract of *Petrosiidae* sponge concluded with the discovery of two important novel phormidolides, phormidolide B and phormidolide C (Figure 20) [91]. Their structural similarity to phormidolide A [90] and oscillariolide [87] helped in the establishment of their overall structure by NMR techniques.

**Figure 20.** Structure of phormidolides B-D.

These new compounds present cytotoxic activity against three human tumor cell lines, lung (A-549), colon (HT-29), and breast (MDA-MB-231), with an unknown mechanism of action. Their challenging structure has attracted the interest of synthetic chemists who have developed different strategies to access either the macrolide ring [91–93] or the polyhydroxylated chain [94,95].

Phormidolides could be divided into three molecular fragments with two main disconnections: a macrocyclic core, a polyhydroxylated chain containing a tetradecanoic fatty acid, and a propargylic organometallic (Scheme 27). Synthetic approaches to each individual fragment have been described, although no completed synthesis of any of these compounds has been reported so far [93].

Focusing on the tetrahydrofuran-containing macrolactone, Álvarez et al. published an approach to its synthesis starting from commercially available 2-D-deoxyribose [91]. The key steps of this synthesis are the simultaneous formation of a trisubstituted double bond and a new stereocenter through the stereoselective 1,5-*anti*-addition of an allylstannane **146** and ribose-derived aldehyde **147**. Then, **148** was subjected to final Shiina macrolactonization affording the desired **149** (Scheme 28).

**Scheme 28.** Retrosynthesis of phormidolide macrocycle.
