2.6.2. Plakortones

Ten lactone metabolites, known as plakortones (**174**–**183**), have been isolated from the marine sponge of the genus *Plakortis*. Plakortones belong to a big family of oxygenated polyketide metabolites, the structures of which contain a bicyclic system composed of a tetrahydrofuran fused to a γ-butyrolactone ring (Figure 27). Some of them have been discovered and characterized during the 20th century [117,118], while plakortone L, N, P, and Q were recently isolated [119,120].

**Figure 27.** Structure of plakortones.

Since their discovery, numerous studies can be found in the literature with different approaches towards the synthesis of these natural products, their epimers [121] or analogues [122]. A palladium-(II)-mediated hydroxycyclization-carbonylation-lactonization cascade [123] was the general methodology applied to obtain the plakortone core in some cases [122,124,125]. There, from diols **184**, the byclyclic diastereomers **185** or **186** can be accessed (Scheme 33).

**Scheme 33.** Synthesis of plakortone core.

The synthesis of the four possible diastereoisomers and comparison with the natural product allowed Wong and co-workers to determine the absolute configuration of the four stereocenters of plakortone B [126]. Thus, retrosynthetic analysis revealed butenolide **187** as the potential precursor of the bicyclic lactone. Formation of butenolide required ten steps from D-mannitol. The bicyclic framework **188** was directly formed with a 90% yield by the reaction of butenolide with 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU), in a domino Michael addition followed by transesterification. Total synthesis of plakortone B was achieved in 22 further steps with a low overall yield (<1%) (Scheme 34).

Another biomimetic approach converted plakortide E derivative **189** into plakortone B [127]. Treatment of **189** with zinc in acetic acid broke the peroxy O-O bond and provided diol intermediate **190**. Further intramolecular oxa-Michael addition/lactonization cascade reaction afforded the desired product with high yield (90%) (Scheme 35).

**Scheme 35.** Synthesis of plakortone B via plakortide E derivative.

In 2014, the total synthesis of plakortone L was also reported [128]. In this case, the strategy to obtain the tetrahydrofuran ring was a [3+2] annulation. Thus, the tetrahydrofuranyl ring **191** was obtained by the reaction of isopropylidene-protected D-arabinose **192** and protected methallyl alcohol **193** in the presence of BF3·OEt2. Fourteen further

steps were required to accomplish the total synthesis of plakortone L with 6% overall yield (Scheme 36).

**Scheme 36.** Synthesis of plakortone L.

In terms of their biological activity, plakortones A-D belong to the class of activators of cardiac sarcoplasmic reticulum Ca2+-pumping ATPase at micromolar concentrations, specially plakortone D [117]. Plakortones B-F exhibit in vitro cytotoxic activity on a murine fibrosarcome cell line [122]. However, plakortone Q, being the only member of the family which contains a hydroxyl group in the ring system, is not active against any of the tested tumor cell lines [129].
