3.1.2. Furoplocamioids

Furoplocamioids A–C **38–40** (Figure 9) are monoterpenes that were isolated in 2001 from the red marine alga *Plocamium cartilagineum* [32]. They bear an unusual polyhalogenated tetrahydrofuranyl ring. Their structural similarity to pantofuranoids suggests a close relationship between the species that produce them. This is an interesting fact, since *Plocamium cartilagineum* and *Pantoneura plocamioides* are classified in different orders, Gigartinales and Ceramiales. Therefore, a taxonomic revision could be required. Later, the Darias group determined the C7 relative stereochemistry by comparison with the NMR spectra of similar reported terpenes [33]. González-Coloma and coworkers found that **38** and **40** show antifeedant effects against *Leptinotarsa decemlineata*. It was shown that **40** was also an efficient aphid repellent (against *Mizuspersicae* and *Ropalosiphumpadi*) and selective insect cell toxicant. In addition, both compounds showed low mammalian toxicity and phytotoxic effects [34].

**Figure 9.** Structure of furoplocamioids A–C (**38–40**).

*3.2. Sesquiterpenes*

3.2.1. Heronapyrrols

Heronapyrrols A–C are pyrroloterpenes that were isolated in 2010 from a marine *Streptomyces* sp. CMB-M0423 [35]. They present bioactivity against Gram-positive bacteria *Staphylococcus aureus* ATCC 9144 and *Bacillus subtilis* ATCC 6633 but no mammalian cytotoxicity. Heronapyrrol C (**41**), apart from the characteristic and unusual 2-nitropyrrol moiety of this family, presents a *bis*-tetrahydrofuran core. Later, Capon and Stark first synthesized and then isolated heronapyrrol D (**42**) (Figure 10) from the same marinederived microbe [36]. Heronapyrrol D displays bioactivity against Gram-positive bacteria *Staphylococcus aureus* ATCC 25923 (IC50 = 1.8 μM), *Staphylococcus epidermidis* ATCC 12228 (IC50 = 0.9 μM), and *Bacillus subtilis* ATCC 6633 (IC50 = 1.8 μM). However, it is inactive against the Gram-negative bacteria *Pseudomonas aeruginosa* ATCC 10145 and *Escherichia coli* ATCC 25922.

**Figure 10.** Structure of (+)-heronapyrrol C (**41**) and (+)-heronapyrrol D (**42**).

To determine the relative and absolute stereochemistry of **(+)-41**, Stark and coworkers proposed and synthesized the most likely stereostructure of its enantiomer **(***−***)-41**, based on a biomimetic polyepoxide cyclization [37]. The same authors also reported the preparation of a bioisosteric carboxylate analog of **(***−***)-41** [38].

The first total synthesis of **(+)-41** was reported in 2014 by Brimble and coworkers, who used as key steps to introduce the five stereogenic centers a Julia–Kocienski coupling, a Shi epoxidation, and a catalytic epoxide-opening reaction [39]. The same year, the first total synthesis of **(+)-42** was achieved by Capon and Stark using a similar approach [36]. In 2016, Brimble and Furkert reviewed the isolation and synthesis of this family of compounds [40].

Later on, the same authors reported another total synthesis for both **(+)-41** and **(+)- 42 [41]**. Shi epoxidation of diol **43**, followed by CSA-catalyzed epoxide opening and cyclization, produces diastereomerically pure **44** in 75% yield over two steps. A further eight steps, with 31% yield over them, produces intermediate **45**, which deprotection gives (+)-heronapyrrol D (**42**). Epoxidation of **42** with a Shi ketone catalyst, followed by CSAcatalyzed epoxide opening, produced enantiomerically pure (+)-heronapyrrol C (**41**) in 75% yield (Scheme 4).

**Scheme 4.** Synthesis of (+)-heronapyrrol C (**41**) and (+)-heronapyrrol D (**42**).

Other synthetic approaches towards the 2-nitropyrrole system have been investigated by Brimble and Furkert, finding that Sonogashira coupling of 4-iodo-2-nitropyrrole with the appropriate alkyne was more effective than an approach relying on Stille coupling [42].

3.2.2. Kumausallene and Kumausyne

(−)-Kumausallene (**46**) was isolated in 1983 from the marine red alga *Laurencia nipponica* Yamada [43]. This compound belongs to a family of non-isoprenoid sesquiterpenes that contain a 2,6-dioxa-bicyclo [3.3.0]octane core with an *exo*-cyclic bromoallene (Figure 11).

**Figure 11.** Structure of kumausallene.

In 1993, the first total synthesis of **(***±***)-46** was reported by Overman, who chose a hexahydrobenzofuranone **47** (obtained by a Prins cyclization–pinacol rearrangemen<sup>t</sup> from **48**) as the key intermediate for the construction of the *bis*-tetrahydrofuran unit (Scheme 5). Further transformation of **47** into bicyclic lactone **49** (within three further steps) and final methanolisis and tandem cyclization of the corresponding hydroxyester provided, in good yield, the desired dioxabicyclo [3.3.0]octane **50** [44].

**Scheme 5.** Synthesis of the dioxabicyclo [3.3.0]octane unit of (±)-kumausallene (**46**) by Overman.

In 2011, a synthetic approach for **(***−***)-46** by Tang employed a desymmetrization strategy for the formation of the 2,5-*cis*-substituted THF ring [45]. *C2*-symmetric diol **51** is desymmetrized by a palladium-catalyzed cascade reaction to form lactone **52** in 87% yield (Scheme 6). The total synthesis comprised just 12 steps from commercial acetylacetone. In 2015, Ramana et al. published a different formal total synthesis of **(***−***)-46** based on a chiral pool approach [46].

**Scheme 6.** Synthesis of the tetrahydrofuranyl ring of **(***−***)-46** through desymmetrization by Tang.

(+)-*Trans*-Kumausyne (**53**) (Figure 12) is a halogenated non-isoprenoid sesquiterpene isolated in 1983 from red alga *Laurencia nipponica* Yamada [47]. Its first total synthesis was achieved in 1991 by Overman and coworkers [48]. A review covering the synthetic approaches towards kumausallene and kumausyne, and other natural products containing a 2,3,5-trisubstituted tetrahydrofuran moiety, was published by Fernandes in 2020 [18].

**Figure 12.** Structure of (+)-*trans*-Kumausyne (**53**).
