3.3.2. Uprolides

Cembranolides are a family of compounds related to cembrene, which is a 14-membered macrocyclic diterpene with multiple (*E*)-double bonds. Among them, uprolides are a subfamily of compounds named after the University of Puerto Rico. Uprolides A–G were

isolated in 1995 by Rodríguez and coworkers from the Caribbean gorgonian *Eunicea Mammosa* and their structure was assigned by spectroscopic methods and chemical interconversion [52,53]. They are the first natural cembranolides from a Caribbean gorgonian that bear a double bond at C6 or C8. While uprolides A–C show an epoxy moiety, uprolides D–G seemed to contain a tetrahydrofuran moiety instead. Uprolides D (**58**), D acetate (**59**), D diacetate (**60**), and E acetate (**61**) (Figure 14) present a moderate cytotoxicity against HeLa cells ((IC50 = 2.5 to 5.1 μg/ ml). Moreover, **59** shows cytotoxicity against the following human tumor cell lines: CCRF-CEM T-cell leukemia (IC50 = 7.0 μg/mL), HCT-116 colon cancer (IC50 = 7.0 μg/mL), and MCF-7 breast adenocarcinoma (IC50 = 0.6 μg/mL).

**Figure 14.** Structure of tetrahydrofuran-containing members of the uprolide family.

Later structural revisions determined the presence of a tetrahydropyran ring, instead of the previously proposed tetrahydrofuran, in uprolides F diacetate and G acetate, hypotheses that were confirmed by asymmetric total synthesis of these natural products [54–57].

In 2007, a synthetic approach to obtain the macrocyclic core of **58** was proposed by Ramana [58]. The formation of the macrocyclic core is produced by ring-closing metathesis (RCAM) using a Grubbs' first-generation catalyst. The RCAM of acetate **62** produces 13-membered macrocyclic **63** in 67% yield (Scheme 8). The macrocyclic core of uprolide E could not be synthesized using the same methodology.

**Scheme 8.** Synthesis of macrocyclic core of uprolide D by Ramana.

Marshall developed a synthetic route for C1/C14 *bis*-epimer of **58** in which the macrocyclization is produced by an intramolecuar Barbier reaction [59]. Some years later, other members of the uprolide family, which lack the tetrahydrofuran ring, have been isolated from the gorgonian octocoral *Eunicea succinea* [60].
