Obtusallenes

Obtusallenes are C15-halogenated acetogenins that contain a 12-membered ether ring. Obtusallene I was isolated in 1982 from red algae *Laurencia obtusa* and its structure was elucidated by NMR and X-ray crystallographic methods. Since, other obtusallenes have been described: obtusallene II (**157**) and III (**158**) [107], obtusallene IV (**159**) [108], obtusallenes V-VII (**160**-**162**), and obtusallenes VIII-IX [109]. The structure of **160**-**162** was corrected in 2008 by Braddock due to unambiguously solved X-ray crystallography and

biosynthetic studies [110,111]. Among the obtusallenes, compounds **157**-**162** contain a tetrahydrofuran motif (Figure 24).

**Scheme 29.** Synthesis of bis-THF core of acetogenins.

**Figure 24.** Structures of tetrahydrofuran-containing obtusallenes II-VII.

The first synthesis of tetrahydrofuran rings of compounds **157** and **159** was reported in 2007 [112]. In this synthesis, diene **163** was transformed into tetrahydrofuran **164** with 18% yield and >95% purity in a one-pot reaction (with the sequential addition of *m*-CPBA, TMSCl and PPh3, TBAF, and then TBCO) (Scheme 30).

**Scheme 30.** One pot reaction for THF core of obtusallenes 157 and 159.

Parallelly, a synthesis of the C8–C15 fragment of obtusallene III **158** was described [113]. The Pd-catalyzed cyclization of triol **165** produced 2,5-disubstituted 3-hydroxytetrahydrofuran **166** with an 82% yield. The chemo- and diastereoselective cyclization implies the direct effect of a noncovalent interaction of the counterion carboxylate with the OH groups of the cationic π-allyl-Pd(II) intermediate (Scheme 31).

**Scheme 31.** Synthesis of C8-C15 fragment of obtusallene **158**.

Braddock reported the only known total synthesis of a member of this family to date: obtusallene X (**167**) [114]. The key step of this synthesis is the cyclization of clorhydrine intermediate **168** through a stereoselective bromoetherification process.

Five additional steps from **169** afforded acyclic diene **170**, which, under ring-closing metathesis with a second-generation Hoveyda−Grubbs precatalyst, produces macrocyclic **171**. Six additional steps were needed to obtain **167** with a 7% overall yield from **168** (Scheme 32).

**Scheme 32.** Synthesis of obtusallene X (**167**).
