2.1.4. Formosalides

Formosalides A and B (Figure 11) are 17-membered macrolides isolated from marine dinoflagellate *Prorocentrum* sp. [50]. Their structures and relative stereochemistries were determined by spectroscopic techniques. Cytotoxicty of the formosalides was significantly lower than amphidinolide N or caribenolide I, despite their structural similarity. Formosalides A and B showed in vitro moderate cytotoxic activity against CCRF-CEM human T-cell acute lymphoblastic leukemia cells (LD50 [A] = 0.54 μg/mL and LD50 [B] = 0.43 μg/mL) and DLD-1 human colon adenocarcinoma cells (LD50 [A] > 40 μg/mL and LD50 [B] = 2.73 μg/mL) [50]. The structure and absolute configuration were confirmed by Fürstner and co-workers recently by total synthesis of different stereoisomers [51].

**Figure 11.** Structure of formosalides A and B.

As said, Fürstner's group has accomplished the synthesis of both macrolides and two other isomers [51]. The required *trans*-disubstituted tetrahydrofuran ring **68** was prepared by stereoselective cobalt-catalyzed oxidative cyclization of bishomoallylic alcohol **69**, with excellent yield and selectivity (Scheme 12).

**Scheme 12.** Synthesis of THF in formosalides.

Following, the coupling of THF-carbaldehyde **68** with fragment **70** by an Evans– Tishchenko reaction led to intermediate **71**, which was subjected to ring closing alkyne metathesis to yield macrocycle **72** with good yield. The final installation of the side chain, achieved by Stille-Migita coupling of vinyliodide **73** with the appropriate vinylstannane derivative, and deprotection of the TBS group led to both formosalides due to unexpected partial hydrolysis of the ketal (Scheme 13).

**Scheme 13.** Synthesis of formosalides by Fürstner.

Mohapatra and co-workers have also reported a stereoselective synthesis of the C1- C16 fragment of formosalide B [52]. A one-pot Sharpless asymmetric dihydroxylation of <sup>α</sup>,β-unsaturated ester **74**, followed by intramolecular S*N*2 displacement, produced the desired *trans*-tetrahydrofuran **75** with a high 88% yield and total stereoselectivity (Scheme 14).

**Scheme 14.** Synthesis of THF-containing fragment in formosalides by Mohapatra and co-workers.
