2.1.6. Iriomoteolides

Iriomoteolides are a recent class of macrolides isolated from a marine benthic dinoflagellate of the *Amphidinium* species [64]. Among all members of this family, iriomoteolide-2a (**94**) [65], 10a (**95**) [66], and 13a (**96**) [67] present at least a substituted tetrahydrofuran ring (Figure 14). They stand up for their potent biological activity against human cervix adenocarcinoma HeLa cells (IC50 = 0.03 μg/mL, 1.5 μM and 0.5 μg/mL, respectively) and other cell lines, human B lymphocyte DG-75 (IC50 [2a] = 6 ng/mL and IC50 [10a] = 1.2 μM), and murine hepatocellular carcinoma MH134 cells (IC50 [10a] = 3.3 μM).

**Figure 14.** Structure of THF-containing iriomoteolides.

Despite their biological interest, there is no total synthesis reported for the 21-membered macrolide **95**, nor the 22-membered macrolide **96**, probably due to their complexity. On the contrary, the synthesis of **94** was accomplished by Fuwa and co-workers recently and it led to a structural revision [68,69].

Iriomoteolide-2a was the first 23-membered macrolide isolated from nature. Its structure contains two contiguous tetrahydrofuran rings embedded in the macrolide skeleton

and a side chain containing three chiral centers. Two key steps made up the synthetic approach devised by Fuwa [68], a Suzuki-Miyaura coupling reaction between a vinyl iodide **97** and an olefin **98**, and a ring closing metathesis with **99** to build the macrolactone (Scheme 17).

**Scheme 17.** Retrosynthesis of iriomoteolide-2a.

A convergen<sup>t</sup> strategy allowed the synthesis of the different possible stereoisomers of iriomoteolide-2a. Having discarded the original proposed configuration, the construction of the correct bis-THF fragment was achieved by two sequential cycloetherifications. Thus, Sharpless asymmetric epoxidation of **100** provided diepoxide **101**, which in situ underwent epoxide opening cascade with formation of the desired bis-THF **102**. The relative configuration of this bis-tetrahydrofuran was established by ROE experiments (Scheme 18).

**Scheme 18.** Synthesis of contiguous THF in iriomoteolide-2a.

In this synthesis macrocyclization was performed at a very late stage. Thus, ring closing methathesis of precursor **103**, with a second-generation Grubbs catalyst (G-II), led to macrocycle **104**, which after final deprotection step afforded the desired iriomoteolide-2a (Scheme 19).

Thanks to this total synthesis it was possible to establish the absolute configuration of iriomoteolide-2a and to re-study the biological activity of synthetic compounds [69]. By comparing the spectral data, the correct stereochemistry of the natural compound could be assigned, which differed from the first proposed assignment [65]. Surprisingly, in contrast to the potent cytotoxic activity reported for the natural product, the synthetic iriomoteolide-2a only showed marginal antiproliferative activity in HeLa cells (IC50 = 60 μM). A plausible explanation for the high cytotoxicity measured in natural iriomoteolide-2a is the presence of traces of a highly potent contaminant in the sample.

**Scheme 19.** Engame to iriomoteolide-2a by Fuwa.
