2.1.7. Mandelalides

Mandelalides A-D (**105**-**108**) (Figure 15) are a group of marine macrolides isolated in 2012 from a species of *lissoclinum* ascidian [70]. Their macrocyclic core has two cyclic moieties embedded, a glycosylated 2,6-*cis*-substituted tetrahydropyran and a 2,5-*cis*-substituted tetrahydrofuran. Within them, the natural isolated compounds **105** and **106** yielded nanomolar IC50 values against mouse Neuro2A neuroblastoma cells and human NCI-H460 lung cancer cell lines. Their complex structure was elucidated by 1D and 2D NMR experiments and mass spectrometry, although the stereochemistry of Mandelalide A was definitively established after its total synthesis by Xu and Ye [71].

**Figure 15.** Structure of mandelalides.

Years later, new members of this family were isolated, namely mandelalide E-L [72,73]. This has permitted the study of structure-activity relationship, showing that glycosylation is essential for their biological activity.

Since the discovery of mandelalide A, different researchers have proposed approaches for its total synthesis [12]. The main difference between them lies in the key reaction steps. Tao Ye and co-workers reported the use of Rychnovsky–Bartlett cyclization for the preparation of the tetrahydrofuran moiety and an Horner–Wadsworth–Emmons for the macrocyclization [71]. Amos B. Smith developed an anion relay chemistry (ARC)

strategy [74] to synthesize the tetrahydrofuran and tetrahydropyran structural motifs which were joined by Yamaguchi esterification [75]. Intramolecular Heck cyclization [76], Sharpless asymmetric dihydroxylation [77] or Julia olefination [78] were also employed in other total syntheses.

As an example, we want to highlight the convergen<sup>t</sup> total synthesis reported by Altmann [79]. In this synthesis, the highly oxygenated tetrahydrofuran **109** was constructed from compound **110** by acetal cleavage/epoxide opening cascade reaction. Then, substitution of the primary OH with iodine (**111**) and subsequent radical alkynylation with sulfone **112** afforded **113**. After further elaboration, the tetrahydrofuran fragment **114** was accessed (Scheme 20).

**Scheme 20.** Synthesis of the trisubstituted THF in mandelalides.

With the needed building blocks in hand, tetrahydropyran **115** and tetrahydrofuran **114** moieties were united via Sonogashira coupling to afford enyne **116**. Then, Shiina macrolactonization was used to access macrolactone **117**, which was transformed to the desired natural product in four additional steps and a 2.15% overall yield (Scheme 21).

**Scheme 21.** Macrocyclization and final steps for the synthesis of mandelalide A.

Biological studies of synthetic mandelalide A revealed a potent inhibitory activity of the proliferation of H460 and A549 lung carcinoma cells, but not cytotoxic activity at least within the concentration range studied [70,79]. In general, mandelalides have shown to have highly cell-type dependent bioactive effects.
