Amphidinolides T

Amphidinolides T (**28**–**32**), 19-membered lactones containing a trisubstituted tetrahydrofuran ring and seven or eight stereocenters (Figure 7), were first isolated by Kobayashi [35–37]. They showed cytotoxic activity against murine leukemia L1210 cells in vitro with an IC50 value of 18 μg/mL.

**Figure 7.** Structure of amphidinolides T.

In 2013, Clark reported a total synthesis of T1, T2, and T4 from a common intermediate **33** (Scheme 6) [38]. Synthesis of the tetrahydrofuran-containing fragment 35 started

from the allyl ether **36** of a commercially available alcohol, which was transformed into the α-diazo ketone **37** by sequential saponification, formation of the corresponding mixed anhydride derivative and reaction with diazomethane. Treatment of **37** with a catalytic amount of (Cu(acac)2) stereoselectively afforded the *trans* dihydrofuranone **38** in high yield. Six further steps led to the desired THF-containing fragment (Scheme 7). The total syntheses of amphidinolide T1, T3, and T4 were completed in 17 steps from a common precursor with 6.9%, 5.9%, and 5.5% overall yield, respectively.

**Scheme 6.** Retrosynthesis of amphidinolides T from a common intermediate.

**Scheme 7.** Synthesis of THF fragment of amphidinolides T.

2.1.2. Haterumalides and Biselides

Haterumalides (**39**–**44**) (Figure 8) were isolated at the end of the 20th century from the Okinawan ascidian *Lissoclinum* sp. (haterumalide B) [39] and the Okinawan sponge *Iricinia* sp. (haterumalides NA-NE) [40]. Their cytotoxic activity against different targets made them secondary metabolites of grea<sup>t</sup> interest. However, no approaches towards their synthesis have been described in recent years [10,11].

**Figure 8.** Structure of haterumalides.

Biselides (**45**–**49**) (Figure 9), C-20 oxygenated analogues of haterumalides, are a family of polyketides which were isolated from the Okinawan ascidian *Didemnidae* sp. [41]. Their structure was determined by spectroscopic analysis and their biological activity was tested against tumor cell lines, due to their similarity to haterumalides. Cytotoxic activity of biselides A and C against various human cancer cells are comparable to cisplatin, the known anticancer drug. Notably, and unlike their haterumalide congeners, biselides A and C did not show toxicity against brine shrimp even at 50 μg mL−1, which makes them potential anticancer drug candidates.

**Figure 9.** Structure of biselides.

In the last years, two total syntheses of biselide A have been published [42,43]. Kigoshi developed synthetic approaches towards both the core carbon fragment [44] and the macrolactone moiety [45]. Relying on these methodologies, Kigoshi and Hayakawa finally accomplished the total synthesis of biselide A [42]. The key step for the construction of the 3-hydroxy tetrahydrofuran unit was accomplished by intramolecular oxy-Michael cyclization of intermediate **50**, which was obtained in four steps from D-mannose. Further 27 steps were required to obtain natural biselide A (Scheme 8).

**Scheme 8.** Synthesis of biselide A by Kigoshi, Hayakawa, and co-workers.

Likewise, Kigoshi has also described the total synthesis of biselide E, from common advanced intermediate **52** [46].

On the other hand, Britton and coworkers have proposed a concise synthesis of biselide A in 20 linear steps from L-serine [43]. In this case the stereoselective formation of the tetrahydrofuran moiety **55** was done by microwave cyclization of chlorodiol intermediate **54** (Scheme 9).

**Scheme 9.** Synthesis of THF moiety of biselide A in Britton's total synthesis.

The key to building the macrocyclic ring was the use of an intramolecular Reformatsky cyclization from intermediate **56**, which led to a 3.5:1 ratio of epimers of the desired macrolactone. A sequence of oxidation/reduction was used to convert **57** in the desired epimer **58**. Further five steps, including deprotection and installation of the side chain, provided biselide A with ca. 2% overall yield in 20 steps from L-serine (Scheme 10).

**Scheme 10.** Reformatsky macrocyclization to biselide A by Britton and coworkers.
