Amphidinolide E

Amphidinolide E (**10**) presents a 19-membered macrolactone ring, bearing a tetrahydrofuran moiety and eight stereocenters (Figure 3).

**Figure 3.** Structure of amphidinolide E.

Total syntheses of **10** have already been developed by Lee [20,21] and Roush [22–24]. Recently, Vilarrasa and Costa presented a different approach to its total synthesis. Though no significant improvement was made in terms of yield or number of steps, this work provides interesting insights into Julia-Kocienski olefinations [25]. Thus, epoxidation of alcohol **11** directly afforded tetrahydrofuran **12**, through a tandem epoxidation-cyclization reaction. Subsequent Swern oxidation, followed by Julia-Kocienski reaction with sulfone **13**, provided the northern C10–C21 fragment of amphidinolide E (Scheme 2).

**Scheme 2.** Synthesis of C10-C21 fragment of amphidinolide E.

Amphidinolide K

Amphidinolide K (**15**) (Figure 4) has also a 19-membered macrolactone, but with a simpler side chain. Regarding its biological properties, amphidinolide K has shown a strong stabilizing effect on actin filaments (F-actin).

**Figure 4.** Structure of amphidinolide K.

Vilarrasa proposed a total synthesis of **15** relying on a Hosomi-Sakurai reaction as a key step [26]. The tetrahydrofuran ring **17** was formed by cyclization of alcohol **16**, followed by elimination of the pyridylselenenyl group with Dess-Martin oxidation. Further deprotection of the O-PMB group and extension of the chain, through Swern oxidation and Wittig reaction, led to the C9–C22 fragment **18** (Scheme 3). Subsequent Hosomi-Sakurai reaction with allylsilane **19**, using Yamamoto's chiral (acyloxy)borane (CAB), provided **20** with a good yield.

## Amphidinolide N/caribenolide I

Amphidinolide N (**21**) is a 25-membered macrolide which contains a 2,5-*trans*-disubstituted tetrahydrofuran, an allylic epoxide, and 13 stereocenters (Figure 5). Amphidinolide N is the most potent cytotoxic member of this family against murine lymphoma L1210 (IC50 = 0.05 ng/mL) and human epidermoid carcinoma KB cell lines (IC50 = 0.06 ng/mL). However, despite the efforts of different researchers, no total synthesis of this compound has been reported so far. There are different approaches focused on the synthesis of the fragment which contains the tetrahydrofuran ring [27–30], a total synthesis of 7,10-epimer [31,32], and a recently described enantioselective synthesis of des-epoxy-amphidinolide N, which failed in the last epoxidation step towards amphidinolide N [33].

**Scheme 3.** Synthesis of C9–C22 fragment of amphidinolide K.

**Figure 5.** Structure of amphidinolide N.

Both Sasaki's [27] and Kuwahara's [29] strategies to build the tetrahydrofuran moiety consisted of an intramolecular cyclization of a diol mesylate obtained by Sharpless asymmetric dihydroxylation (SAD) of mesyl protected alkenol **22** using AD-mix-β. Subsequent cyclization, mediated by base, afforded the desired 2,5-*trans-*disubstituted tetrahydrofuran **23** (Scheme 4).

**Scheme 4.** Synthesis of THF of amphidinolide N by Sasaki and Kuwahara.

Recently, Fuwa proposed the application of cobalt-catalyzed Hartung-Mukaiyama cyclization of γ-hydroxy olefins to obtain the tetrahydrofuran fragment [30]. Mukaiyama cyclization is known to afford 2,5-*trans* substituted tetrahydrofurans with a 2-hydroxy substituent. Hartung's modification allows the access to 2-alkyl-substituted tetrahydrofurans, ideal for the synthesis of tetrahydrofuran-containing fragment **25** of amphidinolide N from

alkenol **24** (Scheme 5). It is remarkable that unprotected hydroxy groups and somewhat bulky substituents are well-tolerated.

**Scheme 5.** Synthesis of THF fragment of amphidinolide N by Fuwa.

With close structural similarity, other macrolides have been discovered recently, namely isocaribenolide-I (**26**) and chlorohydrin (**27**) [34]. They were isolated from a free-swimming dinoflagellate Amphidinium species (KCA09053 and KCA09056 strains), together with amphidinolide N. Both have a 26-membered macrolide core, and present high cytotoxicity against human cervix adenocarcinoma HeLa cells (IC50 = 0.02 for isocaribenolide-I and 0.06 nM for chlorohydrin). Isocaribenolide-I presents a characteristic isobutyl side chain, and chlorohydrin is distinguished by a homonymous moiety (Figure 6).

**Figure 6.** Structure of isocaribenolide I and chlorohydrin.
