2.1.5. Halichondrins

Halichondrins (**76**–**84**) (Figure 12) are a family of polyether macrolides isolated in the 20th century from a marine sponge, *Halichondria okadai* Kadota [53]. According to their structure, they are classified in A–C halichondrins, norhalichondrins, and homohalichondrins (Figure 12). All have been found in natural sources except halichondrin A. Their complex structure is composed of a polyether macrolide with several fused five- and six-membered oxacycles.

**Figure 12.** Structure of halichondrins, norhalichondrins and homohalichondrins.

Great efforts by Kishi's group have been devoted to the synthesis of this family of compounds. To finally reach the total synthesis, Kishi et al. first established the synthesis of different fragments of halichondrins such as: C1–C19, through key Ni/Cr-mediated coupling of polyhalogenated nucleophiles [54,55], C14–C38 fragment, by oxy-Michael cyclization [56,57], and those combined led to the C1–C37 right halves of halichondrins A-C [58]. In 2017, Kishi and co-workers accomplished a general and scalable total synthesis of halichondrins [59]. In this paper, a new Zr/Ni-mediated one-pot ketone synthesis gave the key to couple the right (**85**) and the left (**86**) halves of all types of halichondrins, including homo- and reluctant norhalichondrins (Scheme 15). Then, after fluoride deprotection of the silyl groups, ketone **87** was transformed to the spiroketal **88**. By coupling different halves, halichondrins, norhalichondrins and homohalichondrins were accessed. To exemplify

the success of this strategy, an overall yield of 14.3% was obtained for the synthesis of halichondrin B from commercial D-galactal.

**Scheme 15.** Key step in the total synthesis of halichondrins by Kishi.

Recently, Nicolaou and coworkers described a reverse approach for the total synthesis of halichondrin B [60]. The strategy consisted of first forming the C-O bonds and then the C-C bonds of the cyclic moieties, which is opposite of the usual methods that first form C-C bonds and then rely on C-O bond-forming cyclizations. As an example, we can see in Scheme 16 the formation of linear ethers **89a** and **89b** by Nicholas etherification of alcohols **90** and **91**. The required diastereoisomer **89b** was subjected to radical cyclization to close the THF ring in **92**. This methodology was applied throughout the total synthesis of halichondrin B, which was synthesized in just 25 linear steps from commercial materials.

**Scheme 16.** Reverse approach to halichondrin B by Nicolaou.

Biological studies demonstrated that the right half of this class of natural products showed potent in vitro and in vivo antitumor activity [61], which led to the approval of eribulin mesylate (Figure 13) by the FDA for the treatment of late-stage breast cancer. This compound is known under the commercial name of Halaven®. The mechanism and pharmacokinetics of eribulin and its use in numerous Phase I, II, and III clinical trials have been described in different reviews [62,63].

**Figure 13.** Structure of the anticancer drug eribulin.
