2.1.8. Mangromicins

Mangromicin A (**118**) and B (**119**) (Figure 16) were the first members of this family isolated from actinomycete *Lechevalieria aerocolonigenes* [80], followed by six new analogues, mangromicins D-I [81]. The mangromicins contain a cyclopentadecaene skeleton with a 5,6-dihydro-4-hidroxy-2-pyrone moiety and a tetrahydrofuran unit. All mangromicins show important biological activities. Special effects have been found in Mangromicin A, which exhibits potent antitrypanosomal activity against Trypanosoma brucei brucei GUTat 3.1 strain (IC50 = 2.4 in vitro essays) and cytotoxicity against MRC-5 cells.

**Figure 16.** Structure of mangromicins.

The first and unique enantioselective total synthesis of mangromicin A was reported by Takahashi and coworkers [82]. Deprotection of the OTBS group in compound **126** led to hydroxyketone **127**, in equilibrium with its hemiketal. Then, a Mukaiyama-type vinylogous alkylation was used as key step to synthesize the desired tetrahydrofuran moiety (-)-**128**, bearing a C-2 quaternary carbon with the desired configuration. A further 21 steps, including a crucial Dieckmann cyclization to generate the 4-hydroxydihydropyrone unit, were needed to complete the total synthesis of mangromicin A (Scheme 22) [82].

## 2.1.9. Nonalides: Cytospolides

Cytospolides (Figure 17), which belong to a nonalide family, are a group of compounds which were isolated in Gomera island (Spain) from an endophytic fungus, *Cytospora* sp., by Zhang and co-workers in 2011 [83]. The different structures and absolute configurations of cytospolides were first elucidated and established by spectroscopic analysis, chemical derivatization, and X-ray diffraction [83]. Almost all members of this family contain a 10-membered lactone. Additionally, cytospolides M (**129**), cytospolide N (**130**), and cytospolide O (**131**) are tetrahydrofuran-containing nonalides. Cytospolide Q (**132**) is the exception, containing a 15-carbon skeleton with two different rings, a tetrahydrofuran and a γ-butyrolactone.

**Figure17.**Structure ofcytospolides.

Stark et al. have reported the total synthesis of cytospolide D and its conversion into cytospolides M, O, and Q (Scheme 23) [84]. Cytospolide M was obtained in a single step with a 86% yield from cytospolide D, by diastereoselective epoxidation. Subsequent opening of cytospolide M with potassium trimethylsilanolate, followed by spontaneous recyclization during the workup, allowed the preparation of the desired cytospolide Q. On the other hand, cytospolide O was obtained through an oxa-Michael addition from a close precursor of cytospolide D in three steps.

**Scheme 23.** Synthesis of cytospolides.

In a different approach, a convergen<sup>t</sup> route for the total synthesis of cytospolide Q has been proposed in 10 linear steps, with an overall yield of 2.8%, from known intermediate

135 [85]. A set of cascade reactions are the key to build the tetrahydrofuran ring and the γ-butyrolactone moiety (Scheme 24).

**Scheme 24.** Retrosynthesis of cytospolide Q.

Nine linear steps from **136** were needed to prepare the required precursor (**137**). A set of convenient cascade reactions, such as acid-catalyzed acetal deprotection, subsequent tetrahydropyranyl formation by epoxide opening with the appropriate hydroxyl group and final γ-lactonization allowed the formation of cytospolide Q in a single step from **137** (Scheme 25).

**Scheme 25.** Total synthesis of cytospolide Q.

The moderate cytotoxic activity against tumor cell lines of some members of the cytospolide family [83] has prompted researchers to synthesize structurally diverse derivatives which may have improved properties [85]. Thus, Stark and Erlich [86] envisioned the synthesis of cytospolide analogues **138** and **139** from a modified cytospolide D intermediate **140** in which an alkynyl side chain was used as a versatile handle for further functionalization (Scheme 26).

**Scheme 26.** Synthesis of cytospolide analogues.
