4.1.5. (+)-Varitriol

(+)-Varitriol (**(+)-123)** (Figure 31) was isolated in 2002 from a marine-derived strain of the fungus *Emericella variecolor* [104]. Its structure and relative stereochemistry were determined by NMR studies. It displays low cytotoxic activity against leukemia, ovarian, and colon cells, but its response to renal, CNS, and breast cancer cell lines was very promising (of the range of GI50 = 1.63–2.44·10−<sup>7</sup> M). In 2006, Jennings and coworkers achieved the first total synthesis of its enantiomer **(-)-123** and, thus, determined its absolute stereochemistry [105].

**Figure 31.** Structure of (+)-varitriol (**(+)-123**) and (−)-varitriol (**(***−***)-123**).

Its activity towards the mentioned cancer cell lines attracted the attention of synthetic chemists; different synthetic approaches for **(+)-123** appeared in the next few years [106]. Taylor employed a known tetrahydrofuran-2,3,4-triol derivative as the starting material for the synthesis (in three further steps) of the desired **(***−***)-123** and its 3--epi-derivative [107]. Srihari also achieved the synthesis of **(***−***)-123**, **(+)-123**, and its 6--epi-derivative starting from commercial D-(−)-ribose [108,109]. Krause performed a modular synthesis of **(+)-123** in 10 steps, with an overall yield of 6,4% [110]. The key tetrahydrofuran with the appropriate four stereocenters **124** was prepared in four linear steps from a known enyne. Thus, Sharpless epoxidation and benzylation of (*E*)-hex-2-en-4-yn-1-ol provided propargyl epoxide **125** in 47% yield over two steps. A copper hydride-catalyzed reduction of **125**, followed by a gold-catalyzed cycloisomerization, furnished the key dihydrofuranyl intermediate **126**, with two of the required stereogenic centers. Final Sharpless dihydroxylation of **126** afforded **124** as a satisfactory 78:22 mixture of diastereoisomers. The desired natural product was obtained in a further four steps (Scheme 14).

**Scheme 14.** Modular synthesis of (+)-varitriol (**(+)-123**) by Krause.

A recent example of the total synthesis of **(+)-123** was reported by Cordero-Vargas [111]. In this approach, the tetrahydrofuranyl key intermediate **127**, bearing the four precise sterocenters, was obtained from commercial L-ribono-1,4-lactone in six steps. The key step in this process is the stereocontrolled nucleophilic addition to five-membered oxocarbenium ions directed by the protecting groups. Thus, TBS-protected lactone **128**, obtained in four conventional steps from L-ribono-1,4-lactone, undergoes acetylide addition; a subsequent Lewis acid promoted oxocarbenium ion formation. The following stereoselective hydride attack provides tetrahydrofuran **127** as a single diastereomer in 60% yield. The final synthesis of **(+)-123** is achieved in a further four steps with 31% yield over them (Scheme 15).

**Scheme 15.** Protecting group-directed nucleophilic addition for the synthesis of (+)-varitriol (**123**).

Later on, Qin developed a direct cross-coupling between terminal alkynes and glycosyl acetates, which was applied to the formal synthesis of **(+)-123** and analogues [112]. More recently, Wang and coworkers reported another formal synthesis of **(+)-123** [113]. They developed a chromium-catalyzed enantioconvergent allenylation of aldehydes to synthesize α-allenols from racemic propargyl halides. Starting from silylated propargyl bromide **129** and benzyloxyacetaldehyde, allenol **130** can be accessed through the developed procedure. The chromium catalyst was formed in situ by the addition of chromium chloride and the oxazoline ligand **(***R***,***S***)-131**. Manganese acted as a reducing agent, and Cp2ZrCl2 as a

dissociation reagent. Then, removal of the silyl group with tetrabutylammonium fluoride gave advanced intermediate **132** in 82% yield, thus accomplishing the formal synthesis of the desired **(+)-123** (Scheme 16).

**Scheme 16.** Application of allenylation of aldehydes to the formal synthesis of (+)-varitriol by Wang.
