A short total synthesis of parvaquone

Parvaquone 1 , a hydroxylated naphthoquinone with antiviral properties, was prepared in 26% overall yield in a straightforward manner starting from diisopropylsquarate 3 . The key features of the synthesis include addition of commercial cyclohexylmagnesium chloride to 3 , followed by acid-catalyzed rearrangement to furnish the cyclohexyl-substituted isopropylsquarate 2 . Further addition of phenyllithium to 2 , thermal cyclization and deprotection with BBr 3 gave 1 .


Introduction
Hydroxylated quinones often possess interesting biological activity and there is an increasing interest to develop new and efficient ways to prepare them. 1 Examples of biologically active hydroxy-substituted quinones range from those of relatively simple structure, i.e.Echinochrome A, 2 to examples of high complexity, i.e. conocurvone. 3arvaquone 1, is another example of a hydroxyquinone that displays interesting biological properties.It has been used against theileria parva, a microscopic parasite that causes East Coast Fever (theileriosis). 4East Coast fever (ECF), a form of bovine theileriosis, is a ticktransmitted protozoal disease of cattle characterized by high fever and lymphadenopathy.The disease causes high mortalities in breeds nonindigenous to the endemic areas, and is confined to eastern, central, and parts of southern Africa.We wish to report the total synthesis of 1, based on the chemistry of squaric acid esters developed by Liebeskind, Moore and others. 5

Results and Discussion
Despite the fact that Kerr et al. 4 have reported an efficient chromium carbene-based synthesis of parvaquone, it was considered that a chromium-free alternative was worth pursuing.Thus, the preparation of 1 was envisioned as illustrated in Figure 1.The synthesis was begun with the addition of commercially available cyclohexylmagnesium chloride to diisopropylsquarate 3 6 at -78 °C in THF.Quenching the reaction mixture at low temperature to give the corresponding 1,2-adduct followed by acid-catalyzed rearrangement, produced the cyclohexyl-substituted dione 2 in 68% overall yield (eq. 1).
The efficiency of the previous reaction was improved when the protocol introduced by Moore was used, i. e., low temperature trifluoroacetic anhydride (TFAA) quench of the 1,2adduct gave 2 in 93% yield (eq. 2). 8 Nucleophilic addition of phenyllithium to the more electrophilic carbonyl group of 2, followed by aqueous quench furnished alcohol 4 in modest yield (eq.3).Finally, parvaquone 1 was synthesized by treating 6 with an excess of BBr 3 to yield a yellow crystalline solid with identical spectral properties as those reported previously (eq.4). 4 (Z) In conclusion, a straightforward synthesis of parvaquone was developed with a 26% overall yield.Most of the steps in the synthetic sequence are efficient and the starting materials are either commercially available or readily prepared.Moreover, this method offers the possibility for the preparation of a host of parvaquone analogues by the addition of aryllithium derivatives with different substitution patterns.
Analytical thin-layer chromatography was performed on Merck silica gel plates with F-254 indicator.Acid-pretreated silica gel plates were used to monitor the final deprotection of 2. Visualization was accomplished by UV-light, iodine, or p-anisaldehyde solution.Medium pressure liquid chromatography (MPLC) was performed as described by Baeckström et al. 9 using gradient solutions with the indicated solvent systems.THF was dried over sodium and stored over activated 4Å molecular sieves.All reactions were performed under a dry N 2 atmosphere in oven-and or flame-dried glassware.

Commercial chemicals.
The following materials were obtained from commercial sources: C 6 H 11 MgCl, PhLi, TFAA, and BBr 3 .