1. Formal synthesis of (+)-citreoviral 2. Synthetic studies on arenaric acid

Abstract

(+)- Citreoviral 2, a highly substituted tetrahydrofuran natural product, is a precursor to a potent anti- HIV agent (-)- Citreoviridin 1. Herein, a formal synthesis of 2 has been developed starting from chiral benzoate 59 obtained from desymmetrization of 2-methylglycerol. The skeleton and chiral centers of 2 were installed by Wittig olefination and modified Sharpless asymmetric dihydroxylation. The iodocyclization of the triol 70 rendered the tetrahydrofuran core 73 stereoselectively. The configuration of the resulting tetrahydrofuran was confirmed by nOe experiment. Deiodination of 73 and further lactonization followed by Wittig olefination gave the conjugated ester 78 which is known as an advanced intermediate to (+)-citreoviral. The key features in our synthetic approach are the desymmetrization of the 2-methylglycerol and the efficiently diastereoselective formation of the tetrahydrofuran moiety. Arenaric acid 80, a metabolite of an actinomycete strain, was isolated from the Streptomycessp since 1999. Its family, for example K41-A 82 and oxolonomycin 81, possesses antibacterial and potent antimalarial activity. The polycyclic back-bond of these compounds which confers the lipophilic character and a terminal carboxyl group plays an important role in the formation of an oxygen-rich internal cavity which is capable of binding to metal ions. The Arenaric Acid 80 was disconnected at C11-C12 bond to give two fragments 84 and 85, each of them contains one tertiary chiral center which was installed by our desymmetrization method at the starting point. In the synthesis of the eastern part 85, several strategies have been studied. The first attempts were to construct the cis-THF ring prior to the trans-THF ring. The trials via iodocyclization failed to give the desired cis- stereoisomer with different substrates (87, 145, 150, 153, 154) and various reaction conditions. In the next attempts, the formation of cis-THF was efficiently accomplished by using oxidative ...