- Keteneylidenetriphenylphosphorane as a Versatile C-2 Building Block Leading to Tetronic Acids with Potential Herbicidal and anti-HIV Activity (2004)
- The cumulated ylide keteneylidenetriphenylphosphorane (Ph3PCCO) has shown great potential in the construction of heterocyclic compounds. The formation of heterocycles arises from the unique dipolar electronic structure of the cumulated ylide, which combines ylide and ketene properties. Upon reaction of alcohols, amines and thiols with keteneylidenetriphenylphosphorane the intermediate ketene cation gets intercepted by the more strongly nucleophilic counter anion (alkoxide, amide, thiolate) yielding monomer “acyl” ylides. Since acyl ylides enter into Wittig alkenation reactions far more quickly than the starting ylide, multi-component or domino reactions between the latter and a carbonyl compound becomes possible leading to beta,gamma-unsaturated carbonyl derivatives. A further strength of keteneylidenetriphenylphosphorane is its low toxicity, easy accessibility, simple handling and its ability to enter into extended domino reactions, thus this molecule is extremely useful in modern synthetic applications. Our group has recently extended this procedure to the formation of tetronates from keteneylidenetriphenylphosphorane and alpha-hydroxycarboxylic esters. In cases were the ester contains an beta,gamma-unsaturated alkene the corresponding tetronates can be easily converted to either tetronic acids or 3-dispirodihydrofurandiones by careful control of the reaction conditions. Tetronic acids are an important class of heterocycles which exhibit a large array of biological properties. In recent years tetronic acids derivatives have been found to be important HIV-1 protease inhibitors. This work is concerned with using keteneylidenetriphenylphosphorane as a new route to highly functionalised HIV-protease inhibitors. New synthetic techniques such as microwave irradiation is investigated as a means to accelerate Claisen rearrangement reactions. The mechanistic pathway of Claisen/abnormal Claisen rearrangements is investigated in detail. Further examples of 3-dispirodihydrofurandiones are provided with a more in-depth study of the reaction mechanism. The nucleophilic ring opening of these 3-dispirodihydrofurandiones to give 3-substituted tetronic acids is also investigated. These tetronic acids have been found to have potential as lead compounds in the herbicidal industry.