What does Andy Liepa, a chief research chemist with Australia's CSIRO (Commonwealth Scientific and Industrial Research Organisation) have in common with the legendary Emil Fischer, Nobelist E.J. Corey, fellow Australian Arthur Birch, and a few hundred other famous and not-so-famous chemists? All have achieved chemical immortality by having chemical reactions named after them. The honor is especially sweet for Liepa, who joins a very select group of Australian organic chemists achieving this accolade.
Liepa's process, now officially called the "Liepa phenanthrene synthesis," facilitates production of both natural and manmade three-ring fused aromatics, from which a host of important chemicalsdyes and drugs among themare synthesized. Liepa developed the synthesis as a postdoctoral fellow in the US during the early ‘70s. He went on to further demonstrate its use after moving back to Australia, and later at CSIRO's Molecular Science division.
According to Liepa, the process involves a breakthrough in controlling formation of aromatic rings, the most basic of which is benzene. Much of modern organic chemistry focuses on aromatic addition, substitution, and cyclization. Liepas' technique removes one electron (an oxidation) from benzene, creating a highly reactive phenyl free radical that reacts vigorously but selectively with other species. The synthesis is particularly valuable in simplifying alkaloid synthesis. Found in plants, many alkaloids are biologically active; quite a few form the basis of treatments for such indications as cancer, gout, analgesia, high blood pressure, and malaria.
"As a result of synthetic work I was doing with benzylisoquinoline alkaloids, I came to the conclusion that it might be possible to achieve a direct, non-phenolic, aryl-to-aryl coupling between aromatic rings, as long as they were sufficiently activated by electron-donating groups such as alkoxy, alkyl, or (substituted) amino," Liepa told DrugDiscovery Online. "If this were indeed possible, it would simplify and facilitate the synthesis of a considerable number of target compounds. I was fortunate to discover a set of conditions which did, in fact, enable this type of transformation."
Liepa's key reagent is vanadium trifluoride oxide in trifluoroacetic acid. In its first practical application, it was used to convert of ± laudanosine into ± glaucine. Later, Liepa used his method to cyclize stilbenes to phenanthrenesthe heart of the Liepa phenanthrene reaction for forming the backbone of the phenanthroindolizine alkaloid tylphorine.
The reaction proceeds through removal of an electron from the aromatic sextet of an electron-rich aromatic ring to generate a radical cation species, at the same time reducing vanadium (V) to vanadium (IV). The highly active radical cation can do several tricks, among them dimerizing to form an aryl-aryl bond.
The Liepa phenanthrenes method is mainly a research tool. Like many name reactions, however, it has occasionally struck gold, for example in the production of Vancomycin, an antibiotic of last resort for antibiotic-resistant Staphylococcus aureus.
Pharmaceutical chemists often dream of having a reaction named after them: The DePalma "It Cures Everything, Take It!" Synthesis, for example, has a certain ring to it. According to Liepa, "After the first feeling of surprise subsided, I better appreciated just how rarely chemists are granted either the opportunity or the good fortune to have their names linked with a piece of chemical research. Now, I just feel grateful to have been so fortunate."
For more information: Andy Liepa, CSIRO Molecular Science Division, Bayview Avenue, Clayton South, Bag 10, Victoria 3169, Australia. Tel: +61 3-9545-2576. Fax: +61 3-9545-2446 Email: firstname.lastname@example.org.
By Angelo DePalma