New Developments on CeCl3-Promoted Reactions in the Synthesis of Heterocycles

Synthetic chemistry is the science of constructing complex molecules from simpler ones, and one of the most important developments in this area of research is the total synthesis of biologically or pharmaceutically interesting molecules. In synthetic organic chemistry, the term total synthesis refers to the step-by-step design of the chemical synthesis of a molecule, usually a natural product, from relatively simple and hopefully cheap and commercially available starting materials. ''There is excitement, adventure, and challenge, and there can be great art in organic synthesis'' said Woodward in Perspectives in Organic Chemistry about total synthesis. While challenge and adventure are some of its exciting characteristics, organic synthesis is founded on the systematic study of a strategy and a tactic, and is achieved by a scrupulous retrosynthetic analysis. As a field, organic synthesis can be divided into two major areas: total synthesis and methods-oriented synthesis. The investigation, discovery, and development of new synthetic reactions, reagents, and catalysts are grouped under the second area, known as synthetic methodology. Total synthesis is almost always the synthesis of natural products because of the great importance of these compounds in biological, medicinal and pharmaceutical sciences. As Corey said: ''Nature continues to be exceedingly generous to the synthetic chemist in providing ample opportunity for discovery and creative endeavor of highest magnitude and in surrounding him with an incredible variety of fascinating and complicated structures''; nature is a continuous source of molecules with intricate structures and pharmaceutical properties for the research chemist to reproduce in the laboratory. Even if in the classical era of organic synthesis the purpose of a total synthesis was to confirm the molecular structure of a natural product, now other reasons for total synthesis have arisen. Amongst the most important are: a) the challenge, often irresistible to those who appreciate and practice the art, of synthesizing a naturally occurring substance of novel architecture; b) the opportunity to discover and develop new synthetic chemistry that will solve not only the problem under consideration, but also problems of broader interest; c) the ability to make contributions in biology by providing not only the natural substance but also by making available designed molecules that may mimic or inhibit the action of the natural product. Every year many natural products are isolated from plants, microorganisms, etc. and the challenge for organic chemists is to study new approaches to make them quickly and efficiently, while pharmaceutical and medicinal chemists are interested in exploiting their biological and pharmaceutical properties. The Marcantoni research group has been interested in both fields of organic synthesis: the total synthesis and the development of new synthetic methodologies. In the past years, the Marcantoni group has focused their interest not only on the total synthesis of small biologically active molecules, and of useful building blocks for the synthesis of antibiotics and natural products;4 but also on the development of new methodologies involving the use of the CeCl3⋅7H2O Lewis acid, especially in combination with NaI, as a promoter system in carbon-carbon and carbonheteroatom bond forming reactions. This thesis work is borderline between these two fields of interest, as illustrated by the different nature of the projects it is comprised of the study of a new approach to the total synthesis of (+)-furanomycin, and the total synthesis of Climacostol, constitute the total synthesis portion of this work, while the syntheses of polyhydroxyalkyl furans and of alkyl 9H- β-Carboline-4-carboxylate are part of a broader study on the use of the CeCl3⋅7H2O-NaI combination as a promoter system in organic synthesis. [...] In the first project we developed a new strategy for the total synthesis of (+)-furanomycin involving the synthesis of a useful building block for the natural antibiotic by nucleophilic addition of an organocerium compound to the (R)-Garner-type aldehyde. In the second project, the Lewis acid CeCl3⋅7H2O was used in combination with NaI to promote the Knoevenagel condensation between sugars and 1,3-diones to give polyhydroxyalkyl furans. The third project focused on the use of the CeCl3⋅7H2O-NaI system to promote the Michael addition of indoles to nitroalkenes to then use the Michael adducts thereby obtained as building blocks in the synthesis of β-Carboline derivatives. (+)-Furanomycin, polyhydroxylalkyl furans, and β- Carbolines are all heterocyclic compounds. In particular, (+)-furanomycin and polyhydroxylalkyl furans are heterocyclic compounds containing a 2,5- dihydrofuran ring and a furan ring, respectively. In Chapter 1 are reported a few examples of molecules illustrating the widespread presence and importance of furan, dihydrofuran, and tetrahydrofuran moieties in the core structure of naturally occurring substances. The project on the total synthesis of Climacostol, a natural product of great interest for its biological and pharmaceutical properties, was initiated because, although a small molecule to date no efficient protocol for its total synthesis has been reported. The third project was carried out in the Ciufolini group at UBC. The Ciufolini group is skilful and experienced in the retrosynthetic analysis and in the total synthesis of big and complex molecular structures. Among the many research avenues pursued in the Ciufolini group, the work here presented was part of their project on the synthesis of tetrodotoxin. One key step in the Ciufolini approach to the total synthesis of the potent neurotoxin is an asymmetric Henry reaction and this work focused on the synthesis of the chiral ligand for the copper catalyst used in the asymmetric step. Since most of the natural products we are interested in contain heterocyclic rings a brief overview on the presence of heterocycles in nature is presented in Chapter 1, with an emphasis on the oxolane ring structure.