Alumina Directed Ortho Allylation of Phenols

Abstract

The structures of natural products have long inspired and motivated innovation in organic chemistry. Chemists strive to compete with the efficiency and selectivity of biological enzymatic reactions. This thesis describes the development of a new synthetic methodology that enables a regioselective allylation of phenols that is analogous to the remarkable transformations done by prenyltransferase enzymes. The main topic of this thesis is covered in Chapters 1 and 2. In Chapter 1 prenyltransferase enzymes are introduced and the significance of aromatic allylation chemistry in Nature is discussed. Synthetic methods for the allylation of phenols are thoroughly reviewed. This research begins with the use of alumina, a heterogeneous reagent, to promote an indole alkylation reaction. Next, the discovery and development of an alumina-directed ortho-selective allylation of phenols is described. Mechanistic investigations and reaction optimization are described. The robust substrate scope of this reaction is illustrated via the synthesis of 52 allylic phenols and this new methodology is applied to the synthesis of anti-inflammatory drug candidate L-651896. In Chapter 2, this new methodology is applied to the synthesis of five natural products. Natural products have long been of interest in pharmaceutical sciences, originating long before modern medicine with thousands of years of treatment of disease with traditional plant-based remedies. Studies of traditional medicines and natural products led to the discoveries some modern drugs such as aspirin, digitoxin, morphine, quinine and pilocarpine. Prenylated phenols are ubiquitous among natural products in the plant kingdom and in traditional medicine. In this chapter, our alumina-directed ortho-selective allylation has been applied in the efficient synthetic preparation of five plant-derived prenylated phenolic natural products: cannabigerol, grifolin, piperogalin, amorphastibol, and iroko. In Chapter 3, the total synthesis of the alkaloid natural product veranamine is described followed by the synthesis and biological evaluation of a library of veranamine analogues. Veranamine binds to sigma 1 and 5HT2B receptors and has demonstrated potent antidepressant activity in a mouse assay. The synthesis of one of the veranamine analogues is made possible by the alumina-directed ortho-allylation methodology that is the main focus of this thesis.