SUBSTITUENT EFFECTS ON THE CLAISEN REARRANGEMENT

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The aliphatic Claisen rearrangement is one of the most useful and powerful reactions in organic synthesis. While the basic Claisen rearrangement usually occurs only at high temperatures, a variety of "modified" Claisen rearrangements of much more general utility have been developed. Virtually without exception, these variants succeed because of the presence of a substituent which provides a strong rate accelerating effect. However, the understanding of substituent effects lags far behind the elegant synthetic studies which apply these effects. The goals of this project are twofold: 1) to provide a more detailed understanding of the origins of substituent effects by rate studies, variation of the nature and location of substituents, and study of medium effects, and 2) to combine this new information with existing knowledge to design useful substituent- controlled Claisen rearrangements. Both synthetic and bioorganic applications of these concepts are envisioned. Proposals to develop facile new variants of the Claisen rearrangement with unique synthetic advantages are presented. Development of a synthetic approach to the pyranonaphthoquinones, an important family of antitumor antibiotics, is already in progress and future plans are outlined. Finally, the rational design of transition state inhibitors of the enzyme chorismate mutase, a key link in the shikimate pathway, is proposed. This enzyme catalyzes the only known biological Claisen rearrangement. Since this pathway to folic acid and important aromatic amino acids is an essential element of lower plant and bacteria metabolism and not an element of human metabolism, the discovery of new herbicides and antibacterial agents could result.