PROJECT SUMMARY, ABSTRACT The objective of this program is to develop broadly effective chemistry for the stereocontrolled chemical synthesis of complex structures of use to chemists and medicinal chemists. The research plan is divided into two Specific Aims, each opening access to distinct classes of natural products. Aim 1 describes the development of an unexplored, dearomative-Claisen rearrangement, which allows functionalization of the C2 position of indoles, thereby enabling the stereocontrolled, asymmetric synthesis of 2,2-disubstituted indoline derivatives. This new Claisen rearrangement transform will be incorporated into the design of efficient strategies to indoline-containing natural products. Aim 2 presents the development of two [4+3]-cycloaddition based routes for the synthesis of indole-fused cycloheptanes and the application of this chemistry to the synthesis of the intricate and bioactive ambiguine natural products. The research plan is supported throughout with compelling preliminary results, and the synthesis applications are designed to make maximal use of the methodology, while addressing unmet synthetic challenges posed by the complex targets. The new chemistry is expected to be broadly useful to organic and pharmaceutical chemists involved in drug development, chemical synthesis, and natural product research. The final products of the total synthesis efforts and many advanced intermediates will be submitted to a screening facility for biological testing. The proposed projects will provide excellent training to graduate students and postdoctoral associates in chemical synthesis and problem solving, preparing them for successful careers in the pharmaceutical industry and academia.