The overall goal of this proposal is to develop new chemical technologies based on ring-forming reactions of oxyallyl cations followed by fragmentation of the resultant products to deliver novel molecular entities that are of biomedical interest. This contribution is significant because it will fuel cross-disciplinary discoveries by providing synthetic approaches to structurally unique indolines alkaloids with important biological properties. This project is innovative because we will develop a unified strategic vision for making both our target molecules and also compounds belonging to several important classes of monoterpene indoline alkaloids. Thus, we will pursue the following three specific aims. Aim #1: Complete the total synthesis of strychnochromine and cabucraline, Aim #2: Develop an efficient route to structurally-informed vinblastine variants with a novel C7 carboxylate, and Aim #3: Invent new (3+2) annulation and Beckmann fragmentation reactions. Strychnochromine is the only molecule found in nature or of anthropogenic origin that possesses the densely-functionalized pentacyclic ring system comprising its core. It was found to have anti-protozoal activity and no total synthesis of strychnochromine has been reported to date. Cabucraline is an akuammiline alkaloid that is distinct from all the other members previously synthesized at the configuration of the C2 stereocenter, and it has never been made before. Its synthesis will require the development of a novel regioselective (3+2) annulation reaction with a heterocyclic oxyallyl cation. The proposed vinblastine analogue is unique by virtue of the unprecedented C7 carboxylate and structural modifications at C3−C5. Natural vinblastine is an anti-cancer drug that is on the WHO list of essential medicines, but its clinical use is accompanied by undesirable side-effects. In addition, vinblastine-resistant cancer cell lines are becoming increasingly problematic. Due to its predicted greater efficacy, we hypothesize that these variants may require smaller therapeutic dosages vis-à-vis vinblastine, thereby resulting in lower occurrences of adverse side- effects. Structural differences of the analogues may also address issues related to vinblastine resistance. All of the proposed syntheses in the first two specific aims will feature the novel dearomative (3+2) indole annulation followed by fragmentation discovered by our research group. In the third aim, we seek to develop strategies that significantly broaden the scope of our dearomative (3+2) annulation technology by applying innovative methods for generating key reactive oxyallyl cation intermediates. In short, we will invent new tandem processes that result in the formation of densely-functionalized tetrahydrocarbazoles products with unique and stereodefined substitution patterns.