# Novel Dearomative Indole Annulation Reactions, Beckmann Fragmentations, and Their Applications to Synthesis

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $395,845

## Abstract

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.

## Key facts

- **NIH application ID:** 10501186
- **Project number:** 1R01GM147650-01
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** JIMMY WU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $395,845
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501186

## Citation

> US National Institutes of Health, RePORTER application 10501186, Novel Dearomative Indole Annulation Reactions, Beckmann Fragmentations, and Their Applications to Synthesis (1R01GM147650-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10501186. Licensed CC0.

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