Asymmetric Synthesis of Dictyoxetane

Lead Research Organisation: University of Birmingham
Department Name: School of Chemistry


Dictyoxetane is a naturally occurring organic compound which was isolated from a marine sponge harvested in the Indian Ocean. Sufficient quantities were obtained to allow chemists to determine its structure, which revealed an unprecedented and to this day still unique ring system among natural products. Although dictyoxetane is related to other diterpenoids (natural products containing 20 carbon atoms) of the dolabellane family, it has a highly unusual oxidation pattern which results in a complex ring system containing two oxygen atoms. One of these oxygen atoms is part of a 4-membered ring, an oxetane. Oxetanes are rarely found in natural products but one of the most notable examples, taxol, is now used as a treatment for cancer.
The biological activity of dictyoxetane is not known. Determining the biological activity is hampered by the lack of material - the original source has never been reharvested, and that which was isolated is no longer available. Total synthesis potentially offers a solution, but it took until 2016, over 30 years since the initial report on the structure of dictyoxetane, for the first and to date only total synthesis to be achieved, such are the challenges associated with preparing this compound. In the interim, important developments were made however, including the preparation of simplified analogues of dictyoxetane, some of which were found to show promising cytostatic activity against cancer cell lines.
In 2012 our research group reported the synthesis of a substructure of dictyoxetane, the "trans-hydrindane" ring system. The aim of the current project is to now convert this trans-hydrindane to dictyoxetane, which involves the annelation, or joining on, of the more complex oxetane ring system. We believe we have a chemical method to do this, but it has only been tested on a much simpler system, and extension to a synthesis of the natural product itself is a considerable challenge. Our new method is based on the use of photochemistry to build the oxetane ring, an approach which has not been used before but offers significant opportunities for synthesizing "dictyoxetane-like" molecules from simpler starting materials. Indeed, a future goal of this project is to synthesize a library of dictyoxetane-like molecules for biological evaluation. Although natural products have evolved to have a biological role, and often show interesting biological activity, like dictyoxetane, they are often structurally highly complex and difficult to make, they are not easily modified through chemical synthesis, and do not have the right initial properties for rational development into drugs. Once we have completed the total synthesis of dictyoxetane, we will therefore embark on the preparation of simplified dictyoxetane analogues, specifically designed (using tools and chemical reactions typically used in medicinal/pharmaceutical chemistry research) to have more drug-like properties from the outset. These new compound libraries possess advantageous 3-dimensional frameworks, are completely novel, and will be screened against a range of targets to look for potential biological activity.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509590/1 01/10/2016 30/09/2021
1947209 Studentship EP/N509590/1 01/10/2017 30/09/2020 Joseph Benford Ward
Description Natural products are of special interest to the pharmaceutical industry, with 30-40% of all drugs having been made from either natural products, or close analogues. Dictyoxetane is a marine natural product with a unique structure, and no biological activity has yet been published on this substance. However, interesting antitumour activity has been published on simplified models of the structure.
The work funded by this award is pursuing a synthetic strategy not only to make the compound, with the aim being to understand any biological activity it has, but to establish easy routes to analogues with only minor changes in the synthesis. Current progress has advanced the groups previous synthetic work closer to the target but has yet to reach it.
Exploitation Route When the target is made its biological activity could be tested which may lead to new pharmaceuticals, or analogues derived from minor changes of the synthesis may show activity toward some biological application. Furthermore, publication of the method of synthesis informs others of useful chemical transformations, but also of not-so useful ones and potentially saves other chemists time when trying to find useful chemistry.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology