Total Synthesis of Daphniphyllum Alkaloids

Lead Research Organisation: University of Oxford


This project falls within the EPSRC Synthetic Organic Chemistry research area.
The Daphniphyllum alkaloids are structurally diverse family of natural products isolated from
Daphniphyllum genus, evergreen trees and shrubs endemic to Asia. To this day, more than 320
Daphniphyllum alkaloids displaying a significant range of anticancer, antioxidant or
vasorelaxant activities, among others, have been isolated. Due to the size of this family of
natural products, these alkaloids have been divided into 35 classes base on their distinct
skeletal form and the Caliciphylline A-type subfamily, named after the first isolated member of
this class, being one of them.
The structural complexity and biological significance of members of this class have led to
significant interest from the synthetic community, including our group. Since many
Caliciphylline-A type alkaloids differ only in one distinct region of otherwise very complex
molecule, it was envisioned that these compounds could be accessible from one common
advanced intermediate. Previous synthetic studies carried out within our group resulted in the
development of the synthesis of such a potential common intermediate, however, despite
intensive synthetic efforts the collective synthesis of Calyciphylline A-type alkaloids still
remains an unsolved challenge.
Based on these preliminary synthetic studies, we have envisioned a new synthetic strategy that
would lead to multigram quantities of the advanced intermediate in a very short synthetic
sequence by coupling 3 fragments of similar complexity. The conversion of this advanced
intermediate into the final natural product would then require only a few chemical
manipulations. This so-called convergent approach allows a rapid construction of complexity,
reduces the linear length of the synthesis and thus increases its overall yield. Moreover, the
use of convergent strategy provides access to new derivatives by a simple modification of the
used coupling partners.
In summary, this project aims to synthesise Caliciphylline A-type alkaloids, a family of
structurally complex natural products with interesting biological activity. The proposed
synthetic strategy should allow the preparation of multiple natural products as well as their
synthetic analogues from a late intermediate, by a simple modification of the used coupling
partners. Moreover, the high material throughput and access to multigram quantities of key
advanced intermediates should provide a potential for further investigation of the biological
activity of this family of natural products.

Planned Impact

This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.

This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.

We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.

The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.

We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.

We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).

Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.

The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.


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