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Skeletal Alteration of Bioactive Polycyclic Molecules by Catalytic Ring-Opening/Cross-Metathesis

Project description

Advanced chemical synthesis for bioactive compounds

Catalytic olefin metathesis is a chemical reaction in which carbon-carbon double bonds (olefins) are broken and reformed in a new arrangement. This reaction, facilitated by a catalyst, can produce a wide variety of valuable chemical products, including polymers, pharmaceuticals, and petrochemicals. Catalytic olefin metathesis has revolutionised synthetic organic chemistry, providing a powerful tool for constructing complex molecular architectures with precision. Funded by the Marie Skłodowska-Curie Actions programme, the METEDIT project aims to overcome technical challenges associated with catalytic olefin metathesis and develop a strategy that involves 3 simple ring opening steps. This approach will enable the creation of modified analogues of bioactive compounds, aiding new drug development and lead discovery.

Objective

Catalytic olefin metathesis is a transformative transformation with many unique attributes, one being the possibility of converting a ring to a modifiable acyclic diene by ring-opening cross-metathesis (ROCM). However, the existing methods are rare and limited to those that generate E-enoates. To the best of our knowledge, there are no available methods for ROCM reactions that can be used to access Z-alkenes from reactions involving five- to eight-membered rings.
To address this, we will develop a ROCM method for converting the small rings to readily alterable acyclic dienes efficiently and in high Z:E ratios. On the basis of preliminary (unpublished) results, a set of molybdenum alkylidene complexes recently designed by the host group will be utilized. We will investigate and develop a method for ROCM of cyclohexene with several commercially available Z- and E-alkenyl halides. The strategy will then be extended to five-, seven- and eight-membered ring alkenes. The diene products can be used for rapid synthesis of bioactive compounds, such as antitumor tetrahydrosiphonodiol, and their specifically altered analogs.
Another notable aspect of the project will be application to precise skeletal alterations of polycyclic bioactive compounds. We will exploit the presence of an olefin within a bioactive compound as the launching point for brief sequences leading to various specific modifications. This will obviate the need for lengthy and tedious de novo synthesis of each analog. More specifically, we will develop the open ring modify close ring (OMC) strategy, and by using it prepare an assortment of specifically modified analogs of androstadiene and vindoline. Through collaboration with experts, these compounds will be tested for in vitro bioactivity. Catalyst and method development will thus be applied to accessing formerly uncharted chemical space, which is central to new lead discovery and drug development.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

UNIVERSITE DE STRASBOURG
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 211 754,88
Address
RUE BLAISE PASCAL 4
67081 STRASBOURG
France

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Activity type
Higher or Secondary Education Establishments
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Total cost

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