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Novel catalysts that unleash access to tetrasubstituted olefins for drug discovery
Tetrasubstituted olefins, hydrocarbons with double carbon bonds which have had four hydrogens replaced by another atom or group, can provide direct access to both biological molecules and intermediates and are key to the drug discovery process. Olefin metathesis offers an efficient and stereodivergent route to such entities. However, the reactions and catalysts needed to achieve the desired repertoire of products pose numerous challenges. The European Research Council-funded HISUBMET project intends to overcome these challenges. The team will design a new class of molybdenum and tungsten catalysts that can be used to promote efficient ring-closing metathesis and cross-metathesis reactions that generate a wide range of readily modifiable tetrasubstituted olefins. Other catalysts will be developed as well.
Tetrasubstituted olefins are key to drug discovery, and the ability to such entities is a compelling goal. Pioneering studies have led to a number of noteworthy advances by significant shortcomings remain. For example, it is especially challenging to access tetrasubstituted alkenes that contain four sizeable substituents or a F atom and/or a CF3 unit. Most protocols can only afford one of the possible isomers.
Tetrasubstituted alkenes that contain multiple modifiable substituents are particularly attractive, because they can serve as diversification points that lead to a large assortment of desirable compounds. Olefin metathesis offers a strategically distinct, efficient, and stereodivergent route to such entities. Yet, there are only a few reported olefin metathesis reactions that generate a cyclic tetrasubstituted olefin that does not contain two methyl substituents at each carbon (i.e. no stereochemistry). A much smaller number (four cases) are RCM reactions that afford cyclic tetrasubstituted olefins with one modifiable C–Cl bond. All involve a Ru catalyst. However, olefin metathesis reactions that can generate poly-halogenated olefins cannot be effected with a Ru catalyst (rapid decomposition). Only a Mo or a W catalyst must be used, but such complexes do not exist.
We will design a new class of pivoting Mo and W catalysts that can be used to promote efficient RCM and cross-metathesis (CM) reactions that generate a wide range of readily modifiable tetrasubstituted olefins. We will accomplish this by designing catalysts wherein the rotation of the imido and aryloxide ligands is synchronized, so that a proper binding pocket is made available. The expected products, which can serve as versatile diversification points, will contain 2-3 easily modifiable units.
We will also design an entirely new class of cyclic Mo and W catalysts for CM between easily accessible trisubstituted alkenes and polyhalogenated alkenes. A unique feature of these catalysts is that intra |
