Diasteroselective Grignard Reaction – New paper in Nature Communications

The Grignard addition is one of those reactions you learn during your first year of Organic chemistry and probably the last you forget when you become a computational chemist. It was Victor Grignard who became one of the earliest Nobel Laureate in Chemistry ever, and I know it took me a while to recognize it as an organometallic reaction. But the Grignard reaction is far from simple and its versatility keeps it as a rich source of study.

This new study demonstrates that alkylmagnesium iodide (RMgI) reagents exhibit markedly higher diastereoselectivity compared to their chloride (RMgCl) or bromide (RMgBr) counterparts whenever preorganization is possible as is the case with the β-hydroxy ketones under study. Our DFT calculations at the M06-2X(SMD=CH₂Cl₂)/def2-TZVPP//M06-2X/6-31+G(d) level of theory, reveal that this halide effect is attributed to the ability of the iodide-bound magnesium species to form more Lewis acidic chelates, which in turn guide the addition reaction with greater selectivity. The resulting modified nucleosides are of great interest in medicinal chemistry, as they play crucial roles in the development of antiviral agents (e.g., against HIV and hepatitis B) and anticancer therapies. This approach could provide a high-yield pathway for producing these bioactive molecules with high diastereocontrol.

According to our energy decomposition studies, the iodide anion, more than chloride or bromide, stabilizes the key transition states via stronger electrostatic interactions, effectively lowering the activation energy of the diastereoselective pathway. Additionally, transition state geometry optimizations indicate that the iodide-bound magnesium complexes adopt a more rigid and preorganized structure, which favors selective addition on one side of the carbonyl. Population-based energy decomposition analysis confirms that electronic and steric effects synergistically contribute to the observed selectivity trends.

For more details, check out our full article in Nature Communications: "Unmasking the halide effect in diastereoselective Grignard reactions applied to C4´ modified nucleoside synthesis" DOI: https://doi.org/10.1038/s41467-025-56895-7. I'm deeply thankful to my friend Dr. Guillermo Caballero for bringing me on board of this wonderful study; I look forward to new collaborations with the group of Robert Britton at Simon Fraser University.

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