(Press-News.org)
Scientists at Institute of Science Tokyo (Science Tokyo) have successfully realized the highly selective asymmetric 1,6-addition of aliphatic Grignard reagents to α,β,γ,δ-unsaturated carbonyl compounds. This new methodology employs an iron catalyst in combination with a chiral N-heterocyclic carbene ligand, which suppresses undesired side reactions and drives highly regio-, stereo-, and enantioselective alkyl migration. The achievement represents a major advance in organic synthesis, offering new opportunities for drug discovery, materials chemistry, and the fine-chemical sector.
In organic chemistry, the conjugate addition of a nucleophile to an α,β-unsaturated carbonyl compound, also known as the Michael addition, is a foundational reaction. It enables the formation of carbon–carbon (C–C) bonds in a single step. This strategy enables researchers to construct complex molecules efficiently and is widely used in the synthesis of pharmaceuticals, natural products, and polymeric materials.
Extending this framework to the 1,6-addition of α,β,γ,δ-unsaturated carbonyl compounds can significantly increase molecular complexity. Such compounds are commonly found in natural products. However, these transformations present major challenges, including the need for precise regioselective control and mitigation of side reactions such as β-hydride elimination. Achieving enantioselective 1,6-addition is even more demanding. Existing reports rely predominantly on precious-metal catalysts, such as palladium and rhodium, and typically suffer from limited substrate scope or selectivity.
In a breakthrough, a research team led by Associate Professor Takeshi Hata from the School of Life Science and Technology at Institute of Science Tokyo (Science Tokyo), Japan, has successfully achieved highly regio-, stereo-, and enantioselective 1,6-addition of aliphatic Grignard reagents to α,β,γ,δ-unsaturated carbonyl compounds. “Achieving precise control over 1,6-addition reactions of α,β,γ,δ-unsaturated carbonyl compounds expand the synthetic toolbox far beyond what was previously possible,” explains Hata. “By combining an iron catalyst with a chiral N-heterocyclic carbene (NHC) ligand, we have established a highly selective platform for aliphatic nucleophile addition.” The study was published in Angewandte Chemie International Edition on November 6, 2025, as a VIP (Very Important Paper).
In earlier work, the team demonstrated that aryl Grignard reagents undergo highly cis-selective 1,6-addition to electron-deficient conjugated dienes under iron catalysis. However, this reactivity did not extend to aliphatic nucleophiles. In the current study, the researchers introduced a rigid, tetracyclic chiral NHC ligand to address this limitation. This key innovation suppressed competing β-hydride elimination and enabled highly selective 1,6-addition of aliphatic Grignard reagents, furnishing single cis-olefin isomers in up to 99% ee and 92% yield. The reaction displays broad substrate scope, including linear, branched, and functionalized alkyl reagents as well as a wide range of conjugated carbonyl compounds.
Mechanistic investigations using deuterium-labeling experiments provided further insight into the catalytic process. The results indicate the formation of an iron-NHC-alkyl complex, followed by an s-cis-diene–alkyl–iron intermediate. Subsequent alkyl migration generates a magnesium enolate, which undergoes protonation to deliver the 1,6-addition product. The high selectivity stems from the rigid architecture of the chiral NHC ligand, which builds a defined asymmetric chiral pocket around the iron center, guiding the reaction pathway.
“This is the first example of a highly selective and sustainable asymmetric C–C bond-forming reaction involving aliphatic Grignard reagents and α,β,γ,δ-unsaturated carbonyl compounds, enabled by a common, earth-abundant metal rather than precious metals,” concludes Hata. “We anticipate that this platform will open new directions in organic synthesis and provide valuable impact across drug discovery, materials science, and industrial fine chemistry.”
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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”
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