The mechanism of the previously reported stereoselective (4+2) cycloaddition of N-protected 6-methyluracil-5-carbaldehydes and (E)-β-nitrostyrenes catalyzed by Takemoto's tertiary amine/thiourea organocatalyst was explored, using density functional theory (DFT) calculations on a model representative reaction. The cyclization reaction, which afforded notable enantioenrichedcarbocycle-fused uracils embedding three contiguous stereocenters, was here proven to be the result of a four-step sequence comprising a key stereo-defining Michael addition, followed by a completely diastereoselective intramolecular Henry reaction. Going beyond the hitherto reported activation modes, a complex and unprecedented network of hydrogen-bonding interactions between the chiral catalyst and the reaction partners has been disclosed, in which the protonated tertiary amine and the thiourea moiety ofthe catalyst simultaneously activate both the electrophile and the nucleophile components. By applying the Energetic Span Model (ESM) to four competitive energetic profiles, we unveiled the most plausible reaction pathways best fitting the experimental data, with close correlationwith the observed enantiomeric ratio of the product.

Mechanistic Insights into the Stepwise (4+2) Cycloaddition toward Chiral Fused Uracil Derivatives / Lombardo, Marco; Curti, Claudio; Zanardi, Franca; Marcantonio, Enrico. - In: ADVANCED SYNTHESIS & CATALYSIS. - ISSN 1615-4150. - 365:(2023), pp. 1531-1539. [10.1002/adsc.202300045]

Mechanistic Insights into the Stepwise (4+2) Cycloaddition toward Chiral Fused Uracil Derivatives

Curti, Claudio
;
Zanardi, Franca;Marcantonio, Enrico
2023-01-01

Abstract

The mechanism of the previously reported stereoselective (4+2) cycloaddition of N-protected 6-methyluracil-5-carbaldehydes and (E)-β-nitrostyrenes catalyzed by Takemoto's tertiary amine/thiourea organocatalyst was explored, using density functional theory (DFT) calculations on a model representative reaction. The cyclization reaction, which afforded notable enantioenrichedcarbocycle-fused uracils embedding three contiguous stereocenters, was here proven to be the result of a four-step sequence comprising a key stereo-defining Michael addition, followed by a completely diastereoselective intramolecular Henry reaction. Going beyond the hitherto reported activation modes, a complex and unprecedented network of hydrogen-bonding interactions between the chiral catalyst and the reaction partners has been disclosed, in which the protonated tertiary amine and the thiourea moiety ofthe catalyst simultaneously activate both the electrophile and the nucleophile components. By applying the Energetic Span Model (ESM) to four competitive energetic profiles, we unveiled the most plausible reaction pathways best fitting the experimental data, with close correlationwith the observed enantiomeric ratio of the product.
2023
Mechanistic Insights into the Stepwise (4+2) Cycloaddition toward Chiral Fused Uracil Derivatives / Lombardo, Marco; Curti, Claudio; Zanardi, Franca; Marcantonio, Enrico. - In: ADVANCED SYNTHESIS & CATALYSIS. - ISSN 1615-4150. - 365:(2023), pp. 1531-1539. [10.1002/adsc.202300045]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2943872
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