Systematic Parameter Determination Aimed at a Catalyst-Controlled Asymmetric Rh(I)-Catalyzed Pauson–Khand Reaction

Abstract

Transition metal-catalyzed carbocyclization reactions have revolutionized the synthesis of complex cyclic organic compounds. Yet, subtle substrate changes can significantly alter reaction pathways. The asymmetric Rh(I)-catalyzed Pauson–Khand reaction (PKR) exemplifies such a reaction, hindered by a narrow substrate scope and competing reactivity modes. In this study, we identified parameters predictive of the yield and enantioselectivity in the catalyst-controlled asymmetric PKR, using 1,6-enynes with a 2,2-disubstituted alkene. In this way, ring-fused cyclopentenones can be formed with chiral quaternary carbon centers. Using bisphosphine ligand parameters from palladium complexes, including the energy of the Pd lone pair orbital and the angle formed by the phosphorus aryl groups on the ligand, we established strong correlations with experimental ln(er) (R² = 0.99 and 0.91) for two distinct precursors. Solvent dipole moments correlated with ln(er) for high-dipole-moment precursors (R² = 0.94), while Abraham’s hydrogen bond basicity is more relevant for low-dipole-moment precursors (R² = 0.93). Additionally, counterions were found to have a significant impact on the PKR reactivity and selectivity, as does the steric demand of the alkyne substituent of the enyne precursor. In the latter case, ln(er) correlates with Sterimol B₁ values for products from different alkyne substituents (R² = 0.99). Furthermore, the computed C≡C wavenumber of the enyne precursor can be directly aligned with the yield of asymmetric PKRs.