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

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.