Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling

Abstract

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium‐labeled substrates, and control experiments revealed that nucleophilic attack to the π‐allylpalladium intermediate is the enantio‐determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C−O bonds at fully substituted carbon centers in the synthesis of chiral 2,2‐disubstituted benzomorpholines.

A Combined DFT, Energy Decomposition, and Data Analysis Approach to Investigate the Relationship Between Noncovalent Interactions and Selectivity in a Flexible DABCOnium/Chiral Anion Catalyst System

“…The range in the observed enantioselectivity values inspired a statistical fitting analysis, , which has been successfully utilized in chiral anion catalyzed reactions with configurationally flexible, doubly axial chiral phosphoric acids . Following this workflow, the goal was to relate the observed regio- and enantioselectivities to parameters derived from computed ground-state geometries of the DABCOnium cations.…”

Recent Advances in the Synthesis of Five‐membered Nitrogen Heterocycles Induced by Palladium Ions and Complexes

“…Toste and co‐workers performed an impressive analysis with respect to the formation of allyl‐substituted chiral pyrrolidines via synergistic palladium and doubly‐axially chiral phosphoric acid (DAP) catalysis [19] . Their method allowed the synthesis of vinyl‐substituted pyrrolidines with N ‐sulfonamide protecting groups (compounds 3 ) with low to 100 % conversion and low to excellent enantioselectivities utilizing DAP‐Cy ligand (L 2 , Scheme 6).…”

Identifying the true origins of selectivity in chiral phosphoric acid catalyzed N-acyl-azetidine desymmetrizations

“…6 A different approach to model stereoselective reactions without explicitly computing TSs is the statistical modeling, as popularized by Sigman. [7][8][9][10][11][12][13][14][15][16] Such multivariate analyses allow for excellent quantitative predictions of enantioselectivity based on fitting experimental results to a set of physical organic chemistry descriptors, but their mechanistic interpretation is obfuscated behind complex equations often comprising cross-terms of parameters that have to be redefined for most regressions. Depending on the situation, chemically-intuitive or statistical modeling approaches can each be useful and should be considered as complementary instead of competing tools toward understanding and improving stereoselective transformations.…”