Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates

Abstract

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a Chiral Anion Phase Transfer (CAPT) process is presented. Kinetic analysis, labeling, competition and non-linear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst’s structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed DFT transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis setting the foundation for future applications.

Combining traditional 2D and modern physical organic-derived descriptors to predict enhanced enantioselectivity for the key aza-Michael conjugate addition in the synthesis of Prevymis™ (letermovir)

“…Once identified, QSAR models can rapidly provide activity and selectivity estimates for new structures, thus enabling high-throughput virtual assessment of key structural components for the target of interest. Furthermore, highly weighted descriptors in the QSAR model may indicate structural features that influence the desired activity 2,3…”

Enantioselective Synthesis ofN,S‐Acetals by an Oxidative Pummerer‐Type Transformation using Phase‐Transfer Catalysis

“…[15] A set of parameters for several phosphates 1a–1h (see SI for full set of catalysts) was computed using the molecular model in Figure 1a. [16] This parameter set included IR vibrational frequencies ( ν ) and intensities ( i ), [17] NBO charges, and Sterimol steric descriptors ( B1 , B5 and L ). [18] When the parameters acquired were correlated with the measured ee expressed as ΔΔG ‡ , the multidimensional model in Figure 1a was obtained.…”

Transition‐Metal‐Catalyzed Three‐Component Difunctionalizations of Alkenes

“…For inactive alkenes there is no similar effect to stabilize the Heck‐type intermediate alkylpalladium species, thus β‐hydride elimination usually occurs to generate a new alkene and a PdH complex. Fortunately, under suitable reaction conditions, the resulting alkene could reinsert into the PdH species to form a new alkylpalladium intermediate, which undergoes further transmetalation with a nucleophile and reductive elimination to produce a 1,1‐difunctionalized product (Scheme ) . Sigman et al.…”

“…have made a great contribution to this field in recent years . For example, they applied a palladium catalyst, which was capable of 1,2‐difunctionalizing 1,3‐dienes, in a reaction of simple terminal alkenes with alkenyl triflates and arylboronic acids to produce 1,1‐difunctionalized products . The 1,1‐difunctionalization of inactive alkenes with ArN 2 BF 4 and ArB(OH) 2 was also achieved with use of [Pd 2 (dba) 3 ]⋅CHCl 3 as a catalyst .…”