Insights on Absolute and Relative Stereocontrol in Stereodivergent Cooperative Catalysis

Abstract

An increasing number of examples demonstrate that the use of two mutually compatible chiral catalysts in one-pot conditions can help realize the long-cherished goal of simultaneous control of absolute and relative configurations in asymmetric catalysis. Engaging two transition metal catalysts for this goal presents a considerable degree of mechanistic challenge to control the mode of substrate activation as well as origin of enantio- and diastereoselectivities, both of which are central to the burgeoning domain of stereodivergent catalysis. We have employed density functional theory (B3LYP-D3) computations to investigate an important stereodivergent reaction between azaaryl acetamide and cinnamyl methyl carbonate. These compounds participate in the stereocontrolling C–C bond formation in the form of activated substrates, respectively, when bound to chiral Cu-Walphos and Ir-phosphoramidite catalysts. Herein, we provide the molecular origin of how all four stereoisomers of the product bearing two contiguous stereogenic centers could be accessed by changing the combinations of chiral catalysts (C1(R,R p) or C2(S,S p) of Cu-Walphos in conjunction with P1(R,R,R) or P2(S,S,S) of Ir-phosphoramidite catalysts). The origin of stereodivergence is identified to depend on the differences in the number and nature of noncovalent interactions (NCIs) in the stereocontrolling transition states. In particular, NCIs between the chiral catalysts (C–H···π in C1–P1 catalyst dyad and C–H···π, C–H···F, and π···π in C2–P1) in stereocontrolling transition states are found to be the differentiating factors rendering one of the four stereochemically distinct transition states to be the lowest energy one for a given catalyst combination. These molecular insights suggest that subtle modifications to the catalyst framework could be further exploited in stereodivergent catalysis.

Stereodivergent Pd/Cu Catalysis for Asymmetric Desymmetric Alkylation of Allylic Geminal Dicarboxylates

“…Similar trends were found with the combinations of Pd/(R)-L4 and Cu/(S,S p )-L5), giving the major (S,S)-linear product (Figure S1). [87][88][89] These theoretical calculations are in good consistent with the experimental results.…”

Data-driven catalyst optimization for stereodivergent asymmetric synthesis of α-allyl carboxylic acids by iridium/boron hybrid catalysis

“…1b and 1d) is the hub intermediate in the selectivity-determining step of the present Ir/B dual catalysis 45 (Ir complexes and allyl groups correspond to catalysts and substrates, respectively), we utilized this complex for MFA. Importantly, since the Ir--allyl complex is the common intermediate in determining all the four reaction outcomes (b/l and dr in reactions using ligand S or R) [46][47][48] , one set of molecular fields calculated from the complex can be used to analyze four sets of the target variables as shown in Fig. 1d.…”

“…Furthermore, the information affords insights into selectivity induction mechanisms without performing transition state density functional theory calculations (see Supplementary figs. S19 and S20) [46][47][48] .…”

Molecular insights into chirality transfer from double axially chiral phosphoric acid in a synergistic enantioselective intramolecular amination

“…16 The discussions in this manuscript are presented on the basis of the Gibbs free energies as obtained at the SMD (toluene) /B3LYP-D3/6-31G**,Pd(SDD) level of theory. 17 The noncovalent interactions in the transition states were identified using the topological analyses of electron densities within the Bader's Atoms-in-Molecule (AIM) formalism 18 by using the AIM2000 program. 19 Further, the reduced density plots were generated for qualitative graphical analysis of the noncovalent interactions by using the NCIPLOT 3.0.…”