Ir and NHC Dual Chiral Synergetic Catalysis: Mechanism and Stereoselectivity in γ-Butyrolactone Formation

Abstract

Cooperative dual catalysis is a powerful strategy for achieving unique reactivity by combining catalysts with orthogonal modes of action. This approach allows for independent control of the absolute and relative stereochemistry of the product. Despite its potential utility, the combination of N-heterocyclic carbene (NHC) organocatalysis and transition metal catalysis has remained a formidable challenge as NHCs readily coordinate metal centers. This characteristic also makes it difficult to rationalize or predict the stereochemical outcomes of these reactions. Herein, we use quantum mechanical calculations to investigate formation of γ-butyrolactones from aldehydes and allyl cyclic carbonates by means of an NHC organocatalyst and an iridium catalyst. Stereoconvergent activation of the racemic allyl cyclic carbonate forms an Ir-π-allyl intermediate and activation of an unsaturated aldehyde forms an NHC enolate, the latter of which is rate-limiting. Union of the two fragments leads to stereodetermining C-C bond formation and ultimately ring closure to generate the product lactone. Notably, CO₂ loss occurs after formation of the C-C bond and Et₃NH⁺ plays a key role in stabilizing carboxylate intermediates and in facilitating proton transfer to form the NHC enolate. The computed pathways agree with the experimental findings in terms of the absolute configuration, the enantiomer excess, and the different diastereomers seen with the (R)- and (S)-spiro-phosphoramidite combined with the NHC catalyst. Calculations reveal the lowest energy pathway includes both an NHC ligand and a phosphoramidite ligand on the iridium center. However, the stereochemical features of this Ir-bound NHC were found to not contribute to the selectivity of the process.

Figure 1.

Relative Gibbs free energy profile (kcal/mol) diagram and corresponding optimized transition states for the formation of NHC-enolate from the NHC and aldehyde calculated with CPCM(toluene)/B3LYP-D3/6-31G**//B3LYP-D3/6-31G**.

Figure 2.

Relative Gibbs free energy (kcal/mol) profile and corresponding transition state geometries of the formation of 8 from the racemic allyl cyclic carbonate 6 with Ir-(S)-spiro-phosphoramidite calculated with CPCM(toluene)/B3LYP-D3/6-31G**/SDD(Ir)//B3LYP-D3/6-31G**/SDD(Ir). The line-angle version shows transition states.

Figure 3.

Relative Gibbs free energy profile diagram and corresponding transition states of the formation of γ-lactones from Ir-π-allyl 8. All energy values were calculated with CPCM(toluene)/B3LYP-D3/6-31G**/SDD(Ir)//B3LYP-D3/6-31G**/SDD(Ir).

Figure 4.

The stereocontrolling C-C bond forming transition states between the Ir-π-allyl and NHC-enolate for the P-N1, P-N2 and P_ent-N2 catalyst combinations showing the favorable interactions between the Ir-π-allyl and NHC-enolate components in the Si-Si case. See Figure S9 for electrostatic potential maps highlighting electrostatic interactions.

Figure 5.

Distortion-interaction analysis (kcal/mol) of the C–C bond forming transition states with the P-N1 and P-N2 catalyst combinations [B3LYP-D3/6-31G**,SDD(Ir)].

Figure 6.

Optimized geometries (space-filling model = Ir-π-allyl; stick model = NHC-enolate) of the stereocontrolling C-C bond formation transition states between Ir-π-allyl and NHC-enolate in the case of the P-N1 catalyst combinations.

Figure 7.

Optimized geometries (space-filling model = Ir-π-allyl; stick model = NHC-enolate) of the stereocontrolling C-C bond formation transition states between Ir-π-allyl and NHC-enolate in the case of the P_ent-N2 catalyst combinations.

Figure 8.

Relative Gibbs free energy profile diagram showing the mechanistic proposal of γ-lactone formation from aldehydes and allyl cyclic esters using NHC and Ir-phosphoramidites.

Figure 9.

Interactions of chiral and achiral NHC ligand in the C-C bond forming transition state [9–10]^‡ in Figure 7.

Scheme 1.

cis-Selective formation of lactones from aldehydes and allyl cyclic carbonates using Ir-phosphoramidite and NHC dual chiral catalytic systems.

Scheme 2.

General mechanism of the Ir-spiro-phosphoramidite/NHC dual-catalyzed lactone formation.

Scheme 3.

Possible routes for the formation of Ir-NHC complex 1e with substrate. The relative Gibbs free energies are reported from CPCM(toluene)/B3LYP-D3/6-31G**/SDD(Ir)//B3LYP-D3/6-31G**/SDD(Ir).

Scheme 4.

Formation of Ir-allyl-carbonates from allyl cyclic carbonates using Ir-P-NHC catalyst in the presence of a Bronsted acid (protonated triethylamines = Et₃NH⁺) generated during the formation of the NHC catalyst in the presence of Et₃N calculated with CPCM(toluene)/B3LYP-D3/6-31G**/SDD(Ir)//B3LYP-D3/6-31G**/SDD(Ir). C2 is labeled and highlighted with a gray circle.

Scheme 5.

Reaction paths from Ir-π-allyl 8 to the lactone product 13.

Scheme 6.

Effect of achiral NHC ligand on stereoselectivity step.