Enantioselective synthesis of α,α-diarylketones by sequential visible light photoactivation and phosphoric acid catalysis

Abstract

Chiral ketones and their derivatives are useful synthetic intermediates for the synthesis of biologically active natural products and medicinally relevant molecules. Nevertheless, general and broadly applicable methods for enantioenriched acyclic α,α-disubstituted ketones, especially α,α-diarylketones, remain largely underdeveloped, owing to the easy racemization. Here, we report a visible light photoactivation and phosphoric acid-catalyzed alkyne-carbonyl metathesis/transfer hydrogenation one-pot reaction using arylalkyne, benzoquinone, and Hantzsch ester for the expeditious synthesis of α,α-diarylketones with excellent yields and enantioselectivities. In the reaction, three chemical bonds, including C═O, C─C, and C─H, are formed, providing a de novo synthesis reaction for chiral α,α-diarylketones. Moreover, this protocol provides a convenient and practical method to synthesize or modify complex bioactive molecules, including efficient routes to florylpicoxamid and BRL-15572 analogs. Computational mechanistic studies revealed that C-H/π interactions, π-π interaction, and the substituents of Hantzsch ester all play crucial roles in the stereocontrol of the reaction.

Fig. 1.. Designing strategies for constructing chiral α,α-diarylketones.

(A) Natural products and drug molecules containing α,α-diarylketones and derivatives. (B) Previous work to chiral α,α-diarylketones. (C) New strategy for chiral synthetic blocks. (D) Our strategy: Alkyne-carbonyl metathesis/transfer hydrogenation one-pot reaction for the synthesis of chiral α,α-diarylketones.

Fig. 2.. Reaction scope of alkylarylalkynes.

Performed with compounds 1 (0.2 mmol) and 2 (0.1 mmol) in CH₂Cl₂, with stirring for 4 hours under 2 × 35 W blue LEDs at room temperature. Compound 3f (0.15 mmol), 4 Å MS (60 mg), and (R)-C7 (0.005 mmol) were added, with stirring at −60°C for 3 hours. Yield of isolated product. ee determined by HPLC analysis using a chiral stationary phase.

Fig. 3.. Reaction scope of diarylalkynes.

Performed with compounds 1′ (0.2 mmol) and 2 (0.1 mmol) in CH₂Cl₂, with stirring for 4 hours under 2 × 35 W blue LEDs at room temperature. Compound 3f (0.15 mmol), 4 Å MS (60 mg), and (R)-C2 (0.005 mmol) were added, with stirring at −60°C for 3 hours. Yield of isolated product. ee determined by HPLC analysis using a chiral stationary phase.

Fig. 4.. The functionalization of complex molecules derived from natural products and pharmaceuticals.

Fig. 5.. Synthetic applications.

(A) Scale-up reactions. (B) Reduction of compound 59. (C) Asymmetric synthesis of florylpicoxamid analog. (D) Stereodivergent synthesis of 2-(diarylmethyl)oxirane and BRL-15572 analogs.

Fig. 6.. Control experiments.

(A) Nonlinear effect study of 10. (B) Nonlinear effect study of 48. (C) Racemization studies of 10. (D) Racemization studies of 48.

Fig. 7.. Proposed reaction pathways.

Fig. 8.. DFT-calculated stereo-determining transition structures for the formation of 4 catalyzed by (R)-C7.

The first row is for the hydride transfer from Hantzsch ester 3f to the Re-face of p-QM intermediate and the second row to the Si-face. The third column visualizes the interactions by the IRI method, where negative values indicate favorable and positive values indicate unfavorable, and the different interactions between the two TSs are shown in the inserted graphs. The relative free energies and enthalpies (in parentheses) at 213.15 K are also given in kilocalories per mole.

Fig. 9.. DFT-calculated stereo-determining transition structures for the formation of 48 catalyzed by (R)-C2.

The first row is for the hydride transfer from Hantzsch ester 3f to the Re-face of p-QM intermediate and the second row to the Si-face. The third column visualizes the interactions by the IRI method, where negative values indicate favorable and positive values indicate unfavorable, and the different interactions between the two TSs are shown in the inserted graphs. The relative free energies and enthalpies (in parentheses) at 213.15 K are also given in kilocalories per mole.