Diversity-oriented synthesis of P-stereogenic and axially chiral monodentate biaryl phosphines enabled by C-P bond cleavage

Abstract

Chiral monodentate biaryl phosphines (MOPs) have attracted intense attention as chiral ligands over the past decades. However, the creation of structurally diverse chiral MOPs with both P- and axial chirality is still in high demand but challenging. Here, we show a distinct strategy for diversity-oriented synthesis of structurally diverse MOPs containing both P- and axial chirality enabled by enantioselective C-P bond cleavage. The key chiral Pd^II intermediates, generated through the stereoselective oxidative addition of C-P bond, could be trapped by alkynes, R₃Si-Bpin, diboron esters or reduced by H₂O/B₂pin₂, leading to enantioenriched structurally diverse MOPs in excellent diastereo- and enantioselectivities. Based on the outstanding properties of the parent scaffolds, the P- and axially chiral monodentate biaryl phosphines serve as excellent catalysts in asymmetric [3 + 2] annulation of MBH carbonate affording the chiral functionalized bicyclic imide.

Fig. 1. Diversity-oriented synthesis of structurally diverse monodentate biaryl phosphines containing both P- and axial chirality.

a Monodentate biaryl phosphines with various chiral elements. b Transition-metal catalyzed achiral alkynylation of the C–P bond. c Enantioselective C–P bond arylation (our previous work). d Diversity-oriented synthesis of structurally diverse P- and axially chiral monodentate biaryl phosphines (this work).

Fig. 2. Substrate scope of enantioselective alkynylation of C–P bond.

Reaction conditions: 1 (0.20 mmol), 2 (2.0 equiv), [Pd(Allyl)Cl]₂ (2.5 mol%), L6 (11 mol%), CuBr (1.0 equiv), Cs₂CO₃ (2.0 equiv), 2-Me-THF (2.0 mL) at 45 °C for 36 h, then S₈ (5 equiv) or BH₃·SMe₂ (2 equiv, 10 M in Me₂S), unless otherwise stated. Isolated yields were reported. ee values of the major isomers are shown and determined by chiral HPLC analysis. dr values were determined by ¹H NMR analysis of the crude reaction mixtures; ^a60 h; ^b1 (0.05 M); ^cthe reaction was conducted at 60 °C; ^dwith bis(trimethylsilyl)acetylene as the coupling partner; ^e0.10 mmol scale.

Fig. 3. Substrate scope of enantioselective silylation of C–P bond.

Reaction conditions: 1 (0.20 mmol), R₃Si-Bpin 4 (2.0 equiv), [Pd(Allyl)Cl]₂ (2.5 mol%), L6 (11 mol%), CuCl (0.75 equiv), Cs₂CO₃ (2.0 equiv), 2-Me-THF (2.0 mL) at 60 °C for 12 h, then S₈ (5 equiv) or BH₃·SMe₂ (2 equiv, 10 M in Me₂S), unless otherwise stated. Isolated yields were reported. ee values of the major isomers are shown and determined by chiral HPLC analysis. dr values were determined by ¹H NMR analysis of the crude reaction mixtures; ^athe reaction was conducted at 45 °C for 36 h; ^b0.10 mmol scale.

Fig. 4. Substrate scope of enantioselective borylation of C-P bond.

Reaction conditions: 1 (0.10 mmol), B₂neop₂ (2.0 equiv), [Pd(Allyl)Cl]₂ (5 mol%), L5 (22 mol%), CuCl (0.75 equiv), Cs₂CO₃ (2.0 equiv), p-xylene (1.0 mL) for 12 h, then S₈ (5 equiv) or BH₃·SMe₂ (2 equiv, 10 M in Me₂S), unless otherwise stated. Isolated yields were reported. ee values of the major isomers are shown and determined by chiral HPLC analysis. dr values were determined by ¹H NMR analysis of the crude reaction mixtures; ^athe reaction was conducted at 35 °C for 36 h; ^b0.10 mmol scale.

Fig. 5. Substrate scope of enantioselective reduction of C–P bond.

Reaction conditions: 1 (0.20 mmol), B₂pin₂ (1.2 equiv), H₂O (4.0 equiv), [Pd(Allyl)Cl]₂ (5.0 mol%), L6 (22 mol%), CuCl (0.75 equiv), Cs₂CO₃ (2.0 equiv), TBME (2.0 mL) at 60 °C for 12 h, then S₈ (5 equiv) or BH₃·SMe₂ (2 equiv, 10 M in Me₂S), unless otherwise stated. Isolated yields were reported. ee values of the major isomers are shown and determined by chiral HPLC analysis. dr values were determined by ¹H NMR analysis of the crude reaction mixtures; ^athe reaction was conducted at 30 °C for 24 h; ^bthe reaction was conducted at 45 °C for 24 h; ^c0.10 mmol scale.

Fig. 6. Synthetic utility and control experiments.

a Reduction of the alkyne moiety to E-alkenyl group; b Oxidation of the C–B bond to C–O bond; c Converted the C–B bond to C–H bond; d Preparation of the D-substituent product; e The non-linear effect studies of the enantioselective alkynylation of C–P bond with terminal alkynes. f Control study of the protonation of C–B bond; g Control study of the reduction of C–P bond without B₂pin₂.

Fig. 7. Proposed reaction mechanism for the enantioselective cross-coupling and reduction of C–P bond.

Cycle I: Phosphonium salts (S_a)-1a and (R_a)-1a are in rapid equilibrium with each other via the rotation of the C–C single bond. The oxidative addition of Pd⁰ with substrate (R)-1a cleaves C–P bond a to form enantio-enriched biaryl intermediate A. Subsequent transmetallation of intermediate A with the terminal alkynes, R₃Si-Bpin or diboron esters form the Pd^II species B. Reductive elimination of B furnishes the chiral phosphine product with concurrent regeneration of Pd⁰L* catalyst. Cycle II: The reaction of Pd^II intermediate A and water affords complex C. The transmetallation of complex C with the B₂pin₂ provides complex D. The reaction of complex D and water furnishes complex E. 1,4-D migration from E provides complex F. Reductive elimination of F delivers the desired product 7 with concurrent regeneration of Pd⁰L* catalyst.