Inverting External Asymmetric Induction via Selective Energy Transfer Catalysis: A Strategy to β‐Chiral Phosphonate Antipodes

Abstract Enantiodivergent, catalytic reduction of activated alkenes relays stereochemical information encoded in the antipodal chiral catalysts to the pro‐chiral substrate. Although powerful, the strategy remains vulnerable to costs and availability of sourcing both catalyst enantiomers. Herein, a stereodivergent hydrogenation of α,β‐unsaturated phosphonates is disclosed using a single enantiomer of the catalyst. This enables generation of the R‐ or S‐configured β‐chiral phosphonate with equal and opposite selectivity. Enantiodivergence is regulated at the substrate level through the development of a facile E → Z isomerisation. This has been enabled for the first time by selective energy transfer catalysis using anthracene as an inexpensive organic photosensitiser. Synthetically valuable in its own right, this process enables subsequent RhI‐mediated stereospecific hydrogenation to generate both enantiomers of the product using only the S‐catalyst (up to 99:1 and 3:97 e.r.). This strategy out‐competes the selectivities observed with the E‐substrate and the R‐catalyst.

: Emission spectrum of the utilised UVA LED (365 nm).

General procedure B for the Isomerisation of E-Vinylphosphonates
The specified E-vinylphosphonate (0.10 mmol, 1.00 eq.) and anthracene (0.9 mg, 0.005 mmol, 5 mol%) were dissolved in acetonitrile (1.5 mL) and the solution was stirred under UV light irradiation at 365 nm at ambient temperature for 18 h. After removal of the solvent, E-and Z-isomer were isolated by column chromatography. Yields were determined by mass recovery; Z:E ratios were determined by integration of peaks in the 31 P NMR spectrum and confirmed by integration the olefinic proton peaks in the 1 H NMR spectrum of both isomers.

General Procedure C for the Hydrogenation of Vinylphosphonates
In a glovebox, Rh(COD)2BF4 (1.3 mg, 0.0032 mmol, 3.2 mol%) and (SC,SP)-WalPhos (2.3 mg, 0.0035 mmol, 3.5 mol%) were added to a vial and dissolved in DCM (1 mL). After stirring for 15 min, the specified vinylphosphonate (0.10 mmol, 1.00 eq.) was added and the vial was transferred to an autoclave. The autoclave was charged with H2 (10 bar) and the solution was stirred at room temperature for 24 h. After carefully releasing the pressure and evaporation of the solvent, n-pentane (3 mL) was added and filtration through a plug of silica or a glass microfiber filter with subsequent elution with n-pentane (2 x 2 mL) yielded the products as clear oils. The enantiomeric ratios were determined by HPLC analysis using a chiral stationary phase.

As a representative example the reaction was repeated using the opposite catalyst enantiomer
According to general procedure C, using (RC,RP)-WalPhos instead of (SC,SP)-WalPhos,

Catalyst Screening for the E → Z Isomerisation of Vinylphosphonates
Vinylphosphonate E-1 (25.4 mg, 0.10 mmol, 1.00 eq.) and the specified catalyst (0.005 mmol, 5 mol%) were dissolved in acetonitrile (1.5 mL) and the solution was stirred under UV or visible light irradiation at the given wavelength at ambient temperature for 18 h. After removal of the solvent, E-1 and Z-1 were isolated by column chromatography (SiO2, ethyl acetate). Yields were determined by mass recovery; Z:E ratios were determined by integration of peaks in the 31 P NMR spectrum and confirmed by integration the olefinic proton peaks in the 1 H NMR spectrum of both isomers.

Reaction Optimisation for the E → Z Isomerisation of Vinylphosphonates
Vinylphosphonate E-1 (25.4 mg, 0.10 mmol, 1.00 eq.) and anthracene (0.9 mg, 0.005 mmol, 5 mol%) were dissolved in the specified solvent (1.5 mL) and the solution was stirred under UV light irradiation at 365 nm at ambient temperature. After removal of the solvent, E-1 and Z-1 were isolated by column chromatography (SiO2, ethyl acetate). Yields were determined by mass recovery; Z:E ratios were determined by integration of peaks in the 31 P NMR spectrum and confirmed by integration the olefinic proton peaks in the 1 H NMR spectrum of both isomers.

Control Experiments for the E → Z Isomerisation of Vinylphosphonates
According to general procedure B, control experiments with vinylphosphonate E-1 (25.4 mg, 0.10 mmol, 1.00 eq.) and anthracene (0.9 mg, 0.005 mmol, 5 mol%) were performed in the dark, without catalyst, and in the dark without catalyst. E-1 and Z-1 were isolated by column chromatography (SiO2, ethyl acetate). Yields were determined by mass recovery; Z:E ratios were determined by integration of peaks in the 31 P NMR spectrum and confirmed by integration the olefinic proton peaks in the 1 H NMR spectrum of both isomers.

Verification of the Photostationary State
According to general procedure B, control experiments with vinylphosphonates E-and Z-4 (33.3 mg, 0.10 mmol, 1.00 eq.) and anthracene (0.9 mg, 0.005 mmol, 5 mol%) were performed. E-4 and Z-4 were isolated by column chromatography (SiO2, ethyl acetate). Yields were determined by mass recovery; Z:E ratios were determined by integration of peaks in the 31 P NMR spectrum and confirmed by integration the olefinic proton peaks in the 1 H NMR spectrum of both isomers.