Visible light-promoted CO2 fixation with imines to synthesize diaryl α-amino acids

Light-mediated transformations with CO2 have recently attracted great attention, with the focus on CO2 incorporation into C–C double and triple bonds, organohalides and amines. Herein is demonstrated visible light -mediated umpolung imine reactivity capable of engaging CO2 to afford α-amino acid derivatives. By employing benzophenone ketimine derivatives, CO2 fixation by hydrocarboxylation of C=N double bonds is achieved. Good to excellent yields of a broad range of α,α–disubstituted α-amino acid derivatives are obtained under mild conditions (rt, atmospheric pressure of CO2, visible light). A procedure that avoids tedious chromatographic purification and uses sustainable sunlight is developed to highlight the simplicity of this method.

Upon completion, the amino acid product was converted into its methyl ester. The crude product was purified by chromatography on silica gel (eluted with petroleum ether/EtOAc = 3/1) to give the desired product (46.5 mg, 73% yield) as colorless oil.
Upon completion, the amino acid product was converted into its methyl ester. The crude product was purified by chromatography on silica gel (eluted with petroleum ether/EtOAc = 30/1) to give the desired product (56.7 mg, 82% yield) as colorless oil.
Upon completion, the amino acid product was converted into its methyl ester. The crude product was purified by chromatography on silica gel (eluted with petroleum ether/EtOAc = 30/1) to give the desired product ( Ketimine 1 (0.2 mmol), catalyst Ir-7 (0.9 mg, 0.5 mol %), Cy 2 NMe (85.6 µL, 0.4 mmol), MeCN (2 mL) and a magnetic stirring bar were charged into an oven-dried 5 mL vial under nitrogen. The vial was sealed with a septum. CO 2 gas in a balloon was bubbled into the mixture under stirring for 30 seconds through a needle, which was then lifted up out of the solution and was kept in the vial. The mixture was placed under a 20 W blue LED light source and stirred at ambient temperature (15-20 o C). White precipitates appeared as the reaction proceeded. Upon completion of the reaction as monitored by TLC, the vial was opened and cooled down in an ice bath. The precipitates were collected by filtration, and washed using cold MeCN (3 X 0.4 mL). The desired compound 4 was obtained after drying under reduced pressure.

Gram-Scale Synthesis of 4 Using Sunlight
Corresponding ketimine (1.0 g, 3.7 mmol), catalyst Ir-7 (16.6 mg, 0.0185 mmol, 0.5 mol %), Cy 2 NMe (1.58 mL, 7.4 mmol), MeCN (37 mL) and a magnetic stirring bar were charged into an oven-dried 50 mL Schlenk tube under nitrogen. The tube was sealed with a septum. CO 2 gas in a balloon was bubbled into the mixture under stirring for 2 minutes through a needle, which was then lifted up out of the solution and was kept in the tube. The mixture was placed under outdoor sunlight and stirred at ambient temperature (~ 16 o C). White precipitates appeared as the reaction proceeded. Upon completion of the reaction, the tube was opened and cooled down in an ice bath. The precipitates were collected by filtration, and washed using cold MeCN (3 X 4 mL). The desired compound was obtained after drying under reduced pressure (4aa:1.7 g, 91%. 4ak: 1.7 g, 90%. Supplementary Figure 2).

Debenzylation Procedure to Synthesize Free Amino Acid
Compound 4aa (2.0 g, 4.0 mmol), catalyst Pd/C (848 mg, 0.2 eq, 10% Pd, wet), MeOH (20 mL) and a magnetic stirring bar were charged into an 50 mL Schlenk flask under nitrogen. The flask was sealed with a septum. The nitrogen was replaced with hydrogen gas using vacuum and a hydrogen gas balloon. The hydrogen gas balloon was kept in the flask and the mixture was stirred at ambient temperature (25-30 o C). Upon completion of the reaction as monitored by TLC (~ 24 h), the flask was opened and the solvent was removed using rotary evaporator under vacuum. The crude product was dissolved in aqueous NaOH solution (10 mL, 1 M). Pd/C and Cy 2 NH were removed by filtration through a Celite column, and the Celite cake was washed with aqueous NaOH solution (3 X 3 mL, 1 M). The filtrate was collected and the pH was titrated to 6 using HCl aqueous solution (2 M). Most of the solvent (~ 25 mL) was removed using rotary evaporator under vacuum and the product was precipitated. The solid was collected by filtration and dried under vacuum to give the final product 6aa (0.81 g, 89%). s20 This is a known compound, and its characterization data is consistent with the reported data.

UV-visible Absorption Analysis
The UV-visible absorption of the substrates N-benzyl-1,1-diphenylmethanimine (1a), Cy 2 NMe, and of the reaction mixture without catalyst was determined at a diluted solution ( The photoredox catalyst (Ir-7) is the only species that absorbs light at 400 nm according to the UV/vis spectra.

Stern-Volmer Luminescence Quenching Analysis
A 2 X 10 -5 M solution of photoredox catalyst (Ir-7) and variable concentrations of N-benzyl-1,1-diphenylmethanimine (1a) or Cy 2 NMe in dry MeCN were used for the Stern-Volmer luminescence quenching studies at room temperature under an argon atmosphere. The samples were prepared in 3 mL quartz cuvettes, equipped with PTFE stoppers and sealed with parafilm inside an glovebox. The solutions were irradiated at 400 nm and the luminescence was measured at 574 nm. The ratio of I 0 /I was plotted as a function of the quencher concentration (I 0 = emission intensity of the photocatalyst; I = observed emission intensity of the photocatalyst with quencher). The results are summarized in Supplementary Figure 49.
The results prove that the photoredox catalyst is only quenched by Cy 2 NMe. This indicates that Cy 2 NMe acts as electron donor and reduces the excited catalyst [Ir] 3+ * in the catalytic cycle.

Chemical Synthesis of Unnatural GLP1 Fragment
In addition to incorporation of unnatural amino acids into proteins using genetic code expansion techniques, chemical synthesis of peptides using unnatural amino acids is an alternative pathway. Thus, the chemical synthesis of unnatural GLP1 fragment was tested. Fmoc-His(Boc)-OH (47.8 mg, 0.1 mmol, 1 eq.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (23 mg, 0.12 mmol, 1.2 eq.), 4-dimethylaminopyridine (1.2 mg, 0.01 mmol, 0.1 eq.), dichloromethane (0.4 mL) and a magnetic stirring bar were charged into an 5 mL flask under nitrogen. The flask was sealed with a septum. After stirring for 5 minutes at room temperature, dichloromethane (0.2 mL) solution of diphenylglycine methyl ester (28.9 mg, 0.12 mmol, 1.2 eq.) was added. The mixture was stirred at ambient temperature (25-30 o C). Upon completion of the reaction as monitored by TLC (~ 10 h), the flask was opened and the solvent was removed using rotary evaporator under vacuum. The residue was purified by flash chromatography on silica gel using ethyl acetate and petroleum ether (50/1) as eluents to give the desired product (57.5 mg, 82% yield).