Palladium-catalyzed asymmetric three-component reaction between glyoxylic acid, sulfonamides and arylboronic acids for the synthesis of α-arylglycine derivatives

A palladium-catalyzed asymmetric three-component synthesis of α-arylglycine derivatives starting from glyoxylic acid, sulfonamides and arylboronic acids is reported. This novel, operationally simple method offers access to the α-arylglycine scaffold in good yields and enantioselectivities. The utilization of α tailored catalyst system enables the enantioselective synthesis of the desired α-arylglycines despite a fast racemic background reaction. The obtained products can be directly employed as building blocks in peptide synthesis.

in Hz and the observed signal multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet.
Mass spectrometry -Mass spectra (MS) were measured using ESI (electrospray ionization) techniques. High resolution mass spectra (HRMS) were acquired on a Waters GCT Premium using electron ionization mass spectroscopy (EI-MS-TOF).
Infrared spectroscopy -Infrared spectra (IR) were recorded on a FT-IR (Fourier transform infrared spectroscopy) spectrometer including a diamond universal ATR sampling technique (attenuated total reflectance) from 4000-400 cm -1 . The absorption bands were reported in wave numbers (cm -1 ).
Optical rotations -Rotation values (α) were measured using with an analog type 243B polarimeter from PerkinElmer, equipped with a sodium lamp source (589 nm), at 20 °C in 10 cm cell and the indicated solvent. The specific rotation values are reported as [α]λ T (mass concentration (c) in g*100 mL -1 , solvent) and are quoted in deg*mL*dm -1 *g -1 .
Analytical chiral HPLC -Enantiomeric ratios (e.r.) and accordingly enantiomeric excesses (e.e.) were determined by normal phase high performance liquid chromatographic (HPLC) analysis with a Hewlett Packard TM system (G1322A degasser, G1311 quadruple pump, G1316A diode array detector with visualization at 254 nm) and the use of a Chiralpak ® IA, Chiralcel ® OD-H or OJ-H as chiral column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. Elution conditions for specific compounds are reported in the SI.
Melting points -Melting points are uncorrected.

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Preparation and analytical data

General procedures (GP)
GP1 (Initial experiments) -A 10 mL screw cap glass vial was charged with a magnetic stirring bar, sulfonamide 12 (134.7 mg, 0.50 mmol, 1.0 equiv), glyoxylic acid (59.8 mg, 0.65 mmol, 1.3 equiv), phenylboronic acid (121.9 mg, 1.00 mmol, 2.0 equiv), Pd(TFA)2 (8.3 mg, 25 µmol, 0.05 equiv), S,S'-iPrBox L1 (8.4 mg, 37.5 µmol, 0.075 equiv) and nitromethane (0.25 M referring to sulfonamide, 2 mL) as solvent. Then the vial was closed with a teflon lined screw cap and the resulting reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with acetone and filtered through a short plug of celite and silica gel. The filter pad was rinsed with additional acetone and the combined filtrates were concentrated under reduced pressure. Purification of the crude residue by flash column chromatography afforded the analytically pure product.
GP2 (Ligand variation) -A 10 mL screw cap glass vial was charged with a magnetic stirring bar, sulfonamide 12 (134.7 mg, 0.50 mmol, 1.0 equiv), glyoxylic acid (59.8 mg, 0.65 mmol, 1.3 equiv), phenylboronic acid (121.9 mg, 1.00 mmol, 2.0 equiv), Pd(TFA)2 (8.3 mg, 25 µmol, 0.05 equiv), ligand (37.5 µmol, 0.075 equiv) and nitromethane (0.25 M referring to sulfonamide, 2 mL) as solvent. Then the vial was closed with a teflon lined screw cap and the resulting reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with acetone and filtered through a short plug of celite and silica gel. The filter pad was rinsed with additional acetone and the combined filtrates were concentrated under reduced pressure. Purification of the crude residue by flash column chromatography afforded the analytically pure product.
Then the vial was closed with a teflon lined screw cap and the resulting reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with acetone and filtered through a short plug of celite and silica gel. The filter pad was rinsed with additional acetone and the combined filtrates were concentrated under reduced pressure. Purification of the crude residue by flash column chromatography afforded the analytically pure product.
GP4 (Boronic acid variation) -A 10 mL screw cap glass vial was charged with a magnetic stirring bar, Pd(TFA)2 (16.6 mg, 50 µmol, 0.1 equiv), L1 (16.8 mg, 75 µmol, 0.15 equiv) and nitromethane (1 mL) as solvent. After 30 min at 40 °C the sulfonamide 12 (134.7 mg, 0.50 mmol, 1.0 equiv), glyoxylic acid (59.8 mg, 0.65 mmol, 1.3 equiv), arylboronic acid (1.00 mmol, 2.0 equiv) were added and the inner wall was rinsed with 1 mL nitromethane. Then the vial was closed with a teflon lined screw cap and the resulting reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with acetone and filtered through a short plug of celite and silica gel. The filter pad was rinsed with additional acetone and the combined filtrates were concentrated under reduced pressure. Purification of the crude residue by flash column chromatography afforded the analytically pure product.
GP6 (Deprotecting of Pbf-group) -The N-Pbf-group was removed by a method according to known literature. 1 The N-Pbf-protected α-arylglycine-derivative (1.0 eq) was added to a suitable round flask and a solution of TFA (69 equiv, 23.4 mmol, 1.8 mL) and DMS (8.0 equiv, 2.7 mmol, 0.2 mL) GP7 (Sulfonamide variation) -A 10 mL screw cap glass vial was charged with a magnetic stirring bar, Pd(TFA)2 (16.6 mg, 50 µmol, 0.1 equiv), L1 (16.8 mg, 75 µmol, 0.15 equiv) and nitromethane (1 mL) as solvent. After 30 min at 40 °C the sulfonamide (0.50 mmol, 1.0 equiv), glyoxylic acid (59.8 mg, 0.65 mmol, 1.3 equiv), phenylboronic acid (121.9 mg, 1.00 mmol, 2.0 equiv) were added and the inner wall was rinsed with 1 mL nitromethane. Then the vial was closed with a teflon lined screw cap and the resulting reaction mixture was stirred at 40 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with acetone and filtered through a short plug of celite and silica gel. The filter pad was rinsed with additional acetone and the combined filtrates were concentrated under reduced pressure. Purification of the crude residue by flash column chromatography afforded the analytically pure product.