Direct Access to Unnatural Cyclobutane α-Amino Acids through Visible Light Catalyzed [2+2]-Cycloaddition

In this work, we report the first selective, photocatalyzed [2+2]-cycloaddition of dehydroamino acids with styrene-type olefins. This simple, mild, and scalable approach relies on the use of the triplet energy transfer catalyst [Ir(dFCF3ppy2)dtbpy]PF6 under visible light irradiation and provides fast access to value-added substituted strained cyclobutane α-amino acid derivatives.


S5
.0]undec-7-en (DBU) (29.9 µL, 0.2 mmol, 0.1 equiv.) was added and the mixture was stirred at room temperature for an additional 8 h. Afterwards, 10 mL EtOAc and 10 mL water was added and the phases were separated. The aqueous phase was extracted three times with 10 mL EtOAc. The combined organic phases were washed with 1 M HCl and brine, dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The crude was purified by flash column chromatography (5% to 10% EtOAc/pentane), obtaining the product

Methyl 2-(((benzyloxy)carbonyl)amino)acrylate (1e)
D,L-Serine methyl ester hydrochloride (1.00 g, 6.4 mmol, 1.0 equiv.) was suspended in 20 mL CH2Cl2. Et3N (2.7 ml, 19.3 mmol, 3.0 equiv.) was added and the mixture was stirred for 20 min. Cbz-Cl (1.14 mL, 7.7 mmol, 1.2 equiv.) was added and stirred at room temperature for 16 h. Water (20 mL) was added and the mixture was extracted three times with CH2Cl2. The combined organic layer was washed with 1 M HCl, brine and dried over anhydrous MgSO4. After drying under vacuum, the product was obtained as colorless oil. The residue was re-dissolved in 10 mL anhydrous CH2Cl2. At 0 °C, methyl sulfonyl chloride (0.62 mL, 8.0 mmol, 1.25 equiv.) was added and S7 stirred at the same temperature for 10 min. Then, triethylamine (2.7 ml, 19.3 mmol, 3.0 equiv.) was added at 0 °C, stirred at the same temperature for an additional 30 min and at room temperature for 16 h. The reaction was quenched with 15 mL water. The mixture was extracted three times with CH2Cl2, washed with NaHCO3 (sat.), brine, dried over MgSO4 and the solvent was removed under vacuum. The residue was purified by flash column chromatography (5% to 10% EtOAc/pentane), obtaining the product (929.4 mg, 3.95 mmol, 61%) as a colorless oil. 1
The crude product was purified by flash column chromatography (50% EtOAc/pentane) to obtain the desired product as a mixture of diastereoisomers 2
The crude product was purified by flash column chromatography (25% to 33% EtOAc/pentane) to obtain the desired product as a mixture of diastereoisomers with 4:1 d.r. (5.6 mg, 15.4 µmol, 8%) as a pale yellow oil. Only the major isomer could be isolated as the pure substance. Major isomer 3ga:

Cyclic Voltammetry
The cyclic voltammogram of methyl 2-acetamidoacrylate (1a) was taken on a Metrohm Autolab PGSTAT204 potentiostat using a platinum wire working electrode, a platinum mesh counter electrode and a silver reference electrode, which was referenced externally against the Fc/Fc+ couple. The pH was not adjusted and the voltammogram was taken at room temperature in a 0.1 M CH3CN solution of tetrabutylammonium hexafluorophosphate containing 10 mM of the designated substrate. The scan rate was 50 mV/s. Ferrocene was added as internal standard. It is known that the Fc/Fc+ couple is 0.38 V more positive than the SCE. This value may be subtracted from the obtained difference to determine the potential against SCE.   for the observed data and wR2 = 12.86% for all data. The goodness-of-fit was 1.050. The largest peak in the final difference electron density synthesis was 0.354 e -/Å 3 and the largest hole was -0.185 e -/Å 3 with an RMS deviation of 0.041 e -/Å 3 . On the basis of the final model, the calculated density was 1.201 g/cm 3 and F(000), 1120 e -. The hydrogen at N1 atom was refined freely.
A colorless plate-like specimen of C15H19NO3, approximate dimensions 0.042 mm x 0.114 mm x 0.148 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured on a single crystal Bruker D8 Venture Photon III Diffractometer system equipped with a micro focus tube CuKa (CuKa, l = 1.54178 Å) and a MX mirror monochromator. A total of 1766 frames were collected. The total exposure time was 23.20 hours.
The frames were integrated with the Bruker SAINT software package using a wide-frame algorithm. The integration of the data using a monoclinic unit cell yielded a total of 14459 reflections to a maximum q angle of 68.20° (0.83 Å resolution), of which 2498 were independent (average redundancy 5.788, The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P21, with Z = 4 for the formula unit, C24H35NO3. The final anisotropic full-matrix least-squares refinement on F 2 with 522 variables converged at R1 = 8.51%, for the observed data and wR2 = 22.51% for all data. The goodness-of-fit was 0.957. The largest peak in the final difference electron density synthesis was 0.303 e -/Å 3 and the largest hole was -0.279 e -/Å 3 with an RMS deviation of 0.084 e -