Photoredox-Enabled Decarboxylative Synthesis of Unnatural α-Amino Acids

Abstract

Recently, development of general synthetic routes to unnatural α-amino acids has gained a significant momentum, driven by the high demand for such building blocks in fundamental research within molecular and structural biology, as well as for development of new pharmaceuticals. Herein, we highlight the recent progress in employing photoredox-mediated synthetic methods for accessing unnatural α-amino acids with a focus on various decarboxylative radical-based strategies.

Pd(II) Complexes of Chiral Proline-Derived Ligands: Application for Dynamic Thermodynamic Resolution of α-Amino Acids and Their Antibacterial Activities

“….20 (ddt, J = 8.9, 7.7, 3.9 Hz, 3H), 7.12 (ddd, J = 8.9, 6.8, 2.5 Hz, 1H), 6.81−6.77 (m, 1H), 6.70 (d, J = 2.6 Hz, 1H), 4.78 (dd, J = 6.7, 4.9 Hz, 1H), 4.28 (d, J = 12.6 Hz, 1H), 3.70 (dd, J = 10.5, 7.0 Hz, 1H), 3.57−3.50 (m, 2H), 3.34 (dd, J = 13.9, 4.9 Hz, 1H), 3.25 (dd, J = 13.9, 6.6 Hz, 1H), 2.64−2.52 (m, 1H), 2.48 (td, J = 10.8, 6.9 Hz, 1H), 2.42−2.24 (m, 1H), 1.97−1.89 (m, 1H). 13 Hz, 1H), 2.74−2.45 (m, 3H), 2.19 (dddd, J = 12.2, 8.0, 5.9, 2.3 Hz, 1H), 1.83−1.63 (m, 2H), 1.60−1.37 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 179.9, 179.8, 167.…”

“…13 Hz, 1H), 2.74−2.45 (m, 3H), 2.19 (dddd, J = 12.2, 8.0, 5.9, 2.3 Hz, 1H), 1.83−1.63 (m, 2H), 1.60−1.37 (m, 2H), 0.71 (t, J = 7.2 Hz, 3H). 13 C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 179.9, 179.8, 167. 5, 140.6, 133.9, 133.8, 133.7, 133.6, 133.0, 132.9, 132.8, 130.7, 130.6, 130.4, 129.4, 129.3, 128.8, 127.6, 127.5, 126.0, 123.5, 74.2, 72.6, 64.4, 60.1, 37.3, 30.6, 23.4, 18.5, 13.6.…”

“…Although α-amino acids commonly found in nature are predominantly presented in the (S)-config-uration, α-amino acids in the (R)-configuration equally play a significant role in drug development. 13 For instance, (R)-αamino acids are often introduced into peptide drugs to improve metabolic stability by avoiding the recognition of protease, which is also known as the reverse peptide strategy. 14 While the α-amino acid derivatives obtained by such DKR of azlactones are almost in (S)-configuration, the purely chemical synthesis of (R)-α-amino acids is disproportionally less developed.…”

“…−7.11 (m, 2H), 7.03 (dq, J = 7.6, 1.0 Hz, 1H),6.78 (d, J = 2.6 Hz, 1H), 4.76 (dd, J = 6.4, 4.2 Hz, 1H), 4.26 (d, J = 12.7 Hz, 1H), 3.65 (dd, J = 10.7, 6.8 Hz, 1H), 3.51 (t, J = 11.5 Hz, 2H), 3.10 (dd, J = 13.6, 4.1 Hz, 1H), 2.90 (dd, J = 13.6, 6.4 Hz, 1H), 2.46 (dddd, J = 25.8, 12.5, 10.7, 7.9 Hz, 2H), 2.12−1.90 (m, 2H), 1.81− 1.72 (m, 1H) 13. C{ 1 H} NMR (125 MHz, CDCl 3 ) δ 179.1, 177.7, 168.4, 147.0, 142.7, 140.7, 133.5, 133.3, 133.2, 133.1, 133.0, 132.7, 132.4, 130.5, 130.3, 130.2, 129.8, 129.4, 129.1, 127.5, 127.1, 127.0, 125.6, 123.1, 122.8, 73.5, 72.6, 64.1, 59.6, 39.1, 30.1, 22.3.…”

“…(S)-2-Amino-3-(4-chlorophenyl)propanoic Acid (S)-2e. White solid, 92 mg, yield 92%; mp 261−262 °C; [α] D 20 = −5.0 (c 0.100 g/100 mL, MeOH); 1 H NMR (400 MHz, D 2 O) δ 7.25 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H),3.80 (t, J = 6.5 Hz, 1H), 3.08 (dd, J = 13.8, 5.0 Hz, 1H), 2.94 (dd, J = 14.6, 7.8 Hz, 1H) 13. C{ 1 H} NMR (125 MHz, D 2 O) δ 173.8, 133.8, 132.8, 130.9, 128.9, 55.9, 35.8.…”