Stereoselective Synthesis of syn-γ-Hydroxynorvaline and Related α-Amino Acids

Abstract

The total syntheses of three enantiomerically pure non-proteinogenic amino acids, l-norvaline, γ-oxonorvaline, and syn-γ-hydroxynorvaline, are reported. The chromatography-free route pivoted on the construction of highly enantiomerically enriched substituted α-amino-γ-oxopentanoic acid, from which all three members were accessed divergently via chemoselective and stereoselective reductions. The rapid synthesis of this key α-amino-γ-oxopentanoic acid was achieved by a highly diastereoselective crystallisation-driven three-component Mannich reaction from the readily available building blocks acetone, glyoxylic acid monohydrate, and (S)-(4-methoxyphenyl)ethylamine. The enantiomeric purity of all target molecules was confirmed by HPLC analysis, either of the amino acids or their derivatives.

Silver‐Catalyzed Diastereoselective Synthesis of Spirocyclic Pyrrolidine‐Lactones by 1,3‐Dipolar Cycloaddition

“…The synthesis of enantiomerically enriched aminolactone 23a was reported by us following the chemical sequence depicted in Scheme . The sequence started with a crystallisation‐induced asymmetric transformation (CIAT)‐aza‐Michael addition of amine ( R )‐ 18 to 3‐acetylacrylic acid 19a affording enantiomerically pure (99:1 dr ) adduct 20a in 92 % yield.…”

“…Compound 23a was prepared according to the literature. [22] Analytical TLC was performed on Schleicher & Schuell F1400/LS 254 silica gel plates, and the spots were visualized under UV light (λ = 254 nm). Melting points were determined with a Reichert Thermovar hot plate apparatus and are uncorrected.…”

“…5, 127.5, 130.7, 132.0, 132.2, 137.1, 137.8, 138.2, 170.1, 188. (m, 2H), 7.77 (m, 1H), 7.92-8.04 (m, 2H) ppm; 13 C NMR (75 MHz,[D 6 ]acetone/DCl) δ C = 20.7, 53.3, 53.3, 55.6, 59.3, 115.2, 123.1, 128.1, 128.2, 130.8, 131.4, 131.6, 137.1, 161.2, 169.3, 195 17-7.31 (m, 2H), 7.34-7.55 (m, 4H) ppm; 13 C NMR (75 MHz, CD 3 OD) δ C = 20.5, 39.3, 56.1, 57.1, 59.2, 70.8, 115.9, 123.3, 125.6, 128.0, 129.6, 130.6, 131.4, 131.7, 147.1, 161.9, 169.7 17-7.29 (m, 3H), 7.07-7.12 (m, 1H), 7.31-7.35 (m, 1H), 7.40-7.44 (m, 1H) ppm; 13 C NMR (75 MHz, CDCl 3 ) δ C = 24.8, 38.8, 54.5, 55.4, 57.2, 77.5, 114.0, 123.0, 123.6, 128.1, 128.2, 130.5, 131.4, 136.8, 141.8, 159.0, 177 3S,3′R,3a′S,5R,6a′R)-5,5′-Dimethyl-3′-phenylhexahydro-2H,4′Hspiro[furan-3,1′-pyrrolo[3,4-c]pyrrole]-2,4′,6′(5′H)-trione (17aa): White solid (84.6 mg, 90 % yield, 90:10 dr); without purification; mp: 234°C; [α] D 25.7 = -51.7 (c 0.50, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ H = 1.56 (d, J = 5.1 Hz, 3H, CH 3 ), 1.94 (t, J = 11.4 Hz, 1H, CH 2 ), 2.70 (m, 1H, CH 2 ), 2.91 (s, 3H, NCH 3 ), 3.37 (d, J = 6.7 Hz, 1H, CCH), 3.62 (bs, 1H, NCHCH), 4.64 (d, J = 6.8 Hz, 1H, NCH), 4.81 (bs, 1H, CHCH 3 ), 7.38 (bs, 5H, ArH) ppm; 13 C NMR (CDCl 3 ) δ C = 20.5 (CHCH 3 ), 25.3 (NCH 3 ), 46.3 (CH 2 ), 51.0 (CHCO), 54.6 (CHCO), 64.7 (NCH), 69.8 (NC), 73.6 (CHCH 3 ), 127. 0,128.5,128.6,135.8 (ArC), 174.2 (CO), 174.6 (CO), 175.1 (CO) ppm; IR (ATR) ν: 3025,2981,2926,1770,1697,1438,1389,1286, 1201 cm -1 ; MS (EI): m/z 314 (M + , 8 %), 270 (27), 256 (18), 255 (100), 242 (14), 241 (22), 156 (11); HRMS calcd. for C 17 H 18 N 2 O 4 : 314.1267, found 314.1278.…”

“…(3S,3′R,3a′S,5R,6a′R) 26.2 = -68.5 (c 0.71, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ H = 1.55 (d, J = 6.1 Hz, 3H, CH 3 ), 1.97 (dd, J = 12.3, 11.0 Hz, 1H, CH 2 ), 2.44 (s, 3H, CCH 3 ) 2.74 (dd, J = 12.5, 4.6 Hz, 1H, CH 2 ), 2.85 (s, 3H, NCH 3 ), 3.39 (d, J = 7.7 Hz, 1H, CCH), 3.69 (t, J = 7.9 Hz, 1H, NCHCH), 4.7 (d, J = 8.1 Hz, 1H, NCH), 4.77-4.87 (m, 1H, CHCH 3 ), 7.20-7.35 (m, 4H, ArH) ppm; 13 C NMR (CDCl 3 ) δ C = 19.8 (CH 3 ), 20.5 (CH 3 ), 25.3 (NCH 3 ), 45.9 (CH 2 ), 48.5 (CHCO), 54.2 (CHCO), 61.1 (NCH), 69.2 (NC), 73.6 (CHCH 3 ), 124. 8, 126.4, 128.2, 130.5, 134.2, 135.6 (ArC), 173.8 (CO), 174.6 (CO), 175.0 (CO) ppm; IR (ATR) ν: 3022,2977,2932,1773,1699,1434,1285,1198, 1095 cm -1 ; MS (EI): m/z 320 (16), 278 (43), 276 (22), 261 (100), 248 (18), 247 (22), 209 (11), 164 (10), 96 (12); HRMS calcd. for C 18 H 20 N 2 O 4 : 328.1423, found 328.1430.…”

“…(3S,3′R,3a′S,5R,6a′R)-3′-(4-Methoxyphenyl)-5,5′-dimethylhexahydro-2H,4′H-spiro[furan-3,1′-pyrrolo[3,4-c]pyrrole]-2,4′,6′(5′H)trione (17ai): White solid (87.8 mg, 85 % yield, 89:11 dr); Precipitation CHCl 3 /n-Hexane; mp: 184°C; [α] D 24.6 = -151.9 (c 0.5, CHCl 3 ); 1 H NMR (300 MHz, CDCl 3 ) δ H = 1.54 (d, J = 6.1 Hz, 3H, CH 3 ), 2.03 (t, J = 11.6 Hz, 1H, CH 2 ), 2.68 (dd, J = 12.5, 4.5 Hz, 1H, CH 2 ), 2.86 (s, 3H, NCH 3 ), 3.38 (t, J = 7.7 Hz, 1H, CCH), 3.60 (t, J = 7.8 Hz, 1H, NCHCH), 3.81 (s, 3H, OCH 3 ), 4.65 (d, J = 8.1 Hz, 1H, NCH), 4.73-4.83 (m, 1H, CHCH 3 ), 6.9 (d, J = 8.7 Hz, 1H, ArH), 7.26 (d, J = 8.7 Hz, 1H, ArH) ppm; 13 C NMR (CDCl 3 ) δ C = 20.4 (CHCH 3 ), 25.4 (NCH 3 ), 45.9 (CH 2 ), 50.7 (CHCO), 54.5 (CHCO), 55.4 (OCH 3 ), 64.5 (NCH), 69.7 (NC), 73.8 (CHCH 3 ), 114. 0,127.0,128.3,159.7 (ArC), 174.1 (CO), 174.4 (CO), 174.9 (CO) ppm; IR (ATR) ν: 2981, 2911, 1774, 1693, 1245 cm -1 ; MS (EI): m/z 344 (M + , 30 %), 300 (26), 299 (13), 286 (20), 285 (100), 273 (16), 271 (10), 270 (22), 233 (43), 188 (17), 187 (13), 173 (13), 134 (10), 121 (12); HRMS calcd. for C 18 H 20 N 2 O 5 : 344.1372, found 344.1375.…”