Synthesis of Optically Pure (S,E)-2-Amino-5-arylpent-4-enoic Acids by Heck Reactions of Nickel Complexes

Abstract

Starting from commercially available building blocks a variety of enantiomerically pure (S)-2-amino-4-enoic acids has been synthesized by the Heck reaction using Ni-(S)-BPB {Nickel-N-[(S)-benzylprolyl]aminobenzophenone} as a chiral auxiliary. The reactions proceeded in very good yields and with high E-selectivity.

Key words

amino acids - Heck reaction - catalysis - chiral auxiliary - ­enantioselectivity

• References and Notes

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• 21 (S,E)-2-Amino-2-methyl-5-[phenyl]pent-4-enoic acid–Ni–(S)-BPB (3a) Compound 2b (221 mg, 1.0 equiv), Pd(PPh₃)₄(23 mg, 0.05 equiv), and bromobenzene (72 μl, 1.7 equiv) were added to a pressure tube and dissolved in 1,4-dioxane (6 ml, 15 l/mol 2b) and HN ⁱ Pr₂ (6 mL, 15 l/mol 2b). The mixture was stirred at 101 °C for 24 h. After cooling to room temperature it was diluted with ethyl acetate and washed with water. The organic layer was dried with Na₂SO₄ and filtered. The solvent was removed under reduced pressure, and the residue was purified by silica column chromatography (ethyl acetate/heptanes, 2:1 >> 1:0) to yield 3a as a red solid; yield 88%, mp 112–113 °C. ¹H NMR (250 MHz, CDCl₃): δ = 1.27 (s, 3 H, CH₃), 1.35–1.74 (m, 1 H, CH₂), 1.82–1.99 (m, 1 H, CH₂), 2.01–2.25 (m, 2 H, CH₂), 2.48–2.73 (m, 3 H, CH₂), 3.27 (dd, ³ J = 9.8 Hz, ³ J = 7.1, 1 H, CH), 3.42–3.55 (m, 1 H, CH₂), 3.61 (d, ² J = 12.7 Hz, 1 H, CH₂Ph), 4.40 (d, ² J = 12.7 Hz, 1 H, CH₂Ph), 6.58–6.74 (m, 3 H, CH), 6.85–7.00 (m, 1 H, CH), 7.03–7.19 (m, 2 H, CH), 7.21–7.57 (m, 11 H, CH), 7.61–7.74 (m, 1 H, CH), 7.96–8.10 (m, 3 H, CH). ¹³C NMR (63 MHz, CDCl₃): δ = 23.1 (CH₃), 29.7, 30.7, 43.9, 63.6 (CH₂), 70.2 (CH), 78.7 (C), 120.9, 124.0, 124.2, 126.8, 127.2, 127.7, 128.0, 128.3 (CH), 128.7 (C) 128.8, 129.0, 129.1, 129.7, 130.8, 131.9 (CH), 133.5 (C), 133.7, 134.7 (CH), 136.8, 137.3, 142.0 (C), 172.8 (C=N), 180.7 (C=O), 181.9 (C=O). IR (ATR): ν = 3057 (w), 3025 (w), 2922 (br, w), 2867 (w), 1668 (m), 1634 (s), 1594 (w), 1574 (w), 1534 (w), 1495 (w), 1469 (w), 1436 (m), 1355 (s), 1331 (m), 1312 (w), 1287 (w), 1250 (s), 1163 (m), 1118 (w), 1062 (w), 1000 (w), 964 (m), 927 (w), 885 (w), 824 (w), 748 (s), 695 (s), 618 (w), 563 (w), 540 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 627 (5) [M⁺], 585 (15), 584 (13), 583 (32), 510, (7), 492 (4), 440 (4), 439 (4), 425 (4), 347 (1), 328 (2), 280 (2), 278 (2), 161 (9), 160 (89). ESI-HRMS: m/z calcd for C₃₇H₃₆N₃NiO₃ [M + H⁺]: 628.21047; found: 628.20997; m/z calcd for C₃₇H₃₆N₃ ⁶⁰NiO₃ [M + H⁺]: 630.20798; found: 630.20805; m/z calcd for C₃₇H₃₅N₃NiNaO₃ [M + Na⁺]: 650.19241; found: 650.19232; m/z calcd for C₃₇H₃₅N₃Na⁶⁰NiO₃ [M + Na⁺]: 652.18992; found: 652.18952.
• 22 (S,E)-2-Amino-2-methyl-5-[phenyl]pent-4-enoic acid (4a) Compound 3a (190 mg, 1.0 equiv) was dissolved in MeOH/H₂O (10 ml/5 ml), and HCl (12 M, 1.5 ml) was added dropwise. The stirred mixture was heated to reflux for 20 min (during which time the color changed from red to green). After cooling to room temperature the mixture was diluted with water and extracted with DCM four times. The aqueous layer was treated with 5% aq NH₃solution to reach pH 2. The solution was further purified by cation exchange column (Dowex 50WX8 H⁺, see Supporting Information for details) to yield 4a as white solid; yield 85%, mp 267–268 °C. ¹H NMR (300 MHz, CD₃OD): δ = 1.64 (s, 3 H, CH₃), 2.79 (dd, ³ J = 7.6 Hz, ² J = 14.5 Hz, 1 H, CH₂), 2.87 (dd, ³ J = 7.6 Hz, ² J = 14.5 Hz, 1 H, CH₂), 6.21 (dt, ³ J = 7.6 Hz, ³ J = 15.4 Hz, 1 H, C=C), 6.65 (d, ³ J = 15.4 Hz, 1 H, C=C), 7.19–7.34 (m, 3 H, Ph), 7.40–7.45 (m, 2 H, Ph). ¹³C NMR (75 MHz, CD₃OD): δ = 22.7 (CH₃), 41.8 (CH₂), 61.2 (C), 121.8 (CH), 127.7, 129.1, 129.7, 137.8 (CH), 138.1 (C), 173.5 (COOH). IR (ATR): ν = 3000 (br, m), 1656 (br, w), 1540 (w), 1573 (s), 1494 (w), 1450 (w), 1397 (s), 1366 (m), 1287 (w), 1264 (w), 1239 (w), 1130 (w), 1070 (w), 965 (s), 883 (w), 788 (w), 739 (s), 690 (s), 629 (w), 587 (w), 553 (w) cm^–1. MS (EI, 70 eV): m/z (%) = 206 (4), 205 (2) [M⁺], 194 (5), 193 (13), 178 (4), 161 (6), 160 (64), 159 (12), 144 (12), 143 (16), 129 (13), 128 (34), 118 (31), 117 (87), 116 (50), 115 (86), 102 (12), 91 (60), 90 (6), 89 (42), 88 (100), 80 (16), 77 (15), 65 (13), 63 (11). HRMS (EI): m/z calcd for C₁₂H₁₆NO₂ [M + H⁺]: 206.11756; found: 206.11778.