Enantioselective Organocatalytic Thiol Addition to α,β-Unsaturated α-Amino Acid Derivatives

Abstract

A new class of Michael acceptors based on α,β-unsaturated amino acids has been prepared and applied in asymmetric ­organocatalysis. With the use of thiourea derivatives of cinchona alkaloid-derived catalysts, efficient addition of thiols to the ­dehydroamino acids occurred with formation of β-thiol functionalized α-amino acids in high yields, moderate diastereoselectivities and ee values up to 95%.

Key words

organocatalysis - cinchona alkaloids - amino acids - thiols - conjugate addition

• References and Notes


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• 19 Synthesis of 7: Oxazolidinone (5.0 g, 57.4 mmol, 2.3 equiv) was dissolved in anhydrous THF (250 mL), and NaH (1.3 g, 55 mmol, 2.2 equiv) was added in portions. The resulting mixture was stirred for 30 min, then a solution of 5a (8.0 g, 25 mmol, 1 equiv) in anhydrous THF (50 mL) was added dropwise and stirring was continued for 30 min. Saturated NH₄Cl was added and the resulting mixture was extracted three times with EtOAc. The organic layers were combined, washed with brine and dried with MgSO₄. The product was purified by column chromatography (PE–EtOAc, 2:1) yielding a 1:10 mixture of E/Z-isomers 7a (5.3 g, 15.5 mmol, 62%). The Z-isomer was obtained by recrystallization (EtOAc–PE). Compound (Z)-7: ¹H NMR (400 MHz, CDCl₃): δ = 8.64 (s, 1 H), 7.47–7.40 (m, 5 H), 6.94 (s, 1 H), 4.44 (t, J = 7.6 Hz, 2 H), 4.05 (t, J = 7.6 Hz, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 164.5, 155.5 (q, J = 38.0 Hz), 152.9, 132.2, 131.6, 128.8, 129.4, 129.0, 125.6, 115.4 (q, J = 286.0 Hz), 63.0, 42.9. Compound (E)-7: ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (s, 1 H), 7.49–7.42 (m, 5 H), 6.65 (s, 1 H), 4.43 (t, J = 8.0 Hz, 2 H), 4.07 (t, J = 8.0 Hz, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ = 162.3, 155.7 (q, J = 38.0 Hz), 151.9, 132.0, 130.1, 129.7, 129.5, 129.1, 125.9, 115.4 (q, J = 286.0, 62.5, 42.0 Hz); IR (neat): 3253, 1617, 1717, 1685, 1529, 1388, 1209, 1184, 1155 cm^–1; HRMS (FAB): m/z [M + H]⁺ calcd. for C₁₄H₁₂F₃N₂O₄: 329.0749; found: 329.0746
• 20 Vakulya B, Varga S, Csampai A, Soos T. Org. Lett. 2005; 7: 1967
• 21 In addition to the cinchona derivatives, we performed a series of experiments with the thiourea catalyst developed by Takamoto.^6,8 With this organocatalyst, the reaction between thiophenol and (Z)-7a yielded the products in a diastereomeric ratio of 95:5 in CH₂Cl₂ but both isomers were formed in an unsatisfactory ee (i.e., 70% ee for the major diastereomer and 36% for the minor isomer). With 4-methoxybenzylthiol as the nucleophile, the reaction with the (Z)-7a catalyzed by the Takamoto thiourea led to the formation of products in a diastereomer ratio of 63:37 and in poor enantioselectivity (25% ee for the major isomer and 24% for the minor isomer)
• 22 Synthesis of 12: Compound 7a (885 mg, 2.69 mmol) and catalyst B (207 mg, 0.27 mmol) were dissolved in CH₂Cl₂ (13 mL). 4-methoxybenzylthiol (1.12 mL, 8.07 mmol) was added and the resulting mixture was stirred overnight. The product was concentrated and purified by column chromatography (PE–EtOAc, 2:1), yielding a 33:67 mixture of syn/anti-isomers of a slowly solidifying oil (1.24 g, 2.58 mmol, 96%). ¹H NMR (400 MHz, CDCl₃): δ = 7.53 (dd, J = 8.4, 1.6 Hz, 1 H), 7.41–7.32 (m, 3 H), 7.28–7.26 (m, 1 H), 7.16 (dd, J = 6.4, 2 Hz, 1.33 H), 7.10 (dd, J = 6.4, 2 Hz, 0.67 H), 7.00 (d, J = 9.6 Hz, 1 H), 6.87 (dd, J = 6.4, 2 Hz, 0.67 H), 6.84 (dd, J = 6.4, 2 Hz, 1.33 H), 6.33 (t, J = 7.6 Hz, 0.67 H), 6.02 (dd, J = 8.4, 5.2 Hz, 0.33 H), 4.46 (t, J = 8 Hz, 1.33 H), 4.36 (m, 0.33 H), 4.29 (d, J = 5.2 Hz, 0.33 H), 4.23 (d, J = 7.6 Hz, 0.67 H), 4.15 (m, 0.67 H), 4.06 (m, 0.67 H), 3.98–3.92 (m, 1.33 H), 3.83 (s, 1 H), 3.83 (s, 2 H), 3.73 (d, J = 12.8 Hz, 0.67 H), 3.65–3.60 (m, 0.67 H), 3.34 (d, J = 13.6 Hz, 0.33 H); ¹³C NMR (100 MHz, CDCl₃): δ = 168.6, 168.2, 158.9, 158.8, 156.6 (q, J = 38 Hz), 156.5 (q, J = 38 Hz), 152.9, 152.5, 136.8, 136.3, 130.2, 130.1, 129.3, 129.1, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 121.6, 115.5 (q, J = 286 Hz), 113.9, 62.6, 62.4, 56.4, 55.3, 54.1, 50.7, 49.4, 42.6, 42.5, 35.4, 34.6; IR (neat): 3319, 1779, 1728, 1698, 1537, 1214, 1173, 702 cm^–1; HRMS (FAB): m/z [M + H]⁺ calcd for C₂₂H₂₂F₃N₂O₅S: 483.1202; found: 483.1207; HPLC [Daicel Chiralcel AD; i-PrOH–heptane, 15:85 (0–40 min) then 30:70 (40–120 min); 1.0 mL/min; λ = 220nm]: t_R (major diastereoisomer) = 21.5 (minor), 110.8 (major) min; t_R (minor diastereoisomer) = 14.9 (minor), 21.5 (major) min. Recrystallization of the crude product (EtOAc–PE) gave the minor syn-isomer as a racemate (120 mg, 0.25 mmol, 9%). The mother liquor was concentrated and further recrystallized (EtOAc–PE) to give the anti-isomer as a pure enantiomer (503 mg, 1.04 mmol, 39%). Mp 142–144 °C; [α]_D –203.4 (c = 0.42, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (m, 3 H), 7.28 (m, 2 H), 7.16 (d, J = 8.4 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H), 6.32 (t, J = 8.4 Hz, 1 H), 4.48 (t, J = 8.0 Hz, 2 H), 4.23 (d, J = 7.2 Hz, 1 H), 4.07–4.01 (m, 1 H), 3.99–3.94 (m, 1 H), 3.81 (s, 3 H), 3.74 (d, J = 8.8 Hz, 1 H), 3.63 (d, J = 8.8 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 168.6, 158.8, 156.5 (q, J = 38 Hz), 152.8, 136.8, 136.3, 130.2, 129.3, 128.7, 128.6, 128.4, 115.5 (q, J = 286 Hz), 113.9, 62.4, 55.2, 54.1, 50.7, 42.5, 35.4
• 23a Crystal Structure Data for Compound 12: M _w = 482.27; colorless platelet; 0.27 × 0.22 × 0.06 mm; orthorhombic; P2₁2₁2₁; a = 10.0062(7) Å, b = 11.8687(4) Å, c = 18.6029(12) Å; V = 2209.3(2) Å³; Z = 4; D = 1.451 g·cm^–3; μ = 0.209 mm^–1. 66682 reflections were measured with a Nonius KappaCCD diffractometer (Mo radiation, graphite monochromator, λ = 0.71073 Å) up to a resolution of sinθ/λ = 0.65 Å^–1 at 208 K. 5067 reflections were unique (R _int = 0.0423) of which 4371 were observed with I_o ≥ 2σ(I_o). The structure was solved by direct methods with the PATTY option of the DIRDIF program system^23b,c and refined against F ² using SHELXL.^23d All non-hydrogen atoms were refined with anisotropic temperature factors. The hydrogen atoms were placed at calculated positions and refined isotropically in riding mode. The three fluorine atoms could not be refined adequately because of rotational disorder. The absolute structure was determined based on the anomalous dispersion of 2199 Friedel pairs, Flack parameter = 0.00(12), the Hooft parameter y = 0.014(16). R ₁ = 0.0685 [I ≥ 2σ(I)]; R ₁ = 0.0806 [all reflections]; S = 1.537. Residual electron density between 1.334 and –0.562 e·Å^–3. The data were deposited with the Cambridge Crystallographic Data Centre (CCDC 882528). More detailed information can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
• 23b Beurskens PT, Beurskens G, Bosman WP, de Gelder R, García-Granda S, Gould RO, Israël R, Smits JM. M. DIRDIF-96. Crystallography Laboratory; University of Nijmegen (The Netherlands): 1996
• 23c Beurskens PT, Beurskens G, Strumpel M, Nordman CE In Patterson and Pattersons . Glusker JP, Patterson BK, Rossi M. Clarendon Press; Oxford: 1987: 356-367
• 23d Sheldrick GM. SHELXL-97. University of Göttingen; Germany: 1997
• 24 Experimental procedure for the conversion of 12 into the β-phenyl-substituted cysteine 20: Enantiomerically pure compound 12 (200 mg, 0.41 mmol) was dissolved in a 1:2 mixture of 2 M KOH and MeOH (12 mL total volume) and stirred overnight. The resulting mixture was neutralized with 2 M HCl and the methanol was removed by evaporation. Ammonium bicarbonate (328 mg, 4.15 mmol) and a solution of Fmoc-OSu (138 mg, 0.41 mmol) in MeCN (4 mL) was added and the resulting mixture was stirred for 4 h. The mixture was acidified with 2 M HCl until pH 2. The mixture was extracted three times with EtOAc and the organic layers were combined, washed with brine and dried with MgSO₄. The solvents were evaporated and the product was purified by column chromatography (PE–EtOAc–AcOH, 3:2:0.1) yielding 20 (134 mg, 0.25 mmol, 60%) as a white solid. Mp 60–62 °C; [α]_D –72.1 (c = 0.37, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 4.4 Hz, 2 H), 7.58 (t, J = 8.0 Hz, 2 H), 7.49–7.31 (m, 9 H), 7.18 (d, J = 5.5 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 5.27 (d, J = 9.2 Hz, 1 H), 4.94 (m, 1 H), 4.44 (d, J = 6.8 Hz, 1 H), 4.35 (t, J = 7.2 Hz, 1 H), 4.26 (m, 2 H), 3.79 (s, 3 H), 3.68 (d, J = 13.2 Hz, 1 H), 3.56 (d, J = 13.2 Hz, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 174.1, 158.6, 143.7, 141.2, 136.4, 132.5, 130.5, 130.1, 129.7, 129.0, 128.7, 128.6, 128.2, 127.7, 127.1, 125.2, 125.1, 124.9, 119.9, 113.9, 67.4, 57.4, 55.2, 50.5, 47.0, 35.2; IR (neat): 3063, 3032, 2953, 1710, 1511, 1478, 1247, 1214, 1175, 701 cm^–1; HRMS (FAB): m/z [M + H]⁺ calcd for C₃₂H₃₀NO₅S: 540.1839; found: 540.1877
• 25 Although the ee values of 20 and 21 could not be readily measured by using HPLC techniques, the absence of any epimerization according to ¹H HMR spectroscopic analysis is a strong indication that these compounds are enantiopure