Organocatalytic Enantioselective Hydrazination of 1,3-Dicarbonyl ­Compounds: Asymmetric Synthesis of α,α-Disubstituted α-Amino Acids

Abstract

The organocatalytic α-hydrazination of β-keto esters using a bifunctional urea as catalyst and azodicarboxylates as electrophiles has been investigated and is shown to proceed in high yields and with good enantioselectivity. The scope of the reaction is de­monstrated for various substrates and the urea catalyst 1b was revealed to be superior to thiourea 1a. Furthermore, transformation of the obtained product 4aa into optically active amino acid derivative 10 is also presented.

Key words

addition reactions - amino acids - asymmetric synthesis - keto esters - organocatalysts

References and Notes

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14

General Experimental Procedure.
To a stirred solution of 1,3-dicarbonyl compound 3 (0.11 mmol, 110 mol%) and urea catalyst 1b (4.0 mg, 0.010 mmol) in toluene (1 mL) was added di-tert-butyl azodicarboxylate (2a, 23.0 mg, 0.10 mmol) at the temperature described in Table [2] . The resulting yellow solution was stirred at the same temperature until the yellow color of the solution disappeared. The reaction mixture was concentrated in vacuo and the obtained residue was purified by silica gel column chromatography to give the desired product 4.
All new compounds 4 gave satisfactory spectral data. Selected characterization data: Compound 4f (Table [2] , entry 5): the enantioselectivity was determined to be 89% ee by chiral HPLC using a Chiralpak OD-H column [hexane-i-PrOH = 95:5, 0.5 mL/min, λ = 210 nm, t _R(major) = 9.4 min, t _R(minor) = 11.8 min]. [α]_D ²⁵ +22.4 (c 0.33, CHCl₃). IR (CHCl₃): ν = 3370, 2936, 2253, 1726, 1240 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.40 (br s, 1 H), 2.60 (m, 1 H), 2.22 (m, 1 H), 1.93 (m, 1 H), 1.66 (m, 1 H), 1.49 (m, 6 H), 1.47 (s, 9 H), 1.46 (s, 9 H), 1.44 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 169.9, 156.5, 155.9, 155.5, 81.4, 60.3, 52.7, 52.5, 40.6, 39.4, 34.7, 30.3, 28.1, 28.0, 27.9, 25.7, 23.7. MS (FAB^-): m/z (%) = 443 (80) [MH⁺], 275 (100). HRMS (FAB⁺): m/z calcd for [C₂₂H₃₉N₂O₇]⁺: 443.2757; found: 443.2763.
Compound 4g (Table [2] , entry 6): the enantioselectivity was determined to be 90% ee by chiral HPLC using a Chiralpak AD-H column [hexane-EtOH = 90:10, 0.25 mL/min, λ = 254 nm, t _R (major) = 25.4 min, t _R(minor) = 18.9 min]. [α]_D ²⁵ +50.9 (c 0.10, CHCl₃). IR (CHCl₃): ν = 3156, 2985, 2360, 1725, 1152 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.74 (m, 1 H), 7.60 (d, J = 6.41 Hz, 1 H), 7.48 (d, J = 7.63 Hz, 1 H), 7.35 (d, J = 7.93 Hz, 1 H), 6.73 (br s, 1 H), 4.20 (d, J = 16.8 Hz, 1 H), 3.75 (d, J = 16.5 Hz, 1 H), 1.49 (s, 9 H), 1.41 (s, 9 H), 1.29 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 171.2, 154.9, 154.2, 153.7, 135.9, 135.3, 133.6, 127.4, 126.0, 124.8, 82.6, 82.0, 81.4, 81.1, 60.3, 28.1, 27.8, 27.6. MS (FAB⁺): m/z (%) = 463 (70) [MH⁺], 295 (100). HRMS (FAB⁺): m/z calcd for [C₂₄H₃₅N₂O₇]⁺: 463.2444; found: 463.2440.