Investigations on the [2,3]-Wittig Rearrangement of Chiral 4-Aminopropargyloxy Acetates to Novel α-Hydroxy-γ-amino Acids Containing an Allene Unit

Abstract

The [2,3]-Wittig rearrangement of propargyloxy acetates bearing a propargylic stereocenter opposite to the oxyacetic acid moiety gives α-hydroxy-γ-amino acids containing an allene unit under high stereocontrol. The resulting product displays a novel type of γ-amino acid with a potentially intriguing biological profile.

Key words

Wittig rearrangement - propargyloxy acetates - γ-amino acids - allenes

• References and Notes

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• 10 Synthesis of tert-Butyl (2R,4S)-4-[(tert-Butoxycarbonyl)amino]-2-hydroxy-6-methyl-3-(2-methylprop-1-en-1-ylidene)heptanoate (13): Under an atmosphere of argon, i-Pr₂NH (230 mg, 2.27 mmol) was dissolved in anhydrous THF (2 mL) and charged with n-BuLi (1.6 M in n-hexane, 2.16 mmol, 1.33 mL) at –78 °C. The solution was stirred at –78 °C for 1 h followed by the dropwise addition of 12 (210 mg, 0.55 mmol) dissolved in anhydrous THF (3 mL). The mixture was stirred at 78 °C for 1 h and at –70 °C for 3 d. The mixture was quenched with sat. aq NaHCO₃ (5 mL). H₂O (2 mL) was added and the mixture was extracted with Et₂O (3 ×). The combined organic phases were washed with brine and sat. aq NaHCO₃. Subsequently, the organic phase was dried and concentrated. The crude product was analyzed by ¹H and ¹³C NMR spectroscopy. The spectra showed only signals of 12 and 13. The corresponding stereoisomer of 13 was not observed. Finally, the residue was purified on silica gel (Et₂O–pentane, 1:4 v/v). Yield: 21 mg (0.05 mmol, 14% based on recovered starting material). ¹H NMR (200 MHz, CDCl₃): δ = 0.91 [d, J = 6.8 Hz, 3 H, CH₂-CH(CH ₃)₂], 0.93 [d, J = 6.8 Hz, 3 H, CH₂-CH(CH ₃)₂], 1.30–1.49 [m, 2 H, CH ₂-CH(CH₃)₂], 1.44 [br s, 9 H, C(CH ₃)₃], 1.48 [s, 9 H, C(CH ₃)₃], 1.59–1.67 [m, 1 H, CH₂CH(CH₃)₂], 1.71 and 1.72 [2 s, 6 H, C=C=C(CH ₃)₂], 3.54 (d, J = 7.6 Hz, 1 H, CHOH), 4.27–4.33 (m, 1 H, NHCH), 4.42 (d, J = 9.6 Hz, 1 H, NHCH), 4.46 (d, J = 7.6 Hz, 1 H, CHOH). ¹³C NMR (50 MHz, CDCl₃): δ = 20.04, 20.36, 22.36, 22.83, 24.99, 28.09, 28.41, 43.97, 48.17, 71.12, 79.36, 81.99, 101.20, 104.57, 155.40, 172.58, 199.06. MS (EI): m/z (%) = 29 (17.25), 41 (27.93), 57 (100.00), 86 (59.50), 124 (11.85), 130 (42.03), 136 (12.08), 226 (10.12), 253 (22.69); MS (CI, NH₃): m/z = 384 [M + H]⁺. Anal. Calcd for C₂₁H₃₇NO₅ (384.53): C, 65.77; H, 9.72; N, 3.65. Found: C, 65.80; H, 9.66; N, 3.66