Synthesis of a Novel Rhizobitoxine-Like Triazole-Containing Amino Acid

Abstract

The synthesis of the four stereoisomers of a new 1,2,3-triazole analogue of rhizobitoxine from serine is described. The key step is a Huisgen 1,3-dipolar cycloaddition on an ethynylglycine synthon.

Key word

rhizobitoxine - triazole amino acid - Huisgen cycloaddition - ethynylglycine synthon - chiral HPLC

• References and Notes

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• 44 General Synthetic Procedure for Click-Chemistry Reaction for the Synthesis of 2 (S)-Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(4-{(S)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}-1H-1,2,3-triazol-1-yl)propanoate [(1S,2S)-2, (Scheme 4, Path a] To a solution of (2S, 4S)-11 (0.337 g, 0.72 mmol) in MeOH (5 mL) was added PTSA·H₂O (0.137 g, 0.72 mmol). The reaction mixture was stirred for 2 h at room temperature and sat. aq NaHCO₃ solution (40 mL) was poured into the solution. The aqueous solution was extracted with EtOAc (3 × 40 mL). The organic phases were combined, washed with sat. aq NaHCO₃ solution (40 mL), sat. aq NaCl solution (40 mL), dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc–PE = 0:100, increasing to 100:0, v/v) to give the desired compound (1S, 2S)-2 (0.053 g, 17%) as a white solid and recovered starting material (2S, 4S)-11 (0.184 g, 55%). Analytical Data R_f = 0.26 (EtOAc); mp 55–57 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.42 [s, 18 H, C(CH₃)₃], 2.89 (br s, 1 H, OH), 3.79 (s, 3 H, CO₂CH₃), 3.84–3.87, 4.10–4.12 (2 m, 2 H, CH₂O), 4.70–4.86 (m, 4 H, 2 CH, CH₂N), 5.43 (br s, 1 H, NH), 5.59 (br s, 1 H, NH), 7.57 (s, 1 H, CH_triazole). ¹³C NMR (75 MHz, CDCl₃): δ = 28.4, 28.5 [2 s, 18 H, C(CH₃)₃], 48.2 (CH), 51.5 (CH₂N), 53.4 (CO₂CH₃), 53.9 (CH), 65.0 (CH₂O), 80.1 [C(CH₃)₃], 81.0 [C(CH₃)₃], 123.9 (CH_triazole), 147.1 (C_triazole), 155.2 (NCO₂), 155.8 (NCO₂), 169.5 (CO₂CH₃). [α]_D ²⁰ +49.9 (c 0.91, CHCl₃). HRMS (ES⁺): m/z [M + H]⁺ calcd for C₁₈H₃₂N₅O₇: 430.2302; found: 430.2303. HPLC: purity = 99.6%, t _R = 12.43 min. IR: 3358, 2362, 2338, 1742, 1683 cm^–1. Nitrogen inversion in the oxazolidine ring or slow interconversion of both amide or carbamate conformers of compounds 4, 11, and 2 causes considerable line broadening and duplication of signals in the ¹H NMR and ¹³C NMR spectra (see Supporting Information). General Synthetic Procedure for Click-Chemistry Reaction for the Synthesis of 2 (S)-Methyl 2-[(tert-Butoxycarbonyl)amino]-3-(4-{(S)-1-[(tert-butoxycarbonyl)amino]-2-hydroxyethyl}-1H-1,2,3-triazol-1-yl)propanoate [(1S,2S)-2, Scheme 4, Path b) Azide 3 (0.420 g, 1.72 mmol) and alkyne 12 (0.318 g, 1.72 mmol) were dissolved in a mixture of t-BuOH–H₂O (10 mL, 1:1, v/v). Sodium l-asborbate (0.068 g, 20 mol%) and CuSO₄·5H₂O (0.041 g, 10 mol%) were added. The reaction mixture was stirred at room temperature for 24 h, the solution was concentrated under vacuum and diluted with H₂O (70 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL). The organic phases were combined, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc–PE = 0:100, increasing to 100:0, v/v) to give the desired compound (1S,2S)-2 as a white solid (0.480 g, 65% yield). The compound exhibited the same analytical properties as described above. See Supporting Information for the characterization data of other products