New Nonnatural α-Amino Acid Derivatives with Carboranyl Fragments in α- and β-Positions

Abstract

A simple and effective method of the synthesis of derivatives of α-carboranyl-α-trifluoromethyl-α-amino acid and β-carboranyl-α-trifluoromethyl-α-amino acid is presented. The structures of β-carboranyl-α-trifluoromethyl-α-amino acid esters with differently protected amino groups were determined by single crystal X-ray analysis.

fluorinated α-amino acids - carborane - imines - syn­thesis - X-ray crystal structure - boron neutron capture therapy for cancer

References

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Reaction of tert -Butoxycarbonylimine of Methyltri-fluoropyruvate with Methylcarboranyllithium: Butyllithium (3.95 mL, 1.6 M solution in hexanes) was added dropwise at 0 °C to a stirred solution of methyl-o-carborane (1.0 g, 6.3 mmol) in Et₂O (30 mL). The reaction mixture was allowed to warm up to 20 °C and was refluxed for 0.5 h. After cooling, the solution of imine (1.6 g, 6.3 mmol) in Et₂O (5 mL) was added at -78 °C to the mixture. The reaction was allowed to warm up to 20 °C and was stirred overnight at this temperature. Then the reaction was quenched with 1 N HCl (50 mL), the organic layer was treated with H₂O, brine and then it was dried over MgSO₄. The solvent was evaporated under reduced pressure and crude product was purified by column chromatography on silica gel (eluent: petroleum ether-EtOAc) to give analytically pure product 4a (89% yield).
Compound 4a: ¹H NMR (CDCl₃): δ = 5.27 s (1 H, NH), 3.89 (s, 3 H, OCH₃), 3.50-1.30 (br s, 10 H, BH), 2.26 (s, 3 H, CH₃), 1.42 (s, 9 H, t-Bu). ¹⁹F NMR (CDCl₃): δ = 9.02 s (3 F, CF₃). Anal. Calcd for C₁₂H₂₆B₁₀F₃NO₄: C, 34.85; H, 6.29; B, 25.10; N, 3.38. Found: C, 34.89; H, 6.33; B, 25.42; N, 3.19.

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Removal of the Boc-protecting group was carried out according to usual procedure by treating 4a (1.0 g) in CH₂Cl₂ (20 mL) at 0 °C with trifluoroacetic acid (10 mL). The crude product was purified by column chromatography on silica gel (eluent: petroleum ether-EtOAc) to give analytically pure product 4b (82% yield).
Compound 4b: ¹H NMR (CDCl₃): δ = 3.92 s (3 H, OCH₃), 3.10-1.25 (br s, 10 H, BH), 2.37 (br s, 2 H, NH₂), 2.29 s (3 H, CH₃). ¹⁹F NMR (CDCl₃): δ = 7.65 (br s, 3 F, CF₃). Anal. Calcd for C₇H₁₈B₁₀F₃NO₂: C, 25.36; H, 5.43; B, 34.50; N, 4.22. Found: C, 25.94; H, 5.76; B, 35.39; N, 4.17.

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General Procedure for the Reaction of Imines with Bromomethyl Carborane: Grignard reagent (solution in Et₂O) obtained from bromomethyl-o-carborane (3.0 mmol) and magnesium (4.0 mmol) was added dropwise to a stirred solution of imine (3.2 mmol) in Et₂O (25 mL) at -70 °C. After stirring for 1 h at -78 °C the reaction mixture was allowed to warm up to 20 °C and to stir for 6 h. Then the reaction was quenched with a sat. solution of NH₄Cl and extracted with Et₂O (2 × 20 mL). The combined organic layer was washed with brine (25 mL), dried over MgSO₄, and filtered. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography (EtOAc-petrol ether).
Compound 5a (R = Boc): mp 94-95 °C, 75% yield. ¹H NMR (CDCl₃): δ = 5.91 (s, 1 H, NH), 4.92 (s, 1 H, -CH-carb.), 4.06 (d, 1 H, J = 20.0 Hz, CH₂), 3.95 (s, 3 H, OCH₃), 3.23 (d, 1 H, J = 20.0 Hz, CH₂), 3.10-1.30 (br s, 10 H, BH), 1.48 (s, 9 H, t-Bu). ¹⁹F NMR (CDCl₃): δ = 2.39 (s, 3 F, CF₃). Anal. Calcd for C₁₂H₂₆B₁₀F₃NO₄: C, 34.86; H, 6.34; B, 26.15. Found: C, 34.89; H, 6.33; B, 26.42.
Compound 5b (R = COCF₃): mp 81-82 °C, 76% yield. ¹H NMR (CDCl₃): δ = 7.59 (s, 1 H, NH), 4.11 (d, 1 H, J = 16.0 Hz, CH₂), 4.04 (s, 3 H, OCH₃), 3.70 (s, 1 H, -CH-carb.), 3.35 (d, 1 H, J = 16.0 Hz, CH₂), 3.00-1.50 (br s, 10 H, BH). ¹⁹F NMR (CDCl₃): δ = 3.60 (s, 3 F, CF₃), 1.62 (s, 3 F, CF₃). Anal. Calcd for C₈H₁₇B₁₀F₆NO₃: C, 24.18; H, 4.31. Found: C, 24.35; H, 4.30.
Compound 5c (R = SO₂Ph): mp 164-165 °C, 72% yield. ¹H NMR (CDCl₃): δ = 7.80 (m, 5 H, Ph), 6.24 (s, 1 H, NH), 4.37 (s, 1 H, -CH-carb.), 3.95 (s, 3 H, O CH₃), 3.72 (d, 1 H, J = 16.0 Hz, CH₂), 3.22 (d, 1 H, J = 16.0 Hz, CH₂), 3.10-1.00 (br s, 10 H, BH). ¹⁹F NMR (CDCl₃): δ = 5.33 (s, 3 F, CF₃). Anal. Calcd for C₁₃H₂₂B₁₀F₃NO₄S: B, 23.84. Found: B, 23.84.

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Detailed crystallographic data for 5b and 5c were deposited at the Cambridge Crystallographic Data Centre (deposition number CCDC 231182 and CCDC 231183, respectively). Copies of this information can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK; fax:[phone]; e-mail: [e-mail]; or www: http://www.ccdc.cam.ac.uk.