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Synlett 2004(7): 1247-1248  
DOI: 10.1055/s-2004-825594
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Irina P. Beletskaya*a, Vladimir I. Bregadzeb, Sergey N. Osipovb, Pavel V. Petrovskiib, Zoya A. Starikovab, Sergey V. Timofeevb
a Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie Gori. 119992, Moscow, Russia
Fax: +7(95)9393618; e-Mail: beletska@org.chem.msu.ru;
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str. 28, 119991, Moscow, Russia
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Publication History

Received 20 February 2004
Publication Date:
10 May 2004 (online)

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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.

Key words

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

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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:+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk; or www: http://www.ccdc.cam.ac.uk.