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Synlett 2003(10): 1399-1402
DOI: 10.1055/s-2003-40834
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of a Glycosylated ortho-Carboranyl Amino Acid

Christian Thimona,b, Luigi Panzab, Christophe Morin*a
a Laboratoire d’Etudes Dynamiques et Structurales de la Sélectivité (associé au CNRS, UMR 5616), Départment de Chimie, Université Joseph Fourier, B.P. 53-X, 38041 Grenoble, France
Fax: +33(476)514927; e-Mail: christophe.morin@ujf-grenoble.fr;
b Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Viale Ferrucci 33, 28100 Novara, Italy
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Publikationsverlauf

Received 24 May 2003
Publikationsdatum:
24. Juli 2003 (online)

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Abstract

The preparation of an ortho-carborane derivative bearing both carbohydrate and amino acid substituents is presented; opening of a glucofuranuro-γ-lactone derivative with propargylamines, cycloaddition of decaborane to an acetylenic bond and amidation with a N-Fmoc-glutamate derivative are the key-steps in this synthesis.

Key words

amino acids - boron - carbohydrates - carboranes - cyclo­additions

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11

General procedure for opening of lactone 2 with amines (5-15 mmole scale): To a solution of lactone in acetonitrile (10 mL/mmole) was added an excess of amine (2-4 equiv) and the mixture was stirred overnight after which time volatiles were removed. Compound 4 was obtained quantitatively without purification while isolation of pure 6 (87%) and 7 (98%) was performed by flash chromatography on silica gel (eluent:CH2Cl2/CH3OH, 95:5). 4: 1H NMR (300 MHz,, CDCl3): 7.38 (t, J = 5.4 Hz, 1 H, NH); 5.97 (d, J 1,2 = 3.6 Hz, 1 H, H-1); 4.84-4.07 (m, 8 H); 2.32 (t, J 1 ′,3 ′ = 2.5 Hz, 1 H, H-3′); 1.48 (s, 3 H, CH3); 1.31 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): 172.3 (C-6); 112.2 (C-1); 105.2 [C(CH3)2]; 85.1; 80.8; 79.1 (C-3′); 75.2; 72.0 (C-2′); 69.7; 29.2 (C-1′); 26.8 (CH3); 26.2 (CH3). 6: 1H NMR (300 MHz,, CDCl3): 5.96 (d, J 1,2 = 3.5 Hz, 1 H, H-1); 4.76-4.43 (m, 4 H); 4.10-3.82 (m, 3 H); 3.40-3.10 (m); 3.16 (s, H-1′′); 3.09 (s, H-1); 2.32 (t, J 1 ′-3 ′ = 2.4 Hz, H-3′); 2.26 (t, J 1 ′-3 ′ = 2.4 Hz, H-3′); 1.46 (s, 3 H, CH3); 1.31 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): 172.9 and 172.8 (C-6); 112.1 [C(CH3)2]; 112.0 [C(CH3)2]; 105.6 (C-1); 84.5; 82.7*; 77.9; 75.7; 75.6; 73,3; 72.7; 65.9; 39.0 (C-1′); 37.6 (C-1′); 34.6 (C-1′′); 34.1 (C-1′); 26.9 (CH3); 26.3 (CH3). 7 1H NMR (300 MHz, CD3OD): 5.90 (d, J 1,2 = 3.6 Hz, 1 H, H-1); 4.47 (d, J 1,2 = 3.6 Hz, 1 H, H-2); 4.34-4.37 (dapp, J app = 6.0 Hz, 1 H,); 4.26-4.16 (m, 4 H); 4.08-4.05 (tapp, J app = 1.9 Hz, 2 H,); 1.44 (s, 3 H, CH3); 1.29 (s, 3 H,CH3). 13C NMR (75 MHz, CD3OD): 174.3 (C-6); 112.9 [C(CH3)2]; 106.4 (C-1); 86.4; 82.3; 81.9; 81.3; 75.9; 71.0; 50.7 (C-4′); 29.6 (C-1′); 271 (CH3); 264 (CH3). [α]20 D -13 (c 6; MeOH).

18

To a solution of 7 (1g; 3.3 mmol) in acetone (30 mL) were added under stirring 2,2- dimethoxypropane (20 mL, 164 mmol; 50 equiv) and camphorsulfonic acid (77 mg, 0.33 mmol; 0.1 equiv). After 24 h stirring, NaHCO3 (2 g) was added and after further 15 min stirring the mixture was filtered on celite. The oil (crude 11) obtained after evaporation of the volatiles was dissolved in methanol (50 mL) containing AcOH (170 µL of 60% aqueous solution) and stirred at 50 °C for 80 min then cooled rapidly to r.t. Sodium hydrogen carbonate (2 g) was added and the solution was stirred for 15 min before filtration. Compound 12 (1.010 g, 3 mmol 90%) was obtained pure after column chromatography (silica gel, CH2Cl2/CH3OH: 95/5) as a white foam 1H NMR (300 MHz, CDCl3): 6.57 (l s, 1 H, NH); 6.04 (d, J 1,2 = 3.7 Hz, 1 H, H-1); 4.60-4.50 (m, 2 H); 4.30-4.11 (m, 6 H); 1.49 (s, 3 H, CH3); 1.42 (s, 3 H, CH3); 1.39 (s, 3 H, CH3); 1.32 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): 169.3 (C-6); 112.1 [C(CH3)2)]; 107.8 (C-1); 101.0 [C(CH3)2]; 83.0; 82.2; 80.3 (C-2′, C-3′); 78.6; 74.2; 71.2; 50.3 (C-4′); 28.8 (C-1′); 26.5 (CH3); 26.0 (CH3); 23.9 (CH3); 23.2 (CH3).

19

Mesylate 13 was obtained conventionally (triethylamine, mesyl chloride, 2.2 equiv each, in CH2Cl2, 2 h, 98%). 1H NMR (300 MHz, CDCl3): 6.53 (s l, 1 H, NH); 6.04 (d, J 1,2 = 3.7 Hz, 1 H, H-1); 4.90-4.85 (m, 2 H, W1/2 = 33 Hz); 4.60-4.50 (m, 2 H); 4.10-4.25 (m, 4 H); 3.12 (s, 3 H, H-1′′); 1.49 (s, 3 H, CH3); 1.43 (s, 3 H, CH3); 1.40 (s, 3 H, CH3); 1.32 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): 169.8 (C-6); 112.4 [C(CH3)2]; 106.5 (C-1); 101.3 [C(CH3)2]; 85.6 (CCH2); 83.6; 79.3; 75.6 (CCH2); 74.9; 71.9; 57.6 (C-4′); 39.1 (C-1′′); 28.9 (C-1′); 27.2 (CH3); 26.6 (CH3); 24.6 (CH3); 23.9 (CH3).

22

Amine 15 was obtained by reaction of mesylate 13 with 25% aq. ammonia/dioxane (5/1) 35 °C, 80 min Yield: 95%. 1H NMR (300 MHz, CDCl3): 6.56 (s l, 1 H, NH); 6.04 (d, J 1-2 = 3.7 Hz, 1 H, H-1); 4.59-4.55 (m, 2 H); 4.24-4.08 (m, 4 H); 3.46-3.44 (m, 2 H, J app = 2 Hz); 1.70 (s l, 2 H, NH2); 1.48 (s, 3 H, CH3); 1.43 (s, 3 H, CH3); 1.39 (s, 3 H, CH3); 1.32 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): 169.5 (C-6); 112.3 [C(CH3)2]; 106.4 (C-1); 101.1 [C(CH3)2]; 84.3; 83.6; 79.1; 74.8; 71.8 (C-2, C-3, C-4, C-5); 67,1; 31.6 (C-4′); 29.1 (C-1′); 27.1 (CH3); 26.6 (CH3); 24.6 (CH3); 23.8 (CH3).

23

N-Fmoc amino acid 16: Condensation of amine 15 in CH2Cl2 with commercially available benzyl ester of N-Fmoc glutamic acid in the presence of 1 equiv of DCC: 82%. 1H NMR (300 MHz, CDCl3): 7.75-7.26 (m, 13 H, H ar); 6.71 (s l, 1 H, NH); 6.59 (s l, 1 H, NH); 6.04 (dapp, J app = 7.95 Hz, NH); 6.00 (dapp, J app = 3.7 Hz, 1 H, H-1); 5.15 [s, 2 H, CH2 (Bn)];.4.58-3.98 (m, 12 H); 2.50-1.50 (m l, 4 H); 1.44 (s, CH3); 1.38 (s, CH3); 1.34 (s, CH3); 1.29 (s, CH3). 13C NMR (75 MHz, CDCl3): 171.9 (C-5′′); 169.7 (C-6); 156.3 [OC(O)NH]; 143.9, 143.7, 141.3 (Cquat Fmoc); 135.2 (OCH2C); 128.6; 128.5; 128.3; 127.7; 127.1; 125.1; 120.0; 112.3 [C(CH3)2]; 106.3 (C-1); 101.2 [C(CH3)2]; 83.5; 79.4; 79.3; 78.2; 77.6; 74.8; 71.8; 67,.2 (OCH2CH); 67.0 (OCH2CH); 53.7 (C-2′′); 47.1 (OCH2CH); 32.0; 29.2; 28.9; 27.9; 27.0 (CH3); 26.5 (CH3); 24.4 (CH3); 23.7 (CH3).

24

Carborane 17: Under argon, a solution of decaborane (20 mg; 0.17 mmol, 1.3 equiv) in toluene (2 mL) and acetonitrile (68 µL; 1.3 mmol, 10 equiv) was heated at 110 °C for 1 h then cooled to r.t. before the addition of 16 (100 mg; 0.13 mmol). The mixture was stirred at reflux for 5 h and methanol (0.5 mL) was added to destroy the excess of decaborane. After evaporation of the volatiles, column chromatography on silica gel (CH2Cl2/EtOAc: 8.5/1.5) gave carborane 17 (50 mg, 46%) as a white powder. 1H NMR (300 MHz, CDCl3): 7.74 (dapp, J app = 7.5 Hz, 2 H); 7.58 (dapp, J app = 7.2 Hz, 2 H); 7.5-7.2 (m, 11 H); 6.00 (d, J = 3.6 Hz, 1 H, H-1); 5.87 (d, J = 7.9 Hz, 1 H, NH); 5.17 (s l, 2 H, CCH2O); 4.55-4.08 (m, 12 H); 2.28-2.02 (m); 1.44 (s, CH3); 1.39 (s, CH3); 1.36 (s, CH3); 1.28 (s, CH3). 13C NMR
(75 MHz, CDCl3): 172.4 (C-1′′); 171.7 (NHCO); 170;6 (NHCO); 156.6 [OC(O)NH]; 143.9; 143.7; 141.4 (Cquat Fmoc); 135.2 (OCH2C); 128.7; 128.6; 128.4; 127.8; 127.2; 125.2; 120.1; 112.6 [C(CH3)2]; 106.5 (C-1); 101.6 [C(CH3)2]; 83.5; 81.0 (CB); 79.7; 78.2; 75.1; 71.8; 67.5 (OCH2CH); 67.2 (OCH2CH); 53.6 (C-2′′); 47.2 (OCH2CH); 42.0 (CH2N); 41.1 (CH2N); 32.0; 28.4; 27.1 (CH3); 26.6 (CH3); 24.2 (CH3); 23.7 (CH3). Anal. C43H57B10N3O11-0.25 CH2Cl2. Calcd.: C 56.39, H 6.29, B 11.73, N 4.56; found C 56.48, H 6.35, B 11.75, N 4.55. MS (electrospray):
(M + Na)+ centered at m/z = 923.5 (cluster from m/z = 919.5 to 926.5 with relative intensities matching the calculated spectrum for C43H57B10N3O11).