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DOI: 10.1055/s-2003-40834
Synthesis of a Glycosylated ortho-Carboranyl Amino Acid
Publication History
Publication Date:
24 July 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
- 1
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4-Hydroxy-but-2-ynamine was prepared by overnight stirring of a solution of 4-tosyloxybut-2-yn-1-ol in ammonium hydroxide, followed by evaporation and treatment of the crude solid with Dowex 1X8 R3N+Cl- pre-washed with 4% NaOH aq solution. The brown oil thus obtained should be used without delay.
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Analytical data for the tosylate salt: mp 94-96 °C. 1H NMR (300 MHz, D2O) 7.60 (d, 2 H, J = 7.1 Hz, ArH), 7.27 (d, 2 H, J = 7.1 Hz, ArH), 4.18 (s, 2 H, H-4), 3.77 (s, 2 H, H-1), 2.30 (s, 3 H, CH3). 13C NMR 140.0 (Cquat Ar), 137.9 (Cquat Ar); 127.2 (CH Ar), 123.1 (CH Ar), 82.5 and 73.8 (C-2, C-3), 47.1 and 27.0 (C-1, C-4), 18.3 (CH3).
-
12e Similarly, but-2-yn-1,4-diamine
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12f
Analytical data for its bis mesylate salt: mp 160 (dec.) 1H NMR (300 MHz, D2O) 3.77 (s, 4 H, H-1/H-4), 2.58 (s, 6 H, CH3). 13C NMR 79.1 (C-2/
C-3), 39.2 (CH3), 29.8 (C-1/C-4). - 13 Such a derivative could be useful
in the preparation of bis-glycosyl-carboranes (Panza, L. et al., manuscript in preparation), see:
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Nabakka JM.Harwell DE.Knobler CB.Hawthorne MF. J. Organomet. Chem. 1998, 550: 423 - 25 For a synthesis of 10B
enriched decaborane, see:
Adams L.Tomlison S.Wang J.Hosmane SN.Maguire JA.Hosmane NS. Inorg. Chem. Commun. 2002, 5: 765 - For some reviews about ‘chemistry and BNCT’, see:
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Soloway AH.Tjarks W.Barnum BA.Rong F.-G.Barth RF.Codogni IW.Wilson JG. Chem. Rev. 1998, 98: 1515
References
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).
18To 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).
19Mesylate 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).
22Amine 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).
23N-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).
24Carborane 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).