Synthesis of a Glycosylated ortho-Carboranyl Amino Acid

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

References

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• For examples in the meta-carborane series, see:
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• 12a

  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.

• 12b For more information on 4-hydroxy-but-2-ynamine, see: Marszak-Fleury A. Laroche J. Bull. Soc. Chim. Fr.  1963,  1270 
• 12c For more information on synthetic procedure, see: Dumez E. Faure R. Dulcere J.-P. Eur. J. Org. Chem.  2001,  2577 
• 12d

  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 was prepared from 1,4-bis-mesyloxy-but-2-yne, see: Haslinger H. Soloway AH. J. Med. Chem.  1966,  9:  792 
• 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: Giovenzana GB. Lay L. Monti D. Palmisano G. Panza L. Tetrahedron  1999,  55:  14123 
• 14 Fein M. Grafstein D. Paustian JE. Bobinski J. Lichstein BM. Myes N. Schwartz NS. Cohen MS. Inorg. Chem.  1963,  2:  1115 
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• 16 Blériot Y. Masaguet CF. Charlwood J. Winchester BG. Lane AL. Crook S. Watkin DJ. Fleet GWJ. Tetrahedron  1997,  53:  15135 
• 17 Barili PL. Berti G. Catelani G. Colonna F. Marra A. Tetrahedron Lett.  1986,  27:  2307 
• 20 Cundari S. Dalpozzo R. De Nino A. Procopio A. Sindona G. Athanassopulos K. Tetrahedron  1999,  55:  10155 
• 21 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:
• 26a Hawthorne MF. Angew. Chem., Int. Ed. Engl.  1993,  32:  950 
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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 (d_app, J _app = 6.0 Hz, 1 H,); 4.26-4.16 (m, 4 H); 4.08-4.05 (t_app, 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, W_1/2 = 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 (d_app, J _app = 7.95 Hz, NH); 6.00 (d_app, 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 (C_quat 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 (d_app, J _app = 7.5 Hz, 2 H); 7.58 (d_app, 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 (C_quat 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).