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.

amino acids - boron - carbohydrates - carboranes - cyclo­additions

References

1 Bregadze VI. Chem. Rev.  1992,  92:  209 

2 Valliant JF. Guenther KJ. King AS. Morel P. Schaffer P. Sogbein OO. Stephenson KA. Coord. Chem. Rev.  2002,  232:  173 

For examples in the meta-carborane series, see:

3a Das BC. Kabalka GW. Srivastava RR. Bao W. Das S. Li G. J. Orgmet. Chem.  2000,  614-615:  255 

3b Das BC. Das S. Li G. Bao W. Kabalka GH. Synlett  2001,  1417 

3c Kabalka GW. Das BC. Das S. Li G. Srivastava RR. Natarajan N. Khan MK. Coll. Czech. Chem. Commun.  2002,  67:  836 

4 Kane RR. Pak RH. Hawthorne FW. J. Org. Chem.  1993,  58:  991 

5a Holman GD. Rees WD. Biochim. Biophys. Acta  1982,  685:  78 

5b Joost H.-G. Thorens B. Mol. Membr. Biol.  2001,  18:  247 

5c Dwyer DS. Vannucci SJ. Simpson IA. Int. Rev. Neurobiol.  2002,  51:  159 

5d Medina RA. Owen GI. Biol. Res.  2002,  35:  9 

6a Gomez FA. Hawthorne MF. J. Org. Chem.  1992,  57:  991 

6b Vinas C. Benakki R. Texidor F. Casabo J. Inorg. Chem.  1995,  34:  991 

7 Heying TL. Ager JW. Clark SL. Mangold DJ. Goldstein HJ. Hillman M. Polak RJ. Szymanski JW. Inorg. Chem.  1963,  2:  1089 

8 Kitahara T. Ogawa T. Naganuma T. Masui M. Agric. Biol. Chem.  1974,  38:  2189 

9 Bleriot Y. Veighey CR. Smelt KH. Cadefeau J. Stalmans W. Biggadike K. Lane AL. Muller M. Watkin DJ. Fleet GWJ. Tetrahedron: Asymmetry  1996,  7:  2761 

10a Owen LN. Peat S. Jones WGJ. J. Chem. Soc.  1941,  339 

10b Abbadi M. Holman GD. Morin C. Rees WD. Yang J. Tetrahedron Lett.  1999,  40:  5861 

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).

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 

15 Bagget N. Smithson A. Carbohydr. Res.  1982,  108:  59 

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 

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).

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 

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).

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 

26b Morin C. Tetrahedron  1994,  50:  12521 

26c Soloway AH. Tjarks W. Barnum BA. Rong F.-G. Barth RF. Codogni IW. Wilson JG. Chem. Rev.  1998,  98:  1515