Daniels et al. 10.1073/pnas.0506627102. |
Supporting Text
Chemistry.
The a-amino derivative of oxymorphone 1 (1) and the 7'-amino derivative of naltrindole (NTI) 2 were the key intermediates used. The 7'-amino group of NTI does not radically change its selectivity or potency (2), and the amino groups of both pharmacophores served as a point of attachment for the spacer. The synthetic route, outlined in Fig. 4, starts with the synthesis of the spacers. The mono-carbobenzoxy (Cbz)-protected diamines were either purchased from Aldrich or synthesized directly from the nonprotected diamines (2). The diamines were condensed with diglycolic anhydride to give spacers 15–19. DCC mediated coupling of these spacers with a-oxymorphamine afforded intermediates 20–25. Subsequent deprotection of the amine spacer by using catalytic transfer hydrogenation produced compounds 26–31. 7'-Amino-NTI was condensed with diglycolic anhydride to give 32. Bivalent ligands 3–8 (MDAN-16–MDAN-21) were prepared by coupling the a-oxymorphamine intermediates 26–31 with 32 by using dextran-coated charcoal. The m agonist monovalent analogs 9–13 (MA-16–MA-21) were prepared in a similar fashion by using the N-methyl analog 34 instead of the NTI intermediate 32 in the final coupling step.The NTI monovalent ligand 14 was prepared as outlined in Fig. 5. 7'-Amino NTI was coupled to spacer 18 followed by deprotection to afford intermediate 33. Methyl amine was condensed with diglycolic acid to give 34. Subsequent coupling of 33 and 34 afforded the d-antagonist monovalent ligand 14 (DN-20).
Experimental Procedures
General
. All reactions involving moisture sensitive reagents were conducted in oven-dried glassware under nitrogen atmosphere. Solvents were dried when necessary. All other chemicals and solvents were reagent grade unless specified otherwise and were obtained from Aldrich Chemical Co., Milwaukee, WI. 1H-NMR spectra were recorded on a Varian 300 MHz spectrometer and referenced to the solvent. Chemical shifts are expressed in ppm and coupling constants (J) are in hertz (Hz). Peak multiplicities are abbreviated: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet. Fast-atom bombardment (FAB) mass spectra (MS) were obtained on a VG 7070E-HF instrument. Flash chromatography was performed on Merck Science silica gel 60 (230-400) mesh. Thin layer chromatography (TLC) was performed on analytical Uniplate silica gel GF glass plates (250 mm by 2.5 × 20 cm2). Preparative TLC was performed on 1.0 or 0.5 mm Analtech silica gel plates. Plates were visualized by UV light, iodine vapor, or ninhydrin solution.7'-{2-[(2-{2-[({(5a,6a)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)-methoxy]-acetylamino}-ethylaminocarbonyl)-methoxy]-acetylamino}-naltrindole,
MDAN-16 (3). A solution of carboxylic acid 32 (0.220 g, 0.404 mmol, 1.1 eq), N,N'-dicyclohexylcarbodiimide (DCC) (0.083 g, 0.404 mmol, 1.1 eq), and HOBt (0.055 g, 0.404 mmol, 1.1 eq) (eq, equivalents) in N,N-dimethylformamide (DMF) (2 ml) was reacted with stirring at room temperature for 20 min. Amine 26 (0.169 g, 0.367 mmol, 1.0 eq) was added in one portion, and the reaction mixture was stirred under N2 at 50°C for 24 h. The N,N'-dicyclohexylurea (DCU) precipitate was collected via vacuum filtration, and the filtrate was added to ethyl ether (100 ml) to facilitate precipitation of the crude product. The crude product was isolated by vacuum filtration; further purification via flash chromatography (silica gel, starting with D/M/A, 94.5/5/0.5, vol/vol/vol and switching to dichloromethane/methanol/ammonium hydroxide (D/M/A), 89/10/1, vol/vol/vol, midway through) gave 3 as an off-white solid (50.0%); retention factor (Rf ) 0.35 (silica gel, D/M/A. 89/10/1. vol/vol/vol); melting point (mp) 228°C (decomposes); 1H-NMR [dimethyl sulfoxide (DMSO)-d6] chemical shift in ppm (d) 10.74 (s, 1H), 9.64 (s, 1H), 8.81 (br s, 2H), 8.15 (t, 1H), 8.08 (t, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 6.39-6.32 (m, 3H), 5.38 (s, 1H), 4.65 (br s, 1H), 4.60 (br s, 1H), 4.33 (d, J = 3.3 Hz, 1H), 4.25-4.18 (m, 1H), 4.09 (s, 2H), 3.95 (s, 2H) 3.84 (s, 2H), 3.82 (s, 2H), 3.15 (s, 1H), 3.12- 3.10 (m, 4H), 2.95-2.87 (m, 2H), 2.66-2.49 (m, 4H), 2.41-2.21 (m, 6H), 2.14 (s, 3H), 2.05-1.97 (m, 3H), 1.47-1.39 (m, 2H), 1.22-1.13 (m, 3H), 0.88-0.76 (m, 2H), 0.38-0.34 (m, 2H), 0.02-0.00 (m, 2H); HR-FAB MS m/z 988.4517 (M + H)+, C53H61N7O12 requires 987.4378.MDAN-17 (4) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 10.75 (s, 1H), 9.64 (s, 1H), 8.83 (br s, 2H), 8.09 (t, J = 5.7 Hz, 1H), 8.00 (t, J = 6.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H) 7.13 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.77 (t, J = 7.8 Hz, 1H), 6.45-6.31 (m, 4H), 5.38 (s, 1H), 4.63 (br s, 2H), 4.33 (d, J = 3.3 Hz, 1H), 4.21 (m, 1H), 4.09 (s, 2H), 3.94 (s, 2H) 3.85 (s, 2H), 3.81 (d, J = 1.5 Hz, 2H) 3.16-3.14 (m, 1H), 3.03-3.01 (m, 4H), 2.95-2.86 (m, 2H), 2.65 – 2.53 (m, 4H), 2.41 – 2.22 (m, 6H), 2.14 (s, 3H), 2.05-1.97 (m, 3H), 1.49-1.38 (m, 4H), 1.26-1.09 (m, 3H), 0.83 – 0.69 (m, 2H), 0.38 – 0.34 (m, 2H) 0.02 – 0.00 (m, 2H); HR-FAB MS m/z 1002.466 (M + H)+, C54H63N7O12 requires 1001.454 Anal. (C54H63N7O12 • 2.0 HCl) calculated: C 60.33, H 6.09, N 9.12; found: C 60.89, H 6.09, N 9.08.
MDAN-18 (5) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 10.77 (s, 1H), 9.68 (s, 1H), 8.81 (br s, 2H), 8.04 (t, J = 5.1 Hz, 1H), 7.92 (t, J = 5.7 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H) 7.13 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.76 (t, J = 7.8 Hz, 1H), 6.44-6.30 (m, 4H), 5.36 (s, 1H), 4.63 (br s, 1H), 4.59 (br s, 1H), 4.31 (d, J = 3.0 Hz, 1H), 4.24-4.14 (m, 1H), 4.07 (s, 2H), 3.94 (s, 2H), 3.82 (s, 2H), 3.80 (s, 2H), 3.11 (s, 1H), 2.98-2.94 (m, 4H), 2.94-2.86 (m, 2H), 2.64-2.48 (m, 4H), 2.42-2.20 (m, 6H), 2.13 (s, 3H), 2.04-1.96 (m, 3H), 1.47-1.38 (m, 2H), 1.28 (br s, 4H), 1.24-1.16 (m, 3H), 0.84-0.70 (m, 2H), 0.38-0.30 (m, 2H), 0.02-0.00 (m, 2H); HR-FAB MS m/z 1016.4 (M + H)+, C55H65N7O12 requires 1015.469.
MDAN-19 (6) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 10.77 (s, 1H), 9.69 (s, 1H), 8.81 (br s, 1H), 8.04 (t, J = 5.7 Hz, 1H), 7.92 (t, J = 5.1 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H) 7.15 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.46-6.32 (m, 4H), 5.38 (s, 1H), 4.66 (br s, 1H), 4.61 (br s, 1H), 4.32 (d, J = 3.9 Hz, 1H), 4.25-4.18 (m, 1H), 4.10 (s, 2H), 3.96 (s, 2H) 3.84 (s, 2H), 3.82 (d, J = 2.4 Hz, 2H), 3.14 (d, J = 6.0 Hz, 1H), 2.99-2.87 (m, 6H), 2.65-2.50 (m, 4H), 2.41-2.18 (m, 6H), 2.14 (s, 3H), 2.05-1.93 (m, 3H), 1.47-1.13 (m, 11H), 0.86-0.70 (m, 2H), 0.38-0.34 (m, 2H), 0.02-0.00 (m, 2H); HR-FAB MS m/z 1030.4851 (M + H)+, C56H67N7O12 requires 1029.4848; Anal. (C56H67N7O12 • 2HCl) calculated: C 60.97, H 6.30, N 8.89; found: C 60.89, H 6.34, N 8.88.
MDAN-20 (7) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 10.77 (s, 1H), 9.69 (s, 1H), 8.80 (br s, 1H), 8.04 (t, J = 5.1 Hz, 1H), 7.91 (t, J = 6.0 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H) 7.15 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.46-6.32 (m, 4H), 5.38 (s, 1H), 4.66 (br s, 1H), 4.61 (br s, 1H), 4.32 (d, J = 3.3 Hz, 1H), 4.28-4.17 (m, 1H), 4.09 (s, 2H), 3.96 (s, 2H) 3.84 (s, 2H), 3.82 (d, J = 3.6 Hz, 2H), 3.15 (d, J = 6.6 Hz, 1H), 2.99-2.87 (m, 6H), 2.65-2.50 (m, 4H), 2.41-2.18 (m, 6H), 2.14 (s, 3H), 2.05-1.93 (m, 3H), 1.47-1.39 (m, 2H), 1.33-1.23 (m, 11H), 0.86-0.71 (m, 2H), 0.38-0.34 (m, 2H), 0.02-0.00 (m, 2H); HR-FAB MS m/z 1044.514 (M + H)+, C57H69N7O12 • H+ requires 1044.508; Anal. (C57H69N7O12 • 2.75TFA) calculated: C 55.43, H 5.34, N 7.23; found: C 55.47, H 5.31, N 7.10.
MDAN-21 (8) Prepared in a similar fashion as above. 1H NMR (DMSO-d6) d 10.78 (s, 1H), 9.69 (s, 1H), 8.81 (br s, 2H), 8.04 (t, J = 6.0 Hz, 1H), 7.91 (t, J = 5.7 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H) 7.15 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.78 (t, J = 8.1 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 6.39-6.32 (m, 3H), 5.37 (s, 1H), 4.66 (br s, 1H), 4.62 (br s, 1H), 4.33 (d, J = 3.3 Hz, 1H), 4.20 (m, 1H), 4.09 (s, 2H), 3.95 (s, 2H) 3.84 (d, J = 1.8 Hz, 2H), 3.81 (d, J = 3.3 Hz, 2H) 3.15 (d, J = 5.7 Hz, 1H), 2.98-2.86 (m, 6H) 2.65 – 2.54 (m, 4H), 2.41 – 2.22 (m, 6H), 2.14 (s, 3H), 2.05-1.97 (m, 3H), 1.46-1.38 (m, 2H), 1.26 – 1.16 (m, 7H), 1.11 (s, 6H), 0.83 – 0.71 (m, 2H), 0.38 - 0.34 (m, 2H) 0.02 - 0.00 (m, 2H); UHR-ESI MS m/z 1080.7 (M + Na)+, C58H71N7O12 requires 1057.52; Anal. (C58H71N7O12 • 2HCl) calculated: C 61.59, H 6.50, N 8.67; found: C 61.65, H 6.45, N 8.62.
(5a,6a)-6-{2-[(2-{2-[(Methylaminocarbonyl)-methoxy]-acetylamino}-ethylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan,
MA-16 (9). A solution of carboxylic acid 34 (0.053 g, 0.363 mmol, 1.1 eq), HOBt (0.049 g, 0.363 mmol, 1.1 eq), DCC (0.075 g, 0.363 mmol, 1.1 eq), and 3 Å molecular sieves (0.50 g) in DMF (0.5 ml) was incubated with stirring for 30 min. Amine 26 (0.152 g, 0.330 mmol, 1.0 eq) dissolved in DMF (1 ml) was added in one portion. The reaction mixture was sealed under N2 and stirred at 70°C (with a reflux condenser present) for 18 h. After which time TLC (D/M/A, 89/10/1, vol/vol/vol) showed the reaction to be complete. The DCU precipitate was collected via vacuum filtration and the filtrate was added to ethyl ether (100 ml) to facilitate precipitation of the crude product. This solid was collected via vacuum filtration and continuously washed with diethyl ether (50 ml), followed by hexanes (50 ml) to prevent the solid from "oiling out." Further purification via flash chromatography (silica gel, starting with D/M/A, 94.5/5/0.5, vol/vol/v and switching to D/M/A, 89/10/1, vol/vol/vol, midway through) gave 9 as a light yellow solid (20%); Rf 0.54 (silica gel, D/M/A. 89/10/1. vol/vol/v); mp 75°C (softens), 95°C (melts); 1H NMR (DMSO-d6) d 8.98 (br s, 1H), 8.24 (t, 1H), 8.14 (t, 1H), 7.94 (d, 1H), 7.52 (d, J = 7.5 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H) 6.47 (d, J = 7.5 Hz, 1H), 4.84 (br s, 1H), 4.47 (d, J = 3.3 Hz, 1H), 4.40-4.32 (m, 1H), 3.99 (s, 2H), 3.97 (s, 2H), 3.90 (s, 4H), 3.22-3.21 (m, 4H), 3.05 (d, J = 18.9 Hz, 1H), 2.78-2.72 (d, 1H), 2.64 (d, J = 4.8 Hz, 3H), 2.54(d, 1H), 2.41 (d, 1H), 2.30 (s, 3H), 2.20-2.10 (m, 2H), 1.63-1.52 (m, 1H), 1.43-1.22 (m, 3H), 1.02-0.90 (m, 1H); HR-FAB MS m/z 590.2789 (M + H)+, C28H39N5O9 requires 589.2748.MA-17 (10) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 8.94 (br s, 1H), 8.12 (t, J = 6.0 Hz, 1H), 8.05 (t, J = 6.0 Hz, 1H), 7.92 (q, 1H), 7.51 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H) 6.44 (d, J = 8.1 Hz, 1H), 4.78 (br s, 1H), 4.44 (d, J = 3.9 Hz, 1H), 4.36-4.29 (m, 1H), 3.96 (s, 2H), 3.95 (s, 2H), 3.87 (s, 2H), 3.86 (s, 2H), 3.12-3.07 (m, 4H), 3.03 (d, J = 18.9 Hz, 1H), 2.72-2.69 (d, 1H), 2.61 (d, J = 4.8 Hz, 3H), 2.51 (d, J = 6.0 Hz, 1H), 2.35 (d, J = 9.3 Hz, 1H), 2.26 (s, 3H), 2.16-2.08 (m, 2H), 1.59-1.50 (m, 3H), 1.37-1.24 (m, 3H), 0.95-0.86 (m, 1H); HR-FAB MS m/z 604.297 (M + H)+, C29H41N5O9 • H+ requires 604.298.
MA-19 (11) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 8.94 (br s, 1H), 8.07-7.99 (m, 3H), 7.55 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H) 6.48 (d, J = 8.1 Hz, 1H), 4.81 (br s, 2H), 4.47 (d, J = 3.9 Hz, 1H), 4.38-4.31 (m, 1H), 3.98 (s, 2H), 3.96 (d, J = 3.0 Hz, 2H), 3.90 (s, 4H), 3.12-3.01 (m, 5H), 2.77-2.72 (d, 1H), 2.64 (d, J = 4.5 Hz, 3H), 2.55 (d, 1H), 2.40-2.37 (m, 1H), 2.29 (s, 3H), 2.19-2.09 (m, 2H), 1.64-1.52 (m, 1H), 1.47-1.23 (m, 9H), 1.00-0.86 (m, 1H); HR-FAB MS m/z 632.3294 (M + H)+, C31H45N5O9 requires 631.3217; Anal. (C31H45N5O9) calculated: C 58.94, H 7.18, N 11.09; found: C 59.01, H 7.24, N 11.15.
MA-20 (12) Prepared in a similar fashion as above. 1H-NMR (DMSO-d6) d 8.87 (br s, 1H), 8.01-7.93 (m, 3H), 7.50 (d, J = 7.8 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H) 6.46 (d, J = 8.1 Hz, 1H), 4.77 (br s, 2H), 4.42 (d, J = 3.9 Hz, 1H), 4.37-4.29 (m, 1H), 3.96 (s, 2H), 3.93 (d, J = 3.3 Hz, 2H), 3.87 (s, 4H), 3.10-2.99 (m, 5H), 2.71 (d, J = 6.0 Hz, 1H), 2.62 (d, J = 4.5 Hz, 3H), 2.53 (d, J = 6.6 Hz, 1H), 2.36 (d, J = 6.9 Hz, 1H), 2.27 (s, 3H), 2.17-2.06 (m, 2H), 1.59-1.51 (m, 1H), 1.40-1.23 (m, 11H), 0.93-0.86 (m, 1H); HR-FAB MS m/z 646.345 (M + H)+, C32H47N5O9• H+ requires 646.345; Anal. (C32H47N5O9) calculated: C 59.52, H 7.34, N 10.85; found: C 59.38, H 7.27, N 10.71.
MA-21 (13) Prepared in a similar fashion as above. 1H NMR (DMSO-d6) d 8.89 (br s, 1H), 8.02-7.95 (m, 3H), 7.51 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H) 6.47 (d, J = 8.1 Hz, 1H), 4.79 (br s, 2H), 4.46 (d, J = 3.6 Hz, 1H), 4.40-4.30 (m, 1H), 3.97 (s, 2H), 3.95 (d, J = 3.0 Hz, 2H), 3.89 (s, 4H), 3.12-3.01 (m, 5H), 2.73 (d, J = 6.3 Hz, 1H), 2.64 (d, J = 4.8 Hz, 3H), 2.54 (d, J = 6.3 Hz, 1H), 2.38 (d, J = 7.5 Hz, 1H), 2.28 (s, 3H), 2.19-2.07 (m, 2H), 1.60-1.52 (m, 1H), 1.43-1.24 (m, 13H), 0.99-0.87 (m, 1H); HR-FAB MS m/z 660.361 (M + H)+, C33H49N5O9• H+ requires 660.361; Anal. (C33H49N5O9) calculated: C 60.07, H 7.49, N 10.61; found: C 60.09, H 7.44, N 10.80.
7'-{2-[(6-{2-[(Methylaminocarbonyl)-methoxy]-acetylamino}-hexylaminocarbonyl)-methoxy]-acetylamino}-naltrindole,
DN-20, 14. A solution of carboxylic acid 34 (0.244 g, 1.658 mmol, 1.1 eq), HOBt (0.224 g, 1.658 mmol, 1.1 eq), and DCC (0.342 g, 1.658 mmol, 1.1 eq) in DMF (2 ml) were incubated with stirring for 60 min. Amine 33 (0.970 g, 1.507 mmol, 1.0 eq) was added to the above reaction mixture. The reaction was stirred at 60°C for 48 h. The DCU precipitate was collected via vacuum filtration and the solvent was removed from the filtrate in vacuo. Further purification by flash chromatography (silica gel with D/M/A, 94.5/5/0.5, vol/vol/vol) gave 14 as a off white solid (40.2%); Rf 0.55 (silica gel, D/M/A. 89/10/1. vol/vol/vol); mp 130°C; 1H NMR (DMSO-d6) d 10.77 (br s, 1H), 9.69 (s, 1H), 8.81 (br s, 1H), 8.04 (t, J = 5.1 Hz, 1H), 7.89-7.85 (m, 2H) 7.15 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.39-6.32 (m, 2H), 5.38 (s, 1H), 4.63 (br s, 1H), 4.09 (s, 2H), 3.95 (s, 2H), 3.75 (s, 4H), 3.16-3.13 (m, 1H), 2.99-2.89 (m, 5H), 2.64-2.53 (m, 3H), 2.49 (d, J = 4.5 Hz, 3H), 2.36 (m, 1H), 2.28-2.25 (m, 2H) 2.21-2.14 (m, 1H), 2.05-1.97 (m, 1H), 1.45 (d, J = 11.1 Hz, 1 H), 1.29 (m, 4H), 1.13 (s, 4H), 0.80-0.72 (m, 1H), 0.41-0.34 (m, 2H), 0.02-0.00 (m, 2H) ; HR-FAB MS m/z 773.3933 (M + H)+, C41H52N6O9 requires 772.3796.[(2-Benzyloxycarbonylamino-ethylaminocarbonyl)-methoxy]-acetic acid
(15). The mono Cbz salt of ethylene diamine (2.20 g, 9.54 mmol) was suspended in tetrahydrofuran (THF) (10 ml) containing triethylamine (1.06 g, 10.49 mmol). A solution (10 ml) of diglycolic anhydride (1.11 g, 9.54 mmol) was added in small portions. The reaction was allowed to proceed overnight. The precipitate was filtered and the filtrate was dissolved in ethyl acetate (100 ml) and washed with water (twice). The solvent was removed in vacuo to afford 15, (76.4%) as a clear oil. Purification by recrystallization in hot ethyl acetate (EtOAc) (15 ml) gave a white crystalline solid; 1H-NMR (DMSO-d6) d 7.93 ( (t, J = 5.4 Hz, 1H) 7.33 (m, 5H) 5.05 (s, 2H) 4.18 (s, 2H) 3.95 (s, 2H) 3.146 (m, 4H).[(4-tert-Butoxycarbonylamino-butylcarbamoyl)-methoxy]-acetic acid (16).
Prepared in a similar fashion as described above, except that this compound utilizes the Boc protecting group instead of the Cbz protecting group. In the subsequent deprotection step, the Boc group is cleaved under acidic conditions and not by catalytic transfer hydrogentation; 1H-NMR (DMSO-d6) d 12.76 (br s, 1H), 7.81 (dd, 1H, J = 5.1 Hz), 6.74 (br s, 1H), 4.07 (s, 2H), 3.91 (s, 2H), 3.05 (q, 2H, J = 11.7, 6.0 Hz), 2.86 (q, 2H, 11.7, 5.7 Hz), 1.34 (br s, 13H); 13C NMR (DMSO-d6) d 172.13, 169.26, 156.25, 78.00, 70.81, 68.52, 38.54, 28.93, 27.59, 27.20.[(5-Benzyloxycarbonylamino-pentylaminocarbonyl)-methoxy]-acetic acid
(17). Prepared in a similar fashion as described above for compound 15. 1H-NMR (DMSO-d6) d 12.83 (b s, 1H), 7.84 (t, J = 6.0 Hz, 1H), 7.38-7.26 (m, 5H), 7.23 (t, J = 5.4 Hz, 1H), 4.99 (s, 2H), 4.09 (s, 2H), 3.93 (s, 2H), 3.06 (q, J = 12.9, 6.3 Hz, 2H), 2.96 (q, J = 12.9, 6.6 Hz, 2H), 1.39 (s, 4H), 1.22 (s, 2H); 13C NMR (DMSO-d6) d 170.2, 169.5, 156.8, 138.0, 129.0, 128.2, 70.5, 68.4, 65.6, 39.0, 29.8, 29.6, 24.0.[(6-Benzyloxycarbonylamino-hexylaminocarbonyl)-methoxy]-acetic acid
(18). Prepared in a similar fashion as described above for compound 15. 1H-NMR (DMSO-d6) d 7.94 (t, J = 6.0 Hz, 1H), 7.38-7.26 (m, 5H), 7.25 (t, J = 6.0 Hz, 1H), 5.00 (s, 2H), 4.07 (s, 2H), 3.93 (s, 2H), 3.07 (q, 2H), 2.97 (q, 2H), 1.38 (s, 4H), 1.23 (s, 4H).[(7-Benzyloxycarbonylamino-heptylaminocarbonyl)-methoxy]-acetic acid
(19). Prepared in a similar fashion as described above for compound 15. 1H-NMR (DMSO-d6) d 7.81 (t, 1H), 7.36-7.23 (m, 5H), 7.20 (t, J = 5.1 Hz, 1H), 4.97 (s, 2H), 4.07 (s, 2H), 3.91 (s, 2H), 3.07 (q, J = 6.6, 13.2 Hz, 2H), 2.95 (q, J = 6.6, 12.9 Hz, 2H), 1.36 (m, 4H), 1.21 (s, 6H).(5a,6a)-6-{2-[(2-Benzyloxycarbonylamino-ethylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(20). Carboxylic acid 15 (0.85 g, 2.728 mmol, 1.1 eq) was activated with DCC (0.56 g, 2.728 mmol, 1.1 eq), and HOBt (0.37 g, 2.728 mmol, 1.1 eq) in DMF (10 ml) at rt for 10 min. a-Oxymorphamine (0.75 g, 2.48 mmol, 1.0 eq) was added in one portion, and the reaction mixture was stirred under N2 at 45°C for 3 days. The DCU precipitate was collected via vacuum filtration and the filtrate was added to ethyl ether (100 ml) to facilitate precipitation of the crude product. The crude product was isolated via vacuum filtration; further purification by flash chromatography (silica gel, starting with D/M/A, 94.5/5/0.5, vol/vol/vol and switching to D/M/A, 89/10/1, vol/vol/vol, midway through) gave 20 as an off-white solid (35.9%); Rf 0.58 (silica gel, D/M/A. 89/10/1. vol/vol/v); mp 79°C; 1H NMR (DMSO-d6) d 8.97 (br s, 1H), 8.12 (t, J = 5.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H) 7.33-7.27 (m, 6H), 6.58 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.99 (s, 2H), 4.81 (br s, 1H), 4.47 (d, J = 3.3 Hz, 1H), 4.39-4.32 (m, 1H), 3.98 (s, 2H) 3.95 (s, 2H), 3.17-3.01 (m, 5H), 2.73 (d, J = 6.0 Hz, 1H) 2.54 (d, J = 6.3 Hz, 1H), 2.37 (d, J = 7.2 Hz, 1H), 2.28 (s, 3 H), 2.18-2.11 (m, 2H), 1.60-1.52 (m, 1H), 1.41-1.33 (m, 1H), 1.00-0.93 (m, 1H).(5a,6a)-6-{2-[(3-Benzyloxycarbonylamino-propylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(21). a-Oxymorphamine was condensed with diglycolic anhydride to yield a carboxylic acid that was subsequently coupled with mono-Cbz-protected diaminopropane to afford 21. The a-oxymorphamine-diglycolic acid (1.50 g, 3.584 mmol, 1.0 eq), DCC (0.814 g, 3.942 mmol, 1.1 eq), and HOBt (0.727 g, 5.376 mmol, 1.5 eq) in DMF (20 ml) was reacted with stirring at rt for 15 min. Mono-Cbz-protected diaminopropane (HCL salt) (1.00 g, 4.301 mmol, 1.2 eq) was added in one portion along with the base DIPEA (0.556 g, 4.301 mmol, 1.2 eq) to the reaction mixture. This mixture was stirred under N2 at rt for 5 days. The DCU precipitate was collected via vacuum filtration and the solvent was removed from the filtrate in vacuo. Further purification via flash chromatography (silica gel, starting with D/M/A, 95.9/3.6/0.5, vol/vol/vol and switching to D/M/A, 95.3/4.2/0.5, vol/vol/vol, midway through) gave 21 as an off-white solid (19.7%); Rf 0.60 (silica gel, D/M/A. 89/10/1. vol/vol/vol); mp 82°C; 1H NMR (DMSO-d6) d 8.94(br s, 1H), 8.05 (t, J = 6.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H) 7.31 (m, 5H), 7.22 (t, J = 5.7 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.80 (br s, 1H), 4.45 (d, J = 3.6 Hz, 1H), 4.34-4.31 (m, 1H), 3.97 (s, 2H), 3.94 (d, J = 2.1 Hz, 2H), 3.12-2.95 (m, 5H), 2.71 (d, J = 6.3 Hz, 1H) 2.53 (d, J = 5.7 Hz, 1H), 2.36 (d, J = 7.2 Hz, 1H), 2.27 (s, 3 H), 2.17-2.06 ( m, 2H), 1.62-1.49 (m, 3H), 1.39-1.25 (m, 3H), 0.99-0.87 (m, 1H).(5a,6a)-6-{2-[(4-tert-Butoxycarbonylamino-butylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(22). Prepared in a similar fashion as described above for compound 20 (except this is the Boc protected intermediate instead of the Cbz protected compound). 1H-NMR (DMSO-d6) d 8.95 (br s, 1H), 8.06 (t, J = 5.7 Hz,1H), 7.50 (d, J = 8.1 Hz, 1H) 6.83 (t, J = 6.0 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.1,1H), 4.80 (s, 1H), 4.47 (d, J = 3.3 Hz, 1H), 4.39-4.32 (m, 1H), 3.98 (s, 2H) 3.95 (s, 2H), 3.14-2.99 (m, 5H), 2.73 (d, J = 6.0 Hz, 1H), 2.55 (d, J = 6.9 Hz, 1H), 2.38 (d, J = 6.9 Hz, 1H), 2.29 (s, 3H), 2.33-2.12 (m, 2H), 1.61-1.53 (m, 1H), 1.42-1.27 (m, 16H), 0.98-0.88 (m, 1H).(5a,6a)-6-{2-[(5-Benzyloxycarbonylamino-pentylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(23). Prepared in a similar fashion as described above for compound 20. 1H-NMR (DMSO-d6) d 8.93 (br s, 1H), 8.04 (t, J = 6.0 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H) 7.33-7.27 (m, 5H), 7.22 (t, J = 5.1 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.99 (s, 2H), 4.80 (br s, 1H), 4.46 (d, 1H), 4.40-4.33 (m, 1H), 3.98 (s, 2H) 3.96 (s, 2H), 3.10-2.92 (m, 5H), 2.72 (d, J = 6.3 Hz, 1H) 2.54 (d, J = 6.9 Hz, 1H), 2.37 (d, J = 7.5 Hz, 1H), 2.28 (s, 3 H), 2.23-2.07 (m, 2H), 1.63-1.52 (m, 1H), 1.45-1.33 (m, 7H), 1.30-1.20 (m, 2H), 0.95-0.87 (m, 1H).(5a,6a)-6-{2-[(6-Benzyloxycarbonylamino-hexylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(24). Prepared in a similar fashion as described above for compound 20. 1H-NMR (DMSO-d6) d 8.94 (br s, 1H), 8.04 (t, J = 6.0 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.32-7.27 (m, 5H), 7.22 (t, J = 5.7 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.98 (s, 2H), 4.80 (br s, 1H), 4.46 (d, J = 4.2 Hz, 1H), 4.38-4.31 (m, 1H), 3.98 (s, 2H) 3.95 (s, 2H), 3.10-2.92 (m, 5H), 2.72 (d, J = 5.7 Hz, 1H) 2.53 (d, J = 6.6 Hz, 1H), 2.37 (d, J = 4.5 Hz, 1H), 2.28 (s, 3 H), 2.23-2.07 (m, 2H), 1.60-1.52 (m, 1H), 1.40-1.31 (m, 7H), 1.30-1.11 (m, 4H), 0.99-0.85 (m, 1H).(5a,6a)-6-{2-[(7-Benzyloxycarbonylamino-heptylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(25). Prepared in a similar fashion as described above for compound 20. 1H-NMR (DMSO-d6) d 8.92 (br s, 1H), 8.03 (t, J = 6.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.31 (m, 5H), 7.21 (t, J = 5.7 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.79 (br s, 1H), 4.45 (d, J = 3.9 Hz, 1H), 4.37-4.30 (m, 1H), 3.96 (d, J = 1.8 Hz, 2H), 3.94 (d, J = 2.4 Hz, 2H), 3.10-3.03 (m, 2H), 2.99-2.91 (m, 3H), 2.71 (d, J = 6.3 Hz, 1H) 2.52 (d, J = 6.9 Hz, 1H), 2.35 (d, J = 7.1 Hz, 1H), 2.26 (s, 3H), 2.17-2.09 (m, 2H), 1.59-1.51 (m, 1H), 1.35 (m, 7H), 1.20 (b s, 6H), 0.95-0.86 (m, 1H).(5a,6a)-6-{2-[(2-Amino-ethylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(26). A solution of 20 (0.24 g, 0.404 mmol, 1.0 eq) in methanol (MeOH) (3 ml) was added to a round bottom flask (25 ml) containing 10% Pd/C (0.10 g). 1,4-Cyclohexadiene (0.32 g, 4.04 mmol, 10 eq) was added to this reaction mixture and heated to reflux (»70°C) under a N2 atmosphere. After 1.5 h, TLC analysis (D/M/A, 89/10/1, vol/vol/vol) confirmed the starting material had all been consumed. The catalyst was removed via vacuum filtration by using celite as a filter aid. Concentration in vacuo gave the free amine 26 (95.0%); mp 96°C; 1H NMR (DMSO-d6) d 8.04 (t, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.79 (s, 1H), 4.46 (d, J = 3.6 Hz, 1H), 4.38-4.32 (m, 1H), 3.98 (s, 2H), 3.96 (s, 2H), 3.14-3.10 (m, 2H), 3.04 (d, J = 18.6 Hz, 1H), 2.72 (d, J = 6.3 Hz, 1H), 2.61 (t, J = 6.0 Hz, 1H), 2.47 (m, 2H), 2.37 (d, J = 8.1 Hz, 1H), 2.28 (s, 3H), 2.19-2.11 (m, 2H), 1.60-1.52 (m, 1H), 1.40-1.27 (m, 2H), 1.00-0.91 (m, 1H).(5a,6a)-6-{2-[(3-Amino-propylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(27). Prepared in a similar fashion as described above for compound 26. 1H-NMR (DMSO-d6) d 8.16 (t, 1H), 7.54 (d, J = 7.6 Hz, 1H), 6.55 (d, J = 5.1 Hz, 1H), 6.45 (d, J = 7.8 Hz, 1H), 4.78 (br s, 1H), 4.44 (d, J = 3.9 Hz, 1H), 4.37-4.30 (m, 1H), 3.96 (s, 2H), 3.94 (s, 2H), 3.37 (br s, 2H), 3.14 (m, 2H), 3.03 (d, J = 18.6 Hz, 1H), 2.70 (d, J = 6.0 Hz, 1H), 2.58-2.51 (m, 3H), 2.36 (d, J = 6.9 Hz, 1H), 2.26 (s, 3H), 2.16-2.06 (m, 2H), 1.58-1.51 (m, 3H), 1.49-1.32 (m, 3H), 1.26-0.85 (m, 1H).(5a,6a)-6-{2-[(4-Amino-butylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(28). The Boc protected intermediate 22 (0.175 g, 0.297 mmol, 1.0 eq) was placed in a round-bottomed flask (100 ml) and sealed with a septum. Using a syringe (10 ml), 1M HCl/EtOAc (3.0 ml, 3.0 mmol, 10 eq) was transferred to the rb flask and stirred at rt. It was hard to tell if the starting material had completely dissolved, therefore, MeOH (3 ml) was added after 2 h to help solublize everything. After 24 h, TLC analysis (D/M/A, 89/10/1, vol/vol/vol) confirmed the starting material had all been consumed. The solvents were removed in vacuo to afford 28 as a clear oil (quantitative). 1H-NMR (28•HCl, DMSO-d6) d 9.12 (br s, 1H), 8.17 (t, 1H) 7.99 (s, 3H), 7.69 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 4.58 (br s, 1H) 4.30-4.15 (m, 2H), 3.99 (s, 2H), 3.94 (s, 2H), 3.62-3.52 (m, 4H), 3.40-3.28 (m, 2H), 3.13-2.94 (m, 3H), 2.79-2.66 (m, 4H), 1.86-1.75 (m, 1H), 1.58-1.40 (m, 2H), 1.30-1.20 (m, 4H), 1.40-1.92 (m, 1H)(5a,6a)-6-{2-[(5-Amino-pentylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(29). Prepared in a similar fashion as described above for compound 26. The product was used "as is" for the next reaction.(5a,6a)-6-{2-[(6-Amino-hexylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(30). Prepared in a similar fashion as described above for compound 26. 1H-NMR (DMSO-d6) d 8.05 (t, J = 6.0 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.79 (s, 1H), 4.46 (d, J = 3.6 Hz, 1H), 4.39-4.31 (m, 1H), 3.98 (s, 2H), 3.94 (d, J = 3.0 Hz, 2H), 3.12-3.01 (m, 3H), 2.72 (d, J = 6.3 Hz, 1H), 2.55 (m,1H), 2.52-2.48 (m, 2H), 2.37 (d, J = 6.9 Hz, 1H), 2.28 (s, 3H), 2.23-2.07 (m, 2H), 1.63-1.52 (m, 1H), 1.36-1.25 (m, 10H), 1.00-0.88 (m, 1H).(5a,6a)-6-{2-[(7-Amino-heptylaminocarbonyl)-methoxy]-acetylamino}-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan
(31). Prepared in a similar fashion as described above for compound 26. 1H-NMR (DMSO-d6) d 8.05 (t, J = 6.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 6.6 Hz, 1H), 6.45 (d, J = 6.6 Hz, 1H), 4.45 (br s, 1H), 4.44 (d, J = 4.2 Hz, 1H), 4.38-4.29 (m, 1H), 3.96 (d, J = 2.4 Hz, 2H), 3.93 (d, J = 3.9 Hz, 2H), 3.11-3.03 (m, 2H), 3.00 (d, 1H), 2.71 (d, J = 6.3 Hz, 1H), 2.53 (d, 1H), 2.47 (m, 2H), 2.36 (d, J = 7.2 Hz, 1H), 2.26 (s, 3H), 2.17-2.05 (m, 2H), 1.58-1.51 (m, 1H), 1.39-1.21 (m, 12H), 0.96-0.87 (m, 1H).[(Naltrindol-7'-ylaminocarbonyl)-methoxy]-acetic acid
(32). To a stirred solution of 7'NH2-NTI (0.762 g, 1.78 mmol, 1.0 eq) in THF (10 ml), diglycolic anhydride (0.206 g, 1.78 mmol, 1.0 eq) was added (as a solid) in one portion. The flask was sealed with a septum and allowed to stir at room temperature for 18 h. A precipitate formed over time. The product was then collected via vacuum filtration (washed with THF) to afford 32 as a light brown solid (84.2%); mp 216°C (decomposes); 1H NMR (DMSO-d6) d 11.45 (br s, 1H), 11.26 (s, 1H), 8.93 (br s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 7.5 Hz, 1H), 6.56 (t, J = 7.8 Hz, 1H), 6.25-6.19 (m, 2H), 5.31 (s, 1H), 3.84-3.57 (m, 4H), 3.25 (d, 1H), 2.95 (d, J = 19.5 Hz, 1H), 2.75-2.40 (m, 6H), 2.19 (m, 2H), 0.72-0.62 (m, 1H), 0.32-0.22 (m, 2H), 0.00 (m, 2H).7'-{2-[(6-Amino-hexylaminocarbonyl)-methoxy]-acetylamino}-naltrindole
(33). A solution of carboxylic acid 18 (1.18 g, 3.23 mmol, 1.1 eq), DCC (0.667 g, 3.23 mmol, 1.1 eq), and HOBt (0.436 g, 3.23 mmol, 1.1 eq) in DMF (10 ml) were incubated with stirring at rt for 60 min. 7'NH2-NTI (1.26 g, 2.94 mmol, 1.0 eq) was then added in one portion, and the reaction mixture was stirred under N2 at 45°C for 48 h. The DCU precipitate was collected via vacuum filtration, and the solvent was removed from the filtrate in vacuo. Further purification via flash chromatography (silica gel, starting with D/M/A, 94.5/5/0.5, vol/vol/vol and switching to D/M/A, 89/10/1, vol/vol/vol, midway through) gave the NTI intermediate as an off-white solid (59.1%); Rf 0.56 (silica gel, D/M/A. 89/10/1. vol/vol/v); mp 210°C (decomposes); 1H NMR (DMSO-d6) d 10.76 (s, 1H), 9.69 (s, 1H), 8.81 (br s, 1H), 8.04 (t, J = 5.4 Hz, 1H), 7.24-7.13 (m, 5H), 7.07, (d, J = 7.8 Hz, 1H), 6.78 (t, J = 7.5 Hz, 1H), 6.39-6.33 (m, 2H), 5.38 (s, 1H), 4.85 (s, 2H), 4.61 (s, 1H), 4.10 (s, 2H), 3.98-3.93 (m, 4H), 3.14 (d, 1H), 3.03-2.80 (m, 5H), 2.65-2.54 (m, 3H), 2.36-2.27 (m, 3H), 2.25-2.14 (m, 1H), 2.05-1.98 (m, 1H), 1.45 (d, J = 11.1 Hz, 1H), 1.31-1.22 (m, 4H), 1.12 (s, 4H), 0.77-0.73 (m, 1H), 0.42-0.34 (m, 2H), 0.04-0.00 (m, 2H). The purified NTI intermediate (1.31 g, 1.68 mmol, 1.0 eq) in MeOH (5 ml) was added to a round bottom flask (50 ml) containing 10% Pd/C (0.30g). 1,4-Cyclohexadiene (1.34g, 16.85 mmol, 10 eq) was added to this reaction mixture and heated to reflux (»65°C) under a N2 atmosphere. After 4.0 h, TLC analysis (D/M/A, 89/10/1, vol/vol/vol) confirmed the starting material had all been consumed. The catalyst was removed via vacuum filtration using celite as a filter aid. Concentration in vacuo gave the free amine 33 (99.0%); mp 221°C (decomposes); 1H NMR (DMSO-d6) d 10.85 (br s, 1H), 9.70 (s, 1H), 8.08 (t, J = 6.0 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.46-6.31 (m, 2H), 5.37 (s, 1H), 4.60 (br s, 1H), 4.09 (s, 2H), 3.95 (s, 2H), 3.14 (d, J = 6.6 Hz, 1H), 3.02-2.89 (m, 3H), 2.64-2.54 (m, 3H), 2.40-2.24 (m, 5H), 2.18-2.09 (m, 1H), 2.05-1.98 (m, 1H), 1.45 (d, J = 12.3 Hz, 1H), 1.31-1.28 (m, 4H), 1.22-1.12 (m, 4H), 0.80-0.72 (m, 1H), 0.38-0.34 (m, 2H), 0.02-0.00 (m, 2H).Methylaminocarbonylmethoxy-acetic acid
(34). In a round-bottomed flask (100 ml) containing diglycolic anhydride (5.0 g, 43.08 mmol, 1.0 eq), a 2 M solution of methyl amine (25 ml, »43 mmol) (prepared by bubbling methyl amine gas through THF) was added in two portions. After 18 h TLC (D/M/A, 89/10/1, vol/vol/vol; staining with ninhydrin) showed the disappearance of methylamine. The reaction mixture was concentrated in vacuo to afford 34 as a clear, colorless oil (quantitative). After further drying on a vacuum pump (24 h), followed by exposure to atmospheric pressure (24 h), the product crystallized (white) to the sides of the round-bottomed flask; mp 57°C; 1H NMR (DMSO-d6) d 12.76 (b s, 1H), 7.78 (br s, 1H), 4.08 (s, 2H), 3.93 (s, 2H), 2.61 (d, J = 4.8 Hz, 3H); 13C NMR (DMSO-d6) d 172.2, 170.0, 71.0, 69.5, 25.8, 25.01. Sayre, L. M. & Portoghese, P. S. (1980) J. Med. Chem. 45, 3366–3368.
2. Portoghese, P. S., Sultana, M., Nelson, W. L., Klein, P. & Takemori, A. E. (1992) J. Med. Chem. 35, 4089–4091.
3. Atwell, G. J. & Denny, W. A. (1984) Synthesis 12, 1032–1033.