Synthesis of Isoxazoline-Substituted Symmetrical Diketopiperazines

Abstract

A synthesis of racemic isoxazoline substituted symmetrical diketopiperazines has been achieved by twice utilizing a dia­stereoselective 1,3-dipolar cycloaddition step - mediated by intermolecular hydrogen-bonds between the Boc-NH of 2 and the requisite nitrile oxide (RCN⁺-O^-) - to control alkene face selectivity. Dehydrative cyclization of the amide-linked amino acid 6 delivered diketopiperazine 8.

Key words

diketopiperazine (DKP) - isoxazoline - 1,3-dipolar cycloaddition - isoxazoline-substituted symmetrical DKPs

References

• 1 Avendano Lopez C. Gonzalez Trigo G. Adv. Heterocycl. Chem.  1985,  38:  177 
• 2a Khalil MA. Maponya MF. Ko D.-H. You Z. Oriaku ET. Lee HJ. Med. Chem. Res.  1996,  6:  52 
• 2b Groutas WC. Venkataraman R. Chong LS. Yooder JE. Epp JB. Stanga MA. Kim E.-H. Bioorg. Med. Chem.  1995,  3:  125 
• 2c Levin JI. Chan PS. Coupet J. Bailey TK. Vice G. Thibault L. Lai F. Venkatesan AM. Cobuzzi A. Bioorg. Med. Chem. Lett.  1994,  4:  1703 
• 2d Simoni D. Manfredini S. Tabrizi MA. Bazzanini R. Guarneri M. Ferroni R. Tranielo F. Nastruzzi C. Feriotto G. Gambari R. Top. Mol. Org. Eng.  1991,  8:  119 
• 3 Palacin S. Chin DN. Simanek EE. MacDonald JC. Whitesides GM. McBride MT. Palmore GTR. J. Am. Chem. Soc.  1997,  119:  11807 
• 4 MacDonald JC. Whitesides GM. Chem. Rev.  1994,  94:  2383 
• 5a Bergeron RJ. Phanstiel OIV. Yao GW. Milstein S. Weimar WR. J. Am. Chem. Soc.  1994,  116:  8479 
• 5b Jagadish B. Williams LJ. Carducci MD. Bosshard C. Mash EL. Tetrahedron Lett.  2000,  41:  9483 
• For reviews of nitrile oxide-isoxazoline methodology, see:
• 6a Curran DP. In Advances in Cycladdition   Vol. 1:  Curran DP. JAI Press INC.; Greenwich, Connecticut: 1988.  p.129-189  
• 6b Torssel KBG. In Organic Nitro Chemistry Series. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis. Novel Strategies in Synthesis   Feuer H. VCH Publishers; Weinheim: 1988.  p.55-74  
• 7 Christl M. Huisgen R. Chem. Ber.  1973,  106:  3345 
• 8 Mukaiyama T. Hoshino T. J. Am. Chem. Soc.  1960,  62:  5339 
• 9a Reddy AV. Ravindranath B. Int. J. Peptide Protein Res.  1992,  40:  472 
• 9b Fusaoka Y. Ozeki E. Kimura S. Imanishi Y. Int. J. Peptide Protein Res.  1989,  34:  104 
• 9c Lee BH. Gerfen GJ. Miller MJ. J. Org. Chem.  1984,  49:  2418 
• 9d Buyle R. Helv. Chim. Acta  1966,  49:  1425 
• 10 Nitecki DE. Halpern B. Westley JN. J. Org. Chem.  1968,  33:  864 
• 11 Park K.-H. Olmstead MM. Kurth MJ. J. Org. Chem.  1998,  63:  113 
• 12a

  See ref. [11]

• 12b Park K.-H. Kurth MJ. J. Org. Chem.  2000,  65:  3520 

13

Typical procedures:
Preparation of 2: 1-Amino-cyclopent-3-enecarboxylate (1; 4 g, 25.8 mmol) was treated with di-tert-butyl dicarbonate (5.63 g, 25.8 mmol) in CH₂Cl₂ (100 mL) at reflux overnight. The solvent was removed under reduced pressure and the residue was recrystallized (EtOAc and hexane) to give 2 (6 g, 23.5 mmol, 91%) as a solid. Mp: 82 °C; ¹H NMR (300 MHz, CDCl₃) δ 5.65 (s, 2 H), 5.10 (s, br, 1 H), 4.20 (q, 2 H, J = 7.1 Hz), 3.05 (d, 2 H, J = 15.6 Hz), 2.6 (d, 2 H, J = 15.6 Hz), 1.43 (s, 9 H), 1.27 (t, 3 H, J = 7.1 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 174.3, 154.9, 127.7, 64.3, 61.5, 44.9, 28.3, 27.4, 14.2.
Preparation of 2-1: The mixture of compound 2 (3.5 g, 13.72 mmol) and sodium hydroxide (1.09 g, 27.4 mmol) in EtOH/H₂O (20 mL/20 mL) was refluxed overnight. The solvent was removed under reduced pressure, and 1 N HCl was added to the reaction mixture until the pH reached to 2-3. Ethyl acetate (40 mL × 2) extraction, drying over anhydrous MgSO₄, and removal of solvent under reduced pressure gave compound 2-1 (2.7 g, 11.8 mol, 87%) as a solid. Mp: 137 °C; ¹H NMR (300 MHz, CDCl₃) δ 5.66 (s, 2 H), 5.14 (s, br, 1 H), 3.13 (d, 2 H, J = 16.3 Hz), 2.64 (d, 2 H, J = 16.3 Hz), 1.44 (s, 9 H); ¹³C NMR (75 MHz, CDCl₃) δ 155.8, 127.6, 64.4, 44.8, 28.3, 27.4.
Preparation of 3 (R = ethyl): Compound 2 (2 g, 7.84 mmol) in THF (50 mL) was treated with 1-nitropropane (0.7g, 7.84 mmol), phenyl isocyanate (1.87 g, 15.68 mmol), and Et₃N (0.01 mL), then the reaction mixture was refluxed for a day. Removal of the solvent under reduced pressure, followed by column chromatography (20% ethyl acetate in hexane), afforded compound 3 (1.6 g, 62%) as a solid. Mp: 102 °C; ¹H NMR (300 MHz, CDCl₃) δ 5.10 (m, 1 H), 5.09 (s, 1 H), 4.27-4.09 (m, 2 H), 3.74 (t, 1 H, J = 9.1 Hz), 2.76 (d, 1 H, J = 14.2 Hz), 2.58 (dd, 1 H, J = 14.2 Hz, 9.1 Hz), 2.40 (dd, 1 H, J = 16.1 Hz, 7.7 Hz), 2.29-2.18 (m, 3 H), 1.41 (s, 9 H), 1.25 (t, 3 H, J = 7.2 Hz), 1.20 (t, 3 H, J = 7.5 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 172.4, 162.3, 154.5, 84.0, 79.5, 65.2, 61.3, 53.8, 45.8, 36.8, 27.9, 19.7, 13.8, 10.4.
Preparation of 4 (R = ethyl): The reaction mixture of compound 3 (2 g, 6.13 mmol) in TFA/CH₂Cl₂ (15 mL/15 mL) was stirred at rt for 1 h. Solvent removal under reduced pressure, followed by short column chromatography (ethyl acetate), afforded compound 4 (1 g, 72%) as a liquid. ¹H NMR (300 MHz, CDCl₃) δ 5.13 (t, 1 H, J = 8.10 Hz), 4.15 (dt, 2 H, J = 7.2 Hz, 0.8 Hz), 3.70 (t, 1 H, J = 9.5 Hz), 2.52-2.23 (m, 4 H), 2.10 (d, 1 H, J = 14.6 Hz), 1.92 (d, 1 H, J = 13.4 Hz), 1.68 (s, 2 H), 1.25 (dt, 3 H, J = 7.2 Hz, 0.8 Hz), 1.17 (dt, 3 H, J = 7.4 Hz, 0.8 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 175.4, 162.0, 85.2, 65.2, 61.2, 54.4, 47.2, 42.2, 19.9, 13.9, 10.5.
Preparation of 5 (R = ethyl): Equimolar amount of compound 4 (1.46 g, 6.48 mmol) and compound 2-1 (1.47 g, 6.48 mmol) were dissolved in CH₂Cl₂ (50 mL)_. The reaction mixture was cooled to 0 °C, and DCC (1.34 g, 6.48 mmol) was added. After 30 min, DMAP (20 mg) was added at r.t., and the reaction mixture was stirred at r.t. for 3 days. After filtering the precipitate, the filtrate was concentrated under reduced pressure. By column chromatography compound 5 (2.03 g, 72%) was obtained as a solid. Mp: 157 °C. ¹H NMR (300 MHz, CDCl₃) δ 6.80 (s, 1 H), 5.82 (m, 1 H), 5.76 (m, 1 H), 5.67 (s, 1 H), 5.11 (dd, 1 H, J = 9.1 Hz, 5.1 Hz), 4.15 (m, 2 H), 3.72 (t, 1 H, J = 9.2 Hz), 2.96-2.74 (m, 3 H), 2.65 (dd, 1 H, J = 14.4 Hz, 9.9 Hz), 2.49-2.36 (m, 2 H), 2.31-2.15 (m, 2 H), 1.42 (s, 9 H), 1.25 (t, 3 H, J = 7.1 Hz), 1.17 (t, 3 H, J = 7.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 173.9, 171.4, 162.1, 154.3, 129.6, 128.9, 84.6, 79.3, 65.4, 63.4, 61.2, 53.2, 44.8, 43.2, 42.2, 37.3, 27.9, 19.7, 13.7, 10.2.
Preparation of 6 and 7 (R = ethyl): Compound 5 (2 g, 4.6 mmol) in THF (100 mL) was treated with 1-nitropropane (0.41 g, 4.6 mmol), phenyl isocyanate (1.1 g, 9.21 mmol), and Et₃N (40 mg), then the reaction mixture was refluxed for 2 days. Removal of the solvent under reduced pressure, followed by short column chromatography (20% ethyl acetate in hexane), afforded the mixture of compound 6 and 7 (1.44 g, 62%) as a solid. Compound 6 (as a major from recrystallized mixture); ¹H NMR (300 MHz, CDCl₃) δ 7.59 (s, 1 H), 7.47 (s, 1 H), 5.11 (m, 2 H), 4.16 (m, 2 H), 3.71 (m, 2 H), 2.85 (d, 1 H, J = 14 Hz), 2.61-2.10 (m, 11 H), 1.44 (s, 9 H), 1.26-1.21 (m, 6 H), 1.17 (t, 3 H, J = 7.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 171.6, 171.5, 162.2, 162.0, 154.9, 84.7, 84.2, 80.2, 66.5, 65.3, 61.4, 53.7, 53.4, 45.3, 44.9, 36.9, 35.1, 28.1, 28.0, 19.9, 19.8, 13.9, 10.5.
Preparation of 8a and 9a: The mixture of compounds 6 and 7 (0.52 g, 1.02 mmol) was treated with formic acid (96%, 30 mL) for 30 min at r.t. After removing formic acid under reduced pressure, the residue was dissolved in sec-butanol/xylene (40 mL/10 mL), and then boiled for 3 h. Removal of the solvent under reduced pressure, followed by fractional recrystallization (EtOH/MeOH/hexane), afforded 8a (0.11 g, 30%) and 9a (0.103 g, 28%) as a solid. Compound 8a; Mp > 300 °C; ¹H NMR (300 MHz, DMSO-d ₆) δ 7.96 (s, 2 H), 5.03-4.97 (m, 2 H), 3.73-3.68 (dd, 2 H, J = 17.3 Hz, 9.2 Hz), 2.51-2.19 (m, 8 H), 1.92-1.80 (m, 4 H), 1.05 (t, 6 H, J = 7.6 Hz); ¹³C NMR (75 MHz, DMSO-d ₆) δ 169.6, 161.5, 84.3, 65.3, 53.5, 45.4, 41.3, 19.0, 10.2. Crystallographic data for 8a: C₁₈H₂₄N₄O₄, colorless needle, triclinic, space group P1, a = 6.0067(9) Å, a = 87.8760(11)°, b = 6.0102(8) Å, b = 86.761 (11)°, c = 14.110 (2) Å, g = 60.959 (9)°, U = 444.61 (11) ų, Z = 1, D_c = 1.346 Mg/m³, m = 0.797 mm^-1,
R = 0.0569, wR = 0.1409, GOF = 1.029, T = 130 (2) K, F(000) = 192, 1154 independent reflections were collected on a Siemens P4 (wavelength = 1.54178 Å). Compound 9a; Mp: 221 °C; ¹H NMR (300 MHz, CDCl₃) δ 8.01 (s, 2 H), 5.00-4.96 (m, 2 H), 3.77-3.71 (dd, 2 H, J = 17.2 Hz, 9.2 Hz), 2.51-2.20 (m, 8 H), 1.90-1.82 (m, 4 H), 1.06 (t, 6 H, J = 7.6 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 169.9, 161.6, 84.6, 65.5, 53.6, 45.1, 42.1, 19.3, 10.6.
Preparation of 8b and 9b: Compound 8b; Mp > 300 °C; ¹H NMR (300 MHz, DMSO-d ₆) δ 8.17 (s, 2 H), 7.68-7.66 (m, 4 H), 7.45-7.43 (m, 6 H), 5.25-5.21 (m, 2 H), 4.30-4.25 (dd, 2 H, J = 18.8 Hz, 8.8 Hz), 2.75-2.71 (m, 2 H), 2.65-2.61 (dd, 2 H, J = 13.3 Hz, 7.1 Hz), 2.02-1.98 (dd, 2 H, J = 13.6 Hz, 6.4 Hz), 1.88-1.83 (m, 2 H) ¹³C NMR (75 MHz, DMSO-d ₆) δ 169.8, 158.6, 129.8, 128.7, 128.5, 126.7, 86.1, 65.6, 51.5, 45.7, 42.8.
Compound 9b; Mp > 300 °C; ¹H NMR (300 MHz, DMSO-d ₆) δ 8.18 (s, 2 H), 7.67-7.65 (m, 4 H), 7.44-7.43 (m, 6 H), 5.29-5.24 (m, 2 H), 4.26-4.20 (dd, 2 H, J = 18.6 Hz, 9.0 Hz), 2.75-2.71 (m, 2 H), 2.64-2.59 (dd, 2 H, J = 13.2 Hz, 6.8 Hz), 2.05-2.01 (dd, 2 H, J = 13.6 Hz, 6.3 Hz), 1.85-1.80 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆) δ 169.7, 158.6, 129.7, 128.7, 128.5, 126.7, 86.3, 65.7, 51.4, 45.3, 43.4. Crystallographic data for 9b with 2 DMSO: C₃₀H₃₆N₄O₆S₂, colorless needle, triclinic, space group P1, a = 10.560 (3) Å, a = 104.603 (18)°, b = 11.492(3)Å, b = 91.87 (2)°, c = 13.927 (3) Å,
g = 106.57 (2)°, U = 1557.7 (7) ų, Z = 2, Dc = 1.306 Mg/m³, m = 1.949 mm^-1, R = 0.0503, wR = 0.1011, GOF = 1.030, T = 130 (2) K, F(000) = 648, 4104 independent reflections were collected on a Siemens P4 (wavelength = 1.54178 Å).
Preparation of 8c and 9c: Compound 8c; Mp > 300 °C; ¹H NMR (300 MHz, DMF-d ₇) δ 8.02 (s, 2 H), 7.72-7.68 (m, 8 H), 5.36-5.31 (m, 2 H), 4.39-4.33 (dd, 2 H, J = 18 Hz, 10 Hz), 2.89-2.85 (m, 2 H), 2.78-2.74 (m, 2 H), 2.21-2.17 (dd, 2 H, J = 13.6 Hz, 6.0 Hz), 2.07-2.03 (dd, 2 H, J = 13.2 Hz, 8.3 Hz); ¹³C NMR (75 MHz, DMF-d ₇) δ 171.0, 159.2, 132.8, 129.6, 129.2, 124.2, 88.0, 67.1, 52.6, 47.0, 44.2. Crystallographic data for 8c with 2 DMF: C₃₂H₃₆Br₂N₆O₆, colorless plate, monoclinic, space group P21/c, a = 14.891 (2), a = 90°, b = 5.8278 (11) Å, b = 90.955 (12)°, c = 18.276 (3) Å, g = 90°, U = 1585.8 (5) ų, Z = 2, Dc = 1.593 Mg/m³, m = 3.703 mm^-1, R = 0.0462, wR = 0.1051, GOF = 1.051,
T = 130(2) K, F(000) = 776, 2093 independent reflections were collected on a Siemens P4 (wavelength = 1.54178 Å). Compound 9c; Mp > 300 °C; ¹H NMR (300 MHz, DMF-d ₇) δ 8.04 (s, 2 H), 7.70-7.68 (m, 8 H), 5.40-5.37 (m, 2 H), 4.34-4.28 (dd, 2 H, J = 18.2 Hz, 9.2 Hz), 2.90-2.85 (m, 2 H), 2.78-2.73 (m, 2 H), 2.24-2.20 (dd, 2 H, J = 13.7 Hz, 6.0 Hz), 2.04-1.99 (dd, 2 H, J = 13.2 Hz, 8.4 Hz); ¹³C NMR (75 MHz, DMF-d ₇) δ 170.9, 159.3, 132.7, 129.6, 129.2, 124.2, 88.2, 67.2, 52.4, 46.6, 44.7. Crystallographic data for 9c with 2.25 DMSO: C_30.50H_35.50Br₂N₄O_6.25S_2.25, colorless parallelepiped, monoclinic, space group C2/c, a = 18.034(4) Å, a = 90°,
b = 13.184 (3) Å, b = 91.165 (15)°, c = 30.183 (5) Å, g = 90°, U = 7175 (3) ų, Z = 8, Dc = 1.463 Mg/m³, m = 4.476 mm^-1, R = 0.0804, wR = 0.2110, GOF = 1.044, T = 130 (2) K, F(000) = 3220, 4719 independent reflections were collected on a Siemens P4 (wavelength = 1.54178 Å).