Synlett 2013; 24(8): 1006-1010
DOI: 10.1055/s-0032-1316911
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Functionalized Diketopiperazines as Cyclotryprostatin and Tryprostatin Analogues

Tuyen Nguyen Van
,
Pieter Claes
,
Norbert De Kimpe*
Further Information

Publication History

Received: 31 January 2013

Accepted after revision: 19 March 2013

Publication Date:
09 April 2013 (online)


Abstract

Various ketopiperazines were synthesized as (cyclo)tryprostatin analogues. Construction of the skeleton started with a Pictet–Spengler reaction followed by acylation or alkylation of the piperidine nitrogen and condensation with a primary amine. 2-Chloroacetyl tetrahydro-β-carbolines rearranged towards the corresponding 2-chloro-N-[2-(1H-indol-3-yl)ethyl]acetamide deriv-atives upon treatment with NBS. These compounds were cyclized with primary amines towards the corresponding functionalized diketopiperazines.

Supporting Information

 
  • References and Notes

  • 1 Current address: Institute of Chemistry, Vietnam Academy of Science & Technology, 18 Hoang Quoc Viet, Cau Giay, Ha Noi, Vietnam.
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    • 5c For a recent review on diketopiperazines, see: Borthwic AD. Chem. Rev. 2012; 112: 3641
  • 6 cis- and trans-Ethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 6a and 7a: A solution of l-tryptophan ethyl ester 4 (2.9 g, 11.74 mmol) and benz-aldehyde (5a; 1.25 g, 11.74 mmol) in benzene (50 mL) was refluxed for 48 h. Then, the solvent was evaporated to give a crude product, which was extracted with EtOAc (3 ×). The combined organic phases were washed with sat. NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (hexane–EtOAc, 4:6) gave trans-isomer 6a (1.1 g, 30%) and cis-isomer 7a (2.3 g, 61%). trans-Ethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate (6a): Yield: 30%; white powder; mp 151–151.5 °C; [α]D 15 –3.4° (c = 0.59, CH2Cl2). 1H NMR (270 MHz, CDCl3): δ = 1.33 (t, J = 7.3 Hz, 3 H, Me), 2.19 (br s, 1 H, NH), 3.02 (ddd, J = 2.0, 11.2, 15.2 Hz, 1 H, H-4a), 3.20 (ddd, J = 1.7, 4.3, 15.2 Hz, 1 H, H-4b), 3.90 (dd, J = 11.2, 4.3 Hz, 1 H, H-3), 4.22–4.31 (m, 2 H, OCH2), 5.23 (dd, J = 1.7, 2.0 Hz, 1 H, H-1), 7.10–7.25 (m, 3 H, 3 × =CH), 7.34–7.39 (m, 5 H, 5 × =CH), 7.43 (br s, 1 H, H-9), 7.55 (dd, J = 7.9, 2.0 Hz, 1 H, H-5). 13C NMR (68 MHz, CDCl3): δ = 14.23 (Me), 25.68 (C-4), 56.94 (C-3), 58.69 (C-1), 61.20 (OCH2), 108.97 (Cquat), 110.89 (C-8), 118.22 (C-5), 119.59 (C-6), 121.90 (C-7), 127.13 (Cquat), 128.57 (=CH), 128.62 (2 × =CH), 128.95 (2 × =CH), 134.73 (Cquat), 136.14 (Cquat), 140.77 (Cquat), 172.76 (C=O). IR (KBr): 3387 (NH), 1720 (C=O), 1625, 1490, 1470, 1455, 1368, 1324, 1267, 1226, 1144, 1034, cm–1. MS: m/z (%) = 221 (100) [M + H+], 221 (30), 220 (50). cis-Ethyl-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate (7a): Yield: 61%; white powder; mp 167.5–168 °C; [α]D 15 –4.1° (c = 0.48, CH2Cl2). 1H NMR (270 MHz, CDCl3): δ = 1.26 (t, J = 6.9 Hz, 3 H, Me), 2.39 (br s, 1 H, NH), 3.10 (ddd, J = 1.8, 7.0, 15.5 Hz, 1 H, H-4a), 3.28 (ddd, J = 1.0, 5.3, 15.5 Hz, 1 H, H-4b), 3.94 (dd, J = 7.0, 5.3 Hz, 1 H, H-3), 4.11–4.23 (m, 2 H, OCH2), 5.40 (br s, 1 H, H-1), 7.10–7.16 (m, 2 H, H-6, H-7), 7.18–7.36 (m, 6 H, 5 × =CH, H-8), 7.57 (d, J = 8.9 Hz, 1 H, H-5), 7.63 (br s, 1 H, H-9). 13C NMR (68 MHz, CDCl3): δ = 14.19 (Me), 24.69 (C-4), 52.49 (C-3), 54.97 (C-1), 61.04 (OCH2), 108.53 (Cquat), 110.87 (C-8), 118.25 (C-5), 119.48 (C-6), 121.92 (C-7), 127.02 (Cquat), 128.08 (=CH), 128.41 (2 × =CH), 128.75 (2 × =CH), 133.20 (Cquat), 136.15 (Cquat), 142.04 (Cquat), 173.67 (C=O). IR (KBr): 3400 (NH), 1737 (C=O), 1625, 1455, 1335, 1214, 1124 cm–1. MS: m/z (%) = 221 (100) [M + H+], 221 (20), 220 (50).
    • 7a Sandrin J, Soerens D, Cook JM. Heterocycles 1976; 4: 1249
    • 7b Ungemach F, Soerens D, Weber R, DiPierro M, Campos O, Mokry P, Cook JM, Silverton J. J. Am. Chem. Soc. 1980; 102: 6976
  • 8 cis- and trans-Ethyl-2-(2-chloroacetyl)-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate 9a and 8a: To a solution of the cis-isomer 6a (800 mg, 2.5 mmol) in a sat. solution of NaHCO3 (20 mL) and EtOAc (20 mL) was added chloroacetyl chloride (333 mg, 3 mmol). The reaction mixture was stirred at 0 °C for 30 min. Afterwards, the solvent was evaporated and the residue was extracted with CH2Cl2. The combined organic phases were washed with sat. NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (hexane–EtOAc, 6:4) gave compound 9a in 91% yield (900 mg). cis-Ethyl-2-(2-chloroacetyl)-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate (9a): Yield: 91%; white powder; mp 156.5–158 °C; [α]D 15 –2.12° (c = 0.47, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 0.62–0.90 (m, 3 H, Et), 2.98–3.12 (m, 1 H, CHAHBO), 3.17 (dd and m, J = 6.9, 15.7 Hz, 2 H, CHAHB-4, CHAHBO), 3.67–3.75 (m, 1 H, CHAHB-4), 4.21 (d, J = 12.4 Hz, 1 H, CHAHBCl), 4.35 (d, J = 12.4 Hz, 1 H, CHAHBCl), 4.91 (d, J = 4.4 Hz, 1 H, CH-3), 6.95 (s, 1 H, CH-1), 7.13–7.36 (m, 8 H, 8 × CHAr), 7.60 (d, J = 9.9 Hz, 1 H, CHAr), 7.80 (br s, 1 H, NH). 13C NMR (68 MHz, CDCl3): δ = 13.55 (Et), 21.58 (CH2-4), 42.24 (CH2Cl), 52.32 (CH-1), 53.74 (CH-3), 61.77 (CH2O), 107.83 (Cquat), 111.13 (2 × CHAr), 118.70 (2 × CHAr), 119.92 (CHAr), 122.64 (CHAr), 126.46 (Cquat), 128.35 (CHAr), 128.35 (CHAr), 129.65 (CHAr), 136.52 (Cquat), 139.06 (Cquat), 167.15 (C=O), 169.64 (C=O). IR (KBr): 3367, 3315 (NH), 1741, 1728 (C=O), 1658 (C=O), 1626, 1492, 1455, 1425, 1319, 1262, 1238, 1206 cm–1. MS: m/z (%) = 397, 399 (199) [M + H+], 351 (30). trans-Ethyl-2-(2-chloroacetyl)-1-phenyl-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate (8a): Yield: 96%; white powder; mp 216.5–218 °C; [α]D 15 –38.4° (c = 0.65, CH2Cl2). 13C NMR (68 MHz, CDCl3): δ = 13.54 (Me), 21.60 (C-4), 42.21 (C-2′), 52.35 (C-3), 53.77 (C-1), 61.75 (OCH2), 107.88 (Cquat), 111.12 (C-8), 118.70 (C-5), 119.94 (C-6), 122.66 (C-7), 126.47 (Cquat), 128.44 (C-2′, C-6′), 129.64 (C-3′, C-5′, Cquat), 136.52 (Cquat), 139.06 (Cquat), 167.16 (C=O), 169.62 (C=O). IR (KBr): 3391 (NH), 1714, 1667 (C=O), 1609, 1511, 1452, 1387, 1367, 1242, 1029 cm–1. MS: m/z (%) = 397, 399 (100) [M + H+], 351 (25).
  • 9 cis- and trans-6-Phenyl-2-propyl-2,3,6,7,12,12a-hexa-hydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione 11a and 10a: A mixture of 9a (100 mg, 0.25 mmol) and propylamine (64 mg, 1.25 mmol) in anhyd EtOH (10 mL) was stirred for 24 h at r.t. Then, the mixture was poured in H2O and extracted with EtOAc (3 ×). The combined organic phases were washed, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (hexane–EtOAc, 1:1) gave pure compound 11a (88 mg, 94%). cis-6-Phenyl-2-propyl-2,3,6,7,12,12a-hexahydropyr-azino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (11a): Yield: 94%; white powder; mp 254–255.5 °C; [α]D 15 –35° (c = 0.4, CH2Cl2). 1H NMR (270 MHz, CDCl3): δ = 0.92 (t, J = 7.3 Hz, 3 H, Me), 1.53–1.67 (m, 2 H, H-2′ ), 3.19–3.34 (m, 2 H, overlap, H-12a, H-1′a), 3.48–3.61 (m, 1 H, H-1′b), 3.75 (dd, J = 17.2, 4.6 Hz, 1 H, H-12b), 3.89 (d, J = 17.5 Hz, 1 H, H-3a), 4.06 (d, J = 17.5 Hz, 1 H, H-3b), 4.31 (dd, J = 10.2, 3.3 Hz, 1 H, H-13), 6.26 (br s, 1 H, H-6), 7.13–7.32 (m, 8 H, 5 × =CH, H-8, H-9, H-10), 7.59 (dd, J = 8.9, 3.0 Hz, 1 H, H-11), 8.01 (br s, 1 H, H-7). 13C NMR (68 MHz, (CDCl3): δ = 11.14 (Me), 20.20 (C-2′), 23.55 (C-12), 47.89 (C-1′), 50.26 (C-3), 56.17 (C-13), 56.73 (C-6), 108.54 (Cquat), 111.21 (C-8), 118.59 (C-11), 120.03 (C-10), 122.41 (C-9), 126.18 (Cquat), 126.93 (2 × =CH), 127.80 (=CH), 128.71 (2 × =CH), 132.81 (Cquat), 136.51 (Cquat), 141.38 (Cquat), 166.39 (C=O), 167.17 (C=O). IR (KBr): 3317 (NH), 2955, 1671 (C=O), 1656 (C=O), 1623, 1426, 1310, 1271, 1226, 1209, 1155 cm–1. MS: m/z (%) = 374 (100) [M + H+]. trans-6-Phenyl-2-propyl-2,3,6,7,12,12a-hexahydropyr-azino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (10b): Yield: 90%; white powder; mp 192–193.5 °C; [α]D 15 –240° (c = 0.5, CH2Cl2). 1H NMR (270 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3 H, Me), 1.49–1.63 (m, 2 H, H-2′), 2.90 (ddd, J = 1.1, 11.6, 15.2 Hz, 1 H, H-12a), 3.02–3.12 (m, 1 H, H-1′a), 3.47–3.54 (m, 2 H, overlap, H-1′b, H-12b), 3.84 (d, J = 17.8 Hz, 1 H, H-3a), 4.40 (d, J = 17.8 Hz, 1 H, H-3b), 4.24 (dd, J = 11.6, 4.0 Hz, 1 H, H-13), 7.02 (br s, 1 H, H-6), 7.08–7.28 (m, 8 H, 5 × =CH, H-8, H-9, H-10), 7.51 (dd, J = 8.9, 2.9 Hz, 1 H, H-11), 8.58 (br s, 1 H, H-7). 13C NMR (68 MHz, CDCl3): δ = 11.02 (Me), 19.59 (C-2′), 27.60 (C-12), 47.48 (C-1′), 49.24 (C-3), 51.99 (C-6), 52.13 (C-13), 108.68 (Cquat), 111.09 (C-8), 118.26 (C-11), 119.80 (C-10), 122.43 (C-9), 126.15 (Cquat), 128.61 (2 × =CH), 128.72 (3 × =CH), 129.62 (Cquat), 136.30 (Cquat), 138.22 (Cquat), 161.59 (C=O), 165.14 (C=O). IR (KBr): 3219 (NH), 2929, 1662 (C=O), 1653 (C=O), 1620, 1495, 1455, 1335, 1262, 1164 cm–1. MS: m/z (%) = 374 (100) [M + H+], 149 (20), 102 (20).
  • 10 trans-Ethyl-2-(2-bromoethyl)-1-phenyl-2,3,4,9-tetra-hydro-1H-β-carboline-3-carboxylate (12): A mixture of 6a (800 mg, 2.5 mmol), 1,2-dibromoethane (5.52 g, 60.4 mmol) and K2CO3 (380 mg, 2.75 mmol) was stirred at reflux for 24 h. Then, the mixture was poured in H2O and extracted with EtOAc (3 ×). The combined organic phases were washed with sat. NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (hexane–EtOAc) gave pure 12 in 48% yield as a yellow oil. 1H NMR (300 MHz, CDCl3): δ = 1.19 (t, J = 7.2 Hz, 3 H, Me), 3.00 (dd, J = 3.6, 9.1 Hz, 1 H, H-4a), 3.10–3.22 (m, overlap, 3 H, H-4b, H-1′), 3.29–3.35 (m, 2 H, H-2′), 4.01–4.17 (m, overlap, 3 H, H-3, OCH2), 5.42 (s, 1 H, H-6), 7.05–7.16 (m, 3 H, 3 × =CH), 7.24–7.39 (m, 5 H, 5 × =CH), 7.51 (br d, J = 8.8 Hz, 1 H, H-5). 13C NMR (68 MHz, CDCl3): δ = 14.21 (Me), 24.94 (C-2′), 31.42 (C-4), 54.70 (C-1′), 59.51 (C-3), 60.61 (OCH2), 61.62 (C-1), 106.14 (Cquat), 110.81 (C-8), 118.22 (C-5), 119.36 (C-6), 121.70 (C-7), 126.88 (Cquat), 128.37 (=CH), 128.78 (2 × =CH), 129.01 (2 × =CH), 134.86 (Cquat), 136.48 (Cquat), 141.82 (Cquat), 173.18 (C=O). IR (KBr): 3396 (NH), 2927, 2854, 1731 (C=O), 1603, 1493, 1463, 1455, 1268, 1186, 1113, 1028 cm–1. MS: m/z (%) = 443, 445 (10) [M + H+], 426, 428 (10), 426, 428 (30), 363, 365(10), 348 (27), 347 (100), 220 (32).
  • 11 trans-2-Methyl-6-phenyl-3,4,6,7,12,12a-hexahydro-2H-pyrazino[1′,2′:1,6]pyrido[3,4-b]indol-1-one (13a): A mixture of 12 (100 mg, 0.25 mmol) and the appropriate amine (1.25 mmol) in anhyd EtOH (10 mL) was stirred for 24 h at r.t. Then, the solvent was evaporated and the residue was extracted with EtOAc. The combined organic phases were washed with sat. NaHCO3, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (hexane–EtOAc) gave pure 13a. Yield: 94%; white powder; mp 253.4–255.8 °C. 1H NMR (300 MHz, CDCl3): δ = 2.48 (ddd, J = 4.0, 9.2, 12.1 Hz, 1 H, H-3a), 2.93 (s, 3 H, Me), 2.95 (dd, J = 11.0, 15.9 Hz, 1 H, H-12a), 3.05 (dt, J = 12.1, 4.0 Hz, 1 H, H-3b), 3.20 (dt, J = 11.6, 4.0 Hz, 1 H, H-4a), 3.48 (dd, J = 15.9, 4.7 Hz, 1 H, H-12b), 3.58 (ddd, J = 4.0, 9.2, 11.6 Hz, 1 H, H-4b), 3.70 (dd, J = 11.0, 4.7 Hz, 1 H, H-13), 5.11 (s, 1 H, H-6), 7.08–7.20 (m, 4 H, 4 × =CH), 7.22–7.33 (m, 4 H, 4 × =CH), 7.58 (br d, J = 8.8 Hz, 1 H, H-11), 7.78 (br s, 1 H, H-7). 13C NMR (68 MHz, CDCl3): δ = 24.87 (C-12), 34.39 (Me), 46.70 (C-3), 48.41 (C-4), 54.66 (C-13), 63.13 (C-6), 109.21 (Cquat), 110.84 (C-8), 118.59 (C-11), 119.58 (C-10), 122.04 (C-9), 126.89 (Cquat), 128.37 (3 × =CH), 129.52 (2 × =CH), 131.93 (Cquat), 136.39 (Cquat), 137.21 (Cquat), 169.93 (C=O). IR (KBr): 3219 (NH), 2924, 2853, 1632 (C=O), 1493, 1454, 1333, 1164, 1074 cm–1. MS: m/z (%) = 332 (80) [M + H+], 328 (10), 221 (10), 220 (100).
  • 12 Wang H, Ganesan A. J. Org. Chem. 2000; 65: 4685
  • 13 Ethyl-3-[2-(4-methoxybenzoyl)-1H-indol-3-yl]-2-(2-chloroacetylamino)propionate (18b): Compound 9b (500 mg, 0.226 mmol) and NBS (65 mg, 1.13 mmol) in a mixture of THF (10 mL), AcOH (10 mL) and H2O (10 mL) were stirred at 0 °C for 15 min and subsequently at r.t. for 3 h. Then, the mixture was poured in H2O and extracted with EtOAc (3 ×). The combined organic phases were washed with aq Na2CO3, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (hexane–EtOAc, 4:6) gave pure 18b (460 mg, 88%) as a white powder; mp 175.5 °C. 1H NMR (300 MHz, CDCl3): δ = 1.25 (td, J = 7.4, 1.7 Hz, 3 H, Et), 3.51–3.60 (m, 2 H, CH-3), 3.84 (d, J AB = 14.8 Hz, 1 H, CHAHBCl), 3.92 (s, 3 H, OMe), 3.97 (d, J AB = 14.8 Hz, 1 H, CHAHBCl), 4.04–4.21 (m, 2 H, Et), 4.73 (q, J = 6.6 Hz, 1 H, CH-2), 7.01–7.04 (m, 2 H, 2 × CHAr), 7.19–7.25 (m, 1 H, CHAr), 7.38–7.40 (m, 2 H, 2 × CHAr), 7.76–7.86 (m, 3 H, 3 × CHAr), 8.38 (br d, J = 5.5 Hz, 1 H, NH), 8.49 (br s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 14.07 (Et), 26.50 (CH2-3), 42.26 (CH2Cl), 54.91 (CH-2), 55.66 (OMe), 61.74 (Et), 112.60 (CHAr), 114.14 (2 × CHAr), 119.01 (Cquat), 120.46 (CHAr), 121.07 (CHAr), 126.38 (CHAr), 127.59 (Cquat), 130.67 (Cquat), 132.05 (2 × CHAr), 132.40 (Cquat), 136.41 (CHAr), 163.58 (CquatOMe), 166.86 (HNC=O), 171.39 (EtOC=O), 187.36 (PhC=O). IR (ATR): 3253 (NH), 2982, 1732 (C=O), 1650 (C=O), 1626, 1597, 1531, 1509, 1252, 1170, 1024 cm–1. MS: m/z (%) = 443 (100) [M + H+], 445 (40).
    • 14a De Kimpe N, Schamp N. Org. Prep. Proced. Int. 1979; 11: 115
    • 14b De Kimpe N, Verhé R, De Buyck L, Schamp N. Org. Prep. Proced. Int. 1980; 12: 149
  • 15 3-[2-(4-Methoxybenzoyl)-1H-indol-3-ylmethyl]-1-propylpiperazine-2,5-dione (19b): A mixture of 18b (100 mg, 0.226 mmol) and propylamine (65 mg, 1.25 mmol) in anhyd EtOH (10 mL) was stirred for 24 h at r.t. Then, the mixture was poured in H2O and extracted with EtOAc (3 ×). The combined organic phases were washed, dried (MgSO4) and evaporated in vacuo. Purification by means of column chromatography on silica gel (EtOAc–MeOH, 9:1) gave pure 19b (76 mg, 80%) as a pale white powder; mp 210.5 °C. 1H NMR (300 MHz, CDCl3): δ = 0.82–0.89 (m, 3 H, Et), 1.38–1.48 (m, 2 H, Et), 3.03–3.64 (m, 6 H, NCH2, CH2-1′, CH2-6), 3.80 (s, 3 H, OMe), 4.06–4.18 (br s, 1 H, CH-3), 6.76 (d, J = 8.3 Hz, 2 H, 2 × CHAr), 6.95 (br s, 1 H, NH), 7.18–7.48 (m, 2 H, 2 × CHAr), 7.41 (d, J = 8.3 Hz, 2 H, 2 × CHAr), 7.58 (d, J = 8.0 Hz, 1 H, CHAr), 7.75 (d, J = 8.0 Hz, 1 H, CHAr), 10.23 (br s, 1 H, NH). 13C NMR (75 MHz, CDCl3): δ = 11.05 (Et), 19.77 (Et), 28.82 (CH-1′), 47.68 (NCH2), 49.16 (CH2-6), 55.59 (OMe), 56.29 (CH-3), 112.90 (CHAr), 113.73 (2 × CHAr), 117.65 (Cquat), 120.91 (CHAr), 121.13 (CHAr), 126.28 (CHAr), 127.36 (Cquat), 130.90 (Cquat), 131.90 (2 × CHAr), 133.06 (Cquat), 136.99 (Cquat), 163.12 (CquatOMe), 166.02 (HNC=O), 166.29 (HNC=O), 187.53 (PhC=O). IR (ATR): 3396 (NH), 3257 (NH), 1683 (C=O), 1651 (C=O), 1627 (C=O), 1606, 1463, 1423, 1316, 1253, 1031 cm–1. MS: m/z (%) = 420 (100) [M + H+].