Synlett 2015; 26(04): 552-556
DOI: 10.1055/s-0034-1379948
letter
© Georg Thieme Verlag Stuttgart · New York

Preliminary Studies on the Synthesis of (–)-Shikimic Acid Based 1,2,3,4-Tetrahydrobenzo[b]phenanthridine-7,12-diones

Mauricio A. Cuellar*
a   Facultad de Farmacia, Universidad de Valparaíso, 2360102, Valparaíso, Chile   eMail: mauricio.cuellar@uv.cl
,
Natalia Quiñones
a   Facultad de Farmacia, Universidad de Valparaíso, 2360102, Valparaíso, Chile   eMail: mauricio.cuellar@uv.cl
,
Viviana Vera
a   Facultad de Farmacia, Universidad de Valparaíso, 2360102, Valparaíso, Chile   eMail: mauricio.cuellar@uv.cl
,
Cristian O. Salas
b   Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile, 702843 Santiago, Chile
,
Juan C. Estévez
c   Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain   eMail: ramon.estevez@usc.es
,
Ramón J. Estévez*
c   Departamento de Química Orgánica and Centro Singular de Investigación en Química Biológica y Materiales Moleculares, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain   eMail: ramon.estevez@usc.es
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 20. November 2014

Accepted: 28. November 2014

Publikationsdatum:
13. Januar 2015 (online)


Abstract

Six new angucyclinone aza-analogues containing an embedded shikimic acid moiety have been prepared by a synthetic sequence involving the construction of their tetracyclic framework by a regiocontrolled hetero-Diels–Alder reaction of shikimic acid derived 1-azadiene 7- and 2-haloquinones.

 
  • References and Notes

  • 1 Eijman JA. Recl. Trav. Chim. Pays-Bas 1885; 4: 32
  • 2 Gurib-Fakim A. Mol. Aspects Med. 2006; 27: 1
  • 4 Zhang Y, Liu A, Ye ZG, Lin J, Xu LZ, Yang SL. Chem. Pharm. Bull. (Tokyo) 2006; 54: 1459
  • 5 Sanchez-Abella L, Fernandez S, Verstuyf A, Verlinden L, Gotor V, Ferrero M. Bioorg. Med. Chem. 2008; 16: 10244
    • 6a Sanchez-Abella L, Fernandez S, Verstuyf A, Verlinden L, Gotor V, Ferrero M. J. Med. Chem. 2009; 52: 6158
    • 6b Sanchez-Abella L, Fernandez S, Verstuyf A, Verlinden L, Ferrero M, Gotor V. Bioorg. Med. Chem. 2007; 15: 4193
    • 7a Sieveking I, Thomas P, Estevez JC, Quinones N, Cuellar MA, Villena J, Espinosa-Bustos C, Fierro A, Tapia RA, Maya JD, Lopez-Munoz R, Cassels BK, Estevez RJ, Salas CO. Bioorg. Med. Chem. 2014; 22: 4609
    • 7b Tapia RA, Salas CO, Vazquez K, Espinosa-Bustos C, Soto-Delgado J, Varela J, Birriel E, Cerecetto H, Gonzalez M, Paulino M. Bioorg. Med. Chem. Lett. 2014; 24: 3919
    • 7c Cuellar MA, Salas C, Cortes MJ, Morello A, Diego Maya J, Preite MD. Bioorg. Med. Chem. 2003; 11: 2489
  • 8 Cuellar MA, Alegria LK, Prieto YA, Cortes MJ, Tapia RA, Preite MD. Tetrahedron Lett. 2002; 43: 2127
  • 9 Kharel MK, Pahari P, Shepherd MD, Tibrewal N, Nybo SE, Shaaban KA, Rohr J. Nat. Prod. Rep. 2012; 29: 264
  • 10 Carreño MC, Urbano A. Synlett 2005; 1
  • 11 Guo ZK, Liu SB, Jiao RH, Wang T, Tan RX, Ge HM. Bioorg. Med. Chem. Lett. 2012; 22: 7490
  • 12 Manzanaro S, Vicent MJ, Martin MJ, Salvador-Tormo N, Perez JM, del Mar Blanco M, Avendano C, Menendez JC, de la Fuente JA. Bioorg. Med. Chem. 2004; 12: 6505
  • 13 Nebois P, do Nascimento SC, Boitard M, Bartoli MH, Fillion H. Pharmazie 1994; 49: 819
  • 14 Tapia RA, Alegria L, Pessoa CD, Salas C, Cortes MJ, Valderrama JA, Sarciron ME, Pautet F, Walchshofer N, Fillion H. Bioorg. Med. Chem. 2003; 11: 2175
  • 15 Methyl shikimate (1a) was synthesized as described previously: Tavassoli A, Duffy JE. S, Douglas W, Young DW. Org. Biomol. Chem. 2006; 4: 569
  • 16 All new compounds gave satisfactory analytical and spectroscopic data. Selected Physical and Spectroscopic Data Compound 1b: yellow oil (1.51 g, 95%); [α]D 20 +9.0 (c 4.45). 1H NMR (400 MHz, CDCl3): δ = 6.83 (1 H, br s, H-6), 4.69 (1 H, br s, H-1), 4.06–4.05 (2 H, m, H-2 + H-3), 3.75 (3 H, s, CO2CH3), 2.55 (1 H, br d, J = 16.4 Hz, H-4), 2.30 (1 H, br d, J = 16.8 Hz, H-4), 1.37 [6 H, s, C(CH3)2], 0.85 [9 H, s, SiC(CH3)3], 0.08 (3 H, s, SiCH3), 0.06 (3 H, s, SiCH3). 13C NMR (100 MHz, CDCl3): δ = 166.8 (CO2CH3), 134.4 (C-6), 129.0 (C-5), 109.2 [C(CH3)2], 76.7 (C-2), 72.2 (C-1), 68.5 (C-3), 51.7 (CO2 CH3), 29.3 (C-4), 27.8 [C(CH3)2], 25.9 [C(CH3)2], 25.6 [SiC(CH3)3], –4.9 (SiCH3), –5.0 (SiCH3). Compound 5: colorless oil (0.82 g, 95%); [α]D 20 +54.2 (c 5.17). 1H NMR (400 MHz, CDCl3): δ = 5.80 (1 H, br s, H-6), 4.65 (1 H, br s, H-1), 4.07–3.97 (3 H, m, CH 2OH + H-3), 3.92–3.87 (1 H, m, H-2), 2.24 (1 H, dd, J = 4.0, 16.0 Hz, H-4), 2.02 (1 H, dd, J = 8.0, 16.0 Hz, H-4), 1.45 [3 H, s, C(CH3)2], 1.38 [3 H, s, C(CH3)2], 0.88 [9 H, s, SiC(CH3)3], 0.10 (3 H, s, SiCH3), 0.10 (3 H, s, SiCH3). 13C NMR (100 MHz, CDCl3): δ = 140.1 (C-6), 118.7 (C-5), 108.9 [C(CH3)2], 78.7 (C-2), 72.9 (C-1), 69.9 (C-3), 66.2 (CH2OH), 30.3 (C-4), 28.3 [C(CH3)2], 26.2 [C(CH3)2], 25.9 [SiC(CH3)3], 18.2 [SiC(CH3)3], –4.3 (SiCH3), –4.6 (SiCH3). Compound 6: white solid (0.47 g, 77%); mp 70.5–71.0 °C; [α]D 20 +23.0 (c 3.92). 1H NMR (400 MHz, CDCl3): δ = 6.93 (1 H, s, CH=N), 5.75 (1 H, d, J = 2.6 Hz, H-6), 4.75 (1 H, t, J = 4.6 Hz, H-1), 4.04 (1 H, t, J = 6.6 Hz, H-2), 3.93–3.88 (1 H, m, H-3), 2.86 [6 H, s, N(CH3)2], 2.71 (1 H, dd, J = 4.4, 17.2 Hz, H-4), 2.21 (1 H, dd, J = 7.9, 17.2 Hz, H-4), 1.44 [3 H, s, C(CH3)2], 1.39 [3 H, s, C(CH3)2], 0.88 [9 H, s, SiC(CH3)3], 0.09 (3 H, s, SiCH3), 0.07 (3 H, s, SiCH3). 13C NMR (100 MHz, CDCl3): δ = 137.5 (C-5), 134.6 (CH=N), 122.6 (C-6), 108.8 [C(CH3)2], 78.8 (C-2), 73.3 (C-1), 69.8 (C-3), 42.7 [N(CH3)2], 29.8 (C-4), 28.2 [C(CH3)2], 26.1 [C(CH3)2], 25.8 [SiC(CH3)3], 18.4 [SiC(CH3)3], –4.6 (SiCH3), –4.7 (SiCH3). Compound 10: orange oil (30%). 1H NMR (400 MHz, CDCl3): δ = 8.76 (1 H, s, H-6), 7.07 (1 H, d, J = 10.4 Hz, H-9), 7.00 (1 H, d, J = 10.4 Hz, H-10), 6.32 (1 H, d, J = 5.8 Hz, H-13c), 4.36 (2 H, d, J = 4.6 Hz, H-3a + H-4), 3.18 (1 H, d, J = 15.0 Hz, H-5), 2.84 (1 H, d, J = 12.0 Hz, H-5), 1.51 [3 H, s, C(CH3)2], 1.26 [3 H, s, C(CH3)2], 0.70 [9 H, s, SiC(CH3)3], 0.07 (3 H, s, SiCH3), 0.02 (3 H, s, SiCH3). 13C NMR (100 MHz, CDCl3): δ = 186.5 (C-7), 183.2 (C-10), 154.9 (C-5), 147.4 (C-6a), 143.9 (C-12b), 139.9 (C-4a), 136.9 (C-8)*, 136.4 (C-9)*, 126.3 (C-10a), 109.2 (C-11), 76.4 (C-2), 70.0 (C-1), 67.9 (C-3), 31.3 (C-4), 27.1 [C(CH3)2], 25.5 [(CH3)3CSi], 24.9 [C(CH3)2], 17.8 [(CH3)3 C], –4.8 (CH3Si), –4.9 (CH3Si); (*) interchangeable signals. HRMS (ES+): m/z calcd for [C17H25N2O3]+: 305.1865; found: 305.1871. Compound 11a: purple oil (30%). 1H NMR (400 MHz, CDCl3): δ = 8.13 (1 H, d, J = 7.6 Hz, H-12), 7.98 (1 H, d, J = 7.6 Hz, H-9), 7.70 (1 H, dd, J = 7.1, 7.5 Hz, H-10), 7.60 (1 H, dd, J = 7.4, 7.5 Hz, H-11), 6.86 (1 H, br s, H-7), 6.02 (1 H, d, J = 3.8 Hz, H-6), 4.23 (2 H, m, H-13c + H-4), 4.00 (1 H, dd, J = 4.5, 4.7 Hz, H-3a), 3.96 (1 H, d, J = 8.7 Hz, H-13b), 2.56 (1 H, dd, J = 4.5, 14.1 Hz, H-5), 2.07 (1 H, dd, J = 4.0, 14.1 Hz, H-5), 1.79 [3 H, s, C(CH3)2], 1.33 [3 H, s, C(CH3)2], 0.88 [9 H, s, (CH3)3CSi], 0.08 [6 H, s, (CH3)2Si]. 13C NMR (100 MHz, CDCl3): δ = 182.7 (C-12), 180.6 (C-7), 139.7 (C-6a), 134.5 (C-8), 133.5 (C-7a), 131.9 (C-10), 130.1 (C-11a), 126.6 (C-11), 125.6 (C-9), 119.8 (C-5), 112.7 (C-4a), 110.0 (C-12a), 109.1 [C(CH3)2], 79.9 (C-2), 79.8 (C-1), 68.9 (C-3), 36.7 (C-12b), 36.0 (C-4), 28.0 [C(CH3)2], 26.2 [C(CH3)2], 25.8 [(CH3)3C], 18.1 [(CH3)3 CSi], –4.75 (CH3Si), –4.78 (CH3Si). HRMS m/z calcd for C26H33NO5Si [M + H]+: 467.2128; found: 466.2049. Compound 11b: purple oil (20%). 1H NMR (400 MHz, CDCl3): δ = 7.88 (1 H, d, J = 7.5 Hz, H-12), 7.60 (1 H, t, J = 7.8 Hz, H-11), 7.28 (1 H, d, J = 8.4 Hz, H-10), 6.04 (1 H, s, H-6), 4.27 (1 H, br s, H-7), 4.10 (1 H, d, J = 3.8 Hz, H-6), 4.00 (1 H, m, H-4 + H-13c), 3.86 (1 H, d, J = 8.8 Hz, H-13b), 2.68 [6 H, s, (CH3)2N], 2.51 (1 H, dd, J = 3.8, 14.0 Hz, H-4), 2.40 [3 H, s, (CO2CH3)], 2.11 (1 H, dd, J = 3.2, 14.0 Hz, H-4), 1.58 [3 H, s, C(CH3)2], 1.25 [3 H, s, C(CH3)2], 0.91 [9 H, s, (CH3)3CSi], 0.10 (3 H, s, CH3Si), –0.003 (3 H, s, CH3Si). 13C NMR (100 MHz, CDCl3): δ = 181.8 (C-12), 180.3 (C-7), 169.7 [CO2CH3], 148.4 (C-8), 144.2 (C-6a), 134.9 (C-11a), 133.0 (C-10), 128.8 (C-9), 124.6 (C-11), 123.5 (C-7a), 119.2 (C-12a), 119.1 (C-5), 115.9 (C-4a), 109.2 (C-13), 80.2 (C-2)*, 79.9 (C-1)*, 68.7 (C-3), 36.3 (C-12b), 36.2 (C-4), 27.7 [C(CH3)2], 26.3 [C(CH3)2], 25.8 [(CH3)3CSi], 21.2 (C-24), 18.0 [(CH3)3 CSi], –4.8 (CH3Si), –4.9 (CH3Si); (*) interchangeable signals. HRMS m/z calcd for C30H40N2O7Si [M + H]+: 568.2605; found: 524.2104 [M – NMe2]+. Compound 11c: purple oil (48%). 1H NMR (400 MHz, CDCl3): δ = 12.63 (1 H, s, 9-OH), 7.46–7.45 (2 H, m, H-11 + H-12), 7.16 (1 H, dd, J = 2.4, 8.0 Hz, H-10), 6.08 (1 H, s, H-6), 4.27 (1 H, d, J =3.9 Hz, H-4), 4.09 (1 H, dd, J = 8.6, 5.0 Hz, H-6), 4.00 (1 H, dd, J =3.9, 5.0 Hz, H-3a), 3.87 (1 H, d, J = 8.6 Hz, H-13b), 2.68 [6 H, s, (CH3)2N], 2.57 (1 H, dd, J = 3.9, 13.9 Hz, H-4), 2.13 (1 H, dd, J = 3.9, 13.9 Hz, H-4), 1.75 [3 H, s, C(CH3)2], 1.59 [3 H, s, C(CH3)2], 0.84 [9 H, s, (CH3)3CSi], 0.11 [6 H, s, (CH3)2Si]. 13C NMR (100 MHz, CDCl3): δ = 188.1 (C-12), 180.4 (C-7), 160.1 (C-8), 146.6 (C-6a), 134.3 (C-10), 133.1 (C-11a), 123.7 (C-9), 119.1 (C-5), 118.3 (C-11), 116.4 (C-12a), 115.5 (C-4a), 114.7 (C-7a), 109.3 (C-13), 80.2 (C-1), 79.8 (C-2), 68.8 (C-3), 36.3 (C-4), 35.8 (C-12b), 27.9 [C(CH3)2], 26.1 [C(CH3)2], 25.8 [(CH3)3CSi], 18.0 [(CH3)3 CSi], –4.8 [(CH3)2Si]. HRMS m/z calcd for C28H38N2O6Si [M + H]+: 526.2499; found: 482.2041 [M – NMe2]+. Compound 12a: red oil (25%). 1H NMR (400 MHz, CDCl3): δ = 12.90 (2 H, s, 9-OH + 11-OH), 8.85 (1 H, s, H-6), 7.36 (2 H, s, H-10 + H-11), 6.55 (1 H, d, J = 6.0 Hz, H-13c), 4.14-4.09 (2 H, m, H-3a + H-4), 3.24 (1 H, dd, J = 2.3, 16.0 Hz, H-5), 2.89 (1 H, dd, J = 3.0, 16.3 Hz, H-5), 1.39 [3 H, s, C(CH3)2], 1.23 [3 H, s, C(CH3)2], 0.8 [9 H, s, (CH3)3CSi], 0.11 [6 H, s, (CH3)2Si]. 13C NMR (100 MHz, CDCl3): δ = δ: 188.4 (C-12), 185.1 (C-7), 158.2 (C-8)*, 157.9 (C-11), 155.8 (C-5), 148.9 (12b), 145.0 (C-6a), 137.2 (C-4a), 130.3 (C-9)#, 129.4 (C-10)#, 128.0 (C-12a), 113.2 (C-7a)+, 112.4 (C-11a)+, 109.2 [C(CH3)2], 76.6 (C-2), 70.6 (C-3), 68.0 (C-1), 31.5 (C-4), 25.7 [(CH3)3C], 25.5 [C(CH3)2], 24.9 [C(CH3)2], 17.9 [(CH3)3 CSi], –4.9 [(CH3)2Si], –4.8 [(CH3)2Si]; (#)(+) interchangeable signals. HRMS m/z calcd for C26H31NO7Si [M + H]+: 497.1870; found: 498.1978. Compound 12b: orange oil (16%). 1H NMR (400 MHz, CDCl3): δ = 8.82 (1 H, s H-6), 8.36–8.34 (1 H, m, H-12), 8.32–8.31 (1 H, m, H-9), 7.84–7.80 (2 H, m, H-10 + H-11), 6.51 (1 H, d, J = 6.1 Hz, H-13c), 4.40–4.37 (2 H, m, H-3a + H-4), 3.23 (1 H, d, J = 16.0 Hz, H-5), 2.87 (1 H, dd, J = 3.0, 16.0 Hz, H-5), 1.55 [3 H, s, C(CH3)2], 1.27 [3 H, s, C(CH3)2], 0.71 [9 H, s, (CH3)3CSi], 0.03 (3 H, s, CH3Si), –0.02 (3 H, s, CH3Si). 13C NMR (100 MHz, CDCl3): δ = 184.5 (C-7), 181.7 (C-12), 155.3 (C-5), 149.0 (C-6a), 144.7 (C-12b), 136.6 (C-4a), 134.5 (C-9)*, 134.2 (C-10)*, 134.1 (C-11a), 132.4 (C-7a), 128.0 (C-12a), 127.6 (C-8), 127.3 (C-11), 109.1 [C(CH3)2], 76.6 (C-2), 70.6 (C-1), 68.1 (C-3), 31.4 (C-4), 27.1 [C(CH3)2], 25.5 [(CH3)3CSi], 25.0 [C(CH3)2],17.8 [(CH3)3 CSi), –4.8 (CH3Si), –4.9 (CH3Si); (*) interchangeable signals. HRMS m/z calcd for C26H31NO5Si [M + H]+): 465.1971; found: 466.2058.
  • 17 Synthesis of (3aR,4R,11cR)-4-[(tert-Butyldimethylsilyl)oxy]-2,2-dimethyl-3a,4,5,11c-tetrahydro-[1,3]dioxolo[4,5-k]-phenanthridine-8,11-dione (10) Azadiene 6 (100 mg, 0.50 mmol) was added to a solution of benzoquinone 7b (54 mg, 0.50 mmol) in anhydrous MeCN (10 mL) and NaHCO3 (42 mg, 0.50 mmol). The mixture was heated to reflux for 72 h. Removal of the solvent under reduced pressure resulted in a residue that was purified by column chromatography (eluent: CH2Cl2–EtOAc, polarity gradient, 0–100%) to give 35 mg (30% yield) of tetrahydrophenanthridine-8,1-dione 10, as an orange oil
  • 18 Kitani Y, Morita A, Kumamoto T, Ishikawa T. Helv. Chim. Acta 2002; 85: 1186