Total Synthesis and Stereochemical Assignment of (–)-Zenkequinone B

Abstract

The first enantioselective total synthesis and a concise racemic synthesis of zenkequinone B are reported here by utilizing a sequential enyne metathesis, Diels–Alder and aromatization reactions.

Key words

Sharpless epoxidation - enyne metathesis - Diels–Alder reaction - total synthesis

• References and Notes

• 1a Kharel MK, Pahari P, Shepherd MD, Tibrewal N, Nybo SE, Shaaban KA, Rohr J. Nat. Prod. Rep. 2012; 29: 264
• 1b Carreño MC, Urbano A. Synlett 2005; 1
• 1c Krohn K, Rohr J. Top. Curr. Chem. 1997; 188: 127
• 1d Rohr J, Thiericke R. Nat. Prod. Rep. 1992; 103

For selected recent reports, see:
• 2a Hsu D.-S, Huang J.-Y. J. Org. Chem. 2012; 77: 2659
• 2b Chen Q, Mulzer M, Shi P, Beuning PJ, Coates GW, O’Doherty GA. Org. Lett. 2011; 13: 6592
• 2c Yang X, Fu B, Yu B. J. Am. Chem. Soc. 2011; 133: 12433
• 2d Kesenheimer C, Kalogerakis A, Meißner A, Groth U. Chem.–Eur. J. 2010; 16: 8805
• 3 Schindler PW. Biotech. Forum 1989; 2: 142
• 4a Krohn K, Agocs A, Bäuerlein CJ. J. Carbohydr. Chem. 2003; 22: 579
• 4b Caygill GB, Larsen DS, Broker S. J. Org. Chem. 2001; 66: 7427
• 4c Rozek T, Bowie JH, Pyke SM, Skelton BW, White AJ. J. Chem. Soc., Perkin Trans. 1 2001; 1826
• 4d Kraus GA, Zhang N, Melekhov A, Jensen JH. Synlett 2001; 521
• 4e Krohn K, Michael J, Zukowski M. Tetrahedron 2000; 56: 4753
• 4f Matsuo G, Miki Y, Nakata M, Matsumura S, Toshima KJ. J. Org. Chem. 1999; 64: 7101
• 4g Krohn K, Micheel J. Tetrahedron 1998; 54: 4827
• 4h Larsen DS, O’Shea MD. J. Chem. Soc., Perkin Trans.1 1995; 1019
• 4i Matsumoto T, Sohma T, Yamaguchi H, Murata S, Suzuki K. Tetrahedron 1995; 51: 7347
• 4j Larsen DS, O’Shea MD. Tetrahedron Lett. 1993; 34: 1373
• 4k Krohn K, Ballwanz F, Baltus W. Liebigs Ann. Chem. 1993; 911
• 4l Guingant A, Barreto MM. Tetrahedron Lett. 1987; 28: 1307
• 5a Kim K, Boyd VA, Sobti A, Sulikowski GA. Isr. J. Chem. 1997; 37: 3
• 5b Boyd VA, Sulikowski GA. J. Am. Chem. Soc. 1995; 117: 8472
• 5c Kim K, Sulikowski GA. Angew. Chem., Int. Ed. Engl. 1995; 34: 2396
• 5d Boyd VA, Drake BE, Sulikowski GA. J. Org. Chem. 1993; 58: 3191
• 6 Krohn K, Sohrab MH, Flörke U. Tetrahedron: Asymmetry 2004; 15: 713
• 7 Motoyoshiya J, Masue Y, Iwayama G, Yoshioka S, Nishii Y, Aoyama H. Synthesis 2004; 2099
• 8a Carreño MC, Somoza A, Ribagorda M, Urbano A. Chem.–Eur. J. 2007; 23: 879
• 8b Carreño MC, Urbano A, Di Vitta C. Chem.–Eur. J. 2000; 6: 906
• 8c Carreño MC, Urbano A, Di Vitta C. Chem. Commun. 1999; 817
• 8d Carreño MC, Urbano A, Di Vitta C. J. Org. Chem. 1998; 63: 8320
• 8e Carreño MC, Urbano A, Fischer J. Angew. Chem., Int. Ed. Engl. 1997; 36: 1621
• 9a Landells JS, Larsen DS, Simpson J. Tetrahedron Lett. 2003; 44: 5193
• 9b Larsen DS, O’Shea MD, Broker S. Chem. Commun. 1996; 203
• 9c Larsen DS, O’Shea MD. J. Org. Chem. 1996; 61: 5681
• 10a Lenta BN, Vonthron-Senecheau C, Soh RF, Tantangmo F, Ngouela S, Kaiser M, Tsamo E, Anton R, Weniger B. J. Ethnopharmacol. 2007; 111: 8
• 10b Lenta BN, Weniger B, Antheaume C, Noungoue DT, Ngouela S, Assob JC. N, Vonthron-Senecheau C, Fokou PA, Devkota KP, Tsamo E, Sewald N. Phytochemistry 2007; 68: 1595
• 11 Rammohan D, Yung-Son H. Tetrahedron Lett. 2011; 52: 3183
• 12a Vanga DG, Kaliappan KP. Eur. J. Org. Chem. 2012; 2250
• 12b Kaliappan KP, Ravikumar V. J. Org. Chem. 2007; 72: 6116
• 12c Kaliappan KP, Ravikumar V. Synlett 2007; 977
• 13a Subrahmanyam AV, Palanichamy K, Kaliappan KP. Chem.–Eur. J. 2010; 16: 8545
• 13b Kaliappan KP, Subrahmanyam AV. Org. Lett. 2007; 9: 1121
• 13c Kaliappan KP, Ravikumar V. Org. Biomol. Chem. 2005; 3: 848
• 14 Callier-Dublemchet AC, Cassayre J, Gagosz F, Quiclet-Sire B, Sharp LA, Zard SZ. Tetrahedron 2008; 64: 4803
• 15 Rosillo M, Casarrubios L, Domínguez G, Pérez-Castells J. Tetrahedron Lett. 2001; 42: 7029
• 16 Wilson MS, Woo JC. S, Dake GR. J. Org. Chem. 2006; 71: 4237
• 17 Foote KM, Hayes CJ, John MP, Pattenden G. Org. Biomol. Chem. 2003; 1: 3917
• 18 HPLC separation conditions: The ee value was determined by CHIRALCEL OD-H, n-hexane–2-PrOH = 90:10, flow rate: 0.5 mL/min, λ = 256 nm.
• 19 (R)-[(1-Methyl-4-vinylcyclohex-3-enyloxy)methyl]benzene (20) A solution of enyne 21 (500 mg, 2.19 mmol) in CH₂Cl₂ (60 mL) was treated with Grubbs’ first-generation catalyst (17; 133 mg, 7 mol%) and then refluxed for 8 h. The reaction mixture was cooled to r.t. and stirred with DMSO (50 equiv with respect to the catalyst) for 6 h to remove the metal impurities. Evaporation of the solvent and purification by silica gel flash column chromatography (10% EtOAc in hexanes) provided 1,3-diene 20 (460 mg, 92%); R_f = 0.7 (EtOAc–hexanes, 1:9); [α]_D ²¹ +67.6 (c 3.6, CHCl₃). IR (neat): 2929, 2846, 1645, 1614, 1513, 1462, 1378, 1247, 1129, 1098, 1036, 821, 758 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.35–7.28 (m, 4 H), 7.26–7.20 (m, 1 H), 6.37 (dd, J = 17.5, 10.7, Hz, 1 H), 5.64 (s, 1 H), 5.08 (d, J = 17.5 Hz, 1 H), 4.93 (d, J = 10.7 Hz, 1 H), 4.51, 4.44 (ABq, J = 18.0 Hz, 2 H), 2.45 (d, J = 18.2 Hz, 1 H), 2.40–2.32 (m, 1 H), 2.20 (d, J = 18.2 Hz, 1 H), 2.17–2.12 (m, 1 H), 1.97–1.90 (m, 1 H), 1.78–1.71 (m, 1 H), 1.30 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 139.9, 139.5, 135.4, 128.4, 127.4, 127.2, 127.0, 110.6, 73.6, 63.6, 37.6, 32.6, 23.6, 22.1. ESI-HRMS: m/z calcd for C₁₆H₂₀O [M + Na]⁺: 251.1412; found: 251.1404.
• 20 (R)-2-(Benzyloxy)-2-methyl-1,2,3,4-tetrahydrotetraphene-7,12-dione (27) A solution of naphthoquinone 12 (228 mg, 1.44 mmol) and diene 20 (300 mg, 1.31 mmol) in toluene was heated at 80 °C for 12 h and then at 100 °C for 2 h. After the solvent was removed in vacuo, the crude Diels–Alder adduct was dissolved in CHCl₃ (2 mL), treated with Et₃N (1 mL) and silica gel (1 g) and stirred for 4 h. The solvent was removed in vacuo and purified by a silica gel flash column chromatography (20% EtOAc in hexanes) to afford the tetracycle 27 (460 mg, 91%) as a pale yellow solid; R_f = 0.6 (EtOAc–hexanes, 1:3); mp 163–165 °C; [α]_D ²¹ –233.55 (c 1.1, CHCl₃). IR (neat): 3021, 2961, 2926, 2857, 1663, 1581, 1566, 1454, 1326, 1299, 1270, 1099, 1045, 740 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.24–8.19 (m, 2 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.79–7.71 (m, 2 H), 7.52 (d, J = 8.0 Hz, 1 H), 7.15–7.05 (m, 5 H), 4.53, 4.43 (ABq, J = 11.7 Hz, 2 H), 3.85 (d, J = 19.0 Hz, 1 H), 3.26–3.20 (m, 1 H), 3.22 (d, J = 19.0 Hz, 1 H), 2.92–2.85 (m, 1 H), 2.22–2.17 (m, 1 H), 1.87–1.79 (m, 1 H), 1.56 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 185.9, 183.7, 145.0, 139.6, 138.7, 135.2, 134.3, 134.1, 133.4, 133.3, 132.7, 131.7, 128.2, 127.2, 127.1, 126.5, 125.2, 72.9, 63.8, 39.9, 32.1, 27.6, 25.4. ESI-HRMS: m/z calcd for C₂₆H₂₂O₃ [M + Na]⁺: 405.1467; found: 405.1475.
• 21 (–)-Zenkequinone B (19) A solution of benzyl ether 27 (50 mg, 0.13 mmol) in a mixture of CH₂Cl₂ (10 mL) and pH 7 buffer (0.5 mL) at 0 °C was treated with DDQ (59 mg, 0.26 mmol) portionwise and allowed to stir at r.t. for 12 h. The reaction mixture was treated with a sat. solution of NaHCO₃ and extracted with CH₂Cl₂. The organic layer was washed with brine, dried (Na₂SO₄), concentrated, and purified by silica gel column chromatography to afford target compound 19 (33 mg, 87%) as a pale yellow solid; R_f = 0.40 (EtOAc–hexanes, 1:2); mp 202–204 °C; [α]_D ²¹ –195.33 (c 0.06, acetone). IR (neat): 3463, 3082, 2961, 2927, 1663, 1579, 1561, 1368, 1329, 1303, 1275, 1092, 1045, 759 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.21–8.15 (m, 2 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.76–7.70 (m, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 3.57 (d, J = 18.8 Hz, 1 H), 3.35 (d, J = 18.8 Hz, 1 H), 3.27–3.18 (m, 1 H), 2.91 (dt, J = 16.4, 4.4 Hz, 1 H), 1.98–1.92 (m, 1 H), 1.85–1.77 (m, 1 H), 1.47 (s, 3 H). ESI-HRMS: m/z calcd for C₁₉H₁₆O₃ [M + Na]⁺ 315.0997; found: 315.0994.