Synthesis of (±)-Centrolobine Using a Gold-Catalyzed Cycloetherification

Abstract

A total synthesis of the diarylheptanoid (±)-centrolobine is described. The 2,6-cis-tetrahydropyran core of the natural product was constructed using a gold-catalyzed intramolecular cyclization of a secondary alcohol onto an allyl aryl ether. A B-alkyl Suzuki cross-coupling of the vinyl tetrahydropyran fragment with an aryl iodide completed the assembly of the centrolobine skeleton.

Key words

catalysis - cyclization - Mitsunobu reaction - stereoselectivity - total synthesis

• References and Notes

• 1a Obradors C, Echavarren AM. Acc. Chem. Res. 2014; 47: 902
• 1b Modern Gold Catalyzed Synthesis . Hashmi AS. K, Toste FD. Wiley-VCH; Weinheim: 2012
• 1c Shapiro ND, Toste FD. Synlett 2010; 675
• 1d Li Z, Brouwer C, He C. Chem. Rev. 2008; 108: 3239
• 1e Hashmi AS. K. Chem. Rev. 2007; 107: 3180
• 1f Hashmi AS. K, Hutchings GJ. Angew. Chem. Int. Ed. 2006; 45: 7896
• 2a Yang W, Hashmi AS. K. Chem. Soc. Rev. 2014; 43: 2941
• 2b Winter C, Krause N In Modern Gold Catalyzed Synthesis . Hashmi AS. K, Toste FD. Wiley-VCH; Weinheim: 2012: 363-389
• 2c Zhang Z, Widenhoefer RA. Angew. Chem. Int. Ed. 2007; 46: 283
• 3a Li A, Capretto DA, He C In Modern Gold Catalyzed Synthesis . Hashmi AS. K, Toste FD. Wiley-VCH; Weinheim: 2012: 297-302
• 3b Li A, Capretto DA, He C In Modern Gold Catalyzed Synthesis . Hashmi AS. K, Toste FD. Wiley-VCH; Weinheim: 2012: 303-308
• 4a Shen HC. Tetrahedron 2008; 64: 3885
• 4b Dorel R, Echavarren AM. Chem. Rev. 2015; 115: 9028
• 5a Muzart J. Tetrahedron 2008; 64: 5815
• 5b Corma A, Leyva-Perez A, Sabater MJ. Chem. Rev. 2011; 111: 1657
• 5c Debrouwer W, Heugebaert TS. A, Roman BI, Stevens CV. Adv. Synth. Catal. 2015; 357: 2975
• 6a Mukherjee P, Widenhoefer RA. Chem. Eur. J. 2013; 19: 3437
• 6b Cera G, Chiarucci M, Bandini M. Pure Appl. Chem. 2012; 84: 1673
• 7a Aponick A, Li C.-Y, Biannic B. Org. Lett. 2008; 10: 669
• 7b Aponick A, Biannic B. Synthesis 2008; 3356
• 7c Aponick A, Biannic B. Org Lett. 2011; 13: 1330
• 7d Biannic B, Ghebreghiorgis T, Aponick A. Beilstein J. Org. Chem. 2011; 7: 802
• 7e Ghebreghiorgis T, Biannic B, Kirk BH, Ess DH, Aponick A. J. Am. Chem. Soc. 2012; 134: 16307
• 7f Ketcham JM, Cardoso FS. P, Biannic B, Piras H, Aponick A. Isr. J. Chem. 2013; 53: 923
• 8 Vyvyan JR, Dimmitt HE, Griffith JK, Steffens LD, Swanson RA. Tetrahedron Lett. 2010; 51: 6666
• 9a Hanzawa Y, Hiromichi K, Takeo T. Heterocycles 2004; 62: 297
• 9b Trost BM, Alphonse T. Tetrahedron Lett. 1998; 29: 2927
• 10 Characterization Data for 2 FTIR (ATR): 3420, 3081, 3016, 2934, 2860, 1648, 1456, 1440, 1427, 1374, 1200, 1095, 1077, 1046, 993, 924 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 5.87 (ddd, J =17.1, 10.3, 5.4 Hz, 1 H), 5.24 (dt, J =17.1, 1.5 Hz, 1 H), 5.10 (dt, J =10.3, 1.5 Hz, 1 H), 3.88 (ddddd, J = 9.3, 5.4, 2.5, 1.5, 1.5 Hz, 1 H), 3.61 (m, 1 H), 3.54 (m, 2 H), 2.19 (s, 1 H), 1.90 (m, 1 H), 1.67 (m, 1 H), 1.58 (qt, J =13.2, 3.9 Hz, 1 H), 1.50 (m, 1 H), 1.29 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 139.2, 114.7, 78.1, 78.0, 66.3, 31.4, 26.8, 22.9. ESI-HRMS: m/z calcd for [C₈H₁₄O₂ + Na]⁺: 165.0892; found: 165.0891.
• 11a Clarke PA, Santos S. Eur. J. Org. Chem. 2006; 2045
• 11b Larrosa I, Romea P, Urpí F. Tetrahedron 2008; 64: 2683
• 11c Fuwa H. Heterocycles 2012; 85: 1255
• 11d Nasir NM, Ermanis K, Clarke PA. Org. Biomol. Chem. 2014; 12: 3323
• 12a Lv H, She G. Nat. Prod. Commun. 2010; 5: 1687
• 12b Dong S.-H, Nikolic D, Simmler C, Qiu F, van Breemen RB, Soejarto DD, Pauli GF, Chen S.-N. J. Nat. Prod. 2012; 75: 2168
• 12c Dong S.-H, Nikolic D, Simmler C, Qiu F, van Breemen RB, Soejarto DD, Pauli GF, Chen S.-N. J. Nat. Prod. 2013; 76: 2005
• 13a De Albuquerque IL, Galeffi C, Casinovi CG, Marini-Bettolo GB. Gazz. Chim. Ital. 1964; 94: 287
• 13b Craveiro AA, Prado AC, Gottlieb OR, Welerson de Albuquerque PC. Phytochemistry 1970; 9: 1869
• 13c Jurd L, Wong RY. Aust. J. Chem. 1984; 37: 1127
• 13d Alcântara AF. de C, Souza MR, Piló-Veloso D. Fitoterapia 2000; 71: 613
• 14a Marumoto S, Jaber J, Vitale JP, Rychnovsky SD. Org. Lett. 2002; 4: 3919
• 14b Chan K.-P, Loh T.-K. Org. Lett. 2005; 7: 4491
• 14c Sabitha G, Reddy KB, Reddy GS. K. K, Fatima N, Yadav JS. Synlett 2005; 2347
• 14d Lee C.-HA, Loh T.-P. Tetrahedron Lett. 2006; 47: 1641
• 14e Dziedzic M, Furman B. Tetrahedron Lett. 2008; 49: 678
• 14f Zhou H, Loh T.-P. Tetrahedron Lett. 2009; 50: 4368
• 14g Yadav VK, Verma AK, Kumar P, Hulikal V. Chem. Commun. 2014; 50: 15457
• 14h Nagarjuna B, Thirupathi B, Rao CV, Mohapatra DK. Tetrahedron Lett. 2015; 56: 4916
• 15 Clarke PA, Martin WH. C. Tetrahedron Lett. 2004; 45: 9061
• 16a Colobert F, Des Mazery R, Solladié G, Carreño MC. Org. Lett. 2002; 4: 1723
• 16b Evans PA, Cui J, Gharpure SJ. Org. Lett. 2003; 5: 3883
• 16c Reddy CR, Madhavi PP, Chandrasekhar S. Synthesis 2011; 123
• 17a Boulard L, BouzBouz S, Cossy J, Franck X, Figadére B. Tetrahedron Lett. 2004; 45: 6603
• 17b Jennings MP, Clemens RT. Tetrahedron Lett. 2005; 46: 2021
• 17c Böhrsch V, Blechert S. Chem. Commun. 2006; 1968
• 17d Schmidt B, Hölter F. Chem. Eur. J. 2009; 15: 11948
• 17e Mohapatra DK, Pal R, Rahaman H, Gurjur MK. Heterocycles 2010; 80: 219
• 17f Schmidt B, Hölter F, Kelling A, Schilde U. J. Org. Chem. 2011; 76: 3357
• 17g Yang Z, Kim H.-D. Tetrahedron: Asymmetry 2014; 25: 305
• 17h Kim H, Lee D. Synlett 2015; 26: 2583
• 18 Latif M, Yun JI, Seshadri K, Kim HR, Park CH, Park H, Kim H, Lee J. J. Org. Chem. 2015; 80: 3315
• 19a Rogano F, Rüedl P. Helv. Chim. Acta 2010; 93: 1281
• 19b Sudarshan K, Aidhen IS. Eur. J. Org. Chem. 2013; 2298
• 20a Chandrasekhar S, Prakash SJ, Shyamsunder T. Tetrahedron Lett. 2005; 46: 6651
• 20b Fuwa H, Noto K, Sasaki M. Heterocycles 2010; 82: 641
• 20c Xie J.-H, Guo L.-C, Yang X.-H, Wang L.-X, Zhou Q.-L. Org. Lett. 2012; 14: 4758
• 21 Chaladaj W, Kowalczyk R, Jurczak J. J. Org. Chem. 2010; 75: 1740
• 22 Takeuchi T, Matsuhashi M, Nakata T. Tetrahedron Lett. 2008; 49: 6462
• 23 Preparation of Diol 6 A 50 mL two-necked flask with stir bar was charged with Grubbs II catalyst (0.0410 g, 0.0483 mmol) and put under argon. CH₂Cl₂ (15 mL) was added via syringe followed by (Z)-but-2-en-1,4-diol (0.80 mL, 0.85 g, 9.7 mmol) and 1-(4-methoxyphenyl)hex-5-en-1-ol (0.503 g, 2.44 mmol), and the mixture was stirred at r.t. for 3 d, at which time additional (Z)-but-2-en-1,4-diol (0.40 mL, 0.43 g, 4.8 mmol) and Grubbs II catalyst (0.0412 g, 0.0485 mmol) were added. After stirring 3 more days, the reaction mixture was heated to reflux for 18 h. The reaction mixture was then concentrated and purified via flash chromatography (hexanes–EtOAc, 1:2) followed by radial chromatography (2 mm rotor; hexanes–EtOAc, 1:1) to give 6 (0.391 g, 1.65 mmol, 68%) as a pale yellow oil. FTIR (ATR): 3331, 3000, 2933, 2859, 1685, 1611, 1586, 1512, 1458, 1441, 1243, 1175, 1088, 969, 831 cm^–1. ¹H NMR (CDCl₃, 300 MHz): δ = 7.24 (m, 2 H), 6.87 (m, 2 H), 5.62 (m, 2 H), 4.59 (t, J = 6.6 Hz, 1 H), 4.04 (d, J = 4.9 Hz, 2 H), 3.79 (s, 3 H), 2.05 (dt, J = 6.8, 6.8 Hz, 2 H), 1.79 (dddd, J = 12.7, 10.7, 7.3, 5.4 Hz, 1 H), 1.67 (dddd, J = 13.7, 11.2, 5.9, 5.9 Hz, 1 H), 1.47 (dddd, J = 12.7, 12.7, 7.3, 5.4 Hz, 1 H), 1.33 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 158.9, 136.8, 132.6, 129.2, 127.1, 113.7, 73.9, 63.5, 55.2, 38.2, 31.9, 25.2. ESI-HRMS: m/z calcd for [C₁₄H₂₀O₃ + Na]⁺: 259.1310; found: 259.1302.
• 24 Mitsunobu O. Synthesis 1981; 1
• 25 Preparation of Ether 7 A THF solution of diol 6 (0.331 g, 1.40 mmol), Ph₃P (0.386 g, 1.47 mmol), 2,4,6-trimethylphenol (0.208 g, 1.52 mmol), and DIAD (0.290 mL, 0.300 g, 1.47 mmol) was stirred at r.t. for 66 h. The reaction mixture was diluted with Et₂O, washed with 10% NaOH solution (3 × 10 mL) and dried over anhydrous Na₂SO₄. The solvent was removed by rotary evaporation, and the crude product was purified via radial chromatography using a gradient elution of hexanes–EtOAc, 19:1 → 3:1) to give 7 (0.197 g, 0.557 mmol, 40%) as a yellow oil. FTIR (ATR): 3415, 2999, 2919, 2858, 2836, 1670, 1611, 1586, 1511, 1482, 1462, 1441, 1373, 1304, 1244, 1209, 1174, 1146, 969, 1034, 853, 830 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.26 (d, J = 8.2 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.81 (s, 2 H), 5.76 (m, 2 H), 4.62 (ddd, J = 6.5, 6.5, 2.3 Hz, 1 H), 4.20 (d, J = 4.1 Hz, 2 H), 3.81 (s, 3 H), 2.22 (m, 9 H), 2.11 (m, 2 H), 1.90–1.62 (m, 3 H), 1.60–1.30 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 159.1, 153.7, 136.9, 134.6, 132.9, 130.6, 129.3, 127.1, 126.2, 113.8, 74.1, 73.1, 55.3, 38.4, 32.1, 25.2, 20.6, 16.3. ESI-HRMS: m/z calcd for [C₂₃H₃₀O₃ + Na]⁺: 377.2093; found: 377.2093.
• 26 Preparation of 8 A culture tube with a stir bar was charged with Ph₃PAuCl (0.0215 g, 0.0435) and AgOTf (0.0113 g, 0.0440 mmol) and put under argon. Dry DCE (5 mL) was added via syringe, and this was stirred for 90 min. A solution of 7 (0.151 g, 0.424 mmol in 1 mL DCE) was added to the catalyst mixture via syringe. The reaction was stirred for 22 h, filtered through a plug of silica gel with hexanes–EtOAc (3:1) and concentrated. The crude product was purified by flash chromatography (hexanes–EtOAc, 12:1) to give 8 (0.0520 g, 0.238 mmol, 56%) as an oil. FTIR (ATR): 3075, 2998, 2934, 2835, 1645, 1612, 1585, 1513, 1244, 1174, 1077, 1034, 914, 827, 812 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.31 (m, 2 H), 6.87 (m, 2 H), 5.95 (ddd, J = 17.6, 10.6, 5.8 Hz, 1 H), 5.30 (ddd, J = 17.6, 1.5, 1.5 Hz, 1 H), 5.11 (ddd, J = 10.6, 1.5, 1.5 Hz, 1 H), 4.39 (dd, J = 11.2, 1.8 Hz, 1 H), 4.03 (m, 1 H), 3.80 (s, 3 H), 1.98 (m, 1 H), 1.85–1.34 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 158.8, 139.5, 135.6, 127.2, 114.4, 113.6, 79.4, 78.7, 55.3, 33.5, 31.3, 23.9. ESI-HRMS: m/z calcd for [C₁₄H₁₈O₂ + Na]⁺: 241.1205; found: 241.1210.
• 27 Chemler SR, Trauner D, Danishefsky SJ. Angew. Chem. Int. Ed. 2001; 40: 4544
• 28 Godt A. J. Org. Chem. 1997; 62: 7471
• 29 Preparation of 9 A 25 mL two-necked flask with a stir bar was put under argon, and 9-BBN in hexanes (0.5 M, 0.53 mL, 0.26 mmol) was added via syringe. A solution of 8 (0.0446 g, 0.204 mmol) in dry, degassed THF (2 mL) was added to the 9-BBN solution via syringe, and the mixture was stirred for 4.25 h. A degassed NaOH solution (1 M, 0.675 mL, 0.675 mmol) was added via syringe, and the solution was stirred for 10 min. A separate 25 mL two-necked flask with a stir bar was charged with 2-(4-iodophenoxy)tetrahydro-2H-pyran (0.0681 g, 0.225 mmol), Pd(dppf)Cl₂ (0.0333 g, 0.0408 mmol), and AsPh₃ (0.0133 g, 0.0434 mmol) and put under argon. Degassed THF (1.5 mL) was added followed by the borane reaction solution from the first reaction flask. The reaction mixture turned from bright orange to brown and this mixture was stirred at r.t. for 17 h and then refluxed for 3 h. The reaction was quenched with sat. NH₄Cl (25 mL), diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (20 mL), and the organic layers were combined, dried over anhydrous Na₂SO₄, filtered, and concentrated. Purification of the crude product by flash chromatography (hexanes–EtOAc, 12:1) to give 9 of sufficient purity to carry forward in the reaction sequence (0.0262 g 0.0661 mmol, 32.3%). ¹H NMR (500 MHz, CDCl₃): δ = 7.31 (m, 2 H), 7.10 (m, 2 H), 6.96 (m, 2 H), 6.88 (m, 2 H), 5.37 (m, 1 H), 4.30 (dt, J = 11.2, 2.0 Hz, 1 H), 3.94 (ddd, J = 12.2 ,9.8, 4.0 Hz, 1 H), 3.80 (s, 3 H), 3.60 (m, 1 H), 3.44 (m, 1 H), 2.70 (m, 2 H), 2.05–1.25 (series of overlapping m, 14 H). ¹³C NMR (125 MHz, CDCl₃): δ = 158.8, 155.0, 135.9, 135.6, 129.3, 127.1, 116.3, 113.6, 96.5, 79.0, 77.1, 62.1, 55.3, 38.2, 33.3, 31.3, 30.8, 30.5, 25.3, 24.0, 18.9. ESI-HRMS: m/z calcd for [C₂₅H₃₂O₄ + Na]⁺: 419.2198; found: 419.2201.
• 30 Preparation of (±)-Centrolobine (5) A flask containing 9 (0.0200 g, 0.0504 mmol) was charged with PTSA (0.0005 g, 0.003 mmol) and anhydrous MeOH (1.0 mL) was added. The reaction was stirred for 1 h and then concentrated, diluted with CH₂Cl₂ (2 mL), and washed with water (5 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 3 mL). The organic layers were combined, dried with anhydrous MgSO₄, filtered, and concentrated. The crude product purified via flash chromatography (hexanes–EtOAc, 6:1) to give centrolobine (5) (0.0116 g, 0.0371 mmol, 74%). FTIR (ATR): 2972, 2943, 2921, 2871, 2850, 1585, 1572, 1483, 1233, 1000, 1174, 1113, 1036, 1010, 872, 820 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.31 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.3 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.72 (d, J = 8.8 Hz, 2 H), 4.71 (s, 1 H), 4.29 (dd, J = 11.2, 2.0 Hz, 1 H), 3.81 (s, 3 H), 3.43 (m, 1 H), 2.76–2.61 (m, 2 H), 1.96–1.26 (m, 8 H). ¹³C NMR (125 MHz, CDCl₃): δ = 158.7, 153.4, 135.8, 134.7, 129.5, 127.1, 115.1, 113.6, 79.1, 77.1, 55.3, 38.3, 33.3, 31.2, 30.7, 24.0. ESI-HRMS: m/z calcd for [C₂₀H₂₄O₃ + Na]⁺: 335.1623; found: 335.1627.