Synthetic Studies of Daphniphyllum Alkaloids: A New Method for the Construction of [7-5-5] All-Carbon Tricyclic Skeleton

Abstract

Daphniphyllum alkaloids have complex molecular structures; consequently, their synthesis can be challenging. A new method for the construction of the [7-5-5] tricyclic core of Daphniphyllum alkaloids was developed. The bicyclo[5.3.0]decane skeleton was constructed through a divinylcyclopropane rearrangement of a cyclopentenone derivative with a vinylcyclopropyl group at the β-position. After introduction of a 2-iodoethyl group by a regioselective Michael addition with phenyl vinyl selenone, the [7-5-5] tricyclic system was formed by intramolecular alkylation of a cyclopentadienyl anion species.

Key words

alkaloids - divinylcyclopropane rearrangement - cyclopentadienes - Michael addition - cyclization

Publikationsverlauf

Eingereicht: 20. Oktober 2021

Angenommen nach Revision: 29. Oktober 2021

Accepted Manuscript online:
29. Oktober 2021

Artikel online veröffentlicht:
22. November 2021

• References and Notes


For reviews, see:
• 1a Kobayashi J.-i, Kubota T. Nat. Prod. Rep. 2009; 26: 936
• 1b Kang B, Jakubec P, Dixon DJ. Nat. Prod. Rep. 2014; 31: 550
• 1c Chattopadhyay AK, Hanessian S. Chem. Rev. 2017; 117: 4104
• 1d Guo L.-D, Chen Y, Xu J. Acc. Chem. Res. 2020; 53: 2726
• 2a Weiss ME, Carreira EM. Angew. Chem. Int. Ed. 2011; 50: 11501
• 2b Shvartsbart A, Smith AB. III. J. Am. Chem. Soc. 2014; 136: 870
• 2c Chen Y, Zhang W, Ren L, Li J, Li A. Angew. Chem. Int. Ed. 2018; 57: 952
• 2d Chen X, Zhang H.-J, Yang X, Lv H, Shao X, Tao C, Wang H, Cheng B, Li Y, Guo J, Zhang J, Zhai HD. Angew. Chem. Int. Ed. 2018; 57: 947
• 3a Li J, Zhang W, Zhang F, Chen Y, Li A. J. Am. Chem. Soc. 2017; 139: 14893
• 3b Zhang W, Ding M, Li J, Guo Z, Lu M, Chen Y, Liu L, Shen Y.-H, Li A. J. Am. Chem. Soc. 2018; 140: 4227
• 4 Guo L.-D, Zhang Y, Hu J, Ning C, Fu H, Chen Y, Xu J. Nat. Commun. 2020; 11: 3538

For selected synthetic approaches to [7-5-5] all-carbon tricyclic core, see:
• 5a Weyermann P, Keese R. Tetrahedron 2011; 67: 3874
• 5b Darses B, Michaelides IN, Sladojevich F, Ward JW, Rzepa PR, Dixon DJ. Org. Lett. 2012; 14: 1684
• 5c Hayakawa I, Niida K, Kigoshi H. Chem. Commun. 2015; 51: 11568
• 5d Kitabayashi Y, Fukuyama T, Yukoshima S. Org. Biomol. Chem. 2018; 16: 3556
• 6a Yamada T, Yoshimura F, Tanino K. Tetrahedron Lett. 2013; 54: 522
• 6b Tanino K, Yamada T, Yoshimura F, Suzuki T. Chem. Lett. 2014; 43: 607

For reviews of divinylcyclopropane rearrangement reactions, see:
• 6c Hudlicky T, Fan R, Reed JW, Gadamasetti KG. Org. React. 1992; 41: 1
• 6d Davies HM. L. Tetrahedron 1993; 49: 5203
• 6e Krüger S, Gaich T. Beilstein J. Org. Chem. 2014; 10: 163
• 7 Magnus P, Mugrage B. J. Am. Chem. Soc. 1990; 112: 462
• 8 Okugawa S, Masu H, Yamaguchi K, Takeda K. J. Org. Chem. 2005; 70: 10515
• 9 The stereochemistry of enone 12a was determined by a NOESY experiment (Figure 2).
• 10a Nicolaou KC, Montagnon T, Baran PS. Angew. Chem. Int. Ed. 2002; 41: 993
• 10b Nicolaou KC, Gray DL. F, Montagnon T, Harrison ST. Angew. Chem. Int. Ed. 2002; 41: 996
• 11 An attempted conjugate addition reaction of 14 with methyl acrylate, a less electrophilic Michael acceptor than methyl 2-chloroacrylate, did not proceed.

For selected examples on the application of phenyl vinyl selenone, see:
• 12a Marini F, Sternativo S, Del Verme F, Testaferri L, Tiecco M. Adv. Synth. Catal. 2009; 351: 103
• 12b Bagnoli L, Scarponi C, Rossi MG, Testaferri L, Tiecco M. Chem. Eur. J. 2011; 17: 993
• 12c Buyck T, Wang Q, Zhu J. Angew. Chem. Int. Ed. 2013; 52: 12714
• 12d Buyck T, Pasche D, Wang Q, Zhu J. Chem. Eur. J. 2016; 22: 2278
• 12e Palomba M, Scarcella E, Sancineto L, Bagnoli L, Santi C, Marini F. Eur. J. Org. Chem. 2019; 5396
• 13 CCDC 2122370 and 2122371 contain the supplementary crystallographic data for compounds 23 and 25, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 14 Synthesis of Hydroazulenone 14 from Ketone 9a DBU (155 μL, 1.04 mmol) and TMSCl (120 μL, 0.950 mmol) were added to a stirred solution of 9a (304 mg, 0.875 mmol) in anhyd CH₂Cl₂ (3.5 mL) at rt, and the mixture was stirred for 1 h at rt. Et₃N (700 μL) was added, and the mixture was diluted with sat. aq NaHCO₃ and hexane. The aqueous and organic layers were separated, and the aqueous layer was extracted with hexane. The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give crude 11a, which was used in the next step without further purification. To a stirred solution of the crude 11a in anhyd DMSO (1.9 mL) was added a 0.4 M solution of IBX in DMSO (2.3 mL, 0.92 mmol) at rt, and the mixture was stirred at 30 °C for 12 h. The reaction was then quenched with sat. aq NaHCO₃, and the mixture was extracted with Et₂O. The combined organic layers were washed with H₂O and brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give crude 12a, which was used in the next step without further purification. A mixture of the crude 12a in 1,2,4-TCB (7.5 mL) was stirred at 160 °C for 30 min, then cooled to rt. PPTS (9.4 mg, 0.037 mmol) was added and the mixture was stirred at 80 °C for 10 min, then cooled to rt. The resulting mixture was directly purified by column chromatography [silica gel, hexane–EtOAc (gradient 10:1 to 5:1)] to give 14 as a yellow oil; yield: 240 mg (6.94 mmol, 79%). IR (ATR): 2944, 2893, 2867, 1706, 1634, 1463, 1383, 1363, 1275, 1198, 1178, 996, 925, 880, 861, 739, 683 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.59 (s, 1 H), 3.73 (br s, 1 H), 2.90–2.78 (m, 2 H), 2.65–2.42 (m, 4 H), 2.33–2.17 (m, 2 H), 1.25 (sept, J = 7.4 Hz, 3 H), 1.09 (d, J = 7.4 Hz, 18 H). ¹³C NMR (126 MHz, CDCl₃): δ = 206.3, 160.2, 154.2, 135.9, 118.3, 96.4, 34.4, 33.8, 33.7, 29.2, 25.0, 17.8 (6 C), 12.3 (3 C). HRMS (FD): m/z [M]⁺ calcd for C₂₀H₃₁NO₂Si: 345.2124; found: 345.2140. Synthesis of Tricyclic Compound 22 from a Mixture of 19a and 19b
  A 1.0 M solution of LHMDS in THF (181 μL, 0.181 mmol) was added to a stirred solution of a mixture of 19a and 19b (108 mg, 0.165 mmol) and HMPA (72 μL, 0.41 mmol) in anhyd THF (3.3 mL) at –78 °C, and the mixture was slowly warmed to 0 °C for 1 h. The reaction was then quenched with sat. aq NaHCO₃, and the mixture was extracted with hexane. The combined organic layers were washed with H₂O and brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give a crude mixture of 21a and 21b, which was used for the next step without further purification. A stirred solution of the crude mixture of 21a and 21b in anhyd THF (1.1 mL) was treated with MsOH (21 μL, 0.33 mmol) at –78 °C, and the mixture was stirred at –78 °C for 1 h. The reaction was then quenched with sat. aq NaHCO₃, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure to give an oily residue that was purified by flash chromatography [silica gel, hexane–EtOAc (gradient 5:1 to 2:1)] to give 22 as a yellow oil [yield: 42 mg (0.11 mmol, 67%)], together with crude 21b (32 mg). 22 IR (ATR): 2945, 2892, 2868, 1712, 1629, 1463, 1376, 1361, 1269, 1191, 995, 992, 882, 860, 745, 685 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.51 (s, 1 H), 3.26–3.22 (m, 1 H), 3.07–3.02 (m, 1 H), 2.76–2.71 (m, 2 H), 2.59 (dd, J = 18.6, 4.9 Hz, 1 H), 2.33–2.27 (m, 2 H), 2.19–2.12 (m, 2 H), 1.82 (dd, J = 13.5, 13.5 Hz, 1 H), 1.29–1.22 (m, 4 H), 1.09 (d, J = 6.9 Hz, 18 H). ¹³C NMR (126 MHz, CDCl₃): δ = 207.0, 168.0, 160.3, 132.3, 121.6, 95.9, 42.2, 41.8, 40.5, 40.1, 34.1, 30.9, 30.1, 17.9 (6 C), 12.5 (3 C). HRMS (FD): m/z [M]⁺ calcd for C₂₂H₃₃NO₂Si: 371.2281; found: 371.2280.

For examples of the intramolecular alkylation reaction of a cyclopentadienyl anion species in natural-product synthesis, see:
• 15a Ohta H, Kobori T, Fujisawa T. J. Org. Chem. 1977; 42: 1231
• 15b Lei B, Fallis AG. J. Am. Chem. Soc. 1990; 112: 4609
• 15c Wang Y, Mukherjee D, Birney D, Houk KN. J. Org. Chem. 1990; 55: 4504