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

• References and Notes


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• 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:
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