Studies Towards the Total Synthesis of Populusone: Stereoselective Construction of Functionalized 2-Oxa-bicyclo[2.2.2]octenes

Abstract

A short and efficient synthetic access to functionalized compounds displaying major structural elements of the natural product populusone is elaborated by exploiting a diastereoselective Mukaiyama aldol addition followed by a triflic anhydride-induced oxa-Michael addition to construct the sensitive 2-oxa-bicyclo[2.2.2]octene unit as an enol triflate, which is directly used in a subsequent Suzuki cross-coupling. While attempts to close the strained 10-membered ring by means of Ru-catalyzed ring-closing metathesis were not successful, the developed synthetic scheme opens a rapid synthetic access to advanced intermediates, which may allow the completion of the total synthesis of populusone in the future.

Key words

diterpenoids - Mukaiyama aldol reaction - 10-membered rings - oxa-Michael addition - Suzuki coupling - ring-closing metathesis

Publication History

Received: 20 October 2022

Accepted after revision: 20 November 2022

Accepted Manuscript online:
20 November 2022

Article published online:
13 December 2022

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• 12 Detailed experimental procedures and characterization data are given in the Supporting Information. Synthesis of rac-8 To a solution of silyldienyl ether 6 (15.6 g, 85.8 mmol, 1.0 equiv.) and ethyl pyruvate (5) (9.5 mL, 85.6 mmol) in dry Et₂O (350 mL) at –78 °C was added BF₃·Et₂O (11 mL, 88 mmol). The dry ice bath was removed and the mixture was stirred at room temp for 17 h. After addition of HCl (1 M, 100 mL), the aqueous phase was extracted with MTBE (3 × 200 mL). The combined organic phases were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO₂, CyHex/EtOAc = 2:1) to yield rac-8 (13.8 g, 61 mmol, 71%) as a colorless oil. FT-IR (ATR): 3508 (br), 1728 (s), 1664 (s), 1255 (s), 1217 (s), 1168 (s), 1112 (s), 1095 (s) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.84 (s, 1 H), 4.31–4.19 (m, 2 H), 3.35 (s, 1 H), 2.88 (dd, J = 13.9, 4.7 Hz, 1 H), 2.49–2.32 (m, 2 H, 2.23–2.11 (m, 1 H), 2.05–1.96 (m, 1 H), 1.95 (s, 3 H), 1.34 (s, 3 H), 1.28 (td, J = 7.1, 0.8 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 198.8, 177.2, 163.0, 126.8, 73.5, 61.8, 52.9, 31.1, 24.3, 24.0, 22.5, 14.2. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₈O₄Na: 249.1097; found: 249.1097. Synthesis of rac-22 To a solution of rac-8 (202 mg, 0.89 mmol) and DTBMP (366 mg, 1.78 mmol) in dry CH₂Cl₂ (8.0 mL) was added Tf₂O (0.22 mL, 1.34 mmol) at 0 °C, and the resulting mixture was stirred for 30 min at room temperature. After addition of sat. aq. NaHCO₃ (10 mL), the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phases were dried over MgSO₄ and the solvent was removed under reduced pressure to give crude rac-9 (≤0.89 mmol), which was directly used as described below. In a separate flask, diolefin 21 (238 mg, 1.2 mmol) was dissolved in dry THF (10 mL) and 9-BBN (2.4 mL, 0.5 M in THF, 1.2 mmol) was added dropwise at 0 °C and stirring was continued for 45 min at room temperature before a solution of rac-9 (≤0.89 mmol) in 1,4-dioxane (4.5 mL), Pd(PPh₃)₄ (31 mg, 0.027 mmol, 3 mol%), Cs₂CO₃ (870 mg, 2.67 mmol) and water (4.5 mL) were added. The mixture was stirred at 90 °C for 4.5 h, cooled to room temperature and extracted with MTBE (3 × 15 mL). The combined organic layers were stirred with Quadrasil AP (10 mg) for 10 min, dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (Si02, CyHex/EtOAc = 30:1 → 2:1) to yield rac-22 (188 mg, 0.46 mmol, 52%) as a colorless oil. FT-IR (ATR): 2954 (m), 2930 (m), 1754 (m), 1720 (m), 1106 (s), 1067 (s), 835 (s), 775 (s) cm^–1. ¹H NMR (600 MHz, CDCl₃,): δ (1:1 mixture of diastereomers) = 5.80–5.73 (m, 2 H), 5.12 (ddt, J = 17.1, 7.4, 1.5 Hz, 1 H), 5.03 (dddd, J = 10.4, 4.1, 1.8, 1.1 Hz, 1 H), 4.13 (dqd, J = 10.8, 7.1, 1.5 Hz, 1 H), 4.10–4.05 (m, 1 H), 4.01 (dqd, J = 10.8, 7.1, 0.6 Hz, 1 H), 2.70–2.67 (m, 1 H), 2.21–2.04 (m, 2 H), 1.99–1.91 (m, 1 H), 1.76–1.70 (m, 1 H), 1.67–1.57 (m, 1 H), 1.56–1.49 (m, 1 H), 1.41 (s, 3 H), 1.40 (d, J = 0.8 Hz, 3 H), 1.24–1.18 (m, 5 H), 0.89 (2 × s, 9 H), 0.05 to –0.02 (m, 6 H). ¹³C NMR (150 MHz, CDCl₃): δ (1:1 mixture of diastereomers) = 175.5/175.4, 146.7/146.7, 141.6/141.4, 128.5/128.4, 114.0/113.9, 78.3, 73.6/73.6, 72.7/72.7, 60.6/60.5, 41.1/41.1, 35.1/35.1, 33.1/33.1, 29.6/29.6, 25.9/25.9, 24.7, 24.3, 23.4/23.4, 18.5/18.5, 14.3, –4.30/–4.35, –4.80/–4.83. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₄₀O₄SiNa: 431.2588; found: 431.2584.