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DOI: 10.1055/a-1983-1694
Studies Towards the Total Synthesis of Populusone: Stereoselective Construction of Functionalized 2-Oxa-bicyclo[2.2.2]octenes
This work was supported by the Universität zu Köln (University of Cologne).
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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 metathesisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-1983-1694.
- Supporting Information
Publikationsverlauf
Eingereicht: 20. Oktober 2022
Angenommen nach Revision: 20. November 2022
Accepted Manuscript online:
20. November 2022
Artikel online veröffentlicht:
13. Dezember 2022
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References and Notes
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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.
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