A Concise Asymmetric Total Synthesis of (+)-8-Epigrosheimin via Catalyst-Free Tandem Allylboration–Lactonization

Dedicated to Professor B. C. Ranu on the occasion of his 75^th birthday

Abstract

A concise and scalable asymmetric synthesis of (+)-8-epigrosheimin is reported in nine steps using only three column chromatographic purifications with an overall yield 47.0% from (R)-(–)-carvone. Two synthetic routes are evaluated by catalyst-free tandem allylboration–lactonization of two carvone-derived aldehydes and subsequent ene cyclization, where strategy via Lee–Lay aldehyde is found to be more effective for 8-epigrosheimin.

Key words

guaianolides - sesquiterpene lactone - tandem allylboration–lactonization - catalyst-free - ene reaction - 8-epigrosheimin

Publication History

Received: 09 August 2024

Accepted after revision: 10 September 2024

Accepted Manuscript online:
10 September 2024

Article published online:
09 October 2024

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• 17 Synthesis of Compound 13 Trifluoroethanol (15 mL) was stirred with a mixture of solid anhydrous NaHCO₃ and a pinch of solid anhydrous MgSO₄ and filtered through a sintered glass funnel. A solution of (R)-carvone-derived aldehyde 2 (1.7 g, 5.95 mmol, 1.3 equiv.) and O-TBS allylboronate 4 (1.7 g, 4.75 mmol, 1.0 equiv.) in pretreated trifluoroethanol (10 mL) were charged in a sealed tube and it was heated to 90 °C in a pre-heated oil bath. After 3.0 days, the reaction mixture was cooled to room temperature. Trifluoroethanol was removed in vacuo and recovered for reuse in the next batch. The crude materials were dissolved in a 1:1 mixture of THF (20 mL) and MeOH (20 mL). 1(N) HCl (10 mL) was then added and stirred at rt for 3 h. The reaction mixture was diluted with a saturated aqueous KH₂PO₄ solution and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo affords crude oil. The purification of crude product using flash chromatography (silica gel, EtOAc/PE = 3:2) yielded lactone alcohol 13 (0.88 g, 3.2 mmol, 70%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 6.29 (d, J = 2.7 Hz, 1 H), 5.69 (d, J = 2.4 Hz, 1 H), 4.93 (s, 1 H), 4.86 (s, 1 H), 4.38 (dd, J = 5.2, 2.6 Hz, 1 H), 4.22 (m, 1 H), 3.72 (dd, J = 6.3, 10.7 Hz, 2 H), 3.11–3.01 (m, 1 H), 2.95 (m, 1 H), 2.14–1.89 (m, 4 H), 1.78 (s, 3 H), 1.71 (dd, J = 13.1, 6.2 Hz, 2 H), 1.12 (d, J = 6.5 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.5, 144.0, 136.3, 123.2, 112.9, 81.0, 74.4, 64.0, 50.7, 46.2, 45.5, 39.2, 38.3, 23.4, 16.2. [α]_D ²⁵ 46.25 (c 0.16, CHCl₃). HRMS (ESI): m/z calcd for C₁₅H₂₃O₄ [M + H]⁺: 267.1591; found: 267.1585; C₁₅H₂₂NaO₄ [M + Na]⁺: 289.1410; found: 289.1403.
• 18 Synthesis of (+)-8-Epigrosheimin 1 from Compound 13 To a stirred solution of lactone alcohol 13 (0.12 g, 0.45 mmol, 1.0 equiv.) in CH₂Cl₂ (4.5 mL) at 0 °C Dess–Martin periodinane (0.76 g, 1.8 mmol, 4.0 equiv.) and H₂O (0.032 mL, 1.8 mmol, 4.0 equiv.) were added successively. The mixture was stirred at rt for 6 h. After the total consumption of lactone alcohol 13, saturated aqueous NaHCO₃ was added dropwise, followed by a saturated aqueous Na₂S₂O₃ solution. Two layers were separated after standing. The aqueous layer was extracted with CH₂Cl₂ (3 × 5 mL). First, the combined organic layers were washed with NaHCO₃, then brine, dried over anhydrous MgSO₄, and filtered. The CH₂Cl₂ solution (ca. 20 mL) was charged in a flame-dried two-neck round-bottomed flask and flashed with Ar. The reaction mixture was stirred for ca. 0.5 h at –78 °C. Et₂AlCl (0.5 mL, 0.45 mmol, 1.0 equiv., 0.9 M in toluene) was added dropwise. After 0.5 h, a saturated aqueous KH₂PO₄ solution was added and stirred at rt for 2 h. Finally, the aqueous layer was extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo afforded crude product. The purification of the crude mixture using flash chromatography (silica gel, MeOH/CH₂Cl₂ = 1:50) yielded 1 (80 mg, 0.31 mmol, 78%; dr >99:1) as a white solid; mp 132–135 °C, lit.⁸ 137–138 °C (diethyl ether/petroleum ether); [[α]_D ²⁵ 30.5 (c 0.24, CHCl₃), lit.⁸ [α]_D ²⁵ 31.5 ± 1 (c 0.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.45 (d, J = 3.5 Hz, 1 H), 5.68 (d, J = 3.0 Hz, 1 H), 5.09 (s, 1 H), 4.84 (s, 1 H), 4.55 (t, J = 9.2 Hz, 1 H), 4.46 (s, 1 H), 3.17–3.12 (m, 1 H), 3.06 (td, J = 8.1, 3.3 Hz, 1 H), 2.69 (dd, J = 13.9, 3.0 Hz, 1 H), 2.60–2.54 (m, 2 H), 2.50 (dd, J =13.7, 4.1 Hz, 1 H) 2.39–2.24 (m, 2 H), 1.28 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 219.2, 169.5, 143.8, 136.2, 122.2, 116.2, 81.2, 66.2, 50.5, 48.7, 47.3, 46.8, 44.0, 40.1, 14.4. HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ [M + Na]⁺: 285.1097; found: 285.1085.
• 19 Fernandes RA, Ramakrishna GV. J. Org. Chem. 2024; 89: 815
• 20 Synthesis of (+)-8-Epigrosheimin 1 from Compound 16 To a stirred solution of 16 (0.03 g, 0.12 mmol, 1.0 equiv.) in CH₂Cl₂ (3 mL) at 0 °C, m-CPBA (65 wt%, 0.03 g, 0.12 mmol, 1.0 equiv.) was added to it at the same temperature. The resulting suspension was stirred for 1 h at the same temperature. After complete consumption 16, the reaction was quenched with saturated Na₂SO₃ solution (30 mL). The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated to afford crude epoxide product 17. The crude product 17 was used directly in the next step. ¹H NMR (400 MHz, CDCl₃): δ = 6.41 (d, J = 3.6 Hz, 1 H), 5.57 (d, J = 3.2 Hz, 1 H), 5.00 (d, J = 1.8 Hz, 1 H), 4.84 (d, J = 1.8 Hz, 1 H), 4.40 (dd, J = 11.2, 8.3 Hz, 1 H), 4.29 (td, J = 8.0, 3.4 Hz, 1 H), 3.37 (s, 1 H), 3.04–2.92 (m, 2 H), 2.74 (dd, J = 13.6, 8.0 Hz, 1 H), 2.28 (dd, J = 11.3, 8.4 Hz, 1 H), 2.10–2.00 (m, 2 H), 1.83 (dd, J = 14.3, 11.0, 1 H), 1.59 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.6, 142.22, 135.5, 122.0, 117.6, 75.7, 66.5, 66.0, 63.3, 51.3, 49.4, 45.1, 37.2, 33.1, 18.4. HRMS (ESI): m/z calcd for C₁₅H₁₈NaO₄ [M + Na]⁺: 285.1097; found: 285.1085. The crude product 17 was used directly in the next step. To a stirred solution of epoxide (0.12 mmol) in dry CH₂Cl₂ (5 mL) at 0 °C, BF₃·OEt₂ (35 mg, 0.14 mmol, 2.0 equiv.) was added under nitrogen at the same temperature and stirred for 1 h. After complete consumption of 17 monitored by TLC, a saturated NaHCO₃ solution was added to it to quench the reaction. The aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were washed with saturated NaHCO₃, brine, dried over Na₂SO₄, filtered, and concentrated to afford crude product 1 (dr: 5:1). The purification of the crude product using flash chromatography (silica gel, MeOH/CH₂Cl₂ = 1:50) yielded 1 (22 mg, 0.084 mmol, 70%; dr >99:1) as a white solid.