Consecutive Ireland–Claisen Enyne-Metathesis Strategy Enables Rapid Assembly of Cyclic Imine Core Cyclohexene Motif

Abstract

An efficient strategy for rapid assembly of the complex substituted cyclohexene core that is present in several cyclic imine marine toxins is presented. Several of these toxins, including pinnatoxin A and recently discovered portimine A, have been the focus of much attention due to their fascinating biological activities. We demonstrate that the substituted cyclohexene-diene motif, which is a challenging feature to access synthetically, can be prepared through a stepwise Ireland–Claisen rearrangement/enyne metathesis procedure beginning from chiral esters. This approach enables a divergent strategy that can be implemented in syntheses of cyclic imines or derivatives thereof.

Key words

enyne metathesis - Ireland–Claisen - cyclic imine - portimine - pinnatoxin - kabirimine

Publication History

Received: 23 October 2023

Accepted after revision: 21 November 2023

Accepted Manuscript online:
21 November 2023

Article published online:
20 December 2023

• References and Notes

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• 10 General Procedure for Ireland–Claisen Rearrangement A solution of chiral lithium amide (2.930 g, 10.23 mmol, 3.3 equiv) was dissolved in THF (30 mL) and cooled to –78 °C under an atmosphere of argon. n-Butyl lithium (3.7 mL, 9.3 mmol, 3.0 equiv, 2.5 M in hexanes) was added dropwise, and the solution stirred at this temperature for 15 min was warmed to 0 °C for 15 min and cooled back to –78 °C. A solution of allylic ester (3.10 mmol) was added dropwise as a solution in THF (6 mL + 2 × 2 mL rinses) and stirring continued for 1 h, at which point TMSCl (1.2 mL, 9.76 mmol, 3.15 equiv) was added dropwise. After stirring for an additional 1 h at –78 °C, the reaction was warmed to rt, and then heated to 50 °C. After 48 h, the reaction was cooled to 0 °C and quenched with DI H₂O and diluted with EtOAc. The mixture was transferred into a separatory funnel containing a 1:1 mixture of hexanes and 1 M HCl (the chiral amine was later recovered from this acidic aqueous phase by basification with NaOH and extraction with CH₂Cl₂). The biphasic mixture was extracted with EtOAc, and the organic extracts were dried over anhydrous Na₂SO₄, concentrated, and the crude material was purified by column chromatography on silica gel.
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• 14 Preparation of Acid 8 The acid 8 was prepared according to the general procedure.¹⁰ After purification by column chromatography (5% EtOAc in hexanes to 30% EtOAc in hexanes + 1% AcOH), the acid 8 was obtained as a colorless oil (1.916 g, 3.02 mmol, 98% yield, 9:1 d.r. The d.r. was determined by ¹H NMR spectroscopy). [α]_D ²¹ 0.5978° (c 0.100, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.20–7.18 (m, 4 H), 6.86–6.78 (m, 2 H), 5.58 (ddd, J = 17.2, 10.7, 9.2 Hz, 1 H), 5.22–5.14 (m, 2 H), 4.40 (s, 2 H), 4.12 (dd, J = 10.7, 5.5 Hz, 1 H), 3.90 (q, J = 5.3 Hz, 1 H), 3.73 (s, 3 H), 3.61 (dt, J = 6.7, 4.1 Hz, 2 H), 3.50 (dd, J = 10.7, 5.6 Hz, 1 H), 3.05 (t, J = 10.1 Hz, 1 H), 2.26–2.10 (m, 3 H), 1.87 (dt, J = 14.2, 6.5 Hz, 1 H), 1.78 (dt, J = 11.4, 5.6 Hz, 2 H), 1.30 (d, J = 5.9 Hz, 3 H), 1.23 (s, 3 H), 0.83 (s, 9 H), 0.07 (d, J = 4.2 Hz, 9 H), 0.00 (d, J = 3.1 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 181.38, 159.33, 134.00, 130.37, 129.41, 129.36, 129.30, 120.98, 113.94, 108.08, 108.02, 106.83, 84.48, 78.68, 77.41, 77.16, 76.91, 76.34, 72.86, 66.91, 62.78, 55.37, 49.81, 46.56, 34.58, 31.07, 27.75, 26.19, 26.07, 25.50, 18.65, 15.38, 0.27, –5.09, –5.12. HRMS (TOF MS ES): m/z calcd for C₃₄H₅₅O₇Si₂ [M – H]^–: 631.3486; found: 631.3505.
• 15 Preparation of Enyne 9 A solution of 8 (0.568 g, 0.897 mmol) in a 4:1 mixture of benzene (7.2 mL) to methanol (1.8 mL) was cooled to 0 °C, and TMSCHN₂ (1.0 mL, 1.07 mmol, 1.2 equiv, 1.05 M in hexanes) was added dropwise. The solution was warmed to rt and stirred for 30 min, at which point the reaction was concentrated in vacuo and redissolved in methanol (9 mL). Potassium carbonate (0.495 g, 3.58 mmol, 4.0 equiv) was added and the solution stirred at rt for 18 h. Upon completion, the mixture was diluted with DI H₂O and extracted with EtOAc. The organic extracts were dried over anhydrous Na₂SO₄, concentrated, and the crude material was purified by column chromatography on silica gel (10% EtOAc in hexanes) to afford the product 9 (0.489 g, 0.850 mmol, 95% yield). [α]_D ¹⁸ 5.6540° (c 1.00, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.71–5.58 (m, 1 H), 5.28–5.18 (m, 2 H), 4.42 (s, 2 H), 4.16 (dd, J = 10.8, 5.3 Hz, 1 H), 3.93 (d, J = 5.3 Hz, 1 H), 3.80 (s, 3 H), 3.74 (dd, J = 10.7, 4.8 Hz, 1 H), 3.69–3.59 (m, 5 H), 3.53 (dd, J = 10.7, 5.9 Hz, 1 H), 3.11–3.02 (m, 1 H), 2.23 (d, J = 2.5 Hz, 1 H), 2.19–2.11 (m, 1 H), 2.07 (d, J = 2.6 Hz, 1 H), 2.00–1.79 (m, 4 H), 1.35 (s, 3 H), 1.28 (s, 5 H), 0.91 (s, 9 H), 0.07 (d, J = 3.8 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 175.56, 175.17, 159.22, 135.13, 134.26, 134.10, 130.58, 130.48, 129.33, 129.26, 129.09, 120.80, 120.69, 118.94, 113.83, 107.84, 107.79, 107.72, 85.07, 84.27, 78.63, 76.39, 72.79, 72.73, 68.42, 68.35, 68.27, 66.98, 66.49, 66.46, 62.70, 61.58, 55.31, 51.68, 51.41, 51.35, 50.58, 49.51, 49.48, 47.22, 47.13, 46.73, 34.77, 33.09, 32.54, 31.65, 31.57, 31.39, 28.11, 28.07, 27.10, 26.13, 26.00, 25.42, 24.84, 22.72, 18.61, 18.33, 14.72, 14.19, 14.08, 13.97, –5.17, –5.18. HRMS (TOF MS ES): m/z calcd for C₃₂H₅₀O₇SiNa [M + Na]⁺: 597.3224; found: 597.3245.
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• 17 Preparation of Cyclohexene 10 A 100 mL round-bottom flask equipped with a stir bar was flame-dried under vacuum and cooled under argon, and 9 (0.378 g, 0.657 mmol) was added, followed by HG II (27 mg, 0.032 mmol, 0.08 equiv). Toluene (34 mL, freshly distilled over Na and degassed by sparging with argon for 1 h) was added to the flask, and the mixture was sparged with ethylene gas (1 party balloon full of ethylene). The reaction was fitted with a reflux condenser and a full balloon of ethylene gas to maintain the atmosphere of ethylene, and the temperature was increased to 110 °C. After 24 h, completion was observed by TLC, and the reaction was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (10% EtOAc in hexanes) to provide 10 (0.322 g, 0.560 mmol, 86%) as a 7:1 mixture of the desired cyclohexene 10 to the triene 11 (ratio of 10/11 was determined by ¹H NMR spectroscopy). Cyclohexene 10 [α]_D ²² 23.4716° (c 1.00, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.26 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 2 H), 6.28 (dd, J = 17.5, 10.7 Hz, 1 H), 5.45 (s, 1 H), 5.06 (d, J = 17.0 Hz, 1 H), 4.96 (d, J = 10.3 Hz, 1 H), 4.53–4.38 (m, 2 H), 4.16 (dt, J = 8.6, 4.3 Hz, 1 H), 4.01–3.87 (m, 2 H), 3.80 (s, 4 H), 3.73 (dd, J = 10.4, 8.6 Hz, 1 H), 3.67–3.55 (m, 5 H), 3.48 (dd, J = 10.1, 4.0 Hz, 1 H), 3.35 (d, J = 11.4 Hz, 1 H), 2.32–2.09 (m, 4 H), 1.90 (dd, J = 10.7, 6.6 Hz, 1 H), 1.87–1.79 (m, 1 H), 1.79–1.68 (m, 1 H), 1.28 (d, J = 9.2 Hz, 6 H), 0.88 (s, 9 H), 0.06 (d, J = 7.0 Hz, 6 H). ¹³C NMR (126 MHz, CDCl₃): δ = 177.81, 159.22, 139.11, 138.70, 135.55, 134.49, 133.75, 130.95, 129.39, 129.36, 127.49, 120.59, 116.01, 113.90, 113.88, 113.82, 113.50, 111.60, 107.75, 107.59, 78.78, 77.99, 77.34, 76.66, 72.74, 67.47, 67.22, 66.79, 62.79, 62.43, 55.39, 51.57, 47.71, 45.76, 42.73, 41.98, 34.80, 31.72, 31.52, 29.15, 28.43, 28.33, 27.74, 26.63, 26.51, 26.19, 26.13, 26.06, 25.97, 25.55, 25.41, 25.18, 22.79, 21.18, 20.83, 18.39, 14.25, –5.10, –5.44. HRMS (TOF MS ES): m/z calcd for C₃₂H₅₀O₇SiNa [M + Na]⁺: 597.3224; found: 597.3206. Triene 11 [α]_D ²¹ –19.3102° (c 0.8, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.24 (d, J = 8.4 Hz, 3 H), 6.86 (d, J = 8.0 Hz, 3 H), 6.34 (dt, J = 17.7, 8.9 Hz, 1 H), 5.66 (d, J = 3.5 Hz, 1 H), 5.25–4.89 (m, 5 H), 4.39 (s, 2 H), 3.80 (s, 5 H), 3.67–3.59 (m, 3 H), 3.57 (s, 3 H), 3.55–3.43 (m, 3 H), 3.03 (s, 1 H), 2.23–3.59 (m, 3 H), 2.13–2.07 (m, 3 H), 2.01–1.98 (m, 4 H), 1.89–1.83 (m, 4 H), 1.25 (s, 19 H), 0.89 (s, 17 H), 0.07 (s, 17 H). ¹³C NMR (126 MHz, CDCl₃): δ = 176.83, 159.23, 139.70, 136.21, 132.29, 132.22, 130.74, 129.38, 128.79, 128.61, 113.84, 110.92, 108.36, 107.85, 75.58, 72.82, 66.95, 61.94, 55.42, 51.90, 47.19, 41.25, 32.08, 31.77, 29.85, 29.52, 28.25, 27.96, 26.86, 26.64, 26.08, 26.01, 25.20, 24.97, 22.84, 21.65, 21.13, 18.39, 14.27, 1.17, –2.77, –5.28, –5.30. HRMS (TOF MS ES): m/z calcd for C₃₄H₅₄O₇SiNa [M + Na]⁺: 625.3536; found: 625.3516.
• 18 Villar H, Frings M, Bolm C. Chem. Soc. Rev. 2007; 36: 55