Synthetic Studies on Cyclocitrinol: Construction of the ABC Ring System Based on Epoxy–Nitrile Cyclization

Abstract

The stereoselective synthesis of a model compound containing the ABC ring system of cyclocitrinol was accomplished. After connecting a C ring allyltitanium segment with an A ring bi­cyclo[4.1.0]heptanone segment, the seven-membered B ring moiety was constructed by an intramolecular cyclization reaction of an epoxy nitrile. The enone moiety was introduced through an oxidative decyanation reaction, and the bicyclo[4.4.1]undecane skeleton with the highly strained olefin moiety was formed through a ring-opening reaction of the bicyclo[4.1.0]heptane substructure.

Key words

natural product - total synthesis - allyl titanocene - epoxy nitrile - cyclization reaction - cyclopropane ring opening - cyclocitrinol

Publication History

Received: 11 November 2020

Accepted after revision: 10 December 2020

Accepted Manuscript online:
10 December 2020

Article published online:
11 January 2021

• References and Notes

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• 20 The stereochemistry of cyclopropane ring-opening product was determined by NOE experiment of 24 converted from 20. Transformation of 24 into 5 was also achieved in three steps as follows, indicating that the configuration of compound 5 corresponds to that of the ABC ring system of natural product (Scheme 5).
• 21 Synthesis of Compound 6 (Coupling Reaction of Ketone 10) To a cooled (–78 °C) suspension of Cp₂TiCl₂ (1.50 g, 6.0 mmol) in THF (8.0 mL) was added n-BuLi (2.67 M in hexane, 4.5 mL, 12.0 mmol). After being stirred for 1 h, a THF solution (1.0 mL) of S3 (490 mg, 2.4 mmol, see the Supporting Information) was added, and stirring was continued for 10 min at the same temperature and then at 0 °C for 1 h. After cooling to –78 °C, ketone 10 (300 mg, 2.0 mmol) in THF (1.0 mL) was added. After being stirred for 1 h, a 1 M aqueous NaOH solution was added, and the mixture was filtered through a pad of Celite. The insoluble materials were washed with EtOAc, and the filtrate was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 75:15) to afford 9 as a yellow oil (370 mg, 1.5 mmol, 75%, single isomer). IR (neat): ν = 2926, 2853, 2360, 2341, 1638, 1447, 1420, 1386, 1113, 1059, 995, 984, 953, 891 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 4.90 (1 H, s), 4.83 (1 H, s), 2.33 (1 H, dd, J = 9.0, 6.0 Hz), 2.26 (1 H, q, J = 6.5 Hz), 2.21 (1 H, t, J = 4.6 Hz), 2.11 (1 H, dd, J = 12.6, 4.0 Hz), 2.04 (2 H, d, J = 5.2 Hz), 1.87 (1 H, d, J = 10.3 Hz), 1.82–1.74 (3 H, m), 1.53–1.40 (4 H, m), 1.31–1.23 (4 H, m), 0.55 (2 H, dt, J = 17.9, 6.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 149.33, 118.37, 108.47, 71.97, 56.65, 38.97, 38.11, 29.41, 29.00, 28.94, 26.15, 24.38, 21.12, 13.79, 5.83. HRMS (FI): m/z calcd for C₁₆H₂₃NO [M]⁺: 245.1780; found: 245.1773. Synthesis of Compound 7 (Cyclization Reaction of Epoxy Nitrile) To a cooled (–78 °C) solution of LTMP, which was freshly prepared from tetramethylpiperidine (250 μL, 1.45 mmol) in THF (6.3 mL) and n-BuLi (2.67 M in hexane, 540 μL, 1.45 mmol), was added a solution of 8 (200 mg, 0.727 mmol) in THF (1.0 mL). After being stirred for 30 min, the reaction mixture was slowly warmed up to room temperature. After being stirred for 1 h, the reaction was quenched with a saturated aqueous NH₄Cl solution. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 75:15) to afford 7 as a white solid (146 mg, 0.531 mmol, single isomer); mp 207–209 °C. IR (neat): ν = 3381, 2960, 2939, 2919, 2872, 2359, 2225, 1496, 1296, 1237, 1061, 1036, 1004, 978 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.39 (1 H, dd, J = 10.9, 7.4 Hz), 3.17 (3 H, s), 2.36 (1 H, dd, J = 14.0, 12.3 Hz), 2.12–2.08 (2 H, m), 2.01 (2 H, t, J = 14.9 Hz), 1.90 (1 H, q, J = 4.4 Hz), 1.83 (1 H, dd, 12.0, 6.3 Hz) 1.75–1.66 (2 H, m), 1.58 (2 H, m), 1.47 (1 H, s), 1.41 (1 H, dt, J = 14.1, 3.9 Hz), 1.33–1.22 (4 H, m), 1.17 (1 H, dd, J = 15.2, 8.9 Hz), 1.03 (1 H, td, J = 8.9, 4.6 Hz), 0.85 (1 H, d, J = 14.3 Hz), 0.29 (1 H, q, J = 5.5 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 124.41, 74.74, 72.16, 50.72, 47.09, 46.26, 36.05, 34.52, 31.38, 30.97, 27.75, 25.69, 23.90, 23.39, 18.87, 13.91, 12.66. HRMS (FI): m/z calcd for C₁₇H₂₅NO₂ [M]⁺: 275.1885; found: 275.1884. Synthesis of Compound 5 (Cleavage of the Cyclopropane Moiety Followed by Saponification) To a cooled (0 °C) mixture of 6 (40 mg, 0.162 mmol) and AcOH (200 μL) in CH₂Cl₂ (400 μL) was added BF₃·OEt₂ (2.0 μL, 0.016 mmol). The reaction mixture was warmed up to room temperature and was stirred for 1 h. After cooling to 0 °C, a saturated aqueous NaHCO₃ solution was added, and the mixture was separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 9:1) to afford 23 as a yellow oil (34 mg, 0.123 mmol, 76%). IR (CHCl₃): ν = 2931, 2856, 2365, 2342, 1656, 1617, 1460, 1437, 1363, 1326, 1162, 1108, 1085, 1020, 970, 888, 867, 850, 751 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.76 (1 H, s), 5.61 (1 H, t, J = 7.4 Hz), 4.52–4.48 (1 H, m), 2.87–2.80 (2 H, m), 2.74 (1 H, d, J = 5.2 Hz), 2.65 (1 H, q, J = 6.7 Hz), 2.54–2.43 (2 H, m), 2.33–2.29 (2 H, m), 2.18 (1 H, dd, J = 14.9, 12.6 Hz), 2.01 (3 H, s), 1.91–1.77 (3 H, m), 1.80 (1 H, td, J = 12.2, 4.4 Hz), 1.73 (1 H, d, J = 12.6 Hz), 1.43 (2 H, dtd, J = 47.7, 15.3, 8.6 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 204.20, 169.97, 156.94, 146.84, 125.82, 121.11, 67.48, 53.75, 48.32, 37.62, 37.36, 32.65, 31.13, 27.32, 27.15, 25.22, 21.38. HRMS (FI): m/z calcd for C₁₇H₂₂O₃ [M]⁺: 274.1569; found: 274.1572. A mixture of 23 (33 mg, 0.123 mmol) and K₂CO₃ (50 mg, 0.362 mmol) in MeOH (500 μL) was stirred at room temperature for 3 h. To this was added EtOAc and brine. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 2:1) to afford 5 as a white solid (27.0 mg, 0.118 mmol, 96%); mp 114–117 °C. IR (neat): ν = 3298 (br), 2927, 2853, 2366, 2358, 2342, 1655, 1614, 1031 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.75 (1 H, s), 5.57 (1 H, t, J = 7.4 Hz), 3.50 (1 H, t, J = 11.2 Hz), 2.86 (2 H, m), 2.71 (1 H, t, J = 6.0 Hz), 2.64 (1 H, q, J = 6.7 Hz), 2.49 (2 H, dt, J = 17.2, 8.3 Hz), 2.33–2.16 (3 H, m), 1.88 (2 H, t, J = 16.3 Hz), 1.70 (2 H, m), 1.50–1.37 (2 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 205.01, 157.10, 146.37, 125.82, 121.62, 64.68, 53.84, 48.58, 41.71, 37.34, 35.66, 31.11, 27.31, 27.30, 25.23. HRMS (FD): m/z calcd for C₁₅H₂₀O₂ [M]⁺: 232.1463; found: 232.1458.