Synthetic Studies toward Tubiferal A: Asymmetric Synthesis of a Model ABC-Ring Compound

Abstract

Synthetic studies on an ABC-ring model of tubiferal A, a triterpenoid isolated from the fruit bodies of the Tubifera dimorphotheca myxomycete, are described. The stereogenic centers at the angular positions were constructed through the stereoselective addition of a C-ring allylborane followed by an Eschenmoser–Claisen rearrangement reaction prior to the formation of the AB-ring system by a double intramolecular alkylation reaction of a dichloro nitrile intermediate.

Key words

cyclization reactions - allylboranes - nitriles - epoxides - natural products

• References and Notes

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For reviews on cyclic nitriles, see:
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• 4 For intramolecular alkylation reactions of chloro nitriles, see: Fleming FF, Wei Y, Liu W, Zhang Z. Tetrahedron 2008; 64: 7477
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• 8 For the method used to determine the optical purity of the alcohol, see the Supporting Information.
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• 15 A small amount of each diastereomer in pure form was obtained through incomplete separation of the isomeric mixture of 26 by silica gel chromatography. Upon treatment with mCPBA, the major isomer of 26 was selectively converted into epoxide 27a, and the minor diastereomer of 26 afforded a mixture of epoxides 27b and 27c. Since the stereochemistry of 27c was determined by X-ray crystallography (see the Supporting Information), we could assign the configuration of epoxide 27b having the same AB ring moiety with 27c. The configuration of epoxide 27a was expected by assuming the oxidation reaction of the major isomer of 26 from the convex face.
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• 17 Synthesis of Compound 20 (Reaction of Aldehyde 19 with Allylborane (R)-9) To a solution of aldehyde 19 (1.28 g, 3.29 mmol) in CH₂Cl₂ (10 mL) was added a solution of allylboronate (R)-9 (1.43 g, 3.62 mmol) in CH₂Cl₂ (5 mL), and the mixture was stirred at room temperature. After completion of the reaction, which was monitored by TLC, the reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (SiO₂, n-hexane/EtOAc = 5:1) afforded alcohol 20 (1.99 g, 3.24 mmol, 99%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃): δ = 5.84 (1 H, s), 4.89 (1 H, d, J = 6.9 Hz), 4.79 (1 H, J = 6.9 Hz), 4.72 (1 H, d, J = 6.3 Hz), 4.69 (1 H, d, J = 6.9 Hz), 4.62–4.60 (1 H, m), 4.24 (1 H, d, J = 12.0 Hz), 4.09 (1 H, J = 11.5 Hz), 4.04–4.01 (1 H, m), 3.81 (1 H, d, J = 5.8 Hz), 3.75 (1 H, dd, J = 10.3, 6.3 Hz), 3.67 (1 H, dd, J = 10.3, 6.9 Hz), 3.50 (1 H, s), 3.42 (3 H, s), 3.39 (3 H, s), 2.44 (1 H, br), 2.03 (2 H, br), 1.90–1.80 (1 H, m), 1.75–1.66 (1 H, m), 1.51–1.45 (1 H, m), 1.29 (6 H, s), 0.89 (18 H, s), 0.08 (6 H, s), 0.07 (6 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 136.0, 129.2, 98.4, 97.1, 91.0, 82.1, 82.0, 77.8, 67.5, 64.1, 63.8, 56.2, 55.7, 43.2, 35.5, 28.0, 25.9 (6 C), 25.3, 25.2, 24.8, 21.0, 18.22, 18.19, –5.3, –5.4 (2 C), –5.5. IR (ATR): ν = 2952, 2929, 2887, 2853, 2335, 1471, 1253, 1102, 1030, 834, 775 cm^–1. HRMS (FD): m/z calcd for C₃₂H₆₃O₇Si₂ [M + H]⁺: 615.4112; found: 615.4103; [α]_D ²⁶ +101 (c 1.03, CHCl₃). Synthesis of Compound 26 (Double Cyclization of Nitrile 25) To a cooled (–78 °C) solution of dichloride 25 (292 mg, 0.648 mmol) and HMPA (248 μL, 1.43 mmol) in THF (3.2 mL) was added LiNEt₂ (1.0 M in THF, 1.43 mL, 1.43 mmol). After 30 min, the reaction was quenched with acetic acid in THF (ca. 1.0 M, 500 μL, 0.5 mmol) at –78 °C, followed by a saturated aqueous NaHCO₃ solution at 0 °C. After the layers were separated, the aqueous layer was extracted with Et₂O. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. Purification by flash column chromatography (SiO₂, n-hexane/EtOAc = 7:1) afforded tricyclic nitrile 26 (225 mg, 0.597 mmol, 92%, dr = 2:1) as a yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 5.81 (0.67 H, s), 5.44 (0.33 H, s), 4.90 (0.33 H, d, J = 6.9 Hz), 4.75–4.66 (3 H, m), 4.62 (0.67 H, d, J = 6.9 Hz), 3.86–3.81 (1 H, m), 3.50 (0.67 H, d, J = 5.2 Hz), 3.41 (2 H, s), 3.40 (1 H, s), 3.374 (2 H, s), 3.370 (1 H, s), 2.95 (0.33 H, d, J = 9.2 Hz), 2.51–2.39 (1.33 H, m), 2.20 (0.33 H, dd, J = 13.2, 4.6 Hz), 2.12–1.35 (13.01 H, m), 1.27 (2 H, s), 1.25–1.20 (1 H, m), 1.11–1.08 (0.33 H, m), 1.04 (1 H, s), 1.03 (1 H, s), 0.98 (2 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 35.5, 134.2, 127.5, 126.9, 126.7, 124.3, 99.0, 97.8, 96.7, 95.7, 87.3, 82.8, 75.6, 74.7, 56.3, 56.2, 55.6, 55.5, 52.4, 50.8, 49.5, 47.7, 41.9 40.7, 40.2, 39.9, 39.1, 38.4, 37.3, 37.1, 35.3. 34.7, 30.0, 29.5, 28.8, 27.3, 26.3, 25.8, 25.7, 24.4, 23.0, 19.7, 18.7, 15.5. IR (ATR): ν = 2927, 2857, 1456, 1147, 1098, 1026, 917, 753 cm^–1. HRMS (FD): m/z calcd for C₂₂H₃₅NO₄ [M]⁺: 377.2566; found: 377.2553; [α]_D ²⁶ –27.3 (c 0.87, CHCl₃). Synthesis of Compound 29 (Formation of the Diene Moiety) To a mixture of epoxides 27a and 27b (122 mg, 0.311 mmol) in THF (1.5 mL) was added LiNEt₂ (1.0 M in THF, 778 μL, 0.778 mmol), followed by t-BuOK (1.0 M in THF, 1.56 mL, 1.56 mmol) at –78 °C, and the mixture was vigorously stirred at the same temperature for 0.5 h. After neutralization of the bases using equimolar amounts of acetic acid (1.0 M in THF solution, 3.1 mL), Ac₂O (293 μL, 3.1 mmol) followed by DMAP (1 chip) was added. After stirring at room temperature for 1.5 h, the reaction was quenched with a saturated aqueous NaHCO₃ solution at 0 °C. After the layers were separated, the aqueous layer was extracted with Et₂O. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The residue was passed through a short pad of silica, using eluent n-hexane/EtOAc = 2:1. The crude mixture of acetate 28a and 28b was used for the next step without further purification. To a cooled (–78 °C) solution of the crude mixture of acetate 28a and 28b in THF (3.1 mL) was dropwise added LDBB (1.0 M in THF, 1.2 mL), during which the mixture turned dark green. After 20 min, (CH₂Cl)₂ (500 μL) was added, and the color of the mixture turned orange. A saturated aqueous NH₄Cl solution was added, and the mixture was warmed up to room temperature. After the layers were separated, the aqueous layer was extracted with Et₂O. The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. Purification by flash column chromatography (SiO₂, n-hexane/EtOAc = 50:1 to 10:1) afforded diene 29 (66.0 mg, 0.188 mmol, 60% for 2 steps) as a pale-yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 5.90 (1 H, s), 5.61 (1 H, s), 4.91 (1 H, d, J = 6.3 Hz), 4.73 (1 H, d, J = 6.9 Hz), 4.72 (1 H, d, J = 6.9 Hz), 4.69 (1 H, d, J = 6.9 Hz), 3.57–3.62 (1 H, m), 3.43 (3 H, s), 3.38 (3 H, s), 3.09 (1 H, d, J = 9.2 Hz), 2.54 (1 H, dd, J = 13.2, 5.7 Hz), 2.19–2.06 (5 H, m), 2.00 (1 H, t, J = 13.8 Hz), 1.73 (2 H, d, J = 12.1 Hz), 1.43–1.48 (2 H, m), 1.20–1.38 (3 H, m), 1.03 (3 H, s), 0.77 (3 H, s). ¹³C NMR (125 MHz, CDCl₃): δ = 140.1, 132.8, 131.1, 129.8, 99.0, 96.3, 88.1, 78.6, 56.3, 55.4, 49.9, 46.0, 42.4, 41.0, 31.9, 31.8, 29.0, 26.1, 24.9, 22.0, 15.9. IR (ATR): ν = 2925, 2851, 2826, 1441, 1148, 1103, 1026, 979, 915, 755 cm^–1. HRMS (FD): m/z calcd for C₂₁H₃₄O₄ [M]⁺: 350.2457; found: 350.2463; [α]_D ²⁶ +46.7 (c 1.22, CHCl₃).