Concise Asymmetric Synthesis of Kweichowenol A

Dedicated to E.J. Corey on the Occasion of his 90^th BirthdayPublished as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

An asymmetric 11-step synthesis of the polyoxygenated cyclohexene natural product kweichowenol A from the traditional Chinese medicinal herb Uvaria kweichowesis is reported. The oxygenation pattern was installed on a linear precursor by exploiting the acyclic stereocontrol of the Kiyooka aldol reaction, as well as Cram chelate-controlled Grignard reactions. Ring-closing metathesis and a selective benzoylation then gave the natural product.

Key words

kweichowenol A - Kiyooka aldol - asymmetric synthesis - natural product synthesis - acyclic stereocontrol

• References and Notes

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• 22 Kiyooka Aldol Reaction Procedure for the Synthesis of 12 N-Ts-d-valine (SI-1, 7.82 g, 28.6 mmol, 1.1 equiv) was dissolved in CH₂Cl₂ (130 mL), cooled to 0 °C, and BH₃·THF (1 M in THF, 26.0 mL, 26.0 mmol, 1.0 equiv) was added dropwise over a period of 10 min. The suspension was stirred at 0 °C for 30 min before warming to rt and stirring for 1 h. Continuous bubbling was observed, and the white solid slowly dissolved to give a clear solution. After cooling the solution to –78 °C, cinnamaldehyde (11, 3.27 mL, 26.0 mmol, 1.0 equiv) in CH₂Cl₂ (70 mL) and TBS ketene acetal (9, 8.56 mL, 31.2 mmol, 1.2 equiv) in CH₂Cl₂ (70 mL) were successively added via syringe pump (2.5 mL/min). Stirring was continued for 10 min at –78 °C and PB pH 7 (30 mL) was added at –78 °C. The mixture was diluted with Et₂O (500 mL), and the organic layer was washed with PB pH 7/sat. aq. NaCl (4:1, 250 mL), sat. aq. NaHCO₃ (200 mL), and sat. aq. NaCl (200 mL) before drying over Na₂SO₄. Concentrating the organic phase under reduced pressure provided an oily residue which was directly dissolved in EtOH/H₂O (9:1, 57.2 mL). After addition of NaHSO₃ (2.70 g, 26.0 mmol, 1.0 equiv), the sus­pension was heated to 37 °C for 3 h followed by filtration through Celite and rinsing of the filter cake with Et₂O. The ­filtrate was concentrated in vacuo, redissolved in Et₂O (100 mL) and filtered again through Celite. Rotary evaporation gave an oily residue that was purified via flash column chromatography (­pentane/Et₂O = 185:15) to give an intractable diasteromeric mixture of (1S,E)-1-[(4R)-4-{[(tert-butyldimethylsilyl)oxy](methoxy)methyl}-2,2-dimethyl-1,3-dioxolan-4-yl]-3-phenylprop-2-en-1-ol (12, 7.08 g, 17.3 mmol, 67%) as a clear oil.Analytical Data of 12-1 R_f (pentane/Et₂O = 9:1) = 0.24. (UV, CAM). ¹H NMR (400 MHz, CD₂Cl₂): δ = 7.42–7.38 (m, 2 H), 7.34–7.28 (m, 2 H), 7.25–7.19 (m, 1 H), 6.65 (dd, J = 16.0, 1.6 Hz, 1 H), 6.41 (dd, J = 16.0, 5.4 Hz, 1 H), 4.80 (s, 1 H), 4.46 (td, J = 6.0, 1.7 Hz, 1 H), 4.00 (q, J = 9.3 Hz, 2 H), 3.44 (s, 3 H), 3.14 (d, J = 6.1 Hz, 1 H), 1.43 (s, 6 H), 0.92 (s, 9 H), 0.17 (s, 3 H), 0.17 (s, 3 H) ppm. ¹³C NMR (101 MHz, CD₂Cl₂): δ = 137.8, 130.8, 129.3, 129.0, 127.8, 126.9, 111.3, 102.0, 86.4, 73.7, 67.8, 57.7, 27.1, 26.7, 26.1, 18.5, –4.1, –4.2 ppm. HRMS (EI): m/z calcd for C₂₁H₃₃O₅Si⁺ [M − CH₃ ^–]⁺: 393.2097; found: 393.2095. IR (Diamond-ATR, neat): ν_max = 3504 (vw), 2955, 2931 , 2897 (vw), 2858 (vw), 1741 (vw), 1496 (vw), 1472, 1463, 1449 (vw), 1380, 1370, 1252, 1210, 1063 (vs), 1005, 968, 939, 834 (vs), 778, 750, 693, 670 cm^–1. [α]_D ²⁰ –8.00 (c = 1.99, EtOAc).
• 23 Selective Benzoylation Procedure for the Synthesis of ­Kweichowenol A (1)Diol (17, 4.7 mg, 15 μmol, 1.0 equiv) was dissolved in pyridine (0.15 mL), cooled to –27 °C, and BzCl (1.78 μL, 15.4 μL, 1.05 equiv) in pyridine (0.1 mL) was added dropwise. The solution was allowed to warm to –20 °C over a period of 15 min and stirring was continued at the same temperature for 40 min. Thereafter, 3% aq. KHSO₄ (1 mL) was added, and the mixture was diluted with EtOAc (30 mL). The organic layer was washed with 3% aq. KHSO₄ (10 mL), sat. aq. NaCl (10 mL), dried over Na₂SO₄, and concentrated. Purification via flash column chromatography (pentane/EtOAc = 9:1 → 8:1) afforded kweichowenol A (1, 4.3 mg, 10 μmol, 69%) as a white solid.Analytical Data of Synthetic Kweichowenol A (1) R_f (pentane/EtOAc = 19:1) = 0.21. (UV, CAM). ¹H NMR (600 MHz, C₆D₆): δ = 8.17–8.14 (m, 2 H), 8.10–8.08 (m, 2 H), 7.62–7.56 (m, 2 H), 7.50–7.44 (m, 4 H), 5.85–5.79 (m, 2 H), 5.79–5.78 (m, 1 H), 5.61 (ddd, J = 8.6, 2.5, 1.4 Hz, 1 H), 4.38 (d, J = 8.4 Hz, 1 H), 4.33 (d, J = 8.4 Hz, 1 H), 4.28 (d, J = 8.5 Hz, 1 H), 2.64 (s, 1 H), 1.46 (s, 3 H), 1.32 (s, 3 H) ppm. ¹³C NMR (151 MHz, C₆D₆): δ = 166.5, 166.0, 133.6, 133.5, 130.2, 130.0, 129.77, 129.76, 129.4, 128.7, 128.6, 127.5, 111.1, 85.6, 74.2, 73.8, 72.4, 64.5, 27.0, 26.2 ppm. HRMS (ESI): m/z calcd for C₂₆H₂₇O₉ ^– [M + CH₃COO^–]^–: 483.1661; found: 483.1665. IR (Diamond-ATR, neat): ν_max = 3588 (vw), 2920, 2851 (vw), 2166, 1714, 1600 (vw), 1453, 1382 (vw), 1369, 1316, 1268 (vs), 1206, 1177, 1147 1111, 1089, 1064 (vs), 1023, 962, 881, 863, 798, 780, 701 (vs), 668 cm^–1. [α]_D ²⁰ –168° (c = 0.538, CHCl₃).
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