CC BY ND NC 4.0 · Synlett 2019; 30(04): 383-386
DOI: 10.1055/s-0037-1610390
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Concise Asymmetric Synthesis of Kweichowenol A

a  Department of Chemistry, Ludwig-Maximilans University Munich, Butenandtstraße 5-13, 81377 München, Germany
,
Bilal Kicin
a  Department of Chemistry, Ludwig-Maximilans University Munich, Butenandtstraße 5-13, 81377 München, Germany
,
a  Department of Chemistry, Ludwig-Maximilans University Munich, Butenandtstraße 5-13, 81377 München, Germany
b  Department of Chemistry, New York University, 100 Washington Square East, Room 712, New York, 10003, USA   Email: dirktrauner@nyu.edu
› Author Affiliations
Further Information

Publication History

Received: 22 August 2018

Accepted after revision: 24 October 2018

Publication Date:
17 December 2018 (eFirst)

 

Dedicated to E.J. Corey on the Occasion of his 90th 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.

Supporting Information

 
  • 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 Rf (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): νmax = 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) Rf (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): νmax = 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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