Synlett 2019; 30(18): 2091-2095
DOI: 10.1055/s-0039-1690696
letter
© Georg Thieme Verlag Stuttgart · New York

Preparation of Bicyclic Ketal Skeletons with Aldehyde and α-Ketone Acid through Cascade Friedel–Crafts Reaction and Stereoselective Acetalization in One Pot

Ling Li
a   College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, P. R. of China   Email: gzhao@scu.edu.cn
,
Ying-wei Wang
a   College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, P. R. of China   Email: gzhao@scu.edu.cn
,
Shi-qi Zhang
a   College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, P. R. of China   Email: gzhao@scu.edu.cn
,
Xiong-fei Deng
a   College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, P. R. of China   Email: gzhao@scu.edu.cn
,
Guang-xun Li
b   Natural Products Research Center Chengdu Institution of Biology Chinese Academy of Science, Chengdu, Sichuan 610041, P. R. of China   Email: ligx@cib.ac.cn   Email: tangzhuo@cib.ac.cn
,
Gang Zhao
a   College of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, P. R. of China   Email: gzhao@scu.edu.cn
,
Zhuo Tang
b   Natural Products Research Center Chengdu Institution of Biology Chinese Academy of Science, Chengdu, Sichuan 610041, P. R. of China   Email: ligx@cib.ac.cn   Email: tangzhuo@cib.ac.cn
› Author Affiliations
We are grateful for the financial support from the Sichuan Science and Technology Program (No. 2019JDRC0106).
Further Information

Publication History

Received: 19 July 2019

Accepted after revision: 17 September 2019

Publication Date:
07 October 2019 (online)


Abstract

Bicyclic ketal skeletons are important structure fragments that are frequently contained in natural products. A novel tandem Friedel–Crafts reaction and subsequent stereoselective acetalization were developed with readily available aldehyde and ketone acid. The reaction proceeded smoothly in the presence of catalytic Brønsted acid and afforded the corresponding product with moderate yield and high stereoselectivity.

Supporting Information

 
  • References and Notes

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  • 12 General Procedure for the Preparation of 3a–q To a stirred solution of α-arylaldehyde 1 (0.2 mmol) and TfOH (0.06 mmol) in toluene (2 mL, 0.1 M) was added arylglyoxylic acid 2 (or hydroxyl acetone 5a) (0.24 mmol, 1.2 equiv) at room temperature, then the reaction mixture was stirred for 12 h at 50 °C under nitrogen atmosphere. After completion of the reaction (TLC), the mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, filtered, and the solvent was removed by rotary evaporator. The crude products were purified by column chromatography (eluting with petroleum ether/DCM/EtOAc) to give bicyclic ketal lactone derivative 3 (or 6a). In some cases the products should be further crystallized from DCM containing traces of hexane to give pure compounds. 7,8-Dimethoxy-1,5,5-trimethyl-4,5-dihydro-1,4-epoxybenzo[d]oxepin-2(1H)-one (3a) Yield: 44.5 mg (80%). 1H NMR (400 MHz, CDCl3): δ = 6.77 (s, 1 H), 6.71 (s, 1 H), 5.58 (s, 1 H), 3.91 (s, 6 H), 1.87 (s, 3 H), 1.42 (s, 3 H), 1.35 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 173.28 (s), 150.35 (s), 147.92 (s), 133.50 (s), 124.59 (s), 109.78 (s), 107.45 (s), 106.58 (s), 76.21 (s), 56.11 (d, J = 2.3 Hz), 38.04 (s), 28.84 (s), 22.82 (s), 16.87 (s). HRMS (ESI): m/z neutral mass calcd for C15H18O5: 278.11542; found: 279.12291 [M + H].
  • 13 CCDC 1956192 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 14 Procedure for the Conversion of 3a into 6a A solution of LiAlH4 (4.6 mg, 0.12 mmol, 1.2 equiv) in anhydrous THF (5 mL) was cooled to –20 °C, and a solution of 3a (27.8 mg, 0.1 mmol) in anhydrous THF was added slowly. The reaction mixture was stirred at –20 °C for 3 h. The mixture was diluted with HCl (6 M, 5 mL) and extracted with ethyl acetate (2 × 50 mL), and the organic layer was separated, washed with saturated sodium bicarbonate (1 × 50 mL) and brine (1 × 50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel with 20% EtOAc/petroleum ether as eluent to furnish 6a (15.8 mg, 47% yield) as a white solid. Yield: 14.2 mg (54%). 1H NMR (400 MHz, CDCl3): δ = 6.77 (s, 1 H), 6.65 (s, 1 H), 5.24 (s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.82 (d, J = 6.2 Hz, 1 H), 3.58 (d, J = 6.2 Hz, 1 H), 1.79 (s, 3 H), 1.31 (s, 3 H), 1.28 (s, 3 H). 13C NMR (101 MHz, CDCl3): δ = 148.71 (s), 146.94 (s), 134.18 (s), 131.47 (s), 109.85 (s), 108.42 (s), 105.97 (s), 79.22 (s), 77.49 (s), 56.06 (d, J = 6.7 Hz), 40.64 (s), 28.70 (s), 24.08 (s), 18.94 (s). HRMS (ESI): m/z neutral mass calcd for C15H20O4: 264.13616; found: 265.14328 [M + H] and 287.12833 [M + Na].