Overview of enterolactone biological properties and total synthesis

Abstract

Dedicated to Prof. Gordon Gribble on the occasion of his retirement and for his outstanding contributions to science and mentoring of students.Received 12-23-2017 Accepted 02-17-2018 Published on line 03-04-2018 AbstractLignans are a class of compounds found in plants, especially fiber-rich foods such as flax seeds, whole grains, berries and vegetables. A diet rich in lignans is believed to be protective against cancer, inflammation, viral infection, stroke, and cardiovascular diseases. Enterolactone, a mammalian lignan, has been investigated extensively due to its potential therapeutic properties. A variety of approaches to synthesize enterolactone have been reported. This account summarizes some of the biological studies and reported syntheses of enterolactone found in literature.

Using α- and β-Epimerizations of cis-2,3-Bis(hydroxymethyl)-γ-butyrolactone for the Synthesis of Both Enantiomers of Enterolactone

“…1 H NMR spectra were recorded on JEOL JNM-ECA600 NMR or Bruker Avance III 700 NMR spectrometer. 13 ESI mass spectra were recorded on a THERMO LTQ Orbitrap XL spectrometer. CSI mass spectra were recorded on a Bruker micrOTOF II spectrometer with cryospray unit.…”

“…After being stirred at 30 °C for 15 min, solvent was removed by evaporation under reduce pressure. The crude product was purified by C-2 silica chromatography (ether/hexane = 1/2) to give the desired product (25.4 mg, 92%) as a colorless oil: 1 H NMR (600 MHz, CDCl 3 ) δ 4.48 (dd, J = 8.9, 7.6 Hz, 1H), 3.96 (t, J = 8.9 Hz, 1H), 3.52 (dd, J = 10.7, 5.2 Hz, 1H), 3.47−3.43 (m, 2H), 3.31 (dd, J = 11.0, 6.9 Hz, 1H), 2.75−2.66 (m, 2H); 13 (−)-Enterolactone (3). A catalytic amount of iodine (6.6 mg, 0.026 mmol) was added to a suspension of activated zinc dust (16.9 mg, 0.259 mmol) in DMF (0.1 mL) in a Schlenk tube.…”

“…To a solution of cis-8 (30 mg, 0.078 mmol) in 1,2dichloroethene (0.9 mL) was added DBU (12 mg, 0.078 mmol) and stirred at 65 °C for 12 h. Then the solvent was evaporated under reduced pressure. The crude mixture (trans-8/cis-8 = 10/1) was purified by HPLC to give desired product (26.8 mg, 89%) as a colorless oil: 1 H NMR (700 MHz, CDCl 3 ) δ 7.21 (dd, J = 9.0, 2.4 Hz, 4H), 6.87 (t, J = 8.5, 2.3 Hz, 4H), 4.49−4.34 (m, 5H), 4.07 (dd, J = 8.8, 7.3 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.75 (dd, J = 9.5, 4.9 Hz, 1H), 3.67 (dd, J = 9.4, 3.5 Hz, 1H), 3.53 (dd, J = 9.5, 4.9 Hz, 1H), 3.45 (dd, J = 9.4, 6.6 Hz, 1H), 2.87−2.82 (m, 1H), 2.65−2.63 (m, 1H); 13 (2R,3R)-2,3-Bis(hydroxymethyl)-γ-butyrolactone (ent-2). To a solution of trans-8 (19.4 mg, 0.05 mmol) in 2,2,2-trifluoroethanol (1 mL) and CHCl 3 (0.25 mL) was added 5% Pd/C powder (10.7 mg, refer to 10 mol % Pd).…”

“…The suspension was stirred under H 2 (0.65 MPa) at 15 °C for 8 h. Then the suspension was filtered with a membrane filter and concentrated under reduced pressure at 40 °C. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate = 2/1, then 0/1) to give the desired product (7.4 mg, >99%) as a colorless oil: 1 H NMR (600 MHz, CD 3 OD) δ 4.41 (t, J = 8.6 Hz, 1H), 4.09 (t, J = 8.2 Hz, 1H), 3.89 (dd, J = 11.0, 4.5 Hz, 1H), 3.79 (dd, J = 11.0, 3.4 Hz, 1H), 3.69 (dd, J = 11.0, 5.5 Hz, 1H), 3.64 (dd, J = 11.0, 6.2 Hz, 1H), 2.80−2.74 (m, 1H), 2.60− 2.57 (m, 1H); 13 The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c02801.…”

“…12 Based on these biological activities, many scientists are actively studying the asymmetric synthesis of enterolactones. 13 Sibi's group reported the asymmetric synthesis of enterolactones in high total yields using oxazolidinone as a chiral auxiliary group. 14 Doyle's group reported a rhodium-catalyzed enantioselective C−H insertion reaction for the synthesis of enterolactones, 15 while Yan and Spilling reported a Ti-catalyzed enantioselective hydrophosphonylation as the key reaction for the synthesis of enterolactones.…”