Asymmetric one-pot transformation of isoflavones to pterocarpans and its application in phytoalexin synthesis

Phytoalexins have attracted much attention due to their health-promoting effects and their vital role in plant health during the last years. Especially the 6a-hydroxypterocarpans glyceollin I and glyceollin II, which may be isolated from stressed soy plants, possess a broad spectrum of bioactivities such as anticancer activity and beneficial contributions against western diseases by anti-oxidative and anti-cholesterolemic effects. Aiming for a catalytic asymmetric access to these natural products, we establish the asymmetric syntheses of the natural isoflavonoids (−)-variabilin, (−)-homopterocarpin, (−)-medicarpin, (−)-3,9-dihydroxypterocarpan, and (−)-vestitol by means of an asymmetric transfer hydrogenation (ATH) reaction. We successfully adapt this pathway to the first catalytic asymmetric total synthesis of (−)-glyceollin I and (−)-glyceollin II. This eight-step synthesis features an efficient one-pot transformation of a 2′-hydroxyl-substituted isoflavone to a virtually enantiopure pterocarpan by means of an ATH and a regioselective benzylic oxidation under aerobic conditions to afford the susceptible 6a-hydroxypterocarpan skeleton.


Synthesis of Iodobenzene 32
Iodophenol 31 2 (1.653 g, 6.61 mmol) was dissolved in DCM (6.6 mL) and N,N-diisopropylethylamine (1.7 mL, 9.92 mmol, 1.5 equiv.) in a 10 mL round-bottomed flask and cooled to 0 °C. Methoxymethyl chloride (0.65 mL, 8.60 mmol, 1.3 equiv.) was added, and the reaction mixture was stirred at room temperature for 15 minutes. Saturated aqueous NH4Cl solution was added. The aqueous layer was extracted three times with DCM, the combined organic layers were dried over MgSO4, and the solvents were removed in vacuo.

Supplementary Note 4 First-Generation Synthesis: Preparation of Isoflavanone 9
Isoflavanone 18 (731.8 mg, 1.74 mmol, 1.0 equiv.) was dissolved in THF (25 mL) and methanol (25 mL) in a 100 mL round-bottomed flask. Hydrochloric acid (8.7 mL, 6 M in water, 52 mmol, 30 equiv.) was added, and the reaction mixture was stirred at 60 °C for 35 min. The reaction mixture was cooled to room temperature, and saturated aqueous NaHCO3 solution was added.
The aqueous layer was extracted three times with EtOAc, the combined organic layers were dried over MgSO4, and the solvents were removed in vacuo.

Supplementary Note 5 First-Generation Synthesis: Preparation of Isoflavan-4-ol 8 from Isoflavanone 9
Preparation of the catalyst solution: [Ru(p-cym)Cl2]2 (22.3 mg, 36.4 µmol) and (R,R)-TsDPEN (27.3 mg, 72.8 µmol) were dissolved in EtOAc (2.2 mL) in a 5 mL round-bottomed flask. Another flask containing triethylamine (1.5 mL) was cooled to 0 °C, and formic acid (0.5 mL) was added. The mixture was stirred vigorously for 5 min at room temperature. An aliquot of this mixture (1.14 mL) was added to the ruthenium catalyst, and the resulting solution was stirred for another 5 min.

Reaction:
In a 5 mL round-bottomed flask isoflavanone 9 (450.9 mg, 1.20 mmol, 1.0 equiv.) was suspended in EtOAc (1.5 mL) at 45 °C, and an aliquot of the catalyst solution (2.73 mL, ca. 5 mol% catalyst) was added. The reaction mixture was stirred at 45 °C to 50 °C for 1.5 h, cooled to room temperature, and saturated aqueous NH4Cl solution was added. The aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, the solvents were removed in vacuo, and the residue was purified by flash chromatography (DCM:EtOAc 10:1 v/v) to afford isoflavanol 8 (403.2 mg, 89 %, >99 % ee) as a white solid. Hz, 1H) ppm; 13

Synthesis of 1 and 2: Preparation of Isoflavone 13 via Suzuki Coupling
Iodochromone 36 was synthesized over three steps from acetophenone 35 in a procedure adapted from Gammill, 11 and the boronic acids 39 and 40 were obtained from the reported 4bromoresorcinol derivates 37 and 38. 12,13 Unfortunately, purification of the products 13 (after acidic work-up) and 41 of the Suzuki coupling proved to be very difficult, and the yields were poor. Therefore, deprotection of 41 was not even attempted.

Preparation of Iodide 36
In a 50 mL round-bottomed flask enamine 43 (2.000 g, 7.32 mmol) was dissolved in chloroform (14.6 mL), and pyridine (0.89 mL, 11.0 mmol, 1.5 equiv.) and iodine (3.714 g, 14.6 mmol, 2.0 equiv.) were added successively. The reaction mixture was stirred for 1 h at room temperature, and then quenched with saturated aqueous sodium thiosulfate solution (23 mL). The mixture was stirred for 5 min and diluted with water. The aqueous layer was extracted three times with DCM, the combined organic layers were dried over MgSO4, and the solvents were removed in vacuo. The residue was purified by flash chromatography (isohexane: