First syntheses of the biologically active fungal metabolites pestalotiopsones A, B, C and F

Abstract

A synthetic approach accessing the pestalotiopsones, fungal chromones possessing a rare skeletal subtype, is reported for the first time. The synthesis of pestalotiopsone A (1) has been achieved in 7 linear steps (28%), from commercially available 3,5-dimethoxybenzoic acid and subsequently the first syntheses of pestalotiopsone B (2), C (3) and F (4) were performed utilising this chemistry. The key steps include a newly described homologation of a substituted benzoic acid to afford phenylacetate derivatives utilising Birch reductive alkylation conditions, a microwave mediated chromanone formation proceeding through an oxa-Michael cyclisation, and an IBX induced dehydrogenation to the desired chromone skeleton. The synthetic natural products were completely characterised for the first time, confirming their structures and their biological activities evaluated against a panel of bacterial pathogens.

Syntheses of the Fungal Metabolites Boletopsins 7, 11, and 12 from the Papua New Guinea Medicinal Mushroom Boletopsis sp.

“…Purification was achieved via flash column chromatography on silica using 50% EtOAc in petroleum ether as eluent (R f = 0.4), yielding a white amorphous solid (40%, 78.0 mg, 0.160 mmol). 1 [1,3]dioxol-5-yl Formate (5). 6 (78.0 mg, 0.160 mmol) was added to a solution of potassium fluoride (46 mg, 0.800 mmol) and m-CPBA (50%, 55 mg, 0.160 mmol) in CH 2 Cl 2 (20 mL) at 0°C.…”

“…Purification was achieved by trituration from 50% EtOAc in petroleum ether, providing the title compound as an amorphous white solid (86%, 2.31 g, 10.7 mmol). 1 [1,3]dioxole-5-carbaldehyde (13). Sesamol (1.00 g, 7.25 mmol) was dissolved in CH 2 Cl 2 (20 mL), tin(IV) chloride (1.02 mL, 2.27 g, 8.70 mmol) was added, and the solution was cooled to 0°C.…”

“…. 1 4,benzo[d] [1,3]dioxole-5-carbaldehyde (8). Sodium hydride (60% oil dispersion, 0.25 g, 6.20 mmol) was washed with petroleum spirits and then added to a solution of 8 (1.00 g, 3.10 mmol) in DMF (10 mL) at 0°C, and the solution was stirred for 30 min.…”

“…Purification was achieved via flash column chromatography on silica using 25% EtOAc in petroleum ether as eluent (R f = 0.2), yielding a white amorphous solid (48%, 190 mg, 0.413 mmol). 1 [1,3]dioxole-5-carbaldehyde (6). A solution of 15 (190 mg, 0.413 mmol), 9 (69 mg, 0.454 mmol), cesium carbonate (269 mg, 826 mmol), water (0.20 mL), and toluene (10 mL) was degassed by a freeze/thaw process three times and placed under an atmosphere of argon.…”

“…Purification was performed by flash column chromatography on silica using 50% EtOAc in petroleum ether as eluent (R f = 0.4), yielding the title compound as a colorless amorphous solid (49%, 40.0 mg, 0.0796 mmol). 1 4, 118.2, 113.7 (3″,5″-C), 112.4, 109.9, 101.7 (2-C) 8,benzo [b] [1,3]dioxolo [4,5-e]benzofuran (4). A solution of 5 (75 mg, 0.149 mmol) and copper(I) oxide (108 mg, 0.750 mmol) in anhydrous pyridine (5 mL) was degassed via a freeze/thaw process three times.…”