Fully Biocatalytic Rearrangement of Furans to Spirolactones

A multienzymatic pathway enables the preparation of optically pure spirolactone building blocks. In a streamlined one-pot reaction cascade, the combination of chloroperoxidase, an oxidase, and an alcohol dehydrogenase renders an efficient reaction cascade for the conversion of hydroxy-functionalized furans to the spirocyclic products. The fully biocatalytic method is successfully employed in the total synthesis of the bioactive natural product (+)-crassalactone D, and as the key module in a chemoenzymatic route yielding lanceolactone A.


General procedures A for preparation of 1a, 1b, 1c and 1d
To the solution of E-3-(2-furyl)acrylic acid (5 g, 36.2 mmol) in methanol (50 mL), was added conc. H2SO4 (0.5 mL), and then the mixture was refluxed. After complete disappearance of the starting material monitored by TLC, the solvent was evaporated under reduced pressure. Water (20 mL) was added and the mixture was extracted with diethyl ether (3 × 15 mL 5mL). The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure, giving 1,4-addition product, which was used in the next step without purification. To a solution of crude methyl 3-methylfuran-2carboxylate in anhydrous THF (10 mL) was added sodium dihydrido-bis(2-methoxyethoxy)aluminate (Red-Al) (1.5 equiv.) at 0 °C under argon, and the reaction mixture was stirred for 1 h. The reaction was then quenched with saturated aqueous NH4Cl solution, extracted with diethyl ether (3 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, pentane/ethyl ether, 3/1) to yield alcohol 1a-1d.

General procedure B for preparation of 1e, 1f and 1g
To a solution of substituted triethyl 2-phosphonoacetate (15.6 mmol, 1.5 equiv.) in THF (20 mL), was added sodium hydride (60% in mineral oil, 15.6 mmol, 1.5 equiv.) slowly at 0 °C for 1h. The reaction was cooled to -78 °C and a solution of aldehyde (1g, 10.4 mmol, 1 equiv.) in THF was added dropwise. The mixture was stirred for another 2h at the same temperature. The reaction was quenched with aqueous saturated NH4Cl solution, extracted with diethyl ether (3 x 15 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, pentane/diethyl ether, 50/1) to give corresponding trans-acrylate.
To a solution of acrylate (500 mg) in methanol (20 mL) was added Palladium on charchoal (10 wt. %, 50 mg) at 0 °C with a balloon of hydrogen, the reaction was stirred for 1.5 h. The reaction was filtered through a pad of celite, then concentrated under reduced pressure to give ethyl 3-(furan-2-yl)propanoate, which was used in the next step without purification. To a solution of ethyl 3-(furan-2-yl)propanoate in anhydrous THF was added Red-Al (1.5 equiv.) at 0 °C under argon, and the reaction mixture was stirred for 1h. The reaction was then quenched with saturated aqueous NH4Cl solution, extracted with diethyl ether (3 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, pentane/ethyl ether, 3/1) to yield racemic 3-(furan-2-yl) propanol as colorless liquid.
According to a literature procedure, 23 to a solution of rac-alcohol (0.3 mmol) and vinyl acetate (0.3 mmol) in dry toluene (4 mL) was added Amano lipase PS (5 mg), the reaction was stirred at 20 °C, and the reaction progress was monitored by HPLC. The reaction mixture was filtered through a pad of Celite, concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, pentane/ethyl acetate, 5/1) to yield 1e, 1f and 1g as colorless liquid
To a solution of rac-1h (0.3 mmol) and vinyl acetate (0.3 mmol) in dry toluene (4 mL) was added Amano lipase PS (5 mg), the reaction was stirred at 20 °C, which was monitored by HPLC. General procedure C for preparation of 1i, 1j and 1k To a solution of furan (3 equiv) in anhydrous THF was added a solution of n-BuLi (2.0 equiv, 2.0 M in hexane). The solution was stirred under argon at -78 °C for 4h. A solution of allyl bromide (1 equiv) in anhydrous THF was added dropwise and further stirring for 10h at the same temperature. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with diethyl ether three times. The combined organic phases dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residual was purified by flash column chromatography (SiO2, n-pentane) to give pure allylfuran.
To a solution of allylfuran (1 equiv) in tert-butanol and Η2Ο (1/1 v/v) was added AD-mix-β (1 equiv) and methanesulfonamide (1 equiv) at 0 °C. The reaction mixture was stirred for 24h at the same temperature until complete consumption of substrate was indicated by TLC. The mixture was stirred for 30 min after addition of solid Na2SO3 (10 equiv), and then extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residual was purified by flash column chromatography (SiO2, heptane/ethyl acetate, 2/1) to give alcohols 1i, 1j, 1k.