Total Syntheses of 11‐Acetoxy‐4‐deoxyasbestinin D, 4‐Deoxyasbestinin C, Asbestinin‐10, ‐20, ‐21 and ‐23

Abstract Six members of the asbestinin family of marine diterpene natural products have been synthesized in an efficient and stereoselective manner from a single oxa‐bridged intermediate. Five of these natural products have not been synthesized previously and the structures of four of them have been confirmed as those proposed originally or following revisions to the original structures. The fifth natural product—asbestinin‐21—has been shown to be a diastereomer of the compound that had been proposed previously.


General Experimental
Reagents and solvents were purchased from commercial suppliers and were used without further purification, unless otherwise stated.
Air and/or moisture sensitive reactions were performed under an atmosphere of argon in flame-dried apparatus. THF, toluene, acetonitrile, dichloromethane and diethyl ether were IR spectra were recorded as thin films employing a Shimadzu FTIR-8400S spectrometer equipped with a Pike Technologies MIRacle ATR accessory; selected frequencies (νmax) are reported. NMR spectra were recorded using dilute solutions in CDCl3 or C6D6 on a Bruker AvanceIII 400 MHz, or Bruker AvanceIII UltraShield 500 MHz spectrometer using the deuterated solvent as the internal deuterium lock. 1  Melting points were recorded using a Barnstead Electrothermal 9100 melting point apparatus.
Where no solvent is indicated, the solid obtained from the described procedure was melted directly without recrystallisation. Optical rotations ([α]D) were determined using a Rudolph Research Analytical Autopol IV or V digital polarimeter. Elemental analyses were performed using an Exeter Analytical Elemental Analyser EA 440. X-ray crystallography was performed at the University of Glasgow by Dr Claire Wilson. 2
The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give the crude aldehyde, which was used in the next step without further purification.
To a stirred solution of aldehyde and potassium carbonate (1.41 g, 10.2 mmol) in anhydrous methanol (100 mL) at room temperature was added Bestmann-Ohira reagent (1.30 mL, 8.66 mmol) dropwise over 5 minutes. The resulting solution was stirred for 16 hours before the reaction was quenched by the addition of a saturated aqueous solution of sodium bicarbonate (40 mL). The resulting mixture was diluted with water (80 mL) and ethyl acetate (200 mL), and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 × 80 mL) and the combined organic extracts were washed with brine (150 mL), dried (MgSO4) and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 100:1) to afford the alkyne 24 (1.29 g, 86% over two steps) as a colourless oil. Rf = 0.83 (petroleum ether-ethyl acetate, 3 317.1898, found 317.1907 (Δ +3.0 ppm). Anal. calcd for C17H30O2Si: C, 69.33%; H, 10.27%.
The NMR ( 1 H and 13 C), IR and mass spectrometry data were consistent with those reported for compound 23 previously. 1

14-one-3-yl]prop-2-en-1-yl acetate (31).
To a stirred solution of diol 30 (820 mg, 2.45 mmol), DMAP (299 mg, 2.45 mmol) and distilled triethylamine (0.68 mL, 4.9 mmol) in anhydrous dichloromethane (98 mL) at 0 °C was added distilled acetic anhydride (13.5 mL of a 0.2 M solution in dichloromethane, 2.70 mmol). The resulting solution was warmed to room temperature and stirred for 45 minutes. The mixture was cooled to 0 °C and the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (75 mL) and the mixture was diluted with diethyl ether (200 mL). The phases were separated and the aqueous phase was extracted with diethyl ether (3 × 40 mL). The organic extracts were combined and washed with brine (75 mL), dried (MgSO4) and concentrated under reduced pressure to give crude acetate S1, which was used in the next step without purification.
To a stirred solution of acetate S1 in anhydrous dichloromethane (38 mL) at room temperature was added pyridine (0.79 mL, 9.8 mmol) and Dess-Martin periodinane (1.87 g, 4.41 mmol) in one portion. The mixture was stirred for 2 hours then diluted with diethyl ether (80 mL). The reaction was quenched by the addition of a saturated aqueous solution of sodium thiosulfate (40 mL). The mixture was stirred for 5 minutes and a saturated aqueous solution of sodium bicarbonate (10 mL) was then added. The resulting mixture was stirred vigorously for 30 minutes. The phases were separated and the aqueous phase was extracted with diethyl ether (3 × 20 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 4:1) to give the ketone 31 (905 mg, 98%) as a colourless oil.     To a solution of ketone 34 (64 mg, 0.20 mmol) in anhydrous DMF (2.1 mL) in a sealed tube was added Bredereck's reagent [tert-butoxy bis(dimethylamino)methane] (0.14 mL, 0.68 mmol) in one portion and the resulting solution was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate (15 mL) and water (5 mL). The phases were separated and the organic phase washed successively with water (3 × 5 mL), a 10 mol% aqueous solution of lithium chloride (5 mL) and brine (5 mL).
The organic phase was then dried (MgSO4) and concentrated under reduced pressure to give a residue that was purified by flash column chromatography on silica gel (petroleum etherethyl acetate, gradient elution 2:1 → 1:5) to give the enaminone 35 as a pale yellow solid. The enaminone 35 was used directly in the next step without further purification.
To a stirred solution of the enaminone 35 in anhydrous dichloromethane (2.6   in one portion. The resulting mixture was heated to 100 °C and stirred at this temperature for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (5 mL) and water (2 mL). The phases were separated and the organic phase was washed successively with water (3 × 2 mL), a 10 mol% aqueous solution of lithium chloride (3 mL) and brine (3 mL 2, 131.6, 128.9, 90.3, 76.6, 76.2, 67.2, 52.9, 45.7, 41.6, 41.4, 39.5, 37.4, 37.0, 35.2, 29.4, 26.3, 23.2, 16.0, 11.3  to stir for a further 1 hour. A solution of iodomethane (0.12 mL, 1.9 mmol) in anhydrous dichloromethane (3.5 mL) was added and the resulting solution was stirred for 1 hour. The mixture was cooled to 0 °C and a saturated aqueous solution of potassium sodium tartrate (5 mL) was added followed by diethyl ether (5 mL). The resulting mixture was warmed to room temperature and stirred vigorously for 1 hour (two clear phases were obtained). The phases were separated and the aqueous phase was extracted with diethyl ether (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure to give crude enone 36, which was used in the next step without purification.
To a stirred solution of Stryker's reagent [(triphenylphosphine)copper hydride hexamer] (0.47 mL of a 0.2 M solution in benzene, 94 μmol) in anhydrous and de-gassed toluene (3.3 mL) at −10 °C was added dropwise a solution of enone 36 in anhydrous and de-gassed toluene (6 mL) over 10 minutes. The resulting solution was stirred for 1 hour and the reaction was then quenched by the addition of water (5 mL). The mixture was warmed to room temperature and diluted with ethyl acetate (5 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) to afford the diastereoisomeric ketones 38a (15 mg, 25% over 3 steps) and 38b (22 mg, 37% over 3 steps) as colourless solids. Spectroscopic data were in accordance with that previously reported for compounds 38a and 38b.

Epimerisation of Ketone 38b.
To a stirred solution of ketone 38b (39 mg, 0.12 mmol) in anhydrous methanol (2.5 mL) at room temperature was added potassium carbonate (20 mg, 0.14 mmol) and the resulting solution was stirred for 16 hours. The mixture was diluted with a saturated aqueous solution of ammonium chloride (5 mL) and ethyl acetate (5 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) to afford the diastereomeric ketones 38a (15.9 mg, 41%) and 38b (23 mg, 59%) as colourless solids.

Epimerisation of Ketone 38a.
To a stirred solution of ketone 38b (12.6 mg, 39.6 μmol) in anhydrous methanol (0.8 mL) at room temperature was added potassium carbonate (6.6 mg, 48 μmol) and the resulting solution was stirred for 16 hours. The mixture was diluted with a saturated aqueous solution of ammonium chloride (3 mL) and ethyl acetate (5 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether-ethyl acetate, 10:1) to afford the diastereomeric ketones 38a (4.5 mg, 36%) and 38b (6.2 mg, 49%) as colourless solids.

Method A: Silylation and ring opening of epoxide 40a
To a stirred solution of epoxide 40a (18 mg, 0.048 mmol) in anhydrous dichloromethane (1.0 mL) at 0 °C was added 2,6-lutidine (28 μl, 0.24 mmol) followed by tert-butyldimethylsilyl trifluoromethanesulfonate (0.16 mL of a 0.5 M solution in THF, 0.080 mmol). The mixture was stirred for 3 hours and then the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (3 mL). The mixture was diluted with ethyl acetate (5 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 × 3 mL) and the combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting crude TBS-protected allylic alcohol was used in the subsequent step without purification.
To a stirred solution of TBS-protected allylic alcohol in THF (1.0 mL) at room temperature was added tetrabutylammonium fluoride (0.19 mL of a 1.0 M solution in THF, 0.19 mmol) in one portion. The mixture was stirred for 16 hours and then diluted with diethyl ether (5 mL) and water (3 mL). The phases were separated and the aqueous phase extracted with diethyl ether (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and 22 concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane-ethyl acetate, gradient elution 2:1 → 1:1) to afford asbestinin-20 (6) (7.0 mg, 39%) as a colourless solid.
The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and 23 concentrated under reduced pressure to give crude TBS protected allylic alcohol, which was used in the next step without purification.
The reaction was quenched by the addition of a saturated aqueous solution of sodium thiosulfate (2 mL) and the mixture was stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (0.5 mL) was then added and the resulting mixture was stirred vigorously for 30 minutes. The phases were separated and the aqueous phase was extracted with diethyl ether (3 × 1 mL). The combined organic extracts were washed with brine (3 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (pentane-ethyl acetate, 1:2) to give 7-epi-asbestinin-21 (16) (9.1 mg, 87%) as a colourless oil.
The reaction was quenched by the addition of a saturated aqueous solution of sodium metabisulfite (3 mL) and the resulting mixture was stirred for 30 minutes. The mixture was diluted with ethyl acetate (5 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3 × 3 mL) and the combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (pentane-ethyl acetate, gradient elution 1:2 → 1:5) to afford the diols 41a and 41b (>12:1, 4.6 mg, 23%) as a colourless solid and 7-epi-asbestinin-21 (16) (9.1 mg, 46%) as a colourless oil.

29
To a stirred solution of 11-acetoxy-4-deoxyasbestinin D (1) (26.0 mg, 72 μmol) in anhydrous THF (1.4 mL) at 0 °C was added BH3•THF (0.2 mL of a 1.0 M solution in THF, 0.2 mmol). The resulting mixture was stirred for 2.5 hours and then the reaction was quenched by the addition of water (2 mL) and sodium perborate tetrahydrate (84 mg, 0.55 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. The mixture was diluted with diethyl ether (5 mL) and the phases were separated. The aqueous phase was extracted with diethyl ether (3 × 2 mL) and the combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting crude mixture of alcohols was used in the subsequent reaction without purification.
To a stirred solution of alcohols in anhydrous dichloromethane (1.4 mL) at room temperature was added pyridine (0.30 mL, 0.37 mmol) and Dess-Martin periodinane (73 mg, 0.17 mmol) in one portion. The resulting mixture was stirred for 2 hours and then diluted with diethyl ether (5 mL). The reaction was quenched by the addition of a saturated aqueous solution of sodium thiosulfate (2 mL) and the mixture was stirred for 5 minutes. A saturated aqueous solution of sodium bicarbonate (0.5 mL) was added and the resulting mixture was stirred vigorously for 30 minutes. The phases were separated and the aqueous phase was extracted with diethyl ether (3 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (pentane-ethyl acetate, gradient elution 10:1 → 2:1) to deliver asbestinin-23 (20) (5.3 mg, 20%) and 7-epi-asbestinin-23 (43) (13.4 mg, 49%) as colourless