Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

The formal total synthesis of macarpine was accomplished by the construction of a naphthol intermediate in Ishikawa’s synthetic route with two different synthetic routes. The convergent synthetic strategies feature the utilization of Au(I)-catalyzed cycloisomerizations of a 1,5-enyne and alkynyl ketone substrates, which were prepared by Sonogashira coupling reactions.


General information
Unless otherwise stated, the reagents were commercially available and can be used without further purification. THF and Et2O were distilled from sodium under a nitrogen atmosphere. DCM was distilled from calcium hydride (CaH) under a nitrogen atmosphere. TLC analysis of the reaction mixtures was performed on Dynamicadsorbents silica F-254 TLC plates. Flash column chromatography was performed on Zeoprep 60 (200-300 mesh) silica gel. 1 H and 13 C NMR spectra were recorded on a Bruker Avance-III 600 spectrometer with reference to CDCl3 and DMSO-d6. HRMS-ESI were recorded on Bruker micro-TOFQ-Q instrument. IR spectra were recorded on Bruker IFS 55 spectrometer. Melting points were tested on a Thomas Hoover capillary melting point apparatus.

General procedures for the preparation of 3-5, 8-12 and characterization data
In a manner analogous to literature [s1] , a magnetically stirred emulsion of 6bromopiperonal (15.00 g, 65.79 mmol), Pd(Ph3P)2Cl2 (1.39 g, 1.97 mmol), and CuI (1.25 g, 6.58 mmol) in degassed THF (200.0 mL) at 60 °C under an atmosphere of nitrogen was treated with TEA (18.5 mL, 131.58 mmol) and trimethylethynylsilicon (9.69 g, 98.69 mmol). The resulting mixture was stirred until the terminal alkyne was completely consumed. After the reaction is completed, the reaction solution is concentrated and purified by a flash column chromatography on silica gel to afford the product 3 (14.40 g, 58.55 mmol, 89%) as a yellow solid.
To a solution of the crude product obtained above in MeOH (40.0 mL) was added K2CO3 (370 mg, 2.70 mmol) and the resulting mixture was stirred at room temperature for 3 h. After completion of the reaction, it was quenched with saturated aqueous solution of NH4Cl (5.0 mL), extracted with DCM (5.0 mL × 3), and washed with water.
The organic layers were washed with brine and dried over anhydrous Na2SO4. Then, the organic layers were filtered, concentrated under reduced pressure, and purified by flash column chromatography on silica gel to afford the product 5 (487 mg, 2.60 mmol, 96% for 2 steps) as a yellow oily liquid.

1-(6-Ethynylbenzo[d][1,3]dioxol-5-yl)ethan-1-one (5)
Yellow oily liquid (487 mg In a manner analogous to literature [s4,s5] , to a solution of sesamol (1.00 g, 7.24 mmol) and K2CO3 (1.00 g, 7.24 mmol) in dry MeOH (30.0 mL) was added MeI (2.5 mL, 40.10 mmol) at room temperature with stirring under a nitrogen atmosphere. After the addition was completed, the reaction solution was stirred 65 °C overnight. After the reaction was completed, the reaction solution was removed and the resulting residue was diluted with water and extracted with EtOAc (10.0 mL × 3). The combined organic S5 layers were dried over anhydrous Na2SO4 and concentrated.
To a solution of the crude product obtained above in MeCN (20.0 mL) was added NIS (2.00 g, 8.89 mmol) and TFA (0.1 mL, 1.10 mmol). The resulting mixture was stirred at 40 °C for 3 h. After completion of the reaction, it was quenched with saturated aqueous solution of Na2S2O3 (20.0 mL), extracted with EtOAc (10.0 mL × 3), and washed with water. The organic layers were washed with brine and dried over anhydrous Na2SO4. Then, the organic layers were filtered, concentrated under reduced pressure, and purified by a flash column chromatography on silica gel to afford the product 8 (1.35 g, 4.85 mmol, 67% for 2 steps) as a white solid.  [s4,s5] In a manner analogous to the literature [s3] , a magnetically stirred emulsion of 8 (2.00 g, 11.00 mmol), Pd(Ph3P)2Cl2 (39 mg, 0.55 mmol), and CuI (21 mg, 1.10 mmol) in degassed THF (50.0 mL) at room temperature under an atmosphere of nitrogen was treated with TEA (7.7 mL, 55.00 mmol) and 5 (3.10 g, 11.00 mmol). The resulting mixture was stirred for 2 h sequentially. After the consumption of the starting material, the emulsion was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain product 9 (3.50 g, 10.50 mmol, 95%) as a black solid.
The reaction was quenched with a saturated aqueous solution of NH4Cl (30.0 mL) and extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with brine (20.0 mL) and dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel to afford the product 10 (1.10 g, 2.50 mmol, 87%) as a yellow solid.