A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

Summary A common approach to the important protein kinase inhibitor (−)-balanol and an azepine-ring-modified balanol derivative has been developed using an efficient fragment coupling protocol which proceeded in good overall yield.

S3 come to room temperature over 2 h and then cooled to 0 °C before being quenched with saturated aqueous NH 4 Cl (5 mL). It was extracted with ethyl acetate (2 × 50 mL) and the combined organic extract was washed successively with water (50 mL) and brine (50 mL). It was then dried (Na 2 SO 4 ), filtered and the filtrate was concentrated in vacuo to leave a crude mass which was purified by chromatography over silica gel using a mixture of petroleum ether/ethyl acetate (85:15) as eluent to provide compound 10 as a colourless viscous liquid (0.6 g, 75%). IR (KBr): 3469, 2928, cm -1 . 1

2-(2,6-Bis(benzyloxy)-4-((tert-butyldiphenylsilyloxy)methyl)benzoyl)-3-(methoxymethoxy)benzaldehyde (12):
p-Toluenesulfonic acid (25 mg) was added to a solution of the benzophenone 11 (0.81 g, 1 mmol) in acetone/water (20 mL, 9:1) and the resulting solution was refluxed gently for 4 h. It was allowed to come to room temperature, concentrated in vacuo and then diluted with ethyl acetate (200 mL). The ethyl acetate extract was washed successively with water (100 mL) and brine (100 mL), and then dried (Na 2 SO 4 ). It was filtered and the filtrate was concentrated in vacuo to leave a crude mass which was purified by chromatography over silica gel using a mixture of petroleum ether/ethyl acetate General procedure of the NaClO 2 -oxidation of an aldehyde to a carboxylic acid: Aq. NaH 2 PO 4 (1.5 mL, 1 M), 1-methylcyclohexene (120 μL, 1 mmol) and NaClO 2 (181 mg, 2 mmol) were sequentially added to a solution of the aldehyde (0.5 mmol) in THF-t-BuOH-water (5 mL, 4:4:1), and the resulting mixture was stirred for 6-8 h at room temperature before being treated with aqueous KHSO 4 (5 mL, 0.5 M). The resulting reaction mixture was concentrated in vacuo and then extracted with ethyl acetate (2 × 50 mL). The combined organic extract was washed successively with water (50 mL), saturated aqueous sodium sulfite (10 mL) and brine (50 mL). It was then dried (Na 2 SO 4 ), filtered and the filtrate was concentrated in vacuo to leave a crude mass which was purified by chromatography over silica gel to produce the corresponding pure carboxylic acid.

(R)-tert-Butyl 4-((allylamino)methyl)-2,2-dimethyloxazolidine-3-carboxylate (18):
A solution of Garner's aldehyde 17 (1.15 g, 5 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature with allyl amine (410 μL, 5.5 mmol) and MgSO 4 (2.65 g, 22 mmol) under nitrogen for S7 12 h. Then it was cooled to 0 °C and NaBH 4 (0.208 g, 5.5 mmol) was added in portions under nitrogen atmosphere. The reaction mixture was allowed to come to room temperature and stirred for 12 h. It was then quenched by adding of 5% NH 4 Cl solution at 0 °C. It was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed successively with water (2 × 50 mL) and brine (50 mL). It was then dried (Na 2 SO 4 ), filtered and the filtrate was concentrated in vacuo to leave a pale yellow liquid which was purified by chromatography over silica gel using a mixture of petroleum ether/ethyl acetate (93:7) as eluent to give the product 18 as a colourless liquid (1.28 g, 94%

(R)-benzyl allyl(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)carbamate (20)
Hydrochloric acid (1.25 mL, 5%) was added dropwise while stirring to an ice-cooled solution of compound 19 (0.5 g, 1.24 mmol) in methanol (10 mL) and stirring was continued for 1 h at 0 °C, and then at room temperature for 5 h. The reaction mixture was quenched with saturated sodium bicarbonate solution and then extracted with ethyl acetate (2 x 25 mL). The combined organic extract was washed successively with water (10 mL), brine (10 mL) and then dried (Na 2 SO 4 ). It was filtered and the filtrate was concentrated under reduced pressure to leave a crude product which on chromatography over silica gel using a mixture of petroleum ether/ethyl acetate  and then with water (20 mL) and brine (20 mL). It was then dried (Na 2 SO 4 ), filtered and the filtrate was concentrated in vacuo to leave a crude product which was used without further purification for the next step. A solution of this crude product in methanol/water (10 mL, 9:1) was stirred with K 2 CO 3 (350 mg, excess) for 4 h. Then the reaction mixture was filtered and concentrated in vacuo, diluted with ethyl acetate (25 mL), washed with water (20 mL) and brine (20 mL), and then dried (Na 2 SO 4 ), filtered and concentrated in vacuo to provide a crude liquid which was purified by column chromatography over silica gel using a mixture of petroleum ether/ethyl acetate (85:15) to produce compound 22 as colourless liquid (140 mg, 72%). S10

(3R,4R)-5-(N-Benzyloxycarbonyl(allyl)amino)-4-(tert-butoxycarbonylamino)pent-1-en-3-yl acetate (24):
Acetic anhydride (71 μL, 0.75 mmol) and DMAP (0.01 g) were added to a stirred solution of the alcohol 22 (195 mg, 0.5 mmol) in CH 2 Cl 2 (5 mL) at room temperature under nitrogen and the reaction mixture was stirred for 12 h before being poured into ice-cooled water (20 mL). The resulting mixture was stirred for 30 min and then extracted with CH 2 Cl 2 (2 × 25 mL). The combined organic extract was washed with H 2 O (2 × 25 mL) followed by brine (25 mL). It was dried over Na 2 SO 4 , filtered and the filtrate was concentrated in vacuo to leave a crude product which was purified by column chromatography over silica gel using a mixture of petroleum ether/ethyl acetate

Balanol (1):
To a solution of protected balanol 31 (20 mg, 0.018 mmol) in formic acid (5 mL) was added palladium black (50 mg) and the reaction mixture was allowed to stir vigorously for 18 h. The reaction mixture was then filtered through a pad of silica gel and the filtrate was concentrate under vacuo to provide a crude mass which on repeated purification by preparative TLC following Nicolaou's protocol provided (−)-balanol (1) as yellowish amorphous powder (4 mg, 41%).