Efficient syntheses of (–)-crinine and (–)-aspidospermidine, and the formal synthesis of (–)-minfiensine by enantioselective intramolecular dearomative cyclization† †Electronic supplementary information (ESI) available. CCDC 1444649 and 1537084. For ESI and crystallographic data in CIF or other elec

Palladium-catalyzed enantioselective dearomative cyclization has enabled the concise and enantioselective total syntheses of (–)-crinine and (–)-aspidospermidine, as well as a formal total synthesis of (–)-minfiensine.


Preparation of phenol 12
To a flame-dried Schlenk flask equipped with a magnetic stirring bar was added aniline 11 (30.0 g, 50 mmol) and THF (300 mL). LiHMDS (75 mL, 75 mmol, 1.5 equiv, 1.0 M in n-hexane) was added dropwise over 30 min at -10 o C and the resulting mixture was stirred at 0 o C for 2 h. ClP(NMe2)2 (11.0 mL, 75 mmol, 1.5 equiv) was added dropwise and the resulting mixture was allowed to warm to rt and stirred overnight.
To the mixture at 0 o C was added 30% H2O2 (20 mL) and the resulting mixture was further stirred at the same temperature for 30 min. A saturated NaHSO3 solution (100 mL) was added carefully to quench the excess H2O2. The organic layer was separated and the aqueous layer was extracted with EtOAc (100   mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford light yellow oil, which was used for the next operation without further purification.

Preparation of diol 14
To a stirred solution of compound 13 (  To a stirred solution of the above product (6.0 g, 11.2 mmol) in MeOH (110 mL) was added CeCl3•7H2O (8.3 g, 22.4 mmol) at 0 o C. After 10 min, NaBH4 (560 mg, 14.6 mmol) was added in small portions and the resulting mixture was stirred at 0 o C for 30 min. The reaction was quenched by addition of acetone (50 mL) and the resulting mixture was stirred at rt for additional 15 min, and then poured into H2O (100 mL) and stirred for 30 min. The mixture was concentrated to remove most of organic solvent and the residue was further treated with DCM (100 mL). The aqueous layer was extracted with DCM (50 mL×4). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated to afford a light yellow oil, which was used for the next operation without further purification.
To the aforementioned yellow oil in THF (50 mL

Preparation of Compound 15
To a stirred solution of diol 14 (3.2 g, 7.6 mmol) in DCM (50 mL) was added TEA (5.5 mL, 38 mmol) and triphosgene (3.4 g, 11.4 mmol) at 0 o C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h, then quenched by addition of H2O (25 mL). The organic phase was separated and the aqueous layer was extracted with DCM (100 mL×4

Preparation of (-)-Crinine
To a  THF/AcOH (10/1, v/v, 20 mL) was added via syringe and the resulting mixture was stirred at rt for 1 h.
The reaction mixture was filtered over a pad of Celite and the filtrate was concentrated. The residue was dissolved with DCM (100 mL), washed with saturated NaHCO3 solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil, which was used directly for next operation without further purification.
To a stirred solution of the aforementioned oil in MeOH (20 mL) was added K2CO3 (

Synthesis of amabiline (18)
To a solution of compound 15 (66 mg, 0.228 mmol, 1 equiv) in THF (2 mL) at 0 o C was added dropwise a solution of LiBEt3H in THF (0.456 mmol, 1.0 M, 2 equiv) over 2 minutes. The desired mixture was stirred at 40 o C for 8 h. After cooled to rt, the reaction was quenched by addition of 1 N NaOH (2 mL).

Model reactions using diarylamine substrates
To demonstrate whether an asymmetric dearomative cyclization could be applied to the enantioselective synthesis of aspidospermidine, model reactions were conducted initially to investigate the influence of N-R protecting groups on enantioselective dearomative cyclization for the synthesis of chiral carbazolone products. Bromo aniline substrates 19a and 19b were prepared and subjected to dearomative cyclization conditions employed in crinine synthesis with a Pd-(S)-AntPhos catalyst. We were pleased to find that substrate 19b led to the formation of the desired chiral carbazolone 20b in 71% yield and 89% ee. The  2, 173.2, 145.1, 144.0, 133.2, 128.8, 128.7, 123.2, 120.9, 115.5, 106.7, 50.7, 37.9, 36.7, 36
The organic layer was separated and the aqueous layer was extracted with DCM (30 mL3), the combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure.
To the above residue (3.0 g, 10.1 mmol, 1 equiv) in dry DMF (20 mL) was added NaH (811 mg, 20.2 mmol, 2 equiv, 60 wt% in mineral oil) at 0 ℃. The desired mixture was stirred at 40 ℃ for 40 min, and then BnBr (3.4 g, 20.2 mmol, 2 equiv) was added at 0 ℃. The mixture was stirred at rt for 4 h and the reaction was quenched by addition of saturated NH4Cl (20 mL) and heaxane/EtOAc (100 mL, 1/1). The organic layer was separated and the aqueous layer was extracted with hexane/EtOAc (1/1) (20 mL3), the combined organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (Eluents: Hexane/ EtOAc = 10:1) to give the title compound 20 (6.6 g, 67%) as an oil
The mixture was filtered through a pad of Celite and the catalyst was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure to afford the desired compound 21 (

S36
To a solution of compound 24 (280 mg, 0.509 mmol, 1 equiv) in DCM (12 mL) at 0℃ was added TMSOTf (564 mg, 2.54 mmol, 5 equiv) and the resulting mixture was stirred at 0 ℃ for 5 min. The reaction was quenched by adding saturated NaHCO3 (20 mL) until PH > 7. The organic layer was separated and the aqueous layer was extracted with DCM (310 mL). The combined organic layer was washed with saturated NH4Cl (aq), dried over sodium sulfate, concentrated and the residue was purified by

Preparation of compound 28
A mixture of 27 (42 mg, 0.087 mmol, 1 equiv), PdCl2 (4.6 mg, 0.026 mol, 0.3 equiv) and MeOH (4 mL) was stirred at 30 ℃ under 1 atm hydrogen atmosphere for 12 h. The mixture was filtrated through a pad of S39 Celite. The filtrate was concentrated and the residue was directly used for next step without further purification.