Selective syntheses of leuconolam, leuconoxine, and mersicarpine alkaloids from a common intermediate through regiocontrolled cyclizations by Staudinger reactions

Selective syntheses of alkaloids bearing distinct core structures were enabled by chemically programmed polycyclizations using water as a switch.

1 H NMR and 13 C NMR spectra were recorded on a Bruker AVANCE AV400 (400MHz and 100MHz). Signal positions were recorded in ppm with the abbreviations s, d, t, m, and bs denoting singlet, doublet, triplet, multiplet, and broad singlet respectively. All NMR chemical shifts were referenced to residual solvent peaks or to Si(CH 3 ) 4 as an internal standard, spectra recorded in CDCl 3 were referenced to residual CHCl 3 at 7.26 ppm for 1 H NMR or 77.0 ppm for 13 C NMR. All coupling constants J are quoted in Hz. FTIR spectra were obtained with a Bruker Tensor 27 instrument. All IR samples were prepared as thin film and reported in wave numbers (cm -1 ). High resolution mass spectra (HRMS) were obtained on an IonSpec QFT mass spectrometer with ESI ionization.

Preparation of compound 14
To a solution of compound 13 (21 mg, 0.1 mmol, 1 equiv) in CH 2 Cl 2 (2 mL) was added DIBAL-H (1.0 M in toluene, 0.15 mmol, 1.2 equiv) at -78 °C slowly. After stirred for 30 min at the same temperature, the mixture was quenched with MeOH (2 mL) carefully. Anhydrous K 2 CO 3 (27.2 mg, 0.2 mmol, 2 equiv) and dimethyl-1-diazo-2-oxopropylphosphonate (28.8 mg, 1.5 mmol, 1.5 equiv) was added. The mixture was stirred at room temperture for 8 h. The reaction mixture was diluted with Et 2 O (15 mL), washed with water (3×5 mL), dried over anhydrous Na 2 SO 4 , and filtered. Solvent was removed under reduced pressure to give a light yellow oil. The crude product was purified by column chromatography

Preparation of compound 15
To a solution of compound 14 (209 mg, 1.0 mmol, 1 equiv) in acetone (10 mL) was added a solution of CrO 3 in H 2 SO 4 (8 N, about 2 mL) at 0 °C dropwise until the solution remained orange. The mixture was stirred for 10 min before water (20 mL) was added. The reaction mixture was extracted with Et 2 O (5×5 mL), dried over anhydrous Na 2 SO 4 , and filtered. Solvent was removed under reduced pressure to give a brown oil. The crude product was diluted with MeOH (10 mL) at 0 °C and AcCl (0.2 mL) was added. After stirred for 2 h, the mixture was concentrated and purified by column chromatography To a stirred mixture of Pd(PPh 3 ) 2 Cl 2 (90 mg, 0.13 mmol, 5 mol%), and CuI (34 mg, 0.18 mmol, 7 mol%) was added a solution of compound S3 (610 mg, 2.57 mmol, 1 equiv) and S4 (1.64 g, 5.15 mmol, 2.0 equiv) in a mixture of NEt 3 (6 mL) and THF (6 mL) at -78 °C under Argon. The reaction mixture was then degassed by freeze-thaw cycles before it was stirred at room temperature for 12 h. The reaction mixture was filtered through a pad of Celite. Solvents were removed under reduced pressure and the crude product was purified by column chromatography

Preparation of compound 16
To a solution of compound 15 (730 mg, 1.36 mmol, 1 equiv) in CCl 4 (6 mL) and MeCN (6 mL) was added NaIO 4 (732 mg, 3.40 mmol, 2.5 equiv) in H 2 O (9 mL). The reaction mixture was stirred vigorously while RuO 2 •H 2 O (9.0 mg, 0.067 mmol, 5 mol%) was added. The reaction mixture was stirred vigorously in air for 2 h before filtered through a pad of silica gel with CH 2 Cl 2 as the eluent. The filtrate was washed with an aqueous solution of NaOH (1.0 N, 2×5 mL) and dried over anhydrous Na 2 SO 4 , and filtered. Solvent was removed under reduced pressure to give a dark color oil. The crude product was purified by column chromatography

Preparation of compound 17
To a solution of compound 16 (35 mg, 0.076 mmol, 1 equiv) and 2,6-lutidine (163 mg, 1.52 mmol, 20 equiv) in CH 2 Cl 2 (4 mL) was added TMSOTf (169 mg, 0.76 mmol, 10 equiv) was added dropwise at 0 °C . The reaction mixture was stirred for 1 h and then diluted with CH 2 Cl 2 (10 mL) at 0 °C , washed with a cold aqueous solution of HCl (1%, 4×5 mL) quickly and dried over anhydrous MgSO 4 , and filtered. Solvent was removed under reduced pressure to give a brown oil. The crude product was purified by column chromatography

Preparation of compound 11
To a solution of compound 18 (100 mg, 0.32 mmol, 1 equiv) in toluene (5 mL) was added NaH (washed with hexane, 12 mg, 0.50 mmol, 1.5 equiv) in one portion. The suspension was stirred at 50 °C for 12 h before the reaction was quenched with a saturated aqueous solution of NH 4 Cl. The mixture was extracted with EtOAc (3×5 mL). The combined solution was dried over anhydrous MgSO 4 , and filtered. Solvent was removed under reduced pressure. The crude product was purified by column chromatography

Preparation of compound 19
To compound 11 (80 mg, 0.28 mmol, 1 equiv) was added Ac 2 O (5 mL). The solution was stirred at room temperature for 12 h before concentrated under reduced pressure. The residue was purified by column chromatography

Synthesis of leuconodine B (3)
To a solution of compound 19 (10 mg, 0.031 mmol, 1 equiv) in THF (3 mL) was added LDA (2.0 M in THF，30.0 L, 0.06 mmol, 2 equiv) at -78 °C. The reaction mixture was stirred for 2 h before it was quenched by dropwise addition of a saturated aqueous solution of NH 4 Cl. The mixture was warmed to room temperature, diluted with water (5 mL), extracted with EtOAc (3×5 mL). The combined solution was dried over anhydrous MgSO 4 , and filtered. Solvent was removed under reduced pressure. The crude product was purified by column chromatography (4:1 petroleum ether:ethyl acetate) to give leuconodine B (3) (7.2 mg, 0.022 mmol, 72%) as a white powder.

Preparation of compound 20
To leuconodine B (3) (2 mg, 6.1 mol, 1 equiv) was added SOCl 2 (1.5 mL) at room temperature. The reaction mixture was stirred for 1 h before SOCl 2 was removed under reduced pressure. The residue was purified by column chromatography

Synthesis of leuconolam (5)
To a solution of compound 20 (12 mg, 0.035 mmol, 1 equiv) in THF (1.5 mL) was added DBU (27 mg, 0.175 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 8 h. H 2 SO 4 (3N, 2 mL) was added to the mixture, then the mixture was heated to 50 °C . After stirring for 1 h, the solution was extracted with EtOAc (3×2 mL). The combined solution was dried over anhydrous MgSO 4 , and filtered. Solvent was removed under reduced pressure. The crude product was purified by column chromatography (1:1 petroleum ether:ethyl acetate) to give leuconolam (5)

Synthesis of melodinine E (4)
To a solution of compound 20 (12 mg, 0.035 mmol, 1 equiv)in THF (1.5 mL) was added DBU (27 mg, 0.175 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 8 h. Water (2 mL) was added to the mixture, and the mixture was extracted with EtOAc (3×2 mL). The combined solution was dried over anhydrous MgSO 4 , and filtered. Solvent was removed under reduced pressure. The crude product was purified by column chromatography (4:1 petroleum ether:ethyl acetate) to give melodinine E (4) (9.

Synthesis of leuconoxine (2)
To a solution of melodinine E (4) (2.0 mg, mol) in EtOAc (5 mL) was added Pd/C S-11 (0.2 mg, 10% w/w). The reaction mixture was purged with H 2 and stirred under a pressure of H 2 (4 atm) at room temperature for 8 h. The reaction mixture was filtered through a pad of Celite, and washed with EtOAc (3×5 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (4:1 petroleum ether:ethyl acetate) to give leuconoxine (2) (2.0 mg, 6.5 mol, 99%) as a white powder. Data for leuconoxine (2)

Preparation of (-)-12
To a solution of 24 (143 mg, 0.498 mmol) in ethanol (10 mL) was added NaBH 4 (188 mg, 4.98 mmol) portionwise at 0 °C. After the starting material was shown to be consumed by TLC analysis, 2 M aqueous NaOH (0.30 mL) was added to the reaction mixtureat 0 °C. The resulting mixture was slowly warmed up to room temperature and stirred overnight. 1M aqueous HCl, saturated Rochelle's salt aqueous solution and CH 2 Cl 2 were added to the reaction mixture. The mixture was stirred for 2 h and the phases were separated. The aqueous phase was extracted with CH 2 Cl 2 twice. The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude product was used for the next reaction without further purification.