Asymmetric total synthesis of yuzurimine-type Daphniphyllum alkaloid (+)-caldaphnidine J

Ever since Hirata’s report of yuzurimine in 1966, nearly fifty yuzurimine-type alkaloids have been isolated, which formed the largest subfamily of the Daphniphyllum alkaloids. Despite extensive synthetic studies towards this synthetically challenging and biologically intriguing family, no total synthesis of any yuzurimine-type alkaloids has been achieved to date. Here, the first enantioselective total synthesis of (+)-caldaphnidine J, a highly complex yuzurimine-type Daphniphyllum alkaloid, is described. Key transformations of this approach include a highly regioselective Pd-catalyzed hydroformylation, a samarium(II)-mediated pinacol coupling, and a one-pot Swern oxidation/ketene dithioacetal Prins reaction. Our approach paves the way for the synthesis of other yuzurimine-type alkaloids and related natural products.


Supplementary Note 2
Procedure to prepare the precursors of carbocyclization cascade and Nazarov cyclization.

Synthesis of compound 5
In a glovebox, a flask was charged with dry CeCl 3 (7.39 g, 30.0 mmol, 6.0 equiv) and then flushed with argon, and dry THF (75 mL) was added. After being stirred for 2 h at room temperature, the reaction mixture was cooled to 0 °C. Methyl magnesium bromide (30 mL, 30.0 mmol, 1.0 M in THF, 6.0 equiv) was added dropwise to this stirred suspension at 0 °C. The resulting mixture was stirred at the same temperature for 1.5 h providing a yellow-orange cloudy solution of the organocerium reagent, then a solution of ketone 4 1,2 (2.48 g, 5.00 mmol, 1.0 equiv) in THF (10 mL) was added over 20 min. After being stirred for 1.5 h at 0 °C, 2 N HCl (40 mL) was added. THF was removed under reduced pressure, and then the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product (2.62 g) was used directly for the next step without further purification.
To a solution of the aforementioned crude product (2.62 g) in DCM (100 mL) was added Pb(OAc) 4 (3.33 g, 7.50 mmol, 1.5 equiv). After being stirred for 40 min at room temperature, saturated aqueous NaHCO 3 (150 mL) was added. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was filtered through Celite (eluent: EtOAc). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1/4 to 1/3) to give compound 5 (2.32 g, yield: 91%, over 2 steps) as a yellow foam.

Synthesis of compound 6
A solution of methoxymethyl triphenylphosphonium chloride (5.65 g, 16.5 mmol, 4.0 equiv) in dry THF (60 mL) was cooled to −78 °C and KHMDS (31.4 mL, 0.5 M in toluene, 3.8 equiv) was added dropwise. The resulting red suspension was allowed to warm up to 0 °C and stirred for 1 h. A solution of aldehyde 5 (2.10 g, 4.12 mmol, 1.0 equiv) in THF (20 mL) was added via cannula over 10 min at −78 °C. After being stirred for 1.5 h at that temperature, the reaction was warmed up to 0 °C and stirred for 1 h. The reaction mixture was then quenched with saturated aqueous NaHCO 3 (50 mL) and extracted with EtOAc (3 × 80 mL). The combined organics were washed with brine (40 mL), dried over MgSO 4 , and concentrated in vacuo. The resulting residue was used directly for the next step without further purification.

Synthesis of compound S1
To a solution of compound 6 (1.71 g, 3.00 mmol, 1.0 equiv) and PhNTf 2 (1.52 g, 4.50 mmol, 1.5 equiv) in THF (20 ml) was added a solution of 0.5 M KHMDS (12.0 mL, 6.00 mmol, 2.0 equiv) in toluene at −78 °C. After being stirred for 2 h at that temperature, the reaction mixture was quenched with saturated aqueous NH 4 Cl (30 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1/20 to 1/6) to give compound S1 (2.00 g, yield: 95%) as a white foam.

Synthesis of compound 7
A solution of compound S1 (701.8 mg, 1.00 mmol, 1.0 equiv) in pyridine (25 mL) was stirred for 14 h at 70 ℃. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE = 1/5) to give the compound 7 (518.6 mg, yield: 94%) as a white foam.

Synthesis of compound 3
To a solution of Pd(PPh 3 ) 2 Cl 2 (35.0 mg, 0.050 mmol, 0.10 equiv ), CuI (104.7 mg, 0.55 mmol, 1.1 equiv) and vinyl bromide (12.5 mL, 25 equiv, 1 M in THF) in THF (10 mL) was added TEA (0.70 mL, 5.0 mmol, 10 equiv). The color of mixture changed to black from yellow. A solution of compound 7 (276 mg, 0.50 mmol, 1.0 equiv) in THF (6 mL) was added dropwise over 0.5 h and the reaction mixture was stirred for 24 h at the room temperature. The reaction mixture was poured into saturated aqueous NH 4 Cl (100 mL) and ethyl acetate (100 mL), and extracted with EtOAc (3 × 100 mL). The extract was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure.
The residue was purified by flash chromatography (eluent: EtOAc/PE = 1/7) to give the compound 3 (144.4 mg, yield: 50%) as a colorless foam. To a solution of compound 7 (276 mg, 0.50 mmol, 1.0 equiv) in THF (5 mL) at −78 ℃ was added n-BuLi (0.38 mL, 1.6 M in Hexane, 1.1 equiv) dropwise, and the mixture was stirred for 1 h at that temperature. To a solution of p-tolyl disulfide (184.8 mg, 0.75 mmol, 1.5 equiv) at room temperature, iodomethane (0.047 mL, 0.75 mmol, 1.5 equiv) was added, and the mixture was stirred for 1 h. The latter mixture was added dropwise to the former mixture at −78 ℃, and the reaction mixture was stirred for 2.5 h at that temperature. The reaction was quenched with saturated aqueous NH 4 Cl (10 mL), and the organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent:
The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The resulting residue was used directly for the next step without further purification.
To a solution of the aforementioned crude product, PPh 3 (681 mg, 2.60 mmol, 1.3 equiv) and imidazole (177 mg, 2.60 mmol, 1.3 equiv) in THF (20 mL), I 2 (660 mg, 2.60 mmol, 1.3 equiv) was added in one portion at 0 ℃. The ice bath was removed and the brown reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaHCO 3 (50 mL) and saturated aqueous Na 2 S 2 O 3 (20 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (3 × 60 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE, 1/9) to give the corresponding iodoalkane S2 (1.09 g, yield: 88%, over two steps) as a colorless gum. Rf = 0.80 (silica, EtOAc/PE = 1:2);

Synthesis of compound 13
To a cooled (−20 ℃) solution of compound S2 (1.24 g, 2.00 mmol, 1.0 equiv) in THF (55 mL) was added LDA (3.5 mL, 2 M in THF, 3.5 equiv) dropwise over 1 h. The mixture was stirred for another 0.5 h at that temperature and quenched with saturated aqueous NH 4 Cl (25 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine, dried over anhydrous   In a glovebox, a flask was charged with dry CeCl 3 (7.39 g, 30.0 mmol, 6.0 equiv) and then flushed with argon, and dry THF (75 mL) was added. After being stirred for 2 h at room temperature, the reaction mixture was cooled to 0 °C. Allyl magnesium bromide (30.0 mL, 30.0 mmol, 1.0 M in THF, 6.0 equiv) was added dropwise to this stirred suspension at 0 °C. The resulting mixture was stirred at the same temperature for 1.5 h providing a yellow-orange cloudy solution of organocerium reagent, then a solution of ketone 4 1,2 (2.48 g, 5.00 mmol, 1.0 equiv) in THF (10 mL) was added over 20 min. After being stirred for 1.5 h at 0 °C, 2 N HCl (40 mL) was added. THF was removed under reduced pressure, and then the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product (2.56 g) was used directly for the next step without further purification.
A small amount of material was purified by flash chromatography on silica gel (eluent: EtOAc/PE, 3/10) to give compound S3 (single isomer) as a colorless foam.

S3
To a solution of the aforementioned compound (crude, 2.56 g) in DCM (100 mL) was added Pb(OAc) 4 (3.33 g, 7.50 mmol, 1.5 equiv). After being stirred for 30 min at room temperature, saturated aqueous NaHCO 3 (150 mL) was added. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was filtered through Celite (eluent: EtOAc). The organic phase was separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was used directly for the next step without further purification.
To a solution of the aforementioned crude mixture in THF (50 mL) and MeOH (50 mL) was added NaBH 4 (380 mg, 10.0 mmol, 2.0 equiv) in one portion, the resulting mixture was stirred at room temperature for 15 min, and then quenched with 2 N HCl (20 mL) and stirred for 0.5 h. Volatiles were removed under reduced pressure, and the aqueous phase was extracted with EtOAc (4 × 80 mL). The

Synthesis of compound 17
To a mixture of Pd(OAc) 2

Synthesis of compound 20
A solution of compound 19 (1.65 g, 3.00 mmol, 1.0 equiv) in THF (20 mL) was added dropwise to the solution of SmI 2 in THF (180 mL, 0.1 M in THF, 6.0 equiv) over 2.5 h at room temperature. The reaction was stirred for 0.5 h and quenched slowly with saturated aqueous NH 4 Cl (120 mL). Volatiles were removed under reduced pressure, and the aqueous phase was extracted with EtOAc (4 × 80 mL). The

Synthesis of compound S4
To a solution of compound 20 (850 mg, 1.50 mmol, 1.0 equiv) and DMAP (25 mg, 0.15 mmol, 0.10 equiv) in pyridine (50 mL), was added acetic anhydride (1.40 mL, 15.0 mmol, 10 equiv) dropwise and stirred for 14 h at room temperature. MeOH (20 mL) was added and stirred for another 0.5 h. Volatiles were removed under reduced pressure, and the saturated aqueous NaHCO 3 (100 mL) was added. The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was

Synthesis of compound 22
To a suspension of compound 21 (250 mg, 0.490 mmol, 1.0 equiv) and NaHCO 3 (212 mg, 2.00 mmol, 4.0 equiv) in DCM (80 mL) was added Dess-Martin periodinane (3.39 g, 8.00 mmol, 2.0 equiv) in one portion. After being stirred for 1 h, the mixture was cooled to 0 ℃ and quenched with saturated aqueous NaHCO 3 (40 mL) and saturated aqueous Na 2 S 2 O 3 (40 mL). The aqueous phase was extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography

Synthesis of compound 26
To a solution of DMSO (2.13 mL, 30.0 mmol, 60 equiv) in DCM (25 mL), was added TFAA (2.12 mL, 15.0 mmol, 30 equiv) dropwise at -78 °C and stirred for 40 min. A solution of compound 25 (280 mg, 0.500 mmol, 1.0 equiv) in DCM (30 mL) was added dropwise over 15 min at that temperature. After being stirred for another 3 h at -78 °C, TEA (6.25 mL, 45 mmol, 90 equiv) was added dropwise over 30 min and stirred for another 2 h at that temperature. The reaction was quenched with water (30 mL) and extracted with DCM (4 × 20 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.

Synthesis of compound 27
To a solution of compound 26 (152 mg, 0.250 mmol, 1.00 equiv) in MeOH (20 mL), DCM (10 mL) and water (0.5 mL) were sequentially added NaHCO 3 (286 mg, 3.40 mmol, 13.6 equiv) and I 2 (431 mg, 1.70 mmol, 6.80 equiv). The mixture was stirred for 10 min and cooled to 0 ℃. After being quenched with saturated aqueous NaHCO 3 (20 mL) and saturated aqueous Na 2 S 2 O 3 (20 mL), the resulting mixture was filtered and concentrated under reduced pressure. The residue was extracted with DCM (3 × 20 mL) and the combined organic phase was sequentially washed with a saturated aqueous brine, dried over

Synthesis of compound 31
A solution of n Bu 3 SnH (0.055 mL, 0.20 mmol, 2.0 equiv) and AIBN (6.6 mg, 0.040 mmol, 0.40 equiv) in PhMe (2 mL) was added dropwise over 0.5 h to a solution of compound 30 (44.8 mg, 0.10 mmol, 1.0 equiv) in PhMe (5 mL) at 90 °C. After being stirred for another 12 h at 90 ºC, the solution was cooled to room temperature. PhMe was removed under reduced pressure and the residue was dissolved in DCM (5 mL), p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol, 10 equiv) was to the resulting solution at room temperature. After being stirred for 12 h, the reaction mixture was quenched with saturated aqueous NaHCO 3 (15 mL) and 15% aqueous NaOH (1.5 mL). After being stirred for 30 min, the organic phase was separated and the aqueous phase was extracted with DCM (4 × 8 mL). The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: EtOAc/PE, 1/10, then TEA/MeOH/DCM, 1/10/100) to give compound 31 (19.3 mg, yield: 55%) as a colorless oil.

X-Ray Crystallographic Data
The crystal structure and X-ray crystallographic data of compound 22 (CCDC 1986889)   The crystal structure and X-ray crystallographic data of compound 24 (CCDC 1986960)   Supplementary References