Total Synthesis of (±)-Aspidospermidine, (±)-Aspidofractinine, (±)-Limaspermidine, and (±)-Vincadifformine via a Cascade and Common Intermediate Strategy

A concise strategy for the total synthesis of several Aspidosperma alkaloids is reported. A Suzuki–Miyaura cross-coupling provides access to a 2-vinyl indole that undergoes a Diels–Alder cascade reaction with butyn-2-one to deliver a pyrroloindoline intermediate. This undergoes cascade amidation, reduction, skeletal rearrangement, and intramolecular Michael addition to provide a common intermediate containing the full framework of the Aspidosperma alkaloids. The utility of this intermediate is shown in the synthesis of four different natural products.

An oven-dried flask with stir bar was charged with NaH (184 mg, 4.61 mmol, 1.2 equiv). The flask was sealed with a septum and N2 line fitted before addition of THF (7.6 mL) via syringe. The mixture was cooled to 0 °C before slow addition of a solution of compound 7 (1 g, 3.84 mmol, 1 equiv) in THF (7.6 mL) via syringe. The resulting mixture was stirred for 30 min at 0 °C before dropwise addition of benzyl bromide (0.68 mL, 5.76 mmol, 1.5 equiv) via syringe. The mixture was stirred for 5 min then allowed to warm to room temperature where it was stirred for 3 h. After the reaction was complete, water (20 mL) was added, and the organics were extracted with EtOAc (3 × 20 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 0-10% EtOAc in petroleum ether 40-60°) to afford the product as pale yellow oil (1.11 g, 83%).

Compound 9
An oven-dried 2-necked flask with stir bar was charged with compound 8 (350 mg, 1 mmol, 1 equiv). The flask was sealed with a septum and fitted with N2 line before charging with THF:CHCl3 (1:1, 10 mL) via syringe. The solution was cooled to -20 °C and stirred for 15 mins. Pyridinium tribromide (recrystallized; 390 mg, 1.54 mmol, 1.22 equiv) was then added portion-wise under N2 flow over 1 h at -20 °C. The reaction mixture was stirred for 20 min at -20 ºC then quenched with sat. aq. Na2SO3 solution (20 mL), and following a colour change to light yellow, sat. aq. NaHCO3 solution (20 mL) was added. The mixture was extracted with CH2Cl2 (3 × 40 mL), and the combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (0-10% EtOAc in petroleum ether) to afford the desired product as a white solid (317 mg, 74%).

Compound 11
An oven-dried 20 mL MW vial (20 mL) with stir bar was charged with compound 10 (470 mg, 1.25 mmol, 1 equiv). The vial was then capped and purged and N2 line fitted before addition of 3-butyn-2-one (488 µL, 6.25 mmol, 5 equiv), 1,4-dioxane (5 mL), and BF3•OEt2 (246 µL, 2 mmol, 1.6 equiv) sequentially via syringe. The reaction was then stirred at room temperature for 16 h. After the reaction was complete, the vial was vented and de-capped. MeOH (10 mL) was added and the mixture was concentrated under reduced pressure. The residue was treated with sat. aq. NaHCO3 solution (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (silica gel, 0-30% EtOAc in CH2Cl2) to afford the desired product as a white solid (200 mg, 47%).
The resulting mixture was cooled to 0 °C. Acryloyl chloride (44.5 µL, 0.53 mmol, 1.3 equiv) was then added dropwise via syringe. Then reaction mixture was stirred and allowed to warm to room temperature, then stirred for 3 h. The reaction mixture was then cooled to 0 °C, before TFA (94 µL, 1.23 mmol, 3 equiv) was added via syringe. After 25 min, under N2 flow, the flask was opened and NaHB(OAc)3 (347 mg, 1.64 mmol, 4 equiv) was added. The flask was sealed and N2 line fitted, and the reaction mixture was allowed to warm to room temperature and stirred stir for 24 h. After the reaction was complete, sat. aq. NaHCO3 solution (20 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (0-30% EtOAc in CH2Cl2) to afford the product as a pale yellow oil (114 mg, 70%).

Compound 13
An oven-dried 20 mL MW vial was charged with compound 10 (752 mg, 2 mmol, 1 equiv). The vial was then capped and purged with N2 line fitted. 1,4-Dioxane (8 mL) was added by syringe before 3-butyn-2-one (0.31 mL, 4 mmol, 2 equiv) and BF3•OEt2 (123 µL, 1 mmol, 0.5 equiv) were added sequentially via syringe. The reaction was then stirred at room temperature for 4 h. After the reaction was complete the reaction mixture was vented and de-capped. The mixture was treated with MeOH (25 mL) and concentrated. The residue was then treated with sat. aq. NaHCO3 solution (30 mL) and the organics were extracted with EtOAc (3 × 30 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% EtOAc in hexane) to afford the desired product as a mixture of rotamers as a white solid (735 mg, 83%).

Compound 14
An oven-dried 5 mL MW vial with stir bar was charged with compound 13 (111 mg, 0.25 mmol, 1 equiv) and NaHB(OAc)3 (66.1 mg, 0.31 mmol, 1.25 equiv). The vial was then sealed and purged with N2 line fitted before addition of CH2Cl2 (5 mL). The mixture was cooled to 0 °C and stirred for 15 min before addition of TFA (76.5 µL, 1 mmol, 4 equiv) via syringe. The reaction was stirred and allowed to reach room temperature and stir for 6 h. After the reaction was complete, the vial was vented and de-capped. The mixture was then quenched with sat. aq. NaHCO3 solution (30 mL) and extracted with CH2Cl2 (3×25 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-40% EtOAc in hexane) to yield the product as pale yellow oil (99.3 mg, 89%) as an inconsequential mixture of diastereomers (0.62:0.38 ratio).

S8
was allowed to warm to room temperature and stirred for a further 1.5 h. After the reaction was complete, the mixture was treated with sat. aq. NaHCO3 solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure to yield the product as a yellow solid (15.3 mg, 98%). Data as reported below.
From compound 14: An oven-dried flask with stir bar was charged with compound 14 (223 mg, 0.5 mmol, 1 equiv). The flask was then sealed and purged with N2 line fitted before addition of TFA (0.96 mL, 12.5 mmol, 25 equiv) via syringe. The reaction mixture was stirred at room temperature for 1.5 h. The vial was vented and decapped before the mixture was concentrated under reduced pressure and azeotroping with PhMe (3 × 20 mL) in the same flask. The flask was sealed and purged with N2 line fitted before dissolving the residue in THF (10 mL). Et3N (0.22 mL. 1.55 mmol, 3.1 equiv) was added and the mixture was cooled to 0 °C and stirred. After 15 min, acryloyl chloride (62.7 µL, 0.75 mmol, 1.5 equiv) was added dropwise via syringe. The reaction was allowed to reach room temperature and was stirred for a further 3 h. After the reaction was complete, sat. aq. NaHCO3 solution (20 mL) was added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was carried forward without further purification.
A stir bar was added to the flask containing the residue and the flask was sealed with a septum and purged with N2 line fitted. The residue was dissolved in THF (5 mL), cooled to 0 °C, and stirred. After 15 min, NaH (200 mg, 5 mmol, 10 equiv) was added portionwise under N2 flow. The flask was sealed and stirred for 10 min before allowing to warm to room temperature and stir for 14 h. After the reaction was complete, the mixture was cooled to 0 °C and quenched with water (30 mL). The mixture was allowed to reach room temperature then extracted with CH2Cl2 (3 × 30 mL). The combined organics were then washed once with brine (30 mL).
The organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-50% MeCN in CH2Cl2) to afford the desired product as a beige solid (86.9 mg, 43%).

Compound 17
An oven-dried round bottomed flask with stir bar and condenser was purged and sealed with N2 line fitted before charging with a solution of compound 16 (290 mg, 0.72 mmol, 1 equiv), Na (2.9 g, 126 mmol, 174 equiv), and hydrazine monohydrate (9 mL, 185 mmol, 256 equiv) in ethylene glycol (72.4 mL). The mixture was heated at 160 °C for 1 h, 190 °C for 2.5 h, and 210 °C for 18 h. The resulting mixture was allowed to cool to room temperature before quenching with water (75 mL) and extracted with EtOAc (5 × 50 mL). The combined organic extracts were washed with brine (5 × 50 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure, to give a pale yellow oil crude residue, which was carried through to the next step without further purification.
An oven-dried flask with stir bar was sealed and purged with N2 line fitted and charged with a solution of the crude residue in THF (29 mL) was added and subsequently cooled to 0 °C. LiAlH4 (578 mg, 14.5 mmol, 20 N Bn H N Me S9 equiv) was then added under N2 flow. The mixture was stirred at room temperature for 30 min then heated to 70 °C for 2 h. After the reaction was complete, the mixture was cooled to 0 °C and diluted with Et2O (30 mL). The mixture was then treated sequentially with water (0.6 mL), 15% aq. NaOH solution (0.6 mL), and water (1.8 mL) with intervals of 5 min of stirring between each addition. The mixture was allowed to warm to room temperature before the organics were separated, dried with MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (0-40% Et2O in petroleum ether) to afford the product as a colourless oil (156 mg, 58%).

Compound 18
An oven-dried flask with stir bar was sealed and purged with N2 line fitted then charged with CH2Cl2 (2.9 mL). The flask was cooled to −78°C before addition of oxalyl chloride (37 µL, 0.43 mmol, 1.5 equiv) and the mixture was stirred for 30 min. DMSO (83 µL, 1.16 mmol, 4 equiv) dissolved in CH2Cl2 (0.3 mL) was then added by syringe and the reaction mixture was stirred for 30 min at −78 °C. A solution of compound 1 (81.9 mg, 0.29 mmol, 1 equiv) in CH2Cl2 (2.6 mL) was added dropwise and the mixture was stirred for 1 h at −78 °C. Et3N (204 µL, 1.45 mmol, 5 equiv) was added dropwise via syringe at −78 °C, before the cooling bath was removed and the reaction mixture was allowed to warm to a room temperature over 1 h. After the reaction was complete, sat. aq. NaHCO3 solution (20 mL) was added and the mixture was extracted with CH2Cl2 (3 × 30 mL). The combined organics were then washed once with brine (20 mL) before being dried with Na2SO4, filtered, and concentrated under reduced pressure, to give a pale brown oil crude residue, which was carried through to the next step without further purification.
An oven-dried 5 mL MW vial with stir bar was sealed and purged with N2 line fitted then charged with a solution of the crude residue in THF (2.9 mL) under N2 atmosphere. The mixture was cooled to −78 °C and stirred for 5 min before dropwise addition of n-butyl lithium (2.3 M in hexane, 0.2 mL, 0.46 mmol, 1.6 equiv). The resulting mixture was stirred for 40 min at −78 °C, before dropwise addition of methyl cyanoformate (37 µL, 0.46, 1.6 equiv). The resulting mixture was stirred for 30 min at −78 °C then allowed to warm to room temperature over 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (0-10% EtOAc in hexane) to afford the product as a colourless oil (14 mg, 14%). Data in agreement with that reported in the literature. 5

Compound 19
An oven-dried flask with stir bar was charged with compound 16 (676 mg, 1.69 mmol, 1 equiv) then sealed with a septum and purged with N2 line fitted. THF (17 mL) was added via syringe and the mixture was subsequently cooled to 0 °C. LiAlH4 (1.35 g, 33.8 mmol, 20 equiv) was then added under N2 flow. The mixture was stirred for 30 min then heated to 70 °C for 2 h. After the reaction was complete, the mixture was cooled to 0 °C and diluted with Et2O (20 mL). Water (1.35 mL), 15% aq. NaOH solution (1.35 mL), and water (4.05 mL) were then added sequentially with intervals of 5 minutes stirring between each addition. The mixture was allowed to warm room temperature and the organics were separated, dried with MgSO4, filtered, and concentrated under reduced pressure to yield the product as a beige foam solid (578 mg, 88%) as an inconsequential inseparable mixture of diastereomers

Compound 20
An oven-dried 25 mL MW vial with stir bar was charged with compound 19 (180 mg, 0.46 mmol, 1 equiv) and Martin Sulfurane (649 mg, 0.93 mmol, 2 equiv). The vial was sealed and purged with N2 line fitted before addition of CHCl3 (9.3 mL) via syringe. The reaction mixture was then stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by column chromatography (silica gel, 0-10% EtOAc in hexane with 1% Et3N additive) to afford the desired product as a pale yellow solid (138 mg, 80%).  Data in agreement with that reported in the literature. 5

Compound 21
An oven-dried 25 mL MW vial with stir bar was sealed and purged with N2 line fitted then charged with compound 20 (151 mg, 0.41 mmol, 1 equiv) as a solution in THF (3.4 mL) via syringe. The mixture was then cooled to 0 °C and stirred for 5 min before addition of 9-BBN in THF (0.5 M, 1.63 mL, 0.82 mmol, 2 equiv) dropwise via syringe. The reaction mixture was stirred and allowed to warm to room temperature then heated to 60 °C for 18 h. The mixture was cooled to 0 °C and stirred for 15 min. H2O2 (aq. 30% w/v, 0.83 mL, 8.15 mmol, 20 equiv) and 2 M NaOH solution (0.82 mL, 1.63 mmol, 4 equiv) were added sequentially via syringe. The reaction was stirred, allowed to reach room temperature, and stirred for 1 h. After the reaction was complete, the mixture was cooled to 0 ºC and stirred before carefully quenching with sat. aq. Na2S2O3 solution and stirring until effervescence ceased. The via was vented and uncapped and the mixture was treated with sat. aq. NH4Cl solution (20 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-30% EtOAc in hexane + 1% Et3N additive) to afford the desired product as a beige solid (115 mg, 73%). purged with N2. EtOH (9.9 mL) was added and the reaction mixture was sparged with H2. The resulting mixture was stirred at room temperature for 26 h under H2 atmosphere. After the reaction was complete, the vial was purged with N2, decapped, and the mixture was filtered through a pad of Celite®. The filtrate was concentrated to a crude residue, which was purified by column chromatography (silica gel, 0-100% EtOAc in hexane + 1% Et3N additive) to afford the product as a white solid (70.2 mg, 79%). Data in agreement with that reported in the literature. 7

Compound 23
An oven-dried MW vial was charged with stir bar, Pearlman's catalyst (20% Pd(OH)2/C; 324 mg, 0.46 mmol, 1.85 equiv), and compound 16 (100 mg, 0.097 mmol, 1 equiv). The vial was then capped and purged. EtOH (8.3 mL) was added and the vial was sparged with H2. The resulting mixture was stirred at room temperature for 26 h under H2 atmosphere. After the reaction was complete, the vial was purged with N2, decapped, and the mixture was filtered through a pad of Celite®. The filtrate was concentrated to a crude residue, which was purified by column chromatography (0-10% MeOH in CH2Cl2) to afford the product as a pale yellow solid (45.9 mg, 59%).

S13
An oven-dried, purged, and capped MW vial equipped with stir bar with N2 line fitted was charged with CH2Cl2 (11.5 mL). The vessel was cooled to -60 °C, before oxalyl chloride (39 µL, 0.46 mmol, 1.2 equiv) was added. A solution of DMSO (58 µL, 0.81 mmol, 2.1 equiv) in CH2Cl2 (3 mL) was added, and the mixture was stirred for 15 min. A solution of compound 23 (120 mg, 0.39 mmol, 1 equiv) in CH2Cl2 (3 mL, 0.018 M) was then added via syringe and the mixture was stirred for 30 min at -60 °C. Et3N (269 µL, 0.34 mmol, 5 equiv) was then added dropwise and the reaction mixture was allowed to warm to room temperature over 45 min. After the reaction was complete, water (20 mL) was added, and the organics were extracted with CH2Cl2 (3 × 25 mL). The combined organics were then washed with brine (20 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure, to give a pale yellow oil, which was carried through to the next step without further purification.
In a round bottom flask, the crude residue was dissolved in ethanol (60 mL, 0.007 M), and conc. HCl (5 N, 6 mL) was added. The reaction mixture was then refluxed for 18 h. The mixture was concentrated under reduced pressure to remove the volatile organics. The mixture was then treated with 5% aq. Na2CO3 solution (100 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (0-10% MeOH in EtOAc) to afford the product as a beige solid (51.1 mg, 43%).

Compound 25
An oven-dried round bottomed flask with stir bar and condenser was purged and sealed with N2 line fitted before charging with a solution of compound 24 (50 mg, 0.162 mmol, 1 equiv), Na (650 mg, 28.2 mmol, 174 equiv), and hydrazine monohydrate (1.95 mL, 40.2 mmol, 248 equiv) in ethylene glycol (16.2 mL). The mixture was heated at 160 °C for 1 h, 190 °C for 2.5 h, and 210 °C for 18 h. The resulting mixture was allowed to cool to room temperature before quenching with water (25 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (5 × 50 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure, to give a pale yellow oil crude residue, which was carried through to the next step without further purification.
An oven-dried flask with stir bar was sealed and purged with N2 line fitted and charged with a solution of the crude residue in THF (6.5 mL) was added and subsequently cooled to 0 °C. LiAlH4 (129 mg, 3.24 mmol, 20 equiv) was then added under N2 flow. The mixture was stirred at room temperature for 30 min then heated to 70 °C for 2 h. After the reaction was complete, the mixture was cooled to 0 °C and diluted with Et2O (20 mL). The mixture was then treated sequentially with water (0.2 mL), 15% aq. NaOH solution (0.2 mL), and water (0.6 mL) with intervals of 5 min of stirring between each addition. The mixture was allowed to warm to room temperature before the organics were separated, dried with MgSO4, filtered, and concentrated under reduced pressure. The organics were separated and dried with MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (0-10% MeOH in CH2Cl2) to afford the product as a pale yellow oil. The product was further purified by acid-base extraction: the material was treated with 2 M HCl (20 mL) and extracted with CH2Cl2 (2 × 20 mL; discarded). The aqueous phase was then basified with 2 M aq. NaOH solution (25 mL) and extracted with CH2Cl2 (2 × 20 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure to give the product as a yellow oil (32.9 mg, 72%). Compound S1 An oven-dried 5 mL MW vial with stir bar was charged N-(2-(1-benzyl-2-vinyl-1H-indol-3-yl)ethyl)acetamide (79.5 mg, 0.25 mmol, 1 equiv). The vial was capped and purged before sequential addition of addition of 3butyn-2-one (98 µL, 1.25 mmol, 5 equiv), 1,4-dioxane (1 mL) and BF3•OEt2 (49 µL, 0.5 mmol, 1.6 equiv) via syringe. The reaction was then stirred at 25 °C for 4 h. After the reaction was complete the reaction mixture was vented and de-capped. The reaction mixture was treated with MeOH (5 mL) and concenyrated under reduced pressure. The residue was treated with sat. aq. NaHCO3 solution (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-20% EtOAc in CH2Cl2) to afford the product as a pale yellow solid (149 mg, 77%). Crystal growth by solvent diffusion using CH2Cl2/pentane.