Enantioselective Total Synthesis of (−)‐Limaspermidine and (−)‐Kopsinine by a Nitroaryl Transfer Cascade Strategy

Abstract We report an intramolecular conjugate addition/Truce‐Smiles/E1cb cascade of 2‐nitrobenzenesulfonamide‐functionalized cyclohexenones as a new entry to the core scaffold of monoterpene indole alkaloids. The method was applied to the asymmetric total synthesis of (−)‐limaspermidine, (−)‐kopsinilam, and (−)‐kopsinine, as well as the framework of the kopsifoline alkaloids, thus highlighting its complementarity to existing approaches involving the use of indole‐based starting materials or the interrupted Fischer indole synthesis. Furthermore, we show that the cascade tolerates various substituents on the nitroarene, opening the way to other natural products as well as non‐natural analogues.

[c] Determined by chiral SFC-MS (Method A, see general information).
[d] Did not show conversion after 7 days.
[e] Performed at 16 g scale, with lower catalyst loading [1 mol% Pd2(dba)3, 4 mol% ligand], leading to an extended reaction time of 6 days to reach full completion.

Allyl 4-isobutoxy-2-oxocyclohex-3-ene-1-carboxylate (S2)
A flame-dried flask was charged with diisopropyl amine (34.4 mL, 244 mmol, 2.05 eq.) and toluene (500 mL) and was cooled to -78 °C, after which a solution of n-buthyllithium (11 M in hexanes, 21.8 mL, 240 mmol, 2.0 eq.) was added dropwise. The mixture was stirred at -78 °C for 20 minutes and a solution of ketone S1 (20.0 g, 119 mmol, 1 eq.) in toluene (150 mL) was added dropwise, resulting in an orange solution that was stirred for 1.5 h at -78 °C. Allyl chloroformate (13.9 mL, 131 mmol, 1.1 eq.) was added dropwise at -78 °C and the reaction was kept at this temperature for 15 minutes, after which it was allowed to warm to room temperature. After 18 h, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulphate. The crude product (~33 g) could directly be used in the next step without any further purification. The product can be obtained as a colourless oil after flash chromatographic purification (silica gel, 15% ethyl acetate in cyclohexane

Allyl 1-(2-cyanoethyl)-4-isobutoxy-2-oxocyclohex-3-ene-1-carboxylate (18)
A flame-dried flask was charged with crude β-keto ester S2 (33 g), acetonitrile (300 mL), potassium carbonate (32.9 g, 238 mmol, 2.0 eq.) and acrylonitrile (15.7 mL, 238 mmol, 2 eq.). The resulting suspension was heated to reflux for 6 h. The reaction mixture was quenched with aqueous hydrochloric acid (1 M) and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate. The product was purified by flash column chromatography (silica gel, 15% ethyl acetate in cyclohexane) and isolated as a yellow oil (30 g, 98 mmol, 82% over two steps) that solidified in the freezer.  General procedure for the Tsuji-Trost decarboxylative allylation, ligand screening In a flame dried Schlenk flask, under argon atmosphere, Pd2(dba)3 (4.60 mg, 5.0 µmol, 2.5 mol%) and ligand (20 µmol, 10 mol%) were dissolved in degassed solvent (1.00 mL). The resulting mixture was stirred at room temperature for 15 minutes until no purple colour was observed anymore. A solution of allylic ester 18 (61.0 mg, 0.20 mmol, 1 eq.) in solvent (3.00 mL) was added to the catalytic mixture, which was then heated to the indicated temperature until full conversion of starting material was observed on TLC. The mixture was cooled down to room temperature and all volatiles were removed in vacuo. The product was purified by automated column chromatography (silica gel, eluting at 25% EtOAc in cyclohexane) and isolated as a yellow oil. Enantiomeric excess was determined using chiral SFC (method A).

(S)-N-(3-(1-allyl-4-oxocyclohex-2-en-1-yl)propyl)-2-nitrobenzenesulfonamide (16)
In a flame-dried flask, nitrile 17 (13.2 g, 50.3 mmol, 1 eq.) was dissolved in dry THF (500 mL) and cooled to −78 °C. A solution of diisobutylaluminium hydride in hexanes (1.0 M, 56 mL, 56 mmol, 1.1 eq.) was added dropwise to the mixture and the reaction was allowed to room temperature slowly overnight. The reaction mixture was transferred to a dropping funnel and slowly added to a pre-cooled suspension of lithium aluminium hydride (5.78 g, 151 mmol, 3.0 eq.) in dry THF (200 mL) at 0 °C. The resulting mixture was allowed to room temperature and stirred overnight. The reaction was diluted with diethyl ether (500 mL), cooled to 0 °C and quenched with water (8 mL, NOTE: violent gas evolution!), aqueous sodium hydroxide (15% m/v, 8 mL) and water (23 mL). The mixture was stirred for 15 minutes after which anhydrous sodium sulphate was added. The mixture was stirred for 15 minutes and filtered over celite, washing the residue extensively with diethyl ether and THF. All volatiles were removed in vacuo and the crude amino alcohol (12.7 g) was used directly in the next step. The amino alcohol of the previous step was dissolved in dry DCM (250 mL) and triethyl amine (21 mL, 151 mmol, 3.0 eq.). The solution was cooled to 0 °C and 2-nitrobenzenesulfonyl chloride (16.7 g, 75.5 mmol, 1.5 eq.) was added portion wise over 10 minutes. The reaction mixture was allowed to room temperature and stirred overnight. All volatiles were thoroughly removed in vacuo and the residue was taken up in methanol (200 mL) and aqueous hydrochloric acid (1.0 M, 200 mL). Minimal amounts of DCM (~25 mL) were added to create two clear layers, which were then vigorously stirred for 1 hour. The whole mixture was extracted three times with DCM, and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica gel, 10-40% EtOAc in cyclohexane) to give the title compound as slightly yellow oil (13.2 g, 34. 9 mmol, 69%) with trace impurities of the intramolecular Michael adduct. Rf (50% EtOAc in cyclohexane): 0.49 (visualized by UV and KMnO4 stain).  [α]D 20 -24 (c = 1.0, CHCl3).

4a-allyloctahydroquinolin-7(1H)-one (S3)
In a flame-dried flask, cyanide 17 (13.2 g, 50.3 mmol, 1 eq.) was dissolved in dry THF (500 mL) and cooled to -78 °C. Then, a solution of diisobutylaluminium hydride in hexanes (1 M, 56 mL, 56 mmol, 1.1 eq.) was added dropwise to the mixture and the reaction was allowed to room temperature slowly overnight. The reaction mixture was transferred to a dropping funnel and slowly added to a pre-cooled suspension of lithium aluminium hydride (5.78 g, 151 mmol, 3.0 eq.) in dry THF (200 mL) at 0°C. The resulting mixture was allowed to room temperature and stirred overnight. The reaction was diluted with diethyl ether (500 mL), cooled to 0 °C and quenched with water (8 mL, NOTE violent gas evolution!), aqueous sodium hydroxide (15% m/v, 8 mL) and water (23 mL). The mixture was stirred for 15 minutes after which anhydrous sodium sulphate was added. The mixture was stirred for 15 minutes and filtered over celite, washing the residue extensively with diethyl ether and THF. All volatiles were removed in vacuo and the crude amino alcohol (12.7 g). This residue was taken up in methanol (200 mL) and aqueous hydrochloric acid (1 M, 200 mL). Minimal amounts of DCM (~25 mL) were added to create two clear layers, which were then vigorously stirred for 1 hour. Subsequently, the mixture was basified to pH>14 and extracted three times with DCM The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine and dried over magnesium sulphate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica gel, cyclohexane/EtOAc/Et3N 16:8:1) to give the title compound as colourless oil (13.2 g, 34. 9 mmol, 69%). General procedure for the synthesis of ortho-substituted 2-nitrobenzenesulfonyl chlorides [2] 2-Fluoronitrobenzene S4 (1.5 mmol, 1 eq.) was dissolved in methanol (10.0 mL) and a solution of sodium sulphite (0.38 g, 3.0 mmol, 2 eq.) in water (7 mL) was added. Nitrogen gas was bubbled through the solution for 15 minutes and the mixture was heated to reflux for 24 h. After full conversion of the starting fluoride, the reaction mixture was allowed to room temperature and acidified with aqueous HCl (2M) to pH<3. After removal of all solvents in vacuo, the product was recrystallized from boiling brine (6 mL) and collected by vacuum filtration (avoiding washing with water). The sulfonic acid was dissolved in thionyl chloride (1.1 mL, 11 mmol, 7 eq.) and catalytic DMF (48 µL, 0.62 mmol, 0.41 eq.) was added. The reaction mixture was heated to reflux for 24 h, after which it was allowed to room temperature. Evaporation of all volatiles in vacuo (caution! Thionyl chloride vapours are highly corrosive) yielded a solid that could be dissolved in DCM and water. After extraction of the aqueous layer with DCM, the combined organic layers were washed with brine and dried over sodium sulphate. Filtration and evaporation of the solvents in vacuo yielded the crude sulfonyl chlorides that were used immediately without further purification. Purity of the material was confirmed by 1 H NMR spectroscopy.

3-methoxy-2-nitrobenzenesulfonyl chloride (S5a)
Isolated as a brown solid. General procedure for the synthesis of aryl-substituted 2-nitrobenzenesulfonamides Secondary amine S3 (100 mg, 0.52 mmol, 1 eq.) was dissolved in dry DCM (5.0 mL) and triethylamine (0.22 mL, 1.6 mmol, 3.0 eq.). The mixture was cooled to 0 °C and the appropriately substituted ortho-nitrobenzenesulfonyl chloride (0.78 mmol, 1.5 eq.) was added in one portion. The reaction mixture was allowed to room temperature and was stirred for 18 h, after which water was added. The aqueous layer was extracted with DCM and the combined organic layers were washed with aqueous hydrochloric acid (1 M), saturated aqueous sodium bicarbonate and brine, before it was dried over sodium sulphate. Concentration of the crude in vacuo and purification by flash column chromatography (silica gel, 10% EtOAc in toluene) yielded the 2-nitrobenzenesulfonamides described below.

Optimized nitroaryl transfer/acylation cascade procedures (S)-2-(2-nitrophenyl)cyclohexenone 25a
From open sulfonamide 16: To a solution of ortho-nitrobenzenesulfonamide 16 (2.03 g, 5.36 mmol, 1 eq.) in acetone (50 mL) was added caesium carbonate (3.42 g, 10.5 mmol, 2.0 eq.) and the resulting suspension was stirred vigorously at reflux for 18 h. The reaction mixture was allowed to room temperature and chloroacetyl chloride (4.2 mL, 53 mmol, 10 eq.) in acetone (40 mL) was added dropwise, after which the mixture was stirred for another 18 h at room temperature. The reaction mixture was concentrated in vacuo and water (50 mL) and DCM (50 mL) were added. The organic layer was collected, and the aqueous layer was extracted twice more with DCM (50 mL). The combined organic layers were washed with brine and dried over magnesium sulphate. Evaporation of all volatiles in vacuo and purification by flash column chromatography (silica gel, 0.5% acetic acid and 30% EtOAc in cyclohexane) provided the product as a slightly yellow oil (1.0 g, 2.6 mmol, 48%).

2-(4-chloro-2-nitrophenyl)cyclohexenone 25c
To a solution of ortho-nitrobenzene sulfonamide 26c (45 mg, 0.11 mmol, 1 eq.) in acetone (2 mL) was added caesium carbonate (72 mg, 0.22 mmol, 2.0 eq.) and the resulting suspension was stirred vigorously at reflux for 3 h. The reaction mixture was allowed to room temperature and pyridine (89 µL, 1.1 mmol, 10 eq.) and chloroacetyl chloride (80 μL, 1.0 mmol, 10 eq.) were added dropwise, after which the mixture was stirred for another 18 h at room temperature. The reaction mixture was concentrated in vacuo and aqueous sodium hydroxide (1M, 5 mL) and DCM (5 mL) were added. The organic layer was collected, and the aqueous layer was extracted thrice more with DCM (5 mL). The combined organic layers were washed with aqueous hydrochloric acid (1 M), brine and dried over magnesium sulphate. Evaporation of all volatiles in vacuo and purification by flash column chromatography (silica gel, 30% EtOAc in toluene) provided the product as a yellow oil (23 mg, 55 µmol, 60%).

2-(2-nitro-4-(trifluoromethyl)phenyl)cyclohexenone 25d
To a solution of ortho-nitrobenzene sulfonamide 26d (134 mg 0.30 mmol, 1 eq.) in acetone (6 mL) was added caesium carbonate (195 mg, 0.20 mmol, 2.0 eq.) and the resulting suspension was stirred vigorously at reflux for 2 h. The reaction mixture was allowed to room temperature and chloroacetyl chloride (240 μL, 1.0 mmol, 10 eq.) was added dropwise, after which the mixture was stirred for another 18 h at room temperature. The reaction mixture was concentrated in vacuo and water (15 mL) and DCM (15 mL) were added. The organic layer was collected, and the aqueous layer was extracted twice more with DCM (10 mL). The combined organic layers were washed with brine and dried over magnesium sulphate. Evaporation of all volatiles in vacuo and purification by flash column chromatography (silica gel, 0.5% acetic acid and 40% EtOAc in cyclohexane) provided the product as a yellow oil (32.5 mg, 24%), inseparable from compound S6 (molar ratio 1:0.26, mass ratio: 1:0.15), corrected product yield: 21%. Rf (50% EtOAC in cyclohexane): 0.39 (visualized by UV and KMnO4 stain).

2-(4-methoxy-2-nitrophenyl)cyclohexenone 25e
To a solution of ortho-nitrobenzene sulfonamide 26e (41 mg, 0.10 mmol, 1 eq.) in acetone (2 mL) was added caesium carbonate (65 mg, 0.20 mmol, 2.0 eq.) and the resulting suspension was stirred vigorously at reflux for 3 days. The reaction mixture was allowed to room temperature and chloroacetyl chloride (80 μL, 1.0 mmol, 10 eq.) was added dropwise, after which the mixture was stirred for another 18 h at room temperature. The reaction mixture was concentrated in vacuo and water (5 mL) and DCM (5 mL) were added. The organic layer was collected, and the aqueous layer was extracted twice more with DCM (5 mL). The combined organic layers were washed with brine and dried over magnesium sulphate. Evaporation of all volatiles in vacuo and purification by flash column chromatography (silica gel, 0.5 % acetic acid and 50% EtOAc in cyclohexane) provided the product as a yellow oil (23.5 mg, 56%). Rf (50% EtOAC in cyclohexane): 0.19 (visualized by UV and KMnO4 stain).

Tetracyclic indole 27 [3]
A nitrogen-flushed and flame-dried Schlenk flask equipped with reflux condenser was charged with nitroaryl chloroacetamide 25a (0.99 g, 2.5 mmol, 1 eq.) and thoroughly degassed acetic acid (51 mL). Iron dust (0.71 g, 13 mmol, 5 eq.) was added and the reaction mixture was heated to 85 °C and stirred vigorously for 18 h. The mixture was then allowed to room temperature and all volatiles were removed in vacuo. The residue was taken up in water and ethyl acetate, extracting the aqueous layer twice more with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulphate. After evaporation of all solvents, the product was obtained by flash column chromatography (silica gel, 0-20% EtOAc in cyclohexane) as a colourless crystalline powder (0.54 g, 1.58 mmol, 62%) that could be recrystallized from acetone.  [α]D 20 -132 (c = 2.0, CHCl3).

Pentacyclic indolenine 14 [4]
Indole 27 (40 mg, 0.12 mmol, 1 eq.) and sodium iodide (175 mg, 1.17 mmol, 10 eq.) were dissolved in acetone (6 mL) and the mixture was heated to reflux for 2 h, resulting in an off-white precipitate. The mixture was allowed to room temperature and water (6 mL) and EtOAc (6 mL) were added. The organic layer was drained off and the aqueous layer was extracted once more with EtOAc (6 mL). The combined organic layers were washed with brine and dried over sodium sulphate. Evaporation of all volatiles yielded the iodide as a yellow foam that was immediately dissolved in THF (6 mL) and cooled to 0 °C. Then, in the dark, silver triflate (76 mg, 0.29 mmol, 2.5 eq.) was added in one portion and the mixture was stirred at 0 °C for 0.5 h. Water (6 mL) and EtOAc (12 mL) were added, and the aqueous layer was quickly extracted (to avoid excessive precipitation) with EtOAc (2 x 6 mL). The combined organic layers were washed with brine and dried over sodium sulphate. Evaporation of all volatiles yielded the indolenine as a pinkish foam that could be purified by flash column chromatography (silica gel, EtOAc) to provide a white foam with minor inseparable impurities (29 mg, 81%). The product showed quick (<1 week) decomposition, even when stored under argon at -20 °C.  [α]D 20 -549 (c = 0.10, CHCl3).

Crystallographic data for 27
A block-like specimen of C20H23ClN2O, approximate dimensions 0.300 mm x 0.200 mm x 0.150 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured (λ = 1.54178 Å). A total of 720 frames were collected. The total exposure time was 0.40 hours. The frames were integrated with the Bruker SAIN T software package using a narrow-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 26169 reflections to a maximum θ angle of 68.27° (0.83 Å resolution), of which 3152 were independent (average redundancy 8.302, completeness = 98.6%, Rint = 2.51%, Rsig = 2.05%) and 3095 (98.19%) were greater than 2σ(F 2 ). The final cell constants of a = 8.7525(2) Å, b = 11.1428(2) Å, c = 17.9882(4) Å, volume = 1754.34(6) Å 3 , are based upon the refinement of the XYZ-centroids of 9932 reflections above 20 σ(I) with 9.335° < 2θ < 136.5°. Data were corrected for absorption effects using the Multi-Scan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.605.
The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P 21 21 21, with Z = 4 for the formula unit, C20H23ClN2O. The final anisotropic full-matrix least-squares refinement on F 2 with 227 variables converged at R1 = 2.26%, for the observed data and wR2 = 5.80% for all data. The goodness-of-fit was 1.018. The largest peak in the final difference electron density synthesis was 0.157 e -/Å 3 and the largest hole was -0.160 e -/Å 3 with an RMS deviation of 0.032 e -/Å 3 . On the basis of the final model, the calculated density was 1.298 g/cm 3 and F(000), 728 e -.