First Synthesis of Marine Alkaloid (±)-Bengacarboline

Abstract

Bengacarboline 1, a marine alkaloid, potent inhibitor of topoisomerase II, has been synthesized in nine steps from indol-3-carboxylic acid and tryptamine.

alkaloid - indole - imine - cyclization - total synthesis

References

1 Foderato TA. Barrows LR. Lassota P. Ireland CM. J. Org. Chem.  1997,  62:  6064 

2 For a review concerning the Pictet-Spengler cyclization, see: Cox ED. Cook JM. Chem. Rev.  1995,  95:  1797 

3a Mouhaddid A. Joseph B. Hasnaoui A. Mérour J.-Y. Synthesis  2000,  549 

3b Bennasar ML. Roca T. Griera R. Bassa M. Bosh J. J. Org. Chem.  2002,  67:  6268 

4 For a review concerning the use of POCl₃, see: Sharma SD. Kanwar S. Indian J. Chem., Sect. B  1998,  37:  965 

For a related reaction, see:

5a Siddiqui S. Siddiqui BS. Naeed A. Begum S. Khan KA. Ahmad A. Fitoterapia  1990,  5:  425 

5b Faizi S. Naz A. Tetrahedron  2002,  58:  6185 

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A mixture of compound 3 (236 mg, 0.4 mmol), tryptamine (131 mg, 0.8 mmol), ZnCl₂ (24 mg, 0.18 mmol) in xylene (0.7 mL) was irradiated under microwave (Synthewave 402, Prolabo) at 130 °C for 60 min. After evaporation under vacuum, the crude residue was purified by chromatography (SiO₂, EtOAc-heptane 40:60) affording imine 10 (197 mg, 67%).

For other examples of Pictet-Spengler cyclization between indole and ketimine, see:

7a Spadoni G. Balsamini C. Bedini A. Duranti E. Tontini A. J. Heterocycl. Chem.  1992,  29:  305 

7b Rodriguez JG. Gil-Lopetegui P. J. Heterocycl. Chem.  1993,  30:  373 

7c Carrasco N. Urzua A. Cassels BK. J. Org. Chem.  1973,  38:  4342 

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Typical Procedure for Preparation of Compound 11:
A solution of imine 10 (392 mg, 0.55mmol) and trifluoro-acetic anhydride (2 mL) in CH₂Cl₂ (20 mL) was stirred at 45 °C for 15 h. After cooling at r.t., the solution was concentrated in vacuo. The residue was dissolved in CH₂Cl₂ and washed with an aq solution of NaHCO₃ (10%). The layers were separated and the aq solution was extracted additionally with CH₂Cl₂. The combined organic layers were washed with H₂O, dried over anhyd Na₂SO₄, filtrated and evaporated in vacuo yielding crude carboline 11. Purification by flash chromatography (SiO₂, EtOAc-heptane 40:60) afforded compound 11 (306 mg, 67%).
Analytical data: ¹H NMR (250MHz, CDCl₃): δ = 7.88 (d, J = 7.6 Hz, 1 H), 7.79 (d, J = 6.9 Hz, 2 H), 7.53 (d, J = 6.9 Hz, 1 H), 7.57-7.06 (m, 17 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), 5.28 (d, J = 12.5 Hz, 1 H), 5.13 (bs,
1 H), 5.08 (d, J = 12.5 Hz, 1 H), 3.79 (d, J = 9.7 Hz, 1 H), 3.44-3.15 (m, 4 H), 2.98-2.74 (m, 2 H), 2.73-2.57 (m, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 157.62, 138.22-118.89, 113.51, 112.47, 109.61, 105.23, 67.48, 60.21, 41.33, 38.22, 24.68, 22.21. IR(film): ν = 3324, 3060, 2928, 1700 cm^-1. MS(electrospray): m/z = 838 [M + Na], 816 [M + H]. HRMS: Calcd for C₄₅H₃₆F₃N₅O₅SNa: 838.2287. Found: 838.2254. (±)-Bengacarboline (1). HRMS: Calcd for C₂₉H₂₈N₅ [M + H]: 446.2345. Found: 446.2347.

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A solution of compound 11 (0.06 mmol) in THF (2 mL) was treated at -78 °C under argon with KHMDS in solution in toluene (3 equiv) for 30 min. p-Nitrosulfonyl chloride (1.5 equiv) in THF (0.8 mL) was added. After 45 min, the reaction mixture was warmed to r.t. in 1 h and 30 min. The reaction mixture was extracted with CH₂Cl₂, washed with an aq solution of Na₂CO₃ (10%). After evaporation, the crude mixture was purified by chromatography (SiO₂, EtOAc-heptane 50:50) affording compound 12 in 73% yield.

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The details of X-ray structure of compound 12 (Figure [1] ) will be given in a full paper (Service de cristallochimie, Institut de Chimie des Substances Naturelles).