Stereoselective Synthesis of Functionalized Tetrahydro-β-Carbolines via Pictet–Spengler Reaction

Dedicated to Prof. Habib Bagheri on the occasion of his birthday

Abstract

A TFA-catalyzed Pictet–Spengler reaction of synthesized tryptophan propargyl ester with aromatic and heteroaromatic aldehydes resulted in cis-tetrahydro-β-carbolines with remarkably high stereocontrol under kinetically controlled conditions. In another approach, a diastereomeric mixture of tetrahydro-β-carboline hydrazides was synthesized. The tetrahydro-β-carboline hydrazides were prepared through the reaction of tryptophan hydrazide with carbonyl compounds via Pictet–Spengler reaction.

Key words

tetrahydro-β-carboline - Pictet–Spengler reaction - l-tryptophan - asymmetric synthesis

• References and Notes

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• 22 Synthesis of Tryptophan Propargyl Ester (7) Fmoc-Trp(Boc)-OH (5, 5.27 g, 10 mmol) was added to O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.52 g, 11 mmol), N,N-diisopropylethylamine (3.9 mL, 22 mmmol), and hydroxybenzotriazole hydrate (1.48 g, 11 mmol) in DMF, (5mL). The mixture was left at r.t. for 10 min, then propargyl alcohol (1.2 mL, 20 mmol) was added and the reaction mixture stirred for 3 h until completion (monitored by TLC). It was diluted with EtOAc (50 mL) and then washed with Na₂CO₃ solution (3%), H₂O, and finally brine three times in each case. The organic phase was collected and dried over MgSO₄ followed by filtering and evaporation of the solvent to obtain pure 6 (2.98 g. 78%) as a pale yellow oil. In the Fmoc deprotection compound 6 was dissolved in MeCN (6 mL) and stirred at r.t. in the presence of Et₂NH (10 mL). After completion of the reaction (1 h), the solvent was evaporated under reduced pressure, the residue was diluted twice with MeCN (10 mL), and the solvent was removed under reduced pressure to remove the residual Et₂NH. The viscous oil obtained was purified by column chromatography (gradient eluting from 100% PE to 50:50 PE–EtOAc) affording the pure intermediate as a viscous oil (90%). Finally, Boc deprotection was accomplished by reagent K (a mixture of TFA, PhOH, ethanedithiol, triethylsilane, and thioanisol in H₂O). Purified intermediate was added to cooled reagent K (ice-water bath, 20 mL). After 2 h, the TFA was removed, H₂O was added (20 mL), and the mixture was extracted with Et₂O (40 mL), followed by washing the organic extract with H₂O, drying over MgSO₄, filtering, and removing the solvent under reduced pressure to obtain pure tryptophan propargyl ester (7) as a yellow oil (85%). ¹H NMR (500 MHz, CDCl₃): δ = 2.50 (t, J = 2.4 Hz, C≡CH), 3.11 (dd, J = 14.4, 7.4 Hz, 1 H, ArCHH), 3.31 (dd, J = 14.4, 4.8 Hz, 1 H, ArCHH), 3.80 (dd, J = 7.4, 4.9 Hz, 1 H, ArCH₂CH), 4.71 (d, J = 2.4 Hz, 2 H, OCH ₂C≡CH), 7.08–7.66 (m, 5 H, ArH), 8.17 (s, 1 H, indole NH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 25.9, 38.6, 53.8, 76.0, 76.4, 105.7, 111.7, 118.0, 119.7, 122.3, 125.6, 126.4, 136.3, 168.5 ppm.
• 23 General Procedure of the Synthesis of cis-Tetrahydro-β-carboline Propargyl Esters 3a–g The general procedure for PSR was followed by addition of tryptophan propargyl ester (7, 2.42 g, 1 mmol) to a solution of the appropriate aldehyde (1.2 mmol) in CH₂Cl₂ (10 mL) cooled in an ice-bath (0 °C). Then, TFA (0.23 g, 2 mmol) was slowly added to the reaction mixture. After the reaction was complete (monitored by TLC), it was quenched by the addition of CH₂Cl₂ (20 mL) and a solution of NaHCO₃ (10 mL, 10%). The organic phase was separated, washed with brine, dried over MgSO₄, filtered, and the solvent removed under reduced pressure. The pure product was obtained after thick-layer chromatography. (1S,3S)-Prop-2-ynyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4b]indole-3-carboxylate (3a) Pale oil, 73% yield. IR (KBr): ν = 3388, 3281, 2135, 1750 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.06 (br s, 1 H, NH), 2.54 (t, J = 2.5 Hz, C≡CH), 3.05 (ddd, J = 15.0, 11.2, 2.2 Hz, 1 H, H_4a), 3.15 (ddd, ­J = 15.0, 4.2, 2.2 Hz, 1 H, H_4b), 4.07 (dd, J = 11.2, 4.2 Hz, 1 H, H₃), 4.81 (dABq, J = 15.6, 2.5 Hz, 2 H, OCH ₂C≡CH), 5.23 (s, 1 H, H₁), 7.12–7.27 (m, 3 H, ArH), 7.39 (s, 5 H, ArH),7.52 (s, 1 H, indole NH), 7.57 (m, 1 H, ArH) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 25.7, 52.6, 56.8, 58.6, 75.4, 77.3, 108.7, 110.9, 118.2, 119.6, 121.9, 127.1, 128.6, 129, 134.6, 136.2, 140.7, 172.0 ppm. EI-MS: m/z (%) = 331 23) [M⁺ + 1], 330 (87) [M⁺], 291 (26), 247 (56), 218 (100), 204 (11), 169 (24), 144 (30), 57 (13), 43 (26). Anal. Calcd for C₂₁H₁₈N₂O₂ (330.38): C, 76.34; H, 5.49; N, 8.47. Found: C, 76.14; H, 5.36; N, 8.38; O, 9.53.
• 24 Synthesis of Tryptophan Hydrazide (10) Hydrazine monohydrate (80%, 0.16 mL, 3.4 mmol) was added to a mixture of tryptophan methyl ester (9, 218 mg, 1 mmol) in MeOH (2.5 mL), and the mixture was stirred for 72 h, monitoring by TLC. After evaporation of the solvent, a yellow oil was obtained. IR (KBr): ν = 3420, 1681 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.77 (dd, 1 H J = 7.5, 15 Hz, H_a), 3.05 (dd, 1 H J = 6.0, 15 Hz, H_a′), 3.48 (t, 1 H J = 7.2 Hz, CHN), 4.46 (br s, 4 H, NHNH ₂, CHNH ₂), 7.15 (s, 1 H, CH_indol), 6.96 (t, 1 H, J = 6.8 Hz, HAr), 7.04 (d, 1 H J = 7.0 Hz, HAr), 7.34 (d, 1 H J = 8.0 Hz, HAr), 7.55 (d, 1 H, J = 8.0 Hz, HAr), 11.00 (s, 1 H, NHNH₂), 11.04 (s, 1 H, NH_Indole) ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 31.3, 54.3, 110.5, 111.6, 118.4, 118.6, 121.0, 124.0, 128.0, 136.3, 174.0 ppm.
• 25 General Procedure for the Synthesis of cis- and trans-Tetrahydro-β-carboline Hydrazide 4a–e The general procedure of PSR was followed by addition of tryptophan hydrazide (10, 218 mg, 1 mmol) to a solution of the appropriate aldehyde (2 mmol) in MeOH (5 mL) containing a catalytic amount of TFA (100 μL), and the mixture was stirred at r.t. for 24 h monitoring by TLC. Then CH₂Cl₂ (10 mL) was added, and the resultant precipitate of the product was collected by filtration. Column chromatography was also used for further purification of 4b–e. (S,E)-N′-(4-Chlorobenzylidene)-1-(4-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (4a) White solid. IR (KBr): ν = 3349, 1694 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ (cis/trans = 1:2) =3.10–3.40 [m, 4 H, H_4a,_a′ (for two diastereomers)], 3.25–3.45 [m, 2 H, H₃ (for two diastereomers)], 4.08 [t, 1 H, J = 6.7 Hz, H₁ (cis)], 4.89 [t, 1 H, J = 6.3Hz, H₁ (trans)], 6.98 [t, 1 H, HAr (for two diastereomers)], 7.07 [t, 1 H, HAr (for two diastereomers)], 7.21 [br s, 1 H, NH (trans)], 7.30 [d, 1 H, J = 7.8 Hz, HAr (trans)], 7.36 [d, 1 H, J = 8.1 Hz, HAr (cis)], 7.44 [d, 2 H, J = 8.1 Hz, HAr (for two diastereomers)], 7.51 [d, 2 H, J = 8.1 Hz, HAr (for two diastereomers)], 7.53 [d, 2 H, J = 8.1 Hz, HAr (for two diastereomers)], 7.56 [d, 2 H, J = 8.1 Hz, HAr (for two diastereomers)], 7.66 [d, 1 H, J = 7.5 Hz, HAr (cis)], 7.74 [d, 1 H, J = 8.4 Hz, HAr (trans)], 8.02 [br s, 1 H, NH (cis)], 8.22 [br s, 1 H, =CH (cis)], 8.32 [br s, 1 H, =CH (trans)], 10.99 [s, 1 H, NH amide (trans)], 11.06 [s, 1 H, NH amide (cis)], 11.95 [br s, 1 H, NH indole (trans)], 12.18 [br s, 1 H, NH indole (cis)] ppm. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 26.6 [C_4a,_a′ (trans)], 27.3 [C_4a,_a′ (cis)], 50.3, 52.3 [C_1′, C₃ (for two diastereomers)], 106.7, 108.9, 111.7, 115.3, 117.9, 118.5, 119.3, 121.2, 124.8, 127.0, 128.6, 128.8, 128.9, 129.0, 132.5, 132.7, 134.6, 134.9, 136.3, 144.1, 147.3 (for two diastereomers), 158.0 [C=N (cis)], 158.4 [C=N (trans)], 158.4 [C=O (cis)], 158.4 [C=O (trans)] ppm. ESI-HRMS: m/z calcd for C₁₈H₁₇ClN₄O [(M – C₇H₃Cl) + H]⁺: 341.11627; found: 341.11629.