Construction of tetrahydro-β-carboline skeletons via Brønsted acid activation of imide carbonyl group: syntheses of indole alkaloids (±)-harmicine and (±)-10-desbromoarborescidine-A

Abstract

Indole, a π-nucleophile, reacts with Brønsted acid activated imide carbonyl group in an intramolecular fashion via a 6-exo-trig cyclization, to deliver a condensed tetrahydro-β-carboline unit. This methodology is effectively applied to assemble the tetrahydro-β-carboline skeleton containing alkaloids such as harmicine and 10-desbromoarborescidine-A.

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Terpene indole alkaloids, with a tetrahydro-β-carboline (THBC) subunit, have been isolated from various plants and animals.¹ The structural diversity of these complex natural products account for the plethora of biological activities.² For example, the alkaloid (+)-yohimbine has been used to treat erectile dysfunction;³ (+)-vincamine, a vasodilator, has been used to increase the blood flow in brain;⁴ and the alkaloid (−)-reserpine, has been used to treat the hypertension⁵ (Fig. 1).

Fig. 1 Indole alkaloids.

This synthetically and biologically important structural class demands the development of simple and efficient synthetic methodologies. Usually the assemblage of this heterocyclic system employs reactions such as the Pictet–Spengler reaction,⁶ Bischler–Napieralski reaction,⁷N-acyliminium ion cyclization,⁸ cycloaddition reaction,⁹ and keteniminium Pictet–Spengler reaction.¹⁰ These methods generally require either harsh conditions and/or several steps.

Matching the electrophilicity of the imide carbonyl carbon through Lewis acid or Brønsted acid activation with the nucleophilicity of π-nucleophiles, such as aromatic systems, may result in C–C bond formation. Recently, we have demonstrated this concept to effect the intramolecular cyclization of phenethylimides via imide carbonyl activation to generate tetrahydroisoquinolines.¹¹ This observation prompted us to investigate the feasibility of assembling the tetrahydro-β-carboline skeleton through imide carbonyl activation.

Accordingly, the phthalimido derivative of tryptamine 1a was treated with 2 equivalents of trifluoromethanesulfonic acid (TfOH) in dichloromethane, which failed to generate the cyclized product. Though, the theoretically predicted global nucleophilicity of indole was found to be higher than anisole,¹² it failed to react intramolecularly with the activated imide carbonyl group. However, we earlier witnessed, the successful cyclization of methoxy substituted benzene through imide carbonyl activation using acids at room temperature.^11b This difference may be due to the existence of protonated species I in the presence of TfOH (pK_a = −14), similar to the protonated indole (pK_a = −3.6) existing in the strong acid medium (Fig. 2).¹³

Fig. 2 Protonation of indole moiety.

When the reaction was performed with TfOH (4 equiv.) in dichloromethane only 22% of cyclized product 2 was produced, even after 24 h. Whereas the imide 1a underwent cyclization on treatment with TfOH (4 equiv.) in the presence of powdered and freshly dried 4 Å molecular sieves to afford the expected tetrahydro-β-carboline 2 with increased yield (29%) in a shorter reaction time (12 h). The THBC derivative 2 with 81% yield was realized when the imide 1a was treated with TfOH (10 equiv.) in the presence of 4 Å molecular sieves (Scheme 1). In the absence of molecular sieves, the substrate 1a produced the THBC 2 in 44% yield upon treatment with TfOH (10 equiv.) in dichloromethane. Hence, we presume that the molecular sieves may be facilitating the formation of the fused cyclic acyl iminium ion II via hydroxy lactam formation. Though the starting material was completely consumed, the isolation of the cyclized hydroxy lactam 2 became cumbersome due to its polar nature. Hence, in situ reduction of the hydroxy lactam using NaBH₄/CF₃COOH¹⁴ after neutralizing the reaction mixture with solid NaHCO₃ followed by neutral alumina column chromatography, furnished the heterocyclic lactam 2a in 83% yield (Scheme 1).

Scheme 1 Cyclization of the phthalimido derivative of tryptamine.

Successful cyclization of the phthalimide derivative of tryptamine prompted us to investigate the electronic effect of substituents on the internal nucleophile (indole ring) in this reaction. The imide derivatives of tryptamines are usually prepared by direct condensation of substituted tryptamines with anhydrides in refluxing toluene.^10a However, the cost of substituted tryptamines intrigued us to develop a simple methodology to synthesize the imide derivatives of substituted tryptamines. Thus, we have adopted the methodology that has been utilized to prepare N,N-dimethyltryptamines.¹⁵ The imide derivatives of substituted tryptamines were produced in moderate yield from the imide derivative of 4-amino-1-butanol via Swern oxidation, in situ aldehyde protection using propane-1,3-diol, followed by indolization using 4% sulphuric acid (Table 1, entries 1–7). Here, the primary amine, protected as an imide, was intact during this sequence of reactions. This methodology can be used as a general tool to synthesize the imide derivative of tryptamines.

Table 1 Synthesis of imide derivatives of substituted tryptamines^a

Entry	Substituted phenylhydrazine hydrochloride	Phthalimide derivative of tryptamines	Succinimide derivative of tryptamines
a Reaction conditions: 7 or 9 (2.0 mmol), substituted phenyl hydrazine hydrochloride (2.0 mmol), 4% H2SO4 (100 ml), 80 °C, 12 h.
1
2
3
4
5
6
7

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A wide substrate scope for this cyclization strategy can be envisaged as most of the phthalimide derivatives of substituted tryptamines produced the expected tetrahydro-β-carboline derivatives, 2b–h (Table 2, entries 1–7). Under this cyclization conditions, the indole ring, with both electron releasing and withdrawing functional groups, furnished the expected pentacyclic lactams in moderate to good yields (Table 2, entries 1–7).

Table 2 Cyclization of phthalimide derivatives of substituted tryptamines^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1) 1b–h (0.344 mmol), TfOH (3.444 mmol), CH2Cl2 (20 ml), rt, 12 h; 2), NaHCO3 (3.788 mmol), NaBH4 (1.549 mmol), CF3COOH (4.649 mmol), rt, 12 h. b Isolated yield.
1			79
2			78
3			73
4			71
5			74
6			66
7			60

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Most of the indole alkaloids that occur in nature possess a tetrahydro-β-carboline skeleton fused with pyrrolidine or piperidine units. Therefore, the alicyclic imide derivatives of tryptamines were subjected to the cyclization reaction using TfOH/MS 4 Å followed by reduction using NaBH₄/MeOH in dichloromethane. As expected, the condensed tetracyclic or pentacyclic heterocycles were generated in good yields (Table 3, entries 1–10).

Table 3 Cyclization of aliphatic imides of substituted tryptamines^a

Entry	Substrate	Product	Yield^b (%)
a Reaction conditions: 1) 1i–q (0.4132 mmol), TfOH (4.132 mmol), CH2Cl2 (20 ml), rt, 12 h; 2) NaBH4 (1.859 mmol), MeOH (3 ml), 30 min. b Isolated yield.
1			82
2			65
3			88
4			85
5			81
6			80
7			70
8			65
9			62
10			87

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The formation of these tetrahydro-β-carboline derivatives was unambiguously confirmed by IR, NMR (¹H and ¹³C), and HRMS data. The structure of the compounds 2, 2e, 2h, 2o and 2q were further confirmed by single crystal X-ray crystallography¹⁶ (Fig. 3). Notably the cis-cyclohexane-1,2-dicarboximide derivative of tryptamine 1q underwent diastereoselective cyclization to produce one diastereomer, 2q (Table 3, entry 9) in which the hydrogens on the fused carbons are cis to each other as evident from the single crystal structural analysis (Fig. 3).

Fig. 3 ORTEP diagrams of compounds 2, 2e, 2h, 2o and 2q.

The synthetic efficiency of this methodology was further exemplified through the syntheses of indole alkaloids such as (±)-harmicine,¹⁷ isolated from Kopsia griffithii, and (±)-10-desbromoarborescidine-A,¹⁸ isolated from Pseudodistoma arborescens in racemic form from the corresponding imide derivatives of tryptamine. The successful assemblage of (±)-harmicine and (±)-10-desbromoarborescidine-A was effected by the initial condensation of tryptamine with succinic anhydride and glutaric anhydride followed by TfOH treatment and reduction using NaBH₄/MeOH. The precursors 2i and 2r were produced in 82% and 87% yields respectively from imides 1i and 1r. The precursors 2i and 2r, upon reduction using LiAlH₄, effectively furnished the natural products (±)-harmicine 4 and (±)-10-desbromoarborescidine-A 5 in 78% and 63% yields respectively (Scheme 2).

Scheme 2 Synthesis of (±)-harmicine and (±)-10-desbromoarborescidine-A.

In conclusion, we have demonstrated the Brønsted acid assisted 6-exo-trig cyclization of imide derivatives of tryptamine through imide carbonyl activation to assemble the tetrahydro-β-carboline derivatives. The utility of this methodology was exemplified by the successful and short synthesis of (±)-harmicine and (±)-10-desbromoarborescidine-A. Using this methodology as a key step, the synthesis of indole alkaloids with further structural complexity are progressing in this laboratory.

Acknowledgements

We thank the Council of Scientific and Industrial Research, India, and the Department of Science and Technology, India for financial support. S. M. thanks the University Grants Commission, India for the fellowship. We are grateful to the Central Instrumentation Facility, Pondicherry University for IR and NMR (¹H and ¹³C) data. Single Crystal X-ray facility (DST-FIST sponsored), Department of Chemistry, Pondicherry University is gratefully acknowledged. We thank SAIF, IITM, Chennai for HRMS data.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data, NMR spectra for new compounds. CCDC & X-ray crystallography details for compounds 2, 2e, 2h, 2o and 2q. CCDC reference numbers 876034–876038. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21734a

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